Description of the Prior Art Small peptides are excellent starting points for drug design because they have the potential to overcome the pharmacokinetic shortcomings of larger peptides, yet retain the desirable quality ofmolecular recognition. A number of dipeptides are currently being developed as novel pharmaceutical agents (see e. g., Blackburn et al., Bioorg. Med. Chem. Lett., 7: 823-26 (1997); Schullek et al., Anal. Biochem., 246: 20-29 (1997), each incorporated by reference herein). Unfortunately, even small peptides suffer from proteolytic instability which limits their use as drug candidates.

Anhydrides and their derivatives have a rich history both in terms of their synthetic utility as well as their biological relevance (see e. g., Tarbell, Accounts Chem. Res., 2: 296-300 (1969); Martin et al., Chem., 27: 90-95 (1987), each incorporated by reference herein). Anhydrides are widely known to serve as potent inhibitors of a variety of enzymes (see e. g., Karibian et al., Biochemistry, 13: 2891 (1974), incorporated by reference herein), with a number of anhydrides recently being reported as effective inactivators of various serine proteases (see e. g., Iijima et al., Biorg. Med. Chem. Lett., 9: 413 (1999), incorporated by reference herein).

Pyrophosphate and related analogs are a class of phosphorus-based anhydrides that have gained attention for their ability to inhibit osteoclastic bone resorption, and therefore are useful therapeutic agents to treat and prevent osteoporosis (see e. g., Sato et al., J Med. Chem., 42: 1 (1999), incorporated by reference herein). Biphosphonates, synthetic nonhydrolyzable P-C-P analogs of pyrophosphates, are highly effective agents for inhibiting osteoclastic bone resorption (see e. g., Russell et al., Bone, 25: 97 (1999); Teronen et al., Ann. N. Y Acad. Sci., 878: 453-65 (1999), each incorporated by reference herein). Biphosphonic acids have also proven to be effective inhibitors of squalene synthase, a crucial enzyme in the role of cholesterol biosynthesis.

Thus, there is a need to develop new pyrophosphate analogs which improve the therapeutic properties of biphosphonates.

SUMMARY OF THE INVENTION The present invention is broadly concerned with new phosphonamide compounds and methods of forming such compounds.

In more detail, the compounds are phosphonamidic anhydrides, and more particularly chiral phosphonamidic anhydrides. The preferred compounds are represented by a formula selected from the group consisting of and wherein: each X is individually selected from the group consisting of oxygen,-NH, and-NOR' ; each R'is individually selected from the group consisting of hydrogen, substituted and unsubstituted amino acid side chains, and 2-15 mer peptides; and each W is individually selected from the group consisting of hydrogen, branched and unbranched alkyl groups (preferably Cl-Cl8, more preferably Cl-C8), branched and unbranched alkenyl groups (preferably C2-Cl8, more preferably C2-Cg), branched and unbranched alkynyl groups (preferably C2-Cl8, more preferably C2-

C8), allyl groups, acyl groups (preferably C2-Cl8, more preferably C2-C8) aryl groups (preferably c6-c12), 2-15 mer peptides, and benzyl groups.

Preferably at least one R'group comprises an amino acid side chain selected from the group consisting of wherein each R3 is individually selected from the group consisting of hydrogen, branched and unbranched alkyl groups (preferably Cl-Cl8, more preferably C-C8), branched and unbranched alkenyl groups (preferably c2-c18, more preferably c2-c8), branched and unbranched alkynyl groups (preferably c2-c18, more preferably c2-c8), allyl groups, aryl groups (preferably c6-c12), acyl groups (preferably c2-c18, more preferably c2-c8), and benzyl groups.

In a preferred embodiment, each R'is individually selected from the group consisting of -CH3, -CH2CH(R4)2, -CH2R4, and-CH (R4) 2, with each R4 being individually selected from the

group consisting of alkyl groups (preferably methyl), aryl groups (preferably phenyl), and benzyl groups, and each W is individually selected from the group consisting of-CH3 and-CHCH2.

Two particularly preferred compounds according to the invention comprise a formula selected from the group consisting of The inventive compounds are formed by reacting an allylated compound with a phosphonic compound to form an intermediate compound which is the dimerized. Preferred allylated compounds comprise the formula wherein: R'is selected from the group consisting of hydrogen, substituted and unsubstituted amino acid side chains, and 2-15 mer peptides; and is selected from the group consisting of hydrogen, branched and unbranched alkyl groups (preferably Cl-C18, more preferably Cl-C8), branched and unbranched alkenyl groups (preferably C2-Cls, more preferably C2-Cs), branched and unbranched alkynyl groups (preferably c2-c18, more preferably c2-c8), allyl groups, aryl groups (preferably C6-Cl2), acyl groups (preferably c2-c18 more preferably C2-C8), 2-15 mer peptides, and benzyl groups.

Preferred phosphonic compounds comprise the formula R4POY2,

wherein: R4 is selected from the group consisting of hydrogen, branched and unbranched alkyl groups (preferably Cl-Cl8, more preferably c1-c8), branched and unbranched alkenyl groups (preferably c2-c18, more preferably C2-C8), branched and unbranched alkynyl groups (preferably C2-Cl8, more preferably C2-C8), allyl groups, aryl groups (preferably c6-c12), acyl groups (preferably C2-Cl8, more preferably C2-C8), 2-15 mer peptides, and benzyl groups; and each Y is individually selected from the group consisting of the halogens.

The intermediate compound comprises a formula selected from the group consisting of and wherein: R'is selected from the group consisting of hydrogen, substituted and unsubstituted amino acid side chains, and 2-15 mer peptides; R2 is selected from the group consisting of hydrogen, branched and unbranched alkyl groups (preferably C-Cl8, more preferably c1-c8), branched and unbranched alkenyl groups (preferably c2-c18, more preferably C2-C8), branched and unbranched alkynyl groups (preferably C2-Clg, more preferably C2-C8), allyl

groups, aryl groups (preferably C6-CI2), acyl groups (preferably C2-Cl8, more preferably C2-C8), 2-15 mer peptides, and benzyl groups; and each Y is individually selected from the group consisting of the halogens.

Preparing the phosphonamide compounds according to the inventive methods results in a yield of those compounds of at least about 70%, and preferably at least about 95%, wherein the theoretical yield is taken as 100%.

Optionally, the phosphonamide compound can be subjected to a ring-closing metathesis reaction in the presence of a ring-closing catalyst to yield a bicyclic phosphonamide. Preferred ring-closing catalysts are olefin metathesis catalysts such as Grubbs catalysts (see e. g., U. S.

Patent Nos. 6,048,993,5,917,071,5,750,815,5,710,298,5,342,909, and 5,312,940, each incorporated by reference herein) as well as those disclosed by the following references, each also incorporated by reference herein: Matthias, Org. Ltrs., 1 (6): 953-56 (1999); Schrock, Macromolecules, 29 (19): 6114-25 (1996); Zhu et al., J Amer. Chem. Soc., 121 (36): 8251-59 (1999); Alexander et al., J ; Amer. Chem. Soc., 120 (16): 4041-42 (1998); and Kingsbury et al., J.

Amer. Chem. Soc., 121 (4): 791-99 (1999).

Particularly preferred Grubbs catalysts are those selected from the group consisting of Preferably the reacting step is carried out at a temperature of from about 15-80°C, and more preferably from about 30-55 °C. Furthermore, the reacting step should be carried out in a solvent system comprising a solvent selected from the group consisting of toluene, benzene,

chlorobenzene, dichlorobenzene, methylene chloride, dimethoxyethane (DME), and mixtures thereof.

It will be appreciated that the inventive methods allow for the synthesis of a wide array of both symmetric and unsymmetric cyclic and acyclic phosphonamide compounds.

