Synthesis of an advanced intermediate toward the hNK-1 antagonist with the cyclopentane core

Article abstract of DOI:10.1055/s-0031-1289863

Allylic substitution of monomethoxyacetate of 4-cyclopentene-1,3-diol (91% ee) with 4-FC₆H₄ZnBr (4 equiv) and CuCl (30 mol%) gave anti-S_N2 product, which upon epoxidation with MCPBA afforded -epoxide stereoselectively. The epoxide was reduced with LiEt₃BH, and the resulting alcohol was converted into the targeted amine by using Mitsunobu reactions twice with 3,5-(O₂N)₂C₆H ₃CO₂H and then with phthalimide. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289863

2872
LETTER
Synthesis of an Advanced Intermediate toward the hNK-1 Antagonist with the
Cyclopentane Core
A
mine Intermediat
e
e
nya Nakata,a Yohei Kiyotsuka,a Tomoya Kitazume,b Yuichi Kobayashi*a
a
Department of Biomolecular Engineering, Tokyo Institute of Technology, Box B52, Nagatsuta-cho 4259, Midori-ku,
Yokohama 226-8501, Japan
Fax +81(45)9245789; E-mail: ykobayas@bio.titech.ac.jp
Department of Bioengineering, Tokyo Institute of Technology, Box B44, Nagatsuta-cho 4259, Midori-ku, Yokohama 226-8501, Japan
b
Received 7 September 2011
1
tio, determined by H NMR spectroscopy. The mixture
Abstract: Allylic substitution of monomethoxyacetate of 4-cyclo-
pentene-1,3-diol (91% ee) with 4-FC6H4ZnBr (4 equiv) and CuCl
(30 mol%) gave anti-SN2¢ product, which upon epoxidation with
MCPBA afforded a-epoxide stereoselectively. The epoxide was re-
was treated with LiOH in THF–MeOH–H2O (3:1:1) to
produce alcohol 5 in 84% yield. The 1H NMR spectrosco-
py and TLC analysis definitely disclosed that the alcohol
duced with LiEt3BH, and the resulting alcohol was converted into was free from the regioisomer 15 (Figure 1),7 which was
the targeted amine by using Mitsunobu reactions twice with 3,5-
synthesized regioselectively from the racemic monoace-
(O2N)2C6H3CO2H and then with phthalimide.
tate rac-7, 4-FC6H4MgCl (3 equiv), and CuI (0.3 equiv) in
THF according to the published procedure.11
Key words: substitution, copper, cyclopentane, Grignard reaction,
hNK-1 antagonist
Me
F
F3C
O
In an effort to establish a method to install a side chain on
the ring of the monoester of 4-cyclopentene-1,3-diol, we
H
recently published CuCl-catalyzed allylation with aryl
N
CF3
N
O
zinc reagents to afford anti SN2¢ products highly regio-
and stereoselectively.1 To demonstrate the synthetic ap-
plication of the reaction we selected the cyclopentane de-
rivative 1, which is the human neurokinin-1 (hNK-1)
antagonist2 with a binding affinity of IC50 = 0.18 nM
(Scheme 1).3,4 Previously, the Merck group achieved a
synthesis of 1 through Curtius rearrangement of the car-
boxylic acid derivative 2 to insert a nitrogen atom into the
C–CO2H bond.3,5,6 In contrast, we targeted amine 3 as an
advanced intermediate, and envisioned a synthesis of 3
from the allylation product 57 as delineated in Scheme 2.
The key steps are the epoxide ring opening of 6 by a hy-
dride and the subsequent substitution of the resulting alco-
hol by an amine nucleophile to construct the amine moiety
of 3.
