Acyl transfer-enabled catalytic asymmetric Michael addition of α-hydroxy-1-indanones to nitroolefins

INTRODUCTION

Acyl transfer presents an omnipresent and efficient chemoselective ligation process in biological systems^[1], which has attracted extensive attention in the chemical community in recent years^[2]. In order to circumvent intrinsic reactivity or selectivity issues associated with mono-activated reactants, acyl transfer strategy utilizes the acyl group as a transient activating group to produce bis-activated reactants [Scheme 1A]. Such a chemical event involves a reaction cascade of X-Y bond formation, intramolecular cyclization, and the retro-Claisen reaction, where the challenging mono-activated function could be implemented formally. In this context, several catalytic asymmetric acyl transfer methods have been developed based on nucleophile activation [Scheme 1B]. For example, Mondal, Song et al. developed the asymmetric cascade Michael/acyl transfer reactions of α-nitroketones and 1,3-diketones using bifunctional organocatalysts^[3-11]. Rodriguez and Luo reported the secondary or primary amine-catalyzed acyl transfer reactions^[12-16]. Very recently, Yi et al. have established an elegant iridium-catalyzed asymmetric cascade allylation/acyl transfer reaction for the synthesis of enantiomerically enriched 3-hydroxymethyl pentenal units^[17]. Besides, using acyl transfer, Zhou, Yang et al. prepared the medium-sized-ring lactams from cyclobutanone β-ketoamides^[18-21]. Despite these achievements via nucleophile activation, acyl transfer via electrophile activation remains far less developed [Scheme 1C]. As far as we know, there was only one example from the Pan group, where nitroenone was used as an electrophilic acyl transfer reagent in catalytic asymmetric Friedel-Crafts and Michael reactions^[22]. Therefore, the development of new catalytic asymmetric acyl transfer methods via electrophile activation is highly desired.

Scheme 1. Acyl transfer strategies in asymmetric synthesis.

Our group has a long-standing interest in developing facile protocols for synthesizing biologically important molecules. Recently, we have discovered that α-hydroxy-1-indanones could serve as a valid synthon in cyclization reactions with activated Michael acceptors via chiral dinuclear zinc catalysis^[23,24]. Along this line, we envisioned that dinuclear zinc-catalyzed asymmetric acyl transfer reaction between α-hydroxy-1-indanones 1 and nitroenones 2 was feasible via less-explored electrophile activation mechanism, generating thereby the protected cyclic tertiary α-hydroxyketones 3 in an enantioselective, step- and atom-economic manner. As illustrated in Scheme 2, the reaction cascade was triggered by dinuclear zinc-catalyzed Michael reaction^[25,26], which led to the intermediate Int-1. The subsequent intramolecular cyclization/retro-Claisen reaction resulted in the acyl transfer product 3. However, therein lie several synthetic organic chemistry challenges to this reaction proposal, which include: the enantioselective formation of the tetrasubstituted stereocenter, the side-formations of potential interruption product hemiketal Int-2 and dehydration product dihydrofuran 4. Herein, we introduce a highly enantioselective acyl transfer protocol via under-exploited electrophile activation by making use of dinuclear zinc-catalyzed Michael/cyclization/retro-Claisen reaction cascade, which led to a step- and atom-economic access to a variety of protected cyclic tertiary α-hydroxyketones in good yields with excellent enantioselectivities.

Scheme 2. Our designed catalytic asymmetric acyl transfer methods via electrophile activation.

