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A Model for the Enantioselectivity of Asymmetric Intramolecular Alkylations by bis-Quaternized Cinchona Alkaloid-Derived Catalysts Cyndi Qixin He, Adam Simon, Yu-hong Lam, Andrew P. J. Brunskill, Nobuyoshi Yasuda, Jiajing Tan, Alan M. Hyde, Edward C. Sherer, and Kendall N. Houk J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01577 • Publication Date (Web): 21 Jul 2017 Downloaded from http://pubs.acs.org on July 21, 2017

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The Journal of Organic Chemistry

A Model for the Enantioselectivity of Asymmetric Intramolecular Alkylations by bis-Quaternized Cinchona Alkaloid-Derived Catalysts †

†

†

‡

‡

Cyndi Qixin He, Adam Simon, Yu-hong Lam, Andrew P. J. Brunskill, Nobuyoshi Yasuda, Jiajing Tan,∥ Alan M. Hyde,‡ Edward C. Sherer,‡ and K. N. Houk*† †

Department of Chemistry and Biochemistry, University of California, Los Angeles, 607 Charles E. Young Drive East, Los Angeles, CA 90095-1569. ‡ Department of Process Chemistry, Merck and Co., Inc., P.O. Box 2000, Rahway, NJ 07065. ∥

Department of Organic Chemistry, Faculty of Science, Beijing University of Chemical Technology, Beijing 100029, China Supporting Information Placeholder

ABSTRACT: A model for the stereoselectivity of intra-

molecular alkylations by N,N′-disubstituted cinchona alkaloids reported by Xiang et al. was established using density functional theory (DFT) calculations. The stereocontrol is based on the minimal distortion of the TS and catalyst required to achieve favorable electrostatic interactions in the favored TS. Counterions must be included in computational modeling of ion-paired catalysis in order to reproduce experimental enantioselectivity.

Scheme 1. The Enantioselective Step in the Asymmetric Synthesis of (+)-Indacrinone and Two Models for the Origins of Enantioselectivity

INTRODUCTION Cinchona alkaloids are popular organocatalysts because of their excellent availability and diversity.1 Cinchona-derived phase-transfer catalysts were discovered in the early 1980s.2,3 They are cinchona alkaloids that are alkylated at the quinuclidine nitrogen. Since then, diverse generations of ion-paired catalysts have been developed for various asymmetric syntheses under phase-transfer conditions.4-17 The first application of such catalysts is the asymmetric α-substitution in the synthesis of (+)-indacrinone reported by Dolling, Davis, and Grabowski in 1984 (Scheme 1).2 Based on a single-crystal X-ray structure of the benzyl cinchoninium ion, Dolling and coworkers hypothesized that the reaction proceeds via an enolate–cinchoninium ion pair, where the C9-hydroxyl group of 2 hydrogen-bonds with the enolate, while the quinoline ring of 2 π-stacks with the methoxydichlorobenzo moiety of the substrate 1.3 The Si face of the enolate is blocked by the catalyst, and approach of the electrophile (CH3Cl) to the Re face accounts for enantiocontrol. Recently, Pliego studied the phase-transfer mechanism of this reaction by DFT computations and proposed an alternative model that features electrostatic stabilization of the chloride leaving group by the monoquaternized catalyst,18,19 in addition to the hydrogen bond originally proposed by Dolling. These

models are shown in Scheme 1. They reported that the differences in energy between the transition states were due to the distance between the chloride leaving group and positively charged nitrogen. Until recently, the structures of cinchona alkaloid-based phase-transfer catalysts had only been modified by functionalization of the C9-hydroxy group and alkylation of the bridgehead amine.20 In search of an efficient phase-transfer catalyst for the asymmetric intramolecular alkylation in the preparation of a class of drug candidates for the treatment of migraine, a novel class of N,N′-disubstituted cinchona alkaloids 5 was discovered by Xiang et al. (Scheme 2).21 In this new generation of phase-transfer catalysts, the quinuclidine nitrogen and the quinoline nitrogen are both alkylated.7

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Scheme 2. Asymmetric Spirocyclization Catalyzed by Doubly Quaternized Cinchona Alkaloid Derivatives

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chona-derived phase-transfer catalyst, the catalyst–substrate complex, and the transition state structures.

