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Wu et al. Chem Synth 2023;3:6 https://dx.doi.org/10.20517/cs.2022.42 Page 9 of 17

Scheme 4. Suggested reaction pathway.

products [90-92] , bioactive molecules [93,94] and chiral catalysts or ligands [95-101] . Although a number of axially
chiral indole-based scaffolds, such as N-arylindoles [102-110] , 3-arylindoles [111-120] , 2-arylindoles [121-127] , 3-
quinonylindoles [128,129] , isochromenone-indoles , bisindoles [131-135] and other indole derivatives [136-143] , have
[130]
been successfully synthesized, the catalytic asymmetric construction of axially chiral 3, 4-dihydrocyclopenta
[b]indole scaffolds is unknown. As shown in Table 2, a series of chiral phosphoric acids (CPAs) [144-151] 5-7
were chosen as chiral organocatalysts to promote the reaction between 1a and 2a (entries 1-13). As
expected, axially chiral cyclopenta[b]indole 3aa could be obtained in an atroposelective manner.
Particularly, when CPA (S)-5f was used as a chiral organocatalyst, axially chiral product 3aa was generated
with an atroposelectivity of 47% ee, albeit with an extremely low yield of 7% (entry 6). Under the catalysis of
CPA (S)-5f, several different types of solvents were examined (entries 14-18), which disclosed that only
toluene could serve as an effective reaction media to deliver axially chiral product 3aa in 69% ee and 11%
yield (entry 14). Subsequently, to further improve the atroposelectivity and the yield of product 3aa, we
attempted to modulate the catalyst loading in the reaction (entries 19 and 20). When the catalyst loading of
(S)-5f was increased to 20 mol%, product 3aa was generated in a slightly improved yield of 20% with the
retained atroposelectivity of 69% ee (entry 20). These preliminary results implied that simultaneously
controlling both the enantioselectivity and the yield of this organocatalytic asymmetric Nazarov-type
cyclization is a significant challenge. Although the yield and atroposelectivity of axially chiral product 3aa in
this organocatalytic asymmetric version are not satisfactory, this organocatalytic asymmetric Nazarov-type
cyclization provides an optional strategy for the atroposelective construction of this new class of axially
chiral cyclopenta[b]indole scaffolds.

Finally, to obtain the two enantiomers of axially chiral 3aa, we tried using the strategy of chiral resolution
[Scheme 5]. In detail, the racemic compound rac-3aa was subjected to the acylation reaction with (R)-(-)-O-
formylmandeloyl chloride (R)-8 as a resolution reagent in the presence of DMAP, which gave rise to two
separable diastereomers (S , R)-9 and (R , R)-9. By treating with hydrazine hydrate, the two diastereomers
a
a
were then easily transformed into the corresponding single enantiomers (S )-3aa and (R )-3aa, respectively,
a
a
in high yields with excellent atroposelectivities. In this manner, the first preparation of axially chiral 3, 4-
dihydrocyclopenta[b]indoles with optical purity was established, which could serve as a complementary
method to catalytic asymmetric approaches. Moreover, the absolute configuration of product (S )-3aa was
a