Stereoselective synthesis of (2S,3S)-3-hydroxy-2-phenylpiperidine from d-mannitol

Article abstract of DOI:10.1016/j.tetasy.2008.12.005

A novel stereoselective synthesis of N-Boc-(2S,3S)-3-hydroxy-2-phenylpiperidine was achieved from d-mannitol involving the highly stereoselective addition of phenyl Grignard to an allyl imine (de >98%) and ring-closing metathesis (RCM) in the key steps.

Full text of DOI:10.1016/j.tetasy.2008.12.005

Tetrahedron: Asymmetry 20 (2009) 198–201
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective synthesis of (2S,3S)-3-hydroxy-2-phenylpiperidine
from D-mannitol
Mallam Venkataiah a,b, B. Venkateswara Rao b, Nitin W. Fadnavis a,
*
a Biotransformation Laboratary, Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Organic Division-III, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel stereoselective synthesis of N-Boc-(2S,3S)-3-hydroxy-2-phenylpiperidine was achieved from
Received 13 November 2008
Accepted 3 December 2008
Available online 10 January 2009
D
-mannitol involving the highly stereoselective addition of phenyl Grignard to an allyl imine (de >98%)
and ring-closing metathesis (RCM) in the key steps.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
11 is obtained as a single syn-diasteromer in the key step
through stereoselective chelation controlled Grignard addition
reaction on a chiral imine.
Functionalized piperidines are useful as biologically active
agents, and several methods have been developed for the syn-
thesis of substituted piperidines in a diastreo- and enantio-
selective manner.1 N-Boc-(2S,3S)-3-Hydroxy-2-phenylpiperidine
1 is an important intermediate from which non-peptidic neu-
rokinin NK1 receptor antagonists 22 and 33 have been prepared
(Fig. 1). These non-peptidic ligands 2 and 3 are known to ex-
2. Results and discussion
The synthesis of N-Boc-(2S,3S)-3-hydroxy-2-phenylpiperidine 1
(shown in Scheme 2) commenced from alcohol 4, which was pre-
pared from D
-mannitol11 in 50% overall yield. Compound 4 was
converted to allylic alcohol 612 in two steps, involving the forma-
tion of chloride 5 with triphenyl phosphine (TPP) in CCl4 (92%) fol-
lowed by Na-mediated elimination to furnish allylic alcohol 6
(85%). The resulting secondary hydroxyl group was protected as
its benzyl ether 7, and then the acetonide group was removed
using 90% TFA to afford the corresponding diol 8, in 80% yield,
which was cleaved with NaIO4 to give aldehyde 9, in 90% yield. This
aldehyde was converted to imine 10, in 85% yield using allylamine
in the presence of anhydrous MgSO4, and was subsequently re-
acted with phenylmagnesium bromide in diethylether under ice
cold conditions. This Grignard reaction proceeded with excellent
stereoselectivity and afforded the corresponding amine 11, in
78% yield as a single diastereomer. In the 1H NMR spectrum, the
C2–H resonates as triplet at 3.82 ppm (J = 7.9 Hz) and the C1–H as
a doublet at 3.69 ppm (J = 8.12 Hz). No other peaks corresponding
to other diastereomers were observed in the 3.5–4.0 ppm region.
The syn-configuration of the amino alcohol derivative 11 was con-
firmed from the stereochemistry of the final product. Our results
are in agreement with those observed by Cativiela et al.13 who
have reported high stereoselectivity during the Grignard reaction
hibit
a variety of biological activities including neurogenic
inflammation,4 pain transmission and regulation of the immune
response.5 They have also been implicated in a variety of dis-
orders including migraine,6 rheumatoid arthritis7 and pain.8
Considering their pharmacological importance,9 various meth-
ods have been developed to access compound 1.10 These in-
clude the introduction of stereogenic centres via Sharpless
epoxidations and one-pot aza Witting reactions,10a Sharpless
asymmetric dihydroxylations of silyl enol ethers,10b Sharpless
asymmetric aminohydroxylations10c or Jacobson’s asymmetric
epoxidations followed by ring expansions.10d Although these
methods are fairly efficient (ee 94–99%, yields 65–75%), they
require expensive chiral ligands to induce chirality or highly
toxic Osmium complexes. Other strategies involve intermedi-
ates derived from amino acids such as
L
-phenylglycine10e–g
and
L
-glutamic acid.10h,10i However, these methods produce
the key chiral intermediate in either low yield (58%) or with
low diastereoselectivity (90%). Herein, we report a far simpler,
novel stereoselective synthesis of N-Boc-(2S,3S)-3-hydroxy-2-
phenylpiperidine
1 starting with naturally occurring, easily
available -mannitol possessing the required stereochemistry.
