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Organic Chemistry Highlights

Total Synthesis

Monday, April 1, 2013
Douglass F. Taber
University of Delaware

The Vanderwal Synthesis of Echinopine B

Intramolecular cyclopropanation has long been a powerful strategy for stereoselective polycarbocyclic construction. For many years, this was limited to diazo carbonyl insertion. More recently, alternative strategies for intramolecular cyclopropane construction have been developed. The power of such an approach is illustrated by the total synthesis of Echinopine B (3) reported (Angew. Chem. Int. Ed. 2012, 51, 7572. DOI: 10.1002/anie.201203147) by Christopher D. Vanderwal of the University of California, Irvine.

The starting material for the synthesis was the commercial keto ester 4. Enol ether formation followed by cyclopropanation set the stage for fragmentation to the enone 7. The cyclopentannulation reagent 9 was prepared in two steps from butynol 8. Following the precedent of Heathcock (J. Am. Chem. Soc. 1983, 105, 2354. DOI: 10.1021/ja00346a041), conjugate addition proceeded with significant diastereocontrol, to give the ketone 10. Exposure of the derived tosylate to less than one equivalent of lithium diisopropylamide gave clean cyclization to the bicyclic ketone 11. It is a measure of the brevity of this approach that the cyclization of 10 to 11 was reported on a five gram scale.

Relatively little is known about conformational preference around seven-membered rings. Methylenation of 12 followed by reduction of the ester delivered the aldehyde 13. Epimerization of the aldehyde with methanolic K2CO3 gave a 4:1 mixture, with the new aldehyde dominating. Inclusion of the Ohira reagent 13 in the same pot with 11 gave the alkyne 15, also as a ~ 4:1 mixture of diastereomers. Alkylation with MOM-Cl then completed the assembly of 1.

Warming of 1 with a catalytic amount of PtCl2 led to the cyclopropane 2. This reaction apparently proceeded through a series of steps leading to a Pt carbene, that then underwent β-hydride elimination to give the enol ether. On oxidation, the enol ether was smoothly converted to the methyl ester, Echinopine B (3).

In this synthesis, the targeted natural product included a cyclopropane. Fused cyclopropanes are also versatile precursors to other polycyclic ring systems. Future developments in intramolecular cyclopropane construction will open efficient new strategies for polyalicyclic synthesis.

D. F. Taber, Org. Chem. Highlights 2013, April 1.