Asymmetric Total Synthesis of Hispidanin A

Abstract

Asymmetric total synthesis of the dimeric diterpenoid hispidanin A was accomplished by non-catalytic Diels-Alder cycloaddition at room temperature. The synthesis relies on iron-catalyzed coupling to construct a Z-configured trisubstituted alkene, an iron-catalyzed radical cascade to generate a labdane-type diene, and both Yamamoto cationic polyene cyclization and palladium-catalyzed Stille coupling to generate a totarane-type dienophile.

Cobalt‐Catalyzed Hydrogen‐Atom Transfer Induces Bicyclizations that Tolerate Electron‐Rich and Electron‐Deficient Intermediate Alkenes

“…Conversely, closure of the final ring proceeded with similarly modest selectivity regardless of the catalyst structure (ratio 18 + 20:19). It is likely that cis-decalin formation (19)i so nly kinetically feasible without an axial methyl group on C4, which is consistent with the sole formation of trans-decalins with the disubstituted alkene substrates used in Figure 2a nd in many other related systems. [26] Collectively,t hese results suggest that the reaction of 17 is stereoselective but not stereospecific with respect to the trisubstituted alkene and is thus likely to involve radical intermediates.H owever,t his tentative conclusion cannot be directly transferred to the reactions described in Figure 1, because in that case oxidation of the initially formed radical to at ertiary carbocation could reasonably occur.…”

“…In this case the key ironcatalyzed, HAT-initiated bicyclization terminated onto an electron-poor alkene and was not fully stereoselective. [19] The meta-substituted anisole substrate gave a1 .7:1 para/ortho mixture of regioisomers (6b). Thearyl bromide functionality in 5c was tolerated under the reaction conditions.N aphthyl and toluyl substrates underwent cyclization in moderate yields (products 6d and 6e), suggesting that electron-rich arenes are the best terminators for this process.ABocprotected indole substrate cyclized to give an indoline product 6f along with as mall quantity of the anticipated indole product;the same was observed for the corresponding N-tosyl substrate yielding 6g.T he indoline product might be produced by acompetitive silane reduction of apost-cyclization cationic intermediate (see below).…”

Total synthesis of complex terpenoids employing radical cascade processes

“…Indeed, 99 has already seen two distinct total syntheses by the groups of Liu and the combined efforts of Lan, Gong, and Yang. 80,81 Of these, Liu’s synthesis features a radical cascade for the assembly of the labdane-type diene ( 100 ) needed for downstream, biomimetic union with the totarane-derived fragment.…”

Recent Developments in Polyene Cyclizations and Their Applications in Natural Product Synthesis

“…In 2017, Liu and co-workers reported the synthesis of (-)-hispidanin A (200), a natural product with promising anticancer properties, via a hydrogen atom transfer (HAT) mediated triene cyclization to construct the tricyclic core of (-)-hispidanin A (200) (Scheme 39). 49 The use of iron(III) acetylacetonate and triphenylsilane as hydrogen source smoothly furnished tricyclic lactone 199 from alkene 198 (45% over 2 steps) after deprotection, thereby establishing two quaternary and four contiguous stereocenters in one step. In a 2018 follow-up paper, Liu and co-workers reported further mechanistic studies, producing deuteration at the α-position of the lactone, supporting the hypothesis that the reaction involves the formation of an enolate anion.…”