The compounds disclosed in the above United States Patent Application are inhibitors of the virally encoded protease, an essential enzyme that processes the gag/pol polyproteins to generate viral enzymes and structural proteins of the developing virus. Thus, the compounds have been shown to inhibit the HIV protease and are potential anti-HIV agents useful in treating AIDS. Particularly valuable as an anti-AIDS agent is (S)-3 -(2-tert-Butyl-4-hydroxymethyl-5-methyl- phenylsulfanyl)-4-hydroxy-6- [2-(4-hydroxy-phenyl)-ethyl] -6-isopropyl-5,6- dihydro-pyran-2-one.

Key intermediates in the preparation of the aforementioned compounds are substituted 5,6-dihydro-pyran-2-ones. A synthetic procedure for preparing these intermediates is disclosed in copending United States Patent Application Serial No. 08/883,743 filed June 27, 1997. This procedure has possible drawbacks including occasional low yields and the need for a resolution step.

We have surprisingly and unexpectedly found that the 5,6-dihydro-pyran- 2-ones of the present invention can be obtained by an enantioselective synthesis in high yield. Additionally, the chiral auxiliaries used in this process may be recycled.

The object of the present invention is an improved, efficient, and economical process for the preparation of substituted 5,6-dihydro-pyran-2-ones.

Thus, the present method avoids the disadvantages of the prior method and is amenable to large-scale synthesis, as well as for the preparation of radio-labeled compounds.

amenable to large-scale synthesis, as well as for the preparation of radio-labeled compounds.

SUMMARY OF THE INVENTION Accordingly, a first aspect of the present invention is an improved process for the preparation of a compound of Formula I wherein: R1 is H, 2- or 3- or 4- (CH2)n' OR' or (CH2)n' N(R')2 where n' is 0 or 1 and wherein 2- or 3- or 4- refer to the point of substitution on the phenyl ring; R2 and R3 are independently H, OR, N(R)2, a straight or branched alkyl of 1-4 carbons, a cycloalkyl of 3-6 carbons, F, C1, Br, NRCOR, COR, CON(R)2, OCOR, CO2R, NRSO2R, SO2N(R)2, NRSO3R, NRSO2N(R)2, NRCON(R)2, or R2 and R3 may be taken together to form a ring of 5-6 atoms optionally containing 1 or 2 heteroatoms; R4 is a straight or branched alkyl of 1-7 carbons, a cycloalkyl of 3-7 carbons, a heterocycle of 4-7 atoms containing 1-2 heteroatoms, or (CH2)nPh (phenyl) wherein n is zero or an integer of 1 to 3, all of which may be optionally substituted by F, Cl, Br, R, OR, SR, N(R)2, CON(R)2, NRCOR, SO2R, and COR; R is independently H, a straight or branched alkyl of 1-5 carbons, a -(CH2)n-cycloalkyl wherein the cycloalkyl is of 3-6 carbons and n is as defined above, -(CH2)m-Ph, a (CH2)m-heterocycle wherein the heterocycle is of 5-6 atoms with 1-3 heteroatoms and wherein m is zero or an integer of 1 to 3, and wherein the (R)2 in N(R)2 may be a heterocycle containing the nitrogen, all optionally substituted by F, C1, Br, =O (the =O represents a ketone), -CN, -CF3, OR', COR', N(R')2, CON(R')2, or NR'COR'; and R' is H, a straight or branched alkyl of 1-3 carbons, or Ph which comprises: Step (a) treating a compound of Formula XIV wherein PG is a protecting group and R4 is as defined above with the compound of Formula XIII in a solvent to afford a compound of Formula XII wherein PG and R4 are as defined above; Step (b) treating a compound of Formula XII with an oxidizing reagent in a solvent to afford a compound of Formula XI

Step (c) treating a compound of Formula XI with a Wittig type reagent in a solvent to afford a compound of Formula X wherein R4 is as defined above; Step (d) treating a compound of Formula X with a compound of Formula IX wherein R1, R2, and R3 are as defined above in a solvent to afford a compound of Formula VIII

wherein R1, R2, R3, and R4 are as defined above; Step (e) treating a compound of Formula VIII with a hydride reagent in a solvent to afford a compound of Formula VII wherein R1, R2, R3, and R4 are as defined above; Step (f) treating a compound of Formula VII with hydrogen in the presence of a catalyst in a solvent to afford a compound of Formula VI wherein R1, R2, R3, and R4 are as defined above; Step (g) treating a compound of Formula VI with a hydroxyl activating moiety in a solvent followed by addition of an alkali metal cyanide in a solvent to afford a compound of Formula V

wherein R1, R2, R3, and R4 are as defined above; Step (h) treating a compound of Formula V with a hydride reagent in a solvent to afford a compound of Formula IV wherein R1, R2, R3, and R4 are as defined above; Step (i) treating a compound of Formula IV with an oxidizing reagent in a solvent to afford a compound of Formula III wherein R1, R2, R3, and R4 are as defined above; Step (j) treating either a compound of Formula IV with the compound of Formula N2-CH2-C02-C2H5

in a solvent or treating the compound of Formula III with 1,1'-carbonyldiimidazole in a solvent and subsequent treatment of the imidazolide in situ with magnesium ethyl malonate in a solvent to afford a compound of Formula II wherein R1, R2, R3, and R4 are as defined above; and Step (k) treating a compound of Formula II with a base in a solvent followed by acidification with an acid to afford a compound of Formula I.

A second aspect of the present invention is a novel intermediate of Formula XII wherein: R4 is a straight or branched alkyl of 1-7 carbons, a cycloalkyl of 3-7 carbons, a heterocycle of 4-7 atoms containing 1-2 heteroatoms, or (CH2)nPh wherein n is zero or an integer of 1 to 3, all of which may be optionally substituted by F, C1, Br, R, OR, SR, N(R)2, CON(R)2, NRCOR, SO2R, and COR;

R is independently H, a straight or branched alkyl of 1-5 carbons, a -(CH2)n-cycloalkyl wherein the cycloalkyl is of 3-6 carbons and n is as defined above, -(CH2)m-Ph, a (CH2)m-heterocycle wherein the heterocycle is of 5-6 atoms with 1-3 heteroatoms and wherein m is zero or an integer of 1 to 3, and wherein the (R)2 in N(R)2 may be a heterocycle containing the nitrogen, all optionally substituted by F, C1, Br, =O (the =O represents a ketone), -CN, -CF3, OR', COR', N(R')2, CON(R')2, or NR'COR'; and R' is H, a straight or branched alkyl of 1-3 carbons, or Ph; and PG is a protecting group.

A third aspect of the present invention is a novel intermediate of Formula XI wherein: R4 is a straight or branched alkyl of 1-7 carbons, a cycloalkyl of 3-7 carbons, a heterocycle of 4-7 atoms containing 1-2 heteroatoms, or (CH2)nPh wherein n is zero or an integer of 1 to 3, all of which may be optionally substituted by F, C1, Br, R, OR, SR, N(R)2, CON(R)2, NRCOR, SO2R, and COR; R is independently H, a straight or branched alkyl of 1-5 carbons, a -(CH2)n-cycloalkyl wherein the cycloalkyl is of 3-6 carbons and n is as defined above, -(CH2)m-Ph, a (CH2)m-heterocycle wherein the heterocycle is of 5-6 atoms with 1-3 heteroatoms and wherein m is zero or an integer of 1 to 3, and wherein the (R)2 in N(R)2 may be a heterocycle

containing the nitrogen, all optionally substituted by F, C1, Br, =O (the =O represents a ketone), -CN, -CF3, OR', COR', N(R')2, CON(R')2, or NR'COR'; and R' is H, a straight or branched alkyl of 1-3 carbons, or Ph.

