Theory and Modeling of Asymmetric Catalytic Reactions - Accounts of

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Theory and Modeling of Asymmetric Catalytic Reactions Published as part of the Accounts of Chemical Research special issue “Computational Catalysis for Organic Synthesis”. Yu-hong Lam, Matthew N. Grayson, Mareike C. Holland, Adam Simon, and K. N. Houk* Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, California 90095-1569, United States

CONSPECTUS: Modern density functional theory and powerful contemporary computers have made it possible to explore complex reactions of value in organic synthesis. We describe recent explorations of mechanisms and origins of stereoselectivities with density functional theory calculations. The specific functionals and basis sets that are routinely used in computational studies of stereoselectivities of organic and organometallic reactions in our group are described, followed by our recent studies that uncovered the origins of stereocontrol in reactions catalyzed by (1) vicinal diamines, including cinchona alkaloid-derived primary amines, (2) vicinal amidophosphines, and (3) organo-transition-metal complexes. Two common cyclic models account for the stereoselectivity of aldol reactions of metal enolates (Zimmerman−Traxler) or those catalyzed by the organocatalyst proline (Houk−List). Three other models were derived from computational studies described in this Account. Cinchona alkaloid-derived primary amines and other vicinal diamines are venerable asymmetric organocatalysts. For α-fluorinations and a variety of aldol reactions, vicinal diamines form enamines at one terminal amine and activate electrophilically with NH+ or NF+ at the other. We found that the stereocontrolling transition states are cyclic and that their conformational preferences are responsible for the observed stereoselectivity. In fluorinations, the chair seven-membered cyclic transition states is highly favored, just as the Zimmerman−Traxler chair six-membered aldol transition state controls stereoselectivity. In aldol reactions with vicinal diamine catalysts, the crown transition states are favored, both in the prototype and in an experimental example, shown in the graphic. We found that low-energy conformations of cyclic transition states occur and control stereoselectivities in these reactions. Another class of bifunctional organocatalysts, the vicinal amidophosphines, catalyzes the (3 + 2) annulation reaction of allenes with activated olefins. Stereocontrol here is due to an intermolecular hydrogen bond that activates the electrophilic partner in this reaction. We have also studied complex organometallic catalysts. Krische’s rutheniumcatalyzed asymmetric hydrohydroxyalkylation of butadiene involves two chiral ligands at Ru, a chiral diphosphine and a chiral phosphate. The size of this combination strains the limits of modern computations with over 160 atoms, multiple significant steps, and a variety of ligand coordinations and conformations possible. We found that carbon−carbon bond formation occurs via a chair Zimmerman−Traxler-type transition structure and that a formyl CH···O hydrogen bond from aldehyde CH to phosphate oxygen, as well as steric interactions of the two chiral ligands, control the stereoselectivity.

1. INTRODUCTION Since the 1980s, our group has studied computationally both stereoselectivity and catalysis. Initially, only small model systems and very approximate quantum mechanics could be employed. The emphasis was on models to understand the principal factors contributing to selectivity.1 The idea that anything quantitative was possible or that we could calculate real systems, not just simplified models, did not occur to us at all! Now, we are able to study very complex catalytic systems. This Account describes the developments that have made this possible and a recent body of © XXXX American Chemical Society

work from our lab on asymmetric catalytic reactions involving both organocatalysts and transition metal catalysts with chiral ligands. The development of density functionals that gave excellent geometries and reasonable energetics for organic reactions came only 20 years ago2 and made it possible to study stereoselectivities directly. Previously, we did calculations on model Received: January 6, 2016

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DOI: 10.1021/acs.accounts.6b00006 Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Accounts of Chemical Research

Figure 1. General summary of workflow common in computational investigations of mechanisms and selectivities.

systems and developed force fields to study large systems.3 The main developments that make current studies possible are the availability of fast and inexpensive computers and the creation of accurate density functionals. Our general approach to the exploration of a mechanism, catalytic or otherwise, involves the use of calculations to test hypotheses. We have not reached the day, and we probably never will, where we can just ask the computer to predict mechanisms and catalytic cycles, although some groups are developing algorithms that purport to do just that.4,5 As outlined in Figure 1, we use computation to determine whether various hypotheses are energetically feasible and, if so, which of these are energetically best. Initial geometries are acquired by conformational searches with force fields. Input geometries of the transition structures are identified either from experience or through scanning along the reaction coordinate. Density functional theory (DFT) computations are used for optimizations and energy calculations. If results are in agreement with experiment, we analyze the transition states, and the structural factors responsible for asymmetric induction are proposed. Qualitative models are developed to understand and to make new predictions for catalyst and reaction design. The quantum chemical methods we use after the years of experience of our group and others6 are listed in Table 1. The use of B3LYP with the 6-31G(d) basis set has proved robust in optimizing transition structure geometries of most systems. Although the use of triple-ζ basis sets in geometry optimizations and frequency calculations has been advocated in the literature,7 B3LYP/6-31G(d) remains the best compromise between cost and efficiency in the face of multiple conformers and reaction pathways that need to be considered for the organic reactions we study. The shortcomings of the B3LYP functional,8 particularly its underestimation of dispersion forces,9 have been critically reviewed. Nevertheless, satisfactory agreement with experimental selectivities can be obtained by evaluating single-point energies of the optimized structures using a dispersion-inclusive density functional6 (such as Truhlar’s M06 suite,10 B3LYP with Grimme’s D3 dispersion corrections,11 and Head-Gordon’s ωB97XD functional)12 in conjunction with a triple-ζ basis set. Solvation effects are taken into account by using the PCM13 or SMD14 models.

