New aminopropandiol derivatives as orally available and short-acting calcium-sensing receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2010.04.035

Synthesis and structure-activity relationship studies on a new aminopropandiol class of derivatives as calcium-sensing receptor antagonists are described. Modification of the phenolic moiety of a calcilytic compound NPS 2143 led to the identification of a

Full text of DOI:10.1016/j.bmcl.2010.04.035

Bioorganic & Medicinal Chemistry Letters 20 (2010) 3809–3813
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
New aminopropandiol derivatives as orally available and short-acting
calcium-sensing receptor antagonists
*
*
Yuko Shinagawa , Teruhiko Inoue, Kazuyuki Hirata, Takeo Katsushima , Takashi Nakagawa,
*
Yushi Matsuo, Masanori Shindo, Hiromasa Hashimoto
Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis and structure–activity relationship studies on a new aminopropandiol class of derivatives as
calcium-sensing receptor antagonists are described. Modification of the phenolic moiety of a calcilytic
compound NPS 2143 led to the identification of an orally available compound (R,R)-31 which demon-
strated a rapid and transient stimulation of PTH release in rats.
Received 8 January 2010
Revised 31 March 2010
Accepted 10 April 2010
Available online 14 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Calcium-sensing receptor
Antagonist
CaSR antagonist
PTH
Osteoporosis
Calcilytics
Osteoporosis is a bone disease associated with progressive de-
crease in bone mass and strength, leading to a significant increase
in the risk of fracture. More than 75 million people in Japan, US,
and Europe suffer from osteoporosis today, resulted in more than
2.3 million osteoporotic fractures every year in the US and Europe.1
The prevention and treatment for the disease is increasingly linked
with the growth of the elderly population in those countries.
The current drug therapies for osteoporosis are mainly bisphos-
phonates and include other anti-resorptive agents such as estrogen
and selective estrogen receptor modulators (SERM).2
In recent reports, daily subcutaneous injection of Teriparatide, a
recombinant 1–34 amino acid fragment of human parathyroid hor-
mone (PTH 1–34) in postmenopausal women improved bone min-
eral density in the lumbar spine and reduced fracture rates by
65%.3 Teriparatide has been approved by the FDA as an anabolic
agent.
The search for anabolic agents other than PTH has focused on
orally available calcium-sensing receptor (CaSR) antagonists, and
has developed into a competitive research area. CaSR is a heptah-
elical G-protein-coupled receptor expressed on the surface of para-
thyroid cells and regulates PTH secretion by detecting extracellular
calcium ion concentrations. Lower extracellular Ca2+ levels attenu-
ate CaSR signaling and lead to a stimulation of PTH release.4 Antag-
onists acting on the parathyroid CaSR, known as calcilytics, could
mimic low extracellular Ca2+ concentrations and stimulate PTH
secretion. Although intermittent exposure to PTH by subcutaneous
injection stimulates new bone formation and leads to bone mass
increase, prolonged exposure to elevated PTH increases bone turn-
over and results in the loss of bone.5 Thus, PTH can act both as an
anabolic and as a catabolic agent, depending on the pattern of the
exposure. The profile needed for an orally available anabolic agent
is one, that is, rapidly absorbable and short acting. Pharmaceutical
companies have directed much effort toward the discovery of a
small molecule CaSR antagonist with these desired characteristics.
Several classes of compounds have been reported recently6 and
several compounds including Ronacaleret7 and JTT-305 (MK-
5442)8 have been advanced to clinical trials.
NPS 2143 (Fig. 1) is one of the first reported orally available
small molecule calcilytics which has been shown to stimulate
PTH secretion.9 However, this compound did not exert a net in-
crease in bone mass in ovariectomized (OVX) rats due to the long
plasma half-life resulting in sustained high PTH levels and thereby
CN
OH
H
N
O
Cl
* Corresponding authors.
E-mail addresses: yuko.shinagawa@jt.com (Y. Shinagawa), takeo.katsushima@
jt.com (T. Katsushima), hiromasa.hashimoto@jt.com (H. Hashimoto).
