A stereoselective synthesis of (+)-L-733,060 from ethyl (R)-(+)-2,3-epoxypropanoate

Article abstract of DOI:10.1016/j.tetasy.2009.12.010

An asymmetric synthesis of neurokinin substance P receptor antagonist (+)-L-733,060 starting from enantiomerically pure ethyl (R)-(+)-2,3-epoxypropanoate (ethyl glycidate) is described. The synthesis relies on a diastereoselective reductive amination, regioselective intramolecular epoxide opening, and in situ cyclization as the key steps.

Full text of DOI:10.1016/j.tetasy.2009.12.010

Tetrahedron: Asymmetry 21 (2010) 16–20
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A stereoselective synthesis of (+)-L-733,060 from ethyl (R)-(+)-2,3-epoxy-
propanoate
*
*
Sébastien Prévost, Phannarath Phansavath , Mansour Haddad
Chimie ParisTech (Ecole Nationale Supérieure de Chimie de Paris), Laboratoire Charles Friedel CNRS UMR 7223, 11 Rue Pierre et Marie Curie, 75231 PARIS Cedex 05, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An asymmetric synthesis of neurokinin substance P receptor antagonist (+)-L-733,060 starting from
enantiomerically pure ethyl (R)-(+)-2,3-epoxypropanoate (ethyl glycidate) is described. The synthesis
relies on a diastereoselective reductive amination, regioselective intramolecular epoxide opening, and
in situ cyclization as the key steps.
Received 2 October 2009
Accepted 21 December 2009
Available online 18 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
In recent years, due to their valuable biological profiles, several
syntheses of these compounds have been reported.5–7 In connec-
2,3-Disubstituted piperidines are found in numerous natural
products and are common subunits in several drug candidates.
Accordingly, numerous methods have been developed for the
diastereo- and enantioselective synthesis of the substituted piperi-
dines.1 Examples of biologically active 2,3-disubstituted piperidines
include (+)-L-733,0602 and (+)-CP-99,994,3 which are potent neu-
rokinin substance P receptor antagonists, and the antimalarial agent
(+)-febrifugine4 (Fig. 1).
tion with our continuous efforts toward the synthesis of biologi-
cally relevant natural products and pharmaceutical compounds,8
we were interested in a synthesis of (+)-L-733,060 using ethyl
(R)-(+)-2,3-epoxypropanoate (ethyl glycidate) as the chiral source.9
This chiral epoxide has previously been used as a starting material
for the total synthesis of the multidrug-resistance reversing agent
hapalosin.10 Herein we report a stereoselective synthesis of (+)-L-
733,060 using a diastereoselective reductive amination and regio-
selective intramolecular epoxide opening as the key steps, starting
from ethyl glycidate.
Retrosynthetically, the target compound was envisioned to be
available from A by cyclization into the corresponding piperidi-
none followed by a reduction of the lactam carbonyl (Scheme 1).
Compound A in turn would result from aldehyde B via Horner–
Wadsworth–Emmons olefination and a subsequent reduction of
the alkene functionality. Aldehyde B would be obtained with good
diastereoselectivity by reductive amination and intramolecular
opening of epoxyketone C, followed by oxidation of the resulting
primary alcohol.
CF3
H
O
N
CF3
OMe
N
H
Ph
N
H
Ph
(+)-L-733,060
(+)-CP-99,994
OH
N
O
2. Results and discussion
O
N
N
H
The synthesis of (+)-L-733,060 began with the addition of phen-
yllithium to ethyl glycidate 1 at low temperature (Scheme 2).11
Under these conditions, epoxyketone 2 was obtained in 90%
yield. The subsequent diastereoselective reductive amination of 2
gave the corresponding anti aminoepoxide12 as a single diastereo-
mer in 60% yield after separation by flash chromatography. Conver-
sion of the aminoepoxide into oxazolidinone 4 was achieved in a
straightforward manner through regioselective intramolecular
epoxide opening by heating 3 in di-tert-butyldicarbonate.13 At this
point, all attempts to oxidize 4 (Swern, Dess–Martin or PCC) into
(+)-febrifugine
Figure 1. Biologically active 2,3-substituted piperidines.
