Practical and highly stereoselective approaches to the total synthesis of (-)-codonopsinine

Article abstract of DOI:10.1016/j.tetasy.2006.05.007

The enantiopure total synthesis of (-)-codonopsinine is described using two effective chiron approaches starting either from commercially available l-xylose or from readily available Garner aldehyde. The key steps included Julia trans-olefination, highly

Full text of DOI:10.1016/j.tetasy.2006.05.007

Tetrahedron: Asymmetry 17 (2006) 1380–1386
Practical and highly stereoselective approaches to the total
synthesis of (ꢀ)-codonopsinineI
Srivari Chandrasekhar,* Birudaraju Saritha, Vannada Jagadeshwar and Samala Jaya Prakash
Organic Chemistry Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 28 March 2006; accepted 2 May 2006
Abstract—The enantiopure total synthesis of (ꢀ)-codonopsinine is described using two effective chiron approaches starting either from
commercially available L-xylose or from readily available Garner aldehyde. The key steps included Julia trans-olefination, highly diaste-
reoselective alkylation and cascade epoxidation–cyclization strategies.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
ses use chiral pool starting materials such as sugars and
hydroxy acids.
(ꢀ)-Codonopsinine 1, and (ꢀ)-codonopsine 2 are rather
complex pyrrolidine alkaloids, isolated from Codonopsis
clematidea1 for the first time in 1969.2 These compounds
exhibit antibiotic activity and hypotensive activity without
affecting the central nervous system.3 The total synthesis of
this class of compounds has always interested synthetic
organic chemists, not only because many have significant
biological activity, but also due to their complex structures
and the synthetic challenges they pose. Interest in the syn-
thesis of codonopsine and codonopsinine stems mainly
from their pharmacological activity associated with the
synthetic challenge they constitute in view of their
1,2,3,4,5-pentasubstituted pyrrolidine nucleus bearing four
contiguous stereogenic centres (2R,3R,4R,5R) with substit-
uents trans relative to each other. For the reasons described
above, some elegant synthetic approaches for the synthesis
of (ꢀ)-codonopsinine 1 have been described.4 Most synthe-
Over the course of our programme directed towards the
synthesis of bioactive compounds,5 we herein report in
detail our synthetic endeavour towards the construction
of (ꢀ)-codonopsinine 1 by two effective chiron approaches
starting either from a pentose sugar namely L-xylose 6 or
from D-serine derived Garner’s aldehyde 96 (Scheme 1).
2. Results and discussion
2.1. Synthesis of (ꢀ)-codonopsinine 1 starting from L-xylose
6
The synthesis of (ꢀ)-codonopsinine 1 starting from L-xy-
lose 6 was begun with the transformation of L-(ꢀ)-xylose
6 in to 1,2-O-isopropylidine-a-L-xylofuranose 11 by a
known route.7 The primary alcohol in 11 was selectively
tosylated by treating with p-tosyl chloride and triethyl-
amine in dichloromethane to give 12 in 90% yield, which
on reduction with lithium aluminium hydride in THF
afforded 13 in 88% yield. Protection of the hydroxy group
in 13 using p-methoxybenzyl bromide and NaH in THF
gave 5 in 94% yield, which on hydrolysis of the 1,2-aceto-
nide with catalytic H2SO4 and 60% aq AcOH furnished
14 in 87% yield. Oxidative cleavage of 14 with NaIO4 in
MeOH–H2O (8:2) and subsequent Julia olefination of the
unstable aldehyde 15 with sulfone 16 which was prepared
from p-methoxybenzyl bromide and mercaptobenzothi-
azole,8 gave 4 in 72% yield. The formyl group in compound
HO
OH
R
N
H3C
Me
OMe
1: R = H (-)-Codonopsinine
2: R = OMe (-)-Codonopsine
q IICT Communication No. 050710.
*
Corresponding author. Tel.: +91 40 7193434; fax: +91 40 27160512;
e-mail: srivaric@iict.res.in
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.05.007

S. Chandrasekhar et al. / Tetrahedron: Asymmetry 17 (2006) 1380–1386
OMe
1381
OMe
PMBO
HO
O
OH
OH
HO
PMBO
1
O
HO
O
O
NHBoc
OCHO
L
-xylose 6
5
3
4
OH
OH
CHO
O
HO
O
+
NBoc
OMe
NBoc
HNBoc
OMe
OMe
Garner aldehyde
8a
10
7
9
Scheme 1.
4 was subjected to de-O-formylation with NaBH4 in
MeOH to afford 17 in 97% yield. The hydroxy group in
compound 17 was treated with mesyl chloride and triethyl-
amine in dichloromethane and subsequent azidation with
NaN3 in hot DMF (70 ꢁC) gave 18 in 89% overall yield.
Removal of the PMB group in 18 with ZrCl4 in CH3CN
gave allyl alcohol9 19 in 86% yield. The azide group in 19
was subjected to reduction and protection using PPh3 in
benzene and water at 45 ꢁC followed by exposure to
(Boc)2O to furnish 3 in 88% yield.
of 9:1 with a combined yield of 89% in a single pot trans-
formation (Scheme 2). The absolute stereochemistry of
the newly created diol was confirmed, based on the litera-
ture precedent10 and from the spectral data of the final
compound. The regioselective opening of epoxide with
the internal nitrogen nucleophile in an endo fashion is
facilitated by the 4-methoxy phenyl group which allows
facile benzylic cleavage. The major isomer was easily iso-
lated by flash column chromatography using 38% EtOAc
in hexane. Finally, the Boc group in 20a was converted
to a methyl group using Red-Al in toluene at reflux11
for 2 h to yield (ꢀ)-codonopsinine 1 in 83% yield (Scheme
2).
