on the occasion of his 81st birthday
The Henry (nitro-aldol) reaction is one of the most valuable methods for carbonÀcarbon bond formation and its stereochemical control continues to be a challenge for organic chemists. [1±6] Specifically, an efficient synthesis of medicinally important intermediates such as phenylnorstatine through a diastereoselective catalytic (rare earth-Li-(R)-BINOL) asymmetric nitro-aldol reaction of optically active a-amino aldehydes with nitromethane has been reported. Tetrabutylammonium fluoride has been also used, albeit with less success. [5] More recently, Corey and Zhang employed a rigid chiral quaternary ammonium salt for this reaction, which leads to a highly stereoselective synthesis of the HIV protease inhibitor amprenavir. [6] More generally, nitro-aldol adducts provide ready access to non-natural 3-amino-2-hydroxy acids and 1,3diamino-2-hydroxy units, which are substructures of medicinally important compounds. [7, 8] One of us previously demonstrated that the Henry reaction is highly accelerated by pressure. [9] However, to our knowledge, no attempts have ever been made to perform a diastereoselective nitro-aldol reaction without a catalyst. [10] We envisaged that the amino group of optically active a-amino aldehydes might act as a base, and that such aldehydes would react with nitromethane under high pressure without a catalyst, thus offering a clean reaction system. Herein, we report the first example of the diastereoselective nitro-aldol reaction without any added catalyst.
N,N-Dibenzyl a-amino aldehydes 1 (Scheme 1) were chosen as a model substrate since they bear a free amino group and are relatively stable. The adducts may serve as versatile synthetic intermediates for the synthesis of non-natural Scheme 1. Reaction of a-amino aldehydes 1 with nitroalkanes 2. 599.53, a 10.465(8), b 15.279(8), c 15.425(12) ä, b 104.60(5)8, V 2387(3) ä 3 , Z 4, 1 calcd 1.668 g cm À3 , m 1.827 mm À1 , F(000)