Stereospecific 1,3-H Transfer of Indenols Proceeds via Persistent Ion

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Stereospecific 1,3-H Transfer of Indenols Proceeds via Persistent Ion-Pairs Anchored By NH··· Pi Interactions David M. H. Ascough, Fernanda Duarte, and Robert S. Paton J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 19 Oct 2018 Downloaded from http://pubs.acs.org on October 19, 2018

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Journal of the American Chemical Society

Stereospecific 1,3-H Transfer of Indenols Proceeds via Persistent Ion-Pairs Anchored By NH··· Interactions David M. H. Ascough†, Fernanda Duarte†, Robert S. Paton*†‡ ‡ Department † Chemistry

of Chemistry, Colorado State University, Fort Collins, CO 80523, USA. Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, UK.

Abstract: The base-catalyzed rearrangement of arylindenols is a rare example of a suprafacial [1,3]-hydrogen atom transfer. The mechanism has been proposed to proceed via sequential [1,5]-sigmatropic shifts, which occur in a selective sense and avoid an achiral intermediate. A computational analysis using quantum chemistry casts serious doubt on these suggestions: these pathways have enormous activation barriers and in constrast to what is observed experimentally, they overwhelmingly favor a racemic product. Instead we propose that a suprafacial [1,3]prototopic shift occurs in a two-step deprotonation/reprotonation sequence. This mechanism is favored by 15 kcal mol-1 over that previously proposed. Most importantly, this is also consistent with stereospecificity since reprotonation occurs rapidly on the same -face. We have used explicitly-solvated molecular dynamics studies to study the persistence and condensed-phase dynamics of the intermediate ion-pair formed in this reaction. Chirality transfer is the result of a particularly resilient contact ion-pair, held together by electrostatic attraction and a critical NH··· interaction which ensures that this species has an appreciable lifetime even in polar solvents such as DMSO and MeOH. Introduction: Thermally activated, concerted suprafacial [1,3]hydrogen atom transfers, while geometrically plausible, are forbidden by orbital symmetry.1 Chemists’ attention has therefore turned to the catalysis of formal [1,3]-allylic rearrangements in a stepwise fashion.2 Given their stepwise nature, such reactions need not be stereospecific. Chiral catalysts can be used to control product stereoselectivity and asymmetric examples of olefin isomerization have been reported.3 However, examples of stereospecific [1,3]allylic rearrangements showing complete suprafacial transfer of reactant chirality to product are rare.4,5 Working toward the synthesis of endothelin receptor antagonists based on an indane scaffold, researchers at SmithKline Beecham discovered the stereospecific [1,3]-allylic rearrangement of chiral 3arylindenols in 1998 (Figure 1a, transformation A to B).6 Formally a suprafacial [1,3]-hydrogen atom transfer, this rearrangement is catalyzed by 1,4-diazabicyclo[2.2.2]octane (DABCO) with almost complete retention of chirality. Andersson applied this method in the asymmetric total synthesis of (R)-Tolterodine, treating indenol C with DABCO in THF at reflux to form the indanone D, again with almost complete chirality transfer (Figure 1b).7 These transformations are highly stereoselective, as well as stereospecific, since the product absolute configuration results from the reactant’s stereochemistry. they with stereospecific Aryl-indenol substrate (E) 2H-labelled at C1 reacts under the same conditions with complete deuterium transfer to the C3 position (I), confirming the intramolecular nature of this rearrangement. The same outcome is obtained in the absence of light, ruling out a photochemical transformation. On the basis of these results the reaction mechanism has been proposed6 to proceed via a sequence of three thermallyallowed suprafacial [1,5]-H shifts (Figure 1c), each of which are accelerated by alcohol deprotonation by the amine base. To account for the stereospecificity and complete deuterium transfer to C3, these [1,5]-shifts must occur selectively in the (anti-clockwise as drawn) direction shown, via intermediates G and H. This is a necessary requirement, since a [1,5]-sigmatropic shift in the opposite (clockwise from the viewpoint of Figure 1) sense would result in intermediate J, which would lead to incomplete [1,3]-deuterium transfer since a [1,5]-H atom shift will also occur. A primary kinetic isotope effect would further reduce the likelihood of the [1,5]deuterium shift required to form I. Furthermore, for unlabeled substrates A and C, the clockwise pathway (EJ) results in an achiral intermediate, inconsistent with the observed stereospecificity. The proposed mechanism for the tertiary amine base-catalyzed [1,3]-rearrangement of arylindenols requires sigmatropic shifts to