* Corresponding authors. Tel.: +33 1 44276742; fax: +33 1 44071062 (P.P); tel.:
E-mail addresses: phannarath-phansavath@chimie-paristech.fr (P. Phansavath),
mansour-haddad@chimie-paristech.fr (M. Haddad).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.12.010

S. Prévost et al. / Tetrahedron: Asymmetry 21 (2010) 16–20
17
CF3
appeared that the presence of a benzylamine moiety was inconsis-
tent with the oxidation reaction, we chose to replace the benzyl
group with a tert-butylcarboxyl protecting group. To this end, oxa-
zolidinone 4 was first converted into the protected aminoalcohol 5
upon heating at 60 °C in 3 M NaOH/EtOH followed by a selective
protection of the primary alcohol as the tert-butyldimethylsilyl
ether. The benzylamine functionality was then converted directly
into the corresponding tert-butyl carbamate by hydrogenolysis
with Pd/C in the presence of di-tert-butyl dicarbonate, delivering
6 in 90% yield. Treatment of 6 with dimethoxypropane followed
by deprotection of the primary alcohol afforded oxazolidine 7 in
good overall yield. Dess–Martin oxidation provided the corre-
sponding aldehyde while the subsequent Horner–Wadsworth–Em-
OP1
O
O
Ph
CF3
Ph
MeO
NH2
N
H
Ph
A
(+)-L-733,060
OP1
O
O
Ph
O
NHP2
B
C
Scheme 1. Retrosynthetic analysis for (+)-L-733,060. P1, P2: protecting groups.
mons reaction afforded the
a,b-unsaturated ester in 67% overall
yield. In order to carry out the cyclization of 8 into the correspond-
ing piperidinone, the 1,2 aminoalcohol moiety had to first be un-
masked. For this purpose, 8 was heated in methanol in the
presence of catalytic HCl. Hydrogenolysis of the resulting free ami-
no alcohol with Pd/C then delivered the saturated ester which al-
lowed the in situ cyclization into piperidinone 9. The next steps
involved the reduction of the lactam carbonyl with lithium alumin-
ium hydride and Boc protection to afford N-protected piperidine
10. Finally, the synthesis of (+)-L-733,060 was completed by ether-
ification of the hydroxyl function with 3,5-bis(trifluoro-
methyl)benzyl bromide and sodium hydride, followed by Boc
removal with TFA. The physical and spectroscopic data of the final
compound were consistent with those reported in the literature
the aldehyde required for the Horner–Wadsworth–Emmons
reaction were unsuccessful in giving the desired compound in
satisfactory yields and complex mixtures were obtained. Since it
BnNH2, AcOH
O
O
Me4NHB(OAc)3
PhLi
Et2O, −78 ºC
90%
OEt
Ph
O
O
DCM, rt
70% (dr = 85:15)
1, 99% ee
2
O
O
NHBn
Ph
{½a 2D4
ꢀ
¼ þ34:8 (c 0.9, CHCl3), lit.5j
½
a 2D5
ꢀ
¼ þ34:29 (c 1.32, CHCl3),
Boc2O, 60-70 °C then
NBn
lit.5e
½
a 2D5
ꢀ
¼ þ36:2 (c 0.66, CHCl3)}.
HO
O
3M NaOH, MeOH, rt
72%
Ph
3
4
3. Conclusion
In conclusion, the total synthesis of neurokinin substance P
receptor antagonist (+)-L-733,060 has been achieved starting from
enantiomerically pure ethyl glycidate. The key steps of this synthe-
sis include the diastereoselective reductive amination of a chiral
epoxyketone and regioselective opening of an anti aminoepoxide,
while the piperidine ring formation relied on one-pot alkene
reduction/lactamization.
