Total synthesis of (?)-codonopsinine via regioselective and diastereoselective amination using chlorosulfonyl isocyanate

Article abstract of DOI:10.1016/j.tet.2017.06.002

The total synthesis of (?)-codonopsinine (1) from the readily available (S)-3-chloropropan-1,2-diol is described. The key steps for the preparation of (?)-codonopsinine (1) involve the regioselective and diastereoselective amination of anti-1,2-dibenzyl ether 11 using chlorosulfonyl isocyanate and intramolecular amidomercuration to form the pyrrolidine ring. Notably, the reaction between anti-1,2-dibenzyl ether and chlorosulfonyl isocyanate in toluene at 0 °C produced the corresponding anti-1,2-amino alcohol 12a as a major product with excellent diastereoselectivity (anti:syn = 29:1). This observation can be explained by the neighboring group participation leading to the retention of stereochemistry.

Full text of DOI:10.1016/j.tet.2017.06.002

Tetrahedron xxx (2017) 1e6
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Tetrahedron
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Total synthesis of (ꢀ)-codonopsinine via regioselective and
diastereoselective amination using chlorosulfonyl isocyanate
Young Jae Choi, Yoo Chang Kim, Sook Jin Park, Jun Min Jung, Yeon Su Kim, In Su Kim,
Young Hoon Jung*
School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
The total synthesis of (ꢀ)-codonopsinine (1) from the readily available (S)-3-chloropropan-1,2-diol is
described. The key steps for the preparation of (ꢀ)-codonopsinine (1) involve the regioselective and
diastereoselective amination of anti-1,2-dibenzyl ether 11 using chlorosulfonyl isocyanate and intra-
molecular amidomercuration to form the pyrrolidine ring. Notably, the reaction between anti-1,2-
dibenzyl ether and chlorosulfonyl isocyanate in toluene at 0 ꢁC produced the corresponding anti-1,2-
amino alcohol 12a as a major product with excellent diastereoselectivity (anti:syn ¼ 29:1). This obser-
vation can be explained by the neighboring group participation leading to the retention of
stereochemistry.
Received 26 April 2017
Received in revised form
2 June 2017
Accepted 5 June 2017
Available online xxx
Keywords:
Amidomercuration
Amination
© 2017 Elsevier Ltd. All rights reserved.
Chlorosulfonyl isocyanate
Codonopsinine
Natural product
1. Introduction
antihypertensive effects without affecting the central nervous
system.7 Owing to interesting biological activity and unique
Polyhydroxylated alkaloids are among the most notable
achievements in the field of natural products1 due to remarkable
therapeutic potential for the treatment of viral infections, cancer,
AIDS, diabetes, and etc.2 With considerable progress in medicinal
chemistry, a range of natural and unnatural polyhydroxylated al-
kaloids have been prepared and evaluated for clinical trial.3 Indeed,
miglitol (Glyset™) and N-butyldeoxynojirimycin (Zavesca™) are
currently on the market as commercial drugs for the treatment of
type II diabetes and Gaucher's disease.4 In particular, poly-
hydroxylated pyrrolidine alkaloids are widely found to be biologi-
cally relevant scaffolds in natural products and pharmaceuticals.
Representative examples of polyhydroxylated pyrrolidine alka-
loids, (ꢀ)-codonopsinine (1) and (ꢀ)-codonopsine (2) are first
isolated from Codonopsis clematidea5 in 1969 and their absolute
stereochemistry was determined by the same group in 1972
(Fig. 1).6 Notably, these compounds have attracted considerable
attention due to the challenging penta-substituted pyrrolidine core
containing four stereogenic centers with indiscrete trans-stereo-
chemistry and diverse biological activities as antibiotic and
structural feature, various synthetic routes for the preparation of
(ꢀ)-codonopsinine (1) have been studied.8 For example, Rao have
been reported the total synthesis of (ꢀ)-codonopsinine (1) via the
DDQ-promoted benzylic sp3 CeH activation reaction8a and acid-
catalyzed amidocyclization8e for the stereoselective intra-
molecular CeN bond formation. Davies described the ring-closing
iodoamination reaction of homoallylic amines for the synthesis of
polysubstituted pyrrolidines and its application to the asymmetric
synthesis of 1.8b,c Ooi demonstrated the efficient synthesis of 1
through the organocatalytic asymmetric Henry reaction between
ynals and nitromethane leading to the formation of anti-vicinal
amino alcohols.8d Goti and Merino disclosed the construction of
(ꢀ)-codonopsinine (1) and its analog based on the iterative
organometallic addition to chiral hydroxylated cyclic nitrones.8g
As part of an ongoing research program aimed at developing
asymmetric total synthesis of biologically active compounds via the
stereoselective amination of chiral allylic and benzylic ethers using
chlorosulfonyl isocyanate (CSI),9 we herein describe an asymmetric
total synthesis of (ꢀ)-codonopsinine (1) starting from commer-
cially available (S)-3-chloropropan-1,2-diol via chelation-
controlled Grignard reaction, diastereoselective amination of anti-
vicinal dibenzyl ether and intramolecular cyclization by amido-
mercuration as the key steps.
