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 %.
Highlights
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
As the main constituent of opium, morphines pain relieving properties have been exploited for thousands of years, and in modern times have resulted in its place on the World Health Organizations list of essential medicines.[2]
Its correct structure was proposed by Robinson in 1925,[3] and was confirmed by Gates[4] and Hodgkin.[5]
Summary
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. Ene–yne–ene ring closing metathesis from the heavily functionalized benzofuran 3.[11,12] A metathesis cascade cyclization offers the potential for a new end-game to the total synthesis of morphine in which the requisite functional groups are installed prior to the formation of the B and C rings.
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