Asymmetric Dual Chiral Catalysis using Iridium Phosphoramidites and

Subscriber access provided by UNIVERSITY OF ADELAIDE LIBRARIES

Article

Asymmetric Dual Chiral Catalysis using Iridium-Phosphoramidites and Diarylprolinol Silyl Ethers: Insights on Stereodivergence Bangaru Bhaskararao, and Raghavan B. Sunoj ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b02776 • Publication Date (Web): 21 Aug 2017 Downloaded from http://pubs.acs.org on August 21, 2017

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

ACS Catalysis is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 33

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

Asymmetric Dual Chiral Catalysis using Iridium-Phosphoramidites and Diarylprolinol Silyl Ethers: Insights on Stereodivergence Bangaru Bhaskararao and Raghavan B. Sunoj* Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076 ABSTRACT Recent examples on asymmetric dual chiral catalysis (ADCC), where two chiral catalysts are employed in one-pot reaction conditions, have demonstrated how all stereoisomers of a product could be effectively accomplished through changing the catalyst chirality. Insufficient mechanistic details on the action of two chiral catalysts and molecular insights on the origin of stereodivergence prompted us to undertake a comprehensive density functional theory (B3LYPD3) investigation on an α-allylation reaction of an aldehyde by using an allyl alcohol resulting in two new chiral centers in the product. The structural and energetic features of the stereocontrolling transition states helped us delineate how all four product stereoisomers could be accessed by using suitable combinations of chiral iridium-phosphoramide and diarylprolinol silyl ether in this ADCC reaction. The covalent activation of the pro-nucleophile (aldehyde) by the organocatalyst furnishes a chiral enamine whereas the action of the transition metal catalyst (chiral Ir-phosphoramidite, P) on racemic allyl alcohol offers an Ir-π-allyl phosphoramidite complex [IrCl(P)2(π-allyl)], which servers as the electrophilic partner. The enantioselectivity is directly controlled by the sense of axial chirality of the Ir-bound phosphoramidite ligand, which impacts whether R or S stereocenter would be generated at the β-carbon of the product. The ‘recognition/interaction’ between the two chiral catalysts in the diastereocontrolling C−C bond formation transition states through a series of weak non-covalent interactions (C-H···π, C

1 ACS Paragon Plus Environment

ACS Catalysis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

H···O, C-H···Cl, C-H···F and lone pair···π) is identified as playing a pivotal role in influencing the favorable mode of addition of the si or re face of chiral enamine to Ir-π-allylphosphoramidite (si-si/re-re) and hence controls the chirality at the α-carbon atom of the developing product. KEY WORDS: Asymmetric Dual Chiral Catalysis, Asymmetric Induction, Transition States, Noncovalent Interactions, Ir-π-allyl-phosphoramidites, Diarylprolinol Silyl Ethers. INTRODUCTION Control of stereochemical outcome in organic reactions has long remained an important endeavor in asymmetric catalysis.1 Traditional protocols in asymmetric catalysis typically employ one chiral catalyst in a given reaction.2 The source of chirality, which is responsible for stereoinduction, generally stems from chiral elements such as a center or axis of chirality present in a chiral ligand in the domain of transition metal catalysis and inherent chiral elements in an organic molecule in organocatalysis.3 Both these forms of asymmetric catalysis that harness the catalytic abilities of transition metals or that of a simpler organic molecule flourished, for decades, as independent areas of remarkable acceptance. The last few years witnessed interesting strides when the practitioners began using both transition metal catalysts and organo catalysts together in one-pot conditions.4 The consequent emergence of cooperative asymmetric catalysis demonstrated that improved stereocontrol could be accomplished through a myriad of dual and multi-catalytic combinations.5 While the early attempts in cooperative multi-catalysis involved the combination of one chiral catalyst with another achiral one, the more exciting recent examples employ two chiral catalysts.6 The dual chiral catalyst combination is far more intricate as the chirality transfer to the developing stereocenter(s) in the product may result in competing and undesirable effects. In


Page 2 of 33

Page 3 of 33

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

other words, not all catalyst combinations may circumvent the issue of match-mismatch, even though they may chemically be compatible in terms of retaining the respective catalytic activities. The key issue in such situations becomes that of gaining predictable enantio- and diastero-control over the possible range of product stereoisomers. Equally significant are the questions on how each such chiral catalysts are involved in reactant activation. It may appear comparatively more obvious in some instances that the substrates are covalently activated prior to the stereocontrolling bond formation step. However, potential role of non-covalent interactions in the vital stereocontrolling transition states would require careful scrutiny.7 More molecular insights in this domain would help further the growth of asymmetric dual chiral catalysis (ADCC). A fascinating feature of asymmetric dual chiral catalysis is that it can provide control over multiple chiral centers and can offer stereodivergence.8-10 In a stereodivergent catalytic approach, one aims to produce all the desired stereoisomers in high enantio- and diasteroselectivities. It is rather conspicuous that two or more catalysts might be required toward realizing this goal. Through an appropriate choice of the sense of chirality in each catalyst one can steer the stereodivergence to the desired stereoisomer in ADCC reactions. The most recent examples indicate that accomplishing high diastereoselectivity are now becoming increasingly more realistic while maintaining superior enantiocontrol. Achieving good stereodivergence is a formidable task without the use of two chiral catalysts. The current interests in this front are propelled by the hope that ADCC can provide access to all stereoisomers with high yield and excellent stereocontrol.8 Contemporary efforts in ADCC make use of metal-metal (Ir-phosphoramidite and Znprophenol ligand),9 metal-organo (Ir-phosphoramidites complexes with organo catalysis such as


ACS Catalysis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

cinchona, diarylprolinol silyl ethers and so on)10 and organo-organo (proline-cinchona)11 dual chiral catalyst combinations. Quite expectedly, mechanistic details on ADCC continue to remain much less understood at this stage. In particular, the origin of stereodivergence demands closer perusal of the stereocontrolling transition states. Among the most recent examples on dual catalysis involving transition metal catalyst and organocatalyst, we became interested in examining the mechanism and origin of stereodivergence in an α-allylation reaction of α-aminoacetaldehydes by racemic allyl alcohols as shown in Scheme 1.10c This method offers interesting access to β,β'-disubstituted α-amino acid derivatives, which are valuable synthetic intermediates as well as used as conformational constraints in peptidomimetics.12 In this example two chiral catalysts are employed; one catalyst makes use of organocatalytic enamine mode of substrate activation provided by diarylprolinol silyl ether whereas the other relies on the reactivity of chiral Ir-π-allyl intermediate derived from allyl alcohol.10c In this manuscript, we wish to present (a) a detailed mechanistic picture on the action of chiral catalysts in substrate activation, (b) interesting molecular insights on how two chiral catalysts work together in the stereocontrolling step, (c) the origin of enantio- and diastereo-selectivities in the formation of the products. COMPUTATIONAL METHODS Computations were performed using Gaussian 09 (Revision D.01) suite of quantum chemical program.13 The geometries were optimized using the B3LYP-D3 hybrid density functional theory14 with Pople’s 6-31G** basis set for all atoms, except iridium. The Los Alamos pseudopotential (LANL2DZ) basis set consisting of an effective core potential (ECP) for 60 core electrons and a double-ζ quality valence basis set for 17 valence electrons was employed for Iridium atom.15 All minima and maxima were respectively characterized by the number of imaginary frequencies as zero and one. The transition states were verified by examining whether


