Syntheses of codonopsinine and 4-epi-codonopsinine
M Yamaguchi et al
5
NMR spectral data were identical with those reported13; 1H NMR (400 MHz, concentrated under reduced pressure. The residue was purified by preparative
CDCl3, a mixture of rotamers) δ 7.18 (d, J =8.8 Hz, 0.9H), 7.08 (d, J = 8.8 Hz, TLC on silica gel (hexanes/AcOEt= 2:1) to afford the titled trans-diol (5.5 mg,
20 μmol, 60%) as a clear oil; its 1H NMR spectral data were identical with those
1.1H), 6.86 (d, J = 8.8 Hz, 0.9H), 6.82 (d, J =8.8 Hz, 1.1H), 5.80–5.73 (m, 1H),
reported13; 1H NMR (400 MHz, C5D5N, a mixture of rotamers) δ 7.65
(d, J = 7.6 Hz, 1H), 7.45 (br s, 1H), 6.93 (d, J = 8.4 Hz, 2H), 4.66 (br s, 1H),
4.61–4.33 (m, 2H), 3.69 (br s, 1H), 3.60 and 3.59 (s, 3H), 3.48 (s, 3H), 1.93
(d, J = 6.4 Hz, 1.8H), 1.75 (d, J =6.4 Hz, 1.8H).
5.64 (ddd, J = 6.4, 2.0, 0.5 Hz, 0.5H), 5.61 (ddd, J = 6.4, 2.0, 0.5 Hz, 0.5H), 5.48
(m, 0.5H), 5.39 (m, 0.5H), 4.89–4.80 (m, 0.5H), 4.78–4.70 (m, 0.5H), 3.79
(s, 1.6H), 3.78 (s, 1.4H), 3.63 (s, 1.4H), 3.42 (s, 1.6H), 1.44 (d, J = 6.0 Hz,
1.6H), 1.36 (d, J = 6.0 Hz, 1.4H).
(2R*,3R*,4S*,5R*)-3,4-Dihydroxy-2-(4-methoxyphenyl)-5-
methylpyrrolidine-1-carboxylic acid methyl ester
(2R*,3R*,4R*,5R*)-2-(4-Methoxyphenyl)-1,5-dimethylpyrrolidine-
3,4-diol; codonopsinine (1)
To a solution of 3-pyrroline derivative 10 (15.2 mg, 61.5 μmol) and N-
methylmorpholine N-oxide (NMO) (10.8 ml, 92.3 μmol) in acetone
(0.50 ml) and H2O (0.12 ml) was added OsO4 (1.0% in H2O, 78 μl, 3.1 μmol).
After stirring for 5 days at room temperature, the reaction was quenched with
saturated aqueous NaHSO3, and the mixture was extracted with AcOEt three
times. The combined organic extracts were washed with brine, dried over
Na2SO4, filtered and concentrated under reduced pressure. The residue was
purified by preparative TLC on silica gel (hexanes/AcOEt= 1:1) to afford the
titled cis-diol (15.6 mg, 55.5 μmol, 90%) as a colorless oil; Rf = 0.20 (silica gel,
hexanes/AcOEt= 1:1); IR (neat) 3419, 3303, 2937, 1680, 1612, 1513, 1455,
To a solution of trans-diol compound (8.5 mg, 30.2 μmol) in toluene (0.15 ml)
was added Red-Al (65% w/v in toluene, 233 μl) at 0 °C. After heating at reflux
for 45 h, the reaction was quenched with saturated aqueous Rochell’s salt at
0 °C, and the mixture was extracted with AcOEt three times. The combined
organic extracts were washed with brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by preparative
TLC on silica gel (CHCl3/MeOH= 4:1) to afford
(1) (4.5 mg, 19 μmol, 63%) as a white solid; Mp 155–157 °C; IR (neat) 3365,
2919, 2837, 1611, 1514, 1459, 1249, 1180, 1035, 837 cm− 1 1H NMR
( )-codonopsinine
;
(600 MHz, C5D5N) δ 7.58 (d, J =8.4 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 4.60
(dd, J = 6.0, 4.8 Hz, 1H), 4.36 (dd, J =6.0, 4.8 Hz, 1H), 4.02 (d, J = 6.0 Hz, 1H),
3.67 (qd, J = 6.4, 3.6 Hz, 1H), 3.66 (s, 3H), 2.20 (s, 3H), 1.31 (s, J = 6.4 Hz,
3H); 13C NMR (150 MHz, C5D5N) δ 159.0, 134.7, 129.5, 113.8, 86.9, 84.7, 74.0,
64.7, 54.8, 34.4, 13.6; ESI-MS m/z Calcd for C13H20NO3 (M++H) 238.1438,
found 238.1435.
