A computational study on the stereo- and regioselective formation of

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A computational study on the stereo- and regioselective formation of the C4#-C6’ bond of tethered catechin moieties by an exhaustive search of the transition states Keisuke Fukaya, Akiko Saito, Noriyuki Nakajima, and Daisuke Urabe J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03263 • Publication Date (Web): 31 Jan 2019 Downloaded from http://pubs.acs.org on February 3, 2019

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The Journal of Organic Chemistry

A computational study on the stereo- and regioselective formation of the C4-C6’ bond of tethered catechin moieties by an exhaustive search of the transition states Keisuke Fukaya,1 Akiko Saito,2 Noriyuki Nakajima,3 Daisuke Urabe*,1

1Biotechnology

Research Center and Department of Biotechnology, Toyama Prefectural University 5180 Kurokawa, Imizu, Toyama 939-0398, Japan

2Graduate

School of Engineering, Osaka Electro-Communication University 18-8 Hatsu-cho, Neyagawa, Osaka 572-8530, Japan

3Biotechnology

Research Center and Department of Pharmaceutical Engineering, Toyama Prefectural University 5180 Kurokawa, Imizu, Toyama 939-0398, Japan

Graphic Abstract

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ABSTRACT We previously reported the total synthesis of procyanidin B6 by using the stereo- and regioselective C-C bond formation of tethered catechin moieties as the key step. The reaction afforded the product bearing a new C4-C6’ bond linkage instead of the inherently preferable C4-C8’bond. However, the origin of this selectivity remained unclear due to the complex structure of the substrate. Here we report the results of computational exploration of this C-C bond formation to gain mechanistic insights into the selectivity. The computational study of highly flexible compounds was realized by an exhaustive search of transition states. A large library of candidate transition states was generated by a conformational search of constrained models using molecular mechanics simulations and semi-empirical molecular orbital calculations. Subsequent DFT-based transition state calculations provided 367 transition states for C4-C6’ and C4-C8’ bond formations. Comparison of the geometries and energies showed that the C4-C6’ linkage is preferentially formed via two competing transition states, leading to a C6’-diastereomeric mixture. Interactive atomic distances and visualization of the non-bonding interactions suggest the importance of non-classical hydrogen bonding, and CH-π, π-π and lone pair-π interactions in stabilizing the two transition states. The present study supports preferential C4-C6’ bond formation of the tethered catechins.


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INTRODUCTION Proanthocyanidins are polyphenolic, plant-derived flavonoid natural products1

that are

characterized by the oligomeric structures of flavan-3-ols exemplified by catechin and epicatechin.2 The variety of linkages of flavan-3-ols through their C-C and C-O bonds provides a large family of structurally diverse secondary polyphenols that show a broad spectrum of beneficial biofunctions such as anti-oxidant, anti-inflammatory, and anti-tumor activities.3

The complex structures of

proanthocyanidins have challenged synthetic chemists to develop strategies for regioselective bond formation in the catechin and epicatechin moieties.4 OH HO

O

H OH OH

OH OH

HO

7

catechin

1

8

O C

A 6

OH HO

O

HO

H

4

OH HO

H 8'

OH O

A'

8'

OH

H OH

H 6'

7'

OH

1'

O H

OH

2 3

4

5

OH

B

H

OH OH

5' 4'

C' 2'

3'

B' OH

OH OH procyanidin B3 (1)

OH

OH procyanidin B6 (2)

Figure 1. Structures of catechin, procyanidin B3 (1), and procyanidin B6 (2) Procyanidin B3 (1) and procyanidin B6 (2) are isomeric proanthocyanidins composed of two catechins (Figure 1). These natural compounds share an -oriented C4-linkage on the C-ring of one catechin monomer, while the other catechin is connected at the C8’-position in 1 and at the C6’ position in 2.5 Synthetic efforts to date have mostly focused on the formation of the C4-C8’ bond embedded in procyanidin B3 (1) because of the abundance of this linkage in natural proanthocyanidins.6 We have been involved in developing protocols for the Lewis-acid promoted coupling of catechin moieties by stereo- and regioselective C4-C8’ bond formation.7 Scheme 1A shows a representative example, in which 3 and 4 were coupled by the action of TMSOTf to quantitatively provide 5. This example demonstrates that the new C-C bond forms preferentially from the opposite side of the C3-functional



