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Organic Chemistry Highlights

Total Synthesis

Monday, November 5, 2012
Douglass F. Taber
University of Delaware

The Carreira Synthesis of Indoxamycin B

Some members of the indoxamycin family show potent antineoplastic activity. The key cyclopentene-forming step in the route to Indoxamycin B (3) devised (Angew. Chem. Int. Ed. 2012, 51, 3474. DOI: 10.1002/ange.201109175) by Erick M. Carreira of ETH Zürich was the Pd-catalyzed cyclization of 1 to 2.

The starting material for the preparation of 1 was the symmetrical methyl benzoate 4. Dissolving metal reduction followed by alkylation of the resulting ester enolate delivered the diene 5. Reduction and protection followed by allylic oxidation converted 5 into 6, which was carried on to 8 as a mixture of geometric isomers. The dissociated potassium alkoxide of 8 underwent smooth oxy-Cope rearrangement, to give an enolate that was trapped as the silyl ether 1. Pd-catalyzed oxidative cyclization then completed the synthesis of 2.

With the ketone 2 in hand, two challenges remained: distinguishing the two hydroxymethyl groups, and functionalizing the allylic methine to construct the third quaternary center. Both problems were solved by the V-mediated epoxidation of the diol corresponding to 2. In situ, the anti hydroxyl opened the epoxide, to give the cyclic ether. Gold-mediated rearrangement of the O-propargylated enol ether 10 delivered an allene, that was selectively reduced to the alcohol 11. A second gold-mediated cyclization then completed the synthesis of 12.

Indoxamycin B had been assigned as having the butenyl sidechain as the more stable endo diastereomer, so the synthesis was initially finished that way. When that product proved to not be congruent with the natural material, it seemed likely that the butenyl sidechain was in fact exo. Selective hydration of 12 gave a mixture of all four alcohol diastereomers. The two exo diastereomers were separated and oxidized to the ketone 13. Wittig olefination gave a pair of geometric isomers, that were separated. The cyclic ether of the E isomer 14 was reduced to give a keto alcohol, that was oxidized to the keto aldehyde. Horner-Wadsworth-Emmons chain extension gave 15, that was carried on to Indoxamycin B (3).

One can imagine an alternative construction of 3 by intramolecular carbene insertion into the allyic methine of 2. The protocol developed by Alexei V. Novokov of the University of North Dakota (Tetrahedron Lett. 2009, 50, 6963, DOI: 10.1016/j.tetlet.2009.09.147; Heterocycles 2009, 78, 2531, DOI: 10.3987/COM-09-11788) could, for instance, be employed with the secondary alcohol corresponding to 2.

D. F. Taber, Org. Chem. Highlights 2012, November 5.