Efficient synthesis of 5-alkoxy-(3r)-hydroxy-2,3-dihydrospiro[indene-1, 4?-piperidines]: A novel scaffold for renin inhibitors

Article abstract of DOI:10.1055/s-0029-1217818

We report herein, an efficient synthetic method for the preparation of a 5-alkoxy-(3R)-hydroxy-2,3-dihydrospiro[indene-1,4-piperidines] scaffold using a regioselective intermolecular ?reaction and a stereoselective reduction as key steps. Compound 2, base

Full text of DOI:10.1055/s-0029-1217818

LETTER
2521
Efficient Synthesis of 5-Alkoxy-(3R)-hydroxy-2,3-dihydrospiro[indene-1,4¢-
piperidines]: A Novel Scaffold for Renin Inhibitors
Synthesis of
a
N
ov
u
el Scaffold
f
j
or Re
n
i
in Inhibitors Nakamura,a Takaaki Jojima,b Chie Suzuki,a Shojiro Miyazaki,a Takahide Nishi*a
a
Medicinal Chemistry Research Laboratories I, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
Fax +81(3)54368563; E-mail: nishi.takahide.xw@daiichisankyo.co.jp
b
Medicinal Chemistry Research Laboratories II, Daiichi Sankyo Co., Ltd., 1-16-13 Kita-kasai, Edogawa-ku, Tokyo 134-8630, Japan
Received 5 June 2009
a few synthetic approaches have been reported.5 These
routes utilize Friedel–Crafts acylation toward (4-phe-
nylpiperidin-4-yl)acetic acid analogues, and intermolecu-
lar cyclizaion of indene with dialkyl halides. However,
Abstract: We report herein, an efficient synthetic method for the
preparation of a 5-alkoxy-(3R)-hydroxy-2,3-dihydrospiro[indene-
1,4¢-piperidines] scaffold using a regioselective intermolecular
reaction and a stereoselective reduction as key steps. Compound 2,
based on this scaffold, showed moderate in vitro binding affinity for some problems remain, such as the generation of regioiso-
purified human renin.
mers and the multi-step nature of the reactions. The key
features of our strategy are regioselective construction of
a spiro-piperidine ring at the 1-position of silyl enol ether
4, and stereoselective reduction at the 3-position of ketone
5 (Scheme 1). We planned to utilize 4 and N-Boc dichlo-
ride 6 for the preparation of 5, and a Corey–Bakshi–
Shibata (CBS) reduction6 for the preparation of (R)-3.
Key words: CBS reduction, regioselectivity, spiro-piperidine,
stereoselectivity, renin
Structural motifs that are commonly found in several se-
ries of inhibitors or ligands against different drug targets,
are known as privileged structures.1 2,3-Dihydrospiro[in-
dene-1,4¢-piperidine] (1) is one of these privileged struc-
tures for the broad class of seven-transmembrane G-
protein coupled receptor ligands (Figure 1).2 In recent
years, small molecule renin inhibitors having novel 4-phe-
nylpiperidine moieties as the central scaffold have been
reported.3 Based on this information, we designed and
prepared several 2,3-dihydrospiro[indene-1,4¢-piperi-
dine]-based compounds as replacements for the piperi-
dine. As a result, the 3,5-disubstituted derivative of 1,
compound 2, displayed moderate binding affinity
(IC50 = 33 nM) to human renin.4 This result indicated that
derivatives having suitable substituents at the 3- and 5-
positions of 1 could become new molecule leads for renin
inhibitors.
OH
O
R
R
N
N
Boc
Boc
3
5
OTBS
R
Boc
+
N
Cl
Cl
4
6
O
O
R =
MeO
O
O
Scheme 1
5
MeO
OMe
The preparation of 5 is described in Scheme 2. Commer-
cially available 6-hydroxy-1-indanone (7) was alkylated
O
N
R
O
with
1-[(3-bromopropoxy)methyl]-2-methoxybenzene
3
OMe
HN
(8) in the presence of potassium carbonate and treated
with a catalytic amount of potassium iodide to afford 6-
alkoxy-1-indanone 9 in 90% yield. The reaction of 9 with
tert-butyldimethylsilyl chloride (TBSCl) and 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU) gave 4 in 98% yield. The
first key reaction, regioselective construction of the spiro-
piperidine ring, was achieved by the following procedure.
Deprotonation of 4 with lithium hexamethyldisilazide
(LHMDS) at –78 °C and the subsequent reaction of the
lithium salt with 6 at 0 °C, afforded spiro-piperidine 10 in
65% yield. In this reaction, no other regioisomers were
observed. Other bases, such as potassium hexamethyldi-
silazide (KHMDS) and lithium diisopropylamide (LDA),
2: IC50 = 33 nM
1
Figure 1
In this paper, we report an efficient synthetic method for
the preparation of 3,5-disubstituted (R)-3 derivatives us-
ing easily available indanones as starting materials. Re-
garding the synthesis of the central spiro-piperidine unit,
SYNLETT 2009, No. 15, pp 2521–2523
x
x
.x
x
.2
0
0
9
Advanced online publication: 17.08.2009
DOI: 10.1055/s-0029-1217818; Art ID: U06009ST
© Georg Thieme Verlag Stuttgart · New York

