A concise enantioselective synthesis of L-(-)-733,061 and (2S,3S)-methyl 3-aminopiperidine-2-carboxylate using catalytic enantioselective aza-Henry reaction as key step

Article abstract of DOI:10.1016/j.tet.2011.02.031

An efficient enantioselective synthesis of L-(-)-733,061 and (2S,3S)-methyl 3-aminopiperidine-2-carboxylate is accomplished by means of catalytic enantioselective aza-Henry reaction. A key feature of this protocol is organocatalysis as genesis of chiralit

Full text of DOI:10.1016/j.tet.2011.02.031

Tetrahedron 67 (2011) 2536e2541
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A concise enantioselective synthesis of
3-aminopiperidine-2-carboxylate using catalytic enantioselective aza-Henry
reaction as key step
L
-(ꢀ)-733,061 and (2S,3S)-methyl
*
Gullapalli Kumaraswamy , Arigala Pitchaiah
Organic Division III, Indian Institute of Chemical Technology, Hyderabad500 607, Andra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient enantioselective synthesis of
L
-(ꢀ)-733,061 and (2S,3S)-methyl 3-aminopiperidine-2-carb-
Received 30 December 2010
Received in revised form 11 February 2011
Accepted 12 February 2011
Available online 18 February 2011
oxylate is accomplished by means of catalytic enantioselective aza-Henry reaction. A key feature of this
protocol is organocatalysis as genesis of chirality to ensure high degree of distereo- and enantiocontrol.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalysis
Piperidine motif
L
-(ꢀ)-733061
(2S,3S)-Methyl 3-aminopiperidine-2-
carboxylate
aza-Henry reaction
Febrifugine
Glycosidase inhibitors
1. Introduction
on a program to synthesize
L
-(ꢀ)-733061 1, synthetic variants of
chiral piperidine derivatives, such as (2S,3S)-methyl 3-amino-
piperidine-2-carboxylate 2, and their C3 epimers, 1a and 2a. Fur-
ther, we are interested to evaluate their biological activities based
on functional modifications (Fig. 2).
Piperidine motif containing alkaloids are medicinally significant
owing to their anaesthetic, analgesic and antibiotic activity.1 In
general, substituted piperidines are becoming progressively more
important because of their distinctive biological activities, such as
neurokinin-1 (NK-1) receptor antagonist and as a glycosidase in-
hibitors.2 Recently, potential therapeutic value was recognized for
substituted piperidines, for instance, in (2R,3R)-3-hydroxypipecolic
acid, febrifugine, (þ)-epi-deoxoprosopinine and (ꢀ)-cassine mole-
cules3 (Fig. 1).
2. Results and discussion
Herein, we report a highly practical and organocatalyzed
enantioselective synthetic route to
L-(ꢀ)-733060 1, (2S,3S)-methyl
The successful methods that provide enantioselective routes to
chiral substituted piperidine derivatives are based on the chiral
pool, especially aminoacids; the use of the reagent that utilize
chiral catalyst and chiral auxiliaries.4 It was pragmatic that chiral
functional group variation on piperidine ring is expected to gen-
erate distinctive properties, that enhance the therapeutic potential
of the compounds for the treatment of diseases.
OH
N
OH
O
N
N
H
N
H
CO2H
O
(2R,3R)--3-Hydroxy
(-)-Febrifugine
pipecolic acid
OH
OH
HO
With this initiative, and our continued interest in developing
catalytic routes to bioactive small molecules,5 we have embarked
O
N
H
N
H
8
9
(+)-2-epi-deoxoprosopinine
(-)-cassine
* Corresponding author. Tel.: þ91 40 27193154; fax: þ91 40 27193275. E-mail
address: gkswamy_iict@yahoo.co.in (G. Kumaraswamy).
Fig. 1. Substituted piperidine motif molecules.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.031

G. Kumaraswamy, A. Pitchaiah / Tetrahedron 67 (2011) 2536e2541
2537
the presence of 15 mol % of Cat A0 under identical conditions led to
the complete racemic mixture of the expected product.
CF3
CF3
Thus, oxidation of nitro functionality 5 by Gissot’s protocol
(NaNO2 (6 equiv),7 DMF/H2O (7:1; 0.4 M), 45 ꢁC, 12 h)7 led to keto
compound 7 in 68% yield. Then, the amino ketone 7 was reduced
with NaBH4 under Luche’s conditions (CeCl3$7H2O, CH2Cl2/EtOH
[1:1]) furnished a syn-selective (dr¼9:1) secondary alcohol 8 (74%).
The secondary alcohol 8 was protected with 3,5-bistriflouromethyl
benzyl bromide under basic conditions resulted in a separable pure
syn-isomer 9 (74% yield) and then following deprotection of TBS
(TBAF, THF, 0 ꢁC, 3 h) led to a primary alcohol in 80% yield. Mesyla-
tion of primary alcohol followed removal of N-Boc group with TFA
results TFA salt. Then, cyclization under basic condition (Et3N,
MeOH, 2 h, 60 ꢁC) resulted in the desired compound 1 in 65% iso-
latedyield (over three steps).10 The spectral and analyticaldata of 14j,
3
2
O
3
2
O
CF3
CF3
N
H
N
H
(2R,3S),1a
L-(-)-733,061,1
3
NH2
NH2
2
N
H
CO2Me
N
H
2
CO2Me
2a
Fig. 2. Synthetic variants of chiral substituted piperidine derivatives.
1a4f,g were in full agreement with that reported data, 1 [
a
]
25 ꢀ32.56
D
(c 0.60, CHCl3); {lit.4 [
a
]
25 þ34.29 (c 0.99, CHCl3)} (Scheme 1).
D
NHBoc
NHBoc
NHBoc
NO2
SO2-Tol
NO2
a
+
+
b
3
4
OTBS
OTBS
OTBS
5'
O2N
5, dr = 85:15 (syn : anti )
ee = 94%, Yield, 85%
NHBoc
O
NHBoc
NHBoc
d
c
O
OTBS
OTBS
OH
OTBS
8, dr = 9:1
CF3
68%Y
7
9
Yield, 74%
CF3
F3C
O
e, f, g, h
CF3
N
N
Cl
HO
Cl
+
N
H
Ph
HO
+
MeO
MeO
1
N
Cat. A'
N
Cat. A
Scheme 1. (a) Cat A (15 mol %), CsOH H2O (1.3 equiv), toluene (0.8 M), ꢀ55 ꢁC, 44 h; (b) NaNO2 (6 equiv), DMF/H2O (7:1), 45 ꢁC, 12 h; (c) NaBH4, CeCl3 7H2O, ꢀ78 ꢁC to ꢀ40 ꢁC; (d)
(i) NaH, TBAI, THF, (ii) 3,5-bis trifluromethyl benzyl bromide, 12 h, rt; (e) TBAF, 0 ꢁC, THF; (f) MeSO2Cl, Et3N, CH2Cl2; (g) TFA, CH2Cl2; (h) Et3N, MeOH, 2 h, 60 ꢁC.
