CA1273352A - Intermediates useful in the preparation of hmg-coa reductase inhibitors - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

There is provided compounds having the follow-ing formula:

Description

5~

- 1 - 171~4 This is a divisional of Canadian Application S.'N. 495,158.
s ~ACKGROUND OF THE INVENTION
End~ e~ al., J Antibiotlcs, X~IX, 1346 (1976) de~cribed a fermentation product, ML-236B, with potent antihypercholesterolemic activity which act~ by inhibiting HMG-CoA reducta~e. This material, named compactin by Brown e~ al., J Chem. So~., Perkin I, 1165 (1976) wa~ ~hown to have a desmethyl mevalonolactone part~al 6tructure and the stereochemistry wa6 studiea.
Shortly thereafter a chemically simila~, natural product MX-~03 (mevinolin), ,obtained by fermentation, was isolatea and characterlzed, ~y ~onaghan ee al., U.S. Pat. No. 4,231,938. It has been 6how~ to have the ~ame desmethyl mevalonolactone ~,,~.~.,0 ~:73~

- 2 - 17194 partial structure and the absolute stereochemical configuration has been determined and described in EPO publication No. 0,022,478 of Merck & Co., Inc.
Totally synthetic analogs of these natural inhibitors have been prepared and described in Sankyo's U.S. Pat. No. 4,198,425 and Sankyo's U.S.
Pat No. 4,255,444 with no attempt being made to separate the s~ereo- and optical isomers.
Subsequently, as described in Merck's EPO publication No. 0,024,348 and by Meyer, Ann. Chem., (1979), pages 484-491, similar totally synthetic analogs were separated into their stereoisomers and optical enantiomers. Furthermore, it was shown in EPO
publication No. 0,024,348 that essentially all of the HMG-CoA reductase activity resides in the 4(R)-trans species as is the case with the naturally occurring compounds compactin and mevinolin.
In most of the prior art process for preparing the totally synthetic compounds, the lactone moiety of each compound had to be elaborated by a lengthy series of synthetic operations followed by very tedious and expensive chromatographic separation of the cis, trans racemates, or enantiomers, following which, the inactive cis-isomer would be discarded.
A process for the preparation of the lactone ring system in the correct optically active form was recently reported by Majewski et al., Tetrahedron Lett., 1984, 2101-2104 utilizing a (3S,5S) iodoketal of the following formula:

3~
- 3 _ 17194L

X~oCH2 Ph I

DETAILED DESCRIPTION OF T~IE I~TION
The present invention relates to a novel compound having the follow~ng general formula C9~:

Y~ Co2R5 PrO OR
(9) wherein Y is chloro or ~romo;
Pr is a protecting group selected from benzoyl, acetyl, triphenylsilyl or t-~utyldiphenylsilyl;
2~ R5 is Cl 5 alkyl or ~enzyl; and R is Cl_5 alkyl, ~enzyl, C2_5 alkoxyalkyl or C3_6 alkoxyalkoxyalkyl, and wherein Pr is a protecting group selected from ~enzoyl, acetyl, tr~phenylsilyl, or tert-butyldiphenyl~
silyl~ This novel compound is useful ~n preparing a compound having the following general formula R70 o ~ ~R5 >~H (II) ~2~733~2

- 4 - 171g4 wherein R5 and R7 are as previougly defined.
~ he compound of formula ~ is use~ul in preparing ant~ypercholesterolem~c age~ts haY~ng khe following general structural formula CIl:
: HO O

lQ R ~ (I) whereln Rl i~ 6elected from the group consistlng o~:
(a) O
CH / ~ O CH2 R CH ~ CH3 ~

w~erein Q is R ~- or R6- ~ R6 is H or OH:

R is hydrogen or methyl, and a, b, c, and d represent optional double bond~, e6peciallr wherein b and d ~ep~esent doubl~ bonds o~ a, b, c, and d are all 3~ single bond~: or ~ ~7~

- 5 - 1719 R4 ~ R~
~/
l ll ~3 wherein R and R are independently Cl 3 alkyl or halo tF, Cl or Br) and R i8 hydrogen, phenyl, benzyloxy, sub~titut0d phenyl or ~ub~tituted benzyloxy in which the phenyl group in each ca~e i~ 6ubstituted w~th one or more ~ub~tituents select~d from Cl 3 alkyl and halo.
The co~pounds o~ ~ormula CC~ axe pxepa~ed ~y:
(A) reacting a compound of .he for~ula (II):

~ O O
~ bR5 ~ H (II) ~"
. O

w~erein ~5 i~ Cl_5 alkyl or benzyl and ~7 i8 Cl 5 alkyl, benzyl. C2 5 alkoxyalkyl, ~uch as CH3OCH2, o~ C3 6 alkoxyalkoxyalkyl, 8uch a8 CH3OCH2CH2OCH2, with a ~ompound o~ the formula (III):