* Corresponding author.
E-mail address: yhjung@skku.edu (Y.H. Jung).
http://dx.doi.org/10.1016/j.tet.2017.06.002
0040-4020/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Choi YJ, et al., Total synthesis of (ꢀ)-codonopsinine via regioselective and diastereoselective amination using
chlorosulfonyl isocyanate, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.06.002

2
Y.J. Choi et al. / Tetrahedron xxx (2017) 1e6
Table 1
Lewis acid-mediated addition of vinylmagnesium bromide to aldehyde 9.a
Entry
Lewis acid
Solvent
Ratio (10a:10b)b
Yield (%)c
1
2
3
4
5
6
e
THF
THF
CH2Cl2
THF
CH2Cl2
THF
2.0:1
2.8:1
4.9:1
3.1:1
15.7:1
13.9:1
58
77
62
73
63
86
MgBr2$OEt2
MgBr2$OEt2
CeCl3
ZnCl2
ZnCl2
a
Reaction conditions: 9 (1 equiv.), vinylmagnesium bromide (3 equiv.), Lewis acid
(1.5 equiv.) at 0 ꢁC for 3 h.
b
Diastereomeric ratio was determined by HPLC analysis.
Isolated combined yield of 10a and 10b by flash column chromatography.
c
complex between aldehyde group and
a-OBn group, which
smoothly participates in nucleophilic addition with vinyl-
magnesium bromide to deliver syn-isomer 10a as a major dia-
steromer (Fig. 2). The stereochemistry of 10a can be confirmed by
the full agreement of spectral data between our synthesized
(ꢀ)-codonopsinine (1) and reported literature.8a,e
Fig. 1. Structure of representative polyhydroxylated pyrrolidines.
2. Results and discussion
As illustrated in Scheme 2, protection of the hydroxyl group of
10a was subjected with Ac2O to give the corresponding acetate 11
in 91% yield. Next, the reactivity and diastereoselectivity of 11 with
chlorosulfonyl isocyanate were examined under various reaction
conditions, and the selected results are summarized in Table 2. The
reaction of 11 with CSI in CH2Cl2 at 0 ꢁC gave the inseparable
mixture of desired product 12a and its diastereomer 12b in 6:1
ratio in 84% yield (Table 2, entry 1). The screening of other solvents
under identical reaction conditions showed that toluene was the
most effective solvent for this reaction (Table 2, entry 4) to afford
anti-vicinal amino alcohol 12a in 73% yield with excellent diaster-
eoselectivity (anti:syn ¼ 29:1 as obtained by 1H NMR and HPLC
analysis), which was directly used in the next step. The diaster-
eoselectivity of this reaction can be explained by the neighboring
group effect, where the NHCbz group orientation retained its
original configuration in benzyl ether via double inversion of the
configuration (Fig. 3).12
Total synthesis of (ꢀ)-codonopsinine (1) was accomplished by
using anti-vicinal dihydroxy ester 6 as a starting material, which
can be readily prepared from (S)-3-chloropropan-1,2-diol (5) as
reported in the literature (Scheme 1).10 The diol 6 was easily con-
verted into anti-1,2-dibenzyl ether 7 upon treatment with sodium
hydride and benzyl bromide. The reduction of 7 and subsequent
Swern oxidation afforded the corresponding aldehyde 9 in 77%
yield for two steps. Next, we screened the Lewis acid-mediated
Grignard-type addition reaction of 9 with vinylmagnesium bro-
mide to yield 1,2-syn-allyl alcohol 10a. The selected results are
summarized in Table 1.11
As shown in entry 1, in the absence of Lewis acid, the addition of
vinylmagnesium bromide to aldehyde 9 provided a mixture of 10a
and 10b with 2:1 ratio in 58% yield. In addition, MgBr2$OEt2 as a
Lewis acid in THF or CH2Cl2 solvents afforded our desired product
10a, albeit resulting in low diastereoselectivity (Table 1, entries 2
and 3). After further evaluation of Lewis acids, we found that a
combination of ZnCl2 and THF solvent proved to be the most
effective reaction condition furnishing 10a as a major product with
excellent diastereoselectivity of 13.9:1 (Table 1, entry 6). These re-
sults suggest that ZnCl2 can initiate the formation of chelation
Next, we focused on the synthesis of (ꢀ)-codonopsinine (1)
from Cbz-protected amine 12a, as illustrated in Scheme 3. The
intramolecular amidomercurative cyclization13 of 12a with
Hg(CF3SO3)2, NaHCO3 and KBr in nitromethane furnished the
Scheme 1. Synthesis of 1,2-syn-allyl alcohol 10a.
Please cite this article in press as: Choi YJ, et al., Total synthesis of (ꢀ)-codonopsinine via regioselective and diastereoselective amination using
chlorosulfonyl isocyanate, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.06.002

Y.J. Choi et al. / Tetrahedron xxx (2017) 1e6
3
Fig. 2. Transition state model for the formation of 10a.
