Origins of Enantioselectivity in Asymmetric Radical Additions to

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Origins of Enantioselectivity in Asymmetric Radical Additions to Octahedral Chiral-at-Rhodium Enolates: A Computational Study Shuming Chen, Xiaoqiang Huang, Eric Meggers, and Kendall N. Houk J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b08650 • Publication Date (Web): 16 Nov 2017 Downloaded from http://pubs.acs.org on November 16, 2017

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Journal of the American Chemical Society

Origins of Enantioselectivity in Asymmetric Radical Additions to Octahedral Chiral-at-Rhodium Enolates: A Computational Study Shuming Chen,† Xiaoqiang Huang,‡ Eric Meggers,‡ and K. N. Houk*,† † ‡

Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, United States Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Strasse 4, 35043 Marburg, Germany

ABSTRACT: The origin of asymmetric induction in the additions of carbon- and nitrogen-centered radicals to octahedral centrochiral rhodium enolates has been investigated with Density Functional Theory (DFT) calculations. Computed free energies of activation reproduce the preference for the experimentally observed major enantiomer. Good levels of enantioselectivity are maintained upon replacement of the bulky tert-butyl substituents on the ligands with methyl groups. Distortion-interaction analysis indicates that for both carbon-and nitrogen-centered radicals, which have relatively early and late transition states, respectively, the difference in the distortion energies controls the enantioselectivity. In the enolate derived from the Λ-configured catalyst, the tert-butyl group that shields the si face of the substrate plays the most sterically significant steric role by directly hindering access to the enolate double bond. Exploration of the effect of the N substituent size and shape on the imidazole substrate shows that compared to N-Me, N-iPr and N-Ph variants, the N-o-tolyl variant of the rhodium enolate results in the most substantial improvement in stereodiscrimination, a finding that is in agreement with experimental ee values.

INTRODUCTION Photoredox catalysis has received intense interest in the past decade. It constitutes a method to generate highly reactive intermediates in a novel and controlled fashion, enabling the facile assemblage of C–C and C–heteroatom bonds under mild conditions.1 Photoredox chemistry can be coupled with other modes of catalysis to achieve excellent levels of enantioselectivity in synthetically important transformations involving highly reactive species.2–3 While theoretical inquiries of radical additions to π systems have been undertaken since decades ago,4 there are relatively few computational studies that seek to elucidate the transition state geometries and mechanistic details in reactions involving transition metals in radical pathways, which would facilitate the rational design and application of these catalysts to a wider range of chemical transformations.5 Among the methods that have been developed for asymmetric catalysis coupled with photoredox chemistry, the configurationally inert and substitutionally labile chiral-at-metal complexes introduced by one of our groups were found to provide high levels of enantioselectivity.6 These catalysts rely entirely on the centrochirality of the metal coordination sphere for asymmetric induction, thus eliminating the need of using chiral ligands. By coordinating to the substrate, they serve the dual function of activating the substrate as a Lewis acid7 and generating the necessary chiral environment around the reactive carbon site for asymmetric induction. A range of asymmetric additions to enones6f and enolates,6a–c,e,g–i which enable the enantioselective construction of desirable α- and β-functionalized carbonyl compounds, have been successfully demonstrated with these centrochiral octahedral complexes.

Scheme 1 shows the proposed catalytic cycle of additions of radicals to chiral-at-metal enolates. The acyl imidazole substrate coordinates to the substitutionally labile metal catalyst to give complex A, which is deprotonated in the presence of base to yield electron-rich metal enolate B. The transfer of chirality occurs in the stereodetermining addition of electron-deficient carbon- or nitrogen-centered radicals to the metal enolate to provide ketyl radical C, a strong reductant that either feeds an electron into the photoredox cycle or directly reduces the radical precursor to afford chain propagation. Ketyl radical C is oxidized to cationic intermediate D, which then releases the product and coordinates to another molecule of the substrate to begin a new catalytic cycle.8 Scheme 1 [M]

O

N [M]

st

R2

[M]

O

O

R1

N

R1

X

[M]

st

R2

N

R1

R1

X

X C

R2 N

O

R2

O

N

N

g

ep

EWG N

in

in

[M]

