Asymmetric Catalysis

Enantioselective Intramolecular Allylic Substitution via SynergisticPalladium/Chiral Phosphoric Acid Catalysis: Insight into Stereo-induction through Statistical Modeling**Cheng-Che Tsai+, Christopher Sandford+, Tao Wu, Buyun Chen, Matthew S. Sigman,* andF. Dean Toste*

Abstract: The mode of asymmetric induction in an enantio-selective intramolecular allylic substitution reaction catalyzedby a combination of palladium and a chiral phosphoric acidwas investigated by a combined experimental and statisticalmodeling approach. Experiments to probe nonlinear effects,the reactivity of deuterium-labeled substrates, and controlexperiments revealed that nucleophilic attack to the p-allylpal-ladium intermediate is the enantio-determining step, in whichthe chiral phosphate anion is involved in stereoinduction.Using multivariable linear regression analysis, we determinedthat multiple noncovalent interactions with the chiral environ-ment of the phosphate anion are integral to enantiocontrol inthe transition state. The synthetic protocol to form chiralpyrrolidines was further applied to the asymmetric construc-tion of C@O bonds at fully substituted carbon centers in thesynthesis of chiral 2,2-disubstituted benzomorpholines.

Introduction

Chiral phosphoric acids (CPAs) serve as versatile catalystsin organocatalyzed asymmetric transformations, and as effec-tive co-catalysts in transition metal-catalyzed reactions.[1] Thecombination of CPAs with transition metal catalysts impartsnew reactivity (and selectivity) manifolds that are notaccessible by their individual catalytic components.[2, 3] Spe-cifically, enantioselective allylic substitution reactions ofnonderivatized (unactivated) allylic alcohols are desirable asa step-economic approach to the formation of key carbon–carbon and carbon–heteroatom bonds.[4] The synergy be-tween two distinct catalysts allows for unique reactivity of

these substrates, often with enhanced enantio- and diastereo-control.[5]

As an example, CPAs were found to be effective co-catalysts for asymmetric induction in Pd-catalyzed enantio-selective allylic substitutions (Scheme 1).[6] List and co-work-ers reported the combination of Pd and CPA catalysts in theenantioselective allylation of branched aldehydes (Scheme1a),[6a] wherein the CPA is the sole source of chiralinformation responsible for enantioinduction. In contrast,CPAs have also been leveraged to enhance the enantioselec-tivity of an allylic substitution reaction in which the primarysource of asymmetric induction is a chiral phosphoramiditeligand for Pd, as demonstrated by the groups of Gong[6c] andBeller[6d] (Scheme 1b and c, respectively). Despite the rapiddevelopment in this field, insights into the origin of asym-metric induction by CPAs in these complicated reactionprocesses remains challenging.[7]

In this context, we report herein our investigation into theorigin of asymmetric induction in Pd/CPA-catalyzed enantio-

Scheme 1. a–c) Literature examples of synergistic Pd/CPA-catalyzedenantioselective allylic substitutions of unactivated alcohols. d) Intra-molecular reactions studied herein.

[*] Dr. C.-C. Tsai,[+] Dr. T. Wu, B. Chen, Prof. Dr. F. D. TosteDepartment of Chemistry, University of California, BerkeleyBerkeley, CA 94720 (USA)E-mail: fdtoste@berkeley.edu

Dr. C. Sandford,[+] Prof. Dr. M. S. SigmanDepartment of Chemistry, University of Utah315 South 1400 East, Salt Lake City, UT 84112 (USA)E-mail: sigman@chem.utah.edu

Dr. C.-C. Tsai[+]

Present address: Department of Chemistry, Tunghai UniversityTaichung City 40704 (Taiwan)

[++] These authors contributed equally to this work.

[**] A previous version of this manuscript has been deposited ona preprint server (https://doi.org/10.26434/chemrxiv.11965521.v1).

Supporting information and the ORCID identification number(s) forthe author(s) of this article can be found under:https://doi.org/10.1002/anie.202006237.

AngewandteChemieResearch Articles

How to cite: Angew. Chem. Int. Ed. 2020, 59, 14647–14655International Edition: doi.org/10.1002/anie.202006237German Edition: doi.org/10.1002/ange.202006237

14647Angew. Chem. Int. Ed. 2020, 59, 14647 – 14655 T 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

selective allylic substitutions using a combination of exper-imental studies and statistical modeling (Scheme 1d).[8, 9] Indoing so, we are able to identify noncovalent interactions(NCIs) between the substrate and chiral phosphate anion thatdifferentiate the energy of the transition states leading to thestereoisomeric products. The knowledge gained from thesemechanistic studies allows for expansion of synthetic scope tothe formation of chiral benzomorpholines, a compound classcontaining fully substituted carbon centers.