~2733~

- 6 - 1719g R X (III) wherein Rl is defined above, X is a me~al atom or metal complex 6elected from Li, MgCl, MgBr, (CuMgCl)lj2 or (CuMgBr)~/2 or an alkali metal (Li, Na, or K) plu5 an aryl 8ulf onyl group selected from ~ S2 or CH3 ~ ~2~ followed by the removal of the aryl sulfonyl group Trost et al. Tetrahedron Lett., 1976, 3477]
to afford a compound of ~he formula (IV):

bR5 H
1~
R (IV) (~) lactonizing the compound of the formula (IV) under standard acidic conditions to afford ~he compound of formula (V):

~-/o ~
R (V) 5~

- 7 - 171 . 7 and (C) removing the R group by suitaole ~ethods known in the art [T. Greene, Protective GrouP6 In Qr~anic S~nthesis, John Wiley Sons~ 1981, æP 10-36] or with an organoboron halide to af~ord the compound of formula (I).
In a preferred em~odiment, t~e c~mpounds of-formula (I~ are those wherein Rl is ~al and RS i6 hydrogen and R i8 hydrogen or methyl and b and d repre6ent double bonds or a, b, c and d are single bond~.
In a second preferred embodiment, the compounds of formula CI~ are those wherein R
is tb), R2 and ~ independently are chloro, fluoro or methyl and R4 i8 hydrogen, 4-fluoro-3-methylphenyl or 4-Sluorobenzyloxy. The most preferred compounds are thos~ wherein (1) R2 and R3 are methyl a~d R i8 ~-fluoro-3-methylphenyl:
(2) R2 and R3 are methyl and R4 i~ 4-fluoro-benzyloxy: and (3) R2 and R3 are chloro and R4i~ hydroge~.
The reaction o~ the compound of the formula (II) with the compound of the ~or~ula (III) i8 conducted at a temeerature between -78 and 0C.
preferably at -78C with warming to -20C ~or a period of from 1 to 12 hour8, ~05t preferably 1 hour at -78aC and 1 hour at -23C, in an inert solvent.
Illustrative of ~uch inert ~olvent~ are: ether~ or thioe~hers or mixtures thereo~, such as diethyl ether, t*trahyd-ofuran, di~ethoxyethane, dimethylsulfide and the like.

_ g _ 17~94 The amounts of reactants that are employed -in thi~ reaction may vary between 0.1 and 1.0 equivalents of the compound of the formula (II) to each equivalent of the compound of the formula ~III). However, 0.4 equivalents of the compound of the ~ormula (II) is preferred. The compound of ~he formula (III) wherein ~ i8 (CuMgBr)l/2 i8 a preferred reactant.
The lactonization of the compound of the formula tIV) is conducted at a temperature between 0 and 25C, preferably at ambient tempera~ure, for a period of from 1 to 12 hours~ preferably 3 hou~6 in an inert ~olvent wlth a catalytic amount of an acid.
Illustrative of such inert solvent6 are:
hydrocarbons, such as, hexane, toluene, benzene, cyclohexane and the like: and ethers, such às, diethylether, tetrahydrofuran, dimethoxyethane and the like. Illustrative of such acids are organic acid6, 6uch as, p-toluenesulfonic, benzenesulfonic and the like and inorganic acids, ~uch as, hydrochloric. The preferred acid utilized in the lactonization is p-toluenesulfonic acid.
The removal of the R protecting group i8 conducted at a temperature between -78 and 0C, preferably at -78 for a ~eriod from l to 12 hours, preferably 1 hour in an inert solvent in the presence of an organoboron halide. Illu6trative of 6uch inert solvent~ are: chlorinated hydrocarbons, such as, methylene chloride, chloroform, dichloroethane or low melting mixtures thereof and the like.

73~
- 9 - 171~4 The organoboron halids reactan~ ~ B
-represented by the following formula:
R8R9B~f wherein R and R independently are Cl ~ alkyl, S phenyl or when taken together with the boron a~om ts which they are attached form a 5, 6 or 7 membe~ed ring or a bicyclic ring and Y i6 chloro Ol broms.
The preferred organoboron halide i8 dimethylboron bromide. The amount of the organoboron hallde utilized may vary betwee~ 1 and 10 equivalent6 for each equivalent of the compound of the formula (V), with 4 equivalent6 being pre~erred.
The starting material6 are either known or readily prepared according to the synthetic ~athways described belo~.
For compounds of the formula (III) wherein R iB (a) and ~ i8 a metal atom or metal complex, Tetrahedron Lett., pp. 1373-6 (1983) describe6 a procedure for preparing compound~ which can be readily converted into the desired compounds of the formula (III) u~ing 6tandard reaction conditions.
For compound6 of the formula (III) wherein X iB

~ S02 or C~ ~ S02, Tetrahedron Lett., pp.

