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Origins of Stereoselectivity in Mannich Reactions Catalyzed by Chiral Vicinal Diamines Shuming Chen, and Kendall N. Houk J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00037 • Publication Date (Web): 13 Feb 2018 Downloaded from http://pubs.acs.org on February 14, 2018

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The Journal of Organic Chemistry

Origins of Stereoselectivity in Mannich Reactions Catalyzed by Chiral Vicinal Diamines Shuming Chen and K. N. Houk* Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569 ABSTRACT: The origins of the enantio- and diastereoselectivities in the Mannich reactions between aldehydes and ketimines catalyzed by chiral vicinal diamines have been determined by density functional theory calculations and distortion-interaction analysis. Computational results indicate a strong energetic preference for hydrogen-bonded nine-membered cyclic transition states. The favored transition states involve eight heavy-atoms in the crown (chair-chair) conformation, using the nomenclature of the analogous cyclic hydrocarbons. Energetic discrimination in the chirality-imparting step arises from pseudo-gauche-butane-type interactions in the disfavored transition states, as well as steric clashes between the N-Boc protecting group and the ammonium N-substituents.

INTRODUCTION Organocatalysis relying on enamine/iminium chemistry provides a powerful tool for the stereoselective synthesis of molecules of biological and medicinal interest.1,2 Cinchona alkaloids3 and other chiral vicinal diamines4 are known to catalyze asymmetric aldol reactions, and the nature of the transition states involved has been characterized computationally.5 We recently showed that the conformational preferences of these transition states involving eight heavy atoms exert stereocontrol5b–e, 6 in a manner similar to 6membered Zimmerman-Traxler-type transition states.7 Here we show that this transition state model can be extended to Mannich reactions, another important vicinal diaminecatalyzed reaction recently disclosed by the Zhihui Shao group at Yunnan University.8 The Mannich reactions between isatin-derived N-Boc ketimines 1 and acetaldehyde 2a catalyzed by chiral primarytertiary diamine catalysts 3 (Scheme 1) were reported by the Shao group (Dai et al.).8 In the absence of a strong acid, the reaction proceeded with low levels of enantioselectivity. With triflic acid as an additive, the enantioselectivity was dramatically improved (from 25% to 91% ee) when the R2 substituent on the vicinal diamine catalyst 3 was a tert-butyl group. The addition of water and 3-nitrobenzoic acid was shown to have a beneficial impact on the yields, although the effect on the ee was negligible. With R2 = benzyl on the catalyst, much lower levels of enantioselectivity (18% ee) were observed. Aldehydes with α-substituents yielded the anti diastereomers of the Mannich adducts 5 as the major products (Scheme 1b). Endocyclic ketimines 6 were also shown to undergo the Mannich reaction with acetaldehyde 2a to furnish 7 in an enantioselective manner (90–95% ee, Scheme 1c). We have elucidated the origins of these enantioand diastereoselectivities and demonstrate how they are controlled by conformational preferences of the cyclic transition states. Scheme 1. Enantioselective and Diastereoselective Mannich Reactions Between Ketimines and Aldehydes Catalyzed by Chiral Vicinal Diamines

R2 NBoc O

O N R1 1

N NH2 R3

R3

OH (20 mol %)

BocHN

3

TfOH (10 mol %)

NaBH4

H2O/THF, RT, 72 h

THF -20 °C

2a

O N R1 4

R1 = Bn, R2 = t-Bu, R3 = Et: 80% yield, 92% ee R1 = Me, R2 = t-Bu, R3 = Et: 76% yield, 94% eea R1 = Bn, R2 = t-Bu, R3 = i-Pr: 53% yield, 88% ee R1 = Bn, R2 = Bn, R3 = Et: 46% yield, 18% ee a

t-Bu

NBoc O

N 3a NH2 Et

O N R1 1

R2

Performed with 20 mol % m-NO2C6H4CO2H

Et

TfOH (10 mol %)

NaBH4

THF, RT

THF -20 °C

2b–e

R2

BocHN

(20 mol %)

OH O

N R1 5

R1 = Bn, R2 = Me: 87% yield, >20:1 anti/syn, 93% ee R1 = Bn, R2 = Et: 88% yield, >20:1 anti/syn, 92% ee R1 = Bn, R2 = allyl: 79% yield, 9:1 anti/syn, 92% ee R1 = Bn, R2 = Bn: 82% yield, 11:1 anti/syn, 92% ee R1 = Me, R2 = Me: 86% yield, >20:1 anti/syn, 92% ee CF3

t-Bu O

N

R1 N

O

R2 6

2a

3a NH2

N Et

OH

Et

F3C

(20 mol %)

