Total synthesis of (-)-codonopsinol and (+)-2-epi codonopsinol via acid catalyzed amido cyclisation

Article abstract of DOI:10.1016/j.tet.2009.12.035

A short and stereoselective synthesis of (-)-codonopsinol 5 and its C-2 epimer 6 were accomplished from commercially available starting material d-1,5-gluconolactone, using acid mediated amido cyclisation as the key step. The inhibitory activitiy of these

Full text of DOI:10.1016/j.tet.2009.12.035

Tetrahedron 66 (2010) 1202–1207
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of (ꢀ)-codonopsinol and (þ)-2-epi codonopsinol
via acid catalyzed amido cyclisation
,
b
Y. Jagadeesh a, J. Santhosh Reddy a, B. Venkateswara Rao a , J. Lakshmi Swarnalatha
*
a Organic Division III, Indian Institute of Chemical Technology, Hyderabad 500607, India
b Bio-transformations Laboratory, Indian Institute of Chemical Technology, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A short and stereoselective synthesis of (ꢀ)-codonopsinol 5 and its C-2 epimer 6 were accomplished
from commercially available starting material -1,5-gluconolactone, using acid mediated amido cycli-
sation as the key step. The inhibitory activitiy of these compounds against glucosidase and galactosidase
Received 16 July 2009
Received in revised form
8 December 2009
Accepted 12 December 2009
Available online 16 December 2009
D
has been studied.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
as the natural product rotation is [
configuration of the molecule 5 can be considered as (2R,3R,4R,5R)
a
]
D ꢀ3.5. Therefore the absolute
Synthesis of natural and synthetic polyhydroxylated pyrrolidines
is gaining more and more importance because of their highly active
and efficient glycosidase inhibitory activity.1 Polyhydroxylated
pyrrolidine alkaloids containing an aromatic substituent on the
iminosugar ring are of a rare class found in nature (Fig. 1).
(ꢀ)-Codonopsinine 1 and (ꢀ)-codonopsine 2 are the first two ex-
amples in this unusual category, initially isolated in 1969 from
Codonopsis clematidea.2,3 These two compounds display antibiotic as
well as hypotensive activities without affecting the central nervous
system in animal tests.4 Radicamine A 3 and radicamine B 4 are
another examples for this category, isolated from Lobelia chinensis
LOUR (Campanulaceae) by Kusano et al. and exhibited glycosidase
inhibitory activity.5,6 Recently, Ishida and co-workers reported an-
other new codonopsine related alkaloid (ꢀ)- codonopsinol 5 from
the aerial parts of C. clematidea.7a The aerial parts of C. clematidea are
well known for their medicinal properties in treating liver diseases.
The (ꢀ)-codonopsinol 5 is also known for its inhibitory activity
at the four stereogenic centers as per the synthesis.
HO
OH
HO
HO
OH
OH
MeO
MeO
HO
MeO
N
N
N
OH
MeO
H
(+)-Radicamine A 3
(-)-Codonopsinine 1
(-)-Codonopsine 2
HO
OH
4
HO
HO
OH
OH
MeO
MeO
MeO
8
7
3
5
12
2
6
N1
N
N
MeO
9
OH
H
OH
11
OH
HO
10
(+)-2-epi-codonopsinol 6
(-)-Codonopsinol 5
(+)-Radicamine B 4
Figure 1.
In continuation of our efforts in the synthesis of poly-
hydroxylated pyrrolidine alkaloids and azasugars,9 here in we wish
to report the total synthesis of (ꢀ)-codonopsinol 5 and 2-epi-
codonopsinol 6 and their inhibitory activity against glucosidases
and galactosidases. So far only one synthesis for 5 is reported.7b
Recently we developed a strategy for the synthesis of phenyl
substituted polyhydroxylated pyrrolidines3a and its application to
codonopsinine 1 using acid catalyzed amido cyclisation, taking
advantage of the stability of the benzylic carbocation.10 Based on
this protocol we envisaged the following retro synthesis for
(ꢀ)-codonopsinol 5 (Scheme 1). The pyrrolidine core skeleton can
be obtained from protected amino alcohol 7 by means of acid cat-
alyzed cyclisation through intramolecular SN1 reaction based on
our earlier observation for the synthesis of codonopsinine 1. The
against the a-glucosidase of yeast and bacillus stearothermophilus
lymph.7b Ishida et al. established the relative stereochemistry of the
molecule 5 by nuclear Overhauser enhancement (NOE) correla-
tions.7a These correlations were found to be same as those of
codonopsine 2,3b,d,f,8 where all the four contiguous stereogenic
centers are situated in all trans positions. Later Tsou et al.7b syn-
thesized (2R,3R,4R,5R) isomer of codonopsinol 5, whose spectral
data was very much in agreement with the reported values. The
specific rotation of synthetic sample is found to be [a]D ꢀ15, where
* Corresponding author. Tel./fax: þ91 040 27193003.
compound 7 can be obtained from commercially available
gluconolactone 8.
D-1,5-
E-mail addresses: venky@iict.res.in, drb.venky@gmail.com (B. Venkateswara
Rao).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.12.035

Y. Jagadeesh et al. / Tetrahedron 66 (2010) 1202–1207
1203
mechanism3a where acetate presence directs the nucleophile to
under go cyclisation to give single isomer (Scheme 3). The mech-
anism of formation of cyclic compounds 17a and 17b from 16 can be
explained as shown in Scheme 4.
HO
OH
MeO
MeO
OAc NHCbz
OBn
N
MeO
MeO
OH
5 (-)-codonopsinol
OAc OAc
Acid catalysed
cyclisation
7
MeO
O
NHCbz
OBn
O
NHCbz
OBn
O
O
b
a
HO
HO
H
NH2 introduction
MeO
13
OH
O
O
OH
16
O
OH
14
8
D-1,5-gluconolactone
HO
OH
HO
OH
Scheme 1.
c
N
N
Cbz
MeO
Cbz
OBn
MeO
MeO
OBn
2. Results and discussions
MeO
17a
2.5
17b
D
-Gluconolactone 8 on treatment with 2,2-DMP in presence of
:
1
catalytic amount of PTSA in acetone, methanol gave -hydroxy
a
Scheme 3. Reagents and conditions: (a) H5IO6, Ether, 0 ꢁC-rt, 6 h; (b) 3,4-dimethoxy
phenyl magnesium bromide (15), THF, 0 ꢁC-rt, 16 h, 65%; (c) TFA,CH2Cl2, 0 ꢁC-rt, 4 h, 80%.
ester 9 in 76% yield.11 Reduction of the ester functionality of 9 with
LAH afforded diol 10. Regioselective benzylation of diol 10 with
dibutyl tin oxide in toluene followed by the addition of benzyl
bromide in presence of catalytic TBAI gave compound 11 in 89%
yield. Compound 11 on treatment with MsCl/Et3N gave corre-
sponding mesylate derivative, which up on treatment with NaN3/
DMF yielded corresponding azido derivative 12 in 80% yield. Re-
duction of the azido functionality with LiAlH4/THF gave amine,
which was immediately treated with CbzCl/Na2CO3 in CH2Cl2
affording the fully protected compound 1312 (Scheme 2).
