Stereoselective Total Synthesis of the Dimeric Naphthoquinonopyrano-γ-lactone (−)-Crisamicin A: Introducing the Dimerization Site by a Late-Stage Hartwig Borylation

Abstract

The first stereoselective total synthesis of the dimeric naphthoquinonopyrano-γ-lactone (−)-crisamicin A was realized (13 steps, 5% overall yield). 1,4,5-Trimethoxynaphthalene, reached in five known steps, was brominated at C-3 to install a but-3-enoic ester by an ensuing Heck coupling. An asymmetric Sharpless dihydroxylation followed and gave a β-hydroxy-γ-lactone with >99.9% ee. Its OH substituent and acetaldehyde established the dihydropyran ring in a completely diastereoselective oxa-Pictet−Spengler cyclization. The 2,3fused anisole moiety allowed the C 5 −H bond under Hartwig's conditions to be borylated. This set the stage for engaging the resulting C 5 −B bond in an oxidative dimerization, which led to a binaphthohydroquinon-5-yl. The latter was advanced to synthetic crisamicin A by a double CAN oxidation (→ a binaphthoquinon-5-yl) and a double demethylation.

Derivatization of 2,1,3-Benzothiadiazole via Regioselective C–H Functionalization and Aryne Reactivity

“…Oxidation of 3a using Oxone gave phenolic derivative 7 in near-quantitative yield, which we expect to serve as a convenient basis for generating new BTD-based push–pull systems. Boronic ester 3a also underwent oxidative Pd-catalyzed homocoupling 36 to the heterobiaryl system 8 , which has been of interest recently as a component of electrochromic polymers. 37 The synthesis of 8 previously proceeded by condensation of SOCl 2 and 3,3′,4,4′-tetraaminobiphenyl.…”

Fe(III)‐Catalyzed Aerobic Oxidation of 1,4‐Diols†

“…γ‐Butyrolactone is a very common unit in natural products and drugs. [ 6 ] For example, n ‐butylphthalide (NBP) is a marketed antiplatelet drug for ischemia‐cerebral apoplexy. [ 7,8b ] Canonne's group used 3‐hydroxyisobenzofuran‐1(3 H )‐one and n ‐butyl magnesium bromide to afford NBP.…”

Sharpless Asymmetric Dihydroxylation: An Impressive Gadget for the Synthesis of Natural Products: A Review

“…Different strategies have been proposed for the total synthesis of crisamacin due to its medicinal and biological applications [ 113 ]. Kopp et al [ 114 ] in 2020 reported the total synthesis of crisamicin A by carrying out Sharpless asymmetric dihydroxylation, oxa-Pictet–Spengler cyclization, Heck coupling and Hartwig borylation. Total synthesis began with the generation of 262 by Heck coupling of 259 and 261, which were prepared independently from compounds 258 and 260 .…”