Description A METHOD FOR THE SYNTHESIS OF COMPOUNDS OF FORMULA 1 AND DERIVATIVES THEREOF Field of the Invention The present invention relates to mono-substituted and di-substituted alpha-amino acids and derivatives thereof, such as but not limited to esters, amides and salts. The alpha-amino acid compounds and their derivative compounds are substituted at the alpha position with one (mono-) or two (di-) substituents (R2 and/or R3) as shown in Formula 1 below: N (R4R5) C (R2R3) CO (OR1) Formula 1 where the moieties R', R2, R3, R4, and R5 are as defined below. Mono- substituted and di-substituted alpha-amino acids and derivatives thereof are useful, for instance, as raw materials for pharmaceutical and agro-chemical products.

Table of Abbreviations Ac acetyl Alloc allyloxycarbonyl Bn benzyl BOC tert-butyloxycarbonyl CBZ benzyloxycarbonyl

Et ethyl Fmoc 9-fluorenylmethyloxycarbonyl h hour IR infrared MS mass spectroscopy Me methyl mL milliliter NMR nuclear magnetic resonance OTBDMS tert-butyl dimethyl silyl Ph phenyl RT room temperature Su succinamide t-Bu tertiary-butyl Background of the Invention As reported in the literature, a number of routes are known for the synthesis of alpha-amino acids. The best-known route is the Strecker synthesis route (see, Introduction to Organic Chemistry, Streitwieser and Heathcock, Macmillan Publishing Co., Inc. New York, 1981). In this method a suitable aldehyde is treated with ammonia and HCN, so that an alpha- amino nitrile is formed, which is subsequently subjected to a hydrolysis reaction to provide the corresponding alpha-amino acid.

Also, it has been shown (see, Ugi, I. Angew. Chem., Intl. Ed. Engl., 1982, Vol. 21, pp. 810-819, and Ugi, I. et al., J. Prokt. Chem., 1997, Vol.

339, p. 499) that the reaction of an isocyanide (X'NC) with a carboxylic acid (X2COOH), an aldehyde (X3CHo) and an amine (X4NH2) under the

appropriate conditions provided the corresponding dipeptide (N-alkyl-N-acyl- alpha amino amide) as follows: X1-NC + X2-COOH + X3-CHO + X4NH2 --po. X2-CO-NX4-CHX3-CO-NX'H N-alkyl-N-acyl-alpha amino amide (i. e., a dipeptide) In an attempt to convert the dipeptides to their corresponding alpha- amino acids, Ugi used chiral ferrocenylamine in the above-mentioned reaction. The desired amino acids were obtained with low to modest diastereoselectiveity. (See, Ugi I. et al., Tetrahedron Lett., 1986, Vol. 42, pp.

5931-5940).

Furthermore, the use of a convertible isocyanide in the Ugi reaction, namely cyclohexene-isocyanide, followed by hydrolysis to provide the corresponding peptide carboxylic acid, has been demonstrated (see, Armstrong, R. W. et al., J. Am. Chem. Soc., 1996, Vol. 118, p. 2574) as follows: N-alkyl-N-acyl-alpha amino acid (i. e., a peptide carboxylic acid) In addition, the use of phenyl-isocyanide and pyridyl-isocyanide was demonstrated in the conversion of dipeptides made by Ugi into pyrrole derivatives (see, Mjalli, et al., Tet. Lett., 1996, Vol. 37, pp. 2943-2946).

Moreover, the use of sugar derivatives (protected galactososylamine and arabinopyranosylamine) as chiral amines with t-butyl-isocyanide converted the dipeptides made by Ugi into the corresponding sugar dipeptides, which were then converted in four chemical steps: (1) HCI, MeOH, 0° C to RT, 4 h; (2) H20,12 h, RT; (3) 6N HCI, 80° C, 24 h; and (4) Amberlite, IR 200 using very harsh conditions to the corresponding alpha-amino acids as shown below: X2-CO-N (sugar)-CHX3-CO-NH-C (CH3) 3 _ NH3CI-CHX3-COOH where used was an aldehyde, X3CHo, where X3 = Ph, t-Bu, (CH2) 3 COOH, Bn, or para-CI-Ph (see, Kunz, H. et al., Tet. Lett., 1988, Vol. 29, p. 5487, and Kunz, H. et al., Tet. Lett., 1989, Vol. 30, pp. 4109-4110).

This sugar amine was also described being made by utilizing different isocyanides and then being converted in three chemical steps: (1) HCI, MeOH, 0° C to RT, 4 h; (2) H20,12 h, RT; and (3) 2N HCI, 60° C, 24 h as shown below: CH2-OTBDMS H X2-CO-N (sugar)-CHX3-CO- N < X3-CHNH3CI-COOH

where used was an aldehyde, X3CHo, where X3 = Ph, t-Bu, (CH2) 4COOH, Bn, or H2CF=CH (see, Linderman, R. J., J. Am. Chem. Soc., 1999, Vol. 64, pp. 336-337).

Also, it has been reported (see, Ugi et al., Angew. Chem. Intl. Ed.

Engl., 1996, Vol. 35, p. 173) that the reaction of unprotected alpha-amino acids (namely valine, phenyl alanine and proline) with a series of isocyanides and aldehydes in MeOH provided the corresponding three amino peptides with excellent yield and good diastereoselectivity as shown below: X4-NC + NH2-CXH-COOH + X3-CHO #X4-NH-CO-CHX3-NH-CHX-COOMe N-alkyl-N-acyl-alpha amino amide More specifically, the synthesis of the following three compounds has been reported by this method:

Summary and Objects of the Invention The present invention provides mono-substituted and di-substituted alpha-amino acids and derivatives thereof, such as but not limited to esters, amides and salts. The alpha-amino acids and their derivatives are of Formula 1 and are substituted at the alpha position with one or two substituents as shown below: N(R4R5)C(R2R3)CO(OR1) Formula 1 where R', R2, and R3 are the same or different and are selected from: (a) H, with the proviso that at least one of R2 and R3 is not H, (b) mono-, di-, and tri-substituted aryl, and (c) C1-C10substitutedalkyl,C1-C10substitutedalkyl-alkyl, aryl, C1-C10 substituted alkenyl, and Ci-Cio substituted alkenyl aryl, where the substituents of (b) and (c) are selected from: H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, C1-C10 alkyloxy, C1-C10 alkyloxy aminoalkyl,C1-C10alkylamino,C1-C10aminoalkylC1-C10 aryl, Ci-Cio aminocarbonyl, Ci-Cio aminocarbonylalkyl-aryl, Ci-Cio thioalkyl, C1-C10 alkylsulfoxide,C1-C10alkylsulfone,C1-C10C1-C10 alkylsulfonamide, aryl,C1-C10alkylsulfoxidearyl,C1-alkylsulfonamide C10C1-C10alkyl,aminocarbonylaminoC1-C10alkyl,C1-C10aryl, C1-C10alkylaryl,C1-C10alkyloxycarbonylC1-C10alkylaminocarbon ylamino alkyloxycarbonylC1-C10alkylaryl,C1-C10carboxyalkyl,C1-C10alk yl,C1-C10

