Mechanism of amido-thiourea catalyzed enantioselective imine hydrocyanation: Transition state stabilization via multiple non-covalent interactions

Journal of the American Chemical Society

Volumn 131, Issue 42, 2009, Pages 15358-15374

  Zuend, Stephan J ^a   Jacobsen, Eric N ^a  

^a HARVARD UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

COMPUTATIONAL INVESTIGATION; DIASTEREOMERIC; DIRECT ACTIVATION; ENANTIOSELECTIVE; HYDROCYANATION; IMINIUM; ION PAIRS; ISOCYANIDES; NON-COVALENT INTERACTION; RELATED SYSTEMS; TRANSITION STATE STABILIZATION;

AMIDES; CATALYSTS; CYANIDES; ENANTIOSELECTIVITY; HYDROGEN; PROTON TRANSFER; THIOUREAS; UREA;

CATALYSIS;

AMIDE; CYANIDE; HYDROGEN ISOCYANIDE; IMINE; NITRILE; THIOUREA DERIVATIVE; UNCLASSIFIED DRUG; UREA;

ARTICLE; CATALYSIS; CATALYST; CHEMICAL BOND; CHEMICAL INTERACTION; CYANATION; ENANTIOMER; ENANTIOSELECTIVITY; HYDROCYANATION; ION PAIR EXTRACTION; MATHEMATICAL MODEL; MOLECULAR INTERACTION; MOLECULAR STABILITY; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; PROTON TRANSPORT; STRUCTURE ACTIVITY RELATION;

AMINES; CATALYSIS; HYDROGEN BONDING; HYDROGEN CYANIDE; IMINES; MAGNETIC RESONANCE SPECTROSCOPY; MODELS, MOLECULAR; MOLECULAR STRUCTURE; STEREOISOMERISM; THIOUREA;

EID: 70350329273     PISSN: 00027863     EISSN: None     Source Type: Journal    
DOI: 10.1021/ja9058958     Document Type: Article

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68. Larger differences in rate between reactions promoted by 4a and 5 are observed with more electron-deficient substrates (Figures 4 and 5). (The experiments that led to Figures 4 and 5 are run under identical conditions, except that the concentration of 5 is 2.5-fold greater than that of 4a.).
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90. This simplified model system predicts a small preference for formation of (S)-α-aminonitrile, whereas (R)-α-aminonitrile is obtained from hydrocyanation reactions using the full catalyst. For consistency, all schemes in this chapter depict formation of (R)-α-aminonitrile. The corresponding schemes for formation of (S)-α-aminonitrile are included in the Supporting Information.
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108. Statistical analysis was performed using SigmaPlot 10.0 purchased from Systat Software.
109. Alanine-derived catalyst 4h represents the large positive outlier in Figures 11 and 12. This catalyst is also substantially less reactive than any other catalyst, perhaps as a result of catalyst aggregation. It is likely that the experimentally measured enantioselectivity reflects a significant background racemic pathway and therefore underestimates the intrinsic enantioselectivity for this catalyst.
110. B3LYP has been shown to under-estimate the energy of some attractive non-covalent interactions, whereas MP2 over-estimates the energy of these interactions. In this reaction, enantioselectivity is controlled only by non-covalent interactions between substrates and catalysts, and the correlation in Figures 10-12 might be expected to depend strongly of the level of theory used. This is not the case. This conclusion may be ascribed to the observation that the calculated (and experimental; see Figure 4) transition structures are highly charged, and thus the non-covalent interactions responsible for asymmetric induction are expected to have a large electrostatic component. Even ab initio computational methods that do not account for electron correlation (i.e., Hartree-Fock) can account for electrostatic contributions of otherwise complex non-covalent interactions: Mecozzi, S.; West, A. P., Jr.; Dougherty, D. A. J. Am. Chem. Soc. 1996, 118, 2307-2308.
111. Calculated versus experimental selectivity plots for HCN addition are included in the Supporting Information. Statistically significant positive linear correlation is observed in all cases. HCN addition is disfavored compared with HNC addition for each catalyst at each level of theory examined (by 0.2-3.7 kcal/mol). The transition structures for HNC addition and HCN addition are similar, and the ion pairs formed from HNC addition and HCN addition are almost identical; it is thus not possible to further distinguish between these two mechanistic proposals, and it is possible that both play a role in catalytic imine hydrocyanation.
112. The length of the N-H bond between imine and proton is 1.03-1.04 Å in the transition structure, and is thus effectively fully formed (i.e., the transition structure has nearly complete iminium ion character).
113. This analysis ignores any role of bond angle in determining bond energy, and ignores the possibility that bond strength does not necessarily depend linearly on bond length.
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130. M values less than 0.5 would be detectable. The differences in binding constant observed in the two analyses may be ascribed to differences in reaction temperature (-78 °C versus 0°C) and/or to the imine N-protecting group (allyl versus benzhydryl).
131. Even in cases in which electrophile-thiourea interactions are productive, the binding geometry in the ground state can differ substantially from that in the transition state. For example, ketone-thiourea binding can occur through one or both lone pairs of the carbonyl group, and the calculated energies of these binding modes are nearly identical (Fuerst, D. E. Unpublished results from this laboratory). In the nucleophilic addition transition structure, the partially formed alkoxide binds in a way that resembles neither of the low-energy ground state structures (ref 16c).
132. For a related analysis comparing binding geometries of carbonyl compounds to chiral diols in the ground state and transition state, see: Gómez-Bengoa, E. Eur. J. Org. Chem. 2009, 1207-1213.
133. For an alternative approach, see: (a) Pluth, M. D.; Bergman, R. G.; Raymond, K. N. Science 2007, 316, 85-88.
134. (b) Pluth, M. D.; Bergman, R. G.; Raymond, K. N. J. Org. Chem. 2009, 74, 58-63, and refs therein.