Scheme 2. Synthesis of anti-vicinal amino alcohol 12a.
corresponding organomercuric bromides 13a and 13b in 70%
combined yield with diastereoselectivity of 3:1 between 2,5-trans
and 2,5-cis.14 The demercuration reaction of 13a with NaBH4 fol-
lowed by reduction of a Cbz group led to the formation of com-
pound 15. Finally, the benzyl group was removed via hydrogenation
to yield (ꢀ)-codonopsinine (1), which has spectral properties (1H
and 13C NMR) and specific rotation in full agreement with previous
reports.8a,e
constants (J) are reported in hertz (Hz). IR spectra were recorded on
a JASCO FT/IR-4600 and reported as cmꢀ1. Optical rotations were
measured with a JASCO P1020 polarimeter and are reported as
[a]t D (concentration g/100 mL, solvent). Thin layer chromatog-
raphy was carried out using plates coated with Kieselgel 60F254
(Merck). For flash column chromatography, E. Merck Kieselgel 60
(230e400 mesh) was used. High-performance liquid chromatog-
raphy (HPLC) was recorded on an Agilent 1200 series. High-
resolution mass spectra (HRMS) were recorded on a JEOL JMS-
700 mass spectrometer.
3. Conclusions
In conclusion, we have developed a method for a highly regio-
selective and diastereoselective introduction of an NHCbz group to
anti-vicinal dibenzyl ethers using chlorosulfonyl isocyanate (CSI).
Moreover, we illustrated the application of this methodology to the
total synthesis of (ꢀ)-codonopsinine (1). We believe that this
synthetic strategy can be applied to the preparation of various
polyhydroxylated alkaloids or other natural products containing a
nitrogen atom in the ring.
4.2. Methyl-(2R,3R)-2,3-bis(benzyloxy)-3-(4-methoxyphenyl)
propanoate (7)
To a suspension of NaH (3.6 g, 89.1 mmol, 60% in mineral oil) in
DMF (150 mL) was added dropwise a solution of 6 (6.72 g,
29.7 mmol) in DMF (60 mL) at ꢀ20 ꢁC. After stirring for 30 min at
the same temperature, benzyl bromide (8.12 mL, 68.3 mmol) was
added slowly over 10 min, and stirred further for 1 h at ꢀ20 ꢁC. The
temperature was slowly raised to 0 ꢁC over 30 min, and the reaction
mixture was further stirred for 30 min at 0 ꢁC. The reaction mixture
was quenched with saturated solution of NH4Cl (150 mL) and the
solution was extracted with CH2Cl2 (200 mL ꢂ 2). The combined
4. Experimental section
4.1. General
Commercially available reagents were used without additional
purification, unless otherwise stated. All reactions were performed
under an inert atmosphere of nitrogen or argon. Nuclear magnetic
resonance spectra (1H and 13C NMR) were recorded on a Varian
Unit 400 (400 MHz for 1H NMR and 100 MHz for 13C NMR) or
Bruker Unit 400 (400 MHz for 1H NMR and 100 MHz for 13C NMR)
Table 2
Diastereoselective amination of 11 with chlorosulfonyl isocyanate.a
Entry
Solvent
Time (h)
Ratio (12a:12b)b
Yield (%)c
1
2
3
4
CH2Cl2
Et2O
n-hexane
toluene
6
8
24
10
6:1
84
71
52
73
19:1
20:1
29:1
instrument with CDCl3 or CD3OD as solvent and residual CHCl3
7.26 ppm) or CH3OH (
3.31 ppm) as internal standard for 1H NMR
and CDCl3 ( 77.0 ppm) or CD3OD (
(d
d
a
Reaction conditions: (i) 11 (1 equiv.), chlorosulfonyl isocyanate (4.5 equiv.),
Na2CO3 (6.8 equiv.) at 0 ꢁC, 10 h; (ii) aqueous solution of 25% Na2SO3 at room
temperature for 24 h.
d
d 49.0 ppm) as internal standard
for 13C NMR. Resonance patterns are reported with the notations s
(singlet), d (doublet), t (triplet), q (quartet), and m (multiplet). In
addition, the notation br is used to indicate a broad signal. Coupling
b
Diastereomeric ratio was determined by HPLC analysis.
