Theoretical Investigation of Regioselectivity and Stereoselectivity in

Article pubs.acs.org/JPCB

Theoretical Investigation of Regioselectivity and Stereoselectivity in AIBN/HSnBu3‑Mediated Radical Cyclization of N‑(2-Iodo-4,6dimethylphenyl)‑N,2-dimethyl-(2E)‑butenamide Bai-jian Li, Hua Zhong,* and Hai-tao Yu* Key Laboratory of Functional Inorganic Material Chemistry (Ministry of Education of China) and School of Chemistry and Materials Science, Heilongjiang University, Harbin 150080, P. R. China S Supporting Information *

ABSTRACT: In this study, we employed the density functional method to simulate AIBN/HSnBu3-mediated radical cyclizations with different axially chiral conformers of N-(2-iodo-4,6-dimethylphenyl)-N,2-dimethyl-(2E)-butenamide as substrates. We constructed a reaction potential energy profile using the Gibbs free energies of the located stationary points. The thermodynamic and kinetic data of the profile were further used to evaluate the regioselectivity, stereoselectivity, and product distribution of the cyclizations. Additionally, we compared the present HSnBu3mediated radical cyclization with the experimentally available Heck reaction and found that such a radical cyclization can convert (M,Z) and (P,Z) o-iodoanilide substrates to centrally chiral products with high chirality transfer. The goal of this study was to estimate the practicality of theoretically predicting the memory of chirality in such radical cyclizations. The present results can provide a strategy from a theoretical viewpoint for experimentally synthesizing highly stereoselective carbocyclic and heterocyclic compounds using radical cyclization methods.

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INTRODUCTION Radical cyclization is an important aspect of radical reactions.1 Recognition of the importance of radical cyclization in organic synthesis has increased2−6 with the development of radical chemistry.2−5 Presently, such a technique often enables access to very complex carbocyclic7−12 and heterocyclic compounds.13−17 In various radical cyclizations, investigators have found that some given axially chiral radicals can cyclize to give ring-closure products with not only high regioselectivity but also high stereoselectivity,3,4 that is, the axially chiral element disappears in the reaction processes, accompanied by the formation of a certain stereocenter in the resulting product structure, often termed a “transfer of chirality”.18−20 Chirality transfer is a type of “memory of chirality”,18 in which the stereochemical elements in the products and reactants are different. In 1999, Curran and co-workers conducted separate 5-exo radical cyclizations with the M and P axially chiral enantiomers of o-iodoanilide 1 as the substrate21 (Scheme 1). The resulting bicyclic product, 2, was obtained with high stereoselectivity, with a chirality transfer of approximately 94%. Similarly, in another experiment,22 o-iodoanilide (M)-3 (98.5/1.5 enantiomer ratio (er)) and its enantiomer (P)-3 (99.5/0.5 er) underwent intramolecular 5-exo radical cyclization to yield dihydroindolones (R)-4 (93.5/6.5 er) and (S)-4 (96.5/3.5 er) with high chirality transfers of 95 and 97%, respectively, as shown in Scheme 2. These two available experiments indicate that such 5exo cyclizations are very fast under standard radical cyclization © 2016 American Chemical Society

Scheme 1. Stereoselectivity and Chirality Transfer in Radical Cyclization of o-Iodoanilide 1

conditions (Et3B/O2 or AIBN/HSnBu3).23−26 Furthermore, the fact that these fast radical cyclizations can highly stereoselectively convert axial chirality into central chirality implies very low rotational rates of the N-aryl bonds in these o-iodoanilides and intermediates, which effectively prevent racemization of the products.21,27 Received: October 12, 2016 Revised: November 22, 2016 Published: November 28, 2016 12950