The allyl alcohol in 3 was epoxidized with m-CPBA in
CH2Cl2 to furnish pyrrolidine diols, 20a and 20b in a ratio
HO
HO
HO
O
PMBO
O
O
O
ref. 7
a
b
c
L-xylose
O
O
O
O
HO
TsO
O
O
O
O
6
12
5
11
13
OPMB
OPMB
PMBO
PMBO
OH
OH
CHO
OCHO
15
f
h
e
g
d
OH
O
OCHO
N
S
O
OMe
OMe
S
4
17
O
14
16
OMe
OH
OH
HO
OH
HO
OH
OPMB
k
j
i
+
N
N
N3
NHBoc
N3
OMe
OMe
OMe
Boc
20b
Boc
OMe
OMe
(9:1)
18
19
3
20a
l
1
Scheme 2. Reagents and conditions: (a) TsCl, Et3N, CH2Cl2, 0 ꢁC to rt, 90%; (b) LiAlH4, THF, 0 ꢁC to rt 88%; (c) PMBBr, NaH, THF, 94%; (d) 60% aq
AcOH, cat. H2SO4, 87%; (e) NaIO4, MeOH–H2O; (f) NaHMDS, THF, ꢀ78 ꢁC, 72% (for steps); (g) NaBH4, MeOH, 97%; (h) (i) MsCl, Et3N, 0 ꢁC; (ii)
NaN3, DMF, 70 ꢁC, 89% (for two steps); (i) ZrCl4, acetonitrile, 86%; (j) (i) TPP, benzene, H2O, 45 ꢁC; (ii) (Boc)2O, Et3N, 88% (for two steps); (k) m-
CPBA, CH2Cl2, 0 ꢁC, 89%; (l) Red-Al, toluene, reflux, 83%.

1382
S. Chandrasekhar et al. / Tetrahedron: Asymmetry 17 (2006) 1380–1386
Br
Br
CHO
a
b
MeO
MeO
MeO
OMe
10
21
22
OH
OH
CHO
c
O
O
O
+
NBoc
+
NBoc
NBoc
OMe
OMe
8b
10
8a
9
(9:1)
OH
OH
HO
e
d
O
8a
HNBoc
NBoc
23
OMe
OMe
7
OH
OH
g
f
O
7
+
HNBoc
NH
OMe
OMe
O
3
24
Scheme 3. Reagents and conditions: (a) CBr4–TPP, Et3N, CH2Cl2, ꢀ30 ꢁC to rt; (b) nBuLi, THF, ꢀ78 ꢁC, 75% (for two steps); (c) nBuLi, THF, ꢀ78 ꢁC,
90%; (d) Red-Al, ether, 0 ꢁC, 89%; (e) 60% aq AcOH, 84%; (f) i. TsCl, Et3N, Bu2SnO, 0 ꢁC; ii. NaBH4, DMSO, 70 ꢁC, 85% (for two steps); (g) (Boc)2O,
then Cs2CO3 0 ꢁC to rt.
2.2. Synthesis of (ꢀ)-codonopsinine 1 starting from Garner’s
molecular cyclization cascade as an efficient sequence for
the synthesis of polyhydroxylated pyrrolidines. The total
synthesis of similar molecules using this strategy is cur-
rently being explored.
aldehyde 9
Initially, anisaldehyde 21 was subjected to the Corey–
Fuchs protocol12 using CBr4 and TPP in dichloromethane
to afford the dibromo olefine 22, which was subsequently
n
treated with BuLi in THF at ꢀ78 ꢁC to yield p-methoxy-
4. Experimental
4.1. General
phenyl acetylene 10 in 75% yield for the two steps. Garner
aldehyde 9, derived from D-serine,6 was reacted with lithi-
ated p-methoxyphenyl acetylide in THF at ꢀ78 ꢁC13 to
produce readily separable acetylene alcohols 8a and 8b in
a 9:1 ratio, respectively (Scheme 3). Acetyleneic alcohol
8a was reduced to allyl alcohol 23 using Red-Al in dry
ether at 0 ꢁC in 89% yield. The acetonide group of 23
was cleanly deprotected using 60% aq AcOH to afford ami-
no protected diol 7. The primary alcohol of diol 7 was
selectively deoxygenated using p-toluene sulfonyl chloride,
triethylamine and Bu2SnO in dichloromethane14 at 0 ꢁC
and subsequently treated with sodium borohydride in
DMSO to afford amino protected alcohol 3 in 85% yield
along with an oxazolidinone 24 as a side product in 10%
yield which was converted to required diol 7 using (Boc)2O
Commercial reagents were used without further purifica-
tion. All solvents were purified by standard techniques.
