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Cite This: J. Org. Chem. 2018, 83, 3333−3338

Origin of Stereocontrol in Photoredox Organocatalysis of Asymmetric α‑Functionalizations of Aldehydes Man Li,† Yueqian Sang,† Xiao-Song Xue,*,† and Jin-Pei Cheng†,‡ †

State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Collaborative Innovation Center of Chemical Science and Engineering, Nankai University, Tianjin 300071, China ‡ Center of Basic Molecular Science, Department of Chemistry, Tsinghua University, Beijing 100084, China S Supporting Information *

ABSTRACT: The merger of the common photoredox catalyst Ru(bpy)3Cl2 with an imidazolidinone organocatalyst by MacMillan et al. has enabled a series of highly enantioselective α-functionalizations of aldehydes, a landmark discovery in photoredox organocatalysis. Herein, we present the theoretical investigation into the origin of enantioselectivity in asymmetric radical additions to the MacMillan imidazolidinone enamines, the key stereocontrolling step in photoredox organocatalysis of asymmetric α-functionalizations of aldehydes. The calculations reveal a hidden but crucial role of E-cis enamine in enantiocontrol. The enantioselectivity in the radical additions is mainly determined by steric effects. A model based on the pseudo C2-symmetric arrangement of the methyl and tert-butyl moieties on the catalyst is proposed. This rationalizes the stereoselective outcome of these reactions and provides a good model to understand MacMillan’s imidazolidinone/photoredox dual catalysis. The insights obtained from this study should be valuable in future efforts toward the design and development of new enantioselective catalytic radical reactions.

1. INTRODUCTION The first successful execution of the dual photoredox organocatalysis strategy was realized by MacMillan and Nicewicz1 in 2008 for enantioselective α-alkylation of aldehydes using α-bromocarbonyls as radical precursors (Scheme 1A, a). The authors demonstrated that a wide range of α-ketoradicals, generated from photoreduction of α-bromocarbonyls, react efficiently and highly enantioselectively with chiral enamines derived from aldehydes and the MacMillan imidazolidinone2 catalyst.1 Subsequently, the same group successfully applied this dual photoredox organocatalysis strategy to a series of highly enantioselective α-functionalizations of aldehydes,1,3−5 such as trifluoromethylation and perfluoroalkylation,3a benzylation,3b and cyanoalkylation3c (Scheme 1A). The general mechanism of MacMillan’s photoredox organocatalysis1,3a−c is outlined in Scheme 1B. As shown, the merger of photoredox catalysis with organocatalysis occurs in the key alkylation step via addition of electron-deficient radicals to the facially biased electronrich enamines. It has been postulated that the stereoselectivity is controlled by shielding of the Re face of the E-trans enamine, leaving the Si face exposed toward electrophilic radical addition. The dual photoredox organocatalysis has evolved into a versatile platform for the development of new, highly enabling synthetic methodologies,6,7 yet there are few mechanistic and computational studies of asymmetric photoredox organocatalysis reported,8 and there is little known about the structural origin of stereoselection. We report the first theoretical © 2018 American Chemical Society

investigation into the origin of stereoselection for the key radical addition step of MacMillan’s photoredox organocatalytic asymmetric α-trifluoromethylation,3a α-alkylation,1 α-benzylation,3b and α-cyanoalkylation3c of aldehydes. Present calculations reveal a hidden but crucial role of E-cis enamine in enantiocontrol for these transformations. The stereoselectivity results from the pseudo C2-symmetric arrangement of the methyl and tert-butyl moieties on the catalyst system.

2. COMPUTATIONAL METHODS Geometry optimizations were performed using Gaussian 099 at the M06-2X10/6-31+G(d) level of theory in conjunction with the SMD11 model to account for the solvation effects of N,N-dimethylformamide (DMF, for α-trifluoromethylation3a and α-alkylation1) and dimethyl sulfoxide (DMSO, for α-cyanoalkylation3c and α-benzylation3b), the solvents used experimentally. All of the optimized geometries were verified as minima or transition state structures by frequency calculation. Thermal free energy corrections were obtained at the reaction temperatures (253.15 K for α-trifluoromethylation,3a 296.15 K for α-alkylation1 and α-cyanoalkylation,3c and 298.15 K for α-benzylation3b) to match the experimental conditions. For more accurate electronic energies to be obtained, single-point energy calculations were performed at the (SMD)-ωB97X-D12/6-311++G(2d, p) and (SMD)-B2PLYP-D3(BJ)13/6-311++G(2d, p) level with the (SMD)-M06-2X/6-31+G(d)optimized structures. The two methods yield identical tendencies and similar magnitudes of relative activation free energies (ΔΔG⧧) of the Received: February 17, 2018 Published: February 26, 2018 3333