HO
OH
HO
OH
MeO
OBn
MeO
OBn
TFA in DCM
16
HN
HN
Cbz
Cbz
MeO
MeO
HO
OH
HO
OH
N
O
OH
N
Cbz
Cbz
MeO
MeO
MeO
OBn
OBn
b
a
OMe
O
O
HO
HO
O
MeO
17a
17b
O
O
O
OH
Scheme 4.
OH
O
8
9
O
OH
OH
The major isomer 17a was treated with LAH in THF under reflux
OH
OBn
for 5 h, to give N-methyl derivative 18a in 82%. Compound 18a on
catalytic hydrogenation with PdCl2/H2 in methanol gave
(ꢀ)-codonopsinol 5 in 85% isolated yield. The spectral and analyt-
ical data of synthetic (ꢀ)-codonopsinol 5 were in excellent agree-
ment with the reported values7b (Scheme 5). Our synthesis further
confirms the absolute stereochemistry of the molecule 5.
d
c
O
O
O
O
O
O
O
10
11
O
NHCbz
OBn
O
N3
e
OBn
O
O
O
O
O
HO
OH
HO
OH
13
12
b
a
Scheme 2. Reagents and conditions: (a) 2,2-DMP, PTSA, Acetone, MeOH, 0 ꢁC-rt, 50 h,
76%; (b) LiAlH4, THF, 0 ꢁC-rt, 4 h, 93%; (c) (i) Bu2SnO, Toluene, reflux, 8 h; (ii) BnBr,
TBAI, reflux, 16 h, 89%; (d) (i) MsCl, N(Et)3, CH2Cl2, 0 ꢁC-rt, 3 h; (ii) NaN3, DMF, 80 ꢁC,
24 h, 80%; (e) (i) LiAlH4, THF, 0 ꢁC-rt, 5 h; (ii) CbzCl, Na2CO3, CH2Cl2, 0 ꢁC-rt, 8 h, 87%.
17a
N
N
MeO
MeO
MeO
MeO
OBn
OH
18a
5
Scheme 5. Reagents and conditions: (a) LiAlH4, THF, 0–60 ꢁC, 5 h, 82%; (b) PdCl2/H2,
MeOH, 12 h, 70%.
Selective deprotection of the terminal acetonide of 13 and in situ
oxidative cleavage13 of the resulting diol with periodic acid in ether
gave aldehyde 14. The aldehyde 14 was treated with the freshly
prepared Grignard reagent from 3,4-dimethoxybromobenzene and
Mg in THF to give diastereomeric mixture 16 in 65% yield (w3:1
ratio based on 1H NMR signals). Initially it was planned to deprotect
the acetonide of 16 and convert the hydroxyls to acetate groups to
conduct amido cyclisation in presence of TFA.
Basically the presence of acetate helps in fixing the stereo-
chemistry exclusively on benzylic carbon during cyclisation by its
participation as neighboring group.3a Interestingly when the al-
coholic mixture was treated with TFA/CH2Cl2 (1:1) for 4 h gave
directly trans pyrroilidine compound 17a as a major isomer along
with cis isomer 17b (2.5:1) in 80% isolated yield.14 The formation of
mixture of products (17) further confirmed our earlier proposed
The minor isomer 17b was transferred to (þ)-2-epi-codonop-
sinol 6 following similar reaction pathway used for the preparation
of 5 in 65% yield for two steps (Scheme 6). The stereochemistry of
compound 6 was confirmed with 1D nuclear Overhauser en-
hancement (NOE) correlations.15
HO
OH
HO
OH
a
b
17b
N
N
MeO
MeO
MeO
MeO
OBn
OH
18b
6
Scheme 6. Reagents and conditions: (a) LiAlH4, THF, 0–60 ꢁC, 5 h, 82%; (b) PdCl2/H2
MeOH, 12 h, 70%.

1204
Y. Jagadeesh et al. / Tetrahedron 66 (2010) 1202–1207
3. Assay of enzyme inhibition
SEPA-300 digital polarimeter. Accurate mass measurement was
performed on Q STAR mass spectrometer (Applied Biosystems,
USA).
Glucosidase and galactosidase inhibitory activities of 5 and 6
were determined by measuring the enzyme activity in presence
of the compounds on
a
Perkin–Elmer Lambda
2
UV-visible
5.1.1. (R)-Methyl
4,40-bi(1,3-dioxolan)-5-yl) acetate 9. To a stirred suspension of
-glucono-1,5-lactone 8 (10.0 g, 56.0 mmol) in a mixture of 2,
2-hydroxy-2-((4R,40R,5R)-2,2,20,20-tetramethyl-
spectrophotometer equipped with temperature control and PECSS
software. All enzyme assays were performed at 25 ꢁC. All experi-
ments were repeated three times and were reproducible within
ꢂ5%. The enzymes and corresponding substrates used for assay
D
2-dimethoxypropane (20 mL), acetone (6 mL) and methanol (2 mL)
was added catalytic amount of p-toluenesulfonic acid (150 mg) at
0 ꢁC under nitrogen atmosphere. Then the reaction mixture was
allowed to stir for 50 h at room temperature. TLC indicated com-
plete conversion of the starting material to a major product. So-
dium hydrogen carbonate (1.5 g) was added for neutralization and
the reaction mixture was stirred for 1 h and filtered through Celite.
The filtrate was evaporated under reduced pressure; the residue
was dissolved in dichloromethane (100 mL) and washed with wa-
ter (20 mL). The aqueous phase was extracted with dichloro-
methane (40 mL) and the combined organic extracts were dried
over Na2SO4 and concentrated under reduced pressure. The residue
was purified by flash chromatography (ethyl acetate/hexane¼1:3)
were as follows: a-glucosidase from yeast (4-nitrophenyl-a-D-glu-
copyranoside),
b-glucosidase from almonds (2-nitrophenyl-b-D-
glucopyranoside),
a-galactosidase from green coffee beans
(4-nitrophenyl-
a
-D-galactopyranoside), and b-galactosidase from
Kluyveromyces lactis (p-nitrophenyl-b-D-galactopyranoside).