Infrared (IR) spectra were recorded on Perkin–Elmer 683
spectrometer. Optical rotations were obtained on Jasco
Dip 360 digital polarimeter. Melting points are uncor-
rected. NMR spectra were recorded in CDCl3 and deuter-
ated pyridine solvent on a Varian Gemini 200, Bruker 300
or Varian Unity 400 NMR spectrometers. Chemical shifts
(d) are quoted in ppm and are referenced to the tetrameth-
ylsilane (TMS) as internal standard. Coupling constants (J)
are quoted in hertz. Column chromatographic separations
were carried out on silica gel (60–120 mesh) and flash
chromatographic separation was carried out using
230–400 mesh size silica gel. Mass spectra were obtained
on Finnegan MAT 1020B or micromass VG 70-70H spec-
trometer operating at 70 eV using direct inlet system.
15
followed by treating with Cs2CO3 (Scheme 3).
The alcohol 3 was transformed to (ꢀ)-codonopsinine 1 as
illustrated in Scheme 2.
4.1.1. 6-Hydroxy-2,2-dimethyl-5-(4-methylphenylsulfonyl-
oxymethyl)-(3aS,5S,6R,6aS)-perhydrofuro[2,3-d][1,3]diox-
ole 12. To a stirred solution of diol 11 (5.0 g, 26.3 mmol)
was added triethylamine (9.25 mL, 65.7 mmol) at 0 ꢁC under
a nitrogen atmosphere in DCM was added p-toluenesulf-
onyl chloride (5.01 g, 26.3 mmol) very slowly and the reac-
tion mixture allowed to stir at rt for 24 h. To the reaction
3. Conclusion
In conclusion, two effective chiron approaches have been
described for the synthesis of natural (ꢀ)-codonopsinine
1. We have also shown the effect of a Julia olefination,
highly diastereoselective alkylation and epoxidation–intra-

S. Chandrasekhar et al. / Tetrahedron: Asymmetry 17 (2006) 1380–1386
1383
mixture water, was added and extracted with dichloro-
methane (2 · 100 mL). The combined organic extracts were
washed with water, brine, dried over anhydrous sodium
sulfate and concentrated to yield a crude tosylated com-
pound, which was purified by silica gel column chromato-
graphy using 20% of EA in hexane as an eluent to afford
13C NMR (50 MHz, CDCl3): d 159.1, 129.5, 129.0, 113.6,
110.8, 104.5, 82.5, 82.1, 75.9, 71.1, 55.0, 26.4, 25.9, 13.1;
HRMS calcd for C16H22O5Na [M+Na]+ 317.1364, found
317.1361.
4.1.4. 4-(4-Methoxybenzyloxy)-5-methyl-(3S,4R,5S)-tetra-
hydro-2,3-furandiol 14. Compound 5 was hydrolyzed
using 60% AcOH (40 mL) and catalytic amount of concen-
trated H2SO4. The reaction mixture was stirred at room
temperature for 12 h. After completion of the reaction
the reaction mixture was diluted with ethyl acetate and
stirred for 30 min. after which it was extracted with ethyl
acetate (3 · 100 mL). The combined organic layers were
neutralized with solid NaHCO3 and stirred for one more
hour, then filtered. The organic layer was separated and
concentrated to afford a residue, which was purified by col-
umn chromatography on silica gel (EA/hexane in 4/6) to
furnish pure compound 14 (3.38 g, 87% yield) as a colour-
less syrup. Compound 14 colourless syrup: 1H NMR
(200 MHz, CDCl3): d 7.20 (d, J = 12.3 Hz, 2H), 6.78 (d,
J = 12.3 Hz, 2H), 5.36 (s, 1H), 4.55 (d, J = 12.3 Hz, 1H),
4.38–4.22 (m, 2H), 4.12–4.05 (m, 1H), 3.75 (s, 3H), 3.66
(s, 1H), 1.15 (d, 3H); 13C NMR (50 MHz, CDCl3): d
159.2, 129.2, 127.9, 114.5, 99.4, 82.6, 78.2, 75.3, 71.2,
55.3, 13.2; HRMS calcd for C13H18O5Na [M+Na]+
277.1051, found 277.1047.
compound 12 (8.16 g, 90% yield) as a semi-solid. Com-
20
pound 12 semi-solid: ½aꢁD ¼ þ13:8 (c 1.0, CH3OH); IR
(neat): 3498, 2930, 1360, 1176, 1074 cmꢀ1 1H NMR
;
(200 MHz, CDCl3): d 7.80 (d, J = 6.8 Hz, 2H), 7.35 (d,
J = 6.8 Hz, 2H), 5.80 (s, 1H), 4.47 (s, 1H), 4.34–4.25 (m,
3H), 4.10–3.98 (m, 1H), 2.45 (s, 3H), 1.45 (s, 3H), 1.28 (s,
3H); 13C NMR (50 MHz, CDCl3): d 145.2, 132.2, 129.9,
127.9, 112.0, 104.9, 84.9, 77.5, 74.1, 66.4, 26.7, 26.1, 21.6;
HRMS calcd for C15H21O7S [M+H]+ 345.1008, found
345.1012.
