An improved cyclization protocol for the synthesis of diazabicyclo[4.3.0] alkanes

Article abstract of DOI:10.1016/j.tetlet.2005.04.082

We have recently described the synthesis of diazabicyclo[4.X.0]alkanes and their use as ligands for the prostate specific membrane antigene (PSMA). The key step of our synthetic route toward these diazabicycloalkanes is an oxidative cleavage of a bicyclic diol moiety followed by the attack of a nitrogen nucleophile to the resulting intermediate bisaldehyde. We herein describe the mechanism of this ring closure and its stereochemical consequences. In addition, we report a convenient method for trapping intermediate bisaldehydes by Wittig reagents. This trapping allows the synthesis of 3,5-disubstituted proline derivatives, which are shown to be versatile precursors for functionalized diazabicycloalkane dipeptide mimetics.

Full text of DOI:10.1016/j.tetlet.2005.04.082

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4373–4376
An improved cyclization protocol for the synthesis
of diazabicyclo[4.3.0]alkanes
Daniel C. Grohs and Wolfgang Maison*
University Hamburg, Institute of Organic Chemistry, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
Received 9 February 2005; revised 2 March 2005; accepted 20 April 2005
Available online 10 May 2005
Abstract—We have recently described the synthesis of diazabicyclo[4.X.0]alkanes and their use as ligands for the prostate specific
membrane antigene (PSMA). The key step of our synthetic route toward these diazabicycloalkanes is an oxidative cleavage of a
bicyclic diol moiety followed by the attack of a nitrogen nucleophile to the resulting intermediate bisaldehyde. We herein describe
the mechanism of this ring closure and its stereochemical consequences. In addition, we report a convenient method for trapping
intermediate bisaldehydes by Wittig reagents. This trapping allows the synthesis of 3,5-disubstituted proline derivatives, which
are shown to be versatile precursors for functionalized diazabicycloalkane dipeptide mimetics.
Ó 2005 Elsevier Ltd. All rights reserved.
Conformationally constrained peptide mimetics are use-
ful entities for medicinal chemistry as their preorganized
conformations allow improved recognition by certain
receptors, by reducing the entropy penalty for the recep-
tor-binding event.1 Furthermore, such peptidomimetics
show fairly good pharmacological profiles. In particular,
fused bicyclic systems of the aza- and diazabicyclo-
alkane type (structures 1–3 in Fig. 1), as well as hetero-
analogs thereof have therefore found numerous applica-
tions in medicinal chemistry in order to probe confor-
mation–activity relationships or as turn mimetics.2
tuned by variation of stereochemistry and ring sizes (n
and m) within the bicyclic ring system.
We have recently reported an efficient method for the
preparation of bicyclic dipeptide mimetics of general
type 3 and accomplished the synthesis of various di-
azabicycloalkanes 3 mimicking polar dipeptides.6 Key
intermediates of our route are dipeptides 4, that upon
O
O
NHR
O
O
NHR
R2
O
RHN
R1
R2
In consequence, a number of different methods for the
synthesis of these scaffolds have been developed.3 Most
of these approaches target azabicycloalkane structures
of type 1 and 24 mimicking turn structures or cis-prolyl
fragments and less effort has been devoted to the synthe-
sis of diazabicycloalkanes 35 which are complementary
scaffolds to 1 and 2 mimicking more extended peptide
conformations. Key aspects of these sequences are stereo-
selectivity as well as variability with respect to ring sizes
and stereochemistry. The backbone dihedral angles w,
x, and / as well as at least the first side chain
torsional angle v of the imitated dipeptide unit in 1–3
(backbone indicated with bold lines in Fig. 1) might be
RHN
R1
N
N
H
φ
ψ
ω
χ
n
n
m
1
O
O
RHN
R1
RHN
R1
N
NH
R2
R2
m
NHR
NHR
O
2
O
O
NHR
R2
O
NHR
R2
O
R1
R1
N
N
H
RN
NHR
n
m
3
Keywords: Peptide mimetics; Heterocycles; Stereoselective synthesis;
Cyclization.
Figure 1. Aza- and diazabicycloalkane dipeptide mimetics 1–3. R1, R2:
amino acid side chains (N-terminal in green, C-terminal in red); the
peptide backbone is indicated with bold lines.
