Enantioselective synthesis of (+)-l-733,060

Article abstract of DOI:10.1016/j.tetasy.2007.04.006

An efficient enantioselective synthesis of (+)-l-733,060 from cinnamyl alcohol is described. The key steps include a Sharpless asymmetric epoxidation, a regioselective allyl opening of an epoxide and piperidine ring formation via a one pot Staudinger/aza-Wittig reaction.

Full text of DOI:10.1016/j.tetasy.2007.04.006

Tetrahedron: Asymmetry 18 (2007) 982–987
Enantioselective synthesis of (+)-L-733,060
Shijo K. Cherian and Pradeep Kumar*
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411 008, India
Received 9 March 2007; accepted 4 April 2007
Abstract—An efficient enantioselective synthesis of (+)-L-733,060 from cinnamyl alcohol is described. The key steps include a Sharpless
asymmetric epoxidation, a regioselective allyl opening of an epoxide and piperidine ring formation via a one pot Staudinger/aza-Wittig
reaction.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
shown that the cis-relationship between C2 and C3 substit-
uents on the piperidine ring of 2 and 3 is required for opti-
mum binding activity.6 Routes leading to the valuable
intermediate 1 and compounds 2 and 3 mainly rely on race-
mic synthesis followed by resolution techniques2b or
lengthy asymmetric synthesis of 1 and 2, which has been
reported in recent literatures.8 In continuation of our
research programme aimed at developing enantioselective
synthetic routes to the lactones9 and amino alcohols,10
we have developed a new asymmetric synthetic strategy
to (+)-L- 733,060 2. In this strategy the chirality was intro-
duced by a Sharpless asymmetric epoxidation (AE) while
piperidine ring formation was achieved by one pot Stau-
dinger/aza-Wittig reaction.
The peptide neurotransmitter, Substance P (SP) involves a
variety of biological actions, such as pain transmission,
vasodilation, smooth muscle contraction and neurogenic
inflammation.1 This tachykinin family peptide member
preferentially binds to the NK1 receptor. The search for
non-peptide antagonists of the NK1 receptor led to the dis-
covery of 2,3-disubstituted piperidine derivatives L-733,060
22 and CP-99,994 33 (Fig. 1). They have excellent affinity
and selectivity with human NK1 receptors and possess
potent antiemetic activity.4 They are expected to act as a
remedy for a wide range of diseases, including arthritis,
asthma and migrain.5
HN
CF3
BocN
2. Results and discussion
O
As shown in Scheme 1, the synthesis of (+)-L-733,060 was
initiated by AE of commercially available cinnamyl alcohol
OH
CF3
1
2
(+)-L-733,060
HN
4 to afford trans-epoxide 5 in 89% yield with >99% ee. (After
27
recrystallization) ½aꢀD ¼ þ48:7 (c 2.4, CHCl3) {lit.11
25
½aꢀD ¼ ꢁ49:6 (c 2.4, CHCl3) for (ꢁ)-5}. The regioselective
HN
(+)-CP-99,994
epoxide opening of 5 with NaN3 gave a single regioisomer
6 in excellent yield.12 In order to establish the desired cis-
configuration, we planned a three-step sequence involving
the chemoselective pivalation13 of diol 6, mesylation of sec-
ondary hydroxyl 7 using MsCl and final treatment of crude
mesylate 8 with K2CO3 in methanol to furnish the appropri-
ately oriented cis-azido-epoxide 9 in 80% overall yield.
3
OMe
Figure 1.
In recent years, there have been several reports on the syn-
thesis and structural modification studies of the above
compounds. Structure–activity relationship studies have
With a substantial amount of epoxide 9 in hands, our next
aim was to elongate the chain through regioselective
ring opening of epoxide 9 by allylation (Scheme 2). The
*
Corresponding author. Tel.: +91 20 25902050; fax: +91 20 25902629;
e-mail: pk.tripathi@ncl.res.in
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.04.006

S. K. Cherian, P. Kumar / Tetrahedron: Asymmetry 18 (2007) 982–987
983
N3
N3
N3
N3
O
reagent
and conditions
b
a
OH
OH
OH
X
O
+
OH
10
OH
OH
(table 1)
9
5
6
11
4
N3
N3
Scheme 2.
e
c
OR1
O
N3
N3
OR2
9
b
O
7 : R1 = Piv, R2 = H
8 : R1 = Piv, R2 = Ms
a
d
10
OTBS
OTBS
12
13
Scheme 1. Reagents and conditions: (a) (S,S)-(ꢁ)-DET, Ti(OPr-i)4,
˚
TBHP, MS 4 A, CH2Cl2, ꢁ20 ꢁC, 3 h, 89%; (b) NaN3, NH4Cl, MeOH/
HN
BocN
H2O (8:1), 65 ꢁC, 5 h, 98%; (c) PivCl, Py/CH2Cl2 (1:1), 0 ꢁC–rt, 5 h; (d)
MsCl, Et3N, DMAP, CH2Cl2, 0 ꢁC–rt, 1 h; (e) K2CO3, MeOH, rt,
overnight, 80% (overall 3 steps).
