Letter Cite This: Org. Lett. 2018, 20, 7535−7538
pubs.acs.org/OrgLett
Unraveling and Manipulating the Stereospecific Retro-Aldol Reaction in the Organocatalytic Asymmetric Aldol Reaction of Isatin and Cyclohexanone Jing Wang,† Zhi-Xiong Deng,† Chao-Ming Wang,† Peng-Ju Xia,† Jun-An Xiao,‡ Hao-Yue Xiang,*,† Xiao-Qing Chen,*,†,§ and Hua Yang*,†,§ †
College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, P. R. China Key Laboratory of Hunan Province for Water Environment and Agriculture Product Safety, Central South University, Changsha 410083, P. R. China ‡ College of Chemistry and Materials Science, Guangxi Teachers Education University, Nanning 530001, Guangxi, P. R. China
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§
S Supporting Information *
ABSTRACT: An L-pyroglutamic acid-derived bifunctional organocatalyst was designed and applied in an organocatalytic asymmetric direct aldol reaction between isatins and cyclohexanone, in which an erosion of enantiomeric excess of aldol adduct was unexpectedly observed. Through closely monitoring the reaction and performing extensive control experiments, it was determined that the erosion of ee was attributed to a rare stereospecific retro-aldol process. Moreover, effective manipulation of the retro-aldol process by tuning the use of starting materials was ultimately accomplished, leading to evidently upgraded enantioselectivity and functional group tolerance. This study demonstrates the impact of the hidden reaction pathway on the enantioselectivity in asymmetric transformation. As is well known, the acidity of the α-proton in the aldol adduct might cause undesirable racemization as widely observed (Scheme 1).8 This inherent issue in asymmetric aldol chemistry has drawn much attention so that extra care is usually paid to the basicity of the reaction conditions to avoid the unexpected erosion of enantioselectivity in the progress of the aldol
T
he rapid development of asymmetric catalytic transformations has enabled the successful synthesis of many valuable pharmaceuticals and natural products in enantioselective fashion.1 Among these, the asymmetric aldol reaction is one of the most powerful transformations for C−C bond formation in modern synthetic organic chemistry, having served as a versatile synthetic tool to a vast array of chiral compounds.2 Noticeably, Evans’ asymmetric aldol reactions have inspired intensive efforts at developing effective chiral ligands.3 Thereafter, Barbas,4 List,5 and MacMillan’s6 elegant works on the organocatalytic direct aldol reaction have given rise to a renaissance in this chemistry, and they have remarkably broadened the synthetic utilization of this classical transformation. Consequently, numerous efforts have been focused on developing new organocatalytic systems by thoroughly exploiting structural variation of the catalyst and reaction parameters.7 While these strategies have proven effective, the impact of the nature of the aldol reaction on the enantioselectivity in the process seems to have been neglected, receiving only sparse attention. © 2018 American Chemical Society
Scheme 1. Asymmetric Direct Aldol Reaction and Potential Erosion of Enantiomeric Excess
Received: October 15, 2018 Published: November 9, 2018 7535
DOI: 10.1021/acs.orglett.8b03292 Org. Lett. 2018, 20, 7535−7538
Letter
Organic Letters reaction.9 Gratifyingly, the mildness of the reaction conditions usually circumvents this intrinsic problem in organocatalytic aldol reactions. On the other hand, it is commonly believed that a facile proton-transfer process in the organocatalytic aldol reaction would maximally avoid the undesirable retro-aldol process, which has hardly impacted the level of enantioselectivity in previous studies of organocatalytic asymmetric direct aldol transformations (Scheme 1). To date, only Maruoka has observed an erosion of ee induced by the retro-aldol process in an organocatalytic direct aldol reaction of glycinate Schiff base with aldehydes catalyzed by chiral quaternary ammonium salt.10 It can be rationalized that divulging the hidden relationship between the retro-aldol process and enantioselectivity would help us to gain deeper mechanistic insight into the stereocontrol in the transformation, enabling the accomplishment of higher levels of enantiopurity in the aldol adduct. Herein, we describe our serendipitous findings on the erosion of ee in an asymmetric direct aldol reaction of cyclohexanone with isatin, which presumably stemmed from a stereospecific retro-aldol reaction. Given the fact that chiral tetrasubstituted 3-hydroxyoxindoles are widely found in many natural products and biologically active compounds,11,12 novel organocatalytic systems have persistently been pursued to facilitate their preparation in an asymmetric manner. Conceivably, the asymmetric direct aldol reaction of isatins surely provides the most straightforward pathway. A rationally designed organocatalyst is crucial for the manipulation of enantioselectivity in this transformation. On the basis of our previous work on pyroglutamic acid derived organocatalysts,13 we designed and prepared new bifunctional primary amine catalysts through a direct coupling of cyclohexanediamine and pyroglutamic acid, and these were expected to demonstrate superior capability in the isatin-involved asymmetric transformations. To our delight, excellent enantioselectivity (94% ee) and diastereoselectivity (>20:1 dr) for the corresponding aldol adduct 4a were achieved by extensively optimizing