Development of chiral bisphosphoric acid/boronic acid co-catalyst system for enantioselective SN2’ reaction

Article abstract of DOI:10.1016/j.tet.2021.132412

An enantioselective intramolecular S_N2’ reaction of geometrically defined allylic substrates was developed by introducing a co-catalyst system composed of chiral bisphosphoric acid and phenylboronic acid. In the enantioselective nucleophilic su

Full text of DOI:10.1016/j.tet.2021.132412

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Development of chiral bisphosphoric acid/boronic acid co-catalyst
system for enantioselective SN2’ reaction
Satavisha Kayal, Jun Kikuchi, Naoya Shinagawa, Shigenobu Umemiya, Masahiro Terada*
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai, 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An enantioselective intramolecular SN2’ reaction of geometrically defined allylic substrates was devel-
oped by introducing a co-catalyst system composed of chiral bisphosphoric acid and phenylboronic acid.
In the enantioselective nucleophilic substitution reaction using chiral phosphoric acids and derivatives
(CPAs) as the catalyst, the formation of the corresponding CPA ester, which is afforded through the SN2
reaction of the substrate with the nucleophilic phosphate anion generated during the activation of a
leaving group, has been a serious problem because of the catalyst deactivation. The developed co-catalyst
system surmounted this fundamental problem by efficiently suppressing the catalyst deactivation pro-
cess to afford enantioenriched vinyl epoxides in good yields with moderate to high enantioselectivities.
Mechanistic elucidation of the present enantioselective intramolecular SN2’ reaction using the co-catalyst
system revealed that the leaving group is involved in the enantio-determining transition states, and the
anti-SN2’ pathway is considered to be the rational mechanism of the present allylic substitution reaction.
In addition, the stereospecific Meinwald rearrangement of the thus-formed enantioenriched vinyl
epoxide was aided by an equimolar amount of a Lewis acid, affording the corresponding all-carbon
Received 6 July 2021
Received in revised form
18 August 2021
Accepted 19 August 2021
Available online xxx
Keywords:
Chiral Brønsted acid
Organocatalysis
Quaternary stereogenic center
SN2’ reaction
Vinyl epoxides
quaternary
a
-vinyl cyclohexanone without marked loss of enantiomeric purity.
© 2021 Elsevier Ltd. All rights reserved.
1. Introduction
an intramolecular SN2’ reaction (Scheme 1) [7]. The enantiose-
lective SN2’ reaction under acidic conditions is beneficial for the
construction of the enantioenriched tetrasubstituted carbon center
because, in general, the SN2’ reaction is initiated by the activation of
a leaving group by an acid catalyst, in which the introduction of
multiple substituents to the reaction site leads to the stabilization
of a positively charged transition state. Hence, it facilitates the
formation of a tetrasubstituted carbon center [8] despite the in-
crease in steric congestion around the reaction site.
In our previous study shown in Scheme 1a, we have disclosed
the method in detail and discussed the mechanistic insight into the
SN2’ reaction on the basis of experimental and theoretical studies
[7a]. It was experimentally and theoretically clarified that the re-
Over the past decades, a variety of chiral Brønsted acids have
been developed as an efficient enantioselective organocatalyst in
asymmetric synthesis [1]. In particular, binaphthol (BINOL)-derived
phosphoric acids and derivatives (CPAs) have emerged as privileged
organocatalysts [2,3], and a diverse range of enantioselective re-
actions catalyzed by CPAs have been developed. In most cases,
catalysis by CPAs has been applied to nucleophilic addition re-
actions. Meanwhile, an enantioselective nucleophilic substitution
reaction, which is one of the representative covalent bond forma-
tion reactions along with the nucleophilic addition reaction, has
been achieved using CPAs as an efficient chiral Brønsted acid
catalyst in recent years [4,5]. The vinylogous analogue of an allylic
substitution reaction, namely, the SN2’ reaction, has also been re-
ported by several groups [6,7]. Among the allylic substitution re-
actions using CPAs, our group successfully developed an
enantioselective construction of a tetrasubstituted carbon center by
action proceeded through
a synchronous anti-SN2’ pathway,
whereas the formation of phosphorimidate ester A through the SN2
reaction of phosphoramide catalyst (R)-1a with the allylic substrate
deactivated the catalyst and retarded the reaction markedly. Thus,
in general, the main drawback associated with the enantioselective
nucleophilic substitution reaction is the generation of a nucleo-
philic phosphate anion from the CPAs during the activation of a
leaving group, which would undergo the SN2 reaction with the
substrate to result in the catalyst deactivation. Although some
* Corresponding author.
E-mail address: mterada@tohoku.ac.jp (M. Terada).
https://doi.org/10.1016/j.tet.2021.132412
0040-4020/© 2021 Elsevier Ltd. All rights reserved.
Please cite this article as: S. Kayal, J. Kikuchi, N. Shinagawa et al., Development of chiral bisphosphoric acid/boronic acid co-catalyst system for
enantioselective SN2’ reaction, Tetrahedron, https://doi.org/10.1016/j.tet.2021.132412

S. Kayal, J. Kikuchi, N. Shinagawa et al.
Tetrahedron xxx (xxxx) xxx
Scheme 2. Enantioselective intramolecular SN2’ reaction of allylic substrate (E)-2
promoted by CPAs and Lewis acidic additive co-catalyst system.
the use of a weak Lewis acidic additive [10], the acidity of which is
insufficient for the activation of LG. We anticipated that the Lewis
acidic additive would interact with the conjugate base of a CPA
catalyst to reduce its nucleophilicity, and hence the intended SN2’
reaction would dominate over the formation of CPA ester C through
the SN2 reaction. Herein we report the development of an efficient
co-catalyst system composed of CPAs and a weakly Lewis acidic
additive to avoid the catalyst deactivation. The established co-
catalyst system afforded vinyl epoxides 3 in good yields with
moderate to high enantioselectivities [11]. In addition, the Mein-
wald rearrangement of epoxide 3 was also demonstrated using a
Lewis acid to derivatize all-carbon quaternary
without marked loss of enantiomeric purity.
a-vinyl ketone 4
2. Results/discussion
Scheme 1. Enantioselective allylic substitution and related reactions catalyzed by CPAs
(R)-1 for the construction of a tetrasubstituted carbon center. (a) Enantioselective
intramolecular SN2’ reaction. (b) Enantioselective Wagner-Meerwein shift.