DOI: 10.1021/acs.jpcb.6b10344 J. Phys. Chem. B 2016, 120, 12950−12958

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The Journal of Physical Chemistry B

as shown in Scheme 4. This suggested reaction mechanism is supported by numerous experiments.40−42 Therefore, under the standard HSnBu3-mediated conditions, whether the five pairs of enantiomers of o-iodoanilide 5 (see Scheme 4) can be highly stereoselectively transformed into the corresponding bicyclic products through such a mechanism becomes an interesting question. To better understand the configuration distribution of possible products and the chirality transfer in HSnBu3-mediated cyclizations with 5 as the substrate, several aspects must be carefully considered. The first aspect is whether kinetic resolution can effectively separate the chiral configurations of 5 because an enantio-enriched reactant is highly likely to provide an enantiopure product.43 The second aspect involves the possible axial chirality transformations of the substrate and intermediate radical resulting from the deiodination reaction of the substrate. If parts of the reactants and intermediates undergo racemization via N-aryl bond rotation, the resulting products will possibly be a mixture of enantiomers,44 even entirely racemic.45 The third aspect involves competitive 5-exo and 6-endo cyclizations, which will give different regioselective products.46,47 The first and second aspects are largely determined by the preference of atropisomerization through rotation about the Naryl bond relative to the deiodination and cyclization reactions; however, the third aspect hinges on the kinetic barriers of the cyclizations and/or the thermodynamic stabilities of the products. In this study, we performed a quantum chemistry computational analysis to investigate the radical cyclization reaction with 5 as the substrate, for which we mainly considered the aforementioned three aspects to further the possibility of using the standard HSnBu3-mediated radical cyclization reaction instead of the Heck reaction to conduct such radical cyclization reactions.

Scheme 2. Stereoselectivity and Chirality Transfer in Radical Cyclization of o-Iodoanilide 3

In addition to the HSnBu3-mediated radical cyclization reactions in the presence of a radical initiator, the Heck reaction is also frequently used to synthesize carbocyclic and heterocyclic molecules with high stereoselectivity.23,28,29 For instance, in 2007, Curran conducted a Pd-catalyzed Heck reaction at room temperature with o-iodoanilides (M,E)- and (P,E)-5a as the substrate, and the er value and chirality transfer were both higher than 85%,28 as outlined in Scheme 3. Generally, most Heck Scheme 3. Stereoselectivity and Chirality Transfer in the Heck Reaction of o-Iodoanilide 5

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COMPUTATIONAL DETAILS The present investigation was performed at the level of the density functional theory with the BHandHLYP48 method in combination with the 6-311++G(d,p)49,50 (for C, H, O, and N atoms) and double-zeta LANL2DZ51−53 (for Sn and I atoms) basis sets, as implemented in the Gaussian 09 code.54 After geometric optimization of the reactants, intermediates, and transition states without any symmetry constraints, the stationary points were confirmed as local minima (all true vibrational modes) or transition states (only one imaginary vibrational mode) by computing their harmonic vibrational frequencies within the harmonic approximation at the same level of theory. To consider the solvent effect, a self-consistent reaction field55,56 calculation using the standard polarizable continuum model57−60 with a cavity generated using the united-atom topological model was performed with toluene as the solvent. Furthermore, the thermal correction for electronic total energies was computed to evaluate the temperature dependencies of the chirality transfer and product distribution. The reaction rate constants used to determine chirality transfer were computed using the traditional transition state theory (TST).61−63 The relevant equations and derivations are available in the Supporting Information. Additionally, all geometries in Cartesian coordinates are provided in the Supporting Information. In a thermodynamic equilibrium system containing m components, the mole fraction (Xi) of the component i can be expressed as64

reactions require Pd- or Ni-based catalysts and organophosphorus compounds as an auxiliary ligand.30−33 Although often producing high yields and/or high stereoselectivities,28,29 the Heck reaction is not suitable for many organic syntheses, and the factors limiting its use often involve the high price of the catalysts, harsh experimental conditions, and strong toxicity of organic phosphine compounds.34−37 Of the experimentally available radical cyclization reactions, the standard tributyltin hydride-mediated method (AIBN/HSnBu3) is used much more frequently than the Heck reaction due to various advantages, such as rapid and controllable reaction processes, mild reaction conditions, and high regioselectivity and stereoselectivity.1,38,39 If AIBN/HSnBu3 is used in the aforementioned experiment conducted by Curran28 (see Scheme 3), the iodine atom of the o-iodoanilide 5a substrate should be readily abstracted by •SnBu3 to generate an aryl radical, followed by a 5-exo or 6-endo intramolecular cyclization of the carbon-centered radical onto the unsaturated CC double bond and further oxidation by • SnBu3 to yield the corresponding bicyclic nonradical products, 12951


