Flow Chemistry‐Enabled Divergent and Enantioselective Total Syntheses of Massarinolin A, Purpurolides B, D, E, 2,3‐Deoxypurpurolide C, and Structural Revision of Massarinolin A

Abstract

Massarinolin A and purpurolides are bioactive bergamotane sesquiterpenes condensed with a variety of synthetically challenging ring systems: a bicyclo[3.1.1]heptane, an oxaspiro[3.4]octane, and a dioxaspiro[4.4]nonane (oxaspirolactone). Herein, we report the first enantioselective total syntheses of massarinolin A, purpurolides B, D, E, and 2,3deoxypurpurolide C. Our synthesis and computational analysis also led to a structural revision of massarinolin A. The divergent approach features an enantioselective organocatalyzed Diels-Alder reaction to install the first stereogenic center in high ee, a scalable flow photochemical Wolff rearrangement to build the key bicyclo[3.1.1]heptane, a furan oxidative cyclization to form the oxaspirolactone, a late-stage allylic CÀH oxidation, and a Myers NBSH-promoted sigmatropic elimination to install the exo methylene group of massarinolin A.

Ring contraction in synthesis of functionalized carbocycles

“…Very recently, Dai and co-workers reported the first total syntheses of complex bergamotane sesquiterpenes massarinolin A (27) and its congeners featuring a scalable flow photochemical Wolff rearrangement as a key reaction 117 (Scheme 6(G)) (contractive synthesis: steps, 13 steps; 117 alternative synthesis: N/A).…”

“…(F) Wolff rearrangement used to prepare tricycle 129 in the enantiospecific synthesis of (À)-presilphiperfolan-8-ol (26) 116. A flow Wolff rearrangement of 131 to give 132 as an key intermediate toward the preparation of massarinolin A(27) 117.…”

Direct synthesis of oxaspirolactones in batch, photoflow, and silica gel-supported solvent-free conditionsviavisible-light photo- and heterogeneous Brønsted acid relay catalysis

“…1B-2). 20 A more recent application of this tactic has been reported in the total syntheses of the abeo-steroid (−)-spirochensilide A 7b-d and in the divergent preparation of massarinolin A, purpurolides B, D, and E, and 2,3-deoxypurpurolide C. 21 In this study, we report an improved protocol for the direct synthesis of oxaspirolactones through the utilization of the synergistic action of energy transfer and Brønsted acid catalysis. Sequential [4 + 2] photooxygenation of a hydroxyalkyl furan substrate and its concomitant Brook rearrangement 22 towards hydroxybutenolide II, then acid-catalyzed ketalization, affords oxaspirolactones in an overall one-pot, one-step process with no need for column chromatographic purification (Fig.…”

“…1B-2). 20 A more recent application of this tactic has been reported in the total syntheses of the abeo -steroid (−)-spirochensilide A 7 b–d and in the divergent preparation of massarinolin A, purpurolides B, D, and E, and 2,3-deoxypurpurolide C. 21…”

Entry to new spiroheterocycles via tandem Rh(II)-catalyzed O–H insertion/base-promoted cyclization involving diazoarylidene succinimides

“…For example, spirocyclic Δ α,β -butenolides (furan-2(5 H )-ones) represent a valuable class of molecular frameworks for drug design and are abundant in nature [ 15 ]. Bioactive naturally occurring spiro Δ α,β -butenolides include spirofragilide (with anti-inflammatory, antibiotic, antitumor, anti-HIV activity) [ 16 ], ramariolide A (antitubercular) [ 17 ], (+)-massarinolin A (antibacterial) [ 18 ], anemonin (antiparasitic) [ 19 ], (+)-pyrenolide D (cytotoxic) [ 20 ], and (+)-crassalactone D (antitumor) [ 21 ]. Synthetic or semisynthetic spiro Δ α,β -butenolides have also shown a range of biological properties including aldosterone receptor antagonistic [ 22 ], anti-inflammatory [ 23 ], and anti-HIV [ 24 ] activity.…”