Results and Discussion

Initial Results

We commenced our study with the Pd-catalyzed enantio-selective intramolecular allylic amination of allylic alcohol 1awith privileged CPA, (R)-TCYP 3, as a co-catalyst (Table 1).For comparative purposes, we also investigated the samereaction in the absence of Pd, according to work reported bythe Takasu group in which a CPA catalyzes the allylicsubstitution when the alcohol is replaced by an activatedtrichloroacetimidate leaving group, substrate 1a’’.[10]

In the initial study, the substitution of allylic alcohol 1awas carried out in the presence of 10 mol% of both (R)-TCYP 3 and Pd(PPh3)4, resulting in pyrrolidine product (S)-2a in full conversion with 84 % ee (entry 1). In contrast, thereaction of 1a’’ with (R)-TCYP 3 under metal-free conditionsgave the opposite enantiomer of the product, (R)-2a, in 78%

ee (entry 2). Given that the Takasu group has demonstratedthat the reaction in the absence of Pd likely proceeds bynucleophilic attack on the p-system antiperiplanar to theactivated leaving group (an SN2’-type mechanism),[10a] theenantio-divergence in the presence of Pd provides evidence ofa distinct mechanism. To gain insight into the origins of thisenantio-divergence, control experiments were performed: thereaction of 1a without Pd gave no product (entry 3), while thePd/CPA-catalyzed reaction of activated substrate 1 a’’ gave(S)-2a in only 9% ee (entry 4), as a consequence of back-ground reactivity (entry 5).

To probe the origin(s) of enantiocontrol, nonlinear effect(NLE)[11] studies of both the synergistic Pd/CPA and SN2’reactions were performed (Figure 1). Both reactions exhib-ited linear correlations (R2> 0.99) between the product andcatalyst ee, consistent with models reported by Takasu[10a] andBeller,[6d] which propose that a single CPA is involved in theenantio-determining transition state.

To enhance the enantioselectivity of the reaction, weturned our attention towards examining alternative CPAscaffolds. We recently developed a new class of CPA catalysts,doubly axially chiral phosphoric acids (DAPs), which possessa larger chiral pocket derived from two homocoupled BINOLscaffolds.[13] The use of DAPCy catalyst 4a resulted in anincrease in enantioselectivity for both the synergistic Pd/CPAand SN2’ reactions to 95% and 90% ee, respectively (Table 1,entries 6 and 7).

During optimization, we observed that the identity ofboth the DAP catalyst and the sulfonamide protecting groupon the nucleophilic nitrogen of the substrate play animportant role in the enantioselectivity of the reaction, withdifferent trends associated with the two strategies. Thedependency of these two modular components of the reactionpresented an ideal case study for utilizing statistical modelingtools to probe the origins of enantio-divergence between thetwo processes.

Statistical Modeling of the Substrate Variation

In our statistical modeling approach to investigatingmolecular interactions in transition states,[8] parameter sets

Table 1: Initial results and control experiments for intramolecularsubstitutions.[a]

Entry Substrate Catalyst(s) Conv. [%][b] ee [%][c]

1 1a Pd(PPh3)4/3 100 842 1a’’ 3 100 @783 1a 3 0 n.d.4 1a’’ Pd(PPh3)4/3 100 95 1a’’ Pd(PPh3)4 70 06 1a Pd(PPh3)4/4a 100 (85) 957 1a’’ 4a 86 (77) @90

[a] The reaction was carried out with 10 mol% of Pd(PPh3)4 and/or CPA3/4a in toluene at ambient temperature. [b] Conv. represents conversionmeasured by crude 1H NMR analysis; yields of isolated product inparentheses. [c] ee of product 2a, determined using HPLC equipped witha chiral column, wherein a positive ee corresponds to (S)-2a, anda negative ee to (R)-2a, as the major configuration. n.d. = notdetermined.

Figure 1. Nonlinear effect studies comparing the ee of (R)-TCYP 3 withthe ee of the product (R/S)-2a, both a) in the presence of Pd(PPh3)4

with substrate 1a, and b) in the absence of Pd(PPh3)4 with substrate1a’’. Conditions are the same as in Table 1, entries 1 and 2, respective-ly.[12]

AngewandteChemieResearch Articles

14648 www.angewandte.org T 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2020, 59, 14647 – 14655

describing molecular properties of the substrate and/orcatalyst are related to the enantioselectivity of the reaction,expressed as DDG*. The combination of multiple parametersin the mathematical expression defining DDG* providesinsight into the overlapping factors contributing to stereo-control.

To formulate such an equation, it is first necessary todefine a set of parameters that describes electronic and stericproperties of the molecular structure. In this case, we opted tosimulate trends in structural variation of the sulfonamideprotecting group by truncating the substrate to an ArSO2NH2

group (see the Supporting Information). DFT properties ofthese truncated structures were collated, and, through aniterative multivariable linear regression modeling process,models describing the effect of sulfonamide variation on theenantioselectivity were obtained. Both leave-one-out (Q2)and external validation (R2

valid.) statistics were used, whereappropriate, to identify a statistically robust model.

A combination of the asymmetric IR stretching frequencyof the NH2 group nNH2 ,asym with the partial charge according toNBO on the sulfur (NBOS) was necessary to describe theimpact of the variation of the protecting group in theenantiocontrol of the SN2’ reaction (Figure 2a and b). Theseparameters can be compared directly with transition statescomputed by Takasu and co-workers,[10a] in which theasymmetric IR stretching frequency defines the propensityof the amine N–H group to undergo hydrogen-bonding toform a hydrogen bond with the phosphoric acid P=O motif inthe transition state. The partial charge according to NBO onthe sulfur atom predominantly describes a correctional factorfor ortho-substituents, a steric property that results in a changein conjugation with the aromatic ring.

