Mechanistic investigation on the remote stereocontrol in the chiral Lewis base-catalyzed, SiCl4-promoted kinetic resolution of chlorinated cis-vinyl epoxides

Article abstract of DOI:10.1016/j.tet.2020.131763

It has been known that the enantioselectivity of the chiral Lewis base-catalyzed, SiCl₄-promoted kinetic resolution of α,β-dichloro cis-vinyl epoxide is highly influenced by the configuration of the distal β-chlorine-bearing stereocenter. In th

Full text of DOI:10.1016/j.tet.2020.131763

Journal Pre-proof
Mechanistic investigation on the remote stereocontrol in the chiral Lewis base-
catalyzed, SiCl -promoted kinetic resolution of chlorinated cis-vinyl epoxides
4
Jungi Jung, Mugeon Song, Jun-Ho Choi, Won-jin Chung
PII:
S0040-4020(20)30998-4
https://doi.org/10.1016/j.tet.2020.131763
TET 131763
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 17 July 2020
Revised Date: 22 October 2020
Accepted Date: 8 November 2020
Please cite this article as: Jung J, Song M, Choi J-H, Chung W-j, Mechanistic investigation on the
remote stereocontrol in the chiral Lewis base-catalyzed, SiCl -promoted kinetic resolution of chlorinated
4
cis-vinyl epoxides, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131763.
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Jung, Song, Choi,* and Chung*
Page 1
Mechanistic investigation on the remote stereocontrol in the chiral Lewis base-catalyzed, SiCl4-
promoted kinetic resolution of chlorinated cis-vinyl epoxides
Jungi Jung, Mugeon Song, Jun-Ho Choi,* and Won-jin Chung*
Department of Chemistry, Gwangju Institute of Science and Technology, 123 Cheomdan-gwagi-ro, Buk-gu,
Gwangju 61005, Republic of Korea.
Submitted to Tetrahedron
Corresponding authors
Tel.: +82-62-715-4626; fax: +82-62-715-2866; e-mail: junhochoi@gist.ac.kr (J.-H. Choi)
Tel.: +82-62-715-2847; fax: +82-62-715-2866; e-mail: wjchung@gist.ac.kr (W.-j. Chung)
Abstract
It has been known that the enantioselectivity of the chiral Lewis base-catalyzed, SiCl4-promoted kinetic
resolution of α,β-dichloro cis-vinyl epoxide is highly influenced by the configuration of the distal β-chlorine-
bearing stereocenter. In this report, the precise nature of this unusual remote stereocontrol was investigated
both experimentally and theoretically. Upon examination of a substrate that has an alkyl group in place of the
β-chlorine substituent, the spatial location of major catalyst-substrate interaction was determined.
Subsequently, through computational analysis of transition states, the steric repulsion by the β-substituents as
well as the additional C–H/π hydrogen bond by the alkyl substituent were proposed as the crucial stereo-
determining factors.
Keywords
epoxide opening; kinetic resolution; Lewis base catalysis; silicon tetrachloride; C–H/π hydrogen bond