2522
Y. Nakamura et al.
LETTER
resulted in poor yields. Spiro-piperidine 10 was easily
converted into 5 by treatment with tetrabutylammonium
fluoride (TBAF) in 85% yield. Alternatively, conversion
of 10 into 5 was accomplished by adding aqueous hydro-
gen chloride to the reaction mixture.
Table 1 CBS Reduction of 5 Catalyzed by (R)-2-Methyl-CBS-
oxazaborolidine with BH3–THF
O
OH
BH3⋅THF
R
R
(R)-2-methyl-CBS-
oxazaborolidine
THF
Br
O
N
N
Boc
Boc
(S)-3
8
MeO
K2CO3, KI
O
O
5
HO
R
DMF
90%
Entry BH3
Catalyst
Temp
(°C)
Yield
(%)
ee
(equiv)
(equiv)
0.05
0.1
(%) of (S)-3
7
9
1
2
3
4
0.6
–10
–10
–30
20
86
92
88
86
70
89
83
94
DBU
TBSCl
OTBS
R
1) LHMDS, THF
0.6
benzene
Boc
N
2)
Cl
Cl
0.6
0.1
6
4
98%
65%
0.6
0.1
OTBS
O
R
R
and 14b) that possess electron-withdrawing or electron-
donating substituents (Scheme 4). We believe that this
synthetic method will also be applicable to the preparation
of 6-substituted 3-hydroxy-2,3-dihydrospiro[indene-1,4¢-
piperidines] by using the corresponding 5-substituted 1-
indanones as starting materials.
TBAF
THF
85%
N
N
Boc
10
Boc
5
Scheme 2
O
OH
R
R
BH3⋅THF
(S)-2-methyl-CBS-
oxazaborolidine
Next, we focused our efforts on the second key reaction,
the CBS reduction of 5. Asymmetric reduction to afford
alcohol (S)-3 using (R)-2-methyl-CBS-oxazaborolidine as
a catalyst, was investigated under various conditions
(temperature, solvent, and amount of catalyst and reduc-
ing agent), and the results are summarized in Table 1. Ini-
tially, we obtained (S)-3 with 70% ee7 in 86% yield (entry
1). Using 0.1 equivalent of catalyst led to improved results
(89% ee, entry 2), but lowering the reaction temperature
(–30 °C) decreased the enantioselectivity (83% ee, entry
3). To our delight, the highest ee was achieved when the
reduction was carried out at 20 °C (94% ee, entry 4). We
assumed that the coordination of the catalyst–BH3 com-
plex with 5 would be the determining step for the enantio-
selectivity. Because the coordination would be slower at
low temperature, the non-catalyzed reduction of 5 with
BH3–THF would lead to a drop in the ee value. Other
THF
90%
N
N
Boc
Boc
5
(R)-3 (98% ee)
OMe
OMe
O
Br
OMe
O
11
O
R
KHMDS
THF
61%
MeO
N
Boc
12
TMSI
2
CH2Cl2
asymmetric
reductions
using
(+)-B-chlorodiiso-
pinocampheylborane8 did not proceed.
69%
Scheme 3
Under conditions similar to those given in entry 4, ketone
5 was reduced with (S)-2-methyl-CBS-oxazaborolidine to
afford (R)-3 with 98% ee in 90% yield (Scheme 3).
Deprotonation of 3 with KHMDS, followed by alkylation
of the resulting alkoxide with 4-(bromomethyl)-1-meth-
oxy-2-(3-methoxypropoxy)benzene (11), afforded benzyl
ether 12 in 61% yield. In the final step, the removal of the
Boc group with trimethylsilyl iodide (TMSI) gave the de-
sired compound 2 in 69% yield. This synthetic strategy
was also proven to be effective in the preparation of other
5-substituted spiro[(2-indanone)-1,4¢-piperidines] (14a
O
R
OTBS
R
1) LHMDS
2) 6
3) aq HCl
N
Boc
13a: R = Br
13b: R = OCH2CH=CH2
14a: 84%
14b: 58%
Scheme 4
Synlett 2009, No. 15, 2521–2523 © Thieme Stuttgart · New York