3-aminopiperidine-2-carboxylate 2 and stereoisomer 2a. In prin-
ciple, the stereogenic centers at C2 and C3 in
-(ꢀ)-733061 1, and
(2S,3S)-methyl 3-aminopiperidine-2-carboxylate could be
En route to the synthesis of
L
-(ꢀ)-733,061, we have also con-
L
sidered the synthesis of chiral substituted piperidine derivatives,
(2S,3S)-methyl 3-aminopiperidine-2-carboxylate 2, and stereoiso-
mer 2a (Scheme 2). Consequently, the reaction of N-Boc-sulfone 10
with nitro compound 4 in the presence of Cat A (15 mol %) in tol-
uene at ꢀ50 ꢁC for 44 h resulted in the desired product 11 in 81%
yield with 80:20 diastereomeric ratio in favour of syn isomer with
92% ee. The ee was assessed by chiral HPLC analysis using corre-
sponding racemic mixture [Chiralpak AD-H, 220 nm, flow
rate¼0.5 mL/min, n-hexane/2-propanol (95:5)]. The absolute ste-
reochemistry of major diastereomer 11 was assigned by analogy.6
Reduction of 11 with sodium borohydride in the presence of
NiCl2$6H2O (ꢀ5 ꢁC, MeOH, 15 min) led to amine, which on pro-
tection with CbzCl under basic conditions afforded 12 in 78% yield.
Exposure of 12 to TBAF in THF at ambient temperature led to
desilylation, and resulting primary alcohol was then converted to
mesylate 13 under basic conditions. Deprotection of N-Boc under
acidic conditions (TFA in CH2Cl2) followed by cyclization using
Et3N/MeOH at ambient temperature led to 14 (65%). Subsequent
2
accessed through a catalytic syn-selective aza-Henry reaction with
high degrees of diastereo- and enantioselectivity using N-Boc-sul-
fone 3,10 and nitro compound 4. To this end, we have appraised the
recently reported Palomo-reaction6 conditions for this trans-
formation. Accordingly, the reaction of N-Boc-sulfone 3 with nitro
compound 4 employing phase transfer catalyst 15 mol % of Cat A in
toluene at ꢀ55 ꢁC for 44 h resulted in the anticipated product 5 in
85% yield with 85:15 diastereomeric ratio in favour of syn isomer.
The ee of major syn isomer 5 estimated by chiral HPLC analysis in
comparison with a racemic mixture and was found to be 94%
[corresponding TBS deprotected alcohol 6, Chiralpak AD-H, 210 nm,
flow rate¼1 mL/min, n-hexane/EtOH (85:15)6c]. The absolute ste-
reochemistry of major diastereomer 5 was assigned by analogy.6 It
was anticipated that the use of complementary sense Cat A0, i.e.,
quinidine salt would generate the anti-selective diastereomer 50.
Nevertheless, subjecting N-Boc-sulfone 3 and nitro compound 4 in

2538
G. Kumaraswamy, A. Pitchaiah / Tetrahedron 67 (2011) 2536e2541
NHBoc
NO2
two stereo centers are delivered with high degree of diastereo- and
NHBoc
O
enantioselectivity in single operation by means of a catalytic enan-
tioselective aza-Henry reaction. Further work is under progress for
the synthesis of chiral hetero-analogues of piperidine moiety.
a
OTBS
+
O
O2N
SO2-Tol
OTBS
4
11, dr = 80:20 ( syn:anti)
ee = 95%, Yield, 81%
10
4. Experimental
NHBoc
NHCbz
NHBoc
NHCbz
O
O
d
c
b
4.1. General information
13
OH
12
OTBS
Starting materials: DCM was distilled from P2O5, THF from so-
dium benzophenone ketyl. All other chemicals used were com-
mercially available. All reactions were conducted under an
atmosphere of nitrogen (IOLAR Grade I). Progress of the reactions
was monitored by TLC on Merck Silica Gel 60 F-254 precoated.
Evaporation of solvents was performed at reduced pressure on
a Buchi rotary evaporator. Column chromatography was carried out
with silica gel grade 60e120 and 100e200 mesh. 1H NMR spectra
were recorded at 300, 400 and 500 MHz and 13C NMR 75 and
125 MHz in CDCl3. J values were recorded in hertz and abbrevia-
tions used were s-singlet, d-doublet, m-multiplet, br-broad.
NHCbz
O
NHCbz
O
NHCbz
O
f
e
+
N
N
Cbz
N
H
Cbz
15
14
15a
8:2
NH2
NHCbz
CO2Me
N
CO2Me
N
H
Cbz
16
Chemical shifts (
d
) are reported relative to TMS (
d
¼0.0) as an in-
Scheme 2. (a) Cat A (15 mol %), CsOH H2O (1.3 equiv), toluene (0.8 M), ꢀ55 ꢁC, 44 h; (b)
(i) NiCl2 6H2O, NaBH4, MeOH, (ii) CbzCl, NaHCO3, MeOH; (c) (i) TBAF, THF, rt, (ii) MeSO2Cl,
Et3N, 30 min, (iii) TFA, 0 ꢁC, 2 h CH2Cl2; (d) Et3N, MeOH, 3 h, 90 ꢁC; (e) CbzCl, NaHCO3,
MeOH; (f) (i) RuCl3ꢂH2O (2 mol %), NaIO4, EtOAc/CH3CN/H2O, (ii) CH2N2, Et2O.
ternal standard. IR spectra were recorded on Thermo Nicolet FT/IR-
5700. Mass spectral data were compiled using MS (ESI), HRMS data
obtained using quadrupole time-of-flight (QTOF) mass spectrom-
eter (QSTAR XL, Applied Biosystems MDS Sciex, Foster City, USA).
Optical rotations were recorded on HORIBA high sensitive polar-
imeter with 10 mm cell. Concentration of the samples was
expressed as g/mLꢂ100. HPLC was carried on a Shimadzu LC-
10ATvp dual pump system.
secondary amine protection with CbzCl furnished 15 and 15a as
separable diastereomeric mixture. The major diastereomer 15 was
separated by column chromatography (silica gel) and the relative
stereochemistry was determined by 2DNMR experiment by using
NOESY and DQFCOSY.
4.1.1. tert-Butyl
(1R,2S)-5-(tert-butyldimethylsilyloxy)-2-nitro-1-
phenylpentylcarbamate (5). To a mixture of N-Boc sulfone 3 (1.81 g,
5 mmol), and Cat A (0.342 g, 0.75 mmol) in anhydrous toluene (0.8
M) at ꢀ55 ꢁC were added 4 (5.13 g, 25 mmol) and CsOH.H2O (1.09 g,
6.5 mmol) successively under inert atmosphere. The resulting re-
action mixture was stirred vigorously for 40 h at ꢀ55 ꢁC. Then, it
was quenched with 0.1 N HCl (20 mL), and the reaction mixture
was slowly allowed to warm to ambient temperature. The aqueous
layer was extracted with CHCl3 (3ꢂ20 mL), washed with brine
(2ꢂ10 mL). The combined organic extracts were dried over anhy-
drous Na2SO4, and contents were evaporated under reduced pres-
sure. The crude residue was purified over silica gel column
chromatography with hexane/EtOAc (9:1) as eluent to afford 5 as
semi solid (1.86 g, 85%). The dr and ee were determined by HPLC
using chiral AD-H of corresponding primary alcohol (220 nm, 95:5
hexane/IPA, 0.5 mL/min). The dr of syn/anti was found to be 85:15
H2
R1
R
H4'
RHN
'3H
N
H5'
R = Cbz
R1= 2-furyl
H1
H4
H3
H5
15
Fig. 3. Noe correlation of 15.
