TITLE OF THE INVENTION

8A-AZA AND 9A-AZA MACROLIDE ANTIBIOTICS, AND A

PROCESS FOR PRODUCING SAME AND METHODS OF USE

BACKGROUND OF THE INVENTION

The present invention relates to macrolide and azalide antibiotics which are useful in the therapy of bacterial infections in mammals.

Prior to the present invention, modifications of the western fragment of erytheromycin A have been difficult to obtain. The present invention provides compounds with modified western fragments, as well as processes of manufacture, methods of treatment and compositions containing such modified macrobides. These compounds are useful antibacterial agents.

Erythromycin A has been the subject of investigation for many years. However, hydrolysis and alcohoysis of the lactone to form the linear seco acid or ester has only recently been reported. In part, preservation of the appropriate stereochemistry in the eastern fragement has proven difficult to preserve.

Erythromycin A has the following structural formula:

It has now been recognized that base catalyzed reactions can be conducted which lead to rupture of the ring and formation of the Cl carboxylate. This rection can be generally as follows:

The present invention related to the formation of novel macrolides and azalides, by combining the eastern fragments described above with an appropriate fragment which becomes the western portion of the molecule. Thus, a wide variety of macrolides and ozelides can now be produced as describned in detail below.

DETAILED DESCRIPTION

The following terms are used herein and have the meanings set forth below unless otherwise indicated.

Erythromycin A has the structure shown above. Numbering of the molecule, as well as derivatives thereof, is

conventional, starting with the ring lactone heteroatom. Likewise, other fragment and compounds names are as follows:

8a-aza fragment (Ilia) 9-deoxo-8a-aza-8a-homoerythromycin A

9a-aza fragment (IVa) 9-deoxo-9a-aza-9a-homoerythromycin A

These fragments are useful intermediates in the synthesis of azalide antibiotics which have high structural homology to 9-deoxo-8a- aza-8a-homoerythromycin A and 9-deoxo-9a-aza-8a-homoerythromycin A in their "eastern" sides, but which are free to diverge in structure by an arbitrary amount in their "western" sides (western side shall be

understood to be any portion of the macrocyclic ring not part of the eastern side, as eastern is defined above). The term alkyl refers to a hydrocarbon group with 1 to 7 carbon atoms contained therein. Alkyl groups can be straight or branched. Preferred alkyl groups include methyl, ethyl, propyl, butyl, t-butyl, pentyl and hexyl.

Aryl refers to an aromatic ring e.g., phenyl, or rings fused, e.g., naphthalenyl, drawn as containing from 5 to 15 carbon atoms, and showing alternating double bonds in the ring structure. The preferred aryl group is phenyl.

Aralkyl is a specie of substituted alkyl, containing up to three aryl groups substituted on a straight, branched or cycloalkyl group. The most preferred aralkyl specie is benzyl. Cycloalkyl refers to a hydrocarbon ring or rings containing 3 to 15 carbon atoms. When more than one ring is present, the rings can be fused. Cycloalkyl does not contain alternating double bonds, as in aryl. The preferred cycloalkyl groups are cyclopentyl and cyclohexyl.

Alkavediyl refers to a divalent hydrocarbon chain, e.g., -alkylene-, which may be substituted or unsubstituted as appropriate. Typically there are two to five carbon atoms in alkavediyl, which may form a ring by attaching to two other atoms joined directly or through other atoms.

When any of the groups noted above is termed "substituted", up to 6, and preferably 1-3 such substitutions are included at any available point of attachment. Preferred substitute groups used herein are Cl-7alkyl groups, OR 10 where R 10 is H or alkyl and fluoroalky.

The term "cyclic carbonate" refers to -OC(0)0- which is divalent, it forms a 5 membered ring when attached to joined atoms. Likewise the term "cyclic acetonide" refers to -OC(Me)2θ- which forms a ring when attached to joined atoms.

It will also be noted that the stereochemical configuration of the compounds of the invention can be varied within wide limits, depending on the stating materials and reaction parameters selected. All

such stereo configurations are included herein, in pure form as well as in mixtures.

The present invention also includes a method of making macrolide and azalide antiobiotics, which are useful in the therapy of bacterial infections in mammala. The process of manufacture described herein thus comprises the synthesis steps which are useful to make a compound of formula I, II or III. Generally, the process of manufacture is comprised of reacting a natural or synthesized western fragment, in protected or partially protected form with a heteroatom of the eastern fragment. This is followed by cyclizing to form the target compound.

The method begins with a 9a-aza or 8a-aza fragment (3 or 4 respectively) which can be derived from erythromycin or its derivatives. The conversion of erythromycin A to the prototypical fragments 3a and 4a is shown in the following figure:

Fragments 1 and 2 can be elaborated into 8a-azalides 3 and 9a-azalides 4, respectively.

The process for producing the compounds of the present invention initially involves synthesis or procurement of an appropriate fragment which will become the western portion of 1 or 2. Normally this will be a carbon chain of 2 to 6 atoms which will bear an aldehyde or ally lie acetate function at one end and a protected amino or protected hydroxy group at the other. This chain may contain unsaturation or be interrupted by a heteratom, heterocycle, or aromatic ring, and may bear a variety of substituents, including hydrogen, alkyl, aryl, aralkyl, protected hydroxy, cyclic carbonate, cyclic acetonide, protected amino, cyclic carbamate, and halogen. Hereafter this will be referred to as the chimeric segment (-A-).

The chimeric segment is then attached to the 8a or 9a amino group of 1 or 2, respectively, which may be followed by protection of the resulting secondary amine so as to render it non- nucleophilic. If the chimeric segment is an aldehyde, attachment may commonly be achieved by reductive amination. If the chimeric segment is an allylic acetate, attachment can be achieved by catalyzed coupling e.g., Pd. Naturally, other chimeric segments can be attached in other ways. Preferred protecting groups for the resulting secondary amine include benzenesulfonyl and benzyloxycarbonyl, but others are also suitable.

The amino or hydroxy group on the chimeric segment can then be deprotected, such that it may be converted to the carboxylate, and then cyclized. Cyclization to form a macrolactone is normally accomplished using the Mitsunobu reaction, in which an activated hydroxy on the chimeric segment is displaced by the nucleophilic carboxylate. There are a wealth of cyclization methods which activate the carboxylate for attack by the nucleophilic hydroxy group, such as the Keck and Yamaguchi methods. Use of these methods is complicated by facile cyclization of the activated carboxylate onto the 6-OH or 2'- OH group to form undesired lactones, but these methods prove valuable

in some particular cases. Cyclization to form a macrolactam is usually accomplished using diphenylphosphoryl azide, which activates the carboxyate for attack by a nucleophilic amine on the chimeric segment.

The newly formed macrolactone or macrolactam can thereafter be deprotected. The benzenesulfonyl group on the ring nitrogen may be removed, as well as any protecting groups on the chimeric segment. Removal of the benzenesulfonyl group from the ring nitrogen can be accomplished using Na(Hg) and K ₂ HPO ₄ in MeOH, but the presence of methoxide in the reaction may lead to a ring opened product. A superior method of removing the benzenesulfonyl group is the photochemical procedure reported by Yonemitsu et. al: the benzenesulfonamide is photolyzed in aqueous ethanol with 1 ,8- dimethoxynaphthalene and a reductant such as ascorbic acid or hydrazine. Other amines on the chimeric segment may be protected as benzenesulfonamides, and are liberated simultaneously with the ring nitrogen. Hydroxy groups on the chimeric segment are conveniently protected as benzyl ethers, and are easily liberated in the final step by catalytic hydrogenation.

Alternatively, it is possible to attach the chimeric segment to the carboxyate group by forming an amide or ester bond, and subsequently cyclizing the other end of the chimeric segment onto the ring nitrogen.

Simple chimeric segments can be constructed from common ,ω-hydroxyaldehydes, a,o-diols and a,o-hydroxyamines (e.g. 1,5-pentanediol or 1 ,2-benzenedimethanol). Carbohydrates represent a large and versatile pool of precusors for polyhydroxylated chimeric segments of various lengths and stereochemistries. Amino acids can similarly be converted into amine containing chimeric segments. Many other desirable chimeric segments can be simply prepared by asymmetric total synthesis.

Compounds 3 and 4 can be prepared readily according to the following detailed descriptions and accompanying examples or modifications thereof using readily available starting materials, reagents and conventional synthesis procedures. The following discussion will

focus on the conversion of amine fragment 1 to the family of 8a- azalides 3. However, the methods described apply to the conversion of amine fragments 2 to 9a-azalides 4.

The chimeric segment is attached to the amine of fragment 1 or 2. The chimeric segment typically contains an aldehyde function, and the attachment is accomplished via reductive amination. The preferred method of reductive amination uses sodium cyanoborohydride in a minimum of methanol, with heating as necesssary.

Other means of reductive amination, such as formic acid in methylene chloride, may also be used.

In variations of the invention, other means of attaching an alkyl chain to a primary amine may be used. For example, if the chimeric segment contains an allylic acetate instead of an aldehyde, the attachment may be accomplished by palladium catalyzed coupling to produce an allylic amine.

Macrolactonization

Preferably macrolactonization utilizes a secondary nitrogen at the 8a or 9a position, and the sequence works much better if this secondary amine is protected by a group that eliminates its basicity, such as alkyl and aralkyloxycarbonyl or arylsulfonyl. The most preferred group for this purpose is benzenesulfonyl. The benzenesulfonyl group may be introduced using benzenesulfonyl chloride in methylene chloride with triethylamine and N,N-dimethylaminopyridine. Hydroxy groups are also preferably protected such as via benzyl or other aralkyl ethers, or trialkylsilyl ethers. Amino groups can be protected with alkyl and aralkyloxycarbonyl or arylsulfonyl groups. Diols may be protected as cyclic acetals or ketals, or cyclic carbonates. An amine and a hydroxy can together be protected as a cyclic carbamate.

A single hydroxy group can be deprotected. Most preferably, there is a single hydroxy group protected as a t- butyldimethylsilyl or t-butyldiphenylsilyl ether, and any other hydroxy groups on the chimeric segment are protected as methyl or benzyl ethers. In this case, the single hydroxy group is revealed by reaction with tetra-n-butylammonium fluoride in tetrahydrofuran.

The macrolactonization reaction typically begins with hydrolysis of an ester. This is normally accomplished using a mixture of tetrahydrofuran, methanol and 1 N aq. NaOH. After saponification, the mixture can be neutralized, the solvent removed and the residue used in the cyclization reaction without purification. The most preferred method of macrolactonization is a Mitsunobu cyclization: reaction of a dilute solution of the hydroxycarboxylate with diethyl or diisopropyl azodicarboxylate and triphenylphosphine. This normally gives satisfactory cyclization onto primary and some secondary hydroxy groups. Other proximate nucleophiles can effect displacement. The unprotected hydroxy groups at C2', C4" and C6, and the basic amine at C3' generally do not pose a problem in the cyclization.

Once cyclization has occurred, protecting groups may be removed from the ring nitrogen and from oxygens or nitrogens as

appropriate. When the ring nitrogen and also any nitrogens on the chimeric segment are protected with the benzenesulfonyl group, these can be deprotected together. One preferred method of removing the benzenesulfonyl group is that described by Yonemitsu, involving photolysis in ethanol, 1 ,5-dimethoxynaphthalene and a reducing agent such as ascorbic acid or hydrazine. Sodium amalgam in buffered methanol can also be used to effect this deprotection.

Hydroxy groups on the chimeric segment can also be protected as benzyl ethers. These can be removed by catalytic hydrogenation, either before or after the deprotection of the nitrogen.

It should be noted that deprotection of hydroxy groups on the chimeric segment sometimes results in translactonization. Diols on the chimeric segment are often protected as cyclic carbonates, and these can be deprotected with mild base, as described in example

The above sequence is summarized in flow chart 1.

FLOW CHART 1

Macrolactamization

An important difference between the macrolactonization and macrolactamization sequences is that the basic "ring" nitrogen (8a or 9a) does not interfere with the macrolactamization reaction as long as it is a tertiary amine (tertiary amines on the chimeric segment are likewise tolerated.) After attachment of the chimeric segment, the 8a or 9a nitrogen may be benzenesulfonlylated to produce 8a or 9a-NH macrocycles, or alkylated to produce 8a or 9a-N-alkyl macrocycles. The ring nitrogen can be methylated as appropriate at this point using formaldehyde and sodium cyanoborohydride. Other reductive amination methods, such as the Eschweiler-Clark procedure (formic acid and formaldehyde) may also be used.

Suitable protecting groups for an amine on the chimeric segment include the alkyl and aralkyloxycarbonyl groups, with the benzyloxycarbonyl group being most preferred. If the ring nitrogen is alkylated, arylsulfonyl groups may be used. The benzyloxycarbonyl group can be removed at this stage by catalytic hydrogenation. However, when the chimeric segment bears an amine equivalent, usually azide, this can be converted to an amine by reduction. The most preferred method for reduction of the azide is reaction with triphenylphosphine in aqueous tetrahydrofuran, although other methods, such as catalytic hydrogenation, may also be used.

The next stage of the macrolactamization reaction, typically begins with hydrolysis of a methyl ester. This is normally accomplished using a mixture of tetrahydrofuran, methanol and 1 N aq. NaOH. After saponification is complete, the mixture is neutralized, the solvent is removed, and the residue is used in the cyclization reaction without purification.

The most preferred method of macrolactamization is reaction of the aminocarboxylate with diphenylphosphorylazide at low temperature.

After cyclization, if the ring nitrogen was protected as N- benzenesulfonyl, this group may be removed to produce the 8a or 9a- NH macrocycle as described above for the macrolactams.

The above sequence is summarized in flow chart 2.

FLOW CHART 2

The invention described herein includes a pharmaceutical composition comprised of a compound of formula I, II or III in an amount effective to treat a bacterial infection in a mammalian patient. The pharmaceutical composition may include a pharmaceutically acceptable carrier.

The pharmaceutical composition typically contains the compound in the form of a salt or solvate. Examples include the hydrochloride, citrate, tartrate, succinate and similar salts, as well as various states of hydration. All such forms of the compounds are included herein.

Precise doses of the compounds of formula I, II and III can be determined by those skilled in treating bacterial infections of susceptible organisms taking into account the potency of the compound, the susceptibility of the offending microorganism and other factors, e.g., incidence or severity of any side effects. Generally, the doses can vary from as low as about 0.1 mg/kg/day to as high as about 250 mg/kg/day in single or divided doses, by any acceptable route of administration. Preferably the compound is administered orally or parenterally, e.g., intravenously or intramuscularly. The most preferred route of administration is oral, in the form of a tablet, capsule, suspension or solution. Such doses can be administered once daily, up to several times a day, as high as about every 3 hours.

The method of treatment described herein is comprised of administered to a mammal in need of such treatment an atibacterially effective amount of a compound of formula I, II or III.

EXAMPLE 1

Preparation of (S)-3-t-Butyldimethylsilyloxybutanal

TBDMSOTf 2,6-lutidine

To a 500 ml round bottom flask was introduced 2.54 g (21.5 mmol) of methyl (S)-3-hydroxybutanoate (Aldrich Chemicals), to which was added 70 ml CH2CI2, and 5 ml of 2,6-lutidine. The reaction was stirred in an ice bath, and 4.94 ml (5.68 g, 21.5 mmol) of t- butyldimethylsilyl triflate was added dropwise. After stirring for 1 hour, the reaction was diluted with 250 ml of CH2CI2 and extracted three times with 50 ml of water. The organic layer was dried over MgSθ4 and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel using 10% ethyl acetate in hexane. This afforded 4.3 g (86%) of the product, methyl (S)-3-r- butyldimethylsilyloxybutanoate.

To a 50 ml round bottom flask was introduced 200 mg (0.86 mmol) of methyl (S)-3-t-butyldimethylsilyloxybutanoate, to which was added 2.5 ml dry CH2CI2. The reaction was stirred in a dry ice/acetone bath, and 1.72 ml (2 eq.) of 1 M diisobutylaluminum hydride in toluene was added dropwise. After stirring for 1 hour at -78°C, the reaction was quenched with 2 ml of MeOH and warmed to room temperature. The reaction was diluted with 25 ml of CH2CI2 and 8 ml saturated aq. potassium sodium tartrate was added. The organic layer was separated and dried over MgS04 and the solvent was removed under reduced pressure. Thin layer chromatography using 10% ethyl acetate in hexane showed complete and clean conversion to a lower Rf

spot. This afforded 170 mg (98%) of the product, (S)-3-f- butyldimethylsilyloxybutanal, which was used without purification to avoid racemization.

EXAMPLE 2

General Preparation of t-Butyldimethylsilyloxy Aldehydes from

Hydroxyesters

Following the procedure given in example 1 , a variety of hydroxyesters can be converted to f-butyldimethylsilyloxy aldehydes. A representative but nonlimiting sampling of the compounds that can be produced in this manner include those in the following table:

TABLE 1

EXAMPLE 3

Preparation of 3-t-butyldimethylsilyloxypropanal

To a 500 ml round bottom flask was introduced 5.23 g (27.5 mmol) of 3-t-butyldimethylsilyloxypropanol (prepared according to the method of McDougal et al, J. Org. Chem. 1986, 57, 3388), to which was added 175 ml CH2CI2, and 8.13 g (36.4 mmol, 1.3 eq) of pyridinium chlorochromate. The reaction was stined 90 minutes, diluted with ether, and filtered through Florisil. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel using 10% ether in hexane. This afforded 2.63 g (50%) of the product, 3-r-butyldimethylsilyloxypropanal.

