An asymmetric aminohydroxylation route to (+)-L-733,060

Article abstract of DOI:10.1016/j.tetasy.2005.09.010

An enantioselective synthesis of (+)-L-733,060 starting from cinnamic acid using Sharpless asymmetric aminohydroxylation and Wittig reactions as the key steps is described.

Full text of DOI:10.1016/j.tetasy.2005.09.010

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3579–3583
An asymmetric aminohydroxylation route to (+)-L-733,060
Subba Rao V. Kandula and Pradeep Kumar*
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411008, India
Received 26 July 2005; revised 12 September 2005; accepted 13September 2005
Available online 2 November 2005
Abstract—An enantioselective synthesis of (+)-L-733,060 starting from cinnamic acid using Sharpless asymmetric aminohydroxyl-
ation and Wittig reactions as the key steps is described.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
variety of biological activities since a cis-relationship
between the two substituents on the piperidine ring is
essential for high-affinity binding to the human NK1
receptor. Various synthetic strategies have been reported
for the valuable intermediate 18 and a few asymmetric
syntheses for 2,9 mainly using chiral pool starting mate-
rials. As a part of our research program aimed at devel-
oping enantioselective syntheses of naturally occurring
lactones10 and amino alcohols,11 we became interested
in developing a practical and concise route to (+)-L-
733,060. Herein, we report a new and enantioselective
synthesis of (+)-L-733,060 employing a Sharpless asym-
metric aminohydroxylation as the source of chirality
(Fig. 1).
Substance P (SP), a peptide neurotransmitter, is a mem-
ber of the tochynin family of peptides, which includes
neurokinins A and B (NKA and NKB).1 These peptides
bind to a series of three neurokinin receptors, NK1, NK2
and NK3, which have a selective affinity for SP, NKA
and NKB, respectively.2 Substance P shows a number
of biological activities such as neurogenic inflamma-
tion,3 pain transmission, regulation of the immune
response,4 rheumatoid arthritis,5 ulcerative colitis,6 and
migraine.7 The nonpeptidic neurokinin NK1 receptor
antagonists 2 and 3 are good synthetic targets due to a
CF3
Boc
HN
2. Results and discussion
N
The synthesis of (+)-L-733,060 commenced from cin-
namic acid 4, a commercially available starting material,
as illustrated in Scheme 1. Cinnamic acid 4 was first
converted to isopropyl cinnamate 5 using isopropanol
and a catalytic amount of HCl under reflux conditions.
Compound 5 was subjected to a Sharpless asymmetric
aminohydroxylation12 using (DHQ)2PHAL ligand,
freshly prepared N-bromoacetamide13 as the nitrogen
source and potassium osmate as the oxidant to give
O
CF3
OH
(+)-L-733,060
2
1
HN
HN
the desired amino alcohol 612 as a single isomer in
25
76% yield and with >99% ee12c ½aŠ ¼ þ28:5 (c 1.0,
OMe
D
18
D
CHCl3) {lit.12c ½aŠ ¼ þ28:3 (c 1.0, CHCl3)}. The phys-
(+)-CP-99,994
3
ical and spectroscopic data of 6 were in full agreement
with those reported.12c Furthermore, in order to achieve
the synthesis of target compound 2 from 6, we required
a suitable amino protecting group for further synthetic
manipulations. To this end, amide 6 was subjected to
hydrolysis in methanol under reflux to furnish the
Figure 1.