We initially confirmed the efficiency of acidic N-triflyl phos-
phoramide derivative (R)-1 (5 mol%) in the intramolecular SN2’
reaction of (E)-2a without using any additive in accordance with
our previous studies (Scheme 1) [7]. As expected, in the presence of
triflyl phosphoramide catalyst (R)-1c, a considerable amount of
starting material (E)-2a remained unreacted, and the reaction
completely stopped after 12 h in CHCl3 even at room temperature,
affording epoxide 3a in poor yield (16%) (Table 1, entry 1). In
examples have emerged indicating that CPAs undergo an SN2 re-
action with the substrate to generate the corresponding CPA esters
as a reactive intermediate for further transformations [9], the for-
mation of the CPA esters through the SN2 reaction would lead to a
serious problem in the establishment of an efficient enantiose-
lective nucleophilic substitution reaction using CPAs as the chiral
Brønsted acid catalyst.
addition,
a-vinyl ketone 4a was formed as the major product
through the Wagner-Meerwein shift, albeit in a racemic form. We
then turned our attention to employing slightly less acidic
bisphosphoric acid (R)-5 as the catalyst [5c,12], instead of (R)-1. The
use of bisphosphoric acid (R)-5a resulted in the formation of 3a
predominantly over 4a with moderate enantioselectivity (entry 2).
However, the conversion of (E)-2a was not improved, and the for-
mation of 3a failed to progress completely, even after continuing
the reaction for 48 h. The introduction of sterically hindered aryl
substituent G to bisphosphoric acid (R)-5b did not have a marked
effect on both yield and enantioselectivity (entry 3). At this point, a
quick solvent screening was performed using catalyst (R)-5b, and
the screening revealed that Et2O is the optimum solvent in terms of
enantioselectivity (entries 4e6). In all cases, epoxide 3a was ob-
tained as the sole product but only with poor to moderate yields,
and a substantial amount of 2a was recovered. In Et2O, the use of
(R)-5b (entry 6) exhibited better ee than that of (R)-5a (entry 7). An
increase in catalyst loading to 10 mol% slightly improved the yield
of epoxide 3a without affecting the enantioselectivity (entry 8 vs.
6), however 2a remained unconsumed considerably. More impor-
tantly, in a 31P NMR analysis of the crude mixtures, several un-
identified peaks other than (R)-5b were observed, suggesting the
formation of phosphate esters through the SN2 reaction of (R)-5b
In order to surmount this fundamental problem of suppressing
CPA ester formation and develop efficient enantioselective substi-
tution reactions catalyzed by CPAs, we adopted an intramolecular
allylic substitution reaction of (E)-2 as the model reaction (Scheme
2). The proposed reaction system resembles our previous report, as
shown in Scheme 1b [7b]; we employed an alternative substrate
having a normal ring, instead of a substrate having a strained
cyclobutene unit. In our previous study, trichloroacetimidate (LG) is
activated by acid catalyst (R)-1b to generate positively charged
allylic species B, and the Wagner-Meerwein shift through path a
affords the corresponding a-vinyl ketone by releasing cyclobutane
ring strain. In contrast, in the proposed reaction system (Scheme 2),
the direct SN2’ displacement from the hydroxy group would
become predominant, which would result in the formation of
epoxide 3 likely through path b shown in Scheme 1b, due to the
near-zero ring strain in allylic substrate 2. Therefore, the catalyst
deactivation, namely, the formation of CPA ester C, would compete
with the desired epoxide formation because the construction of
strained epoxide 3 would be energetically unfavorable. With the
aim of establishing an efficient enantioselective intramolecular SN2’
reaction of geometrically pure allylic substrate (E)-2, we envisioned
2

S. Kayal, J. Kikuchi, N. Shinagawa et al.
Tetrahedron xxx (xxxx) xxx
Table 1
Screening for CPAs and conditionsa.
Entry
CPA
Solvent
Conditions
Recovery of 2a (%)
Combined yield (%)b
3a/4ac
% ee of 3a/4ad
1
2
3
4
5
6
7
8e
(R)-1c
(R)-5a
(R)-5b
(R)-5b
(R)-5b
(R)-5b
(R)-5a
(R)-5b
CHCl3
CHCl3
CHCl3
Toluene
CH2Cl2
Et2O
rt, 12 h
rt, 48 h
rt, 48 h
rt, 48 h
rt, 48 h
rt, 36 h
rt, 36 h
rt, 36 h
47
50
50
50
85
40
57
45
39
40
40
40
15
37
41
42
41 : 59
95 : 5
95 : 5
>99 : 1
>99 : 1
>99 : 1
58:42
N.D./racemic
46/N.D.
38/N.D.
65/-
N.D./-
87/-
Et2O
Et2O
81/20
87/-
>99 : 1
a
Unless otherwise noted, all reactions were carried out using 5 mol% of CPAs, 0.05 mmol of (E)-2a, in the indicated solvent (0.5 mL).
The combined yield of 3a and 4a is indicated.
b
c
The ratio was determined by 1H NMR analysis of the crude reaction mixture using CH2Br2 as the internal standard.
d
e
Enantiomeric excess (ee) of 3a was determined by HPLC analysis using a chiral stationary phase column. N.D.: ee of 3a or 4a was not determined.
10 mol% of (R)-5b was used.