Jung, Song, Choi,* and Chung*
Page 2
1. Introduction
Epoxide is one of the most versatile functional groups in organic synthesis, and thus a number of synthetic
methods have been developed for the enantioselective formation of chiral epoxide [1]. Enantioenrichment can
also be achieved by the enantioselective opening of optically inactive epoxide via either desymmetrization of
meso-epoxide [2] or kinetic resolution of racemic epoxide [3], typically in the presence of chiral Lewis acid.
Denmark and coworkers developed a chiral Lewis base catalysis for the generation of highly active chiral
silicon Lewis acids by taking advantage of Lewis base activation of Lewis acids phenomenon [4], and the
utility of such catalytic system was demonstrated in the desymmetrization of meso-epoxide with chiral
phosphoramide catalyst and silicon tetrachloride [5]. Since this seminal report, various types of chiral Lewis
base including N-oxide [6], phosphines [7], and phosphine oxides [8] were developed by several research
groups, and highly selective epoxide desymmetrization was accomplished, illustrating the efficiency of the
Lewis base-SiCl4 system [9]. Later, the scope of Denmark’s chiral phosphoramide-catalyzed, enantioselective
epoxide opening has been successfully extended to the kinetic resolution of racemic cis-vinyl epoxide (1) by
Vanderwal and coworkers during the enantioselective total synthesis of chlorosulfolipids (Fig. 1A) [10]. In
this case, the dimeric bisphosphoramide 2 performed better than the monomeric catalyst even though it was an
inferior catalyst for desymmetrization. Interestingly, the selectivity of the kinetic resolution is highly affected
by the configuration of a relatively remote β-stereocenter. Under the identical catalytic conditions with 2, anti-
α,β-dichloride (R = n-C6H13) was resolved much more effectively than the related syn-α,β-dichloride (R = n-
C8H17). Recently, a preliminary mechanistic study on the stereo-controlling effect of these chlorine-bearing
stereocenters was reported by our group (Fig. 1B) [11]. Through a systematic examination of α- or β-
monochlorinated substrates 4–6, we have demonstrated that both α- and β-chlorine substituents are required
for the high level of enantio-differentiation. In addition, computational analysis was performed for the
aliphatic side chain conformation of α,β-dichlorinated vinyl epoxide in order to rationalize the cooperative
action of the two stereocenters. It was suggested that the allylic 1,3-like strain at the α-stereocenter as well as
the preferred gauche conformation between the α- and β-chlorine-bearing carbons result in a fairly well-
defined spatial arrangement of the substituents. Then, upon examination of the ground state of a representative
catalyst-substrate complex, it was proposed that the dichloroalkyl side chain could be placed near the chiral

Jung, Song, Choi,* and Chung*
Page 3
catalyst pocket depending on the epoxide configuration, and the conformationally rigid α-center would direct
the aliphatic residue toward the catalyst. Thus, the enantiomer with its alkyl side chain in a less crowded space
(i) is likely to be activated preferentially to result in the selective epoxide opening whereas the other
enantiomer-catalyst complex (ii) is energetically less favorable because of the destabilizing steric interaction
between the β-substituents of the side chain and the catalyst. The degree of such interaction appears to be
finely controlled by the position and property of the substituents at the β-center. In the current study, the
influence of the remote site was further evaluated by employing a substrate with two β-alkyl groups (Fig. 1C).
This type of substrate can be considered as an alkyl analog of α,β-dichloro cis-vinyl epoxide, in which the β-
chlorine is replaced by an alkyl group. Then, a more precise computational analysis was conducted via
transition state calculation to support our stereochemical model and to rationalize the observed remote
configuration-dependency. Herein, we describe the results from these mechanistic investigations that led to a
plausible proposal on the nature of the catalyst-substrate interaction.
A. Kinetic resolution of cis-vinyl epoxide (Vanderwal et al., ref 10)
Large influence of the remote -stereocenter on selectivity factor
Cl
Cl
OH
O
(R,R)-2, SiCl4
Cl
+
( )-1
R
R
S = 27 for , -anti
S = 4 for , -syn
Cl
Cl
( )-3
( )-1
Me
Me
N
N
O
O
P
P
N
N
N
N
Me
Me
Me
Me
(R,R)-2: Denmark's dimeric catalyst
B. Previous mechanistic study (Chung et al., ref 11)
Cooperative stereocontrol by two Cl's
- low selectivity factors with only one Cl (R = n-C10H21
)
Cl
Cl
6:
O
O
O
R
R
R
Cl
4:
5:
S = 1.2
S = 1.4
S = 1.1
Computational analysis of catalyst-substrate complex
- A1,3-like strain at the -stereocenter
- gauche conformation of the vicinal Cl's (X,Y = Cl or R)
- asymmetric shielding by the catalyst
Si
O
Si
O
- catalyst-substrate
interaction
- key stereo-controlling
element
*
H
H
*
H
H
H
H
vs
H
H
Y
Y
X
X
Cl
i: side chain outside
C. This work
Cl
Cl
Cl
ii: side chain inside
- further evaluation of the influence of the -stereocenter
- computational analysis of the transition states
- identification of the nature of the catalyst-substrate interaction

