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Organic Chemistry Highlights

Total Synthesis

Monday, January 2, 2006
Douglass Taber
University of Delaware

Synthesis of (-)-Littoralisone

The loss of mental function associated with aging is thought to be due at least in part to the degradation of neurite connections between neurons. Natural products such as (-)-littoralisone (3) that promote neurite outgrowth in cell culture are therefore interesting lead compounds for pharmaceutical discovery. The synthesis of 3 recently reported (J. Am. Chem. Soc. 2005, 127, 3696. DOI: 10.1021/ja050064f) by David W. C. MacMillan of Caltech uses organocatalysis to assemble 1, to control the relative configuration of the ring system of 2, and to assemble the glucose component of 3.

The preparation of 1 began with commercial enantiomerically-pure citronellol 4. Ozonolysis of the ester delivered the aldehyde 5, which was hydroxylated with high diastereocontrol (enantiocontrol), using the proline-catalyzed procedure developed by MacMillan (Org. Chem. Highlights 2004, January 26. Link). Protection and homologation of 6 then gave 1.

With most catalysts the dialdehyde 1 cyclized predominantly to the trans-fused product. With the correct enantiomer of the organocatalyst, however, the cyclization could be directed toward the desired cis-fused 2. Vilsmeier homologation of the electron-rich alkene followed by oxidation and lactonization then delivered 8.

A glucose derivative such as 12 would usually be prepared over several protection and deprotection steps from a commercially-available form of glucose. The authors took a different approach, using the method for protected glucose synthesis they have developed (Org. Chem. Highlights 2005, March 21. Link). Thus, proline-catalyzed dimerization of 9 gave 10, which after condensation with 11 and benzylation gave 12.

Condensation of 12 with 8 gave the exo glycoside 13. Brief exposure of 13 to 350 nm irradiation followed by debenzylation then gave 3. It is interesting to note that the photocyclization of 13 proceeded slowly even under ambient laboratory light, suggesting that this step in the biosynthesis of 3 need not be enzyme-mediated.

D. F. Taber, Org. Chem. Highlights 2006, January 2.