New synthesis and application of 3-substituted prolinols

Article abstract of DOI:10.1055/s-2004-816001

Carbon skeleton of polysubstituted pyroglutamates with three contiguous asymmetric centers was built up in one base-induced coupling/cyclization reaction of α-sulfonylacetamide with 2-bromo-2-propenoates. A simple transformation to 3-substituted prolinols

Full text of DOI:10.1055/s-2004-816001

840
PAPER
New Synthesis and Application of 3-Substituted Prolinols
New
Synthesis and
A
p
e
plication of
n
3-Substitute
g
d Prolinols -Yang Chang,*a Chung-Yi Chen,b Min-Ruey Tasi,b Tze-Wei Tseng,b Nein-Chen Chang*b
a
Department of Applied Chemistry, National University of Kaohsiung, Kaohsiung 811, Taiwan
b
Department of Chemistry, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
Fax +886(7)5919348; E-mail: mychang@nuk.edu.tw
Received 11 December 2003; revised 3 February 2004
esters 2.8–10 We have successfully accomplished the syn-
theses of several natural products and potential drugs via
this facile [3+3] annulation. In continuation of our previ-
ous investigation on the chemistry of 1, we have devel-
Abstract: Carbon skeleton of polysubstituted pyroglutamates with
three contiguous asymmetric centers was built up in one base-in-
duced coupling/cyclization reaction of a-sulfonylacetamide with 2-
bromo-2-propenoates. A simple transformation to 3-substituted
prolinols can be easily achieved via reduction and desulfonation. A oped an efficient synthesis of N-benzyl ethyl
ring expansion of prolinol has been used as the key step in the for-
mal synthesis of isoguvacine and paroxetine. The one-pot conver-
sion of 3-substituted prolinol to the 3-substituted pyroglutamic acid
mal [3+2] cycloaddition reaction (Equation 1). We have
is also reported.
polysubstituted pyroglutamates 3, which are potential pre-
cursors of the corresponding pyroglutamic acids, by for-
also reported the facile route for preparing the racemic
drug by the above-mentioned method.11
Keywords: glutarimides, stepwise [3+2] annulation, pyro-
glutamates, prolinol, isoguvacine, paroxetine
R3
O
S
O
O
O
R1
S
R1
R3
CO2R5
R4
O
R1
S
NaH, THF
O
Pyroglutamic acid derivatives are prevalent scaffolds that
serve as crucial building blocks for numerous syntheses of
natural products and nitrogen heterocycles.1 The modifi-
cation and functionalisation of the carboxylic group and
the lactam ring allows the preparation of many types of
natural products as well as biologically active molecules.
These interesting compounds can be derived from the fol-
lowing basic carbon skeletons: (i) prolines2 and kainoid
acid derivatives3 (ii) pyrrolizidines, indolizidines4 and
other fused azabicyclic compounds5 (iii) N-bridge bicy-
clic compounds6 (iv) different substituted a- or g-amino
acid derivatives7 (Scheme 1). As a result, pyroglutamic
acid derivatives have become target molecules for many
synthetic efforts. It is necessary to develop new and short-
er routes to this class of compounds.
or
O
O
R3
R4
O
O
NH
R2
N
R2
N
R2
CO2R5
4 = Br
R
4 = Br
R
Equation 1
Our interest in synthesizing the 3-substituted prolinol (2-
hydroxymethylpyrrolidine) was piqued on the different
biological properties and on the fact that it is a key inter-
mediate for preparing the skeleton of substituted pipe-
ridines and prolines.12 Prolinol is an a-aminoalcohol with
a unique nature inducing specific electronic and geo-
metric features. The presence of such a ring in the chemi-
cal structure restricts its conformational flexibility, which
may efficiently modify the binding affinity to its target.
Previously, we reported an efficient synthesis of 3- or 4-
substituted 5-sulfonylglutarimides via a stepwise [3+3]
strategy with a-sulfonylacetamide 1 and a,b-unsaturated
There are significant similarities in the all carbon frame-
work of the pyroglutamates 3 and prolinols 4, which are
R1
R2
CO2H
R2 NHBn
HO
OH
N
R1
R2
O
R1
O
H
COOEt
O
N
Bn
R1
R2
R1
R2
pyroglutamate
N
H
N
n
n=1,2
Scheme 1 Applications of pyroglutamate
SYNTHESIS 2004, No. 6, pp 0840–0846
x
x
.
x
x
.2
0
0
4
Advanced online publication: 04.03.2004
DOI: 10.1055/s-2004-816001; Art ID: F12603SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
New Synthesis and Application of 3-Substituted Prolinols
841
based on the 3-substituted pyrrolidine ring. The syntheses In order to prevent ring-opening of pyrrolidine, we first
of 3 and 4 have attracted the attention of synthetic chem- reduced 3b into 2-hydroxylactam using LiAlH4 reduction.
ists because of their biological properties. We now wish to Then the resulting product was treated with Na/Hg fol-
report the stepwise reduction of 3-substituted pyro- lowed by another reduction with LiAlH4 smoothly yield-
glutamates leading to 3-substituted prolinols as illustrated ing the compound 4b. In summary, we have utilized a
in Scheme 2. There are two remarkable steps for the syn- simple and standard transformation (LiAlH4, Na/Hg,
thesis of 4. One step is the rapid access to produce a wide LiAlH4) with high overall yields to obtain the prolinols 4
variety of N-benzyl ethyl pyroglutamates 3 by formal from 3 in three steps. Some results are listed in
[3+2] annulation. The other step is the simple transforma- Equation 2. With a general access to compounds 4, we an-
tion from 3 to 4, which contained two LiAlH4-mediated ticipated that 4d and 4f could be the key compounds for
reductions and one desulfonation by Na/Hg.
synthesizing the intermediates of isoguvacine10c and par-
oxetine.14a The development of general methods for the
synthesis of isoguvacine and paroxetine has been our fo-
cus.