D
of N-benzylimine derived from 2-O-benzyl-D-glyceraldehyde and
Most steps are straightforward and are high yielding (overall
yield 24% from 4 in 10 steps). The required chiral intermediate
phenyl and methyl magnesium bromide under similar conditions.
The formation of the syn-product can be explained on the basis of a
chelation-controlled Cram model14 involving coordination of the
O-benzyl lone pair with the metal ion prior to nucleophilic attack
(Scheme 1).
* Corresponding author. Tel.: +91 40 27191631; fax: +91 40 27160512.
E-mail addresses: fadnavisnw@yahoo.com, fadnavis@iict.res.in (N.W. Fadnavis).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.12.005

M. Venkataiah et al. / Tetrahedron: Asymmetry 20 (2009) 198–201
199
CF3
H
N
OH
O
OMe
CF3
N
N
N
H
H
Boc
1
3: (+)-(2S,3S)-L-733,060
2: (+)-(2S,3S)-CP-99,994
Figure 1.
Protection of amine 11 with (Boc)2O to give 12 followed by ring-
closing metathesis (RCM)15 of 12 using Grubbs’s first generation
catalyst, Cl2Ru(@CHPh)(PCy3)2 (5 mol %), in DCM at RT proceeded
to give 13 in 92% yield. Saturation of the double bond and deben-
zylation were carried out with H2/Pd–C in EtOH to furnish the tar-
get molecule 1, in 93% yield. The physical and spectroscopic data of
1 were in full agreement with those reported in the literature.10f
3. Conclusion
In conclusion, we have carried out a highly stereoselective syn-
thesis of N-Boc-(2S,3S)-3-hydroxy-2-phenylpiperidine starting
with D-mannitol. Naturally occurring mannitol provides one ste-
Nu
reocentre while the stereoselective addition of phenyl Grignard
to an allyl imine derivative provides the second stereocentre with
very high diastereoselectivity. This strategy can be used for making
analogues by changing the Grignard reagent. Finally, ring-closing
metathesis (RCM) provides the required appropriately substituted
piperidine ring.
H
Ph
H
N
N
H
Bn
H
O
M
M
O
Bn
4. Experimental
NH
Ph
H
4.1. General experimental
N
H
H
Bn
All reagents were purchased from Aldrich. IR spectra were re-
corded on a Perkin–Elmer RX-1 FT-IR system. 1H NMR (200 MHz)
spectra were recorded on a Varian Gemini-200 MHz spectrometer.
1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were recorded
OBn
O
11
Scheme 1.
O
O
O
O
O
ref 11
O
OH
O
Cl
O
b
a
D-mannitol
O
O
OH
6
4
5
O
OH
O
HO
d
c
O
e
H
OBn
OBn
OBn
9
7
8
N
NBoc
NH
f
g
h
H
OBn
10
OBn
OBn
OH
11
12
OBn
j
i
N
N
Boc
Boc
1
13
Scheme 2. Reagents and conditions: (a) CCl4, TPP, NaHCO3, reflux 1 h, 92%; (b) Na, dry E2O, 0 °C to rt, 12 h, 85%; (c) NaH, BnBr, dry DMF, 0 °C to rt, 1 h, 84%; (d) 90% CF3COOH
in water, 0 °C, 4 h, 80%; (e) NaIO4, 60% CH3CN, 0 °C to rt, 1 h, 90%; (f) allylamine, anhydrous MgSO4, dry ether, 0 °C to rt, 2 h, 85%; (g) phenyl magnesium bromide, dry ether,
0 °C to rt, 6 h, 78%; (h) Boc2O, Et3N, DCM, rt,1 h, 90%; (i) Grubbs, I, DCM, rt, 12 h, 92%; (j) H2/Pd–C, EtOH, 4 h, 93%.