Jung, Song, Choi,* and Chung*
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Fig. 1. Chiral Lewis base-catalyzed kinetic resolution of chlorinated cis-vinyl epoxide.
2. Results and discussion
2.1. Kinetic resolution of α-chloro cis-vinyl epoxide with two β-alkyl substituents
To probe the role of the β-substituents, two alkyl moieties were installed at the β-position of α-chloro cis-vinyl
epoxide (Scheme 1A). A cyclohexyl group was employed in order to avoid the creation of an additional
stereocenter as well as to increase the molecular weight for convenient handling. First, commercially available
2-cyclohexylethanol (7) was oxidized to aldehyde 8 via the Swern oxidation [12]. Then, α-chlorination was
accomplished with the combination of NCS and (±)-proline to give (±)-9 [13]. At this point, a sequence of
diastereoselective bromoallylation and ring closure afforded the desired racemic cis-vinyl epoxide (±)-10 [14].
The kinetic resolution of (±)-10 was performed under the previously reported conditions (Scheme 1B) [10]. In
the presence of 20 mol% of (R,R)-2, (±)-10 was slowly resolved at –78 °C with moderate selectivity (S = 3,
ΔΔG‡ = 0.4 kcal/mol).
A. Substrate preparation
(COCl)2
DMSO, Et3N
O
O
OH
76%
H
H
(±)-proline
NCS
78%
7
8
LiTMP, Et2AlCl
allyl bromide
O
then, aq. NaOH
n-Bu4NBr, 65%
Cl
Cl
( )-9
( )-10
B. Kinetic resolution
(R,R)-2 (20 mol%)
SiCl4 (1.0 equiv)
i-Pr2NEt (1.0 equiv)
OH
O
Cl
+
( )-10
CH2Cl2, 78 C, 96 h
Cl
( )-11: 23%, 28:72 er
Cl
( )-10: 56%, 42:58 er
S = 3
Scheme 1. Preparation and evaluation of a cis-vinyl epoxide substrate with two alkyl substituents at the β-
position.
This result is compared with the literature data from the kinetic resolution of syn- and anti-α,β-dichloro cis-
vinyl epoxides (Fig. 2) [10]. The illustration depicts the catalyst/substrate interaction in the transition structure
of the less reactive enantiomer, which is thought to be responsible for the energy difference between the two
diastereomeric transition states. The similar selectivity factors obtained with 10 and α,β-syn-1 (S = 4, ΔΔG‡ =

Jung, Song, Choi,* and Chung*
Page 5
0.5 kcal/mol) indicate that the β-chlorine substituent of α,β-syn-1 is essentially uninfluential and thus not in
close contact with the catalyst. On the other hand, it appears that the β-chlorine substituent of α,β-anti-1 has a
significant impact on the selectivity (S = 27, ΔΔG‡ = 1.3 kcal/mol). Therefore, it is highly probable that this
position (highlighted in blue) is the site of important catalyst-substrate interaction (X of ii in Fig 1B). Among
these three structures, only α,β-anti-1 has a different substituent (Cl) at that position, and thus the noticeably
high selectivity of this substrate can be rationalized by invoking a destabilizing interaction between the
chlorine and the catalyst.
Fig. 2. Comparison of catalyst/substrate interactions.
In addition, the differential activation parameters were obtained experimentally by performing the kinetic
resolution of (±)-10 at various temperatures ranging from –80 to –20 °C (See the SI for details). Each data
point was duplicated, and the average values of selectivity factor were used for the plot. During the course of
this study, the experimental results often suffered from irreproducibility, probably caused by the adventitious
moisture even though the reactions were conducted in the presence of i-Pr2NEt as an acid scavenger [15,16].
Gratifyingly, the addition of molecular sieve alleviated this problem without affecting the stereoselectivity.
From the differential Eyring plot with these data, ΔΔH‡ and ΔΔS‡ were determined to be –1.1 kcal/mol and –
3.8 cal/molK, respectively (Fig 3). The differential enthalpy and entropy contribute to the differential Gibbs
free energy in comparable degrees (–T·ΔΔS‡ = 0.7 kcal/mol at –78 °C) but in the opposite directions. Thus, in
theory, the reversal of enantioselection can be observed at high temperature [17]. Unfortunately, the estimated
selectivity factor is only 2 even at 200 °C (ΔΔG‡ = 0.7 kcal/mol favoring the other enantiomer), which is far
from being practical.