Table 1. Levels of Theory Used in Computational Studies of Stereoselectivity functionals basis sets solvation models

B3LYP,a M06,a,b M06-2X,a,b B3LYP-D3(BJ),b ωB97XDa,b 6-31G(d),a SDD,a,b LANL2DZ,a,b 6-311G(d,p),b def2TZVPPb IEF-PCM,a,b SMDa,b

a

Used in geometry optimizations. calculations of optimized structures.

b

Used in single-point energy

Scheme 1. Houk−List Model

2. ORGANOCATALYSIS 2.1. General Introduction

Our early entry into this field involved the investigation of the origin of stereoselectivity in proline-catalyzed aldol reactions, which led to what has since become known as the Houk−List model (Scheme 1).15−17 We also studied MacMillan’s imidazolidinone catalysts operating through iminium activation18,19 (Scheme 2) and SOMO activation.20 These chiral amines have been used in a wide variety of reactions. Our models to explain their stereoselectivities have proven robust and have recently been applied by our group to complex reactions of value in synthesis.21 The emphasis of our computational work is on stereoselectivity. We sometimes cannot study the full catalytic cycle. In particular, the steps in enamine formation most likely involve multiple B


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Accounts of Chemical Research Scheme 2. Stereoselectivity Model for Iminium Catalysis by MacMillan’s Imidazolidinones

Scheme 4. Cinchona Alkaloid-Derived Primary Amines

proton transfers to and from solvent and are thus computationally intractable at the QM level of theory.22 Consequently, many experimental studies have been devoted to the detection and formation pathways of the enamine intermediate.23 One important advance involved our collaboration with the late Carlos Barbas on the prediction of new catalysts for anti-selective Mannich reactions (Scheme 3). Whereas proline

Scheme 5. Cinchona Amine-Catalyzed Fluorinationa

Scheme 3. Mannich Reactions Catalyzed by Proline and Designed Proline Analogues

a

produces the syn-Mannich adducts,24 computational screening led to the prediction of catalysts including 1−3 that proved to be anti-selective by experiment.25 In 2011, our group published a review in Chemical Reviews that discusses all of the computational studies of organocatalytic reactions.26

All relative free energies are given in kcal/mol.

Scheme 6. Catalytic Cycle for the Cinchona Amine-Catalyzed Fluorination

2.2. Cinchona Alkaloid Primary Amines and Other Vicinal Diamines

The Houk−List model has inspired the design and organocatalytic applications of a variety of vicinal diamines, where a protonated amine acts as the general acid.27 The vicinal diamine motif is also found in a major class of cinchona alkaloid derivatives in which the hydroxyl group on C9 is substituted (with inversion) by a primary amine (Scheme 4). These cinchona amines are especially effective in catalyzing reactions of sterically demanding carbonyl groups, which are challenging for catalysis by secondary amines.28 There is a paucity of understanding of asymmetric induction for these reactions. Various ad hoc models based on steric hindrance have been proposed.27,29 Prior to our studies, there were only two reports on the mechanism and stereocontrol of cinchona amine-catalyzed reactions, both proceeding through iminium catalysis.30,31 2.2.1. Cinchona Amine-Catalyzed Fluorinations. We have studied the origins of stereocontrol of the cinchona aminecatalyzed fluorination of cyclic ketones reported by MacMillan

(Scheme 5),32 assuming the catalytic cycle shown in Scheme 6 featuring dual activation of the fluorine source33 and the ketone. For the fluorination of cyclohexanone, the (R)-TS is 6.8 kcal/mol lower in energy than the (S)-TS, consistent with the sense and level of enantioselectivity experimentally observed. As shown in Figure 2, both transition structures are similar (view (i)), but the key structural difference lies in the conformation of the seven-membered fluorine transfer rings (view (ii)). The favored TS features a chair conformation in which the quinoline ring is C


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Scheme 7. Vicinal Diamine-Catalyzed Intermolecular Aldol Reactions

Figure 2. Stereocontrolling transition structures for cinchona aminecatalyzed fluorination of cyclohexanone (B3LYP-D3(BJ)/def2TZVPP−IEF-PCM(THF)//B3LYP/6-31G(d)−IEF-PCM(THF)). Adapted with permission from ref 33. Copyright 2014 American Chemical Society.

equatorial, while the disfavored TS displays a boat conformation in which the quinoline ring is pseudoaxial. 2.2.2. Vicinal Diamine-Catalyzed Aldol Reactions. We have explored various intermolecular (Scheme 7) and intramolecular (Scheme 8) aldol additions catalyzed by vicinal diamines.27,29,34 2.2.2.1. Intermolecular Aldol Reactions. To understand the intrinsic conformational preferences of the cyclic transition states, we computed the transition structures for the aldol addition of formaldehyde and the enamine formed from acetaldehyde and ethylenediamine (Scheme 7, eq 1).35a As shown in Figure 3, the four lowest-energy transition structures are nine-membered hydrogen bonded rings with conformations that are comparable to the conformers of cyclooctane.36 The crown (or the chair−chair; TS-12a; Figure 3) is slightly more stable than the chair−boat transition states (TS-12b), but both TS-12a and TS-12b feature s-trans enamines and are more stable than the boat−chair (TS-12c) and the boat−boat transition states (TS-12d), which are destabilized by eclipsing forming C−C bonds and unfavorable s-cis enamine conformations. The preferred transition states corroborate the Zimmerman−Traxler transition state for diastereoselective aldol additions.37 We now understand the stereocontrol in a wide range of aldol reactions catalyzed by vicinal diamines. In 2002, Yamamoto reported the first asymmetric bimolecular aldol reaction catalyzed by a vicinal diamine (Scheme 7, eq 2).27 The lowestenergy transition structures are both crowns (Figure 4). The (R)-TS, which bears an equatorial aryl group, is 2.1 kcal/mol lower in energy than the (S)-TS, in which the aryl group is axial. Here the new chiral center is at the electrophilic aldehyde carbon. For bimolecular aldol reactions catalyzed by cinchona amines (Scheme 7, eq 3−5),29,34,35b the enantioselectivities are determined by differences in energy between the crown

Scheme 8. Vicinal Diamine-Catalyzed Intramolecular Aldol Reactions

and chair-boat transition structures. Here the new chiral center is at the electrophilic carbonyl carbon and, in reaction 3, at the nucleophilic enamine carbon. 2.2.2.2. Intramolecular Aldol Reactions. In 2008, List reported that cinchona amines 4 and 6 catalyze the intramolecular aldol condensations of a variety of 4-substituted heptane-2,6-diones to form 5-substituted cyclohexenones with good enantiocontrol (Scheme 8, eq 1).38 D


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Figure 3. Transition structures for reaction 1 in Scheme 7 (M06-2X/ def2-TZVPP//B3LYP/6-31G(d)). Adapted with permission from ref 35a. Copyright 2016 American Chemical Society.