A fourth aspect of the present invention is a novel intermediate of Formula X wherein: R4 is a straight or branched alkyl of 1-7 carbons, a cycloalkyl of 3-7 carbons, a heterocycle of 4-7 atoms containing 1-2 heteroatoms, or (CH2)nPh wherein n is zero or an integer of 1 to 3, all of which may be optionally substituted by F, C1, Br, R, OR, SR, N(R)2, CON(R)2, NRCOR, S02R, and COR; R is independently H, a straight or branched alkyl of 1-5 carbons, a -(CH2)n-cycloalkyl wherein the cycloalkyl is of 3-6 carbons and n is as defined above, -(CH2)m-Ph, a (CH2)m-heterocycle wherein the heterocycle is of 5-6 atoms with 1-3 heteroatoms and wherein m is zero or an integer of 1 to 3, and wherein the (R)2 in N(R)2 may be a heterocycle containing the nitrogen, all optionally substituted by F, Cl, Br, =O (the =O represents a ketone), -CN, -CF3, OR', COR', N(R')2, CON(R')2, or NR'COR'; and R' is H, a straight or branched alkyl of 1-3 carbons, or Ph.

A fifth aspect of the present invention is a novel intermediate of Formula VIII wherein: R1 is H, 2- or 3- or 4- (CH2)n' OR' or (CH2)nt N(R')2 where n' is 0 or 1 and wherein 2- or 3- or 4- refer to the point of substitution on the phenyl ring; R2 and R3 are independently H, OR, N(R)2, a straight or branched alkyl of 1-4 carbons, a cycloalkyl of 3-6 carbons, F, Cl, Br, NRCOR, COR, CON(R)2, OCOR, CO2R, NRSO2R, SO2N(R)2, NRSO3R, NRSO2N(R)2, NRCON(R)2, or R2 and R3 may be taken together to form a ring of 5-6 atoms optionally containing 1 or 2 heteroatoms; R4 is a straight or branched alkyl of 1-7 carbons, a cycloalkyl of 3-7 carbons, a heterocycle of 4-7 atoms containing 1-2 heteroatoms, or (CH2)nPh wherein n is zero or an integer of 1 to 3, all of which may be optionally substituted by F, Cl, Br, R, OR, SR, N(R)2, CON(R)2, NRCOR, SO2R, and COR; R is independently H, a straight or branched alkyl of 1-5 carbons, a -(CH2)n-cycloalkyl wherein the cycloalkyl is of 3-6 carbons and n is as defined above, -(CH2)m-Ph, a (CH2)m-heterocycle wherein the heterocycle is of 5-6 atoms with 1-3 heteroatoms and wherein m is zero or an integer of 1 to 3, and wherein the (R)2 in N(R)2 may be a heterocycle containing the nitrogen, all optionally substituted by F, Cl, Br, =O (the =O represents a ketone), -CN, -CF3, OR', COR', N(R')2, CON(R')2, or NR'COR'; and

R' is H, a straight or branched alkyl of 1-3 carbons, or Ph.

A sixth aspect of the present invention is a novel intermediate of Formula VII wherein: R1 is H, 2- or 3- or 4- (CH2)nt OR' or (CH2)no N(R')2 where n' is 0 or 1 and wherein 2- or 3- or 4- refer to the point of substitution on the phenyl ring; R2 and R3 are independently H, OR, N(R)2, a straight or branched alkyl of 1-4 carbons, a cycloalkyl of 3-6 carbons, F, Cl, Br, NRCOR, COR, CON(R)2, OCOR, C02R, NRS02R, S02N(R)2, NRSO3R, NRSO2N(R)2, NRCON(R)2, or R2 and R3 may be taken together to form a ring of 5-6 atoms optionally containing 1 or 2 heteroatoms; R4 is a straight or branched alkyl of 1-7 carbons, a cycloalkyl of 3-7 carbons, a heterocycle of 4-7 atoms containing 1-2 heteroatoms, or (CH2)nPh wherein n is zero or an integer of 1 to 3, all of which may be optionally substituted by F, Cl, Br, R, OR, SR, N(R)2, CON(R)2, NRCOR, SO2R, and COR; R is independently H, a straight or branched alkyl of 1-5 carbons, a -(CH2)n-cycloalkyl wherein the cycloalkyl is of 3-6 carbons and n is as defined above, -(CH2)m-Ph, a (CH2)m-heterocycle wherein the heterocycle is of 5-6 atoms with 1-3 heteroatoms and wherein m is zero or an integer of 1 to 3, and wherein the (R)2 in N(R)2 may be a heterocycle containing the nitrogen, all optionally substituted by F, Cl, Br, =O (the =O

represents a ketone), -CN, -CF3, OR', COR', N(R')2, CON(R')2, or NR'COR'; and R' is H, a straight or branched alkyl of 1-3 carbons, or Ph.

A seventh aspect of the present invention is a novel intermediate of Formula VI wherein: R1 is H, 2- or 3- or 4- (CH2)n' OR' or (CH2)n' N(R')2 where n' is 0 or 1 and wherein 2- or 3- or 4- refer to the point of substitution on the phenyl ring; R2 and R3 are independently H, OR, N(R)2, a straight or branched alkyl of 1-4 carbons, a cycloalkyl of 3-6 carbons, F, Cl, Br, NRCOR, COR, CON(R)2, OCOR, CO2R, NRSO2R, SO2N(R)2, NRSO3R, NRSO2N(R)2, NRCON(R)2, or R2 and R3 may be taken together to form a ring of 5-6 atoms optionally containing 1 or 2 heteroatoms; R4 is a straight or branched alkyl of 1-7 carbons, a cycloalkyl of 3-7 carbons, a heterocycle of 4-7 atoms containing 1-2 heteroatoms, or (CH2)nPh wherein n is zero or an integer of 1 to 3, all of which may be optionally substituted by F, C1, Br, R, OR, SR, N(R)2, CON(R)2, NRCOR, SO2R, and COR; R is independently H, a straight or branched alkyl of 1-5 carbons, a -(CH2)n-cycloalkyl wherein the cycloalkyl is of 3-6 carbons and n is as defined above, -(CH2)m-Ph, a (CH2)m-heterocycle wherein the heterocycle is of 5-6 atoms with 1-3 heteroatoms and wherein m is zero or

an integer of 1 to 3, and wherein the (R)2 in N(R)2 may be a heterocycle containing the nitrogen, all optionally substituted by F, C1, Br, =O (the =O represents a ketone), -CN, -CF3, OR', COR', N(R')2, CON(R')2, or NR'COR'; and R' is H, a straight or branched alkyl of 1-3 carbons, or Ph.