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group to generate the -oriented C4-linkage, and that the C8’ position of catechin is more nucleophilic than the C6’ position. In addition to C4-C8’ bond formation, C4-C6’ bond formation has also been developed as a complimentary approach to diverse proanthocyanidins.8,9 Specifically, SnCl4-treatment of 6 tethering two catechin moieties provided 7 in 72% yield as a single product (Scheme 1B). Furthermore, the total synthesis of procyanidin B6 from 7 has recently been reported.8,10 A. The C4-C8' bond formation in the total synthesis of 1 (ref. 7a). OBn BnO

O

OBn

H OBn 3

4

OAc

OBn OEE 3

–78 °C quant. OBn

+ 8'

BnO

O

BnO

O

TMSOTf CH2Cl2

8'

OAc

OBn

H

O

OBn

OBn

OBn

5 (dr at C4 = >48:1)

OH OBn

H

OH

H

6'

OBn 3

4

OBn BnO

H

4

B. The C4-C6' bond formation in the total synthesis of 2 (ref. 8). OBn BnO

O

3

4

OBn

H O O

OBn

OBn OEE 6' TBSO O O 8'

O H

BnO

OAc

O

3

4

SnCl4 CH2Cl2 –20 °C 72%

OBn TBSO

H

O O

OBn

O O

6'

O H

OTBS OTBS 6

H

OAc

OTBS OTBS 7

Scheme 1. Stereo- and regioselective coupling of catechins toward the total synthesis of 1 and 2. Ac = acetyl, Bn = benzyl, EE = 2-ethoxyethyl, TBS = tert-butyldimethylsilyl.

The key strategy for C4-C6’ bond formation over the inherently preferred C4-C8’ bond is to tether the catechin moieties. However, the mechanism for retaining stereoselectivity but switching regioselectivity remains unclear because exploring plausible transition states for C-C bond formation is complicated by the structures of the possible intermediates. The highly flexible intermediates,


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possessing a long chain tether and two pyrane rings with catechol moieties and C3-oxygen functional groups, can generate multiple conformational isomers, resulting in a large number of transition states that need to be considered. The difficulty of evaluating the structures and relative stabilities of the transition states led us to examine C-C bond formation computationally. DFT-based analysis of transition states is a powerful tool for gaining insights into reaction mechanisms and has been used to explore the origins of unique transformations of complex intermediates in natural product synthesis.11 Although computer-aided study of highly flexible catechin moieties is challenging,12 the optimized geometry of the transition state and accurate knowledge of its energy could help elucidate crucial mechanistic characteristics of C-C bond formation.13 Here we report a method for exhaustively searching the transition states for the C4-C6’ and C4-C8’ bond formations of tethered catechins to explore the origin of the stereo- and regioselective C4-C6’ bond formation of 6. The application of molecular mechanics simulation and semi-empirical molecular orbital calculations to constrained models of 6 enabled generation of a library of suitable structures for the transition state calculation using DFT methods.

RESULTS AND DISCUSSION Prior to the computational study, we designed 12 as a model for 6 to simplify the calculation (Scheme 2). The catechol moieties (B and B’-rings) of 6 were truncated to Ph groups because the four benzyl ethers were separated from the reactive C4, C6’ and C8’-sites and thus would not be involved in C-C bond formation. The other functional groups (two benzyl ethers on the A-ring and a TBS ether on the A’-ring) were replaced with methyl ethers and a TMS ether, respectively.



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R1 R 2O

O

R1

B

H

A

O O

4

R 2O

R1

O

H

4

OR2 OEE R 3O O O A'

Lewis acid

OR2 R 3O

R1

O O

6'

O O

8'

O H

O H

OAc

OAc

B' R4

R4

R4

R4 8: R1 = OBn, R2 = Bn R3 = TBS, R4 = OTBS 13: R1 = R4 = H, R2 = Me, R3 = TMS

6: R1 = OBn, R2 = Bn R3 = TBS, R4 = OTBS 12: R1 = R4 = H, R2 = Me, R3 = TMS path 'a'

path 'b'

R1 R 2O

O

H O O

4

OR R 3O

H H

2 6'

R1

R1 R 2O

O

H R1

4

O O

O H

OR2 R 3O

8'