RESULTS AND DISCUSSION We have recalculated the transition structures reported by Pliego19 at the B3LYP/6-31G(d) level of theory, which are illustrated in Figure 1. These structures were previously computed at the M08 and DP4 levels of theory. Figure 1A shows the lowest-energy major and minor transition structures in Pliego’s work. The minor TS is 7.9 kcal/mol less stable than the major TS in the gas phase, or 6.3 kcal/mol in toluene.

The spirocyclization with 5a was scalable under mild conditions and catalyst loadings as low as 0.3 mol%. Respectable selectivity was achieved with 5b, where the quinoline nitrogen is methylated. The original mono-quaternized catalyst (5c) was not stereoselective in this reaction. Mechanistic studies have described several stereoselectivity models for cinchonabased phase transfer organocatalysis,2,13,19 however they do not account for the observed stereoselectivity in these systems. We propose a general model to explain enantioselectivity based on the conformations of the alkylation transition state and stabilization of the enolate and leaving group by the cinchona alkaloid. In addition, we revisit previous calculations by Pliego to elucidate further the source of stereoselectivity in the methylation reaction shown in Scheme 1.

COMPUTATIONAL METHODS Quantum mechanical computations were performed using Gaussian 09.22 The geometries were fully optimized at the B3LYP23/6-31G(d) level of theory with the SMD implicit solvation model24 to account for the solvation effects of toluene, the solvent used experimentally.25 All of the optimized geometries were verified by frequency computations as minima (zero imaginary frequencies) or transition structures (a single imaginary frequency). Single-point energies of the optimized geometries were then evaluated using the dispersioncorrected density functional method B3LYP-D326a (with a Becke−Johnson (BJ) damping function26b,c) and the 6311+G(d,p) basis set. The thermal corrections evaluated from the unscaled vibrational frequencies at the B3LYP/6-31G(d) level on the optimized geometries were then added to the B3LYP-D3(BJ)/6-31+G(d,p) electronic energies to obtain the free energies. The free energy corrections were calculated using Truhlar’s quasiharmonic approximation.27 We have also performed optimization and frequency calculations of the low-energy transition states using the M06-2X28 functional with the 6-31G(d) basis set. Single points using M06-2X and the larger 6-311+G(d,p) basis set were also calculated. The transition structures resulting from these calculations are shown in Figure S8. We have found that the energetics between the major and minor transition structures were comparable to those optimized at the B3LYP/6-31G(d) level of theory with higher-level single point energies. Monte Carlo conformational searches were carried out with the MMFFs force field implemented in MacroModel29 to identify the lowest-energy conformers of the new dicationic cin-

Figure 1. A) The Pliego model for the transformation mediated by the monoquaternized cinchoninium catalyst. B) A new complementary minor TS to the Pliego model. All energies are in kcal/mol. The Grabowski-type major TS (Figure S1), where the leaving chloride points away from the catalyst, is 11.2 kcal/mol higher in energy. In agreement with Pliego’s conclusion, the Grabowski/Dolling model is disfavored. The distinct difference between the major and minor TS is the position of the leaving chloride ion. Pliego proposed that the relative stabilization of the transition states depends on the distance between the negatively charged chloride and the positively charged nitrogen center of the cinchoninium catalyst.19 We have discovered a new minor TS that offers a clearer picture to the origins of stereoselectivity for this phase-transfer catalysis (Figure 1B). The new minor TS is 4.3 kcal/mol more stable than the original Pliego minor TS, and the position of the chloride in the new minor TS is similar to that in the major TS. Comparing the two minor TSs, we see a recurring theme that the position of the chloride with respect to the electropositive pocket around the quinuclidinium nitrogen is important. Specifically, it is the C–H bonds polarized by N+ that interact and stabilize the leaving group. We then studied the enantioselectivity of the bis-quaternary salt catalysis depicted in Scheme 2. The enantioselectivity of