An eighth aspect of the present invention is a novel intermediate of Formula V wherein: R1 is H, 2- or 3- or 4- (CH2)nt OR' or (CH2)n' N(R')2 where n' is 0 or 1 and wherein 2- or 3- or 4- refer to the point of substitution on the phenyl ring; R2 and R3 are independently H, OR, N(R)2, a straight or branched alkyl of 1-4 carbons, a cycloalkyl of 3-6 carbons, F, C1, Br, NRCOR, COR, CON(R)2, OCOR, CO2R, NRS02R, SO2N(R)2, NRSO3R, NRSO2N(R)2, NRCON(R)2, or R2 and R3 may be taken together to form a ring of 5-6 atoms optionally containing 1 or 2 heteroatoms; R4 is a straight or branched alkyl of 1-7 carbons, a cycloalkyl of 3-7 carbons, a heterocycle of 4-7 atoms containing 1-2 heteroatoms, or (CH2)nPh wherein n is zero or an integer of 1 to 3, all of which may be optionally substituted by F, C1, Br, R, OR, SR, N(R)2, CON(R)2, NRCOR, SO2R, and COR; R is independently H, a straight or branched alkyl of 1-5 carbons, a -(CH2)n-cycloalkyl wherein the cycloalkyl is of 3-6 carbons and n is as

defined above, -(CH2)m-Ph, a (CH2)m-heterocycle wherein the heterocycle is of 5-6 atoms with 1-3 heteroatoms and wherein m is zero or an integer of 1 to 3, and wherein the (R)2 in N(R)2 may be a heterocycle containing the nitrogen, all optionally substituted by F, C1, Br, =O (the =O represents a ketone), -CN, -CF3, OR', COR', N(R')2, CON(R')2, or NR'COR'; and R' is H, a straight or branched alkyl of 1-3 carbons, or Ph.

A ninth aspect of the present invention is a novel intermediate of Formula IV wherein: R1 is H, 2- or 3- or 4- (CH2)n' OR' or (CH2)n' N(R')2 where n' is 0 or 1 and wherein 2- or 3- or 4- refer to the point of substitution on the phenyl ring; R2 and R3 are independently H, OR, N(R)2, a straight or branched alkyl of 1-4 carbons, a cycloalkyl of 3-6 carbons, F, Cl, Br, NRCOR, COR, CON(R)2, OCOR, CO2R, NRSO2R, SO2N(R)2, NRS03R, NRSO2N(R)2, NRCON(R)2, or R2 and R3 may be taken together to form a ring of 5-6 atoms optionally containing 1 or 2 heteroatoms; R4 is a straight or branched alkyl of 1-7 carbons, a cycloalkyl of 3-7 carbons, a heterocycle of 4-7 atoms containing 1-2 heteroatoms, or (CH2)nPh wherein n is zero or an integer of 1 to 3, all of which may be optionally substituted by F, Cl, Br, R, OR, SR, N(R)2, CON(R)2, NRCOR, S02R, and COR;

R is independently H, a straight or branched alkyl of 1-5 carbons, a -(CH2)n-cycloalkyl wherein the cycloalkyl is of 3-6 carbons and n is as defined above, -(CH2)m-Ph, a (CH2)m-heterocycle wherein the heterocycle is of 5-6 atoms with 1-3 heteroatoms and wherein m is zero or an integer of 1 to 3, and wherein the (R)2 in N(R)2 may be a heterocycle containing the nitrogen, all optionally substituted by F, C1, Br, =O (the =O represents a ketone), -CN, -CF3, OR', COR', N(R')2, CON(R')2, or NR'COR'; and R' is H, a straight or branched alkyl of 1-3 carbons, or Ph.

A tenth aspect of the present invention is a novel intermediate of Formula III wherein: R1 is H, 2- or 3- or 4- (CH2)nt OR' or (CH2)nZ N(R')2 where n' is 0 or 1 and wherein 2- or 3- or 4- refer to the point of substitution on the phenyl ring; R2 and R3 are independently H, OR, N(R)2, a straight or branched alkyl of 1-4 carbons, a cycloalkyl of 3-6 carbons, F, Cl, Br, NRCOR, COR, CON(R)2, OCOR, C02R, NRSO2R, SO2N(R)2, NRSO3R, NRSO2N(R)2, NRCON(R)2, or R2 and R3 may be taken together to form a ring of 5-6 atoms optionally containing 1 or 2 heteroatoms; R4 is a straight or branched alkyl of 1-7 carbons, a cycloalkyl of 3-7 carbons, a heterocycle of 4-7 atoms containing 1-2 heteroatoms, or (CH2)nPh wherein n is zero or an integer of 1 to 3, all of which may be optionally

substituted by F, Cl, Br, R, OR, SR, N(R)2, CON(R)2, NRCOR, S02R, and COR; R is independently H, a straight or branched alkyl of 1-5 carbons, a -(CH2)n-cycloalkyl wherein the cycloalkyl is of 3-6 carbons and n is as defined above, -(CH2)m-Ph, a (CH2)m-heterocycle wherein the heterocycle is of 5-6 atoms with 1-3 heteroatoms and wherein m is zero or an integer of 1 to 3, and wherein the (R)2 in N(R)2 may be a heterocycle containing the nitrogen, all optionally substituted by F, C1, Br, =O (the =O represents a ketone), -CN, -CF3, OR', COR', N(R')2, CON(R')2, or NR'COR'; and R' is H, a straight or branched alkyl of 1-3 carbons, or Ph.

An eleventh aspect of the present invention is a novel intermediate of Formula II wherein: R1 is H, 2- or 3- or 4- (CH2)n' OR' or (CH2)n' N(R')2 where n' is 0 or 1 and wherein 2- or 3- or 4- refer to the point of substitution on the phenyl ring; R2 and R3 are independently H, OR, N(R)2, a straight or branched alkyl of 1-4 carbons, a cycloalkyl of 3-6 carbons, F, Cl, Br, NRCOR, COR, CON(R)2, OCOR, C02R, NRSO2R, SO2N(R)2, NRSO3R, NRSO2N(R)2, NRCON(R)2, or R2 and R3 may be taken together to form a ring of 5-6 atoms optionally containing 1 or 2 heteroatoms;

R4 is a straight or branched alkyl of 1-7 carbons, a cycloalkyl of 3-7 carbons, a heterocycle of 4-7 atoms containing 1-2 heteroatoms, or (CH2)nPh wherein n is zero or an integer of 1 to 3, all of which may be optionally substituted by F, Cl, Br, R, OR, SR, N(R)2, CON(R)2, NRCOR, S02R, and COR; R is independently H, a straight or branched alkyl of 1-5 carbons, a -(CH2)n-cycloalkyl wherein the cycloalkyl is of 3-6 carbons and n is as defined above, -(CH2)m-Ph, a (CH2)m-heterocycle wherein the heterocycle is of 5-6 atoms with 1-3 heteroatoms and wherein m is zero or an integer of 1 to 3, and wherein the (R)2 in N(R)2 may be a heterocycle containing the nitrogen, all optionally substituted by F, Cl, Br, =O (the =O represents a ketone), -CN, -CF3, OR', COR', N(R')2, CON(R')2, or NR'COR'; and R' is H, a straight or branched alkyl of 1-3 carbons, or Ph.

DETAILED DESCRIPTION OF THE INVENTION In this invention, the term "alkyl" means a straight or branched hydrocarbon radical having from 1-12 carbon atoms unless otherwise specified and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, undecyl, and dodecyl. The alkyl groups may contain one or more sites of unsaturation such as double or triple carbon-carbon bonds. The alkyl group is unsubstituted or substituted by from 1-3 substituents selected from alkyl, alkoxy, thioalkoxy all as defined herein, hydroxy, thiol, nitro, halogen, amino, formyl, carboxyl, nitrile, -NH-CO-R, -CO-NH-, -CO2R, -COR, aryl, or heteroaryl wherein alkyl (R), aryl, and heteroaryl are as defined herein.

The term "cycloalkyl" means a hydrocarbon ring which contains from 3-12 carbon atoms unless otherwise specified, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl. Where possible, the

cycloalkyl group may contain double bonds. The cycloalkyl ring may be unsubstituted or substituted by from 1-3 substituents selected from alkyl, alkoxy, thioalkoxy all as defined herein, hydroxy, thiol, nitro, halogen, amino, formyl, carboxyl, nitrile, -NH-CO-R, -CO-NHR-, -C02R, -COR, aryl, or heteroaryl wherein alkyl (R), aryl, and heteroaryl are as defined herein.

