Direct Bifunctional Squaramide-Catalyzed Asymmetric N-Nitroso Aldol Reaction of Tertiary β-Carbonyl Esters

Abstract

N -N i t r o s o A l d o l R e a c t i o n o f T e r t i a r y b -C a r b o n y l E s t e r s w i t h S q u a r a m i d e C a t a l y s t s SYNLETT 2012, 23, 948-950x x . x x . 2 0 1 2 Advanced online publication: 15.03.2012 Abstract: Enantioselective asymmetric N-nitroso aldol reaction of tertiary b-carbonyl esters using the bifunctional squaramide organanocatalysts is described. These adducts have been obtained in moderate yields and with up to 98% ee.Key words: N-nitroso aldol reaction, bifunctional squaramide catalysts, asymmetric catalysis, b-carbonyl esters, nitrosobenzene Asymmetric N-nitroso aldol reaction is a powerful synthetic tool for the expedient formation of C-N bond, which can be used to construct optically active a-hydroxyamino carbonyl compounds. 1 The enantioselective catalytic version of N-nitroso aldol reaction was pioneered in 2003 by Yamamoto et al. using a chiral silver complex as catalyst. 2 This seminal work was later followed up by the excellent studies of Yoshida 3 and others. 4 Among them, significant advances have been made in the improvement to the reaction using metal-based catalytic systems. Although, thus far, several organocatalytic a-hydroxyamination reactions of aldehydes, ketones and isolated enolate precursors have been achieved using chiral secondary amines 5 or TADDOL derivatives 6 as the catalyst, enantioselective constructions of quaternary stereocenters by the direct N-nitroso aldol reaction are rare. 4b,7 Jørgensen 7a et al. and Chen 7b et al. reported cinchona alkaloid derivatives promoted a-hydroxyamination of tertiary esters and lactams, respectively, and only gave enantioselectivities ranging from 22 to 72%.Recently, our group and others reported a series of investigation on chiral squaramide derivatives promoted enantioselective organic transformations. 8 We reasoned that the reaction substrates, like nitrosobenzene and b-carbonyl esters, could be activated via the hydrogen-bonding interaction with squaramide moiety and deprotonation by the neighboring tertiary amino group. Herein we present a direct enantioselective a-hydroxyamination of tertiary bcarbonyl esters catalyzed by chiral squaramide catalysts.The reaction of ethyl 2-oxocyclopentanecarboxylate and nitrosobenzene was selected as a model. We screened the reaction conditions including: catalysts, temperature, solvents, and concentrations of substrate. The results are summarized in Table 1. All four chiral catalysts were synthesized according to the methods described before by our laboratory 8j and other groups. 9,8b,d In these catalysts, 3a-c bearing both a tertiary amine moiety and a squaramide or thiourea within the same molecule can be easily prepared by condensation of a chiral amine and a monosubstituted squaric ester or isothiocyanate, and 3d contains a squaramide linked to two quinine amine groups. The structure of these catalysts is shown in Figure 1. In an initial screening of catalysts, we found that 3a was an excellent catalyst for the model reaction and gave the corresponding a-hydroxyamino...