Phosphoramidate compounds and methods of use

Abstract

Phosphoramidate derivatives of nucleotides and their use in the treatment of cancer are described. The base moieties of, for example, each of deoxyuridine, cytarabine, gemcitabine and citidine may be substituted at the 5-position. The phosphoramidate moiety has attached to the P atom an aryl-O moiety and an -amino acid moiety. The -amino acid moiety may correspond to or be derived from either a naturally occurring or a non-naturally occurring amino acid.

Claims

.[.1. A chemical compound having formula I: ##STR00118## wherein: R is selected from the group comprising alkyl, aryl and alkylaryl; R and R are independently selected from the group comprising H, alkyl and alkylaryl, or R and R together form an alkylene chain so as to provide, together with the C atom to which they are attached, a cyclic system; Q is selected from the group comprising O and CH.sub.2; X and Y are independently selected from the group comprising H, halogen, OH and CH.sub.3; Ar is a monocyclic aromatic ring moiety or a fused bicyclic aromatic ring moiety, either of which said ring moieties is carbocyclic or heterocyclic and is optionally substituted, any such substituent being selected from the group comprising halogen, halomethyl, oxo, hyroxy, carboxy, carboxyC.sub.1-16 alkyl, alkoxy, alkoyl, alkoyloxy, aryloxy, aryloyl, aryloyloxy, amino, C.sub.1-6alkylamino, diC.sub.1-6alkylamino, cyano, azide, nitro, thiol, C.sub.1-6 alkylthiol, sulphony, sulphoxide, heteocyclic groups, alkyl groups and aryl groups; Z is H, n is 0, Z is NH.sub.2 and a double bond exists between position 3 and position 4, or a pharmaceutically acceptable derivative of a compound of formula I the derivative which upon administration to a recipient is capable of providing directly or indirectly a compound of formula I..].

.[.2. A compound according to claim 1 wherein R is selected from the group comprising a C.sub.1-16 primary or secondary alkyl group, a C.sub.5-7 carbocyclic aryl group or a C.sub.1-6alkylC.sub.5-11 aryl group..].

.[.3. A compound according to claim 2 wherein R is selected from the group CH.sub.3, C.sub.2H.sub.5 and CH.sub.2C.sub.6H.sub.5..].

.[.4. A compound according to claim 3 wherein R is CH.sub.2C.sub.6H.sub.5..].

.[.5. A compound according to claim 1 wherein Ar is an optionally substituted C.sub.6 monocyclic aromatic ring moiety..].

.[.6. A compound according to claim 5 wherein Ar is selected from the group comprising C.sub.6H.sub.5, pCF.sub.3C.sub.6H.sub.4, pFC.sub.6H.sub.4, pNO.sub.2C.sub.6H.sub.4, pClC.sub.6H.sub.4 and oClC.sub.6H.sub.4..].

.[.7. A compound according to claim 1 wherein R and R are, independently, selected from the group comprising H, C.sub.1-6 primary, secondary and tertiary alkyl, C.sub.1-3alkylC.sub.5-7 aryl, or, when together they form an alkylene chain, they provide, together with the C atom to which they are attached, a C.sub.3-8 carbocyclic aliphatic ring..].

.[.8. A compound according to claim 7 wherein R and R are, independently, selected from the group comprising H, methyl, benzyl and CH.sub.2CH(CH.sub.3).sub.2, or, R and R together with the C atom to which they are attached, provide a C.sub.5-6 ring..].

.[.9. A compound according to claim 8 wherein R and R are each methyl..].

.[.10. A compound according to claim 8 wherein one of R and R is H and one of R and R is methyl..].

.[.11. A compound according to claim 8 wherein R and R, together with the C atom to which they are attached, provide a pentyl ring..].

.[.12. A compound according to claim 1 wherein R and R correspond to the side chains of a naturally occurring amino acid..].

.[.13. A compound according to claim 1 wherein Q is O..].

.[.14. A compound according to claim 1 wherein, each of X and Y is F..].

.[.15. A compound according to claim 1 wherein, X is OH and Y is H..].

.[.16. A compound according to claim 1 wherein, X is H and Y is OH..].

.[.17. A compound selected from the group comprising: Gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate; Gemcitabine-[para-chlorophenyl-(benzoxy-L-alaninyl)]-phosphate and Gemcitabine-[para-chlorophenyl-(benzoxy-,-dimethylglycinyl)]-phosphate..].

.[.18. A compound according to claim 1 for use in the treatment of cancer..].

.[.19. A method for the treatment of cancer comprising administration to a patient in need of such treatment an effective dose of a compound according to claim 1..].

.[.20. A pharmaceutical composition comprising a compound according to claim 1 with a pharmaceutically acceptable carrier, diluent or excipient..].

.[.21. A method of preparing a pharmaceutical composition comprising the step of combining a compound according to claim 1 with a pharmaceutically acceptable excipient, carrier or diluent..].

.[.22. A process for the preparation of a compound of formula I according to claim 1, the process comprising reacting of a compound of formula (III): ##STR00119## with a compound of formula (IV) ##STR00120## wherein Ar, n, Q, R, R, R, X, Y, Z and Z have the meanings described in claim 1 and a double bond exists between position 3 and position 4..].

.Iadd.23. A compound of formula: ##STR00121## wherein Bn is benzyl..Iaddend.

.Iadd.24. A pharmaceutical composition comprising an effective amount of the compound of claim 23 and a pharmaceutically acceptable excipient, carrier, or diluent..Iaddend.

.Iadd.25. A method for the treatment of cancer comprising administering to a patient in need thereof an effective amount of the compound of claim 23..Iaddend.

Description

EXPERIMENTAL PROCEDURE

(1) General Methods

(2) The following anhydrous solvents and reagents were bought from Aldrich with sure stopper: dichloromethane (DCM), diethyl ether (Et.sub.2O), tetrahydrofuran THF), N-methylimidazole (NMI), methanol (MeOH), dimethylformamide (DMF), 1,4-dioxane. triethylamine was dried on molecular sieves of 4 Angstrom.

(3) Thin Layer Chromatography

(4) Thin layer chromatography (TLC) was performed on commercially available Merck Kieselgel 60 F.sub.254 plates and separated components were visualized using ultraviolet light (254 nm and 366 nm).

(5) Column Chromatography

(6) Columns were performed using (Kieselgel 60, 35-70 m, Fluka) as the stationary phase. Samples were applied as a concentrated solution in the same eluent, or pre-adsorbed onto silica gel.

(7) NMR Spectroscopy

(8) .sup.1H, .sup.13C and .sup.31P-NMR were recorded on a Bruker Avance DPX300 spectrometer with operating frequencies of 300 MHz, 75 MHz and 121 MHz respectively. .sup.31P-NMR spectra are reported in units of relative to 85% phosphoric acid as external standard, positive shifts are downfield. The following abbreviations are used in the assignment of NMR signals: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), bs (broad signal), dd (doublet of doublet), dt (doublet of triplet). Starred signal signal are splitted due to stereoisomeric mixtures.

(9) Standard Procedures

(10) For practical purposes, standard procedures are given where applicable.

(11) Standard Procedure 1: Synthesis of Amino Ester Hydrochloride Salts.

(12) To a stirring solution of anhydrous alcohol (10 mol eq.) was added thionyl chloride (2 mol eq.) at 0 C., and the resulting solution stirred for 1 hr. After warming to room temperature, the appropriate amino acid (1 mol eq) was added and the reaction heated at reflux for 6-16 hrs. Removal of solvent and recrystallisation from methanol/ether gave the amino ester hydrochloride salts.

(13) Standard Procedure 2: Synthesis of Amino Benzyl Ester Hydrochloride Salts.

(14) The appropriate amino acid (1.0 mol eq.), p-toluene sulfonic acid (1.0 mol eq.) and anhydrous benzyl alcohol (4.1 mol eq.) were heated at reflux in toluene (10 mol eq.) with Dean-Stark trap for 24 hrs. On cooling to room temperature, Et.sub.2O was added and the mixture was left in ice bath for 1 hr then filtrated and washed with Et.sub.2O. The solid was dissolved in DCM and washed with 10% K.sub.2CO.sub.3 and water. The organic layer was dried over MgSO.sub.4, filtered and the solvent removed under reduced pressure to give an oil. This was solubilized in acetone and neutralized with 1 M HCl. Et.sub.2O was added and the solid was filtered and washed with Et.sub.2O to give a white solid.

(15) Standard Procedure 3: Synthesis of Phosphorodichloridate Species.

(16) Phosphorus oxychloride (1.0 mol eq.) and the appropriate substituted phenol (1.0 mol) were stirred with anhydrous diethylether (31 mol eq.). To this was added anhydrous triethylamine (1.0 mol eq) at 80 C. and left to rise to room temperature over 16 hrs the triethylamine hydrochloride salt was filtered off, and the filtrate reduced to dryness to give the crude product as a clear liquid.

(17) Standard Procedure 4: Synthesis of Phosphochloridate Species.

(18) Phosphodichloridate (1.0 mol eq.) and the appropriate amino ester hydrochloric salt (1.0 mol eq.) were suspended in anhydrous DCM. Anhydrous triethylamine was added dropwise at 80 C. and after 1 hr the reaction was left to rise to room temperature. The formation of phosphochloridate was monitored by .sup.31P-NMR. After 2-5 hrs the solvent was removed under reduced pressure and the solid obtained washed with anhydrous ether (220 ml), filtered, and the filtrate reduced to dryness to give the products as crude oil. These oils were usually used without further purification.

(19) Standard Procedure 5: Synthesis of Phosphoroamidate Derivatives.

(20) To a stirring solution of (E)-5-(2-bromovinyl)-2-deoxyuridine (1.0 mol eq.) and the appropriate phosphochloridate (2.0-3.0 mol eq) in anhydrous THF at 80 C. was added dropwise over 1 min NMI (5.0 mol eq.). After 15 mins the reaction was left to rise to room temperature and stirred at room temperature for 2-19 hrs. The solvent was removed under reduced pressure and the yellow oil obtained was dissolved in DCM, washed with 0.5 M HCl, and water. The organic layer is dried over MgSO.sub.4, filtered, reduced to dryness and purified by flash chromatography (Chloroform/Methanol 97/3, Dichloromethane/Methanol 97/3).

Synthesis of Methyl-1-amino-1-cyclopentanoate hydrochloride salt

(21) C.sub.6H.sub.14ClNO.sub.3, MW=179.68.

(22) ##STR00012##

(23) This was synthesised according to Standard Procedure 1, using 1-amino-1-cyclopentanecarboxylic acid (3.876 g, 30 mmol) with thionyl chloride (4.44 mL, 45 mmol,) and anhydrous methanol (15.5 mL). The product was isolated as a white solid (4.81 g, yield 89%).

(24) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 9.1 (3H, bs, NH.sub.3.sup.+Cl.sup.), 3.85 (3H, s, OCH.sub.3), 2.3-2.2 (4H, m, 4H cyclopentane), 2.15 (2H, 2H cyclopentane), 1.95 (2H, m, 2H cyclopentane).

(25) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 26.6 (2CH.sub.2 cyclopent), 38.1 (2CH.sub.2 cyclopent), 54.8 (CH.sub.3O), 66.6 (Cq cyclopentane), 174.1 (COOMe).

Synthesis of Ethyl-1-amino-1-cyclopentanoate hydrochloride salt

(26) C.sub.8H.sub.16ClNO.sub.2, MW=193.71.

(27) ##STR00013##

(28) This was synthesised according to Standard Procedure 1, using 1-amino-1-cyclopentanecarboxylic acid (5.0 g, 38.6 mmol) with thionyl chloride (5.72 mL, 58 mmol) and anhydrous ethanol (29 mL). The product was isolated as a white solid (6.98 g, yield 93%).

(29) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 9.0 (3H, bs, NH.sub.3.sup.+Cl.sup.), 4.3 (2H, q, .sup.3J=8, OCH.sub.2CH.sub.3), 2.3-2.2 (4H, m, 4H cyclopentane), 2.15 (2H, 2H cyclopentane), 1.95 (2H, m, 2H cyclopentane), 1.4 (3H, t, .sup.3J=8, OCH.sub.2CH.sub.3).

(30) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 14.5 (CH.sub.3CH.sub.2), 25.8 (2CH.sub.2 cyclopent), 37.4 (2CH.sub.2 cyclopent), 63.0 (CH.sub.3CH.sub.2), 66.2 (Cq cyclopentane), 172.1 (COOEt).

Synthesis of Benzyl-1-amino-1-cyclopentanoate hydrochloride salt

(31) C.sub.14H.sub.18ClNO.sub.2, MW=255.78.

(32) ##STR00014##

(33) This was synthesised according to Standard Procedure 2, using 1-amino-1-cyclopentanecarboxylic acid (3.682 g, 28.5 mmol) with p-toluene sulfonic acid monohydrate (5.625 g, 29.55 mmol) and anhydrous benzylic alcohol (12 mL, 116 mmol), in Toluene (20 mL). The product was isolated as a white solid (6.441 g, yield 88.5%) Hydrochloride salt. .sup.1H-NMR (CDCl.sub.3; 300 MHz): 9.05 (3H, bs, NH.sub.3.sup.+Cl.sup.), 7.4-7.25 (5H, m, Ph), 5.15 (2H, s, CH.sub.2Ph), 2.3 (4H, m, 4H cyclopentane), 2.15 (2H, 2H cyclopentane), 1.95 (2H, m, 2H cyclopentane).

(34) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 25.9 (2CH.sub.2 cyclopent), 37.3 (2CH.sub.2 cyclopent), 66.3 (Cq cyclopentane), 68.3 (CH.sub.2Ph), 129.2, 129.0, 128.8 (o, m, CH.sub.2Ph), 135.5 (p, CH.sub.2Ph), 172.1 (COOBn).

Synthesis of methyl-2-amino-2-methylpropanoate hydrochloride salt

(35) C.sub.5H.sub.12ClNO.sub.3, MW 153.61.

(36) ##STR00015##

(37) This was synthesised according to Standard Procedure 1, using 2-amino-isobutyric acid (5.102 g, 48.49 mmol) with thionyl chloride (11.538 g, 96.98 mmol, 7.04 mL) and anhydrous methanol (19.6 mL). The product was isolated as a white solid (6.636 g, yield 89.2%).

(38) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 8.81 (3H, bs, NH.sub.3Cl), 3.83 (3H, s, OCH.sub.3), 1.74 (6H, s, [CH.sub.3].sub.2C).

(39) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 24.1, 24.3 ([CH.sub.3].sub.2C), 57.9 (C[CH.sub.3].sub.2), 172.4 (COOCH.sub.3).

Synthesis of ethyl-2-amino-2-methylpropanoate hydrochloride salt

(40) C.sub.6H.sub.14ClNO.sub.2, MW 167.63.

(41) ##STR00016##

(42) This was synthesised according to Standard Procedure 1, using 2-amino-isobutyric acid (5.102 g, 48.49 mmol) with thionyl chloride (11.772 g, 98.95 mmol, 7.2 mL) and anhydrous ethanol (29 mL). The product was isolated as a white solid (7.159 g, yield 86.3%).

(43) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 8.93 (3H, bs, NH.sub.2Cl), 4.3 (2H, q, .sup.3J=7.1 Hz, OCH.sub.2CH.sub.3), 1.75 (6H, s, [CH.sub.3].sub.2C), 1.33 (3H, t, .sup.3J=7.1 Hz, OCH.sub.2CH.sub.3).

(44) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 14.4 (CH.sub.3CH.sub.2O), 24.3 ([CH.sub.3].sub.2C), 57.9 (C[CH.sub.3].sub.2), 63.1 (OCH.sub.2CH.sub.3), 171.6 (COOCH.sub.2CH.sub.3).

Synthesis of benzyl-2-amino-2-methylpropanoate hydrochloride salt

(45) C.sub.11H.sub.16ClNO.sub.2, MW 229.70.

(46) ##STR00017##

(47) This was synthesised according to Standard Procedure 2, using 2-amino-isobutyric acid (1.960 g, 19.00 mmol) with p-toluene sulfonic acid monohydrate (3.750 g, 19.7 mmol) and benzylic alcohol (8.360 g, 77.30 mmol, 8 mL), in toluene (20 mL). The product was isolated as a white solid (2.556 g, yield 87.4%)

(48) p-toluenesulfonate salt: .sup.1H-NMR (CDCl.sub.3, 300 MHz): 8.40 (3H, bs, NH.sub.3Cl), 7.79 (2H, d, .sup.3J=8.0 Hz, m p-TSA), 7.34 (5H, m, CH.sub.2Ph), 7.14 (2H, d, .sup.3J=8.0 Hz, o p-TSA), 5.16 (2H, s, CH.sub.2Ph), 2.38 (3H, s, CH.sub.3 p-TSA), 1.57 (6H, s, [CH.sub.3].sub.2C)

(49) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 21.8 (CH.sub.3, p-TSA), 23.9 ([CH.sub.3].sub.2C), 57.8 (C[CH.sub.3].sub.2), 68.3 (CH.sub.2Ph), 126.55, 128.5, 128.8, 129.0, 129.3 (CH.sub.2Ph+p-TSA), 135.4 (ipso, CH.sub.2Ph), 140.8 (p, p-TSA), 141.9 (ipso, p-TSA), 171.9 (COOCH.sub.2Ph).

(50) Hydrochloride salt: .sup.1H-NMR (CDCl.sub.3; 300 MHz): 9.10 (3H, bs, NH.sub.3Cl), 7.41-7.31 (5H, m, CH.sub.2Ph), 5.27 (2H, s, CH.sub.2Ph), 1.77 ([CH.sub.3].sub.2C).

(51) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 24.2 ([CH.sub.3].sub.2C), 58.0 (C[CH.sub.3].sub.2), 68.5 (CH.sub.2Ph), 128.62, 129.0, 129.1 (o, m, p, CH.sub.2Ph), 135.2 (ipso, CH.sub.2Ph), 171.8 (COOCH.sub.2Ph).

Synthesis of (E)-5-(2-bromovinyl)-2-deoxyuridine

(E)-5-(2-Carbomethoxyvinyl)-2-deoxyuridine

(52) ##STR00018##

(53) A mixture of Pd(OAc).sub.2 (0.316 g, 1.41 mmol), PPh.sub.3 (0.741 g, 2.82 mmol), and triethylamine (4.9 mL) in 1,4-dioxane (50 mL) was stirred at 70 C. until an intense red colour had developed. To this 5-iodo-2-deoxyuridine (10 g, 28.24 mmol) and methylacrilate (4.862 g, 56.48 mmol, 5.1 mL) in 1,4-dioxane (20 mL) were added and the mixture stiffed at refluxed for 30 mins. The reaction was filtered while still hot and the 20 filtrate cooled over night at 4 C. The resulting pale yellow precipitate was filtered, washed with DCM and dried in vacuo to give the product as white solid (6.2 g, yield 70.7%).

(54) .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) 11.64 (1H, bs, NH-3), 8.42 (1H, s, H-6), 7.37 (1H, d, .sup.3J=15.8 Hz, H vinylic), 6.86 (1H, d, .sup.3J=15.8 Hz, H vinylic), 6.13 (1H, t, .sup.3J=6.5 Hz, H-1), 5.27-5.20 (2H, 2bs, OH-3, OH-5), 4.27 (1H, m, H-3), 3.81 (1H, m, H-4), 3.68 (3H,s CH.sub.3), 3.60 (2H, m, H-5), 2.18 (2H, m, H-2).

(55) .sup.13C-NMR (DMSO-d.sub.6; 75 MHz): 40.4 (C-2), 51.6 (CH.sub.3), 66.7 (C-5), 70.0 (C-3), 85.2 (C-4), 88.0 (C-1), 108.5 (C-5), 116.5 (C-5b), 138.5 (C-5a), 144.4 (C-6), 149.6, 162.1 (C-2, C-4),167.6 (COO).

(E-5-(2-Carboxyvinyl)-2-deoxyuridine

(56) ##STR00019##

(57) (E)-5-(2-carbomethoxyvinyl)-2-deoxyuridine (6.0 g, 19.33 mmol) was dissolved in 300 mL of 1 M NaOH and the mixture stirred at room temperature for 3 hrs, filtered and the filtrate adjusted to pH 2 with 1M HCl. On cooling at 4 C. a white precipitate formed. This was filtered off and washed with cold water (220 ml) and acetone (220 mL) and dred to give a white solid (4.441 g, yield 77.1%).

(58) .sup.1H-NMR (DMSO-d.sub.6; 300 MHz): 12.18 (1H, bs, CO.sub.2H), 11.64 (1H, s, NH-3), 8.40 (1H, s, H-6), 7.30 (1H, d, .sup.3J=15.6 Hz, H vinylic), 6.78 (1H, d, .sup.3J=15.8 Hz, H vinylic), 6.14 (1H, t, .sup.3J=6.4 Hz, H-1), 5.38-5.08 (2H, bs, OH-3, OH-5), 4.26 (1H, m, H-3), 3.80 (1H, m H-4), 3.64 (2H, m, H-5), 2.18 (2H, m, H-2).

(59) .sup.13C-NMR (DMSO-d.sub.6; 75 MHz): 40.1 (C-2), 61.2 (C-5), 70.1 (C-3), 85.1 (C-4), 88.0 (C-1), 108.7 (C-5), 118.0 (C-5b), 137.9 (C-5a), 143.9 (C-6), 149.6, 162.1 (C-2, C-4), 168.4 (COOH).

(E)-5-(2-bromovinyl)-2-deoxyuridine

(60) ##STR00020##

(61) To a solution of (E)-5-(2-carboxyvinyl)-2-deoxyuridine (5.777 g, 19.37 mmol) in dimethylforamide (29 mL) was added K.sub.2CO.sub.3 (5.890 g, 42.61 mmol) and the suspension stirred at room temperature for 15 mins. A solution of N-bromosuccinimide (3.655 g, 20.53 mmol) was added dropwise over 30 mins at 20 C. The resulting suspension was filtered and the solid washed with DMF. The combined filtrate and washings were evaporated to dryness in vacuo and the residue dissolved in MeOH. To this silica gel was added and the suspension evaporated to dryness and the solid applied to the top of chromatographic column. The column was eluted with chloroform/methanol 92/8 to give a white solid (5787 g, 71.9%). Crystallisation from water gave a white powder.

(62) .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) 11.59 (1H, bs, NH-3), 8.08 (1H, s, H-6), 7.25 (1H, d, .sup.3J=13.6 Hz, H-5b), 6.85 (1H, d, .sup.3J=13.6 Hz, H-5a), 6.13 (1H, t, .sup.3J=6.5 Hz, H-1), 5.29 (1H, bs, OH-3), 5.13 (1H, bs, OH-5), 4.24 (1H, m, H-3), 3.79 (1H, m, H-4), 3.66 (2H, m, H-5), 2.51 (1H, m, H-2), 2.14 (1H, m, H-2).

(63) .sup.13C-NMR (DMSO-d.sub.6; 75 MHz): 40.2 (C-2), 61.3 (C-5), 70.3 (C-4), 84.8 (C-3), 87.8 (C-1), 108.9 (C-5b), 110.0 (C-5), 130.3 (C-5a), 149.6, 162.1 (C-2, C4).

Synthesis of (E)-5-(2-Bromovinyl)-2-deoxyuridine-5-[phenyl-(methoxy-L-alaninyl)]-phosphate (CPF 1)

(64) C.sub.21H.sub.25BrN.sub.3O.sub.9P, MW 574.32.

(65) ##STR00021##

(66) This was synthesised according to Standard procedure 5, using BVdU (300 mg, 0.90 mmol), Phenyl-(methoxy-L-alaninyl)-phosphorochloridate (472 mg, 1.7 mmol), NMI (4.5 mmol, 378 L) in THF (9 mL) for 2 hrs. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 97:3 to give the pure product as a white foamy solid (356 mg, yield 69%).

(67) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 4.72, 4.40.

(68) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 9.9 (1H, bs, H-3), 7.64 (1H, 2s, H-6), 7.44-7.39 (1H, 2d, .sup.3J=14 Hz, H-5b), 7.37-7.15 (5H, m, OPh), 6.75-6.67 (1H, 2d, .sup.3J=14 Hz, H-5a), 6.30-6.21 (1H, 2t, .sup.3J=6 Hz, H1), 4.57-4.29 (3H, m, H-5+H-3), 4.2-3.96 (3H, H-4, NH, CHala), 3.72 (3H, s, CH.sub.3O), 2.49-2.40 (1H, m, one of H-2), 2.12-2.01 (1H, m, one of H-2), 1.38 (3H, d, .sup.3J=7 Hz, CH.sub.3 ala).

(69) .sup.13C-NMR (DMSO; 75 MHz): 22.4 (CH.sub.3 ala), 41.9, 41.8 (C-2), 51.9 (CH[CH.sub.3]), 54.3 (CH.sub.3O), 67.5 (C-5), 72.3, 71.9 (C-3), 87.3, 87.2, 86.9, 86.8 (C-1, C-4), 110.6 (C-5b), 113.1 (C-5), 121.7 (o, OPh), 127.0 (p, OPh), 130.1 (C-5a), 131.5 (m, OPh), 139.2 (C-6),150.9 (ipso, OPh) 151.9 (C-4), 163.2(C-2), 175.7 (COOCH.sub.3).

Synthesis of (E)-5-(2-Bromovinyl)-2-deoxyuridine-5-[phenyl-(ethoxy-L-alaninyl)]-phosphate(CPF 3)

(70) C.sub.22H.sub.27BrN.sub.3O.sub.9P, MW=588.34.

(71) ##STR00022##

(72) This was synthesised according to Standard procedure 5, using BVdU (150 mg, 0.45 mmol), Phenyl-(ethoxy-L-alaninyl)-phosphorochloridate (249 mg, 0.9 mmol), NMI (2.8 mmol, 190 L) in THF (4 mL) for 2 hrs. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 97:3 to give the pure product as a white foamy solid (145 mg, yield 55%).

(73) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 4.48, 4.86.

(74) .sup.1H-NMR (CDCl.sub.3, 300 MHz): 7.65 (1H, 2s, H-6), 7.44-7.39 (1H, 2d, .sup.3J=13 Hz, H-5b), 7.35-7.10 (5H, m, OPh), 6.78-6.65 (1H, 2d, .sup.3J=13 Hz, H-5a), 6.35-6.25 (1H, 2t, .sup.3J=6 Hz, H1), 4.62-3.95 (8H, m, H-5, H-3, H-4, CHala, NH, CH.sub.3CH.sub.2O), 2.49-2.40 (1H, m, one of H-2), 2.10-2.00 (1H, m, one of H-2), 1.40 (3H, d, .sup.3J=7 Hz, CH.sub.3 ala), 1.25 (3H, 2t, .sup.3J=7 Hz, CH.sub.4CH.sub.2O).

(75) .sup.13C-NMR (CDCl.sub.3, 75 MHz): 14.5 (CH.sub.3CH.sub.2O) 21.2, 21.1 (CH.sub.3ala), 40.9, 40.7 (C-2), 50.8, 50.7 (CHala), 62.2, 62.1 (CH.sub.3CH.sub.2O), 66.5, 66.3 (C-5), 70.9, 70.6 (C-3), 86.0, 85.6 (C-1, C-4), 110.1 (C-5b), 111.8 (C-5), 120.6 (o, OPh), 125.0 (p, OPh), 129.0 (C-5a), 130.2 (m, OPh), 138.2 (C-6), 149.9 (C-4), 150.7 (ipso, OPh), 162.3 (C-2), 174.2, 174.1 (COOCH.sub.2CH.sub.3).

