Mechanisms of Carbonyl Activation by BINOL N ... - ACS Publications

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Mechanisms of Carbonyl Activation by BINOL N‑Triflylphosphoramides: Enantioselective Nazarov Cyclizations Joseph P. Lovie-Toon,† Camilla Mia Tram,†,‡,∥ Bernard L. Flynn,§ and Elizabeth H. Krenske*,† †

School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland 4072, Australia University of Copenhagen, Universitetsparken 5, DK-2100 Copenhagen Ø, Denmark § Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia ‡

S Supporting Information *

ABSTRACT: BINOL N-triflylphosphoramides are versatile organocatalysts for reactions of carbonyl compounds. Upon activation by BINOL N-triflylphosphoramides, divinyl ketones undergo rapid and highly enantioselective (torquoselective) Nazarov cyclizations, making BINOL N-triflylphosphoramides one of the most important classes of catalysts for the Nazarov cyclization. However, the activation mechanism and the factors that determine enantioselectivity have not been established until now. Theoretical calculations with ONIOM and M06-2X are reported which examine how BINOL N-triflylphosphoramides activate divinyl ketones and control the torquoselectivity of the cyclization. Unexpectedly, the computations reveal that the traditionally accepted mechanisms for these catalysts (i.e., NH···O C hydrogen bonding or proton transfer) are not the dominant activation mechanisms. Instead, the active catalyst is a less-stable tautomer of the phosphoramide containing a P(NTf)OH group. Proton transfer from the catalyst to the substrate occurs concomitantly with ring closure. The enantioselectivities of Nazarov cyclizations of three different classes of divinyl ketones are shown to depend on a combination of factors, including catalyst distortion, the degree of proton transfer, intramolecular substrate stabilization, and intermolecular noncovalent interactions between the substrate and catalyst in the transition state, all of which relate to how well the cyclizing divinyl ketone fits into the chiral binding pocket of the catalyst. KEYWORDS: BINOL N-triflylphosphoramide, Nazarov cyclization, Brønsted acid, tautomerism, density functional theory, noncovalent interactions

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INTRODUCTION Chiral phosphoric acids derived from the enantiomers of BINOL (1, Figure 1) occupy a prominent role in the field of

cyclization. Some of the most efficient asymmetric Nazarov cyclizations reported to date have involved 2 as chiral catalysts.4 Scheme 1 shows three examples, which showcase the ability of N-triflylphosphoramides 2 to activate divinyl ketones at low catalyst loadings, leading to rapid and highly enantioselective cyclizations.5−7 Indeed, the versatility and success of phosphoramides 2 have significantly boosted the utility of the Nazarov cyclization as a method for the asymmetric synthesis of multistereocenter-containing cyclopentanoids.4 There have been many theoretical studies on BINOL phosphoric acid (1) catalyzed reactions.8,9 The stereoselectivities of reactions catalyzed by 1 depend on a rather complex combination of covalent and noncovalent interactions which occur in the transition state (TS). Noncovalent interactions that have been found to play a role in BINOL phosphoric acid catalyzed reactions include steric crowding, hydrogen bonding, CH−O, π−π, CH−π, cation−π, and electrostatic interactions.10 While some general predictive rules have emerged,9 the exact

Figure 1. BINOL-derived phosphoric acids 1 and N-triflylphosphoramides 2.

organocatalysis.1 Their ability to activate basic substrates by hydrogen bonding or proton transfer and the ability to tune the chiral binding pocket by varying the 3- and 3′-Ar substituents have led to many applications of 1 as chiral catalysts. However, certain classes of substratesnotably, carbonyl compounds are resistant to activation by 1. For these challenging substrates, the more acidic BINOL N-triflylphosphoramides 22 have emerged as powerful activating agents.1d,e,3 One important application of BINOL N-triflylphosphoramides 2 to carbonyl activation has been the Nazarov © XXXX American Chemical Society

Received: January 27, 2017 Revised: March 22, 2017

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DOI: 10.1021/acscatal.7b00292 ACS Catal. 2017, 7, 3466−3476

Research Article

ACS Catalysis Scheme 1. Enantioselective Nazarov Cyclizations Catalyzed by BINOL N-Triflylphosphoramides 25−7

during the conrotatory 4π electrocyclic ring closure for 6 but anticlockwise for 3 (see red arrows in Scheme 1). Third, we examine the Nazarov cyclization of 8 (reaction C). This reaction was developed by Tius as part of an elegant strategy for the construction of vicinal all-carbon quaternary stereocenters.7 Cyclization of 8, catalyzed by 2d, gave after loss of the stable diphenylmethyl cation the sterically congested cyclopentenone (S,S)-9 in an enantiomeric ratio (er) of 98:2 (clockwise conrotation). Catalyst 2e, containing Ph groups instead of tBuC6H4 groups, gave lower selectivity. Little is known about the factors that determine the direction of conrotatory ring closure in N-triflylphosphoramide-catalyzed Nazarov cyclizations.14 A recent paper by Tu and co-workers reported computations on a phosphoramide-catalyzed Nazarov cyclization/semipinacol rearrangement cascade which led to spiro[4.4]nonane derivatives.15 On the basis of density functional theory (DFT) calculations with B3LYP, the authors suggested that steric clashing between the substrate and the catalyst controlled the stereoselectivity in that case. Equally importantly, the exact mechanism of activation of divinyl ketones by N-triflylphosphoramides 2 is unknown. Different authors have depicted these reactions as involving either NH··· OC hydrogen bonding or the transfer of a proton from 2 to the carbonyl group to form a chiral contact ion pair (Scheme 1, lower right).1d,e,3−7 Here, we use density functional theory calculations to address this question and to explain the enantioselectivities of the three reactions depicted in Scheme 1. Unexpectedly, the calculations reveal that catalysts 2 do not use either of the traditionally drawn activation modes (Scheme 1). Instead, the active catalyst is a less-stable tautomer of 2 containing a P(NTf)OH group. This discovery has significant implications for the understanding and development of BINOL N-triflylphosphoramide-catalyzed reactions.

