An improved synthesis of (lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptane

Article abstract of DOI:10.1016/j.cclet.2013.12.006

An improved and efficient method for synthesis of (lS,4S)-2-oxa-5- azabicyclo[2.2.1]heptane (1) from trans-4-hydroxy-l-proline was developed. Using benzyloxycarbonyl (Cbz) as protection group of amine, the reactions were in mild conditions, and the title compound 1 was accomplished in six steps in overall yield of 70%.

Full text of DOI:10.1016/j.cclet.2013.12.006

Chinese Chemical Letters 25 (2014) 479–481
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
An improved synthesis of (lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptane
Dong-Feng Zhang, Peng Li, Zi-Yun Lin, Hai-Hong Huang *
Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College & Chinese
Academy of Medical Sciences, Beijing 100050, China
A R T I C L E I N F O
A B S T R A C T
Article history:
An improved and efficient method for synthesis of (lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptane (1) from
Received 4 September 2013
Received in revised form 19 November 2013
Accepted 27 November 2013
Available online 7 December 2013
trans-4-hydroxy-L-proline was developed. Using benzyloxycarbonyl (Cbz) as protection group of amine,
the reactions were in mild conditions, and the title compound 1 was accomplished in six steps in overall
yield of 70%.
ß 2013 Hai-Hong Huang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
Keywords:
Synthesis
trans-4-Hydroxy-
L-proline
Bridged morpholine
1
. Introduction
synthetic approach of this bridged morpholine from the cheap,
commercially available trans-4-hydroxy-L-proline (2) as the
Bridged bicyclic morpholines have been developed as morpho-
starting material.
line isosteres due to their similarity in structure and properties
such as lipophilicity [1]. The bicyclic morpholine (1S,4S)-2-oxa-5-
azabicyclo[2.2.1]heptane (1) has been utilized successfully as a
morpholine surrogate in drug design [2]. Given the structural
similarity between 1 and morpholine (Fig. 1) and potential
similarities in physicochemical and pharmacokinetic property of
compounds containing 1 moiety compared to those of morpholine
derivatives, it is anticipated that this bicyclic morpholine 1 will
become an important building block in medicinal chemistry
research.
Encouraged by the promising result of almost quantitative yield
from trans-4-hydroxy- -proline (2) to N-benzyloxycarbonyl-trans-
4-hydroxy- -proline and benzyloxycarbonyl (Cbz) protecting
group can be removed smoothly by catalytic hydrogenation [6],
herein, we report a facile six-step synthesis of (1S,4S)-2-oxa-5-
azabicyclo[2.2.1]heptane (1) in excellent total yield of 70% using N-
Cbz protected protocol (Scheme 2).
L
L
2. Experimental
Despite the potential of bridged bicyclic morpholine 1 to
become a useful morpholine isostere, to the best of our knowledge,
only two synthetic routes with the same strategy have been
1
13
The H NMR and C NMR spectra were recorded in CDCl
3
solution on a Varian mercury-400 at 400 and 100 MHz respective-
ly. H NMR and C NMR spectra were reported in parts per million
using TMS ( 0.00) as an internal standard. High-resolution mass
1
13
reported on the synthesis of 1, using trans-4-hydroxy-L-proline (2)
d
as the starting material with the main difference on the N-
protection group [3–5]. The first synthesis was reported by
Portoghese in 1971 using N-benzoyl protected group, with a total
yield of 59% in a seven-step procedure [3,4]. After that, in Sun’s
method in 2006, Boc group was utilized in a six-step procedure but
without yields reported [5]. Although Portoghese’s protocol
spectra were measured on a Theromo Extractive Orbitrap plus
mass spectrometer (ESI). The optical rotation was measured on a
PerkinElmer 241MC polarimeter. All of the reagents and solvents
were purchased from commercial sources.