Me
N
N
H
1
F
F
OR
OTBS
or
CO2H
NH2
2
3
literature
intermediate
advanced
intermediate
Scheme 1 Cyclopentane-based compound of high-binding affinity
to human neurokinin-1 (hNK-1) and its intermediates
A successful sequence of reactions to the amine 3 is sum-
marized in Scheme 3. Since an attempt to synthesize
monomethoxyacetate (1R)-4 by asymmetric hydrolysis of
the corresponding meso-dimethyoxyacetate using en-
zymes was not completely successful,8 monoacetate (1R)-
7, prepared easily by PPL-assisted hydrolysis of the diac-
etate,9 was converted into (1R)-4 (91% ee)10 through 8 and
9 in 73% yield over four steps. The zinc reagent, 4-
FC6H4ZnBr, was prepared from 1-fluoro-4-iodobenzene
(4 equiv) by lithiation with n-BuLi (4 equiv) in Et2O fol-
lowed by transmetalation with ZnBr2 (4 equiv) in THF.
The zinc reagent thus prepared was subjected to reaction
with (1R)-4 to afford 5 and its methoxyacetate in a 10:1 ra-
OH
F
OH
4-F-C6H4ZnBr
CuCl cat.
1
2
1
O
OMe
5
O
(1S,2R)-isomer
(1R)-4
F
OR
epoxidation
3
6
O
SYNLETT 2011, No. 19, pp 2872–2874
Advanced online publication: 09.11.2011
x
x
.x
x
.2
0
1
1
(1) H–
(2) NH2
–
DOI: 10.1055/s-0031-1289863; Art ID: U06511ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Synthetic of 3

LETTER
Amine Intermediate
2873
OH
OTBS
OTBS
C6H4-4-F
Ph
O
phthalimide, Ph3P, DIAD
THF, 0 °C to r.t., 2 h
11
N
C6H4-4-F
16
O
15
17
Figure 1
OTBS
C6H4-4-F
90 °C, 12 h
We then explored the transformation of 5 to b-alcohol 13.
Initially, epoxidation of a model compound 16 was stud-
ied with MCPBA, which unfortunately showed a low b
selectivity.12 In addition to the result, regioselectivity in
HO(CH2)2NH2
NH2
18, 67% from 11
the b-epoxide opening with a hydride reagent appeared Scheme 4 Synthesis of diastereomer 18
uncertain due to the absence of the directive moiety. By
these reasons, 5 was subjected to hydroxy-directive epoxi-
Finally, the nitrogen atom was attached to 13 through
Mitsunobu reaction with phthalimide. The phthaloyl moi-
ety of the resulting 14 was removed by stirring in
HO(CH2)2NH2 at 90 °C to furnish the amine 3 in 44%
yield from ester 12.
dation with MCPBA to yield a mixture of a- and b-
epoxides 6a and 10. The mixture was separated by chro-
matography, and a-epoxide 6a was isolated in 72% yield
[Rf values: 6a, 0.37; 10, 0.23 (hexane–EtOAc = 2:1)]. The
stereochemistry of the epoxide was tentatively assigned
on the basis of the directive effect, and later confirmed by
NOE experiment of the final compound 3. Epoxide 6a
was silylated with TBSCl. The resulting silyl ether 6b was
then subjected to epoxide ring opening with LiEt3BH,
which proceeded regioselectively to afford alcohol 11
solely in 91% yield. Mitsunobu inversion of 11 with 3,5-
(O2N)2C6H3CO2H, Ph3P, and DIAD [(i-PrOCON=)2]
gave ester 1213 in 86% yield. Methanolysis of the ester
furnished alcohol 13, which was free from contamination
of 11, analyzed by 1H NMNR spectroscopy [13: d = 4.55–
4.60 (m, 1 H); 11: d = 4.23 (quint, J = 6 Hz, 1 H)].
