Nickel-catalyzed dimerization of pyrrolidinoindoline scaffolds: systematic access to chimonanthines, folicanthines and (+)-WIN 64821

Abstract

While metal-promoted activation of tertiary alkyl halides often causes elimination and hydrodehalogenation, we have developed a nickel-catalyzed reductive dimerization that allows the generation of a potently reactive tertiary radical equivalent to form a very congested C(sp 3 )-C(sp 3 ) bond even below room temperature. The catalytic protocol is applicable to the dimerization of several pyrrolidinoindoline scaffolds through an appropriate choice of catalyst to accommodate different substrate reactivities with functional group compatibilities. The efficiency of the nickel-catalyzed protocol was successfully demonstrated through systematic total synthesis 10 of chimonanthines, folicanthines and (+)-WIN 64821.

Collective Synthesis and Biological Evaluation of Tryptophan‐Based Dimeric Diketopiperazine Alkaloids

“…as a bioinspired dimerization reaction in a seven‐step sequence with a fully protected d ‐tryptophan derivative and expanded it to the preparation of related natural products, including WIN 64745 ( 7 ), cristatumin C ( 8 ), and asperdimin ( 9 ) . More recently, an alternative approach by using a nickel‐catalyzed reductive dimerization reaction of C3‐brominated pyrrolidinoindoline derivatives to prepare WIN 64821 ( 1 ) was developed by Oguri and co‐workers . The first total synthesis and structure revision of naseseazine A ( 10 ) and naseseazine B ( 11 ) were achieved by Kim and Movassaghi in 2011 by using a Friedel–Crafts‐type coupling reaction as a bioinspired heterodimerization reaction .…”

Stereodivergent Synthesis of Bispyrrolidinoindoline Alkaloidal Scaffolds and Generation of a Lead Candidate with Stereospecific Antiproliferative Activity

“…The asymmetric total synthesis of (+)‐WIN 64821 ( 1 ) was achieved previously by employing nickel‐catalyzed reductive dimerization of a tertiary benzylic bromide as the key skeleton‐constructing reaction . Our synthetic protocol for the dimerization allowed efficient installation of the adjacent quaternary centers connecting the northern and southern hemispheres at the 3‐ and 3′‐positions .…”

“…To this end, tertiary bromide 6 , readily synthesized from l ‐tryptophan, was used as the monomeric component. The nickel‐catalyzed reductive dimerization of 6 was applicable for multigram synthesis (>5 g) of the BPI scaffold 7 in up to 80 % yield . The diastereomeric isomers 16 and 17 , featuring syn stereochemical relationships between the 3‐/3′‐ and 11‐/11′‐positions, were synthesized from 9 by condensation with phenylalanine units followed by cyclization to produce the DKP rings.…”

CH Functionalization/Asymmetric Michael Addition Cascade Enabled by Relay Catalysis: Metal Carbenoid Used for CC Bond Formation

“…[22][23][24]26] In the progress towards enantioselective construction of the core dimeric hexahydropyrroloindoles, we reported the first catalytic asymmetric total synthesis of (+)-folicanthine. [22a] Later, Kanai and Matsunaga developed a chiral manganese-complex-catalyzed double Michael addition of bis(oxindole) for the synthesis of (+)-folicanthine.…”

“…Referring to the known procedure, [24,26] the (À)-folicanthine could be obtained in a 39 % overall yield from 7.…”