Isolated yield by flash column chromatography.
c
Please cite this article in press as: Choi YJ, et al., Total synthesis of (ꢀ)-codonopsinine via regioselective and diastereoselective amination using
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4
Y.J. Choi et al. / Tetrahedron xxx (2017) 1e6
Fig. 3. Proposed reaction mechanism for the diasteroselective amination of 11 with CSI.
organic layers were washed with water and brine, dried over
Na2SO4, and concentrated in vacuo. The residue was purified by
flash column chromatography (n-hexanes/EtOAc ¼ 5:1) to afford
to afford 8 (6.8 g, 91%) as a colorless oil; ½a D23
ꢃ
ꢀ48.8 (c 1.0, CHCl3); IR
(neat)
n
3493, 3026, 2907, 1609, 1587, 1509, 1450 cmꢀ1 1H NMR
;
(400 MHz, CDCl3)
d 7.39e7.25 (m, 10H), 7.10e7.08 (m, 2H), 6.97 (d,
compound 7 (9.4 g, 78%) as a colorless oil; ½a D20
ꢃ
ꢀ35.1 (c 1.0, CHCl3);
J ¼ 8.8 Hz, 2H), 4.53 (d, J ¼ 11.6 Hz, 1H), 4.46 (d, J ¼ 7.6 Hz, 1H),
4.37e4.29 (m, 2H), 4.23 (d, J ¼ 11.2 Hz, 1H), 3.89 (s, 3H), 3.87e3.84
(m, 2H), 3.66e3.62 (m, 1H), 2.49 (br s, 1H); 13C NMR (100 MHz,
IR (neat)
n
3061, 3028, 2899, 1741, 1609, 1509, 1453 cmꢀ1; 1H NMR
(400 MHz, CDCl3)
d 7.23e7.47 (m, 10H), 7.06e7.08 (m, 2H), 6.95 (d,
J ¼ 8.0 Hz, 2H), 4.65 (d, J ¼ 7.6 Hz,1H), 4.51e4.57 (m, 2H), 4.29e4.35
CDCl3) d 159.5, 138.0, 137.9, 131.2, 129.0, 128.4, 128.3, 128.0, 127.9,
(m, 2H), 4.11 (d, J ¼ 7.6 Hz, 1H), 3.86 (s, 3H), 3.76 (s, 3H); 13C NMR
127.8, 127.7, 113.8, 82.4, 81.2, 72.9, 70.4, 62.5, 55.3; HRMS (EI) calcd
(125 MHz, CDCl3)
d 171.7, 159.7, 137.8, 136.9, 130.1, 129.2, 128.3,
for C24H26O4 [M]þ 378.1831, found 378.1827.
128.2,127.9,127.8,127.7,127.6,113.7, 81.9, 80.5, 72.8, 70.5, 55.2, 51.9;
HRMS (EI) calcd for C25H26O5 [M]þ 406.1780, found 406.1779.
4.4. (2R,3R)-2,3-Bis(benzyloxy)-3-(4-methoxyphenyl)propanal (9)
4.3. (2S,3R)-2,3-Bis(benzyloxy)-3-(4-methoxyphenyl)propan-1-ol
(8)
To a stirred solution of oxalyl chloride (2.01 mL, 23.78 mmol) in
CH2Cl2 (50 mL) was added dropwise DMSO (3.38 mL, 47.55 mmol)
and CH2Cl2 (50 mL) at ꢀ78 ꢁC. The reaction mixture was stirred for
1 h at ꢀ78 ꢁC and 8 (6.0 g, 15.85 mmol) in CH2Cl2 (100 mL) was
added to resulting solution. After stirring for 1 h at same temper-
ature, Et3N (11.04 mL, 79.24 mmol) was added dropwise. The re-
action mixture was further stirred for 0.5 h at ꢀ78 ꢁC and carefully
quenched with H2O (100 mL). The organic layer was separated,
washed with brine (100 mL), dried over MgSO4, and concentrated
in vacuo. The residue was purified by flash column chromatography
To a stirred solution of 7 (8.0 g, 19.7 mmol) in THF (80 mL) was
added LiAlH4 (1.12 g, 29.5 mmol) slowly at 0 ꢁC. The mixture was
stirred for 1 h at room temperature and quenched with 3 M HCl
(15 mL). The resulting mixture was extracted with EtOAc (160 mL).
The organic layer was washed with H2O (2 ꢂ 60 mL), brine (60 mL),
dried over MgSO4, and concentrated in vacuo. The residue was
purified by flash column chromatography (n-hexanes/EtOAc ¼ 3:1)
Scheme 3. Synthesis of (ꢀ)-codonopsinine (1).
Please cite this article in press as: Choi YJ, et al., Total synthesis of (ꢀ)-codonopsinine via regioselective and diastereoselective amination using
chlorosulfonyl isocyanate, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.06.002

Y.J. Choi et al. / Tetrahedron xxx (2017) 1e6
5
(n-hexanes/EtOAc ¼ 5:1) to afford 9 (5.07 g, 85%) as a colorless oil;
a 2D0
ꢀ37.8 (c 1.0, CHCl3); IR (neat) 3020, 2730, 1730, 1620, 1575,
1509, 1450 cmꢀ1 1H NMR (400 MHz, CDCl3)
9.67 (d, J ¼ 2.4 Hz,
1H), 4.19e4.14 (m, 2H), 3.38 (d, J ¼ 9.6 Hz, 1H), 3.87 (s, 3H), 3.64
(dd, J ¼ 8.8, 2.8 Hz, 1H), 1.99 (s, 3H); 13C NMR (100 MHz, CDCl3)
½
ꢃ
n
;
d
d 170.1, 159.6, 138.7, 137.4, 134.2, 131.1, 129.5, 128.5, 128.3, 128.0, 127.7,
1H), 7.34e7.16 (m, 10H), 7.05e7.01 (m, 2H), 6.88e6.83 (m, 2H),
4.61e4.50 (m, 3H), 4.39 (d, J ¼ 12.0 Hz, 1H), 4.26 (d, J ¼ 12.0 Hz, 1H),
3.92 (dd, J ¼ 2.8, 7.0 Hz, 1H), 3.84 (s, 3H); 13C NMR (100 MHz, CDCl3)
127.6, 117.6, 113.8, 83.7, 78.6, 75.0, 74.0, 70.0, 55.3, 21.1; HRMS (EI)
calcd for C28H30O5 [M]þ 446.2093, found 446.2097.