H H

O

O

R4

O H OAc

OAc

R4

O O

R4 R4 9: R1 = OBn, R2 = Bn R3 = TBS, R4 = OTBS 14a-d: R1 = R4 = H, R2 = Me, R3 = TMS

10: R1 = OBn, R2 = Bn R3 = TBS, R4 = OTBS 16a-d: R1 = R4 = H, R2 = Me, R3 = TMS

H+

H+ R

2

R O

O

H

4

OR2 R 3O

1

H 6'

O O

R 2O

O

H R1

4

O O

O H

R1

R1

OR2 R 3O

H 8'

O

O

O H OAc

OAc

R4 R4

O R4

O

R4 7ab: R1 = OBn, R2 = Bn R3 = TBS, R4 = OTBS 15ab: R1 = R4 = H, R2 = Me, R3 = TMS

11ab: R1 = OBn, R2 = Bn R3 = TBS, R4 = OTBS 17ab: R1 = R4 = H, R2 = Me, R3 = TMS

Scheme 2. The two SN1 reaction pathways (path ‘a’ and ‘b’) from 6 to 7. TMS = trimethylsilyl. Scheme 2 illustrates two plausible pathways from 6 to 7 through widely accepted SN1 mechanisms


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for the Lewis acid-promoted coupling of catechin derivatives.6 C4-carbocation intermediate 8 is generated from 6 by the action of a Lewis acid and a C-C bond is formed by the nucleophilic attack of the A’-ring. Path ‘a’ leads to formation of the C4-C6’ bond to produce 9, followed by deprotonation to afford 7. In contrast, isomer 11 is formed via path ‘b’, which includes formation of the C4-C8’ bond and deprotonation. We hypothesized that the deprotonation would be a rapid and irreversible aromatization process, and the C-C bond formation would be responsible for the stereo- and regioselective generation of 7. Therefore, we computationally explored the two transformations of 13 to 14 and 13 to 16. The first step in the computational assessment of C4-C6’ bond formation (path ‘a’) was to generate a library of candidate structures for the transition state calculation. The success of transition state calculations is highly dependent on the submitted structure and thus creation of a high quality library is very important. Furthermore, the library should contain a large number of structures to comprehensively cover all possible conformational isomers of the transition states. We first used reactant 13 and product 14 as template structures to create the library. Conformational searches of 13 and 14 using OPLS3 provided a large number of structures whose C4-C6’ bonds were then adjusted to 1.8-2.1 Å, a range of lengths suitable for transition state calculations. However, the next DFT calculation using these created structures did not provide plausible transition states but rather structures that were significantly different from the ideal transition state geometries. We therefore used a constrained model for 13 in the conformational search in which the constrained bond distance between the C4 and C6’ positions was 2.1 ± 0.2 Å and the C4-C6’-H6’ angle was 90 ± 10°. The OPLS3-minimization generated 825 structures with energies up to 5.0 kcal·mol−1 higher than the most stable structure. The distance between C4 and C6’ of the obtained structures was fixed at 2.0 Å and the resultant structures were then optimized by semi-empirical molecular orbital calculations (PM6).14 The obtained structures were subjected to transition state calculations using the DFT method (B3LYP/6-31G(d), 1 atm, 253 K),15 leading to plausible transition states. Duplicate structures with RMSDs of 0.01 Å were removed to provide 288 transition

states.

Subsequent

single

point

energy

calculations

at

the

M06-2X/6-311+G(d,p)-SMD(CH2Cl2) level of theory afforded the energy of each structure.16 The DFT-optimized transition states were classified into four clusters, leading to diastereomers 14a-d at the



C4 and C6’ positions on the C- and A’-ring, respectively. In each cluster, the structures TS-A, TS-B, TS-C, and TS-D with the lowest energy were evaluated as transition states for C4-C6’ bond formation. IRC calculations of TS-A, TS-B, TS-C, and TS-D provided 13a-d and pro-14a-d, which are pre-organized carbocation intermediates of the transition states and the products preceding those in the ground states, respectively.

