Total synthesis of the alkaloid (-)-codonopsinine from L-xylose

Article abstract of DOI:10.1016/j.tetlet.2005.02.140

The enantiopure total synthesis of (-)-codonopsinine is described from commercially available L-xylose in 20% overall yield. The key steps included Julia trans olefination and cascade epoxidation-cyclisation strategies.

Full text of DOI:10.1016/j.tetlet.2005.02.140

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3127–3129
Total synthesis of the alkaloid (ꢀ)-codonopsinine from L-xyloseI
S. Chandrasekhar,* V. Jagadeshwar and S. Jaya Prakash
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 22 December 2004; revised 11 February 2005; accepted 18 February 2005
Available online 18 March 2005
Abstract—The enantiopure total synthesis of (ꢀ)-codonopsinine is described from commercially available L-xylose in 20% overall
yield. The key steps included Julia trans olefination and cascade epoxidation–cyclisation strategies.
Ó 2005 Elsevier Ltd. All rights reserved.
The total synthesis of alkaloids has always fascinated
synthetic organic chemists, not only because many have
significant biological activity, but also due to their
complex structures and the synthetic challenges they
pose. (ꢀ)-Codonopsinine 1 and (ꢀ)-codonopsine 2 are
two such alkaloids isolated from Codonopsis clemati-
dea1 in 1969, their structures with absolute stereochem-
istry being reported in 1972 by the same group.2
Despite the fact that these compounds were isolated
three decades ago, they continue to attract both syn-
thetic and medicinal chemists due to the challenging
penta-substituted pyrrolidine nucleus (four asymmetric
carbons with substituents trans relative to each other)
and varied biological activity as antibiotics and as anti-
hypertensive agents without any effect on the central
nervous system.3 Some elegant synthetic approaches
for the synthesis of (ꢀ)-codonopsinine 1 have been
described.4
Our continued interest in the chiral synthesis of bioac-
tive compounds following a chiron approach prompted
us to explore the possibility of synthesising (ꢀ)-codon-
opsinine starting from a pentose sugar namely L-xylose
(Scheme 1).
For the synthesis of (ꢀ)-codonopsinine 1, L-(ꢀ)-xylose
was transformed by a known route in to 1,2-O-isopro-
pylidine-a-L-xylofuranose 7.5 The primary alcohol in 7
was selectively tosylated by treating with p-tosyl chlo-
ride and triethylamine in dichloromethane giving 8 in
90% yield, which on reduction with lithium aluminium
hydride in THF afforded 9 in 88% yield. Protection of
the hydroxy group in 9 using p-methoxybenzyl bromide
(PMBBr) and NaH in THF gave 5 in 94% yield, which
on hydrolysis of the 1,2-acetonide with catalytic H2SO4
and 60% aq AcOH furnished 10 in 87% yield. Oxidative
cleavage of 10 with NaIO4 in MeOH–H2O (8:2) and
subsequent Julia olefination of the unstable aldehyde
11 with sulfone 12 which was prepared from p-meth-
oxybenzyl bromide and mercaptobenzothiazole6 gave
4 in 72% yield. The formyl group in compound 4 was
subjected to de-O-formylation with NaBH4 in MeOH
to afford 13 in 97% yield. The hydroxy group in com-
pound 13 was treated with mesyl chloride and
triethylamine in dichloromethane and subsequent
azidation with NaN3 in hot DMF (70 °C) gave 14 in
89% overall yield.
HO
H3C
OH
R
N
CH3
OMe
1: R = H (-)-codonopsinine
2: R = OMe (-)-codonopsine
Removal of the PMB group in 14 with ZrCl4 in CH3CN
gave allyl alcohol7 15 in 86% yield. The azide group in 15
was subjected to reduction and protection using PPh3 in
benzene and water at 45 °C followed by exposure to
(Boc)2O furnishing 3 in 88% yield. The allyl alcohol in
3 was epoxidised with m-CPBA in CH2Cl2 to furnish
Keywords: Julia olefination; Intramolecular cyclisation.
q IICT Communication No. 041224.
*
Corresponding author. Tel.: +91 40 27193434; fax: +91 40
27160512; e-mail: srivaric@iict.res.in
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.140