With agreement between our modeling and transitionstates computed by Takasu and co-workers in the absence ofpalladium, we next turned to using statistical modeling toprobe the dual catalysis manifold. According to the workflowdescribed above, we obtained a model (Figure 2c) for theprotecting group variance in which the dominant parameter isthe asymmetric IR stretching frequency of the SO2 group(nSO2 ,asym). Interestingly, this key parameter corresponds toa hydrogen bond (or other noncovalent interaction) to theprotecting group oxygen in the transition state; however, thisinteraction is opposite in directionality to the hydrogen bondof the SN2’ mechanism identified above.

At this stage, we identified two possibilities for the originof this discrepancy: 1) the amine is deprotonated prior to theenantio-determining step, whereby the phosphoric acid O–Hbinds to the SO2 group as part of an inner-sphere Tsuji–Trostmechanism,[14] or 2) the vibrational stretching frequency issignifying a molecular interaction between the sulfonamideoxygens and an alternative hydrogen (or Lewis acid). In orderto differentiate these possibilities, it was necessary to gainfurther insight into the mechanism of the enantio-determiningstep in the reaction.

To determine whether an inner- or outer-sphere Tsuji–Trost mechanism is in operation, we synthesized deuterium-labeled, enantiomerically enriched (er = 3.4/1) allylic alcohol(S,E)-5a along with its corresponding trichloroacetimidatederivative (S,E)-5a’’ (Figure 3a). In this experiment, an inner-

sphere process should afford the E-isomer of the deuteratedolefin, and the Z-isomer results from an outer-sphereprocess.[15] The absolute configuration of 5a and 5a’’ was

Figure 2. a) Variance of the nitrogen protecting group. b) Model de-scribing the protecting group variance in the absence of Pd, in which(R)-2 is formed as the major enantiomer. c) Model describing theprotecting group variance in the presence of Pd, in which (S)-2 isformed as the major enantiomer.

AngewandteChemieResearch Articles

14649Angew. Chem. Int. Ed. 2020, 59, 14647 – 14655 T 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org

determined by Mosher ester analysis, in comparison with1H NMR spectra of analogues reported in the literature (seethe Supporting Information).[15c,d] In the SN2’ reaction, thecyclized product (R)-6a was obtained in 93 % ee with 3.4:1Z :E selectivity, consistent with a transition state in which thenucleophile attacks the p-system on the opposite face to thedeparting leaving group.

In the presence of palladium, cyclized product (S)-6a wasobtained with 95 % ee and 2.0:1 Z :E selectivity, indicative ofan outer-sphere mechanism. It is notable that the minor E-isomer of the product is also formed in high enantio-enrich-ment with the same absolute configuration as the Z-isomer.We propose that this may result from a second-order processin Pd, in which a second Pd0 molecule attacks the PdII–allylintermediate, leading to a switch in the facial position of thepalladium (Figure 3b).[16] Rapid p-s-p isomerization mustthen occur to form the observed isomers of deuteratedproduct. In this scenario, the reaction operates under Curtin–Hammett control, in which outer-sphere attack of the nitro-gen nucleophile is enantio-determining.[17] Alternatively, thep-allylpalladium precursor to the (S,E)-isomer could begenerated directly from a slightly less favorable syn-ioniza-tion of (S,E)-5a,[18] whereby formation of the PdII–allylintermediate is enantio-determining. To examine these pos-sibilities, we repeated the reaction with half the palladiumloading, and observed an increase in selectivity to 2.6:1 Z :E,in agreement with slowing the second-order Pd process of thefirst scenario. From these experiments, an inner-sphere Tsuji–Trost mechanism can be excluded, and the enantio-determin-ing attack of the nucleophile occurs through a transition statein which the DAP catalyst is a phosphate anion (havingpreviously protonated the OH leaving group). This leads tothe conclusion that the asymmetric SO2 vibrational stretchingfrequency corresponds to a noncovalent interaction (NCI)other than a hydrogen bond from the phosphoric acid O–H.

With this in mind, we turned to symmetry-adaptedperturbation theory (SAPT) computations to probe the

energetics of an NCI to the sulfonamide oxygens.[13a, 19] Inthis approach, the hydrogen of a benzene probe was used todetermine the maximum magnitude interaction energy andcorresponding equilibrium binding distance to the protectinggroup. The magnitude of the interaction energy was alsoseparated into constituent energies corresponding to electro-statics, exchange interactions, induction, and dispersion. Withthese new parameters, an improved statistical model (Fig-ure 3c) was afforded with the equilibrium binding distance(Dmin), alongside a cross-term of the dispersion energy of theinteraction (Edisp). The negative coefficient of Dmin defines thebenefit of an interaction with a smaller equilibrium distance(stronger interaction) for improved stereocontrol, while thecross-term compensates for the additional dispersion ob-tained with a protecting group bearing an ortho-substituenton the aromatic ring. Analyzing these results, the statisticalmodeling suggests that an NCI with the sulfonamide oxygensis the most important molecular interaction responsible fordifferentiating the major and minor transition states in thepresence of palladium.