Table 2
room temperature, whereas the enantioselectivity remained the
same (88% ee) (entry 1). When phenylboronic acid (6) was used as
the additive, an enhancement of the reaction rate was observed,
affording epoxide 3a within 30 min as a single product with a slight
enhancement of the yield (64%) and similar enantioselectivity (89%
ee) (entry 2) [15,16]. Furthermore, the addition of MS 4A along with
5 mol% of 6 was effective to preserve the catalytic activity, and the
yield of 3a was improved to 70% while maintaining the enantio-
selectivity (89% ee) (entry 3). As shown in entry 4, the yield was
improved further (75%) when MS 5A was employed. These results
clearly indicate that additive 6 primarily functions as the deterrent
reagent of the catalyst deactivation, i.e., reduction of nucleophilicity
of the phosphate anion, and has no influence on the enantiose-
lectivity [15]. Further screening for the additive, 2-naphthylboronic
acid, showed that it did not exhibit any beneficial effect on the yield
and the enantioselectivity (entry 5). Lowering the temperature
to ꢀ40 ꢁC enhanced the enantioselectivity to 97% ee at the expense
of the reaction rate (entry 6). Increasing the amount of additive 6 to
10 mol% slightly improved the yield of 3a at ꢀ40 ꢁC, and these
reaction conditions were considered optimum for the intra-
molecular SN2’ reaction (entry 7).
With the optimized catalyst and reaction conditions in hand, we
applied our strategy to several allylic substrates 2. As shown in
Table 3, substrates 2bef having a substituent at the para-position of
the aryl moiety were examined, and these allylic substrates were
converted into corresponding vinyl epoxides 3bef exclusively. The
yields and the enantioselectivities were highly dependent on the
electronic property of the substituent. The introduction of an
electron-donating group to the aryl moiety of 2 enhanced the re-
action rate but reduced the enantioselectivity considerably. The use
of an electron-withdrawing group decelerated the reaction mark-
edly, and hence an elevated temperature was required, which
Additive effect on intramolecular SN2’ reactiona.
Entry
Additive
Conditions
% yieldb
3a/4ac
% eed
1
2
3
4
5
Ag2CO3
rt, 2 h
60
64
70
75
68
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
88
89
89
89
88
6: PhB(OH)2
6, MS 4A
6, MS 5A
rt, 0.5 h
rt, 0.5 h
rt, 0.5 h
rt, 1 h
MS 5A
6
7
6, MS 5A
‒40 ꢁC, 24 h
‒40 ꢁC, 24 h
72
75
>99 : 1
>99 : 1
97
97
6e, MS 5A
a
Unless otherwise noted, all reactions were carried out using 10 mol% of (R)-5b,
0.05 mmol of (E)-2a, 5 mol% of additive, and MS (20 mg) in Et2O (0.5 mL).
b
Isolated yield of 3a.
c
The ratio was determined by 1H NMR analysis of the crude reaction mixture
using CH2Br2 as the internal standard.
d
Enantiomeric excess (ee) was determined by HPLC analysis using a chiral sta-
tionary phase column.
e
10 mol% of PhB(OH)2 (6) was used.
with 2a [13]. As predicted initially, the generation of the nucleo-
philic phosphate anion leads to the serious problem of catalyst
poisoning, which was thoroughly studied in our previous report of
the intramolecular SN2’ reaction [7a].
To put our reaction design principles into practice, we screened
for several weak Lewis acidic additives in an effort to suppress the
nucleophilicity of the conjugate base of (R)-5b (Table 2). The
introduction of 5 mol% of silver carbonate [14] along with
bisphosphoric acid (R)-5b led to the formation of epoxide 3a pre-
dominantly with the enhancement of the yield (60%) within 2 h at
resulted in the reduction of enantioselectivity.
b-Naphthyl sub-
strate 1g also worked well. In the case of 6-membered ring sub-
strate 1h, the reaction proceeded smoothly, and desired epoxide 3h
was obtained in good yield with high enantioselectivity.
The present co-catalyst system is reliable enough to perform on
3

S. Kayal, J. Kikuchi, N. Shinagawa et al.
Tetrahedron xxx (xxxx) xxx
Table 3
purity turned out to be extremely challenging as there is a possi-
bility of the formation of a stabilized tertiary carbocation during the
course of the rearrangement. Indeed, we initially applied a slightly
modified method (1.0 equiv. of Et2AlCl in toluene at ꢀ60 ꢁC for 2 h)
originally reported by Shi and co-workers [17], but observed a
considerable decrease in enantiomeric purity: when 3a with 97% ee
was used, 4a was obtained with 81% ee. After an extensive opti-
mization of the reaction conditions (see Supplementary Material
for details), we found that using n-hexane as the solvent and
further lowering the temperature to ꢀ78 ꢁC improved the enan-
tioselectivity at the expense of the reaction rate. All-carbon qua-
Substrate scopea.
Entry
2: Ar and n
Conditions
% yieldb
% eec
1
2
3
4
5
6
7
b: 4-MeOC6H4, n ¼ 1
c: 4-MeC6H4, n ¼ 1
d: 4-ClC6H4, n ¼ 1
e: 4-PhC6H4, n ¼ 1
f: 4-CF3C6H4, n ¼ 1
g: 2-naphthyl, n ¼ 1
h: C6H5, n ¼ 2
‒40 ꢁC, 24 h
‒30 ꢁC, 24 h
82
66
82
73
63
64
84
43
84
85
95
69
82
91
ternary
a-vinyl cyclohexanone 4a was obtained in 95% yield
0
ꢁC, 48 h
without marked loss of enantiomeric purity (94% ee). 4a was
determined to be an (R)- isomer after derivatization into a stereo-
chemically known compound [19]. Therefore, epoxide 3a was
assigned to (R)-isomer on the basis of the reaction mechanism of
the enantiospecific Meinwald rearrangement, in which Lewis acid-
mediated conversion generally proceeds through inversion at the
stereogenic center.
