An enantiodivergent and formal synthesis of paroxetine enantiomers by asymmetric desymmetrization of 3-(4-fluorophenyl)glutaric anhydride with a chiral SuperQuat oxazolidin-2-one

Article abstract of DOI:10.1016/j.tetasy.2012.08.001

The asymmetric desymmetrization of 3-(4-fluorophenyl)glutaric anhydride 9 with lithiated chiral oxazolidin-2-one 8 has been studied. The desymmetrized product was formed with >90% de and converted into known intermediates for both (+)- and (-)-paroxetines.

Full text of DOI:10.1016/j.tetasy.2012.08.001

Tetrahedron: Asymmetry 23 (2012) 1206–1212
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An enantiodivergent and formal synthesis of paroxetine enantiomers by
asymmetric desymmetrization of 3-(4-fluorophenyl)glutaric anhydride with
a chiral SuperQuat oxazolidin-2-one
⇑
Narendra R. Chaubey, Sunil K. Ghosh
Bio-Organic Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 July 2012
Accepted 2 August 2012
The asymmetric desymmetrization of 3-(4-fluorophenyl)glutaric anhydride 9 with lithiated chiral oxaz-
olidin-2-one 8 has been studied. The desymmetrized product was formed with >90% de and converted
into known intermediates for both (+)- and (ꢀ)-paroxetines.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
The asymmetric desymmetrization of symmetric anhydrides16–
19 has been a particular focus of interest because the enantioselec-
The piperidine ring system is widely found in biologically active
natural products as well as in many synthetic drugs.1,2 As a conse-
quence, a considerable amount of synthetic effort has been made
to develop the enantioselective syntheses of piperidine deriva-
tives,3–6 especially for 4-arylpiperidines such as paroxetine 1,
femoxetine 2 and Roche-1 3 (Fig. 1).7 (ꢀ)-Paroxetine 1 (PaxilÒ) is
a trans-3,4-disubstituted piperidine and is a selective serotonin
(5-hydroxy-tryptamine, 5-HT) reuptake inhibitor, which is used
tive total synthesis of a number of classes of natural products has
been achieved based on this reaction. Recently we introduced a
general method for the desymmetrization of 3-substituted glutaric
anhydrides20,21 and meso-anhydrides22 using lithiated chiral oxaz-
olidin-2-ones 4–8 (Fig. 2) with varying and divergent diastereose-
lectivity depending upon the structure of the anhydrides,
oxazolidin-2-ones and reaction conditions. Some of these interme-
diates have also been applied to the synthesis of hydroxylated pyr-
rolidine23,24 and piperidine25 based natural products. We were
interested in the asymmetric synthesis of 4-arylpiperidine based
bio-active molecules such as 1–3 based on the asymmetric desym-
metrization of 3-aryl substituted glutaric anhydrides and chose
paroxetine 1 as the target. Herein we report a strategy involving
for the treatment of depression, anxiety, and panic disorders.8
A
large number of enantioselective synthetic methods have been re-
ported7,9–15 for (ꢀ)-1 including resolutions, chiral auxiliaries, chiral
bases, use of the chiral pool, enantioselective catalysis, and enzy-
matic asymmetrizations.
F
Cl
O
MeO
O
MeO
O
O
O
N
N
H
N
Me
Me
1
2
3
paroxetine
femoxetine
Roche-1
Figure 1. Biologically active 4-arylpiperidines.
⇑
Corresponding author. Tel.: +91 22 25595012; fax: +91 22 25505151.
E-mail address: ghsunil@barc.gov.in (S.K. Ghosh).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.08.001

N. R. Chaubey, S. K. Ghosh / Tetrahedron: Asymmetry 23 (2012) 1206–1212
1207
F
F
F
F
F
O
O
O
O
O
O
N
H
O
N
N
O
N
H
O
O
O
Bn
Bn
(-)-1
(+)-10
9
(-)-10
(+)-1
Scheme 1. Retrosynthetic analyses for paroxetine enantiomers.
F
O
F
F
CH2(CO2Me)2
NaCH(CO2Me)2
77%
HN
O
piperidinium
benzoate
CO2Me
CO2Me
R1
R2
R1
77%
CHO
1
2
4
; R = H; R = PhCH2-
11
5; R1 = H; R2 = Me2CH-
O
O
O
F
1
2
6
; R = H; R = Ph2CH-
F
7; R1= Ph; R2 = Me2CH-
9
1
8
; R = 2-MeO-5-Me-C6H3-;
R2 = Me2CH-;
1. KOH
2. H3O+
3. Ac2O
Figure 2. Structures of oxazolidin-2-ones 4–8 and anhydride 9.
MeO2C
CO2Me
CO2Me
65%
O
O
O
the asymmetric desymmetrization of 3-(4-fluorophenyl)glutaric
anhydride 9 with a SuperQuat26 oxazolidin-2-one 8 as the key step
for the synthesis of piperidones (+)-10 and (ꢀ)-10 (Scheme 1), key
intermediates for (ꢀ)-paroxetine 1 and its enantiomer (+)-1.
MeO2C
9
12
Scheme 2. Synthesis of anhydride 9.
2. Results and discussion
[DMPU = 1,3-dimethyl-3,4,5,6-tetrahydropyrimidin-2(1H)-one]
(4/1) to give a quantitative mixture of diastereoisomeric acids 13a
and 13b in a ratio of 95:521 (estimated by 1H NMR spectroscopy
after diazomethane esterification) (Scheme 3).