1655-8 (1984) describe6 a procedure for preparinq compound~ which can be readily converted into the desired compounds of the formula (III) u6ing 6tandard conditions. The compounds of the formula (III) wherein Rl i8 (b) are known in the art.
The compound of the formula (II) wherein R5 and R7 are de6cribed above are read~ly prepared according to the following synthetic pathway from (S)-malic acid:

~733~
- 10 - 171g4 H02CV'\Co2H > O/\~OH ~= ~O

OE~ 'r O H
~1) t2) (3) > /~CozR5 ~ Pr~C02 ~O HO
(~) (5) -~_ C02R <~H /C2R

Pr~ PrO
(6) (7) \ /

Y ~ C2R ~ Y 3 CO2R > (II) PrO OH PrO OR
(~ ~9) (S)-~alic acid (1) i8 reduced under standard reduction condition~ u~ing BH3.THF and then ketalized with acetone to give compound (2).
Compound (2) is subjected to a Swern oxidation to yield compound (3), which, without i~olation, i8 treated under W~ttig condition~ with Ph3PCHCO2R5 to give Compound (g). Compound (4) i~ hydrolyzed under acid condition6 and ~electively protected to give Compound (5) wherein Pr i a proteceing group selected from benzoyl, acetyl, triphenyl~ilyl or tert-butyld~phenyl~ilyl, preferably t-butyl-diphenyl~ilyl. Compound (5) i6 cyclized to Compound~

~b73~5~

~6) and (7) under basic conditions with concomitant migration of the Pr gcoup. Compound (7) may be i~omarized to the desired Compound (6) under basic conditions. Compound (6) i8 converted to Compound

(8) u~ing an organoboranhalide R8R9BY, preferably dimethylboron bromide. Compound (B) is treated with R7-halide to get Compound (9) which i~ treated with tetraalkylammonium fluoride oranalkalimetal alkoxide to afford the compound of formula (II).
10The following Examples illustrate the present invention and as such are not to be considered as limiting the invention set forth in the claims appended hereto.

SteD (a): Preparation of (S)-1,2-0-Isopropylidene-butane 1,2 4 4-triol To a cold (0C), well-stirred solution of (S)-malic acid (1~.4 g, 100 mmol) in 300 ml dry tetrahydrofuran, under argon, was added dropwise (via capillary) a tetrahydrofuran solution of borane-THF
complex (300 ml, 300 mmol) over a period of 3 hour~.
The cooling bath was removed and the resultant slurry wa6 stirred at room temperature for 15 hours. The reaction mixture was then cooled to 0C and carefully treated with dry methanol ~100 ml). AfteL warming to room temperature, the solvent was evaporated. The residue was evaporated three times with dry methanol (100 ml each) to ensure complete methanolysis of the reduction intermediate. Brief drying (0.1 mm) gave 10.3 g of the crude triol.

This material was dissolved in acetone (300 ml) and a catalytic amount of ~-TsOH.H2O (0.g5 g, 5 mmol) added. After 12 hours at room temperature the reaction mixture was quenched with triethylamine (0.70 ml, 5 mmol) and concentrated. The resultant oil was dissolved in ether (400 ml) and ~ashed with water (3x50 ml) and brine (50 ml) and dried over MgSO4. Concentration and bulb-to-bulb distillation of the residue (air-bath temperature 85-95C, 0~15 mm; lit.l 55-61C, 0.05 mm) gave 11.7 g (80%) of the desired product. lH NMR (CDC13) analysis showed that this material contained ~10% of the isomeric acetonide (S)-2,4-O-isopropylidene butane-1,2,4-trioll'2 and was used without further -purification. This material exhibited IR (film) 3450, 2950, 1380 and 1050 cm 1; lH NMR (250 MHz, CDC13) S 1.38 (s, 3H), 1.43 (s, 3H), 1.79-1.88 (m, 2H), 2.55 (broad s, lH), 3.61 (d,d, J=7.7Hz, lH), 3.80 (t, J-5.9Hz, 2H), 4.10 (d,d, J=7.0, 7.7Hz, lH), 4.28 (m, lH).

A. I. Meyers and J. P. Lawson, Tetrahedron Lett., 23, 4883 (1982).
S. Hanessian, A. Ugolini and M. Therien, J. Org.
Chem., 48, 4427 (1983).

Step (b): Preparation of Ethyl (E)-(S)-_-Isopropyli-dene-5,6-dihydroxy-2-hexenoate A cold (-78C) stirred solution of oxalyl chloride (1.92 ml, 22 mmol) in 50 ml of dry methylene chloride, under argon, was treated with a solution of DMSO (3.55 ml, 25 mmol) in the same solvent (10 ml).
After stirring at-78C for 10 minutes a solution of 5~

