Short and efficient synthesis of diazabicycloalkane dipeptide mimics

Article abstract of DOI:10.1055/s-2002-34901

A new synthetic route to enantiomerically pure diazabicycloalkanes is reported. Key step of this synthesis is an oxidative cleavage of azabicycloalkene precursors that are synthesized in enantiomerically pure form via aza-Diels-Alder reaction. A range of diazabicycloalkanes with different amino acid side chains have been synthesized and their structure has been elucidated by NMR analysis.

Full text of DOI:10.1055/s-2002-34901

LETTER
1795
Short and Efficient Synthesis of Diazabicycloalkane Dipeptide Mimics
S
hor
t
and
E
fficient Synt
o
hesis of
D
iaz
l
abicyc
f
loalkane
g
D
ipeptide
M
a
imic
s
ng Maison,* Daniela Küntzer, Daniel Grohs
Institut für Organische Chemie der Universität Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
Fax +49(40)428382495; E-mail: maison@chemie.uni-hamburg.de
Received 14 August 2002
In contrast to azabicycloalkanes like II, synthesis and
structural properties of diazabicycloalkanes similar to I
have rarely been reported so far.5 In the course of a project
directed to the development of rigid bioactive peptidomi-
metics, that should serve as modular ligands for cancer
specific receptors,6 we became interested in highly func-
tionalized diazabicycloalkane derivatives of the general
structure I (Figure 1) in enantiomerically pure form.
Abstract: A new synthetic route to enantiomerically pure diazabi-
cycloalkanes is reported. Key step of this synthesis is an oxidative
cleavage of azabicycloalkene precursors that are synthesized in
enantiomerically pure form via aza-Diels–Alder reaction. A range
of diazabicycloalkanes with different amino acid side chains have
been synthesized and their structure has been elucidated by NMR
analysis.
Key words: Diels–Alder reactions, heterocycles, peptides, dihy-
droxylations, peptide mimics
Although a multistep protocol to a proline derivative sim-
ilar to structure I is known,5 a more general synthetic
scheme for the synthesis of new bicyclic compounds V
(Scheme 1) with various side chains R1 and R2 is needed.
Such a general route to diazabicycloalkanes V would be
especially desirable if both residues R1 and R2 were easily
converted into a range of different groups mimicking the
side chains of -amino acids and thus offering a route to
constrained dipeptide mimics. Since it is important for us
to conjugate these dipeptides to fluorescence7 or radio-
pharmaceutical markers,8 we wanted to establish a syn-
thetic route that yields polyfunctional diazabicyclo-
alkanes like V. Within these structures, the aminal OH
should be easily converted into a suitable anchor group by
standard N-acyliminium chemistry.9
Interactions of peptides with receptors and enzymes are
important for a great number of physiological processes.
In consequence, many peptides serve as lead structures for
the development of new pharmaceuticals. However, pep-
tides are not ideal drug candidates due to their low meta-
bolic stability, poor oral availability and rapid excretion.1
In addition, many small peptides lack selectivity to a cer-
tain receptor due to their high conformational flexibility.
A common strategy to overcome these problems is the
synthesis of conformationally constrained peptide ana-
logues mimicking the bioactive conformation of native
peptides at the receptor level.2 These rigid peptidomimet-
ics should then bind with high affinity and specificity to
the receptor and have improved pharmacological profiles.
In this context, fused bicyclic systems play an important
role in the field of drug discovery. Especially azabicy-
cloalkanes of type II in Figure 1 have been used as tools
for rigidifying peptide structures in order to probe confor-
mation-activity relationships.3 A number of structurally
related bicyclic peptide mimics with different ring sizes
and heteroatoms have been prepared and incorporated
into peptides for example as turn mimics.3,4
We have recently demonstrated that azabicycloalkenes
III are ideal precursors for substituted derivatives of pro-
line and pipecolic acid like VI.10 Since these substituted
analogues of cyclic amino acids are key components for
the synthesis of the target compounds V, bicyclic alkenes
III may thus also serve as intermediates for diazabicy-
cloalkanes V as depicted in Scheme 1. A possible route to
peptidomimetics like V would thus require synthesis of
suitable cyclic amino acids VI, peptide coupling to their
N-terminus and subsequent intramolecular ring closure.
However, peptide couplings to sterically hindered 5-sub-
stituted prolines VI (n = 0) and especially 6-substituted
pipecolic acids VI (n = 1) are problematic in general.