Figure 1. Structure of NPS 2143.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.04.035

3810
Y. Shinagawa et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3809–3813
Table 1
accelerated bone turnover. We were interested in this molecule
and considered that the undesired pharmacokinetic character
could be revised by changing the molecular structure. Here, we re-
port a new aminopropandiol class of compounds which evoked ra-
pid and transient increases of plasma PTH levels in rats after oral
administration.
In vitro hCaSR antagonist activity of the aminopropandiol derivatives
OH
H
O
N
R
The compounds synthesized for this study were tested in the
human CaSR reporter gene assay using PC12h cells transfected
with zif promoter/luciferase and hCaSR plasmids.10 We started
our investigation from the phenoxy part of the molecule to evalu-
ate if we could change the structure while keeping the high antag-
onist potency. Our first attempt was to replace the phenyl ether
bond with a metabolically unstable ester (compound 1) or benzyl
ether (compound 2), which resulted in loss of the activity in the es-
a
Compd
R
hCaSR IC50
0.026
(lM)
NPS 2143
*
1
>30
O
2
3
0.56
0.22
ter 1 but maintained an antagonist activity with IC50 of 0.56 lM in
*
*
the benzyl ether 2 (Table 1). Although the potency of compound 2
was ꢀ20-fold weaker compared with that in NPS 2143, it was
acceptable as a starting point. An introduction of a Me group (3)
on the benzylic position slightly increased the potency compared
to 2, while further addition of a second Me group, dimethyl com-
pound 4, decreased the potency ꢀ10-fold. Lengthening the chain
to a phenethyl substituent (compounds 5 and 6) showed 2- to 4-
fold decrease in potency compared with 3, and the phenyl propyl
compound 7 exhibited no improvement in potency. Changing the
benzene ring to pyridine (8) or naphthyl rings (9, 10) had no effect.
Therefore, the benzyloxy derivative was the optimal structure.
We then focused on the substituent at the benzylic position
(Table 2). Addition of an ethyl group (11) slightly increased the po-
tency compared to Me (3). The vinyl group (12), n-Pr (13), i-Pr (14)
and n-Bu (15) groups were as potent as Me (3), while the more
bulky t-Bu group (16) decreased the potency. Small size cycloalkyl
4
5
2.24
0.44
*
*
*
6
7
8
9
0.81
0.30
0.42
0.55
*
*
N
substituents (cyclopropyl 17, IC50 of 0.070
lM and cyclobutyl 18,
*
IC50 of 0.074 M) showed a threefold increased activity compared
l
to 3 and were about eightfold more potent than the non-substi-
tuted benzyloxy derivative 2. Expansion of the ring size to cyclo-
pentyl (19) and cyclohexyl (20) decreased the potency in
accordance with the ring size. Changing to an aromatic ring, Ph
(21), also decreased the potency.
*
10
0.36
We then examined the substituent on the phenyl ring (Table 3).
Introduction of a Cl atom (22–24) or Me group (25–27) showed
similar potencies regardless of the position on the phenyl ring.
Since it was unknown if these new compounds are orally avail-
able at this stage, we tested compounds 22–27 for PTH secretion
study in rats and compared the outcomes with NPS 2143.11 Sub-
stantial increases of endogenous plasma PTH (PTH 1–34) levels
equivalent to the increases in NPS 2143 after oral administration
of the compounds were observed only for the 2-Me derivative 25
(Table 3). Then, other substituents on the 2 position were exam-
ined. The 2-OMe (28) and 2-CN (29) derivatives showed similar
IC50 values, while 2-NO2 (30) decreased the potency. Among these,
28 showed a comparable efficacy as 25 in the PTH secretion study.
Given these results, we chose the 2-Me and 2-OMe groups for the
substituents on the phenyl ring and synthesized cyclopropyl deriv-
atives at the benzylic position. Both 31 and 32 showed increased
antagonist potencies compared to the corresponding methyl ver-
sions 25 and 28, and demonstrated robust increases in PTH levels
a
In vitro hCaSR antagonist activity was determined in PC12h cells, as described
in Ref. 10. Values are means of two or more experiments.