The significant NOE correlations are shown in Fig. 3. In the major
diastereomer 15, observation of strong NOE between H1eH3,
H1eH5 and H2eH40 confirms that they are spatially closer and
hence considered to be the H1eH2 are in a trans-relationship
(JH1eH2¼8.7 Hz).
and the major syn isomer ee was 95%. [
a
]
25 ꢀ16.8 (c 1.5, CHCl3); Rf
D
(20% EtOAc/Hex) 0.60; 1H NMR (CDCl3, 300 MHz):
d 7.28e7.12 (m,
5H, ArH), 5.61 (d, J¼9.8 MHz, 1H, NHCO), 5.08e4.97 (dd, J¼6.8,
9.8 MHz, 1H, CHNH), 4.83e4.70 (m, 1H, CHNO), 3.61e3.44 (m, 2H,
CHOSi), 1.91e1.73 (m, 2H, CHNO), 1.56e1.42 (m, 2H, CHCH2), 1.35 (s,
9H, t-Bu), 0.76 (s, 9H, t-Bu), ꢀ0.54 (d, 6H, (CH3)2); 13C NMR (CDCl3,
The oxidative cleavage of furyl moiety of 15 (RuCl3, NaIO4),9
followed by esterification of resulting acid (CH2N2, Et2O) pro-
vided 16 (62%), which on then hydrogenation under balloon
pressure (10% PdeC/H2) resulted in the desired diamino compound
2 in 85% yield. The analytical data is in agreement with proposed
structure. The minor diastereomer 15a was also subjected to
oxidation/esterification and hydrogenation (vide infra) led to 2a in
83% yield (Scheme 2). As logical extension, further, in an effort to
synthesize (2S,3S)-3-hydroxy pipecolicacid using similar strategy
was failed.8
75 MHz): d 145.1, 137.6, 128.9, 128.3, 126.2, 92.0, 61.6, 56.0, 28.5 and
ꢀ5.4; IR (neat): 2923, 2854, 2362, 1695, 1518, 1460, 1263 cmꢀ1
;
ESIMS: 461 (MþNa)þ; HRMS calcd for C22H38N2O5NaSi 461.2447
and found 461.2428.
4.1.2. tert-Butyl(1R,2S)-5-hydroxy-2-nitro-1-phenylpentylcarbamate
(6). To the solution of 5 (1.38 g, 3.1 mmol) in THF (10 mL) was
added TBAF (6.0 mL, 6 mmol, 1 M in THF) at 0 ꢁC. The reaction
mixture was stirred for 2 h at room temperature. Then, it was
quenched with an aqueous solution of NH4Cl (5 mL) and aqueous
layer was extracted with CH2Cl2 (3ꢂ10 mL). The combined organic
extracts were dried over anhydrous Na2SO4, filtered and evaporated
under reduced pressure. The crude residue was purified with silica
gel column chromatography with hexane/EtOAc (6:4) as eluent to
3. Conclusions
A highly practical, organocatalyzed enantioselective synthesis of
L
-(ꢀ)-7330611 and (2S,3S)-methyl 3-aminopiperidine-2-carboxylate
2 has been accomplished. The salient feature of this protocol is that

G. Kumaraswamy, A. Pitchaiah / Tetrahedron 67 (2011) 2536e2541
2539
afford 6 as white solid (0.85 g, 83%). Mp 152e153. The dr and ee
were determined by HPLC analysis (Chiralpak AD-H, 85/15 hexane/
EtOH, 1.0 mL/min, 210 nm). The dr of syn/anti was found to be
85:15. The major diastereomer was determined to have 94% ee by
chiral HPLC analysis tR (major)¼5.92 min, tR (minor)¼7.92 min; and
the minor diastereomer was determined to have 86% ee under the
same HPLC analysis conditions: tR (major)¼16.1 min, tR (minor)¼
dispersion in mineral oil, 1.54 mmol) was added in two portions
over 5 min, and stirring was continued for 30 min. Then, the re-
action mixture was quenched with aqueous NH4Cl (10 mL), and the
aqueous layer was extracted with EtOAc (3ꢂ10 mL). The combined
organic layer was washed with water (2ꢂ10 mL) followed by brine
solution (1ꢂ15 mL) and dried over anhydrous Na2SO4. Filtered the
solids and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography with hexane/EtOAc
17.5 min; [
a
]
25 ꢀ3.95 (c 2.10, CHCl3) (lit. [
a
]
D
25 þ3.72 (c 1.50, CHCl3));
D
Rf (60% EtOAc/hexane) 0.45; 1H NMR (CDCl3þDMSO-d6, 300 MHz):
(9:1) to afford 9 (0.61 g, 70%) as a semi solid (syn/anti, 9:9a, 9:1); 9;
25
d
7.36e7.20 (m, 5H, ArH), 5.78 (d, J¼6.8 Hz, 1H, NHCO), 5.22e4.88
[a
]
ꢀ16.62 (c 0.8, CHCl3); Rf (20% EtOAc/Hex) 0.65; 1H NMR
D
(m, 2H, NHCH, NOCH), 3.70e3.58 (m, 2H, CHOSi), 2.05e1.88 (m, 2H,
(CDCl3, 300 MHz): 7.81 (s, 1H, ArH), 7.53 (br d, 2H, ArH), 7.24e7.19
(m, 5H, ArH), 5.17 (d, J¼8.4 Hz, 1H, NHCO), 4.73 (s, 2H, CHAr), 4.61
(t, J¼5.4 Hz, 1H, CHNH), 4.33 (d, J¼12.2 Hz, 1H, CHOAr), 3.65e3.53
(m, 2H, CHOSi),1.79e1.69 (m, 2H, CHCH),1.63e1.52 (m, 2H, CHCH2),
1.38 (s, 9H, t-Bu), 0.83 (s, 9H, t-Bu), 0.02(s, 6H, (CH3)2); 13C NMR
CHNO), 1.69e1.53 (m, 2H, CHCH2), 1.42 (s, 9H, t-Bu); 13C NMR
(CDCl3, 75 MHz):
d 145.1, 137.6, 128.9, 128.3, 126.2, 92.0, 82.2, 61.6,
56.0, 28.5, 28.1, 26.4; IR (neat): 2975, 1690, 1549, 1499, 1365, 1250,
1164 cmꢀ1; ESIMS: 347 (MþNa)þ; HRMS calcd for C16H24N2O5Na
347.1582, found 347.1593.
