Page 181 - Read Online

Page 2 of 9 He et al. Chem Synth 2023;3:35 https://dx.doi.org/10.20517/cs.2023.14

cloud density, adjusting steric hindrance, and realizing post-functionalization. In recent years, asymmetric
[1-9]
catalytic reactions based on indole skeletons have emerged as a new research field .
Indole-2-yl-pyrans are the basic structural framework for numerous biologically active natural products and
[10]
drugs. Two novel alkaloids isolated from plant roots have an indole-C-glucoside core . Indole-C-
glucopyranoside A showed cytotoxic activity against human myeloid leukemia HL60 cells (IC = 1.3 mM)
50
and human hepatocellular carcinoma HepG2 cells. Isomer B showed cytotoxic activity against both HL60
cells and human myeloid leukemia Mata cells (IC ) [Figure 1].
50

Given the importance of the indole skeleton, the selective functionalization of this skeleton catalyzed by N-
heterocyclic carbene (NHC) has been gaining increasing interest in recent years. Armido Studer and other
chemists reported intra- and intermolecular cycloaddition by NHC catalysis to construct spirocyclic indole
skeletons by introducing formyl benzyl groups, -CHO, -OH, alkenyl groups, and other functional groups
into the indole structure [11-19] . Balanna et al. reported the NHC-catalyzed construction of the indole skeleton
by introducing -CHO, -CH , -NO , and other groups into the indole structure [20-23] . Liu et al. also reported
2
3
the NHC-catalyzed construction of polycyclic substrates by designing the indole skeleton [24-27] . Du et al.
[28]
studied the construction of an axially chiral indole skeleton . In addition, Chi et al. and Gong et al.
developed acyclic aldol reactions of the indole skeleton to form quaternary stereogenic centers by post-aldol
stereochemistry control [29,30] .

Although the NHC-catalyzed synthesis of indole derivatives is widely studied, the application of NHC
[31]
catalysis for the synthesis of indole-pyran skeletons has received limited attention. In 2013, Chi et al.
developed the direct β-carbon functionalization of saturated aldehydes through oxidative NHC catalysis,
leading to dihydropyranone with high enantioselectivity [Scheme 1A]. Subsequently, Sundén et al. used O
2
instead of high molecular weight stoichiometric oxidants and introduced a system of electron transfer
mediators (ETMs) to realize β-carbon functionalization of unsaturated aldehydes [Scheme 1B] . Although
[32]
preliminary achievements have been made in the construction of the dihydropyranone skeleton, the
avoidance of any oxidants and additives remains a challenge. Our research group has reported the
construction of spiroindole skeleton compounds catalyzed by NHC . Our continuous interest in NHC-
[12]
catalyzed cycloaddition inspired us to construct chiral 6-(indole-2-yl)-3,4-dihydropyran-2-one derivatives
by NHC-catalyzed [3 + 3] cycloaddition reactions between β-ketoester indole and α-bromocinnamaldehydes
[Scheme 1C].

EXPERIMENTAL
To an oven-dried 10 mL vial, β-ketoester indole 1 (0.1 mmol, 1.0 equiv), β-bromo-α,β-unsaturated aldehyde
2 (0.1 mmol, 1.2 equiv), cat. A (7.4 mg, 0.02 mmol, 0.2 equiv), NaHCO (12.6 mg, 0.15 mmol, 1.5 equiv)
3
were added, followed by 1.5 mL of THF. The mixture was stirred overnight at room temperature. Once the
reaction was completed (monitored by TLC), the desired product 3 was purified by silica gel column
chromatography with EA/PE (1:10) as an eluent.

RESULTS AND DISCUSSION
In view of the fact that some enantioenriched indole and pyran derivatives are pharmaceutically attractive
compounds, we chose β-ketoester indole 1a and α-bromocinnamaldehyde 2a as model reaction substrates to
optimize the reaction conditions [Figure 2]. After evaluating triazolium pre-catalysts A-C, we found that
pre-catalyst A gave the product 3a in 67% yield and 45% ee, while pre-catalyst C, bearing C F substituents,
6 5
did not provide the desired product. Installing a NO group to the indane moiety of pre-catalyst A (to get
2
pre-catalyst B) led to a small improvement on the reaction yield but with a decrease in enantioselectivity