Graham Meek

A synthetic approach towards the aromatic macrocyclic core of diazonamide A based on sp2-sp2 coupling protocols

Abstract The scope for a range of sp 2 -sp 2 coupling protocols to elaborate the phenyl-indole, indole-oxazole, oxazole-oxazole, and quaternary carbon units in the marine natural product diazonamide A 1 are described, leading to the synthesis of the benzofuran oxazoles 11a and 18 , the benzofuran/biphenyl/indole 16 , and the indole- bis -oxazole, 25 .

Approaches to the quaternary stereocentre and to the heterocyclic core in diazonamide A using the Heck reaction and related coupling reactions

In model studies towards the quaternary centre at the heart of diazonamide A (early structure 2; revised structure 1), cyclisations of the alkene-substituted iodoaryls 4, 13, 18 and 23, under Heck reaction conditions, were shown to lead to the corresponding benzodihydrofuran 5, benzofuranone 14 and the oxindoles 19 and 24 respectively, in 50-80% yield. Further manipulation of the benzodihydrofuran 5 then led to the intermediates 30, 33 and 39, which make up parts of the oxazole-indole heterocyclic core in diazonamide A. Attempts to perform a corresponding 13-exo-trig Heck cyclisation from the precursor 46a, prepared from 44 and 45, leading to 47 were not successful. A similar outcome was obtained during attempts to effect Heck cyclisations from the ester 57 and the related ether 59. Treatment of the chromene-substituted iodoaryl 62 with Pd(OAc)2, PPh3 and Ag2CO3 led to the spirocycle 64 as a crystalline solid. X-Ray crystal structure analysis established that the quaternary centre in 64 had the same configuration as that present in diazonamide A (1).

A novel synthesis of 5-hydroxy-2,2-dimethyl-10-propyl-2H-pyrano[2,3-f]chromen-8-one

A concise synthesis of 5-hydroxy-2,2-dimethyl-10-propyl-2H-pyrano[2,3-f]chromen-8-one utilising a novel selective desulfonylation protocol is described. This method provides facile access to a key intermediate for the asymmetric synthesis of calanolide A.