Convenient synthesis of (+)-cis-4-(N-adamantyl-N-methylamino)-2,3-methano-2-phenylbutan-1-ol as a candidate of anti-Alzheimer's medicine via catalytic enantioselective Simmons-Smith reaction using l-phenylalanine-derived disulfonamide

Article abstract of DOI:10.1016/j.tetlet.2015.12.113

The catalytic enantioselective Simmons-Smith reaction of (Z)-4-tert-butyldiphenylsiloxy-3-phenylbut-2-en-1-ol using l-phenylalanine-derived disulfonamide afforded (+)-cis-4-tert-butyldiphenylsiloxy-2,3-methano-3-phenylbutan-1-ol in quantitative yield with 71% ee. The 2,3-methano-3-phenylbutan-1-ol was easily converted to the corresponding 2,3-methano-3-phenylbutanoic acid, followed by amidation of the carboxylic acid with 1-adamantanamine sulfate in aqueous organic solvent to afford the corresponding 2,3-methano-3-phenylbutanamide in excellent yields. Convenient enantioselective synthesis of (+)-cis-4-(N-adamantyl-N-methylamino)-2,3-methano-2-phenylbutan-1-ol ((+)-AMMP) was achieved in 35% overall yield from the starting 1,4-diol via our developed key reactions.

Full text of DOI:10.1016/j.tetlet.2015.12.113

Tetrahedron Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Convenient synthesis of (+)-cis-4-(N-adamantyl-N-methylamino)-2,
3-methano-2-phenylbutan-1-ol as a candidate of anti-Alzheimer’s
medicine via catalytic enantioselective Simmons–Smith reaction
using L-phenylalanine-derived disulfonamide
⇑
Yuya Kawashima, Tetsuya Ezawa, Mai Yamamura, Taisuke Harada, Takuya Noguchi, 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:
The catalytic enantioselective Simmons–Smith reaction of (Z)-4-tert-butyldiphenylsiloxy-3-phenylbut-2-
en-1-ol using -phenylalanine-derived disulfonamide afforded (+)-cis-4-tert-butyldiphenylsiloxy-2,3-
Received 21 October 2015
Revised 15 December 2015
Accepted 28 December 2015
Available online xxxx
L
methano-3-phenylbutan-1-ol in quantitative yield with 71% ee. The 2,3-methano-3-phenylbutan-1-ol
was easily converted to the corresponding 2,3-methano-3-phenylbutanoic acid, followed by amidation
of the carboxylic acid with 1-adamantanamine sulfate in aqueous organic solvent to afford the
corresponding 2,3-methano-3-phenylbutanamide in excellent yields. Convenient enantioselective
synthesis of (+)-cis-4-(N-adamantyl-N-methylamino)-2,3-methano-2-phenylbutan-1-ol ((+)-AMMP)
was achieved in 35% overall yield from the starting 1,4-diol via our developed key reactions.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Alzheimer’s disease
Sigma receptor agonist
Regioselective acetylation
Simmons–Smith reaction
Amidation
Alzheimer’s disease (AD) is the most common type of dementia
and a progressive brain disease that destroys cognitive function,
then eventually leads to death. The increase in degenerative brain
diseases including AD has become a social issues as the global
aging proceeds. According to the world health organization
clinical symptoms of AD and protect against associated neu-
ropathologic changes. Indeed, tetrahydro-N,N-dimethyl-2,2-diphe-
nyl-3-furanmethanamine hydrochloride (ANAVEX2-73) has been
examined in Phase I for AD trial as a sigma-1 receptor agonist since
1
5
March of 2011. On the other hand, (+)-cis-4-(N-adamantyl-N-
(
WHO), dementia sufferers including AD were nearly 35.6 million
people in 2012. This number is expected to double by 2030
65.7 million) and more than triple by 2050 (115.4 million). There-
methylamino)-2,3-methano-2-phenylbutan-1-ol ((+)-AMMP) was
reported as a high affinity probe for sigma receptors by Marrazzo
et al. However, the overall yield was 9% from (+)-2,3-methano-
6
(
fore, pathological elucidation of AD and urgent development of
medicine for AD are demanded.
2-phenyllactone as the starting material and the reagents used in
the total synthesis of (+)-AMMP were relatively expensive.