combination of interactions that controls the selectivity in any given example can only be understood through TS modeling. Asymmetric organocatalysis involving BINOL phosphoramides 2 has recently begun to attract the attention of theoretical chemists. Goodman and Grayson11 studied phosphoramide-catalyzed asymmetric propargylations of aldehydes by allenyl boronates. They modeled the TS as a hydrogen-bonded complex containing an NH···O hydrogen bond between the catalyst and one of the boronate oxygens. The differing levels of stereoselectivity provided by Ntriflylphosphoramide versus phosphoric acid catalysts in the propargylation reactions were explained by analyzing how the CF3 group altered the shape of the binding pocket. Houk and Rueping12 examined N-triflylphosphoramide-catalyzed cycloadditions of hydrazones and alkenes. They used theoretical calculations to explore the catalyst−substrate binding modes and to determine whether catalysis involved hydrogen bonding from the acidic NH group to the substrate or proton transfer. In this paper we use theoretical calculations to investigate how N-triflylphosphoramides 2 activate divinyl ketones and control enantioselectivity, in three distinct Nazarov cyclizations (Scheme 1). The first of our three case studies focuses on the cyclization of dihydropyranyl vinyl ketone 3 (reaction A). This reaction was reported by Rueping in his original publication, which introduced 1 and 2 as Nazarov cyclization catalysts.5,13 Both 1 and 2 catalyzed the cyclization of 3, giving mixtures of cis- and trans-cyclopentenones 4 and 5. The electrocyclization installs the chiral center at C4, favoring C4-S. Enolization of the product then gives a mixture of C5 epimers (4 and 5). Phosphoramides 2 gave superior enantioselectivities in comparison to 1, with enantiomeric excesses (ees) as high as 95%. Our second case study focuses on the Nazarov cyclization of divinyl ketone 6 (reaction B). This reaction was employed by Flynn et al. in a concise formal synthesis of the anticancer natural product (+)-roseophilin.6 Nazarov cyclization of 6, catalyzed by 2b or 2c, followed by hydrolytic trapping of the intermediate oxonium ion gave (R,R)-7 in up to 82% ee. The torquoselectivity of ring closure of 6 was opposite to that for Rueping’s substrate 3 with the same enantiomer of catalyst. That is, the termini of the divinyl ketone rotate clockwise

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THEORETICAL CALCULATIONS Density functional theory calculations were performed with Gaussian 09.16 To explore the mechanism of divinyl ketone activation by phosphoramides 2, we performed computations on a model system consisting of phosphoramide 10 and 1,4pentadien-3-one. The computations on this system employed M06-2X/6-311+G(d,p)17 and modeled the solvent (chloroform) with the SMD 18 continuum model. Vibrational 3467


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RESULTS AND DISCUSSION Activation Mechanism. There are multiple ways in which an N-triflylphosphoramide can interact with a divinyl ketone. Potentially, the phosphoramide can adopt three different tautomeric forms and each tautomer could form either a hydrogen-bonded complex or a chiral contact ion pair with the divinyl ketone. In order to identify the catalyst−substrate binding modes relevant to the Nazarov cyclization, we examined a model system consisting of N-triflylphosphoramide 10 and 1,4-pentadien-3-one (Figure 2). Phosphoramide 10 has

frequency calculations were used to characterize each stationary point as a minimum or first-order saddle point and to calculate thermochemical data. The reactant and product to which each TS was directly connected were determined by means of intrinsic reaction coordinate (IRC)19 calculations. The procedure for locating TSs for the asymmetric Nazarov cyclizations of 3, 6, and 8 catalyzed by BINOL phosphoramides 2 commenced with the computation of TSs for the corresponding model proton-catalyzed cyclizations. Conformer searching of each proton-catalyzed TS was performed with B3LYP/6-31G(d).20 Those TSs lying within 3 kcal/mol of the most stable TS were then used to build transition states for the phosphoramide-catalyzed reaction. The relevant catalyst was combined with the TS such that the acidic proton of 2 took the place of the catalytic H+ from the proton-catalyzed TS. The accessible conformations of each catalyst−TS complex were then explored by means of a conformational search in MacroModel 10.6.21 The conformer search employed the MCMM algorithm in conjunction with the OPLS_2005 force field,22 in vacuum, with the atoms of the divinyl ketone held fixed. Catalyst−TS complexes identified as lying within 2.4 kcal/ mol (10 kJ/mol) of the global minimum from each conformer search were then fully optimized as transition states in Gaussian 09 using a two-layer ONIOM23 protocol. The inner (highlevel) layer consisted of the entire divinyl ketone together with the NH, SO2CF3, and PO3 groups of the catalyst and was treated with B3LYP/6-31G(d). The outer (low-level) layer consisted of the binaphthyl unit and the 3- and 3′-aryl groups of the catalyst and was treated with UFF.24 Goodman has employed a similar ONIOM(B3LYP/6-31G(d):UFF) protocol to model a variety of BINOL phosphoric acid catalyzed reactions.8b,c,9a,b The catalyst was modeled as either the P( O)NHTf or P(NTf)OH tautomer, and hydrogen-bonding and ion-pairing activation modes were computed for each case. Harmonic vibrational frequency calculations on the optimized TSs confirmed the presence of a single imaginary frequency corresponding to C−C bond formation. A single-point energy calculation was then performed for each TS at the M06-2X/6311+G(d,p) level of theory in the solution phase (chloroform) as modeled using the SMD implicit solvent model. Gibbs free energies in solution were calculated by adding the thermochemical corrections derived from the ONIOM frequency calculations to the M06-2X solution-phase potential energies and are reported at a standard state of 298.15 K and 1 mol/L. For comparison with the M06-2X energies, calculations were also performed with several other density functionals, including B3LYP-D325 and B97-D3.25,26 Details of the computations performed with these other methods are reported in the Supporting Information. Briefly, computations with B3LYP-D3 and B97-D3 were found not to provide as close an agreement with the experimentally observed stereoselectivities as was obtained with M06-2X. All three functionals predicted the correct major enantiomer for reaction B, but some departures from experiment with respect to the major enantiomer were found for reactions A and C. These differences were larger for B97-D3 than for B3LYP-D3. All three functionals, however, were in general agreement with respect to the identity of the active catalyst, predicting that transition states involving the P(NTf)OH tautomer of the phosphoramide were usually lower in energy than those involving the P(O)NHTf tautomer (vide infra). Molecular structures were drawn with CYLview.27