(CDCl3, 75 MHz): d 155.3, 141.1, 138.9, 131.7, 131.5, 128.4, 127.5, 127.4,
121.4 (q), 82.5, 70.5, 62.7, 56.2, 29.7, 28.9, 28.2, 26.6, 25.9, ꢀ5.4; IR
4.1.3. (R)-tert-Butyl 5-(tert-butyldimethylsilyloxy)-2-oxo-1-phenyl-
pentylcarbamate (7). To the stirred solution of 5 (1.8 g, 4.1 mmol) in
DMF/H2O (7:1, 0.4 M) was added solid NaNO2 (1.70 g, 24.6 mmol) at
room temperature. The resulting reaction mixture was heated to
45 ꢁC for 12 h. Then, it was quenched with H2O (10 mL), and
extracted with CH2Cl2 (3ꢂ20 mL). The organic extracts were
washed water (2ꢂ10 mL) and brine (2ꢂ10 mL). The combined
organic layers were dried over anhydrous Na2SO4, filtered and
evaporated under reduced pressure. The crude residue was purified
(neat): 2956, 2862, 1703, 1498, 1364, 1279, 1133 cmꢀ1; ESIMS: 658
(MþNa)þ; HRMS calcd for C31H43F6NO4NaSi 658.2658, found
25
658.2662; 9a (0.068 g); [
a
]
þ18.50 (c 0.8, CHCl3); Rf (20% EtOAc/
D
Hex) 0.60; 1H NMR (CDCl3, 300 MHz):
d 7.77 (s, 1H, ArH), 7.70 (br s,
2H, ArH), 7.35e7.22 (m, 5H, ArH), 5.15 (d, J¼8.6 Hz, 1H, NHCO), 4.92
(br s, 1H, CHNH), 4.65 (q, J¼8.8 Hz, 2H, CHOAr), 3.70 (br d, J¼3.3 Hz,
1H, CHNH), 3.58e3.48 (m, 2H, CHOSi), 1.78e1.43 (m, 4H, CHCH2,
CHOH),1.39 (s, 9H, t-Bu), 0.83 (s, 9H, t-Bu), ꢀ0.03 (s, 6H, (CH3)2); 13
C
NMR (CDCl3, 75 MHz): d 140.5, 135.5, 128.4, 127.8, 127.5, 127.4, 127.1,
by silica gel column chromatography with hexane/EtOAc (9:1) as
126.2, 122.4 (q), 83.8, 71.1, 62.8, 56.3, 29.6, 28.9, 28.3, 25.9, 22.6,
25
eluent to afford 7 (1.14 g, 68%) as semi yellow solid [
a
]
ꢀ9.65 (c
ꢀ5.3; IR (neat): 2953, 2860, 1702, 1496, 1368, 1276, 1132 cmꢀ1
;
D
1.2, CHCl3); Rf (20% EtOAc/Hex) 0.70; 1H NMR (CDCl3, 300 MHz):
ESIMS: 658 (MþNa)þ; HRMS calcd for C31H43F6NO4NaSi 658.2763,
d
7.34e7.25 (m, 5H, ArH), 5.83 (d, J¼3.9 Hz, 1H, NHCO), 5.22 (d,
found 658.2738.
J¼5.6 Hz, 1H, NHCH), 3.53e3.44 (m, 2H, CHOSi), 2.49e2.33 (m, 2H,
COCH), 1.77e1.60 (m, 2H, CHCH2), 1.39 (s, 9H, t-Bu), 0.82 (s, 9H, t-
4.1.6. (2R,3R)-3-(3,5-Bis(trifluoromethyl)benzyloxy)-2-phenyl-
piperidine (1). To a solution of 8 (0.31 g, 0.5 mmol) in THF was
added TBAF (2.0 mL, 2.0 mmol 1 M in THF) at 0 ꢁC. The resulting
solution was stirred for 2 h at room temperature. The reaction was
quenched with aqueous NH4Cl (10 mL), aqueous layer was extrac-
ted with EtOAc (3ꢂ10 mL). The combined organic layer was washed
with brine solution, dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure. To a cooled (0 ꢁC) solution of
the above crude alcohol (0.20 g, 0.4 mmol) and Et3N (0.4 g,
0.4 mmol) in CH2Cl2 (10 mL) was added drop wise MsCl (0.50 g,
0.4 mmol), and the mixture was stirred at 0 ꢁC for 30 min, diluted
with Et2O (30 mL) and washed successively with saturated aqueous
NaHCO3 and brine, dried over (Na2SO4), filtered and concentrated
under reduced pressure. The resultant crude product dissolved in
CH2Cl2, and to this added TFA (0.58 g, 2.6 mmol) via syringe. The
resulting reaction mixture was stirred for 3 h. Then, the reaction
mixture was concentrated under reduced pressure led to the crude
TFA salt, which was again dissolved in dry MeOH (10 mL). To this
stirred solution, Et3N (0.21 g, 2.0 mmol) was added slowly and
refluxed for 2 h at 60 ꢁC. The solvent was removed under reduced
pressure; the crude residue was purified by silica gel column
Bu), ꢀ0.04 (s, 6H, (CH3)2); 13C NMR (CDCl3, 75 MHz):
d 176.3, 154.9,
137.6, 129.0, 128.3, 126.3, 61.8, 56.3, 29.3, 28.6, 28.2, 25.8, 18.2, ꢀ5.0;
IR (neat): 2928, 2857, 1710, 1695, 1551, 1495, 1363, 1250, 1165,
1097 cmꢀ1; ESIMS: 430 (MþNa) þ; HRMS calcd for C22H37NO4SiNa
430.2389, found 430.2385.
