Stereoselective synthesis of novel dipeptide β-turn mimetics targeting melanocortin peptide receptors

Article abstract of DOI:10.1021/ol0351347

(Matrix presented) The novel dipeptide β-turn mimetic, 4,8-disubstituted azabicyclo[4.3.0]nonane amino acid ester (15), has been synthesized to serve as a peptide mimetic of the dipeptide Phe-Arg, which contains two important pharmacophore elements in melanotropin peptides. Introduction of side-chain functionality at C-8 was achieved by using β-functionalized pyroglutamate (8) as a synthetic precursor. The side chain at C-4 was introduced by bromination of dehydroamino acid intermediate (10) followed by Suzuki cross-coupling.

Full text of DOI:10.1021/ol0351347

ORGANIC
LETTERS
2003
Vol. 5, No. 17
3115-3118
Stereoselective Synthesis of Novel
Dipeptide â-Turn Mimetics Targeting
Melanocortin Peptide Receptors
Junyi Zhang, Chiyi Xiong, Jinfa Ying, Wei Wang,† and Victor J. Hruby*
Department of Chemistry, UniVersity of Arizona, 1306 East UniVersity BouleVard,
Tucson, Arizona 85721
hruby@u.arizona.edu
Received June 19, 2003
ABSTRACT
The novel dipeptide â-turn mimetic, 4,8-disubstituted azabicyclo[4.3.0]nonane amino acid ester (15), has been synthesized to serve as a
peptide mimetic of the dipeptide Phe-Arg, which contains two important pharmacophore elements in melanotropin peptides. Introduction of
side-chain functionality at C-8 was achieved by using â-functionalized pyroglutamate (8) as a synthetic precursor. The side chain at C-4 was
introduced by bromination of dehydroamino acid intermediate (10) followed by Suzuki cross-coupling.
As part of our ongoing program for the design of novel
melanotropin peptide mimetics, we have identified the core
Scheme 1. Melanotropin Peptide Mimetic Dipeptide
bioactive sequence of melanotropin peptides as His-(D/L)-
Phe-Arg-Trp1 and found a â-turn structural feature which
includes the Phe and Arg residues.2 Based on these findings,
we have initiated a program to examine the structure-activity
relationship of melanocyte stimulating hormone (MSH)
peptides by replacing the dipeptide Phe-Arg with â-turn
dipeptide mimetics, such as azabicyclo[4.3.0]nonane amino
acids 1 (Scheme 1).
Analogues
In our efforts to implement this plan, we need to develop
a flexible synthetic approach to dipeptide mimetics such as
* To whom correspondence should be addressed. Phone: (520) 621-
6332. Fax: (520) 621-8407.
† Genomics Institute of the Novartis Research Foundation, 10675 John
Jay Hopkins Drive, San Diego, CA 92121.
(1) (a) Hruby, V. J.; Wilkes, B. C.; Hadley, M. E.; Al-Obeidi, F.; Sawyer,
T. K.; Staples, D. J.; DeVaux, A. E.; Dym, O.; Castrucci, A. M. L.; Hintz,
M. F.; Riehm, J. P.; Rao, K. R. J. Med. Chem. 1987, 30, 2126. (b) Haskell-
Luevano, C.; Miwa, H.; Dickinson, C.; Hruby, V. J.; Yamada, T.; Gantz,
I. Biochem. Biophys. Res. Commun. 1994, 204 (3), 1137. (c) Haskell-
Luevano, C.; Toth, K.; Boteju, L.; Job, C.; Castrucci, A. M. L.; Hadley,
M. E.; Hruby, V. J. J. Med. Chem. 1997, 40, 2740.
(2) (a) Sawyer, T. K.; Hruby, V. J.; Darman, P. S.; Hadley, M. E. Proc.
Natl. Acad. Sci. U.S.A. 1982, 79, 1751. (b) Hruby, V. J.; Han, G. In The
Melanocotrin Receptors; Cone, R. D., Ed.; Humana Press: Totowa, NJ,
2000; pp 239-261. (c) Al-Obeidi, F.; O’Connor, S. D.; Job, C.; Hruby, V.
J.; Pettitt, B. M. J. Peptide Res. 1998, 51, 420.
1 (Scheme 1). Some successful methodologies have been
reported for the synthesis of indolizidinone amino acids.3
However, to the best of our knowledge, little success has
been reported in the synthesis of indolizidinone amino acids
with appropriate side-chain functionalities which correspond
to the side chains of natural amino acids.4 Many studies have
10.1021/ol0351347 CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/24/2003

