Stereoselective bromination-suzuki cross-coupling of dehydroamino acids to form novel reverse-turn peptidomimetics: substituted unsaturated and saturated indolizidinone amino acids.

Article abstract of DOI:10.1021/ol020160a

A general and efficient methodology has been developed to prepare the C4-substituted dipeptide reverse-turn mimetics unsaturated (9a, 10a) and saturated (11a) azabicyclo[4.3.0] alkane amino acid derivatives. The side chain was introduced by bromination of

Full text of DOI:10.1021/ol020160a

ORGANIC
LETTERS
2002
Vol. 4, No. 23
4029-4032
Stereoselective Bromination−Suzuki
Cross-Coupling of Dehydroamino Acids
To Form Novel Reverse-Turn
Peptidomimetics: Substituted
Unsaturated and Saturated
Indolizidinone Amino Acids
Junyi Zhang, Chiyi Xiong, Wei Wang,† Jinfa Ying, and Victor J. Hruby*
Department of Chemistry, UniVersity of Arizona, Tucson, Arizona 85721
hruby@u.arizona.edu
Received August 9, 2002
ABSTRACT
A general and efficient methodology has been developed to prepare the C4-substituted dipeptide reverse-turn mimetics unsaturated (9a, 10a)
and saturated (11a) azabicyclo[4.3.0] alkane amino acid derivatives. The side chain was introduced by bromination of dehydroamino acid
intermediates followed by Suzuki coupling. Hydrogenation of the bicyclic dehydroamino acid 9a afforded saturated bicyclic lactam 11a. This
approach can be further explored for the synthesis of a variety of such â-turn mimetics with aryl and alkyl side chain functionalities.
During the past years, we and other research groups have
developed synthetic routes for the preparation of enantiopure
indolizidinone type bicyclic lactam systems.1 However, these
approaches suffer from some limitations. For example, the
introduction of side chain functionalities at the C4 position
of azabicyclo[X.Y.0] alkane amino acids generally was not
accessible, or required a long synthetic sequence;2 most
methodologies have no way to introduce a phenyl or a
p-hydroxyl phenyl group, which corresponds to the side
chains in the amino acids Phe and Tyr, respectively. Moeller
and co-workers chose a benzyl group to substitute for a
phenyl group. However, their studies showed that the extra
methylene group interfered badly in the binding to the
TRH-R receptor.3 In this paper, we report a novel methodol-
ogy that can allow for the synthesis of 4-phenyl- or
p-hydroxylphenyl-substituted saturated and unsaturated in-
dolizidinone amino acids. Such reverse turn mimetics could
be used to serve as surrogates of dipeptides Phe-Ala and
Tyr-Ala. Their potential applications include our ongoing
R-MSH (melanocyte stimulating hormones) and opioid
peptide programs, and the TRH-R peptide.3,4
* Author to whom correspondence should be addressed at the University
of Arizona. Phone: (520) 621-6332. Fax: (520) 621-8407.
† Current address: Genomics Institute of the Novartis Research Founda-
tion, 9390 Towne Centre Dr., Suite 200, San Diego, CA 92121.
(1) (a) Mueller, R.; Revesz, L. Tetrahedron Lett. 1994, 34, 4091-4092.
(b) Lombart, H.-G.; Lubell, W. D. J. Org. Chem. 1996, 61, 9437-9446.
(c) Kim, H.-O.; Kahn, M. Tetrahedron Lett. 1997, 37, 6483-6484. (d)
Wang, W.; Xiong, C.; Hruby, V. J. Tetrahedron Lett. 2001, 42, 3159-
3161.
Some groups have reported on the preparation of indoliz-
idinone type compounds through dehydroamino acid inter-
mediates.5 Further applications to these methodologies have
been successfully developed in our group to introduce side
(2) Li, W.; Hanau, C. E.; d’Avignon, A.; Moeller, K. D. J. Org. Chem.
1995, 60, 8155-8170.
(3) Li, W.; Moeller, K. D. J. Am. Chem. Soc. 1996, 118, 10106-10112.
10.1021/ol020160a CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/24/2002