O
O
Tol
S
R
R
R
O
Tol
S
Br
3
O
+
O
CO2Et
CH2OH
N
N
O
CO2Et
O
NH
Bn
Bn
Bn
Tol
O
S
R
R
1) LAH, THF
4
3
1
2
OH
O
CO2Et
N
N
2) Na(Hg), MeOH
3) LiAlH4, THF
Scheme 2 Retrosynthesis of 3-substituted prolinols 4
Bn
Bn
3
4
The synthesis began from 3, which were cycloadducts us-
ing one-pot reaction of 1 with 2. Benzylamine was treated
with chloroacetyl chloride and Et3N to produce a-chloro
acetamide, which was then treated with p-toluenesulfinic
acid sodium salt to give 1. Treatment of aldehydes with
Ph3P=C(Br)CO2Et gave a-bromoesters 2. Acetamide 1
and esters 2 were the reasonable starting materials for the
synthesis of pyroglutamate skeleton via the stepwise
[3+2] reaction. The synthesis proceeded through the
stereo- and regioselective annulation, resulting in the sin-
gle isomer 3 with three contiguous chiral centers. The
mechanism for the outstanding stereoselectivity of the an-
nulation reaction has been recently proposed.11
a, R=H, 70%; b, R=CH3, 75%; c, R=CH2CH2CH3, 80%;
d, R=CH(OCH3)2, 82%; e, R=C6H5, 73%; f, R=4-FC6H4, 75%;
g, R=4-ClC6H4, 69%; h, R=3-OC5H9-4-OCH3-C6H3, 81%
Equation 2
Isoguvacine is a potent and selective g-Abu (g-aminobu-
tyric acid, GABAA) agonist that interacts specifically with
the g-Abu receptor and shows considerable pharmacolog-
ical potential, among a variety of g-Abu analogs. Isoguva-
cine is more active than g-Abu in cells (in vivo and in
vitro); these findings prompted us to develop a new syn-
thetic strategy for this compound.10c Paroxetine, marketed
as Paxil/Saroxat, is a selective serotonin (5-hydrox-
ytryptamine) reuptake inhibitor used as an anti-depressant
and anti-Parkinson agent. Its high sales in excess of $ 1.5
billion/year have induced many attempts to synthesize
it.14a Physical resolution and enzymatically assisted kinet-
ic resolution of an advanced racemic intermediate were
the most common methods employed.
With 3 in hand, we turned to the reduction reaction. We
initially used 3b, 3d and 3h as model substrates to synthe-
size prolinols in two steps [alane reduction (LiAlH4–
AlCl3) and desulfonation (Na/Hg)]. Alane reduction of
3b, 3d and 3h gave the 3-substituted-4-sulfonylprolinol 5
(Scheme 3). However, desulfonation of 5b with Na/Hg
produced 6 with terminal olefin group. The five-mem-
bered ring opened and produced the amino alcohol analog
as the major product in the basic desulfonation.13a Com-
pound 6 is a reasonable precursor for synthesizing the
building block of funebrine and funebral.13b The desired
3-methylprolinol was not obtained in the desulfonation re-
action.
As shown in Scheme 4, a ring expansion of prolinol into
piperidine ring was a key step for the formal synthesis of
isoguvacine and paroxetine. The reaction has been well
known for a long time.14 Ring expansion of prolinol 4d or
4f by addition of mesyl chloride on an ice bath followed
by the addition of Et3N at reflux temperature and then
treatment of hydrochloride solution provided the expected
O
S
O
S
CH3
Tol
O
R
Tol
R
Na(Hg), MeOH
O
LiAlH4, AlCl3
OH
(for b, 77%)
CH2OH
O
CO2Et
N
N
HN
Bn
Bn
Bn
6
3
5
b, R=CH3, 81%; d, R=CH(OCH3)2, 74%;
h, R=3-OC5H9-4-OCH3-C6H3, 69%
Scheme 3 Alane reduction of pyroglutamates 3
Synthesis 2004, No. 6, 840–846 © Thieme Stuttgart · New York

842
M.-Y. Chang et al.
PAPER
4-substituted piperidines 7 and 8 in modest yields. Prod-
uct 7 was a known intermediate for the synthesis of isogu-
vacine.10c Allylic oxidation of 8 with pyridinium
dichromate and NaOAc generated enone and followed by
the hydrogenation of the resulting enone to yield an inter-
mediate 9 for the synthesis of paroxetine.14a
THF was distilled prior to use from a deep-blue solution of sodium–
benzophenone ketyl. All other reagents and solvents were obtained
from commercial sources and used without further purification. Re-
actions were routinely carried out under an atmosphere of anhy-
drous N2 with magnetic stirring. Organic layers were dried with
anhydrous MgSO4 before concentration in vacuo. Crude products
were purified using preparative TLC or column chromatography on
silica gel. All reported melting points were uncorrected.
