Letter pubs.acs.org/OrgLett
Reversing Enantioselectivity Using Noncovalent Interactions in Asymmetric Dearomatization of β‑Naphthols: The Power of 3,3′ Substituents in Chiral Phosphoric Acid Catalysts Avtar Changotra, Sandip Das, and Raghavan B. Sunoj* Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India S Supporting Information *
ABSTRACT: The sense of enantioselectivity in asymmetric dearomative amination of β-naphthols is reported to pivotally depend on the 3,3′ substituents on the chiral BINOL− phosphoric acid (CPA) catalysts. The origin of reversal in the sense of stereoinduction from R to S, when the aryl substituent is changed from 3,5-(CF3)2-C6H3 (CPA-1) to 9-anthryl (CPA2), has been identified as arising due to the change in the pattern of noncovalent interactions (from predominantly C−H···F to C−H···π interactions) in the stereocontrolling transition states.
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Scheme 1. Chiral BINOL−Phosphoric Acid Catalyzed Asymmetric Dearomative Amination of β-Naphthol10
n the past few years, chiral phosphoric acid (CPA) catalysis has evolved as a powerful tool in asymmetric transformations.1 In general, a prototypical CPA such as BINOL− phosphoric acid, simultaneously activates both the electrophilic and nucleophilic reacting partners through a bifunctional mode of action.2 The source of chirality in CPA is the axis of chirality along the binaphthyl rings. In addition, in such reactions the nature of substituents at the 3,3′ positions of the BINOL backbone is known to play a critical role.3 Despite the immense popularity of BINOL−phosphoric acids, rationalization of the origin of enantioselectivity relies heavily on qualitative working hypotheses based on steric interactions.4 Some of the recent studies have offered interesting insights that allude to the potential of harnessing the noncovalent interactions between the substrates (reactants) and the 3,3′ substituents on the BINOL framework for possible enantiocontrol.5 Interestingly, several CPA-catalyzed reactions (such as asymmetric transfer hydrogenation,6 aza-Friedel−Crafts alkylation,7 cycloaddition,8 and desymmetrization9) even afforded a reversal in enantioselectivity by varying the nature of substituents at the 3,3′ positions. Very recently, the You group has demonstrated that the change of 3,3′ substituents from 3,5-(CF3)2-C6H3 to 9-anthryl group leads to an inversion of enantioselectivity in an asymmetric dearomative amination of naphthols with diethyl azodicarboxylate (DEAD) (Scheme 1).10 A reversal of sense of enantioselectivity from R to S could be accomplished without altering the axial chirality of BINOL from its native S configuration. It is equally important to note that products obtained through dearomatization of naphthols, such as the α-amino β-naphthalenone skeletons with a chiral quaternary carbon center, are of high current significance.11,12 To establish the origin of how the 3,3′ aryl groups induce such a strong reversal in asymmetric dearomatization of βnaphthols, we have examined the mechanism and the enantiocontrolling transition states of the title reaction. Density functional theory computations at the SMD(toluene)/B3LYP-D3/ © 2017 American Chemical Society
6-311+G**//SMD (toluene) /M06-2X-D3/6-31G** level of theory has been employed in this study.13 The Gibbs free energies obtained by incorporating the thermal and entropic corrections as obtained at the SMD(toluene)/M06-2X-D3/631G** level of theory to the energies in the condensed phase at Received: March 26, 2017 Published: April 18, 2017 2354
DOI: 10.1021/acs.orglett.7b00890 Org. Lett. 2017, 19, 2354−2357
Letter
Organic Letters
with the experimental value of 81%. The agreement of the predicted sense and extent of enantioselectivity with that of the experimental observations engenders additional credence to our transition-state models toward rationalizing an important problem on the origin of stereoinduction. The critical question at this stage is therefore on the factors that lead to the reversal of enantioselectivity from R to S α-amino-β-naphthalenone when the 3,3′ substituents are changed from 3,5-(CF3)2-C6H3 to 9-anthryl groups. We sought molecular insight by analyzing the stereocontrolling transition states for the C−N bond formation. First, the differences in the size of the chiral cavity offered by the catalysts, where the substrates dock in for the reaction, were examined. Computed solvent accessible surface area (SASA) and solvent volume (SV) of the cavity in the respective transition states indicated that CPA-2 provides a larger cavity than CPA-1.18 Interestingly, the larger cavity and its ability to accommodate the reactants are also reflected in the minimal geometric deviation of the catalyst framework in CPA-2. For instance, the dihedral angle Φ1(C1−C2−C3−C4) defined by carbon atoms 1−4 with the aryl ring X1, as shown in Figure 2b,