occur selectively in anti-clockwise (as depicted in Figure 1c) sense, avoiding intermediate J. However, the preferred pathway involves a disruption of benzene’s 6-aromaticity (i.e., in intermediates F and G) and there appeared (at least to us) no obvious reason why anticlockwise rotation should be strongly favored. This prompted us to undertake a computational study of these competing pathways.

Figure 1 | The stereospecific [1,3]-allylic rearrangement of 3-arylindenols (a) reported by SmithKline Beecham;6 (b) by Andersson;7 (c) results of 2Hlabelling studies and mechanism proposed in the literature.

Using both quantum chemical (QM) calculations and classical molecular dynamics (MD) simulations we demonstrate that the proposed pericyclic mechanism for the [1,3]-allylic rearrangement of chiral 3-arylindenols is unfeasible and occurs in a sense which is inconsistent with stereospecificity. We find an alternative mechanism which is contrary to previous proposals: a deprotonation/reprotonation pathway which is kinetically viable,

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consistent with labelling studies, and accounts for the stereochemical outcome. Chirality transfer requires the formation of a contact ionpair between substrate and base; the persistence of which we have studied by explicitly solvated molecular dynamics simulations. An NH··· noncovalent interaction between aromatic carbanion and ammonium counterion results in a persistent ion-pair in solvents across a range of polarities, preserving chiral information. Results and Discussion: We began our study by exploring the thermally-allowed suprafacial [1,5]-H shifts mechanism (Figure 1c) proposed in the literature,6 using quantum chemical calculations. We optimized structures at the M06-2X/6-311++G(d,p) level of theory for which single point energies were obtained with domain-based local pair-natural orbital coupled-cluster theory, at the DLPNOCCSD(T)/ma-def2-TZVP level including an implicit (SMD) description of THF solvent.8 Gibbs energies are reported at 60 °C relative to a standard state of 1M using a quasi-RRHO treatment,9 without any ad hoc corrections to the translational entropies.10 We have assumed that the final enol-keto tautomerization step is relatively facile and have not explicitly calculated mechanisms for (a)

this final step. In general, the comparison of computed mechanisms should be done with some caution, particularly where charged species are concerned. For example, errors up to 5 kcal mol-1 with respect to experiment have been suggested for a similar methodology to that employed here.11 As we describe below, our conclusions are based on Gibbs energy differences between competing mechanisms of 15 kcal mol-1 and larger, while the previously proposed mechanism also predicts the wrong stereochemical outcome by more than 13 kcal mol-1. We consider these differences to be significant enough on which to base firm conclusions. The computed pericyclic mechanisms of arylindenol 01 in the absence of DABCO confirmed our suspicions that the postulated [1,5]-sigmatropic shifts are very unlikely indeed (Figure 2a and Figure S1). The highest barrier is 50 kcal mol-1 in an anti-clockwise sense (TS 04) and 37 kcal mol-1 in a clockwise sense (TS 08). These barriers are extremely high. More importantly, the racemic pathway is favored overwhelmingly, by 13 kcal mol-1. The tertiary amine catalyst would need to overturn this substantial innate selectivity in order to promote a stereospecific transformation, as occurs experimentally.

H OH

OH

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H OH

H

OH

OH

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TS-08 37

TS-10 37

OH

Ph

+

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H H

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09 15

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Ph

TS-02 40

Ph

H

Ph

clockwise: racemic

Ph

Ph

H

anti-clockwise: stereospecific

H Ph

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(b)

NR3 O H

H O H NR 3

H H

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+

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NR3 O H

01·DABCO 2

clockwise: racemic

Ph

H H O

H

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05·DABCO 27 NR3 O H

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anti-clockwise: stereospecific

H Ph

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NR3 O H

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TS-10·DABCO TS-08·DABCO 39 37

rac-07·DABCO -2

H O H NR 3

07·DABCO -2

NR3 O H

Ph

H

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Figure 2 | SMD(THF)-DLPNO-CCSD(T)/ma-def2-TZVP//M06-2X/6-311++G(d,p) Gibbs energy (kcal mol-1) profiles at 60 °C and a standard state of 1 mol l-1, comparing sequential [1,5] H-shifts in an anti-clockwise, stereospecific manner (in green) and clockwise, unselective manner (in gold) for (a) uncatalyzed and (b) DABCO-promoted pathways.

