Biomimetic Total Syntheses of Borreverine and Flinderole Alkaloids

Abstract

Dimeric indole alkaloids represent a structurally unique class of natural products having interesting biological activities. Recently, we reported the first total synthesis of flinderoles B and C, structurally unique and potent antimalarial natural products. Central to the design of the approach and by virtue of a one-pot, acid-catalyzed dimerization reaction, the route also provided total synthesis of the borreverine class of natural products. This full account details the progress of efforts that culminated in the protecting-group-free, six-step total synthesis of all of the flindersia alkaloids: dimethylisoborreverine, isoborreverine, flinderoles A-C, and their analogues. A biomimetic approach featuring a scalable and catalytic formal [3 + 2] cycloaddition and Diels-Alder reaction is outlined in detail. On the basis of the experimental observations, a detailed mechanism has been proposed for the dimerization of tertiary alcohol 28.

Simple indole alkaloids and those with a nonrearranged monoterpenoid unit

“…Borreverines 963 and 964 were derived from [4 + 2] adduct 969, and formal [3 + 2] adduct 970 was transformed into inderoles 965, 966, and 967 (Scheme 185). 305 The biomimetic synthesis of indersial alkaloids inderoles A (965) and B (966), desmethylinderole C (971), inderole C (967), isoborreverine (964), dimethylisoborreverine (963), and borreverine (972) was reported based on an acid-mediated dimerization of natural product borrerine (973), which began with acidic opening of 973 to iminium and diene (Scheme 186). 306 Bisindolylmethanes are present in many natural products, exhibiting a broad range of biological activity.…”

“…10) 120. Eight new alkaloids, 10-demethoxy-12-hydroxy-17,19-epoxygeissovelline (304), (Z)-10-demethoxy-12-hydroxygeissovelline(305), (E)-10-demethoxy-12-hydroxygeissovelline (306), geissospermidine (307), 10-methoxygeissospermidine (308), N-de-Scheme 62 Reagents and conditions: (i) AuCl, toluene, rt; (ii) NBS, CCl 4 , rt; (iii) t-BuOK, DMSO, THF, O 2 , rt; (iv) KH, THF, rt, then n-BuLi, DMF, À30 C; (v) BBr 3 , CH 2 Cl 2 , À78 C; (vi) KH, THF, rt, then n-BuLi, CO 2 , À78 C; (vii) MeI, NaHCO 3 , DMF; (viii) BBr 3 , CH 2 Cl 2 , À78 C. Scheme 63 Reagents and conditions: (i) t-BuOLi, TMEDA, THF, À60 C; (ii) KOH, H 2 O, MeOH, reflux; (iii) MeI, DBU; (iv) MeI, K 2 CO 3 , acetone. Scheme 64 Reagents and conditions: (i) CAN, SiO 2 , MeCN, rt; (ii) Ac 2 O, HBF 4 , 70 C; (iii) CH 2 N 2 , CH 2 Cl 2 ; (iv) MeLi, THF, À78 C to rt.…”

New Perspectives in the Indole Ring Functionalization using 2‐Indolylmethanols

“…The reaction of 2,3‐indolyldimethanols with enaminones 34 using a chiral phosphoric acid as activator shows the exclusive preference of these substrates for addition on the C‐3 arylmethyl framework . In a study directed toward the synthesis of the alkaloid isoborreverine, 2‐indolylmethanol 39 has been made to react with ethyl 3‐indolylacrylate 38 in the presence of a catalytic amount of boron trifluoride etherate (Scheme ) . The Lewis acid is able to promote the formation of carbocation I and the enol of the acrylate ester II which react together leading to adduct III with high diastereoselectivity.…”

A Three‐Component Reaction of Aryldiazonium Tetrafluoroborates, Sulfur Dioxide, and 1‐(Prop‐2‐yn‐1‐yl)indoles under Catalyst‐Free Conditions

“…[1b-d] Additionally, they act as useful intermediates for the synthesis of complex biologically important compounds. [2] Moreover, 9H-pyrrolo [1,2-a]indoles have been applied in material chemistry, showing unique electrical and optical properties. [3] Thus, extensive efforts have been made for the generation of 9H-pyrrolo [1,2-a]indole scaffold.…”