EXAMPLE 4

General Preparation of t-Butyldimethylsilyloxy Aldehydes from

Symmetric Diols

In a two step sequence, beginning with t-butyldimethyl- silylation according to the method of McDougal et al, J. Org. Chem. 1986, 57, 3388, and followed by oxidation according to the procedure given in example 3, a variety of symmetric diols can be converted to t- butyl-dimethylsilyloxy aldehydes. A representative but nonlimiting sampling of the compounds that can be produced in this manner include those in the following table:

TABLE 2

Starting Diol t-Butyldimethylsilyl Aldehyde

EXAMPLE 5

Preparation of 2-(R)-3-(S)-4-(R)-trialkoxy-5-t-butyldimethylsilyloxy- pentanal

Preparation of 2-(R)-3-(S)-4-(R)-trimethoxy-5-t-butyldimethylsilyloxy- pentanal

To a 100 ml round bottom flask was introduced 164 mg (1 mmol) of methyl-β-D-xylopyranoside, to which was added 10 ml dry DMSO and 0.28 ml Mel (4.5 eq.). This mixture was stirred at room temperature and 120 mg (4.5 eq.) of NaH (80% oil dispersion) was added in several small portions. The reaction was stined for 18 hours and then added to 250 ml of methylene chloride and extracted four times with 50 ml of water. The organic layer was dried over magnesium sulfate and the solvent was removed under vacuum. This

afforded 181 mg (88%) of 2,3,4-tris-(0-methyl)-methyl-β-D- xylopyranoside which was sufficiently pure to be used directly in the next reaction.

To a 100 ml round bottom flask was introduced 310 mg (1.5 mmol) of 2,3,4-tris-(0-methyl)-methyl-β-D-xylopyranoside, to which was added 15 ml dry CH ₂ CI ₂ and 0.23 ml 1 ,3-propanedithiol (248 mg, 2.30 mmol, 1.5 eq.). This mixture was stined in an ice bath and 1.15 ml (1.32 g, 9.36 mmol, 6.2 eq.) of boron trifluoride etherate was added dropwise. The reaction was stined for 3 hours at 0°C, at which time it was judged to be complete by TLC (2 : 1 EtOAc/hexane, product is lower Rf). The reaction was quenched with 15 ml of aq. sat. NaHCθ3, and the organic layer was separated and extracted twice with 5 ml of aq. sat. NaHCθ3. The organic layer was dried over magnesium sulfate and the solvent was removed under vacuum. The residue was chromatographed on silica, eluting with 66% ethyl acetate/hexane. This afforded 157 mg (37%) of 2-(R)-3-(S)-4-(R)-trimethoxy-5- hydroxypentanal-1 ,3-dithiane.

To a 100 ml round bottom flask was introduced 116 mg (0.41 1 mmol) of 2-(R)-3-(S)-4-(R)-tris(methoxy)-5-hydroxypentanal- 1,3-dithiane, to which was added 10 ml dry THF and 0.270 ml 2,6- lutidine (248 mg, 2.32 mmol, 5.6 eq.). This mixture was stined in an ice bath and 0.295 ml (339 mg, 1.28 mmol, 3.1 eq.) of t- butyldimethylsilyl triflate was added dropwise. The reaction was stined for 30 minutes at 0°C, at which time it was judged to be complete by TLC (1 : 4 EtOAc/hexane, product is higher Rf). The reaction was diluted with 200 ml of CH2CI2 and extracted twice with 15 ml of aq. sat. NaHCθ3. The organic layer was dried over magnesium sulfate and the solvent was removed under vacuum. The residue was chromatographed on silica, eluting with 7.5% ethyl acetate/hexane. This afforded 143 mg (82%) of 2-(R)-3-(S)-4-(R)-trimethoxy-5-r- butyldimethylsilyloxypentanal- 1 ,3-dithiane.

To a 100 ml round bottom flask was introduced 71 mg (0J8 mmol) of 2-(R)-3-(S)-4-(R)-trimethoxy-5-t- butyldimethylsilyloxypentanal-l ,3-dithiane, to which was added 3 ml 4 :

1 acetonitrile/water and 0.200 ml Mel (456 mg, 3.21 mmol, 17.8 eq.). This mixture was heated to 55°C and stined for 18 hours, at which time it was judged to be complete by TLC (1 : 1 EtOAc/hexane, product is slightly lower Rf). The reaction was diluted with 200 ml of CH2CI2 and extracted twice with 15 ml of aq. sat. NaHCθ3. The organic layer was dried over magnesium sulfate and the solvent was removed under vacuum. The residue was chromatographed on silica, eluting with 7.5% ethyl acetate/hexane. This afforded 40 mg (73%) of 2-(R)-3-(S)-4-(R)- trimethoxy-5-r-butyldimethylsilyloxypentanal.

Selected spectral data for 2-(R)-3-(S)-4-(R)-trimethoxy-5- t-butyldimethylsilyloxyρentanal.:

iH NMR (400 MHz, CDCI3) δ 9.68 (s, 1 H), 3.81 (d, 1 H), 3.70 (m, 2 H), 3.50 (s, 3 H), 3.47 (s, 3 H), 3.39 (m, 1 H), 3.27 (s, 3 H), 0.86 (s, 9 H), 0.04 (s, 6 H).

Preparation of 2-(R)-3-(S)-4-(R)-tribenzyloxy-5-t-butyldimethylsilyl- oxy-pentanal

To a 50 ml round bottom flask was introduced 2.44 g (14.8 mmol) of methyl-β-D-xylopyranoside, to which was added 65 ml dry DMSO, 3 g of tetra-n-butylammonium iodide and 6.5 ml benzyl bromide (9.4 g, 55 mmol, 3.7 eq.). This mixture was stined at room temperature and 1.65 g (55 mmol, 3.7 eq.) of NaH (80% oil dispersion) was added in several portions. The reaction was stined for 18 hours and then added to 800 ml of methylene chloride and extracted four times with 200 ml of water. The organic layer was dried over magnesium sulfate and the solvent was removed under vacuum. The residue was chromatographed on silica, eluting with 10% ethyl acetate/hexane. This afforded 6.26 g (88%) of 2,3,4-tris-(0-benzyl)- methyl-β-D-xylopyranoside. Following the procedures given above for the three subsequent steps afforded 2-(R)-3-(S)-4-(R)-tris(benzyloxy)-5- t-butyldimethylsilyloxypentanal.

Selected spectral data for 2-(R)-3-(S)-4-(R)-tribenzyloxy- 5-t-butyldimethylsilyloxypentanal.:

iH NMR (400 MHz, CDCI3) δ 9.75 (s, 1 H), 7.3 (m, 15 H), 4.8 (d, 1 H), 4.79 (d, 1 H), 4.66 (d, 1 H), 4.52 (m, 2 H), 4.50 (d, 1 H), 4.00 (m, 1 H), 3.92 (d, 1 H), 3.7 (m, 2 H), 3.57 (m, 1 H), 0.90 (s, 9 H), 0.01 & -0.01 (singlets, 3 H each).

EXAMPLE 6

General Preparation of Carbohydrate Derived t-Butyldimethylsilyl- oxyalkanals

Using the procedure given in example 5, a wide variety of monosaccharides can be converted into a t-butyldimethylsilylalkanal. A representative but nonlimiting sampling of the compounds that can be produced in this manner include those in the following table:

TABLE 2-1

t-Butyldimethylsilyl Aldehyde

Starting Carbohydrate R = Me or Bn

TABLE 2-2 t-Butyldimethylsilyl Aldehyde

Starting Carbohydrate R = Me or Bn

TABLE 2-3

EXAMPLE 7

Preparation of 2-(R)-hexyl-3-(R)-hydroxy-4-hydroxy-4-methyl-5-t- butyldiphenylsilyloxypentanal 3-0.4-O-acetonide

Preparation of 3-(l-Oxo-2-(R)-hexyl-3-(R)-hydroxy-4-methyl-4- pentenylV4- RV(phenylmethylV2-oxazolidinone

This material was prepared from (R)-3-(l-oxooctyl)-4- (phenylmethyl)-2-oxazolidinone and methacrolein following the method of Evans and Gage, as described in Org. Syn., Vol. 68, 1989, p. 83.

Selected spectral data for 3-(l -oxo-2-(R)-hexyl-3-(R)-hydroxy-4- methyl-4-pentenyl)-4-(R)-(phenylmethyl)-2-oxazolidinone

l H NMR (400 MHz, CDCI3) δ 7.25 (m, 5 H), 5.07 (s, 1 H), 4.92 (s, 1 H), 4.68 (m, 1 H), 4.31 (br s, 1 H), 4.15 (m, 2 H), 3.32 (dd, 1 H), 1.73 (s, 3 H), 0.83 (br t, 3 H).

Preparation of 2-(R)-hexyl-3-(R)-hydroxy-4-methyl-4-hydroxymethyl- butyrolactone

To a 100 ml round bottom flask was introduced 340 mg (0.91 mmol) of 3-(l -oxo-2-(R)-hexyl-3-(R)-hydroxy-4-methyl-4- pentenyl)-4-(R)-(phenylmethyl)-2-oxazolidinone, to which was added 14 ml THF, 0.36 ml water, and 532 mg 4-methylmorpholine /V-oxide (4.55 mmol, 5 eq.). The reaction was stined at room temperature and 0.36 ml of 0.25 M Os04 in THF was added dropwise. After 1 hour, the reaction was quenched with 2 ml of 20% aq. NaHS03, added to 30 ml of ethyl acetate and extracted twice with 10 ml 20% aq. NaHS03 then with 10 ml water. The organic layer was separated, dried over MgS04, and the solvent was removed under vacuum. A 400 MHz proton NMR of the crude reaction product revealed that a mixture of diastereomers at C-4 was formed in about an 8 to 1 ratio, with the stereochemistry of the major product uncertain. The residue was taken up in 60% hexane/ethyl acetate and chromatographed on silica gel using the same solvent mixture. The two diastereomers and the chiral auxilliary proved to be difficult to cleanly separate from each other by chromatography: the minor diastereomer elutes first, followed by the major diastereomer, followed by the chiral auxilliary. Careful chromatography afforded fractions enriched in each product. The total mass of the three products combined was 318 mg (86%).

Selected spectral data for 2-(R)-hexyl-3-(R)-hydroxy-4-methyl-4- hydroxymethylbutyrolactone (major stereoisomer at C-4) lH NMR (400 MHz, CDCI3) δ 4.32 (d, 1 H), 3.68 (d, 1 H), 3.58 (d, 1 H), 2.64 (m, 1 H).

Selected spectral data for 2-(R)-hexyl-3-(R)-hydroxy-4-methyl-4- hydroxymethylbutyrolactone (minor stereoisomer at C-4)

l H NMR (400 MHz, CDCI3) δ 3.97 (d, 1 H), 3.86 (d, 1 H), 3.72 (d, 1 H), 2.77 (m, 1 H).

Preparation of 2-(R)-hexyl-3-(R)-hydroxy-4-methyl-4-t-butyldiphenyl- silyloxymethylbutyrolactone

To a 100 ml round bottom flask was introduced a mixture of 68 mg (0.30 mmol) of 2-(R)-hexyl-3-(R)-hydroxy-4-methyl-4- hydroxy-methylbutyrolactone (major stereoisomer at C-4 from the previous reaction) and 117 mg of the chiral auxilliary which failed to be separated after the previous reaction, to which was added 2 ml sieve dried CH2CI2, 15 mg of dimethylaminopyridine, 0.276 ml sieve dried triethylamine (202 mg, 2 mmol, 6.7 eq.), and 0.156 ml t- butyldiphenylsilyl chloride (166 mg, 0.6 mmol, 2 eq.). The reaction was stined at 50°C for 24 hours, then introduced directly to a silica column and chromatographed with 85% hexane/ethyl acetate. This afforded 40 mg (50%) of 2-(R)-hexyl-3-(R)-hydroxy-4-methyl-4-t- butyldiphenylsilyloxymethylbutyrolactone.

Selected spectral data for 2-(R)-hexyl-3-(R)-hydroxy-4-methyl-4-t- butyldiphenylsilyloxymethylbutyrolactone (major isomer at C-4) lH NMR (400 MHz, CDCI3) δ 4.32 (dd, 1 H), 3.71 (d, 1 H), 3.67 (d, 1 H), 2.60 (m, 1 H), 1.95 (d, 1 H), 1.26 (s, 3 H), 1.05 (s, 9 H).

Selected spectral data for 2-(R)-hexyl-3-(R)-hydroxy-4-methyl-4-t- butyldiphenylsϊlyloxymethylbutyrolactone (minor isomer at C-4) lH NMR (400 MHz, CDCI3) δ 3.99 (dd, 1 H), 3.89 (d, 1 H), 3.76 (d, 1 H), 2.90 (m, 1 H), 1.95 (d, 1 H), 1.28 (s, 3 H), 1.07 (s, 9 H).

Preparation of l-Hydroxy-2-(S)-hexyl-3-(R)-hydroxy-4-hydroxy-4- methyl-5-t-butyldiphenylsilyloxypentane

To a 50 ml round bottom flask was introduced a mixture of 62 mg (0J3 mmol) of 2-(R)-hexyl-3-(R)-hydroxy-4-methyl-4-t-butyl-

diphenylsilyloxymethylbutyrolactone (major isomer at C-4), to which was added 2 ml sieve dried THF and 0.270 ml of 1 M LiBH4 in THF (0.27 mmol, 2 eq.). The reaction was stined at 50°C for 24 hours, then added to 10 ml of water in a separatory funnel and the pH was adjusted to 3-5 with dilute HCl, at which point 10 ml of brine was added and the aqueous layer was extracted three times with 20 ml of methylene chloride. The organic layer was separated, dried over MgS04, and the solvent was removed under vacuum. The residue was chromatographed with 80% hexane/ethyl acetate. This afforded 40 mg (55%) of 1 - hydroxy-2-(S)-hexyl-3-(R)-hydroxy-4-hydroxy-4-methyl-5-t- butyldiphenylsilyloxy-pentane.

Selected spectral data for l-hydroxy-2-(S)-hexyl-3-(R)-hydroxy-4- hydroxy-4-methyl-5-t-butyldiphenylsilyloxypentane iH NMR (400 MHz, CDCI3) δ 7.65 (m, 4 H), 7.40 (m, 6 H), 4.32 (dd, 1 H), 3.72 (d, 1 H), 3.65 (m, 3 H), 3.56 (d, 1 H), 3.12 (br s, 1 H), 2.78 (br m, 1 H), 2.42 (d, 1 H), 1.18 (s, 3 H), 1.08 (s, 9 H), 0.86 (br t, 3 H),

Preparation of l-Hydroxy-2-(S)-hexyl-3-(R)-hydroxy-4-hydroxy-4- methyl-5-t-butyldiphenylsilyloxypentane 3-0.4-O-acetonide

To a 50 ml round bottom flask was introduced a mixture of 7 mg (0.02 mmol) of l-hydroxy-2-(S)-hexyl-3-(R)-hydroxy-4- hydroxy-4-methyl-5-t-butyldiphenylsilyloxypentane, to which was added 3 ml sieve dried acetone, 15 mg of pyridinium p- toluenesulfonate, and 25 mg anh. Q1SO4. The reaction was stined at 85°C for 24 hours, then the solvent was removed under reduced pressure, at which point 10 ml of brine/aq. sat. NaHCθ3 and 20 ml methylene chloride was added. The aqueous layer was extracted three times with 10 ml of methylene chloride. The combined organic layers were dried over MgS04, and the solvent was removed under vacuum. The residue was chromatographed with 80% hexane/ethyl acetate. This afforded 7 mg (95%) of l -hydroxy-2-(S)-hexyl-3-(R)-hydroxy-4- hydroxy-4-methyl-5-t-butyldiphenylsilyloxypentane 3-0,4-O-acetonide.

Selected spectral data for l-hydroxy-2-(S)-hexyl-3-(R)-hydroxy-4- hydroxy-4-methyl-5-t-butyldiphenylsilyloxypentane 3-0,4-O-acetonide iH NMR (400 MHz, CDCI3) δ 7.65 (m, 4 H), 7.40 (m, 6 H), 3.81 (d, 1 H), 3.73 (d, 1 H), 3.70 (m, 2 H), 3.30 (d, 1 H), 1.95 (m, 1 H), 1.54 (s, 3 H), 1..40 (s, 3 H), 1.29 (s, 3 H), 1.05 (s, 9 H), 0.86 (br t, 3 H),

Preparation of 2-(S)-hexyl-3-(R)-hydroxy-4-hydroxy-4-methyl-5-t- butyldiphenylsilyloxypentanal 3-0.4-O-acetonide

To a 50 ml round bottom flask was introduced a mixture of 7 mg (0.02 mmol) of l-hydroxy-2-(S)-hexyl-3-(R)-hydroxy-4- hydroxy-4-methyl-5-t-butyldiphenylsilyloxypentane 3-0,4-O-acetonide, to which was added 1 ml sieve dried isopropyl acetate and 0.010 ml DMSO (ca. 10 eq.). The reaction was stined at -25°C and 25 ml of sieve dried triethylamine (ca. 12 eq) followed by 11 ml of phenyldichlorophosphate (ca. 5 eq.) The reaction was stined at 0°C for 5 hours, after which the reaction was introduced directly to a silica column and chromatographed with 90% hexane/ethyl acetate. This afforded 5 mg (70%) of l-hydroxy-2-(S)-hexyl-3-(R)-hydroxy-4- hydroxy-4-methyl-5-t-butyldiphenylsilyloxypentanal 3-0,4-O-acetonide.