NOE 14.4%
NOE 4.6%
Hc
Ha
F
Hc
Ha
F
TBSO
TBSO
Hc
Hc
Hb
Hb
H2N
H2N
NOE 16.7%
NOE 0%
3
18
Figure 2 NOE experiment of 3 and the diastereomer 18
1) 4-F-C6H4ZnBr (4 equiv)
CuCl (30 mol%)
THF–Et2O, r.t., 11 h
OH
OTBS
TBSCl, imidazole
DMF, r.t., 2 h
1) MeOCH2COCl, pyridine
CH2Cl2, r.t., 1 h
(1R)-4
5
2) LiOH, THF–MeOH–H2O
r.t., 1 h
2) TBAF, THF, r.t., 1.5 h
84%
73% from (1R)-7
OAc
OR
8, R = Ac
9, R = H
(1R)-7
LiOH aq
r.t., 40 min
3,5-(NO2)2C6H3CO2H,
Ph3P, DIAD
OR
OH
C6H4-4-F
+
OTBS
LiEt3BH (4 equiv)
THF, r.t., 1 h
C6H4-4-F
OH
C6H4-4-F
MCPBA, NaHCO3
(each 2 equiv)
91%
CH2Cl2, 0 °C to r.t., 6 h
THF, 0 °C to r.t., 3 h
86%
O
O
6a, R = H, 72%
6b, R = TBS
(10, 18%, separated)
11
TBSCl, imidazole
DMF, r.t., 3 h
83%
OTBS
OTBS
OTBS
phthalimide, Ph3P, DIAD
(each 2 equiv)
C6H4-4-F
O
Et3N (5 equiv)
MeOH, r.t., 10 h
C6H4-4-F
C6H4-4-F
OH
90 °C, 10 h
3
N
THF, 0 °C to r.t., 10 h
HO(CH2)2NH2
OCO-3,5-(O2N)2C6H3
44% from 12
O
13
12
14
Scheme 3 Synthesis of the target compound 3
Synlett 2011, No. 19, 2872–2874 © Thieme Stuttgart · New York

2874
K. Nakata et al.
LETTER
(6) (a) Kuethe, J. T.; Wong, A.; Wu, J.; Davies, I. W.; Dormer,
P. G.; Welch, C. J.; Hillier, M. C.; Hughes, D. L.; Reider, P.
J. J. Org. Chem. 2002, 67, 5993. (b) Desai, R. C.; Cicala, P.;
Meurer, L. C.; Finke, P. E. Tetrahedron Lett. 2002, 43, 4569.
(7) Another synthesis of 5: Menard, F.; Chapman, T. M.;
Dockendorff, C.; Lautens, M. Org. Lett. 2006, 8, 4569.
(8) Asymmetric hydrolysis of dimethyoxyacetate i (Figure 3)
at r.t. was summarized in Table 1 (see Supporting
Information). Novozyme 435 afforded (1R)-4 with a
sufficiently high ee, but in a low yield (supporting
Information, Table 1, entry 1), whereas lipases (entries 3–5),
olipase 2S (entry 6), and PLE (entry 7) were less effective
than Novozyme 435.
To confirm the stereochemistry of 3, diastereomer 18 was
also synthesized through the Mitsunobu inversion of alco-
hol 11 with phthalimide (Scheme 4). The observed NOE
summarized in Figure 2 is consistent with the relative ste-
reochemistry predicted by the transformations of
Schemes 3 and 4.
In summary, we studied the synthesis of amine 3, an ad-
vanced intermediate for the synthesis of the cyclopentane
antagonist 1 against the human neurokinin-1 (hNK-1), to
demonstrate the synthetic potency of the CuCl-catalyzed
allylation of (1R)-4 with aryl zinc reagents. The key trans-
formation was the regioselective construction of the
amine moiety to 5, which was achieved selectively
through epoxide 6a.14
RO
OR
i, R = C(=O)CH2OMe
Figure 3
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(9) (a) Sugai, T.; Mori, K. Synthesis 1988, 19. (b) Laumen, K.;
Schneider, M. P. J. Chem. Soc., Chem. Commun. 1986,
1298.
Acknowledgment
(10) Checked by chiral HPLC; [a]D24 +62 (c 0.286, CHCl3).
(11) Igarashi, J.; Ishiwata, H.; Kobayashi, Y. Tetrahedron Lett.
2004, 45, 8065.
This work was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Science, Sports, and Culture, Ja-
pan.