Furthermore, the inventive methods allow for preparation of, or selection of, templates having particular functional groups bonded thereto which are then readily formed into the desired phosphonamide in a controlled and repeatable manner. Because the method can be adapted to form phosphonamide compounds comprising one or more amino acid side chains or peptides bonded thereto, the inventive compounds can be used to inhibit enzymes (such as squalene synthetase), to act as osteoporitic agents, and to regulate plant growth.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLES The following examples set forth preferred methods in accordance with the invention.

It is to be understood, however, that these examples are provided by way of illustration and nothing therein should be taken as a limitation upon the overall scope of the invention.

A number of abbreviations are used herein. These abbreviations and the term or terms that they represent are set forth in Table A.

Table A Abbreviation Term (s) hex hexane Bn benzyl Ph phenyl Me methyl Et ethyl Bocbutoxy carbonyl EtOAc ethyl acetate Et3N triethyl amine tBuO tert-butoxy Grubbs Catalysts were used in some of the following Examples. These catalysts are referred to as follows:

Grubbs Catalyst 1 Grubbs Catatlyst 2 Grubbs Catalyst 3 EXAMPLE 1 Scheme A depicts the general overall reaction scheme followed in Parts 1-11 below, as well as the various compounds which can be prepared according to the procedure described in this example.

Scheme A

In this and the following procedure descriptions, the number/letter abbreviation depicted in the particular reaction scheme follows the chemical name of the particular compound (e. g., "(20)" follows "allylated leucine methyl ester").

I. Preparation of Leucine-Derived Methyl Phosphonamidic Chloridates (26PSS and 26PRS) Methylphosphonic dichloride (23) (1.0 mL, 11.04 mmol) and CH2C12 (20 mL) were added to a flame-dried 100 mL round bottom flask under argon atmosphere. The reaction flask was cooled to 0°C, and Et3N (6.26 mL, 45.0 mmol) was added dropwise, followed by a catalytic amount of 4-dimethylaminopyridine (DMAP) (5 mol %). After stirring at 0°C for 5 minutes, 0.98 equivalents of allylated leucine methyl ester (20) (2.0 g, 10.82 mmol) in CH2C12 (5 mL) was added via cannulae. The reaction mixture was refluxed and monitored by TLC. Once complete, the reaction mixture was concentrated under reduced pressure, diluted with EtOAc, filtered, and further concentrated under reduced pressure. Flash chromatography (Si02, 3: 1 Hex/EtOAc) gave 2.94g (95%) of a light yellow oil consisting solely of the two diastereomeric chloridates (26pua and (26PRS) (see Scheme B). Further chromatography (SiO2, 8: 1 Hex/EtOAc) yielded portions of the separated isomers for characterization.

Scheme B 26PSS 26PRS The leucine-derived methyl phosphonamidic chloridate (26PSS or 26PRS, top Rf) was characterized as follows: TLC Rf = 0.39 (1: 1 Hex: EtOAc); [a] 25 =-42. 3 (c = 2.44, CHC13) ;.

FTIR 1742,1445,1368,1240 (P=O) cm-1 ;'HNMR (400 MHz, CDCl3) 8 5.78 (dddd, 16.9,10.2, 6.5,6.5 Hz, 1H), 5.22 (dd, J= 17. 2,1.2 Hz, 1H), 5.14 (d, J = 10. 1 Hz, 1H), 4.40 (ddd, JEffl = 12. 1 Hz, JHH = 7.5,7.5 Hz, 1H), 3.75-3.67 (m, 2H), 3.68 (s, 3H), 1.96 (d, Jap 16. 3 Hz, 3H), 1.70 (dd,

J= 7.3,6.3 Hz, 2H), 1.65-1.52 (m, 1H), 0.91 (d, J= 6.4 Hz, 3H), 0.90 (d, J= 6.5 Hz, 3H) ;"C NMR (100 MHz, CDC13) 8 172. 37,134.68 (d, JCP = 3.0 Hz), 118.04,55.87,52.05,47.16 (d, Jcp = 4.5 Hz), 38.49 (d, Jcp = 5. 7 Hz), 24.52,22.65 (d, JCP = 118. 9 Hz), 22.65,21.53 ; 31p NMR (162 MHz, CDCl3) 8 48.02; HRMS calculated for C11H23ClNO3P (M+H) + required 282.1026, found 282.1049.

The leucine-derived methyl phosphonamidic chloridates (26PRS or 26pus, bottom Rf) were characterized as follows: TLC Rf= 0.38 (1: 1 Hex: EtOAc); [a] 25 =-13.1 (c = 1. 44, CHCL) ; FTIR 1742,1440,1373,1245 (P=O) cm-1; 1H NMR (400 MHz, CDC13) 8 5.81-5.69 (m, 1H), 5.20-5.08 (m, 2H), 4.51 (ddd, Je = 9.2 Hz, JHH = 6.2,6.2 Hz, 1H), 3.76-3.66 (m, 2H), 3.62 (s, 3H), 1.98 (d, JHP = 16.0 Hz, 3H), 1.73-1.64 (m, 2H), 1.64-1.51 (m, 1H), 0.89 (d, J= 6. 3 Hz, 3H), 0.88 (d, J= 6.5 Hz, 3H) ; 13C NMR (100 MHz, CDC13) 6172. 56 (d, Jcp = 6.2 Hz), 134.08 (d, Jcp =2. 8 Hz), 118.06,55.35 (d, Jcp=2. 0Hz), 51.97,46.47 (d, Jcp= 5.1 Hz), 37.14 (d, Jcp=2. 1 Hz), 24.31,22.80,22.28 (d, Jcp = 117.3 Hz), 21.20 ; 3'P NMR (162 MHz, CDC13) 8 47.98; HRMS calculated for C11H23ClNO3P (M+H) + required 282.1026, found 282.1047.

II. Preparation of Leucine-Derived VInyl Phosphonamidic Chloridates (30PSS and 30PRS) CH2Cl2 (36 mL) and vinylphosphonic acid (1 mL, 12.86 mmol) were added to a flame- dried 100 mL round bottom flask under an inert atmosphere. The reaction mixture was stirred vigorously, and oxalyl chloride (3.36 mL, 38. 6 mmol) was added followed by the addition of a catalytic amount of dimethyl formamide (DMF) (1 drop). The system was stirred for 2 hours (until gas evolution was no longer apparent). Upon completion of the reaction, the mixture was concentrated under reduced pressure to yield the vinylphosphonic dichloride (24) as a yellow oil.

This oil was diluted with CH2Cl2 (20 mL) while precaution was taken to avoid exposure to moisture. The mixture was then cooled to 0°C and Et3N (6.26 mL, 45.0 mmol) was added dropwise followed by DMAP (5 mol %). After stirring the reaction mixture at 0°C for 5 minutes, allylated leucine methyl ester (20) (2.38g, 12.86 mmol) in CH2C12 (5 mL) was added via cannulae. The reaction mix was refluxed and monitored by TLC. Once complete, the reaction mixture was concentrated under reduced pressure, diluted with EtOAc, filtered, and further concentrated under reduced pressure. Flash chromatography (3: 1 Hexane/EtOAc) gave the two diastereomeric leucine-derived phosphonamidic chloridates (30PS and 30PS (3.58 g,

95%) (see Scheme C) as a light yellow oil. These phosphonamidic chloridates were not further characterized.

Scheme C 30PSS 30PRS In Parts I-II of this procedure, methylene chloride was the solvent utilized. However, acetonitrile, chloroform, toluene, benzene, tetrahydrofuran (THF), diethyl ether, dimethoxyethane (DME), and mixtures thereof are also suitable solvents. Furthermore, while Et3N was used as the base, other bases which could be used include pyridine, NaHC03, Na2CO3, K2CO3, NaH, KH, any tertiary amine, and mixtures thereof. Finally, while the procedure was carried out at temperatures of 0-20 ° C, temperatures of anywhere from about-20-20 ° C would also be suitable.

EXAMPLE 2 Scheme D depicts the general overall reaction scheme followed in Parts I-VIII below, as well as the various compounds which can be prepared according to the procedure described in this example.