3.1. Enzyme assay
The p-nitrophenyl derivative of the substrate (1.6 mM) in
phosphate buffer (0.25 M, pH 6.8, 2.0 mL) was placed in a cuvette,
and the enzyme solution (1 mg/mL, 100
absorbance due to release of p-nitrophenol was monitored at
410 nm (molar extinction coefficient at 410 nm, D3 8800 Mꢀ1 cmꢀ1
for 3–5 min. Similar experiments were performed in presence of
the compounds 5 and 6 at concentrations varying from 1 M to
mL) was added. Change in
to afford 9 (12.38 g, 76%) as a colorless oil. Rf (30% ethyl acetate/
28
hexane) 0.6; [
a]
þ2.4 (c 0.8, CHCl3) {lit.11, [
a]
20 1.7 (c 1.18, CHCl3)};
D
D
)
IR (neat) nmax 3498, 2988, 2936, 1748, 1377, 1252, 1215, 1133, 1072,
846 cmꢀ1; 1H NMR (200 MHz, CDCl3)
d 1.33 (s, 3H, CH3), 1.35 (s, 3H,
m
CH3), 1.37 (s, 3H, CH3), 1.38 (s, 3H, CH3), 2.88 (d, 1H, J¼9.06 Hz, OH),
2 mM. The values of IC50 were calculated using non-linear re-
gression analysis of GraphPad Prism Version 5. The values are given
in Table 1. The compound 5 has better activity than 6 against glu-
cosidases. Probably the all trans configuration as in 5 may be an
essential feature for the activity. This fact further requires to be
established by making and scanning more analogues. Both the
compounds have not shown inhibition against galactosidases at
1 mM.
3.84 (s, 3H, OMe), 3.91–4.19 (m, 5H, CH2OH and 3CHO–), 4.26 (dd,
1H, J¼1.17, 8.59 Hz, CHOH); 13C NMR (75 MHz, CDCl3)
d 24.9, 26.2,
26.4, 26.9, 52.4, 67.6, 69.2, 76.2, 77, 80.6, 109.6, 109.8, 172.7; ESI/MS
(m/z) 313 (MþþNa); HRMS calcd for C13H22O7Na 313.126, found
313.1258.
5.1.2. (S)-1-((4R,40R,5R)-2,2,20,20-Tetramethyl-4,40-bi-(1,3-dioxolan)-
5-yl)ethane-1,2-diol 10. To
a suspension of LiAlH4 (2.04 g,
53.79 mmol) in anhydrous THF (50 mL) at 0 ꢁC was added methyl
ester 9 (12.0 g, 41.38 mmol) in THF (30 mL) drop wise over a period
of 20 min. After being stirred for 4 h at room temperature, the re-
action mixture was quenched with water (2.0 mL), 15% NaOH
(2.0 mL), and water (6.0 mL) drop wise sequentially at 0 ꢁC. After
completion of the addition, the reaction mixture was allowed to stir
at room temperature for 2 h, filtered through a pad of Celite, and
the filtrate was evaporated under reduced pressure. The crude
residue was purified by silica gel column chromatography (ethyl
Table 1
IC50 values in
mm
Compound IC50
(mm)
a
-glucosidase
54
b
-glucosidase
53.8
a
-galactosidase
b-galactosidase
5
6
NIa
NIa
NIa
NIa
457
137
a
No inhibition at 1 mm.
4. Conclusion
acetate/hexane¼1:1.5) to give 10 (10.1 g, 93%) as white solid. Rf (40%
28
ethyl acetate/hexane) 0.16; mp 50–52 ꢁC; [
a]
ꢀ34.14 (c 0.3,
D
In summary, we developed a novel synthetic approach for the
CHCl3); IR (neat) nmax 3445, 2987, 2927, 1376, 1251, 1216, 1156, 1069,
natural (ꢀ)-codonopsinol 5 and its epimer, (þ)-2-epi-codonopsinol
847 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
1.32 (s, 3H, CH3), 1.36 (s, 3H,
6 from D-1,5-gluconolactone, using stereoselective intramolecular
CH3), 1.40 (s, 3H, CH3), 1.41 (s, 3H, CH3), 2.53 (br s, 1H, OH), 2.68 (d,
1H, J¼7.93 Hz, OH), 3.63–3.80 (m, 3H, CH2OH and CHO–), 3.92–4.07
(m, 4H, CH2O– and 2CHO–), 4.09–4.18 (m, 1H, CHO–); 13C NMR
SN1 cyclisation protocol as the key step.
5. Experimental section
5.1. General
(75 MHz, CDCl3) d 25.1, 26.4, 26.7, 26.9, 64.6, 67.7, 70.5, 77.1, 77.2,
81.1, 109.6, 109.8; ESI/MS (m/z) 285 (MþþNa); HRMS calcd for
C12H22O6Na 285.1314, found 285.1302.