chain functionalities at the C7 and C8 positions.6 Presently,
we have extended these methodologies to introduce aryl
groups at position 4 through Suzuki cross-couplings. The
general retrosynthetic strategy is given in Scheme 1. The
Scheme 2a
Scheme 1. Retrosynthetic Analysis
unsaturated bicyclic lactam system could be approached from
a dehydroamino acid intermediate, which can be prepared
by Horner-Emmons olefination of a proline aldehyde
derivative. Two challenges must be faced in our synthetic
approach to the novel targets. The first is the introduction
of the side chain functionality at the C4 position from the
precursor dehydroamino acid derivative. Second, the major
Z dehydroamino acid products formed from the Horner-
Emmons reaction may restrict the cyclization in the following
step. We postulated that bromination of the dehydroamino
acid could be a solution to these two problems. Bromination
can generate a reactive site for Suzuki cross-coupling and
also can provide the geometry required for cyclization. With
this methodology, we also can introduce side chain func-
tionalities at both C4 and C7 or C8 positions using the
corresponding chiral pyroglutamic ester derivatives prepared
by chemistries previously developed in our laboratory.7 In
this paper, we have demonstrated the synthetic method with
side chain functionalities at the C4 position.
a Conditions: (a) (i) Super-Hydride, THF, -78 °C; (ii) p-TsOH
(cat.), MeOH; (b) BF3-Et2O, Me3SiCH2CHdCH2, three steps:
77%; (c) OsO4, NaIO4, THF/H2O, 4 h; (d) (MeO)2P(O)CH(NHCbz)-
COOCH3, DBU, DCM, rt, 8 h, two steps: 63%; (e) (i) NBS, CHCl3,
rt, 80 min; (ii) Dabco, CHCl3, rt, 24 h; (f) RB(OH)2, Pd(OAc)2,
P(o-tolyl)3, Na2CO3, DME, 80 °C; (g) (i) 20% TFA, DCM, rt, 30
min; (ii) NaHCO3; (iii) CHCl3, rt, 24 h.
Our approach to the synthesis of 4-substituted azabicyclo-
[4.3.0] alkane amino acid derivatives 9a and 10a is illustrated
(4) (a) Hruby, V. J.; Wikes, B. C.; Hadley, M. E.; Al-Obeidi, F.; Sawyer,
T. K.; Staples, D. J.; deVaux, A. E.; Dym, O.; Castrucci, A. M. F.; Hintz,
M. E.; Riehem, J. P.; Rao, R. J. Med. Chem. 1987, 30, 2126-2130. (b)
Sawyer, T. K.; Hruby, V. J.; Darman, P. S.; Hadley, M. E. Proc. Natl.
Acad. Sci. U.S.A. 1982, 79, 1751-1755. (c) Hruby, V. J.; Gehrig, C. A.
Med. Res. ReV. 1989, 9, 343-401. (d) Mosberg, H. I.; Hurst, R.; Hruby,
V. J.; Gee, K.; Yamamura, H. I.; Galligan, J. J.; Burks, T. F. Proc. Natl.
Acad. Sci. U.S.A. 1983, 80, 5871-5874.
(5) (a) Mulzer, J.; Schu¨lzchen, F.; Bats, J.-W. Tetrahedron 2000, 56,
4289-4298. (b) Angiolini, M.; Araneo, S.; Belvisi, L.; Cesarotti, E.;
Checchia, A.; Crippa, L.; Manzoni, L.; Scolastico, C. Eur. J. Org. Chem.
2002, 2571-2581.
(6) Wang, W.; Yang, J.; Ying, J.; Xiong, C.; Zhang, J.; Cai, C.; Hruby,
V. J. J. Org. Chem. 2002, 67, 6353-6370.
(7) (a) Ezquerra, J.; Pedregal, C.; Rubio, A.; Yruretagoyena, B.;
Escribano, A.; Sanchez-Ferrando, F. Tetrahedron 1993, 49, 8665-8678.
(b) Soloshonok, V. A.; Cai, C.; Hruby, V. J. Tetrahedron Lett. 2001, 41,
135-139. (c) Soloshonok, V. A.; Cai, C.; Hruby, V. J. Angew. Chem., Int.
Ed. 2000, 39, 2172-2175. (d) Soloshonok, V. A.; Cai, C.; Hruby, V. J.
Org. Lett. 2000, 2, 747-750. (e) Soloshonok, V. A.; Cai, C.; Hruby, V. J.;
Van Meervelt, L.; Yamazaki, T. J. Org. Chem. 2000, 65, 6688-6696. (f)
Soloshonok, V. A.; Cai, C.; Hruby, V. J.; Van Meervelt, L. Tetrahedron
1999, 55, 12045-12058.
in Scheme 2. The readily available (S)-pyroglutamate 1 was
reduced to the methoxy aminal 2 by treatment with Super-
Hydride (LiBEt3H) in THF at -78 °C, and then with
methanol in the presence of a catalytic amount of p-TsOH.
The crude product 2 was directly subjected to allyltrimeth-
ylsilane in the presence of boron trifluoride without further
purification. The allylsilane addition to the N-acyliminium
compound derived from 2 afforded a 3:1 cis/trans mixture
of proline ester 3. The intermediate 3 underwent osmylation
and subsequent oxidation with NaIO4 to give aldehyde 4. A
cis/trans dehydroamino acid mixture 5 was obtained in a
3:1 ratio via Hornor-Emmons olefination of 4.8
(8) The ratio was determined based on 1H NMR spectra. The assignment
of the major product to a cis isomer was achieved according to the
literature: Mulzer, J.; Schu¨lzer, F.; Bats, J.-W. Tetrahedron 2000, 56, 4289-
4298. It was further confirmed by the stereochemistry of the final product.
4030
Org. Lett., Vol. 4, No. 23, 2002

