Cascade Reactions Involving Formal [2+2] Thermal Cycloadditions: Total Synthesis of Artochamins F, H, I, and J

Abstract

Dedicated to Masakatsu Shibasaki on the occasion of his 60th birthdayThe Artocarpus genus encompasses approximately 60 species of trees that are distributed throughout the tropical regions of Asia. Selected members of this family of plants have been used as traditional folk medicines in Sri Lanka, Taiwan, Thailand, and Indonesia. [1][2][3][4] A search for the bioactive ingredients of these plants led to the isolation of several bioactive prenylated flavanoids from the roots of Artocarpus chama, [5] and more recently a number of weakly cytotoxic prenylated stilbenes and their derivatives.[6] Artochamins F, H, I, and J (1-4, Scheme 1) are among the most structurally fascinating members of this group of compounds. Herein we describe the total synthesis of all four natural products through an expedient route that involves a cascade sequence featuring a novel formal [2+2] thermal cycloaddition reaction.The unique bicyclo[3.2.0]heptane carbon frameworks of artochamins H-J (2-4) would appear to be biogenetically derived from artochamin F (1), or a derivative thereof, through a formal [2+2] cycloaddition reaction between the stilbene alkene and one of the prenyl groups.[6] Furthermore, the racemic nature [7] of 2-4 could implicate a non-enzymatic process for this transformation, given the pairwise enantiotopic relationship between both the top and bottom faces of the two prenyl moieties. We were intrigued by the possibility of accomplishing the required cycloaddition under thermal conditions [8] since we speculated that the realization of such a reaction would lead to a concise synthetic approach to the artochamins from stilbenes 5 a and/or 5 b through a cascade sequence that involved, in addition to the key cyclobutaneforming process, two consecutive Claisen rearrangements. Furthermore, protecting-group design on the intermediates was expected to modulate the cascade reaction and allow selective pathways so as to deliver any of the four targeted natural products (1-4).The first objective was the stereoselective construction of an appropriately functionalized stilbene derivative from which the formal [2+2] cycloaddition reaction within the projected cascade could be investigated. The Julia-Kocienski olefination [9] was chosen [10] as the key step for this initial construction as shown in Scheme 2.Thus, the substituted phenyltetrazolesulfones 7 a and 7 b were prepared from 3,4-dihydroxybenzaldehyde (6) in a straightforward manner that involved protection (either as the corresponding Boc derivative or silyl ether), reduction with NaBH 4 , and Mitsunobu coupling with 1-phenyl-1H-tetrazole-5-thiol, followed by molybdenum-catalyzed oxidation of the resulting sulfides to the desired sulfones 7 a (73 % overall yield from 6) and 7 b (77 % overall yield from 6). The preparation of the other required coupling partner, aldehyde 10, began with methyl ester 8, [11] which was converted into the corresponding bis-reversed prenylated ester 9 through a copper-catalyzed etherification [12] with 1,1-dimethylpropynyl carbonate and Lindlar h...

Microwave-assisted cycloaddition reactions

“…Nicolaou and co-workers 30 have shown that the synthesis of the key artochamin intermediate could be generated via a cascade sequence involving a microwave-assisted [3,3] sigmatropic rearrangement of the appropriately functionalized stilbene, followed by a [2+2] cycloaddition of the generated intermediate at 180 1C in the presence of a catalytic amount of Ph 3 PO in o-xylene for 20 min (Scheme 24). The precise role of Ph 3 PO is unclear.…”

Elimination

“…Nicolaou et al (2007) have carried out the synthesis of the key artochamin intermediate via a cascade sequence involving a microwave-assisted [3,3] sigmatropic rearrangement of the appropriately functionalized stilbene, which was followed by a [2+2] cycloaddition of the generated intermediate at 180°C in the presence of a catalytic amount of Ph 3 PO in o-xylene in 20 min. The yield of 55% was obtained.…”

Enantioselective Total Syntheses of (+)‐Gallocatechin, (−)‐Epigallocatechin, and 8‐C‐Ascorbyl‐(−)‐epigallocatechin

“…[26] We therefore adopted a reverse deprotection sequence, with the debenzylation being affected first followed by LiAlH 4 -mediated depivoylation. [27] Pleasingly, this new protocol allowed for the successful synthesis of (+)-gallocatechin (3) in 42 % yield via a debenzylation-depivoylation sequence (Scheme 6).…”