Efficient Access to the Iboga Skeleton: Optimized Procedure to Obtain Voacangine from Voacanga africana Root Bark

Iboga alkaloids are
a group of monoterpenoid indole alkaloids with
promising and intriguing biological activities. Ibogaine is the representative
member of the series and has become widely known as a potent atypical
psychedelic with promising effects to treat substance use disorder.
Nowadays, an efficient and scalable enantioselective total synthesis
of ibogaine and related iboga alkaloids is still lacking, so direct
extraction from natural sources or semi-synthetic schemes are the
methods of choice to obtain them in a preparative scale. In particular,
ibogaine can be obtained either by a low yielding direct isolation
from Tabernanthe iboga or using a semi-synthetic
procedure from voacangine, an iboga alkaloid occurring in a higher
yield in the root bark of Voacanga africana. In this work, we describe an optimized process to obtain voacangine
from V. africana root bark as a precursor
of the iboga scaffold. Using a direct acetone-based extraction procedure
(0.5 kg of root bark), voacangine was isolated in ∼0.8% of
root bark dried weight, while the major alkaloids isolated from the
bark were identified as iboga-vobasinyl dimers (∼3.7%) such
as voacamine and voacamidine. Since these alkaloids contain the voacangine
moiety in their structure, the cleavage of the dimers was further
optimized, affording an extra amount of voacangine in ∼50%
isolated molar yield. In this manner, the total amount of voacangine
obtained by application of the whole procedure to the plant material
(extraction and dimer cleavage) could almost duplicate the content
originally found in the root bark.

伊波加生物碱（iboga alkaloids）是一类兼具良好应用前景与独特生物活性的单萜吲哚生物碱（monoterpenoid indole alkaloids）。伊博加因（ibogaine）作为该类生物碱的代表性成员，作为一种强效非典型致幻剂广为人知，其在物质使用障碍（substance use disorder）治疗领域展现出可观的应用潜力。目前，学界仍缺乏高效且可规模化的伊博加因及相关伊波加生物碱对映选择性全合成（enantioselective total synthesis）路线，因此制备规模获取此类化合物仍需依赖天然来源直接提取或半合成工艺（semi-synthetic schemes）。其中，伊博加因既可通过低产率的依波高木（Tabernanthe iboga）直接分离获得，也可通过以文卡新碱（voacangine）为原料的半合成工艺制备——文卡新碱是一种伊波加生物碱，在非洲伏康树（Voacanga africana）根皮中的含量较高。本研究报道了一种从非洲伏康树根皮中提取制备伊波加骨架前体文卡新碱的优化工艺。采用直接丙酮萃取法（acetone-based extraction procedure）处理0.5 kg根皮，可从根皮干重中分离得到约0.8%的文卡新碱；同时从该根皮中分离得到的主要生物碱为伊波加-沃巴辛基二聚体（iboga-vobasinyl dimers），占根皮干重约3.7%，包括沃卡明（voacamine）与沃卡米定（voacamidine）。鉴于此类二聚体结构中含有文卡新碱单元，本研究进一步优化了二聚体的裂解（cleavage）工艺，最终可获得额外约50%摩尔收率（isolated molar yield）的文卡新碱。通过将萃取与二聚体裂解整套工艺应用于植物原料，最终得到的文卡新碱总含量几乎可达到根皮中原生含量的两倍。