Aldol condensation, acid catalyzed enantioselection

This review covers the catalytic literature on condensation reactions to form ketones, by various routes. The focus is on newer developments from the past 15 years, although some older references are included to put the new work in context. Decarboxylative condensations of carboxylic acids and aldehydes, multistep aldol transformations, and condensations based on other functional groups such as boronic acids are considered. The composition of successful catalysts and the important process considerations are discussed. The treatment excludes enantioselective aldehyde and ketone additions requiring stoichiometric amounts of enol silyl ethers (Mukaiyama reaction) or other silyl enolates, and aldol condensations catalyzed by enzymes (aldolases) or catalytic antibodies with aldolase activity. It also excludes condensations catalyzed at ambient conditions or below by aqueous base. Recent reviews on these topics are those of Machajewski and Wong, Shibasaki and Sasai, and Lawrence. " The enzymatic condensations produce mainly polyhydroxyketones. The Mukaiyama and similar reactions require a Lewis acid or Lewis base as catalyst, and the protecting silyl ether or other group must be subsequently removed. However, in some recent work the silane concentrations have been reduced to catalytic amounts (or even zero) this work is discussed. 

Hajos and Parrish at Hoffmann La Roche discovered that proline-catalyzed intramolecular aldol reactions of triketones such as 104 and 107 furnish al-dols 105 and 108 in good yields and vith high enantioselectivity (Scheme 4.17). Acid-catalyzed dehydration of the aldol addition products then gave condensation products 106 and 109 (Eqs. (1) and (2)). Independently, Eder, Sauer, and Wiechert at Schering AG in Germany directly isolated the aldol condensation products vhen the same cyclizations vere conducted in the presence of proline (10-200 mol%) and an acid co-catalyst (Eqs. (3) and (4)). 

CAB 2, R = H, derived from monoacyloxytartaric acid and diborane is also an excellent catalyst (20 mol %) for the Mukaiyama condensation of simple enol silyl ethers of achiral ketones with various aldehydes. The reactivity of aldol-type reactions can, furthermore, be improved, without reducing the enantioselectivity, by use of 10-20 mol % of 2, R = 3,5-(CF3)2C6H3, prepared from 3,5-bis(trifluoromethyl)phenyl-boronic acid and a chiral tartaric acid derivative. The enantioselectivity could also be improved, without reducing the chemical yield, by using 20 mol % 2, R = o-PhOCgH4, prepared from o-phenoxyphenylboronic acid and chiral tartaric acid derivative. The CAB 2-catalyzed aldol process enables the formation of adducts in a highly diastereo- and enantioselective manner (up to 99 % ee) under mild reaction conditions [47a,c]. These reactions are catalytic, and the chiral source is recoverable and re-usable (Eq. 62). 

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