Malic acid reduction with borane

Scheme 4 outlines the synthesis of key intermediate 7 in its correct absolute stereochemical form from readily available (S)-(-)-malic acid (15). Simultaneous protection of the contiguous carboxyl and secondary hydroxyl groups in the form of an acetonide proceeds smoothly with 2,2 -dimethoxypropane and para-toluene-sulfonic acid and provides intermediate 26 as a crystalline solid in 75-85 % yield. Chemoselective reduction of the terminal carboxyl group in 26 with borane-tetrahydrofuran complex (B H3 THF) affords a primary hydroxyl group that attacks the proximal carbonyl group, upon acidification, to give a hydroxybutyrolactone. Treat-... 

The way they solved the problem was this. (S )-(-)-Malic acid is available cheaply. Its dimethyl ester 127 could be chemoselectively reduced by borane to give 128. Normally borane does not reduce esters and clearly the borane first reacts with the OH group and then delivers hydride to the nearer carbonyl group. The primary alcohol was chemoselectively tosylated 129 and the remaining (secondary) OH protected with a silyl group 130 (TBDMS stands for t-butyldimethylsilyl and is sometimes abbreviated to TBS). Now the remaining ester can be reduced to an aldehyde 131 and protected 132. Displacement of tosylate by cyanide puts in the extra carbon atom 133 and reduction gives 134, that is the dialdehyde 126 in which one of the two aldehydes is protected. This compound was used in the successful synthesis of lipstatin. 

Segment Cl was synthesized from (tf)-malic acid as a starting material in the following three steps (Scheme 27) (I) diesterification with acetyl chloride in methanol, (II) selective reduction of a-hydroxy ester with boran dimethylsulfide complex and sodium borohydride in THF, and (III) acid catalyzed lactonization of 145 (90). 

Borane reduces esters very slowly and ketones or aldehydes are selectively reduced in the presence of esters. The most widely used application of borane is for the selective reduction of carboxylic acids, even in the presence of halides, esters, nitriles, and ketones.200 since LiAlH4 reduces both acids and esters and NaBH4 does not reduce acids (and often reduces esters with difficulty), borane is the reagent of choice for selective reduction of carboxylic acids in the presence of an ester group. The reduction occurs without racemization of adjacent chiral centers, as in the borane reduction of (-)-malic acid to generate (5)-l,2,4-butanetriol in 92% yield.201 Seki and Kondo s reduction of the acid moiety in 173 to alcohol 174 (in a synthesis of orally active carbapenams), without reduction of the benzylthio or ester groups also demonstrates this selectivity.202 Borane can reduce imides to give an amine.203 Borane also reduces epoxides at the less hindered carbon when mixed with catalytic amounts of sodium borohydride.204... 

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