TBSO
NHBn
Ph
H2, 10% Pd/C
1. 3M NaOH, EtOH, 60 ºC
2. TBSCl, Et3N, DCM, rt
78% (2 steps)
Boc2O, THF, rt
90%
OH
5
1. 2,2-dimethoxypropane
PTSA, DCM, rt
TBSO
NHBoc
Ph
O
NBoc
Ph
HO
4. Experimental
2. nBu4NF, THF, rt
OH
4.1. General experimental procedures
86% (2 steps)
7
6
All reactions were performed under an atmosphere of argon
with magnetic stirring using freshly distilled solvents unless other-
wise indicated. Dichloromethane, methanol, and DMF were dis-
tilled from calcium hydride. Tetrahydrofuran and diethyl ether
were distilled from sodium and benzophenone. Triethylamine
was distilled from potassium hydroxide. All other commercially
available reagents were used as received unless otherwise speci-
fied. All reactions were monitored by thin layer chromatography
(TLC) using MERCK precoated Silica Gel 60 F254. Flash column
chromatography was carried out on Merck silica gel (0.040–
0.063 mesh).
Proton magnetic resonance spectra were recorded on Bruker
Avance 400, Avance 300, or Avance 200 spectrometers. Chemical
shifts (d) are reported in (parts per million)ppm and are referenced
to the residual non-deuterated solvent peak (7.26 ppm for CHCl3 of
CDCl3). Coupling constants (J) are reported in hertz. Data are re-
ported as follows: s, singlet; d, doublet; t, triplet; q, quartet; qn,
quintuplet; m, multiplet; and br, broad. Carbon magnetic reso-
nance spectra were recorded on Bruker Avance 400, Avance 300,
or Avance 200 spectrometers operating at 100, 75 and 50 MHz,
respectively. Chemical shifts (d) are reported in ppm and are refer-
enced to the deuterated solvent peak (77.0 ppm for 13C of CDCl3).
1. Dess-Martin periodinane, DCM, rt
2. (MeO)2P(O)CH2CO2Me
O
NBoc
MeO2C
tetramethylguanidine, THF, rt
67% (2 steps)
Ph
8
OH
Ph
1. LiAlH4, THF, rt
2. Boc2O, Et3N
1. conc. HCl, MeOH, 50 ºC
O
N
H
DMAP, DCM, rt
81% (2 steps)
2. H2, 10% Pd/C, THF, rt
68% (2 steps)
9
CF3
1. 3,5-(CF3)2C6H4CH2Br
NaH, DMF, rt
OH
Ph
O
Ph
CF3
2. TFA, DCM, rt
52% (2 steps)
N
N
H
Boc
10
(+)-L-733,060
Scheme 2. Total synthesis of (+)-L-733,060.

18
S. Prévost et al. / Tetrahedron: Asymmetry 21 (2010) 16–20
Infrared spectra (IR) were recorded on a FTIR Nicolet 205 spectro-
photometer. Optical rotations were measured on a Perkin–Elmer
2H), 7.20–7.28 (m, 6H), 7.37–7.43 (m, 2H); 13C NMR (CDCl3,
75 MHz) d 46.0, 60.2, 61.8, 82.3, 127.4, 128.3, 128.5, 128.7, 129.0,
129.3, 135.1, 137.3, 158.1. Anal. Calcd for C17H17NO3 (283.32): C,
72.06; H, 6.05; N, 4.94. Found: C, 72.77; H, 6.01; N, 4.92.
241 polarimeter at the sodium D line (589 nm) and are reported
ꢁC
as follows: ½a tD
ꢀ
(concentration in g/100 mL, solvent). Mass spectra
(MS) were measured on a Nermag R10-10C mass spectrometer
(DCI/NH3) and on a PE Sciex API 3000 mass spectrometer (ESI) at
Ecole Nationale Supérieure de Chimie de Paris. Elemental analyses
were performed by the Service de Microanalyse de l’Université
Pierre et Marie Curie.
4.5. (1S,2R)-1-(Benzylamino)-3-(tert-butyldimethylsilyloxy)-1-
phenylpropan-2-ol 5
Oxazolidinone 4 (2.6 g, 9.18 mmol) was dissolved in EtOH
(30 mL) and 3 M NaOH (10 mL) and the mixture was heated at
60 °C for 12 h. After cooling to room temperature, H2O (50 mL)
was added and the solution was extracted with EtOAc (2 ꢃ 30
mL). The combined organic layers were washed with brine, dried
over Na2SO4, filtered, and concentrated under reduced pressure
to give the corresponding crude diol (2.3 g, 97%) which was used
in the next step without further purification. To a solution of the
above diol (2.3 g, 8.94 mmol) in CH2Cl2 (40 mL) were added at
0 °C triethylamine (2.5 mL, 17.8 mmol) and tert-butyldimethylsilyl
chloride (1.41 g, 9.4 mmol). After being stirred at room tempera-
ture for 12 h, the reaction mixture was quenched with brine, ex-
tracted with CH2Cl2, dried (MgSO4), and concentrated.