200
M. Venkataiah et al. / Tetrahedron: Asymmetry 20 (2009) 198–201
on Bruker Avance-300 MHz spectrometer. Optical rotations were
measured with Horiba-SEPA-300 digital polarimeter. Mass mea-
surement was performed on Q STAR mass spectrometer (Applied
Biosystems, USA).
119.39, 127.45, 127.65, 128.18, 135.08, 138.00; EI-MS: m/z =
271.2 [M+Na]+.
4.5. (2R,3S)-3-(Benzyloxy)-4-pentene-1,2-diol 8
Compound 7 (2 g, 8 mmol) was dissolved in 90% aq CF3COOH
(15 mL) at 0 °C and the mixture was stirred at the same tempera-
ture for 4 h. The reaction mixture was extracted with CH2Cl2
(3 ꢀ 50 mL). The collected organic layers were combined, washed
with 10% NaHCO3, water and brine, dried over Na2SO4 and concen-
trated in vacuo. The residual oil was purified by silica gel column
chromatography using ethyl acetate/ hexane (1:3) to give 8
4.2. 1,2:3,4-Di-O-isopropylidene-(2R,3R,4S)-5-chloropentane-
1,2,3,4-tetraol 5
Compound 4 (8 g, 34.5 mmol) was dissolved in CCl4 (15 mL).
Triphenyl phosphine (13.6 g, 51.7 mmol) and NaHCO3 (5.8 g,
69 mmol) were added with stirring and the reaction mixture was
refluxed at 80 °C for 1 h. The contents were then cooled to room
temperature and extracted with CHCl3 (2 ꢀ 100 mL). The combined
organic extracts were washed with brine (50 mL), dried over anhy-
drous Na2SO4, concentrated under reduced pressure and purified
by column chromatography (ethyl acetate/hexane) (5:95) to afford
(1.34 g, 80%) as a syrup. ½a D25
¼ þ55:0 (c 1, CHCl3); IR (neat,
ꢁ
cmꢂ1): mmax 3410, 2966, 2931, 2877, 1713, 1455, 1274, 1070,
1024, 701; 1H NMR (200 MHz, CDCl3): d 2.15–2.23 (br s, 1H),
2.57–2.64 (br s, 1H), 3.51–3.74 (m, 3H), 3.85–3.95 (m, 1H), 4.32–
4.65 (m, 2H), 5.27–5.45 (m, 2H), 5.70–5.92 (m, 1H); 13C NMR
(75 MHz, CDCl3): d 63.14, 70.47, 73.30, 81.71, 119.80, 127.59,
127.69, 128.28, 134.90, 137.82; EI-MS: m/z = 231.0 [M+Na]+.
pure 5 (7.94 g, 92%) as a pale yellow oil. ½a D25
¼ þ13:2 (c 1, CHCl3);
ꢁ
IR (neat, cmꢂ1): mmax 3446, 2988, 2935, 2882, 1373, 1218, 1155,
1069, 841; 1H NMR (300 MHz, CDCl3): d 1.34 (s, 3H), 1.39 (s,
3H), 1.42 (s, 3H), 1.44 (s, 3H), 3.65 (dd, J = 5.28, 12.08 Hz, 1H),
3.76 (t, J = 7.55 Hz, 1H), 3.80–3.85 (m, 1H), 3.93–4.06 (m, 2H),
4.09–4.16 (m, 2H); 13C NMR (75 MHz, CDCl3): d 25.04, 26.60,
26.90, 27.04, 44.62, 67.54, 76.82, 78.16, 79.73, 109.65, 109.91; EI-
MS: m/z = 273.5 [M+Na]+.