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The Journal of Physical Chemistry B Scheme 4. Stereoisomers and Predicted Cyclization Pathways of o-Iodoanilide 5

Figure 1. Computed Gibbs free energy profiles of deiodination with (M,E)-5 (a) and (M,Z)-5 (b) as substrates at the BHandHLYP/6-311++G(d,p) level of theory at 298.15 K. The energy values in parentheses are the relative enthalpies.

Xi =

e−ΔGi / RT m ∑ j = 1 e−ΔGj / RT

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RESULTS AND DISCUSSION Because there is only one chiral element in 5, the reaction potential energy profile with (P)-5 as the substrate has mirror symmetry with that using (M)-5 as the substrate. Thus, we mainly used (M)-5 as the reactant to discuss the reaction mechanism. Furthermore, for compound 5 containing a CC

(1)

where ΔGj is the relative Gibbs free energy of component j. When several isomers are in equilibrium, their relative concentrations can be computed using eq 1. 12952


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Figure 2. Computed Gibbs free energy profiles of the atropisomerization of reactant radical 8 with E (a) and Z (b) configurations at the BHandHLYP/6311++G(d,p) level of theory at 298.15 K.

bond, we used E and Z to describe its cis and trans structures, respectively, as shown in Scheme 4. Rotational Isomerization and Deiodination of Substrates. In the optimizations, three (M,E) (5a−5c) and two (M,Z) (5d and 5e) conformers were located on the basis of the different orientations of the CC unsaturated double bond in (M)-5. Figure 1 gives the potential energy profiles for the deiodination and isomerization of the (M,E) and (M,Z) conformers. The energies of the relevant stationary points are provided in Tables S1−S4. The computed results indicate that three (M,E) conformers, 5a−5c, can isomerize into each other by rotations about C−C single bonds with transition state heights of 2.61 kcal mol−1 (TS4), 3.23 kcal mol−1 (TS6), and 4.53 kcal mol−1 (TS5) (see Figure 1a). Similarly, (M,Z)-5d and (M,Z)-5e can interconvert via the separating transition state TS12 located at 5.94 kcal mol−1 (see Figure 1b). Such low-lying transition states mean rapid transformations among (M,E)-5a, (M,E)-5b, and (M,E)-5c and between (M,Z)-5d and (M,Z)-5e. The equilibrium concentration ratios of (M,E)-5a/(M,E)-5b/(M,E)-5c and (M,Z)-5d/ (M,Z)-5e computed using eq 1 are approximately 64.5:17.9:17.6 and 79:21, respectively. In addition to rotational isomerization, (M,E)-5a, (M,E)-5b, and (M,E)-5c can also undergo deiodination by radical •SnBu3 to give radical reactants (M,E)-8a, (M,E)-8b, and (M,E)-8c via the deiodination transition states TS1 (13.49 kcal mol−1), TS2 (14.84 kcal mol−1), and TS3 (13.39 kcal mol−1), respectively, as shown in Figure 1a. The low activation barriers of approximately 14.0 kcal mol−1 and the favorable reaction enthalpy changes of approximately −11.0 kcal mol−1 (see Figure 1a) imply that these deiodination reactions easily occur in the ambient atmosphere. The relative energy differences of the resulting radical reactants (M,E)-8a, (M,E)-8b, and (M,E)-8c are within only 1.13 kcal mol−1 (Gibbs free energy) and 1.05 kcal mol−1 (enthalpy) of one