Scheme D R1 RZ O RZ O R1 "I pl-I 1-1p,'i", O Cl N 0 O SPsPsS t f j OMe J SPSPSS C2-Symmetric C2-Symmetric 4-lla 25-32-PSS Et3N or O RZ Rl (neat) P'*% oye \pu OMe = i P P !)) MeOzC N"0 N"COzMe 0 25-32-PRS SPRPRS 25: Rl=CH3 ; R2=CH3 C2-Symmetric 26: Rl = CH2CHMe2 ; R2 = CH3 4-llb 27: Rl = CH2Ph ; R2 = CH3 or 28: Rl = CHMe2 ; R2 = CH3 29:Rl = CH3 ; R2 = CHCH2 Rl R2 0 R2 0 30: R'= CH2CHMe2 ; R2=CHCH2 31: R'= CH2Ph ; R2=CHCH2 MeO2C N O N CO2Me 32: Rl=CHMe2 ; RZ = CHCHZ SPRPSS Pseudo-Meso 4-llc 4: R1 = CH3 ; R2 = CH3 5: R1 = CH2CHMe2; R2 = CH3 6: R1 = CH2Ph ; R2 = CH3 7: R1 = CHMe2 ; R2 = CH3 8: R1 = CH3 ; R2 = CHCH2 9: R1 = CH2CHMe; R2 = CHCH2 10: R1 = CH2Ph; R2 = CHCH2 11: R1 = CHMe2 ; R2 = CHCH2

I. Preparation ofAlanine-Derived Methyl Phosphonamidic Anhydrides (4a-c) A neat mixture of the diastereomeric leucine phosphonamidic chloridates (25PRS) and (25PA (500 mg, 2.09 mmol) was allowed to sit at ambient temperature over a period of 2-4 days. The slurry was partitioned between EtOAc and water. The water layer was re-extracted with EtOAc, and the organic layers were combined, dried with Na2SO4, and concentrated under reduced pressure to leave a crude oil. Flash chromatography (SiO2, EtOAc) afforded 120 mg (27%) of the pseudo-meso diastereomer (4c) and 137 mg (31%) of an inseparable mixture of C2- symmetric diastereomers (4a) and (4b), both as colorless oils. Scheme E depicts each of these compounds.

Scheme E CH3 Me O Me O g3 Cg3 Me O Me O = 1/=//_ =/l 1 P P P Pw MeO2C N O N CO2Me MeO2C N O N CO2Me SPSPSS SPRPRS C2-Symmetric C2-Symmetric 4a 4b CH30 Me, 0 CH MeO2C N O N CO2Me SPRPSS Pseudo-Meso 4e The C2-symmetric alanine-derived methyl phosphonamidate anhydrides (4a, b) were characterized, as a mixture, as follows: TLC Rf = 0. 10 (EtOAc); FTIR 2992, 2951,1740,1457, 1437,1382,1232,1170 cm- 1; 1H NMR (400 MHz, CDCl3) 8 5.82-5.72 (m, 4H, mix), 5.23-5.07 (m, 8H, mix), 4.54-4.48 (m, 2H, mix), 4.42-4.33 (m 2H, mix), 3.79-3.61 (m, 8H, mix), 3.67 (s,

6H), 3.66 (s, 6H), 1.73 (d, JHP = 16.6 Hz, 6H), 1.71 (d, JHP = 16.9 Hz, 6H), 1.43 (d, J= 7.2 Hz, 6H), 1.42 (d, J= 7.3 Hz, 6H) ; 13C NMR (100 MHz, CDCl3) 8 173.46,173.20,135.71,135.33, 117.30,117.08,53.49,52.99,52.02,52.02,46.52,46.32,16.97,16.1 0,15.53 (dd, Jcp = 137.7, 6.2 Hz), 14.99 (dd, Jcp = 136. 6,4.6 Hz); 3'P NMR (162 MHz, CDCl3) 8 29.47,29.41; HRMS calculated for C16H31N2O7P2 (M+H) + required 425.1614, found 425.1612.

The pseudo-meso alanine-derived methyl phosphonamidic anhydride (4c) was characterized as follow: TLC Rf = 0.15 (EtOAc); [a] 25 =-0.33 (c = 0.60, CHCl3) ; FTIR 2989, 2950,1740,1457,1437,1381,1241 cm-1 ; 1H NMR (400 MHz, CDCl3) b 5.84- 5.72 (m, 2H), 5.18 (dd, J = 17. 3,1. 3 Hz, 1H), 5.16 (dd, J= 17. 2,1.3 Hz, 1H), 5.10-5.05 (m, 2H), 4.52 (dq, JHP = 11. 1 Hz, JHH= 7.3 Hz, 1H), 4.23 (dq, JHP = 14. 3 Hz, JHH = 7. 1 Hz, 1H), 3.75-3.59 (m, 4H), 3.66 (s, 3H), 3.65 (s, 3H), 1.72 (d, JHP = 16. 5 Hz, 3H), 1.66 (d, JHP = 16. 6 Hz, 3H), 1.45 (d, J= 7. 2 Hz, 3H), 1.41 (d, J= 7.3 Hz, 3H) ; 13C NMR (100 MHz, CDCl3) 8 173.48,173.08,135.35,135.35, 117.40,117. 32,53.90,53.06,52.02,51.98,47.14,46.25,17.05,15.96,15.23 (dd, JCP = 140.2, 6.5 Hz), 14.77 (dd, Jcp = 139. 6,6.9 Hz) ; 3'P NMR (162 MHz, CDCl3) 8 28.95 (d, Jpp = 34.4 Hz), 28.94 (d, Jpp = 34.4 Hz); HRMS calculated for C16H31N2O7P2 (M+H) + required 425.1614, found 425.1606.

II. Preparation of Leucine-Derived Methyl Phosphonamidic Anhydrides (5a-c) Et3N (450, uL, 3.22 mmol) was added to a neat solution of a mixture of the diastereomeric leucine phosphonamidic chloridates (26PRS) and (26PA (260 mg, 0.92 mmol) at 0°C. The mixture was heated at 45 ° C and monitored by TLC and 31P NMR. The resulting salty slurry was diluted with EtOAc (10 mL), filtered (10 mL), and concentrated under reduced pressure to yield 236 mg (quantitative) of a mixture of the three diastereomeric anhydrides as a yellow oil. Flash chromatography (Si02, 1: 1 Hex/EtOAc) afforded 46 mg (20%) ofthe pseudo-meso diastereomer (5c) and 132 mg (56%) of a mixture of the C2-symmetric diastereomers (5a) and (5b). The mixture comprised of 16 mg (7%) of a single C2-symmetric diastereomer (5a) or (5b), 104 mg (44%) of a mixture of C2-symmetric diastereomers (5a) and (5b), and 12 mg (5%) of a sample of C2-symmetric diastereomer (5b) or (5a) at 90% purity, all as colorless oils.

The pseudo-meso leucine-derived methyl phosphonamidic anhydride (5c) was characterized as follows: TLC Rf= 0.4 (EtOAc); [a] 25 = -17. 06 (c = 0.59, CHCl3) ; FTIR 1749, 1714,1422, 1363, 1222 (P=O) cm-1 ;'H NMR (400 MHz, CDCl3) 8 5.87-5.75 (m, 2H), 5.18 (dd,

J = 17. 1,1.3 Hz, 1H), 5.14 (dd, J= 17. 1,1.3 Hz, 1H), 5.12-5.06 (m, 2H), 4.49 (ddd, JHP = 10. 7 Hz, JHH = 10.7,5.4 Hz, 1H), 4.34 (ddd, JHP = 9.2 Hz, JHH = 9.2,5.3 Hz, 1H), 3.75-3.58 (m, 4H), 3.68 (s, 3H), 3.66 (s, 3H), 1.83-1.60 (m, 6H), 1.74 (d, JHP = 16. 8 Hz, 3H), 1.69 (d, JHP = 16. 7 Hz, 3H), 0.92 (d, J= 6.2 Hz, 6H), 0.91 (d, J= 6.2 Hz, 6H) ;"C NMR (100 MHz, CDCl3) 8 173.67 (d, JCP = 2. 2Hz), 173.20,135.34,135.34,117.77,117.48,56.32 (d, JCP = 2.9 Hz), 55.93 (d, JCP = 3. 6 Hz), 51.94,51.90,47.24 (d, Jcp = 4.9 Hz), 46.45 (d, Jcp = 4.9 Hz), 38. 98 (d, Jcp = 3.7 Hz), 37.57 (d, Jcp=2. 6 Hz), 24.51,24.19,22.95,22.87,21.51,21.33,15.49 (dd, Jcp = 129. 5,4.3 Hz), 14.80 (dd, Jcp = 127. 7,4.5 Hz) ; 31P NMR (162 MHz, CDCl3) 8 29.19 (d, JPP = 35. 5 Hz), 28.41 (d, Jpp = 35. 5 Hz); HRMS calculated for C23H43N2O7P2(M+H)+ required 509.2546, found 509.2545.

