Discodermolide, asymmetric aldol

Even with more atom-economical, catalytic, asymmetric aldol options available, the use of chiral auxiliaries on large scale should not always be avoided based on the perception of poor AE. The following example toward discodermolide (82) from Novartis Process Chemistry, where AE, process greenness, and waste minimization are of great concern, demonstrates that aldol transformations with auxiliaries are possible on multi-kg scale [66] (Scheme 13.12). After aldol reaction and cleavage of the chiral controller to produce 80, they were able to recover 81 in 67% yield via crystallization. 

Paterson, I., Delgado, O., Florence, G.J., Lyothier, I., Scott, J.P., Sereinig, N. (2003) 1,6-Asymmetric Induction in Boron-Mediated Aldol Condensations Application to a Practical Total Synthesis of (-F)-Discodermolide. Organic Letters, 5, 35-38. 

Paterson developed asymmetric enolboration-aldolization involving diisopinocampheylboron triflate (57, 32), He has shown the utility of enolboration for the synthesis of various macrolide molecules. His recently completed target molecules include Concanamycin F (33) and the potential anticancer agent, Discodermolide (34) (Figure 6). 

Altogether, our total synthesis of (+)-discodermolide uses four asymmetric boron aldol reactions and proceeds in 27 steps and 7.7% overall yield (for the longest linear sequence starting from commercial methyl (S)-3-hydroxy-2-methylpropionate). 

Paterson, I. and Florence, G.J. (2000) Synthesis of (+)-discodermolide and analogues by control of asymmetric induction in aldol reactions of y-chiral (Z)-enals. Tetrahedron Lett., 41, 6935-6939. 

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