Application of Electrocyclic Ring-Opening and Desymmetrizing Nucleophilic Trappings of meso-6,6-Dibromobicyclo[3.1.0]hexanes to Total Syntheses of Crinine and Haemanthamine Alkaloids

The
thermally induced electrocyclic ring-opening of C2-symmetric
(meso) 6,6-dibromobicyclo[3.1.0]­hexanes
such as 10 in the presence of the chiral, nonracemic
1°-amine 28 afforded a ca. 1:1 mixture of the diastereoisomeric
and chromatographically separable 1-amino-2-bromo-2-cyclohexenes 37 (42%) and 38 (45%). Each of these was elaborated
over 13 steps, including Suzuki–Miyaura cross-coupling, radical
cyclization, and Pictet–Spengler reactions, into (−)-
or (+)-crinane (1 or ent-1, respectively). Variations on these protocols were applied to the
total syntheses of (+)- and (−)-11-hydroxyvattitine [(+)- and
(−)-3], (+)- and (−)-bulbispermine [(+)-
and (−)-4], (+)- and (−)-haemanthamine
[(+)- and (−)-5], (+)- and (−)-pretazettine
[(+)- and (−)-6], and (+)- and (−)-tazettine
[(+)- and (−)-7] as well as (±)-hamayne [(±)-8] and (±)-apohaemanthamine [(±)-9].
A number of these alkaloids were synthesized for the first time.

在具有手征性且非外消旋性的伯胺28存在下，热诱导的电环开环反应作用于C2对称（中位）的二溴双环[3.1.0]己烷，如10，生成约1:1的立体异构体混合物，包括可通过色谱法分离的1-氨基-2-溴-2-环己烯37（产率42%）和38（产率45%）。这些化合物均通过13个步骤进行合成，包括 Suzuki–Miyaura 键偶联反应、自由基环化反应和 Pictet–Spengler 反应，最终得到（-）-或（+）-crinane（1或ent-1，分别）。这些合成方法在 (+)-和（-）-11-羟基瓦替丁 [(+)-和（-）-3]、(+)-和（-）-球状阿米定 [(+)-和（-）-4]、(+)-和（-）-血见愁 [(+)-和（-）-5]、(+)-和（-）-铁线莲 [(+)-和（-）-6]、(+)-和（-）-石蒜 [(+)-和（-）-7]以及（±）-哈梅因 [(±)-8]和（±）-反血见愁 [(±)-9]的全合成中得到了应用。其中，许多生物碱为首次合成。