‒30 ꢁC, 24 h
rt, 48 h
‒30 ꢁC, 48 h
0
ꢁC, 24 h
a
Unless otherwise noted, all reactions were carried out using 10 mol% of (R)-5b,
10 mol% of PhB(OH)2 (6), 0.05 mmol of (E)-2, and MS 5A (20 mg) in Et2O (0.5 mL).
b
Isolated yield of 3 is indicated.
Enantiomeric excess (ee) was determined by HPLC analysis using a chiral sta-
c
Finally, we focused on the mechanistic elucidation of the pre-
sent enantioselective intramolecular SN2’ reaction using (R)-5b and
the phenylboronic acid co-catalyst system. We first confirmed from
LG-dependent experiments that LG markedly influenced product
formation. When trifluoroacetimidate derivative (E)-2a’ [7], instead
of (E)-2a having trichloroacetimidate as the LG, was used under the
optimized reaction conditions [(R)-5b/6 co-catalyst (10 mol% each),
in Et2O at ꢀ40 ꢁC to reflux temperature for 24 h], starting material
(E)-2a′ was recovered in a nearly quantitative manner, and no
product was formed at all (Scheme 5a). This result confirms that the
SN2 reaction of (E)-2a’ with the phosphate anion generated from
(R)-5b predominates over the desired intramolecular SN2’ reaction
in this case [13]. More importantly, the phosphate ester once
formed through the SN2 reaction results in the catalyst deactivation
[20]. Hence, considering this result and our previous mechanistic
studies of the intramolecular SN2’ and related reactions catalyzed
by CPAs [7], we deduced that trichloroacetimidate as the LG is
involved in the enantio-determining transition states. To gain
further insight into the reaction mechanism, we employed enan-
tioenriched (S,E)-d-2a containing deuterium at the allylic position
[7,21] (Scheme 5b). In the proposed deuterated substrate study, the
tionary phase column.
Scheme 3. Gram scale experiment of co-catalyst system.
a gram scale. The reaction of (E)-2a (1.0 g, 2.8 mmol) proceeded
well even by the reduced loading of (R)-5b and phenylboronic acid
(6) co-catalyst to 5 mol% each to afford 3a as the sole product
without significant loss of yield and enantioselectivity (Scheme 3).
Because we were interested in the further transformation of
enantioenriched all-carbon quaternary a-vinyl cyclohexanone, we
embarked on the development of a Lewis acid-mediated enantio-
specific Meinwald rearrangement of corresponding enantioen-
riched epoxide 3a (Scheme 4) [17]. During our investigations, two
reports appeared regarding the CPA-catalyzed Meinwald rear-
rangement of tetrasubstituted epoxides [18]. The reports clearly
stated that an epoxide having an electron-rich substituent, such as
an aryl ring having a hydroxy or methoxy group at the para-
position, was the most crucial criterion for achieving good enan-
tioselectivity. The development of a Lewis acid-mediated enantio-
specific Meinwald rearrangement to obtain an all-carbon
quaternary a-substituted cyclohexanone would be an alternative
approach to overcome the limitations described in the previous
reports. However, this transformation without loss of enantiomeric
Scheme 5. Mechanistic studies. (a) The reaction of (E)-2a′ having the tri-
fluoroacetimidate leaving group. (b) The reaction of enantioenriched deuterated sub-
strate (S,E)-d-2a.
Scheme 4. Enantioselective Meinwald rearrangement for accessing all-carbon qua-
ternary a-vinyl cyclohexanone.
4

S. Kayal, J. Kikuchi, N. Shinagawa et al.
Tetrahedron xxx (xxxx) xxx
stereochemical relationship between the chirality at the deuterated
carbon as well as the geometry of starting (S,E)-d-2a and the ge-
ometry of the migrated double bond, in combination with the
newly generated stereogenic center, would offer important infor-
mation of the reaction pathway, namely, whether anti- or syn-SN2’
is the plausible mechanism. As shown in Scheme 5b, enantioen-
riched (R,Z)-d-3a (95% ee) was obtained in good yield with high (Z)-
selectivity, clearly suggesting that the anti-SN2’ pathway is the
rational mechanism for the present intramolecular allylic substi-
tution reaction, as illustrated by D in Scheme 5b. In our previous
work (Scheme 1a), we have proven that the intramolecular allylic
substitution reaction proceeds in the anti-SN2’ fashion [7a], which
is consistent with the present study of the epoxide formation re-
action, whereas the oxygen atom serving as the nucleophile leads
to the formation of a small three-membered ring.
(4.6 mm
F
* 250 mm length). Optical rotations were measured on a
Jasco P-1020 digital polarimeter with a sodium lamp and reported
as follows; [
mass spectra analysis was performed on a Bruker Daltonics solariX
9.4T FT-ICR-MS spectrometer and a JEOL JMS-T100GCV Time-of-
Flight Mass Spectrometer at the Research and Analytical Center for
Giant Molecules, Graduate School of Science, Tohoku University.
T
ꢁC
a
]
(c ¼ g/100 mL, solvent, % ee). High resolution
D
4.2. General procedure for the enantioselective SN2’ reaction
In an oven and vacuum-dried reaction tube, MS 5A (20 mg),
catalyst (R)-5b (6.2 mg, 5
mmol, 10 mol%) and PhB(OH)2 (0.6 mg,
5
mmol, 10 mol%) were taken with 0.25 mL of Et2O. The reaction
mixture was stirred at room temperature for 15 min and then
cooled to ꢀ40 ꢁC. To the reaction mixture was added a solution of
2a (18.1 mg, 0.05 mmol) in Et2O (0.25 mL) at the same temperature.
