Insights on the Origin of Regiodivergence in the Parallel Kinetic

Subscriber access provided by UNIV OF NEW ENGLAND ARMIDALE

Article

Insights on the Origin of Regiodivergence in the Parallel Kinetic Resolution of rac-Aziridines using a Chiral Lanthanum-Yttrium Bimetallic Catalyst Hemanta K. Kisan, and Raghavan B. Sunoj ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b02435 • Publication Date (Web): 11 Jul 2018 Downloaded from http://pubs.acs.org on July 11, 2018

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 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 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.

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 40 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

Insights on the Origin of Regiodivergence in the Parallel Kinetic Resolution of rac-Aziridines using a Chiral Lanthanum-Yttrium Bimetallic Catalyst Hemanta K. Kisana and Raghavan B. Sunoj*,b a

Present address: Department of Chemistry, Utkal University, Bhubaneswar, Odisha 751004, India

b

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

Abstract Parallel kinetic resolution of racemic mixtures is an important method used in asymmetric synthesis of chiral compounds. In a recent example, a rac-cis-2,3substituted chiral N-benzoyl aziridine was reacted with dimethyl malonate, in the presence of a La-Y hetero-bimetallic chiral BINAM Schiff base (L) catalyst, to form enantiomerically pure (ee > 98%) γ-amino acid derivatives through a ring-opening reaction in near-quantitative yields from both the enantiomers (~48%). High regioand enantio-selectivities even with a rac-aziridine, having C2 and C3 substituents as similar as ethyl and n-propyl. Through a comprehensive computational investigation, we delineate the origin of regio-divergent and enantioselective formation of γ-amino ester derivatives. The Gibbs free energy of the transition state for the ring-opening at the propyl substituted C2 carbon leading to 3-benzamidoheptan-4-yl malonate is found to be 7.2 kcal/mol lower than that at the ethyl substituted C3 carbon in the case of (2R,3S)-aziridine. A reversal of the regio-chemical preference for its enantiomeric (2S,3R)-aziridine is noted where the ring-opening occurs at the ethyl substituted C3 carbon. The La-Y catalyst is found to initially ‘recognize’ both the enantiomers of the rac-aziridine rather indiscriminately. The activation barriers for the most preferred

1 Environment ACS Paragon Plus

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

ring-opening for each enantiomer are found to be closely similar, suggesting that both enantiomers would react. The high regio-selectivity in the addition of lanthanumbound malonate to the aziridine anchored on to the yttrium center is due to a unique geometric disposition of the aziridine in the stereocontrolling ring-opening transition state. The lowest energy ring-opening transition state for each enantiomer of aziridine exhibited very similar geometries while notable geometric distortions is identified in the malonate addition to less preferred site of the same enantiomer. Key Words: Parallel kinetic resolution, regioselectivity, enantioselectivity, transition states, density functional theory.

Introduction The quest for optically pure compounds led to the development of newer catalytic methods in asymmetric synthesis over the last several decades. The drive to make catalytic processes more atom-economic and environmentally benign has resulted in increasingly more efficient methods. Among these, various forms of kinetic resolution are widely used in the separation of enantiomerically pure compounds from a racemic mixture.1-15 In parallel kinetic resolution (PKR), both enantiomers react in such a way that two optically pure products can be isolated.16-25 Although the differences between various forms of kinetic resolution methods are often described on the basis of reversibility, racemization, faster/slower reacting partners and so on, the underlying semi-quantitative energetic details are not readily available. The utility of new catalytic methods is often times demonstrated by its ability to generate certain class of building blocks for subsequent synthetic transformations. For instance, enantioselective ring-opening of suitably substituted aziridines can provide a wide range of nitrogen-containing chiral structural motifs such as amino


Page 2 of 40

Page 3 of 40 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

acids.26-28 Stereoselective ring-opening of aziridines, either through desymmetrization of meso-aziridines or through kinetic resolution of rac-aziridines are noteworthy.29-31 Most of asymmetric synthesis in contemporary practice makes use of transition metal catalysts. The domain of kinetic resolution is no exception to this trend owing to improved efficiencies offered by transition metal catalysis.32-34 Although palladium is the most widely used transition metal in catalysis,35-38 use of other transition metals has also witnessed a steady progress.39-46 Interestingly, transition metals are now being employed in conjunction with rare earth metals as well as alkali metals for various catalytic applications.47-50 A series of newer family of catalysts have emerged in the recent times that harness the catalytic attributes of rare earth metals and other transition metals in onepot conditions.47-50 Some such bimetallic catalysts are even considered analogous to multi-metallic enzyme active sites.51-55 Some of the bimetallic catalysis involving lanthanides has been effectively employed the parallel kinetic resolution.56,57 In one of the elegant reports, the Shibasaki group has demonstrated a regio-divergent parallel kinetic resolution of racemic cis-aziridines using a bimetallic system derived from a chiral Schiff base template (Scheme 1).58 The fascinating aspect of this reaction is that the action of malonate on the racemic aziridine, that consists of two enantiomers of cis-aziridine, namely 2(2R,3S) and 2'(2S,3R), leads to regiochemically unique γamino acid derivatives 4 and 5 in high yield (as close to the upper bound of 50% in a kinetic resolution) and high enantiomeric excess. For instance, near exclusive formation of 4-heptanyl malonate (4) and 3-heptanyl malonate (5) are noticed as the regio-isomeric products respectively from (2R,3S)-aziridine and its enantiomeric (2S,3R) counterpart.


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 4 of 40

O

CO2Me nPr

O

CO2Me

La(O iPr) 3, Y(OTf)3, 1 (1: 1: 1 mol %)

Ar

CO 2Me

DMAP, MS 4Å Toluene/Et 2O, 35 ˚C

N Et

nPr R

CO2Me

Et S NH Ar

2 (rac)

3

OMe N N

OH

N

O

CO2Me CO 2Me

O

5

Yield = 47% ee = 99%

OH

nPr S NH Et R

4

Ar = 3,5-(CF3) 2-C6H 3

Ar

Yield = 47% ee = 98%

O

∗ N

O

OMe

O

Schiff base 1

Scheme 1. Parallel kinetic resolution of rac-aziridine using a regio-divergent and enantioselective ring-opening by a malonate nucleophile using a La-Y heterobimetallic chiral Schiff base (1) catalyst. The Schiff base with an axially chiral BINAM backbone provides a chiral environment for effective transfer of the chiral information to the developing product. While there have been experimental studies focusing on the mechanism of rare earthalkali metal BINOL catalyst (known as REMB), analogous efforts on heterobimetallic chiral Schiff base family of catalysts are much less reported.59-62 In an earlier report by Rajanbabu, certain questions such as the likely active species as well as mode of substrate activation in bimetallic Schiff base catalytic systems were reported. However, the factors that dictate the origin of unique regio-selectivity and high enantio-selectivities within each of the regio-isomeric products, have not been answered. Efforts in this direction require deeper understanding of the transition states involved in the reaction mechanism and the corresponding energetic details. In this article, we wish to present molecular insights on hetero-bimetallic lanthanum-yttrium chiral Schiff base catalyzed regio-divergent and enantioselective parallel kinetic resolution.


Page 5 of 40 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

Computational Methods We have carried out density functional theory computations using the B3LYP-D3 functional,63 as implemented in Gaussian 09 Rev D.01.64 LANL2DZ effective core potential and a double-zeta quality valence basis were employed for both yttrium and lanthanum.65,66 All other elements were represented using the 6-31G** basis set.67,68 The geometries of reactants, intermediates and transition states were first optimized in the gas phase at the B3LYP-D3/6-31G**,LANL2DZ level of theory. The nature of the stationary points was characterized by examining the Hessian indices. All transition states were found to exhibit one imaginary frequency, as expected for the bond forming event. These transition state geometries were additionally subjected to IRC (intrinsic reaction coordinate) calculations to check how these are connected to the reactant/product on either side of the first order saddle point.69,70 Single point energies were subsequently evaluated for all stationary points in the condensed phase using the Minnesota solvation model (SMD) developed by Cramer and Truhlar.71 For these computations, 28 and 46 core electrons respectively for yttrium and lanthanum, were replaced with effective core potentials and a triple-zeta valence basis set were used.72,73 Thus, the single point energies are at the SMD(Et2O)/B3LYP-D3/6311G**,def2-TZVP//B3LYP-D3/6-31G**,LANL2DZ level of theory. The zero-point vibration energies, thermal and entropic corrections as obtained from the gas phase computations at 298 K and 1 atm pressure have been applied to the single point energies from the solvent phase calculations. The discussions in this manuscript are presented on the basis of the Gibbs free energies in the condensed phase. The topographic steric maps of the stereocontrolling transition states were generated using the SambVca 2 web application.74


