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Organic Chemistry Highlights

Total Synthesis

Monday, October 3, 2016
Douglass F. Taber
University of Delaware

The Maimone Synthesis of 6-epi-Ophiobolin N

Although the enzymes of terpene synthesis efficiently cyclize acyclic precursors in a stereocontrolled fashion to the 5-8-5 ring system of the ophiobolins, as exemplified by 6-epi-ophiobolin (3), the usual tools of organic synthesis have struggled with this ring system (The Nakada Synthesis of (+)-Ophiobolin A 2014, February 3). Thomas J. Maimone of the University of California, Berkeley envisioned (Science 2016, 352, 1078. DOI: 10.1126/science.aaf6742) a bold solution to this problem, the reductive radical cyclization of 1 to 2.

The two components that were combined to prepare 1 were each assembled from terpene precursors. Grubbs cyclization of linalo÷l (4) using a Hoveyda catalyst delivered the cyclopentene 5, that was protected, then oxidized to the cyclopentenone 6.

The starting material for the other fragment was farnesol (7). Enantioselective cyclopropanation by the Charette protocol followed by Appel iodination yielded 8. On Li-I exchange, the initially-formed organometallic opened to give a new organolithium. The conjugate addition to 6 of the derived alkyl cuprate was guided by the steric and stereoelectronic directing effect of the adjacent ether oxygen. Trapping of the resulting enolate with trichloroacetyl chloride completed the assembly of 9, that was reduced and protected to give 1.

The reductive cyclization of 1 to 2 set three new stereogenic centers. The two ring centers followed from the natural scaffolding of the developing rings, and for the known propensity for radical cyclization to favor cis 1,2-substitution. Control of the third stereogenic center, on the freely-rotating sidechain, was more problematic. Reasoning that an S-H could be the H-atom donor that set this center, the authors explored a range of sterically-biased mercaptans, ending with 10 as the catalyst of choice.

Despite the crowded environment, the ketone of 2 could be converted to the epoxide by exposure to the ylide 11. On exposure to Li/naphthalene, both chlorides were reduced. This led to the elimination of the proximal epoxide oxygen, to give the diol 12. Oxidation to 13 and acid-mediated β-elimination then completed the synthesis of 6-epi-ophiobolin N (3).

The key radical cyclization of 1 to 2 was initiated by Et3B/O2. Dennis P. Curran of the University of Pittsburgh reported (J. Am. Chem. Soc. 2016, 138, 7741. DOI: 10.1021/jacs.6b04014) a detailed investigation of the several permutations of this radical-initiating mixture. Note also that AIBN is only one of a series of commercial VAZO initiators, each with its own thermal range. The VAZO initiators, including AIBN, can also be promoted photochemically.

D. F. Taber, Org. Chem. Highlights 2016, October 3.