Highly Diastereo‐ and Enantioselective Synthesis of Cyclohepta[b]indoles by Chiral‐Phosphoric‐Acid‐Catalyzed (4+3) Cycloaddition

Abstract

Ah ighly enantio-and diastereoselective formal (4+ +3) cycloaddition of 1,3-diene-1-carbamates with 3-indolylmethanols in the presence of achiral phosphoric acid catalyst is reported. The approachd escribed herein provides efficient access to 6-aminotetrahydrocyclohepta [b]indoles in good yields with mostly complete diastereoselectivity and excellent levels of enantioselectivity (> 98:2 dr and up to 98 %ee). Mild reaction conditions,facile scale-up,and versatile derivatization highlight the practicality of this methodology.Amechanistic study suggests that cycloaddition occurs in astepwise fashion, after the formation of an ion pair between the chiral catalytic phosphate and the intermediate carbocation. Conflict of interestTheauthors declare no conflict of interest.

Asymmetric Brønsted Acid Catalyzed Cycloadditions of ortho-Quinone Methides and Related Compounds

“…41 Subsequently, the same group extended this concept to phosphoric acid catalyzed [3+4]-cycloadditions with 1-amino-substituted 1,3-butadienes 59 , which delivered cyclohepta[ b ]indoles 60 in good yields and with excellent stereocontrol as well. 42 Control experiments and the isolation of reaction intermediates suggested a stepwise reaction pathway in both cases, comprising an initial conjugate addition followed by cyclization from the indole-2-carbon. This mechanistic picture suggested that 2-alkylindoles might deviate from this pathway and cyclize from the more nucleophilic and more readily accessible indole-3-carbon atom leading to spiro­cyclic indolenines.…”

An Update on Cyclohepta[b]indoles

“…[23] In 11). [25] In the event, substituted indolyl methanols 36 reacted with Cbz-protected dienamines 37 in the presence of the chiral phosphoric acid TRIP (À )-38.…”

“…reported the synthesis of substituted non‐racemic cyclohepta[ b ]indoles 39 by organocatalytic intermolecular (4+3) cycloaddition (Figure 11). [25] In the event, substituted indolyl methanols 36 reacted with Cbz‐protected dienamines 37 in the presence of the chiral phosphoric acid TRIP (−)‐ 38 .…”

Synthesis of Cyclohepta[b]indoles by (4 + 3) Cycloaddition of 2-Vinylindoles or 4H-Furo[3,2-b]indoles with Oxyallyl Cations

“… 5 The most representative and versatile protocols involve (4 + 3) 6 cycloadditions ( Scheme 1 ) and were developed, beyond the examples reported by Gaich and Stempel, also in their enantioselective version. 7 …”

“…5 The most representative and versatile protocols involve (4 + 3) 6 cycloadditions (Scheme 1) and were developed, beyond the examples reported by Gaich and Stempel, also in their enantioselective version. 7 In these cycloaddition reactions, the indolyl moiety functions as the 3C partner, whereas (4 + 3) cycloaddition reactions having indoles as the 4C component have become operative only more recently (Scheme 2). 8 For example, in 2017, Zhang and co-workers reported a regioselective gold-catalyzed (4 + 3) cascade cycloaddition/ CH functionalization of 2-vinylindoles and propargylic esters leading to highly substituted derivatives.…”