We next computed competing pericyclic transformations in the presence of DABCO (Figure 2b and Figure S2). The literature proposal involves indenol O-H deprotonation by DABCO. Our attempts to characterize such ion-pairs led to proton transfer back to oxygen (including optimization in continuum solvent), indicative that deprotonation is unfavorable. The large difference in non-aqueous pKa values of secondary alcohols such as iPrOH (29.3 in DMSO) and DABCO (8.9 in DMSO) are consistent with this computational result.12 In THF, negligible O-H deprotonation by DABCO will occur. Nevertheless, we reasoned that activation by DABCO may be possible due to an increase in O-H···N hydrogen-bond strength along the reaction coordinate as this proton becomes enolic. Sigmatropic shifts can be promoted catalytically through “transition state complexation” or by “intervention”, in which the mechanism changes to a multistep process.13 In the first category, an increase in partial charge in a [3,3]-sigmatropic rearrangement transition structure (TS) can be stabilized by a bifunctional hydrogen bond donor catalyst14 or through partial protonation by an ammonium cation.15 An increase in O-H acidity along the reaction coordinate could be preferentially stabilized by partial deprotonation. Our computations revealed no such activation. Barrier heights are unchanged to within 2-3 kcal mol-1 of the uncatalyzed reaction (Figure 2b). There is some structural evidence of N-H bond shortening along the reaction coordinate, consistent with activation by partial deprotonation, e.g., from 1.84 to 1.73 Å in TS 08. However, there is also an unfavorable entropic cost of association (relative to the uncatalyzed pathway in Figure 2a), such that the barrier-lowering effect on the Gibbs energy surface is negligible. Overall, just as we found for the uncatalyzed reaction, activation

barriers in the presence of DABCO are extremely high (the stereospecific pathway being higher) and, most importantly, they fail to account for the observed stereospecificity: the racemic (clockwise) pathway is favored by 14 kcal mol-1. With the limits of computational accuracy in mind, this energetic difference is still significant and contrary to experiment. This led us to consider alternatives to the original mechanistic proposal.16 Since O-H deprotonation by DABCO is unfeasible, we considered C-H deprotonation at C1 as a possible alternative. The pKa of indene is 20.1 (DMSO),17 several orders of magnitude more acidic than a secondary alcohol. This is attributable to the 10 Hückel-aromaticity of the indenyl anion. With CPCM-M06-2X/6-311++G(d,p) calculations we obtained a difference of 9.4 pKa units in DMSO (13 kcal mol-1) for indene and iPrOH, compared to an experimental difference of 9.2. Experimental acidities in THF are not similarly available, however, computations suggest indene is more acidic by 20 kcal mol-1, or 14.4 pKa units. With thermodynamic factors clearly favoring C-H over O-H deprotonation, we set out to locate transition structures to explore the feasibility of such a process (Figure 3).

3



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Figure 3 | SMD(THF)-DLPNO-CCSD(T)/ma-def2-TZVP//M06-2X/6-311++G(d,p) Gibbs energies (kcal mol-1) at 60 °C and 1 mol l-1 standard state for a deprotonation/reprotonation sequence. The intermediate, a contact ion-pair is shown with added Bondi van der Waals surface and a Non-Covalent Interaction isosurface using the M06-2X density. Gibbs energies are relative to separated 1 and DABCO. Key interatomic distances in Å.

