A Cascade Strategy Enables a Total Synthesis of (±)‐Morphine

Abstract

Morphine has been a target for synthetic chemists since Robinson proposed its correct structure in 1925, resulting in a large number of total syntheses of morphine alkaloids. Here we report a total synthesis of (±)‐morphine that employs two key strategic cyclizations: 1) a diastereoselective light‐mediated cyclization of an O‐arylated butyrolactone to form a tricyclic cis‐fused benzofuran and 2) a cascade ene–yne–ene ring closing metathesis to forge the tetracyclic morphine core. This approach enables a short and stereoselective synthesis of morphine in an overall yield of 6.6 %.

Visible Light Photocatalysis of 6π Heterocyclization

“…[4][5][6] This reaction offers ad iastereoselective route to cis-fused heterocycles useful in ar ange of synthetic endeavours,which we exploited in arecent total synthesis of morphine. [7] Although the Schultz photocyclization reaction was the key stereodefining step in our total synthesis,t he reactivity of the products under high intensity UV light and the sensitivity of conversion to varying substitution on the aromatic ring motivated us to find an alternative method to achieve this valuable transformation. In principle,visible light photoredox catalysis [8] or triplet energy transfer [9] from an appropriately activated sensitizer could both offer solutions to this problem.…”

Current Applications of Suzuki–Miyaura Coupling Reaction in The Total Synthesis of Natural Products: An update

“…This reaction gave the required functionalized butenolide 511 as an important intermediate in 58% yield. The latter after several steps can be converted to Morphine 506 (Scheme ) …”

“…The latter after several steps can be converted to Morphine 506 (Scheme 87). [272] Avermectins 512 initially were isolated from the culture broth of Streptomyces avermitilis by Ōmura and his SCHEME 86 Total Synthesis of Hybrubin A SCHEME 87 Total Synthesis of Morphine group. [273] It exhibited anthelmintic and insecticidal activities.…”

A new strategy to design a graphene oxide supported palladium complex as a new heterogeneous nanocatalyst and application in carbon–carbon and carbon‐heteroatom cross‐coupling reactions

“…These reactions provide new roads for design and preparation of drug substances . For example, the cross‐coupling reactions are considered as key steps in production of Losartan®, Zyprexa, Singulair, (+)‐Dynemicin, Morphine and Paclitaxel . The importance of scientific advances associated with cross‐coupling was demonstrated by awarding Richard F. Heck, Ei‐ichi Negishi and Akira Suzuki the Nobel Prize in chemistry in 2010 for the development of palladium‐catalyzed cross coupling …”