Diastereospecific synthesis of (S,S)-2-substituted-4,4-diphenyl-3,1-oxazabicyclo[3.3.0]octanes

Article abstract of DOI:10.1002/hc.10064

(S,S)-2-substituted-4,4-diphenyl-3,1-oxazabicyclo[3.3.0]octanes were synthesized from aldehydes and (S)-2-(hydroxy-diphenylmethyl)pyrrolidine, which was obtained from L-proline. The stereospecificity of the condensation reaction was discussed. The stereo-structure of each product in the condensation was found to be in agreement with the product of a similar reaction of (S)-phenylglycinol with an aldehyde. The method was found to be useful for the synthesis of cis 3,1-oxazabicyclo[3.3.0]octane derivatives.

Full text of DOI:10.1002/hc.10064

Heteroatom Chemistry
Volume 14, Number 1, 2003
Diastereospecific Synthesis of
(S,S )-2-Substituted-4,4-diphenyl-
3,1-oxazabicyclo[3.3.0]octanes
Gang Zuo, Qihan Zhang, and Jiaxi Xu
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education,
College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, P.R. China
Received 12 December 2001; revised 19 February 2002
ing biological activity [1]. The development of the
ABSTRACT: (S,S)-2-Substituted-4,4-diphenyl-3,1-
methodology for the preparation of highly function-
oxazabicyclo[3.3.0]octanes were synthesized diaster-
alized pyrrolidines has attracted considerable in-
eospecifically from aldehydes and (S)-2-(hydroxy-
terest recently [1–4]. The trans bicyclic derivatives
diphenylmethyl)pyrrolidine, which was obtained
of pyrrolidine, trans-3,1-oxazabicyclo[3.3.0]octan-8-
from L-proline, under acid-catalyzed conditions in
one derivatives, can be synthesized mainly from
anhydrous toluene. The stereospecificity of the conden-
aldehydes and related chiral hydroxymethylpyrro-
ꢀ
C
sation reaction is discussed. 2003 Wiley Periodicals,
lidinones, which are derived from L-pyroglutamic
Inc. Heteroatom Chem 14:42–45, 2003; Published online
acid [1–4,13]. Herein we report the preparation of
in Wiley InterScience (www.interscience.wiley.com). DOI
cis bicyclic derivatives of pyrrolidine, chiral cis-3,1-
10.1002/hc.10064
oxazabicyclo[3.3.0]octanes, from aldehydes and (S)-
2-(hydroxydiphenylmethyl)pyrrolidine, which was
obtained from L-proline.
INTRODUCTION
Naturally occurring amino acids constitute an im-
portant and inexpensive chiral pool for the synthe-
RESULTS AND DISCUSSION
sis of complex natural products and chiral drugs.
During the last decade, pyroglutamic acid, the cy-
clized form of glutamic acid, has been widely
studied for the synthesis of pyrrolidine derivatives
[1–4]. Functionalized pyrrolidines are compounds
(S)-2-(Hydroxydiphenylmethyl)pyrrolidine (1) was
prepared according to the procedure given in
Ref. [14]. L-Proline reacted with ethyl chlorofor-
mate in the presence of potassium carbonate in
anhydrous methanol to produce N-carboxyethyl
L-proline methyl ester (2). The N-protected proline
methyl ester 2 was then reacted with phenylmag-
nesium bromide to yield (S)-1-carboxyethyl-2-
(hydroxydiphenylmethyl)pyrrolidine (3) in anhy-
drous tetrahydrofuran. After hydrolysis with
potassium hydroxide in methanol, (S)-2-(hydroxy-
diphenylmethyl)pyrrolidine (1) was obtained in
80% yield. It was refluxed with aldehydes (4),
in the presence of p-toluenesulfonic acid (PPTS)
as an acid catalyst, in anhydrous toluene, using
a Dean–Stark water separator, and by vigorous
of considerable importance since they are
a
source of useful synthetic intermediates [5–7],
chiral auxiliaries [8,9], and ligands [10–12]. They
also occur in a variety of natural products and
pharmaceutically active compounds, either as iso-
lated ring systems or embedded in more com-
plex structures, which often possess wide rang-
Correspondence to: Jiaxi Xu; e-mail: jxxu@chem.pku.edu.cn.
Contract grant sponsor: NSFC.
2003 Wiley Periodicals, Inc.
c
ꢀ
42