the SMD(toluene)/B3LYP-D3/6-311+G** level is employed for discussions.14 The catalytic action can be considered to begin with the formation of a recognition complex 4, wherein the catalyst (1) interacts with the substrates (2 and 3) primarily through hydrogen bonding, as shown in Scheme 1(b).15 The key step in dearomatization then takes place in a concerted manner via transition state [4−5]⧧ wherein the nucleophilic carbon of βnaphthol adds to the electrophilic nitrogen of DEAD with a concomitant proton transfer from the catalyst to the second nitrogen of the diazo linkage. In this step, the proton from the phenolic end of β-naphthol is recovered by the catalyst.16 Each such stereochemically unique mode of approach can lead to α-amino β-naphthalenone product with a well-defined configuration at the newly generated chiral carbon. Although it might qualitatively appear rather straightforward, the identification of the most preferred transition state would certainly demand consideration of several conformational and configurational possibilities of the substrate. For instance, the orientation of each of the ester carbonyl groups could either be syn or anti with respect to the diazo double bond of DEAD, as shown in Figure 1.17
Figure 1. Different conformers for the addition of si and re prochiral faces of the activated β-naphthol to trans-DEAD in [4−5]⧧, respectively, leading to S- and R-aminated β-naphthalenone. Relative Gibbs free energies (kcal/mol) are provided in parentheses in pink (CPA-1) and green (CPA-2) colors.
Figure 2. Catalyst backbone geometry as noted in the respective lowest energy transition state for CPA-1 and CPA-2. For improved clarity, both substrates (β-naphthol and DEAD) are deleted in (a) and (b). Space-filling models for [4−5]R-1aa⧧ and [4−5]S-2aa⧧ are, respectively, shown as (c) and (d).
In the case of CPA-1, the energetically most preferred transition state [4−5]R-1aa⧧ is found to be about 1.7 kcal/mol lower than the corresponding lower energy diastereomeric transition state [4−5]S-1as⧧. Here, the transition-state notations employ the configuration of the chiral center in the ensuing product and conformational features of the diazo ester. When CPA-1 is the catalyst, addition of the re prochiral face of β-naphthol to the anti-anti (aa) conformer of DEAD is found to be the most preferred mode and results in the R enantiomer of the product. This energy difference corresponds to an enantiomeric excess of 89%, which is in good agreement with the experimental observation of 80% in favor of the R enantiomer. However, the preferred mode of addition for CPA-2 is found to be when the si face of β-naphthol adds to the anti−anti conformer of DEAD, resulting in a reversal in enantioselectivity in favor of the S enantiomer. The energy difference between the lowest energy [4−5]S-2aa⧧ and its diastereomeric analogue [4−5]R-2aa⧧ is 1.2 kcal/mol, which is equivalent to an enantiomeric excess of 76%, in good accord
changes from 76° in the native geometry of CPA-2 to 73° in the lowest energy transition state [[4−5]S-2aa⧧]. Similarly, an equivalent dihedral angle Φ2 (C1−C2−C3−C4) with the other aryl ring X2 exhibits a modest deviation from −110° to −111°. However, in the case of CPA-1, much larger deviations in Φ1 and Φ2 from 124° (X1) and −137° (X2) in the native catalyst geometry to 110° and −128°, respectively, in the lowest energy transition state is noticed ([4−5]R-1aa⧧, Figure 2a). These changes indicate a larger deviation in CPA-1 in the stereocontrolling transition states.19 Since the reactants involved in this geometric analysis are the same, it appears more evident that the catalyst distortion directly depends on the nature of substituents at the 3,3′ positions of the BINOL backbone. The vital difference between the most preferred transition states with CPA-1 and CPA-2 catalysts, i.e., between [4−5]R1aa⧧ and [4−5]S-2aa⧧, is in the orientation of the substrates in the chiral pocket. The space-filling model, as given in Figure 2c, 2355
DOI: 10.1021/acs.orglett.7b00890 Org. Lett. 2017, 19, 2354−2357
Letter
Organic Letters conveys that in CPA-1 the reactants are positioned somewhat perpendicular with respect to the 3,3′ aryl substituents. On the other hand, a parallel orientation of the reactants with respect to the 3,3′ anthryl substituents is noticed in CPA-2.20 Such variance in the preferred orientation of the substrates leads to differences in the type of interactions between the catalyst arms at the 3,3′ positions and the substrates. These interactions, shown in the optimized geometries of the transition states (Figure 3), are critical to the successful transfer of chiral
Figure 4. NCI plots for stereocontrolling transition states [4−5]R1aa⧧ and [4−5]S-2aa⧧ (blue: strong attractive; green: weak attractive; and red: strong repulsive).