4.1.4. tert-Butyl (1R,2R)-5-(tert-butyldimethylsilyloxy)-2-hydroxy-1-
phenylpentylcarbamate (8). To the stirred solution of keto compound
6
(1.1 g, 2.70 mmol) in EtOH/CH2Cl2 (1:1, 10 mL) was added
CeCl3$6H2O (1.0 g, 2.7 mmol) at room temperature. Then, the result-
ing suspension was cooled to ꢀ78 ꢁC followed by addition of NaBH4
(0.12, 3.24 mmol) under nitrogen atmosphere. Stirring was continued
for 5 h at ꢀ78 ꢁC and for 2 h at ꢀ40 ꢁC. The reaction mixture was
quenched with saturated NH4Cl (10 mL). The aqueous layer was
extracted with CH2Cl2 (3ꢂ20 mL), and the combined organic extracts
were washed with brine (2ꢂ10 mL). The organic contents were dried
over anhydrous Na2SO4, filtered and evaporated under reduced
pressure. The resulting residue was purified by silica gel column
chromatographywithhexane/EtOAc(7:3), furnishedalcohol8(0.82 g,
74%) as a dense liquid [
a
]
25 ꢀ28.65 (c 1.5, CHCl3); Rf (30% EtOAc/Hex)
D
0.40; 1H NMR (CDCl3, 300 MHz):
d
7.32e7.18 (m, 5H, ArH), 5.47 (d,
chromatography using CHCl3/MeOH (85:15) as eluent gave to 1
26
J¼8.3 Hz,1H, NHCO), 4.54 (br s,1H, CHNH), 3.89e3.82 (m,1H, CHOH),
3.66e3.49 (m, 2H, CHOSi), 2.89 (br s, 1H, OHCH), 1.66e1.58 (m, 4H,
CHCH2, CHOH),1.39 (s, 9H, t-Bu), 0.82 (s, 9H, t-Bu), 0.01(s, 6H, (CH3)2);
(0.11 g, 65%) as light brown liquid; [
a
]
ꢀ32.56 (c 0.60, CHCl3); Rf
D
(10% EtOAc/MeOH) 0.50; 1H NMR (CDCl3, 300 MHz):
d 7.69 (br s, 1H,
ArH), 7.42 (br d, J¼5.8 Hz, 2H, ArH), 7.41e7.28 (m, 5H, ArH), 4.52(d,
J¼12.8 Hz, 1H, OCHAHB), 4.11(d, J¼12.8 Hz, 1H, CHACH), 3.83 (br s,
1H, H-2), 3.68 (s, 1H, H-2), 3.26 (m, 1H, H-6), 2.85 (td, J¼3.2, 12.8 Hz,
1H, H-6), 2.22 (br d, J¼13.2 Hz, 1H, H-4), 1.95 (br s, 1H, CH),
1.88e1.75 (qt, J¼4.3, 13.2 Hz, 1H, H-5), 1.64e1.48 (m, 1H, H-5); 13C
NMR (CDCl3, 75 MHz): 141.4, 141.2, 131.3 (q, J¼33.3 Hz), 128.1, 127.4,
127.1, 126.7, 123.2 (q, J¼272.6 Hz), 121.3 (quint), 77.4, 70.0, 64.6,
46.8, 28.2, 20.2: IR (CHCl3) 2924, 2855, 1734, 1694, 1461, 1278, 1175,
1138 cmꢀ1; ESIMS m/z 404.1 (MþH)þ; HR-ESI-MS m/z calcd for
13C NMR (CDCl3, 75 MHz):
d 155.4,144.5,128.2,127.9,127.4, 73.8, 63.2,
31.5, 29.7, 29.2, 28.3, 18.2, ꢀ5.5; IR (neat): 3438, 2925, 2855, 2362,
1693, 1497, 1463, 1366, 1251, 1169, 1095 cmꢀ1; ESIMS: 410 (Mþ1)þ;
HRMS calcd for C22H39NO4Si 410.2726, found 410.2741.
4.1.5. tert-Butyl
(1R,2R)-2-(3,5-bis(trifluoromethyl)benzyloxy)-5-
(tert-butyldimethylsilyloxy)-1-phenylpentylcarbamate (9). To a DMF
solution containing 8 (0.63 g, 1.54 mmol), 3,5-(CF3)2C6H3CH2Br
(0.945 g, 3.08 mmol) and TBAI (0.56 g, 1.54 mmol) was cooled to
0 ꢁC under nitrogen atmosphere. To this, NaH (70 mg, 60%
C20H20F6NO (MþH)þ 404.1449, found 404.1429; 1a; [
a
]
26 þ38.45 (c
D
0.40, CHCl3); a light yellow liquid (0.012 g); Rf (10% EtOAc/MeOH)

2540
G. Kumaraswamy, A. Pitchaiah / Tetrahedron 67 (2011) 2536e2541
0.45; 1H NMR (CDCl3, 300 MHz):
d
7.68 (s, 1H, ArH), 7.45e7.29 (m,
28.3, 25.9 and ꢀ05.4; IR (neat): 2931, 2362, 1693, 1518, 1247, 1166,
1096 cmꢀ1; ESIMS: 555 (MþNa)þ; HRMS calcd for C28H44N2O6NaSi
555.2866, found 555.2859.
7H, ArH), 4.45 (d, J¼12.1 Hz, 1H, OCHCHB), 4.07 (d, J¼12.1 Hz, 1H,
OCHACH), 3.52 (d, J¼9.1 Hz, 1H, H-2), 3.43e3.35 (dt, J¼4.5, 10.6 Hz,
1H, H-2), 3.13e3.01 (m, 1H, H-6), 2.77e2.66 (td, J¼1.8, 11.3 Hz, 1H,
H-6), 2.36e2.26 (dd, J¼3.0, 12.1 Hz, 1H, H-4), 1.98 (br s, 1H, CH),
1.88e1.79 (m, 1H, H-5), 1.77e1.66 (m, 1H, H-5), 1.54e1.41 (m, 1H, H-
4.1.9. tert-Butyl(1S,2S)-5-1-(furan-20-yl)-2-Cbz-amino-
pentylcarbamate (13). To the stirred solution of TBS ether 12 (1.33 g,
2.5 mmol) was added TBAF solution (4 mL, 4 mmol, 1 M in THF) via
syringe in dry THF at 0 ꢁC. The resulting reaction mixture was
stirred at room temperature. After 2 h, the reaction was quenched
with saturated ammonium chloride (10 mL) and extracted with
EtOAc (2ꢂ10 mL). The combined organic layers were dried over
anhydrous NaSO4, filtered and concentrated under reduced pres-
sure. The crude residue was purified by column chromatography
4); 13C NMR (CDCl3, 75 MHz):
d 154.2, 141.8141.1, 128.3127.9, 127.5,
127.3 (q), 121.2 (quint), 81.4, 70.0, 67.7, 46.7, 31.9, 31.4, 29.7, 25.0; IR
(neat): 2918, 2852, 1732, 1689, 1466, 1274, 1172, 1135 cmꢀ1; ESIMS
m/z 404.1 (MþH)þ; HR-ESI-MS m/z calcd for C20H20F6NO, 404.1327
and found 404.1338.
4.1.7. tert-Butyl (1S,2S)-5-(tert-butyldimethylsilyloxy)-1-(furan-2-
yl)-2-nitropentylcarbamate(11). To the stirred solution of N-Boc-
sulfone 10 (1.75 g, 5 mmol), Cat A (0.342 g, 0.75 mmol) in dry tol-
uene (0.8 M) was added nitro compound 3 (5.13 g, 25 mmol) and
CsOH H2O (1.09 g, 6.5 mmol) sequentially under inert atmosphere
at ꢀ55 ꢁC. The reaction mixture was stirred vigorously for 40 h and
thereafter, quenched with 0.1 N HCl (20 mL). The resulting reaction
mixture was slowly warmed to ambient temperature. The aqueous
layer was extracted with CHCl3 (3ꢂ20 mL), washed with brine
(2ꢂ10 mL). The combined organic extracts were dried over anhy-
drous Na2SO4, evaporated under reduced pressure. The crude res-
idue was purified by silica gel column chromatography with
hexanes/EtOAc (9:1) as eluent afforded 11 (1.72 g, 81%) as an oily
liquid. The dr and er were determined by HPLC using chiral AD-H
(220 nm, hexane/IPA (95:5), 0.5 mL/min). The dr is 80:20 (syn/anti)
and the major diastereomer was determined to have 92% ee by
chiral HPLC analysis tR (major)¼11.32 min, tR (minor)¼12.27 min;
and the minor diastereomer was determined to have 99% ee under
using acetone/hexane (6:4) as eluent to give deprotected alcohol as
25
a white solid (0.84 g, 80%); [
a
]
ꢀ20.50 (c 1.0, CHCl3); Rf (60% ac-
D
etone/hexane) 0.40; 1H NMR (CDCl3, 400 MHz):
d 7.36e7.25 (m, 6H,
ArH), 6.28 (d, J¼1.7 Hz, 1H, ArH), 6.21 (d, J¼2.8 Hz, 1H, ArH), 5.38 (d,
J¼9.6 Hz,1H, NHCO), 5.32 (d, J¼8.5 Hz,1H, NHCO), 5.20 (d, J¼7.7 Hz,
1H, CHNH), 4.86e4.79 (d, J¼8.4 Hz, 2H, CHOCN), 4.16e4.03 (m, 1H,
CHNH), 3.67e3.52 (m, 2H, CHOSi), 2.07e1.66 (m, 2H, CHCH),
1.65e1.48 (m, 2H, CHCH2), 1.42 (s, 1H, t-Bu); 13C NMR (CDCl3,
75 MHz): d 156.6, 155.0, 142.1, 128.4, 128.3, 128.0, 127.9, 110.3, 107.9,
96.1, 66.8, 61.9, 62.1, 54.1, 51.9, 28.7, 28.5, 26.6; IR (neat): 2932,
2362, 1690, 1518, 1241, 1163 cmꢀ1; ESIMS: 441 (MþNa)þ; HRMS
calcd for C22H30N2O6Na 441.2001, found 441.2013.
