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Title:
A COMBINATORIAL LIBRARY OF MOENOMYCIN ANALOGS AND METHODS OF PRODUCING SAME
Document Type and Number:
WIPO Patent Application WO/1999/026956
Kind Code:
A1
Abstract:
A combinatorial chemical library of compounds structurally related to the moenomycin class of antibiotics has formula (I) wherein D is a donor mono- or disaccharide, A is an acceptor monosaccharide, and P-R is a lipophosphoglycerate mimetic group. Members of the library have a glycosidic linkage between the anomeric carbon of D and the C2 carbon of A, and the D-A moiety is in turn covalently linked through the anomeric carbon of A to the P-R group. Members of the library exhibit their greatest structural diversity in terms of substitutions occurring at the C3 position of the A residue, substitutions at the C2 position of the D residue, and different P-R groups used in assembling the compounds. Members of the library are preferably synthesized by solid phase techniques involving stepwise coupling of the respective units to a support, functionalizing the A and/or D saccharides either before or after immobilizing them on the support, and cleaving the assembled compounds from the support. Preferred functionalities attached to the sugar residues are amides, carbamates, ureas, sulfonamides, substituted amines, esters, carbonates, and sulfates. Exemplary P-R groups are derivatives of homoserine, glyceric acid, salicylates and mandelic acid. Members of the library can be screened for anti-microbial activity by contacting them with a culture of microbes and monitoring the growth rate of the microbes.

Inventors:
Allanson, Nigel Mark (2 Merritt Lane Rocky Hill, NJ, 08553, US)
Chan, Tin Yau (26 Barlow Road Edison, NJ, 08817, US)
Hatzenbuhler, Nicole T. (61 Totten Drive Bridgewater, NJ, 08807, US)
Jain, Rakesh K. (14126 E. Run Drive Lawrenceville, NJ, 08648, US)
Kakarla, Ramesh (111 B Taylor Avenue East Brunswick, NJ, 08816, US)
Liang, Rui (54-07 Quail Ridge Drive Plainsboro, NJ, 08904, US)
Liu, Dashan (70 Rice Run East Brunswick, NJ, 08816, US)
Silva, Domingos (3-08 Fox Run Drive Plainsboro, NJ, 08536, US)
Sofia, Michael (3 Holly Lane Lawrenceville, NJ, 08648, US)
Application Number:
PCT/US1998/024406
Publication Date:
June 03, 1999
Filing Date:
November 17, 1998
Export Citation:
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Assignee:
INCARA PHARMACEUTICAL CORP. (P.O. Box 14287 Research Triangle, NC, 27709, US)
Allanson, Nigel Mark (2 Merritt Lane Rocky Hill, NJ, 08553, US)
Chan, Tin Yau (26 Barlow Road Edison, NJ, 08817, US)
Hatzenbuhler, Nicole T. (61 Totten Drive Bridgewater, NJ, 08807, US)
Jain, Rakesh K. (14126 E. Run Drive Lawrenceville, NJ, 08648, US)
Kakarla, Ramesh (111 B Taylor Avenue East Brunswick, NJ, 08816, US)
Liang, Rui (54-07 Quail Ridge Drive Plainsboro, NJ, 08904, US)
Liu, Dashan (70 Rice Run East Brunswick, NJ, 08816, US)
Silva, Domingos (3-08 Fox Run Drive Plainsboro, NJ, 08536, US)
Sofia, Michael (3 Holly Lane Lawrenceville, NJ, 08648, US)
International Classes:
C12Q1/02; A61K31/7016; A61K31/702; A61P31/04; C07H1/02; C07H5/08; C07H11/04; C07H15/04; C07H15/203; C07B61/00; (IPC1-7): C07H1/00; C07H5/00; C07H15/00
Attorney, Agent or Firm:
Villacorta, Gilberto M. (Pepper Hamilton LLP 600 Fourteenth Street, N.W. Washington, DC, 20005-2004, US)
Download PDF:
Claims:
WHAT IS CLAIMED IS:
1. A compound having the formula: wherein D represents a monosaccharide or disaccharide, A represents a monosaccharide, and PR represents a lipophosphoglycerate mimetic group that is not a phospholipid group of moenomycin A or a saturated form thereof, wherein the anomeric carbon atom of D is covalently linked to the C2 carbon atom of A through a glycosidic linkage and the anomeric carbon atom of A is covalently bonded to PR through an oxygen atom.
2. The compound of claim 1, wherein A represents a pyranosiduronic acid, a pyranosiduronamide, a furanosiduronic acid, or a furanosiduronamide.
3. The compound of claim 1, wherein A is an a or P isomer of a D or L form of a glucopyranosiduronamide, a galactosiduronamide, a 4Cmethyl glucopyranosiduronamide, a 4Cmethylgalactopyranosiduronamide, a 3amino3deoxy analog thereof, or an epimer thereof.
4. The compound of claim 1, wherein A has a formula selected from the group consisting of : wherein R3 is XY, where X is Oor NH, and Y is H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, C (O) R, C (O) NHR, C (O) OR, or S02R, where R is H, alkyl, cycloalkyl, alkenyl, aryl, alkaryl, or heterocycle, or XY combine to form N3 ; R4 is OX, where X is H, alkyl, cycloalkyl, alkenyl, acyl, benzoyl, aryl or aralkyl; and R6 is OH, NH2, or NHMe.
5. The compound of claim 1, wherein D is an a or ß isomer of a D or L form of a glucopyranoside, a galactopyranoside, a mannopyranoside, a fucopyranoside, or an epimer thereof.
6. The compound of claim 1, wherein D has a formula selected from the group consisting of: wherein R2 is XY, where X is Oor NH, and Y is H, alkyl, cycloalkyl, alkenyl, C (O) R, C (O) NHR, C (O) OR, or SO2R, where R is H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, or heterocycle, or XY combine to form N3, or phthalimido; R3 is XY, where X is Oor NH, and Y is H, alkyl, cycloalkyl, alkenyl, C (O) R, C (O) NHR, C (O) OR, or SOzR, where R is H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, or heterocycle, or XY combine to form N3, phthalimido, or a monosaccharide residue; R4 is XY, where X is Oor NH, and Y is H, alkyl, cycloalkyl, alkenyl, C (O) R, C (O) NHR, C (O) OR, or SO2R, where R is H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, or heterocycle, or XY combine to form N3, phthalimido, or a monosaccharide residue, or R3 and R4 combine to form carbonato; and R6 is H or XY, where X is Oor NH, and Y is H, alkyl, cycloalkyl, alkenyl, C (O) R, C (O) NHR, C (O) OR, or SO2R, where R is H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, or heterocycle, or XY combine to form N3, phthalimido, or a monosaccharide residue.
7. The compound of claim 1, wherein the PR group contains at least two electronegative functionalities independently selected from the group consisting of phosphate, phosphoanhydride, phosphonate, sulfonate, carboxylate, hydroxyl, hydroxylamine, and acylsulfonamido groups.
8. The compound of claim 7, wherein first and second electronegative functionalities are separated through space at a distance of 2.5 to 10 angstroms. 9.
9. The compound of claim 7, wherein first and second electronegative functionalities are separated from each other by 1 to 8 chemical bonds.
10. The compound of claim 7, wherein APR is represented by one of the following formulas: wherein W = O, CH2, OCH2, orCH2CH2 ; X is a single bond, CH2, O, NH, or S; Y = 0, NH, S, or CH; Z = H, halogen, or NO2 ; R is H,alkyl, cycloalkyl, alkenyl, acyl, benzoyl, aryl, aralkyl, or such group substituted with at least one heteroatom; m is an integer of 02; n is an integer of 02; and position isomers thereof.
11. A phenyl 1thio monosaccharide having a formula selected from the group consisting of : wherein R3 is XY, where X is Oor NH, and Y is alkyl, cycloalkyl, alkenyl, C (O) R, C (O) NHR, C (O) OR, or S02R, where R is alkyl, cycloalkyl, alkenyl, aryl, aralkyl, or heterocycle, or XY combine to form N3; R4 is OX, where X is H, alkyl, cycloalkyl, alkenyl, acyl, benzoyl, aryl or araLkyl; and R6 is OH, NH2, or NHMe.
12. A phenyl 1thio saccharide having a formula selected from the group consisting of : wherein Z is O or is absent; R2 is XY, where X is Oor NH, and Y is alkyl, cycloalkyl, alkenyl, C (O) R, C (O) NHR, C (O) OR, or S02R, where R is alkyl, cycloalkyl, alkenyl, aryl, aralkyl, or heterocycle, or XY combine to form N3 or phthalimido; R3 is XY, where X is Oor NH, and Y is alkyl, cycloalkyl, alkenyl, C (O) R, C (O) NHR, C (O) OR, or S02R, where R is alkyl, cycloalkyl, alkenyl, aryl, aralkyl, or heterocycle, or XY combine to form N3, phthalimido, or a monosaccharide residue; R4 is XY, where X is Oor NH, and Y is alkyl, cycloalkyl, alkenyl, C (O) R, C (O) NHR, C (O) OR, or SOIR, where R is alkyl, cycloalkyl, alkenyl, aryl, aralkyl, or heterocycle, or XY combine to form N3, phthalimido, or a monosaccharide residue, or R3 and R4 combine to form carbonato; and R6 is H or XY, where X is Oor NH, and Y is alkyl, cycloalkyl, alkenyl, C (O) R, C (O) NHR, C (O) OR, or S02R, where R is alkyl, cycloalkyl, alkenyl, aryl, aralkyl, or heterocycle, or XY combine to form N3, phthalimido, or a monosaccharide residue.
13. A combinatorial chemical library of moenomycin analog compounds comprising a plurality of the compounds of claim 1.
14. A method of synthesizing at least one compound having the formula comprising the steps of : (a) covalently linking an acceptor monosaccharide (A) to a support by forming a carboxylate or carboxyamide linkage between the C6 carbon of A and the support, with A substituted at its anomeric carbon with a thiophenyl group; (b) covalently linking the anomeric carbon of a donor saccharide (D) via an Oglycosidic linkage to the C2 carbon of A to form a DA moiety linked to the support; (c) coupling a lipophosphoglycerate mimetic group (PR) to the anomeric position of the A residue of the DA moiety to form a DAPR moiety linked to the support; and (d) cleaving the DAPR moiety from the support, thereby affording said at least one compound.
15. The method of claim 14, further comprising forming an amide, carbamate, urea, sulfonamide, substituted amine, ester, carbonate or sulfate functionality at the C3 position of A before or after performing step (b).
16. The method of claim 14, further comprising forming an amide, carbamate, urea, sulfonamide, substituted amine, ester, carbonate or sulfate functionality at the C2 position of D before or after performing step (b).
17. The method of claim 14, further comprising forming the PR group prior to performing step (c).
18. The method of claim 14, further comprising removing protecting groups from the D APR moiety prior to performing step (d).
19. The method of claim 14, wherein the support is selected from the group consisting of a resin having a photoor acidcleavable linker, silica, controlled porosity glass, polystyrene, polyethylene glycol, and grafted polymers.
20. A method of screening a compound of claim 1 for antimicrobial activity, comprising contacting said compound with a culture of microbes, and monitoring the growth rate or inhibition of peptidoglycan synthesis of the microbes.
Description:
A COMBINATORIAL LIBRARY OF MOENOMYCIN ANALOGS AND METHODS OF PRODUCING SAME Technical Field The present invention is for a combinatorial chemical library of compounds structurally related to the moenomycin class of antibiotics, and methods of preparing the compounds. Members of the library comprise disaccharides and trisaccharides covalently bonded to a lipid or lipid mimetic through a phosphorus linkage.

Background of the Invention The moenomycin antibiotics are naturally-occurring phosphoglycolipids, which have been isolated from several strains of Streptomyces. These antibiotics have a wide range of antimicrobial activity, which is believed due to their ability to inhibit the transglycosylase activities of the bi-functional penicillin binding proteins (PBPs). These proteins catalyze the transfer of a disaccharide unit to a growing peptidoglycan chain during the biosynthesis of bacterial cell walls. To date, the moenomycins are the only known inhibitors of this enzyme activity. The structure of the disaccharide substrate is shown hereinbelow: OH OH 0 OH 0 HO OH HX X Ol O O AC O P-O P-O-C55-lipid \ HO OH HO OH O HN pentapeptide

The moenomycins are active against several bacterial strains, including those resistant to beta-lactam antibiotics. They are currently marketed under the tradename Flavomycin as an additive in cattle feed, where the efficacy in promoting animal growth is believed due to their antimicrobial activity. The moenomycins are particularly potent against gram-positive bacteria and less potent against gram-negative microbes.

The potential for moenomycin antibiotics as human therapeutics has not been studied in detail, but is expected to be limited by poor bioavailability and unfavorable pharmacodynamics. The unique mode of action and wide range of activity of this class of antibiotics makes them attractive for the study of related compounds having more favorable pharmacological properties.

At present, moenomycins A, Cl, C2, C3, Al2, and pholipomycin compose the class of moenomycin antibiotics. Of this class, the most studied member is moenomycin A-a pentasaccharide linked to a C25 lipid group through a phosphate moiety. The structure of moenomycin A is shown hereinbelow. The structural similarity of this compound to the transglycosylase substrate mentioned above is readily apparent and suggests that moenomycin A acts as a competitive inhibitor of transglycosylase activity.

moenomycin A In the above structure, it is known that a disaccharide-phospholipid degradation product of moenomycin A is equipotent (100% minimum inhibitory concentration (MIC) at 1tg/mL) to the parent natural product [EP Publn. No. 130327]. In particular, it has been shown that the A, B, C and D units of moenomycin A are unimportant to the inhibition of transglycosylase activity, but that the E, F, G, H, and I groups are essential [Welzel, P., et al., (1984), (1987); Moller, U., et al., (1993); Marzian, S., et al., (1994)].

The lipid moiety I can be fully hydrogenated without substantially affecting its activity.

However, a free carboxylic acid function for the glyceric acid unit H appears to be necessary for inhibition. Furthermore, the structural requirements within the F-G-H region appear to be rather strict [Fehlhaber, H-W., et al., (1990); Moller, U., et al., (1993); Luning, J., et al., (1994); Heuer, M., et al., (1994)]. The structure of a fully active disaccharide degradation product of moenomycin A is shown hereinbelow:'

The other moenomycin compounds mentioned above differ structurally from moenomycin A principally by the number of sugar residues in the molecule and by the configuration of groups at the C4 position of the F sugar unit. In particular, only moenomycins A and An have a D sugar residue attached to the E unit. Moenomycins C3, C4 and pholipomycin are tetrasaccharide-phospholipids, which differ from each other by the presence or absence of hydroxyl groups at the C6 positions of the C and E sugar units [Hessler-Klintz, M., et al., (1993); Scherkenbeck, J., et al., (1993)].

Moenomycin C, also is a tetrasaccharide and, as with moenomycin Ai2, lacks the branching methyl group and has a change of configuration at the C4 position of the F

sugar unit, i. e., the F unit is a galactopyranosiduronamide. In contrast to the other moenomycins, degradation studies of moenomycins C, and Al 2 reveal that the smallest antibiotically active products for these F unit galactopyranosiduronamide compounds are trisaccharide derivatives, which include the C, E and F sugar units. It has been suggested that the additional saccharide unit (C) is required for these compounds in order to achieve the necessary hydrogen bonding environment within the active site, which is otherwise attained with a disaccharide unit in the 4-C-methyl glucopyranosiduronamide compounds [Hessler-Klintz, M., et al., (1993); Donnerstag, A., et al., (1995)]. In a recent series of papers, Welzel and coworkers describe the synthesis and antibiotic properties of some C- E-F trisaccharide derivatives ofmoenomycin Au [Ritzeler, O., et al., (1997a); Ritzeler, O., et al., (1997b); Range, G., et al., (1997)].

The biosynthesis of moenomycin in an aerobic fermentation process is the subject of U. S. Patent No. 3,992, 263, issued to Dietrich et al. Enzymatic methods for degrading moenomycin to defined end products, i. e., pentasaccharide and phospholipid products, are disclosed by U. S. Patent Nos. 5,206,405,5,260,206, and 5,506,140, all issued to Aretz et al., which propose that these end products can be used as building blocks in the synthesis of new transglycosylase inhibitors. An enzymatic method of cleaving the phosphate group from the aforementioned phospholipid is described in U. S. Patent Nos.

5,315,038 and 5,316,929, issued to Aretz et al.

A study of the activities of several moenomycin analogs against the Helicobacter pylori bacillus is the subject of EP 655249, issued to Hoechst AG.

It is desired to synthesize and study a library of compounds having several of the basic structural features of the moenomycin degradation products discussed above, which

retain anti-microbial activity. Of particular interest are compounds having better pharmacological properties yet retaining the broad spectrum of moenomycin activities.

Of particular interest are activities against resistant strains of microorganisms. Generally speaking, it is desired to broaden the spectrum of activities and/or enhance the potencies of moenomycin antibiotics, particularly against clinically relevant microbes.

Summarv of the Invention The present invention is for a combinatorial chemical library of moenomycin analogs, the members of which are represented by the following formula: In the formula,"D"represents one or more"donor"saccharide residue (s), as defined hereinafter, and is preferably a mono-or disaccharide. The"A"group in the formula represents an"acceptor"saccharide residue, as defined hereinafter, and is a monosaccharide. The"P-R"group of the formula represents a lipophosphoglycerate mimetic group, as defined hereinafter, and differs from the phospholipid group of moenomycin A and partially or fully saturated forms thereof. Compounds represented by the above formula have a chemical structure analogous to the antibiotically active disaccharide moenomycin fragment discussed hereinabove. Accordingly, compounds represented by this formula are said to belong to a"directed"chemical library of moenomycin analogs.

In a preferred aspect of the invention, the C I (anomeric) position of donor saccharide residue D is covalently bonded to the C2 position of acceptor saccharide

residue A, e. g., through a glycosidic linkage. Also, it is preferred that the Cl (anomeric) position of A is covalently bonded to the lipophosphoglycerate mimetic group P-R through an O atom, which links A to a phosphorus atom of the P-R group.

Typically, the P-R group contains a phosphoester, phosphoanhydride, or phosphonate linkage, which joins an oxidized form of phosphorus to a negatively charged functional group, e. g., a carboxyl or sulfate group. While not wishing to be bound by any particular theory, it is believed that the dianion afforded by the P-R group is attracted to positive charges, e. g., a divalent metal ion, within the active site of the transglycosylase enzyme, thereby inhibiting its activity.

An aromatic or aliphatic moiety, sometimes referred to herein as a"lipid" moiety, can be covalently linked to the aforementioned oxidized form of phosphorus and the negatively charged functional group to provide the lipophosphoglycerate mimetic group. A synthetic or natural lipid moiety can form an integral part of the lipophosphoglycerate mimetic group by constituting part of the backbone joining the oxidized phosphorus to the negatively charged functional group. More typically, however, the lipid moiety is linked to the aforesaid groups through an ether, amide or carbon-carbon single bond.

Members of a library of the present invention display the greatest diversity of structural features in respect to: (i) substitutions occurring at the C3 position of residue A, (ii) substitutions occurring at the C2 position of the D saccharide, and (iii) the selection of the P-R group. Preferred substituents at the C3 position of A and the C2 position of D are amides, carbamates, ureas, sulfonamides, substituted amines, esters, carbonates, and sulfates, as described herein. Preferred P-R groups are derived from homoserine,

glyceric acid, salicylates, mandelic acid compounds, and phthalide phosphoric acids due to their ready availability.

Also contemplated is a method of preparing a library of compounds having the formula presented above. The synthesis can be performed in solution or on a support, and is preferably carried out on a solid phase support. A solid phase synthesis of the invention comprises the steps of : (a) covalently linking an acceptor monosaccharide (A) to the support by forming a carboxylate or carboxamido linkage between the C6 carbon of A and the support, with A substituted at its anomeric carbon with a thiophenyl group; (b) covalently linking the anomeric carbon of a donor saccharide (D) through an O-glycosidic linkage to the C2 carbon of the A residue to form a D-A moiety linked to the support; (c) coupling a lipophosphoglycerate mimetic group (P-R) to the anomeric position of the A residue of the D-A moiety to form a D-A-P-R moiety linked to the support; and (d) cleaving the target D-A-P-R compound from the support.

The D-A coupling step (b) is preferably performed using a C 1-thiophenyl donor saccharide that has been converted to its Cl-sulfoxide form by a conventional method prior to reacting it with A. A preferred method of converting C 1-thiophenyl sugars to their C 1-sulfoxides is described in U. S. Serial No. 08/281,167, the disclosure of which is incorporated herein by reference.

Before or after performing step (b), the C3 position of A and/or the C2 position of D can be functionalized. Preferred substituents at these sites are amide, carbamate, urea,

sulfonamide, substituted amine, ester, carbonate, and sulfate groups, as described more fully hereinafter. The hydroxyl groups of the A and/or D residues can be orthogonally protected to permit independent functionalization of their hydroxyl groups and it is generally preferred that protecting groups be cleaved from the assembled molecule prior to cleaving it from the support in step (d).

Preferably, coupling step (c) is performed by attaching a preformed P-R group to A. However, the P-R group can alternatively be assembled stepwise on A by first attaching a phosphorus-containing group, followed by an organic moiety that is negatively charged or that can be converted to have a negative charge, such that a lipophosphoglycerate mimetic (P-R) is linked to A.

A method of screening members of the present library for anti-microbial activity is also contemplated. Such method comprises contacting a member of the library with a culture of microbes, and monitoring the growth rate of the microbes. An observation that the growth rate has ceased or diminished is an indication that the compound has anti- microbial activity. Screening may also be performed by directly assaying for peptidoglycan synthesis in the microbes.

A fuller understanding of the present invention can be obtained from a consideration of the figures and detailed description provided hereinbelow.

Brief Description of the Drawings Fig. 1 depicts Scheme 1 for synthesizing acceptor saccharides of the invention according to Example I-1.

Fig. 2 depicts a reaction scheme for synthesizing an acceptor saccharide of the invention according to Scheme 2, which is discussed in Example 1-2.

Fig. 3 depicts reaction schemes for synthesizing acceptor saccharides of the invention according to Scheme 3, which is discussed in Example 1-3.

Fig. 4 depicts Scheme 4 for synthesizing an acceptor saccharide of the invention according to Example I-4.

Fig. 5 depicts Scheme 5 for synthesizing an acceptor saccharide of the invention according to Example I-5.

Figs. 6-7 depict a reaction scheme for synthesizing acceptor saccharides of the invention according to Scheme 6, which is discussed in Example 1-6.

Fig. 8 depicts Scheme 7 for synthesizing an acceptor saccharide of the invention according to Example I-7.

Fig. 9 depicts Scheme 8 for synthesizing an acceptor saccharide of the invention according to Example 1-8.

Fig. 10 depicts Schemes 9 and 10 for synthesizing donor saccharides of the invention, as discussed in Examples II-1 and 11-2.

Fig. 11 depicts Schemes 11 and 12 for synthesizing donor saccharides of the invention, as discussed in Examples 11-3 and 11-4.

Fig. 12 depicts Schemes 13 and 14 for synthesizing donor saccharides of the invention, as discussed in Examples 11-5 and 11-6.

Fig. 13 depicts Scheme 15 for synthesizing a donor saccharide of the invention according to Example 11-7.

Fig. 14 depicts Scheme 16 for synthesizing a donor saccharide of the invention according to Example 11-8.

Fig. 15 depicts Schemes 17 and 18 for synthesizing donor saccharides of the invention, as discussed in Examples 11-9 and 11-10.

Fig. 16 depicts Scheme 19 for synthesizing a donor saccharide of the invention, including conversion to its sulfoxide form, according to Example II-11.

Fig. 17 depicts Scheme 20 for synthesizing lipid groups for incorporation into the lipophosphoglycerate mimetics used in preparing the moenomycin analogs of the present invention, as discussed in Examples III-1, III-2 and III-3.

Figs. 18-19 depict Scheme 21 for assembling moenomycin analogs on a solid support according to the principles of the present invention.

Fig. 20 depicts mass spectra for two moenomycin analogs prepared according to principles of the present invention.

Detailed Description of the Invention The present invention is described herein by way of certain specialized abbreviations and terms, the meanings of which are set forth as follows: List of Abbreviations All allyl Bn benzyl Bz benzoyl CAN cerium ammonium nitrate CEDIPAPC1 2-cyanoethyl diisopropylamino phosphorus chloride DCC dicyclohexylcarbodiimide DCM dichloromethane DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DIPEA N, N-diisopropyl ethylamine DMAP 4-N, N-dimethylamino pyridine DMF dimethylformamide

EA ethyl acetate ESMS electrospray mass spectrometry FAB fast atom bombardment HATU 0- (7-azabenzotriazol-1-yl)-1, 1, 3, 3,-tetramethyluronium hexafluorophosphate Lev levulinoyl mCPBA m-chloroperbenzoic acid Phth phthalimido PDC pyridinium dichromate Pv/Piv pivaloyl Py pyridine RT room temperature TBAF tetrakis (n-butyl) ammonium fluoride TBDMSC1 tert-butyl dimethylsilyl chloride TEA triethylamine TFA trifluoroacetic acid TFAA trifluoroacetic acid anhydride Tf2O trifluoromethanesulfonic anhydride TLC thin layer chromatography TrCl trityl chloride TsOH/pTSA p-toluenesulfonic acid Glossary of Terms Acceptor Saccharide-An acceptor saccharide (A), as used herein,"accepts"a donor saccharide to form a di-or trisaccharide residue of a moenomycin analog of the present invention. The acceptor saccharide is a natural or nonnatural hexose oxidized at its C6 position to either a carboxylate or carboxyamido group. In the final moenomycin analog compound, the acceptor residue is covalently linked at its Cl (anomeric) position with a lipophosphoglycerate mimetic group, and is covalently linked at its C2 position with a donor saccharide. The acceptor saccharide can be chemically modified (derivatized) at any of its normal hydroxyl sites (C1-C4 for pyranoses and C1-C3 and C5 for furanoses), with the preferred site for derivatization being the C3 position. Whenever the acceptor is a nonnatural hexose, it is typically an epimer of a naturally occurring monosaccharide. Additionally, C3 amino sugars are preferred acceptor saccharides.

Donor saccharide-A donor saccharide (D), as used herein,"donates"a mono-or di-saccharide group to an acceptor saccharide to form a di-or trisaccharide moenomycin analog of the present invention. The donor saccharide is formed from one or two natural or nonnatural hexoses. Whenever two hexoses are employed as the donor saccharide, they are covalently bonded together, e. g., through a (1o4) or (1->6) glycosyl linkage.

The donor can be chemically modified (derivatized) at any of its normal hydroxyl sites (C1-C4 and C6 for pyranoses and C1-C3 and C5-C6 for furanoses). Typically, whenever a donor is derivatized, it is derivatized at the C2 position of the saccharide residue proximate the acceptor residue in the final molecule. Whenever the donor is a nonnatural hexose, it is typically an epimer of a naturally occurring monosaccharide.

Epimers-Sugar molecules differing in configuration at a single asymmetric center of the saccharide ring.

Lipophosphoglycerate mimetic-A chemical moiety having formula P-R that is covalently bonded to the Cl (anomeric) position of A through an O atom. The P-R group contains at least two electronegative functionalities separated by a predefined distance.

These electronegative functionalities include independent selections from among phosphate, phosphoanhydride, phosphonate, sulfonate, carboxylate, hydroxyl, hydroxylamine, and acylsulfonamido groups. The electronegative functionalities can be an integral component of the backbone of the P-R structure or they can be attached as appendages to the backbone. Exemplary of these structures are integral (divalent) functionalities, such as phosphate and phenolate groups, and appendage (monovalent) functionalities, such as aliphatic hydroxyl and carboxylate. Two of the electronegative functionalities are spaced apart in the P-R group at a distance comparable to that of the

phosphate and carboxylate groups (units G and H) of moenomycin A. This simulation of the electronic structure present in moenomycin A gives rise to the description herein of the P-R group as being a"mimetic"of the corresponding phosphoglycerate moiety of moenomycin A. Under biological conditions of interest, the aforementioned electronegative substituents typically release a proton, thereby leaving behind a negatively charged center. Preferably, a P-R group of the invention contains a phosphate group linked to another electronegative functionality. The phosphate group is bonded to an A residue through an O atom, and is linked to the second electronegative functionality, e. g., through a phosphoester, phosphoanhydride, or phosphonate linkage. The second electronegative functionality is preferably a carboxylic acid group. An aromatic or aliphatic moiety (also referred to herein as a"lipid") can be covalently linked to the aforementioned negatively charged functional group of the P-R group, e. g., through an ether, amide or single C-C bond, to provide the lipophosphoglycerate mimetic P-R. The aromatic or aliphatic moiety can form all or part of the backbone joining the negatively charged group to the oxidized phosphorus atom. Preferred P-R groups are discussed more fully hereinafter.

Position isomer-A structural isomer of another compound, particularly one having a cyclic or aromatic structure, which is formed by relocation of one or more substituent group (s) or by movement of one or more heteroatom (s) about the ring.

A combinatorial chemical library of the present invention is represented by the following formula:

In. the formula, D represents a donor saccharide, A represents an acceptor saccharide, and P-R represents a lipophosphoglycerate mimetic group, as defined hereinabove.

Preferably, the D residue is a mono-or disaccharide, which is covalently bonded to A through a glycosidic linkage. A is an oxidized monosaccharide, such as a pyranosiduronic acid, pyranosiduronamide, furanosiduronic acid, or furanosiduronamide, and is covalently bonded through an O atom to the P-R group. Preferably, the Cl position of D is linked to the C2 position of A and the Cl position of A is covalently bonded to P-R. The P-R group is not a phospholipid group of moenomycin A or a saturated form thereof.

In a preferred aspect of the invention, residue A of a member of the library is an a or ß isomer of a D or L form of a glucopyranosiduronamide, a galactosiduronamide, a 4- C-methyl-galactopyranosiduronamide, a 4-C-methyl-glucopyranosiduronamide, a 3- amino-3-deoxy-analog thereof, or an epimer thereof.

More preferably, an A residue of a member of an instant library has a formula selected from among the following structures:

wherein R3 is X-Y, where X is O-or NH-, and Y is H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, C (O) R, C (O) NHR, C (O) OR, or S02R, where R is H, alkyl, cycloalkyl, alkenyl, aryl, alkaryl, or heterocycle, or X-Y combine to form N3 ; R4 is O-X, where X is H, alkyl, cycloalkyl, alkenyl, acyl, benzoyl, aryl or aralkyl; and R6 is OH, NH2, or NHMe.

