天然产物Combretastatin A-1和Combretastatin B-1的合成

基于Perkin反应策略合成了具有强效抗肿瘤、抗血管活性的天然产物Combretastatin A-1(CA1)和Combretastatin B-1(CB1).以2,3,4-三羟基苯甲醛(1)为起始物, 经单甲基化反应得到2,3-二羟基-4-甲氧基苯甲醛(2), 再经酚羟基保护得到2,3-二异丙基-4-甲氧基苯甲醛(3), 该化合物与3,4,5-三甲氧基苯乙酸(4)发生Perkin反应分离得到E-2-(3,4,5-三甲氧基苯基)-3-(2',3'-二异丙氧基-4'-甲氧基)丙烯酸(E-5), 经脱羧反应得到Z-3,4,4',5-四甲氧基-2',3'-二异丙氧基二苯乙烯(6), 最后经脱保护反应得到CA1.另外, 将E-2-(3,4,5-三甲氧基苯基)-3-(2',3'-二异丙氧基-4'-甲氧基)丙烯酸(E-5)脱去保护基得到E-2-(3,4,5-三甲氧基苯基)-3-(2',3'-二羟基-4'-甲氧基)丙烯酸(7), 该化合物经脱羧-异构化反应得到E-3,4,4',5-四甲氧基-2',3'-二羟基二苯乙烯(E-CA1), 最后经催化氢化得到CB1.

Synthesis of Natural Products Combretastatin A-1 and Combretastatin B-1

A new synthetic protocol based on Perkin reaction for access to the antivascular and antitumor natural products combretastatin A-1(CA1) and combretastatin B-1(CB1) was developed. Starting from 2,3,4-trihydroxybenzaldehyde(1), 2,3-dihydroxy-4-methoxybenzaldehyde(2) could be readily obtained via monomethylation, subsequent protection reaction was performed to afford the catechol protected intermediate 2,3-diisopropyloxy-4-methoxybenzylaldehyde(3). Perkin condensation between compound 3 and 3,4,5-trimethoxyphenylacetic acid(4) gave E-2-(3,4,5-trimethoxyphenyl)-3-(2',3'-diisopropyloxy-4'-methoxybenzyl)acrylic acid(E-5) which underwent a decarboxylation reaction to afford Z-2',3'-diiso-propyloxy-3,4,4',5-tetramethoxystilbene(6), and CA1 could then be obtained by deprotection reaction. In addition, E-2-(3,4,5-trimethoxyphenyl)-3-(2',3'-dihydroxy-4'-methoxybenzyl)acrylic acid(7) could be obtained by deprotection reaction, followed by a decarboxylation-isomerization reaction to afford E-combretastatin A-1(E-CA1). Finally, CB1 could be obtained via catalytic hydrogenation.