states. The unique interaction in [4−5]R-1aa⧧ is C−H···F, operating between the aryl CF3 groups of the 3,3′ substituents on the catalyst and the C−H bonds of (i) ethyl group of DEAD and (ii) aryl as well as the methyl groups of β-naphthol. Similarly, other noncovalent interactions such as lone pair···π and C−H···π are identified as well. Two types of lone pair···π interactions, first one between the carbonyl oxygen of DEAD and the catalyst aryl group (X1) and another one between the phosphate oxygen of the catalyst and the carbonyl carbon of DEAD, are noticed. Important C−H···π contacts are between (i) the ethyl group of DEAD and the catalyst aryl ring (X1) and (ii) the methyl of β-naphthol and the other aryl substituent (X2) on the catalyst. These noncovalent interactions operating in concert render additional stabilization to the transition state for the addition of the re prochiral face of β-naphthol to the anti−anti conformer of DEAD leading to the R enantiomer of the product. The pattern of noncovalent interaction exhibits interesting variations when the 3,3′ positions are decorated with 9-anthryl groups in CPA-2. The noncovalent interactions in the most preferred [4−5]S-2aa⧧ are dominated by C−H···π interactions between (i) the ethyl group of DEAD with the anthryl ring (X1) of the catalyst and (ii) the methyl group of β-naphthol with the second anthryl ring (X2) of the catalyst. The presence of more C−H···π interactions with both the anthryl arms of the catalyst and the absence of aryl CF3 groups (which precludes C−H···F interactions) in the CPA-2 system results in a change in the preferred prochiral face involved in the C−N bond formation between β-naphthol and DEAD. In conclusion, the differences in the preferred orientation of the substrates (with respect to the 3,3′ substituents) in the chiral cavity of the catalyst in the stereocontrolling transition state and the associated changes in the set of weak noncovalent interactions between CPA-1 (predominantly C−H···F interactions) and CPA-2 (C−H···π interactions) are responsible for the inversion in the sense of enantioselectivity. The pivotal role of the aryl substituents at the 3,3′ positions, as noted here, could suitably be used toward steering enantioselectivities in asymmetric transformations catalyzed by chiral BINOLphosphoric acids.
Figure 3. Stereocontrolling transition states for the C−N bond formation. Interatomic contacts that correspond to noncovalent interactions between the catalyst and substrates are in angstroms, and the corresponding electron densities (ρ × 10−2 au) at the bcps are given in parentheses. Only selected hydrogen atoms are shown for improved clarity.
information from the catalyst to the center of chirality developing in the product. What is conspicuous at this juncture is that the substrates in the chiral cavity of the catalyst interact with the aryl groups primarily through a series of weak noncovalent interactions. To identify the presence of such weak interactions, the topological features of the electron density distribution are examined using the atoms in molecule (AIM)21 and noncovalent interaction (NCI) plots.22 The presence of bond paths between the interacting pair of atoms and the corresponding electron densities at the bond critical points (bcp) are provided in parentheses beside the interatomic distances in Figure 3. The lowest energy transition state [4−5]R-1aa⧧ with CPA-1 enjoys a series of C−H···F (a, b, c, d, e, f) interactions, offered by the −CF3 substituents on the catalyst. In addition, interactions such as C−H···O (k, l, m, n), lone pair···π (g, h), and C−H···π (i, j) are also noticed. In the case of CPA-2, the lowest energy transition state [4−5]S-2aa⧧ exhibits a more prominent number of C−H···O interactions (k′, l′, m′, n′) and