DOI: 10.1021/acs.joc.8b00469 J. Org. Chem. 2018, 83, 3333−3338

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The Journal of Organic Chemistry Scheme 1. (a) MacMillan’s Photoredox Organocatalysis Asymmetric α-Functionalizations of Aldehydes and (b) the Proposed Catalytic Cycles

Figure 1. (SMD)-ωB97X-D/6-311++G(2d, p)//M06-2X/6-31+G(d) and (SMD)-B2PLYP-D3(BJ)/6-311++G(2d, p)//M06-2X/631+G(d) (in parentheses) computed structures and relative energies (in kcal mol−1) of the enamine intermediates.

between the substituents on the C2C3 bond and the Me (tert-butyl) adjacent to the N1 atom in the pyrrolidine ring. 3.2. Origin of Enantioselectivity. Figure 2 shows the transition state structures for the stereocontrolling addition step of the trifluoromethyl radical to imidazolidinone-enamines (E-cis and E-trans). The calculated bond lengths for forming carbon−carbon bonds are ∼2.7 Å, a typical early transition state for radical addition.17 Unexpectedly, TS1S-A, where the incoming trifluoromethyl radical attacks on the top face (Si face) of E-cis enamine, is the lowest energy TS, leading to the major product observed experimentally. MacMillan previously proposed transition state TS1S-B, which corresponds to the trifluoromethyl radical attacking on the bottom face (Si face) of E-trans enamine, is actually 1.5 kcal mol−1 higher in energy. Why is the trifluoromethyl radical approach to the top face of E-cis enamine (TS1S-A) preferred over the approach to the bottom face of E-trans enamine (TS1S-B)? A closer inspection of the two TS structures (Figure 2) reveals that, although the hindrance of the methyl group on the pyrrolidine ring is avoided, the incoming trifluoromethyl radical suffers steric repulsion with the bulky tert-butyl group when approaching the bottom face of E-trans enamine (TS1S-B). Notably, on the basis of Taft steric substituent constants, the size of the CF3 group is similar to that of a sec-butyl group.18 In contrast, steric repulsion from both the methyl group and the tert-butyl group can be avoided when the trifluoromethyl radical approachs the top face of E-cis enamine (TS1S-A). The trifluoromethyl radical attack on the top face (Re face) of E-trans enamine (TS1R-A) or the bottom face (Re face) of E-cis enamine (TS1R-B) gives the minor product (Figure 2). TS1R-B is 1.4 kcal mol−1 less stable than TS1R-A, mostly due to a larger steric hindrance suffering from the bulkier tert-butyl group than from the methyl group (Figure 2). TS structures involving Z-trans and Z-cis enamines are at least 3.1 and 4.4 kcal mol−1 higher in energy relative to TS1S-A, respectively (see Figure S1). With these TSs in hand, the Boltzmann distribution analysis predicted an ee value for the model reaction to be 93% (S), corresponding well with the enantioselectivity from the experimental observation of 99% (S) ee.3a Notably, the calculated ee based on MacMillan’s previously proposed stereocontrol model is less than 10% (S) and thus unable to reproduce the observed excellent enantioselectivity.

stereoisometric transition structures (TSs). Structures were generated using CYLview.14 All energies reported throughout the text are in kcal mol−1, and bond lengths are in angstroms (Å).

3. RESULTS AND DISCUSSION As known previously, addition of electron deficient radicals to the facially biased electron-rich enamines is the stereocontrolling step in MacMillan’s photoredox organocatalytic asymmetric α-functionalization of aldehydes.1,3a−c Therefore, we first focused on the key radical addition step and studied the photoredox imidazolidinone-catalyzed α-trifluoromethylation of octanal3a as a model reaction. 3.1. Conformers of Pivotal Enamine Intermediate. There are four major conformers expected for the pivotal enamine intermediate (Figure 1).15,16 The lowest energy conformer E-trans enamine is in accordance with MacMillan’s proposal, although the preference over E-cis enamine is only ∼0.4 kcal mol−1. The enamines with a Z configuration of the C2C3 bond were calculated to be disfavored by 1.2 kcal mol−1 (Z-trans) and 3.3 kcal mol−1 (Z-cis), mostly due to the steric repulsion 3334

DOI: 10.1021/acs.joc.8b00469 J. Org. Chem. 2018, 83, 3333−3338

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Figure 2. (SMD)-ωB97X-D/6-311++G(2d, p)//M06-2X/6-31+G(d) and (SMD)-B2PLYP-D3(BJ)/6-311++G(2d, p)//M06-2X/6-31+G(d) (in parentheses) computed TS structures for the CF3-radical addition along with their relative free energies (kcal mol−1).

Figure 3. Stereocontrol model for radical coupling with MacMillan’s imidazolidinone-derived enamines.

3.3. Enantiocontrol Model and Its Applications. On the basis of the results presented above, we proposed an enantiocontrol model for the coupling of electrophilic radical with the MacMillan imidazolidinone-derived enamines (Figure 3): (1) The stereoselectivity is primarily controlled by two TSs: the one of the incoming radical attack on the top face (Si face) of E-cis enamine leading to the major product and the one of the incoming radical attack on the top face (Re face) of E-trans enamine leading to the minor product. The catalyst has nearly C2 symmetry and attack in the upper-right and lower-left quadrants is favored over attack in the upper-left and lower-right quadrants. (2) The bulky tert-butyl group on the imidazolidinone scaffold shields the bottom face of E-cis (Re face) and E-trans (Si face) enamines. (3) The enantioselectivity in radical

additions to the MacMillan imidazolidinone enamines is determined by steric factors. To further test and demonstrate the predictive power of the proposed enantiocontrol model, we applied it to other types of substrates and electrophilic radicals.1,3a−c The calculated enantiocontrolling TS structures together with their relative free energies are presented in Figure 4 (for other electrophilic radicals including •CH2CN, •CH(CO2Et)2, and •CH2(2,4(NO2)2C6H3)) and Figures S2 and S3 (for other substrates including 2-cyclohexylacetaldehyde and 2-(4-methoxyphenyl)acetaldehyde). The predicted ee values are summarized in Table 1. For all cases studied, the enantiocontrol model works; the incoming radical attack on the top face (Si face) of E-cis enamine is most favorable and gives the major product. As displayed in Table 1, the stereoselectivities of different type of aldehydes 3335

DOI: 10.1021/acs.joc.8b00469 J. Org. Chem. 2018, 83, 3333−3338

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Figure 4. (SMD)-ωB97X-D/6-311++G(2d, p)//M06-2X/6-31+G(d) and (SMD)-B2PLYP-D3(BJ)/6-311++G(2d, p)//M06-2X/6-31+G(d) (in parentheses) computed enantiocontrolling transition state structures for •CH2CN, •CH(CO2Et)2, and •CH2(2,4-(NO2)2C6H3) radical addition along with their relative free energies (in kcal mol−1).

Table 1. Experimental and Theoretical ee Values Predicted by (SMD)-ωB97X-D/6-311++G(2d,p)//M06-2X/6-31+G(d) and (SMD)-B2PLYP-D3(BJ)/6-311++G(2d,p)//M06-2X/ 6-31+G(d) (in Parentheses)

4. CONCLUSIONS In summary, we have reported the first theoretical investigation into the origin of enantioselectivity in asymmetric radical additions to the MacMillan imidazolidinone enamines, the key stereocontrolling step in photoredox organocatalytic asymmetric α-functionalizations of aldehydes. Calculations reveal that the long-neglected E-cis enamine plays a crucial role in enantiocontrol. The enantioselectivity in radical additions is governed by steric factors. An enantiocontrol model based on the pseudo C2-symmetric arrangement of the methyl and tert-butyl moieties on the catalyst rationalizes the stereoselective outcome of these reactions and may serve as a good model for the MacMillan imidazolidinone/photoredox dual catalysis. Given that the dual photoredox organocatalysis strategy offers an exciting opportunity in developing highly enantioselective radical reactions,6,19 this study has important implications for the future development of new enantioselective catalytic radical reaction, a type of reaction that has daunted organic chemists for decades.20,21

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ASSOCIATED CONTENT

S Supporting Information *

From ref 3a. bFrom ref 3c. cFrom ref 1. dFrom ref 3b.

Figures S1−S6 and optimized geometries of all species. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00469. Computational details, optimized C−CF3 bond-forming transition state structures of the model reaction, enantiocontrolling transition state structures along with their relative free energies, and (SMD)-M06-2X/6-31+G(d) calculated Cartesian coordinates and energies (PDF)

can be reproduced well (Table 1, entries 1−3). Moreover, the predicted ee values for other electrophilic radicals (Table 1, entries 4−6) are in excellent agreement with experimental observations. Obviously, these cases verified well the reliability and feasibility of the proposed enantiocontrol model in predicting the enatioselectivity of asymmetric photoredox organocatalytic radical α-alkylation of aldehydes. 3336

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Xiao-Song Xue: 0000-0003-4541-8702 Jin-Pei Cheng: 0000-0001-8822-1577 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for the financial support from the Natural Science Foundation of China (Grants 21390400, 21772098, and 21402099), the Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), and the State Key Laboratory on Elemento-organic Chemistry. We thank Prof. Kendall N. Houk (UCLA) for his insightful comments and suggestions.

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DEDICATION We dedicate this work to Professor Kendall N. Houk on the occasion of his 75th birthday. REFERENCES

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DOI: 10.1021/acs.joc.8b00469 J. Org. Chem. 2018, 83, 3333−3338

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DOI: 10.1021/acs.joc.8b00469 J. Org. Chem. 2018, 83, 3333−3338