(S)-1,2-Q-isopropylidene butane-1,2,4~trlol (2.92 g, 20 mmol) in 15 ml of methylen2 chloride was added.
The resultant 61urry waR stirred at -78C for 40 minutes, then treated with diisopropylethylamine (17.5 ml, 100 mmol). Th~ cooling bath was removed and the reaction mixture was ~tirred at room temperature or 1 hour to afford a yellow solution of (S)-O-i60propylidene 4-oxy-butane-1,2-diol.
Thi~ ~olution was cooled to 0C and treated with carbethoxymethylenetriphenylphosphorane (17.4 g, 50 mmol) at 0C for 1 hour and at room temperature ~or 4 hours. The re~ultant solution wa~ diluted with ether (300 ml), wa~hed with water ~3x50 ml), 10%
aqueous NaHSO~ (50 ml) and brine (2x50 ml) and dried over MgS04. Removal of solvent gave a viscous oil. Ether (150 ml) and hexane (150 ml) were added and the mixture kept at -10C for 15 hour6.
~iltration of the white precipitate (Ph3P=O) and removal of 601vent gave the crude produ~t. Fla~h 20 chromatography (hexane-ethyl acetate 85:15) gave 3.60 g (84%) of ethyl ~E)-(S)-O-isopropylidene-5,6~
dihydroxy-2-hexenoate: ta]D -18.0 (c 2.43, MeOH); IR (film) 2994, 1727, 1661, 1372, 1269, 1172 and 1064 cm 1; lH NMR (CDC13) 1.30 (t, 25 J=7.0Hz, 3H), 1.36 (~, 3H), 1.43 (B, 3H), 2.39-2.60 (m, 2H), 3.59 (m, lH), 4.07 (m, lH), 4.16-4.30 ~buried m, lH), 4.20 (q, J-7.0Hz, 2H), 5.92 (d,t, J~15.5, 1.5Hz, lH), 6.92 (d,t, J=15.5, 7.2 Hz): MS
m/e (relative intensity) 199 (43), 101 (100).
Anal. calcd. for CllH1804:
C, 61.66: H, 8.47.
Found: C, 61.42; H, 8.44.

- 1~ - 17~g4 SteP (c~: Preparation of Ethyl (~)-(S)-5,6 d~hydroxy-2-hexenoate ___ ~o a solu~ion of e~hyl-(E)-(S~-Q-isopropyli-- dene-5,6-dihydroxy-2-hexenoate (5.35 g, 25 mmol) in 100 ml tetrahydrofuran ~a~ added lN HCl ~66 ml). The reaction mixture was ~tirred at room temperature for 18 hour~. NaCl (10 g) and ethyl acetate (400 ml) were added. The organic layer wa6 60parated and washed with brine (2xS0 ml3. The aqueous washing~
were extrac~ed with ethyl acetate ~2xlOO ml), the extracts washed with brine (25 ml) and the organic layers combined. Drying (MgS04) and removal of solvent gave 4.04 g (93%) of a vi~cous oil. Thi~
material exhibited: IR (film) 3400, 1720, 1657 and 10~0 cm 1; lH NMR (CDC13) 1.28 (t, J=7.0Hz, 3H~, 2.25 (broad ~, lH), 2.39 (m, 2H), 2.58 (broad 8, lH), 3.43-3.55 (m, lH), 3.63-3,73 (m, 1~), 3.81-3,92 (m, lH), 4.1B (q, J=7.0Hz, 2H), 5.91 (d, J=16Hz, 1~), 6.96 (dt, J--16, 6.6Hz, lH).
Anal. calcd. for C8H1404:
C, 55.16; H, 8.10.
Found: C, 55.52; H, 8.08.

SteP td~: Preparation of Ethyl (E)-(5)-6-t-butyldi-phenvl~iloxv-S_hvdroxY-2-hexenoate To a cold (0C), stirred ~olution of the diol from Step (c) (4.04 g, 23.2 mmol) in 116 ml dry methylene chloride, under argon, was sequentially added diisopropylethylamine (6.08 ml, 34.8 mmol) 4-dimethylamino pyridine ~280 mg, 2.3 mmol) and t-butyldiphenyl~ilyl chloride (7.54 ml, 29 mmol).
The reaction mixture was stirred at 0c for 1 hour and then at room temperature for 18 hour~. Water ~ 15 - 17194 (100 ml) and ether (q00 ml) were added. The organic layer was separated, washed with water (100 ml), saturated aqueou~ NaHCO3 (50 ml), 10% aqueou6 NaH50~ (50 ml), and brine (S0 ml). Drying (MgS04) and removal of 601vent gave the crude product. ~urification by ~la~h chroma~ography (300 g, SiO2, hexane-ethyl acetate 85:15) gave 9.41 g (98%) of e~entially pure mono-~iloxy alcohol. This material exhibited: ~a]D -10.0 (c 1.23, MeOH):
IR (~ilm) 3480, 2940, 1723, 165~, 1594, 1431, 1114 and 704 cm ; H NMR (CDC13) 1.07 (~, 9H), 1.28 (t, J=7.2Hz, 3H), 2.36 (broad t, J=6.5Hz, 2H), 2.53 (d, J,4.4Hzc lH), 3.53 (d,d, J2l0.2, 6.7Hz, lH), 3.67 (d,d, J=10.2, 3.7 Hz, lH), 3.85 (m, lH), 4.18 (q, J=7.2Hz, 2H), 5.87 (d, J=15.5Hz, lH), 6.94 (d,d, J=15.5, 7.3Hz, lH), 7.34 7.43 (m, 6H), 7.60-7.68 (m, 4H); MS m/e (relative intensity) 355 (5), 199 (100).
Anal. calcd. for C24H34O4Si:
C, 69.87; H, 7.82.
Found: C, 70.22: H, 7.60.