Jung, Song, Choi,* and Chung*
Page 6
Fig. 3. Differential Eyring plot for kinetic resolution of (±)-10.
2.2. Computational analysis
2.2.1. Computational method
Approximate coordinates for transition states were obtained by the PM3 semi-empirical method using
MOPAC 2016 [18], and then those were optimized sequentially by ab initio calculation at the HF/6-31G(d)
then 6-31G(d,p) level of theory with Grimme’s dispersion correction (D3) [19] using the GAMESS(US)
software package [20]. The resulting structures were further refined by density functional theory (DFT)
calculation at the B3LYP-D3/6-31G(d,p) level of theory [21] using the Gaussian 16 suite of programs [22].
For the solvation effect of CH2Cl2, the polarizable continuum model (PCM) was employed [23]. The validity
of the resulting transition structures was supported by the presence of a single negative frequency that
corresponds to the epoxide opening as well as the formation of reactant and product from the Intrinsic
Reaction Coordinate (IRC) calculation at the same level of theory. The single point energies were obtained by
DFT calculation at the B3LYP-D3/6-311++G(d,p) level of theory. The 3-D illustrations were produced using
CYLview [24].
2.2.2. Transition state calculation for kinetic resolution of chlorinated cis-vinyl epoxides
Through an extensive mechanistic study on the complexation between (R,R)-2 and SiCl4 by Denmark and
coworkers, it was revealed that the tethered bisphosphoramide Lewis base forms cis-chelation around the
silicon center in the catalytically active species [25]. The subsequent coordination of an electrophile would
generate an octahedral species [26], in which the position of electrophile, epoxide in our case, has two

Jung, Song, Choi,* and Chung*
Page 7
possibilities, trans to either phosphoramide or chloride (Fig. 4). The relative stability of two isomers was
estimated computationally at the inexpensive HF/6-31G(d) level of theory using a simple cis-dimethyl
epoxide prior to the transition state calculation. After a systematic analysis of the conformation around the Si-
O(epoxide) bond in each isomer, it was found that the epoxide prefers to occupy the trans position to
phosphoramide (ΔG = 1.2 kcal/mol). This result is consistent with the orbital analysis of hypervalent
octahedral silicon complexes, which has been previously done for chiral Lewis base-catalyzed,
enantioselective aldol addition of trichlorosilyl ketene acetal [27]. According to the analysis, two
electronegative chlorine atoms favor to constitute a hypervalent 3-center-4-electron bond (blue) and thus
maintain a trans relationship, leaving the epoxide no choice but to be placed at the position trans to
phosphoramide. An important consequence of this ligand arrangement is the electrophilic activation of
epoxide by the formation of a dative bond to silicon through an electron-withdrawing sp-orbital (red).
Fig. 4. Analysis of [(R,R)-2·SiCl3·epoxide]+ complex structure with respect to the position of epoxide.
(Hydrogens of the catalyst are omitted for clarity.)
Using the geometry of the most stable conformer as a starting point, transition states for the (R,R)-2-catalyzed
opening of each enantiomer of anti- and syn-α,β-dichloro cis-vinyl epoxides were calculated (Fig. 5). To
simplify the computation process, the long aliphatic group at the side chain was replaced by a methyl group.
In the complexes of (αS,βR)-anti- and (αS,βS)-syn-dichlorides (TS-1 and TS-3), the α,β-dichlorinated alkyl