(ꢀ)-Paroxetine 1 has previously been synthesized by the asym-
metric desymmetrization of 3-(4-fluorophenyl)glutaric anhydride
9 with (S)-methylbenzylamine.27 Although this reported asymmet-
ric desymmetrization selectivity was highly improved over Sch-
wartz and Carter0s28 first published selectivity, the chiral amine
was not recoverable due to its destruction during its removal.
We have recently reported that (S)-valine-derived SuperQuat oxaz-
olidin-2-one 8 is a good reagent for the asymmetric desymmetriza-
tion of 3-substituted glutaric21 and other anhydrides.22 There are
certain advantages when using 5,5-disubstituted oxazolidin-2-
ones, also known as SuperQuats. They have been used as chiral
auxiliaries mainly to obviate problems such as purification of prod-
ucts by crystallization, and to limit endocyclic cleavage during re-
moval, which is known to be problematic with Evans’ oxazolidin-
2-one.29 It is also important to note the general importance of
these auxiliary types, due to their superior exo cleavage,30 confor-
mational bias,31 and versatility.32 More recently, other research
groups have used these auxiliaries and shown them to be excellent
and versatile.
We prepared 4-isopropyl-5,5-diaryloxazolidin-2-one 8 from
(S)-valine following the reported procedure.21,33 Anhydride 9 was
synthesized from 4-fluorobenzaldehyde as shown in Scheme 2. Di-
methyl 4-fluorobenzylidene malonate 11, the Knoevenagel con-
densation product of 4-fluorobenzaldehyde and dimethyl
malonate, upon treatment with dimethyl malonate/NaOMe gave
tetraester 12 (77%). This tetraester, upon hydrolysis and decarbox-
ylation, gave the intermediate diacid, which when treated with
acetic anhydride gave the anhydride 9 (65%).
For the synthesis of (ꢀ)-paroxetine 1, the mixture of acids 13a
and 13b obtained from the asymmetric desymmetrization experi-
ment was converted into benzyl amide 14 (85%) after which oxaz-
olidin-2-one 8 was removed using LiOH/H2O2 with 92% recovery of
8. The resulting acid 15 (79%) was converted into alcohol 16 (94%)
via mixed anhydride formation with isobutyl chloroformate fol-
lowed by sodium borohydride reduction. The alcohol group was
tosylated and subsequently subjected to known27 cyclization con-
ditions using NaH in THF to give the known piperidone (+)-1034,35
(65%), from which (ꢀ)-paroxetine 1 has already been synthesized
(Scheme 4).35 In comparison to the literature value, the lower spe-
cific rotation value of 10 {½a D23
ꢁ
¼ þ7:8 (c 0.9, CHCl3) lit.34
:
½
a 2D1
ꢁ
¼ þ34 (c 1.09, CHCl3) for a sample of 99% ee} surprised us.
We checked the enantiomeric purity of 10 by HPLC using a chiral
column (AD-H) and the enantiomeric excess was found to be
ꢂ9%. The experiment was repeated a few times wherein the spe-
cific rotation value of 10 varied between +7.8 to +16. This indicated
that a significant amount of epimerization at the benzylic position
had taken place during the process because we had started with an
asymmetric desymmetrization product with a de P90%.
We envisaged that epimerization of the benzylic centre could
happen during the use of strong bases in the oxazolidin-2-one 8 re-
moval with LiOH/H2O2 and/ or NaH-mediated cyclization of the
tosylate derived from alcohol 16. In order to determine in which
step the epimerization took place, we reacted the mixture of acids
13a and 13b, obtained from the asymmetric desymmetrization
experiment, with (S)-methylbenzylamine in the presence of DCCI
to give the corresponding amide 17 (77%); the oxazolidin-2-one
The lithiated oxazolidin-2-one 8 in THF was made using n-BuLi
at 0 °C and reacted with anhydride 9 at ꢀ78 °C in THF-DMPU

1208
N. R. Chaubey, S. K. Ghosh / Tetrahedron: Asymmetry 23 (2012) 1206–1212
F
F
O
1. n-BuLi, THF-DMPU,
-78°C
O
HN
O
O
O
O
O
O
+
R1
2.
9
HO
N
O
HO
N
O
R1
R1
R1
R1
R1
8; R1 = 2-MeO-5-Me-C6H3-
13a
1
1
; R = 2-MeO-5-Me-C6H3-
13b
; R = 2-MeO-5-Me-C6H3-
Scheme 3. Desymmetrization of anhydride 9 with SuperQuat oxazolidin-2-one 8.
F
F
LiOH, H2O2
THF/H2O
O
O
O
BnNH2, DCCI, DMAP,
CH2Cl2
O
O
13a
+
13b
BnHN
N
O
79%
BnHN
F
OH
85%
R1
15
R1
1
14
; R = 2-MeO-5-Me-C6H3-
F
1. i-BuOCOCl
1. TsCl, pyridine
2. NaH, THF, 80°C
Et3N, CH2Cl2
2. NaBH4
O
65%
94%
BnHN
OH
O
N
Bn
(+)-10
16
Scheme 4. Synthesis of (+)-10, a key intermediate for (ꢀ)-paroxetine 1.