Page 4 of 33

Page 5 of 33

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

it has a unique imaginary frequency representing the desired reaction coordinate. Intrinsic reaction coordinate (IRC) calculations were additionally carried out to further examine the true nature of the transition states.16 The geometries obtained at the end of IRC runs on either side of the IRC trajectories were subjected to further geometry optimization to identify the reactant and product that arise from the transition state. The effect of a solvent continuum, in dichloroethane (DCE), was evaluated using the Cramer−Truhlar SMD continuum solvation model that employs quantum mechanical charge densities of solutes.17 Vibrational partition functions are calculated using Truhlar’s quasi-harmonic approximation, wherein the vibrational frequencies < 100 cm−1 are raised to 100 cm−1.18 A comparison of such energetics was also carried out by correcting the low frequency vibrational modes using the rigid rotor harmonic oscillator (RRHO) approximation.19 This approach is suggested to partly address the issues arising due to the breakdown of the harmonic oscillator approximation. The Gibbs free energies are reported using the corrected vibrational modes with lower frequencies.20 The zero-point vibrational energy (ZPVE) and thermal and entropic corrections obtained at 298.15 K and 1 atm pressure derived from the gas-phase computations at the B3LYP-D3/6-31G**,LANL2DZ(Ir) level of theory have been applied to the electronic energies as obtained from the single-point energy evaluations in the solvent phase at the SMD(DCE)/B3LYP-D3/6-311G**,def2-TZVP(Ir) level of theory to estimate the Gibbs free energies of solutes in the condensed phase. The discussions in the text are

presented

using

the

SMD(DCE)/B3LYP-D3/6-311G**,def2-TZVP(Ir)//B3LYP-D3/6-

31G**,LANL2DZ(Ir) level of theory, unless otherwise specified. Energies were additionally evaluated for the stereo-controlling transition states by using different other functionals such as ωB97XD, M06, and M06-D3 to find that the results are consistent with the B3LYP-D3 level (See Table S6 in the Supporting Information).21 Graphical rendering of the optimized geometries


ACS Catalysis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

were obtained by using the graphical user interface, namely, CYLView.22 Topological analyses of electron densities were carried out using Bader’s Atoms-in-Molecule (AIM) formalism wherein bond paths and bond critical points are identified.23 AIM bond paths were used as a preliminary indicator of weak interactions in the transition states. The Gibbs free energies of the C−C bond formation transition states were employed to calculate the Boltzmann population at a given temperature.24

RESULTS AND DISCUSSIONS The present reaction, as shown in Scheme 1, employs two chiral catalysts in dichloroethane (DCE) solvent. The reaction procedure involved the initial mixing of transition metal pre-catalyst [Ir(COD)Cl]2 and phosphoramidite ligand (P1 or P2) followed by the introduction of racemic allylic alcohol. Aldehyde was sequentially added into the mixture with the organocatalyst (A1 or A2) and dichloroacetic acid (DCA) as a protic additive. In the overall reaction, the reactant αbranched aldehyde is allylated by using an allyl alcohol under a dual catalytic condition.


Page 6 of 33

Page 7 of 33

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

Scheme 1. α-allylation reaction using a cooperative asymmetric dual catalytic method employing a chiral phosphoramidites (P) and secondary amine catalysts (A) (ref 10c) (1) Reactant Activation In the initial phase of the reaction, catalysts can activate the reactants to render the desired reactivity. It has been documented that the action of transition metal catalysts on allyl alcohol in the presence of protic additives could provide an activated π-allyl electrophilic species.25 The formation of iridium-π-allyl species can serve as the electrophilic allyl source in the allylation of aldehydes. The dissociation of dimeric catalyst precursor [Ir(COD)Cl]2 and ligand exchange of COD (cycloocta-1,5-diene) with chiral phosphoramidites (P) can provide the most likely active species [Ir(Cl)(P)2] as shown in Scheme 2(a).26 The reactant allyl alcohol can undergo dehydroxylation by the action of dichloroacetic acid (DCA) when bound to Ir-phosphoramidite.27 In a most recent study by the Carreira group reported the characterization of a catalyst-substrate complex closely similar to 3 as shown in Figure 2(a).28 NMR and X-ray crystallographic probes confirmed the presence of a bis-phosphoramidite complex ([Ir(Cl)(π-allyl alcohol)(P)2]) wherein one of the ligands bind to iridium through both phosphorous and π-olefin of dibenzazepine and the other one only through the phosphorous. Computed energetics indicate that the sense of axial chirality of the Ir-bound phosphoramidite ligand has a direct influence on whether an endo-Ir-π-allyl (4) or exo-Ir-π-allyl intermediate is produced in the dehydroxylation step (vide infra).29 We use endo and exo as the configurational descriptors by using the relative dispositions of C2−H and Ir−Cl bonds in the Ir-π-allyl complex. An anti orientation of C2−H and Ir−Cl bond is denoted as endo (which offers the si-face) whereas the corresponding syn orientation is termed as exo.27,30


ACS Catalysis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

(a)

2

[IrCl(P) 2]

(b)

Scheme 2. Activation of (a) allyl alcohol by [Ir(Cl)(bis)-phosphoramidite] leading to an Ir-πallyl complex, and (b) aldehyde by the action of diarylprolinol silyl ether in the form an enamine intermediate. More mechanistic details and the corresponding Gibbs free energy profiles are provided in the Supporting Information (Scheme S4 and Figure S6). The activation of the other reactant partner, namely, the α-branched aldehyde in the form an enamine intermediate, can be achieved by the action of α-substituted pyrrolidine catalyst, as described below. In the two-step reaction, first a carbinol amine between the aldehyde and pyrrolidine is considered, which upon dehydration yields the enamine intermediate. Acid additives are known to play an important role in the generation of enamines from aldehydes.31 Surprisingly, energetic details on the role of protic additives in the formation of enamine between diarylprolinol silyl ether and aldehydes have not been reported as yet.32 We note that explicit involvement of two molecules of dichloroacetic acid (DCA) in the dehydration transition state renders additional stabilization (~2 to 4 kcal/mol) and leads to a lower energy pathway to


