The formal synthesis of isofebrifugine using stereoselective intramolecular Michael addition

Article abstract of DOI:10.1016/j.tetasy.2008.08.021

The formal synthesis of isofebrifugine, a bioactive alkaloid, was achieved via a stereoselective intramolecular Michael addition reaction from d-mannitol.

Full text of DOI:10.1016/j.tetasy.2008.08.021

Tetrahedron: Asymmetry 19 (2008) 2153–2158
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
The formal synthesis of isofebrifugine using stereoselective intramolecular
Michael addition
Neela Sudhakar a, Gannoju Srinivasulu b, Ganipisetti Srinivas Rao a, Batchu Venkateswara Rao a,
*
a Organic Division III, Indian Institute of Chemical Technology, Hyderabad 500067, India
b Nuclear Magnetic Resonance Division, Indian Institute of Chemical Technology, Hyderabad 500067, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The formal synthesis of isofebrifugine, a bioactive alkaloid, was achieved via a stereoselective intramolec-
Received 19 July 2008
Accepted 20 August 2008
Available online 1 October 2008
ular Michael addition reaction from D-mannitol.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
(Scheme 1).2a The scarcity of these alkaloids from natural sources
has spurred much research on the synthesis of febrifugine 1, iso-
febrifugine 2, and their analogues with the aim of developing
new antimalarial drugs.4,6 Kobayashi et al. synthesized isofebrifu-
gine 2 and febrifugine 1 from 3 and 4, respectively, in two-step
Febrifugine 1 and isofebrifugine 2 are active principals against
malaria,1 occurring in the roots of Dichroa febrifuga (Chinese name:
Chang Shan)2 and related hydrangea plants.3 These alkaloids are
approximately 100 times as effective as quinine against Plasmodia
lophurae in ducks.2a The absolute structures of these alkaloids
were elucidated by the asymmetric total synthesis achieved by
Kobayashi et al.4 It is also known that there is a equilibrium be-
tween these alkaloids under acidic conditions.5 Moreover, isofeb-
rifugine 2 can be transformed into febrifugine 1 by heating
reaction sequence.4 Herein, we report the synthesis of 3 from
D-
mannitol via enone 5, using base-induced intramolecular Michael
addition reaction as the key step. The key aspect of the synthesis is
to study the stereochemical outcome of the intramolecular
Michael addition of 5 in the construction of the piperidine
skeleton.
H+
N
N
HO
O
HO
O
N
N
N
N
H
H
febrifugine
isofebrifugine
O
O
1
2
BnO
O
BnO
O
Br
N
Br
Boc
N
Boc
3
4
BnO
HN
Boc
O
5
Scheme 1.
* Corresponding author. Tel./fax: +91 40 27193003.
E-mail addresses: venky@iict.res.in, drb.venky@gmail.com (B. V. Rao).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.08.021

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N. Sudhakar et al. / Tetrahedron: Asymmetry 19 (2008) 2153–2158
17b (Fig. 1). This internal strain might have allowed the Michael
2. Results and discussion
addition to proceed to give the axial orientation of 2-oxopropyl
units in 16a and 17a probably under thermodynamic control.11
When the minimum energy conformation was generated in SYBYL
6.8 using the Tripose Force Field, the energy of the 2,3-diaxial
conformation of 17a was found to be 8.8 kcal/mol, whereas that
for the 2,3-diequatorial conformation of 17b was 12.224 kcal/mol
(Fig. 2).
