Synthesis of (±)‐β‐Allokainic Acid

Abstract

The total synthesis of kainoid alkaloid, (+/–)‐β‐allokainic acid is reported. The key step is a vinylogous Cloke–Wilson rearrangement followed by Lewis acid and transition metal induced transformations to prepare a highly functionalized pyrrolidine suitable for conversion to the target molecule.

Cloke–Wilson rearrangement: a unique gateway to access five-membered heterocycles

“…During this transformation, the key step involved the Lewis acid-promoted Cloke–Wilson rearrangement of 258 (achieved by the reaction of cyclopentadiene 257 with substituted diazo compound 134 ) to the formation of the substituted 2,5-dihydrooxepine ring 259 , followed by the transition metal-induced transformations to produce pyrrolidine core 260 , which was suitable for the generation of a target molecule 261 (Scheme 73). 25…”

“…Owing to the requirement of high temperature (200-500 °C) for this strategy, its scope and applications are limited. 40 However, many activation methods have been developed including transition metal catalysis, 8b,41 photocatalysis, 40d,42 cyclopropylcarbaldehyde-promoted activation, 43 organocatalysis, 44 Lewis acid catalysis, 25,[54][55][56][57][58][59][60][61][62][63][64][65] Brønsted acid catalysis, [66][67][68][69][70][71][72][73][74]89,90,93 and Brønsted base catalysis 68 to carry out this transformation. Cloke-Wilson rearrangement also nds applications in the total synthesis of natural products.…”

“…Cloke-Wilson rearrangement also nds applications in the total synthesis of natural products. 21,25,[91][92][93][94] Thus, the construction of ve-membered O-, N-, and S-heterocycles can be easily achieved via Cloke-Wilson rearrangement. reaction in moderate reaction conditions.…”

“…7 a Besides its application in the synthesis of diverse heterocycles, 24 this rearrangement is also involved in the total synthesis of various natural products. 25 The [3 + 2] cycloaddition reaction of cyclopropanes with aldehydes results in the synthesis of furans, 26 a but the synthetic route to the furan moiety via the rearrangement of cyclopropyl ketone is a highly efficient and cost-effective protocol. 26 b The transition metal-catalyzed synthesis of functionalized furans by the ring-opening/closure of cyclopropanyl ketones is another facile and efficacious synthetic pathway.…”

An approach towards (+)-allokainic acid via diphenylprolinol-catalyzed direct cross-aldol reaction

“…There are more than fifteen enantioselective 10 synthesis of allokainic acid 1 and six reports highlight the racemic 11 versions. Majority of the synthetic endeavors cannot be used to modify the C4 position of pyrrolidine ring.…”