g
e
c, d
OTBS
OR
14
R=TBS
R= H
15
1
f
results are summarized in Table 1. Opening of epoxide 9
with allylmagnesium bromide14a (entry 1) gave only halide
opened byproducts. Similarly the use of BF3ÆOEt2 with all-
ylsilane was also disappointing as it resulted in poor yields
of the desired product 10 (entries 2 and 3) along with the
hydroxyl opened product as major one. The reaction
with allylstannane and TiCl4 in CH2Cl2 at ꢁ78 ꢁC14b
(entry 4) also failed to give allylated product 10. The use
of 1:1 equiv amounts of allylsilane and TiCl4 in CH2Cl2
at ꢁ78 ꢁC gave 10 in moderate yield (entry 5). We were
finally able to improve the yield of 10 by using 3 equiv of
allylsilane with slow addition of freshly distilled TiCl4
(entry 6). The subsequent protection of the secondary
hydroxyl group as a TBS ether was successfully carried
out using TBS triflate and 2,6-lutidine15 to afford 12 in
95% yield (Scheme 3).
BocN
CF3
h
2
O
CF3
16
Scheme 3. Reagents and conditions: (a) TBSOTf, 2,6-lutidine, 0 ꢁC, 1 h,
95%; (b) OsO4, NaIO4, 2,6-lutidine, 1,4-dioxane/H2O (3:1), 0 ꢁC, 3 h; (c)
PPh3, THF, rt, 16 h; (d) NaBH4, MeOH, 0 ꢁC, 30 min, (65% yield from
12); (e) Boc2O,Et3N, CH2Cl2, 2 h, 95%; (f) TBAF, THF, 0 ꢁC–rt, 10 h,
90%; (g) 3,5-bis(trifluoromethyl)benzyl bromide, NaH, dry DMF, 80 ꢁC,
12 h, 78%; (h) CF3COOH, MeOH, rt, 12 h, 70%.
yields. The physical and spectroscopic data of 2 were in full
agreement with those reported.7b
3. Conclusion
According to our synthetic strategy, compound 12 had all
the ideal functionalities to carry out the required hetero-
cyclic ring formation reaction. The oxidation of olefin16
12 gave the crucial azido-aldehyde intermediate 13 required
for the one pot Staudinger/aza-Wittig reaction.17 Without
further purification of aldehyde 13, the Staudinger reduc-
tion was performed by the addition of triphenylphosphine
to azido-aldehyde 13 in dry THF. The resulting aza-ylide
was condensed intramolecularly with aldehyde to provide
a six membered imine. The in situ reduction of the imine
with NaBH4 and methanol in the same reaction medium
provided the free amine 14 in good yield. Subsequently free
amine 14 was protected as a Boc derivative and TBS was
selectively deprotected using TBAF to obtain compound
118 in 90% yields. Etherification of the hydroxy group of
1 with 3,5-bis(trifluoromethyl)benzyl bromide in the pres-
ence of NaH afforded 16.7b Finally N-Boc deprotection
of 16 using TFA furnished the target molecule 2 in good
In conclusion, a flexible and highly enantioselective synthe-
sis of (+)-L-733,060 has been achieved by employing a
Sharpless asymmetric epoxidation and a one pot Stau-
dinger/aza-Wittig reaction as key steps. The synthetic strat-
egy described herein has significant potential for further
extension to other NK1 receptor antagonists. Studies are
currently in progress in this direction.
4. Experimental
4.1. General experimental
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
Table 1. Allyl opening of epoxide 9 by different nucleophiles under various reaction conditions
Entry
Reaction conditions
Yield % of 10
Yield % of 11
1
2
3
4
5
6
Allylmagnesium bromide, CuI, THF, 0 ꢁC–rt, over night
Allyltrimethylsilane, BF3ÆOEt2, CH2Cl2, ꢁ78 ꢁC, 2 h
Allyltrimethylsilane, BF3ÆOEt2, CH2Cl2, ꢁ30 ꢁC to 0 ꢁC, 3 h
Allyltributylstannane, TiCl4, CH2Cl2, ꢁ78 ꢁC, 1 h
—
5
8
—
55
65
90% X = Br, I
75% X = OH
60% X = OH
90% X = Cl
25% X = Cl
10% X = Cl
Allyltrimethylsilane (1 equiv), TiCl4, CH2Cl2, ꢁ78 ꢁC, 1 h
Allyltrimethylsilane (3 equiv), TiCl4, CH2Cl2, ꢁ78 ꢁC, 1 h

984
S. K. Cherian, P. Kumar / Tetrahedron: Asymmetry 18 (2007) 982–987
sodium D line on a JASCO-P-1020-polarimeter. Infrared
spectra were recorded on Perkin–Elmer FT-IR spectro-
meter. Enantiomeric excess was measured using either the
chiral HPLC or by comparison with specific rotation.