Statistical Modeling of the Variation in DAP Catalyst

To gain insight into the molecular interactions with thechiral phosphate anion which govern selectivity, it wasnecessary to consider the flexibility of the catalyst. Giventhe configurational flexibility of the central axis of the DAPscaffold,[13a] we subjected TAPPhtBu (triply axially chiralphosphate) catalyst 4m, where configurational flexibility isprevented, to our reaction conditions in the presence of Pd(Figure 4a), providing a direct comparison with the enantio-mer of (Ra,Ra,Ra)-DAPPhtBu 4e. We observed a reducedenantioenrichment of product (R)-2a of 84%, when com-pared to the ee of (S)-2 a of 93% with 4e.[20] While the reducedenantioselectivity may result from changes in the catalystpocket from the additional methyl substituents, it also

Figure 3. a) Deuterium-labeling experiment to probe outer- or inner-sphere Tsuji–Trost mechanism. PG=SO2-1-naphthyl. b) Rationale for majorand minor isomers in the presence of palladium. c) Model for protecting group variance in the presence of palladium using parameters derivedfrom SAPT computations. Outlier 2h was generated from 1h, which was not fully soluble in the reaction mixture, and is not included in thecorrelation statistics (also an outlier in Figure 2c).

AngewandteChemieResearch Articles

14650 www.angewandte.org T 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2020, 59, 14647 – 14655

suggested the possibility that the higher energy (Ra,Sa,Ra)-configuration of the DAP anion may be catalytically active.We modeled both configurations separately,[21] and obtainedmore interpretable multivariable linear regression modelswith the (Ra,Sa,Ra)-configuration. With these data in agree-ment, it suggests that the higher energy configuration of thecatalyst may be operational. Consequently, we believe thatconfigurational flexibility is important in successful catalysis,and we proceed to discuss molecular interactions associatedwith the (Ra,Sa,Ra)-configuration of the catalyst.

Parameters associated with the variation of the DAPcatalysts (Figure 4a) were obtained from truncated DFTstructures (see the Supporting Information). With moleculardescriptors in hand, we obtained a bivariable model (Fig-ure 4b) to describe enantiocontrol in the synergistic Pd/CPAcatalytic reaction, using the combination of the partial chargeaccording to NBO on the reactive phosphate oxygen (NBOO)with the dihedral angle about the naphthyl–naphthyl bond(DihedNap-Nap). We ascribe the dihedral angle parameter toa classification for the partial charge, where the angle altersthe delocalization across the conjugated ring system. The signof the NBOO term leads to the conclusion that the morenegative the phosphate oxygen, the lower the degree ofenantiocontrol. This is consistent with the statistical modelingof the protecting groups, since it showcases the opposite trendto one expected if deprotonation of the amine represents thekey defining molecular interaction. Indeed, it suggests thatthe major factor that controls stereochemistry is an NCI fromthe phosphate oxygen that stabilizes the minor transition stateand leads to reduced enantioselectivity.

It is interesting to compare these predicted NCIs withtransition states calculated by Jindal and Sunoj[7f] for the Pd/CPA reaction developed by List and co-workers (Scheme1a).[6a] While statistical modeling does not enable theidentification of the precise molecular interactions involved,it does highlight both an NCI from the sulfonamide oxygenthat stabilizes the major transition state, and an NCI from thephosphate oxygen that stabilizes the minor transition state. Inthe transition states computed by Jindal and Sunoj, thegreatest change in bond distances between the major andminor transition states is for an NCI between the phosphateoxygen and a hydrogen of the PPh3 ligand, in which the bonddistance is shorter (stronger NCI) in the minor transitionstate.[7f] While the exact nature of the system is different inthis study to the work of Jindal and Sunoj, it is possible thatthe statistical model is describing a similar NCI.

Moving to the analysis of catalyst effects without Pd,a univariate correlation with the dihedral angle of the variedsubstituent was observed for DAP catalysts with a dihedralangle > 6088 (Figure 4c). However, no statistically robustmodels were obtained to define the variance in catalysts witha dihedral angle < 6088, which is likely a consequence of themodest spread of enantioselectivity (between 2.1 and 2.4 kcalmol@1). Nonetheless, we propose that the threshold effect ofthe dihedral angle defines the size of the catalyst pocket,whereby a larger dihedral angle leads to an increase in thepocket size and greater flexibility in substrate binding, leadingto the observed reduction in enantioselectivity.

Figure 4. a) Variance of DAP and TAP catalysts. b) Model describingthe DAP catalyst variance in the presence of Pd, in which (S)-2a isformed as the major enantiomer. c) Model describing the DAP catalystvariance in the absence of Pd, in which (R)-2a is formed as the majorenantiomer.

AngewandteChemieResearch Articles

14651Angew. Chem. Int. Ed. 2020, 59, 14647 – 14655 T 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org

Formation of Fully Substituted Stereocenters inBenzomorpholine Motifs

Having established evidence for the proposed mechanism,we reasoned that the combination of the configurational andconformational flexibility of the DAP catalyst may allowdynamics to alleviate the constraints of a more stericallycrowded transition state.[22] Consequently, we sought to applyour synergistic reaction conditions to a more demandingbond-formation reaction, and, to test our hypothesis, wetargeted the formation of 2,2-disubstituted benzomorpho-lines.

