Hypercoordinate Iodine Catalysts in Enantioselective Transformation

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Hypercoordinate Iodine Catalysts in Enantioselective Transformation: The Role of Catalyst Folding in Stereoselectivity A Sreenithya, Chandan Patel, Christopher M. Hadad, and Raghavan B. Sunoj ACS Catal., Just Accepted Manuscript • Publication Date (Web): 15 May 2017 Downloaded from http://pubs.acs.org on May 15, 2017

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Hypercoordinate Iodine Catalysts in Enantioselective Transformation: The Role of Catalyst Folding in Stereoselectivity A. Sreenithya,a Chandan Patel,a Christopher M. Hadad,b and Raghavan B. Sunoja,* a

Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India b

Department of Chemistry and Biochemistry, The Ohio State University, 100 West 18th Avenue, Columbus, Ohio 43210, USA e-mail: [email protected]

Abstract: The need for metal-free environmentally benign catalysts has provided a strong impetus to the emergence of hypercoordinate iodine reagents. At this stage of its development, molecular insights on the mechanism and origin of stereoselectivity are quite timely. In this study, the origin of stereoinduction in a class of iodoresorcinol based chiral hypercoordinate iodine catalyzed synthesis of biologically important spirocyclic bisoxindoles from aryl dianilides has been established by using density functional computations. Formation of an interesting helical fold by the 2,6-chiral amide arms on the resorcinol framework is found to be facilitated by a network of non-covalent interactions. In the chiral environment provided by the helical fold, enantioselectivity is surprisingly controlled in a mechanistic event prior to the ring closure to the final spirocyclic product, unlike that commonly found in spirocyclic ring formation. A vital 1,3-migration of the chiral aryl iodonium (Ar*-I(CF3COO)) in an O-iodonium enolate to the corresponding C-iodonium enolate, which retains the chiral memory, holds the key to the enantiocontrol in this reaction and thus renders ring closure to be stereospecific.

Keywords: Hypervalent iodine, Asymmetric catalysis, Transition state, Helical chirality, Reaction mechanism, Stereoselectivity

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Introduction Development of catalytic methods for the generation of enantiopure compounds has remained in the forefront of chemical synthesis. In asymmetric catalysis, the chiral information from the catalyst that manifest in the form of centre, axis, plane, or helical chirality, is transferred to the products in the stereocontrolling step of the reaction. Chiral induction using helical chirality (helicity) is much less explored, barring a few examples on the use of helicene derived chiral catalysts1 and DNA-based hybrid catalysts.2 While a plethora of transition metal and organocatalysts have been employed in modern asymmetric catalysis, a new family of chiral hypercoordinate iodine catalysts with a helical fold appears to emerge into prominence in the most recent years.3 Hypercoordinate iodine compounds are one of the promising candidates toward efficient, low toxic and environmentally benign synthesis. They exhibit transition metal like activity and have been employed as oxidants as well as electrophilic reagents in many metalfree reactions. The electrophilic nature of hypercoordinate iodine and the pronounced leaving group ability of iodoarenes offer unique reactivity to this genre of reagents.4 While a good majority of hypercoordinate iodine promoted reactions requires the use of near-stoichiometric quantities of the iodine reagent, the quest for rendering such transformations catalytic has been on for some years now. Some impressive developments toward asymmetric transformations using in situ generated chiral hypercoordinate iodine as the catalysts are particularly noteworthy.5 Chiral iodoarenes (Ar*−I) are employed in conjunction with a suitable oxidizing agent in such catalytic transformations.6 Although a handful of chiral hypercoordinate iodine compounds have been reported, achieving excellent stereoselectivity still remains a formidable task. A major breakthrough in this area came about in the form of Kita’s spiro-biindane hypercoordinate iodine catalysts.7 Ishihara and co-workers have designed another class of C22 Environment ACS Paragon Plus

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symmetric catalysts by affixing conformationally flexible chiral arms on an iodoresorcinol core,3 which are found to be efficient in a range of reactions.8 The key hypothesis for the iodoresorcinol catalysts was that the weak interactions between the chiral arms with either the (a) electrophilic I(III) centre or (b) with the ligands on I(III) would provide a suitable chiral environment. In most of these reactions, the mechanistic understanding and the origin of stereoinduction continue to remain largely qualitative and occasionally speculative as well. Computational studies have been quite helpful toward understanding the mechanism of catalytic reactions,9 including the ones promoted by hypercoordinate iodine reagents.10 Very recently, Gong and co-workers have reported an elegant asymmetric oxidative C−H functionalization using an in situ generated catalytic chiral iodine(III) species.11 The iodoresorcinol based chiral pre-catalyst Ar*−I is first oxidized to a catalytically active Ar*−I(TFA)2 by the action of trifluoroacetic acid (TFAH) in the presence of peracetic acid oxidant. This protocol offers a C(sp2)−C(sp3) coupling under metal free conditions and provides access to biologically important spiro-bisoxindoles with a chiral quaternary carbon in good enantioselectivity (Scheme 1).12 An important question that invites attention is on how the chiral catalyst is able to impart enantioselectivity to the developing spirocyclic ring junction. Considering that catalytic asymmetric variants of hypercoordinate iodine based reactions are in the emerging phase, molecular insights on the mechanism and stereoselectivity are quite timely and important.