Step (e): ~reparation of Ethyl 2(R~ (S)-tert-butyl-diphenylsiloxytetrahydrofuran)acetate and it~ 2tS~,4(5)-isomer ~o a cold (0C), fitirred ~olution of ethyl (E)-(S)-6-tert-butyldiphenylsiloxy-(5)-hydroxy-2-hexenoate (9.41 g, 23.0 mmol) in 200 ml dry ethanol, under argon, was added a solution of ~odium ethoxide (2.3 mmol) in ethanol (30 ml). Stirring wa~
continued at room temperature for 2 hours ~nd at 65C
for 4 hour6. The reaction mixture wa~ then cooled to room temperature and quenched with acetic acid (2.3 mmol). Concentration provided the crude product as a - 16 - 1719~

yellow oil (9.5 g). TLC (hexane-ethyl acetate, 4:1) and H NMR (250 MHz, CDC13) analyses of the crude product indicated the pre~ence of the de~i~ed ~ (R~
0.55) and a (R~ 0.53) produc~ isomer6 in a ratio of 2:1 along with a ~mall amount o~ starting material. This material was purified in two batche~
by careful fla~h chlomatography (300 g SiOz, eluant: hexane-ethyl acetate, 95:5) to afford after concentration of the appropriate fractions 4.51 g of pure 2(R),4(S)~ omer.
Further elution of the column (hexane-e~hyl acetate, 4:1) and combination of ehe appropriate fractions gave 4.80 g of a mixture of the 2(R),4(S)-and 2(S) ,4(5)-i60mer5 along with a small amount of starting material. This material wa6 di6solved in ethanol (160 ml) and resubjected to the equilibration conditions (1.16 mmol NaOEt) at 65C for 5 hours.
Work-up and purification a~ outlined a~o~e (300 g SiO2, eluant: hexane-ethyl acetate, 95:5 then 20 4:1) gave 2.27 g o~ pure 2(R),4(S)-A-i~omer (total yield 6.77 g, 72~). taiD 7.~1 (c 2.08, MeOH), IR
(film) 3080, 2940, 1738, 1593, 1115 and 703 cm lH NMR (250 MHz, CDC13) 1.06 [8, 9H), 1.26 (t, J=7.2Hz, lH), 1.55 td,d,d, J=15.4, 9.6, 5.6Hz, lH), 25 2.07 (d,d,d, J=15.4, 5.6, 1.8Hz, lH), 2.44 (d,d, J=15.4, 5.9Hz, lH), 2.57 (d,d, J=1S.2~ 7.2Hz, lH), 3.72 (d,d,d, J-9.4, 2.6, 0.8~z, lH), 3.84 (d,d, J-9.4, 4.6Hz, lH), 4.15 (q, J=7.2Hz, 2H), 4.45 (m, lH), 4.57 (m, lH); 7.33-7.50 (m, 6H), 7.60-7.76 (m, 30 4H); MS m/e (rela~ive intensity) 355 (11), 199 (100).
Anal. calcd. for C24H32o45i:
C, 69.B7; H, 7.~2.
Found: C, 70.15; H, 7.73.

3~

Further elution of the column (hexane-ethyl acetate, 4:1~ and collection of the appropriate fraction~ gave o.ga g (10%) of the 2(S),4(S~-a-isomer. IR ~film) 3081, 2942, 1730, 1593, 1113 and 705 cm ; H NMR (250 MHz, CDC13) 1.07 (8, 9H~, 1.27 (t, J=7.2Hz, 3H), 1.75 (d,d,d,d, J=13.1, 5.7, 3.4, O.9Hz, lH~, 2.16 (d,d,d, J313.1,7.5, 6.3Hz, lH), 2.66 (d,d, J-~15.4, 6.4Hz, lH), 2.84 (d,d, J=15.4, 7.3Hz, lH), 3.62 (d,d, J-9.4, 4.9Hz, lH), 3.81 (d,d,d, J=9.4, 2.8, O.9Hz, lH), 4.16 (q, J=7.2Hz, 2H), 4.31 (m, lM), 4.43 (m, 1~), 7.33-7.50 (m, 6H), 7.62-7.77 (m, 4H); ~S m/e (relative inten~ity) 367 (14), 355 (100), 199 (61).

* 1.01 g (11~) of a mixture of the ~- and ~-isomer6 was al~o recovered.