8 was subsequently removed using LiOH/H2O2 to give the known
acid 18 (91%) (Scheme 5).27 The specific rotation of amide 18
lithiated chiral SuperQuat oxazolidin-2-one as the key step. The
chiral reagent, SuperQuat oxazolidin-2-one is recoverable and
recyclable. We have found for the first time that the benzylic ste-
reogenic centre is prone to epimerization under drastic conditions,
such as the use of NaH at elevated temperatures. Although NaH has
frequently been used in the synthesis of paroxetine,, no one has
encountered or reported an epimerization at the benzylic centre.
{½a 2D6
ꢁ
¼ ꢀ74 (c 1, MeOH); lit.27: ½a D25
¼ ꢀ78 (c 1, MeOH)} was in
ꢁ
close agreement with the literature value, indicating that the oxaz-
olidin-2-one removal took place without any epimerization thus
confirming that NaH-mediated cyclization was the problematic
step.
For the synthesis of (+)-paroxetine 1, the mixture of diastereo-
isomeric acids 13a and 13b, obtained from the asymmetric desym-
metrization of anhydride 9 with lithiated oxazolidin-2-one 8, was
converted into alcohol 19 (96%) by selective reduction of the car-
boxylic acid group to the alcohol using the borane–dimethyl sul-
phide complex in THF. Alcohol 19 was converted into the
intermediate mesylate and subsequently reacted with benzyl-
amine to give the known piperidone (ꢀ)-1035 (78%) from which
(+)-paroxetine 1 has already been synthesized (Scheme 6).35 The
enantiomeric purity of (ꢀ)-10 has also been checked by HPLC using
a chiral column (AD-H) and the enatiomeric excess was found to be
89%. During the process, oxazolidin-2-one 8 was also recovered
(87% recovery).
4. Experimental
4.1. General
All reactions were performed in oven-dried (120 °C) or flame-
dried glass apparatus under dry N2 or an argon atmosphere. Tetra-
hydrofuran (THF) was dried from sodium/benzophenone. n-BuLi
(1.5 M in hexane) was purchased from Aldrich. Oxazolidin-2-one
8 was prepared following our published procedure.21 Column chro-
matography was performed on silica gel (230–400 mesh). The 1H
NMR and 13C NMR spectra were recorded with Bruker 200/300/
500/700 MHz spectrometers. The spectra were referenced to resid-
ual chloroform (d 7.25 ppm, 1H; d 77.00 ppm, 13C). High resolution
mass spectra (HRMS) were recorded with a Waters Micromass Q-
TOF spectrometer (ESI, Ar). The IR spectra were recorded with a
JASCO FT IR spectrophotometer in NaCl cells or in KBr discs. Peaks
are reported in cmꢀ1. Melting points (Mp) were determined on a
Fischer John’s melting point apparatus and are uncorrected. Optical
rotations were measured with a JASCO DIP-360 polarimeter. Since
3. Conclusion
In conclusion, a highly stereoselective method for the prepara-
tion of key intermediates for the synthesis of paroxetine enantio-
mers
has
been
described
involving
an
asymmetric
desymmetrization of 3-(4-fluorophenyl)glutaric anhydride with a

N. R. Chaubey, S. K. Ghosh / Tetrahedron: Asymmetry 23 (2012) 1206–1212
1209
F
F
Me
O
Me
O
O
Me
O
O
LiOH, H2O2
THF/H2O
13a
+
Ph
NH2
13b
Ph
N
H
N
O
Ph
N
H
OH
91%
DCCI, DMAP, CH2Cl2
77%
R1
18
R1
17; R1 = 2-MeO-5-Me-C6H3-
Scheme 5. Study of epimerization.
F
F
1. MsCl, Et3N, Tol
2. BnNH2, Et3N
DMF, 100°C
O
O
13a
BH3.Me2S, THF
96%
+
13b
HO
N
O
78%
R1
N
O
R1
Bn
19; R1 = 2-MeO-5-Me-C6H3-
(-)-10
Scheme 6. Synthesis of (ꢀ)-10, a key intermediate for (+)-paroxetine 1.
the 5,5-aryl groups in oxazolidin-2-one 8 are diastereotopic and
magnetically non equivalent, some of the aromatic protons and
carbons for these aryls are discernable by NMR. Similar NMR dif-
ferences of the aryl groups were also observed for acylated oxazoli-
din-2-ones 13a, 14, 17 and 19 (vide infra).
tetraester 12 (18 g, 77%). Mp 90–92 °C. Rf = 0.17 (hexane/ethyl ace-
tate, 10/90); IR (CHCl3 film) 3006, 2955, 2846, 1738, 1605, 1510,
1435 cmꢀ1
;
1H NMR (200 MHz, CDCl3) d 3.48 (s, 6H, 2 ꢃ CO2Me),
3.68 (s, 6H, 2 ꢃ CO2Me), 4.05–4.24 (m, 3H, 3 ꢃ CH), 6.89–6.99 (m,
2H, Ar), 7.22–7.31 (m, 2H, Ar); 13C NMR (50 MHz, CDCl3) d 43.2,
52.2 (2C), 52.6 (2C), 54.6 (2C), 114.9 (d, J = 21 Hz, 2C), 130.9 (d,
J = 7 Hz, 2C), 133.0, 162.0 (d, J = 245 Hz), 167.6, 167.7, 168.0, 168.1.