4.1.2. 2,2,5-Trimethyl-(3aS,5S,6R,6aS)-perhydrofuro[2,3-d]-
[1,3]dioxol-6-ol 13. To a cooled mechanically stirred
suspension of powdered LAH (1.76 g, 46.3 mmol) in anhy-
drous THF (80 mL) was added slowly a compound 12 (8 g,
23.1 mmol) in anhydrous THF (30 mL). After addition was
completed the reaction mixture stirred for 4 h and then
excess LAH was quenched by sequential addition of water,
15% NaOH solution and water. The mixture was filtered
and the solids were extracted with ethyl acetate. The com-
bined organic extracts were dried over anhydrous sodium
sulfate and concentrated to furnish methyl compound 13
(3.54 g, 88% yield). Purification on silica gel column chro-
matography using 22% of EA in hexane as an eluent affor-
4.1.5.
2-(4-Methoxybenzyloxy)-4-(4-methoxyphenyl)-1-
methyl-(1S,2S,3E)-3-butenyl formate 4. To a solution of
compound 14 (3 g, 11 mmol) in methanol and water (8:2)
was added NaIO4 (6.31 g, 29 mmol) at 0 ꢁC. The reaction
mixture was brought to rt and allowed to stir for 4 h.
The methanol was then removed under reduced pressure
and the residue extracted with CHCl3 (3 · 100 mL). Com-
bined organic layers were washed with water, brine and
dried over anhydrous sodium sulfate. The solvent was
removed under vacuum to yield the crude aldehyde, which
was used for further reaction. To a stirred solution of the
sulfone 16 (3.67 g, 11.5 mmol) in anhydrous THF at
ꢀ78 ꢁC under nitrogen atmosphere was added NaHDMS.
The mixture was then stirred for 30 min before addition
of the above crude aldehyde in anhydrous THF (5 mL).
After stirring for a further 3 h at ꢀ78 ꢁC the reaction mix-
ture was allowed to warm to rt and stirred for 3 h where
upon water and ether were added and the mixture was sha-
ken well. The organic layer was separated, dried over anhy-
drous sodium sulfate and concentrated under reduced
pressure, after which the crude residue was purified by sil-
ica gel column chromatography using EA/hexane (1:9) as
an eluent to furnish compound 15 (2.94 g, 72% yield) as a
ded pure compound 13 as a colourless liquid. Compound
20
13 colourless liquid: ½aꢁD ¼ þ22:4 (c 1.0, CH3OH); IR
(neat): 3445, 2989, 2938, 1385, 1011 cmꢀ1 1H NMR
;
(200 MHz, CDCl3): d 5.85 (s, 1H), 4.45 (s, 1H), 4.30–4.21
(m, 1H), 3.88 (br s, 1H), 1.48 (s, 3H), 1.45 (s, 3H), 1.26
(s, 3H); 13C NMR (50 MHz, CDCl3): d 109.6, 104.2,
81.9, 79.2, 72.8, 26.3, 26.1, 13.5; HRMS calcd for
C8H14O5 [M]+ 174.0892, found 174.0894.
4.1.3.
6-(4-Methoxybenzyloxy)-2,2,5-trimethyl-(3aS,5S,-
6R,6aS)-perhydrofuro[2,3-d][1,3]dioxole 5. To a stirred
suspension of freshly activated NaH (1.24 g, 51 mmol)
(60% w/v dispersion in mineral oil) in anhydrous THF
(60 mL) was added alcohol 13 (3 g, 17.2 mmol) in dry
THF (20 mL) at 0 ꢁC. After 30 min, p-methoxybenzyl bro-
mide (4.15 g, 20 mmol) was added and the reaction mixture
brought to room temperature and stirred for 12 h. Ice
pieces were then added to quench the reaction and then
the THF was separated and the aq layer extracted with
ether (3 · 100 mL). The combined organic layers were
washed with water, brine and dried over anhydrous sodium
sulfate. After removing the volatiles under reduced pres-
sure, crude p-methoxybenzyl ether was purified by silica
gel column chromatography using 10% EA in hexane as
colourless liquid. Compound
4
colourless liquid:
20
½aꢁD ¼ þ17:7 (c 1.0, CH3OH); IR (neat): 1706, 1607,
1
1510, 772 cmꢀ1; H NMR (200 MHz, CDCl3): d 8.10 (s,
1H), 7.39–7.20 (m, 4H), 6.86–6.82 (m, 4H), 6.58 (d,
J = 15.5 Hz, 1H), 5.94 (dd, J = 8.1, 14.6 Hz, 1H), 5.18–
5.02 (m, 1H), 4.62 (d, J = 9.8 Hz, 1H), 4.38 (d,
J = 9.8 Hz, 1H), 3.86 (t, J = 4.0 Hz, 1H), 3.80 (s, 6H),
1.28 (d, J = 6.5 Hz, 3H); 13C NMR (50 MHz, CDCl3): d
160.8, 159.7, 159.2, 130.2, 129.9, 129.4, 129.3, 127.8,
126.9, 113.8, 113.6, 81.0, 74.5, 72.4, 55.3, 55.2, 16.3; HRMS
calcd for C21H24O5Na [M+Na]+ 379.1521, found
379.1523.
an eluent to furnish 5 (4.75 g, 94% yield) as a colourless
20
liquid. Compound 5 colourless liquid: ½aꢁD ¼ þ20:3 (c 1,
CH3OH); IR (neat): 2989, 2936, 1613, 1514, 1249 cmꢀ1
;
1H NMR (200 MHz, CDCl3): d 7.20 (d, J = 6.8 Hz, 2H),
6.82 (d, J = 6.8 Hz, 2H), 5.82 (s, 1H), 4.62–4.50 (m, 2H)
4.38 (d, J = 6.2 Hz, 1H), 4.30–4.20 (m, 1H), 3.78 (s, 3H),
3.65 (br s, 1H), 1.45 (s, 3H), 1.28 (s, 3H), 1.24 (s, 3H);

1384
S. Chandrasekhar et al. / Tetrahedron: Asymmetry 17 (2006) 1380–1386
4.1.6.