performed using density functional theory (DFT),23 mechanisms that proceed via ion-pairs have proved challenging to compute. A lack of directionality in ion-pairing interactions often leads to a vast conformational space. To address this, classical conformational sampling techniques have been combined with DFT calculations in the study of catalytic processes involving ion-pairs.25-28 Classical molecular dynamics (MD) simulations have been extensively used to study the structure and dynamics of imidazolium-based ionic liquid pairs.29 However, the use of MD for studying catalyst binding was only recently demonstrated. MD simulations and QM calculations were used to elucidate the dominant binding modes and origins of stereoselectivity in the nucleophilic ring opening reactions of episulfonium cations.30,31 In light of this, we reasoned that MD simulations of ion-pair intermediate 12 would enable us to investigate its stability and chiral integrity as a function of time in solution. We therefore performed classical MD simulations of ion-pair 12 explicitly solvated by THF (ε= 7.6), the experimental solvent. Simulations were also run in dichloromethane (DCM, ε = 8.9) and methanol (MeOH, ε = 32.6) for comparison. OPLS-AA compatible parameters were used to model the ion-pair complex, with charges obtained using the restricted electrostatic potential (RESP) approach. Full details of simulation set-up are given in the Supporting Information. MD simulations were initiated using the DFT optimized geometry as starting point and equilibrated under position restraints. For each solvent, simulations were run for 100 ns in three replicas (defined as independent trajectories, initiated with different random velocities). In MeOH, where the stability of the ion-pair is compromised due to the polarity of the solvent (ε = 32.6), a further 47 independent replicas of 10 ns each were carried out. For kinetic analysis, the first 1 ns of each simulation was removed (see Supporting Information for details).

Deprotonation at C1 by DABCO (TS 11) has a barrier height of 24 kcal mol-1, much lower than the pericyclic mechanisms discussed already and the reaction is now feasible at 60 °C (t1/2 = 10 mins). We also located the TS for the subsequent reprotonation of intermediate 12 at C3 via TS 13. This barrier is smaller than the reverse reaction by 6 kcal mol-1 and forms the product of the formal [1,3]-allylic rearrangement! Taken together, these two steps (via TS 11 and TS 13) constitute a proton slide, in which the non-bonding electrons of DABCO facilitate proton transfer.18 Consistent with experiment, we also found that pyridine is an ineffective base, since deprotonation is kinetically inaccessible with a barrier of 29 kcal mol-1 (Figure S4). The lower basicity of pyridine vs. DABCO (by 5.5 pKa units, in DMSO) is responsible for this lack of reactivity. We also evaluated reprotonation at C2 via TS 14. This pathway, potentially leading to a loss of stereochemistry, is uncompetitive by more than 11 kcal mol-1 compared to protonation at C3, as a dearomatized conjugate base is formed. Overall, barriers for this prototopic [1,3]-shift19 shuttled by DABCO are clearly more palatable than those obtained for [1,5]rearrangements (Figure 2), but is this mechanism consistent with suprafacial migration? C-H deprotonation produces intermediate 12, consisting of an ammonium cation and an indenyl anion. Both species are achiral, an apparent contradiction with the stereospecific nature of the [1,3]-rearrangement. However, the structure of intermediate 07 shows the close association between these two species as a contact (or equivalently, intimate) ion-pair. The dominant attractive force between cation and anion is electrostatic in origin, although an appreciable N-H··· interaction is evident along with multiple weak non-covalent contacts in Figure 3 (NCI analysis). Previous theoretical studies on neutral arene:amine complexes suggest an N-H··· strength around 2.5-3.0 kcal mol-1.20 Provided this tight association mode persists in solution, proton transfer to C3 will occur in a suprafacial fashion. Stereospecificity requires that reprotonation via TS 13 is faster than contact ion-pair separation, otherwise chiral information will be lost.21 Ion-pairing interactions have long been recognized as a versatile strategy to induce reactivity and selectivity in organic chemistry.22,24 However, while many computational studies of selectivity have been

(a) DCM

(b) THF

(c) MeOH

COM

top face bottom face COM

O

O

O

Figure 4 | Top: MD simulations of ion-pair 12 in explicit (a) DCM, (b) THF and (c) MeOH solvents. Illustrated are the NH··· distance (blue) and center of mass (COM) separation between cation and anion (red) during 100 ns of unrestrained MD simulations, or until dissociation in the case of MeOH. Bottom: heat plots

