An efficient synthesis of cyclic β-amino acid derivatives as β-turn mimetics

Article abstract of DOI:10.1055/s-2005-863719

Seven-, eight-, and nine-membered cyclic β-amino acids, precursors of platelet aggregation inhibitors, were synthesized for the first time starting from N-alkenyl amines and ethyl acrylate via ring-closing metathesis (RCM) as the key reaction. Synthesis o

Full text of DOI:10.1055/s-2005-863719

LETTER
631
An Efficient Synthesis of Cyclic b-Amino Acid Derivatives as b-Turn Mimetics
S
ynthesis of Cy
o
clic
b
-Amino
s
A
cid D
e
h
rivatives as
b
i
-Turn
o
Mimetic
s
Yamanaka,*a,b Mitsuru Ohkubo,*a Masayuki Kato,a Yasufumi Kawamura,b Akinori Nishi,b
Takahiro Hosokawab
a
Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6 Kashima, Yodogawa-Ku, Osaka 532-8514, Japan
b
Department of Environmental Systems Engineering, Kochi University of Technology, Tosayamada, Kochi 782-8502, Japan
Fax +81(6)63045435; E-mail: toshio_yamanaka@po.fujisawa.co.jp
Received 3 December 2004
R
Abstract: Seven-, eight-, and nine-membered cyclic b-amino ac-
R'
N
NH
H
ids, precursors of platelet aggregation inhibitors, were synthesized
for the first time starting from N-alkenyl amines and ethyl acrylate
via ring-closing metathesis (RCM) as the key reaction. Synthesis of
the corresponding enantiomerically pure b-amino acids was also ac-
complished in a similar manner using Evans’ asymmetric allylation.
O
O
O
HN
N
H
HN
NH
NH2
CO2H
RGD (Arg-Gly-Asp)
Key words: cyclic b-amino acid, b-turn mimetics, ring-closing
metathesis, asymmetric allylation, platelet aggregation inhibitor
β-turn structure
n
O
N
O
The mimetics of RGD
β-turn structure
The turn structure in peptides plays a crucial role in
biological molecular recognition.1 One representative ex-
ample is recognition of the b-turn structure in the RGD
(Arg-Gly-Asp) peptide sequence of fibrinogen by the gly-
coprotein IIb/IIIa (GPIIb/IIIa) on the surface of platelets,
which induces platelet aggregation. In the course of our
study of non-peptide platelet aggregation inhibitors,2,3 we
designed novel RGD b-turn mimetics 1 containing cyclic
b-amino acids based on the view that the ring moiety of 1
could serve as a mimetic of the b-turn of the RGD peptide
(Figure 1). In order that the mimetics 1 can act as anti-
platelet agents, incorporation of a carboxylic acid and an
amine functional group at appropriate separation is
obviously essential.
HN
CO2H
1
n
N
H
BocN
*
CO2H
n = 1, 2, 3
Figure 1
prepared from alkenyl amines 2a–c8 via three steps: (i)
conjugate addition to ethyl acrylate, (ii) Boc protection of
the NH group, and (iii) allylation at the a-position of the
resulting esters 3a–c. Cyclization of 4a,b using Grubbs’
first generation catalyst 59 took place smoothly to give the
corresponding 7- and 8-membered ring cyclic b-amino
acid derivatives 7a,b (n = 1, 2) in identical 90% yields
(Table 1). However, construction of the 9-membered ring
from 4c (n = 3) was difficult, probably because of its con-
formational inadaptability. In addition, the cyclization of
4c was accompanied by olefin isomerization10 of the N-
alkenyl moiety (Scheme 2) to yield 7b (n = 2) via 4d
along with 7c (n = 3) (7c:7b = 4:1, 24% yield). The use of
easily handled Grubbs’ second generation catalyst 611 was
also effective for the syntheses of 7a,b. Hydrogenation of
7a–c in the presence of Pd/C gave the corresponding
saturated ring compounds 8a–c in good yields.
