Investigations of an Unexpected [2+2] Photocycloaddition in the Synthesis of (−)-Scabrolide A from Quantum Mechanics Calculations

Abstract

We utilize ab initio quantum mechanics calculations to evaluate a range of plausible mechanistic pathways for the unexpected formation of a [6−4−4] ring system from an enone− olefin photocycloaddition in the synthesis of (−)-scabrolide A, previously reported by our group. We present a mechanistic analysis that is consistent with all current experimental observations, including the photoexcitation, the C−C bond formation, and the associated chemo-and diastereoselectivity.

Total synthesis of (−)-scabrolide A and (−)-yonarolide

“…Based upon these results, we can infer the mechanistic scenario outlined in Scheme 9. 36 Initially, photoexcited enone 65 can undergo either a 1,5cyclization (Scheme 9, top pathway, red) or a 1,7-cyclization (bottom pathway, blue). Considering rst the top pathway, this initial 1,5-cyclization between C(3) and C( 13) would need to proceed with a dr of 2 : 1, favoring attack from the concave face of the enone, to align with the experimentally observed result.…”

The origin of [2+2] photocycloaddition reaction in the solid state driving ACQ-to-AIE transformation

“…28 Stoltz et al reported the PD reaction of the intramolecular enoneolefin compound by combining the CASSCF/NEVPT2 with DFT calculations and demonstrated that the ring closure of cyclobutane through the second C-C bond formation occurs after the ISC process from the triplet to the open-shell singlet surface. 29 Although several theoretical studies have explored the mechanism of PD reactions of organic dyes in the gas phase or solution, the underlying mechanism of the PD reaction in the solid state is still elusive.…”

Divergent Synthesis of Scabrolide A and Havellockate via an exo-exo-endo Radical Cascade

“…The unique structural complexity and the demand for further biological studies have made these molecules high-profile targets in the synthetic community. Since the first report from the Stoltz lab on the total synthesis of scabrolide A ( 1 ), the groups of Fürstner, Romo, Wood, Sarlah, and Zhang have published in total eight successful syntheses of 1 – 6 . Among these creative solutions, two-electron transformations play a dominate role in the construction of the central ring system and the polycyclic structures.…”