4.6. N-Allyl-N-[(1S,2S)-2-(benzyloxy)-phenyl-3-butenyl] amine
11
To a solution of 8 (1 g, 4.8 mmol) in 60% aq CH3CN (20 mL) was
added NaIO4 (2.14 g, 10 mmol) in one portion. The mixture was
stirred at room temperature for 1 h and filtered. Acetonitrile was
evaporated on a rotavaporator and the residue was extracted with
CH2Cl2. The combined organic layers were washed with brine,
dried over Na2SO4 and concentrated in vacuo to give aldehyde 9
(0.762 g, 90%) as a colourless oil. The crude aldehyde 9 (0.762 g,
4.32 mmol) was dissolved in dry diethyl ether (15 mL), and anhy-
drous MgSO4 (2 g) followed by allylamine (0.34 mL, 4.33 mmol)
was added at 0 °C with vigorous stirring. After 30 min, the cooling
bath was removed and stirring was continued at room temperature
for 2 h. After completion of the reaction, the solution was filtered
and the filtrate was concentrated in vacuo to give imine 10
(0.8 g, 85%) as a yellow syrup. This was dissolved in dry diethyl
ether (10 mL) and was added dropwise over 30 min to a stirred
solution of phenyl magnesium bromide (0.5 M in diethyl ether,
18.4 mL, 9.2 mmol) at 0 °C under nitrogen atmosphere. After being
stirred for 6 h at room temperature, the reaction mixture was
poured into saturated aqueous NH4Cl (20 mL), the organic layer
was dried over Na2SO4 and concentrated in vacuo. The residue
was purified by silica gel column chromatography using ethyl ace-
4.3. (1S)-1-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-2-propen-1-
ol 6
Compound 5 (6 g, 24 mmol) was dissolved in dry ether (50 mL)
at 0 °C and shining Na pieces (1.66 g, 72 mmol) were added under a
nitrogen atmosphere. After stirring at room temperature for 12 h,
the reaction mixture was quenched with methanol (10 mL) and fil-
tered. The residue was washed with diethyl ether and the com-
bined filtrate was concentrated in vacuo. The oily residue was
dissolved in EtOAc (50 mL) and the organic layer was washed with
brine, and dried over anhydrous Na2SO4. After removing the sol-
vent under reduced pressure, the residue was purified by column
chromatography (ethyl acetate/hexane) (15:85) to afford pure 6
(3.22 g, 85%) as a pale yellow oil. ½a D25
¼ þ2:8 (c 1, CHCl3); IR (neat,
ꢁ
cmꢂ1): max 3449, 2923, 2854, 1648, 1022, 754; 1H NMR (300 MHz,
m
CDCl3): d 1.36 (s, 3H), 1.44 (s, 3H), 2.07 (d, J = 3.02 Hz, 1H), 3.83–
3.95 (m, 2H), 4.07 (q, J = 4.53, 6.79 Hz, 1H), 4.24 (m, 1H), 5.21–
5.42 (m, 2H), 5.76–5.87 (m, 1H); 13C NMR (75 MHz, CDCl3): d
25.03, 26.33, 64.79, 71.87, 78.05, 109.34, 116.72, 136.24; EI-MS:
m/z = 181 [M+Na]+.
tate/hexane (1:9) to give 11 (0.84 g, 78%) as
a yellow oil.
½
a 2D5
ꢁ
¼ þ51:0 (c 1, CHCl3); IR (neat, cmꢂ1): mmax 3435, 3060, 3028,
2924, 2856, 1641, 1452, 1064, 923, 769, 699; 1H NMR (300 MHz,
CDCl3): d 1.67–1.92 (br s, 1H), 2.85–3.13 (m, 2H), 3.69 (d, J =
8.12 Hz, 1H), 3.82 (t, J = 7.9 Hz, 1H), 4.3–4.6 (m, 2H), 4.92–5.15
(m, 5H), 5.47–5.64 (m, 1H), 5.73–5.9 (m, 1H); 13C NMR (75 MHz,
CDCl3): d 29.9, 49.8, 66.8, 70.9, 85.2, 115.7, 119.1, 127.5, 127.9,
128.1, 128.4, 128.8, 135.6, 137.0, 138.4, 140.3; EI-MS: m/z = 294.2
[M+1]+. HRMS (EI): m/z calcd for C20H24NO: 294.1857; found:
294.1856.