4.1.10. Benzyl (2S,3S)-2-(furan-20-yl)piperidin-3-ylcarbamate (14).
To the stirred solution of above deprotected alcohol (0.80 g,
1.92 mmol) in CH2Cl2 was added Et3N (0.192 g, 1.93 mmol) followed
by MeSO2Cl (0.22 g, 1.93 mmol) at 0 ꢁC. The reaction mixture was
stirred for 15 min and then quenched with aqueous NH4Cl (10 mL).
The aqueous layer was extracted with CH2Cl2 (3ꢂ10 mL). The
combined organic extracts were dried over anhydrous Na2SO4, fil-
tered and concentrated under reduced pressure. The resultant
crude product dissolved in CH2Cl2, and was added TFA (0.58 g,
5.1 mmol) via syringe. The resulting reaction mixture was stirred
for 3 h. Then, the reaction mixture was concentrated under reduced
pressure led to the crude TFA salt, which was again dissolved in dry
MeOH (10 mL). To this stirred solution, Et3N (0.34 g, 3.4 mmol) was
added slowly and refluxed for 3 h at 90 ꢁC. The solvent were re-
moved under reduced pressure; the crude residue was purified by
the same HPLC analysis conditions: tR (minor)¼13.79 min, tR
25
(major)¼16.25 min; [
a]
ꢀ13.6 (c 1.6, CHCl3); Rf (10% EtOAc/hex-
D
ane) 0.60; 1H NMR (CDCl3, 400 MHz):
d 7.32 (s, 1H, ArH), 6.28e6.27
(dd, J¼1.8, 3.0 Hz, 1H, ArH), 6.24e6.21 (m, 1H, ArH), 5.43 (d, 1H,
NHCO), 5.24e5.16 (d, J¼7.8 Hz, 1H, CHNH), 4.81e4.76 (m, 1H,
CHNO), 3.66e3.54 (m, 2H, CHOSi), 2.10e2.00 (m, 1H, CHCHN),
1.99e1.89 (m, 1H, CHCH), 1.58e1.48 (m, 2H, CHCH), 1.42 (s, 9H, t-
Bu), 0.85 (s, 9H, t-Bu), 0.01 (s, 6H, (CH3)2); 13C NMR (CDCl3,
100 MHz):
d 144.4, 111.5, 108.4, 107.8, 90.0, 62.6, 52.0, 28.8, 28.4,
27.3, 26.7, 26.2, 18.9 and ꢀ05.4; IR (neat): 3417, 2925, 2855, 1695,
1456, 1371, 1277, 1172, 1129 cmꢀ1; ESIMS: 451 (MþNa); HRMS calcd
for C20H36N2O6Si 451.1449, found 451.1429.
silica gel column chromatography using CHCl3/MeOH (85:15) as
25
eluent gave a yellow liquid (0.36 g, 65%) (over three steps); [a]
D
4.1.8. tert-Butyl(1S,2S)-5-(tert-butyldimethylsilyloxy)-1-(furan-20-yl)-
2-Cbz-aminopentylcarbamate (12). The nitro compound 11 (1.50 g,
3.5 mmol) and NiCl2$6H2O (0.83 g, 3.5 mmol) were dissolved in dry
MeOH (15 mL) and cooled to ꢀ5 ꢁC. To this, NaBH4 (0.65 g,
17.5 mmol) was added portion wise over a period of 10 min. The
resulting reaction mixture was stirred for 15 min at the same tem-
perature. The reaction was quenched with saturated NaHCO3
(10 mL). To this biphasic reaction mixture CbzCl (1.53 mL, 4.5 mmol
50% w/v in toluene) was added, and stirred for 3 h at room tem-
perature. The aqueous layer was extracted with EtOAc (3ꢂ10 mL),
and the combined organic layer washed with brine and dried over
anhydrous NaSO4. The organic layers were filtered and evaporated
under reduced pressure. The resulting crude residue was purified by
silica gel column chromatography with hexane/acetone (7:3) to af-
ꢀ62.4 (c 1.2, MeOH); Rf (10% EtOAc/MeOH) 0.60; 1H NMR
(CDCl3þDMSO-d6, 400 MHz):
d 7.35e7.20 (m, 5H, ArH), 6.23 (dd,
J¼1.8, 3.0 Hz, 1H, ArH), 6.12(d, J¼3.0 Hz, ArH), 5.65 (d, J¼8.8 Hz, 1H,
NHCO), 5.01(d, J¼6.8 Hz, 2H), 4.96 (d, J¼9.8 Hz, 1H, CHACHB), 4.11
(d, J¼6.0 Hz,1H, CHBNH), 3.13 (m,1H, H-1), 2.92e2.73 (m, H-2), 2.57
(br s, 1H, NH), 1.82e1.48 (m, 4H, H-3, H-4, H-5, H-6); 13C NMR
(CDCl3þDMSO-d6, 75 MHz):
d 160.6, 142.6, 128.4, 127.9, 127.7, 119.1,
110.6, 66.1, 49.3, 47.6, 30.6, 29.5, 21.3; IR (neat): 2924, 2856, 2362,
1694, 1249, 1153 cmꢀ1; ESIMS: 301 (Mþ1)þ; HRMS calcd for
C17H21N2O3 301.1522 and found 301.1566.
