Advancements in Visible-Light-Mediated Photocatalysis for Natural Product Synthesis
1. Synthesis of Aspidosperma Alkaloids: Building on our success with cyclohepta[b]indole alkaloids, we extended our synthetic strategy to the total synthesis of Aspidosperma alkaloids. Utilizing a diverse array of tryptamine-substituted cyclobutenones, we employed a photoinduced electron transfer (PET)-initiated [2+2] cyclization under blue LED light with an Ir-photocatalyst. This approach efficiently yielded cyclohexa[b]indoles, achieving the synthesis of natural products (±)-limaspermidine and (±)-aspidospermidine in 6 and 10 steps, respectively. Mechanistic insights from density functional theory (DFT) studies revealed an unconventional formal 1,3-C shift in the PET-initiated cationic radical-derived reaction, highlighting mechanistic innovation in ring strain release.
2. Total Synthesis of (+)-Haperforin G: Expanding on the capabilities of visible-light-mediated photocatalysis, we completed a 14-step total synthesis of the complex polycyclic natural product (+)-haperforin G. This achievement, reported in the Journal of the American Chemical Society (JACS, 2020, 142, 19487), involved utilizing light-initiated photocatalysis for a convergent and asymmetric cross-coupling of an iodide-derived unstabilized C(sp3)-radical with an enone (Figure 3a). Our convergent strategy underscored the utility of light-initiated radical reactions in accessing complex natural products. Notably, this synthesis was highlighted on the cover of Dr. D. F. Taber's edited book "Organic Synthesis – State of the Art 2020-2021," emphasizing its significance in contemporary organic chemistry.
We then extended this synthetic strategy for the total synthesis of Aspidosperma alkaloids. To this end, structurally diverse of tryptamine-substituted cyclobutenones were made and then carried out the PET-initiated [2+2] cyclization under blue LED in the presence of an Ir-photocatalyst, as expected, cyclohexa[b]indoles were obtained in good to excellent yields (Figure 2b). As a result, natural products (±)-limaspermidine and (±)-aspidospermidine have been synthesized in 6 steps and 10 steps, respectively. During DFT study of the [2+2] cyclization, we found that the observed PET-initiated cationic radical-derived reaction proceeds via an unconventional formal 1,3-C shift, which is neither concerted nor stepwise. These findings shed light on the mechanistic innovation of a PET-initiated radical-derived reaction that was driven by the ring strain releasing.
Since visible-light-mediated photocatalysis has emerged as a powerful new technology in synthetic organic chemistry. Central to this is the harnessing of light to access reactive intermediates, providing novel bond-forming protocols that are not readily accessible under thermal control. Continuing our work in the area of total synthesis of biologically important terpenoids, we completed a 14-step synthesis of the complex, polycyclic natural product (+)-haperforin G (see: J. Am. Chem. Soc. 2020, 142, 19487) by exploring the light-initiated photocatalysis for convergent and asymmetric cross-coupling of the iodide-derived unstabilized C(sp3)-radical with an enone (Figure 3a). The presented convergent strategy using the unstabilized C(sp3)-radical as a coupling partner demonstrates the power of light-initiated radical reaction in the synthesis of complex natural products. This total synthesis has been selected as a cover by Dr. D. F. Taber in his edited book, “Organic Synthesis – State of the Art 2020-2021.