Figure 2. Computed energies of (a) the tautomers of model Ntriflylphosphoramide 10, (b) a variety of catalyst−substrate complexes formed from 10 and 1,4-pentadien-3-one, and (c) transition states for the Nazarov cyclization of 1,4-pentadien-3-one catalyzed by 10. The zero of energy is taken as the separated 10a and divinyl ketone. ΔH and ΔG values (kcal/mol) and distances (Å) were computed with M06-2X/6-311+G(d,p)-SMD(CHCl3).

the three tautomers 10a−c (Figure 2a). Computations with M06-2X/6-311+G(d,p) in SMD continuum solvent (chloroform) predict that the most stable tautomer is 10a, which has a P(O)NHTf group. Tautomer 10b, containing a P( NTf)OH group, is 3.9 kcal/mol higher in energy than 10a (ΔG), while tautomer 10c, containing a S(NR)OH group, is 16.4 kcal/mol higher in energy. The X-ray crystal structure of an H8-BINOL phosphoramide, reported by Rueping,28 showed 3468


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ACS Catalysis Scheme 2. Low-Energy Dimerization-Based Mechanism for the Tautomerization Reaction 10a → 10ba

a

Distances are given in Å and ΔH and ΔG values in kcal/mol.

pentadienyl cation characterand not merely polarization to a δ+ stateto be activated to undergo electrocyclization. Unexpectedly, the TS for the electrocyclization catalyzed by phosphoramide tautomer 10a (TS1) is 3.1 kcal/mol higher in energy than that for the reaction catalyzed by the less-stable tautomer 10b (TS2). Both barriers are calculated with respect to the divinyl ketone plus 10a. This result challenges the traditional understanding of phosphoramide-catalyzed Nazarov cyclizations. Quite reasonably, previous studies1d,e,3−7 have represented the active catalyst as the P(O)NHTf tautomer, which is the major tautomer present at equilibrium. However, TS1 and TS2 indicate that the activation via OH···OC hydrogen bonding or ion pairing with the P(NTf)OH tautomer cannot be discounted and is actually preferred. This finding reflects the higher acidity of the P(NTf)OH group of 10b in comparison to the P(O)NHTf group of 10a. Proton transfer from 10b is easier because it requires less stretching of the O−H bond (rO−H = 1.53 Å in TS2 vs rN−H = 1.65 Å in TS1).29,30 Since the lower-energy transition state contains the higherenergy catalyst tautomer, there is the question of whether the tautomerization (10a → 10b) would be fast enough to allow electrocyclization to proceed predominantly through TS2 under the conditions of the reaction. Tautomerization via a four-centered intramolecular proton transfer is calculated to have a high barrier (ΔG⧧ = 38.1 kcal/mol, see the Supporting Information) and is unlikely to occur under the experimental conditions. A more likely, low-energy pathway for the tautomerization is shown in Scheme 2. This pathway commences with two molecules of 10a combining to form dimer 12a. Double proton transfer through an eight-membered transition state (TS3) leads to the product dimer 12b, which then dissociates to give two molecules of 10b. The proton transfer is facile (TS3, ΔG⧧ = 3.5 kcal/mol relative to dimer 12a and −3.0 kcal/mol relative to phosphoramide 10a) and the overall ΔG value of the reaction (2 × 10a → 2 × 10b) is 7.7 kcal/mol. Provided that the dimer−monomer equilibria are also facile, the equilibration of 10a and 10b would be much faster than electrocyclization, which has ΔG⧧ ≥ 22.6 kcal/mol. Thus, a Curtin−Hammett scenario would be established and the electrocyclization would proceed primarily via TS2. That is, 10b is indeed the active catalyst.31 For BINOL N-triflylphosphoramides 2, the P(O)NHTf group is located deep within a pocket lined by the binaphthyl and 3,3′-Ar groups. The reported X-ray structure of an H8BINOL phosphoramide28 showed that these groups do not inhibit the formation of a dimer akin to 12a. It is therefore likely that BINOL N-triflylphosphoramides 2 undergo tautomerization through a dimerization-based mechanism in solution. Furthermore, the dimer−monomer equilibria must be rapid, because if they were not, the phosphoramide would become trapped as the dimer (cf. ΔG = −6.5 kcal/mol for 2 ×

