[reaction: see text] Sn-chelated glycine ester enolates are efficient nucleophiles for highly stereoselective 1,4-additions toward nitroolefins and subsequent reductions of the nitronate intermediates formed, giving rise to amino acid nitriles.

[reaction: see text] Chelated amino acid ester enolates undergo 1,4-addition toward nitroalkenes in a highly stereoselective fashion. Trapping the nitronates formed in the addition step with chloroformates or acyl chlorides gives rise to highly reactive intermediates that directly undergo cyclization. Depending on the N-protecting group (PG) used, iminoxazines or azetidinimines are formed in a simple one-pot protocol.

Highly reactive chelated enolates are versatile nucleophiles that underwent Michael additions towards nitroalkenes. The yields and selectivities obtained depend on the protecting groups and metal salts used. Zinc enolates in general give the best yields and the selectivities are high with tosylated glycinates. The best selectivities are obtained using tin enolates in combination with the TFA-protecting groups.Michael additions belong to the most popular C-C bond forming reactions, which might be explained by the high variability of the reaction partners. Very attractive Michael acceptors are nitroalkenes, 1 especially because the strong electron-withdrawing nitro group can be converted into a wide range of other functionalities. 2 Typical examples are the Nef reaction 3 (conversion into aldehydes) or reductions to oximes 4 and amines. 5 Oximes can be further transformed into nitriles, 6 which can also be obtained from nitro compounds directly. 7,8 Schöllkopf et al. investigated Michael additions of bislactim ethers towards nitro alkenes, and obtained best results using the corresponding titanium enolates. 9 This is in good agreement with the observations made by Seebach et al. using N-acyl oxazolidinones as nucleophiles. 10 Reduction of the nitro group gives rise to g-amino acids which are interesting building blocks.Our group has been involved in amino acid synthesis for several years, using chelated amino acid ester enolates as nucleophiles for a wide range of reactions such as Claisen rearrangements, 11 palladium-catalyzed allylic alkylations 12 and Michael additions towards a,b-unsaturated esters. 13 Because of the high synthetic potential of nitro groups, we turned our attention also to the Michael addition towards nitroalkenes.Based on the good results obtained in palladium-catalyzed reactions and Michael additions, we choose the zinc enolate of trifluoroacetyl (TFA)-protected Gly-Ot-Bu (1a) as nucleophile and commercially available (E)-nitrostyrene (2a) as Michael acceptor (Scheme 1). 8 The nitroalkene was added to the enolate at -78 °C and the reaction was monitored by TLC. Complete consumption of the nitroalkene was observed after 2 hours at this temperature and the Michael adduct 3aa was obtained in excellent yield but as a diastereomeric mixture with moderate selectivity. The anti-product was formed preferentially. Obviously the zinc enolates are highly reactive as expected, but with respect to selectivity, the results obtained were far from optimal.Therefore we varied the metal salt and the relative amount used ( Table 1). The reaction mixtures were allowed to warm to room temperature overnight. Increasing the amount of ZnCl 2 to 2.5 equivalents (entry 2) had no significant effect on either yield or selectivity. This observation was also confirmed with the other metal salts used. Magnesium enolates (entries 3 and 4) showed a comparable selectivity but the syn-product was formed preferentially with this and all other salts investigated. Slightly better selectivities were obtained with ClTi(Oi-Pr) 3 as...

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Diastereoselective Michael Additions of Chelated Enolates Towards Nitroalkenes. -The yield and stereoselectivity are dependent on the N-protecting group, the metal salt and the steric nature of substituent R 1 . Tin enolates generally give better selectivity, whereas zinc enolates provide higher yields. -(MENDLER, B.; KAZMAIER*, U.; Synthesis 2005, 13, 2239-2245; Inst. Org. Chem., Univ. des Saarlandes, D-66123 Saarbruecken, Germany; Eng.) -Jannicke 52-166