Purification of the residue by flash column chromatography (30%
AcOEt in cyclohexane) afforded 5 as a colorless oil (2.6 g, 78%).
4.2. (R)-Oxiran-2-yl(phenyl)methanone 2
To a solution of (R)-(+)-2,3-epoxypropanoate (5.0 g, 43 mmol)
in Et2O (40 mL) and pentane (40 mL) was added at ꢂ78 °C, a solu-
tion of phenyllithium (2 M in hexanes, 23.7 mL, 47.4 mmol). The
mixture was stirred at this temperature for 3 h, then quenched
with saturated NH4Cl, and extracted with Et2O (2 ꢃ 30 mL). The
combined organic layers were dried (MgSO4) and concentrated in
vacuo. Purification of the residue by flash chromatography (30%
AcOEt in cyclohexane) afforded 2 as a white solid (5.75 g, 90%).
Mp 80–81 °C; ½a 2D5
ꢀ
¼ þ53:7 (c 1.1, CH2Cl2) {lit.14
½
a 1D5
ꢀ
¼ þ54:95 (c
0.74, CH2Cl2)}; IR
m = 3025, 2990, 2916, 2827, 1683, 1591, 1575,
1451, 1388, 1231 cmꢂ1 1H NMR (CDCl3, 300 MHz) d 2.89 dd,
;
J = 6.6 and 2.4 Hz, 1H), 3.04 (dd, J = 6.6 and 4.5 Hz, 1H), 4.16 (dd,
J = 2.4 and 4.5 Hz, 1H), 7.40–7.45 (m, 2H), 7.52–7.58 (m, 1H),
7.95–7.99 (m, 2H); 13C NMR (CDCl3, 75 MHz) d 47.5, 51.1, 128.3,
128.8, 133.9, 135.4, 194.6. Anal. Calcd for C9H8O2 (148.16): C,
72.79; H, 5.44. Found: C, 72.69; H, 5.65.
½
a 2D4
ꢀ
¼ þ32:2 (c 1.7, CH2Cl2). IR (neat):
m
= 3414, 2948, 2928,
;
2854, 1627, 1453, 1403, 1251, 844 cmꢂ1
1H NMR (CDCl3,
300 MHz) d 0.01 (s, 6H), 0.86 (s, 9H), 2.74 (br s, 2H), 3.33 (dd,
J = 4.4 and 10.4 Hz, 1H), 3.45 (dd, J = 2.6 and 10.4 Hz, 1H), 3.50 (d,
J = 13.2 Hz, 1H), 3.66 (d, J = 13.2 Hz, 1H), 3.68 (s, 2H), 7.23–7.36
(m, 10H); 13C NMR (CDCl3, 75 MHz) d ꢂ5.4, 18.2, 25.9, 51.2, 64.0,
64.2, 75.4, 126.8, 127.6, 127.9, 128.1, 128.2, 128.3, 128.5, 140.4,
140.6; MS (CI, NH3) m/z = 372 [M+H]+.