*
Corresponding author. Tel.: +91 20 25902050; fax: +91 20
25893614; e-mail: pk.tripathi@ncl.res.in
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.09.010

3580
S. R. V. Kandula, P. Kumar / Tetrahedron: Asymmetry 16 (2005) 3579–3583
O
HN
O
O
COOH
b
a
O
O
OH
6
5
4
NHBoc
NHBoc
NHBoc
COOMe
COOMe
OH
c
e
d
OTBS
OH
OTBS
7
8
9
NHBoc
OH
O
NHBoc
OH
O
NHBoc
h
OH
g
OEt
f
OEt
12
OTBS
11
10
Boc
CF3
Boc
CF3
HN
N
N
k
j
i
O
O
CF3
CF3
OH
2
1
13
Scheme 1. Reagents and conditions: (a) isopropanol, HCl (cat.), reflux, 12 h, 76%; (b) (DHQ)2PHAL, K2[OsO2(OH)4], CH3CONHBr, LiOH, t-
BuOH–H2O (1:1), ꢀ5 ꢁC, 4 h, 76%; (c) (i) 0.5 M HCl, MeOH, reflux, 15 h, (ii) Boc2O, Et3N, dry CH2Cl2, 0–25 ꢁC, 24 h, 94%; (d) TBDMSCl,
imidazole, DMAP(cat.), dry CH2Cl2, 25 ꢁC, 10 h, 91%; (e) DIBAL-H, dry CH2Cl2, 0–25 ꢁC, 3h, 93%; (f) (i) PCC, anhyd CH 3COONa, Celite, 5 h,
25 ꢁC, (ii) Ph3P@CHCOOEt, dry THF, 25 ꢁC, 24 h, 91%; (g) 10% Pd/C, MeOH, 25 ꢁC, 6 h, 93%; (h) DIBAL-H, dry CH2Cl2, 0–25 ꢁC, 3h, 90%; (i)
CH3SO2Cl, Et3N, dry CH2Cl2, ꢀ78 ꢁC, 1 h, 77%; (j) 3,5-bis-(trifluoromethyl)benzyl bromide, NaH, dry DMF, 80 ꢁC, 12 h, 78%; (k) CF3COOH,
methanol, 25 ꢁC, 1 h, 70%.
free amine with concomitant transesterification to the
methyl ester.12c The successive conversion of the amine
into the Boc protected amino alcohol 7 was carried
out using Boc2O in the presence of triethyl amine. It is
noteworthy that although compound 7 has been pre-
pared in a straightforward manner by the Sharpless
asymmetric aminohydroxylation of methyl cinnamate
using t-butyl carbamate as a nitrogen source, the enan-
tiomeric purity obtained for 7 was not very high (80%
ee).14 Therefore, in order to prepare the enantiomeri-
cally pure aminohydroxy compound 7, we followed a
sequence of reaction from 4 to 7 as depicted in Scheme 1.
Having achieved the synthesis of 7 in high enantiomeric
purity, we then proceeded with the protection of the
hydroxyl group as the TBS–ether to afford 8 in 91%
yield. The ester group of 8 was reduced to the corre-
sponding alcohol 9 using DIBAL-H at 0 ꢁC–rt. The
oxidation of alcohol 9 was carried out using PCC to give
the corresponding aldehyde which on subsequent, Wit-
tig reaction with (ethoxycarbonylmethylene)triphenyl-
phosphorane, afforded olefin 10 in good yield. The
olefin reduction by hydrogenation using 10% Pd/C
resulted in the concomitant deprotection of the TBS
group to furnish compound 11 in excellent yield. The
subsequent ester reduction with DIBAL-H in dry
CH2Cl2 at 0 ꢁC–rt afforded amino diol 12, which was
subjected to cyclization using methanesulfonyl chloride
and triethyl amine at ꢀ78 ꢁC to furnish the piperidine
derivative 19a in 77% yield. Etherification of the hydroxyl
group with 3,5-bis(trifluoromethyl)benzyl bromide using
NaH as base gave 13 in 78% yield. Finally, N-Boc depro-
tection of 139a using TFA afforded the target molecule
(2S,3S)-(+)-L-733,060 in good yield. The physical and
spectroscopic data of 2 were in full agreement with those
reported.9a
3. Conclusion
In conclusion, a highly enantioselective synthesis of (+)-
L-733,060 has been achieved by employing a Sharpless
asymmetric aminohydroxylation and Wittig reaction as
key steps. The merits of this synthesis are high yielding
steps and high enantioselectivity. To the best of our
knowledge, this is the first asymmetric synthesis employ-
ing a Sharpless asymmetric aminohydroxylation as the

S. R. V. Kandula, P. Kumar / Tetrahedron: Asymmetry 16 (2005) 3579–3583
3581
source of chirality. The synthetic strategy described
herein has significant potential for further extension to
other NK1 receptor antagonists.
NMR (CDCl3, 200 MHz): d 1.31 (d, J = 6.4 Hz, 6H),
2.02 (s, 3H), 3.32 (br s, 1H, OH), 4.49 (dd, J = 2.2,
3.6 Hz, 1H), 5.10–5.15 (m, 1H), 5.57 (d, J = 10 Hz,
1H), 6.27 (d, J = 10 Hz, 1H), 7.31–7.41 (m, 5H).