X
4-FC6H4
R
MsCl, Et3N
then H+
1) PDC, NaOAc
Formal [3+2] Cycloaddition Reaction using N-Benzyl a-Sulfo-
nylacetamides 1 and Esters 2; General Procedure
OH
N
2) H2, Pd/C
(X=4-FC6H4,
two steps 43%)
N
N
O
Bn
A solution of 2 (1.0 mmol) in THF (30 mL) was carefully added to
a rapidly stirred suspension of sodium hydride (3.1 mmol, 60%) in
THF (30 mL). After the reaction mixture was stirred at r.t. for 15
min, a solution of 1 (1.1 mmol) in THF (30 mL) was added. The re-
sulting mixture was stirred for 6 h at refluxed temperature,
quenched with aq NH4Cl (2 mL) in an ice bath, and concentrated
under reduced pressure. Water (20 mL) was added to the crude
product, and extracted with EtOAC (3 × 50 mL). The combined or-
ganic layers were washed with brine (2 × 20 mL), dried, filtered and
evaporated. Purification of the crude product by column chromatog-
raphy on silicagelwith hexane–EtOAc(4:1→2:1→1:1)produced3
in 41–61% yields. These data have been already reported in ref.11
Bn
Bn
4
7 X=CHO (for 4d, 44%)
8 X=4-FC6H4 (for 4f, 41%)
9
ref 10c
ref 14a
O
O
4-FC6H4
CO2H
O
N
H
N
H
paroxetine
Isoguvacine
Prolinols 4 in Three-step Strategy; General Procedure
A solution of 3 (0.8 mmol) in THF (10 mL) was added to a solution
of LiAlH4 (57 mg, 1.5 mmol) in THF (10 mL) via syringe at 0 °C.
The mixture was refluxed for 2 h, quenched with aq NH4Cl (1 mL)
under cooling, and concentrated. The residue was diluted with water
(15 mL) and extracted with EtOAc (3 × 30 mL). The organic layer
was washed with brine and water, dried, filtered and concentrated
to produce crude compound. 6% Sodium amalgam (Na/Hg, 300
mg) was added to a solution of the resulting alcohol and sodium
phosphate (143 mg, 1.0 mmol) in MeOH (5 mL). The mixture was
vigorously stirred for 2 h at r.t. Water (2 mL) was added to the res-
idue. The residue was filtered and washed with MeOH (2 × 10 mL).
The combined layers were concentrated to get the crude desulfonat-
ed product. A solution of the resulting product in THF (10 mL) was
added to a solution of LiAlH4 (57 mg, 1.5 mmol) in THF (10 mL)
via syringe at 0 °C. The mixture was refluxed for 2 h, quenched with
aq NH4Cl (1 mL) under cooling, and concentrated. The residue was
diluted with water (15 mL) and extracted with EtOAc (3 × 30 mL).
The organic layer was washed with brine and water, dried, filtered
and concentrated to produce crude compound. Purification on silica
gel (EtOAc–MeOH, 9:1 → 6:1) produced 4a–4h in 69–82% yield.
Scheme 4 Formal syntheses of isoguvacine and paroxetine
In the view of trans-3-substituted proline, the synthesis of
3-methyl,15a 3-propyl,15b 3-phenyl15c and other substituted
prolines were produced from the prolinol 4 under the oxi-
dation condition using TEMPO–NaClO216a and Jones re-
agent.16b Oxidation of prolinols 4e–g by the RuCl3–NaIO4
(in situ generated RuO4) produced the pyroglutamic acids
10 (Equation 3). Recently, Qing and Ganesh have investi-
gated the related oxidation reaction.17 We describe herein
this methodology for the efficient construction potentially
useful pyroglutamic acids from prolinols.
R
R
RuCl3, NaIO4
OH
O
CO2H
N
N
MeCN/CCl4/H2O=2/2/3
Bn
Bn
10
4
1-Benzylprolinol (4a)
Yield: 70%.
e, R=C6H5, 65%; f, R=4-FC6H4, 57%; g, R=4-ClC6H4, 52%
IR (CHCl3): 3417, 2953, 1639, 1422, 1051, 773 cm–1.
Equation 3
1H NMR (500 MHz, CDCl3): d = 7.33–7.26 (m, 5 H), 3.98 (d, J =
13.0 Hz, 1 H), 3.66 (dd, J = 3.5, 11.0 Hz, 1 H), 3.44 (dd, J = 2.5,
11.0 Hz, 1 H), 3.38 (d, J = 13.0 Hz, 1 H), 3.01–2.97 (m, 1 H), 2.77–
2.74 (m, 1 H), 2.75 (br s, 1 H), 2.31 (dd, J = 9.5, 17.0 Hz, 1 H), 1.96–
1.90 (m, 1 H), 1.87–1.80 (m, 1 H), 1.73–1.67 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 139.11, 128.71 (2 C), 128.31 (2
C), 127.06, 64.29, 61.73, 58.52, 54.39, 27.71, 23.41.