4.4. (4R)-4-[(1S)-1-(Benzyloxy)-2-propenyl]-2,2-dimethyl-1,3-
dioxolane 7
To a stirred suspension of NaH (0.91 g, 38 mmol) in dry DMF
(20 mL) was added a solution of 6 (3 g, 19 mmol) in dry DMF
(10 mL) dropwise at 0 °C under a nitrogen atmosphere. After stir-
ring at room temperature for 15 min, benzyl bromide (2.20 mL,
19 mmol) was added and the reaction mixture was stirred over-
night. The reaction was quenched with saturated aq NH4Cl at
0 °C and extracted with ether (2 ꢀ 100 mL). The combined organic
extracts were washed with brine, dried over anhydrous Na2SO4,
concentrated under reduced pressure and purified by column chro-
matography (ethyl acetate/hexane) (5:95) to afford pure 7 (3.95 g,
4.7. tert-Butyl N-allyl-N-[(1S,2S)-2-(benzyloxy)-1-phenyl-3-
butenyl] carbamate 12
To compound 11 (0.3 g, 1.02 mmol) in dry DCM (10 mL), Et3 N
(0.14 ml, 1.02 mmol) followed by Boc2O (0.59 mL, 2.56 mmol)
was added at 0 °C. The reaction mixture was stirred at room tem-
perature for 24 h. The reaction mixture was then washed with sat-
urated NH4Cl (10 mL) and extracted with CH2Cl2 (3 ꢀ 50 mL). The
collected organic layers were combined, washed with brine, dried
over Na2SO4 and concentrated in vacuo. The residue was purified
through silica gel column chromatography using ethyl acetate/
84%) as a yellow oil. ½a D25
ꢁ
¼ þ49:2 (c 1, CHCl3); IR (neat, cmꢂ1): mmax
3403, 2926, 2876, 1719, 1643, 1454, 1394, 1277, 1211, 1066, 933,
699; 1H NMR (200 MHz, CDCl3): d 1.35 (s, 3H), 1.41 (s, 3H), 3.74 (t,
J = 5.85, 7.31 Hz, 1H), 3.84–3.93 (m, 1H), 4.02–4.17 (m, 2H), 4.36–
4.68 (m, 2H), 5.30–5.43 (m, 3H), 5.74–5.92 (m, 1H); 13C NMR
(75 MHz, CDCl3): d 25.16, 26.40, 66.6 70.37, 77.67, 80.82, 109.51,

M. Venkataiah et al. / Tetrahedron: Asymmetry 20 (2009) 198–201
201
hexane (2:98) to give 11 (0.362 g, 90%) as a syrup. ½a D25
¼ þ46:0 (c
ꢁ
Acknowledgement
1, CHCl3); IR (neat, cmꢂ1):
mmax 3448, 3067, 2975, 2927, 1691, 1451,
1396, 1363, 1248, 1172, 923, 769, 699; 1H NMR (300 MHz, CDCl3):
d 1.44 (s,9H), 3.67 (d, J = 5.3 Hz, 2H), 4.29–4.69 (m, 3H), 4.76–4.98
(m, 2H), 5.1 (d, J = 7.55 Hz, 1H), 5.16–5.33 (m, 2H), 5.44–5.60 (m,
1H), 5.61–5.75 (m, 1H), 7.15–7.42 (m, 10H); 13C NMR (75 MHz,
CDCl3): d 28.4, 29.6, 47.7, 62.4, 69.9, 79.5, 115.2, 119.4, 127.3,
127.4, 127.5, 127.8, 128.1, 129.3, 135.9, 138.2,138.8, 140.5, 156.4;
EI-MS: m/z = 416.0 [M+Na]+. HRMS (EI): m/z calcd for C25H31NO3-
Na: 416.2201; found: 416.2217.
We thank CSIR, New Delhi, for financial assistance.
References
1. (a) Reddy, M. S.; Narender, M.; Rao, K. R. Tetrahedron 2007, 63, 331–
336; (b) Radha Krisha, P.; Dayaker, G. Tetrahedron Lett. 2007, 48, 7279–
7282; (c) Yokoyama, K.; Ejiri, H.; Miyajawa, M.; Yamaguchi, S.; Hirai, Y.