After being stirred for 24 h at ꢀ40 ꢁC, the reaction mixture was
3. Conclusion
quenched with NEt3 (10 mL) and directly purified by flash column
chromatography (Hexane/EtOAc ¼ 10:1) to give 3a. The enantio-
meric excess was determined by chiral stationary phase HPLC
analysis.
In the enantioselective nucleophilic substitution reaction using
CPAs, the catalyst deactivation has been a serious problem because
the nucleophilic phosphate anion generated during the activation
of a leaving group undergoes the SN2 reaction with the substrate,
resulting in catalyst poisoning. In order to overcome this funda-
mental problem and develop an efficient substitution reaction us-
ing CPAs, we employed a less Lewis acidic additive to establish a
CPA/additive co-catalyst system, and applied this co-catalyst sys-
tem to an intramolecular SN2’ reaction as the model reaction. The
chiral bisphosphoric acid/phenylboronic acid co-catalyst system
was successfully developed for the enantioselective intramolecular
SN2’ reaction in which the catalyst deactivation process was effi-
ciently suppressed, affording enantioenriched vinyl epoxides in
good yields with moderate to high enantioselectivities. Our chiral
bisphosphoric acid/phenylboronic acid co-catalyst system would
serve as a potential method for similar types of transformations. In
addition, with the help of the Lewis acid-mediated enantiospecific
Meinwald rearrangement of the vinyl epoxide, the corresponding
4.2.1. (R)-2-Phenyl-2-vinyl-1-oxaspiro[2.4]heptane (3a)
75% yield (7.5 mg); colorless oil; [
a
]
27 þ60.7 (c 0.56, CHCl3, 97%
D
ee); Rf ¼ 0.71 (Hexane/EtOAc ¼ 4/1); 1H NMR (600 MHz, CDCl3):
d
7.36e7.31 (m, 4H), 7.29e7.26 (m, 1H), 6.06 (dd, J ¼ 17.4, 10.8 Hz,
1H), 5.30 (dd, J ¼ 11.0, 1.4 Hz, 1H), 5.18 (dd, J ¼ 17.2, 1.4 Hz, 1H),
2.07e2.02 (m, 1H), 1.86e1.82 (m, 1H), 1.78e1.70 (m, 2H), 1.67e1.62
(m, 1H),1.57e1.52 (m, 2H), 1.46e1.41 (m, 1H),1.30e1.25 (m,1H); 13
C
NMR (151 MHz, CDCl3): d 138.6, 137.3, 128.2, 127.3, 127.1, 118.8, 67.9,
31.9, 30.5, 25.4, 25.2; IR (ATR): 2924, 2360, 2309, 1731, 1459, 1219,
772 cmꢀ1; HRMS(ESI) m/z: [MþNa]þ Calcd for C14H16NaO 223.1093,
Found:
223.1093.;
HPLC
analysis:
CHIRALCEL
OD-3
(Hexane:iPrOH ¼ 99.3/0.7, 1.0 mL/min, 40 ꢁC, 220 nm) 4.3 min
(minor), 4.6 min (major). Configuration Assignment: The absolute
configuration was assigned as (R) by derivatization.
all-carbon quaternary
a-vinyl cyclohexanone was also accessed
without marked loss of enantiomeric purity. Further studies of the
development of enantioselective substitution reactions using the
present co-catalyst system are in due course in our laboratory.
4.2.2. (R)-2-(4-methoxyphenyl)-2-vinyl-1-oxaspiro[2.4]heptane
(3b)
82% yield (9.4 mg); colorless oil; [
a
]
25 þ28.6 (c 0.72, CHCl3, 43%
D
ee); Rf ¼ 0.67 (Hexane/EtOAc ¼ 4/1); 1H NMR (600 MHz, CDCl3):
d
7.24 (dt, J ¼ 8.4 Hz, 3.0 Hz, 2H), 6.89 (dt, J ¼ 9.0 Hz, 3.0 Hz, 2H),
4. Experimental section
6.03 (dd, J ¼ 17.4,10.8 Hz,1H), 5.28 (dd, J ¼ 16.8,1.2 Hz,1H), 5.16 (dd,
J ¼ 18.0, 1.8 Hz, 1H), 3.81 (s, 3H), 2.06e2.00 (m, 1H), 1.88e1.80 (m,
1H), 1.77e1.69 (m, 2H), 1.68e1.61 (m, 1H), 1.58e1.51 (m, 1H),
1.50e1.44 (m, 1H), 1.31e1.25 (m, 1H); 13C NMR (151 MHz, CDCl3):
4.1. General information
All reactions were carried out under nitrogen atmosphere in
flame-dried glassware. CH2Cl2 and Et2O were supplied from Kanto
Chemical Co., Inc. As “Dehydrated solvent system”. Other solvents
and reagents were purchased from commercial suppliers and used
without further purification. Purification of reaction products was
carried out by flash column chromatography using silica gel 60 N
d
158.8, 137.6, 130.7, 128.2, 118.7, 113.6, 77.3, 67.6, 55.4, 32.0, 30.5,
25.4, 25.2; IR (ATR): 3091, 2869, 2837, 1613, 1582, 1463, 1440, 1400,
1377, 1363, 1299, 1219, 1172, 1107, 1080, 1036, 991, 956 cmꢀ1
;
HRMS(FDþ) m/z: [M] Calcd for
C15H18O2 230.1307, Found:
230.1306.; HPLC analysis: CHIRALCEL OD-3 (Hexane:iPrOH ¼ 99.3/
0.7, 1.0 mL/min, 40 ꢁC, 220 nm) 5.8 min (minor), 6.3 min (major).
Configuration Assignment: The absolute configuration was
assigned as (R) by analogy.