The C2-symmetric leucine-derived methyl phosphonamidic anhydride, single diastereomer (5a or 5b, top Rf) was characterized as follows: TLC Rf= 0.22 (EtOAc); [a] 25 = -37.8 (c = 0.32, CHCl3) ; FTIR 1740,1437,1387,1241 (P=O) cm-1 ;'H NMR (400 MHz, CDCl3) 8 5.79 (dddd, J= 16.9,10.2,6.2,6.2 Hz, 2H), 5.21 (dd, J= 15. 9,1.2 Hz, 2H), 5.12 (dd, J= 9.8, 0.9 Hz, 2H), 4.49-4.42 (m, 2H), 3.79-3.57 (m, 4H), 3.67 (s, 6H), 1.81-1.59 (m, 6H), 1.75 (d, JHP = 17. 0 Hz, 6H), 0.94 (d, J= 6.0 Hz, 6H), 0.93 (d, J= 6.2 Hz, 6H) ; 13C NMR (100 MHz, CDCl3) # 173. 33,135.59,117.62,56.11,51.95,46.95,38.71,24.57,22.94,21.31,1 5.67 (dd, JCP = 130. 9, 5.6 Hz); 3'P NMR (162 MHz, CDCl3) 8 29.88; HRMS calculated for C23H43N2O7P2 (M+H)+ required 509.2546, found 509.2526.

The C2-symmetric leucine-derived methyl phosphonamidic anhydride, single diastereomer (5b or 5a, bottom Rf at 90% purity) was characterized as follows: TLC Rf = 0.22 (EtOAc) ; [a] 25 = -5. 0 (c = 0. 24, CHCl3) ; FTIR 1740,1437,1387,1241 (P=O) cm-1 ;'HNMR (400 MHz, CDCl3) 8 5.79 (dddd, J = 16. 8,10.1,6.6,6.6 Hz, 2H), 5.17 (dd, J= 16. 7,1.3 Hz, 2H), 5.10 (dd, J= 9.1,1.0 Hz, 2H), 4.52-4.42 (m, 2H), 3.66-3.54 (m, 4H), 3.68 (s, 6H), 1.80 (d, JHP = 15. 8 Hz, 6H), 1.78-1.53 (m, 6H), 0.94 (d, J= 6.0 Hz, 6H), 0.93 (d, J= 6.2 Hz, 6H) ; 13C NMR (100 MHz, CDCl30 8 173.48,135.13,117.47,55.65,51.91,46.35,37.46,24.34,22.99,21. 21,15.27 (dd, Jcp = 130.9,5.6 Hz); 3'P NMR (162 MHz, CDCl3) 8 30.14 HRMS calculated for C23H43N2O7P2 (M+H)+ required 509.2546, found 509.2561.

In this part of this example, Et3N was used as the base. However, other bases could be used, including pyridine, NaHC03, Na2CO3, K2CO3, NaH, KH, any tertiary amine, and mixtures thereof. Finally, while the procedure was carried out at temperatures of 0-20°C, temperatures of from about -20-20°C would also be suitable.

III. Preparation of Phenylalanine-Derived Methyl Phosphonamidic Anhydrides (6a-c) A mixture of the diastereomeric vinyl chloridates 27PSS) and (27PRS) (820 mg, 2.60 mmol) was subjected to the conditions described in Part I of this example. Flash chromatography (SiO2, 1: 1 Hex/EtOAc) afforded 195 mg (26%) of the pseudo-meso diastereomer (6c) and 172 mg (23%) of an inseparable mixture of C2-symmetric diastereomers (6a) and (6b), both as colorless oils.

The pseudo-meso phenylalanine-derived methyl phosphonamidic anhydride (6c) was characterized as follows: TLC Rf= 0.4 (EtOAc); [a] 25 = -11. 79 (c = 0. 60, CHCl3) ; FTIR 1739, 1455,1437,1379,1241, 1169 cm-1; 1H NMR (400 MHz, CDCl3) 8 7.36-7.15 (m, 10H), 5.80-5.65 (m, 2H), 5.19 (dd, J= 17. 1,0.9 Hz, 2H), 5.11 (d, J = 10.1 HZ, 2H), 4.68 (ddd, J =12. 9Hz, J = 9. 6,5.9 Hz, 1H), 4.64 (ddd, JHP = 13. 4 Hz, JHH = 10. 0,6.0 Hz, 1H), 3.69 (s, 3H), 3.68 (s, 3H), 3.65-3.61 (m, 2H), 3.61-3.42 (m, 2H), 3.35 (ddd, JHH = 14.3, 5.7 Hz, JHP = 5.7 Hz, 2H), 3.09 (ddd, J= 14. 4,9.9,2.8 Hz, 2H), 1.59 (d, JHP = 16. 9 Hz, 3H), 0.97 (d, J= JHP = 16. 8 Hz, 3H) ; 13C NMR (100 MHz, CDCl3) 8 172.41,172.25,137.62,137.51,134.75,134.59,129.35,129.31, 128.38,128.36,128.26,126.57,126.50,118.25,117.98,59.03 (d, JCP = 4.0 Hz), 58.96 (d, JCP= 4.1 Hz), 52.03,51.96,47.05 (d, JCP = 5.4Hz), 46.90 (d, Jcp=4. 9Hz), 35.94,35.30,14.92 (d, JCP = 128.0 Hz), 14.00 (d, JCP = 126.6 Hz); 3'P NMR (162 MHz, CDCl3) 28.96 (d, Jpp = 36.7 Hz), 28.12 (d, Jpp = 36.7 Hz); HRMS calculated for C28H39N2O7P2 (M+H0+ required 577.2233, found 577.2232.

The C2-symmetric phenylalanine-derived methyl phosphonamidic anhydride, single diastereomer (6a or 6b, top Rf) was characterized as follows (contamination with other diastereomer does not allow for optical rotation measurement): TLC Rf= 0.15 (EtOAc); FTIR 1746,1456, 1437,1313,1218, 737, 702 cm-1; 1H NMR (400 MHz, CDCl3) 7. 35-7. 18 (m, 1 OH), 5.75-. 35 (m, 2H), 5.17-5.04 (m, 2H), 4.65-4.54 (m, 2H), 3.71-3.57 (m, 4H), 3.69 (s, 6H), 3.33- 3.26 (m, 2H), 3.14-3.08 (m, 2H), 1.53 (d, JHP = 17.2 Hz, 6H) ; 13C NMR (100 MHz, CDCl3) 8 172.41,137.45,134.28,129.12,128.20,126.27,117.90,58.33,51.87 ,46.90,34.92,15.13 (dd, Jcp = 135. 7,4.3 Hz); 31p NMR (162 MHz, CDCl3) 8 29.36; LRMS calculated for C28H39N2O7P2 (M+H)+ required 577.6, found 577.6.