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

Results and Discussions The overall catalytic reaction, shown in Scheme 1, can be considered as involving three important steps on the basis of the timing of the mechanistic events. In this reaction, the pre-catalytic species is mixed in the reaction vessel instead of directly employing the actual hetero-bimetallic La-Y catalyst. In view of this, first, we present various scenarios for the in situ formation of the hetero-bimetallic La-Y catalyst. The experimental procedure further involved the introduction of the pro-nucleophilic malonic ester and a base (DMAP), which was then followed by the addition of raccis-aziridine. Hence, the formation of metal-bound malonate is presented next. In the most important section, the discussions on the regio- and enantioselective ring opening of aziridine are provided. (1) Generation of the active catalyst from the pre-catalysts The setting up of the reaction involved sequential addition of lanthanum isopropoxide to a solution of Schiff base ligand in THF first, followed by the introduction of yttrium triflate (Scheme 2). Large metal ions such as lanthanum and yttrium can exhibit diverse coordination patterns leading to a multitude of possibilities. As a starting point in the present investigation, we have computed the Gibbs free energies of formation of various mono-metallic and hetero-bimetallic complexes to understand what ligand combinations at each of metal ions are energetically preferred in the corresponding Schiff base complex. While a more exhaustive array of such Schiff base complexes are provided in the Supporting Information, only those, which are energetically favorable and most likely to be involved in the catalytic cycle, are presented here.75


Page 6 of 40

Page 7 of 40 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

L1 O H

N

O

∗ H O

N

O

N

La(O iPr) 3(THF) 4

L2

THF

La

∗

Schiff base 1

L3 + nL n

L4

N

O

L1 O

O

THF

L2

O

O

N

Y(OTf) 3(THF) 4

La L 4 Y

∗ N

L5 L6 L7

O O L3 La-N2O2-Y-O2O2

O

La-N2O2

where L1, L 2, L 3, L 4 = THF or OiPr or HO iPr L 5, L 6, L 7 = THF or OiPr or OTf

Scheme 2. Generation of monometallic and hetero-bimetallic complexes by the action of metal salts on the chiral Schiff base. We envisaged that the addition of La(OiPr)3 to a THF solution of the native phenolic form of the chiral ligand will lead to a N2O2 chelated salen complex. The notations N2O2 and O2O2 are used here to designate the site of coordination of a metal in the Schiff base ligand scaffold. The N2O2 inner coordination refers to the binding of the metal to the imino nitrogen atoms of the BINAM backbone and with the phenoxide oxygen atoms whereas the O2O2 refers to the outer coordination of metal with the phenoxide and methoxy oxygen atoms of the aryl group (Scheme 2). The mono-metallic N2O2 complex can be formed through protonation of two of the isopropoxide ligands of La(OiPr)3 by the phenolic ligand. Such ligand exchanges wherein two of the native isopropoxide ligands get converted to labile isopropanol obviously lead to a lot more additional possibilities. Considering that the most commonly noticed coordination number of La(III) is 7,76 we have considered La(OiPr)3(THF)4 as the reference for the pre-catalyst. Similarly, Y(OTf)3(THF)4 is taken as the pre-catalyst in the computation of hetero-bimetallic systems. Table 1. The Computed Relative Gibbs Free Energiesa (in kcal/mol) of the Monometallic and Hetero-bimetallic Complexes of Chiral Schiff Base Ligand a) monometallic complex La-N2O2 Entry

L1

L2

L3

L4

Complex

∆Gb

1

OiPr

iPrOH

iPrOH

THF

A-1

-57.8


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 8 of 40

2

OiPr

THF

THF

-

A-2

-54.0

3

OiPr

THF

THF

THF

A-3

-49.8

b) monometallic La-O2O2 complex 4

OiPr

iPrOH

iPrOH

-

A-4

-36.0

5

OiPr

THF

THF

-

A-5

-33.9

6

OiPr

iPrOH

iPrOH

THF

A-6

-34.0

7

OiPr

THF

THF

THF

A-7

-37.2

c) hetero-bimetallic La-N2O2-Y-O2O2 complex Entry

L1

L2

L3

L4

L5

L6

L7

Complex

∆Gc

8

iPrOH

iPrOH

THF

OTf

OTf

OTf

B-1

-50.8

9

OiPr OiPr

THF

-

OTf

THF

OTf

OTf

B-2

-66.1

10

OTf

THF

-

OiPr

OTf

OTf

THF

B-3

-71.7

a

The relative Gibbs free energies in kcal/mol computed at the SMD(THF)/B3LYP-D3/6-311G**,def2TZVP(Y,La)//B3LYP-D3/6-31G**,LANL2DZ level of theory with respect to the separated reactants. Since the hetero-bimetallic complex was generated in THF solvent, computations were also carried out for this part of the mechanism in a THF continuum. b The relative Gibbs free energies with respect to the chiral Schiff base 1 and La(OiPr)3(THF)4. c The relative Gibbs free energies with respect to the chiral Schiff base 1, La(OiPr)3(THF)4 and Y(OTf)3(THF)4.

The computed Gibbs free energies of formation for a select group of monometallic Schiff base complexes and the accompanying generation of labile ligands such as iso-propanol (iPrOH) or triflic acid (HOTf) is provided in Table 1. Although either of the metal ions could occupy the two coordination sites of the Schiff base ligand, the first metal salt that is added in to the reaction mixture occupies the N2O2 binding site.40,47,56,57 Since the bi-metallic catalyst is generated in situ by the sequential addition of lanthanum and yttrium salts to the Schiff base, it is quite likely that the larger rare earth metal occupies the inner N2O2 coordination site as shown in Scheme 2. The most preferred mono-metallic complex is A-1 wherein the native isopropoxide ligands are retained as isopropanol bound to the lanthanum center (entry 1, Table 1). The ligand exchange with the neutral solvent molecules (THF) can lead to


Page 9 of 40 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

A-2 or A-3 complexes, but those are found to be of higher energies. The fit of lanthanum ion to the O2O2 outer coordination site is also evaluated by considering complexes such as A-4. It is noticed that such possibilities are about 22 kcal/mol higher in energy as compared to the binding at the N2O2 site. The introduction of Y(OTf)3 into the reaction mixture can now lead to the formation of a hetero-bimetallic complex. While various ligand combinations may prevail, one of the most likely ones is B-1 where the lanthanum retains its native ligands as in A-1 (OiPr, HOiPr, HOiPr, THF) and Y(OTf)3 fits into the O2O2 outer coordination site. The labile ligands such as isopropanol and THF can exchange at a given metal center or the relatively less labile ligands interchange their positions between the metal centers. The exchange of isopropanol with THF appears to provide lower energy complexes such as B-2. Similarly, the interchange of triflate and isopropoxide between yttrium and lanthanum results in lower energy heterobimetallic complex B-3. In the lowest energy hetero-bimetallic complex B-3, a triflate is bound to the lanthanum while an isopropoxide serves as a bridging ligand. We have considered B-3 as the most likely active catalyst entering the catalytic cycle, as show in Figure 1.

3.57

C

N

O

F

S

La

Y

Figure 1. The optimized geometry of hetero-bimetallic complex B-3 computed at the B3LYP-D3/6-31G**,LanL2DZ(La,Y) level of theory. Hydrogen atoms are omitted


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

for clarity. We notice that the inter-metallic distance in B-3 is as high as 3.57 Å, suggesting that the interaction between the metal centers is less likely to have any pronounced effect. The coordination environment around the lanthanum consists of a triflate, a THF, a bridging isopropoxide besides the N2O2 core offered by the Schiff base backbone. Similarly, yttrium also exhibits a hepta-coordinate binding with various ligands such as two triflates, a THF, a bridging isopropoxide in addition to the O2O2 binding provided by the chiral Schiff base. Interestingly, a crystal structure by the Mazzanti group and mass spectral studies by the Shibasaki group have earlier inferred the participation of hetero-bimetallic catalytic species of similar kind in asymmetric catalysis.47,77,78 (2) Binding of substrates and the generation of the actual reacting partners Details of preferred binding site for each reactant are vital toward understanding the origin of regioselective ring-opening of aziridine under the chiral environment provided by the Schiff base backbone. The regiochemical preference for the attack of the malonate at C2 or C3 carbon of the aziridine is expected to depend on its orientation and proximity to the chiral axis of the binapthyl backbone. The orientation of aziridine would also depend on the nature of other ligands on the La-Y heterobimetallic catalyst. The reactants, malonic ester and aziridine, can bind to either of the metal centers. Similarly, various other ligand combinations are equally possible in these complexes. The presence of DMAP prompted us to consider it as a potential ligand on the metal centers, at this stage of the reaction. Among the hetero-bimetallic La-Y complexes with a bound malonate and aziridine, the one with DMAP on lanthanum is noted as energetically more favorable than when isopropanol is bound to lanthanum (intermediates I1 versus I2, in Figure 2). The catalyst-substrate complex


Page 10 of 40

Page 11 of 40 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

with malonic ester (or malonate) and DMAP on lanthanum and aziridine on yttrium is considered henceforth in this study (Figure 2).

