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Totally Synthetic by Paul H. Docherty, 16 March 2009

Total Synthesis of ent-Malbrancheamide B


F. Frebault, N. S. Simpkins, A. Fenwick, J. Am. Chem. Soc. 2009, 131, 4214-4215.

DOI: 10.1021/ja900688y

This is a very short paper, but Nigel Simpkins manages to pack in quite a lot of very interesting information. A quick examination of the structure reveals a similarity to the stephacidin family, which has appeared in two previous posts here, one by Robert Williams, the other by Phil Baran. However, Malbrancheamide B is not part of the ‘family’ - they’re just bicyclo[2.2.2]diazaoctane containing natural products. They might be lacking in family identity, but the three stereocenters provide quite a challenge.

Simpkins begins the synthesis with a piece of classic stereochemical control - Dieter Seebach’s self-reproduction of chirality. In fact, Simpkins uses a system identical to that in Seebach’s original paper - key to this it the presence of proline at the core of the starting material, which is condensed with pivaldehyde to generate a new stereocenter via 1,3-control. Then, quoting Seebach: “The original centre is destroyed by deprotonation to give a chiral, nonracemic enolate. Attack at this enolate … is subject to asymmetric induction by the acetal centre. After this diastereoselective reaction, the auxiliary centre can be removed … to give the product of overall substitution with retention of configuration.” To reinforce what he means by self-reproduction - he means stereocenter A informs creation of stereocenter B. If A is destroyed, it can be recreated with overall retention by B. And it works very well for Simpkins!

Removal of the pivolyl N,O-acetal (Seebach’s acetal) to form a O-benzylhydroxamic acid, then coupling with a chloroindole derivative gave them the starting material for formation of the bicycle. First, the SEM protecting group was removed using rather exotic conditions - carbon tetrabromide in isopropanol. Simpkins explains that TBAF and HF didn’t remove the group. This deprotection reveals an α-keto amide, which then forms a diketopiperazine. Clearly, this acetal centre with the N-O bond looks particularly labile.

So addition of TMS triflate removed the hydroxyl group forming a carbocation as the reactive intermediate which reacts with the isoprene group and the indole to give both remaining rings in one process. This penultimate intermediate is in compliance with the Williams synthesis, completing a rather nice piece of work.