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Organic Chemistry Highlights

Total Synthesis

Monday, May 2, 2016
Douglass F. Taber
University of Delaware

The Yamashita Synthesis of Limonin

Limonin (3) features a trans relationship between the two angular methyl groups. In approaching the first total synthesis of 3, Shuji Yamashita of Tohoku University hypothesized (Angew. Chem. Int. Ed. 2015, 54, 8538. DOI: 10.1002/anie.201503794) that the trans 1,3-dimethyl substitution of 2 and so of 3 could be established by the oxidative free radical cyclization of the β-keto ester 1.

The starting point for the preparation of 1 was the chlorination of geraniol (4). Epoxidation gave 5, that was coupled with 6, then rearranged to 7. The conversion of 7 to the chloride proceeded with the expected allylic rearrangement, to give an intermediate that was used to alkylate the dianion 8, leading to 9.

In the event, 1, prepared by desilylation of 9, indeed cyclized to give predominantly the crystalline tetracyclic ketone 2 having the desired cis 6/5 ring fusion. Robinson annulation converted 2 into 11, that was methylated to give 12.

Reduction of 12 and selective epoxidation led to 13. In a remarkable transformation, warming of the epoxide with NaCN in DMSO led to the ketone 14. Allylic oxidation gave 15, that was carried on via dissolving metal reduction and Pd-mediated oxidation to the dienyl triflate 16. Rather than install the easily oxidized furan directly, 16 was coupled with 17, to give an intermediate that was converted to the endoperoxide. Reduction and dehydration then completed the assembly of the furan 18.

In another remarkable transformation, the endoperoxide was rearranged with a Ru catalyst to the epoxy ketone 19. Baeyer-Villiger oxidation under alkaline conditions gave the δ-lactone, that was deprotected and oxidized by the Suárez protocol to 20. Deprotection followed by oxidation then completed the synthesis of Limonin (3).

The absolute configuration of 3 was set by the cyclization of the prochiral 1 to 2. Dan Yang of Hong Kong University has described (Catalytic Enantioselective Carbon-Carbon Ring Construction 2007, August 20), a Se modification of this sort of racidal cyclization that delivered the product in high ee.

D. F. Taber, Org. Chem. Highlights 2016, May 2.