O

N

m

A

R2

N

e-

B

er

R2 N

– 2 x MeCN

radical precursor

X EWG

N

1 er R eo -d et

N

R1

R2

N

H+ N

X = NH, NR, CH2, CHR or CR2

O

e-

EWG PC chain process or photoredox catalysis

EWG

D

R1

Scheme 1. Proposed catalytic cycle of the asymmetric addition of electron-deficient radicals to chiral-at-metal enolates. (PC = photocatalyst)

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The recent computational study by Wiest and Meggers9 provided valuable insight into the Lewis acid-catalyzed acceleration and the stereoinduction in the 1,4-addition of carbon-centered radicals to enones mediated by these chiral-at-metal catalysts. However, at the time of writing, it remains unclear what controls stereoselectivity and how variations in the substitution patterns on the ligand framework and the substrate influence the asymmetric induction in 1,3-additions to these Rh enolates. We describe the first computational study elucidating the origins of stereoselectivity by way of distortion-interaction analysis in this catalytic system. COMPUTATIONAL METHODS All computations were performed with the Gaussian 0910 suite of programs. Ground state and transition state geometries were optimized in the gas phase using the B3LYP11 functional using the LANL2DZ12 effective core potential for Rh, and 631G(d) for all other atoms. Frequency calculations were performed at the same level of theory as that used for geometry optimization to determine whether the structures are minima (no imaginary frequencies) or saddle points (one imaginary frequency) on the potential energy surface, and to obtain thermal corrections to the Gibbs free energies. Single point energies were computed with the M0613 functional using the SDD14 basis set for Rh and 6-311G++(d,p) for all other atoms. Solvation effects were included using the SMD15 solvation model with acetone as the solvent. For distortion-interaction analysis, fragment distortion and interaction energies were computed at the M06/6311G++(d,p)-SDD level using the B3LYP/6-31G(d)LANL2DZ geometries obtained in the gas phase. Gibbs free energies reported below include zero-point energies and thermal corrections calculated at 298.15 K and 1 atm. Solvation entropy corrections of -1.89 kcal/mol were applied to reflect the conversion from 1 atm to the 1 M solution phase standard state in bimolecular reactions.16 Molecular structures were visualized using CYLview.17 Monte Carlo conformational searches were carried out with the Merck molecular force field (MMFF) implemented in Spartan ’16 to ensure that the lowest energy conformations of intermediates and transition states are presented. A more detailed discussion of alternative conformations explored can be found in the Supporting Information. RESULTS AND DISCUSSION We explore the additions of electron-deficient ester and perfluorinated anilinyl radicals to acyl imidazole 1 mediated by catalysts Λ-RhS1 and Λ-RhS2.18 These reactions proceed at room temperature and furnish products 4 and 5 with excellent yields and enantioselectivities (Scheme 2).6h To support the assertion that the reaction proceeds through a Rh enolate enolate, the Rh enolate was synthesized independently in a previous work6h and characterized by X-ray crystallographic analysis. Competence of the Rh enolate as a catalyst in the amination and alkylation reactions shown in Scheme 2 has also been experimentally confirmed.6h

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N

Λ-RhS (cat.) Ru(bpy)3(PF6)2 (cat.) Na2HPO4 (20 mol %) acetone/DMSO/H2O, rt 21 W CFL

Ph N

O

radical addition

O

1

R1 O

N2

EtO

R3

S

2

N

or

N

Rh

Ar N3 3

N

Me

C

N

Ph N

4

OEt

R1 O

Λ-RhS1 R1 = Me: 87% ee Ph: 92% ee o-tolyl: 97% ee Λ-RhS2 R1 = Ph: 88% ee O

C

Me

N

N

Ph

or

S

R3

Λ-RhS1: R3 = t-Bu Λ-RhS2: R3 = Me

N

HN Ar R1 5

Λ-RhS1 R1 = Ph: 98% ee (ArN3 = F5C6N3)

Scheme 2. Experimental conditions of model enantioselective radical additions to Rh enolates investigated in this study.6h (a)

R2

S N

O N

Ph N

R1

Rh

1

N N

N S

1a: R1 = Ph 1b: R1 = o-tolyl 1c: R1 = Me 1d: R1 = i-Pr

C

R2

S N

Me

Rh

C

Me

–2 x MeCN

R2

O N

1 N R

N S

R2

6a: R1 = Ph, R2 = t-Bu 6b: R1 = o-tolyl, R2 = t-Bu 6c: R1 = Me, R2 = t-Bu 6d: R1 = i-Pr, R2 = t-Bu 6e: R1 = Ph, R2 = Me

