Absolute configuration and total synthesis of (−)-cabenegrin A-I

Heck-oxyarylation of 2-phenyl-2H-chromenes and 1,2-dihydronaphthalenes

“…methylendioxyphenol), 3,4-dimethoxyphenol and 3,4-diethoxyphenol and phenol by mercury (II) acetate, respectively, under the conditions used earlier by two of us. 23 The TLC monitoring of oxyarylation of (±)-4b with 5a has clearly shown that the conversion of the starting material [(±)-4b] reached about 50 % in three hours and then changed very slowly with longer reaction time.…”

“…23 Due to its bridged structure, the C-6 phenyl and H-12 adopt necessarily cis equatorial orientations implying a (6R, 12R) relative configuration. It is to be noted that neither the diastereomer of (±)-8b with (6R, 6aR, 11aR) relative configuration, nor the regioisomeric (±)-13b bearing the 3,4-methylenedioxyphenyl group at C-4 of the flavane skeleton could be isolated.…”

“…entry 2) is significantly smaller than that of (8a:12a) (entry 1) obtained in the reaction of 7-benzyloxy-2H-chromene (4a) with 5a. 23 The formation of the bridged product was also facilitated further by using the 5b or 5c dialkoxy chloromercuriphenols possessing an increased nucleophilicty of their hydroxy group (entry 3 and 4). Thus the proposed cationic mechanism of the Heckoxyarylation of 2H-chromenes (1) with 2-chloromercuriphenols (2) in the presence of of Li 2 [PdCl 4 ] catalyst is justified.…”

“…7 In contrast to the reports of Breytenbach 17 we have found that the oxyarylation of 7-benzyloxy-2H-chromene (4a) with 2-chloromercuri-3,4-methylenedioxyphenol (5a) under the conditions published by Horino and Inoue 7 did not take place with complete regioselectivity (4a+5a→6a→7a→8a), but additional coupled products 12a and 13a were also obtained (Scheme 2), probably via 10a→11a and 10a carbocation intermediates, respectively. 23 In order to study the factors that determine the nature and ration of the three possible products, we studied the effect of an additional C-2 phenyl group on the 2H-chromene ring and replacement of its oxygen by a methylene group as well as different substitution pattern of the 2-chloromercuriphenol. Thus Heck-oxyarylations of racemic 2-phenyl-2H-chromene [(±)-4b] and 1,2-dihydronaphthalenes (14a,b) were carried out with three 2-chloromercuriphenols (5a-c) in the presence of Li 2 [PdCl 4 ] at room temperature.…”

Further insight into the mechanism of Heck oxyarylation in the presence of chiral ligands

“…2 Nakanishi and co-workers 3 also demonstrated that two representatives of these natural products, cabenegrin A-(I) (1) and cabenegrin A-(II) (2), showed activity against snake and spider venom but their mode of action is still to be explored. Although we have published 4 the total synthesis of (-)-6aR,11aR-1 via (-)-6aR,11aR-maackiain [(-)-3], the synthesis of (-)-3 suffered from limitations such as (i) the need of equimolar amounts of palladium(II) salt in the Heck-oxyarylation reaction of 7-benzyloxy-2H-chromene (13) and 2-chloromercury-3,4-methylenedioxyphenol resulting in the racemic precursor 4 in 53% yield and (ii) the low yield in the resolution of rac-maackiain (3). Recently, a convenient modification of this Heck-oxyarylation step has also been described 5,6 by the replacement of the toxic chloromercury-phenol derivatives with 2-iodophenols which allowed to considerably decrease the amount of the expensive palladium(II) salt (from 100 mol % to 10 mol %) in the presence of triphenylphosphine and silver carbonate in acetone or in ionic liquids such as 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim][PF 6 ]).…”