Enantioselective chlorinative aldol reaction of α-substituted acroleins catalyzed by chiral phosphine oxides

Article abstract of DOI:10.1016/j.tetasy.2017.01.006

The enantioselective chlorinative aldol reaction of α-substituted acroleins with aldehydes catalyzed by chiral phosphine oxides is described. A hypervalent silicon complex-derived chloride adds to the α-substituted acroleins to form the corresponding sily

Full text of DOI:10.1016/j.tetasy.2017.01.006

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective chlorinative aldol reaction of
acroleins catalyzed by chiral phosphine oxides
a-substituted
a
a
a
a
Shunsuke Kotani a,b, , Takuya Hanamure , Hirono Nozaki , Masaharu Sugiura , Makoto Nakajima
⇑
a Graduate School of Pharmaceutical Sciences Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
b Priority Organization for Innovation and Excellence, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantioselective chlorinative aldol reaction of
a
-substituted acroleins with aldehydes catalyzed by
Received 11 October 2016
Revised 17 December 2016
Accepted 21 December 2016
Available online xxxx
chiral phosphine oxides is described. A hypervalent silicon complex-derived chloride adds to the
stituted acroleins to form the corresponding silyl enol ethers in situ, which subsequently reacts with
aldehydes to produce the -chloromethyl aldol adducts bearing a quaternary stereogenic center in good
a-sub-
a
yields and stereoselectivities. When activated by a phosphine oxide catalyst, trichlorosilyl triflate acts as
an effective promoter for the chlorinative aldol reaction as well as the chloride source; this discovery
enabled the enantioselective chlorinative aldol reaction of
a
-substituted acroleins.
Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The asymmetric tandem reaction is one of the most efficient
synthetic strategies leading to chiral complex molecules in a
single operation, and has been an attractive research area in
recent years.1 In particular, asymmetric tandem reactions
involving nucleophilic addition/aldol reaction sequences, such as
reductive aldol reactions2 and alkylative aldol reactions,3 have
seen sustained interest because these reactions produce multi-
ple stereogenic centers in a single operation. An asymmetric
halogenative aldol reaction is a valuable tandem approach for
introducing a halogen atom into substrates along with the stere-
oselective carbon–carbon bond formation.4–6 The highly function-
alized products contain a carbonyl group, a hydroxy group, and a
halogen atom, representing a marked increase in complexity
when compared to the starting materials. However, there are
few reports on enantioselective halogenative aldol reactions of
Our research group has explored chiral Lewis base catalysis7
and developed several stereoselective transformations using chiral
phosphine oxide catalysts.8 A chiral phosphine oxide coordinates
with a chlorosilyl reagent to form a chiral hypervalent silicon
complex that consists of a highly electrophilic silicon center
adjacent to the nucleophilic site.7,9 Such
a chiral complex
effectively promoted an addition of a chloride to a substrate aided
by activation from the electrophilic silicon center, facilitating
the ring-opening of meso-epoxides,10 the phosphonylation of
aldehydes,11 and a Morita–Baylis–Hillman-type reaction.12 We
herein describe chiral phosphine oxide as a chiral catalyst for
the stereoselective chlorinative aldol reaction of
acroleins with aldehydes using trichlorosilyl triflate.
a-substituted
Our research started with the chlorinative aldol reaction of
methacrolein 1a and benzaldehyde 2a. The reaction was initially
conducted using SiCl4 in the presence of 10 mol % of (S)-BINAP
dioxide C1 (BINAPO) and N,N-diisopropylethylamine in CH2Cl2 at
0 °C; however, these reaction conditions gave no desired adducts.
It seemed likely that the silyl enol ether intermediate was indeed
generated in the reaction mixture,12 but the decreased nucle-
a,b-unsaturated enones or enals because of ready conversion to
Morita–Baylis–Hillman adducts or dehydrated adducts (Fig. 1-a).
Reports describing enantioselective halogenative aldol reactions
have been limited to
-alkylated acroleins appear usable as an aldol donor to furnish
a
,b-unsaturated ynones.2q,6 Although
a
halogenative aldol adducts that cannot undergo a subsequent
elimination reaction (Fig. 1-b), such a methodology has not yet
been reported.
ophilicity of the silyl enol ether because of the a-substituent of
1a rendered it unreactive with the aldehyde acceptor. We then
applied the more reactive trichlorosilyl triflate 3 as a chlorosilyl
reagent to the reaction (Table 1, entry 1),13 and the expected
adduct 4aa was formed. Due to the ease of purification and analy-
sis, the yields and stereoselectivities were quantified for diol 5aa
after the reduction with NaBH4 in methanol.14 After screening
⇑
Corresponding author.
http://dx.doi.org/10.1016/j.tetasy.2017.01.006
0957-4166/Ó 2017 Elsevier Ltd. All rights reserved.
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2
S. Kotani et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
(a) With α-enones or α-enals
us to obtain product 5aa in 91% yield and with good
enantioselectivity (entry 6). We then examined various chiral
phosphine oxide catalysts other than (S)-BINAPO (Fig. 2). (R,R)-
DIOPO C2 was ineffective for the reaction (entry 7), and (S)-
SEGPHOSO C3 and (S)-H8-BINAPO C4, both bearing a biphenyl
skeleton, provided results slightly inferior to (S)-BINAPO C1
(entries 8 and 9). (S)-4,40-Br2-BINAPO C5 afforded the chloro
aldol adduct 5aa in similar yield and stereoselectivities to those
with (S)-BINAPO C1 (entry 10).15
Addition of
O
O
OH
X
O
RCHO
X–
R
X
enolate
–H2O
–HX
Elimination
O
OH
O
With the optimized reaction conditions in hand, we set out to
investigate various substrates for the enantioselective chlorinative
aldol reaction (Table 2). a-n-Alkylated acroleins 1a–c gave the cor-
R
R
X
responding adducts 5aa–ca with good enantioselectivities, but
increasing steric hindrance of alkyl substituents decreased the
Morita-Baylis-Hillman
adduct
Dehydrated adduct
diastereoselectivity (entries 1–3).