Moisture- and oxygen- sensitive reactions were carried out
under nitrogen gas atmosphere. All solvents and reagents were
purified by standard techniques. TLC was performed on Merck
Kiesel gel 60, F254 plates (layer thickness 0.25 mm). Column chro-
matography was performed on silica gel (60–120 and 100–
200 mesh) using ethyl acetate, hexane and chloroform, methanol as
eluents. Melting points were determined on a Fisher John’s melting
point apparatus and are uncorrected. IR spectra were recorded on
a Perkin–Elmer RX-1 FTIR system. 1H NMR (400, 300 and 200 MHz)
and 13C NMR (75 and 100 MHz) spectra were recorded on corre-
sponding MHz. Chemical shifts were reported in parts per million
with respect to TMS as an internal standard. Coupling constants (J)
are quoted in Hertz. Optical rotations were measured with Horiba-
5.1.3. (S)-2-(Benzyloxy)-1-((4R,40R,5R)-2,2,20,20-tetramethyl-4,40-
bi(1,3-dioxolan)-5-yl)ethanol 11. To a stirred solution of compound
10 (8 g, 30.53 mmol) in dry toluene (60 mL) was added dibutyl tin
oxide (9.87 g, 39.69 mmol) at room temperature. The reaction was
slowly heated to 80 ꢁC, after being stirred for 8 h, the reaction
mixture was allowed to room temperature. Benzyl bromide (4 mL)
and catalytic amount of TBAI was added to the cooled reaction
mixture and stirred for 16 h at 80 ꢁC. The reaction mixture was
cooled to room temperature and evaporated the solvent under
reduced pressure. The residue was purified by silica gel column
chromatography (ethyl acetate/hexane¼1:7) to give benzyl de-
rivative 11 (9.6 g, 89%) as thick syrup. Rf (30% ethyl acetate/hexane)
28
0.8; [
a
]
þ4.60 (c 1.55, CHCl3)IR (neat) nmax 3479, 2986, 2928, 1627,
D

Y. Jagadeesh et al. / Tetrahedron 66 (2010) 1202–1207
1205
1455, 1375, 1247, 1214, 1151, 1070, 846 cmꢀ1
;
1H NMR (300 MHz,
5.05 (dd, 2H, J¼12.27, 15.01 Hz, PhCH2O), 5.32 (d, 1H, J¼8.12 Hz,
NH), 7.19–7.34 (m, 10H, Ph); 13C NMR (75 MHz, CDCl3)
25.2, 26.2,
CDCl3) 1.30 (s, 3H, CH3), 1.34 (s, 3H, CH3), 1.37 (s, 3H, CH3), 1.38 (s,
d
d
3H, CH3), 2.22 (d, 1H, J¼7.74 Hz, OH), 3.53 (d, 2H, J¼6.04 Hz,
CH2OBn), 3.85–4.02 (m, 5H, CH2OH, 2CHO–and CHOH), 4.05–4.12
(m, 1H, CHO–), 4.55 (dd, 2H, J¼12.08, 18.50 Hz, PhCH2O), 7.20–7.34
27.2, 27.5, 53.6, 66.6, 67.5, 68.6, 73.1, 76.9, 78.5, 79.9, 109.6, 109.9,
127.4, 127.9, 128, 128.2, 128.3, 136.3, 138.0, 155.9; ESI/MS (m/z) 508
(MþþNa); HRMS calcd for C27H35NO7Na 508.2311, found 508.2328.
(m, 5H, Ph); 13C NMR (75 MHz, CDCl3)
d 25.2, 26.5, 26.8, 27.1, 67.7,
68.9, 71.9, 73.2, 77, 77.1, 80.1, 109.4, 109.6, 127.6, 127.6, 128.2, 137.9;
ESI/MS (m/z) 375 (MþþNa); HRMS calcd for C19H28O6Na 375.1783,
found 375.1797.
5.1.6. Benzyl(R)-2-(benzyloxy)-1-((4R,5R)-5-((3,4-dimethoxy-phenyl)
(hydroxy)methyl)-2,2-dimethyl-1,3-dioxol-an-4-yl)ethylcarbamate
16. To a solution of 13 (1 g, 2.06 mmol) in dry ether (20 mL) was
added periodic acid (704 mg, 3.09 mmol) portion wise at 0 ꢁC
under nitrogen atmosphere. After being stirred for 6 h at room
temperature, the reaction mixture was neutralized with NaHCO3,
filtered through a pad of Celite, and the filtrate was concentrated
under reduced pressure to give crude aldehyde derivative 14, which
was carried to the next step without any purification.
5.1.4. (4S,40R,5R)-5-((R)-1-Azido-2-(benzyloxy)ethyl)-2,2,20,20-tetra-
methyl-4,40-bi(1,3-dioxolane) 12. To a stirred solution of 11 (6 g,
17.04 mmol) in dry CH2Cl2 (35 mL) was added N(Et)3 (7.1 mL,
51.13 mmol) at 0 ꢁC under nitrogen atmosphere. After 5 min. stir-
ring, methane sulfonylchloride (1.6 mL, 20.45 mmol) was added
drop wise to the reaction mixture and allowed to stir at room
temperature for 3 h, the reaction mixture was diluted with CHCl3
(80 mL). The organic solution was washed with water (30 mL),
brine (10 mL), dried over Na2SO4 and evaporation of the solvent
under reduced pressure afforded corresponding mesyl derivative as
yellow oil, which was carried to the next step without any
purification.
To a stirred solution of 3,4-dimethoxy phenyl magnesium bro-
mide 15{freshly prepared with Mg (465 mg, 19.4 mmol) and 3,4-
dimethoxybromobenzene (1.4 ml, 9.69 mmol) in dry THF (15 mL) at
80 ꢁC for 2 h under stirring} was added aldehyde 14 in dry THF
(20 mL) drop wise at 0 ꢁC under nitrogen atmosphere. After being
stirred for 12 h at room temperature, the reaction mixture was
quenched with saturated aqueous NH4Cl at 0 ꢁC, THF was removed
under reduced pressure and the residue was extracted with ethyl
acetate (3ꢃ50 mL). The combined organic extracts were washed
with brine (30 mL), dried over anhydrous Na2SO4, concentrated
under reduced pressure and purified by silica gel column chro-
matography (ethyl acetate/hexane¼1:5) to afford diastereomeric
mixture 16 (0.7 g, 65%) as pale brown oil. Rf (40% ethyl acetate/
hexane) 0.43; IR (neat) nmax 3436, 2934, 1714, 1514, 1457, 1260,
To a stirred solution of above mesylate derivative in dry DMF
(20 mL) was added NaN3 (3.32 g, 51.13 mmol) under nitrogen at-
mosphere at room temperature, the reaction was slowly heated to
80 ꢁC, after being stirred for 24 h, the reaction mixture was allowed
to room temperature, poured in to ice cold water (20 mL), and
extracted with diethyl ether (3ꢃ50 mL). The combined organic
extracts were washed with brine (20 mL), dried over anhydrous
Na2SO4 and concentrated under reduced pressure and purified by
silica gel column chromatography (ethyl acetate/hexane¼1:19) to
1030, 748 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 1.45 (s, 3H), 1.51 (s,
3H), 2.68(d, 1H, OH), 3.45–3.61(m, 1H), 3.62–3.97 (m, 8H), 4.07and
4.26 (2 m, 2H), 4.4–4.81 (m, 4H), 5 (m, 2H), 6.58–6.93 (m, 3H) 7.14–
7.38 (m, 10H); ESI/MS (m/z) 574 (MþþNa); HRMS calcd for
C31H37NO8Na 574.2416, found 574.2397.