Typical procedure for the preparation of (2S,4R)-1-benzylox-
ycarbonyl-4-hydroxypyrrolidine-2-carboxylic acid (10): A solu-
(
Scheme 1) was in good total yield, the deprotection of benzoyl
2
tion of 2 (6.56 g, 0.05 mol) in H O (50 mL) was added NaOH (4 g,
group seemed to be tedious, and using diazomethane to generate
methyl ester 4 is toxic and dangerous. Keeping these aspects in
mind, efforts were focused on developing a facile and green
0
.1 mol) at 0 8C. Benzyl chloroformate (8.5 g, 0.05 mol) was then
added dropwise at 0 8C and stirred for 5 h at room temperature.
The reaction mixture was extracted with ether (20 mL), and the
aqueous layer was neutralized with 2 mol/L HCl to pH 2, and
extracted with ethyl acetate (30 mL ꢀ 3). The organic layer was
*
Corresponding author.
2 4
combined, washed with brine, dried over Na SO , and concentrat-
E-mail address: joyce@imm.ac.cn (H.-H. Huang).
ed under vacuum to give the target compound (12.1 g, yield: 91%).
1
001-8417/$ – see front matter ß 2013 Hai-Hong Huang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.12.006

4
80
D.-F. Zhang et al. / Chinese Chemical Letters 25 (2014) 479–481
O
8.7 mmol) was added in one portion and stirred for 15 h at room
temperature. The mixture was washed with water and brine, dried
over Na SO and concentrated under vacuum. The residue was
O
HN
O
2
4
N
H
N
H
purified by flash column chromatography (EA in PE: 30–40%) to
1
give a colorless oil (3.2 g, yield: 93%). The H NMR spectra were in
1
Morpholine
1
accordance with the literature data [9]. H NMR (400 MHz, CDCl
3
):
Fig. 1. Morpholine and bridged bicyclic morpholine: (1S,4S)-2-oxa-5-
d 7.76 (d, 2 H, J = 8.0 Hz), 7.29–7.37 (m, 7 H), 4.99–5.20 (m, 3 H),
azabicyclo[2.2.1]heptane (1).
4.45–4.48 (m, 1 H), 3.53 and 3.75 (each s, total 3 H), 3.63–3.72 (m, 2
H), 2.55–2.60 (m, 1 H), 2.43 and 2.46 (each s, total 3 H), 2.16–2.21
1
(
m, 1 H).
Typical procedure for the preparation of (2S,4R)-1-benzylox-
ycarbonyl-2-hydroxymethyl-4-(tosyloxy)pyrrolidine (13): NaBH
2.27 g, 60 mmol) was added to a solution of 12 (4.33 g, 10 mmol)
The H NMR spectra were in accordance with the literature data
1
[
7]. H NMR (400 MHz, CDCl
3
):
d
7.27–7.32 (m, 5 H), 6.17 (brs, 1 H),
5
(
.09–5.12 (m, 2 H), 4.45–4.51 (m, 2 H), 3.60 (brs, 2 H), 2.14–2.30
m, 2 H).
Typical procedure for the preparation of methyl (2S,4R)-1-
benzyloxycarbonyl-4-hydroxypyrrolidine-2-carboxylate (11):
SOCl (3.83 g, 32.2 mmol) was added to a solution of 10 (7.78 g,
9.3 mmol) in CH OH (25 mL) dropwise at 0 8C, and the mixture
4
(
in ethanol (50 mL) and THF (30 mL) in one portion at 0 8C. The
mixture was stirred for 16 h at room temperature. Glacial acetic
acid (4.25 mL) was added carefully at 0 8C, and then the mixture
was evaporated to remove the solvent. Water and ethyl acetate
were added to the residue. The aqueous layer was extracted with
ethyl acetate (30 mL ꢀ 3), while the organic layer was combined,
2
2
3
was stirred for 2.5 h at room temperature. The solvent was
concentrated under vacuum to afford a viscous oil (7.86 g, yield:
6%). The H NMR spectra were in accordance with the literature
data [8]. H NMR (400 MHz, CDCl
m, 2 H), 4.50–4.54 (m, 2 H), 3.75 and 3.54 (each s, total 3 H), 3.65–
.70 (m, 2 H), 2.25–2.35 (m, 1 H), 2.05–2.18 (m, 2 H).