Diastereospecific Synthesis of Chiral 3,1-Oxazabicyclo[3.3.0]octanes 43
1
Tables 1 and 2). According to H NMR monitoring,
only one diastereomer of each of the compounds
5a–e was found in the reaction mixture. This
result could be rationalized as shown in Scheme 2.
(S)-2-(Hydroxydiphenylmethyl)pyrrolidine (1) re-
acted with aldehydes 4a–e under acid-catalyzed con-
ditions to first form (E)-iminium intermediates 6.
Then the hydroxy group attacks the iminium group
of the intermediates 6. The attack should occur
from the upper side of the iminium bond since it
is located over the iminium bond. After the release
of a proton, a kind of cis cyclized hemiaminal
ether product, (S,S)-2-substituted-4,4-diphenyl-3,1-
oxazabicyclo[3.3.0]octanes 5a–e, is formed in each
case. The stereo-structure of each product in the con-
densation is also well in agreement with the product
of a similar reaction of (S)-phenylglycinol with an
SCHEME 1 Synthesis of (S,S)-2-substituted-4,4-diphenyl-
3,1-oxazabicyclo[3.3.0]octanes.
stirring in an oil bath to yield (S,S)-2-substituted-
4,4-diphenyl-3,1-oxazabicyclo[3.3.0]octanes 5a–e
and (S)-4,4-diphenyl-3,1-oxazabicyclo[3.3.0]octane
5f in satisfactory yields [13] (Scheme 1).
The proposed structures for 5a–f are based on
1H NMR, mass spectral, and elemental analyses (See
TABLE 1 Physical and Spectral Data
Yield
(%)
[α] D
(c, acetone)
MS/FAB
1H NMR (CDCl3/TMS)
20
Compound
R
m.p. (◦C)
m/z (MH+)
δ (ppm), J (Hz)
5a
Ph
67
78
85
61
139–140
−84.5 (1.30)
342
376
376
372
7.61–7.17 (15H, m, aromatic), 5.53 (1H, s,
NCHO), 4.49 (1H, t, J = 7.2, CHN),
3.14–3.03 (1H, m, 1H in CH2N),
2.94–2.81 (1H, m, 1H in CH2N),
1.87–1.60 (4H, m, CH2CH2)
7.49–7.17 (14H, m, aromatic), 5.52 (1H, s,
NCHO), 4.45 (1H, t, J = 7.2, CHN),
3.12 (1H, dt, J = 11.5, 7.2, 1H in
CH2N), 2.86 (1H, dt, J = 11.5, 5.5, 1H
in CH2N), 1.87–1.64 (4H, m, CH2CH2)
7.85–7.16 (14H, m, aromatic), 5.51 (1H, s,
NCHO), 4.45 (1H, t, J = 7.0, CHN),
3.17–3.06 (1H, m, 1H in CH2N),
2.89–2.75 (1H, m, 1H in CH2N),
1.85–1.62 (4H, m, CH2CH2)
7.65–7.48 (6H, m, aromatic), 7.38–7.13
(6H, m, aromatic), 6.99–6.92 (2H, m,
aromatic), 5.52 (1H, s, NCHO), 4.59
(1H, t, J = 7.0, CHN), 3.84 (3H, s,
CH3O), 2.58 (1H, dt, J = 9.2, 7.0 1H in
CH2N), 2.47 (1H, dt, J = 2.8, 9.2, 1H
in CH2N), 1.94–1.81 (1H, m, 1H in
CH2CH2), 1.63–1.27 (3H, m, 3H in
CH2CH2)
5b
5c
5d
o-ClPh
p-ClPh
57–58
−148 (0.57)
−101 (0.71)
−119 (1.05)
126–127
153–154
p-MeOPh
5e
5f
n-C4H9
Oil
−87.9 (0.84)
−325 (1.10)
322
266
7.54–7.15 (10H, m, aromatic), 4.67 (1H, t,
J = 5.1, NCHO), 4.39 (1H, t, J = 6.4,
CHN), 3.17–3.05 (1H, m, 1H in CH2N),
2.79 (1H, dt, 1H, J = 7.3, 10.4, 1H in
CH2N), 1.88–0.85 (13H, m, CH2CH2
and (CH2)3CH3)
7.53–7.12 (10H, m, aromatic), 4.50 (1H,
d, J = 6.1, 1H in NCH2O), 4.44 (1H,
dd, J = 7.2, 14.0, CHN), 4.28 (1H, d,
J = 6.1, H in NCH2O), 3.31–2.20 (1H,
m, 1H in CH2N), 2.86–2.73 (1H, m, 1H
in CH2N), 1.74–1.62 (3H, m, 3H in
CH2CH2), 1.28–1.11 (1H, m, 1H in
CH2CH2)
H
81
84–85