LETTER
Synthesis of a Novel Scaffold for Renin Inhibitors
2523
(7) The ee of 3 was determined by HPLC analysis
(CHIRALCEL OJ-H; 4.6 × 250 mm; n-hexane–EtOH,
80:20; 0.5 mL/min), tR of (S)-isomer = 24.6 min; tR of
(R)-isomer = 23.0 min.
(8) Brown, H. C.; Chandrasekharan, J.; Ramachandran, P. V.
J. Am. Chem. Soc. 1988, 110, 1539.
In conclusion, we have achieved the development of an
efficient synthetic method for the preparation of (R)-3.9 In
this method, its regio- and stereoselectivity were almost
completely controlled and the total yield was satisfactory,
whereas the yield of the spiro annulation reaction (4 to 9)
was moderate. With a practical synthetic route to (R)-3 in
hand, further chemical modifications aimed at exploring
novel renin inhibitors using (R)-3 as a key intermediate
are under way. The results of this work will be published
elsewhere.
(9) Synthesis of spiro-piperidine 5: To a solution of silyl enol
ether 4 (1.0 g, 2.30 mmol) in anhydrous THF (4.5 mL), was
added LHMDS (1.0 M in THF, 5.8 mL, 5.8 mmol) at –78 °C.
The mixture was stirred at the same temperature for 30 min,
then a solution of N-Boc dichloride 6 (0.67 g, 2.79 mmol) in
anhydrous THF (2.3 mL) was added. The mixture was
warmed to 0 °C and stirred at the same temperature. After 8
h, 1N HCl (9.2 mL, 9.2 mmol) was added and the resulting
mixture was stirred for a further 1 h. After extraction of
the reaction mixture with EtOAc, the organic extract was
washed with H2O, sat. aq NaHCO3, and brine then dried over
anhydrous Na2SO4. The solvent was removed in vacuo, and
the residue was purified by silica gel flash column chroma-
tography (n-hexane–EtOAc, 2:1) to afford spiro-piperidine 5
(0.58 g, 51% yield) as a colorless oil. 1H NMR (500 MHz,
CDCl3): d = 7.39–7.33 (m, 2 H), 7.26–7.23 (m, 1 H), 7.20
(dd, J = 8.3, 2.4 Hz, 1 H), 7.16 (d, J = 2.4 Hz, 1 H), 6.92 (t,
J = 7.6 Hz, 1 H), 6.85 (d, J = 8.3 Hz, 1 H), 4.56 (s, 2 H), 4.22
(br s, 2 H), 4.15–4.10 (m, 2 H), 3.81 (s, 3 H), 3.69 (t, J = 6.1
Hz, 2 H), 2.84 (br s, 2 H), 2.63 (s, 2 H), 2.13–2.08 (m, 2 H),
1.98–1.92 (m, 2 H), 1.50 (s, 9 H), 1.46 (br s, 2 H). MS-FAB:
m/z = 496 [M + H]+.
Acknowledgment
We are grateful to Dr. Mizuki Takahashi for evaluation of the X-ray
crystal structure of compound 2. We are also grateful to
Dr. Kazuhiko Tamaki for useful comments and suggestions.
References and Notes
(1) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.;
Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber,
D. F.; Anderson, P. S.; Chang, R. S. L.; Lotti, V. J.; Cerino,
D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.; Springer,