Page 8 of 33

Page 9 of 33

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

the enamine intermediate, as compared to when only one molecule of DCA was considered.33 Since the chiral enamine derived from diarylprolinol silyl ether is a vital intermediate involved in the stereocontrolling C−C bond formation with the chiral Ir-π-allyl species, it is highly desirable that the conformational features are carefully considered at this juncture. As one can imagine, diarylprolinol silyl ether enamine could exist in several different conformers34 due to (a) puckering of the pyrrolidine ring leading to up and down conformers (indicated using the position of C4 ring carbon as shown in Figure 1), (b) orientation of the enamine double bond with respect to the α-substituent on the pyrrolidine ring giving rise to anti and syn forms of a given configuration at the enamine double bond (E-enamine is shown here), and (c) rotation within the α-substituent.35 On the basis of the conformational analysis, we could note that the C4 up conformer of anti-(E)-enamine is the lowest energy than all other conformers (such as anti-(E)-enamine with C4 down, syn-(E)-enamine with C4 up as well as C4 down). In this study, we employed the most preferred conformer in our initial guess geometries of the transition states. Additional conformational analysis of the C−C bond formation transition states is also carried out so as to locate the most preferred transition state for the stereocontrolling step of the reaction (vide infra). anti (E)-enamine up

syn (E)-enamine down

up

down

Figure 1. A simplified representation of important conformers of diarylprolinol silyl ether enamine and the corresponding relative Gibbs free energies (in kcal/mol). The red and blue


ACS Catalysis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

spheres respectively represent diarylprolinol silyl ether and N-phthalimide (NPhth) (2) Reaction between Enamine and Ir-π-allyl species (C−C bond Formation) The nucleophilic and the electrophilic partners in this reaction are associated with a chiral catalyst. An axially chiral Ir-phosphoramidite is the source of chirality in electrophilic Ir-π-allyl species, while the α-chiral center of diarylprolinol silyl ether makes the enamine chiral as well. In the present study, we compare different stereochemical modes of C−C bond formation between these two activated nucleophile and electrophile leading to two new chiral centers in the product.36 In particular, molecular insights on the origin of stereodivergence with different combinations of catalyst chirality are delineated. Although we have investigated all four combinations of catalysts, only two representative sets, A1-P1 and A2-P1 (Scheme 1) are presented here.37 The catalysts A1 and A2 respectively represent the R and S configurations at the α-chiral center of the diarylprolinol silyl ether. P1 indicates the use of (R)-phosphoramidite as the axially chiral ligand on the iridium center. It has been generally known with Ir-π-allyl systems that the nucleophile adds to the more substituted carbon of the allyl moiety resulting in a branched product.38 Indeed our computations revealed that the transition states leading to branched products are about 15 kcal/mol lower than the pathway toward the linear products.39 On the basis of the earlier experimental report as well as our computed data, discussions are confined to the formation of only the branched products, as shown in Scheme 3. In this scheme, a summary of stereodivergent set of products, as noted in earlier the experimental studies and a comparison with the computed stereoselectivities are provided. Since the product formed as a result of the addition of enamine (shown in blue) to Ir-πallyl species (shown in red) bears two chiral centers, four stereoisomers are theoretically


Page 10 of 33

Page 11 of 33

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

possible. However, the experimental product distribution conveys high enantio- and diastereoselectivities for each catalyst combination. For example, with A1-P1, (2S,3R) is the major stereoisomer with an enantiomeric excess of >99% and a diastereomeric excess of 80%.10c,40 It can be further noted that by changing the configuration of diarylprolinol silyl ether, i.e., by using A2-P1 as the catalytic dyad, the product configuration becomes (2R,3R). In other words, the chirality of the α-chiral and β-chiral centers in the product could be respectively inverted by changing the configuration of enamine and the axially chiral phosphoramidite. In other words, the use of suitable combinations of catalysts A1 and A2 with P1 and P2 can provide all four stereoisomers.

Scheme 3. Different likely approaches between the prochiral faces of prolinol−enamine and Ir-πallyl(bis)-phosphoramidite in the stereocontrolling C−C bond formation. Stereodivergence leading to the formation of different stereoisomers and the computed enantio- and diastereoselectivities are given. Experimental values of ee and de are provided in parentheses (ref 10c).37 The most important aspect at this juncture is to probe how two chiral catalysts work together and the stereoelectronic factors in the key transition states that diligently control the


ACS Catalysis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

stereochemical course of this reaction. Before addressing the intricacies of diastereoselectivity, it is of high significance to pay close attention to how the enantioselectivity is set up in this dual chiral catalytic reaction. We noticed an interesting and direct correlation between the sense of axial chirality of the iridium-bound phosphoramidite and the product configuration. When (R)phosphoramidite (P1) is the ligand, the energetics associated with the formation of Ir-π-allyl intermediate is found to be in favor of the endo configuration. The formation of a recognition complex, as shown in Figure 2, between Ir(Cl)(bis)-(R)-phosphoramidite and R-allyl alcohol (leads to endo) is 7.9 kcal/mol more favorable than that with S-allyl alcohol (leads to exo). A low barrier dehydroxylation (~8 kcal/mol) assisted by two explicit DCA molecules can now provide endo-Ir-π-allyl intermediate form R-allyl alcohol.41 In other words, only endo-Ir-π-allyl intermediate is selectively formed when the catalyst is Ir(Cl)(bis)-(R)-phosphoramidite. It is important to note that the endo-Ir-π-allyl intermediate can react only through the open si prochiral face whereas exo-Ir-π-allyl can provide only the re prochiral face for the nucleophilic attack by the incoming enamine. As can be noted from Scheme 1 that the reaction employs racemic allyl alcohol and the overall yield of the reaction is up to 74%. This situation indicates that both R and S enantiomers of the alcohol undergo dehydroxylation to form the Ir-π-allyl intermediate en route to the final product. An alternative hydronium ion promoted dehydroxylation pathway (formed by the action of DCA on water) can provide an indirect access to endo Ir-π-allyl intermediate from S-alcohol.42 In such a pathway, the S alcohol is bound to the iridium center with the hydroxyl group pointing in the opposite face. It is interesting to note that both these catalyst-substrate complexes (Figure 2(a) and (b)) formed between [Ir(P1)2Cl] and allyl alcohol (R or S) has been characterized in one of the most recent studies by Carreira and coworkers.28 We propose that when Ir(Cl)(bis)-(R)-phosphoramidite is the catalyst, the racemic


Page 12 of 33

Page 13 of 33

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

allyl alcohol undergoes a stereoconvergent dehydroxylation to endo-Ir-π-allyl intermediate, thereby providing exclusive access to only one of the product enantiomers.

