From macrocycle dipeptide lactams to azabicyclo[X.Y.0]alkanone amino acids: A transannular cyclization route for peptide mimic synthesis

Article abstract of DOI:10.1021/ol0609863

Macrocyclic and fused bicyclic dipeptides are complementary motifs for mimicry of different types of β-turn geometry. Macrocyclic dipeptide mimics have served as precursors for the synthesis of their bicyclic counterparts using electrophilic transannular

Full text of DOI:10.1021/ol0609863

ORGANIC
LETTERS
2006
Vol. 8, No. 13
2851-2854
From Macrocycle Dipeptide Lactams To
Azabicyclo[X.Y.0]alkanone Amino Acids:
A Transannular Cyclization Route for
Peptide Mimic Synthesis
Simon Surprenant and William D. Lubell*
De´partement de Chimie, UniVersite´ de Montre´al, C.P. 6128, Succursale Centre Ville,
Montre´al, Que´bec, Canada H3C 3J7
lubell@chimie.umontreal.ca
Received April 25, 2006
ABSTRACT
Macrocyclic and fused bicyclic dipeptides are complementary motifs for mimicry of different types of
â
-turn geometry. Macrocyclic dipeptide
mimics have served as precursors for the synthesis of their bicyclic counterparts using electrophilic transannular cyclizations of 9- and
10-membered ring lactams 9 12 to form azabicyclo[4.3.0]- and -[5.3.0]alkanone amino esters 13 16.
−
−
Peptides are important endogenous molecules responsible for
a multitude of roles in human physiology; however, their
therapeutic potential is often limited because of their poor
bioavailability, rapid metabolism, and short duration of
action. Peptide mimics have thus been developed to retain
the desired biological effects of the parent peptide and to
remove such undesirable characteristics.1 In this respect,
azabicyclo[X.Y.0]alkanone amino acids have proven to be
effective dipeptide mimics because their fused bicyclic ring
system can constrain the backbone dihedral angle geometry
to induce secondary structures such as â-turns. Although
many approaches have been conceived for making azabicy-
cloalkanone amino acids,2 few examples have made practical
use of common precursors for making a set of ring systems.
The introduction of a set of dipeptide mimics is often
desired to provide detailed information about the conforma-
tion specifically required by the peptide to effectively bind
and activate the receptor. The acquisition of a set of
azabicycloalkanone amino acids requires, however, perform-
ing a series of multistep syntheses because few dipeptide
mimics are commercially available. For example, to study
opioid receptor-like 1 (ORL1) receptor antagonists,3 replace-
ment of the commercially available fused-6,5 thiaindoliz-
idinone amino acid with fused-6,5, -5,6, and -6,6 azabicy-
cloalkanone amino acids required syntheses of seven, seven,
and five steps, respectively, from suitably protected amino
dicarboxylic acids in overall yields ranging from 45% to
61%.4 The use of such a tour de force of peptide scaffolds
(1) (a) Ripka, A. S.; Rich, D. H. Curr. Opin. Chem. Biol. 1998, 2, 441.
(b) Adang, A. E. P.; Hermkens, P. H. H.; Linders, J. T. M.; Ottenheijm, H.
C. J.; Vanstaveren, C. J. Recl. TraV. Chim. Pays-Bas 1994, 113, 63. (c)
Gante, J. Angew. Chem., Int. Ed. 1994, 33, 1699. (d) Olson, G. L.; Bolin,
D. R.; Bonner, M. P.; Bos, M.; Cook, C. M.; Fry, D. C.; Graves, B. J.;
Hatada, M.; Hill, D. E.; Kahn, M.; Madison, V. S.; Rusiecki, V. K.; Sarabu,
R.; Sepinwall, J.; Vincent, G. P.; Voss, M. E. J. Med. Chem. 1993, 36,
3039. (e) Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. 1993, 32, 1244.
(f) Marshall, G. R. Tetrahedron 1993, 49, 3547.
(2) (a) Cluzeau, J.; Lubell, W. D. Biopolymers 2005, 80, 98. (b) Maison,
W.; Prenzel, A. H. G. P. Synthesis 2005, 1031 (c) Hanessian, S.;
McNaughtonSmith, G.; Lombart, H. G.; Lubell, W. D. Tetrahedron 1997,
53, 12789.
(3) (a) Van Cauwenberghe, S.; Simonin, F.; Cluzeau, J.; Becker, J. A.
J.; Lubell, W. D.; Tourwe, D. J. Med. Chem. 2004, 47, 1864. (b) Halab,
L.; Becker, J. A. J.; Darula, Z.; Tourwe, D.; Kieffer, B. L.; Simonin, F.;
Lubell, W. D. J. Med. Chem. 2002, 45, 5353.
(4) Halab, L.; Gosselin, F.; Lubell, W. D. Biopolymers 2000, 55, 101.
10.1021/ol0609863 CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/03/2006