d
201.1, 159.7, 137.6, 137.0, 129.5, 129.1, 128.4, 128.3, 128.0, 127.9,
4.8. (3R,4R,5R)-4-(Benzyloxy)-5-(benzyloxycarbonylamino)-5-(4-
127.8, 127.7, 113.9, 85.5, 79.8, 72.9, 70.3, 55.3; HRMS (FAB) calcd for
C
methoxyphenyl)pent-1-en-3-ylacetate (12a)
24H25O4 [MþH]þ 377.1753, found 377.1752.
To a stirred solution of 11 (3.40 g, 7.61 mmol) in anhydrous
toluene (26 mL) was added Na2CO3 (5.48 g, 51.75 mmol) and
chlorosulfonyl isocyanate (3.0 mL, 34.25 mmol) at 0 ꢁC under N2
atmosphere. The reaction mixture was stirred for 10 h at 0 ꢁC
and quenched with H2O (50 mL). The aqueous layer was extracted
with EtOAc (2 ꢂ 50 mL). The organic layer was added to a solution
of 25% aqueous solution of Na2SO3 (150 mL), and the reaction
mixture was further stirred for 24 h at room temperature. The
organic layer was washed with brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by flash column
chromatography (n-hexanes/EtOAc ¼ 3:1) to afford 2.72 g of 12a
4.5. (3R,4S,5R)-4,5-Bis(benzyloxy)-5-(4-methoxyphenyl)pent-1-
en-3-ol (10a)
To a stirred solution of aldehyde 9 (5.97 g, 15.85 mmol) in THF
(50 mL) was slowly added ZnCl2 (3.24 g, 23.78 mmol) at 0 ꢁC under
N2 atmosphere. Then, vinylmagnesium bromide solution (47.55 mL,
47.56 mmol, 1.0 M in THF) was added at 0 ꢁC and stirred for 1 h at
0 ꢁC. The reaction mixture was quenched with saturated solution of
NH4Cl (100 mL) and the aqueous layer was extracted with
dichloromethane (2 ꢂ 100 mL). The organic layer was washed with
H2O (2 ꢂ 100 mL) and brine (100 mL), dried over MgSO4, and
concentrated in vacuo. The residue was purified by flash column
chromatography (n-hexanes/EtOAc ¼ 8:1) to afford 5.14 g of 10a
(12.71 mmol, 80%) and 0.37 g of 10b (0.91 mmol, 5.8%), respec-
(5.56 mmol, 73%) as a colorless syrup; ½a D20
ꢃ
þ33.9 (c 1.03, CHCl3); IR
(neat)
n
3353, 1732, 1683, 1530, 1454, 1230 cmꢀ1 1H NMR
;
(400 MHz, CDCl3)
d
7.35e7.21 (m, 12H), 6.82 (d, J ¼ 8.4 Hz, 2H),
5.81e5.72 (m, 1H), 5.44 (d, J ¼ 9.2 Hz, 1H), 5.25e5.13 (m, 3H),
5.07e4.96 (m, 2H), 4.85e4.81 (m, 1H), 4.70 (d, J ¼ 10.8 Hz, 1H), 4.51
(d, J ¼ 11.2 Hz, 1H), 3.89 (br s, 1H), 3.78 (s, 3H), 1.98 (s, 3H); 13C NMR
tively; colorless oil; ½a D25
ꢃ
þ16.2 (c 1.0, CHCl3); IR (neat)
n 3472, 3029,
2894, 1735, 1609, 1541, 1453 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
7.37e7.22 (m, 10H), 6.99e6.92 (m, 4H), 6.09e6.00 (m, 1H),
(100 MHz, CDCl3) d 169.7,159.2,155.4,137.9,136.4,132.7,13.3,129.4,
5.43e5.22 (m, 2H), 4.49e4.45 (m, 3H), 4.26 (d, J ¼ 10.8 Hz, 2H), 4.02
128.6, 128.1, 128.1, 128.0, 127.9, 119.6, 113.9, 82.4, 75.4, 75.1, 66.7,
55.2, 21.2; HRMS (FAB) calcd for C29H32NO6 [MþH]þ 490.2230,
found 490.2233; HPLC (Waters X-Bridge C18 column,
(d, J ¼ 11.2 Hz, 1H), 3.86 (s, 3H), 3.59 (dd, J ¼ 8.0, 3.2 Hz, 1H), 3.06 (d,
J ¼ 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 159.5, 139.2, 138.0,
137.6, 131.2, 130.2, 129.4, 129.0, 128.2, 128.1, 127.8, 127.7, 115.4, 113.7,
83.6, 80.9, 74.0, 71.9, 70.5, 55.3; HRMS (EI) calcd for C26H28O4 [M]þ
404.1988, found 404.1984; HPLC (Waters X-Bridge C18 column,
MeCN:H2O
¼
50:50 (0.1% TFA), 0.8 mL/min, 254 nm):
tmajor ¼ 19.6 min, tminor ¼ 21.1 min, dr ¼ 29:1.