afford 12 (5.14 g, 80%) as yellowish oil. Rf (20% ethyl acetate/hexane)
28
0.85; [
a
]
þ9.09 (c 2.02, CHCl3); IR (neat) nmax 2987, 2932, 2101,
D
1455, 1375, 1253, 1214, 1154, 1067, 847 cmꢀ1
;
1H NMR (300 MHz,
CDCl3) 1.30 (s, 3H, CH3), 1.34 (s, 3H, CH3), 1.35 (s, 3H, CH3), 1.38
d
(s, 3H, CH3), 3.56 (dd, 1H, J¼7.55, 9.82 Hz, CHHOBn), 3.66–3.79
(m, 2H, CHHOBn and CHN3), 3.89 (m, 2H, CHHO and CHO–), 4.01 (m,
2H, CHHO and CHO–), 4.07 (dd, 1H, J¼6.23, 8.42 Hz, CHO–) 4.55 (s,
2H, PhCH2O), 7.23–7.34 (m, 5H, Ph); 13C NMR (75 MHz, CDCl3)
5.1.7. (2R,3R,4R,5R/S)-Benzyl 2-(benzyloxymethyl)-5-(3,4-dimethoxy-
phenyl)-3,4-dihydroxypyrrolidine-1-car-boxylate 17a/17b. To a stir-
red solution of diastereomeric mixture 16 (800 mg, 1.45 mmol) in
CH2Cl2 (5 mL) was added TFA (5 mL) drop wise at 0 ꢁC. After
completion of the addition, the reaction mixture was warmed to
room temperature and stirring was continued at the same tem-
perature for 12 h. The reaction mixture was neutralized with
NaHCO3 at 0 ꢁC and filtered through the Celite pad and washed
with the chloroform (2ꢃ20 mL). The chloroform layer was washed
with water and brine, dried over Na2SO4 and concentrated under
vacuum. The crude residue was purified through silica gel column
chromatography.
d
25.2, 26.3, 27.1, 27.3, 62.6, 67.2, 69.6, 73.3, 76.8, 78.7, 79.4, 109.7,
110.0, 127.5, 127.7, 128.3, 137.6; ESI/MS (m/z) 400 (MþþNa); HRMS
calcd for C19H27N3O5Na 400.1848, found 400.1834.
5.1.5. Benzyl (R)-2-(benzyloxy)-1-((4S,40R,5R)-2,2,20,20-tetramethyl-
4,40-bi(1,3-dioxolan)-5-yl) ethylcarbamate 13. To a suspension of
LiAlH4 (523 mg, 13.79 mmol) in dry THF (15 mL) was added com-
pound 12 (4 g, 10.61 mmol) in dry THF (20 mL) drop wise at 0 ꢁC
under nitrogen atmosphere. After being stirred for 5 h at room
temperature, the reaction mixture was quenched with water
(0.5 mL), 15% aq NaOH (0.5 mL), water (1.5 mL) successively at 0 ꢁC.
After 1 h stirring at room temperature, the reaction mixture filtered
through a pad of Celite and filtrate was evaporated under reduced
pressure. The crude residue dissolved in CH2Cl2 (20 mL), to it was
added Na2CO3 (1.12 g, 10.61 mmol) and CbzCl (3.55 mL,
21.22 mmol) drop wise at 0 ꢁC. After being stirred for 8 h at room
temperature, the reaction mixture was diluted with CHCl3 (50 mL).
The organic solution was washed with water (20 mL), brine
(10 mL), dried over Na2SO4, evaporation of the solvent under re-
duced pressure and purification by silica gel column chromatog-
raphy (ethyl acetate/hexane¼1:6) afforded 13 (4.46 g, 87%) as
The faster moving trans cyclised compound 17a (400 mg, 59%)
was eluted in the column (ethyl acetate/hexane¼2:3) as a major
isomer and as a white solid. Rf (50% ethyl acetate/hexane) 0.28; mp
25
152–154 ꢁC; [
a
]
ꢀ43.5 (c 0.86, CHCl3); IR (neat) nmax 3420, 2924,
D
1694, 1514, 1455, 1411, 1349, 1260, 1025, 751 cmꢀ1
;
1H NMR
(400 MHz, CDCl3) 1.67 (OH, 1H), 3.57–3.93 (m, 8H, include 2-
d
OMe’s), 4.06–4.34 (2s, 2H), 4.31 (dd, 1H, J¼2.93, 9.89 Hz), 4.42–4.72
(m, 2H), 4.74–4.95 (m, 2H), 5.05 (d, 1H), 6.67–6.88 (m, 3H), 7.10–
7.42 (m, 10H) (Because of the rotameric nature of compound, NMR
is not resolved clearly); 13C NMR (100 MHz, CDCl3)
d
*55.7, 55.8,
*66.7, *67.4, *67.9, *71.8, *73.9, *80.8, *83.3, *109.4, *110.9, *117.5, 127.4,
*127.6, *127.9, *128.1, *128.3, *128.6, *133.9, *136.1, *136.5, *147.8,
*148.9, *154.7; (*rotamer); ESI/MS (m/z) 516 (MþþNa); HRMS calcd
for C28H31NO7Na 516.1998, found 516.1992.
crystalline solid. Rf (30% ethyl acetate/hexane) 0.52; mp 53–55 ꢁC;
28
[
a]
ꢀ56 (c 1.90, CHCl3); IR (neat) nmax 3424, 2986, 2927, 1721, 1517,
The slower moving diastereomeric compound 17b (150 mg,
D
1374, 1215, 1061, 754 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
1.26 (s, 3H,
21%) was eluted in the column (ethyl acetate/hexane¼2:3) as
25
CH3), 1.29 (s, 3H, CH3), 1.35 (s, 6H, 2-CH3’s), 3.68 (br s, 2H, CH2OBn),
3.83 (dd, 2H, J¼5.28, 8.12 Hz, CHO– and CHNH), 3.92 (m, 2H, CHHO
and CHO–), 4.10 (m, 2H, CHHO and CHO–), 4.53 (s, 2H, PhCH2O),
a thick syrup. Rf (50% ethyl acetate/hexane) 0.25; [
a
]
þ3 (c 1.6,
D
CHCl3); IR (neat) nmax 3421, 2929, 1694, 1515, 1457, 1411, 1347, 1260,
1136, 1028, 751, 698 cmꢀ1 1H NMR (300 MHz, CDCl3)
2.40 (OH,
;
d

1206
Y. Jagadeesh et al. / Tetrahedron 66 (2010) 1202–1207
1H), 3.5–4.31 (m, 12H, include 2-OMe’s), 4.48–4.75 (m, 2H), 4.8–
5.20 (m, 3H), 6.61–6.92 (m, 3H), 6.97–7.52 (m, 10H); (Because of the
rotameric nature of compound, NMR is not resolved clearly). 13C
120.6, 127.5, 127.7, 128.4, 129.7, 137.7, 148.3, 148.8; ESI/MS (m/z) 374
(MþþH); HRMS calcd for C21H28NO5 374.1967, found 374.1960.