4


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showing the position of the ammonium proton above the indenyl anion. Each heat plot is formed from 30,000 frames of contact ion-pairs, corresponding to 300 ns of combined simulation.

shared ion pairs were defined as having an inter-ion separation of greater than 5 Å, but less than 10 Å and solvent-separated ions as those having inter-ion distances greater than 10 Å. By treating the 50 independent replica simulations as an ensemble, we can apply first-order kinetics to derive a rate constant, and therefore an energy barrier for ion-pair dissociation in MeOH. The dissociation of ion-pairs to solvent-separated ion-pairs in this ensemble as a function of time is plotted in Figure 5. The plot is consistent with first-order kinetics with a rate constant of 2.2 × 108 s-1 (t1/2 = 3.1 ns), derived from a log plot with R2 = 0.983. This corresponds to a barrier for ion-pair separation, ΔG‡TST, of ca. 7 kcal mol-1 in explicit solvent. There is no saddle-point on the DFTcomputed PES corresponding to the separation of ion-pair 12, and so it is not possible to compute this barrier directly. Nevertheless, we can indirectly estimate this barrier using the free energy change for dissociation (to infinite separation), from which it is possible to estimate ion-pair half-life. Comparison of the ion-pair lifetime in MeOH from MD simulation (3.1 ns) with QM in this way (5.5 ns) shows sensible agreement. The lifetime of 12 in THF is substantially longer, making it difficult to obtain from MD simulations without enhanced sampling, however, QM results suggest that this is around a factor of 103 longer than in MeOH; this increases to 106 in DCM. Conversely, in more polar solvents (DMSO and H2O) the lifetime decreases. While these results conform qualitatively to chemical intuition, they also permit a quantitative comparison of dissociation against reprotonation barriers. In THF, reprotonation is preferred over dissociation by 5 kcal mol-1, consistent with a high-degree of chirality transfer, whereas in MeOH this preference drops to 2 kcal mol-1, such that a small loss of stereochemical integrity would be expected to occur in this solvent. It is, however, remarkable that even in polar solvents such as MeOH and DMSO the ion-pair is predicted to be sufficiently stable that the [1,3]-shift occurs without significant levels of racemization.

The results of MD analysis are shown in Figure 4. In THF and DCM a stable contact ion-pair is observed. In our analysis, contact ion-pairs were defined as having an inter-ion separation of < 5 Å. Here, inter-ion separations refer to the shortest distance between a nucleus of the cation and a nucleus of the anion unless otherwise stated. The mean separation of the ion-pairs for THF and DCM are 2.13 ± 0.12 Å and 2.12 ± 0.10 Å, respectively. During the 300 ns of total simulation time, no dissociation nor face swapping was observed, i.e. no loss of chiral integrity. In both solvents, the ammonium ion is predominantly coordinated directly above the center of the five-membered ring (Figure 4a/b), although some ‘wandering’ to the center of the six-membered ring was also observed. The mean distance between the ammonium N-H and the plane of the 5-membered ring are 2.02 ± 0.13 Å and 2.00 ± 0.10 Å for THF and DCM respectively. Due to thermal motion these values are slightly longer than the DFT optimized geometry (1.81 Å), however, evidently the complex remains bound. In THF, we occasionally observed the loss of the N-H··· interaction, but with maintained inter-ion separation of < 5 Å. The situation is markedly different in the more polar protic solvent MeOH (ε = 32.6). Here, we observe several dissociation events leading to formation of both solvent-shared (i.e. ions are separated by a shared solvation shell) and solvent-separated ion pairs (i.e. ions having their own solvation shell). Analysis of the trajectories reveals that chiral integrity can be lost without full dissociation, with inversion of solvent-shared ion-pairs as well as contact ion-pairs. One mechanism of inversion of the contact ion-pair occurs via the ammonium sliding from the ring center to hydrogen bond with the arylindenol oxygen, facilitating the inversion whilst minimizing the loss of inter-ion interactions (Figure S5). In our analysis, solvent-

Figure 5 | (a) SMD(THF)-DLPNO-CCSD(T)/ma-def2-TZVP//M06-2X/6-311++G(d,p) Gibbs energy change (kcal mol-1) for the dissociation of ion-pair 12, estimated half-life (s), and reprotonation barriers in different solvents; (b) Time for ion-pair separation in 50 MD trajectories of 12 run in MeOH.