a-Isopropylated acrolein 1d
showed lower reactivity, resulting in low yield, and the syn-isomer
syn-5da was predominantly produced (entry 4). The reversal of
diastereoselectivity indicates that the geometry of silyl enol ether
intermediates was inverted and this inversion was observed
(b) With α−substituted acroleins
O
OH
O
Addition of
X–
RCHO
O
H
R
H
H
absolutely in the reaction of
a-benzylacrolein 1e, producing only
X
X
syn-5ea (entry 5). We then performed the reaction with various
aldehyde acceptors 2 to react with methacrolein 1a (entries
6–10). p-Bromobenzaldehyde 2b gave the similar yields and stere-
oselectivities to the parent aldehyde 2a (entry 6), whereas the yield
decreased in the reaction of p-anisaldehyde 2c. 2-Naphthaldehyde
2d afforded product 5ad in good yield and stereoselectivities
(entry 8), but 1-naphthaldehyde 2e produced 5ae in decreased
yield and diastereoselectivity (entry 9). Cinnamaldehyde 2f reacted
smoothly to afford adduct 5af, albeit in low enantioselectivity
(entry 10). The absolute configuration of the major product of
5ae was assigned to be (1S,2R) based on single-crystal X-ray anal-
ysis (Fig. 3).16
The proposed reaction mechanism is shown in Fig. 4.
Chlorosilane 3 coordinates to acrolein 1 and then a chloride
anion attacks the b-carbon atom to form silyl enol ether inter-
mediate 6. The chloride attacks the acrolein 1 in the s-trans
conformation to give (E)-6, whereas (Z)-6 is obtained from
the s-cis conformation. (E)- and (Z)-6 react with aldehyde 2
via 6-membered chair-like transition state to produce anti-7
and syn-7, respectively.7,8 Therefore, the E/Z ratio of the
α-substituted
halo aldol adduct
a,b-unsaturated carbonyl compounds
acrolein
Figure 1. Halogenative aldol reactions of
with aldehydes.
several amine bases, sterically congested amine, N,N-dicyclo-
hexylisobutylamine13b
dramatically improved the
diastereoselectivity of the reaction to produce 5aa (entry 2). The
steric hindrance of the amine could suppress the coordination to
highly electrophilic trichlorosilyl triflate preventing excess
formation of chloride in situ. Varying the stoichiometry of the
substrates led us to increase the product yield to 55% at 0 °C
(entry 3). Lowering the reaction temperature to ꢀ40 °C improved
both the yield and enantioselectivity (entry 4). However,
precipitation of N,N-dicyclohexylisobutylamine at ꢀ60 °C
decreased the yield and diastereoselectivity (entry 5). We
therefore switched to N,N-diisopropylisobutylamine, a sterically
congested amine that is soluble even at ꢀ60 °C, and this allowed
silyl enol ether intermediates
6
directly determines the
Table 1
Optimization of enantioselective chlorinative aldol reactions of methacrolein 1a and benzaldehyde 2a catalyzed by chiral phosphine oxidesa
&ꢃꢄ&ꢅ ꢆꢃꢇꢈPROꢈꢉꢊ
DPLQHꢈꢆꢋꢌꢋꢈHTXLYꢊ
+2
2
+2
2+
2
1D%+ꢂ
0H2+
ꢀ
ꢀ
6L&Oꢁ27I
0H
3K&+2
ꢋD
3K
&O
+
3K
&O
+
&+ꢋ&Oꢋ
ꢁ
ꢆꢋꢌꢇꢈHTXLYꢊ
ꢃD
ꢆꢋꢌꢇꢈHTXLYꢊ
ꢂDD
ꢅDD
Entry
Catalyst
Amine
Temp (°C)
Time (h)
Yield (%)
drb
eec (%)
1d
2d
3
4
5
6
7
8
9
C1
C1
C1
C1
C1
C1
C2
C3
C4
C5
iPr2NEt
0
0
0
2.5
2.5
2.5
20
24
24
24
24
24
24
22
27
55
65
25
91
14
81
86
93
53/47
98/2
86/14
95/5
63/37
91/9
68/32
83/17
85/15
97/3
38
42
46
66
66
75
14
67
74
75
Cy2NiBu
Cy2NiBu
Cy2NiBu
Cy2NiBu
iPr2NiBu
iPr2NiBu
iPr2NiBu
iPr2NiBu
iPr2NiBu
ꢀ40
ꢀ60
ꢀ60
ꢀ60
ꢀ60
ꢀ60
ꢀ60
10
a
b
c
Unless otherwise noted, the reaction was conducted with 1a (2.0 equiv) and 2a (0.5 mmol), 3 (2.0 equiv), amine (2.2 equiv), and a phosphine oxide (10 mol %) in CH2Cl2.
Ratio of anti/syn was determined by 1H NMR and HPLC analysis.
Ee of anti-5aa.
d
1a (1.0 equiv), 2a (1.2 equiv).
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S. Kotani et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
O
O
P
O
P
O
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
P
O
O
O
O
Ph
Ph
Ph
P
P
P
O
O
O
O
(S)-BINAPO C1
(R,R)-DIOPO C2
(S)-SEGPHOSO C3
Br
O
P
O
P
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
P
P
O
O
Figure 3. X-ray crystal structure of 5ae. Thermal ellipsoids are shown at 20%
probability.
