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

Abstract

A highly enantio- and diastereoselective formal (4+3) cycloaddition of 1,3-diene-1-carbamates with 3-indolylmethanols in the presence of a chiral phosphoric acid catalyst is reported. The approach described 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. A mechanistic study suggests that cycloaddition occurs in a stepwise fashion, after the formation of an ion pair between the chiral catalytic phosphate and the intermediate carbocation.

Brønsted Acid‐Catalysed Dehydrative Substitution Reactions of Alcohols

“… [52] This was subsequently extended to formal [4+3] cycloadditions using dienecarbamates 41 catalysed by phosphoric acid 16 (5 mol %) to form substituted indoles such as 42 , again with excellent stereoselectivity (Scheme 22 b). [53] In both cases, the reaction is tolerant of a range of substituents, forming the polycyclic products in good yields with excellent stereoselectivity. The reactions are proposed to occur via a stepwise mechanism, with dual hydrogen‐bonding activation of the intermediate vinyliminium and enecarbamate required for enantioselectivity.…”

Recent Advances in Transition-Metal-Free (4+3)-Annulations

“…Masson presented the catalytic asymmetric (4+3)-annulation using a H 8 -CPA, setting three stereocenters in a single step. 108 Similarly, a 3-indolylmethanol 5.2.7a was used in combination with a dienecarbamate 5.2.7b to generate the cycloadduct 5.2.7c.…”

Alkyl Carbagermatrane Enabled Synthesis of Seven-Membered Carbocycle-Fused Aromatics through Catellani Strategy

“…NMR (400 MHz, CDCl 3 ):  = 6.32 (d, J = 2.5 Hz, 1 H),6.31 (d, J = 2.6 Hz, 1 H), 3.78 (s, 3 H), 3.77 (s, 3 H), 2.82-2.77 (m, 2 H), 2.77-2.72 (m, 2 H), 1.84-1.78 (m, 2 H), 1.66-1.60 (m, 2 H), 1.58-1.51 (m, 2 H). 13 C NMR (101 MHz, CDCl 3 ):  = 158.1, 157.5, 146.3, 124.2, 106.1, 96.3, 56.0, 55.3, 37.2, 33.0, 28.4, 28.0, 25.0.…”

“…4 It should be noted that construction of ring system including seven-membered carbocycles through a norbornene-mediated annulation strategy has been well established by Lautens and other groups. 5 Limited examples involving cycloaddition, 6 ring expansion, 7 and other methods [8][9][10] have also been reported. Nevertheless, a simple, general method for construction of seven-membered carbocycles still need to be disclosed.…”