Compound 16a was converted into silyl enol ether 18, and
treatment with NBS in CH2Cl2 afforded 3 in 70% overall yield
(Scheme 3).6n,8 Similarly, compound 17a was also converted into
brominated compound 4 in 72% overall yield (Scheme 4).9 Isofeb-
rifugine 2 and febrifugine 1 were synthesized from compounds 3
and 4 by Kobayashi et al. in a two-step reaction sequence.4
As shown in Scheme 2, enantiomerically pure (R)-2,3-O-isopro-
pylidene glyceraldehyde 6 was prepared from D-mannitol in two
steps as per the literature.7 Compound 6 underwent a Wittig
reaction with PPh3CHCOOEt in CH2Cl2 resulted in compound 7,
as mixture of cis- and trans-isomers (Z/E 2:8). Compound 7 upon
hydrogenation using H2–Pd/C in MeOH followed by reduction with
LiAlH4 in THF gave compound 8. The alcohol functionality of com-
pound 8 was converted into the corresponding mesylate, which
afforded the azido compound 9, on heating at 90 °C with sodium
azide in DMF. Deprotection of the acetonide group in compound
9 was achieved using 80% aqueous acetic acid to give compound
10. Selective protection of the primary hydroxyl group in com-
pound 10 as its TBS ether yielded compound 11. The secondary hy-
droxyl group in 11 was protected as its benzyl ether to give 12. The
silyl group in compound 12 was deprotected using TBAF in THF to
give 13. Azide 13 was reduced with triphenylphosphine to gener-
ate a primary amine, which was protected in situ with Boc2O to
provide the Boc-amide 14. Compound 14 upon Swern oxidation
followed by Wittig reaction with PPh3CHCOCH3 in toluene at reflux
gave trans olefin 5 exclusively with 89% overall yield. In order to
determine the stereochemical outcome of the intramolecular Mi-
chael addition, compound 5 was treated with NaH in THF at 0 °C
to give compounds 16a and 17a as cis- and trans-isomers in 8:2 ra-
tio in 98% yield. The confirmation of structures 16a and 17a was
elucidated by detailed 1D and 2D NMR studies including DQFCOSY
and NOESY experiments. For 16a, NOE cross peaks were observed
between the C6Ha–C7H, C4Ha–C7H, and C3Ha–C5Ha, whereas for
17a, the NOE cross peaks were observed between the C6Ha–C7H,
C4Ha–C7H and C4Ha–C6Ha (Fig. 1).
3. Conclusions
In conclusion, we have developed a strategy for the formal
synthesis of isofebrifugine 2 and febrifugine 1 using a base-in-
duced intramolecular Michael addition reaction, which is also
useful to make febrifugine and isofebrifugine analogues and also
differentially substituted piperidines for improved therapeutic
activity.
4. Experimental
IR spectra were recorded on a Thermo Nicolet Nexus 670 FT-IR
spectrometer. ESI mass spectra were recorded on an AUTO SPEC-M
(Manchester, UK) mass spectrometer. 1H NMR spectra were re-
corded at 200 MHz on a Varian Gemini, 300 MHz on a Bruker
Avance, 400 MHz on a Varian Unity, and 500 MHz on a Varian
Inova FT-NMR spectrometer. 13C NMR spectra were recorded at
From the above results, it is clear that the 2-oxopropyl unit is
oriented in an axial position in both compounds 16a and 17a, as
shown in Figure 1.The axial orientation is because of the minimiza-
tion of the A(1,3) strain between the N-acyl and the axial 2-oxopro-
pyl units. It is well documented in the literature10 that N-
acylpiperidines are known to show significant A(1,3) strain between
the N-acyl unit and a 2-equatorial substituent as shown in 16b and
50 MHz on
a Varian Gemini, 75 MHz on a Bruker Avance,
100 MHz on a Varian Unity, and 125 MHz on a Varian Inova FT-
NMR spectrometer. Optical rotations were measured with a JASCO
DIP-370 instrument. For column chromatography, silica gel 60–
120 mesh was used. For TLC, Silica Gel 60 F254 (Merck) was used.
O
O
H
OEt
OH
a
ref. 7
b
D-mannitol
O
O
O
O
O
O
6
7
8
N3
N3
N3
e
c
d
O
O
HO
HO
OH
TBSO
OH
11
10
9
h
g
f
i
N3
N3
NHBoc
TBSO
OBn
OBn
HO
OBn
12
13
14
BnO
HO
BnO
O
BnO
O
O
j
k
NHBoc
N
N
N
Boc
Boc
Boc
OBn
5
16a
17a
15
Scheme 2. Reagents and conditions: (a) PPh3CHCOOEt, CH2Cl2, rt, 4 h, 87%; (b) (i) 10% Pd/C, H2, MeOH, 6 h; (ii) LiAlH4, THF, rt, 2 h (82% for two steps); (c) (i) MsCl, Et3N, DMAP
(cat), 0 °C–rt, 1 h; (ii) NaN3, DMF, 90 °C, 8 h (93% for two steps); (d) 80% aq AcOH, rt, 8 h, 94%; (e) TBSCl, imidazole, DMAP (cat), CH2Cl2, rt, 12 h, 90%; (f) BnBr, THF, NaH (60%
w/w), 0 °C–rt, 5 h, 92%; (g) TBAF, THF, rt, 3 h, 95%; (h) TPP, MeOH, rt, 4 h then (Boc)2O, 6 h, 96%; (i) DMSO, (COCl)2, DCM, ꢀ78 °C, 2 h then DIPEA; (j) PPh3CHCOCH3, toluene,
reflux, 8 h (89% for two steps); (k) NaH, THF, 0.5 h, 0 °C, 98% (16a/17a = 8:2 ratio).

