Conversion of spirostane and solanidane into pregnane (1) introduction of oxygen function into C-23

Article abstract of DOI:10.1248/cpb.60.150

A spirosolane derivative possessing a hydroxyl group at C-23, esculeogenin A, a sapogenol of tomato saponin, was found to be easily converted into the corresponding pregnane derivative by refluxing with aqueous pyridine. Therefore, introduction of a hydroxyl group into the C-23 of diosgenin (as representative of spirostane derivatives) and solasodine (as representative of spirosolane derivatives) was attempted by the reaction of NaNO₂-BF₃ · Et₂O. In diosgenin, the objective compound was obtained by the reaction in AcOH. However, in solasodine, we obtained a 23-nitroso derivative by the reaction in AcOH and 23,24-bisnorcholanic acid 22-16 lactone, or vespertilin, in AcOH and CHCl₃.

Full text of DOI:10.1248/cpb.60.150

—
150
Note
Chem. Pharm. Bull. 60(1) 150 153 (2012)
Vol. 60, No. 1
Conversion of Spirostane and Solanidane into Pregnane (1)
Introduction of Oxygen Function into C-23
,a
Nodoka Nakata,a Asami Tokudome,b Hiroyuki Yanai,b and Toshihiro Nohara*
a Faculty of Medical and Pharmaceutical Scieces, Sojo University; 4–22–1 Ikeda, Kumamoto 860–0082, Japan: and
b Faculty of Medical and Pharmaceutical Scieces, Kumamoto University; 5–1 Oe-honmachi, Kumamoto 862–0973,
Japan. Received August 24, 2011; accepted October 11, 2011; published online October 18, 2011
A spirosolane derivative possessing a hydroxyl group at C-23, esculeogenin A, a sapogenol of tomato
saponin, was found to be easily converted into the corresponding pregnane derivative by refluxing with
aqueous pyridine. Therefore, introduction of a hydroxyl group into the C-23 of diosgenin (as representative
of spirostane derivatives) and solasodine (as representative of spirosolane derivatives) was attempted by the
reaction of NaNO2–BF3 ·Et2O. In diosgenin, the objective compound was obtained by the reaction in AcOH.
However, in solasodine, we obtained a 23-nitroso derivative by the reaction in AcOH and 23,24-bisnorchola-
nic acid 22-16 lactone, or vespertilin, in AcOH and CHCl3.
Key words spirost-23-hydroxylation; diosgenin; solasodine; nitroso derivative; bisnorcholanic acid
Nohara et al. found that the spirosolane sapogenol of toma- (40mL), NaNO2 (3.0g) and BF3 ·Et2O in ether (4.5mL) were
to saponin, (5α,22S,23S,25S)-3β,23,27-trihydroxyspirosolane, added gradually with stirring for 1h at rt. After 1.5h, the
or esculeogenin A (1),1) was converted to 3β,16β-dihydroxy- reaction mixture was treated in the usual manner to give
5α-pregna-20-one (2) by refluxing with diluted aqueous a product that was chromatographed on silica gel with n-
pyridine.2,3) Its reaction was considered to be triggered by the hexane:acetone=4:1 3:1 to give compounds 4 (349mg,
→
existence of the 23-hydroxyl group on the spirosolane skele- 33.8%) and 5 (137mg, 11.9%).
—
Compound 4 consisted of colorless needles (mp 199
ton. Preparation of steroidal hormones depends mainly upon
the Marker degradation.4) When the 23-hydroxyspirostane, 202 C; [α]D −84.4 [CHCl3]). High-resolution fast atom
spirosolane, and tomatidane compounds are prepared, the bombardment mass spectrometry (HR-FAB-MS) revealed a
pregnane compound might be derived from them by a similar molecular ion at m/z 451.2826, indicating a molecular formula
simple reaction. Therefore, we first tried to introduce an oxy- of C27H40O4+Na (Calcd: 451.2824), and a carbonyl group ap-
gen group at C-23 in them by the reported method.5,6) In this peared at 1732cm−1 in the IR spectrum.
°
°
report, diosgenin (a representative spirostane) and solanidine
(a representative spirosolane derivative) were used as crude groups at δ 0.79 (3H, s, H3-18) and 1.02 (3H, s, H3-19); two
original substances.
The 1H-NMR spectrum exhibited two tertiary methyl
secondary methyl groups at δ 0.93 (6H, d, J=6.7Hz, H3-21,
First, to a suspension of diosgenin (3, 1g) in acetic acid H3-27); two methylene protons at δ 3.59 and 3.78 (1H, m and
Chart 1. Mechanism for Conversion of Esculeogenin A (1) into Pregnane Derivative (2)
*To whom correspondence should be addressed. e-mail: none@ph.sojo-u.ac.jp
© 2012 The Pharmaceutical Society of Japan