44 Zuo, Zhang, and Xu
TABLE 2 Elemental Analysis Data
Cald.
H
Found
H
Compound
Molecular Formula
Molecular Weight
C
N
C
N
5a
5b
5c
5d
5e
5f
C24H23NO
C24H22ClNO
341.45
375.89
375.89
371.47
321.46
265.35
84.42
76.69
76.69
80.83
82.20
81.47
6.79
5.90
5.90
6.78
8.47
7.22
4.10
3.73
3.73
3.77
4.36
5.28
84.16
76.70
76.37
80.89
82.01
81.29
6.59
6.04
5.92
7.00
8.59
7.41
4.07
3.80
3.67
3.89
4.18
5.30
C
C
C
C
24H22ClNO
25H25NO2
22H27NO
18H19NO
aldehyde, reported in Ref. [15]. The stereo-chemistry
of the products was confirmed by NOE experiments
[3]. For example, the NOE difference spectrum of
product 5a shows that the hydrogen atoms located at
C2 and C5 have a cis relationship. The newly formed
chiral carbon atom C2 can be assigned the (S)-
configuration based on the known (S)-configuration
of carbon atom C5 (Scheme 2). Although hydrox-
ymethylpyrrolidinone undergoes this reaction to
form trans 3,1-oxazabicyclo[3.3.0]octanone deriva-
tives as reported in previous papers [1,3,13], in
our case, 2-hydroxymethylpyrrolidine gives cis 3,1-
oxazabicyclo[3.3.0]octanes. It is a useful method
for the synthesis of cis 3,1-oxazabicyclo[3.3.0]octane
derivatives.
was prepared according to the procedure given in
Ref. [14].
General Procedure for the Synthesis
of (S,S)-2-Substituted-4,4-diphenyl-3,
1-oxazabicyclo[3.3.0]octanes 5a–e and
(S)-4,4-Diphenyl-3,1-oxazabicyclo[3.3.0]-
octanes 5f
A mixture of (S)-2-(hydroxydiphenylmethyl)pyrrol-
idine (1) (200 mg, 0.8 mmol), aldehyde 4 (0.9 mmol),
and p-toluenesulfonic acid (PPTS) (20 mg, 0.1 mmol)
in toluene (20 ml) was refluxed using a Dean–
Stark water separator and by vigorous stirring in
an oil bath. After 4 h, the collection of water was
stopped. The cooled reaction mixture was washed
with saturated aqueous sodium bicarbonate solution
(2 × 10 ml), saturated sodium bisulfite solution (2 ×
10 ml), water, and brine. The organic layer was dried
over sodium sulfate and concentrated to afford an
oily residue. It was separated on a silica gel column
with a mixture of petroleum ether (60–90◦C)/ethyl
acetate (10:1) as the eluent to give colorless crystals
of 5.
EXPERIMENTAL
Melting points were obtained on a Yanaco MP-500
melting point apparatus and are uncorrected. Ele-
mental analyses were carried out on an Elementar
1
Vario EL elemental analyzer. The H NMR spectra
were recorded on a Varian Mercury 200 spectrometer
with TMS as an internal standard, in CDCl3. The IR
spectra were taken on a Brucker Vector 22 FT-IR
spectrophotometer in KBr pellets. Mass spectra
were obtained on a VG ZAB-HS mass spectrome-
ter. Optical rotations were measured on a Perkin-
Elmer 341LC polarimeter with a thermally jack-
eted 10 cm cell (concentration c given as g/100 ml).
TLC separations were performed on silica gel G
plates with petroleum ether (60–90◦C)/ethyl acetate
(10:1) as eluent, and the plates were visualized with
UV light. (S)-2-(Hydroxydiphenylmethyl)pyrrolidine
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SCHEME 2 Stereospecificity in condensation reaction.

Diastereospecific Synthesis of Chiral 3,1-Oxazabicyclo[3.3.0]octanes 45
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