arylindenol [1,3]-rearrangmenents is overdue. Our proposed mechanism is consistent with physical-organic studies on the stereospecific tautomeric rearrangements of alkylindenes,32,33 for which Cram coined the term “conducted tour” mechanism to refer to the movement of an ammonium ion along the -face of an indenyl anion. For rearrangements in THF, 100% stereospecificity was observed, whereas this dropped to 97% in DMSO, both using an amine base (DABCO/nPrNH2).29a These figures are also consistent with our computational results in Figure 5. Our proposed mechanism

The rate-determining step associated with this [1,3]-prototopic shift is deprotonation (via TS 11), with a computed activation barrier of 24 kcal mol-1. This is more than 15 kcal mol-1 lower than barriers for the previously proposed pathway involving [1,5]-H shifts, which itself favors a racemic product by a further 14 kcal mol-1 over the stereospecific rearrangement. In contrast, a proton-slide mechanism favors stereospecificity by 5 kcal mol-1 in THF. Our computational results therefore strongly suggest a revision to the mechanism of 5



can thus be summarized by Figure 6. The ease of formation of the key ion-pair intermediate is attributable to the aromatic carbanion and a strong N-H··· interaction which maintains a persistent ionpair. [1,3]-transfer occurs more quickly than dissociation in almost all solvent systems.

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Discovery Environment (XSEDE) through allocation TGCHE180056. XSEDE is supported by the National Science Foundation (ACI-1548562).Error! Reference source not found. References 1. Woodward, R. B.; Hoffmann, R. Stereochemistry of Electrocyclic Reactions. J. Am. Chem. Soc. 1965, 87, 395. 2. By convention square brackets [1,3] refer to numbers of atoms involved in the sigmatropic change, in contrast with usage for cycloadditions, where they refer to numbers of electrons. 3. (a) Hintermann, L.; Schmitz, M. Enantioselective Synthesis of Phospholenes via Asymmetric Organocatalytic Alkene Isomerization. Adv. Synth. Catal. 2008, 350, 1469; (b) Saga, Y.; Motoki, R.; Makino, S.; Shimizu, Y.; Kanai, M.; Shibasaki, M. Catalytic Asymmetric Synthesis of R207910. J. Am. Chem. Soc. 2010, 132, 7905; (c) Wu, Y.; Deng, L. Asymmetric Synthesis of Trifluoromethylated Amines via Catalytic Enantioselective Isomerization of Imines. J. Am. Chem. Soc. 2012, 134, 14334; (d) Lee, J. H.; Deng, L. Asymmetric Approach toward Chiral Cyclohex-2-enones from Anisoles via an Enantioselective Isomerization by a New Chiral Diamine Catalyst. J. Am. Chem. Soc. 2012, 134, 18209; (e) Wu, Y.; Singh, R. P.; Deng, L. Asymmetric Olefin Isomerization of Butenolides via Proton Transfer Catalysis by an Organic Molecule. J. Am. Chem. Soc. 2011, 133, 12458. 4. Dabrowski, J. A.; Haeffner, F.; Hoveyda, A. H. Combining NHC-Cu and Brønsted Base Catalysis: Enantioselective Allylic Substitution/Conjugate Additions with Alkynylaluminum Reagents and Stereospecific Isomerization of the Products to Trisubstituted Allenes. Angew. Chem., Int. Ed. 2013, 52, 7694. 5. Martinez-Erro, S.; Sanz-Marco, A.; Gómez, A. B.; VázquezRomero, A.; Ahlquist, M. S. G.; Martín-Matute, B. BaseCatalyzed Stereospecific Isomerization of Electron-Deficient Allylic Alcohols and Ethers through Ion-Pairing. J. Am. Chem. Soc. 2016, 138, 13408. 6. Clark, W. M.; Tickner-Eldridge, A. M.; Huang, G. K.; Pridgen, L. N.; Olsen, M. A.; Mills, R. J.; Lantos, I. Baine, N. H. A Catalytic Enantioselective Synthesis of the Endothelin Receptor Antagonists SB-209670 and SB-217242. A Base-Catalyzed Stereospecific Formal 1,3-Hydrogen Transfer of a Chiral 3Arylindenol. J. Am. Chem. Soc. 1998, 120, 4550. 7. Hedberg, C.; Andersson, P. G. Catalytic Asymmetric Total Synthesis of the Muscarinic Receptor Antagonist (R)Tolterodine. Adv. Synth. Catal. 2005, 347, 662. 8. DFT calculations were performed with Gaussian 09, rev. D.01: Frisch, M. J. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, G. A. Petersson, H. Nakatsuji, X. Li, M. Caricato, A. Marenich, J. Bloino, B. G. Janesko, R. Gomperts, B. Mennucci, H. P. Hratchian, J. V. Ortiz, A. F. Izmaylov, J. L. Sonnenberg, D. Williams-Young, F. Ding, F. Lipparini, F. Egidi, J. Goings, B. Peng, A. Petrone, T. Henderson, D. Ranasinghe, V. G. Zakrzewski, J. Gao, N. Rega, G. Zheng, W. Liang, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, K. Throssell, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, T. Keith, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, J. M. Millam, M. Klene, C. Adamo, R. Cammi, J. W. Ochterski, R. L. Martin, K. Morokuma, O. Farkas, J. B. Foresman, and D. J. Fox,Gaussian, Inc., Wallingford CT, 2016; Single point energy calculations were performed with Orca v. 4.0.1: Neese, F. Software update: the ORCA program system, version 4.0. WIREs Comput. Mol. Sci. 2018, 8, e1327. Full details and references are in the Supporting Information. 9. (a) Grimme, S. Chem. Eur. J. 2012, 18, 9955; (b) Funes-Ardoiz, I.; Paton, R. S. GoodVibes v2.0.2 DOI: 10.5281/zenodo.595246