(a) R-alcohol

(b) S-alcohol

(c) Ir(P1)2Cl-endo-π-allyl

Figure 2. Catalyst-substrate complexes formed between [Ir(P1)2Cl] and racemic allyl alcohol (R or S). The preferred binding modes of R and S alcohols are different. From both these complexes, stereoconvergent dehydroxylation leads to an endo-π-allyl intermediate. The configurational descriptor endo refers to an anti disposition of C2−H and Ir−Cl bonds in the Ir-π-allyl complex (c). Next, we take A1-P1 catalyst combination as a representative case to describe interesting features of the stereodetermining bond formation step. As shown in Scheme 3 and Table 1, four key modes of C−C bond formation can be envisaged that differ in terms of the conformational features and in the prochiral faces of the enamine involved. The orientation of the enamine double bond with respect to the pyrrolidine α-substituent has an implicit influence on the prochiral face available for the C−C bond formation. For instance, owing to the presence of the bulky diarylprolinol silyl ether group, the anti enamine is expected to react through its si prochiral face and syn enamine through the re prochiral face, as shown in Figure 3.43 Identification of the most preferred transition state is a non-trivial task as the substituents (such


ACS Catalysis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 14 of 33

as diarylprolinol silyl ether) as well as the pyrrolidine ring puckering (C4 up and C4 down ring conformers) could span a fairly large conformational space. In addition, the difference in the relative orientations of the reactants along the incipient C−C bond could give rise to additional possibilities.44 After an exhaustive sampling of more than 80 transition states for the addition of enamine to Ir-π-allyl species in the case of A1-P1 catalyst combination, we could identify the most preferred mode of addition. Similar approach with all other catalyst combinations was also carried out and the details are provided in the Supporting Information (Figures S13-S15 and Tables S4-S5). The relative Gibbs free energies of the transition states given in Figure 3 indicate that the most preferred mode involves the addition of anti-(E)-enamine to the si-face of endo-Irπ-allyl species. Such an addition corresponds to the formation of (2S,3R) stereoisomer of the product, which is in agreement with the experimentally observed major enantiomer with A1-P1 catalyst combination. It should be noted that with anti-(E)-enamine, the si face is the preferred prochiral face for the C−C bond formation whereas only the re face can react with Ir-π-allyl species in the case of syn-(E)-enamine.

anti-(E)-enamine

syn-(E)-enamine

0.0

16.7


Page 15 of 33

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

3.8

1.0

Figure 3. Qualitative representation of different modes of C−C bond formation transition states involving endo Ir-π-allyl intermediate with A1-P1 catalyst combination. The relative Gibbs free energies (in kcal/mol) obtained at the SMD(DCE)/B3LYP-D3/6-311G**,def2-TZVP(Ir)//B3LYPD3/6-31G**,LANL2DZ(Ir) level of theory is provided.

Table 1. Relative Gibbs Free Energies (in kcal/mol) for the C−C Bond Formation Transition States between the Prochiral Faces of the Nucleophile and the Electrophile Obtained at the SMD(DCE)/B3LYP-D3/6-311G**,def2-TZVP(Ir)//B3LYP-D3/6-31G**,LANL2DZ(Ir) Level of Theory for Different Catalyst Combinations (phosphoramidites (P1 and P2) and enamines (A1 and A2)

NucleophileElectrophile

Product configuration

A1-P1

A2-P1

A1-P2

A2-P2

si-si

(2S,3R)

0.0

1.8

5.3

8.5

re-si

(2R,3R)

1.0

0.0

6.1

10.0

re-re

(2R,3S)

8.5

5.3

1.8

0.0

si-re

(2S,3S)

10.0

6.1

0.0

1.0


ACS Catalysis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 33

(3) Origin of Diastereoselectivity The analysis of the stereocontrolling transition states is vital toward gaining deeper understanding of stereoinduction. For easier comprehension of these relatively complex transition states, herein we use three modes of illustration, each with an increasing order of information contained in it. First, a standard drawing that clarifies the prochiral faces and the enamine conformers involved in the bond formation with endo-Ir-π-allyl species (Figure 3). The next layer of detail is provided in Figure 4 that shows a smooth space-filling representation of the endo-Ir-π-allyl and a stick model of the enamine, as seen in the lower energy transition states. After analyzing the gross topology of the transition states and the relative orientations of the reacting partners, the nature of weak non-covalent interactions and the differences in such interactions between the stereocontrolling transition states are mapped in Figures 6 and 8.

si-si (anti-E-enamine)

re-si (syn-E-enamine)

Figure 4: Space-filling model of the stereocontrolling C−C bond formation transition states with A1-P1 catalyst combination. In anti-(E)-enamine (left), shown using a stick representation, the si-face is a relatively more open prochiral face while in syn-(E)-enamine (right) it is the re-face that forms a new bond with the si-face of Ir-π-allyl intermediate (shown as a smooth surface).


Page 17 of 33

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

The transition state geometries provided in Figure 4 conveys that the less hindered face of the anti-(E)-enamine is involved in the bond formation with the Ir-π-allyl species in the si-si mode of addition. The si prochiral face of the enamine double bond is opposite to the diaryl prolinol silyl ether making its approach to Ir-π-allyl species feasible. Interestingly, in the case of syn-(E)-enamine, the re prochiral face is open and less hindered for the C−C bond formation. While analysis of this sort, based on the hindered versus open prochiral face of the enamine offers a preliminary clue on the likely facial selectivity, a detailed picture can emerge only through mapping of weak interactions as well as distortion (of catalysts and substrates) in the stereocontrolling transition states. The lowest energy transition state belonging to the si-si mode of addition is responsible for the formation of (2S,3R) product as the major enantiomer. The enantiomeric excess would depend on the relative population of the transition state for the si-si mode as compared to the rere mode of addition. In the present reaction, when the axial chirality of the iridium-bound phosphoramidite ligand is R, the formation of only endo-Ir-π-allyl intermediate from the racemic allyl alcohol is found to be energetically favorable.27 This implies that the si prochiral face of endo-Ir-π-allyl is exclusively involved in the C−C bond formation with the si or re prochiral faces of the incoming enamine. In other words, the configuration at the ensuing β-chiral center in the product is fixed as R in a mechanistic event prior to the C−C bond formation. This is found to be a direct consequence of the configuration of the phosphoramidite ligand on the iridium center. Due to the aforementioned stereochemical features of this dual chiral catalysis reaction, the question of overall stereoselectivity percolates down more to that of diastereoselectivity. In the following section, we shed light on the origin of diastereoselectivity and how two chiral catalysts control the formation of the diastereomers.