The term "alkylcycloalkyl" means a cycloalkyl group as defined above attached directly to an alkyl group as defined above.

The terms "alkoxy" and "thioalkoxy" are O-alkyl or S-alkyl as defined above for alkyl.

The term "spirocycle" refers to a carbocyclic or heterocyclic ring whose ends meet at a single carbon in a chain or another ring.

The terms "heteroaryl" and "heterocycle" mean a heterocyclic radical which is 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isaxazolyl, 3- or 5- 1,2,4-triazolyl, 4- or 5- 1,2,3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridinyl, 3-, 4-, or 5-pyridazinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-, or 7-benzothiazolyl, 1- or 2-piperazinyl, 2-, 3-, or 4-morpholinyl, 2-, 3-, or 4-thiomorpholinyl, 1-, 2-, or 3-pyrrolidinyl, 2- or 3-tetrahydrofuranyl, 2-, 3-, or 4-tetrahydropyranyl, 2- 3-, or 4-piperidinyl, 1-, 2-, 4-, 5-, or 6-tetrahydropyrimidinyl, 2-dioxolinyl, 2-, 4-, or 5-imidazolidinyl, 1-, 2-, 3-, 4-, 5-, 6-, or 7-indolinyl, unsubstituted or substituted by 1-2 substituents selected from alkyl as defined above, aryl as defined herein, alkoxy as defined above, thioalkoxy as defined above, hydroxy, thiol, nitro, halogen, formyl, amino, carboxyl, nitrile, -NHCOR, -CO2R, -COR, wherein alkyl is as defined above or phenyl. For heterocycles containing sulfur, the oxidized sulfur heterocycles containing SO or S02 groups are also included.

The term "aryl" means an aromatic radical which is a phenyl group, a phenyl group substituted by 1 to 4 substituents selected from alkyl as defined

above, alkoxy as defined above, thioalkoxy as defined above, hydroxy, halogen, trifluoromethyl, amino, alkylamino as defined above for alkyl, dialkylamino as defined above for alkyl, nitro, cyano, carboxy, S03H, 0 CHO, C-alkyl as defined above for alkyl, 0 0 0 II II II -C-NH2, -C-NH-alkyl, NH-C-alkyl, as defined above for 0 alkyl, -C-N(alkyl)2 as defined above for alkyl, -(CH2)n2-NH2 wherein n2 is an integer of 1 to 5, -(CH2)n2-NH-alkyl as defined above for alkyl and n2, -CH2)n2-N(alkyl)2 as defined above for alkyl and n2, 0 -(CH2)n2-NH-C-alkyl as defined above for alkyl, and n2 and 0 -(CH2)n2-N-C-alkyl I alkyl as defined above for alkyl and n2.

"Halogen" is fluorine, chlorine, bromine, or iodine.

"Alkali metal" is a metal in Group IA of the periodic table and includes, for example, lithium, sodium, potassium and the like.

"Alkaline-earth metal" is a metal in Group IIA of the periodic table and includes, for example, calcium, barium, strontium, and the like.

"Silyl protecting group" is a silyl ether commonly used to protect a hydroxyl functionality such as, for example, trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tertiary-butyldimethylsilyl, and the like.

"Jones reagent" refers to oxidations using chromic acid and sulfuric acid in water in acetone.

Some of the compounds of Formula 1 are capable of further forming pharmaceutically acceptable acid-addition and/or base salts. All of these forms are within the scope of the present invention.

Pharmaceutically acceptable acid addition salts of the compounds of the present invention include salts derived from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinates suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzensoulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like.

Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge S.M., et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1977).

The acid addition salt of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner.

Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like.

Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge S.M., et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1977).

The base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner.

Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated

forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.

Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in the R(D) or S(L) configuration. The present invention includes all enantiomeric and epimeric forms as well as the appropriate mixtures thereof.

A preferred compound of Formula I prepared by the improved process of the present invention is one wherein R1 is H, 2- or 3- or 4- (CH2)n' OH' or (CH2)nt NH2 where n' is 0 or 1; R2 and R3 are independently H, an alkyl of 1-3 carbons, F, C1 Br, or R2 and R3 may be taken together to form a 5-membered ring optionally containing 1 or 2 heteroatoms; R4 is a straight or branched alkyl of 1-7 carbons, a cycloalkyl of 3-7 carbons, a heterocycle of 4-7 atoms containing 1-2 heteroatoms, or (CH2)nPh wherein n is zero or an integer of 1 to 2, all of which may be optionally substituted by F, C1, Br, R, OR, SR, N(R)2, CON(R)2, NRCOR, SO2R, and COR; R is independently H, a straight or branched alkyl of 1-5 carbons, a -(CH2)m-cycloalkyl wherein the cycloalkyl is of 3-6 carbons and wherein m is zero or an integer of 1 to 3, -(CH2)m-Ph, a (CH2)m-heterocycle wherein the heterocycle is of 5-6 atoms with 1-3 heteroatoms and wherein m is zero or an integer of 1 to 3, and wherein the (R)2 in N(R)2 may be a heterocycle containing the nitrogen, all optionally substituted by F, C1, Br, -CN, -CF3, OR', COR', N(R')2, CON(R')2, NR'COR'; and R' is H, a straight or branched alkyl of 1-3 carbons, or Ph.

Another preferred compound of Formula I prepared by the improved process of the present invention is one wherein R1 is H, 3- or 4- (CH2)nt OH or (CH2)nt NH2 where n' is 0 or 1; R2 and R3 are independently H, an alkyl of 1-3 carbons, F, C1, or Br;

R4 is a straight or branched alkyl of 1-5 carbons, a cycloalkyl of 3-6 carbons, a heterocycle of 5-6 carbons containing one heteroatom or Ph, all of which may be optionally substituted by OR, N(R)2, SO2R, and COR; R is independently H, a straight or branched alkyl of 1-5 carbons, a -(CH2)m-cycloalkyl wherein the cycloalkyl is of 3-6 carbons and wherein m is zero or an integer of 1 to 3, -(CH2)m-Ph, a (CH2)m-heterocycle wherein the heterocycle is of 5-6 atoms with 1-3 heteroatoms and wherein m is as defined above, and wherein the (R)2 in N(R)2 may be a heterocycle containing the nitrogen, all optionally substituted by F, C1, Br, -CN, -CF3, OR', COH, N(R')2, CON(R')2, or NR'COR'; and R' is H, a straight or branched alkyl of 1-3 carbons, or Ph.

Another preferred compound of Formula I prepared by the improved process of the present invention is one wherein R1 is H; R2 and R3 are H; R4 is phenyl or pyridinyl optionally substituted by OR, SR, N(R)2, CON(R)2, NRCOR, SO2R, or COR; R is a (CH2)m-heterocycle of 5-6 atoms with 1-2 heteroatoms optionally substituted by OR', N(R')2, CON(R')2, or NR'COR'; mis an integer of from 2 to 3; and R' is H, a straight or branched alkyl of 1-3 carbons, or Ph.

A still further preferred compound of Formula I prepared by the improved process of the present invention is one wherein R1 is 3- or 4- (CH2)nROH or a (CH2)nRNH2 where n' is 0 or 1; R2 and R3 are independently H, an alkyl of 1-3 carbons, F, C1, or Br; R4 is a straight or branched alkyl of 1-6 carbons, or a cycloalkyl of 3-6 carbons.

Another preferred compound of Formula I prepared by the improved process of the present invention is one wherein

R1 is 3- or 4- (CH2)ntOH or a (CH2)ntNH2 where n' is 0 or 1; R2 and R3 are H; and R4 is a straight or branched alkyl of 1-6 carbons, or a cycloalkyl of 3-6 carbons.