(12) Epoxidation of ii afforded a-epoxide iii as a major product,
whereas TBS ether 16 gave a 1:1 mixture of a- and b-
epoxides (Scheme 5).
References and Notes
OR
(1) Nakata, K.; Kiyotsuka, Y.; Kitazume, T.; Kobayashi, Y.
Org. Lett. 2008, 10, 1345.
Ph
ii, R = H
16, R = TBS
(2) Reviews: (a) Yasuda, N.; Klapars, A.; Kohmura, Y.;
Campos, K. R.; Ishibashi, H.; Pollard, D.; Takezawa, A.;
Waldman, J. H.; Wallace, D. J.; Chen, C.-y.; Mase, T.
J. Synth. Org. Chem. 2011, 69, 579. (b) Rameshwar, P.;
Reddy, B. Y.; Trzaska, K. A.; Murthy, R. G.; Navarro, P.
Curr. Drug Discovery Technol. 2008, 5, 15. (c) Chen,
L.-W.; Yung, K. K. L.; Chan, Y. S. Curr. Drug Targets
2004, 5, 197.
(3) (a) Finke, P. E.; Meurer, L. C.; MacCoss, M.; Mills, S. G.;
Sadowski, S.; Cascieri, M. A.; Metzger, J.; Eiermann, G.;
MacIntyre, D. E. Abstract 98, 2000, 219th National Meeting
of the ACS, San Francisco, CA, March 2000. (b) Meurer,
L. C.; Finke, P. E.; MacCoss, M.; Mills, S. G.; Sadowski, S.;
Cascieri, M. A.; Metzger, J.; Eiermann, G.; MacIntyre, D.
E.; Rupniak, N. M. J.; Tatersall, F. D.; Hargreaves, R.
Abstract 99, 219th National Meeting of the ACS, San
Francisco, CA, March 2000.
MCPBA (2 equiv)
NaHCO3 (4 equiv)
CH2Cl2, 0 °C to r.t.
R = H, 2 h; R = TBS, 60 h
OR
OR
Ph
Ph
iii/iv = 85:15
v/vi = 48:52
+
O
O
iii, R = H
v, R = TBS
iv, R = H
vi, R = TBS
Scheme 5
(4) Related compounds with a cyclopentane ring: (a) Kuethe,
J. T.; Marcoux, J.-F.; Wong, A.; Wu, J.; Hillier, M. C.;
Dormer, P. G.; Davies, I. W.; Hughes, D. L. J. Org. Chem.
2006, 71, 7378. (b) Finke, P. E.; Meurer, L. C.; Levorse,
D. A.; Mills, S. G.; MacCoss, M.; Sadowski, S.; Cascieri, M.
A.; Tsao, K.-L.; Chicchi, G. G.; Metzgerd, J. M.; MacIntyre,
D. E. Bioorg. Med. Chem. Lett. 2006, 16, 4497.
(c) Campos, K. R.; Klapars, A.; Kohmura, Y.; Pollard, D.;
Ishibashi, H.; Kato, S.; Takezawa, A.; Waldman, J. H.;
Wallace, D. J.; Chen, C.-y.; Yasuda, N. Org. Lett. 2011, 13,
1004.
(13) Mitsunobu inversion of 11 with PhCO2H afforded the
benzoate. However, attempted hydrolysis gave the olefin viii
as the sole product (Figure 4).
OTBS
C6H4-4-F
vii
(5) Meurer, L. C.; Finke, P. E.; Owens, K. A.; Tsou, N. N.; Ball,
R. G.; Mills, S. G.; MacCoss, M.; Sadowski, S.; Cascieri,
M. A.; Tsao, K.-L.; Chicchi, G. G.; Egger, L. A.; Luell, S.;
Metzger, J. M.; MacIntyre, D. E.; Rupniak, N. M. J.;
Williams, A. R.; Hargreaves, R. J. Bioorg. Med. Chem. Lett.
2006, 16, 4504.
Figure 4
(14) Experimental procedures are presented in Supporting
Information.
Synlett 2011, No. 19, 2872–2874 © Thieme Stuttgart · New York

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