Λ-RhS1: R2 = t-Bu Λ-RhS2: R2 = Me

R2

S N

X

O

Rh

1 N R

N

N S

X

EWG enantioselective radical addition

R2

EWG 7: X = CH2, EWG = CO2Me 8: X = NH, EWG = C6F5

(c)

(b) re face approach N

S N N

O

si face blocked

Rh N S

Figure 1. (a) Stereodetermining step of radical additions to Rh enolates showing the range of structures surveyed in this study; (b) steric model for asymmetric induction in radical addition to Rh enolates; (c) computed structure of Rh enolate 6a, with the site of radical addition highlighted in green. The range of structures explored computationally in this study for the chirality-imparting step of the radical additions is shown in Figure 1a. A steric model proposed by one of our groups,19 which qualitatively rationalizes the asymmetric induc-


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Journal of the American Chemical Society tion, is shown in Figure 1b for the bis-cyclometalated Rh enolate 6a, which is generated from the coordination of 1a to ΛRhS1, replacing two molecules of labile MeCN, followed by deprotonation by base. In this steric model, the coordinated substrate is sterically shielded from below (the si face) by the C5 alkyl substituent on the benzothiazole ligand of the C2-symmetrical catalyst, but not from above (the re face). A larger C5 alkyl substituent, such as a tert-butyl group, can therefore be expected to provide better steric shielding of the si face, leading to higher levels of enantioselectivity. To investigate the validity of this steric model, we first explored the addition of the carbon-centered methyl ester radical 7 to Rh enolate 6a. (To simplify the calculations, the experimentally used ethyl ester radical is modeled with a methyl ester radical.) Figure 2a shows the geometries of the two possible transition states, TS-1aR and TS-1aS, for the stereodetermining step in the catalytic cycle, where radical 7 adds to the chiral-atmetal enolate 6a to yield a ketyl radical. The calculated lengths of the forming C–C bonds are 2.32 Å in TS-1aR and 2.35 Å in TS-1aS, respectively. The calculated Gibbs free energies of activation are 8.9 kcal/mol for TS-1aR and 11.8 kcal/mol for TS1aS. These free energy values indicate generally small intrinsic barriers for radical additions to Rh enolates, and are numerically comparable to the barriers of activation calculated for trifluoromethyl radical additions catalyzed by chiral-at-rhodium complexes.5d The 2.9 kcal/mol difference in free energies of activation is in good agreement with the high level of enantioselectivity (92% ee) observed experimentally. (a) TS-1aS

TS-1aR

ΔG‡ = +8.9 ΔE‡ = -5.3 (b)

ΔEdist‡ (ester) +2.5

ΔEdist‡ (ester) +2.7 ΔEdist‡ (Rh) +3.4

ΔG‡ = +11.8 ΔE‡ = –1.8

–11.3 ΔEint‡

–11.5 ΔEint‡

ΔEdist‡ (Rh) +7.2

ΔE‡ –5.3 ΔE‡

–1.8

Figure 2. (a) Optimized transition state structures for ester radical addition to Rh enolate 6a; (b) distortion-interaction analysis for transition states of ester radical addition to 6a. Atomic distances denoted in Ångström; energies denoted in kcal/mol. Figure 3a shows the the two possible transition states, TS1bR and TS-1bS, for the radical addition to Rh enolate 6b, with an N-o-tolyl group replacing the N-phenyl group in 6a. The calculated lengths of the forming C–C bonds are 2.32 Å in TS-1bR and 2.35 Å in TS-1bS, respectively. TS-1bR and TS-1bS have free energies of activation separated by 5.6 kcal/mol, which is 2.7 kcal/mol higher than the free energy difference between TS1aR and TS-1aS, indicating that the addition of a methyl substituent in the ortho position of the N-phenyl substituent significantly improves stereodiscrimination.