1386, 1249 cm–1 1H NMR (400 MHz, CD3CN, 60 °C) δ 7.08–7.00 (m, 2H),
;
6.92–6.80 (m, 2H), 4.72 (br s, 1H), 4.29–4.18 (m, 1H), 4.17–4.09 (m, 1H), 3.86
(br s, 1H), 3.78–3.72 (m, 3H), 3.67–3.29 (m, 4H), 3.14 (br s, 1H), 1.35–1.33
(m, 1H); 13C NMR (100 MHz, CD3CN, 60 °C) δ 160.1, 156.4, 130.3, 127.9,
115.1, 114.1, 70.9, 68.6, 64.3, 57.2, 56.2, 52.5; ESI-MS m/z Calcd for
C14H19NNaO5 304.1155 (M++Na), found 304.1157.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
(2R*,3R*,4S*,5R*)-2-(4-Methoxyphenyl)-1,5-dimethylpyrrolidine-
3,4-diol; 4-epi-( )-codonopsinine (2)
To a solution of the above cis-diol (12.1 mg, 43.0 μmol) in toluene (0.22 ml)
was added Red-Al (65% w/v in toluene, 129 μl) at 0 °C. After heating at reflux
for an hour, the reaction was quenched with saturated aqueous Rochell’s salt at
0 °C. The resulting mixture was extracted with AcOEt three times. The
combined organic extracts were washed with brine, dried over Na2SO4, filtered
and concentrated under reduced pressure. The residue was purified by
preparative TLC on silica gel (CHCl3/MeOH = 3:1) to afford 4-epi-( )-codo-
ACKNOWLEDGEMENTS
This work was financially supported by the Cabinet Office, Government of
Japan through its ‘Funding Program for Next Generation World-Leading
Researchers (LS008), a Grant-in-aid for Scientific Research (A) (26253001) and
for Young Scientists (B) (24790003) and Platform for Drug Discovery,
Informatics, and Structural Life Science from the MEXT, Japan.
1
nopsinine (2) (5.8 mg, 24.4 μmol, 57%) as a white solid; its H NMR spectral
data were identical with those reported9; 1H NMR (400 MHz, CDCl3) δ 7.21
(d, J = 8.4 Hz, 2H), 6.88 (d, J =8.4 Hz, 2H), 4.28 (dd, J = 6.4, 6.4 Hz, 1H), 4.06
(dd, J = 6.4, 5.2 Hz, 1H), 3.81 (s, 3H), 3.66 (d, J = 5.2 Hz, 1H), 3.53–3.45
(m, 1H), 2.64 (br s, 1H), 1.12 (s, 3H).
1
2
3
4
Matkhalikova, S. F., Malikov, V. M. & Yunusov, S. Y. Alkaloids of Codonopsis
clematidea. Khim. Prir. Soedin. 5, 30–32 (1969); Chem. Abstr. 71, 13245z.
Matkhalikova, C. F., Malikov, V. M. & Yunusov, S. Y. Structure of codonopsine. Khim.
Prir. Soedin. 5, 606–607 (1969); Chem. Abstr. 73, 15050x.
Matkhalikova, S. F., Malikov, V. M. & Yunusov, S. Y. Structure of codonopsinine. Khim.
Prir. Soedin. 5, 607 (1969); Chem. Abstr. 73, 25712d.
Yagudaev, M. R., Matkhalikova, S. F., Malikov, V. M. & Yusunov, S. Y. Study of
stereochemistry of alkaloids of codonopsine and codonopsinine by NMR
spectroscopy method. Khim. Prir. Soedin. 8, 495 (1972).