H R H

iPr

O

La

∗ N

OTf OTf

O O

L1

O

O La

∗ N

Y O

L 1 = DMAP = iPrOH

OTf OTf OTf

O

O

TS1 [ 19.8 ]

Ar

O

N

OTf

Y O

R

R Ar

O

O

N

O

O

O

N

H

N

R

nPr

Et

nPr

Et

I1 [ -5.9 ] I2 [ 3.8 ]

Figure 2. Transition state for deprotonation of malonic ester assisted by iPrO and the resulting hetero-bimetallic complexes with malonate and (2R,3S)-aziridine bound respectively to lanthanum and yttrium. The values in the square brackets are the relative Gibbs free energies obtained at the SMD(Et2O)/B3LYP-D3/6-311G**,def2TZVP(Y,La)//B3LYP-D3/6-31G**,LanL2DZ level of theory with the respect to the hetero-bimetallic complex B-3. Where R = –OMe and Ar = 3,5-(CF3)2-C6H3. We have considered the deprotonation of the pro-nucleophile when bound to the catalyst. The binding as well the deprotonation of malonic ester is found to be more favorable when it is attached to lanthanum than to yttrium.79 In the ligandassisted deprotonation, the lanthanum-bound iso-propoxide provides an energetically reasonable access to the desired malonate nucleophile (TS1, Figure 2).80

(3) Aziridine ring-opening The nucleophilic malonate and the electrophilic aziridine are now brought together in the chiral environment of the hetero-bimetallic La-Y catalyst framework. In the most important mechanistic event at this stage, malonate attacks the aziridine ring to form γ-amino ester derivatives as the final product. A more interesting goal is to examine whether there are energetic preferences for regio-selective addition of the malonate to the aziridine. Since the ring carbon atoms of the aziridine are differently substituted


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 12 of 40

with ethyl and n-propyl, the formation of regiodivergent γ-amino ester can be envisaged (Scheme 3). In fact, the earlier experimental study reported the formation of two regio-isomeric products, namely, 4-heptanyl malonate (4) and 3-heptanyl malonate (5). Each product is formed in high enantiomeric excess, as confirmed through chiral HPLC profiles that exhibited only a negligible area under the peak for the enantiomeric product other than what is shown in Scheme 3. CO2 Me nPr R

CO2Me

4 3

Et S

2 3

NH

Ar

O

(2R ,3S)

nPr

Ar N

Et

2

4 ( 4R,3S) yield = 47% ee = 99%

2

+ O

O

(2S,3R)

nPr 3

Et

racemic mixture atom numbering in Reactant Product C2 C4 C3 C3

Ar

nPr S

O

Et R

N

2'

Ar NH

4 3

CO2Me CO 2Me

5 ( 4S,3R ) yield = 47% ee = 98%

Scheme 3. Formation of regiodivergent γ-amino ester products (4 and 5) from racaziridine by the action of malonate using a chiral Schiff base La-Y hetero-bimetallic catalyst. Note that the stereochemical notation for the products are deliberately written with C4 ahead of C3 to make the mapping of atom numbering between the reactant and product more clear. As stated earlier, the reaction employs a racemic mixture of cis-aziridine. Hence, we have examined the mechanism of ring-opening of both (2R,3S) and (2S,3R) enantiomers. Answers to critical questions on the energetic origin of the observed regio-selectivity are not known. The regioselectivity can be described by using the product distribution wherein the (4R,3S) enantiomer of 3-benzamidoheptan4-yl malonate (4) is exclusively produced by the addition of malonate on the nPrsubstituted ring carbon (C2 carbon) of (2R,3S)-aziridine. The other regio-isomeric product, namely (4S,3R) is 4-benzamidoheptan-3-yl malonate (5), formed by ringopening at the ethyl substituted carbon (C3 carbon) of (2S,3R)-aziridine. Considering


Page 13 of 40 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

that steric and electronic features of an ethyl and a propyl group are virtually the same, the exclusive regio-selective ring-opening therefore is an incredibly interesting problem. In fact, our computations on parent aziridine, in the absence of the chiral hetero-bimetallic catalyst, revealed that the transition states for C2 and C3 attack of malonate are degenerate.81 Hence, the key objective here is to decipher how the catalyst steers the flight path of the malonate exclusively to the n-propyl substituted C2 position in the case of (2R,3S) aziridine whereas addition to ethyl substituted C3 position occurs in (2S,3R) enantiomer. As described in the earlier section, the preferred sites for anchoring malonate and aziridine are respectively on lanthanum and yttrium. Multiple modes of binding at a given metal site, depending on whether both or only one of the carbonyl oxygen atoms of the malonate interact with the metal center, are also considered. A possibility where both malonate and aziridine are bound to the same metal center is also examined. While the full details of all such alternatives can be found in the Supporting Information (Tables S3-S6 and Figure S5), some of the important results are summarized here. It is intended to convey that the ring-opening transition states presented in this section are energetically the most preferred ones and have been identified through rigorous sampling of several alternative possibilities. On the basis of the orientation of the N-benzoyl substituent of the aziridine, syn/anti notations, as shown in Figure 3, are used. A syn geometry refers to the orientation of C2-propyl, C3-ethyl and N-benzoyl all on the same side whereas when N-benzoyl group is opposite to the substituents at the C2 and C3, it is denoted as anti. The Gibbs free energy of the anti isomer is found to be only 3.3 kcal/mol lower in comparison to the syn isomer. Further, the barrier for aziridine ring inversion at the nitrogen for anti to syn conversion is about 6 kcal/mol.82 To avoid the likely issues


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

with what could possibly act as a reactive conformer, we have separately examined the energetics for ring-opening with both anti and syn aziridine conformers. Note that the study is on the ring-opening reaction of both enantiomers of the cis configuration of aziridine.

Figure 3. syn and anti geometries of (2R,3S) and (2S,3R) enantiomers of cis-aziridine and the corresponding relative Gibbs free energies (in kcal/mol) computed at the SMD(Et2O)/B3LYP-D3/6-311G**//B3LYP-D3/6-31G** level of theory. The most preferred transition state for the ring-opening in the case of (2R,3S) enantiomer of cis-aziridine is TS-I-C2-a when malonate attacks at the propyl substituted C2 carbon leading to the major product 4 (Figure 4). In TS-I-C2-a, both the carbonyl oxygen atoms of the malonate are coordinated to the lanthanum and the cis-(2R,3S)-aziridine in the anti geometry is bound to the yttrium center through its benzoyl group. A qualitative representation of a few of these transition states is summarized in Figure 4.83 The Gibbs free energies of these transition states are compared with the most preferred transition state TS-I-C2-a. In comparison to TS-IC2-a, the other transition states wherein (i) both reactants are bound to the lanthanum center (TS-I-C2-e) is 14 kcal/mol higher, (ii) malonate is bound to the lanthanum only through one of its enolate oxygen atoms is 18 kcal/mol higher (TS-I-C2-c), and (iii) aziridine is coordinated to the lanthanum and malonate to the yttrium is higher by 40 kcal/mol (TS-I-C2-g). Another important aspect to note here is that the transition states in the case of syn isomer of cis-(2R,3S)-aziridine (TS-I-C2-b in Figure 4) are


Page 14 of 40

Page 15 of 40 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

more than 30 kcal/mol higher than that for the corresponding anti isomer (TS-I-C2a). Different ligand combinations on these ring-opening transition states at propyl substituted C2 carbon are also considered in the case of cis-(2R,3S)-aziridine.84 For improved clarity in discussions, we focus only on the energetically most preferred mode of aziridine ring-opening in the following sections.85

TS-I-C2-a (11.7)

TS-I-C2-e (25.8)

TS-I-C2-b (42.7)

TS-I-C2-g (52.2)

TS-I-C2-c (30.6)

Schiff base backbone (1)

Figure 4. The lower energy transition states obtained in different possible modes of (2R,3S)-aziridine (2) ring-opening at the propyl substituted C2 carbon catalyzed by La-N2O2-Y-O2O2 hetero-bimetallic complex. Value in parenthesis are the relative Gibbs free energies (kcal/mol) with respect to the hetero-bimetallic complex B-3 and