ACS Catalysis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 18 of 33

The mapping of important weak interactions in the transition states helped us gain some vital molecular insights. For improved organization of the discussions, these interactions are categorized into three types, as shown in Figure 5. First type is Cat-M···Sub-B, Cat-O···Sub-A, and Sub-A···Sub-B. Here, Cat-M and Cat-O are respectively the transition metal catalyst and organocatalyst and the allyl and enamine regions of the reacting partners are respectively denoted as Sub-A and Sub-B. Another interesting set of interactions between the two catalysts (Cat-M···Cat-O) is also identified. In a dual chiral catalytic reaction, Cat-M···Cat-O interactions could assume additional significance as it represents how catalysts ‘recognize’ or ‘communicate’ with each other in the stereocontrolling transition states. The third type is interactions within a given catalyst, denoted as Cat-M···Sub-A (Ir-π-allyl) and Cat-O···Sub-B (enamine). Metal Catalyst (Cat-M)

*

O O

N Me 3SiO

P Cl

N

Ar'

Ir P O

Organo Catalyst (Cat-O)

O

*

H

H

Cat-M•••Sub-B

Ar'

Cat-O•••Sub-A Sub-A•••Sub-B

N

H

H

H

NPhth

Ph Sub-A

Major Interactions in Transition States

Cat-M•••Cat-O Cat-M•••Sub-A Cat-O•••Sub-B

Sub-B

Figure 5. Qualitative classification of intramolecular interactions in the stereocontrolling transition state geometries. The optimized geometries of the key transition states for the stereocontrolling C−C bond formation in the case of A1-P1 catalyst combination is provided in Figure 6. In all these transition state geometries, the actual reaction coordinate for the C−C bond formation is shown in red dashed lines. The distances shown in pink are for Cat-M···Sub-B, Cat-O···Sub-A, and Sub-A···Sub-B interactions and that in green color is for Cat-M···Sub-A and Cat-O···Sub-B


Page 19 of 33

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

interactions. Only one interaction (d1), noted within the Ir-π-allyl species is shown in Figures 6 and 8, although there are more non-covalent interactions within the enamine moiety (not shown here).45 The most important among these interactions is Cat-M···Cat-O, shown in blue color in the inset. The above-mentioned modes of interactions in the stereocontrolling transition states consist of a rich set of C-H···π, C-H···O, C-H···Cl, C-H···F and lone pair···π non-covalent interactions.46 Alphabetical notations C-H···π (a1,a2,...), C-H···O (b1,b2,...), C-H···F (c1, c2, ...) and C-H···Cl (d1,d2,…) are employed in Figures 6 and 8 to classify these vital interactions.

si-si (0.0)


ACS Catalysis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 20 of 33

re-si (1.0) Figure 6. Optimized geometries of the stereocontroling transition states in the case of A1-P1 catalyst combination. (One of the aryl C-H of BINOL moiety is represented using a short hand notation ‘C-H’ in the inset in the case of si-si mode of addition) There are many common interactions in the diastereomeric transition states si-si and re-si of A1-P1 catalyst combination, as shown in Figure 6. Some of these interactions are unique in a particular diastereomeric transition state and are therefore encircled. For instance, a C-H···O (b4) is unique to the lower energy si-si transition state whereas a lone pair···π (k1) is present only in the higher energy re-si addition. In Cat-M···Cat-O group of interactions, a3 (C-H···π ) are found only in si-si transition state while C-H···F (c1, c3) is unique to re-si mode of addition. Although, we noted that the total number of non-covalent interactions are similar in both the diastereomeric transition states, their cumulative strength approximately estimated as the sum of electron


Page 21 of 33

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

densities at the bond critical points (ρbcp) as obtained through AIM computations, are higher in the case of si-si transition states than in re-si (Table S9).47 In addition, the activation strain analysis revealed that the favorable interaction energy between the reacting partners Ir-π-allyl and enamine is 9.7 kcal/mol higher in the lower energy si-si transition state than in the re-si transition state.48 However, the reactants tend to get more distorted (8.6 kcal/mol) in the lower energy si-si mode of addition. The net effect of these opposing factors is in favor of the lower energy transition state. All the above-mentioned weak non-covalent interactions and the differential noted in si-si and re-si transition states contribute to the associated energy difference of 1.0 kcal/mol that corresponds to a predicted de of 70.4%. The predicted de is in line with the experimentally reported value of 80.0%. Although the enantioselectivity in this reaction is much superior, a similar control over diastereoselectivity appears relatively harder to achieve. This is an important aspect that we wish to emphasize here. A comparison with the diasterocontrolling transition states of the A2-P1 catalyst combination would therefore be most pertinent at this juncture. Before presenting a detailed mapping of intramolecular interactions in the stereocontrolling transition states, it is of importance to examine the major and visible differences between A1-P1 and A2-P1 first. A graphical comparison of the most preferred transition state belonging to A1-P1 and A2-P1 catalyst combinations is provided in Figure 7. In this representation, the Ir-π-allyl species is shown using a smooth space-filling model and is maintained in the same orientation so that the difference in the position and orientation of the enamine is made clear. It is conspicuous that A2 chiral enamine docks into a different region of the chiral cavity provided by Ir-π-allyl complex as compared to the fit of A1. As shown, A1 enamine prefers region-I of the Ir-π-allyl complex


ACS Catalysis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 22 of 33

whereas the most preferred site for the attack of A2 enamine is region-II. In other words, the chirality of incoming enamine influences the ‘recognition’ process between the chiral catalysts. Interestingly, the important difference between A1 and A2 is identified as due to the change in Cat-M···Cat-O type interactions. An obvious question to ask is whether A1 enamine can fit to region-II and A2 to region-I. Such ‘mismatched’ recognitions are found to be 5.8 and 9.0 kcal/mol higher in energy respectively for A1 and A2 enamines. These are interesting molecular insights on how two chiral catalysts interact in the stereocontrolling step. A1-P1 (si-si)

A2-P1 (re-si)

(i)

(ii)

region-I (occupied) region-I (free)

region-II (free)

region-II (occupied)

Figure 7. Stick and space filling model of the lower energy (leading to the major products)


Page 23 of 33

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

diastereomeric transition states of A1-P1 and A1-P2 catalyst combinations. Next, a detailed comparison of the geometric features and differences in the intramolecular interactions in the stereocontrolling transition states are undertaken when the enamine is changed from A1 to A2. For this purpose, the geometries of the diastereomeric transition states for A2-P1 combination is shown in Figure 8. It can be gleaned from the geometries given in Figure 8 that mode of coordination of the two phosphoramidite ligands to iridium are not the same. One of the phosphoramidite ligands is bound to iridium center both through the phosphorous and the π-olefin moiety of dibenzazepine (bi-dentate binding). On the other hand, only the phosphorous of the second phosphoramidite is bound to iridium in a monodentate fashion. In the most preferred transition state with A1-P1, the mono-coordinated phosphoramidite ligand engages in largest number of interactions (shown as region-I in Figure 7). With A2-P1, much of the interactions between the electrophilic and nucleophilic partners are found to be with the bidentate phosphoramidite (region-II).

re-si (0.0)