4. Experimental
4.4. Synthesis of methyl (2R,3S)-3-(tert-butoxy carbon-
ylamino)-2-hydroxy-3-phenylpropionate 7
4.1. General information
Amino alcohol 6 (0.52 g, 1.95 mmol) was treated with
0.5 M HCl in methanol (50 mL) and heated under reflux
for 15 h. After removal of the solvent under reduced
pressure, the residue was dissolved in fresh methanol
(2 · 50 mL) and evaporated. Dry CH2Cl2 (20 mL) was
added to the residue and the solution cooled to 0 ꢁC.
To this suspension was added triethyl amine (0.68 mL,
4.08 mmol) in dry CH2Cl2 (3mL) followed by Boc 2O
(0.67 mL, 2.9 mmol) in dry CH2Cl2 (2 mL). The reaction
mixture was stirred for 30 min at 0 ꢁC and then for 24 h
at room temperature. After TLC diagnosis, the reaction
mixture was evaporated to near dryness and purified by
silica gel column chromatography using EtOAc–pet.
The solvents were purified and dried by the standard
procedures prior to use; petroleum ether of boiling range
60–80 ꢁC was used. Optical rotations were measured
using a sodium D line on a JASCO-P-1020-polarimeter.
Infrared spectra were recorded on Perkin–Elmer FT-IR
1
spectrometer. H and 13C NMR spectra were recorded
on
a Bruker AC-200 spectrometer. Enantiomeric
excesses were measured using either the chiral HPLC or
by comparison with optical rotation. Elemental analyses
were carried out with a Carlo Erba CHNS–O analyzer.
4.2. Synthesis of trans-isopropyl cinnamate 5
ether (3:7) to afford 7 (0.54 g) as a white crystalline solid.
25
D
To a solution of cinnamic acid 4 (10 g, 67.49 mmol) in
isopropanol (60 mL) was added a cat. amount of HCl.
The reaction mixture was refluxed for 12 h neutralized
with solid NaHCO3 and filtered off. The solvent was
evaporated and the residue obtained, purified by silica
gel column chromatography using EtOAc–pet. ether
(0.5:9.5) as eluent to give 5 (9.76 g) as a colourless oil.
Yield: 76%; IR (neat, cmꢀ1): mmax 1713, 1620, 1502,
1486, 1393; 1H NMR (CDCl3, 200 MHz): d 1.32 (d,
J = 5 Hz, 6H), 5.14–5.17 (m, 1H), 6.43(d, J = 20 Hz,
1H), 7.38–7.52 (m, 3H), 7.50 (d, J = 20 Hz, 1H), 7.68
(d, J = 20 Hz, 2H); 13C NMR (CDCl3, 50 MHz): d
21.8, 67.6, 118.7, 127.8, 128.7, 129.9, 134.4, 144.1,
166.3. Anal. Calcd for C12H14O2 (190.24): C, 75.76; H,
7.42. Found: C, 75.72; H, 7.39.
Yield: 94%; mp: 129 ꢁC; ½aŠ ¼ ꢀ7:1 (c 0.89, CHCl3)
25
D
{lit.12c ½aŠ ¼ ꢀ7:3 (c 1, CHCl3)}; IR (CHCl3, cmꢀ1):
1
mmax 3521, 3362, 1722, 1682, 1517; H NMR (CDCl3,
200 MHz): d 1.43 (s, 9H), 1.62 (br s, 1H), 3.84 (s, 3H),
4.48–4.49 (m, 1H), 5.22 (d, J = 8 Hz, 1H), 5.40 (d,
J = 6 Hz, 1H), 7.29–7.37 (m, 5H); 13C NMR (CDCl3,
50 MHz): d 28.1, 52.8, 56.0, 73.4, 78.9, 126.6, 127.5,
128.4, 139.0, 155.1, 173.2.