Elemental analyses were carried out with a Carlo Erba
CHNS-O analyzer.
4.4. Synthesis of (2R,3S)-2-(azido-phenyl-methyl)-oxirane 9
Diol 6 (7.0 g, 36.23 mmol) was dissolved in dry pyridine
(40 mL) and dry CH2Cl2 (40 mL) at 0 ꢁC under argon
and pivaloyl chloride (4.44 mL, 36.23 mmol) was added
dropwise over a period of 30 min. The mixture was stirred
at room temperature for 5 h. Concentration followed by
azeotropic removal of pyridine gave compound 7, which
was used in the next reaction without any further
purification.
4.2. Synthesis of (2R,3R)-(3-phenyl-oxiranyl)-methanol 5
To a stirred solution of (S,S)-(ꢁ)-diisopropyl tartrate
(0.83 mL, 0.92 g, 3.91 mmol) in CH2C12 (450 mL) at
˚
ꢁ20 ꢁC, 2.8 g activated powdered 4 A molecular sieves,
Compound 7 was then dissolved in dry CH2Cl2 (30 mL)
under argon and treated with MsCl (2.80 mL, 36.23 mmol),
Et3N (6.0 mL, 43.34 mmol) and a catalytic amount of
DMAP. The reaction mixture was stirred at room temper-
ature for 1 h, then quenched with water. The water layer
was extracted with CH2Cl2 (3 · 25 mL) and the combined
organic layers were washed with brine, dried over Na2SO4
and concentrated to give a crude product 8, which was
dissolved in MeOH (20 mL) and treated with K2CO3
(5.0 g, 36.23 mmol). This mixture was stirred overnight at
room temperature and then filtered through Celite.
Removal of the volatiles under reduced pressure, fol-
lowed by column chromatography on silica gel (eluent:
petroleum ether/EtOAc 19:1) produced epoxide 9 (5.08 g,
Ti(OPr-i)4 (0.78 mL, 0.74 g, 2.61 mmol) and 3 M solution
of TBHP in toluene (34.78 mL, 104.34 mmol) were added
sequentially. The mixture was allowed to stir at ꢁ20 ꢁC
for 1 h and then a solution of freshly distilled (E)-3-phen-
yl-2-propenol (cinnamyl alcohol) (7.0 g, 52.17 mmol) in
10 mL of CH2C12 was added dropwise over 30 min. After
3 h at ꢁ20 ꢁC, the reaction was quenched at ꢁ20 ꢁC with
10% aqueous solution of NaOH saturated with NaCl
(4.2 mL). After diethyl ether (60 mL) was added the cold
bath was allowed to warm to 10 ꢁC, stirring was main-
tained at 10 ꢁC while MgSO4 (5 g) and Celite (500 mg) were
added. After another 15 min of stirring, the mixture was
allowed to settle and clean solution was filtered through a
pad of Celite and washed with diethyl ether. Azeotropic re-
moval of TBHP with toluene at a reduced pressure and
subjection to high vacuum gave 5 as a yellow oil. Recrystal-
lization from petroleum ether/diethylether gave yellow
crystals of 5 (6.97 g, 89%, >99% ee determined by spectro-
overall yield 80% from 6) as
a
yellow liquid.
27
½aꢀD ¼ þ139:0 (c 1.1, CHCl3); IR (CHCl3, cmꢁ1): 3019,
2927, 2106, 1601, 1493, 1455, 1251, 1123, 863, 758; 1H
NMR (CDCl3, 500 MHz): 2.77–2.78 (m, 1H), 2.84 (m,
1H), 3.28–3.30 (m, 1H), 4.29 (d, J = 6 Hz, 1H), 7.39–7.45
(m, 5H); 13C NMR (CDCl3, 100 MHz): 44.84, 54.72,
66.89, 127.28, 128.95, 135.73. Anal. Calcd for C9H9N3O
(175.19): C, 61.70; H, 5.18; N, 23.99. Found: C, 61.81; H,
5.15; N, 23.91.
