Photooxygenation of the Helimers of (−)-Isocolchicine:  Regio- and Facial Selectivity of the [4 + 2] Cycloaddition with Singlet Oxygen and Surprising Endoperoxide Transformations

Abstract

Photooxygenation of the helimeric mixture of (-)-(M,7S)/(P,7S)-isocolchicine (6) with the superdienophile singlet oxygen has been studied. Cycloaddition occurred with high regioselectivity at the 7a,11-positions of the alkaloid and predominantly at the diene face anti to the amidic substituent at the stereogenic center C-7, leading to two endoperoxides 7 (syn) and 8 (anti) with an 1:7 ratio. The structure of the minor product 7 was established by X-ray analysis. Investigation of the triethylamine induced transformation of the predominant endoperoxide 8 furnished a mixture of two isomers (M,7S)-10a/(M,7S)-10b in a 2:1 ratio possibly with constitutional interconversion and with (M,7S)-9 as plausible intermediate. Treatment of this mixture with silica gel/ethyl acetate at ambient temperature surprisingly led to an atropenantiomerically pure colchicinoid (M,7S)-12 characterized by an eightmembered oxocine B-ring, the structure and absolute configuration of which could be determined by X-ray analysis. For the unprecedented formation of the novel colchicinoid (M,7S)-12 a plausible reaction pathway is suggested, involving a complete transfer of the (M) helical asymmetry of the intermediate (M)-11 into (S) asymmetry of the newly formed carbon center of (M,7S)-12. Prerequisite for such a scenario is the configurational stability of the intermediate pseudobiaryl (M)-11, under the conditions employed, allowing to transmit the axial chirality onto the chiral center of the product (M,7S)-12.

Synthesis of Cyclic Peroxides

“…These, and additional results from experiments with carbonyl, cyclic ketal and thioketal derivatives were attributed to electrostatic interaction between approaching singlet oxygen and the heteroatom 416,417 . Similar electronic effects were observed in studies on singlet oxygen [4 + 2]-cycloaddition to the naturally occurring alkaloid (−)-colchicine 418,419 , but the opposite facial selectivity was reported for the isomeric (−)-isocolchicine 420 .…”

β-Phenylethylamines and the isoquinoline alkaloids

“…Treatment of 204 with triethylamine afforded an inseparable mixture of the isomeric hemiketals 205 and 206, which in ethyl acetate were converted by silica gel into the cyclic ether 207. 535 The carbene-chromium carbonyl complex 209, formed from 208, has been annulated to the allocolchinoid compound 210. 536 Patents for the preparation of derivatives of N-deactylthiocolchicine 537,538 and of colchinol 539,540 have been published.…”

Singlet Oxygen: Discovery, Chemistry, C60‐Sensitization†

“…They are useful as a model compounds, in biochemical studies e.g. in biosynthesis of prostaglandins (50), as well as the synthesis of allocolchinoids (51). The [4 + 2] cycloadditions of singlet oxygen have been utilized for the synthesis of cyclic peroxy ketals, compounds with biological activity, chondrillin and plakorin (52), as well as in the synthesis of taxol (53) and brevetoxin A (54).…”

“…However, many of them show remarkable stability. A few stable ones are shown in Scheme 12 (51,(55)(56)(57)(58)(59)(60)(61)(62)(63).…”