Enantioselective Synthesis of Protected Nitrocyclohexitols with Five Stereocenters. Total Synthesis of (+)-Pancratistatin.

Fernando Cagide-Fagín, Olaia Nieto-García, Hugo Lago-Santomé, and Ricardo Alonso
J. Org. Chem.
DOI: 10.1021/jo3022567

alonso1

Six-membered all-carbon rings are common substructures in a range of natural products, making their synthesis a challenging target for organic chemists. The concise stereoselective synthesis of such molecules is an even greater challenge.

alonso2

Organocatalysis and more specifically enamine catalysis is one of the most elegant process for stereoselective synthesis alongside stereoselective cycloadditions. The combination of the two has been shown to provide a facile and concise stereoselective synthesis of six-membered all-carbon rings in a recent publication by Cagide-Fagín F. et al.
The authors treat a dioxanone with (R)-2-methoxymethyl pyrrolidine and the readily formed enamine reacts with a β-(hetero)aryl-α-nitro-α,β-enal to give the product of a formal [3+3] cycloaddition. The stereochemistry is controlled by the preference for the formation of the (E)-enamine intermediate over the (Z) and the facial selectivity provided by the substituents at the 2-postition of the pyrrolidine.

alonso3

It is a one-pot procedure and all reaction components are readily commercially available or can be synthesised in two steps. The authors demonstrated the applicability of their new method by stereoselectively synthesising Pancrastatin in nine simple steps starting from the achiral dioxanone.

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The stereoselective synthesis of Pancrastatin has been previously reported in twelve steps starting from pinitol[1] or 21 steps starting from a non-cyclic building block.[2]

Despite the low relatively low yields of the [3+3] annulation process, this methodology provides a facile and concise way of constructing six-membered all-carbon rings. Hopefully, this report will provide incentive for future studies to further optimising the process.

1. Zhou, P. et al. Tetrahedron Lett. 2006, 47, 3707–3710
2. Kim, D. et al. Org Lett. 2002, 4, 1343-1345

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