As used herein, the term"alkyl"refers to straight and branched chain hydrocarbons containing 1 to 30 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. The term"lower alkyl"refers to alkyl groups having 1 to 7 carbon atoms, various branched chain isomers thereof, and the like. The terms"alkyl"and"lower alkyl"also include such groups having one or more halo-substituents, such as F, Cl, Br, I, CF3, an alkoxy substituent, an aryl substituent, an alkyl-aryl substituent, a haloaryl substituent, a cycloalkyl substituent, an alkylcycloalkyl substituent, a hydroxyl group, an alkylamino substituent, an alkanoylamino substituent, an arylcarbonylamino substituent, a nitro group, a cyano group, a thiol group, or an alkylthio substituent.

The term"cycloalkyl"is a cyclic alkyl group that includes saturated hydrocarbon groups containing 3 to 12 carbon atoms, typically 3 to 8 carbons, and includes cyclopropyl, cylcopentyl, cyclohexyl, cycloheptyl, and cyclodecyl. A cycloalkyl group can be substituted with one or more halogen, lower alkyl, lower alkoxy group, hydroxy, alkylamino group, alkanoylamino, arylcarbonylamino group, aminogroup, nitro group, cyano group, thiol group or alkylthio group.

As used herein, the term"alkylene"or"alkenyl"refers to mono-, di-, tri-or higher unsaturated straight and branched chain hydrocarbons containing 1 to 30 carbon atoms, such as ethenyl, propenyl, butylenyl, hexenyl, octenyl, decenyl, and dodecenyl.

The term"lower alkenyl"refers to alkylene groups having 2 to 8 carbon atoms, various branched chain isomers thereof, and the like. The terms"alkenyl"and"lower alkenyl" also include such groups having one or more halo-substituents, such as F, Cl, Br, I, CF3, an alkoxy substituent, an aryl substituent, an alkyl-aryl substituent, a haloaryl substituent,

a cycloalkyl substituent, an alkylcycloalkyl substituent, hydroxy, an alkylamino substituent, an alkanoylamino substituent, an arylcarbonylamino substituent, a nitro group, a cyano group, a thiol group, or an alkylthio substituent.

The term"acyl"or"alkanoyl", either alone or as a part of another group, as used herein refers to an alkylcarbonyl or alkenylcarbonyl group, with the alkyl and alkenyl groups being those defined above. A"lower acyl","lower alkanoyl"or"lower alkenoyl", either alone or as a part of another group, refers to a lower alkylcarbonyl or lower alkenylcarbonyl group, with the lower alkyl and lower alkenyl groups being those defined above. A formyl group is considered herein to be a lower acyl group.

The term"aryl"as used herein refers to monocyclic or bicyclic aromatic groups from 6 to 10 carbons in a ring, such as phenyl, naphthyl, substituted phenyl or substituted napthyl, wherein the substituent may be one or more lower alkyl groups, halogen, lower alkoxy, hydroxy, phenyl, alkanoyloxy, benzoyloxy, haloalkyl halophenyl, allyl, cycloalkylalkyl, adamantylalkyl, alkylamino, alkynoylamino, arylcarbonylamino, amino, nitro, cyano, thiol, alkylthio. The aryl group can be substituted with 1,2, or 3 of the above substituents. The aryl can also be substituted in the ring with 1,2 or 3 heteroatoms, in which case the group is referred to as a"heteroaryl"or"heterocycle".

The term"benzoyl"as used herein refers to an arylcarbonyl group, wherein the aryl group is as defined above.

The term"aralkyl","aryl-alkyl", or"alkaryl", as used herein refers to a lower alkyl group having an aryl substituent as defined above, such as benzyl.

The term"lower alkoxy","alkoxy","aralkylthio", refers to a lower alkyl, aralkyl, or aryl group linked to an oxygen atom.

The term"lower alkylthio","alkylthio","arylthio"or"aralkylthio", refers to a lower alkyl, alkyl, aryl, or aralkyl group linked to a sulfur atom.

The term"lower alkylamino","alkylamino","arylamino"or"aralkylamino", refers to a lower alkyl, alkyl, aryl or aralkyl group linked to an nitrogen atom.

A"halogen"or"halo"as used herein refers to a halogen atom or halogen- containing group, such as or CF3, F, Cl, Br or I.

A"heteroatom"as used herein refers to O, N, or S.

In another preferred aspect of the invention, a D residue of a member of an instant chemical library is an a or P isomer of a D or L form of a glucopyranoside, a galactoside, a mannopyranoside, a fucopyranoside, or an epimer thereof. More preferably, the D residue has a formula selected from among the following structures:

wherein R2 is X-Y, where X is O-or NH-, and Y is H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, C (O) R, C (O) NHR, C (O) OR, or S02R, where R is H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, or heterocycle, or X-Y combine to form N3, or phthalimido; R3 is X-Y, where X is O-or NH-, and Y is H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, C (O) R, C (O) NHR, C (O) OR, or SOIR, where R is H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, or heterocycle, or X-Y combine to form N3, phthalimido, or a monosaccharide residue; R4 is X-Y, where X is O-or NH-, and Y is H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, C (O) R, C (O) NHR, C (O) OR, or SO2R, where R is H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, or heterocycle, or X-Y combine to form N3, phthalimido, or a monosaccharide residue, or R3 and R4 combine to form carbonato; and R6 is H or X-Y, where X is O-or NH-, and Y is H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, C (O) R, C (O) NHR, C (O) OR, or SO2R, where R is H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, or heterocycle, or X-Y combine to form N3, phthalimido, or a monosaccharide residue.

In a further preferred aspect of the invention, the P-R group of a member of an instant library contains at least two of the same or different electronegative functionalities. At least two of the electronegative functionalities are separated by a distance approximating that between the phosphate and carboxylate groups in moenomycin A, which is about 5.27 angstroms. Thus, a preferred lipophosphoglycerate mimetic (P-R) has a through-space charge separation in the range of 2.5 to 10 angstroms, more preferably 5-6 angstroms. An alternative formulation of this distance is expressed

in terms of the number of contiguous chemical bonds separating the functionalities.

Under this formulation, from 1 to 8 bonds separate the electronegative functionalities in the P-R group. By this convention, 3 chemical bonds separate the phosphate and carboxylate functionalities in moenomycin A.

Particularly preferred members of an instant library have a structural formula for A-P-R represented by one of the following formulas, or a position isomer thereof.

In the above formulas for a P-R group of the invention, the following designations have the indicated meanings: W represents O, CH2, O-CH2-, or-CH2-CH2-and is a spacer between the negative charges presented by the oxidized phosphorus atom and the negatively charged functional group of the P-R moiety; X represents a single bond, CH2, O, NH, or S, and is an optional spacer between the backbone of the lipophosphoglycerate moiety and an R group, as defined hereinbelow; Y is O, NH, S, or CH and is an atom (with the exception of CH) in an aromatic ring, which affords a"lipid"moietv of the P-R group; Z is H, halogen, or Nô ;, and represents a non-alkyl or non-aryl substituent on an aromatic ring, which affords a lipid moiety of the P-R group; R is H, alkyl, cycloalkyl, alkenyl, acyl, aryl, benzoyl, aralkyl, or other such group substituted with one or more heteroatom. Preferred aliphatic R groups include (CH2) 2CH (CH3) 2, (CH2) lCH3, and (CH2) 2iCH3; m is an integer of 0, 1. or 2 that indicates the number of methylene groups in the alkyl spacer group, which separates the oxidized phosphorus atom and the negatively charged functional group of the P-R unit; and n is an integer of 0,1, or 2 that indicates the number of methylene groups separating the negatively charged functional group, e. g., COOH, from an aromatic ring in a P-R unit.

Exemplary of the above formulas are mandelic acid derivatives (in which m=0, X is absent, and R is aryl), phthalide phosphoric acids (in which W = CH2, n=0, Z=H) and salicylic acid derivatives (in which W = O, m=0, and n=0), to name a few. These compounds are available from commercial sources or accessible by well-known methods.

Also contemplated within the invention is a phenyl 1-thio saccharide that can be used as an acceptor molecule for constructing moenomycin analogs of the present invention. Preferred acceptor molecules are among the following compounds :

wherein R3 is X-Y, where X is O-or NH-, and Y is alkyl, cycloalkyl, alkenyl, C (O) R, C (O) NHR, C (O) OR, or S02R, where R is alkyl, cycloalkyl, alkenyl, aryl, aralkyl, or heterocycle, or X-Y combine to form N3 ;

R4 is O-X, where X is H, alkyl, cycloalkyl, alkenyl, acyl, benzoyl, aryl or aralkyl; and R6 is OH, NH2, or NHMe.

Also contemplated are donor molecules that can be used in assembling the moenomycin analogs of the present invention. The donor molecules are typically prepared first as protected phenyl 1-thio saccharides, and are then converted by previously known methods, such as described in U. S. Serial No. 08/281,167 and 60/013,800, and by the instant methods into their phenylsulfenyl counterparts, as described hereinbelow. Thus, preferred donor molecules have a formula selected from among the following:

wherein Z is O or is absent; R2 is X-Y, where X is O-or NH-, and Y is alkyl, cycloalkyl, alkenyl, C (O) R, C (O) NHR, C (O) OR, or S02R, where R is alkyl, cycloalkyl, alkenyl, aryl, aralkyl, or heterocycle, or X-Y combine to form N3 or phthalimido; R3 is X-Y, where X is O-or NH-, and Y is alkyl, cycloalkyl, alkenyl, C (O) R, C (O) NHR, C (O) OR, or SOIR, where R is alkyl, cycloalkyl, alkenyl, aryl, aralkyl, or heterocycle, or X-Y combine to form N3, phthalimido, or a protected monosaccharide residue; R4 is X-Y, where X is O-or NH-, and Y is alkyl, cycloalkyl, alkenyl, C (O) R, C (O) NHR, C (O) OR, or S02R, where R is alkyl, cycloalkyl, alkenyl, aryl, aralkyl, or heterocycle, or X-Y combine to form N3, phthalimido, or a protected monosaccharide residue, or R3 and R4 combine to form carbonato; and R6 is H or X-Y, where X is O-or NH-, and Y is alkyl, cycloalkyl, alkenyl, C (O) R, C (O) NHR, C (O) OR, or S02R, where R is alkyl, cycloalkyl, alkenyl, aryl, aralkyl, or heterocycle, or X-Y combine to form N3, phthalimido, or a protected monosaccharide residue.

As used herein, a"protected monosacccharide"is a monosaccharide that has had its hydroxyl and/or amino groups temporarily made non-reactive by masking groups.

Another aspect of the invention pertains to a method of synthesizing a combinatorial library of moenomycin analogs according to the principles of the present invention. Such a method involves synthesizing at least one compound having the formula:

wherein D, A, and P-R have the meanings described hereinabove. Accordingly, a preferred method of the present invention comprises the steps of : (a) covalently linking an acceptor monosaccharide (A) to a support by forming a carboxylate or carboxyamide linkage between the C6 carbon of A and the support, wherein A is substituted at its anomeric carbon with a thiophenyl group; (b) covalently linking the anomeric carbon of a donor saccharide (D) via an O-glycosidic linkage to the C2 carbon of A to form a D-A moiety linked to the support; (c) coupling a lipophosphoglycerate mimetic group (P-R) to the anomeric position of the A residue of the D-A moiety to form a D-A-P-R moiety linked to the support; and (d) cleaving the D-A-P-R moiety from the support, which thereby affords the target compound.

In order to provide a wide range of structural diversity among the various members of an instant moenomycin analog library, hydroxyl groups on the acceptor and/or donor saccharide residues can be converted (derivatized) into other functionalities.

For example, a hydroxyl group can be converted to an ester, carbamate, carbonate or sulfate functionality by reacting it with the appropriate compound. Alternatively, an azido group on a saccharide residue can be reduced to an amine, which can then be converted into an amide, carbamate, urea, sulfonamide, or substituted amine functionality. Reactants and reaction conditions for performing these conversions are well-known to those skilled in the art. Preferred methods of performing these functionalizations on a solid phase support have been reported by R. Liang, et al.,

Science, 274: 1520 (1996) and are the subject of U. S. Serial No. 08/823,328, filed March 21,1997, as well as U. S. Provisional application Serial No. 60/047946, filed May 29, 1997, the disclosures of which are incorporated herein by reference.

The above-mentioned functionalizations are preferably performed at the C3 position of residue A and/or the C2 position of residue D before or after performing the above step (b), which joins residues A and D via an O-glycosidic linkage.

The lipophosphoglycerate mimetic (P-R) group is linked to residue A after the A- D linkage has been made. The P-R group can be attached to A piecewise, that is, by attaching an oxidized phosphorus group first, followed by attaching a negatively charged functionality. However, it is generally preferable to form the P-R group separately prior to performing the above coupling step (c).

Various protecting groups, e. g., acetyl, benzoyl, levulinoyl, Nfmoc (N- fluorenylmethyloxycarbonyl), N-trifluoroacetamido, phthalimido, and the like, are used to direct the desired bond formations, as illustrated herein. These protecting groups will usually have been removed in the final moenomycin analog compound in order to restore the underlying chemical functionality, e. g., a hydroxyl group or an amino group.

Generally, the protecting groups will be removed from the assembled D-A-P-R moiety after final assembly of the target molecule. Whenever the assembly is performed on a support, the removal of protecting groups is usually performed prior to cleaving the molecule from the support in step (d).

Although the above-described assembly steps can be performed without a support, i. e., in solution phase, use of a support is preferred since it permits the use of excess reactants to drive a reaction to completion and since physical separation of excess

reactants and side products from the target compound can be performed through convenient wash steps. Solid phase supports are preferred, such as resins having a photo- or acid-cleavable linker, e. g., Rink amine resins, as well as silica, controlled porosity glass, polystyrene, and grafted polymers. Polyethylene glycol (PEG) is another type of support that can be employed.

A method of screening an instant library of compounds for anti-microbial activity is also contemplated. Such method comprises contacting a member of the library with a culture of target microbes and monitoring their rate of growth, such as after a predefined incubation period. Alternatively, a direct assay of anti-microbial activity entails determining peptidoglycan synthesis of the microbes is inhibited in the presence of the compound, as is discussed hereinafter.

The invention will now be described with reference to certain Schemes (shown in the Figures) and Examples. These Schemes and Examples illustrate but do not limit the invention. The compounds described hereinbelow are assigned numerical designations corresponding to the number of the scheme in which they are depicted and the compound number within that scheme.

PART I. SYNTHESIS OF ACCEPTOR SACCHARIDES Example I-1: Synthesis of Phenyl 3-azido-3-deoxy-4-O-benzovl-1-thio- (3-D- glucopyranosiduronic acid (compound 1.11) As shown in Scheme 1, trifluoromethanesulfonic anhydride (25mL; 41.9g; 148.7mmol) is added dropwise over 10 min to a stirred solution of 1,2: 5,6-di-O- isopropylidene-D-allofuranose (35g; 35.0mmol), commercially available from Pfanstiehl

Laboratories, Inc. (Waukegan, IL), in dry pyridine (150mL) under argon at-20 °C. The reaction mixture is allowed to warm to room temperature over 2 h, then diluted with ethyl acetate (250mL) and washed with ice-cold brine (800mL). The aqueous layer is extracted once with a further portion of ethyl acetate (250mL), then the combined organic layers are washed with 3N citric acid (2 x 500mL) and brine (lOOmL), then dried over Na2S04 and evaporated to give compound 1.1 as a yellow brown oil (49.3g; 125mmol; 93%): Rf (30% ethyl acetate-hexane): 0.39. 1H NMR (300 MHz, CDC13): 8 1.32,1.36, 1.43,1.56 (12H, 4 x s, isopropylidene, CH3, s); 3.88 (1H, dd, J = 4.8 and 8.7 Hz); 4.07- 4.19 (3H, m); 4.75 (1H, t, J = 5. 7 Hz), 4.89 (1H, dd, J = 5.1 and 6. 9 Hz), 5.82 (1H, d, J = 3.9 Hz, H-1). MS m/e 415 [M+Na] Compound 1.1 (49.30g; 126mmol) and sodium azide (16.40g; 252mmol) are stirred in dry DMF (200mL) at 100 °C for 30 min. The reaction mixture is cooled to room temperature, filtered, then diluted with water (200mL) and extracted with ethyl acetate (2 x 150mL). The organic layers are washed with water (2 x 300mL) then brine (lOOmL), dried over Na2SO4, and concentrated under reduced pressure to give compound 1.2 as a light yellow oil (37.3 g, quantitative yield); Rf (50% ethyl acetate-hexane): 0.64.

'H NMR (300 MHz, CDC13): 5 1.32,1.36,1.43,1.51 (12H, 4 x s, isopropylidene CH3 s); 3.99 (1H, dd); 4.08-4.25 (4H, m); 4.62 (1H, d, J = 3.3 Hz), 5.86 (1H, d, J = 3.3 Hz); MS m/e 308 [M+Na].

Compound 1.2 (106g; 372mmol) is dissolved in a mixture of trifluoroacetic acid (50mL), dioxane (200mL) and 1.1 M aqueous HC1 (90mL), and heated at 50-60 °C for 21 h. The reaction mixture is neutralized with sodium hydroxide and concentrated to give a

quantitative yield of compound 1.3 as a brown oil. lH NMR (300 MHz, CD30D): 6 3.1- 3.75 (10H, m), 4.55 (1/2H, d, H-1); 5.05 (1/2H, d, H-1). MS FAB: m/e 228 [M+Na].

A stirred solution of compound 1.3 (38.6g; 180mmol) in pyridine containing a catalytic amount of DMAP (0. 5g) is treated dropwise with acetic anhydride (147g; 1.44mol). The reaction mixture is stirred overnight at room temperature then diluted with water (600mL). After stirring for 20 min, the reaction mixture is extracted with ethyl acetate (2 x 500mL). The combined organic phases are washed with saturated sodium bicarbonate solution (2 x 400mL), 2N HC1 (2 x 300mL) and brine (200mL), then dried over Na, S04 and evaporated to give compound 1.4 as a brown oil 166mmol); Rf (50% ethyl acetate-hexane): 0.45. 1H NMR (300 MHz, CDC13): 6 (2: 1 mixture of ß: a anomers at C-1) 2.04-2.11 (12H, 8s, 4x [O2CCH3]) ; 3.66 (1H, dd, J = 9.0 and 9.9 Hz, H- 3p); 3.76 (1H, m, H-5ß); 3.94 (1 H, t, J = 10.2 Hz, H-3a); 3.98-4.23 (3H, m); 4.88-5.03 (2H, m); 5.64 (2/3H, d, J = 8.1 Hz, H-lp); 6.26 (1/3H, d, J = 3.6 Hz, H-la). MS FAB: m/e 396 [M+Na] BF3. EtZU (50mL; 40.6mmol) is added to a stirred solution of compound 1.4 150mmol) and thiophenol (30ml; 28.7mmol) in dry dichloromethane (125mL).

The reaction mixture is heated under reflux for 6 h then kept at room temperature for 16 h. The reaction mixture is diluted with dichloromethane (300mL) and washed with water (300mL), saturated sodium bicarbonate solution (3 x 600mL), 2N hydrochloric acid (2 x 500mL), water (600mL) and brine (2 x 500mL), then dried over Na2SO4 and evaporated to a yellow solid (72 g). The crude product containing both the alpha and beta isomers is recrystallized from ethyl acetate/hexane to give compound 1.5 (37.96g; 90mmol; 60%) as a white solid. mp 135 °C. Rf (50% ethyl acetate-hexane): 0.53.'H NMR (300 MHz,

CDC13): 8 2.07,2.11 and 2.17 (9H, 3 x s, 3 x 02CCH3); 3.66 (2H, t and m, Jt = 9.9 Hz, H-3 and H-5), 4.17 (2H, m, 2 x H-6); 4.65 (1H, d, J = 9. 8 Hz, H-lß); (2H, 2 x t, H-4 and H-2), 7.27-7.52 (5H, m, Ar-H). FAB MS: m/e 445 [M+Na] A stirred suspension of compound 1.5 90mmol) in dry methanol (250mL) is treated with sodium methoxide 18.5mmol) at room temperature under argon.

After 2 h, the reaction mixture is adjusted to pH=7 with Dowex 50 (H+) resin, then filtered and the filtrate is evaporated to give compound 1.6 as a white solid (28.0g; quantitative yield). mp 159-160 °C. Rf (ethyl acetate): 0.44.'H NMR (300 MHz, CD30D): 6 3.18-3.39 (4H, m), 3. 66 (1H, dd, J = 10.5 and 5.4 Hz, H-6); 3.84 (1H, d, J = 10.5 and 2.0 Hz, H-6'); 4.64 (1 H, d, J = 9.8 Hz, H-1); 7.27-7.33 (3H, m, Ar-H); 7.53- 7.56 (2H, d, Ar-H); MS m/e 320 [M+Na].

Compound 1.6 (28g; 94mmol) and trimethyl orthobenzoate (39mL; 230mmol) are stirred in anhydrous acetonitrile (250mL) containing a catalytic amount of p-TSA (1.34 g) for 3 h at room temperature. The solvent is evaporated and the residue is redissolved in fresh anhydrous acetonitrile (250mL) and stirred for a further 2 h. Solid sodium bicarbonate is added (8.6g) and the crude compound 1.7 is concentrated under reduced pressure to a slurry. MS m/e 438 [M+Na] and 384 [M-OMe]. The mixture is treated with acetic anhydride (17mL; 165mmol), pyridine (80mL) and 4-dimethylamino pyridine (70mg) and the reaction mixture is stirred overnight at room temperature. (TLC 10% ethyl acetate-hexane showed no starting material.) The reaction mixture is poured into water (500mL) and extracted with ethyl acetate (200mL). The organic phase is washed with water (2 x 500mL), saturated sodium bicarbonate solution (2 x 500mL), 3N citric acid solution (2 x 500mL) then water (2 x 500mL) and dried over sodium sulfate. The

solution is concentrated at 80°C to remove most of the remaining trimethyl orthobenzoate, giving compound 1.8 as a yellow gel quantitative yield). Rf (10% ethyl acetate-hexane): 0.31.'H NMR (300 MHz, CDC13): 6 2.18 (3H, s, 02CCH3) ; 3.09 (3H, s,-OCH3); 3.56 (1H, dt, H-5); 3.75 (1H, t, J = 10.2 Hz, H-3); 4.00-4.10 (2H, m, 2 x H-6); 4.18 (1H, t, J = 10. 2 Hz, H-4); 4.72 (lH, d, J = 10. 0 Hz, H-1); 4.90 (1H, t, J = 10.0 Hz, H-2); 7.26-7.60 (10H, m, Ar-H).

A solution of compound 1.8 (50.1g; 94mmol) in acetonitrile (lOOmL) is treated with a 9: 1 (v: v) mixture of trifluoroacetic acid and water (20mL). The solution turns reddish and a white precipitate is formed after 1 min. The suspension is stirred for 2 h then filtered to remove the solid 6-0-benzoate product (12g). A second crop of the 6-O- benzoate is obtained by concentration of the filtrate to 40mL and the remainder is evaporated to a yellow oil, containing primarily compound 1.9a with a little of the 6-O- benzoate regioisomer 1.9b and methyl benzoate. The crude product is triturated from diethyl ether-hexane to give compound 1.9a as a yellow-white solid (18.7g; 42.3mmol; 45%); mp 98-99°C. Alternatively, the crude product can be purified by column chromatography eluent; 20-50% ethyl acetate-hexane followed by 10% methanol dichloromethane.

Phenvl 2-O-acetvl-3-azido-3-deoxv-4-O-benzovl-1-thio-ß-D-Rlucopvra noside (compound 1.9a) <BR> <BR> <BR> <BR> <BR> Rf (50% ethyl acetate-hexane): 0.33.'H NMR (300 MHz, CDC13): 8 2.18 (3H, s,<BR> <BR> <BR> <BR> <BR> <BR> <BR> 02CCH3); 3.6-3.8 (3H, m, H-5,2 x H-6); 3.89 (1H, t, J = 9.8 Hz, H-3); 4.78 (1H, d, J = 10. 0 Hz, H-1); 4.98 (1H, t, J = 9. 8 Hz, H-2); 5.12 (1H, t, J=9.5 Hz, H-4); 7.31-7.35

(3H, m,-SAr-H); 7.44-7.51 (4H, m, 2 x-SPh-Ho, 2 x-Bz-Hm); 7.61 (1H, t, Bz-Hp); 8.03 (2H, d, Bz-Ho). MS m/e 466 [M+Na] Phenvl2-O-acetvl-3-azido-3-deoxv-6-O-benzovl-1-thio-3-D-gluc opyranoside (compound 1.9b) Rf (50% ethyl acetate-hexane): 0.48.'H NMR (300 MHz, CDCl3) : 8 2.17 (3H, s, O2CCH3) ; 2.49 (1H, br s, OH); 3.47 (1H, t, J = 9.5 Hz); 3.61 (1H, t, J = 9.5 Hz); 3.67 (lH, m, H-5); 4.59 (1H, dd, J=2.2 and 12.2 Hz, H-6); 4.67 (1H, d, J= 10. 0Hz, H-l); 4.68 (1H, dd, J = 4.6 and 12.2 Hz, H-6); 5.36 (1H, t, J = 9.8 Hz, H-4); 7.14-7.26 (3H, m,- SAr-H); 7.44-7.49 (4H, m, 2 x-SPh-Ho, 2 x-Bz-Hm); 7.60 (1H, t, Bz-Hp); 8.03 (2H, d, Bz- Ho). MS m/e 466 [M+Na].

Preparation of Phenvl 2-O-acetvl-3-azido-3-deoxv-4-O-benzovl-1-thio-ß-D- glucopvranosiduronic acid (compound 1.10) To a solution of compound 1.9a (4.88g; 11.0mmol) in acetone (75mL) is added Jones reagent (25mL) [prepared from chromium trioxide 11.3 g, concentrated sulfuric acid (lOmL) and water (74mL)] and the reaction mixture is sonicated in a sonicator bath for 1 h at a temperature of about 35°C. A further portion of Jones reagent (IOmL) is added and the reaction mixture is sonicated for a further lh. Isopropanol is added (10mL) and the reaction mixture is stirred for 20 min to destroy the excess oxidant. The top layer is decanted, and the green aqueous lower layer is extracted with more acetone (3 x 50mL). The combined organic layers are combined and evaporated to give a greenish- white solid. The solid is taken up in ethyl acetate (150mL) and extracted with 2N aq.

HC1 (20mL) to remove the green color. Drying over sodium sulfate and evaporation gives compound 1.10 (5.1g, quantitative yield) as a white solid. mp 170-172 °C. Rf (15%

methanol-dichloromethane): 0.48. NMR (300 MHz, CDC13): 8 2.21 (3H, s, 02CCH3); 3.97 (1H, t, J = 9. 8 Hz, H-3); 4. 21 (1H, d, J = 9. 8 Hz, H-5); 4.85 (1H, d, J = 10.1 Hz, H-1); 5.01 (1H, t, J = 10.0 Hz, H-2); 5.36 (1H, t, J = 9.8 Hz, H-4); (8H, m, Ar-H); 8.03 (2H, dd, OBz ortho protons). FAB MS: m/e 480 [M+Na] and 502 [M+2Na-H].

Guanidine hydrochloride (2.08g; 21.88mmol) is dissolved in ethanol (60mL) and treated with sodium methoxide (1.16g; 21.88mmol). Sodium chloride is filtered off, and the filter cake is washed once with ethanol (60mL) which is combined with the filtrate.

This solution is added to a suspension of compound 1.10 4.37mmol) in 9: 1 ethanol-dichloromethane (20mL) and stirred at room temperature for 4 h, at which time the reaction is shown to be complete by thin layer chromatography. Dowex 50 H+ resin is added to neutralize the base, the resin is filtered off, and the filtrate is concentrated.

Chromatography on silica eluent 2-15% methanol-DCM gives compound 1.11 as a white solid (1.72g; 91%) mp 93-95 °C. Rf (15% methanol-DCM): 0.41.'H NMR (300 MHz, CDC13-CD30D): 6 3.30 (1H, m, OH); 3.50 (1H, t, J = 9.8 Hz); 3.75 (1H, t, J = 9.5 Hz); 3.96 (1H, d, J = 9.8 Hz, H-5); 4.73 (1H, d, J = 9.8 Hz, H-1); 5.15 (1H, t, J = 9.8 Hz, H-4); 7.22-7.57 (8H, m, Ar-H); 7.98-8.03 (2H, d, OBz ortho protons); FAB MS: m/e 438 [M+Na] and 460 [M+2Na-H].

Example 1-2. Svnthesis of Phenyl 3-azido-3-deoxv-4-O-methvl-l-thio- (3-D-gluco- pvranosiduronic acid (compound 2.4).

As is depicted in Scheme 2, to a solution of compound 2.1 (16g; 0.037 mol) in anhydrous DMF (200mL) is added silver oxide (16 g) with stirring. (The preparation of compound 2.1, which is also compound 1.9b, is described hereinabove.) Methyl iodide

(25mL; 0.401mol) is added to the resulting suspension and the mixture is stirred at room temperature for 24 h. The reaction mixture is diluted with ethyl acetate (400mL), filtered, washed with water, washed with brine, dried (Na2SO4) and concentrated. The crude compound is purified by flash column chromatography eluting with 20% EtOAc/ hexane to afford compound 2.2 (15g; 91%) as a white solid; mp 75-77 °C;'H NMR (300 MHz, CDC13): 8 8.01 (d, J = 8.1 Hz, 2H, ArH), 7.5-7.4 (m, 5H, ArH), 7.3-7.1 (m, 3H, ArH), 4.84 (t, J = 10.2 Hz, 1H, H-2), 4.71 (dd, J = 12,2.1 Hz, IH, H-6 pseudo equatorial), 4.64 (d, J = 9Hz, 1 H, H-1), 4.44 (dd, J = 12,6 Hz, 1H, H-6 pseudo axial), 3.71-3.53 (m, 2H, H-3 and H-5, containing a singlet at 3.55, OMe), 3.21 (t, J = 9.3 Hz, 1H, H-4), 2.18 (s, 3H, OAc).'3C NMR (75 MHz, CDC13): 8 169.15,165.85,133.15,132.68,132.65, 67,78.46,69.90, 67.84,63.00,60.66,60.63,20.75; FAB MS: m/z 480 (M+Na].

To a stirred solution of compound 2.2 (15g; 0.033mol) in anhydrous methanol (200mL) is added sodium methoxide (3.65g; 0.067mol). The reaction mixture is stirred for 4 h at room temperature by which time all the starting material has been consumed (TLC analysis). Excess base is neutralized with Amberlite-H+ resin, filtered and concentrated to afford compound 2.3 as a white solid in quantitative yield (mp 182- 185°C).

