A concise, catalytic, and general strategy that allowed efficient total syntheses of 22 natural 13-methylprotoberberines within four steps for each molecule is reported. This synthesis represents the most efficient and shortest route to date, featuring three catalytic processes: CuI-catalyzed redox-A³ reaction, Pd-catalyzed reductive carbocyclization, and PtO₂-catalyzed hydrogenation. Importantly, this new strategy to the tetracyclic framework has also been applied to the collective concise syntheses of >30 natural protoberberines (without 13-methyl group) and five aporhoeadane alkaloids.

The first, asymmetric total synthesis of the proposed structure of (+)-uprolide G acetate (UGA) is reported, and the spectral properties of the synthetic compound clearly differed from those reported for natural UGA. On the basis of comprehensive analysis of the NMR data, two possible structures for the natural UGA were proposed and their total synthesis achieved, thus leading to the identification and confirmation of the correct structure and absolute configuration of the natural UGA. This synthesis was enabled by development of a novel synthetic strategy, which revolved around three key cyclization reactions: an Achmatowicz rearrangement, Sharpless asymmetric dihydroxylation/lactonization, and ring-closing metathesis. These synthetic studies pave the way for further studies on this class of structurally unusual cytotoxic cembranolides.

Fully functionalized pyranuloses derived from Achmatowicz rearrangement (AR) are versatile building blocks in organic synthesis. However, access to trans-2,6-dihydropyrans from pyranuloses remains underexplored. Herein, we report a new two-step trans arylation of AR products to access 2,6-trans-dihydropyranones. This new trans-arylation method built on numerous plausible, but unsuccessful, direct arylation reactions, including Ferrier-type and Tsuji–Trost-type reactions, was finally enabled by an unprecedented, highly regioselective γ-deoxygenation of AR products by using Zn/HOAc and a diastereoselective Heck–Matsuda coupling. The synthetic utility of the reaction was demonstrated in the first asymmetric total synthesis of (−)-musellarins A–C and 12 analogues in 11–12 steps. The brevity and efficiency of our synthetic route permitted preparation of enantiomerically pure musellarins and analogues (>20 mg) for preliminary cytotoxicity evaluation, which led us to identify two analogues with three-to-six times greater potency than the musellarins as promising new leads.

The first, asymmetric total synthesis of the proposed structure of (+)-uprolide G acetate (UGA) is reported, and the spectral properties of the synthetic compound clearly differed from those reported for natural UGA. On the basis of comprehensive analysis of the NMR data, two possible structures for the natural UGA were proposed and their total synthesis achieved, thus leading to the identification and confirmation of the correct structure and absolute configuration of the natural UGA. This synthesis was enabled by development of a novel synthetic strategy, which revolved around three key cyclization reactions: an Achmatowicz rearrangement, Sharpless asymmetric dihydroxylation/lactonization, and ring-closing metathesis. These synthetic studies pave the way for further studies on this class of structurally unusual cytotoxic cembranolides.