Total Synthesis of Dimeric HPI Alkaloids

Abstract

In this paper, we report a full account of the synthesis of dimeric hexahydropyrroloindole alkaloids and its analogues. The key feature of our new strategy is the novel catalytic copper (10 %) mediated intramolecular arylations of o-haloanilides followed by intermolecular oxidative dimerization of the resulting oxindoles in one pot. This sequential reaction leads to the key intermediates for the synthesis of (+)-chimonanthine, (+)-folicanthine, (−)-calycanthine and (−)-ditryptophenaline.Graphical Abstract In the presence of catalytic amount of cuprous iodide (10 %), an intramolecular arylation of o-haloanilides followed by an intermolecular oxidative dimerization of the resulting oxindoles leads to a common intermediate for the synthesis of (+)-chimonanthine, (+)-folicanthine and (−)-calycanthine. Based on this cascade sequence, we also developed a flexible strategy towards the asymmetric syntheses of dimeric HPI alkaloids (−)-ditryptophenaline and its analogues.Electronic supplementary materialThe online version of this article (doi:10.1007/s13659-016-0092-8) contains supplementary material, which is available to authorized users.

Copper(I)‐Catalyzed Cascade Cyclization to the Total Synthesis of Hexahydropyrroloindole Alkaloids: Flustramine B and Debromoflustramine B

“…For alcohols 10, which was synthesized from aniline 11 and γbutyrolactone 12 by an ammonolysis and alkylation process, and then oxidized to aldehyde and condensed with S-tertbutylsulfonamide to give imine 9 (Scheme 2). [25][26][27][28] Initially, we commenced our investigations starting from the commercially available 2,5-dibromoaniline 11 and γbutyrolactone 12 which underwent an ammonolysis and alkylation process in the presence of trimethylaluminum (AlMe 3 ), providing alcohol derivative 13 with 95 % yield. Nisopentenylation of the alcohol 13 offered the compound 10 in 94 % yield under a basic condition, which was then oxidized by Dess-Martin periodinane (DMP) to give the corresponding aldehyde 14 with 91 % yield.…”

“…For the past decades, many novel synthetic routes have been reported for the construction of these architectures, and to further access hexahydropyrroloindole (HPI) alkaloids, [13][14][15][16][17][18][19][20][21] such as MacMillan, Trost, Zhang, You and Zhao et al To our knowledge, most routes often relied on substituted indoles or tryptophan derivatives as starting materials, however, only a few reports were based on non-indole or nonoxindole. [15,[22][23][24] To address these limitations, Zhang group [25][26][27][28][29] has developed a novel copper(I)-catalyzed tandem reaction strategy to achieve several natural products of hexahydropyrroloindole alkaloids, such as (À )-Debromoflustramine E, (+)-Chimonanthine, (À )-Ditryptophenaline and (+)-Nocardioazine B et al Based on previous work, to continue our interest in studying the total synthesis of Hexahydropyrroloindole (HPI) alkaloids, herein we report a complementary route for the total synthesis of Flustramine B and Debromoflustramine B via a cascade cyclization process starting from non-indole or non-oxindole catalyzed by Copper (I).…”

Catalytic Function of Cu (I) and Cu (II) in Total Synthesis of Alkaloids

“…Amidostyrene 107 under bimetal-catalyzed reaction using bis Scheme 11. Shen's total synthesis of (À )-ditryptophenaline (74).…”

“…Several alkaloids such as (+)-chimonanthine (64), (À )calycanthine (65), (+)-folicanthine (66), and (À )-ditryptophenaline (74) have hexahydropyrroloindole (HPI) as a scaffold in the dimeric form in their complex structures. A typical HPI in the natural product is physostigmine, which can be isolated from the seeds of the Calabar bean plant utilized for the treatment of myasthenia gravis, Alzheimer disease, hypotension and so on.…”

“…A typical HPI in the natural product is physostigmine, which can be isolated from the seeds of the Calabar bean plant utilized for the treatment of myasthenia gravis, Alzheimer disease, hypotension and so on. [73] In 2016 Shen et al [74] reported an effective Cu-catalyzed intramolecular arylation reaction as key step for the synthesis of a series of dimeric hexahydropyrroloindole alkaloids and its analogues. In their strategy, the total synthesis of (+)-chimonanthine was started from market purchasable o-bromoaniline and γ-butyrolactone to produce 59.…”