Rearrangement of a Cyclohexyl Radical to a Cyclopentylmethyl Radical on the Avermectin Skeleton

Abstract

The rearrangement of a substituted cyclohexyl radical to a cyclopentylmethyl radical on the skeleton of avermectin B1 was observed experimentally and explored computationally. The Stork-Nishiyama methodology was applied to the macrocycle of interest followed by a Tamao oxidation. The expected 5-6 fused ring product was observed in minor amounts. The major product was a 5-5 fused ring resulting from apparent conversion of the initially formed cyclohexyl radical to a cyclopentylmethyl radical. Preliminary computational results indicate that substituents in the macrocycle induce the rearrangement.

Reaction mechanisms : Part (i) Radical and radical ion reactions

“…Rather than a 1,2-shift, this rearrangement occurred via a series of cascading radical processes (Scheme 31). 64 Wille and coworkers report formation of bicyclic ketones (after hydrolysis) via a radical translocation/cyclization cascade initiated by nitrogen-centered radicals (aminium or amidyl, Scheme 32). 65 Other noteworthy examples of multistep radical rearrangements were reported, and the interested reader is directed to the pertinent reports for the details.…”

Substituent Effects on the Rearrangements of Cyclohexyl to Cyclopentyl Radicals Involving Avermectin-Related Radicals

“…We recently reported on our studies dedicated towards understanding structure-activity relationships of Avermectin B 1 , 1 , the extraordinary, highly potent macrolide discovered more than two decades ago at Merck 4,5. During the synthesis of an Avermectin analogue, an apparent radical ring-cleavage followed by a ring-closure produced a ring-contracted product, Scheme 1 5.…”

“…During the synthesis of an Avermectin analogue, an apparent radical ring-cleavage followed by a ring-closure produced a ring-contracted product, Scheme 1 5. This rearrangement from a cyclohexyl radical to a cyclopentylmethyl radical was unforeseen, since previous reports demonstrated that tin hydride typically traps the cyclohexyl radical 1o,6…”

“…We recently reported on our studies dedicated toward understanding structure−activity relationships of avermectin B 1 , 1 , the extraordinary, highly potent macrolide discovered more than two decades ago at Merck. , During the synthesis of an avermectin analogue, an apparent radical ring cleavage followed by a ring-closure produced a ring-contracted product, Scheme . This rearrangement from a cyclohexyl radical to a cyclopentylmethyl radical was unforeseen, since previous reports demonstrated that tin hydride typically traps the cyclohexyl radical. , …”

Enantioselective Total Synthesis of a Natural Iridoid

“…Silylation of cyclopentenol 14 with (bromomethyl) chlorodimethyl silane 15 yielded the bromosilyl ether, which was directly subjected to the radical cyclization . Intramolecular radical cyclization of the labile silyl ether intermediate with Et 3 B and Bu 3 SnH afforded the desired cis -fused oxasilole 16 in good yield.…”