N. Sudhakar et al. / Tetrahedron: Asymmetry 19 (2008) 2153–2158
2155
H
Bn
O
H
O
H
H
H
5
Me
H
6
NBoc
1
H
H
7
2
4
3
6
2
H
5
H
4
H
O
H
1
N
H
Bn
3
7
H
H
H
Me
Boc
H
H
H
O
17a
16a
H
Bn
H
O
H
5
1
H
5
1
OtBu
Me
6
N
OtBu
Me
H
6
N
H
H
3
3
2
H
2
H
4
O
H
O
4
H
O
H
H
Bn
O
O
16b
17b
Figure 1.
Figure 2.
BnO
O
BnO
OTMS
BnO
O
a
ref.4
b
isofebrifugine
Br
N
N
N
Boc
Boc
Boc
16a
18
3
Scheme 3. Reagents and conditions: (a) LHMDS, THF, ꢀ78 °C, 1 h, then TMSCl, 1 h; (b) NBS, NaHCO3, CH2Cl2, 0 °C, 2 h (70% for two steps).
BnO
O
BnO
OTMS
BnO
O
ref. 4
a
b
febrifugine
Br
N
N
N
Boc
Boc
Boc
19
17a
4
Scheme 4. Reagents and conditions: (a) LHMDS, THF, ꢀ78 °C, 1 h, then TMSCl, 1 h; (b) NBS, NaHCO3, CH2Cl2, 0 °C, 2 h (72% for two steps).
4.1. (S,E/Z)-Methyl 3-(2,2-dimethyl-1,3-dioxolan-4-yl) acrylate
7
27.69 mmol) and stirred at room temperature for 4 h. The reaction
mixture was quenched with water and extracted with CH2Cl2
(2 ꢁ 75 mL). The organic layer was washed with water and brine,
dried over anhydrous Na2SO4, and concentrated. The residue was
then chromatographed on silica gel (ethyl acetate/hexane = 1:4)
To an ice-cooled, stirred solution of aldehyde
6 (3 g,
23.07 mmol) in CH2Cl2 (40 mL), was added PPh3CHCOOEt (9.6 g,

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N. Sudhakar et al. / Tetrahedron: Asymmetry 19 (2008) 2153–2158
to give compounds trans-7 and cis-7 (4.0 g, 87% in 8:2 ratio) as col-
4.4. (S)-5-Azidopentane-1,2-diol 10
orless liquids. Data for trans-7: ½a D25
¼ þ4:3 (c 1.8, CHCl3); IR mmax
ꢂ
(neat, cmꢀ1): 2986, 1722, 1375, 1303, 1261, 1215, 1181, 1061;
1H NMR (300 MHz, CDCl3): d 6.83 (dd, 1H, J = 5.28, 15.48 Hz),
6.05 (dd, 1H, J = 1.13, 15.48 Hz), 4.62 (dt, 1H, J = 1.13, 6.79 Hz),
4.19 (q, 2H, J = 7.17 Hz), 4.15 (dd, 1H, J = 6.79, 8.31 Hz), 3.63 (t,
1H, J = 7.55 Hz), 1.43 (s, 3H), 1.38 (s, 3H), 1.30 (t, 3H, J = 7.17 Hz);
A solution of compound 9 (1.1 g, 5.94 mmol) in 80% aqueous
acetic acid (10 mL) was stirred for 8 h. The reaction mixture was
neutralized by the cautious addition of saturated NaHCO3 solution
and extracted with EtOAc (2 ꢁ 40 mL). The organic layer was
washed with brine, dried over anhydrous Na2SO4, and concen-
trated. The residue was then chromatographed on silica gel (ethyl
acetate/hexane = 1:2) to give diol compound 10 (0.81 g, 94%) as an
MS (ESI): 223 [M+Na]+. Data for cis-7: ½a 2D5
¼ ꢀ48:0 (c 1.1, CHCl3);
ꢂ
1H NMR (300 MHz, CDCl3): d 6.35 (dd, 1H, J = 6.42, 11.71 Hz), 5.82
(dd, 1H, J = 1.51, 11.71 Hz), 5.46 (ddd, 1H, J = 1.51, 6.79, 8.31 Hz),
4.36 (dd, 1H, J = 7.17, 8.31 Hz), 4.16 (q, 2H, J = 7.17 Hz), 3.58 (dd,
1H, J = 6.79, 8.30 Hz), 1.43 (s, 3H), 1.38 (s, 3H), 1.30 (t, 3H,
J = 7.17 Hz); MS (LC): 223 [M+Na]+.
oily liquid: ½a 2D5
ꢂ
¼ ꢀ7:4 (c 1.2, CHCl3); IR mmax (neat, cmꢀ1): 3372,
2938, 2874, 2100, 1258, 1061; 1H NMR (300 MHz, CDCl3): d 3.64
(dd, 1H, J = 2.64, 11.33 Hz), 3.50–3.76 (m, 2H), 3.43 (dd, 1H,
J = 7.55, 10.95 Hz), 3.34 (t, 2H, J = 6.79 Hz), 1.56–1.87 (m, 2H),
1.42–1.55 (m, 2H); 13C NMR (75 MHz, CDCl3): d 71.68, 66.56,
51.41, 29.99, 25.05; MS (ESI): 168 [M+Na]+; HRMS (ESI): calcd for
C5H11N3O2 [M+Na]+ = 168.0748, found: 168.0746.
