Design and synthesis of a 1,5-diazabicyclo[6,3,0] dodecane amino acid derivative as a novel dipeptide reverse-turn mimetic

Article abstract of DOI:10.1016/j.tetlet.2006.04.053

N-Boc-1,5-diazabicyclo[6,3,0] dodecane amino acid tert-butyl ester (3), designed as a novel dipeptide reverse-turn mimetic, was synthesized in a concise method from the known compound 4 in an overall yield of 47%.

Full text of DOI:10.1016/j.tetlet.2006.04.053

Tetrahedron Letters 47 (2006) 4769–4770
Design and synthesis of a 1,5-diazabicyclo[6,3,0] dodecane
amino acid derivative as a novel dipeptide reverse-turn mimetic
Yuefeng Peng, Haiying Sun and Shaomeng Wang*
Departments of Internal Medicine, Medicinal Chemistry and Pharmacology and Comprehensive Cancer Center,
University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, United States
Received 20 January 2006; accepted 12 April 2006
Abstract—N-Boc-1,5-diazabicyclo[6,3,0] dodecane amino acid tert-butyl ester (3), designed as a novel dipeptide reverse-turn
mimetic, was synthesized in a concise method from the known compound 4 in an overall yield of 47%.
Ó 2006 Elsevier Ltd. All rights reserved.
Design and synthesis of conformationally constrained
non-peptidic mimetics of natural peptides, has attracted
much attention among organic and medicinal chemists.1
Such mimetics have the promising potential to overcome
a number of major intrinsic limitations associated with
natural peptides such as poor cell-permeability, poor
in vivo stability and bioavailability, while maintaining
the desired conformation of natural peptides and their
biological activities.1,2
Since the side chain in reverse-turn peptides is often
involved in interactions with its targeted protein, we
are interested in introducing a substituent into the bicy-
clic structures of azabicyclo[x,y,0] alkyl amino acid
derivatives in order to probe such interactions. One ap-
proach is to replace one of the carbon atoms in the bicy-
clic structure with a nitrogen atom, which can be used as
the basic key intermediate to synthesize a series of side
chain-containing reverse-turn mimetics by linking the
side chains to the amino group with the formation of
an amide or amine. To this end, 5-aza-pyrroloazepin-
2,6-dione N-(Cbz)-amino acid ethyl esters, such as 2
(Scheme 1), were designed, but selective reduction of
the secondary amide in these compounds has proved
to be difficult to achieve.5 Accordingly, we have designed
N-Boc-1,5-diazabicyclo[6,3,0]dodecane amino acid tert-
butyl ester (3, Scheme 1) as a novel, conformational
constrained dipeptide reverse-turn mimetic. Herein, we
report an efficient synthetic method for this compound.
Reverse-turn is an important secondary structure fre-
quently observed in proteins. It describes a site where
the peptide backbone adopts a U-shaped conformation,
reversing the geometrical direction of propagation. Aza-
bicyclo[x,y,0] alkyl amino acid derivatives, such as 1
(Scheme 1), have been designed as dipeptide reverse-turn
mimetics and several research groups have reported the
synthesis of this type of compound.3 Recently, we have
employed compound 1 as a conformationally con-
strained reverse-turn dipeptide mimetic in the design
and synthesis of a class of novel, high-affinity, Smac
mimetics as modulators of cellular apoptosis.4
A retrosynthetic analysis is shown in Scheme 2. The
key step in this synthesis is 4 ! 3, the formation of the
O
HN
HN
O
O
OHC
N
N
N
N
3
N
O
HO
CbzHN
BocHN
O
O
O
BocHN
COOEt
C
O
CbzHN
O
Bn
O
O
O
O
3
NHBoc
2
1
4
5
Scheme 1. Chemical structures of compound 1, 2 and 3.
Scheme 2. Retrosynthetic analysis of compound 3.
*
Corresponding author. Tel.: +1 734 615 0362; fax: +1 734 647 9647; e-mail: shaomeng@umich.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.053