Recently, we have developed useful reactions such as the
regioselective acetylation using porcine pancreas lipase (PPL),7
the catalytic enantioselective Simmons–Smith reaction in the pres-
Sigma receptor has recently attracted attention as a new action
site of therapeutic medicine for AD. The two established subtypes,
sigma-1 and sigma-2, are both highly expressed in the central ner-
vous system (CNS) and can be distinguished by their distinct phar-
macological profiles and molecular characteristics. Particularly, it
was reported that sigma-1 receptor regulates protein folding/
degradation, endoplasmic reticulum (ER)/oxidative stress, and cell
survival through the molecular chaperone activity.2 In addition, a
ence of L
-phenylalanine-derived disulfonamide as a chiral ligand,8
and the convenient amidation of mixed carbonic carboxylic anhy-
9
drides in aqueous organic solvent. It is simple and inexpensive to
carry these reactions out. The high regioselective monoacetylation
of 2-substituted (Z)-but-2-ene-1,4-diols has been achieved easily
7
variety of sigma agonists protect against amyloid b (Ab)25–35
-
in the presence of PPL. Substituted cinnamyl alcohols were con-
3
induced toxicity in cultured neurons, and prevent memory deficits
verted to the corresponding 2,3-methanopropan-1-ols up to quan-
titative yield and 86% ee by the catalytic enantioselective
Simmons–Smith reaction in the presence of our developed chiral
4
when Ab25–35 is injected intracerebroventricularly in mice. There-
fore, induction or activation of sigma-1 receptors could improve
ligand which was prepared cheaply and easily from L-phenylala-
8
nine in five steps. Then, the amidations of mixed carbonic
carboxylic anhydrides afforded dipeptides, primary amides, and
⇑
Corresponding author. Tel./fax: +81 479 30 4610.
E-mail address: nimai@cis.ac.jp (N. Imai).
http://dx.doi.org/10.1016/j.tetlet.2015.12.113
040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
0
Please cite this article in press as: Kawashima, Y.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2015.12.113

2
Y. Kawashima et al. / Tetrahedron Letters xxx (2016) xxx–xxx
P-Cl, pyridine,
MeONa, MeOH,
rt, 3 h
anilides in the presence of primary amines, ammonium chloride,
and anilines in aqueous organic solvent.
Ph
OAc
rt, 24 h or 90 h
Ph
OAc
Ph
OH
9
or
or
HO
PO
PO
(
Me
Et N, DMAP
THF, rt, 24 h
3
Si)
3
SiCl,
DIBAL-H, THF,
Herein, we describe convenient enantioselective synthesis of
o
2
3a (P = t-BuPh Si): quant.
1
3
2a (P = t-BuPh Si): 97%
2
-78 C, 24 h
(
+)-AMMP via our developed reactions as shown in Scheme 1.
-O-Protected (Z)-3-phenylbut-2-en-1-ols 3a–3e were initially
2b (P = t-BuMe Si): 96%
3b (P = t-BuMe
3c (P = (t-BuO)Ph
3d (P = (Me Si) Si): 83%
2
Si): 90%
2
2
2
2
c (P = (t-BuO)Ph
2
Si): 91%
Si ): 86%
C): 94%
2
Si): quant.
4
d (P = (Me
e (P = Ph
3
Si)
3
3
3
3
3e (P = Ph C): 68%
3
prepared for substrates in the catalytic enantioselective Simmons–
Smith reaction in order to select the suitable protecting group as
indicated in Scheme 2. The monoacetate 1 was easily prepared in
the regioselective monoacetylation of (Z)-2-phenylbut-2-ene-1,4-diol
Scheme 2. Preparation of 4-O-protected (Z)-3-phenylbut-2-en-1-ols 3a–3e.