4.2. (S)-3-(2,2-Dimethyl-1,3-dioxolan-4-yl) propan-1-ol 8
Hydrogenation of compound 7 (2.0 g, 10 mmol) was carried out
with a catalytic amount of 10% Pd/C in MeOH (15 mL). After being
stirred for 6 h at room temperature, the catalyst was removed by
filtration. The filtrate was concentrated in vacuo to give the satu-
rated ester.
4.5. (S)-5-Azido-1-(tert-butyldimethylsilyloxy) pentan-2-ol 11
To a stirred solution of 10 (0.70 g, 4.82 mmol) in CH2Cl2 (10 mL)
were added imidazole (0.82 g, 12.06 mmol) and TBDMSCl (0.73 g,
4.82 mmol) and DMAP (5 mg) at room temperature and stirred
for 12 h. The reaction mixture was then poured into water
(20 mL) and extracted with CH2Cl2 (3 ꢁ 20 mL). The combined or-
ganic layers were washed with brine and dried over anhydrous
Na2SO4. Evaporation of the solvent followed by silica gel column
chromatography of the crude residue (ethyl acetate/hexane = 1:5)
To a suspension of LiAlH4 (0.42 g, 11.0 mmol) in dry THF
(10 mL) was added a solution of crude ester in THF (15 mL) at
0 °C. The reaction mixture was brought to room temperature and
stirred for 2 h. The mixture was hydrolyzed by the cautious addi-
tion of water and 15% NaOH solution. The fine white precipitate
which formed was washed with ethyl acetate and discarded. The
filtrate was concentrated and purified by column chromatography
(ethyl acetate/hexane = 1:3) to give alcoholic compound 8 (1.31 g,
afforded the silyl ether 11 (1.12 g, 90%) as a liquid. ½a D25
¼ þ1:1 (c
ꢂ
1.0, CHCl3); IR mmax (neat, cmꢀ1): 3454, 2932, 2860, 2097, 1255,
1093, 838; 1H NMR (300 MHz, CDCl3): d 3.60–3.70 (m, 2H), 3.25–
3.45 (m, 3H), 2.47 (d, 1H, J = 2.50 Hz), 1.58–1.92 (m, 2H), 1.43–
1.56 (m, 2H), 0.90 (s, 9H), 0.08 (s, 6H); 13C NMR (50 MHz, CDCl3):
d 71.25, 67.13, 51.46, 29.82, 25.85, 25.18, 18.26, ꢀ5.43; MS (ESI):
282 [M+Na]+; HRMS (ESI): calcd for C11H25N3O2Si [M+Na]+ =
282.1613, found: 282.1610.
82% for two steps) as a liquid. ½a D25
¼ þ7:4 (c 1.3, CHCl3); IR mmax
ꢂ
(neat, cmꢀ1): 3442, 2940, 1375, 1219, 1056; 1H NMR (300 MHz,
CDCl3): d 4.09–4.21 (m, 1H), 4.06 (dd, 1H, J = 6.04, 7.55 Hz), 3.62–
3.75 (m, 2H), 3.54 (dd, 1H, J = 7.55 Hz), 2.06 (br s, 1H), 1.60–1.74
(m, 4H), 1.42 (s, 3H), 1.37 (s, 3H); 13C NMR (75 MHz, CDCl3): d
108.97, 75.97, 69.47, 62.64, 30.27, 29.20, 26.89, 25.71; MS (ESI):
183 [M+Na]+; HRMS (ESI) calcd for C8H16O3 [M+Na]+ = 183.0997,
found: 183.0993.