4770
Y. Peng et al. / Tetrahedron Letters 47 (2006) 4769–4770
Ref. 6
Acknowledgments
a
O
COOH
O
HO
b
N
six steps
N
H
O
We are grateful for the financial support from the
National Cancer Institute, National Institutes of Health
(1R01CA109025 to S.W.).
Bn
6
5
O
O
HO
CbzHN
N
TBSO
N
H
O
O
O
References and notes
7
BocHN
8
O
1. Recent reviews: (a) Souers, A. J.; Ellman, J. A. Tetrahedron
2001, 57, 7431–7448 (Review); (b) Loughlin, W. A.;
Tyndall, J. D. A.; Glenn, M. P.; Fairlie, D. P. Chem. Rev.
2004, 104, 6085–6118 (Review); (c) Hanessian, S.;
Mcnaughton-Smith, G.; Lombart, H. G.; Lubell, W. D.
Tetrahedron 1997, 53, 12789–12854; (d) Polyak, F.; Lubell,
W. D. J. Org. Chem. 1998, 63, 5937 (Review); (e) Cluzeau,
J.; Lubell, W. D. Biopolymers 2005, 80, 98–150 (Peptide
Science); (f) Zhang, J.; Xiong, C.; Wang, W.; Ying, J.;
Hruby, V. J. Org. Lett. 2002, 4, 4029–4032; (g) Polyak, F.;
Lubell, W. D. J. Org, Chem. 1998, 63, 5937–5949.
2. (a) Etzkorn, F. A.; Guo, T.; Lipton, M. A.; Goldberg, S.
D.; Bartlett, P. A. J. Am. Chem. Soc. 1994, 116, 10412; (b)
Haubner, R.; Schmitt, W.; Holzemann, G.; Goodman, S.
L.; Jonczyk, A.; Kessler, H. J. Am. Chem. Soc. 1996, 118,
7881; (c) Li, W.; Moeller, K. D. J. Am. Chem. Soc. 1996,
118, 10106–10112; (d) Belvisi, L.; Riccioni, T.; Marcellini,
M.; Vesci, L.; Chiarucci, I.; Efrati, D.; Potenza, D.;
Scolastico, C.; Manzoni, L.; Lombardo, K.; Stasi, M. A.;
Orlandi, A.; Ciucci, A.; Nico, B.; Ribatti, D.; Giannini, G.;
Presta, M.; Carminati, P.; Pisano, C. Mol. Cancer Ther.
2005, 4, 1670.
3. (a) Angiolini, M.; Araneo, S.; Belvisi, L.; Cesarotti, E.;
Checchia, A.; Crippa, L.; Manzoni, L.; Scolastico, C. Eur.
J. Org. Chem. 2000, 2571–2581; (b) Dietrich, E.; Lubell, W.
D. J. Org. Chem. 2003, 68, 6988, and the paper cited
therein; (c) Duggan, H. M. E.; Hitchcock, P. B.; Young, D.
W. Org. Biomol. Chem. 2005, 3, 2287–2295.
4. (a) Sun, H.; Nikolovska-Coleska, Z.; Yang, C.-Y.; Xu, L.;
Liu, M.; Tomita, Y.; Pan, H.; Yoshioka, Y.; Krajewski, K.;
Roller, P. P.; Wang, S. J. Am. Chem. Soc. 2004, 126, 16686–
16687 (Communication); (b) Sun, H.; Nikolovska-Coleska,
Z.; Yang, C.-Y.; Xu, L.; Tomita, Y.; Krajewski, K.; Roller,
P. P.; Wang, S. J. Med. Chem. 2004, 47, 4147–4150 (Letter);
(c) Sun, H.; Nikolovska-Coleska, Z.; Yang, C.-Y.; Wang, S.
Tetrahedron Lett. 2005, 46, 7015–7018.
O
N
c
d
3
O
CbzHN
BocHN
O
4
Scheme 3. Reagents and conditions: a. (i) TBSCl, N,N-diisopropyl-
ethyl amine, CH2Cl2; (ii) H2, 10% Pd–C, EtOAc, 88% over two steps,
b. (i) Boc-Dap(Z)-OH, EDC, HOBt, N,N-diisopropylethyl amine,
CH2Cl2, (ii) TBAF, THF, 87% over two steps; c. Dess–Martin
periodinane, CH2Cl2, 96%; d. 10% Pd–C, H2, MeOH, 64%.
eight-membered ring. This was approached by intra-
molecular condensation of the amino aldehyde formed
by the removal of the carbobenzoxy group from 4.
Compound 4canbe obtainedfrom the known compound 5.
As outlined in Scheme 3, compound 5 was prepared in
six steps from pyroglutamic acid (6) by previously re-
ported methods.6 Protection of the hydroxyl group in
5 as the tert-butyldimethylsilyl (TBS) ether, followed
by the removal of the benzyl group by hydrogenation,
gave the amine 7. Condensation of 7 with N-a-(tert-but-
oxylcarbonyl)-N-b-benzoxylcarbonyl)-L-diamino-propi-
onic acid (Boc-Dap(Z)-OH) followed by the removal of
the TBS group, yielded amide 8 in high yield. Oxidation
of the hydroxyl group in 8 by Dess–Martin periodinane
furnished aldehyde 4 in nearly quantitative yield.
Finally, removal of the Cbz protecting group in com-
pound 4 by hydrogenation, intramolecular condensation
of the amine with the aldehyde and subsequent reduc-
tion of the resulted enamine were carried out in one
pot to give the desired compound 3.7 Hence, starting
from compound 5, this synthetic route involved six steps
and achieved an overall yield of 47%.
5. Curran, T. P.; Marcaurelle, L. A.; O’Sullivan, K. M. Org.
Lett. 1999, 1, 1225–1228.
6. Petersen, J. S.; Fels, G.; Rapoport, H. J. Am. Chem. Soc.
1984, 106, 4539–4547.
20
7. Chemical data for compound 3: ½aꢀD ꢁ8.4 (c 0.65, CHCl3);
In summary, we have designed a 1,5-diazabicyclo[6,3,0]
dodecane amino acid derivative (3) as a novel reverse-
turn dipeptide mimetic and developed an efficient method
for the synthesis of this compound. The application of
this mimetic in the design and synthesis of novel Smac
mimetics with different side chains on the eight-mem-
bered ring is in progress in our laboratory and will be
reported in due course.
1H NMR (300 MHz, CDCl3, TMS)
d 5.49 (br d,
J = 8.1 Hz, 1H), 4.70 (m, 1H), 4.41 (t, J = 9.3 Hz, 1H),
4.30 (m, 1H), 3.25–3.18 (m, 2H), 2.89 (m, 1H), 2.75 (dd,
J = 13.5, 11.1 Hz, 1H), 2.34 (m, 1H), 2.18–1.60 (m, 6H),
1.49 (s, 9H), 1.44 (s, 9H); 13C NMR (75 MHz, CDCl3) d
171.8, 170.4, 155.2, 81.7, 79.5, 60.6, 58.5, 54.9, 52.3, 46.9,
37.5, 32.1, 28.3, 28.0, 27.0; HRMS: calcd m/z 406.2318 for
[M+Na]+; found 406.2317.