First synthesis of 2,6-diazabicyclo[3.2.0]heptane derivatives

Article abstract of DOI:10.1016/j.tetlet.2009.10.028

The first synthesis of 6-phenyl-2,6-diazabicyclo[3.2.0]heptane 1 and its orthogonally protected precursor 2 is herein reported. Our strategy enables to chemically address the two nitrogen atoms of 2,6-diazabicyclo[3.2.0]heptane core individually and selectively, thus allowing rapid access to several subsets of widely substituted fused azetidines.

Full text of DOI:10.1016/j.tetlet.2009.10.028

Tetrahedron Letters 50 (2009) 7280–7282
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Tetrahedron Letters
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First synthesis of 2,6-diazabicyclo[3.2.0]heptane derivatives
Carmela Napolitano a, , Manuela Borriello b,à, Francesca Cardullo b, , Daniele Donati b,§, Alfredo Paio b,
*
Stefano Manfredini a,
*
a Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara, 17-19, I-44100 Ferrara, Italy
b GlaxoSmithKline, Neurosciences Centre of Excellence for Drug Discovery, Medicine Research Centre, via Fleming, 4, I-37135 Verona, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The first synthesis of 6-phenyl-2,6-diazabicyclo[3.2.0]heptane 1 and its orthogonally protected precursor
2 is herein reported. Our strategy enables to chemically address the two nitrogen atoms of 2,6-diazabi-
cyclo[3.2.0]heptane core individually and selectively, thus allowing rapid access to several subsets of
widely substituted fused azetidines.
Received 15 July 2009
Revised 4 October 2009
Accepted 7 October 2009
Available online 13 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
While fused 2-azetidinones, commonly known as b-lactams, are
among the most useful aza heterocyclic compounds from both syn-
thetic and medicinal chemistry points of view, the potential appli-
cation of fused azetidines has been marginally explored. In 1991
Jacquet and collaborators reported the synthesis of racemic 3,6-
diazabicyclo[3.2.0]heptanes,1 but only very recently it has been
demonstrated the ability of this core in reducing the conforma-
tional complexity of nicotinic receptor ligands and in enhancing
the ligand subtype affinity.2 As part of our efforts towards the iden-
tification and synthesis of constrained bis-amine building blocks
able to modulate the activity of different active compounds, we be-
came intrigued by the possibility to explore a synthetic approach
to 6-phenyl-2,6-diazabicyclo[3.2.0]heptane. Since the synthesis of
b-lactams is well documented, in a first attempt 1 was envisaged
to derive from azetidinone 3, which can be readily prepared start-
treatment with borane–THF complex quantitatively led to the
monocyclic opened product 5. This occurrence was attributed to
the unprotected lactam N–H. To overcome this drawback, we
decided to revert our strategy by first introducing the aromatic ring
on 3 and then attempting reduction to amine. The use of Buch-
wald–Hartwig’s reaction conditions7 in the presence of Pd2(dba)3
as the catalyst was found to be successful for the N-arylation reac-
tion, although 6 was isolated in poor yield. To our regret all at-
tempts to reduce 6 proved ineffective thereby precluding access
to 1.
In order to devise an alternative route to access 1 via 2-azetid-
inone, a longer but efficient strategy was planned, assembling the
azetidine ring with a cis-pyrrolidine approach, involving facile dis-
placement of primary mesylate by
a Cbz-protected amine.