Chiral benzoxazines, including benzomorpholines, areimportant precursors in the synthesis of many bioactivenatural products and pharmaceuticals.[23] In particular, 2,2-disubstituted benzoxazines are core structures in renininhibitors developed by Pfizer.[24] However, stereocontrol inthe formation of a C@O bond at a fully substituted carboncenter remains challenging.[25] Although fully substitutedchiral chromans have been successfullysynthesized throughallylic substitution,[17, 26] there are no reports, to the best of ourknowledge, of the formation of 2,2-disubstituted benzomor-pholines via a Tsuji–Trost reaction.

To initiate this part of the study, the enantioselectiveintramolecular allylic substitution of allylic alcohol 7 a wascarried out with 10 mol% of Pd(PPh3)4 and DAPCy 4a,according to the previous conditions for pyrrolidine forma-tion, affording cyclized product (R)-8a in only 25 % con-version and 5% ee (Table 2, entry 1). Addition of water wasfound to improve the conversion of the reaction (entry 2),[27]

and replacement of the cyclohexyl group on the DAP catalystwith an aromatic substituent (R = Ph and 4-tBu-C6H4) led toa significant improvement in enantioselectivity (50 % and86% ee, entries 3 and 4). Since several DAP catalysts wereineffective in the transformation, full analysis of the catalystvariance could not be made, but models of further datapresented in the Supporting Information suggest that stericsmay be more significant for catalyst selection in this reactionthan for pyrrolidine formation, which is in agreement with theformation of a more sterically encumbered fully substitutedstereocenter. Lastly, optimization of the solvent enabledproduct 8a to be isolated in 89% yield with 93% ee (entry 5,see the Supporting Information for details). In contrast, usingprivileged CPA 3 in the synergistic catalysis gave only traceproduct (entry 6), while the SN2’ reaction of 7a’’ withDAPPhtBu 4e gave the opposite enantiomer, (S)-8a, in24% conversion and only 15% ee (entry 7). These compara-tive results demonstrate the power of the DAP family ofcatalysts to expand the synthetic applications of CPA catalysisbeyond those of existing scaffolds.

We next investigated the scope of the reaction (Fig-ure 5a), and determined that the protecting group on theamine was again important for enantiocontrol (8b–e), eventhough variation is distal to the bond-forming centers. Addi-tionally, manipulations of the phenol substituents were foundto be significant for enantioselectivity (8a,b, 8 f,p); theintroduction of para electron-withdrawing groups led tosignificant erosion of enantioselectivity (3 % ee for 8 n).Correlating the result of variance in both the phenol

substitution and protecting group, we found a strong corre-lation between DDG* and the HOMO energy, indicative ofthe requirement for a highly nucleophilic phenoxide forenantiocontrol (Figure 5b). This suggests that the protectinggroup can be used to modulate the enantioselectivity of thereaction through orbital control, rather than through theadoption of noncovalent interactions, as observed in theabove study of pyrrolidine formation. Despite the differentdemands on the transition states imposed by the two substrateclasses studied, the flexibility of the DAP catalyst familyenables the phosphate anion to afford reactivity and selec-tivity in both settings.

Finally, to test the limitation of the substrate scope, themethyl group in allylic alcohol 7a was replaced by alternativesubstituents. Changing to either a hydrogen atom or ethylsubstituent did not inhibit cyclization, affording products 8rand 8t in 86 % yield with 83 % ee, and 68 % yield with 84% ee,respectively. However, allylic alcohols 7u and 7 v, with benzylor phenyl substituents, were unreactive under the standardreaction conditions, representing the limits of our currentapproach.

Conclusion

We report herein mechanistic studies on the asymmetricinduction of Pd/CPA-catalyzed enantioselective allylic sub-stitutions. Several notable observations and conclusions can

Table 2: Optimization of benzomorpholine formation.[a]

Entry Substrate Catalyst(s) Conv. [%][b] ee [%][c]

1[d] 7a Pd(PPh3)4/4a 25 52 7a Pd(PPh3)4/4a 72 93 7a Pd(PPh3)4/4c 100 504 7a Pd(PPh3)4/4e 59 865[e] 7a Pd(PPh3)4/4e 100 (89) 936 7a Pd(PPh3)4/3 trace n.d.7[d] 7a’’ 4e 24 @15

[a] The reaction was carried out with 10 mol% of Pd(PPh3)4 and/or CPA3/4 in toluene/H2O (10/1 v/v) at ambient temperature. [b] Conv.represents conversion measured by crude 1H NMR analysis, yields ofisolated product in parentheses. [c] ee of product 8a, determined usingHPLC equipped with a chiral column, wherein a positive ee correspondsto (R)-8a, and a negative ee to (S)-8a, as the major configuration.n.d. = not determined. [d] Toluene was used as solvent. [e] PhCF3/H2O(10/1 v/v) was used as solvent, reaction duration 48 h.

