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.

在热诱导的电环开环反应中，C2对称（中位）6,6-二溴双环[3.1.0]己烷，如10，在具有手性、非外消旋性的1°-胺28存在下，产生了一种约1:1的混合物，包括顺式异构体和色谱可分离的1-氨基-2-溴-2-环己烯37（产率42%）和38（产率45%）。这些化合物均经过13步反应合成，包括Suzuki–Miyaura交叉偶联、自由基环化和Pictet–Spengler反应，最终得到（-）-或（+）-克里纳烷（1或ent-1，分别）。基于这些方法，对（+）-和（-）-11-羟基瓦提汀[(+)-和(−)-3]、（+）-和（-）-球状百部碱[(+)和(−)-4]、（+）-和（-）-血见愁碱[(+)-和(−)-5]、（+）-和（-）-假黄连碱[(+)-和(−)-6]、（+）-和（-）-天门冬碱[(+)-和(−)-7]以及（±）-哈曼因[(±)-8]和（±）-反血见愁碱[(±)-9]的完全合成进行了变体应用。其中，许多生物碱为首次合成。