14.0

ΔG‡ (kcal·mol-1)

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

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12.0

TS-C (12.9)

10.0

TS-D (10.7)

pro-14d (3.0)

TS-B (8.7)

8.0

pro-14c (2.7)

TS-A (8.5)

pro-14b (0.6)

6.0 4.0

13c (3.6)

2.0

13b (1.8)

0.0 13 (0.0)

-2.0

pro-14a (−1.4)

13a (1.2)

14d (1.8)

13d (1.0)

14c (−2.7) 14a (−3.3)

-4.0

14b (−4.4)

-6.0

MeO

O C

H

4

OMe TMSO

6'

A' O H

13

MeO O O O O

OAc

O

H

4

OMe TMSO 6'

H H

O H

14a

MeO O O O O

OAc

O

H

4

OMe TMSO 6'

H H

O H

MeO O O O O

O

H

4

OMe 6' TMSO

OAc

14b

H H

O H

MeO O O O O

O

H

4

OMe TMSO 6'

OAc

14c

H H

O H

O O O O

OAc

14d

Figure 2. Energy diagram for C4-C6’ bond formation and the difference in Gibbs free energy at the M06-2X/6-311+G(d,p)-SMD(CH2Cl2)//B3LYP/6-31G(d) level of theory (253 K, 1 atm).

TS-A is the most stable (ΔG‡ = 8.5 kcal·mol −1, Figure 2) of the four transition states. TS-A leads to the formation of cation intermediate 14a by the approach of the nucleophilic A’-ring to the C4-carbocation from the -face of the C-ring, resulting in formation of the C4 bond. TS-B is slightly higher in energy than TS-A (ΔΔG‡ = 0.2 kcal·mol−1) and also forms the correct C4-configuration to generate C6’-diastereomer 14b. The negligible difference in energy between TS-A and TS-B suggests


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that the C4-C6’ bond is formed via these two competing transition states, resulting in the generation of both the 14a and 14b C6-diastereomers. Rapid deprotonation of 14a and 14b could afford the same product. In contrast, TS-C and TS-D are destabilized by 4.4 and 2.2 kcal·mol−1 (ΔΔG‡), respectively, compared to TS-A. The higher activation energies of TS-C and TS-D indicate that formation of the C4 bond via approach of the A’-ring from the -face of the C-ring is a less favorable pathway. Searching transition states using a library containing structures that are conformationally distinct from the reactant and product can provide valuable insights into conformational dynamics. Specifically, comparison of the structure of 13 with pre-organized 13a, and of pro-14a with ground state 14a, shows significant conformational change before and after C4-C6’ bond formation (Figure 3). Comparison of 13 and 13a shows that both axial C2,3-substituents on the C-ring in 13 are equatorial in 13a, bringing the A’-ring close to the reactive C4-carbocation. The dynamics indicates that the protected C4-carbocation by interaction with the proximal carbonyl group is exposed to the nucleophilic C6’ carbon for subsequent reaction. Furthermore, reorganization from pro-14a to 14a results in significant change in the conformation of the 15-membered ring, thereby releasing ring strain.



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Figure 3. Conformational dynamics of C4-C6’ bond formation from 13 to 14a. Although positive charge symbols are not shown, all structures are cationic.

The detection of non-bonding interactive atoms within the sum of their van der Waals radii aids in understanding the stability of transition states but it is often difficult to assess whether short atomic distances contribute to stabilization or destabilization of the transition state. We therefore used NCIPLOT to visualize the attractive and repulsive non-bonding interactions in the transition states.17 The attractive interactions in TS-A and TS-B between several O and H atoms are indicated as blue surfaces in Figure 4. The short distances of H2···O=C and H6’···O=C in TS-A (2.33, 2.29 Å) and H6’···O=C, H of C5MeO···O=C, H3’···O=C and H3···O=C (2.25, 2.32, 2.33, 2.36 Å) in TS-B suggest non-classical hydrogen bonding between the electron-rich carbonyl group and the electron-deficient H atoms.18 These interactions could stabilize the geometries of the transition states to decrease the energy barriers. Green surfaces in Figure 4 indicate multiple CH-π, π-π and lone pair-π interactions to help stabilize the structures of TS-A and TS-B.19 Intriguingly, CH-π interactions between the CH3 of the axial C3’-acetate with the B-ring are clearly evident in TS-A. The unique conformation of TS-A, where the two bulky C2’-phenyl and C3’-acetoxy groups are axial, could be also attributed to CH-π interactions. Both TS-A and TS-B contain characteristic donut-shape surfaces that are red on the outside and blue on the inside and may signify that bond formation involves both repulsive and attractive interactions. Similar to TS-A and TS-B, TS-C and TS-D contain a hydrogen bonding system involving H-O interactions (H3···O=C: 2.18 Å, H2···O7’: 2.21 Å for TS-C, H2···O5’: 2.24 Å, H3···O=C: 2.20 Å, H3’···O=C: 2.22 Å for TS-D), and π-π and lone pair-π interactions (Figure 5). However, these two transition states are higher in energy than TS-A and TS-B. The high energy barriers would result from unfavorable steric interactions between H4-C5’ (2.59 Å) for TS-C and H4-C7’ (2.57 Å) for TS-D, as indicated by the red swollen donut-shape surface in the forming bond.