3-(4-Methoxybenzyloxy)-5-(4-methoxyphenyl)-
3.3 mmol) in dry acetonitrile was added ZrCl4 (0.67 mmol)
and the mixture stirred at rt for 2 h. The solvent was re-
moved under reduced pressure and the residue treated with
ethyl acetate (20 mL). This was washed with water, brine,
dried over anhydrous sodium sulfate and concentrated
under reduced pressure. The residue was purified by
column chromatography on silica gel using EA/hexane
(1:9) as an eluent to furnish the alcohol 19 (681 mg, 86%
(2S,3S,4E)-4-penten-2-ol 17. Compound 4 (2.8 g, 7.80
mmol) was taken in methanol (30 mL), and cooled to
0 ꢁC at which point NaBH4 (3.8 g, 11 mmol) was added
in small portions under a nitrogen atmosphere. After com-
plete addition, the reaction mixture was brought to room
temperature and allowed to stir for 2 h. Methanol was re-
moved under reduced pressure, and the residue was dis-
solved in water and extracted with CHCl3. The combined
organic layers were washed with aq NaHCO3, water, brine,
dried over anhydrous sodium sulfate and concentrated to
give crude residue which was purified by column chroma-
tography on silica gel using 20% of EA in hexane to afford
yield) as a viscous liquid. Compound 19 viscous liquid:
25
½aꢁD ¼ þ17:1 (c 0.8, MeOH); IR (KBr): 2103, 3446 cmꢀ1
;
1H NMR (200 MHz, CDCl3): d 7.31 (d, J = 10.8 Hz,
2H), 6.84–6.72 (m, 2H), 6.64 (d, J = 15.5 Hz, 1H), 6.31
(dd, J = 8.1, 15.5 Hz, 1H), 3.84–3.78 (m, 1H), 3.82 (s,
3H), 3.58–3.49 (m, 1H), 1.22 (d, J = 7.3 Hz, 3H); 13C
NMR (50 MHz, CDCl3): d 154.5, 131.8, 126.2, 120.9,
113.1, 112.8, 77.8, 60.6, 55.2, 14.5; HRMS calcd for
C12H15N3O2 [M+H]+ 234.1242, found 234.1245.
alcohol 17 (2.4 g, 97% yield) as a colourless liquid. Com-
20
pound 17 colourless liquid: ½aꢁD ¼ þ74:7 (c 1.1, CH3OH);
IR (neat): 3559, 1608, 1510, 1249, 1034 cmꢀ1; H NMR
1
(200 MHz, CDCl3): d 7.35 (d, J = 10.8 Hz, 2H), 7.28–
7.20 (m, 3H), 6.78 (d, J = 10.8 Hz, 3H), 6.58 (d,
J = 16.8 Hz, 1H), 5.90 (dd, J = 12, 18 Hz, 1H), 4.60 (d,
J = 12 Hz, 1H), 4.32 (d, J = 12 Hz, 1H), 3.82 (s, 3H) 3.80
(s, 3H), 3.78–3.70 (m, 1H), 3.64 (t, J = 10.8 Hz, 1H), 1.14
(d, J = 5.8 Hz, 3H); 13C NMR (50 MHz, CDCl3): d
159.4, 159.1, 134.4, 130.0, 129.4, 128.8, 127.6, 124.0,
113.6, 113.5, 85.4, 69.8, 55.1, 55.0, 29.5, 18.3; HRMS calcd
for C20H25O4 [M+H]+ 329.1752, found 329.1748.
4.1.9. 2-[tert-Butoxy carbonylamino]-(2R,3S,4E)-5-(4-meth-
oxyphenyl)-pent-4-en-3-ol 3. To a stirred solution of com-
pound 19 (500 mg, 2.1 mmol) in benzene (10 mL) at 45 ꢁC
was added TPP (1.12 g, 4.2 mmol). After 30 min, water was
added and stirring continued at 45 ꢁC for 11 h. The mixture
was cooled to room temperature and extracted with ethyl
acetate, washed with saturated NH4Cl, dried over anhy-
drous sodium sulfate, filtered and concentrated to give
the amine product (350 mg) which was used without any
for further purification for the subsequent reaction. To a
solution of the above crude amine (300 mg, 1.6 mmol) in
dry THF (20 mL) were added triethyl amine (0.35 mL,
2.5 mmol) and (Boc)2O (442 mg, 2.0 mmol) at 0 ꢁC. The
mixture was stirred at rt for 12 h. The solvent was evapo-
rated under vacuum and the residue was purified by col-
umn chromatography on silica gel (EA/hexane 2/8) to
4.1.7. 1-[4-Azido-3-(4-methoxybenzyloxy)-(E,3S,4R)-1-pen-
tenyl]-4-methoxybenzene 18. To a stirred solution of alco-
hol 17 (2.3 g, 7 mmol) in dry DCM at ꢀ10 ꢁC temperature,
was added triethyl amine (1.47 mL, 10.5 mmol) under a
nitrogen atmosphere. To this was added methanesulfonyl
chloride (0.65 mL, 8.4 mmol) very slowly. The reaction
mixture was allowed to stir at room temperature for 2 h.
