Synthesis of orthogonally protected 3,8-diazabicyclo[3.2.1]octane-2- carboxylic acid - A versatile building block for the synthesis of cocaine analogues

Article abstract of DOI:10.1016/j.tetlet.2003.12.031

An eight-step synthesis of an orthogonally protected 3,8-diazabicyclo[3.2. 1]octane from commercially available pyroglutamic acid was developed. The target compound can be used as a versatile building block for combinatorial synthesis of pharmacologically useful compounds and features a hidden α-, β-, δ- and ε-amino acid, which can also be seen as an example of a new class of cocaine analogues.

Full text of DOI:10.1016/j.tetlet.2003.12.031

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1481–1483
Synthesis of orthogonally protected 3,8-diazabicyclo[3.2.1]octane-2-
carboxylic acid––a versatile building block for the synthesis of
cocaine analogues
Stefan Pichlmair,* Kurt Mereiter and Ulrich Jordis*
Department of Chemistry, Vienna University of Technology, Getreidemarkt 9, A-1060 Vienna, Austria
Received 13 October 2003;revised 3 December 2003;accepted 8 December 2003
Abstract—An eight-step synthesis of an orthogonally protected 3,8-diazabicyclo[3.2.1]octane from commercially available pyro-
glutamic acid was developed. The target compound can be used as a versatile building block for combinatorial synthesis of
pharmacologically useful compounds and features a hidden a-, b-, d- and e-amino acid, which can also be seen as an example of a
new class of cocaine analogues.
ꢀ 2003 Elsevier Ltd. All rights reserved.
O
The demand for multi-functionalized building blocks
with pharmaceutical applications is growing. Many
drugs in modern medicinal chemistry have been devel-
oped, which contain piperazine as subunits.1a–e 2-Car-
boxyl-piperazine subunits have been incorporated into a
number of medicinally useful compounds: for example,
O
PG2
N
1
O
Ph
1
O
Ph
N
MeN
MeN
H
CO2Me
PG1
CO2H
H
CO2Me
H
Cocaine
Pseudococaine
1
N-methyl-D
-aspartate (NMDA) antagonists,2a HIV
protease inhibitors and metalloproteinase inhibitors.2b–f
Bridged piperazine analogues have been studied exten-
sively for treating immune disorders, as constrained
bicyclic peptidomimetic synthons,3a;b as dopamine
uptake inhibitors for the treatment of cocaine abuse
and as analogues of the potent natural analgesic
epibatidine.3c;d
Starting from 5-methoxy-3,4-dihydro-2H-pyrrole-2-car-
boxylic acid methyl ester 2 prepared by esterification
and O-methylation of commercially available pyroglu-
tamic acid,4g;5 heating with stoichiometric amounts of
methyl nitroacetate afforded 3 as a mixture of E=Z iso-
mers in 44% yield. Hydrogenation of 3 resulted in
cyclization of the intermediate to the methyl 3,8-diaza-
bicyclo[3.2.1]octane-2-carboxylate 4 as a mixture of the
axial and equatorial products. Isolation of the equato-
rial product was achieved by crystallization of the
fumarate in 57% yield.6
Several syntheses of the 3,8-diazabicyclo[3.2.1]octane
skeleton have been reported.3a;b;4 The synthesis of an
orthogonally protected 3,8-diazabicyclo[3.2.1]octane-2-
carboxylic acid, featuring an a-, b-, d- and e-amino acid
has, to date, not been reported. This structure can also
be envisioned as an aza analogue of pseudococaine.
Herein we report the synthesis of the orthogonally
Protection of 4 with di-tert-butyl dicarbonate (Boc2O),
followed by protection of the sec-amide with allyl
chloroformate (AllocCl) using n-BuLi as base followed
by reduction with Super Hydride (LiBHEt3) gave
hemiaminal 6. Neither the reaction with Et3SiH/BF3–
OEt2 nor O-acetylation followed by NaBH4 reduction
led to the desired compound (Scheme 1) 7.7
protected
[3.2.1]octane 1.
and
functionalized
3,8-diazabicyclo-
Keywords: Orthogonal amine protection groups;3,8-Diazabicy-
clo[3.2.1]octane;Building block;Cocaine analogue.
* Corresponding authors. Tel.: +43-1-58801-15401;fax: +43-1-58801-
15499;e-mail addresses: stefan.pichlmair@univie.ac.at; ujordis@
pop.tuwien.ac.at
Selective reduction of the amide 4 to the diamine 8
and protection with di-tert-butyl dicarbonate yielded
65% of monoprotected product 10 and 16% of dipro-
tected product 9. Compound 9 was deprotected with
0040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.031