Selected spectral data for l-hydroxy-2-(S)-hexyl-3-(R)-hydroxy-4- hydroxy-4-methyl-5-t-butyldiphenylsilyloxypentanal 3-0,4-O-acetonide iH NMR (400 MHz, CDCI3) δ 9.70 (d, 1 H), 7.63 (d, 4 H), 7.40 (m, 6 H), 4.10 (d, 1 H), 3.65 (d, 1 H), 3.23 (d, 1 H), 3.04 (m, 1 H), 1.95 (m, 1 H), 1.31 (s, 3 H), 1.29 (s, 3 H), 1.26 (s, 3 H), 1.04 (s, 9 H), 0.86 (br t, 3 H),

EXAMPLE 8

General Preparation of 2-(X)-alkyl-3-(X)-hydroxy-4-hydroxy-4-alkyl- 5-t-butyldiρhenylsilyloxypentanal 3-0.4-O-acetonide (X = R or S

Following the procedure given in example 7, a variety of 2-(X)-alkyl-3-(X)-hydroxy-4-hydroxy-4-alkyl-5-t-butyldipheny l- silyloxypentanal 3-0,4-O-acetonides (X = R or S) can be prepared. A

representative but nonlimiting sampling of the compounds that can be produced in this manner include those in the following table:

TABLE 4

Starting Material Product

EXAMPLE 9

Preparation of 2-(R)-hexyl-3-(R)-hydroxy-4-hydroxy-4-methyl-5-t- butyldiphenylsilyloxypentanal 3-0.4-O-carbonate

Preparation of 1 -Triphenylmethoxy-2-(S)-hexyl-3-(R)-hydroxy-4- hvdroxy-4-methyl-5-t-butyldiphenylsilyloxypentane l-Hydroxy-2-(S)-hexyl-3-(R)-hydroxy-4-hydroxy-4- methyl-5-t-butyldiphenylsilyloxypentane (prepared as described in example 7) in dimethylformamide is reacted with triphenylmethyl chloride in the presence of 4-N,N-dimethylaminopyridine according to Greene & Wuts, Protecting Groups in Organic Synthesis, 2nd ed., John Wiley & Sons, Inc. New York, 1991, p. 60 to afford 1-triphenyl- methoxy-2-(S)-hexyl-3-(R)-hydroxy-4-hydroxy-4-methyl-5-t-but yl- diphenylsilyloxypentane.

Preparation of 1 -Triphenylmethoxy-2-(S)-hexyl-3-(R)-hydroxy-4- hvdroxy-4-methyl-5-t-butyldiphenylsilyloxypentane 3-0.4-O-carbonate l -Triphenylmethoxy-2-(S)-hexyl-3-(R)-hydroxy-4- hydroxy-4-methyl-5-t-butyldiphenylsilyloxypentane in pyridine is reacted with phosgene according to Greene & Wuts, Protecting Groups in Organic Synthesis, 2nd ed., John Wiley & Sons, Inc. New York, 1991 , p. 140 to afford l -triphenylmethoxy-2-(S)-hexyl-3-(R)-hydroxy- 4-hydroxy-4-methyl-5-t-butyldiphenylsilyloxypentane 3-0,4-0- carbonate.

Preparation of l-Hydroxy-2-(S)-hexyl-3-(R)-hydroxy-4-hydroxy-4- methyl-5-t-butyldiphenylsilyloxypentane 3-0.4-O-carbonate

Cleavage of the trityl group from l-triphenylmethoxy-2- (S)-hexyl-3-(R)-hydroxy-4-hydroxy-4-methyl-5-t-butyldiphenyl - silyloxy-pentane 3-0,4-O-carbonate is accomplised according to Greene & Wuts, Protecting Groups in Organic Synthesis, 2nd ed., John Wiley & Sons, Inc. New York, 1991, p. 61 to afford l-hydroxy-2-(S)-hexyl-3- (R)-hydroxy-4-hydroxy-4-methyl-5-t-butyldiphenylsilyloxypent ane 3- 0,4-O-carbonate.

Preparation of 2-(S)-Hexyl-3-(R)-hydroxy-4-hydroxy-4-methyl-5-t- butyldiphenylsilyloxypentanal 3-0.4-O-carbonate l-Hydroxy-2-(S)-hexyl-3-(R)-hydroxy-4-hydroxy-4- methyl-5-t-butyldiphenylsilyloxypentane 3-0,4-O-carbonate is oxidized to 2-(S)-hexyl-3-(R)-hydroxy-4-hydroxy-4-methyl-5-t-butyldi- phenylsilyloxy-pentanal 3-0,4-O-carbonate using DMSO and phenyldichlorophosphate with triethylamine in methylene chloride as described in example 7.

EX AMPLE 10

General Preparation of 2-(X)-alkyl-3-(X)-hydroxy-4-hydroxy-4-alkyl- 5-t-butyldiphenylsilyloxypentanal 3-0.4-O-carbonate (X = R or S)

Following the procedure given in example 9, a variety of 2-(X)-alkyl-3-(X)-hydroxy-4-hydroxy-4-alkyl-5-t-butyldipheny l- silyloxy-pentanal 3-0,4-O-carbonates (X = R or S) can be prepared. A representative but nonlimiting sampling of the compounds that can be produced in this manner include those in the following table:

TABLE 5

Starting Material Product

EXAMPLE 1 1

Preparation of 2-(R)-Methyl-3-(S)-alkoxy-4-(S)-methyl-5-t-butyl- dimethylsilyloxypentanal

Preparation of 3-( 1 -Oxo-2-(R)-methyl-3-(R)-hydroxy-4-(S)-methyl-5-t- butyldimethylsiloxypentylV4-(RHphenylmethvD-2-oxazolidinone

This material is prepared from (R)-3-(l-oxopropyl)-4- (phenylmethyl)-2-oxazolidinone and 2-(S)-methyl-3-t-butyldimethyl- siloxypropanal following the method of Evans and Gage, as described in Org. Syn., Vol. 68, 19xx, p. 83.

Preparation of N-Methoxy-N-memyl-2-(R)-methyl-3-(R)-hydroxy-4-

(S)-methyl-5-t-butyldimethylsiloxypentanamide

This material is prepared from 3-(l-oxo-2-(R)-methyl-3- (R)-hydroxy-4-(S)-methyl-5-t-butyldimethylsiloxypentyl)-4-(R )- (phenyl-methyl)-2-oxazolidinone following the procedure described by Weinreb et al. in Tetrahedron Lett. 1977, 4171 and Synth. Commun. 1982, 72, 989.

Preparation of N-Methoxy-N-methyl-2-(R)-methyl-3-(R)-benzyloxy-4-

(SVmethyl-5-t-butyldimethylsiloxypentanamide

This material is prepared from N-methoxy-N-methyl-2- (R)-methyl-3-(R)-hydroxy-4-(S)-methyl-5-t-butyldimethylsilox y- pentanamide using the reagent benzyltrichloroacetimidate and following the procedure described by Bundle et al. in J. C. S. Chem. Comm. 1981 , 1240.

Preparation of 2-(R)-Methyl-3-(R)-benzyloxy-4-(S)-methyl-5-t-butyl- dimethylsiloxypentanal

This material is prepared from N-methoxy-N -methyl -2- (R)-methyl-3-(R)-benzyloxy-4-(S)-methyl-5-t-butyldimethylsil oxy- pentanamide following the procedure described by Weinreb et al. in Tetrahedron Lett. 1977, 4171.

EXAMPLE 12

General Preparation of 2-(X)-alkyl-3-(X)-alkoxy-4-substituted-5-t- butyldimethylsilyloxypentanals (X = R or S)

Following the procedure given in example 11, a variety of 2-(X)-alkyl-3-(X)-alkoxy-4-substituted-5-t-butyldimethylsily loxy- pentanals (X = R or S) can be prepared. A representative but nonlimiting sampling of the compounds that can be produced in this manner include those in the following table:

TABLE 6-1

Starting Materials Products

TABLE 6-2

EX AMPLE 13

Preparation of 8a-methyl-8a-aza-9-deoxo-10-demethyl-l 1-deoxy- 12,13,14, 15-tetrakisnor-8a-homoerythromycin A

Preparation of 8a-(3-t-butyldimethylsilyloxypropyl)-8a-aza-

9.10.1 1.12.13.14.15-heptanor-8a-homoervthrom vein

To a 100 ml round bottom flask was introduced 370 mg (0.625 mmol) of 8a-aza-9, 10,11 ,12,13, 14, 15-heptanor-8a-homoery- thromycin A, to which was added 15 ml MeOH, 135 mg (0.720 mmol, 1 J5 eq.) of the aldehyde starting material, 3-(t-butyldimethylsilyloxy)- propanaldehyde 65 mg NaH3BCN (0.97 mmol, 1.55 eq.), and 0.400 ml of AcOH. The reaction was stirred at room temperature and monitored by TLC (93 : 7 : 1 CH2Cl2/MeOH/aq. NH3, product is higher Rf than starting material). After 24 hours, the reaction was not complete as judged by TLC, and 65 mg more NaH3BCN (0.97 mmol, 1.55 eq.) was added. After stirring an additional 10 hours, only a small amount of starting material remained as judged by TLC. The solvent was removed under vacuum and the residue was taken up in 95 : 5 : 1 CH2θ2/MeOH/aq. NH3 and chromatographed on silica gel using the same solvent mixture. This afforded 282 mg (59%) of the desired product.

Selected spectral data for 8a-(3-t-butyldimethylsilyloxy- propy l)-8a-aza-9, 10, 11 , 12, 13, 14, 15-heptanor-8a-homoerythromycin A:

iH NMR (400 MHz, CDCI3) δ 4.62 (d, H-l"), 4.32 (d, H- 1 '), 4.06 (dd, H-3), 3.96 (m, H-5"), 3.64 (s, COOCH3), 3.68 (t, H-l 1), 3.49 (H-5), 3.30 (H-2 '), 3.24 (s, OCH3), 2.96 (d, H-4"), 2.78 (dq, H-2), 2.51 (m, H-3'), 2.27 (s, N(CH3)2), 1.28 & 1.18 (singlets, 6-Me and 3"- Me), 1.36, 1.21 , 1.20, 1.13 & 1.04 (methyl doublets), 0.85 & 0.02 (singlets, TBDMS).

FAB MS: 766 (M + H+)

Preparation of 8a-(3-t-butyldimethylsilyloxypropyl)-8a-benzene- sulfonyl-8a-aza-9.10.1 1.12.13.14.15-heptanor-8a-homoervthromycin A

To a 100 ml round bottom flask was introduced 282 mg (0.369 mmol) of 8a-(3-t-butyldimethylsilyloxypropyl)-8a-aza-

9,10,l l ,12,13,14,15-heptanor-8a-homoerythromycin A, to which was added 5 ml CH2CI2, 0.85 ml triethylamine and 0.280 ml of benzenesulfonyl chloride (2.20 mmol, 6.0 eq.). The reaction was stirred at room temperature and monitored by TLC (93 : 7 : 1 CH2θ2/MeOH/aq. NH3, product is higher Rf than starting material). After 2 hours, the reaction was judged to be complete by TLC. The solvent was removed under vacuum and the residue was taken up in 94 : 6 : 1 CH2Cl2/MeOH/aq. NH3 and chromatographed on silica gel using the same solvent mixture. This afforded 235 mg of the desired product (70%).

Selected spectral data for 8a-(3-t-butyldimethylsilyloxy- propyl)-8a-benzenesulfony l-8a-aza-9, 10,11,12,13,14,15 -heptanor-8a- homoerythromycin A:

lH NMR (400 MHz, CDCI3) δ 7.87 (d, C6H5SO2-), 7.45 (m, C6H5SO2-), 4.57 (d, H-l"), 4.33 (d, H-l '), 4.33 (m, H-9), 4.08 (dd, H-3), 3.99 (m, H-5"), 3.67 (s, COOCH3), 3.59 (t, H-l l), 3.31 (dd, H- 2'), 3.23 (s, OCH3), 2.95 (br t, H-4"), 2.55 (dq, H-2), 2.54 (m, H-3'), 2.28 (s, N(CH3)2), 2.24 (d, H-2"), 1.21 & 1.17 (singlets, 6-Me and 3"- Me), 1.27, 1J9, 1.09, 1.03 & 1.02 (methyl doublets), 0.80 & 0.01 (singlets, TBDMS).

13C NMR (100 MHz, CDCI3) δ 176.0, 140.9, 132.0, 128.7, 127.4, 105.3, 96.2, 87.3, 79.8, 77.8, 73.2, 72.7, 70.4, 69.9, 65.5, 65.0, 60.7, 51.8, 50.0, 49.4, 44.5, 41.5, 41.4, 40.3, 37.6, 35.2, 34.5, 28.9, 25.9, 24.4, 21.6, 21.2, 17.8, 10.7, 9.7, -5.4.

FAB MS: 905 (M + H+)

Preparation of 8a-(3-hydroxypropyl)-8a-benzenesulfonyl-8a-aza-

9.10.1 1.12.13.14.15-heptanor-8a-homoervthromvcin A

To a 100 ml round bottom flask was introduced 235 mg (0.260 mmol) of 8a-(3-t-butyldimethylsilyloxypropyl)-8a-

benzenesulfony l-8a-aza-9, 10, 1 1 , 12, 13 , 14, 15-heptanor-8a- homoerythromycin A, to which was added 10 ml THF dried over 3 A molecular sieves, and 0.470 ml 1 M tetrabutylammonium fluoride in THF (0.470 mmol, 1.8 eq.). The reaction was stirred at room temperature and monitored by TLC (93 : 7 : 1 CH2Cl2/MeOH/aq. NH3, product is lower Rf than starting material). After 24 hours, the reaction was judged to be complete by TLC. After the solvent was removed under vacuum, the residue was taken up in 95 : 5 : 1 CH2Cl2/MeOH/aq. NH3 and chromatographed on silica gel using the same solvent mixture. NMR revealed that the chromatographed material was contaminated with tetrabutylammonium salts. This afforded 174 mg (85% yield) of the desired product.

Selected spectral data for 8a-(3-hydroxypropyl)-8a- benzenesulfony l-8a-aza-9, 10,1 1,12,13,14,15-heptanor-8a-homoery- thromycin A:

iH NMR (400 MHz, CDCI3) δ 7.85 (d, C6H5SO2-), 7.45 (m, C6H5SO2-), 4.60 (d, H-l "), 4.32 (d, H-l'), 4.30 (m, H-9), 4.04 (m, H-3), 3.98 (m, H-5"), 3.64 (s, COOCH3), 3.55 (m, H-l 1), 3.32 (H-5), 3.28 (d, H-2'), 3.23 (s, OCH3), 2.95 (br t, H-4"), 2.60 (dq, H-2), 2.48 (m, H-3'), 2.26 (s, N(CH3)2), 2.23 (d, H-2"), 1.18 & 1.15 (singlets, 6- Me and 3"-Me), 1.23, 1.17, 1.09, 1.05 & 1.01 (methyl doublets).

FAB MS: 792 (M + H+)

Preparation of 8a-benzenesulfonyl-8a-aza-9-deoxo-10-demethyl-l 1 - deoxy- 12_.13_.14_. ! 5-tetrakisnor-8a-homoerythromycin A

To a 100 ml round bottom flask was introduced 174 mg (0.220 mmol) of 8a-(3-hydroxypropyl)-8a-benzenesulfonyl-8a-aza- 9,10,1 1 ,12,13, 14, 15-heptanor-8a-homoerythromycin A, to which was added 8.5 ml THF, 4.5 ml MeOH and 1.6 ml 1 N NaOH (1.6 mmol, 7.3 eq.). The reaction was stirred at room temperature and monitored by TLC (93 : 7 : 1 CH2Cl2/MeOH/aq. NH3, product is baseline). After 36

hours, the reaction was judged to be complete by TLC. The reaction mixture was diluted with 25 ml water and brought to pH = 7 with aq. HCl. The solvent was removed under vacuum and the residue was dried for 12 hours under high vacuum. To the residue was added 150 ml of dry THF and the flask was sonicated for 5 minutes to insure proper mixing. To this cloudy mixture was added 370 mg (1.42 mmol, 6.4 eq.) of triphenylphosphine followed by 0.260 ml (267 mg, 1.32 mmol, 6.0 eq.) diisopropyl azodicarboxylate. The reaction was stirred at room temperature and monitored by TLC (93 : 7 : 1 CH2Cl2/MeOH/aq. NH3, product is mid Rf.) After 1 hour the reaction was judged to be complete by TLC (no material remained at the baseline). The solvent was removed under vacuum and the residue was taken up in 94 : 6 : 1 CH2θ2/MeOH/aq. NH3 and chromatographed on silica gel using the same solvent mixture. This afforded 125 mg (75%) of the desired product.