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

the reactants. Where R = –OMe, DMAP = 4-Dimethylaminopyridine and Ar = 3,5(CF3)2-C6H3. The difference in Gibbs free energies between the lowest energy transition states for ring-opening at the C2 position of (2R,3S)-aziridine and at the C3 position of (2S,3R)-aziridine is found to be less than a kcal/mol.86 Hence, both enantiomers of the rac-aziridine can be regarded as equally reactive toward the malonate under the present reaction condition.87 In other words, the computed energetics suggests that both the enantiomeric constituents of the rac-aziridine are recognized equally well by the chiral catalyst and would undergo ring-opening reaction. This prediction is in line with the features of a parallel kinetic resolution. Notably, the yields of the regioisomeric γ-amino ester products obtained from enantiomeric aziridines were reported to be the same in this reaction (Scheme 1). The chiral HPLC profiles of the product mixture indicated a near-exclusive formation of only one enantiomer of a given regio-isomeric product. For instance, product 4-malonate (4) produced by the attack of malonate at the n-Pr bearing C2 position is the only product formed from (2R,3S) enantiomer of the parent aziridine (2). The malonate attack at the C3 position could have yielded the enantiomer of the other regio-isomeric product (5'), i.e., a 3-malonate (Figure 5). The energy difference between the corresponding transition states is found to be as high as 7.2 kcal/mol, suggesting that from a given enantiomer of the reactant, an exclusive regio-isomeric product having a particular configuration is only likely. It is also important, at this stage, to note that the high enantio-selectivity is inseparably linked to the ringopening step in this reaction. In the most preferred ring-opening modes, both the alkyl substituents on the aziridine ring are positioned away from the hetero-bimetallic framework. Alternative pathways when the alkyl substituents point toward the La-Y


Page 16 of 40

Page 17 of 40 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

are found to be much higher in energy.88 With the latter mode of binding of the aziridine and the associated ring-opening, the enantiomer of the same product regioisomer could have been generated. This prediction again indicates that the high degree of enantio control is due to the nearly regio-specific ring-opening involved in the mechanism. The extent of enantioselectivity for the ring-opening of each aziridine enantiomer from the racemic mixture can be calculated on the basis of the Boltzman distribution of relevant transition states. For example, the %ee of the γ-amino ester 4 can be calculated using the difference in Gibbs free energies of TS-I-C2-a and TS-IIC2-a (which is 7.1 kcal/mol, Figure 5). Similarly for product 5, the Gibbs free energy difference of 6.3 kcal/mol between TS-II-C3-a and TS-I-C3-a would yield the corresponding enantiomeric excess. The computed enantioselectivities for γ-amino ester products 4 and 5 are in excellent agreement with the experimental ee of >98 % reported earlier.58 (a) (2R,3S)-aziridine

CO 2Me nPr R

H R nPr Et H

R

R

nPr Et N

R O

O

H

Ar H

La

*

O

Et

H O O H TS-I-C2-a (11.7)

Y R

S NHCOAr

4 Major

TS-I-C3-a (18.9)

nPr H R Et

R

4 3

NHCOAr

H

R

R O *

O

La

Et nPr N HH

O

H R Et nPr NHCOAr O

O H

NHCOAr

nPr R

H

CO2Me

Et S

CO 2Me

HH OO (b) (2S,3R)-aziridine

CO 2Me

4 3

NHCOAr

5' Minor nPr S NHCOAr 4 3

Et R

CO 2Me CO 2Me

TS-II-C3-a (12.6)

Ar

5 Major TS-II-C2-a (18.8)

Y R

Et H R nPr NHCOAr HH O O

CO2Me nPr S 4 3

CO2Me

Et R NHCOAr

4' Minor


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

Figure 5. Regiodivergence in the formation of different product enantiomers (4 and 4', 5 and 5'). The values in parentheses are relative Gibbs free energies (in kcal/mol) with respect to hetero-bimetallic complex B-3 and the reactants.

(4) Origin of Regiodivergence in the Ring-Opening Step To delineate the origin of how the regioselectivity depends on the configuration of aziridines, we herein consider (2R,3S) enantiomer as a representative example. The lowest energy transition state in this case is TS-I-C2-a for the ring-opening at the propyl substituted C2 position of the aziridine. The Gibbs free energy of the corresponding lowest transition state (TS-I-C3-a) for the malonate attack at the C3 position is 7.2 kcal/mol higher. Such an energy difference indicates an exclusive formation of only the major regio-isomeric product 4 (3-benzamidoheptan-4-yl malonate) with (4R,3S) configuration, which in concert with the earlier experimental results.58 In addition to the high regio-control as noted here, a more intriguing feature pertains to the formation of (4R,3S) enantiomer as the only product from (2R,3S)aziridine. The key issue is to the rationalize such an overwhelming preference predicted for the malonate attack at the C2 position, particularly when the substituents at C2 and C3 are respectively n-propyl and ethyl groups. To this end, first, we focused on the important geometric differences between the transition states for C2 (TS-I-C2-a) and C3 (TS-I-C3-a) ring-opening of (2R,3S)-aziridine. Due to the potential complexity involved in effectively conveying these differences, we use a simplified set of graphical representations before presenting the full geometries of the transition states. Here, the overall geometry of the transition states is considered as consisting of three subunits such as I (chiral Schiff base backbone), II (La(malonate)(DMAP)), and III


Page 18 of 40

Page 19 of 40 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

(Y(aziridine)(OTf)3), as shown in Figure 6. Each subunit conveys how the position (and orientation) of the ligands or the substrate(s) change depending on the site of attack of the malonate on (2R,3S)-aziridine. Here the geometric differences between C2 and C3 ring-opening transition states for (2R,3S)-aziridine is analyzed by comparing a suitably chosen constituents shown in Figure 6. It can be noticed that the chiral BINAM backbone (shown as I), in the higher energy transition state for the C3 ring-opening (TS-I-C3-a) exhibits only minimal geometric changes as compared to the lowest energy transition state TS-IC2-a. However, the imino methoxy phenoxide ring (hereafter imino aryl), which could be regarded as a carrier of the chiral information from the axially chiral BINAM core to the reacting substrates, shows certain interesting differences. In particular, of the two methoxy groups, the orientation of the one which is not bound to the yttrium center is quite different in TS-I-C2-a and TS-I-C3-a. Such a difference could have a critical effect on the pattern of interaction between the chiral ligand and aziridine. In subunit II, the malonate remains in very similar geometries in both lower and higher energy TSs.89 The largest variance is found in subunit III wherein the aryl group, triflate ligands on yttrium, and aziridine all exhibit notable differences in the higher energy TS-I-C3-a as compared to the lower energy TS-I-C2-a. It therefore appears that the malonate addition at the less preferred site (C3) triggers a cascade of geometric distortions in the Y-bound aziridine and the catalyst.


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

I II III Schiff base La(malonate)(DMAP) Y(aziridine)(OTf)3 Figure 6. Overlaid images of different regions of the ring-opening transition states TS-I-C2-a (blue, lower energy 11.7 kcal/mol) at the C2 position and TS-I-C3-a (yellow, higher energy 18.9 kcal/mol) at the C3 position for (2R,3S)-aziridine. Only select atoms are shown for clarity. Note that the truncated geometries shown here are obtained from the full geometries of the transition states by suitably deleting the less important atoms/regions for improved clarity in our discussion. After analyzing the differences in the geometric features of the C2 and C3 ring-opening transition states for the (2R,3S) enantiomer of rac-aziridine, we have performed another important comparison between the most preferred ring-opening transition states for (2R,3S)-aziridine and that of its enantiomeric (2S,3R)-aziridine. A truncated depiction of an important region of the overall geometry of these two transition states is shown in Figure 7. From the overlaid images, as shown in Figure 7(a), it can be noticed that the orientation of the aziridine ring in the lowest energy transition states is very similar for both the enantiomers. This can also be understood by independently focusing on the aziridine orientations for the C2 ring-opening via TS-I-C2-a (blue) in the case of (2R,3S)-aziridine and for C3 ring-opening via TS-IIC3-a (green) for (2S,3R)-aziridine. In this example, the change in aziridine configuration from (2R,3S) to (2S,3R) is essentially due to the interchange of positions between ethyl and n-propyl substituents. It is further noted that the geometric features of the aziridine ring in the most preferred ring-opening transition states for both the enantiomers (i.e., (2R,3S) and (2S,3R)) are nearly identical. In other words, the aziridine ring is oriented toward the incoming malonate in the same welldefined manner in the most preferred transition state, irrespective of the alkyl substituent attached to the ring carbon atom. The success of this parallel kinetic


Page 20 of 40

Page 21 of 40 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

resolution appears to stem from the ability of the chiral La-Y catalyst to hold both the enantiomers of the aziridine in such a geometry, which is most conducive for ringopening by the malonate.

(a) The most preferred ring-opening TSs for (2R,3S)-aziridine and enantiomeric (2S,3R)-aziridine and the corresponding Gibbs free energies in kcal/mol

TS-I-C2-a TS-II-C3-a (11.7) (12.6) overlaid (2R,3S)-aziridine (C2) (2S,3R)-aziridine (C3) (b) The most preferred and less preferred ring-opening TSs for (2R,3S)-aziridine

TS-I-C3-a (18.9) overlaid (2R,3S)-aziridine (C3) Figure 7. The most important region of the ring-opening transition state geometry taken from the full geometry. The first row (a) shows an overlaid image of the most preferred ring-opening TSs for (2R,3S)-aziridine and its enantiomeric (2S,3R)aziridine respectively at the C2 (blue) and C3 (green) positions. The second row (b) is the overlaid images for the most preferred ring-opening TS for (2R,3S)-aziridine at C2 carbon (blue) and the higher energy TS for ring-opening at the C3 carbon (yellow). The geometries are truncated by suitably deleting the less important atoms/regions from the full transition state geometry for improved clarity.