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Figure 4. Optimized transition states TS-A and TS-B, selected atomic distances within the sum of the van der Waals radii, and non-bonding interactions visualized by NCIPLOT (s = 0.5, −0.03 < sign(λ2)ρ < +0.03 au). Blue, green and red surfaces indicate attractive, van der Waals, and repulsive interactions, respectively. Although positive charge symbols are not shown, all structures are cationic.


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Figure 5. Optimized transition states TS-C and TS-D, selected atomic distances within the sum of the van der Waals radii, and non-bonding interactions visualized using NCIPLOT (s = 0.5, −0.03 < sign(λ2)ρ < +0.03 au). Blue, green and red surfaces indicate attractive, van der Waals, and repulsive interactions, respectively. Although positive charge symbols are not shown, all structures are cationic.

16.0

TS-E (13.7)

14.0

TS-F (12.1)

12.0

TS-H (11.3)

10.0 ΔG‡ (kcal·mol-1)

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

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pro-16a (4.3)

TS-G (10.5)

8.0

pro-16b (3.0)

6.0

pro-16d (−0.3)

4.0

13e (4.5)

2.0

13f (3.5)

0.0

13h (2.2)

16d (−2.4)

-2.0

13g (1.5)

16b (−2.7)

13 (0.0)

pro-16c (−1.8)

16c (−3.5)

-4.0

16a (−3.6)

-6.0

MeO

O C

H

4

OMe TMSO A'

O O O O

MeO

O

H

4

H H

OMe TMSO 8'

8'

O H

MeO O

O 4

O

H H

OMe TMSO 8'

O

H

H OAc

OAc

O

H H

OMe TMSO 8'

O

H

4

O

MeO O

H H

OMe TMSO 8'

O

H

4

O

O

O

O H OAc

O O

16b

O

H OAc

O O

16a

O

H OAc

O O

MeO

O O

16c

16d

13

Figure 6. Energy diagram for C4-C8’ bond formation and the difference in Gibbs free energy at the M06-2X/6-311+G(d,p)-SMD(CH2Cl2)//B3LYP/6-31G(d) level of theory (253 K, 1 atm).

We next explored the transition states for C4-C8’ bond formation in 13 (path ‘b’) by first creating 368 structures using an OPLS3 conformational search followed by PM6 geometry optimization using a constrained model (C4-C8’distance: 2.1 ± 0.2 Å, C4-C8’-H8’ angle: 90 ± 10°). Transition state calculation, removal of duplicate structures, and a single point energy calculation provided 79 transition


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states of which four transition states (TS-E, TS-F, TS-G, TS-H) with the lowest energy in the diastereomeric clusters to afforded the four diastereomers 16a-d were evaluated. IRC calculations for TS-E, TS-F, TS-G and TS-H provided the pre-organized carbocation intermediates 13e-h and pro-16a-d, the precursors of products 16a-d in the ground state. The energy diagram shown in Figure 6 demonstrates that TS-G is the most stable of the four transition states (ΔG‡ = 10.5 kcal·mol−1). TS-G forms a C4 bond linkage by the approach of the A’-ring from the -face of the C-ring, resulting in formation of the opposite C4-configuration to that of the experimentally obtained product. In contrast to TS-A and TS-B, TS-E and TS-F that lead to C4 bond linkages are higher in energy than TS-G (ΔΔG‡ = 3.2 and 1.6 kcal·mol−1). Computation of the 8 transition states for C4-C6’ and C4-C8’ bond formation enabled comparison of the energy of the most stable transition state in each pathway. The results demonstrated that TS-A is more stable than TS-G (ΔΔG‡ = 2.0 kcal·mol−1), in support of C4-C6’ bond formation being preferred over C4-C8’ bond formation. Several non-bonding interactions, including hydrogen bonding (H3···O=C: 2.18, H3’···O=C: 2.37, H6’···O=C 2.21, H8’···O5: 2.38 Å, Figure 7) and the lone pair-π interaction between the O3 atom and the A’-ring, suggest that TS-G is a low energy structure, but repulsive interactions between H4 and C9’, as well as H8’ and C10, increase the energy of this transition state.