carboxyalkyl carbonylalkyl,C1-C10carbonylalkylaryl,C1-C10C1-C10 <BR> <BR> <BR> <BR> <BR> alkyloxycarbonylamino alkyl, Cl-Clo alkyloxycarbonylamino alkyl aryl, guanidino, Ci-Cio alkylCOOH, Ci-Cio alkylCONH2, C1-C10 alkenylCOOH, C1- C, alkenyl CONH2, and where the aryl group of (b) and (c) is selected from: phenyl, biphenyl, 2-napthyl, 1-napthyl, pyridyl, furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, <BR> <BR> <BR> <BR> <BR> pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl,<BR> <BR> <BR> <BR> <BR> <BR> pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, benzoxazolyl; and where R4 and R5 are the same or different and are selected from: (d) H, and (e) an amine protecting group.

The present invention also provides for a method for the synthesis of compounds of Formula 1, where R', R2, R3, R4, and R5 are as defined above, by reacting (1) a suitable carbonyl compound, such as an aldehyde or a ketone, (2) an amino acid (employed as an amino acid/removable chiral auxiliary), and (3) a convertible isocyanide using appropriate reaction conditions to provide compounds Formula 2 below: Formula2 that are then subjected in situ, or after isolation and purification, to mild amide hydrolysis or cleavage to provide compounds of Formula 1 as

racemates or in optically pure form. More particularly, the method comprises: (i) reacting an amino acid/removable chiral auxiliary or salt thereof, a convertible isocyanide, and at least one of an aldehyde and a ketone, in an alcohol or alcohol-containing solvent to obtain a compound of Formula 2 Formula 2 and (ii) subjecting the compound of Formula 2 to aryl amine cleavage/hydrolysis, including catalytic hydrogenation, and to amide cleavage/hydrolysis to obtain the compound of Formula 1, and preferably, step (ii) comprises that the aryl amine cleavage/hydrolysis and the amide cleavage/hydrolysis are followed by an amine protection reaction to place at least one amine protection group on the N of Formula 1.

Hence, it is an object of the invention to provide certain novel alpha- amino acids.

Some of the objects of the invention having been stated above, other objects will become evident as the description proceeds, when taken in connection with the Laboratory Examples as best described below.

Detailed Description of the Invention The present invention involves the preparation of mono-substituted and di-substituted alpha-amino acids and their derivatives as shown in Formula 1 below: N (R4R5) C (R2R3) CO (OR) Formula 1 where the alpha-amino acids and their derivatives may be N-protected with a substituent, such as but not limited to tert-butyloxycarbonyl (BOC), 9- fluorenylmethyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), butyloxycarbonyl (CBZ) and salts thereof, as represented in Formula 1 by R4 and R5. The alpha position is substituted with one or two substituents, as represented in Formula 1 by R2 and R3. The nature of the starting carbonyl (aldehyde or ketone) compounds selected determines the nature of the desired alpha-amino acid (mono-, di-, cyclic and acylic) substituents, R2 and R3. The acid functionality, as represented by R1 in Formula 1, may be H or may be a suitable functional group to provide derivatives such as but not limited to esters, amides, and salts, as represented by R1 in Formula 1.

The process according to the invention is technically simple and economically attractive. With the process according to the invention, high yields are obtained with a minimal number of chemical steps. Also, the process according to the invention not only provides a wide range of currently available amino acids and derivatives, but also provides new amino acids and derivatives.

An amino acid/chiral auxiliary component is used in a reaction with a carbonyl compound (a ketone or an aldehyde) and an isocyanide to provide compounds as shown in Formula 2 below: N (HR4) C (O) C (R2R3) N (H) C (HR) C (O) (oR1) Formula 2 that can be converted (by cleavage/hydrolysis and amine protection) to compounds of Formula 1. Both the isocyanide portion represented by R4- NH in Formula 2 and the amino acid/removable chiral auxiliary portion represented by NHC (HR) COOR' in Formula 2 are converted stepwise in any order or concurrently under mild conditions (such as but not limited to strong acid, catalytic hydrogenation, electron transfer reactions, basic conditions, or nucleophilic additions) to provide the corresponding alpha-amino acids and their derivatives as shown in Formula 1.

Moreover, besides racemates, synthesis of an enantiomerically pure compound can result from the amino acid/removable chiral auxiliary being a chiral inducer chemically to provide a majority of a single isomer of a compound of Formula 2. The major isomer can then be separated using standard chromatography techniques or crystallization prior to hydrolysis of both residues (the isocyanide and the chiral auxiliary) to provide an enantiomerically pure compound of Formula 2. After cleavage of the isocyanide and amino acid/removable chiral auxiliary portions, an enantiomerically pure compound of Formula 1 is obtained. Alternatively, the amino acid/removable chiral auxiliary can create two diastereomers of various or similar ratios of a compound of Formula 2. The diastereomers can then be separated using standard chromatography techniques or

crystallization prior to hydrolysis of both residues (the isocyanide and the chiral auxiliary moieties) to provide an enantiomerically pure compound of Formula 2. The enantiomerically pure compound of Formula 2 then can be converted separately to an optically pure compound of Formula 1 upon the removal of both residues (the isocyanide and the chiral auxiliary).

More particularly, the present invention provides compounds of Formula 1

Formula 1 where: R', R2, and R3 are the same or different and are selected from: (a) H, with the proviso that at least one of R2 and R3 is not H, (b) mono-, di-and tri-substituted aryl, and (c) C1-C10 substitutedalkyl,C1-C10substitutedC1-C10 alkyl-aryl, C1-C10 substituted alkenyl, and Ci-Cio substituted alkenyl aryi, where the substituents of (b) and (c) are selected from: H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, Ci-Cio alkyloxy, C1-C10 alkyloxy aryl, C1-C10alkylamino,C1-C10aminoalkylaminoalkyl, aryl, C1-C10aminocarbonylalkyl-aryl,C1-C10thloalkyl,aminocarbonyl, C1-C10alkylsulfoxide,C1-C10alkylsulfone,C1-C10C1-C10thioalky l-aryl, alkylsulfonamidearyl,C1-C10alkylsulfoxidearyl,C1-alkylsulfon amide,C1-C10

CIO alkylsulfone aryl, Ci-Cio alkyl, aminocarbonylamino Ci-Cio alkyl, C-C0 C1-C10alkylarykl,C1-C10alkyloxycarbonylC1-C10alkylaminocarbo nylamino alkyloxycarbonylC1-C10alkylaryl,C1-C10carboxyalkyl,C1-C10alk yl,C1-C10 carboxyalkyl aryl, C1-C10 carbonylalkylaryl,C1-C10C1-C10 C1-C10alkyloxycarbonylaminoalkylaryl,alkyloxycarbonylaminoal kyl, guanidino, C1-C10alkylCONH2,C1-C10alkenylCOOH,C1-alkylCOOH, C, alkenyl CONH2, and the like, and where the aryl group of (b) and (c) is selected from: phenyl, biphenyl, 2-napthyl, 1-napthyl, pyridyl, furyl, thiophenyl, <BR> <BR> <BR> <BR> <BR> indolyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, isoquinolyl,benzofuryl,isoberzofuryl,benzothienyl,pyrimidyl, quinlyl, pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, benzoxazolyl, and the like, and where: R4 and R5 are the same of different and are selected from: H and an amine protecting group such as but not limited to phenyl, cyclohexenyl, cyclohexyl, t-butyl, Fmoc, BOC, Alloc, CBZ and the like.