7
a
using PPL. The hydroxy group of the monoacetate 1 was protected
by various protecting groups to give the corresponding protected
monoacetates 2a–2e in 86–97% yields, followed by deacetylation
to afford the desired 3a–3e in 68%-quantitative yields.10
Table 1
Simmons–Smith reaction of 4-O-protected (Z)-3-phenylbut-2-en-1-ols 3a–3ea
Ph
In
butyldiphenylsiloxy-3-phenylbut-2-en-1-ol (3a) with 2.0 equiv of
Et Zn and 3.0 equiv of CH in the presence of 0.1 equiv of chiral
ligand 4 in anhydrous CH Cl at 0 °C for 3 h afforded (+)-cis-4-
a
preliminary investigation, the reaction of (Z)-4-tert-
4
∗
Ph
OH
MsHN
NHTs
Ph ∗
OH
2
2
I
2
P
O
Et Zn, CH I , CH Cl ,
2
2
2
2
2
P
O
3a-3e
5a-5e
0 oC, 24 h
2
2
tert-butyldiphenylsiloxy-2,3-methano-3-phenylbutan-1-ol
in quantitative yield with 71% ee (see entry 1 of Table 1).
(5a)
1
1
Entry
Product
P
Yield (%)
ee (%)
b
(
Z)-4-tert-Butyldimethylsiloxy-3-phenylbut-2-en-1-ol (3b) was
converted to the corresponding 2,3-methano-3-phenylbutan-1-ol
b in 93% yield with 48% ee (see entry 2). Then, lower enantioselec-
tivities (21% and 2% ee) were obtained in the reactions of 4-siloxy
Z)-3-phenylbut-2-en-1-ols 3c and 3d, respectively (see entries 3
1
2
3
4
5
5a
5b
5c
5d
5e
t-BuPh
t-BuMe
t-BuOPh
(Me Si)
Ph
2
Si
Quant.
93
66
38
89
71
48
21
2
2
Si
2
Si
5
3
3
Si
3
C
19
(
a
All reactions were carried out with 4-O-protected (Z)-3-phenylbut-2-en-1-ol 3,
.0 equiv of Et Zn, and 3.0 equiv of CH in anhydrous CH Cl
Determined by HPLC analysis with a 95:5 mixture of hexane and 2-propanol as
and 4). The reaction of (Z)-4-triphenylmethoxy-3-phenylbut-2-
en-1-ol (3e) proceeded to give the corresponding 2,3-methano-3-
phenylbutan-1-ol 5e in 89% yield, but the enantioselectivity
2
2
2
I
2
2
2
.
b
an eluent using Chiralcel OD (1.0 mL/min).
(
19% ee) was also low (see entry 5). The results of these reactions
are summarized in Table 1.
Subsequently, the 2,3-methano-3-phenylbutan-1-ol 5a was oxi-
dized with 2-iodoxybenzoic acid (IBX) in dimethylsulfoxide
O
O
I
O
(
DMSO) at rt for 3 h to afford the corresponding 2,3-methano-3-
phenylbutan-1-al 6a in 94% yield, which was converted with
NaClO , H , and NaH PO in acetonitrile (MeCN)–H O at rt for
h to the corresponding 2,3-methano-3-phenylbutanoic acid 7a
∗
∗
∗
Ph ∗
OH (IBX)
O
Ph
H
2 2 2
NaClO , H O
Ph ∗
OH
∗
O
O
7a
t-BuPh
2
SiO
5a
DMSO,
rt, 3 h
t-BuPh
2
SiO
NaH PO , MeCN-H O, t-BuPh SiO
2
2
O
2
2
4
2
6
a
2
4
2
2
rt, 3 h
3
9
4%
98%
in 98% yield as indicated in Scheme 3.
Next, we undertook to examine the amidation of 3-phenylpro-
Scheme 3. Preparation of the 2,3-methano-3-phenylbutanoic acid 7a.