Page 16 of 26

Figure 7. Optimized transition state TS-G, selected atomic distances within the sum of the van der Waals radii, and non-bonding interactions visualized using NCIPLOT (s = 0.5, −0.03 < sign(λ2)ρ < +0.03 au). Blue, green and red surfaces indicate attractive, van der Waals, and repulsive interactions, respectively. Although positive charge symbols are not shown, all structures are cationic.

SUMMARY We explored the transition states for the stereo- and regioselective transformation of 6 to 7 in the total synthesis of procyanidin B6 (2). The use of constrained models of 13 enabled exhaustive conformational searches to create a library of candidate transition states. Subsequent transition state calculations using the DFT method provided 367 transition states which clustered into 8 groups, leading to the products 14a-d and 16a-d. Computation showed that the C-C bond formation is via the two competing transition states TS-A and TS-B, leading to the C6-diastereomers 14a and 14b that can be transformed into the same product via deprotonation. The computational results support the preferential pathway in which the C4-bond linkage is formed from the lower side of the C-ring by C6’-nucleophilic


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attack of the A’-ring. Detailed analysis of the transition states suggests synergetic effects between non-classical hydrogen bonding and CH-π, π-π, and lone pair-π πinteractions to stabilize the transition states. The present study demonstrated that DFT-based computation of the transition states identified by exhaustive conformational searches of a constrained model enables the exploration of reasonable reaction mechanisms of highly complex molecular systems. Further application of this method to complex intermediates in natural product synthesis is in progress.

EXPERIMENTAL SECTION Computational Details. Conformational searches were performed with MacroModel version 11.8 implemented in the Maestro 11.4 software package.20 All DFT-based calculations were performed with the Gaussian 09 Rev E.01 program.21 Semi-empirical calculations were carried out with Spartan’16 V2.0.722 for the unconstrained models and Gaussian 09 for the constrained structures. Parts of these computations were conducted using the Fujitsu PRIMERGY CX400 multi-node server (Information Technology Center of Nagoya University). Molecular structures were visualized using CYLview.23 NCI surfaces were calculated with NCIPLOT17 and visualized with VMD24. Cartesian coordinates of the structures described in this manuscript are included in the Supporting Information.

Procedure for evaluating the lowest energy structures of the transition states. The conformational search on 13 was first conducted by molecular mechanics simulation with the constraints 2.1 Å ± 0.2 Å (force constant: 1000 kJ/mol·Å2) for the C4-C6’ distance and 90 ± 10° (force constant: 1000 kJ/mol·rad2) for the C4-C6’-H6’ angle. Conformers were generated using the Monte-Carlo Multiple Minimum (MCMM) method in 10000 steps using PRCG energy minimization by the OPLS3 force field (gas phase), and 825 conformational isomers were obtained with energies within 5.0 kcal/mol of the most stable structure. The distance between C4 and C6’ of each structure was fixed at 2.0 Å by modifying the Cartesian coordinates and then these constrained structures were optimized using the PM6 semi-empirical method. The next optimization step of the transition state was performed at the



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B3LYP/6-31G(d) level of theory (gas phase). Frequency calculations were carried out at the same level of theory to confirm the sole imaginary frequency and to obtain thermal corrections. The removal of identical structures using a threshold of 0.01 Å RMSD provided 288 transition states. After single-point energies for these structures were calculated at the M06-2X functional and the 6-311+G(d,p) basis set with solvation effects using the SMD solvation model (CH2Cl2), the thermal corrections at the B3LYP/6-31G(d) level were added to obtain the Gibbs free energies at 1 atm, 253 K. The lowest energy transition state leading to 14a-d was defined as TS-A, TS-B, TS-C and TS-D. IRC calculation at the B3LYP/6-31G(d) level confirmed that the transition states were connected to reactant 13 and products 14a-d, and generated the pre-optimized structures for 13a-d and pro-14a-d, respectively. The above procedure was also used to create the lowest energy conformers of the transition states TS-E, TS-F, TS-G and TS-H. A conformational search on 13 was first conducted by molecular mechanics simulation with the constraints 2.1 Å ± 0.2 Å (force constant: 1000 kJ/mol·Å2) for the C4-C8’ distance and 90 ± 10° (force constant: 1000 kJ/mol·rad2) for the C4-C8’-H8’ angle. The obtained 368 structures were optimized using the PM6 semi-empirical method, keeping the C4-C8’ bond length at 2.0 Å. DFT-based transition state calculations and the removal of duplicate structures provided 79 structures. After calculation of the single-point energies and clustering of the structures leading to 16a-d, the lowest energy structure in each cluster was defined as TS-E, TS-F, TS-G and TS-H, respectively. IRC calculations at the B3LYP/6-31G(d) level confirmed that the transition states were connected to the reactant 13 and the products 16a-d and generated the pre-optimized structures for 13e-h and pro-16a-d, respectively.