The C2-symmetric phenylalanine-derived methyl phosphonamidate anhydride, single diastereomer (6a or 6b, bottom Rf) was characterized as follows (contamination with other diastereomer does not allow for optical rotation measurement): TLC Rf = 0.15 (EtOAc); FTIR

1746, 1456,1437,1313, 1218,737, 702 cm-1; 1H NMR (400 MHZ, CDCl3) # 7.35-7.18 (m, 10H), 5.75-5.35 (m, 2H), 5.17 (d, J= 17. 1 Hz, 2H), 5.10 (d, J= 10. 5 Hz, 2H), 4.68-4.61 (m, 2H), 3.71- 3.57 (m, 4H), 3.66 (s, 6H), 3.38-3.33 (m, 2H), 3.15-3.11 (m, 2H), 1.48 (d, JHP = 17. 0 Hz, 6H); "C NMR (100 MHz, CDCl3) 8 172.23,137.45,134.48,129.08,128.12,126.44,118.08,58.90, 51.92,47.40,36.12,14.96 (dd, JCP = 134.6,4.4 Hz) ; 31P NMR (162 MHz, CDCl3) 8 30.10; LRMS calculated for C28H39N2O7P2 (M+H) + required 577.6, found 577.6.

IE Preparation of Valine-derived Methyl Phosphonamidic Anhydrides (7a-c) A mixture of the diastereomeric vinyl chloridates (28PSS) and (28PRS) (505 mg, 1.89 mmol) was subjected to the conditions described in Part I of this example. Flash chromatography (Si02, 1: 1 Hex/EtOAc) afforded 91 mg (20%) ofthe pseudo-meso diastereomer (7c) and 195 mg (43%) of an inseparable mixture of C2-symmetric diastereomers (7a) and (7b), both as colorless oils.

The characterization of the pseudo-meso valine-derived methyl phosphonamidic anhydride (7c) was as follows: TLC Rf= 0.20 (EtOAc); [a] 25 = -60. 51 (c = 0.43, CHCl3) ; FTIR 1739,1437,1371,1311,1246,1204cm-' ;'HNMR (400 MHz, CDCl3) 8 5.86-5.71 (m, 2H), 5.14 (dd, J= 17.1,1.3 Hz, 2H), 5.09-5.05 (m, 2H), 3.96-3.85 (m, 2H), 3.81-3.71 (m, 2H), 3.69-3.61 (m, 2H), 3.67 (s, 3H), 3.66 (s, 3H), 2.33-2.16 (m, 2H), 1.67 (d, JHP = 16. 5 Hz, 3H), 1.65 (d, JHP = 16. 6 Hz, 3H), 0.97 (d, J= 6.7 Hz, 3H), 0.93 (d, J= 6.7 Hz, 3H), 0.89 (d, J= 6.6 Hz, 3H), 0.88 (d, J= 6.5 Hz, 3H) ; 13C NMR (100 MHz, CDCl3) 8 172.12,171.79,135.18,135.08,117.67, 117. 45,63.51,63.49,51.57,51.49,46.44 (d, JCP = 3.9 Hz), 45.92 (d, JCP = 3.3 Hz), 27.59 (d, JCP = 3.0 Hz), 26.81,19.72,19.62,19.39,19.39,15.60 (dd, Jcp = 132.7,8.8 Hz), 15.63 (dd, JCP = 134.8,8.4 Hz) ; 3'P NMR (162 MHz, CDCl3) 8 29.19 (d, Jpp = 35.4 Hz), 28.4119 (d, Jpp = 35.4 Hz). HRMS calculated for C20H39N207P2 (M+H) + required 481.2233, found 481.2234.

Characterization ofthe C2-symmetric valine-derived methyl phosphonamidate anhydride, single diastereomer (7a or 7b, top Rf) was as follows (contamination with other diastereomer does not allow for optical rotation measurement): TLC Rf= 0.10 (EtOAc); FTIR 1739,1436, 1370,1309,1245,1204 cm-' ;'H NMR (400 MHz, CDCl3) 8 5.76-5.61 (m, 2H), 5.10-5.01 (m, 4H), 3.86-3.80 (m, 2H), 3.78-3.42 (m, 4H), 3.60 (s, 6H), 2.25-2.13 (m, 2H), 1.70 (d, JHP = 16. 7 Hz, 3H), 1.67 (d, JHP = 16. 8 Hz, 3H), 0.90-0.83 (m, 12H) ; 13C NMR (100 MHz, CDCl3) 6 172. 17, 134.91,117.67,63.37,51.65,45.91,27.75,26.91,19.79,16.03 (dd, JCP = 133.6,3.8 Hz); 31p

NMR (162 MHz, CDCl3) 8 30.20; LRMS calculated for C20H39N2O7P2 (M+H)+ requried 480.1, found 480. 1.

Characterization of the C2-symmetric valine-derived methyl phosphonamidate anhydride, single diastereomer (7a or 7b, bottom Rf) was as follows (contamination with other diastereomer does not allow for optical rotation measurement): TLC Rf= 0.10 (EtOAc); FTIR 1739,1436, 1370, 1309, 1245,1204 cm-1; 1H NMR (400 MHz, CDC13) 8 5.84-5.73 (m, 2H), 5.19 (dd, J= 15.9,1.1 Hz, 2H), 5.12 (d, J= 8.8 Hz, 2H), 3.95-3.89 (m, 2H), 3.83-3.74 (m, 2H), 3.71-3.58 (m, 2H), 3.68 (s, 6H), 2.33-2.20 (m, 2H), 1.78 (d, JHP = 16. 9 Hz), 1.75 (d, JHp = 17. 1 Hz), 0.98-0.91 (m, 12H) ; 13C NMR (100 MHz, CDCl3) 8 172.16,135.25,117.77,63.24,51.62,46.37,27.75, 26.91,19.72,15.32 (dd, Jcp = 134.3,4.8 Hz); 3'P NMR (162 MHz, CDCl3) 8 29.94; LRMS calculated for C20H39N2O7P2 (M+H) + required 480.1, found 480.1.

V. Preparation ofAlanihe-Derived Vinyl Phosphonamidic Anhydrides (8a-c) A mixture of the diastereomeric vinyl chloridates (29PA and (29PRS) (1.22g, 4.86 mmol) was subjected to the conditions described in Part I of this example. Flash chromatography (SiO2, 1 : 1 Hex/EtOAc) afforded 338 mg (31%) ofthe pseudo-meso diastereomer (8c) and 218 mg (20%) of an inseparable mixture of C2-symmetric diastereomers (8a) and (8b), both as colorless oils.

The characterization ofthe pseudo-meso alanine-derived vinyl phosphonamidic anhydride (8c) was as follows: TLC Rf = 0.20 (EtOAc); [a] 25 = 2.93 (c = 0.82, CHCl3) ; FTIR 1738,1448, 1382,1221,1170 cm-1 ;'H NMR (400 MHz, CDCl3) 5 6. 38-6. 22 (m, 4H), 6.19-6.12 (m, 1H), 6.10-5.99 (m 1H), 5.82-5.69 (m, 2H), 5.14 (dd, J= 17. 1,1.3 Hz, 1H), 5.11 (dd, J= 17. 2,1.3 Hz, 1H), 5.07-5.02 (m, 2H), 4.45 (dq, JHP = 12. 0 Hz, J. = 7.3 Hz, 1H), 4.20 (dq, JHP = 14. 4 Hz, JHH = 7.2 Hz, 1H), 3.70-3.62 (m, 4H), 3.64 (s, 3H), 3.63 (s, 3H), 1.44 (d, J= 7.3 Hz, 3H), 1.40 (d, J= 7. 3 Hz, 3H) ; 13C NMR (100 MHz, CDCl3) # 173. 31 (d, JCP = 2.8 HZ), 173.00,135.25,135.10, 133.96,133.64,128.21 (dd, Jcp = 180.3,5.8 Hz), 127.09 (dd, Jcp = 181. 3,5.2 Hz), 117.62, 117.58,53.69 (d, Jcp = 3.7 Hz), 52.79 (d, Jcp = 4.1 Hz), 51.93,51.89,47.17 (d, Jcp = 4.3 Hz), 46.41 (d, Jcp 4.3 Hz), 16.90,15.76; 3'P NMR (162 MHz, CDCl3) 6 16.40 (d, JPP = 34. 5 Hz), 16.25 (d, Jpp = 34. 5 Hz); HRMS calculated for C18H31N2O7P2 (M+H) + required 449.1607, found 449.1613.