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

In sharp contrast is the geometric features of the less preferred transition state for the C3 ring-opening (TS-I-C3-a) of the (2R,3S) enantiomer of aziridine. From the overlaid images (Figure 7(b)) we note that the orientation of the aziridine ring in this TS is substantially different in comparison to that in the corresponding TS for the C2 ring-opening.90 As noted earlier, C3 ring-opening TS (TS-I-C3-a) is more than 7 kcal/mol higher in energy than that for C2 ring-opening. Similar features are also noted with the (2S,3R) enantiomer of aziridine where the ring-opening at the C3 is more preferred.91,92 Next, the fit of reactants, i.e., cis-(2R,3S)-aziridine and malonate, to the chiral hetero-bimetallic catalyst is analyzed by using a space-filling model (Figure 8). Two orientations of the chiral Schiff base backbone in the lowest energy transition states for ring-opening at C2 (TS-I-C2-a) and C3 (TS-I-C3-a) positions of (2R,3S)aziridine (2) are shown in Figure 8. The blue circular regions A and B are the sites respectively for La(malonate)(DMAP) and Y(OTf)3((2R,3S)-aziridine). The black circular region E indicates the methoxy substituent on the phenoxy ring of the chiral Schiff base and blue circular region F indicates the region where the three triflate ligands (-OTf) are located. Comparison of TS-I-C2-a and TS-I-C3-a reveals that the region B is larger in the former case, offering more space for the substrate aziridine to fit in. The methoxy substituent (region E) in the higher energy TS-I-C3-a is found to bent more towards region F as compared to that in TS-I-C2-a, resulting in a relatively smaller and constrained space in region F. Accommodating three triflate ligands in region F therefore leads to greater distortion in the Schiff base. It should be noted that of the two methoxy groups of the imino aryl arm, one is bound to yttrium whereas the orientation of the other shows interesting variation depending on the site of attack of the malonate (see subunit I in Figure 6). These geometric differences between the


Page 22 of 40

Page 23 of 40 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

most preferred and the higher energy transition states hint at a likely role of relative distortion in contributing to the energy difference between the C2 and C3 ringopening transition states. Similar geometric features are noticed with the (2S,3R)aziridine (2') as given in Figure S8 in the Supporting Information. orientation-1

orientation-2

TS-I-C2-a TS-I-C3-a TS-I-C2-a TS-I-C3-a Figure 8. Space-filling representation of the chiral Schiff base backbone (1) as seen in the regiocontrolling transition states. These are simplified representations of the stereocontrolling transition states, derived from the full geometry by deleting all other ligands and substrates. To gain additional insights into the origin of the energetic preference for the C2 ring-opening via TS-I-C2-a, we have performed activation strain analysis wherein the transition state geometry is appropriately partitioned to capture the distortion in each fragment and interaction energies between such distorted fragments.93,94 The distortion in the chiral Schiff base in the higher energy TS-I-C3-a for the ringopening at C3 carbon is 2.8 kcal/mol more than that in TS-I-C2-a.95 All the abovementioned features of the regiocontrolling transition states suggest that positioning aziridine ring with the C3 carbon toward the incoming malonate can lead to a cascade of geometric distortions in the chiral Schiff base, in particular, in the orientation of the methoxy group. After inspecting at the gross geometric features of the ring-opening transition states, we have analyzed the finer details by mapping out all important weak


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

interactions (shown in Figure 9). Certain important differences in the pattern of noncovalent interactions in the transition states, depending on the site of malonate attack could be derived. These intramolecular interactions are characterized by the presence of bond paths and bond critical points by using the atoms in molecules (AIM) formalism.96,97 Non-covalent interactions such as C‒H…π (b, f, n), C‒H…O (a, d, e, j, k, l), C‒H…F (i) and lone pair…π (g, h) are noted in both transition states for C2 (TSI-C2-a) and C3 (TS-I-C3-a) ring-opening. While some of these interactions are unique to a given transition state, others are common and found in both transition states. Non-covalent interactions such as these are known to impact the stereochemical outcome of asymmetric transformations.98,99 On the basis of the electron densities at the bond critical points (ρbcp) pertaining to interatomic contacts shown in the figure, we note that the efficiency of interactions which are common in both the transition states are marginally better in the lower energy transition state TSI-C2-a for the C2 addition than the higher energy alternative for ring-opening at the C3 (TS-I-C3-a) position. Interestingly, total number of non-covalent interactions is higher in TS-I-C3-a, suggesting that the energy difference might arise due to factors other than weak interactions in the transition states (vide supra). As described in the previous section, the distortion of the chiral Schiff base plays a key role in rendering one of the C2 or C3 ring-opening more preferred, depending on which enantiomer is the reactant. Similar pattern of interactions is also noticed in the ring-opening transition states with the enantiomeric (2S,3R)-aziridine (2'), in which case the lower energy C3 ring-opening mode is equivalent to the C2 ring-opening described here for (2R,3S)-aziridine. Additional details are provided in Figure S12 in the Supporting Information. We have also extended these transition state models to other closely related rac-aziridines bearing ethyl and methyl substituents instead of ethyl and n-


Page 24 of 40

Page 25 of 40 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

propyl groups. The transition states for the most preferred as well as other higher energy regioisomeric ring-opening pathways are identified. We noted a similar regioand enantio-selectivities in the formation γ-amino esters with this minimally modified aziridines as well. More importantly, the predicted regio- and enantio-selectivities with such substrates are also found to be consistent with the known experimental observations.58,100

CF3

2.06 2.35

g f d

a b

CF3 2.49

i

S O

S

S

CF3

O

F 3C

k h g f CF3 nO O

a

e

O

2.12

l

j

h

O

F 3C

O

C−H⋅⋅⋅π C−H⋅⋅⋅O b = 2.88 (0.57) a = 2.47 (1.02) f = 2.87 (0.62) d = 2.60 (0.78) e = 2.61 (0.69) lone pair⋅⋅⋅π C H⋅⋅⋅F g = 3.20 (0.72) h = 3.09 (0.84) i = 2.40 (0.91)

O

CF3 O O S F3C O

b

CF3

C−H⋅⋅⋅π C−H⋅⋅⋅O b = 2.80 (0.65) a = 2.79 (0.54) f = 2.75 (0.66) j = 2.36 (1.20) n = 2.77 (0.64) k = 2.75 (0.62) l = 2.49 (0.88) lone pair⋅⋅⋅π g = 3.17 (0.74) h = 3.36 (0.76)

C

N

O

F

S

Y

TS-I-C2-a [11.7] TS-I-C3-a [18.9] Figure 9. The optimized geometry of ring-opening transition states at C2 (TS-I-C2-a) and C3 (TS-I-C3-a) positions of (2R,3S)-aziridine (2), respectively leading to γamino esters 4 and 5'. The values in the square brackets are the relative Gibbs free energy with respect to the hetero-bimetallic complex B-3 and the reactants. The distances are in Å. Only select atoms (H, C, O, and F) are shown for improved clarity. Electron densities at the bond critical points (ρbcp x 10-2) are given beside the interatomic contacts.

Conclusions


La

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

Detailed

density

functional

theory

investigations

Page 26 of 40

(SMD(Et2O)/B3LYP-D3/6-

311G**,def2-TZVP(Y,La)) on the mechanism of a catalytic parallel kinetic resolution of a racemic mixture of 1,2-dialkyl cis-aziridines have provided valuable molecular insights. The alkyl substituents on the aziridine rings examined in this study are ethyl and n-propyl. A comprehensive consideration of various ligand combinations arising from the use of La(iOPr)3, Y(OTf)3, THF, and DMAP and the likely range of coordination numbers at both lanthanum and yttrium centers, revealed that a isopropoxy-bridged hetero-bimetallic La-Y complex is likely the active catalyst. In the active catalyst, the lanthanum is found to fit to the N2O2 and yttrium to the O2O2 core of the chiral BINAM Schiff complex. The reactants, dimethyl malonate and aziridine respectively at the La-N2O2 and Y-O2O2 sites of the La-Y hetero-bimetallic catalyst is noted as the most preferred pre-reacting species. Deprotonation of the pronucleophile by La-bound isopropoxide furnishes nucleophilic malonate, which in turn triggers the aziridine ring-opening. When (2R,3S) enantiomer of aziridine is the reactant, the transition state for ring-opening at the n-propyl bearing C2 carbon is found to be more than 7 kcal/mol lower in energy than that for C3 ring-opening. This large difference in energy is the origin of exclusive formation of only one regioisomer of γ-amino ester as the product (3-benzamidoheptan-4-yl malonate) with (4R,3S) configuration. Interesting reversal in the regiochemical preference for the enantiomeric (2S,3R)-aziridine, where the most preferred transition state is for the ring-opening at the ethyl substituted C3 carbon atom leading to 4-benzamidoheptan3-yl malonate as the product with a (4S,3R) configuration. The origin of how the La-Y hetero-bimetallic chiral Schiff base complex function as an effective catalyst for parallel kinetic resolution are traced to (a) both enantiomers of the racemic aziridine are equally well recognized by the catalyst, (b)


Page 27 of 40 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 aziridine ring in the lowest energy ring-opening transition states for each enantiomer remains in a very similar geometry and hence found to be of similar energies, (c) the ring-opening at the less preferred site is more than 7 kcal/mol higher in energy, resulting in a near exclusive regio-selectivity. The geometries of the ringopening transition states for the same enantiomer at C2 and C3 sites exhibit noticeable differences. In particular, dispositions of the methoxy of the BINAM backbone, the N-aryl group of aziridine, triflate ligands on yttrium all were different. In summary, the transition state models presented in this article offers a cogent rationalization of regio-divergent parallel kinetic resolution.