Table 2
In vitro hCaSR antagonist activity of the benzyloxy analogues
OH
H
O
N
R
a
Compd
R
hCaSR IC50 (lM)
11
12
13
14
15
16
17
18
19
20
21
Et
0.092
0.21
0.15
0.20
0.17
0.57
0.070
0.074
0.20
0.61
0.73
in rats. We identified compound 31 (IC50 = 0.037 lM) as the most
potent candidate of all those shown in Table 3.
vinyl
n-Pr
i-Pr
n-Bu
t-Bu
Cyclopropyl
Cyclobutyl
Cyclopentyl
Cyclohexyl
Ph
Compound 31 has two chiral centers and is a diastereomixture
of the cyclopropyl group possessing the (R)-configuration of the
secondary alcohol in the aminopropandiol unit. We prepared all
four enantiomers to investigate the effect of the stereochemistry
on the antagonist activity (Table 4). Diastereomers having an (R)-
configuration of the cyclopropyl group, (R,R)-31 and (R,S)-31,
appeared more potent than the corresponding (S)-diastereoiso-
mers, (S,R)-31 and (S,S)-31, showing a preference for the (R)-con-
a
Values are means of two or more experiments.

Y. Shinagawa et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3809–3813
3811
Table 3
In vitro hCaSR antagonist activity and rat in vivo PTH secretion activity of the
substituted benzyloxy analogues
OH
R2
H
O
N
R1
R1
R2
hCaSR IC50 (lM)
PTH secretionb
a
Compd
22
23
24
25
26
27
28
29
30
31
32
Me
Me
Me
Me
Me
Me
Me
Me
2-Cl
3-Cl
4-Cl
0.14
0.22
0.20
0.20
0.17
0.14
0.12
0.54
0.16
0.037
0.041
N.E.
N.E.
—
++
+
N.E.
++
N.E.
+
++
++
2-Me
3-Me
4-Me
2-OMe
2-NO2
2-CN
2-Me
2-OMe
Figure 2. Time courses of PTH 1–84 levels after oral administration of (R,R)-31 1/2
fumarate in rats. Data are expressed as mean values standard deviation, n = 5.
Me
Cyclopropyl
Cyclopropyl
a
Values are means of two or more experiments.
Serum PTH 1–34 increases (D) from the basal levels at 30 min and 60 min after
b
commercially available alcohols 35 by alkylation with (R)-(À)-glyc-
idyl 3-nitrobenzenesulfonate in the presence of NaH in DMF to give
a glycidyl ether 36, followed by the epoxide-opening reaction with
the amine 34 (Scheme 2). Other compounds in Tables 1–3 were
synthesized from the corresponding secondary alcohol 39, pre-
pared either from the aldehyde 37 by Grignard reaction in THF or
the ketone 38 by the reduction with LiAlH4 or NaBH4 (Scheme 3).
The alcohol 39 was converted to the glycidyl ether 40 and then
to compounds 8, 11, 13, 18–20, 25, 26, 28–32 by the same method
described above. The syntheses of the four stereoisomers of com-
pound 31 are described in Scheme 4. 2-Methylbenzoylchloride
was converted to the Weinreb amide and reacted with cyclopropyl
magnesium bromide to give a ketone 41. Hydrogenation (0.5 MPa)
of the ketone in the presence of RuCl2[(S)-BINAP](dmf)n-(S,S)-1,2-
diphenylethylenediamine13 and KOt-Bu in i-PrOH at room temper-
ature gave an (R)-alcohol 42 in 74% ee, which was converted to a
glycidyl ether 43 by the alkylation with (R)-(À)-glycidyl 3-nitro-
benzenesulfonate. An epoxy-opening reaction by the amine 34
oral administration of the compounds (100 mg/kg) in rats (n = 5) were compared
with the increases (10–24 pg/mL) in NPS 2143 (100 mg/kg, po). ++: >80% of NPS
2143, +: 50–80% of NPS 2143, N.E.: <50% of NPS 2143.
Table 4
Effect of the stereochemistry in compound 31 on in vitro hCaSR antagonist activity
OH
H
O
N
*
*
a
Compd
Cyclopropyl
OH
hCaSR IC50 (lM)
(R,R)-31
(S,R)-31
(R,S)-31
(S,S)-31
R
S
R
S
R
R
S
S
0.023
0.083
0.31
0.76
a
Values are means of two or more experiments.
b, c
a
O
O
O
HO
figuration on the benzylic position. Diastereomers possessing the
(R)-configuration of the OH group are 10-fold more potent than
the corresponding (S)-OH diastereomers respectively ((R,R)-31 ver-
sus (R,S)-31, (S,R)-31 versus (S,S)-31). Consequently, of all four iso-
mers, (R,R)-31 was found to be the most potent variant with an IC50
O
33
OH
H
N
O
value of 0.023 lM, and is as potent as NPS 2143.
