A total synthesis of the putative structure of nagelamide D from imidazole is described. A Stille cross-coupling is used to construct the bis imidazole skeleton, and the pyrrolecarboxamides are introduced via a double Mitsunobu reaction using a pyrrolehydantoin derivative. Discrepancies between the published spectroscopic data and that reported in the literature cast doubts either on the assigned structure or the reported data.The oriodin alkaloids are a growing family of pyrrole-imidazole alkaloids produced by members of the Agelisida, Axinellida, and Halichondrida orders of marine sponges (Figure 1). 1 These natural products range in complexity from the simple monomeric parent system oroidin (1) 2 to the most complex member reported to date, the tetrameric styllisadine A. 3 Formally, these natural products arise from a variety of oxidation and oligomerization pathways of the basic building block oroidin (1) and congeners, but little is known about the details of their biosynthesis. 4, 5 In large part due to the challenging structural problems presented by the dimeric members of this group, we and others have become interested in developing general synthetic approaches to the pyrrole-imidazole alkaloids including ageliferin (2), 6 axinellamine A, 7 palau'amine, 8 and the nagelamides (3-6). 9-11 The original group of nagelamides, is a collection of eight oroidin dimers, which were isolated from an Okinawan marine sponge, Agelas sp. by Kobayashi and coworkers. 9 Subsequently, additional members of this subfamily have emerged which reinforce the structural diversity found in the oroidin natural products. Of the initial collection of natural products, two broad groups of compounds were described
Various 4-vinylimidazole derivatives have been prepared from the corresponding 4-iodoimidazoles or from urocanic acid. Several methods for the elaboration of these vinylimidazoles and their Diels-Alder reactions are reported. All of the vinylimidazoles prepared in the course of this study react with N-phenylmaleimide quite readily with mild thermal activation providing a single cycloadduct, in most cases the initial, nonaromatic adduct. With more electron rich substrates, there is a tendency for these initial cycloadducts to undergo aromatization, ene reaction, and oxidation although this can be circumvented to a large extent by the choice of reaction conditions. Limited reactions were observed with other dienophiles, providing the expected cycloadducts in most cases, although an abnormal adduct was obtained in one case with dimethyl acetylene dicarboxylate. These substrates also participate in regioselective Diels-Alder reactions with monoactivated dienophiles, but require fairly forcing conditions, thus only providing the aromatized cycloadducts in modest yields. An investigation of substituent effects at the 2-position of the imidazole moiety was undertaken, in which electron-donating and weakly electron-withdrawing substituents are tolerated. In addition, several substrates with terminally substituted vinyl moieties have been investigated.
The first total synthesis of the Leucetta alkaloid calcaridine A is described based on a biosynthetic postulate. Application of an oxidative rearrangement of a 4,5-disubstituted imidazole leads to the formation of both calcaridine A and epi-calcaridine A. An X-ray crystal structure determination on the latter has allowed the assignment of the relative configuration of the epimeric natural product and calcaridine A by extrapolation.2-Aminoimidazole-containing alkaloids isolated from marine sponges have recently captured the attention of a number of synthetic groups, in particular several members of the oroidin family. 1-6 Other families of imidazole-containing alkaloids, including examples isolated from Leucetta sponges, have similarly attracted the attention of several groups. 7-9 Recently Crews and coworkers reported a series of structurally novel natural products 1-4 isolated from a Fijian marine sponge, Leucetta sp., some of which have modest anti-bacterial activity. 10, 11 Some concerns have been raised based on synthetic studies directed towards spiroleucettadine (2) with respect to the accuracy of the assigned structure. 12-14 This structural ambiguity notwithstanding, within each of these compounds a 2-aminoimidazole moiety and two benzyl moieties can be identified, although there are differences in the position of oxidation. There are obvious, if experimentally undefined, biosynthetic relationships between these molecules, and thus an approach to one may provide intermediates that can be used en route to other family members. In both the Crews reports ,11 and in a subsequent report by Watson and co-workers of an approach to the assigned structure of spiroleucettadine (2), 12 it is suggested that calcaridine A (1) and the other congeners 2-4 are derived from rearrangement and/or oxidation chemistry of naamine A 15-17 (14-desmethoxy 6) or a closely related derivative. 10-12 This particular postulate led us to speculate that calcaridine A, at least, is formed by an oxidative rearrangement of an intermediate that we term 14-methoxynaamine A (6). Although 6 appears to be unknown in the literature at the present time, several years ago the N-substituted derivative, 14-methoxynaamidine A (5) was isolated from a Leucetta sp. sponge, and therefore it is tempting to speculate that 6 is a biosynthetic precursor to both (1) and (5). 18 In this communication, we describe the successful execution of a "biomimetically-inspired" approach to (±)-calcaridine A (1) which employs our recently discovered oxidative rearrangement of 4,5-disubstituted imidazoles to the corresponding 4,4-disubstituted-5-imidazolone. 19-21 Although calcaridine A may not be considered a complex and challenging natural product per se, it contains two vicinal stereocenters for which neither the absolute nor the relative lovely@uta.edu. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript stereochemistry were reported (our synthetic studies have led to the assignment of the relative stereochemistry). In...
A silver(I) complex derived from a polyfluorinated tris(pyrazolyl)borate effectively catalyzes carbene transfer to allylic and propargylic halides, leading to the formation of alpha-haloacetate derivatives.
The total syntheses of oroidin, hymenidin and clathrodin are reported via the intermediacy of an imidazo[1,2-a]pyrimidine derivative. The chemistry described herein obviates the need for expensive guanidine reagents, multiply protected prefunctionalized 2-aminoimidazole synthons, or the need for laborious olefinations thereby achieving synthetic efficiency amenable to scale-up. The approach outlined in this manuscript provides an opportunity for further functionalizations through the imidazo[1,2-a]pyrimidine core and through functional groups placed strategically on the side chain.
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