MeCN:H2O
¼
50:50 (0.1% TFA), 1.0 mL/min, 254 nm):
4.9. (((2S,3R,4R,5R)-3-Acetoxy-4-(benzyloxy)-1-
(benzyloxycarbonyl)-5-(4-methoxyphenyl)pyrrolidin-2-yl)methyl)
mercury(II)bromide (13a)
tminor ¼ 20.6 min, tmajor ¼ 21.5 min; dr ¼ 13.9:1.
4.6. (3S,4S,5R)-4,5-Bis(benzyloxy)-5-(4-methoxyphenyl)pent-1-en-
3-ol (10b)
A stirred solution of compound 12a (2.70 g, 5.51 mmol) in
nitromethane (30 mL) was added mercury triflate (4.13 g,
8.27 mmol) at room temperature. After the reaction mixture was
stirred for 30 min and then saturated solution of KBr (13.7 mL) and
NaHCO3 (13.7 mL) was added. The resulting mixture was further
stirred for 30 min and the resulting solution was extracted with
EtOAc (2 ꢂ 30 mL). The organic layer was washed with H2O, dried
over MgSO4, and concentrated in vacuo. The residue was purified
by flash column chromatography (n-hexanes/EtOAc ¼ 3:1) to afford
a separable mixture of 13a and 13b (2.97 g, 3.86 mmol, 70% com-
bined yield of 13a and 13b) as a yellowish syrup. The diastereomer
ratio of 13a and 13b was determined to be 3:1 by NMR spectra with
Colorless oil; ½a D20
ꢃ
þ9.2 (c 0.8, CHCl3); IR (neat)
n
3471, 2894,
7.31e7.21
1733, 1609, 1540, 1453 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
(m, 10H), 6.99e6.93 (m, 4H), 6.07e5.98 (m, 1H), 5.33 (d, J ¼ 17.6 Hz,
1H), 5.21 (d, J ¼ 11.2 Hz, 1H), 4.45e4.35 (m, 3H), 4.22e4.18 (m, 2H),
3.86 (d, J ¼ 11.2 Hz, 1H), 3.83 (s, 3H), 3.55 (dd, J ¼ 8.2, 5.6 Hz, 1H),
3.14 (br s, 1H); 13C NMR (100 MHz, CDCl3)
d 159.5, 139.8, 138.6,
137.2, 131.24, 129.0, 128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0,
127.9,127.8, 127.7,116.5,114.0,113.8, 84.8, 82.4, 75.6, 74.6, 70.1, 55.3;
HRMS (EI) calcd for C26H28O4 [M]þ 404.1988, found 404.1989.
4.7. (3R,4S,5R)-4,5-Bis(benzyloxy)-5-(4-methyoxyphenyl)pent-1-
en-3-yl acetate (11)
the crude material before purified; ½a D25
ꢃ
ꢀ17.3 (c 1.03, CHCl3); IR
(neat) n ;
2924, 1733, 1690, 1669, 1510, 1401, 1346, 1225 cmꢀ1 1H
NMR (400 MHz, CDCl3) d 7.39e7.30 (m, 6H), 7.22e7.13 (m, 3H), 6.91
To a stirred solution of 10a (3.6 g, 8.90 mmol) in CH2Cl2 (40 mL)
was added Et3N (2.5 mL, 17.8 mmol), 4-dimethylaminopyridine
(0.22 g, 1.78 mmol) and acetic anhydride (1.36 g, 14.34 mmol) at
0 ꢁC. The reaction mixture was stirred for 2 h at room temperature
and diluted with dichloromethane (20 mL). The resulting mixture
was washed with water and brine, dried over Na2SO4, and concen-
trated in vacuo. The residue was purified by flash column chroma-
tography (n-hexanes/EtOAc ¼ 5:1) to afford 3.62 g of 11 (8.10 mmol,
(d, J ¼ 8.4 Hz, 2H), 6.81e6.74 (m, 3H), 5.24e5.09 (m, 1H), 5.07e5.03
(m, 2H), 4.92e4.65 (m, 4H), 3.85e3.72 (m, 1H), 3.78 (s, 3H), 2.59
(dd, J ¼ 12.4, 5.6 Hz, 1H), 2.32 (dd, J ¼ 12.4, 6.4 Hz, 1H), 1.83 (s, 3H);
13C NMR (100 MHz, CDCl3)
d 169.9, 158.6, 154.6, 136.7, 135.9, 132.0,
130.8,128.7, 128.5,128.4,128.3,128.1,127.6, 127.5,126.8,113.7,113.5,
87.3, 82.4, 68.1, 67.1, 66.5, 55.3, 35.2, 20.8; HRMS (FAB) calcd for
C
29H31O6NBrHg [MþH]þ 770.1041, found 770.1047.