O
· HCl
Compound (R,R)-31 was advanced to a PTH secretion time
course study in rats. A rapid and transient increase of endogenous
plasma PTH 1–84 levels, maximal at 30 min and restored to base-
line within 2 h, was observed from a 10 mg/kg oral administration
of (R,R)-31 (Fig. 2). This result meets the needed PTH response pro-
file for a bone anabolic agent. A pharmacokinetic study of this com-
1
Scheme 1. Reagents and conditions: (a) benzoyl chloride, Et3N, CHCl3; (b) [1,1-
dimethyl-2-(2-naphthalenyl)ethyl]amine (34), EtOH, 60 °C; (c) 4 N HCl/AcOEt, Et2O.
pound in rats (10 mg/kg, po) showed plasma Cmax of 0.3 lM, Tmax of
OH
H
1 h, and T1/2 of 2 h, suggesting a rapid absorption and a short dura-
tion of action, although bioavailability was low (13%). Unfortu-
nately, this compound showed a strong inhibition for cytochrome
b, c
O
a
O
N
R OH
O
R
R
35
36
P450 2D6 with an IC50 of 0.5 lM.
HCl salt: 2-6,9,10,12,15,16,21-23,27
Free amine: 7,14,17,24
The syntheses of the compounds tested in this Letter are de-
scribed in Schemes 1–4.12 Glycidol was benzoylated to give a glyc-
idyl ester 33, which was reacted with an amine 3410 in EtOH at
60 °C to afford compound 1 (Scheme 1). Compounds 2–7, 9, 10,
12, 14–17, 21–24 and 27 were prepared from the corresponding
Scheme 2. Reagents and conditions: (a) (R)-(À)-glycidyl 3-nitrobenzenesulfonate,
NaH, DMF, rt; (b) [1,1-dimethyl-2-(2-naphthalenyl)ethyl]amine (34), EtOH, 60 °C;
(c) 4 N HCl/AcOEt, Et2O, (except for 7, 14, 17, 24).

3812
Y. Shinagawa et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3809–3813
afforded (R,R)-31 in 74% de. Recrystallization from n-hexane raised
a
Ar CHO
the de to >95%. The absolute configuration was established by sin-
gle-crystal X-ray diffraction analysis of (R,R)-31 HCl salt (Fig. 3).14
Alkylation of 42 with (S)-(+)-glycidyl 3-nitrobenzenesulfonate to
give a glycidyl ether 44 followed by the epoxide-opening reaction
afforded (R,S)-31 (74% de). The (S)-alcohol 45 was prepared from
the ketone 41 by the hydrogenation using (R)-BINAP-Ru-(R,R)-dia-
mine catalyst in 74% ee, and converted to (S,R)-31 and (S,S)-31 in
74% de via the glycidyl ethers 46 and 47, respectively, by the same
method described above.
37
O
Ar
O
Ar
OH
b or c
d
Ar
O
R1
R1
R1
38
39
40
OH
e, f
H
N
Ar
O
R1
In conclusion, we have identified a new orally available amino-
propandiol class of calcilytics. The most potent compound (R,R)-
31 significantly stimulated endogenous PTH secretion in rats with
a rapid and transient increase of plasma PTH levels, which is an
needed profile for an anabolic effect. Further study toward the
development of a clinical candidate will be reported in due
course.