Selected spectral data for 8a-benzenesulfonyl-8a-aza-9- deoxo-10-demethyl-l l-deoxy-12,13,14,15-tetrakisnor-8a- homoerythromycin A:

lH NMR (400 MHz, CDCI3) δ 7.87 (d, C6H5SO2-), 7.45 (m, C6H5SO2-), 4.63 (d, H-l"), 4.40, 4.35 & 3.83 (multiplets, H-9 and H13), 4.36 (d, H-l'), 4J 8 (m, H-3), 3.93 (m, H-5"), 3.50 (m, H-5'), 3.49 (m, H-5), 3.26 (s, OCH3), 2.98 (t, H-4"), 2.57 (dq, H-2), 2.46 (m, H-3'), 2.30 (d, H-2"), 2.27 (s, N(CH3)2), L64 (br d, H-4'), 1.19 & 1.15 (singlets, 6-Me and 3"-Me), 1.21 , 1.15, 1.11, 1.09 & 1.05 (methyl doublets).

13c NMR (100 MHz, CDCI3) δ 175.8, 141.1 , 132.2, 128.8, 127.2, 103.9, 96.1, 87.1 , 78.6, 77.7, 73.9, 72.7, 70.5, 69.6, 65.6, 65.2, 62.6, 51.3, 49.3, 44.9, 43.4, 42.9, 40.4, 34.7, 30.2, 28.9, 23.0, 21.5, 21.1 , 17.8, 12.9, 9.6.

FAB MS: 760 (M + H+)

Preparation of 8a-aza-9-deoxo-10-demethyl-l l -deoxy-12,13, 14,15- tetrakisnor-8a-homoervthromycin A

To a 4 ml screw cap borosilicate glass vial was introduced 33 mg (0.046 mmol) of 8a-benzenesulfonyl-8a-aza-9-deoxo-10- demethyl- 11 -deoxy- 12,13,14,15-tetrakisnor-8a-homoerythromy cin A , 35 mg of 1 ,5-dimethoxynaphthalene, 25 mg of ascorbic acid and 3.5 ml of 95% ethanol. The solution was stirred magnetically, cooled under a vigorous stream of air, and irradiated with a high pressure Hanovia lamp. After 1 hour, the reaction was judged to be complete by thin layer chromatography (94 : 6 : 1 CH2d2/MeOH/aq. NH3, product is lower Rf than starting material). The reaction was added to 150 ml of methylene chloride and extracted with 0J N aq. NaOH. The organic layer was dried over MgSθ4 and concentrated under vacuum. The residue was taken up in 94 : 6 : 1 CH2θ2/MeOH/aq. NH3 and chromatographed on silica gel using the same solvent mixture. This afforded 16 mg (59%) of the desired product.

Selected spectral data for 8a-aza-9-deoxo-10-demethyl-l 1 - deoxy-12,13,14,15-tetrakisnor-8a-homoerythromycin A:

lH NMR (400 MHz, CDCI3) δ 4.77 (d, H-l "), 4.35 (d, H- 1"), 4.21 (d, H-3), 4.15 & 4.0 (m, H-9 and/or 1 1 ), 4.00 (m, H-5"), 3.48 (d, H-5), 3.45 (m, H-5'), 3.28 (s, OCH3), 3J9 (dd, H-2'), 3.00 (t, H-4"), 2.70 (dq, H-2), 2.43 (m, H-3'), 2.33 (d, H-2"), 2.25 (s, N(CH3)2), 1.37 & 1.20 (singlets, 6-Me and 3"-Me), 1.28, 1.19, 1.1 1 , 1 JO & 1.07 (methyl doublets).

High resolution FAB MS: MH+ = 619.4194 (error = 2.5 mmu)

Elemental analysis: Calcd for C31H58N2O10Η2O: C, 58.47; H, 9.50; N, 4.40. Found: C, 58.32; H, 9J3; N, 4.41.

Preparation of 8a-methyl-8a-aza-9-deoxo-10-demethyl-l l-deoxy- π.π. H. lS-tetrakisnor-Sa-homoervthromvcin A:

To a 50 ml round bottom flask was introduced 1 1 mg (0.018 mmol) of 8a-aza-9-deoxo-10-demethyl-l l-deoxy-12,13,14,15- tetrakisnor-8a-homoerythromycin A, to which was added 2 ml MeOH, 0.050 ml 37% aq. formaldehyde (ca. 0.6 mmol, 34 eq.), and 15 mg sodium cyanoborohydride (0.238 mmol, 13 eq.). The reaction was stirred at room temperature and monitored by TLC (93 : 7 : 1 CH2Cl2/MeOH/aq. NH3). After 1 hour, TLC showed complete converstion to a higher Rf spot. The reaction was added to 50 ml of CH2CI2 and extracted with 0.1 N NaOH. The organic layer was dried over MgS04 and concentrated under vacuum. The residue was taken up in 94 : 6 : 1 CH2Cl2/MeOH/aq. NH3 and chromatographed on silica gel using the same solvent mixture. This afforded 8 mg (72%) of the desired product.

Selected spectral data for 8a-methyl-8a-aza-9-deoxo-10- demethy 1- 11 -deoxy- 12,13,14, 15-tetrakisnor-8a-homoery thromycin

lH NMR (400 MHz, CDCI3) δ 4.78 (d, H-l "), 4.36 (d, H- 1'), 4.18 (d, H-3), 3.9 (m, H-l l), 3.9 (m, H-5"), 3.49 (d, H-5), 3.44 (m, H-5'), 3.29 (s, OCH3), 3.19 (dd, H-2'), 3.01 (br t, H-4"), 2.71 (dq, H- 2), 2.46 (m, H-3'), 2.34 (d, H-2"), 2.28 (s, N(CH3)2), 2.21 (s, ring N- CH ₃ ), 1.40 & 1.20 (singlets, 6-Me and 3"-Me), 1.28, 1.20, 1 JO, 1.08 & 0.91 (methyl doublets).

High resolution FAB MS: MH+ = 633.4312 (error = -1.5 mmu)

Elemental analysis: Calcd for C31H58N2O10T/2H2O: C, 59.88; H, 9.58; N, 4.36. Found: C, 59.64; H, 9.35; N, 4.37.

EX AMPLE 14

General Preparation of 13-Membered Azalides

Following the procedure given in example 13, 8a-aza-8a- homo-9,10,l l ,12,13,14,15-heptanorerythromycin A and various trialkylsiloxyaldehydes (which may be prepared as taught in examples 1 through 4) are used as starting materials for 13-membered azalides, as diagrammed below:

R ₃ Si = t-butyldimethylsilyl or t-butyldiphenylsilyl

Examples of the compounds of the invention that can be produced in this manner include those in the following table:

TABLE 7-1

TABLE 7-2

aldehyde macrocycle (R' = PhS0 ₂ -, H or Me)

EX AMPLE 15

Preparation of 8a-benzenesulfony l-8a-aza-9-deoxo- 10-demethyl- 10-(S)- hvdroxy-1 l-deoxy-12J3J4J5-tetrakisnor-8a-homoervthromvcin A

To a 100 ml round bottom flask was introduced 15 mg (0.019 mmol) of 8a-benzenesulf onyl-8a-aza-9-deoxo-l 0-demethyl- 10- (S)-benzyloxy-l l -deoxy-12,13,14,15-tetrakisnor-8a-homoerythromycin A, to which was added 4 ml 95% EtOH, 0.250 ml of AcOH and 50 mg of 10% Pd/C. The reaction was evacuated and filled with H2, then stirred vigorously at room temperature. After 24 hours, TLC (93 : 7 : 1 CH2θ2/MeOH/aq. NH3) showed complete conversion to lower Rf product. The reaction mixture was centrifuged and decanted away from the catalyst, added to 100 ml of CH2CI2, and extracted twice with 0.1 N aq. NaOH. The organic phase was dried with MgSθ4, and the solvent was removed under vacuum. The residue was taken up in 94 : 6 : 1 CH2θ2/MeOH/aq. NH3 and chromatographed on silica gel using the same solvent mixture. This afforded 5 mg (38%) of the desired product.

Selected spectral data for 8a-benzenesulfonyl-8a-aza-9- deoxo- 10-demethyl- 10-(S)-hydroxy- 11 -deoxy- 12, 13, 14,15-tetrakisnor- 8a-homo-erythromycin A:

IH NMR (400 MHz, CDCI3) δ 7.89 (d, 8.6 Hz, 2H), 7.5 (m, 3H), 4.71 (dd, J = 6.1 Hz, 1 1 Hz), 4.66 (d, J = 4.4 Hz, H-l "), 4.56 (br s, IH), 4.35 (d, J = 7.3 Hz, H-l '), 4.33 (br m, IH), 4.16 (br m , IH), 3.94 (m, H-5"), 3.82 (br s, IH), 3.75 (d, J = 1 1.4 Hz, H-l '), 3.50 (m, H-5'), 3.40 (dd, J = 6.5 Hz, 9.44 Hz, IH), 3.30 (d, J = 8.0 Hz, IH), 3.27 (s, OCH3), 2.97 (br t, H-4"), 2.33 (s, N(CH3)2), 1.20 & 1.12 (singlets, 6-Me and 3"-Me), 1.21 (J = 6.1 ), 1.16, 1.15, 1.13 & 1.09 (J = 7.0) (methyl doublets).

High Res FAB MS: MH+ = 775.4055 (error = 0.4 mmu)

Elemental analysis: Calcd for C37H62N2O13S-H2O: C, 56.04; H, 8.14; N, 3.53. Found: C, 56.30; H, 8.10; N, 3.74.

EXAMPLE 16

Preparation of 8a-methyl-8a-aza-9-deoxo- 10-demethyl- 1 1 -deoxy- 12- demethyl- 12-deoxy- 13.14.15-trisnor-8a-homoerythromycin A

Preparation of 8a-(4-t-butyldimethylsilyloxybutyl)-8a-aza-

9.10.1 1.12.13.14.15-heptanor-8a-homoervthromvcin A

To a 100 ml round bottom flask was introduced 370 mg (0.625 mmol) of 8a-aza-9,10,l 1 ,12,13, 14,15-heptanor-8a-homoeryth- romycin A to which was added 15 ml MeOH, 145 mg (0.718 mmol, 1.15 eq.) of the aldehyde starting material, 65 mg NaH3BCN, and 0.400 ml of AcOH. The reaction was stirred at room temperature and monitored by TLC (93 : 7 : 1 CH2Cl2/MeOH/aq. NH3, product is higher Rf than starting material). After 24 hours, the reaction was not quite complete as judged by TLC, and 40 mg more NaH3BCN was added. After stirring an additional 10 hours, no starting material remained as judged by TLC. The solvent was removed under vacuum and the residue was taken up in 95 : 5 : 1 CH2θ2/MeOH/aq. NH3 and chromatographed on silica gel using the same solvent mixture. This afforded 317 mg (65%) of the desired adduct, as well as a small amount of the bis-reductive amination adduct (faster eluting.)

Selected spectral data for 8a-(4-t-butyldimethylsilyloxy- butyl)-8a-aza-9,10,l l,12,13,14,15-heptanor-8a-homoerythromycin A:

lH NMR (400 MHz, CDCI3) δ 4.59 (d, H-l "), 4.32 (d, H- 1'), 4.07 (dd, H-3), 3.98 (m, H-5"), 3.63 (s, COOCH3), 3.57 (t, H-12), 3.49 (H-5), 3.26 (dd, H-2'), 3.24 (s, OCH3), 2.95 (br d, H-4"), 2.79 (dq, H-2), 2.50 (m, H-3'), 2.26 (s, N(CH3)2), 1.28 & 1.17 (singlets, 6- Me and 3"-Me), 1.21 , 1.20, 1.10 & 1.04 (methyl doublets), 0.84 & -0.01 (singlets, TBDMS).

FAB MS: 780 (M + H+)

Preparation of 8a-(4-t-butyldimethylsilyloxybutyl)-8a-benzenesulfonyl-

8a-aza-9J0,l 1 ,12, 13.14.15-heptanor-8a-homoervthromycin A

To a 100 ml round bottom flask was introduced 317 mg (0.406 mmol) of 8a-(4-t-butyldimethylsilyloxybutyl)-8a-aza- 9,10,1 1 ,12, 13,14, 15-heptanor-8a-homoerythromycin A, to which was

added 25 ml CH2CI2, 1 ml triethylamine & 0.317 ml of benzenesulfonyl chloride (2.49 mmol, 6.1 eq.). The reaction was stirred at room temperature and monitored by TLC (93 : 7 : 1 CH2Cl2/MeOH/aq. NH3, product is higher Rf than starting material). After 14 hours, the reaction was judged to be complete by TLC. The solvent was removed under vacuum and the residue was taken up in 95 : 5 : 1 CH2θ2/MeOH/aq. NH3 and chromatographed on silica gel using the same solvent mixture. This afforded 284 mg (76%) of the desired product.

Selected spectral data for 8a-(4-t-butyldimethylsilyloxy- butyl)-8a-benzenesulfonyl-8a-aza-9, 10,11 ,12, 13, 14,15-heptanor-8a- homoeryth-romycin A:

lH NMR (400 MHz, CDCI3) δ 7.85 (d, C6H5SO2-), 7.45 (m, C6H5SO2-), 4.59 (d, H-l"), 4.33 (d, H-l '), 4.30 (m, H-9), 4.08 (dd, H-3), 3.98 (m, H-5"), 3.66 (s, COOCH3), 3.56 (t, H-12), 3.36 (H-5), 3.30 (dd, H-2'), 3.24 (s, OCH3), 2.95 (br t, H-4"), 2.59 (dq, H-2), 2.53 (m, H-3'), 2.28 (s, N(CH3)2), 2.26 (d, H-2"), 1.20 & 1.16 (singlets, 6- Me and 3"-Me), 1.26, 1.19, 1.11, 1.04 & 1.03 (methyl doublets), 0.85 & 0.00 (singlets, TBDMS).

FAB MS: 925 (M + Li+)

Preparation of 8a-(4-hydroxybutyl)-8a-benzenesulfonyl-8a-aza-

9.10.1 1.12.13.14.15-heptanor-8a-homoerythromvcin A

To a 100 ml round bottom flask was introduced 284 mg (0.309 mmol) of 8a-(4-t-butyldimethylsilyloxybutyl)-8a- benzenesulf ony l-8a-aza-9, 10,11,12,13,14,15 -heptanor-8a- homoerythromycin A, to which was added 10 ml THF dried over 3 A molecular sieves, and 0.570 ml 1 M tetrabutylammonium fluoride in THF (0.570 mmol, 1.84 eq.). The reaction was stirred at room temperature and monitored by TLC (93 : 7 : 1 CH2Cl2/MeOH/aq. NH3, product is lower Rf than starting material). After 5 hours, the reaction

was judged to be complete by TLC. The reaction mixture was diluted with 25 ml methylene chloride and extracted with water and then brine. The organic layer was dried over magnesium sulfate and the solvent was removed under vacuum. The residue was taken up in 95 : 5 : 1 CH2Cl2/MeOH/aq. NH3 and chromatographed on silica gel using the same solvent mixture. NMR revealed that the chromatographed material was contaminated with tetrabutylammonium salts. The material was dissolved in 50 ml methylene chloride and extracted twice with 0.5 N NaOH, followed by drying with magnesium sulfate and removal of solvent under vacuum. This afforded 223 mg (90%) of the desired product.

Selected spectral data for 8a-(4-hydroxybutyl)-8a- benzenesulf ony l-8a-aza-9, 10, 11 , 12, 13 , 14, 15 -heptanor-8a-homo- erythromycin A:

IH NMR (400 MHz, CDCI3) δ 7.86 (d, C6H5SO2-), 7.45 (m, C6H5SO2-), 4.60 (d, H-l"), 4.34 (d, H-l '), 4.26 (m, H-9), 4.05 (dd, H-3), 3.98 (m, H-5"), 3.64 (s, COOCH3), 3.60 (m, H-12), 3.37 (H-5), 3.24 (s, OCH3), 2.95 (br t, H-4"), 2.65 (dq, H-2), 2.50 (m, H-3'), 2.27 (s, N(CH3)2), 2.26 (d, H-2"), 1.19 & 1.17 (singlets, 6-Me and 3"-Me), 1.24, 1 J 8, 1 JO, 1.07 & 1.03 (methyl doublets).