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Scheme 1. a) Chiral hypercoordinate iodine catalyzed enantioselective spiro-bisoxindole formation from anilides. b) Nature of the catalytically active species A (Ar*−I(TFA)2).

Computational Methods All electronic structure calculations were performed using Gaussian09 suite of quantum chemical program.13 The hybrid density functional M06-2X was used for geometry optimization with 6-31G** basis set for all atoms, except iodine.14,15 For iodine, the StuttgartDresden double-ζ zeta basis set (SDD) with effective core potential was used.16 All geometry optimizations were done in the solvent phase, using the SMD continuum solvation model developed by Truhlar and Cramer.17 Since the reaction was performed in nitromethane, a continuum solvent dielectric of ε= 36.6 was employed in our computations. All stationary points were verified by vibrational frequency analysis, where the number of imaginary frequencies is zero and one respectively for minimum energy structures (reactants, products, intermediates) and transition states. Further verification of transition states was done using intrinsic reaction coordinate (IRC) calculations.18 Topological analysis of the electron densities was carried out by using Atoms In Molecule (AIM) Method using the AIM2000 software to characterize weak inter-atomic interactions.19 For comparative purpose, the stereocontrolling transition states were also optimized using the range-separated hybrid functional, namely ω-B97XD.20 4 Environment ACS Paragon Plus

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To examine the origin of energy difference between the stereocontrolling transition states activation-strain formalism was employed in the present study.21 In activation-strain model, activation barrier (∆E‡) is considered as the sum of (a) destabilizing distortion energies (∆Ed‡) in the reactants (and catalysts) while going from their ground state geometries to that in the transition states and (b) stabilizing interaction energy between such deformed reactants (∆Ei‡) in the TS geometry. This approach would help quantify the relative distortion energies between the stereocontrolling transition states as well as to estimate how the reacting partners interact in the transition state. The discussion is presented on the basis of the Gibbs free energies obtained at the SMD(CH3NO2)/M06-2X/6-31G**,SDD(I) level of theory. Gibbs free energies are corrected using Truhlar’s quasi-harmonic approximation wherein the vibrational frequencies lower than 100 cm−1 are raised to 100 cm−1, to correct for the issues with the harmonic oscillator approximation for lower frequency modes.22

Results and Discussion Prior to discussing the origin of enantioselectivity in the spiro-bisoxindole formation, it is of interest to closely examine the stereoelectronic features of the in situ generated catalyst Ar*−I(TFA)2, namely, A. A detailed conformational analysis of active species A, bearing an (S)-prolinol ester substituent on flexible chiral arms, is undertaken first using molecular mechanics and subsequently using DFT (SMD(nitromethane)/M06-2X/6-31G**,SDD(I)) methods to identify the lowest energy conformer.23 In the most preferred conformer, the resorcinol arms are found to organize in a C2 symmetric helical assembly with a right handed P helicity, as shown in Figure 1. Helical fold of the arms is induced by the chiral carbon centre positioned close to the iodoarene. Interestingly, the corresponding M helical assembly with the same catalyst is found to be more than 5 kcal/mol higher in energy.24 We note that the


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helical assembly creates a chiral space around the iodine centre, between the two arms attached to the 2,6 positions of the iodoresorcinol core. Two TFA¯ ligands on I(III) make use of this chiral environment and fit well through forming a network of non-covalent interactions with the chiral arms as shown in Figure 1(i). Both TFA¯ ligands are dispositioned at a dihedral angle θ1= θ2 ~ -60° (where θ1 = C1-C2-I4-O6 and θ = C3-C2-I4O5) with respect to the iodoarene ring. Another conformer with θ1= θ2 ~ -120° is found to be more than 3 kcal/mol higher in energy.24 This conformational feature of the chiral arms, where weak non-covalent interactions leads to a helical structure, could be considered analogous to that in biomolecules.