TfOH (10 mol %)

NaBH4

m-NO2C6H4CO2H (20 mol %) THF, RT

THF -20 °C

R1

NH

R1 N

O

R2 7

R2

= H, = PMB: 79% yield, 95% ee R1 = 7-Cl, R2 = PMB: 83% yield, 95% ee R1 = 6-Me, R2 = PMB: 78% yield, 94% ee R1 = 7-Cl, R2 = H: 75% yield, 91% ee

COMPUTATIONAL METHODS Computations were performed with the Gaussian 099 software package. Ground state and transition state geometries were optimized in the gas phase using the B3LYP10 functional augmented with the D3 version of Grimme’s empirical dispersion correction11 employing the 6-31G(d) basis set. Solvation effects were included in the geometry optimizations and modeled using the SMD12 solvation model with tetrahydrofuran as the solvent. Frequency calculations were carried out at the same level of theory as that used for geometry optimization to characterize the stationary points as either

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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. Intrinsic Reaction Coordinate (IRC) calculations were performed to ensure that the saddle points found were true transition states connecting the reactants and the products. Single point energies were calculated with the M06-2X13 functional and the def2TZVPP14 basis set. Solvation effects were included using the SMD solvation model with tetrahydrofuran or water as the solvent. For distortion-interaction analysis, single-point energies of the molecular fragments were computed at the M062X/def2-TZVPP level of theory using the B3LYP-D3/6-31G(d) geometries. Select low-energy transition states were also reoptimized at the M06-2X/6-31G(d) level of theory, and single point calculations were performed with M06-2X/def2-TZVPP, SMD (THF) based on these geometries (see Supporting Information). Molecular structures were visualized using CYLview.15 Reiterative Monte Carlo conformational searches were performed 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 in the manuscript. Optimization and single point energy calculations were also carried out with other DFT methods (see Table S1), which yielded the same trends and similar magnitudes in the relative free energies of activation (ΔΔG⧧). A more detailed discussion on the choice of computational methods and alternative conformers explored in this study can be found in the Supporting Information.

activates the C=N bond more strongly toward nucleophilic addition, which lowers the energy of the transition state. We were not able to locate any transition states with the ammonium H on 3 hydrogen bonding primarily to O3 or O4 on 1. These results show that 9-membered transition states are preferred in these Mannich reactions even when alternative macrocyclic hydrogen-bonding modes are possible. (a)

(b)

B3LYP-D3/6-31G(d), SMD(THF)

R1 O O

3 (–0.25)

R2

N

N

(–0.47) 2

1 (–0.24)

NH2

O N

(–0.54) 4 3a: R2 = t-Bu 3b: R2 = Me

1a: R1 = t-Bu 1b: R1 = Me

(c)

5 (–0.12) 1a

O

R1 R2

NH

N NH2 R3

R3

t-Bu

H 3 R N

R2

2

R3

O

O

1a

H

1 2 N3 N

8

N H

O

N

R3 R3

R2

3

(d) M06-2X/def2-TZVPP, SMD(THF)//B3LYP-D3/6-31G(d), SMD(THF) TS-1aR–N (favored)