Optionally, R2 and R3 in Formula 1 are joined together to form cyclic compounds of Formula 1 a with a ring size of 3-8 as follows: Formula 1a For instance, the ring system may be selected from substituted- cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl as shown in compounds of Formulae 1 b and 1 c as follows:

Formula1b Formula 1c selected from substituted-cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl as in compounds of Formula 1 d as follows:

Formula 1d where R5 and R7, R6 and R10, or R9 and R10 may be joined together as a ring to form a fused system with the cyclopentene ring, where the aryl and its substituents are as defined belowvis-à-vis (e) and (f), or selected from substituted heterocyclic compounds, where A is O, S, SO, SO2, NH, S02NHR, NCONHR, NCOOR, or NR inserted in the ring systems as in compounds of Formulae 1e and 1f as follows:

Formula 1e Formula 1f where the substituents R4 and R5 in Formulae 1a-1f are as defined above and where the substituents (R6, R7, R8, R9, and R'°) in Formulae 1a-1f are the same or different and are selected from: (d) H, (e) mono-, di-, and tri-substituted aryl, and (f) Ci-Cio substituted alkyl, C1-C10 substituted alkyl-aryl, C1-C10 substituted alkenyl, and Ci-Cio substituted alkenyl aryl, where the substituents of (e) and (f) are selected from: H, chloro, fluoro, bromo, iodo, nitro, cyano, amino, Ci-Cio alkyloxy, aryl,C1-C10aminoalkyl,C1-C10alkylamino,C1-C10aminoalkylC1-C1 0alkyloxy aryl, C1-C10aminocarbonylalkyl-aryl,C1-C10thioalkyl,aminocarbonyl, C1-C10alkylsulfoxide,C1-C10alkylsulfone,C1-C10C1-C10thioalky l-aryl, alkylsulfonamidearyl,C1-C10alkylsulfoxidearyl,C1-alkylsulfon amide,C1-C10 C10C1-C10alkyl,aminocarbonylaminoC1-C10alkyl,C1-C10aryl, C1-C10alkylaryl,C1-C10alkyloxycarbonylC1-C10alkylaminocarbon ylamino alkyloxycarbonylC1-C10alkylaryl,C1-C10carboxyalkyl,C1-C10alk yl,C1-C10 C1-C10carbonylalkyl,C1-C10carbonylalkylaryl,C1-C10carboxyalk ylaryl, C1-C10alkyloxycarbonylaminoalkylaryl,alkyloxycarbonylaminoal kyl, guanidino, C1-C10alkylCONH2,C1-C10alkenylCOOH,C1-alkylCOOH, Cio alkenyl CONH2, and the like,

and where the aryi group of (e) and (f) is selected from: phenyl, biphenyl, 2-napthyl, 1-napthyl, pyridyl, furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, <BR> <BR> pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, benzoxazolyl, and the like.

The invention relates to a synthesis where a convertible isocyanide, such as but not limited to cyclohexenyl, t-butyl, cyclohexyl, or phenyl, is used in conjunction with an appropriate"chiral auxiliary"as an amino acid input (amino acid/removable chiral auxiliary) in the three component condensation reaction to provide (after hydrolysis of both the amine and isocyanide moieties) the corresponding alpha-amino acids and their derivatives as represented by Formula 1.

Compounds of Formula 1 are synthesized according to the following reaction mechanism: R4NC + NH2-CHR-COOH + R3-CO-R2 convertible isocyanide chiral auxiliary ketone or aldehyde Formula 2 R3 R2 1) aryl amine cleavage/hydrolysis a4 o 2) amide cleavage or hydrolysis*, and R4 o 3) optional amine protection with R5 Formula 1

*It is noted that when proceeding from Formula 2 to Formula 1,1) may be performed prior to 2), 2) may be performed prior to 1), or 1) and 2) may be performed concurrently.

Reaction of an appropriate aldehyde or ketone (such as but not limited to phenyl-acetaldehyde or cyclohexanone) with an amino acid/removable chiral auxiliary or salt thereof (such as but not limited to phenyl glycine, i. e., R is phenyl) and an appropriate convertible isocyanide (such as but not limited to R4 is phenyl-, cyclohexenyl-, cyclohexyl-, or t- butyl-) utilizing an appropriate solvent and reaction conditions (such as but not limited to R'OH is methanol, ethanol, or isopropanol, at about-80°C to 220°C) provided compounds of Formula 2. Then, after cleavage of both the chiral auxiliary amine and the amide portions, compounds of Formula 2 provided the corresponding alpha-amino acids and their derivatives of Formula 1.

The desired alpha-amino acid of Formula 2 has a removable amino acid/chiral auxiliary and preferably is selected from compounds where R is mono, di-, tri-, tetra-or penta-substituted aryl, where the aryl is selected from: phenyl, biphenyl, 2-naphtyl, 1-naphtyl, and the like, and the substituents are selected from: H, cyano, amino, C1-C10 alkyl, C1-C10 alkyloxy, Ci-Cio alkyloxy aryl, Cl-Clo aminoalkyl, Cl-Clo alkylamino, Cl-Clo aminoalkyl aryl, and the like.

As shown in the Laboratory Examples beiow, compounds of Formula 2 were separated using standard separation techniques, such as but not limited to chromatography separation and crystallization, to provide

enantiomerically pure compounds of Formula 2. Then, the enantiomerically pure compounds of Formula 2 were subjected to amide cleavage conditions, such as but not limited to acidic reaction conditions, such as HCI/MeOH or aqueous HCI, to provide the corresponding acid, followed by benzyl amine or derivative cleavage conditions, such as but not limited to a catalytic hydrogenation reaction, such as but not limited to H2 with Pd (OH) 2 on carbon, to provide the corresponding amine, followed by acidic hydrolysis such as HCI/methanol or aqueous HCI to provide the corresponding enantiomerically pure amino acids of Formula 1.

Compounds were synthesized in accordance with the following Laboratory Examples.