(Merck 40e63 mm). Analytical thin layer chromatography (TLC) was
performed on Merck precoated TLC plates (silica gel 60 GF 254,
0.25 mm). 1H NMR spectra were recorded on a JEOL ECA-600
(600 MHz) spectrometer. Chemical shifts are reported in ppm
from tetramethylsilane or solvent resonance as the internal stan-
dard (CDCl3: 7.26 ppm, TMS: 0.00 ppm). 13C NMR spectra were
recorded on a JEOL ECA-600 (151 MHz) spectrometer with com-
plete proton decoupling. Chemical shifts are reported in ppm from
the solvent resonance as the internal standard (CDCl3: 77.16 ppm).
Infrared spectra were recorded on a Jasco FT/IR-4100 spectrometer.
Chiral stationary phase HPLC analysis was performed on a Jasco LC-
2000 Plus Series system with DAICEL chiral analytical column
4.2.3. (R)-2-(p-tolyl)-2-vinyl-1-oxaspiro[2.4]heptane (3c)
66% yield (7.1 mg); colorless oil; [
a
]
22 þ65.4 (c 0.89, CHCl3, 84%
D
ee); Rf ¼ 0.32 (Hexane/EtOAc ¼ 10/1); 1H NMR (600 MHz, CDCl3):
d
7.21 (dt, J ¼ 7.8 Hz, 1.8 Hz, 2H), 7.15 (d, J ¼ 7.8 Hz, 2H), 6.05 (dd,
J ¼ 17.4 Hz, 10.8 Hz, 1H), 5.28 (dd, J ¼ 10.8 Hz, 1.2 Hz, 1H), 5.17 (dd,
J ¼ 16.8 Hz, 1.8 Hz, 1H), 2.35 (s, 3H), 2.06e2.00 (m, 1H), 1.87e1.79
(m, 1H), 1.77e1.60 (m, 3H), 1.56e1.50 (m, 1H), 1.48e1.42 (m, 1H),
1.31e1.24 (m, 1H); 13C NMR (151 MHz, CDCl3):
d 137.5, 136.8, 135.6,
5

S. Kayal, J. Kikuchi, N. Shinagawa et al.
Tetrahedron xxx (xxxx) xxx
128.9, 127.0, 118.6, 77.3, 67.8, 32.0, 30.5, 25.4, 25.2, 21.3; IR (ATR):
2957, 2926, 2856, 2372, 1462, 1377, 925 cmꢀ1; HRMS(FDþ) m/z: [M]
Calcd for C15H18O 214.1358, Found: 214.1356.; HPLC analysis:
CHIRALCEL OD-3 (Hexane:iPrOH ¼ 99.9/0.1, 1.0 mL/min, 40 ꢁC,
220 nm) 6.2 min (minor), 7.1 min (major). Configuration Assign-
ment: The absolute configuration was assigned as (R) by analogy.
125.9, 125.3, 119.2, 68.0, 32.1, 30.6, 25.4, 25.2; IR (ATR): 3057, 3019,
2959, 2868, 1633, 1506, 1451, 1434, 1399, 1351, 1271, 1218, 1166,
1130, 1020, 984, 956 cmꢀ1; HRMS(FDþ) m/z: [M] Calcd for C18H18
O
250.1358, Found: 250.1356.; HPLC analysis: CHIRALPAK IA-3
(Hexane:iPrOH ¼ 99.3/0.7, 1.0 mL/min, 40 ꢁC, 220 nm) 5.5 min
(major), 5.9 min (minor). Configuration Assignment: The absolute
configuration was assigned as (R) by analogy.
4.2.4. (R)-2-(4-chlorophenyl)-2-vinyl-1-oxaspiro[2.4]heptane (3d)
82% yield (9.6 mg); colorless oil; [
a
]
22 þ18.5 (c 0.63, CHCl3, 85%
4.2.8. (R)-2-Phenyl-2-vinyl-1-oxaspiro[2.5]octane (3h)
D
ee); Rf ¼ 0.72 (Hexane/EtOAc ¼ 4/1); 1H NMR (600 MHz, CDCl3):
84% yield (9.0 mg); colorless oil; [
a
]
23 þ22.7 (c 0.96, CHCl3, 91%
D
d
7.33 (dt, J ¼ 9.0 Hz, 2.4 Hz, 2H), 7.28e7.25 (m, 2H), 6.02 (dd,
ee); Rf ¼ 0.70 (Hexane/EtOAc ¼ 4/1); 1H NMR (600 MHz, CDCl3):
J ¼ 17.4 Hz, 10.8 Hz, 1H), 5.31 (dd, J ¼ 10.2 Hz, 1.2 Hz, 1H), 5.17 (dd,
J ¼ 17.4 Hz, 1.8 Hz, 1H), 2.06e2.00 (m, 1H), 1.88e1.80 (m, 1H),
1.78e1.69 (m, 2H), 1.68e1.60 (m, 1H), 1.56e1.50 (m, 1H), 1.44e1.38
d
7.35e7.32 (m, 4H), 7.28e7.25 (m,1H), 6.18 (dd, J ¼ 16.8 Hz,10.8 Hz,
1H), 5.28 (dd, J ¼ 17.4 Hz, 1.8 Hz, 1H), 5.23 (dd, J ¼ 16.8 Hz, 1.2 Hz,
1H), 1.79e1.69 (m, 3H), 1.56e1.48 (m, 2H), 1.48e1.36 (m, 2H),
1.31e1.25 (m, 2H), 1.21e1.16 (m, 1H); 13C NMR (151 MHz, CDCl3):
(m, 1H), 1.30e1.23 (m, 1H); 13C NMR (151 MHz, CDCl3):
d 137.1,
136.8, 133.1, 128.5, 128.4, 119.2, 77.5, 67.4, 31.5, 30.5, 25.4, 25.2; IR
(ATR): 2958, 2869, 1713, 1633, 1491, 1453, 1399, 1278, 1219, 1091,
1015, 991, 930 cmꢀ1; HRMS(FDþ) m/z: [M] Calcd for C14H15ClO
234.0811, Found: 234.0808.; HPLC analysis: CHIRALPAK IA-3
(Hexane:iPrOH ¼ 99.3/0.7, 1.0 mL/min, 40 ꢁC, 220 nm) 5.0 min
(minor), 5.4 min (major). Configuration Assignment: The absolute
configuration was assigned as (R) by analogy.