Our work demonstrates that trans 3-substituted prolinols
can be obtained with a one-step [3+2] strategy that is use-
ful for constructing pyroglutamates with three contiguous
chiral centers. Ring expansion was applied to prolinols
with a process of mesyl chloride and Et3N to synthesize
the intermediate for the isoguvacine and paroxetine. The
one-pot efficient conversion between reduction of pyro-
glutamates and oxidation of prolinols with different re-
agents is also investigated. We are currently studying the
scope of this process as well as additional applications of
the methodology to the synthesis of pyrrolizidines and in-
dolizidines.
EI–MS: m/z (%) = 91 (100), 160 (30), 191 (1) [M+].
HRMS (EI): m/z calcd for C11H14N [M+ – 31]: 160.1121; found:
160.1120.
Anal. Calcd for C12H17NO: C, 75.35; H, 8.96. Found: C, 75.52; H,
8.82.
Synthesis 2004, No. 6, 840–846 © Thieme Stuttgart · New York

PAPER
New Synthesis and Application of 3-Substituted Prolinols
843
1-Benzyl-3-methylprolinol (4b)
Yield: 75%.
IR (CHCl3): 3432, 1639, 1206, 760 cm–1.
13C NMR (125 MHz, CDCl3): d = 144.13, 138.50, 128.72 (2 C),
128.61 (2 C), 128.45 (2 C), 127.80 (2 C), 127.25, 126.46, 73.32,
58.57, 58.17, 53.82, 46.05, 31.81.
1H NMR (500 MHz, CDCl3): d = 7.33–7.26 (m, 5 H), 4.03 (d, J =
13.0 Hz, 1 H), 3.72 (dd, J = 3.0, 11.0 Hz, 1 H), 3.55 (dd, J = 1.0,
11.0 Hz, 1 H), 3.39 (d, J = 13.0 Hz, 1 H), 3.27 (br s, 1 H), 3.01–2.96
(m, 1 H), 2.46 (dd, J = 8.5, 17.5 Hz, 1 H), 2.29–2.19 (m, 2 H), 1.97–
1.89 (m, 1 H), 1.39–1.33 (m, 1 H), 1.04 (d, J = 6.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 138.39, 128.85 (2 C), 128.40
(2 C), 127.27, 72.96, 59.51, 58.57, 52.54, 34.53, 31.39, 19.44.
1-Benzyl-3-(4-fluorophenyl)prolinol (4f)
Yield: 75%.
IR (CHCl3): 3456, 3030, 1592, 1221, 762 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.36–7.18 (m, 9 H), 4.08 (d, J =
13.0 Hz, 1 H), 3.71 (dd, J = 3.0, 11.5 Hz, 1 H), 3.51 (dd, J = 1.5,
11.5 Hz, 1 H), 3.46 (d, J = 13.0 Hz, 1 H), 3.42–3.35 (m, 1 H), 3.19–
3.14 (m, 1 H), 2.76–2.65 (m, 2 H), 2.45 (br s, 1 H), 2.25–2.18 (m, 1
H), 1.95–1.89 (m, 1 H).
13C NMR (125 MHz, CDCl3): d = 144.00, 138.42, 129.12, 129.14,
128.81 (2 C), 128.61 (2 C), 128.46 (2 C), 127.31, 126.49, 73.32,
58.61, 58.19, 53.75, 46.03, 31.78.
EI–MS: m/z (%) = 91 (100), 174 (72), 205 (1) [M+].
HRMS (EI): m/z calcd for C12H16N [M+ – 31]: 174.1277; found:
174.1277.
Anal. Calcd for C13H19NO: C, 76.06; H, 9.33. Found: C, 76.23; H,
9.41.
1-Benzyl-3-(4-chlorophenyl)prolinol (4g)
Yield: 69%.
1-Benzyl-3-n-propylprolinol (4c)
IR (CHCl3): 3444, 3046, 1592, 1221, 758 cm–1.
Yield: 80%.
IR (CHCl3): 3401, 2968, 1592, 1221, 758 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.34–7.25 (m, 5 H), 4.00 (d, J =
13.0 Hz, 1 H), 3.72 (dd, J = 3.0, 11.0 Hz, 1 H), 3.51 (dd, J = 2.0,
11.0 Hz, 1 H), 3.35 (d, J = 13.0 Hz, 1 H), 2.99–2.95 (m, 1 H), 2.40
(dd, J = 9.0, 17.5 Hz, 1 H), 2.33 (br s, 1 H), 2.15–2.09 (m, 1 H),
1.92–1.84 (m, 1 H), 1.44–1.23 (m, 6 H), 0.92 (t, J = 7.0 Hz, 3 H).
1H NMR (300 MHz, CDCl3): d = 7.32–7.16 (m, 9 H), 4.03 (d, J =
12.0 Hz, 1 H), 3.67 (dd, J = 3.0, 12.0 Hz, 1 H), 3.47 (d, J = 12.0 Hz,
1 H), 3.39 (d, J = 12.0 Hz, 1 H), 3.38–3.32 (m, 1 H), 3.19–3.13 (m,
1 H), 2.77–2.63 (m, 2 H), 2.33 (br s, 1 H), 2.24–2.18 (m, 1 H), 1.94–
1.89 (m, 1 H).
