shown that amino acid side-chain moieties are involved
directly in interactions between peptide ligands and receptors/
acceptors that are critical for the biological activities and
receptor selectivities.5 Herein, we would like to report the
first synthesis of indolizidinone amino acid ester with
appropriate amino acid side-chain functionalities at both C4
and C8 positions.
requirements prompted us to choose the phthalimide group
to doubly protect the amine group. Our first synthetic target
was the novel pyroglutamic acid derivative with the desired
functionality at the â-position. The synthesis started from
readily available N-(3-hydroxypropyl) phthalimide 2 (Scheme
3). Aldehyde 3 was prepared in good yield by PCC oxidation
The retrosynthetic analysis of the target mimetic 1 is de-
scribed in Scheme 2. The bicyclic lactam system could be
Scheme 3. Synthesis of â-Functionalized Pyroglutamate 8a
Scheme 2. Retrosynthetic Analysis of Dipeptide Mimetic 1
approached from a dehydroamino acid intermediate. The
functional group at C-4 was introduced by bromination of
the dehydroamino acid intermediate followed by Suzuki
coupling. Stereoselectively introducing allyl groups at the
C-5 position of â-functionalized pyroglutamates and ap-
propriate elaboration could afford dehydroamino acid inter-
mediates. The novel â-functionalized pyroglutamic acid was
prepared from readily available compounds by Ni(II) com-
plex chemistry.
As illustrated in Scheme 2, the proposed approach would
include diverse reactions. Therefore, it was important to
identify the proper protecting group for the amino group in
the starting material which would later be functionalized in
the final step. This protecting group should be sufficiently
robust to survive the projected reactions, and also should be
orthogonal to other functionalities and be labile enough to
be removed in the final step. Furthermore, based on our
earlier studies, it seems likely that a mono protected nitrogen
would interfere with the aldehyde intermediate.6 All of these
a Reagents: (a) oxalyl chloride, DMSO, TEA, CH2Cl2, 86%; (b)
t-BuOCOCH2PPh3Br, NaOH, TEA, CH2Cl2, H2O, 95%; (c) TFA
(50% in CH2Cl2); (d) t-BuCOCl, TEA, THF, -78 °C; (e) (S)-4-
phenyl-2-oxazolidinone, n-BuLi, THF, -78 °C, 89%; (f) DBU (15
mol %), DMF, rt; (g) 3 N HCl, MeOH; (h) NH4OH; (i) SOCl2,
MeOH; (j) (Boc)2O, DMAP, acetonitrile, 54%.
of alcohol 2 following the literature procedure.7 However,
when the reaction was performed on a large scale, the
reduced chromium byproduct made workup difficult. Thus,
we employed the Swern oxidation as a good alternative
synthetic method to prepare 3 on a large scale. Wittig
olefination of aldehyde 3 with (tert-butoxycarbonylmethyl)-
triphenylphosphonium bromide in the presence of NaOH and
triethylamine in a two-phase system of dichloromethane/H2O
gave the (E)-5-N-phthalimido-R,â-unsaturated tert-butyl ester
4 in excellent yield. The tert-butyl protecting group was
removed by treatment with 50% TFA in dichloromethane,
(3) (a) Mueller, R.; Revesz, L. Tetrahedron Lett. 1994, 34, 4091. (b)
Lombart, H.-G.; Lubell, W. D. J. Org. Chem. 1996, 61, 9437. (c) Wang,
W.; Xiong, C.; Hruby, V. J. Tetrahedron Lett. 2001, 42, 3159. (d) Mulzer,
J.; Schu¨lzchen, F.; Bats, J.-W. Tetrahedron 2000, 56, 4289. (e) Angiolini,
M.; Araneo, S.; Belvisi, L.; Cesarotti, E.; Checchia, A.; Crippa, L.; Manzoni,
L.; Scolastico, C. Eur. J. Org. Chem. 2002, 2571. (f) Li, W.; Hanau, C. E.;
d′Avignon, A.; Moeller, K. D. J. Org. Chem. 1995, 60, 8155.
(4) Wang, W.; Yang, J.; Ying, J.; Xiong, C.; Zhang, J.; Cai, C.; Hruby,
V. J. J. Org. Chem. 2002, 67, 6353.
(5) (a) Hruby, V. J. Life Sci. 1982, 31, 189. (b) Kessler, H. Angew. Chem.,
Intl. Ed. Engl. 1982, 21, 512. (c) Hruby, V. J.; Al-Obeidi, F.; Kazmierski,
W. Biochem. J. 1990, 268 (2), 249. (d) Hruby, V. J. Nature ReV. Drug
DiscoVery 2002, 1 (11), 847.
(6) Wang, W.; Xiong, C.; Yang, J.; Hruby, V. J. Synthesis 2002, 1, 94.
(7) Adams, L.; Luzzio, F. J. Org. Chem. 1989, 54, 5387.
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