Laboratory Examples Example I (Preparation of Intermediarv Compound of Formula 2) Several compounds of Formula 2, where R'was Me, were synthesized according to Scheme 1 as follows: to RT, 1 to 2 days Formula 2 Scheme 1 General Procedure To a cooled mixture of an amino acid (1 mmol) in methanol (8 mL), at -78°C, was added an aldehyde or a ketone (1 mmol in 1 mL of MeOH) and

an isocyanide (1 mmol in 1 mL MeOH). Each respective resulting mixture was allowed to warm to room temperature or reflux and stir between 3 h to 48 h. The crude reaction for each was concentrated and dissolve in 10 ml of Et20. After filtration (to remove the remaining amino acid), each respective filtrate was concentrated and purified by column chromatography on silica gel, resulting in the following compounds of Formula 2: 84% yield (at 92% conversion), ratio 3: 2. MS (ESP+) m/z 471.20, (MH+) 493.16 (M+Na). <BR> <BR> <BR> <BR> <BR> <BR> <P>H1 NMR (CD30D, 300MHz, major diastereoisomer): 8 7.77 (dd, 1H), 7.45- 7.10 (m, 8H), 4.84 (d, 1H, 13.3Hz), 4.72 (d, 1H, 13.3Hz), 4.47 (s, 1H), 3.64 (s, 3H), 2.95 (t, 1H, 6.4Hz), 1.73 (dq, 2H), 0.95 (t, 3H, 7.4Hz), 0.88 (s, 9H), 0.08 (s, 3H), 0.03 (s, 3H).

H1 NMR (CD30D, 300MHz, minor diastereoisomer): 8 7.77 (dd, 1H), 7.45- 7.10 (m, 8H), 4.60 (d, 1 H, 13.3Hz), 4.52 (d, 1H, 13.3Hz), 4.41 (s, 1H), 3.69 (s, 3H), 3.16 (t, 1H, 6.4Hz), 1.83 (dq, 2H), 1.05 (t, 3H, 7.4Hz), 0.81 (s, 9H),- 0.02 (s, 3H),-0.07 (s, 3H).

70% yield, ratio 2: 1. MS (ESP+) m/z 525.37 (MH+). <BR> <BR> <BR> <BR> <P>H1 NMR (CD30D, 300MHz, major diastereoisomer): # 7.75 (dd, 1H), 7.42-<BR> <BR> <BR> <BR> 7.10 (m, 8H), 4.85 (d, 1H, 13Hz), 4.72 (d, 1 H, 13Hz), 4.40 (s, 1H), 3.64 (s,<BR> <BR> <BR> <BR> <BR> 3H), 2.79 (d, 1H, 5.9 Hz), 1.9-1.5 (m, 11 H), 0.88 (s, 9H), 0.09 (s, 3H), 0.03 (s, 3H). <BR> <BR> <BR> <BR> <P>H1 NMR (CD30D, 300MHz, minor diastereoisomer): 8 7.77 (dd, 1H), 7.45-<BR> <BR> <BR> <BR> 7.10 (m, 8H), 4.56 (d, 1H, 13Hz), 4.50 (d, 1H, 13Hz), 4.36 (s, 1H), 3.68 (s,<BR> <BR> <BR> <BR> <BR> 3H), 3.03 (d, 1H, 5.9 Hz), 1.9-1.5 (m, 11H), 1.05 (t, 3H), 0.82 (s, 9H),-0.02 (s, 3H),-0.06 (s, 3H).

75% yield (at 93% conversion). MS (ESP+) m/z 511.71 (MH+).

H1 NMR (CD30D, 300MHz): # 7.66 (dd, 1H, 8.6-1.3 Hz), 7.39 (dd, 2H, 7.7-2 Hz), 7.31-7.17 (m, 5H), 7.06 (dt, 1H, 7.7-1.3 Hz), 4.49 (d, 1H, 13 Hz), 4.40 (s, 1H), 4.28 (d, 1H, 13 Hz), 3.58 (s, 3H), 2.1-1.3 (m, 10H), 0.89 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H).

88% yield. MS (ESP+) m/z 569.71. (MH+) 591.21 (M+Na).

H1 NMR (CD30D, 300MHz): 8 7.67 (dd, 1H, 8.8-1.5 Hz), 7.40 (dd, 2H, 7.8- 1.8 Hz), 7.32-7.20 (m, 5H), 7.08 (dt, 1H, 7.6-1.3 Hz), 4.53 (d, 1H, 13.5 Hz), 4.38 (s, 1H), 4.36 (d, 1H, 13.5 Hz), 3.90 (s, 2H), 3.59 (s, 3H), 2.19 (m, 1H), 2.04 (m, 1 H), 1.90-1.48 (m, 6H), 0.89 (s, 9H), 0.06 (s, 3H), 0.03 (s, 3H).

71% yield (at 69% conversion). MS (ESP+) m/z 513.. 68 (MH+). H1 NMR (CD30D, 300MHz): 8 7.67 (dd, 1H, 8.5-1.5 Hz), 7.41 (dd, 2H, 7.9-1.9 Hz), 7.33-7.21 (m, 5H), 7.10 (dt, 1H, 7.6-1.4 Hz), 4.54 (d, 1H, 13.2 Hz), 4.43 (s, 1 H), 4.37 (d, 1H, 13.2 Hz), 3.9-3.55 (m, 4H), 3.60 (s, 3H), 2.25-1.65 (m, 4H), 0.88 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H).

99% yield (at 53% conversion). MS (ESP+) m/z 529.43 (MH+), 551.17 (M+Na). H1 NMR (CD30D, 300MHz): 8 7.67 (dd, 1H, 8.8-1.6 Hz), 7.41 (dd, 2H, 7.7-1.9 Hz), 7.33-7.20 (m, 5H), 7.09 (dt, 1H, 7.6-1.4 Hz), 4.53 (d, 1H, 13.4 Hz), 4.41 (s, 1H), 4.36 (d, 1H, 13.4 Hz), 3.60 (s, 3H), 3-2.8 (m, 2H), 2.78-2.55 (m, 2H), 2.5-2.15 (m, 2H), 2.05-1.8 (m, 2H), 0.89 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H).

75% yield, ratio 2: 1. H1 NMR (CDCl3, 300MHz, major diastereoisomer): 5 8.21 (d, 1H), 7.36-7.03 (m, 13H), 6.88 (dd, 1H), 4.77 (d, 1H, 12.9 Hz), 4.60 (d, 1 H, 12.9 Hz), 4.35 (br d, 1 H, 9Hz), 3.61 (s, 3H), 3.24 (dd, 1H), 3.17 (dd, 1 H), 2.74 (dd, 1 H), 2.64 (br d, 1 H), 0.89 (s, 9H), 0.07 (s, 3H),-0.02 (s, 3H).

MS (ESP+) m/z 533.69 (MH+), 555.21 (M+Na).