AngewandteChemieResearch Articles

14652 www.angewandte.org T 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2020, 59, 14647 – 14655

be drawn from these studies: 1) CPAs catalyze both palla-dium- and Brønsted acid catalyzed allylic substitution reac-tions with high enantioselectivity. 2) Deuterium-labeling ex-periments are consistent with an outer-sphere nucleophilicaddition to a p-allylpalladium intermediate, in which the CPAacts as a chiral anion in the enantio-determining step. Incontrast, the CPA directly participates in the Brønsted acidcatalyzed SN2’-type substitution. Overall, these divergentmechanistic paradigms allow for the preparation of bothenantiomers of the product using a single enantiomer of theCPA catalyst. 3) The origin of this enantio-divergence wasinvestigated by statistical modeling, providing correlations tounderstand the noncovalent interactions for both reactionpathways. Remarkably, catalyst flexibility allows the CPA toadapt to leverage these NCIs, despite the different require-ments for enantioselectivity in each. 4) Finally, the Pd/CPA-catalyzed reaction allowed for the asymmetric construction ofC@O bonds at fully substituted carbon centers, givingchallenging chiral 2,2-disubstituted benzomorpholine motifs.In combination, these results highlight that chiral phosphoric

acid catalysis with DAPs, in both palladium and directphosphate catalysis, enables unique reactivity in accessingboth divergent enantioselectivity with a single catalyst andunprecedented access to tertiary ether stereocenters.

Acknowledgements

F.D.T. thanks the National Institutes of Health (R35GM118190) and M.S.S. thanks the National Institutes ofHealth (GM121383) for support of this work. C.-C.T. thanksthe Ministry of Science and Technology, Taiwan, for a post-doctoral fellowship (106-2917-I-564-056). C.S. thanks the EUfor Horizon 2020 Marie Skłodowska-Curie Fellowship (grantno. 789399). Resources from the Center for High Perfor-mance Computing at the University of Utah, and the ExtremeScience and Engineering Discovery Environment (XSEDE,supported by the NSF (ACI-1548562) and provided throughallocation TG-CHE190060), are gratefully acknowledged. Wethank Dr. Javier Arenas and Dr. Suhong Kim (Berkeley), Dr.

Figure 5. a) Scope of benzomorpholine synthesis. The reaction was carried out with 10 mol% of Pd(PPh3)4 and DAPPhtBu 4e in PhCF3/H2O (10/1 v/v) at ambient temperature. Duration of reaction was 48 h, except for 8e, 8m, 8n, 8p, and 8 t, for which the duration was 72 h. Yields reportedare yields of isolated products, ee was determined using HPLC equipped with a chiral column.[a] PhCF3 was used as solvent. [b] Toluene was usedas solvent. [c] Toluene/H2O (10/1 v/v) was used as solvent. b) Correlation of enantioselectivity with the HOMO energy for substrates 8a–o. 8pwas excluded as the only example with significantly altered steric properties.

AngewandteChemieResearch Articles

14653Angew. Chem. Int. Ed. 2020, 59, 14647 – 14655 T 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org

Tobias Gensch (Utah), Ms. Soumi Trebedi and Prof. Rag-haven Sunoj (IIT Bombay), for useful discussions.

Conflict of interest

The authors declare no conflict of interest.

Keywords: allylic substitution · asymmetric catalysis ·noncovalent interactions · palladium · statistical modeling

[1] For reviews on CPAs in asymmetric catalysis, see: a) D. Parmar,E. Sugiono, S. Raja, M. Rueping, Chem. Rev. 2014, 114, 9047;b) A. Zamfir, S. Schenker, M. Freund, S. B. Tsogoeva, Org.Biomol. Chem. 2010, 8, 5262.

[2] For a review on transition metal/CPA combined catalysis, see:G.-C. Fang, Y.-F. Cheng, Z.-L. Yu, Z.-L. Li, X.-Y. Liu, Top. Curr.Chem. 2019, 377, 23.

[3] For examples of transition metal/CPA combined catalysis, see:a) Y. Reddi, C.-C. Tsai, C. M. Avila, F. D. Toste, R. B. Sunoj, J.Am. Chem. Soc. 2019, 141, 998; b) C. M. Avila, J. S. Patel, Y.Reddi, M. Saito, H. M. Nelson, H. P. Shunatona, M. S. Sigman,R. B. Sunoj, F. D. Toste, Angew. Chem. Int. Ed. 2017, 56, 5806;Angew. Chem. 2017, 129, 5900; c) M. Terada, Y. Ota, F. Li, Y.Toda, A. Kondoh, J. Am. Chem. Soc. 2016, 138, 11038; d) J.-S.Lin, X.-Y. Dong, T.-T. Li, N.-C. Jiang, B. Tan, X.-Y. Liu, J. Am.Chem. Soc. 2016, 138, 9357; e) S. Narute, R. Parnes, F. D. Toste,D. Pappo, J. Am. Chem. Soc. 2016, 138, 16553; f) H. M. Nelson,B. D. Williams, J. Mirl, F. D. Toste, J. Am. Chem. Soc. 2015, 137,3213; g) K. Saito, Y. Kajiwara, T. Akiyama, Angew. Chem. Int.Ed. 2013, 52, 13284; Angew. Chem. 2013, 125, 13526; h) S. Zhou,S. Fleischer, K. Junge, M. Beller, Angew. Chem. Int. Ed. 2011, 50,5120; Angew. Chem. 2011, 123, 5226; i) B. Zhao, H. Du, Y. Shi, J.Org. Chem. 2009, 74, 8392; j) G. L. Hamilton, E. J. Kang, M.Mba, F. D. Toste, Science 2007, 317, 496.