another. In addition, the lower transition state energies of rotations about C−C single bonds of these reactants compared to those of radical atropisomerization and the subsequent cyclization reactions (see discussion below) demonstrate that the three radicals can rapidly reach thermodynamic equilibrium. The computed concentration ratio of (M,E)-8a/(M,E)-8b/(M,E)-8c in equilibrium is 8.2:36.4:55.4, being strongly biased in favor of (M,E)-8b and (M,E)-8c. An analogous situation can be found for (M,Z)-5d and (M,Z)5e. As illustrated in Figure 1b, the deiodination of (M,Z)-5d and (M,Z)-5e can proceed through the transition states TS10 and TS11 with Gibbs free energy heights of 13.55 and 14.60 kcal mol−1 to generate radical products (M,Z)-8d and (M,Z)-8e, respectively. On the basis of the listed energies in Figure 1b, we can determine that the deiodination reactions are thermodynamically and kinetically favorable. The resulting radical (M,Z)8d can isomerize to (M,Z)-8e via the separating transition state TS13 with somewhat high forward and reverse Gibbs free energy barriers of 7.34 and 8.62 kcal mol−1, respectively, relative to its isomerization into (M,Z)-8f via TS14 with a forward barrier of only 0.47 kcal mol−1. Atropisomerization of Substrates and Radical Reactants. Before investigating the radical cyclization reactions, we explored the possible atropisomerizations leading to the interconversion between M and P axial chiralities, which mainly involves substrate 5 and radical reactant 8 from the deiodination of 5. For substrate 5 bearing ortho −CH3 and −I groups on the phenyl ring, the steric hindrance between the two ortho groups and two N-substituents can effectively prevent N-aryl bond rotation. In this theoretical study, although many attempts were made, we did not locate the transition states of the atropisomerizations of the substrates. Therefore, the atropisomerization reactions of 5 should be very slow, and one enantiopure stereoisomer can be used as the substrate. This is 12953


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Figure 3. Computed Gibbs free energy profile of radical cyclization reactions of (M,E)- and (P,E)-8 at the BHandHLYP/6-311++G(d,p) level of theory at 298.15 K.

Figure 4. Computed Gibbs free energy profile of radical cyclization reactions of (M,Z)- and (P,Z)-8 at the BHandHLYP/6-311++G(d,p) level of theory at 298.15 K.

ortho −CH3 group was successfully separated by Curran as a single enantiomer in a high er.28 Therefore, the next discussion only involves atropisomerizations among the stereoisomers of radical reactant 8. Figure 2 shows the isomeric potential energy profiles of radical reactant 8 with E and Z configurations. The energies of the relevant stationary points are listed in Tables S5−S8. As shown in Figure 2a, (M,E)-8a and (M,E)-8b cannot directly isomerize by N-aryl bond rotation into (P,E)-8c because of the steric

sufficiently supported by previous experimental studies,20,21,27,28,65−71 that is, the N-aryl rotation barrier is approximately 23 kcal mol−1 for o-iodoanilides without other ortho groups;28 however, when o-iodoanilide possesses a second ortho substituent, the atropisomerization barrier is higher than 27 kcal mol−1,28 as shown in Figure S1. Such high barriers imply that the enantiopure atropisomers of o-iodoanilide can be experimentally separated by dynamic kinetic resolution. As an example, the presently investigated o-iodoanilide 5 bearing an 12954


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Figure 5. Computed reaction pathways and product distribution using (M,E)- and (M,Z)-5 as substrates at the BHandHLYP/6-311++G(d,p) level of theory. k1−k6 are the reaction rate constants of the corresponding elementary reaction steps, and the listed energies of the transition states are the relative Gibbs free energies in kcal mol−1.