Jones reagent (0.7M; 36mL) is added to a solution of compound 2.3 (9.67g; 0.033mol) in acetone (150mL) and the mixture is sonicated. After one hour, another portion (0.7M ; 30mL) of Jones reagent is added and the sonication is continued for 45 mins. After TLC analysis, excess reagent is quenched with isopropanol (lOOmL) and the chromate salt is filtered off through a pad of Celite. The green solid residue obtained

after concentration is purified by flash chromatography eluting with 5% methanol/methylene chloride to afford compound 2.4 as a white foamy solid (mp 182- 185 °C).'H NMR (300MHz, CDCl3) : 8 7.21-7.75 (m, 5H, ArH), 4.58 (d, J = 9.3 Hz, 1H, H-1), 3.93 (d, J = 9.3 Hz, H-5), 3.44-3.62 (m, 1H, H-3, containing a singlet at 3.54-OMe), <BR> <BR> <BR> <BR> <BR> 3.26-3.42 (m, 2H, H-2,4); 3C NMR (75 MHz, CDCl3) : 8 171.56,132.91,132.42,130.80, 129.11,128.48,88.72,79.23,77.66,70.61,68.72,60.50; FAB MS: calcd for Cl3o5SHlsN3 325. Found 324 (-ve mode), 343 (+ ve mode, M +18 (NH4)).

Example 1-3. Synthesis of Phenvl 3-azido-3-deoxy-4-O-benzovl-1-thio--D- galactopvranosiduronic acid (compound 3.9) and Phenvl 3-azido-3-deoxy-4-O-methvl-1- thio-ß-D-galactopvranosiduronic acid (compound 3.14) As depicted in Scheme 3, phenyl 3-azido-3-deoxy-1-thio-p-D-glucopyranoside (compound 3.1) is prepared from 1,2-5,6-di-O-isopropylidene-a-D-allofuranose following the procedure described in Example I-1 for the preparation of compound 1.6.

To a stirred solution of compound 3.1 (5.0g; 16.8mmol) in DMF (50mL) are added p-toluenesulfonic acid (0.5g) and anisaldehyde dimethyl acetal (lOmL). The stirring is continued for 3h at room temperature. The acid is neutralized with triethylamine, and the solution is concentrated under reduced pressure. The residue is dissolved in ethyl acetate and washed with aq. NaHC03 solution, water and concentrated.

Treatment of the residue with ether-hexane gives pure compound 3.2 (5.9g; 87% yield); 'H NMR (300 MHz, CDCl3) : b 7.41-6.87 (m, 9H, arom.), 5.51 (s, 1H, acetal H), 4.61 (d, J=9.6Hz, 1 H, H-1), 4.37 (dd, 1H, H-3), 3.79 (s, 3H, OMe), 3.72 (t, 1H, H-2), 3.48 (d, J=9.3Hz, 1 H, H-5).

To an ice-cooled solution of compound 3.2 (5.7g; 14.2mmol) in pyridine (50mL) containing DMAP (0.2g) is added acetic anhydride (25mL) and stirring is continued for 3h at room temperature. The solvent is evaporated under reduced pressure and the last traces of solvent are removed by co-evaporation with toluene. The residue is dissolved in ethyl acetate and washed with aq. NaHCO3 solution, water, dried over Na2SO4 and concentrated in vacuo. The residue gives compound 3.3 as a white amorphous solid 95% yield) from ether-hexane ; 1H NMR (300 MHz, CDC13): 8 7.45-6.87 (m, 9H, arom.), 5.53 (s, 1H, acetal H), 4.89 (t, 1H, H-2), 4.73 (d, J=9.9Hz, lH, H-1), 4.37 (dd, lH, H- 3), 3.79 (s, 3H, OMe), 2.18 (s, 3H, OAc).

To a cold (0°C bath) stirred mixture of compound 3.3 (5.5g; 12.5mmol), sodium cyanoborohydride (3.8g; 52mmol) and powdered 3A molecular sieves (lOg) in dry DMF (80mL) is added dropwise a TFA solution (9. OmL; 117mmol) in DMF (20mL). Stirring is continued at room temperature for 72h. The mixture is diluted with ethyl acetate, and the solids are filtered through Celite and washed with ethyl acetate. The combined filtrate is washed with aq. NaHC03 solution, water, dried and concentrated under reduced pressure. The residue is purified on a column of silica gel and eluted with hexane-ethyl acetate (4: 1->1 : 1 v/v) to afford compound 3.4 as an amorphous solid 90%);'H 1H NMR (300 MHz, CDCl3): 8 7.43-6.81 (m, 9H, arom.), 4.81 (t, 1H, H-2), 4.60 (d, J=9.9Hz, 1 H, H-1), 4.43 (dd, lH, H-3), 3.73 (s, 3H, OMe), 2.11 (s, 3H, OAc); 13C NMR: 8 132. 39-127.79 (aromatic C), 86.05 (C-1), 78.51 (C-5), 73.23 (OCH2), 70.40 (C-3), 70.36 (C-6), 70.10 (C-2), 67.92 (C-4), 55.06 (OCH3), 20.68 (COCH3).

To a stirred solution of triflic anhydride 18mmol) in CH2C12 (120mL) at a temperature of-15°C is added dropwise pyridine 43mmol) followed by a

solution of compound 3.4 (5.0g; 10. 9mmol) in CH2CI2 (lOOmL). After 3h at the same temperature, the solution is diluted with DCM, washed with 10% aq. citric acid, aq.

NaHC03 solution, water, dried over Na2SO4 and concentrated under reduced pressure. To a solution of this triflate (compound 3.5) in dry toluene (150mL) is added tetrabutyl ammonium benzoate 1.5 equivalent). The reaction is stirred at room temperature for 0.5h. The solvent is evaporated in vacuo and the residue is purified on a silica gel column by using hexane-ethyl acetate (4: 143: 1; v/v) as eluent to give compound 3.6 (5.3g; 92%);'H NMR (300 MHz, CDCl3) : 5 7.89-6.75 (m, 14H, arom.), 5.73 (d, J=2.7Hz, 1H, H-4), 5.22 (t, 1 H, H-2), 4.71 (d, J=9.9Hz, l H, H-1), 3. 92 (t, 1 H, H-3), 3.72 (s, 3H, OMe), 2.15 (s, 3H, OAc); 13C NMR: 5 133.39-128. 11 (aromatic C), 85.77 (C-1), 77.43 (C-5), 73.25 (OCH2), 68.44 (C-3&C-6), 67.64 (C-2), 63.68 (C-4), 55.11 (OMe), 20.82 (COCH3).

To a solution of compound 3.6 (5.2g; 9.3mmol) in CHzClz (150mL) saturated with water is added DDQ (5.2g; 23mmol) and stirring is continued for 2h. The organic layer is washed with cold aq. NaHC03 solution, water, dried and concentrated under reduced pressure. The residue is purified by column chromatography using a solvent gradient consisting of (4: 1 + 1 : 1, v/v) hexane-ethyl acetate to give compound 3.7 (3.7g; 90%); lH NMR (300 MHz, CDC13): 8 7.89-7.32 (m, 10H, arom.), 5.59 (d, J=3. 0Hz, lH, H-4), 5.32 (t, 1H, H-2), 4.73 (d, J=9.6Hz, lH, H-1), 3.83 (t, lH, H-3), 2.18 (s, 3H, OAc); 13C NMR: 8 169.24 & 166.57 (2xCO), 133. 39-128. 35 (aromatic C), 85.77 (C-1), 78.25 (C-5), 69.22 (C- 3), 68.38 (C-2), 63.01 (C-4), 60.36 (C-6), 20.85 (COCH3).

A mixture of compound 3.7 (3.6g; 8.1mmol) in acetone (100mL) containing Jones reagent (13.8mL) is sonicated for Ih. Then, another batch of Jones reagent (13.8mL) is

added to the reaction mixture and sonication is performed for another lh. Isopropanol is added to decompose the excess of reagent. The reaction mixture is filtered through Celite and the solid is washed with an excess of acetone. The solvent is removed under reduced pressure and the residue is dissolved in ethyl acetate and washed with aq. NaCl solution, dried over NazS04, and concentrated. It is purified on a silica gel column using CH2Cl2 - acetone (4: 14 1: l, v/v) as eluent to give compound 3.8 (2.9g; 78%);'H NMR (300 MHz, CD30D): 8 7.87-7.38 (m, 10H, arom.), 6.025 (dd, J=1.2Hz, lH, H-4), 5.13 (t, lH, H-2), 4.95 (d, J=9.9Hz, lH, H-1), 4.67 (d, J=1. 2Hz, lH, H-5), 4.19 (dd, lH, H-3), 2.18 (s, 3H, OAc); '3C NMR : ã (3xCO), 135.32-129.54 (aromatic C), 86. 17 (C-1), 77.07 (C-5), 71.23 (C-3), 69.21 (C-2), 64.23 (C-4), 20.86 (COCH3).

To a solution of compound 3.8 (1.9g) in methanol (lOOmL) is added 7.4% (w/v) mg (OMe) 2 solution in methanol (8mL; lequiv.), which is stirred at room temperature for 16h. Excess base is neutralized with glacial acetic acid and concentrated under reduced pressure. The residue is dissolved in ethyl acetate and washed with aq.

NaCl solution, dried over Na2SO4 and evaporated in vacuo. The residue is purified on a silica gel column using a solvent gradient consisting of 10-15% MeOH in CH2Cl2 to give compound 3.9 (1.6g; 93%) ; 1H NMR (300 MHz, CD30D): # 7.87-7.38 (m, 10H, arom.), 5.95 (d, J=2.4Hz, lH, H-4), 4.75 (d, J=9.6Hz, 1 H, H-1), 4.54 (bs,1H, H-5), 3.92 (dd, 1H, H-3), 3.68 (t, lH, H-2); 13C NMR: # 166.51&166.52 (2xCO), 135.12-129.18 (aromatic C), 88.87 (C-1), 71.69 (C-3), 69.07 (C-2), 66.72 (C-4): IR (KBr): 2111.97 (N3), 1727.61 (CO).

ESMS: Calcd. For ClsHl7N3so6 (4ls); Found: 414 [M-1]- To a solution of triflate 3.5 in dry DMF (lOOmL) is added NaN02 (12g; 8 equiv.).

The reaction mixture is stirred at room temperature for lh and is diluted with ethyl

acetate and washed with water, aq. NaHC03 solution, dried over Na2SO4 and concentrated in vacuo. The residue is purified on a silica gel column using hexane-ethyl acetate (4: 1 3 : 2; v/v) as eluent to give compound 3.10 75%); 1H NMR (300 MHz, CDCl3) : # 7.50-6.87 (m, 9H, arom.), 5.33 (t, lH, H-2), 4.67 (d, J=9.9Hz, lH, H-1), 4.50 (d, J=1.5Hz, lH, H-4), 4.15 (t, 1H, H-3), 3.81 (s, 3H, OMe), 2.16 (s, 3H, OAc); 13C NMR: 5 132.83-127.86 (aromatic C), 86.85 (C-1), 77.54 (C-5), 73.47 (OCH2Ph), 69.21 (C-6), 69.00 (C-3), 68.37 (C-2), 64.92 (C-4), 55.26 (OCH3), 20.87 (COCH3).

A mixture of compound 3.10 15. 2mmol), Ag2O (28g), and CH3I (21mL) in dry DMF (1 00mL) is stirred for 24h at room temperature. The mixture is diluted with ethyl acetate, and the solids are removed by filtration through a Celite bed and thoroughly washed with ethyl acetate. The combined filtrate is washed with aq. sodium thiosulfate, water, dried over Na2SO4 and evaporated under reduced pressure. The residue gives compound 3.11 (5.0g; 69%) as an amorphous solid from ether-hexane.

'H NMR (300 MHz, CDCI3): 8 7.48-6.87 (m, 9H, arom.), 5.31 (t, lH, H-2), 4.65 (d, J=10.2Hz, 1 H, H-1), 4.47 (d, J=1. 8Hz, 1H, H-4), 3.81 (s, 3H, OMe), 3.72 (dd, 1 H, H-3), 3.54 (s, 3H, OMe), 2.14 (s, 3H, OAc); 13C NMR: 8 133.51-127.60 (aromatic C), 87.14 (C-1), 77.78 (C-4), 77.60 (C-5), 73.24 (OCH2Ph), 68.53 (C-6), 67.53 (C-3), 64.25 (C-2), 61.38 (OCH3), 55.24 (OCH3), 20.84 (COCH3).

To a solution of compound 3.11 (5.0g; 10.6mmol) in CH2CI2 (150mL) saturated with water is added DDQ (5.5g; 24.4mmol) and stirring is continued for 2h. The organic layer is washed with cold aq. NaHC03, water, dried over Na2S04 and concentrated in vacuo. The residue yields compound 3.12 83%) as an amorphous solid from ether- hexane. NMR (300 MHz, CDC13): 8 7.45-7.28 (m, 5H, arom.), 5.31 (t, 1H, H-2),

4.68 (d, J=9.9Hz, lH, H-1), 3.64 (d, J=3.3Hz, lH, H-4), 3.55 (s, 3H, OMe), 3.39-3.34 (dd, lH, H- 3), 2.15 (s, 3H, OAc); 13C NMR: 8 169.45 (CO), 133.25-127. 68 (aromatic C), 86.92 (C-1), 79.70 (C-4), 78.09 (C-5), 68.56 (C-3), 64.27 (C-2), 61.47 (OCH3), 20.84 (COCH3).

A mixture of compound 3.12 (1.2g; 3.4mmol) in acetone (30mL) containing Jones reagent (SmL) is sonicated for lh. Then, another batch of Jones reagent (2.5mL) is added to the reaction mixture and sonicated for another lh. Isopropanol is added to decompose the excess of reagent. The reaction mixture is filtered through Celite and the solid is washed with excess of acetone. The solvents are removed under reduced pressure and the residue is dissolved in ethyl acetate and washed with aq. NaCl solution, dried over Na2SO4 and concentrated in vacuo. It is purified by silica gel column using 10-15% MeOH in CH2CI2 as eluent to give compound 3.13 (0.8g; 64%);'H NMR (300 MHz, CD30D): 8 7.58-7.33 (m, 5H, arom.), 5.22 (t, lH, H-2), 4.87 (d, J=9.6Hz, lH, H-1), 4.37 (d, J=1.2Hzl H, H-5), 4.18-4.16 (dd, J=1.2Hz, 1 H, H-4), 3.77-3.73 (dd, J=3.3Hz, 1 H, <BR> <BR> <BR> <BR> <BR> H-3), 3.35 (s, 3H, OMe), 2.17 (s, 3H, OAc); 13C NMR: 8 (2xCO), 133.25- 128.93 (aromatic C), 87.78 (C-1), 80.53 (C-4), 77.83 (C-5), 69.52 (C-3), 65.00 (C-2), 61.52 (OCH3), 20.84 (COCH3).

To a solution of compound 3.13 (1.2g) in MeOH (lOOmL) is added 1M MeONa (15mL) and the resultant is stirred at room temperature for 3h. The base is neutralized with IR-120 H+ resin, filtered and concentrated under reduced pressure. The residue is purified on a silica gel column using a solvent gradient consisting of 10-15% MeOH in <BR> <BR> <BR> <BR> <BR> CH2C12 to give compound 3.14 (0.9g; 85% yield). 1H NMR (300 MHz, CD30D): 8 7.64- 7.31 (m, 5H, arom.), 4.67 (d, J=9.6Hz, lH, H-1), 4.30 (bs, 1 H, H-5), 4.04 (d, J=2.4Hz, lH, H-4),

3.78 (t, lH, H-2), 3.54 (s, 3H, 170.89 (CO), 134.97-128. 55 (aromatic C), 90.41 (C-1), 80.53 (C-4), 77.78 (C-5), 69.20 (C-3), 67.34 (C-2), 61.53 (OCH3).

ES-MS: Calcd. For Cl3HIsN3OsS (325): Found: 324 [M-1]-, 343 [M+NH4] +, 348 [M+Na] +.

Example I-4: Svnthesis ofPhenyl 4-0-benzovl-3-0-levulinovl-l-thio-B-D- galactopyranosiduronic acid (compound 4.10) As shown in Scheme 4,1,2,3,4,6-penta-O-acetyl-D-galactopyranose (compound 4.1) (58g; 131mmol), commercially available from Pfanstiehl Laboratories, Inc.

(Waukegan, IL), is reacted with BF3. etherate (28mL; 233mmol) and thiophenol (25mL; 227mmol) in CH2CI2 (500mL) at room temperature to give compound 4.2. De-O- acetylation with methanolic sodium methoxide provides compound 4.3 in 75% yield. To an ice-cold solution of compound 4.3 (20g; 73.5mmol), imidazole (17g; 250mmol) in dry DMF (200mL) and tert-butyldimethylsilyl chloride (18g; 120mmol) are added with stirring, and stirring is continued for 3h at 0°C. The reaction mixture is poured into an ice-water mixture and extracted with ethyl acetate, dried over Na2SO4 and the solvent is removed under reduced pressure. The residue is purified on a column of silica gel with 60-80% ethyl acetate in hexane as the eluent to give compound 4.4 (22.2g; 78%); IH NMR (300 MHz, CDCl3): 8 7.53-7.25 (m, 5H, arom.), 4.53 (d, J=9.9Hz, lH, H-1), 0.89 (s, 9H, CMe3), 0. 085 and 0.07 (each s, 6H, SiMe2).

To a solution of compound 4.4 (lOg; 25.9mmol) in dry toluene (150mL) are added triethyl orthobenzoate (15mL) and p-toluenesulfonic acid (0. lg). After stirring for lh at room temperature, triethylamine is added and the solution is washed with water and

is concentrated under reduced pressure. To a solution of this orthoester in dry DMF (100mL) is added NaH (1.34g, 60% mineral in oil suspension) at-20°C. After 0.5h, allyl bromide (2.8mL) is added and stirring is continued for 2h at the same temperature. The reaction mixture is diluted with ethyl acetate, washed with water and solvent is removed under reduced pressure. The residue is dissolved in 80% aq. acetic acid (300mL) and stirred for 1 h at room temperature. Acetic acid is evaporated in vacuo, and the last trace is removed by co-evaporation with toluene. The crude product is purified on a silica gel column by using a solvent gradient consisting of (3: 1 o 1: 4, v/v) hexane-ethyl acetate to give compound 4.5 (7.5g, 44%); lu NMR (300 MHz, CDC13): 8 8.04-7.32 (m, 10H, arom.), 6.05-5.88 (m, lH, allylic H), 5.68 (d, J=3.3Hz, lH, H-4), 5.27-5.15 (2d, 2H, vinylic H), 4.65 (d, J=9.6Hz, lH, H-1), 0.83 (s, 9H, CMe3),-0. 03-0. 07 (each s, 6H, SiMe2). The loss of a silyl group from compound 4.5 also gives compound 4.6 (4.2g, 25%) ; 1H NMR (300 MHz, CDC13): # 7.98-7.30 (m, lOH, arom.), 6.04-5.88 (m, lH, allylic H), 5.51 (d, J=3.3Hz, lH, H-4), 5.27-5.17 (2d, 2H, vinylicH), 4.63 (d, J=9.6Hz, lH, H-l).

To a stirred solution of compound 4.5 (7g; 13.2mmol) in CH2CI2 (lOOmL) are added levulinic acid 41.8mmol), DCC (5.5g; 26.7mmol) and DMAP (0.4g) and stirring is continued for 3h at room temperature. The precipitate is removed by filtration and the filtrate is washed with aq. NaHC03, water, and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is applied to a column of silica gel and is eluted with hexane-ethyl acetate (3: 1, v/v) to give compound 4.7 (8.2g; 98%).

'H NMR (300 MHz, CDCl3)) : 8 7.98-7.33 (m, 10H, arom.), 5.81-5.94 (m, lH, allylicH), 5.70 (d. J=3.3Hz, 1 H, H-4), 5.25-5.10 (m, 3H, H-3&vinylicH), 4.69 (d, J=9.6Hz, lH, H-1),

2.85-2. 37 (m, 4H, 2xCOCH2), 2.11 (s, 3H, COCH3), 0.81 (s, 9H, CMe3),-0. 05 and-0. 10 ( each s, 6H, SiMe2).

To a stirred solution of compound 4.7 12mmol) in CH2CI2 (120mL) is added BF3. etherate (1.8mL; 14.3mmol) and stirring is continued at room temperature for 4h. The organic layer is washed with aq. NaHCO3 solution, dried over Na2S04 and concentrated in vacuo. The crude material is purified on a silica gel column using hexane ethyl acetate (3: 2#2 : 3) as eluent to give compound 4.8 (5.1g; 83%) ; 1H NMR (300 MHz, CDCl3) : 8 7.97-7.33 (m, lOH, arom.), 5.97-5.83 (m, lH, allylic H), 5.60 (d, J=3.3Hz, lH, H- 4), 5.26-5.09 (m, 3H, H-3&vinylic H), 4.71 (d, J=9.6Hz, lH, H-1), 2.89-2.34 (m, 4H, 2xCOCH2), 2.07 (s, 3H, COCH3); 13C NMR: 8 (aromatic C), 117.24 (=CH), 86.97 (C-1), 77.42 (C-2), 74.74 (C-5), 74.17 (C-3), 68.93 (C-4), 60.90 (C- 6), 37.73 and 27.82 (CH2&CH3).

A mixture of compound 4.8 (5.5g; 10.7mmol) in acetone (lOOmL) containing Jones reagent (28mL) is sonicated for 2h. Then, isopropanol is added to decompose excess of reagent. The reaction mixture is filtered off through Celite and the solid is washed with acetone. The solvent is removed under reduced pressure and the residue is dissolved in ethyl acetate and washed with aq. NaCl solution, dried over Na2S04 and concentrated. The product is purified on a silica gel column using 10-15% MeOH in CH2C12 as eluent to give compound 4.9 (2.6g; 46%); IH NMR (300 MHz, CD30D): 5 (m, 10H, arom.), 5.99 (d, J=3.3Hz, lH, H-4), 5.95-5.81 (m, 1H, allylic H), 5.21- 5.04 (m, 3H, H-3&vinylic H), 4.81 (d, J=9.6Hz, lH, H-1), 4.32 (bs, lH, H-5), <BR> <BR> <BR> 3.64 (dd, J=9.6Hz, lH, H-2), 2.78-2.35 (m, 4H, 2xCOCH2), 2.05 (s, 3H, COCH3);"C NMR: 8

(aromatic C), 117.25 (=CH), 87.75 (C-1), 78.29 (C-5), 76.29 (C-2), 75.54 (C- 3), 72.13 (C-4), 38.42,29.59 &28.97 (CH2&CH3).

A mixture of compound 4.9 (l. Og; 1. 9mmol), 10% Pd-C (l. Og) and p- toluenesulfonic acid monohydrate (0.25g) in MeOH (43mL) and water (8mL) is refluxed with stirring for 72h. The solid material is then filtered off through Celite and the filtrate is concentrated under reduced pressure. The residue is dissolved in ethyl acetate and washed with aq. NaCl solution, dried and evaporated under pressure. Column chromatographic purification on silica gel with 15-20% MeOH in CH2C12 gives compound 4.10 (0.3g; 40%); lH NMR (300 MHz, CD30D): # 7.98-7.35 (m, 10H, arom.), 5.99 (d, J=2.7Hz, 1H,,H4), 5.09 (dd, 1H, H3), 4.78 (d, J=9.9Hz, lH, H-l), 4.37 (bs, 1H,H-5), 2.73-2. 34 (m, 4H, 2xCOCH2), 2.07 (s, 3H, COCH3) ; 13C NMR: 8 134.69-126.95 (aromatic C), 88.53 (C-1), 78.31 (C-5), 76.57 (C-3), 72.03 (C-4), 67.61 (C-2), 38.52,29.60&28.93 (CH2&CH3). FAB-MS: Calcd. For C24H2409S (488); Found: 487 [M- H]-and 533 [M+2Na] + Example I-5 : Synthesis of Phenvl 3-0-levulinoyl-4-0-benzoyl-1-thio- (3-D- glucoperanosiduronic acid (compound 5.14) As depicted in Scheme 5,1,2,3,4, 6-penta-O-acetyl-D-glucopyranose (compound 5.1) (lOOg; 255mmol), commercially available from Pfanstiehl or Aldrich Chemical (Milwaukee, WI)2 is reacted with BF3. etherate 492mmol) and thiophenol (55mL; 534mmol) in CH2Cl2 (500mL) at room temperature for 16h to give compound 5.2 82%) ; 1H NMR (300 MHz, CDCl3) : 8 7.48-7.30 (m, 5H, arom.), 5.21

(t, J=9.3Hz, lH, H-4), 5.03 (t, J=10.2Hz, lH, H-3), 4.96 (t, J=10.2Hz, lH, H-2), 4.70 (d, J=10.2Hz, lH, H-1), (each s, 12H, 4xOAc).

De-O-acetylation of 5.2 (50g) with methanolic sodium methoxide provides compound 5.3 (28g; 91% yield);'H NMR (300 MHz, CD30D): 8 7.57-7.23 (m, 5H, arom.), 4.60 (d, J=9.6Hz, 1 H, H-1), 3.84 (dd, 1H, H-4), 3.59 (dd, lH, H-3); 13C NMR <BR> <BR> <BR> <BR> <BR> 6 132.64-128.27 (aromatic C) 89.35 (C-1), 81.97 (C-5), 79.63 (C-3), 73.72 (C-2), 71.29 (C- 4), 62.83 (C-6).

To a stirred solution of compound 5.3 (20g; 73.5mmol) in DMF (150mL) are added p-toluenesulfonic acid (0.8g) and anisaldehyde dimethyl acetal (30mL; 176mmol).

Stirring is continued for 3h at room temperature. The acid is neutralized with triethylamine, and the solution is concentrated under reduced pressure. The residue is dissolved in ethyl acetate and washed with aq. NaHC03 solution, water, dried and concentrated. Treatment of the residue with ether-hexane gives compound 5.4 (23g; 80%) ; 1H NMR (300 MHz, CDCl3): 8 7.53-7. 30 (m, 7H, arom.), 6.87 (d, J=8.7Hz, 2H, arom.), 5.51 (s, 1H, acetal H), 4.69 (d, J=9.9Hz, lH, H-l), 4.25 (t, J=10.2Hz, lH, H-4), 3.77 (s, 3H, OMe), 3.72 (t, J=9.9Hz, lH, H-3), 3.67 (dd, lH, H-2).

A mixture of compound 5.4 18mmol) in CH2CI2 (300mL), 5% aq. NaOH solution (30mL), allyl bromide 3 1 mmol) and tetrabutylammonium hydrogen sulfate 6. 0mmol) is refluxed for 72h, and the two layers are separated. The organic layer is washed with water, dried over Na2SO4, and evaporated to give a crude product which is purified by column chromatography using hexane-ethyl acetate (4: 1+3: 2, v/v) to afford di-O-allyl derivative 5.5 (1.2g; 14%), 3-O-allyl compound 5.6 (0.7g; 9%) and the desired 2-O-allyl compound 5.7 (5. lg; 66%); IH NMR (300 MHz, CDC13): S 7.54-

7.31 (m, 7H, arom.), 6.88 (d, J=8. 1Hz, 2H, arom.), 6.12-5.82 (m, lH, allylicH), 5.48 (s, lH, acetal H), (m, 2H, vinylic H), 4. 68 (d, J=9. 3Hz, lH, H-1), 3.78 (s, 3H, OMe); 13C NMR: 8 134.60-127.54 (aromatic C), 117.51 (=CH), 101.66 (acetal C), 87.83 (C-1), 80.42 (C-5), 80.16 (C-2), 75.24 (C-4), 74.30 (OCH2), 70.01 (C-3), 68.51 (C-6), 55.22 (OMe).

To a stirred solution of compound 5.7 (5.0g; 11.7mmol) in CH2CI2 (50mL) are added levulinic acid 46.5mmol), DCC (5.5g; 26.7mmol) and DMAP (0.6g).

Stirring is continued for 2h at room temperature. The precipitate is removed by filtration and the filtrate is washed with aq. NaHC03, water and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is applied to a column of silica gel and is eluted with hexane-ethyl acetate (4: 1->3: 2, v/v) to give compound 5.8 83%);'H NMR (300 MHz, CDCl3): 8 7.54-7.31 (m, 7H, arom.), 6.86 (d, J=9. OHz, 2H, arom.), 6.02- 5.87 (m, 1 H, allylic H), 5.43 (s, 1 H, acetal H), 5.31 (t, J=9. OHz, lH, H-3), 5.29- 5.17 (m, 2H, vinylic H), 4.75 (d, J=8.7Hz, lH, H-1), 3.78 (s, 3H, OMe), 2.81- 2.61 (m, 4H, COCH2), 2.14 (s, 3H, COCH3) ; 13C NMR : 8 134.30-127.42 (aromatic C), 117.51 (=CH), 101.21 (acetal C), 88.30 (C-1), 78.73 (C-5), 78.36 (C-2), 74.71 (C-4), 74.09 (OCH2), 70.31 (C-3), 68.46 (C-6), 55.22 (OMe), 37.83,29.80&27.96 (CH2&CH3).

A solution of compound 5.8 (3.5g) in CH2C12 (50mL) and trifluoroacetic acid (5. OmL) is stirred at room temperature for lh. After the solvent is removed under reduced pressure, the residue is chromatographed using a solvent gradient consisting of CH2C12- acetone (4: l- 3 : 2, v/v) to give compound 5.9 (1.8g; 66%) ; 1H NMR (300 MHz, CDC13): 8 7.51-7.28 (m, 5H, arom.), 5.95-5.78 (m, 1H, allylicH), 5.25-5.13 (m, 2H, vinylicH), 5.06 (t, J=9.3Hz, lH, H-3), 4.70 (d, J=9.6Hz, 1H, H-1), 3.64 (t, J=9.3Hz, 1H, H-4), 3.34 (t,: 9.3Hz, lH, H-2), 2.95-2.43 (m, 4H, COCH2), 2.17 (s, 3H, COCH3); 13C NMR : 8

134.36-127.70 (aromaticC) 117.31 (=CH), 87.28 (C-1), 79. 32 (C-5), 79.21 (C-2), 77.91 (C- 3), 73.78 (OCH2), 69.75 (C-4), 62.43 (C6), 38.26,29.78&28.19 (CH2&CH3).

To an ice-cold, stirred solution of compound 5.9 (1.8g; 4.4mmol) and imidazole (0.68g; l Ommol) in dry DMF (1 SmL) is added tert-butyldimethylsilyl chloride (0.72g; 4.8mmol), and stirring is continued for I h at 0°C. The reaction mixture is diluted with ethyl acetate and washed with water, dried over Na2SO4 and solvent is removed in vacuo.