that the phosphoramide existed as the P(O)NHTf tautomer in the solid state, where it formed a hydrogen-bonded dimer. Six possible catalyst−substrate binding modes for 10 and the model divinyl ketone are shown in Figure 2b. In these complexes, the divinyl ketone was modeled in the U-shaped (strans/s-trans) conformation, which is the conformation closest in geometry to that of the transition state for electrocyclization. The three catalyst−substrate complexes 11a−c are derived from phosphoramide tautomers 10a−c, respectively, and are bound by a hydrogen bond between the acidic proton of 10 and the carbonyl oxygen of the divinyl ketone. Transfer of the acidic proton to the carbonyl oxygen in these three complexes leads to ion pairs 11d−f. Exploration of the potential energy surface of 11 located the four complexes 11a,b,e,f. Complexes 11c,d could not be located and instead underwent proton transfer upon attempted geometry optimization. Complex 11e is formally an ion pair, but the ionic interaction is very short, and the pair of complexes 11b/11e together constitute an example of low-barrier hydrogen bonding. Complexes 11a,b,e are the most stable and have similar energies (ΔG = −0.3 to 0.2 kcal/mol relative to the divinyl ketone plus phosphoramide). The enthalpies of formation of complexes 11a,b,e are favorable by about 8−10 kcal/mol, but the entropic penalty leads to ΔG values which are close to 0. It is likely that a mixture of these three complexes would exist in equilibrium with the divinyl ketone and phosphoramide. Complex 11f is high in energy (8.0 kcal/mol) and is unlikely to be present in significant quantities. Even though the most stable tautomer of the catalyst (10a) is favored by ≥3.9 kcal/mol relative to the other two, it does not form the most stable complexes with the divinyl ketone. The complexes involving the P(NTf)OH tautomer 10b are slightly (0.2−0.5 kcal/mol) more stable than those involving 10a. A related observation was reported by Houk and Rueping in their study of the binding of a hydrazonium cation (R2C NH−NHR)+ to an N-triflylphosphoramide anion.11 The cation formed several ion pairs with the phosphoramide anion, in which the cation interacted with the PO, SO, and/or P N groups. These ion pairs had energies similar to that of a hydrogen-bonded complex of the neutral species. Transition states for the Nazarov cyclization of 1,4pentadien-3-one catalyzed by the two low-energy tautomers of 10 are shown in Figure 2c. Intrinsic reaction coordinate calculations indicated that the acidic proton is transferred from the catalyst to the substrate during the electrocyclization. That is, the electrocyclization reaction commences with the hydrogen-bonded complex of the divinyl ketone with the neutral phosphoramide and leads to an ion pair of the hydroxyallyl cation and phosphoramide anion. By the stage the TS is reached, proton transfer is almost complete (rOH = 1.01 Å). Transition states containing a hydrogen-bonded activation mode could not be located for this reaction. This suggests that it is necessary for the divinyl ketone to assume complete 3469


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Figure 3. Transition states for the Nazarov cyclization of dihydropyranyl vinyl ketone 13 (highlighted in light blue) catalyzed by 2c, leading to (S)14 or (R)-14. Two views of each TS are shown. Also shown is the lowest-energy TS for the H+-catalyzed Nazarov cyclization of 13 (TS13). Distances are given in Å and energies in kcal/mol.

10a → 12a), thereby preventing the acidic proton from being available to activate the divinyl ketone. Reaction A. Our first case study of BINOL phosphoramide controlled enantioselectivity focuses on the Nazarov cyclization of Rueping’s5 dihydropyranyl vinyl ketone 3 (Scheme 1, reaction A). We modeled Rueping’s dihydropyranyl vinyl ketone as the dimethyl derivative 13 (Figure 3). Our study commenced with computations on the transition state for the proton-catalyzed cyclization of 13. At the B3LYP/6-31G(d) level of theory, the lowest-energy TS adopts the conformation shown in Figure 3 (TS13). The OH proton points toward the dihydropyranyl oxygen, where it can engage in a stabilizing electrostatic interaction. This OH−O interaction provides about 3 kcal/mol of stabilization to the transition state, in comparison to other TS conformers where the interaction is absent. Transition-state modeling of the corresponding phosphoramide-catalyzed electrocyclization was performed using the catalyst 2c. The 3- and 3′-Ar substituents in 2c are 9anthracenyl groups. Catalyst 2c was not reported in Rueping’s original publication, but the reactions studied therein with either 2a (Ar = 1-naphthyl) or 2b (Ar = 9-phenanthryl) displayed consistently high selectivities across a range of substrates, suggesting that the nature of the 3,3′-Ar groups has only a small effect on the enantioselectivity of this cyclization. We chose to use 2c (with symmetrical Ar groups) in order to reduce the conformational space needing to be sampled. Geometry optimizations of the transition states were performed

with an ONIOM protocol (B3LYP/6-31G(d):UFF) similar to that used by Goodman for many BINOL phosphoric acid catalyzed reactions.8b,c,9a,b After optimization with ONIOM, single-point energies were calculated with M06-2X/6-311+G(d,p) in SMD chloroform in order to provide a more complete description of quantum mechanical dispersion and solvent effects. On the basis of the results of our model study (Figure 2), we computed transition states derived from both the P( O)NHTf and P(NTf)OH tautomers of 2c and we explored both hydrogen-bonding and ion-pairing activation modes. An extensive conformational search was performed, involving a total of 106 ONIOM optimizations. Of these, only 4 TS conformers were found to contribute significantly to the reaction (≥1% of the population in a Boltzmann distribution). Figure 3 shows the lowest-energy TSs for clockwise and anticlockwise conrotation. The calculations correctly predict that anticlockwise conrotation (TS13S) is favored relative to clockwise conrotation (TS13R). Experimentally, the Nazarov cyclizations of 3 with catalysts 2a,b favored anticlockwise conrotation, giving the C4-S products in 89−95% ee.5 Theory predicts that the energy difference between TS13S and TS13R (ΔΔG⧧) is 1.4 kcal/mol. This value corresponds to a predicted enantiomeric excess of 87% at the experimental temperature of 0 °C. A Boltzmann analysis of all calculated TSs predicts an ee of 84%. These values are in good agreement with the reported enantioselectivities. For comparison, the geometries of selected TSs were reoptimized with a fully quantum mechanical treatment using 3470


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Scheme 3. Analysis of the Enantioselectivity of Nazarov Cyclization of 13 Catalyzed by 2c Using the Distortion/Interaction Model and Computations on Structural Fragments of the Transition Statesa

a

Energies are given in kcal/mol.