H1 NMR (CD30D, 300MHz, minor diastereoisomer): 8 8.15 (d, 1H), 7.37- 7.11 (m, 12H), 7.11 (dd, 1H), 7.03 (td, 1H), 4.42 (d, 1H, 13.7 Hz), 4.33 (d, 1H, 13.7 Hz), 4.30 (br, 1H), 3.56 (s, 3H), 3.50 (dd, 1H), 3.28 (dd, 1H), 2.95 (dd, 1H), 2.66 (br, 1H), 0.80 (s, 9H),-0.06 (s, 3H),-0.12 (s, 3H). MS (ESP+) m/z 533.70 (MH+), 555.18 (M+Na).

88% yield (at 85% conversion). MS (ESP+) m/z 547.70 (MH+), 569.22 (M+Na). H1 NMR (CDCl3, 300MHz, mixture of diastereoisomers 2: 2: 1): 8 7.98,7.83 and 7.76 (d, 1H), 7.61,7.50 and 7.42 (d, 1H), 7.35-6.88 (m, 12H), 4.76 and 4.64 (d, 2H), 4.44 (d, 1H), 4.31,4.26, and 4.14 (s, 1 H), 3.59 and 3.56 (s, 3H), 3.34 (m, 1H), 1.45 and 1.38 (d, 3H), 0.92,0.89 and 0.85 (s, 9H), 0.11, 0.10 and 0.01 (s, 3H), 0.05,0.03 and-0.02 (s, 3H).

quantitative yield, ratio 7: 3. MS (ESP+) m/z 369.24 (MH+), 391.21 (M+Na).

H1 NMR (CDCl3, 300MHz, major diastereoisomer): # 7.36-7.13 (m, 8H), 6.87 (d, 2H), 4.11 (s, 1H), 3.55 (s, 3H), 3.24 (dd, 1H, 9.9-4.2 Hz), 3.18 (dd, 1H, 13.6-4.2 Hz), 2.80 (dd, 1 H, 13.6-9.9 Hz), 1.19 (s, 9H).

H1 NMR (CD30D, 300MHz, minor diastereoisomer): 8 7.36-7.13 (m, 8H), 7.08 (d, 2H), 4.14 (s, 1 H), 3.62 (s, 3H), 3.12 (dd, 1 H, 13.6-4.2 Hz), 2.97 (dd, 1 H, 9. 9-4. 2 Hz), 2.63 (dd, 1 H, 13.6-9.9 Hz), 1.36 (s, 9H).

79% yield, ratio 2: 1. MS (ESP+) m/z 361.65 (MH+), 383.14 (M+Na).

H1 NMR (CD30D, 300MHz, major diastereoisomer): 5 7.74 (d, 2H), 7.42- 7.10 (m, 7H), 4.85 (d, 1H, 13Hz), 4.72 (d, 1H, 13Hz), 4,40 (s, 1H), 3, 64 (s, 3H), 2.79 (d, 1H, 5.9Hz), 1.72 (m, 11H), 0.88 (s, 9H), 0.09 (s, 3H), 0.03 (s, 3H).

H1 NMR (CD30D, 300MHz, minor diastereoisomer): 8 7.76 (d, 2H), 7.42- 7.10 (m, 7H), 4.56 (d, 1H, 13Hz), 4.50 (d, 1H, 13Hz), 4.36 (s, 1H), 3.68 (s, 3H), 3.03 (d, 1 H, 5.9Hz), 1.72 (m, 11 H), 0.82 (s, 9H),-0.02 (s, 3H),-0.06 (s, 3H).

77% yield (at 40% conversion).

H1 NMR (CDCl3, 300MHz): å 7.42-7.27 (m, 5H), 4.22 (s, 1H), 3.66 (s, 3H), 2.94 (br s, 1H), 2.33 (m, 1H), 2.07 (m, 1H), 1.90-1.20 (m, 8H), 1.02 (s, 9H).

MS (ESP+) m/z 347.64 (MH+), 369.17 (M+Na).

81% yield (at 64% conversion).

H1 NMR (CDCI3,300MHz): 8 7.40-7.26 (m, 5H), 6.60 (br s, 1H), 3.90 (m, 4H), 3.64 (s, 3H), 2.50 (t, 2H, 6.9Hz), 2.00 (t, 2H, 6.9Hz), 1.62 (m, 4H), 1.06 (s, 9H). MS (ESP+) m/z 405.68.

77% yield (at 50% conversion).

H1 NMR (CDCl3, 300MHz): 8 7.42-7.35 (m, 5H), 6.61 (s, 1H), 4.25 (s, 1H), 3.93 (m, 2H), 3.68 (m, 2H), 3.67 (s, 3H), 2.30 (ddd, 1H), 1.98 (ddd, 1H), 1.57-1.42 (2H), 1.07 (s, 9H). MS (ESP+) m/z 349.19 (MH+), 371.17 (M+Na). quantitative yield (at 40% conversion). H1 NMR (CDCl3, 300MHz) 8 7.4-7.27 (m, 5H), 6.54 (br s, 1 H), 4.23 (s, 1 H), 3.67 (s, 3H), 2.85 (m, 2H), 2.58 (m, 2H), 2.40 (m, 1H), 2.15 (m, 1H), 1.80 (m, 2H). MS (ESP+) m/z 365.17 (MH+), 387.17 (M+Na).

58% yield. MS (ESP+) m/z 368.24 (MH+).

H1 NMR (CDCI3,300MHz) 5 7.42-7.25 (m, 5H), 6.62 (s, 1H), 4.24 (d, 1H), <BR> <BR> 3.04 (dt, 1 H), 2.93-2.70 (m, 5H), 2.20 (ddd, 1 H), 1.90 (ddd, 1H), 1.10 (s, 9H).

88% yield, ratio 2: 1. MS (ESP+) m/z 321.26 (MH+), 343.22 (M+Na).

H1 NMR (CDCl3, 300MHz, major diastereoisomer): 8 7.40-7.27 (m, 5H), 6.90 (s, 1H), 4.18 (s, 1H), 3.68 (s, 3H), 2.85 (d, 1H, 4.5Hz), 2.12 (m, 1H), 1.21 (s, 9H), 1.04 (d, 3H, 6.9Hz), 0.93 (d, 3H, 6.9Hz).

H1 NMR (CDCI3, 300MHz, minor diastereoisomer): # 7.40-7.27 (m, 5H), 6.86 (s, 1H), 4.22 (s, 1H), 3.64 (s, 3H), 2.57 (d, 1H, 4.5Hz), 2.02 (m, 1H), 1.37 (s, 9H), 0.85 (d, 3H, 6.9Hz), 0.83 (d, 3H, 6.9Hz).

61 % yield, ratio 4: 3. MS (ESP+) m/z 356.21 (MH+), 378.17 (M+Na).

H1 NMR (CDC13,300MHz, major diastereoisomer): 8 8.55 (m, 1H), 7.66 (m, 1H), 7.54 (m, 1H), 7.38-7.25 (m, 5H), 7.20 (m, 1H), 4.36 (s, 1H), 4.17 (s, 1 H), 3.65 (s, 3H), 1.21 (s, 9H).