*
Corresponding author. Tel.: +49 40 428382813; fax: +49 40
428382495; e-mail: maison@chemie.uni-hamburg.de
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.082

4374
D. C. Grohs, W. Maison / Tetrahedron Letters 46 (2005) 4373–4376
stituted proline derivatives, a class of compounds with
R1
CbzHN
HO
R1
CbzHN
interesting structural properties.8 In addition, 13a–d
are excellent intermediates for 5-substituted di-
azabicycloalkanes like 14a–d. Cyclization of bisolefines
13 to diazabicycloalkanes 14 was achieved with potas-
sium tert-butoxide in a diastereoselective Michael type
addition of the carbamate NH-group to the vinylogous
ester in 5-position of the proline scaffold. The remaining
olefin in 14d was then cleaved by ozonolysis to give
dipeptide mimetic 159 with an aldehyde function in
8-position. Since the aldehyde function is easily con-
verted to a number of different amino acid side chains,
compounds like 15 are extremely versatile precursors
O
HO
O
NaIO4
N
N
O
O
CO2R
4
CO2R
5
O
5
O
CO2R
CO2R
R2
R1
CbzN
R1
R3N
N
H
N
5
R2
H
OH
6
7
for various mimetics of dipeptides Glu-XAA
.
Scheme 1. Intramolecular cyclization to 6 and conversion to diaza-
bicycloalkane dipeptide mimetics 7.
The route depicted in Scheme 3 addresses one of the ma-
jor drawbacks of our previously published protocol,
because it allows the introduction of orthogonally pro-
tected side chains in 5-position of the diazabicycloalkane
core. These side chains can be used to conjugate dipep-
tide mimetics like 15 to other functional molecules such
as reporter groups for imaging10 or a solid phase for
applications in combinatorial chemistry.11
oxidative cleavage give intermediate bisaldehydes 5
(Scheme 1), that were cyclized to aminals 6.
Varying the amino acid side chain R1 as well as the ester
moiety R, we have recently found that the efficiency of
the cyclization to 6 is dependent on the steric demand
of residues R1 and R in 4. The cyclization was further-
more found to be sensitive to reaction conditions, with
fastest conversion to 6 being observed under slightly
acidic conditions. In addition, we observed variable
stereochemistry at C5 in different solvents. All these
observations prompted us to investigate this piper-
azinone formation in more detail.
A 3,5-cis configuration was assigned to all diaza-
bicycloalkanes 11, 12, 14, and 15 by 2D-NOESY analy-
sis. The NOESY spectra indicated strong crosspeaks
for 3-H, 5-H, and 8-H in accordance with relative con-
figurations depicted in Schemes 2 and 3.
In contrast, direct NMR spectroscopic analysis12 of the
crude mixture derived from periodate cleavage of 8a in
acetone/water revealed that the 3,5-trans configured
aminal 11 (structure not shown in Scheme 2) is the kinet-
ically favored product. However, trans-11 is not stable
and rearranges slowly on standing at room temperature
or, more rapidly, under acid catalysis to give the ther-
modynamically stable diastereoisomer cis-11. Stability
of cis-11 is most likely a consequence of pseudo allylic
1,3-strain13 of residues in 3- and in 5-position with the
We started a detailed study with model compound 8a
featuring a N-terminal glutamate and tert-butyl esters
for protection of carboxylates. Immediately after addi-
tion of periodate, two products were detected by
NMR-spectroscopy: a small portion of the desired ami-
nal 11 and a larger portion of dihydrate 10 which is sta-
ble in THF and DMSO but not in chloroform. Ring
closure of 10 to 11 is apparently a slow process in ace-
tone/water or other non acidic reaction media. However,
it is accelerated dramatically under slightly acidic condi-
tions. To drive cyclization to completion, a solution of
10 and 11 in chloroform was thus prepared leading to
quantitative formation of 11 after 14 h at room temper-
ature. Treatment of aminal 11 with a Wittig reagent
gave diazabicycloalkane 127 in 83% yield from dipeptide
8a. We were thus able to improve the yield for dipeptide
mimetic 12 significantly in comparison to our previously
reported protocol (21% from 8a).6
tBuO2C
N
tBuO2C
CbzHN
tBuO2C
CbzHN
CbzHN
HO
HO
O
O
(HO)2HC
(HO)2HC
i
H O
2
N
N
O
O
O
t
t
t
CO2 Bu
10
CO2 Bu
8a
CO2 Bu
9
CHCl3
With this finding, we were able to use 8a–d as suitable
precursors for both, the preparation of diazabicycloalk-
anes such as 11 by intramolecular aminal formation and
3,5-disubstituted proline derivatives by trapping both
aldehyde functions in 9. The latter reaction was achieved
by the addition of a Wittig reagent and sodium perio-
date to a solution of dipeptides 8a–d in diethylether to
give prolines 13a–d in up to 55% yield.