Figure 5. Stereocontrolling transition structures for reaction 1 in Scheme 8 (B3LYP-D3(BJ)/def2-TZVPP−IEF-PCM//B3LYP/ 6-31G(d)−IEF-PCM(toluene)). Adapted with permission from ref 39. Copyright 2015 American Chemical Society.

Figure 4. Stereocontrolling transition structures for reaction 2 in Scheme 7 (M06-2X/def2-TZVPP−IEF-PCM(acetone)//B3LYP/ 6-31G(d)−IEF-PCM(acetone)). Adapted with permission from ref 35a. Copyright 2016 American Chemical Society.

We modeled the stereoisomeric transition structures for the aldol addition step (Figure 5).39 For 4-methylheptane-2,6dione, the TS leading to the (3S,5S)-aldol, which gives the major (S)-enantiomer after dehydration, is lower in energy than the (3R,5R)-TS by 1.6 kcal/mol, agreeing well with the level and sense of the enantioselectivity experimentally observed. The (3S,5R)- and (3R,5S)-transition structures are significantly higher in energy and thus insignificant under the experimental conditions. The levels of enantioselectivity computed for the isopropyl- and phenyl-substituted diketones are also in good agreement with the experimental results. In the preferred transition structures, the forming six-membered ring is a chair, and the R group at C5 and the quinoline ring are equatorial. This cyclic transition state is a boat−chair in the (3S,5S)-TS and a crown in the (3R,5R)-TS. The boat−chair TS is preferred here. Luo reported that a tert-leucine-derived primary amine catalyzes the formation of Hajos−Parrish and Wieland−Miescher ketones through a Robinson annulation.40 They computed the aldol transition structures by B3LYP and noted that the enantioselectivity was overestimated. We computed dispersion-inclusive single-point energies by B3LYP-D3(BJ)/def2-TZVPP (Figure 6), and the free energy difference is in much improved agreement with experiment. Once again, the transition structures that lead to the

Figure 6. Stereocontrolling transition structures for reaction 2 in Scheme 8 (B3LYPD3(BJ)/def2-TZVPP//B3LYP/6-31G(d)).

major and the minor enantiomers are a boat−chair and a crown, respectively. Several predictions we made about stereoselectivities of modified cinchona amine catalysts are currently being tested experimentally in collaboration with Scott Denmark. E


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Accounts of Chemical Research 2.3. Amino Acid-Derived Organophosphines

using PMe3 and simple model reactants led to the mechanism shown in Figure 7, with stepwise formation of the two C−C bonds.47 The rate-determining step is the nucleophilic addition of the phosphine catalyst to the allenoate to give a phosphonium enolate. The most stable conformation of this zwitterion, which has also been characterized by X-ray crystallography,48

Chiral β-amidophosphines, such as those derived from naturally occurring amino acids (Scheme 9),41−45 are another class of emerging bifunctional organocatalysts. They are widely used in annulation reactions for the construction of highly substituted heterocycles.46 Early computational work by Dudding and Yu

Scheme 9. Asymmetric 3 + 2 Annulation Reactions Catalyzed by Bifunctional Amino Acid-Derived β-Aminophosphines and Proposed Models for Stereocontrol

Figure 7. Mechanism of the organophosphine catalyzed 3 + 2 annulation (ref 47). F


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Figure 8. Free energy reaction profile of the two C−C bond-forming events of Miller’s 3 + 2 annulation (Scheme 9, eq 1) (M06-2X/def2-TZVPP/IEFPCM(toluene)//B3LYP/6-31G(d)/IEF-PCM(toluene)). Reproduced with permission from ref 49. Copyright Wiley-VCH Verlag GmbH & Co. KGaA.

displays a close P+···O− contact and additional H-bonding interactions. The origins of stereocontrol in asymmetric 3 + 2 annulations catalyzed by chiral β-amidophosphines were not previously investigated computationally. All of the catalysts in Scheme 9 contain an N−H hydrogen bond donor vicinal to the nucleophilic phosphine moiety. Bifunctional activation and stereocontrol by the catalyst are thus possible. Various authors have attributed the stereocontrol to different intramolecular and intermolecular hydrogen-bonding interactions involving the phosphonium enolate during the formation of the first C−C bond.41−45 Thus, we studied the origins of enantioselectivity in the seminal example of an organocatalytic 3 + 2 annulation reported by Miller using an 41,49 L-serine-derived phosphine (Scheme 9, eq 1). The computed free energy reaction profile for Miller’s reaction is shown in Figure 8. Consistent with previous studies,47 the formation of the first C−C bond is higher in energy than the second and is thus enantiocontrolling. A proton-transfer sequence catalyzed by trace amounts of water subsequent to ring closing is believed to be responsible for regeneration of the catalyst. In the transition state, an intermolecular hydrogen bond is present between the carbamate N−H of the phosphonium enolate and the carbonyl group of the enone substrate, and this is responsible for the high levels of enantioinduction (Figure 9). This intermolecular hydrogen bond activates the enone and stabilizes the forming negative charge as the addition proceeds. In contrast, in the transition state proposed by Miller,41 the hydrogen bond is intramolecular and stabilizes the enolate of the intermediate, and the facial selectivity with respect to the enone, which governs the enantioselectivity, was proposed to be due to steric shielding of one of the phenyl groups. A transition state featuring an intramolecular hydrogen bond was found to be >10 kcal/mol higher in energy. Additional intermolecular interactions are present between the acidified hydrogens at the α- and β-positions to the phosphonium moiety, further stabilizing the transition state for the major enantiomer.