The stereoselective â-bromination of dehydroamino acid
esters has been well documented.9 Nunami and co-workers
described that the Z-selectivity of the bromination was
improved by increasing the bulkiness of â-substituents.10
Carpenter and co-workers proposed that the Z-vinyl bromide
was the thermodynamically more stable product and the
kinetically formed E-vinyl bromide could be interconverted
to the Z-isomer through DABCO-induced isomerization.11
In our case, we treated the dehydroamino acid ester 5 with
N-bromosuccinimide (NBS) to produce R-bromo-imines,
which underwent tautomerization to afford (Z)-â-bromo-R,
â-dehydroamino acids 6a,b upon treatment with an amine
base. We examined various amine bases which could be used
in the tautomerization step. The results showed that the use
of DABCO instead of Et3N and DBU as a base improved
Z-selectivity and gave the Z-isomer exclusively. This result
was consistent with the observations of Carpenter and co-
workers.11 The cis/trans isomers 6a,b were able to be
separated at this point by column chromatography eluting
with hexanes/ethyl acetate (4/1). However, the attempts to
purify compound 6b were not successful due to a contamina-
tion of the R-bromo-imine intermediate in this reaction.
We then investigated the Suzuki cross-coupling of 6a with
aryl boronic acids. We chose phenyl boronic acid and
4-methoxyphenyl boronic acid to use in the couplings
because Phe and Tyr are two important amino acid moieties
in our R-MSH and δ-opioid studies. Suzuki coupling went
smoothly to afford 7a and 8a, in 76% and 79% yields,
respectively. Deprotection of the NR-Boc group was per-
formed in 20% TFA in dichloromethane (DCM) at room
temperature (rt). The TFA was neutralized with NaHCO3,
and the reaction was stirred in chloroform at room temper-
ature for 48 h. Deprotected 7a, 8a underwent slow cyclization
to afford 9a, 10a in good yields.
because the NOE spectrum was complicated due to the
overlap of proton peaks. Thus, we evaluated the other
bridgehead stereoisomer. We used the crude compound 6b
in Suzuki coupling and the crude product was cyclized to
give 8b in 34% overall yield from 6b. The stereochemistry
of 8b was assigned with the use of a 1D-NOE experiment
(Table 1).
Once the unsaturated bicyclic lactams 9a, 10a were
obtained, we investigated the possibility of converting the
unsaturated bicyclic structures to the saturated structures by
hydrogenation. The literature reported that the hydrogenation
of dehydroamino acids in open chain substrates proceeded
with poor stereoselectivity.5b However, the restricted con-
formation in the bicyclic compound provided an asymmetric
environment in hydrogenation. As we expected, compound
9a was hydrogenated (Pd-C, H2, 75 psi) to give 11a
Scheme 3
exclusively (Scheme 3).12 The stereochemistry of 11a was
determined based on the NOE data (Table 2), and the relative
Table 2. NOE Data for 11a
Table 1. NOE Data for 8b
protons
NOE (%)
H5â
H5R
H5â
H5R
H5â
H5R
H6
H6
H4
H4
H3
H3
0.35
1.15
0.50
1.25
n.o.a
0.05
protons
NOE (%)
a NOE not observed.
H9
H9
H6
H6
H8â
H8â
H6
H6
H8R
H8â
H8R
H8â
H7R
H7â
H7R
H7â
1.93
0.39
n.o.a
0.68
0.47
1.30
0.26
2.01
configuration between the C3 and C4 protons was further
confirmed by the J coupling constants.13 The backbone
conformations of the compound best fit the criteria for type
II′ and V′ â-turn structures.14
a NOE not observed.
(9) (a) Olsen, R. K.; Hennen, W. J.; Wardke, R. B. J. Org. Chem. 1982,
47, 7, 4605-5611. (b) Coleman, R. S.; Carpenter, A. J. J. Org. Chem. 1992,
57, 5813-5815. (c) Armstrong, R. W.; Moran, E. J. J. Am. Chem. Soc.
1992, 114, 371-372.
(10) Yamada, M.; Nakao, K.; Fukui, T.; Nunami, K.-I. Tetrahedron 1996,
52, 5751-5764.
The configuration of the bridgehead proton in 9a, 10a has
been described in the literature.5a Our efforts to further
confirm the stereochemistry by NMR led to difficulty
(11) Coleman, R. S.; Carpenter, A. J. J. Org. Chem. 1993, 58, 4452-
4461. Please see the reaction mechanism in the Supporting Information.
Org. Lett., Vol. 4, No. 23, 2002
4031