4.3. (S)-N-Benzyl-1-((S)-oxiran-2-yl)-1-phenylmethanamine 3
To a solution of 2 (2.0 g, 13.5 mmol) in CH2Cl2 (50 mL) were
added sequentially activated 4 Å molecular sieves (beads, 1.0 g),
benzylamine (1.94 mL, 17.5 mmol), acetic acid (1.0 mL,
17.5 mmol), and Me4NHB(OAc)3 (7.1 g, 27.0 mmol) in small por-
tions. The mixture was stirred for 48 h at room temperature and
filtered through a pad of Celite. The filtrate was washed with satu-
rated NaHCO3 and brine, dried over MgSO4 and concentrated. Puri-
fication of the crude product by column chromatography on silica
gel (30% AcOEt in cyclohexane) afforded 3 as a pale yellow oil
4.6. tert-Butyl (1S,2R)-3-(tert-butyldimethylsilyloxy)-2-hydro-
xy-1-phenylpropylcarbamate 6
To a solution of 5 (2.6 g, 7 mmol) and 10% Pd/C (150 mg,
0.14 mmol) in degassed THF (30 mL) was added Boc2O (2.28 g,
10.5 mmol). The resulting mixture was purged by three vacuum/
hydrogen cycles at room temperature, placed under 1 atm of
hydrogen (balloon) and allowed to stir for 12 h at room tempera-
ture. The reaction mixture was then filtered through a Celite pad
and concentrated in vacuo. Purification of the residue by flash col-
umn chromatography (20% AcOEt in cyclohexane) afforded 6 as a
(1.8 g, 56%). ½a 2D5
ꢀ
¼ þ57:8 (c 1.8, CH2Cl2); IR (neat):
m = 3320,
3060, 3025, 2990, 2916, 2827, 1491, 1456 cmꢂ1
;
1H NMR (CDCl3,
300 MHz) d 1.91 (br s, 1H), 2.73–2.76 (m, 1H), 2.88–2.91 (m, 1H),
3.18–3.22 (m, 1H), 3.63 (d, J = 13.2 Hz, 1H), 3.77 (d, J = 13.2 Hz,
1H), 3.91 (d, J = 4.5 Hz, 1H), 7.26–7.48 (m, 10H); 13C NMR (CDCl3,
75 MHz) d 44.5, 50.8, 55.1, 61.3, 125.8, 127.4, 127.63, 127.8,
128.1, 128.3, 128.4, 139.6, 140.0. Anal. Calcd for C16H17NO
(239.31): C, 80.30; H, 17.13; N, 5.85. Found: C, 80.44; H, 16.98;
N, 5.79.
pale yellow oil (2.4 g, 90%). ½a D25
ꢀ
¼ þ17:2 (c 1.1, CH2Cl2) {lit.15
½
a 2D3
ꢀ
¼ þ2:65 (c 1.1, CHCl3)}; IR (neat):
m = 3421, 2951, 2924,
2854, 1693, 1495, 1363, 1254 cmꢂ1 1H NMR (CDCl3, 300 MHz) d
;
0.07 (s, 6H), 0.91 (s, 9H), 1.45 (s, 9H), 2.69 (br s, 1H), 3.51 (dd,
J = 6.6 and 10.0 Hz, 1H), 3.62 (dd, J = 4.9 and 10.0 Hz, 1H), 3.84
(br s, 1H), 4.69 (br s, 1H), 5.58 (d, J = 7.7 Hz, 1H), 7.22–7.32 (m,
5H); 13C NMR (CDCl3, 75 MHz) d ꢂ5.4, 18.2, 25.8, 26.9, 28.3, 55.5,
64.2, 74.5, 79.4, 126.8, 127.3, 128.4, 140.9, 155.8; MS (CI, NH3)
m/z = 399 [M+NH4]+, 382 [M+H]+.
4.4. (4S,5R)-3-Benzyl-5-(hydroxymethyl)-4-phenyloxazolidin-
2-one 4
A mixture of 3 (3.4 g, 14.2 mmol) and Boc2O (10.0 g, 45.8 mmol)
was heated at 60–70 °C for 48 h, then allowed to return to room
temperature. Methanol (30 mL) and 3 M NaOH (10 mL) were suc-
cessively added and the solution was stirred for 12 h at room tem-
perature. After the addition of H2O (50 mL) and extraction with
EtOAc (2 ꢃ 40 mL), the organic phase was dried (MgSO4) and con-
centrated to give a syrup which was purified by column chroma-
tography (40% AcOEt in cyclohexane) to afford 4 (2.9 g, 72%) as a
4.7. (4S,5R)-tert-Butyl 5-(hydroxymethyl)-2,2-dimethyl-4-phe-
nyloxazolidine-3-carboxylate 7
To a solution of 6 (1.8 g, 4.72 mmol) in CH2Cl2 (30 mL) were
added 2,2-dimethoxypropane (1.74 mL, 14.1 mmol) and p-toluene-