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the spirocyclization is excellent with catalyst 5a, when substituents on both nitrogen atoms are 2-bromo-5methoxybenzyl; respectable selectivity was achieved with 5b, where the quinoline nitrogen is methylated. The selectivity decreases drastically if the quinolone is not alkylated (5c). We have identified an explanation for the origins of the enantioselective phase-transfer catalysis by these N,N′-disubstituted cinchona alkaloids. For this phase-transfer process, we assume an interfacial mechanism6,19,30 similar to the reaction in Scheme 1. Substrate 4 is predominantly in the organic phase, while the dicationic catalyst is in the aqueous phase. A complex of the salt with the hydroxide base (catalyst–OH−) is transported to the toluene layer, where 4 is deprotonated to form the corresponding enolate. The catalyst–enolate complex undergoes reaction in the organic phase, where the neutral product remains. We investigated the conformational preferences for the dialkylated quinidine-derived phase-transfer catalysts 5 in toluene and in water. Figure 2 shows model catalyst 5b′ in four lowenergy conformations. The vinyl group on the quinuclidinium ring is replaced by a methyl group to reduce the number of redundant conformations. This substitution has been shown to be inconsequential for the origins of enantiocontrol.31-33 The doubly quaternized catalyst is most stable in the anti-open conformation. The syn-open conformer is more than 2 kcal/mol higher in energy in both toluene and water implicit solvation. The closed conformations are at least 5 kcal/mol higher than the anti-open conformer and are, therefore, not significant. Additional anti-open conformers are in Figure S2. We explored the possible transition states of the dicationic catalyst, including Grabowski/Dolling- and Pliego-type modes of activation. Figure 3 shows the lowest-energy transition states corresponding to the former two models as well as a lowest-energy alternative model. The Pliego-type TS, in which the leaving chloride associates with the quinuclidinium binding pocket, is 19.0 kcal/mol more stable than the Grabowskitype TS in the gas phase. This agrees with the current views,18,19 about the monoquaternized catalyst. The enolate oxygen is hydrogen-bonded and near the quinolinium. Note that the Grabowski-type TS is stabilized in implicit toluene by 10.2 kcal/mol. However, it is still energetically disfavored because the building negative charge on the leaving chloride is not stabilized by the catalyst. The third mode of activation, we call the “reverse-Pliego,” is unique to the diquaternized catalyst; the quinolinium group creates a second positively-

Figure 2. Four low-energy conformations of model catalyst 5b′. All energies are in kcal/mol. charged site for coordination of the chloride leaving group, and the enolate oxygen is now in the quinuclidinium site. We also explored the possible role of the second counterion to the dication. We scrutinized possible modes of interactions between the dicationic catalyst, a bromide ion, and the enolate.34 The global minimum complex is shown in Figure 4a. The catalyst adopts the anti-open conformation in the complex. The enolate oxygen forms a hydrogen bond interaction with the C9-hydroxyl group of the catalyst, while the quinolinium ring interacts with the enolate double bond by π-π stacking. The C–Cl bond points away from the catalyst. These interactions resemble the interactions proposed in Dolling’s model.3 The bromide ion is associated via electrostatic interactions with the catalyst’s C–H bonds attached to the quinuclidinium nitrogen and in the quinolinium ring.35 This is consistent with the position of the bromide ion in the X-ray structure of a similar doubly quaternized cinchona alkaloid derivative 5d (Figure 4b).

Figure 3. Three transition state for catalysis by the diquaternized cinchona-alkaloid derived phase-transfer catalyst. All energies are in kcal/mol.