Synthesis of (E)-5-(2-Bromovinyl)-2-deoxyuridine-5-[phenyl-(benzoxy-L-alaninyl)]-phosphate (CPF 2)

(76) C.sub.27H.sub.29BrN.sub.3O.sub.9P, MW=649.08.

(77) ##STR00023##

(78) This was synthesised according to Standard procedure 5, using BVdU (150 mg, 0.45 mmol), Phenyl-(benzyloxy-L-alaninyl)-phosphorochloridate (249 mg, 0.9 mmol), NMI (2.8 mmol, 190 L) in THF (5 mL) for 2 hrs. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 97:3 to give the pure product as a white foamy solid (228 mg, yield 78%).

(79) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 4.74, 4.44.

(80) .sup.1H-NMR (CDCl.sub.3, 300 MHz): 10.31 (1H, bs, H-3), 7.63 (1H, 2s, H-6), 7.45-7.14 (11H, m, OPh+CH.sub.2Ph, H-5b), 6.75-6.66 (1H, 2d, .sup.3J=14 Hz, H-5a), 6.30-6.25 (1H, m, H-1), 5.18-50.9 (1H, s, CH.sub.2Ph), 4.70-4.04 (6H, m, H-3, H-5,H-4, NH, CHala), 2.42 (1H, m, one of H-2), 2.02 (1H, m, one of H-2), 1.40 (3H, d, .sup.3J=7 Hz, CH.sub.3ala).

(81) .sup.13C-NMR (CDCl.sub.3, 75 MHz): 20.7, 20.8 (CH.sub.3ala), 40.4 (C-2), 50.4 (CHala), 66.0 (C-5) 67.4 (CH.sub.2Ph), 70.6 (C-3), 85.4, 85.5, 85.6, 85.8 (C-1, C-4), 109.9 (C-5b), 111.5 (C-5b), 120.2 (o, OPh), 125.4 (p, OPh), 128.5, 128.6, 129.9 (m OPh, Bn, C-5a), 135.1(ipso, CH.sub.2Ph) 137.8 (C-6), 149.8 (C-4) 150.2 (ipso, OPh), 161.8 (C-2), 173.6 (COOBn).

Synthesis of (E)-5-(2-Bromovinyl)-2-deoxyuridine-5-[para-fluorophenyl-(methoxy-L-alaninyl)]-phosphate (CPF 5)

(82) C.sub.21H.sub.24BrFN.sub.3O.sub.9P, MW=592.31.

(83) ##STR00024##

(84) This was synthesised according to Standard procedure 5, using BVdU (200 mg, 0.60 mmol), para-fluorophenyl-(methoxy-L-alaninyl)-phosphorochloridate (442 mg, 1.5 mmol), NMI (4.98 mmol, 332 L) in THF (5 mL) for 2 hrs. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 97:3 to give the pure product as a white foamy solid (177 mg, yield 50%).

(85) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 5.10, 4.81.

(86) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 10.1 (1H, bs, H-3), 7.60 (1H, 2s, H-6), 7.39-7.32 (1H, 2d, .sup.3J=14 Hz, H-5b), 7.20-6.95 (4H, m, OPh), 6.70-6.60 (1H, 2d, .sup.3J=14 Hz, H-5a), 6.30-6.15 (1H, 2t, .sup.3J=6 Hz, H1), 4.55-4.29 (3H, m, H-5+H-3), 4.15 (1H, NH), 4.05-3.85 (2H, H-4, CHala), 3.72 (3H, 2s, CH.sub.3O), 2.49-2.32 (1H, m, one of H-2), 2.15-2.05 (1H, m, one of H-2), 1.35 (3H, 2d, .sup.3J=6 Hz, CH.sub.3 ala).

(87) .sup.13C-NMR (DMSO; 75 MHz): 21.2 (CH.sub.3 ala), 40.8 (C-2), 50.8, 50.6 (CH[CH.sub.3]), 53.2 (CH.sub.3O), 66.7, 66.3 (C-5), 71.9, 71.8 (C-3), 86.1, 85.7, 85.8 (C-1, C-4), 110.3 (C-5b), 111.9 (C-5), 117.0, 116.7 (o, OPh), 122.0 (m, OPh), 128.2 (C-5a), 138.2 (C-6), 149.0 (ipso, OPh) 149.9 (C-4), 158.5 (p, OPh), 163.2(C-2), 175.1 (COOCH.sub.3).

Synthesis of (E)-5-(2-Bromovinyl)-2-deoxyuridine-5-[para-fluorophenyl-(ethoxy-L-alaninyl)]-phosphate (CPF 6)

(88) C.sub.22H.sub.26BrFN.sub.3O.sub.9P, MW=606.33.

(89) ##STR00025##

(90) This was synthesised according to Standard procedure 5, using BVdU (200 mg, 0.60 mmol), para-fluorophenyl-(ethoxy-L-alaninyl)-phosphorochloridate (464 mg, 1.5 mmol), NMI (4.98 mmol, 332 L) in THF (5 mL) for 2 hrs. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 97:3 to give the pure product as a white foamy solid (240 mg, yield 66%).

(91) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 5.14, 4.88.

(92) .sup.1H-NMR (CDCl.sub.3, 300 MHz): 10.25 (1H, bs, H-3), 7.85 (1H, 2s, H-6), 7.44-7.39 (1H, 2d, .sup.3J=14 Hz, H-5b), 7.3-7.0 (4H, m, OPh), 6.8-6.65 (1H, 2d, .sup.3J=14 Hz, H-5a), 6.35-6.25 (1H, 2t, .sup.3J=6 Hz, H1), 4.6-4.1 (6H, m, H-5, H-3, CHala, NH, CH.sub.3CH.sub.2O), 4.02 (1H, m, H-4), 2.55-2.45 (1H, m, one of H-2), 2.20-2.10 (1H, m, one of H-2), 1.40 (3H, d, .sup.3J=8 Hz, CH.sub.3 ala), 1.25 (3H, 2t, .sup.3J=7 Hz, CH.sub.3CH.sub.2O).

(93) .sup.13C-NMR (CDCl.sub.3, 75 MHz): 14.5 (CH.sub.3CH.sub.2O) 21.3 (CH.sub.3ala), 40.8, 40.7 (C-2), 50.8, 50.7 (CHala), 62.3 (CH.sub.3CH.sub.2O), 66.7, 66.3 (C-5), 71.1, 70.7 (C-3), 86.1, 85.8, 85.6, 85.4 (C-1, C-4), 110.4 (C-5b), 111.9 (C-5), 117.0 (o, OPh), 122.2 (m, OPh), 128.9 (C-5a), 138.2 (C-6), 146.4 (ipso, OPh), 149.9 (C-4), 158.5 (p, OPh), 162.2, 161.8 (C-2), 174.2 (COOCH.sub.2CH.sub.3).

Synthesis of (E-5-(2-Bromovinyl)-2-deoxyuridine-5-[para-fluorophenyl-(benzoxy-L-alaninyl)]-phosphate (CPF 7)

(94) C.sub.27H.sub.28BrFN.sub.3O.sub.9P, MW=668.40.

(95) ##STR00026##

(96) This was synthesised according to Standard procedure 5, using BVdU (200 mg, 0.60 mmol), para-fluorophenyl-(benzyloxy-L-alaninyl)-phosphorochloridate (556 mg, 1.5 mmol), NMI (4.98 mmol, 332 L) in THF (5 mL) for 2 hrs. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 97:3 to give the pure product as a white foamy solid (256 mg, yield 64%).

(97) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 4.74, 4.44.

(98) .sup.1H-NMR (CDCl.sub.3, 300 MHz): 7.69 (1H, 2s, H-6), 7.45-7.39 (1H, 2d, .sup.3J=14 Hz, H-5b), 7.37-7.00 (9H. m, OPh+CH.sub.2Ph), 6.75-6.65 (1H, 2d, .sup.3J=14 Hz, H-5a), 6.30-6.2 (1H, 2t, .sup.3J=6 Hz, H-1), 5.2 (1H, 2s, CH.sub.2Ph), 4.85-4.00 (6H, m, H-3, H-5,H-4, NH, CHala), 2.47 (1H, m, one of H-2), 2.0-2.15 (1H, m, one of H-2), 1.38 (3H, d, .sup.3J=7 Hz, CH.sub.3ala).

(99) .sup.13C-NMR (CDCl.sub.3, 75 MHz): 21.2, 21.1 (CH.sub.3ala), 40.7 (C-2), 50.4 (CHala), 66.7, 66.4 (C-5), 67.8 (CH.sub.2Ph), 71.1, 70.7 (C-3), 86.0, 85.7, 85.4, 85.3 (C-1, C-4), 110.4 (C-5b), 111.9 (C-5), 117.0 (o, OPh), 122.0 (m, OPh), 128.7, 128.6 (Bn, C-5a), 135.4(ipso, CH.sub.2Ph) 138.2 (C-6), 146.5 (ipso, OPh), 149.9 (C-4), 158.5 (p OPh), 162.2 (C-2), 173.9 (COOBn).

Synthesis of (E)-5-(2-Bromovinyl)-2 -deoxyuridine-5-[para-nitrophenyl-(methoxy-L-alaninyl)]-phosphate (CPF 10)

(100) C.sub.21H.sub.24BrN.sub.4O.sub.11P, MW=619.31.

(101) ##STR00027##

(102) This was synthesised according to Standard procedure 5, using BVdU (200 mg, 0.60 mmol), para-nitrophenyl-(methoxy-L-alaninyl)-phosphorochloridate (483 mg, 1.5 mmol), NMI (4.98 mmol, 332 L) in THF (5 mL) for 2 hrs. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 97:3 to give the pure product as a white foamy solid (211 mg, yield 57%).

(103) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 4.95.

(104) .sup.1H-NMR (MeOD; 300 MHz): 8.3-8.2 (2H, m, OPh) 7.8-7.75 (1H, 2s, H-6), 7.35-7.30, 7.55-7.4 (2H, m, OPh), 7.35-7.30 (1H, 2d, .sup.3J=14 Hz, H-5b), 6.80-6.70 (1H, 2d, .sup.3J=14 Hz, H-5a), 6.30-6.2 (1H, 2t, .sup.3J=6 Hz, H1), 4.5-4.3 (3H, m, H-5,H-3), 4.2-4.0 (2H, m, H-4, CHala), 3.72 (3H, 2s, CH.sub.3O), 2.35-2.15 (2H, n, 2 H-2), 1.35 (3H, 2d, .sup.3J=7 Hz, CH.sub.3 ala).

(105) .sup.13C-NMR (DMSO; 75 MHz): 20.9 (CH.sub.3 ala), 41.6, 41.5 (C-2), 52.0, 51.9 (CH[CH.sub.3)), 53.4 (CH.sub.3O), 68.5 (C-5), 72.4, 72.3 (C-3), 87.7, 87.4, 87.0, 86.9 (C-1, C-4), 109.8 (C-5b), 112.8 (C-5), 122.6 (o, OPh), 127.1 (m, OPh), 130.8 (C-5a), 140.3 (C-6), 146.5 (ipso, OPh), 151.4 (C-4), 157.2 (p, OPh), 163.9 (C-2), 175.8, 175.5 (COOCH.sub.3).

Synthesis of (E)-5-(2-Bromovinyl)-2-deoxyuridine-5-[para-nitrophenyl-(ethoxy-L-alaninyl)]-phosphate (CPF 9)

(106) C.sub.22H.sub.26BrN.sub.4O.sub.11P, MW=633.34.

(107) ##STR00028##

(108) This was synthesised according to Standard procedure 5, using BVdU (200 mg, 0.60 mmol), para-nitrophenyl-(ethoxy-L-alaninyl)-phosphorochloridate (504 mg, 1.5 mmol), NMI (4.98 mmol, 332 L) in THF (5 mL) for 1 hr. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 97:3 to give the pure product as a white foamy solid (232 mg, yield: 61%).

(109) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 4.28.

(110) .sup.1H-NMR (CDCl.sub.3, 300 MHz): 10.25 (1H, bs, H-3), 8.25-8.2 (2H, 2d, .sup.3J=9 Hz OPh), 7.7 (1H, 2s, H-6), 7.5-7.45 (2H, 2d, .sup.3J=9 Hz, OPh), 7.4-7.35 (1H, 2d, .sup.3J=14 Hz, H-5b), 6.7-6.65 (1H, 2d, .sup.3J=14 Hz, H-5a), 6.3-6.2 (1H, 2t, .sup.3J=6 Hz, H1), 4.8-4.1 (7H, m, H-5, H-4 H-3, CHala, NH, CH.sub.3CH.sub.2O), 2.45-2.4 (1H, m, one of H-2), 2.20-2.10 (1H, m, one of H-2), 1.40 (3H, d, .sup.3J=8 Hz, CH.sub.3 ala), 1.3 (3H, 2t, .sup.3J=7 Hz, CH.sub.3CH.sub.2O).

(111) .sup.13C-NMR (CDCl.sub.3, 75 MHz): 14.5 (CH.sub.3CH.sub.2O) 21.1 (CH.sub.3ala), 40.6 (C-2), 50.8, 50.7 (CHala), 62.5 (CH.sub.3CH.sub.2O), 66.9, 66.8 (C-5), 71.2, 70.9 (C-3), 86.3, 85.9, 85.4, 85.3 (C-1, C-4), 110.3 (C-5b), 111.8 (C-5), 121.3 (o, OPh), 126.1 (m, OPh), 128.8 (C-5a), 138.4 (C-6), 145.1 (ipso, OPh), 149.9 (C-4), 155.5 (p, OPh), 162.3 (C-2), 174.0, 173.9 (COOCH.sub.2CH.sub.3).

Synthesis of (E)-5-(2-Bromovinyl)-2-deoxyuridine-5-[para-nitrophenyl-(benzoxy-L-alaninyl)]-phosphate (CPF 8)

(112) C.sub.27H.sub.28BrN.sub.4O.sub.11P, MW=695.41.

(113) ##STR00029##

(114) This was synthesised according to Standard procedure 5, using BVdU (200 mg, 0.60 mmol), para-nitrophenyl-(benzyloxy-L-alaninyl)-phosphorochloridate (597 mg, 1.5 mmol), NMI (4.98 mmol, 332 L) in THF (5 mL) for 2 hrs. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 97:3 to give the pure product as a white foamy solid (228 mg, yield 55%).

(115) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 4.74, 4.44.

(116) .sup.1H-NMR (CDCl.sub.3, 300 MHz): 10.4-10.3 (1H, bs, H-3), 8.2-8.1 (2H, m, OPh), 7.69 (1H, 2s, H-6), 7.4-7.2 (1H, 2d, .sup.3J=14 Hz, H-5b), 7.37-7.00 (7H. m, OPh+CH.sub.2Ph), 6.75-6.65 (1H, 2d, .sup.3J=14 Hz, H-5a), 6.25-6.15 (1H, 2t, .sup.3J=6 Hz, H-1), 5.2 (1H, d, CH.sub.2Ph), 4.87 (1H, m, H-3), 4.6-4.2 (3H, m, H-5, CHala) 4.2-4.00 (2H, m, H-4, NH,), 2.55-2.45 (1H, m, one of H-2), 2.2-2.05 (1H, m, one of H-2), 1.38 (3H, d, .sup.3J=7 Hz, CH.sub.3ala).

(117) .sup.13C-NMR (CDCl.sub.3, 75 MHz): 21.2, 21.1 (CH.sub.3ala), 40.6 (C-2), 50.9 (CHala), 67.1, 670 (C-5), 68.0 (CH.sub.2Ph), 71.3, 70.9 (C-3), 86.3, 86.0, 85.3, 85.2 (C-1, C-4), 110.4 (C-5b), 111.9, 111.8 (C-5), 121.3 (o, OPh), 126.2-126.1 (m, OPh), 129.1, 128.7, 128.6 (Bn, C-5a), 135.4 (ipso, CH.sub.2Ph), 138.3 (C-6), 145.1 (ipso, OPh), 149.9 (C4), 155.6 (p OPh), 162.2 (C-2), 173.8,173.7 (COOBn).

Synthesis of (E)-5-(2-bromovinyl)-2-deoxyuridine-5-[para-(trifluoromethyl)-phenyl-(methoxy-L-alaninyl)]-phosphate (CPF 15)

(118) C.sub.22H.sub.24BrF.sub.3N.sub.3O.sub.9, MW=642.31.

(119) ##STR00030##

(120) This was synthesised according to Standard procedure 5, using BVdU (200 mg, 0.60 mmol), phenyl-(methoxy-L-alaninyl)-phosphorochloridate (518.8 mg, 1.5 mmol), NMI (246.3 mg, 3.0 mmol, 239 L) in THF (5 mL) for 4 hrs. The crude product was purified by column chromatography, eluting with chloroform/methanol 97:3 to give the pure product as a white foamy solid (211.1 mg, yield 54.7%).

(121) .sup.31P-NMR (MeOD, 121 MHz): 5.23, 5.07.

(122) .sup.1H-NMR (MeOD, 300 MHz): 7.80 (1H, s, H-6), 7.70 (2H, d, .sup.3J=8.7 Hz, OPh), 7.47-7.42 (2H, m, OPh), 7.37 (1H, d, .sup.3J=13.6 Hz, H-5b), 6.82-6.78 (1H, d, 3J=13.6 Hz, H-5a), 6.30-6.23 (1H, m, H-1), 4.52-4.29 (3H, m, H-3+H-5), 4.17-4.13 (1H, m, H-4), 4.05-3.91 (1H, m, CHCH.sub.3), 3.67 (3H, s, OCH.sub.3), 2.35-2.32 (1H, m, one of H-2), 2.23-2.16 (1H, m, one of H-2), 1.37-1.34 (3H, d, .sup.3J=7.1 Hz, CHCH.sub.3.

(123) .sup.13C-NMR (MeOD, 75 MHz): 20.6, 20.7, 20.8, 20.9 (CHCH.sub.3), 41.5, 41.7 (C-2), 51.9, 52.0 (CHCH.sub.3), 68.2, 68.3 (C-5), 72.4, 72.5 (C-3), 87.1, 87.2, 87.4, 87.6 (C-1, C-4), 109.7 (C-5b), 112.6 (C-5), 122.5, 122.7 (o, OPh), 125.8 (CF.sub.3, J=269 Hz), 128.7 (m, OPh), 128.8 (p, J=33 Hz, OPh), 130.9 (C-5a), 140.3 (C-6), 151.4, 151.5 (ipso, OPh), 155.1, 155.2 (C-4), 164.0 (C-2), 175.6, 175.9, (COOCH.sub.3).

Synthesis of (E)-5-(2-bromovinyl)-2-deoxyuridine-5-[para-(trifluoromethyl)-phenyl-ethoxy-L-alaninyl)]-phosphate (CPF 25)

(124) C.sub.23H.sub.26BrF.sub.3N.sub.3O.sub.9P, MW=656.34.

(125) ##STR00031##

(126) This was synthesised according to Standard procedure 5, using BVdU (200 mg, 0.60 mmol), phenyl-(ethoxy-L-alaninyl)-phosphorochloridate (539.5 mg, 1.5 mmol), NMI (246.3 mg, 3.0 mmol, 239 L) in THF (5 mL) for 20 hrs. The crude product was purified by column chromatography, eluting with dichloromethane/methanol 95:5 to give the pure product as a white foamy solid (172.6 mg, yield 43.8%).

(127) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 4.65, 4.35.

(128) .sup.1H-NMR (CDCl.sub.3, 300 MHz): 10.05 (1H, s, H-3), 7.69-7.64 (3H, m, H-6+OPh), 7.46-7.39 (3H, m, OPh+H-5b), 6.76-6.68 (1H, 2d, .sup.3J=13.6 Hz, H-5a), 6.34-6.25 (1H, m, H-1), 4.57-4.35 (4H, m, H-3+H-5+NH, 4.27-4.13 (4H, m, H-4+OCH.sub.2CH.sub.3+OH-3), 4.12-3.98 (1H, m, CHCH.sub.3), 2.53-2.47 (1H, m, one of H-2), 2.21-2.12 (1H, m, one of H-2), 1.43-1.40 (3H, d, .sup.3J=7.0 Hz, CHCH.sub.3), 1.28, 1.27 (3H, 2t, .sup.3J=7.0 Hz, OCH.sub.2CH.sub.3)

(129) .sup.13C-NMR (CDCl.sub.3, 75 MHz): 14.5 (CH.sub.3CH.sub.2O), 21.2, 21.3 (CHCH.sub.3), 40.7 (C-2), 50.8, 50.9 (CHCH.sub.3), 62.4 (CH.sub.3CH.sub.2O), 66.3, 66.7 (C-5), 70.7, 71.1 (C-3), 85.3, 85.4, 85.8, 86.1 (C-1, C-4), 110.5 (C-5b), 112.0 (C-5), 122.0 (o, OPh), 124.2 (CF.sub.3, J=271 Hz), 127.7, 127.8, 128.7 (m, p, OPh), 128.8 (C-5a), 138.0 (C6), 149.7 (ipso, OPh), 153.2 (C-4), 161.9 (C-2), 174.0, 174.1 (COOCH.sub.2CH.sub.3).

Synthesis of (E)-5-(2-Bromovinyl)-2-deoxyuridine-5-[para-trifluorophenyl-(benzoxy-L-alaninyl)]-phosphate (CPF 4)

(130) C.sub.28H.sub.28BrF.sub.3N.sub.3O.sub.9P, MW=718.41.

(131) ##STR00032##

(132) This was synthesised according to Standard procedure 5, using BVdU (200 mg, 0.60 mmol), para-trifluorophenyl-(benzyloxy-L-alaninyl)-phosphorochloridate (632 mg, 1.5 5 mmol), NMI (4.98 mmol, 332 L) in THF (6 mL) for 2 hrs. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 97:3 to give the pure product as a white foamy solid (308 mg, yield 71%).

(133) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 5.31, 4.87.

(134) .sup.1H-NMR (CDCl.sub.3, 300 MHz): 10.05 (1H, bs, H-3), 7.7, 7.25 (11H. m, H-5b, H-6 OPh+CH.sub.2Ph), 6.75-6.65 (1H, 2d, .sup.3J=14 Hz, H-5a), 6.35-6.2 (1H, 2t, .sup.3J=6 Hz, H-1), 5.15 (1H, 2s, CH.sub.2Ph), 4.6-4.25 (4H, m, H-5, H-3, CHala) 4.2-4.00 (2H, m, H-4, NH,), 2.55-2.4 (1H, m, one of H-2), 2.2-2.05 (1H, m, one of H-2), 1.38 (3H, d, .sup.3J=7 Hz, CH.sub.3ala).

(135) .sup.13C-NMR (CDCl.sub.3, 75 MHz): 21.2, 21.1 (CH.sub.3ala), 40.7 (C-2), 50.9, 50.8 (CHala), 67.1, 67.0 (C-5), 68.0 (CH.sub.2Ph), 71.2, 70.9 (C-3), 86.1, 85.8, 85.5, 85.4 (C-1, C-4), 110.2 (C-5b), 111.9, 111.8 (C-5), 121.1 (o, OPh), 125.1 (d, J=270 Hz, CF.sub.3), 127.6 (m, OPh), 129.1, 128.7, 128.6 (Bn, C-5a), 130.1 (p,q, J=32 Hz, OPh) 135.4 (ipso, CH.sub.2Ph) 138.2 (C-6), 150.2, 150.1 (C4), 153.6 (ipso OPh), 162.7 (C-2), 173.9, 173.6 (COOBn).

Synthesis of (E)-5-(2-bromovinyl)-2-deoxyuridine-5-[4-chlorophenyl-(methoxy-L-alaninyl)]-phosphate (CPF 13)

(136) C.sub.21H.sub.24BrClN.sub.3O.sub.9P, MW=608.76.

(137) ##STR00033##

(138) This was synthesised according to Standard procedure 5, using BVdU (200 mg, 0.60 mmol), 4-chlorophenyl-(methoxy-L-alaninyl)-phosphorochloridate (374.5 mg, 1.2 mmol), NMI (246.3 mg, 3.0 mmol, 239 L) in THF (8 mL) for 5 hrs. The crude product was purified by column chromatography, eluting with Chloroform/Methanol 97:3 to give the pure product as a white foamy solid (139.0 mg, yield 38.0%).

(139) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 4.81, 4.54.

(140) .sup.1H-NMR (CDCl.sub.3, 300 MHz): 10.11 (1H, bs, H-3), 7.68 (1H, s, H-6), 7.46-7.40 (1H, d, .sup.3J=13.6 Hz, H-5b), 7.35-7.20 (4H, m, OPh), 6.76-6.67 (1H, 2d, .sup.3J=13.6 Hz, H-5a), 6.34-6.24 (1H, m, H-1), 4.58-4.40 (5H, m, H-3+H-5+NH), 4.36-4.19 (1H, m, H-4), 4.07-3.99 (1H, m, CHCH.sub.3), 3.75 (3H, s, OCH.sub.3), 2.49-2.48 (1H, m, one of H-2), 2.17-2.15 (1H, m, one of H-2), 1.42-1.39 (3H, d, .sup.3J=7.0 Hz, CHCH.sub.3).

(141) .sup.13C-NMR (CDCl.sub.3, 75 MHz): 21.2 (CHCH.sub.3), 40.7, 40.8 (C-2), 50.6, 50.8 (CHCH.sub.3), 53.2, 53.3 (OCH.sub.3), 66.4, 66.7 (C-5), 70.8, 71.2 (C-3), 85.4, 85.5, 85.8, 86.2 (C-1, C-4), 110.5 (C-5b), 111.9, 112.0 (C-5), 122.0 (o, OPh), 128.9 (C-5a), 130.3 (m, OPh), 131.1 (p, OPh), 138.2 (C-6), 149.1, 149.2 (ipso, OPh), 149.8 (C-4), 162.1, 162.2 (C-2), 174.5, 174.6 (COOCH.sub.3).

Synthesis of (E)-5-(2-bromovinyl)-2-deoxyuridine-5-[4-chlorophenyl-(ethoxy-L-alaninyl)]-phosphate (CPF 11)

(142) C.sub.22H.sub.26BrN.sub.3O.sub.9P, Mw=622.79.

(143) ##STR00034##

(144) This was synthesised according to Standard procedure 5, using BVdU (300 mg, 0.90 mmol), 4-chlorophenyl-(ethoxy-L-alaninyl)-phosphorochloridate (557.7 mg, 1.71 mmol), NMI (221.7 mg, 2.7 mmol, 215 L) in THF (10 mL) for 16 hrs. The crude product was purified by column chromatography, eluting with dichloromethane/methanol 97:3 to give the pure product as a white foamy solid (168.4 mg, yield 30.0%).

(145) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 4.88, 4.65.