Although some cyclic b-amino acid derivatives have been
prepared,4 there have been no practical synthetic method
of higher membered cyclic b-amino acids except for 7-
membered ring ones prepared by classical manipulations.5
In addition, there has been no document for the corre-
sponding optically active cyclic b-amino acids or their de-
rivatives. Under such backgrounds, we wish here to report
an efficient synthesis of higher membered cyclic b-amino
acid derivatives and their enantiomerically pure forms as
the precursors of 1. In this method, the ruthenium-cata-
lyzed ring-closing metathesis (RCM)6 and Evans’ asym-
metric allylation7 serve as the key reaction. Remarkable in
this approach is that the Evans’ asymmetric allylation
proceeds with high diastereoselectivity and predictable
stereoselection. Furthermore, this strategy appears to be-
come a general method for the synthesis of cyclic b-amino
acid derivatives.
Since racemic 7- and 8-membered cyclic b-amino acid de-
rivatives 7 and 8 (n = 1 and 2) were successfully prepared,
our effort was then directed towards the synthesis of
optically pure cyclic b-amino acids in a similar manner.
For this purpose, we prepared enantiomerically pure sub-
strates for RCM by using Evans’ asymmetric allylation.7
Among various chiral auxiliaries,12 we chose Evans’
oxazolidinone and conducted the synthesis of 10a,b as
The synthetic sequences developed here are shown in
Scheme 1. Thus, the substrates 4a–c for RCM were firstly
SYNLETT 2005, No. 4, pp 0631–0634
0
4.
0
3.
2
0
0
5
Advanced online publication: 22.02.2005
DOI: 10.1055/s-2005-863719; Art ID: U33104ST
© Georg Thieme Verlag Stuttgart · New York

632
T. Yamanaka et al.
LETTER
outlined in Scheme 3. Thus, hydrolysis of N-alkenyl b-
amino esters 3a,b followed by treatment with t-BuCOCl
in the presence of Et3N gave the corresponding acid anhy-
drides which were reacted with N-lithium (R)-4-benzyl-2-
oxazolidinone generated in situ to give 9a and 9b in 78%
and 79% yield, respectively. The oxazolidinones 9a,b
were then allowed to react with allyl iodide (3.5 equiv) in
the presence of NaN(TMS)2 (1.1 equiv) at –78 °C to 0 °C
in THF. In this reaction, allyl iodide must approach the
diastereoface of the enolate formed in situ avoiding the
steric bulkiness of the (4R)-benzyl group in the oxazoli-
dinone auxiliary. This process results in the R-configura-
tion at the 2¢-position. Indeed, the 2¢-R-configuration
products 10a,b were obtained in 68% and 71% yields with
87% and 89% de, respectively. Purification of crude prod-
ucts 10a,b by column chromatography gave diastereo-
merically pure 10a,b in 64% and 57% yield, respectively.
The stereochemical assignment of the 2¢-R-configuration
in 10a is described later. The ring-closing metathesis of
10a,b using 6 (reflux in CH2Cl2) took place smoothly to
give 11a,b in good yields with no loss of optical purity.13
Removal of the oxazolidinone auxiliary by LiOOH14,15 at
0 °C in THF provided the cyclic b-amino acids 12a,b in
good yields.16 Subsequent hydrogenation with Pd/C gave
the corresponding saturated cyclic compounds 13a,b
quantitatively.17 The enantiomeric excesses of 12 and 13
were >98% by HPLC analysis.
a,b
c
n
n
n
BocN
BocN
NH2
CO2Et
CO2Et
3a–c
4a–c
2a: n = 1
2b: n = 2 (HCl salt)
2c: n = 3 (HCl salt)
n
d
e
n
BocN
BocN
CO2Et
CO2Et
7a–c
8a–c
P(Cy)3
Ru
N
N
Cl
Cl
Cl
Cl
Ph
Ru
P(Cy)3
P(Cy)3
Ph
5
6
Scheme 1 Reagents and conditions: (a) ethyl acrylate, Et3N (in the
cases of 2b,c), EtOH, r.t.; (b) (Boc)2O, CH2Cl2, r.t., 82% for 3a, 56%
for 3b, 40% for 3c in 2 steps; (c) LiN(TMS)2, –78 °C, THF, then allyl
iodide, 67% for 4a, 57% for 4b, 73% for 4c; (d) Grubbs’ catalyst 5 or
6, CH2Cl2, reflux (see Table 1); (e) H2 (1 atm), Pd/C, EtOH, r.t., 90%
for 8a, 88% for 8b, 95% for 8c.
