A formal total synthesis of (+)-apicularen A: base-induced conversion of apicularen-derived intermediates into salicylihalamide-like products

Abstract

A synthesis of apicularen precursor (-)-6 in 18 steps from D-glucal is reported. As (+)-6 has been converted into the potent, naturally occurring salicylate anti-cancer agent, (-)-apicularen A in 8 steps, this study constitutes a formal total synthesis of (+)-apicularen A. Key steps in the synthetic route include: (i) useful D-glucal elaboration processes, (ii) organometallic displacements at carbohydrate C-6 triflates using Knochel-type and related functionalised, aromatic Grignard reagents, (iii) stereoselective allyltrimethylsilane-acetal reactions generating C-allyl systems, (iv) stereocontrolled aldehyde allylation processes from both substrate and reagent, and (v) a novel Keck-type macrolactonisation. In addition, preliminary studies are reported in which a procedure has been devised to convert apicularen-derived intermediates into salicylihalamide-like products.

Angular tricyclic benzofurans and related natural products of fungal origin. Isolation, biological activity and synthesis

“…This compound features a furan moiety as a joint protecting group for a salicylaldehyde moiety. 107 Tricycle 187 was easily made available by oxidation of the double bond of the side chain with peracetic acid and cleavage of the so produced diol 108 with periodate (79% overall yield). This was followed by acetalization (185) and quantitative dehydration of the resulting phenylacetic acid derivative 186 under p-tosic acid promotion.…”

Processing Aryllithium and Hetaryllithium Intermediates: Formation of Halogen and Chalcogen Derivatives

“…Those involving aryllithiums include the preparation of complex arenes [73][74][75][76][77][78] as well as precursors to natural products. [79][80][81][82] Similarly, those involving hetaryllithiums report both complex heterocycle [83][84][85][86][87] and natural product preparation. [88][89][90] Use of aryllithium iodination is uniquely suited for synthesis of certain radiolabeled compounds.…”

Synthesis of 2,3-Unsaturated Alkynyl O-Glucosides from Tri-O-acetyl-d-glucal by Using Montmorillonite K-10/Iron(III) Chloride Hexahydrate with Subsequent Copper(I)-Catalyzed 1,3-Dipolar Cycloaddition

“…A diversity of strategies have been described for the synthesis of building blocks of neoglycoconjugates. 1,2 With regard to new approaches for synthesizing natural scaffolds, glycals have been used as versatile chiral synthetic intermediates in total syntheses such as those of (+)-apicularen A, 3 (+)blasticidin S, 4 and cryptopyranmoscatone A1. 5 The glycosylation reaction is a protocol that permits the linking of a donor (a sugar moiety) with an anomeric activated leaving group and a nucleophilic acceptor (e.g., an alcohol or glycosyl compound).…”