Scheme 1. Conversion of Macrocyclic Dipeptides into
Bicyclic Dipeptides by Electrophilic Transannular Cyclization
Scheme 2. Unsaturated Macrocyclic Dipeptide Lactam
Synthesisa
a Dmb ) 2,4-dimethoxybenzyl.
scribed protocol6 (Scheme 2). Briefly, suitably Fmoc- and
Boc-protected allyl- and homoallylglycines 1-3 were coupled
to homoallylglycine methyl ester 5 using TBTU and DIEA
and to N-(Dmb)homoallylglycine methyl ester 4 using HATU
and DIEA in yields varying between 75% and 87% (Dmb
) 2,4-dimethoxybenzyl). Annulation of the dipeptides 6-8
bearing two olefinic side chains was achieved using the first
generation of Grubbs catalyst to afford the macrocyclic
unsaturated lactams 9-11 in yields between 71% and 77%.
Finally, the Dmb group, which was essential for the
annulation of the nine-membered lactams, was removed by
treatment with 50% TFA in CH2Cl2 to afford quantitatively
the secondary amide 12.
did deliver analogues with remarkable potency and selectivity
for the ORL1 receptor over the other opioid receptor
subtypes. For such structure-activity studies to become more
practical, however, a more efficient methodology is needed
for making such mimics.
Considering that electrophilic transannular cyclization of
unsaturated macrocyclic lactams of 9- and 10-membered
rings has been previously used to prepare indolizidinone
and quinolizidinone ring systems,5 we have pursued this
approach for converting macrocyclic dipeptide surrogates into
their azabicycloalkanone amino acid counterparts (Scheme
1).
The electrophilic transannular cyclization was initially
performed on 9- and 10-membered lactams 9-12 using
iodine as the source of electrophile (Scheme 1). Treatment
of the Fmoc-protected, nine-membered lactam 12 with 4
equiv of I2 in THF at reflux gave two isomeric bicyclic
products (3S,5R,6R,9S)- and (3S,5S,6S,9S)-13 in 46% and
27% respective yields (see below for stereochemical assign-
ments). On the other hand, treatment of the corresponding
tertiary Dmb-amide 9 under similar conditions afforded
bicycle (3S,5R,6R,9S)-13 as a single product in 86% yield.
The set of 9- and 10-membered unsaturated macrocyclic
dipeptides 9-12 was synthesized using our recently de-
(3S,6R,7S,10S)-Azabicyclo[5.3.0]alkanone 14 was simi-
larly prepared in 45% yield by treating Fmoc-protected
secondary lactam 10, bearing the trans double bond, with
iodine in THF at reflux. Loss of the Boc group was observed
(5) (a) Wilson, S. R.; Sawicki, R. A. J. Org. Chem. 1979, 44, 330. (b)
Wilson, S. R.; Sawicki, R. A. J. Heterocycl. Chem. 1982, 19, 81. (c) Kahn,
M.; Devens, B. Tetrahedron Lett. 1986, 27, 4841. (d) Kahn, M.; Chen, B.;
Zieske, P. Heterocycles 1987, 25, 29. (e) Edstrom, E. D. J. Am. Chem.
Soc. 1991, 113, 6690. (f) Diederich, M.; Nubbemeyer, U. Chem.-Eur. J.
1996, 2, 894. (g) Sudau, A.; Munch, W.; Nubbemeyer, U.; Bats, J. W. J.
Org. Chem. 2000, 65, 1710.
(6) (a) Kaul, R.; Surprenant, S.; Lubell, W. D. J. Org. Chem. 2005, 70,
3838. (b) Addition/Correction: Kaul, R.; Surprenant, S.; Lubell, W. D. J.
Org. Chem. 2005, 70, 4901.
2852
Org. Lett., Vol. 8, No. 13, 2006

