Stereoselectivity enamine catalysis

Scheme 18.6 Stereoselective reaction by combination of iminium and enamine catalysis with imidazolidinones.

Introducing heteroatoms in the a-position of carbonyl groups in a direct approach is one of the types of transformations that have benefitted the most from recent progress in the field of enamine catalysis (105-109). Besides the development of suitable methods for the stereoselective introduction of O- and N-heteroatoms,... 

It has been discussed in Sect. 2.6 that the combination of different organocatalytic activation modes for the efficient and short syntheses of complex structural moieties has attracted considerable interest over the last few years (30, 32, 176-178). As depicted in Schemes 48 and 49, the use of different enamine-catalysis based stereoselective transformations has given access to such highly functionalized and complex natural products like brasoside (198), littoraUsone (199) (115), and caUipeltoside C (206) (184), in an elegant and highly efficient way. 

Different groups reported in 2007 on the use of C9 amino cinchona alkaloids as catalysts for the stereoselective functionaUzation of branched carbonyl compounds. Connon and coworkers demonstrated that the C9 amino derivative of epidihydro-quinine (40) and epidihydroquinidine (41) were effective catalysts for the conjugate addition of aldehydes and (cyclic) ketones to nitroalkenes via enamine catalysis [99] (Scheme 6.46). The catalysts with the same configuration at C9 as in the natural cinchona alkaloid gave poor results, in line with the results obtained for... 

Organocatalytic Stereoselective Sul-Type Reactions with Enamine Catalysis 733... 

In contrast to the early report of intramolecular desymmetrization reactions [6], the intramolecular ring-closing reactions of achiral substrates via enamine catalysis were not disclosed until the beginning of the twenty-first century. In 2003, list reported the first highly stereoselective intramolecular aldol reaction of achiral dicarbonyl compounds. Cyclic aldol products 6a-< were delivered from heptanedials 5 with excellent diastereo- and enantioselectivity by the catalysis of L-proline (Scheme 36.2). The cyclization of ketoaldehyde 7 afforded alcohol 8 as a 2 1 diastereomeric mixture but with 99% ee. This strategy could provide P hydroxyl carbonyl derivatives that are of potential applications in organic synthesis [7aj. 

Although attempts to catalyze bimolecular aldol condensations without resorting to enamine chemistry have not yet been successful, the Schultz group92 has prepared an antibody against the phosphinate hapten 115 that catalyzes the retro aldol reaction of 116 (kcJKm = 125 M-1 s l). The equilibrium in this case strongly disfavors the condensation product, and a histidine induced in response to the phosphinate may be involved in catalysis. Interestingly and in contrast to the previous examples, the stereoselectivity of the antibody is modest. The syn diastereomer of 116 was found to be the better substrate for the antibody by 2 1 over the anti diastereomer, but no evidence of enantioselectivity was observed. 

In 2010, Enders and co-workers developed a quadruple cascade AFC/ Michael/Michael/aldol condensation reaction of indoles, acrolein, and nitroalkenes under the catalysis of diphenylprolinol TMS-ether catalyst (S)-104 following an iminium/enamine/iminium/enamine activation sequence (Scheme 6.42). " The reaction provided a straightforward and efficient entry to 3-(cyclohexenylmethyl)-indoles 105 bearing three stereogenic centers in moderate to excellent yields (23-82%) and excellent stereoselectivity (91 9->95 5 dr and 94->99% ee). 

---