EXPERIMENTAL

Under a nitrogen atmosphere, a solution of diethylzinc (20 μL, 1.0 M in hexane, 0.02 mmol) was added dropwise to a solution of L4 (0.01 mmol, 9.6 mg) in MeCN (2 mL). After the mixture was stirred for 30 min at 30 ^oC, 1a (0.2 mmol, 29.6 mg) and 2a (0.2 mmol, 50.6 mg) were added. The reaction mixture was stirred for 48 h at the same temperature. The reaction was quenched with HCl solution (1 M, 2 mL), and the organic layer was extracted with CH₂Cl₂ (3 × 5 mL). The combined organic layer was washed with brine and dried over Na₂SO₄. The solvent was removed under reduced pressure by using a rotary evaporator. The residue was purified by flash chromatography with petroleum ether/ethyl acetate (4:1) to afford the desired chiral product 3a.

RESULTS AND DISCUSSION

The model reaction between α-hydroxy-1-indanone 1a and 2-nitro-1,3-diphenylprop-2-en-1-one 2a was initially performed in the presence of 10 mol % of dinuclear zinc catalyst in situ generated from 10 mol % of ligand L1 and 20 mol % of ZnEt₂ in tetrahydrofuran (THF) at 30 ^oC oC Figure 1. The desired product 3a was obtained in 56% yield with 1.5:1 diastereoselectivity and 39% ee value [Table 1, entry 1]. The screening of different chiral ligands including ProPhenol ligands (L2-L5) and AzePhenol ligands (L6-L8) indicated that L4 bearing 4-CF₃C₆H₄ groups was the best ligand [Table 1, entries 2-8]. Subsequently, the examination of solvent effect demonstrated that MeCN could give a high ee value of 84% [Table 1, entries 9-13]. Unfortunately, raising or lowering the reaction temperature failed to optimize the efficiency and stereoselectivity. [Table 1, entries 14-17]. Finally, we turned our attention to investigating the catalyst loading, and found that by utilizing 5 mol % of ligand L1 and 10 mol % of ZnEt₂, the yield and stereoselectivity could be improved to a high level (82% yield, 88% ee, 3:1 dr) [Table 1, entries 18-20].

Figure 1. Reaction condition screening.

With the best conditions in hand, the scope of both nitroenones and α-hydroxy-1-indanones for the projected reaction was examined [Scheme 3]. Firstly, the Ar¹ group of nitroenones was studied. A range of ortho-, meta-, para-substituted phenyl substrates 2 had been successfully employed to afford the corresponding products 3b-3f in 56%-74% yields, 1.5:1-8.3:1 diastereoselectivities and 82%-94% enantioselectivities. In addition, 1-naphthyl group was also well tolerated, giving the desired product 3g in 54% yield, 4.5:1 dr and 82% ee value. Next, the scope of Ar² group appended to the double bond of nitroenones was investigated. As illustrated in Scheme 3, both electron-rich and electron-deficient aryl groups could be tolerated, delivering the corresponding products 3h-3k in 54%-79% yields, 2.8:1-9:1 diastereoselectivities and 79%-91% enantioselectivities. Furthermore, incorporating a heteroaromatic group (Ar² = 2-furyl) or a sterically bulky group (Ar² = 1-naphthyl) did not affect the efficiency of the reaction (3l and 3m). Currently, only nitroenones bearing different aromatic substituents have been examined. Subsequently, we investigated the substrate generality of α-hydroxy-1-indanones by reacting them with 1-(2-methoxyphenyl)-2-nitro-3-phenylprop-2-en-1-one 2f. Different substituents (from electron-donating to electron-withdrawing) at the C-4 to 6 positions of α-hydroxy-1-indanones 1 participated in the cascade reactions to give the desired products 3n-3x in 62%-81% yields, 4.3:1-13:1 diastereoselectivities and 86%-96% enantioselectivities. Notably, the absolute configuration of the major isomer of product 3f was determined by the X-ray crystallographic analysis and that of other products was assigned by analogy^[27].

Scheme 3. Reaction scope. Reaction conditions: Unless otherwise noted, all reactions were conducted with 5 mol% of L4, 10 mol % of ZnEt₂, 0.20 mmol 1 and 0.20 mmol 2 in 2 mL MeCN. Isolated yields. The diastereomeric ratio parameter of 3 was detected by ¹H NMR of the crude reaction mixture. The enantiomeric excess (ee) value was determined by HPLC analysis.