(146) .sup.1H-NMR (CDCl.sub.3, 300 MHz): 9.51 (1H, bs, H-3), 7.69-7.68 (1H, 2s, H-6), 7.49-7.43 (1H, 2d, .sup.3J=13.6 Hz, H-5b), 7.37-7.22 (4H, m, OPh), 6.79-6.71 (1H, 2d, .sup.3J=13.6 Hz, H-5a), 6.33-6.24 (1H, m, H-1), 4.62-4.34 (3H, m, H-3+H-5), 4.28-3.89 (5H, m, H-4+OCH.sub.2CH.sub.3+CHCH.sub.3+NH), 2.59-2.45 (1H, m, one of H-2), 2.22-2.14 (1H, m, one of H-2), 1.43-1.41 (3H, d, .sup.3J=7.0 Hz, CHCH.sub.3), 1.33-1.28 (3H, 2t, .sup.3J=7.2 Hz, OCH.sub.2CH.sub.3).

(147) .sup.13C-NMR (CDCl.sub.3, 75 MHz): 14.5 (CH.sub.3CH.sub.2O), 21.2, 21.3 (CHCH.sub.3), 40.7 (C-2), 50.7, 50.8 (CHCH.sub.3), 62.4 (CH.sub.3CH.sub.2O), 66.7 (C-5), 70.8, 71.2 (C-3), 85.4, 85.8, 86.1 (C-1, C-4), 110.4 (C-5b), 112.0 (C-5), 122.0, 122.1 (o, OPh), 128.9 (C-5a), 130.3 (m, OPh), 131.1 (p, OPh), 138.2 (C-6), 149.2 (ipso, OPh), 150.0 (C-4), 162.2 (C-2), 174.1, 174.2 (COOCH.sub.2CH.sub.3).

Synthesis of (E)-5-(2-bromovinyl)-2-deoxyuridine-5-[4-chlorophenyl-(benzoxy-L-alaninyl)]-phosphate (CPF 12)

(148) C.sub.22H.sub.26BrN.sub.3O.sub.9P, MW=622.79.

(149) ##STR00035##

(150) This was synthesised according to Standard procedure 5, using BVdU (300 mg, 0.90 mmol), 4-chlorophenyl-(benzoxy-L-alaninyl)-phosphorochloridate (698.7 mg, 1.80 mmol), NMI (369.5 mg, 4.5 mmol, 358.7 L) in THF (10 mL) for 2 hrs. The crude product was purified by column chromatography, eluting with dichloromethane/methanol 95:5 to give the pure product as a white foamy solid (310.0 mg, yield 50.3%).

(151) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 4.81, 4.53.

(152) .sup.1H-NMR (CDCl.sub.3, 300 MHz): 10.10 (1H, bs, H-3), 7.65-7.63 (1H, 2s, H-6), 7.69-7.68 (1H, 2s, H-6), 7.46, 7.41 (1H, 2d, .sup.3J=13.6 Hz, H-5b), 7.40-7.17 (9H, m, OPh), 6.75-6.66 (1H, 2d, .sup.3J=13.6 Hz, H-5a), 6.33-6.23 (1H, 2t, .sup.3J=6.0 Hz, H-1), 5.17 (2H, s, CH.sub.2Ph), 4.60-4.23 (4H, m, H-3+H-5+NH), 4.20-3.97 (2H, m, H-4+CHCH.sub.3), 2.48-2.44 (1H, m, one of H-2), 2.15-2.05 (1H, m, one of H-2), 1.43-1.40 (3H, d, .sup.3J=7.0 Hz, CHCH.sub.3).

(153) .sup.13C-NMR (CDCl.sub.3, 75 MHz): 21.2 (CHCH.sub.3), 40.7 (C-2), 50.8, 50.9 (CHCH.sub.3), 66.6 (C-5), 67.9 (CH.sub.2Ph), 70.7, 71.1 (C-3), 85.4, 85.5, 85.8, 86.1 (C-1, C-4), 110.5 (C-5b), 111.9, 112.0 (C-5), 122.0, (o, OPh), 128.7, 129.0, 129.1, 130.3 (m, OPh+C-5a), 131.1 (ipso, CH.sub.2Ph), 135.4 (p, OPh), 138.2 (C-6), 149.1 (ipso, OPh), 150.0 (C-4), 162.1 (C-2), 173.9, 174.0 (COOCH.sub.2Ph).

Synthesis of (E)-5-(2-bromovinyl)2-deoxyuridine-5-[phenyl-(methoxy-,-dimethylglycinyl)]-phosphate (CPF 26)

(154) C.sub.22H.sub.27BrN.sub.3O.sub.9P, MW 588.34.

(155) ##STR00036##

(156) This was synthesised according to Standard procedure 5, using BVdU (200 mg, 0.60 mmol), phenyl-(methyl-2-amino-2-methylpropanoate)-phosphorochloridate (437.5 mg, 1.5 mmol), NMI (246.3 mg, 3.0 mmol, 239.1 L) in THF (5 mL) for 4 hrs. The crude product was purified by column chromatography, eluting with chloroform/methanol 97:3 to give the pure product as a white foamy solid (117 mg, yield 33.1%).

(157) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 3.36, 3.14

(158) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 9.91 (1H, bs, H-3), 7.73, 7.65 (1H, 2s, H-6), 7.50-7.43 (1H 2d, .sup.3J=13.6 Hz, H-5b), 7.41-7.02 (5H, m, OPh), 6.81-6.71 (1H, 2d, .sup.3J=13.6 Hz, H-5a), 6.34-6.28 (1H, m, H1), 4.55-4.17 (6H, m, H-5+H-4+H-3, NH, OH-3), 3.78 (3H, s, CH.sub.3O), 2.53-2.39 (1H, m, one of H-2), 2.25-1.99 (1H, m, one of H-2), 1.60 (6H, s, [CH.sub.3].sub.2C).

(159) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 27.5, 27.4, 27.2 ([CH.sub.3].sub.2C), 40.7, 40.6 (C-2), 53.5 (CH.sub.3O), 57.6 (C[CH.sub.3].sub.2), 66.5, 66.2 (C-5), 70.7, 71.1 (C-3), 85.4, 85.6, 85.5, 85.9 (C-1, C-4), 110.4 (C-5b), 111.9 (C-5), 120.5, 120.6 (o, OPh), 125.7 (p, OPh), 128.9 (C-5a), 130.3 (m, OPh), 138.0, 138.3 (C-6), 149.8 (ipso, OPh) 150.9, 150.8 (C-4), 162.0, 162.1 (C-2), 176.4, 176.2 (COOCH.sub.3).

Synthesis of (E)-5-(2-bromovinyl)-2-deoxyuridine-5-[phenyl-(ethoxy-,-dimethylglycinyl)]-phosphate (CPF 27)

(160) C.sub.23H.sub.29BrN.sub.3O.sub.9P, MW=602.37

(161) ##STR00037##

(162) This was synthesised according to Standard procedure 5, using BVdU (200 mg, 0.60 mmol), phenyl-(ethyl-2-amino-2-methylpropanoate)-phosphorochloridate (458.0 mg, 1.5 mmol), NMI (246.3 mg, 3.0 mmol, 239.1 L) in THF (5 mL) for 5 hrs. The crude product was purified by column chromatography, eluting with chloroform/methanol 97:3 to give the pure product as a white foamy solid (106 mg, yield 29.3%).

(163) .sup.31P-NMR (MeOD, 121 MHz): 3.91, 3.85

(164) .sup.1H-NMR (MeOD, 300 MHz): 7.84, 7.81 (1H, 2s, H-6), 7.44-7.20 (6H, m, OPh+H-5b), 6.88-6.81 (1H, 2d, .sup.3J=13.6 Hz, H-5a), 6.34-6.28 (1H, m, H-1), 4.50-4.34 (3H, m, H-5+H-3), 4.23-4.15 (3H, m, H-4+CH.sub.3CH.sub.2O), 2.38-2.28 (1H, m, one of H-2), 2.22-2.09 (1H, m, one of H-2), 1.51 (6H, s, [CH.sub.3].sub.2C), 1.29 (3H, t,.sup.3J=7 Hz, CH.sub.3CH.sub.2O)

(165) .sup.13C-NMR (MeOD, 75 MHz): 14.9 (CH.sub.3CH.sub.2O) 27.9, 28.3 ([CH.sub.3].sub.2C), 41.5 (C-2), 58.51 (C[CH.sub.3].sub.2), 63.1 (CH.sub.3CH.sub.2O), 68.2 (C-5), 72.6 (C-3), 87.1, 87.4 (C-1, C-4), 109.6 (C-5b), 112.7 (C-5b), 122.0, 122.1, 122.2, (o, OPh), 126.7 (p, OPh), 131.0, 131.2 (C-5a, m OPh), 140.4 (C-6), 151.4 (ipso, OPh) 152.5 (C-4), 164.0 (C-2), 177.2 (COOCH.sub.2CH.sub.3).

Synthesis of (E)-5-(2-bromovinyl)-2-deoxyuridine-5-[phenyl-(benzoxy-,-dimethylglycinyl)]-phosphate (CPF 14)

(166) C.sub.28H.sub.31BrN.sub.3O.sub.9P, MW=664.44.

(167) ##STR00038##

(168) This was synthesised according to Standard procedure 5, using BVdU (242 mg, 0.73 mmol), phenyl-(benzyl-2-amino-2-methylpropanoate)-phosphorochloridate (533.0 mg, 2.0 mmol), NMI (298.0 mg, 3.63 mmol, 289 L) in THF (5 mL) for 4 hrs. The crude product was purified by column chromatography, eluting with chloroform/methanol 97:3 to give the pure product as a white foamy solid (129.0 mg, yield 26.7%).

(169) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 3.39, 3.12.

(170) .sup.1H-NMR (CDCl.sub.3, 300 MHz): 9.92 (1H, bs, H-3), 7.67-7.60 (1H, 2s, H-6), 7.48-7.41 (1H, 2d, .sup.3J=13.6 Hz, H-5b), 7.40-7.16 (10H. m, OPh+CH.sub.2Ph), 6.78-6.67 (1H, 2d, .sup.3J=13.6 Hz, H-5a), 6.31-6.25 (1H, m, H-1), 5.18 (1H, s, CH.sub.2Ph), 4.50-4.09 (6H, m, H-3+H-5+H-4, NH, OH-3), 2.48-2.25 (1H, m, one of H-2), 2.16-1.82 (1H, m, one of H-2), 1.60 (6H, s, [CH.sub.3].sub.2C).

(171) .sup.13C-NMR (CDCl.sub.3, 75 MHz): 27.3, 27.4, 28.5 ([CH.sub.3].sub.2C), 40.6, 40.7 (C-2), 57.6, 57.6 (C[CH.sub.3].sub.2), 66.2, 66.5 (C-5), 68.1 (CH.sub.2Ph), 70.6, 71.1 (C-3), 85.4, 85.5, 85.6, 85.8 (C-1, C-4), 110.4 (C-5b), 112.0 (C-5), 120.4, 120.5, 120.6, 125.7, 128.4, 128.5, 128.8, 128.9, 130.3 (OPh, C-5a), 135.7(ipso, CH.sub.2Ph) 138.1, 138.3 (C-6), 149.8, 150.8, 150.9 (ipso OPh, C-4), 162.1 (C-2), 177.5, 175.7 (COOCH.sub.2Ph).

Synthesis of (E)-5-(2-bromovinyl)-2-deoxyuridine-5-[4-nitrophenyl-(methoxy-,-dimethylglycinyl)]-phosphate (CPF 45)

(172) C.sub.22H.sub.26BrN.sub.4O.sub.11P, MW=633.34.

(173) ##STR00039##

(174) This was synthesised according to Standard procedure 5, using BVdU (150 mg, 0.45 mmol), 4-nitrophenyl-(methyl-2-amino-2-methylpropanoate)-phosphorochloridate (378.8 5 mg, 1.13 mmol), NMI (184.7 mg, 2.25 mmol, 179.4 L) in THF (5 mL) for 3 hrs. The crude product was purified by column chromatography, eluting with dichloromethane/methanol 97:3 to give the pure product as a white foamy solid (145.7 mg, yield 50.9%).

(175) .sup.31P-NMR (MeOD, 121 MHz): 3.61, 3.56.

(176) .sup.1H-NMR (MeOD, 300 MHz): 8.30-8.25 (2H, 2d, .sup.3J=9.0 Hz, OPh), 7.79-7.78 (1H, 2s, H-6), 7.49-7.46 (2H, d, .sup.3J=9.0 Hz, OPh), 7.37-7.32 (1H, 2d, .sup.3J=13.6 Hz, H-5b), 6.79-6.72 (1H, 2d, .sup.3J=13.6 Hz, H-5a), 6.32-6.25 (1H, m, H-1), 4.48-4.35 (3H, m, H-3+H-5), 4.15-4.14 (1H, m, H-4), 3.71 (3H, s, CH.sub.3O), 2.41-2.17 (2H, m, H-2), 1.51 (6H, s, [CH.sub.3].sub.2C.

(177) .sup.13C-NMR (CDCl.sub.3, 75 MHz): 28.0, 28.1, 28.2, 28.3 ([CH.sub.3].sub.2C), 41.4, 41.5 (C-2), 53.6 (CH.sub.3O), 58.7 (C[CH.sub.3].sub.2), 68.5 (C-5), 72.3, 72.4 (C-3), 86.9, 87.0, 87.4, 87.5 (C-1, C-4), 109.7 (C-5b), 112.6 (C-S), 122.8, 122.9 (o, OPh), 127.0 (m, OPh), 130.9 (C-5a), 140.5 (C-6),146.5 (p, OPh), 151.5 (ipso, OPh), 157.3 (C-4), 164.0 (C-2), 177.5 (COOCH.sub.3).

Synthesis of (E)-5-(2-bromovinyl)-2-deoxyuridine-5-[4-nitrophenyl-(ethoxy-,-dimethylglycinyl)]-phosphate (CPF 46)

(178) C.sub.23H.sub.28BrN.sub.4O.sub.11P, MW=647.3.

(179) ##STR00040##

(180) This was synthesised according to Standard procedure 5, using BVdU (150 mg, 0.45 mmol), 4-nitrophenyl-(ethyl-2-amino-2-methylpropanoate)-phosphorochloridate (442.1 mg, 1.26 mmol), NMI (184.7 mg, 2.25 mmol, 179.4 L) in THF (5 mL) for 4 hrs. The crude product was purified by column chromatography, eluting with dichloromethane/methanol 97:3 to give the pure product as a white foamy solid (152.9 mg, yield 52.5%).

(181) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 3.00, 2.96.

(182) .sup.1H-NMR (CDCl.sub.3, 300 MHz): 10.28 (1H, bs, H-3), 8.25.-8.12 (2H, 2d, .sup.3J=9.0 Hz, OPh), 7.68-7.67 (1H, 2s, H-6), 7.46-7.32 (3H, m, OPh+H-5b), 6.69-6.67 (1H, 2d, .sup.3J=13.5 Hz, H-5a), 6.32-6.26 (1H, m, H-1), 4.75-4.36 (5H, m, H-3+H-5+NH), 4.25-4.17 (3H, m, OCH.sub.2CH.sub.3, H-4), 2.60-2.98 (1H, m, one of H-2), 2.31-2.10 (1H, m, one of H-2), 1.58 (6H, s, [CH.sub.3].sub.2C), 1.30-1.28 (3H, 2t, .sup.3J=7.1 Hz, OCH.sub.2CH.sub.3).

(183) .sup.13C-NMR (CDCl.sub.3, 75 MHz): 14.5 (CH.sub.3CH.sub.2O), 27.1, 27.2, 27.3, 27.4 ([CH.sub.3].sub.2C), 40.6 (C-2), 57.7 (C[CH.sub.3].sub.2), 62.7 (CH.sub.3CH.sub.2O), 67.0 (C-5), 71.0, 71.2 (C-3), 85.4, 85.9, 86.1 (C-1, C-4), 110.3 (C-5b), 111.9 (C-5), 121.2, 121.3 (o, OPh), 126.2 (m, OPh), 128.8 (C-5a), 138.4 (C-6), 145.0 (p, OPh), 150.0 (C-4), 155.7-155.9 (ipso, OPh), 162.2 (C-2), 175.0-175.1 (COOCH.sub.2CH.sub.3).

Synthesis of (E)-5-(2-bromovinyl)-2-deoxyuridine-5-[4-nitrophenyl-(benzoxy-,-dimethylglycinyl)]-phosphate (CPF 47)

(184) C.sub.28H.sub.30BrN.sub.4O.sub.11P, MW=709.44.

(185) ##STR00041##

(186) This was synthesised according to Standard procedure 5, using BVdU (100 mg, 0.30 mmol), 4-nitrophenyl-(benzyl-2-amino-2-methylpropanoate)-phosphorochloridate (309.6 mg, 1.07 mmol), NMI (123.7 mg, 1.5 mmol, 120.1 L) in THF (5 mL) for 5 hrs. The crude product was purified by column chromatography, eluting with dichloromethane/methanol 97:3 to give the pure product as a white foamy solid (160.2 mg, yield 50.2%).

(187) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 2.95, 2.89.

(188) .sup.1H-NMR (CDCl.sub.3, 300 MHz): 10.16 (1H, bs, H-3), 8.26-8.24 (2H, 2d, .sup.3J=9.1 Hz, OPh), 7.71-7.69 (1H, 2s, H-6), 7.48-7.37 (8H, m, OPh+CH.sub.2Ph, H-5b), 6.75-6.72 (1H, 2d, .sup.3J=13.5 Hz, H-5a), 6.36-6.29 (1H, m, H-1), 5.24 (2H, s, CH.sub.2Ph), 4.81-4.40 (5H, m, H-3+H-5+OH-3, NH, 4.22-4.21 (1H, m, H-4), 2.57-2.36 (1H, m, one of H-2) 2.27-2.22 (1H, m, one of H-2), 1.64 (6H, s, [CH.sub.3].sub.2C).

(189) .sup.13C-NMR (CDCl.sub.3, 75 MHz): 27.4 ([CH.sub.3].sub.2C), 40.6 (C-2), 57.8 (C[CH.sub.3].sub.2), 67.0 (C-5), 68.2 (CH.sub.2Ph), 71.1, 71.2 (C-3), 85.3, 86.2 (C-1, C-4), 110.5 (C-5b), 111.9 (C-5), 111.9 (C-5), 121.2, 126.2, 128.5, 128.8, 129.0, 129.1 (o, m, p, CH.sub.2Ph+OPh+C-5a), 135.5 (ipso, CH.sub.2Ph), (C-5a), 138.4 (C-6), 145.0 (p, OPh), 150.0 (C-4), 155.7 (ipso, OPh), 162.2 (C-2), 175.4-175.5 (COOCH.sub.2Ph).

Synthesis of (E)-5-(2-bromovinyl)-2-deoxyuridine-5-[4-chlorophenyl-(methoxy-,-dimethylglycinyl)]-phosphate (CPF 42)

(190) C.sub.22H.sub.26BrClN.sub.3O.sub.9P, MW=622.79.

(191) ##STR00042##

(192) This was synthesised according to Standard procedure 5, using BVdU (150 mg, 0.45 mmol), 4-chlorophenyl-(methyl-2-amino-2-methylpropanoate)-phosphorochloridate (440.2 mg, 1.35 mmol), NMI (184.7 mg, 2.25 mmol, 179.4 L) in THF (5 mL) for 6 hrs. The crude product was purified by column chromatography, eluting with dichloromethane/methanol 97:3 to give the pure product as a white foamy solid (146.7 mg, yield 56.5%).

(193) .sup.31P-NMR (MeOD, 121 MHz): 3.98 (s).

(194) .sup.1H-NMR (MeOD, 300 MHz): ), 7.71-7.69 (1H, 2s, H-6), 7.31-7.13 (5H, m, OPh+H-5b) 6.73-6.66 (1H, 2d, .sup.3J=13.6 Hz, H-5a), 6.23-6.16 (1H, m, H-1), 4.39-4.22 (3H, m, H-3+H-5), 4.05-4.03 (1H, m, H-4), 3.61 (3H, s, CH.sub.3O), 2.29-2.19 (1H, m, one of H2), 2.15-2.05 (1H, m, one of H-2), 1.38 (6H, s, [CH.sub.3].sub.2C).

(195) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 28.0, 28.2, 28.3, 28.4 ([CH.sub.3].sub.2C), 41.5, 41.6 (C-2), 53.5, 53.6 (CH.sub.3O), 58.6 (C[CH.sub.3].sub.2), 68.2 (C-5), 72.4, 72.5 (C-3), 87.1, 87.2, 87.3, 87.4 (C-1, C-4), 109.7 (C-5b), 112.7 (C-5), 123.7, 123.8 (o, OPh), 130.9, 131.1 (m, OPh+C-5a), 131.9 (p, OPh), 140.4 (C-6), 151.1, 151.2, 151.4 (ipso, OPh+C-4), 164.0 (C-2), 177.6, 177.7 (COOCH.sub.3).

Synthesis of (E)-5-(2-bromovinyl)-2-deoxyuridine-5-[4-chlorophenyl-(ethoxy-,-dimethylglycinyl)]-phosphate (CPF 43)

(196) C.sub.23H.sub.28BrClN.sub.3O.sub.9P, MW=636.81.

(197) ##STR00043##

(198) This was synthesised according to Standard procedure 5, using BVdU (150 mg, 0.45 mmol), 4-chlorophenyl-(ethyl-2-amino-2-methylpropanoate)-phosphorochloridate (413.3 mg, 1.22 mmol), NMI (184.7 mg, 2.25 mmol, 179.3 L) in THF (5 mL) for 16 hrs. The crude product was purified by column chromatography, eluting with dichloromethane/methanol 97:3 to give the pure product as a white foamy solid (74 mg, yield 25.8%).

(199) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 3.47, 3.33.

(200) .sup.1H-NMR (CDCl.sub.3, 300 MHz): 10.03-9.99 (1H, 2bs, H-3), 7.70-7.67 (1H, 2s, H-6), 7.47-7.43 (1H, 2d, .sup.3J=13.6 Hz, H-5b), 7.35-7.20 (4H, m, OPh), 6.77-6.68 (1H, 2d, .sup.3J=13.6 Hz, H-5a), 6.33-6.27 (1H, m, H-1), 4.55-4.29 (5H, m, H-3+H-5+OH-3+NH), 4.22-4.17 (2H, q, .sup.3J=7.1 Hz, OCH.sub.2CH.sub.3+H-4), 2.53-2.42 (1H, m, one of H-2), 2.22-2.08 (1H, m, one of H-2), 1.57-1.54 (6H, 2s, [CH.sub.3].sub.2C), 1.31-1.30 (3H, 2t, .sup.3J=7.1 Hz, OCH.sub.2CH.sub.3).

(201) .sup.13C-NMR (CDCl.sub.3, 75 MHz): 14.5 (CH.sub.3CH.sub.2O), 27.2, 27.3, 27.4 ([CH.sub.3].sub.2C), 40.7 (C-2), 57.6 (C[CH.sub.3].sub.2), 62.6 (CH.sub.3CH.sub.2O), 66.5, 66.6 (C-5), 70.8, 71.1 (C-3), 85.5, 85.74, 86.0 (C-1, C-4), 110.4 (C-5b), 112.0 (C-5), 121.9, 122.0, 122.1 (o, OPh), 128.9, 130.2 (m, OPh+C-5a), 130.9 (p, OPh), 138.3 (C-6), 149.4 (ipso, OPh), 149.9 (C-4), 162.1, 162.2 (C-2), 175.7-175.9 (COOCH.sub.2CH.sub.3).

Synthesis of (E)-5-(2-bromovinyl)-2-deoxyuridine-5-[4-chlorophenyl-(benzoxy-,-dimethylglycinyl)]-phosphate (CPF 44)

(202) C.sub.28H.sub.30BrClN.sub.3O.sub.9P, MW=698.88.

(203) ##STR00044##

(204) This was synthesised according to Standard procedure 5, using BVdU (150 mg, 0.45 mmol), 4-chlorophenyl-(benzyl-2-amino-2-methylpropanoate)-phosphorochloridate (505.0 mg, 1.25 mmol), NMI (184.7 mg, 2.25 mmol, 179.3 L) in THF (5 mL) for 16 hrs. The crude product was purified by column chromatography, eluting with dichloromethane/methanol 97:3 to give the pure product as a white foamy solid (134.8 mg, yield 42.9%).

(205) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 3.44, 3.26.

(206) .sup.1H-NMR (CDCl.sub.3, 300 MHz): 9.96-9.93 (1H, 2bs, H-3), 7.66-7.65 (1H, 2s, H-6), 7.47-7.41 (1H, 2d, .sup.3J=13.5, H-5b), 7.39-7.18 (9H, m, OPh+CH.sub.2Ph) 6.74-6.69 (1H, 2d, .sup.3J=13.5 Hz, H-5a), 6.31-6.25 (1H, m, H-1), 5.19 (2H, CH.sub.2Ph), 4.51-4.29 (4H, m, H-3+H-5+NH), 4.15-4.12 (2H, m, H-4+OH-3), 2.48-2.40 (1H, m, one of H-2), 2.18-2.05 (1H, m, one of H-2), 1.60-1.59 (6H, 2s, [CH.sub.3].sub.2C).

(207) .sup.13C-NMR (CDCl.sub.3, 75 MHz): 27.1, 27.5 ([CH.sub.3].sub.2C), 40.7 (C-2), 57.7 (C[CH.sub.3].sub.2), 66.4, 66.6 (C-5), 68.2 (CH.sub.2Ph), 70.7, 71.1 (C-3), 85.4, 85.5, 85.7, 86.0 (C-1, C-4), 110.5 (C-5b), 112.0 (C-5), 121.9, 122.0, 128.4, 128.5, 128.9, 129.1 (o, m, p, CH.sub.2Ph+OPh+C-5a), 131.0 (ipso, CH.sub.2Ph), 135.6 (p, OPh), 138.1 (C-6), 149.3 (ipso, OPh), 149.8 (C-4), 162.1 (C-2), 175.6 (COOCH.sub.2Ph).

Synthesis of (E)-5-(2-bromovinyl)-2-deoxyuridine-5-[para-(trifluoromethyl)phenyl-(benzoxy-,-dimethylglycinyl)]-phosphate (CPF 48)

(208) C.sub.29H.sub.30BrF.sub.3N.sub.3O.sub.9P, MW=732.44.

(209) ##STR00045##

(210) This was synthesised according to Standard procedure 5, using BVdU (150 mg, 0.45 mmol), 4-(trifluoromethyl)-phenyl-(benzyl-2-amino-2-methylpropanoate)-phosphorochloridate (529.4.5 mg, 1.22 mmol), NMI (184.7 mg, 2.25 mmol, 179.4 L) in THF (5 mL) for 4 hrs. The crude product was purified by column chromatography, eluting with dichloromethane/methanol 97:3 to give the pure product as a white foamy solid (142.1 mg, yield 43.1%).

(211) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 3.16, 3.01.