The (S)-TS is most stable, in agreement with the experimental selectivity of 80% ee at −25 °C (ΔΔG⧧(expt) = 1.1 kcal/mol). The TS for the minor product also exhibits the same kind of hydrogen-bond interactions (Figure 10). There are eight additional transition structures within 1.5 kcal/mol of the (R)-TS shown. Both the (S)-TS and (R)-TS have the same type of hydrogen bonding that stabilizes the developing enolate, but we found that the origin of the difference in energy of these transition structures is that to afford the minor enantiomer, the catalyst must be distorted into an unfavorable conformation when the carbamate oxygen is brought near the partially negatively charged ester group (3.60 Å). The features of this mode of catalysis are likely to be general: the most favorable transition state features coordination to the electrophile by means of an intermolecular hydrogen bond and thus stabilizes the developing negative charge.

3. ORGANOMETALLIC CATALYSIS 3.1. General Introduction

We have been involved in numerous collaborations aimed at understanding transition metal-catalyzed reactions, sometimes involving asymmetric catalysis. Our first investigation, before the days of DFT, involved a collaboration with Paul Wender on the stereoselectivity of his Ni-catalyzed 4 + 4 cycloadditions,50 a reaction related to a Ni-catalyzed 4 + 4 + 2 reaction that we studied in 2014 with Phil Baran.51 Our study of Ni-catalyzed reactions expanded in this century into studies of the mechanisms of reductive couplings,52,53 including stereoselectivity with chiral ligands and a Rh(I) catalyst.54 We also studied various palladium-catalyzed transformations. In collaboration with Jin-Quan Yu, we investigated the origins of diastereoselectivity in his oxazoline-directed, Pd(II)-catalyzed sp3 C−H bond iodination and acetoxylation reactions.55 In 2013, and in collaboration with Brian Stoltz, we studied his palladiumcatalyzed conjugate addition of arylboronic acids to β-substituted cyclic enones.56 Here we describe the computations that led G


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Figure 9. Transition states for the major (S) enantiomer in Miller’s reaction featuring an (A) intermolecular and (B) intramolecular hydrogen bond (B3LYP-D3(BJ)/def2-TZVPP/IEF-PCM(toluene)//B3LYP/6-31G(d)/IEF-PCM(toluene)). Reproduced with permission from ref 49. Copyright Wiley-VCH Verlag GmbH & Co. KGaA.

Figure 10. Transition states for the minor (R) enantiomer featuring an intermolecular (A) and an intramolecular (B) hydrogen bond (B3LYP-D3(BJ)/ def2-TZVPP/IEF-PCM(toluene)//B3LYP/6-31G(d)/IEF-PCM(toluene)). Upper half of the figure is reproduced with permission from ref 49. Copyright Wiley-VCH Verlag GmbH & Co. KGaA.

ruthenium-catalyzed asymmetric hydrohydroxyalkylation of butadiene, which uses two chiral ligands: (S)-SEGPHOS and either the TADDOL-derived phosphate 22a or the BINOLderived phosphate 23a (Scheme 10).57,58 The diastereoselective outcome of the reaction can be controlled through choice of

to a surprising conclusion about how dual chiral catalysts control stereoselectivity. 3.2. Krische’s Hydrohydroxyalkylation of Butadiene

Many modern asymmetric catalytic reactions are discovered by screening available ligands. A striking example is Krische’s H


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The ruthenium-catalyzed hydrohydroxyalkylation of butadiene involves hydrometalation of butadiene to form the interconverting π-crotylruthenium species, which then yield the (E)- and (Z)-σ-crotylruthenium aldehyde complexes (Scheme 11). The final product distribution is controlled by the kinetics of C−C bond formation.59 The crotylation product is released by exchange with a reactant alcohol. Regeneration of the ruthenium hydride by dehydrogenation affords the aldehyde needed for crotylation. The syn-π-allyl species was calculated to be thermodynamically preferred over the anti-π-allyl species by 6.4 kcal mol−1 for the TADDOL-derived catalyst system, but Curtin−Hammett conditions cause the diastereoselectivity of the reaction to be determined by the kinetics of C−C bond formation. The calculated TSs that lead to each of the experimental products are shown in Figure 11. TS-24(3R,4R) leads to the formation of the major product observed experimentally and is the lowest-energy TS. A hydrogen-bonding interaction between the formyl proton of the aldehyde and the PO oxygen is seen in this TS and TS-24(3S,4R). This has been observed in allylborations as well.60 TS-24(3R,4R) is lower in energy than TS-24(3S,4R) because gauche interactions between the aldehyde substituent and methyl group destabilize TS-24(3S,4R). TS-24(3S,4R) is further destabilized by the proximity of the crotyl methyl group to the chiral phosphate. TS-24(3R,4S) and TS-24(3S,4S) are less stable because they lack the formyl hydrogen bond. The proximity of the pseudoaxial methyl group to the chiral phosphate in TS-24(3S,4S) further destabilizes this TS. For the BINOL-derived catalyst system, the calculated TSs are shown in Figure 12. TS-25(3R,4S) leads to the major product observed experimentally. TS-25(3S,4S) is destabilized relative to TS-25(3R,4S) by the proximity of the pseudoaxial methyl group to the chiral phosphate. The TS that leads to the minor enantiomer (TS-25(3S,4R)) is destabilized relative to

Scheme 10. Krische’s Ruthenium-Catalyzed Diastereo- and Enantioselective Hydrohydroxyalkylation of Butadiene

Reprinted with permission from ref 59. Copyright 2015 American Chemical Society

chiral phosphoric acid: TADDOL-derived phosphate ligands lead to syn-diastereoselectivity and H8-BINOL-derived phosphates lead to anti-diastereoselectivity. The reaction involves the Ru(II)-catalyzed cycle shown in Scheme 11. The total numbers of atoms in the systems we have modeled using our slightly truncated ligands 22b and 23b are 183 and 160, respectively. With this many atoms, multiple significant steps, and a variety of ligand coordinations and conformations possible, this example strains the limits of modern computations. Furthermore, the observed diastereoselectivities are very modest while the impressive enantioselectivities are the result of only a few kcal mol−1 energy differences. Despite these challenges, modern DFT computations do reproduce stereoselectivities and reveal how stereocontrol is achieved.59

Scheme 11. Proposed Catalytic Cycle for Butadiene Hydrohydroxyalkylation

Reprinted with permission from ref 59. Copyright 2015 American Chemical Society. I


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Figure 11. C−C bond forming TSs for reaction 1 in Scheme 10. Activation free energies relative to TS-24(3R,4R), M06/SDD6-311G(d,p)−IEFPCM(acetone)//B3LYP/SDD-6-31G(d). Noncritical hydrogen atoms omitted for clarity. All energies in kcal mol−1. TS-24(3S,4R) is destabilized by a phosphate−substrate steric interaction (green line). Reprinted with permission from ref 59. Copyright 2015 American Chemical Society.