tBuO2C
tBuO2C
t
O
t
O
CO2 Bu
CO2 Bu
N
H
ii
N
H
CbzN
5
CbzN
5
t
O
CO2 Bu
OH
11
OH
12
Scheme 2. Tandem sequence of oxidative cleavage of 8 and cyclization
of bisaldehyde 9 to diazabicycloalkane 11 and its subsequent conver-
sion to olefin 12. Reagents and conditions: (i) NaIO4, acetone/
H2O, 0 °C to rt, 30 min, then CHCl3, rt, 14 h, 100%; (ii)
Ph3P@CHCO2C(CH3)3, THF, rt, 12 h, 83%.
Bisolefines 13a–d are interesting dipeptides incorporat-
ing an unnatural cyclic amino acid and are good
synthetic precursors for a number of different 3,5-disub-

D. C. Grohs, W. Maison / Tetrahedron Letters 46 (2005) 4373–4376
4375
In addition, 3,5-disubstituted prolines have been shown
to be versatile precursors for 5-substituted diaza-
bicycloalkanes like 15. These compounds are of special
value to us because they permit the conjugation of
diazabicycloalkanes to other functional molecules, such
as reporter groups or a solid phase. In consequence, di-
azabicycloalkanes 15 are modular dipeptide mimetics15
and might be useful scaffolds for tumor imaging and
applications in combinatorial chemistry.
O
t
CbzHN
HO
CO2 Bu
R
R
N
HO
i
3
5
N
CbzHN
O
t
CO2 Bu
t
CO2 Bu
8a-d
13a-d
ButO2C
ii
HO
t
O
N
t
O
5
CO2 Bu
CO2 Bu
R
N
iii
8
5
CbzN
Acknowledgements
CbzN
t
O
CO2 Bu
H
H
t
t
CO2 Bu
We gratefully acknowledge material support and helpful
discussions of Professor Dr. Chris Meier. We thank the
Department of Chemistry of the University of Ham-
burg, Deutsche Forschungsgemeinschaft (MA 2529)
and the Fonds der Chemischen Industrie for financial
support. Furthermore, we are grateful to BASF AG,
Bayer AG, VWR International GmbH, and Degussa
AG for generous donations of chemicals. D.C.G.
thanks the Fonds der Chemischen Industrie for a
Promotionsstipendium.
CO2 Bu
14a-d
15
Scheme 3. Synthesis of 3,5-disubstituted prolines 13a–d and the
two-step conversion to 5-substituted diazabicycloalkane 15. Residue
t
t
R: (CH2)2CO2 Bu (a); CH2CO2Me (b); (CH2)2CO2 Bu (c); (CH2)2O-
TBDMS (d); Reagents and conditions: (i) NaIO4, Ph3P@CHCO2R2,
Et2O/H2O, rt, 12 h (13–55%); (ii) KOtBu, THF/H2O, reflux, 6 h, rt,
15 h (37–54%); (iii) O3, DCM, À78 °C (50%).
carbamate, making the 3,5-trans substitution a less
favorable configuration. This hypothesis is in accor-
dance with findings from a periodate cleavage of dipep-
tide 16 with glycine as a C-terminal amino acid (Scheme
4).5a,14
References and notes
1. (a) Gante, J. Angew. Chem. 1994, 106, 1780–1802; Angew.
Chem., Int. Ed. Engl. 1994, 33, 1699–1720; (b) Giannis, A.;
Kolter, T. Angew. Chem. 1993, 105, 1303–1326; Angew.
Chem., Int. Ed. Engl. 1993, 32, 1244–1267.
2. Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.;
Lubell, W. D. Tetrahedron 1997, 53, 12789–12854.
3. For a review see: Maison, W.; Prenzel, A. H. G. P.
Synthesis 2005, 1031–1049.
In this case, the oxidative cleavage gives aminal 17 as a
mixture of C5-epimers. After reduction of the aldehyde
function in 17, both diastereoisomers (5S)-18 and (5R)-
18 were fairly stable and separated by column chroma-
tography on silica gel.