B3LYP-D3/6-31G(d), using Grimme’s D3 correction25 to capture intra- and intermolecular dispersive interactions. Structural differences between the DFT-optimized and ONIOM-optimized TSs were mostly small, although the DFT-optimized TSs displayed more advanced proton transfer (see the Supporting Information). We used the distortion/interaction model8,32 to analyze the origins of enantioselectivity. In this model, the activation barrier (ΔE⧧) of the Nazarov cyclization is the sum of three components: (i) the energy required to distort the divinyl ketone from its ground-state geometry to its transition-state geometry (ΔEdist(DVK)), (ii) the energy required to distort the catalyst from ground-state to transition-state geometry (ΔEdist(Cat)), and (iii) the interaction energy between the distorted substrate and catalyst in the TS (ΔEint). The results of the distortion/interaction analysis are shown in Scheme 3. The first structure in Scheme 3 shows how the distortion and interaction energies in the disfavored TS13R differ with respect to those in the favored TS13S. The remainder of Scheme 3 shows a series of structural fragments of the TSs, whose distortion energies were computed to help analyze the TS energies. The distortion/interaction analysis is based on M062X/6-311+G(d,p)-SMD(CHCl3) single-point energy calculations. The structural fragments 13, 2c′, and A−E were obtained by deleting certain portions of the TSs and filling any free valences with hydrogen atoms.

The total difference in energy between TS13S and TS13R (ΔΔE⧧) is 1.3 kcal/mol. The difference in energy between the divinyl ketone fragments (13′) in the two TSs is small: 0.8 kcal/mol. The OH proton is syn to the dihydropyranyl oxygen in both TSs, similar to the case for TS13. In contrast, the distorted catalysts (2c′) differ by 6.7 kcal/mol, with the catalyst fragment from TS13R being more distorted than that from TS13S. Further computations on substructures A and B of the catalyst allow the location of this distortion to be pinpointed more precisely. Thus, fragments A, which represent the aromatic moiety of the catalyst in the two TSs, differ by only 0.5 kcal/mol, whereas fragments B, representing the Ntriflylphosphoramide moiety, differ by a larger 4.8 kcal/mol, with TS13R being more distorted. This distortion can be traced to the P−O−H bond angle. In order to bind the substrate, the P−O−H angle of TS13R has widened to 136° (Figure 3), whereas TS13S has a P−O−H angle of 120°, closer to ideal. This difference suggests that, in the R transition state, the cyclizing divinyl ketone is a less ideal fit for the binding pocket of the catalyst. In order to activate the divinyl ketone to cyclize to the R product within the binding pocket, the POH group has to deviate significantly from its ideal angle. Considered together, the distortions of the catalyst and substrate in the disfavored TS13R amount to a total ΔEdist that is 5.9 kcal/mol larger than that in the favored TS13S (ΔΔEdist(total)). However, the total energy difference between the TSs (ΔΔE⧧) is only 1.3 kcal/mol. This indicates that in 3471


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Figure 4. Transition states for the Nazarov cyclization of divinyl ketone 15 (highlighted in pink) catalyzed by 2c, leading to (R,R)-16 or (S,S)-16. Two views of each TS are shown. Also shown is the lowest-energy TS for the H+-catalyzed Nazarov cyclization of 15 (TS15). The distortion/ interaction analysis in the center of the figure shows how the catalyst distortion energy, substrate distortion energy, and TS interaction energy in TS15S differ from those TS15R. Distances are given in Å and energies in kcal/mol.

where the N-triflylphosphoramide moiety of the catalyst has been removed, indicate that the divinyl ketone interacts more strongly with the N-triflylphosphoramide moiety in the favored TS13S than in TS13R. Short CH−F (2.34 Å) and CH−O (2.79 Å) interactions and a stabilizing electrostatic interaction between the CF3 group and the cyclizing pentadienyl cation (3.22 Å) are found in TS13S. Consistent with the results reported above for the model system (Figure 2), all of the low-energy TSs for the cyclization of 13 involve the P(NTf)OH tautomer of catalyst 2c. Transition states containing the P(O)NHTf tautomer are at least 4.2 kcal/mol higher in energy than those discussed here. The energy difference is smaller when the TSs are reoptimized with B3LYP-D3 (2.2 kcal/mol), but the OH tautomer is still more active. Indeed, a correct prediction of the stereoselectivity of this reaction requires that the OH tautomer be included in the model. A Boltzmann analysis based on only the TSs derived from the P(O)NHTf catalyst predicts that the cyclization would favor the R product with 40% ee, opposite from the experimental result. Reaction B. Our second case study examines the Nazarov cyclization of divinyl ketone 6, employed by Flynn et al.6 in their roseophilin synthesis (Scheme 1, reaction B). Divinyl ketone 6 was modeled as 15 (Figure 4). First, transition-state modeling of the proton-catalyzed cyclization of 15 revealed an interesting stabilizing feature, not previously observed in the

TS13R there are stronger stabilizing interactions between the substrate and catalyst, which reduce the difference between the energies of the TSs by 4.6 kcal/mol (ΔΔEint). Insights into the specific interactions involved are provided by the calculations on the lower set of fragments in Scheme 3.33 When the lower anthracenyl group of the catalyst is removed (fragment C), the remaining portion of TS13R is 3.5 kcal/mol higher in energy than the corresponding fragment of TS13S. This indicates that the lower anthracenyl group interacts more strongly with the divinyl ketone in TS13R than in TS13S. Figure 3 (red arrows) indicates that in TS13R there is a strong cationic CH−π interaction (2.92 Å) between the proton at C3 of the pentadienyl cation and the central aromatic ring of the lower anthracenyl group, which stabilizes the TS. The closest similar interaction in TS13S is longer (3.01 Å) and involves a less acidic proton (a CH2 proton from the dihydropyranyl ring), consequently providing less stabilization. When the upper anthracenyl group of the catalyst is removed (D), an opposite result is obtained: the remaining portion of TS13R is 0.7 kcal/mol lower in energy than that of TS13S. This indicates that the upper anthracenyl group interacts more strongly with the divinyl ketone in the favored TS13S. This can be traced to a weak CH−π interaction (3.67 Å) between the divinyl ketone and upper anthracenyl group in TS13S (in comparison, in TS13R the substrate lies ≥4 Å from this anthracenyl group). Finally, computations on structure E, 3472


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Figure 5. Transition states for Nazarov cyclization of divinyl ketone 8 (highlighted in gold) catalyzed by 2d, leading to (S,S)-17 or (R,R)-17. Two views of each TS are shown. Also shown is the lowest-energy TS for the H+-catalyzed Nazarov cyclization of 8 (TS8). The distortion/interaction analysis in the center of the figure shows how the catalyst distortion energy, substrate distortion energy, and TS interaction energy in TS8R differ from those in TS8S. Distances are given in Å and energies in kcal/mol.