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.
3116
Org. Lett., Vol. 5, No. 17, 2003

and S-4-phenyl-2-oxazolidinone was coupled to deprotected
4 as the chiral auxiliary for asymmetric functionalization of
the â-position in the next step. Michael acceptor 5 underwent
asymmetric Michael addition with the Ni(II) complex 68 to
give a mixture of (2S,3S)-7a and (2R,3S)-7b. Our previous
studies have shown that the addition reaction with Ni(II)
complex 6 will provide excellent stereoselectivities (>95%)
in the preparation of â aryl- or alkyl-substituted pyroglutamic
acid derivatives.9 In this case, however, treatment of 5 with
DBU and Ni(II) complex 6 at room temperature did not
afford such excellent stereoselectivity. Two critical reaction
conditions, reaction time and temperature, were investigated
in order to optimize stereoselectivity and yield. The reaction
at room temperature for 5 min provided moderate selectivity
and excellent yields. More reaction time was expected to
improve the selectivity for the more thermodynamically
stable product. However, prolonged reaction time did not
make much difference in stereoselectivity and resulted in
lower yield due to decomposition of the product. At low
temperature, the reaction proceeded extremely slowly and
resulted in no reaction at -40 °C or very low yields at 0
°C. However, when the reaction was run from 0 °C to room
temperature in 30 min, greatly improved stereoselectivities
(7a/7b ) 10:1) and yields (93%) were obtained.
Scheme 4. Synthesis of 4,8-Disubstituted Indolizidinone
Amino Acid Ester 15a
Hydrolysis of the Ni(II) complex 7a followed by cycliza-
tion under basic conditions afforded the corresponding
â-functionalized pyroglutamic acid (Scheme 3). Attempts to
purify the amino acid by Dowex ion-exchange resin column
were not successful probably due to a contamination of the
uncyclized product. Instead the crude amino acid was
protected directly to give the NR-Boc pyroglutamate 8 which
was purified by flash column chromatography. The config-
uration was confirmed by X-ray crystallographic analysis
(Figure 1). The lactam moiety of pyroglutamate usually could
a Reagents: (a) DIBAL-H, THF, -78 °C; (b) Ts-OH, MeOH;
(c) BF3‚Et2O, Me3SiCH2CHdCH2, Et2O, -40 °C, 64%; (d) OsO4,
NaIO4, THF/H2O; (e) DBU, (MeO)2P(O)CH(NHCbz)COOCH3,
CH2Cl2, rt, 79%; (f) NBS, CHCl3; (g) DABCO, CHCl3, 78%; (h)
PhB(OH)2, Pd(OAc)2, P(o-tolyl)3, Na2CO3, DME, 80 °C; (i) 20%
TFA, CH2Cl2, rt; (j) CHCl3, rt, 24 h, 61%; (k) NH2NH2, EtOH,
CH3Cl; (l) N,N′-bis(tert-butoxycarbonyl)-N′′-triflylguanidine, TEA,
CH2Cl2, 83%.
afforded the methoxy aminal which was directly subjected
to allyltrimethylsilane and boron trifluoride in ether without
further purification. As a result of a neighboring group
participation of the methyl ester3d and the steric effect of
the â-substituent, the allylsilane addition to the N-acylimin-
Figure 1. X-ray structure of compound 8.
be reduced selectively by Super-Hydride (LiBEt3H).10 How-
ever, in agreement with a previous report,11 the treatment of
8 with Super-Hydride (LiBEt3H) also resulted in the reduc-
tion of the phthalimide protecting group. Therefore, we chose
to use DIBAL-H which the phthalimide group is stable to.
The reduction by DIBAL-H followed by treatment with
methanol in the presence of a catalytic amount of p-TsOH
(8) Chiral Ni(II) complex (S)-6 was prepared according to a literature
procedure; see: Belokon, Y. N.; Bulychev, A. G.; Vitt, S. V.; Struchkov,
Y. T.; Batsanov, A. S.; Timofeeva, T. V.; Tsyryapkin, V. A.; Ryzhov, M.
G.; Lysova, L. A.; Bakhmutov, V. I.; Belikov, V. M. J. Am. Chem. Soc.
1985, 107, 4252.
(9) Soloshonok, V. A.; Cai, C.; Hruby, V. J. Org. Lett. 2000, 2, 747.
Org. Lett., Vol. 5, No. 17, 2003
3117