Scheme 3 outlines the achieved synthesis of monoprotected 2,6-
ing from commercially available trans-3-hydroxy-
hydroxamate-mediated cyclization3 (Scheme 1). The trans-3-hy-
droxy- -proline was protected as N-tert-butylcarbamate and then
L
-proline via
diazabicyclo[3.2.0]heptane. Mesylate 8 was readily prepared in
three steps starting from trans-3-hydroxy-L-proline. Treatment of
L
8 with NaN3 afforded a mixture of azide 9 and the unsaturated es-
ter 108 in a 2:1 ratio.9 After reduction under Staudinger’s condition,
the amino ester 11a10 was protected as the N-derivative 11b,
which was reduced to yield the alcohol 12a. Whereas classical
reduction using LiAlH4 in THF failed, treatment with DIBAL-H in
the presence of BF3ÁEt2O gave 12a in satisfactory yield. The alcohol
was converted into mesylate 12b,11 which was suitable to undergo
an intramolecular cyclization to 2.12 Deprotection of the azetidinyl
N-atom afforded 2-monoprotected 2,6-diazabicyclo[3.2.0]heptane
coupled with O-benzylhydroxylamine using the water-soluble
EDC to afford an intermediate hydroxamate, which was cyclized
to 4 in excellent yield under Mitsunobu conditions (Scheme 2).4,5
Direct cleavage of the N–O bond of 4 could not be easily accom-
plished using most common N–O bond reduction protocols. The
samarium diiodide-mediated reduction reported by Romo6 was
unsuccessful. Instead catalytic hydrogenolysis on Ni/Ra afforded
quantitatively lactam 3 (Scheme 2). Unfortunately, this compound
proved unsuitable for further elaborations. Reduction with LiAlH4
in THF or Et2O failed, yielding only starting material, whereas
OBn
O
OH
COOH
* Corresponding authors.
NH
O
N
N
E-mail address: francesca.cardullo@gsk.com (F. Cardullo).
Present address: School of Chemistry, National University of Ireland, Galway,
Ireland.
N
N
N
H
N
H
H
Boc
à
Present address: Rothpharma, Via Valosa di Sopra, 9, I-20052 Monza (MI), Italy.
Present address: Nerviano Medical Sciences, Viale Pasteur, 10, I-20014, Nerviano
1
3
4
§
(Mi), Italy.
Scheme 1. Retrosynthetic analysis.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.028

C. Napolitano et al. / Tetrahedron Letters 50 (2009) 7280–7282
7281
OBn
PPh3, DEAD,
THF
EDC, HOBT,
BnONH2, THF
OH
COOH
OH
CONHOBn
N
N
O
quantitative
91%
N
R
N
Boc
Boc
Boc2O, NaOH,
THF/H2O
quantitative
R=H
R=Boc
4
Ra-Ni, H2,
MeOH
quantitative
1) BH3THF, THF;
2) Piperazine, H2O
Boc
NH
O
N
N
Buckwald-Hartwig
13%
O
NH
N
N
quantitative
Boc
HO
Boc
5
3
6
Scheme 2. First attempt to 1.
MsCl, TEA,
CH2Cl2
OH
COOMe
N3
OMs
SOCl2,
MeOH
quantitative
OH
COOH
NaN3, DMF
COOMe
N
Boc
10
COOMe
N
Boc
COOMe
96%
N
N
N
Pg
Boc
8
H
9
7a Pg=H
7b Pg=Boc
Boc2O, TEA,
CH2Cl2, 82%
PPh3,
THF/H2O
55% over 2 steps
BF3Et2O,
Cbz
N
H2, Pd/C,
MeOH
NHCbz
OR
NHR
DIBAL-H,
Toluene
54%
NH
t-BuOK, THF
48%
COOMe
N
Boc
quantitative
N
N
Boc
N
Boc
Boc
13
2
12a R=H
11a R=H
11b R=Cbz
12b R=Ms
MsCl, TEA,
CH2Cl2, 46%
CbzCl, NaOH,
Toluene, 94%
Scheme 3. Total synthesis of 2,6-diazabicyclo[3.2.0]heptane core.
PhBr, t-BuONa,
rac-BINAP,
Pd2(dba)3,
Toluene
Acknowledgements
Ph
NH
N
TFA, CH2Cl2
The authors wish to thank A. Casolari and E. Durini for careful
assistance in NMR experiments and structure assignments.
1
98%
32%
N
N
Boc
Boc
References and notes
13
14
Scheme 4. Derivatization to 1.
1. Jacquet, J.-P.; Bouzard, D.; Kiechel, J.-R.; Remuzon, P. Tetrahedron Lett. 1991,
32(12), 1565.
2. (a) Ji, J.; Schrimpf, M. R.; Sippy, K. B.; Bunnelle, W. H.; Li, T.; Anderson, D. J.;
Faltynek, C.; Surowy, C. S.; Dyhring, T.; Ahring, P. K.; Meyer, M. D. J. Med. Chem.