Nazarov cyclization.34 In the most stable TS (TS15), the ketone carbonyl group is located above the cyclizing pentadienyl cation, 3.06 Å from the center of the ring and 2.61 Å from the proton on the terminus of the pentadienyl cation. The resulting cation−lone pair and CH−O interactions contribute about 3 kcal/mol of stabilization to the TS. To model the cyclization of 15 catalyzed by BINOL Ntriflylphosphoramide 2c, ONIOM optimizations were performed on a total of 127 transition state conformers. Of these, 3 were found to contribute significantly to the reaction. The lowest-energy TS for each direction of conrotation is shown in Figure 4 (TS15R and TS15S). Experimentally, in the cyclization of 6 catalyzed by 2c, the R,R product is preferred, in 72% ee (room temperature). The calculations correctly match this outcome, predicting that TS15R is 1.0 kcal/mol lower in energy than TS15S. The ee predicted on the basis of this value of ΔΔG⧧ is 71%, and the ΔΔG⧧ value on the basis of

a Boltzmann analysis of all TSs is also 71%, almost identical with the value obtained experimentally for 6. A distortion/interaction analysis of the two TSs is shown in the center of Figure 4. The energy difference (ΔΔE⧧) between the TSs is slightly negative (−0.4 kcal/mol), i.e. opposite in sign to the value of ΔΔG⧧, indicating that entropic effects are important for the calculated enantioselectivity of this reaction. Nevertheless, the distortion/interaction analysis reveals two significant contributions to the TS energies. First, the catalyst is much more distorted in the disfavored TS15S than in favored TS15R (ΔΔEdist(Cat) = 37.1 kcal/mol), but this penalty is offset by a much stronger catalyst−substrate interaction (ΔΔEint = −42.5 kcal/mol). These large values can be traced to the different degrees of proton transfer in the two TSs. In TS15R, the breaking O−H bond of the catalyst has stretched to 1.66 Å, in comparison with 1.36 Å in TS15S, explaining the much higher distortion energy in TS15R. The large difference in interaction energies reflects the strong ion pairing interaction 3473


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divinyl ketone CO2Ph group in TS8R (2.74 Å). Experimentally, the tBu groups of the catalyst were found to be important for obtaining high levels of enantioselectivity (Scheme 1). This appears to be mainly due to the steric bulk of the tBu groups creating a tighter binding pocket rather than engaging in any specific interactions that would stabilize the TS leading to the major product. In this reaction, transition states derived from the P(O)NHTf tautomer of the catalyst lie ≥15 kcal/mol higher in energy than the P(NTf)OH transition states and are predicted not to contribute significantly to the reaction. Considered together, a multitude of covalent and noncovalent interactions are present in the transition states of BINOL N-triflylphosphoramide catalyzed Nazarov cyclizations. Intermolecular CH−π, cation−π, CH−O, CH−F, and cation− lone pair interactions play a role in the three examples discussed here. In these three cases, the degree of proton transfer from the catalyst to the substrate is an important stereodiscriminating factor, which depends on how well the substrate fits into the binding pocket and is manifested in both the catalyst distortion energy and the interaction energy. We have also observed that, in the favored TS for each reaction, the divinyl ketone has a conformation similar to that of the TS for the corresponding proton-catalyzed cyclization. In the disfavored TS, the divinyl ketone sometimes departs from this conformation and loses the benefit of intramolecular stabilizing interactions such as the ketone−pentadienyl cation interaction found in reaction B.

in TS15S in comparison to the weaker hydrogen bond found in TS15R. Second, the divinyl ketone distortion in the disfavored TS15S is 5.0 kcal/mol larger than that in the favored TS15R. In TS15R, the substrate has a conformation similar to that of the proton-catalyzed TS (TS15), with the ketone oxygen positioned near the cyclizing pentadienyl cation, where it can engage in stabilizing CH−O and cation−lone pair interactions. In TS15S, the side chain has a different conformation which places the ketone oxygen farther away from the CH proton (3.42 Å in comparison to 2.67 Å; see red arrows in Figure 4). Furthermore, TS15R also benefits from a stabilizing CH−π interaction between the CH proton of the pentadienyl cation and the lower anthracenyl group (2.68 Å). In this reaction, the preferred TSs are derived from the P( NTf)OH tautomer of the catalyst. The P(O)NHTf tautomer is predicted to play a small role, most notably in the formation of the major product. Thus, while TS15R leads to 77% of the total product according to a Boltzmann analysis, a further 7% of the product comes from an ion-paired R-configured NH transition state which lies 1.4 kcal/mol above TS15R (see the Supporting Information). Reaction C. Our final case study involves the Nazarov cyclization of 8 (Scheme 1, reaction C), developed by Tius for the construction of vicinal quaternary stereocenters.7 The substrate was modeled in its entirety without truncation. The preferred conformation of the TS for the H+-catalyzed cyclization of 8 is shown in Figure 5 (TS8). Experimentally, the product (9) is isolated after loss of the CHPh2+ cation. An IRC calculation indicates that the loss of CHPh2+ occurs in a separate step, after the cyclization. Modeling of the transition states for the 2d-catalyzed Nazarov cyclization of 8 considered a total of 90 TS conformers. Three conformers were found to contribute >1% to the total population in a Boltzmann distribution. The lowestenergy TSs for each conrotatory mode are shown in Figure 5. The calculations predict that clockwise conrotation leading to the S,S product is favored by 1.2 kcal/mol. This value corresponds to an er of 89:11, while a Boltzmann analysis of all TSs predicts an er of 84:16. These values are slightly lower than the experimental er (98:2), but they correctly predict the configuration of the major product (and have been computed without including any special treatment of the contribution of low-frequency vibrational modes to the vibrational entropy). Inclusion of the P(NTf)OH tautomer in the model is essential for the correct prediction of stereoselectivity. A Boltzmann analysis based solely on the TSs derived from the P(O)NHTf tautomer predicts almost 100% selectivity in favor of the R,R product, opposite from experiment.35 A distortion/interaction analysis of the two TSs (Figure 5, center) indicates that, similar to reaction B (Figure 4), the ΔE⧧ value for the favored TS in reaction C is higher than that for the disfavored TS (ΔΔE⧧ = −2.3 kcal/mol); that is, entropic effects are important for the observed enantioselectivity. The favored TS8S has a larger catalyst distortion energy than the disfavored TS8R (ΔΔEdist(Cat) = −17.5 kcal/mol) and a more stabilizing interaction energy (ΔΔEint = 14.9 kcal/mol), reflecting the more advanced proton transfer from catalyst to substrate in TS8S. The most important noncovalent interactions between the catalyst and the substrate are a CH−π interaction between a divinyl ketone Me group and the lower tBuC6H4 group in TS8S (3.18 Å, see red arrow in Figure 5) and a CH−π interaction between the lower tBuC6H4 group of the catalyst and the