sulfonic acid monohydrate (15 mg, 0.078 mmol). The resulting
mixture was stirred at room temperature for 2 h, then washed with
saturated NaHCO3, and brine. The organic phase was dried over
MgSO4 and concentrated under reduced pressure to afford the cor-
responding crude oxazolidine which was used directly in the next
step. To a solution of this oxazolidine in THF (25 mL) was added
tetrabutylammonium fluoride (1 M in THF, 7 mL, 7 mmol). The
mixture was stirred at room temperature for 3 h and water
white solid. Mp 104–105 °C; ½a D24
¼ þ21:1 (c 1.0, CH2Cl2); IR
ꢀ
(KBr):
m
= 3423 (br), 1740, 1449, 1384, 1351 cmꢂ1; 1H NMR (CDCl3,
300 MHz) d 2.05 (br s, 1H), 3.60 (dd, J = 3.6 and 12.7 Hz, 1H), 3.68
(d, J = 15.0 Hz, 1H), 3.86 (dd, J = 2.9 and 12.7 Hz, 1H), 4.34–4.38 (m,
1H), 4.44 (d, J = 7.0 Hz, 1H), 4.85 (d, J = 15.0 Hz, 1H), 7.10–7.13 (m,

S. Prévost et al. / Tetrahedron: Asymmetry 21 (2010) 16–20
19
(40 mL) was added. After extraction with ethyl acetate (2 ꢃ 30 mL),
4.10. (2S,3S)-tert-Butyl-3-hydroxy-2-phenylpiperidine-1-car-
boxylate 10
the organic layers were dried over MgSO4, and the solvent was
evaporated in vacuo. Flash chromatography (30% AcOEt in cyclo-
hexane) yielded the title compound 7 as a pale yellow oil (1.25 g,
To a suspension of LiAlH4 (89 mg, 2.35 mmol) in THF (2 mL) was
added a solution of 9 (90 mg, 0.47 mmol) in THF (2 mL) at 0 °C. The
resulting mixture was refluxed for 4 h and then cooled to 0 °C. SiO2
86%). ½a 2D4
ꢀ
¼ þ31:8 (c 1.1, CH2Cl2); IR (neat):
m = 3459, 2982,
2932, 2879, 1692, 1605, 1453 cmꢂ1
;
1H NMR (CDCl3, 400 MHz) d
0.99 (s, 9H), 1.67 (s, 3H), 1.70 (s, 3H), 2.00 (br s, 1H), 3.57 (broad
d, J = 10.8 Hz, 1H), 3.77 (dd, J = 2.6 and 12.2 Hz, 1H), 3.90 (ddd,
J = 2.9, 3.6 and 8.6 Hz, 1H), 4.59 (br d, J = 7.6 Hz, 1H), 7.20–7.31
(m, 5H); 13C NMR (CDCl3, 75 MHz) d 25.7, 26.3, 27.9, 60.4, 62.4,
79.7, 82.8, 94.8, 126.3, 127.3, 128.5, 140.7, 151.9; MS (ESI) m/
z = 330.5 [M++Na].
(100 mg), water (100 lL), and 10% NaOH (100 lL) were added, the
mixture was stirred for 20 min at 0 °C and filtered. The filtrate was
concentrated in vacuo to afford the crude 5-hydroxy-6-phenyl-
piperidine which was used in the next step without further purifi-
cation. To a solution of this compound in CH2Cl2 (1 mL) were added
di-tert-butyl dicarbonate (110 mg, 0.50 mmol), dimethylaminopyr-
idine (3 mg, 0.02 mmol) and triethylamine (77 lL, 0.55 mmol) at
4.8. (4S,5S)-tert-Butyl 5-((E)-3-methoxy-3-oxoprop-1-enyl)-2,2-
dimethyl-4-phenyloxazolidine-3-carboxylate 8
0 °C. The solution was stirred at room temperature for 3 h and sat-
urated NH4Cl was added. The mixture was extracted with CH2Cl2,
the combined organic layers were washed with brine, dried over
MgSO4, and concentrated. Purification of the residue by column
chromatography (25% AcOEt in cyclohexane) afforded 10 as a col-
To a 0 °C solution of alcohol 7 (640 mg, 2.08 mmol) in CH2Cl2
(20 mL), was added Dess–Martin periodinane (0.47 M in CH2Cl2,
6.6 mL, 3.12 mmol). The reaction mixture was stirred for 3 h at
room temperature, then diluted with CH2Cl2 and quenched with
saturated aqueous NaHCO3. The layers were separated and the
aqueous phase was extracted with CH2Cl2 (2 ꢃ 20 mL). The com-