1
2 4
washed with brine, dried over Na SO , and concentrated under
9
1
vacuum to give the target compound (4.05 g, yield: 100%). The
1
3
): d 7.30–7.35 (m, 5 H), 5.09–5.21
H NMR spectra were in accordance with the literature data
(
3
1
[10]. H NMR (400 MHz, CDCl
3
):
d
7.75–7.77 (m, 2 H), 7.32–7.39
(
3
(
m, 7 H), 5.08–5.15 (m, 2 H), 5.02 (brs, 1 H), 4.09–4.13 (m, 1 H),
.77–3.83 (m, 2 H), 3.50–3.57 (m, 2 H), 2.44 (s, 3 H), 2.19–2.24
m, 1 H), 1.78–1.84 (m, 1 H).
Typical procedure for the preparation of methyl (2S,4R)-1-
benzyloxycarbonyl-4-(tosyloxy)pyrrolidine-2-carboxylate (12): A
solution of compound 11 (2.22 g, 7.95 mmol), Et N (0.88 g,
.7 mmol), and DMAP (0.97 g, 7.95 mmol) in CH Cl (30 mL)
3
Typical procedure for the preparation of (1S,4S)-5-benzylox-
8
2
2
ycarbonyl-2-oxa-5-azabicyclo[2.2.1]heptane (14): A mixture of 13
was cooled to 0 8C. Then, p-toluenesulfonyl chloride (1.67 g,
HO
TsO
HO
HO
a
b
c
COOCH3
COOCH3
COOH
COOH
N
N
N
N
H
O
O
O
2
3
4
5
TsO
O
O
O
OH
d
e
f
g
N
N
N
N
H
HCl
O
O
6
7
8
9
Scheme 1. Portoghese’s synthesis of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (9). Reagents and conditions: (a) NaOH, benzoyl chloride, Et
2
O, r.t., 24 h, 90%;
/THF, 0 8C to
(
b) CH , MeOH, r.t., 98%; (c) TsCl, Py, 5 8C, 60 h, 94%; (d) LiBH , 1,2-dimethoxyethane, 0 8C to r.t., 4 h, 93%; (e) NaOMe, MeOH, EtOH, reflux, 2 h, 90%; (f) BH
2
N
2
4
3
reflux, 1 h, 100%; (g) 10% Pd/C, H
2
, 2 mol/L HCl, 85%.
HO
HO
HO
i
ii
v
iii
COOH
COOH
COOCH3
N
H
N
N
Cbz
Cbz
2
10
11
O
TsO
TsO
O
vi
iv
OH
COOCH3
N
N
N
N
H
Cbz
Cbz
Cbz
1
2
13
14
1
Scheme 2. Synthesis of (lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptane (1). Reagents and conditions: (i) NaOH, CbzCl, H
2
O, 0 8C to r.t., 5 h, 91%; (ii) SOCl
2
, MeOH, 0 8C to r.t., 2.5 h,
, MeOH, 4 h, 100%.
9
6%; (iii) TsCl, DMAP, Et N, CH Cl , 0 8C to r.t., 15 h, 93%; (iv) NaBH , EtOH/THF, 0 8C to r.t., 16 h, 100%; (v) NaOMe, MeOH, reflux, 4 h, 86%; (vi) 10% Pd/C, H
3
2
2
4
2

D.-F. Zhang et al. / Chinese Chemical Letters 25 (2014) 479–481
481
Table 1
triethylamine as the base and one equivalent of DMAP as a catalyst
was beneficial to promote the transformation at room temperature
in terms of reaction time and yield. Reduction of methyl ester to
The exploration of reaction conditions for the synthesis of tosylate 12.