Br
(S)-4,4'-Br2-BINAPO
C4
(S)-H8-BINAPO
C5
Figure 2. Chiral phosphine oxides used in this study.
the transition state bearing the R2 group in axial position lead-
ing to decrease the diastereoselectivity. After the formation of
the CAC bond, the product remains in the silylated form 7,
preventing a retro-aldol reaction and resulting in a high-yield-
ing transformation.
diastereoselectivity in the chlorinative aldol reaction. This
assumption is supported by the results in Table 2. Methacro-
lein 1a, bearing a small methyl group, may prefer an s-trans
conformation to produce the anti-isomer (Table 2, entry 1),
3. Conclusion
whereas a bulky
a-substituent, such as an isopropyl group,
forces the acrolein to be in the s-cis conformation, resulting
in the formation of the syn-isomer (Table 2, entry 4). The
decrease of the diastereoselectivity in the investigation of alde-
hydes might be explained by the steric environment around
the carbonyl in aldehydes in the chair-like six-membered tran-
sition state. The hindered aldehyde makes it hard to make the
cyclic transition state, undergoing the reaction via acyclic tran-
sition state to decrease the diastereoselectivity. On the other
hand, a less hindered aldehyde around the carbonyl could form
We have demonstrated the enantioselective chlorinative aldol
reaction of a-alkylated acroleins with aldehydes, which has never
before been described in the literature. The combination of
trichlorosilyl triflate and chiral phosphine oxide catalysts
effectively facilitated the reaction to furnish highly functionalized
aldol adducts bearing a quaternary stereogenic center in good
yields and stereoselectivities. Further research is currently ongoing
to both improve the stereoselectivity and develop different
transformations.
Table 2
Enantioselective chlorinative aldol reactions of
a
-substituted acroleins and aldehydes catalyzed by C1a
ꢃꢊ
&ꢃꢆꢃꢇꢈPROꢈꢉꢊ
L3Uꢋ1L%XꢈꢆꢋꢌꢋꢈHTXLYꢊ
&+ꢋ&Oꢋꢍꢈದꢎꢇꢈr&ꢍꢈꢋꢂꢈK
2
+2
5ꢋ
&O
2+
5ꢃ
5ꢋ&+2
ꢋ\
ꢀ
ꢀ
6L&Oꢁ27I
+
ꢋꢊꢈ1D%+ꢂꢍꢈ0H2+
ꢁ
5ꢃ
ꢅ[\
ꢆꢋꢌꢇꢈHTXLYꢊ
ꢃ[
ꢆꢋꢌꢇꢈHTXLYꢊ
5ꢃ ꢈ0Hꢍ ꢃD
5ꢃ ꢈ(Wꢍ ꢃE
5ꢋ ꢈ3Kꢍ ꢋD
5ꢋ ꢈꢂꢄ%Uꢄ&ꢎ+ꢂꢍ ꢋE
5ꢋ ꢈꢂꢄ0H2ꢄ&ꢎ+ꢂꢍ ꢋF
5ꢋ ꢈꢋꢄQDSKWK\Oꢍ ꢋG
5ꢋ ꢈꢃꢄQDSKWK\Oꢍ ꢋH
5ꢋ ꢈ3K&+ &+ꢍ ꢋI
5ꢃ ꢈQ3HQWꢍ ꢃF
5ꢃ ꢈL3Uꢍ ꢃG
5ꢃ ꢈ&+ꢋ3Kꢍ ꢃH
Entry
1x
2y
5xy
Yield (%)
drb
eec (%)
1
2
3
4
5
6
7
8
9
10
1a
1b
1c
1dd
1e
1a
1a
1a
1a
1a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
5aa
5ba
5ca
5da
5ea
5ab
5ac
5ad
5ae
5af
91
90
95
17
83
94
56
82
32
56
91/9
75
61
69
61
41
73
74
72
78
4
66/34
62/38
28/72
0/100
87/13
73/27
87/13
59/41
71/29
a
The reaction was conducted with an acrolein 1 (2.0 equiv) and an aldehyde 2 (0.5 mmol), silyl reagent 3 (2.0 equiv), N,N-diisopropylisobutylamine (2.2 equiv), and C1
(10 mol %) in CH2Cl2.
b
Ratio of anti/syn was determined by 1H NMR and HPLC analysis.
Ee for major isomer.
4.0 equiv.
c
d
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4
S. Kotani et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
(S)-BINAPO
(S)-BINAPO
H
TfOCl2SiO
O
HO
R2
Cl
OH
OSiCl2OTf
H
(S)-BINAPO
SiCl3OTf
O
1) workup
R1
2
2
SiCl2OTf
R2
R CHO
R1
O
R2
H
H
2) reduction
R1
R1
Cl
O
Cl
Cl
anti-7
5
R1
anti-
s-trans-1
6
(E)-
(S)-BINAPO
(S)-BINAPO
H
TfOCl2SiO
O
HO
R2
Cl
OH
O
(S)-BINAPO
SiCl3OTf
OSiCl2OTf
1) workup
2
SiCl2OTf
O
2
R CHO
R2
R2
Cl
H
H
Cl
H
R1
Cl
Figure 4. Proposed reaction course of the chlorinative aldol reaction.
R1
R1
2) reduction
R1
R1
O
7
5
syn-
syn-
s-cis-1
(Z)-6
NaHCO3 (20 mL) and brine (20 mL), and dried over Na2SO4. After
filtration and concentration, the crude material was obtained and
used in the next step without any purification. The crude material
was dissolved in methanol (3 mL), and then NaBH4 (94.6 mg,
2.5 mmol, 5.0 equiv) was added to the solution. After being stirred
for 30 min at 0 °C, the reaction was quenched with H2O (5 mL). The
two layer mixture was extracted with CH2Cl2 (3 ꢁ 20 mL). The
combined organic layers were washed with brine (20 mL) and
dried over Na2SO4. Evaporation of the solvent furnished the crude
product, which was purified by column chromatography (SiO2,
hexane/EtOAc = 5:1) to give the diol 5aa (97.8 mg, 91% yield,
anti/syn = 91/9, 75% ee (anti), 68% ee (syn)).
4. Experimental
4.1. General
Melting points (mp) are uncorrected. 1H and 13C NMR spectra
were measured in CDCl3 with JEOL JNM-ECX400 spectrometer.
Tetramethylsilane (TMS) (d = 0 ppm) and CDCl3 (d = 77.0 ppm)
served as an internal standard for 1H and 13C, respectively. Infrared
spectra were recorded on Perkin Elmer Frontier or JEOL JIR-6500W.
Mass spectra were measured with JEOL JMS-700MStaion. Optical
rotations were recorded on JASCO P-1010 polarimeter. High-pres-
sure liquid chromatography (HPLC) was performed on JASCO P-
2080 and UV-2075. Thin-layer chromatography (TLC) analysis
was carried out using Merck silica gel plates. Visualization was
accomplished with UV light, phosphomolybdic acid and/or
anisaldehyde. Column chromatography was performed using
4.3.1. 2-(Chloromethyl)-2-methyl-1-phenyl-1,3-propanediol
5aa
Data for the anti-isomer: State; 97.8 mg, 91% yield (anti/syn =
91/9); TLC: Rf 0.40 (hexane/EtOAc = 2:1, stained blue with phos-
Kanto Chemical Silica Gel 60N (spherical, 63–210 lm). Dehydrated
phomolybdic acid/EtOH); [
[a]
a]
D
28 = ꢀ7.6 (c 1.00, EtOH) for 75% ee,
stabilizer-free dichloromethane (CH2Cl2) was purchased from
Kanto Chemical Co. Inc. All reactions were performed under argon
atmosphere. Chiral phosphine oxides were prepared by oxidation
of the corresponding phosphine with hydrogen peroxide in ace-
tone.17 Methacrolein derivatives 1c–e were synthesized according
to the literature.18 All other chemicals were purified based on stan-
dard procedures or used as received otherwise noted.
435 = ꢀ16.4 (c 1.00, EtOH) for 75% ee; 1H NMR (400 MHz, CDCl3):
28
d 0.75 (s, 3H), 3.15 (br s, 1H), 3.40 (d, 1H, J = 3.7 Hz), 3.52–3.77 (m,
4H), 4.87 (d, 1H, J = 3.7 Hz), 7.21–7.44 (m, 5H); 13C{1H} NMR
(100 MHz, CDCl3): d 16.6, 43.4, 50.4, 66.6, 78.2, 127.4, 128.0,
128.1, 140.2; IR (film): 3346 cmꢀ1; LRMS (EI): m/z 214 (M+), 196,
107, 77; HRMS (EI): Calcd for C11H15ClO2 214.0761, found
214.0764. The enantiomeric excess was determined to be 75% ee
(anti) and 68% ee (syn) by chiral HPLC with Daicel Chiralpak
AD-H column and Daicel Chiralpak IE-3 column [eluent:
hexane/IPA = 92:8; flow rate: 1.0 mL/min; detection: 220 nm; tR:
29.5 min (anti-major), 31.0 min (syn-major), 33.7 min (anti-minor),
39.8 min (syn-minor)].
4.2. Preparation of trichlorosilyl triflate 313,19
Trifluoromethanesulfonic acid (2.66 mL, 30.0 mmol, 1.0 equiv)
was added to phenyltrichlorosilane (5.05 mL, 31.5 mmol,
1.05 equiv). After stirring for 4 h at 60 °C, the reaction mixture
was diluted with dry CH2Cl2 and the solution was stocked in a
screw-top test tube with a Teflon packing.
4.3.2. 2-(Chloromethyl)-2-ethyl-1-phenyl-1,3-propanediol 5ba
Data for the anti-isomer: State; 103.0 mg, 90% yield
(anti/syn = 66/34); TLC: Rf 0.27 (hexane/EtOAc = 4:1, stained blue
4.3. Typical procedure for asymmetric chlorinative aldol
reaction
with phosphomolybdic acid/EtOH); [
for 61% ee, [a]
a]
29 = ꢀ3.9 (c 0.70, CHCl3)
D
435 = ꢀ7.5 (c 0.70, CHCl3) for 61% ee; 1H NMR
29
(400 MHz, CDCl3): d 0.85 (t, 3H, J = 7.6 Hz), 1.03–1.22 (m, 2H),
3.01 (br s, 1H), 3.12 (br s, 1H), 3.69 (d, 2H, J = 4.1 Hz), 3.82 (d,
1H, J = 11.5 Hz), 4.02 (d, 1H, J = 11.5 Hz), 5.00 (d, 1H, J = 4.6 Hz),
7.15–7.48 (m, 5H); 13C{1H} NMR (100 MHz, CDCl3): d 7.2, 22.3,
45.3, 47.1, 65.1, 78.4, 127.4, 128.0, 128.1, 140.3; IR (ATR):
3307 cmꢀ1; LRMS (EI): m/z 228 (M+), 210, 107, 79; HRMS (EI):
Calcd for C12H17ClO2 228.0917, found 228,0920. The enantiomeric
excess was determined to be 61% ee (anti) and 62% ee (syn) by
chiral HPLC with Daicel Chiralpak IE-3 column [eluent: hexane/
IPA = 30:1; flow rate: 1.0 mL/min; detection: 220 nm; tR:
30.0 min (syn-major), 32.5 min (anti-major), 38.9 min (syn-minor),
51.7 min (anti-minor)].
A solution of trichlorosilyl triflate 3 in CH2Cl2 (2.0 M, 0.5 mL,
1.0 mmol, 2.0 equiv) was added dropwise to a solution of N,N-
diisopropylisobutylamine (0.22 mL, 1.1 mmol, 2.2 equiv) and
methacrolein 1a (2.0 M, 0.5 mL, 1.0 mmol, 2.0 equiv), in CH2Cl2
(5.0 mL) at ꢀ60 °C. After being stirred for 0.5 h, (S)-BINAPO
(32.7 mg, 0.05 mmol, 10 mol %), and a solution of benzaldehyde
2a in CH2Cl2 (2.0 M, 0.25 mL, 0.5 mmol) were added to the result-
ing solution. After being stirring for 24 h at the same temperature,
the reaction was quenched with aqueous 1.5 M KF/3.0 M HCOOH
(5.0 mL), and then the slurry was stirred for 1 h at room tempera-
ture. The aqueous layer was extracted with EtOAc (3 ꢁ 30 mL). The
combined organic layers were washed with 10% HCl (20 mL), satd
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S. Kotani et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
29
4.3.3. 2-(Chloromethyl)-2-pentyl-1-phenyl-1,3-propanediol 5ca
ꢀ3.7 (c 0.90, EtOH) for 73% ee, [ 435 = ꢀ9.8 (c 0.40, EtOH) for
a
]
Data for the anti-isomer: State; 128.5 mg, 95% yield
(anti/syn = 62/38); TLC: Rf 0.31 (hexane/EtOAc = 4:1, stained blue
73% ee; 1H NMR (400 MHz, CDCl3): d 0.78 (s, 3H), 2.62 (br s, 1H),
3.12 (br s, 1H), 3.55–3.77 (m, 4H), 4.91 (s, 1H), 7.27 (d, 2H,
J = 8.2 Hz), 7.50 (d, 2H, J = 8.2 Hz); 13C{1H} NMR (100 MHz, CDCl3):
d 16.5, 43.5, 50.1, 66.8, 77.5, 121.9, 129.1, 131.2, 139.3; IR (ATR):
3259 cmꢀ1; LRMS (FAB): m/z 317, 315 (M+Na)+, 154; HRMS
(FAB): Calcd for C11H14BrClNaO2 314.9763, found 314.9763. The
enantiomeric excess was determined to be 73% ee (anti) and 74%
ee (syn) by chiral HPLC with Daicel Chiralpak AD-3 column and
Daicel Chiralcel OJ-H column [eluent: hexane/IPA = 24:1; flow rate:
1.0 mL/min; detection: 254 nm; tR: 71.8 min (anti-major), 78.9 min
(anti-minor), 96.1 min (syn-major), 110.9 min (syn-minor)].
with phosphomolybdic acid/EtOH); [
a
]
D
17 = ꢀ10.9 (c 1.14, CHCl3)
for 69% ee; 1H NMR (400 MHz, CDCl3): d 0.86 (t, 3H, J = 7.1 Hz),
0.96–1.10 (m, 2H), 1.11–1.38 (m, 6H), 2.89–3.01 (m, 1H), 3.02–
3.14 (m, 1H), 3.69 (d, 2H, J = 5.0 Hz), 3.84 (d, 1H, J = 11.5 Hz),
3.99 (d, 1H, J = 11.5 Hz), 4.99 (d, 1H, J = 5.0 Hz), 7.29–7.45 (m,
5H); 13C{1H} NMR (100 MHz, CDCl3): d 14.0, 22.3, 22.5, 29.7,
32.4, 45.4, 47.7, 65.4, 78.6, 127.4, 128.0, 128.2, 140.4; IR (ATR):
3304 cmꢀ1; LRMS (FAB): m/z 293 (M+Na)+; HRMS (FAB): Calcd
for C15H23ClNaO2 293.1284, found 293.1297. The enantiomeric
excess was determined to be 69% ee (anti) and 68% ee (syn) by chi-
ral HPLC with Daicel Chiralpak ID-3 column [eluent: hexane/
IPA = 30:1; flow rate: 1.0 mL/min; detection: 220 nm; tR:
14.4 min (syn-minor), 15.4 min (anti-minor), 18.7 min (syn-major),
22.3 min (anti-major)].
4.3.7. 2-(Chloromethyl)-1-(4-methoxyphenyl)-2-methyl-1,3-
propanediol 5ac
Data for the anti-isomer: State; 68.5 mg, 56% yield
(anti/syn = 73/27); TLC: Rf 0.32 (hexane/EtOAc = 2:1, stained blue
with phosphomolybdic acid/EtOH); [a]
29 = +4.4 (c 0.40, CHCl3) for
D
74% ee, [a]
435 = +10.9 (c 0.40, CHCl3) for 74% ee; 1H NMR
29
4.3.4. 2-(Chloromethyl)-2-isopropyl-1-phenyl-1,3-propanediol
5da
(400 MHz, CDCl3): d 0.79 (s, 3H), 2.63–2.74 (m, 2H), 3.61–3,80
(m, 4H), 3.82 (s, 3H), 4.91 (d, 1H, J = 3.2 Hz), 6.90 (d, 2H,
J = 8.7 Hz), 7.32 (d, 2H, J = 8.7 Hz); 13C{1H} NMR (100 MHz, CDCl3):
d 16.6, 43.6, 50.4, 55.3, 66.8, 77.9, 113.5, 128.5, 132.3, 159.3; IR
(film): 3363 cmꢀ1; LRMS (FAB): m/z 267 (M+Na)+, 227, 137; HRMS
(FAB): Calcd for C12H17ClNaO3 267.0764, found 267.0769. The
enantiomeric excess was determined to be 74% ee (anti) and 75%
ee (syn) by chiral HPLC with Daicel Chiralpak AD-H column and
Daicel Chiralpak IE-3 column [eluent: hexane/IPA = 19:1; flow
rate: 1.0 mL/min; detection: 220 nm; tR: 75.1 min (anti-major),
81.2 min (anti-minor), 83.6 min (syn-major), 88.1 min (syn-
minor)].
Data for the diastereomeric mixture: State; 20.7 mg, 17% yield
(anti/syn = 28/72); TLC: Rf 0.28 (hexane/EtOAc = 4:1, stained blue
with phosphomolybdic acid/EtOH); [
61% ee (syn), 51% ee (anti), anti/syn = 21/79; 1H NMR (400 MHz,
CDCl3): 0.78 (d, 3H(anti), J = 6.9 Hz), 0.91 (d, 3H(anti),
a]
30 = +4.7 (c 0.70, CHCl3) for
D
d
J = 6.9 Hz), 0.99 (d, 3H(syn), J = 6.9 Hz), 1.16 (d, 3H(syn),
J = 6.9 Hz), 1.78 (sep, 1H(anti), J = 6.9 Hz), 2.25 (sep, 1H(syn),
J = 6.9 Hz), 2.77 (br s, 1H(anti)), 2.85 (br s, 1H(syn)), 3.18 (br s, 1H
(anti)), 3.23 (br s, 1H(syn)), 3.28 (d, 1H(syn), J = 11.5 Hz), 3.64 (d,
1H(syn), J = 11.5 Hz), 3.67–3.79 (m, 2H(syn), 1H(anti)), 3.83 (d, 1H
(anti), J = 12.4 Hz), 4.00 (d, 2H(anti), J = 2.3 Hz), 5.04 (d, 1H(anti),
J = 4.1 Hz), 5.16 (d, 1H(syn), J = 2.7 Hz), 7.05–7.59 (m, 5H(syn), 5H
(anti)); 13C{1H} NMR (100 MHz, CDCl3): d 17.8, 18.0, 18.06, 18.13,
28.9, 29.7, 45.7, 46.7, 46.8, 47.1, 64.2, 64.8, 77.86, 77.90, 127.6,
128.1, 128.3, 128.4, 140.7, 141.2 (two carbons overlapped); IR
(ATR): 3305 cmꢀ1; LRMS (EI): m/z 224, 118, 107, 105; HRMS (EI):
Calcd for C13H17ClO 224.0968, found 224.0961. The enantiomeric
excess was determined to be 61% ee (syn) and 51% ee (anti) by chi-
ral HPLC with Daicel Chiralpak AD-H column and Daicel Chiralpak
IE-3 column [eluent: hexane/IPA = 24:1; flow rate: 1.0 mL/min;
detection: 220 nm; tR: 47.5 min (syn-major), 51.0 min (syn-minor),
54.5 min (anti-major), 65.6 min (anti-minor)].
4.3.8. 2-(Chloromethyl)-2-methyl-1-(2-naphthyl)-1,3-propane-
diol 5ad
Data for the anti-isomer: State; 108.1 mg, 82% yield
(anti/syn = 87/13); TLC: Rf 0.39 (hexane/EtOAc = 2:1, stained blue
with phosphomolybdic acid/EtOH); [
a
]
29 = ꢀ4.5 (c 1.06, EtOH) for
D
29
72% ee,
[a]
435 = ꢀ10.3 (c 1.06, EtOH) for 72% ee; 1H NMR
(400 MHz, CDCl3): d 0.84 (s, 3H), 2.73 (t, 1H, J = 5.5 Hz), 2.98 (d,
1H, J = 4.4 Hz), 3.63–3.90 (m, 4H), 5.11 (d, 1H, J = 4.4 Hz), 7.44–
7.60 (m, 3H), 7.78–7.94 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3):
d 16.8, 43.8, 50.4, 66.8, 78.3, 125.3, 126.2, 126.3, 126.4, 127.6,
127.7, 128.0, 132.9, 133.1, 137.8; IR (film): 3350 cmꢀ1; LRMS
(FAB): m/z 287 (M+Na)+, 217, 157, 69; HRMS (FAB): Calcd for
4.3.5. 2-Benzyl-2-(chloromethyl)-1-phenyl-1,3-propanediol 5ea
Data for the syn-isomer: State; 120.6 mg, 83% yield
(anti/syn = 0/100); TLC: Rf 0.30 (hexane/EtOAc = 4:1, stained blue
with phosphomolybdic acid/EtOH); mp: 157.0–159.0 °C;
C
15H17ClNaO2 287.0815, found 287.0824. The enantiomeric excess
was determined to be 72% ee (anti) and 63% ee (syn) by chiral HPLC
with Daicel Chiralpak AD-H column [eluent: hexane/IPA = 9:1;
flow rate: 1.0 mL/min; detection: 254 nm; tR: 13.4 min (anti-
minor), 15.3 min (anti-major), 18.1 min (syn-major), 20.1 min
(syn-minor)].
[
a]
D
29 = ꢀ21.3 (c 1.00, CHCl3) for 41% ee; 1H NMR (400 MHz, CDCl3):
d 2.61 (br s, 2H), 2.83–2.94 (m, 2H), 3.39 (d, 1H, J = 11.0 Hz), 3.64
(dd, 1H, J = 5.5 Hz, 11.7 Hz), 3.75 (dd, 1H, J = 5.5 Hz, 11.7 Hz), 3.97
(d, 1H, J = 11.0 Hz), 5.25 (d, 1H, J = 3.7 Hz), 7.11–7.18 (m, 2H),
7.18–7.28 (m, 3H), 7.34–7.46 (m, 3H), 7.47–7.54 (m, 2H); 13C{1H}
NMR (100 MHz, CDCl3): d 35.4, 46.2, 47.3, 65.6, 78.2, 126.7,
127.7, 128.28, 128.33, 130.5, 136.0, 139.9 (one carbon overlapped);
IR (ATR): 3271 cmꢀ1; LRMS (FAB): m/z 313 (M+Na)+, 289, 255, 107;
HRMS (FAB): Calcd for C17H19ClNaO2 313.0971, found 313.0970.