4.2. Dimethyl-2-(4-fluorobenzylidine)malonate 11
A mixture of 4-fluorobenzaldehyde (12.7 mL, 120 mmol), di-
methyl malonate (11.4 mL, 100 mmol) and piperidinium benzoate
(6.2 g, 30 mmol) in benzene (120 mL) was refluxed (with Dean-
Stark apparatus) for 24 h. The mixture was cooled and washed
with water. The organic layer was dried over MgSO4 and evapo-
rated to give a crude residue, which was purified by distillation
(125–140 °C/0.3 mmHg) to give 11 (18.2 g, 77%). Rf = 0.38 (hex-
ane/ethyl acetate, 90/10); IR (CHCl3 film) 2954, 1732, 1631, 1602,
1510, 1438 cmꢀ1; 1H NMR (200 MHz, CDCl3) d 3.84 (s, 6H, CO2CH3),
7.02–7.11 (m, 2H, Ar), 7.38–7.45 (m, 2H, Ar), 7.72 (s, 1H, CH-4-F-
Ph); 13C NMR (50 MHz, CDCl3) d 52.6 (2C), 116.0 (d, J = 21.8 Hz,
2C), 125.1, 128.8 (d, J = 3.1 Hz), 131.4 (d, J = 8.7 Hz, 2C), 141.4,
163.8 (d, J = 251.2 Hz), 164.3, 166.9.
4.4. 3-(4-Fluorophenyl)glutaric anhydride 9
Tetraester 12 (17 g, 45.9 mmol) was dissolved in a 10% KOH
solution in ethanol/water (2/1) (170 mL) and heated at reflux for
3 h. The solvent was evaporated under reduced pressure and the
residue was acidified with 10% aqueous sulphuric acid and refluxed
for 6 h. The reaction mixture was saturated with sodium chloride
and extracted with ethyl acetate (3 ꢃ 150 mL). The organic extract
was dried (Na2SO4) and evaporated to give 3-(4-fluorophenyl)glu-
taric acid, which was purified by crystallization (7.1 g, 68%). Mp
146–147 °C (lit.27 Mp 146–146.5 °C).
A solution of the diacid (7.1 g, 31 mmol) in acetic anhydride
(15 mL) was heated at 100 C under nitrogen for 2.5 h. After cooling
to room temperature, the excess acetic anhydride and acetic acid
were removed under high vacuum. The residue was crystallized
from ethyl acetate to give 9 (6.1 g, 95%). Mp 100–101 °C (lit.27
Mp 99 °C). Rf = 0.6 (hexane/ethyl acetate, 60:40); 1H NMR
(200 MHz, CDCl3) d 2.83 (dd, J = 11.2, 17 Hz, 2H, 2 ꢃ CHAHBCO),
3.07 (dd, J = 4.4 Hz, 17.2 Hz, 2H, 2 ꢃ CHAHBCO), 3.35–3.50 (m, 1H,
CH), 7.01–7.25 (m, 4H, Ar); 13C NMR (50 MHz, CDCl3) d 33.3, 37.0
(2C), 116.2 (d, J = 21.5 Hz, 2C), 127.9 (d, J = 8.1 Hz, 2C), 134.9 (d,
J = 3 Hz), 162.1 (d, J = 245.6 Hz), 165.8 (2C).
4.3. Tetramethyl-2-(4-fluorophenyl)propane-1,1,3,3-tetracarb
oxylate 12
A solution of dimethyl malonate (9.7 mL, 85 mmol) in dry
MeOH (10 mL) was added to a stirred solution of sodium methox-
ide [prepared using sodium (1.96 g, 85 mmol) in dry methanol] in
dry MeOH (20 mL) at 0 °C under an argon atmosphere. After the
addition was over, the mixture was stirred at room temperature
for 30 min. A solution of malonate 11 (15 g, 63 mmol) in dry MeOH
(20 mL) was added to the above mixture at 0 °C and the mixture
was stirred at room temperature for 3 d. The solvent was evapo-
rated and the residue was dissolved in ethyl acetate. The mixture
was neutralized with dilute HCl and the organic layer was sepa-
rated. The organic phase was washed with water, dried over MgSO4
and the solvent was evaporated. The residue was purified by
recrystallization (hexane/ethyl acetate) to give white crystals of
4.5. (30R,4S)-5,5-Di(2-methoxy-5-methylphenyl)-3-[3-(4-fluoro-
phenyl)-4-methoxycarbonyl-1-oxobutyl]-4-isopropyloxazolidin-
2-one 13a
n-Butyl lithium (1.8 mL, 1.5 M in hexane, 2.7 mmol) was slowly
added to a suspension of oxazolidin-2-one 8 (922 mg, 2.5 mmol) in
dry THF (12.5 mL) at 0 °C under an argon atmosphere until a clear

1210
N. R. Chaubey, S. K. Ghosh / Tetrahedron: Asymmetry 23 (2012) 1206–1212
solution was obtained (30 min). The reaction mixture was cooled
to ꢀ78 °C and dry DMPU (6 mL) was added followed by a solution
of the anhydride 9 (562 mg, 2.7 mmol) in dry THF (12.5 mL). After
4 h at ꢀ78 °C, the reaction mixture was acidified with 5% citric acid
solution and extracted with ethyl acetate. The extract was concen-
trated under reduced pressure and the residue was dissolved in
benzene. The benzene solution was washed several times with
water, dried over MgSO4 and concentrated under reduced pressure
to give crude 13a (1.5 g, ‘100%’) contaminated with about 5% of its
diastereoisomer 13b (vide infra). A small amount of the residue
was treated with ethereal diazomethane and concentrated under
reduced pressure. The 1H NMR analysis of the resulting methyl es-
ter indicated that the diastereoisomeric ratio was 95:5.