NMR (100 MHz, CDCl3)
d
55.6, 55.8, 65.7, 66.9, 69.7, 73.8, 77.9, 110.5,
5.1.11. (2S,3R,4R,5R)-2-(3,4-Dimethoxyphenyl)-5-(hydroxymethyl)-
1-methylpyrrolidine-3,4-diol [(þ)-2-epi codonopsinol] 6. An etha-
nolic solution of 18b (40 mg, 0.1 mmol) in 6 mL was stirred at rt in
the presence of PdCl2 (catalytic amount) under hydrogen atmo-
sphere for 12 h. The catalyst was removed by filtration and the
reaction mixture was concentrated. Further evaporation under high
110.9, 119.4, 127.9, 128.1, 128.6, 137, 148.2, 148.8; ESI/MS (m/z) 516
(MþþNa); HRMS calcd for C28H31NO7Na 516.1998, found 516.1989.
5.1.8. (2R,3R,4R,5R)-2-(Benzyloxymethyl)-5-(3,4-dimethoxyphenyl)-
1-methylpyrrolidine-3,4-diol 18a. To a stirred suspension of LiAlH4
(0.07 g, 183 mmol) in THF (3 mL) was added pyrrolidine de-
rivative 17a (0.3 g, 0.6 mmol) in THF (5 mL) at 0 ꢁC. After the
completion of addition the reaction mixture was refluxed for 5 h.
The reaction mixture was cooled to 0 ꢁC, quenched with water
(0.07 mL), 15% NaOH (0.07 mL) and water (0.20 mL) successively.
After 15 min stirring at room temperature, the reaction mixture
was filtered through the Celite pad, washed with ethyl acetate
(3ꢃ10 mL) and the filtrate was evaporated under vacuum. The
residue was purified through silica gel column chromatography
vacuum gave (2)-epi codonopsinol 6 (25 mg, yield, 80%) as a thick
25
syrup. Rf (20% MeOH/CHCl3) 0.23; [
a
]
D
þ103.9 (c 1.81, MeOH); IR
(KBr) 3376, 2939, 1514, 1460, 1262, 1137, 1026 cmꢀ1
(400 MHz, CD3OD)
;
1H NMR
d
2.20 (3H, s, NMe), 2.43 (td, 1H, J¼3.7, 4.1 Hz,
H5), 3.65 (d, 1H, J¼4.5 Hz, H2), 3.72–3.86 (m, 9H, H3,H12and 2-
OMe’s), 3.98 (dd, 1H, J¼3.7, 1.2 Hz, H4), 6.88–6.97 (m, 2H, H10and
H11), 7.10 (s, 1H, H7); 13C NMR (100 MHz, CD3OD)
d 40.23, 56.4, 56.5,
62.3, 75.2, 75.8, 80.2, 80.5, 112.5, 114.1, 122.7, 131.9, 149.7, 150.2; ESI/
MS (m/z) 284 (MþþH); HRMS calcd for C14H22NO5 284.1497, found
284.1488.
(CHCl3/MeOH¼7:1) to afford the N-methyl derivative 18a (0.112 g,
25
74%) as white solid. Rf (ethyl acetate) 0.1; mp 65–67 ꢁC; [
a]
D
ꢀ25.1(c 2.58, CDCl3); IR (KBr) 3414, 2931, 1514, 1456, 1261, 1136,
1026, 754 cmꢀ1 1H NMR (300 MHz, CDCl3)
2.20 (s, 3H, NMe),
Acknowledgements
;
d
3.01–3.41 (m, 3H, 2-OH’s and H5), 3.53–3.69 (m, 2H, H2and H3),
3.75–3.95 (m, 8H, H12and 2-OMe’s), 4.10 (br s,1H, H4), 4.55 (s,2H,
PhCH2O), 6.74–6.95 (m, 3H, Ph), 7.22–7.49(m, 5H, Ph); 13C NMR
Y. Jagadeesh thanks CSIR, New Delhi, J. Santhosh reddy thanks
UGC, New Delhi for the research fellowship. The authors also thank
Dr. N. W. Fadnavis for his help and Dr. J. S. Yadav and Dr. A. C.
Kunwar for their support and encouragement. We also thank DST
(SR/S1/OC-14/2007), New Delhi for financial support.
(75 MHz, CDCl3) d 34.3, 55.8, 62.5, 68.4, 68.7, 73.6, 75.7, 80.5, 85.5,
110.2, 110.8, 119.9, 127.8, 127.9, 128.5, 133.5, 137.4, 148.3, 149.1;
ESI/MS (m/z) 374 (MþþH); HRMS calcd for C21H28NO5 374.1967,
found 374.1967.
Supplementary data
5.1.9. (2R,3R,4R,5R)-2-(3,4-Dimethoxyphenyl)-5-(hydroxymethyl)-1-
methylpyrrolidine-3,4-diol [(ꢀ)-codonopsinol] (5). An ethanolic so-
lution of 18a (100 mg, 0.27 mmol) in 6 mL was stirred at room
temperature in the presence of PdCl2 (catalytic amount) under
hydrogen atmosphere for 12 h. The catalyst was removed by fil-
tration and the reaction mixture was concentrated. Further evap-
oration under high vacuum gave codonopsinol 5 (65 mg, yield, 85%)
as a white powder. Rf (20% MeOH/CHCl3) 0.25; mp 150–152 ꢁC;
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.12.035.
References and notes
1. (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry
2000, 11, 1645; (b) Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.; Nash,
R. J. Phytochemistry 2001, 56, 265; (c) Asano, N. Curr. Top. Med. Chem. 2003, 3,
471; (d) Ayad, T. Y.; Genisson, Y.; Balts, M. Curr. Top. Med. Chem. 2004, 8, 1211.