Figure 1. i) Optimized geometry of the chiral hypercoordinate iodine catalyst A (Ar*−I(TFA)2) obtained at the SMD(nitromethane)/M06-2X/6-31G**,SDD(I) level of theory. Selected weak interactions (a-f) contributing to the helical assembly are shown. All distances are in Å and dihedrals are in °. ii) A qualitative depiction of the helical assembly of chiral arms around I(III). The broad features of the mechanism of formation of the final product spirobisoxindole, from dianilide 1a, can be described as follows. The substrate undergoes a sequential two-step cyclization, wherein the mono-oxindole 1b formed through an initial cyclization undergoes another similar sequence of steps to yield spiro-bisoxindole product p (Scheme 2). Catalytic cycle begins with a nucleophilic substitution of one of the


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trifluoroacetate ligands (TFA¯) by the incoming substrate 1a. Proton abstraction from the active methylene (C11) group by the departing TFA¯ then leads to the formation of an Oiodonium enolate intermediate (3a). The ensuing 1,3-migration of aryl iodonium (Ar*−I(TFA)) from O6 to C11 in 3a generates a lower energy C-iodonium enolate intermediate 4a, wherein iodonium–TFA¯ bond becomes weaker and remains like an ionpair. Subsequent SN2 type C−C bond formation between the ortho carbon of the N8'-phenyl group and the methylenic carbon (C11) yields mono-oxindole 1b. The C−C bond formation is accompanied by a concomitant deprotonation of the ortho C−H of the N8'-phenyl group by TFA¯. 1b undergoes a similar reaction sequence i.e., TFA¯ displacement, sequential formation of O-iodonium enolate (3b) and C-iodonium enolate (4b), followed by ring closure to form the chiral spiro-bisoxindole product p. Interestingly, O-iodonium enolate was proposed as the key intermediate in α-functionalization of ketone.25 However, the direct ring closure of O-iodonium enolate was noted to be of higher energy in the current reaction, which can be attributed to the dearomatization of N-phenyl ring in the transition state as well as in the resulting intermediate.26


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Ph

8N O 6' 6 11 8' O 7 7' N

TS(2a-3a)

Ar*

O

I

Ar* Ph

TFA

[O]

O

3a

N H O

Ph N

TS(3a-4a)

1b O TS(4a-1b)

O Ar*

N I

HH

I

4a

TFAH Ar* I

N

TS(2b-3b) 2b

TFAH

TFA

spiro-bisoxindole formation

TFA

N

H H

H O

TFA

TFA

mono-oxindole formation

N

I

TFA

Ph

O

O

1b Ar*

2a

Ar*

1a

TFA

TFAH

N

TS(1a-2a)

H HH

I

H

N

TS(1b-2b)

H

N

p

N

O

N

N

O

Ar*

O

O

3b

I TFA

TS(4b-p)

N

H

TS(3b-4b)

4b O TFA

TFA

N I

O Ar*

Scheme 2. Mechanism for the Ar*−I(TFA)2 catalyzed formation of spiro-bisoxindole product p from dianilide 1a. Some of the interesting features of the reaction sequence can be described as follows. A stereocenter is created during the initial ring closure to form mono-oxindole (1b). However, this chiral information should be regarded as lost during the second proton abstraction (TS(2b-3b)) to form the O-iodonium enolate 3b. Hence, the stereoselectivity of the final product should dependent entirely on the mechanistic events leading to the second ring closure. With the prime objective of establishing the enantio-controlling factors using hypercoordinate iodine catalysts, we have focused on the energetics of the second ring closure leading to the spiro-bisoxindole. The nucleophilic attack of substrate 1b on I(III) can take place either through the oxindole ring carbonyl (denoted as C1 carbonyl) or through anilide carbonyl (denoted as C2 carbonyl), as shown in Figure 2. Nucleophilic attack through C1 carbonyl is associated with a barrier of 14.8 kcal/mol whereas that through C2 carbonyl proceeds with a lower barrier of 10.2 kcal/mol. In the resulting catalyst-substrate complexes, C1 carbonyl coordination (2b-C1) is preferred by ~2 kcal/mol over the C2 carbonyl coordination (2b). Subsequent enolate 8 Environment ACS Paragon Plus

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formation from 2b-C1 and 2b proceeds with a barrier of 5.1 and 8.1 kcal/mol to form the endocyclic enolate 3b-C1 and exo-cyclic enolate 3b respectively. Ensuing 1,3-migration of the aryl iodonium from endo-cyclic 3b-C1 has a barrier of 21.4 kcal/mol whereas that from exo-cyclic 3b has a barrier of only 5.7 kcal/mol. This difference in barrier indicates that the reaction should prefer to proceed through the C2 carbonyl coordination.27 1,3-migration of aryl iodonium leads to the exoergic (by ~19 kcal/mol) formation of highly reactive C-iodonium enolate intermediate 4b. TFA¯ assisted ring closure in the subsequent step proceeds with a lower barrier of 3.3 kcal/mol to form the final spirocyclic product p.28

Figure 2. Gibbs free energy profile (in kcal/mol) for the hypercoordinate iodine catalyzed coupling reaction. Reaction path involving oxindole ring carbonyl (C1 carbonyl) is shown in red.