2007, 50, 5493; (b) Ji, J.; Bunnelle, W. H.; Li, T.; Pace, J. M.; Schrimpf, M. R.;
Sippy, K. B.; Anderson, D. J.; Meyer, M. D. Pure Appl. Chem. 2005, 77(12), 2041;
(c) Buckley, M. J.; Ji, J. U.S. Patent 2004242644, 2004.; (d) Schrimpf, M. R.;
Tietjie, K. R.; Toupence, R. B.; Ji, J.; Basha, A.; Bunnelle, W. H.; Daanen, J. E.; Pace,
J. M.; Sippy, K. B. International Patent WO0181347, 2001.
13,which could be condensed with bromobenzene to give 1413
with moderate yield. After removal of the Boc-protecting group un-
der acidic conditions the desired 6-phenyl-2,6-diazabicy-
clo[3.2.0]heptane (1) was isolated in almost quantitative yield
(Scheme 4).14
In conclusion, the first synthesis of 2,6-diazabicyclo[3.2.0]hep-
tane, a fused azetidine with high potential to be used as a building
block in medicinal chemistry, has been developed. The successful
3. Miller, M. J. Acc. Chem. Res. 1986, 19, 49.
4. Bellettini, J. R.; Miller, M. J. Tetrahedron Lett. 1997, 38(2), 167.
5. For an alternative synthesis of complex bicyclic b-lactam scaffold and its
synthetic applications, see: Steger, M.; Hubschwerlen, C.; Schmid, G. Bioorg.
Med. Chem. Lett. 2001, 11(18), 2537.
6. Romo, D.; Rzasa, R. M.; Shea, H. A.; Park, K.; Lanhgenhan, J. M.; Sun, L.; Akheizer,
A.; Liu, J. O. Am. Chem. Soc. 1998, 120, 12237.
pathway includes the full derivatization of trans-3-hydroxy-L-pro-
line, yielding monoprotected 2,6-diazabicyclo[3.2.0]heptane 13
after azidation/reduction, ring closure and removal of the Cbz-pro-
tecting group. Buchwald-Hartwig condensation with bromoben-
zene followed by N-deprotection gives access to the desired 6-
phenyl-2,6-diazabicyclo[3.2.0]heptane. The achieved synthetic
route has the advantage of affording orthogonally protected fused
azetidine 2, in which the two nitrogen atoms are chemically
addressable individually and selectively. This will allow the rapid
access to focused subsets of compounds containing the 2,6-diaza-
bicyclo[3.2.0]heptane core with different substituents on the two
nitrogen atoms.
7. (a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131; (b) Hartwig, J. F.
Acc. Chem. Res. 1998, 31, 852.
8. 4,5-Dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ster 2-methyl ester (10): 1H
NMR (200 MHz, CDCl3) d 5.77 (t, J = 3.0 Hz, 1H), 3.95 (d, J = 8.6 Hz, 1H), 3.90 (d,
J = 8.8 Hz, 1H), 3.80 (s, 3H), 2.65 (dd, J = 3.0, J = 8.6 Hz, 1H), 2.60 (dd, J = 2.8,
J = 8.8 Hz, 1H), 1.47, 1.44 (2s, 9H).
9. The 2:1 ratio was established by analysis of 1H NMR spectrum. Azide 9 was not
isolated and reacted in the next reduction step without any purification.