Figure 1. NOESY correlations observed for compounds (3S,5R,-
6R,9S)-13 and (3S,5S,6S,9S)-13.
in the reaction of the corresponding Boc-protected 10-
membered macrocycle 11 with iodine in THF; however,
pyrroloazepinone 14 with the same stereochemistry as its
Fmoc counterpart could be isolated in 48% overall yield after
reprotection using Boc2O and triethylamine in CH2Cl2.
In light of the effective transannular cyclizations using
iodine, a cursory investigation of alternative electrophiles
was performed using macrocycle 9 to examine effects on
reaction stereochemistry and product structure. Treatment of
9 with bromine or N-bromosuccinimide did not afford a
bicycle; instead, bromination of the aromatic ring was
observed by LC/MS. Also, treatment of 9 with mercuric
acetate did not lead to bicyclic products. Alternatively,
exposure of dipeptide 9 to 4 equiv of phenylselenium
bromide in THF at reflux provided bicyclic amino ester 16
in 79% yield (Scheme 1).
The assignment of the structures and stereochemistry of
the different azabicyclo[X.Y.0]alkanone amino acids was
performed using NMR spectroscopy and X-ray crystal-
lography (Supporting Information). For bicycle 13, the ring
protons came at distinct chemical shifts and their sequential
order was assigned using a COSY experiment. Coupling
between the downfield carbamate proton and the proton of
the adjacent backbone carbon was used as the starting point
for tracing the through-bond connectivities of the various
protons around the bicycle. With the through-bond connec-
tivities ascertained, the through-space connectivities observed
in the NOESY spectra were used to assign relative stereo-
chemistry. In the NOESY spectrum of indolizidinone (5R,6R)-
13, long-distance transfer of magnetization between the C3
proton and the iodinated C5 and ring-fusion C6 protons,
respectively, confirmed the concave bicycle structure and
the trans relation between the ring-fusion proton and the
iodide (Figure 1). In (5S,6S)-13, the bridgehead stereochem-
istry was assigned on the basis of NOE with the C8 â-proton
which came downfield relative to its R-proton counterpart
due to the anisotropic effect of the C9 carboxylate (â is on
the same face as the C3 amine).7 In the cases of fused-7,5
systems 14 and 15, the relative stereochemistry of the newly
formed centers was confirmed by X-ray crystallographic
analysis of crystals from acetone/hexanes and ethyl acetate/
hexanes, respectively (Figure 2).8 The cis relationship among
Figure 2. X-ray crystal structures of 14 (top) and 15 (bottom).
the iodide and the bridgehead proton and the convex bicycle
was observed in both structures.
In concurrence with an earlier computational study of
the parent pyrroloazepinone,9 in their respective X-ray
structures, the ψ and æ dihedral angles within bicycles 14
(-64.1°; -49.4°) and 15 (-63.5°; -46.6°) were similar to
ideal values for the central residues in a type I â-turn (-30°;
-90°);10 however, they were less similar than the dihedral
(8) (a) Crystallographic data for 14: C26H27IN2O5; Mw ) 574.40;
orthorhombic crystals; space group P212121; unit cell dimensions, a )
5.7630(2) Å, b ) 17.0035(8) Å, c ) 25.3668(11) Å; volume of unit cell,
2485.72(18) Å3; Z ) 4; d ) 1.535 g/cm3; Rf ) 0.0354, Rw ) 0.0565 for all
data; GOF ) 1.005. (b) Crystallographic data for 15: C16H25IN2O5; Mw
)
452.28; monoclinic crystals; space group P21; unit cell dimensions, a )
11.6497(11) Å, b ) 5.8377(6) Å, c ) 13.4469(14) Å, â ) 100.394(5) Å;
volume of unit cell, 899.48(16) Å3; Z ) 2; d ) 1.670 g/cm3; Rf ) 0.0998,
Rw ) 0.2443 for all data; GOF ) 1.005. The author has deposited the atomic
coordinates for the structures of 14 and 15 with the Cambridge Crystal-
lographic Data Centre. The coordinates can be obtained, on request, from
the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, U.K.
(7) (a) Dietrich, E.; Lubell, W. D. J. Org. Chem. 2003, 68, 6984. (b)
Mauger, A. B.; Irreverre, F.; Witkop, B. J. Am. Chem. Soc. 1966, 88, 2019.
(9) Belvisi, L.; Bernardi, A.; Manzoni, L.; Potenza, D.; Scolastico, C.
Eur. J. Org. Chem. 2000, 2563.
Org. Lett., Vol. 8, No. 13, 2006
2853