t-Bu O

O

1 2 N3 H H N N O N t-Bu

ΔΔG‡ = 0.0

RESULTS AND DISCUSSION We explored different hydrogen-bonding modes for the transition states in the chirality-imparting C–C bond formation step. A catalytic amount of triflic acid was found to be essential to obtain high levels of asymmetric induction, and we presumed that the protonated tertiary amine (ammonium) moiety on 3 acts as a hydrogen bond donor in the transition state, a role that chiral vicinal diamines are known to play in asymmetric aldol reactions.6 Isatin-derived ketimines 1 possess multiple heteroatoms capable of acting as hydrogen bond acceptors (Figure 1b). The transition state model proposed by the Shao group features a hydrogen bonding interaction between the ammonium hydrogen on 3 and O2 on 1 (Figure 1c). A second hydrogen bonding interaction between the enamine NH and O4 was also proposed to be involved.8 To determine if this model, or some other model, controls stereoselectivity, we optimized possible transition states for the C–C bond formation step in the asymmetric Mannich reaction between isatin-derived imine 1a and acetaldehyde with (S)-3a as the catalyst. (To simplify the calculations, the NEt2 group on 3 was modeled with a NMe2 group.) Figure 1d shows the C–C bond-forming transition states TS-1aR-N and TS-1aR-O, with the ammonium H on 3a hydrogen bonding primarily to N1 and O1 on 1, respectively. The 9-membered TS-1aR-N was calculated to be favored by 10.9 kcal/mol over the 11membered TS-1aR-O. While both TS-1aR-N and TS-1aR-O have staggered conformations about the forming C–C bond, TS-1aR-O has a s-cis enamine conformation of the catalyst, whereas TS-1aR-N has an energetically more favorable s-trans enamine. Though TS-1aR-O has the ammonium hydrogen bonding to O2 (1.66 Å) and N1 (2.31 Å) simultaneously, TS1aR-N likewise features a second stabilizing hydrogen bonding interaction between the enamine NH and O2 (2.26 Å). Presumably, hydrogen bonding primarily to N1 over O2 also

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TS-1aR–O (disfavored)

t-Bu 3

ΔΔG‡ = 10.9

O 2 H 2 N H N N N1 O t-Bu O

5 5 4

4

Figure 1. (a) Model structures of isatin-derived ketimine 1 and vicinal diamine catalyst 3 surveyed in this study. (b) Mulliken charge analysis of isatin-derived ketimine 1a. (c) Hydrogenbonding model proposed by Shao et al. for the Mannich reaction between 1 and 2 catalyzed by 3. (d) Possible transition states for the C–C bond formation step in the asymmetric Mannich reaction between imine 1a and enamine of acetaldehyde formed from (S)-3a. C–H hydrogen atoms are omitted for clarity. Distances are given in Ångströms, and energies are denoted in kcal/mol. Figure 2a shows the diastereomeric transition states for the C–C bond forming step in the Mannich reaction between 1a and 2a catalyzed by (S)-3a. TS-1aR-N and TS-1aS-N lead to the major and the minor product enantiomers, respectively. The 2.2 kcal/mol difference in the free energies of activation (ΔΔG‡) is in reasonable agreement with the experimental value of 1.8 kcal/mol. Both transition states have staggered conformations about the forming C–C bonds, and have s-trans enamine configurations of the catalyst. The eight heavy atoms in the 9membered cycle in TS-1aR-N are in a crown (chair-chair) conformation. In TS-1aS-N the preference for the catalyst's tertbutyl substituent to be pseudo-equatorial forces the eight heavy atoms to adopt a less favored chair-boat conformation. Newman projections about the C7–N6 bond reveal two unfavorable


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The Journal of Organic Chemistry pseudo-gauche-butane type interactions in TS-1aS-N that are absent in TS-1aR-N. In TS-1aS-N, the stabilizing hydrogen bonding interaction between O2 and the enamine NH is weaker (O2···HN distance 2.46 Å) compared to in TS-1aR-N (O2···HN distance 2.26 Å). In addition, the chair-boat conformation adopted by TS-1aS-N means that the pseudo-axial N-Me group on the catalyst clashes sterically with the N-Boc group on 1a, with the proximal H···H distance being 2.33 Å. In TS-1aR-N, in contrast, the catalyst N-Me substituents do not clash with the ketimine N-Boc group. Although the catalyst t-Bu group is closer to the N-Boc group in TS-1aR-N than in TS-1aS-N, the proximal H···H distance between these groups is longer at 2.40 Å, and the repulsion is less severe. To further probe the role played by the N-Boc group in stereodiscrimination, we optimized the analogous diastereomeric transition states with O-Me instead of O-t-Bu (Figure 2b). TS-1bR-N and TS-1bS-N are only separated by a ΔΔG‡ value of 0.2 kcal/mol, indicating that the bulky O-t-Bu group in the N-Boc moiety is important for asymmetric induction. We also performed a distortion-interaction analysis16 to elucidate what causes the difference in energies between TS1aR-N and TS-1aS-N (Figure 2c). The distortion energy, Edist, is defined as the energy required to deform each fragment from the ground state into the transition state geometry. (The ground state geometries are defined as the geometries adopted by the optimized enamine 8 and N-Boc imine 1, as the formation of a hydrogen-bonded complex between these reactants was calculated to be energetically uphill.) The interaction energy, Eint, is obtained by taking the difference between the activation energy and the sum of the distortion energies (Eint = Eact – Edist). For TS-1aR-N and TS-1aS-N, the distortion-interaction analysis reveals that the difference in Edist (catalyst), the distortion energies of the catalyst fragment (highlighted in blue in Figure 2c), contributes 1.5 kcal/mol to the 2.5 kcal/mol overall difference in Eact, with the remaining 1.0 kcal/mol of the difference attributed to stronger favorable interactions in TS1aR-N.