0
pionic acid (7 ) with sterically hindered 1-adamantanamine in
aqueous organic solvent in order to optimize the reaction
conditions. The results are summarized in Table 2. Treatment
Table 2
0
of
7
with 1.1 equiv of 1-adamantanamine hydrochloride
The amidation of 3-phenylpropionic acid (7
conditions
0
)
for optimization of the reaction
Ò
a
2
(amantadine ) in the presence of 1.1 equiv of ClCO Et and 1.1 equiv
of Et
3
N in MeCN–H
2
O afforded N-adamantyl-3-phenylpropanamide
0
O
ClCO
2 3
Et, Et N
O
O
(8 ) in 27% yield (see entry 1). The reaction of 1-adamantanamine
Ò
Ph
OH
acetone,
Ph
O
OEt
O
sulfate, which is cheaper than amantadine , did not afford the cor-
responding amide 8 because 1-adamantanamine sulfate is hardly
0 oC, 30 min
0
7'
dissolved in organic solvents nor water (see entry 2). The amida-
tion of 7 with 1-adamantanamine sulfate in the presence of
1
-Ad-NH
2
2 4
1/2H SO
0
Ad
Ph
N
H
1.0 M aq. base
2
.0 equiv of 1.0 M aqueous NaHCO
3
and NaOH solution gave the
8
'
Entry
Base
equiv of base
Time (h)
Yieldd (%)
b
Me
1
Free
Free
—
—
6
8
20
1
27
0
∗
∗
H
N
c
Ph∗
HO
N
Ph∗
amidation
∗
2
Ph∗
OH
Ad
Ad
3
4
5
6
7
8
9
NaHCO
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
3
2.0
2.0
2.0
2.0
2.0
1.1
3.0
16
42
58
84
82
46
65
O
O
P
O
P
O
(
+)-AMMP
6
24
48
24
24
catalytic enantioselective
Simmons-Smith reaction
∗
Ph∗
OH
Ph
OH
P
O
P O
a
0
All reactions were carried out with 0.5 mmol of 3-phenylpropionic acid (7 ),
.1 equiv of 1-adamantanamine sulfate (1-Ad-NH SO ), 1.1 equiv of ClCO Et,
ꢀ1/2H
and 1.1 equiv of Et N in 10 mL of acetone.
-adamantanamine hydrochloride (Ad-NH
P = protecting group
1
2
2
4
2
3
b
Ph
OAc
regioselective acetylation
Ph
OH
1
2
ꢀHCl) was used instead of 1-
adamantanamine sulfate (1-Ad-NH
ꢀ1/2H
2 2 4
SO ) in a mixture of 10 mL of MeCN and
HO
HO
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
Scheme 1. Retrosynthetic analysis of (+)-AMMP via the three key reactions.
Please cite this article in press as: Kawashima, Y.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2015.12.113

Y. Kawashima et al. / Tetrahedron Letters xxx (2016) xxx–xxx
3
∗
1) ClCO Et, Et N, acetone, 0
o
C, 30 min
∗
H
enantioselective Simmons–Smith reaction in the presence of
Ph ∗
OH
2
3
Ph ∗
N
Ad
8
L-phenylalanine-derived disulfonamide, and the convenient
O
7
2) 1-Ad-NH2 1/2H SO ,
O
t-BuPh
2
SiO
2
4
t-BuPh
2
SiO
amidation of mixed carbonic carboxylic anhydrides in aqueous
a
1.0 M aq. NaOH, 0 C, 24 h
o
8a
8
2% ee
9
organic solvent. Currently, we are still working on enantioselective
8
8%
synthesis of (+)-AMMP analogs.
Scheme 4. Preparation of the 2,3-methano-3-phenylbutanamide 8a.
References and notes
H
N
Me
1. (a) Querfurth, H. W.; LaFerla, F. M. N. Engl. J. Med. 2010, 362, 329–344; (b)
Hardy, J.; Selkoe, D. J. Science 2002, 297, 353–356.
∗
H
N
Ph ∗
∗
MeI
∗
Ad
LiAlH
toluene,
C to 100 C, 18 h
2 %
4
Ph ∗
HO
Ph ∗
HO
N
Ad
Ad
O
a
DMF,
2. (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.
3. (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.
t-BuPh
2
SiO
8
70
o
o
9a
6% ee
80 C, 2 h
o
8
(
+)-AMMP
7
68%
Scheme 5. Synthesis of (+)-AMMP via reduction and methylation from the 2,3-
methano-3-phenylbutanamide 8a.
4
.
(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.
(a) Froestl, W.; Muhs, A.; Preifer, A. J. Alzheimers Dis. 2014, 41, 961–1019; (b)
Villard, V.; Espallergues, J.; Keller, E.; Vamvakides, A.; Maurice, T. J.
Psychpharmacol. 2011, 25, 1101–1117.