10. 1-tert-Butyl 2-methyl 3-aminopyrrolidine-1,2-dicarboxylate (11a): Step 1: NaN3
(0.24 g, 3.71 mmol) was added to a solution of 8 (1.0 g, 3.10 mmol) in dry DMF
(12 mL). The mixture was warmed to 100 °C and stirred at that temperature for
7 h. After cooling to room temperature, EtOAc was added. The organic layer
was washed twice with saturated aqueous NH4Cl solution, then dried (Na2SO4),
filtered and concentrated under vacuum to afford a crude mixture of 9 and 10

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C. Napolitano et al. / Tetrahedron Letters 50 (2009) 7280–7282
(0.73 g). Step 2: To a stirred 10:1 THF/H2O emulsion (13.2 mL) containing that
13. 2,6-Diaza-bicyclo[3.2.0]heptane-2-carboxylic acid tert-butyl ester (14): A mixture of
amine 13 (0.064 g, 0.325 mmol), bromobenzene (0.051 mL, 0.487 mmol) and
t-BuONa (0.047 g, 0.487 mmol) in dry toluene (3 mL) was degassed and purged
withargonthreetimesbeforetheadditionofrac-BINAP(0.012 g, 0.019 mmol)and
Pd2(dba)3 (0.006 g, 0.0065 mmol). Theresulting mixture washeated to 100 °C and
stirred at that temperature for 10 h. After coolingto room temperature, EtOAcwas
added. The organic layer was washed with brine, dried (Na2SO4), filtered and
evaporated under vacuum. Chromatography of the crude residue over silica gel
(CH2Cl2) afforded 14 as pale yellow oil (0.028 g, 32%). 1H NMR (200 MHz, CDCl3) d
7.20 (dd, J = 1.2, J = 8.4 Hz, 2H), 6.75 (t, J = 7.6 Hz, 1H), 6.46 (dd, J = 1.4, J = 8.8 Hz,
2H), 4.65 (t, J = 5.4 Hz, 1H), 4.33–4.59 (m, 1H), 3.77–4.02 (m, 2H), 3.55–3.76 (m,
2H), 2.15 (dd, J = 6.4, J = 13.0 Hz, 1H), 1.73–1.97 (m, 1H), 1.48 (s, 9H).
mixture (0.73 g) PPh3 (0.91 g, 3.48 mmol) was added. The reaction mixture was
heated to reflux and stirred at that temperature for 4 h. Volatiles were
evaporated under vacuum. Chromatography of the crude residue over silica gel
(CHCl3/MeOH = 8:2) afforded 11a as pale yellow oil (417 mg, 55% over 2 steps).
1H NMR (200 MHz, CDCl3) d 4.28 (dd, J = 7.8, J = 13.8 Hz, 1H), 3.51–3.86 (m,
5H), 3.23–3.45 (m, 1H), 2.00–2.20 (m, 1H), 1.68–1.98 (m, 1H), 1.39, 1.43 (2s,
9H).
11. All pyrrolidine derivatives appear in NMR spectra as distinct pair of rotamers.
12. 2,6-Diaza-bicyclo[3.2.0]heptane-2,6-dicarboxylic acid 6-benzyl ester 2-tert-butyl
ester (2): Compound 12b (0.10 g, 0.23 mmol) was dissolved in dry THF (2 mL)
and t-BuOK (0.039 g, 0.345 mmol) was added. The mixture was stirred for 48 h
at room temperature. EtOAc was added; the organic phase was washed twice
with H2O, then dried (Na2SO4), filtered and concentrated under vacuum.
Chromatography of the crude residue over silica gel (PE/EtOAc = 7:3) afforded
2 as pale yellow oil (37 mg, 48%). 1H NMR (200 MHz, CDCl3) d 7.27–7.42 (m,
5H), 5.09 (s, 2H), 4.89 (t, J = 5.4 Hz, 1H), 4.24–4.58 (m, 1H), 4.02–4.21 (m, 1H),
3.73–3.97 (m, 1H), 3.40–3.59 (m, 2H), 2.08–2.39 (m, 1H), 1.67–1.82 (m, 1H),
1.44 (s, 9H).
14. 6-Phenyl-2,6-diaza-bicyclo[3.2.0]heptane (1): TFA (2.5 mL) was added to
a
solution of 14 (0.07 g, 0.26 mmol) in CH2Cl2 (20 mL). After 2 h volatiles were
evaporated under vacuum to afford 1 as its trifluoroacetic salt (0.075 g, 98%).
1H NMR (200 MHz, DMSO-d6) d 9.44 (br s, 1H), 9.09 (br s, 1H), 7.17 (t, J = 7.4 Hz,
2H), 6.69 (t, J = 7.4 Hz, 1H), 6.48 (dd, J = 1.0, J = 7.6 Hz, 2H), 4.70 (t, J = 4.6 Hz,
1H), 4.11–4.60 (m, 1H), 3.33–4.05 (m, 4H), 2.20 (dd, J = 5.6, J = 14.0 Hz, 1H),
1.68–1.91 (m, 1H).