Jung, Song, Choi,* and Chung*
Page 8
side chains are exposed to vacant space without experiencing meaningful interaction with the catalyst. In
contrast, the side chains of (αR,βS)-anti- and (αR,βR)-syn-dichlorides (TS-2 and TS-4) are located near the
catalyst pocket, causing steric destabilization. These results are consistent with the simple stereochemical
model from our previous study (Fig. 1B), and the computational analysis of transition states correctly predicts
the absolute sense of enantioselection. The preferential activation of (–)-(αS,βR)-anti- and (–)-(αS,βS)-syn-
+
dichlorides by (R,R)-2-SiCl3 will lead to the selective consumption of these reactive enantiomers via epoxide
opening. Consequently, (+)-(αR,βS)-anti- and (+)-(αR,βR)-syn-dichlorides will be left unreacted in an
enantioenriched form. Furthermore, the structural characteristics and the relative single point energy values of
these diastereomeric transition states can account for the different behavior of syn- and anti-dichloro cis-vinyl
epoxides in the kinetic resolution. As alluded to earlier, the degree of interaction between the substrate and the
catalyst is significantly altered by the configuration change of the β-stereocenter (TS-2 vs TS-4), which is
embedded in the most crowded area. In addition, the computationally estimated ΔΔG‡ values correspond well
with the experimentally obtained S factors as ΔΔG‡ = 1.2 and 0.4 kcal/mol correspond to S = ca. 22 and 3 at
195 K, respectively.
Fig. 5. Transition state calculation for each enantiomer of anti- and syn-α,β-dichloro cis-vinyl epoxides.
(Hydrogens of the catalyst are omitted for clarity.)
To elucidate the precise nature of the catalyst-substrate interaction, the transition structures with the side chain
in the catalyst pocket were carefully inspected (Fig. 6). It was found that the β-chlorine substituent in TS-2 is

Jung, Song, Choi,* and Chung*
Page 9
in close contact with a naphthyl ring of the catalyst, and the distance to the center of the arene ring (3.58 Å) is
only slightly longer than the sum of the van der Waals radii (1.75 Å for Cl, 1.70 Å for C). Therefore, the
repulsive steric hindrance between the chlorine and the catalyst must be responsible for the destabilization of
TS-2 as expected. On the other hand, the β-methyl group in TS-4 appears to engage in a C–H hydrogen bond
with the neighboring aromatic π system [28]. A C–H bond is pointing toward a naphthyl ring in roughly
perpendicular orientation, and the distance between the proton and the center of the arene ring (2.75 Å) is
shorter than the sum of the van der Walls radii (1.20 Å for H, 1.70 Å for C), indicating that there is a bonding
interaction. The computed C–H/arene distance is in good agreement with the experimentally measured range
of sp3 C–H/arene distances [28h]. The nearby electron-withdrawing chlorine substituents could also assist this
interaction by enhancing the C–H acidity. We propose that this weakly stabilizing C–H/π interaction
attenuates the degree of destabilization of TS-4 to a lesser extent. Consequently, the energy difference
between the competing TS’s (TS-3 and TS-4) becomes smaller, thus resulting in a lower selectivity factor for
syn-dichloride.
Fig. 6. Alteration of catalyst-substrate interaction by β-stereocenter: steric repulsion (TS-2) vs C–H/π
hydrogen bond (TS-4). (Hydrogens of the catalyst are omitted for clarity. The distances to the center of the
arene ring are shown.)
A transition state calculation was also performed for the opening of the simplest β-gem-dimethyl analog to
account for the kinetic resolution result with (±)-10 (Fig. 7). It was revealed that the catalyst-substrate
interaction is similar to that of syn-α,β-dichloro cis-vinyl epoxide (TS-4 vs TS-6). The distance between the β-
methyl proton and the nearby arene ring (2.71 Å) implies that the degree of C–H/π hydrogen bond in TS-6 is
roughly equivalent to that in TS-4. Thus, the comparable level of enantioselection for the syn-α,β-dichloride