Couplings to azabicycloalkanes (like IV in Scheme 1) in
contrast, are known to proceed in good yields under stan-
dard peptide coupling conditions.11 Compounds IV were
therefore key intermediates of our synthetic plan for the
preparation of dipeptide analogues V depicted in
Scheme 1. Peptide coupling to these azabicycloalkanes
should be easy to perform and a periodate cleavage of the
diol function should lead to a bisaldehyde, that in turn
should spontaneously form bicyclic structures V by in-
tramolecular cyclization with the previously coupled ami-
no acid.
O
CO2H
O
Y
CO2H
R
R
H2N
N
N
X
*
*
*
*
PgN
*
n
Z
n
OH
I
II
Pg = protecting group; n = 0, 1
X, Y, Z = N, O or S
Figure 1 Proposed (I) and known (II) bicyclic dipeptide mimics.
Synlett 2002, No. 11, Print: 29 10 2002.
Art Id.1437-2096,E;2002,0,11,1795,1798,ftx,en;G23602ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1796
W. Maison et al.
LETTER
CO2R
R1
R*
lit.10
R*
N
HN
N
n
+
R
CO2R
n
CO2R
n
III
VI
difficult coupling,
ring closure
bishydroxylation
RO
O
CO2R
1. coupling,
2. oxidative
cleavage
R* = chiral auxiliary
Pg = protecting group
n = 0, 1
RO
R2
PgN
R1
N
NH
n
n
OH
CO2R
IV
V
Scheme 1 Retrosynthetic analysis of dipeptide mimics V.
The bicyclic alkene 1 is conveniently prepared via stereo- Hydrolysis of the acetonides in 4a and 4b required strong-
selective aza-Diels–Alder reaction of a cyclic diene and a ly acidic conditions that are not compatible with acid la-
chiral imine derived from enantiomerically pure (R)-phe- bile protecting groups like Boc or t-butyl of side chain
nylethylamine following a known protocol.12 Acetonide 2 functionalized amino acids. Therefore, we tried a direct
was prepared by bishydroxylation of alkene 1 with a cat- coupling of Boc/Cbz-protected lysine and Cbz-protected
alytic amount of K2OsO2(OH4) and K3Fe(CN)6 and subse- methionine to the unprotected amino alcohol 6, which was
quent protection of the intermediate diol with obtained in good yield over two steps from alkene 1
dimethoxypropane in a good yield over two steps. The N- (Scheme 2). The desired dipeptides 5c and 5d, respective-
benzyl group in 2 was removed with palladium on activat- ly, were obtained in good yields following the standard
ed charcoal to give secondary amine 3 in excellent yield. coupling procedure (DCC/HOBt), indicating that protec-
Cbz-protected glycine and valine, respectively, were sub- tion of the intermediate diol prior to peptide coupling is
sequently coupled to the N-terminus of 3 under standard not essential. With diols 5a and 5b in hand, we synthe-
conditions (DCC/HOBt) to give 4a and 4b in good yields. sized bicyclic dipeptide mimics 7a and 7b by cleavage of
Finally, hydrolysis of the acetonide yielded diols 5a and the diol group and subsequent intramolecular cyclization
5b in good yields.
of the intermediate bisaldehyde. The resulting aminals 7a
Me
Me
Me
O
O
Me
O
O
c
a, b
NH
N
N
Me
Me
CO2Et
CO2Et
CO2Et
3, 98 %
1
2, 81 %
d
a, c
Me
Me
HO
HO
HO
HO
O
O
O
O
N
NHCbz
NH
e
d
N
NHCbz
R
CO2Et
CO2Et
6, 89 %
R
CO2Et
5a, R = -H, 71 %
4a, R = H, 80 %
4b, R = -CH(CH3)2, 82 %
5b, R = -CH(CH3)2, 82 %
5c, R = -(CH2)4NHBoc, 72 %
5d, R = -(CH2)2SMe, 73 %
Scheme 2 Conversion of azabicyclooctene 1 to dipeptides 5. Reagents and conditions: a) Cat. K2OsO2(OH)4, K3Fe(CN)6, K2CO3, tert-BuOH/
H2O, 12 h, r.t.; b) PTSA, 2,2-dimethoxypropane, MeOH, 3 h, r.t.; c) H2 (1 atm), 5% Pd/C, EtOH, r.t., 24 h; d) Cbz-protected amino acid, DCC,
HOBt, DMF, 12 h, r.t.; e) 2 N HCl, THF, 45 min, 60 °C.