2. For isolation of codonopsinine 1 and codonopsine 2, see: (a) Matkhalikova, S. F.;
Malikov, V. M.; Yunusov, S. Y. Khim. Prir. Soedin. 1969, 5, 30; Chem. Abstr. 1969,
71, 132545z; (b) Matkhalikova, S. F.; Malikov, V. M.; Yunusov, S. Y. Khim. Prir.
Soedin. 1969, 5, 606; Chem. Abstr. 1970, 71, 25712d.
3. For synthesis of codonopsinine 1 and codonopsine 2, see: (a) Reddy, J. S.; Rao,
B. V. J. Org. Chem. 2007, 72, 2224; (b) Iida, H.; Yamazaki, N.; Kibayashi, C. J. Org.
Chem. 1987, 52, 1956; (c) Wang, C. L. J.; Calabrese, J. C. J. Org. Chem. 1991, 56,
4341; (d) Tashkhodzaev, B.; Aripova, S. F.; Turgunov, K. K.; Abdilalimov, O.
Chem. Nat. Compd. 2004, 40, 618; (e) Yoda, H.; Nakajima, T.; Takabe, K. Tetra-
hedron Lett. 1996, 37, 5531; (f) Oliveira, D. F.; Severino, E. A.; Correia, C. R. D.
Tetrahedron Lett. 1999, 40, 2083; (g) Severino, E. A.; Correia, C. R. D. Org. Lett.
2000, 2, 3039; (h) Toyao, A.; Tamura, O.; Takagi, H.; Ishibashi, H. Synlett 2003,
35; (i) Haddad, M.; Larcheveque, M. Synlett 2003, 274; (j) Goti, A.; Cicchi, S.;
Mannucci, V.; Cardona, F.; Guarna, F.; Merino, P.; Tejero, T. Org. Lett. 2003, 5,
4235; (k) Chandrasekhar, S.; Jagadeshwar, V.; Prakash, S. J. Tetrahedron Lett.
2005, 46, 3127; (l) Chandrasekhar, S.; Saritha, B.; Jagadeshwar, V.; Prakash, S. J.
Tetrahedon: Asymmetry 2006, 17, 1380; (m) Iida, H.; Yamazaki, N.; Kibayashi, C.
Tetrahedron Lett. 1985, 26, 3255.
4. Khanov, M. T.; Sultanov, M. B.; Egorova, M. R. Farmakal. AlkaloidovSerdech.
Glikoyidov 1971, 210; Chem. Abstr. 1972, 77, 135091r.
5. For isolation of radicamine 4, see: (a) Shibano, M.; Tsukamoto, D.; Masuda, A.;
Tanaka, Y.; Kusano, G. Chem. Pharm. Bull. 2001, 49, 1362; (b) Shibano, M.; Tsu-
kamoto, D.; Kusano, G. Heterocycles 2002, 57, 1539.
6. For synthesis of radicamine 4, see: (a) Ribes, C.; Falormi, E.; Carda, M.; Marco, J.
A. J. Org. Chem. 2008, 73, 7779; (b) Gurjar, M. K.; Borhade, R. G.; Puranik, V. G.;
Ramana, C. V. Tetrahedron Lett. 2006, 47, 6979; (c) Merino, P.; Delso, I.; Teiero, T.;
Cardona, F.; Goti, A. Synlett 2007, 2651; (d) Zhou, X.; Liu, W.-J.; Ye, J.-L.; Huang,
P.-Q. Tetrahedron 2007, 63, 6346; (e) Yu, C. Y.; Huang, M. H. Org. Lett. 2006, 8,
3021; (f) Merino, M.; Delso, L.; Tejero, T.; Cardona, F.; Marradi, M.; Faggi, F.;
Parmeggiani, C.; Goti, A. Eur. J. Org. Chem. 2008, 2929; (g) Liu, C.; Gao, J.; Yang,
G.; Wightman, R. H.; Jiang, S. Lett. Org. Chem. 2007, 4, 556.
25
20
[
a]
ꢀ13 (c 1.37, MeOH) {lit.6
[a
]
ꢀ15 (c 0.22, MeOH)}; IR (KBr)
D
D
3356, 2933, 1593, 1515, 1261, 1142, 1026 cmꢀ1 1H NMR (400 MHz,
;
CD3OD)
d
2.20 (s, 3H, NMe), 3.10 (m, 1H J¼7.78, 4.09 Hz, H5), 3.66 (d,
1H, J¼6.6 Hz, H2), 3.78–3.87 (m, 8H, H12and 2-OMe’s), 3.94 (dd, 1H,
J¼5.0, 6.4 Hz, H3), 4.03 (t, 1H, J¼4.4, 4.4 Hz, H4), 6.90 (s, 2H, H10and
H11), 7.03 (s, 1H, H7); 13C NMR (100 MHz, CD3OD)
d 35.1, 56.5, 56.6,
60.9, 71.2, 75.9, 80.1, 85.8, 112.5,112.6, 122.4, 134.6, 149.9,150.5; ESI/
MS (m/z) 284 (MþþH); HRMS calcd for C14H22NO5 284.1497, found
284.1503.
5.1.10. (2R,3R,4R,5S)-2-(Benzyloxymethyl)-5-(3,4-dimethoxy-
ph-enyl)-1-methylpyrrolidine-3,4-diol 18b. To a stirred suspension
of LiAlH4 (0.023 g, 0.6 mmol) in THF (2 mL) was added pyrrolidine
derivative 17b (0.1 g, 0.2 mmol) in THF (5 mL) at 0 ꢁC. After the
completion of addition the reaction mixture was refluxed for 5 h.
The reaction mixture was cooled to 0 ꢁC, quenched with water
(0.023 mL), 15% NaOH (0.023 mL) and water (0.7 mL) successively.
After 15 min stirring at room temperature, the reaction mixture
was filtered through the Celite pad, washed with ethyl acetate
(3ꢃ5 mL) and evaporated under vacuum. The residue was purified
through silica gel column chromatography (CHCl3/MeOH¼7:1) to
afford the N-methyl derivative 18b (0.06 g, 79%) as a thick syrup. Rf
25
(ethyl acetate) 0.08; [
a]
þ87.9 (c 0.79, CHCl3); IR (KBr) 3420, 2929,
D
1513, 1456, 1262, 1026, 754 cmꢀ11H NMR (400 MHz, CDCl3)
d 2.22
7. (a) For isolation of codonopsinol 5, see Ishida, S.; Okasaka, M.; Ramos, F.;
Kashiwada, Y.; Takaishi, Y.; Kodzhimatov, O. K.; Ashurmetov, O. J. Nat. Med.
