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Organic Chemistry Highlights

Total Synthesis

Monday, April 1, 2024
Douglass F. Taber
University of Delaware

The White/Banwell/Lan Synthesis of Codeine

Since the pioneering work of Gates in 1952, a great deal of effort and creative imagination has gone into the synthesis of the morphine alkaloids. Building on that effort, Lorenzo V. White, now at the University of Sydney and Martin G. Banwell and Ping Lan of Jinan University, developed a simple, scalable synthesis of codeine (3), based on the Pd-mediated cyclization of 1 to 2 (Angew. Chem. Int. Ed. 2022, 61, e202203186, DOI: 10.1002/anie.202203186; Synthesis 2023, 55, 1700, DOI: 10.1055/a-1948-3335).

The convergent assembly of 1 began with the conversion of the commercial aldehyde 4 to the alkenyl bromide 5. Although the Wittig reaction initially delivered 5 as a mixture of geometric isomers, irradiation equilibrated that mixture to the crystalline 5.

Following the protocol of Singaram, reduction of the commercial enone 6 delivered 7 in high ee. Suzuki-Miyaura cross-coupling with the borane 8 delivered the allylic alcohol 9. Mitsunobu coupling of 9 with the phenol 5 proceeded with the expected inversion to give the ether 1.

The Pd-mediated intramolecular Heck cyclization of 1 presumably proceeded to give initially the diene 10. This was not isolated, but was carried on in situ to the desired tetracyclic 2.

The cyclization of 2 to 11 is a modern-day version of the radical anion cyclization pioneered by Parker. It is a tribute to the practicality of the approach to the morphine alkaloids outlined here that the experimental procedure for this cyclization used 1.3 grams of the starting carbamate. Allylic oxidation of 11 to the enone 12 followed by reduction completed the synthesis of codeine (3).

The route to codeine outlined here is an illustration of the power of a single oxygenated stereogenic center to direct the absolute sense of a total synthesis. In this context, it is intriguing to consider applications of a temporary oxygenated stereogenic center, such as that of the acetal 15, readily assembled from 13 and 14 following the protocol described by Shaozhong Wang of Nanjing University (Chem. Eur. J. 2023, 29, e202301883. DOI: 10.1002/chem.202301883).

D. F. Taber, Org. Chem. Highlights 2024, April 1.