The residue is purified in a column of silica gel with hexane-ethylacetate (4: 1#1 : l, v/v) as an eluent to give compound 5.10 91%) ; lH NMR (300 MHz, CDCI3): 8 7.52- 7.26 (m, 5H, arom.), 5.95-5.78 (m, 1 H, allylicH), 5.24-5.12 (m, 2H, vinylic H), 5.07 (t, J=9.3Hz, lH, H3), 4.64 (d, J=9.9Hz, lH, H-1), 2.85-2.53 (m, 4H, COCH2), <BR> <BR> <BR> <BR> 2.18 (s, 3H, COCH3), 0.90 (s, 9H, CMe3), 0.08&0.07 (eachs, 6H, 8 134.36- 127.44 (aromatic C), 117.20 (=CH), 87.31 (C-1), 79.04 (C-5&C-2), 77.63 (C-3), 73.70 (OCH2), 70.55 (C-4), 63.73 (C-6), 38.19,29.80&28.18 (CH3&CH2).

To an ice cold solution of compound 5.10 3.8mmol) in pyridine (30mL) containing DMAP (0.1 g) is added benzoyl chloride (l. 1mL ; 9.8mmol) and stirring is continued for 16h at room temperature. The solvent is evaporated under reduced pressure and the last traces are removed by co-evaporation with toluene. The residue is dissolved in ethyl acetate and washed with aq. NaHC03 solution, water, dried over Na2S04 and concentrated in vacuo. Chromatographic purifaction with a solvent gradient consisting of hexane-ethyl acetate (4: 1o3 : 1, v/v) as an eluent gives compound 5.11 88%) as a <BR> <BR> <BR> <BR> syrup;'H NMR (300 MHz, CDCI3): 8 7.98-7.28 (m, 10H, arom.), 5.98-5.81 (m, 1H, allylic H), 5.37 (dd, J=9.6&9. 0Hz, lH, H-4), 5.22 (dd, J=9.6&9. 0Hz, lH, H-3), 5.24- 5.13 (m, 2H, vinylic H), 4.71 (d, J=9.6Hz, lH, H-1), 3.46 (t, J=9. OHz, lH, H-2), 2.58-

2.35 (m, 4H, COCH2), 2.00 (s, 3H, COCH3), 0.85 (s, 9H, CMe3),-0. 01-0. 04 (each s, 6H, SiMe2); 13c NMR: b (aromatic C), 117.47 (=CH), 87.33 (C-1), 78.93 (C-5), 77.69 (C-2), 77.42 (C-3), 73.84 (OCH2), 69.24 (C-4), 62.58 (C-6), 37.70, 27.98&25.77(CH2&CH3).

To a stirred solution of compound 5.11 (1.9g; 3mmol) in CH2CI2 (20mL) is added BF3. etherate (0.45mL; 3.6mmol) and stirring is continued at room temperature for 2h.

The organic layer is washed with aq. NaHC03 solution, dried over Na2S04 and concentrated in vacuo. The product is purified on a silica gel column by using hexane- ethyl acetate (3: 2->2: 3, v/v) as eluent to give compound 5.12 (1.3g; 84%);'H NMR (300 MHz, CDC13): 6 7.96-7.28 (m, 10H, arom.), 5.94-5.81 (m, lH, allylic H), 5.41 (t, J=9.6Hz, 1 H, H-4), 5.25-5.11 (m, 3H, H-3&vinylic H), 4.72 (d, J=9.9Hz, 1 H, H-1), 3.45 (t, 1 H, H-2), 2.76-2.28 (m, 4H, 2xCOCH2), 1.96 (s, 3H, COCH3); 13C NMR: 8 134.09- 127.71 (aromatic C), 117.45 (=CH), 87.25 (C-1), 78.18 (C-5), 77.78 (C-2), 75.28 (C-3), 73.78 (OCH2), 69.16 (C-4), 61.30 (C-6), 37.56,29.35&27.80 (CH2&CH3).

A mixture of compound 5.12 (1.5g; 2.9mmol) in acetone (50mL) containing Jones reagent (7.0mL) is sonicated for 2h. Isopropanol is then added to decompose the excess of reagent. The solid is filtered off through Celite and the solid is washed with an excess of acetone. The solvent is removed under reduced pressure and the residue is dissolved in ethyl acetate and washed with aq. NaCI solution, dried over Na2S04, and concentrated.

The product is purified on a silica gel column using 10-15% methanol in CH2CI2 as eluent to give compound 5.13 (0.8g; 52%);'H NMR (300 MHz, CD30D): 6 7.96- 7.32 (m, 10H, arom.), 5.98-5.85 (m, 1 H, allylic H), 5.49 (t, J=9.6Hz, lH, H-4), 5.31 (t, J=9.6Hz, lH, H-3), 5.26-5.11 (m, 2H, vinylic H), 4.94 (d, J=9.6Hz, lH, H-l),

4.34 (d, J=9.6Hz, lH, H-5), 2.62-2.34 (m, 4H, 2xCOCH2), 1.97 (s, 3H, COCH3); 13c NMR: â 135.82 (aromaticC), 117. 62 (=CH), 88.26 (C-1), 78.99 (C-5), 76.62 (C-2), 76.40 (C-3), 74.88 (OCH2), 71.59 (C-4), 38.36,29.49&28.99 (CH2&CH3).

A mixture of compound 5.13 (0.4g; 0.8mmol), 10% Pd-C (0.4g), p- toluenesulfonic acid (0.13g), methanol (20mL) and water (4.0mL) is refluxed with stirring for 16h. The solid material is then filtered off through Celite and the filtrate is concentrated under reduced pressure. The residue is dissolved in ethyl acetate and washed with aq. NaCI solution, dried over Na2SO4 and concentrated. The residue is purified on a silica gel column using a solvent gradient consisting of 15-20% methanol in CH2CI2 to give compound 5.14 (0.06g; 16%) ; 1H NMR (300 MHz, CD30D): S 7.96- 7.32 (m, 10H, arom.), 5.35 (t, J=9.3Hz, lH, H-4), 5.25 (t, J=9.6Hz, lH, H-3), 4.85 (d, J=9.9Hz, 1H,H-1), 4.29 (d, J=9.6Hz, lH, H-5), 3.53 (t, J=9.6Hz, lH, H-2), 2.63- 2.42 (m, 4H, 2xCOCH2), 1.97 (s, 3H, 8 134.47-129.04 (aromatic C), 89.20 (C-1), 77.29 (C-5&C-3), 71.69 (C-2), 71.46 (C-4), 38.56,29.58 & 28.99 (CH2&CH3).

ESMS: Calcd. For C24H2409S (488); Found: 487 [M-H]-.

Example I-6: Svnthesis of Phenvl 3-O-levulinovl-4-O-benzovl-l-thio-a-D- glucopvranosiduronic acid (compound 6.18) Methyl 2-O-allyl-4, 6-O-benzvlidene-a-D-glucopvranoside (compound 6.2) As depicted in Scheme 6, compound 6.1, methyl 4,6-O-benzylidene-a-D- glucopyranoside (lOOg; 354mmol), which is obtained from reaction of methyl a-D- glucopyranoside and benzaldehyde dimethyl acetal according to the procedure of M. E.

Evans, Carbohvdr. Res., 21: 473 (1972), and dibutyltin oxide (88.0g, 354mmol) in toluene

(400mL) are heated to reflux with a Dean-Stark trap overnight. The solvent is evaporated and the residue is dissolved in allyl bromide (250mL) and heated at refluxing for 20 h.

Solvent is removed and the residue is precipitated in ethyl acetate/hexane to give the product (49g). The oil portion is purified with column chromatography to give additional product (25g). The two portions of product are combined to give compound 6.2 (74g; <BR> <BR> <BR> <BR> <BR> 64.5%): TLC (40% ethyl acetate in hexane): Rf 0. 47.'H NMR (300 MHz, CDCI3): 8<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> 7.85 (m, 2H), 7.35 (m, 3H), 5.95 (m, 1H), 5.53 (s, 1H), 5.35-5.20 (m, 2H), 4.84 (d, 1H, J =<BR> <BR> <BR> <BR> <BR> <BR> <BR> 3.9Hz,), 4.30-4.05 (m, 3H), 3.90-3.70 (m, 2H), 3.50 (t, 1H), 3.45 (s, 3H), 2.58 (d, 1H, J = 2.1Hz), 1.59 (bs, 1H).

Compound 6.2 (45g; 140mmol), levulinic acid 210mmol), DCC (46g; 224mmol) and DMAP (Ig) in DCM (400mL) are stirred at RT for 16 h. The reaction mixture is filtered and concentrated. The residue is re-dissolved in DCM, filtered and concentrated to give a solid product, which is re-crystallized from ethyl acetate/hexane to give product 6.4c as a white solid (50g; 85%). TLC (50% ethyl acetate in hexane): Rf <BR> <BR> <BR> <BR> <BR> 0.53.'H NMR (300 MHz, CDC13): 8 7.42-7. 31 (m, 5H), 5.90 (m, 1H), 5.47 (s, 1H), 5.35- 5.20 (m, 2H), 4.84 (d, 1H, J = 3.9Hz,), (m, 3H), 3.90-3.70 (m, 2H), 3.50 (t, 1H), 3.43 (s, 3H), 2.72 (m, 2H), 2.63 (m, 2H), 2.16 (s, 3H).

To a solution of compound 6.4c (50g; 120mmol) and triethylsilane (90mL) in DCM (400mL) at 0°C is added dropwise TFA (48mL) over 20 min. The reaction mixture is stirred at RT for Ih, washed with cold saturated Na2CO3 solution, and dried overmgSO4. The solvent is removed to give product 6.6c as an oil, which is used for the next reaction without purification. TLC (50% ethyl acetate in hexane): Rf 0. 23.'H NMR (300 MHz, CDCI3): 8 7.34 (m, 5H), 5.90 (m, IH), 5.35-5.10 (m, 2H), 4.84 (d, 1H, J =

3.9Hz,), 4.60 (m, 2H), 4.10-4.05 (m, 3H), 3.70 (m, 2H), 3.50 (t, 1H), 3.42 (s, 3H), 2.72 (m, 2H), 2.63 (m, 2H), 2.18 (s, 3H).

To a solution of compound 6.6c (crude product) in pyridine containing DMAP (Ig) at 0°C is added dropwise benzoyl chloride. The reaction mixture is stirred at RT overnight. Solvent is evaporated and the residue is washed with 2M aq. HCl and saturated NaHC03 in DCM, dried, then purified with column chromatography (10-50% ethyl acetate in hexane) to give compound 6.8c as an oil (41g; 65% based on 6.4c). TLC (50% ethyl acetate in hexane): 0.55. NMR (300 MHz, CDCl3): 8 8.0 (m, 2H), 7.60-7.10 (m, 9H), 5.90 (m, IH), 5.60 (t, 1H, J = 9.6Hz), 5.40-5.15 (m, 3H), 4.90 (d, 2H, J = 3.9Hz), 4.50 (m, 2H), 4.05 (m, 2H), 3.60 (m, 2H), 3.48 (s, 3H), 2.60-2.40 (m, 4H), 2.01 (s, 3H).

NaBH4 (610mg) is added portionwise to a solution of compound 6.8c (9.7g; 16.8mmol) in methanol (45mL) at 0°C. The solution is stirred at RT for 0.5 h., diluted with ethyl acetate (lOOmL), washed with 2.5% aq. AcOH, and dried over Na2SO4. The solvent is removed and the residue is re-dissolved in ethyl acetate, dried, and evaporated to give compound 6.12 as an oil (lOg; 100%). TLC (50% ethyl acetate in hexane): Rf <BR> <BR> <BR> <BR> <BR> 0.46.'H NMR (300 MHz, CDCI3): 8 8.0 (m, 2H), 7.60-7.10 (m, 8H), 5.90 (m, 1H), 5.60 (t, 1H), 5.40-5.15 (m, 3H), 4.90 (d, 2H, J = 3.9Hz), 4.50 (m, 2H), 4.05 (m, 2H), 3.60 (m, 2H), 3.48 (s, 3H), 2.35 (m, 2H), 1.60 (m, 2H), 0.99 (m, 3H). FAB MS: 551 (M + Na).

To a mixture of ZnI2 (138g; 432mmol) and Bu4NI (80g; 216mmol), which is dried at 60°C under vacuum for 2 h, is added a solution of compound 6.12 (43g; 72mmol) in 1,2-dichloroethane (450mL), followed by phenylthiotrimethylsilane (109.2g; 114mL; 600mmol). The mixture is stirred at 60°C for 6h, cooled, diluted with DCM, washed with water, and dried. Column chromatography (5%-60% ethyl acetate in hexane) gives

compound 6.14 (20g; 54%). TLC (50% ethyl acetate in hexane): Rf 0. 28.'H NMR (300 <BR> <BR> <BR> <BR> <BR> <BR> MHz, CDC13): 8 8.0 (m, 2H), 7.60-7.10 (m, 8H), 5.90 (m, 1H), 5.80 (d, 0.91H, J = 5.1Hz), 5.65 (t, 1H), 5.33-5.18 (m, 3H), 4.75 (d, 0.09H, J = 7Hz), 4.40 (m, 1H), 4.25-4.05 (m, 2H), 3.95 (m, 1H), 3.65 (bs, 2H), 2.35 (m, 2H), 1.60 (m, 2H), 0.99 (m, 3H). FAB MS: 539 (M + Na).

Compound 6.14 (20g; 39mmol) and pyridinium dichromate (126g; 335mmol) are stirred in DMF (300mL) at RT for 24 h, poured into H20 (1.5 L), and extracted with ether (10 x 40mL). The organic layer is dried and evaporated, and the residue is purified with column chromatography (50% ethyl acetate in hexane, then 5%-10% methanol in DCM) to give compound 6.16 (lOg; 48.5%). TLC (10% methanol in DCM): Rf 0.33.'H NMR (300 MHz, CD30D): 8 7.86 (m, 2H), 7.47-7.10 (m, 9H), 5.85 (m, 1H), 5.81 (d, 1H, J = 5.1Hz), 5.40-5.05 (m, 4H), (m, 4H), 2.54 (m, 2H), 2.37 (m, 2H), 1.88 (s, 3H).

FAB MS: 573 (M + 2Na-1).

Compound 6.16 (400mg; 0.75mmol), Pd on carbon (10%), p-toluenesulfonic acid (lOOmg) in methanol (20mL) and water (3mL) are heated at reflux for 20 h, filtered, concentrated and purified with a column chromatograph (5-10% methanol in DCM) to give compound 6.18 (80mg; 22%). TLC (10% methanol in DCM): Rf 0. 23. 1H NMR (300 MHz, CD30D): 5 7.86 (m, 2H), 7.45-7.15 (m, 9H), 5.69 (d, 0.91H, J = 5.4Hz), 5.26 (m, 2H), 4.70 (m, 1H), 4.10 (m, 1H), 2.49-2.30 (m, 4H), 1.85 (s, 3H). FAB MS: 533 (M+2Na-1).

Other C3 Substituents for 2-O-allvl Glucopyranosides (1) To a solution of compound 6.2 28mmol), triethylamine (19mL), DMAP (1. lg) in DCM (120mL) at-15°C is added formic acid (2.2mL) followed by acetic

anhydride (14mL) dropwise over 0.5 h. The mixture is stirred at 0°C for 0.5 h. Methanol (lOmL) is added and the reaction mixture is concentrated, redissolved in ethyl acetate, washed with I M aq. HCl and saturated Na2CO3, and dried. The crude product containing compound 6.4a is treated with TFA and triethylsilane in DCM to give compound 6.6a in the same manner as described above for compound 6.6c. The crude product containing compound 6.6a is dissolved in pyridine (120mL) containing DMAP (500mg). To this solution at 0°C is added dropwise benzoyl chloride (5mL). The mixture is stirred at RT overnight, concentrated, dissolved in DCM, washed with 1M aq. HCl and saturated Na2CO3, and dried. Column chromatography (10-30% ethyl acetate in hexane) gives compound 6.8a (9.9g, 77% from compound 6.2). TLC (30% ethyl acetate in hexane): Rf 0.45.'H NMR (300 MHz, CDCI'): 8 8.05 (s, 1H), 7.96 (m, 2H), 7.44-7.19 (m, 9H),.

5.90 (m, 1H), 5.60 (t, I H, J = 9.6Hz), 5.40 (t, IH, J = 9.6Hz), 5.30-5.20 (m, 2H), 4.92 (d, 2H, J = 3.6Hz), 4.50 (m, 2H), 4.10 (m, 3H), 3.60 (m, 2H), 3.49 (s, 3H). FAB MS: 479 (M+Na).

(2) To a solution of compound 6.2 (30g; 93.7mmol) in pyridine (200mL) containing DMAP (Ig) at 0°C is added dropwise benzoyl chloride (19.6g; 16mL; 140mmol). The mixture is stirred at RT overnight, concentrated, washed with 1M aq.

HCl and saturated NaHC03 in ethyl acetate, and dried. The crude product 6.4b is treated with TFA and triethylsilane in DCM to give compound 6.6b in the same manner as described above for compound 6.6c. The crude product (20g) is treated with benzoyl chloride (9.9g; 70.4mmol) in pyridine (250mL) containing DMAP (585mg) in the same manner as described above for compound 6.8a to give compound 6.8b (22g, 88.4%). <BR> <BR> <BR> <P> TLC (30% ethyl acetate in hexane): Rf 0. 36.'H NMR (300 MHz, CDC13): S 8.15-7.15 (m,

15H), 5.88 (t, 1H, J = 9.7Hz), 5.75 (m, 1H), 5.52 (t, 1H, J = 9.7), 5.14 (m, 2H), 4.97 (d, 1H, J = 3.3Hz), 4.53 (m, 2H), 4.20-4.06 (m, 3H), 3.78 (m, 1H), 3.62 (m, 1H), 3.52 (s, 3H).

Methvl 2-O-benzvl-4,6-O-benzvlidene-a-D-glucopvranoside (compound 6.3) Compound 6.3 is prepared from compound 6.1 in the same manner as described above for compound 6.2 with benzyl bromide replacing allyl bromide. The benzylation reaction is carried out at 80-90°C for 30 h. (75%). TLC (40% ethyl acetate in hexane): Rf 0.5.'H NMR (300 MHz, CDC13): 8 7.50-7.33 (m, 10H), 5.51 (s, 1H), 4.73 (dd, 2H, J = 14.7,12.0Hz), 4.60 (d, 1H, J = 3.9Hz), 4.25 (m, 1H), 3.90-3.70 (m, 2H), 3.50 (m, 2H), 3.36 (s, 1H).

Compound 6.9a, and intermediate compounds 6.5a and 6.7a, are prepared from compound 6.3 in the same manner as described above for synthesizing compound 6.8a.

Compound 6.9a: TLC (30% ethyl acetate in hexane): Rf 0. 5. 1H NMR (300 MHz, CDC13): 8 7.99 (m, 3H), 7.60-7.10 (m, 13H), 5.65 (t, 1H, J = 9.6Hz), 5.35 (t, 1H, J = 9.6Hz), 4.75-4.47 (m, 6H), 4.02 (m, 1H), 3.70-3.50 (m, 2H), 3.43 (s, 3H). FAB MS: 529 (M+Na).

Compound 6.13, and intermediate compounds 6.5b, 6.7b, 6.9b, are prepared from compound 6.3 in the same manner as described above for preparing the corresponding 2- O-allyl compounds from compound 6.2. Compound 6.13: TLC (40% ethyl acetate in hexane) Rf 0. 27.'H NMR (300 MHz, CDCl3) : 8 8.0 (m, 2H), 7.60-7.10 (m, 13H), 5.65 (t, 1H, J = 9.6Hz), 5.30 (t, 1H, J = 9.6Hz), (m, 5H), 3.70-3.50 (m, 4H), 3.48 (s, 3H), 2.3a5 (m, 2H), 1.60 (m, 2H), 0.99 (m, 3H).

Compounds 6.10a, 6.10b, 6.11a, and 6.15 are prepared from compounds 6.8a, 6.8b, 6.9a, and 6.13, respectively, as described above for converting compound 6.12 to

compound 6.14, i. e., in 1,2-dichloroethane at 60-65°C. Reactant equivalents, reaction times, and yields are shown in Table 1 hereinafter. The compounds were characterized as follows: Compound 6.10a: TLC (20% ethyl acetate in hexane): Rf 0. 11. 1H NMR (300 <BR> <BR> <BR> <BR> <BR> <BR> MHz, CDC13): 6 8.10 (s, 1 H), 8.03 (m, 2H), 7.70-7.20 (m, 8H), 5.90 (m, 1H), 5.85 (d, 0.91H, J = 5.4Hz), 5.70 (t, 1H, J = 9.6Hz), 5.30-5.20 (m, 3H), 4.75 (d, 0.09H, J = 7Hz), 4.40 (m, 2H), 4.30-3.90 (m, 4H). FAB MS 539 (M+Na).

Compound TLC (30% ethyl acetate in hexane): Rf 0. 26. iH NMR (300 MHz, CDC13): 8 7.90 (m, 2H), 7.55-7.20 (m, 11H), 5.95-5.65 (m, 3H), 5.40 (t, 1H, J = 9.6Hz), (m, 2H), 4.50 (m, 1H), 4.10 (m, 3H), 3.70 (m, 2H).

Compound 6.11 a: TLC (20% ethyl acetate in hexane): Rf 0. 40. 1H NMR (300 MHz, 30% ethyl acetate in hexane): 8 8.06-8.10 (m, 3H), 7.60-7.20 (m, 13H), 5.75- 5.65 (m, 2H), 5.22 (t, 1H, J = 9.6Hz), 4.70 (m, 2H), 4.40 (m, 1H), 3.95 (m, 1H), 3.61 (m, 2H). FAB MS 517 (M+Na).

Compound 6.15:'H NMR (300 MHZ, CDC13): 5 8.05 (m, 2H), 7.60-7.20 (m, 13H), (m, 2H), 5.08 (t, 1H, J = 9.6Hz), 4.70 (m, 2H), 4.40 (m, 1H), 3.95 (m, IH), 3.61 (m, 2H). FAB MS 589 (M+Na).

Compound 6.17 is prepared in the same manner as described above for synthesizing compound 6.16. TLC (10% methanol in DCM): Rf 0. 35.'H NMR (300 <BR> <BR> <BR> <BR> <BR> <BR> MHz, CD30D): 8.02 (m, 2H), 7.60-7.15 (m, 13H), 5.73 (d, J = 4.5Hz, 1H), 4.86 (d, J = 9Hz), 4.64 (m, 2H), 4.20-3.85 (m, 3H), 2.54 (m, 2H), 2.37 (m, 2H) 1.88 (s, 3H). FAB MS: 623 (M+2Na-1).

Table1 Starting Material Reaction Condition Product Yield Mol. Equiv.; (h).a/ (5 BnOn Me3SiSPh, 5.2 7 O 46% ° aZo B, O-o Znl2, OHCC, OHC AIIO OMe Bu4NI, 1.3 (3) AIIO SPh 10 : 1 8a 10a 10 : 1 BnO Me3SiSPh, 6 0 69% ° s.o- Ego Allô S 10 : 1 BnO Me3SiSPh, 5 41% BO zn12, 3 0 H C C 17. OHCO- »/ BNI, 1. S 3 e a SPh tn1 Bn0 pMe 1 v. 1 9a BnO o Me3SiSPh, 8. 3"° 0 54% BnOnMe3SiSPh, 8. 35O 54%Bzo 0 Znl2, 6 BzO 0 0 BnO OMe Bu4NI, 3 0 BnO bPh SPh ) 13 (6)) r5 i OH OH 10: 1

Example 1-7. Synthesis of Phenvl 2, 5-di-O-acetvl-1-thio-a-D-glucofuranosiduronic acid (compound 7.3).

As shown in Scheme 7,3,6-glucuronolactone (5.0g; 28.4mmol) is dissolved in acetic anhydride (30mL) and acetic acid (20ml + 0.5ml conc. sulfuric acid), and stirred for 3h at RT. In 15 min the starting material is completely dissolved and in 30 min the product precipitates. The reaction mixture is chilled, and compound 7.1 (3.6g; 40%) is filtered off. IR: 1806 cm-1 (lactone carbonyl), 1745 cm~' (Ac), no absorbance in range 3000-3600 ciri t.

Compound 7.1 (2.8g; 9.27mmol), thiophenol (1.53g; 14mmol), and BF3. Et2O 14mmol) are stirred in dichloromethane (30mL) for 12h. The reaction mixture is washed with sodium bicarbonate, brine, dried and purified on a column (EA-Hexane, 20% of EA) to give compound 7.2 (Phenyl 2,5-di-O-acetyl-l-thio-a-D- glucofuranosidurono-6,3-lactone) (1.8g; 52%) and compound 7.3 (0.8g, 23%), which are then eluted with 100% EA.

Compound 7.2: TLC (EA/Hex 1: 1): Rf=0.55. MS: 352 (M+).'H NMR (300 MHz, CDC13): 8 7.38-7.20 (5H, m, arom.), 5.60 (1H, s. H-5), 5.41 (1H, s, H-2), 5.34 (1H, d, J=4Hs, H-1), 5.20 (1H, m, H-3), 5.05 (1H, m, H-4), 2.05 (3H, s, AcO), 2.03 (3H, s, AcO).

Compound 7.3: TLC (EA/Hex.-+: 1): Rf=0. 15. MS : 393 (M+Na+).

Example 1-8. Synthesis of Phenyl 3-O-levulinovl-4-C-methvl-l-thio-ß-D- glucopvranosiduronic acid (compound 8.10).

As shown in Scheme 8, phenyl 1-thio-p-D-galactoside (compound 4.3) (335g; 1.23mol) is reacted with trityl chloride (357g; 1.28mol) and DMAP (5g) in anhydrous pyridine (I L) at reflux temperature for 6h. The reaction mixture is poured into ice-cold water (4L) and stirred for 10 min then filtered. The precipitate is dissolved in CH2CI2 (1L), washed with water (2 x IL), dried over sodium sulfate (200g) and the solvent is evaporated to give compound 8.1 (632.2g; quantitative yield);'H NMR (300 MHz, <BR> <BR> <BR> <BR> <BR> CDC13 +2 drops D20): 8 7.62-7.15 (m, 5H, arom.), 4.52 (d, J = 9.6Hz, 1 H, H-1), 3.85 (d, J = 3Hz, (1H, H-4), 3.66 (t, J = 9.6Hz, 1H, H-2), 3.52-3.45 (m, 3H, H-3,-6a and-6b) and 3.33-3.26 (m, 1H, H-5).

To a solution of compound 8.1 (350g; 0.68mol) in anhydrous DMF under argon are added imidazole (53.6g; 0.8mol) and tert-butyldimethylsilyl chloride (108g; 0.72mol). After stirring for 2h at RT, the reaction mixture is poured into ice-cold water (6L) and stirred for 15 min and filtered. The precipitate is washed with water (2 x IL), dissolved in CH2C12 (1 L), dried over sodium sulfate (200g) and the solvent is evaporated.

The oily residue is purified using flash silica gel chromatography with a solvent gradient of 5 to 10% ethyl acetate in hexane to give compound 8.2 70% yield);'H NMR <BR> <BR> <BR> <BR> <BR> <BR> (300 MHz, CDC13 +2 drops D20): 8 7.62-7.10 (m, 5H, arom.), 4.53 (d, J = 9.6Hz, 1H, H- 1), 3.72-3.52 (m, 5H, H-2, H-3, H-4,-6a and-6b), 3.30-3.24 (m, 1H, H-5), 0.88 (s, 9H, Si- CMe3), 0.12 and 0.10 (each s, 6H. SiMe2).

To a solution of compound 8.2 0.36mol) in anhydrous pyridine under argon at 5 °C are added acetic anhydride 0.375mol) and DMAP (5g). After stirring for 3h between 5-10 °C, the reaction mixture is poured into ice-cold water (6L) and stirred for 15 min, then filtered. The precipitate is washed with water (2 x IL), dissolved in CH2CI2 (IL), dried over sodium sulfate (200g) and the solvent is evaporated to give compound 8.3 (252g; quantitative yield);'H NMR (300 MHz, CDC13 +2 drops D20): 8 7.60-7.10 (m, 5H, arom.), 5.16 (t, J = 9.6Hz, 1H, H-2), 4.54 (d, J = 9.6Hz, 1H, H-1), 3.75-3.50 (m, 4H, H-3, H-4,-6a and-6b), 3.28-3.20 (m, 1H, H-5), 2.10 (s, 3H, OCOCH3), 0.85 (s, 9H, Si-CMe3), 0.06 and 0.05 (each s, 6H, SiMe2).

To a stirred mixture of pyridinium dichromate (112.9g; 0.3mol) and compound 8.3 (179g; 0.267mol) in anhydrous CH2CI2 (700mL) at 45 °C is added acetic anhydride (90mL; 0.9mol) dropwise. After stirring for 2h at 45 °C, the reaction mixture is poured into hexane (2L) and stirred for 15 min. The hexane-CH2CI2 layer is passed through a

plug of silica (1 kg) and is further eluted with 20% CH2Cl2 in hexane to furnish 8.4 (125g; 70% yield) as a white foam;'H 1H NMR (300 MHz, CDCl3) : 5 7.62-7.10 (m, 5H, arom.), 5.18 (t, J = 9.6Hz, 1H, H-2), 5.01 (d, J = 9.6Hz, 1H, H-3), 4.18 (d, J = 9.6Hz, 1H, H-1), 3.96-3. 92 (m, 1H, H-5), 3.60-3.55 (m, 2H, H-6a and-6b), 2.14 (s, 3H, OCOCH3), 0.84 (s, 9H, Si-CMe3), 0.07 and 0.04 (each s, 6H, SiMe2).

To a solution of compound 8.4 (103.7g; 0.155mol) in anhydrous toluene under argon at-78°C are added cerium chloride (lOg) and methylmagnesium chloride in THF (207mL; dropwise addition). The cooling bath is removed and the reaction mixture is stirred for 36 hours at RT. The reaction mixture is cooled to-10 °C (ice-salt bath) and a saturated aqueous sodium chloride solution (250mL) is added dropwise.

After filtering, the precipitate is washed with CH2Cl2 (2 x 200mL), the filtrate is evaporated and the residue is purified on a flash silica column using eluants of 5-8% ethyl acetate in hexane to give compound 8.5 (39.16g; 40% yield) ; 1H NMR (300 MHz, CDC13): 6 7.70-7.20 (m, 5H, arom.), 4.61 (d, J = 9.6Hz, 1H, H-l), 3.52-3.40 (m, 3H), 3.26-3.16 (m, 2H), 2.79 (s, 1H, C4-OH), 2.27 (d, J = 2.4Hz, C2-OH), 0.90 (s, 3H, 4-C- Me). 13C NMR (75 MHz, CDC13 +2 drops D20): S 20.7 (4-C-CH3), 0.85 (s, 9H, Si- CMe3), 0.09 and 0.07 (each s, 6H, SiMe2).