d 138.8, 136.2, 128.1, 127.2, 127.0, 118.4, 70.5, 70.0, 31.7, 30.2, 25.7,
25.3, 24.7; IR (ATR): 2930, 2857, 1492, 1448, 1400, 1218, 985,
925 cmꢀ1; HRMS(FDþ) m/z: [M] Calcd for C15H18O 214.1358, Found:
214.1355.; HPLC analysis: CHIRALCEL OD-3 (Hexane:iPrOH ¼ 99.3/
0.7, 1.0 mL/min, 40 ꢁC, 220 nm) 4.0 min (minor), 4.4 min (major).
Configuration Assignment: The absolute configuration was
assigned as (R) by analogy.
4.2.5. (R)-2-([1,10-biphenyl]-4-yl)-2-vinyl-1-oxaspiro[2.4]heptane
4.3. Gram scale experiment
(3e)
73% yield (10.1 mg); colorless oil; [
a]
23 þ41.7 (c 0.76, CHCl3, 95%
In an oven and vacuum-dried reaction tube, MS 5A (1.1 g),
catalyst (R)-5b (171 mg, 0.14 mmol, 5 mol%) and PhB(OH)2 (16.8 mg,
0.14 mol, 5 mol%) were taken with 14 mL of Et2O. The reaction
mixture was stirred at room temperature for 15 min and then
cooled to ꢀ40 ꢁC. To the reaction mixture was added a solution of
2a (1.0 g, 2.8 mmol) in Et2O (14 mL) at the same temperature. After
being stirred for 48 h at ꢀ40 ꢁC, the reaction mixture was quenched
ee); Rf ¼ 0.71 (Hexane/EtOAc ¼ 4/1); 1DH NMR (600 MHz, CDCl3):
d
7.62e7.56 (m, 4H), 7.44 (t, J ¼ 7.8 Hz, 2H), 7.40 (d, J ¼ 8.4 Hz, 2H),
7.34 (tt, J ¼ 7.8 Hz, 1.2 Hz, 1H), 6.10 (dd, J ¼ 17.4 Hz,10.8 Hz, 1H), 5.33
(dd, J ¼ 10.8,1.2 Hz,1H), 5.24 (dd, J ¼ 18.0,1.8 Hz,1H), 2.09e2.03 (m,
1H), 1.89e1.82 (m, 1H), 1.80e1.71 (m, 2H), 1.70e1.62 (m, 1H),
1.60e1.54 (m, 1H), 1.54e1.46 (m, 1H), 1.37e1.31 (m, 1H); 13C NMR
(151 MHz, CDCl3):
d
140.9, 140.1, 137.6, 137.1, 128.9, 127.5, 127.4,
with NEt3 (600 mL) and directly purified by flash column chroma-
127.2, 126.9, 118.9, 77.5, 67.8, 32.0, 30.6, 25.4, 25.3; IR (ATR): 2920,
2860, 2312, 1730, 1600, 1459, 1219, 1086 cmꢀ1; HRMS(FDþ) m/z:
[M] Calcd for C20H20O 276.1514, Found: 276.1512.; HPLC analysis:
CHIRALCEL OD-3 (Hexane:iPrOH ¼ 99.3/0.7, 1.0 mL/min, 40 ꢁC,
220 nm) 5.2 min (minor), 5.5 min (major). Configuration Assign-
ment: The absolute configuration was assigned as (R) by analogy.
tography (Hexane/EtOAc ¼ 10:1) to give 3a (376 mg, 68%). The
enantiomeric excess was determined by chiral stationary phase
HPLC analysis.
4.4. Derivatization of product 3a to all-carbon quaternary
cyclohexanone 4a
a-vinyl
4.2.6. (R)-2-(4-(trifluoromethyl)phenyl)-2-vinyl-1-oxaspiro[2.4]
To a solution of 3a (10.0 mg, 0.05 mmol) in hexane (1.0 mL) was
added 1.0 M solution of Et2AlCl in n-hexane (50 L, 1.0 equiv.)
heptane (3f)
m
25
63% yield (8.5 mg); colorless oil; [
a]
þ4.7 (c 0.68, CHCl3, 69%
at ꢀ78 ꢁC. After the reaction mixture was stirred for 3 h at the same
temperature, the resulting mixture was quenched with NaHCO3 aq.
The resulting solution was extracted with EtOAc. The combined
EtOAc extracts were washed with brine, dried over Na2SO4 and
concentrated after filtration. The residual crude was purified by
flash column chromatography (Hexane/EtOAc ¼ 19/1) to give the
4a. The enantiomeric excess was determined by chiral stationary
phase HPLC analysis.