4. (a) Belvisi, L.; Colombo, L.; Manzoni, L.; Potenza, D.;
Scolastico, C. Synlett 2004, 1449–1471; (b) Halab, L.;
Gosselin, F.; Lubell, W. D. Biopolymers 2000, 55, 101–
122; (c) Hruby, V. J.; Li, G.; Haskell-Luevano, C.;
Shenderovich, M. Biopolymers 1997, 43, 219–266.
In summary, we have presented a short and efficient syn-
thetic route to 3,5-disubstituted proline derivatives and
their conversion to 5-substituted diazabicycloalkanes
via a base mediated intramolecular Michael type addi-
tion. Key step is an oxidative cleavage of dipeptide 8
to give bisaldehyde 9. Depending on steric demand
and solvent effects, these intermediate bisaldehydes can
be trapped by Wittig reagents to give 3,5-disubstituted
proline derivatives like 13 or cyclized to bicyclic aminals
like 11. Yields of this cyclization can be significantly
improved in slightly acidic solvents like chloroform.
5. (a) Maison, W.; Kuntzer, D.; Grohs, D. Synlett 2002,
¨
1795–1798; (b) Tong, Y.; Fobian, Y. M.; Wu, M.; Boyd,
N. D.; Moeller, K. D. J. Org. Chem. 2000, 65, 2484–2493;
(c) Chan, M. F.; Raju, B. G.; Kois, A.; Varughese, J. I.;
Varughese, K. I.; Balaji, V. N. Heterocycles 1999, 51, 5–8;
(d) St. Denis, Y.; Augelli-Szafran, C. E.; Bachand, B.;
Berryman, K. A.; DiMaio, J.; Doherty, A. M.; Edmunds,
J. J.; Leblond, L.; Levesque, 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,
3193–3198; (e) Plummer, J. S.; Berryman, K. A.; Cai, C.;
Cody, W. L.; DiMaio, J.; Doherty, A. M.; Edmunds, J. J.;
He, J. X.; Holland, D. R.; Levesque, S.; Kent, D. R.;
Narasimhan, L. S.; Rubin, J. R.; Rapundalo, S. T.;
Siddiqui, M. A.; Susser, A. J.; St. Denis, Y.; Winocourt, P.
D. Bioorg. Med. Chem. Lett. 1998, 8, 3409–3414.
O
5
CO2Et
N
H
OH
CbzN
ii
CbzHN
HO
O
5
CO2Et
OH
HO
N
H
(5S)-18, 41 %
O
N
O
i
6. Maison, W.; Grohs, D. C.; Prenzel, A. H. G. P. Eur. J.
Org. Chem. 2004, 1527–1543.
CbzN
+
O
5
CO2Et
CO2Et
OH
17
7. Tandem sequence of oxidative cleavage of 8 and cycliza-
tion of bisaldehyde 9 to give diazabicycloalkane 11 was
carried out in analogy to the method previously
described,6 however, the crude product that was obtained
after oxidative cleavage was dissolved in CHCl3 and
stirred for 14 h at rt before the solvent was evaporated to
give 11 in quantitative yield.
N
H
OH
16
CbzN
OH
(5R)-18, 17 %
Scheme 4. Periodate cleavage of glycine containing dipeptide 16.
Reagents and conditions: (i) NaIO4, acetone/H2O, À25 °C, 30 min;
(ii) NaBH4, MeOH, 0 °C, 1 h.
8. Beausoleil, E.; LÕArcheveque, B.; Belec, L.; Atfani, M.;
Lubell, W. D. J. Org. Chem. 1996, 61, 9447–9454;

4376
D. C. Grohs, W. Maison / Tetrahedron Letters 46 (2005) 4373–4376
3,5-substituted prolines have been incorporated into
dry dichloromethane. The solution was allowed to reach rt
and the solvent was evaporated in vacuo. The crude
product was purified by column chromatography (EA/PE,
gradient) to give the TBDMS-deprotected compound 15
in 18.2 mg (32.3 lmol, 50%) yield. Compound 15: 1H
NMR (500 MHz, CDCl3, 1:1 mixture of rotamers):
d = 9.74 (s, 1H), 7.29–7.43 (m, 5H), 5.07–5.29 (m, 3H),
4.76 (dd, 0.5H, J = 6.5, 7.5 Hz), 4.68 (d, 1H, J = 7.9 Hz),
4.61 (dd, 0.5H, J = 3.2, 8.5 Hz), 4.08–4.20 (m, 1H), 3.59–
3.74 (m, 2H), 2.99–3.07 (m, 1H), 2.45–2.56 (m, 1H), 2.35–
2.44 (m, 0.5H), 2.14–2.33 (m, 2.5H), 1.68–1.83 (m, 2H),
1.47 (s, 9H), 1.41 (s, 9H). HRMS (FAB) calcd for
C29H41N2O9(M+H)+: 561.2812, found: 561.2780.