Tetrahedron: Asymmetry 2007, 18, 852–856; (d) Zhu, S.; Meng, L.;
Zhang, Q.; Wei, L. Bioorg. Med. Chem. Lett. 2006, 16, 1854–1858; (e)
Kandula, S. R. V.; Kumar, P. Tetrahedron: Asymmetry 2005, 16, 3268–
3274; (f) Bates, R. W.; Sa-Ei, K. Tetrahedron 2002, 58, 5957–5978; (g)
Wilkinson, T. J.; Stehla, N. W.; Beak, P. Org. Lett. 2000, 2, 155–158; (h)
Lasschat, S.; Dickner, T. Synthesis 2000, 13, 1781–1813. and references
cited therein.
4.8. tert-Butyl (2S,3S)-3-(benzyloxy)-2-phenyl 1,2,3,6-
tetrahydro-1-pyridine carboxylate 13
2. (a) Baker, R.; Harrison, T.; Hollingworth, G. J.; Swain, C. J.; Williams, B. J. EP
528,495 A1, 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.; Lefkowitz, S. L.; Thadeio, P. F.; Longo, K. P.; Snider, R. M. J. Med.
Chem. 1992, 35, 4911–4913.
4. Lotz, M.; Vaughan, J. H.; Carson, D. A. Science 1988, 241, 1218–1221.
5. Perianan, A.; Snyderman, R.; Malfroy, B. Biochem. Biophys. Res. Commun. 1989,
161, 520–524.
6. Moskowitz, M. A. Trends Pharmacol. Sci. 1992, 13, 307–311.
7. Lotz, M.; Vaughan, J. H.; Carson, D. A. Science 1987, 235, 893–895.
8. Otsuka, M.; Yanagisawa, M. J. Physiol. (London) 1988, 395, 255–270.
9. (a) Giardina, G. A. M.; Raveglia, L. F.; Grugni, M. Drugs Future 1997, 22, 1235–
1257; (b) Chandrasekhar, S.; Mohanty, P. K. Tetrahedron Lett. 1999, 40, 5071–
5072.
10. (a) Cherian, S. K.; Kumar, P. Tetrahedron: Asymmetry 2007, 18, 982–987;
(b) Stadler, H.; Bos, M. Heterocycles 1999, 51, 1067–1071; (c) Kandula, S.
R. V.; Kumar, P. Tetrahedron: Asymmetry. 2005, 16, 3579–3583; (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) Yoon, Y.-J.; Joo, J. E.; Lee, K.-
Y.; Kim, Y.-H.; Oh, C.-Y.; Ham, W.-H. Tetrahedron Lett. 2005, 46, 739–741;
(f) Bhaskar, G.; Rao, B. V. Tetrahedron Lett. 2003, 44, 915–917; (g) Bodas
Mandar, S.; Upadhyay Puspesh, K.; Kumar, P. Tetrahedron Lett. 2004, 45,
987–988; (h) Huang, P.-Q.; Liu, L.-X.; Wei, B.-G.; Ruan, Y.-P. Org. Lett.
2003, 5, 1927–1929; (i) Calvez, O.; Langlois, N. Tetrahedron Lett. 1999, 40,
7099–7100.
Diene 12 (0.25 g, 0.64 mmol) was dissolved in dry CH2Cl2
(25 mL). Grubbs’s first generation catalyst (52 mg, 0.064 mmol,
0.1 equiv) was added and the resulting purple solution turned
brown after 10 min. The reaction mixture was stirred at room tem-
perature for 12 h, then concentrated in vacuo. The residue was
purified by column chromatography (ethyl acetate/hexane)
(3:97) and the title compound 13 (0.21 g) was obtained as a colour-
less oil. Yield: 92%; ½a D25
ꢁ
¼ þ44:0 (c 1, CHCl3); IR (neat, cmꢂ1): mmax
3445, 2975, 2924, 2852, 1694, 1402, 1167,1089, 750, 698; 1H NMR
(300 MHz, CDCl3): d 1.48 (s, 9H), 3.24 (dd, J = 3.02, 18.88 Hz, 1H),
3.99–4.22 (m, 1H), 4.4–4.5 (m, 1H), 4.51–4.63 (m, 2H), 5.58–5.72
(m, 2H), 5.97 (d, J = 9.82 Hz, 1H), 7.1–7.58 (m, 10H); 13C NMR
(75 MHz, CDCl3): d 28.4, 29.6, 40.6, 70.7, 73.0, 80.3, 124.4, 127.0,
127.2, 127.5, 127.7, 127.86, 128.3, 129.1, 137.1, 137.9, 154.6; EI-
MS: m/z = 388.8 [M+Na]+. HRMS (EI): m/z calcd for C23H27NO3Na:
388.1888; found: 388.1892.