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A closer inspection of the mechanistic details conveys that the TFA¯ assisted SN2 type ring closure in 4b can generate the chiral quaternary center of the spiro-bisoxindole p. In the ring closure between the ortho aryl carbon of the N-aryl group and the oxindole in 4b, the C–C bond formation with the oxindole ring can occur only through the opposite side of the C–I(III) bond, indicating that this step is stereospecific. This means that the energetically preferred mode of generation of 4b in the preceding step dictates the chirality of the ensuing product, which is reminiscent of chiral memory effect (Scheme 2). It is interesting to note here that unlike the usually proposed C–C bond formation as the stereocontrolling step in similar spirocycle formations,29 we find that the 1,3-migration of the chiral aryl iodonium (Ar*–I(TFA)) from the enolate oxygen to the favorable prochiral face of the enolate carbon through TS(3b-4b) is the actual stereoselectivity determining step. This constitutes an intriguing example of stereoinduction wherein a mechanistic event prior to the formation of the final stereocentre through the ring closure influences the enantioselectivity of the reaction. The origin of this interesting observation could be traced to the geometric features of chiral C-iodonium enolate intermediate 4b and that of the ring closing transition state TS(4bp). The geometry of TS(4b-p), as shown in Figure 3, reveals that the departure of Ar*–I is quite advanced as compared to the extent of formation of the new C–C bond (I−Cenolate and Caryl−Cenolate distances are respectively 3.87 and 2.31 Å). The Ar*-I is positioned far away from the substrate and hence, it is not expected to have a direct impact on the stereochemistry of the ring closure event. Herein, we focus on the stereoselective 1,3-migration of the Ar*I(TFA) from the enolate oxygen to carbon to understand how stereo-differentiation is accomplished.


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Figure 3. Optimized geometries of 4b and TS(4b-p) at the SMD(nitromethane)/M06-2X/631G**,SDD(I) level of theory. All distances are in Å. In light of the above-mentioned features, the migration of Ar*-I(TFA) from Oiodonium enolate in 3b to C-iodonium enolate via TS(3b-4b) is considered in detail. This migration can occur either to the si or re prochiral face of the enolate carbon. Transition state for migration to the si face (TS(3b-4b)si) that leads to the C-iodonium enolate intermediate 4bsi

is found to be 2.1 kcal/mol lower than that to the re face (TS(3b-4b)re). Subsequent ring

closure in intermediate 4b-si can lead only to the S-spiro-bisoxindole (pS) as the product whereas that in 4b-re would provide exclusive access to R-spiro-bisoxindole (pR). An energy difference of 2.1 kcal/mol between these two diastereomeric transition states for the 1,3migration step corresponds to an enantiomeric excess of >94% in favor of the pS enantiomer. This prediction is in good agreement with the experimentally observed sense and extent of enantioselectivity (85% ee).


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Figure 4. Optimized geometries of the transition states for 1,3-migration of chiral aryl iodonium moiety (Ar*-I(TFA)) obtained at the SMD(nitromethane)/M06-2X/6-31G**,SDD(I) level of theory. Selected weak intramolecular interactions are shown as a-f. All distances are in Å. Dihedrals are in °. Electron densities (ρ x10-2 au) at the bond critical points along the bond paths are shown in parentheses. Only selected hydrogen atoms are shown for improved clarity. A closer inspection of the diastereomeric transition states for 1,3-migration of the Ar*-I(TFA) that converts the O-iodonium- (3b) to C-iodonium- enolate (4b) helped us to delineate the enantio-controlling factors. In the migration to the si face, the enolate develops a set of dispersed weak C−H···O interactions with both the chiral arms of the catalyst (a-f in Figure 4). These multi-point weak interactions offered by the chiral arms hold the substrate in an orientation with relatively lower strain. On the other hand, in the migration to the re face, interaction of the enolate is found to be more localized and confined to only one of the chiral arms of the catalyst. In this case, the substrate reorganizes so as to maximize its favorable interactions with the catalyst arm, however, at the expense of a larger geometric distortion in the substrate. The topology of electron density distribution in the diastereomeric TSs were