A most preferred compound of Formula I prepared by the improved process of the present invention is one wherein R1 is 4-OH or NH2; R2 and R3 are H; and R4 is isopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

A second preferred compound of Formula I prepared by the improved process of the present invention is one wherein R1 is 3-OH or NH2; R2 and R3 are H; and R4 is isopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

Particularly preferred compounds of Formula I prepared by the improved process of the present invention are selected from the group consisting of: (S)-4-Hydroxy-6- [2-(4-hydroxy-phenyl)-ethyl] -6-methyl-S ,6-dihydro- pyran-2-one; (S)-4-Hydroxy-6- [2-(4-hydroxy-phenyl)-ethyl] -6-isopropyl-5 ,6-dihydro- pyran-2-one; (S)- 6-Butyl-4-hydroxy- 6- [2-(4-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran- 2-one; (S)-6-Cyclohexyl-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl] -5 ,6-dihydro- pyran-2-one; (S)-N-(4- [2-(4-Hydroxy-6-oxo-2-phenyl-3 ,6-dihydro-2H-pyran-2-yl)- ethyl] -phenyl) -acetamide; <BR> <BR> <BR> <BR> (S)-6- (4- [2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy] -phenyl } -4-hydroxy- <BR> <BR> <BR> <BR> <BR> <BR> 6-phenethyl-5 ,6-dihydro-pyran-2-one; <BR> <BR> <BR> <BR> <BR> (S)-4-Hydroxy-6- [2-(4-hydroxy-phenyl)-ethyl] -6-phenyl-5, 6-dihydro- pyran-2-one;

(S)-4-Hydroxy-6- [2-(3 -hydroxy-phenyl)-ethyl] -6-phenyl-5 ,6-dihydro- pyran-2-one; (S)-4-Hydroxy-6-phenethyl-6-phenyl-5 ,6-dihydro-pyran-2-one; (S)-4-(2- { [4-Hydroxy-6-oxo-2-phenethyl-3 ,6-dihydro-2H-pyran-2-yl] - phenoxy) ethyl)-piperazine-l -carboxylic acid tert-butyl ester; (S)-4-Hydroxy-6-(3 -methyl-butyl)-6-phenethyl-5 ,6-dihydro-pyran-2-one; (S)-((4-[2-(4-Hydroxy-2-isopropyl-6-oxo-3,6-dihydro-2H-pyran -2-yl) ethyl] -phenyl)-carbamic acid tert-butyl ester; (S)-6-[2-(3 -Benzyloxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-5,6- dihydro-pyran-2-one; and (S)-6-Cyclopentyl-4-hydroxy-6- [2-(3 -hydroxy-phenyl)-ethyl] -5,6- dihydro-pyran-2-one.

The following list contains abbreviations and acronyms used within the schemes and text: TBDMSi C1 tert-Butyldimethylsilyl chloride Zn 12 Zinc iodide CH2C12 Methylene dichloride THF Tetrahydrofuran NaClO2 Sodium chlorite DMF Dimethylformamide NaH Sodium hydride NO4 CM Ammonium chloride n-Bu4NF Tetrabutylammonium fluoride DMSO Dimethylsulfoxide EtOAc Ethyl acetate TiC14 Titanium tetrachloride 1H-NMR Proton nuclear magnetic resonance NaOH Sodium hydroxide K2C03 Potassium carbonate TLC Thin layer chromatography Pd/C Palladium on carbon KCN Potassium cyanide Cr03 Chromium trioxide HCl Hydrogen chloride Ph Phenyl Mesyl chloride Methanesulfonyl chloride Tosyl chloride para-Toluenesulfonyl chloride L-Selectride Lithium tri sec-butylborohydride The process of the present invention is a new, improved, economical, and commercially feasible method for preparing substituted 5,6-dihydro-2H-pyran-2- ones. The process of the present invention is outlined in the following Scheme 1.

Scheme 1 Scheme 1 (cont'd)

Thus, a compound of Formula XIV wherein R4 is a straight or branched alkyl of 1-7 carbons, a cycloalkyl of 3-7 carbons, a heterocycle of 4-7 atoms containing 1-2 heteroatoms, or (CH2)nPh wherein n is zero or an integer of 1 to 3, all of which may be optionally substituted by F, Cl, Br, R, OR, SR, N(R)2, CON(R)2, NRCOR, S02R and COR; R is independently H, a straight or branched alkyl of 1-5 carbons, a -(CH2)n-cycloalkyl wherein the cycloalkyl is of 3-6 carbons and wherein n is as defined above, -(CH2)m-Ph, a (CH2)m-heterocycle wherein the heterocycle is of 5-6 atoms with 1-3 heteroatoms and wherein m is zero or an integer of 1 to 3, and wherein the (R)2 in N(R)2 may be a heterocycle containing the nitrogen, all optionally substituted by F, C1, Br, =O (the =O represents a ketone), -CN, -CF3, OR', COR', N(R')2, CON(R')2, or NR'COR'; and R' is H, a straight or branched alkyl of 1-3 carbons, or Ph; and PG is an alcohol protecting group such as, for example, tert-butyldimethylsilyl, a tetrahydropyranyl protecting group, a ketal protecting group, a hemi-ketal protecting group and the like is treated with the compound of Formula XIII in a solvent such as, for example, diethyl ether, tetrahydrofuran, toluene and the like in the presence of a base such as, for example, sodium hydride and the like to afford a compound of Formula XII wherein R4 and PG are as defined above. Preferably, the reaction is carried out in toluene in the presence of sodium hydride.

Treatment of a compound of Formula XII with an oxidizing reagent such as, for example, Swern reagent, pyridinium dichromate, pyridinium chromate and the like in a solvent such as, for example, methylene chloride, dimethylformamide, pyridine, and the like to afford a compound of Formula XI wherein R4 is as defined above. Preferably, the reaction is carried out using Swern oxidation conditions in methylene chloride.

Treatment of a compound of Formula XI with a Wittig type reagent such as, for example, zinc-diiodomethane or methylene dibromide-titanium tetrachloride, a Nysted reagent ({cyclo-dibromodi ,u-methylene[R- (tetrahydrofuran)]trizinc}), a Wittig reagent, a Peterson reagent, and the like in a solvent such as, for example, diethyl ether, tetrahydrofuran, methylene chloride and the like to afford a compound of Formula X wherein R4 is as defined above.

Preferably, the reaction is carried out with zinc-diiodomethane-titanium tetrachloride in tetrahydrofuran.

Treatment of a compound of Formula X with a compound of Formula IX wherein R1 is H, 2- or 3- or 4- (CH2)n' OR' or (CH2)nt N(R')2 where n' is 0 or 1 and wherein 2- or 3- or 4- refer to the point of substitution on the phenyl ring; R2 and R3 are independently H, OR, N(R)2, a straight or branched alkyl of 1-4 carbons, a cycloalkyl of 3-6 carbons, F, C1, Br, NRCOR, COR, CON(R)2, OCOR, C02R, NRS02R, S02N(R)2, NRS03R, NRSO2N(R)2, NRCON(R)2, or R2 and R3 may be taken together to form a ring of 5-6 atoms optionally containing 1 or 2 heteroatoms; R is independently H, a straight or branched alkyl of 1-5 carbons, a -(CH2)n-cycloalkyl wherein n is zero or an integer of 1 to 3 and cycloalkyl is of 3-6 carbons, -(CH2)m-Ph, a (CH2)m-heterocycle wherein the heterocycle is of 5-6 atoms with 1-3 heteroatoms and wherein m is zero or an integer of 1 to 3, and wherein the (R)2 in N(R)2 may be a heterocycle containing the nitrogen, all optionally substituted by F, C1, Br, =O (the =O represents a ketone), -CN, -CF3, OR', COR', N(R')2, CON(R')2, or NR'COR'; and R' is H, a straight or branched alkyl of 1-3 carbons, or Ph in the presence of a base such as, for example, a trialkylamine, for example, triethylamine and the like in a solvent such as, for example, hexane, cyclohexane, toluene,

diethyl ether and the like to afford a compound of Formula VIII wherein R1, R2, R3, and R4 are as defined above.