(212) .sup.1H-NMR (CDCl.sub.3, 300 MHz): 10.06-10.02 (1H, 2bs, H-3), 7.67-7.66 (1H, s, H-6), 7.64-7.60 (2H, 2d, .sup.3J=8.8 Hz, OPh), 7.46-7.32 (8H, m, OPh+CH.sub.2Ph+H-5b), 6.77-6.68 (1H, 2d, .sup.3J=13.6 Hz, H-5a), 6.31-6.26 (1H, m, H-1), 5.18 (2H, s, CH.sub.2Ph), 4.61-4.32 (4H, m, H-3+H-5+NH), 4.16-4.15 (2H, m, H-4+OH-3), 2.48-2.41 (1H, m, one of H-2), 2.23-2.09 (1H, m, one of H-2), 1.60-1.58 (6H, 2s, C[CH.sub.3].sub.2)

(213) .sup.13C-NMR (CDCl.sub.3, 75 MHz): 27.0, 27.4, 27.5 (C[CH.sub.3].sub.2), 40.6 (C-2), 57.7, 57.8 (C[CH.sub.3).sub.2), 66.8, 66.5 (C-5), 68.2 (CH.sub.2Ph), 70.8, 71.1 (C-3), 85.4, 85.7, 86.0 (C-1, C-4), 110.4 (C-5b), 111.9 (C-5), 120.8, 120.9, 121.0, 127.6, 127.7, 128.0, 128.5, 128.8, 129.0 (o, m, p, OPh+CH.sub.2Ph+C-5a), 124.2 (CF.sub.3, J=267 Hz), 135.6 (ipso, CH.sub.2Ph), 138.2 (C-6),149.9 (C-4), 153.3 (ipso, OPh), 162.1 (C-2),175.4 (COOCH.sub.2Ph).

Synthesis of (E)-5-(2-Bromovinyl)-2-deoxyuridine-5-[phenyl-(methoxy-,-cycloleucinyl)]-phosphate (CPF 16)

(214) C.sub.24H.sub.29BrN.sub.3O.sub.9P, MW=614.38.

(215) ##STR00046##

(216) This was synthesised according to Standard procedure 5, using BVdU (250 mg, 0.75 mmol), Phenyl-(methoxy-,-cycloleucinyl)-phosphorochloridate (589 mg, 1.87 mmol), NMI (6.2 mmol, 415 L) in THF (7 mL) for 3 hrs. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 97:3 to give the pure product as a white foamy solid (234 mg, yield 51%).

(217) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 3.87, 3.82.

(218) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 10.35-10.2 (1H, bs, H-3), 7.65 (1H, 2s, H-6), 7.44-7.39 (1H, 2d, .sup.3J=13 Hz, H-5b), 7.37-7.15 (5H, m, OPh, 6.8 (1H, 2d, .sup.3J=13 Hz, H-5a), 6.30 (1H, 2t, .sup.3J=6 Hz, H1), 4.4-4.2 (4H, m, H-5, H-3, NH), 4.1 (1H, H-4), 3.72 (3H, 2s, CH.sub.3O), 2.49-2.40 (1H, m, one of H-2), 2.35-2.01 (5H, m, one of H-2+4H cyclopentane), 1.8-1.6 (4H, m, 4H cyclopentane).

(219) .sup.13C-NMR (DMSO; 75 MHz): 24.4, 24,3, 24.2 (2CH.sub.2 cyclopent), 39.2, 38.6, 38.5 (2CH.sub.2 cyclopent), 40.0 (C-2), 53.2 (CH.sub.3O), 66.4 (Cq cyclopentane), 66.6 (C-5), 70.9 (C-3), 85.8, 85.6, 85.4, 85.3 (C-1, C-4), 110.2 (C-5b), 111.9 (C-5), 120.7-120.6 (o, OPh, 125.7 (p, OPh, 129.0 (C-5a), 130.2 (m, OPh), 138.5 (C-6), 149.9 (C-4), 150.9, 150.8 (ipso, OPh), 162.3(C-2), 176.3, 176.2 (COOCH.sub.3).

Synthesis of (E)-5-(2-Bromovinyl)-2-deoxyuridine-5-[phenyl-(ethoxy-, -cycloleucinyl)]-phosphate (CPF 17)

(220) C.sub.25H.sub.31BrN.sub.3O.sub.9P, MW=628.41.

(221) ##STR00047##

(222) This was synthesised according to Standard procedure 5, using BVdU (250 mg, 0.75 mmol), Phenyl-(ethoxy-,-cycloleucinyl)-phosphorochloridate (642 mg, 1.87 mmol), NMI (6.2 mmol, 415 L) in THF (7 mL) for 2 hrs. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 97:3 to give the pure product as a white foamy solid (258 mg, yield 55%).

(223) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 4.23, 4.1.

(224) .sup.1H-NMR (CDCl.sub.3, 300 MHz): 10.3-10.1 (1H, bs, H-3), 7.8-7.75 (1H, 2s, H-6), 7.51 (1H, 2d, .sup.3J=14 Hz, H-5b), 7.45-7.10 (5H, m, OPh), 6.8 (1H, 2d, .sup.3J=14 Hz, H-5a), 6.22 (1H, 2t, .sup.3J=4 Hz, H1), 4.55-4.05 (7H, m, H-5, H-3, H-4, NH, CH.sub.3CH.sub.2O), 2.50-2.40 (1H, m, one of H-2), 2.35-1.95 (5H, m, one of H-2+4H cyclopentane), 1.95-1.75 (4H, m, 4H cyclopentane), 1.25 (3H, 2t, .sup.3J=7 Hz, CH.sub.3CH.sub.2O).

(225) .sup.13C-NMR (CDCl.sub.3, 75 MHz): 14.5 (CH.sub.3CH.sub.2O), 24.5, 24,4 (2CH.sub.2 cyclopent), 39.2, 38.9 38.8, 38.4 (2CH.sub.2 cyclopent), 40.6 (C-2), 62.2, 62.1 (CH.sub.3CH.sub.2O), 66.2 (Cq cyclopentane), 66.6 (C-5), 70.8 (C-3), 85.7, 85.5 (C-1, C-4), 110.2 (C-5b), 111.5 (C-5), 120.7, 120.6 (o, OPh, 125.6 (p, OPh), 129.7 (C-5a), 130.2 (m, OPh), 138.5, 138.3 (C-6), 149.7 (C-4), 150.9, 150.8 (ipso, OPh), 162.3 (C-2),176.3 (COOCH.sub.2CH.sub.3).

Synthesis of (E)-5-(2-Bromovinyl)-2-deoxyuridine-5-[phenyl-(benzoxy-, -cycloleucinyl)]-phosphate (CPF 18)

(226) C.sub.30H.sub.33BrN.sub.3O.sub.9P, MW=690.48.

(227) ##STR00048##

(228) This was synthesised according to Standard procedure 5, using BVdU (200 mg, 0.6 mmol), Phenyl-(benzyloxy-,-cycloleucinyl)-phosphorochloridate (589 mg, 1.5 mmol), NMI (4.98 mmol, 332 L) in THF (5 mL) for 10 hrs. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 97:3 to give the pure product as a white foamy solid (127 mg, yield 31%).

(229) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 4.11, 4.01.

(230) .sup.1H-NMR (CDCl.sub.3, 300 MHz): 10.2 (1H, bs, H-3), 7.8-7.6 (1H, 2s, H-6), 7.45-7.4 (1H, 2d, .sup.3J=14 Hz, H-5b), 7.40-7.10 (10H. m, OPh+CH.sub.2Ph), 6.85 (1H, 2d, .sup.3J=14 Hz, H-5a), 6.20 (1H, m, H-1), 5.15 (1H, s, CH.sub.2Ph), 4.4-4.2 (3H, m, H-3,H-4, NH), 4.1 (2H, m, H-5), 2.45-2.35 (1H, m, one of H-2), 2.35-1.95 (5H, m, one of H-2+4H cyclopentane), 1.95-1.75 (4H, m, 4H cyclopentane).

(231) .sup.13C-NMR (CDCl.sub.3, 75 MHz): 24.4, 24,3, 24.2 (2CH.sub.2 cyclopent), 39.9, 39.7 38.6, 38.5 (2CH.sub.2 cyclopent), 40.5 (C-2), 66.2 (Cq cyclopentane), 66.5 (C-5), 67.8 (CH.sub.2Ph), 70.8, 70.7 (C-3), 85.7, 85.6, 85.5, 85.4 (C-1, C-4), 110.2 (C-5b), 111.8, 118.7 (C-5b), 120.7, 120.5 (o, OPh), 125.7 (p, OPh), 130.2, 129.0, 128.8, 128.7, 128.5 (m OPh, Bn, C-5a), 135.8(ipso, CH.sub.2Ph) 138.4, 138.2 (C-6), 149.8 (C-4), 150.9, 150.8 (ipso, OPh), 162.2 (C-2), 175.7, 175.5 (COOBn).

Synthesis of (E)-5-(2-Bromovinyl)-2-deoxyuridine-5-[para-nitrophenyl-(methoxy-,-cycloleucinyl)]-phosphate (CPF 19)

(232) C.sub.24H.sub.28BrN.sub.4O.sub.11P, MW=659.38.

(233) ##STR00049##

(234) This was synthesised according to Standard procedure 5, using BVdU (200 mg, 0.60 mmol), para-nitrophenyl-(methoxy-,-cycloleucinyl)-phosphorochloridate (543 mg, 1.5 mmol), NMI (4.98 mmol, 332 L) in THF (5 mL) for 2 hrs. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 97:3 to give the pure product as a white foamy solid (239 mg, yield 60%).

(235) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 3.73.

(236) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 10.5-10.2 (1H, bs, H-3), 8.35-8.25 (2H, 2d, .sup.3J=6 Hz OPh) 7.8-7.75 (1H, 2s, H-6), 7.47 (2H, 2d, .sup.3J=6 Hz, OPh), 7.45-7.35 (1H, 2d, .sup.3J=14 Hz, H-5b), 6.75-6.67 (1H, 2d, .sup.3J=14 Hz, H-5a), 6.30 (1H, 2t, .sup.3J=6 Hz, H1), 4.65-4.4 (3H, m, H-5,H-3), 4.25-4.20 (1H, m, H-4), 3.79 (3H, s, CH.sub.3O), 2.6-2.4 (1H, m, one of H-2), 2.3-1.98 (5H, m, one of H-2+4H cyclopentane), 1.9-1.76 (4H, m, 4H cyclopentane).

(237) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 24.4, 24,3, 24.2 (2CH.sub.2 cyclopent), 39.2, 39.1 (2CH.sub.2 cyclopent), 40.5 (C-2), 53.4, 53.3 (CH.sub.3O), 66.8 (Cq cyclopentane), 67.1 (C-5), 70.9 (C-3), 86.1, 86.0, 85.5, 85.4 (C-1, C-4), 110.2 (C-5b), 111.8 (C-5), 121.3, 121.2 (o, OPh), 126.2 (m, OPh), 128.9 (C-5a), 138.6 (C-6), 144.9 (ipso, OPh) 149.9 (C-4), 155.9, 155.8 (p, OPh), 162.3 (C-2), 176.3 (COOCH.sub.3).

Synthesis of (E)-5-(2-Bromovinyl)-2-deoxyuridine-5-[para-nitrophenyl-(ethoxy-,-cycloleucinyl)]-phosphate (CPF 20)

(238) C.sub.25H.sub.30BrN.sub.3O.sub.11P, MW=673.4.

(239) ##STR00050##

(240) This was synthesised according to Standard procedure 5, using BVdU (200 mg, 0.60 mmol), para-nitrophenyl-(ethoxy-,-cycloleucinyl)-phosphorochloridate (563 mg, 1.5 mmol), NMI (4.98 mmol, 332 L) in THF (5 mL) for 1 hr. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 97:3 to give the pure product as a white foamy solid (240 mg, yield: 59%).

(241) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 3.83, 3.79.

(242) .sup.1H-NMR (CDCl.sub.3, 300 MHz): 8.25-8.2 (2H,2d,.sup.3J=9 Hz OPh), 7.66 (1H, s, H-6), 7.4 (2H, 2d, .sup.3J=9 Hz, OPh), 7.3 (1H, 2d, .sup.3J=14 Hz, H-5b), 6.85 (1H, 2d, .sup.3J=14 Hz, H-5a), 6.3-6.2 (1H, m, H1), 4.7-4.45 (4H, m, H-5, H-3, NH), 4.2-4.05 (3H, m, H-4, CH.sub.3CH.sub.2O), 2.55-2.4 (1H, m, one of H-2), 2.2-1.95 (5H, m, one of H-2+4H cyclopentane), 1.95-1.8 (4H, m, 4H cyclopentane), 1.2 (3H, 2t, .sup.3J=8 Hz, CH.sub.3CH.sub.2O).

(243) .sup.13C-NMR (CDCl.sub.3, 75 MHz): 14.9 (CH.sub.3CH.sub.2O), 24.5, 24,4 (2CH.sub.2 cyclopent), 39.1, 39.0, 38.8 (2CH.sub.2 cyclopent), 40.7 (C-2), 62.4 (CH.sub.3CH.sub.2O), 66.5 (Cq cyclopentane), 67.0 (C-5), 70.9 (C-3), 85.9, 85.4 (C-1, C-4), 110.2 (C-5b), 111.8 (C-5), 121.3 (o, OPh), 126.2 (m, OPh), 128.8 (C-5a), 138.5 (C-6), 144.9 (ipso, OPh), 149.9 (C-4), 155.5 (p, OPh), 162.3 (C-2), 175.8, 175.7 (COOCH.sub.2CH.sub.3).

Synthesis of (E)-5-(2-Bromovinyl)-2-deoxyuridine-5-[para-nitrophenyl-(benzoxy-,-cycloleucinyl)]-phosphate (CPF 21)

(244) C.sub.30H.sub.32BrN.sub.4O.sub.11P, MW=735.47.

(245) ##STR00051##

(246) This was synthesised according to Standard procedure 5, using BVdU (200 mg, 0.60 mmol), para-nitrophenyl-(benzyloxy-,-cycloleucinyl)-phosphorochloridate (656 mg, 1.5 mmol), NMI (4.98 mmol, 332 L) in THF (5 mL) for 3 hrs. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 97:3 to give the pure product as a white foamy solid (269 mg, yield 61%).

(247) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 3.72.

(248) .sup.1H-NMR (CDCl.sub.3, 300 MHz): 10.3 (1H, bs, H-3), 8.22-8.12 (2H, 2d, J=7 Hz, OPh), 7.65 (1H, 2s, H-6), 7.45-7.30 (8H, m, H-5b+OPh+CH.sub.2Ph), 6.72-6.65 (1H, 2d, .sup.3J=14 Hz, H-5a), 6.28 (1H, 2t, .sup.3J=6 Hz, H-1), 5.15 (1H, d, CH.sub.2Ph), 4.6-4.35 (4H, m, H-3, H-5, H-4, NH,), 2.55-2.4 (1H, m, one of H-2), 2.3-1.92 (5H, m, one of H-2+4H cyclopentane), 1.85-1.6 (4H, m, 4H cyclopentane).

(249) .sup.13C-NMR (CDCl.sub.3, 75 MHz): 24.4, 24,3, 24.2 (2CH.sub.2 cyclopent), 39.1, 38.9, 38.7 (2CH.sub.2 cyclopent), 40.5 (C-2), 66.9 (cyclopentane), 67.1 (C-5), 68.0 (CH.sub.2Ph), 70.9 (C-3), 85.3, 85.0 (C-1, C-4), 110.3 (C-5b), 111.8 (C-5), 121.2 (o, OPh), 126.1 (m, OPh), 129.0, 128.8 (Bn, C-5a), 135.7 (ipso, CH.sub.2Ph), 138.5 (C-6), 144.9 (ipso, OPh), 149.9 (C-4), 155.8 (p OPh), 162.3 (C-2), 175.6 (COOBn).

Synthesis of (E)-5-(2-Bromovinyl)-2-deoxyuridine-5-[para-fluorophenyl-(methoxy-,-cycloleucinyl)]-phosphate (CPF 22)

(250) C.sub.24H.sub.28BrFN.sub.3O.sub.9P, MW=632.37.

(251) ##STR00052##

(252) This was synthesised according to Standard procedure 5, using BVdU (200 mg, 0.60 mmol), para-fluorophenyl-(methoxy-,-cycloleucinyl)-phosphorochloridate (503 mg, 1.5 mmol), NMI (4.98 mmol, 332 L) in THF (5 mL) for 2 hrs. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 97:3 to give the pure product as a white foamy solid (251 mg, yield 66%).

(253) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 4.22.

(254) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 10.3 (1H, bs, H-3), 7.70 (1H, 2s, H-6), 7.4 (1H, 2d, .sup.3J=14 Hz, H-5b), 7.25-7.15 (2H, m, OPh), 7.1-6.95 (2H, m, OPh), 6.70 (1H, 2d, .sup.3J=14 Hz, H-5a), 6.30-6.15 (1H, 2t, .sup.3J=5 Hz, H1), 4.55-4.05 (5H, m, H-5+H-3, NH, H-4), 3.72 (3H, 2s, CH.sub.3O), 2.55-2.35 (1H, m, one of H-2), 2.25-1.92 (5H, m, one of H-2+4H cyclopentane), 1.85-1.6 (4H, m, 4H cyclopentane).

(255) .sup.13C-NMR (DMSO; 75 MHz): 24.4, 24,3, 24.2 (2CH.sub.2 cyclopent), 39.3, 39.2, 38.9, 38.5 (2CH.sub.2 cyclopent), 40.6 (C-2), 53.3, 53.2 (CH.sub.3O), 66.5 (Cq cyclopentane), 66.7 (C-5), 70.9 (C-3), 85.8, 85.7, 85.4 (C-1, C-4), 110.2 (C-5b), 111.9 (C-5), 116.9, 116.6 (o, OPh), 122,2, 122.0 (m, OPh), 128.5 (C-5a), 138.5 (C-6), 146.7 (ipso, OPh) 149.9 (C-4), 158.5 (p, OPh), 162.3(C-2), 176.4, 176.3 (COOCH.sub.3).

Synthesis of (E)-5-(2-Bromovinyl)-2-deoxyuridine-5-[para-fluorophenyl- (ethoxy-,-cycloleucinyl)]-phosphate (CPF 23)

(256) C.sub.25H.sub.30BrFN.sub.3O.sub.9P, MW=646.4.

(257) ##STR00053##

(258) This was synthesised according to Standard procedure 5, using BVdU (200 mg, 0.60 mmol), para-fluorophenyl-(ethoxy-,-cycloleucinyl)-phosphorochloridate (524 mg, 1.5 mmol), NMI (4.98 mmol, 332 L) in THF (5 mL) for 2 hrs. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 97:3 to give the pure product as a white foamy solid (274 mg, yield 71%).

(259) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 5.30.

(260) .sup.1H-NMR (CDCl.sub.3, 300 MHz): 10.35 (1H, bs, H-3), 7.7 (1H, 2s, H-6), 7.44 (1H, 2d, .sup.3J=14 Hz, H-5b), 7.25-7.15 (2H, m, OPh), 7.1-6.95 (2H, m, OPh), 6.7 (1H, 2d, .sup.3J=14 Hz, H-5a), 6.30 (1H, 2t, .sup.3J=6 Hz, H1), 4.55,4.3 (3H, m, H-5, H-3), 4.2-4.1 (4H, m, NH, H-4, CH.sub.3CH.sub.2O), 2.55-2.4 (1H, m, one of H-2), 2.22-1.90 (5H, m, one of H-2+4H cyclopentane), 1.8-1.6 (4H, m, 4H cyclopentane), 1.3-1.2 (3H, 2t, .sup.3J=7 Hz, CH.sub.3CH.sub.2O).

(261) .sup.13C-NMR (CDCl.sub.3, 75 MHz): 14.5 (CH.sub.3CH.sub.2O), 24.6, 24,4, 24.3 (2CH.sub.2 cyclopent), 39.3, 39.2, 38.9, 38.6 (2CH.sub.2 cyclopent), 40.6 (C-2), 62.2 (CH.sub.3CH.sub.2O), 66.5 (Cq cyclopentane) 66.7 (C-5), 71.0 (C-3), 85.8, 85.7, 85.5, 85.4 (C-1, C-4), 110.2 (C-5b), 111.9 (C-5), 116.9, 116.5 (o, OPh), 122.2, 122.1 (m, OPh), 129.0 (C-5a), 138.5 (C-6), 146.8, 146.7 (ipso, OPh), 149.9 (C-4), 158.5 (p, OPh), 162.3 (C-2), 175.9, 175.8 (COOCH.sub.2CH.sub.3).

Synthesis of (E)-5-(2-Bromovinyl)-2-deoxyuridine-5-[para-fluorophenyl-(benzoxy-,-cycloleucinyl)]-phosphate (CPF 24)

(262) C.sub.30H.sub.32BrN.sub.3O.sub.9P, MW=708.47.

(263) ##STR00054##

(264) This was synthesised according to Standard procedure 5, using BVdU (200 mg, 0.60 mmol), para-fluorophenyl-(benzyloxy-,-cycloleucinyl)-phosphorochloridate (616 mg, 1.5 mmol), NMI (4.98 mmol, 332 L) in THF (5 mL) for 2 hrs. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 97:3 to give the pure product as a white foamy solid (283 mg, yield 67%).

(265) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 4.27.

(266) .sup.1H-NMR (CDCl.sub.3, 300 MHz): 10.3-9.85 (1H, bs, H-3), 7.65 (1H, 2s, H-6), 7.45-7.35 (1H, 2d, .sup.3J=14 Hz, H-5b), 7.40-7.30 (5H. m, CH.sub.2Ph), 7.25-7.15 (2H, m, OPh), 7.05-6.95 (2H, m, OPh), 6.71 (1H, 2d, .sup.3J=14 Hz, H-5a), 6.27 (1H, 2t, .sup.3J=6 Hz, H-1), 5.15 (1H, s, CH.sub.2Ph), 4.45 (1H, m, H-3), 4.40-4.30 (2H, m, H-5) 4.20-4.05 (2H, m, H-4, NH), 2.5-2.4 (1H, m, one of H-2), 2.25-1.9 (5H, m, one of H-2+4H cyclopentane), 1.8-1.6 (4H, m, 4H cyclopentane).

(267) .sup.13C-NMR (CDCl.sub.3, 75 MHz): 24.5, 24,3, 24.2 (2CH.sub.2 cyclopent), 39.7, 39.6, 39.3, 39.2 (2CH.sub.2 cyclopent), 40.5, 40.0 (C-2), 66.6 (Cq cyclopentane), 67.2, 66.7 (C-5), 67.9 (CH.sub.2Ph), 70.8, 70.7 (C-3), 85.8, 85.7, 85.4, 85.3 (C-1, C-4), 110.3 (C-5b), 111.8 (C-5), 116.9, 116.6 (o, OPh), 122.2, 122.1 (m, OPh), 129.0, 128.9, 128.6, 128.5 (Bn, C-5a), 135.8(ipso, CH.sub.2Ph) 138.5 (C-6), 146.8, 146.7 (ipso OPh), 149.9 (C-4), 158.5 (p OPh), 162.2 (C-2), 175.7, 175.0 (COOBn).

Synthesis of (E)-5-(2-Bromovinyl)-2-deoxyuridine-5-[para-chlorophenyl-(methoxy-,-cycloleucinyl)]-phosphate (CPF 32)

(268) C.sub.24H.sub.28BrClN.sub.3O.sub.9P, MW=648.82.

(269) ##STR00055##

(270) This was synthesised according to Standard procedure 5, using BVdU (150 mg, 0.45 mmol), para-chlorophenyl-(methoxy-,-cycloleucinyl)-phosphorochloridate (475 mg, 1.35 mmol), NMI (4.5 mmol, 300 L) in THF (5 mL) for 2 hrs. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 97:3 to give the pure product as a white foamy solid (187 mg, yield 64%).

(271) .sup.31P-NMR (MeOD, 121 MHz): 4.64.

(272) .sup.1H-NMR (MeOD; 300 MHz): 7.75 (1H, 2s, H-6), 7.32 (1H, 2d, .sup.3J=14 Hz, H-5b), 7.32-7.27 (2H, m, OPh), 7.20-7.11 (2H, m, OPh), 6.72 (1H, 2d, .sup.3J=14 Hz, H-5a), 6.27-6.20 (1H, 2t,.sup.3J=6 Hz, H1), 4.35 (1H, m, H-3), 4.30 (2H, m, H-5) 4.1 (2H, m, H-4), 3.72 (3H, 2s, CH.sub.3O), 2.32-2.20 (1H, m, one of H-2), 2.20-1.92 (5H, m, one of H-2+4H cyclopentane), 1.8-1.6 (4H, m, 4H cyclopentane).

(273) .sup.13C-NMR (MeOD; 75 MHz): 25.7, 25.6 (2CH.sub.2 cyclopent), 41.7, 41.6, 41.4, 41.3 (2CH.sub.2 cyclopent), 42.7 (C-2), 54.1, 53.9 (CH.sub.3O), 67.8 (Cq cyclopentane), 69.1, 69.0 (C-5), 73.8 (C-3), 88.4, 88.3, 88.2 (C-1, C-4), 110.2 (C-5b), 111.8 (C-5), 122.1, 121.9 (o, OPh), 128.9 (C-5a), 130.6 (m, OPh), 130.8 (p, OPh), 138.5 (C-6), 149.5, 149.4 (ipso, OPh), 149.9 (C-4), 162.2(C-2), 175.6 (COOCH.sub.3).

Synthesis of (E)-5-(2-Bromovinyl)-2-deoxyuridine-5-[para-chlorophenyl-(ethoxy-,-cycloleucinyl)]-phosphate (CPF 33)

(274) C.sub.25H.sub.30BrClN.sub.3O.sub.9P, MW=662.85.

(275) ##STR00056##

(276) This was synthesised according to Standard procedure 5, using BVdU (150 mg, 0.45 mmol), para-chlorophenyl-(ethoxy-,-cycloleucinyl)-phosphorochloridate (495 mg, 1.35 mmol), NMI (4.5 mmol, 300 L) in THF (5 mL) for 2 hrs. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 97:3 to give the pure product as a white foamy solid (240 mg, yield 66%).

(277) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 4.15.

(278) .sup.1H-NMR (CDCl.sub.3, 300 MHz): 10.25-10.1 (1H, bs, H-3), 7.65 (1H, 2s, H-6), 7.4-7.3 (1H, 2d, .sup.3J=14 Hz, H-5b), 7.25-7.20 (2H, m, OPh), 7.20-7.10 (2H, m, OPh), 6.75 (1H, 2d, .sup.3J=14 Hz, H-5a), 6.20 (1H, m, H1), 4.35 (3H, m, H-3, H-5), 4.2-4.0 (4H, m, H-4, NH, CH.sub.3CH.sub.2O), 2.45-2.25 (1H, m, one of H-2), 2.25-1.85 (5H, m, one of H-2+4H cyclopentane), 1.75-1.55 (4H, m, 4H cyclopentane), 1.2 (3H, 2t, .sup.3J=7 Hz, CH.sub.3CH.sub.2O).

(279) .sup.13C-NMR (CDCl.sub.3, 75 MHz): 14.5 (CH.sub.3CH.sub.2O), 24.5, 24,4 (2CH.sub.2 cyclopent), 39.3, 39.2, 38.8, 38.6 (2CH.sub.2 cyclopent), 40.5 (C-2), 62.3 (CH.sub.3CH.sub.2O), 66.1 (Cq cyclopentane), 66.7 (C-5), 70.8 (C-3), 85.8, 85.4 (C-1, C-4), 110.3 (C-5b), 111.9 (C-5), 122.1, 121.9 (o, OPh), 129.0 (C-5a), 130.2 (m, OPh), 130.8 (p, OPh), 138.5 (C-6), 149.5, 149.4 (ipso, OPh), 149.9 (C-4),162.3 (C-2), 175.9 (COOCH.sub.2CH.sub.3).