the reaction conditions (see the Supporting Information for details). Encouraged by these preliminary results, the generality of this developed catalytic system was then evaluated. Astonishingly, compared with the model reaction, the enantioselective levels for diversely substituted substrates were evidently eroded to as low as 5% ee, though good chemical yields and excellent diastereoselectivities (>20:1 dr) were constantly achieved (Scheme 2). This uncommon tolerance of functional group in terms of the enantioselectivity drew our attention as the introduction of substituents that seemed comprehensively detrimental to the stereocontrol, no matter what the electronic nature of substituents. We postulated that closely monitoring the progress of the model reaction might be conducive to understanding the dilemma. Surprisingly, the ee of adduct 4a persistently decreased after the end point of the reaction. At this point, this observation hinted that the observed poor functional tolerance might be mainly related with the inherent nature of aldol adduct, which was also observed by Maruoka.10 As a consequence, extensive studies on the corresponding adduct were then performed. First, the model reaction forming 4a was performed in different solvents including DMF, THF, CH3CN, and MeOH, respectively, and the ee of 4a was closely monitored in during the entire reaction progress (Figure 1a). It is worth mentioning that the concentration of isatin was reduced to 0.2 mol/L to completely dissolve all reactants, which can essentially rule out the impact of solubility for reactants. In general, the ee value for 4a was found to degrade as a function of time, though good
Scheme 2. Rationale for Catalyst Design and Its Performance in Asymmetric Direct Aldol Reactiona
a
All experiments were performed on 0.2 mmol scale in DMF (0.1 mL) with 0.2 mmol of 3, 0.24 mmol of 2, and catalyst 1 (20 mol %).
Figure 1. Monitoring progress of enantiomeric excess erosion. (a) Monitoring ee of 4a for the reaction in different solvents. The reaction was carried out with isatin 3a (0.2 mmol) and cyclohexanone 2 (0.24 mmol) in the presence of catalyst 1 (20 mol %) in solvent (1 mL). (b) Monitoring ee of 4a for reaction at different concentrations. The reaction was carried out with isatin 3a (0.2 mmol) in the presence of catalyst 1 (20 mol %) in DMF. (c) Monitoring ee of 4a in the mixture of 4a (0.2 mmol) and cyclohexanone 2 (0.24 mmol) in the presence of 1 (20 mol %) in solvent (1 mL). (d) Erosion of enantiomeric excess for different substrates. The reaction was carried out with isatin 3 (0.2 mmol) and cyclohexanone 2 (1 mmol) in the presence of catalyst 1 (20 mol %) in DMF (0.1 mL).
enantioselectivity for 4a was initially observed in all of the tested solvents. Interestingly, when cyclohexanone was used as the solvent, the ee of 4a kept increasing gradually in the first 6 h and then started to decline slowly after 12 h. These results suggest 7536
DOI: 10.1021/acs.orglett.8b03292 Org. Lett. 2018, 20, 7535−7538
Letter
Organic Letters that using cyclohexanone as the solvent might effectively suppress the erosion of ee for the aldol adduct and affect the stereochemical outcomes. Moreover, different concentrations of the reaction mixture were also evaluated (Figure 1b), and it was found that the erosion of the ee became pronounced at higher concentration. At this stage, we suspected that the observed erosion of ee originated from intrinsic characteristics of the aldol adduct. Aiming to deeply understand the variation of ee for adduct 4a, we mixed enantiopure 4a (95% ee) with catalyst 1 (0.2 equiv) in various solvents (1 mL) and monitored the change of ee for 4a as a function of time. It was observed that the ee of 4a decreased from 95% to 70% sharply within 15 min so that this progress could hardly be monitored. It was observed that adding a small amount of cyclohexanone (1.2 equiv) would reasonably modulate the reaction progress. Then various solvents were evaluated with addition of 1.2 equiv of cyclohexanone, which allowed us to closely monitor the ee erosion of 4a (Figure 1c). In general, the ee of 4a underwent a rapid decline within the first 5 h and slowly increased to approach an equilibrium except in cyclohexanone. In cyclohexanone, the ee of 4a slightly decreased and remained unchanged after 4 h. It should be noted that the diastereomeric excess of 4a was constant during the whole process, meaning that the racemization of adduct 4a promoted by catalyst 1 could be ruled out in the reaction system. Several substrates bearing different substituents were also tested under the same conditions to secure the change of ee in the reaction process (Figure 1d). Interestingly, 5-F and 5-Cl isatins showed even broader variation ranges, and the ee of the corresponding adduct was even reversed to −25% ee. Comparatively, variation of the ee for 5-Br isatin was much milder (from 70% ee to 55% ee). Moreover, this phenomenon was also observed in the reaction between isatin and acetone under similar conditions (see the Supporting Information for details). Obviously, the erosion of ee is universal in this reaction system. Undoubtedly, understanding the origin of this phenomenon could help us to fully appreciate the potency of the transformation. Considering the reversibility of the aldol reaction, we speculated that a retro-aldol reaction might be responsible for the ee erosion. Other commonly used organocatalysts including pyrrolidine, L-proline sulphonamide, and (1R,2R)-(−)-1,2diaminohexane were also examined by mixing them with enantiopure 4a, respectively, and monitoring the variation of enantiopurity simultaneously. No variation of enantiopurity for both enantiomers of 4a was observed, indicating that this observed ee erosion might be closely related to the structural features and stereochemical information on catalyst 1. Given this information, 4a and ent-4a were intentionally mixed with 1 and ent-1, respectively. Intriguingly, the enantiopurity of 4a was dramatically eroded in the presence of 1 (20 mol %), and starting materials 2 and 3 were detected by HRMS and TLC. However, the ee of 4a was perfectly maintained with ent-1. A similar phenomenon was also observed for ent-4a (as shown in Scheme 3, top). These results suggest that stereochemical recognition between 4a and 1 is a prerequisite for the retro-aldol process, leading to stereoselective erosion of aldol adducts promoted by the corresponding catalyst. Presumably, this stereospecific retro-aldol process was mainly responsible for the ee erosion of 4a. Based on the obtained results and previous reports, we proposed a plausible pathway for the ee erosion (as shown in Scheme 3, bottom). Initially, the corresponding aldol adduct 4
Scheme 3. Stereospecific Erosion of ee and Plausible Mechanism
was formed in high enantioselectivity catalyzed by 1. Subsequently, driven by catalyst 1, the major enantiomer of 4 underwent a stereospecific retro-aldol reaction to regenerate starting materials, while the minor enantiomer was essentially unrecognizable toward catalyst 1 and remained unchanged. The cycling of the aldol and retro-aldol process would result in accumulation of minor enantiomer and diminishment of the major enantiomer. It can be imagined that this dynamic process would slowly approach an equilibrium, whereas the ee of 4 remained constant at the end of the reaction. Next, we questioned whether this newly discovered stereospecific retro-aldol process could be intentionally bypassed, resulting in boosting ee of the aldol adduct. It should be noted that no obvious erosion occurred in first 6 h when the reaction was carried out in cyclohexanone (Figure 1a). It could be reasoned that increasing the equivalents of cyclohexanone in the reaction system should effectively suppress the retro-aldol process to give a higher enantioselective level for the aldol adduct. Moreover, the enantioselectivity of this reaction in THF was reasonably high as the erosion rate was found to be quite slow in THF initially. Thus, we proposed a straightforward strategy to manipulate the reaction pathway by employing a mixture of THF and cyclohexanone as the solvent (v/v, 1:1) to orient the direction of the aldol reaction as expected. Gratifyingly, as shown in Scheme 4, the obtained enantioselectivities for five substrates were tremendously improved to 83−95% ee with excellent yields and excellent diastereoselectivities (>20:1 dr), showing good substrate tolerance. Moreover, enantioselective levels of these reactions in the mixture of DMF and cyclohexanone (v/v, 1:1) were also significantly elevated compared to those by using DMF as the sole solvent, and the corresponding yields were persistently reserved (Scheme 4). Presumably, this stereospecific erosion was maximally inhibited and the initial enantioselectivity was well preserved. More broadly, this strategy could serve as an effective tool to circumvent the unwanted stereospecific retro-aldol process and minimize its adverse impact on the asymmetric aldol reaction. In conclusion, we have identified a rare case of erosion of enantiomeric excess in the organocatalytic asymmetric aldol reaction of isatin and cyclohexanone which was catalyzed by a 7537
DOI: 10.1021/acs.orglett.8b03292 Org. Lett. 2018, 20, 7535−7538
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Scheme 4. Enhancement of Substrate Tolerancea
All reactions were performed on a 0.2 mmol scale with 3 (0.2 mmol) and catalyst 1 (0.04 mmol, 20 mol %) in solvent (1 mL).
newly designed L-pyroglutamic acid derived bifunctional organocatalyst. A hidden stereospecific retro-aldol process was found to be responsible for the unexpected erosion of ee through extensive monitoring of the reaction system. Modulating the use of the starting material offered a straightforward solution to bypass the retro-aldol process, which could effectively suppress the erosion of ee and ultimately improve the enantioselective level and functional group tolerance in this protocol. This study exemplifies how the nature of the asymmetric transformation intrinsically affects the stereoselective performance, which might broaden our horizon toward asymmetric catalysis.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03292. Experimental procedures, compound characterization data, NMR spectra, and enantiopurity analysis of products (PDF)
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REFERENCES
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Hao-Yue Xiang: 0000-0002-7404-4247 Xiao-Qing Chen: 0000-0002-8768-8965 Hua Yang: 0000-0002-5518-5255 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We gratefully acknowledge financial support from the National Natural Science Foundation of China (21576296, 21776318, 21676302, 81703365), Natural Science Foundation of Hunan Province (2017JJ3401), China Postdoctoral Science Foundation (2017M610504), Central South University, and Guangxi Teachers Education University. 7538
DOI: 10.1021/acs.orglett.8b03292 Org. Lett. 2018, 20, 7535−7538