4.5. Synthesis of methyl (2R,3S)-3-(tert-butoxycarbon-
ylamino)-2-(tert-butyldimethyl-silanyloxy)-3-phenyl-
propionate 8
To a solution of 7 (0.3g, 1.02 mmol), in dry CH 2Cl2
(10 mL) were added imidazole (72 mg, 1.06 mmol),
TBDMSCl (0.24 g, 1.59 mmol) and cat. DMAP
(6 mg, 0.051 mmol) sequentially. The resulting solution
was stirred at rt for 10 h. The solvent was evaporated
under reduced pressure and the residue extracted with
dichloromethane. The organic layer was separated
and dried over Na2SO4. The crude product was puri-
fied by silica gel column chromatography using
4.3. Synthesis of isopropyl (2R,3S)-3-(acetylamino)-2-
hydroxy-3-phenylpropionate 6
K2[OsO2(OH)4] (90 mg, 1.5 mol %) was dissolved with
stirring in 60 mL of aqueous solution of LiOHÆH2O
(0.69 g, 16.42 mmol). After the addition of t-BuOH
(90 mL), (DHQ)2PHAL [123mg, 1 mol %] was added
and the mixture immersed in a cooling bath set at 4 ꢁC.
After the addition of isopropyl cinnamate 5 (3g,
15.77 mmol), N-bromo acetamide (2.37 g, 17.77 mmol)
was added in one portion, which resulted in an immedi-
ate colour change to green and the mixture vigorously
stirred at the same temperature. The reaction was moni-
tored by TLC, and pH (full conversion is indicated when
the reaction mixture attains pH 7). After 4 h, the reaction
mixture was treated with Na2SO3 (2.5 g) and stirred at rt
for 30 min. The organic layer was separated and the
water layer extracted with ethyl acetate (3 · 60 mL).
The combined organic extracts were washed with brine
and dried over Na2SO4. The residue was purified by silica
gel column chromatography using EtOAc–pet. ether
(6:4) to afford 6 (3.2 g) as a white solid. Yield: 76%;
EtOAc–pet. ether (1:9) to give 8 (0.38 g) as a colourless
25
liquid. Yield: 91%; ½aŠ ¼ þ11:0 (c 0.92, CHCl3); IR
D
(CHCl3, cmꢀ1): mmax 3368, 1734, 1634, 1533, 1414; H
NMR (CDCl3, 200 MHz): d ꢀ0.17 (s, 3H), ꢀ0.08 (s,
3H), 0.75 (s, 9H), 1.43 (s, 9H), 3.78 (s, 3H), 4.44 (d,
J = 10 Hz, 1H), 5.21 (d, J = 9.2 Hz, 1H), 5.53(d,
J = 8.7 Hz, 1H), 7.24–7.34 (m, 5H); 13C NMR (CDCl3,
50 MHz): d ꢀ6.1, ꢀ5.7, 0.9, 18.0, 25.3, 28.1, 52.0, 57.0,
75.7, 126.4, 127.2, 128.1, 139.5, 155.0, 171.6. Anal.
Calcd for C21H35NO5Si (409.57): C, 61.58; H, 8.61;
N, 3.42. Found. C, 61.43; H, 8.57; N, 3.39.
1
4.6. Synthesis of (2R,3S)-2-[(tert-butyldimethyl-silanyl-
oxy)-3-hydroxy-1-phenylpropyl]-carbamic acid tert-butyl
ester 9
25
D
18
D
½aŠ ¼ þ28:5 (c 1.0, CHCl3) {lit.12c ½aŠ ¼ þ28:3 (c 1.0,
To a solution of 8 (0.225 g, 0.57 mmol) in dry dichloro-
methane (5 mL) was added a 1 M solution of DIBAL-
H (1.42 mL, 1.42 mmol) dropwise at 0 ꢁC and reaction
CHCl3)}; mp: 112 ꢁC [lit.12c mp 111–112 ꢁC]; IR (CHCl3,
cmꢀ1): mmax 3492, 3362, 1713, 1620, 1562, 1446, 1343; 1H

3582
S. R. V. Kandula, P. Kumar / Tetrahedron: Asymmetry 16 (2005) 3579–3583
25
D
mixture stirred for 3h. The solution was cooled to 0 ꢁC
and quenched with saturated sodium potassium tartrate
(2 mL), filtered through Celite pad and concentrated to
near dryness. The crude product was purified by silica
gel column chromatography using EtOAc–pet. ether
½aŠ ¼ þ10:8 (c 0.68, CHCl3); IR (CHCl3, cmꢀ1): mmax
1722, 1533, 1462, 1366, 1252; 1H NMR (CDCl3,
200 MHz): d 0.93(t, J = 9.2 Hz, 3H), 1.45 (s, 9H),
1.84–1.94 (m, 2H), 2.02 (br s, 1H), 2.41–2.50 (m, 2H),
3.87–3.90 (m, 1H), 4.12 (q, J = 8 Hz, 2H), 4.74–4.81
(m, 1H), 5.44 (d, J = 4 Hz, 1H), 7.19–7.40 (m, 5H);
13C NMR (CDCl3, 50 MHz): 14.0, 25.3, 26.3, 29.2,
64.8, 66.7, 67.8, 71.7, 126.8, 127.8, 127.9, 128.3, 157.2,
170.0. Anal. Calcd for C18H27NO5 (337.40): C, 64.07;
H, 8.07; N, 4.15. Found: C, 64.03; H, 8.02; N, 4.13.