Jung, Song, Choi,* and Chung*
Page 10
(S = 4) and (±)-10 (S = 3) could be rationalized. Moreover, the calculated ΔΔG‡ value (0.6 kcal/mol, S = 5 at
195 K) correlates reasonably well with the observed selectivity factor.
Fig. 7. Transition state calculation for a simple β,β-dialkyl analog. (Hydrogens of the catalyst are omitted for
clarity. The distance to the center of the arene ring is shown.)
3. Conclusions
In summary, we have conducted experimental and theoretical mechanistic investigations on the kinetic
resolution of chlorinated cis-vinyl epoxides to elucidate the origin of the remarkable stereo-controlling effect
of the remote β-stereocenter, which has been observed with α,β-dichloro cis-vinyl epoxides. Through a control
experiment with a β,β-dialkyl analog, the site of predominant catalyst-substrate interaction was identified (X
in Fig. 1B). Furthermore, DFT calculation of the transition states suggests the presence of a weakly stabilizing
C–H/π hydrogen bond between a proton of a β-alkyl group and an arene ring of the catalyst, which was
presumed to be responsible for the attenuated performance of syn-α,β-dichloro cis-vinyl epoxide compared to
the corresponding anti-dichloride. These calculation data also account for the absolute sense of
enantioselection and support the stereochemical model that has been previously proposed by our group.
4. Experimental section
4.1. General experimental
All reactions were performed in oven-dried (140 °C) or flame-dried glassware under an atmosphere of
dry argon unless otherwise noted. Purification of solvents and reagents are described in the Electronic
and column chromatography were performed using Merck silica gel
Supporting Information. Filtration
(SiO ) 60 Å (0.040 0.063 mm). Analytical thin-layer chromatography (TLC) was conducted on Merck silica
–
2
gel 60 F254 TLC plates. Visualization was accomplished with UV (254 nm) as well as KMnO4 and
p-

Jung, Song, Choi,* and Chung*
Page 11
13
1
1H and C NMR spectra were recorded on a JEOL ECS400 (400 MHz, H;
staining solutions.
anisaldehyde
13
1
13
100 MHz, C) spectrometer and referenced to residual chloroform (7.26 ppm, H; 77.0 ppm, C). Chemical
shifts are reported in ppm, and multiplicities are indicated by s (singlet), d (doublet), t (triplet), q (quartet), br
(broad), and m (multiplet). Coupling constants, J, are reported in Hertz. Analytical chiral stationary phase
gas chromatography (CSP-GC) was performed on an Agilent Technologies 7890B gas chromatograph
equipped with a flame ionization detector (FID) and a B-DM (Agilent, ϕ = 0.250 mm, l = 30 m) capillary
column. EI-HRMS was performed on a JEOL JMS-700 MStation mass spectrometer with magnetic sector-
. Data are
electric sector double focusing mass analyzer at Korea Basic Science Institute (KBSI), Daegu Center
reported in the form of m/z. Optical rotation was measured on a JASCO P-2000 WI digital polarimeter at
Functional Organic Molecules Synthesis Laboratory, Gwangju Institute of Science and Technology. Data are
reported as follows: concentration and solvent.
4.2. Preparation of (±)-10
4.2.1. 2-Cyclohexylethanal (8) [12]
To a stirred solution of oxalyl chloride (1.0 mL, 12 mmol) in CH2Cl2 (40 mL) was added DMSO (1.4 mL, 20
mmol) at –78 °C under Ar. After 10 minutes, 2-cyclohexylethanol (7, 1.4 mL, 10 mmol) was added dropwise.
After 30 minutes, triethylamine (5.6 mL, 40 mmol) was added over 25 minutes. The reaction mixture was
warmed to 0 °C and stirred for 90 minutes. The reaction was quenched with sat. aq NaHCO3 (50 mL). The
organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (50 mL × 3). The combined
organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash
column chromatography (SiO2, EtOAc:hexanes = 1:40, Rf = 0.2, KMnO4) to give 8 (960 mg, 76%) as a
colorless oil. 8 was used for the next reaction without further purification because of its high volatility. Data
for 8 [8]: 1H NMR (400 MHz, CDCl3) δ 9.76 (t, J = 2.4, 1H), 2.29 (dd, J = 6.8, 2.4, 2H), 1.89 (m, 1H), 1.76
1.62 (m, 5H), 1.35 1.23 (m, 2H), 1.22 1.10 (m, 1H), 1.06 0.94 (m, 2H).
–
–
–
–
4.2.2. 2-Chloro-2-cyclohexylethanal ((±)-9) [13b]
To a stirred solution of 8 (960 mg, 7.6 mmol) and (±)-proline (89 mg, 0.76 mmol) in CH2Cl2 (15 mL) was
added NCS (1.3 g, 9.9 mmol) at 0 °C. After 5 minutes, the ice bath was removed. After 18.5 hours, the