(a) TS-1aR–N crown (favored)

TS-1aS–N chair-boat (disfavored)

3

3

2

2

1 1 5 6

5 4

4

6

7

7

ΔΔG‡ = 0.0

ΔΔG‡ = 2.2 H

R'

HH

t-Bu t-Bu

RH

R

R’

(b) TS-1bR–N crown

TS-1bS–N chair-boat 3

3

2

2 1

1

6

5

6 4

5

7

ΔΔG‡ = 0.0

(c)

ΔΔG‡ = 0.2

t-Bu

N

Edist (ketimine) = 19.3

O

O (R)

7

4

N O

H

H N N

TS-1aR–N

t-Bu

t-Bu

(S)

Eint = -36.6 Eact = -7.4

N

Edist (ketimine) = 19.4

O

O

Edist (catalyst) = 9.9

N O


H

H N N t-Bu

Eint = -35.7 Eact = -4.9

TS-1aS–N

Figure 2. (a) Calculated diastereomeric transition states for the C–C bond formation step in the asymmetric Mannich reaction between ketimine 1a and acetaldehyde 2a catalyzed by (S)-3a. C–H hydrogen atoms are omitted for clarity. Atomic distances are denoted in Ångströms, and energies are denoted in kcal/mol. (b) Transition states for the C–C bond formation step in the Mannich reaction between 1b and 2a catalyzed by (S)-3a. (b) Distortion-interaction analysis of transition states TS-1aR-N and TS-1aS-N. We next investigated the role that the catalyst t-Bu substituent plays in stereodiscrimination by switching it to a less sterically demanding Me group (Figure 3a). This serves as a surrogate for the benzyl group for which stereoselectivity drops to 18% ee. While the Me group has a less strong preference for the pseudo-equatorial position than the bulkier tBu group, transition states with the Me group in pseudo-axial positions were all higher in energy by at least 4.8 kcal/mol (see Supporting Information). Similar to the other crown/chair-boat transition state pairs, Newman projections about the C7–N6 bond show two unfavorable pseudo-gauche-butane type interactions in TS-1cS-N that are absent in TS-1cR-N. The proximal H···H distance of 2.34 Å in TS-1cS-N between the pseudo-axial N-Me and the N-Boc group indicates an unfavorable steric interaction. The O2 hydrogen bond to the enamine NH in TS-1cS-N is weaker (2.52 Å) compared to in TS-1cR-N (2.37 Å). The diminished ΔΔG‡ value of 1.2 kcal/mol between TS-1cR-N (crown) and TS-1cS-N (chair-boat) is in qualitative agreement with the experimental value of 0.2 kcal/mol. This result indicates that the enantiodiscrimination is significantly affected by the steric properties of the C7 substituent.



TS-1cR–N

TS-1cS–N

crown (favored)

chair-boat (disfavored) 2

2 1

1

5

5 4

ΔΔG‡

pseudo-gauche-butane type interactions in TS-2S,R that are absent in TS-2R,S. The hydrogen bond between O2 and the enamine NH is longer (2.43 Å) in the disfavored TS-2S,R compared to 2.29 Å in TS-2R,S. The proximal H···H distance between the pseudo-axial N-Me and the N-Boc group is 2.36 Å, indicating a steric clash that destabilizes the disfavored transition state.

