Highly Enantioselective Hydrogenation of Ethyl 5,5‐Dimethoxy‐3‐oxopentanoate and its Application for the Synthesis of a Statin Precursor

Abstract

The highly enantioselective hydrogenation of ethyl 5,5-dimethoxy-3-oxopentanoate (3) to ethyl 3-hydroxy-5,5-dimethoxypentanoate (4) -a key intermediate in the synthesis of pharmacologically important statin drugs -has been investigated. The stereochemistry of the catalytic hydrogenation of the β-keto ester in the presence of a number of homogeneous chiral Rh I and Ru II complexes with phosphane ligands has been studied. The highest enantioselectivity for the homo-

Highly stereoselective hydrogenations—As key‐steps in the total synthesis of statins

“…42 A route to the required chiral methyl 3-hydroxy-5,5-dimethoxypentanoate (18) had been already reported by Genêt et al 42 who hydrogenated the corresponding b-keto ester 17 in the presence of Ru(BINAP)Br 2 (2 mol % catalyst, room temperature, 1 atm H 2 pressure) and obtained 18 in 86% yield and with enantioselectivity >95% ee. According to our recently published results, 39 the hydrogenation of b-keto ester 17 proceed in MeOH with an initial H 2 -pressure of 50 bar to give b-hydroxy ester (R)-18 with an enantiose- lectivity of 98.7% (entry 11). The reaction was complete within 3 h at a ratio of S/C 5 500 (entry 11) and within 10 h at a ratio of S/C 5 1000 (entry 12).…”

“…39,40 The first part covers the asymmetric hydrogenation of ethyl 5,5-dimethoxy-3-oxopentanoate (17) to ethyl 3-hydroxy-5,5-dimethoxypentanoate (18) (Scheme 6). 41 From the retrosynthetic analysis depicted in Scheme 6 it follows that the chiral side chain of rosuvastatin acid A can be created by diastereoselective and chemoselective reduction of the keto group in structure B.…”

“…The protected hydroxy ylide (R)-19 was postulated as a possible building block for the preparation of B, as long as the Wittig coupling reaction with the corresponding aldehyde could be performed and the HO-protecting group subsequently removed. Ylide (R)-19 could be prepared 39 starting from methyl 3,3-dimethoxypropanoate (16) by two-carbon elongation followed by the enantioselective hydrogenation of the prochiral keto group in b-keto esters 17 to give finally b-hydroxy ester (R)-18. Protection of the HO-group and transformation of the (MeO) 2 CH-moiety should accomplish the synthesis of ylide (R)-19.…”

“…Enantiomeric compositions for b-hydroxy ester 18 were determined with help of the chlorophosphite chiral derivatizing agent (R)-21 (Scheme 9), 39 prepared from PCl 3 and (R)-BINOL. Chlorophosphite (R)-21 reacted quantitatively and rapidly with alcohol 18 to give phosphites 22a and 22b.…”

A New Approach to the Total Synthesis of Rosuvastatin

“…Part III: Ref. [14] velopment of new and efficient strategies for their synthesis, capable of providing the drug in a cheaper and more convenient manner, is therefore extremely important and relevant. The newest of the statins, rosuvastatin, [6] has been called a super-statin, because it appears to reduce low-density lipoprotein (LDL) cholesterol to a greater degree than rivals in its class without additional adverse effects.…”