ACS Catalysis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

si-si (1.8) Figure 8. Optimized geometries of the stereocontroling transition states in the case of A2-P1 catalyst combination. Another major change, when A1 enamine is changed to A2, primarily manifests in the form of differences in Cat-M···Cat-O interactions. For instance, the number of Cat-M···Cat-O interactions is nearly identical in the si-si and re-si diastereomeric transition states of A1-P1 (Figure 6). Interestingly, in the case of A2-P1, more number of interactions is noticed in the lower energy re-si transition state than in the higher energy si-si mode (shown in inset, Figure 8).49 Further, both number and efficiency of interactions in the re-si mode (leads to major product) is higher than in si-si (leads to minor product) in A2-P1. A direct impact of these noncovalent interaction appears in the form of excellent diastereoselectivity for A2-P1 which is >90% in favor of (2R,3R) diastereomer. On the other hand, with A1-P1, number of interactions are found to be the same in both si-si and re-si transition states. Additionally, we have also


Page 24 of 33

Page 25 of 33

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

estimated the interaction energies between various sub-units in the C-C bond formation transition states.50 The sum of electron densities at the bond critical points (as obtained through AIM analysis can approximately be regarded as the total strength of interactions) in the lower energy si-si transition state is only marginally higher than that in the re-si transition state, suggesting a relatively less efficient diastereoselectivity.47 An alternative way of analyzing the noncovalent interactions is by using the NCI plot. We have examined the lowest energy transition state in the case of A1-P1 (si-si) catalyst combination using the NCI plot.51 Molecular details obtained through these analyses indicate that the interaction between the chiral catalysts in the stereocontrolling transition state is a vital aspect in asymmetric dual chiral catalysis described in this study. These are the first transition state models for the fast developing domain of ADCC. The molecular insights suggest that suitable modifications in the appropriate region in the catalysts might help maintain high diastereocontrol in dual chiral catalysis. For example, substituents can be suitably included such that the catalyst-catalyst interaction is modulated, which would have a direct impact on the diastereoselectivity.52 Hence, modulation of non-covalent interactions operating between the chiral catalysts in the diasterocontrolling transition states should be regarded as an important feature in asymmetric dual chiral catalytic reactions. Conclusions In summary, we have gained interesting molecular insights on the mechanism and the origin of stereodivergence in an asymmetric dual chiral catalysis (ADCC) reaction using DFT(B3LYPD3) computational tools. Two covalently activated substrates (a) an aldehyde, which gets activated as a nucleophilic enamine by the action of α-diarylprolinol silyl ethers (R and S) and (b) a racemic allyl alcohol that forms an Ir-π-allyl intermediate through an enantioconvergent


ACS Catalysis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

dehydroxylation to an electrophilic endo-π-allyl species when the chiral ligand on iridium is Rphosphoramidite (and exo-Ir-π-allyl intermediate with S-phosphoramidite). The open prochiral face available for reaction with the incoming nucleophile for endo-Ir-π-allyl intermediate is only the si face whereas exo-Ir-π-allyl provides only the re face. The configuration at the β-carbon in the product is found to be controlled by the axial chirality of the iridium-bound phosphoramidite ligand. On the other hand, diastereoselectivity exclusively depends on the chirality of the diaryl prolinol silyl ethers (R and S) involved in the enamine formation. In the reaction of the enamine tethered to (R)-diarylprolinol silyl ether, the addition of the si face enamine is more preferred than the re face. Similarly the re face can be accessed by making use of (S)-diarylprolinol silyl ether. Both chiral catalysts are involved in the diastereocontrolling C−C bond transition states and the non-covalent interactions between the chiral catalysts are found to play a vital role. The origin of diastereoselectivity could be traced to the differences in non-covalent interactions in the transition states. In the case of A1-P1 catalyst combination, the transition state geometries responsible for major and minor diastereomeric products exhibited very similar pattern of catalyst-catalyst non-covalent interactions (C-H···π, C-H···O and C-H···F) leading to a relatively smaller difference in energies and lower diastereoselectivities. Improved diastereoselectivity with A2-P1 could be attributed to larger differences in non-covalent interactions between the catalysts in the transition state leading to the major and minor diastereomers. The predicted enantio and diastereo-selectivities are found to be in very good agreement with the experimental observations. The insight on catalyst-catalyst interaction could be used as a lead for catalyst modifications in asymmetric dual chiral catalytic reactions. Acknowledgments: Generous computing time from IIT Bombay supercomputing facility is acknowledged. B.B. is grateful to UGC-New Delhi for a Senior Research Fellowship. R.B.S


Page 26 of 33

Page 27 of 33

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

acknowledges Council of Scientific and Industrial Research (CSIR), New Delhi for funding through 02(0052)/12/EMR-II. Supporting Information Available: Optimized geometries, additional schemes, figures, and tables are provided. This material is available free of charge via the Internet at http://pubs.acs.org. REFERENCES (1) (a) Walsh, P. J.; Kozlowski, M. C. Fundamentals of Asymmetric Catalysis; University Science Books: Sausalito, 2008. (b) Comprehensive Chirality; Carreira, E. M., Yamamoto, H., Eds.; Elsevier Science: Amsterdam, 2012; Vols. 1-9. (2) (a) Trost, B. M.; Lee, C. B. In Catalytic Asymmetric Synthesis II; Ojima, I., Ed.; Wiley-VCH: Weinheim, 2000; 593−650. (b) List, B. Asymmetric Organocatalysis; Springer: Heidelberg, Germany, 2009. (c) Transition Metals in Organic Synthesis: A Practical Approach; Gibson, S. E., Ed.; Oxford University Press: 1997. (3) (a) Dalko, P. I. Comprehensive Enantioselective Organocatalysis: Catalysts, Reactions, and Applications; Wiley-VCH: Weinheim, Germany, 2013. (b) Transition Metal Catalyzed Enantioselective Allylic Substitutions in Organic Synthesis; Kazmaier, U., Ed.; Springer: Berlin, 2012. (c) Reid, J. P.; Simón, L.; Goodman, J. M. Acc. Chem. Res. 2016, 49, 1029-1041. (4) (a) Jellerichs, B. G.; Kong, J.-R.; Krische, M. J. J. Am. Chem. Soc. 2003, 125, 7758-7759. (b) Sammis, G. M.; Danjo, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 9928-9929. (c) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 15051-15053. (d) Ibrahem, I.; Cόrdova, A. Angew. Chem., Int. Ed. 2006, 45, 1952-1956. (e) Nicewicz, D. A.; MacMillan, D. W. C. Science. 2008, 322, 77-80. (f) Santoro, S.; Deiana, L.; Zhao, G. –L.; Lin, S.; Himo, F.; Córdova, A. ACS Catal. 2014, 4, 4474-4484.