4.6. (S)-(5-Azido-2-(benzyloxy) pentyloxy)(tert-butyl)
dimethylsilane 12
4.3. (S)-4-(3-Azidopropyl)-2,2-dimethyl-1,3-dioxolane 9
To a suspension of NaH (0.31 g, 60% w/w, 7.72 mmol) in anhy-
drous THF (5 mL), alcohol 11 (1.0 g, 3.86 mmol) in anhydrous
THF (10 mL) was slowly added at 0 °C, stirred for 15 min, followed
by addition of benzyl bromide (0.50 mL, 4.63 mmol) and a catalytic
amount of TBAI. The resulting mixture was stirred at room temper-
ature for 5 h, quenched with saturated aqueous NH4Cl solution,
and extracted with ethyl acetate. The organic layer was washed
with brine, dried over anhydrous Na2SO4, and concentrated in va-
cuo. The residue was purified over silica gel column chromatogra-
phy (ethyl acetate/hexane = 1:19) to give 12 (1.24 g, 92%) as a
Compound 8 (1.1 g, 6.87 mmol) was taken in dry CH2Cl2
(10 mL), cooled to 0 °C and treated with Et3N (2.4 mL, 17.18 mmol),
DMAP (3 mg), and mesyl chloride (0.65 mL, 8.25 mmol). The reac-
tion mixture was then stirred at room temperature until consump-
tion of the starting material (about 30–45 min). It was then poured
into water (20 mL) and extracted with CH2Cl2 (2 ꢁ 20 mL). The
combined organic layers were washed with brine and dried over
anhydrous Na2SO4. Evaporation of the solvent provided the crude
mesylate, which was directly used in the next step.
To a stirred solution of the crude mesylate obtained above in
dry DMF (10 mL) was added NaN3 (0.89 g, 13.69 mmol). The mix-
ture was heated to 90 °C and stirred for approximately 8 h. The
reaction was monitored by TLC until all starting material disap-
peared, then the mixture was diluted with water and extracted
with EtOAc (3 ꢁ 40 mL). The organic phase was dried over anhy-
drous Na2SO4 and concentrated. Purification of the residue by silica
gel column chromatography (ethyl acetate/hexane = 1:6) gave
pure azido compound 9 (1.18 g, 93% for two steps) as a liquid.
colorless liquid. ½a D25
ꢂ
¼ ꢀ21:6 (c 2.1, CHCl3); IR mmax (neat, cmꢀ1):
2930, 2859, 2096, 1254, 1100, 837; 1H NMR (300 MHz, CDCl3): d
7.20–7.39 (m, 5H), 4.59 (ABq, 2H, J = 11.80 Hz), 3.12–3.91 (m,
5H), 1.42–1.83 (m, 4H), 0.90 (s, 9H, J = 5.53 Hz), 0.05 (s, 6H); MS
(ESI): 372 [M+Na]+; HRMS (ESI): calcd for C18H31N3O2Si
[M+Na]+ = 372.2083, found: 372.2073.
4.7. (S)-5-Azido-2-(benzyloxy) pentan-1-ol 13
To a solution of 12 (0.60 g, 1.72 mmol) in THF (8 mL) was added
TBAF (3.4 mL of 1 M solution in THF, 3.43 mmol) at 0 °C and stirred
at room temperature for 3 h. It was then poured into water (20 mL)
and extracted with EtOAc (2 ꢁ 20 mL). The combined organic lay-
ers were washed with brine and dried over Na2SO4. Evaporation
of solvent followed by silica gel column chromatography of the
crude residue (ethyl acetate/hexane = 1:4) afforded 13 (0.38 g,
½
a 2D5
ꢂ
¼ þ6:5 (c 1.5, CHCl3); IR (neat, cmꢀ1): 2987, 2931, 2097,
1375, 1250, 1220, 1064; 1H NMR (300 MHz, CDCl3): d 4.01–4.16
(m, 2H), 3.53 (dd, 1H, J = 6.79, 7.17 Hz), 3.33 (t, 2H, J = 5.66 Hz),
1.54–1.85 (m, 4H), 1.41 (s, 3H), 1.35 (s, 3H); 13C NMR (100 MHz,
CDCl3): d 108.86, 75.34, 69.19, 51.18, 30.61, 26.79, 25.61, 25.27;
MS (ESI): 208 [M+Na]+; HRMS (ESI) calcd for C8H15N3O2
[M+Na]+ = 208.1061, found: 208.1061.
95%) as a syrupy liquid. ½a D25
¼ ꢀ5:0 (c 0.9, CHCl3); IR mmax (neat,
ꢂ

N. Sudhakar et al. / Tetrahedron: Asymmetry 19 (2008) 2153–2158
2157
cmꢀ1): 3425, 2927, 2870, 2096, 1455, 1065, 740; 1H NMR
(300 MHz, CDCl3): d 7.23–7.38 (m, 5H), 4.56 (s, 2H), 3.61–3.72
(m, 1H), 3.41–3.55 (m, 2H), 3.25 (t, 2H, J = 6.42 Hz), 1.89 (br s,
1H), 1.44–1.75 (m, 4H); 13C NMR (75 MHz, CDCl3): d 138.15,
128.48, 127.83, 127.78, 78.88, 71.62, 63.89, 51.42, 28.05, 24.79;
MS (ESI): 258 [M+Na]+.
