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Organic Chemistry Highlights

Total Synthesis

Monday, October 2, 2017
Douglass F. Taber
University of Delaware

The Fukuyama Synthesis of Morphine

Almost thirty years ago, the late Jean d'Angelo of ESPCI Paris described (Tetrahedron Lett. 1990, 31, 875. DOI: 10.1016/S0040-4039(00)94652-5) the enantioselective assembly of the aldol product 1. Tohru Fukuyama of Nagoya University effected (Chem. Eur. J. 2017, 23, 6993. DOI: 10.1002/chem.201701438) the elegant acid-mediated cyclization of 1 to 2, opening the way to an efficient synthesis of morphine (3).

The d'Angelo synthesis of 1 began with the commercial tetralone 4. Formation of the enamine allowed alkylation with the bromoacetate 5 to give 6. Imine formation between 6 and 7 followed by the addition of methyl ketone led after hydrolysis to the solid aldol product 1. The amine 7 could be recovered and reused. A gram of the starting ketone 4 led to an approximately equal mass of the enantiomerically pure ester 1.

Note that the benzene ring of the starting material 4 is missing one of the ether oxygens of morphine, and so is considerably less expensive than the dimethoxy alternative. One of the elegant aspects of the current approach was the recognition that on exposure to triflic acid, 1 could be cyclized to 2, enabling, after later Baeyer-Villiger oxidation, the insertion of the missing oxygen into the C-H of the benzene ring.

Oxidative selenation of 2 followed by elimination led to 9, that on exposure to base could be rearranged to 10. Baeyer-Villiger oxidation gave 11, that was opened and esterified, leading to 12. Reduction followed by exposure to acid cyclized 12 to the diene 13. Singlet oxygenation of 13 failed, but reduction followed by Mitsunobu coupling with the N-methyl sulfonamide 14 gave 15, that on photo-oxygenation followed by dehydration was converted to the known morphine intermediate 16.

Following literature precedent, deprotection of 16 led to codeinone (17). Reduction followed by demethylation converted 17 into morphine (3).

D. F. Taber, Org. Chem. Highlights 2017, October 2.