C−H···π contacts (i′, j′, j″, j‴).23 The ρbcp values for all these interactions, as given in Figure 3, are found to be consistent with related weak noncovalent interactions reported in the literature.24 The regions of the above-mentioned noncovalent interactions in [4−5]R-1aa⧧ and [4−5]S-2aa⧧ can also be noted in the NCI plots given in Figure 4. Important noncovalent interactions, particularly that between the catalyst and the substrates, are encircled. Among these, the C−H···O interactions between the phosphate oxygen of BINOL− phosphoric acid and the ethyl and methyl groups, respectively, of DEAD and β-naphthol, are common in both these transition
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00890. 2356
DOI: 10.1021/acs.orglett.7b00890 Org. Lett. 2017, 19, 2354−2357
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(14) (a) All computations were performed using Gaussian09.. (b) Gaussian 09, revision D.01: Frisch, M. J. et al. Gaussian, Inc.: Wallingford, CT, 2013. (c) A representative set of transition-state geometries were also subjected to full optimization at the SMD(toluene)/ B3LYP-D3/6-31G** level of theory, and it was noted that the trends are the same. See the Supporting Information for the full citation and additional details. (15) More details of the inclusion complexes are provided in Figure S1. (16) Intrinsic reaction coordinate (IRC) calculations and Wiberg indices revealed that the transition state connects smoothly to the product without the involvement of any intermediate (see Figures S2− S5). (17) The relative Gibbs free energies of 16 such transition states (Tables S1 and S2) are provided in the Supporting Information. (18) (a) The volume of the inner cavity is estimated using the Voss Volume Voxelator 3V computational protocol. The solvent volume of the cavity is determined by subtracting the solvent-excluded volume from the shell volume (ref 18b). For more details, see Tables S3−S5. (b) Voss, N. R.; Gerstein, M. Nucleic Acids Res. 2010, 38, W555. (c) Ruan, Y.; Wang, B.-Y.; Erb, J. M.; Chen, S.; Hadad, C. M.; Badjic, J. D. Org. Biomol. Chem. 2013, 11, 7667. (19) (a) Activation Strain Analysis showed a similar trend (see Table S6).. (b) Bickelhaupt, F. M. J. Comput. Chem. 1999, 20, 114. (c) van Zeist, W.-J.; Bickelhaupt, F. M. Org. Biomol. Chem. 2010, 8, 3118. (e) Duan, A.; Yu, P.; Liu, F.; Qiu, H.; Gu, F. L.; Doyle, M. P.; Houk, K. N. J. Am. Chem. Soc. 2017, 139, 2766. (20) In CPA-1, parallel (with respect to aryl substituents) orientation is of higer energy whereas perpendicular orientation of the reactants of higher energy in CPA-2. See Figure S6. (21) (a) Bader, R. F. W. Chem. Rev. 1991, 91, 893. (b) All of the noncovalent interactions have been analyzed by AIM (see Figures S7 and S8 and Tables S7 and S8). (22) (a) Johnson, E. R.; Keinan, S.; Mori-Sanchez, P.; ContrerasGarcia, J.; Cohen, A. J.; Yang, W. T. J. Am. Chem. Soc. 2010, 132, 6498. (b) For NCI plots, see Figures S9 and S10. (23) (a) Neel, A. J.; Hilton, M. J.; Sigman, M. S.; Toste, F. D. Nature 2017, 543, 637. (b) Seguin, T. J.; Wheeler, S. E. ACS Catal. 2016, 6, 7222. (c) Seguin, T. J.; Wheeler, S. E. Angew. Chem., Int. Ed. 2016, 55, 15889. (d) Levandowski, B. J.; Houk, K. N. J. Am. Chem. Soc. 2016, 138, 16731. (24) (a) Manin, A. N.; Voronin, A. P.; Shishkina, A. V.; Vener, M. V.; Churakov, A. V.; Perlovich, G. L. J. Phys. Chem. B 2015, 119, 10466. (b) Wang, H.; Wang, W.; Jin, W. J. Chem. Rev. 2016, 116, 5072.
Optimized geometries and other relevant materials (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected] ORCID
Raghavan B. Sunoj: 0000-0002-6484-2878 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Computing time from IIT Bombay supercomputing and a senior research fellowship from UGC-New Delhi (A.C.) are acknowledged.