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Br NMe N

Cl O– H

3.57

N O

N

N

H

Br –

OMe

Br

global minimum 5bʹ Br−enolate ion triplet b I–

Me N N

H

OH Br –

NO 2

5d

Figure 4. (a) The global minimum of the catalyst(Br−)–enolate complex. The quinuclidinium ring is rendered in gray for clarity. (b) X-ray crystal structure of an analogous N,N′diquaternized cinchona alkaloid derivative (5d). In the schematic drawings, atoms closer to the viewer are represented by larger font sizes. The stereo-determining transition states leading to the major and minor stereoisomers were calculated including the bromide counterion (Figure 5). A counterion is required to reproduce the experimental enantioselectivity. It has been reported that DFT calculations of charged complexes require counterions for accuracy.36 These results are discussed further in the Supporting Information, Figure S8.

Eπ-π = −4.4

Eπ-π = −3.8

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Figure 5 shows the lowest-energy transition structures that lead to the major and the minor enantiomer. The major TS is lower in energy than the minor TS by 2.1 kcal/mol with single points performed in the gas phase and in toluene, which is in reasonable agreement with the experimentally observed enantioselectivity (1.3 kcal/mol). The calculated selectivity in implicit water solvation is 3.0 kcal/mol. The Dolling-type major TS is 7.7 kcal/mol higher in energy (see Figure S7). The global minimum of the complex (Figure 4) prefers the Grabowski/Dolling-type conformation, but the transition state differs. This is due to the lack of leaving group stabilization in the complex geometry. Common features can be found in the major and the minor TS. The quinolinium ring, the C9-O bond, and the substituted phenyl ring with one of its adjacent methylene C–H bonds lie approximately in the same plane (perpendicular to the plane of the paper in Figure 3).37 In both structures, the leaving Cl− is stabilized by hydrogen bonding with the α C–H bonds of the quinuclidinium, the hydrogen geminal to the C9-OH group, and the 5′-H atom of the quinolinium ring. The enolate oxygen is stabilized by hydrogen bonding with the C9-hydroxyl group. Unlike its position in the substrate complex, the bromide ion is situated near the quinolinium ring in the transition state, which is where the iodide ion resides in the X-ray structure (Figure 4b). This is in line with recent computational models that revealed the preferred ion-paired complex is not necessarily the lowest-energy ion pair in the transition state.33 The main difference between the two transition structures is the relative position of the cyclization TS and the catalyst. This leads to two different π stacking interactions for the major and minor transition structures. In the major TS, the substituted benzyl group on the quinuclidinium nitrogen of the catalyst is involved, while in the minor TS, the quinolinium ring forms π–π stacking with the pyridine moiety of the substrate. A closer look at the two π–π stacking interactions suggests that the one present in the major TS is slightly more stabilizing due to the parallel and closer alignment of the aromatic rings (−4.4 versus −3.8 kcal/mol). This factor by itself is not sufficient to explain the experimentally observed and theoretically predicted enantioselectivity, however. a

Ea

Eint

11.8 24.1

12.0 21.7 6.5

Edist,cat (Br–) 5.2 Br –

Br –

R N

R N N

H

O

H H OCl H

H

OMe

N H

N

N

Br

H Cl

N

H

OMe

b

N N

R N

O

N

H H OCl H

H

H

N

matched

Figure 5. Lowest-energy stereocontrolling TSs for the reaction in Scheme 2. In the schematic drawings, atoms closer to the viewer are represented by larger font sizes. All energies are in kcal/mol.

Br

H Cl

N Br

N

H

Br

OMe

N N

B3LYP-D3(BJ)/6-311+G(d,p)//B3LYP/6-31G(d) B3LYP-D3(BJ)/6-311+G(d,p)–SMD(toluene)//B3LYP/6-31G(d) B3LYP-D3(BJ)/6-311+G(d,p)–SMD(water)//B3LYP/6-31G(d)

Br –

R N H

minor TS ∆G‡ = 9.5, 22.0, 21.5 ∆∆G‡ = 2.1, 2.1, 3.0

minor TS

Br –

O

H

major TS ∆G‡ = 7.4, 19.9, 18.5 ∆∆G‡ = 0.0

OH H Br

5.8

major TS

N

H

Br

Br

Edist,substrate 4.6

complex (Br –) 0

H

OH H Br

OMe

O

H

N N

twisted

Figure 6. (a) Distortion-interaction analysis for reaction catalyzed by 5b′. All energies are in kcal/mol. (b) Electrostatic interactions between the catalyst and the enolate in the stereocontrolling TSs. Atoms closer to the viewer are represented by larger font sizes.


