Short Total Synthesis of (±)-Sceptrin

Abstract

Gifted with novel chemical features and extraordinary biological activity, sceptrin has remained a prominent unanswered synthetic challenge since its characterization in 1981 by Faulkner and Clardy. A concise and practical solution to the myriad of chemical challenges posed by sceptrin is reported in this Communication. Thus, through a sequence involving rearrangement of an oxaquadricyclane, a new method for chemo- and regioselective halogenation, a mild sequence for 2-aminoimidazole formation, and careful synthetic choreography, (+/-)-sceptrin is obtained in a minimum of steps and in 24% overall yield from dimethyl acetylenedicarboxylate without a single use of chromatography.

Sceptrin as a Potential Biosynthetic Precursor to Complex Pyrrole–Imidazole Alkaloids: The Total Synthesis of Ageliferin

“…Given the thermal instability of sceptrin [3] and ageliferin, it is quite surprising that this reaction proceeds cleanly and reproducibly. In fact, decomposition begins after only 90 seconds at 195 8C.…”

“…The ambivalent reactivity of the 2-aminoimidazole C4ÀC5 double bond contrasts sharply with that of previously studied olefins in this rearrangement. [12] For example, simply heating 1 at 80 8C in CD 3 Incidentally, this appears to be the first report of deuterium exchange at a carbon center on a 2-aminoimidazole under neutral conditions. It is postulated that the tautomeric form of sceptrin (1), structure 4, is involved in this proton-addition/proton-loss sequence.…”

“…[16] In summary, we have completed the first total synthesis of ageliferin (2, Scheme 1), identified the first vinyl cyclobutane rearrangement of a natural product, and advanced an alternative biosynthetic hypothesis for the formation of complex pyrrole-imidazole alkaloids. The synthesis adds merely one additional step to the concise, practical, and analogue-friendly sceptrin synthesis developed in our laboratory, [3] and it can thus easily be scaled up to allow for a full evaluation of the biological potential and structure-activity relationships of these intriguing alkaloids. Efforts are underway to harness the innate symmetry and reactivity of 1 and related structures to effect conversion into other naturally occurring pyrrole-imidazole alkaloids.…”

“…[2] Recently, the long-standing synthetic challenge posed by sceptrin (1) was solved with a concise sequence that proceeds in approximately 24 % overall yield, can be conducted on a preparative scale, and does not necessitate chromatography. [3] Ageliferin (2), [4] isolated in 1986 from Agelas conifera by Rinehart, is an antiviral agent [4b] and may be a useful chemical tool for mechanistic studies of actin-myosin contractile systems.…”

“…We also present an alternative biogenetic hypothesis commencing from 1 rather than 3 for other complex dimeric pyrrole-imidazole alkaloids, including the axinellamines [10] and palau'amines. [11] Our explorations began with several unsuccessful attempts to effect photochemical [1,3] sigmatropic rearrangement of 1. Thus, exposure of 1 to a 450-W Hanovia lamp (quartz or pyrex filter) for several days led only to gradual decomposition.…”