Jung, Song, Choi,* and Chung*
Page 12
reaction was quenched with sat. aq Na2SO3 (20 ml) and H2O (40 ml). The organic layer was separated, and the
aqueous layer was extracted with CH2Cl2 (60 ml × 3). The combined organic layers were dried over MgSO4,
filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2,
EtOAc:hexanes = 1:40, Rf = 0.2, KMnO4) to give (±)-9 (990 mg, 78%) as a colorless oil ((±)-9/dichloro
1
aldehyde = 93/7). Data for (±)-9 [9a]: H NMR (400 MHz, CDCl3) δ 9.47 (d, J = 3.2, 1H), 3.97 (dd, J = 6.2,
3.4, 2H), 1.97 (m, 1H), 1.86–1.75 (m, 3H), 1.73–1.65 (m, 2H) 1.34–1.14 (m, 5H).
4.2.3. (±)-(3S,4R,5S)-5-Chloro-5-cyclohexyl-3,4-epoxy-1-pentene ((±)-10) [10a]
To a stirred solution of TMP (2.3 mL, 14 mmol) in THF (18 mL) was added n-BuLi (7.9 mL, 13 mmol)
dropwise over 6 minutes at
–78 °C under Ar. After 1 hour, the LiTMP solution was cannulated into a solution
of allyl bromide (1.2 mL, 13 mmol) and Et2AlCl (1.0 M in hexanes, 25 mL, 25 mmol) in THF (18 mL) at
–
78 °C. After 10 minutes, (±)-9 (990 mg, 6.2 mmol) in THF (3.0 mL) was added. After 4 hours, the reaction
mixture was poured into an ice-cold 5 M aq NaOH (50 mL) solution. n-Bu4NBr (20 mg, 0.060 mmol) was
added, and the biphasic mixture was vigorously stirred at room temperature. After 1 hour, the mixture was
diluted with hexanes. The organic layer was separated, and the aqueous layer was extracted with hexanes (50
mL × 3). The combined organic layers were washed with brine (100 mL) and sat. aq NH4Cl (100 mL), dried
over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography
(SiO2, EtOAc:hexanes = 1:40, Rf = 0.2, p-anisaldehyde) to give (±)-10 (802 mg, 65%) as a colorless oil. Data
for (±)-10: 1H NMR (400 MHz, CDCl3) δ 5.80 (ddd, J = 17.2, 10.8, 6.0, 1H), 5.49 (ddd, J = 17.2, 1.6, 0.8, 1H),
5.42 (ddd, J = 10.4, 1.6, 0.8, 1H), 3.53 (m, 1H), 3.42 (dd, J = 9.6, 6.8, 1H) 3.30 (dd, J = 9.6, 4.0, 1H), 2.00–
1.92 (m, 1H), 1.87–1.75 (m, 4H), 1.72–1.64 (m, 1H), 1.34–1.12 (m, 5H). 13C NMR (100 MHz, CDCl3) δ
130.8, 121.0, 63.3, 59.0, 56.6, 43.6, 29.8, 28.6, 26.2, 26.0, 25.8. HRMS (EI) calcd for C11H1735ClO [M]+
200.0968, found 200.0965. [α]D25 = 2.6 (c 0.53, CHCl3).
4.3. Kinetic resolution of (±)-10 [10a]
To a stirred solution of (±)-10 (110 mg, 0.50 mmol) and (R,R)-2 (85 mg, 0.10 mmol) in CH2Cl2 (5 mL) were
added i-Pr2NEt (90 μL, 0.50 mmol) and silicon tetrachloride (60 μL, 0.50 mmol) at
–78 °C under Ar. After 96
hours, propylene oxide (530 μL, 7.5 mmol) was added. After 1 minute, a solution of MeOH/Et3N/CH2Cl2