(a) TS-1bR

TS-1bS

ΔG‡ = +14.1 ΔE‡ = -0.5

ΔG‡ = +8.5 ΔE‡ = -5.6 (b)

ΔEdist‡ (ester) +2.6

ΔEdist‡ (ester) +2.7 ΔEdist

‡

(Rh) +3.6

–11.9

ΔEint‡

–11.9 ΔEint‡


ΔE‡ –5.6 ΔE‡ –0.5

Figure 3. (a) Optimized transition state structures for ester radical addition to Rh enolate 6b; (b) distortion-interaction analysis for transition states of ester radical addition to 6b. Atomic distances denoted in Ångström; energies denoted in kcal/mol. To further investigate the effect of the imidazole N-substituent and the benzothiazole C5 substituent on the stereodetermining step of the reaction, we calculated transition state structures and energies for the addition of 1 to Rh enolates 6b–6e. Table 1 summarizes the differences in free energies found in the transition states leading to the major and minor enantiomers in each case. While the ΔΔG‡ values fall in the range of 2.8–3.1 kcal/mol for N substituent sizes ranging from methyl to phenyl, which yields experimental ee values of 87% to 92%, the N-otolyl substituted enolate, 6c, provides by far the greatest separation in computed free energies of activation (5.6 kcal/mol). This is in qualitative agreement with the experimental observation that the N-o-tolyl substituted Rh enolate provides the best enantioselectivity (97%). For Rh enolate 6e, derived from catalyst Λ-RhS2, the computed ΔΔG‡ of 1.0 kcal/mol predicts 68% ee, which is lower than the experimentally observed value of 88% (corresponding to 1.6 kcal/mol ΔΔG‡). Rh enolate

Parent Catalyst

N-substituent

ΔΔ G‡

Experimental ee (%)

6a

Λ-RhS1

Ph

2.9

92

6b

Λ-RhS1

o-tolyl

5.6

97

6c

Λ-RhS1

Me

3.1

87

6d

Λ-RhS1

i-Pr

2.8

-

6e

Λ-RhS2

Ph

1.0

88

Table 1. Differences in free energy of activation computed for transition states leading to major enantiomers (TS-1R) and minor enantiomers (TS-1S). ΔΔG‡ values are denoted in kcal/mol. To establish the source of the difference in the free energies of activation between the transition states, we performed a distortion-interaction analysis.20 These results are given in Figures 2b and 3b. The distortion energy refers to the energy required to deform the reactants into their transition state geometries. The interaction energy encompasses both destabilizing steric repulsions and stabilizing electrostatic and orbital interactions. The distortion-interaction analysis showed that in cases where high enantioselectivity is observed, the stereodiscrimination stems almost entirely from the differences between distortion energies. The benzothiazole C5 tert-butyl substituent shielding



the si face is key in forcing the benzothiazole ligand framework into a more highly distorted geometry, resulting in higher total distortion energies in all the disfavored transition states surveyed (TS-1aS–TS-1eS). Additionally, the imidazole N-otolyl substituent provides improved stereodistinction by interacting sterically with both the C5 tert-butyl at the re face of the substrate and the approaching radical in the disfavored transition state TS-1bS, resulting in the highest level of enantioselectivity among the imidazole substitution patterns surveyed. In Figure 2b, ΔEdist‡ (Rh) is the energy required to distort the Rh catalyst and its ligands into the transition state geometry, while ΔEdist‡ (ester) is the energy used to distort the methyl ester radical into the transition state geometry. The interaction energy between the distorted Rh catalyst-ligand complex and the ester radical is denoted by ΔEint‡. The energy of activation, ΔE‡, is the sum of ΔEdist‡ (Rh), ΔEdist‡ (ester) and ΔEint‡. For the tert-butyl-substituted Rh enolate 6a, the distortioninteraction analysis (Figure 2b) reveals that the 3.5 kcal/mol difference in ΔE‡ for TS-1aR and TS-1aS is almost entirely attributable to the difference in total distortion energies. The main source of difference in the total distortion energies is ΔEdist‡ (Rh), which is 3.4 kcal/mol for TS-1aR and 7.2 kcal/mol for TS1aS. These results indicate that the distortion of the Rh catalyst framework and its acyl imidazole ligand is more severe in the disfavored transition state TS-1aS. In TS-1aS, the ester radical has a hydrogen-hydrogen distance of 2.33 Å with the tert-butyl group blocking the re face of the substrate, leading to substantial steric repulsion and subsequent deformation of the ligand geometry. The substantial energy expenditure required to bend and deform the relatively rigid Rh catalyst is responsible for the experimentally observed enantioselectivity. For the addition of 1 to Rh enolate 6b, the distortion-interaction analysis (Figure 3b) showed that the difference in distortion energies is basically the sole source of the 5.1 kcal/mol overall difference in ΔE‡ between TS-1bR and TS-1bS. Distortion energy of the Rh enolate, represented by ΔEdist‡ (Rh), is again the dominating factor, being 5.3 kcal/mol higher for TS-1bS than for TS-1bR. A steric interaction with a hydrogen-hydrogen distance of 2.39 Å is observed between the ester radical and the tert-butyl group shielding the si face. The approach of the ester radical forces the N-o-tolyl group to rotate to avoid a clash between the radical and the methyl group. This rotation places the methyl group on the N-o-tolyl substituent in a position to clash with the benzothiazole C5 tert-butyl substituent at the re face of the substrate, which constitute an additional source of steric strain that accounts for the significantly increased stereodiscrimination. Close examination of the transition state geometry of the benzothiazole ligand “propeller leaf” shielding the re face indicates that it is significantly more distorted compared to its counterpart shielding the si face, presumably to avoid steric clashes with the N-o-tolyl group (vide infra). These results show that the N-o-tolyl substituent on the acyl imidazole ligands plays a sterically significant role in inducing more severe distortion of the benzothiazole framework in the disfavored transition state TS-1bS, an effect similar to that found for N-Ph substituted substrates in the transition state energies previously computed for asymmetric Giese reactions performed using the same catalyst system.9 The considerable difference in distortion energies between the transition state pairs, and in particular the ΔEdist‡ (Rh) values, suggest that the degree of deformation in the Rh enolate geometry should be readily observable. A quantitative understanding

