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Organic Chemistry Highlights

Total Synthesis

Monday, October 4, 2004
Douglass Taber
University of Delaware

Synthesis of Deacetoxyalcyonin Acetate

Deacetoxyalcyonin acetate 1 and euncellin 2 are representative members of the eunicellin class of diterpenes. The synthesis of deacetoxyalcyonin acetate 2 by Gary Molander of the University of Pennsylvania (J. Am. Chem. Soc. 2004, 126, 1642. DOI: 10.1021/ja0398464) illustrates the power of intramolecular organometallic carbonyl addition for ring construction.

The six-membered ring of 1 was commerically available in enantiomerically-pure form as α-phellandrene 3. The challenge was to stitch the highly-substituted ten-membered ring of 1 onto the disubstituted alkene of 3. The strategy that was conceived was to first construct the seven-membered ring of 8, then effect three-carbon ring expansion to give 11.

The plan for seven-membered ring construction was to effect stepwise 4 + 3 cycloaddition of 6 to the protected dialdehyde 5. The preparation of 5 began began with 2+2 cycloaddition between 3 and methoxy ketene, to give 4 with high regio- and diastereocontrol. Photochemical cleavage then gave 5. The acid-mediated 4 + 3 proceeded via initial addition to the less congested ionized aldehyde, to give the β-keto ester 7. Alkylation of the dianion of 7 followed by ester hydrolysis and selenation /oxidation established the enone 8.

Three-carbon ring expansion was carried out in two stages. First, two-carbon homologation of the exo methylene ketone 8 followed by trapping of the intermediate enolate as the triflate led to 9. Nozaki-Hiyama-Kishi coupling followed by acetylation smoothly converted 9 into 10.

The trisubstituted alkene of 10 was more readily oxidized than was the congested tetrasubstituted alkene, so the more reactive alkene was temporarily epoxidized. After ozonolysis, the epoxide was reduced off using the Sharpless protocol. It is a tribute to the specificity of this reagent that the easily-reduced α-acetoxy ketone is not affected. Selective silylation of the more accessible ketone followed by methylenation, hydrolysis and addition of methyl lithium to the outside face of the previously protected carbonyl then delivered 1.

D. F. Taber, Org. Chem. Highlights 2004, October 4.