To showcase the synthetic utility of this protocol, a gram-scale synthesis of 3f was carried out by using 5 mmol of 1a and 5 mmol of 2f. Under the standard condition, the reaction proceeded smoothly to give product 3f in 69% yield (1.48 g) with 10:1 dr and 93% ee [Scheme 4A]. Further reduction of nitro group with the NiCl₂/NaBH₄ system and hydrolysis of the ester group took place in one-pot and afforded the indeno[1,2-b]pyrrol-(3H)-ol derivative 5 [Scheme 4B].

Scheme 4. Gram-scale reaction (A) and derivatization (B).

As previously described, a plausible reaction mechanism for this acyl transfer-enabled catalytic asymmetric Michael addition was illustrated in Scheme 5. Firstly, α-hydroxy-1-indanone 1a and nitroenone 2a were coordinated to the two zinc atoms in the chiral pocket of the dinuclear zinc complex in a less hindered manner. Then, the enantioselective Michael addition led to the intermediate B. Next, an intramolecular hemiketalization proceeded in the same chiral pocket to give intermediate C, which underwent the retro-Claisen reaction to afford the complex D. Finally, the catalytic cycle was restarted after a proton exchange of intermediate D with another α-hydroxy-1-indanone 1a, followed by the release of product 3a.

Scheme 5. Proposed reaction mechanism.

DFT calculations were performed on the enantioselectivity-determining step to elucidate the origins of selectivity. Model catalyst IN1 [Figure 2] was used for the calculation. The ligand exchange of substrate 1a and ethane leads to IN2, which is exergonic by 21.5 kcal/mol, followed by the Michael addition step. Our calculations show that the pathway leading to the major RR-enantiomer (via transition state TS3-RR) has a free energy barrier of 13.8 kcal/mol, which is 2.3 kcal/mol more favorable than that leading to the minor SS-enantiomer (via transition state TS3-SS) and agrees with experiment. Detailed analyses indicate that there is favorable C-H…π interactions between the C-H bond adjacent to C¹ in 1a and the phenyl ring connecting to C² in 2a (2.69 Å, Figure 2) in TS3-RR. On the other hand, however, unfavorable steric repulsion was found between hydrogen atoms of the two substrates in TS3-SS (the closest H-H distance is 2.04 Å, Figure 2). The steric repulsion between the two substrates in TS3-SS would retard the C¹-C² bond formation, as manifested by the much longer C¹-C² distance in TS3-SS (2.29 Å) than in TS3-RR (2.16 Å). Thus, our computations reveal that both the C-H…π interaction in TS3-RR and the steric effect in TS3-SS account for the observed enantioselectivity.

Figure 2. The calculated free energy profile and geometries of the key transition states for the enantioselectivity-determining Michael addition step (calculations were performed at the M06/6-311++G(d,p)/SDD//B3LYP-D3BJ/6-31G(d,p)/LANL2DZ//SMD(solvent=Acetonitrile) level of theory; bond distances are given in Å).

CONCLUSION

In conclusion, we have disclosed a novel acyl transfer-enabled catalytic asymmetric Michael reaction of α-hydroxy-1-indanones with nitroolefins via an underexplored electrophilic mode of activation. The chemical event underwent a reaction cascade of dinuclear zinc-catalyzed asymmetric Michael addition, intramolecular cyclization, and the retro-Claisen reaction. Good yields and stereoselectivities of the desired products were obtained with a wide substrate scope under mild conditions. In the activation mode, the dinuclear zinc complex acted as a bifunctional catalyst, wherein one zinc atom worked as a Lewis acid and the another functioned as a Brønsted base. Further applications of this catalytic asymmetric acyl transfer via electrophile activation for the synthesis of polyfunctional heterocycles are ongoing in our laboratory.