Figure 12. C−C bond forming TSs for reaction 2 in Scheme 10. Free activation energies relative to TS-25(3R,4S), M06/SDD-6-311G(d,p)− IEFPCM(acetone)//B3LYP/SDD-6-31G(d). Noncritical hydrogen atoms omitted for clarity. All energies in kcal mol−1. Reprinted with permission from ref 59. Copyright 2015 American Chemical Society.

TS-25(3R,4S) by unfavorable steric interactions with the chiral phosphate, which are the result of coordinating the aldehyde to site 2. The formyl hydrogen bond is absent in the lowest-energy TS because the Ru−O−P angle must increase in order for the chiral phosphate to establish this hydrogen bond (Figure 13). This increase in Ru−O−P angle can be accommodated in the TADDOL-derived system because the phosphate framework fits between the steric demands of the phosphine (“From above”, Figure 13). In contrast, increasing the Ru−O−P angle in the BINOL-derived system is opposed by a clash between the BINOL framework and a phenyl group of the phosphine, which overrides the benefit of the formyl hydrogen bond and destabilizes TS-25(3R,4R) relative to TS-25(3R,4S).

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Funding

This work was funded by the NIGMS, NIH (Grant GM-36700), the NSF (Grant CHE-1361104), The English-Speaking Union (Lindemann Trust Fellowship to M.N.G.), and the German Academic Exchange Service DAAD (P.R.I.M.E. fellowship to M. C. Holland). Notes

The authors declare no competing financial interest.

4. CONCLUSION This Account of our recent investigations exemplifies the state of the art in computational chemistry of asymmetric catalysis. Reactions of significant experimental interest can now be explored with chemical accuracy, and general principles that lead to useful qualitative models can be extracted. As computational technology and methods continue to improve, the predictive capacity of quantum chemical computations will expand to larger systems.

Biographies Yu-hong Lam received his Master of Chemistry degree in 2005 from the University of Oxford, where he worked with Véronique Gouverneur in organofluorine chemistry. He stayed in the same group for his doctoral studies, obtaining his D.Phil. in 2009. He is now a postdoctoral fellow in the Houk group, specializing in catalyst design and reaction discovery using computational chemistry. J


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K. N. Houk is the Saul Winstein Chair in Organic Chemistry at UCLA. He is a computational organic chemist. He received his Ph.D. at Harvard with R. B. Woodward in 1968, doing experimental work in orbital symmetry-predicted chemistry. He has published extensively on pericyclic reactions, stereoselectivity, molecular recognition, and enzyme design. He is a Fellow of the American Academy of Arts and Sciences and a member of the National Academy of Sciences.

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REFERENCES

(1) Houk, K. N.; Paddon-Row, M. N.; Rondan, N. G.; Wu, Y. D.; Brown, F. K.; Spellmeyer, D. C.; Metz, J. T.; Li, Y.; Loncharich, R. J. Theory and Modeling of Stereoselective Organic Reactions. Science 1986, 231, 1108−1117. (2) (a) Becke, A. D. Density-Functional Exchange-Energy Approximation with Correct Asymptotic Behavior. Phys. Rev. A: At., Mol., Opt. Phys. 1988, 38, 3098−3100. (b) Vosko, S. H.; Wilk, L.; Nusair, M. Accurate Spin-Dependent Electron Liquid Correlation Energies for Local Spin Density Calculations: a Critical Analysis. Can. J. Phys. 1980, 58, 1200−1211. (c) Lee, C.; Yang, W.; Parr, R. G. Development of the Colle-Salvetti Correlation-Energy Formula Into a Functional of the Electron Density. Phys. Rev. B: Condens. Matter Mater. Phys. 1988, 37, 785−789. (d) Becke, A. D. Density-Functional Thermochemistry. III. the Role of Exact Exchange. J. Chem. Phys. 1993, 98, 5648−5652. (e) Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J. Ab Initio Calculation of Vibrational Absorption and Circular Dichroism Spectra Using Density Functional Force Fields. J. Phys. Chem. 1994, 98, 11623−11627. (3) Eksterowicz, J. E.; Houk, K. N. Transition-State Modeling with Empirical Force Fields. Chem. Rev. 1993, 93, 2439−2461. (4) Maeda, S.; Morokuma, K. Finding Reaction Pathways of Type A+B -> X: Toward Systematic Prediction of Reaction Mechanisms. J. Chem. Theory Comput. 2011, 7, 2335−2345. (5) Wang, L.-P.; Titov, A.; McGibbon, R.; Liu, F.; Pande, V. S.; Martínez, T. J. Discovering Chemistry with an Ab Initio Nanoreactor. Nat. Chem. 2014, 6, 1044−1048. (6) Simón, L.; Goodman, J. M. How Reliable Are DFT Transition Structures? Comparison of GGA, Hybrid-Meta-GGA and Meta-GGA Functionals. Org. Biomol. Chem. 2011, 9, 689−700. (7) Schenker, S.; Schneider, C.; Tsogoeva, S. B.; Clark, T. Assessment of Popular DFT and Semiempirical Molecular Orbital Techniques for Calculating Relative Transition State Energies and Kinetic Product Distributions in Enantioselective Organocatalytic Reactions. J. Chem. Theory Comput. 2011, 7, 3586−3595. (8) Kruse, H.; Goerigk, L.; Grimme, S. Why the Standard B3LYP/631G* Model Chemistry Should Not Be Used in DFT Calculations of Molecular Thermochemistry: Understanding and Correcting the Problem. J. Org. Chem. 2012, 77, 10824−10834. (9) (a) Grimme, S. Density Functional Theory with London Dispersion Corrections. WIREs Comput. Mol. Sci. 2011, 1, 211−228. (b) Wagner, J. P.; Schreiner, P. R. London Dispersion in Molecular Chemistry-Reconsidering Steric Effects. Angew. Chem., Int. Ed. 2015, 54, 12274−12296. (10) Zhao, Y.; Truhlar, D. The M06 Suite of Density Functionals for Main Group Thermochemistry, Thermochemical Kinetics, Noncovalent Interactions, Excited States, and Transition Elements: Two New Functionals and Systematic Testing of Four M06-Class Functionals and 12 Other Functionals. Theor. Chem. Acc. 2008, 120, 215−241. (11) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. A Consistent and Accurate Ab Initio Parametrization of Density Functional Dispersion Correction (DFT-D) for the 94 Elements H-Pu. J. Chem. Phys. 2010, 132, 154104. (12) Chai, J.-D.; Head-Gordon, M. Long-Range Corrected Hybrid Density Functionals with Damped Atom-Atom Dispersion Corrections. Phys. Chem. Chem. Phys. 2008, 10, 6615−6620. (13) Tomasi, J.; Mennucci, B.; Cammi, R. Quantum Mechanical Continuum Solvation Models. Chem. Rev. 2005, 105, 2999−3093. (14) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Universal Solvation Model Based on Solute Electron Density and on a Continuum Model of