3

3

6

4

= 0.0

R'

H

6

7

7 ΔΔG‡

Page 4 of 6

= 1.2

TS-2R,S crown (favored)

TS-2S,R chair-boat (disfavored)

HH

Me Me

RH

R

3

3 2

2 1

R’

1

9

9

5

Figure 3. Calculated diastereomeric transition states for the C– C bond formation step in the asymmetric Mannich reaction between ketimine 1a and acetaldehyde 2a catalyzed by (S)-3b. C–H hydrogen atoms are omitted for clarity. Atomic distances are denoted in Ångströms, and energies are denoted in kcal/mol. To assess how having different R2 substituents (Figure 1a) on the vicinal damine catalyst would impact the enantiodiscrimination, we calculated the relative energies of crown and chair-boat transition states with a range of R2 substituents (Table 1). When R2 = H, the chair-boat TS is favored by 0.3 kcal/mol. Isopropyl and phenyl groups as R2 substituents are predicted to only slightly favor the crown TSs, while a 2-adamantyl group is calculated to give a 2.9 kcal/mol difference in free energies between the crown and the chair-boat TSs. These results show that the placement of an appropriate R2 alkyl substituent alone is sufficient for providing high levels of asymmetric induction. R2 Substituent

Crown TS

Chair-Boat TS

ΔΔG‡

t-Bu

TS-1aR-N

TS-1aS-N

2.2

Me H

R

S

TS-1c -N TS-1d

TS-1c -N

crown

TS-1d

chair-boat

1.2 -0.3

i-Pr

TS-1eR-N

TS-1eS-N

0.2

Ph

TS-1fR-N

TS-1fS-N

0.8

1-adamantyl 2-adamantyl

R

S

TS-1g -N

TS-1g -N

R

S

TS-1h -N ‡

TS-1h -N ‡

‡(chair-boat)

1.5 2.9 ‡(crown)

Table 1. Calculated ΔΔG [ΔΔG = ΔG – ΔG ] for C–C forming transition states in asymmetric Mannich reactions catalyzed by vicinal diamines with different R2 substituents. Another important feature of these Mannich reactions is that aldehydes with α-substituents yielded the anti Mannich adducts with high levels of enantio- and diastereoselectivities. To elucidate the origins of these stereoselectivities, we calculated the structures of the four diastereomeric transition states (TS2R,S, TS-2S,R, TS-2R,R, TS-2S,S) for the C–C bond formation step (Figures 4a and 5a). TS-2R,S, which leads to the experimentally observed major enantio- and diastereomer, had the lowest free energy of activation (3.2 kcal/mol lower than TS-2S,R and 5.9 kcal/mol lower than TS-2S,S). TS-2R,S (crown) and TS-2S,R (chair-boat) lead to the major and minor product enantiomers, respectively (Figure 4). The 3.3 kcal/mol difference in the free energies of activation (ΔΔG‡) is rather large compared to the experimental value of 1.5 kcal/mol. Both transition states have s-trans enamine conformations of the catalyst, and have staggered conformations at the forming C–C bonds. Newman projections about the C7–N6 bond show two

5 8 4

6

ΔΔG‡ = 0.0

4

8

7

6

7

ΔΔG‡ = 3.2

staggered

staggered

TS-2R,R twist-boat-boat (disfavored)

TS-2S,S twist-chair-boat (disfavored) 3

2

2

8 9

1

5 4

ΔΔG‡ = 10.0

partially eclipsed

3 6

1 7

9 5

8

6

7

4

ΔΔG‡ = 5.9

partially eclipsed

Figure 4. Calculated transition states leading to the four possible stereoisomers in the Mannich reaction between ketimine 1a and aldehyde 2b catalyzed by (S)-3a. C–H hydrogen atoms are omitted for clarity. Atomic distances are denoted in Ångströms, and energies are denoted in kcal/mol. TS-2R,S and TS-2S,S lead to anti (R,S) and syn (S,S) product diastereomers, respectively (Figure 4). Both transition states have s-trans enamine conformations of the catalyst. The disfavored TS-2S,S, which is 5.9 kcal/mol higher in energy, is in a twist-chair-boat conformation. The magnitude of this difference in energy is very similar to the 5.8 kcal/mol energy difference between prototypical crown and twist-chair-boat TSs previously found for aldol reactions catalyzed by vicinal diamines.6a Because of the downward-pointing position of the enamine NH, the hydrogen bond between O2 and the enamine NH is not feasible in TS-2S,S; instead, the enamine NH hydrogen bonds to O4. Due to the rigidity of the isatin amide moiety, the O4···HN hydrogen bond in TS-2S,S is 0.1 Å longer (2.39 Å) than the O2···HN hydrogen bond in TS-2R,S (2.29 Å), making it less stabilizing. Similar to the chair-boat transition states, the twist-chair-boat transition state TS-2S,S has two pseudo-gauche-butane type interactions about the C7–N6 bond, which are not found in the crown transition state TS-2R,S. In addition, TS-2S,S is further destabilized by partial eclipsing interactions about the forming C8–C9 bond. Lastly, the proximal H···H distance between the N-Boc group and the pseudo-equatorial N-Me substituent is 2.32 Å, indicating a