EI–MS: m/z (%) = 91 (100), 236, (20), 270 (4), 301 (1) [M+].
13C NMR (125 MHz, CDCl3): d = 139.22, 128.79 (2 C), 128.38 (2
C), 127.21, 71.54, 60.08, 58.57, 52.82, 39.94, 37.28, 29.51, 21.09,
14.23.
HRMS (EI): m/z [M+ – 31] calcd for C17H17ClN: 270.1044; found:
270.1045.
EI–MS: m/z (%) = 91 (100), 202 (72), 233 (1) [M+].
HRMS (EI): m/z calcd for C14H20N [M+ – 31]: 202.1590; found:
1-Benzyl-3-(3-cyclopentyloxy-4-methoxyphenyl)prolinol (4h)
Yield: 81%.
IR (CHCl3): 3432, 1592, 1221, 760 cm–1.
202.1591.
1H NMR (500 MHz, CDCl3): d = 7.35–7.26 (m, 5 H), 6.82–6.74 (m,
3 H), 4.78–4.76 (m, 1 H), 4.06 (d, J = 13.0 Hz, 1 H), 3.83 (s, 3 H),
3.71 (dd, J = 3.0, 11.5 Hz, 1 H), 3.51 (d, J = 11.0 Hz, 1 H), 3.44 (d,
J = 13.0 Hz, 1 H), 3.29 (dd, J = 9.0, 16.5 Hz, 1 H), 3.17–3.12 (m, 1
H), 2.69–2.64 (m, 2 H), 2.22–2.15 (m, 1 H), 1.94–1.81 (m, 8 H),
1.65–1.59 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 149.22, 147.65, 138.54, 137.44,
128.77 (2 C), 128.43 (2 C), 127.25, 119.58, 114.97, 112.15, 80.45,
73.26, 58.62, 58.11, 56.15, 53.69, 45.60, 32.82 (2 C), 31.83, 24.03
(2 C).
Anal. Calcd for C15H23NO: C, 77.21; H, 9.93. Found: C, 77.32; H,
9.98.
1-Benzyl-3-dimethoxymethylprolinol (4d)
Yield: 82%.
IR (CHCl3): 3448, 2953, 1608, 1067, 742 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.33–7.26 (m, 5 H), 4.25 (d, J =
7.5 Hz, 1 H), 4.01 (d, J = 13.0 Hz, 1 H), 3.68 (dd, J = 4.0, 11.0 Hz,
1 H), 3.61 (dd, J = 2.0, 11.0 Hz, 1 H), 3.39 (s, 3 H), 3.38 (br s, 1 H),
3.36 (d, J = 13.0 Hz, 1 H), 3.32 (s, 3 H), 2.94 (t, J = 7.5 Hz, 1 H),
2.64 (br s, 1 H), 2.53–2.47 (m, 1 H), 2.38–2.33 (m, 1 H), 1.87–1.79
(m, 1 H), 1.71–1.66 (m, 1 H).
EI–MS: m/z (%) = 91 (100), 190 (8), 350 (58), 381 (1) [M+].
HRMS (EI): m/z calcd for C23H28NO2 [M+ – 31]: 350.2115; found:
13C NMR (125 MHz, CDCl3): d = 138.43, 128.85 (2 C), 128.36 (2
C), 127.24, 106.70, 67.14, 61.64, 58.40, 54.91, 53.17, 52.47, 43.34,
25.41.
350.2116.
Anal. Calcd for C24H31NO3: C, 75.56; H, 8.19. Found: C, 75.71; H,
8.03.
EI–MS: m/z (%) = 75 (100), 91 (80), 234 (29), 265 (1) [M+].
4-Sulfonylprolinols 5 by Alane Reduction; General Procedure
A solution of 3b, 3d or 3h (0.8 mmol) in THF (10 mL) was added
to a solution of LiAlH4 (57 mg, 1.5 mmol) and AlCl3 (214 mg, 1.6
mmol) in THF (10 mL) via syringe at 0 °C. The mixture was re-
fluxed for 2 h, quenched with aq NH4Cl (1 mL) under cooling, and
concentrated. The residue was diluted with water (15 mL) and ex-
tracted with EtOAC (3 × 30 mL). The organic layer was washed
with brine and water, dried, filtered and concentrated to produce
crude compound. Purification on silica gel (hexane–EtOAc 1:1 →
1:2) produced 5b, 5d or 5h.
HRMS (EI): m/z calcd for C14H20NO2 [M+ – 31]: 234.1489; found:
234.1490.
Anal. Calcd for C15H23NO3: C, 67.90; H, 8.74. Found: C, 67.96; H,
8.62.
1-Benzyl-3-phenylprolinol (4e)
Yield: 73%.
IR (CHCl3): 3466, 1607, 1268, 742 cm–1.
1H NMR (500 MHz, CDCl3) d = 7.36–7.23 (m, 10 H), 4.06 (d, J =
13.0 Hz, 1 H), 3.71 (dd, J = 3.0, 11.5 Hz, 1 H), 3.49 (d, J = 11.0 Hz,
1 H), 3.43 (d, J = 13.0 Hz, 1 H), 3.37 (dd, J = 9.0, 16.5 Hz, 1 H),
3.16 (td, J = 4.0, 9.5 Hz, 1 H), 2.74–2.66 (m, 2 H), 2.25–2.17 (m, 1
H), 2.10 (br s, 1 H), 1.95–1.89 (m, 1 H).
