Enantioselective (formal) aza-Diels-Alder reactions between acylhydrazones and nonDanishefsky-type dienes have been developed. The reactions are promoted by a simple and economical chiral silicon Lewis acid, and are typically conducted at ambient temperature. Both glyoxylate and aliphatic aldehyde-derived hydrazones may be employed, as may variously substituted dienes, leading to the synthesis of a diverse array of tetrahydropyridines with good to excellent levels of enantioselectivity.On any list of important heterocycles, both for natural products chemistry and medicinal chemistry, piperidines would figure most prominently. While countless methods may be imagined for the synthesis of such structures, the diene-imine [4+2] cycloaddition (azaDiels-Alder, ADA) reaction must surely rank as one of the more direct and potentially versatile methods. 1 Despite this, it is only recently that the first examples of enantioselective variants of this reaction have been developed. 2 The highly enantioselective reactions that have been reported are mostly limited to the use of Danishefsky-type dienes, however, significantly limiting the scope of the reaction. We describe here the development of enantioselective (formal) ADA reactions with non-Danishefsky-type dienes employing a simple and practical silane Lewis acid.We have previously reported the use of silane 1 3 with acylhydrazones in [3+2] cycloaddition reactions with electron-rich alkenes. 4 Attempts to divert the reaction course to a [4+2] pathway focused first on cyclopentadiene, but when the complex formed from the reaction of hydrazone 2a with silane 1 was treated with cyclopentadiene, pyrazolidine 3 was the exclusive product (Scheme 1). However, when 2,3-dimethyl-1,3-butadiene was employed, a 1:1 mixture of [3+2] product 4a and [4+2] product 5a was obtained in 76% yield. We have established that the [3+2] cycloaddition reaction proceeds in a stepwise fashion, 4 and these results may be rationalized using this framework. Thus, initial attack of the diene on the silane-hydrazone complex results in an allyl cation intermediate (6), which can collapse to give the [3+2] product 4a (path a) or the [4+2] product 5a (path b).Electronic tuning of the hydrazone aryl group was pursued as a means of perturbing the ratio of products. Thus, whereas electron-poor hydrazone 2b gave a 1:1.5 ratio of products 4b and 5b, electron-rich hydrazone 2c led to a 1.8:1 ratio of products 4c and 5c (Scheme 2).* leighton@chem.columbia.edu .
Supporting Information Available:Experimental procedures, characterization data, and stereochemical proofs. This material is available free of charge via the internet at http://pubs.acs.org. Interestingly, however, ortho-methoxybenzoyl-hydrazone 2d favored the production of the [4+2] product 5d (1:1.8), suggesting that steric factors might play an important role as well. This led to examination of pivaloyl hydrazone 2e, which produced 5e as the exclusive product in 69% yield. It was subsequently found that the reaction was best conducted at room te...