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of the major deformations taking place in disfavored transition states can be expected to aid in the development of novel catalysts with ligand scaffolds that are more difficult to distort, and provide superior stereodiscrimination. Figure 4 shows the top view of Rh enolate 6c and the two transition states, TS-1bR and TS-1bS. It is clear that while the favored transition state, TS1bR, does not exhibit readily discernible distortion, TS-1bS shows substantial deformation of the benzothiazole ligand framework, including a large change in the dihedral angles between the two polyaromatic ring systems, as well as bending of the polyaromatic ring systems themselves. Representative bond lengths show that coordinative bonds to Rh do not shorten or lengthen significantly in either transition state. The C4–Rh1– C8 angle widens from 91.7° in enolate 6b to 95.5° in the disfavored transition state TS-1bS, indicating deviation from octahedral geometry to be a substantial source of strain in TS-1bS. Within the polycyclic benzothiazole ligand skeleton, the most severe deformations from ground-state enolate geometry were observed in the Rh-containing 5-membered rings. Interestingly, even though radical attack occurs at the si face in TS-1bS, the “propeller leaf” shielding the re face is considerably more distorted than the one shielding the si face, with larger dihedral angles indicating more compromised planarity in both the Rhand the sulfur-containing 5-membered rings. This result confirms the steric significance of the N-o-tolyl group, which, through rotation, relays the steric strain from the si face to the re face of the enolate.


6

7

5 3

2 1

4

8

9 10

13 12

Rh1–N2: 2.12 Å Rh1–N9: 2.09 Å Rh1–C4: 2.01 Å Rh1–C8: 2.01 Å ∠C4–Rh1–C8: 91.7° ∠C3–N2–Rh1–C4: 7.6° ∠C6–C5–N2–C3: 1.1° ∠C10–N9–Rh1–C8: 5.4° ∠C12–C13–N9–C10: 1.4°

11

6b

6

7

5 3

2 1

4

8

9 10

13 12


11

TS-1bR

6

7

5 3

2 1

4

8

9 13 12

TS-1bS

10

11


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Journal of the American Chemical Society Figure 4. Rh enolate and transition state geometries and representative parameters showing modes of distortion in the benzothiazole ligand framework. We also explored the origin of enantioselectivity in the addition of the nitrogen-centered 2,3,4,5,6-pentafluoroanilinyl radical 8 to Rh enolate 6a. Figure 5a shows the two possible transition states, TS-2R and TS-2S, for this transformation, with TS2R leading to the experimentally observed major enantiomer. The forming C–N bonds are 2.06 Å in TS-2R and 2.11 Å in TS2S, indicating that these nitrogen radical additions have considerably later transition states compared to the addition of carboncentered ester radicals (vide sufra), an expected result given the more endothermic nature of the nitrogen radical additions. The free energy of activation for TS-2R is 2.3 kcal/mol lower than that of TS-2S, which is consistent with the experimentally observed levels of enantioselectivity. Distortion-interaction analysis (Figure 5b) indicates that distortion also controls stereoselectivity for the anilinyl radical addition. Despite a 0.05 Å difference in the forming C–C bond length between TS-2R and TS2S, the interaction energies are essentially the same between these two transition states. These results show that for radical additions with both early and late transition states in these chiral-at-metal catalyst systems, distortion energy is consistently the dominant force controlling enantioselectivity. (a) TS-2S