S~ep ~f): Preparation of Ethyl 6-bromo-5(S)-tert-bu~yldi~æhenvlsiloxY-3LR)-hydroxvhexanoate To a cold (0C), ~tirred mixture o~ ethyl 2(R)-(4(S)-tert~butyldiphenyl6iloxytetrahydcofuran)-acetate (1.21 g, 2.93 mmol) and dii~opropylethylamine (51 ~1, 0.29 mmol) in 16.5 ml dry methylene chloride, under argon, was added a solution of dimethylboron bromide (3.46 ml, 5.98 mmol) ln methylene chlo~ide. The reaction mixture wa6 then 6tirred at room temperature for 2 hour~, diluted ~ith ether (100 ml) and quenched with 6aturated aqueous NaHC03 (10 ml). The organic layer wa6 ~eparated, wa~hed with 10 ml portions of saturated aqueou6 NaHC03, water and brine and dried over MgS04.
Removal of solvent gave a yellow oil whlch was subjected to fla~h chromatography on ~ilica gel (eluant: hexane-ethyl acetate, 4:1) to afford 1.19 g 3~r~:

(32%) of ~he purified product as a colorles~ oll.
This material exhibited [a]D ~2.81 (c 1.67, MeOH): IR (film) 3430, 2938, 1725, 1590, 1430, 1112 and 700 cm 1 lH NMR (250 MHz, CDC13) 1.08 (s, 9H), 1.26 (t, J=7.2Hz, 3H), 1.82 (m, 2H), 2.30 (m, 2H), 3.05 (broad 8, lH), 3.39 (d, J=3.7Hz, 2H), 4.10 (m, lH), 4.15 (q, J=7.2Hz, 2H), 7.34-7.48 (m, 6H), 7.S4-7.70 (m, 4H); MS m/e (relative intensity) ~47 (4), 435 (2), 199 (100).
10 Anal. calcd. for C24~3304SiBr:
C, 58.41: H, 6.74.
Found: C, 58.19: H, 6.73.

Step (q): Preparation of Ethyl 6-bromo-5(S)-tert-butyldiphenylsiloxy-(3)-(R)-(methoxy-methoxY)hexanoate To a cold (-10C), ~tirred solution of ethyl 6-bromo-5(S)-tert-butyldiphenylsiloxy-(3)-(R)-hydroxy-hexanoate (0.84 g, 1.70 mmol) in 5.15 ml of dry acetonitrile, under argon, were sequentially added dii~opropylethylamine (O.ag ml, 5.10 mmol), 4-N,N-dimethylamin~pyridine (21 mg, 0.17 mmol) and chloromethyl methyl ether (1.03 ml, 13.6 mmol). The argon inlet was removed and the reaction mixture was stored at -3C for 24 hours. The reaction mixture was then quenched with saturated (aqueou~) NaHC03 (3 ml) and diluted with ether (60 ml). The organic layer was separated, washed with satura~ed aqueous NaHC03 (2xlO ml), water (10 ml), 10~ aqueous 30 NaHS04 (10 ml) water (10 ml) and brine (10 ml).
Drying (MgS04) and concentration gave a pale yellow oil. Purification by ~lash chromatography on silica gel (60 g, eluant: hexane-ethyl acetate, 4:1) provided 0.85 g (94~) of ~u~e product. This material exhibited: ~a]D = 0.77 (c 1.68, CHC13): IR
~film) 3075, 2935, 1738, 1589, 142a, 1031 and 701 cm ; H NMR (250 MHz, CDC13) 1.08 (B, 9H), 1.24 (t, J-7.1Hz, 3H), 1.94 (broad t, J=6.0Hz, 2H), 2.26 (d,d, J=15.3, 5.2Hz, lH)o 2.39 ~d,d, J=15.3, 7.3Hz, lH), 3.18 (8, 3H), 3.37 (d, J-4.3H2, 2H~, 3.92 (m, lH), 4.04 (m, lH), 4.12 tq, J=7.lHz, 2H), 4.50 (d, J=7.1Hz, A part of AB, lH), 4.58 (d, J57.1Hz, B
part of AB, lH), 7.33-7.46 (m, 6H), 7.65-7.74 (m, 4H); ~S m/e (relative intensity) 479 (28), 213 (1003.
Anal. calcd. for C26H37055iBr:
C, 58.09; H, 6.97; Br, 14.86.
Found: C, 58.33; H, 7.02; Br, 14.79.
Step (h): Preparation of Ethyl 5(S),6-epoxy-3tR)-(methoxymethoxy)hexanoate ~ cold (0C), 6tirred 601ution of ethyl 6-bromo-5(S)-tert-butyldiæhenylsiloxy-3(R)-(methoxy-methoxy)hexanoate (0.80 g, 1.49 mmol) in 3.8 ml dry tetrahydrofuran (THF), under argon, wa6 treated with a ~olu~ion o~ tetra-n-butylammonium fluoride (4.47 ml, 4.47 mmol; l.OM ~olution in THF). The cooling bath was removed and the reaction mixture wa6 stirred at room temperature for 3 hours. Ether (50 ~1) wa6 then added and the mixture wa~hed with water (5 ml), 10~ aqueou6 NaHS04 (5 ~1), ~ater (5 ml) and brine (5 ml). Drying (Mg504) and re~oval of 801vent gave a pale yellow oil which wa6 sub3ected to flash chromatography on ~ilica gel (20 g, hexane-ethyl acetate, 4:1) to provide 0.241 g t74%) of the de6ired epoxide, ~a]D -31.5 (c 0.98, MeOH). IR (film) 2938, 17~6 and 1035 c~-l; lH NMR (250 MHz, - 20 ~ 1719 CDC13) 1.23 (t, J_7.2Hz, 3H), 1.70-1.82 (m, lH), 1.86-1.99 (m, lH), 2.49 (m, lH), 2.56 (d,d, J=15.6, 5.0Hz, lH), 2.71 (d,d, J=15.6, 6.0~z, lH), 2,77 (m, lH), 3.08 (m, lH), 3.38 ts, 3H), 4.16 (q, J=7.2Hz, 2H), 4.29 (m, lH), 4.67 (d, A part of AB, J=7.8Hz, lH), 4.72 (d, B part o~ AB, J=7.8Hz, lH).
Anal. calcd. for Cl~H1~05:
C, 55.03; ~, 8.31.
Found: C, 54.82; H, 8.39.
EX~MPLE_?~
Step ~L~ Preparation of 2,4-Dichlorobenzylmagne~ium bromide To stirred magnesium metal (0.121 g, 5 mmol) in 1.0 ml of dry ether, under argon, was added 0.5 ml of an ether ~olution of 2,4-dichlorobenzyl bromide ~1.20 g, 5 mmol in 4.0 ml dry ether). A small crystal of iodine was added and initiation of the reàction took place (exothermic) within 5 minute6.
20 The remaining 601ution of 2,4-dichlorobenzyl bromide was then added dropwise at such a rate a6 to malntain a mild reflux. After the addition wa~ complete the reaction mixture was refluxed for 1 hour to a~ford a colorle~s 601ution of 2,4-dichlorobenzylmagnesium bromide in ether tabout l.OM).