Data for 16a: ½a 2D5
ꢂ
¼ þ22:0 (c 1.7, CHCl3); IR mmax (neat, cmꢀ1):
2934, 1692, 1412, 1365, 1256, 1154; 1H NMR (500 MHz, DMSO
at 50 °C): d 7.25–7.37 (m, 5H, –Ph), 4.87 (br s, 1H, C2He), 4.52 (d,
1H, –CH2Ph, J = 12.3 Hz), 4.50 (d, 1H, –CH2Ph, J = 12.3 Hz), 3.74
(dd, 1H, C6He, J = 5.1, 14.0 Hz), 3.43 (td, 1H, C3Ha, J = 5.0, 11.3 Hz),
2.73 (dd, 1H, C7H, J = 5.4, 15.0 Hz), 2.70 (t, 1H, C6Ha, J = 14.0 Hz),
2.50 (m, 1H, C7H), 2.07 (s, 3H, –COCH3), 1.82 (dq, 1H, C4He,
J = 5.1, 14.0 Hz), 1.62 (m, 1H, C5He), 1.45 (dq, 1H, C4Ha, J = 5.1,
14.0 Hz), 1.38 (s, 9H, –But), 1.30 (tq, 1H, C5Ha, J = 5.0, 14.0 Hz);
13C NMR (125 MHz, DMSO at 50 °C): d 206.97, 154.55, 139.25,
128.91, 128.11, 79.86, 79.72, 75.87, 70.49, 55.50, 50.73, 38.56,
30.70, 28.69, 25.71, 24.34; MS (ESI): 370 [M+Na]+; HRMS (ESI):
calcd for C20H29NO4 [M+Na]+ = 370.1994, found: 370.2001. Data
4.8. (S)-tert-Butyl 4-(benzyloxy)-5-hydroxypentylcarbamate 14
The azido compound 13 (0.25 g, 1.06 mmol) was dissolved in
MeOH (5 mL), and triphenyl phosphine (0.55 g, 2.12 mmol) was
added. The mixture was stirred for 4 h at ambient temperature,
and then di-tert-butoxycarbonyl dicarbonate (0.5 mL, 2.12 mmol)
was added. Stirring was continued for 6 h, after which the solvent
was evaporated. Column chromatography of the residue over silica
gel (ethyl acetate/hexane = 1:9) gave 14 (315 mg, 96%) as an oily
for 17a: ½a 2D5
ꢂ
¼ ꢀ42:3 (c 1.1, CHCl3); IR mmax (neat, cmꢀ1): 2934,
1690, 1419, 1366, 1271, 1167; 1H NMR (500 MHz, CD3OD at
45 °C): d 7.21–7.40 (m, 5H, –Ph), 4.94 (dt, 1H, C2H, J = 1.5,
7.5 Hz), 4.67 (d, 1H, –CH2Ph, J = 12.0 Hz), 4.52 (d, 1H, –CH2Ph,
J = 12.0 Hz), 3.96 (dd, 1H, C6He, J = 4.3, 13.0 Hz), 3.45 (q, 1H, C3H,
J = 3.0 Hz), 2.87 (td, 1H, C6Ha, J = 3.3, 13.0 Hz), 2.72 (d, 2H, C7H,
J = 7.5 Hz), 2.17 (s, 3H, –COCH3), 1.85 (m, 1H, C5He), 1.82 (m, 1H,
C4He), 1.72 (m, 1H, C4Ha), 1.42 (s, 9H, –But), 1.38 (m, 1H, C5Ha);
13C NMR (125 MHz, CD3OD at 45 °C): d 209.60, 157.97, 141.04,
130.09, 129.35, 82.04, 76.28, 72.16, 52.10, 50.49, 50.27, 44.80,
41.20, 29.59, 29.53, 26.12, 21.46; MS (ESI): 370 [M+Na]+; HRMS
(ESI): calcd for C20H29NO4 [M+Na]+ = 70.1994, found: 370.2000.
liquid: ½a 2D5
ꢂ
¼ ꢀ13:2 (c 0.8, CHCl3); IR mmax (neat, cmꢀ1): 3354,
2929, 1693, 1519, 1251, 1170; 1H NMR (400 MHz, CDCl3): d 4.56
(ABq, 2H, J = 11.72 Hz), 4.47–4.54 (m, 1H), 3.61–3.73 (m, 1H),
3.42–3.58 (m, 2H), 2.94–3.26 (m, 2H), 1.99 (br s, 1H), 1.47–1.74
(m, 4H), 1.44 (s, 9H); 13C NMR (75 MHz, CDCl3): d 156.01, 138.29,
128.48, 127.79, 79.20, 71.63, 64.00, 40.47, 28.39, 28.04, 25.93;
MS (ESI): 332 [M+Na]+; HRMS (ESI): calcd for C17H27NO4
[M+Na]+ = 332.1837, found: 332.1831.