Table 1 Ring-Closing Metathesis (RCM) of 4a–ca
Substrate
n
1
1
2
2
3
3
Catalyst
Product
7a
Yield (%)b
O
O
a,b
c
4a
4a
4b
4b
4c
4c
5
6
5
6
5c
6
90
97
90
98
24d
0e
n
n
N
BocN
BocN
CO2Et
7a
(R)
O
CH2Ph
3a: n = 1
7b
9a,b
3b: n = 2
7b
O
O
7c
O
O
n
e
n
*
BocN
N
7c
N
BocN
*
(R)
(R)
CH2Ph
(R)
a Reaction conditions: 4a–c (1.0 mmol), catalyst 5 or 6 (10 mol%), dry
CH2Cl2 (40 mL), reflux, 2 h, under N2 atmosphere.
b Isolated yields after purification by silica gel column chromato-
graphy.
(R)
O
O
CH2Ph
11a,b (>99% de)
10a,b (87–89% de)
10a, b (>99% de)
d
c 20 mol% of catalyst 5 was used.
d Isolated as a mixture of 7c and 7b (7c:7b = 4:1).
e Compound 7b was isolated in 5% yield.
n
g
f
n
*
BocN
OH
*
BocN
OH
4c
7c
(R)
(R)
O
O
13a,b (>98% ee)
12a,b (>98% ee)
Scheme 3 Reagents and conditions: (a) 1 N aq NaOH, THF, EtOH,
r.t.; (b) t-BuCOCl, Et3N, THF, then (R)-4-benzyl-2-oxazolidinone,
n-BuLi, 78% for 9a, 79% for 9b in 2 steps; (c) NaN(TMS)2, THF,
–78 °C, then allyl iodide allowed to warm to 0 °C, 71% for 10a, 68%
for 10b; (d) medium pressure column chromatography on silica gel,
64% for 10a, 57% for 10b from 9a,b; (e) 6 (10 mol%), CH2Cl2, reflux,
97% for 11a, 96% for 11b; (f) LiOOH, THF, 0 °C, 87% for 12a, 93%
for 12b; (g) H2 (1 atm), Pd/C, EtOH, r.t., 100% for 13a, 100% for 13b.
7b
BocN
CO2Et
4d
Scheme 2
Synlett 2005, No. 4, 631–634 © Thieme Stuttgart · New York

LETTER
Synthesis of Cyclic b-Amino Acid Derivatives as b-Turn Mimetics
(4) (a) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991.
633
The stereochemical assignment of the 2¢-R-configuration
in 10a was determined as follows: the oxazolidinone
auxiliary of 10a was removed by LiOOH, and subsequent
esterification by (trimethylsilyl)diazomethane18 and
deprotection of the Boc group by trifluoroacetic acid
(TFA) gave allyl amine 14. The N-allyl group in 14 was
then removed by Pd(PPh3)4 catalyst in the presence of 3,5-
dimethylbarbituric acid19 to give 15 via Boc-protection of
the resulting NH2 group. Hydrolysis of 15 yielded a-allyl-
b-amino acid 16, the optical rotation of which was found
to be ‘+’. Comparison with the reported data20 allowed us
to assign the configuration as R (Scheme 4).
(b) Chippindale, A. M.; Davies, S. G.; Iwamoto, K.; Parkin,
R. M.; Smethurst, C. A. P.; Smith, A. D.; Rodriguez-Solla,
H. Tetrahedron 2003, 59, 3253. (c) Gardiner, J.; Anderson,
K. H.; Downard, A.; Abell, A. D. J. Org. Chem. 2004, 69,
3375. (d) Abell, A. D.; Gardiner, J. Org. Lett. 2002, 4, 3663.
(e) Fustero, S.; Bartolomé, A.; Sanz-Cervera, J. F.; Sánchez-
Roselló, M.; Soler, J. G.; Ramírez de Arellano, C.; Fuentes,
A. S. Org. Lett. 2003, 5, 2523.
(5) (a) Lee, D. L.; Morrow, C. J.; Rapoport, H. J. Org. Chem.
1974, 39, 893. (b) Krogsgaard-Larsen, P.; Thyssen, K.;
Schaumburg, K. Acta Chem. Scand. Ser. B 1978, 32, 327.
(6) (a) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34,
18. (b) Fürstner, A. Angew. Chem. Int. Ed. 2000, 39, 3021.