Figure 6 | Revised mechanism on the basis of this study.

Conclusion: The previously proposed mechanism for the basecatalyzed [1,3]-rearrangement of arylindenols has extremely high activation barriers and overwhelmingly favors a racemic product, inconsistent with experimental stereospecificity. In contrast, we propose that a suprafacial prototopic shift is mediated by the amine base in a two-step deprotonation/reprotonation sequence. This mechanism is favored by 15 kcal mol-1 over that previously proposed. Most importantly, this is also consistent with stereospecificity since reprotonation occurs rapidly on the same face. MD studies confirm that the intermediate ion-pair is stable in a variety of solvents, and furthermore observation of ion-pair dynamics during classical simulations allowed us to calibrate DFT studies on the ease of ion-pair dissociation. Chirality transfer is achieved through a resilient contact ion-pair, held together by electrostatic attraction and an NH··· interaction ensures that this species has an appreciable lifetime even in solvent such as DMSO and MeOH. Supporting Information: Analysis of MD simulations; energetics for the different reaction pathways; absolute energies (a.u.) and selected distances for all DFT computed structures (PDF). Archive of Cartesian coordinates (in xyz format) for computed stationary points (ZIP). Archive of MD containing topologies and input files (ZIP). Corresponding Author *

[email protected]

Acknowledgements R. S. P. thanks Prof. Tom Rovis for stimulating discussions during a sabbatical period at Colorado State University which motivated this work, and Dr John M. Brown at Oxford for helpful insights. We acknowledge the EPSRC Centre for Doctoral Training in Synthesis for Biology and Medicine (EP/L015838/1) for a studentship to D. M. H. A., generously supported by AstraZeneca, Diamond Light Source, Defense Science and Technology Laboratory, Evotec, GlaxoSmithKline, Janssen, Novartis, Pfizer, Syngenta, Takeda, UCB and Vertex, and the Royal Society for a Newton International Fellowship to F. D. We used the Dirac cluster at Oxford supported by the EPSRC Centre for Doctoral training for Theory and Modelling in Chemical Sciences (EP/L015722/1); the RMACC Summit supercomputer supported by the National Science Foundation (ACI1532235 and ACI-1532236), the University of Colorado Boulder and Colorado State University; the Extreme Science and Engineering 6


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Stereospecific 1,3-H Transfer of Indenols Proceeds via Persistent Ion

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