153.6, 156.1, 161.5 (d, J = 243 Hz), 170.4, 170.6; HRMS: Calcd for
40H44FN2O6 (M++H) 667.3183. Found: 667.3201.
C
4.8. (S)-4-(Benzylcarbamoyl)-3-(4-fluorophenyl)butanoic acid
15
Hydrogen peroxide (420 lL, 30% v/v) was added to the solution
of amide 14 (666 mg, 1 mmol) in THF (7.5 mL) and water (3 mL) at
0 °C. Lithium hydroxide (84 mg, 2 mmol) was then added and the
mixture was stirred at 0 °C for 2 h. The mixture was allowed to re-
turn to room temperature and the solvent was evaporated. The res-
idue was diluted with water and filtered. The filtrate was extracted
with chloroform and the aqueous phase was acidified with aque-
ous sodium bisulphate solution. The aqueous phase was extracted
with ethyl acetate, dried over MgSO4 and evaporated to obtain acid
4.6. Data for the methyl ester of 13a
15 (250 mg, 79%). ½a D23
ꢁ
¼ þ1:8 (c 1.1, MeOH); 1H NMR (CDCl3,
Mp 95–98 °C. ½a 2D3
ꢁ
¼ ꢀ173:1 (c 0.84, MeOH); Rf = 0.46 (hexane/
1H
300 MHz) d 1.75 (s, broad, 1H, CO2H), 2.48 (dd, J = 8.1, 14 Hz, 1H,
COCHAHB), 2.67 (dd, J = 5.4, 14 Hz, 1H, COCHAHB), 2.68 (dd, J = 7.2,
14 Hz, 1H, COCHAHB), 2.80 (dd, J = 7.5, 14 Hz, 1H, COCHAHB),
3.63–3.73 (m, 1H, ArCH), 4.27 (dd, J = 5.4, 14.7 Hz, 1H,
CHAHBNHBn), 4.39 (dd, J = 6, 14.7 Hz, 1H, CHAHBNHBn), 5.62 (s,
1H, NH), 6.96–7.03 (m, 4H, Ar), 7.15–7.21 (m, 2H, Ar), 7.26 (s,
broad, 3H, Ar); 13C NMR (175 MHz, CD3OD) d 38.5 (d, J = 14.8 Hz),
40.3, 42.3, 42.4, 114.7 (d, J = 21 Hz, 2C), 126.6, 126.9 (2C), 127.9
(2C), 129.1 (2C), 138.3, 138.5, 161.7 (d, J = 242 Hz), 172.1, 173.9;
HRMS: Calcd for C18H19FNO3 (M++H) 316.1349. Found: 316.1346.
The chloroform extract was evaporated to give oxazolidin-2-one
8 (340 mg, 92%).
ethyl acetate 85/15); IR (KBr) 1765, 1736, 1706, 1504 cmꢀ1
;
NMR (CDCl3, 200 MHz) d 0.69 (d, J = 6.6 Hz, 3H, H3CHCH3), 0.88
(d, J = 6.6 Hz, 3H, CH3CHCH3), 1.55–1.72 (m, 1H, CH3CHCH3), 2.02
(s, 3H, ArCH3), 2.34 (s, 3H, ArCH3), 2.53 (dd, J = 8.2, 15.4 Hz, 1H,
CHAHBCO2Me), 2.65 (dd, J = 6.8, 15.4 Hz, 1H, CHAHBCO2Me), 3.16
(dd, J = 5.6, 17.2 Hz, 1H, NCOCHAHB), 3.36 (dd, J = 9.2, 17.2 Hz, 1H,
NCOCHAHB), 3.39 (s, 3H, ArOCH3), 3.42 (s, 3H, ArOCH3), 3.56 (s,
3H, CO2CH3), 3.66–3.84 (m, 1H, ArCH), 5.70 (d, J = 1.8 Hz, 1H,
NCH), 6.59 (d, J = 8.2 Hz, 1H, Ar), 6.62 (d, J = 8.4 Hz, 1H, Ar), 6.79–
7.04 (m, 5H, Ar), 7.09–7.16 (m, 2H, Ar), 7.65 (d, J = 2 Hz, 1H, Ar);
13C NMR (50 MHz, CDCl3) d 15.9, 20.4, 20.6, 22.4, 29.8, 36.8, 40.4,
41.0, 51.4, 55.3, 55.8, 62.0, 89.2, 111.0, 113.6, 115.1 (d,
J = 21.1 Hz, 2C), 126.4, 127.3, 127.6, 128.5, 128.7, 128.8, 128.9
(2C), 129.1, 130.0, 138.3, 152.6, 153.5, 156.0, 161.4 (d,
J = 243 Hz), 170.6, 171.8; ESI MS: m/z (%) = 592 (10) (M++H), 548
(100); HRMS: Calcd for C34H39NO7F (M++H) 592.2711. Found:
592.2715.
4.9. (R)-N-Benzyl-3-(4-fluorophenyl)-5-hydroxypentanamide 16
Isobutyl chloroformate (160
wise to a solution of acid 15 (315 mg, 1 mmol) and triethylamine
(180
L, 1.3 mmol) in dry THF (12 mL) at ꢀ78 °C. The solution
lL, 1.25 mmol) was added drop-
l
was allowed to return to room temperature and stirred overnight.