FAB MS: 812 (M + Li+), 806 (M + H+)

Preparation of 8a-benzenesulfonyl-8a-aza-9-deoxo-l 0-demethyl- 11- dehydroxy- 12-demethyl- 12-dehydroxy- 13,14, 15-trisnor-8a-homo- ervthromycin A

To a 100 ml round bottom flask was introduced 223 mg (0.275 mmol) of 8a-(4-hydroxybutyl)-8a-benzenesulfonyl-8a-aza- 9,10,1 1 ,12, 13, 14, 15-heptanor-8a-homoerythromycin A, to which was added 1 1 ml THF, 5.5 ml MeOH and 2 ml 1 N NaOH (2 mmol, 7.3 eq.). The reaction was stirred at room temperature and monitored by TLC (93 : 7 : 1 CH2Cl2/MeOH/aq. NH3, product is baseline). After 36

hours, the reaction was judged to be complete by TLC. The reaction mixture was diluted with 25 ml water and brought to pH = 7 with aq. HCl. The solvent was removed under vacuum and the residue was dried for 12 hours under high vacuum. To the residue was added 200 ml of dry THF and the flask was sonicated for 5 minutes to insure proper mixing. To this cloudy mixture was added 200 mg (0.764 mmol, 2.8 eq.) of triphenylphosphine (PI13P) followed by 0J40 ml (144 mg, 0.71 1 mmol, 2.6 eq.) diisopropyl azodicarboxylate (DIAD). The reaction was stirred at room temperature and monitored by TLC (93 : 7 : 1 CH2Cl2/MeOH/aq. NH3, product is mid Rf.) After 1 hour the reaction was judged to be only about 25% complete by TLC. Another 220 mg (0.840 mmol, 3J eq.) of triphenylphosphine and 0.150 ml of diisopropyl azodicarboxylate (154 mg, 0.762 mmol, 2.8 eq.)was added. After 1 hour the reaction was judged to be complete by TLC (no material remained at the baseline). The solvent was removed under vacuum and the residue was taken up in 94 : 6 : 1 CH2θ2/MeOH/aq. NH3 and chromatographed on silica gel using the same solvent mixture. This afforded 125 mg (58%) of the desired product.

Selected spectral data for 8a-benzenesulfonyl-8a-aza-9- deoxo- 10-demethyl- 11 -dehydroxy-12-demethyl- 12-dehydroxy- 13,14,15-trisnor-8a-homoerythromycin A:

lH NMR (400 MHz, CDCI3) δ 7.85 (d, C6H5SO2-), 7.45 (m, C6H5SO2-), 4.62 (d, H-l"), 4.42, 4.34 & 3.94 (multiplets, H-9 and H12), 4.46 (d, H-l'), 4.25 (m, H-3), 3.93 (m, H-5"), 3.51 (m, H-5'), 3.44 (m, H-5), 3.29 (s, OCH3), 3.24 (dd, H-2'), 2.63 (dq, H-2), 2.44 (m, H-3'), 2.31 (d, H-2"), 2.26 (s, N(CH3)2), 1.64 (br d, H-4'), 1.21 & 1.19 (singlets, 6-Me and 3"-Me), 1.23, 1.20, 1.13, 1.06 & 0.95 (methyl doublets).

13c NMR (100 MHz, CDCI3) δ 175.6, 141.2, 132.1, 128.9, 127.1, 102.6, 95.6, 85.2, 78.2, 77.8, 73.8, 72.9, 70.6, 69.5, 65.7,

65.4, 62.8, 50.4, 49.3, 44.2, 44.1, 42.4, 42.0, 40.4, 34.8, 28.7, 26.8, 25.4, 22.5, 21.6, 21.2, 20.0, 17.8, 12.8, 9.4.

FAB MS: 775 (M + H+)

Preparation of 8a-aza-9-deoxo- 10-demethyl- 1 1-dehydroxy- 12- demethyl- 12-dehydroxy- 13.14.15-trisnor-8a-homoerythromycin A: To a 50 ml round bottom flask was introduced 120 mg (0J55 mmol) of 8a-benzenesulfonyl-8a-aza-9-deoxo-10-demethyl-l l - dehydroxy- 12-demethyl- 12-dehydroxy- 13,14, 15-trisnor-8a- homoerythromycin A and 5 ml sieve dried THF and the mixture was cooled in an acetone/dry ice bath. Lithium naphthalide solution (prepared by adding 69 mg (10 mmol, 2 eq.) of finely chopped lithium to 5 ml of a 1 M solution of naphthalene in THF, sonicating until it turned green, and then stirring for 30 minutes at room temperature) was added dropwise until the green color persisted, and the the reaction was allowed to stir for 10 minutes, with an additional drop of naphthalide solution added periodically as the green color faded. The reaction was then quenched with 0.5 ml of saturated aqueous NaHC03 and allowed to warm to room temperature. The reaction was added to 150 ml of CH2CI2 and extracted with 0J N NaOH. The organic layer was dried over MgS04 and concentrated under vacuum. The residue was taken up in 94 : 6 : 1 CH2Cl2/MeOH/aq. NH3 and chromatographed on silica gel using the same solvent mixture. This afforded 80 mg (80%) of the desired product.

Selected spectral data for 8a-aza-9-deoxo-l 0-demethyl- 1 1 - dehydroxy- 12-demethyl- 12-dehydroxy- 13,14,15-trisnor-8a-homo- erythromycin A:

lH NMR (400 MHz, CDCI3) δ 4.66 (d, H-l"), 4.45 (d, H- 3), 4.41 (d, H-l'), 4.14 (m, H-12), 3.99 (m, H-5"), 3.93 (d, H-12), 3.64 (d, H-5), 3.47 (m, H-5'), 3.29 (s, OCH3), 3.18 (dd, H-2'), 2.99 (d, H- 4"), 2.64 (dq, H-2), 2.42 (m, H-3'), 2.32 (d, H-2"), 2.24 (s, N(CH3)2),

2.00 (m, H-4), 1.29 & 1.20 (singlets, 6-Me and 3"-Me), 1.28, 1.19, 1.14, 1.12 & 1.09 (methyl doublets).

13C NMR (100 MHz, CDCI3) δ 176.0, 102.9, 96.1 , 82.5, 78.8, 78.0, 75.3, 72.8, 70.8, 69.1, 65.6, 65.4, 65.0, 49.4, 49.3, 44.8, 42.4, 41.8, 40.3, 40.2, 35.1 , 28.7, 27.1 , 26.9, 24.7, 21.6, 21.3, 21.1 , 18.1 , 13.3, 9.6.

FAB MS: 634 (M + H+)

Preparation of 8a-methyl-8a-aza-9-deoxo-l 0-demethyl- 1 1-dehydroxy- 12-demethyl- 12-dehvdroxy- 13.14.15-trisnor-8a-homoervthromvcin A :

To a 50 ml round bottom flask was introduced 43 mg (0.068 mmol) of 8a-aza-9-deoxo- 10-demethyl- 11 -dehydroxy-12- demethyl-12-dehydroxy-13,14,15-trisnor-8a-homoerythromycin A, to which was added 5 ml MeOH, 0.050 ml 37% aq. foπnaldehyde (ca. 0.6 mmol, 9 eq.), and 15 mg sodium cyanoborohydride (0.238 mmol, 3.5 eq.). The reaction was stirred at room temperature and monitored by TLC (93 : 7 : 1 CH2Cl2/MeOH/aq. NH3). After 1 hour, TLC showed no starting material and two higher Rf spots. The reaction was added to 50 ml of CH2CI2 and extracted with 0.1 N NaOH. The organic layer was dried over MgSθ4 and concentrated under vacuum. The residue was taken up in 94 : 6 : 1 CH2Cl2/MeOH/aq. NH3 and chromatographed on silica gel using the same solvent mixture. This afforded 16 mg (37%) of the higher Rf spot, which proved to be the desired product and 22 mg (51 %) of the lower spot, which proved to be acyclic methyl ester resulting from opening of the lactone with methanol.

Selected spectral data for 8a-methyl-8a-aza-9-deoxo-10- demethy 1- 1 1 -dehydroxy- 12-demethyl- 12-dehydroxy- 13,14,15-trisnor- 8a-homoerythromycin A:

IH NMR (400 MHz, CDCI3) δ 4.85 (d, H-l "), 4.70 (d, H- 3), 4.32 (d, H-l '), 4.11 (m, H-12), 4.01 (m, H-5"), 3.95 (d, H-12), 3.63

(d, H-5), 3.42 (m, H-5'), 3.27 (s, OCH3), 3J7 (dd, H-2'), 2.98 (br t, H- 4"), 2.75 (dq, H-2), 2.45 (m, H-3'), 2.32 (d, H-2"), 2.27 (s, ring N- CH ₃ ), 2.24 (s, N(CH3)2), 2.09 (m, H-4), 1.42 & 1.20 (singlets, 6-Me and 3"-Me), 1.32, 1.20, 1.17, 1.16 & 0.85 (methyl doublets).

FAB MS: 647 (M + H+)

Elemental analysis: Calcd for C33H62N2O10-1/2H2O: C, 60.43; H, 9.68; N, 4.27. Found: C, 59.87, 60.07; H, 9.61, 9.85; N, 4.59, 4.36.

EXAMPLE 17

General Preparation of 14-Membered Azalides

Following the procedure given in Example 13, 8a-aza-8a- homo-9,10,l l ,12,13,14,15-heptanorerythromycin A and various trialkylsioloxyaldehydes (which may be prepared as taught in examples 4, 6 and 12) are used as starting materials for 14-membered azalides, as diagrammed below:

ilyl lyl

where Rl is benzenesulfonyl, hydrogen or methyl; one of R-2 and R is hydrogen and the other is hydrogen or Ci to C7 alkyl, cycloalkyl or aryl, which may be substituted with Rl°0, C ₆ H ₅ S0 ₂ HN or F; R , R , R6 and R7 are hydrogen, Ci to C7 alkyl, fluoroalkyl, cycloalkyl or aryl, RlOo, C ₆ H ₅ S0 ₂ HN or F; RIO is benzyl, Ci to C7 alkyl, fluoroalkyl, cycloalkyl or aryl.

Examples of the compounds that can be produced in this manner include those in the following table:

TABLE 8-1

aldehyde (R' = Me, Bn) macrocycle (R = PhS0 ₂ -, H or Me)

Following the procedure given in example 13, 8a-aza-8a-homo- 9,10,11,12,13, 14, 15-heptanorerythromycin A and various trialkylsiloxyaldehydes (which may be prepared as taught in examples 4, 6 and 12) are used as starting materials for 14-membered azalides, as diagrammed below:

TABLE 8-2

TABLE 8-3

EX AMPLE 18

Preparation of 8a-methyl-8a-aza-9-deoxo- 10-demethyl- 11-deoxy- 12- demethyl- 12-deox v- 14.15-bisnor-8a-homoervthromycin A

Preparation of 8a-(5-t-butyldimethylsilyloxypentyl)-8a-aza-

9, 10, 1 1 , 12, 13, 14, 15-heptanor-8a-homoerythromycin A

To a 100 ml round bottom flask was introduced 332 mg (0.625 mmol) of 8a-aza-9,10,l l ,12,13,14,15-heptanor-8a-homo- erythromycin A, to which was added 15 ml MeOH, 150 mg (0.694 mmol, 1.11 eq.) of the aldehyde starting material, 65 mg NaH3BCN (0.97 mmol, 1.55 eq.), and 0.400 ml of AcOH. The reaction was stirred at room temperature and monitored by TLC (93 : 7 : 1 CH2θ2/MeOH/aq. NH3, product is higher Rf than starting material). After 24 hours, the reaction was not complete as judged by TLC, and 130 mg (0.601 mmol, 0.96 eq.) of the aldehyde and 65 mg more NaH3BCN (0.97 mmol, 1.55 eq.) was added. After stirring an additional 10 hours, only a small amount of starting material remained as judged by TLC. The solvent was removed under vacuum and the residue was taken up in 95 : 5 : 1 CH2θ2/MeOH/aq. NH3 and chromatographed on silica gel using the same solvent mixture. This afforded 271 mg (72% corrected for recovered starting material) of the desired adduct, and 40 mg recovered starting material.

Selected spectral data for 8a-(5-t-butyldimethylsilyloxy- penty l)-8a-aza-9, 10, 1 1 , 12, 13, 14, 15-heptanor-8a-homoerythromycin A:

IH NMR (400 MHz, CDCI3) δ 4.62 (d, H-l "), 4.37 (d, H- 1'), 4.10 (dd, H-3), 4.00 (m, H-5"), 3.63 (s, COOCH3), 3.57 (t, H-13), 3.51 (H-5), 3.26 (s, OCH3), 2.97 (br d, H-4"), 2.82 (dq, H-2), 2.50 (m, H-3'), 2.26 (s, N(CH3)2), 1.29 & 1.19 (singlets, 6-Me and 3"-Me), 1.22, 1.21 , 1.11 & 1.08 (methyl doublets), 0.85 & 0.02 (singlets, TBDMS).

FAB MS: 794 (M + H+)

Preparation of 8a-benzenesulfonyl-8a-(5-t-butyldimethylsilyloxypentyl)-

8a-aza-9J0J 1.12J 3J4J 5-heptanor-8a-homoerythromycin A:

To a 100 ml round bottom flask was introduced 271 mg (0.342 mmol) of 8a-(5-t-butyldimethylsilyloxypentyl)-8a-aza-

9,10,1 1 ,12, 13, 14, 15-heptanor-8a-homoerythromycin A, to which was added 5 ml CH2CI2, 0.8 ml triethylamine & 0.271 ml of benzene¬ sulfonyl chloride (2J3 mmol, 6.2 eq.). The reaction was stirred at room temperature and monitored by TLC (93 : 7 : 1 CH2θ2/MeOH/aq. NH3, product is higher Rf than starting material). After 36 hours, the reaction was judged to be complete by TLC. The solvent was removed under vacuum and the residue was taken up in 94 : 6 : 1 CH2Cl2/MeOH/aq. NH3 and chromatographed on silica gel using the same solvent mixture. This afforded 342 mg of the desired product contaminated with triethylamine, but deemed sufficiently pure for use in the next reaction.

Selected spectral data for 8a-benzenesulfonyl-8a-(5-t-butyl- dimethy lsi ly loxypenty l)-8a-aza-9 , 10,11,12,13,14,15 -heptanor-8a-homo- erythromycin A:

H NMR (400 MHz, CDCI3) δ 7.86 (d, C6H5SO2-), 7.45 (m, C6H5SO2-), 4.60 (d, H-l"), 4.34 (d, H-l'), 4.29 (m, H-9), 4.08 (dd, H-3), 3.98 (m, H-5"), 3.67 (s, COOCH3), 3.55 (t, H-13), 3.30 (dd, H- 2'), 3.25 (s, OCH3), 2.95 (br t, H-4"), 2.61 (dq, H-2), 2.52 (m, H-3'), 2.28 (s, N(CH3)2), 2.26 (d, H-2"), 1.20 & 1.16 (singlets, 6-Me and 3"- Me), 1.26, 1 J9, 1.11, 1.04 & 1.03 (methyl doublets), 0.85 & 0.00 (singlets, TBDMS).

13C NMR (100 MHz, CDCI3) δ 176.0, 141.2, 132.0, 128.7, 127.3, 126.3, 105.0, 96.2, 86.7, 79.9, 77.8, 73.4, 72.7, 70.5, 69.8, 65.5, 65.1, 63.0, 51.8, 50.8, 49.4, 44.6, 44.5, 41.5, 40.3, 37.6, 35.2, 32.4, 31.3, 28.9, 26.0, 24.2, 23.5, 21.6, 21.5, 21.2, 17.8, 10.7, 10.0, -5.3.

FAB MS: 934 (M + H+)

Preparation of 8a-benzenesulfonyl-8a-(5-hydroxypentyl)-8a-aza-

9.10.1 1.12.13.14.15-heptanor-8a-homoervthromvcin A

To a 100 ml round bottom flask was introduced 342 mg (0.367 mmol) of 8a-benzenesulfonyl-8a-(5-t-butyldimethyl- sily loxypenty l)-8a-aza-9, 10, 1 1 , 12, 13 , 14, 15-heptanor-8a-homo- erythromycin A, to which was added 10 ml THF dried over 3 A molecular sieves, and 0.540 ml 1 M tetrabutylammonium fluoride in THF (0.540 mmol, 1.47 eq.). The reaction was stirred at room temperature and monitored by TLC (93 : 7 : 1 CH2Cl2/MeOH/aq. NH3, product is lower Rf than starting material). After 24 hours, the reaction was judged to be complete by TLC. After the solvent was removed under vacuum, the residue was taken up in 94 : 6 : 1 CH2θ2/MeOH/aq. NH3 and chromatographed on silica gel using the same solvent mixture. NMR revealed that the chromatographed material was contaminated with tetrabutylammonium salts. This afforded 210 mg (70% yield) of the desired product.

Selected spectral data for 8a-benzenesulfonyl-8a-(5- hydroxypentyl)-8a-aza-9, 10, 11 , 12, 13 , 14, 15-heptanor-8a- homoerythromycin A:

lH NMR (400 MHz, CDCI3) δ 7.85 (d, C6H5SO2-), 7.45 (m, C6H5SO2-), 4.59 (d, H-l "), 4.33 (d, H-l '), 4.26 (m, H-9), 4.05 (m, H- 3), 3.98 (m, H-5"), 3.65 (s, COOCH3), 3.58 (t, H-13), 3.37 (H-5), 3.24 (s, OCH3), 2.62 (dq, H-2), 2.51 (m, H-3'), 2.27 (s, N(CH3)2), 2.23 (d, H-2").