Ph
OAc
Ph
OAc
MeONa
Ph
OH vinyl acetate, PPL
,4-dioxane, rt, 24 h HO
1%
t-BuPh
2
SiCl
1
pyridine, rt, 24 h t-BuPh
2
SiO
MeOH,
rt, 3 h
quant.
HO
1
2a
9
97%
5.
Ph
4
∗
Ph
OH
∗
Ph ∗
H
MsHN
NHTs
Ph ∗
t-BuPh SiO
OH
IBX
O
6a
t-BuPh
2
SiO
Et Zn, CH I , CH Cl ,
DMSO, t-BuPh SiO
6. Marrazzo, A.; Prezzavento, O.; Pappalardo, M. S.; Bousquet, E.; Indanza, M.;
Pike, V. W.; Ronsisvalle, G. Farmaco 2002, 57, 45–53.
7. (a) Koyata, N.; Nagai, T.; Kawasaki, M.; Noguchi, T.; Kirihara, M.; Imai, N. Chem.
Lett. 2009, 38, 892; (b) Miura, T.; Umetsu, S.; Kanamori, D.; Tsuyama, N.; Jyo, Y.;
Kawashima, Y.; Koyata, N.; Murakami, Y.; Imai, N. Tetrahedron 2008, 64, 9305–
2
2
2
2
2
2
3
a
2
5a
1% ee
o
rt, 3 h
0
C, 24 h
7
9
4%
quant.
∗
o
NaClO
NaH PO , MeCN-H
2
, H
2
O
2
Ph ∗
OH
1) ClCO Et, Et N, acetone, 0
2
3
C, 30 min
9308; (c) Miura, T.; Okazaki, K.; Ogawa, K.; Otomo, E.; Umetsu, S.; Takahashi,
O
2
4
2
O,
t-BuPh SiO
2
2) 1-Ad-NH2 1/2H SO ,
2
4
M.; Kawashima, Y.; Jyo, Y.; Koyata, N.; Murakami, Y.; Imai, N. Synthesis 2008,
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.
rt, 3 h
7a
1.0 M aq. NaOH, 0 C, 24 h
o
9
8%
88%
Me
N
∗
∗
H
∗
H
Ph ∗
HO
Ph ∗
N
Ph ∗
N
Ad
Ad
LiAlH
toluene,
4
Ad
MeI, NaHCO3
O
t-BuPh
2
SiO
HO
DMF,
80 C, 2 h
8%
8. (a) Koyata, N.; Miura, T.; Akaiwa, Y.; Sasaki, H.; Sato, R.; Nagai, T.; Fujimori, H.;
Noguchi, T.; Kirihara, M.; Imai, N. Tetrahedron: Asymmetry 2009, 20, 2065–
70 oC to 100 oC, 18 h
72%
8
a
9a
86% ee
o
(
+)-AMMP
8
2% ee
6
2
3
071; (b) Miura, T.; Murakami, Y.; Imai, N. Tetrahedron: Asymmetry 2006, 17,
067–3069; (c) Imai, N.; Nomura, T.; Yamamoto, S.; Ninomiya, Y.; Nokami, J.
3
5% overall yield
Tetrahedron: Asymmetry 2002, 13, 2433–2438; (d) Imai, N.; Sakamoto, K.;
Maeda, M.; Kouge, K.; Yoshizane, K.; Nokami, J. Tetrahedron Lett. 1997, 38,
Scheme 6. Convenient enantioselective total synthesis of (+)-AMMP.
1423–1426.
9.
(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.
0
desired amide 8 in 16% and 42% yield, respectively (see entries 3
0
and 4). Moreover, the amidation of 7 with 1-adamantanamine sul-
fate in the presence of 2.0 equiv of 1.0 M aqueous NaOH solution
0
was carried out for 6, 24, and 48 h to afford the amide 8 in 58%,
8
10. The protected allylic alcohols 3a–3c were prepared from the corresponding
2a–2c by the reaction with a catalytic amount (3 drops) of 28% MeONa solution
in MeOH in 20 mL of an additional MeOH. The protected allylic alcohols 3d, 3e
were prepared from the corresponding 2d, 2e by the reaction with 2.0 equiv of
diisobutylalminium hydride (DIBAL-H) in 5 mL of tetrahydrofuran (THF).