Synlett 2002, No. 11, 1795–1798 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Short and Efficient Synthesis of Diazabicycloalkane Dipeptide Mimics
1797
O
CO2Et
HO
HO
R
O
a
N
O
N
NHCbz
CbzN
R
CO2Et
5a, R = -H
OH
7a, R = -H, 65 %
7b, R = -CH(CH3)2, 71 %
5b, R = -CH(CH3)2
O
O
CO2Et
CO2Et
c
N
b
N
OH
OH
7a
100 %
HN
58 %
CbzN
R1
R2
9
8a, R1 = -H, R2 = -OH, 41 %
8b, R1 = -OH, R2 = -H, 17 %
Scheme 3 Synthesis of dipeptide mimics 7, 8 and 9. Reagents and conditions: a) NaIO4, acetone/H2O, –25 °C, 30 min; b) NaBH4, MeOH,
0 °C, 1 h; c) H2 (1 atm), 5% Pd/C, EtOH, r.t., 24 h.
and 7b were obtained as 1:1 mixtures of stereoisomers at monstrated the synthetic potential of bicyclic compounds
the aminal position, which can be separated by column 7 by the synthesis of Gly-Hse mimic 9 and evaluated its
chromatography on silica gel if needed. Oxidative cleav- structure by NMR. To the best of our knowledge our route
age of diols 5a and 5b was achieved by treatment with so- is the shortest and most versatile synthetic protocol for
dium periodate at 0 °C for 45 minutes affording bicyclic enantiomerically pure diazabicycloalkanes V known so
aminals 7a and 7b in reasonable yields. It should be noted far. It should be noted that it could be easily expanded to
that reaction conditions of this periodate cleavage have to the synthesis of further diazabicycloalkanes with different
be controlled carefully, as prolonged reaction times and ring sizes and stereochemistry by varying the azabicy-
higher temperatures lead to decomposition of the product cloalkene input. The resulting different dipeptide mimics
resulting in complex product mixtures. Azabicycloal- V (Scheme 1) can therefore be used to systematically
kanes 7a and 7b with suitable functional groups right in screen certain dihedral angles in bioactive dipeptides. We
place for further manipulation were thus synthesized in are currently probing these compounds for their potential
only 4 steps and good overall yield from readily available as modular ligands for cancer cell specific enzymes.
azabicycloalkene 1. Treatment of compound 7a with
NaBH4 (Scheme 3) reduced selectively the free aldehyde
function to give the corresponding primary alcohol as a
Acknowledgement
We gratefully acknowledge material support as well as helpful dis-
cussions of Prof. Dr. Chris Meier and are grateful to BASF AG and
Degussa AG for the donation of chemicals. We thank the Fonds der
Chemischen Industrie for financial support.
mixture of diastereoisomers 8a and 8b. The structure of
both diastereoisomers was determined by 2D-NOESY-
NMR. The combined diastereoisomers 8a and 8b were
subsequently Cbz-deprotected and reduced with hydrogen
and Pd/C to give quantitatively the bicyclic compound 9.
References
As illustrated by the synthesis of Gly-Hse mimic 913
(Scheme 3) from 7a, aminals of the general structure 7
and 8 may serve as versatile educts for the preparation of
a range of different dipeptide analogues as the aldehyde
may be converted into different side chain functionalities.
Furthermore, the aminal OH might be easily modified to
a conjugation site by standard N-acyliminium chemistry.9
The stereochemistry of compound 9 was determined un-
ambiguously by 2D-NOESY-NMR and is in accordance
with a recently published X-ray structure of a pipecolic
acid derivative, which was also synthesized from azabicy-
clooctene 1.10
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B.; Scolastico, C. Tetrahedron 2001, 57, 6463.
In summary, we presented an efficient synthesis of poly-
functional diazabicycloalkanes 7 in enantiomerically pure
form. These versatile precursors for dipeptide mimics
were synthesized in only 4 steps starting from azabicy-
cloalkene 1 that in turn can be prepared via stereoselective
aza-Diels–Alder reaction on a large scale. We have de-
(d) Angiolini, M.; Araneo, S.; Belvisi, L.; Cesarotti, E.;
Checchia, A.; Crippa, L.; Manzoni, L.; Scolastico, C. Eur. J.
Org. Chem. 2000, 2571. (e) Sun, H.; Moeller, K. D. Org.
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P.; Rigo, B.; Houssin, R.; Hénichart, J.-P. Tetrahedron Lett.