Ste~_(bl: Preparation of Ethyl 7-(2,4-dichloro phenyl-5(R)-hydroxy-3tR)-(methoxymethoxy)-hePtanoate To a cold t-78C), fitirred sus~en6ion of cuprous bromide-dimethyl sulfide complex (88 mg, 0.43 mmol) in a mixture o~ dimethyl sulfide tl.3 ml) and ether t0-4 ml), under argon, wa~ added dropwise a - 21 - 171g4 solu~ion of 2,4-dichlorobenzylmagnesium bromide ~0.88 ml, 0.88 mmol; l.OM in ether). The resultant orange solution was stirred at -78C for 15 minutes. A
601ution of ethyl 5(S),6-epoxy-3(R)-(methoxymethoxy)-hexanoate (72 mg, 0.33 mmol) in 0.5 ml dry ether wa~
then added dropwi~e over a perio~ oP 3 minuteB. The reaction mixture was 6tirred at -78C for 1 hour and at -23C for 1 hour. Satura~ed aqueous NH4Cl (0.5 ml) adjusted to pH B with concentrated NH40H. and ether t20 ml) were added. After warming to room temperature the organic layer was separated, washed with 5 ml portion6 of saturated aqueous NH4Cl (pH
8), water and brine and dried over MgS04.
Concentration and purification by fla6h chromato-graphy on ~ilica gel (eluant: hexane-ethyl acetate, 7:3) gave pure product, 124 mg ~100%). This material exhibited: ta]D +5.37 (c 0.85, MeOH~: IR (~ilm) 3480, 2943, 1738, 1591, 1477 and 1136 cm 1 lH
NMR (250 MHz, CDC13~ 1.26 (t, J~7.2Hz, 3H), 1.66-1.87 (m, 4H), 2.50 (d,d, J-15.0, 6.4Hz, lH), 2.71 (dod, J=15.0, 6.3Hz, lH), 2.74-2.96 tm, 2H), 3.11 (broad , lH), 3.39 (s, 3H), 3.80 (m, lH), 4.14 (q, J=7.2Hz, 2H), 4.22 (m, lH), 4.69 td, A part of AB, J=6.7Hz, lH), ~.75 (d, B part of AB, J-6.7Hz), 7.18 (m, 2H), 7.34 (m, lH): MS m/e (relative intensity) 159 (100).
Anal.~calcd. for C17H2405C12:
C, 53.84; H, 6.3B.
Found: C, 53.91; H, 6.50.

~2~733~;~

S~eP tc~: Preparation of 6(R)-[2-(Z,4-dichloro-phenyl)ethyl]-4(R)-(methoxymethoxy)tetra-hvdro-2H-pyran-2-one A mixture of 7-(2,4-dichlorophenyl)-5(R)-hydroxy-3(R)-(methoxymethoxy)heptanoate (100 mg, 0.26 mmol) and P-TsOH.H20 (5 mg, 0.026 mmol) in 1.30 ml benzene, under argon, wa~ ~tirred at room temperature for 3 hours. The reaction mixture was ~hen diluted with ether (20 ml), wa6hed with 2 ml portions of ~aturated aqueous NaHC03, water and brine and dried over MgS04. Concentration and purification of the residue by flash chromatography (eluant: hexane-ethyl acetate, 4:1) afforded 78 mg (90%) of the de~ired lactone, [a~D ~3Z.4 (c 0.71, MeOH). IR
(film) 2940, 1740, 1590, 1475 and 1040 cm ; H
NMR (250 MHz, CDC13) 1.75 (m, lH), 1.94 (m, 2H), 2.07 (m, lH), 2.65-3.05 (m, 4H), 3.35 (6, 3H), 4.20 (m, lH), 4.63 (m, lH), 4.67 (8, 2H), 7.19 (~, 2H), 7.37 (s~ lH): MS m/e (relative intensity) 332 (13), 159 (100).