scopic analysis of the ester derived from (+)-MTPA chlo-
27
ride) mp = 53.5–54 ꢁC ½aꢀD ¼ þ48:7 (c 2.4, CHCl3) {lit.11
25
½aꢀD ¼ ꢁ49:6 (c 2.4, CHCl3) for (ꢁ)-5}. IR (CHCl3,
cmꢁ1): 3428, 3017, 2927, 2871, 1606, 1462, 1392, 1256,
1
1108, 1068, 1027, 881, 863, 840, 758; H NMR (CDCl3,
200 MHz): 2.25 (br s, 1H), 3.26–3.32 (m, 1H), 3.76–3.84
(d, J = 4.6, 12.8 Hz, 1H), 3.93–3.94 (d, J = 2.5 Hz, 1H),
4.02–4.10 (dd, J = 2.57, 12.76 Hz, 1H), 7.2–7.42 (m, 5H);
13C NMR (CDCl3, 100 MHz): 55.58, 61.23, 62.44,
127.57, 128.08, 128.28, 136.48. Anal. Calcd for C9H10O2
(150.18): C, 71.98; H, 6.71. Found. C, 71.94; H, 6.82.
4.5. Synthesis of (1S,2S)-1-azido-1-phenyl-hex-5-en-2-ol 10
To a stirred solution of 9 (3.0 g, 17.12 mmol) and allylTMS
(8.16 g, 51.37 mmol) in CH2Cl2 (50 mL) at ꢁ78 ꢁC, a solu-
tion of TiC14 (1.88 mL, 17.12 mmol) in CH2Cl2 (35 mL)
was added through the cold inner surface of the flask over
a period of 30 min. The mixture was stirred at this temper-
ature for 1 h and then the cold bath removed. Subse-
quently, 30% aqueous NaHCO3 (5 mL) and ether
(50 mL) were added, and the mixture stirred vigorously
while being allowed to return to room temperature. The
organic phase was separated, washed with brine, dried over
Na2SO4 and purified by silica gel column chromatography
4.3. Synthesis of (2S,3S)-3-azido-3-phenyl-propane-1,2-diol
6
The epoxy alcohol 5 (6.0 g, 39.95 mmol), NaN3 (5.19 g,
79.90 mmol) and NH4Cl (4.27 g, 79.90 mmol) in a solvent
mixture of methanol (32 mL) and water (4 mL) were
warmed at 65 ꢁC for 5 h. The reaction mixture was cooled
and the solid filtered. The filtrate was concentrated to a resi-
due, which was taken into ethyl acetate, washed with brine
and water, dried and concentrated to give a syrup, which
was purified by column chromatography (eluent: petroleum
(eluent: petroleum ether/EtOAc 20:1) to give 10 as a yellow
27
liquid, (2.42 g, 65%) ½aꢀD ¼ þ178:4 (c 1.0, CHCl3);
IR (CHCl3, cmꢁ1): 3430, 3031, 2977, 2921, 2103, 1640,
1
1603, 1493, 1453, 1080, 995, 913, 874, 757, 701; H NMR
ether/EtOAc 7:3) to yield a yellow liquid 6, 7.56 g (98%).
(CDCl3, 400 MHz): 1.42–1.52 (m, 1H), 1.62–1.71 (m,
1H), 1.84 (br s, 1H), 2.05–2.18 (m, 1H), 2.23–2.31 (m,
1H), 3.80–3.84 (m, 1H), 4.49–4.50 (d, J = 5.8 Hz, 1H),
4.97–5.0 (m, 1H), 5.02–5.07 (m, 1H), 5.75–5.86 (m, 1H),
7.36–7.44 (m, 5H); 13C NMR (CDCl3, 100 MHz): 29.78,
31.68, 70.52, 73.50, 115.12, 127.95, 128.78, 136.13,
137.97, 138.58. Anal. Calcd for C12H15N3O (217.27): C,
66.34; H, 6.96; N, 19.34. Found: C, 66.27; H, 6.91; N,
19.36.
27
½aꢀD ¼ þ166:3 (c 1.2, CHCl3); IR (CHCl3, cmꢁ1): 3392,
3032, 2932, 2871, 2099, 1602, 1493, 1454, 1384, 1100,
1039, 877, 828, 759; 1H NMR (CDCl3, 200 MHz): 3.38
(br s, 2H), 3.58–3.75 (m, 2H), 3.78–3.86 (m, 1H), 4.57–
4.67 (d, J = 7 Hz, 1H), 7.2–7.47 (5H, m); 13C NMR
(CDCl3, 50 MHz): 62.83, 66.97, 73.97, 127.76, 128.76,
128.92, 136.02. Anal. Calcd for C9H11N3O2 (193.21): C,
55.95; H, 5.74; N, 21.75. Found: C, 55.91; H, 5.73; N, 21.84.