11. A typical procedure of cyclopropanation of 3a in the presence of a catalytic amount
of 4 as follows: To a colorless solution of 201 mg (0.50 mmol) of 3a and 19 mg
4%, and 82% yield, respectively (see entries 5–7). Then, the reac-
tion 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).
Furthermore, the amidation of the 2,3-methano-3-phenyl-
butanoic acid 7a with 1-adamantanamine sulfate was performed on
the optimized conditions to afford the 2,3-methano-3-phenyl-
(
0.05 mmol, 0.1 equiv) of the disulfonamide 4 in 7.5 mL of anhydrous CH
were added dropwise at ꢁ40 °C under argon atmosphere 1.0 mL (1.0 mmol, 2.0
equiv) of 1.0 M Et Zn solution in hexane and 121 L (1.5 mmol, 3.0 equiv) of
CH I . After stirring at 0 °C for 3 h, the reaction mixture was quenched with
2 2
Cl
2
l
1
2
2
2
butanamide 8a in 88% yield as indicated in Scheme 4. It was
achieved to convert from (+)-cis-4-tert-butyldiphenylsiloxy-
0
.3 mL of Et
combined, washed with 5 mL of brine, dried over MgSO
evaporated. The crude product was purified by column chromatography on
silica gel with 8:1 mixture of hexane and EtOAc to afford 208 mg
(quantitative yield) of the corresponding 2,3-methano-3-phenylbutan-1-ol
3
N and extracted with 20 mL ꢂ 3 of EtOAc. The organic layers were
4
,
filtered, and
2
,3-methano-3-phenylbutan-1-ol (5a) to the corresponding
,3-methano-3-phenylbutanamide 8a in three steps without the
Fortunately, treatment of the
,3-methano-3-phenylbutanamide 8a with 5.0 equiv of lithium
aluminium hydride in anhydrous toluene afforded the correspond-
ing 2,3-methano-2-phenylbutan-1-ol 9a in 72% yield with 86% ee
through two reductions in the amide part and the silyl group
simultaneously.
Finally, (+)-AMMP was acquired in 68% yield by methylation
of the amino alcohol 9a with methyl iodide as shown in Scheme 5.
In conclusion, we have succeeded in a convenient enantioselec-
tive synthesis of (+)-cis-4-(N-adamantyl-N-methylamino)-2,3-
methano-2-phenylbutan-1-ol ((+)-AMMP) in 35% overall yield
without the loss of enantiomeric excess as summarized in
Scheme 6. The reagents used in our synthetic route are relatively
cheap. Then, the following three reactions are utilized as a key
reaction; the regioselective acetylation using PPL,7 the catalytic
a
2
13
loss of enantiomeric excess.
28
1
5
a. 5a: colorless oil; 71% ee; [
D 3 3
a] +51.2 (c 1.02, CHCl ); H NMR (CDCl ): d 0.69
2
(t, J = 5.3 Hz, 1H, CHA of cyclopropane), 0.96 (s, 9H, C(CH ) ), 0.96–0.99 (m, 1H,
3
3
CH
OH), 3.55 (d, J = 11.2 Hz, 1H, CH
CH OSiPh Bu-tert), 4.12–4.19 (m, 1H, CH
B
B
of cyclopropane), 1.81–1.89 (m, 1H, CHCH
O SiPh Bu-tert), 4.06 (d, J = 11.2 Hz, 1H,
OH), 7.05–7.07, 7.11–7.15, 7.28–7.45,
2 A
OH), 3.45–3.59 (m, 2H, CH OH,
1
4
A
2
B
2
13
7.56–7.59 (m, m, m, m, 2H, 2H, 9H, 2H, C H5 ꢂ 3); C NMR (100 MHz, CDCl ) d
6
3
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,
1
5
130.6, 131.7, 132.7, 135.4, 135.5, 143.9; HRMS (ESI-TOF): Calcd for
+
C
27
H
32
O
2
SiNa (M+Na) : 439.2064, Found: 439.2069.