SteP ~d): Prepa~ation of 6(R)-[2-(2,4-dichloro-phenyl)ethyl]-4(R)-hydroxy-tetrahydro-2H-~yran-2-one To a cold (-78C), ~tirred solution of the corresponding methoxymethyl ether derivative from Step (c) (65 mg, 0.20 mmol) in 1.50 ml dry methylene chloride, under argon, was added a solution of dimethylboron bromide (1.56M) (0.51 ml, 0.80 mmol) in methylene chloride. Stirring was continued at -78C
for 1 hour. The reaction mixture wa~ then added to a room temperature stirred mixture of tetrahydrofuran ~2.0 ml) and saturated aqueous NaHC03 (2 ml).

~2~5;Z
~~ - 23 - 17194 After 3 minute6 ether (20 ml) wa~ added and the organic layer wa6hed with 2 ml portion~ of ~aturated aqueou~ NaHC03, water and brine. Drying (Mg504) and concentration gave the crude product.
~urification by fla6h chromatography (6 g, SiO2, eluant: hexane-ethyl acetate, 4:1) gave 46 mg ~79~) of the desired product, ta]D ~59 7 (c 1.10, CHC13). IR tfilm) 3440, 17Z8, 1476, 1~60 and 1050 cm ;; H NMR (250 MHz, CDC13) 1.78 (m, lH)!
1.88-2.10 (m, 3H), 2.20 (d, J=3.6Hz, lH), 2.64 (d,d,d, J-16, 3.4, O.9Hz, lH), 2.76 (d,d, J=16, 4Hz, lH), 2.77-3.05 (m, 2H), 4.41 (broad m, lH), 4.71 (broad m, lH), 7.18 (6, 2H), 7.36 (s, lH); MS m/e (relative inten~ity) 288 (15), 159 (100).
Anal. calcd. for C13H1403C12:
C, 54.00; H, 4.88.
Found: C, 54.02; H, 4.89.

~33:~
- - 2~ - 1719 EX~MPLES 3-12 Utilizing the general procsdures of Example 2 and sta~ting from the appropriately ~ubstituted compound~ of the ~ormula (III) and ethyl 5(s)~6-epoxy-3(R)-(me~hoxymethoxy)hexanoa~e the followi~g compounds of the formula (I) are prepared:

Compound Number Rl CH3~\~U\Q CH2 3 CH3~ ~ CH3 CH3 ~

CH3 ~ CHz 4 CH3 CH3 ~ CH3 O

CH ~ o H CH2 CH3 ~ CH3 Compound Number _ R

CH3~ CH2 6 Cl13 CE~3~ CH3 ~.

3 \L ~CH3 2 0 CH3 ~ CH2 8 3 CH ~CH3 O

CH3/~\O H CH2 3 0 9 CH3~;~cH3 W

Compound N mber Rl C~3 C~I3~ CE~3 W

1~
11 C~clj3 12 ~ CH20~c 3 ~\ I
~.

Claims (4)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. Process for preparing a compound having the following formula (9):

wherein Y is chloro or bromo;
Pr is a protecting group selected from benzoyl, acetyl, triphenylsilyl or t-butyldiphenylsilyl;
R5 is C1-5 alkyl or benzyl; and R7 is C1-5 alkyl, benzyl, C2-5 alkoxyalkyl or C3-6 alkoxyalkoxyalkyl, which comprises reacting a compound having the following formula (8):

wherein R5 and Pr are as previously defined with an R7-halide and recovering the desired product.

2. Process for prepariny ethyl 6-bromo-5(S)-tert-butyldiphenylsiloxy-3(R)-(methoxymethoxyl)-hexanoate which comprises reacting ethyl 6-bromo-5-(S)-tert-butyldiphenylsiloxy-3(R)-hydroxyhexanoate with diisopropylethylamine, 4-N,N-dimethylaminopyridine and chloromethyl methyl ether and recovering the desired product.

3. A compound having the following formula (9):

wherein Y is chloro or bromo;
Pr is a protecting group selected from benzoyl, acetyl, triphenylsilyl or t-butyldiphenylsilyl;
R5 is C1-5 alkyl or benzyl; and R7 is C1-5 alkyl, benzyl, C2-5 alkoxyalkyl or C3-6 alkoxyalkoxyalkyl, when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.

4. Ethyl 6-bromo-5(S)-tert-butyldiphenyl-siloxy-3(R)-(methoxymethoxy)hexanoate, when prepared by the process defined in Claim 2 or by an obvious chemical equivalent.