The mixture was filtered through a silica gel pad and washed with
a small amount of THF. The filtrate was cooled on an ice-bath and
sodium borohydride (122 mg, 3.2 mmol) was added to it followed
by the dropwise addition of water (0.7 mL). The reaction mixture
was stirred for 4 h and filtered through a Celite pad. After evapora-
tion of the solvent, the aqueous layer was extracted several times
with ethyl acetate. The organic extract was washed with brine,
dried over magnesium sulphate and concentrated to obtain 16
(284 mg, 94%). Rf = 0.16 (hexane/ethyl acetate, 50/50);
4.7. (30R,4S)-5,5-Di(2-methoxy-5-methylphenyl)-3-[3-(4-fluoro
phenyl)-4-benzylcarbamoyl-1-oxobutyl]-4-isopropyloxazoli
din-2-one 14
A solution of DCCI (495 mg, 2.4 mmol) in dry dichloromethane
(5 mL) was added dropwise to a stirred solution of acid 13a
(1.15 g, 2 mmol), benzylamine (260 lL, 2.4 mmol) and DMAP
(12 mg, 0.1 mmol) in dry dichloromethane (10 mL) under argon
atmosphere at 0 °C. The resulting mixture was allowed to return
to room temperature and stirred overnight. The mixture was fil-
tered and the filtrate was evaporated. The resulting residue was
dissolved in ethyl acetate, filtered and the filtrate was evaporated.
This was done several times, after which the resulting residue was
chromatographed to obtain pure amide 14 (1.13 g, 85%). Rf = 0.3
½
a 2D3
ꢁ
¼ ꢀ12:5 (c 0. 4, CHCl3); IR (CHCl3 film) 3437, 3018, 2927,
1658, 1510, 1216 cmꢀ1 1H NMR (CDCl3, 700 MHz) d 1.87–1.91
;
(m, 1H, CHAHBCH2OH), 1.93–1.97 (m, 1H, CHAHBCH2OH), 2.11 (s,
broad, 1H, OH), 2.44 (dd, J = 8.4, 14 Hz, 1H, COCHAHBCH), 2.62
(dd, J = 5.6, 14 Hz, 1H, COCHAHBCH), 3.36–3.42 (m, 1H, ArCH),
3.50–3.55 (m, 1H, CHAHBOH), 3.56–3.62 (m, 1H, CHAHBOH), 4.27
(dd, J = 2.1, 14.7 Hz, 1H, PhCHAHBNH), 4.41 (dd, J = 6.3, 14.7 Hz,
1H, PhCHAHBNH), 5.68 (s, 1H, NH), 6.98–7.00 (m, 2H, Ar), 7.03 (d,
J = 6.3 Hz, 2H, Ar), 7.16–7.21 (m, 2H, Ar), 7.25–7.20 (m, 3H, Ar);
13C NMR (CDCl3, 175 MHz) d 38.3, 38.9, 43.5, 44.0, 60.3, 115.5 (d,
J = 21 Hz, 2C), 127.4, 127.5 (2C), 128.6 (2C), 128.8, 128.9, 137.9,
139.4, 161.6 (d, J = 243 Hz), 171.3; HRMS: Calcd for C18H21FNO2
(M++H) 302.1556. Found: 302.1555.
(hexane/ethyl acetate, 70/30); ½a D23
¼ ꢀ192 (c 0.5, CHCl3); IR
ꢁ
(CHCl3 film) 3010, 2964, 2931, 1771, 1703, 1651, 1504,
1374 cmꢀ1 1H NMR (CDCl3, 300 MHz) d 0.69 (d, J = 6.6 Hz, 3H,
;
CH3CHCH3), 0.88 (d, J = 7.2 Hz, 3H, CH3CHCH3), 1.51–1.53 (m, 1H,
CH3CHCH3), 2.01 (s, 3H, ArCH3), 2.35 (s, 3H, ArCH3), 2.30–2.40
(m, 1H, CHAHBCON) 2.57 (dd, J = 6.1, 14 Hz, 1H, CHAHBCONH),
3.19 (dd, J = 5.1, 17.1 Hz, 1H, CHAHBCON), 3.35–3.5 (m, 1H, CHAHB-
CON), 3.39 (s, 3H, ArOCH3), 3.42 (s, 3H, ArOCH3), 3.79–3.90 (m, 1H,
ArCH), 4.22 (dd, J = 5.2, 14.9 Hz, 1H, PhCHAHBNH), 4.39 (dd, J = 6,
14.7 Hz, 1H, PhCHAHBNH), 5.58 (s, broad, 1H, NH), 5.71 (s, 1H,
NCH), 6.59–6.64 (m, 2H, Ar), 6.81–6.87 (m, 2H, Ar), 6.94–7.05 (m,
6H, Ar), 7.11–7.16 (m, 2H, Ar), 7.23–7.26 (m, 2H, Ar), 7.66 (s, 1H,
Ar); 13C NMR (125 MHz, CDCl3) d 16.0, 20.4, 20.6, 22.4, 29.8, 37.6,
40.4, 43.3, 44.1, 55.3, 55.9, 62.0, 89.3, 111.1, 113.8, 115.2 (d,
J = 21 Hz, 2C), 126.5, 127.3, 127.4, 127.5 (3C), 127.7, 128.5 (2C),
128.6, 128.8, 128.9, 129.0, 129.2, 130.0, 138.0, 138.4, 152.7,
4.10. (R)-1-Benzyl-4-(4-fluorophenyl)piperidin-2-one (+)-10
4-Toluenesulphonyl chloride (109 mg, 0.57 mmol) was added
to a solution of alcohol 16 (171 mg, 0.57 mmol) in dry pyridine
(1 mL) at 0 °C. After 2 days at 0 °C, the reaction mixture was diluted
with water and extracted with dichloromethane. The organic ex-
tract was washed with dilute HCl and water. The organic extract
was dried over magnesium sulphate and concentrated under re-

N. R. Chaubey, S. K. Ghosh / Tetrahedron: Asymmetry 23 (2012) 1206–1212
1211
duced pressure to give the intermediate tosylate. A solution of this
tosylate (214 mg, 0.47 mmol) in dry THF (2.5 mL) was added to a
suspension of NaH (16 mg, 0.66 mmol) at 0 °C under an argon
atmosphere. The mixture was allowed to return to room tempera-
ture and stirred for 2 h. The reaction mixture was slowly cooled in
an ice bath and quenched with methanol (1 mL). After evaporation
of the solvent, the residue was diluted with ethyl acetate and then
washed with brine. The organic layer was filtered through a silica
gel pad. After the removal of solvent, the crude solid was recrystal-
lized from ethyl acetate and hexanes to obtain (+)-10 (86 mg, 65%).
