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Organic Chemistry Highlights

Total Synthesis

Monday, February 4, 2008
Douglass F. Taber
University of Delaware

The Maier Synthesis of Cruentaren A

Cruentaren A (3), isolated from the myxobacterium Byssovorax cruenta, is an inhibitor of mitochondrial F-ATPase. The synthesis of 3 (Org. Lett. 2007, 9, 655, DOI: 10.1021/ol0629317; Angew. Chem. Int. Ed. 2007, 46, 5209. DOI: 10.1002/anie.200701423) by Martin E. Maier of the Universität Tübingen illustrates the power of alkyne metathesis as a tool for the synthesis of complex natural products. Very recently, Alois Fürstner of the Max-Planck-Institut, Mülheim, reported (Angew. Chem. Int. Ed. 2007, 46, 9275. DOI: 10.1002/anie.200703839) an alternative synthesis, also based on alkyne metathesis, of cruentaren A (3).

The alcohol portion of 1 was prepared by Marshall homologation of 4 with 5, leading to 6. Homologation of the derived epoxide 7 then gave 8. Note that the homologation of 7 to 8 required three steps. This might have been accomplished more directly with the Li salt of 1-propyne, easily prepared from commercial 1- or 2-bromopropene.

Evans auxiliary-controlled homologation of 9 set the relative and absolute configuration of 10, which was carried on to 12. To effect coupling, the acid of 12 was activated with carbonyl diimidazole, then condensed with the bis-alcoholate of 8. This acylation was highly regioselective, giving 1 as the only observed product.

Cruentaren A (3) has two Z alkenes, so the authors chose a bis-alkyne strategy, with a partial hydrogenation of both alkynes at the end of the synthesis. To this end, alkyne metathesis was accomplished with the Schrock tungsten carbine catalyst 13. Homologation to 15 followed by deprotection and hydrogenation then gave enantiomerically pure cruentaren A (3).

D. F. Taber, Org. Chem. Highlights 2008, February 4.