This week’s offering comes from The University of Oxford in the UK, and deals with the first asymmetric synthesis of Nakinadine A presented by the group of Prof. S. G. Davies.

This family of alkaloid was isolated from an Okinawan sponge in 2007-2008 by a Japanese group. The key reaction in this synthesis is, of course, the introduction of the chirality with something that allows functionalisation at one of the ends in order to attach the alkyl- or alkenyl-pyridine chains. The approach used here was the diastereoselective addition of nucleophiles to an imine derived from tert-butylsulphinamide in a Mannich type of reaction.

The addition product A can be obtained in with high diastereoselectivity. The ratio is around 80:20 and this can easily be purified up to >97:3 of the desired diastereoisomer. The formation of a major diastereoisomer from this asymmetric Mannich-type reaction is explained by the reaction proceeding via the chairlike transition state B (where the nucleophile is the enolate of phenylacetic acid). The ratio of E:Z enolates can be determined by NMR (in the case of the Li enolate), this was apparently not possible in the case of the Mg enolate:

This was  proposed in order to rationalise the diastereoselectivity of this type of reaction. The facial selectivity for attack at the N-tert-butylsulfinyl imine is either determined by chelation or steric factors, for example, orientation of the S- lone pair toward the approaching enolate. With the key intermediate in hand the rest of the synthesis is uncomplicated: Cleavage of the t-butylsulphinamide under acidic conditions provides the amine which then can be persuaded to undergo a reductive amination using sodium tri-acetoxyborohydride and the aldehyde C :

So the target compound was prepared in 10 steps from 11-bromoundecan-1-ol with an overall yield of 10% and in >98% ee and a diastereoisomeric ratio of 97:3. With the enantiomeric purity of the sulphonamide being >98% it follows that the % ee of the product can confidently placed at a similar figure.

A comparison of spectral data with the published values indicated that these compounds indeed have this structure and stereochemistry. All in all a nice piece of chemistry from Oxford.