Figure 13. Comparison of TSs with and without the formyl hydrogen bond, M06/SDD-6-311G(d,p)−IEFPCM(acetone)//B3LYP/SDD6-31G(d). Measured angle highlighted in green. Noncritical hydrogen atoms omitted for clarity. Reprinted with permission from ref 59. Copyright 2015 American Chemical Society. Matthew N. Grayson is a Girton College Tucker-Price Research Fellow in Organic Chemistry at the University of Cambridge. Matt was born in the U.K. in 1988 and read Natural Sciences at Cambridge. He obtained his Ph.D. at Cambridge in 2014 with Jonathan Goodman. In 2014, he began an independent Girton College Research Fellowship at Cambridge. He conducted postdoctoral research in the Houk group at UCLA as a Lindemann Trust Fellow during 2015 before returning to Cambridge to continue his fellowship. Mareike C. Holland (born 1987 in Mainz, Germany) was educated at the ETH Zurich, Switzerland (M.Sc. 2010; Ph.D. 2014). She worked with Ryan Gilmour in stereoselective organocatalysis. She received a postdoctoral DAAD fellowship (2014) to work with Prof. K. N. Houk at UCLA on the computational investigation of stereoinduction in asymmetric organocatalysis. Currently, she is working with Prof. R. Gilmour at the University of Münster, Germany, during the return part of her scholarship. Adam Simon was born in Tarzana, California, in 1990. He received his B.S. in Chemistry with High Distinction from the University of California, San Diego, in 2014, and is currently a Ph.D. candidate working with Prof. K. N. Houk at UCLA. Adam is a Chemistry-Biology Interface Trainee and specializes in using quantum chemical calculations for discovering the origins of stereoselectivity and mechanisms of enzymatic and organocatalyzed reactions. K