■ ASSOCIATED CONTENT Author Information Corresponding author: [email protected] Additional Information Authors

declare

no competing

financial interests.

Supporting

information

accompanies this paper at http://pubs.acs.org. Correspondence and requests for materials should be addressed to R.B.S. Supporting Information Optimized geometries, additional illustrations, figures, and tables (transition state geometries, topological analysis of electron density) are provided. This material is available free of charge via the Internet at http://pubs.acs.org. Acknowledgements H.K. acknowledges a senior research fellowship from the Council of Scientific and Industrial Research (CSIR, New Delhi) in the initial phase of this project. The SpaceTime supercomputing facility at IIT Bombay is gratefully acknowledged for providing generous computing time.


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

References (1) Coric, I.; List, B. Asymmetric spiroacetalization catalysed by confined Brønsted acids. Nature 2012, 483, 315−319. (2) Wanner, B.; Kreituss, I.; Gutierrez, O.; Kozlowski, M. C.; Bode, J. W. Catalytic Kinetic Resolution of Disubstituted Piperidines by Enantioselective Acylation: Synthetic Utility and Mechanistic Insights. J. Am. Chem. Soc. 2015, 137, 11491−11497. (3) Kuwano, S.; Harada, S.; Kang, B.; Oriez, R.; Yamaoka, Y.; Takasu, K.; Yamada, K. Enhanced Rate and Selectivity by Carboxylate Salt as a Basic Cocatalyst in Chiral N-Heterocyclic Carbene-Catalyzed Asymmetric Acylation of Secondary Alcohols. J. Am. Chem. Soc. 2013, 135, 11485−11488. (4) Lorenz, H.; Seidel-Morgenstern, A. Processes To Separate Enantiomers. Angew. Chem., Int. Ed. 2014, 53, 1218−1250. (5) Allen, S. E.; Hsieh, S.-Y.; Gutierrez, O.; Bode, J. W.; Kozlowski, M. C. Concerted Amidation of Activated Esters: Reaction Path and Origins of Selectivity in the Kinetic Resolution of Cyclic Amines via N-Heterocyclic Carbenes and Hydroxamic Acid Cocatalyzed Acyl Transfer. J. Am. Chem. Soc. 2014, 136, 11783−11791. (6) Xiao, K.-J.; Chu, L.; Chen, G.; Yu, J.-Q. Kinetic Resolution of Benzylamines via Palladium(II)-Catalyzed C–H Cross-Coupling. J. Am. Chem. Soc. 2016, 138, 7796−7800. (7) Vedejs, E.; Jure, M. Efficiency in Nonenzymatic Kinetic Resolution. Angew. Chem., Int. Ed. 2005, 44, 3974−4001. (8) Gustafson, J. L.; Lim, D.; Miller, S. J. Dynamic kinetic resolution of biaryl atropisomers via peptide-catalyzed asymmetric bromination. Science 2010, 328, 1251−1255.


Page 28 of 40

Page 29 of 40 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

(9) Bhat, V.; Welin, E. R.; Guo, X.; Stoltz, B. M. Advances in Stereoconvergent Catalysis from 2005 to 2015: Transition-Metal-Mediated Stereoablative Reactions, Dynamic Kinetic Resolutions, and Dynamic Kinetic Asymmetric Transformations. Chem. Rev. 2017, 117, 4528−4561. (10) Yang, L.; Zheng, H.; Luo, L.; Nan, J.; Liu, J.; Wang, Y. Luan, X. PalladiumCatalyzed Dynamic Kinetic Asymmetric Transformation of Racemic Biaryls: Axialto-Central Chirality Transfer. J. Am. Chem. Soc. 2015, 137, 4876−4879. (11) Yamaguchi, A.; Matsunaga, S.; Shibasaki, M. Catalytic Asymmetric Synthesis of α-Alkylidene-β-hydroxy Esters via Dynamic Kinetic Asymmetric Transformation Involving Ba-Catalyzed Direct Aldol Reaction. J. Am. Chem. Soc. 2009, 131, 10842−10843. (12) Tran, D. N.; Cramer, N. Rhodium-Catalyzed Dynamic Kinetic Asymmetric Transformations of Racemic Allenes by the [3+2] Annulation of Aryl Ketimines. Angew. Chem., Int. Ed. 2013, 52, 10630−10634. (13) Trost, B. M.; Toste, F. D. Palladium Catalyzed Kinetic and Dynamic Kinetic Asymmetric Transformations of γ-Acyloxybutenolides. Enantioselective Total Synthesis of (+)-Aflatoxin B1 and B2a. J. Am. Chem. Soc. 2003, 125, 3090−3100. (14) Wang, Y.-M.; Kuzniewski, C. N.; Rauniyar, V.; Hoong, C.; Toste, F. D. Chiral (Acyclic

Diaminocarbene)Gold(I)-Catalyzed

Dynamic

Kinetic

Asymmetric

Transformation of Propargyl Esters. J. Am. Chem. Soc. 2011, 133, 12972−12975. (15) Zhang, H.; Lin, S.; Jacobsen, E. N. Enantioselective Selenocyclization via Dynamic Kinetic Resolution of Seleniranium Ions by Hydrogen-Bond Donor Catalysts. J. Am. Chem. Soc. 2014, 136, 16485−16488.


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

(16)

Kreituss,

I.;

Bode,

J.

W.

Flow

chemistry

Page 30 of 40

and

polymer-supported

pseudoenantiomeric acylating agents enable parallel kinetic resolution of chiral saturated N-heterocycles. Nature Chem. 2017, 9, 446−452. (17) Loh, C. C. J.; Schmid, M.; Webster, R.; Yen, A.; Yazdi, S. K.; Franke, P. T.; Lautens, M. Rhodium-Catalyzed Asymmetric Cycloisomerization and Parallel Kinetic Resolution of Racemic Oxabicycles. Angew. Chem., Int. Ed. 2016, 55, 10074−10078. (18) Mulzer, M.; Ellis, W. C.; Lobkovsky, E. B.; Coates, G. W. Enantioenriched βlactone and aldol-type products from regiodivergent carbonylation of racemic cisepoxides. Chem. Sci. 2014, 5, 1928−1933. (19) Kamlet, A. S.; Préville, C.; Farley, K. A.; Piotrowski, D. W. Regioselective Hydroarylations and Parallel Kinetic Resolution of Vince Lactam. Angew. Chem., Int. Ed. 2013, 52, 10607−10610. (20) Miller, L. C.; Sarpong, R. Divergent reactions on racemic mixtures. Chem. Soc. Rev. 2011, 40, 4550−4562. (21) Gansäuer, A.; Shi, L.; Otte, M. Catalytic Enantioselective Radical Cyclization via Regiodivergent Epoxide Opening. J. Am. Chem. Soc. 2010, 132, 11858−11859. (22) Russell, T. A.; Vedejs, E. Separation of Enantiomers: Synthetic Methods; 1st ed.; Todd, M., Ed.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2014. (23) Walsh, P. W.; Kozlowski, M. C. Fundamentals of Asymmetric Catalysis; University Science Books: Sausalito, CA, 2009. (24) Dehli, J. R.; Gotor, V. Parallel kinetic resolution of racemic mixtures: a new strategy for the preparation of enantiopure compounds? Chem. Soc. Rev. 2002, 31, 365−370.


