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

Shuyu Chu; Niels Münster; Tudor Balan; Martin D Smith

doi:10.1002/anie.201608526

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

Angew Chem Int Ed Engl. 2016 Nov 7;55(46):14306-14309. doi: 10.1002/anie.201608526. Epub 2016 Oct 13.

Authors

Shuyu Chu¹, Niels Münster¹, Tudor Balan¹, Martin D Smith²

Affiliations

¹ Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.
² Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK. martin.smith@chem.ox.ac.uk.

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 %.

Keywords: cascade reactions; metathesis; morphine; photochemistry; total synthesis.

Publication types

Research Support, Non-U.S. Gov't