4.9. (S,E)-tert-Butyl 4-(benzyloxy)-7-oxooct-5-enylcarbamate 5
4.11. (2S/R,3S)-tert-Butyl 3-(benzyloxy)-2-(3-bromo-2-
To a solution of (COCl)2 (0.15 mL, 1.62 mmol) in CH2Cl2 (3 mL)
was added DMSO (0.23 mL, 3.24 mmol) at ꢀ78 °C, and the mixture
was stirred for 10 min. A solution of alcohol 14 (0.25 g, 0.81 mmol)
in CH2Cl2 was added to the resulting mixture, and stirred it for 1 h
at ꢀ78 °C. Then, DIPEA (0.55 mL, 3.24 mmol) was added at ꢀ78 °C
and the reaction mixture was warmed to 0 °C for 20 min. Water
(20 mL) was added to quench the reaction mixture, and the aque-
ous mixture was extracted with CH2Cl2 (2 ꢁ 20 mL), dried over
anhydrous Na2SO4. Evaporation of solvent provided crude 15,
which was used directly in the next step.
To a solution of 15 in toluene (5 mL), PPh3CHCOCH3 (0.40 g,
1.21 mmol) was added. The mixture was heated at reflux with stir-
ring for about 8 h, until TLC showed disappearance of 15. The reac-
tion mixture was quenched with water and extracted with ethyl
acetate. The organic layer was washed with water and brine, and
dried over anhydrous Na2SO4. The solvent was removed under va-
cuo and column chromatography of the residue over silica gel
(ethyl acetate/hexane = 1:5) gave 5 (0.25 g, 89% for two steps) as
oxopropyl) piperidine-1-carboxylate 3/4
A solution of lithium hexamethyldisilazide (0.25 mL 1 M solu-
tion in toluene, 0.25 mmol) in dry THF (2.0 mL) was cooled to
ꢀ78 °C, and to this solution was slowly added compound 16a
(70 mg, 0.20 mmol) in THF (2 mL). After 1 h, TMSCl (0.65 mL,
0.50 mmol) was added to the mixture, which was further stirred
for 1 h. The reaction mixture was diluted with 10 mL of hexane
at ꢀ78 °C and washed quickly with water, saturated aqueous NaH-
CO3, and brine. The organic layer was dried over Na2SO4 and con-
centrated under reduced pressure which gave silyl enol ether 18.
The crude silyl enol ether 18 was dissolved in CH2Cl2 (2 mL), and
to this solution were added NaHCO3 (68 mg, 0.80 mmol) and NBS
(54 mg, 0.30 mmol) at 0 °C, and stirring was continued for 2 h at
0 °C. Then, the reaction mixture was diluted with water and ex-
tracted with CH2Cl2 (2 ꢁ 15 mL). The combined organic extracts
were washed with brine and dried over anhydrous Na2SO4. The sol-
vent was removed under vacuo and column chromatography of the
residue over silica gel (ethyl acetate/hexane = 1:14) gave 3 (60 mg,
a syrupy liquid. ½a D25
ꢂ
¼ ꢀ15:2 (c 1.2, CHCl3); IR mmax (neat, cmꢀ1):
2974, 2933, 1697, 1517, 1365, 1254, 1169; 1H NMR (200 MHz,
CDCl3): d 7.22–7.41 (m, 5H), 6.59 (dd, 1H, J = 6.25, 16.02 Hz), 6.19
(d, 1H, J = 16.02 Hz), 4.56 (d, 1H, J = 11.72 Hz), 4.35 (d, 1H,
J = 11.72 Hz), 4.35–4.51 (m, 1H), 3.87–4.05 (m, 1 H), 2.97–3.24
(m, 2H), 2.25 (s, 3H), 1.45–1.71 (m, 4H), 1.43 (s, 9H); MS (ESI):
370 [M+Na]+; HRMS (ESI): calcd for C20H29NO4 [M+Na]+ =
370.1994, found: 370.1991.