7c, respectively, whereas cyclization of (P,Z)- and (M,Z)-8f proceeds either in 5-exo mode to give (R)- and (S)-7c or in 6endo mode to afford (R)- and (S)-9b (see Figure 4), respectively. Note from the listed Cartesian coordinates in the Supporting Information that the −CH3 groups linked to the radical carbon atoms in the 6-endo cyclization products 9a and 9b are different in orientation; thus, 9a and 9b with identical central chirality are conformational isomers, whereas 9a and 9b with different central chiralities are diastereomers. Regioselectivity and Stereoselectivity of Cyclizations. On the basis of the data listed in Figures 3 and 4, we can determine that the transition states for the 6-endo radical cyclizations are at least 7.0 kcal mol−1 higher than those for the 5exo cyclizations. The 6-endo regioselective ring-closure reactions are thus kinetically less favorable, and the 5-exo products should be dominant. Therefore, the 6-endo cyclization pathways and products are of minor importance and will be ignored in the next discussion. As shown in Figures 3 and 4, the 5-exo cyclization product Ror S-7b can isomerize to the same chiral conformers 7a and 7c with very low activation barriers. Further considering the close energy difference among 7a−7c, we believe that these species are coexistent. Thus, we did not consider their relative concentration distribution in the next discussion and used R- or S-7 to represent them. Note that the lowest activation barrier of radical 7 toward oxidation to a nonradical product is only 10.55 kcal mol−1, which is somewhat lower than the barrier to the corresponding ringopening reactions. Thus, the reverse ring-opening reactions of 7 are kinetically less favorable, as shown in Figure S2 and Tables S13 and S14. Therefore, in the next discussion, we will use the R/ S ratio of 7 to replace that of the nonradical products. To better understand the effect of each reaction step on the stereoselectivity, we list the key reaction steps and the energies of the relevant stationary points in Figure 5. Note that the reaction

hindrance between the C−C double bond and phenyl ring but proceed preferentially via intermediates (M,E)-8b, (M,E)-8i, and (P,E)-8h. Similarly, as shown in Figure 2b, the transformations from (M,Z)-8d and (M,Z)-8f to (P,Z)-8e can occur through intermediates (M,Z)-8k and (P,Z)-8j. Note that the transformations from (P,E)-8a and (P,E)-8b to (M,E)-8c and from (P,Z)-8d and (P,Z)-8f to (M,Z)-8e have mirror symmetry to the processes outlined in Figure 2a,b, respectively, and are thus not shown in the two figures. On the basis of the listed energies in Figure 2, one can observe that the key separate transition states in Figure 2a (TS15 and TS18) and 2b (TS22 and TS25) are located at higher than 15 kcal mol−1, and these atropisomerizations are thus less favorable than the subsequent irreversible cyclizations with activation barriers of lower than 8.5 kcal mol−1 (see discussion below). These less favorable M−P atropisomerizations are absolutely crucial for radical cyclizations with high chirality transfer. Radical Cyclization Pathways. Figures 3 and 4 illustrate the radical cyclization reaction profiles starting from the E and Z configurations of radical reactant 8, respectively. The relevant energies are listed in Tables S9−S12. Note that the left part is of mirror symmetry with the right part in each profile. In the optimizations, we found that the orientation of the CC bond determines which configurations are prone to radical cyclization. Among all of the located radical reactants, only the E conformers 8c and 8b and the Z conformers 8e and 8f are predisposed to cyclization. As shown in Figure 3, the 5-exo ring-closure reactions of the Econfigurations (P,E)- and (M,E)-8c give the bicyclic radical products (S)- and (R)-7b, respectively; however, (P,E)- and (M,E)-8b can undergo not only 5-exo cyclization to provide (R)and (S)-7b but also 6-endo cyclization to generate (S)- and (R)9a, respectively. For the Z-configuration radical reactants, (P,Z)and (M,Z)-8e can cyclize in 5-exo mode to generate (S)- and (R)12955