3128
S. Chandrasekhar et al. / Tetrahedron Letters 46 (2005) 3127–3129
HO
H3C
OH
OMe
HO
N
CH3
NHBoc
OMe
(-)-Codonopsinine
1
3
OMe
PMBO
PMBO
HO
O
OH
OH
O
HO
O
O
OCHO
6
5
4
L-Xylose
Scheme 1.
HO
O
O
HO
O
HO
O
PMBO
O
ref. 5
b
a
O
c
L-xylose
O
HO
TsO
O
O
O
O
O
7
8
5
9
6
OPMB
OPMB
PMBO
PMBO
OH
OH
h
g
CHO
OCHO
e
d
f
OH
O
OMe
N
S
OCHO
O
13
S
OMe
O
4
OMe
1
10
12
HO
OH
HO
OH
OH
OH
OPMB
j
k
i
+
N
N
N3
NHBoc
N3
OMe
OMe
OMe
Boc
OMe
Boc
OMe
15
14
16a
16
3
(9:1)
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. H2O4, 87%; (e) NaIO4, MeOH–H2O; (f) NaHMDS, THF, ꢀ78 °C, 72% (for two 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%.
pyrrolidine diols, 16 and 16a in a ratio of 9:1 with a com-
bined yield of 89% in a single pot transformation. The
absolute stereochemistry of the newly created diol was
confirmed based on literature precedence8 and by the
spectral data of the final compound. The major compar-
ison with isomer was easily isolated by flash column
chromatography using 38% EtOAc in hexane. Finally,
the Boc group in 16 was converted to a methyl group
using red-Al in toluene under reflux9 for 2 h yielding
(ꢀ)-codonopsinine10 in 83% yield (Scheme 2).
Acknowledgements
V.J. and S.J.P. thank CSIR, New Delhi for financial
assistance. S.C.S. thanks DST, New Delhi for funding
the project.
Supplementary data
Supplementary data associated with this article can be
found, in the online version at doi:10.1016/j.tetlet.
2005.02.140.
In conclusion, we have shown how a Julia olefination
and epoxidation–intramolecular cyclisation cascade
can provide an extremely convenient strategy for the
synthesis of polyhydroxylated pyrrolidines. The total
synthesis of similar molecules using this strategy is
currently being pursued.
References and notes
1. (a) Matkhalikova, S. F.; Malikov, V. M.; Yunusov, S. Y.
Khim. Prir. Soedin 1969, 5, 606–607; Chem. Abstr. 1970,