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CONCLUSIONS We have used theoretical calculations to explore the mechanism and enantioselectivities of BINOL N-triflylphosphoramidecatalyzed Nazarov cyclizations. The calculations have revealed the unexpected discovery that it is the P(NTf)OH tautomer of the phosphoramide, and not the more stable P(O)NHTf tautomer, that is the most active catalyst in these reactions. Interconversion between tautomers is calculated to be fast, relative to electrocyclization. This discovery challenges the previously accepted models for carbonyl activation by Ntriflylphosphoramides, which proposed that the P(O)NHTf catalyst activates the substrate through either NH···OC hydrogen bonding or proton transfer.1d,e,3−7 Houk and Rueping, in their recent study of phosphoramide-catalyzed hydrazone cycloadditions,12 showed that the cationic substrate interacted with the catalyst PO and SO groups in the TS, but not with the nitrogen atom. In that case, however, proton transfer from the catalyst preceded cycloaddition in a separate chemical step. This meant that the stereoselectivity did not depend on which tautomer of the catalyst protonated the substrate. The Nazarov cyclizations considered here represent a fundamentally different scenario, where proton transfer occurs concomitantly with electrocyclization in the rate- and stereoselectivity-determining step. In this scenario, the different tautomers of the phosphoramide react via different mechanistic pathways. It is likely that P(NTf)OH tautomers of BINOL N-triflylphosphoramides are also important even in reactions that only involve hydrogen bonding, not proton transfer from the phosphoramide to the substrate. These discoveries, which expose the importance of P(NTf)OH tautomerism, will inform the future understanding, modeling, and development of N-triflylphosphoramide-catalyzed reactions. 3474


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S.; Gridnev, I. D.; Terada, M. Chem. Sci. 2014, 5, 3515−3523. (o) Calleja, J.; González-Pérez, A. B.; de Lera, Á . R.; Á lvarez, R.; Fañanás, F. J.; Rodríguez, F. Chem. Sci. 2014, 5, 996−1007. (9) For reviews, see: (a) Simón, L.; Goodman, J. M. J. Org. Chem. 2011, 76, 1775−1788. (b) Reid, J. P.; Simón, L.; Goodman, J. M. Acc. Chem. Res. 2016, 49, 1029−1041. (c) Sunoj, R. B. Acc. Chem. Res. 2016, 49, 1019−1028. (10) For reviews of noncovalent interactions in transition states and their roles in stereoselectivity, see: (a) Krenske, E. H.; Houk, K. N. Acc. Chem. Res. 2013, 46, 979−989. (b) Wheeler, S. E.; Seguin, T. J.; Guan, Y.; Doney, A. C. Acc. Chem. Res. 2016, 49, 1061−1069. (c) Walden, D. M.; Ogba, O. M.; Johnston, R. C.; Cheong, P. H.-Y. Acc. Chem. Res. 2016, 49, 1279−1291. (11) Grayson, M. N.; Goodman, J. M. J. Am. Chem. Soc. 2013, 135, 6142−6148. (12) Hong, X.; Başpınar Kücu̧ ̈k, H.; Sudan Maji, M.; Yang, Y.-F.; Rueping, M.; Houk, K. N. J. Am. Chem. Soc. 2014, 136, 13769−13780. (13) For further applications of these phosphoramide-catalyzed Nazarov cyclizations, see: (a) Rueping, M.; Ieawsuwan, W. Adv. Synth. Catal. 2009, 351, 78−84. (b) Rueping, M.; Ieawsuwan, W. Chem. Commun. 2011, 47, 11450−11452. (c) Raja, S.; Ieawsuwan, W.; Korotkov, V.; Rueping, M. Chem. - Asian J. 2012, 7, 2361−2366. (14) For theoretical studies of other catalytic asymmetric Nazarov cyclizations, see: (a) Kitamura, K.; Shimada, N.; Stewart, C.; Atesin, A. C.; Ateşin, T. A.; Tius, M. A. Angew. Chem., Int. Ed. 2015, 54, 6288− 6291. (b) Asari, A. H.; Lam, Y.-h.; Tius, M. A.; Houk, K. N. J. Am. Chem. Soc. 2015, 137, 13191−13199. (c) Raja, S.; Nakajima, M.; Rueping, M. Angew. Chem., Int. Ed. 2015, 54, 2762−2765. (15) Yang, B.-M.; Cai, P.-J.; Tu, Y.-Q.; Yu, Z.-X.; Chen, Z.-M.; Wang, S.-H.; Wang, S.-H.; Zhang, F.-M. J. Am. Chem. Soc. 2015, 137, 8344− 8347. (16) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö .; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Revision E.01; Gaussian, Inc., Wallingford, CT, 2013. (17) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215−241. (18) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B 2009, 113, 6378−6396. (19) (a) Gonzalez, C.; Schlegel, H. B. J. Chem. Phys. 1989, 90, 2154− 2161. (b) Gonzalez, C.; Schlegel, H. B. J. Phys. Chem. 1990, 94, 5523− 5527. (20) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B: Condens. Matter Mater. Phys. 1988, 37, 785−789. (b) Becke, A. D. J. Chem. Phys. 1993, 98, 1372−1377. (c) Becke, A. D. J. Chem. Phys. 1993, 98, 5648−5652. (d) Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J. J. Phys. Chem. 1994, 98, 11623−11627. (21) (a) MacroModel, version 10.6; Schrödinger, LLC, New York, 2014. (b) Maestro, version 9.9; Schrödinger, LLC, New York, 2014. (22) Banks, J. L.; Beard, H. S.; Cao, Y.; Cho, A. E.; Damm, W.; Farid, R.; Felts, A. K.; Halgren, T. A.; Mainz, D. T.; Maple, J. R.; Murphy, R.; Philipp, D. M.; Repasky, M. P.; Zhang, L. Y.; Berne, B. J.; Friesner, R. A.; Gallicchio, E.; Levy, R. M. J. Comput. Chem. 2005, 26, 1752−1780. (23) (a) Dapprich, S.; Komáromi, I.; Byun, K. S.; Morokuma, K.; Frisch, M. J. J. Mol. Struct.: THEOCHEM 1999, 461−462, 1−21. (b) Vreven, T.; Byun, K. S.; Komáromi, I.; Dapprich, S.; Montgomery, J. A., Jr.; Morokuma, K.; Frisch, M. J. J. Chem. Theory Comput. 2006, 2, 815−826.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.7b00292. Computational data including calculations with different DFT methods (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail for E.H.K.: [email protected]. ORCID