HCl salt: 8,11,13,18-20,25,26,28-30
Free amine: 31,32
Scheme 3. Reagents and conditions: (a) R1MgBr , THF, 0 °C to rt; (b) LAH, THF, 0 °C
to rt; (c) NaBH4, MeOH, 0 °C to rt; (d) (R)-(À)-glycidyl 3-nitrobenzenesulfonate,
NaH, DMF, rt; (e) [1,1-dimethyl-2-(2-naphthalenyl)ethyl]amine (34), EtOH, 60 °C;
(f) 4 N HCl/AcOEt, Et2O (except for 31 and 32).
e, f
OH
O
O
Cl
H
N
O
R
d
O
R
O
OH
g
43
(R,R)-31
>95% de
c
a, b
42
e
OH
O
H
R
O
O
O
N
S
O
44
(R,S)-31
74% de
74% de
h
41
e
e
OH
O
O
d
H
O
S
N
R
OH
g
46
(S,R)-31
45
OH
H
S
O
N
S
47
74% de
(S,S)-31
Scheme 4. Reagents and conditions: (a) N,O-dimethyl hydroxylamine hydrochloride, Et3N, CH2Cl2, rt; (b) cyclopropyl magnesium bromide, THF, 0 °C to rt; (c) H2 (0.5 MPa),
RuCl2[(S)-BINAP](dmf)n, (S,S)-1,2-diphenylethylenediamine, KOt-Bu, i-PrOH, rt, 74% ee; (d) (R)-(À)-glycidyl 3-nitrobenzenesulfonate, NaH, DMF, rt; (e) [1,1-dimethyl-2-(2-
naphthalenyl)ethyl]amine (34), EtOH, 60 °C; (f) recrystallization from n-hexane; (g) (S)-(+)-glycidyl 3-nitrobenzenesulfonate, NaH, DMF, rt; (h) H2 (0.5 MPa), RuCl2[(R)-
BINAP](dmf)n, (R,R)-1,2-diphenylethylenediamine, KOt-Bu, i-PrOH, rt, 74% ee.
Figure 3. Crystal structure of (R,R)-31 HCl salt by single-crystal X-ray diffraction.

Y. Shinagawa et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3809–3813
3813
Li, M.; Li, Y.; Neagu, C.; Oliver, R.; Piotrowski, D. W.; Price, D.; Qi, H.; Simmons,
H. A.; Southers, J.; Wei, L.; Zhang, Y.; Paralkar, J. M. Bioorg. Med. Chem. Lett.
2009, 19, 3328.
Acknowledgments
The authors wish to thank our Analytical Research and Develop-
ment Laboratories for collecting analytical data, Mr. Mitsuru
Takahashi for the pharmacokinetic study and Dr. Yasushi Ono for
the crystal structure Dr. Jun-ichi Haruta is also acknowledged for
his continuous encouragement.
7. Fitzpatrick, L. A.; Brennan, E.; Kumar, S.; Matheny, C.; Yi, B.; McLaughlin, M.;
Phillips, J.; Skordos, L.; Ethgen, D. Women. ASBMR 30th Annual
Meeting_FINAL_Abstract_Book 2008, 50, 1174.
8. Fukumoto, S.; Nakamura, T.; Nishizawa, Y.; Hayashi, M.; Matsumoto, T. J. Bone
Miner. Res. 24. Available at http://www.asbmr.org/Meetings/AnnualMeeting/
AbstractDetail.aspx?aid=f7a434e5-ad26-4aa0-930d-5bca406c9317. Accessed
October 10, 2009.
9. (a) Nemeth, E. F.; Delmar, E. C.; Heaton, W. L.; Miller, M. A.; Lambert, L. D.;
Conklin, R. L.; Gowen, M.; Gleason, J. G.; Bhatnagar, P. K.; Fox, J. J. Pharm. Exp.
Ther. 2001, 299, 323; (b) Gowen, M.; Stroup, G. B.; Dodds, R. A.; James, I. E.;
Votta, B. J.; Smith, B. R.; Bhatnagar, P. K.; Lago, A. M.; Callahan, J. F.; Del Mar, E.
G.; Miller, M. A.; Nemuth, E. F.; Fox, J. J. Clin. Invest. 2000, 105, 1595.
10. Shinagawa, Y.; Katsushima, T.; Nakagawa, T. U.S. Patent 6,916,956 B2,
2005.
References and notes
1. Report of a WHO Scientific Group, Geneva, World Health Organization, 2003
(WHO Technical Report Series No.921). Available at http://whqlibdoc.who.int/
trs/WHO_TRS_921.pdf.