(7:3) as eluent to give 9 (0.195 g) as a colourless oil. Yield:
25
93%; ½aŠ ¼ þ34:3 (c 1, CHCl3); IR (CHCl3, cmꢀ1): mmax
D
3520, 3312, 1562, 1423, 1399; 1H NMR (CDCl3,
200 MHz): d ꢀ0.17, (s, 3H), ꢀ0.08 (s, 3H), 0.75 (s, 9H),
1.43(s, 9H), 1.62, (br s, 1H, OH), 3.78 (d, J = 8.7 Hz,
2H), 4.38–4.41 (m, 1H), 4.71 (d, J = 9.2 Hz, 1H), 5.53
(d, J = 8.7 Hz, 1H), 7.24–7.34 (m, 5H); 13C NMR
(CDCl3, 50 MHz): d ꢀ5.7, ꢀ5.4, 17.8, 25.5, 28.2, 29.6,
60.1, 64.6, 70.4, 126.5, 126.7, 127.5, 128.4, 137.2, 153.6.
Anal. Calcd for C20H35NO4Si (381.56): C, 62.95; H,
9.25; N, 3.67. Found: C, 62.92; H, 9.21; N, 3.62.
4.9. Synthesis of (4S,5S)-(2,5-dihydroxy-1-phenyl-
pentyl)-carbamic acid tert-butyl ester 12
To a stirred solution of 11 (0.19 g, 0.56 mmol) was
added DIBAL-H (2.3M solution in toluene, 0.8 mL,
2.5 mmol) at 0 ꢁC. The reaction mixture was stirred
for another 3h at room temperature and then quenched
with saturated sodium potassium tartrate, filtered
through Celite powder and concentrated to near dry-
ness. The crude product was purified by silica gel col-
umn chromatography using EtOAc–pet. ether (3:7) as
4.7. Synthesis of (4S,5S)-5-tert-butoxycarbonylamino-4-
[(tert-butyldimethylsilanyloxy)-5-phenylpent-2-enoic acid
ethyl ester 10
To a mixture of PCC (0.144 g, 0.67 mmol), Celite pow-
der (200 mg) and anhydrous CH3COONa (0.54 g,
0.67 mmol) in dry CH2Cl2 (5 mL) was added alcohol 9
(0.17 g, 0.45 mmol) at 0 ꢁC. The reaction mixture was
stirred for 5 h at rt. The solvent was evaporated and
to the residue added ether. The slurry was stirred and fil-
tered through a pad of Celite. The residue was washed
4–5 times with ether. The filtrate was concentrated to
give the aldehyde, which was used in the next reaction
without any further purification.
eluent to give 12 (0.15 g) as a colourless liquid. Yield:
25
90%; ½aŠ ¼ þ15:1 (c 0.32, CHCl3); IR (CHCl3, cmꢀ1):
D
1
mmax 3541, 3326, 1523, 1463, 1262; H NMR (CDCl3,
200 MHz): d 1.44–1.48 (m, 4H), 1.46 (s, 9H), 2.12 (br
s, 2H), 3.52–3.57 (m, 2H), 4.52–4.63 (m, 1H), 4.73 (d,
J = 12 Hz, 1H), 5.54 (d, J = 12.5 Hz, 1H), 7.19–7.42
(m, 5H); 13C NMR (CDCl3, 50 MHz): 26.7, 27.0, 29.3,
29.6, 63.3, 70.6, 77.6, 124.2, 126.4, 127.1, 129.3, 156.5.
Anal. Calcd for C16H25NO4 (295.36): C, 65.06; H,
8.53; N, 4.74. Found. C, 65.03; H, 8.50; N, 4.72.