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α,β-Unsaturated Carbonyl Compounds with Hydrogen Peroxide. J. Am. Chem. Soc. 2013, 135, 6677−6693. (31) Moran, A.; Hamilton, A.; Bo, C.; Melchiorre, P. A Mechanistic Rationale for the 9-Amino(9-deoxy)epi Cinchona Alkaloids Catalyzed Asymmetric Reactions via Iminium Ion Activation of Enones. J. Am. Chem. Soc. 2013, 135, 9091−9098. (32) Kwiatkowski, P.; Beeson, T. D.; Conrad, J. C.; MacMillan, D. W. C. Enantioselective Organocatalytic α-Fluorination of Cyclic Ketones. J. Am. Chem. Soc. 2011, 133, 1738−1741. (33) Lam, Y.-h.; Houk, K. N. How Cinchona Alkaloid-Derived Primary Amines Control Asymmetric Electrophilic Fluorination of Cyclic Ketones. J. Am. Chem. Soc. 2014, 136, 9556−9559. (34) Zheng, B.-L.; Liu, Q.-Z.; Guo, C.-S.; Wang, X.-L.; He, L. Highly Enantioselective Direct Aldol Reaction Catalyzed by Cinchona Derived Primary Amines. Org. Biomol. Chem. 2007, 5, 2913−2915. (35) (a) Simon, A.; Lam, Y.-h.; Houk, K. N. Transition States of Vicinal Diamine-Catalyzed Aldol Reactions. J. Am. Chem. Soc. 2016, 138, 503− 506. (b) Simon, A.; Yeh, A. J.; Lam, Y.-h.; Houk, K. N. manuscript in preparation. (36) Wiberg, K. B. The C7−C10 Cycloalkanes Revisited. J. Org. Chem. 2003, 68, 9322−9329. (37) Zimmerman, H. E.; Traxler, M. D. The Stereochemistry of the Ivanov and Reformatsky Reactions. I. J. Am. Chem. Soc. 1957, 79, 1920− 1923. (38) Zhou, J.; Wakchaure, V.; Kraft, P.; List, B. Primary-AmineCatalyzed Enantioselective Intramolecular Aldolizations. Angew. Chem., Int. Ed. 2008, 47, 7656−7658. (39) Lam, Y.-h.; Houk, K. N. Origins of Stereoselectivity in Intramolecular Aldol Reactions Catalyzed by Cinchona Amines. J. Am. Chem. Soc. 2015, 137, 2116−2127. (40) Xu, C.; Zhang, L.; Zhou, P.; Luo, S.; Cheng, J.-P. A Practical Protocol for Asymmetric Synthesis of Wieland-Miescher and HajosParrish Ketones Catalyzed by a Simple Chiral Primary Amine. Synthesis 2013, 45, 1939−1945. (41) Cowen, B. J.; Miller, S. J. Enantioselective [3 + 2]-Cycloadditions Catalyzed by a Protected, Multifunctional Phosphine-Containing αAmino Acid. J. Am. Chem. Soc. 2007, 129, 10988−10989. (42) Xiao, H.; Chai, Z.; Zheng, C.-W.; Yang, Y.-Q.; Liu, W.; Zhang, J.K.; Zhao, G. Asymmetric [3 + 2] Cycloadditions of Allenoates and Dual Activated Olefins Catalyzed by Simple Bifunctional N-Acyl Aminophosphines. Angew. Chem., Int. Ed. 2010, 49, 4467−4470. (43) Fang, Y. Q.; Jacobsen, E. N. Cooperative, Highly Enantioselective Phosphinothiourea Catalysis of Imine−Allene [3 + 2] Cycloadditions. J. Am. Chem. Soc. 2008, 130, 5660−5661. (44) Han, X.; Wang, Y.; Zhong, F.; Lu, Y. Enantioselective [3 + 2] Cycloaddition of Allenes to Acrylates Catalyzed by Dipeptide-Derived Phosphines: Facile Creation of Functionalized Cyclopentenes Containing Quaternary Stereogenic Centers. J. Am. Chem. Soc. 2011, 133, 1726− 1729. (45) Deng, H.-P.; Wang, D.; Wei, Y.; Shi, M. Chiral multifunctional thiourea-phosphine catalyzed asymmetric [3 + 2] annulation of MoritaBaylis-Hillman carbonates with maleimides. Beilstein J. Org. Chem. 2012, 8, 1098−1104. (46) Xiao, Y.; Sun, Z.; Guo, H.; Kwon, O. Chiral phosphines in nucleophilic organocatalysis. Beilstein J. Org. Chem. 2014, 10, 2089−2121. (47) (a) Mercier, E.; Fonovic, B.; Henry, C.; Kwon, O.; Dudding, T. Phosphine triggered [3 + 2] allenoate−acrylate annulation: a mechanistic enlightenment. Tetrahedron Lett. 2007, 48, 3617−3620. (b) Liang, Y.; Liu, S.; Xia, Y.; Li, Y.; Yu, Z.-X. Mechanism, Regioselectivity, and the Kinetics of Phopshine-Catalyzed [3 + 2] Cycloaddition Reactions of Allenoates and Electron-Deficient Alkenes. Chem. - Eur. J. 2008, 14, 4361−4373. (48) Zhu, X.-F.; Henry, C. E.; Kwon, O. Stable Tetravalent Phosphonium Enolate Zwitterions. J. Am. Chem. Soc. 2007, 129, 6722−6723. (49) Holland, M. C.; Gilmour, R.; Houk, K. N. Intermolecular Hydrogen Bonds Control Stereoselectivity in Allene-Enone (3 + 2) Annulations Catalyzed by a Bifunctional, Amino Acid Derived Phosphine Catalyst. Angew. Chem., Int. Ed. 2016, 55, 2022−2027.

the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface Tensions. J. Phys. Chem. B 2009, 113, 6378−6396. (15) Bahmanyar, S.; Houk, K. N. The Origin of Stereoselectivity in Proline-Catalyzed Intramolecular Aldol Reactions. J. Am. Chem. Soc. 2001, 123, 12911−12912. (16) Allemann, C.; Gordillo, R.; Clemente, F. R.; Cheong, P.; Houk, K. N. Theory of Asymmetric Organocatalysis of Aldol and Related Reactions: Rationalizations and Predictions. Acc. Chem. Res. 2004, 37, 558−569. (17) Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. Quantum Mechanical Predictions of the Stereoselectivities of Proline-Catalyzed Asymmetric Intermolecular Aldol Reactions. J. Am. Chem. Soc. 2003, 125, 2475−2479. (18) Gordillo, R.; Houk, K. N. Origins of Stereoselectivity in Diels− Alder Cycloadditions Catalyzed by Chiral Imidazolidinones. J. Am. Chem. Soc. 2006, 128, 3543−3553. (19) Gordillo, R.; Carter, J.; Houk, K. N. Theoretical Explorations of Enantioselective Alkylation Reactions of Pyrroles and Indoles Organocatalyzed by Chiral Imidazolidinones. Adv. Synth. Catal. 2004, 346, 1175−1185. (20) Um, J. M.; Gutierrez, O.; Schoenebeck, F.; Houk, K. N.; MacMillan, D. W. C. Nature of Intermediates in Organo-SOMO Catalysis of α-Arylation of Aldehydes. J. Am. Chem. Soc. 2010, 132, 6001−6005. (21) Hooper, J. F.; James, N. C.; Bozkurt, E.; Aviyente, V.; White, J. M.; Holland, M. C.; Gilmour, R.; Holmes, A. B.; Houk, K. N. Medium Ring Effects on the Endo/Exo Selectivity of the Organo-Catalytic Intramolecular Diels-Alder Reaction. J. Org. Chem. 2015, 80, 12058−12075. (22) Plata, R. E.; Singleton, D. A. A Case Study of the Mechanism of Alcohol-Mediated Morita Baylis−Hillman Reactions. the Importance of Experimental Observations. J. Am. Chem. Soc. 2015, 137, 3811−3826. (23) Haindl, M. H.; Hioe, J.; Gschwind, R. M. The Proline Enamine Formation Pathway Revisited in Dimethyl Sulfoxide: Rate Constants Determined via NMR. J. Am. Chem. Soc. 2015, 137, 12835−12842. (24) Notz, W.; Tanaka, F.; Watanabe, S.-I.; Chowdari, N. S.; Turner, J. M.; Thayumanavan, R.; Barbas, C. F. The Direct Organocatalytic Asymmetric Mannich Reaction: Unmodified Aldehydes as Nucleophiles. J. Org. Chem. 2003, 68, 9624−9634. (25) (a) Mitsumori, S.; Zhang, H.; Cheong, P. H.-Y.; Houk, K. N.; Tanaka, F.; Barbas, C. F. Direct Asymmetric Anti-Mannich-Type Reactions Catalyzed by a Designed Amino Acid. J. Am. Chem. Soc. 2006, 128, 1040−1041. (b) Zhang, H.; Mitsumori, S.; Utsumi, N.; Imai, M.; Garcia-Delgado, N.; Mifsud, M.; Albertshofer, K.; Cheong, P. H.-Y.; Houk, K. N.; Tanaka, F.; Barbas, C. F. Catalysis of 3-Pyrrolidinecarboxylic Acid and Related Pyrrolidine Derivatives in Enantioselective AntiMannich-Type Reactions: Importance of the 3-Acid Group on Pyrrolidine for Stereocontrol. J. Am. Chem. Soc. 2008, 130, 875−886. (26) Cheong, P. H.-Y.; Legault, C. Y.; Um, J. M.; Ç elebi-Ö lçüm, N.; Houk, K. N. Quantum Mechanical Investigations of Organocatalysis: Mechanisms, Reactivities, and Selectivities. Chem. Rev. 2011, 111, 5042−5137. (27) (a) Nakadai, M.; Saito, S.; Yamamoto, H. Diversity-Based Strategy for Discovery of Environmentally Benign Organocatalyst: Diamine−Protonic Acid Catalysts for Asymmetric Direct Aldol Reaction. Tetrahedron 2002, 58, 8167−8177. (b) Saito, S.; Yamamoto, H. Design of Acid-Base Catalysis for the Asymmetric Direct Aldol Reaction. Acc. Chem. Res. 2004, 37, 570−579. (28) Melchiorre, P. Cinchona-Based Primary Amine Catalysis in the Asymmetric Functionalization of Carbonyl Compounds. Angew. Chem., Int. Ed. 2012, 51, 9748−9770. (29) (a) Guo, Q.; Zhao, J. C.-G. Primary Amine Catalyzed Aldol Reaction of Isatins and Acetaldehyde. Tetrahedron Lett. 2012, 53, 1768− 1771. (b) Kumar, A.; Chimni, S. S. Catalytic Asymmetric Direct Aldol Reaction of Pyruvic Aldehyde Dimethyl Acetal with Isatin Derivatives. Eur. J. Org. Chem. 2013, 2013, 4780−4786. (30) Lifchits, O.; Mahlau, M.; Reisinger, C. M.; Lee, A.; Farès, C.; Polyak, I.; Gopakumar, G.; Thiel, W.; List, B. The Cinchona Primary Amine-Catalyzed Asymmetric Epoxidation and Hydroperoxidation of L