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REFERENCES
(1) (a) Akiyama, T. Chem. Rev. 2007, 107, 5744. (b) Yamanaka, M.; Kondoh, A.; Terada, M. J. Am. Chem. Soc. 2015, 137, 1048. (c) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev. 2014, 114, 9047. (2) (a) Champagne, P. A.; Houk, K. N. J. Am. Chem. Soc. 2016, 138, 12356. (b) Reid, J. P.; Simón, L.; Goodman, J. M. Acc. Chem. Res. 2016, 49, 1029. (c) Monaco, M. R.; Fazzi, D.; Tsuji, N.; Leutzsch, M.; Liao, S.; Thiel, W.; List, B. J. Am. Chem. Soc. 2016, 138, 14740. (d) Sai, M.; Yamamoto, H. J. Am. Chem. Soc. 2015, 137, 7091. (e) Seguin, T. J.; Wheeler, S. E. ACS Catal. 2016, 6, 2681. (f) Wang, Z.; Law, W. K.; Sun, J. Org. Lett. 2013, 15, 5964. (3) (a) Akiyama, T.; Mori, K. Chem. Rev. 2015, 115, 9277. (b) Rueping, M.; Nachtsheim, B. J.; Ieawsuwan, W.; Atodiresei, I. Angew. Chem., Int. Ed. 2011, 50, 6706. (4) (a) Hatano, M.; Moriyama, K.; Maki, T.; Ishihara, K. Angew. Chem., Int. Ed. 2010, 49, 3823. (b) Khomutnyk, Y. Y.; Argüelles, A. J.; Winschel, G. A.; Sun, Z.; Zimmerman, P. M.; Nagorny, P. J. Am. Chem. Soc. 2016, 138, 444. (5) (a) Neel, A. J.; Hehn, J. P.; Tripet, P. F.; Toste, F. D. J. Am. Chem. Soc. 2013, 135, 14044. (b) Zhou, F.; Yamamoto, H. Angew. Chem., Int. Ed. 2016, 55, 8970. (d) Sunoj, R. B. Acc. Chem. Res. 2016, 49, 1019. (6) (a) Kang, Q.; Zhao, Z.-A.; You, S.-L. Org. Lett. 2008, 10, 2031. (b) Reid, J. P.; Goodman, J. M. J. Am. Chem. Soc. 2016, 138, 7910. (7) Yu, X.; Wang, Y.; Wu, G.; Song, H.; Zhou, Z.; Tang, C. Eur. J. Org. Chem. 2011, 2011, 3060. (8) Feng, J.; Yan, W.; Wang, D.; Li, P.; Sun, Q.; Wang, R. Chem. Commun. 2012, 48, 8003. (9) Gu, Q.; Rong, Z.-Q.; Zheng, C.; You, S.-L. J. Am. Chem. Soc. 2010, 132, 4056. (10) Wang, S.-G.; Yin, Q.; Zhuo, C.-X.; You, S.-L. Angew. Chem., Int. Ed. 2015, 54, 647. (11) (a) Xu, R.-Q.; Yang, P.; Tu, H.-F.; Wang, S.-G.; You, S.-L. Angew. Chem. 2016, 128, 15361. (b) Wang, L.; Yang, D.; Li, D.; Wang, P.; Wang, K.; Wang, J.; Jiang, X.; Wang, R. Chem. - Eur. J. 2016, 22, 8483. (c) Zhu, G.; Bao, G.; Li, Y.; Yang, J.; Sun, W.; Li, J.; Hong, L.; Wang, R. Org. Lett. 2016, 18, 5288. (12) These are valuable structural motifs in various biologically active natural products and therapeutics. See: Randolph, J. T.; Flentge, C. A.; Huang, P. P.; Hutchinson, D. K.; Klein, L. L.; Lim, H. B.; Mondal, R.; Reisch, T.; Montgomery, D. A.; Jiang, W. W.; Masse, S. V.; Hernandez, L. E.; Henry, R. F.; Liu, Y.; Koev, G.; Kati, W. M.; Stewart, K. D.; Beno, D. W. A.; Molla, A.; Kempf, D. J. J. Med. Chem. 2009, 52, 3174. (13) For reliable predictions on stereoselectivity empirical dispersion correction of Grimme or other dispersion corrected functionals are recommended. See: (a) Grandner, J. M.; Cacho, R. A.; Tang, Y.; Houk, K. N. ACS Catal. 2016, 6, 4506. (b) Xie, Y.; Cheng, G.-J.; Lee, S.; Kaib, P. S. J.; Thiel, W.; List, B. J. Am. Chem. Soc. 2016, 138, 14538. (c) Ehrlich, S.; Moellmann, J.; Grimme, S. Acc. Chem. Res. 2013, 46, 916. 2357
DOI: 10.1021/acs.orglett.7b00890 Org. Lett. 2017, 19, 2354−2357