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analyzed using Atoms-in-Molecules formalism to identify the weak non-covalent interactions between the substrate and catalyst. The electron densities at the bond critical points corresponding to these interactions (a-f in Figure 4) indicate that the catalyst-substrate stabilizing interactions do not differ much in both diastereomeric TSs. In TS(3b-4b)re, Nmethyl and N-phenyl are found to remain closer to the chiral arm and participate in interactions that results in more out of plane geometry around the anilide nitrogen (θ3(C7-C9-N8C10)

= 166.5°) compared to that in TS(3b-4b)si (θ3 = 174.7°). Quantification of geometric

distortion in the transition states by using activation-strain analysis shows that higher energy TS(3b-4b)re has higher distortion (3.4 kcal/mol), primarily originating from the distortion in the substrate moiety (2.8 kcal/mol). This geometric distortion is noted to lead to a lower delocalization of the anilide lone pair to the N-phenyl group as indicated by Natural Bond Orbital (NBO) analysis. TS(3b-4b)re exhibits modestly higher catalyst-substrate interaction (by -0.7 kcal/mol). These results suggest that the extent of substrate distortion is a critical factor that controls the stereochemical course of this reaction.30 We have explored the stereoinduction with substrates bearing different substituents on the di-anilide nitrogen, such as di-N-benzyl and N-methyl, N-benzyl combinations. Also with these substrates, the transition states for the re face migration exhibit higher distortion, primarily in the enolate partner, as compared to the si face migration.31 It is also noticed that the 1,3-migration to the si face is preferred with other related variants of catalyst A.32 In effect, the chiral space provided by the P-helical framework prefers migration to the si face of the enolate, where it interacts with both the chiral arms with minimum distortion in enolate as well as in catalyst.33 After gaining molecular insights on stereoinduction by using catalyst A, we have examined the origin of relatively ineffective stereoinduction with other catalysts such as catalyst B consisting of a methoxy (-OMe) group and catalyst C consisting of a secondary amine (-NHC6H2(Me)3) decoration on the chiral arms in place of the proline ester. In catalyst


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B, conformers with TFA¯ ligands disposition at θ1= θ2 ~ -60° and θ1= θ2 ~ -120° differ by 2.0 kcal/mol making the later one lower in energy.34 In catalyst C, the lowest energy conformer acquires a disposition of the TFA¯ ligands on I(III) with a dihedral of θ1= θ2 ~ 120.0°. More non-covalent interactions, including a hydrogen bonding between the amide N−H and TFA¯ ligands are found to be involved in maintaining this orientation (Figure 5(a)).3,35 Another conformer of catalyst C with θ1 = θ2 ~ -60.0° is found to be 3.3 kcal/mol higher in energy. Chiral space provided by the helical fold is found to be relatively more confined in the case of catalyst A, which has longer chiral arms, as compared to that with catalysts B and C with shorter arms.


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a)

b)

A B C Figure 5. (a) Optimized geometries of catalysts B and C at the SMD(nitromethane)/M06-2X/631G**,SDD(I) level of theory. Selected weak intramolecular interactions are shown as a-e. All distances are in Å. (b) A qualitative depiction of the helical assembly of chiral arms around I(III) in catalyst A, B and C.


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Figure 6. Optimized geometries of 1,3-migration of chiral aryl iodonium moiety (Ar*I(TFA)) to the si face of enolate with catalyst B (TS(3b-4b)si-B) and C (TS(3b-4b)si-C) obtained at the SMD(nitromethane)/M06-2X/6-31G**,SDD(I) level of theory. Selected weak intramolecular interactions are shown as a-e. All distances are in Å. After developing sufficiently convincing molecular insights into the geometry of catalysts B and C, the corresponding stereocontrolling transition states for 1,3-migration are also located for each catalyst with a substrate bearing a benzyl substituent on one of the dianilide nitrogen and a methyl substituent on the other nitrogen.36 The energy difference between the si and re face migration (TS(3b-4b)si-B and TS(3b-4b)re-B) is found to be only 0.4 kcal/mol for catalyst B favoring the si face migration which is in agreement with the experimentally reported low ee of 22%. It appears that catalyst B with relatively shorter chiral arms fails to provide an effective chiral space for this reactant, which will interact with the substrate, and hence transfer of chiral information to the substrate becomes ineffective. In fact, it is noticed that substrate and the chiral arms of the catalyst do not exhibit any noncovalent interactions in the stereocontrolling transition state. In secondary amide catalyst C, negligible energy difference (~0.1 kcal/mol) is noted between the two diastereomeric transition states (TS(3b-4b)si-C and TS(3b-4b)re-C), which is


