Biosynthesis of macrolide antibiotics. 4. Stereochemistry of hydrogen labeling of brefeldin A by [2-2H3]acetate

Direct evidence for bromine-olefin charge-transfer complexes as essential intermediates of the fast ionic addition of bromine to cyclohexene

“…Bromine-olefin CTC's as essential intermediates of an ionic mechanism have also been inferred from the concentration dependence of the third-order rate constants and from competitive brominations in a nonpolar solvent as carbon tetrachloride.9 Evidence has been produced,10,11 however, against pathways involving the intermediate formation of ionic species in the slow bromine additions occurring in nonpolar media, where a molecular mechanism involving a 2:1 bromine-olefin complex has been proposed instead. 3,12 In spite of this presumedly widespread involvement of molecular complexes in the bromine addition reactions, bromine-olefin CTC's have so far been directly observed only in a very limited number of circumstances, all of which have in common a highly reduced reactivity of the olefin-bromine system. These include the following:…”

Production of brefeldin-A

“…The 7-(R) epimer has been reported from a different microbial source [8]. Biosynthesis of brefeldin-A has been investigated by Hutchinson and others [6,12,13,29,31 ]. Several total syntheses have been reported [2,5,9,11,14,18].…”

Special issue of The Journal of Antibiotics dedicated to the late Professor C Richard Hutchinson

“…Even to this day his studies on camptothecin represent most of what we know about the biosynthesis of this important clinical compound. [2][3][4][5] He extended his work into microbial natural products, beginning with macrolide brefeldin A [6][7][8][9][10][11] and polyether lasalocid A [12][13][14][15][16] in the late 1970s. In the early 1980s, attracted to microbial genetics, he gradually and, eventually, entirely shifted the focus of his biosynthetic work toward a genetic and biochemical approach.…”

“…While his early work on brefeldin A still represents some of the best examples of fungal polyketide biosynthesis by the traditional approaches, [6][7][8][9][10][11] Professor Hutchinson returned to fungal polyketides in the 1990s, but adopting a more contemporary approach. Recognizing that fungal PKSs are mechanistically and structurally distinct from bacterial PKSs and that fungal polyketides represent a major source of clinically important natural products, he worked on lovastatin biosynthesis in Aspergillus terreus as a model system for polyketide biosynthesis in fungi.…”