ACS Catalysis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 28 of 33

(5) (a) Bihania, M.; Zhao, J. C.-G. Adv. Synth. Catal. 2017, 359, 534. (b) Afewerki, S.; Córdova, A. Chem. Rev., 2016, 116, 13512-13570. (c) Meazza, M.; Rios, R. Synthesis 2016, 48, 960-963. (d) Chen, D.-F.; Han, Z.-Y.; Zhou, X.-L.; Gong, L.-Z. Acc. Chem. Res. 2014, 47, 2365-2377. (e) Deng, Y.; Kumar, S.; Wang, H. Chem. Commun. 2014, 50, 4272-4284. (f) Du, Z.; Shao, Z. Chem. Soc. Rev. 2013, 42, 13371378. (d) Allen, A. E.; MacMillan. W. C. Chem. Sci., 2012, 3, 633. (h) Zhong, C.; Xiaodong; Shi, X. Eur. J. Org. Chem. 2010, 2999-3025. (6) (a) Schindler, C. S.; Jacobsen, E. N. Science 2013, 340, 1052-1053. (b) Oliveira, M. T.; Luparia, M.; Audisio, D.; Maulide, N. Angew. Chem., Int. Ed. 2013, 52, 13149-13152. (7) Wheeler, S. E.; Seguin, T. J.; Guan, Y.; Doney, A. C. Acc. Chem. Res. 2016, 49, 1061-1051. (8) Krautwald, S.; Carreira, E. M. J. Am. Chem. Soc. 2017, 139, 5627-5639. (9) Huo, X.; He, R.; Zhang, X.; Zhang, W. J. Am. Chem. Soc., 2016, 138, 11093-11096. (10) (a) Krautwald, S.; Sarlah, D.; Schafroth, M. A.; Carreira, E. M. Science 2013, 340, 1065-1068. (b) Krautwald, S.; Schafroth, M. A.; Sarlah, D.; Carreira, E. M. J. Am. Chem. Soc. 2014, 136, 3020-3023. (c) Sandmeier, T.; Krautwald, S.; Zipfel, H. F.; Carreira, E. M. Angew. Chem. Int. Ed. 2015, 54, 1436314367. (d) Jiang, X.; Beiger, J. J.; Hartwig, J. F. J. Am. Chem. Soc., 2017, 139, 87-90. (e) Cruz, F. A.; Dong, V. M. J. Am. Chem. Soc., 2017, 139, 5627-5639. (11) (a) Huang, H.; Konda, S.; Zhao. J. C.-G. Angew. Chem. Int. Ed. 2016, 55, 2213-2216. (b) Rana, N. K.; Huang, H.; Zhao. J. C.-G. Angew. Chem. Int. Ed. 2014, 53, 7619-7623. (c) Mandal, T.; Zhao, C.-G. Angew. Chem. Int. Ed. 2008, 47, 7714-7717. 12 (a) Noisier, A. F. M.; Brimble, M. A. Chem. Rev. 2014, 114, 8775-8806. (b) Grauer, A.; König, B. Eur. J. Org. Chem. 2009, 5099-5111. (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.;


Page 29 of 33

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

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, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Revision D.01; Gaussian, Inc.: Wallingford, CT, 2013. (14) (a) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. J. Chem. Phys. 2010, 132, 154104-154115. (b) Sperger, T.; Sanhueza, I. A.; Kalvet, I.; Schoenebeck, F. Chem. Rev. 2015, 115, 9532-9586. (c) Hopmann, K. H. Organometallics 2016, 35, 3795-3894. (15) (a) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 270. (b) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 299-310. (16) (a) Gonzalez, C.; Schlegel, H. B. J. Chem. Phys. 1989, 90, 2154-2161. (b) Gonzalez, C.; Schlegel, H. B. J. Phys. Chem. 1990, 94, 5523-5527. (c) Santoro, S.; Kalek, M.; Huang, G.; Himo, F. Acc. Chem. Res. 2016, 49, 1006-1018. (17) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B. 2009, 113, 6378-6396. (18) (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. (19) Grimme, S. Chem. - Eur. J. 2012, 18, 9955−9964. (20) (a) Ribeiro, R. F.; Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B 2011, 115, 1455614562. (b) Ayala, P. Y.; Schlegel, H. B. J. Chem. Phys. 1998, 108, 2314-2323. (21) (a) Weigend, F.; Ahlrichs, R. Phys. Chem. Chem. Phys. 2005, 7, 3297. (b) Weigend, F. Phys. Chem. Chem. Phys., 2006, 8, 1057-1065. (c) Chai, J. -D.; Head-Gordon, M. J. Chem. Phys., 2008, 128, 084106084121. (d) Chai, J. -D.; Head-Gordon, M. Phys. Chem. Chem. Phys., 2008, 10, 6615-6620. (e) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215-241.


ACS Catalysis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 30 of 33

(22) Legault, C. Y. CYLview, 1.0 b, Université de Sherbrooke, Quebec (Canada), 2009, (http ://www.cylview.org). (23) (a) Bader, R. F. W. Chem. Rev. 1991, 91, 893-928. (b) AIM2000 Version 2.0; Buro fur Innovative Software, SBK-Software: Bielefeld, Germany, 2002. (c) Matta, C. F.; Boyd. R. J. Quantum theory of atoms in molecules: Recent progress in theory and application; Wiley-VCH: Weinheim, 2007. (24) (a) Balcells, D.; Maseras, F. New J. Chem. 2007, 31, 333-343. (b) Goodman, J. M.; Kirby, P. D.; Haustedt, L. O. Tetrahedron Letters 2000, 41, 9879-9882. (25) The chemistry of Pd- π-allyl and Ir- π-allyl has found wider applications in transition metal catalysis. (a) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921-2944. (b) Hartwig, J. F.; Stanley, L. M. Acc. Chem. Res. 2010, 43, 1461-1475. (c) Liu, Y.; Han, S.-J.; Liu, W.-B.; Stoltz, B. M. Acc. Chem. Res. 2015, 48, 740-751. (26) Linden, A.; Dorta, R. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2010, C66, m290-m293. (27) Bhaskararao. B.; Sunoj, R. B. J. Am. Chem. Soc. 2015, 137, 15712-15722. (28) Rössler, S. L.; Krautwald, S.; Carreira, E. M. J. Am. Chem. Soc. 2017, 139, 3603-3152. (29) (a) The computed energetics of an unbound allyl alcohol was noted to involve higher barrier (~ 21 kcal/mol) (b) Additional details are provided in Figure S1 in the Supporting Information. (30) The chemdraw geometries of endo-Ir-π-allyl and exo-Ir-π-allyl intermediates have shown in Figure S3. (31) (a) Y. Chi, S. M. Gellman, Org. Lett. 2005, 7, 4253-4256. (b) Zheng, Z.; Perkins, B. L.; Ni, B. J. Am. Chem. Soc. 2010, 132, 50-51. (c) Komisarska, K. P.; Benohoud, M.; Ishikawa, H.; Seebach, D.; Hayashi, Y. Helv. Chim. Acta. 2011, 94, 719-745. (d) Cheong, P. H.-Y.; Legault, C. Y.; Um, J. M.; Ҫelebi-Ӧlҫüm, N.; Houk, K. N. Chem. Rev. 2011, 111, 5042-5137. (32) (a) It is noticed that most of the earlier reports either directly assume the formation of enamine or adopt a similar set of mechanistic steps as known for analogous proline family of secondary amines. (b) Halskov, K. S.; Donslund, B. S.; Paz, B. M.; Jørgensen, K. A. Acc. Chem. Res. 2016, 49, 974-986. (c)