1-Benzyl-3-methyl-4-(4-methylphenylsulfonyl)prolinol (5b)
Yield: 81%.
IR (CHCl3): 3494, 1623, 1299, 1144, 758 cm–1.
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M.-Y. Chang et al.
PAPER
1H NMR (500 MHz, CDCl3): d = 7.69 (d, J = 8.0 Hz, 2 H), 7.31–
7.27 (m, 5 H), 7.13 (d, J = 6.5 Hz, 2 H), 3.92 (d, J = 13.5 Hz, 1 H),
3.74 (dd, J = 2.5, 11.5 Hz, 1 H), 3.47 (dd, J = 11.5 Hz, 1 H), 3.37
(dd, J = 2.0, 12.0 Hz, 1 H), 3.16 (ddd, J = 2.5, 6.0, 8.5 Hz, 1 H), 3.08
(d, J = 13.5 Hz, 1 H), 2.73–2.66 (m, 1 H), 2.61 (dd, J = 9.5, 12.0 Hz,
1 H), 2.45 (s, 3 H), 2.26 (br s, 1 H), 2.22 (d, J = 8.5 Hz, 1 H), 1.06
(d, J = 7.0 Hz, 3 H).
mixture was poured into Et3N (253 mg, 2.5 mmol) in an ice bath for
10 h. 2 N HCl (5 mL) was poured into the mixture and then stirred
for 2 h at reflux temperature. The residue was diluted with sat. aq
NaHCO3 (2 × 5 mL) and extracted with EtOAc (3 × 30 mL). The
combined organic layers were dried, filtered and evaporated. Puri-
fication on silica gel (hexane–EtOAc, 2:1) yielded 7 or 8.
1-Benzyl-4-formyl-1,2,3,6-tetrahydropyridine (7)
Yield: 44%.
IR (CHCl3): 3008, 2840, 1758, 1178 cm–1.
13C NMR (125 MHz, CDCl3): d = 144.69, 137.29, 134.27, 129.66
(2 C), 129.17 (2 C), 128.35 (4 C), 127.32, 72.18, 68.29, 57.62,
56.55, 53.17, 35.86, 21.56, 18.23.
EI–MS: m/z (%) = 91 (100), 172 (83), 328 (8), 359 (1) [M+].
HRMS (EI): (m/z) calcd for C19H22NO2S [M+ – 31]: 328.1366;
1H NMR (500 MHz, CDCl3): d = 9.48 (s, 1 H), 7.35–7.27 (m, 5 H),
6.72 (t, J = 1.5 Hz, 1 H), 3.67 (br s, 2 H), 3.28 (br s, 2 H), 2.64 (br
s, 2 H), 2.37 (br s, 2 H).
13C NMR (125 MHz, CDCl3): d = 192.82, 139.54, 130.10, 129.10
(2 C), 128.42 (3 C), 127.42, 62.25, 52.87, 48.69, 22.34.
found: 328.1368.
Anal. Calcd for C20H25NO3S: C, 66.82; H, 7.01. Found: C, 66.94; H,
6.89.
EI–MS: m/z (%) = 91 (100), 110 (56), 201 (44) [M+ + 1].
1-Benzyl-3-dimethoxymethyl-4-(4-methylphenylsulfonyl)proli-
nol (5d)
Yield: 74%; mp 162–163 °C.
HRMS (ESI): m/z calcd for C13H15NO [M+]: 201.1154; found:
201.1160.
IR (CHCl3): 3479, 3030, 1608, 1221, 1067, 760 cm–1.
1-Benzyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (8)
Yield: 41%.
IR (CHCl3): 3030, 1623, 1237, 742 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.70 (d, J = 8.5 Hz, 2 H), 7.34–
7.24 (m, 7 H), 4.29 (br s, 1 H), 3.97 (d, J = 13.0 Hz, 1 H), 3.70 (d,
J = 11.5 Hz, 1 H), 3.55 (d, J = 11.5 Hz, 1 H), 3.56–3.48 (m, 1 H),
3.35 (s, 6 H), 3.40–3.30 (m, 3 H), 3.06–3.03 (m, 1 H), 2.85 (br s, 1
H), 2.62 (br s, 1 H), 2.44 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 144.92, 134.23, 129.76 (2 C),
129.12 (4 C), 128.48 (3 C), 127.61, 105.71, 65.80, 63.46, 60.13,
56.93, 56.23, 55.31, 53.80, 43.74, 21.62.
1H NMR (500 MHz, CDCl3): d = 7.41–7.34 (m, 5 H), 7.31–7.28 (m,
2 H), 7.03–6.99 (m, 2 H), 6.03–6.01 (m, 1 H), 3.66 (s, 2 H), 3.19–
3.17 (m, 2 H), 2.73 (t, J = 7.0 Hz, 2 H), 2.56–2.54 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 162.90, 160.95, 138.11, 136.93,
136.90, 133.96, 129.16, 128.23, 127.09, 126.37, 126.31, 121.74,
115.05, 114.88, 62.64, 53.18, 49.83, 28.12.