ium intermediate gave exclusively the trans product 9 related
to the â-substituent (Scheme 4). The optically pure interme-
diate 9 underwent osmylation and subsequent oxidation with
NaIO4 to afford the aldehyde intermediate. The dehydro-
amino acid ester 10 was obtained via the Horner-Emmons
olefination of the aldehyde intermediate (Scheme 4).
Table 1. NOE Data of 15
With the dehydroamino acid ester 10 in hand, we treated
it with N-bromosuccinimide (NBS) in chloroform to produce
the R-bromo imines (Scheme 4). Upon treatment with an
amine base, the R-bromo imine intermediates underwent
tautomerization to afford the (Z)-â-bromo-R,â-dehydroamino
acid 11. We have observed that using DABCO instead of
TEA and DBU in the tautomerization step results in the Z
isomers exclusively.12 Coleman and Carpenter13 have sug-
gested that DABCO-induced isomerization can interconvert
the kinetically formed E-vinyl bromide to the thermodynami-
cally favored Z isomer through a Michael addition-elimina-
tion reaction sequence. Suzuki coupling of 11 with phenyl
boronic acid introduced the phenyl side-chain at the â
position of dehydroamino acid. The crude product of Suzuki
coupling 12 was deprotected and then cyclized to furnish
13 in good yield (Scheme 4). Deprotection of the phthalimide
protecting group in 13 was accomplished by treatment with
hydrazine at room temperature for 24 h. Workup and
purification of free amine 14 after the deprotection gave poor
yields. Thus, the crude free amine 14 was directly guanidi-
nated to give 15 (Scheme 4), using the commercially
available guanidinating reagent, N,N′-Bis(tert-butoxycarbo-
nyl)-N′′-triflylguanidine. Although an initial attempt using
DMAP as base failed, the guanidinating reaction with
triethylamine afforded 15 in good yield. The configuration
of 15 was confirmed by NOE (Table 1).
protons
NOE
H8
H8
H6
H6
H6
H6
H7R
H7â
H7R
H7â
H8
0.80
1.46
1.05
0.66
n.o.a
0.20
H9
a NOE not observed.
In conclusion, we have developed an efficient approach
to the synthesis of dipeptide â-turn mimetics 1 which can
serve as mimetics of the dipeptide Phe-Arg in our R-MSH
program. The synthesis of other diastereomers of the â-turn
mimetics 1, the incorporation of them into melanotropin
peptides, and the study of their structure-activity relation-
ships are under investigation.
Acknowledgment. This work was supported by U.S.
Public Health Service Grant Nos. DK 17420, DA 13449,
and DA 06284. The opinions expressed are those of the
authors and not necessarily those of the U.S. Public Health
Service.
Supporting Information Available: Experimental details
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(10) Dieter, R. K.; Sharma, R. R. J. Org. Chem. 1996, 61, 4180.
(11) Brodney, M.; Padwa, A. Tetrahedron Lett. 1997, 38, 6153.
(12) Zhang, J.; Xiong, C.; Wang, W.; Ying, J.; Hruby, V. J. Org. Lett.
2002, 4, 4029.
(13) Coleman, R. S.; Carpenter, A. J. J. Org. Chem. 1993, 58, 4452.
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