H1 NMR (CDC13,300MHz, minor diastereoisomer): 8 8.50 (m, 1H), 7.59 (m, 1 H), 7.47 (m, 1H), 7.38-7.25 (m, 5H), 7.16 (m, 1 H), 4.44 (s, 1H), 4.06 (s, 1 H), 3.69 (s, 3H), 1.32 (s, 9H).

48% yield, ratio 3: 2. MS (ESP+) m/z 356.67 (MH+), 378.19 (M+Na).

H1 NMR (CDCI3,300MHz, major diastereoisomer): 8 8.47 (d, 1 H), 8.52 (dd, 1 H), 7.68 (dt, 1H), 7.58 (dt, 1H), 7.39-7.21 (m, 5H), 6.99 (br s, 1H), 4.33 (s, 1 H), 4.00 (s, 1 H), 3.70 (s, 3H), 1.36 (s, 9H).

H1 NMR (CDCl3, 300MHz, minor diastereoisomer): 8 8.60 (d, 1H), 8.56 (dd, 1H), 7.49 (dt, 1 H), 7.47 (dt, 1 H), 7.39-7.21 (m, 5H), 7.01 (br s, 1 H), 4.28 (s, 1 H), 4.08 (s, 1 H), 3.70 (s, 3H), 1.27 (s, 9H).

50% yield, ratio 1: 1. MS (ESP+) m/z 356.24 (MH+), 378 (M+Na).

H1 NMR (CDC13, 300MHz, mixture of diastereoisomers): 8 8.59 and 8.53 (d, 1 H, 6.1Hz), 7.39-7.25 (m, 5H), 7.18 and 7.14 (d, 2H), 6.94 and 6.84 (br s, 1 H), 4.31 and 4.27 (s, 1 H), 4.04 and 3.97 (s, 1 H), 3.71 (s, 3H), 1.34 and 1.25 (s, 9H).

40% yield, ratio 1: 1. MS (ESP+) m/z 351.13 (MH+), 373.12 (M+Na).

H1 NMR (CDC13,300MHz): 8 7.43-7.23 (m, 5H), 4.23 and 4.20 (s, 1H), 3.67 and 3.66 (s, 3H), 3.21 (s, 2H), 3.03 (t, 2H, 7.2Hz), 2.59 (t, 2H, 7.2Hz), 1.13 and 1.02 (s, 9H). quantitative yield, ratio 1: 1.

H1 NMR (CDCl3, 300MHz): 8 7.42-7.08 (m, 8H), 6.89 (d, 2H), 4.20 (s, 1H), 3.67 and 3.60 (s, 3H), 3.40 and 3.12 (dd, 1H, 8.2-4.5 Hz), 3.26 and 3.20 (dd, 1 H, 13.8-4.5), 2.89 and 2.68 (dd, 1 H, 13.8-8.2Hz), 1.99-0.85 (m, 1 OH).

quantitative yield, ratio 2: 1. MS (ESP+) m/z 393.19 (MH+), 415.17 (M+Na).

H1 NMR (CDC13, 300MHz, major diastereosiomer): 8 8.00 (s, 1H), 7.39-7.36 (m, 10H), 6.07 (m, 1H), 4.15 (s, 1H), 3.54 (s, 3H), 3.35 (dd, 1H, 8.6-4.0 Hz), 3.25 (dd, 1 H, Hz), 2.82 (dd, 1 H, 13.7-8.6Hz), 2.08 (m, 2H), 1.90 (m, 2H), 1.57 (m, 4H).

H1 NMR (CDCl3, 300MHz, minor diastereosiomer): 5 8.35 (s, 1H), 7.27-7.03 (m, 8H), 6.78 (d, 2H0, 6.22 (m, 1H), 4.15 (s, 1H), 3.61 (s, 3H0, 3.20 (dd, 1H, 13.8-4.0 Hz), 3.08 (dd, 1H, 9.9-4. 0Hz), 2.61 (dd, 1H, 13.8-9.9Hz), 2.15 (m, 3H), 1.78-1.56 (m, 5H).

86% yield. MS (ESP+) m/z 438.65 (MH+).

MS (ESP+) m/z 438.33.

NMR, MS, IR and yield not determined.

MS (ESP+) m/z 424.25 (MH+).

Example II (Preparation of Intermediary Compound of Formula 3 and Conversion Thereof into Desired Compound of Formula 1) The respective compounds of Formula 3 were obtained according to Scheme 2 as follows: Formula 2 RT, 1 to 2 Formula 3

Scheme 2 General Procedure Several of the compounds of Formula 2 (made as shown above in Example I) were each respectively dissolve in MeOH (10mL/mmol) and Pd (OH) 2 (0.2 to 0.8 eq) was added. Each respective mixture was degassed and H2 gas was added. This procedure was repeated three times. Then, each respective mixture was allowed to stir under a H2 atmosphere until the reaction was complet.

Each respective crude concentrate mixture was filtered through Celte tu and washed with MeOH (10 ml/mmol). Each respective filtrate was concentrated to lead to a crude.

Each respective crude concentrate was dissolve in Et20 and washed with 2N HCI (10 mUmmol) twice. The combined aqueous layers were basified to pH-8 by addition of K2CO3 solid, and then extracted with Et20 (10 mUmmol) twice. The combined organic layers were dried over Na2SO4 and concentrated to lead to the desired products of Formula 3 as follows: major

73% yield. MS (ESP+) m/z 231.17 (M+Na). <BR> <BR> <P>H1 NMR (CD30D, 300MHz): # 7.74 (d, 1H, 8.4Hz), 7.38 (d, 1H, 8.4Hz),<BR> <BR> 7.30 (td, 1H, 7.6-1.7Hz), 7.17 (td, 1H, 7.6-1.7Hz), 4.64 (s, 2H), 3.44 (dd, 1H, 6-6.6Hz), 1.86 (m, 1H), 1.70 (m, 1H), 1.05 (t, 3H). minor 57%yield. <BR> <BR> <P>H1 NMR (CD30D, 300MHz): 8 7.67 (dd, 1H), 7.34-7.22 (m, 7H), 7.13 (td,<BR> <BR> 1H), 4.40 (s, 2H), 3.72 (dd, 1H, 7.6-6. 1Hz), 3.11 (dd, 1H, 13.4-6. 1Hz), 2.94<BR> <BR> (dd, 1 H, 13.4-7.6Hz). MS (ESP+): m/z 271.04 (MH+), 293.04 (M+Na). major 72%yield.

H1 NMR (CD30D, 300MHz): 8 7.73 (d, 1H), 7.35-7.23 (m, 7H), 7.13 (td,<BR> 1H), 4.52 (s, 2H), 3.81 (dd, 1H, 7.2-6.4Hz), 3.14 (dd, 1H, 13.3-6.4 Hz), 3.00 (dd, 1 H, 13.3-7.2Hz), 0.89 (s, 9H), 0.06 (s, 3H), 0.03 (s, 3H). MS (ESP+): m/z 385.29 (MH+), 407.30 (M+Na). major

NMR, MS, IR and yield not determined. 0 11 HZN CN H major NMR, MS, IR and yield not determined.