91%) as a white solid; m.p. 83e85 ꢁC; ½a D25
ꢃ
ꢀ46.4 (c 0.9, CHCl3);
4.10. (((2R,3R,4R,5R)-3-Acetoxy-4-(benzyloxy)-1-
(benzyloxycarbonyl)-5-(4-methoxyphenyl)pyrrolidin-2-yl)methyl)
mercury(II) bromide (13b)
IR (neat) n ;
3029, 2902, 1729, 1610, 1513, 1374, 1245, 1178, 1111 cmꢀ1
1H NMR (400 MHz, CDCl3)
d 7.41e7.20 (m, 10H), 7.01e6.94 (m,
4H), 5.92e5.83 (m, 1H), 5.74e5.72 (m, 1H), 5.36 (d, J ¼ 16.0 Hz, 1H),
5.23 (d, J ¼ 10.4 Hz, 1H), 4.43 (d, J ¼ 11.6 Hz, 1H), 4.34 (d, J ¼ 8.4 Hz,
IR (neat)
n 2922, 2914, 1731, 1691, 1660, 1508, 1400, 1225, 1012,
Please cite this article in press as: Choi YJ, et al., Total synthesis of (ꢀ)-codonopsinine via regioselective and diastereoselective amination using
chlorosulfonyl isocyanate, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.06.002

6
Y.J. Choi et al. / Tetrahedron xxx (2017) 1e6
941 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
7.37e7.06 (m, 12H), 6.84 (d,
4.40 (dt, J ¼ 6.4, 6.8 Hz, 1H), 4.04 (d, J ¼ 6.0 Hz, 1H), 3.68 (m, 4H),
2.23 (s, 3H), 1.34 (d, J ¼ 6.4 Hz, 3H); 13C NMR (100 MHz, CD3OD)
J ¼ 8.7 Hz, 2H), 5.16e4.97 (m, 2H), 4.90e4.66 (m, 2H), 4.55 (s, 2H),
4.06 (t, J ¼ 4.8 Hz,1H), 3.84e3.76 (m, 4H), 2.22e1.94 (m, 2H),1.88 (s,
d
159.1, 135.0, 129.6, 113.8, 86.9, 84.8, 74.1, 64.8, 54.9, 34.5, 13.7;
3H); 13C NMR (100 MHz, CDCl3)
d
169.8, 158.7, 155.8, 137.3, 135.8,
HRMS (EI) calcd for C13H19NO3 [M]þ 237.1365, found 237.1363.
131.9, 128.6,128.3,128.2,128.1,128.0,127.9, 127.8, 127.6, 127.5,127.0,
113.9, 85.5, 77.1, 72.2, 67.3, 65.6, 58.4, 55.2, 20.7; HRMS (FAB) calcd
for C29H31O6NBrHg [MþH]þ 770.1041, found 770.1046.
Acknowledgement
This paper was supported by Sungkyun Research Fund, Sung-
kyunkwan University, 2016.
4.11. Benzyl-(2R,3R,4R,5R)-3-acetoxy-4-(benzyloxy)-5-(4-
methoxyphenyl)-2-methylpyrrolidine-1-carboxylate (14)
Appendix A. Supplementary data
To a stirred solution of 13a (1.0 g, 1.3 mmol) in DMF (4 mL) was
added NaBH4 (0.098 g, 2.6 mmol) at room temperature. After stir-
ring for 1 h, the reaction mixture was quenched with H2O (12 mL)
and extracted with ethyl acetate (2 ꢂ 15 mL). The combined organic
layers were washed with brine, dried over MgSO4, and concen-
trated in vacuo. The residue was purified by flash column chro-
matography (n-hexanes/EtOAc ¼ 3:1) to afford 0.53 g of 14
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2017.06.002.
References
(1.09 mmol, 84%) as a colorless oil; ½a D23
þ19.8 (c 1.0, CHCl3); IR
ꢃ
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2933,1737, 1698,1511,1402,1348,1227, 1106,1027 cmꢀ1; 1H
NMR (400 MHz, CDCl3)
d 7.37e7.28 (m, 7H), 7.23e7.05 (m, 4H),
6.82e6.76 (m, 3H), 5.20e4.94 (m, 3H), 4.84e4.63 (m, 3H), 4.36 (dq,
J ¼ 12.4, 6.8 Hz, 1H), 3.85 (d, J ¼ 11.6 Hz, 1H), 3.79 (s, 3H), 1.83 (s,
(b) Somsak L, Nagya V, Hadady Z, Docsa T, Gergely P. Curr Pharm Des. 2003;9:
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loidov Serdech Glikoyidov. 1971:210.