D
ee); Rf ¼ 0.33 (Hexane/EtOAc ¼ 10/1); 1H NMR (600 MHz, CDCl3):
d
7.61 (d, J ¼ 8.4 Hz, 2H), 7.46 (d, J ¼ 7.8 Hz, 2H), 6.05 (dd, J ¼ 17.4 Hz,
10.8 Hz, 1H), 5.34 (dd, J ¼ 10.2 Hz, 0.6 Hz, 1H), 5.18 (dd, J ¼ 17.4 Hz,
1.2 Hz,1H), 2.08e2.02 (m,1H),1.89e1.81 (m,1H),1.80e1.70 (m, 2H),
1.69e1.61 (m, 1H), 1.59e1.51 (m, 1H), 1.40e1.35 (m, 1H), 1.29e1.23
(m, 1H); 13C NMR (151 MHz, CDCl3):
d 142.7, 136.4, 129.6 (q,
J ¼ 31.7 Hz), 127.5, 125.2 (q, J ¼ 4.2 Hz), 124.3 (q, J ¼ 271.8 Hz), 119.4,
77.6, 67.5, 31.9, 30.5, 25.3, 25.2; IR (ATR): 2957, 2924, 2854, 2372,
2320, 1465, 1325, 1261, 1023 cmꢀ1; HRMS(FDþ) m/z: [M] Calcd for
4.4.1. (R)-2-Phenyl-2-vinylcyclohexan-1-one (4a)
25
C
15H17F3O 268.1075, Found: 268.1074.; HPLC analysis: CHIRALCEL
95% yield (9.5 mg), colorless oil; [
a
]
‒74.8 (c 0.38, CHCl3, 94%
D
OD-3 (Hexane:iPrOH ¼ 99.9/0.1, 1.0 mL/min, 40 ꢁC, 220 nm) 4.8 min
(minor), 5.0 min (major). Configuration Assignment: The absolute
configuration was assigned as (R) by analogy.
ee); 1H NMR (600 MHz, CDCl3):
d
7.37 (t, J ¼ 7.9 Hz, 2H), 7.28e7.26
(m, 1H), 7.19e7.18 (m, 2H), 6.25 (dd, J ¼ 17.5, 10.7 Hz, 1H), 5.12 (d,
J ¼ 10.3 Hz,1H), 4.56 (d, J ¼ 17.9 Hz,1H), 2.65 (qd, J ¼ 7.0, 3.1 Hz,1H),
2.46e2.38 (m, 2H), 2.01e1.94 (m, 2H), 1.82e1.76 (m, 3H); 13C NMR
4.2.7. (R)-2-(naphthalen-2-yl)-2-vinyl-1-oxaspiro[2.4]heptane (3g)
(151 MHz, CDCl3): d 212.5,143.3,139.7,128.9,127.6,127.1,115.0, 61.2,
64% yield (8.0 mg); colorless oil; [
a
]
22 þ58.1 (c 0.90, CHCl3, 82%
40.2, 36.3, 28.2, 21.6; IR (ATR): 3391, 3086, 2866, 2370, 1601, 1513,
1495, 1449, 1377, 1311, 1246, 1219, 1185, 1120, 1080, 1030, 967,
D
ee); Rf ¼ 0.71 (Hexane/EtOAc ¼ 4/1); 1H NMR (600 MHz, CDCl3):
d
7.86e7.11 (m, 4H), 7.50e7.43 (m, 3H), 6.14 (dd, J ¼ 17.4, 10.8 Hz,
920 cmꢀ1
;
HRMS (ESI) m/z: [MþNa]þ Calcd for C14H16NaO
1H), 5.34 (dd, J ¼ 10.8, 1.2 Hz, 1H), 5.21 (dd, J ¼ 16.8, 1.2 Hz, 1H),
2.14e2.05 (m, 1H), 1.90e1.78 (m, 2H), 1.78e1.64 (m, 2H), 1.60e1.51
(m, 1H), 1.49e1.42 (m, 1H), 1.33e1.25 (m, 1H); 13C NMR (151 MHz,
223.1093, Found: 223.1093.; HPLC analysis: Chiralpak OJ-H
(Hexane:iPrOH ¼ 99.5/0.5, 1.0 mL/min, 25 ꢁC, 220 nm) 11.3 min
(minor), 13.0 min (major). Configuration Assignment: The absolute
configuration was assigned as (R) by derivatization.
CDCl3): d 137.2, 136.2, 133.3, 132.8, 128.1, 127.83,127.79, 126.3, 126.0,
6

S. Kayal, J. Kikuchi, N. Shinagawa et al.
Tetrahedron xxx (xxxx) xxx
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(2015) 2139e2184;
(h) X.-P. Zeng, Z.-Y. Cao, Y.-H. Wang, F. Zhou, J. Zhou, Chem. Rev. 116 (2016)
7330e7396;
Declaration of competing interest
The authors declare the following financial interests/personal
relationships which may be considered as potential competing
interests: Masahiro Terada reports financial support, administrative
support, article publishing charges, equipment, drugs, or supplies,
statistical analysis, travel, and writing assistance were provided by
Government of Japan Ministry of Education Culture Sports Science
and Technology.
(i) J. Feng, M. Holmes, M.J. Krische, Chem. Rev. 117 (2017) 12564e12580.
[9] For the formation of reactive intermediates through nucleophilic substitution
reactions of phosphoric acid catalysts, (see): (a) N.D. Shapiro, V. Rauniyar,
G.L. Hamilton, J. Wu, F.D. Toste, Nature 470 (2011) 245e249;
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Acknowledgements
(e) J.-H. Tay, A.J. Argüelles, M.D. DeMars II, P.M. Zimmerman, D.H. Sherman,
P. Nagorny, J. Am. Chem. Soc. 139 (2017) 8570e8578.
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[12] For chiral bisphosphoric acid catalysts, (see): (a) N. Momiyama, T. Konno,
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This work was partially supported by a Grant-in-Aid for Scien-
tific Research on Innovative Areas “Hybrid Catalysis for Enabling
Molecular Synthesis on Demand” (JP17H06447) from MEXT, Japan.
(M. T.).
Appendix A. Supplementary data
(c) J. Kikuchi, K. Takano, Y. Ota, S. Umemiya, M. Terada, Chem. Eur J. 26 (2020)
11124e11128.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.132412.
[13] 31P NMR analysis of the reaction mixture indicated that catalyst (R)-5b was
completely disappeared and several new peaks were observed. It is consid-
ered that these new peaks originate from the formation of the phosphate
esters through the SN2 reaction of (R)-5b with (E)-2a’ because these peaks
were split into coupling pattern with protons under 1H non-decoupling 31P
NMR measurement. See Supporting Material for details.
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7