Further elution with ethyl acetate/hexane (3: 1) affords C4 epimer 8.6 (21.3g; <BR> <BR> <BR> <BR> <BR> 26%);'H 1H NMR (300 MHz, CDC13 +2 drops D20): b 7.69-7.22 (m, 5H, arom.), 4.56 (d, J = 9.6Hz, 1H, H-1), 3.65 (t, J = 9.6Hz, 1H, H-2), 3.57-3.25 (m, 3H, H-5,-6a and-6b), 3.17 (d, J = 9.6Hz, 1H, H-3), 0.95 (s, 3H, 4-C-Me). 13C NMR (75 MHz, CDC13 +2 drops D2O) : 8 20.7 (4-C-CH3).

To a solution of compound 8.5 (27.4g; 42.67mmol) in anhydrous THF (42mL) is added dropwise a solution of Bu4NF in THF (42mL; 1.0 M, 42mmol). The reaction mixture is stirred for 25 min at RT, concentrated at reduced pressure, and the gummy yellow liquid obtained is purified by silica gel chromatography eluting with 15% EA/ hexane to afford compound 8.7 (19g; 70% yield) as a foamy solid; 1H NMR (300 MHz, <BR> <BR> <BR> <BR> <BR> CDC13): 8 7.45-7.05 (m, 20H, arom), 4.51 (d, J= 9.6 Hz, IH, H-l), 3.4-3.1 (m, 5H, H-2, H-3, H-5, H-6), 2.78 (brs, 1H, OH), 2.45 (brs, 1H, OH), 0.9 (s, 3H, 4-C-Me), 0.84 (s, 9H, <BR> <BR> <BR> <BR> Si-CMe3), 0.11 and 0.05 (each s, 6H, SiMe2); 13C NMR (75 MHz, CDC13): 8-4. 22,3.79, 15.23,18.39,26.06,62.71,72.89,79.96,81.21,87.43,89.62,126.92 ,127.12,127.90, 128.52,128.82,130.60,134.89,143.46.

To a solution of levulinic acid (4mL) in anhydrous CH2CI2 (40mL) are added DCC (8g; 39.2mmol) and DMAP (1.2g) followed by addition of compound 8.7 (6.3g; 9.8mmol) in anhydrous CH2CI2 (20mL). After 16 h at reflux the byproduct is filtered off, and washed with CH2C12. The combined organic layers are washed with water, brine, dried over NaS04, and concentrated. The organic residue is purified using silica-gel chromatography eluting with 30% EA/hexane to afford compound 8.8 (4.75g, 65% yield) as a foamy solid;'H NMR (300 MHz, CDC13): 5 7.62-7.11 (m, 20H, arom), 4.94 (d, J = 9Hz, 1H, H-3), 4.75 (d, J = 9.3 Hz, 1H, H-1), 3.65-3.55 (m, 2H, H-2, H-5), 3.35 (d, J = 5.4 Hz, 2H, H-6), 2.91-2.39 (m, 4H, lev CH2's), 2.14 (s, 3H, COCH3), 1.04 (s, 3H, 4-C-Me), 0.88 (s, 9H, Si-CMe3), 0.22 and 0.05 (each s, 6H, SiMe2); 13C NMR (75 MHz, CDCI3): 6-3. 84,16.21,18.07,25.85,29.70,29.71,38.52,62.38,71.05,72.95,81. 60, 82.42,86.92,88.91,126.92,126.98,127.77,128.65,128.95,130.53, 143.81,173.37, 207.67.

To a solution of compound 8.8 (2.5g, 3.36mmol) in CHCN: H20 (9: 1; 25mL) is added DDQ (470mg, 2.06mmol) under argon and refluxed for 3 h. TLC indicates the formation of a mixture of two compounds, due to deprotection of trityl and tert- butyldimethylsilyl groups as well as deprotection of the trityl group alone. An additional amount of DDQ (470mg) is added, and reflux is continued for 2 h. The reaction mixture is concentrated under reduced pressure, and the residue is passed through a pad of NaHCO3 and then chromatographed (silica-gel) and eluted with 10% methanoVethyl acetate to afford compound 8.9 as a dark brown colored solid (1.25g; 91% yield); lH <BR> <BR> <BR> <BR> <BR> <BR> NMR (300 MHz, CDCI,): b 7.54-7.28 (m, SH, arom), 4.99 (d, J = 9.6 Hz, 1H, H-3), 4.66 (d, J = 9.6 Hz, 1H, H-l), 4.01-3.11 (m, 7H, H-2, H-5, H-6, two OH), 2.75 (m, 2H, lev group CH2), 2.11 (s, 3H, COCH3), 1.04 (s, 3H, 4-C-CH3); 13C NMR (75 MHz, CDC13): 5 13.93,15.14,27.93,29.57,37.97,60.26,60.53,69.32,69.31,72.31, 80.85,82.33,87.09 , 127.60,127.74,127.86,128.72,131.31,131.70,173.29,208.61.

To a solution of compound 8.9 (1g; 2.6mmol) in acetone (lOmL) is added Jones reagent (5.5mL; 0.7 M), the resulting mixture is sonicated for 30 mins, and then quenched with isopropanol (20mL). The reaction mixture is filtered, concentrated and purified by silica-gel chromatography eluting with 20% MeOH-DCM to afford compound 8.10 as a foamy solid (400mg; 40% yield);'H NMR (300 MHz, CDC13): 8 7.61-7.21 (m, 5H, arom), 4.82 (d, J = 9.6 Hz, IH, H-3), 4.61 (d, J = 9.6 Hz, 1 H, H-1), 3.27-3.22 (m, 1H, H-5), 3.18 (t, J = 9.6 Hz, 1H, H-2), 2.80-2.52 (m, 4H, lev group CH2), 2.10 (s, 3H, COCH3), 1.06 (s, 3H, 4-C-CH3). i3c NMR (75 MHz, CDCl3): b 16.73,29.05,29.78,38.73,70.4,81.55,89.05,129.08,130.10,132.3 6,133.54,134.35, 173.87,208.61.

PART II. SYNTHESIS OF DONOR SACCHARIDES Example II-1: Svnthesis of Phenvl 234*6-tetra-O-pivalovl-I-thio-D-mannopvranoside (compound 9.3).

As depicted in Scheme 9, to a stirred solution of D-mannose 9.1 (20g; 0.1 lmol) in anhydrous pyridine (150mL) is added a catalytic amount of DMAP (200mg). The resulting solution is cooled to 0°C and pivaloyl chloride (109mL; 0.88mol) is added dropwise over 30 min. The reaction mixture is stirred at 80°C (oil-bath) for 48 h, and then poured into 800mL of water to obtain a gummy solid. This semi-solid mass is filtered, washed several times with water, and dissolved in methylene chloride (500mL).

The methylene chloride layer is washed with NaHCO3 solution (400mL), water, brine, and concentrated. The crude compound is crystallized from EtOH/H2O to afford compound 9.2 71 % yield) as a white solid, mp 118-120 °C ; IH NMR (300 MHz, CDC13): 8 5.83 (d, J = 1.2 Hz, IH, H-1), 5.45-5.52 (m, 2H, H-2 and H-4), 5.17 (dd, J = H-3), 4.15-4.25 (m, 2H, H-6), 3.85 (ddd, J = 10.2,3.9,2.1 Hz, 1H, H-5), 1.12,1.16,1.17,1.24,1.31 (5s, 45H, pivaloyl).

Treatment of compound 9.2 with thiophenol in the presence of BF3-etherate at 50°C provides the thiophenyl derivative 9.3 in 77% yield. The amount of compound 9.3 obtained is 35 g (the a-anomer is the major product). Thus, to a stirred solution of compound 9.2 0.077mol) in anhydrous methylene chloride (150mL) is added thiophenol (17mL; 0.17mol) and BF3-etherate (9mL; 0.076mol). The reaction is allowed to stir overnight at 50°C, by which time all the starting material has been consumed (TLC analysis). The reaction mixture is diluted with methylene chloride (250mL), washed with

10% Na2CO3 solution (200mL), water, brine and dried (Na2SO4). The residue is purified by flash column chromatography eluting with 7% EtOAc/hexane to afford two fractions of compound 9.3 (first fraction: 35g, 60% yield, >99% pure by NMR; second fraction: 10g, 17%, >95% pure by NMR) as a foamy solid (mp 88-90 °C); IR (KBr): 2973,2874, 1738,1479 cm-','H NMR (300MHz, CDC13): 8 7.2-7.6 (m, 5H, ArH), 5.59-5.51 (m, 2H, H-2 and H-4), 5.44 (d, J = 1.5 Hz, 1H, H-1), 5.33 (dd, J = 10.2,3.3 Hz, H-3), 4.55-4.65 (m, IH, H-5), 4.25 (dd, J = 12.9,4.8 Hz, IH, H-6), 4.11 (dd, 10.8,1.5 Hz, 1H, H-6), 1.26, <BR> 1.21,1.16,1.14,1.13 (5s, 45H, pivaloyl). l3C NMR (75 MHz, CDCl3) : 8 178.06,177.12, 176.91,176.61,132.93,131.98,129.19,129.01,128.92,128.86,128. 02,86.31,70.88, 38.81,38.79,38.72,27.08,27.04. FAB MS: for C3209SH4gNa 631,499 (MH-SPh).

Example 11-2: Synthesis of Phenvl 234-tri-O-acetvl-1-thio-L-fucopvranoside (compound 10.3), Phenvl-1-thio-L-fucopvranoside (compound 10.4), and Phenvl 2. 34-tri-O- pivalovl-1-thio-L-fucopvranoside (compound 10.5): As shown in Scheme 10, treatment of L-fucose (compound 10.1) with acetic anhydride and pyridine provides compound 10.2, which upon treatment with thiophenol in the presence of BF3-etherate affords the thiophenyl derivative 10.3.

To a stirred solution of compound 10.3 (46g; 0.12mol) in anhydrous methanol (200mL) is added sodium methoxide 0.13mol), and the mixture is stirred at room temperature for 2 h. The resulting solution is neutralized with H+ resin (Amberlite IR- 120), filtered, washed with methanol (200mL), and dried. The crude compound 10.4 (31g; 0.12mol) is dissolved in anhydrous pyridine (200mL), and then charged with

pivaloyl chloride (119mL; 0.97mol), followed by a catalytic amount of DMAP (200mg).

The reaction mixture is stirred at 80 °C for 48 h, poured into 800mL of water, and then extracted with methylene chloride (2 x 300mL). The methylene chloride extract is washed with water (2 x 300mL), saturated NaHCO3 solution (500mL), water, brine, and dried (Na2SO4). The crude product is purified by flash chromatography, eluting with 10% EtOAc/hexane, to afford compound 10.5 as a colorless liquid (44g; 72%), IR (neat): 2972,1738,1479 cm-' ; 1H NMR (300 MHz, CDCl3): 8 7.51-7.56 (m, 2H, ArH), 7.30- 7.32 (m, ArH, 3H, ArH), 5.91 (d, j = 4.5 Hz, 1Hα), 5.31-5.36 (m, H-4α, H-3a, H-2a), 5.24 (d, J = 3.3Hz, 1H, H-4p), 5.19 (t, J = 10.2 Hz, H-2p), 5.09 (dd, J = 10.2,3.3 Hz, 1H, H-3ß), 4.68 (d, J = 9.3 Hz, 1H, H-1ß), 3.90 (dd, J = 12.6,6.3 Hz, 1H, H-5ß), 1.21,1.17, 1.08 (3s, 27H, pivaloyl); 13 C NMR (75 MHz, CDCI3): 5 36,133.59, 131.24,128.66,128.17,85.15,73.40,72.61,70.00,66.35,38.94,38. 64,27.09,26.97, 16.40; Fab for C2707SH4Na 531,399 (MH-SPh).

Example II-3 : Synthesis of Phenvl 2-phthalimido-2-deoxy-3*4*6-tri-O-acetyl-1-thio-ß-D- galactopvranoside (compound 11.5).

As depicted in Scheme 11, D-Galactosamine hydrochloride (compound 11.1) (25g; 0. 116mol) is stirred with 200g of a wet strong basic resin in OH-form (Aldrich, Amberlite IRA-400 (OH)) to produce compound 11.2 in 300mL of methanol and 15mL triethylamine for 3h at room temperature under nitrogen. The resin is filtered and washed with MeOH (200mL). The filtrate is transferred into a 1 L three-neck flask, phthalic anhydride (18.9g; 0.128mol) is added with stirring, TEA (15mL) is poured into the reaction mixture and it is stirred under nitrogen at room temperature overnight. The

solvent is evaporated under vacuum at 60°C to a residue volume in the flask of about 100mL. It is poured dropwise with stirring in 300ml of EA to give a solid or oil that turns to a solid while chilling in an ice bath. This solid compound 11.3 is treated with pyridine (lOOmL), acetic anhydride (lOOmL), DMAP (1. Og) in DCM (200mL) and refluxed for Ih. The reaction is quenched by pouring the mixture on ice. The reaction mixture is transferred to a separatory funnel and washed with 5% HCl (200mL), water, sodium bicarbonate, brine, and dried. The solvent is evaporated and the residue is purified on a column in EA-hexane to give compound 11.4 (17g; 41.6mmol; 36% yield based on compound 11.1).

Compound 11.4 (17g; 41.6mmol) is dissolved in 200mL of DCM. Thiophenol (8.3g; IOmL; 74.9mmol) and BF3-etherate (18mL) are added and the reaction mixture is stirred at room temperature for 18h, then it is refluxed for lh, chilled to room temperature, transferred into a separatory funnel and washed with sodium carbonate (3 x 300ml), brine, and dried. The solvent is evaporated, the residue is dissolved in EA- hexane 20ml (2: 1), and is purified on a column to give 13g of compound 11.5, as white or slightly yellow crystals, mp 91 °C. Yield 86%.

TLC (1: 1 Ethyl acetate/Hexane): R f =0. 55.'H NMR (300MHz, CDC13): 8 7.2-7.9 (9H, m, arom), 5.85 (1H, dd, H-3), 5.72 (1H, d, J=8Hz, H-1), 5.50 (1H, d, H-4), 4.63 (1H, t, H-2), 4.05-4.25 (3H, m. H-5 +H2-6). IR, neat, v: 1746,1722,1379,1229,1073,912,726 crri 1.

FAB MS: m/z, 550 (M+Na+). Anal. Calc. for C26H25NO9S: C, 59.20; H, 4.74; N, 2.65; S, 6.07. Found: C, 59.83; H, 5.01; N, 2.59; S, 6.22.

Example 11-4: Senthesis of Phenyl 2-azido-2-deoxv-3 4-di-O-acetvl-1-thio-D- fucopvranoside (compound 12.8).

As shown in Scheme 12, D-Fucose (compound 12.1) (25g; 0.152mol) is dissolved in pyridine (500mL), chilled in an ice-water bath and acetic anhydride (125mL) is added. The reaction mixture is kept at room temperature 18h. Pyridine and excess of acetic anhydride are evaporated (100mm Hg, 75°C). The oily residue is dissolved in dichloromethane (300mL) and washed with dilute HC1 (5%, 200mL), a saturated solution of sodium bicarbonate (200mL x 2), brine, then dried and evaporated to give compound 12.2 (48g; 98% yield) as a thick oil. Rf is 0.4 in EA-Hex, 1: 1.

Compound 12.2 0.126mol) is dissolved in 110mL of a AcOH-Ac2O mixture (77mL+33mL), chilled in ice-water bath and then 140mL of the 30% HBr in AcOH is added dropwise. The reaction mixture is kept in an ice bath for 1 hour and after 2 hours at room temperature EA (600mL) is added. The reaction mixture is transferred to a separatory funnel, washed with ice-water (2 x 500mL), sodium bicarbonate, brine, dried over sodium sulfate and then decanted to a 2-neck flask equipped with mechanical stirrer.

This EA solution contains compound 12.3 in about 90% purity.

Activated Zn (85g) and N-methylimidazole (13mL) are added to the EA solution of compound 12.3 at room temperature. The reaction mixture is heated to reflux over 20 min and is stirred very vigorously over 30 min at reflux, chilled to room temperature, filtered through Celite, and the filter cake is washed with EA. The filtrate is washed with 2% sulfuric acid (200mL x 2), sodium bicarbonate (300mL), brine (lOOmL), dried and evaporated at +70°C to give diacetyl fucal compound 12.4 as a thick oil (19g; 71% yield).

After 1-3 days the oil turns to crystalline product, mp 47°C.

TLC (1: 1 Ethylacetate/Hexane): Rf = 0.50. tu NMR (300 MHz, CDCl3): 8 6. 35 (in, d, H- 1), 5.48 (1H, dd, H-4), 5.18 (1H, dd, H-3), 4.55 (1H, m, H-5), 4.12 (1H, m, H-2), 2.05 (3H, s, Ac), 1.92 (3H, s, Ac), 1.18 (3H, d, H3-6). FAB MS m/z, 215 (M+H+).

Compound 12.4 (19g; 89mmol) is dissolved in acetone (SOOmL), chilled to-16°C, then (NH4) 2Ce (NO3) 6 (100g; 0.182 mol) is added. Sodium azide (lOg, 0.15mol) is added to the suspension at-15-18°C, kept at this temperature 8 hours with good mechanical stirring. The reaction mixture is transferred to a separatory funnel containing 750mL of water and 500mL of ether. The water phase is extracted with ether one more time. The organic layer is separated, washed with water (4 x 300mL), brine, dried and evaporated to give a thick oil (22.7g; 85% yield). The oil is a mixture of compound 12.5 (70%) and compound 12.6 (30%). The Rf is 0.6 and 0.2, respectively (EA/Hex 1: 1).

The oil is dissolved in AcOH (1 l OmL + 2mL of conc. H2S04) and Ac2O is added at +4°C. The reaction mixture is kept at 36-38°C for 2h, then neutralized with sodium acetate (6.5g). The mixture is transferred into a separatory funnel with dichloromethane (400mL) and water (500mL). The water extraction is repeated, then the organic layer is extracted with sodium bicarbonate (2 x 300mL), brine, dried, and evaporated to dryness to give a thick oil. Upon chilling and scratching the oil turns to a crystalline product, which is washed with cold ether (lOmL) and dried to give compound 12.7 62% yield relative to compound 12.4), mp 156 °C.

TLC (EA: Hexane 1: 1): Rf =0.4. IR, neat 2116,1753,1372,1220. Anal. Calc. for C,2H17N307. C, 45.7; H, 5.39; N, 13.33. Found: C, 45.63; H, 5.38; N, 13.25.

Compound 12.7 55. 7mmol), thiophenol 111. 4mmol) and BF3. Et20 (7.8g; 6.8mL; 55mmol) are mixed in DCM (200mL) and stirred overnight at room

temperature. The reaction mixture is washed with sodium carbonate (200mL), water, brine, dried, and evaporated at +70°C. The oily residue is purified on a column in EA- Hexane system and the product is eluted at 20% of EA. The appropriate fractions after evaporation afford compound 12.8 89% yield), which consists of the a-and (3- isomers in ratio 2: 1. The (3-isomer is crystalline at room temperature and is isolated by recrystallization from ether, mp 55°C. The a-isomer is isolated with 90% purity as a liquid.

TLC (1: 1 Ethyl acetate/Hexane): Rf=0.6.'H NMR (300MHz, CDCl3): 8 7.28- 7.65 (5H, m, arom.), 5.62 (1H, d, J=3Hz, H-l, a), 5. 32 (lH, d, H-4, ß), 5.20 (1H, m, H- 3) 5.15 (1H, d, H-4, a), 4.85 (1H, dd, H-2, P), 4.61 (1H, q, H-5, a), 4.49 (lH, d, J=9Hz, H-l, P), 4.28 (1 H, dd, H-2a), 3.78 (1H, q. H-5, P). FAB MS m/z: 383 (M+NH4). Anal. Calc. for C16H19N3O5S : C, 52.60; H, 5.20; N, S, 8.76. Found: C, 52.58; H, 5.24; N, 11.40; S, 8.80.

Example ofPhenyl2-azido-2-deoxy-3,4,-di-O-acetyl-1-thio-L-Synthesis fucopvranoside (compound 13.7), Phenyl 2-azido-2-deoxv-1-thio-L-fucopvranoside (compound 13.8), and Phenyl 2-azido-2-deoxv-3*4-carbonate-1-thio-L-fucopvranoside (compound 13.9).

As depicted in Scheme 13, L-Fucose (25g; 152mmol) is dissolved in pyridine (300mL) and acetic anhydride (100mL) is added. The reaction mixture is stirred at room temperature for 24 h and then evaporated at +65°C to afford 55g of compound 13.1 as a thick colorless oil. Compound 13.1 (45g crude or 41g pure; 123mmol) is dissolved in a mixture of 74mL of AcOH and 30ml of Ac20 at room temperature, chilled to 0°C, and

130ml of 30% HBr in AcOH is added dropwise while chilling. The reaction mixture is kept I h at 0°C and then 3h at room temperature, poured into a separatory funnel with water-ice (1L) and EA (0.5 L), washed with water three times, then with a saturated solution of NaHC03 (3 x 300mL), brine, and dried. This solution contains bromide derivative 13.2, which does not need to be isolated. To this solution in a 2-neck 1L flask, activated Zn (78g) and N-methyl-imidazole (11. 5mL) are added, and the mixture is heated under reflux with vigorous mechanical stirring for lh, and chilled to room temperature. The Zn is filtered through Celite and the filtrate is washed with water, NaHC03, brine, dried, and evaporated to give an oil. The weight of the crude product is 24g (93%). After flash chromatography purification the 3,4-O-diacetyl-L-fucal compound 13.3 is isolated (13.4g; 52% yield based on L-fucose), mp 46°C.

Compound 13.3 (13.4g; 62.6mmol), (NH4) 2Ce (NO3) 6 (67g; 122mmol) and sodium azide 107mmol) are mixed in 350ml of dry acetone at-16°C. With very vigorous stirring, the reaction mixture is kept for 8h at-16°C, poured into a separatory funnel with ice-water (I L) and ether (0.5L), washed with NaHC03, brine, dried, and evaporated to an oily residue. The product of the reaction is a mixture of compound 13.4 (Rf 0.3) and compound 13.5 (Rf 0.65, EA-Hex 2: 8). The IR spectrum shows signals of the azido group (2116 cm-') and carbonyl (1750 cl-1).

The oily mixture of compounds 13.4 and 13.5 (16.8g) is dissolved in 80mL of Ac2O and 80mL of 2% (vol.) sulfuric acid in AcOH at room temperature and kept for 2h at + 37 °C, neutralized with sodium acetate (6.0g) with chilling, and poured into dichloromethane-water (300mL-I. OL). The organic layer is washed with NaHC03, brine, dried, and is evaporated to dryness. Chilled ether (lOmL) is added to the residue to

give a white crystalline precipitate of compound 13.6 (10.8g; 55% yield based on fucal 13.3), which is the a-isomer, mp 159 °C. The ether soluble fraction is the p-isomer (5.1g), which is an oil. Total yield is 70% based on fucal 13.3. TLC shows the two isomers have the same Rf 0.30.

Compound 13.6 (15.9g; 50. 4mmol), thiophenol (11. 1 g; 100mmol) and BF3. Et20 (6.7mL) are mixed in DCM (200mL) and stirred at reflux 2.5 hours, chilled and poured into 2L separatory funnel, washed with NaHC03 (3 x 300mL), brine, dried, and evaporated to a thick oily residue. Purification by flash column chromatography in a EA- hexane system affords compound 13.7 91%) as a mixture of the a-and p-isomers in a ratio 2.5: 1.0. TLC Rf=0.45 (20% ethyl acetate, 80% hexane).

FAB MS: found 388 (M+Na). Anal. Calc. : C, 52. 60 ; H, 5. 2 ; N, 11. 51 ; S, 8. 76.

C16Hl9N305S: Found: C, 52.67; H, 5.26; N, 11.45; S, 8.65.'H NMR (300 MHz, CDC13): 8 1.13 (d. 3H), 2.06 (s, 3H), 2.18 (s, 3H), 4.20 (q, 1H, H-5,-isomer), 4.29 (dd, 1H, H-2), 4.5 (d, 1H, H-1,-isomer), 4.62 (q, 1 H, H-5, a-isomer), 5.15-5.2 (dd, 1 H, H-4), 5.63 (dd, lH, H-3), 5.64 (d, lH, H-1, a-isomer), 7.3-7.6 (m, 5H, arom.) To a solution of compound 13.7 (4.8g; 13. lmmol) in 120mL of MeOH is added potassium carbonate 36.2mmol). The reaction mixture is stirred for l. Oh at room temperature, filtered, the filtrate is acidified with AcOH to pH 6-7, and is concentrated to dryness. The crystalline residue is treated with 50ml DCM and purified by flash chromatography in 5% MeOH-DCM. The starting material in EA-Hex (2: 8) has Rf 0.50 and the product (compound 13.8) has Rf 0.05. In 5% MeOH-DCM compound 13.8 has Rf 0.55. The appropriate fractions give compound 13.8 (3.3g; 89%), m. p. 119-121°C. MS found 304 (M+Na+).

Compound 13.8 (3.3g; 11.7mmol) and 1,1'-carbonylimidazole (3. 8g ; 23. 4mmol) are dissolved in DCM (120mL) at 0°C, kept for 15 min, and 15 min at room temperature, washed with water (2 x 200mL), brine, and purified on a flash chromatography column in EA-Hexane. Three fractions of product (compound 13.9) are collected. The first at Rf 0.35 is the a-isomer (1.8g; 5.9mmol; 50%), the second at Rf0. 15 is the p-isomer (0.4g; 1.3mmol; 12%), and a mixed two isomer fraction (0.28g; 0.9mmol; 8%), total 2.48g (70%). All fractions are a colorless thick oil. <BR> <BR> <BR> <BR> <BR> a-isomer, H NMR (300 MHz, CDCI3): 8 1. 36 (3H, d, CH3), 4.28 (1H, t, H-2), 4.46 (1H, q, H-5), 4.65 (1H, dd, H-3), 4.89 (1H, d. d, H-4), 5.635 (1H, dd, J=5.4Hz, a H-1), 7.30-7.50 (5H, m, arom.). IR, neat, v : 2114,1813 cm~'. <BR> <BR> <BR> <BR> <BR> p-isomer:'H NMR (300 MHz, CDC13): 8 1.43 (d., 3H, CH3), 3.50 (d. d., lH, H-2), 3.84 (q., 1H, H-5), 4.44 (d., 1 H., J=9.9 Hz, P-l-H), 4.53 (d. d., 1 H, H-4), 4.60 (t., (1H, H-3), 7.35- 7.48 (m., 5H, arom.). IR, neat: 2116 (N3), 1805 (C=O).

Example 11-6: Synthesis of Phenvl 2-phthalimido-2-deoxv-34-di-O-acetvl-l-thio-ß-D- fucopvranoside (compound 14.5).

As shown in Scheme 4-tri-O-acetyl-2-azido-2-deoxy-D-Fucose (compound 14.1) 9.5mmol), which is prepared as described for compound 12.7, is dissolved in acetone (50mL), and half a teaspoon of Pd/C catalyst (under nitrogen) is added. Then 3mL of ether and saturated HCl are added and the reaction mixture is reduced with hydrogen (40psi) for 2h. The catalyst is filtered and washed with MeOH.

The filtrate is evaporated, dissolved in 10ml of MeOH and compound 14.2 (1.85g; 60%

yield) is precipitated with ether (20mL). Anal. Ci2Hi9N07. HCI, Calc.: C 44.2; H 6.14; N 4.30; CL 10.91. Found: C 43.97; H 6.08; N 4,25; CL 11.04%.

Compound 14.2 (l. lg; 3.38mmol) is dissolved in MeOH (lOmL). An ion- exchange resin in OH-form (Amberlite IRA-400,2g) is added and the reaction mixture is stirred at room temperature for 2h. The Rf of the base of compound 14.2 is 0.9 (EA-Hex, 1: 1). The TEA- (0. 5mL) is dropped to the reaction mixture, stirred for 15 min, filtered, and washed with MeOH. The filtrate is treated with phthalic anhydride (0.6g; 4mmol) with stirring at room temperature for lh to give compound 14.3, which is not isolated (Rf 0.05).

The solvent is evaporated (70°C, 120mmHg) to give a solid semi-crystalline mass, which is treated with Ac2O (8mL) and pyridine (SmL) for lh at 100°C in a water bath to give compound 14.4, which is separated from the reaction mixture using column chromatography. The chromatography column hydrolyzes some of the product to give some compound 14. 5. The compound 14.5 is reacetylated with acetic anhydride in pyridine to produce compound 14.4.

The solution containing compound 14.4 is evaporated under vacuum (120 mmHg, 80°C). A crystalline residue is azeotroped with toluene and is dissolved in dichloromethane (30mL) and treated with thiophenol (l. OmL) and BF3. Et2O (2mL) for lh at reflux. The TLC of the reaction mixture shows a presence of the target product compound 14.6 (Rf 0.65). The solvent is evaporated and the residue is purified by flash- chromatography column in a EA-Hexane isocratic (30% of EA) system. The appropriate fractions are combined and evaporated to give compound 14.6 (0.55g; 35% yield) as a

crystalline yellowish powder. After washing with MeOH, the product turns to white crystals, mp 193°C.

Rf 0.2 (EA-Hex 2: 8); MS 492 (M+Na). tH NMR (300 MHz, CDCl3) : 6 7.2-7.8 (m, 9H, arom.), 5.75 (1H, dd, H-2), 5.60 (d, J 9Hz, H-1, (3-anomeric substituent), 5.25 (1H, m, H-3), 4. 58(1H, tr, H-4), 3.96 (1H, q, H-5). Analysis: Calc.: C 61.40; H 4.90; N 2.99; S 6.82.

C24H23NS07. Found: C 61.28; H 4.93; N 2.95; S 6.83%.

Example 11-7: Synthesis of Phenyl 2-azido-2-deoxy-hexa-O-acetyl-l-thio- (3-D- gentiobiopyranoside (compound 15.7).

As depicted in Scheme 15, gentiobiose 8.77mmol) is stirred overnight at room temperature in a mixture of pyridine (60mL) and Ac2O (36mL). The pyridine and excess of acetic anhydride are evaporated at 70°C to give a crystalline residue of compound 15.1 100%). Crystallization of 0.2g of compound 15.1 from EA (5mL) gives fine crystals, m. p. 188°C. MS found 701 (M+Na+).

Compound 15.1 is dissolved in a mixture of AcOH (12mL), Ac2O (9mL) and a 30% solution of HBr in AcOH (20mL) at 0°C, and is stirred 16h at room temperature.

The reaction mixture is poured into a separatory flask containing cold water (300mL) and EA (200mL). The organic phase is separated, washed with water (200mL), aqueous NaHC03 (200mL), and brine (200mL), and is dried over sodium sulfate to give compound 15.2.

Activated Zn dust (lOg) and N-methylimidazole (1.5mL) are added to the EA solution containing compound 15.2 and refluxed for 40 min. The reaction mixture is chilled to room temperature, decanted and the organic phase is washed with water,

NaHCO3, and brine, and is dried over Na2SO4 and evaporated to give compound 15.3 (4.6g; 94%) as an oil. The product should be purified by flash-chromatography in EA- Hexane system. Total amount of fractions is 50, the fractions 37-50 were combined to a weight of 3.3g (67%), mp 94°C. MS found 583 (560+Na+).

Compound 15.3 7.14mmol) is dissolved in dry acetone (lOOmL), and ammonium cerium (IV) nitrate (7.8g; 14.3mmol) and sodium azide (0.8g; 12.1mmol) are added. The reaction mixture is stirred mechanically at-15 to-20°C for 6h and is treated with 40% aq. EA (500mL), NaHC03, brine, dried and evaporated to give the oily residue of compounds 15.4 and 15.5 in the ratio 4: 1 (4.2g, about 95%).

The oil is hydrolyzed in a mixture of Ac20 (20mL) and 20mL of 2% H2SO4 for 2h at 37°C. The sulfuric acid in the mixture is neutralized by addition of sodium acetate (1.5g). The neutralized solution is poured into DCM-water, washed with sodium bicarbonate, brine, dried and evaporated to give a semi-crystalline compound 15.6 (2.2g; 45% yield). The IR spectrum contains peaks of azido group (2115cm-1) and carbonyl groups (1752 cm~'), with no peaks for OH groups (3000-3600 cl-1).

Compound 15.6 (2.2g; 3.3mmol) is dissolved in 20ml of DCM and thiophenol (0.76g; 0.68mL; 6.6mmol) and BF3. Et2O (3.5mL) are added. The reaction mixture is stirred at room temperature for 18h. The mixture is brown and is poured into a separatory funnel and washed with water, sodium bicarbonate, brine. The organic phase is dried and evaporated to give a brown oil. The oil is dissolved in EA-Hexane (20mL, 1: 1) and is purified on a column to give compound 15.7 (1.4g; 61% yield). TLC (EA- Hexane 1: 1), Rf=0.4.

MS found 734 (M+Na+). : 8 7.2-7.4 (5H, m, arom.), 5.40 (1H, d, H'-1), 5.05 (1H, d, H-1), 5.3 (1H, m, H-3), 5.1 (1H, m, H'3), 4.95 (1H, m, H-4), 4.5 (1H, q, H'-4), 4.0-4.28 (3H, m, H-6, H-6'), 3.8 (1H, t, H-5), 3.6 (lH, t, H'-5).

IR, neat: 2110,1750,1370,1228,1042, 735cm-1. Compound 15.7 exists as a mixture of a and P-isomers. This mixture is separated by flash chromatography in EA-Hexane (20% EA, 80% Hexane). From 500mg of the mixture, 350mg of the a-isomer (Rf 0.30, m. p. 76-78°C) and 50mg of ß-isomer (Rf 0.35, m. p. 69-70°C) are obtained.

Example II-8 : Synthesis of Phenyl 6-0-(2 3. 4 6-tetra-O-acetvl-ß-D-glucopyranosyl)- <BR> <BR> <BR> <BR> <BR> (I 6)-2-phthalimido-2-deoxv-3. 4-di-O-acetyl-I-thio-ß-D-glucopvranoside (compound 16.9) and Intermediate 2-N-phthalimido Donor Monosaccharides.

As depicted in Scheme 16, D-Glucosamine. HCl (compound 16.1) (60g; 0.27mol) is added to a solution of NaOMe in MeOH [prepared from Na (6.3g; 0.27mol) and MeOH (270mL)] at room temperature with stirring. The mixture is stirred for 20 min. and filtered. Phthalic anhydride (19.8g; 1.3mmol) and triethylamine (38.6mL) are added to the filtrate and stirred for 30 min., then another batch of phthalic anhydride (21.6g; 1.4mmol) is added. A mass of solid is separated out. Ether is added to the reaction mixture and the solid is filtered off and treated with pyridine (350mL) and acetic anhydride (200mL) for 16h. The product is evaporated under reduced pressure. The residue is dissolved in CH2CI2 and washed with aq. NaHCO3 solution, dried over Na2SO4 and evaporated under reduced pressure. It is purified on silica gel by using hexane-ethyl acetate (1: 1@2: 3, v/v) as an eluent to give compound 16.2 (69g; 52%).

Compound 16.2 (67g; 140.5mmol) is reacted with BF3. etherate (34.6mL; 281mmol) and thiophenol (28.8mL; 282.3mmol) in CH2CI2 (500mL) at room temperature for 16h. The reaction mixture is washed with aq. NaHC03 solution and dried over Na2SO4. filtered, and solvent is removed under reduced pressure. Addition of ether to the residue gives compound 16.3 as an amorphous solid (57. 1g; 77%); 1 H NMR (300 MHz, CDCl3): 8 (m, 9H, arom.), 5.77 (dd, J=9.3Hz, lH, H-4), 5.70 (d, J=10. 5Hz, 1H, H-1), 5.12 (dd, J=9.3Hz, lH, H-3), 4.33 (dd, J=10.5Hz, 1H, H-2), 2.07,2.00,1.81 (each s, 9H, 3xOAc).

De-O-acetylation of compound 16.3 (4.5g) with MeOH-MeONa for 4h gives <BR> <BR> <BR> <BR> compound 16.4 73%);'H NMR (300 MHz, CD30D): 6 7.98-7.19 (m, 9H, arom.), 5.58 (d, J=10.5Hz, 1H, H-1), 4.27 (dd, lH, H-4), 4.16 (dd, lH, H-3).

To an ice cooled, stirred solution of compound 16.4 (2.4g; 6mmol) and imidazole (1.02g; 15mmol) in dry DMF (25mL) is added tert-butyldimethylsilyl chloride (l. lg; 7.3mmol) and stirring is continued for Ih at 0°C. The reaction mixture is poured into an ice-water mixture and the resulting solid is filtered and washed with hexane to give compound 16.5 97%) ; 1H NMR (300 MHz, CDCl3): 8 7.86- 7.24 (m, 9H, arom.), 5.64 (d, J=10. 5Hz,1H,H-1), 4.36 (dd, J=8.1 Hz, 1H, H-4), 4.20 (dd, lH, H- 2), 0.93 (s, 9H, CMe3), 0.13&0.12 (each s, 6H, SiMe2).

Compound 16.5 (3.2g) is dissolved in pyridine-acetic anhydride (2: 1; 75mL) and stirred for 16h at room temperature. The solvents are removed under reduced pressure and the residue is dissolved in CH2CI2 and washed with aq. NaHC03 solution, water, dried and concentrated in vacuo to give compound 16.6 (3.4g; 91%) as an amorphous solid from ether-hexane ; 1H NMR (300 MHz, CDCI3): 8 7.88-7.25 (m, 9H, arom.), 5.80 (dd, J=9.3Hz, l H, H-4), 5.72 (d, J=10. 5Hz, l H, H-1), 5.18 (dd, 1 H, H-3),

4.33 (dd, J=10.5Hz, lH, H-2), (each s, 6H, 2xOAc), 0.92 (s, 9H, CMe3), 0.099&0.064 (each s, 6H, SiMe2).

To a solution of compound 16.6 5mmol) in CH2CI2 (50mL) is added BF3. etherate (0.75mL; 6.1mmol) and stirring is continued at room temperature for Ih.

The organic layer is washed with aq. NaHC03 solution, dried over Na2SO4 and concentrated in vacuo. This residue from ether gives compound 16.7 (2.4g; 99%) as a white solid compound;'H NMR (300 MHz, CDC13): 8 7.89-7.27 (m, 9H, arom.), 5.84 (dd, J=9.3Hz, lH, H-4), 5.76 (d, J=10.5Hz, 1H, H-1), 5.10 (dd, J=9.3Hz, lH, H-3), 4.35 (dd, J=l0. SHz, IH, H-2), 2.05&1.85 (each s, 6H, 2xOAc); 13C NMR: b 133.11- 123.68 (aromatic C), 82.95 (C-1), 78.26 (C-5), 71.43 (C-3), 68.99 (C-4), 61.56 (C-6), 53.69 (C-2), 20.64&20.40 (COCH3).

A solution of compound 16.7 (0.5g; 1.03mmol) and acetobromoglucose (compound 16.8) (0.62g; 1.5mmol), obtained from Sigma Chemical Co. (St. Louis, MO), in 3: 2 (v/v) CH2CI2-toluene (25mL) is stirred for 0.5h with 4A° molecular sieves (3g) under protection of light and moisture. Then, silver triflate (0.4g; 1.5mmol) and 2,6-di- tert-butyl-4-methyl pyridine (0.15g; 0.73mmol) is added to the reaction mixture at-20°C.

The reaction mixture is warmed to-10°C and stirred at the same temperature for 1. 5h.

The saturated aq. NaHCO3 solution is added to reaction mixture and filtered through Celite. The filtrate is washed with aq. NaHC03, water, dried over Na2S04, and concentrated to a small volume. The concentrate is applied to a column of silica gel and elution is performed with hexane-ethyl acetate (1: 1--> 1 : 4; v/v) to give compound 16.9 (0.55g; 65%) as an amorphous solid. 1H NMR (300 MHz, CDCl3): 8 7.86 (m, 9H, arom.), 5.76 (dd, J=9.3Hz, lH, H-4), 5.70 (d, J=10.5Hz, lH, H-1), 5.18-4.91 (m, 4H, H-3, H-4', H-3', H-

2'), 4.57 (d, J=8.1Hz, lH, H-1'), 2.09,2.02,2.01,1.99,1. 97&1.81 (each s, 18H, 6xOAc); 13 NMR: 6 [GlcNPhth residue] 132.69-123.65 (aromatic C), 82.93 (C-1), 77.63 (C-5), 71.43 (C-3), 68.27 (C-6), 68.19 (C-4), 53.53 (C-2); [Glc residue]: 100.56 (C-1), 72.78 (C-3), 71.81 (C-2), 69.23 (C-5), 68.19 (C-4), 61.72 (C-6). FAB MS: calcd. For C38H4, NOI7S ( 815): m/z 838 [M+Na] +.

Example ofPhenyl2,3,6-tri-O-pivaloyl-4-O-(tetra-O-pivaloyl-ß-D-Synt hesis glucopvranosyl)-1-thio- (3-D-glucopvranoside (compound 17.4).

As shown in Scheme 17, Octa-O-acetyl-D-cellobiose (compound 17.1) (58 g; 85.5mmol), is dissolved in thiophenol (lOmL; 97.3mmol) and CH2CI2 (180mL). The system is cooled to 0°C, and BF3. OEt2 (25mL; 198mmol) is added dropwise. The reaction mixture is stirred at room temperature for 18 hours, then cooled to 0°C, and more thiophenol (5mL; 48.7mmol) and BF3. OEt2 (5mL; 39mmol) are added. The solution is stirred at room temperature for 66 hours more and poured into aqueous saturated NaHC03 solution (500mL). The organic phase is washed with a saturated NaHCO3 solution (1 x 250mL) and brine (1 x 250mL), dried over anhydrous Na2S04 and concentrated to yield a yellowish solid. The solid is powdered, treated with boiling hexane (500mL) and filtered. The solid consists of nearly pure compound 17.2 (58.1 g; 79.7mmol; 93.3% yield). lH NMR (300 MHz, CDCl3) : 8 7.49-7.33 (m; 2H), 7.31- 7.25 (m; 3H), 5.21-5.02 (m; 3 H), 4.94-4.87 (m; 2H), 4.65 (d; J= 10.5 Hz; 1H), 4.55 (dd; J= 1. 8 Hz, 12. 0 Hz ; lH), 4.48 (d; J= 8. 1 Hz; 1H), 4.37 (dd; J=4. 5Hz, 1H), 4.12- 3.99 (m; 2H), 3.75-3.60 (m; 3H), 2.11 (s; 3H), 2.09 (s; 3H), 2.08 (s; 3H); 2.02 (s; 3H); 2.00 (s; 3H), 1.98 (s; 3H). i3C NMR (75.4 MHz, CDCl3): # 179.04,178.81,178.35,178.13,

177.91,177.63,141.67,140.35,137.50,136.93,109.36,94.11,85.35 ,84.96,82.19, 81.52,80.58,80.19,78.76,76.35,70.61,70.13,29.44-29.15 (br). TLC Rf = 0.64 (60% ethyl acetate-hexane). FAB MS: for C32H4oSOi7 [MNa] calcd m/z 751, found m/z 751.

Compound 17.2 is dissolved in MeOH (800mL) and THF (600mL). The yellowish solution is cooled to 0 °C, and NaOMe (3.0 g; 55.6mmol) is added under stirring. The reaction mixture is allowed to reach room temperature over a 90 min period, then more NaOMe (0.3 g; 5.6mmol) is added. After 3 hours of reaction, acidic resin (Dowex 500w8 200 resin, previously washed with water and methanol) is added until a pH 7 is obtained. The resin is filtered and the solution is concentrated under vacuum. Compound 17.3 is isolated as a light yellow solid in nearly quantitative yield and used in the next step without further purification.'H NMR (300 MHz, CD30D): 8 7.57-7.54 (m; 2H), 7.32-7.25 (m; 3H), 4.61 (d; J= 9.6 Hz; 1H), 4.41 (d; J= 7.8 Hz; 1H), 3.86 (m; 2H), 3.64 (dd; J = 5.4 Hz, 12.0 Hz; 1H), 3.55 (t; J= 7.2 Hz; IH), 3.45-3.19 (m; <BR> <BR> <BR> <BR> <BR> 8H).'3CNMR (75. 4MHz, CD30D) : 6 142.15,140.19,137.16,135.71,111.71,96.35, 87.73,87.42,85.32,85.17,85.05,82.12,80.76,78.60,69.69,69.19. TLC Rf = 0.54 (30% methanol-methylene chloride). FAB MS: for Cz8H26SOlo [MNa] calcd m/z 457, found m/z 457.

Compound 17.3 is azeotroped twice with toluene, dissolved in dry pyridine (150mL; 1.86mol), and DMAP (2.0 g; 16.4mmol) and pivaloyl chloride (140mL; 1.14mol) are added. The reaction mixture is heated at 80 °C for 48 hours. The reaction mixture is poured into aqueous saturated NaHC03 solution (500mL) and agitated for 30 minutes. CH2CI2 (250mL) is added and the organic phase is separated. The aqueous phase is back-extracted with CH2CI2 (lOOmL), and the combined organic layers are

concentrated to dryness. The dark brown residue is dissolved in CH2CI2 (250mL), washed with HCl 2N (1 x 250mL), saturated NaHC03 solution (1 x 250mL) and brine (1 x 100mL), dried over anhydrous Na2SO4 and concentrated to an oily residue. The crude product is loaded on a silica gel plug (1.2 L) and eluted with a gradient of 0% to 10% ethyl acetate-hexane. Fractions containing the product (as judged by TLC) are combined and concentrated. The residue (90 g) is immobilized onto silica gel 60 (160 g) and purified by flash chromatography using a gradient of 0% to 12% ethyl acetate-hexane to afford compound 17.4 as a pale-yellow foam (60g; 58.6mmol; 73% yield based on <BR> <BR> <BR> <BR> <BR> compound 17. 2).'H NMR (300 MHz, CDCla-CCL): 6 7.42-7.38 (m; 2H), 7.31-7.20 (m; 3H), 5.22 1H), 5.19 IH), 4.92-4.82 (m; 2H), 4.77 (t; J=9.3 Hz ; 1H), 4.62 (d; J=6.9 Hz ; 1H), 4.51-4.45 (m; 2H), 4.12 (m; 1H), 4.07 (d; J=11.7 Hz ; 1H), 3.94 (dd; J=7.8 Hz, 12.3 Hz; 1 H), 3.77 (t; J= 9.6 Hz; 1H), 3.67 (t; J = 8.7 Hz; 1 H), 3.54 (m; 1H); 1.21 (s; 9H), 1.15 (s; 9H), 1.14 (s; 9H), 1.13 (s; 9H), 1.09 (s; 9H), 1.07 (s; 9H), 1.04 (s; 9H). t3C NMR (75.4 MHz, CDCl3-CC14): 8 61,185.14, 136.89,107.97,94.67,85.88,81.92,81.21, 81.02,79.88,78.46,77.10,70.93,70.68,47.45,47.39,47.35,47.30, 47.25,35.90,35.85, 35.76,35.70,35.60. IR (neat): 2972.35 (s), 2935.99 (m), 2908.41 (m), 2873.15 (m), 1742.63 (s), 1479.99 (s) 1279.66 (s), 1141.22 (s). TLC Rf= 0.61 (20% ethyl acetate- hexane). FAB MS: for C53Hg2SOl7 [M + Na] calcd. m/z 1046, found m/z 1046. Anal.

Calcd. forC53Hs2SOl7 (1023.29): C, 62.21%; H, 8.08%; S, 3.13%. Found: C, 62.09%; H, 8.16%; S, 3.02%.

Example II-10 : Synthesis of Phenvl 2-azido-2-deoxv-36-di-O-acetvl-4-O-(tetra-O- acetvl-ß-D-glucopvranosvl)-l-thio-a-D-glucopvranoside (compound 18.4).

As depicted in Scheme 18, compound 18.1 (30g; 53.5mmol) is dissolved in acetonitrile (210mL, HPLC grade) and transferred to a 3-neck, 1-liter round bottom flask equipped with a condenser and a mechanical stirrer. Hexa-O-acetyl-cellobial (compound 17.1) is prepared in two steps from commercially available a-D-cellobiose octaacetate. a-D-cellobiose octaacetate is quantitatively converted to hepta-O-acetyl cellobiosidyl bromide using a solution of hydrobromic acid in acetic acid [Zemplen, G., Csuros, Z., Bruckner, Z. Ber. (1928), 61: 927]. The bromide is then reduced to the lactal using zinc dust, aqueous acetic acid and chloroplatinic acid (promoter) in nearly quantitative yield [Haworth, W. N., Hirst, E. L., Streight, H. R. L., Thomas, H. A., Webb, J. I. J. Chem.

Soc. (1930), 2639].

The system is cooled to-25 °C in an ethylene glycol-dioxane bath. Under intense stirring, cerium ammonium nitrate (90g; 164mmol) is added to the system in small portions, followed by sodium azide (5.3g; 81.5mmol). The reaction is kept at-25 °C until all starting material has been consumed (6-7 hours of reaction), as judged by TLC (compound 18.1 has Rf= 0.33 in 50% ethyl acetate-hexane). The reaction mixture is then filtered and the residue is washed with toluene (500mL). The filtrate is treated with water (SOOmL), the organic layer is reserved and the aqueous layer is backwashed with ethyl acetate (200mL). The combined organic layers are washed with brine (3 x 100mL), dried over anhydrous Na2SO4 and concentrated under vacuum to afford crude compound 18.2 as a white foam (40g).

Compound 18.2 is dissolved in a solution of glacial acetic acid (1 lOmL), concentrated sulfuric acid (2mL) and acetic anhydride (25mL). The mixture is kept at 40 °C for two hours, cooled to room temperature and poured into a mixture of ice and water

(1 L) under agitation. The white solid formed is collected by filtration and washed with cold water (250mL). The solid is dissolved in methylene chloride (250mL), washed with saturated NaHCO3 solution (2 x 100mL) and brine (1 x 100mL), dried over anhydrous Na2SO4 and concentrated under vacuum to afford compound 18.3 (31g).

Compound 18.3 (31.2g; 47.2mmol) is azeotroped twice from toluene, dissolved in methylene chloride (anhydrous, I 00mL) and treated with thiophenol (10mL ; 97.1 mmol) and BF3-etherate (60mL; 473mmol). The system is refluxed at 50 °C for 2 hours, cooled to room temperature and poured into saturated aqueous NaHCO3 (SOOmL). The organic layer is washed with saturated aqueous NaHC03 (2 x 100mL) and brine (1 x 100mL), dried over anhydrous Na2SO4 and concentrated to dryness. The crude product (42g) is purified by flash chromatography using 40% ethyl acetate-hexane as eluent.

Recrystallization from hexane affords analytically pure compound 18.4 (lOg; 14. 1mmol) <BR> <BR> <BR> <BR> <BR> as a white solid. mp 198-200 °C, dec. lH NMR (300 MHz, CDC13): 6 7.49-7.46 (m; 2H), 7.31-7.26 (m; 3H), 5.58 (d; J = 5. 4 Hz; 1H), 5.29 (dd; J= 9.3 Hz, 10.5 Hz; 1H), 5.15 (t; J= 9.3 Hz; 1H), 5.09 (t; J= 9.6 Hz; 1H), 4.94 (t; J= 9.0 Hz; 1H), 4.51 (d; J= 8.1 Hz; 1H), 4.47 (m; 1H), 4.40 (m; 2H), 4.17 (dd; J = 5. 7 Hz, 12.0 Hz; 1H), 4.05 (dd; J= 2.1 Hz, 12.3 Hz; 1H), 3.96 (dd; J= 5.4 Hz, 10.5 Hz; 1H), 3.74-3.64 (m; 2H), 2.1 l (s; 3H), 2.08 (s; 3H), 2.05 (s; 3H), 2.04 (s; 3H), 2.00 (s; 3H), 1.98 (s; 3H). 63C NMR (75.4 MHz, CDCl3) : õ 179.13,178.91,178.84,177.91,177.64,141.40,140.66,137.81,136. 59,109.42,95.21, 56,70.19,29.43-29.20 (br). IR (neat): 2953.58 (w), 2110.57 (s), 1750.57 (s), 1370.48 (m), 1223.18 (s), 1038.58 (m). TLC Rf= 0.29 (50% ethyl acetate-hexane). Anal. Calcd. for C3oH37N3SO15 (711.70): C, 50.63%;

H, 5.24%; N, 5.90%; S, 4.50%. Found: C, 50.90%; H, 5.36%; N, 5.62%; S, 4.43%.

FAB+ for C30H37N3SOls [MNa] calcd m/z 734, found m/z 734.

Example II-11: Svnthesis of Phenvl 2-deoxv-2-N-trifluoroacetamido-34 6-tri-O-acetvl-1- thio-3L-D-glucopvranose (compound 19.5) and Phenvlsulfenvl-2-deoxy-2-N- trifluoroacetamido-3*4 6-tri-O-acetvl-ß-D-glucopyranose (compound 19.6) As depicted in Scheme 19, D-glucosamine hydrochloride is converted into compound 19.1 according to a procedure adapted from Bergman, M, et al., Chem. Ber., 975 (1931). Glucosamine hydrochloride (50 g; 0.232 mol) is dissolved in 240mL of IM aqueous sodium hydroxide, forming a colorless solution. Anisaldehyde 0. 235 mol) is added via syringe under intense stirring, forming a turbid solution. After several minutes of agitation, a white precipitate is formed. The system is kept in an ice bath for one hour to ensure complete precipitation. The solid is then collected by filtration and washed with water (2 x 200mL) and a 1: 1 mixture of methanol and ether (2 x 200mL).

The precipitate is dried overnight under vacuum, affording compound 19.1 (50 g; 72% <BR> <BR> <BR> <BR> yield).'H NMR (300 MHz, DMSO-d6): 6 8.17 (s, 1H), 7.74 (d, 2H, J= 8.1 Hz), 7.04 (d, 2H, J=7. 8Hz), 6.60 (d, 1H, J=6.6 Hz), 4.99 (d, 1H, J=4.5 Hz), 4.88 (d, 1H, J=4.8 Hz), 4.75 (d, 1H, J= 7.2 Hz), 4.62 (t, 1 H, J = 5.4 Hz), 3.85 (s, 3H), 3.69 (dd, 1H, J=5. 4, 11.1 Hz), (m, 2H), (m, 2H), 2.85 (t, 1H, J= 8.7 Hz). 13C NMR (75.4 MHz, DMSO-d6) : 8 161.24,161.06,129.65,129.11,113.91,95.64,78.21,76.88,74.61, 70.36,61.27,55.29. Anal. Calcd. for C, 4H, 9NO6 (297.31): C, 56.56%; H, 6.44%; N, 4.71%. Found: C, 55.97%; H, 6.38%; N, 4.56%. mp 148-150 °C (dec).

Compound 19.1 (50 g; 0.168 mol) is treated with acetic anhydride (1 SOmL; 1.59 mol), pyridine (79.10 g/mol; 3.34 mol) and DMAP (0.5 g) in an ice-water bath. The solid slowly goes into solution and the reaction mixture is kept at room temperature overnight.

The solution is poured into 1.5L of ice, forming a white crystalline solid. The crystals are collected by filtration, washed with water (2 x 100mL) and ether (2 x 100mL) and dried under vacuum to afford compound 19.2 (60 g; 77% yield). TLC Rf= 0.45 (50% ethyl acetate-hexane).'H NMR (300 MHz, CDCl3) : 8 8.15 (s, 1H), 7.64 (d, 2H, J= 8.4 Hz), 6.91 (d, 2H, J= 8. 7 Hz), 5.94 (d, 1 H, J = 8.1 Hz), 5.42 (t, 1 H, J = 9.3 Hz), 5.14 (t, 1H,J = 9.6 Hz), 4.37 (dd, 1H,J=4.5, 12.3 Hz), 4.12 (dd, 1 H, J = 2. 1,12.6 Hz), 3.97 (ddd, 1H, J= 2.4,4.8,9.6 Hz), 3.84 (s, 3H), 3.44 (t, 1H, J= 9.6 Hz), 2.10 (s, 3H), 2.03 (s, 3H), 2.01 (s, 3H), 1.88 (s, 3H). 13C NMR (75.4 MHz, CDCl3): 8 170.69,169.89,169.54, 168.77,164.27,162.26,130.22,128.24,114.02,93.12,73.20,72.91, 72.72,67.98,61.78, 55.39,20.79,20.67,20.49 (br). IR (neat, cl-'): 2948,2869,1752,1640,1606,1508, 1372,1223,1039. FAB+ for C22H27NOlo: [MH] calcd m/z 466, found m/z 466; [MNa] calcd m/z 488, found m/z 488. Anal. Calcd. for C22H27NOio (465.46): C, 56.77%; H, 5.85%; N, 3. 01%. Found: C, 56.56%; H, 5.90%; N, 2.99%. mp 168-172 °C (dec).

Compound 19.2 (50 g; 0.108 mol) is dissolved in 250mL of refluxing acetone and to this solution is added dropwise 25mL of 5N HCI. After five minutes a white thick precipitate forms and the system is cooled to room temperature. The precipitate is filtered and washed with acetone (100mL) and ether (2 x 250mL). The resulting product, compound 19.3 is dried under vacuum overnight (41.8 g, quantitative).'H NMR (300 MHz, DMSO-dó): 8 8.93 (s, br, 2.6H), 5.97 (d, 1H, J= 8. 7 Hz), 5.42 (t, 1 H, J = 9.9 Hz), 4.99 (t, IH, J= 9. 3 Hz), 4.25 (dd, IH, J= 3.9,12 Hz), 4.11-4.03 (m, 2H), 3.62 (t, IH, J=

9.3 Hz), 2.23 (s, 3H), 2.09 (s, 3H), 2.05 (s, 3H), 2.03 (s, 3H). 13C NMR (75.4 MHz, DMSO-d6): 8 169.98,169.78,169.32,168.67,90.08,71.59,70.31,67.76,61.25,52 .11, 20.97,20.88,20.51,20.37. IR (neat, cm~'): 2805,2745,2683,1757,1595,1519,1366, 1247,1208,1084,1060,1040. FAB+ for C, 4H27NO9CI: [M-Cl] calcd m/z 348, found [MNa-HCl]calcdm/z370,foundm/z370.Anal.Calcd.forC14H22NO9Clm/ z348; (383.78): C, H, 5.78%; N, 3.65%; Cl, 9.24%. Found: C, 43.80%; H, N, 3.57%; Cl, 9.15%. mp > 200 °C.

Compound 19.3 (41.6 g; 0.108 mol) is suspended in pyridine (90mL; 1.11 mol) and methylene chloride (90mL). Trifluoroacetic anhydride (18.5mL; 0.131mol) is slowly added via syringe. The solid slowly goes into solution with a slight rise in temperature.

The reaction mixture is concentrated in vacuo to dryness. The residue is dissolved in 100mL methylene chloride and washed with 2N HCl (1 x 100mL), aqueous NaHC03 (2 x 100mL) and brine (1 x 50mL), and dried over anhydrous Na2SO4. The clear solution is concentrated to dryness affording compound 19.4 quantitative) as an off-yellow solid. TLC Rf= 0.47 (50% ethyl acetate-hexane).'H NMR (300 MHz, CDCl3) : 8 7.24 (d, 1H, J= 9.0 Hz), 5.75 (d, 1H, J = 9.0 Hz), 5.31 (t, IH, J = 10.0 Hz), 5.13 (t, IH, J= 9. 6 Hz), 4.35 (q, IH, J= 9.9 Hz), 4.27 (dd, IH, J= 4. 8,12.6 Hz), 4.15 (dd, 1H, J=2. 1,12.6 Hz), 3.90 (ddd, 1H, J=2. 1,4.8,9.9 Hz), 2.12 (s, 3H), 2.10 (s, 3H), 2.06 (s, 3H), 2.05 (s, 3H). 13C NMR (75.4 MHz, CDC13): # 171.40,170.63,169.74, 169.23,157.12 (q, J= 38 Hz), 133.46,131.10,129.03,128.77,115.54 (J= 288 Hz), 85.95,75.90,73.31,68.209,62.20,53.20,20.72,20.42, 20.37 (br). IR (neat, cm-1): 3326, 3100,2952; 1748,1560,1374,1219,1079,1042. FAB+ forCoNOioFs: [MNa]

calcd m/z 466, found m/z 466. Anal. Calcd. for C16H20NOlOF3 (443. 33): C, H, 4.55%; N, 3.16%. Found: C, 43.16%; H, 4.51%; N, 3.15%.

Compound 19.4 (48.25 g; 0.109 mol) is dissolved in 400mL anhydrous methylene chloride and treated with thiophenol (17mL; 0.166mol) and boron trifluoride etherate (42mL; 0.331 mol). The reaction mixture is left overnight at room temperature and then poured into a solution of 100mL saturated aqueous NaHC03,100mL aqueous Na2CO3 and 50mL brine. The organic layer is further washed with a mixture of 50mL saturated aqueous NaHCO3 and 50mL aqueous Na2CO3. The organic layer is dried over anhydrous Na2SO4 and concentrated under vacuum. The resulting solid is washed with 300mL boiling hexane and filtered. The filtrate is further washed with 300mL ice-cold hexane and dried under vacuum to yield compound 19.5 (49.2 g; 92% yield). TLC Rf= 0.54 (50% ethyl acetate-hexane). NMR (300 MHz, CDC13): 6 7.51-7.48 (m, 2H), 7.33-7.26 (m, 3H), 7.02 (d, 1 H, J = 9.3 Hz), 5.28 (t, 1 H, J = 9.9 Hz), 5.03 (t, 1H, J= 9.6 Hz), 4.78 (d, 1H, J= 10.2 Hz), 4.22-4.13 (m, 2H), 4.08 (q, I H, J = 10.2 Hz), 3.78 (m, 1H), 2.08 (s, 3H), 2.00 (s, 3H), 1.93 (s, 3H). I3C NMR (75.4 MHz, CDC13): 8 168.32, 167.55,166.15,154.03 (q, J = 38 Hz), 130.38,128.02,125.95,125.68,112.46 (q, J =288 Hz), 12,50.12,17.64,17.34,17.29. IR (neat, cm~l): 3302, 3103,2951,2879,1748,1706,1557,1371,1217,1178,1077,1037. FAB+ for C2oH22NSOgF3: [MNa] calcd m/z 516, found m/z 516. mp 178-180 °C (dec).

Compound 19.5 (49 g; 0.099 mol) is dissolved in DCM (SOOmL) and cooled to- 78 °C. Sodium bicarbonate (0.5 g) and mCPBA (26.3 g; 68.7% pure; 0.104 mol) is added, and the temperature is slowly raised to-25 °C. As the reaction progresses, the product precipitates out of solution. When the reaction is complete by TLC, it is

quenched with ImL dimethyl sulfide and allowed to reach room temperature. The reaction mixture is diluted with 200mL water, 200mL aqueous NaHC03 and 100mL CH2Cl2. The organic layer is washed with a mixture of 100mL aqueous Na2CO3 and 100mL brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The solid is washed with 300mL hot ether, filtered, and further washed with 300mL of ice-cold ether and dried under vacuum, yielding compound 19.6 (48 g; 509 g/mol; 0.094 mol; 95% yield). TLC Rif=0.15-0.26 (50% ethyl acetate-hexane). tH NMR (300 MHz, CDC13, <BR> <BR> <BR> <BR> <BR> diastereoisomers in 5: 1 ratio): 8 8.37 (d, 0.16H, J=7. 8Hz), 7.83 (d, 0.84H, J=8. 7Hz), 7.68-7.41 (m, 5H), 5.65 (t, 0.16H, J=9. 9Hz), 5.45 (t, 0.84H, J= 9. 6 Hz), 5.02 (t, 0.16H, J= 9.9 Hz), 4.96-4.88 (m, 1.84H), 4.21-3.94 (m, 3H), 3.81 (ddd, 0.84H, J= 2.7,3.9,10.2 Hz), 3.68 (ddd, 0.16H, J= 2.4,6.0,9.6 Hz), 2.22-1.93 (m, 9H).'3C NMR (75.4 MHz, <BR> <BR> <BR> <BR> <BR> CDCl3, diastereoisomers in 5: 1 ratio): 6 170.76,170.42,169.33,157.27 (q, J= 38 Hz), 137.42,137.00,131.970,131.88,129.08,125.60,125.40,115.23 (q, J= 288 Hz), 92.03, 88.52,76.75,76.28,72.30,71.53,68.23,67.58,61.81,61.33,51.51, 50.17,20.60,20.49, 20.37. IR (neat, cl''): 3232,3070,2955,1750,1372,1222,1182,1110,1037. FAB+ for C2oH27NSO9F3: [MNa] calcd m/z 532, found m/z 532. Anal. Calcd. for C2oH22NSO9F3 (509.45): C, 47.15%; H, 4. 35%; N, 2.75%; S, 6.29%. Found: C, 47.02%; H, 4.34%; N, 2.70%; S, 6,. 21%. mp 134-140 °C (dec).

Example II-12 : Synthesis of Sulfoxides from the Corresponding Thiophenvl Compounds Phenyl 1-thio saccharides of the present invention can be converted into the corresponding sulfoxides by methods described elsewhere and by Methods A and B described hereinbelow. For instance, the sulfoxide compounds M, N and O depicted in

Table 2 hereinbelow can be prepared using the methods described in U. S. Serial No.

08/281,167 and 08/822,131, the disclosures of which are incorporated herein by reference. The thiophenyl (sulfide) starting material for sulfoxide K is synthesized by literature methods [see, e. g., Alper, P. B., et al., Tetrahedron Lett., 34: 6029 (1996); Ferrier, R. J., et al., Carbohltdrate Res., 52: 63 (1976)]. The starting material (sulfide) for sulfoxide L is synthesized using literature methods [see, e. g., Anisuzzaman, A. K. M., et al., Carbohydrate Res., 169: 258 (1987); Broddefalk, J., et al., J. Carbohydrate Chem., 13 (1): 129 (1994); Ferrier, R. J., et al., Carbohydrate Res., 52: 63 (1976)]. Other sulfoxide donor molecules are prepared by the following methods: Method A: To a stirred mixture of appropriate sulfide (0.005 M), AczO (0.0055 M), and silica gel (lg, 230-400 mesh) in CH2CI2 (lOOmL) is added aqueous 30% H202 solution (0.006 M). After being stirred at RT between 2 and 24 h, with the reaction progress being monitored by TLC, the reaction mixture is filtered through a fine frit sintered funnel and the filtrate is washed with aqueous sodium bisulfite (200mL), aqueous NaHC03 (200mL) and brine (200mL). The organic layer is dried over Na2S04 and concentrated under vacuum to furnish a mixture of R and S sulfoxides.

Method B: To a cooled (-78 °C) solution of the appropriate sulfide (0.005 M) in CH2Cl2 (lOOmL), m-CPBA (0.0055 M) is added, and the temperature is slowly raised to- 25 °C over a 2h period. After filtering, the filtrate is washed with aqueous sodium bisulfite (200mL), aqueous NaHCO3 (200mL) and brine (200mL). The organic layer is dried over Na2SO4 and concentrated under vacuum to furnish a mixture of R and S sulfoxides.

Table 2

Reaction yield, TLC,'H NMR, and mass spectral data for the compounds appearing in Table 2 are given below: Phenvlsulfenvl 2 3 4 6-tetra-O-pivalovl-a-D-mannopyranoside (A): 90% Yield, TLC Rf <BR> <BR> 0.4 (1: 2 EtOAc/hexane); NMR (300 MHz, CDCl3) : # 7.65 (m, 2H), 7.54 (m, 3H),<BR> <BR> 5.80-5.54 (m, 3H), 4.80-4.60 (m, 1H), 4.52 (d, 0.6H, J=3.3 Hz), 4.42 (d, 0.4H, J=3.3 Hz), 4.20-4.00 (m, 2H), 1.10-1.02 (m, 36H); MS (fab): 647 (M+Na) +.

Phenvlsulfenvl 2-phthalimido-2-deoxv-3 4 6-tri-O-acetvl-ß-D-galactopvranoside (B): 90% Yield, TLC Rf 0. 25 (1: 1 EtOAc/hexane) ; 1H NMR (300 MHz, COCH) MHz, CDC13) 7.90-7.20 (m, 9H), 5.84 and 5.72 (each dd, 1H, J= 10.2 and 3.5Hz), 5.47 (d, 1H, J=3. 5Hz), 5. 20 and 5.27 (each d, 1H, J=10.2Hz), 5.60 and 4.88 (each t, 1H, J=10.2Hz), 4.20-4.02 (m, 3H), 2.18-1.95 (m, 9H). MS (fab): 566 (M+Na) +.

Phenvlsulfenvl 2-azido-2-deoxv-34-di-O-acetyl-aßD-fucopyranoside (C): 93% Yield, <BR> <BR> TLC Rf0.45 (1: 1 EtOAc/hexane) ; 1H NMR (300 MHz, MHz, CDCI3): 8 7.72-7.54 (m, 5H),<BR> <BR> 5.71 and 5.67 (two d, each 0.3H, J=3.3 Hz), 4.71 (d, 0.4H, J=5.7 Hz), 4.55-4.16 (m, 3H),<BR> <BR> 2.14-2.07 (m, 6H), 1.04-0.92 (m, 3H). MS (fab): 404 (M+Na) +.

Phenylsulfenyl 2-azido-2-deoxv-3, 4-di-0-acetvl-a, B-L-fucopvranoside (D): 83% Yield, <BR> <BR> TLC Rf 0.40 (1: 2 EtOAc/hexane);'H NMR (300 MHz, CDCl3) : 6 7.75-7.50 (m, 5H), 5.65 and 5.62 (each d, 1H, J= 9.6Hz and 3.6 Hz), 5.38 and 5.20 (each d, 1H, J=6.3 Hz), 4.72 (m, 1H), 4.42 (m, 1H), 4.24 (m, 1H), 2.15-2.02 (m, 6H). MS (fab): 404 (M+Na) +.

Phenylsulfenvl 2-azido-2-deoxv-3 4-di-O-carbonvl-a. ß-L-fucopyranoside (E): 93% <BR> <BR> Yield, TLC Rf030 (1: 2 EtOAc/hexane) ; 1H NMR (300 MHz, CDCl3): 8 7.72-7.54 (m, 5H), 5.18 and 5.05 (each dd, 1H, J= 8.4Hz and 3.6 Hz), 4.95 (d, 0.6H, J=3.3 Hz), 4.80- 4.65 (m, 3H), 4.59 (d, 0.4H, J = 4.8 Hz), 1.04-0.92 (m, 3H). MS (fab): 350 (M+Na) +.

Phenvlsulfenvl 2-phthalimido-2-deoxy-3*4-di-O-acetyl-ß-D-fucopyranoside (F): 93% Yield, TLC RfO. 22 (1: 2 EtOAc/hexane);'H NMR (300 MHz, CDCl3): 5 7.80-7.24 (m, <BR> <BR> <BR> <BR> <BR> 5H), 5.82 and 5.65 (each dd, 1H, J= 10.2 Hz and 3.6 Hz), 5.42 and 5.35 (each d, 1H, J = 10.2Hz), 5.25 (m, 1H), 5.02 and 4.81 (each t, IH, J=10. 2 Hz), 4.02 (m, 1H), 1.10-1.02 (m, 3H). MS: 485 (M+ NH4) +.

Phenylsulfenyl 2-phthalimido-2-deoxy-3,4,6-tri-O-acetyl-ß-D-glucopyranosid e (G): 95% Yield, TLC Rf 0.30 (1: 1 EtOAc/hexane);'H 1H NMR (300 MHz, CDCl3): # 7.86-7.06 (m, 9H), 5.80 and 5.76 (2t, 1H, J=9.6Hz), 5.46 and 5.43 (2d, 1H, J=9.6Hz), 5.16 and 5.08 (2t, 1H, J=9.6Hz), 4.91 and 4.68 (2t, 1H, J=9.6Hz), 4.10-4.06 (m, 2H), 3.95 and 3.84 (2m, 1H), 2.05-1.85 (m, 9H). MS (fab): 566 (M+Na) +.

Phenvlsulfenvl 6-0- (2, 3. 4, 6-tetra-0-acetvl-p-D-glucopvranosyl)- (l->6)-2-phthalimido- 2-deoxy-3,4-di-O-acetyl-ß-D-glucopyranoside (H): 85% Yield, TLC Rf0. 15 (2: 1 EtOAc/hexane);'H 1H NMR (300 MHz, CDCl3) : # 7.95-7.40 (m, 9H), 5.82-5.65 (m, 2H), 5.46 and 5.42 (each d, IH, J = 10.2 Hz), 5.30-5.20 (m, 4H), 5.02 (t, 1H, J= 10.2Hz), 4.81 (t, 1H, J= 10.2Hz), (m, 4H), 2.23-1.90 (m, 18H). MS: 849 (M+ NH4) +. <BR> <BR> <BR> <BR> <BR> <P> Phenylsulfenyl4-O-(2,3,4,6-tetra-O-pivaloyl-ß-D-glucopyrano syl)-(1#4)-2,3,6-tri-O- pivaloyl-ß-D-glucopyranoside (I) : 80% Yield, TLC RfO. 35 (1: 2 EtOAc/hexane);'H 1H NMR (300 MHz, CDCl3) : # 7.70-7.50 (m, 5H), 5.40-5.18 (m, 3H), 4.96-4.82 (m, 3H), 4.52-4.42 (m, 2H), (m, 4H), 3.78-3.40 (m, 2H), 1.35-1.07 (m, 63H). MS: 1056 (M+ Nu4).

Phenylsulfenyl4-O-(2,3,4,6-tetra-O-acetyl-ß-D-glucopyranosy l)-(1#4)-2-azido-2- deoxy-3,6-di-O-acetyl-ß-D-glucopyranoside (J): 85% Yield, TLC Rf0. 15 (1: 1 EtOAc/hexane);'H NMR (300 MHz, CDCl3) : # 7.75-7.60 (m, 5H), 5.78 and 5.77 (each

d, 1H, J=5.4 Hz), 5.08 (m, 2H), 5.01 (t, 1H, J=9.6Hz), 4.65 (d, 1H, J = 9.6 Hz), 4.43 (m, 2H), 4.35-4.15 (m, 3H), 3.90-3.50 (m, 4H), 2.05-1.95 (m, 18H). MS: 729 (M+ NH4) +.

Phenylsulfenyl 2-azido-2-deoxv-3.46-tri-O-acetyl-a ß-D-glucopvranoside (K): 92% <BR> <BR> <BR> <BR> <BR> Yield, TLC Rf0. 25 (1: 1 EtOAc/hexane); NMR (300 MHz, CDCl3) : 8 7.65-7.45 (m, 5H), 5.15 (t, J=10 Hz), 4.97 (t, J=10 Hz), 4.23-4.18 (m, 3H), 3.90 (t, J=10 Hz), 3.75-3.70 (m, 1H), 2.1 Or (s, 6H), 2.00 (s, 3H), MS (fab): 462 (M+Na) +.

Phenylsulfenyl 2-azido-2-deoxy-3,4,6-tri-O-acetyl-α,ß-D-galactopyranoside (L): 90% <BR> <BR> <BR> <BR> <BR> Yield, TLC Rf0.35 (1: 1 EtOAc/hexane);'H 1H NMR (300 MHz, CDCl3) : # 7.74-7.53 (m,<BR> <BR> <BR> <BR> <BR> <BR> <BR> 5H), 5.71 and 5.78 (each d, 0.5H, J = 3.3 Hz), 5.29 (t, 0.5H, J=5.7 Hz), 5.36 (d, 0.5H, J = 3.3 Hz), 4.98 (dd, 0.5H, J=10.2 Hz and 3.3 Hz), 4.71 (d, 0.5H, J = 4.8 Hz), 4.50-3.70 (m, 4.5H), 2.15-1.94 (m, 9H). MS (fab): 462 (M+Na) +.

Phenvlsulfenvl 2, 34-tn-O-pivalovl-a X-L-fucopyranoside (M): 73% Yield, TLC Rf0. 3 (1: 2 EtOAc/hexane) ; 1H NMR (300 MHz, CDC13): 5 7.82-7.50 (m, 5H), 5.18 and 4.98 <BR> <BR> <BR> <BR> <BR> (m, 3H), 4.63 and 4.42 (each d, IH, J = 9.9 Hz), 3.94-3.80 (m, 1H), 1.20-0.93 (m, 27H).

MS (fab): 547 (M+Na) +.

Phenvlsulfenvl 2 3*4 6.-tetra-O-pivalovl-ß-D-galactopyranoside (N): 80% Yield, TLC Rf 0.4 (1: 2 EtOAc/hexane); NMR (300 MHz, CDCl3) : # 7.80-7.50 (m, 5H), 5.58-5.06 (m, 3H), 4.65 and 4.43 (each d, 1H, J=9.6 Hz), 4.12-3.70 (m, 3H), 1.15-0.93 (m, 36H); MS (fab): 647 (M+Na) +.

Phenylsulfenyl 2,3,4,6,-tetra-O-pivaloyl-ß-D-glucopyranoside (O) : 88% Yield, TLC Rf <BR> <BR> <BR> 0.3 (1: 2 EtOAc/hexane) ; 1H NMR (300 MHz, CDCl3) : # 7.65-7.54 (m, 5H), 5.38-5.18<BR> <BR> <BR> <BR> <BR> <BR> (m, 2H), 5.04-4.92 (m, 1H), 4.46 and 4.28 (each d, 1H, J=9.6 Hz), 4.20-4.00 (m, 2H),<BR> <BR> <BR> <BR> <BR> <BR> 3.76 and 3.60 (each m, 1H), 1.18-0.92 (m, 36H); MS (fab): 647 (M+Na) +.

PART III. SYNTHESIS OF LIPID GROUPS Example III-1. Synthesis of (R)-methyl-2-isopentoxy-3-hvdroxv-propionate (compound 20.4a).

As shown in Scheme 20, compound 20.1 (1,3 ; 4,6-di-O-benzylidene-D-mannitol [Baggett, N., J. Chem. Soc., Perkins Trans., 1: 1123 (1977)]) (270g; 0.753mol), is added to DMF (anhydrous, 4 L) in a 12-liter, 3-neck round bottom flask under a N2 atmosphere.

Sodium hydride (54.4g; 2.27mol) is slowly added to the stirred mixture (the temperature is kept under 25°C throughout the addition). 1-bromo-3-methylbutane (252.7g; 1.673mol) and DMF (400mL) are sequentially added. The system is stirred at 70 °C for 3 hours and cooled to room temperature overnight. The reaction mixture is diluted with ethyl ether (10 L) and transferred to a 10-gallon separatory funnel containing a mechanical stirrer. Aqueous HCl solution (3 M; 3 L) is slowly added to the system.

After 30 minutes of intense stirring, the layers are separated and the organic layer is washed with water (3 L). The aqueous layers are combined and extracted with ethyl ether (3 L). All the organic layers are combined, washed with brine (3L), dried over anhydrous Na2SO4 (1 kg) and concentrated under vacuum. The dry solid is treated with warm ethyl acetate (1.5 L) and silica gel 60 (600g), and concentrated under vacuum. The immobilized crude product is then purified on a Biotage Flash 75 system (using a stepwise gradient of 5% to 100% ethyl acetate-hexane) to afford compound 20.2a (180g; 48% yield).'HNMR (300 MHz, CDC13): 8 7.51-7.49 (m; 4H), 7.39-7.25 (m; 6H), 5.48 (s; 2H), 4.42 (dd; J= 4.8 Hz, 10.5 Hz; 2H), 3.98 (d; J= 9.0 Hz; 2H), 3.85 (m; J= 5.1 Hz, 9.0 Hz, 10.2 Hz; 2H), 3.70-3.55 (m; 4H), 3.48 (m; 2H), 1.70 (m; J= 6.6 Hz; 2H),

1.42 (m; J= 6.6 Hz; 4H), 0.88 (d; J= 6.6 Hz; 12H). TLC Rf= 0.35 (10% ethyl acetate- hexane). FAB MS: for C30H4206 [MH] calcd m/z 499, found m/z 499.

Compound 20.2a (176g; 0.353mol) is dissolved in ethyl alcohol (2 L) and water (0.48 L) at 40°C, and concentrated HCl (37.6%; 313mL) is added dropwise. The system is refluxed (80°C) overnight and cooled to room temperature. Saturated NaHC03 solution (4 L) is. added dropwise to obtain a final pH of 7, and the mixture is evaporated to dryness. The solid is triturated with boiling ethyl acetate (2 x 3 L) and the resulting solutions are filtered through a heated sintered funnel. The combined organic phases are dried over anhydrous Na2SO4 and concentrated under vacuum, yielding a yellow oil (126g). The oil is treated with hot hexane (2 L) and silica gel 60 (250g) and dried under vacuum. The immobilized crude product is loaded onto a Biotage Flash 75 system and sequentially eluted with 80% ethyl acetate-hexane, 100% ethyl acetate and 20% methanol-methylene chloride. The fractions containing product are concentrated to afford compound 20.3a (65.7g; 58% yield). TLC Rf= 0. 25 (80% ethyl acetate-. hexane). FAB MS: for Cl6H3406 [M+Na] calcd m/z 345, found m/z 345.

To a solution of compound 20.3a (65g; 0.202mol) in THF (3 L) is added a solution of NaI04 (107g; 0.500mol) in water (1.5 L) over the period of 40 minutes. The suspension is cooled to 10 °C and bromine (43.3mL; 0.840mol) is added dropwise over the period of 20 minutes. The reaction mixture is warmed to room temperature and stirred for 2 hours. Diethyl ether (3 L) and 5% aqueous sulfuric acid (1 L) are added.

The organic layer is reserved and the aqueous layer is back-extracted with ether (2 x 1.5L). The red organic layers are combined and treated with an aqueous saturated NaHS03 solution until a light yellow color is obtained (ca. 0.5 1 of saturated NaHS03

solution). The organic layer is washed with water (1.5 L) and brine (2 L), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to an oil (79.4g). The oil is dissolved in methanol (1 L) and treated with concentrated HCl (12 M; 75.6mL). The solution is stirred at 50°C overnight, cooled to room temperature, neutralized with aqueous saturated NaHC03 solution (250mL) and concentrated under vacuum. The residue is treated with methylene chloride (500mL) and filtered. The filtrate is dried over anhydrous Na2SO4, filtered and concentrated under vacuum, affording a dark oil (62.3g).

The oil is directly loaded onto a Biotage Flash 75 system and eluted with a stepwise gradient of 20% to 30% ethyl acetate-hexane, affording compound 20.4a as a clear oil <BR> <BR> <BR> <BR> <BR> (58g; 0. 305mol; 76% yield). 1H NMR (300 MHz, CDCl3) : 8 3.99 (dd; J= 3.6 Hz, 6.3 Hz; IH), 3.88 (dd; J= 3. 6 Hz, 11. 7 Hz; 1H), 3.82-3.70 (m; 5H), 3.45 (m; IH), 1.70 (m; J= 6.6 Hz; 1H), 1.50 (m; J = 6.6 Hz; 2H), 0.88 (d; J= 6.6 Hz; 6H), 13C NMR (75.4 MHz, CDC13): <BR> <BR> <BR> <BR> <BR> 8 179.96,88.35,78.30,71.96,60.61,46.97,33.51,31.18,31.08. IR (neat): 3466.1 (br), 2897.2 (s), 1738.6 (s), 1163.3 (s). TLC Rf= 0.65 (50% ethyl acetate-hexane). FAB MS: for CgHIsO4 [MNa] calcd m/z 213; found m/z 213. Anal. Calcd. for C9Hig04 (190.24): C, 9.54%; H, 56. 82%. Found: C, 9.44%; H, 56.83%.

Example III-2: Svnthesis of (R)-methvl 2-dodecoxy-3-hydroxv-propionate (compound 20.4b).

Compound 20.1 (290g; 0.809mol) is added to DMF (anhydrous, 4 L) in a 12-liter, 3-neck round bottom flask under a N2 atmosphere. Sodium hydride (58g; 2.42mol) is slowly added to the stirred mixture, and the temperature is kept under 25 °C. 1-bromo- dodecane (448g; 1.798mol) and DMF (1,220mL) are sequentially added. The system is

stirred at 70 °C for 4 hours and cooled to room temperature overnight. The dark brown reaction mixture is diluted with ethyl ether (10 L) and transferred to a 10-gallon separatory funnel containing a mechanical stirrer. Aqueous HCI solution (3 M; 4L) is added to the system. After 30 minutes of intense stirring, methylene chloride (6L) and water (3L) are added and the layers are separated. The aqueous layer is backwashed with methylene chloride (2L). The combined organic layers are washed with water (1 x 4L) and brine (1 x 4L). These aqueous washes are extracted with ethyl ether (2L). The combined organic layers are dried over Na2SO4 (1 kg) and concentrated under vacuum, affording the crude product (622g). The dry solid is dissolved in ethyl ether (2.0L), treated with silica gel 60 (600g) and concentrated under vacuum. The crude mixture is then purified on a Biotage Flash 75 system using a stepwise gradient of 0% to 10% ethyl acetate-hexane as eluent. The fractions containing pure compound are combined and concentrated, yielding compound 20.2b (209g; 37% yield).'H NMR (300 <BR> <BR> <BR> <BR> <BR> <BR> MHz, CDC13): 6 7.51-7.49 (m; 4H), 7.39-7.25 (m; 6H), 5.48 (s; 2H), 4.42 (dd; J= 4.8 Hz, 10.5Hz; 2H), 3.98 (d; J= 9.0 Hz; 2H), 3.85 (td; J= 5.1 Hz, 9.0 Hz, 10.2 Hz; 2H), 3.70- 3.55 (m; 4H), 3.48 (m; 2H), 1.55 (m; 4H), 1.30 (m; 36H), 0.85 (t; J= 6.3 Hz; 6H). TLC Rf = 0. 58 (10% ethyl acetate-hexane).

Compound 20.2b (208g; 0.300mol) is dissolved in ethyl alcohol (2L) and water (400mL) at 40 °C, and concentrated HCl (37.6%; 275mL) is added dropwise. The system is refluxed at 80°C overnight and cooled to room temperature. Saturated NaHC03 solution (3L) is added dropwise to obtain a final pH of 7, and the mixture is evaporated to dryness. The solid is triturated with boiling ethyl acetate (4L in the first round; 2L in the second round) and the resulting solutions are filtered through a heated sintered funnel.

The organic phases are dried over anhydrous Na2SO4. Since crystallization of product is observed at this stage, the system is heated to 65°C and filtered through a warm sintered funnel. The solid is rinsed with warm ethyl acetate (2L) and discarded. The organic phase is concentrated to a solid residue (213g). The residue is recrystallized from 80% ethyl acetate-hexane, affording compound 20.3b as a white solid (104g; 67% yield). TLC Rf= 0.29 (80% ethyl acetate-hexane). FAB MS: for C3oH6206 [MNa], calcd m/z 542, found m/z 542.

To a solution of compound 20.3b (104g; 0.199mol) in THF (4L) is added a solution of sodium periodate (106g; 0.495mol) in water (1.5L) over the period of 40 minutes. The resulting suspension is cooled to 5°C and bromine (43mL; 0.839mol) is added dropwise over the period of 20 minutes. The reaction mixture is warmed to room temperature and left overnight under intense stirring. Diethyl ether (4L) and a 5% sulfuric acid solution (IL) are added. The organic layer is reserved and the aqueous layer is back-extracted with ether (3 x 1.5L). The red organic layers are combined and treated with an aqueous saturated NaHS03 solution until a light yellow color is obtained (ca. 1L ofNaHS03 solution). The organic layer is washed with water (1 x 2L) and brine (1 x 3L), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to an oil (118g). The oil is dissolved in methanol (1.68L) and treated with concentrated HCl (12M; 112mL). The solution is stirred at 50°C overnight, cooled to room temperature, neutralized with aqueous saturated sodium bicarbonate solution (1.25L) and concentrated under vacuum. The residue is treated with methylene chloride (2.5L) and filtered. The filtrate is dried over anhydrous Na2SO4, filtered and concentrated under vacuum, affording an oil (107g). The oil is absorbed onto silica gel 60 (225g) using methylene

chloride as solvent, loaded onto a Biotage Flash 75 system and eluted with a stepwise gradient of 15% to 30% ethyl acetate-hexane. Compound 20.4b is isolated as a clear oil <BR> <BR> <BR> <BR> <BR> (98g; 0. 305mol; 85% yield).'H NMR (300 MHz, CDCI3): 8 3.99 (dd; J= 3.6 Hz, 6.0 Hz; 1 H), 3.88 (dd; J= 3. 6 Hz, 11.4 Hz; IH), 3.82-3.70 (m; SH), 3.44 (m; 1H), 1.60 (m; 2H), 1.30 (br; 18H), 0.84 (t; J= 6.3 Hz; 3H). 3C NMR (75.4 MHz, CDC13): 8 179.96,88.34, 58,40.50,38.25,38.22,38.17,38.01,37.94,34.53,31.27,22.68. IR (neat): 3466.1 (br), 2897.2 (s), 1738.6 (s), 1428.0 (m), 1163.3 (s). TLC Rf= 0.62 (50% ethyl acetate-hexane). FAB MS: for Ci6H3204 [MNa] calcd m/z 311; found m/z 311.

Anal. Calcd. for C, 6H3204 (288.43): C, 66.63%; H, 11.18%. Found: C, 63.60%; H, 10.63%.

Example III-3: Synthesis of (R)-methyl-2-docosoxv-3-hvdroxy-propionate (compound 20.4c).

Compound 20.1 (400g; 1.116mol) is added to DMF (anhydrous, 4L) in a 12-liter, 3-neck round bottom flask under a N2 atmosphere. Sodium hydride (80.6g; 3.36mol) is added to the stirred mixture, while the temperature is kept under 25 °C. 1-bromo- docosane (965.6g; 2.479mol) and DMF (800mL) are sequentially added. The system is stirred at 70°C for 6 hours and cooled to room temperature overnight. The dark brown reaction mixture is treated with HCl (3M; 500mL), as the temperature is kept under 40°C.

The reaction mixture is diluted with methylene chloride (4L) and saturated brine (4L), forming a viscous emulsion. The emulsion is shaken with hexane (4L), yielding two distinct layers. The hexane-containing top layer is reserved (fraction A; 840g). The bottom layer is then heated to reflux and transferred to a separatory funnel. Upon

cooling, two layers separate. The aqueous top layer is discarded and the bottom layer is reserved (fraction B; 1240g). Fractions A and B are separately concentrated to dryness, dissolved in hot methylene chloride, immobilized on silica gel 60 (900g and 1240g, respectively), and purified on a Flash 150 Biotage system using a Flash 150 module. In each run, unreacted 1-bromodocosane is eluted with pure hexane and the product is eluted with 5% ethyl acetate-hexane to give compound 20.2c (349g; 0. 358mol; 31.8% <BR> <BR> <BR> <BR> <BR> yield based on compound 20.1).'H NMR (300 MHz, CDC13): S 7.51-7.49 (m; 4H), 7. 39- 7.25 (m; 6H), 5.48 (s; 2H), 4.42 (dd; J= 4.8 Hz, 10.5 Hz; 2H), 3.98 (d; J= 9.0 Hz; 2H), 3.85 (m; J = 5.1 Hz, 9.0 Hz, 10.2 Hz; 2H), 3.70-3.55 (m; 4H), 3.48 (m; 2H), 1.55 (m; 4H), 1.30 (m; 76H), 0.85 (t; J= 6.3 Hz; 6H). TLC Rf= 0.68 (10% ethyl acetate-hexane). FAB MS: for C64Hno06 [MH], calcd m/z 976, found m/z 976; [MNa], calcd m/z 998, found m/z <BR> <BR> <BR> <BR> <BR> 998. Anal. Calcd for C64Hl 10°6 C, 78. 80%; H, 11.36%. Found: C, H, 11.34%.

Compound 20.2c (346.6g; 0.355mol) is dissolved in ethyl alcohol (4.4L) and water (0.97L) at 40 °C, and concentrated HCl (37.6%; 318mL) is added dropwise. The system is refluxed at 80°C overnight and cooled to room temperature. Saturated sodium bicarbonate solution (4L) is added dropwise to obtain a final pH of 7, and the mixture is evaporated to dryness. The solid is triturated with boiling ethyl acetate (2 x 3.5L). The resulting solutions are filtered through a heated sintered funnel, and the remaining final solids are discarded. The combined organic extracts are cooled to 0 °C for a few hours, leading to extensive crystallization. The solid is separated by filtration and reserved. The filtrate is concentrated to half volume and allowed to stand at 4°C overnight. The resulting solid is combined with the previous solid, affording compound 20.3c (282g; 99% yield based on compound 20.2c). TLC Rf= 0.38 (60% ethyl acetate-

hexane). FAB MS: for CsoHio02b [MNa], calcd m/z 822, found m/z 822. Anal. Calcd for C50H, 0206: C, 75.13%; H, 12.86%. Found: C, 75.42%; H, 12.90%.

Compound 20.3c (50g; 0.0626mol) is dissolved in THF (1.63L) at 40°C. To this clear solution is added a solution of NaI04 (54.3g; 0.254mol) in water (0.82L) over the period of 40 minutes; throughout the addition the reaction temperature is maintained at 40°C. The resulting suspension is agitated at 40°C for half an hour and then cooled to 20°C. Bromine (22mL; 0.42mol) is added dropwise over the period of 20 minutes. The reaction mixture is warmed to room temperature and left for 2 hours under intense stirring. Methylene chloride (2L) and a 5% aqueous sulfuric acid solution (SOOmL) are added. The organic layer is reserved and the aqueous layer is back-extracted with methylene chloride (2 x 1.5L). The red organic layers are combined and treated with an aqueous saturated sodium bisulfite solution until a light yellow color is obtained (ca. 1L of NaHS03 solution). The organic layer is washed with water (4L) and brine (3L), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to a white solid (64g). The solid is dissolved in methanol (0.75L) and treated with concentrated HCl (12 M; 50mL). The suspension is stirred at 50°C overnight, cooled to room temperature, neutralized with aqueous saturated NaHC03 solution (525mL) and concentrated under vacuum. The residue is treated with warm methylene chloride (2L) and filtered. The filtrate is dried over anhydrous sodium sulfate, filtered and concentrated under vacuum, affording a white solid (66g). The solid is dissolved in methylene chloride (1L), washed with a combination of water (I L) and brine (1L), dried over anhydrous Na2SO4 and concentrated under vacuum to a solid (43g). The solid is recrystallized from hot hexane, affording pure compound 20.4c (32.3g; 60% yield based on compound 20.3c).

H NMR (300 MHz, CDC13): 6 3.98 (dd; J= 3. 6 Hz, 6.3 Hz; 1H), 3.88 (dd;. l = 3. 9 Hz, 11.5 Hz; 1H), 3.82-3. 70 (m; 5H), 3.44 (m; 1H), 1.60 (m; 2H), 1.30 (br; 38H), 0.84 (t; J= 6.3 Hz; 3H). 13C NMR (75.4 MHz, CDCI3): 8 179.94,88.17,80.08,72.06,60.71,40.57, 38.35,38.31,38.26,38.21,38.06,38.01,34.61,31.35,22.77. IR (neat): 3466.1 (br), 2917.6 (s), 2854.1 (s), 1742.3 (m), 1460.5 (m), 1126.3 (m). TLC Rf=0.36 (40% ethyl acetate-hexane). FAB MS: for C26H5204 [M+Na] calcd m/z 451; found m/z 451. Anal.

Calcd. For C26H5204 (428.69): C, 72. 85%; H, 12.23%. Found: C, 73.06%; H, 12.01%.

PART IV. ASSEMBLY OF SACCHARIDES AND LIPOPHOSPHOGLYCERATE MIMETICS INTO MOENOMYCIN ANALOGS Solid phase techniques for assembling the above-discussed acceptor, donor and lipid groups with phosphorus-containing groups are discussed hereinbelow and are illustrated in Scheme 21. In Scheme 21, the acceptor saccharide is represented by a phenyl 3,4-di-O-substituted-4-C-methyl-1-thio--D-glucopyranosiduron ic acid, the donor molecule is represented by a phenylsulfenyl 3,4, 6-tri-O-substituted-α,ß-D- glucopyranoside, having a masked amine group represented by N*, and the lipophosphoglycerate mimetic moiety is represented generally by O-P (O) (OH)-OR, e. g., where R contains carboxyl and lipid groups.

Step 1. Linking Glucopvranosiduronic Acid to Rink Resin A Rink amine resin is swelled in DMF-DCM (1: 1 v/v) and washed twice with DMF. The solvent can be removed simply by pumping it out using a fritted glass tube (medium porosity). The Fmoc-protecting group of the resin is removed by treating the

resin with 20% piperidine-DMF solution. The resin is then washed 4 times with low amine DMF. The glucopyranosiduronic acid (2 equiv.), HATU (2 equiv.) and DIPEA (2- 4 equiv.) are individually dissolved in low amine DMF. The reagents are added to the resin in the above order. The resin is stirred with the coupling cocktail until it is negative to ninhydrin color test. The coupling cocktail is removed by vacuum filtration. The glycopyranosiduronic acid can be recovered by extracting the cocktail with EtOAc and dilute hydrochloric acid. The resin is washed 4 times with DMF, 4 times with EtOAc, and 4 times with DCM.

Step 2. Solid Phase Glycosylation Reactions-Coupling of Donor to Acceptor Residues Acceptor-loaded resin is swelled in anhydrous EtOAc. The EtOAc is removed and the resin is equilibrated twice with 20% EtOAc-DCM. The EtOAc-DCM wash solvent is removed. The donor phenylsulfenyl saccharide (4 equiv.) and'Bu2Mepy (2 equiv., 4 equiv. can also be used except with 2-NPhth donors) are dissolved in 20% EtOAc-DCM. The donor/base solution is added to the resin. The reaction mixture is stirred under argon at room temperature for 5 minutes. The reaction mixture is cooled to -70°C. TfzO (4 equiv.) is added in a dropwise manner and the reaction mixture is allowed to warm from-50°C to-30 °C and is kept at that temperature for 3-16 hours. The reaction is then quenched with MeOH (10 equiv.) and DIPEA (10 equiv.) in DCM and the reaction mixture is allowed to warm to room temperature. Solvent is removed and the resin is washed (with 5 minutes of stirring) with DMF for 4 times, EtOAc for 4 times and DCM for 4 times.

Step 3. Reduction of azide group The resin is swelled in THF-EtOH (1: 1 v/v) with 10% v/v water.

Trimethylphosphine-THF (4 equiv.) is added and the reaction mixture is stirred at room temperature for 3-4 hours. The reduction of azide can be confirmed with Diffuse Reflectance Infrared Fourier Transform Spectroscopy (DRIFTS). The resin is washed 4 times with THF, 4 times with DCM, and 2 times with DMF.

Step 4. Synthesis of amides from aminosaccharide and carboxvlic acids The amine loaded resin is swelled in DMF, carboxylic acid (4 equiv.), HATU (4 equiv.) and DIPEA (4 equiv.) are added. The reaction mixture is stirred at room temperature until it is negative to ninhydrin color test. The resin is washed 4 times with DMF, 4 times with EtOAc, and 4 times with DCM.

Step 4'. Synthesis of ureas from aminosaccharide and isocyanates The amine loaded resin is swelled in DMF. The DMF is removed by pumping it out using a fritted glass tube (medium pore). The resin is treated with a solution containing the isocyanate (5eq per amine group) and triethylamine (Seq per amine group) in DMF. The reaction mixture is stirred at RT for 4hr or until the resin gives a negative Kaiser test. The supernatant is removed by pumping it out using a fritted glass tube (medium pore). The resin is washed twice with DMF, 4 times with EtOAc, and 4 times with CH2CI2. (Diisopropylethylamine has also been used as a base, but is not preferred since it is immiscible with DMF.)

Step 5. Removal of acyl (levulinovl) protecting group and reaction with isocyanate The resin is swelled in DMF. The DMF is removed with a suction tube, and hydrazine acetate (4 equiv.) is dissolved in DMF with heating. The solution is added to the resin after it is cooled to room temperature. The reaction mixture is stirred at room temperature overnight. The resin is washed 4 times with DMF, 4 times with EtOAc, and 4 times with DCM. The resin appears very sticky on glass surface. The resin is swelled in DCM, and isocyanate (4 equiv.) and triethylamine (4 equiv.) are added. The resin will not stick to glass surface after a short time. The reaction mixture is stirred at room temperature for 4-6 hours. The resin is washed 4 times with DCM.

Step 6. Cleavage of 1-SPh group using mercury trifluoroacetate The resin is swelled in CH2CI2. CH2CI2 is removed by pumping it out using a fritted glass tube (medium porosity). To 20mg of resin (O. Olmmol) is added a solution of mercury trifluoroacetate (4eq) in water-saturated DCM (ImL), which is prepared by mixing DCM and water in a separatory funnel and shaking for a few minutes. The DCM layer is collected and use as prepared. The reaction mixture is stirred at 40°C for 1 hour (using a condenser for reflux). The supernatant is removed by pumping it out using a fritted glass tube. The resin is washed 6 times with DMF and 2 times with either THF or DCM. The resin is now ready for the phosphorylation or P-R amidite coupling step.

Step 7. Solid-phase Phosphorylation (first step) The resin is swelled in CH2C12. The CH2C12 is removed by pumping it out using a fritted glass tube (medium pore). To 20mg of resin (O. lmmol) in dry CH2CI2 (ImL), in a

2-neck round bottom flask under argon, are successively added DIPEA (25eq) and 2- cyanoethyl diisopropylamino phosphorus chloride (25eq). The reaction mixture is stirred at room temperature for 2 hours under argon. The supernatant is removed by pumping it out using a fritted glass tube. The resin is washed 2 times with dry CH2CI2,2 times with dry THF, and 2 times with dry (1: 1) THF-CH3CN. The resin is now ready for the"lipid" coupling step.

Step 7a. Synthesis of C5 lipid amidite To a lipid compound, e. g., compound 20.4a (190mg; lmmol), in dry CHzCIz (lOmL) under argon at room temperature, are successively added DIPEA (0.34mL; 1.95eq) and 2-cyanoethyl diisopropylamino phosphorus chloride (0.25mL; I. lmmol; l. leq). The reaction mixture is stirred at room temperature for 45 min-lhr (the reaction is monitored by TLC in (1: 1) hexane-EtOAc). The reaction mixture is then diluted with CH2C12 and the organic layer is washed successively with ice cold 10% NaHCO3, H20 and saturated NaCI. The organic layer is dried over sodium sulfate and concentrated on a rotary evaporator. It is then dried under vacuum using a vacuum pump for a few hours prior to using it as a crude mixture (a yellowish oil is obtained).

Step 7b. Synthesis ofC12 lipid amidite To a C12 lipid, e. g., compound 20.4b (144mg; 0.5mmol), in dry DCM (5mL) under argon at room temperature are added successively DIPEA 0.975mmol; 1.95eq) and 2-cyanoethyl diisopropylamino phosphorus chloride (0.12mL; 0. 55mmol; 1.1 eq). The reaction mixture is stirred at room temperature for 45 min to 1 hour, with the reaction monitored by TLC in hexane-EA (2: 1). The reaction mixture is then diluted with DCM and the organic layer is washed successively with ice cold 10% sodium

bicarbonate, water and saturated brine. The organic layer is dried over sodium sulfate and concentrated on a rotary evaporator. It is then dried under vacuum using a vacuum pump for a few hours prior to using it as the resulting mixture (yellowish oil).

Step 8. Lipid coupling and oxidation The resin is swelled in THF. The THF is removed by pumping it out using a fritted glass tube (medium pore). To 20mg of resin (O. Olmmol), in a 2-neck round bottom flask, are successively added a solution of the lipid (lOeq) in dry THF (ImL) and a 0.5M solution of tetrazole in acetonitrile (SOeq, I nlL). The reaction mixture is stirred at 60° C overnight (use a condenser for reflux). After overnight stirring, the reaction mixture is cooled down to room temperature. The supernatant is removed by pumping it out using a fritted glass tube. The resin is washed 4 times with THF, and is swelled in 0.5mL of THF. To the resin is added 1.5mL of an iodine solution (I2/THF-pyr-H2O, from Perkin Elmer-Applied Biosystems, Inc.). The reaction mixture is stirred at room temperature for 10 minutes. The supernatant is removed by pumping it out using a fritted glass tube.

The resin is washed 4 times with THF. The resin is now ready for the aqueous LiOH deprotection step.

Step 8a. Lipid amidite coupling and oxidation The resin is swelled in THF. The THF is removed by pumping it out using a fritted glass tube (medium pore). To the resin (20mg; O. Olmmol) in a two-neck round bottom flask is added a premixed solution of lipid amidite, e. g., C5 or C12, (crude, 15eq) in dry THF (1mL) and a 0.5M solution of tetrazole in acetonitrile (ImL; 50eq). The above reagents are premixed for 2-15 minutes prior to addition to the resin. The reaction

mixture is stirred at 60°C overnight using a condenser for reflux. After overnight stirring, the reaction mixture is cooled down to room temperature. The supernatant is removed by pumping it out using a fritted glass tube. The resin is washed 4 times with THF, and is swelled in THF (0.5mL). To the resin is added 1.5mL of an iodine solution (I2/THF-pyr- H2O, from Perkin Elmer-Applied Biosystems, Inc.). The reaction mixture is stirred at room temperature for ten minutes. The supernatant is removed by pumping it out using a fritted glass tube. The resin is washed 4 times with THF. The resin is now ready for the aqueous LiOH deprotection step.

Step 8b. Salicylic acid coupling and oxidation.

The resin is swelled in CH2CI2. The CH2CI2 is removed by pumping it out using a fritted glass tube (medium pore). To the resin (20mg; 0. Olmmol) in dry CH2CI2 (ImL) are successively added DIPEA (25eq) and 2-chloro-4H-1,3,2-benzodioxaphosphorin-4- one (25 eq) dissolved in dry CH2CI2 (ImL). The reaction mixture is stirred at room temperature for 2 hours. The supernatant is removed by pumping it out using a fritted glass tube. The resin is washed 4 times with CH2CI2 and 4 times with THF. The resin is then swelled in THF (0.5mL). To the resin is added 1.5mL of an iodine solution (12 /THF-pyr-H2O, from Perkin Elmer-Applied Biosystems, Inc.). The reaction mixture is stirred at room temperature for ten minutes. The supernatant is removed by pumping it out using a fritted glass tube. The resin is washed 4 times with THF. The resin is now ready for the nonaqueous LiOH deprotection step.

Step 9. Cleavage of cvanoethvl, methyl ester and acetvl groups

The resin is swelled in THF. The THF is removed by pumping it out using a fritted glass tube (medium pore). To 20mg of resin (0. Olmmol) in THF-MeOH (1: 1) (2mL) is added a 0.4M aq LiOH solution (lOeq, 0.25mL) [2eq/group to be cleaved]. The reaction mixture is stirred at room temperature for 2-3 hours. After overnight stirring, the supernatant is removed by pumping it out using a fritted glass tube. The resin is washed 3 times with MeOH, 3 times with THF-MeOH (1: 1), and 4 times with THF. The resin in now ready for the non-aqueous LiOH deprotection step.

Step 9a. Cleavage of benzovl vroup (final deprotection) The resin is swelled in THF. The THF is removed by pumping it out using a fritted glass tube (medium pore). To 20mg of resin (O. Olmmol) is added a solution of LiOH (I Oeq) in THF-MeOH (1: 1) (2mL). The reaction mixture is stirred at room temperature overnight. After overnight stirring, the supernatant is removed by pumping it out using a fritted glass tube. The resin is washed three times with 20% aqueous THF, three times with MeOH, three times with THF-MeOH (1: 1), three times with THF, and four times with CH2Cl2. The resin is now ready for TFA cleavage.

Step 10. Cleavage of product from resin The resin is swelled in CH2CI2. The CH2CI2 is removed by pumping it out using a fritted glass tube (medium pore). To 20mg of resin (O. Olmmol) is added 20% TFA/CHzCI2 (2mL). The reaction mixture is stirred at room temperature for 30 minutes.

The resin is filtered off and the supernatant is transferred to a pre-weighed round bottom flask. The resin is washed twice with CH2C12, the filtrate and washes are pooled and

concentrated under vacuum, and the residue is taken up in dioxane, isopropanol or 20% DMSO/water and stirred for 30 min with pre-washed H+ resin. The resin is filtered off and washed a few times with the solvent used for exchange. The filtrate is then concentrated under vacuum on a rotary evaporator. The sample is analyzed by LC-MS after dissolution in methanol.

Automated Procedure for Svnthesis of Moenomvcin Librarv Analogs This procedure can be carried out simultaneously on two, 48-position Combitec reaction blocks on a TECAN (Switzerland) liquid handling platform. The reaction blocks are assembled as described by TECAN and fitted with 5mL reaction vessels.

One Rink amide-bound disaccharide (pictured below) is illustrated for this particular procedure. 0 NH-polystyrene Mu0 H2N SPh 0 OAc N3 OAc AcO AcO

Phenyl 2-0- (2-azido-2-deoxy-3,4,6-tri-O-acetyl-a-D-glucopyranosyl)- (142)-<BR> <BR> 3-amino-3-deoxy-4-methoxy-1-thio-p-D-glucopyranosiduronic acid

N This disaccharide is functionalized with three carboxylic acids and one isocyanate on the acceptor amine, and four different carboxylic acids at the reduced donor azide. In addition, the anomeric position of the sugar is functionalized as either a C5- phospholipid or a phosphosalicylate. Overall, 96 different products and intermediates are isolated using this scheme. <BR> <BR> <BR> <BR> <BR> <BR> <P> Stirring is conducted magnetically using l Omm stir bars in each reaction flask and a 48-position stir plate.

All washes are performed with 5 minutes of stirring between solvent addition and removal.

Anhydrous grades of dichloromethane (DCM), tetrahydrofuran (THF), ethanol (EtOH) and methanol (MeOH) are purchased from Aldrich for use in these syntheses.

Low amine content N, N-dimethylformamide (DMF) is purchased from PerSeptive Biosystems.

Procedure 1.5g of the resin-bound disaccharide is swelled in 100mL of 4: 1 DCM/THF for 30 minutes. I. OmL of this slurry (15mg, 0.007mmol, 1X) is then robotically dispensed into each position of the 2 reaction blocks. ImL of the solvent mixture is then added to wash the resin down into the reaction vessels.

Each position is then aspirated, washed with 2 x 2mL THF and purged with argon for 60 seconds. a) 0.5ml of a. 057M solution of each carboxylic acid (0.028mmole, 4X, in DMF) is then added. This is followed by the addition of 0.75ml of 0.037M HATU

(0.028mmole, 4X, in DMF) and 0.75ml of 0.037M diisopropylethylamine (0.028mmole, 4X, in DMF). b) ImL of a 1. OM solution of the isocyanate in freshly distilled THF is then added, followed by ImL of a 0. 5M triethylamine solution in THF.

After stirring the reaction mixtures for four hours, each vessel is aspirated and washed with 4 x 2mL THF and 2 x 2mL DMF.

After the addition of 1.1 mL of 9: 2 EtOH/Water to every vessel, 0.9mL of 0.032M trimethylphosphine (0.028mmole, 4X, in THF) is added.

The reaction mixtures are then stirred for 4 hours before aspiration of the solvent.

Each vessel is then washed with 4 x 2ml THF and 2 x 2ml DMF 0.5ml of a 0.057M solution of each carboxylic acid (0.028mmole, 4X, in DMF) is then added. This is followed by the addition of 0.75ml of 0.037M HATU (0.028mmol, 4X, in DMF) and 0.75ml of 0.037M diisopropylethylamine (0.028mmol, 4X, in DMF).

The reaction mixtures were stirred overnight at room temperature before aspiration.

Each was then washed with 4 x 2mL DMF and 2 x 2mL DCM.

After the addition of 2mL of 0.014M mercury (II) trifluoroacetate (0.028M, 4X) in water saturated DCM to the appropriate wells, the mixtures were stirred at 40°C for 1 hour.

After aspiration, the vessels are washed with 4 x 2mL DMF and 2 x 2mL DCM. Each vessel is then purged with argon for 60 seconds.

Procedure for C5 Lipid Attachment 2mL of a 0.053M isopentyl amidite derived from compound 20.4a (0.105mmole, 15X)/0.25M tetrazole solution in 1: 1 THF/acetonitrile is then added to the appropriate vessels. The reaction mixtures are then stirred overnight at 60°C.

Each flask is then aspirated and washed with 4 x 2mL THF.

2mL of iodine solution (IZ/Pyridine/THF/Hz0) is then added to the phosphorylated resins and each is stirred for 10 minutes.

Each vessel is then aspirated and washed with 4 x 2mL THF.

2.0mL of 0.035M lithium hydroxide (LiOH) in 4: 4: 1 THF/MeOH/Water (0.07mmol, 10X) is then added to all of the phosphorylated resins and each is stirred for 2.5 hours at room temperature.

After washing with 3 x 2mL 1: 1 THF/MeOH and 2 x 2mL THF, 2.0ml of 0.035M LiOH in 1: 1 MeOH/THF (0.07mmol, 10X) is added to all of the vessels and the mixtures are stirred overnight.

The mixtures are then aspirated and washed with 3 x 2mL 1: 1 THF/MeOH, 4 x 2mL THF and 3 x 2mL anhydrous DCM.

Each disaccharide is then cleaved from the resin with 30 minutes of stirring in 2.5mL of 20% trifluoroacetic acid in DCM.

The product solutions are then transferred to polyethylene microtiter plates before solvent evaporation in a Speedvac.

After drying, the products are dissolved in 20% aqueous DMSO and passed through a column of Amberlite proton exchange resin.

The resulting solutions are analyzed by LC-MS on a Perkin Liner API100.

Procedure for Cyclic Salicylate Attachment ImL of0.175M diisopropylethylamine (0.105mmol, 15X, in DCM) and I mL of 0.175M (0.105mmol, 15X, in DCM), available from Aldrich Chemical Co., is then added to the appropriate vessels. The reaction mixtures are then stirred at room temperature for 2 hours.

Each flask is then aspirated and washed with 4 x 2ml DCM and 2 x 2ml THF.

Each sample is oxidized with 2mL iodine solution (IZ/Pyr/THF/HZO) for ten minutes.

After being washed with 4 x 2mL THF, every vessel is treated with 2.0mL of 0.035M LiOH in 1: 1 MeOH/THF (0.07mmol, 10X). The reactions are stirred overnight.

The mixtures are then washed with 3 x 2mL 1: 1 THF/MeOH, 4 x 2mL THF and 3 x 2mL anhydrous DCM.

Each disaccharide is then cleaved from the resin with 30 minutes of stirring in 2.5mL of 20% trifluoroacetic acid in DCM.

The product solutions are then transferred to polyethylene microtiter plates before solvent evaporation in a Speedvac.

After drying, the products are dissolved in 20% aqueous DMSO and passed through a column of Amberlite proton exchange resin.

The resulting solutions are analyzed by LC-MS on a Perkin Elmer API100.

Mass Specrtra Representative mass spectra (Fab) for moenomycin analogs of the invention, which were constructed as described hereinabove, are shown in Fig. 20.

PART V. SCREENING OF MOENOMYCIN ANALOGS FOR ANTIMICROBIAL ACTIVITY The following procedures for conducting an assay of bacterial inhibition by a moenomycin analog of the present invention can be performed.

Bacteria. All organisms are grown in a universal rich media to minimize media effects on the inhibition assay. All bacteria are demonstrated to grow in Brain Heart Infusion (BHI) media (Difco, Detroit, MI) supplemented with 0.1% Casamino Acids (CAA) (Difco). The following organisms are used in primary screening: Enterococcus faecium (ATCC 49624) Enterococcusfaecalis (ATCC 29212) Staphylococcus aureus (ATCC 29213) Staphylococcus epidermidis (ATCC 12228) Streptococcus pneumonia (ATCC 49150) Escherichia coli (ATCC 25922) Acinetobacter anitratus (ATCC 43498) The bacteria are streaked for isolation from frozen glycerol stocks onto BHI/CAA plates containing 1.5% Bacto-agar (Difco). An isolated colony from each strain is used to inoculate 5mL of BHI/CAA media and allowed to grow overnight at 37°C with shaking.

The exception is with Streptococcus strains, which are grown in a candle jar at 37°C without shaking. After overnight growth, the organisms are diluted 1: 100 and allowed to incubate until they reach early to mid-logarithmic growth (OD600 0.5). The cells are diluted 100 fold in BHI/CAA containing 0.7% agar maintained at 50°C to a cell density

of approximately 5 X 105 colony forming units (CFU) permL. The agar slurry is poured into an 86 mm X 128 mm assay plate (Nunc), which has the dimensions of a 96-well plate, and allowed to solidify for at least 30 minutes. Streptococcus strains are diluted in BHI/CAA media without agar and 200 p. 1 aliquoted to each well of a 96-well assay plate.

Test Compounds. The test compounds are solubilized in sterile 20% DMSO/water to a concentration of approximately 1-Smg/ml, aseptically aliquoted among several sterile <BR> <BR> <BR> <BR> <BR> <BR> "daughter"plates and frozen at-20°C. Daughter plates are thawed at room temperature or 37°C just prior to assay.

Lawn Assav. A sterilized 96-well replicating device (Boekel) is inserted into the daughter plate and used to deliver the test compound to either a 96-well plate containing Streptococcus, or an agar plate imbedded with bacteria. The replicator pierces the agar and is removed vertically to prevent damage to the agar surface. The appearance of zones of inhibition is monitored after 15 to 24 hr. growth at 37°C. Similarly, Streptococcus inhibition is monitored by no observable turbidity in the wells of the 96-well plate after 24-48 hr. growth.

A control plate containing dilutions of antibiotic standards is run at the time of each assay with each organism. The control antibiotics are Ampicillin, Vancomycin and Moenomycin. Control samples are aliquoted in duplicate in a 96-well array. Each antibiotic is tested at eight serial two fold dilutions. Antibiotic concentrations vary from lOmg/ml to 0. OOlmg/ml.

MIC Assay. Putative actives in the Lawn assay are further screened to determine the minimum inhibitory concentrations (MIC) of each compound for each organism affected.

Test compounds are serially diluted in 20% DMSO/water and added to 96-well plates in a volume of 5 u. Each bacterium, grown as described above and diluted in broth without agar, is added to the diluted compound in a volume of 200 u. The range of concentrations used for each compound in the MIC assay is based on the potency implied by the size of the zone of inhibition in the lawn assay. Each compound is tested at five serial dilutions, ranging anywhere from 1: 40 up to the maximium dilution necessary to alleviate the antimicrobial effect. The effect of the test compound on bacterial growth is measured after 18 hrs of growth at 37°C by determining the turbidity of the medium at 600 nm or by visual inspection. The MIC is defined as the lowest concentration of compound necessary to completely inhibit bacterial growth.

Peptidoglvcan Synthesis Assav. The peptidoglycan polymerization assay is adapted from that described by Mirelman, et al. [Biochemistry 15: 1781-1790 (1976)] and modified by Allen, et al. [FEMS Microbiol. Lett. 98: 109-116 (1992)]. E. coli. (ATCC #23226) are permeabilized with ether according to Mirelman, et al. (1976), and Maas and Pelzer [Arch. Microbiol., 130: 301-306 (19_)], permitting exogenously added radiolabelled and non-radiolabelled cell wall precursors to penetrate the bacterial cell wall. Screening quantities of UDP muramyl-pentapeptide (UDP-N-acetylmuramyl-L-Ala-D-glu-meso- diaminopimelyl-D-ala-D-ala) are isolated by boiling from an aqueous extract of B. cereus (ATCC # 11778) according to published preparative (Kohlrausch and Holtje, FEMS Microbiol. Lett. 78: 253-258 (1991) and analytical HPLC techniques (Kohlrausch, et al.,

J. Gen. Microbiol. 153: 1499-1506 (1989). Bacterial protein is determined by the method of Bradford [Anal. Biochem.. 72: 248 (1976)].

Polymerization assays are conducted in 96-well filter-bottom plates (Millipore GF/C-cat. &num MAFC NOB 10). A Tecan Genesis 150 robot is programmed for all subsequent liquid handling steps. In a final assay volume of 100 IL each well contains: 50 mM Tris-Cl (pH 8.3); 50 mM NH4Cl; 20 mM MgSO4.7 H2O ; 10 mM ATP (disodium salt); 0.5 mM P-mercaptoethanol; 0.15 mM D-aspartic acid; 0. 001mM UDP- N-acetyl ['4C-]-D-glucosamine (DuPontlN. E. N.-265-307 mCi/mmol); 0.05 mM UDP-MurNAc-pentapeptide, 100ug/ml tetracycline and 50ug/well ether-treated bacterial protein. Novel test compounds are solubilized in 10% DMSO/water and screened at a final assay concentration of 10 tg/ml. With the exception of radiolabeled and isolated native pentapeptide, all remaining biochemicals are purchased from Sigma Chemical or Fisher Scientific.

Assay buffer (10 L), ATP (20 pL), UDP pentapeptide (10 uL) and 14C-UDP- GlcNAc (20 U. L) are added to all wells, followed by either test compound, reference standard or buffer vehicle (20 µL). The reactions are then started by adding 20 p, L aliquots of bacterial protein prepared in assay buffer into each well. Plates are covered, mixed for 30 sec., then incubated at 37°C for 120 min. Ice cold 20% TCA (100 |iL) is added to each well, the plates are gently mixed (60 sec), then refrigerated (4°C) for 30 min to assure precipitation of all peptidoglycan.

The plates are placed under vacuum filtration on a Millipore manifold, flitered, and washed 3-4 times with 200 pL/well of 10% TCA. Optiphase scintillation cocktail (30 pL/well) is added, then the plates are incubated overnight prior to counting in a

Wallac Microbeta. Percent inhibition of incorporation of 14C-label into peptidoglycan is computed from control (total incorporation) and background (blank) wells containing 300 . g/ml of vancomycin or 100 pg/ml of moenomycin, which completely inhibit incorporation of radiolabel. All wells are arrayed in duplicates, which usually vary by <20%. Concentration-response curves for reference standards are arrayed on each plate as positive controls (IC50 for inhibition of incorporation: vancomycin = pg/ml; moenomycin = 0.04 +/-0.005 llg/ml).

Several preferred aspects of the present invention have been discussed hereinabove for purposes of illustration and clarification. It is readily apparent to one skilled in the art that certain obvious improvements and modifications of the present invention can be practiced without departing from the scope of the appended claims.

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