Jung, Song, Choi,* and Chung*
Page 13
(1/2/5, 4 mL) was quickly added to the reaction mixture. The resulting solution was vigorously stirred with a
1:1 mixture of sat. aq NaHCO3 (20 mL) and sat. aq KF (20 mL) solution for 2 hours prior to filtration. The
organic layer was separated, and the aquous layer was extracted with CH2Cl2 (30 mL × 3). The combined
organic layers were dried over anhydrous MgSO4, filtered, and concentrated in vacuo. (R,R)-2 was removed
by filtration through a short pad of silica gel, and the residue was purified by column chromatography (SiO2,
EtOAc:hexanes = 1:20, p-anisaldehyde) to give (+)-10 (Rf = 0.6, 56 mg, 56%, 42:58 er) and (+)-11 (Rf = 0.4,
28 mg, 23%, 28:72 er). Data for (+)-10: CSP-GC (B-DM, 34 psi, 70 °C) tR 115 min (42%), 122 min (58%).
Data for (+)-11: 1H NMR (400 MHz, CDCl3) δ 6.07 (ddd, J = 17.0, 10.2, 7.8, 1H), 5.46 (ddd, J = 16.8, 1.2, 1.2,
1H), 5.31 (ddd, J = 10.0, 10.0, 1.0, 1H), 5.11 (dd, J = 7.6, 0.8, 1H), 3.91 (dd, J = 9.8, 2.2, 1H), 3.81 (ddd, J =
9.9, 1.4, 1.3, 1H), 2.14–2.06 (m, 1H), 2.02 (dd, J = 5.0, 1.2, 1 H), 1.82–1.77 (m, 2H), 1.70–1.67 (m, 2H),
1.57–1.43 (m, 2H), 1.34–1.25 (m, 3H), 1.24–1.11 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 135.3, 118.9, 73.7,
67.7, 65.6, 38.2, 31.1, 26.4, 26.2, 25.8, 25.4. HRMS (EI) calcd for C11H1835Cl2O [M]+ 236.0735, found
236.0732. CSP-GC (B-DM, 34 psi, 120 °C) tR 43 min (28%), 52 min (72%). [α]D25 = 8.9 (c 0.21, CHCl3).
4.4. Kinetic resolution at various temperatures for the Eyring plot
The kinetic resolutions for the Eyring plot were performed in a similar manner employing (±)-10 (50 mg, 0.25
mmol), (R,R)-2 (42 mg, 0.050 mmol), 3 Å molecular sieve (100 mg, powder), i-Pr2NEt (5 μL, 0.03 mmol),
and silicon tetrachloride (30 μL, 0.25 mmol) in CH2Cl2 (2.5 mL) at –20, –40, –60, and –80 °C for 1, 2, 3, and
4 days, respectively. The result from each experiment is given in the Supporting Information.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could
have appeared to influence the work reported in this paper.
Acknowledgements
This research was supported by Basic Science Research Program through the National Research Foundation
of Korea (NRF) funded by the Ministry of Science & ICT (NRF-2020R1F1A1076028) and by "GIST
Research Institute (GRI)" grant funded by the GIST in 2020.

Jung, Song, Choi,* and Chung*
Page 14
Supporting Information
Kinetic resolution data at various temperatures, computation data, and copies of NMR spectra for all new
compounds (PDF).
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- The remote stereocontrol in the kinetic resolution of chlorinated vinyl epoxide was investigated
- The role of the β-chlorine-bearing stereocenter has been elucidated by DFT calculation of transition state.
- Non-covalent interactions including C–H/π hydrogen bonding are proposed as key stereodetermining factors.

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: