Convenient synthesis of memantine analogues containing a chiral cyclopropane skeleton as a sigma-1 receptor agonist

Article abstract of DOI:10.1016/j.tetasy.2016.12.010

We have achieved a convenient enantioselective synthesis of memantine analogues containing a chiral cyclopropane skeleton as a sigma-1 receptor agonist in 19–40% overall chemical yields from the corresponding 2-arylbut-2-ene-1,4-diols with moderate to excellent asymmetric yields via regioselective acetylation using porcine pancreas lipase, catalytic enantioselective Simmons-Smith reactions, and amidation in aqueous organic solvent. This synthetic route is more efficient and less expensive than conventional methods.

Full text of DOI:10.1016/j.tetasy.2016.12.010

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Convenient synthesis of memantine analogues containing a chiral
cyclopropane skeleton as a sigma-1 receptor agonist
⇑
Tetsuya Ezawa, Yuya Kawashima, Takuya Noguchi, Seunghee Jung, Nobuyuki Imai
Faculty of Pharmacy, Chiba Institute of Science, 15-8 Shiomi-cho, Choshi, Chiba 288-0025, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We have achieved a convenient enantioselective synthesis of memantine analogues containing a chiral
cyclopropane skeleton as a sigma-1 receptor agonist in 19–40% overall chemical yields from the corre-
sponding 2-arylbut-2-ene-1,4-diols with moderate to excellent asymmetric yields via regioselective
acetylation using porcine pancreas lipase, catalytic enantioselective Simmons-Smith reactions, and ami-
dation in aqueous organic solvent. This synthetic route is more efficient and less expensive than conven-
tional methods.
Received 26 September 2016
Revised 9 November 2016
Accepted 13 December 2016
Available online xxxx
Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction
receptors could improve the clinical symptoms of Alzheimer’s dis-
ease and protect against the associated neuropathologic changes.
Sigma receptors have recently attracted attention as a new
action site of therapeutic medicine for several diseases such as
amnesia, pain, stroke, retinal neuroprotection, HIV infection, can-
cer, amyotrophic lateral sclerosis (ALS), depression, and Alzhei-
mer’s disease.1 Sigma-1 and sigma-2 receptors, as the two
established subtypes, are both highly expressed in the central ner-
vous system (CNS) and can be distinguished by their distinct phar-
macological profiles and molecular characteristics.2 It was reported
that the sigma-1 receptor regulates protein folding/degradation,
endoplasmic reticulum (ER)/oxidative stress, and cell survival
through the molecular chaperone activity.3 Therefore, the sigma-
1 receptor is significantly influential in the homeostasis of tissue,
which is incapable of repairing, and it is anticipated that the ago-
nists activated by the sigma-1 receptor become the therapeutic
agents of diseases caused by cell damage. For instance, it has been
elucidated that patients with ALS carry mutations in the sigma-1
receptor gene and the dysfunction of the sigma-1 receptor pro-
tein.4 It has been suggested that 1-[2-(3,4-dimethoxyphenyl)
ethyl]-4-(3-phenylpropyl)piperazine (SA4503)5 promotes regener-
ation and maturation of nerves as a selective sigma-1 receptor ago-
nist.6 Currently, Phase Ⅱ trials for SA4503 have been carried out in
Europe as a medicine against CNS disorders, which are caused by
major depression and strokes.7 The sigma agonists protect cultured
neurons against amyloid b (Ab)25–35-induced toxicity,8 and prevent
memory deficits when Ab25–35 is injected intracerebroventricularly
in mice.9 Therefore, the induction or activation of sigma-1
Indeed, tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine
hydrochloride (ANAVEX2-73), which exhibits neuroprotective
effects and prevents tau hyperphosphorylation, has been examined
in Phase IIa for Alzheimer’s disease trials as a sigma-1 receptor
agonist since January, 2015.10 As a part of interim studies for the
planned analysis, it was announced that a positive dose–response
relationship has been observed in its ongoing Phase IIa clinical tri-
als of ANAVEX 2–73 as a potential treatment for mild-to-moderate
Alzheimer’s disease by November, 2015. For these reasons, sigma-1
receptor agonists have become key targets for therapeutic
approaches to treat these diseases and have elicited significant
interest in medicinal chemistry.
Recently, (+)-(2R,3S)-4-(N-adamant-1-yl-N-methylamino)-2,3-
methano-2-phenylbutan-1-ol [(+)-AMMP] was reported as a high
affinity probe for sigma receptors by Marrazzo et al.11 However,
the synthetic route of (+)-AMMP afforded 9% overall yield from
2-oxo-1-phenyl-3-oxabicyclo[3.1.0]hexane as the starting material
and the reagents used for the synthesis of (+)-AMMP were rela-
tively expensive. Additionally, it was necessary to prepare various
chiral lactones as the starting materials in order to synthesize the
substituted aryl analogues of (+)-AMMP. Therefore, it was desir-
able to develop a more efficient and inexpensive synthetic method
for synthesis of (+)-AMMP analogues. We have recently reported a
convenient asymmetric synthesis of (+)-AMMP via reactions,12
such as (i) the regioselective acetylation using porcine pancreas
lipase (PPL);13 (ii) the catalytic enantioselective Simmons-Smith
reaction in the presence of our developed chiral ligand which
was prepared cheaply and easily from
L-phenylalanine in five
⇑
Corresponding author. Tel./fax: +81 479 30 4610.
E-mail address: nimai@cis.ac.jp (N. Imai).
steps;14 and (iii) the convenient amidation of mixed carbonic
http://dx.doi.org/10.1016/j.tetasy.2016.12.010
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Ezawa, T.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2016.12.010

2
T. Ezawa et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Me
H
N
Ar
N
Ar
amidation
Ar
OH
Ad
Ad
O
O
HO
(i)
P
O
P
O
(+)-AMMP
catalytic enantioselective
Simmons-Smith reaction
Ar
OH
Ar
OH
P
O
P
O
(ii)
P = protecting group
Ar
OH
Ar
OAc
regioselective acetylation
HO
HO
(iii)
Scheme 1. Retrosynthetic analysis of memantine analogues containing a chiral cyclopropane skeleton via the three key reactions.
carboxylic anhydrides in aqueous organic solvent.15 Particularly,
the cyclopropane moiety with two stereogenic carbon centers
was constructed in quantitative yield and with 71% ee via catalytic
enantioselective Simmons-Smith reaction and the sterically hin-
dered 1-adamantanamine moiety was successfully introduced by
our developed amidation.
Herein we report a convenient enantioselective synthesis of (+)-
AMMP and memantine analogues containing a chiral cyclopropane
skeleton, a 4-substituted aryl group, and a 1-adamantanamine or
memantine (3,5-dimethyl-1-adamantanamine) moiety via our
developed reactions as shown in Scheme 1.
group as indicated in Scheme 2. Monoacetate 1a, a key intermedi-
ate, was easily obtained via regioselective monoacetylation of (Z)-
2-phenylbut-2-ene-1,4-diol using PPL.13a The hydroxy group of
monoacetate 1a was protected by various protecting groups to
give the corresponding protected monoacetates 2aa–2ae in 86–
97% yields, followed by deacetylation to afford the desired 3aa–
3ae in 68%-quantitative yields.
In
a preliminary investigation, the reaction of (Z)-4-tert-
butyldiphenylsiloxy-3-phenylbut-2-en-1-ol 3aa with 2.0 equiv of
Et2Zn and 3.0 equiv of CH2I2 in the presence of 0.1 equiv of the chi-
ral ligand 4 in anhydrous CH2Cl2 at 0 °C for 3 h afforded (+)-cis-4-
tert-butyldiphenylsiloxy-2,3-methano-3-phenylbutan-1-ol 5aa in
quantitative yield and with 71% ee (see entry 1 of Table 1). (Z)-4-
Tris(trimethylsilyl)siloxy-3-phenylbut-2-en-1-ol 3ad was con-
verted into the corresponding 2,3-methano-3-phenylbutan-1-ol
5ad in 90% yield and with 68% ee (see entry 3). Lower enantioselec-
tivities (48% and 21% ee) were obtained in the reactions of 4-siloxy
2. Results and discussion
4-O-Protected (Z)-3-phenylbut-2-en-1-ols 3aa–3ae were ini-
tially prepared for substrates in the catalytic enantioselective
Simmons-Smith reaction in order to select a suitable protecting
MeONa, MeOH,
P-Cl, pyridine,
rt, 24 h or 90 h
Ph
OAc
Ph
O
OAc
Ph
O
OH
rt, 3 h
or
or
HO
P
P
DIBAL-H, THF,
-78 °C, 24 h
(Me3Si)3Si-Cl,
Et3N, DMAP
THF, rt, 24 h
2aa
(P = t-BuPh2Si): 97%
2ab (P = t-BuMe2Si): 96%
2ac
3aa (P = t-BuPh2Si): quant.
3ab
1a
(P = t-BuMe2Si): 90%
3ac (P = (t-BuO)Ph2Si): quant.
3ad
(P = (t-BuO)Ph2Si): 91%
2ad (P = (Me3Si)3Si ): 86%
2ae
(P = (Me3Si)3Si): 83%
3ae (P = Ph3C): 68%
(P = Ph3C): 94%
Scheme 2. Preparation of 4-O-protected (Z)-3-phenylbut-2-en-1-ols 3aa–3ae.
Table 1
Simmons-Smith reaction of 4-O-protected (Z)-3-phenylbut-2-en-1-ols 3aa–3aea
Ph
4
Ph
OH
Ph
OH
MsHN
NHTs
Et2Zn, CH2I2, CH2Cl2,
0 °C, 24 h
P
O
P
O
3aa-3ae
5aa-5ae
Entry
Product
P
Yield (%)
ee (%)b
1c
2
3
5aa
5ab
5ac
5ad
5ae
t-BuPh2Si
t-BuMe2Si
t-BuOPh2Si
(Me3Si)3Si
Ph3C
Quant.
93
66
90
89
71
48
21
68
19
4
5c
a
b
c
All reactions were carried out with 4-O-protected (Z)-3-phenylbut-2-en-1-ols 3aa–3ae, 2.0 equiv of Et2Zn, and 3.0 equiv of CH2I2 in anhydrous CH2Cl2.
Determined by HPLC analysis with a 95:5 mixture of hexane and 2-propanol as an eluent using Chiralcel OD (1.0 mL/min).
Stirred for 3 h.
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T. Ezawa et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
(Z)-3-phenylbut-2-en-1-ols 3ab and 3ac, respectively (see entries
2 and 3). The reaction of (Z)-4-triphenylmethoxy-3-phenylbut-2-
en-1-ol 3ae proceeded to give the corresponding 2,3-methano-3-
phenylbutan-1-ol 5ae in 89% yield, but the enantioselectivity
(19% ee) was low (see entry 5). The results of these reactions are
summarized in Table 1. It is suggested that larger protecting
groups such as tert-butyldiphenylsilyl and tris(trimethylsilyl)silyl
group, are more efficient in terms of the enantioselectivity and that
the silyl groups decrease the Lewis basicity on the oxygen atom of
the hydroxy group and are more suitable than trityl group in this
reaction.
As optimized above, tert-butyldiphenylsilyl group was chosen
for preparation of various 4-O-protected (Z)-3-arylbut-2-en-1-ols
3ba–3ea. The allylalcohols 3ba–3ea were converted from (Z)-3-
arylbut-2-en-1-yl acetates 1b–1e in 87%-quantitative yields in 2
steps, which were prepared by our developed regioselective acety-
lation (see Scheme 3).
Methyl- and halo-substituted cinnamyl alcohols 3ca–3ea gave
the corresponding cyclopropane products 5ca–5ea in excellent
yields and with satisfactory enantioselectivities (see entries 3–5).
However, the reaction of methoxy-substituted cinnamyl alcohol
3ba proceeded in 70% yield and with low enantioselectivity (36%
ee). It was suggested that the oxygen atom of the methoxy group
acts as a Lewis base to the catalyst (see entry 2 of Table 2).
Subsequently, the 2,3-methano-3-arylbutan-1-ols 5aa–5ea
were oxidized with 2-iodoxybenzoic acid (IBX) in dimethylsulfox-
ide (DMSO) at rt for 3 h to afford the corresponding 2,3-methano-
3-arylbutan-1-als 6aa–6ea in 94–96% yields, which were
converted with NaClO2, H2O2, and NaH2PO4 in MeCN–H2O at rt
for 3 h to the corresponding 2,3-methano-3-arylbutanoic acids
7aa–7ea in 95–98% yields as indicated in Scheme 4.
Next, we attempted to introduce 1-adamantanamine with steric
hindrance into carboxylic acids 7aa–7ea. Recently, we reported that
the amidation of a-amino acids with 1.0 M aqueous NH4Cl solution
Next, we attempted the cyclopropanation of (Z)-4-tert-
butyldiphenylsiloxy-3-arylbut-2-en-1-ols 3ba–3ea as shown in
Table 2. The reactions of allylalcohols 3ba–3ea with various
oriented substituents on the aromatic ring worked smoothly.
via the mixed carbonic carboxylic anhydrides provided the corre-
sponding primary amides in excellent yields.15a,c Therefore, we
supposed it was feasible to efficiently introduce the salt of
1-adamantanamine hydrochloride or sulfate into carboxylic acids
MeONa, MeOH,
rt, 3 h
Ar
OAc
Ar
OH
Ar
OAc
t-BuPh2Si-Cl
pyridine, rt, 24 h
or
HO
t-BuPh2SiO
t-BuPh2SiO
DIBAL-H, THF,
-78 °C, 24 h
1b (Ar = 4-MeOC6H4)
1c
3ba: 90%
2ba: Quant.
(Ar = 4-MeC6H4)
1d (Ar = 4-ClC6H4)
1e
3ca
3da
: 95%
2ca
2da
: Quant.
: Quant.
: Quant.
3ea: 95 %
(Ar = 4-BrC6H4)
2ea: 92%
Scheme 3. Preparation of (Z)-4-tert-butyldiphenylsiloxy-3-arylbut-2-en-1-ols 3ba–3ea.
Table 2
Simmons-Smith reaction of (Z)-4-tert-butyldiphenylsiloxy-3-arylbut-2-en-1-ols 3aa–3eaa
Ph
4
Ar
OH
Ar
OH
MsHN
NHTs
Et2Zn, CH2I2, CH2Cl2,
0 °C, 3 h
t-BuPh2SiO
t-BuPh2SiO
3aa-3ea
5aa-5ea
Entry
Product
Ar
Yield (%)
ee (%)b
1
2
3
4
5
5aa
5ba
5ca
5da
5ea
C6H5
Quant.
70
Quant.
97
71
36
4-MeOC6H4
4-MeC6H4
4-ClC6H4
4-BrC6H4
65
66c
73d
97
a
b
c
All reactions were carried out with (Z)-4-tert-butyldiphenylsiloxy-3-arylbut-2-en-1-ols 3aa–3ea, 2.0 equiv of Et2Zn, and 3.0 equiv of CH2I2 in anhydrous CH2Cl2.
Determined by HPLC analysis with a 95:5 mixture of hexane and 2-propanol as an eluent using Chiralcel OD (1.0 mL/min).
Determined by HPLC analysis with hexane containing 0.1% 2-propanol as an eluent using Chiralcel OD-H after acetylation (1.0 mL/min).
Determined by HPLC analysis with a 99:1 mixture of hexane and 2-propanol as an eluent using Chiralcel OD (1.0 mL/min).
d
O
O
I
O
O
Ar
OH
Ar
H
(IBX)
Ar
OH
NaClO2, H2O2
O
DMSO,
rt, 3 h
NaH2PO4, MeCN-H2O,
rt, 3 h
O
t-BuPh2SiO
t-BuPh2SiO
t-BuPh2SiO
5aa (Ar = C6H5)
6aa: 94%
7aa: 98%
6ba
6ca
7ba
7ca
: 94%
: 96%
: 95%
: 96%
5ba
(Ar = 4-MeOC 6H4)
5ca (Ar = 4-MeC6H4)
5da
6da: 96%
7da: 98%
7ea
: 94%
(Ar = 4-ClC6H4)
5ea (Ar = 4-BrC6H4)
6ea
: 96%
Scheme 4. Preparation of the 2,3-methano-3-arylbutanoic acids 7aa–7ea.
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T. Ezawa et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
7aa–7ea. At first, we examined the amidation of 3-phenylpropionic
acid 70 with sterically hindered 1-adamantanamine in an aqueous
organic solvent in order to optimize the reaction conditions. The
results are summarized in Table 3. Treatment of 70 with 1.1 equiv
of 1-adamantanamine hydrochloride (amantadineÒ) in the
presence of 1.1 equiv of ClCO2Et and 1.1 equiv of Et3N in MeCN–
H2O afforded N-adamant-1-yl-3-phenylpropanamide 80 in 27%
yield (see entry 1). The reaction of 1-adamantanamine sulfate,
which is less expensive than amantadineÒ, did not afford the
corresponding amide 80 because 1-adamantanamine sulfate is
hardly dissolved in organic solvents or water (see entry 2). The
amidation of 70 with 1-adamantanamine sulfate in the presence
of 2.0 equiv of 1.0 M aqueous NaHCO3 and NaOH solution gave
the desired amide 80 in 16% and 42% yield, respectively (see
N-adamant-1-yl-3-phenylpropylamine 100 in 6% yield (see entry
1). The use of 5.0 equiv of BH3ꢀSMe2 in anhydrous THF at rt to
40 °C for 71 h gave the desired amine 100 in 58% yield (see entry
3), and 100 was obtained in 69% yield when the reaction was carried
at rt to 70 °C for 23 h in anhydrous toluene (see entry 4). The yield
obtained when Meyer’s method was used was 20% (see entry 5).16
The yield (88%) greatly improved under the conditions using
5.0 equiv of LiAlH4 in toluene at 40 to 70 °C for 19 h (see entry 8).
The reduction of the chiral amide 800 containing a cyclopropane ring
with 5.0 equiv of LiAlH4 proceeded smoothly at 70 °C for 13 h to
afford the corresponding chiral amine 1000 in 92% yield without
cleavage of the cyclopropane skeleton (see entry 9 of Table 4).
Fortunately, the treatment of the chiral 2,3-methano-3-
phenylbutanamide 8aa with 5.0 equiv of LiAlH4 in anhydrous
toluene at 70–100 °C for 18 h afforded the corresponding chiral
2,3-methano-2-phenylbutan-1-ol 10a in 72% yield with 86% ee
through simultaneous reduction of the amide and silyl moieties
as shown in pathway A of Scheme 6.12 In pathway B, the silyl group
of 8aa was cleaved by tetrabutylammonium fluoride (TBAF) to give
the corresponding chiral 4-hydroxyamide 9a in 93% yield, followed
by reduction with LiAlH4 to afford 10a in 87% yield and with 86%
ee. The overall yield in 2 steps was 81%, which is better than the
yield of pathway A.
entries
3
and 4). Moreover, the amidation of 70 with 1-
adamantanamine sulfate in the presence of 2.0 equiv of 1.0 M
aqueous NaOH solution was carried out for 6 h, 24 h, and 48 h to
afford the amide 80 in 58%, 84%, and 82% yield, respectively (see
entries 5, 6, and 7). The reaction with a stoichiometric and an
excess amount of 1.0 M aqueous NaOH solution gave 46% and 65%
yield, respectively (see entries 8 and 9).
Subsequently, the amidation of the 2,3-methano-3-arylbutanoic
acids 7aa–7ea with 1-adamantanamine sulfate was performed
under the optimized conditions to afford the corresponding 2,3-
methano-3-arylbutanamides 8aa–8ea in 73–97% yields as indi-
cated in Scheme 5.
The chiral 2,3-methano-2-arylbutan-1-ols 10b–10e were pre-
pared efficiently from the corresponding chiral amides 8ba–8ea
in excellent yields in two steps as described in Scheme 7. We were
able to convert (+)-cis-4-tert-butyldiphenylsiloxy-2,3-methano-3-
arylbutan-1-ols 5aa–5ea into the corresponding chiral alcohols
10b–10e in five steps without a significant loss of enantiomeric
excess in all cases.
Furthermore, the conditions for the reduction of N-adamant-1-
yl-2,3-methano-3-phenylbutanamide 80 were optimized and the
results are shown in Table 4. The reaction of 80 with 2.0 equiv of
BH3ꢀSMe2 in anhydrous THF at 40 °C for 49 h afforded
Table 3
a
Optimization of the reaction conditions for the amidation of 3-phenylpropionic acid 70
O
O
O
O
1-Ad-NH2·1/2H2SO4
ClCO2Et, Et3N
Ad
Ph
N
H
acetone,
Ph
OH
1.0 M aq. base
Ph
O
OEt
0 °C, 30 min
8'
7'
Entry
Base
Equiv of base
Time (h)
Yield (%)d
1b
2c
3
4
5
6
7
8
9
Free
Free
—
—
6
8
20
1
6
24
48
24
24
27
0
NaHCO3
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
2.0
2.0
2.0
2.0
2.0
1.1
3.0
16
42
58
84
82
46
65
a
All reactions were carried out with 0.5 mmol of 3-phenylpropionic acid 70, 1.1 equiv of 1-adamantanamine sulfate (Ad-NH2ꢀ1/2H2SO4), 1.1 equiv of ClCO2Et, and 1.1 equiv
of Et3N in 10 mL of acetone.
b
1-Adamantanamine hydrochloride (1-Ad-NH2ꢀHCl) was used instead of 1-adamantanamine sulfate (1-Ad-NH2ꢀ1/2H2SO4) in a mixture of 10 mL of MeCN and 0.5 mL of
water.
c
A mixture of 10 mL of MeCN and 1.0 mL of water was used instead of acetone.
Isolated yield.
d
H
Ar
OH
Ar
N
1) ClCO2Et, Et3N, acetone, 0 °C, 30 min
2) 1-Ad-NH2·1/2H2SO4
Ad
O
,
O
t-BuPh2SiO
t-BuPh2SiO
1.0 M aq. NaOH, 0 °C, 24 h
8aa: 88%
8ba: 84%
7aa (Ar = C6H5)
7ba
7ca
(Ar = 4-MeOC6H4)
(Ar = 4-MeC6H4)
8ca
: 97%
8da: 73%
8ea: 78%
7da (Ar = 4-ClC6H4)
7ea
(Ar = 4-BrC6H4)
Scheme 5. Preparation of the 2,3-methano-3-arylbutanamides 8aa–8ea.
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T. Ezawa et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
Table 4
Optimaization of the reaction conditions for reduction of N-adamant-1-yl-2,3-methano-3-phenylbutanamide (80)a
O
O
reductant
Ad
Ad
Ad
Ad
Ph
N
H
Ph
N
H
Ph
N
H
Ph
N
H
solvent, conditions
10'
10"
8'
8"
Entry
Reductant
Equiv
Solvent
Conditions
Yield (%)b
1
2
3
BH3ꢀSMe2
BH3ꢀSMe2
BH3ꢀSMe2
BH3ꢀSMe2
NaBH4, I2
LiAlH4
LiAlH4
LiAlH4
LiAlH4
2.0
2.0
5.0
5.0
2.5, 1.0
5.0
2.5
5.0
5.0
THF
THF
THF
Toluene
THF
40 °C, 49 h
6
50 °C to reflux, 70 h
rt to 40 °C, 71 h
rt to 70 °C, 23 h
40 °C, 72 h
rt to reflux, 65 h
rt to 70 °C, 46 h
40 °C to 70 °C, 19 h
70 °C, 13 h
31
58
69
20
48
54
88
92
4
5c
6
THF
7
Toluene
Toluene
Toluene
8
9d
a
b
c
All reactions were carried out with 50 mg (0.18 mmol) of 80.
Isolated yield.
The reaction was carried out with 50 mg (0.18 mmol) of 80, 2.5 equiv of NaBH4, and 1.0 equiv of I2 in anhydrous THF.
800 was used as the starting material instead of 80.
d
pathway A
H
H
N
Ph
N
Ph
LiAlH4
Ad
Ad
O
toluene, 70 °C to 100 °C, 18 h
72%
t-BuPh2SiO
HO
10a
86% ee
8aa
pathway B
H
Ph
N
LiAlH4
TBAF
Ad
toluene, 70 °C, 24 h
87%
O
THF, rt, 4h
93%
HO
9a
Scheme 6. Preparation of the chiral 2,3-methano-2-pheylbutan-1-ol 10a via two pathways.
H
N
H
N
H
N
Ar
Ar
TBAF
Ar
LiAlH4
Ad
Ad
Ad
toluene,
THF, rt, 4h
O
O
70 °C to 100 °C
HO
t-BuPh2SiO
HO
8ba (Ar = 4-MeOC6H4)
8ca (Ar = 4-MeC6H4)
8da (Ar = 4-ClC6H4)
8ea (Ar = 4-BrC6H4)
9b: 91%, 34% ee
9c: 97%, 58% ee
10b: 85%, 34% ee
10c: 84%, 60% ee
9d
: 91%, 73% ee
10d
: 90%, 75% ee
9e: 97%, 73% ee
10e: 85%, 75% ee
Scheme 7. Preparation of the chiral 2,3-methano-2-arylbutan-1-ols 10b–10e in two steps from the chiral 2,3-methano-3-arylbutanamides 8ba–8ea.
Additionally, (+)-AMMP analogues 11a–11e were acquired in
58–68% yields via methylation of the amino alcohols 10a–10e with
MeI as indicated in Scheme 8.
Finally, we succeeded in synthesizing memantine (3,5-
dimethyl-1-adamantanamine) analogue 15 containing a chiral
cyclopropane skeleton as shown in Scheme 9. The amidation of
the 2,3-methano-3-phenylbutanoic acid 7aa with memantine
hydrochloride worked easily to give the corresponding amide 12
in 84% yield, followed by desilylation, reduction, and methylation
to afford the memantine derivative 15 in 45% overall yield and
with 74% ee from 5aa.
We have recently reported the detail of the cyclopropanation of
various allylic alcohols using L-tyrosine-derived fluorous disulfon-
amide as a chiral ligand and described the proposed reaction path-
way (see Scheme 10) and a possible transition state (see Fig. 1) of
the cyclopropanation.17,18 The iodomethylzinc alkoxide 16 is pro-
duced by the addition of Zn(CH2I)2 to the allylic alcohol 3, and
complex 17 is formed from the species 16 and Lewis acid. The
cyclopropane derivative 5 is generated from the disulfonamide 4-
zinc complex (Lewis acid) via complexes 17 and 18. We propose
a possible transition state for the enantioselective cyclopropana-
Me
H
Ar
N
Ar
N
MeI, NaHCO3
Ad
Ad
DMF,
80 °C, 2 h
HO
HO
10a (Ar = C6H5)
10b
11a
: 68% [(+)-AMMP]
(Ar = 4-MeOC 6H4)
10c (Ar = 4-MeC6H4)
10d
11b: 58%
11c
11d
: 59%
: 65%
(Ar = 4-ClC6H4)
10e (Ar = 4-BrC6H4)
tion with L-phenylalanine-derived disulfonamide 4 as shown in
11e: 58%
Figure 1. We speculated that the zinc derived from the carbenoid
to the double bond of allylic alcohol 3 is accelerated by the oxygen
atom of the methanesulfonamide group. Allylic alcohol 3 would
Scheme 8. Synthesis of (+)-AMMP analogues by methylation from the chiral 2,3-
methano-2-arylbutan-1-ols 10a–10e.
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6
T. Ezawa et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Ph
OH
Ph
OH
1) ClCO2Et, Et3N, acetone, 0 °C, 30 min
2)
O
·HCl
Me
t-BuPh2SiO
t-BuPh2SiO
H2N
Me
5aa: 72% ee
7aa
1.0 M aq. NaOH, 0 °C, 24 h
84%
H
H
N
Ph
N
Ph
HO
LiAlH4
TBAF
Me
Me
O
O
THF, rt, 4 h
91%
toluene,
70 °C, 24 h
Me
t-BuPh2SiO
Me
12
13: 72% ee
88%
Me
N
H
Ph
N
Ph
HO
MeI, NaHCO3
Me
Me
memantine analogue containing
a chiral cyclopropane skeleton
DMF,
80 °C, 1 h
Me
14: 74% ee
Me
HO
15: 45% overall yield
73%
with 74% ee
Scheme 9. Synthesis of memantine analogue containing a chiral cyclopropane skeleton from 5aa.
Et2Zn + 2CH2I2
OH
phenylbutan-1-ol [(+)-AMMP] analogues 11a–11e containing a
2EtI
chiral cyclopropane skeleton in 19–39% overall yields from the
starting 2-arylbut-2-ene-1,4-diols 19a–19e without the significant
loss of enantiomeric excess as summarized in Scheme 11. The
reagents used in our synthetic route are relatively inexpensive,
and the key reactions are as follows; (i) the regioselective acetyla-
tion using PPL,13 (ii) the catalytic enantioselective Simmons-Smith
Zn(CH2I)2
CH3I
Ar
Ar
OZnCH2I
P
O
P
O
16
3
reaction in the presence of
L-phenylalanine-derived disulfon-
Ar
O
amide,14 and (iii) the convenient amidation of mixed carbonic car-
boxylic anhydrides in aqueous organic solvent.15 Additionally, we
have also succeeded in synthesizing memantine analogue 15 con-
taining a chiral cyclopropane skeleton with 74% ee in 45% and 40%
overall yield from the corresponding amide 5aa and 1,4-diol 19a,
respectively.
ZnI
LA
P
O
5
LA
O
LA
O
4. Experimental
4.1. General
Ar
Ar
ZnCH2I
ZnI
P
O
P
O
18
17
All reagents were used without purification except for CH2Cl2.
CH2Cl2 was washed with water twice, dried over molecular sieves
4 Å, heated at reflux for 24 h with CaH2, and distilled before use.
The 1H NMR and 13C NMR spectra were measured with a Bruker
UltrashieldTM 400 Plus (400 MHz) spectrometer. The chemical shifts
are expressed in parts per million downfield from tetramethylsi-
lane (d = 0.00) as an internal standard. Chemical shifts (d) are
reported in ppm, and spin–spin coupling constants (J) are given
in Hertz. Abbreviations to denote the multiplicity of a particular
signal are s (singlet), d (doublet), t (triplet), q (quartet), m (multi-
plet), and br (broad). The high-resolution mass spectra (HRMS) of
the compounds with a high molecular weight were recorded using
a Waters LCT Premier (ESI-TOF-MS) spectrometer. Reactions were
monitored using thin-layer chromatography with silica gel 60
(LA = Lewis acid)
Scheme 10. Proposed reaction pathway of the cyclopropanation.
O
H3C
O
S
N
I
Zn
CH2
Zn
O
L
O
P
N
S
O
CH3
O
Figure 1. Possible transition state of the cyclopropanation.
F254. Purification of the reaction products was carried out by col-
umn chromatography using silica gel (64–210 mesh). HPLC analy-
sis was carried out with Chiralcel OD, OJ, OB, OK (10 mm,
46 ꢁ 250 mm), Chiralpak AD, AS (10 mm, 46 ꢁ 250 mm), and Chi-
ralcel OD-H (5 mm, 46 ꢁ 250 mm) coupled to a photodiode array
detector or a dual k absorbance detector, and HPLC grade solvents
were used for HPLC analysis. Melting points were determined with
a hot plate apparatus. Optical rotations were measured on a digital
polarimeter with a sodium lamp at room temperature. Infrared (IR)
spectra were recorded on HORIBA FT-IR Fourier transform infrared
spectrophotometer.
take the opposite side of the benzene ring derived from L-pheny-
lalanine in order to avoid the steric hindrance, then the carbenoid
approaches the allylic alcohol 3 from the opposite side of the p-
toluenesulfonamide group.
3. Conclusions
We have achieved a convenient enantioselective synthesis
of
(+)-cis-4-(N-adamant-1-yl-N-methylamino)-2,3-methano-2-
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T. Ezawa et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
7
.
Ar
OAc
Ar
OAc
Ar
OH
MeONa
t-BuPh2Si-Cl
vinyl acetate, PPL
MeOH,
rt, 3 h
pyridine, rt, 24 h
1,4-dioxane, rt, 24 h
HO
HO
t-BuPh2SiO
19a (Ar = C6H5)
1a: 91%
2aa: 97%
2ba
1b
: 89%
: Quant.
19b
(Ar = 4-MeOC6H4)
1c: 91%
1d: 86%
2ca: Quant.
2da: Quant.
19c (Ar = 4-MeC6H4)
19d
(Ar = 4-ClC6H4)
1e
2ea
: 74%
: 92%
19e (Ar = 4-BrC6H4)
Ar
OH
Ar
OH
Ar
H
4
chiral ligand
IBX
Et2Zn, CH2I2, CH2Cl2,
0 °C, 3 h
DMSO,
rt, 3 h
O
t-BuPh2SiO
t-BuPh2SiO
5aa
t-BuPh2SiO
3aa
6aa
: 94%
: Quant.
: Quant., 71% ee
3ba: 90%
5ba: 70%, 36% ee
6ba: 94%
3ca
3da
5ca
5da
6ca
6da
: 95%
: Quant.
: Quant., 65% ee
: 97%, 66% ee
: 96%
: 96%
3ea: 95 %
5ea: 97%, 73% ee
6ea: 96%
H
NaClO2, H2O2
Ar
OH
1) ClCO2Et, Et3N, acetone, 0 °C, 30 min
Ar
N
Ad
NaH2PO4, MeCN-H2O,
rt, 3 h
2) 1-Ad-NH2·1/2H2SO4,
1.0 M aq. NaOH, 0 °C, 24 h
O
O
t-BuPh2SiO
t-BuPh2SiO
7aa
8aa
: 88%
: 98%
7ba: 95%
7ca: 96%
8ba: 84%
8ca: 90%
7da
7ea: 94%
8da
: 73%
8ea: 78%
: 98%
Me
N
H
H
Ar
N
LiAlH4
Ar
N
MeI, NaHCO3
Ar
TBAF
Ad
Ad
Ad
DMF,
80 °C, 2 h
toluene,
70 °C to 100 °C
THF, rt, 4 h
O
5 examples
HO
HO
HO
19-39% overall yields
with 34-86% ee
9a: 93%, 82% ee
9b: 91%, 34% ee
10a: 87%, 86% ee
10b: 85%, 34% ee
11a: 68%
11b: 58%
9c
10c
11c
: 59%
: 97%, 58% ee
: 84%, 60% ee
9d: 91%, 73% ee
9e: 97%, 73% ee
10d: 90%, 75% ee
10e: 85%, 75% ee
11d: 65%
11e: 58%
Scheme 11. Convenient enantioselective total synthesis of (+)-AMMP analogues containing a chiral cyclopropane skeleton from 19a–19e.
4.2. Typical procedure for the acetylation of (Z)-2-pheylbut-2-
ene-1,4-diol 19a using PPL
127.6, 132.4, 143.4, 159.5, 171.5; HRMS (ESI-TOF): Calcd for
C
13H16O4Na (M+Na)+: 259.0941, found: 259.0915.
To a pale yellow suspension of 164 mg (1.00 mmol, 1.0 equiv) of
4.2.3. (Z)-4-Hydroxy-3-(4-methylphenyl)but-2-en-1-yl acetate 1c
Colorless oil; 1H NMR (400 MHz, CDCl3): d 2.08 (s, 3H, CH3CO),
2.35 (s, brs, 3H, 1H, ArCH3, OH), 4.59 (d, J = 5.4 Hz, 2H, CH2OH), 4.87
(d, J = 7.4 Hz, 2H, CH2OAc), 5.90 (t, J = 7.4 Hz, 1H, @CH), 7.16, 7.39
(d, d, J = 8.2 Hz, J = 8.2 Hz, 2H, 2H, C6H4); 13C NMR (100 MHz,
CDCl3): d 21.0, 21.1, 60.0, 61.2, 123.4, 126.3, 129.3, 137.1, 137.9,
143.8, 171.4; HRMS (ESI-TOF): Calcd for C13H16O3Na (M+Na)+:
243.0992, found: 243.1007.
(Z)-2-phenylbut-2-ene-1,4-diol
19a,
0.92 mL
(10.0 mmol,
10 equiv) of vinyl acetate, and 82 mg (50 w/w%) of PPL in 3 mL of
1,4-dioxane was stirred at rt for 24 h. The reaction suspension
was diluted with 10 mL of AcOEt and dried over anhydrous MgSO4.
The residue was chromatographed on silica gel with a 1:2 mixture
of AcOEt and hexane to afford 187 mg (91% yield) of 1a.
4.2.1. (Z)-4-Hydroxy-3-phenylbut-2-en-1-yl acetate 1a
Colorless oil; 1H NMR (400 MHz, CDCl3): d 2.08 (s, 3H, CH3CO),
2.45 (brs, 1H, OH), 4.60 (s, 2H, CH2OH), 4.88 (d, J = 7.2 Hz, 2H,
CH2OAc), 5.92 (t, J = 7.2 Hz, 1H, @CH), 7.28–7.38, 7.48–7.50 (m,
m, 3H, 2H, C6H5); 13C NMR (100 MHz, CDCl3): d 21.1, 60.1, 61.2,
124.3, 126.4, 128.0, 128.6, 140.1, 143.9, 171.5; HRMS (ESI-TOF):
Calcd for C12H14O3Na (M+Na)+: 229.0835, found: 229.0815.
4.2.4. (Z)-3-(4-Chlorophenyl)-4-hydroxybut-2-en-1-yl acetate 1d
Colorless oil; 1H NMR (400 MHz, CDCl3): d 2.08 (s, 3H, CH3CO),
2.49–2.54 (m, 1H, OH), 4.56 (d, J = 6.0 Hz, 2H, CH2OH), 4.86 (d,
J = 7.2 Hz, 2H, CH2OAc), 5.90 (t, J = 7.2 Hz, 1H, @CH), 7.31, 7.44 (d,
d, J = 8.6 Hz, J = 8.6 Hz, 2H, 2H, C6H4); 13C NMR (100 MHz, CDCl3):
d 21.1, 59.9, 61.1, 124.7, 127.8, 128.7, 133.9, 138.6, 142.8, 171.5;
HRMS (ESI-TOF): Calcd for C12H13ClO3Na (M+Na)+: 263.0445,
found: 263.0425.
4.2.2. (Z)-4-Hydroxy-3-(4-methoxyphenyl)but-2-en-1-yl acetate
1b
Colorless oil; 1H NMR (400 MHz, CDCl3): d 2.08 (s, 3H, CH3CO),
2.43 (t, J = 6.1 Hz, 1H, OH), 3.81 (s, 3H, OCH3), 4.58 (d, J = 6.1 Hz, 2H,
CH2OH), 4.85 (d, J = 7.4 Hz, 2H, CH2OAc), 5.86 (t, J = 7.4 Hz, 1H,
@CH), 6.91, 7.14 (d, d, J = 8.8 Hz, J = 8.8 Hz, 2H, 2H, C6H4); 13C
NMR (100 MHz, CDCl3): d 21.1, 55.3, 60.0, 61.3, 113.9, 122.5,
4.2.5. (Z)-3-(4-Bromophenyl)-4-hydroxybut-2-en-1-yl acetate 1e
Colorless oil; 1H NMR (400 MHz, CDCl3): d 2.10 (s, 3H, CH3CO),
2.50 (brs, 1H, OH), 4.57 (d, J = 5.5 Hz, 2H, CH2OH), 4.86 (d,
J = 7.4 Hz, 2H, CH2OAc), 5.91 (t, J = 7.4 Hz, 1H, @CH), 7.38, 7.48 (d,
d, J = 8.6 Hz, J = 8.6 Hz, 2H, 2H, C6H4); 13C NMR (100 MHz, CDCl3):
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8
T. Ezawa et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
d 21.1, 59.9, 61.1, 122.0, 124.7, 128.1, 131.6, 139.1, 142.8, 171.5;
HRMS (ESI-TOF): Calcd for C12H13BrO3Na (M+Na)+: 306.9940,
found: 306.9964.
4.3.6. (Z)-4-(tert-Butyldiphenylsiloxy)-3-(4-methoxyphenyl)but-
2-en-1-yl acetate 2ba
Reaction time: 24 h; Colorless oil; 1H NMR (400 MHz, CDCl3): d
0.98 (s, 9H, (CH3)3C), 2.03 (s, 3H, CH3CO), 3.81 (s, 3H, CH3O), 4.57 (s,
2H, CH2OSi), 4.62 (d, J = 6.9 Hz, 2H, CH2OAc), 5.78 (t, J = 6.9 Hz, 1H,
@CH), 6.83, 7.31 (d, d, J = 8.8 Hz, J = 8.8 Hz, 2H, 2H, C6H4), 7.35–
7.45, 7.63–7.65 (m, m, 6H, 4H, C6H5 ꢁ2); 13C NMR (100 MHz,
CDCl3): d 19.2, 21.0, 26.7, 55.3, 61.2, 61.4, 113.5, 122.7, 127.7,
128.0, 129.7, 132.8, 133.3, 135.7, 142.4, 159.1, 170.8; HRMS (ESI-
TOF): Calcd for C29H34O4SiNa (M+Na)+: 497.2119, found: 497.2125.
4.3. Typical procedure for the preparation of (Z)-4-(tert-
butyldiphenylsiloxy)-3-phenylbut-2-en-1-yl acetate 2aa
To a colorless solution of 206 mg (1.00 mmol, 1.0 equiv) of (Z)-
4-hydroxy-3-phenylbut-2-en-1-yl acetate 1a in 5 mL of pyridine
were added 330 mg (1.20 mmol 1.2 equiv) of t-BuPh2SiCl under
an argon atmosphere. After stirring at rt for 24 h, the reaction mix-
ture was quenched with 10 mL of water and extracted with 10 mL
ꢁ3 of AcOEt. The organic layers were combined, washed with 5 mL
of brine, and dried over anhydrous MgSO4. The residue was chro-
matographed on silica gel with a 1:8 mixture of AcOEt and hexane
to afford 431 mg (97% yield) of 2aa.
4.3.7. (Z)-4-(tert-Butyldiphenylsiloxy)-3-(4-methylphenyl)but-
2-en-1-yl acetate 2ca
Reaction time: 24 h; Pale yellow oil; 1H NMR (400 MHz, CDCl3):
d 0.98 (s, 9H, (CH3)3C), 2.03 (s, 3H, CH3CO), 2.34 (s, 3H, CH3), 4.57 (s,
2H, CH2OSi), 4.65 (d, J = 6.9 Hz, 2H, CH2OAc), 5.82 (t, J = 6.9 Hz, 1H,
@CH), 7.10, 7.25–7.27, 7.34–7.45, 7.63–7.65 (d, m, m, m, J = 7.8 Hz,
2H, 2H, 6H, 4H, C6H4, C6H5 ꢁ2); 13C NMR (100 MHz, CDCl3): d 19.2,
21.0, 21.1, 26.7, 61.3, 61.5, 123.6, 126.7, 127.7, 128.8, 129.7, 133.3,
4.3.1. (Z)-4-(tert-Butyldiphenylsiloxy)-3-phenylbut-2-en-1-yl
acetate (2aa)
Reaction time: 24 h; Pale yellow oil; 1H NMR (400 MHz, CDCl3):
d 0.97 (s, 9H, (CH3)3C), 2.03 (s, 3H, CH3CO), 4.60 (s, 2H, CH2OSi),
4.65 (d, J = 6.8 Hz, 2H, CH2OAc), 5.84 (t, J = 6.8 Hz, 1H, @CH),
7.25–7.31, 7.34–7.44, 7.62–7.65 (m, m, m, 3H, 8H, 4H, C6H5ꢁ3);
13C NMR (100 MHz, CDCl3): d 19.1, 20.8, 26.6, 61.0, 61.3, 124.2,
126.8, 127.3, 127.6, 128.0, 129.7, 133.1, 135.5, 140.3, 142.8,
135.7, 137.2, 137.5, 142.7, 170.1; HRMS (ESI-TOF): Calcd for C29
H
-
34O3SiNa (M+Na)+: 481.2175, found: 481.2178.
4.3.8. (Z)-4-(tert-Butyldiphenylsiloxy)-3-(4-chlorophenyl)but-2-
en-1-yl acetate 2da
Reaction time: 24 h; Colorless oil; 1H NMR (400 MHz, CDCl3): d
0.96 (s, 9H, (CH3)3C), 2.04 (s, 3H, CH3CO), 4.56 (s, 2H, CH2OSi), 4.59
(d, J = 6.8 Hz, 2H, CH2OAc), 5.81 (t, J = 6.8 Hz, 1H, @CH), 7.24–7.29,
7.35–7.46, 7.60–7.63 (m, m, m, 4H, 6H, 4H, C6H4, C6H5 ꢁ2); 13C
NMR (100 MHz, CDCl3): d 19.2, 20.9, 26.7, 61.0, 61.1, 124.6,
127.7, 128.2, 129.8, 133.1, 133.3, 135.6, 138.8, 141.9, 170.7; HRMS
(ESI-TOF): Calcd for C28H31ClO3SiNa (M+Na)+: 501.1623, found:
501.1608.
170.5; HRMS (ESI-TOF): Calcd for
467.2013, found: 467.2010.
C
28H32O3SiNa (M+Na)+:
4.3.2. (Z)-4-(tert-Butyldimethylsiloxy)-3-phenylbut-2-en-1-yl
acetate 2ab
Reaction time: 24 h; Colorless oil; 1H NMR (400 MHz, CDCl3): d
0.00 (s, 6H, (CH3)2Si) 0.80 (s, 9H, (CH3)3C), 2.04 (s, 3H, CH3CO), 4.54
(s, 2H, CH2OSi), 4.83 (d, J = 6.8 Hz, 2H, CH2OAc), 5.83 (t, J = 6.8 Hz,
1H, @CH), 7.20–7.29, 7.33–7.36 (m, m, 3H, 2H, C6H5); 13C NMR
(100 MHz, CDCl3): d ꢂ5.4, 18.2, 21.0, 25.8, 61.0, 61.3, 124.3,
126.7, 127.5, 128.1, 140.7, 143.2, 171.0; HRMS (ESI-TOF): Calcd
for C18H28O3SiNa (M+Na)+: 343.1700, found: 343.1694.
4.3.9. (Z)-3-(4-Bromophenyl)-4-(tert-butyldiphenylsiloxy)but-2-
en-1-yl acetate 2ea
Reaction time: 24 h; Colorless oil; 1H NMR (400 MHz, CDCl3): d
0.97 (s, 9H, (CH3)3C), 2.04 (s, 3H, CH3CO), 4.59 (s, 2H, CH2OSi), 4.62
(d, J = 6.9 Hz, 2H, CH2OAc), 5.81 (t, J = 6.9 Hz, 1H, @CH), 7.22, 7.35–
4.3.3. (Z)-4-(tert-Butoxydiphenylsiloxy)-3-phenylbut-2-en-1-yl
acetate 2ac
7.46, 7.60–7.62 (d, m, m, J = 8.6 Hz, 2H, 8H, 4H, C6H4, C6H5 ꢁ2); 13
C
NMR (100 MHz, CDCl3): d 19.2, 20.9, 26.7, 61.0, 61.0, 121.5, 124.7,
127.8, 128.6, 129.8, 131.2, 133.1, 135.6, 139.3, 141.9, 170.7; HRMS
(ESI-TOF): Calcd for C28H31BrO3SiNa (M+Na)+: 545.1118, found:
545.1114.
Reaction time: 24 h; Colorless oil; 1H NMR (400 MHz, CDCl3): d
1.26 (s, 9H, (CH3)3C), 2.04 (s, 3H, CH3CO), 4.67 (d, J = 6.9 Hz, 2H, CH2-
OAc), 4.69 (s, 2H, CH2OSi), 5.85 (t, J = 6.9 Hz, 1H, @CH), 7.26–7.32,
7.36–7.40, 7.55–7.58 (m, m, m, 7H, 4H, 4H, C6H5 ꢁ3); 13C NMR
(100 MHz, CDCl3): d 21.0, 31.9, 60.1, 61.1, 74.0, 124.5, 126.8, 127.5,
127.6, 128.2, 129.9, 134.6, 135.0, 140.4, 142.6, 170.8; HRMS (ESI-
TOF): Calcd for C28H32O4SiNa (M+Na)+: 483.1962, found: 483.1963.
4.4. Typical procedure for the preparation of (Z)-4-(tert-
butyldiphenylsiloxy)-3-phenylbut-2-en-1-ol 3aa
To a colorless solution of 907 mg (2.03 mmol) of (Z)-4-(tert-
butyldiphenylsiloxy)-3-phenylbut-2-en-1-yl acetate 2aa in 58 ml
of 1:1 mixture of Et2O–MeOH was added a catalytic amount (3
drops) of 28% MeONa solution in MeOH. The mixture was stirred
at rt for 5 h and quenched with 5 mL of saturated aqueous NH4Cl.
The organic layer was separated and the aqueous layer was
extracted with 10 mL ꢁ2 of AcOEt. The organic layers were com-
bined, washed with 10 mL of brine, and dried over anhydrous
MgSO4. The residue was chromatographed on silica gel with a
5:1 mixture of hexane and AcOEt to afford 821 mg (quantitative
yield) of 3aa.
4.3.4. (Z)-3-Phenyl-4-{tris(trimethylsilyl)siloxy}but-2-en-1-yl
acetate 2ad
Reaction time: 24 h; Colorless oil; 1H NMR (400 MHz, CDCl3): d
0.19 (s, 27H, (CH3)3Si ꢁ3), 2.08 (s, 3H, CH3CO), 4.42 (s, 2H, CH2OSi),
4.86 (d, J = 6.7 Hz, 2H, CH2OAc), 5.82 (t, J = 6.7 Hz, 1H, @CH), 7.23–
7.37 (m, 5H, C6H5); 13C NMR (100 MHz, CDCl3): d 0.3, 21.0, 61.4,
66.2, 124.4, 126.7, 127.4, 128.1, 140.9, 143.2, 170.9; HRMS (ESI-
TOF): Calcd for C21H40O3Si4Na (M+Na)+: 475.1947, found: 475.1951.
4.3.5. (Z)-3-Phenyl-4-(triphenylmethoxy)but-2-en-1-yl acetate
2ae
Reaction time: 90 h; Colorless oil; 1H NMR (400 MHz, CDCl3): d
2.05 (s, 3H, CH3CO), 4.02 (s, 2H, CH2OCPh3), 4.67 (d, J = 6.9 Hz, 2H,
CH2OAc), 5.96 (t, J = 6.9 Hz, 1H, @CH), 7.21–7.33, 7.41–7.44 (m, m,
14H, 6H, C6H5 ꢁ4); 13C NMR (100 MHz, CDCl3): d 21.0, 61.0, 61.4,
87.1, 125.5, 126.7, 127.1, 127.5, 127.8, 128.1, 128.7, 140.5, 141.2,
143.8, 170.8; HRMS (ESI-TOF): Calcd for C31H28O3Na (M+Na)+:
471.1931, found: 471.1919.
4.4.1. (Z)-4-(tert-Butyldiphenylsiloxy)-3-phenylbut-2-en-1-ol
3aa
Colorless oil; 1H NMR (400 MHz, CDCl3): d 0.98 (s, 9H, (CH3)3C),
1.64 (brs, 1H, OH), 4.16 (dd, J = 6.4, 6.4 Hz, 2H, CH2OH), 4.59 (s, 2H,
CH2OSi), 5.97 (t, J = 6.4 Hz, 1H, @CH), 7.23–7.46, 7.64–7.66 (m, m,
11H, 4H, C6H5ꢁ3); 13C NMR (100 MHz, CDCl3): d 19.1, 26.7, 59.3,
61.6, 126.8, 127.3, 127.7, 128.1, 129.7, 129.8, 133.2, 135.7, 140.8,
Please cite this article in press as: Ezawa, T.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2016.12.010

T. Ezawa et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
9
141.3; HRMS (ESI-TOF): Calcd for C26H30O2SiNa (M+Na)+:
425.1907, found: 425.1915.
NMR (100 MHz, CDCl3): d 0.4, 59.2, 67.1, 126.5, 127.3, 128.2, 130.4,
141.6, 142.7; HRMS (ESI-TOF): Calcd for C19H38O2Si4Na (M+Na)+:
433.1841, found: 433.1854.
4.4.2. (Z)-4-(tert-Butyldimethylsiloxy)-3-phenylbut-2-en-1-ol
3ab
4.5.3. (Z)-3-Phenyl-4-(triphenylmethoxy)but-2-en-1-ol 3ae
Colorless oil; 1H NMR (400 MHz, CDCl3): d 1.71 (brs, 1H, OH),
4.03 (s, 2H, CH2OCPh3), 4.16 (dd, J = 5.2, 6.0 Hz, 2H, CH2OH), 6.10
(t, J = 6.8 Hz, 1H, @CH), 7.21–7.34, 7.41–7.44 (m, m, 14H, 6H,
C6H5ꢁ4); 13C NMR (100 MHz, CDCl3): d 59.4, 61.3, 87.2, 126.7,
127.1, 127.4, 127.7, 127.9, 128.1, 128.2, 128.7, 131.0, 139.7,
141.0, 143.7; HRMS (ESI-TOF): Calcd for C29H26O2Na (M+Na)+:
429.1825, found: 429.1830.
Colorless oil; 1H NMR (400 MHz, CDCl3): d 0.08 (s, 6H, (CH3)2Si)
0.88 (s, 9H, (CH3)3C), 2.25 (t, J = 6.2 Hz, 1H, OH), 4.37 (dd, J = 6.2,
6.6 Hz, 2H, CH2OH), 4.59 (s, 2H, CH2OSi), 6.07 (t, J = 6.6 Hz, 1H,
@CH), 7.25–7.39 (m, 5H, C6H5); 13C NMR (100 MHz, CDCl3): d
ꢂ5.3, 18.2, 25.8, 59.3, 61.7, 126.5, 127.3, 128.3, 130.2, 141.4,
142.2; HRMS (ESI-TOF): Calcd for
301.1594, found: 301.1585.
C
16H26O2SiNa (M+Na)+:
4.4.3. (Z)-4-(tert-Butyldiphenylsiloxy)-3-(4-chlorophenyl)but-2-
en-1-ol 3da
4.5.4. (Z)-4-(tert-Butyldiphenylsiloxy)-3-(4-methoxyphenyl)but-
2-en-1-ol 3ba
Colorless oil; 1H NMR (400 MHz, CDCl3): d 0.97 (s, 9H, (CH3)3C),
1.53 (t, J = 6.2 Hz, 1H, OH), 4.11 (dd, J = 6.2, 6.5, 2H, CH2OH), 4.56 (s,
2H, CH2OSi), 5.93 (t, J = 6.5 Hz, 1H, @CH), 7.24–7.29, 7.36–7.47,
7.62–7.64 (m, m, m, 4H, 6H, 4H, C6H4, C6H5ꢁ2); 13C NMR
(100 MHz, CDCl3): d 19.1, 26.7, 59.2, 61.2, 127.8, 128.1, 128.3,
129.9, 130.0, 133.1, 135.7, 139.1, 140.1; HRMS (ESI-TOF): Calcd
for C26H29ClO2SiNa (M+Na)+: 459.1518, found: 459.1526.
Colorless oil; 1H NMR (400 MHz, CDCl3): d 0.99 (s, 9H, (CH3)3C),
1.55–1.58 (m, 1H, OH), 3.82 (s, 3H, CH3O), 4.13 (dd, J = 6.2, 6.7 Hz,
2H, CH2OH), 4.57 (s, 2H, CH2OSi), 5.92 (t, J = 6.7 Hz, 1H, @CH), 6.82,
7.29 (d, d, J = 8.9 Hz, J = 8.9 Hz, 2H, 2H, C6H4), 7.36–7.46, 7.64–7.67
(m, m, 6H, 4H, C6H5ꢁ2); 13C NMR (100 MHz, CDCl3): d 19.2, 26.7,
55.3, 59.3, 61.6, 113.5, 127.7, 127.9, 128.2, 129.8, 133.2, 135.7,
140.7, 159.0; HRMS (ESI-TOF): Calcd for C27H32O3SiNa (M+Na)+:
455.2013, found: 455.2038.
4.4.4. (Z)-3-(4-Bromophenyl)-4-(tert-butyldiphenylsiloxy)but-
2-en-1-ol 3ea
4.5.5. (Z)-4-(tert-Butyldiphenylsiloxy)-3-(4-methylphenyl)but-2-
en-1-ol 3ca
Colorless oil; 1H NMR (400 MHz, CDCl3): d 0.97 (s, 9H, (CH3)3C),
1.50 (brs, 1H, OH), 4.11 (dd, J = 6.3, 6.6 Hz, 2H, CH2OH), 4.55 (s, 2H,
CH2OSi), 5.94 (t, J = 6.6 Hz, 1H, @CH), 7.21, 7.36–7.47, 7.62–7.64 (d,
m, m, J = 8.6 Hz, 2H, 8H, 4H, C6H4, C6H5ꢁ2); 13C NMR (100 MHz,
CDCl3): d 19.2, 26.7, 59.2, 61.1, 121.3, 127.8, 128.5, 129.9, 130.0,
Colorless oil; 1H NMR (400 MHz, CDCl3): d 0.99 (s, 9H, (CH3)3C),
1.63 (brs, 1H, OH), 2.34 (s, 3H, CH3), 4.15 (dd, J = 6.6, 6.6 Hz, 2H,
CH2OH), 4.57 (s, 2H, CH2OSi), 5.96 (t, J = 6.6 Hz, 1H, @CH), 7.09,
7.24 (d, d, J = 8.2 Hz, J = 8.2 Hz, 2H, 2H, C6H4), 7.36–7.46, 7.64–
7.67 (m, m, 6H, 4H, C6H5ꢁ2); 13C NMR (100 MHz, CDCl3): d 19.2,
21.1, 26.7, 59.3, 61.7, 126.6, 127.7, 128.8, 129.0, 129.8, 133.2,
135.7, 137.0, 137.9, 141.1; HRMS (ESI-TOF): Calcd for C27H32O2-
SiNa (M+Na)+: 439.2064, found: 439.2090.
131.2, 133.1, 135.7, 139.6, 140.1; HRMS (ESI-TOF): Calcd for C26
-
H
29BrO2SiNa (M+Na)+: 503.1012, found: 503.1017.
4.5. Typical procedure for the preparation of (Z)-4-(tert-
butoxydiphenylsiloxy)-3-phenylbut-2-en-1-ol 3ac
4.6. Typical procedure for the cyclopropanation of 3aa in the
presence of a catalytic amount of 4
To a colorless solution of 187 mg (0.41 mmol) of (Z)-4-(tert-
butoxydiphenylsiloxy)-3-phenylbut-2-en-1-yl acetate 2ac in 3 mL
of anhydrous THF were added dropwise 0.84 mL (0.86 mmol,
2.1 equiv) of a 1.02 M DIBAL-H solution in hexane under an argon
atmosphere at ꢂ78 °C. The mixture was stirred at ꢂ78 °C for 24 h
and then quenched at ꢂ78 °C with 2 mL of MeOH. To the reaction
mixture was added a solution of 7.20 g of potassium sodium tar-
tarate in 20 mL of water. After stirring at rt for 3 h, the reaction
mixture was extracted with 20 mL ꢁ3 of AcOEt. The AcOEt layers
were combined, washed with brine, and dried over anhydrous
MgSO4. The residue was chromatographed on silica gel with a
5:1 mixture of hexane and AcOEt to afford 170 mg (quantitative
yield) of 3ac.
To a colorless solution of 201 mg (0.50 mmol, 1.0 equiv) of (Z)-
4-(tert-butyldiphenylsiloxy)-3-phenylbut-2-en-1-ol
3aa
and
19 mg (0.05 mmol, 0.1 equiv) of the disulfonamide 4 in 7.5 mL of
anhydrous CH2Cl2 were added dropwise at ꢂ40 °C under an argon
atmosphere 1.0 mL (1.00 mmol, 2.0 equiv) of 1.0 M Et2Zn solution
in hexane and 121 lL (1.50 mmol, 3.0 equiv) of CH2I2. After stirring
at 0 °C for 3 h, the reaction mixture was quenched with 0.3 mL of
Et3N and extracted with 20 mL ꢁ3 of AcOEt. The organic layers
were combined, washed with 5 mL of brine, and dried over MgSO4.
The residue was chromatographed on silica gel with a 8:1 mixture
of hexane and AcOEt to afford 208 mg (quantitative yield) of 5aa.
4.5.1. (Z)-4-(tert-Butoxydiphenylsiloxy)-3-phenylbut-2-en-1-ol
3ac
4.6.1. (2S,3R)-4-(tert-Butyldiphenylsiloxy)-2,3-methano-3-
phenylbutan-1-ol 5aa
Colorless oil; 1H NMR (400 MHz, CDCl3): d 1.27 (s, 9H, (CH3)3C),
1.51 (t, J = 6.3 Hz, 1H, OH), 4.16 (dd, J = 6.3, 6.7 Hz, 2H, CH2OH),
4.69 (s, 2H, CH2OSi), 5.97 (t, J = 6.7 Hz, 1H, @CH), 7.24–7.42,
7.56–7.59 (m, m, 11H, 4H, C6H5ꢁ3); 13C NMR (100 MHz, CDCl3):
d 31.9, 59.2, 60.2, 74.1, 126.7, 127.3, 127.7, 128.2, 129.8, 130.0,
134.6, 135.0, 140.7, 140.8; HRMS (ESI-TOF): Calcd for C26H30O3SiNa
(M+Na)+: 441.1856, found: 441.1872.
Colorless oil; 71% ee; [a]
28 = +51.2 (c 1.02, CHCl3); 1H NMR
D
(400 MHz, CDCl3): d 0.69 (dd, J = 5.3, 5.3 Hz, 1H, CHA of cyclo-
propane), 0.96 (s, 9H, (CH3)3C), 0.96–0.99 (m, 1H, CHB of cyclo-
propane), 1.81–1.89 (m, 1H, CHCH2OH), 3.45–3.59 (m, 2H,
CHAOH, OH), 3.55 (d, J = 11.2 Hz, 1H, CHAOSi), 4.06 (d, J = 11.2 Hz,
1H, CHBOSi), 4.12–4.19 (m, 1H, CHBOH), 7.05–7.07, 7.11–7.15,
7.28–7.45, 7.56–7.59 (m, m, m, m, 2H, 2H, 9H, 2H, C6H5ꢁ3); 13C
NMR (100 MHz, CDCl3): d 16.0, 19.0, 25.8, 26.7, 32.5, 63.7, 69.2,
126.8, 127.5, 127.9, 128.2, 129.5, 129.8, 130.6, 131.7, 132.7,
135.4, 135.5, 143.9; HRMS (ESI-TOF): Calcd for C27H32O2SiNa (M
+Na)+: 439.2064, found: 439.2069. The enantiomeric ratio was
determined by HPLC (Chiralcel OD: hexane/2-propanol = 95/5)
Tr(major) 5.1 min, Tr(minor) 4.3 min (er 85.7:14.3).
4.5.2. (Z)-3-Phenyl-4-{tris(trimethylsilyl)siloxy}but-2-en-1-ol
3ad
Colorless oil; 1H NMR (400 MHz, CDCl3): d 0.21 (s, 27H, (CH3)3Si
ꢁ3), 2.48 (brs, 1H, OH), 4.31 (d, J = 6.8 Hz, 2H, CH2OH), 4.44 (s, 2H,
CH2OSi), 6.08 (t, J = 6.8 Hz, 1H, @CH), 7.24–7.34 (m, 5H, C6H5); 13C
Please cite this article in press as: Ezawa, T.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2016.12.010

10
T. Ezawa et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
4.6.2. (2S,3R)-4-(tert-Butyldimethylsiloxy)-2,3-methano-3-
(CH3)3C), 1.76–1.84 (m, 1H, CHCH2OH), 3.43–3.59 (m, 3H, OH,
CHAOH, CHAOSi), 3.85 (s, 3H, CH3O), 4.03 (d, J = 11.0 Hz, 1H,
CHBOSi), 4.11–4.18 (m, 1H, CHBOH), 6.85, 7.08–7.16, 7.29–7.45,
7.56–7.59 (d, m, m, m, J = 8.8 Hz, 2H, 4H, 6H, 2H, C6H4, C6H5ꢁ2);
13C NMR (100 MHz, CDCl3): d 16.1, 19.0, 26.0, 26.7, 31.7, 55.4,
63.8, 69.4, 113.5, 127.5, 127.8, 129.5, 129.8, 131.6, 131.8, 132.8,
135.4, 135.6, 136.2, 142.3; HRMS (ESI-TOF): Calcd for
phenylbutan-1-ol 5ab
Colorless oil; 48% ee; [a]
25 = +4.0 (c 0.15, MeOH); 1H NMR
D
(400 MHz, CDCl3): d ꢂ0.28 (s, 3H, CH3Si), ꢂ0.16 (s, 3H, CH3Si),
0.74 (dd, J = 5.1, 5.3 Hz, 1H, CHA of cyclopropane), 0.81 (s, 9H,
(CH3)3C), 1.03 (dd, J = 5.1, 8.5 Hz, 1H, CHB of cyclopropane), 1.69–
1.75 (m, 1H, CHCH2OH), 3.37–3.43 (m, 1H, OH), 3.58–3.64 (m,
2H, CHAOSi, CHAOH), 4.06–4.14 (m, 2H, CHBOSi, CHBOH), 7.20–
7.23, 7.26–7.31, 7.36–7.39 (m, m, m, 1H, 2H, 2H, C6H5); 13C NMR
(100 MHz, CDCl3): d ꢂ6.0, -5.9, 16.1, 18.1, 25.7, 25.8, 32.5, 63.7,
68.8, 126.6, 128.0, 130.1, 144.1; HRMS (ESI-TOF): Calcd for
C
28H34O3SiNa (M+Na)+: 469.2169, found: 469.2178. The enan-
tiomeric ratio was determined by HPLC (Chiralcel OD: hexane/
2-propanol = 95/5) Tr(major) 5.2 min, Tr(minor) 4.7 min (er 68:32).
C
17H28O2SiNa (M+Na)+: 315.1751, found: 315.1725. The enan-
4.6.7. (2S,3R)-4-(tert-Butyldiphenylsiloxy)-2,3-methano-3-(4-
tiomeric ratio was determined by HPLC (Chiralcel OD: hexane/2-
propanol = 95/5) Tr(major) 4.6 min, Tr(minor) 4.2 min (er 74:26).
methylphenyl)butan-1-ol 5ca
Colorless oil; 65% ee; [a]
20 = +56.7 (c 1.05, CHCl3); 1H NMR
D
(400 MHz, CDCl3): d 0.66 (dd, J = 5.2, 5.3 Hz, 1H, CHA of cyclo-
propane), 0.93–0.96 (m, 1H, CHB of cyclopropane), 0.97 (s, 9H,
(CH3)3C), 1.78–1.86 (m, 1H, CHCH2OH), 2.40 (s, 3H, CH3), 3.44–
3.60 (m, 3H, OH, CHAOH, CHAOSi), 4.05 (d, J = 11.1 Hz, 1H, CHBOSi),
4.11–4.18 (m, 1H, CHBOH), 7.05–7.13, 7.27–7.45, 7.56–7.59 (m, m,
m, 6H, 6H, 2H, C6H4, C6H5ꢁ2); 13C NMR (100 MHz, CDCl3): d 16.1,
19.0, 21.1, 25.9, 26.7, 32.0, 63.8, 69.3, 127.5, 127.8, 128.8, 129.5,
129.8, 130.4, 131.8, 132.8, 135.4, 135.6, 136.3, 141.0; HRMS (ESI-
4.6.3. (2S,3R)-4-(tert-Butoxydiphenylsiloxy)-2,3-methano-3-
phenylbutan-1-ol 5ac
Colorless oil; 21% ee; [a]
25 = +2.30 (c 0.19, MeOH); 1H NMR
D
(400 MHz, CDCl3): d 0.71 (dd, J = 5.2, 5.4 Hz, 1H, CHA of cyclo-
propane), 1.00 (dd, J = 5.2, 8.6 Hz, 1H, CHB of cyclopropane), 1.13
(s, 9H, (CH3)3C), 1.79–1.86 (m, 1H, CHCH2OH), 3.38–3.44 (m, 2H,
CHAOH, OH), 3.59 (d, J = 11.2 Hz, 1H, CHAOSi), 4.07–4.14 (m, 1H,
CHBOH), 4.28 (d, J = 11.2 Hz, 1H, CHBOSi), 7.19–7.43, 7.50–7.53 (m,
m, 13H, 2H, C6H5 ꢁ3); 13C NMR (100 MHz, CDCl3): d 16.2, 25.9,
31.7, 32.3, 63.6, 68.2, 74.0, 126.7, 127.7, 127.8, 128.2, 129.9, 130.0,
130.2, 133.6, 134.2, 134.7, 144.0; HRMS (ESI-TOF): Calcd for
TOF): Calcd for
C
28H34O2SiNa (M+Na)+: 453.2220, found:
453.2231. The enantiomeric ratio was determined by HPLC (Chiral-
cel OD: hexane/2-propanol = 95/5) Tr(major) 4.5 min, Tr(minor)
4.1 min (er 82.4:17.6).
C
27H32O3SiNa (M+Na)+: 455.2013, found: 455.2033. The enantiomeric
ratio was determined by HPLC (Chiralcel OD: hexane/2-propanol =
4.6.8. (2S,3R)-4-(tert-Butyldiphenylsiloxy)-3-(4-chlorophenyl)-
95/5) Tr(major) 5.4 min, Tr(minor) 4.4 min (er 60.3:39.7).
2,3-methanobutan-1-ol 5da
Colorless oil; 66% ee; [a]
21 = +75.8 (c 1.01, CHCl3); 1H NMR
D
4.6.4. (2S,3R)-2,3-Methano-3-phenyl-4-{tris(trimethylsilyl)
(400 MHz, CDCl3): d 0.70 (dd, J = 5.3, 5.4 Hz, 1H, CHA of cyclo-
propane), 0.93 (dd, J = 5.3, 8.6 Hz, 1H, CHB of cyclopropane), 0.97
(s, 9H, (CH3)3C), 1.76–1.83 (m, 1H, CHCH2OH), 3.45–3.57 (m, 3H,
OH, CHAOH, CHAOSi), 4.02 (d, J = 10.8 Hz, 1H, CHBOSi), 4.11–4.18
(m, 1H, CHBOH), 7.09–7.12, 7.15–7.19, 7.24–7.46, 7.54–7.56 (m,
m, m, m, 2H, 2H, 8H, 2H, C6H4, C6H5ꢁ2); 13C NMR (100 MHz,
CDCl3): d 16.1, 19.0, 26.0, 26.8, 31.9, 63.6, 69.0, 127.6, 127.8,
128.3, 129.7, 129.9, 131.8, 132.6, 135.4, 135.5, 142.3; HRMS
(ESI-TOF): Calcd for C27H31ClO2SiNa (M+Na)+: 473.1674, found:
473.1676. The enantiomeric ratio was determined by HPLC
(Chiralcel OD-H: hexane/2-propanol = 99.9/0.01) after acetylation
Tr(major) 18.0 min, Tr(minor) 14.5 min (er 83:17).
siloxy}butan-1-ol 5ad
Colorless oil; 68% ee; [a]
22 = +35.0 (c 0.98, CHCl3); 1H NMR
D
(400 MHz, CDCl3): d 0.09 (s, 27H, (CH3)3Si ꢁ3), 0.72 (dd, J = 5.2,
5.3 Hz, 1H, CHA of cyclopropane), 1.05 (dd, J = 5.2, 8.5 Hz, 1H, CHB
of cyclopropane), 1.63–1.70 (m, 1H, CHCH2OH), 3.27–3.33 (m, 1H,
OH), 3.52 (d, J = 10.5 Hz, 1H, CHAOSi), 3.65 (dd, J = 1.2, 11.9 Hz,
1H, CHAOH), 3.87 (d, J = 10.5 Hz, 1H, CHBOSi), 4.08 (dt, J = 11.9,
5.2 Hz, 1H, CHBOH), 7.18–7.22, 7.25–7.29, 7.34–7.37 (m, m, m,
1H, 2H, 2H, C6H5); 13C NMR (100 MHz, CDCl3): d 0.1, 16.2, 26.3,
32.9, 63.7, 73.4, 126.6, 128.1, 130.1, 144.3; HRMS (ESI-TOF): Calcd
for C20H40O2Si4Na (M+Na)+: 447.1998, found: 447.1974. The enan-
tiomeric ratio was determined by HPLC (Chiralcel OD: hexane/
2-propanol = 95/5) Tr(major) 3.5 min, Tr(minor) 3.1 min (er 84:16).
4.6.9. (2S,3R)-3-(4-Bromophenyl)-4-(tert-butyldiphenylsiloxy)-
2,3-methanobutan-1-ol 5ea
4.6.5. (2S,3R)-2,3-Methano-3-phenyl-4-(triphenylmethoxy)butan-
Colorless oil; 73% ee; [a]
22 = +82.6 (c 1.00, CHCl3); 1H NMR
D
1-ol 5ae
(400 MHz, CDCl3): d 0.70 (dd, J = 5.2, 5.2 Hz, 1H, CHA of cyclo-
propane), 0.93 (dd, J = 5.2, 8.6 Hz, 1H, CHB of cyclopropane), 0.97
(s, 9H, (CH3)3C), 1.77–1.81 (m, 1H, CHCH2OH), 3.45–3.57 (m, 3H,
OH, CHAOH, CHAOSi), 4.02 (d, J = 11.2 Hz, 1H, CHBOSi), 4.11–4.18
(m, 1H, CHBOH), 7.09–7.11, 7.16–7.24, 7.32–7.45, 7.54–7.56 (m,
m, m, m, 2H, 4H, 6H, 2H, C6H4, C6H5ꢁ2); 13C NMR (100 MHz,
CDCl3): d 16.1, 19.0, 25.9, 26.8, 32.0, 63.5, 68.9, 120.7, 127.6,
127.9, 129.7, 129.9, 131.2, 131.6, 132.2, 132.6, 135.4, 135.5,
Colorless oil; 19% ee; [a]
25 = +16.0 (c 0.17, MeOH); 1H NMR
D
(400 MHz, CDCl3): d 0.50 (dd, J = 5.1, 5.3 Hz, 1H, CHA of cyclo-
propane), 0.94 (dd, J = 5.1, 8.6 Hz, 1H, CHB of cyclopropane),
1.81–1.88 (m, 1H, CHCH2OH), 2.49 (d, J = 10.0 Hz, 1H, CHAOC),
2.81–2.88 (m, 1H, OH), 3.45 (dd, J = 1.7 11.9 Hz, 1H, CHAOH), 3.85
(d, J = 10.0 Hz, 1H, CHBOC), 3.91 (dt, J = 11.9, 5.0 Hz, 1H, CHBOH),
7.17–7.22 (m, 15H, C6H5 ꢁ3), 7.35–7.39, 7.43–7.47, 7.60–7.62 (m,
m, m, 1H, 2H, 2H, C6H5); 13C NMR (100 MHz, CDCl3): d 16.2, 25.4,
30.7, 63.1, 69.5, 87.1, 127.0, 128.0, 128.2, 128.4, 130.6, 143.4,
143.0; HRMS (ESI-TOF): Calcd for
C
27H31BrO2SiNa (M+Na)+:
517.1169, found: 517.1159. The enantiomeric ratio was deter-
mined by HPLC (Chiralcel OD: hexane/2-propanol = 99/1) Tr(major)
9.0 min, Tr(minor) 8.2 min (er 86.6:13.4).
144.3; HRMS (ESI-TOF): Calcd for
C
30H28O2Na (M+Na)+:
443.1982, found: 443.1961. The enantiomeric ratio was deter-
mined by HPLC (Chiralcel OD: hexane/2-propanol = 95/5) Tr(major)
6.2 min, Tr(minor) 5.6 min (er 59.6:40.4).
4.7. Typical procedure for the oxidation of alcohol 5aa into
aldehyde 6aa
4.6.6. (2S,3R)-4-(tert-Butyldiphenylsiloxy)-2,3-methano-3-(4-
methoxyphenyl)butan-1-ol 5ba
To a solution of 204 mg (0.46 mmol, 1.0 equiv) of (2S,3R)-4-
(tert-butyldiphenylsiloxy)-2,3-methano-3-phenylbutan-1-ol 5aa
in 5 mL of dimethylsulfoxide (DMSO) were added 320 mg
(1.14 mmol, 2.5 equiv) of 2-iodoxybenzoic acid (IBX) at rt. After
Colorless oil; 36% ee; [a]
23 = +34.8 (c 1.01, CHCl3); 1H NMR
D
(400 MHz, CDCl3): d 0.65 (dd, J = 5.2, 5.3 Hz, 1H, CHA of cyclo-
propane), 0.91–0.94 (m, 1H, CHB of cyclopropane), 0.97 (s, 9H,
Please cite this article in press as: Ezawa, T.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2016.12.010

T. Ezawa et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
11
stirring at rt for 3 h, 10 mL of AcOEt were added to the reaction
mixture. The suspension was filtered through Celite. The filtrate
was combined with 10 mL of half brine and extracted with 10 mL
ꢁ3 of AcOEt. The AcOEt layers were combined, washed with brine,
and dried over anhydrous MgSO4. The residue was chro-
matographed on silica gel with a 8:1 mixture of hexane and AcOEt
to afford 191 mg (94% yield) of 6aa.
(dd, J = 5.0, 8.2 Hz, 1H, CHA of cyclopropane), 1.77 (dd, J = 5.0,
5.2 Hz, 1H, CHB of cyclopropane), 2.25 (dt, J = 8.1, 5.2 Hz, 1H,
CHCHO), 3.75 (d, J = 11.1 Hz, 1H, CHAOSi), 4.00 (d, J = 11.1 Hz, 1H,
CHBOSi), 7.21–7.50 (m, 14H, C6H4, C6H5ꢁ2), 9.61 (d, J = 5.2 Hz,
1H, CHO); 13C NMR (100 MHz, CDCl3): d 18.5, 19.1, 26.7, 34.1,
40.5, 66.3, 121.4, 127.6, 127.7, 129.6, 129.8, 131.4, 132.7, 132.8,
135.4, 135.5, 141.1, 199.5; HRMS (ESI-TOF): Calcd for
C
27H29BrO2SiNa (M+Na)+: 515.1012, found: 515.1010.
4.7.1. (2S,3R)-4-(tert-Butyldiphenylsiloxy)-2,3-methano-3-
phenylbutanal 6aa
4.8. Typical procedure for the oxidation of the aldehyde 6aa into
carboxylic acid 7aa
Colorless oil; 71% ee derived from 5aa; [a]
28 = +57.4 (c 1.00,
D
CHCl3); 1H NMR (400 MHz, CDCl3): d 0.96 (s, 9H, (CH3)3C), 1.49
(dd, J = 4.9, 8.1 Hz, 1H, CHA of cyclopropane), 1.79 (dd, J = 4.9,
5.3 Hz, 1H, CHB of cyclopropane), 2.30 (dt, J = 8.1, 5.3 Hz 1H,
CHCHO), 3.76 (d, J = 11.0 Hz, 1H, CHAOSi), 4.04 (d, J = 11.0 Hz, 1H,
CHBOSi), 7.19–7.43, 7.49–7.52 (m, m, 13H, 2H, C6H5 ꢁ3), 9.63 (d,
J = 5.3 Hz, 1H, CHO); 13C NMR (100 MHz, CDCl3): d 18.6, 19.1,
26.6, 34.3, 41.1, 66.5, 127.4, 127.5, 127.7, 128.4, 129.5, 129.7,
129.8, 132.8, 132.9, 135.4, 135.5, 142.0, 200.1; HRMS (ESI-TOF):
Calcd for C27H30O2SiNa (M+Na)+: 437.1907, found: 437.1900.
To a colorless solution of 187 mg (0.45 mmol, 1.0 equiv) of
(2S,3R)-4-(tert-butyldiphenylsiloxy)-2,3-methano-3-phenylbu-
tanal 6aa and 16 mg (0.14 mmol, 0.3 equiv) of NaH2PO4 in 5.5 mL
of
a 10:1 mixture of MeCN and water were added 61 lL
(0.54 mmol, 1.2 equiv) of 35% aq H2O2 solution and a solution of
76 mg (0.68 mmol, 1.5 equiv) of NaClO2 in 2 mL of water at 0 °C.
After stirring at rt for 3 h, 1 mL of sat. aq. Na2SO3 solution was
added to the reaction mixture. The resulted mixture was adjusted
to pH 3 with 1.0 M aq HCl solution and extracted with 10 mL ꢁ3 of
AcOEt. The combined AcOEt layers were washed with brine and
dried over anhydrous MgSO4. The residue was chromatographed
on silica gel with a 5:1 mixture of hexane and AcOEt to afford
190 mg (98% yield) of 7aa.
4.7.2. (2S,3R)-4-(tert-Butyldiphenylsiloxy)-2,3-methano-3-(4-
methoxyphenyl)butanal 6ba
Colorless oil; 36% ee derived from 5ba; [a]
20 = +29.4 (c 1.00,
D
CHCl3); 1H NMR (400 MHz, CDCl3): d 0.97 (s, 9H, (CH3)3C), 1.46
(dd, J = 4.8, 8.1 Hz, 1H, CHA of cyclopropane), 1.76 (dd, J = 4.8,
5.3 Hz, 1H, CHB of cyclopropane), 2.24 (dt, J = 8.1, 5.3 Hz, 1H,
CHCHO), 3.73 (d, J = 11.0 Hz, 1H, CHAOSi), 3.83 (s, 3H, CH3O), 4.02
(d, J = 11.0 Hz, 1H, CHBOSi), 6.85, 7.20–7.43, 7.50–7.52 (d, m, m,
J = 8.8 Hz, 2H, 10H, 2H, C6H4, C6H5ꢁ2), 9.61 (d, J = 5.3 Hz, 1H,
CHO); 13C NMR (100 MHz, CDCl3): d 18.8, 19.1, 26.7, 34.7, 40.4,
55.4, 66.7, 113.7, 127.5, 127.7, 129.5, 129.7, 130.8, 132.9, 133.0,
134.3, 135.5, 135.5, 158.9, 200.2; HRMS (ESI-TOF): Calcd for
4.8.1. (2S,3R)-4-(tert-Butyldiphenylsiloxy)-2,3-methano-3-
phenylbutanoic acid 7aa
Colorless solid; 71% ee derived from 5aa; [a]
28 = +57.4 (c 1.00,
D
CHCl3); mp 143–145 °C; 1H NMR (400 MHz, CDCl3): d 0.92 (s,
9H, (CH3)3C), 1.38 (dd, J = 4.8, 8.0 Hz, 1H, CHA of cyclopropane),
1.55 (dd, J = 4.8, 5.7 Hz, 1H, CHB of cyclopropane), 2.18 (dd,
J = 5.7, 8.0 Hz, 1H, CHCO2H), 3.98 (s, 2H, CH2OSi), 7.15–7.23,
7.28–7.38, 7.43–7.46, 7.50–7.52 (m, m, m, m, 4H, 7H, 2H, 2H,
C6H5ꢁ3), 11.59 (brs, 1H, CO2H); 13C NMR (100 MHz, CDCl3): d
19.2, 24.5, 26.5, 39.6, 66.4, 127.2, 127.4, 127.6, 128.2, 129.3,
129.5, 130.1, 133.2, 133.4, 135.4, 135.5, 142.7, 178.2; HRMS
(ESI-TOF): Calcd for C27H30O3SiNa (M+Na)+: 453.1856, found:
453.1852.
C
28H32O3SiNa (M+Na)+: 467.2013, found: 467.2010.
4.7.3. (2S,3R)-4-(tert-Butyldiphenylsiloxy)-2,3-methano-3-(4-
methylphenyl)butanal 6ca
Colorless oil; 65% ee derived from 5ca; [a]
20 = +53.2 (c 1.13,
D
CHCl3); 1H NMR (400 MHz, CDCl3): d 0.97 (s, 9H, (CH3)3C), 1.46
(dd, J = 4.8, 8.1 Hz, 1H, CHA of cyclopropane), 1.78 (dd, J = 4.8,
5.3 Hz, 1H, CHB of cyclopropane), 2.26 (dt, J = 8.1, 5.4 Hz, 1H,
CHCHO), 2.37 (s, 3H, CH3), 3.75 (d, J = 11.0 Hz, 1H, CHAOSi), 4.04
(d, J = 11.0 Hz, 1H, CHBOSi), 7.12–7.14, 7.19–7.42, 7.50–7.52 (m,
m, m, 2H, 10H, 2H, C6H4, C6H5 ꢁ2), 9.61 (d, J = 5.4 Hz, 1H, CHO);
13C NMR (100 MHz, CDCl3): d 18.7, 19.1, 21.1, 26.7, 34.5, 40.8,
66.6, 127.5, 127.7, 129.0, 129.5, 129.6, 129.7, 132.9, 133.0, 135.5,
135.5, 137.1 139.1, 200.2; HRMS (ESI-TOF): Calcd for C28H32O2SiNa
(M+Na)+: 451.2064, found: 451.2087.
4.8.2. (2S,3R)-4-(tert-Butyldiphenylsiloxy)-2,3-methano-3-(4-
methoxyphenyl)butanoic acid 7ba
Colorless solid; 36% ee derived from 5ba; [a]
20 = +38.0 (c 1.00,
D
CHCl3); mp 93–94 °C; 1H NMR (400 MHz, CDCl3): d 0.94 (s, 9H,
(CH3)3C), 1,32–1.36 (m, 1H, CHA of cyclopropane), 1.52 (dd,
J = 4.9, 5.6 Hz, 1H, CHB of cyclopropane), 2.11–2.16 (m, 1H,
CHCO2H), 3.84 (s, 3H, CH3O), 3.95 (s, 2H, CH2OSi), 6.86, 7.17–
7.39, 7.50–7.52 (d, m, m, J = 8.7 Hz, 2H, 10H, 2H, C6H4, C6H5ꢁ2),
9.55 (brs, 1H, CO2H); 13C NMR (100 MHz, CDCl3): d 19.2, 19.4,
24.6, 26.6, 38.8, 55.4, 66.5, 113.5, 127.4, 127.5, 129.3, 129.5,
131.1, 133.2, 133.4, 134.9, 135.5, 135.5, 158.8, 177.1; HRMS
(ESI-TOF): Calcd for C28H32O4SiNa (M+Na)+: 483.1962, found:
483.1978.
4.7.4. (2S,3R)-4-(tert-Butyldiphenylsiloxy)-3-(4-chlorophenyl)-
2,3-methanobutanal 6da
Colorless oil; 66% ee derived from 5da; [a]D
20 = +69.9 (c 1.00,
CHCl3); 1H NMR (400 MHz, CDCl3): d 0.96 (s, 9H, (CH3)3C), 1.44 (dd,
J = 5.0, 8.2 Hz, 1H, CHA of cyclopropane), 1.77 (dd, J = 5.0, 5.2 Hz,
1H, CHB of cyclopropane), 2.25 (dt, J = 8.2, 5.2 Hz, 1H, CHCHO), 3.75
(d, J = 11.1 Hz, 1H, CHAOSi), 4.00 (d, J = 11.1 Hz, 1H, CHBOSi), 7.21–
7.43, 7.48–7.50 (m, m, 12H, 2H, C6H4, C6H5 ꢁ2), 9.61 (d, J = 5.2 Hz,
1H, CHO); 13C NMR (100 MHz, CDCl3): d 18.6, 19.1, 26.7, 34.2, 40.4,
66.3, 127.6, 127.7, 128.5, 129.6, 129.8, 131.1, 132.7, 132.8, 133.3,
135.4, 135.5, 140.5, 199.6; HRMS (ESI-TOF): Calcd for
4.8.3. (2S,3R)-4-(tert-Butyldiphenylsiloxy)-2,3-methano-3-(4-
methylphenyl)butanoic acid 7ca
Colorless solid; 65% ee derived from 5ca; [a]
25 = +69.3 (c 0.96,
D
CHCl3); mp 124–127 °C; 1H NMR (400 MHz, CDCl3): d 0.92 (s, 9H,
(CH3)3C), 1,32–1.37 (m, 1H, CHA of cyclopropane), 1.53 (dd,
J = 4.8, 5.7, 1H, CHB of cyclopropane), 2.12–2.18 (m, 1H, CHCO2H),
2.39 (s, 3H, CH3), 3.97 (s, 2H, CH2OSi), 7.13–7.38, 7.49–7.53 (m,
m, 12H, 2H, C6H4, C6H5ꢁ2), 11.80 (brs, 1H, CO2H); 13C NMR
(100 MHz, CDCl3): d 19.2, 19.4, 21.1, 24.7, 26.5, 39.2, 66.5, 127.4,
127.5, 128.8, 129.2, 129.4, 129.9, 133.2, 133.4, 135.5, 135.5,
136.8, 139.7, 178.3; HRMS (ESI-TOF): Calcd for C28H32O3SiNa
(M+Na)+: 467.2013, found: 467.2036.
C
27H29ClO2SiNa (M+Na)+: 471.1518, found: 471.1496.
4.7.5. (2S,3R)-3-(4-Bromophenyl)-4-(tert-butyldiphenylsiloxy)-
2,3-methanobutanal 6ea
Colorless oil; 73% ee derived from 5ea; [
a]
19 = +77.5 (c 1.15,
D
CHCl3); 1H NMR (400 MHz, CDCl3): d 0.96 (s, 9H, (CH3)3C), 1.44
Please cite this article in press as: Ezawa, T.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2016.12.010

12
T. Ezawa et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
4.8.4. (2S,3R)-4-(tert-Butyldiphenylsiloxy)-3-(4-chlorophenyl)-
(s, 3H, CH3O), 3.85 (d, J = 10.5 Hz, 1H, CHAOSi), 4.02 (d,
J = 10.5 Hz, 1H, CHBOSi), 5.49 (brs, 1H, NH), 6.83, 7.18–7.21, 7.25–
7.38, 7.48–7.50 (d, m, m, m, J = 8.7 Hz, 2H, 2H, 8H, 2H, C6H4,
C6H5ꢁ2); 13C NMR (100 MHz, CDCl3): d 16.2, 19.2, 26.9, 28.6,
29.5, 36.1, 36.4, 41.8, 52.1, 55.4, 66.1, 113.4, 127.3, 127.4, 129.2,
129.3, 131.1, 133.5, 133.8, 135.6, 135.6, 135.9, 158.5, 169.2; HRMS
(ESI-TOF): Calcd for C38H47NO3SiNa (M+Na)+: 616.3217, found:
616.3202.
2,3-methanobutanoic acid 7da
Colorless solid; 66% ee derived from 5da; [a]
18 = +87.8 (c 1.00,
D
CHCl3); mp 42–44 °C; 1H NMR (400 MHz, CDCl3): d 0.92 (s, 9H,
(CH3)3C), 1,35 (dd, J = 4.8, 8.0 Hz, 1H, CHA of cyclopropane), 1.54
(dd, J = 4.8, 5.9 Hz, 1H, CHB of cyclopropane), 2.11 (dd, J = 5.9,
8.0 Hz, 1H, CHCO2H), 3.93 (d, J = 10.7 Hz, 1H, CHAOSi), 3.97 (d,
J = 10.7 Hz, 1H, CHBOSi), 7.18–7.39, 7.47–7.49 (m, m, 12H, 2H,
C6H4, C6H5 ꢁ2), 11.06 (brs, 1H, CO2H); 13C NMR (100 MHz, CDCl3):
d 19.2, 24.5, 26.6, 38.7, 66.2, 127.5, 127.6, 128.3, 129.4, 129.6,
131.3, 133.0, 133.1, 133.2, 135.4, 135.5, 141.1, 177.0; HRMS (ESI-
4.9.3. (2S,3R)-N-Adamant-1-yl-4-(tert-butyldiphenylsiloxy)-2,3-
methano-3-(4-methylphenyl)butanamide 8ca
TOF): Calcd for
487.1465.
C
27H29ClO3SiNa (M+Na)+: 487.1467, found:
Colorless sticky oil; 65% ee derived from 5ca; [a]
22 = +37.9 (c
D
1.00, CHCl3); 1H NMR (400 MHz, CDCl3): d 0.93 (s, 9H, (CH3)3C),
1.10 (dd, J = 4.7, 8.1 Hz, 1H, CHA of cyclopropane), 1.41 (dd,
J = 4.7, 5.7 Hz, 1H, CHB of cyclopropane), 1.64–1.68 (m, 6H,
CH2ꢁ3 of adamantane), 1.79 (dd, J = 5.7, 8.1 Hz, 1H, CHCO),
2.01–2.08 (m, 9H, CH2ꢁ3 of adamantane, CH ꢁ3 of adamantane),
2.38 (s, 3H, CH3), 3.87 (d, J = 10.5 Hz, 1H, CHAOSi), 4.04 (d,
J = 10.5 Hz, 1H, CHBOSi), 5.50 (brs, 1H, NH), 7.10–7.12, 7.16–
7.20, 7.23–7.38, 7.46–7.49 (m, m, m, m, 2H, 2H, 8H, 2H, C6H4,
C6H5ꢁ2); 13C NMR (100 MHz, CDCl3): d 16.2, 19.2, 21.1, 26.9,
28.4, 29.5, 36.3, 36.4, 41.8, 52.1, 66.1, 127.3, 127.4, 128.7, 129.2,
129.3, 130.0, 133.5, 133.8, 135.6, 135.6, 136.3, 140.6, 169.2; HRMS
4.8.5. (2S,3R)-3-(4-Bromophenyl)-4-(tert-butyldiphenylsiloxy)-
2,3-methanobutanoic acid 7ea
Colorless sticky oil; 73% ee derived from 5ea; [a]
22 = +77.9 (c
D
1.05, CHCl3); 1H NMR (400 MHz, CDCl3): d 0.92 (s, 9H, (CH3)3C),
1,34 (dd, J = 4.9, 8.0 Hz, 1H, CHA of cyclopropane), 1.55 (dd,
J = 4.9, 5.9 Hz, 1H, CHB of cyclopropane), 2.11 (dd, J = 5.9, 8.0 Hz,
1H, CHCO2H), 3.94 (d, J = 10.7 Hz, 1H, CHAOSi), 3.98 (d,
J = 10.7 Hz, 1H, CHBOSi), 7.19–7.50 (m, 14H, C6H4, C6H5ꢁ2), 11.71
(brs, 1H, CO2H); 13C NMR (100 MHz, CDCl3): d 19.2, 24.5, 26.6,
38.9, 66.2, 121.2, 127.5, 127.6, 129.4, 129.6, 131.3, 131.7, 133.0,
133.2, 135.4, 135.5, 141.6, 177.8; HRMS (ESI-TOF): Calcd for
(ESI-TOF): Calcd for
578.3462.
C
38H48NO2Si (M+H)+: 578.3449, found:
C
27H30BrO3Si (M+H)+: 509.1142, found: 509.1157.
4.9. Typical procedure for the amidation of 7aa with 1-
adamantanamine sulfate
4.9.4. (2S,3R)-N-Adamant-1-yl-4-(tert-butyldiphenylsiloxy)-3-
(4-chlorophenyl)-2,3-methanobutanamide 8da
Colorless solid; 66% ee from 5da; [a]
17 = +57.6 (c 1.00, CHCl3);
D
mp 88–89 °C; 1H NMR (400 MHz, CDCl3): d 0.94 (s, 9H, (CH3)3C),
1.09 (dd, J = 4.7, 8.1 Hz, 1H, CHA of cyclopropane), 1.43 (dd,
J = 4.7, 5.7 Hz, 1H, CHB of cyclopropane), 1.64–1.68 (m, 6H,
CH2ꢁ3 of adamantane), 1.76 (dd, J = 5.7, 8.1 Hz, 1H, CHCO), 2.01–
2.08 (m, 9H, CH2ꢁ3 of adamantane, CH ꢁ3 of adamantane), 3.86
(d, J = 10.6 Hz, 1H, CHAOSi), 4.05 (d, J = 10.6 Hz, 1H, CHBOSi), 5.49
(brs, 1H, NH), 7.19–7.39, 7.45–7.48 (m, m, 12H, 2H, C6H4,
C6H5ꢁ2); 13C NMR (100 MHz, CDCl3): d 16.2, 19.2, 26.9, 28.3,
29.5, 36.2, 36.4, 41.8, 52.2, 65.7, 127.4, 127.5, 128.1, 129.4, 129.4,
131.4, 132.5, 133.3, 133.5, 135.5, 135.5, 142.1, 168.8; HRMS (ESI-
To a solution of 124 mg (0.29 mmol, 1.0 equiv) of (2S,3R)-4-(tert-
butyldiphenylsiloxy)-2,3-methano-3-phenylbutanoic acid 7aa in
6 mL of acetone were added dropwise 30
lL (0.32 mmol, 1.1 equiv)
of ClCO2Et and 44 L (0.32 mmol, 1.1 equiv) of Et3N at 0 °C. After
l
stirring at 0 °C for 30 min, 63 mg (0.32 mmol, 1.1 equiv) of 1-
adamantanamine sulfate and 0.58 mL (0.58 mmol, 2.0 equiv) of
1.0 M aq. NaOH solution were added at 0 °C to the colorless suspen-
sion. The mixture was stirred at 0 °C for 24 h, diluted with 30 mL of
AcOEt, washed with 5 mL of brine, and dried over anhydrous
MgSO4. The residue was chromatographed on silica gel with a 6:1
mixture of hexane and AcOEt to afford 143 mg (88% yield) of 8aa.
TOF): Calcd for
620.2724.
C
37H44ClNO2SiNa (M+Na)+: 620.2722, found:
4.9.1. (2S,3R)-N-Adamant-1-yl-4-(tert-butyldiphenylsiloxy)-2,3-
methano-3-phenylbutanamide 8aa
4.9.5. (2S,3R)-N-Adamant-1-yl-3-(4-bromophenyl)-4-(tert-
Colorless oil; 82% ee; [a]
28 = +43.4 (c 1.00, CHCl3); 1H NMR
D
butyldiphenylsiloxy)-2,3-methanobutanamide 8ea
(400 MHz, CDCl3): d 0.92 (s, 9H, (CH3)3C), 1.14 (dd, J = 4.7, 8.1 Hz,
1H, CHA of cyclopropane), 1.43 (dd, J = 4.7, 5.7 Hz, 1H, CHB of cyclo-
propane), 1.65–1.68 (m, 6H, CH2ꢁ3 of adamantane), 1.82 (dd,
J = 5.7, 8.1 Hz, 1H, CHCO), 1.98–2.08 (m, 9H, CH2ꢁ3, CH ꢁ3 of
adamantane), 3.89 (d, J = 10.5 Hz, 1H, CHAO), 4.05 (d, J = 10.5 Hz,
1H, CHBO), 5.51 (brs, 1H, NH), 7.16–7.50 (m, 15H, C6H5 ꢁ3); 13C
NMR (100 MHz, CDCl3): d 16.1, 19.2, 26.8, 28.3, 29.5, 36.4, 36.8,
41.8, 52.1, 65.9, 126.8, 127.3, 127.5, 127.7, 128.0, 129.2, 129.3,
130.1, 133.4, 133.7, 135.6, 143.6, 169.2; HRMS (ESI-TOF): Calcd
for C37H45NO2SiNa (M+Na)+: 586.3112, found: 586.3122. The enan-
tiomeric ratio was determined by HPLC (Chiralcel OD-H: hexane/
iPrOH = 90/10) Tr(major) 8.0 min, Tr(minor) 4.2 min (er 91:9).
Colorless solid; 73% ee derived from 5ea; [a]
19 = +66.7 (c 1.20,
D
CHCl3); mp 79–81 °C; 1H NMR (400 MHz, CDCl3): d 0.94 (s, 9H,
(CH3)3C), 1.08 (dd, J = 4.7, 8.1 Hz, 1H, CHA of cyclopropane), 1.43
(dd, J = 4.7, 5.7 Hz, 1H, CHB of cyclopropane), 1.64–1.70 (m, 6H,
CH2ꢁ3 of adamantane), 1.75 (dd, J = 5.7, 8.1 Hz, 1H, CHCO), 2.02–
2.08 (m, 9H, CH2ꢁ3 of adamantane, CH ꢁ3 of adamantane), 3.85
(d, J = 10.6 Hz, 1H, CHAOSi), 4.06 (d, J = 10.6 Hz, 1H, CHBOSi), 5.49
(brs, 1H, NH), 7.18–7.48 (m, 14H, C6H4, C6H5ꢁ2); 13C NMR
(100 MHz, CDCl3): d 16.1, 19.2, 26.9, 28.2, 29.5, 36.3, 36.4, 41.8,
52.2, 65.7, 120.6, 127.4, 127.5, 129.4, 129.4, 131.1, 131.8, 133.3,
133.5, 135.5, 135.5, 142.6, 168.8; HRMS (ESI-TOF): Calcd for
C
37H45BrNO2Si (M+H)+: 642.2397, found: 642.2396.
4.9.2. (2S,3R)-N-Adamant-1-yl-4-(tert-butyldiphenylsiloxy)-2,3-
4.9.6. (2S,3R)-4-(tert-Butyldiphenylsiloxy)-N-(3,5-
methano-3-(4-methoxyphenyl)butanamide 8ba
Colorless solid; 36% ee derived from 5ba; [a]
19 = +24.2 (c 1.01,
D
dimethyladamant-1-yl)-2,3-methano-3-phenylbutanamide 12
21 = +39.5 (c 1.00, CHCl3);
CHCl3); mp 147–149 °C; 1H NMR (400 MHz, CDCl3): d 0.93 (s, 9H,
(CH3)3C), 1.09 (dd, J = 4.6, 8.1 Hz, 1H, CHA of cyclopropane), 1.39
(dd, J = 4.6, 5.7 Hz, 1H, CHB of cyclopropane), 1.64–1.68 (m, 6H,
CH2ꢁ3 of adamantane), 1.77 (dd, J = 5.7, 8.1 Hz, 1H, CHCO), 2.01–
2.07 (m, 9H, CH2ꢁ3 of adamantane, CH ꢁ3 of adamantane), 3.83
Colorless solid; 72% ee from 5aa; [
a]
D
mp 116–118 °C; 1H NMR (400 MHz, CDCl3):
d
0.81 (s, 6H,
CH3ꢁ2), 0.91 (s, 9H, (CH3)3C), 1.10–1.18 (m, 3H, CH2 of adaman-
tane, CHA of cyclopropane), 1.26–1.38 (m, 4H, CH2ꢁ2 of adaman-
tane), 1.41–1.43 (m, 1H, CHB of cyclopropane), 1.63–1.76 (m, 4H,
Please cite this article in press as: Ezawa, T.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2016.12.010

T. Ezawa et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
13
CH2ꢁ2 of adamantane), 1.80–1.91 (m, 3H, CH2 of adamantane, CH
of adamantane), 2.11–2.14 (m, 1H, CHCO), 3.89 (d, J = 10.5 Hz, 1H,
CHAOSi), 4.04 (d, J = 10.5 Hz, 1H, CHBOSi), 5.56 (brs, 1H, NH), 7.15–
7.23, 7.27–7.38, 7.48–7.50 (m, m, m, 4H, 9H, 2H, C6H5 ꢁ3); 13C
NMR (100 MHz, CDCl3): d 16.0, 19.2, 26.9, 28.2, 30.1, 30.2, 32.4,
36.9, 40.4, 42.7, 42.7, 47.6, 47.8, 50.6, 53.7, 66.0, 126.8, 127.3,
127.5, 128.1, 129.2, 129.3, 130.2, 133.4, 133.7, 135.6, 143.6,
found: 362.2091. The enantiomeric ratio was determined by HPLC
(Chiralcel OD: hexane/2-propanol = 95/5) Tr(major) 10.7 min,
Tr(minor) 9.3 min (er 79:21).
4.10.4. (2S,3R)-N-Adamant-1-yl-3-(4-chlorophenyl)-4-hydroxy-
2,3-methanobutanamide 9d
Colorless solid; 73% ee; [a]
17 = +92.9 (c 1.00, CHCl3); mp 132–
D
169.2; HRMS (ESI-TOF): Calcd for
614.3425, found: 614.3445.
C
39H49NO2SiNa (M+Na)+:
134 °C; 1H NMR (400 MHz, CDCl3): d 1.28–1.32 (m, 1H, CHA of
cyclopropane), 1.67–1.72 (m, 8H, CHA of cyclopropane, CHCO,
CH2ꢁ3 of adamantane), 2.01–2.05 (m, 6H, CH2ꢁ3 of adamantane),
2.07–2.13 (m, 3H, CH ꢁ3 of adamantane), 3.72–3.82 (m, 2H,
CHAOH, OH), 4.11 (dd, J = 6.0, 11.7 Hz, 1H, CHBOH), 5.55 (brs, 1H,
NH), 7.28 (s, 4H, C6H4); 13C NMR (100 MHz, CDCl3): d 16.9, 29.4,
29.5, 36.1, 36.3, 41.6, 52.6, 65.5, 128.6, 129.8, 132.7, 141.8, 171.1;
HRMS (ESI-TOF): Calcd for C21H26ClNO2Na (M+Na)+: 382.1544,
found: 382.1533. The enantiomeric ratio was determined by HPLC
(Chiralcel OD: hexane/2-propanol = 95/5) Tr(major) 11.5 min,
Tr(minor) 9.2 min (er 86.6:13.4).
4.10. Typical procedure for the desilylation of 8aa with TBAF
To a solution of 275 mg (0.49 mmol, 1.0 equiv) of (2S,3R)-
N-adamant-1-yl-4-(tert-butyldiphenylsiloxy)-2,3-methano-3-
phenylbutanamide 8aa in 5 mL of THF were added 980 lL
(0.98 mmol, 2.0 equiv) of a 1.0 M TBAF solution in THF at rt. After
stirring at rt for 3 h, the colorless solution was diluted with
30 mL of AcOEt, washed with 5 mL of half brine, 5 mL of brine,
and dried over anhydrous MgSO4. The residue was chro-
matographed on silica gel with a 2:1 mixture of hexane and AcOEt
to afford 147 mg (93% yield) of 9a.
4.10.5. (2S,3R)-N-Adamant-1-yl-3-(4-bromophenyl)-4-hydroxy-
2,3-methanobutanamide 9e
Colorless solid; 73% ee; [a]
23 = +98.5 (c 1.00, CHCl3); mp 159–
D
4.10.1. (2S,3R)-N-Adamant-1-yl-4-hydroxy-2,3-methano-3-
161 °C; 1H NMR (400 MHz, CDCl3): d 1.27–1.32 (m, 1H, CHA of
cyclopropane), 1.64–1.69 (m, 2H, CHA of cyclopropane, CHCO),
1.67–1.72 (m, 6H, CH2ꢁ3 of adamantane), 2.01–2.07 (m, 6H,
CH2ꢁ3 of adamantane), 2.05–2.13 (m, 3H, CH ꢁ3 of adamantane),
3.71–3.82 (m, 2H, CHAOH, OH), 4.11 (dd, J = 5.9, 11.7 Hz, 1H,
CHBOH), 5.55 (brs, 1H, NH), 7.22, 7.43 (d, d, J = 8.5 Hz, J = 8.5 Hz,
2H, 2H, C6H4); 13C NMR (100 MHz, CDCl3): d 16.9, 29.4, 36.1,
36.3, 41.6, 52.6, 65.5, 120.8, 130.1, 131.6, 142.3, 171.1; HRMS
(ESI-TOF): Calcd for C21H26BrNO2Na (M+Na)+: 426.1039, found:
426.1034. The enantiomeric ratio was determined by HPLC
(Chiralcel OD: hexane/2-propanol = 95/5) Tr(major) 13.7 min,
Tr(minor) 10.2 min (er 86.6:13.4).
phenylbutanamide 9a
Colorless solid; 82% ee; [a]
25 = +73.7 (c 1.00, CHCl3); mp 74–
D
75 °C; 1H NMR (400 MHz, CDCl3): d 1.31–1.36 (m, 1H, CHA of cyclo-
propane), 1.67–1.72 (m, 8H, CHB of cyclopropane, CH2ꢁ3 of
adamantine, CHCO), 2.02–2.05 (m, 6H, CH2ꢁ3 of adamantane),
2.07–2.12 (m, 3H, CH ꢁ3 of adamantane), 3.76–3.85 (m, 2H,
CHAOH, OH), 4.16 (dd, J = 6.4, 11.5 Hz, 1H, CHBOH), 5.55 (brs, 1H,
NH), 7.21–7.35 (m, 5H, C6H5); 13C NMR (100 MHz, CDCl3): d 16.7,
29.4, 29.5, 36.3, 36.8, 41.6, 52.5, 65.5, 126.9, 128.3, 128.5, 143.3,
171.5; HRMS (ESI-TOF): Calcd for
C
21H27NO2Na (M+Na)+:
348.1934, found: 348.1950. The enantiomeric ratio was deter-
mined by HPLC (Chiralcel OD: hexane/2-propanol = 95/5) Tr(major)
12.8 min, Tr(minor) 21.2 min (er 91:9).
4.10.6. (2S,3R)-N-(3,5-Dimethyladamant-1-yl)-4-hydroxy-2,3-
methano-3-phenylbutanamide 13
25
4.10.2. (2S,3R)-N-Adamant-1-yl-4-hydroxy-2,3-methano-3-(4-
Colorless oil; 72% ee; [a]
D + 85.3 (c 1.00, CHCl3); 1H NMR
methoxyphenyl)butanamide 9b
(400 MHz, CDCl3): d 0.87 (s, 6H, CH3ꢁ2), 1.13–1.22 (m, 2H, CH of
adamantane, CHA of cyclopropane), 1.29–1.41 (m, 5H, CH2ꢁ2
of adamantane, CHB of cyclopropane), 1,66–1.71 (m, 6H, CH2ꢁ3
of adamantane), 1.83–1.90 (m, 2H, CH2 of adamantane),
2.15–2.18 (m, 1H, CHCO), 3.76–3.85 (m, 2H, CHAOH, OH), 4.15
(dd, J = 6.4, 11.1 Hz, 1H, CHBOH), 5.60 (brs, 1H, NH), 7.21–7.26,
7.29–7.35 (m, m, 1H, 4H, C6H5); 13C NMR (100 MHz, CDCl3): d
16.7, 29.4, 30.1, 30.1, 32.4, 36.9, 40.2, 42.6, 47.5, 47.6, 50.5, 54.2,
65.5, 126.9, 128.4, 128.5, 143.2, 171.6; HRMS (ESI-TOF):
Colorless solid; 34% ee; [a]
19 = +42.5 (c 1.00, CHCl3); mp 150–
D
152 °C; 1H NMR (400 MHz, CDCl3): d 1.26–1.31 (m, 1H, CHA of
cyclopropane), 1.63–1.66 (m, 2H, CHB of cyclopropane, CHCO),
1.67–1.72 (m, 6H, CH2ꢁ3 of adamantane), 2.02–2.06 (m, 6H,
CH2ꢁ3 of adamantane), 2.06–2.13 (m, 3H, CH ꢁ3 of adamantane),
3.74–3.81 (m, 2H, CHAOH, OH), 3.79 (s, 3H, CH3O), 4.07–4.13 (m,
1H, CHBOH), 5.55 (brs, 1H, NH), 6.84, 7.26 (d, d, J = 8.8 Hz,
J = 8.8 Hz, 2H, 2H, C6H4); 13C NMR (100 MHz, CDCl3): d 16.7, 29.4,
29.5, 36.2, 36.3, 41.6, 52.5, 55.3, 65.7, 113.9, 129.5, 135.4, 158.5,
C
23H31NO2Na (M+Na)+: 376.2247, found: 376.2247. The enan-
171.6; HRMS (ESI-TOF): Calcd for
C
22H29NO3Na (M+Na)+:
tiomeric ratio was determined by HPLC (Chiralcel OD: hexane/
378.2040, found: 378.2039. The enantiomeric ratio was deter-
mined by HPLC (Chiralcel OD: hexane/2-propanol = 95/5) Tr(major)
17.0 min, Tr(minor) 15.4 min (er 67:33).
2-propanol = 95/5) Tr(major) 10.1 min, Tr(minor) 12.7 min (er 86:14).
4.11. Typical procedure for the reduction of 8aa
4.10.3. (2S,3R)-N-Adamant-1-yl-4-hydroxy-2,3-methano-3-(4-
A solution of 96 mg (0.17 mmol, 1.0 equiv) of (2S,3R)-N-ada-
mant-1-yl-4-(tert-butyldiphenylsiloxy)-2,3-methano-3-phenylbu-
tanamide 8aa in 1 mL of anhydrous CH2Cl2 was added at 0 °C under
an argon atmosphere to a suspension of 32 mg (0.85 mmol,
5.0 equiv) of LiAlH4 in 5 mL of anhydrous toluene. After stirring
at 70 °C for 5 h and 100 °C for 13 h, the colorless suspension was
treated with 109 mg (2.55 mmol, 15 equiv) of NaF, diluted with
methylphenyl)butanamide 9c
Colorless solid; 58% ee; [a]
25 = +70.0 (c 1.00, CHCl3); mp 161–
D
163 °C; 1H NMR (400 MHz, CDCl3): d 1.29–1.32 (m, 1H, CHA of
cyclopropane), 1.67–1.72 (m, 8H, CHB of cyclopropane, CHCO,
CH2ꢁ3 of adamantane), 2.02–2.06 (m, 6H, CH2ꢁ3 of adamantane),
2.06–2.12 (m, 3H, CH ꢁ3 of adamantane), 2.32 (s, 3H, CH3), 3.75–
3.83 (m, 2H, CHAOH, OH), 4.13 (dd, J = 6.5, 10.7 Hz, 1H, CHBOH),
5.55 (brs, 1H, NH), 7.12, 7.22 (d, d, J = 7.8 Hz, J = 7.8 Hz, J = 8.1 Hz,
2H, 2H, C6H4); 13C NMR (100 MHz, CDCl3): d 16.7, 21.0, 29.4,
29.5, 36.3, 36.5, 41.6, 52.5, 65.5, 128.2, 129.2, 136.6, 140.3, 171.5;
15 mL of AcOEt, quenched with 61 lL (3.40 mmol, 20 equiv) of
water, and filtered through Celite. The filtrate was evaporated
and the residue was chromatographed on silica gel with a 9:1:0.2
mixture of hexane, AcOEt, and Et3N to afford 38 mg (72% yield)
of 10a.
HRMS (ESI-TOF): Calcd for
C
22H29NO2Na (M+Na)+: 362.2091,
Please cite this article in press as: Ezawa, T.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2016.12.010

14
T. Ezawa et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
4.12. Typical procedure for the reduction of 9a
4.12.4. (2R,3S)-4-(Adamant-1-ylamino)-2-(4-chlorophenyl)-2,3-
methanobutan-1-ol 10d
A solution of 128 mg (0.39 mmol, 1.0 equiv) of (2S,3R)-N-ada-
mant-1-yl-4-hydroxy-2,3-methano-3-phenylbutanamide 9a in
2 mL of anhydrous CH2Cl2 was added at 0 °C under an argon atmo-
sphere to a suspension of 74 mg (1.95 mmol, 5.0 equiv) of LiAlH4 in
5 mL of anhydrous toluene. After stirring at 70 °C for 24 h and at
100 °C for 3 h, the colorless suspension was treated with 246 mg
(5.85 mmol, 15 equiv) of NaF, diluted at 0 °C with 15 mL of AcOEt,
Reaction conditions: at 70 °C for 12 h and 100 °C for 3 h; Color-
less solid; 75% ee; [a]
17 = +18.4 (c 1.00, CHCl3); mp 98–101 °C; 1H
D
NMR (400 MHz, CDCl3): d 0.78 (dd, J = 4.4, 4.4 Hz, 1H, CHA of cyclo-
propane), 1.12 (dd, J = 4.4, 8.5 Hz, 1H, CHB of cyclopropane), 1.23–
1.29 (m, 1H, CHCH2N), 1.56–1.73 (m, 14H, CH2ꢁ6 of adamantane,
OH, NH), 2.04–2.10 (m, 3H, CH ꢁ3 of adamantane), 2.26 (dd,
J = 11.8, 11.8 Hz, 1H, CHAN), 3.39 (dd, J = 7.0, 11.8 Hz, 1H, CHBN),
3.49 (d, J = 12.5, 1H, CHAO), 4.08 (d, J = 12.5 Hz, 1H, CHBO), 7.25,
7.31 (d, d, J = 8.7 Hz, J = 8.7 Hz, 2H, 2H, C6H4); 13C NMR
(100 MHz, CDCl3): d 19.4, 25.5, 29.5, 31.4, 36.6, 40.7, 42.4, 50.7,
67.4, 128.2, 129.5, 131.7, 143.8; IR (KBr, cmꢂ1): 3267, 2906,
2848, 2360; HRMS (ESI-TOF): Calcd for C21H29ClNO (M+H)+:
346.1932, found: 346.1926. The enantiomeric ratio was deter-
mined by HPLC (Chiralcel OD: hexane/2-propanol/Et2-
NH = 95/5/0.1) Tr(major) 7.9 min, Tr(minor) 6.3 min (er 87.6:12.4).
quenched at 0 °C with 140 lL (7.80 mmol, 20 equiv) of water, and
filtered through Celite. The filtrate was evaporated and the residue
was chromatographed on silica gel with a 9:1:0.2 mixture of hex-
ane, AcOEt, and Et3N to afford 105 mg (87% yield) of 10a.
4.12.1. (2R,3S)-4-(Adamant-1-ylamino)-2,3-methano-2-
phenylbutan-1-ol 10a
Colorless solid; 86% ee; [a]
25 = +16.6 (c 1.00, CHCl3); mp 89–
D
90 °C; 1H NMR (400 MHz, CDCl3): d 0.77 (dd, J = 5.1, 5.1 Hz, 1H,
CHA of cyclopropane), 1.14 (dd, J = 5.1, 8.5 Hz, 1H, CHB of cyclo-
propane), 1.27–1.34 (m, 2H, CHCH2NH), 1.60–1.74 (m, 13H,
CH2ꢁ6 of adamantane, OH), 2.05–2.10 (m, 3H, CH ꢁ3 of adaman-
tane), 2.28 (dd, J = 11.7, 11.7 Hz, 1H, CHAN), 3.39 (dd, J = 5.0,
11.7 Hz, 1H, CHBN), 3.51 (d, J = 12.2 Hz, 1H, CHAO), 4.15 (d,
J = 12.2 Hz, 1H, CHBO), 7.17–7.21, 7.27–7.33, 7.37–7.39 (m, m, m,
1H, 2H, 2H, C6H5); 13C NMR (100 MHz, CDCl3): d 19.5, 25.3, 29.5,
31.9, 36.6, 40.8, 42.4, 50.7, 67.6, 126.0, 128.1, 128.2, 145.2; IR
(NaCl, cmꢂ1): 3269, 2906, 2846; HRMS (ESI-TOF): Calcd for
4.12.5. (2R,3S)-4-(Adamant-1-ylamino)-2-(4-bromophenyl)-2,3-
methanobutan-1-ol 10e
Reaction conditions: at 70 °C for 12 h and 100 °C for 3 h; Color-
less solid; 76% ee; [a]
22 = +19.4 (c 1.00, CHCl3); mp 114–117 °C; 1H
D
NMR (400 MHz, CDCl3): d 0.78 (dd, J = 4.4, 4.4 Hz, 1H, CHA of cyclo-
propane), 1.12 (dd, J = 4.4, 8.5 Hz, 1H, CHB of cyclopropane), 1.22–
1.29 (m, 1H, CHCH2N), 1.59–1.73 (m, 14H, CH2ꢁ6 of adamantane,
OH, NH), 2.05–2.11 (m, 3H, CH ꢁ3 of adamantane), 2.26 (dd,
J = 11.7, 11.7 Hz, 1H, CHAN), 3.38 (dd, J = 6.9, 11.7 Hz, 1H, CHBN),
3.48 (d, J = 12.4, 1H, CHAO), 4.08 (d, J = 12.4 Hz, 1H, CHBO), 7.26,
7.41 (d, d, J = 8.6 Hz, J = 8.6 Hz, 2H, 2H, C6H4); 13C NMR
(100 MHz, CDCl3): d 19.4, 25.6, 29.5, 31.4, 36.6, 40.7, 42.4, 50.7,
67.3, 119.8, 129.9, 131.2, 144.3; IR (KBr, cmꢂ1): 3269, 2902,
2846; HRMS (ESI-TOF): Calcd for C21H29BrNO (M+H)+: 390.1427,
found: 390.1417. The enantiomeric ratio was determined by HPLC
(Chiralcel OD: hexane/2-propanol/Et2NH = 95/5/0.1) Tr(major)
8.0 min, Tr(minor) 6.8 min (er 88:12).
C
21H30NO (M+H)+: 312.2327, found: 312.2304. The enantiomeric
ratio was determined by HPLC (Chiralcel OD: hexane/2-propanol/
Et2NH = 95/5/0.05) Tr(major) 12.0 min, Tr(minor) 7.5 min (er 93:7).
4.12.2. (2R,3S)-4-(Adamant-1-ylamino)-2,3-methano-2-(4-
methoxyphenyl)butan-1-ol 10b
Reaction conditions: at 70 °C for 19 h; Colorless solid; 34% ee;
[a]
17 = +5.8 (c 0.99, CHCl3); mp 88–91 °C; 1H NMR (400 MHz,
D
CDCl3): d 0.72 (dd, J = 5.0, 5.0 Hz, 1H, CHA of cyclopropane), 1.08
(dd, J = 5.0, 8.5 Hz, 1H, CHB of cyclopropane), 1.22–1.28 (m, 1H,
CHCH2N), 1.60–1.74 (m, 14H, CH2ꢁ6 of adamantane, OH, NH),
2.03–2.06 (m, 3H, CH ꢁ3 of adamantane), 2.25 (dd, J = 11.8,
11.8 Hz, 1H, CHAN), 3.37 (dd, J = 6.8, 11.8 Hz, 1H, CHBN), 3.48 (d,
J = 11.9, 1H, CHAO), 3.79 (s, 3H, CH3O), 4.06 (d, J = 11.9 Hz, 1H,
CHBO), 6.84, 7.31 (d, d, J = 8.8 Hz, J = 8.8 Hz, 2H, 2H, C6H4); 13C
NMR (100 MHz, CDCl3): d 19.1, 25.0, 29.5, 31.4, 36.6, 40.8, 42.5,
50.7, 55.3, 67.9, 113.6, 129.4, 137.5, 157.9; IR (KBr, cmꢂ1): 3266,
4.12.6. (2R,3S)-4-[(3,5-Dimethyladamant-1-yl)amino]-2,3-
methano-2-phenylbutan-1-ol 14
Colorless oil; 74% ee; [a]
19 = +13.8 (c 1.00, CHCl3); 1H NMR
D
(400 MHz, CDCl3): d 0.77 (dd, J = 5.2, 5.2 Hz, 1H, CHA of cyclo-
propane), 0.85 (s, 6H, CH3ꢁ2 of adamantane), 1.12–1.16 (m, 3H,
CH2 of adamantane, CHB of cyclopropane), 1.23–1.38 (m, 10H,
CH2ꢁ5 of adamantane), 1.45–1.48 (m, 1H, CH of adamantane),
1.56–1.59 (m, 2H, OH, NH), 2.13–2.16 (m, 1H, CHCH2N), 2.27 (t,
J = 11.6, 11.6 Hz, 1H, CHAN), 3.39 (dd, J = 6.8, 11.6 Hz, 1H, CHBN),
3.50 (d, J = 12.3 Hz, 1H, CHAO), 4.14 (d, J = 12.3 Hz, 1H, CHBO),
7.17–7.21, 7.27–7.32, 7.36–7.39 (m, m, m, 1H, 2H, 2H, C6H5); 13C
NMR (100 MHz, CDCl3): d 19.4, 25.4, 30.2, 31.8, 32.4, 41.0, 41.1,
42.9, 48.5, 48.7, 50.9, 52.5, 67.6, 125.9, 128.1, 128.2, 145.2; IR
(NaCl, cmꢂ1): 3263, 2900, 2843, 1600; HRMS (ESI-TOF): Calcd for
2904, 2846; HRMS (ESI-TOF): Calcd for
C
22H32NO2 (M+H)+:
342.2428, found: 342.2437. The enantiomeric ratio was determined
by HPLC (Chiralcel OD: hexane/2-propanol/Et2NH = 95/5/0.1)
Tr(major) 14.8 min, Tr(minor) 11.0 min (er 67:33).
4.12.3. (2R,3S)-4-(Adamant-1-ylamino)-2,3-methano-2-(4-
methylphenyl)butan-1-ol 10c
C
23H34NO (M+H)+: 340.2635, found: 340.2650. The enantiomeric
Reaction conditions: at 70 °C for 14 h and 100 °C for 3 h; Color-
ratio was determined by HPLC (Chiralcel OD: hexane/2-propanol/
Et2NH = 95/5/0.1) Tr(major) 10.0 min, Tr(minor) 7.7 min (er 87:13).
less solid; 60% ee; [
a]
21 = +13.2 (c 1.00, CHCl3); mp 128–130 °C; 1H
D
NMR (400 MHz, CDCl3): d 0.74 (dd, J = 4.4, 4.4 Hz, 1H, CHA of cyclo-
propane), 1.11 (dd, J = 4.4, 8.5 Hz, 1H, CHB of cyclopropane), 1.24–
1.31 (m, 1H, CHCH2N), 1.59–1.73 (m, 14H, CH2ꢁ6 of adamantane,
OH, NH), 2.04–2.10 (m, 3H, CH ꢁ3 of adamantane), 2.26 (dd,
J = 11.7, 11.7 Hz, 1H, CHAN), 2.31 (s, 1H, CH3), 3.38 (dd, J = 5.0,
11.7 Hz, 1H, CHBN), 3.49 (d, J = 12.2, 1H, CHAO), 4.11 (d,
J = 12.2 Hz, 1H, CHBO), 7.11, 7.28 (d, d, J = 7.8 Hz, J = 7.8 Hz, 2H,
2H, C6H4); 13C NMR (100 MHz, CDCl3): d 19.3, 21.0, 25.3, 29.5,
31.5, 36.6, 40.8, 42.5, 50.6, 67.7, 128.0, 128.9, 135.5, 142.3; IR
(KBr, cmꢂ1): 3267, 2902, 2846, 2360; HRMS (ESI-TOF): Calcd for
4.13. Typical procedure for the methylation of 10a
To a colorless solution of 30 mg (0.10 mmol, 1.0 equiv) of
(2R,3S)-4-(adamant-1-ylamino)-2,3-methano-2-phenylbutan-1-ol
10a and 13 mg (0.15 mmol, 1.5 equiv) of NaHCO3 in 3 mL of anhy-
drous DMF were added 12 lL (0.19 mmol, 2.0 equiv) of MeI at rt.
After stirring at 80 °C for 2 h, the reaction mixture was diluted with
20 mL of a 3:1 mixture of AcOEt and hexane, washed with 10 mL of
water and 5 mL of half brine, and dried over anhydrous MgSO4. The
crude product was chromatographed on silica gel with a 9:1:0.1
mixture of hexane, AcOEt, and Et3N to afford 22 mg (68% yield)
of 11a [(+)-AMMP].
C
22H32NO (M+H)+: 326.2478, found: 326.2460. The enantiomeric
ratio was determined by HPLC (Chiralcel OD: hexane/2-propanol/
Et2NH = 95/5/0.1) Tr(major) 11.5 min, Tr(minor) 6.8 min (er 80:20).
Please cite this article in press as: Ezawa, T.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2016.12.010

T. Ezawa et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
15
4.13.1. (+)-(2R,3S)-4-(N-Adamant-1-yl-N-methylamino)-2,3-
4.13.5. (+)-(2R,3S)-4-(N-Adamant-1-yl-N-methylamino)-2-(4-
methano-2-phenylbutan-1-ol 11a [(+)-AMMP]
bromophenyl)-2,3-methanobutan-1-ol 11e
Colorless oil; 86% ee derived from 10a; [
a]
28 = +42.8 (c 0.90,
Colorless solid; 76% ee derived from 10e; [a]
22 = +34.4 (c 1.00,
D
D
CHCl3); 1H NMR (400 MHz, CDCl3): d 0.76 (dd, J = 5.1, 5.1 Hz, 1H,
CHA of cyclopropane), 1.21–1.25 (m, 1H, CHB of cyclopropane),
1.39–1.47 (m, 1H, CHCH2N), 1.60–1.68 (m, 6H, CH2ꢁ3 of adaman-
tane), 1.73–1.77 (m, J = 2.8 Hz, 6H, CH2ꢁ3 of adamantane), 2.07–
2.12 (m, 3H, CH ꢁ3 of adamantane), 2.36 (s, 3H, CH3N), 2.66 (dd,
J = 10.4, 12.7 Hz, 1H, CHAN), 2.81 (dd, J = 5.6, 12.7 Hz, 1H, CHBN),
3.41 (d, J = 12.3 Hz, 1H, CHAO), 4.12 (d, J = 12.3 Hz, 1H, CHBO),
6.73 (brs, 1H, OH), 7.17–7.21, 7.27–7.31, 7.40–7.43 (m, m, m, 1H,
2H, 2H, C6H5); 13C NMR (100 MHz, CDCl3): d 20.8, 24.1, 29.6,
32.2, 32.3, 36.7, 37.9, 48.8, 54.7, 67.4, 125.9, 127.8, 128.2, 145.4;
IR (NaCl, cmꢂ1): 2904, 2850, 2366, 2322; HRMS (ESI-TOF): Calcd
for C22H32NO (M+H)+: 326.2484, found: 326.2498.
CHCl3); mp 108–111 °C; 1H NMR (400 MHz, CDCl3): d 0.78 (dd,
J = 4.4, 4.4 Hz, 1H, CHA of cyclopropane), 1.21 (dd, J = 4.4, 8.5 Hz,
1H, CHB of cyclopropane), 1.33–1.41 (m, 1H, CHCH2N), 1.59–1.68
(m, 6H, CH2ꢁ3 of adamantane), 1.70–1.77 (m, J = 2.7 Hz, 6H,
CH2ꢁ3 of adamantane), 2.07–2.13 (m, 3H, CH ꢁ3 of adamantane),
2.33 (s, 3H, CH3N), 2.65 (dd, J = 10.4, 12.7 Hz, 1H, CHAN), 2.80 (dd,
J = 7.1, 12.7 Hz, 1H, CHBN), 3.39 (d, J = 12.4, 1H, CHAO), 4.07 (d,
J = 12.4 Hz, 1H, CHBO), 6.76 (brs, 1H, OH), 7.29, 7.40 (d, d,
J = 8.6 Hz, J = 8.6 Hz, 2H, 2H, C6H4); 13C NMR (100 MHz, CDCl3): d
20.8, 24.4, 29.5, 31.8, 32.2, 36.7, 37.9, 48.7, 54.8, 67.1, 119.7,
129.5, 131.2, 144.4; IR (KBr, cmꢂ1): 2904, 2846; HRMS (ESI-TOF):
Calcd for C22H31BrNO (M+H)+: 404.1584, found: 404.1582.
4.13.2. (+)-(2R,3S)-4-(N-Adamant-1-yl-N-methylamino)-2,3-
4.13.6. (+)-(2R,3S)-4-[N-(3,5-Dimethyladamant-1-yl)-N-
methano-2-(4-methoxyphenyl)butan-1-ol 11b
methylamino]-2,3-methano-2-phenylbutan-1-ol 15
Colorless oil; 34% ee derived from 10b; [
a]
22 = +13.3 (c 1.00,
Colorless oil; 74% ee derived from 14; [a]
17 = +25.7 (c 0.90,
D
D
CHCl3); 1H NMR (400 MHz, CDCl3): d 0.72 (dd, J = 4.9, 4.9 Hz, 1H,
CHA of cyclopropane), 1.17 (dd, J = 3.8, 4.9 Hz, 1H, CHB of cyclo-
propane), 1.35–1.41 (m, 1H, CHCH2N), 1.60–1.68 (m, 6H, CH2ꢁ3
of adamantane), 1.72–1.75 (m, J = 2.8 Hz, 6H, CH2ꢁ3 of adaman-
tane), 2.07–2.13 (m, 3H, CH ꢁ3 of adamantane), 2.37 (s, 3H,
CH3N), 2.63 (dd, J = 10.5, 12.6 Hz, 1H, CHAN), 2.79 (dd, J = 7.1,
12.6 Hz, 1H, CHBN), 3.39 (d, J = 12.2 Hz, 1H, CHAO), 3.79 (s, 3H,
CH3O), 4.04 (d, J = 12.2 Hz, 1H, CHBO), 6.65 (brs, 1H, OH), 6.84,
7.35 (d, d, J = 8.8 Hz, J = 8.8 Hz, 2H, 2H, C6H4); 13C NMR
(100 MHz, CDCl3): d 20.4, 23.7, 29.6, 31.8, 32.2, 36.7, 37.9, 48.8,
54.8, 55.3, 67.7, 113.6, 129.1, 137.7, 157.9; IR (NaCl, cmꢂ1): 2906,
2848, 2360, 2332; HRMS (ESI-TOF): Calcd for C23H34NO2 (M+H)+:
356.2584, found: 356.2571.
CHCl3); 1H NMR (400 MHz, CDCl3): d 0.77 (dd, J = 5.1, 5.1 Hz, 1H,
CHA of cyclopropane), 0.83–0.87 (m, 6H, CH3ꢁ2 of adamantane),
1.08–1.16 (m, 2H, CH2 of adamantane), 1.22–1.45 (m, 11H,
CH2ꢁ5 of adamantane, CHB of cyclopropane), 1.57–1.62 (m, 1H,
CH of adamantane), 2.15–2.19 (m, 1H, CHCH2N), 2.36 (s, 3H,
CH3N), 2.66 (dd, J = 10.6, 12.5 Hz, 1H, CHAN), 2.81 (dd, J = 7.0,
12.5 Hz, 1H, CHBN), 3.41 (d, J = 12.2 Hz, 1H, CHAO), 4.13 (d,
J = 12.2 Hz, 1H, CHBO), 6.80 (brs, 1H, OH), 7.17–7.21, 7.27–7.31,
7.40–7.43 (m, m, m, 1H, 2H, 2H, C6H5); 13C NMR (100 MHz, CDCl3):
d 20.8, 24.2, 30.2, 30.5, 32.2, 32.4, 32.4, 32.5, 36.3, 43.0, 44.1, 44.2,
49.1, 50.8, 56.7, 67.4, 125.9, 127.7, 128.2, 145.3; IR (NaCl, cmꢂ1):
3201, 2950, 2360, 2341, 1604; HRMS (ESI-TOF): Calcd for
C
24H36NO (M+H)+: 354.2791, found: 354.2786.
4.13.3. (+)-(2R,3S)-4-(N-Adamant-1-yl-N-methylamino)-2,3-
Acknowledgment
methano-2-(4-methylphenyl)butan-1-ol 11c
Colorless solid; 60% ee derived from 10c; [a]
22 = +30.7 (c 1.00,
D
This work was supported in part by the Scientific Research Pro-
ject by CIS (Chiba Institute of Science), Japan.
CHCl3); mp 81–83 °C; 1H NMR (400 MHz, CDCl3): d 0.73 (dd,
J = 4.4, 4.4 Hz, 1H, CHA of cyclopropane), 1.20 (dd, J = 4.4, 8.4 Hz,
1H, CHB of cyclopropane), 1.37–1.42 (m, 1H, CHCH2N), 1.59–1.68
(m, 6H, CH2ꢁ3 of adamantane), 1.73–1.77 (m, 6H, CH2ꢁ3 of
adamantane), 2.07–2.12 (m, 3H, CH ꢁ3 of adamantane), 2.31 (s,
3H, CH3N), 2.36 (s, 3H, CH3C6H4), 2.65 (dd, J = 12.7, 12.7 Hz, 1H,
CHAN), 2.80 (dd, J = 7.1, 12.7 Hz, 1H, CHBN), 3.40 (d, J = 12.1 Hz,
1H, CHAO), 4.08 (d, J = 12.1 Hz, 1H, CHBO), 6.68 (brs, 1H, OH),
7.11, 7.32 (d, d, J = 8.0 Hz, J = 8.0 Hz, 2H, 2H, C6H4); 13C NMR
(100 MHz, CDCl3): d 20.6, 21.0, 23.9, 29.6, 32.0, 32.2, 36.7, 37.9,
48.8, 54.7, 67.5, 127.8, 128.9, 135.4, 142.4; IR (KBr, cmꢂ1): 2902,
2846; HRMS (ESI-TOF): Calcd for C23H34NO (M+H)+: 340.2635,
found:340.2614.
References
1. Several diseases except ALS see: (a) Maurice, T.; Su, T. P. Phamacol. Ther. 2009,
124, 195–206. and references cited therein; ALS see: (b) Mavlyutov, T. A.; Guo,
L. W.; Epstein, M. L.; Ruoho, A. E. J. Phamacol. Sci. 2015, 127, 10–16.
2. (a) Maurice, T.; Su, T. P. Pharmacol. Ther. 2009, 124, 195–206; (b) Quirion, R.;
Bowen, W. D.; Itzhak, Y.; Junien, J. L.; Musacchio, M. J.; Rothman, R. B.; Su, T. P.;
Tam, S. W.; Taylor, D. P. Trends Pharmacol. Sci. 1992, 13, 85–86.
3. (a) Hayashi, T. J. Pharmacol. Sci. 2015, 127, 2–5; (b) Omi, T.; Tanimukai, H.;
Kanayama, D.; Sakagami, Y.; Tagami, S.; Okochi, M.; Moriha, T.; Sato, M.;
Yanagida, K.; Kitasyoji, A.; Hara, H.; Imaizumi, K.; Maurice, T.; Chevallier, N.;
Marchal, S.; Takeda, M.; Kudo, T. Cell Death Dis. 2014, 5, e1332; (c) Hayashi, T.;
Su, T. Cell 2007, 131, 596–610.
4. (a) Prause, J.; Goswami, A.; Katona, I.; Roos, A.; Schnizler, M.; Bushuven, E.;
Dreier, A.; Buchkremer, S.; Johann, S.; Beyer, C.; Deschauer, M.; Troost, D.; Weis,
J. Hum. Mol. Genet. 2013, 22, 1581–1600; (b) Al-Saif, A.; Al-Mohanna, F.;
Bohlega, S. Ann. Neurol. 2011, 70, 913–919.
5. Matsuno, K.; Nakazawa, M.; Okamoto, K.; Kawashima, Y.; Mita, S. Eur. J.
Pharmacol. 1996, 306, 271–279.
6. (a) Banister, S. D.; Kassiou, M. Curr. Pharm. Des. 2012, 18, 884–901; (b) Niitsu,
T.; Iyo, M.; Hashimoto, K. Curr. Pharm. Des. 2012, 18, 875–883; (c) Hayashi, T.;
Tsai, S. Y.; Mori, T.; Fujimoto, M.; Su, T. P. Expert Opin. Ther. Targets 2011, 15,
557–577; (d) Ishikawa, M.; Hashimoto, K. J. Receptor Ligand Channel Res. 2010,
3, 25–36.
7. (a) Urfer, R.; Moebius, H. J.; Skoloudik, D.; Santamarina, E.; Sato, W.; Mita, S.;
Muir, K. W. Stroke 2014, 45, 3304–3310; (b) Simona, C.; Raffaella, G.;
Annamaria, M.; Andrea, B.; Sara, N.; Francesca, N.; Daniela, R. Expert Opin.
Ther. Pat. 2013, 23, 597–613.
8. (a) Behensky, A.; Yasny, I.; Shuster, A.; Seredenin, S.; Petrov, A.; Cuevas, J. J.
Pharmacol. Exp. Ther. 2013, 347, 468–477; (b) Marrazzo, A.; Caraci, F.; Salinaro,
E.; Su, T.; Copani, A.; Ronsisvalle, G. NeuroReport 2005, 16, 1223–1226.
9. (a) Villard, V.; Espallergues, J.; Keller, E.; Alkam, T.; Nitta, A.; Yamada, K.;
Nabeshima, T.; Vamvakides, A.; Maurice, T. Neuropsychopharmacology 2009, 34,
1552–1566; (b) Meunier, J.; Ieni, J.; Maurice, T. Br. J. Pharmacol. 2006, 149, 998–
1012; (c) Maurice, T.; Su, T.; Privat, A. Neuroscience 1998, 83, 413–428.
4.13.4. (+)-(2R,3S)-4-(N-Adamant-1-yl-N-methylamino)-2-(4-
chlorophenyl)-2,3-methanobutan-1-ol 11d
Colorless solid; 75% ee derived from 10d; [a]
17 = +30.9 (c 1.00,
D
CHCl3); mp 100–102 °C; 1H NMR (400 MHz, CDCl3): d 0.78 (dd,
J = 5.0, 5.0 Hz, 1H, CHA of cyclopropane), 1.21 (dd, J = 5.0, 8.5 Hz,
1H, CHB of cyclopropane), 1.35–1.41 (m, 1H, CHCH2N), 1.59–1.65
(m, 6H, CH2ꢁ3 of adamantane), 1.70–1.78 (m, 6H, CH2ꢁ3 of
adamantane), 2.07–2.12 (m, 3H, CH ꢁ3 of adamantane), 2.34 (s,
3H, CH3N), 2.65 (dd, J = 12.6, 12.6 Hz, 1H, CHBN), 3.40 (d, J = 12.2,
1H, CHAO), 4.07 (d, J = 12.2 Hz, 1H, CHAN), 2.80 (dd, J = 6.4,
12.6 Hz, 1H, CHBN), 3.40 (d, J = 12.2, 1H, CHAO), 4.07 (d,
J = 12.2 Hz, 1H, CHBO), 6.75 (brs, 1H, OH), 7.25, 7.35 (d, d,
J = 8.7 Hz, J = 8.7 Hz, 2H, 2H, C6H4); 13C NMR (100 MHz, CDCl3): d
20.8, 24.4, 29.5, 31.8, 32.2, 36.7, 37.9, 48.7, 54.8, 67.1, 128.2,
129.2, 131.6, 143.9; IR (KBr, cmꢂ1): 2910, 2848; HRMS (ESI-TOF):
Calcd for C22H31ClNO (M+H)+: 360.2089, found: 360.2099.
Please cite this article in press as: Ezawa, T.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2016.12.010

16
T. Ezawa et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
10. (a) Froestl, W.; Muhs, A.; Preifer, A. J. Alzheimer’s Dis. 2014, 41, 961–1019; (b)
Villard, V.; Espallergues, J.; Keller, E.; Vamvakides, A.; Maurice, T. J.
Psychopharmacol. 2011, 25, 1101–1117.
11. Marrazzo, A.; Prezzavento, O.; Pappalardo, M. S.; Bousquet, E.; Indanza, M.;
Pike, V. W.; Ronsisvalle, G. IL Farmaco 2002, 57, 45–53.
Akaiwa, Y.; Sasaki, H.; Sato, R.; Nagai, T.; Fujimori, H.; Noguchi, T.; Kirihara, M.
Tetrahedron: Asymmetry 2009, 20, 2065–2071; (c) Miura, T.; Murakami, Y.
Tetrahedron: Asymmetry 2006, 17, 3067–3069; (d) Imai, N.; Nomura, T.;
Yamamoto, S.; Ninomiya, Y. Tetrahedron: Asymmetry 2002, 13, 2433–2438;
(e) Imai, N.; Sakamoto, K.; Maeda, M.; Kouge, K.; Yoshizane, K.; Nokami, J.
Tetrahedron Lett. 1997, 38, 1423–1426.
12. Kawashima, Y.; Ezawa, T.; Yamamura, M.; Harada, T.; Noguchi, T.; Miura, T.;
Imai, N. Tetrahedron Lett. 2016, 57, 668–671.
15. (a) Noguchi, T.; Jung, S.; Imai, N. Tetrahedron Lett. 2014, 55, 394–396; (b) Jung,
S.; Tsukuda, Y.; Kawashima, R.; Ishiki, T.; Matsumoto, A.; Nakaniwa, A.; Takagi,
M.; Noguchi, T.; Imai, N. Tetrahedron Lett. 2013, 54, 5718–5720; (c) Noguchi, T.;
Sekine, M.; Yokoo, Y.; Jung, S.; Imai, N. Chem. Lett. 2013, 42, 580–582; (d)
Noguchi, T.; Jung, S.; Imai, N. Chem. Lett. 2012, 41, 577–579; (e) Noguchi, T.;
Tehara, N.; Uesugi, Y.; Jung, S.; Imai, N. Chem. Lett. 2012, 41, 42–43.
16. McKennon, M. J.; Meyers, A. I.; Drauz, K.; Schwarm, M. J. Org. Chem. 1993, 58,
3568–3571.
13. (a) Koyata, N.; Nagai, T.; Kawasaki, M.; Noguchi, T.; Kirihara, M.; Imai, N. Chem.
Lett. 2009, 38, 892–893; (b) Miura, T.; Umetsu, S.; Kanamori, D.; Tsuyama, N.;
Jyo, Y.; Kawashima, Y.; Koyata, N.; Murakami, Y.; Imai, N. Tetrahedron 2008, 64,
9305–9308; (c) Miura, T.; Okazaki, K.; Ogawa, K.; Otomo, E.; Umetsu, S.;
Takahashi, M.; Kawashima, Y.; Jyo, Y.; Koyata, N.; Murakami, Y.; Imai, N.
Synthesis 2008, 17, 2695–2700; (d) Miura, T.; Kawashima, Y.; Takahashi, M.;
Murakami, Y.; Imai, N. Synth. Commun. 2007, 37, 3105–3109; (e) Miura, T.;
Kawashima, Y.; Umetsu, S.; Kanamori, D.; Tsuyama, N.; Jyo, Y.; Murakami, Y.;
Imai, N. Chem. Lett. 2007, 36, 814–815.
17. Kawashima, Y.; Ezawa, T.; Yamamura, M.; Harada, T.; Noguchi, T.; Miura, T.;
Imai, N. Tetrahedron 2015, 71, 8585–8592.
14. (a) Kawashima, Y.; Ezawa, T.; Harada, T.; Noguchi, T.; Kawasaki, M.; Kirihara,
M.; Imai, N. Bull. Chem. Soc. Jpn. 2016, 89, 257–267; (b) Koyata, N.; Miura, T.;
18. Charette, A. B.; Brochu, C. J. Am. Chem. Soc. 1995, 117, 11367–11368.
Please cite this article in press as: Ezawa, T.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2016.12.010