Article

Accounts of Chemical Research (50) Gugelchuk, M. M.; Houk, K. N. Stereoselective Organometallic Reactions: A Force Field Study of π-Allyl Intermediates in Nickel(0)Catalyzed Cycloadditions. J. Am. Chem. Soc. 1994, 116, 330−339. (51) Hong, X.; Holte, D.; Götz, D. C. G.; Baran, P. S.; Houk, K. N. Mechanism, Reactivity, and Selectivity of Nickel-Catalyzed [4 + 4 + 2] Cycloadditions of Dienes and Alkynes. J. Org. Chem. 2014, 79, 12177− 12184. (52) McCarren, P. R.; Liu, P.; Cheong, P. H.-Y.; Jamison, T. F.; Houk, K. N. Mechanism and Transition-State Structures for Nickel-Catalyzed Reductive Alkyne-Aldehyde Coupling Reactions. J. Am. Chem. Soc. 2009, 131, 6654−6655. (53) Liu, P.; McCarren, P.; Cheong, P. H.-Y.; Jamison, T. F.; Houk, K. N. Origins of Regioselectivity and Alkene-Directing Effects in NickelCatalyzed Reductive Couplings of Alkynes and Aldehydes. J. Am. Chem. Soc. 2010, 132, 2050−2057. (54) Liu, P.; Krische, M. J.; Houk, K. N. Mechanism and Origins of Regio- and Enantioselectivities in RhI-Catalyzed Hydrogenative Couplings of 1,3-Diynes and Activated Carbonyl Partners: Intervention of a Cumulene Intermediate. Chem. - Eur. J. 2011, 17, 4021−4029. (55) Giri, R.; Lan, Y.; Liu, P.; Houk, K. N.; Yu, J.-Q. Understanding Reactivity and Stereoselectivity in Palladium-Catalyzed Diastereoselective sp3 C-H Bond Activation: Intermediate Characterization and Computational Studies. J. Am. Chem. Soc. 2012, 134, 14118−14126. (56) Holder, J. C.; Zou, L.; Marziale, A. N.; Liu, P.; Lan, Y.; Gatti, M.; Kikushima, K.; Houk, K. N.; Stoltz, B. M. Mechanism and Enantioselectivity in Palladium-Catalyzed Conjugate Addition of Arylboronic Acids to β-substituted Cyclic Enones: Insights from Computation and Experiment. J. Am. Chem. Soc. 2013, 135, 14996− 15007. (57) Zbieg, J. R.; Yamaguchi, E.; McInturff, E. L.; Krische, M. J. Enantioselective C-H Crotylation of Primary Alcohols via Hydrohydroxyalkylation of Butadiene. Science 2012, 336, 324−327. (58) McInturff, E. L.; Yamaguchi, E.; Krische, M. J. Chiral-AnionDependent Inversion of Diastereo- and Enantioselectivity in Carbonyl Crotylation via Ruthenium-Catalyzed Butadiene Hydrohydroxyalkylation. J. Am. Chem. Soc. 2012, 134, 20628−20631. (59) Grayson, M. N.; Krische, M. J.; Houk, K. N. Ruthenium-Catalyzed Asymmetric Hydrohydroxyalkylation of Butadiene: The Role of the Formyl Hydrogen Bond in Stereochemical Control. J. Am. Chem. Soc. 2015, 137, 8838−8850. (60) Grayson, M. N.; Pellegrinet, S. C.; Goodman, J. M. Mechanistic Insights into the BINOL-Derived Phosphoric Acid-Catalyzed Asymmetric Allylboration of Aldehydes. J. Am. Chem. Soc. 2012, 134, 2716− 2722.

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