EI–MS: m/z (%) = 91 (100), 267 (23) [M+].
HRMS (EI): m/z calcd for C18H18FN [M+]: 267.1418; found:
EI–MS: m/z (%) = 75 (89), 91 (100), 158 (92), 388 (9), 419 (1) [M+].
HRMS (EI): m/z calcd for C21H26NO4S [M+ – 31]: 388.1577; found:
388.1580.
267.1421.
Anal. Calcd for C22H29NO5S: C, 62.98; H, 6.97. Found: C, 63.11; H,
7.11.
Preparation of Compound 9; Typical Procedure
A solution of 8 (134 mg, 0.5 mmol) in 1,2-dichloroethane (5 mL)
was added to a mixture solution of pyridinium dichromate (750 mg,
2.0 mmol), anhyd NaOAc (164 mg, 2.0 mmol) and Celite (800 mg)
in 1,2-dichloroethane (5 mL). After being stirred at reflux tempera-
ture for 2 d, the mixture was filtered through a short silica gel col-
umn. The filtrate was dried, filtered and evaporated. Without further
purification, 10% Pd/C (100 mg) was added to the solution of the
resulting product (70 mg) in the co-solvent of EtOAc and MeOH
(10 mL, 4:1). Then hydrogen was bubbled into the mixture for 10
min, and the reaction mixture was continued to stir for 12 h at r.t.
The catalyst was filtered through a short plug of Celite and washed
with EtOAc (2 × 10 mL), and the filtrate purification on silica gel
(hexane–EtOAc 3:1 → 1:1) yielded 9 (61 mg, 43%).
1-Benzyl-3-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-meth-
ylphenylsulfonyl)prolinol (5h)
Yield: 69%; mp 152–153 °C.
IR (CHCl3): 3494, 3046, 1608, 1221, 1144, 761 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.65 (d, J = 8.5 Hz, 2 H), 7.37–
7.22 (m, 7 H), 6.70 (d, J = 8.0 Hz, 1 H), 6.56 (dd, J = 1.5, 8.0 Hz, 1
H), 6.50 (d, J = 1.5 Hz, 1 H), 4.66–4.64 (m, 1 H), 4.03 (d, J = 13.0
Hz, 1 H), 3.79 (s, 3 H), 3.75 (dd, J = 2.0, 12.0 Hz, 1 H), 3.69 (dd,
J = 6.0, 8.5 Hz, 1 H), 3.64 (brs, 1 H), 3.63 (d, J = 8.0 Hz, 1 H), 3.41
(d, J = 12.0 Hz, 1 H), 3.27 (d, J = 13.0 Hz, 1 H), 2.89 (dd, J = 9.5,
12.0 Hz, 1 H), 2.71 (d, J = 8.5 Hz, 1 H), 2.45 (br s, 1 H), 2.40 (s, 3
H), 1.90–1.82 (m, 6 H), 1.64–1.61 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 149.13, 147.59, 144.63, 137.14,
134.53, 132.76, 129.62 (2 C), 129.03 (2 C), 128.52 (2 C), 128.48 (2
C), 127.47, 119.63, 114.88, 112.10, 80.39, 73.15, 68.86, 57.36,
56.55, 56.05, 53.88, 46.77, 32.80, 32.73, 24.03, 23.99, 21.57.
EI–MS: m/z (%) = 91 (100), 348 (14), 504 (3), 535 (1) [M+].
HRMS (EI): m/z calcd for C30H34NO4S [M+ – 31]: 504.2203; found:
1-Benzyl-4-(4-fluorophenyl)piperidin-2-one (9)
IR (CHCl3): 3027, 1618 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.35–7.19 (m, 9 H), 4.74 (d, J =
14.5 Hz, 1 H), 4.57 (d, J = 14.5 Hz, 1 H), 3.33–3.24 (m, 2 H), 3.12–
3.06 (m, 1 H), 2.80 (ddd, J = 2.0, 5.5, 17.0 Hz, 1 H), 2.55 (dd, J =
11.0, 17.0 Hz, 1 H), 2.08–2.03 (m, 1 H), 1.94–1.86 (m, 1 H).
13C NMR (125 MHz, CDCl3): d = 169.04, 162.57, 160.62, 139.05,
139.02, 136.98, 128.60, 128.14, 127.93, 127.87, 127.44, 115.57,
115.41, 49.98, 46.19, 39.57, 37.94, 30.26.
504.2201.
Anal. Calcd for C31H37NO5S: C, 69.50; H, 6.96. Found: C, 70.03; H,
7.17.
EI–MS: m/z (%) = 91 (100), 106 (100), 283 (3) [M+].
HRMS (EI): m/z calcd for C18H18FNO [M+]: 283.1367; found:
283.1362.
General Ring Expansion of Prolinols 4d and 4f with MsCl–Et3N
Methanesulfonyl chloride (230 mg, 2.0 mmol) was added to the so-
lution of prolinol 4d or 4f (1.0 mmol) in CH2Cl2 (10 mL) and the
mixture was stirred at reflux temperature. After 5 h, the resulting
Synthesis 2004, No. 6, 840–846 © Thieme Stuttgart · New York

PAPER
New Synthesis and Application of 3-Substituted Prolinols
845
Oxidation of Prolinols 4e–g with RuCl3 and NaIO4; General
Procedure
Anal. Calcd for C18H16ClNO3: C, 65.56; H, 4.89. Found: C, 65.83;
H, 4.77.
