Chemical synthesis of Aspidosperma alkaloids inspired by the reverse of the biosynthesis of the rhazinilam family of natural products.

Pyrrole and pyrroldine heterocycles are ubiquitous structural features in natural products. Nature’s biosynthetic machinery often synthesizes the pyrrole functionality in these molecules from a saturated pyrrolidine as part of its metabolic degradation pathway. Interestingly, the chemical synthesis of substituted pyrroles is usually more straightforward in comparison to that of the corresponding pyrrolidines; the saturated hydrocarbon framework of pyrrolidine is relatively unreactive, usually requiring the presence of additional functional groups to install a particular substituent, thus rendering the synthesis of such compounds difficult in comparison to their aromatic congeners. Therefore, the transformation of a highly substituted pyrrole into an architecturally complex pyrrolidine becomes an attractive and potentially powerful strategy for total synthesis (Figure 1A). Herein, we report the realization of this ideal through a reductive transannular cascade strategy that transforms the pyrrole-containing aromatic metabolite, rhazinilam (1a), directly into aspidospermidine (2), a more complex pyrrolidine-containing natural product possessing a core molecular architecture that is common to a large number of terpene– indole alkaloids (Figure 1B). This strategy exploits the reactivity of the substituted pyrrole ring by triggering a cascade reaction that results in a dramatic structural rearrangement; pyrrole-containing metabolites are transformed into pyrrolidine-containing natural products. Key to the implementation of this synthesis is the use of metalcatalyzed C H bond functionalization to introduce the desired substituents selectively and sequentially around the pyrrole ring, thereby allowing rapid assembly of the core framework of rhazinilam. The confluence of this concise pyrrole functionalization tactic with the complexity-generating cascade delivers a powerful synthetic process capable of converting planar heteroarenes into architecturally complex alkaloid natural products. Moreover, this approach could have great potential in drug-discovery programs because the structural diversification would generate a completely different scaffold that may have biological properties that are different from those of the parent pyrrole compound. Implementing total-synthesis strategies using multiple metal-catalyzed C H bond functionalizations is still a significant challenge. Controlling which C H bond transforms becomes more difficult as the complexity of the molecular environment increase. Accordingly, we envisioned that a metal-catalyzed C H arylation process at the C3 position of a simple pyrrole derivative would give the central biaryl motif, a position that is not normally reactive in conventional pyrrole chemistry (Scheme 1A). Functionalization of the C2 position was planned through a C H alkenylation process that not only builds the all-carbon quaternary center, but also installs the topological features that define the structure of the natural product. Furthermore, commencing our synthesis using 2-carbomethoxypyrrole derivative 5 could provide a handle to control the site selectivity of the two metalcatalyzed C H bond functionalizations on the heteroarene, and also engage a divergent endgame that would deliver rhazinilam (1a), kopsiyunnanine C3 (1b) and other natural-product congeners. We employed the first of our proposed metal-catalyzed C H bond functionalization reactions to build the heterobiaryl fragment (Scheme 1B). While we had used this tactic in our synthesis of rhazinicine, our divergent strategy for the synthesis of rhazinilam and kopsiyunnanine C3 required us to start from a different pyrrole, 8. Pleasingly, application of the Ir-catalyzed C H borylation methodology, developed by the research groups of Smith and Maleczka and the research groups of Hartwig, Miyaura, and Ishiyama, enabled exploitation of the synergistic steric effects of the N-Boc and 2-carbomethoxy groups and led to borylation of the pyrrole at the C4 position—the only C H bond not adjacent to any other substituent. Immediate addition of orthoiodonitrobenzene (6), catalytic Pd(OAc)2, S-Phos, and K3PO4 in nBuOH to the reaction mixture facilitated a Suzuki coupling reaction, which completed the C H arylation process, as well as removal of the Boc group, thus affording the heterobiaryl compound 9 in 63% yield from 8. The process required only one purification step and was amenable to being conducted on multigram scale. In common with our synthesis of rhazinicine, 11 was available in 3 steps from 10, in 79% overall yield (Scheme 1C). Reduction of carboxylic acid 11 with sodium borohydride, via the mixed acylcarbonate, afforded the primary alcohol, which was converted into iodide 12. Fragment union of 9 and 12 [*] L. McMurray, Dr. E. M. Beck, Prof. M. J. Gaunt Department of Chemistry, University of Cambridge Lensfield Road, Cambridge, CB21EW (UK) E-mail: [email protected] Homepage: http://www-gaunt.ch.cam.ac.uk/