The enantiomeric excess was determined to be 41% ee (syn) by
chiral HPLC with Daicel Chiralcel OD-H column [eluent:
hexane/IPA = 19:1; flow rate: 1.0 mL/min; detection: 254 nm; tR:
19.9 min (syn-major), 26.1 min (syn-minor)].
4.3.9. (1S,2R)-2-(Chloromethyl)-2-methyl-1-(1-naphthyl)-1,3-
propanediol 5ae
Data for the anti-isomer: State; 42.2 mg, 32% yield
(anti/syn = 59/41); TLC: Rf 0.41 (hexane/EtOAc = 2:1, stained blue
30
with phosphomolybdic acid/EtOH); mp: 146.0–148.0 °C; [
a]
=
D
+5.4 (c 0.46, CHCl3) for 78% ee (after recrystallization); 1H NMR
(400 MHz, CDCl3): d 0.72 (s, 3H), 2.84 (br s, 1H), 2.99 (br s, 1H),
3.56 (dd, 1H, J = 6.4 Hz, 11.5 Hz), 3.83 (d, 1H, J = 11.0 Hz), 3.94 (d,
1H, J = 11.0 Hz), 4.00 (d, 1H, J = 11.5 Hz), 6.01 (s, 1H), 7.66–7.41
(m, 3H), 7.99–7.76 (m, 3H), 8.12 (d, 1H, J = 8.2 Hz); 13C{1H} NMR
(100 MHz, CDCl3): d 17.5, 44.7, 51.1, 66.4, 72.3, 123.1, 125.2,
125.4, 125.6, 126.2, 128.6, 129.0, 131.6, 133.5, 136.6; IR (ATR):
3255 cmꢀ1; LRMS (EI): m/z 264 (M)+, 157; HRMS (EI): Calcd for
4.3.6. 1-(4-Bromophenyl)-2-(chloromethyl)-2-methyl-1,3-prop-
anediol 5ab
Data for the anti-isomer: State; 138.5 mg, 94% yield
(anti/syn = 87/13); TLC: Rf 0.35 (hexane/EtOAc = 2:1, stained blue
C
15H17ClO2 264.0917, found 264.0913. The enantiomeric excess
33
with phosphomolybdic acid/EtOH); mp: 107.0–109.0 °C; [
a]
=
was determined to be 78% ee (anti) and 81% ee (syn) by chiral HPLC
D
Please cite this article in press as: Kotani, S.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.01.006

6
S. Kotani et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Amorelli, B.; Unger, J. B. J. Am. Chem. Soc. 2008, 130, 14378–14379; (o)
Deschamp, J.; Riant, O. Org. Lett. 2009, 11, 1217–1220; (p) Sugiura, M.; Sato, N.;
Sonoda, Y.; Kotani, S.; Nakajima, M. Chem. Asian J. 2010, 5, 478–481; (q)
Ohmaru, Y.; Sato, N.; Mizutani, M.; Kotani, S.; Sugiura, M.; Nakajima, M. Org.
Biomol. Chem. 2012, 10, 4562–4570; (r) Osakama, K.; Sugiura, M.; Nakajima, M.;
Kotani, S. Tetrahedron Lett. 2012, 53, 4199–4201.
with Daicel Chiralpak IE-3 column [eluent: hexane/IPA = 29:1; flow
rate: 1.0 mL/min; detection: 254 nm; tR: 32.0 min (anti-major),
35.9 min (anti-minor), 37.9 min (syn-major), 51.1 min (syn-
minor)].
3. For reports regarding enantioselective alkylative aldol reactions, see: (a)
Cauble, D. F.; Gipson, J. D.; Krische, M. J. J. Am. Chem. Soc. 2003, 125, 1110–
1111; (b) Agapiou, K.; Cauble, D. F.; Krische, M. J. J. Am. Chem. Soc. 2004, 126,
4528–4529; (c) Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; De Vries, A.
H. M. Angew. Chem., Int. Ed. 1997, 36, 2620–2623; (d) Keller, E.; Maurer, J.;
Naasz, R.; Schader, T.; Meetsma, A.; Feringa, B. Tetrahedron: Asymmetry 1998, 9,
2409–2413; (e) Arnold, L. A.; Naasz, R.; Minnaard, A. J.; Feringa, B. L. J. Am.
Chem. Soc. 2001, 123, 5841–5842; (f) Arnold, L. A.; Naasz, R.; Minnaard, A. J.;
Feringa, B. L. J. Org. Chem. 2002, 67, 7244–7254; (g) Alexakis, A.; Trevitt, G. P.;
Bernardinelli, G. J. Am. Chem. Soc. 2001, 123, 4358–4360; (h) Nicolaou, K. C.;
Tang, W.; Dagneau, P.; Faraoni, R. Angew. Chem., Int. Ed. 2005, 44, 3874–3879;
(i) Brown, M. K.; Degrado, S. J.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2005, 44,
5306–5310; (j) Howell, G. P.; Fletcher, S. P.; Geurts, K.; ter Horst, B.; Feringa, B.
L. J. Am. Chem. Soc. 2006, 128, 14977–14985; (k) Oisaki, K.; Zhao, D.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 7439–7443.
