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Organic Chemistry Highlights

Total Synthesis

Monday, February 6, 2017
Douglass F. Taber
University of Delaware

The Overman Synthesis of (-)-Chromodorolide B

(-)-Chromodorolide B (4), isolated from the nudibranch Chromodoris sp., shows potential for the investigative modification of the Golgi apparatus. Larry E. Overman of the University of California, Irvine envisioned (J. Am. Chem. Soc. 2016, 138, 2186. DOI: 10.1021/jacs.6b00541) the free radical cascade addition (C-C Bond Construction: The Kingsbury Synthesis of (-)-Dihydrocuscohygrine 2014, June 30) of the decarboxylation product from 1 to 2.

The assembly of 1 began with the bicyclic ketone 11. Following the literature procdure, Robinson annulation of the prochiral 5 with the enone 6 delivered 7 in 93% ee, brought to 99% ee by crystallization. The trans ring fusion was established by Pd-mediated reduction of the carbonate 8, and the gem dimethyl group was installed by cyclopropanation of 9 followed by hydrogenolysis of 10.

The coupling partner 14 was prepared from the ketalized tartrate 12. Alkylation gave 13, that was selectively reduced and then reoxidized.

Exposure of the ketone 11 to hydrazine followed by I2 and tetramethylguanidine led to the crystalline alkenyl iodide 15. Coupling with 14 gave 16, that was carried on to the N-acyloxyphthalimide, then rearranged with SOCl2 to give 1.

The free radical addition of the intermediate 17 to 2 proceeded via 18, that then cyclized to 3. From the product distribution, it is apparent that the diastereoselectivity of the initial addition to 2 was very good. The cyclization of 18, on the other hand, gave a 1:1 mixture of the cyclopentane intermediates. Despite this relatively low selectivity, the desired 3 could readily be isolated by chromatography.

The lactone 3 was reduced with DIBAL to the lactol, and protected as the acetate. Hydrogenolysis then delivered the alcohol 19. Oxidation followed by acid treatment and acetylation completed the synthesis of (-)-chromodorolide B (4).

D. F. Taber, Org. Chem. Highlights 2017, February 6.