The reaction mixture was then poured into crushed ice
and extracted with DCM. The combined organic extracts
were washed with water, brine, dried over anhydrous
Na2SO4 and concentrated to yield the mesylate (2.8 g) as
a pale yellow liquid. It was used as such without any
further purification for the following step.
give compound 3 (0.45 g, 88% yield) as a semi-solid. Com-
25
pound 19 semi-solid: ½aꢁD ¼ ꢀ12:6 (c 0.5, MeOH); IR
(neat) : 3552, 1710, 1695, 1512, 1248 cmꢀ1 1H NMR
;
(200 MHz, CDCl3): d 7.35 (d, J = 10.8 Hz, 2H), 6.85 (d,
J = 10.8 Hz, 2H), 6.55 (d, J = 15.6 Hz, 1H), 6.06 (dd,
J = 8.1, 15.6 Hz, 1H), 4.65–4.55 (m, 1H), 4.30–4.10 (m,
1H), 3.80 (s, 3H), 1.40 (s, 9H), 1.15 (d, J = 8.2 Hz, 3H);
13C NMR (50 MHz, CDCl3): d 153.4, 149.2, 128.9, 125.1,
121.8, 112.1, 110.9, 77.2, 71.3, 62.1, 55.4, 20.5, 14.5; HRMS
calcd for C17H26NO4 [M]+ 307.1783, found 307.1780.
A solution of mesylate (2.6 g, 6.4 mmol) in dry DMF
(10 mL) was heated at 80 ꢁC with NaN3 (832 mg,
12.8 mmol) for 6 h. The reaction mixture was brought to
room temperature and diluted with water and extracted
with ether. The combined ether layers were washed with
water, brine, dried over anhydrous Na2SO4, concentrated
and on purification by silica gel column chromatography
(EA/hexane in 1/9) yielded azide 18 (1.5 g, 89%) as a
4.1.10. tert-Butyl 3,4-dihydroxy-2-(4-methoxyphenyl)-5-
methyl-(2R,3R,4R,5R)-tetrahydro-1H-1-pyrrolecarboxylate
20a. To a stirred solution of compound 3 (0.3 g,
0.97 mmol) in dry DCM (50 mL) was added m-CPBA
(0.33 g, 1.9 mmol) in dry CH2Cl2 (10 mL) over a period
of 10 min at 0 ꢁC. The reaction mixture was brought to
room temperature and allowed to stir for 4 h. After com-
pletion of the reaction saturated solution of NaHCO3
was added and stirred for 30 min, then extracted in CH2Cl2
(3 · 100 mL) and the combined organic layers washed with
water, brine and dried over anhydrous sodium sulfate. The
solvent was removed under reduced pressure and the resi-
due was purified by column chromatography on silica gel
using 25% of EA in hexane to give cyclized compound
colourless liquid. Compound 18 colourless liquid:
25
½aꢁD ¼ 70:2 (c 0.5, MeOH); IR (neat) : 2103, 1608, 1512,
1034, 772 cmꢀ1 1H NMR (200 MHz, CDCl3): d 7.35–
;
7.18 (m, 4H), 6.88–6.79 (m, 4H), 6.48 (d, J = 15.5 Hz,
1H), 5.95 (dd, J = 8.1, 14.6 Hz, 1H), 4.58 (d, J = 8.9 Hz,
1H), 4.35 (d, J = 8.9 Hz, 1H), 3.88–3.77 (m, 7H), 3.58–
3.49 (m, 1H), 1.22 (d, J = 7.3 Hz, 3H); 13C NMR
(50 MHz, CDCl3): d 159.5, 159.0, 134.5, 130.1, 129.2,
128.9, 127.8, 123.4, 114.0, 113.7, 82.7, 69.9, 60.7, 55.3,
55.2, 15.2; HRMS calcd for C20H24N3O3 [M+H]+
354.1817, found 354.1815.
20a (252 mg, 90% of 89 % yield) as a semi-solid. Com-
25
4.1.8. 4-Azido-1-(4-methoxyphenyl)-(E,3S,4R)-1-penten-3-ol
19. To a stirred solution of PMB ether 18 (1.2 g,
pound 20a semi-solid: ½aꢁD ¼ ꢀ50:2 (c 1, MeOH); 1H
NMR (300 MHz, CDCl3): d 7.16 (d, J = 9.2 Hz, 2H),

S. Chandrasekhar et al. / Tetrahedron: Asymmetry 17 (2006) 1380–1386
1385
6.88 (d, J = 9.2 Hz, 2H), 4.55 (br s, 1H), 3.99 (m, 2H), 3.80
(m, 4H), 1.38 (d, J = 6.0 Hz, 3H), 1.25 (s, 9H); 13C NMR
(75 MHz): d 158.7, 154.0, 134.6, 127.3, 113.8, 81.7, 79.6,
60.6, 59.3, 55.2, 28.0, 17.7; HRMS calcd for C17H25NO5Na
[M+Na]+ 332.1599, found 332.1603.