To a solution of (ethoxycarbonylmethylene)triphenyl-
phosphorane (0.15 g, 0.43mmol) in dry THF (5 mL)
was added a solution of the above crude aldehyde
(0.12 g, 0.32 mmol) in THF (3 mL) at 0 ꢁC. The ice-bath
was removed and the reaction mixture stirred at rt for
24 h and concentrated. Silica gel column chromatogra-
phy of the crude product using EtOAc–pet. ether
4.10. Synthesis of (2S,3S)-3-hydroxy-2-phenyl-piperidine-
1-carboxylic acid tert-butyl ester 1
To a stirred solution of 12 (0.1 g, 0.34 mmol) in dry
dichloromethane (5 mL) was added methanesulfonyl
chloride (0.028 mL, 0.37 mmol) at ꢀ78 ꢁC followed by
triethyl amine (0.051 mL, 0.37 mmol). After the mixture
was stirred at ꢀ78 ꢁC for 1 h, aqueous ammonium chlo-
ride (3mL) was added. The mixture was warmed to
room temperature and diluted with dichloromethane
(10 mL), washed with brine and dried over Na2SO4.
The solvent was removed and residue was purified by
flash chromatography using EtOAc–pet. ether as eluent
(0.5:9.5) as eluent gave 10 (0.13g) as a colourless liquid.
25
Yield: 91%; ½aŠ ¼ þ10:6 (c 0.74, CHCl3); IR (CHCl3,
D
cmꢀ1): mmax 3342, 1719, 1621, 1522, 1463, 1322; 1H
NMR (CDCl3, 200 MHz): d ꢀ0.23(s, H3 ), 0.04 (s,
3H), 0.77 (s, 9H), 0.86 (t, J = 6.2 Hz, 3H), 1.22 (s,
9H), 4.16 (q, J = 14.2 Hz, 2H), 4.46–4.53(m, 1H), 4.84
(d, J = 7.4 Hz, 1H), 5.28 (d, J = 13.3, 1H), 5.99 (d,
J = 15.1 Hz, 1H), 6.99 (dd, J = 15.6, 4.58 Hz, 1H).
7.20–7.35 (m, 5H); 13C NMR (CDCl3, 50 MHz): d
ꢀ6.0, ꢀ5.0, 0.9, 14.1, 18.0, 25.7, 28.2, 29.6, 60.4, 122.1,
126.4, 127.3, 128.2, 147.6, 155.4, 166.1. Anal. Calcd
for C24H39NO5Si (449.63): C, 64.11; H, 8.74; N, 3.11.
Found. C, 63.98; H, 8.71; N, 3.08.
(8:2) to give 1 (72 mg) as a yellow liquid. Yield: 77%;
25
½aŠ ¼ þ36:2 (c 0.66, CHCl3) {lit.9a +38.3 (c 1.92,
D
CHCl3)}; IR (CHCl3, cmꢀ1): mmax 3445, 2933, 1702,
1
1410, 1352, 1230, 1160; H NMR (CDCl3, 200 MHz):
d 1.40 (s, 9H), 1.52–1.67 (m, 4H), 2.81 (ddd, J = 6.2,
10.5, 12.6 Hz, 1H), 3.88–4.05 (m, 1H), 4.12–4.24 (m,
1H), 4.48 (d, J = 7.5 Hz, 1H), 5.31 (d, J = 5.6 Hz, 1H),
7.17–7.36 (m, 5H); 13C NMR (CDCl3, 50 MHz): d
24.1, 27.3, 28.2, 39.0, 62.1, 69.4, 80.0, 127.1, 128.2,
128.3, 138.0, 156.0.
4.8. Synthesis of (4S,5S)-5-(tert-butoxycarbonylamino)-
4-hydroxy-5-phenylpentanoic acid ethyl ester 11
To a solution of 10 (0.2 g) in methanol (10 mL) was
added 20 mg of 10% Pd/C and mixture stirred under a
hydrogen atmosphere for 6 h. After completion of reac-
tion, the solution was filtered and the filtrate was con-
centrated. The crude product was purified on silica gel
column using EtOAc–pet. ether (1:9) as eluent to give
4.11. Synthesis of (2S,3S)-1-(tert-butyoxycarbonyl)-2-phen-
yl-3-[(3,5)-bis(trifluoromethyl)benzyloxy]piperidine 13
To a stirred solution of sodium hydride (10 mg, 60% dis-
persion in mineral oil, 0.43mmol) and dry DMF (1 mL)
at 0 ꢁC, was added a solution of 1 (0.1 g, 0.36 mmol) and
11 (0.14 g) as
a
viscous liquid. Yield: 93%;

S. R. V. Kandula, P. Kumar / Tetrahedron: Asymmetry 16 (2005) 3579–3583
3583
3. Lotz, M.; Vaughan, J. H.; Carson, D. A. Science 1988,
241, 1218–1221.