4.1.11. (2S,3S)Benzyl 3-(benzyloxycarbonylamino)-2-(furan-20-yl)pi-
peridine-1-carbamate (15). To a stirred methanol solution (5 mL,
0 ꢁC) of secondary amine 14 (0.35 g, 1.2 mmol) were added NaHCO3
(0.26 g, 3 mmol) and benzyl chloroformate (0.64 mL, 1.2 mmol, 50%
w/v in toluene) successively. The reaction mixture was allowed to
stir for 1 h at same temperature followed by evaporation under
reduced pressure resulted in aqueous layer, which was extracted
with EtOAc (2ꢂ10 mL) and washed with brine (10 mL). The organic
extracts were dried over anhydrous NaSO4, filtered and concen-
trated under reduced pressure. The crude residue was purified by
silica gel (100e200 mesh) column chromatography using acetone/
hexane (1:9) as eluent furnished 15 (0.34 g) and 15a (0.09 g) as
ford 12 (1.45 g, 78%) as semi solid; [
a
]
D
25 ꢀ36.00 (c 1.5, CHCl3); Rf (30%
acetone/hexane) 0.60; 1H NMR (CDCl3, 400 MHz):
d 7.54e7.43 (m,
6H, ArH), 6.50e6.45 (d, J¼5.5 Hz, 1H, ArH), 6.43e6.37 (d, J¼7.7 Hz,
1H, ArH), 5.56 (d, J¼8.8 Hz, 1H, NHCO), 5.27 (d, J¼7.7 Hz, 1H, CHNH),
4.89e4.83 (d, J¼8.8 Hz, 2H, CHOCN), 4.27e4.15 (m, 1H, CHNH),
3.79e3.67 (m, 2H, CHOSi), 1.80e1.66 (m, 2H, CHCH), 1.63e1.58 (m,
2H, CHCH2), 1.55 (s, 9H, t-Bu), 1.02 (s, 9H, t-Bu), 0.16 (s, 6H, (CH3)2);
13C NMR (CDCl3, 75 MHz):
d
156.2, 155.8, 152.2, 142.1, 136.5, 128.4,
128.1, 128.0, 110.2, 107.3, 79.8, 66.9, 66.7, 62.4, 55.4, 52.7, 29.1, 28.7,

G. Kumaraswamy, A. Pitchaiah / Tetrahedron 67 (2011) 2536e2541
2541
25
clear liquid; (2S,3S)-major diastereomer 15; [
a
]
ꢀ29.5 (c 1.8,
(MþNH4)þ; HRMS calcd for C23H26N2O6NH4 444.1736, found
D
CHCl3); Rf (20% EtOAc/hexane) 0.50; 1H NMR (CDCl3, 400 MHz):
7.43e7.27 (m, 11H, ArH), 6.30 (s, 1H, ArH), 6.17 (br s, 1H, ARH), 5.59
444.1742.
d
(d, J¼5.1 Hz, 1H, NHCO), 5.29e5.02 (m, 3H, NHCO, CHOCNH), 4.76
(d, J¼9.6 Hz, 1H, CHACHBN), 4.12e3.95 (m, 2H, CHACHBN),
3.09e2.97 (t, J¼11.8 Hz, 1H, CHCHN), 1.96e1.55 (m, 5H, CHCH); 13C
Acknowledgements
We are grateful to Dr. J.S. Yadav, Director, IICT, for his constant
encouragement. Financial support was provided by the DST, New
Delhi, India (Grant No: SR/SI/OC-12/2007) and UGC (New Delhi) is
gratefully acknowledged for awarding the fellowship to A.P. Thanks
are also due to Dr. G.V.M. Sharma for his support.
NMR (CDCl3, 75 MHz):
d 155.4, 155.2, 142.4, 128.5, 128.4, 128.2,
127.9, 110.3, 67.4, 66.8, 51.6, 49.8, 39.9, 31.9, 27.2 and 24.2; IR
(CHCl3) 2927, 2842, 2349, 1668, 1543, 1456, 1235 cmꢀ1; ESIMS: 457
(MþNa)þ; HRMS calcd for C25H26N2O5Na 457.1736 and found
25
457.1732; (2S,3R)-minor diastereomer 15a (0.09 g); [
a
]
D
þ18.5 (c
1.0, CHCl3); Rf (20% EtOAc/hexane) 0.55; 1H NMR (CDCl3, 400 MHz):
Supplementary data
d
7.40e7.28 (m, 13H, ArH), 6.34e6.33 (dd, J¼1.8, 31 Hz, 1H, ArH),
6.16 (br s, 1H, NHCO), 5.27 (d, J¼7.73 Hz, 1H, NHCO), 5.16e5.09 (m,
4H, CHOCNH), 4.39 (d, J¼6.18 Hz, 1H, CHACHBN), 4.08 (dd, J¼6.1,
11.0 Hz, 1H, CHACHBN), 2.97e2.86 (t, J¼11.0 Hz, 1H, CHCHN),
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2011.02.031.
1.84e1.55 (m, 5H, CHCH); 13C NMR (CDCl3, 75 MHz):
d 155.5, 151.0,
References and notes
142.9, 136.3, 128.5, 128.4, 128.2, 128.0, 110.3, 107.5, 67.5, 66.9, 54.4,
46.8, 40.0, 31.9, 29.6, 24.5 and 19.5; IR (CHCl3) 2923, 2854, 2362,
1695, 1518, 1460, 1263 cmꢀ1; ESIMS: 457 (MþNa)þ; HRMS calcd for
C25H26N2O5Na 457.1739 and found 457.1735.
1. (a) Aguinaldo, A. M.; Reaad, R. W. Phytochemistry 1990, 29, 2309; (b) Ahmad, A.;
Khan, K. A.; Ahmad, V. U.; Qazi, S. Planta Med. 1986, 4, 285; (c) Bols, M. Acc.
Chem. Res. 1998, 31, 1; (d) Bailey, P. D.; Millwood, P. A.; Smith, P. D. D. J. Chem.
Soc., Chem. Commun. 1998, 633; (e) Mitchinson, A.; Nadin, A. J. Chem. Soc., Perkin
Trans. 1 1999, 2553.
4.1.12. (2S,3S)-1-Benzyl-2-methoxycarbonyl-3-(benzyloxycarbonyl-
amino) piperidinecarbamate (16). To an ice-cold solution of NaIO4
(0.52 g, 2.41 mmol) in EtOAc (2.5 mL), CH3CN (4.5 mL) and H2O (2
mL) was added RuCl3xH2O (2 mg, 0.007 mol) and stirring continued
for 15min at 0 ꢁC. Thereafter, compound 15 (0.15 g, 0.35 mmol) in
EtOAc (2 mL) was added and continued stirring for additional
10 min at 0 ꢁC. The resultant reaction mixture was quenched with
10 mL of water and aqueous layer was extracted with EtOAc
(3ꢂ15 mL). The combined organic layers were washed with brine
(1ꢂ10 mL), dried over anhydrous NaSO4 and concentrated under
reduced pressure. The crude residue was dissolved in dry CH2Cl2
(15 mL) and benzene (5 mL) solvent mixture at 0 ꢁC. To this, CH2N2
in Et2O (10 mmol) was added. After 3 h of stirring at ambient
temperature, the reaction mixture was concentrated under reduced
pressure and purified by silica gel column chromatography using
acetone/hexane (2:8) as eluent gave 16 (0.093 g, 62%) as a colour-
2. (a) Nemr, A. E. Tetrahedron 2000, 56, 8579; (b) Asano, N.; Nash, R. J.; Molyneux,
R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1645; (c) Longmore, J.;
Swain, C. J.; Hill, R. G. Drug News Perspect. 1995, 8, 5; Moussaoui, S. M.; Montier,
F.; Carruette, A.; Blanchard, J. C.; Laduron, P. M.; Garret, C. A. J. Pharmacol. 1993,
109, 259; (d) Harrison, T.; Williams, B. J.; Swain, C. J.; Ball, R. G. Bioorg. Med.
