Enantioselective Total Synthesis of (+)-Neosymbioimine

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol070049a.html

From Prof. Martin E. Maier's group at Institut für Organische Chemie, Universität Tübingen, Tübingen, Germany

This was a recent Org Lett ASAP paper detailing the first enantioselective total synthesis of (+)-Neosymbioimine. Another entry in this blog was entered last month on an enantioselective total synthesis or a related molecule (+)-Symbioimine. The key step of the current synthesis involved an employment of intramolecular Diels-Alder reaction of a diene generated from HWE olefination.

The retro is as shown below. The plan traced back to citronellol which is commercially available in 92% ee.

The iminium installation was to be accessed via nitrile. Before that, several routine installations of functional groups were planned including the use of protected-TBS ether (4), as a directing group in controlling the enantioselectivity of the IMDA. Secondary alcohol precursor of 4 was to be installed using MacMillan's organocatalytic protocol for enantioselective alpha-hydroxylation of an aldehyde.

The forward direction of the synthesis proceeded as followed. Due to limitations in posting pictures on blogspot, detailed descriptions of reaction conditions were omitted.

The key installation of diene using HWE olefination proceeded in good enantioselectivity to provide a 1:1 mixture of diene 12 and cycloadduct 13. Heating this mixture turned all 12 into 13 with about 5% of uncyclized material present as seen in 1H NMR. This uncyclized material was soon discovered to be epimeric C-sp3 methyl group, which was originally present in commercial (-)-S-citronellol 5. In fact, some impurities (5%) attributed to 5 were observed in NMR of all intermediates 7-13. The cycloadduct was formed as a single diastereomer. The 5% uncyclized material was postulated to arise from the inability of the epimer to overcome the steric hindrance in the transition state of IMDA (Scheme 2).

The other notable step was an unexpected diastereoselectivity observed in methylation alpha to nitrile group (14 to 3). This was attributed to the steric bulk of OTBS group, therefore the approach of MeI from above the aryl ring. Structure of 3 was confirmed by x-ray crystallography.

In the last sequence of reactions, resorcinol was globally sulfated with SO3, followed by selective hydrolysis with water/methanol. The monosulfate natural product 1 was found to hydrolyze slowly. This was attributed to stabilizing effect of inner salt on the remaining sulfate group (Scheme 3).

(+)-Neosymbioimine (1) obtained from selective hydrolysis (as inner salt) could be routinely purified by flash column chromatography on silica gel using CHCl3/MeOH as eluent.