[4] For reviews on transition-metal-catalyzed substitutions of allylicalcohols, see: a) S. L. Rçssler, D. A. Petrone, E. M. Carreira,Acc. Chem. Res. 2019, 52, 2657; b) N. A. Butt, W. Zhang, Chem.Soc. Rev. 2015, 44, 7929; c) B. Sundararaju, M. Achard, C.Bruneau, Chem. Soc. Rev. 2012, 41, 4467.

[5] For examples of dual catalyzed substitutions of allylic alcohols,see: a) Y.-L. Su, Z.-Y. Han, Y.-H. Li, L.-Z. Gong, ACS Catal.2017, 7, 7917; b) M. Yoshida, J. Org. Chem. 2017, 82, 12821; c) H.Zhou, L. Zhang, C. Xu, S. Luo, Angew. Chem. Int. Ed. 2015, 54,12645; Angew. Chem. 2015, 127, 12836; d) L. Næsborg, K. S.Halskov, F. Tur, S. M. N. Mønsted, K. A. Jørgensen, Angew.Chem. Int. Ed. 2015, 54, 10193; Angew. Chem. 2015, 127, 10331;e) S. Krautwald, D. Sarlah, M. A. Schafroth, E. M. Carreira,Science 2013, 340, 1065.

[6] For examples of dual catalyzed enantioselective allylic substitu-tions with Brønsted acids, see: a) G. Jiang, B. List, Angew. Chem.Int. Ed. 2011, 50, 9471; Angew. Chem. 2011, 123, 9643; b) S.Mukherjee, B. List, J. Am. Chem. Soc. 2007, 129, 11336; c) Z.-L.Tao, W.-Q. Zhang, D.-F. Chen, A. Adele, L.-Z. Gong, J. Am.Chem. Soc. 2013, 135, 9255; d) D. Banerjee, K. Junge, M. Beller,Angew. Chem. Int. Ed. 2014, 53, 13049; Angew. Chem. 2014, 126,13265.

[7] a) S. Tribedi, C. M. Hadad, R. B. Sunoj, Chem. Sci. 2018, 9, 6126;b) H. Liu, J.-X. Duan, D. Qu, L.-P. Guo, Z.-Z. Xie, Organo-metallics 2016, 35, 2003; c) K. H. Hopmann, Chem. Eur. J. 2015,21, 10020; d) G. Jindal, R. B. Sunoj, Org. Lett. 2015, 17, 2874;e) G. Jindal, R. B. Sunoj, J. Am. Chem. Soc. 2014, 136, 15998;f) G. Jindal, R. B. Sunoj, J. Org. Chem. 2014, 79, 7600.

[8] For reviews, see: a) C. B. Santiago, J.-Y. Guo, M. S. Sigman,Chem. Sci. 2018, 9, 2398; b) F. D. Toste, M. S. Sigman, S. J. Miller,Acc. Chem. Res. 2017, 50, 609.

[9] For examples, see: a) Y. Kwon, J. Li, J. P. Reid, J. M. Crawford,R. Jacob, M. S. Sigman, F. D. Toste, S. J. Miller, J. Am. Chem.Soc. 2019, 141, 6698; b) M. Orlandi, J. A. S. Coelho, M. J. Hilton,F. D. Toste, M. S. Sigman, J. Am. Chem. Soc. 2017, 139, 6803;c) A. Milo, A. J. Neel, F. D. Toste, M. S. Sigman, Science 2015,347, 737.

[10] a) Y. Kuroda, S. Harada, A. Oonishi, Y. Yamaoka, K. Yamada,K. Takasu, Angew. Chem. Int. Ed. 2015, 54, 8263; Angew. Chem.2015, 127, 8381; for other examples of Brønsted acid catalyzedenantioselective SN2’ reactions, see: b) S. Kayal, J. Kikuchi, M.Shimizu, M. Terada, ACS Catal. 2019, 9, 6846; c) M. Shimizu, J.Kikuchi, A. Kondoh, M. Terada, Chem. Sci. 2018, 9, 5747.

[11] T. Satyanarayana, S. Abraham, H. B. Kagan, Angew. Chem. Int.Ed. 2009, 48, 456; Angew. Chem. 2009, 121, 464.

[12] Catalyst 3 was formulated in 0–80% ee from mixtures of (R)-and (S)-TCYP, resulting in a small error in absolute enantio-purity which explains the non-zero product ee in reactions with0% ee catalyst.

[13] a) J. Mirl, T. Gensch, M. Ellwart, S.-J. Han, H.-H. Lin, M. S.Sigman, F. D. Toste, J. Am. Chem. Soc. 2020, 142, 6390; b) K.Hiramatsu, T. Honjo, V. Rauniyar, F. D. Toste, ACS Catal. 2016,6, 151; c) T. Honjo, R. J. Phipps, V. Rauniyar, F. D. Toste, Angew.Chem. Int. Ed. 2012, 51, 9684; Angew. Chem. 2012, 124, 9822;d) Q.-S. Guo, D.-M. Du, J. Xu, Angew. Chem. Int. Ed. 2008, 47,759; Angew. Chem. 2008, 120, 771.