FAB MS: 820 (M + H+)

Preparation of 8a-benzenesulfonyl-8a-aza-9-deoxo-l 0-demethyl -1 1- deoxy- 12-demethyl- 12-deoxy- 14,15-bisnor-8a-homoerythromycin A To a 100 ml round bottom flask was introduced 210 mg (0.257 mmol) of 8a-benzenesulfonyl-8a-(5-hydroxypentyl)-8a-aza- 9,10,1 1,12, 13, 14, 15-heptanor-8a-homoerythromycin A, to which was added 5 ml THF, 5 ml MeOH and 2 ml 1 N NaOH (2 mmol, 7.8 eq.). The reaction was stirred at room temperature and monitored by TLC

(93 : 7 : 1 CH2Cl2/MeOH/aq. NH3, product is baseline). After 36 hours, the reaction was judged to be complete by TLC. The reaction mixture was diluted with 25 ml water and brought to pH = 7 with aq. HCl. The solvent was removed under vacuum and the residue was dried for 12 hours under high vacuum. To the residue was added 200 ml of dry THF and the flask was sonicated for 5 minutes to insure proper mixing. To this cloudy mixture was added 400 mg (1.53 mmol, 6.0 eq.) of triphenylphosphine followed by 0.280 ml (288 mg, 1.42 mmol, 5.5 eq.) diethyl azodicarboxylate. The reaction was stirred at room temperature and monitored by TLC (93 : 7 : 1 CH2Cl2/MeOH/aq. NH3, product is mid Rf.) After 1 hour the reaction was judged to be incomplete by TLC. Another 200 mg (0.764 mmol, 3.0 eq.) of triphenylphosphine and 0.140 ml of diisopropyl azodicarboxylate (DEAD) (144 mg, 0.711 mmol, 2.8 eq.)was added. After 1 hour the reaction was judged to be complete by TLC (no material remained at the baseline). The solvent was removed under vacuum and the residue was taken up in 94 : 6 : 1 CH2θ2/MeOH/aq. NH3 and chromatographed on silica gel using the same solvent mixture. This afforded 116 mg (57%) of the desired product.

Selected spectral data for 8a-benzenesulfonyl-8a-aza-9- deoxo- 10-demethyl- 11 -deoxy- 12-demethyl- 12-deoxy-l 4, 15-bisnor-8a- homoerythromycin A:

IH NMR (400 MHz, CDCI3) δ 7.82 (d, C6H5SO2-), 7.45 (m, C6H5SO2-), 4.72 (d, H-l "), 4.43, 4.1 & 4.0 (multiplets, H-9 and H13), 4.46 (d, H-l'), 4.08 (m, H-3), 4.0 (m, H-5"), 3.55 (m, H-5'), 3.49 (m, H-5), 3.27 (s, OCH3), 3.0 (br d, H-4"), 2.63 (dq, H-2), 2.49 (m, H-3'), 2.32 (d, H-2"), 2.26 (s, N(CH3)2), 1-64 (br d, H-4'), 1.16, 1.01 & 0.97 (methyl doublets).

FAB MS: 788 (M + H+)

Preparation of 8a-aza-9-deoxo- 10-demethyl- 11 -deoxy- 12-demethyl- 12- deoxy- 14, 15-bisnor-8a-homoerythromycin A

Lithium 4,4'-bis-t-butylbiphenylide solution was prepared by adding 35 mg (5 mmol, 5 eq.) of finely chopped lithium to a solution of 273 mg 4,4'-bis-t-butylbiphenyl (1.03 mmol) in 5 ml of dry THF. The solution was sonicated until it turned green and then stirred for 1 hour in an ice bath.

To a 50 ml round bottom flask was introduced 89 mg (0.113 mmol) of 8a-benzenesulfonyl-8a-aza-9-deoxo-l 0-demethyl- 1 1 - deoxy- 12-demethyl- 12-deoxy- 14, 15-bisnor-8a-homoerythromycin Aand 5 ml sieve dried THF and the mixture was cooled in an acetone/dry ice bath. The lithium 4,4'-bis-t-butylbiphenylide solution prepared as described above was added dropwise until the green color persisted, and the the reaction was allowed to stir for 10 minutes, with an additional drop of biphenylide solution added periodically as the green color faded. The reaction was then quenched with 0.5 ml of saturated aqueous NaHC03 and allowed to warm to room temperature. The reaction was added to 150 ml of CH2CI2 and extracted with 0J N NaOH. The organic layer was dried over MgSθ4 and concentrated under vacuum. The residue was taken up in 94 : 6 : 1 CH2θ2/MeOH/aq. NH3 and chromatographed on silica gel using the same solvent mixture. This afforded 29 mg (40%) of the desired product.

Selected spectral data for 8a-aza-9-deoxo-l 0-demethyl- 1 1 - deoxy- 12-demethyl- 12-deoxy- 14, 15-bisnor-8a-homoerythromycin A:

lH NMR (400 MHz, CDCI3) δ 4.76 (d, H-l "), 4.40 (d, H-3), 4.38 (d, H-l '), 4J2 (m, H-12), 4.02 (m, H-5"), 3.93 (d, H-13), 3.56 (d, H-5), 3.49 (m, H-5'), 3.31 (s, OCH3), 3J9 (dd, H-2'), 3.00 (d, H-4"), 2.70 (dq, H-2), 2.43 (m, H-3'), 2.35 (d, H-2"), 2.25 (s, N(CH3)2), 2.05 (m, H-4), 1.36 & 1.20 (singlets, 6-Me and 3"-Me), 1.29, 1.19, 1.10, 1.08 & 1.06 (methyl doublets).

FAB MS: 647 (M + H+)

Preparation of 8a-methyl-8a-aza-9-deoxo-l 0-demethyl- 11 -deoxy- 12- demethyl-12-deoxy-14,15-bisnor-8a-homoerythromycin A

To a 50 ml round bottom flask was introduced 18 mg (0.028 mmol) of 8a-aza-9-deoxo-10-demethyl-l l-deoxy-12-demethyl- 12-deoxy-14,15-bisnor-8a-homoerythromycin A, to which was added 5 ml MeOH, 0.050 ml 37% aq. formaldehyde (ca. 0.6 mmol, 9 eq.), and 15 mg sodium cyanoborohydride (0.238 mmol, 3.5 eq.). The reaction was stirred at room temperature and monitored by TLC (93 : 7 : 1 CH2Cl2/MeOH/aq. NH3). After 1 hour, TLC showed complete converstion to a higher Rf spot. The reaction was added to 50 ml of CH2CI2 and extracted with 0.1 N NaOH. The organic layer was dried over MgSθ4 and concentrated under vacuum. The residue was taken up in 94 : 6 : 1 CH2Cl2/MeOH/aq. NH3 and chromatographed on silica gel using the same solvent mixture. This afforded 16 mg (90%) of the desired product.

Selected spectral data for 8a-methyl-8a-aza-9-deoxo-10- demethyl-11 -deoxy- 12-demethyl- 12-deoxy- 14,15-bisnor-8a- homoerythromycin A:

lH NMR (400 MHz, CDCI3) δ 4.90 (d, H-l "), 4.41 (d, H-l'), 4.29 (d, H-3), 4.06 (m, H-13), 4.04 (m, H-5"), 3.59 (d, H-5), 3.49 (m, H-5'), 3.32 (s, OCH3), 3.01 (br t, H-4"), 2.74 (dq, H-2), 2.41 (m, H-3'), 2.35 (d, H-2"), 2.25 (s, N(CH3)2), 2.21 (s, ring N-CH ₃ ), 2.09 (m, H-4), 1.39 & 1.21 (singlets, 6-Me and 3"-Me), 1.30, 1.22, 1.13, 1.07 & 0.87 (methyl doublets).

Elemental analysis: Calcd for C34H64N2O10: C, 61.79; H, 9.76; N, 4.24. Found: C, 61.62, 61.70; H, 9.79, 9.84; N, 4.47, 4.33.

FAB MS: 662 (M + H+)

EX AMPLE 19

General Preparation of 15-Membered Azalides

Following the procedure given in example 13, 8a-aza-8a- homo-9,10,l l,12,13,14,15-heptanorerythromycin A and various trialkylsiloxyaldehydes (which may be prepared as taught in examples 4 through 12) are used as starting materials for 15-membered azalides, as diagrammed below:

A representative but nonlimiting sampling of the compounds that can be produced in this manner include those in the following table:

TABLE 9-1

TABLE 9-2

TABLE 9-3

TABLE 9-4 )

TABLE 9-5

aldehyde (R' = Me, Bn) macrocycle (R = PhS0 ₂ -, H or Me)

TABLE 9-6

)

TABLE 9-6 cont'd

aldehyde macrocycle (R = PhS0 ₂ -, H or Me)

TABLE 9-7

aldehyde macrocycle (R = PhS0 ₂ -, H or Me)

TABLE 9-8

aldehyde macrocycle (R = PhS0 ₂ -, H or Me)

TABLE 9-8 cont'd

aldehyde macrocycle (R = PhS0 ₂ -, H or Me)

TABLE 9-9

aldehyde macrocycle (R = PhS0 ₂ -, H or Me)

TABLE 9-9 cont'd

aldehyde macrocycle (R = PhS0 ₂ -, H or Me)

TABLE 9-10

)

TABLE 9-10 cont'd

)

TABLE 9-11

)

TABLE 9-1 1 cont'd

aldehyde macrocycle (R = PhS0 ₂ -, H or Me)

20

25

30

EXAMPLE 20

Preparation of 8a-methyl-8a-aza-9-deoxo-14,15-bisnor-8a-homo- erythromvcin A

Following the procedure of Hunt and Tyler in J. Chem. Soc. Perkin Trans. 2, 1990 2157, a 50 ml round bottom flask is charged with 50 mg of 8a-methyl-8a-aza-9-deoxo-14,15-bisnor-8a-homo- erythromycin A 1 1-0,12-O-carbonate, to which is added 4 ml THF and 1 ml of 0.1 N aq. NaOH. After 41 hours, the reaction is added to ethyl acetate and extracted with water. The organic phase is dried with MgSθ4, and the solvent is removed under vacuum. The residue is taken up in 94 : 6 : 1 CH2θ2/MeOH/aq. NH3 and chromatographed on silica gel using the same solvent mixture. This affords the desired product 8a-methyl-8a-aza-9-deoxo-14,15-bisnor-8a-homoerythromycin A.

EX AMPLE 21

Preparation of 2-(RV3-(S)-4-(R)-trialkoxy-5-azidopentanal

Preparation of 2-(R)-3-(S)-4-(R)-Trimethoxy-5-azidopentanal-l ,3- dithiane

To a 100 ml round bottom flask was introduced 337 mg (1.29 mmol) of 2-(R)-3-(S)-4-(R)-trimethoxy-5-hydroxypentanal-l ,3- dithiane(prepared as described in example 5), to which was added 25 ml dry CH2CI2 and 1.5 ml of triethylamine. This mixture was stirred in an ice bath and 0.210 ml (1.84 mmol, 1.4 eq.) of methanesulfonyl chloride was added dropwise. The reaction was stirred for 1 hour at 0°C, after which time the reaction was diluted with 300 ml of CH2CI2 and extracted twice with 50 ml of water, twice with 50 ml of 0.1 N HCl, twice with 50 ml aq. sat. NaHCθ3 and once with 50 ml of brine. The organic layer was dried over magnesium sulfate and the solvent was removed under vacuum. To the crude residue was added 6 ml of benzene and 800 mg of tetra-n-butylammonium azide (2.8 mmol, 2.2 eq.). The reaction was heated at 65°C for 18 hours, after which time the reaction was diluted with 300 ml of CH2CI2 and extracted twice

with 50 ml of water and once with 50 ml of brine. The organic layer was dried over MgS04 and the solvent was removed under vacuum. The residue was chromatographed on silica, eluting with 1 1 % ethyl acetate/hexane. This afforded 290 mg (85% for two steps) of 2-(R)-3- (S)-4-(R)-trimethoxy-5-azidopentanal- 1 ,3-dithiane.

Preparation of 2-(R -3-(SV4-(RVTrimethoxy-5-azidopentanal

To a 100 ml round bottom flask was introduced 69 mg (0.22 mmol) of 2-(R)-3-(S)-4-(R)-trimethoxy-5-azidopentanal-l ,3- dithiane, to which was added 1.5 ml acetone, 1.5 ml acetonitrile, and 0.5 ml of water. To this mixture was added 0.25 ml of 2,4,6-collidine and 0.1 15 ml of Mel (1.85 mmol, 8.4 eq.). The reaction was heated at 55°C for 7 hours, after which time the reaction was diluted with 300 ml of CH2CI2 and extracted twice with 50 ml of water and once with 50 ml of brine. The organic layer was dried over MgSθ4 and the solvent was removed under vacuum. The residue was chromatographed on silica, eluting with 20% ethyl acetate/hexane. This afforded 26 mg (52%) of 2-(R)-3-(S)-4-(R)-trimethoxy-5-azidopentanal.

Selected spectral data for 2-(R)-3-(S)-4-(R)-trimethoxy-5- azidopentanal.:

IH NMR (400 MHz, CDCI3) δ 9.72 (d, J= 0.7 Hz, 1 H), 3.79 (d, J = 4.4 Hz, 1 H), 3.66 (dd, J = 3.5 Hz, 4.5 Hz, 2 H), 3.50 (s, 3 H), 3.49 (s, 3 H), 3.49 (m, 1 H), 3.43 (m, 1 H), 3.35 (s, 3 H).

Preparation of 2-(R)-3-(SV4-( ^' RVTribenzyloxy-5-azidopentanal Starting with 2-(R)-3-(S)-4-(R)-tribenzyloxy-5- hydroxypentanal-l ,3-dithiane (prepared as described in example 5), the procedures given above are followed to prepare 2-(R)-3-(S)-4-(R)- tribenzyloxy-5-azidopentanal.

EXAMPLE 22

General Preparation of Carbohydrate Derived Azidoalkanals

Using the procedure of example 21 , other monosaccharides can be converted into an azidoalkanal. A representative but nonlimiting sampling of the compounds that can be produced in this manner include those in the following table:

TABLE 10-1

Azido Aldehyde

Starting Carbohydrate R = Me or Bn

TABLE 10-2

TABLE 10-3

Azido Aldehyde

Starting Carbohydrate R = Me or Bn

C H ₃ OH

EXAMPLE 23

Preparation of 2-(R)-hexyl-3-(R)-hydroxy-4-hydroxy-4-methyl-5- azidopentanal 3-0.4-O-acetonide

cat. Os0 ₄ , NMO

Preparation of 2-(R)-hexyl-3-(R)-hydroxy-4-methyl-4-methane- sulfonyloxymethylbutyrolactone

2-(R)-Hexyl-3-(R)-hydroxy-4-methyl-4-hydroxymethyl- butyrolactone (prepared as described in example 7) is reacted with 1 eq. of methanesulfonylchloride and 3 eq. of triethylamine in dry methylene

chloride at 0°C to afford 2-(R)-hexyl-3-(R)-hydroxy-4-methyl-4- methanesulfonyloxymethylbutyrolactone.

Preparation of 2-(R)-hexyl-3-(R)-hydroxy-4-methyl-4-azidomethyl- butyrolactone

2-(R)-hexyl-3-(R)-hydroxy-4-methyl-4-methanesulfonyl- oxymethylbutyrolactone is reacted with 3 eq. of tetra-n-butylammonium azide in benzene at 65°C to afford 2-(R)-hexyl-3-(R)-hydroxy-4- methyl-4-azidomethylbutyrolactone.

Preparation of 2-(S)-hexyl-3-(R)-hydroxy-4-hydroxy-4-methyl-5- azidopentanal 3-(0),4-(Q -acetonide

2-(R)-Hexyl-3-(R)-hydroxy-4-methyl-4-azidomethyl- butyrolactone is converted to 2-(S)-hexyl-3-(R)-hydroxy-4-hydroxy-4- methyl -5 -azidopentanal 3-(0),4-(0)-acetonide in exactly the same fashion that 2-(R)-Hexyl-3-(R)-hydroxy-4-methyl-4-t-butyldiphenyl- silyloxymethylbutyrolactone is converted to 2-(S)-hexyl-3-(R)-hydroxy- 4-hydroxy-4-methyl-5-t-butyldiphenylsilyloxypentanal 3-(0),4-(0)- acetonide as described in example 7.

EXAMPLE 24

General Preparation of 2-(X)-alkyl-3-(X)-hydroxy-4-hydroxy-4-alkyl-

5 -azidopentanal 3-0.4-O-acetonide (X = R or S Following the procedure given in example 23, a variety of

2-(X)-alkyl-3-(X)-hydroxy-4-hydroxy-4-alkyl-5-azidopentan al 3-0,4- O-acetonides (X = R or S) can be prepared. A representative but nonlimiting sampling of the compounds that can be produced in this manner include those in the following table:

TABLE 11-1

Starting Material Product

EXAMPLE 25

Preparation of 2-(R)-hexyl-3-(R)-hydroxy-4-hydroxy-4-methyl-5- azidopentanal 3-0.4-O-carbonate

Preparation of 2-(S)-Hexyl-3-(R)-hydroxy-4-hydroxy-4-methyl-5- azidopentanal 3-0.4-0-carbonate

2-(S)-Hexyl-3-(R)-hydroxy-4-hydroxy-4-methyl-5- azidopentanal 3-0,4-O-carbonate is prepared from l-hydroxy-2-(S)- hexyl-3-(R)-hydroxy-4-hydroxy-4-methyl-5-azidopentane (prepared as described in example 23) in exactly the same fashion that 2-(S)-hexyl-3- (R)-hydroxy-4-hydroxy-4-methyl-5-t-butyldiphenylsiloxypentan al 3- 0,4-O-carbonate is prepared from l-hydroxy-2-(S)-hexyl-3-(R)- hydroxy-4-hydroxy-4-methyl-5-t-butyldiphenylsiloxypentane as described in example 9.

