Organic Chemistry Portal
Organic Chemistry Highlights

Monday, November 18, 2019
Douglass F. Taber
University of Delaware

Alkaloid Synthesis: Dihydro-β-erythroidine (Vital/Kristensen), Cephalezomine C (Kim), Gephyrotoxin (Fan), Qiuinine (Chen), Naltrexone (Ellman), Strychnine (Qin)

Dihydro-β-erythroidine (4) is one of the most potent known inhibitors of the nicotine acetylcholine receptor. Paolo Vital of H. Lundbeck A/S and Jesper L. Kristensen of the University of Copenhagen set the absolute configuration of 4 by the Pd-catalyzed asymmetric Tsuji-Trost allylation of 1 with 2 to give 3 (J. Am. Chem. Soc. 2019, 141, 8783. DOI: 10.1021/jacs.9b04626).

Several strategies have been devised for conserving the enantiomeric purity of proline as it is incorporated into more complex structures. Sanghee Kim of Seoul National University improved the West approach by incorporating the 2,3-dimethylbenzyl protecting group of 5. Diastereoselective N-alkylation with 6 followed by rearrangement led to 7, establishing the key stereogenic centers of cephalezomine G (7) (Org. Lett. 2019, 21, 1121, DOI: 10.1021/acs.orglett.9b00036; Chem. Eur. J. 2019, 25, 2447, DOI: 10.1002/chem.201804965).

Gephyrotoxin (11) is one of the most complex of the Dendrobates alkaloids. Qing-Hua Fan of the Institute of Chemistry, Chinese Academy of Sciences set the relative and absolute configuration of 10 by the hydrogenation of 9 (Angew. Chem. Int. Ed. 2019, 58, 3809. DOI: 10.1002/anie.201812647).

En route to quinine (14), David Y.-K. Chen, also of Seoul National University, prepared the enantiomerically pure alcohol 12. Oxidative cleavage of the symmetrical ring system then led to 13, having three of the four stereogenic centers of 14 (Angew. Chem. Int. Ed. 2019, 58, 488. DOI: 10.1002/anie.201811530).

Naltrexone (17), a derivative of morphine, is not a natural product, but it has saved thousands from opiod overdoses. In the course of a synthesis of 17, Jonathan A. Ellman of Yale University set the absolute configuration of 15 by Sharpless asymmetric dihydroxylation, then cyclized it to 16 with a Rh catalyst (Chem. Sci. 2019, 10, 535. DOI: 10.1039/C8SC03748E).

Yong Qin of Sichuan University described an elegant synthesis of strychnine (21), based on the assembly of 20 by the photoredox cyclization of 18 with 19 (Org. Lett. 2019, 21, 252. DOI: 10.1021/acs.orglett.8b03686). The variety of synthetic approaches to 21 have been nicely summarized in a Wikipedia article.

D. F. Taber, Org. Chem. Highlights 2019, November 18.