12. A typical procedure of the amidation of 7a with 1-adamantanamine sulfate as
follows: To a solution of 124 mg (0.29 mmol) of the acid 7a in 6 mL of acetone
were added dropwise at 0 °C 30
l
L (0.32 mmol, 1.1 equiv) of ClCO
N. After stirring for 30 min at 0 °C, 63 mg
0.32 mmol, 1.1 equiv) of 1-adamantanamine sulfate and 0.58 mL
2
Et and 44 lL
(
(
0.32 mmol, 1.1 equiv) of Et
3
(0.58 mmol, 2.0 equiv) of 1.0 M aqueous NaOH solution were added at 0 °C
to the colorless suspension. The mixture was stirred for 24 h at 0 °C, diluted
with 30 mL of EtOAc, washed with 5 mL of brine, and dried over anhydrous
MgSO
4
. The crude product was chromatographed on silica gel with a 6:1
mixture of hexane and EtOAc to afford 143 mg (88% yield) of the corresponding
Please cite this article in press as: Kawashima, Y.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2015.12.113

4
Y. Kawashima et al. / Tetrahedron Letters xxx (2016) xxx–xxx
2
8
2
1
1
1
2
4
C
4
1
5
,3-methano-3-phenylbutanamide 8a. 8a: colorless oil; 82% ee; [
a
]
D
+43.4 (c
), 1.14 (dd, J = 4.7, 8.1 Hz,
of cyclopropane), 1.43 (dd, J = 4.7, 5.7 Hz, 1H, CH of cyclopropane),
.67 (br s, 6H, CH
ꢂ 3 of adamantane), 1.82 (dd, J = 5.7, 8.1 Hz, 1H, CHCON),
.04 (br s, 9H, CH O),
ꢂ 3, CH ꢂ 3 of adamantane), 3.89 (d, J = 10.5 Hz, 1H, CH
.05 (d, J = 10.5 Hz, 1H, CH O), 5.51 (br s, 1H, NH), 7.16–7.50 (m, 15H,
ꢂ 3); C NMR (100 MHz, CDCl ) d 16.1, 19.2, 26.8, 28.3, 29.5, 36.4, 36.8,
1.8, 52.1, 65.9, 126.8, 127.3, 127.5, 127.7, 128.0, 129.2, 129.3, 130.1, 133.4,
14. Determined by HPLC analysis with a 95:5:0.05 mixture of hexane, EtOH, and
Et NH as an eluent using Chiralcel OD (1.0 mL/min).
15. (+)-AMMP: colorless oil; 86% ee; [
0.76, 1.21–1.25 (t, m, J = 5.1 Hz, 1H, 1H, CH
1H, CHCH N), 1.60–1.68 (m, 6H, CH
ꢂ 3 of adamantane), 2.10 (br s, 3H, CH ꢂ 3 of adamantane), 2.36 (s, 3H,
), 2.66 (dd, J = 10.4, 12.7 Hz, 1H, CH N), 2.81 (dd, J = 5.6, 12.7 Hz, 1H, CH N),
O), 4.12 (d, J = 12.3 Hz, 1H, CH O), 6.73 (br s, 1H,
OH), 7.17–7.21, 7.27–7.31, 7.40–7.43 (m, m, m, 1H, 2H, 2H, C
(100 MHz, CDCl ) 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, cm ): 2904, 2850, 2366, 2322; HRMS
1
.00, CHCl
H, CH
3
); H NMR (CDCl
3
): d 0.92 (s, 9H, C(CH
3
)
3
2
2
8
); 1H NMR (CDCl
): d
3 3
A
B
a
]
D
+42.8 (c 0.90, CHCl
of cyclopropane), 1.39–1.47 (m,
ꢂ 3 of adamantane), 1.76 (d, J = 2.8 Hz, 6H,
2
2
2
A
2
2
B
CH
CH
2
13
6
H
5
3
3
A
B
3.41 (d, J = 12.3 Hz, 1H, CH
A
B
+
13
33.7, 135.6, 143.6, 169.2; HRMS (ESI-TOF): Calcd for C37
86.3112, Found: 586.3122.
H
45
O
2
SiNa (M+Na) :
6 5
H ); C NMR
3
ꢁ
1
1
3. Determined by HPLC analysis with a 95:5 mixture of hexane and 2-propanol as
an eluent using Chiralcel OD-H (1.0 mL/min).
+
(ESI-TOF): Calcd for C22H32NO (M+H) : 326.2484, Found: 326.2498.
Please cite this article in press as: Kawashima, Y.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2015.12.113