Camilla Mia Tram: 0000-0003-4503-9155 Elizabeth H. Krenske: 0000-0003-1911-0501 Present Address ∥

University of Copenhagen, Universitetsparken 5, DK-2100 Copenhagen Ø, Denmark. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the Australian Research Council for financial support (FT120100632 to E.H.K. and DP150103131 to B.L.F. and E.H.K.) and the Australian National Computational Infrastructure National Facility and University of Queensland Research Computing Centre for computer time.

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ACS Catalysis (24) Rappé, A. K.; Casewit, C. J.; Colwell, K. S.; Goddard, W. A., III; Skiff, W. M. J. Am. Chem. Soc. 1992, 114, 10024−10035. (25) (a) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. J. Chem. Phys. 2010, 132, 154104. (b) Grimme, S.; Ehrlich, S.; Goerigk, L. J. Comput. Chem. 2011, 32, 1456−1465. (26) Grimme, S. J. Comput. Chem. 2006, 27, 1787−1799. (27) Legault, C. Y. CYLview, 1.0b; Université de Sherbrooke, Sherbrooke, Canada, 2009; http://www.cylview.org. (28) Rueping, M.; Nachtsheim, B. J.; Koenigs, R. M.; Ieawsuwan, W. Chem. - Eur. J. 2010, 16, 13116−13126. (29) This idea is supported by comparing the energies of the distorted catalysts in the electrocyclization TSs to the energies of the closest fully relaxed conformers of 10a,b. It takes 3.0 kcal/mol more energy (ΔE) to distort 10a into the geometry found in TS1 than it does to distort 10b into the geometry found in TS2. This is almost the same as the total difference in energy between the two transition states (ΔΔG⧧ = 3.1 kcal/mol). (30) Transition states TS1 and TS2 were also computed with B3LYP-D3 and B97-D3. These two functionals predicted that TS2 is 1.5−2.0 kcal/mol lower in energy than TS1 (see the Supporting Information). (31) A transition state for the Nazarov cyclization catalyzed by the S(NR)OH tautomer 10c is computed to lie 3.1 kcal/mol higher in energy than the favored TS2 (see the Supporting Information). (32) (a) Ess, D. H.; Houk, K. N. J. Am. Chem. Soc. 2007, 129, 10646−10647. (b) Ess, D. H.; Houk, K. N. J. Am. Chem. Soc. 2008, 130, 10187−10198. (33) For a similar fragment-based analysis of the selectivity of a BINOL phosphoric acid catalyzed reaction, see ref 8f. (34) Magnus et al. reported an AcBr-activated Nazarov cyclization where the electrocyclization was proposed to be accompanied by cyclization of the C1-OAc group onto C5 to form a 5,5-bicyclic structure. In that case, however, the OAc group was directly bound to the pentadienyl cation and would be unlikely to be able to achieve the geometry needed to engage in stabilizing intramolecular CH−O and cation−lone pair interactions. See: Magnus, P.; Freund, W. A.; Moorhead, E. J.; Rainey, T. J. Am. Chem. Soc. 2012, 134, 6140−6142. (35) In comparison with the M06-2X data, calculations of TS energies with B3LYP-D3 and B97-D3 predict 1−3 kcal/mol smaller differences in energy between the lowest-energy P(NTf)OH and P(O)NHTf TSs for reactions A−C. With each of these three functionals, the lowest-energy P(O)NHTf TS leads to the minor enantiomer of the product in reactions A and C but to the major enantiomer in reaction B. Details are provided in the Supporting Information.

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Mechanisms of Carbonyl Activation by BINOL N ... - ACS Publications

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