S. K. Cherian, P. Kumar / Tetrahedron: Asymmetry 18 (2007) 982–987
985
4.6. Synthesis of (1S,2S)-[1-(azido-phenyl-methyl)-pent-4-
enyloxy]-tert-butyl-dimethyl-silane 12
127.94, 128.40, 142.61. Calcd for C17H29NOSi (291.51):
C, 70.04; H, 10.03; N, 4.80; Si, 9.63. Found: C, 70.05; H,
10.01; N, 4.82; Si, 9.61.
2,6-Lutidine (2.45 mL, 21.17 mmol) was added to a stirred
solution of 10 (2.30 g, 10.58 mmol) in anhydrous CH2Cl2
(20 mL). After the solution was cooled to 0 ꢁC with an
ice-bath, TBSOTf (3.65 mL, 15.87 mmol) was added to it.
The mixture was stirred for 1 h, then quenched with satu-
rated NH4Cl (10 mL), extracted with Et2O (3 · 15 mL)
and dried over anhydrous Na2SO4. After concentration,
the crude product was purified by silica gel column chro-
matography (eluent: petroleum ether/EtOAc 30:1) to afford
4.8. Synthesis of (2S,3S)-1-[3-(tert-butyl-dimethyl-silanyl-
oxy)-2-phenyl-piperidin-1-yl]-2,2-dimethyl-propan-1-one 15
To a suspension of compound 14 (0.6 g, 2.06 mmol) in
CH2Cl2 (10 mL) was added Et3N (0.43 mL, 3.09 mmol).
The mixture was cooled to 0 ꢁC and (Boc)2O (0.71 mL,
3.09 mmol) was added dropwise with stirring. The mixture
was then warmed to room temperature and stirred for 2 h.
The reaction was quenched with saturated NH4Cl
(100 mL) and extracted with CH2Cl2 (3 · 15 mL), dried
over anhydrous Na2SO4. After concentration under re-
duced pressure, the compound was purified by silica gel
column chromatography (eluent: petroleum ether/EtOAc
compound 12, 3.33 g (95%) as
a
brown liquid,
27
½aꢀD ¼ þ75:26 (c 1.1, CHCl3); IR (CHCl3, cmꢁ1): 3018,
2954, 2930, 2896, 2858, 2105, 1640, 1603, 1472, 1453,
1361, 1256, 1104, 1058, 976, 888, 837, 758; 1H NMR
(CDCl3, 200 MHz): ꢁ0.06 (s, 3H), 0.06 (s, 3H), 0.89 (s,
9H), 1.42–1.57 (m, 1H), 1.56–1.81 (m, 1H), 1.94–2.09 (m,
1H), 2.13–2.27 (m, 1H), 3.86–3.96 (m, 1H), 4.56-4.59 (d,
J = 5.05 Hz, 1H), 4.91–4.94 (m, 1H), 4.96–5.04 (m, 1H),
5.67–5.87 (m, 1H), 7.37–7.38 (m, 5H); 13C NMR (CDCl3,
100 MHz): ꢁ4.72, ꢁ4.66, 18.02, 25.79, 28.99, 31.57,
69.72, 75.44, 114.59, 127.83, 128.03, 128.39, 137.13,
138.34. Anal. Calcd for C18H29N3OSi (331.54): C, 65.21;
H, 8.82; N, 12.67; Si, 8.47. Found: C, 65.24, H, 8.83; N,
12.65; Si, 8.45.
8:1) to give 15 as a pale yellow oil 0.77 g, (95%).
27
½aꢀD ¼ þ18:4 (c 1.1, CHCl3); IR (CHCl3, cmꢁ1): 3023,
3018, 2979, 2955, 1696, 1602, 1495, 1418, 1367, 1257,
1168, 1137, 984, 876, 851, 756; 1H NMR (CDCl3,
400 MHz): 0.05 (s, 3H), 0.14 (s, 3H), 0.92 (s, 9H), 1.50 (s,
9H), 1.66–1.69 (m, 2H), 1.77–1.80 (m, 1H), 1.90–1.96 (m,
1H), 2.71–2.78 (m, 1H), 3.96 (d, J = 13 Hz, 1H), 4.06–
4.11 (m, 1H), 5.40 (d, J = 4.5 Hz, 1H), 7.23–7.35 (m,
3H), 7.58–7.60 (m, 2H); 13C NMR (CDCl3, 100 MHz):
ꢁ5.09, ꢁ4.93, 17.99, 23.98, 25.75, 27.88, 28.30, 38.62,
58.68, 71.87, 79.67, 126.44, 127.89, 126.46, 138.85,
155.25. Calcd for C22H37NO3Si (391.63): C, 67.47; H,
9.52; N, 3.58; Si, 7.17. Found: C, 67.43; H, 9.51; N, 3.61;
Si, 7.15.
