Achiral triketones

Pride of place here must go to the asymmetric Robinson annelation, discovered as long ago as 1974, but not appreciated at the time for the landmark that it undoubtedly was.17 The normal Robinson annelation (text chapter 36) is first a Michael addition to produce an achiral triketone 82 which cyclises when the enol of the methyl ketone adds, aldol fashion, to the syn face of either of the other ketones to give 83, and hence the enone 84, the north east corner of a steroid. 

Type I aldolases activate the aldol donor by the formation of enamines with active site amino acids and an alternate approach to the direct catalytic asymmetric aldol reaction centres on mimicking this process using proline-based organocatalysts. In fact, one of the earliest examples of asymmetric catalysis uses (S)-profine (7.66) as a catalyst for the intramolecular aldol reaction (the Hajos-Eder-Saeur-Wiechert reaction).As an example the achiral triketone (7.67) cyclises to give the aldol product (7.68) with good enantioselectivity. 

In this context, it is well worth citing the classic example of the L-proline-catalyzed intramolecular asymmetric aldol reaction, involving cyclodehydration of achiral triketone 1 to yield the unsaturated Wieland-Miescher diketone 2 (Scheme 8.1) [7, 8]. In early papers, it was reported that in the presence of 20 mol% of L-proline, the diketone 2, an important intermediate in steroid synthesis, is obtained in high yield and in approximately 70-90% enantiomeric excess (e.e.). 

Current interest in organocatalysis is focused on asymmetric catalysis with chiral catalysts, or enantioselective organocatalysis (Fig. 2.42). In the asymmetric aldol reaction (Fig. 2.42), naturally occurring chiral proline is the chiral catalyst giving 93% enantiomeric excess when just 3% proline is added to an achiral triketone. 

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