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Organic Chemistry Highlights

Total Synthesis

Monday, June 7, 2004
Douglass Taber
University of Delaware

Synthesis of (+)-4,5-Deoxyneodolabelline

The dolabellanes, represented by 3-hydroxydolabella-4(16), 7, 11(12)-triene-3,13-dione 1 and the neodolabellanes, represented by (+)-4,5-deoxyneodolabelline 2, are isolated from both terrestrial and marine sources. They show cytotoxic, antibiotic and antiviral activity. The recent synthesis of (+)-4,5-deoxyneodolabelline 2 by David Williams of Indiana University (J. Am. Chem. Soc., 2003, 125, 1843. DOI: 10.1021/ja0279803) highlights both the strengths and the challenges of the current state of the art in asymmetric synthesis.

The synthetic plan was to assemble both the dihydropyran 3 and the cyclopentane 4 in enantiomerically-pure form, then to effect Lewis acid-mediated coupling of the allyl silane of 4 with the anomeric ether of 3 to form a new stereogenic center on the heterocyclic ring. A critical question was not just the efficiency of this step, but whether or not the desired stereocontrol could be achieved at C-3.

The construction of the heterocycle 3 started with enantiomerically-pure ethyl lactate. Protection, reduction and oxidation led to the known aldehyde 6. Chelation-controlled allylation gave the monoprotected-diol 7. Formation of the mixed acetal with methacrolein followed by intramolecular Grubbs condensation then gave 3. The dihydropyran 3 so prepared was a 1:1 mixture at the anomeric center.

The preparation of the cyclopentane 4 proved to be more of a challenge. Rather than attempt an enantioselective synthesis, racemic 11 was prepared in straightforward fashion from commercially-available 2-methylcyclopentenone, by conjugate addition followed by alkylation of the regenerated ketone enolate. Ozonolysis followed by selective reduction then led to 11. Resolution was accomplished by enantioselective reduction of the racemic ketone, to give a 1:1 mixture of separable diastereomers. Reoxidation of one of the diastereromers gave ketone 11, which was determined to be a 96:4 mixture of enantiomers. Homologation followed by allylic silylation then gave 4 as an inconsequential mixture of diastereomers.

Condensation of the allyl silane 4 with 3 proceeded to give exclusively the desired trans dihydropyran 5. McMurry coupling of the derived keto aldehyde gave the diol 13 as a mixture of diastereomers. Oxidation of the mixture gave 2 and its C-8 diastereomer in a ratio of 8:1.

D. F. Taber, Org. Chem. Highlights 2004, June 7.