There has been considerable interest in the development of catalytic enantioselective enolate -electrophile bond constructions, which typically have employed metal enolates. 1 While enamines have been well-known as useful enol synthons since the pioneering work by Stork, 2 success in such endeavors for asymmetric induction has proven elusive. The diastereoselective reaction using chiral enamine 3 and asymmetric reaction via a chiral proline enamine and its analogues 4 are recent strategies in this context. However, the corresponding enantioselective process has not been fully realized with achiral enamines as nucleophiles. 5 We report herein the first enantioselective Brønsted acid catalysis 6 of achiral enamine in nitroso aldol synthesis, which proceeds in a completely regio-and highly enantioselective manner (Scheme 1). 7The first nitroso aldol synthesis using enamine was reported in 1972 by Lewis et al. 8 They described that the reaction of morpholine enamine of cyclohexanone provided the N-nitroso aldol product in 30% yield. Surprisingly, we found that a similar reaction using the pyrrolidine enamine of cyclohexanone gave rise to the O-nitroso aldol product exclusively in benzene at 0 °C. 9 Furthermore, these reactions could be accelerated significantly by the addition of Brønsted acids. Although the reaction of morpholine enamine was very slow in toluene at -78°C , rapid access to N-nitroso aldol synthesis was realized in the presence of methanol. 10 Meanwhile, the pyrrolidine enamine gave no nitroso aldol product at -78 °C in toluene but significant acceleration for the O-nitroso aldol pathway took place in the presence of acetic acid. 10 With these observations in hand, a variety of chiral carboxylic acids were examined using the pyrrolidine enamine 1a to produce the O-nitroso aldol product. 11 1-Aryl glycolic acids were identified as the most successful promoters. It was also quite interesting to find a significant effect of solvent on this transformation. The best result was obtained using (S)-1-naphthyl glycolic acid and piperidine enamine 1b in diethyl ether, giving 92% ee and 77% isolated yield.For N-nitroso aldol synthesis, we also screened various alcohols and phenols. 11 We immediately found TADDOL to be a promising Brønsted acid catalyst for our purpose. The best result was obtained when the reaction was conducted with 30 mol % of 1-naphthyl TADDOL in toluene using piperidine cyclohexene enamine (1b); only the N-adduct was produced in 83% ee and 81% isolated yield.Under these optimized conditions, the scope of the reaction was explored (Tables 1 and 2). 12 In general, high enantiomeric excesses are observed for cyclohexene enamines bearing a piperidine-based amine moiety (1b). The most gratifying aspect of this study was the exclusive Supporting Information Available: Text, tables, and figures giving experimental procedures, spectral data for all new compounds, and crystallographic data and an X-ray crystallographic file in CIF format. This material is available free of charge via the Internet at...

The highly enantioselective and O-selective nitroso aldol reaction of tin enolates 2 and nitrosobenzene (1) has been developed with the use of (R)-BINAP-silver complexes as a catalyst. After the various silver salts were surveyed, the AgOTf and the AgClO4 complex were found to be optimal in the O-selective nitroso aldol reaction in both asymmetric induction (up to 97% ee) and regioselection (O/N = >99/1), affording aminooxy ketone 3. The product 3 can be transformed to alpha-hydroxy ketone 5 without any loss of enantioselectivity. Thus, the method provides an efficient approach to the catalytic enantioselective introduction of oxygen alpha- to the carbonyl group.

The selective generation of three different silver-BINAP catalysts has been achieved via the proper combination of metal/ligand ratio and/or choice of silver salt. Indeed, the X-ray crystallographic study has been used to gain insight into the structure of the catalyst. After the evaluation of each species, 1:1 (AgX.(R)-BINAP) complex was found to be the real active species in the O-selective nitroso aldol reaction. On the other hand, a systematic survey of solvent has shown that the optimal 2:1 (AgX.(R)-BINAP) complex is the effective catalyst in the N-selective pathway. Thus, a new method of generation of the silver-BINAP catalyst and the synthetic transformations provide not only new insights into the developing area of catalytic enantioselective nitroso aldol synthesis but also clear guidance for the design of an effective catalyst.

Nitrosobenzene or nitrosopyridine are found to be attractive electrophiles in catalytic enantioselective carbon-nitrogen and/or carbon-oxygen bond forming reactions. In the presence of designer Lewis or Brønsted acid catalysts, catalytic enantioselective O- and N-nitroso aldol reaction or nitroso Diels-Alder reaction proceed smoothly. The scope and limitation of new catalytic processes are described.

This communication presents studies that illustrated nitroso Diels-Alder adduct has been obtained in uniformly high enantioselectivity via a tandem nitroso aldol/Michael reaction using an amine catalyst. The regiochemical outcome of this construction is documented to be the opposite to that of the normal nitroso aldol reaction, which has been determined by X-ray analysis. The reaction of the enone with silver-BINAP catalyst has also been investigated in conjunction with the control of regiochemistry in a stepwise process.