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in line with the experimentally observed low ee (33 %). The interactions between the enolate and N-aryl substituent, marked as a and c in Figure 6, are present in both the diastereomeric transition states for migration to the re or si face. Although the C‒H···π interactions (d and e) between methyl and benzyl groups can contribute toward stereo-differentiation, those are found to be very weak. In effect, catalyst does not develop effective differential interactions with the enolate prochiral faces leading eventually to a poor enantioselectivity. In these catalysts, suitable modifications on the chiral carbon substituents, which are in close vicinity of the enolate may result in better enantioselectivity.9a In this family of catalysts, chirality of the helical fold primarily originates due to the chiral centre on the arms. These chiral centers in the chiral arms are found to exert a direct influence on the enantioselectivity of the reaction as compared to that in the α-chiral center of the proline ring in catalyst A. This observation can further be correlated with the experimental results, where an S-spiro-bisoxindole (ps) was obtained even when the chiral center on proline ester was inverted to R from S.12 One can exploit this molecular insight and could afford a reversal of enantioselectivity by inverting the chiral centers on the iodoresorcinol arms. Energetically most preferred helical fold with R,R configuration of the chiral arms is found to be P, which becomes M upon inverting the stereo-centers to S,S. This idea could be employed to accomplish interesting stereodivergence in the formation of spirobisoxindoles. Conclusions In summary, the first transition state model for stereoinduction using a helical assembly of a chiral iodoresorcinol based hypercoordinate iodine catalyst is reported. A series of noncovalent interactions in Ar*−I(TFA)2, particularly between chiral amide arms attached to the 2,6-positions of iodoresorcinol and the iodine bound TFA¯ have been found to induce a helical fold around the iodine center. Formation of the key C-iodonium enolate intermediate


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through 1,3-migration of the chiral iodonium moiety in O-iodonium enolate is identified as the enantiocontrolling step in the overall reaction, contrary to the typical ring closing leading to the spirocyclic quaternary chiral centre. Stereoselectivity using the helical framework of the catalyst originates from a favorable substrate disposition in the chiral space, which exhibits more dispersed substrate-catalyst interactions in addition to minimum structural distortion within the substrate and catalyst. The molecular insights, such as the knowledge of interactions responsible for the helical fold and its consequent role in inducing chirality in the product are expected to contribute to the design of newer chiral hypercoordinate iodine reagents in the burgeoning domain of catalysts using hypercoordinate iodine compounds.

Supporting Information Cartesian coordinates of all stationary points and other relevant information are available free of charge via the Internet at http:// pubs.acs.org. Acknowledgements Generous computing time from the SpaceTime supercomputing at IIT Bombay as well as the Ohio Supercomputing Center (OSC) are gratefully acknowledged. References 1) (a) Narcis, M. J.; Takenaka, N. Eur. J. Org. Chem. 2014, 2014, 21-34. (b) Lu, T.; Zhu, R.; An, Y.; Wheeler, S. E. J. Am. Chem. Soc. 2012, 134, 3095-3102. 2) (a) Boersma, A. J.; Megens, R. P.; Feringa, B. L.; Roelfes, G. Chem. Soc. Rev. 2010, 39, 2083–2092. (b) Wang, L.-X.; Xiang, J.-F.; Tang, Y.-L. Adv. Synth. Catal. 2015, 357, 13-20. 3) (a) Uyanik, M.; Yasui, T.; Ishihara, K. Angew. Chem. Int. Ed. 2010, 49, 2175-2177. (b) Uyanik, M.; Yasui, T.; Ishihara, K. Tetrahedron 2010, 66, 5841-5851. (c) Haubenreisser, S.;