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We used the distortion/interaction model to elucidate what causes the difference in energy between the major and minor TSs of this reaction (Figure 6a).38-41 Starting from the stable catalyst(Br−)–enolate complex, the distortion energy (Edist) is defined as the energy required to distort each species [catalyst(Br−) and enolate] from reactant geometry to transition state geometry. The positive interaction energies (Eint = Ea − Edist) suggest that the two species are destabilized going from complex to the transition state geometries. While the interaction energies differ only slightly, the distortion of the catalyst and the enolate is most significant in the minor TS (∆Edist,total = 2.5 kcal/mol). The structural origins of this differential distortion are illustrated in Figure 6b. There are π–π stacking interactions with the catalyst in both TSs. The major TS acquires a matched hydrogen bonding interaction involving the two hydrogen-bond donating groups (namely, the C9-OH and one of the α C–H bonds of the quinuclidinium nitrogen) and the two hydrogen-bond accepting groups (the enolate O− and the Cl− leaving group). On the other hand, the enolate in the minor TS is distorted from its optimal geometry to achieve the same interactions with the catalyst. We also studied catalyst 5a′, a truncated version of the best experimentally used catalyst 5a (Figure 7a). The stereocontrolling major and minor TSs were computed for substrate 4 as well as substrates 7 (96% ee) and 8 (65% ee). A linear relationship is obtained between the experimental ∆∆G‡ and the difference in total distortion energies between the major and minor TSs (Figure 7b), suggesting that the level of enantioselectivity is controlled by the extent of distortion of the minor TS.

Like the Dolling and the Pliego models, the interaction of the C9-hydroxyl group with the enolate oxygen is important. The cinchona alkaloid does not act as a steric shield, as Dolling proposed, but stabilizes the transition structure by electrostatic interactions with the leaving chloride ion. We propose that two more interactions are required for enantioselectivity: a chloride-CH interaction for the leaving group, and a π–π stacking interaction between the pyridine of the substrate and the chiral catalyst. We have shown that it is crucial to incorporate the counterion when modeling ion-pair catalysts to predict accurate selectivities. We demonstrate that the stereoselectivity of the alkylation is directly related to the degree of distortion of the catalyst and the substrate necessary to achieve favorable electrostatic interactions.

ASSOCIATED CONTENT Supporting Information.

The Supporting Information is available free of charge on the ACS Publications website at DOI: Computational details and additional figures. Conformational analyses for 5b′ and catalyst(Br−)– enolate complex. X-ray crystal structure of 5d in CIF format. Dolling-type major TS. Cartesian coordinates and thermodynamic parameters (in hartrees) of all stationary points.

AUTHOR INFORMATION Corresponding Author [email protected] Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS Financial support was provided by the National Institute of General Medical Sciences, National Institutes of Health (GM36700). A.S. was supported by the NIH ChemistryBiology Interface Research Training Grant (USPHS National Research Service Award T32GM008496). The computational resources from UCLA Institute for Digital Research and Education, and from the National Science Foundation through XSEDE resources provided by the XSEDE Science Gateways program are gratefully acknowledged. This work used computational and storage services associated with the Hoffman2 Shared Cluster provided by UCLA Institute for Digital Research and Education’s Research Technology Group. We thank Bangping Xiang for helpful discussions. Figure 7. (a) Model catalyst 5a′ and two experimentally used substrates 7, 8. (b) Plot of the difference in total distortion energies (∆Edist = ∆Edist,minor − ∆Edist,major) for all four reactions investigated and the experimental ∆∆G‡ computed from the experimental % ee. All energies are in kcal/mol.

