Evolution of a Strategy for the Enantioselective Total Synthesis of (+)-Psiguadial B

Abstract

(+)-Psiguadial B is a diformyl phloroglucinol meroterpenoid that exhibits anti-proliferative activity against the HepG2 human hepatoma cancer cell line. This full account details the evolution of a strategy that culminated in the first enantioselective total synthesis of (+)-psiguadial B. A key feature of the synthesis is the construction of the trans-cyclobutane motif by a Wolff rearrangement with in situ catalytic, asymmetric trapping of the ketene. An investigation of the substrate scope of this method to prepare enantioenriched 8-aminoquinolinamides is disclosed. Three routes toward (+)-psiguadial B were evaluated that featured the following key steps: 1) an ortho-quinone methide hetero–Diels–Alder cycloaddition to prepare the chroman framework; 2) a Prins cyclization to form the bridging bicyclo[4.3.1]decane system, and 3) a modified Norrish–Yang cyclization to generate the chroman. Ultimately, the successful strategy employed a ring-closing metathesis to form the seven-membered ring and an intramolecular O-arylation reaction to complete the polycyclic framework of the natural product.

Unraveling Plant Natural Chemical Diversity for Drug Discovery Purposes

“…2-epi-narciclasine (Borra et al, 2018) Narcissus sp. (plant) 4 13 3 4 9 4,5 (+)-psiguadial B (Chapman et al, 2018) Psidium guajava (plant) 6 23 1 7 15 1,3…”

A modular approach to prepare enantioenriched cyclobutanes: synthesis of (+)-rumphellaone A

“…We began by investigating the scope of the directed C–H arylation of 8-aminoquinolinamide 4 , which was prepared in three steps and 99% ee from commercially available 2,2-dimethylcyclopentan-1-one 6. Using our previously developed conditions [Pd(OAc) 2 (15 mol%), Ag 2 CO 3 (1.0 equiv.…”

“…We recently reported a synthesis of the natural product (+)-psiguadial B ( 1 ), which featured a tandem Wolff-rearrangement/asymmetric ketene addition to prepare enantioenriched 8-aminoquinolinamide 4 (Scheme 1). 6 Given the short synthesis of 4 from commercial starting materials, we became interested in further applications of this chiral building block. Specifically, we envisioned that directed C–H arylation could enable diversification at the β-position,7 while hydrolysis of the 8-aminoquinolinamide followed by decarboxylative radical cross-coupling could enable diversification at the α-position.…”

Anti-Estrogenic Activity of Guajadial Fraction, from Guava Leaves (Psidium guajava L.)

“…Gas chromatography was the most appropriate analytical technique for the purpose of comparison with data available in the literature [27]. The comparison of tandem mass spectrometry (MS/MS) spectra for the peaks at RT 45.01 and 46.71 min, with reported data by Yang et al [27], allows the confirmation of fragmentation pattern for 1 and 2, isomeric natural products isolated from guava leaves [28], showing major fragments ion peaks at m/z 474, 446, 405, 391, 309, 271, and 241 ( Figure S4B,C). The peak at RT 28.08 min is due phthalate contamination in solvent.…”