1482
S. Pichlmair et al. / Tetrahedron Letters 45 (2004) 1481–1483
O
O
NH
CO2Me
c
b
MeO
a
HN
CO2Me
CO2Me
MeO
N
H
N
H
O2N
2
4
3
O
O
OH
O
selective
reduction
OAllyl
OAllyl
N
N
NH
d, e
N
N
N
O
O
t-BuO
O
CO2Me
CO2Me
CO2Me
H
H
H
t-BuO
t-BuO
6
7
5
Scheme 1. Reagents and conditions: (a) O2NCH2CO2Me, 60 ꢁC, 30 h, neat, 44%;(b) H 2, 10%-Pd/C, MeOH, 4 d, rt, 57% of the equatorial diaste-
reomer;(c) Boc 2O, Et3N, CH2Cl2, )5 ꢁC then warm up to rt, 92%;(d) n-BuLi, dry THF, )78 ꢁC then AllocCl, rt, 1 h, 83%;(e) LiBHEt 3, dry THF,
)78 ꢁC, 30 min, 100%;(Boc 2O ¼ di-tert-butyl dicarbonate, AllocCl ¼ allyloxycarbonyl chloride).
O
Ot-Bu
b
c
N
NH
CO2Me
a
N
4
HN
O
CO2Me
H
H
t-BuO
8
9
16%
+
O
NH
CO2Me
OAllyl
N
d, e
N
O
N
O
CO2H
H
H
t-BuO
t-BuO
10 65%
1
Scheme 2. Reagents and conditions: (a) BH3–SMe2, dry THF, rt, 3 h, 76%;(b) Boc 2O, Et3N, CH2Cl2, 1 h, 0 ꢁC, 65%;(c) CF 3CO2H, CH2Cl2, 3 h, rt,
95%;(d) AllocCl, Et 3N, CH2Cl2, 4 h, 0 ꢁC, 99%;(e) LiOH, Dioxane:H 2O ¼ 1:1, 3 h, rt, 95%.
trifluoroacetic acid in order to recover diamine 8. By
repeating the protection deprotection sequence a second
time, the overall yield of 10 could be raised to 75%.
Protection of compound 10 with allyl chloroformate and
hydrolysis of the methyl ester gave target compound 1 in
94% yield (Scheme 2).8
The stereochemistry of the carboxyl group in 4 (axial or
equatorial) could not be determined from the NMR
spectra. However X-ray crystallography of 5 established
the expected equatorial position for the carboxylate
group (Fig. 1).9
In summary, we have achieved a diastereoselective
synthesis of the 3,8-diazabicyclo[3.2.1]octane-2-carbox-
ylic acid framework, readily available from cheap
pyroglutamic acid. Additionally, we have shown a way
to protect both amino groups orthogonally.
Acknowledgements
The scientific input of Dr. C. Kuehn for the planning of
this synthesis and the discussion of NMR spectra is
gratefully acknowledged.
Figure 1. Structural view of 5 in the solid state.9 Selected bond lengths
References and notes
ꢀ
and angles (A, ꢁ): N(1)–C(1) 1.458(2), N(1)–C(4) 1.468(2), N(1)–C(9)
1.361(2), N(2)–C(2) 1.338(2), N(2)–C(3) 1.458(2), C(1)–C(2) 1.519(2),
C(1)–C(6) 1.527(2), C(3)–C(4) 1.543(2), C(3)–C(7) 1.516(2), C(4)–C(5)
1.538(2), C(5)–C(6) 1.539(2), C(1)–N(1)–C(4) 104.2(1), C(2)–N(2)–C(3)
126.1(1), N(2)–C(2)–C(1) 116.0(1).
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acid
methyl ester 4: 8 g 10%-Pd/C was suspended in 300 mL of
methanol and prehydrogenated at 70 psi for 0.5 h. To this
mixture, the ester 3 (8.00 g, 0.033 mmol) in methanol
(300 mL) was added and hydrogenated at 45 psi for four
days. The catalyst was removed by filtration and the filtrate
was evaporated and dried under high vacuum. Addition of
saturated fumaric acid in ethanol (110 mL) resulted in the