4.7. Synthesis of (2S,3S)-3-(tert-butyl-dimethyl-silanyloxy)-
2-phenyl-piperidine 14
To a solution of compound 12 (1.50 g, 4.52 mmol) in diox-
ane–water (3:1, 20 mL) were added 2,6-lutidine (1.05 mL,
9.04 mmol), OsO4 (0.1 M solution in toluene, 0.78 mL,
0.023 g, 0.09 mmol) and NaIO4 (3.87 g, 18.08 mmol). The
reaction was stirred at 25 ꢁC for 3 h. After the reaction
was complete, water (10 mL) and CH2Cl2 (20 mL) were
added. The organic layer was separated, and the water
layer extracted with CH2Cl2 (3 · 15 mL). The combined or-
ganic layer was washed with brine and dried over Na2SO4.
After concentration, compound 13 was used in the next
reaction without any further purification.
4.9. Synthesis of (2S,3S)-1-(3-Hydroxy-2-phenyl-piperidin-
1-yl)-2,2-dimethyl-propan-1-one: 1
To a solution of 15 (0.60 g, 1.53 mmol) in anhydrous THF
(20 mL) was added TBAF (2.30 mL, 1 M in THF,
2.30 mmol) successively with stirring. The mixture was stir-
red for 10 h, then quenched with water (10 mL) at 0 ꢁC and
diluted with CH2Cl2 (20 mL). After being stirred for about
10 min, the solution was extracted with CH2Cl2
(3 · 15 mL), and dried over anhydrous Na2SO4. After con-
centration, the crude product was purified by silica gel
chromatography (eluent: petroleum ether/EtOAc 8:2) to
To a solution of compound 13 at room temperature in
THF (200 mL) was added solid PPh3 (4.74 g, 18.08 mmol).
The reaction was allowed to stir at room temperature for
16 h until all starting aldehyde was consumed. NaBH4
(0.43 g, 11.30 mmol) and MeOH (0.51 mL, 11.30 mmol)
were added at 0 ꢁC. After stirring for 30 min, the reaction
was quenched with saturated aqueous NaHCO3 and
extracted with CH2Cl2 (3 · 20 mL). The combined organic
extracts were dried over Na2SO4 and concentrated in
vacuum. Purification by neutralized silica gel column
chromatography (eluent: CH2Cl2/MeOH 100:1) afforded
afford product 1, as
a
yellow oil 0.38 g (90%).
27
½aꢀD ¼ þ37:5 (c 1.0, CHCl3); IR (CHCl3, cmꢁ1): 3447,
3018, 2979, 2955, 1676, 1602, 1495, 1418, 1367, 1327,
1168, 1137, 984, 876, 851, 756; 1H NMR (CDCl3,
200 MHz): 1.40 (s, 9H), 1.55–2.01 (m, 5H), 2.74–2.89
(ddd, J = 3.15, 9.73, 12.88 Hz, 1H), 4.0–4.09 (m, 1H),
4.45–4.49 (m, 1H), 5.32 (m, 1H), 7.13–7.35 (m, 5H); 13C
NMR (CDCl3, 100 MHz): 23.98, 25.92, 28.36, 39.90,
60.24, 67.48, 80.11, 126.86, 126.89, 138.15, 156.70. Calcd
for C16H23NO3 (277.37): C, 69.29, H, 8.36, N, 5.05. Found:
C, 69.31; H, 8.32; N, 5.01.
compound 14 (0.86 g, 65% yield) as a pale yellow oil.
27
½aꢀD ¼ þ51:5 (c 1.1, MeOH); IR (CHCl3, cmꢁ1): 3343,
3019, 2930, 2857, 1603, 1472, 1106, 931, 887, 758. 1H
NMR (CDCl3, 200 MHz): ꢁ0.47 (s, 3H), ꢁ0.14 (s, 3H),
0.77 (s, 9H), 1.34 (br s, 1H), 1.44–1.73 (m, 2H), 1.71–1.85
(m, 2H), 2.70–2.83 (m, 1H), 3.12–3.18 (br s, 1H), 3.41–
3.46 (d, J = 8.7 Hz, 1H), 3.52–3.63 (m, 1H), 7.27–7.49
(m, 5H); 13C NMR (CDCl3, 50 MHz): ꢁ5.78, ꢁ4.94,
17.81, 25.31, 25.64, 35.33, 46.75, 69.38, 73.98, 127.33,
4.10. Synthesis of (2S,3S)-1-(tert-butyoxycarbonyl)-2-phen-
yl-3-[(3,5)-bis(trifluoromethyl)benzyloxy]piperidine 16
To a stirred solution of sodium hydride (0.020 mg, 60% dis-
persion in mineral oil, 0.83 mmol ) and dry DMF (3 mL)
at 0 ꢁC, was added a solution of 1 (0.2 g, 0.72 mmol) and

986
S. K. Cherian, P. Kumar / Tetrahedron: Asymmetry 18 (2007) 982–987
1218–1221; (g) Perianan, A.; Snyderman, R.; Malfroy, B.