Synthesis of (E)-5-(2-Bromovinyl)-2-deoxyuridine-5-[para-chlorophenyl-(benzoxy-,-cycloleucinyl)]-phosphate (CPF 34)

(280) C.sub.30H.sub.32BrClN.sub.3O.sub.9P, MW=724.92.

(281) ##STR00057##

(282) This was synthesised according to Standard procedure 5, using BVdU (150 mg, 0.45 mmol), para-chlorophenyl-(benzyloxy-,-cycloleucinyl)-phosphorochloridate (578 mg, 1.35 mmol), NMI (4.5 mmol, 300 L) in THF (5 mL) for 2 hrs. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 97:3 to give the pure product as a white foamy solid (222 mg, yield 68%).

(283) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 4.11, 4.05.

(284) .sup.1H-NMR (CDCl.sub.3, 300 MHz): 7.65 (1H, 2s, H-6), 7.45-7.29 (10H, m, H-5b, 2H OPh+CH.sub.2Ph), 7.20-7.15 (2H, m, OPh), 6.75-6.67 (1H, 2d, .sup.3J=14 Hz, H-5a), 6.28 (1H, 2t, .sup.3J=6 Hz, H-1), 5.15 (1H, 2s, CH.sub.2Ph), 4.5 (1H, m, H-3), 4.35 (2H, m, H-5) 4.1 (H, m, H-4), 4.00 (1H, m, NH), 2.48-2.35 (1H, m, one of H-2), 2.3-1.92 (5H, m, one of H-2+4H cyclopentane), 1.8-1.6 (4H, m, 4H cyclopentane).

(285) .sup.13C-NMR (CDCl.sub.3, 75 MHz): 24.5, 24.4, 24,3, 24.2 (2CH.sub.2 cyclopent), 39.3, 38.8, 38.6 (2CH.sub.2 cyclopent), 40.5 (C-2), 66.7 (Cq cyclopentane), 67.9 (CH.sub.2Ph), 68.4 (C-5), 70.7 (C-3), 85.7, 85.7, 85.4, 85.3 (C-1, C-4), 110.3 (C-5b), 111.8 (C-5), 122.0, 121.9 (o, OPh), 129.1, 128.3, 128.2 (Bn, m, OPh), 130.2 (C-5a), 135.8 (ipso, CH.sub.2Ph), 136.3 (p OPh), 138.2 (C-6), 149.5, 149.3 (ipso, OPh), 149.9 (C-4), 162.2 (C-2), 175.7, 175.5 (COOBn).

Synthesis of (E)-5-(2-Bromovinyl)-2-deoxyuridine-5-[para-trifluorophenyl-(methoxy-,-cycloleucinyl)]-phosphate (CPF 28)

(286) C.sub.25H.sub.28BrF.sub.3N.sub.3O.sub.9P, MW=682.38.

(287) ##STR00058##

(288) This was synthesised according to Standard procedure 5, using BVdU (150 mg, 0.45 mmol), para-trifluorophenyl-(methoxy-,-cycloleucinyl)-phosphorochloridate (521 mg, 1.35 mmol), NMI (4.5 mmol, 300 L) in THF (5 mL) for 2 hrs. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 97:3 to give the pure product as a white foamy solid (199 mg, yield 65%).

(289) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 3.80.

(290) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.70 (1H, 2s, H-6), 7.55 (1H, 2d, .sup.3J=14 Hz, H-5b), 7.45-7.32 (4H, m, OPh), 6.72 (1H, 2d, .sup.3J=14 Hz, H-5a), 6.28 (1H, 2t,.sup.3J=6 Hz, H1), 4.55 (1H, m, H-3), 4.45 (2H, m, H-5), 4.25 (1H, H-4), 4.15 (1H, NH), 3.71 (3H, 2s, CH.sub.3O), 2.6-2.4 (1H, m, one of H-2), 2.3-1.9 (5H, m, one of H-2+4H cyclopentane), 1.85-1.6 (4H, m 4H cyclopentane).

(291) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 24.4, 24,3, 24.2 (2CH.sub.2 cyclopent), 39.2, 39.1, 38.8, 38.6 (2CH.sub.2 cyclopent), 40.5 (C-2), 53.9 (CH.sub.3O), 66.3 (Cq cyclopentane), 66.8 (C-5), 70.9 (C-3), 85.8, 85.4 (C-1, C-4), 110.3 (C-5b), 111.9 (C-5), 125.1 (d, J=270 Hz, CF.sub.3), 127.1, 127.0 (o, OPh), 127.8 (m, OPh), 128.9 (C-5a), 129.0 (p, q, J=32 Hz, OPh), 138.5 (C-6), 149.9 (C-4), 153.5 (ipso, OPh), 162.2 (C-2), 176.3, 176.2 (COOCH.sub.3).

Synthesis of (E)-5-(2-Bromovinyl)-2-deoxyuridine-5-[para-trifluorophenyl-(ethoxy-,-cycloleucinyl)]-phosphate (CPF 29)

(292) C.sub.26H.sub.30BrF.sub.3N.sub.3O.sub.9P, MW=696.40.

(293) ##STR00059##

(294) This was synthesised according to Standard procedure 5, using BVdU (150 mg, 0.45 mmol), para-trifluorophenyl-(ethoxy-,-cycloleucinyl)-phosphorochloridate (540 mg, 1.35 mmol), NMI (4.50 mmol, 300 L) in THF (5 mL) for 2 hrs. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 97:3 to give the pure product as a white foamy solid (185 mg, yield 59%).

(295) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 4.30.

(296) .sup.1H-NMR (CDCl.sub.3, 300 MHz): 10.35 (1H, bs, H-3), 7.70 (1H, 2s, H-6), 7.40 (1H, 2d, .sup.3J=14 Hz, H-5b), 7.28-7.14 (2H, m, OPh), 7.05-6.95 (2H, m, OPh), 6.70 (1H, 2d, .sup.3J=14 Hz, H-5a), 6.3 (1H, m, H1), 4.55-4.3 (3H, m, H-5, H-3), 4.2-4.1 (3H, m, H-4, CH.sub.3CH.sub.2O), 2.5-2.35 (1H, m, one of H-2), 2.20-1.9 (5H, m, one of H-2+4H cyclopentane), 1.85-1.6 (4H, m, 4H cyclopentane), 1.25 (3H, 2t, .sup.3J=7 Hz, CH.sub.3CH.sub.2O).

(297) .sup.13C-NMR (CDCl.sub.3, 75 MHz): 14.5 (CH.sub.3CH.sub.2O), 24.5, 24,4 (2CH.sub.2 cyclopent), 39.3, 39.2, 38.9, 38.5 (2CH.sub.2 cyclopent), 40.6 (C-2), 62.2 (CH.sub.3CH.sub.2O), 66.7 (Cqcyclopentane), 67.4, 67.3 (C-5), 70.9 (C-3), 85.8, 85.7 (C-1, C-4), 110.2 (C-5b), 111.9 (C-5), 116.8, 116.5 (o, OPh), 122.2, 122.1 (m, OPh), 125.1 (d, J=270 Hz, CF.sub.3), 129.0 (C-5a), 131.1 (p, q, J=32 Hz, OPh), 138.5 (C-6), 146.8, 146.7 (ipso, OPh), 149.9 (C-4), 162.3 (C-2), 175.9, 175.8 (COOCH.sub.2CH.sub.3).

Synthesis of (E)-5-(2-Bromovinyl)-2-deoxyuridine-5-[para-trifluorophenyl-(benzoxy-,-cycloleucinyl)]-phosphate (CPF 30)

(298) C.sub.31H.sub.32BrF.sub.3N.sub.3O.sub.9P, MW=758.47.

(299) ##STR00060##

(300) This was synthesised according to Standard procedure 5, using BVdU (150 mg, 0.45 mmol), para-trifluorophenyl-(benzyloxy-,-cycloleucinyl)-phosphorochloridate (623 mg, 1.35 mmol), NMI (4.5 mmol, 300 L) in THF (5 mL) for 2 hrs. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 97:3 to give the pure product as a white foamy solid (218 mg, yield 64%).

(301) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 4.30.

(302) .sup.1H-NMR (CDCl.sub.3, 300 MHz): 10.35 (1H, bs, H-3), 7.65 (1H, 2s, H-6), 7.55 (2H, m, 2H OPh), 7.45-7.25 (8H. m, 2H OPh+CH.sub.2Ph+H-5b), 6.7 (1H, 2d, .sup.3J=14 Hz, H-5a), 6.30 (1H, 2t, .sup.3J=6 Hz, H-1), 5.15 (1H, 2s, CH.sub.2Ph), 4.55-4.35 (3H, m, H-3+H-5), 4.25 (1H, H-4), 4.10 (1H, NH), 2.55-2.35 (1H, m, one of H-2), 2.30-1.92 (5H, m, one of H-2+4H cyclopentane), 1.8-1.6 (4H, m, 4H cyclopentane).

(303) .sup.13C-NMR (CDCl.sub.3, 75 MHz): 25.5, 24.4, 24,3, 24.2 (2CH.sub.2 cyclopent), 39.2, 39.1, 38.7, 38.6 (2CH.sub.2 cyclopent), 40.5, 40.0 (C-2), 66.4 (Cq cyclopentane), 66.8 (C-5), 68.0 (CH.sub.2Ph), 70.9 (C-3), 86.0, 85.8, 85.4, 85.3 (C-1, C-4), 110.3 (C-5), 111.9 (C-5), 121.8, 120.8 (o, m, OPh), 125.2 (d, J=270 Hz, CF.sub.3), 128.5, 127.7, 127.5 (Bn, C-5a), 129,2 (p,q, J=32 Hz, OPh, 135.4 (ipso, CH.sub.2Ph), 138.5 (C-6), 149.9 (C-4), 153.5 (ipso OPh), 162.2 (C-2), 175.6, 175.5 (COOBn).

Synthesis of (E)-5-(2-Bromovinyl)-2 -deoxyuridine-5-[phenyl-(methoxy-L-phenylalaninyl)]-phosphate (CPF 36)

(304) C.sub.27H.sub.29BrN.sub.3O.sub.9P, MW=650.41.

(305) ##STR00061##

(306) This was synthesised according to Standard procedure 5, using BVdU (150 mg, 0.45 mmol), Phenyl-(methoxy-L-phenylalaninyl)-phosphorochloridate (477 mg, 1.35 mmol), NMI (4.42 mmol, 190 L) in THF (5 mL) for 2 hrs. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 97:3 to give the pure product as a white foamy solid (169 mg, yield 58%).

(307) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 4.79, 4.71.

(308) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 9.95 (1H, bs, H-3), 7.60-7.55 (1H, 2s, H-6), 7.48-7.4 (1H, 2d, .sup.3J=14 Hz, H-5b), 7.3-7.1 (10H, m, CH.sub.2Ph+OPh), 6.75-6.65 (1H, 2d, .sup.3J=14 Hz, H-5a), 6.27-6.18 (1H, m, H1), 4.57-4.29 (6H, m, H-5,H-3,H-4, NH, CHphenylala), 3.70 (3H, 2s, CH.sub.3O), 3.01 (2H, m, CH.sub.2Ph), 2.35-2.20 (1H, m, one of H-2), 2.07-1.95 (1H, m, one of H-2).

(309) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 36.3 (CH.sub.2phenylalanine), 41.9, 41.8 (C-2), 53.0 (CH.sub.3O), 56.6, 56.1 (CHphenylala), 67.1 (C-5), 71.3, 70.7 (C-3), 85.7, 85.6, 85.5, 85.4 (C-1, C-4), 110.4 (C-5b), 111.9 (C-5), 120.6, 120.5 (o, OPh), 127.8 (p, OPh), 130.1, 129.9, 129.8, 129.1 (CH.sub.2Ph, C-5a, m OPh), 138.0, 137.9 (C-6), 149.8 (C-4), 150.7, 150.6 (ipso, OPh), 162.1, 162.0 (C-2), 173.5 (COOCH.sub.3).

Synthesis of (E)-5-(2-Bromovinyl)-2-deoxyuridine-5-[phenyl-(methoxy-L-leucinyl)]-phosphate (CPF 35)

(310) C.sub.24H.sub.31BrN.sub.3O.sub.9P, MW=616.40.

(311) ##STR00062##

(312) This was synthesised according to Standard procedure 5, using BVdU (150 mg, 0.45 mmol), Phenyl-(methoxy-L-leucinyl)-phosphorochloridate (432 mg, 1.35 mmol), NMI (4.42 mmol, 190 L) in THF (5 mL) for 2 hrs. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 97:3 to give the pure product as a white foamy solid (167 mg, yield 60%).

(313) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 5.14, 4.60.

(314) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 10.1 (1H, bs, H-3), 7.75 (1H, 2s, H-6), 7.45 (1H, 2d, .sup.3J=14 Hz, H-5b), 7.4-7.2 (5H, m, OPh), 6.85 (1H, 2d, .sup.3J=14 Hz, H-5a), 6.27-6.18 (1H, 2t, .sup.3J=6 Hz, H1), 4.5-4.2 (4H, m, H-5,H-3, NH), 4.1 (1H, m,H-4), 3.95 (1H, m, CHCH.sub.2CH(CH.sub.3).sub.2), 3.70 (3H, 2s, CH.sub.3O), 2.40-2.20 (1H, m, one of H-2), 2.05-1.95 (1H, m, one of H-2), 1.8 (1 H, m, CHCH.sub.2CH(CH.sub.3).sub.2), 1.8-1.5 (2H, m, CHCH.sub.2CH(CH.sub.3).sub.2), 1.0-0.9 (6H, m, CHCH.sub.2CH(CH.sub.3).sub.2).

(315) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 23.2, 23.1, 22.0, 21.9 (2C, CHCH.sub.2CH(CH.sub.3).sub.2), 24.9, 24.7 (CHCH.sub.2CH(CH.sub.3).sub.2), 40.6 (C-2), 43.7, 43.6 (CHCH.sub.2CH(CH.sub.3).sub.2), 53.0 (CH.sub.3O), 53.7, 53.6 (CHCH.sub.2CH(CH.sub.3).sub.2), 66.6, 66.3 (C-5), 71.1, 70.8 (C-3), 86.0, 85.7, 85.6, 85.5 (C-1, C-4), 110.4 (C-5b), 111.9 (C-5), 120.6, 120.5, 120.4 (o, OPh), 125.8, 125.7 (p, OPh), 128.9 (C-5a), 130.2 (m OPh), 138.1 (C-6), 149.9 (C-4), 150.8, 150.7 (ipso, OPh), 162.2 (C-2), 175.1, 174.9 (COOCH.sub.3).

Synthesis of (E)-5-(2-Bromovinyl)-2-deoxyuridine-5-[phenyl-(benzoxy-L-leucinyl)]-phosphate (CPF 37)

(316) C.sub.30H.sub.35BrN.sub.3OP, MW=692.49.

(317) ##STR00063##

(318) This was synthesised according to Standard procedure 5, using BVdU (150 mg, 0.45 mmol), Phenyl-(benzoxy-L-leucinyl)-phosphorochloridate (534 mg, 1.35 mmol), NMI (4.42 mmol, 190 L) in THF (5 mL) for 2 hrs. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 97:3 to give the pure product as a white foamy solid (199 mg, yield 64%).

(319) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 5.18, 4.54.

(320) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 9.95-9.85 (1H, bs, H-3), 7.55 (1H, 2s, H-6), 7.38 (1H, 2d, .sup.3J=14 Hz, H-5b), 7.3-7.1 (5H, m, CH.sub.2Ph+OPh), 6.65 (1H, 2d, .sup.3J=14 Hz, H-5a), 6.26-6.14 (1H, 2t, .sup.3J=6 Hz, H1), 5.1 (2H, 2s, CH.sub.2Ph) 4.4-3.8 (6H, m, H-5,H-3, NH, H-4, CHCH.sub.2CH(CH.sub.3).sub.2), 2.35-2.25 (1H, m, one of H-2), 1.95-1.85 (1H, m, one of H-2), 1.6-1.4 (3H, m, CHCH.sub.2CH(CH.sub.3).sub.2), 0.8 (6H, m, CHCH.sub.2CH(CH.sub.3).sub.2).

(321) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 23.2, 23.1, 22.0, 21.9 (2C, CHCH.sub.2CH(CH.sub.3).sub.2), 24.9, 24.7 (CHCH.sub.2CH(CH.sub.3).sub.2), 40.7 (C-2), 43.9, 43.8 (CHCH.sub.2CH(CH.sub.3).sub.2), 53.9, 53.7 (CHCH.sub.2CH(CH.sub.3).sub.2), 66.4, 66.2 (C-5), 67.8,67.7 (CH.sub.2Ph), 71.1, 70.7 (C-3), 85.9, 85.6, 85.4, 85.3 (C-1, C-4), 110.4 (C-5b), 111.9 (C-5), 120.6, 120.5 (o, OPh), 125.8, 125.7 (p, OPh), 130.2, 129.1, 128.9 (C-5a, CH.sub.2Ph, m OPh), 135.4 (ipso, CH.sub.2Ph), 138.1 (C-6),149.8 (C4),150.2 (ipso, OPh), 162.1 (C-2),175.7, 174.6 (COOBn).

Synthesis of (E)-5-(2-Bromovinyl)-2-deoxyuridine-5-(para-nitrophenyl-(benzoxy-L-leucinyl)]-phosphate (CPF 38)

(322) C.sub.30H.sub.34BrN.sub.4O.sub.11P, MW=737.49.

(323) ##STR00064##

(324) This was synthesised according to Standard procedure 5, using BVdU (150 mg, 0.45 mmol), para-nitrophenyl-(benzoxy-L-leucinyl)-phosphorochloridate (595 mg, 1.35 mmol), NMI (4.42 mmol, 190 L) in THF (5 mL) for 2 hrs. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 97:3 to give the pure product as a white foamy solid (176 mg, yield 53%).

(325) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 5.72, 4.35.

(326) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 10.2 (1H, bs, H-3), 8.1(2H, m, 2H OPh), 7.65 (1H, 2s, H-6), 7.45-7.2 (8H, m, H-5b, CH.sub.2Ph+2H OPh), 6.65 (1H, 2d, .sup.3J=14 Hz, H-5a), 6.35-6.2 (1H, 2t, .sup.3J=6 Hz, H1), 5.15 (2H, 2s, CH.sub.2Ph) 4.7-3.9 (6H, m, H-5,H-3, NH, H-4, CHCH.sub.2CH(CH.sub.3).sub.2), 2.55-2.4 (1H, m, one of H-2), 2.15-2.05 (1H, m, one of H-2), 1.7-1.5 (3H, m, CHCH.sub.2CH(CH.sub.3).sub.2), 0.95-0.8 (6H, m, CHCH.sub.2CH(CH.sub.3).sub.2).

(327) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 23.2, 23.1, 22.0, 21.9 (2C, CHCH.sub.2CH(CH.sub.3).sub.2), 24.9, 24.8 (CHCH.sub.2CH(CH.sub.3).sub.2), 40.6 (C-2), 43.7, 43.6 (CHCH.sub.2CH(CH.sub.3).sub.2), 53.9, 53.7 (CHCH.sub.2CH(CH.sub.3).sub.2), 66.9 (C-5), 67.9 (CH.sub.2Ph), 71.2, 70.8 (C-3), 85.8, 85.3, 85.2 (C-1, C-4), 110.6 (C-5b), 111.9 (C-5), 121.3 (o OPh), 129.2, 129.1, 128.8, 126.2 (C-5a, CH.sub.2Ph, m OPh), 135.4, 135.3 (ipso, CH.sub.2Ph), 138.2 (C-6), 145.2, 145.1 (ipso, OPh), 149.9 (C-4), 155.5 (p, OPh), 162.1 (C-2), 174.2 (COOBn).

Synthesis of (E)-5-(2-Bromovinyl)-2-deoxyuridine-5-[para-chlorophenyl-(benzoxy-L-leucinyl)]-phosphate (CPF 39)

(328) C.sub.30H.sub.34BrClN.sub.3O.sub.9P, MW=726.94.

(329) ##STR00065##

(330) This was synthesised according to Standard procedure 5, using BVdU (150 mg, 0.45 mmol), para-chlorophenyl-(benzoxy-L-leucinyl)-phosphorochloridate (581 mg, 1.35 mmol), NMI (4.42 mmol, 190 L) in THF (5 mL) for 2 hrs. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 97:3 to give the pure product as a white foamy solid (221 mg, yield 68%).

(331) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 5.27, 4.76.

(332) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 10.25-10.15 (1H, bs, H-3), 7.65 (1H, 2s, H-6), 7.45 (1H, 2d, .sup.3J=14 Hz, H-5b), 7.4-7.15 (9H, m, CH.sub.2Ph+OPh), 6.7 (1H, 2d, .sup.3J=14 Hz, H-5a), 6.35-6.2 (1H, 2t, .sup.3J=6 Hz, H1), 5.15 (2H, 2s, CH.sub.2Ph) 4.55-3.9 (6H, m, H-5, H-3, NH, H-4, CHCH.sub.2CH(CH.sub.3).sub.2), 2.5-2.4 (1H, m, one of H-2), 2.15-2.0 (1H, m, one of H-2), 1.7-1.45 (3H, m, CHCH.sub.2CH(CH.sub.3).sub.2), 0.94-0.82 (6H, m, CHCH.sub.2CH(CH.sub.3).sub.2).

(333) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 23.1, 23.0, 22.2, 22.0 (2C, CHCH.sub.2CH(CH.sub.3).sub.2), 24.9, 24.7 (CHCH.sub.2CH(CH.sub.3).sub.2), 40.7 (C-2), 43.9, 43.8 (CHCH.sub.2CH(CH.sub.3).sub.2), 53.9, 53.7 (CHCH.sub.2CH(CH.sub.3).sub.2), 66.7, 66.3 (C-5), 67.8 (CH.sub.2Ph), 71.1, 70.7 (C-3), 85.8, 85.7, 85.4 (C-1, C-4), 110.5 (C-5b), 111.9 (C-5),122.1, 122.0 (o, OPh), 130.2, 129.1, 129.0 (C-5a, CH.sub.2Ph, m OPh), 131.1, 130.9 (p, OPh), 135.5, 135.4 (ipso, CH.sub.2Ph), 138.2 (C-6), 149.2, 149.1 (ipso, OPh), 149.2, 149.1 (C-4),162.2 (C-2), 174.2, 174.2 (COOBn).

Synthesis of Gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate

(334) C.sub.25H.sub.27F.sub.2N.sub.4O.sub.8P, MW=580.47 (CPF 31).

(335) ##STR00066##

(336) This was synthesised according to Standard procedure 5, using gemcitabine (131 mg, 0.5 mmol), Phenyl-(benzoxy-L-alaninyl)-phosphorochloridate (529 mg, 1.5 mmol), NMI (4.42 mmol, 300 L) in THF/pyridine (4/2 mL) for 2 hrs. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 95:5 to give the pure product as a white foamy solid (46 mg, yield 16%).

(337) .sup.31P-NMR (MeOD, 121 MHz): 5.05, 4.94.

(338) .sup.1H-NMR (MeOD, 300 MHz): 7.6-7.5 (1H, 2d, .sup.3J=7 Hz H-6), 7.4-7.2 (10H. m, OPh+CH.sub.2Ph), 6.25 (1H, m, H-1), 5.95 (1H, 2d, .sup.3J=7 Hz, H-5), 5.19 (1H, 2s, CH.sub.2Ph), 4.55-4.1(3H, m, H-3, H-4, CHala), 4.05 (2H, m, H-5), 1.20 (3H, 2t, .sup.3J=6 Hz, CH.sub.3ala).

(339) .sup.13C-NMR (MeOD, 75 MHz): 20.8, 20.7 (CH.sub.3ala), 52.2, 52.0 (CHala), 66.1 (C-5), 68.4 (CH.sub.2Ph), 71.9, 71.3 (C-3), 80.6 (C-4), 85.9 (C-1), 97.1 (C-5), 121.8, 121.6 (o, OPh), 123 (C-2), 126.2 (p, OPh), 131.8, 130.0, 129.7 (m OPh, Bn), 137.9(ipso, CH.sub.2Ph), 142.7, 142.6 (C-6), 152.5, 152.4 (ipso, OPh), 158.2 (C-2), 168.0 (C-4), 175.3, 174.9 (COOBn).

Synthesis of Gemcitabine-[para-chlorophenyl-(benzoxy-L-alaninyl)]-phosphate

(340) C.sub.25H.sub.26ClF.sub.2N.sub.4O.sub.8P, MW=614.92 (CPF 40).

(341) ##STR00067##

(342) This was synthesised according to Standard procedure 5, using gemcitabine (131 mg, 0.5 mmol), para-chlorophenyl-(benzoxy-L-alaninyl)-phosphorochloridate (582 mg, 1.5 mmol), NMI (4.42 mmol, 300 L) in THF/pyridine (4/2 mL) for 2 hrs. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 95:5 to give the pure product as a white foamy solid (76 mg, yield 25%).

(343) .sup.31P-NMR (MeOD, 121 MHz): 5.08.

(344) .sup.1H-NMR (MeOD, 300 MHz): 7.65 (1H, 2d, .sup.3J=7 Hz H-6), 7.5-7.2 (9H. m, OPh+CH.sub.2Ph), 6.2 (1H, m, H-1), 5.9 (1H, 2d, .sup.3J=7 Hz, H-5), 5.12 (1H, 2s, CH.sub.2Ph), 4.6-4.1 (3H, m, H-3, H-4, CHala), 4.05 (2H, m, H-5), 1.45-1.35 (3H, 2t, .sup.3J=6 Hz, CH.sub.3ala).

(345) .sup.13C-NMR (MeOD, 75 MHz): 20.9, 20.7 (CH.sub.3ala), 52.2, 52.0 (CHala), 66.4, 66.2 (C-5), 68.5 (CH.sub.2Ph), 71.5 (C-3), 80.7 (C-4), 86.4 (C-1), 97.2 (C-5), 123.5 (o, OPh), 126.9 (C-2), 131.2, 130.6, 130.3 (m OPh, Bn), 131.9 (p, OPh) 137.5 (ipso, CH.sub.2Ph), 142.8, 142.7 (C-6), 151.4, 151.0 (ipso, OPh), 158.2 (C-2),166.9 (C-4), 175.1, 174.9 (COOBn).

Synthesis of Gemcitabine-[para-chlorophenyl-(benzoxy-,-dimethylglycinyl)]-phosphate (CPF 41)

(346) C.sub.26H.sub.28ClF.sub.2N.sub.4O.sub.8P, MW=628.95.

(347) ##STR00068##

(348) This was synthesised according to Standard procedure 5, using gemcitabine (131 mg, 0.5 mmol), para-chlorophenyl-(benzoxy-,-dimethylglycinyl)-phosphorochloridate (603 mg, 1.5 mmol), NMI (4.42 mmol, 300 L) in THF/pyridine (4/3 mL) for 2 hrs. The crude product was purified by column chromatography, eluting with CH.sub.2Cl.sub.2/Methanol 95:5 to give the pure product as a white foamy solid (163 mg, yield 52%).