crystallization of 4 at )20 ꢁC overnight. The salt was filtered
and washed with diethyl ether (3 · 60 mL) to give 5.57 g of
the fumarate as yellowish crystals. The amine was obtained
by extraction of the aqueous solution (20 mL), basified with
ammonia to pH 11 using chloroform (20 · 20 mL), drying of
the organic phase (Na2SO4) and evaporation gave 3.13 g
(52%) of amine 4. For analytical purposes a small amount
of 4 was crystallized from dry THF to give colorless
crystals. mp: 122–123 ꢁC. 1H NMR (200 MHz, CDCl3): d
6.45 (s, 1H), 4.35 (d, J ¼ 8 Hz, 1H), 3.97–4.08 (m, 1H), 3.75
(s, 3H), 3.72–3.65 (m, 1H), 2.28 (s, 1H), 2.1–1.75 (m, 3H),
1.7–1.4 (m, 1H). 13C NMR (50 MHz, CDCl3): d 173.10 (s),
169.60 (s), 60.50 (d), 59.21 (d), 54.00 (q), 52.44 (d), 30.97 (t),
24.70 (t). Anal. Calcd for C8H12N2O3: C, 52.17;H, 6.57;N,
15.21. Found C, 52.10;H, 6.41;N, 15.17.
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8. 3,8-Diaza-bicyclo[3.2.1]octane-2,3,8-tricarboxylic acid 3-
allyl ester 8-tert-butyl ester 1: 1H NMR (200 MHz,
CDCl3): d 9.20 (br s, 1H), 6.00–5.77 (m, 1H), 5.37–5.11
(m, 2H), 4.65–4.15 (m, 5H), 3.55–3.34 (m, 2H), 2.25–1.58
(m, 4H), 1.48 (s, 9H); 13C NMR (50 MHz, CDCl3):
d 174.00 (s), 158.00 (s), 153.13 (s), 132.146 (d), 117.92 (t),
80.81 (s), 66.70 (t), 60.00 (d), 53.50 (d), 51.65 (d), 49.75 (t),
29.63 (t), 28.30 (q), 24.32 (t); m=z: (APCI, negative
ionization): 339.2 (MÀ, 100%), 281.1 (14%), 207.1 (17%);
m=z (APCI, positive ionization): 241.9 (15%), 241.0 (Mþ-
Boc, 100%), 197.1 (Mþ-Boc-CO2, 11%), 116.1 (10%), 99.1
(6%);Anal. calcd for C 16H24N2O6: C, 56.46;H, 7.11;N,
8.23. Found C, 56.39;H, 7.04;N, 8.34.
4. For
a
racemic synthesis of the 3,8-diazabicyclo-
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1961, 26, 1500–1504, For an asymmetric synthesis of a
corresponding 3,8-diazabicyclo[3.2.1]octan-2-one, see: (g)
Jain, S.;Sujatha, K.;Krishna, K. V. R.;Roy, R.;Singh, J.;
Anand, N. Tetrahedron 1992, 23, 4985–4998;(h) Bergman,
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9. Crystal data for 5: C13H20N2O5, FW ¼ 284.31, ortho-
rhombic, space group Pbca (no 61), Dc ¼ 1:315 g cmÀ3
,
ꢀ
Z ¼ 8, a ¼ 9:487ð2Þ, b ¼ 12:270ð3Þ, c ¼ 24:673ð6Þ A,
3
ꢀ
V ¼ 2872:1ð12Þ A , T ¼ 297ð2Þ K, Bruker AXS SMART
platform 3-circle diffractometer with CCD area detector,
k(MoKa) ¼ 0.71073 A, l ¼ 0:101 mmÀ1. Of 27683 reflec-
ꢀ
tions measured, 2530 were unique. Refinement on F 2
concluded with the values R1 ¼ 0:0342 and wR2 ¼ 0:0900
for 182 parameters and 2005 data with I > 2rI . CCDC-
187193 contains the supplementary crystallographic
data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or
from the CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK;fax: +44-1223-336033;e-mail:
ac.uk).
deposit@ccdc.cam.