EXAMPLE 26

General Preparation of 2-(X)-alkyl-3-(X)-hydroxy-4-hydroxy-4-alkyl-

5-azidopentanal 3-0.4-O-carbonate (X = R or S

Following the procedure given in example 25, a variety of 2-(X)-alkyl-3-(X)-hydroxy-4-hydroxy-4-alkyl-5-azidopentanal 3-0,4- O-carbonates (X = R or S) can be prepared. A representative but nonlimiting sampling of the compounds that can be produced in this manner include those in the following table:

TABLE 12-1

EXAMPLE 27

Preparation of 2-(RVmethyl-3-(SValkoxy-4-(S)-methyl-5-azidopentanal

This material is prepared starting from (R)-3-(l - oxopropyl)-4-(phenylmethyl)-2-oxazolidinone and 2-(S)-methyl-3- azidopropanal following the method given in example 9.

EXAMPLE 28

General Preparation of 2-(X)-alkyl-3-(X)-alkoxy-4-substituted-5- azidoalkanals (X = R or S)

Following the procedure given in example 27, a variety of 2-(X)-alkyl-3-(X)-alkoxy-4-substituted-5-azidoalkanals (X = R or S) can be prepared. A representative but nonlimiting sampling of the compounds that can be produced in this manner include those in the following table:

TABLE 13-1

TABLE 13-2

Starting Materials Products (R = Me, Bn)

TABLE 13-2 - cont'd

EXAMPLE 29

Preparation of (S 3-Azidobutanal

Preparation of Methyl (SV3-Azidobutanoate

To methyl (S)-3-hydroxybutanoate (1 mmol) is added 25 ml dry CH2CI2 and 1.5 ml of triethylamine. This mixture is stirred in an ice bath and 1.4 eq. of methanesulfonyl chloride is added dropwise. The reaction is stirred for 1 hour at 0°C, after which time the reaction is diluted with 300 ml of CH2CI2 and extracted twice with 50 ml of water, twice with 50 ml of 0J N HCl, twice with 50 ml aq. sat. NaHC03 and once with 50 ml of brine. The organic layer is dried over magnesium sulfate and the solvent is removed under vacuum. To the crude residue is added 6 ml of benzene and 2.2 eq. of nBu4N+ N3-. The reaction is heated at 65°C for 18 hours, after which time the reaction is diluted with 300 ml of CH2CI2 and extracted twice with 50

ml of water and once with 50 ml of brine. The organic layer is dried over MgS04 and the solvent is removed under vacuum. The residue is chromatographed on silica, affording methyl (S)-3-azidobutanoate.

Preparation of (S)-3-Azidobutanal

Methyl (S)-3-hydroxybutanoate is reduced with diisobutylaluminum hydride following the procedure given in example 1 to afford (S)-azidobutanal.

EXAMPLE 30

General Preparation of Azido Aldehydes from Hydroxyesters

Following the procedure given in example 29, a variety of hydroxyesters can be converted to azidoaldehydes. A representative but nonlimiting sampling of the compounds that can be produced in this manner include those in the following table:

- Ill -

TABLE 14

hydroxyester azidoaldehyde

25

30

EX AMPLE 31

Preparation of 3-azidopropanal

l-Azido-3-t-butldimethylsiloxypropane

Following the procedure given in example 29, t- butyldimethylsiloxypropanol (prepared according to the method of McDougal et al, J. Org. Chem. 1986, 51, 3388) is first reacted with methanesulfonyl chloride in methylene chloride in the presence of triethylamine, and then the crude mesylate is reacted with tetra-n- butylammonium azide in benzene to afford l-azido-3-t- butylsiloxypropane.

1 -Azido-3-hydroxypropane l-Azido-3-t-butylsiloxypropane is reacted with tetra-n- butylammonium fluoride in anhydrous THF to afford 1 -azido-3- hydroxypropane.

3-Azidopropanal

Following the procedure given in example 3, l-azido-3- hydroxypropane is oxidized with pyridinium chlorochromate in methylene chloride to afford 3-azidopropanal.

EXAMPLE 32

General Preparation of Azido Aldehydes from Symmetric Diols

Beginning with t-butyldimethylsilylation according to the method of McDougal et al, J. Org. Chem. 1986, 51, 3388, and then following the procedure given in example 31 , a variety of symmetric diols can be converted to azido aldehydes. A representative but nonlimiting sampling of the compounds that can be produced in this manner include those in the following table:

TABLE 15

Starting Diol t-Butyldimethylsilyl Aldehyde

(R)-2-Methylglycidol is reacted with lithium azide in 2- methoxyethanol at high temperature to afford (S)-2-hydroxy-2-methyl- 3-azidopropanol, which is purified and oxidized using the Dess-Martin periodinane reagent (described in Dess D. B.; Martin, J. C. J. Am, Chem. Soc, 1991, 113, 7277) to afford (S)-2-hydroxy-2-methyl-3- azidopropanal.

EXAMPLE 34

General Preparation of Azido Aldehydes from Epoxides

Following the procedure given in example 33, a variety of epoxides can be converted to azido aldehydes. A representative but nonlimiting sampling of the compounds that can be produced in this manner include those in the following table:

TABLE 16

Starting Epoxide Azido Aldehyde

EXAMPLE 35

Preparation of 8a-methyl-8a-aza-9-deoxo-l 0-demethyl- 1 1-dehydroxy- 12.13.14,15-tetrakisnor-8a-homoervthromvcin A lactam

Preparation of 8a-(3-benzyloxycarbonylaminopropyl)-8a-aza-

9.10,1 1.12.13J4.15-heptanor-8a-hornoerythromycin A

To a 100 ml round bottom flask was introduced 300 mg (0.507 mmol) of 8a-aza-9,10,l l ,12,13,14,15-heptanor-8a- homoerythromycin A to which was added 10 ml MeOH, 120 mg (0.61 mmol, 1.2 eq.) of the aldehyde starting material, 55 mg NaH3BCN (0.82 mmol, 1.6 eq.), and 400 μl of AcOH. The reaction was stirred at room temperature and monitored by TLC (93 : 7 : 1 CH2θ2/MeOH/aq. NH3, product is higher Rf than starting material). After 24 hours, the reaction was not complete as judged by TLC, and 30 mg (0J5 mmol, 0.3 eq.) of the aldehyde and 30 mg more NaH3BCN (0.97 mmol, 1.55 eq.) was added. After stirring an additional 24 hours, only a small amount of starting material remained as judged by TLC. The solvent was removed under vacuum and the residue was taken up in 94 : 6 : 1 CH2θ2/MeOH/aq. NH3 and chromatographed on silica gel using the same solvent mixture. This afforded 333 mg (83%) of the desired adduct.

Selected spectral data for 8a-(3-benzyloxycarbonylamino- propy l)-8a-aza-9, 10, 11 , 12, 13, 14,15-heptanor-8a-homoerythromy cin A: l H NMR (400 MHz, CDCI3) δ 7.32 (m, 5H), 5.45 (br t, CbzNH), 5.05 (s, PhCH2θ-), 4.65 (d, H-l", J = 4.4 Hz), 4.32 (d, H-l', J = 7.3 Hz), 4.07 (dd, H-3, J = 4.5, 6.1), 3.96 (m, H-5"), 3.64 (s, COOCH3), 3.52 (d, H-5, J = 3.3), 3.30 (dd, H-2'), 3.24 (s, OCH3), 2.97 (d, J = 9.4, H- 4"), 2.78 (dq, H-2), 2.51 (m, H-3'), 2.27 (s, N(CH3)2), ( 68, br d, H- 4'), 1.28 & 1.17 (singlets, 6-Me and 3"-Me), 1.26, 1.22 (J = 6.2), 1.20 (J = 5.9), 1.13 (J = 7.0) & 1.04 (J = 7.1) (methyl doublets).

FAB MS: 784 (M + H+)

Preparation of 8a-memyl-8a-(3-benzyloxycarbonylaminopropyl)-8a- aza-9J 0.1 1.12.13.14.15-heptanor-8a-homoervthrom vein A

To a 50 ml round bottom flask was introduced 330 mg (0.42 mmol) of 8a-(3-benzyloxycarbonylaminopropyl)-8a-aza-

9,10,1 1 ,12, 13, 14, 15-heptanor-8a-homoerythromycin A, to which was added 5 ml MeOH, 0.2 ml 37% aq. formaldehyde and 30 mg NaH3BCN (0.97 mmol, 2.3 eq.) The reaction was stirred at room temperature and monitored by TLC (93 : 7 : 1 CH2Cl2/MeOH/aq. NH3, product is higher Rf than starting material). After 2 hours, the reaction was judged to be complete by TLC. The solvent was removed under vacuum and the residue was taken up in 94 : 6 : 1 CH2Cl2/MeOH/aq. NH3 and chromatographed on silica gel using the same solvent mixture. This afforded 273 mg of the desired product (81 %).

Selected spectral data for 8a-methyl-8a-(3-benzyloxy- carbony laminopropy l)-8a-aza-9, 10, 11 , 12, 13, 14,15-heptanor-8a- homoerythromycin A: lH NMR (400 MHz, CDCI3) δ 7.32 (m, 5H), 5.3 (br t, CbzNH), 5.03 (s, PhCH2θ-), 4.61 (d, H-l", J = 4.5 Hz), 4.36 (d, H-l', J = 7.3 Hz), 4.1 1 (dd, H-3, J = 3.0, 6.7), 3.96 (m, H-5"), 3.59 (s, COOCH3), 3.48 (d, H-5'), 3.23 (s, OCH3), 2.94 (d, J = 9.5, H-4"), 2.80 (m, H-2), 2.46 (m, H-3'), 2.23 (s, N(CH3)2), 2.18 (s, 8a-N-CH3), 1.28 & 1.15 (singlets, 6-Me and 3"-Me), 1.20 (J = 6.3), 1.18 (J = 6.1 ), 1.06 (J = 6.8), 1.06 (J = 6.8) & 0.90 (J = 6.3) (methyl doublets).

FAB MS: 798 (M + H+)

Preparation of 8a-methyl-8a-(3-aminopropyl)-8a-aza- 9.10.11.12.13.14.15-heptanor-8a-homoerythromycin A To a 100 ml round bottom flask was introduced 200 mg

(0.260 mmol) of 8a-methyl-8a-(3-benzyloxycarbonyl-aminopropyl)-8a- aza-9,10,l l ,12,13,14,15-heptanor-8a-homoerythromycin A, to which was added 10 ml 95% EtOH and 0.35 ml AcOH, 480 mg of NaOAc, and 1.5 ml water. The catalyst 10% Pd/C (400 mg) was added and the reaction was stirred at room temperature under a hydrogen atmosphere and monitored by TLC (93 : 7 : 1 CH2Cl2/MeOH/aq. NH3, product is lower Rf than starting material). After 5 hours, the reaction was judged to be complete by TLC. Most of the solvent was removed under vacuum, and the residue was diluted with 300 ml of methylene chloride and extracted 4 times with 50 ml of water. The organic layer was dried

over MgS04 and the solvent was removed under vacuum. NMR revealed that the compound was sufficiently pure to be used directly in the next step. This afforded 140 mg (84% yield) of the desired product.

Selected spectral data for 8a-methyl-8a-(3-aminopropyl)- 8a-aza-9, 10,1 1,12, 13,14, 15-heptanor-8a-homoerythromycin A:

lH NMR (400 MHz, CDC13) δ 4.61 (d, H-l ", J = 4.4 Hz), 4.40 (d, H- 1', J = 7.3 Hz), 4.10 (dd, H-3, J = 2.4, 7.8), 4.02 (m, H-5"), 3.62 (s, COOCH3), 3.53 (d, J = 3.0, H-5), 3.48 (m, H-5'), 3.26 (s, OCH3), 2.95 (d, J = 9.5, H-4"), 2.86 (m, H-2), 2.48 (m, H-3 ^* ), 2.26 (s, N(CH3)2), 2.16 (s, 8a-N-CH3), 1.30 & 1.18 (singlets, 6-Me and 3 "-Me), 1.22 (J = 6.4), 1.20 (J = 6.1), 1.09 (J = 7.2), 1.08 (J = 7.0) & 0.89 (J = 6.6) (methyl doublets).

13c NMR (100 MHz, CDCI3) δ 176.6, 102.8, 95.1 , 81.5, 80.8, 78.0,

75.3, 72.8, 70.6, 69.3, 65.4, 65.1, 55.9, 51.5, 50.3, 49.4, 40.6, 40.4, 39.9, 36.1, 36.0, 35.3, 35.2, 31.1, 29.0, 28.9, 27.0, 21.6, 21.2, 17.9,

12.4, 11.6, 9.9.

FAB MS: 665 (M + H+)

Preparation of 8a-methyl-8a-aza-9-deoxo- 10-demethyl- 1 1-dehydroxy-

12J3.14J5-tetrakisnor-8a-homoervthromvcin A lactam

To a 50 ml round bottom flask was introduced 140 mg (0.210 mmol) of 8a-methyl-8a-(3-aminopropyl)-8a-aza- 9,10,1 1 ,12,13, 14, 15-heptanor-8a-homoerythromycin A, to which was added 3 ml MeOH, 3 ml THF and 1.5 ml 1 N aq. NaOH. The reaction was stirred at room temperature and monitored by TLC (93 : 7 : 1 CH2d2/MeOH/aq. NH3, product is baseline). After 24 hours, the reaction was judged to be complete by TLC (only baseline material.) The reaction was added to 50 ml of water and the pH was adjusted to 7.7 with dilute HCl. All solvent was removed under high vacuum and the sample was dried under high vacuum for 24 hours. To the residue

was added 20 ml of sieve dried DMF and the reaction was cooled in an ice/salt bath to about -10°C, at which time 300 mg NaHC03 and 0J 5 ml of diphenylphosphorylazide (191 mg, 0.70 mmol, 3.3 eq.) was added. The reaction was stirred and allowed to warm to room temperature over several hours. After 24 hours, TLC (93 : 7 : 1 CH2Cl2/MeOH/aq. NH3) of the crude reaction showed no material remaining on the baseline, and formation of a single mid Rf spot. Most of the solvent was removed under high vacuum, and the residue was taken up in 200 ml of methylene chloride and washed three times with water. The organic layer was dried over MgS04 and the solvent was removed under high vacuum. The residue was taken up in 94:6:1 CH2Cl2/MeOH/aq. NH3 and chromatographed on silica gel using the same solvent mixture. This afforded 106 mg (80% yield) of the desired product.

Selected spectral data for 8a-methyl-8a-aza-9-deoxo-l 0-demethyl- 1 1 - dehydroxy-12,13,14,15-tetrakisnor-8a-homoerythromycin A lactam:

lH NMR (400 MHz, CDCI3) δ 4.81 (d, H-l", J = 4.8 Hz), 4.36 (d, H- 1', J = 7.1 Hz), 4.13 (br d, H-3, J = 8 Hz), 4.00 (m, H-5"), 3.58 (d, J = 8.5 Hz, H-5), 3.27 (s, OCH3), 2.99 (br t, H-4"), 2.74 (m, H-2), 2.40 (m, H-3'), 2.23 (s, N(CH3)2), 2.22 (s, 8a-N-CH3), 1.43 & 1.19 (singlets, 6- Me and 3"-Me), 1.30 (J = 6.2 Hz), 1.20, 1.19, 1.08 (J = 7.4) & 0.87 (j = 6.6) (methyl doublets).

13c NMR (100 MHz, CDCI3) δ 175.5, 103.6, 96.5, 82.6, 78.7, 78.0, 72.5, 70.9, 68.9, 65.5, 57.0, 49.5, 47.2, 40.3, 39.3, 38.8, 35.0, 28.6, 21.5, 21.4, 18.6, 17.3, 12.2, 9.6.

FAB MS: 633 (M + H+)

Elemental analysis: Calcd for C31H58N2O10Η2O: C, 59.17; H, 9.70; N, 6.47. Found: C, 59.33, 59.35; H, 9.77, 9.78; N, 6.94, 6.90.