(349) .sup.31P-NMR (MeOD, 121 MHz): 3.56, 3.52.

(350) .sup.1H-NMR (MeOD, 300 MHz): 7.55 (1H, 2d, .sup.3J=7 Hz, H-6), 7.4-7.15 (9H. m, OPh+CH.sub.2Ph), 6.25 (1H, m, H-1), 5.85 (1H, 2d, .sup.3J=7 Hz, H-5), 5.15 (1H, 2s, CH.sub.3Ph), 4.55-4.1 (3H, m, H-3, H-4), 4.05 (2H, m, H-5), 1.50 (6H, m, .sup.3J=6 Hz, 2CH.sub.3dimethygly).

(351) .sup.13C-NMR (MeOD, 75 MHz): 28.2, 28.0 (CH.sub.3 dimethygly), 58.6 (Cq dimethygly), 66.2, 66.1 (C-5), 66.7 (CH.sub.2Ph), 71.5 (C-3), 80.6 (C-4), 86.4 (C-1), 97.0 (C-5), 123.9, 123.6 (o, OPh), 127.3 (C-2), 130.0, 129.7 (m OPh, Bn), 131.8 (p, OPh), 137.6 (ipso, CH.sub.2Ph), 142.8, 142.7 (C-6), 151.2, 151.1 (ipso, OPh), 158.1 (C-2), 167.9 (C-4), 176.8, 176.7 (COOBn).

Synthesis of Phenyl-(methoxy-L-alaninyl)-phosphorochloridate

(352) C.sub.10H.sub.13ClNO.sub.4P, MW=277.64.

(353) ##STR00069##

(354) This is synthesised according to Standard procedure 4, using L-alanine methyl ester hydrochloride (2 g, 14.3 mmol), phenyldichlorophosphate (3.02 g, 2.14 ml, 14.3 mmol), and TEA (2.9 g, 4.0 ml, 28.7 mmol) in DCM (60 mL), to yield 3.91 g (98%) of crude product used without further purification.

(355) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 9.28, 8.97.

(356) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.39-7.34 (2H, m, o OPh), 7.29-7.20 (2H, m m+p OPh), 4.98 (1H, bs, NH), 4.27-4.09 (1H, m, CHala), 3.78 (3H, s, OCH.sub.3), 1.52-1.49 (3H, 2d, .sup.3J=7 Hz, CH.sub.3ala).

(357) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 20.9 (CH.sub.3ala), 51.0 (CHala), 53.6 (OCH.sub.3), 120.9 (oOPh), 126.4 (p, OPh), 130.2 (m, OPh), 150.1 (ipso, OPh), 173.6(COOCH.sub.3).

Synthesis of Phenyl-(ethoxy-L-alaninyl)-phosphorochloridate

(358) C.sub.11H.sub.15ClNO.sub.4P, MW-291.67.

(359) ##STR00070##

(360) This is synthesised according to Standard procedure 4, using L-alanine ethyl ester hydrochloride (770 mg, 5.01 mmol), phenyldichlorophosphate (1.12 g, 5.01 mmol, 749 L), and TEA (1.4 mL, 10.02 mmol) in DCM (40 mL). The crude was purified by flash chromatography (ethyl acetate/petroleum ether 7:3) affording 1.02 (69%) of oil.

(361) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 9.49, 9.07.

(362) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.39-7.34 (2H, m,o OPh), 7.29-7.20 (2H, m, m+p OPh), 4.95 (1H, bs, NH, 4.3-4.1 (3H, m, OCH.sub.2CH.sub.3, CHala), 1.50 (3H, 2d, .sup.3J=7 Hz, CH.sub.3ala), 1.30 (3H, t, .sup.3J=7.1 Hz, OCH.sub.2CH.sub.3).

(363) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 14.5 (CH.sub.3CH.sub.2), 20.9 (CH.sub.3ala), 51.0 (CHala), 62.6 CH.sub.3CH.sub.2), 120.9 (o OPh), 126.5 (p, OPh), 130.1 (m, OPh), 150.1 (ipso, OPh), 175.1 (COOCH.sub.2CH.sub.3).

Synthesis of Phenyl-(benzoxy-L-alaninyl)-phosphorochloridate

(364) C.sub.16H.sub.17ClNO.sub.4P, MW=353.74.

(365) ##STR00071##

(366) This is synthesised according to Standard procedure 4, using L-alanine benzyl ester hydrochloride (1.0 g, 4.64 mmol), phenyl-dichlorophosphate (980 mg, 0.69 ml, 4.64 mmol), and TEA (0.94 g, 1290 L, 9.27 mmol) in DCM (40 mL). The crude was purified by flash chromatography (ethyl acetate/petroleum ether 6:4) affording 1.61 (98%) of oil.

(367) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 9.41, 9.23.

(368) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.41-7.21 (10H, m, OPh+CH.sub.2Ph), 5.24 (2H, s, CH.sub.2Ph), 4.95-4.88 (1H, bs, NH), 4.36-4.15 (1H, m, CHala), 1.52-1.49 (3H, 2d, .sup.3J=7 Hz, CH.sub.3ala).

(369) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 20.8 (CH.sub.3ala), 51.1 (CHala), 68.0 (CH.sub.2Ph), 121.0 (o OPh), 126.4 (p, OPh), 130.3, 129,0, 128.7 (mOPh, CH.sub.2Ph), 135.5 (ipso, CH.sub.2Ph), 150.2 (ipso, OPh), 172.9 (COOCH.sub.2Ph).

Synthesis of p-nitrophenyl-(methoxy-L-alaninyl)-phosphorochloridate

(370) C.sub.10H.sub.12ClN.sub.2O.sub.6P, MW=322.64.

(371) ##STR00072##

(372) This is synthesised according to Standard procedure 4, using L-alanine methyl ester hydrochloride (0.70 g, 5.01 mmol), p-nitrophenyldichlorophosphate (1.362 g, 5.01 mmol), and TEA (1.4 ml, 10 mmol) in DCM (40 mL), to yield 1.60 g (99%) of crude product used without further purification.

(373) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 9.13, 9.03.

(374) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 8.1 (2H, 2d, .sup.3J=8 Hz, OPh), 7.3 (2H, 2d, .sup.3J=8 Hz, OPh), 5.0 (1H, bs, NH), 4.1 (1H, m, CHala), 3.75 (3H, s, OCH.sub.3), 1.5-1.45 (3H, m, CH.sub.3ala).

(375) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 20.8, 20.7 (CH.sub.3ala), 51.1, 50.9 (CHala), 53.2, 53.2 (OCH.sub.3), 121.8, 121.6 (o OPh), 126.5 (m, OPh), 145.7 (ipso, OPh), 154.7, 154.6 (p, OPh), 173.4, 173.2 (COOCH.sub.3).

Synthesis of p-nitrophenyl-(ethoxy-L-alaninyl)-phosphorochloridate

(376) C.sub.11H.sub.14ClN.sub.2O.sub.6P, MW=336.67.

(377) ##STR00073##

(378) This is synthesised according to Standard procedure 4, using L-alanine ethyl ester hydrochloride (770 mg, 5.01 mmol), p-nitrophenyldichlorophosphate (1.362 g, 5.01 mmol), and TEA (1.4 mL, 10.02 mmol) in DCM (40 mL), to yield 1.64 g (98%) of crude product used without further purification.

(379) .sup.31P-NMR(CDCl.sub.3, 121 MHz): 9.06, 8.81.

(380) .sup.1H-NMR (CDCl.sub.3; 300 MHz): & 8.1 (2H, m, OPh), 7.4 (2H, m, OPh), 4.9-4.7 (1H, bs, NH), 4.3-4.1 (3H, m, OCH.sub.2CH.sub.3, CHala), 1.55-1.45 (3H, 2d, .sup.3J=7 Hz, CH.sub.3ala), 1.40 (3H, t, .sup.3J=7 Hz, OCH.sub.2CH.sub.3).

(381) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 14.5 (CH.sub.3CH.sub.2), 21.1, 20.9 (CH.sub.3ala), 51.2, 51.0 (CHala), 62.6_CH.sub.3CH.sub.2), 121.7, 121.3 (o OPh), 126.2, 126.0 (m, OPh), 145.7 (ipso, OPh), 154.5 (p, OPh), 173.4, 173.3 (COOCH.sub.2CH.sub.3).

Synthesis of p-nitrophenyl-(benzoxy-L-alaninyl)-phosphorochloridate

(382) C.sub.16H.sub.16ClN.sub.2O.sub.6P, MW=398.04.

(383) ##STR00074##

(384) This is synthesised according to Standard procedure 4, using L-alanine benzyl ester hydrochloride (1.08 g, 5.01 mmol), para-nitrophenyl-dichloro phosphate (1.362 g, 5.01 mmol), and TEA (1.4 mL, 1.4 mmol) in DCM (40 mL), to yield 1.85 g (93%) of crude product used without further purification.

(385) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 9.15, 9.06.

(386) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 8.15 (2H, m, OPh), 7.45 (2H,m, OPh), 7.35-7.25 (5H, m, CH.sub.2Ph), 5.2 (2H, 2s, CH.sub.2Ph), 5.00 (1H, bs, NH) 4.2 (1H, m, CHala), 1.64 (3H, 2d, J=7 Hz, CH.sub.3ala).

(387) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 20.8 (CH.sub.3ala), 51.1 (CHala), 68.0 (CH.sub.2Ph), 121.4 (o OPh), 126.1 (mOPh), 130.3, 129.0 (CH.sub.2Ph), 145.7 (ipso, CH.sub.2Ph), 150.2 (ipso, OPh), 154.6 (p, OPh), 172.9 (COOCH.sub.2Ph).

Synthesis of p-fluorophenyl-(methoxy-L-alaninyl)-phosphorochloridate

(388) C.sub.10H.sub.12ClFNO.sub.4P, MW=295.63.

(389) ##STR00075##

(390) This is synthesised according to Standard procedure 4, using L-alanine methyl ester hydrochloride (0.70 g, 5.01 mmol), p-fluorophenyldichlorophosphate (1.210 g, 5.01 mmol), and TEA (1.4 ml, 10 mmol) in DCM (40 mL). The crude was purified by flash chromatography (ethyl acetate/petroleum ether 7:3) affording 1.11 g (75%) of oil.

(391) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 9.98, 9.96.

(392) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.1 (2H, m, OPh), 6.95 (2H, m, OPh), 5.0 (1H, bs, NH), 4.25-4.1 (1H, m, CHala), 3.78 (3H, 2s, OCH.sub.3), 1.55 (3H, m, CH.sub.3ala).

(393) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 20.8 (CH.sub.3ala), 51.1, 50.9 (CHala), 53.3 (OCH.sub.3), 117.1, 117.0 (o OPh), 122.6, 122.5 (m, OPh), 146.0 (ipso, OPh), 159.1, 159.0 (p, OPh), 173.4, 173.2 (COOCH.sub.3).

Synthesis of p-fluorophenyl-(ethoxy-L-alaninyl)-phosphorochloridate

(394) C.sub.11H.sub.14ClFNO.sub.4P, MW=309.66.

(395) ##STR00076##

(396) This is synthesised according to Standard procedure 4, using L-alanine ethyl ester hydrochloride (770 mg, 5.01 mmol), p-fluorophenyldichlorophosphate (1.210 g, 5.01 mmol), and TEA (1.4 mL, 10.02 mmol) in DCM (40 mL). The crude was purified by flash chromatography (ethyl acetate/petroleum ether 7:3) affording 1.07 (69%) of oil.

(397) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 10.04, 9.95.

(398) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.1 (2H, m, OPh), 6.95 (2H, m, OPh), 5.0 (1H, bs, NH), 4.25-4.1 (3H, m, OCH.sub.2CH.sub.3, CHala), 1.55 (3H, m, CH.sub.3ala), 1.40 (3H, t, .sup.3J=7 Hz, OCH.sub.2CH.sub.3).

(399) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 14.5 (CH.sub.3CH.sub.2), 21.1, 21.0 (CH.sub.3ala), 51.2, 51.1 (CHala), 62.6_CH.sub.3CH.sub.2), 117.3 (oOPh), 122.2, 122.0 (m, OPh), 145.9, 145.8 (ipso, OPh), 159.0 (p, OPh), 173.6, 173.5 (COOCH.sub.2CH.sub.3).

Synthesis of p-fluorophenyl-(benzoxy-L-alaninyl)-phosphorochloridate

(400) C.sub.16H.sub.16ClFNO.sub.4P, MW=371.73.

(401) ##STR00077##

(402) This is synthesised according to Standard procedure 4, using L-alanine benzyl ester hydrochloride (1.08 g, 5.01 mmol), para-fluorophenyl-dichloro phosphate (1.210 mg, 5.01 mmol), and TEA (1.4 mL, 1.4 mmol) in DCM (40 mL). The crude was purified by flash chromatography (ethyl acetate/petroleum ether 7:3) affording 1.599 (86%) of oil.

(403) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 9.15, 9.06.

(404) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.35-7.25 (5H, m, CH.sub.2Ph), 7.1 (2H, m, OPh), 6.95 (2H, m, OPh), 5.2 (2H, 2s, CH.sub.2Ph), 5.00 (1H, bs, NH), 4.25-4.1 (1H, m, CHala), 1.55 (3H, m, CH.sub.3ala).

(405) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 20.8 (CH.sub.3ala), 51.1, 51.0 (CHala), 68.1 (CH.sub.2Ph), 117.0, 116.9 (o OPh), 122.6 (mOPh), 130.3, 129.0 (CH.sub.2Ph), 135.7 (ipso, CH.sub.2Ph), 146.1, 146.0(ipso, OPh), 158.9 (p, OPh), 173.1 (COOCH.sub.2Ph).

Synthesis of 4-(trifluoromethyl)-phenyl-(methoxy-L-alaninyl)-phosphorochloridate

(406) C.sub.11H.sub.12ClF.sub.3NO.sub.4P, MW=345.64.

(407) ##STR00078##

(408) This is synthesised according to Standard procedure 4, using L-alanine methyl ester hydrochloride (1.0 g, 7.16 mmol), 4-(trifluoromethyl)-phenyl-phosphodichloridate (1.998 g, 7.16 mmol), and TEA (1.449 g, 14.32 mmol, 1916 L) in DCM (30 mL), to yield 2.202 g (89.0%) of crude product used without further purification.

(409) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 9.36, 9.22.

(410) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.66 (2H, d, .sup.3J=8.1 Hz, OPh), 7.44-7.33 (2H, m, OPh), 5.10 (1H, bs, NH), 3.81-3.78 (3H, 2s, CH.sub.3O), 3.77-3.68 (1H, m, CH.sub.3CH), 1.56-1.52 (3H, m, CHCH.sub.3).

(411) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 20.6, 20.7 (CH.sub.3CH), 50.9, 51.1 (CHCH.sub.3), 53.2 (CH.sub.3O), 121.4 (o, OPh), 124.1 (CF.sub.3, J=270 Hz), 128.0 (m, OPh), 128.6 (p, J=34 Hz), 152.4, 152.6 (ipso, OPh), 173.4, 173.5 (COOCH.sub.3).

Synthesis of 4-(trifluoromethyl)-phenyl-(ethoxy-L-alaninyl)-phosphorochloridate

(412) C.sub.12H.sub.14ClF.sub.3NO.sub.4, MW=359.67.

(413) ##STR00079##

(414) This is synthesised according to Standard procedure 4, using L-alanine ethyl ester hydrochloride (1.0 g, 6.50 mmol), 4-(trifluoromethyl)-phenyl-phosphodichloridate (1.813 g, 6.50 mmol), and TEA (1.316 g, 13.00 mmol, 1740 L) in DCM (30 mL), to yield 2.150 g (92.2%) of crude product used without further purification.

(415) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 9.33, 9.28.

(416) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.70 (2H, d, .sup.3J=8.2 Hz, OPh), 7.46-7.39 (2H, m, OPh), 4.78 (1H, bs, NH), 4.33-4.17 (3H, m, CH.sub.3CH.sub.2O+CHCH.sub.3), 1.59-1.55 (1H, m, CHCH.sub.3), 1.56-1.52 (3H, m, CH.sub.2CH.sub.3).

(417) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 14.5 (CH.sub.3CH.sub.2O), 20.8, 20.9 (CH.sub.3CH), 50.3, 50.9 (CHCH.sub.3), 62.3, 62.5 (CH.sub.3CH.sub.2O), 121.4 (o, OPh), 124.1 (CF.sub.3, J=270 Hz), 127.7 (m, OPh), 128.7 (p, J=33 Hz), 152.4 (ipso, OPh), 172.9 (COOCH.sub.2CH.sub.3).

Synthesis of p-trifluorophenyl-(benzoxy-L-alaninyl)-phosphorochloridate

(418) C.sub.17H.sub.16ClF.sub.3NO.sub.4P, MW=421.73.

(419) ##STR00080##

(420) This is synthesised according to Standard procedure 4, using L-alanine benzyl ester hydrochloride (1.08 g, 5.01 mmol), para-trifluorophenyl-dichloro phosphate (1.490 mg, 5.01 mmol), and TEA (1.4 mL, 1.4 mmol) in DCM (40 mL). The crude was purified by flash chromatography (ethyl acetate/petroleum ether 6:4) affording 1.80 (85%) of oil.

(421) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 9.11, 8.84.

(422) .sup.1-NMR (CDCl.sub.3; 300 MHz): 7.65 (2H, m, OPh), 7.4-7.2 (7H, m, CH.sub.2Ph+2H OPh), 5.25 (2H, 2s, CH.sub.2Ph), 4.75-4.55 (1H, bs, NH), 4.25-4.1 (1H, m, CHala), 1.60-1.55 (3H, 2d, .sup.3J=7 Hz, CH.sub.3ala).

(423) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 20.9 (CH.sub.3ala), 51.3, 51.0 (CHala), 68.2, 68.1 (CH.sub.2Ph), 121.4, 120.9 (o, OPh), 125.2 (d, J=270 Hz, CF.sub.3), 126.6 (m, OPh), 129.1, 128.8, 127.8 (Bn), 130.0 (p,q, J=32 Hz, OPh), 135.4 (ipso, CH.sub.2Ph), 153.0 (ipso, OPh), 172.8 (COOCH.sub.2Ph).

Synthesis of 4-chlorophenyl-(methoxy-L-alaninyl)-phosphorochloridate

(424) C.sub.10H.sub.12Cl.sub.2NO.sub.4P, MW=312.09.

(425) ##STR00081##

(426) This is synthesised according to Standard procedure 4, using L-alanine methyl ester hydrochloride (1.0 g, 7.16 mmol), 4-chlorophenylphosphorodichloridate (1.757 g, 7.16 mmol), and TEA (1.449 g, 14.32 mmol, 1995 L) in DCM (30 mL), to yield 1.621 g (72.5%) of crude product used without further purification.

(427) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 9.36, 9.07.

(428) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.35-7.15 (4H, m, OPh), 4.48-4.36 (1H, bs, NH), 4.22-4.04 (1H, m, CHCH.sub.3), 3.76-3.74 (3H, 2s, CH.sub.3O), 1.49-1.46 (3H, m, CHCH.sub.3.

(429) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 21.0 (CH.sub.3CH), 50.8, 51.1 (CHCH.sub.3), 53.4 (CH.sub.3O), 121.9, 122.1, 122.3, 122.4 (o, OPh), 130.6, 130.4, 130.2 (m, OPh), 132.0 (p, OPh), 148.6 (ipso, OPh), 173.5 (COOCH.sub.3).

Synthesis of 4-chlorophenyl-(ethoxy-L-alaninyl)-phosphorochloridate

(430) C.sub.11H.sub.14Cl.sub.2NO.sub.4P, MW=326.11.

(431) ##STR00082##

(432) This is synthesised according to Standard procedure 4, using L-alanine ethyl ester hydrochloride (1.000 g, 6.50 mmol), 4-chlorophenylphosphorodichloride (1.595 g, 6.50 mmol), and TEA (1.315 g, 13.00 mmol, 1810 L) in DCM (20 mL), to yield 1.794 mg (yield 84.7%) of product.

(433) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 9.54, 9.25.

(434) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.44-7.21 (4H, m, OPh), 4.59 (1H, bs, NH), 4.33-4.13 (3H, m, OCH.sub.2CH.sub.3+CHCH.sub.3), 1.57-1.56 (3H, m, CH.sub.3CH), 1.43-1.21 (3H, m, OCH.sub.2CH.sub.3).

(435) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 14.5, 14.6 (OCH.sub.2CH.sub.3), 21.0, 21.5 (CH.sub.3CH), 50.9, 51.2 (CHCH.sub.3), 62.4, 62.5 (OCH.sub.2CH.sub.3), 122.04, 122.3, 122.4 (o, OPh), 130.4 (m, OPh), 131.9 (p, OPh), 148.5, 148.6 (ipso, OPh), 173.0, 173.1 (COOCH.sub.2CH.sub.3).

Synthesis of 4-nitrophenyl-(benzyl-2-amino-2-methylpropanoate)-phosphorochloridate

(436) C.sub.16H.sub.16Cl.sub.2NO.sub.4P, MW=388.18.

(437) ##STR00083##

(438) This is synthesised according to Standard procedure 4, using L-alanine benzyl ester hydrochloride (1.000 g, 4.63 mmol), 4-chlorophenylphosphodichloride (1.136 g, 4.63 mmol), and TEA (937.0 mg, 9.26 mmol, 1290 L) in DCM (40 mL), to yield 1534 mg (yield 86.5%) of crude product used without further purification.

(439) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 9.43, 9.16.

(440) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.42-7.08 (9H, m, OPh+CH.sub.2Ph), 5.19 (2H, s, CH.sub.2Ph), 4.61-4.54 (1H, bs, NH), 4.26-4.10 (1H, m, CHCH.sub.3), 1.42-1.38 (3H, m, CH.sub.3CH).

(441) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 20.9, 21.0 (CH.sub.3CH), 51.0, 51.2 (CHCH.sub.3), 68.1, 68.2 (OCH.sub.2Ph), 122.3, 122.4 (o, OPh), 128.8, 129.1, 130.4 (o, m, p, CH.sub.2Ph+OPh), 131.9 (ipso, CH.sub.2Ph), 135.3 (p, OPh), 148.5 (ipso, OPh), 172.7, 172.8 (COOCH.sub.2Ph).

Synthesis of phenyl-(methyl-2-amino-2-methylpropanoate)-phosphorochloridate

(442) C.sub.11H.sub.15ClNO.sub.4P, MW=291.67.

(443) ##STR00084##

(444) This is synthesised according to Standard procedure 4, using 2-aminoisobutyrate methyl ester hydrochloride (583.5 mg, 3.75 mmol), phenyl dichlorophosphate (791.1 mg, 3.75, 560 L), and TEA (758.9 mg, 7.5 mmol, 1045 L) in DCM (20 mL), to yield 1.041 g (95.2%) of crude product used without further purification.

(445) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 6.99 (s).

(446) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.41-7.17 (5H, m, OPh), 4.98 (1H, bs, NH), 3.80 (3H, s, OCH.sub.3), 1.71-1.69 (6H, 2s, [CH.sub.3].sub.2C).

(447) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 27.3, 27.2, 27.0 ([CH.sub.3].sub.2C), 53.6 (OCH.sub.3), 58.8 (C[CH.sub.3].sub.2), 120.0, 121.1 (o OPh), 126.2 (p, OPh), 130.3 (m, OPh) 145.7 (p, OPh), 150.2, 150.3 (ipso, OPh), 175.6, 175.7 (COOCH.sub.3).

Synthesis of phenyl-(ethyl-2-amino2-methylpropanoate)-phosphorochloridate

(448) C.sub.12H.sub.17ClNO.sub.4P, MW=305.69.

(449) ##STR00085##

(450) This is synthesised according to Standard procedure 4, using 2-aminoisobutyrate ethyl ester hydrochloride (628.6 mg, 3.75 mmol), phenyl dichlorophosphate (791.1 mg, 3.75, 560 L), and TEA (758.9 mg, 7.5 mmol, 1045 L) in DCM (20 mL), to yield 1.018 g (88.8%) of crude product used without further purification.

(451) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 7.02 (s)

(452) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.23-7.37 (5H, m, OPh), 4.98 (1H, bs, NH), 4.24 (2H, q, .sup.3J=7.1 Hz, OCH.sub.2CH.sub.3), 1.70, 1.68 (6H, 2s, [CH.sub.3].sub.2C), 1.30 (3H, t, .sup.3J=7.1 Hz, OCH.sub.2CH.sub.3).

(453) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 14.5 (CH.sub.3CH.sub.2O), 27.3, 26.9 ([CH.sub.3].sub.2C), 58.7 (C[CH.sub.3].sub.2), 62.7 (OCH.sub.2CH.sub.3), 121.1, 121.0 (o, OPh), 127.6 (p, OPh), 130.7 (m, OPh), 150.4 (ipso, OPh), 175.2, 175.1 (COOCH.sub.2CH.sub.3).

Synthesis of phenyl-(benzyl-2-amino-2-methylpropanoate)-phosphorochloridate

(454) C.sub.17H.sub.19ClNO.sub.4P, MWV=367.76.

(455) ##STR00086##

(456) This is synthesised according to Standard procedure 4, using 2-aminoisobutyrate benzyl ester hydrochloride (861.4 mg, 3.75 mmol), phenyl dichlorophosphate (791.1 mg, 3.75, 560 L), and TEA (758.9 mg, 7.5 mmol, 1045 L) in DCM (30 mL). The crude was purified by flash chromatography (ethyl acetate/petroleum ether 6:4) affording 580 mg (42.2%) of oil.

(457) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 6.79 (s)

(458) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.45-7.27 (10H, m, OPh+CH.sub.2Ph), 5.28 (2H, s, CH.sub.2Ph), 4.81, 4.78 (1H, 2bs, NH), 1.78, 1.75 (6H, 2s, [CH.sub.3]C).

(459) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 27.3, 26.9 ([CH.sub.3]C), 53.9 (C[CH.sub.3].sub.2), 60.9 (CH.sub.2Ph), 121.0, 126.3, 128.6, 129.0, 129.1, 130.3, 135.5 (OPh, CH.sub.2Ph), 135.5 (ipso, CH.sub.2Ph), 150.3, 150.2 (ipso, OPh), 175.0, 175.2 (COOCH.sub.2Ph).

Synthesis of 4-nitrophenyl-(methyl-2-amino-2-methylpropanoate)-phosphorochloridate

(460) C.sub.11H.sub.14ClN.sub.2O.sub.6P, MW=336.67.

(461) ##STR00087##

(462) This is synthesised according to Standard procedure 4, using 2-aminoisobutyrate methyl ester hydrochloride (290.0 mg, 1.89 mmol), 4-nitrophenylphosphodichloride (483.3 mg, 1.89 mmol), and TEA (382.5 mg, 3.78 mmol, 526.9 L) in DCM (15 mL), to yield 486 mg (yield 76.4%) of crude product used without further purification.