2002, 43, 5087.
Synlett 2002, No. 11, 1795–1798 ISSN 0936-5214 © Thieme Stuttgart · New York

1798
W. Maison et al.
LETTER
(5) (a) Tong, Y.; Fobian, Y. M.; Wu, M.; Boyd, N. D.; Moeller,
K. D. J. Org. Chem. 2000, 65, 2484. (b) St-Denis, Y.;
Augelli-Szafran, C. E.; Bachand, B.; Berryman, K. A.;
DiMaio, J.; Doherty, A. M.; Edmunds, J. J.; Leblond, L.;
Lévesque, S.; Narasimhan, L. S.; Penvose-Yi, J. R.; Rubin,
J. R.; Tarazi, M.; Winocour, P. D.; Siddiqui, M. A. Bioorg.
Med. Chem. Lett. 1998, 8, 3193. (c) Fai Chan, M.; Raju, B.
G.; Kois, A.; Varughese, J. I.; Varughese, K. I.; Balaji, V. N.
Heterocycles 1999, 51, 5.
Gly-OH were dissolved in 20 mL abs. DMF. 0.63 g (4.65
mmol) HOBt dissolved in 20 mL abs. DMF as well as 1.15
g (5.58 mmol) DCC, dissolved in 10 mL abs. DMF, was
added. The resulting suspension was stirred for 12 h at r.t.
under nitrogen. DCU was filtered off and DMF was removed
in vacuo. The crude product was purified by column
chromatography on silica gel (dichloromethane/MeOH 95:5,
Rf = 0.21) to give 1.34 g (71%) of dipeptide 5a as a
colourless sticky solid. 1H NMR (CDCl3, 500 MHz):
=
(6) Schally, A. V.; Nagy, A. Eur. J. Endocrinol. 1999, 141, 1.
(7) Zaheer, A.; Lenkinski, R. E.; Mahmood, A.; Jones, A. G.;
Cantley, L. C.; Frangioni, J. V. Nature Biotech. 2001, 19,
1148.
7.37–7.33 (m, 5 H), 5.83 (br, 1 H), 4.33 (s, 1 H), 4.26 (q, 2
H, J = 7.1 Hz), 4.13 (dd, 1 H, J = 17.0 Hz, 5.0 Hz), 4.06 (dd,
1 H, J = 17.0 Hz, 3.5 Hz), 3.98–3.93 (m, 2 H), 3.81 (m, 1 H),
3.73–3.71 (br, 1 H), 3.62–3.60 (br, 1 H), 2.36 (m, 1 H), 2.12–
2.10 (m, 1 H), 1.93–1.89 (m, 1 H), 1.77–1.72 (m, 1 H), 1.37–
1.33 (m, 1 H), 1.30 (t, 1 H, J = 7.1 Hz) ppm. HRMS (FAB)
calcd for C20H27N2O7 (MH+): 407.1818. Found: 407.1840.
450 mg (1.11 mmol) of diol 5a were dissolved in 20 mL
acetone/8 mL water and cooled to –25 °C. 400 mg (1.87
mmol) NaIO4 were added and the solution was stirred for 30
min at –25 °C. 50 mL brine were added and the resulting
aqueous solution was extracted with ethyl acetate. The
organics were dried over Na2SO4, filtered and the solvent
was removed in vacuo to give 290 mg (65%) 7a as a
colourless oil. The product contained some minor impurities
but was used without further purification in the next step.
290 mg (0.72 mmol) of aminal 7a were dissolved in 25 mL
abs. MeOH and 65 mg (1.43 mmol) NaBH4 were added at
0 °C. The solution was stirred for 1 h at 0 °C. After addition
of 25 mL water the solution was stirred for additional 15 min
at r.t. The solution was subsequently saturated with NaCl
and extracted with ethyl acetate. Drying of the combined
organics over Na2SO4 and removal of the solvent in vacuo
gave the crude product as a 7:3 mixture of diastereoisomers,
which was purified by column chromatography on silica gel
(hexane/ethyl acetate 1:9, Rf = 0.28, 0.35) to give 119 mg
(41%) of 8a as a first fraction and 51 mg (17%) of 8b as a
second fraction as colourless oils. 1H NMR for the major
diastereoisomer 8a (CDCl3, 500 MHz): = 7.41–7.34 (m, 5
H), 5.59 (m, 1 H), 5.50 (m, 1 H), 5.19 (s, 2 H), 4.45 (d, 1 H,
J = 17.7 Hz), 4.30–4.21 (m, 2 H), 4.05 (d, 1 H, J = 17.7 Hz),
3.82–3.79 (m, 2 H), 3.55–3.50 (m, 2 H), 2.54–2.53 (m, 1 H),
1.85–1.61 (m, 3 H), 1.50–1.42 (m, 1 H), 1.30 (t, 3 H, J = 7.1
Hz) ppm. HRMS (FAB) calcd for C20H26N2O7 (MH+):
407.1818. Found: 407.1815.
(8) (a) Liu, S.; Edwards, D. S. Chem. Rev. 1999, 99, 2235.