Page 31 of 40 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

(25) Tanaka, K.; Fu, G. C. Parallel Kinetic Resolution of 4-Alkynals Catalyzed by Rh(I)/Tol-BINAP:

Synthesis

of

Enantioenriched

Cyclobutanones

and

Cyclopentenones. J. Am. Chem. Soc. 2003, 125, 8078−8079. (26) Lin, T.-Y.; Zhu, C.-Z.; Zhang, P.; Wang, Y.; Wu, H.-H.; Feng, J.-J.; Zhang, J. Regiodivergent Intermolecular [3+2] Cycloadditions of Vinyl Aziridines and Allenes: Stereospecific Synthesis of Chiral Pyrrolidines. Angew. Chem., Int. Ed. 2016, 55, 10844−10848. (27) Li, D.; Wang, L.; Yang, D.; Zhang, B.; Wang, R. Catalytic Desymmetrization of meso-Aziridines with Benzofuran-2(3H)-Ones Employing a Simple In Situ-Generated Magnesium Catalyst. ACS Catal. 2015, 5, 7432−7436. (28) Fujimori, I.; Mita, T.; Maki, K.; Shiro, M.; Sato, A.; Furusho, S.; Kanai, M.; Shibasaki, M. Key Role of the Lewis Base Position in Asymmetric Bifunctional Catalysis: Design and Evaluation of a New Ligand for Chiral Polymetallic Catalysts. J. Am. Chem. Soc. 2006, 128, 16438−16439. (29) Rowland, E. B.; Rowland, G. B.; Rivera-Otero, E.; Antilla, J. C. Brønsted AcidCatalyzed Desymmetrization of meso-Aziridines. J. Am. Chem. Soc. 2007, 129, 12084−12085. (30) Hayashi, M.; Shiomi, N.; Funahashi, Y.; Nakamura, S. Cinchona Alkaloid Amides/Dialkylzinc Catalyzed Enantioselective Desymmetrization of Aziridines with Phosphites. J. Am. Chem. Soc. 2012, 134, 19366−19369. (31) Wu, B.; Gallucci, J. C.; Parquette, J. R.; RajanBabu, T. V. Enantioselective Desymmetrization of meso-Aziridines with TMSN3 or TMSCN Catalyzed by Discrete Yttrium Complexes. Angew. Chem., Int. Ed. 2009, 48, 1126−1129. (32) Huang, C.-Y.; Doyle, A. G. The Chemistry of Transition Metals with Three Membered Ring Heterocycles. Chem. Rev. 2014, 114, 8153−8198.


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

(33) Monaco, M. R.; Poladura, B.; Diaz de los Bernardos Sanchez, M.; Leutzsch, M.; Goddard, R.; List, B. Activation of Carboxylic Acids in Asymmetric Organocatalysis. Angew. Chem., Int. Ed. 2014, 53, 7063−7067. (34) Ohmatsu, K.; Ando, Y.; Ooi, T. Asymmetric Substitution at the Tetrasubstituted Chiral Carbon: Catalytic Ring-Opening Alkylation of Racemic 2,2-Disubstituted Aziridines with 3-Substituted Oxindoles. J. Am. Chem. Soc. 2013, 135, 18706−18709. (35) Ye, J.; Shi, Z.; Sperger, T.; Yasukawa, Y.; Kingston, C.; Schoenebeck, F.; Lautens, M. Remote C−H alkylation and C−C bond cleavage enabled by an in situ generated palladacycle. Nat. Chem. 2017, 9, 361−368. (36) Zhang, Z.; Tanaka, K.; Yu, J.-Q. Remote site-selective C−H activation directed by a catalytic bifunctional template. Nature 2017, 543, 538−542. (37) Wu, Q.-F.; Shen, P.-X.; He, J.; Wang, X.-B.; Zhang, F.; Shao, Q.; Zhu, R.-Y.; Mapelli, C.; Qiao, J. X.; Yu, J.-Q. Formation of α-chiral centers by asymmetric βC(sp3)-H arylation, alkenylation, and alkynylation. Science 2017, 355, 499−503. (38) Topczewski, J. J.; Cabrera, P. J.; Saper, N. I.; Sanford, M. S. Palladium-catalysed transannular C−H functionalization of alicyclic amines. Nature 2016, 531, 220−224. (39) Krautwald, S.; Sarlah, D.; Schafroth, M. A.; Carreira, E. M. Enantio- and diastereodivergent dual catalysis: α-allylation of branched aldehydes. Science 2013, 340, 1065−1068. (40) Du, Z.; Shao, Z. Combining transition metal catalysis and organocatalysis – an update. Chem. Soc. Rev. 2013, 42, 1337−1378. (41) Park, Y. J.; Park, J.-W.; Jun, C.-H. Metal−Organic Cooperative Catalysis in C−H and C−C Bond Activation and Its Concurrent Recovery. Acc. Chem. Res. 2008, 41, 222−234.


Page 32 of 40

Page 33 of 40 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

(42) Chen, D.-F.; Han, Z.-Y.; Zhou, X.-L.; Gong, L.-Z. Asymmetric Organocatalysis Combined with Metal Catalysis: Concept, Proof of Concept, and Beyond. Acc. Chem. Res. 2014, 47, 2365−2377. (43) Camasso, N. M.; Sanford, M. S. Design, synthesis, and carbon-heteroatom coupling reactions of organometallic nickel(IV) complexes. Science 2015, 347, 1218−1220. (44) Cook, A. K.; Schimler, S. D.; Matzger, A. J.; Sanford, M. S. Catalyst-controlled selectivity in the C−H borylation of methane and ethane. Science 2016, 351, 1421−1424. (45) Sperger, T.; Sanhueza, I. A.; Kalvet, I.; Schoenebeck, F. Computational Studies of Synthetically Relevant Homogeneous Organometallic Catalysis Involving Ni, Pd, Ir, and Rh: An Overview of Commonly Employed DFT Methods and Mechanistic Insights. Chem. Rev. 2015, 115, 9532−9586. (46) Park, Y.; Kim, Y.; Chang, S. Transition Metal-Catalyzed C–H Amination: Scope, Mechanism, and Applications. Chem. Rev. 2017, 117, 9247–9301. (47) Handa, S.; Gnanadesikan, V.; Matsunaga, S.; Shibasaki, M. syn-Selective Catalytic

Asymmetric

Nitro-Mannich

Reactions

Using

a

Heterobimetallic

Cu−Sm−Schiff Base Complex. J. Am. Chem. Soc. 2007, 129, 4900–4901. (48) Handa, S.; Gnanadesikan, V.; Matsunaga, S.; Shibasaki, M. Heterobimetallic Transition Metal/Rare Earth Metal Bifunctional Catalysis: A Cu/Sm/Schiff Base Complex for Syn-Selective Catalytic Asymmetric Nitro-Mannich Reaction. J. Am. Chem. Soc. 2010, 132, 4925–4934. (49) Handa, S.; Nagawa, K.; Sohtome, Y.; Matsunaga, S.; Shibasaki, M. A Heterobimetallic Pd/La/Schiff Base Complex for anti-Selective Catalytic Asymmetric


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

Nitroaldol Reactions and Applications to Short Syntheses of β-Adrenoceptor Agonists Angew. Chem., Int. Ed. 2008, 47, 3230–3233. (50) Robinson, J. R.; Fan, X.; Yadav, J.; Carroll, P. J.; Wooten, A. J.; Pericàs, M. A.; Schelter, E. J.; Walsh, P. J. Air- and Water-Tolerant Rare Earth Guanidinium BINOLate Complexes as Practical Precatalysts in Multifunctional Asymmetric Catalysis. J. Am. Chem. Soc. 2014, 136, 8034–8041. (51) Kumagai, N.; Kanai, M.; Sasai, H. A Career in Catalysis: Masakatsu Shibasaki. ACS Catal. 2016, 6, 4699–4709. (52) Park, J.; Hong, S.

Cooperative bimetallic catalysis in asymmetric

transformations. Chem. Soc. Rev. 2012, 41, 6931–6943. (53) Kumagai, N.; Shibasaki, M. Recent Advances in Direct Catalytic Asymmetric Transformations under Proton‐Transfer Conditions. Angew. Chem., Int. Ed. 2011, 50, 4760–4772. (54) Shibasaki, M.; Kanai, M.; Matsunaga, S.; Kumagai, N. Recent Progress in Asymmetric Bifunctional Catalysis Using Multimetallic Systems. Acc. Chem. Res. 2009, 42, 1117–1127. (55) Sammis, G. M.; Danjo, H.; Jacobsen, E. N. Cooperative Dual Catalysis: Application to the Highly Enantioselective Conjugate Cyanation of Unsaturated Imides. J. Am. Chem. Soc. 2004, 126, 9928–9929. (56) Wu, B.; Parquette, J. R.; RajanBabu, T. V. Regiodivergent ring opening of chiral aziridines. Science 2009, 326, 1662. (57) Wu, B.; Gallucci, J. C.; Parquette, J. R.; RajanBabu, T. V. Bimetallic catalysis in the highly enantioselective ring-opening reactions of aziridines. Chem. Sci. 2014, 5, 1102−1117.