(463) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 6.61 (s)

(464) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 8.25 (2H, d, .sup.3J=9.0 Hz, OPh), 7.43 (2H, d, .sup.3J=9.0 Hz, OPh), 4.91-4.87 (1H, 2bs, NH), 3.79 (3H, s, OCH.sub.3), 1.69-1.66 (6H, 2s, [CH.sub.3].sub.2C).

(465) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 27.0, 27.1, 27.3 ([CH.sub.3].sub.2C), 53.8 (OCH.sub.3), 59.2 (C[CH.sub.3].sub.2), 121.7, 121.8 (o OPh), 126.2 (m, OPh), 145.7 (p, OPh), 154.8, 154.7 (ipso, OPh), 175.4, 175.6 (COOCH.sub.3).

Synthesis of 4-nitrophenyl-(ethyl-2-amino-2-methylpropanoate)-phosphorochloridate

(466) C.sub.12H.sub.16ClN.sub.2O.sub.6P, MW=350.69.

(467) ##STR00088##

(468) This is synthesised according to Standard procedure 4, using 2-aminoisobutyrate ethyl ester hydrochloride (270.0 mg, 1.61 mmol), 4-nitrophenylphodichloride (412.3 mg, 1.61 mmol), and TEA (325.8 mg, 3.22 mmol, 448.8 L) in DCM (15 mL), to yield 500 mg (yield 88.5%) of crude product used without further purification.

(469) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 6.64 (s)

(470) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 8.35 (2H, d, .sup.3J=9.0 Hz, OPh), 7.53 (2H, d, .sup.3J=9.0 Hz, OPh), 4.99-4.96 (1H, 2bs, NH), 4.34 (2H, q, .sup.3J=7.1 Hz, OCH.sub.2CH.sub.3), 1.79-1.76 (6H, 2s, [CH.sub.3].sub.2C), 1.40 (3H, t, .sup.3J=7.1 Hz, OCH.sub.2CH.sub.3.

(471) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 14.5 (OCH.sub.2CH.sub.3), 27.0, 27.3 ([CH.sub.3].sub.2C), 59.1, 59.2 (C[CH.sub.3].sub.2), 62.9, 63.0 (OCH.sub.2CH.sub.3), 121.7, 121.8 (o OPh, 126.2 (m, OPh), 145.7 (p, OPh), 154.7, 154.8 (ipso OPh), 175.4, 175.6 (CCOOCH.sub.2CH.sub.3).

Synthesis of 4-nitrophenyl-(benzyl-2-amino-2-methylpropanoate)-phosphorochloridate

(472) C.sub.17H.sub.18ClN.sub.2O.sub.6P, MW=412.76.

(473) ##STR00089##

(474) This is synthesised according to Standard procedure 4, using 2-aminoisobutyrate benzyl ester hydrochloride (578 mg, 2.52 mmol), 4-nitrophenylphosphodichloride (645 mg, 2.52 mmol), and TEA (510 mg, 5.04 mmol, 702.5 L) in DCM (20 mL), to yield 936 mg (yield 90.0%) of crude product used without further purification.

(475) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 6.56 (s)

(476) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 8.29 (2H, d, .sup.3J=9.0 Hz, OPh), 7.47 (2H, d, .sup.3J=9.0 Hz, OPh), 7.40-7.37 (5H, m, CH.sub.2Ph), 5.27 (2H, s, CH.sub.2Ph), 5.04-5.01 (1H, 2bs, NH), 1.77-1.74 (6H, 2s, [CH.sub.3].sub.2C).

(477) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 27.0, 27.3, ([CH.sub.3].sub.2C), 59.2 (C[CH.sub.3].sub.2), 68.5 (OCH.sub.2Ph), 121.6, 121.7, 126.2, 128.6, 129.1, (o, m, p, CH.sub.2Ph+OPh), 135.7 (ipso, CH.sub.2Ph), 145.7 (p, OPh), 154.7, 154.8 (ipso, OPh), 175.8, 175.9 (COOCH.sub.2Ph).

Synthesis of 4-chlorophenyl-(methyl-2-amino-2-methylpropanoate)-phosphorochloridate

(478) C.sub.11H.sub.14Cl.sub.2NO.sub.4P, MW=326.11.

(479) ##STR00090##

(480) This is synthesised according to Standard procedure 4, using 2-aminoisobutyrate methyl ester hydrochloride (280.0 mg, 1.82 mmol), 4-chlorophenylphosphodichloride (447.4 mg, 1.82 mmol), and TEA (368.3 mg, 3.64 mmol, 507.3 L) in DCM (20 mL), to yield 554 mg (yield 91.1%) of crude product used without further purification.

(481) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 7.05 (s)

(482) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.38 (2H, d, .sup.3J=9.0 Hz, OPh), 7.28-7.24 (2H, 2d, .sup.3J=9.0 Hz, OPh), 4.87-4.83 (1H, 2bs, NH), 3.84 (3H, s, OCH.sub.3), 1.73-1.71 (6H, 2s, [CH.sub.3].sub.2C).

(483) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 27.0, 27.3, ([CH.sub.3].sub.2C), 53.7 (OCH.sub.3), 58.9 (C[CH.sub.3].sub.2), 122.5 (o, OPh), 129.7 (m, OPh), 131.8 (p, OPh) 148.7, 148.9 (ipso, OPh), 175.5, 175.7 (COOCH.sub.3).

Synthesis of 4-chlorophenyl-(ethyl-2-amino-2-methylpropanoate)-phosphorochloridate

(484) C.sub.12H.sub.16Cl.sub.2NO.sub.4P, MW=340.14.

(485) ##STR00091##

(486) This is synthesised according to Standard procedure 4, using 2-aminoisobutyrate ethyl ester hydrochloride (293.4 mg, 1.75 mmol), 4-chlorophenylphosphodichloride (430.0 mg, 1.75 mmol), and TEA (354.2 mg, 3.50 mmol, 488.0 L) in DCM (15 mL), to yield 571.7 mg (yield 96.1%) of crude product used without further purification.

(487) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 7.09 (s)

(488) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.38 (2H, d, .sup.3J=9.1 Hz, OPh), 7.26 (2H, d, .sup.3J=9.1 Hz, OPh), 4.88-4.84 (1H, 2bs, NH), 4.29 (2H, q, .sup.3J=7.1 Hz, OCH.sub.2CH.sub.3), 1.74-1.70 (6H, 2s, [CH.sub.3]C), 1.35 (3H, t, .sup.3J=7.1 Hz, OCH.sub.2CH.sub.3).

(489) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 14.5 (OCH.sub.2CH.sub.3), 27.0, 27.3 ([CH.sub.3].sub.2C), 58.9 (C[CH.sub.3].sub.2), 62.8 (OCH.sub.2CH.sub.3), 122.5 (o, OPh), 130.4 (m, OPh), 131.8 (p, OPh), 148.7, 148.8 (ipso, OPh), 175.1, 175.3 (COOCH.sub.2CH.sub.3).

Synthesis of 4-chlorophenyl-(benzyl-2-amino-2-methylpropanoate)-phosphorochloridate

(490) C.sub.17H.sub.18Cl.sub.2NO.sub.4P, MW=402.21.

(491) ##STR00092##

(492) This is synthesised according to Standard procedure 4, using 2-aminoisobutyrate benzyl ester hydrochloride (402.0 mg, 1.75 mmol), 4-chlorophenylphosphodichloride (430 mg, 1.75 mmol), and TEA (354.2 mg, 3.50 mmol, 488.0 L) in DCM (15 mL), to yield 657.9 mg (yield 93.5%) of crude product used without further purification.

(493) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 7.00 (s)

(494) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.39-7.12 (9H, m, CH.sub.2Ph+OPh), 5.18 (2H, s, CH.sub.2Ph), 4.75-4.72 (1H, 2bs, NH), 1.68-1.65 (6H, 2s, [CH.sub.3].sub.2C).

(495) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 27.0, 27.3, ([CH.sub.3].sub.2C), 59.0 (C[CH.sub.3].sub.2), 68.4 (OCH.sub.2Ph), 122.5, 128.6, 129.1, 130.7 (o, m, p, CH.sub.2Ph+OPh), 131.8 (p, CH.sub.2Ph), 135.4 (p, OPh), 148.6, 148.7 (ipso, OPh), 174.9, 175.1 (COOCH.sub.2Ph).

Synthesis of 4-(trifluoromethyl)-phenyl-(benzyl-2-amino-2-methylpropanoate)-phosphorochloridate

(496) C.sub.18H.sub.18ClF.sub.3NO.sub.4P, MW=435.76.

(497) ##STR00093##

(498) This is synthesised according to Standard procedure 4, using 2-aminoisobutyrate benzyl ester hydrochloride (341.0 mg, 1.49 mmol), 4-(trifluoromethyl)-phenyl-phosphodichloridate (414.3 mg, 1.49 mmol), and TEA (300.5 mg, 2.97 mmol, 413.9 L) in DCM (15 mL), to yield 623.9 mg (96.4%) of crude product used without further purification.

(499) .sup.13P-NMR (CDCl.sub.3, 121 MHz): 6.74 (s)

(500) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.66 (2H, d, .sup.3J=8.8 Hz, OPh), 7.42-7.30 (7H, m, OPh+CH.sub.2Ph), 5.25 (2H, s, CH.sub.2Ph), 4.95-4.91 (1H, 2bs, NH), 1.75-1.72 (6H, 2s, (CH.sub.3].sub.2C).

(501) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 26.9, 27.0, 27.3 ([CH.sub.3].sub.2C), 59.1 (C[CH.sub.3].sub.2), 68.4 (CH.sub.2Ph), 121.1, 121.4, 127.7, 128.4, 128.5, 128.6, 128.9 (o, m, p, OPh+CH.sub.2Ph), 124.2 (CF.sub.3, J=265 Hz), 135.4 (ipso, CH.sub.2Ph), 152.6, 152.7 (ipso, OPh), 174.9, 175.0 (COOCH.sub.2Ph).

Synthesis of Phenyl-(methoxy-,-cycloleucinyl)-phosphorochloridate

(502) C.sub.13H.sub.17ClNO.sub.4P, MW=317.70.

(503) ##STR00094##

(504) This is synthesised according to Standard procedure 4, using methyl-1-amino-1-cyclopentanoate hydrochloride salt (0.885 g, 5.01 mmol), phenyldichlorophosphate (1.12 g, 0.749 ml, 5.01 mmol), and TEA (1.4 ml, 10 mmol) in DCM (40 mL), to yield 1.266 g (81%) of crude product used without further purification.

(505) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 7.90.

(506) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.4-7.2 (5H, m, OPh), 4.3 (1H, bs, NH), 3.75 (3H, 2s, OCH.sub.3), 2.15 (4H, m, 4H cyclopentane), 1.9-1.7 (4H, m, 4H cyclopentane).

(507) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 24.4 (2CH.sub.2 cyclopent), 38.8, 38.7, 38.6 (2CH.sub.2 cyclopent), 53.3, 53.2 (CH.sub.3O), 66.6 (Cq cyclopentane), 121.1, 121.0 (o OPh), 126.3 (p, OPh), 130.3, 130.2 (m, OPh), 150.2 (ipso, OPh), 174.8 (COOCH.sub.3).

Synthesis of Phenyl-(ethoxy-,-cycloleucinyl)-phosphorochloridate

(508) C.sub.14H.sub.19ClNO.sub.4P, MW=331.73.

(509) ##STR00095##

(510) This is synthesised according to Standard procedure 4, using ethyl-1-amino-1-cyclopentanoate hydrochloride salt (955 mg, 5.01 mmol), phenyldichlorophosphate (1.12 g, 5.01 mmol, 749 L), and TEA (1.4 mL, 10.02 mmol) in DCM (40 mL). The crude was purified by flash chromatography (ethyl acetate/petroleum ether 7:3) affording 1.457 g (89%) of oil.

(511) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 8.04, 7.97.

(512) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.4-7.1 (5H, m, OPh), 4.7 (1H, bs, NH), 4.2 (2H, 2q, .sup.3J=7.1 Hz, OCH.sub.2CH.sub.3), 2.15 (4H, m, 4H cyclopentane), 1.9-1.7 (4H, m, 4H cyclopentane), 1.30 (3H, t, .sup.3J=7.1 Hz, OCH.sub.2CH.sub.3).

(513) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 14.5 (CH.sub.3CH.sub.2), 24.5 (2CH.sub.2 cyclopent), 38.8, 38.7, 38.6, 38.5 (2CH.sub.2 cyclopent), 62.0_CH.sub.3CH.sub.2), 68.3 (Cq cyclopentane), 120.9 (o OPh), 126.3 (p, OPh), 130.3 (m, OPh), 150.3-150.2 (ipso, OPh), 174.9-174.8 (COOCH.sub.2CH.sub.3).

Synthesis of Phenyl-(benzoxy-,-cycloleucinyl)-phosphorochloridate

(514) C.sub.19H.sub.21ClNO.sub.4P, MW=393.80.

(515) ##STR00096##

(516) This is synthesised according to Standard procedure 4, using benzyl-1-amino-1-cyclopentanoate hydrochloride salt (0.984 g, 3.84 mmol), phenyl-dichlorophosphate (0.577 ml, 3.84 mmol), and TEA (1.08 mL, 7.69 mmol) in DCM (30 mL), to yield 1.485 g (98%) of crude product used without further purification.

(517) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 7.85.

(518) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.3-7.0 (10H, m, OPh+CH.sub.2Ph), 5.2 (2H, s, CH.sub.2Ph), 4.95-4.65 (1H, bs, NH), 2.25-2.1 (4H, m, 4H cyclopentane), 1.9-1.7 (4H, m, 4H cyclopentane).

(519) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 24.4, 24,3 (2CH.sub.2 cyclopent), 38.8, 38.7, 38.5 (2CH.sub.2 cyclopent), 67.3 (Cq cyclopentane), 68.0 (CH.sub.2Ph), 121.0 (o OPh), 126.4 (p, OPh), 130.1, 129.0, 128.8 (mOPh, CH.sub.2Ph), 135.4 (ipso, CH.sub.2Ph), 150.1 (ipso, OPh), 173.4 (COOCH.sub.2Ph),

Synthesis of p-fluorophenyl-(methoxy-,-cycloleucinyl)-phosphorochloridate

(520) C.sub.13H.sub.16ClNO.sub.4P, MW=335.70.

(521) ##STR00097##

(522) This is synthesised according to Standard procedure 4, using methyl-1-amino-1-cyclopentanoate hydrochloride salt (0.885 g, 5.01 mmol), parafluorophenyldichlorophosphate (1.21 g, 5.01 mmol), and TEA (1.4 ml, 10 mmol) in DCM (40 mL), to yield 1.65 g (99%) of crude product used without further purification.

(523) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 8.61.

(524) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.3-7.2 (2H, m, OPh), 7.1-7.0 (2H, m, OPh), 4.7 (1H, bs, NH), 3.78 (3H, 2s, OCH.sub.3), 2.25-2.15 (4H, m, 4H cyclopentane), 2.0-1.8 (4H, m, 4H, m, 4H cyclopentane).

(525) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 24.4 (2CH.sub.2 cyclopent), 38.7, 38.6, 38.5 (2CH.sub.2 cyclopent), 53.3 (CH.sub.3O), 66.3-66.2 (Cq cyclopentane), 117.1-116.8 (o OPh), 122.6-122.5 (m, OPh), 146.1-145.9 (ipso, OPh), 159.0 (p, OPh), 175.3-175.2 (COOCH.sub.3).

Synthesis of p-fluorophenyl-(ethoxy-,-cycloleucinyl)-phosphorochloridate

(526) C.sub.14H.sub.18ClFNO.sub.4P, MW=349.72.

(527) ##STR00098##

(528) This is synthesised according to Standard procedure 4, using ethyl-1-amino-1-cyclopentanoate hydrochloride salt (955 mg, 5.01 mmol), para-fluorophenyldichlorophosphate (1.21 g, 5.01 mmol), and TEA (1.4 mL, 10.02 mmol) in DCM (40 mL), to yield 1.64 g (94%) of crude product used without further purification.

(529) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 8.70.

(530) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.3-7.2 (2H, m, OPh), 7.1-7.0 (2H, m, OPh), 4.8 (1H, bs, NH), 4.2 (2H, 2q,.sup.3J=7.1 Hz, OCH.sub.2CH.sub.3), 2.25-2.1 (4H, m, 4H cyclopentane), 2.0-1.8 (4H, m, 4H cyclopentane), 1.4 (3H, t, .sup.3J=7.1 Hz, OCH.sub.2CH.sub.3).

(531) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 14.4 (CH.sub.3CH.sub.2), 24.4 (2CH.sub.2 cyclopent), 38.8, 38.7, 38.6, 38.5 (2CH.sub.2 cyclopent), 62.3_CH.sub.3CH.sub.2), 68.3 (Cq cyclopentane), 117.4, 117.0 (o OPh), 122.7, 122.6 (m, OPh), 146.1, 146.0 (ipso, OPh), 159.0 (p, OPh), 174.9 (COOCH.sub.2CH.sub.3).

Synthesis of p-fluorophenyl-(benzoxy-,-cycloleucinyl)-phosphorochloridate

(532) C.sub.19H.sub.20ClFNO.sub.4P, MW=411.79.

(533) ##STR00099##

(534) This is synthesised according to Standard procedure 4, using benzyl-1-amino-1-cyclopentanoate hydrochloride salt (1.281 g, 5.01 mmol), para-fluorophenyl-dichlorophosphate (1.21 g, 5.01 mmol), and TEA (1.4 mL, 10 mmol) in DCM (40 mL), to yield 1.85 g (90%) of crude product used without further purification.

(535) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 7.85.

(536) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.65-7.4 (5H, m, CH.sub.2Ph), 7.3-7.2 (2H, m, OPh), 7.1-7.0 (2H, m, OPh), 5.2 (2H, s, CH.sub.2Ph), 4.6 (1H, bs, NH), 2.2-2.1 (4H, m, 4H cyclopentane), 2.0-1.8 (4H, m, 4H cyclopentane).

(537) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 24.5 (2CH.sub.2 cyclopent), 38.9, 38.8, 38.6, 38.5 (2CH.sub.2 cyclopent), 68.1 (Cq cyclopentane), 68.4 (CH.sub.2Ph), 117.0, 116.8 (o OPh), 122.6, 122.5 (mOPh) 129.1, 129.0, 128.8, 128.7 (CH.sub.2Ph), 135.7 (ipso, CH.sub.2Ph), 146.1, 145.9 (ipso, OPh), 159.0 (p, OPh), 174.6 (COOCH.sub.2Ph).

Synthesis of p-nitrophenyl-(methoxy-,-cycloleucinyl)-phosphorochloridate

(538) C.sub.13H.sub.16ClN.sub.2O.sub.6P, MW=362.70.

(539) ##STR00100##

(540) This is synthesised according to Standard procedure 4, using methyl-1-amino-1-cyclopentanoate hydrochloride salt (0.885 g, 5.01 mmol), para-nitrophenyldichlorophosphate (1.632 g, 5.01 mmol), and TEA (1.4 ml, 10 mmol) in DCM (40 mL), to yield 1.601 g (90%) of crude product used without further purification.

(541) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 8.02.

(542) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 8.2 (2H, 2d, .sup.3J=8 Hz, OPh), 7.32 (2H, 2d, .sup.3J=8 Hz OPh), 4.9 (1H, bs, NH), 3.71 (3H, s, OCH.sub.3), 2.25-2.00 (4H, m, 4H cyclopentane), 1.95-1.7 (4H, m, 4H cyclopentane).

(543) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 24.3 (2CH.sub.2 cyclopent), 38.7, 38.6 (2CH.sub.2 cyclopent), 53.3 (CH.sub.3O), 68.6 (Cq cyclopentane), 121.8, 121.7 (o OPh), 126.0 (m, OPh), 145.6 (ipso, OPh), 154.8, 154.7 (p, OPh), 175.1-175.0 (COOCH.sub.3).

Synthesis of p-nitrophenyl-(ethoxy-,-cycloleucinyl)-phosphorochloridate

(544) C.sub.14H.sub.18ClN.sub.2O.sub.6P, MW=376.73.

(545) ##STR00101##

(546) This is synthesised according to Standard procedure 4, using ethyl-1-amino-1-cyclopentanoate hydrochloride salt (955 mg, 5.01 mmol), para-nitrophenyldichlorophosphate (1.362 g, 5.01 mmol), and TEA (1.4 mL, 10.02 mmol) in DCM (40 mL), to yield 1.669 g (90%) of crude product used without further purification.

(547) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 7.95.

(548) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 8.1 (2H, 2d, .sup.3J=8 Hz, OPh), 7.28 (2H, 2d, .sup.3J=8 Hz OPh), 4.8 (1H, bs, NH), 4.2 (2H, 2q, .sup.3J=7.1 Hz, OCH.sub.2CH.sub.3), 2.2-2.0 (4H, m, 4H cyclopentane, 1.95-1.7 (4H, m, 4H cyclopentane), 1.27 (3H, t, .sup.3J=7.1 Hz, OCH.sub.2CH.sub.3.

(549) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 14.4 (CH.sub.3CH.sub.2), 24.4 (2CH.sub.2 cyclopent), 38.8, 38.7 (2CH.sub.2 cyclopent), 62.4_CH.sub.3CH.sub.2), 68.5 (Cq cyclopentane), 121.8, 121.1 (o OPh), 126.1, 125.9 (m, OPh), 145.6 (ipso, OPh), 154.8 (p, OPh), 174.9 (COOCH.sub.2CH.sub.3).

Synthesis of p-nitrophenyl-(benzoxy-,-cycloleucinyl)-phosphorochloridate

(550) C.sub.19H.sub.20ClN.sub.2O.sub.6P, MW=438.80.

(551) ##STR00102##

(552) This is synthesised according to Standard procedure 4, using benzyl-1-amino-1-cyclopentanoate hydrochloride salt (0.835 g, 3.25 mmol), para-nitrophenyl-dichlorophosphate (0.85 g, 3.25 mmol), and TEA (0.91 mL, 6.7 mmol) in DCM (30 mL), to yield 1.215 g (85%) of crude product used without further purification.

(553) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 7.99, 7.90.

(554) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 8.1 (2H, 2d, .sup.3J=8 Hz, OPh), 7.4-7.2 (7H, m, OPh+CH.sub.2Ph), 5.18 (2H, s, CH.sub.2Ph), 5.0 (1H, bs, NH), 2.2-2.0 (4H, m, 4H cyclopentane), 1.95-1.75 (4H, m, 4H cyclopentane).

(555) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 24.4 (2CH.sub.2 cyclopent), 38.8, 38.7, 38.6, 38.5 (2CH.sub.2 cyclopent), 68.0 (CH.sub.2Ph), 68.6 (Cq cyclopentane), 121.8, 121.7 (o OPh), 126.1, 125.9 (mOPh) 129.1, 129.0, 128.8, 128.6 (CH.sub.2Ph), 135.7 (ipso, CH.sub.2Ph), 145.6 (ipso, OPh), 154.8, 154.7 (p, OPh), 174.5, 174.4 (COOCH.sub.2Ph).

Synthesis of p-chlorophenyl-(methoxy-,-cycloleucinyl)-phosphorochloridate

(556) C.sub.13H.sub.16Cl.sub.2NO.sub.4P, MW=352.15.

(557) ##STR00103##

(558) This is synthesised according to Standard procedure 4, using methyl-1-amino-1-cyclopentanoate hydrochloride salt (0.443 g, 2.5 mmol), para-chlorophenyldichlorophosphate (0.613 g, 2.5 mmol), and TEA (0.7 ml, 5 mmol) in DCM (20 mL), to yield 0.852 g (98%) of crude product used without further purification.

(559) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 9.55, 9.5.

(560) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.35-7.15 (4H, m, OPh), 4.95 (1H, bs, NH), 3.78 (3H, s, OCH.sub.3), 2.2-2.00 (4H, m, 4H cyclopentane), 1.95-1.7 (4H, m, 4H cyclopentane).

(561) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 24.3 (2CH.sub.2 cyclopent), 38.7 (2CH.sub.2 cyclopent), 53.3 (CH.sub.3O), 68.6 (Cq cyclopentane), 122.0 (o OPh), 130.1 (m, OPh), 133.2 (p, OPh), 149.9 (ipso, OPh), 175.1-175.0 (COOCH.sub.3).

Synthesis of p-chlorophenyl-(ethoxy-,-cycloleucinyl)-phosphorochloridate

(562) C.sub.14H.sub.18Cl.sub.2NO.sub.4P, MW=366.18.

(563) ##STR00104##

(564) This is synthesised according to Standard procedure 4, using ethyl-1-amino-1-cyclopentanoate hydrochloride salt (0.477 g, 2.5 mmol), para-chlorophenyldichlorophosphate (0.613 g, 2.5 mmol), and TEA (0.7 mL, 5 mmol) in DCM (20 mL), to yield 0.880 g (97%) of crude product used without further purification.

(565) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 9.85, 9.70.

(566) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.35-7.15 (4H, m, OPh), 4.9 (1H, bs, NH), 4.22 (2H, 2q, .sup.3J=7.1 Hz, OCH.sub.2CH.sub.3), 2.2-2.0 (4H, m, 4H cyclopentane), 1.95-1.7 (4H, m, 4H cyclopentane), 1.27 (3H, t, .sup.3J=7 Hz, OCH.sub.2CH.sub.3.

(567) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 14.4 (CH.sub.3CH.sub.2), 24.4 (2CH.sub.2 cyclopent), 38.8, 38.7 (2CH.sub.2 cyclopent), 62.5, 62.4 CH.sub.3CH.sub.2), 68.1 (Cq cyclopentane), 122.2, 122.1 (o OPh), 130.1 (m, OPh), 133.2 (p, OPh), 149.8 (ipso, OPh), 174.8 (COOCH.sub.2CH.sub.3).

Synthesis of p-chlorophenyl-(benzoxy-,-cycloleucinyl)-phosphorochloridate

(568) C.sub.19H.sub.20Cl.sub.2NO.sub.4P, MW=428.25.

(569) ##STR00105##

(570) This is synthesised according to Standard procedure 4, using benzyl-1-amino-1-cyclopentanoate hydrochloride salt (0.640 g, 2.5 mmol), para-chlorophenyl-dichlorophosphate (0.613 g, 2.5 mmol), and TEA (0.7 mL, 5 mmol) in DCM (20 mL), to yield 1.041 g (97%) of crude product used without further purification.

(571) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 9.39, 8.95.

(572) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.4-7.15 (9H, m, OPh+CH.sub.2Ph), 5.20 (2H, s, CH.sub.2Ph), 5.0 (2H, s, CH.sub.2Ph), 5.0 (1H, bs, NH), 2.2-2.0 (4H, m, 4H cyclopentane), 1.95-1.75 (4H, m, 4H cyclopentane).

(573) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 24.4 (2CH.sub.2 cyclopent), 38.8, 38.7, 38.6 (2CH.sub.2 cyclopent), 68.1, 68.0 (CH.sub.2Ph), 68.2 (Cq cyclopentane), 121.9, 121.8 (o OPh), 130.5, 130.4, 129.3, 129.2 (mOPh, CH.sub.2Ph), 133.2 (p, OPh), 135.7 (ipso, CH.sub.2Ph), 149.9 (ipso, OPh), 174.3, 174.2 (COOCH.sub.2Ph).