125 MHz) d 20.7, 38.5, 40.0, 42.2, 48.4, 114.6 (d, J = 21 Hz, 2C),
125.7 (2C), 126.6, 128.0 (2C), 129.0 (d, J = 7 Hz, 2C), 138.5, 143.5,
161.7 (d, J = 242 Hz), 171.2, 173.8. The chloroform extract was
evaporated to give oxazolidin-2-one 8 (86 mg, 86%).
4.13. (30R,4S)-5,5-Di(2-methoxy-5-methylphenyl)-3-[3-(4-flu-
orophenyl)-5-hydroxypentyl]-4-isopropyloxazolidin-2-one 19
Borane dimethyl sulphide complex (95 lL, 1 mmol) was slowly
added to a solution of acid 13a (288 mg, 0.5 mmol) (obtained by
desymmetrization of 9 with 8) in dry THF (2.5 mL) at 0 °C. The mix-
ture was allowed to return to room temperature and stirred for
30 min. The mixture was quenched with methanol (1 mL) and
the solvent was evaporated. The residue was purified by column
chromatography to obtain 19 (270 mg, 96%). Rf = 0.39 (hexane/
M. p. 65 °C. Rf = 0.56 (hexane/ethyl acetate, 40/60); ½a D27
¼ þ7:8 (c
ꢁ
0.9, CHCl3); lit.34: ½a D21
¼ þ34 (c 1.09, CHCl3) for a sample of 99% ee;
ꢁ
IR (CHCl3 film) 3009, 2932, 1632, 1511, 1495, 1454, 1217 cmꢀ1; 1H
NMR (CDCl3, 300 MHz) d 1.82–1.94 (m, 1H, CHAHBCH2N), 2.00–2.10
(m, 1H, CHAHBCH2N), 2.55 (dd, J = 11.1, 17.4 Hz, 1H, COCHAHBCH),
2.82 (dd, J = 3.9, 17.4 Hz, 1H, COCHAHBCH), 3.00–3.10 (m, 1H,
ArCH), 3.20–3.34 (m, 2H, NCH2CH2), 4.52 (d, J = 14.7 Hz, 1H,
PhCHAHBN), 4.72 (d, J = 14.7 Hz, 1H, PhCHAHBN), 6.94–7.03 (m,
2H, Ar), 7.09–7.14 (m, 2H, Ar), 7.23–7.33 (m, 5H, Ar); 13C NMR
(CDCl3, 150 MHz) d 30.2, 37.9, 39.5, 46.1, 49.9, 115.4 (d, J = 21 Hz,
2C), 127.4, 127.8 (d, J, = 7 Hz, 2C), 128.1 (2 C), 128.5 (2 C), 136.9,
139.0, 161.5 (d, J = 244 Hz), 169.0; HPLC (AD-H, 95/5 hexane/iso-
propanol, flow: 1 mL/min, k 210 nm) Rt 30.37 min (45.8%), Rt
32.49 min (54.2%).