Biochem. Biophy. Res. Commun. 1989, 161, 520–524; (h)
Snijdelaar, D. G.; Dirksen, R.; Slappendd, R.; Crul, B. J. P.
Eur. J. Pain 2000, 4, 121–135; (i) Datar, P.; Srivastava, S.;
Coutinho, E.; Govil, G. Curr. Top. Med. Chem. 2004, 4, 75–
103.
3,5-bis(trifluoromethyl)benzyl bromide (0.22 g, 0.72 mmol)
in dry DMF (2 mL). The reaction mixture was stirred for
12 h at 80 ꢁC. The reaction was quenched with water
(5 mL) and extracted with Et2O (3 · 5 mL). The combined
organic layers were washed with brine (5 mL), dried over
anhydrous Na2SO4 and concentrated. The residue was
purified by flash chromatography on silica gel column (elu-
2. (a) Baker, R.; Harrison, T.; Hollingworth, G. J.; Swain, C. J.;
Williams, B. J. EP0528 495A1, 1993; (b) Harrison, T.;
Williams, B. J.; Swain, C. J.; Ball, R. G. Bioorg. Med. Chem.
Lett. 1994, 4, 2545–2550.
3. Desai, M. C.; Lefkwitz, S. L.; Thadeo, P. F.; Longo, K. P.;
Snider, R. M. J. Med. Chem. 1992, 35, 4911–4913.
4. (a) Watson, J. W.; Gonsalves, S. F.; Fossa, A. A.; Mc Lea, S.;
Seeger, T.; Obach, S.; Andrews, P. L. R. Br. J. Pharmacol.
1995, 115, 84–94; (b) Zaman, S.; Woods, A. J.; Watson, J. W.;
Reynolds, D. J. M.; Andrews, P. L. R. Neuropharmacology
2000, 39, 316–323.
5. (a) Lotz, M.; Vaughan, J. H.; Carson, D. A. Science 1987,
235, 893–895; (b) Moskowitz, M. A. Trends Pharmacol. Sci.
1992, 13, 307–311; (c) Takenchi, Y.; Berkley Shand, E. F.;
Beusen, D. D.; Marshall, G. R. J. Med. Chem. 1998, 41,
3609–3623; (d) Swain, C. J. Prog. Med. Chem. 1998, 35, 57–
81.
ent: petroleum ether/EtOAc 7:3) to provide 16 (0.28 g) as a
25
colourless oil. Yield: 78%; ½aꢀD ¼ þ31:4 (c 1.0, CHCl3)
25
{lit.7b ½aꢀD ¼ þ30:4 (c 1.55, CHCl3)}; IR (neat, cmꢁ1):
1
2945, 1644, 1381, 1345, 1253, 1172, 875, 665; H NMR
(CDCl3, 200 MHz): 1.42 (s, 9H), 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.
4.11. Synthesis of (2S,3S)-2-phenyl-3[(3,5)-bis(trifluoro-
methyl)benzyloxy]piperidine: [(+)-L-733,060] 2
6. Boks, G. J.; Tollenacre, J. P.; Kroon, J. Bioorg. Med. Chem.
1997, 5, 535–547.
7. (a) Huang, P.-Q.; Lin, L.-X.; Wei, B.-G.; Ruan, Y.-P. Org.
Lett. 2003, 5, 1927–1929; (b) Bhaskar, G.; Rao, B. V.
Tetrahedron Lett. 2003, 44, 915–917; (c) Mandar, S. B.;
Upadhyay, P. K.; Kumar, P. Tetrahedron Lett. 2004, 45, 987–
988; (d) Atobe, M.; Yamazaki, N.; Kibzyashi, C. J. Org.
Chem. 2004, 69, 5595–5607; (e) Tsai, M.-R.; Chen, B.-F.;
Chang, C.-C.; Chang, N.-C. J. Org. Chem. 2005, 70, 1780–
1785; (f) Lemire, A.; Grenon, M.; Pourashraf, M.; Charette,
A. B. Org. Lett. 2004, 6, 3517–3520.
To an ice-bath solution of 16 (0.10 g, 0.20 mmol) in dry
CH2Cl2 (5 mL) was added trifluoroacetic acid (15 lL,
0.20 mmol). The reaction mixture was stirred at room tem-
perature for 12 h and then quenched with saturated NaH-
CO3 and extracted with CH2Cl2 (3 · 15 mL). The
combined organic layers were washed with brine and dried
over Na2SO4, filtered and concentrated under reduced
pressure. The crude product was purified by silica gel col-
8. (a) Takahashi, K.; Nukano, H.; Fujita, R. Tetrahedron Lett.
