Coupling aldol

Total synthesis of macrolide immunodepressants using 1,3-dithiane aldol couplings and a-bond olefin constructions 98ACR35. 

The issue of stereochemistry, on the other hand, is more ambiguous. A priori, an aldol condensation between compounds 3 and 4 could proceed with little or no selectivity for a particular aldol dia-stereoisomer. For the desired C-7 epimer (compound 2) to be produced preferentially, the crucial aldol condensation between compounds 3 and 4 would have to exhibit Cram-Felkin-Anh selectivity22 23 (see 3 + 4 - 2, Scheme 9). In light of observations made during the course of Kishi s lasalocid A synthesis,12 there was good reason to believe that the preferred stereochemical course for the projected aldol reaction between intermediates 3 and 4 would be consistent with a Cram-Felkin-Anh model. Thus, on the basis of the lasalocid A precedent, it was anticipated that compound 2 would emerge as the major product from an aldol coupling of intermediates 3 and 4. 

Table6 Highly syn-diastereoselective intermolecular Rh-catalyzed hydrogenative aldol coupling of vinyl ketones through the tri-2-furylphosphine effect3...

Scheme 4 syn-Diastereoselective intermolecular hydrogen-mediated aldol coupling employing cationic Rh catalysts ligated by tri-2-furylphosphine... 

Scheme 5 Intermolecular Rh-catalyzed hydrogenative aldol coupling under an atmosphere of deuterium...

Scheme 6 Complementary regioselectivities in direct aldol couplings of 2-butanone and corresponding hydrogen-mediated reductive aldol couplings of MVK...

After the initial two reports of Rh- and Co-catalyzed reductive aldol couplings, further studies did not appear in the literature until the late 1990s. Beyond 1998, several stereoselective and enantioselective reductive aldol reactions were developed, which are catalyzed by a remarkably diverse range of metal complexes, including those based upon Pd, Cu, Ir, and In. In this chapter, transition metal-catalyzed aldol, Michael, and Mannich reactions that proceed via transition metal hydride-promoted conjugate reduction are reviewed. 

Table 22.3 Use of phenyl vinyl ketone (PVK) in intermolecular hydrogen-mediated reductive aldol coupling.

To corroborate the proposed mechanism, the catalytic reductive aldol coupling of acrolein with phenyl glyoxal monohydrate was performed under 1 atmos. elemental deuterium. Exposure of the aldol product to excess hydrazine in situ results in formation of the pyridazine, which incorporates precisely one deuterium atom in a manner consistent with the general mechanism proposed in Scheme 22.4 (Scheme 22.9). 

Thus far, the use of acrylates and related acyl derivatives as nucleophilic partners in hydrogen-mediated reductive aldol coupling has been unsuccessful due to competitive conventional hydrogenation. Although the mechanistic basis of these results remains unclear, it may be speculated that for acrylates and struc-... 

Scheme 22.9 Intermolecular reductive aldol coupling of acrolein and phenyl glyoxal under a D2 atmosphere.a)...

Scheme 22.10 Attempted reductive aldol coupling of ethyl acrylate and related acyl derivatives.

Base for aldol coupling reactions, and tiie syntiiesis of lactone precursors and ketones. ... 

Analysis of the Mukaiyama-type aldol coupling (Eq. 2) and the well-known hydrosilyla-tion of a,/l-unsaturated carbonyl compounds 11 in the presence of a rhodium catalyst, indicate that both can be explained by the intervention of the rhodium enolate 13. This line of reasoning provided the impetus to develop a new crossed aldol coupling using a hydrosilane, an a,yS-unsaturated ketone 11, and an aldehyde to form 15 (Scheme 6.4). 

K. L. Yu, S. Handa, R. Tsang, and B. Fraser-Reid, Carbohydrate-derived partners display remarkably high stereoselectivity in aldol coupling reactions, Tetrahedron 47 189 (1991). 

---