Organic Chemistry Portal
Reactions >> Total Syntheses

Totally Synthetic by Paul H. Docherty, 10 April 2008

Total Synthesis of Stenine & Neostenine


K. J. Frankowski, J. E. Golden, Y. Zheng, Y. Lei, J. Aubé, J. Am. Chem. Soc. 2008, 130, 6018-6024.

DOI: 10.1021/ja800574m

A short and concise total synthesis of three members of the stemona alkaloid family by Jeffrey Aube’s group in Kansas. If you’re unaware of this class of natural products, this paper is an excellent place to start, as Aubé goes through the key disconnnection and step in the syntheses of Hart, Morimoto and Padwa. The biological activities include insecticidal, anthelmintic, antitussive, and various neurochemical effects.

The retrosynthesis of such a small natural product always looks a bit complex, but many reactions can be performed in one pot! The key disconnection is a tandem Diels-Alder (DA) / Schmidt reaction. The dienophile was made using a Horner-Wadsworth-Emmons olefination from two simple precursors. Addition of a Lewis acid then led to two new rings and four stereocenters. They isolated a mixture of diastereoisomers, but the product distribution was in their favour when using tin tetrachloride.

For the synthesis of the tricyclic core, the group profited much from substrate control. Alkylation with ethyl 2-bromoacetate and then a reductive trans-lactonisation delivered the lactone easily, and they used substrate control again to append the missing methyl group. To illustrate how effective the construction of the tricyclic core was, I’ve shown a diagram of the structure with the stereocenters coloured to indicate their source - red stereocenters were all generated in the DA / Schmidt reaction, whilst the blue relied on a few simple substrate controlled steps.

With the possibility of altering the stereochemical outcome of the DA / Schmidt reaction event by changing the Lewis acid used, the group focused on syntheses of other Stemona alkaloids featuring that stereochemistry. Using BF3.OEt2, they got the diastereomer required for Neostenine via an endo DA, and pursued the natural product. However, during construction of the exocyclic methyl group, substrate controlled alkylation delivered the wrong stereochemistry, so they desided to do a substrate-controlled reduction of an exocyclic methylene group. They installed the methylene group using an interesting method developed by Greene:

This sequence starts with an α-carboxylic acid formation, addition of formaldehyde, decarboxylation and then a condensation. A nice protocol and a great total synthesis!