Azides asymmetric conjugate addition

High enantioselectivites in the aza-Michael reaction have been achieved using alternate organocatalysts, and the addition of benzotriazole to nitroolefins occurs with up to 94% ee using bifimctional catalysts such as (11.64). Guerin and Miller have developed an alternate approach to the enantioselective introduction of triazoles based on the asymmetric conjugate addition of azide followed by a 1,3-dipolar cycloaddition of the product with an alkyne. In this approach, the addition of hydrazoic acid to Michael acceptors such as (11.133) proceeds with good ee in the presence of the dipeptide (11.134). ... 

Based on previously performed studies on p-turn peptides for asymmetric acylation reactions, the group of Miller expanded the application of such catalysts to the asymmetric conjugate addition of azides to a,p-unsaturated carbonyl compounds (Scheme 13.9a). A screening of several p-turn containing peptides disclosed catalyst 10 as the appropriate catalyst for the preparation of a series of p-azido-pyrrolidinone-derived imides in good yields and with enantioselectivities up to 85%. The obtained products can be further processed towards N-Boc-protected p-amino acids. Subsequent... 

In 1999, Jacobsen reported on a catalytic asymmetric conjugated addition of hydrazoic acid to unsaturated imide derivatives (Equation 4.1). This breakthrough was possible through the use of aluminium salen azide complex 1 as catalyst. The reaction proceeded in excellent yields and enantioselectivities for alkyl substituted acceptors. Two mechanisms were proposed for this reaction activation of the azide as an aluminium azide as shown by Chung and co-workers or Lewis acid activation of the imide. The first-order dependence of the rate law on catalyst 1 indicated that dual activation was improbable. In 2005, Jacobsen reported on the extension of this methodology to ,j8-unsaturated ketones. 

Scheme 13.9 Asymmetric 1,4-conjugate addition of azide to enoates and application of p-azido alkanoates to enantioemiched triazole synthesis.

A different approach was followed by Miller in 1999. Based on the work of Rao, Uimethylsilyl azide together with acetic acid was employed as a mild and efficient method for the conjugate addition of hydrazoic acid mediated by an organic catalyst. In 2000, Miller reported an asymmetric variation of this method using histidine derived small peptides as catalysts (Equation 4.2). A salient feature of the method is the use of trimethylsilyl azide which is easier to handle than hydrazoic acid. 

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