3H), 1.55 (d, J ¼ 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3);
d 169.9,
158.6, 154.5, 137.5, 136.6, 136.3, 133.1, 132.2, 128.5, 128.2, 127.9,
127.6, 127.5, 127.4, 127.2, 113.7, 113.5, 88.6, 87.9, 81.2, 80.1, 71.7, 67.9,
67.8, 67.1, 66.6, 61.0, 60.5, 55.3, 20.9,18.4, 17.3; HRMS (FAB) calcd for
C
29H32NO6 [MþH]þ 490.2230, found 490.2235.
4.12. (2R,3R,4R,5R)-4-(Benzyloxy)-5-(4-methoxyphenyl)-1,2-
dimethylpyrrolidine-3-ol (15)
To a stirred solution of 14 (0.40 g, 0.82 mmol) in dry toluene
(15 mL) was added Red-Al (1.28 mL, 44.16 mmol, 3.5 M solution in
toluene) at 0 ꢁC. After addition was completed, the reaction mixture
was heated to reflux for 10 h. The reaction mixture was cooled to
0
ꢁC, and quenched with EtOAc (15 mL) and H2O (5 mL). After
stirring for 15 min, the reaction mixture was filtered through a
celite pad and washed with ethyl acetate (3 ꢂ 10 mL). The filtrate
was evaporated in vacuo. The residue was purified by flash column
chromatography (CH2Cl2/MeOH ¼ 20:1) to afford 0.19 g of 15
8. (a) Lingamurthy M, Jagadeesh Y, Ramakrishna K, Rao BV. J Org Chem. 2016;81:
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(b) Davies SG, Lee JA, Roberts PM, Thomson JE, West CJ. Tetrahedron. 2012;68:
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(d) Uraguchi D, Nakamura S, Ooi T. Angew Chem, Int Ed. 2010;49:7562;
(e) Reddy JS, Rao BV. J Org Chem. 2007;72:2224;
(0.59 mmol, 72%) as a colorless oil; ½a D23
ꢃ
ꢀ31.2 (c 1.0, MeOH); IR
(neat)
n 3368, 3063, 3030, 2924, 2852, 1610, 1511, 1455, 1368,
1210 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 7.31e7.19 (m, 7H), 6.58 (d,
(f) Chandrasekhar S, Saritha B, Jagadeshwar V, Prakash SJ. Tetrahedron Asym-
metry. 2006;17:1380;
J ¼ 8.8 Hz, 2H), 4.49 (s, 2H) 3.93e3.89 (m, 2H), 3.82 (s, 3H), 3.70 (d,
J ¼ 5.2 Hz, 1H), 3.38 (dq, J ¼ 7.6, 6.8 Hz, 1H), 2.15 (s, 3H), 1.20 (d,
(g) Goti A, Cicchi S, Mannucci V, et al. Org Lett. 2003;5:4235.
9. (a) Chun JS, Hong SM, Jeon TH, et al. Tetrahedron. 2016;72:8550;
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14. The stereochemistry of 13a was assumed by the full agreement of spectral data
between our synthesized (e)-codonopsinine (1) and cited references 8a and
8e.
J ¼ 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 159.2, 138.0, 131.7,
129.3, 128.3,127.6, 127.5, 113.9, 93.4, 80.6, 72.2, 72.1, 65.9, 55.2, 34.4,
29.7, 11.0; HRMS (FAB) calcd for C20H26O3N [MþH]þ 328.1913,
found 328.1915.
4.13. (ꢀ)-Codonopsinine (1)
To a stirred solution of 15 (0.19 g, 0.58 mmol) and 20% Pd/C
(0.04 g, 20% w/w) in MeOH (6 mL) was shaken for 24 h under 60 psi
hydrogen pressure by using hydrogenator. The reaction mixture
was filtered through
a celite pad and washed with MeOH
(3 ꢂ 10 mL). The filtrate was evaporated in vacuo. The residue was
purified by flash column chromatography (CH2Cl2/MeOH ¼ 9:1)8a
to afford 0.09 g of 1 (0.38 mmol, 63%) as a white solid; m.p.
168e170 ꢁC [Lit.8e m.p. 169e170 ꢁC]; ½a 2D3
ꢃ
ꢀ8.9 (c 0.1, MeOH); [Lit.8e
½
a 2D0
ꢃ
ꢀ8.8 (c 0.1, MeOH)]; IR (neat)
n 3361, 2938, 2361, 1834, 1742,
1698, 1514, 1460 cmꢀ1
; d 7.62 (d,
1H NMR (400 MHz, pyridine-d5)
J ¼ 8.0 Hz, 2H), 6.99 (d, J ¼ 8.0 Hz, 2H), 4.64 (dt, J ¼ 6.4, 6.8 Hz, 1H),
Please cite this article in press as: Choi YJ, et al., Total synthesis of (ꢀ)-codonopsinine via regioselective and diastereoselective amination using
chlorosulfonyl isocyanate, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.06.002