A Divergent Enantioselective Strategy for the Synthesis of Griseusins

Abstract

The first enantioselective total synthesis of griseusin A, griseusin C, 4′-deacetyl-griseusin A, and two non-native counterparts in 11–14 steps is reported. This strategy highlights a key hydroxy-directed C–H olefination of 1-methylene isochroman with an α,β-unsaturated ketone followed by subsequent stereoselective epoxidation and regioselective cyclization to afford the signature tetrahydro-spiropyran ring. Colorectal cancer cell cytotoxicities of the final products highlight the impact of the griseusin tetrahydro-spiropyran ring on bioactivity. As the first divergent enantioselective synthesis, the strategy put forth sets the stage for further griseusin mechanism-of-action and SAR studies.

Controlling the Substitution Pattern of Hexasubstituted Naphthalenes by Aryne/Siloxyfuran Diels–Alder Additions: Regio‐ and Stereocontrolled Synthesis of Arizonin C1 Analogs

“…Each arizonin C1 analog of Figure or Scheme was prepared by an identical series of 4 late steps: 1) Heck‐coupling; 2) asymmetric dihydroxylation; 3) oxa‐Pictet–Spengler reaction; oxidation of the naphthohydroquinone (details: below). This strategy equals one, which we followed in total syntheses of the naphthoquinonopyrano‐γ‐lactone natural products (+)‐kalafungin ( 1a ),[7c] (–)‐arizonin B1 ( 2 ),[7r] (–)‐arizonin C1 ( 3 ),[7s] and (+)‐γ‐actinorhodin , .…”

Nonracemic γ‐Lactones from the Sharpless Asymmetric Dihydroxylation of β,γ‐Unsaturated Carboxylic Esters

“…The structural diversity and biological activity of naturally occurring pyranonaphthoquinone γ‐lactones have piqued the interest of synthetic chemists and pharmacologists , . Some of that work leaned on the SAD strategy reviewed here: a route to 202 , conceived as an eastern building block of synthetic granaticin A ( 203 , Scheme ), syntheses, of unnatural but pharmacologically active model compounds 206a – e (Scheme ), syntheses of the natural products (+)–kalafungin ( 212 ), the antipodal (–)‐nanaomycin ( ent ‐ 212 ), and (+)‐frenolicin B ( 213 , all Scheme ), and totally synthetic accesses to the natural products arizonin C1 ( 222 , Scheme ) and griseusins A ( 233 ) and C ( 232 , both Scheme ). Each of these efforts involved the following steps in the indicated order: (1) preparation of a γ‐arylated β,γ‐unsaturated ester, (2) SAD (69–87 % yield, <95–99.5 % ee ) to give a γ‐lactone, and (3) dihydropyran formation through an “oxa‐Pictet–Spengler cyclization”.…”

“…Enantioselective total synthesis of griseusins A ( 233 ) and C ( 232 ) by Thorson et al Reagents and conditions : (a) Methyl but‐3‐enoate (1.3 equiv. ), Pd(P t Bu 3 ) 2 (1.0 mol‐%), Cy 2 NMe (1.5 equiv.…”

“…In 2015 Thorson et al published the total syntheses of griseusin A ( 233 ) and griseusin C ( 232 ) summarized in Scheme . The authors prepared the bromonaphthalene 225 in six steps (Scheme ).…”

Identification of Neuroprotective Spoxazomicin and Oxachelin Glycosides via Chemoenzymatic Glycosyl-Scanning

“…Natural products (NPs) discovery efforts continue to expose pharmacophores of notable scientific, clinical, and commercial value 1–5 that often inspire synthetic organic chemists 6–12 and reveal unique metabolic pathways that offer new opportunities in mechanistic enzymology, synthetic biology, and biocatalysis. 13–22 For the latter, permissive catalysts involved in late-stage NP tailoring modifications (acylation, alkylation, glycosylation, oxidation) have been particularly enabling in NP core scaffold diversification.…”