Enantioselective synthesis of 6-(Indole-2-yl)-3,4-dihydropyran-2-one skeletons by N-Heterocyclic carbene-catalyzed asymmetric [3 + 3] cycloaddition of α-bromocinnamaldehyde

INTRODUCTION

Indole skeletons are widely present in many important biomolecules and possess a heterocyclic structure with diverse properties. Their structural characteristics can offer unique features, such as modifying electron cloud density, adjusting steric hindrance, and realizing post-functionalization. In recent years, asymmetric catalytic reactions based on indole skeletons have emerged as a new research field^[1-9].

Indole-2-yl-pyrans are the basic structural framework for numerous biologically active natural products and drugs. Two novel alkaloids isolated from plant roots have an indole-C-glucoside core^[10]. Indole-C-glucopyranoside A showed cytotoxic activity against human myeloid leukemia HL60 cells (IC₅₀ = 1.3 mM) and human hepatocellular carcinoma HepG2 cells. Isomer B showed cytotoxic activity against both HL60 cells and human myeloid leukemia Mata cells (IC₅₀) [Figure 1].

Figure 1. Representative natural products and bioactive compounds containing the indole-2-yl-pyrans skeleton.

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, -CH₃, -NO₂, and other groups into the indole structure^[20-23]. Liu et al. also reported the NHC-catalyzed construction of polycyclic substrates by designing the indole skeleton^[24-27]. Du et al. studied the construction of an axially chiral indole skeleton^[28]. 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 catalysis for the synthesis of indole-pyran skeletons has received limited attention. In 2013, Chi^[31]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 O₂ 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]^[32]. Although 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^[12]. Our continuous interest in NHC-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].

Scheme 1. Profile of the construction of NHC-catalyzed construction of dihydropyranone.

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), NaHCO₃ (12.6 mg, 0.15 mmol, 1.5 equiv) 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 C₆F₅ substituents, did not provide the desired product. Installing a NO₂ group to the indane moiety of pre-catalyst A (to get pre-catalyst B) led to a small improvement on the reaction yield but with a decrease in enantioselectivity (entry 2, 72% yield, 35% ee). Various inorganic bases could be used in this transformation (entries 4-5), and NaHCO₃ was found as the most efficient one that could give 3a with good yield and excellent enantioselectivity (entry 5, 75% yield, 94% ee). Screening different reaction solvents did not show further improvements in either yields or enantioselectivities (entries 6-7). When 5 Å MS was used as the additive, the yield and the enantioselectivity increased slightly higher (entry 8, 78% yield, 97% ee). Further optimization studies revealed that high enantioselectivity with low reaction yield (entry 9, 68% yield, 97% ee) was delivered when the reaction was performed with 10 mol% pre-catalyst A. Then, the reaction temperature was investigated. When the reaction proceeded at 0 ℃, the yield was dramatically decreased to 8%, and the enantioselectivity was slightly decreased to 92% [Figure 2] (entry 10). Higher reaction temperature did not result in better yield or enantioselectivity [Figure 2] (entry 11). While the changing of reactant concentration led to lower yields (entries 12-13). The best reaction condition was established with a 20 mol% pre-catalyst, 1.5 equiv NaHCO₃, and 1.0:1.2 reactant ratio at room temperature.

Figure 2. Optimization of the reaction conditions^a. ^aReaction conditions: pre-catalyst (20 mol%), base (1.5 equiv), 1a (0.1 mmol), and 2a (0.12 mmol) in solvent (1.5 mL). ^bIsolated yield. ^cDetermined by chiral HPLC analysis. ^d5Å molecular sieves (10 mg) were used as an additive at room temperature. ^epre-catalyst (10 mol%). ^fThe temperature was 0 °C. ^gThe temperature was 35 °C. ^hTHF = 3 mL. ⁱTHF = 1 mL. Mes = 2,4,6-trimethylphenyl.

After establishing the optimized reaction conditions, the scope of the reaction was examined. First, we studied variations of the β-ketoester indoles [Scheme 2]. Substrates with electron-releasing and electron-withdrawing groups on the benzene ring of the indole group of 1,3-dicarbonyl compound (R³) underwent a cycloaddition reaction, affording the compounds in moderate to good yields (61%-80% yield) and excellent enantioselectivities (3a–3j, 92%-98% ee). It is worth mentioning that the enantioselectivity of the reaction can reach 98% when the C5 position of the indol-phenyls is NO₂. Subsequently, we investigated different N-protecting groups on the indole skeleton, such as Me, PMB, or tert-butyl benzyl. To our great delight, β-ketoester indoles with different N-protecting groups also worked well in this process under the current reaction condition, and the desired products were generated in good to excellent yields and optical purities (3k-3m, 97%-98% ee). However, the N-electron withdrawing protecting group (such as Boc) showed lower reaction activity and enantioselectivities. Furthermore, the enantioselectivity of the reaction has a slight decrease without an N-protecting group (3n, 87% ee). This may be due to the steric resistance effect of the N-protecting group. Encouraged by these results, the generality of α-bromocinnamaldehyde 2 was further investigated with β-ketoester indole 1a [Scheme 2]. Substituents with different electronic properties at the orthoposition (3o, 65% yield, 95% ee) and the paraposition (3p-3r, 93-97% ee) of the phenyl group were well tolerated. Para-F on the phenyl ring led to some decrease in reaction yield (3p, 50% yield). Replacement of the phenyl substituent with 2-furanyl had little effect on the reaction outcomes (3s, 68% yield, 83% ee). In addition, trace desired products were obtained by employing alkyl-substituted aliphatic aldehydes.

Scheme 2. Substrates scope. Reaction conditions: pre-cat. A (20 mol%), NaHCO₃ (1.5 equiv), 1 (0.1 mmol), and 2 (0.12 mmol) in THF (1.5 mL).

To demonstrate the practical nature of the present catalytic asymmetric strategy, a gram-scale preparation of compound 3a was performed [Scheme 3]. Under the standard reaction conditions, amplifying the model reaction to 1.00 mmol straightforwardly gave optically pure 6-(indole-2-yl)-3,4-dihydropyran-2-one 3a without the loss of enantioselectivity in modest yield (56% yield and 96% ee).

Scheme 3. A gram scale reaction.

The absolute configuration of the cycloadduct 3t was determined by X-ray crystallographic analysis as an (S)-configuration [Figure 3]. The absolute configuration of all other products was assigned accordingly (CCDC 2243010, please see the SI for details).

Figure 3. X-ray single crystal data for compound 3t.

The plausible catalytic cyclic for this [3 + 3] cycloaddition pathway is shown in Scheme 4. The cycloaddition reaction begins with the addition of NHC to α-bromocinnamaldehyde 2a, forming a Breslow intermediate, which undergoes tautomerization and debromination to generate form α, β-unsaturated acylazolium III. The Michael addition of enolate generated by β-ketoester indole 1a to intermediate III led to intermediate IV. Intermediate IV undergoes tautomerization and intramolecular esterification to give the desired product 3a and regenerate the NHC catalyst.

Scheme 4. Proposed catalytic pathway and transition state.

CONCLUSIONS

In conclusion, we have developed a mild NHC-catalyzed efficient [3 + 3] cycloaddition reaction between α-bromocinnamaldehyde and β-ketoester indole, avoiding the use of high molecular weight stoichiometric oxidants. This reaction resulted in the highly enantioselective construction of 6-(indole-2-yl)-3,4-dihydropyran-2-one skeleton in good yields and exhibiting excellent enantioselectivities.