10. For reviews on tumor imaging see: (a) Frangioni, J. V.
Curr. Opin. Chem. Biol. 2003, 7, 626–634; (b) Miller, M.
J. Natl. Cancer Inst. 1999, 91, 759–760.
11. Eguchi, M.; McMillan, M.; Nguyen, C.; Teo, J.-l.; Chi,
E. Y.; Henderson, W. R., Jr.; Kahn, M. Comb. Chem.
High Throughput Screening 2003, 6, 611–621.
12. 3,5-Trans configured aminals show chemical shifts for C5
at about d = 80 ppm whereas the thermodynamically more
stable cis configuration causes a chemical shift of C5 at
about 75 ppm.
peptides by oxidative cleavage of azabicycloalkenes
before: Jaeger, M.; Polborn, K.; Steglich, W. Tetrahedron
Lett. 1995, 36, 861–864.
9. Typical experimental procedure is as follows: Synthesis of
peptide mimetic: 15: Preparation of 13d was carried out in
analogy to the method previously described.6 Compound
14d: 0.41 g (0.53 mmol) 13d (1.0 equiv) were dissolved in
10 mL THF and 0.24 g (2.12 mmol) KOtBu (4.0 equiv)
was added. After addition of 1 mL water the resulting
solution was refluxed for 6 h and then stirred for 12 h at rt
The reaction was quenched with 10 mL citric acid (10% in
water) and stirred for another hour at rt. An aqueous
solution of NaOH (2 M) was added to adjust to pH 10–12
before the mixture was extracted with ethyl acetate. The
organic phase was dried with Na2SO4, filtered, and the
solvent was removed in vacuo. This crude product was
purified by column chromatography (EA/PE, gradient) to
give 14d as colorless sticky solid in 150 mg (0.19 mmol,
1
37%) yield. H NMR (500 MHz, CDCl3, 7:3 mixture of
rotamers): d = 7.27–7.31 (m, 5H), 6.61–6.70 (m, 1H), 5.71–
5.83 (m, 1H), 5.13–5.19 (m, 0.5H), 4.99–5.12 (m, 2.5H),
4.42–4.59 (m, 1H), 4.04–4.17 (m, 0.3H), 3.86–4.04 (m,
1.7H), 3.74–3.84 (m, 0.3H), 3.64–3.73 (m, 1H), 3.55–3.64
(m, 0.7H), 2.80–2.86 (m, 0.3H), 2.70–2.80 (m, 0.7H), 2.28–
2.49 (m, 1.4H), 2.00–2.26 (m, 1.6H), 1.67–1.81 (m, 1H),
1.28–1.39 (m, 27H), 0.71–0.77 (m, 9H), À0.17 to À0.05 (m,
6H). HRMS (FAB) calcd for C41H65N2O10Si (M+H)+:
773.4409, found: 773.4412. Compound 15: 50.0 mg
(64.7 lmol) 14d were dissolved in 25 mL dry dichloro-
methane and cooled to À78 °C. Ozone was bubbled
through the solution for 5 min until a blue color persisted.
The solution was purged with nitrogen for 2 min and then
treated with dimethyl sulfide (0.84 g, 13.5 mmol) in 5 mL
13. Seebach, D.; Lamatsch, B.; Amstutz, R.; Beck, A. K.;
Dobler, M.; Egli, M.; Fitzi, R.; Gautschi, M.; Herradon,
B. Helv. Chim. Acta 1992, 75, 913–934.
14. The comparison of 6,6-fused bicyclic systems like 17 and
18 with 6,5-fused systems like 11 seems to be valuable in
this case, because 3-substituted derivatives of 17 and 18
showed the same preference for a 3,5-cis configuration as
compounds 12, for example.
15. Maison, W.; Frangioni, J. V. Angew. Chem. 2003, 115,
4874–4876; Angew. Chem., Int. Ed. 2003, 42, 4726–
4728.