Page 31 of 33

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

Patil, M. P.; Sharma, A. K.; Sunoj, R. B. J. Org. Chem. 2010, 751, 7310. (d) Sharma, A. K.; Sunoj, R. B. Angew. Chem. Int. Ed. 2010, 49, 6373-6377. (33) Full details of formation of syn and anti conformers of (E)-enamine, with one and two DCA molecules, as well as conformers involved in the enamine formation are provided in the Schemes S2-S4, Figures S5-S8 and Table S1 in Supporting Information. (34) (a) Schmid, M. B.; Zeitler, K.; Gschwind, R. M. J. Am. Chem. Soc. 2011, 133, 7065-7074. (b) Schmid, M. B.; Zeitler, K.; Gschwind, R. M. Chem. Sci. 2011, 2, 1793-1803. (c) Patora-Komisarska, K.; Benohoud, M.; Ishikawa, H.; Seebach, D.; Hayashi, Y. Helv. Chim. Acta 2011, 94, 719-745. (d) Seebach, D.; Groselj, U.; Badine, D. M.; Schweizer, W. D.; Beck, A. K. Helv. Chim. Acta 2008, 91, 1999-2034. (e) Hayashi, Y.; Okamoto, D.; Yamazaki, T.; Ameda, Y.; Gotoh, H.; Tsuzuki, S.; Uchimaru, T.; Seebach, D. Chem. Eur. J. 2014, 20, 17077-17088. (35) Additional details on conformational analysis of the enamine intermediates are provided in Table S2 and Figure S9 in the Supporting Information. (36) We have considered an alternative possibility wherein dichloroacetate is explicitly bound to the C−C bond formation transition states. The predicted diastereoselectivities are found to be similar. More details are provided in Scheme S5, Figure S11 and Table S3 in the Supporting Information. (37) See Table S6 in the Supporting Information. (38) Madrahimov, S. T.; Li, Q.; Sharma, A.; Hartwig, J. F. J. Am. Chem. Soc. 2015, 137, 14968-14981. (39) Further comparison of linear and branched pathways are provided in Figure S12 in the Supporting Information (40) Formation of the major and minor diastereomers arises due to the difference in the prochiral faces of the enamine that adds to the endo Ir-π-allyl intermediate. In fact in the earlier experimental report (ref 10c) no trace of products with a 3S configuration was noticed in the HPLC profiles, suggesting only one enantiomer was formed with a given pair of catalyst combination.


ACS Catalysis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 32 of 33

(41) (a) See Scheme S1 and Figure S2 in the Supporting Information for the energies and geometry of the dehydroxylation transition states. (b) An interesting crystal structure of such endo-Ir-π-allyl intermediate (Catalyst-Substrate complexes) has recently been reported by the Carreira group. (b) See ref 28] (42) More details on the transition state for dehydroxylation by the action of hydronium ion is provided in Figure S4 in the Supporting Information. (43) Details of C−C bond formation transition states with exo-Ir-π-allyl species and enamine is provided in Figure S16 in the Supporting Information. (44) Full details of conformational study on the C-C bond formation transition states are provided in the Supporting Information. See Figures S13-S15 and Tables S4-S5. (45) See Figure S17 in the Supporting Information for additional details. (46) (a) Mahadevi, A. S.; Sastry, G. N. Chem. Rev. 2016, 116, 2775-2825. (b) Sunoj, R. B. Acc. Chem. Res., 2016, 49, 1019-1028. (c) Legon, A. C. Phys. Chem. Chem. Phys., 2010, 12, 7736-7747. (47) (a) AIM2000 Version 2.0; Buro fur Innovative Software, SBK-Software: Bielefeld, Germany, 2002. (b) Matta, C. F.; Boyd. R. J. Quantum Theory of Atoms in Molecules: Recent Progress in Theory and Application; Wiley-VCH: Weinheim, 2007. (c) See Tables S8 and S9 in the Supporting Information for more details. (48) (a) Full details of activation strain analysis on the stereocontrolling transition states are provided in Figure S18 and Table S10 in the Supporting Information. (b) Bickelhaupt, F. M. J. Comput. Chem. 1999, 20, 114-128. (c) van Zeist, W.-J.; Bickelhaupt, F. M. Org. Biomol. Chem. 2010, 8, 3118-3127. (49) In addition to the differences in the pattern of weak interactions in the transition states upon going from A1 to A2 enamine, the extent of distortion computed using activation strain analysis, is found to different in Ir-π-allyl fragment. The favorable interaction energy between the reacting partners, i.e., Ir-πallyl and enamine, is 7.6 kcal/mol higher in the lower energy si-si transition state than in the higher energy re-si in the case of A2-P1. However, the reactants tend to get more distorted (5.5 kcal/mol) in the lower energy si-si mode of addition. See Table S10 in the Supporting Information for more details.


Page 33 of 33

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

(50) (a) Seguin, T. J.; Lu, T.; Wheeler, S. E. Org. Lett., 2015, 17, 3066–3069. (b) See Table S11 in the Supporting Information for more details. (c) In the case of A1-P1 catalyst combination, more interaction energy (7.1 kcal/mol) is noticed in the higher energy re-si transition state than in the si-si mode of addition. It is important to consider that the energy ranking is not entirely due to the interaction between various sub-units in the TS. The activation strain analysis indicates that the distortion of the reacting partners also play a major role in this case (Table S10), which appears to offset the effect of the additional stabilization in re-si transition state arising due to better interaction. In A2-P1 case, the interaction energy is 3.7 kcal/mol more in the lower energy re-si TS (0.0) than that in the si-si (1.8) TS. (51) (a) Johnson, E. R.; Keinan, S.; Mori-Sánchez, P.; Contreras-García, J.; Cohen, A. J.; Yang.

W. J. Am. Chem. Soc., 2010, 132, 6498-6506. (b) NCI plot are provided in the form of a movie (Movie S1) in the Supporting Information. (52) As a representative example, we have examined how the substituents on the pyrrolidine impact the diastereoselectivity. See Table S12 in the Supporting Information for more details.

TOC Graphics:


Asymmetric Dual Chiral Catalysis using Iridium Phosphoramidites and

Recommend Documents