Synthesis of p-trifluorophenyl-(methoxy-,-cycloleucinyl)-phosphorochloridate

(574) C.sub.14H.sub.16ClF.sub.3NO.sub.4P, MW=385.70.

(575) ##STR00106##

(576) This is synthesised according to Standard procedure 4, using methyl-1-amino-1-cyclopentanoate hydrochloride salt (0.443 g, 2.5 mmol), para-trifluorophenyldichlorophosphate (0.700 g, 2.5 mmol), and TEA (0.7 ml, 5 mmol) in DCM (20 mL), to yield 0.931 g (97%) of crude product used without further purification.

(577) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 8.80, 8.62.

(578) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.65 (2H, 2d, .sup.3J=8 Hz, OPh), 7.35 (2H, 2d, .sup.3J=8 Hz OPh), 5.02 (1H, bs, NH), 3.78 (3H, s, OCH.sub.3), 2.25-2.05 (4H, m, 4H cyclopentane), 1.95-1.7 (4H, m, 4H cyclopentane).

(579) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 22.8 (2CH.sub.2 cyclopent), 37.5, 37.2 (2CH.sub.2 cyclopent), 51.5 (CH.sub.3O), 68.4 (Cq cyclopentane), 120.0 (o, OPh), 124.8 (d, J=270 Hz, CF.sub.3), 126.6 (m, OPh), 129.5 (p,q, J=32 Hz, OPh), 152.8 (ipso, OPh), 175.2 (COOCH.sub.3).

Synthesis of p-trifluorophenyl-(ethoxy-,-cycloleucinyl)-phosphorochloridate

(580) C.sub.15H.sub.18ClF.sub.3NO.sub.4P, MW=399.73.

(581) ##STR00107##

(582) This is synthesised according to Standard procedure 4, using ethyl-1-amino-1-cyclopentanoate hydrochloride salt (0.477 g, 2.5 mmol), para-trifluorophenyldichlorophosphate (0.700 g, 2.5 mmol), and TEA (0.7 mL, 5 mmol) in DCM (20 mL), to yield 0.950 g (89%) of crude product used without further purification.

(583) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 8.49.

(584) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.45 (2H, m, OPh), 7.2 (2H, m, OPh), 5.12 (1H, bs, NH), 4.05 (2H, m, OCH.sub.2CH.sub.3), 2.15-2.0 (4H, m, 4H cyclopentane), 1.9-1.65 (4H, m, 4H cyclopentane), 1.2 (3H, 2t, .sup.3J=7 Hz, OCH.sub.2CH.sub.3.

(585) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 14.3 (CH.sub.3CH.sub.2), 24.2, 24.1 (2CH.sub.2 cyclopent), 38.6, 38.5, 38.4 (2CH.sub.2cyclopent), 62.0 CH.sub.3CH.sub.2), 68.4 (Cq cyclopentane), 121.5 (o, OPh), 125.0 (d, J=270 Hz, CF.sub.3), 127.5 (m, OPh), 129.9 (p,q, J=32 Hz, OPh), 152.8, 152.7 (ipso, OPh), 174.9, 174.6 (COOCH.sub.2CH.sub.3).

Synthesis of p-trifluorophenyl-(benzoxy-,-cycloleucinyl)-phosphorochloridate

(586) C.sub.20H.sub.20ClF.sub.3NO.sub.4P, MW=461.80.

(587) ##STR00108##

(588) This is synthesised according to Standard procedure 4, using benzyl-1-amino-1-cyclopentanoate hydrochloride salt (0.700 g, 2.73 mmol), para-trifluorophenyl-dichlorophosphate (0.75 g, 2.73 mmol), and TEA (0.75 mL, 5.47 mmol) in DCM (25 mL), to yield 1.089 g (86%) of crude product used without further purification.

(589) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 9.39, 8.95.

(590) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.50 (2H, m, OPh), 7.4-7.15 (7H, m, OPh+CH.sub.2Ph), 5.20 (2H, s, CH.sub.2Ph), 4.95 (1H, bs, NH), 2.2-2.0 (4H, m, 4H cyclopentane), 1.95-1.75 (4H, m, 4H cyclopentane).

(591) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 24.3 (2CH.sub.2 cyclopent), 38.8, 38.7, 38.6 (2CH.sub.2 cyclopent), 68.1, 68.0 (CH.sub.2Ph), 68.2 (Cq cyclopentane), 121.4, 121.3 (o, OPh), 125.1 (d, J=270 Hz, CF.sub.3), 126.6 (m, OPh) 129.2, 128.8, 127.8 (Bn), 129.8 (p,q, J=32 Hz, OPh), 135.7 (ipso, CH.sub.2Ph), 153.5 (ipso, OPh), 174.5, 174.4 (COOCH.sub.2Ph).

Synthesis of Phenyl-(methoxy-L-phenylalaninyl)-phosphorochloridate

(592) C.sub.16H.sub.17ClNO.sub.4P, MW=353.74.

(593) ##STR00109##

(594) This is synthesised according to Standard procedure 4, using L-phenylalanine methyl ester hydrochloride (1.08 g, 5 mmol), phenyldichlorophosphate (1.12 g, 0.75 ml, 5 mmol), and TEA (1.4 ml, 10 mmol) in DCM (40 mL), to yield 1.626 g (92%) of crude product used without further purification.

(595) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 9.1, 8.95.

(596) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.3-7.1 (10H, m, CH.sub.2Ph+OPh), 5.00 (1H, bs, NH), 4.35 (1H, m, CHphenylala), 3.79 (3H, 2s, CH.sub.3O), 3.00 (2H, m, CH.sub.2Ph)

(597) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 36.3 (CH.sub.2phenylalanine), 53.0 (CH.sub.3O), 56.6, 56.5 (CHphenylala), 121.0 (o OPh), 126.4 (p, OPh), 130.2 (m, OPh), 150.2 (ipso, OPh), 174.1 (COOCH.sub.3).

Synthesis of Phenyl-(methoxy-L-leucinyl)-phosphorochloridate C13H19ClNO4P, MW=319.72

(598) ##STR00110##

(599) This is synthesised according to Standard procedure 4, using L-leucine methyl ester hydrochloride (0.91 g, 5 mmol), phenyldichlorophosphate (1.12 g, 0.75 ml, 5 mmol), and TEA (1.4 ml, 10 mmol) in DCM (40 mL), to yield 1.58 g (99%) of crude product used without further purification.

(600) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 9.45. 9.35.

(601) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.4-7.2 (5H, m, OPh), 4.90 (1H, bs, NH), 3.95 (1H, m, CHCH.sub.2CH(CH.sub.3).sub.2), 3.78 (3H, s, OCH.sub.3), 1.8 (1H, m, CHCH.sub.2CH(CH.sub.3).sub.2), 1.8-1.5 (2H, m, CHCH.sub.2CH(CH.sub.3)2), 1.0-0.9 (6H, m, CHCH.sub.2CH(CH.sub.3).sub.2).

(602) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 23.2, 23.1, 22.4, 22.3 (2C, CHCH.sub.2CH(CH.sub.3).sub.2), 24.9, 24.8 (CHCH.sub.2CH(CH.sub.3).sub.2), 43.6 (CHCH.sub.2CH(CH.sub.3).sub.2), 53.2 (CH30), 53.7, 53.6 (CHCH.sub.2CH(CH.sub.3).sub.2), 120.9 (o OPh), 126.4 (p, OPh), 130.2 (m, OPh), 150.1 (ipso, OPh), 173.6 (COOCH.sub.3).

Synthesis of Phenyl-(benzoxy-L-leucinyl)-phosphorochloridate. C19H23ClNO4P, MW=395.82

(603) ##STR00111##

(604) This is synthesised according to Standard procedure 4, using L-leucine benzyl ester hydrochloride (1.29 g, 5.0 mmol), phenyl-dichlorophosphate (1.12 g, 0.75 ml, 5.0 mmol), and TEA (1.4 mL, 10.0 mmol) in DCM (40 mL), to yield 1.88 g (95%) of crude product used without further purification.

(605) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 9.93, 9.57.

(606) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.5-7.2 (10H, m, OPh+CH.sub.2Ph), 5.2 (2H, 2s, CH.sub.2Ph), 4.95 (1H, bs, NH), 4.2-4.1 (1H, m, CHCH.sub.2CH(CH.sub.3).sub.2), 1.95-1.80 (1H, m, CHCH.sub.2CH(CH.sub.3).sub.2), 1.7 (2H, m, CHCH.sub.2CH(CH.sub.3).sub.2), 1.0-0.9 (6H, m, CHCH.sub.2CH(CH.sub.3).sub.2).

(607) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 23.2, 23.1, 22.4, 22.3 (2C, CHCH.sub.2CH(CH.sub.3).sub.2), 24.9 (CHCH.sub.2CH(CH.sub.3).sub.2), 43.5 (CHCH.sub.2CH(CH.sub.3).sub.2), 53.8, 53.3 (CHCH.sub.2CH(CH.sub.3).sub.2), 67.8, 67.7 (CH.sub.2Ph), 120.7 (o OPh), 126.4 (p, OPh), 130.2, 129,1, 128.8, 128.7 (mOPh, CH.sub.2Ph), 135.8 (ipso, CH.sub.2Ph), 150.2 (ipso, OPh), 174.1 (COOCH.sub.2Ph).

Synthesis of p-nitrophenyl-(benzoxy-L-leucinyl)-phosphorochloridate. C19H22ClN2O6P, MW=440.81

(608) ##STR00112##

(609) This is synthesised according to Standard procedure 4, using L-leucine benzyl ester hydrochloride (1.08 g, 5.01 mmol), para-nitrophenyl-dichloro phosphate (1.362 g, 5.01 mmol), and TEA (1.4 mL, 1.4 mmol) in DCM (40 mL), to yield 2.08g (95%) of crude product used without further purification.

(610) .sup.31P-NMR (CDCl.sub.3, 121 MHz); 9.87, 9.38.

(611) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 8.25-8.10 (2H, m, OPh), 7.35-7.25 (7H, m, OPh+CH.sub.2Ph), 5.15 (2H, 2s, CH.sub.2Ph), 4.95 (1 H, bs, NH), 4.15 (1H, m, CHCH.sub.2CH(CH.sub.3).sub.2), 1.95 (1H, m, CHCH.sub.2CH(CH.sub.3)2), 1.7 (2H, m, CHCH.sub.2CH(CH.sub.3)2), 1.0-0.9 (6H, m, CHCH.sub.2CH(CH.sub.3).sub.2).

(612) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 23.2, 23.1, 22.1, 22.0 (2C, CHCH.sub.2CH(CH.sub.3).sub.2), 24.8 (CHCH.sub.2CH(CH.sub.3).sub.2), 43.4, 43.3 (CHCH.sub.2CH(CH.sub.3).sub.2), 54.2, 53.9 (CHCH.sub.2CH(CH.sub.3).sub.2), 68.0 67.9 (CH.sub.2Ph), 121.6 (o OPh), 126.2, 126.1 (mOPh), 129.2, 129.0 (CH.sub.2Ph), 135.4, 135.3 (ipso, CH.sub.2Ph), 145.8, 145.7 (ipso, OPh), 154.7, 154.5 (p, OPh), 173.0, 172.8 (COOCH.sub.2Ph).

Synthesis of pchlorophenyl-(benzoxy-L-leucinyl)-phosphorochloridate. C19H22Cl2NO4P, MW=430.26

(613) ##STR00113##

(614) This is synthesised according to Standard procedure 4, using L-leucine benzyl ester hydrochloride (0.644 g, 2.5 mmol), para-chlorophenyl-dichlorophosphate (0.613 g, 2.5 mmol), and TEA (0.7 mL, 5 mmol) in DCM (20 mL), to yield 0.968 g (90%) of crude product used without further purification.

(615) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 9.71, 9.55.

(616) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.4-7.0 (9H, m, OPh+CH.sub.2Ph), 5.15 (2H, s, CH.sub.2Ph), 4.5 (1H, d, 3J=7 Hz, NH), 4.0 (1H, m, CHCH.sub.2CH(CH.sub.3).sub.2), 1.9-1.8 (1H, m, CHCH.sub.2CH(CH.sub.3).sub.2), 1.7 (2H, m, CHCH.sub.2CH(CH.sub.3).sub.2), 0.85 (6H, m, CHCH.sub.2CH(CH.sub.3).sub.2).

(617) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 23.4, 23.3, 22.5, 22.4 (2C, CHCH.sub.2CH(CH.sub.3).sub.2), 25.0 (CHCH.sub.2CH(CH.sub.3).sub.2), 43.8, 43.7 (CHCH.sub.2CH(CH.sub.3).sub.2), 54.0, 53.8 (CHCH.sub.2CH(CH.sub.3).sub.2), 68.2 (CH.sub.2Ph), 122.5 (o OPh), 130.5, 130.4, 129.3, 129.2 (mOPh, CH.sub.2Ph), 133.2 (p, OPh), 135.7 (ipso, CH.sub.2Ph), 149.9, 149.8 (ipso, OPh), 173.4, 173.2 (COOCH.sub.2Ph).

Synthesis of 4-chlorophenyl-(methyl-2-amino-2-methylpropanoate)-phosphorochloridate. C11H14Cl2NO4P, MW=326.11

(618) ##STR00114##

(619) This is synthesised according to Standard procedure 4, using 2-aminoisobutyrate methyl ester hydrochloride (280.0 mg, 1.82 mmol), 4-chlorophenylphosphodichloride (447.4 mg, 1.82 mmol), and TEA (368.3 mg, 3.64 mmol, 507.3 L) in DCM (20 mL), to yield 554 mg (yield 91.1%) of crude product used without further purification.

(620) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 7.05 (s)

(621) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.38 (2H, d, .sup.3J=9.0 Hz, OPh), 7.29-7.24 (2H, 2d, .sup.3J=9.0 Hz, OPh), 4.87-4.83 (1H, 2bs, NH) 3.84 (3H, s, OCH.sub.3), 1.73-1.71 (6H, 2s, [CH.sub.3].sub.2C)

(622) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 27.0, 27.3, ([CH.sub.3].sub.2C), 53.7 (OCH.sub.3), 58.9 (C[CH.sub.3].sub.2), 122.5 (o, OPh), 129.7 (m, OPh), 131.8 (p, OPh) 148.7, 148.9 (ipso, OPh), 175.5, 175.7 (COOCH.sub.3).

Synthesis of 4-chlorophenyl-phosphodichloridate. C6H4Cl3O2P, MWW=245.43

(623) ##STR00115##

(624) This was synthesised according to Standard procedure 3, using phosphorus-oxychloride 1533 mg, 10.00mmol, 932 L), 4-chlorophenol (1.285 g, 10.00 mmol) and TEA (1.011 g, 0.00 mmol, 1394 L) in ethylether (100 mL) to give an oil (1.897 g, 77.3% yield).

(625) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 5.18.

(626) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.45 (2H, d, 3J=9.0 Hz, OPh), 7.30 (2H, d, .sup.3J=9.0 Hz, OPh).

(627) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 122.5 (o, OPh), 130.6 (m, OPh), 133.2 (p, OPh), 148.5 (ipso, OPh).

Synthesis of 4-(trifluoromethyl)-phenyl-phosphodichloridate. C7H4ClF3O3P, MW=278.98

(628) ##STR00116##

(629) This was synthesised according to Standard procedure 3, using phosphorus-oxychloride (1.570 mg, 10.24 mmol, 954.5 L), 4-trifluoromethylphenol (1660 g, 10.24 mmol) and TEA (1.036 g, 10.24 mmol, 1427 L) in ethylether (100 mL) to give an oil (2.521 g, 88.2% yield).

(630) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 4.75.

(631) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.77 (2H, d, 3J8.4 Hz, OPh), 7.49 (2H, d, .sup.3J=8.4 Hz,

(632) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 121.6 (o, OPh), 123.6 (CF.sub.3, J=271 Hz, OPh), 128.2 (m, OPh), 129.7 (p, J=33 Hz), 152.7 (ipso, OPh).

Synthesis of 4-fluorophenyl-phosphodichloridate. C6H4Cl2FO2P, MW=228.97

(633) ##STR00117##

(634) This was synthesised according to Standard procedure 3, using phosphorus-oxychloride (1.395 mL, 15.00 mmol), 4-chlorophenol (1.68 g, 15.00 mmol) and TEA (2.1 mL, 15.00 mmol) in ethylether (140 mL) to give an oil (3.96 g, 96% yield).

(635) .sup.31P-NMR (CDCl.sub.3, 121 MHz): 5.52.

(636) .sup.1H-NMR (CDCl.sub.3; 300 MHz): 7.15 (2H, d, 3J=8.0 Hz, OPh), 7.05 (2H, d, 3J=8.0 Hz, OPh).

(637) .sup.13C-NMR (CDCl.sub.3; 75 MHz): 116.8 (o, OPh), 122.1 (m, OPh), 146.7 (p, OPh), 158.7 (ipso, OPh).

(638) Experimental data are given in Table I illustrating the activity of compounds embodying the present invention, and of some comparative compounds, with respect to human breast cancer cell line NDA MB231, human colon cancer cell line HT115 and human prostrate cancer cell line PC-3. The compounds include those whose preparations are described above and compounds made by preparative methods corresponding to the methods described above.

(639) The experimental procedures used human colon cancer cell line (HT115), human prostate cancer cell line (PC-3), human breast cancer cell line (MDA MB 231) and normal human umbilical vein endothelial cell (HUVEC). Compounds were diluted over a range of concentrations and added to cells over 1 to 3 days. The cytotoxity was determined using a MTT assay at the end of each experiment.

(640) In the Table:

(641) ArO refers to Ar as defined above with respect to formula I;

(642) J refers to the moiety of the present compounds represented by, respectively, ROCOCRRNH, as defined above with respect to formula I, or, with respect to Examples 51, 52 and 53, HOCOCRRNH, as defined above with respect to formula II; and

(643) B refers to the base moiety of the present compounds as defined above with respect to formula I or formula II.

(644) BVU stands for 2-bromovinyl uridine.

(645) 5-(CCC[O]O)MeU stands for methyl propenoate-2-deoxyuridine.

(646) GemCyt stands for Gemcitabine.

(647) Examples A, 1, 67 and G are comparative Examples.

(648) Example A is 5-(2-Bromovinyl)-2-deoxyuridine.

(649) Example 1 is Example 1 above corresponding to compound (7) above.

(650) Example 67 is propenate-2-deoxyuridine.

(651) Example G is gemcitabine.

(652) Examples 51, 52 and 53 are compounds embodying formula II above.

(653) TABLE-US-00001 TABLE EC50/M Breast EC50/M EC50/M MDA Colon Prostate Ex ArO J B MB231 HT115 PC-3 A BVU 125 78.7 120 1 PhO MeAlaNH BVU 79 244.5 155 2 PhO BnAlaNH BVU 34 1.4 19 3 PhO EtAlaNH BVU 56 52 36 4 p-CF3PhO BnAlaNH BVU 31 7.4 9.3 5 p-FPhO MeAlaNH BVU 159 17 58 6 p-FPhO EtAlaNH BVU 46 11 42 7 p-FPhO BnAlaNH BVU 17 3.5 16 8 p-NO2PhO BnAlaNH BVU 28 9 9 p-NO2PhO EtAlaNH BVU 177 118.7 365 10 p-NO2PhO MeAlaNH BVU 105 96.7 10.4 11 p-CIPhO EtAlaNH BVU 28.7 14.9 3.4 12 p-CIPhO BnAlaNH BVU 6.2 3.4 2.4 13 p-CIPhO MeAlaNH BVU 61 70.2 13 14 PhO Bn(Me2Gly)NH BVU 19 14.5 5.1 15 p-CF3PhO MeAlaNH BVU 47 79.2 15 16 PhO Me(cPntGly)NH BVU 79 77 16 17 PhO Et(cPntGly)NH BVU 44 81.3 41 18 PhO Bn(cPntGly)NH BVU 78 9.7 33 19 p-NO2PhO Me[cPntGly]NH BVU 56 38.2 88 20 p-NO2PhO Et[cPntGly)NH BVU 13 57.3 15 21 p-NO2PhO Bn[cPntGly]NH BVU 8.4 17.2 2.2 22 PFPhO Me[cPntGly]NH BVU 57 59.7 51 23 PFPhO Et[cPntGly]NH BVU 9.9 18.1 2.7 24 PFPhO Bn[cPntGly]NH BVU 9.4 17 3.7 25 p-CF3PhO EtAlaNH BVU 33.8 4.6 26 PhO Me(Me2Gly)NH BVU 41.1 77.9 1.5 27 PhO Et(Me2Gly)NH BVU 217.9 39.7 76.1 28 p-CF3PhO Me(cPntGly)NH BVU 28.8 21.2 29 p-CF3PhO Et(cPntGly)NH BVU 45.6 15.1 4.3 30 p-CF3PhO Bn(cPntGly)NH BVU 6.9 6.4 32 p-CIPhO Me[cPntGly]NH BVU 2.6 99.3 52.2 33 p-CIPhO Et[cPntGly]NH BVU 12 97.9 83.2 34 p-CIPhO Bn[cPntGly]NH BVU 3.9 8.9 6.3 35 PhO MeLeuNH BVU 18.5 7.7 75.7 36 PhO Me[Phe]NH BVU 19.8 32.1 86.9 37 PhO BnLeuNH BVU 2.8 7 7.16 38 p-NO2PhO BnLeuNH BVU 6.3 10.7 7.2 39 p-CIPhO BnLeuNH BVU 4.3 288.5 193.1 42 p-CIPhO Me(Me2Gly)NH BVU 8.7 183.4 441.6 43 p-CIPhO Et(Me2Gly)NH BVU 5.9 174.3 1.15 44 p-CIPhO Bn(Me2Gly)NH BVU 2.3 4.5 9.12 45 p-NO2PhO Me(Me2Gly)NH BVU 9.4 24.7 222.8 46 p-NO2PhO Et(Me2Gly)NH BVU 2 224 82.4 47 p-NO2PhO Bn(Me2Gly)NH BVU 4.5 16.7 27.2 48 p-CF3PhO Bn(Me2Gly)NH BVU 1.3 7 0.61 49 o-CIPhO BnAlaNH BVU 5.4 16.2 5.4 50 o-CIPhO Bn(Me2Gly)NH BVU 5.7 3.9 6.59 51 - L-AlaNH BVU 295.4 52 - LeuNH BVU 438.1 53 - PhAlaNH BVU 66 54 PhO Bn[PhAla]NH BVU 5.1 55 PhO Me[D-Ala]NH BVU 392.7 56 PhO Bn[D-Ala]NH BVU 20.8 57 p-NO2PhO Bn[D-Ala]NH BVU 20.2 58 p-CF3 Me[Me2Gly]NH BVU 83.6 59 p-CF3 Et[Me2Gly]NH BVU 24.7 60 p-FPhO Et[Me2Gly]NH BVU 86.8 61 p-CF3PhO Bn[L-PhAla]NH BVU 6.3 62 p-CF3PhO Bn[L-Leu]NH BVU 1.9 63 PhO tBu[L-Ala]NH BVU 31.5 64 p-NO2PhO Bn[L-PhAla]NH BVU 16.6 65 p-FPhO Me{Me2Gly)NH BVU 66 p-NO2PhO Me(Me2Gly)NH 5-(C 20.7 CC[O]O Me)U 67 5-(C 93.7 CC[O]O Me)U 69 PhO MeMetNH BVU 6.3 70 PhO MeTrpNH BVU 16 71 PhO BnMetNH BVU 6.3 72 PhO BnIleNH BVU 1.6 73 PhO EtIleNH BVU 30.6 74 PhO MeGlyNH BVU 31 75 PhO BnGlyNH BVU 29 77 p-Cl PhO BnGlyNH BVU 150 78 p-CF, PhO BnValNH BVU 1.6 80 PhO Me2AspNH BVU 158 81 PhO Et2GluNH BVU 31 82 m-CIPhO BnAlaNH BVU 21 83 m-CIPhO BnMe2GlyNH BVU 6.3 84 p-Fph0 BnMe2GlyNH BVU 4.5 85 PhO BnVaINH BVU 31.2 86 p-CIPho BnVaINH BVU 0.9 87 p-Fph0 BnVaINH BVU 1.6 88 PhO BnPhGlyNH BVU 0.75 89 p-CIPhO BnPhGlyNH BVU 6.5 91 p-CF3PhO BnPhGlyNH BVU 0.7 94 PhO i-BuAlaNH BVU 51 95 PhO 2-BuAlaNH BVU 6.8 G GemCyt 2.8 606.1 3.12 31 PhO BnAlaNH GemCyt 42.6 5.7 0.22 40 p-ClPhO BuAlaNH GemCyt 9.2 16.1 15.4 41 p-ClPhO Bn[Me2Gly]NH GemCyt 3.1 317.1 68.8

(654) Gemcitabine (Example G in the Table) and compound CPF31 (Example 31 in the Table: gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate) were compared in a mouse model with xenografts of human cancer (colon HT115 and prostrate PC3).

(655) Mice were dosed daily at a range of concentrations (0.01-10 M) and tumour volume assessed versus control.

(656) Kaplan-Meier statistics were computed regarding incident-free survival.

(657) In the attached drawings:

(658) FIG. 1 shows for the mouse xenograft the tumour volume for prostate data at day 13 using Gemzar (gemcitabine available ex. Lilly);

(659) FIG. 2 shows for the mouse xenograft the tumour volume for prostate data at day 13 using CPF31;

(660) FIG. 3 shows the incident free survival functions v. day for each of CPF31 and gemcitabine; and

(661) FIG. 4 shows for the mouse xenograft the tumour volume for colon data at day 24 using, respectively, Gemzar and compound CPF31.

(662) Referring to the drawings, CPF31 can be seen to be significantly less toxic than gemcitabine.

(663) CPF31 was significantly effective at reducing prostate and colon tumour volume relative to control at daily dosing of 5 and 10 M (3 and 6 g/ml). Gemcitabine was not effective at the highest non-toxic concentration.

(664) Gemzar is seen from FIG. 1 to be toxic above 1 M. In contrast, CPF31 is seen from FIG. 2 to have substantially lower toxicity.

(665) FIG. 3 shows that CPF31 has significantly lower side effects on a comparable basis: 3 animals show serious toxicity (10% body mass loss) in GMZ and in CPF31 on day 10, collectively 4 in GMZ and 1 in CPF31 on day 11 and 5 in GMZ and 1 in CPF on day 13. Using Chi square analysis by combining 5 and 10 M groups, the significance is p=0.193, 0,078 and 0.0289 on day 10, 11 and 13. It is clear that by day 13, CPF31 displayed signficantly less side effects, and the anti-cancer effects continue to exceed that of Gemzar.

(666) FIG. 3 shows the Kaplan-Meier survival curve, incidence free survival: based on the loss according to weight loss. A Cox proportion analysis shows that CPF31 is far less toxic than GMZ based on the weight-loss calculated loss (p=0.043).

(667) CPF31 was found to be active at 5 M in vitro, whereas Gemzar was found to be active at 600 M, with respect to the same colon cell line. FIG. 4 shows the results of testing both in vivo at 5 M. The greater activity of CPF31 in reducing tumour volume is shown in FIG. 4.