The characterization of the C2-symmetric alanine-derived vinyl phosphonamidic anhydride, single diastereomer (8a or 8b, top Rf) was as follows (contamination with other diastereomer does not allow for optical rotation measurement): TLC Rf = 0.10 (EtOAc); FTIR 1741,1450,1382,1224, 1170 cm-1; 1H NMR (400 MHz, CDcL3) 8 6.41-6.20 (m, 4H), 6.18-6.13 (m, 1H), 6.06-5.99 (m, 1H), 5.85-5.71 (m, 2H), 5.18 (d, J= 17. 2 Hz, 2H), 5.09 (d, J= 10.4 Hz, 2H) 4.31-4.22 (m, 2H), 3.72-3.62 (m, 4H), 3.67 (s, 6H), 1.48 (d, J= 7.3 Hz, 6H) ; 13C NMR (100 MHz, CDCl3) 8 173.39,135.40,133.99,128.18 (dd, JCP = 173. 2,5.0 Hz), 117.54,53.67,51.99, 47.01,16.94 ; 31p NMR (162 MHz, CDC13) 816. 69; LRMS calculated for C18H31N2O7P2 (M+H)+ required 449.4, found 449.4.

The characterization of the C2-symmetric alanine-derived vinyl phosphonamidic anhydride, single diastereomer (8a or 8b, bottom Rf) was as follows (contamination with other diastereomer does not allow for optical rotation measurement): TLC Rf = 0.10 (EtOAc); FTIR 1741,1450,1382,1224,1170 cm-1; 1H NMR (400 MHz, CDCl3) 8 6.41-6.20 (m, 4H), 6.18-6.13 (m, 1H), 6.06-5.99 (m, 1H), 5.85-5.71 (m, 2H), 5.15 (d, J = 16. 9 Hz, 2H), 5.06 (d, J= 11.0 Hz, 2H), 4.60-4.49 (m, 2H), 3.72-3.62 (m, 4H), 3.66 (s, 6H), 1.45 (d, J= 7.3 Hz, 6H) ; 13C NMR (100 MHz, CDC13) # 173.39, 135. 40,134.11,127.99 (d, JcP= 178. 8 Hz), 117.46,52.83,51.94,46.35, 15.97 ; 3'P NMR (162 MHz, CDCl3) 8 16.70; LRMS calculated for C18H31N2O7P2 (M+H)+ required 449.4, found 449.4.

VI. Preparation of Leucine-Derived Vinyl Phosphonamidic Anhydrides (9a-c) A mixture of the diastereomeric vinylchloridates (30PSS) and (30PRS) (355 mg, 1.21 mmol) was subjected to the conditions described in Part II of this example. Flash chromatogra- phy (Si02, 1: 1 Hex/EtOAc) afforded 135 mg (42%) of the pseudo-meso diastereomer (9c) and 126 mg (39%) of an inseparable mixture of C2-symmetric diastereomers (9a) and (9b), both as colorless oils.

The characterization ofthe pseudo-meso leucine-derived vinyl phosphonamidic anhydride (9c) was as follows: TLC Rf= 0.68 (EtOAc); [a] 25 = -15. 59 (c = 0.68, CHCl3) ; FTIR 1740,1649, 1461,1438,1387,1207 (P=O) cni-' ;'HNMR (400 MHz, CDCl3) #6. 45-6.22 (m, 4H), 6.19-6.11 (m, 1H), 6.06-5.98 (m, 1H), 5.82-5.72 (m, 2H), 5.13 (dd, J= 17.1,1.2 Hz, 2H), 5.09 (dd, J= 17.1,1.2 Hz, 2H), 4.46-4.40 (m, 1H), 4.33 (ddd, J= 13.2,9.5,5.3 Hz, 1H), 3. 64 (s, 3H), 3.64- 3.59 (m, 4H), 3.63 (s, 3H), 1.79-1.56 (m, 6H), 0.88 (d, J= 6.3 Hz, 6H), 0.87 (d, J= 6.2 Hz, 6H);

13C NMR (100 MHZ, CDCl3) # 173. 44 (d, JCP = 2.5 Hz), 173.14,135.05,135.05,133.52,133.52, 128.51 (dd, Jcp = 166. 4,8.2 Hz), 128.33 (dd, Jcp = 166. 4,9.0 Hz), 117.95,117.68,56.08 (d, JCP = 3.4 Hz), 55.68 (d, Jcp = 4.3 Hz), 51.85,51.76,47.11 (d, JCP = 5.2 Hz), 46.52 (d, Jcp = 5.2 Hz), 38. 71 (d, Jcp = 3. 6 Hz), 37. 61 (d, Jcp = 3.0 Hz), 24.32,24.06,22.83,22.83,21.50,21.34; 31p NMR (162 MHz, CDCl3) 8 16.48 (d, Jpp = 37.5 Hz), 15.78 (d, JPP = 37.5 Hz); HRMS calculated for C24H43N2O72 (M+H)+ required 533.2546, found 533.2550.

Characterization ofthe C2-symmetric leucine-derived vinyl phosphonamidic anhydrides (9a, b) as a mixture was as follows: TLC Rf = 0.24 (EtOAc); FTIR 1741,1642,1613,1469, 1438,1370,1233 (P=O), 1207 (P=O) cni-' ;'H NMR (400 MHz, CDCl3) 5 6.37-6.21 (m, 8H), 6.08 (ddd, J= 10.2,8.6,4.2 Hz, 2H), 5.94 (ddd, J= 10.2,8.5,4.3 Hz, 2H), 5.75-5.65 (m, 4H), 5.11-4.96 (m, 8H), 4.40-4.29 (m, 4H), 3.65-3.51 (m, 8H), 3.57 (s, 6H), 3.56 (s, 6H), 1.74-1.49 (m, 12H), 0.87-0.81 (m, 24H) ; 13C NMR (100 MHz, CDCl3) 8 173.05,172.93,135.08,135.01, 133.92,133.86,128.18 (dd, Jcp = 176.8,4.9 Hz), 127.98 (dd, Jcp = 174.9,4.1 Hz), 117.59, 117.33,55.67,55.50,51.66,51.60,46.62,46.22,38.32,37.49,24.17 ,23.98,22.71,22.71,21.13, 21.05 ; 31P NMR (162 MHz, CDCl3) 8 17. 46,16.80; HRMS calculated for C24H43N2O7P2 (M+H) + required 533.2546, found 533.2556.

VII. Preparation of Phenylalanine-Derived Vinyl Phosphonamidic Anhydrides (10a-c) A mixture of the diastereomeric vinyl chloridates (31PSS) and (31PRS) (248 mg, 0.76 mmol) was subjected to the conditions described in Part I of this example. Flash chromatography (SiO2, 1 : 1 Hex/EtOAc) afforded 61 mg (27%) of the pseudo-meso diastereomer (10c) and 64 mg (28%) of an inseparable mixture of c2-symmetric diastereomers (lOa) and (lOb), both as colorless oils.