ture was allowed to warm at 30 ꢁC and stirred for
30 min. The reaction mixture was again cooled to ꢀ78 ꢁC
and to this was added Garner aldehyde 9 (2 g, 8.7 mmol)
in THF over a period of 15 min and stirred for 3 h at
ꢀ78 ꢁC and then quenched by the addition of saturated
NH4Cl. The organic layers were extracted with ethyl ace-
tate (3 · 100 mL). The combined organic layers were
washed with water, brine and dried over anhydrous sodium
sulfate. The solvent was removed under reduced pressure
and the residue purified by column chromatography on sil-
ica gel (EA/hexane 2/8) to afford compound 8a (2.74 g,
4.1.11. (ꢀ)-Codonopsinine 1. To a solution of compound
20a (180 mg, 0.5 mmol) in dry toluene (20 mL) was added
dropwise sodium bis-(2-methoxyethoxy)-aluminium hy-
dride (70% in toluene) (563 g, 2.7 mmol) under an ice cold
temperature. The reaction mixture was heated at reflux for
2 h and then treated with ethanol and water under ice cool-
ing. The insoluble material was removed by filtration; the
filtrate was extracted with ethyl acetate. The organic layer
was dried over anhydrous sodium sulfate and evaporated
under reduced pressure the residue was purified by column
chromatography on silica gel [MeOH/CHCl3 (1:9)] to give
87% yield) as a colourless liquid. Compound 8a colour-
25
less liquid: ½aꢁD ¼ þ26:8 (c 1.4, MeOH); IR (KBr): 3443,
2979, 2936, 2225, 1694 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d 7.35 (d, J = 8.3 Hz, 2H), 6.83 (d, J = 8.3 Hz, 2H), 4.75–
4.65 (m, 1H), 4.30–4.10 (m, 2H), 4.00–3.90 (m, 1H), 3.80
(s, 3H), 1.65 (s, 3H), 1.55 (s, 3H), 1.50 (s, 9H); 13C NMR
(75 MHz, CDCl3): d 154.5, 149.0, 128.0, 109.5, 108.5,
90.0, 80.5, 76.2, 60.5, 59.5, 57.5, 50.2, 23.5, 20.8, 20.5;
HRMS calcd for C20H28NO5 [M+H]+ 362.1967, found
332.1973.
compound 1 (109 mg, 83% yield) as a white solid. Com-
25
pound 1: white solid, mp 168–171 ꢁC; ½aꢁD ¼ ꢀ12:4 (c
20
0.4, MeOH), lit.1 mp 169–170 ꢁC, ½aꢁD ¼ ꢀ8:8 (c 0.1,
MeOH); 1H NMR (300 MHz, pyridine-d5): d 7.60 (d,
J = 8.4 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 4.63 (br t,
J = 3.0, 7.2 Hz, 1H), 4.38 (br t, J = 3.0, 7.2 Hz, 1H), 4.08
(br d, J = 6.0 Hz, 1H), 3.70–3.60 (m, 4H), 2.22 (s, 3H),
1.30 (d, J = 6.0 Hz, 3H); 13C NMR (75 MHz pyridine-
d5): d 159.5, 135.3, 130.0, 114.2, 86.7, 84.7, 74.2, 65.2,
55.1, 34.7, 13.9; HRMS calcd for C13H20NO3 [M+H]+
238.1443, found 238.1439.
4.1.14. tert-Butyl 4-[1-hydroxy-3-(4-methoxyphenyl)-(1S,2E)-
2-propenyl]-2,2-dimethyl-(4R)-1,3-oxazolane-3-carboxylate
23. To a solution of sodium bis (2-methoxyethoxy)
aluminium hydride (9.99 mL, 34.6 mmol, 70% in toluene)
in dry ether (30 mL) at 0 ꢁC under a nitrogen atmosphere
was added compound 8a (2.5 g, 6.9 mmol) in ether
(10 mL) and the reaction mixture allowed to stir for 1 h
at 0 ꢁC. The reaction was quenched by the addition of eth-
anol (two drops) and a saturated solution of potassium
sodium tartarate, then extracted in ether (3 · 100 mL).
The combined organic layers were washed with water,
brine and dried over anhydrous sodium sulfate. The resi-
due was purified by silica gel column chromatography
4.1.12. 1-(1-Ethynyl)-4-methoxybenzene 10. To a solution
of CBr4 (14.6 g, 44.0 mmol) in dry CH2Cl2 (100 mL) under
nitrogen was dropwise added at ꢀ30 ꢁC a solution of TPP
(25.0 g, 88 mmol) over a period of 20 min. The mixture was
allowed to stir for a further 30 min at ꢀ30 ꢁC. Then a solu-
tion of aldehyde 21 (3.0 g, 22.0 mmol) in dry CH2Cl2
(10 mL) was added dropwise to the resultant red coloured
solution. The reaction mixture was allowed to warm up to
30 ꢁC over a period of 3 h. The resultant precipitate was fil-
tered and the filtrate concentrated in vacuum to give the
crude product, which was run through a filter column to
give the dibromo olefin 22. The dibromo olefin 22 (4.0 g,
13.69 mmol) was taken in anhydrous THF at ꢀ78 ꢁC and
to this was added n-BuLi (21 mL, 1.5 M solution in hexane,
34.24 mmol) dropwise over a period of 10 min. The reac-
tion mixture was allowed to warm to 30 ꢁC and quenched
with saturated ammonium chloride solution. The aqueous
layer was extracted with ethyl acetate (3 · 50 mL), washed
with water, brine, dried over sodium sulfate and concen-
trated. The crude product was purified to give the title com-
pound 10 (1.45 g) as a liquid in 75% yield for two steps.