(1S*,2S*,4S*,5R*)-2-(4-Methoxyphenyl)-4-methyl-6-oxa-3-
azabicyclo[3.1.0]hexane-3-carboxylic acid methyl ester (18)
To a solution of pyrroline 10 (14.7 mg, 59.4 μmol) in toluene (0.3 ml) was
added mCPBA (51.0 mg, 0.297 mmol) at 0 °C. After stirring at room
temperature for 28 h, the reaction was quenched with saturated aqueous
NaHCO3, and the resulting mixture was extracted with CH2Cl2 three times.
The combined organic extracts were washed with brine, dried over Na2SO4,
filtered and concentrated under reduced pressure. The residue was purified by
preparative TLC on silica gel (hexanes/AcOEt= 3:7) to afford epoxide 18
5
6
Shibano, M., Tsukamoto, D., Masuda, A., Tanaka, Y. & Kusano, G. Two new pyrrolidine
alkaloids, radicamines
A and B, as inhibitors of α-glucosidase from lobelia
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stereoisomers: stereochemical assignment of natural (–)-codonopsinine. J. Org. Chem.
52, 1956–1962 (1987).
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Iida, H., Yamazaki, N. & Kibayashi, C. Stereochemical revision and absolute config-
uration of codonopsinine. Tetrahedron Lett. 27, 5393–5396 (1986).
Khanov, M. T., Sultanov, M. B. & Egorova, M. R. Pharmacological study of the alkaloid
codonopsine, extracted from Codonopsis clematidea. Farmakol. Alkaloidov Serdech.
Glikoyidov 210–212 (1971); Chem. Abstr. 77, 135091r (1972).
1
(8.6 mg, 33 μmol, 55%) as a clear oil; its H NMR spectral data were identical
with those reported14; 1H NMR (400 MHz, CDCl3) δ 7.14 (d, J =8.4 Hz, 0.9H),
7.08 (d, J =8.8 Hz, 2.1H), 6.92–6.84 (m, 2H), 5.04 (br s, 0.3H), 4.96 (br s,
0.7H), 4.22–4.07 (m, 1H), 3.80 (s, 2.1H), 3.79 (m, 0.9H), 3.76–3.70 (m, 1H),
3.62 (s, 0.9H), 3.52–3.47 (m, 1H), 3.44 (s, 2.1H), 1.58 (d, J = 6.0 Hz, 2.1H),
1.51 (d, J = 6.0 Hz, 0.9H).
9
Kotland, A., Accadbled, F., Robeyns, K. & Behr, J.-B. Synthesis and fucosidase
inhibitory study of unnatural pyrrolidine alkaloid 4-epi-(+)-codonopsinine. J. Org. Chem.
76, 4094–4098 (2011).
10 Johari, S. A. et al. In vitro inhibitory and cytotoxic activity of MFM 501, a novel
codonopsinine derivative, against methicillin-resistant Staphylococcus aureus clinical
isolates. J. Chil. Chem. Soc. 56, 1–9 (2015).
11 Iida, H. Yamazaki & Kibayashi, N. C. Synthesis of (+)-codonopsinine: determination of
absolute configuration of natural ( − )-codonopsinine. Tetrahedron Lett. 26, 3255–3258
(1985).
12 Yoda, H., Nakajima, T. & Takabe, K. Total synthesis of natural (–)-codonopsinine
employing stereoselective reduction of quaternary α-hydroxypyrrolidine. Tetrahedron
Lett. 37, 5531–5534 (1996).
(2R*,3R*,4R*,5R*)-3,4-Dihydroxy-2-(4-methoxyphenyl)-5-
methylpyrrolidine-1-carboxylic acid methyl ester
To a solution of epoxide 18 (8.6 mg, 33 μmol) in 1,4-dioxane (0.13 ml) and
H2O (90 μl) was added dropwise concentrated H2SO4 (9.0 μl). After stirring for
9 h at 90 °C, the reaction was quenched with saturated aqueous NaHCO3. The
resulting mixture was extracted with CH2Cl2 three times. The combined
organic extracts were washed with brine, dried over Na2SO4, filtered and
13 Severino, E. A.
with diazonium salts. Improvements and
(–)-codonopsinine. Org. Lett. 2, 3039–3042 (2000).
&
Correia, C. R. D. Heck arylation of endocyclic enecarbamates
a
concise enantioselective synthesis of
The Journal of Antibiotics