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The Journal of Organic Chemistry steric clash that is absent in TS-2R,S. These results show that the diastereofacial selectivity can be attributed to the high-energy twist-chair-boat conformation that the minor TS must adopt, which leads to a variety of destabilizing interactions, including pseudo-gauche-butane interactions and partial eclipsing about the forming C–C bond. To investigate the applicability of the crown/chair-boat transition state model to endocyclic ketimines, we calculated the C–C forming transition states for the asymmetric Mannich reaction between ketimine 6a and acetaldehyde 2a catalyzed by (S)-3a. TS-3R and TS-3S lead to the major and minor product enantiomers, respectively (Figure 5a). Both transition states have staggered conformations at the forming C–C bonds, and strans enamine conformations of the catalyst. Newman projections about the C4–N3 bond show two unfavorable pseudo-gauche-butane type interactions in TS-3S that are absent in TS-3R. Presumably due to the rigidity of the ketimine substrate 6a, the O2 and enamine NH are too far apart in both transition states for stabilizing hydrogen-bonding interactions. Two +NCH···Oδ− interactions exist between O2 and the polarized ammonium N-alkyl groups in both transition states. In TS-3R, these two +NCH···Oδ− interactions are at 2.36 and 2.50 Å. In the disfavored transition state, these interactions are further apart at 2.59 and 2.72 Å. Thus, attractive hydrogenbonding interactions exist between the carbonyl oxygen O2 and the polarized alkyl groups adjacent to the ammonium nitrogen, which are stronger in the crown TS than in the chair-boat TS. Distortion-interaction analysis (Figure 5b) shows that the catalyst fragment is 2.0 kcal/mol more distorted in the disfavored transition state TS-3S. In addition, the overall interaction energy Eint is more negative by 1.4 kcal/mol in the favored transition state TS-3R. These results indicate that stereodiscrimination in this reaction can be attributed to the crown TS having both less distorted fragment geometries and more favorable interactions.

the tertiary ammonium H-bonded to the imine N, is favored over the 11-membered transition state. The Mannich and aldol TSs catalyzed by vicinal diamines both favor the crown conformation of the eight heavy atoms in the cyclic TS. The major crown TS has a pseudo-equatorial alkyl substituent on the catalyst's chiral center. Transition states leading to minor enantiomers have the chair-boat conformation, which are destabilized by pseudo-gauche-butane interactions and steric clashes. The experimentally observed diastereofacial selectivity is explained by the unfavorable twist-chair-boat conformation that the transition state leading to the minor diastereomer must adopt, which introduces pseudo-gauche-butane interactions and partial eclipsing interactions. We expect these computational insights to enable the design of new and highly enantioselective chiral vicinal diamine catalysts for Mannich reactions, one of the most powerful tools for the construction of enantioenriched nitrogen-containing molecules.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Computational Details, Energies and Cartesian Coordinates of computed structures (PDF)

AUTHOR INFORMATION Corresponding Author *[email protected]

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT

(a) TS-3S chair-boat (disfavored)

TS-3R crown (favored)

1

1 2

3

4 2

ΔΔG‡ = 0.0

3

4

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

ΔΔG‡ = 3.8

1.

(b)

CF3 N N H

H

ON H TS-3R

CF3

Edist (ketimine) = 19.3 N

Eint = -34.4 t-Bu

N


Eact = -4.2

N H

H

ON H TS-3S

Edist (ketimine) = 19.6 N


2.

Eint = -33.0 t-Bu

Eact = -0.5

Figure 5. Calculated transition states leading to the major and minor enantiomers in the Mannich reaction between endocyclic ketimine 6a and aldehyde 2b catalyzed by (S)-3a. C–H hydrogen atoms are omitted for clarity. Atomic distances are denoted in Ångströms, and energies are denoted in kcal/mol. CONCLUSIONS We demonstrate that for Mannich reactions catalyzed by chiral vicinal diamines, the 9-membered transition state, with

3.

4.

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Origins of Stereoselectivity in Mannich Reactions ... - ACS Publications

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