Characterization ofthe pseudo-meso phenylalaninevinyl phosphonamidic anhydride (lOc) was as follows: TLC Rf = 0.60 (EtOAc); [a] 25 = -78. 33 (c = 0.66, CHCl3) ; FTIR 1740,1439, 1379,1242,1166,750,681 cm-' ; 1HNMR (400 MHz, CDCl3)# 7.31-7.12 (m, 10H), 6.34-6.15 (m, 2H), 6.12-5.94 (m, 1H), 5.82-5.55 (m, 5H), 5.17 (dd, J= 17.1,1.0 Hz, 1H), 5.14 (dd, J = 17.1,1.1 Hz, 1H), 5.11-5.06 (m, 2H), 4.69-4.59 (m, 2H), 3.64 (s, 3H), 3.64 (s, 3H), 3.61-3.57 (m, 2H), 3.52-3.48 (m, 2H), 3.36 (dd, J=12. 1,6.6 Hz, 1H), 3.32 (dd, J= 12. 0,6.5 Hz, 1H), 3.09 (dd, J= 14.5,7.8 Hz, 1H), 3.07 (dd, J= 14.6,8.0 Hz, 1H); 13C NMR (100 MHz, CDC13) 8 172.24, 172.12,137.52,137.49,134.57,134.45,133.66,133.55,129.27,129. 25,128.32 (dd, JCP = 181. 2,

7.2 Hz), 128.30,128.26,127.17 (dd, JCP = 184. 4,6.1 Hz), 126.44,126.42,118.30,118.22,58.71, 58.49,51.89,51.77,47.26,47.02,35.85,35.71 ; 3'P NMR (162 MHz, CDCl3) 8 15.90; HRMS calculated for C30H39N2O7P2 (M+H)+ required 601.2233, found 601.2233.

Characterization of the C2-symmetric phenylalanine-derived vinyl phosphonamidic anhydride, single diastereomer (lOa or lOb, top Rf) was as follows (contamination with other diastereomer does not allow for optical rotation measurement): TLC Rf = 0.30 (EtOAc); FTIR 1740,1437,1239,1168,750,681 cm-1; 1H NMR (400 MHz, CDCl3) 6 7.28-7.09 (m, 1 OH), 6.18- 5.43 (m, 8H), 5.16-5.01 (m, 4H), 4.71-4.63 (m, 1H), 4.54-4.46 (m, 1H), 3.59 (s, 6H), 3.55-3.47 (m, 2H), 3.36-3.26 (m, 4H), 3.13-3.03 (m, 2H) ; 13C NMR (100 MHz, CDC13) 8 171. 90,137.31, 134.41,133.63,129.05,128.05 (dd, Jcp = 177. 5,4.4 Hz), 127.99,126.18,117.87,58.64,51.66, 47.18,35.40 ; 3'P NMR (162 MHz, CDC13) 816. 98; LRMS calculated for C30H39N2O7P2 (M+H)+ required 601.3, found 601.3.

The characterization of the C2-symmetric phenylalanine-derived vinyl phosphonamidic anhydride, single diastereomer (lOa or lOb, bottom Rf) yielded the following (contamination with other diastereomer does not allow for optical rotation measurement): TLC Rf = 0.30 (EtOAc); FTIR 1740,1437,1239,1168,750,681 cm-1 ; 1H NMR (400 MHZ, CDCl3) # 7. 28-7.09 (m, 10H), 6.18-5.43 (m, 8H), 5.16-5.01 (m, 4H), 4.71-4.63 (m, 1H), 4.54-4.46 (m, 1H), 3.58 (s, 6H), 3.55-3.47 (m, 2H), 3.36-3.26 (m, 4H), 3.13-3.03 (m, 2H) ; 13C NMR (100 MHz, CDC13) 6 172. 05,137. 18, 134.45,133.75,128.96,128.12,127.39 (dd, Jcp= = 177. 0,4.6 Hz), 126.27,117.96, 58.14,51.64,46.84,35.69; 3'P NMR (162 MHz, CDC13) 8 17.56; LRMS calculated for C30H39N2O7P2 (M+H)+ requried 601.3, found 601.3.

VIII. Preparation of Valine-derived VInyl Phosphonaidic Anhydrides (11a-c) A mixture of the diastereomeric vinyl chloridates (32PSS) and (32PRS) (734 mg, 2.63 mmol) was subjected to the conditions described in Part I of this example. Flash chromatography (SiO2, 1: 1 Hex/EtOAc) afforded 241 mg (40%) of the pseudo-meso diastereomer (11c) and 266 mg (44%) of an inseparable mixture of C2-symmetric diastereomers (lla) and (llb), both as colorless oils.

The characterization ofthe pseudo-meso valine-derived vinyl phosphonamidic anhydride (11c) was as follows: TLC Rf= 0.50 (EtOAc); [a] 25 = -73. 42 (c = 0.54, CHCl3) ; FTIR 1738, 1479,1371,1247,1203 cm-' ; lH NMR (400 MHz, CDCL) 8 6.38-6.20 (m, 4H), 6.17-6.09 (m,

1H), 6.03-5.96 (m, 1H), 5.79 (dddd, J = 16. 9,10.1,6.8,6.8 Hz, 2H), 5.12 (d, J= 17. 1 Hz, 2H), 5.01 (dd, J= 10.0,1.5 Hz, 2H), 3.92 (t, J= 11.3 Hz, 1H), 3.86 (t, J= 11.0 Hz, 1H), 3.81-3.70 (m, 2H), 3.70-3.58 (m, 2H), 3.64 (s, 3H), 3.63 (s, 3H), 2.77-2.17 (m, 2H), 0.94 (d, J= 6.7 Hz, 3H), 0.90 (d, J= 6.7 Hz, 3H), 0.88 (d, J= 6.4 Hz, 3H), 0.87 (d, J= 6.4 Hz, 3H) ; 13C NMR (100 MHz, CDCl3) 8 172.02 (d, JCp=2. 9 Hz), 171.7 (d, Jcp = 1. 3Hz), 135.14,135.14,134.07,133.24, 128.75 (dd, JCP = 182.6,9.0 Hz), 128.12 (dd, JCP = 183.9, JCP = 8.9 Hz), 117.67,117.57,63.71 (d, Jcp = 4.1 Hz), 63.59 (d, JCP = 3.0 Hz), 51.40,51.31,46.45 (d, Jcp = 4.8 Hz), 46.16 (d, JCP = 4.0 Hz), 27.71 (d, Jcp = 3.3 Hz), 27.13 (d, JCP = 2.6 Hz), 19.77,19.65,19.59,19.46 ;"P NMR (162 MHz, CDCl3) 8 16.32 (d, Jpp = 35. Hz), 15.98 (d, Jpp = 35.9 Hz); HRMS calculated for C22H39N2O7P2 (M+H) + required 505.2223, found 505.2227.

The characterization of the C2-symmetric valine-derived vinyl phosphonamidic anhydride, single diastereomer (lla or 11b, top Rf) yielded the following (contamination with other diastereomer does not allow for optical rotation measurement): TLC Rf = 0.40 (EtOAc); FTIR 1738, 1436, 1371, 1243,1204 cm-1 ;'H NMR (400 MHz, CDCl3) S 6.36-6.22 (m, 4H), 6.19-6.10 (m, 1H), 6.03-5.97 (m, 1H), 5.82-5.71 (m, 2H), 5.15-5.02 (m, 4H), 3.94-3.87 (t, J= 11.8 Hz, 1H), 3.83 (t, J= 11. 7 Hz, 1H), 3.79-3.67 (m, 2H), 3.69-3.57 (m, 2H), 3.64 (s, 6H), 2.30- 2.17 (m, 2H), 0.90 (d, J= 6.5 Hz, 6H), 0.87 (d, J= 6.5 Hz, 6H) ; 13C NMR (100 MHz, CDCl3 6 171. 90, 135.06,134.61,127.88 (dd, Jcp = 175. 2,4.6 Hz), 117.72,63.34,51.44,46.25,27.68, 19.67,19.42; 3'P NMR (162 MHz, CDCl3) 816. 87; LRMS calculated for C22H39N2O7P2 (M+H)+ required 505.5, found 505.5.