bined organic layers were dried (MgSO4), filtered, and concen-
trated in vacuo. Filtration of the residue on silica gel (AcOEt)
afforded the corresponding aldehyde which was used in the next
step. Thus, to a solution of this aldehyde in THF (20 mL) were
orless oil (81 mg, 81% for the two steps). ½a D24
ꢀ
¼ þ42:6 (c 0.54,
= 3420,
1H
CHCl3) {lit.5j
½
a 2D5
ꢀ
¼ þ38:30 (c 1.92, CHCl3)}; IR (neat):
m
2976, 2942, 2871, 1689, 1417, 1251, 1174, 1146, 702 cmꢂ1
;
NMR (CDCl3, 300 MHz) d 1.39 (s, 9H), 1.24–1.55 (m, 5H), 3.01 (td,
J = 13.4 and 3.9 Hz, 1H), 3.94–4.13 (m, 2H), 5.34 (d, J = 5.7 Hz,
1H), 7.21–7.37 (m, 3H), 7.46 (d, J = 7.1 Hz, 2H); 13C NMR (CDCl3,
75 MHz) d 23.1, 27.6, 28.3, 39.4, 59.1, 70.0,79.9, 127.1, 128.3,
128.4, 138.4, 155.4.
added tetramethylguanidine (520
lL, 4.16 mmol) and trim-
ethylphosphonoacetate (600 L, 4.16 mmol). The resulting mixture
l
was stirred for 30 min at ꢂ78 °C, then at room temperature for 4 h.
Water (20 mL) was added and the reaction mixture was extracted
with diethyl ether (2 ꢃ 20 mL). The organic layer was dried over
MgSO4, filtered, and concentrated under reduced pressure. Purifi-
cation of the residue by column chromatography (20% AcOEt in
cyclohexane) afforded 8 as a pale yellow oil (0.5 g, 67% for the
4.11. (2S,3S)-3-(3,5-Bis(trifluoromethyl)benzyloxy)-2-phenylpi-
peridine, (+)-L-733,060
To a suspension of sodium hydride (60% dispersion in mineral
oil, 57 mg, 1.43 mmol) in DMF (0.5 mL) was added a solution of
10 (132 mg, 0.47 mmol) in DMF (0.5 mL) at 0 °C. The mixture
was stirred at room temperature for 30 min and 3,5-bis(trifluoro-
two steps). ½a 2D4
ꢀ
¼ ꢂ36:8 (c 0.9, CH2Cl2); IR (neat):
m = 2982,
1795, 1725, 1696, 1453, 1378 cmꢂ1
;
1H NMR (CDCl3, 300 MHz) d
methyl)benzyl bromide (137 lL, 0.71 mmol) was added at 0 °C.
0.98 (s, 9H), 1.64 (s, 6H), 3.66 (s, 3H), 4.36 (m, 2H), 5.95 (d,
J = 15.6 Hz, 1H), 6.80 (dd, J = 4.8 and 15.6 Hz, 1H), 7.15–7.29 (m,
5H); 13C NMR (CDCl3, 75 MHz) d 25.9, 26.8, 27.9, 66.8, 77.2, 79.9,
81.3, 95.2, 122.4, 126.2, 126.3, 127.6, 128.6, 142.5, 151.7, 166.2;
MS (ESI) m/z 384 [M+Na]+.
The mixture was stirred overnight at room temperature, after
which water (5 mL) was added at 0 °C and the mixture was ex-
tracted with Et2O. The combined organic layers were washed
with brine, dried over MgSO4, and concentrated. The residue
was purified by column chromatography (10% AcOEt in cyclohex-
ane) to give (2S,3S)-1-(tert-butoxycarbonyl)-2-phenyl-3-[(3,5-bis-
(trifluoromethyl)benzyl)oxy]piperidine (158 mg, 66%) as a color-
less oil. To a solution of this compound (30 mg, 0.06 mmol) in
4.9. (5S,6S)-5-Hydroxy-6-phenylpiperidin-2-one 9
To a solution of 8 (460 mg, 1.27 mmol) in MeOH (10 mL) were
added two drops of concentrated HCl and the mixture was heated
at 40–50 °C for 12 h then cooled to rt. Aqueous saturated NaHCO3
(3 mL) and water (15 mL) were then added. The solution was ex-
tracted with EtOAc (2 ꢃ 15 mL), washed with brine, and dried over
MgSO4. Removal of the solvent in vacuo gave the corresponding
crude free amino alcohol. To a degassed solution of this free amino
alcohol in THF (15 mL) was added 10% Pd/C (50 mg, 0.047 mmol).