a
Entry
Base
Catalyst
–
Solvent
Time
Yield (%)
alcohol proceeded smoothly by treatment with NaBH
THF, giving alcohol 13 quantitatively. The use of NaBH
LiBH lowered the cost, which was another advantage compared to
4
in EtOH/
1
2
3
Pyridine
Pyridine
7 d
3 d
45%
81%
93%
b
Et
Et
3
N
N
DMAP
CH
CH
2
Cl
Cl
2
2
4
instead of
c
3
DMAP
2
15 h
4
a
Portoghese’s protocol [3]. The formation of the desired bridged
compound 14 was achieved by treatment of the alcohol 13 in good
yield in a solution of NaOMe in MeOH. Finally, the Cbz protecting
group in 14 was removed smoothly by catalytic hydrogenation in
the presence of catalytic amount of Pd/C to afford the bridged
morpholine 1 in quantitative yield. The total yield was 70%. Overall,
this synthetic route was efficient and easy to scale-up.
Isolated yield.
b
c
In the presence of catalytic amount of DMAP.
In the presence of equivalent of DMAP.
(
(
4.05 g, 10 mmol) and NaOMe (0.81 g, 15 mmol) in dry CH
20 mL) was refluxed for 4 h, then cooled to room temperature. The
3
OH
solvent was removed under vacuum, followed by addition of sat.
Na CO (100 mL). The mixture was extracted with ethyl acetate
30 mL ꢀ 3), and the organic layer was combined, washed with
brine, dried over Na SO , and purified by flash column chroma-
tography (EA in PE: 30–50%) to give a colorless oil (2.01 g, yield:
6%). H NMR (400 MHz, CDCl
m, 2 H), 4.54–4.61 (m, 2 H), 3.70–3.92 (m, 2 H), 3.43–3.47 (m, 1 H),
.34–3.39 (m, 1 H), 1.81–1.88 (m, 2 H). C NMR (100 MHz, CDCl
2
3
(
4. Conclusion
2
4
1
8
(
3
3
):
d
7.33–7.35 (m, 5 H), 5.13–5.15
In summary, a short, efficient, and facile synthesis of (1S,4S)-2-
oxa-5-azabicyclo[2.2.1]heptane (1) was accomplished in six steps
in an excellent yield of 70% starting from commercially available
13
3
):
(
7
rotamers)
d
154.5, 136.6, 128.4, 128.0, 127.9, 127.7, 76.3/76.0,
and inexpensive trans-4-hydroxy-L-proline (2). This improved
synthetic method of bridged morpholine 1 will make morpholine
isostere more attractive in medicinal chemistry research.
+
4.2, 66.9/66.7, 57.2/56.9, 54.7/54.5, 36.6/36.1. HRMS (ESI-TOF )
+
Calcd. for C13
H
16NO
3
[M+H] : m/z 234.1125; found, 234.1125.
¼ ꢂ21:3ðc1:6; CHCl Þ.
Typical procedure for the preparation of (1S,4S)-2-oxa-5-
azabicyclo[2.2.1]heptane (1): To a solution of 14 (1.16 g, 5 mmol)
in CH OH (20 mL) was added 10% Pd/C (0.12 g). The mixture was
stirred under H at atmospheric pressure for 4 h at room
2
D
0
½
a
ꢁ
3
References
3
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(
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):
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Þ.
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2
0
aꢁ
¼ þ104:2ðc1:25; CHCl
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D
[
[
[
[
3
. Results and discussion
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The title compound was synthesized by a convenient six-step
procedure as outlined in Scheme 2. In our strategy, the critical step
is to choose benzyloxycarbonyl (Cbz) as the protection group of
amino in trans-4-hydroxy-L-proline (2). Treatment of 2 with
benzylchloroformate (Cbz-Cl) in the presence of NaOH afforded
carbamate 10 conveniently in 91% yield [6]. Moreover, instead of
´
[
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pharmacokinetic study of prolyl-1-piperazinylacetic acid and prolyl-4-piperidi-
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using toxic and dangerous diazomethane, MeOH/SOCl
2
was
2
725–2746.
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employed to make the methyl ester 11 mildly [8]. Several
conditions were also screened for the synthesis of tosylate 12.
The results were summarized in Table 1. It was found that using
[
(