2008, 62, 236; (b) For synthesis of codonopsinol 5, see Tsou, E.-L.; Chen, S.-Y.;
Yang, M.-H.; Wang, S.-C.; Cheng, T.-R. R.; Cheng, W.-C. Bioorg. Med. Chem. 2008,
16, 10198.
(3H, s, NMe), 2.63 (br s, 2H, OH and H5), 3.59–3.91 (m, 10H,
H2,H3,H12and 2-OMe’s), 4.10 (br s, 1H, H4), 4.61 (s,2H, PhCH2O),
6.81–6.98 (m, 3H, Ph), 7.28–7.42 (m, 5H, Ph); 13C NMR (100 MHz,
CDCl3) d 39.7, 55.7, 55.8, 70.6, 72.4, 73.1, 73.5, 79.2, 79.8, 110.9, 111.6,

Y. Jagadeesh et al. / Tetrahedron 66 (2010) 1202–1207
1207
8. Iida, H.; Yamazaki, N.; Kibayashi, C. Tetrahedron Lett. 1986, 27, 5393.
9. (a) Ref. 3a; (b) Kumar, A. R.; Reddy, J. S.; Rao, B. V. Tetrahedron Lett. 2003, 44,
5687; (c) Madhan, A.; Rao, B. V. Tetrahedron Lett. 2005, 46, 323; (d) Reddy, J. S.;
Kumar, A. R.; Rao, B. V. Tetrahedron: Asymmetry 2005, 16, 3154; (e) Chitra, J.;
Kumar, A. R.; Rao, B. V. Tetrahedron: Asymmetry 2008, 19, 2402; (f) Madan, A.;
Rao, B. V. Tetrahedron Lett. 2003, 44, 5641; (g) Chandrasekhar, B.; Madan, A.;
Rao, B. V. Tetrahedron 2007, 63, 8746.
10. (a) The acid catalysed amido cyclisation was also later observed by Ribes
et al. see: Ref. 6a; (b) For the synthesis of 2,5-Di aryl sustituted tetrahy-
dofurans through the acid mediated cyclisation, see: (i) Girotra, N. N.; Biftu,
T.; Ponpipom, M. M.; Acton, J. J.; Alberts, A. W.; Bach, T. N.; Ball, R. G.;
Bugianesi, R. L.; Chabala, J. C. J. Med. Chem. 1992, 35, 3474; (ii) Xiong Cai, X.;
Scannell, R. T.; Yaeger, D.; Hussoin, M. S.; Killian, D. B.; Qian, C.; Eckman, J.;
Hwang, S.-B.; Garahan, L. L.; Yeh, C. G.; Ip, S. H.; Shen, T. Y. J. Med. Chem.
1998, 41, 1970; (c) Some general methods for acid catalyzed N-benzylation
of amides. See: (i) Henneuse, C.; Boxus, T.; Tsebin, L.; Pantano, G.; March-
and-Brynaert, J. Synthesis 1996, 495; (ii) Reddy, D. R.; Iqbal, M. A.; Hudkins,
R. L.; Messina-McLaughlin, P. A.; Mallamo, J. P. Tetrahedron Lett. 2002, 43,
8063; (iii) Noji, M.; Ohno, T.; Fuji, K.; Futaba, N.; Tajima, H.; Ishii, K. J. Org.
Chem. 2003, 68, 9340; (iv) Podder, S.; Choudhury, J.; Roy, S. J. Org. Chem.
2007, 72, 3129.
cyclisation, the mixture 16 was separated by preperative TLC (by running the
plate in solvent system 20% EtOAc/hexane for ten times). The major and minor
isomers were separated and they were subjected to TFA conditions in-
dependently. Both gave the cyclised product 17a and 17b again in 2.5:1 ratio. 1H
NMR data for major isomer (300 MHz, CDCl3)
d 1.38 (s, 3H, CH3), 1.46 (s, 3H,
CH3), 2.65(d, 1H, J¼5.4 Hz, OH), 3.50 (dd, 1H, J¼3.6, 9.3 Hz, CHHO), 3.63–3.93
(m, 8H, CHNH, CHHO and 2-OMe’s), 4.08 (dd, 1H, J¼6.4, 8.7 Hz, CHO–), 4.28 (br
t, 1H, J¼6.4, CHO–), 4.47 (m, 3H, CHOHand PhCH2O), 4.74 (m, 1H, J¼9.3 Hz, NH),
5.02 (m, 2H, PhCH2O), 6.68 (d, 1H, J¼8.2, Ph), 6.78 (br d, 1H, J¼8.2, Ph), 6.86 (br
s, 1H, Ph), 7.19–7.38 (m, 10H, Ph); 1H NMR data for minor isomer (300 MHz,
CDCl3)
d
1.36 (s, 3H, CH3), 1.42 (s, 3H, CH3), 2.41 (br s, 1H, OH), 3.52 (dd, 1H, J¼3.
8, 9.3 Hz, CHHOBn), 3.68–3.88 (m, 8H, CHNH, CHHOBn and 2-OMe’s), 4.20 (m,
2H, 2CHO–), 4.46 (dd, 2H, J¼5.1, 17.3 Hz, PhCH2O), 4.60 (d, 1H, J¼9.3 Hz, NH), 4.
68 (br s, 1H, CHOH), 5.0 (dd, 2H, J¼12.4, 16.5 Hz, PhCH2O), 6.64 (d, 1H, J¼8.2,
Ph), 6.74 (dd, 1H, J¼1.5, 8.2, Ph), 6.84 (d, 1H, J¼1.6, Ph), 7.19–7.38 (m, 10H, Ph).
15. The structure of 2-epi-codonopsinol 6 can be established thorough 1D nuclear
Overhause enhancement (NOE) correlations.
HO
OH
H
11. Long, D. D.; Smith, M. D.; Martin, A.; Wheatley, J. R.; Watkin, D. G.; Muller, M.;
Fleet, G. W. J. J. Chem. Soc., Perkin Trans. 1 2002, 1982.
12. Cbz group is preferred over Boc protection since Cbz is more stable under TFA
conditions thus allowing the cyclisation to better yield.
13. Wu, W.; Wu, Y. J. Org. Chem. 1993, 58, 3586.
14. As per the suggestion of referee to see the influence of the newly generated
chiral center (on benzylic carbon) on the stereochemical out come of the
MeO
MeO
H
H
OH
H
H
N
H
H
H
Me
(+)-epi codonopsinol
6