Characterization of the C2-symmetric valine-derived vinyl phosphonamidic anhydride, single diastereomer (lla or 11b, bottom Rf) resulted in the following (contamination with other diastereomer does not allow for optical rotation measurement): TLC Rf = 0.40 (EtOAc); FTIR 1738,1436,1371,1243,1204 cm-1 ; NMR (400 MHz, CDC13) 8 6.36-6.22 (m, 4H), 6.19-6.10 (m, 1H), 6.03-5.97 (m, 1H), 5.82-5.71 (m, 2H), 5.15-5.02 (m, 4H), 3.94-3.87 (t, J= 11. 8 Hz, 1H), 3.83 (t, J= 11. 7 Hz, 1H), 3.79-3.67 (m, 2H), 3.69-3.57 (m, 2H), 3.62 (s, 6H), 2.30-2.17 (m, 2H), 0.95 (d, J= 6. 6 Hz, 6H), 0.87 (d, J= 6. 5 Hz, 6H); 13C NMR (100 MHz, CDC13) 8171. 90,135.10, 134.02,128.40 (dd, Jcp = 174.5,3.9 Hz), 117.56,63.62,51.39,45.99,27.09,19.72,19.53 ; 31p NMR (162 MHz, CDCl3) 8 17.20; LRMS calculated fo C22H39N2O7P2 (M+H)+ required 505.5, found 505.5.

EXAMPLE 3 Scheme F depicts the general overall reaction scheme followed in Parts 1-11 below, as well as the various compounds which can be prepared according to the procedure described in this example.

Scheme F Catalyst 1 ///"C",//0 0\\ RT, I hr p = \/) 90-100% N 0 N MeO2C N O N CO2Me l} J MeO2C X'CO2Me i rA A 9c 13c Bn C O ('O Bn Catalyst 1 RT 1 hr O O _ / / il'W 1'W 90-100% \Nj'y/P\N MC02C N 0 N CORME MC02C. 0 Bn Bn C02Me lOc 14c I. Preparation of Pseudo-meso Bicyclic Leucine-derived Phosphonamidic Anhydride (13c) Leucine-derived vinyl phosphonamidic anhydride (9c) (88 mg, 0.165 mmol) and CH2C12 (15 mL) were added to a flame-dried 25 mL round bottom flask. The mixture was stirred, and the system was purged with argon for 10 minutes using a gas aerating tube. The Grubbs Catalyst 1 (6.8 mg, 8 pmol) was added under argon, and the reaction mixture was stirred and monitored for disappearance of the starting material. Upon completion, the reaction was concentrated under reduced pressure, passed through a plug of silica using EtOAc, and further concentrated under reduced pressure to give a crude oil. Flash chromatography (sitz, 100% EtOAc) afforded the bicyclic phosphonamidic anhydride (13c) (75 mg, 96%) (see Scheme G) as a colorless oil.

Scheme G

Characterization of the pseudo-meso bicyclic leucine-derived phosphonamidic anhydride (13c) was as follows: TLC Rf= 0.20 (EtOAc); [α]25 = +11. 1 (c = 0.19, CHCl3) ; FTIR 1742, 1587,1451,1390,1346,1241 (P=O), 1199 (P=O) cm-1; 1H NMR (400 MHz, CDC13) 8 7. 11-7.06 (m, 1H), 7.00-6.95 (m, 1H), 6.25 (dd, J= 30. 3,9.0 Hz, 1H), 6.12 (dd, J= 30. 2,9.0 Hz, 1H), 4.47 (ddd, JHP = 9.4 Hz, JHH = 6.5,6.5 Hz, 1H), 4.29 (ddd, JHP = 7.2 Hz, JHH = 7.2,7.2 Hz, 1H), 4.17- 4.06 (m, 2H), 3.76- 3.67 (m, 2 H), 3.67 (s, 3H), 3.65 (s, 3H), 1.67-1.64 (m, 4H), 1.64-1.51 (m, 2H), 0.97 (d, J= 6.3 Hz, 3H), 0.93-0.90 (m, 9H) ; 13C NMR (100 MHz, CDCl3) b 173.60 (d, Jcp = 1. 2 Hz), 173.13 (d, JCP = 1.9 Hz), 146.15 (d, JCP = 17. 0 Hz), 145.75 (d, Jcp = 17. 4 Hz), 119.24 (d, Jcp = 161. 9 Hz), 118.62 (dd, Jcp = 166. 2,2.9 Hz), 52.20 (d, JCP = 4.1 Hz), 52.04 (d, Jcp = 4.5 Hz), 51.84,51.73,47.18 (d, Jcp = 31.8 Hz), 46.82 (d, Jcp = 31. 1 Hz), 39.14 (d, JCP = 3.4 Hz), 38.49 (d, JCP = 3.8 Hz), 24.48,24.47,23.06,22.99,21.28,21.07; 3'P NMR (162 MHz, CDCl3) 8 33. 55 (d, Jpp = 24.0 Hz), 32.38 (d, Jpp = 24.0 Hz); HRMS calculated for C20H35N2O7P2 (M+H)+ required 477.1919, found 477.1911.

II. Preparation of the Pseudo-meso Bicyclic Phenylalanine-Derived Phosphonamidic Anhydride (14c) In a procedure similar to the preparation of the bicyclic leucine-derived phosphonamidic anhydrides (13c) as described in Part I of this example, compound (10c) (102 mg, 0.170 mmol) was subjected to Grubbs Catalyst 1 (7.0 mg, 8, umol) in 15 mL CH2Cl2, Flash chromatography (SiO2, 100% EtOAc) afforded (14c) (86 mg, 93%) (see Scheme H) as a colorless oil.

Scheme H

Characterization of the resulting pseudo-meso bicyclic phenylalanine-derived phosphonamidic anhydride (14c) yielded the following: TLC Rf= 0.37 (EtOAc); [α]25 = -5. 4 (c = 0.74, CHCl3); FTIR 2949, 2923,2854,1740,1454,1439,1348,1318,1239,1207,1177,901, 749,698 cm-' ; IHNMR (400 MHz, CDCl3) 8 7.32-7.18 (m, 10H), 7.08-7.03 (m, 1H), 6.96-6.91 (m, 1H), 6.21 (dd, JHP = 30. 5 Hz, JE= 9.0 Hz, 1H), 5.94 (dd, JHP = 30. 2 Hz, JHH = 8.9 Hz, 1H), 4.66 (ddd, JHP = 7.7 Hz, JHH = 7. 7,7.7 Hz, 1H), 4.59 (ddd, Jlv=7. 8Hz, J =7. 8,7. 8 Hz, 1H), 4.16-4.09 (m, 2H), 3.88-3.77 (m, 2H), 3.63 (s, 3H), 3.86 (s, 3H), 3.32 (dd, J= 14. 1,7.8, Hz, 1H), 3.27 (dd, J= 13. 3,7.1 Hz, 1H), 3.09 (dd, J= 13. 7,8.0 Hz, 1H), 3.03 (dd, J= 14. 0,7.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) 8 172.14,171.95,146.12 (d, Jcp = 11. 5 Hz), 145.95 (d, Jcp = 11. 7 Hz), 136.82,136.26,129.19,128.79,128.53,128.46,126.82,126.77,119. 19 (d, JCP = 164, 4 Hz), 118.7 (d, Jcp = 163.7 Hz), 56.04 (d, Jcp = 4.8 Hz), 55.00 (d, Jcp = 4.3 Hz), 52.01,51.91,48.29 (d, JCP = 31. 3 Hz), 47.62 (d, JCP = 30. 9 Hz), 37. 05,36. 58 (d, Jcp = 3.7 Hz) ; 31P NMR (162 MHz, CDCl3) 8 33. 21 (d, Jpp = 24.9 Hz), 32. 24 (d, Jpp = 24.9 Hz); HRMS calculated for C26H31N2O7P2 (M+H)+ required 545.1606, found 545.1589.

In Parts I-II of this procedure, methylene chloride was the solvent utilized. However, toluene, benzene, chlorobenzene, dichlorobenzene, DME, and mixtures thereof are also suitable solvents. Furthermore, while Grubbs Catalyst 1 was used as the catalyst, it will be appreciated that Grubbs Catalyst 2 or 3 could also be utilized. Finally, while the procedure was carried out at a temperature of 40°C, temperatures of from about 15-80°C would also be suitable.