(c) Connom, S. J.; Blechert, S. Angew. Chem. Int. Ed. 2003,
42, 1900.
O
(7) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc.
1982, 104, 1737.
O
d,e
a,b,c
N
BocN
*
(8) van Benthem, R. A. T. M.; Michels, J. J.; Hiemstra, H.;
Speckamp, W. N. Synlett 1994, 368.
(9) Purchased from Tokyo Chemical Industry (TCI).
(10) (a) Hong, S. H.; Day, M. W.; Grubbs, R. H. J. Am. Chem.
Soc. 2004, 126, 7414. (b) Schmidt, B. Synlett 2004, 1541.
(11) Purchased from Aldrich.
HN
*
(R)
CO2Me
(R)
(R)
O
CH2Ph
10a (87% de)
14
(12) (a) Schöllkopf, U. Tetrahedron 1983, 39, 2085.
(b) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem.,
Int. Ed. Engl. 1997, 35, 2708. (c) Job, A.; Janeck, C. F.;
Battray, W.; Peters, R.; Enders, D. Tetrahedron 2002, 58,
2253.
f
BocHN
*
BocHN
*
CO2Me
CO2H
(R)
(R)
15
16
(13) Procedure for the Preparation of 11a.
To a solution of 10a (735 mg, 1.72 mmol, >99% de) in anhyd
CH2Cl2 (70 mL) was added Grubbs’ catalyst 6 (146 mg,
0.172 mmol). The mixture was refluxed under nitrogen
atmosphere for 1.5 h. After cooling to r.t., solvent was
evaporated in vacuo. The residue was purified by column
chromatography on silica gel (EtOAc–hexane = 1:4) to give
11a (664 mg, 97%) as an amorphous solid. The
Scheme 4 Reagents and conditions: (a) LiOOH, THF, 0 °C, 87%;
(b) TMSCHN2, CH2Cl2, MeOH, r.t.; (c) TFA, CH2Cl2, r.t., 32% in 3
steps; (d) cat. Pd(PPh3)4, 3,5-dimethylbarbituric acid, CH2Cl2, r.t.; (e)
(Boc)2O, 63% in 2 steps; (f) LiOH, THF, MeOH, r.t., 82%; 16: [a]D
+11.0 (c 1.09, CH2Cl2).
26
diastereomeric purity of purified 11a was >99% de
determined by HPLC analysis using CHIRALPAK AD
(DAICEL) with hexane–i-PrOH (85:15). IR (KBr): 2976,
2929, 1772, 1697, 1684, 1456, 1051, 1020, 702 cm–1. 1H
NMR (CDCl3; major rotamer): d = 1.47 (s, 9 H), 2.38–2.58
(m, 2 H), 2.73–2.79 (m, 1 H), 3.28 (dd, J = 13.2, 3.3 Hz, 1
H), 3.65 (dd, J = 13.9, 8.0 Hz, 1 H), 3.79 (dd, J = 13.9, 6.8
Hz, 1 H), 3.85–4.06 (m, 2 H), 4.10–4.27 (m, 3 H), 4.58–4.82
(m, 1 H), 5.62–5.89 (m, 2 H), 7.20–7.36 (m, 5 H). HRMS:
m/z calcd for C22H29N2O5 [M + H]+: 401.2076; found:
401.2069. [a]D27 –42.0 (c 0.525, CHCl3).
Starting from the b-amino acid derivatives 7 and 8, we
prepared the RGD b-turn mimetics 1 shown in Figure 1
and measured the effect on platelet aggregation. As a re-
sult, the compound derived from 7-membered b-amino
acid ester 8a showed good efficacy.21 The details of these
results, including the structure–activity relationships, will
be reported in the near future.
Acknowledgment
(14) (a) Hosokawa, T.; Yamanaka, T.; Itotani, M.; Murahashi, S.-
I. J. Org. Chem. 1995, 60, 6159. (b) Hosokawa, T.;
Yamanaka, T.; Murahashi, S.-I. J. Chem. Soc., Chem.
Commun. 1993, 117.
We are greatly indebted to Dr. David Barrett, Medicinal Chemistry
Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., for his
help in the preparation of this manuscript.
(15) Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett.
1987, 28, 6141.
(16) Procedure for the Preparation of 12a.
References
(1) Hawiger, J.; Kloczewiak, M.; Bednarek, M. A.; Timmons, S.