The resulting mixture was purged by three vacuum/hydrogen
cycles at room temperature, placed under a 1 atm of hydrogen
(balloon) and allowed to stir for 18 h at room temperature. The
reaction mixture was then filtered through a Celite pad and concen-
trated in vacuo. Purification of the residue by flash column chroma-
tography (5% MeOH in dichloromethane) afforded 9 as a white solid
(165 mg, 68% for the two steps). Mp 92 °C {lit.5h mp 87–88 °C};
CH2Cl2 (1 mL) was added trifluoroacetic acid (44 lL, 0.60 mmol)
at 0 °C. The mixture was stirred for 18 h at room temperature,
then 10% NaOH was added at 0 °C. After extraction with CH2Cl2,
the combined organic layers were washed with brine, dried over
MgSO4, and concentrated. Purification of the residue by column
chromatography (5% MeOH in CH2Cl2) afforded (+)-L-733,060
(19 mg, 79%) as a colorless oil. ½a D24
ꢀ
¼ þ34:8 (c 0.9, CHCl3) {lit.5j
½
a 2D5
ꢀ
¼ þ34:29 (c 1.32, CHCl3), lit.5e
½
a 2D5
ꢀ
¼ þ36:2 (c 0.66, CHCl3)};
1H NMR (CDCl3, 200 MHz) d 1.42–2.04 (m, 3H), 2.20 (br d,
J = 13.4 Hz, 1H), 2.56 (br s, 1H), 2.85 (td, J = 12.2 and 2.6 Hz,
1H), 3.31 (br d, J = 12.2 Hz, 1H), 3.69 (br s, 1H), 3.87 (s, 1H),
4.14 (d, J = 12.8 Hz, 1H), 4.52 (d, J = 12.8 Hz, 1H), 7.28–7.45 (m,
5H), 7.45 (s, 2H), 7.69 (s, 1H); 13C NMR (CDCl3, 50 MHz) d
20.1, 28.2, 46.8, 64.1, 70.0, 76.9, 121.2 (m), 123.3 (q,
J = 270.8 Hz), 126.0, 127.4, 127.5, 128.2, 131.3 (q, J = 33.0 Hz),
141.1, 142.0.
½
a 2D5
a 2D5
ꢀ
¼ þ52:0 (c 1.1, CH2Cl2) {lit.16
½
a 2D5
ꢀ
¼ þ38:0 (c 0.8, CH2Cl2), lit.5h
½
ꢀ
¼ þ32:5 (c 1.0, CH2Cl2)}; IR (neat):
m = 3294, 2927, 1649, 1459,
1403, 1376 cmꢂ1
;
1H NMR (CDCl3, 300 MHz) d 1.99–2.07 (m, 2H),
Acknowledgment
2.11–2.16 (m, 1H), 2.39 (ddd, J = 2.9, 6.3 and 18.0 Hz, 1H), 2.72
(ddd, J = 6.4, 11.6 and 18.0 Hz, 1H), 4.07 (m, 1H), 4.66 (d, J =
2.7 Hz, 1H), 5.95 (br s, 1H), 7.31–7.44 (m, 5H); 13C NMR (CDCl3,
75 MHz) d 26.1, 26.6, 61.8, 66.2, 127.1, 128.7, 129.1, 137.8, 172.4.
S.P. thanks the Ministère de l’Education Nationale et de la
Recherche for a grant.

20
S. Prévost et al. / Tetrahedron: Asymmetry 21 (2010) 16–20
Emmanuvel, L.; Kamble, D. A.; Sudalai, A. Tetrahedron: Asymmetry 2009, 20, 84;
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