J. P.; Hirshfield, J. J. Med. Chem. 1988, 31, 2235.
(2) Mason, J. S.; Morize, I.; Menard, P. R.; Cheney, D. L.;
Hulme, C.; Labaudiniere, R. F. J. Med. Chem. 1999, 42,
3251.
(3) (a) Vieira, E.; Binggeli, A.; Breu, V.; Bur, D.; Fischli, W.;
Güller, R.; Hirth, G.; Märki, H. P.; Müller, M.; Oefner, C.;
Scalone, M.; Stadler, H.; Wilhelm, M.; Wostl, W. Bioorg.
Med. Chem. Lett. 1999, 9, 1397. (b) Güller, R.; Binggeli,
A.; Breu, V.; Bur, D.; Fischli, W.; Hirth, G.; Jenny, C.;
Kansy, M.; Montavon, F.; Müller, M.; Oefner, C.; Stadler,
H.; Vieira, E.; Wilhelm, M.; Wostl, W.; Märki, H. P. Bioorg.
Med. Chem. Lett. 1999, 9, 1403. (c) Cody, W. L.;
Holsworth, D. D.; Powell, N. A.; Jalaie, M.; Zhang, E.;
Wang, W.; Samas, B.; Bryant, J.; Ostroski, R.; Ryan, M. J.;
Edmunds, J. J. Bioorg. Med. Chem. 2005, 13, 59.
(4) Compound 2 was evaluated as a 0.5 fumaric acid salt. The
absolute stereochemistry of 2 was determined by an X-ray
crystal structure complex with renin (data not shown).
(5) (a) Efange, S. M. N.; Khare, A. B.; Foulon, C.; Akella, S. K.;
Parsons, S. M. J. Med. Chem. 1994, 37, 2574. (b) Limanto,
J.; Shultz, C. S.; Dorner, B.; Desmond, R. A.; Devine, P. N.;
Krska, S. W. J. Org. Chem. 2008, 73, 1639.
Synthesis of (R)-3: To a solution of (S)-2-methyl-CBS-
oxazaborolidine (1.0 M in toluene, 43 mL, 0.043 mmol) in
anhydrous THF (0.2 mL), a solution of spiro-piperidine 5
(215 mg, 0.43 mmol) in anhydrous THF (0.2 mL) and
BH3·THF complex (1.0 M in THF, 0.26 mL, 0.26 mmol)
were added. The resulting mixture was stirred at r.t. for
30 min, followed by the addition of MeOH and H2O under
ice-cooling. After extraction of the reaction mixture with
EtOAc, the organic extract was washed with brine and dried
over anhydrous Na2SO4. The solvent was then removed in
vacuo, and the residue was purified by silica gel flash
column chromatography (n-hexane–EtOAc, 1:1) to afford
(R)-3 (194 mg, 90% yield) as a colorless oil of optical purity
98% ee. 1H NMR (500 MHz, CDCl3): d = 7.37–7.35 (m,
1 H), 7.27–7.23 (m, 1 H), 7.08 (d, J = 8.3 Hz, 1 H), 6.96–
6.91 (m, 2 H), 6.89–6.83 (m, 2 H), 5.22 (dd, J = 12.2, 6.8 Hz,
1 H), 4.56 (s, 2 H), 4.15–4.03 (m, 4 H), 3.81 (s, 3 H), 3.70 (t,
J = 6.1 Hz, 2 H), 2.98–2.88 (m, 2 H), 2.53 (dd, J = 13.4, 7.1
Hz, 1 H), 2.12–2.07 (m, 2 H), 1.93–1.87 (m, 2 H), 1.73 (d,
J = 6.8 Hz, 1 H), 1.69 (dd, J = 12.5, 4.2 Hz, 1 H), 1.60 (dd,
J = 13.2, 2.0 Hz, 1 H), 1.47 (s, 9 H), 1.37 (br d, J = 13.2 Hz,
1 H). MS-FAB: m/z = 497 [M]+.
(6) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc.
1987, 109, 5551.
Synlett 2009, No. 15, 2521–2523 © Thieme Stuttgart · New York

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