Treatment of a compound of Formula VIII with a hydride reagent such as, for example, L-selectride, lithium aluminum hydride, lithium borohydride with a mole of water and the like in a solvent such as, for example, diethyl ether, tetrahydrofuran and the like to afford a compound of Formula VII wherein R, R1, R2, and R3 are as defined above. Preferably, the reaction is carried out with L-selectride in tetrahydrofuran.

Treatment of a compound of Formula VII with hydrogen in the presence of a catalyst such as, for example, palladium on charcoal and the like in a solvent such as, for example, methanol, ethanol, tetrahydrofuran and mixtures thereof and the like to afford a compound of Formula VI wherein R1, R2, R3, and R4 are as defined above. Preferably, the reaction is carried out in the presence of about 20% palladium on charcoal in methanol.

Treatment of a compound of Formula VI with a hydroxyl activating moiety such as, for example, mesyl chloride, tosyl chloride, triphenyl phosphine and the like in a solvent such as, for example, methylene chloride, tetrahydrofuran and the like in the presence of a base such as, for example, diisopropylethylamine and the like followed by the addition of an alkali metal cyanide such as, for example, sodium cyanide, potassium cyanide or ammonium cyanide and the like in a solvent such as, for example, dimethylsulfoxide, dimethylformamide, acetonitrile and the like to afford a compound of Formula V wherein R1, R2, R3, and R4 are as defined above. Preferably, the reaction is carried out with mesyl chloride in methylene chloride in the presence of diisopropylethylamine followed by optional removal of the solvent and isolation of the mesylate followed by addition of potassium cyanide in dimethylsulfoxide.

Treatment of a compound of Formula V with a hydride reagent such as, for example, diisobutylaluminum hydride and the like in a solvent such as, for example, toluene, tetrahydrofuran, methylene chloride and the like to afford a compound of Formula IV wherein R1, R2, R3, and R4 are as defined above.

Preferably, the reaction is carried out with diisobutylaluminum hydride in tetrahydrofuran.

Treatment of a compound of Formula IV with an oxidizing reagent such as, for example, Jones reagent, sodium chlorite and hydrogen peroxide and the like in a solvent such as, for example, acetone, acetonitrile and water, pyridine, acetic acid and the like to afford a compound of Formula III wherein R1, R2, R3, and R4 are as defined above. Preferably, the reaction is carried out with Jones reagent in acetone.

Treatment of a compound of Formula III with 1, l'-carbonyldiimidazole in a solvent such as, for example, tetrahydrofuran and the like followed by the addition of ethyl magnesium malonate to afford a compound of Formula II wherein R1, R2, R3, and R4 are as defined above. Preferably, the reaction is carried out in tetrahydrofuran. Alternatively, a compound of Formula II is obtained by treating a compound of Formula IV with ethyl diazoacetate in a solvent such as, for example, methylene chloride.

Treatment of a compound of Formula II with a base such as, for example, sodium hydroxide and the like in a solvent such as, for example, tetrahydrofuran and water followed by acidification with an acid such as, for example, hydrochloric acid, a dibasic phosphate and the like affords a compound of Formula I. Preferably, the reaction is carried out with sodium hydroxide in tetrahydrofuran and water followed by acidification with hydrochloric acid.

The protected hydroxy acid of Formula XV is prepared as shown in Scheme 2 by treating an aldehyde of Formula XVII wherein R4 is as defined above with an alkali metal cyanide such as, for example, potassium cyanide and a silylating reagent such as, for example, tert-butyldimethylsilyl chloride and the like in the presence of zinc iodide in a solvent such as, for example, acetonitrile and the like to afford a compound of Formula XVI wherein PG is a silyl protecting group such as, for example, a silyl ether, and R4 is as defined above. Preferably, the reaction is carried out with potassium cyanide in acetonitrile.

Treatment of a compound of Formula XVI with a hydride reagent such as, for example, diisobutylaluminum hydride in a solvent such as, for example,

methylene chloride and the like followed by oxidation of the aldehyde with an oxidizing reagent such as, for example, hydrogen peroxide and sodium chlorite and the like to afford a compound of Formula XV wherein R4 is as defined above.

Preferably, the reaction is carried out with diisobutylaluminum hydride in methylene chloride followed by hydrogen peroxide and sodium chlorite oxidation.

Scheme 2 Treatment of the acid of Formula XV with an acid chloride forming reagent such as, for example, oxalyl chloride and the like in a solvent such as, for example, dimethylformamide and the like affords a compound of Formula XIV wherein R4 is as defined above. Preferably, the reaction is carried out with oxalyl chloride in dimethylformamide.

A compound of Formula IX or the compound of Formula XIII can be obtained from commercial sources or prepared by methods generally known to one skilled in the art.

The aforementioned procedures illustrate the preparation of the S-enantiomer of a compound of Formula I. It is within the skill of the art to use the process of the present invention to prepare the R-enantiomer of a compound of Formula I by employing the appropriate chiral auxiliary.

Copending United States Patent Application Serial Number 08/883,743 discloses the use of substituted 5,6-dihydro-2H-pyran-2-ones in the preparation of dihydropyrones which are useful as anti-HIV agents in the treatment of AIDS.

The following examples are illustrative to show the present process, the preparation of starting materials, and the use of (6S)-6-[2-(4-hydroxy-phenyl)- ethyl]-6-isopropyl-dihydro-pyran-2,4-dione obtained by the present process to

prepare a dihydropyrone, i.e., (S)-3 -(2-tert-butyl-4-hydroxymethyl-5 -methyl- phenylsulfanyl)-4-hydroxy-6 [2-(4-hydroxy-phenyl)-ethyl] -6-isopropyl-5 ,6- dihydro-pyran-2-one which is useful as an anti-HIV agent in the treatment of AIDS.

PREPARATION OF STARTING MATERIALS EXAMPLE A 2-(tert-Butvl-dimethyl-silanvloxv!-3-methyl-butync acid Step A: Preparation of 2-(tert-Butvl-dimethyl-silanyloxy)-3 -methyl-butyronitrile Isobutyraldehyde (19.04 g) was dissolved in dry acetonitrile (800 mL).

Potassium cyanide, 85.9 g (5 eq.), TBDMSi C1, 50 g (1.2 eq.), and anhydrous ZnI2 (1.2 g) were added. The reaction was stirred with a mechanical stirrer overnight at room temperature and filtered to remove solid. It was concentrated on a rotary to an oil, and diethyl ether (500 mL) was added. It was filtered to remove solid which separated. The filtrate was washed with water (200 mL) and dried with anhydrous sodium sulfate. Solvent was removed on a rotary, and the crude product was applied to a column of silica gel. It was eluted with hexane/methylene chloride (1:1) to afford the title compound (40.06 g, 76%).

Step B: Preparation of 2-(tert-Butvl-dimethvl-silanyloxy)-3 -methyl-butvric acid 2-(tert-Butyl-dimethyl-silanyloxy)-3 -methyl-butyronitrile (15.0 g) was dissolved in CH2C12 and cooled to -780C under argon atmosphere.