Compound 4e–g (0.2 mmol) was dissolved in CCl4 (2 mL), MeCN
(2 mL) and water (3 mL) with vigorous stirring. Then sodium peri-
odate (210 mg, 1.0 mmol) and ruthenium(III) chloride hydrate (5
mg) were added. The reaction was stopped after 6 h, diluted with
CH2Cl2 (10 mL) and the organic layer was separated. The aqueous
layer was then extracted with CH2Cl2 (2 × 10 mL) and the organic
layers were filtered on a Celite pad, collected and concentrated. Pu-
rification on silica gel (EtOAc–MeOH 9:1) produced 10e–g.
Acknowledgment
Financial support from the National Science Council of the Repub-
lic of China is gratefully acknowledged.
References
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1-Benzyl-3-phenylpyroglutamic Acid (10e)
Yield: 65%; mp 165–166 °C.
IR (CHCl3): 3440, 3030, 1221, 761 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.27–7.17 (m, 8 H), 7.06–7.03 (m,
2 H), 6.70 (br s, 1 H), 5.18 (d, J = 14.7 Hz, 1 H), 3.98 (d, J = 14.7
Hz, 1 H), 3.95 (d, J = 3.3 Hz, 1 H), 3.59 (td, J = 3.3, 9.4 Hz, 1 H),
3.05 (dd, J = 9.4, 17.4 Hz, 1 H), 2.58 (dd, J = 3.6, 17.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 175.07, 174.00, 142.23, 135.05,
129.00, 128.76, 128.71 (2 C), 128.00, 127.52, 126.39 (4 C), 66.18,
45.88, 41.08, 37.84.
EI–MS: m/z (%) = 91 (100), 104 (35), 250 (26), 295 (7) [M+].
HRMS (EI): m/z [M+] calcd for C18H17NO3: 295.1203; found:
295.1204.
Anal. Calcd for C18H17NO3: C, 73.20; H, 5.80. Found: C, 73.58; H,
6.03.
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1-Benzyl-3-(4-fluorophenyl)pyroglutamic Acid (10f)
Yield: 57%; mp 157–158 °C.
IR (CHCl3): 3440, 3031, 1210, 758 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.55 (br s, 1 H), 7.29–7.17 (m, 5
H), 7.02–6.98 (m, 2 H), 6.94–6.89 (m, 2 H), 5.20 (d, J = 14.7 Hz, 1
H), 3.98 (d, J = 14.7 Hz, 1 H), 3.92 (d, J = 3.0 Hz, 1 H), 3.61 (td,
J = 3.3, 9.4 Hz, 1 H), 3.09 (dd, J = 9.4, 17.4 Hz, 1 H), 2.58 (dd, J =
3.6, 17.4 Hz, 1 H).
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Hosoi, A.; Nozoe, S. Tetrahedron Lett. 1988, 29, 329.
(c) Attwood, M. R.; Carr, M. G.; Jordan, S. Tetrahedron
Lett. 1990, 31, 283.
13C NMR (100 MHz, CDCl3): d = 175.29, 173.30, 163.5, 160.81,
137.92, 137.88, 134.83, 128.85, 128.69, 128.17, 128.04, 127.96,
115.98, 115.76, 66.38, 45.98, 40.47, 37.93.
EI–MS: m/z (%) = 91 (100), 268 (19), 313 (7) [M+].
(8) (a) Chang, M. Y.; Chen, S. T.; Chang, N. C. Heterocycles
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Synth. Commun. 2003, 33, 1375.
HRMS (EI): m/z [M+] calcd for C18H16FNO3: 313.1109; found:
313.1111.
Anal. Calcd for C18H16FNO3: C, 69.00; H, 5.15. Found: C, 68.88; H,
5.22.
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1-Benzyl-3-(4-chlorophenyl)pyroglutamic Acid (10g)
Yield: 52%; mp 168–169 °C.
IR (CHCl3): 3442, 3030, 1221, 742 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.60 (br s, 1 H), 7.28–7.25 (m, 3
H), 7.20–7.17 (m, 4 H), 6.98–6.95 (m, 2 H), 5.20 (d, J = 14.7 Hz, 1
H), 3.98 (d, J = 14.7 Hz, 1 H), 3.91 (d, J = 3.0 Hz, 1 H), 3.58 (td,
J = 3.2, 9.4 Hz, 1 H), 3.08 (dd, J = 9.4, 17.5 Hz, 1 H), 2.56 (dd, J =
3.5, 17.5 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 175.04, 173.31, 140.62, 134.82,
133.42, 129.15 (2 C), 128.88 (2 C), 128.72, 128.20 (2 C), 127.76 (2
C), 66.07, 45.98, 40.53, 37.82.
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references cited therein.
EI–MS: m/z (%) = 91 (100), 284 (17), 329 (6) [M+].
HRMS (EI): m/z calcd for C18H16ClNO3 [M+]: 329.0813; found:
329.0819.
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M.-Y. Chang et al.
PAPER
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Synthesis 2004, No. 6, 840–846 © Thieme Stuttgart · New York