Intramolecular Diels–Alder Reaction of a Silyl-Substituted Vinylimidazole en Route to the Fully Substituted Cyclopentane Core of Oroidin Dimers

Abstract

An intramolecular Diels-Alder reaction of a silyl-substituted vinylimidazole delivers a diastereomeric mixture of C4-silyl functionalized dihydrobenzimidazoles. Subsequent diastereoselective reduction and elaboration of the lactone gives rise to a polysubstituted tetrahydrobenzimidazole, which, upon oxidative rearrangement, affords a single spirofused imidazolone containing all of the relevant functionality for an approach to the oroidin dimers axinellamine, massadine, and palau'amine.

Room Temperature Diels–Alder Reactions of 4-Vinylimidazoles

“…Presumably, therefore, rearomatization must occur via a proton transfer pathway, although in certain cases a radical pathway has been postulated [45]. Although we have no direct evidence for the mechanism [33,34,46], our assumption is that it most likely occurs through C4 protonation followed by deprotonation of C8b. In this manifold, it is not clear what the proton source is or what the proton acceptor is for the second step.…”

“…Not unexpectedly, this reaction has been applied to the synthesis of both simple and complex heterocyclic molecules [9] and, in particular, vinyl heterocycles [10] have proven to be useful in synthesis [11][12][13][14][15][16][17][18][19][20][21][22][23][24]. Our lab has explored the chemistry of 4-vinylimidazoles extensively and has reported both inter-and intramolecular variants for the construction of polysubstituted tetrahydro-and dihydrobenzimidazoles; [25][26][27][28][29][30][31][32][33][34] these investigations continue. Reactions proceed with generally high endo selectivity and produce either the initial adduct or the rearomatized adduct depending on the nature of the substrate and the reaction conditions (Figure 1).…”

Total Synthesis of the Nagelamides – Synthetic Studies toward the Reported Structure of Nagelamide D and Nagelamide E Framework

“…First, we wished to develop chemistry that would ultimately allow us to access several nagelamide family members from a common late stage intermediate in a divergency-oriented strategy (Figure ). Second, our experience in chemistry directed toward other oroidin alkaloids had provided us with access to intermediates, which upon suitable elaboration would provide ideal building blocks for a convergent cross-coupling strategy; as an added benefit, these building blocks were also envisioned as being suitable for other applications. − Based on these considerations, our retrosynthetic analysis is outlined in Figure . Accordingly, disconnection of the two pyrrolecarboxamides and two amino groups gives rise to protected diol 18 (Z = H), which in turn would arise from double metallation at C2 and electrophilic trapping with azide 18 (Z = N 3 ). , The precursor would arise through a cross-coupling reaction between suitably functionalized partners 19 and 20 .…”

“…Several issues had to be resolved prior to beginning our synthetic studies: predominantly, the choice of protecting groups that we would use. Based largely on our efforts toward palau’amine and related molecules, we routinely used the DMAS-(dimethylaminosulfonyl) or Bn-groups, usually as a means to differentiate electronically between two imidazoles in the same molecule. ,, However, our initial inclination was to utilize the sulfonyl urea on both imidazoles as some advantages of the DMAS-group are that it confers crystallinity on many of its derivatives and it raises the acidity of the C2-position of the imidazole, a characteristic on which we would rely later in the synthetic sequence. Accordingly, our synthetic studies began with known diiodimidazole 23 and converting it into corresponding aldehyde 25 (Scheme ).…”

Total Synthesis of (±)-2-Debromohymenin via Gold-Catalyzed Intramolecular Alkyne Hydroarylation

“… − While the precise details of their biosyntheses remain to be fully elucidated, , the origin of these natural products can be formulated in terms of electrophilic or oxidative reactions of oroidin . In the course of our studies toward a number of oroidin dimers, we have used propargylic imidazole − precursors and recognized that they may function as precursors to several monomeric derivatives in their own right. Specifically, we described the use of imidazolyl propargylamides for the synthesis of various frameworks found in the oroidin monomers and completed the formal total synthesis of cyclooroidin ( 4 ) .…”