4. Perianan, A.; Synderman, R.; Malfroy, B. Biochem.
Biophy. Res. Commun. 1989, 161, 520–524.
5. Lotz, M.; Carson, D. A.; Vaughan, J. H. Science 1987,
235, 893–895.
6. Mantyh, C. R.; Gates, T. S.; Zimmerman, R. P.; Welton,
M. L.; Passaro, E. P.; Vigna, S. R.; Maggio, J. E.; Kruger,
L.; Mantyh, P. W. Proc. Natl. Acad. Sci. U.S.A. 1988, 85,
3235–3239.
3,5-bis(trifluoromethyl)benzyl bromide (110 mg, 0.36
mmol) in dry DMF (1 mL). The reaction mixture was
stirred for 12 h at 80 ꢁC. The reaction was quenched with
water (3mL) and extracted with Et 2O (5 mL). The com-
bined organic layers were washed with brine (3mL),
dried over anhydrous Na2SO4, filtered and concentrated.
The residue was purified by flash chromatography on
silica gel column using EtOAc–pet. ether (3:7) to provide
25
13 (0.14 g) as a colourless oil. Yield: 78%; ½aŠ ¼ þ31:4
D
25
D
(c 1.0, CHCl3) {lit.9a ½aŠ ¼ þ30:3 8 (c 1.55, CHCl3)}; IR
7. Goadsby, P. J.; Edvinsson, L.; Ekman, R. Ann. Neurol.
1988, 23, 193–196.
(neat, cmꢀ1): mmax 2945, 1644, 1381, 1345, 1253, 1172,
875, 665; H NMR (CDCl3, 200 MHz): d 1.42 (s, 9H),
1
8. (a) Baker, R.; Harrison, T.; Hollingworth, G. J.; Awain,
C. J.; Williams, B. J. EP 0528495A1, 1993; (b) Harrison,
T.; Williams, B. J.; Swain, C. J.; Ball, R. G. Bioorg. Med.
Chem. Lett. 1994, 4, 2545–2549; (c) Calvez, O.; Langlois,
N. Tetrahedron Lett. 1999, 40, 7099–7100; (d) Mandar, S.
B.; Upadhyay, P. K.; Kumar, P. Tetrahedron Lett. 2004,
45, 987–988.
9. (a) Bhaskar, G.; Rao, B. V. Tetrahedron Lett. 2003, 44,
915–917; (b) Huang, P. Q.; Liu, X. L.; Wei, B. G.; Ruan,
Y. P. Org. Lett. 2003, 5, 1927–1929; (c) Lemire, A.;
Grenon, M.; Pourasharf, M.; Charette, A. B. Org. Lett.
2004, 6, 3517–3520; (d) Yoon, Y. J.; Joo, J. E.; Lee, K. Y.;
Kim, Y. H.; Oh, C. Y.; Ham, W. H. Tetrahedron Lett.
2005, 46, 739–741.
1.32–1.66 (m, 2H), 1.78–2.12 (m, 2H), 2.76 (ddd,
J = 11.2, 9.8, 4.6 Hz, 1H), 3.79–3.98 (m, 2H), 4.66
(d, J = 11.4 Hz, 1H), 4.74 (d, J = 12.2 Hz, 1H), 5.67
(d, J = 4.6 Hz, 1H), 7.22–7.38 (m, 3H), 7.42–7.52
(m, 2H), 7.66 (s, 2H), 7.78 (s, 1H); 13C NMR (CDCl3,
50 MHz): 20.2, 25.3, 26.3, 27.2, 44.4, 63.2, 71.2, 77.0,
120.2, 123.1, 126.7, 127.3, 127.8, 132.4, 141.2, 142.4,
159.0.
4.12. Synthesis of (2S,3S)-2-phenyl-3-[(3,5)-bis(trifluoro-
methyl)benzyloxy]piperidine [(+)-L-733,060] 2
10. (a) Pais, G. C. G.; Fernandes, R. A.; Kumar, P.
