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Page 2 of 17 Wu et al. Chem Synth 2023;3:6 https://dx.doi.org/10.20517/cs.2022.42

INTRODUCTION
Indoles belong to an important nitrogen-containing heterocyclic motif that is present in many bioactive
[1-4]
natural products and pharmaceuticals . Therefore, the construction of indole-based frameworks,
particularly via organocatalysis, has become an important field of study . Among indole-fused rings,
[5-8]
cyclopenta[b]indoles are attractive frameworks [9-13] , which constitute the core structures of many natural
[11]
[10]
[9]
products and biologically important compounds, such as yuehchukene , bruceolline I , fischerindole L ,
thomitrem A and MK-0524 [Figure 1].
[13]
[12]
As a result, the construction of such indole-containing scaffolds has remained a long-standing goal in the
chemistry community [14-20] and many synthetic approaches have been developed for the synthesis of these
important structural units [21-29] . Among these approaches, the Nazarov-type cyclization [30-37] for the
construction of 1, 2, 3, 4-tetrahydrocyclopenta[b]indole scaffolds is undoubtedly one of the most step-
economical and efficient methods [38-47] . However, the classical synthesis of such indole derivatives via
Nazarov-type cyclizations has largely focused on the Lewis acid (LA)-catalyzed 4π-electrocyclizations of
indole-fused 1,4-dien-3-ones, which involve the process of generating a pentadienyl cation (I) intermediate
to form the corresponding 1, 2, 3, 4-tetrahydrocyclopenta[b]indoles [Scheme 1A] [37-41] . Nevertheless, other
Nazarov-type cyclizations for the construction of such scaffolds are rather rare [42-47] . In our previous work,
we designed 3-alkenyl-2-indolylmethanols as a new class of indole-based platform molecules for Brønsted
acid-catalyzed interrupted Nazarov-type cyclizations with various nucleophiles [45-47] based on the formation
of a pentadienyl cation (II) intermediate to construct 1, 2, 3, 4-tetrahydrocyclopenta[b]indole scaffolds
[Scheme 1B]. In spite of these approaches, there are still some challenges in this research field. The first is
that the indole-derived substrates suitable for Nazarov-type cyclizations are confined to indole-fused 1, 4-
dien-3-ones and 3-alkenyl-2-indolylmethanols. The second is that many Nazarov-type cyclizations are
enabled by Lewis acid catalysis and organocatalytic Nazarov-type cyclizations are underdeveloped [40,48-56] ,
even though organocatalysis has been proven to have tremendous advantages [57-63] . Therefore, it has become
an urgent task to design new types of indole-based platform molecules for Nazarov-type cyclizations and
develop organocatalytic Nazarov-type cyclizations for synthesizing indole derivatives.

To overcome these challenges and fulfill this task, based on our long-lasting interests in synthesizing indole
derivatives via designing indole-based platform molecules and their involved organocatalytic reactions ,
[5-8]
we decided to design a new type of indole-based platform molecules for organocatalytic Nazarov-type
cyclizations. In our previous work, we designed t-Bu-substituted 3-alkynyl-2-indolylmethanols for
constructing axially chiral alkene-indole scaffolds via addition reactions [Scheme 2A]. Specifically, in the
presence of a chiral Brønsted acid, this class of 3-alkynyl-2-indolylmethanols transformed into allene-
iminium intermediates, which were readily attacked by nucleophiles to undergo 1, 4-addition, thus giving
axially chiral alkene-indoles. When using dinucleophiles, the OH group of 2-indolylmethanols undergoes
dehydration to give carbocation intermediates [64-72] , which subsequently undergo an intramolecular addition
reaction to generate axially chiral cyclic alkene-indoles [73,74] . In these previous studies, the t-Bu group, as an
aliphatic and bulky group, was detrimental to the delocalization of carbocation, thus making this class of 3-
alkynyl-2-indolylmethanols unsuitable for Nazarov-type cyclizations. On this basis, we considered changing
the t-Bu group to a less steric aryl (Ar) group, thus making aryl-substituted 3-alkynyl-2-indolylmethanols
suitable for Nazarov-type cyclizations [Scheme 2B]. This design is based on the consideration that the
carbocation can readily undergo 4π electron delocalization due to the existence of the terminal aryl group,
therefore undergoing Nazarov-type cyclization and constructing 3, 4-dihydro-cyclopenta[b]indoles.

Based on this concept, we design an organocatalytic Nazarov-type cyclization of aryl-substituted 3-alkynyl-
2-indolylmethanols with 2-naphthols [Scheme 2C]. The selection of 2-naphthols as suitable nucleophiles is