T. Yamanaka et al. / Tetrahedron Letters 45 (2004) 2843–2845
2845
1) EDC / HOBT
BocN
3
2
+
N
OH
2) LiOH
95%
O
O
13
BocN
1) LiOH
2) HCl/ AcOEt
3) Diaion HP20®
4) recrystallization
from EtOH-H2O
H
4
*
N
O
N
CO2Et
*
1
O
EDC / HOBT
quantitative
14
69%
Scheme 5.
various kinds of solvent. As a result, in a mixed solvent
system of 1:2 methylene chloride and diisopropyl ether,
the reaction rate was more than two and a half times
faster than that with other solvents (1,4-dioxane or
methylene chloride). Although the enantioselection was
not perfect, when reaction conversion was about 60%,
the enantiomeric excess of 11 was up to 97% ee, as
determined by HPLC analysis. From the reaction mix-
ture, 10 and 11 were separated by silica gel column
chromatography easily and 11 was isolated in 40% yield
as a white solid.6 The configuration of 11 was deter-
mined to be (S) by optical rotation in comparison with
References and notes
1. For reviews, see; (a) Agah, R.; Plow, E. F.; Topol, E. J.
Platelets 2002, 769; (b) Mousa, S. A. Drug Discovery Today
1999, 4, 552, and references cited therein.
2. (a) Zablocki, J. A.; Rico, J. G.; Garland, R. B.; Rogers,
T. E.; Williams, K.; Schretzman, L. A.; Rao, S. A.; Bovy, P.
R.; Tjoeng, F. S.; Lindmark, R. J.; Toth, M. V.; Zupec, M.
E.; McMackins, D. E.; Adams, S. P.; Miyano, M.; Markos,
C. S.; Milton, M. N.; Paulson, S.; Herin, M.; Jacqmin, P.;
Nicholson, N. S.; Panzer-Knodle, S. G.; Haas, N. F.; Page,
J. D.; Szalony, J. A.; Taite, B. B.; Salyers, A. K.; King, L.
W.; Campion, J. G.; Feigen, L. P. J. Med. Chem. 1995, 38,
2378; (b) Cossy, J.; Schmitt, A.; Cinquin, C.; Buisson, D.;
Belotti, D. Bioorg. Med. Chem. Lett. 1997, 7, 1699; (c)
Topgi, R. S.; Ng, J. S.; Landis, B.; Wang, P.; Behling, J. R.
Bioorg. Med. Chem. 1999, 7, 2221.
an authentic sample synthesized from
L-aspartic acid
dibenzyl ester.7 Optically active 11 was deprotected in
one step by treatment with 5 equiv of aqueous ammonia
in methanol in 71% yield. The deprotected b-lactam 12
was ring-opened and esterified by treatment with 5.8 N
hydrogen chloride solution in ethanol to give ethynyl
b-amino ester 4 in 94% yield. The enantiopurity of 4 was
98% ee, as determined by HPLC analysis.
3. Magnus, P.; Thurston, L. S. J. Org. Chem. 1991, 56, 1166.
4. (a) Nagai, H.; Shiozawa, T.; Achiwa, K.; Terao, Y. Chem.
Pharm. Bull. 1992, 40, 2227; (b) idem, ibid. 1993, 41, 1933.
5. Purchased from Amano Enzyme Inc.
6. The experimental method to obtain 11 was as follows. To a
solution of 9 (200 g, 1.01 mol) in methylene chloride (2.0 L)
and diisopropyl ether (4.0 L) were added Lipase PSâ (152 g)
and vinyl acetate (280 mL, 3.03 mol). This suspension
was stirred vigorously at 37 °C for 12–15 h. After the
reaction conversion was 60%, as confirmed by HPLC
analysis, the lipase was filtered off and washed with
methylene chloride. The filtrate was evaporated under
reduced pressure to afford a residue, which was chroma-
tographed on silica gel to give pure 10. ½a2D8)134.6 (c 1.03,
CHCl3).
The synthesis was completed as shown in Scheme 5.
Compound 2 was coupled with amine 3 in the presence
of EDC and HOBT, followed by hydrolysis of the ethyl
ester by aqueous lithium hydroxide solution under ice
cooling to give 13 in 95% yield as a solid. Compound 13
was coupled with 4 with EDC and HOBT to give 14 in
quantitative yield. The ester and Boc groups were
cleaved by treatment with aqueous lithium hydroxide
solution followed by hydrogen chloride in ethyl acetate,
respectively, to give crude 1 as the hydrogen chloride
salt, which was passed through HP-20â, freeze-dried,
and recrystallized from H2O–EtOH to give pure 1.8
7. (a) Ohkubo, M; Takahashi, F.; Yamanaka, T.; Sakai, H.;
Kato, M. International Patent WO 9508536;
1) TBDMSCl/DIEA/CH2Cl2
(S)
2) NaBH4/MeOH (98%; 2 steps)
3) Swern oxidation
H2N
CO2CH2Ph
*
CO2Et
HCl
*
In conclusion, we have established a simple procedure to
prepare the new GpIIb/IIIa antagonist FR184764. All
synthetic reactions are straightforward, so we have been
able to prepare 180 g (515 mmol) of 1 easily in one batch
with laboratory apparatus. The structure–activity rela-
tionships of FR184764 and other related compounds
will be reported in due course.
NH
O
4) PPh3/CBr4/THF (48%; 2steps)
5) LiN(TMS)2 (2.2 eq) / THF (56%)
6) HCl/EtOH (56%)
[α]25D -7.1 (c1.0, MeOH)
(b) Related synthesis was reported. Boys, M. L. Tetrahe-
dron Lett. 1998, 39, 3449.
8. Spectral data of 1: ½a19)69.5 (c 1.00, CH3OH). IR (KBr)
D
2361, 1726, 1655, 1601, 1277, 1255, 1223, 1194 cmÀ1
.
1H
NMR (DMSO-d6Þ d 1.19–1.41 (m, 2H), 1.59–1.88 (m, 5H),
2.14–2.32 (m, 4H), 2.51–2.76 (m, 4H), 2.89–3.17 (m, 4H),
3.89–4.42 (m, 2H), 3.89–4.42 (m, 2H), 4.60–4.71 (m, 1H),
6.36 (d, J ¼ 15:1 Hz, 1H), 6.57 (dd, J ¼ 15:1, 6.4 Hz, 1H),
8.85 (m, 1H). Mass (m=z) 352 (M+Hþ). Anal. Calcd for
C19H27N3O4Æ1. 1H2O: C, 59.58; H, 7.74; N, 10.77. Found:
C, 59.59; H, 7.78; N, 10.89.
Acknowledgements
We are greatly indebted to Dr. David Barrett, Medicinal
Chemistry Research Laboratories, for his help in the
preparation of this manuscript.