4.9. (2S,3S)-3-Hydroxy-2-phenyl-piperidine-1-carboxylic acid
tert-butyl ester 1
11. Reddy, J. S.; Kumar, A. R.; Rao, B. V. Tetrahedron: Asymmetry 2005, 16, 3154–
3159.
12. Lu, W.; Zheng, G.; Cai, J. Synlett 1998, 737–738.
13. (a) Badorrey, R.; Cativiela, C.; Diaz-de-villegas Marie, D.; Galvez Jose, A.
Tetrahedron 1997, 53, 1411–1416; (b) Cativiela, C.; Diaz-de-villegas, M. D.;
Galvez, J. A. Tetrahedron: Asymmetry 1996, 7, 529–536.
14. (a) Cram, D. J.; Elhafez, F. A. A. J. Am. Chem. Soc. 1952, 74, 5828–5835; (b) Cram,
D. J.; Kopecky, K. R. J. Am. Chem. Soc. 1959, 81, 2748–2755.
15. For syntheses of piperidine moieties using ring-closing metathesis, see: (a)
Cossy, J.; Willis, C.; Bellosta, V.; BouzBouz, S. J. Org. Chem. 2002, 67, 1982–
1992; (b) Ginesta, X.; Pericas, M. A.; Riera, A. Tetrahedron Lett. 2002, 43,
779–782; (c) Davies, S. G.; Iwamoto, K.; Smethurst, C. A. P.; Smith, A. D.;
Rodriguez-Solla, H. Synlett 2002, 1146–1148; (d) Felpin, F.; Girard, S.; Vo-
Thanh, G.; Robins, R. J.; Villieras, J.; Lebreton, J. J. Org. Chem. 2001, 66,
6305–6312; (e) Banba, Y.; Abe, C.; Nemoto, H.; Kato, A.; Adachi, I.;
Takahata, H. Tetrahedron: Asymmetry 2001, 12, 817–819; (f) Pernerstorfer,
J.; Schuster, M.; Blechert, S. Synthesis 1999, 138–144; (g) Zumpe, F. L.;
Kazmaier, U. Synthesis 1999, 1785–1791.
To a solution of 13 (0.2 g) in ethanol (10 mL) was added 20 mg of
10% Pd/C and mixture was stirred under a hydrogen atmosphere for
6 h. Aftercompletionof reaction, thesolutionwasfilteredandthefil-
trate was concentrated. The crude product was purified on silica gel
column using ethyl acetate/hexane (3:7) as eluent to give 1 (0.141 g,
93%) as a viscous liquid. ½a D25
ꢁ
¼ þ39:0 (c 1, CHCl3) {lit.10e +38.3 (c
1.92, CHCl3)}. IR (neat, cmꢂ1): mmax 3441, 2924, 1666, 1415,
1365,1254, 1172; 1H NMR (200 MHz, CDCl3): d 1.37 (s, 9H), 1.60–
1.93 (m, 5H), 2.98 (ddd, J = 4.4,11.5,13.2 Hz, 1H), 3.84–4.18 (m,
2H), 5.26 (d, J = 5.8 Hz, 1H), 7.20–7.49 (m, 5H); 13C NMR (75 MHz,
CDCl3): d 23.19, 27.65, 28.30, 39.41, 59.17, 70.08, 79.85, 127.10,
128.28, 128.36, 138.40, 155.35; EI-MS: m/z = 300.7 [M+Na]+. HRMS
(EI): m/z calcd for C16H23NO3Na: 300.1575; found: 300.1589.