Diisobutylaluminum hydride (DIBAL-H), 1.0 M solution in THF (84.5 mL) was added and stirred at the same temperature for 3 hours. It was poured into a saturated solution of sodium potassium tartrate (400 mL), diluted with methylene chloride (400 mL), and the resulting heterogeneous mixture was stirred vigorously for 1.5 hours. The aqueous portion was extracted with methylene chloride, 3 x 300 mL, and the combined organic phase was washed with brine several times (no more gel formation) and then dried. It was filtered through a pad of Celite and evaporated to afford the aldehyde (13.5 g, 88%). The aldehyde was dissolved in

acetonitrile/water (450:72 v/v) and 2.3 g (0.10 eq.) was added and cooled to 0°C in ice water bath. Hydrogen peroxide (30%), 7.29 mL (1.10 eq.), was added followed by NaClO2, 8.46 g (1.5 eq.). The mixture was stirred vigorously for 2 hours at room temperature and partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate, 3 x 200 mL. The combined organic phase was washed with saturated ammonium chloride, and dried. Solvent was removed to afford the title compound (13.3 g, 91%).

EXAMPLE 1 (65)-6- [2-(4-Hydroxy-i,henyl)-ethyll -6-isopropvl -dihvdro -vran-2,4-dione Step A: Preparation of (1 R)-2-(tert-Butvl-dimethvl-silanyloxy- 1 -(1010- <BR> <BR> <BR> <BR> <BR> dimethyl-3 3 -dioxo-36-thia-4-aza-tricyclo[5 .2.1.01 '5ldec-4-vl)-3-methvl-butan- 1-one The acid, 2-(tert-butyl-dimethyl-silanyloxy)-3-methyl-butyric acid (3.5 g), was suspended in toluene (100 mL), and oxalyl chloride, 6.58 mL (5 eq.), was added followed by a drop of anhydrous DMF. In the meantime, (S)-sultam, 10,10- dimethyl-3-thia-4-aza-tricyclo[5.2.1.01f5]decane 3,3-dioxide, (3.2 g) in anhydrous toluene (120 mL) was treated with NaH (60% dispersion), 720 mg (1.2 eq.), and stirred at room temperature for 2 hours. The acid chloride, 2-[(tert-butyl-dimethyl- silanyl)-methyl]-3-methyl-butyryl chloride, formed as above in 2 hours, was azeotroped with toluene twice. It was redissolved in toluene (20 mL) and added to the sultam. The reaction was stirred at room temperature overnight and poured onto saturated NH4Cl solution (200 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate, 3 x 80 mL. The combined organic phase was dried over anhydrous sodium sulfate and evaporated to afford the title compound (6.0 g, 94%).

Step B: Preparation of 1- [(1R)-10,10-Dimethyl-3,3-dioxo-3#6-thia-4-aza- tricyclo[5.2.1.01 5]dec-4-yl!-3-methyl-butane-l 2-dione (1 R)-2-(tert-butyl-dimethyl-silanyloxy)- 1 -(10,1 0-dimethyl-3,3-dioxo-3#6- thia-4-aza-tricyclo[5 .2.1.01,5]dec-4-yl)-3-methyl-butan-1-one (3.0 g) was dissolved in dry THF (15 mL), and n-Bu4NF (1.0 M solution in THF), 8.4 mL (1.2 eq.), was added and maintained at reflux for 1 hour. It was cooled to room temperature, and the solvent was evaporated. The crude product was applied to a short path silica gel column and eluted first with 10% ethyl acetate in hexane and finally with 40% ethyl acetate in hexane. In the meantime, to a solution of oxalyl chloride, 1.34 mL (2.20 eq.), in methylene chloride (60 mL) maintained at -60°C was added slowly a solution of DMSO, 2.658 mL (5.4 eq.), in methylene chloride (20 mL). It was stirred 2 hours maintained at this temperature, and a solution of the above alcohol in methylene chloride (10 mL) was added slowly. After 15 minutes stirring, triethylamine, 5.12 mL (5.39 eq.), was added in one portion. It was stirred for another 15 minutes and allowed to warm to room temperature for 2 hours. It was diluted with chloroform and washed with water several times, and finally brine. It was dried, and the crude product was passed through a short path silica gel column eluted with 10% EtOAc in methylene chloride to afford the title compound (1.36 g, 65%).

Step C: Preparation of l-T(1R)-lO,l O-Dimethvl-3,3-dioxo-3h6-thia-4-aza- tricydo[5.2.1.01,5]dec-4-yl]-2-isopropyl-prop-2-en-1-one Zinc dust, 2.16 g (8.7 eq.), was suspended in dry THF under argon atmosphere and stirred. Diiodomethane, 1.53 mL (5 eq.), was added, and after 30 minutes at room temperature, it was cooled to -400C and TiC14, 720 mg (1.0 eq.), was added cautiously. It was maintained at this temperature for 45 minutes and slowly warmed (caution ! !) to room temperature. It was stirred at room temperature for 35 minutes, and a solution of l-[(1R)-10,10-dimethyl-3,3- dioxo-3h6-thia-4-aza-tricyclo[5.2. .2.1.01 5]decA-yl)-3-methyl-butane 1 ,2-dione (1.20 g) in dry THF (10 mL) was added slowly. It was stirred for 2 hours at room

temperature and poured onto saturated sodium bicarbonate solution (80 mL). It was diluted with methylene chloride (120 mL), and Celite was added to break the sludge. It was filtered through a pad of Celite, the organic phase was separated, and the aqueous phase extracted (2 x 80 mL). The combined organic phase was dried and evaporated to afford the title compound (820 mg, 69%).

Step D: Preparation of r(5 R)- 3 -(4-Benzvloxv-phenvl) -5 -isoprovl -4.5 - <BR> <BR> <BR> <BR> <BR> dihydro-isoxazol-5-yl]-[(1R)10,10-dimethyl-3,3-dioxo-3#6-thi a-4-aza- <BR> <BR> <BR> <BR> <BR> <BR> <BR> tricyclo[5 .2.1.01 '5ldec-4-yll-methanone <BR> <BR> <BR> <BR> <BR> <BR> <BR> 1 -[(1 R)-10,10-Dimethyl-3,3-dioxo-3X6-thia-4-aza-tricyclo[5.2.1 .ol ,5]dec- 4-yl]-2-isopropyl-prop-2-en-1-one (820 mg) in hexane (20 mL) under argon atmosphere was stirred and p-benzyloxyaldoximinoyl chloride, 3.85 g (5 eq.), was added, followed by triethylamine, 2.05 mL (5 eq.). After overnight at room temperature, it was filtered and then concentrated. The crude product was applied to a silica gel column and eluted first with 10% EtOAc in hexane and finally with 15% EtOAc in hexane to afford the title compound (1.2 g, 82%). 1H- NMR was consistent with the structure.

Step E: Preparation of (5R)-[3-(4-Benzyloxy-phenyl)-5-isopropyl-4,5-dihydro- isoxazol-5 -yll -methanol To a stirred solution of [(SR)-3-(4-benzyloxy-phenyl)-5-isopropyl-4,5- dihydro-isoxazol-5-yl]-[(1R)10,10-dimethyl-3,3-dioxo-3#6-thi a-4-aza- tricyclo[5.2.1.015]dec-4-yl]-methanone (750 mg) in dry THF (20 mL) was added L-selectride (1.0 M solution in THF), 5.5 mL (4 eq.), and stirred overnight at room temperature. Ethanol/water (4:1 v/v) (5 mL) was added followed by dilution with THF (40 mL). It was cooled at 0°C in ice bath, and 3N NaOH (5.5 mL) and 30% hydrogen peroxide (5.5 mL) were added. The aqueous phase was saturated with K2C03 and extracted with diethyl ether/THF (1:1 v/v), 3 x 60 mL. It was dried over sodium sulfate and evaporated. It was chromatographed on silica gel eluting with 45% EtOAc in hexane to give the sultam and then the title compound

(312 mg, 68%). 1H-NMR was consistent with the structure and TLC (45% ethyl acetate in hexane) showed the product to be homogenous.