2005, 46, 8927–8930; (b) Oshitari, T.; Mandai, T. Synlett
2006, 3395–3398; (c) Yoon, Y.-J.; Joo, J.-E.; Lee, K.-Y.; Kim,
Y.-H.; Oh, C.-Y.; Ham, W.-H. Tetrahedron Lett. 2005, 46,
739–741; (d) Lee, J.; Hoang, T.; Lewis, S.; Weissman, S. A.;
Askin, D.; Volante, R. P.; Reider, P. J. Tetrahedron Lett.
2001, 42, 6223–6225; (e) Tsuritani, N.; Yamuda, K.; Yoshi-
kawa, N.; Shibaski, M. Chem. Lett. 2002, 276–277; (f)
Kandula, S. R. V.; Kumar, P. Tetrahedron: Asymmetry 2005,
16, 3579–3583; (g) Stadler, H.; Bos, M. Heterocycles 1999, 51,
1067–1071.
9. (a) Kandula, S. V.; Kumar, P. Tetrahedron Lett. 2003, 44,
6149–6151; (b) Gupta, P.; Naidu, S. V.; Kumar, P. Tetrahe-
dron Lett. 2004, 45, 849–851; (c) Naidu, S. V.; Gupta, P.;
Kumar, P. Tetrahedron Lett. 2005, 46, 2129–2131; (d) Kumar,
P.; Naidu, S. V.; Gupta, P. J. Org. Chem. 2005, 70, 2843–
2846; (e) Kumar, P.; Naidu, S. V. J. Org. Chem. 2005, 70,
4207–4210; (f) Pandey, S. K.; Kumar, P. Tetrahedron Lett.
2005, 46, 6625–6627; (g) Kumar, P.; Gupta, P.; Naidu, S. V.
Chem. Eur. J. 2006, 12, 1397–1402; (h) Kumar, P.; Naidu, S.
V. J. Org. Chem. 2006, 71, 3935–3941.
10. (a) Naidu, S. V.; Kumar, P. Tetrahedron Lett. 2003, 44, 1035–
1037; (b) Gupta, P.; Fernandes, R. A.; Kumar, P. Tetrahe-
dron Lett. 2003, 44, 4231–4232; (c) Kandula, S. V.; Kumar, P.
Tetrahedron Lett. 2003, 44, 1957–1958; (d) Kondekar, N. B.;
Kandula, S. V.; Kumar, P. Tetrahedron Lett. 2004, 45, 5477–
5479; (e) Pandey, S. K.; Kandula, S. V.; Kumar, P.
Tetrahedron Lett. 2004, 45, 5877–5879; (f) Gupta, P.; Naidu,
S. V.; Kumar, P. Tetrahedron Lett. 2004, 45, 9641–9643;
(g) Kumar, P.; Bodas, M. S. J. Org. Chem. 2005, 70, 360–
363.
umn chromatography (eluent: CH3OH/CHCl3 1:9) to give
25
2, 0.056 g yield (70%). ½aꢀD ¼ þ36:2 (c 0.66, CHCl3) {lit.7b
25
½aꢀD ¼ þ34:29 (c 1.32, CHCl3)}; IR (neat, cmꢁ1): 3348,
2990, 2945, 1602, 1380, 1349, 1247, 1172, 875, 667; 1H
NMR (CDCl3, 200 MHz): 1.42–2.04 (m, 3H), 2.20 (br d,
J = 13 Hz, 1H), 2.62 (s, 1H), 2.76–2.81 (m, 1H), 3.23–
3.38 (m, 1H), 3.67 (s, 1H), 3.82 (br s, 1H), 4.14 (d,
J = 12 Hz, 1H), 4.54 (d, J = 12.2 Hz, 1H), 7.20–7.43 (m,
7H), 7.78 (s, 1H); 13C NMR (CDCl3, 50 MHz): 20.2,
28.2, 46.8, 64.0, 69.9, 77.4, 121.2, 123.1, 126.7, 127.3,
127.8, 132.4, 142.2, 142.4.
Acknowledgements
S.K.C. thanks the CSIR, New Delhi, for junior research
fellowship. We are grateful to Dr. M. K. Gurjar for his
support and encouragement. The financial support from
the DST, New Delhi (Grant No. SR/S1/OC-40/2003) is
gratefully acknowledged. This is NCL Communication
No. 6701.
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