70% for two steps) as a syrupy liquid. ½a D25
¼ ꢀ19:3 (c 0.7, CHCl3)
ꢂ
{lit.4 (its enantiomer) ½a 2D5
¼ þ22:5, (c 0.3, CHCl3)}; IR mmax (neat,
ꢂ
cmꢀ1): 2935, 2865, 1687, 1410, 1364, 1152; 1H NMR (300 MHz,
DMSO at 50 °C): d 7.20–7.47 (m, 5H), 4.88 (br, 1H), 4.37-4.60 (m,
2H), 4.32 (d, 1H, J = 14.24 Hz), 4.22 (d, 1H, J = 14.24 Hz), 3.65–
3.85 (m, 1H), 3.35–3.52 (m, 1H), 2.99 (dd, 1H, J = 5.08, 15.26 Hz),
2.58–2.80 (m, 2H), 1.75–1.90 (m, 1H), 1.55–1.71 (m, 1H), 1.37 (s,
9H), 1.14–1.55 (m, 2H); 13C NMR (75 MHz, DMSO at 50 °C): d
198.76, 153.50, 138.08, 127.85, 127.11, 127.07, 78.85, 74.73,
69.51, 36.63, 35.16, 33.50, 27.64, 24.63, 23.17; MS (ESI): 448
[M+Na]+; HRMS (ESI): calcd for C20H28NO4Br [M+Na]+ = 448.1099,
found: 448.1092.
4.10. (2R/S,3S)-tert-Butyl 3-(benzyloxy)-2-(2-oxopropyl)
piperidine-1-carboxylate 16a/17a
To a suspension of NaH (46 mg, 60% w/w, 1.15 mmol) in anhy-
drous THF (4 mL), compound 5 (0.20 g, 0.57 mmol) in anhydrous
THF (10.0 mL) was slowly added at 0 °C. The mixture was stirred
at 0 °C for 30 min, quenched with saturated aqueous NH4Cl solu-
tion, and extracted with ethyl acetate. The organic layer was
washed with brine, dried over anhydrous Na2SO4, and concen-
trated in vacuo. The residue was purified over silica gel column
chromatography (ethyl acetate/hexane = 1:7) to give pure com-
pounds 16a and 17a in an 8:2 ratio (196 mg, 98%) as oily liquids.
Similarly, compound 4 was prepared from 17a in 72% yield.
½
a 2D5
ꢂ
¼ ꢀ32:2 (c 0.5, CHCl3); {lit.4 (its enantiomer) ½a 2D5
¼ þ28:4 (c
ꢂ
0.2, CHCl3)}; IR mmax (neat, cmꢀ1): 2927, 2857, 1685, 1415, 1367,
1170; 1H NMR (200 MHz, CDCl3): d 7.02–7.67 (m, 5H), 4.93 (t,
1H, J = 7.05 Hz), 4.68 (d, 1H, J = 11.91 Hz), 4.48 (d, 1H,
J = 11.91 Hz), 3.85–4.16 (m, 2H), 3.79 (d, 1H, J = 12.28 Hz), 3.33–
3.43 (m, 1H), 2.61–2.98 (m, 3H), 1.42 (s, 9H), 1.13–2.05 (m, 4H);
13C NMR (50 MHz, CDCl3): d 199.65, 155.27, 138.48, 128.28,

2158
N. Sudhakar et al. / Tetrahedron: Asymmetry 19 (2008) 2153–2158
6. (a) Baker, B. R.; McEvoy, F. J.; Schaub, R. E.; Joseph, J. P.; Williams, J. H. J. Org.
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1814; (e) Okitsu, O.; Suzuki, R.; Kobayashi, S. Synlett 2000, 989; (f) Takeuchi, Y.;
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Kobayashi, S. J. Org. Chem. 2001, 66, 809; (l) Sugiura, M.; Hagio, H.; Hirabayashi,
R.; Kobayashi, S. J. Am. Chem. Soc. 2001, 123, 12510; (m) Huang, P. Q.; Wei, B. G.;
Ruan, Y. P. Synlett 2003, 1663; (n) Katoh, M.; Matsune, R.; Nagase, H.; Honda, T.
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127.45, 80.03, 77.20, 73.48, 70.19, 49.49, 39.75, 34.04, 28.33, 24.63,
19.43; MS (ESI): 448 [M+Na]+; HRMS (ESI): calcd for C20H28NO4Br
[M+Na]+ = 448.1099, found: 448.1092.
Acknowledgments
N.S. thanks UGC, New Delhi, G.S. and G.S.R. thank CSIR, New
Delhi for fellowship. The authors thank Dr. A. C. Kunwar for his
fruitful discussion and support. The authors also thank Dr. J. S.
Yadhav and Dr. T. K. Chakraborthy for their support and
encouragement.
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