95% yield.

H1 NMR (CD30D, 300MHz): 8 7.68 (dd, 1H, 8.1-0.9 Hz), 7.20 (d, 1H, 8.1), 7.16 (t, 1H, 8.1), 7.05 (dt, 1H, 8.1-0.9 Hz), 2.26 (s, 3H), 1.99 (m, 2H), 1.75- 1.50 (m, 8H). MS (ESP+): m/z 233.10 (MH+).

58%yield.

H1 NMR (CD30D, 300MHz): 8 7.57 (d, 1H), 7.35-7.25 (m, 2H), 7.06 (td, 1H), 4.61 (m, 4H), 2.27 (m, 2H), 2.25 (s, 3H), 1.85 (m, 2H), 1.72 (m, 2H), 1.62 (m, 2H). MS (ESP+): m/z 291.07 (MH+). 0 H2N to X N H racemic 35%yield. <BR> <BR> <P>H1 NMR (CDC13,300MHz, racemic): # 7.34-7.19 (m, 5H), 3.74 (m, 1H), 3.56<BR> <BR> (dd, 1H, 9.2-4.1 Hz), 3.23 (dd, 1H, 13.9-4.1 Hz), 2.90 (dd, 1H, 13.9-9.2 Hz), 1.85 (m, 2H), 1.68 (m, 2H), 1.6-1.07 (m, 6H). o IF N N racemic ' 77% yield.

H1 NMR (CD30D, 300MHz, racemic): 8 7.30-7.13 (m, 5H), 3.43 (m, 1H), 2.90 (dd, 1 H), 2.77 (dd, 1 H), 1.21 (s, 9H).

71% yield.

H1 NMR (CD30D, 300MHz): 8 1.85 (m, 2H), 1.68-1.44 (m, 8H), 1.30 (s, 9H).

MS (ESP+): m/z 199.22 (MH+), 221.21 (M+Na).

88% yield.

H1 NMR (CD30D, 300MHz): 8 3.81-3.65 (m, 4H), 2.11 (m, 2H), 1.33 (s, 9H), 1.32 (m, 2H). MS (ESP+): m/z 201.22 (MH+), 233.19 (M+Na).

39% yield.

H1 NMR (CD30D, 300MHz): õ 3.91 (m, 4H), 2.62 (m, 4H), 2.28 (m, 4H), 1.35 (s, 9H). MS (ESP+): m/z 257.15 (MH+).

NMR, MS, IR and yield not determined. quantitativeyield.

H1 NMR (CD30D, 300MHz): 8 2.90-2.70 (m, 4H), 2.06 (ddd, 1 H), 1.86 (ddd, 1H), 1.58 (m, 2H), 1.14 (s, 9H). MS (ESP+) m/z 200.06 (MH+).

NMR, MS, IR and yield not determined.

NMR, MS, IR and yield not determined.

NMR, MS, IR and yield not determined.

Then the respective compounds of Formula 1 were obtained according to Scheme 3 as follows: ICI 6N, reflux 18h H2NC iR H2N C RZ H RsR2 OH Formula 3 Formula 1 Scheme 3 General Procedure To each respective compound of Formula 3 was added HCI 6N (10mL/mmol) and the reaction mixture was stirred at reflux for 24 h. Next, each respective mixture was cooled to room temperature and extracted with ether (10 mL/mmol) twice. For each, the aqueous layer was then concentrated to afford the following desired alpha-amino acid compounds of Formula 1 in the form of the hydrochloride salt:

quantitativeyield.

H1 NMR (CD30D, 300MHz, HCI salt): 8 2.11 (m, 2H), 1.84-1.46 (m, 8H).

MS (ESP+): m/z 144.19 (MH+). quantitativeyield.

H1 NMR (CD30D, 300MHz, HCI salt): 8 3.85 (m, 4H), 2.21 (m, 4H), 1.85 (m, 4H). MS (ESP+) m/z 146.02 (MH+).

NMR, MS, IR and yield not determined. major

quantitativeyield.

H1 NMR (CD30D, 300MHz, HCI salt): 8 3.93 (t, 1 H, 6Hz), 1.96 (m, 2H), 1.06 (t, 3H, 7.7Hz). MS (ESP+) m/z 104.22 (MH+). quantitative yield.

H1 NMR (CD30D, 300MHz, racemic HCI salt): 8 7.41-7.25 (m, 5H), 4.25 (dd, 1H, 7.6-5 Hz), 3.31 (dd, 1H, 14.6-5 Hz), 3.14 (dd, 1H, 14.6-7.6 Hz). 0 han OH major H1 NMR (CD30D, 300MHz, HCI salt): 5 7.45-7.29 (m, 5H), 4.24 (dd, 1H, 7.5-5.4 Hz), 3.31 (dd, 1H, 14.2-5.4 Hz), 3.16 (dd, 1H, 14.2-7.5 Hz). MS (ESP+): m/z 165.97 (MH+). αD=+12 (c=0.2, H20). o u OH OH minor U

87% yield.

H1 NMR (CD30D, 300MHz, HCI salt): 8 7.40-7.26 (m, 5H), 4.26 (dd, 1H, 7.8-5.3 Hz), 3.31 (dd, 1H, 14.6-5.3), 3.14 (dd, 1H, 14.6-7.8 Hz). MS (ESP+) 166.00 (MH+).

60%yield.

H1 NMR (CD30D, 300MHz, HCI salt): 8 2.36-2.12 (m, 3H), 2.02-1.69 (m, 5H). MS (ESP+) m/z 155.05 (M-2). quantitativeyield.

H1 NMR (CD30D, 300 MHz, HCI salt): å 3.6-2.96 (m, 4H), 2.67-1.88 (m, 4H).

NMR, MS, IR and yield not determined.

NMR, MS, IR and yield not determined.

NMR, MS, IR and yield not determined.

Example III (Preparation of N-protected Compound of Formula 1) N-Protection with Fmoc.

The respective N-protected compounds of Formula 1 were obtained according to Scheme 4 as follows: FmocOSu, HCI, HZN C dioxane FmocHN C R3XR2 OH b R3XR2 OH 9%NaHCO3 Formula 1 Formula 1 with Fmoc as N-protecting group

Scheme 4 General Procedure Several of the amino-acid compounds (HCI salt) of Formula 1 (made as shown above in Example II) were respectively dissolve in a solution of NaHCO3 (10mL/mmol) and a solution of FmocOSu in dioxan (10mL/mmol) was added to each. Each mixture was stirred for 0.5 h and then diluted with H20 and AcOEt (1 OmL/mmol).