In conclusion, we have successfully developed an approach
to the synthesis of unsaturated and saturated azabicyclo[4.3.0]
alkane amino acids with an aryl side chain at the C4 position.
This methodology potentially can be extended to the
preparation of more complex molecules, such as 7/5 and 5/5
azabicyclo[X.Y.0] alkane amino acids. The synthesis of more
complex bicyclic lactams with side chains at the C4, C7,
and/or C8 positions is under investigation. Future efforts will
aim at the incorporation of these â-turn mimetic molecules
into biologically active peptides and the study of structure-
activity relationships.
V. McGrath for the use of his group’s polarimeter. The
opinions expressed are those of the authors and not neces-
sarily those of the U.S. Public Health Service.
Supporting Information Available: Experimental de-
tails. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL020160A
(13) Our modeling study showed the dihedral angles between H3 and
H4 are 40° and 57° (two conformations) in the syn isomer and -169° in
the anti isomer. The calculation of the J coupling constant was on the basis
of this conclusion: Jsyn ) 4.1 Hz; Janti ) 12.5 Hz. The observed J coupling
constant was 6.9 Hz. Considering the additional fact that syn addition has
been observed in most metal-catalyzed hydrogenations, we drew the
conclusion that the relative configuration of H3 and H4 in compound 11a
is syn.
(14) Superposition of two lowest energy conformations of the compound
11a onto a peptide with various types of â-turn structures using backbone
heavy atoms gave an RMSD of 0.42 Å for the type II′ structure for one
conformation, and an RMSD of 0.56 Å for the type V′ structure for the
other conformation.
Acknowledgment. This work was supported by the U.S.
Public Health Service (DK 17420) and the National Institute
of Drug Abuse (DA 13449). We thank Professor Dominic
(12) We have performed some modeling studies in order to explain the
stereoselectivity of hydrogenation. Please see details in the Supporting
Information.
4032
Org. Lett., Vol. 4, No. 23, 2002