Page 34 of 40

Page 35 of 40 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

(58) Xu, Y.; Kaneko, K.; Kanai, M.; Shibasaki, M.; Matsunaga, S. Regiodivergent Kinetic Resolution of Terminal and Internal rac-Aziridines with Malonates under Dinuclear Schiff Base Catalysis. J. Am. Chem. Soc. 2014, 136, 9190−9194. (59) Robinson, J. R.; Qiao, Y.; Gu, J.; Carroll, P. J.; Walsh, P. J.; Schelter, E. J. The role of dynamic ligand exchange in the oxidation chemistry of cerium(III). Chem. Sci. 2016, 7, 4537−4547. (60) Robinson, J. R.; Gu, J.; Carroll, P. J.; Schelter, E. J.; Walsh, P. J. Exchange Processes in Shibasaki’s Rare Earth Alkali Metal BINOLate Frameworks and Their Relevance in Multifunctional Asymmetric Catalysis. J. Am. Chem. Soc. 2015, 137, 7135−7144. (61) Yamagiwa, N.; Qin, H. B.; Matsunaga, S.; Shibasaki, M. Lewis Acid−Lewis Acid Heterobimetallic Cooperative Catalysis: Mechanistic Studies and Application in Enantioselective Aza-Michael Reaction. J. Am. Chem. Soc. 2005, 127, 13419−13427. (62) Di Bari, L.; Lelli, M.; Pintacuda, G.; Pescitelli, G.; Marchetti, F.; Salvadori, P. Solution versus Solid-State Structure of Ytterbium Heterobimetallic Catalysts. J. Am. Chem. Soc. 2003, 125, 5549−5558. (63) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu. J. Chem. Phys. 2010, 132, 154104−154119. (64) 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, Jr., J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers,


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

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, Inc., Wallingford CT, 2013. (65) Hay, P. J.; Wadt, W. R. Ab initio effective core potentials for molecular calculations. Potentials for K to Au including the outermost core orbitals. J. Chem. Phys. 1985, 82, 299−310. (66) Hay, P. J.; Wadt, W. R. Ab initio effective core potentials for molecular calculations. Potentials for the transition metal atoms Sc to Hg. J. Chem. Phys. 1985, 82, 270−283. (67) Hehre, W. J.; Ditchfield, R.; Pople, J. A. Self-Consistent Molecular Orbital Methods. XII. Further Extensions of Gaussian-Type Basis Sets for Use in Molecular Orbital Studies of Organic Molecules. J. Chem. Phys. 1972, 56, 2257−2261. (68) Hariharan, P. C.; Pople, J. A. The influence of polarization functions on molecular orbital hydrogenation energies. Theor. Chim. Acta. 1973, 28, 213−222. (69) Gonzalez, C.; Schlegel, H. B. An improved algorithm for reaction path following. J. Chem. Phys. 1989, 90, 2154−2161. (70) Gonzalez, C.; Schlegel, H. B. Reaction path following in mass-weighted internal coordinates. J. Phys. Chem. 1990, 94, 5523−5527. (71) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Universal Solvation Model Based on Solute Electron Density and on a Continuum Model of the Solvent Defined by the


Page 36 of 40

Page 37 of 40 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

Bulk Dielectric Constant and Atomic Surface Tensions. J. Phys. Chem. B. 2009, 113, 6378−6396. (72) Weigend, F.; Ahlrichs, R. Balanced basis sets of split valence, triple zeta valence and quadruple zeta valence quality for H to Rn: Design and assessment of accuracy. Phys. Chem. Chem. Phys. 2005, 7, 3297−3305. (73) Weigend, F. Accurate Coulomb-fitting basis sets for H to Rn. Phys. Chem. Chem. Phys. 2006, 8, 1057−1065. (74) Falivene, L.; Credendino, R.; Poater, A.; Petta, A.; Serra, L.; Oliva, R.; Scarano, V.; Cavallo, L. SambVca 2. A Web Tool for Analyzing Catalytic Pockets with Topographic Steric Maps. Organometallics 2016, 35, 2286−2293. (75) See Tables S1-S2 in the Supporting Information for complete details of various other ligand combinations on the metal centers. (76) Nieto, I.; Wooten, A. J.; Robinson, J. R.; Carroll, P. J.; Schelter, E. J.; Walsh, P. J. Synthesis and Catalytic Activity of Heterobimetallic Rare Earth–Zinc Ethyl BINOLate Analogues of Shibasaki’s Catalysts. Organometallics 2013, 32, 7431−7439. (77) Chen, Z.; Morimoto, H.; Matsunaga, S.; Shibasaki, M. A Bench-Stable Homodinuclear Ni2−Schiff Base Complex for Catalytic Asymmetric Synthesis of αTetrasubstituted anti-α,β-Diamino Acid Surrogates. J. Am. Chem. Soc. 2008, 130, 2170−2171. (78) Andrez, J.; Guidal, V.; Scopelliti, R.; Pécaut, J.; Gambarelli, S.; Mazzanti, M. Ligand and Metal Based Multielectron Redox Chemistry of Cobalt Supported by Tetradentate Schiff Bases. J. Am. Chem. Soc. 2017, 139, 8628−8638.


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

(79) Deprotonation of malonic ester by the native triflate ligand at the yttrium center is found to be 21.1 kcal/mol higher in energy than that by the isopropoxide at the lanthanum center. See Figure S1 in the Supporting Information. (80) The intermediate wherein (2R,3S)-aziridine and malonate are coordinated respectively to the lanthanum and yttrium is 32.5 kcal/mol higher in energy as compared to when malonate and aziridine are bound respectively to lanthanum and yttrium. See Figure S1 in the Supporting Information for other higher energy possibilities. (81) See Figure S2 in the Supporting Information for more details. (82) See Figure S3 in the Supporting Information for more details. (83) See Tables S3-S6 and Figure S5 in the Supporting Information for more details. (84) The ring-opening ransition states with other ligand combinations, even the ones similar to B-3 complex, are found to be more than 30 kcal/mol higher than the most preferred TS-I-C2-a reported in the manuscript. More details are provided in Figure S4 in the Supporting Information. (85) Details of higher energy alternative TSs are provided in Tables S3-S5 and Figure S5 in the Supporting Information. (86) A comparison of Gibbs free energies of transition states for the ring-opening at the C2 carbon in (2R,3S)-aziridine (TS-I-C2-a) with that of the C3 carbon in (2S,3R)aziridine (TS-II-C3-a) is provided in Tables S3 and S6 in the Supporting Information. (87) The elementary step barriers computed with respect to the preceding intermediate indicate that the ring-opening at C2 (17.5 kcal/mol) is likely to be faster as compared to that at C3 (19.4 kcal/mol). (88) Such mode of aziridine ring-opening transition states are more than 30 kcal/mol energy as compared to the transition states when n-propyl and ethyl are pointing away


Page 38 of 40

Page 39 of 40 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

from the La-Y framework. See Table S3 in the Supporting Information for additional details. (89) The DMAP orientation can be noted as different in TS-I-C2-a and TS-I-C3-a. However, we have identified alternative TSs for TS-I-C3-a wherein the DAMP orientation is closely similar to that in TS-I-C2-a. However, such TSs are found to be of higher energy. See Table S3 in the Supporting Information. (90) Two major geometric differences in the orientation of aziridine ring are noticed between the most preferred (C2 ring-opening) and higher energy (C3 ring-opening) transition states. One relates to an in-plane rotation of the aziridine ring with respect to the ring centroid and another is a change in the orientation of the azirdine plane. See Figure S7 in the Supporting Information for additional details. (91) In case of (2S,3R)-aziridine, the most preferred transition state for ring-opening at the C3 carbon (TS-II-C3-a) is 6.2 kcal/mol lower in energy as compared to the C2 ring-opening transition state (TS-II-C2-a). See Table S6 in the Supporting Information for more details. (92) See Figure S6 in the Supporting Information for details of distortion in the imino methoxy phenoxide ring. (93) Bickelhaupt, F. M.; Houk, K. N. Analyzing Reaction Rates with the Distortion/Interaction-Activation Strain Model. Angew. Chem., Int. Ed. 2017, 56, 10070−10086. (94) Bickelhaupt, F. M. Understanding reactivity with Kohn–Sham molecular orbital theory: E2–SN2 mechanistic spectrum and other concepts. J. Comput. Chem. 1999, 20, 114−128. (95) Full details of Activation Strain analysis are provided in Table S7 and Figure S9 in the Supporting Information.


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

(96) Bader, R. F. W. A quantum theory of molecular structure and its applications. Chem. Rev. 1991, 91, 893−928. (97) See Table S10 for details of AIM calculations. (98) Sunoj, R. B. Transition State Models for Understanding the Origin of Chiral Induction in Asymmetric Catalysis. Acc. Chem. Res. 2016, 49, 1019−1027. (99) Wheeler, S. E.; Seguin, T. J.; Guan, Y.; Doney, A. C. Noncovalent Interactions in Organocatalysis and the Prospect of Computational Catalyst Design. Acc. Chem. Res. 2016, 49, 1061−1069. (100) See Scheme S1 and Figure S13 in the Supporting Information for additional details.

TOC Graphics


Page 40 of 40

Insights on the Origin of Regiodivergence in the Parallel Kinetic

Recommend Documents