Tetrahedron 1999, 55, 13445–13450; (b) Fernandes, R.
A.; Kumar, P. Tetrahedron: Asymmetry 1999, 10, 4349–
4356; (c) Fernandes, R. A.; Kumar, P. Eur. J. Org. Chem.
2002, 2921–2923; (d) Kandula, S. V.; Kumar, P. Tetra-
hedron Lett. 2003, 44, 6149–6151; (e) Gupta, P.; Naidu, S.
V.; Kumar, P. Tetrahedron Lett. 2004, 45, 849–851; (f)
Naidu, S. V.; Gupta, P.; Kumar, P. Tetrahedron Lett.
2005, 46, 2129–2131; (g) Kumar, P.; Naidu, S. V.; Gupta,
P. J. Org. Chem. 2005, 70, 2843–2846; (h) Kumar, P.;
Naidu, S. V. J. Org. Chem. 2005, 70, 4207–4210.
11. (a) Fernandes, R. A.; Kumar, P. Eur. J. Org. Chem. 2000,
3447–3449; (b) Fernandes, R. A.; Kumar, P. Tetrahedron
Lett. 2000, 41, 10309–10312; (c) Subba Rao, K. V.;
Kumar, P. Tetrahedron Lett. 2003, 44, 1957–1958; (d)
Pandey, R. K.; Fernandes, R. A.; Kumar, P. Tetrahedron
Lett. 2002, 43, 4425–4426; (e) Fernandes, R. A.; Kumar,
P. Synthesis 2003, 129–135; (f) Naidu, S. V.; Kumar, P.
Tetrahedron Lett. 2003, 44, 1035–1037; (g) Kondekar, N.
B.; Rao, K. V. S.; Kumar, P. Tetrahedron Lett. 2004, 45,
5477–5479; (h) Pandey, S. K.; Rao, K. V. S.; Kumar, P.
Tetrahedron Lett. 2004, 45, 5877–5879; (i) Bodas, M. S.;
Kumar, P. Tetrahedron Lett. 2004, 45, 8461–8463; (j)
Kumar, P.; Bodas, M. S. J. Org. Chem. 2005, 70, 360–363.
12. (a) Li, G.; Angert, H. H.; Sharpless, K. B. Angew. Chem.,
Int. Ed. 1996, 35, 2813–2817; (b) Bruncko, M.; Schlingloff,
G.; Sharpless, K. B. Angew. Chem., Int. Ed. 1997, 36,
1483–1487; (c) Lee, S. H.; Yoon, J.; Chung, S. H.; Lee,
Y. S. Tetrahedron 2001, 57, 2139–2145.
To an ice-bath solution of 13 (25 mg, 0.05 mmol) in dry
CH2Cl2 (1 mL) was added trifluoroacetic acid (73 lL,
0.05 mmol). The reaction mixture was stirred at room
temperature for 12 h and then quenched with satu-
rated NaHCO3 and extracted with dichloromethane
(3 · 5 mL). The combined organic layers were washed
with brine and dried over Na2SO4, filtered and con-
centrated under reduced pressure. The crude product
was purified by silica gel column chromatography
using CH3OH–CHCl3 (1:9) as eluent to give 2 (14 mg),
25
25
½aŠ ¼ þ36:2 (c 0.66, CHCl3) {lit.9a ½aŠ ¼ þ34:3
D
D
(c 1.32, CHCl3)}. Yield: 70%. The physical and spectro-
scopic data of 2 were in full agreement with those
reported.9a
Acknowledgements
Subba Rao V. Kandula thanks CSIR, New Delhi, for
senior research fellowship. We are grateful to Dr. M.
K. Gurjar, for his support and encouragement. Finan-
cial support from DST, New Delhi (Grant No. SR/S1/
OC-40/2003) is gratefully acknowledged.
References
13. Oliveto, E. P.; Gerold, C. Org. Synth. Collect. 1963, 4,
104–105.
14. Montiel-Smith, S.; Cervantes-Mejia, V.; Dubois, J.; Gue-
nard, D.; Gueritte, F.; Sandoval-Ramirez, J. Eur. J. Org.
Chem. 2002, 2260–2264.
1. von Euler, U. S.; Gaddum, J. H. J. Physiol. 1931, 72, 74–
87.
2. Guard, S.; Waston, S. P. Neurochem. Int. 1991, 18, 149–
165.