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The Journal of Physical Chemistry B pathways using M reactants are of mirror symmetry with those using P reactants. Thus, in Figure 5, we only list the reaction details with the M conformers as reactants. As shown in Figure 5, the transition states (TS4 and TS5 located at 2.61 and 4.53 kcal mol−1, respectively) separating (M,E)-5a, (M,E)-5b, and (M,E)-5c are somewhat lower than those (TS3, TS1, and TS2 located at 13.39, 13.49, and 14.84 kcal mol−1, respectively) of the deiodination reactions. Thus, the initial concentration distribution of the radical reactants (M,E)8a, (M,E)-8b, and (M,E)-8c is determined by both the thermodynamic distribution and the deiodination reaction rate constants of the radical precursors (M,E)-5a, (M,E)-5b, and (M,E)-5c. However, the 5-exo radical cyclizations of (M,E)-8a, (M,E)-8b, and (M,E)-8c are apparently slower than the interconversion among them, based on the comparison of the listed transition state heights in Figure 5, that is, 8.14 kcal mol−1 (TS26) and 8.47 kcal mol−1 (TS27) for cyclization and 1.43 kcal mol−1 (TS7) and 5.61 kcal mol−1 (TS8) for interconversion. Therefore, the stereoselectivity (R/S ratio) of the final products is largely determined by both thermodynamic equilibrium distribution and cyclization reaction rate constants of the radical reactants (M,E)-8a, (M,E)-8b, and (M,E)-8c. The R/S ratio of product 7, which can be replaced by that of 7b, can be expressed in terms of the cyclization reaction rate constants k1 and k2 (see Figure 5) and the relative Gibbs free energies of (M,E)-8c and (M,E)-8b, ΔG(M,E)‑8c and ΔG(M,E)‑8b, as c(R) ‐ 7b c(S) ‐ 7b

=

k1 e−(ΔG(M ,E)‐ 8c −ΔG(M ,E)‐ 8b)/ RT k2

equilibrium ratio of (M,Z)-5d and (M,Z)-5e but also their deiodination reaction rate constants because of their rapid interconversion relative to the deiodination processes. Although the equilibrium between (M,Z)-8d and (M,Z)-8f can be established very rapidly, the interconversion between (M,Z)-8d and (M,Z)-8e is kinetically less favorable than the subsequent 5exo cyclizations to (R)- and (S)-7. Therefore, the R/S ratio of the radical cyclization product 7 is largely decided by the equilibrium concentration ratios of (M,Z)-5e/(M,Z)-5d and (M,Z)-8e/ (M,Z)-5f and the cyclization reaction rate constants k3−k6 (see Figure 5). The product concentration ratio (R)-7/(S)-7 can be computed by c(R) ‐ 7c c(S) ‐ 7c

=

k6k 3 1 + e−(ΔG(M ,Z)‐ 8d −ΔG(M ,Z)‐ 8f )/ RT k5k4 e−(ΔG(M ,Z)‐ 5d −ΔG(M ,Z)‐ 5e)/ RT

(3)

The derivation process of eq 3 and the computed results are available in the Supporting Information (see Tables S18−S25). As shown in Figure 6 and Table S25, the final calculation results gave R/S ratios of 0.051 and 0.234 at 213.15 and 383.15 K, respectively, which means that in the considered temperature range the R/S ratios of 7 change from 4.89:95.11 to 18.97:81.03 in favor of the S-configuration. Therefore, the chirality transfers from the axially chiral (M,Z)-5 to the centrally chiral (S)-7 are 95.1 and 81.0% at 213.15 and 383.15 K, respectively, as shown in Figure 6. Evidently, when using enantiomer (P,Z)-5 as the substrate, the chirality transfer of (P,Z)-5 → (R)-7 is identical to the reaction of (M,Z)-5 → (S)-7. Furthermore, a lower temperature can improve the chirality transfer of the Zconfiguration substrate (see Figure 6). On the basis of the above discussion, an E-configuration substrate gives the cyclization products with low chirality transfer (approximately 63.8%). However, a Z-configuration substrate can produce a relatively highly stereoselective cyclization product with a chirality transfer of 81.0−95.1%, and its chirality transfer at low temperatures is higher than the experimental chirality transfer from the Heck reaction.28 Therefore, HSnBu3-mediated cyclization with E-configuration 5 as the substrate is a highly promising reaction to replace the Heck reaction to obtain highly stereoselective products.

