The Nicholas Approach to Natural Product Hybrids

Abstract

The intermolecular Nicholas reaction of terpene-based scaffolds is an excellent access to natural product hybrid compounds. These intermolecular reactions have a low selectivity and are scarcely efficient for non-conjugated cations, but they are highly efficient to produce new terpene structures through an intramolecular reaction pathway. The use of cations derived from natural product derived [Co(2)(CO)(6)]-enyne complexes is, in contrast, a highly efficient regio- and stereoselective procedure to prepare very complex structures, incorporating diverse densely functionalized or labile moieties. Thus, beta-pinene-diterpene-alkaloid or homohybrids can be accessed in totally stereo-, regio- and siteselective fashion. This approach efficiently discriminates between different propargylic positions by selecting the nature of the alcohol, being the enyne-derived cations the most reactive. The chimera 38 with a steroid-terpene-indole skeleton was prepared in this way.

Applications of the Nicholas Reaction in the Synthesis of Natural Products

“…Álvaro, de la Torre and Sierra have in a series of papers pursued the synthesis of terpene-hybrids by derivatizing a terpene scaffold via the Nicholas reaction [28][29][30]. This formally does not constitute the synthesis of a natural product, but nevertheless fits well into the context of this review.…”

“…The cobalt-alkyne complexation also affords the possibility of including organometallic entities in the macrocyclic structure, which can be of interest as certain classes of cobalt-alkyne complexes have in recent years been found to possess cytotoxic activity [31]. In a more extensive report, the same authors expanded the range of natural products to include also terpene-alkaloid hybrids as well as a steroid-terpene-indole structure [30]. The synthesis of the latter is depicted in Scheme 10.…”

Substituent effects in the Nicholas epimerization of glycosides

“…Hence, the α:β ratio of a Nicholas epimerization is controlled by the size of the substituents on a thp ring and their positions relative to each other . Luckily, the racemization of the carbocation, and hence the stereochemistry of the Nicholas reaction, can be controlled via the experimental setup, which made the Nicholas reaction a fixture in the synthesis of natural products …”

Synthesis of Aza-brazilin/diarylindan-Based Hybrid

“…天然产物杂合物(Natural product hybrids)的设计合成, 是 20 世纪末 21 世纪初开始出现的 一种从天然产物骨架中去寻找先导化合物的新途径, 其 基本的策略是将不同天然产物的生物活性结构单元与 活性分子或药物分子之间进行有机的组合来形成新的 化合物, 以达到优化、提高单一的天然产物本身的生物 活性, 或者从中发现新的活性化合物的目的 [2,3] .…”

“…天然产物杂合物的设计合成可以用 Tietze 课题组 目前, 天然产物杂合物的设计理念开始受到广泛关 注 [2,3] , 杂合的方式越来越多, 杂合物中的结构单元也由 最初的以天然产物为主, 拓展到药物及其它的活性分 子, 为活性分子的发现与筛选提供了数目巨大且结构非 常多样化的候选分子. 被认为是寻找各种生物活性分 子、药物先导化合物以及其他功能分子的一个前景光 明、充满希望的新方向.…”