Chem. Lett. 1994, 4, 2545.
3. (a) Highet, R. J. J. Org. Chem. 1964, 29, 471; (b) Sansores-Peraza, P.; Rosado-al-
lado, M.; Brito-Loeza, W.; Mena-Rejon, G.J.; Quijano, L. Fitoteirapia. 2000, 71,
690; (c) Kokatla, H. P.; Sagar, R.; Vankar, Y. D. Tetrahedron Lett. 2008, 49, 4728;
(d) Asano, N. Glycobiology 2003, 13, 93.
4. (a) Tsuritani, N.; Yamada, K.-I.; oshikawa, N.; Shibasaki, M. Chem. Lett. 2002,
276; (b) Yamazaki, N.; Atobe, M.; Kibayashi, C. Tetrahedron Lett. 2002, 43, 7979;
(c) Lemire, A.; Grenon, M.; Pourashraf, M.; Charette, A. B. Org. Lett. 2004, 6,
3517; (d) Bhaskar, G.; Rao, B. V. Tetrahedron Lett. 2003, 44, 915; (e) Huang, P.-Q.;
Liu, L.-X.; Wei, B.-G.; Ruan, Y.-P. Org. Lett. 2003, 5,1927; (f) Liu, L.-X.; Peng, Q.-L.;
Huang, P.-Q. Tetrahedron: Asymmetry 2008, 19, 1200; (g) Fu, R.; Zhao, B.; Shi, Y. J.
Org. Chem. 2009, 74, 7577; (h) Cherian, S. K.; Kumar, P. Tetrahedron: Asymmetry
2007, 18, 982; (i) Kandula, S. R. V.; Kumar, P. Tetrahedron: Asymmetry 2005, 16,
3579; (j) Garrido, N. M.; Garcia, M.; Sanchez, M. R.; Diez, D.; Urones, J. G. Synlett
2010, 3, 387 and references cited on; (k) Sarkar, N.; Banerjee, A.; Nelson, S. G.
J. Am. Chem. Soc. 2008, 130, 9222; (l) Han, B.; He, Z.-Q.; Li, J.-L.; Li, R.; Jiang, T.-Y.;
Chen, Y.-C. Angew. Chem., Int. Ed. 2009, 48, 5474; (m) Wang, Y.; Yu, D.-F.; Lin,
Y.-Z.; Wei, H.; Luo, Y.-C.; Dixon, D. J.; Xu, P.-F. Chem.dEur. J. 2010, 16, 3922.
5. (a) Kumaraswamy, G.; Ramakrishna, D.; Santhakumar, K. Tetrahedron: Asymmetry
2010, 21, 544; (b) Kumaraswamy, G.; Ramakrishna, G.; Naresh, P.; Sridhar, B.; Ja-
gadeesh, B.; Sridhar, B. J. Org. Chem. 2009, 74, 8468; (c) Kumaraswamy, G.; Jayap-
rakash, N.; Sridhar, B. J. Org. Chem. 2010, 75, 2745; (d) Kumaraswamy, G.; Sadaiah,
K.; Ramakrishna, D. S.; Naresh, P.; Sridhar, B.; Jagadeesh, B. Chem. Commun. 2008,
5324; (e) Kumaraswamy, G.; Padmaja, M. J. Org. Chem. 2008, 73, 5198.
6. (a) Palomo, C.; Oiarbide, M.; Laso, A.; Lopez, R. J. Am. Chem. Soc. 2005, 127,
17622; (b) Gomez-Bengoa, E.; Linden, A.; Lopez, R.; Mugica-Mendiola, I.;
Oiarbide, M.; Palomo, C. J. Am. Chem. Soc. 2008, 130, 7955; (c) Xu, X.; Furukawa,
T.; Okino, T.; Miyabe, H. ,; Takemoto, Y. Chem.dEur. J. 2006, 12, 466.
7. (a) Mineno, T.; Miller, M. J. J. Org. Chem. 2003, 68, 6591; (b) Barreto, C. B.;
Pereira, V. L. P. Tetrahedron Lett. 2009, 50, 6389; (c) Tokunaga, Y.; Ihara, M.;
Fukumoto, K. J. Chem. Soc., Perkin Trans. 1 1997, 207.
less syrup. The 1H NMR spectra of 16 indicated 1:1 rotamers as
25
a result of N-Cbz and ester functionality; 16; [
a
]
ꢀ7.36 (c 1.2,
D
CHCl3); Rf (20% EtOAc/hexane) 0.60; 1H NMR (CDCl3, 300 MHz):
d
7.43e7.27 (m, 10H, ArH), 6.00e5.79 (dd, J¼8.8 Hz, 1H, NHCO),
5.32e4.97 (m, 4H, CHOCNH), 4.16e3.87 (m, 2H, CHA,CHB), 3.69 (s,
3H, eOMe), 2.89e2.60 (m, 1H, CHBCH), 1.98e1.43 (m, 5H, CH); 13C
NMR (CDCl3, 75 MHz):
d 169.4, 155.3, 151.4, 136.1, 128.6, 128.5,
128.3, 127.6, 66.9, 58.9, 52.5, 46.1, 41.4, 41.0, 37.1, 31.9, 29.3 22.7; IR
(neat): 2964, 2854, 2362, 1696, 1519, 1423, 1246, 1212 cmꢀ1; ESIMS:
444 (MþNH4)þ; HRMS calcd for C23H26N2O6NH4 444.1739 and
25
found 444.1743; (0.052 g) 16a; [
a
]
D
þ3.75 (c 0.45, CHCl3); Rf (20%
EtOAc/hexane) 0.65; 1H NMR (CDCl3, 300 MHz):
d 7.45e7.27 (m,
8. The compound 11 was subjected to Nef-reaction to convert eNO2 to keto
functionality using number of reported conditions (Ref. 7). To our dismay, in
spite of starting material disappearance the required functional transformation
did not occur.
9. Ling, R.; Yoshida, M.; Mariano, P. S. J. Org. Chem. 1996, 61, 4439.
10. Cyclization under reported condition (NaH, tBuOK) generates only 10e15% of 1,
stirring at rt for 44 h. But, deprotection of Boc, followed by cyclization with
Et3N yields 1, with 65%.
10H, ArH), 5.23e5.03 (m, 4H, CHOCNH), 4.97 (br s, 1H, NHCO),
4.56e4.43 (d, J¼6.6 Hz,1H, NHCO), 4.19e4.00 (m, 1H, CHACHB), 3.75
(s, 3H, OMe), 3.12e2.86 (m, 1H, CHBCH), 1.94e1.48 (m, 5H, CH); 13
C
NMR (CDCl3, 75 MHz): d 164.2, 157.7, 136.6, 128.8, 128.4, 128.2, 89.5,
67.8, 67.0, 57.0, 52.6, 49.4, 34.0, 32.2, 29.9, 24.2, 22.9; IR (neat):
2960, 2764, 2652, 1695, 1543, 1246, 1234 cmꢀ1; ESIMS: 444