A counterintuitive approach that destroys stereochemistry twice and then re-introduces it enables a highly selective and protecting-group-free total synthesis of a scarce natural product with interesting biological properties
As a strategy for total synthesis, steps involving catalytic asymmetric transformations are attractive — high enantioselectivities can be achieved, only very small amounts of enantiopure material (in the form of ligands or catalysts) are required as an input, and the resulting stereochemistry can be used to direct the asymmetric construction of the remainder of the molecule. Moreover, catalytic transformations that direct the formation of two stereocentres in a single step are particularly powerful — they reduce the overall number of reaction steps required in a synthesis and can be used to install stereocentres remote from one another in the molecular scaffold.
Such a strategy was chosen by John Enquist Jr and Brian Stoltz1 in their total synthesis of (−)-cyanthiwigin F. A retrosynthetic analysis of the structure led them to a cyclohexadione as a key intermediate. This diketone bears two quaternary stereocentres — one adjacent to each carbonyl group. The construction of this intermediate could be achieved by a double stereoablative approach — where stereochemistry is destroyed — followed by double catalytic asymmetric alkylation. The starting material for this step is easily produced on a multigram scale, but is formed as a mixture of three stereoisomers. Traditionally, these would need to be separated before continuing, but the ablative approach means that a mixture of all three can be used, and even means that the 'wrong' enantiomer of starting material is selectively converted to the 'right' enantiomer of product. This is a rare example of statistics favouring the synthetic chemist — the stereoselectivity of the alkylation reaction is amplified across the two steps and a very high enantiomeric excess is achieved in the product.
The synthesis was completed by a sequence comprising alkylation, a tandem ring-closing metathesis/cross metathesis, and a radical-mediated cyclization. The natural product is produced in just nine steps without the need for protecting groups. This rapid and highly selective synthesis should now enable a deeper investigation of the interesting biological properties of (−)-cyanthiwigin F and related structures.
Enquist, Jr, J. A. & Stoltz, B. M. The total synthesis of (–)-cyanthiwigin F by means of double catalytic enantioselective alkylation. Nature 10.1038/nature07046 (2008).
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Davey, S. Ablation is the answer. Nature Chem (2008). https://doi.org/10.1038/nchem.28