angles of the parent macrocyclic dipeptide, which exhibited
ψ ) -20° and æ ) -107° in the X-ray structure of a model
peptide.11 Moreover, the æ dihedral angle was consistent with
an inverse γ-turn (æ ) -70 to -85°).12 The power to
pass from macrocycle- to bicycle-constrained dipeptide
surrogates provides the opportunity to explore different turn
geometries with mimics derived from a common reaction
sequence.
A novel effective approach for the synthesis of azabicyclo-
[4.3.0]- and -[5.3.0]alkanone amino esters has been devel-
oped featuring the electrophilic transannular cyclization of
9- and 10-membered macrocyclic dipeptides. This approach
offers potential for converting one turn mimic into another.
Furthermore, the resulting iodide provides the opportunity
for the introduction of side chains onto the heterocycle ring.
We are now developing these avenues for peptide mimicry.
Acknowledgment. This work was supported by grants
from Fonds Que´becois de la Recherche sur la Nature et les
Technologies (FQRNT) and the Natural Sciences and
Engineering Research Council of Canada (NSERC). We are
grateful for a Collaborative Research Development Grant
from NSERC, the Canadian Society for Chemistry, Astra-
Zeneca, Boehringer Ingelheim, Merck Frosst, and Shire
Biochem. We thank Mr. Dalbir S. Sekhon and Dr. Alexandra
Fu¨rto¨s from the Regional Laboratory for Mass Spectrometry,
Sylvie Bilodeau from the Regional Laboratory for NMR
Spectroscopy, and Francine Be´langer-Garie´py from the
Regional Laboratory for X-ray Analysis, at the Universite´
de Montre´al, for their assistance in compound analysis.
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 13-16. Copies of
1H and 13C NMR, DEPT 135, COSY, and HMQC spectra
for compounds 13-16, and X-ray data for compounds 14
and 15. This material is available free of charge via the
Internet at http://pubs.acs.org.
(10) Ball, J. B.; Alewood, P. F. J. Mol. Recognit. 1990, 3, 55.
(11) Fink, B. E.; Kym, P. R.; Katzenellenbogen, J. A. J. Am. Chem.
Soc. 1998, 120, 4334.
(12) Rose, G. D.; Gierasch, L. M.; Smith, J. A. AdV. Protein Chem. 1985,
37, 1.
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