After extraction the aqueous layer for each was extracted with AcOEt (10mL/mmol, twice). The combined organic layers were washed by H20 (10mL/mmol). The aqueous phase was acidified with a 2N HCI solution to pH-2 and extracted with AcOEt (10mUmmol, twice). The combined organic layers were dried over Na2SO4 and concentrated to lead to the desired products of N-protected Formula 1 as follows: 0 <\ FmocHN C", N D N H i racemic 61 % yield.

H1 NMR (CDCl3, 300MHz, racemic): 8 7.76 (d, 2H, 7.8Hz), 7.55 (d, 2H, 7.8Hz), 7.40 (t, 2H, 7.8Hz), 7.30 (dt, 2H, 7.8-1.4Hz), 7.27-7.15 (m, 5H), 5.40 (br d, 1H), 4.42 (m, 2H), 4.29 (m, 1H), 4.19 (t, 1H), 1.87 (m, 1H),

25% yield.

H1 NMR (CD30D, 300MHz): å 7.78 (d, 2H, 7.4Hz), 7.68 (d, 2H, 7.4Hz), 7.38 (dt, 2H, 7.4-1.4Hz), 7.30 (dt, 2H, 7.4-1.4 Hz), 4.31 (d, 2H, 6.8 Hz), 4.21 (t, 1H, 6.8 Hz), 2.06 (m, 2H), 1.81 (m, 2H), 1.58 (m, 4H). MS (ESP+) m/z 366.14 (MH+).

97% yield.

H1 NMR (CD30D, 300MHz): å 7.78 (d, 2H, 7.4Hz), 7.67 (d, 2H, 7.4Hz), 7.37 <BR> <BR> (dt, 2H, 7.4-1.3 Hz), 7.29 (dt, 2H, 7.4-1.3 Hz), 4.36 (br d, 2H, 6.2 Hz), 4.20 (t, 1H, 6.2Hz), 3.74 (m, 2H), 3.60 (m, 2H), 2.08 (m, 2H), 1.95 (m, 2H). MS (ESP+) m/z 368.10 (MH+). major 65% yield. H1 NMR (CD30D, 300MHz): 8 7.78 (d, 2H, 7.2 Hz), 7.66 (d, 2H), 7.37 (t,<BR> <BR> 2H), 7.29 (dt, 2H, 7.2-1.3Hz), 4.34 (m, 2H), 4.22 (t, 1H, 7Hz), 4.06 (dd, 1H,<BR> <BR> 5.6-9.6Hz), 1.87 (m, 1H), 1.70 (m, 1H), 0.97 (t, 3H, 7.1Hz). ao=+18 (c=0.16, DMF). MS (ESP+) m/z 326.14 (MH+), 348.08 (M+Na).

ll FmocHNC OH CT /major 44%yield. <BR> <BR> <BR> <BR> <P>H1 NMR (CD30D, 300MHz): 8 7.77 (d, 2H, 7.8Hz), 7.58 (d, 2H, 7.8Hz), 7.38<BR> <BR> <BR> <BR> <BR> (t, 2H, 7.8Hz), 7.31-7.14 (m, 6H), 4.41 (dd, 1H, (m,<BR> <BR> <BR> <BR> 3H), 3.20 (dd, 1H, 14-4.8Hz), 2.93 (dd, 1H, 14-9.2Hz). MS (ESP+) m/z 388.12 (MH+), 410.15 (M+Na).

MS (ESP+) m/z 379.21.

N-Protection with BOC.

The respective N-protected compounds of Formula 1 were obtained according to Scheme 5 as follows: Boy20) O H2N C dioxane BCHf 2 OH 3 2 9%NaHC03

Formula 1 Formula 1 with BOC as N-protecting group Scheme 5 General Procedure Several of the amino-acid compounds (HCI salt) of Formula 1 (made as shown above in Example II) were respectively dissolve in a solution of NaHCO3 (10mL/mmol) and a solution of BOC20 in dioxan (10mUmmol) was added to each. Each mixture was stirred for 0.5 h and then diluted with H20 and AcOEt (10mL/mmol).

After extraction the aqueous layer for each was extracted with AcOEt (10mUmmol, twice). The combined organic layers were washed by H20 (10mUmmol). The aqueous phase was acidified with a 2N HCI solution to pH-2 to 4 and extracted with AcOEt (10mL/mmol, twice). The combined organic layers were dried over Na2SO4 and concentrated to lead to the desired products of N-protected Formula 1 as follows: 0 BOCHN Cl., ND N H jj racemic 54% yield.

H1 NMR (CDC13,300MHz, racemic): 8 7.33-7.14 (m, 5H), 5.40 (br s, 1H), <BR> <BR> 5.10 (br s, 1H), 4.20 (dd, 1H, 8.6-5.8Hz), 3.66 (m, 1H), 3.10 (dd, 1H, 13.2-<BR> <BR> 5.8 Hz), 2.95 (dd, 1H, 13.2-8.6 Hz), 1.85-0.78 (m, 10H), 1.41 (s, 9H).

15%yield.

H1 NMR (CD30D, 300MHz): å 1.96 (m, 2H), 1.78 (m, 2H), 1.64-1.48 (m, 4H), 1.43 (s, 9H). MS (ESP+) m/z 266.11 (M+Na).

46% yield.

H1 NMR (CD30D, 300MHz): 8 3.76 (dt, 2H, 11.9-4.0 Hz), 3.65 (td, 2H, 11.9- 4.0 Hz), 2.07 (m, 2H), 1.92 (m, 2H), 1.42 (s, 9H). MS (ESP+) m/z 268.07 (M+Na).

95% yield. H1 NMR (CD30D, 300MHz): # 3.89 (dd, 1H, 8.2-4.8 Hz), 1.81 (m, 1H), 1.65 (m, 1H), 1.44 (s, 9H), 0.96 (t, 3H, 7.4 Hz). aD=+13 (c=0.15, ethanol). MS (ESP+) m/z 226.02 (M+Na).

0 BOCHN C'OH COOH major major 92%yield. <BR> <BR> <BR> <P>H1 NMR (CD30D, 300MHz): 8 7.30-7.14 (m, 5H), 4.33 (dd, 1H, 9.1-5.1 Hz),<BR> <BR> <BR> 3.14 (dd, 1H, 13.3-5. 1Hz), 2.89 (dd, 1H, 13.3-9. 1Hz), 1.36 (s, 9H). ao=-10 (c=0.2, Ethanol). MS (ESP+) m/z 288.11 (M+Na). 0 ""OH OH minor

32% yield.

H1 NMR (DMSO-d6,300MHz): 8 7.12-7.04 (m, 5H), 4.06 (m, 1H), 2.99 (m, 1 H), 2.79 (m, 1 H). MS (ESP+) m/z 258.05 (M+Na).

MS (ESP) m/z 258.05 (M+Na).

It will be understood that various details of the invention may be changed without departing from the scope of the invention. Furthermore, the above description is for the purpose of illustration only, and not for the purpose of limitation-the invention being defined by the claims.