(2)

The derivation of eq 2 can be found in the Supporting Information. The computed data are given in Tables S15−S18. The R/S ratio of 7 lies in the range of 0.569−0.580 as the temperature increases from 213.15 to 383.15 K, which implies that the R/S ratio of 7 is insensitive to the reaction temperature

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CONCLUSIONS In this study, we simulated the HSnBu3-mediated cyclizations of different stereoisomers of N-(2-iodo-4,6-dimethylphenyl)-N,2dimethyl-(2E)-butenamide. The conclusions are as follows. The atropisomerization of the substrates and radical reactants is kinetically less favorable, which effectively prevents racemization and is quite advantageous to obtain products with high chirality transfer. Using E-configuration 5 as the substrate, the R/ S ratio of the cyclization product is determined by the relative concentrations of the radical reactants and their cyclization reaction rate constants. However, using Z-configuration 5 as the substrate, the corresponding R/S ratio depends on not only the relative concentrations of the radical reactants and their cyclization reaction rate constants but also the concentration distribution of the stereoisomers of the substrate and their deiodination reaction rate constants. For E-configuration 5, the chirality transfer from (M,E)-5 to (S)-7 or from (P,E)-5 to (R)-7 is approximately 63.8% in the temperature range of 213.15−383.15 K. The chirality transfer using E-configuration 5 as the substrate is insensitive to temperature. When using Z-configuration 5 as the substrate, the chirality transfer of (M,Z)-5-to-(S)-7 or (P,Z)-5-to-(R)-7 is

Figure 6. Computed temperature dependence of the chirality transfer with different stereoisomers of 5 as substrates at the BHandHLYP/6311++G(d,p) level of theory.

(see Figure 6), and the chirality transfer from the axially chiral (M,E)-5 to the centrally chiral (S)-7 or from the axially chiral (P,E)-5 to the centrally chiral (R)-7 is approximately 63.8% (see Figure 6 and Table S18). When using (M,Z)-5 as the substrate, a much different reaction mechanism is observed. As shown in Figure 5, the initial concentration distribution of the radical reactants (M,Z)-8d and (M,Z)-8e is associated with not only the thermodynamic 12956