[14] a) L. Hu, A. Cai, Z. Wu, A. W. Kleij, G. A. Huang, Angew.Chem. Int. Ed. 2019, 58, 14694; Angew. Chem. 2019, 131, 14836;b) J. A. Keith, D. C. Behenna, N. Sherden, J. T. Mohr, S. Ma,S. C. Marinescu, R. J. Nielsen, J. Oxgaard, B. M. Stoltz, W. A.Goddard, J. Am. Chem. Soc. 2012, 134, 19050.

[15] a) D.-C. Bai, F.-L. Yu, W.-Y. Wang, D. Chen, H. Li, Q.-R. Liu, C.-H. Ding, B. Chen, X.-L. Hou, Nat. Commun. 2016, 7, 11806;b) J.-P. Chen, Q. Peng, B.-L. Lei, X.-L. Hou, Y.-D. Wu, J. Am.Chem. Soc. 2011, 133, 14180; c) J. S. Cannon, A. C. Olson, L. E.Overman, N. C. Solomon, J. Org. Chem. 2012, 77, 1961; d) J. S.Cannon, S. F. Kirsch, L. E. Overman, H. F. Sneddon, J. Am.Chem. Soc. 2010, 132, 15192.

[16] a) S. Akkarasamiyo, S. Sawadjoon, A. Orthaber, J. S. M. Samec,Chem. Eur. J. 2018, 24, 3488; b) B. M. Trost, F. D. Toste, J. Am.Chem. Soc. 2003, 125, 3090; c) K. L. Granberg, J.-E. B-ckvall, J.Am. Chem. Soc. 1992, 114, 6858.

[17] B. M. Trost, H. C. Shen, L. Dong, J.-P. Surivet, C. Sylvain, J. Am.Chem. Soc. 2004, 126, 11966.

[18] a) L. M. Wolf, W. Thiel, J. Org. Chem. 2014, 79, 12136; b) H.Kurosawa, H. Kajimaru, S. Ogoshi, H. Yoneda, K. Miki, N.Kasai, S. Murai, I. Ikeda, J. Am. Chem. Soc. 1992, 114, 8417.

[19] a) S. Emamian, T. Lu, H. Kruse, H. Emamian, J. Comput. Chem.2019, 40, 2868; b) T. M. Parker, L. A. Burns, R. M. Parrish, A. G.Ryno, C. D. Sherrill, J. Chem. Phys. 2014, 140, 094106; c) E. G.Hohenstein, C. D. Sherrill, WIREs Comput. Mol. Sci. 2012, 2,304.

[20] TAPPhtBu 4m was used in the formation of products 8a and 8s(Figure 5), resulting in @71 % ee (29% conversion) and @50%ee (50% conversion), respectively. As with the pyrrolidinecyclization, the ee was reduced in magnitude when compared tothe same reaction with DAPPhtBu 4e.

[21] For models utilizing parameters obtained from the (Ra,Ra,Ra)-configurations, see Supporting Information.

[22] J. M. Crawford, M. S. Sigman, Synthesis 2019, 51, 1021.[23] a) H.-C. Shen, Y.-F. Wu, Y. Zhang, L.-F. Fan, Z.-Y. Han, L.-Z.

Gong, Angew. Chem. Int. Ed. 2018, 57, 2372; Angew. Chem.2018, 130, 2396; b) M. Pawliczek, Y. Shimazaki, H. Kimura,K. M. Oberg, S. Zakpur, T. Hashimoto, K. Maruoka, Chem.Commun. 2018, 54, 7078; c) N. Hu, K. Li, Z. Wang, W. Tang,

AngewandteChemieResearch Articles

14654 www.angewandte.org T 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2020, 59, 14647 – 14655

Angew. Chem. Int. Ed. 2016, 55, 5044; Angew. Chem. 2016, 128,5128.

[24] N. A. Powell, F. L. Ciske, C. Cai, D. D. Holsworth, K. Mennen,C. A. Van Huis, M. Jalaie, J. Day, M. Mastronardi, P. McConnell,I. Mochalkin, E. Zhang, M. J. Ryan, J. Bryant, W. Collard, S.Ferreira, C. Gu, R. Collins, J. J. Edmunds, Bioorg. Med. Chem.2007, 15, 5912.

[25] A. Khan, S. Khan, I. Khan, C. Zhao, Y. Mao, Y. Chen, Y. J.Zhang, J. Am. Chem. Soc. 2017, 139, 10733.

[26] a) U. Uria, C. Vila, M.-Y. Lin, M. Rueping, Chem. Eur. J. 2014,20, 13913; b) B. M. Trost, H. C. Shen, L. Dong, J.-P. Surivet, J.Am. Chem. Soc. 2003, 125, 9276.

[27] H. Kinoshita, H. Shinokubo, K. Oshima, Org. Lett. 2004, 6, 4085.

Manuscript received: April 30, 2020Revised manuscript received: May 25, 2020Accepted manuscript online: May 26, 2020Version of record online: June 30, 2020

AngewandteChemieResearch Articles

14655Angew. Chem. Int. Ed. 2020, 59, 14647 – 14655 T 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org