S. Chandrasekhar et al. / Tetrahedron Letters 46 (2005) 3127–3129
3129
20
169–170 °C, ½aꢁD ꢀ8.8 (c 0.1, MeOH); 1H NMR
73, 25712d; (b) Matkhalikova, S. F.; Malikov, V. M.;
Yunusov, S. Y. Khim. Prir. Soedin 1969, 5, 30–32; Chem.
Abstr. 1969, 71, 13245z.
(300 MHz, pyridine-d5):
d
7.60 (d, 2H, J =
8.4 Hz), 6.96 (d, 2H, J = 8.4 Hz), 4.63 (br t, 1H, J = 3.0,
7.2 Hz), 4.38 (br t, 1H, J = 3.0, 7.2 Hz), 4.08 (br d, 1H,
J = 6.0 Hz), 3.70–3.60 (m, 4H), 2.22 (s, 3H), 1.30 (d, 3H,
J = 6.0 Hz); 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, 13.8;
MS (FAB): m/z M+ 238, 222, 176, 121, 107, 95. HRMS
(FAB) for C13H20NO3, calculated (M+1) 238.1443. Found
238.1439.
2. Yagudaev, M. R.; Matkhalikova, S. F.; Malikov, V. M.;
Yunusov, S. Y. Khim. Prir. Soedin 1972, 8, 495–498,
Chem. Abstr. 1972, 77, 16490m.
3. (a) Matkhalikova, S. F.; Malikov, V. M.; Yugadaev, M.
R.; Yunosov, S. Y. Farmakol. Alkaloidov Serdech. Glikoy-
idov 1971, 210, Chem. Abstr. 1972, 77, 135091r; (b) Iida,
H.; Yamazaki, N.; Kibayashi, C. Tetrahedron Lett. 1986,
27, 5393–5396.
4. (a) Haddad, M.; Larcheveque, M. Synlett 2003, 274–276;
(b) Toyao, A.; Tamura, O.; Takagi, H.; Ishibashi, H.
Synlett 2003, 35–38; (c) Yoda, H.; Nakajima, T.; Takabe,
K. Tetrahedron Lett. 1996, 37, 5531–5534; (d) Severino, E.
A.; Correia, C. R. D. Org. Lett. 2000, 2, 3039–3042; (e)
Goti, A.; Cicchi, S.; Mannucci, V.; Cardona, F.; Guarna,
F.; Merino, 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.
5. (a) Wang, Z.; Wiebe, L. I.; Balzarini, J.; Clercq, E. D.;
Knaus, E. E. J. Org. Chem. 2000, 65, 9214; (b) Joseph, R.;
Snyder; Serianni, A. S. Carbohydr. Res. 1987, 163, 169–
188.
25
Compound 4 ½aꢁD ꢀ17.40 (c 1, MeOH); 1H NMR
(200 MHz, CDCl3): d 8.10 (s, 1H), 7.39–7.20 (m, 4H),
6.86–6.82 (m, 4H), 6.58 (d, 1H, J = 15.5 Hz), 5.94 (dd, 1H,
J = 8.1, 14.6 Hz), 5.18–5.02 (m, 1H), 4.62 (d,
1H, J = 9.79 Hz), 4.38 (d, 1H, J = 9.79 Hz), 3.86 (t, 1H,
J = 4.0 Hz), 3.80 (s, 6H), 1.28 (d, 3H, J = 6.5 Hz); 13C
NMR (50 MHz, CDCl3): 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; MS (EI): m/z M+ 356. HRMS (EI) for
C21H24O5, calculated 356.1624. Found 356.1621.
25
Compound 14 ½aꢁD ꢀ70.20 (c 0.5, MeOH); 1H NMR
(200 MHz, CDCl3): d 7.35–7.18 (m, 4H), 5.96 (m, 4H), 6.48
(d, 1H, J = 15.5 Hz), 6.00–5.90 (dd, 1H, J = 8.1,14.6 Hz),
4.58 (d, 1H, J = 8.9 Hz), 4.35 (d, 1H, J = 8.9 Hz), 3.88–3.77
(m, 7H), 3.58–3.49 (m, 1H), 1.22 (d, 3H, J = 7.3 Hz); 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; MS (EI): m/z M+ 353.
6. Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A.
Synlett 1998, 26–28.
7. Sharma, G. V. M.; Reddy, C. G.; Krishna, P. R. J. Org.
Chem. 2003, 68, 4574–4575.
8. Benedetti, F.; Berti, F.; Dinon, F.; Nardin, G.; Norbedo,
S. Org. Lett. 2004, 6, 1017–1019.
25
Compound 16 ½aꢁD ꢀ50.18 (c 1, MeOH); 1H NMR
(300 MHz, CDCl3): d 7.16 (d, 2H, J = 9.2 Hz), 6.88 (d,
2H, J = 9.2 Hz), 4.55 (br s, 1H), 3.99 (m, 2H), 3.80 (m, 4H),
1.38 (d, 3H, J = 6.0 Hz), 1.25 (s, 9H); 13C NMR (75 MHz,
CDCl3): d 158.7, 154.0, 134.6,127.3, 113.8, 81.7, 79.6, 60.6,
59.3, 55.2, 28.0, 18.5, 17.7; MS (EI): m/z M+ 323.
9. Tsuzuki, Y.; Tomita, K.; Sato, Y.; Kashimoto, S.; Chiba,
K. J. Med. Chem. 2004, 47, 2097–2109.
10. Spectral data for selected compounds: compound 1: white
25
solid, mp 168–171 °C; ½aꢁD ꢀ12.4 (c 0.4, MeOH), lit.1; mp