Step F: Preparation of (1 R)-2- -(4-Bevloxy-i:,henyfl-ethyl1-3-methyl-butane- 1 2-diol To the isoxazoline, (5R)-[3-(4-benzyloxy-phenyl)-5-isopropyl-4,5-dihydro- isoxazol-5-yl]-methanol (500 mg) in methanol (50 mL), was added a suspension of 20% Pd/C, 300 mg (60% w/w). A balloon of hydrogen was placed on it, and the reaction vessel was degassed. Hydrogen was admitted into the reaction vessel, and the degassing process was repeated twice. The reaction was allowed to stir overnight under a hydrogen atmosphere, and filtered through a pad of Celite.

Solvent was removed to afford the title compound (320 mg, 93%). Identical by TLC (10% ethanol in methylene chloride) and 1H-NMR with reference made by Ad-mix hydroxylation.

Step G: Preparationof(3S!-3-[2-(4-Benzvloxv-phenyl)-ethyl]-3-hydroxy -4 methyl-entanenitrile Diisopropylethylamine, 321 mg (1.25 eq.), was added to a solution of (1 R)-2-[2-(4-benzyloxy-phenyl)-ethyl] -3-methyl-butane-l ,2-diol (625 mg) in methylene chloride (20 mL) at 400 C, and then followed by the cautious addition of methanesulfonyl chloride, 273 mg (1.2 eq.), in a solution of methylene chloride (5.0 mL). The cold bath was removed after addition was completed, and the reaction was stirred at room temperature for 2 hours. It was diluted with diethyl ether (80 mL), washed sequentially with 60 mL each of water, saturated sodium bicarbonate solution, and finally brine. It was dried over anhydrous magnesium sulfate and evaporated at ambient temperature. The mesylate (product) was dissolved in anhydrous DMSO (10 mL) and KCN, 155 mg, (1.2 eq.), was added. It was stirred at 600C overnight under argon, cooled to room temperature, and diluted with water. It was extracted with chloroform, 3 x 80 mL. The combined extract was washed with ice-cold water, 3 x 80 mL, then brine and dried. Solvent was removed to afford the title compound (514 mg, 80%).

Step H: Preparation of (3 S)-3 - [2-A-Benz:yloxy-yhenyl)-ethyll -3-hydroxyA- methyl-pentanoic acid (3 S)-3-[2-(4-Benzyloxy-phenyl)-ethyl]-3-hydroxy-4-methyl-penta nenitrile, 514 mg in dry THF under argon atmosphere, was cooled to -780C in a dry ice/acetone bath. Diisobutylaluminum hydride (DIBAL-H) (1.5 M solution in toluene), 1.27 mL (1.2 eq.), was added slowly while stirring. After addition, it was stirred for 3 hours during which the temperature warmed up to -400C. It was poured onto a saturated solution of sodium potassium tartrate, diluted with methylene chloride, and stirred for 1.5 hours at room temperature. The organic layer was separated, the aqueous layer was extracted with methylene chloride, and the combined organic portions were washed with brine 4 x 30 mL, and dried over magnesium sulfate. Solvent was removed, product was examined by 1H-NMR (9.40 ppm), and the crude product was redissolved in acetone. Jones reagent, (prepared by careful addition of water to 26.73 g of Cr03 in 23 mL of concentrated sulfuric acid to make 100 mL solution) was added dropwise with stirring at room temperature until the reddish pink coloration was permanent. It was stirred for additional 20 minutes, and isopropyl alcohol was added dropwise to reach a greenish color. It was concentrated on a rotary, and diluted with water and extracted with methylene chloride, 3 x 100 mL. The combined organic portion was washed successively with water, brine, and dried. Solvent was removed to afford the title compound (502 mg, 92%). 1H-NMR was identical with authentic reference.

Step I: Preparation of (5S-5--(4-Ben:::vloxy-t,henyl)-ethyl] -5-hydroxy-6- methyl-3-oxo-heptanoic acid ethyl ester To a stirred solution of (3S)-3-[2-(4-benzyloxy-phenyl)-ethyl]-3-hydroxy- 4-methyl-pentanoic acid (1.7 g) in dry THF (15 mL) was added 1,1'-carbonyldiimidazole, 810 mg (1.0 eq.), under argon atmosphere. After 18 hours at room temperature, it was cannulated into a reaction flask containing solid ethyl magnesium malonate prepared as follows. Dibutylmagnesium malonate (1.0 M solution in hexane), 2.5 mL (0.5 eq.), was added dropwise to a stirred

solution of ethyl hydrogen malonate at -780C under argon atmosphere. It was stirred and allowed to warm to room temperature over 2 hours, the solvent was removed, and the solid ethyl magnesium malonate was dried under high vacuum.

After adding the above solution of the imidazolide, the reaction was stirred overnight a room temperature, quenched by adding saturated ammonium chloride solution (5.0 mL), followed by 1.0 N HCl to reach a pH of 2 (with pH paper). It was extracted with ethyl acetate 3 x 80 mL, the combined organic phase was washed with saturated sodium bicarbonate solution, brine, and dried. Product (55)-S - [2-(4-benzyloxy-phenyl)-ethyl] -5 -hydroxy-6-methyl-3 -oxo-heptanoic acid ethyl ester (1.14 g, 55%) was found to be identical by TLC and 1H-NMR (10% ethyl acetate in methylene chloride) with reference compound.

Step J: Preparation of (6S!-6-[2-(4-Hydroxv-phenyl!-ethyl]-6-isopropyl-dihydro- <BR> <BR> <BR> <BR> pvran-24-dione <BR> <BR> <BR> <BR> <BR> <BR> (SS)-5-[2-(4-Benzyloxy-phenyl)-ethyl]-5-hydroxy-6-methyl-3-o xo- heptanoic acid ethyl ester (1.14 g) was dissolved in THF (15 mL), and 0.1N NaOH, 150 mL (27 eq.), was added. It was stirred at room temperature overnight, cooled in ice bath, and 1.ON HCl was added until turbidity resulted. It was extracted with ethyl acetate, 3 x 60 mL. The combined organic phase was washed with brine and dried. Solvent was removed and the product (1.0 g) was dissolved in dry methanol (100 mL), and 20% Pd/C (150 mg) was added. The reaction was degassed and stirred under an atmosphere of hydrogen overnight. It was filtered through a pad of Celite and evaporated to afford the title compound (504 mg, 75%). TLC (35% ethyl acetate in methylene chloride) showed a single spot which co-eluted with reference standard.

EXAMPLE 2 (S)-3-[2-tert-Butyl]-4-hydroxymethyl-5 methyl-phenysulfanyl]-4-hydroxy-6-[2-(4- hydroxy-phenvl)-ethyll -6-isonronyl-5 6-dihydro-nyran-2-one Treatment of (6S)-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-dihydro- pyran-2,4-dione (Example 1) with toluene-4-thiosulfonic acid S-(2-tert-butyl-4- hydroxymethyl-5-methyl-phenyl)ester in the presence of K2CO3 and DMF according to the methodology disclosed in copending United States Patent Application Number 08/883,743 affords the title compound.