Biochemistry 1989, 28, 2909.
To a solution of 11a (560 mg, 1.40 mmol) in THF (28 mL)
and H2O (9 mL) were added 30% H2O2 (1.27 mL, 11.2
mmol, 8.0 equiv) and then 1 N aq LiOH solution (2.8 mL, 2.8
mmol, 2.0 equiv) under ice cooling. The reaction mixture
was stirred at the same temperature for 30 min, then treated
with 20% aq Na2S2O3 solution (55 mL) and stirred for
further 5 min. It was extracted with Et2O. The aqueous phase
was acidified to pH 2 with 10% aq KHSO4, and extracted
with EtOAc twice. The extracts were combined and dried
over MgSO4, filtered, and evaporated in vacuo. The residue
was purified with silica gel short column chromatography on
silica gel (CH2Cl2–EtOAc = 1:1) to give 12a (295 mg, 87%)
(2) For reviews, see: (a) Agah, R.; Plow, E. F.; Topol, E. J.
Platelets 2002, 769. (b) Scarborough, R. M.; Gretler, D. D.
J. Med. Chem. 2000, 43, 3454. (c) Mousa, S. A. Drug
Discovery Today 1999, 4, 552; and references cited therein.
(3) Yamanaka, T.; Ohkubo, M.; Takahashi, F.; Kato, M.
Tetrahedron Lett. 2004, 45, 2843.
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634
T. Yamanaka et al.
LETTER
as an oil. The enantiomeric purity of purified 12a was >98%
ee determined by HPLC analysis using CHIRALPAK AD
column (DAICEL) (hexane–EtOH–TFA = 98:2:0.1). IR
(neat): 2978, 2933, 2866, 1734, 1697, 1419, 1367, 1269,
1252, 1167, 891 cm–1. 1H NMR (CDCl3): d = 1.47 (s, 9 H),
2.43–2.47 (m, 2 H), 2.80–3.15 (m, 1 H), 3.55–4.30 (m, 4 H),
5.55–5.85 (m, 2 H). HRMS: m/z calcd for C12H20NO4 [M +
H]+: 242.1392; found: 242.1387. [a]D26 –23.2 (c 1.01,
CHCl3).
1695, 1481, 1423, 1367, 1163 cm–1. 1H NMR (CDCl3; major
rotamer): d = 1.31–1.96 (m, 5 H), 1.48 (s, 9 H), 2.01–2.08
(m, 1 H), 2.86–2.93 (m, 1 H), 3.13–3.27 (m, 1 H), 3.52 (dt,
J = 13.9, 5.1 Hz, 1 H), 3.60–3.70 (m, 2 H). HRMS: m/z calcd
26
for C12H22NO4 [M + H]+: 244.1549; found: 244.1542. [a]D
–7.7 (c 0.74, CHCl3).
(18) Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull.
1981, 29, 1475.
(19) Garro-Helion, F.; Merzouk, A.; Guibé, F. J. Org. Chem.
1993, 58, 6109.
(17) Procedure for the Preparation of 13a.
To a solution of 12a (48 mg, 0.20 mmol) in MeOH (1.5 mL)
was added 10% Pd/C (24 mg), and the mixture was stirred
under H2 atmosphere (1 atm) at r.t. for 3 h. The catalyst was
filtered off, and the filtrate was evaporated off to give 13a
(48 mg, 100%) as a solid. The enantiomeric purity of
purified 13a was >98% ee determined by HPLC analysis
using CHIRALPAK AD column (DAICEL) with (hexane–
EtOH–TFA = 98:2:0.1). IR (KBr): 2976, 2933, 2866, 1732,
(20) Sibi, M. P.; Deshpande, P. K. J. Chem. Soc., Perkin Trans. 1
2000, 1461.
(21) (a) Ohkubo, M.; Kuroda, S.; Nakamura, H.; Minagawa, M.;
Aoki, T.; Harada, K.; Seki, J. Int. Patent WO 0160813, 2001;
Chem. Abstr. 2001, 135, 180951. (b) Ohkubo, M.;
Takahashi, F.; Yamanaka, T.; Sakai, H.; Kato, M. Int. Patent
WO 9508536, 1995; Chem. Abstr. 1995, 123, 285788.
Synlett 2005, No. 4, 631–634 © Thieme Stuttgart · New York