4.3.10. 2-(Chloromethyl)-2-methyl-5-phenyl-4-pentene-1,3-diol
5af
Data for the anti-isomer: State; 67.0 mg, 56% yield
(anti/syn = 71/29); TLC: Rf 0.32 (hexane/EtOAc = 2:1, stained blue
with phosphomolybdic acid/EtOH); mp: 105.0–107.0 °C;
29
[a
]
D
29 = ꢀ1.4 (c 0.60, CHCl3) for 4% ee, [
a]
435 = ꢀ2.2 (c 0.60, CHCl3)
for 4% ee; 1H NMR (400 MHz, CDCl3): d 0.93 (s, 3H), 2.70 (br s,
1H), 2.78 (br s, 1H), 3.64–3.86 (m, 4H), 4.44 (d, 1H, J = 7.3 Hz),
6.32 (dd, 1H, J = 7.3 Hz, 16.0 Hz), 6.67 (d, 1H, J = 16.0 Hz), 7.20–
7.30 (m, 1H), 7.30–7.37 (m, 2H), 7.37–7.47 (m, 2H); 13C{1H} NMR
(100 MHz, CDCl3): d 16.8, 43.5, 50.0, 66.8, 126.6, 127.4, 128.0,
128.7, 133.1, 136.2 (one carbon overlapped into CDCl3); IR (ATR):
3359 cmꢀ1; LRMS (EI): m/z 240 (M)+, 222, 205, 192, 157, 133,
115, 91, 77; HRMS (EI): Calcd for C13H17ClO2 240.0917, found
240.0912. The enantiomeric excess was determined to be 4% ee
(anti) and 14% ee (syn) by chiral HPLC with Daicel Chiralpak
AD-3 column [eluent: hexane/IPA = 19:1; flow rate: 1.0 mL/min;
detection: 254 nm; tR: 30.3 min (anti-major), 33.3 min (anti-
minor), 37.6 min (syn-major), 40.7 min (syn-minor)].
4. For reports regarding halogenative aldol reactions of a-ynones see: (a) Kataoka,
T.; Kinoshita, H. Eur. J. Org. Chem. 2005, 45–58; (b) Wei, H.-X.; Hu, J.; Purkiss, D.
W.; Paré, P. W. Tetrahedron Lett. 2003, 44, 949–952; (c) Wei, H.-X.; Timmons, C.;
Farag, M. A.; Paré, P. W.; Li, G. Org. Biomol. Chem. 2004, 2, 2893–2896; (d) Wei,
H.-X.; Jasoni, R. L.; Hu, J.; Li, G.; Paré, P. W. Tetrahedron 2004, 60, 10233–10237;
(e) Yadav, J. S.; Reddy, B. V. S.; Gupta, M. K.; Pandey, S. K. J. Mol. Catal. A: Chem.
2007, 264, 309–312.
5. For a report regarding diastereoselective halogenative aldol reactions of
a-
enones, see: Li, G.; Xu, X.; Chen, D.; Timmons, C.; Carducci, M. D.; Headley, A. D.
Org. Lett. 2003, 5, 329–331.
6. For reports regarding enantioselective halogenative aldol reactions of
a-
ynones, see: (a) Chen, D.; Timmons, C.; Liu, J.; Headley, A.; Li, G. Eur. J. Org.
Chem. 2004, 3330–3335; (b) Chen, D.; Guo, L.; Kotti, S. R. S. S.; Li, G.
Tetrahedron: Asymmetry 2005, 16, 1757–1762; (c) Senapati, B. K.; Hwang, G.-S.;
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Acknowledgments
This work was partially supported by the Naito Foundation, JSPS
KAKENHI Grant Number 16K08168, and a Grant-in-Aid for Scien-
tific Research on Innovative Areas ‘Advanced Molecular Transfor-
mations by Organocatalysts’ from The Ministry of Education,
Culture, Sports, Science, and Technology, Japan.
7. For a review regarding Lewis base catalysis, see: Denmark, S. E.; Beutner, G. L.
Angew. Chem., Int. Ed. 2008, 47, 1560–1638.
8. For a review regarding phosphine oxide catalysis, see: (a) Kotani, S.; Sugiura,
M.; Nakajima, M. Chem. Rec. 2013, 362–370; (b) Kotani, S.; Sugiura, M.;
Nakajima, M. Synlett. 2014, 25, 631–640.
9. For
a review regarding hypervalent silicon complexes, see: (a) Orito, Y.;
Nakajima, M. Synthesis 2006, 1391–1401; (b) Benaglia, M.; Guizzetti, S.;
Pignataro, L. Coord. Chem. Rev. 2008, 252, 492–512; (c) Rossi, S.; Benaglia, M.;
Genoni, A. Tetrahedron 2014, 70, 2065–2080; (d) Benaglia, M.; Rossi, S. Org.
Biomol. Chem. 2010, 8, 3824–3830.
A. Supplementary data
10. (a) Tokuoka, E.; Kotani, S.; Matsunaga, H.; Ishizuka, T.; Hashimoto, S.;
Nakajima, M. Tetrahedron: Asymmetry 2005, 16, 2391–2392; (b) Kotani, S.;
Furusho, H.; Sugiura, M.; Nakajima, M. Tetrahedron 2013, 69, 3075–3081.
11. Nakanishi, K.; Kotani, S.; Sugiura, M.; Nakajima, M. Tetrahedron 2008, 64, 6415–
6419.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2017.01.
006.
12. Kotani, S.; Ito, M.; Nozaki, H.; Sugiura, M.; Ogasawara, M.; Nakajima, M.
Tetrahedron Lett. 2013, 54, 6430–6433.
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15. Although catalyst C5 afforded the better result in the reaction of 1a and 2a, it
gave lower yields for the reaction of other
a-substituted acroleins. Therefore,
we selected C1 as a catalyst for the investigation in Table 2.
16. The crystallographic data for this structure have been deposited with the
Cambridge Crystallographic Data Centre as
number CCDC 1487573.
a supplementary publication
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Please cite this article in press as: Kotani, S.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.01.006