CONCLUSIONS We report a model that explains how doubly quaternized cinchona alkaloid derivatives function as phase-transfer catalysts and how they impart stereoselectivity to spirocyclizations giving rise to products with quaternary stereogenic centers.

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(25) B3LYP/6-31G(d) yields adequate geometries in energy calculations with a dispersion-inclusive functional and a large basis set. (a) Krenske, E. H.; Houk, K. N. Acc. Chem. Res. 2013, 46, 979. (b) Lam, Y.-h.; Grayson, M. N.; Holland, M. C.; Simon, A.; Houk, K. N. Acc. Chem. Res. 2016, 49, 750. (c) Simón, L.; Goodman, J. M. Org. Biomol. Chem. 2011, 9, 689. See also ref 21–22. (26) (a) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. J. Chem. Phys. 2010, 132, No. 154104. (b) Goerigk, L.; Grimme, S. Phys. Chem. Chem. Phys. 2011, 13, 6670. (c) Grimme, S.; Ehrlich, S.; Goerigk, L. J. Comp. Chem. 2011, 32, 1456. (27) (a) Ribeiro, R. F.; Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B 2011, 115, 14556. (b) Zhao, Y.; Truhlar, D. G. Phys. Chem. Chem. Phys. 2008, 10, 2813. (28) (a) Zhao, Y.; Truhlar, D. G. Acc. Chem. Res. 2008, 41, 157. (b) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215. (29) (a) MacroModel, Schrödinger, LLC, New York, NY, 2016. (b) Watts, K. S.; Dalal, P.; Tebben, A. J.; Cheney, D. L.; Shelley, J. C. J. Chem. Inf. Model. 2014, 54, 2680. (30) (a) Denmark, S. E.; Gould, N. D.; Wolf, L. M. J. Org. Chem. 2011, 76, 4337. (b) Denmark, S. E.; Weintraub, R. C. Heterocycles, 2011, 82, 1527. (c) Denmark, S. E.; Henle, J. J. Chem. Sci. 2015, 6, 2211. (31) Lam, Y.-h.; Houk, K. N. J. Am. Chem. Soc. 2014, 136, 9556. (32) Lam, Y.-h.; Houk, K. N. J. Am. Chem. Soc. 2015, 137, 2116. (33) Grayson, M. N.; Houk, K. N. J. Am. Chem. Soc. 2016, 138, 1170. (34) For recent theoretical studies on phase-transfer organocatalysis, see: (a) Petrova, G. P.; Li, H.-B.; Maruoka, K.; Morokuma, K. J. Phys. Chem. B 2014, 118, 5154. (b) Kamachi, T.; Yoshizawa, K. Org. Lett. 2014, 16, 472. (c) Kamachi, T.; Yoshizawa, K. J. Chem. Inf. Model. 2016, 56, 347. (35) Interestingly, organocatalysts that utilize the hydrogenbond donating properties of the N+–C–H bonds were explored only recently. Shirakawa, S.; Liu, S.; Kaneko, S.; Kumatabara, Y.; Fukuda, A.; Omagari, Y.; Maruoka, K. Angew. Chem. Int. Ed. 2015, 54, 15767. (36) Grimme found that inclusion of counterions in theoretical calculations significantly improves the agreement with experiment in terms of structure and energetics. Antony, J.; Sure, R.; Grimme, S. Chem. Commun. 2015, 51, 1764. (37) The approximate coplanarity of the two aromatic rings and the C9-O bond in the monoquaternized cinchona alkaloids was also recognized by Dolling and coworkers. See ref. 2 and 3. (38) Ess, D. H.; Houk, K. N. J. Am. Chem. Soc. 2007, 129, 10646. (39) Liu, F.; Paton, R. S.; Kim, S.; Liang, Y.; Houk, K. N. J. Am. Chem. Soc. 2013, 135, 15642. (40) van Zeist, W.-J.; Bickelhaupt, F. M. Org. Biomol. Chem. 2010, 8, 3118. (41) Fernández, I.; Bickelhaupt, F. M. Chem. Soc. Rev. 2014, 43, 4953.


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