2. Deal, C. Clin. Rev. Bone Miner. Metab. 2005, 3, 125.
3. Neer, R. M.; Arnaud, C. D.; Zanchetta, J. R.; Prince, R.; Gaich, G. A.; Reginster, J.
Y.; Hodsman, A. B.; Eriksen, E. F.; Ish-Shalom, S.; Genant, H. K.; Wang, O.;
Mitlak, B. H. N. Engl. J. Med. 2001, 344, 1434.
4. Brown, E. M.; MacLeod, R. J. Physiol. Rev. 2001, 81, 239.
5. Kimmel, D. B.; Bozzato, R. P.; Kronis, K. A.; Coble, T.; Sindrey, D.; Kwong, P.;
Recker, R. R. Endocrinology 1993, 132, 1577.
6. (a) Yang, W.; Wang, Y.; Roberge, J. Y.; Ma, Z.; Liu, Y.; Lawrence, R. M.; Rotella, D.
P.; Seethala, R.; Feyen, J. H. M.; Dickson, J. K., Jr. Bioorg. Med. Chem. Lett. 2005,
15, 1225; (b) Shcherbakova, I.; Balandrin, M. F.; Fox, J.; Ghatak, A.; Heaton, W.
L.; Conklin, R. L. Bioorg. Med. Chem. Lett. 2005, 15, 1557; (c) Shcherbakova, I.;
Huang, G.; Geoffroy, O. J.; Nair, S. K.; Swierczek, K.; Balandrin, M. F.; Fox, J.;
Heaton, W. L.; Conklin, R. L. Bioorg. Med. Chem. Lett. 2005, 15, 2537; (d) Gavai, A.
V.; Vaz, R. J.; Mikkilineni, A. B.; Roberge, J. Y.; Liu, Y.; Lawrence, R. M.; Corte, J.
R.; Yang, W.; Bednarz, M.; Dickson, J. K., Jr.; Ma, Z.; Seethala, R.; Feyen, J. H. M.
Bioorg. Med. Chem. Lett. 2005, 15, 5478; (e) Marquis, R. W.; Lago, A. M.;
Callahan, J. F.; Trout, R. E. L.; Gowen, M.; DelMar, E. G.; Van Vegnan, B. C.; Logan,
S.; Shimizu, S.; Fox, J.; Nemeth, E. F.; Yang, Z.; Roethke, T.; Smith, B. R.; Ward, K.
W.; Lee, J.; Keenan, R. M.; Bhatnagar, P. J. Med. Chem. 2009, 52, 3982; (f) Balan,
G.; Bauman, J.; Bhattacharya, S.; Castrodad, M.; Healy, D. R.; Herr, M.;
Humphries, P.; Jennings, S.; Kalgutkar, A. S.; Kapinos, B.; Khot, B.; Lazarra, K.;
11. The endogenous plasma PTH levels after oral administration of the compounds
in Sprague–Dawley rats were measured using rat PTH 1–34 ELISA kit
(Amersham) or rat PTH 1–84 ELISA kit (Immutopics). See Ref. 10 for the
experimental details. We observed PTH 1–34 in the screening stage (Table 3)
and PTH 1–84 in the time course study for compound (R,R)-31 (Fig. 2).
12. The experimental procedures have been previously disclosed. See Ref. 10. All
the tested compounds were characterized by NMR and MS. The diastereomeric
excess (de) for the (R,R)-31 was determined by reversed-phase HPLC using a
ULTRON ES-OVM column (Shinwa Chemical, 0.46 cm  15 cm, solvent system
A: 20 mM K2HPO4, 5 mM KPF6 (pH 7) B: CH3CN, A:B = 72:28, 1.0 mL/min, 30 °C,
tR: 17.2 min for (R,R)-31, 21.9 min for (R,S)-31, 12.3 min for (S,R)-31, 14.7 min
for (S,S)-31). The de for the (R,S)-31, (S,R)-31 and (S,S)-31 were determined by
1H NMR. The optical purities for 42 and 45 were analyzed by HPLC using a
CHIRALPAK AS column (DAICEL, 0.46 cm  25 cm, solvent system A: n-hexane,
B: i-PrOH, A:B = 98:2, 1.0 mL/min, 35 °C, tR: 12.4 min for 42, 13.6 min for 45).
13. Ohkuma, T.; Ooka, H.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc.
1995, 117, 2675.
14. The data can be obtained from the Cambridge Crystallographic Data Centre
(CCDC 770504).