EXAMPLE 36

General Preparation of 13-Membered Azalactams

Following the procedures given in examples 35, 38 & 40, 8a-aza-8a-homo-9, 10, 10a, 1 1 , 12, 12a, 13 , 14, 15-nonanorerythromy cin A and various azidoaldehydes (which may be prepared as taught in examples 29-34) are used as starting materials for 13-membered azalactams, as diagrammed below:

A representative but nonlimiting sampling of the compounds that can be produced in this manner include those in the following table:

TABLE 17-1

TABLE 17-1 cont'd

TABLE 17-2

aldehyde macrocycle (R = C1 to C7 alkyl or aralky

EXAMPLE 37

Preparation of 8a-Methy l-8a-aza-9-deoxo- 10-demethyl- 10-(S)-hy droxy- 1 l-deoxy-12J3.14.15-tetrakisnor-8a-homoervthromvcin A lactam

Following the procedure given in example 15, 8a-methyl- 8a-aza-9-deoxo- 10-demethyl- 10-(S)-benzy loxy- 1 1 -deoxy- 12,13,14,15- tetrakisnor-8a-homoerythromycin A lactam is reduced using H2 and 10% Pd/C in 95% EtOH with AcOH to afford 8a-methyl-8a-aza-9- deoxo- 10-demethyl- 10-(S)-hydroxy- 1 1 -deoxy- 12,13,14,15-tetrakisnor- 8a-homoerythromycin A lactam.

EXAMPLE 38

Preparation of 8a-aza-9-deoxo-10-deme1hyl-l 1 -deoxy- 12-demethyl- 12- deoxy-13J4J5-trisnor-8a-homoerythromycin A lactam

Preparation of 8a-(4-azidobutyl)-8a-aza-9, 10,1 1 ,12, 13,14, 15-heptanor-

8a-homoervthromvcin A

Following the procedure described in example 40, 8a-aza- 9,10,11 ,12,13, 14, 15-heptanor-8a-homoerythromycin A is reacted with 4-azidobutanal using sodium cyanoborohydride in methanol to afford 8a-(4-azidobutyl)-8a-aza-9,10,l 1 ,12,13, 14,15-heptanor-8a- homoerythromycin A.

Preparation of 8a-benzenesulfonyl-8a-(4-azidobutyl)-8a-aza-

9.10.1 1.12.13.14.15-heptanor-8a-homoervthromvcin A

Following the procedure described in example 13, 8a-(4- azidobutyl)-8a-aza-9,10,l l ,12,13,14,15-heptanor-8a-homoerythromycin A is reacted with benzenesulfonyl chloride and triethylamine in methylene chloride to afford 8a-benzenesulfonyl-8a-(4-azidobutyl)-8a- aza-9, 10,11 ,12,13, 14,15-heptanor-8a-homoerythromycin A.

Preparation of 8a-benzenesulfonyl-8a-(4-aminobutyl)-8a-aza-

9.10.H .12.13.14.15-heptanor-8a-homoervthromvcin A

Following the procedure described in example 40, 8a- benzenesulfonyl-8a-(4-azidobutyl)-8a-aza-9,10,l l ,12,13,14,15- heptanor-8a-homoerythromycin A is reacted with triphenylphosphine in aq. THF to afford 8a-benzenesulfonyl-8a-(4-aminobutyl)-8a-aza- 9,10,11 ,12,13, 14, 15-heptanor-8a-homoerythromycin A.

Preparation of 8a-benzenesulfonyl-8a-aza-9-deoxo-l 0-demethyl- 1 1 - deoxy- 12-demethyl- 12-deoxy- 13, 14, 15-trisnor-8a-homoerythromycin A lactam

Following the procedure described in example 40, 8a- benzenesulfonyl-8a-(4-aminobutyl)-8a-aza-9, 10, 1 1, 12, 13, 14,15- heptanor-8a-homoerythromycin A is hydrolysed with aq. NaOH and then cyclized with diphenylphosphorylazide in DMF to afford 8a- benzenesulfonyl-8a-aza-9-deoxo- 10-demethyl- 1 1 -deoxy- 12-demethyl- 12-deoxy-13,14,15-trisnor-8a-homoerythromycin A lactam.

• Preparation of 8a-aza-9-deoxo- 10-demethyl- 11 -deoxy- 12-demethyl- 12- deoxy-13J4J5-trisnor-8a-homoervthromvcin A lactam

Following the procedure described in example 13, 8a- benzenesulfonyl-8a-aza-9-deoxo-l 0-demethyl- 1 1 -deoxy- 12-demethy 1- 12-deoxy-13,14,15-trisnor-8a-homoerythromycin A lactam is photolyzed in the presence of 1 ,5-dimethoxynaphthalene and hydrazine in 95% ethanol solvent to afford 8a-aza-9-deoxo-l 0-demethyl- 11- deoxy- 12-demethyl- 12-deoxy- 13,14, 15-trisnor-8a-homoerythromycin A lactam.

EXAMPLE 39

General Preparation of 14-Membered Azalactams

Following the procedures given in examples 35, 38 & 40, 8a-aza-8a-homo-9,10,l l,12,13,14,15-heptanorerythromycin A and various azidoaldehydes (which may be prepared as taught in examples 22, 28 and 32) are used as starting materials for 14-membered azalactams, as diagrammed below:

where Rl hydrogen or CI to C7 alkyl or aralkyl; one of R2 and R is hydrogen and the other is hydrogen or CI to C7 alkyl, cycloalkyl or aryl, which may be substituted with RlOo, C ₆ H S0 ₂ HN or F; R ⁴ , R-5, R6 and R7 are hydrogen, CI to C7 alkyl, fluoroalkyl, cycloalkyl or aryl, RlOo, C ₆ H ₅ S0 ₂ HN or F; RlO is methyl, benzyl, or other CI to C7 alkyl, fluoroalkyl, cycloalkyl or aryl.

A representative but nonlimiting sampling of the compounds that can be produced in this manner include those in the following table:

TABLE 18-1

)

TABLE 18-2

TABLE 18-3

or a

EXAMPLE 40

Preparation of 8a-methyl-8a-aza-9-deoxo- 10-demethyl- 10-(S)-methoxy- 11 -O-methy 1- 12-O-methy 1- 12-demethyl- 14,15-bisnor-8a- homoerythromvcin A lactam

^• Preparation of 8a-(2-(S),3-(S),4-(S)-trimethoxy-5-azidopentyl)-8a-aza-

9.10.1 1.12J3.14.15-heptanor-8a-homoervthromvcin A

To a 10 ml round bottom flask was introduced 60 mg (0J01 mmol) of 8a-aza-9,10,l l ,12,13,14,15-heptanor-8a- homoerythromycin A, to which was added 2 ml MeOH, 26 mg (0J2 mmol, 1.2 eq.) of the aldehyde starting material, 15 mg NaH3BCN (0.22 mmol, 2.2 eq.), and 400 μl of AcOH. The reaction was stirred at 60°C for 24 hours. The solvent was removed under vacuum and the residue was taken up in 94 : 6 : 1 CH2Cl2/MeOH/aq. NH3 and chromatographed on silica gel using the same solvent mixture. This afforded 56 mg (83%) of the desired adduct.

Selected spectral data for 8a-(2-(S),3-(S),4-(S)-trimethoxy- 5-azidopenty I)-8a-aza-9, 10, 11, 12, 13, 14,15-heptanor-8a- homoerythromycin A:

lH NMR (400 MHz, CDCI3) δ 4.60 (d, H-l ", J = 4.4 Hz), 4.36 (d, H-l ', J = 7.3 Hz), 4.10 (dd, H-3, J = 2.5, 7.9), 4.00 (m, H-5"), 3.63 (s, COOCH3), 3.51 (d, H-5, J = 2.6), 3.47 (s, OCH3), 3.44 (s, OCH3), 3.38 (s, OCH3), 3.26 (s, OCH3), 2.95 (br t, H-4"), 2.81 (dq, H- 2), 2.50 (m, H-3 ^* ), 2.26 (s, N(CH3)2), 5 (br d, H-4 '), 1.29 & 1.18 (singlets, 6-Me and 3"-Me), 1.22 (d, J=6.3 Hz), 1.21 (d, J = 6.1 Hz), 1.09 (d, J=7.1 Hz), 1.09 (d, J=7.1 Hz), & 1.07 (d, J=8.1 Hz), (methyl doublets).

IR: 2100 cm- ¹ , 1730 cm- ¹

FAB MS: 795 (M + H+)

Preparation of 8a-methyl-8a-(2-(S),3-(S),4-(S)-trimethoxy-5- azidopenty l)-8a-aza-9, 10,1 1 ,12,13,14,15-heptanor-8a- homoervthromvcin A

To a 10 ml round bottom flask was introduced 57 mg (0.071 mmol) of 8a-(2-(S),3-(S),4-(S)-trimethoxy-5-azidopentyl)-8a- aza-9,10,l l,12,13,14,15-heptanor-8a-homoerythromycin A, to which was added 2 ml MeOH, 0J5 ml 37% aq. formaldehyde, and 15 mg triphenylphosphine (0.22 mmol, 3 eq.). The reaction was stirred at room temperature for 0.5 hours. The solvent was removed under vacuum and the residue was taken up in 90 : 10 : 1 CH2Cl2/MeOH/aq. NH3 and chromatographed on silica gel using the same solvent mixture. This afforded 52 mg (89%) of the desired adduct.

Selected spectral data for 8a-methyl-8a-(2-(S),3-(S),4-(S)- trimethoxy-5-azidopentyl)-8a-aza-9, 10, 1 1 , 12, 13, 14, 15-heptanor-8a- homoerythromycin A:

iH NMR (400 MHz, CDC13) δ 4.61 (d, H-l "), 4.39 (d, H- 1', J •= 7.3 Hz), 4.09 (dd, H-3, J = 2.2, 8.1), 4.01 (m, H-5"), 3.63 (s, COOCH3), 3.53 (d, H-5, J = 2.8), 3.49 (s, OCH3), 3.44 (s, OCH3), 3.34 (s, OCH3), 3.26 (s, OCH3), 3.23 (dd, J = 7.3, 10.3, H-2'), 2.96 (d, J = 9.5, H-4"), 2.87 (dq, H-2), 2.49 (m, H-3'), 2.28 (s, N(CH3)2), L64 (br d, H-4'), 1.32 & 1.19 (singlets, 6-Me and 3"-Me), 1.21 (d, J=6.4 Hz), 1.20 (d, J = 6.0 Hz), 1.09 (d, J=6.3 Hz), 1.07 (d, J=6.6 Hz), & 0.93 (d, J=6.5 Hz), (methyl doublets).

FAB MS: 808 (M + H+)

Preparation of 8a-methyl-8a-(2-(S),3-(S),4-(S)-trimethoxy-5- aminopentyl)-8a-aza-9,10,l l,12,13,14,15-heptanor-8a- homoerythromycin A

To a 10 ml round bottom flask was introduced 52 mg (0.064 mmol) of 8a-methyl-8a-(2-(S),3-(S),4-(S)-trimethoxy-5- azidopenty l)-8a-aza-9, 10,11 ,12,13,14,15-heptanor-8a-

homoerythromycin A, to which was added 1.5 ml THF, 0.060 ml water, and 84 mg triphenylphosphine (0.32 mmol, 5 eq.). The reaction was stirred at 60°C for 0.5 hours. The solvent was removed under vacuum and the residue was taken up in 90 : 10 : 1 CH2Cl2/MeOH/aq. NH3 and chromatographed on silica gel using the same solvent mixture. This afforded 48 mg (92%) of the desired adduct.

Selected spectral data for 8a-methyl-8a-(2-(S),3-(S),4-(S)- trimethoxy-5-aminopentyl)-8a-aza-9, 10, 1 1 , 12, 13, 14, 15-heptanor-8a- homoerythromycin A:

^J H NMR (400 MHz, CDCI3) δ 4.59 (d, H-l ", J = 4.7 Hz), 4.38 (d, H- 1 ', J = 7.3 Hz), 4.08 (dd, H-3, J = 2.2, 8.1 ), 4.01 (m, H-5"), 3.63 (s, COOCH3), 3.53 (d, H-5, J = 2.8), 3.50 (s, OCH3), 3.41 (s, OCH3), 3.35 (s, OCH3), 3.26 (s, OCH3), 3.23 (dd, J = 7.3, 10.3, H-2'), 2.95 (d, J = 9.5, H-4"), 2.87 (dq, H-2), 2.49 (m, H-3'), 2.27 (s, N(CH3)2), 2.22 (s, 8a-NCH3), 1.65 (br d, H-4'), 1.31 & 1.18 (singlets, 6-Me and 3"-Me), 1.21 (d, J=6.3 Hz), 1.20 (d, J = 6.0 Hz), 1.09 (d, J=6.1 Hz), 1.08 (d, J=6.8 Hz), & 0.93 (d, J=6.5 Hz), (methyl doublets).

FAB MS: 782 (M + H+)

Preparation of 8a-methyl-8a-aza-9-deoxo-l 0-demethyl- 10-(S)-methoxy- 1 1 -O-methyl- 12-O-methyl- 12-demethyl- 14, 15-bisnor-8a- homoerythromycin A lactam

To a 50 ml round bottom flask was introduced 48 mg (0.061 mmol) of starting material, to which was added 1.5 ml MeOH, 1.5 ml THF and 0.75 ml 1 N aq. NaOH. The reaction was stirred at room temperature and monitored by TLC (93 : 7 : 1 CH2Cl2/MeOH/aq. NH3, product is baseline). After 24 hours, the reaction was judged to be complete by TLC (only baseline material.) The reaction was added to 50 ml of water and the pH was adjusted to 7.7 with dilute HCl. All solvent was removed under high vacuum and the sample was dried under high vacuum for 24 hours. To the residue was added 6 ml of

sieve dried DMF and the reaction was cooled in an ice/salt bath to about -10°C, at which time 100 mg NaHC03 and 0.05 ml of diphenylphosphorylazide (63 mg, 0.23 mmol, 3.8 eq.) was added. The reaction was stirred and allowed to warm to room temperature over several hours. After 24 hours, TLC (93 : 7 : 1 CH2Cl2/MeOH/aq. NH3) of the crude reaction showed no material remaining on the baseline, and formation of a single mid Rf spot. Most of the solvent was removed under high vacuum, and the residue was taken up in 200 ml of methylene chloride and washed three times with water. The organic layer was dried over MgSθ4 and the solvent was removed under high vacuum. The residue was taken up in 94 : 6 : 1 CH2Cl2/MeOH/aq. NH3 and chromatographed on silica gel using the same solvent mixture. This afforded 26 mg (56% yield) of the desired product.

Selected spectral data for 8a-methyl-8a-aza-9-deoxo-10- demethyl-10-(S)-methoxy-l 1 -0-methyl-12-0-methyl-12-demethyl- 14,15-bisnor-8a-homoerythromycin A lactam:

H NMR (400 MHz, CDCI3) δ 4.80 (d, H-l "), 4.32 (d, H-l '), 4.22 (m, H-3), 4.02 (m, H-5"), 3.53 (s, OCH3), 3.41 (s, OCH3), 3.32 (s, OCH3), 3.24 (s, OCH3), 2.97 (br t, H-4"), 2.87 (dq, H-2), 2.49 (m, H-3 ^* ), 2.23 (s, N(CH3)2), 65 (br d, H-4'), 1.35 & 1.18 (singlets, 6-Me and 3"- Me), 1.28 (d, J=6.4 Hz), 1.17 (d), 1.14 (d), 1.09 (d, J=6.8 Hz), & 0.93 (d, J=6.3 Hz), (methyl doublets).

High resolution FAB MS: 750.5125 (error = 0.9 mmu)

Elemental analysis: Calcd for C37H71N3O12T .5H2O: C, 57.19; H, 9.60; N, 5.41. Found: C, 57.09,; H, 8.88; N, 5.39.

EXAMPLE 41

General Preparation of 15-Membered Azalactams

Following the procedures given in example 35, 38 & 41 , 8a-aza-8a-homo-9,10,l l ,12,13,14,15-heptanorerythromycin A and

various azidoaldehydes (which may be prepared as taught in examples 21 -34) are used as starting materials for 15-membered azalactams, as diagrammed below:

A representative but nonlimiting sampling of the compounds that can be produced in this manner include those in the following table:

TABLE 19-1

TABLE 19-1 cont'd

TABLE 19-2

macrocycle (R = H or C1 to C7 alkyl aldehyde (R' = Me, Bn) or aralkyl)

TABLE 19-2 cont'd

macrocycle (R = H or C1 TO C7 aldehyde (R' = Me, Bn) alkyl or aralkyl)

TABLE 19-3

TABLE 19-3 cont'd

TABLE 19-4

7

TABLE 19-4 cont'd

7

TABLE 19-5

TABLE 19-5 cont'd

macrocycle (R = H or C1 to C7 aldehyde (R' = Me, Bn) alkyl or aralkyl)

TABLE 19-6

macrocycle (R = H or C1to C7 alky aldehyde I or aralkyl)

TABLE 19-6 cont'd

macrocycle (R = H or C1to C7 alky aldehyde I or aralkyl)

TABLE 19-7

macrocycle (R = H or C1 to C7 aldehyde alkyl or aralkyl)

TABLE 19-8

macrocycle (R = H or C1 to C7 aldehyde alkyl or aralkyl)

TABLE 19-8 cont'd

macrocycle (R = H or C1 to C7 aldehyde alkyl or aralkyl)

20

25

30

TABLE 19-9

30

TABLE 9-9 cont'd

25

30

TABLE 9-10

30

TABLE 19-10 cont'd

20

25

30

TABLE 19-11

TABLE 19-1 1 cont'd

macrocycle (R = H or C1 to C7 aldehyde alkyl or aralkyl)