Angew.Chem.Int.Ed.http://dx.doi.org/10.1002/acie.201410419(2014)

Hippolachnin A was first isolated from the South China Sea sponge Hippospongia lachne in 2013. Its crowded structure features a highly substituted cyclobutane ring and six contiguous stereocentres. Combined with its biological properties — potent antifungal activity and potential for the treatment of a number of diseases — these features make it an attractive synthetic target. Now, Eric Carreira and co-workers from ETH Zürich have reported the first total synthesis of (±)-hippolachnin A.

The synthesis begins with the construction of the fused cyclobutene intermediate I. A photocycloaddition between hex-3-yne and a readily available cyclopentenone (fragments in red and blue, respectively) produces the fused ring system. Two Grignard additions — one copper-catalysed 1,4-addition and one 1,2-addition — allow installation of the two ethyl side chains (shown in black). Subsequent alkenylation of the resultant tertiary alcohol produces I, which is primed for the tricycle-forming reaction. While iron-catalysed additions (proposed to proceed through activation of the alkene) resulted in tricycle formation, the stereochemistry of the product was found to be incorrect. An alternative rhodium-catalysed process gave the correct stereochemistry, but the product formed suggested that reaction was occurring by a Lewis-acid catalysed ene-type process rather than through β-C-H metalation as initially intended. The tricycle was still only formed in low yield however, and eventually Carreira and co-workers hit upon combined Lewis/Brønsted acid-catalysed conditions to form intermediate II in 65% yield as a 6:1 mixture of olefin diastereomers.

Completion of the synthesis required a stereoselective reduction of the alkene in II followed by oxidation to produce the exocyclic double bond of the natural product. Computational modelling suggested that the desired product of hydrogenation would be thermodynamically less-favoured, but hydrogenation in the presence of Pearlman's catalyst provided the desired kinetic product. α-Phenylselenylation, followed by oxidation and elimination gave (±)-hippolachnin A. The synthesis proceeds in nine linear steps with an overall yield of 9%.