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(11) Luo, Z.; Zhou, B.; Li, Y. C. Total synthesis of (−)-(α)-kainic acid via a diastereoselective intramolecular [3 + 2] cycloaddition reaction of an aryl cyclopropyl ketone with an alkyne. Org. Lett. 2012, 14, 2540− 2543. (12) Miyabe, H. Inter- and intramolecular carbon-carbon bondforming radical reactions. Synlett 2012, 23, 1709−1724. (13) Yu, S.; Ma, S. Allenes in catalytic asymmetric synthesis and natural product syntheses. Angew. Chem., Int. Ed. 2012, 51, 3074−3112. (14) Byers, P. M.; Alabugin, I. V. Polyaromatic ribbons from oligoalkynes via selective radical cascade: Stitching aromatic rings with polyacetylene bridges. J. Am. Chem. Soc. 2012, 134, 9609−9614. (15) Zhu, Z.; Fahrenbach, A. C.; Li, H.; Barnes, J. C.; Liu, Z. C.; Dyar, S. M.; Zhang, H. C.; Lei, J. Y.; Carmieli, R.; Sarjeant, A. A.; et al. Controlling switching in bistable [2]catenanes by combining donoracceptor and radical-radical interactions. J. Am. Chem. Soc. 2012, 134, 11709−11720. (16) Simpkins, N.; Pavlakos, I.; Male, L. Rapid access to polycyclic indolines related to the stephacidin alkaloids using a radical cascade. Chem. Commun. 2012, 48, 1958−1960. (17) Sautier, B.; Lyons, S. E.; Webb, M. R.; Procter, D. J. Radical cyclization cascades of unsaturated meldrum’s acid derivatives. Org. Lett. 2012, 14, 146−149. (18) Zhao, H. W.; Hsu, D. C.; Carlier, P. R. Memory of chirality: an emerging strategy for asymmetric synthesis. Synthesis 2005, 1, 1−16. (19) Curran, D. P.; Eichenberger, E.; Collis, M.; Roepel, M. G.; Thoma, G. Group transfer addition reactions of methyl(phenylseleno)malononitrile to alkenes. J. Am. Chem. Soc. 1994, 116, 4279−4288. (20) Curran, D. P.; Hale, G. R.; Geib, S. J.; Balog, A.; Cass, Q. B.; Degani, A. L. G.; Hernandes, M. Z.; Freitas, L. C. G. Rotational features of carbon-nitrogen bonds in axially chiral o-tert-butyl anilides and related molecules. Potential substrates for the ‘prochiral auxiliary’ approach to asymmetric synthesis. Tetrahedron: Asymmetry 1997, 8, 3955−3975. (21) Curran, D. P.; Liu, W. D.; Chen, C. H.-T. Transfer of chirality in radical cyclizations. Cyclization of o-haloacrylanilides to oxindoles with transfer of axial chirality to a newly formed stereocenter. J. Am. Chem. Soc. 1999, 121, 11012−11013. (22) Lapierre, A. J. B. Chirality Transfer in 5-exo Cyclizations of Axially Chiral o-Iodoanilides; University of Pittsburgh: Pittsburgh, 2005. (23) Majumdar, K. C.; Chattopadhyay, B.; Samanta, S. Synthesis of highly substituted dibenzoazocine derivatives by the aza-Claisen rearrangement and intramolecular Heck reaction via 8-exo-trig mode of cyclization. Tetrahedron Lett. 2009, 50, 3178−3181. (24) Bowman, W. R.; Fletcher, A. J.; Lovell, P. J.; Pedersen, J. M. Synthesis of indoles using cyclization of imidoyl radicals. Synlett 2004, 11, 1905−1908. (25) Bowman, W. R.; Krintel, S. L.; Schilling, M. B. Tributylgermanium hydride as a replacement for tributyltin hydride in radical reactions. Org. Biomol. Chem. 2004, 2, 585−592. (26) Rigby, J. H.; Mateo, M. E. Total synthesis of (±)-α-lycorane and 4,5-dehydroanhydrolycorine. Tetrahedron 1996, 52, 10569−10582. (27) Curran, D. P.; Chen, C. H.-T.; Geib, S. J.; Lapierre, A. J. B. Asymmetric radical cyclization reactions of axially chiral N-allyl-oiodoanilides to form enantioenriched N-acyldihydroindoles. Tetrahedron 2004, 60, 4413−4424. (28) Lapierre, A. J. B.; Geib, S. J.; Curran, D. P. Low-temperature Heck reactions of axially chiral o-iodoacrylanilides occur with chirality transfer: Implications for catalytic asymmetric Heck reactions. J. Am. Chem. Soc. 2007, 129, 494−495. (29) Guthrie, D. B.; Geib, S. J.; Curran, D. P. Radical and Heck cyclizations of diastereomeric o-haloanilide atropisomers. J. Am. Chem. Soc. 2011, 133, 115−122. (30) Yang, D.; Chen, Y.-C.; Zhu, N.-Y. Sterically bulky thioureas as airand moisture-stable ligands for Pd-catalyzed Heck reactions of aryl halides. Org. Lett. 2004, 6, 1577−1580. (31) Donatoni, M. C.; Vieira, Y. W.; Brocksom, T. J.; Rabelo, A. C.; Leite, E. R.; de Oliveira, K. T. One-pot sequential functionalizations of meso-tetrathienylporphyrins via Heck-Mizoroki cross-coupling reactions. Tetrahedron Lett. 2016, 57, 3016−3020.

95.1 and 81.0% at 213.15 and 383.15 K, respectively. Low temperature is favorable for improving the chirality transfer when Z-configuration 5 is used as the substrate. Therefore, using Zconfiguration 5 as the substrate in HSnBu3-mediated cyclization instead of the Heck reaction can yield products with high transfer of chirality.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpcb.6b10344. Computational details of the transfer of chirality; all geometries in Cartesian coordinates optimized with the BHandHLYP method in combination with the 6-311+ +G(d,p) (for C, H, O, and N atoms) and double-zeta LANL2DZ (for Sn and I atoms) basis sets; thermodynamic and kinetic data of all located stationary points; computed reaction rate constants using the traditional TST; R/S ratios of products using different substrates (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (H.Z.). *E-mail: [email protected] (H.-T.Y.). ORCID

Hai-tao Yu: 0000-0003-3764-9201 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank the “National Natural Science Foundation of China” (Project: 21173072) for financial support. REFERENCES

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Theoretical Investigation of Regioselectivity and Stereoselectivity in

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