(b) Mahmood, A.; Kuchma, M. H.; Goldstone, J.; Morse, C.;
Davison, A.; Jones, A. G. In Technetium, Rhenium and other
Metals in Chemistry and Nuclear Medicine, Vol. 5; Nicolini
M., Mazzi U., Servizi Grafici Editoriali: Padova, 1999, 523.
(9) (a) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000,
56, 3817. (b) Thaning, M.; Wistrand, L.-G. Acta Chim.
Scand. 1992, 46, 194. (c) Ludwig, C.; Wistrand, L.-G. Acta
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(13) Typical Procedure for the Synthesis of Peptidomimetics
like 9: 8.86 g (31.0 mmol) of alkene 1 were dissolved in 90
mL tert-BuOH and 90 mL water. 30.4 g (93 mmol)
K3Fe(CN)6, 12.7 g (93 mmol) K2CO3, together with a
catalytic amount (100 mg) K2OsO2(OH)4 were added. The
resulting yellowish slurry was stirred for 12 h at r.t. Addition
of 100 mL water, extraction with ethyl acetate, drying of the
combined organics over Na2SO4 and removal of the solvent
gave the crude product, which was purified by column
chromatography on silica gel (hexane/ethyl acetate 1:1,
Rf = 0.33) to give 7.53 g (23.6 mmol) of the diol as a yellow
oil. This diol was dissolved in abs. EtOH and 500 mg 5% Pd
on activated charcoal was added. The suspension was stirred
for 24 h under a hydrogen atmosphere and subsequently
filtered through a plug of celite. The solvent was removed
under reduced pressure to give 6 as a yellow oil in 5.96 g
(89% over two steps) yield. 1H NMR (MeOH-d4, 500 MHz):
= 4.33–4.21 (m, 2 H), 4.10 (ddd, 1 H, J = 8.5 Hz, 2.8 Hz,
1.4 Hz), 4.06 (ddd, 1 H, J = 8.5 Hz, 3.8 Hz, 1.4 Hz), 3.66–
3.63 (m, 1 H), 2.96–2.94 (m, 1 H), 2.18–2.16 (m, 1 H), 1.96–
1.90 (m, 1 H), 1.89–1.82 (m, 1 H), 1.60–1.51 (m, 1 H), 1.31
(t, 3 H, J = 7.3 Hz), 1.27–1.24 (m, 1 H) ppm. HRMS (FAB)
calcd for C10H17NO4 (MH+): 216.1236. Found: 216.1239.
The combined diastereoisomers 8a and 8b (170 mg, 0.42
mmol) were dissolved in abs. EtOH and 100 mg 5% Pd on
activated charcoal was added. The suspension was stirred for
24 h under a hydrogen atmosphere and subsequently filtered
through a plug of celite. The solvent was removed under
reduced pressure to give 9 as a colourless oil in 107 mg
(100%) yield. Rf = 0.54 (dichloromethane/methanol 8:2). 1H
NMR (CDCl3, 500 MHz): = 5.45 (s, 1 H), 4.15 (q, 1 H,
J = 7.1 Hz), 3.62–3.57 (m, 3 H), 3.53–3.48 (m, 2 H), 3.18–
3.17 (m, 1 H), 2.69–2.65 (m, 1 H), 2.52–2.50 (m, 1 H), 1.68–
1.65 (m, 1 H), 1.60–1.52 (m, 1 H), 1.42–1.31 (m, 2 H), 1.31
(t, 3 H, J = 7.1 Hz) ppm. HRMS (FAB) calcd for
C12H21N2O4 (MH+): 257.1501. Found: 257.1532.
1.00 g (4.65 mmol) of amine 6 and 1.94 g (9.29 mmol) Cbz-
Synlett 2002, No. 11, 1795–1798 ISSN 0936-5214 © Thieme Stuttgart · New York