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Wöste, T. H.; Martínez, C.; Ishihara, K.; Muñiz, K. Angew. Chem. Int. Ed. 2016, 55, 413417. 4) (a) Yoshimura, A.; Zhdankin, V. V. Chem. Rev. 2016, 116, 3328-3435. (b) Li, Y.; Hari, D. P.; Vita, M. V.; Waser, J. Angew. Chem. Int. Ed. 2016, 55, 4436-4454. 5) (a) Liang, H.; Ciufolini, M. A. Angew. Chem. Int. Ed. 2011, 50, 11849-11851. (b) Parra, A.; Reboredo, S. Chem. –Eur. J. 2013, 19, 17244–17260. (c) Berthiol, F. Synthesis 2015, 47, 587-603. 6) (a) Ochiai, M.; Takeuchi, Y.; Katayama, T.; Sueda, T.; Miyamoto, K. J. Am. Chem. Soc. 2005, 127, 12244-12245. (b) Dohi, T.; Maruyama, A.; Yoshimura, M.; Morimoto, K.; Tohma, H.; Kita, Y. Angew. Chem. Int. Ed. 2005, 44, 6193-6196. 7) (a) Dohi, T.; Maruyama, A.; Takenaga, N.; Senami, K.; Minamitsuji, Y.; Fujioka, H.; Caemmerer, S. B.; Kita, Y. Angew. Chem. Int. Ed. 2008, 47, 3787-3790. (b) Dohi, T.; Takenaga, N.; Nakae, T.; Toyoda, Y.; Yamasaki, M.; Shiro, M.; Fujioka, H.; Maruyama, A.; Kita, Y. J. Am. Chem. Soc. 2013, 135, 4558-4566. 8) Some representative examples for iodoresorcinol based hypercoordinate iodine catalyzed asymmetric reactions are: (a) Banik, S. M.; Medley, J. W.; Jacobsen, E. N. Science 2016, 353, 51-54. (b) Molnár, I. G.; Gilmour, R. J. Am. Chem. Soc. 2016, 138, 5004-5007. (c) Mizar, P.; Wirth, T. Angew. Chem. Int. Ed. 2014, 53, 5993-5997. (d) Alhalib, A.; Kamouka, S.; Moran, W. J. Org. Lett. 2015, 17, 1453-1456. (e) Ahmad, A.; Silva, L. F. J. Org. Chem. 2016, 81, 2174-2181. (f) Kong, W.; Feige, P.; de Haro, T.; Nevado, C. Angew. Chem. Int. Ed. 2013, 52, 2469-2473. (g) Farid, U.; Malmedy, F.; Claveau, R.; Albers, L.; Wirth, T. Angew. Chem. Int. Ed. 2013, 52, 7018-7022. (h) Romero, R. M.; Souto, J. A.; Muñiz, K. J. Org. Chem. 2016, 81, 6118-6122. (i) Jobin-Des Lauriers, A. C. Y. Legault, Org. Lett. 2016, 18, 108-111. (j) Uyanik, M.; Sasakura, N.; Mizuno, M.; Ishihara, K. ACS Catal. 2017, 7, 872−876. (k) Muñiz, K.; Barreiro, L.; Romero, R. M.; Martínez, C. J. Am. Chem. Soc. 2017,


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139, 4354−4357. (l) Fujita, M.; Yoshida, Y.; Miyata, K.; Wakisaka, A.; Sugimura, T. Angew. Chem. Int. Ed. 2010, 49, 7068 –7071. 9) Special issue on “Computational Catalysis for Organic Synthesis” Acc. Chem. Res. 2016, 49. 10) Sreenithya, A.; Surya, K.; Sunoj, R. B. WIREs Comput. Mol. Sci. 2017, e1299. doi: 10.1002/wcms.1299. 11) Wu, H.; He, Y.-P.; Xu, L.; Zhang, D.-Y.; Gong, L.-Z. Angew. Chem. Int. Ed. 2014, 53, 3466-3469. 12) Pavlovska, T. L.; Redkin, R. G.; Lipson, V. V.; Atamanuk, D. V. Mol. Diversity, 2016, 20, 299–344. 13) 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, N. J.; 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, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Revision D.01, Gaussian, Inc., Wallingford CT, 2013. 14) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215. 15) (a) Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta 1973, 28, 213-222. (b) Rassolov, V.; Pople, J. A.; Ratner, M.; Windus, T. L. J. Chem. Phys. 1998, 109, 1223-1229.