ethyl acetate, 70/30); ½a D26
¼ ꢀ152 (c 0.84, CHCl3); IR (CHCl3 film)
ꢁ
3516 (br), 3017, 2961, 2926, 1771, 1700, 1606, 1503, 1216 cmꢀ1
;
1H NMR (CDCl3, 300 MHz) d 0.71 (d, J = 6.6 Hz, 3H, CH3CHCH3),
0.84 (d, J = 6.6 Hz, 3H, CH3CHCH3), 1.29 (s, broad, 1H, OH), 1.60–
1.86 (m, 3H, CH3CHCH3, CH2CH2OH), 2.10 (s, 3H, ArCH3), 2.35 (s,
3H, ArCH3), 3.16–3.24 (m, 2H, CH2CON), 3.40–3.50 (m, 2H, CH2OH),
3.42 (s, 3H, ArOCH3), 3.44 (s, 3H, ArOCH3), 3.50–3.60 (m, 1H, ArCH),
5.73 (s, 1H, NCH), 6.60–6.66 (m, 2H, Ar), 6.86–6.92 (m, 2H, Ar),
6.96–7.05 (m, 3H, Ar), 7.12–7.16 (m, 2H, Ar), 7.67 (s, 1H, Ar); 13C
NMR (CDCl3, 125 MHz) d 16.0, 20.5, 20.6, 22.4, 29.8, 37.1, 39.8,
41.3, 55.4, 55.9, 60.2, 62.1, 89.3, 111.1, 113.8, 115.0, 115.1 (d,
J = 21 Hz, 2C), 126.5, 127.4, 127.8, 128.6, 128.9, 129.0 (2C), 129.2,
130.0, 139.3, 152.7, 153.6, 156.1, 161.4 (d, J = 243 Hz), 171.3;
HRMS: Calcd for C33H39FNO6 (M++H) 564.2761. Found: 564.2759.
4.11. (100S,30R,4S)-5,5-Di(2-methoxy-5-methylphenyl)-3-[3-
(4-fluorophenyl)-4-(1-phenylethylcarbamoyl-1-oxobutyl]-4-iso
propyloxazolidin-2-one 17
Amide 17 was prepared from acid 13a (288 mg, 0.5 mmol) and
(S)-phenylethylamine (85
for the preparation of amide 14. Yield 263 mg (77%). Rf = 0.35 (hex-
l
L, 0.65 mmol) following the procedure
4.14. (S)-1-Benzyl-4-(4-fluorophenyl)piperidin-2-one (ꢀ)-10
ane/ethyl acetate, 70/30); IR (CHCl3 film) 3019, 2927, 1770, 1657,
Methanesulphonyl chloride (35
stirred solution of alcohol 19 (173 mg, 0.3 mmol) and triethyl-
amine (65 L, 0.45 mmol) in dichloromethane (5 mL) at 0 °C. After
1 h at 0 °C, the reaction mixture was allowed to attain room tem-
perature and quenched with water. The organic layer was washed
with dilute HCl and then with water. The organic extract was dried
over MgSO4 and concentrated under reduced pressure to give the
crude mesylate. The mesylate was dissolved in dry DMF (0.5 mL)
lL, 0.46 mmol) was added to a
1504 cmꢀ1 1H NMR (CDCl3, 300 MHz) d 0.68 (d, J = 6.6 Hz, 3H,
;
CH3CHCH3), 0.86 (d, J = 6.9 Hz, 3H, CH3CHCH3), 1.24 (d, J = 6.6 Hz,
3H, CHCH3), 1.60–1.70 (m, 1H, CH3CHCH3), 2.01 (s, 3H, ArCH3),
2.29–2.35 (m, 1H, CHAHBCON), 2.35 (s, 3H, ArCH3), 2.52 (dd,
J = 6.0, 14.4 Hz, 1H, CHAHBCON), 3.16 (dd, J = 4.6 Hz, 17.2 Hz, 1H,
CHAHBCONH), 3.33–3.45 (m, 1H, CHAHBCONH), 3.39 (s, 3H, Ar-
OCH3), 3.42 (s, 3H, ArOCH3), 3.70–3.85 (m, 1H, ArCH), 4.93–5.05
(m, 1H, PhCHNH), 5.51 (d, J = 6.6 Hz, 1H, NH), 5.69 (s, 1H, NCH),
6.59–6.64 (m, 2H, Ar), 6.82–6.88 (m, 2H, Ar), 6.93–7.28 (m, 10H,
Ar), 7.66 (s, 1H, Ar); 13C NMR (CDCl3, 75 MHz) d 16.0, 20.5, 20.7,
21.7, 22.5, 29.9, 37.7, 40.5, 44.0, 48.6, 55.4, 55.8, 62.0, 89.4,
111.1, 113.7, 115.2 (d, J = 21 Hz, 2C), 126.1 (2C), 126.4, 127.2,
127.3, 127.6, 128.6 (4C), 129.0 (3C), 129.3, 130.1, 138.6, 143.3,
152.7, 153.8, 156.1, 161.5 (d, J = 244 Hz), 169.9, 170.6; HRMS:
Calcd for C41H46FN2O6 (M++H) 681.3340. Found: 681.3357.
l
and triethylamine (65
lL, 0.46 mmol) was added followed by the
addition of benzylamine (40
lL, 0.37 mmol). The resulting mixture
was stirred at 90 °C for 4 h, cooled to room temperature and di-
luted with water. The reaction mixture was extracted with chloro-
form and the chloroform extract was washed with dilute HCl, dried
over MgSO4 and evaporated under reduced pressure. The residue
was chromatographed to obtain pure lactam (ꢀ)-10 (68 mg,
78%). Rf = 0.56 (hexane/ethyl acetate, 40/60). ½a D25
¼ ꢀ30 (c 0.4,
ꢁ
CHCl3). HPLC (AD-H, 95/5 hexane/isopropanol, flow: 1 mL/min, k
210 nm) Rt 30.39 min (94.25%), Rt 32.68 min (5.75%).
4.12. (3S,10S)-3-(4-Fluorophenyl)-5-oxo-5-(10-phenylethylamino)
pentanoic acid 18
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¼ ꢀ74 (c 1, MeOH); lit.27
:
½
a 2D5
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