Procedure for the optimization and energy evaluation of 13a-h, pro-14a-d and pro-16a-d. The pre-optimized structures for 13a-h, pro-14a-d and pro-16a-d obtained from IRC calculations on TS-A, TS-B, TS-C, TS-D, TS-E, TS-F, TS-G, and TS-H were further optimized at the B3LYP/6-31G(d) level of theory in the gas phase. Frequency calculations of the resulting structures were carried out at the same level of theory to confirm the absence of imaginary frequencies and to obtain thermal corrections. After the single-point energies were calculated at the M06-2X/6-311+G(d,p)-SMD(CH2Cl2) level of theory


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with solvation effects using the SMD solvation model (CH2Cl2), the thermal corrections at the B3LYP/6-31G(d) level were added to obtain the Gibbs free energies at 1 atm, 253 K.

Procedure for the optimization and energy evaluation of 13. In the first step of the conformational search on 13, we ran 10000 steps of the Monte-Carlo Multiple Minimum (MCMM) method with PRCG energy minimization using the OPLS3 force field (gas phase) and obtained 353 conformational isomers with energies within 5.0 kcal/mol of the lowest energy structure. These structures were optimized using PM6, leading to 32 structures whose heats of formation were within 6.0 kcal/mol of the lowest energy structure. The next optimizations were performed at the B3LYP/6-31G(d) level of theory (gas phase). Frequency calculations were carried out at the same level of theory to confirm the absence of imaginary frequencies and to obtain thermal corrections. After the single-point energies were calculated at the M06-2X/6-311+G(d,p) level of theory with solvation effects using the SMD solvation model (CH2Cl2), the thermal corrections at the B3LYP/6-31G(d) level were added to obtain the Gibbs free energies at 1 atm, 253 K. The conformation having the minimum Gibbs free energy was defined as the global minimum energy conformation of 13.

Procedure for the optimization and energy evaluation of products 14a-d and 16a-d. The conformational search on 14a began by applying 10000 steps of the Monte-Carlo Multiple Minimum (MCMM) method with PRCG energy minimization using the OPLS3 force field (gas phase) and 374 conformational isomers with energies within 5.0 kcal/mol of the lowest energy structure were obtained. These structures were optimized using PM6, leading to 97 structures whose heats of formation were within 2.0 kcal/mol of the lowest energy structure. The next optimizations were performed at the B3LYP/6-31G(d) level of theory (gas phase). Frequency calculations were carried out at the same level of theory to confirm the absence of imaginary frequencies and to obtain thermal corrections. After the single-point energies were calculated at the M06-2X/6-311+G(d,p) level of theory with solvation effects using the SMD solvation model (CH2Cl2), the thermal corrections at the B3LYP/6-31G(d) level were added to obtain the Gibbs free energies at 1 atm, 253 K. The conformation having the minimum Gibbs



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free energy was defined as the global minimum energy conformation of 14a. The global minimum energy conformations of 14b, 14c, 14d, 16a, 16b, 16c and 16d were similarly determined using 623, 245, 591, 231, 458, 255 and 390 structures, respectively, as the OPLS3-minimized structures and 37, 93, 58, 50, 7, 22 and 41 structures as the PM6-optimized structures respectively.

ASSOCIATED CONTENT The Cartesian coordinates of TS-A-H, 13, 13a-h, pro-14a-d, 14a-d, pro16a-d, and pro16a-d. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS This research was financially supported by a Grant-in-Aid for Young Scientists (A) (JSPS, 16H06213).

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A computational study on the stereo- and regioselective formation of

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