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16) (a) Andrae, D.; Haussermann, U.; Dolg, M.; Stoll, H.; Preuss, H. Theor. Chim. Acta 1990, 77, 123–141.(b) Fuentealba, P.; Stoll, H.; von Szentpály, L.; Schwerdtfeger, P.; Preuss, H. J. Phys. B: At. Mol. Phys.1983, 16, L323-L328. 17) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B 2009, 113, 6378-6396. 18) (a) Fukui, K. Acc. Chem. Res. 1981, 14, 363. (b) Gonzalez, C.; Schlegel, H. B. J. Chem. Phys. 1989, 90, 2154-. (b) Gonzalez, C.; Schlegel, H. B. J. Phys. Chem. 1990, 94, 5523-5527. 19) Bader, R. F. W. Atoms in Molecules: A Quantum Theory; Clarendon Press: Oxford, 1990. (d) AIM2000, Version 2.0; The Buro fur Innovative Software, SBK-Software: Bielefeld, Germany, 2000. 20) Chai, J.-D.; Head-Gordon, M. Phys. Chem. Chem. Phys. 2008, 10, 6615-6620. 21) (a) Morokuma, K. J. J. Chem. Phys. 1971, 55, 1236. (b) Bickelhaupt, F. M. J. Comput. Chem. 1999, 20, 114-128. (c) van Zeist, W. J.; Bickelhaupt, F. M. Org. Biomol. Chem. 2010, 8, 3118. 22) (a) Ribeiro, R. F.; Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B 2011, 115, 14556-14562. (b) Ayala, P. Y.; Schlegel, H. B. J. Chem. Phys. 1998, 108, 2314-2325. 23) Details of conformational analyses are provided in the Supporting Information. See Figures S4 and S5 in the Supporting Information for important catalyst conformers and the energies associated. 24) See Figure S6 in the Supporting Information. 25) (a) Arava, S.; Kumar, J. N.; Maksymenko, S.; Iron, M. A.; Parida, K. N.; Fristrup, P.; Szpilman, A. M. Angew. Chem. Int. Ed. 2017, 56, 2599-2603. (b) Shneider, O. S.; Pisarevsky, E.; Fristrup, P.; Szpilman, A. M. Org. Lett. 2015, 17, 282-285. (c) Beaulieu, S.; Legault, C. Y. Chem. Eur. J. 2015, 21, 11206–11211. 26) (a) Wang, J.; Yuan, Y.; Xiong, R.; Zhang-Negrerie, D.; Du, Y.; Zhao, K. Org. Lett. 2012, 14, 2210-2213. (b) Sreenithya, A.; Sunoj, R. B. Org. Lett. 2014, 16, 6224–6227.


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27) An alternative lower energy O- to O- migration converts endo-cyclic enolate 3b-C1 to exocyclic enolate 3b. See Figure S9 in the Supporting Information for additional details. 28) All the computaed elementary step barriers, except for the final ring closure, are found to be lower with chiral catalyst A than with achiral PhI(TFA)2 reagent. Elementary step barriers are comparable for ring closure in chiral as well as achiral version. See Table S9 in the Supporting Information for additional details. 29) (a) Jindal, G.; Sunoj, R. B. Org. Lett. 2015, 17, 2874-2877. (b) Zheng, P.-F.; Ouyang, Q.; Niu, S.-L.; Shuai, L.; Yuan, Y.; Jiang, K.; Liu, T.-Y.; Chen, Y.-C. J. Am. Chem. Soc. 2015, 137, 9390-9399. (c) Haddad, S.; Boudriga, S.; Porzio, F.; Soldera, A.; Askri, M.; Knorr, M.; Rousselin, Y.; Kubicki, M.; Golz, C.; Strohmann, C. J. Org. Chem. 2015, 80, 9064-9075. 30) For full details of activation-strain and NBO analyses, see Table S3 and Figure S13 in the Supporting Information. 31) Full details of transition state distortions are provided in Figures S18-S19 and Table S6 in the Supporting Information. 32) Additional calculations were also performed with two other variants of catalyst A; one is a diastereomeric form (A-dia) wherein the proline ester on the chiral arm is changed to the R configuration and another one (A-Me) with a –Me group in place of the –COOMe. See Figures S14-S16 in the Supporting information for more details. With both these catalysts, the si face migration is found to be more preferred over the re face indicating that our TS model is more general and applicable for different catalysts in this type of reactions. 33) These results are found to be consistent with other levels of theory. See Table S5 in the Supporting Information.


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34) Another previously proposed conformer as shown in Figure S20 in the Supporting Information, where the carbonyl groups on chiral arm interact with iodne center is found to be 3.4 kcal/mol higher in energy (ref 9l). 35) (a) Such hydrogen bonding interactions between the amide N−H and ligands on the hypercoordinate iodine was reported using x-ray crystallographic analysis in similar catalysts. See Uyanik, M.; Yasui, T.; Ishihara, K. Angew. Chem., Int. Ed. 2013, 52, 9215-9218. (b) However, no transition state models for asymmetric transformations using helical assembly of hypercoordinate iodine catalysts have been reported as yet. 36) The initial mono-oxindole formation involves the ring closure between the ortho carbon of the phenyl group on the benzyl substituted nitrogen and the methylenic carbon. See Figure S17 in the Supporting Information for the details.

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Hypercoordinate Iodine Catalysts in Enantioselective Transformation

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