TS-2R

well as more severe deformations in the Rh-containing 5-membered rings in the polyaromatic benzothiazole frameworks, account for the higher distortion energies in the disfavored transition states.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Energies and coordinates of computed structures (PDF)

AUTHOR INFORMATION Corresponding Author *[email protected]

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT We are grateful to the National Science Foundation (Grant CHE1059084) for financial support. Calculations were performed on the Hoffman2 cluster at the University of California, Los Angeles, and the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by the National Science Foundation (Grant OCI-1053575).

REFERENCES 1.

ΔG‡ = +10.4 ΔE‡ = -5.6 ΔEdist‡ (ester) +2.2

ΔEdist‡ (ester) +2.2 ΔEdist‡ (Rh) +7.4

(b)

ΔE‡ –5.6

ΔG‡ = +12.7 ΔE‡ = -3.9

–15.2 ΔEint‡


–15.0 ΔEint‡

ΔE‡ –3.9

2.

Figure 5. (a) Optimized transition state structures for anilinyl radical addition to Rh enolate 6a; (b) distortion-interaction analysis for transition states of anilinyl radical addition to 6a. Atomic distances denoted in Ångström; energies denoted in kcal/mol. CONCLUSIONS We have demonstrated that for the chiral-at-rhodium catalysts investigated in this study, distortion of the Rh enolate and its benzothiazole ligand framework is the dominating factor in enforcing enantioselectivity both in earlier transition states observed for carbon radical additions, and later transition states observed for nitrogen radical additions. This study confirms the key role of the tert-butyl group shielding the si face of the substrate in providing steric distinction. In addition, we also find the N-o-tolyl substituent to contribute significantly to improved stereodiscrimination by interacting sterically with the tert-butyl group at the re face to induce more severe distortion of the benzothiazole ligands. Deviations from octahedral geometries, as

3. 4.

5.

6.

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Soc. 2016, 138, 6936. (g) Shen, X.; Harms, K.; Marsch, M.; Meggers, E. Chem. Eur. J. 2016, 22, 9102. (h) Huang, X.; Webster, R. D.; Harms, K.; Meggers, E. J. Am. Chem. Soc. 2016, 138, 12636. (i) Wang, C.; Harms, K.; Meggers, E. Angew. Chem. Int. Ed. 2016, 55, 13495. 7. For other examples of Lewis-acid catalyzed radical additions, see (a) Guindon, Y.; Lavallee, J. F.; Llinas-Brunet, M.; Horner, G.; Rancourt, G. J. J. Am. Chem. Soc. 1991, 113, 9701. (b) Yang, Y.H.; Sibi, M. P. in Encyclopedia of Radicals in Chemistry, Biology and Materials, Vol. 2, Chatgilialoglu, C. Studer, A. Eds., Wiley, Chichester, 2012, 655. 8. For a detailed discussion of experimental evidence that radical pathways, rather than carbene/nitrene pathways, are operational in these aminations and alkylations, see ref 6h. 9. Tutkowski, B.; Meggers, E.; Wiest, O. J. Am. Chem. Soc. 2017, 139, 8062 10. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09; Gaussian Inc.: Wallingford, CT, 2009. 11. (a) Head-Gordon, M.; Pople, J. A.; Frisch, M. J. Chem. Phys. Lett. 1988, 153, 503; (b) Becke, A. D. J. Chem. Phys. 1993, 98, 5648;

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Journal of the American Chemical Society Table of Contents (TOC) Graphic R2

S N Rh

X

O N

1 N R

N Rh

EWG

N S

R2

S

enantioselective radical addition

O N

X

1 N R

N

R2

Distortion or interaction? Substitution effects?

S

chiral-at-Rh enolate

favored TS

disfavored TS


EWG

R2

Origins of Enantioselectivity in Asymmetric Radical Additions to

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