(EA–hexane 1:4) to afford compound 23 (2.2 g, 89%
25
yield). Compound 23: ½aꢁD ¼ ꢀ15:1 (c 1.9, MeOH); IR
(KBr) : 3445, 2978, 1691, 1381, 1101 cmꢀ1 1H NMR
;
(300 MHz, CDCl3): d 7.32–7.24 (m, 2H), 6.80 (d,
J = 8.3 Hz, 2H), 6.58 (d, J = 15.6 Hz, 1H), 6.08–5.98 (m,
1H), 4.41–3.88 (m, 4H), 3.80 (s, 3H), 1.48 (br s, 15H);
13C NMR (75 MHz, CDCl3): d 149.0, 131.0, 127.8,
126.5, 114.2, 108.5, 94.5, 81.2, 74.5, 65.0, 62.2, 55.3,
28.5, 26.7, 24.5; HRMS calcd for C20H29NO5Na
[M+Na]+ 386.1943, found 386.1949.
4.1.15. 2-[tert-Butylcarbonylamino]-(2R,3S,4E)-5-(4-meth-
oxyphenyl)-pent-4-ene-1,3-diol 7. Compound 23 was
hydrolyzed using 60% aq AcOH (30 mL) and the reaction
mixture stirred at room temperature for 12 h. After com-
pletion of the reaction, ethyl acetate was added and stirred
for 30 min then extracted with ethyl acetate. The combined
organic layers were neutralized with solid NaHCO3 and
stirred for a further hour, then filtered and concentrated
to afford the residue, which was purified by column chro-
matography on silica gel (EA–hexane 1:2) to give com-
1
Compound 10: H NMR (200 MHz, CDCl3): d 7.39–7.42
(m, 2H), 6.80–6.90 (m, 2H), 3.85 (s, 3H), 2.85 (s, 1H);
13C NMR (50 MHz, CDCl3): d 149.5, 129.1, 126.3, 119.8,
88.7, 79.1, 55.4; HRMS calcd for C9H8O [M]+ 132.0575,
found 132.0577.
4.1.13. tert-Butyl 4-[1-hydroxy-3-(4-methoxyphenyl)-(1S)-2-
propynyl]-2,2-dimethyl-(4R)-1,3-oxazolane-3-carboxylate 8a.
To a solution of p-methoxy phenyl acetylene 10 (1.38 g,
10.4 mmol) in freshly distilled THF at ꢀ78 ꢁC under
nitrogen atmosphere was added n-BuLi (6.55 mL,
10.4 mmol, 1.6 M solution in hexane). The reaction mix-
pound 7 (1.5 g, 84% yield) as a semi-solid. Compound
25
7 semi-solid: ½aꢁD ¼ ꢀ20:2 (c 1.4, CH3OH); IR (KBr):
3424, 2925, 1607 cmꢀ1 1H NMR (300 MHz, CDCl3): d
;
7.35 (d, J = 8.3 Hz, 2H), 6.87 (d, J = 8.3 Hz, 2H), 6.65
(d, J = 15.8 Hz, 1H), 6.20–6.00 (m, 1H), 5.40–5.32 (m,
1H), 4.60–4.50 (m, 1H), 4.10–4.00 (m, 1H), 3.85 (s, 3H),

1386
S. Chandrasekhar et al. / Tetrahedron: Asymmetry 17 (2006) 1380–1386
3.80–3.70 (m, 1H), 1.42 (br s, 9H); 13C NMR (50 MHz,
CDCl3): d 152.1, 147.2, 129.6, 127.1, 123.4, 112.1, 109.8,
78.9, 72.1, 65.2, 63.7, 55.1, 22.1; HRMS calcd for
C17H25NO5Na [M+Na]+ 346.3789, found 346.3782.
P.; Tejero, T. Org. Lett. 2003, 5, 4235–4238; (f) Oliveira, D.
F.; Severino, E. A.; Correia, C. R. D. Tetrahedron Lett. 1999,
40, 2083–2086; (g) Wang, C. L. J.; Calabrese, J. C. J. Org.
Chem. 1991, 56, 4341–4343; (h) Iida, H.; Yamazaki, N.;
Kibayashi, C. J. Org. Chem. 1987, 52, 1956–1962; (i) Iida, H.;
Yamazaki, N.; Kibayashi, C. Tetrahedron Lett. 1985, 26,
3255–3258, This reference actually marks the first total
synthesis of the unnatural (+)-codonopsinine. However, the
stereochemical representation for (+)-codonopsinine made in
this work was latter revised; see Ref. 2.
Acknowledgements
B.S., V.J. and S.J. thank the CSIR, New Delhi, for a
research fellowship.
5. Chandrasekhar, S.; Jagadeshwar, V.; Prakash, S. J. Tetra-
hedron Lett. 2005, 46, 3127–3129.
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