January 2012
151
1H, t-like, J=11.3Hz, Heq-26, Hax-26, respectively); two oxy- carbon newly occurred at δ 67.4. The structure of compound 6
gen-bearing methine protons at δ 3.51 (1H, m, H-3) and 4.61 was characterized as (22S,23S,25R)-3β,23-dihydroxy-spirost-5-
(1H, dd, J=6.8, 15.7Hz, H-16); and one olefinic proton at δ ene,23S-hydroxydiosgenin.
5.34 (1H, m, H-6). In the 13C-NMR spectrum (in CDCl3), one
Next, to a suspension of solasodine (7, 307mg) in acetic
carbonyl carbon newly occurred at δ 201.8, which correlated acid (18mL), NaNO2 (924mg) and BF3 ·Et2O (4.5mL) were
with H-20 at δ 2.89 (1H, m). Therefore, the structure of com- added gradually with stirring for 1h at rt. After 1.5h, the
pound 4 was characterized as 23-oxodiosgenin.5,6)
reaction mixture was treated in the usual manner to give a
For compound 5, an amorphous powder having [α]D product that was chromatographed on silica gel with n-hex-
°
→
−99.6 (CHCl3), HR-FAB-MS revealed a molecular ion at m/z ane–acetone=4:1 3:1 to give compound 8 (184mg, 56.2%)
540.2935, indicating a molecular formula of C29H43NO7+Na as a major product.
(Calcd: 540.2937). A carbonyl group appeared at 1730cm−1
Compound 8 exhibited [α]D −98.2 (MeOH) and a mo-
°
1
in the IR spectrum. The H-NMR spectrum showed signals lecular formula of C27H42N2O3+Na at m/z 465.3090 (Calcd:
due to H3-18 (3H, s) at δ 0.76, H3-19 (3H, s) at δ 1.02, H3-27 465.3093) in positive HR-FAB-MS. The H-NMR spectrum
1
(3H, d, J=4.3Hz) at δ 0.93, and H3-21 (3H, d, J=4.3Hz) at δ showed two tertiary groups at δ 0.82 (3H, s, H3-18) and 1.00
0.94; one acetyl signal (3H, s) at δ 2.17; H-3 (1H, m) at δ 3.77; (3H, s, H3-19); two secondary methyl groups at δ 0.90 (3H,
Heq-26 (1H, t-like, J=11.2Hz) at δ 3.77; and H-16 (1H, m) at d, J=6.8Hz, H3-27) and 1.17 (3H, d, J=7.5Hz, H3-21); two
δ 4.51. The 13C-NMR spectrum revealed the presence of one oxygen-bearing methine protons at δ 3.50 (1H, m, Hax-26)
hydroxyimino group at δ 178.0, together with one carbonyl and 3.97 (1H, m, Heq-26); one olefinic proton at δ 5.31 (1H,
carbon at δ 201.6 and one acetyl carbonyl carbon at δ 169.5. m, H-6), along with a down-shifted proton at δ 4.66 (1H, dd,
Furthermore, since heteronuclear multiple bond coherence J=3.6, 13.8Hz), which was assigned to H-23 because HMBC
(HMBC) analysis indicated the existence of a hydroxyl group was observed between H-23 and C-22 at δ 102.0; and H-25
at C-5, the presence of an imino group at C-6 is suggested. at δ 44.1. The 13C-NMR spectrum of 7 displayed a total of
The carbonyl group is located at C-23, as in compound 4. The 27 carbon signals, including four methyl carbons at δ 15.0,
acetyl group was estimated to be bound to the hydroxyimino 16.4, 19.1, and 19.5; two oxygen-bearing carbons at δ 74.8 and
group because the H-3 was not down shifted. Therefore, the 83.1; one hemiacetal carbon at δ 102.0; one double bond at δ
structure of compound 5 was characterized as 3β,5-dihydroxy- 121.4 and 140.9; and one nitrogen-bearing methine carbon at
1
6-acetoxyimino-23-oxo-(25R)-spirostane.
δ 44.1. The chemical shifts of H-23 in the H- and 13C-NMR
Next, compound 4 (250mg) was reduced with NaBH4 spectra indicated that an imino group was attached to C-23; its
(200mg) in MeOH (6mL) for 30min at rt. After a small configuration was determined to be equatorial by its coupling
amount of AcOH was added, its reaction mixture was evapo- constants.
rated to give a residue, which was then chromatographed
Next, to increase the solubility of the reaction mixture, a
→
on silica gel with n-hexane–acetone=4:1 3:1 to provide small amount of CHCl3 was added to the reaction. To a solu-
compound 6 (160mg, 64.0%). Compound 6 appeared as col- tion of solasodine (7, 304mg) in AcOH (14mL) and CHCl3
—
°
°
orless needles (mp 212 214 C; [α]D −112.4 [CHCl3]). HR- (5mL), NaNO2 (890mg) and BF3 ethelate (4.5mL) were added
FAB-MS revealed a molecular ion at m/z 494.2877, indicating gradually and left standing at rt for 2h. The usual treatment
°
a molecular formula of C27H42O4+Na (Calcd: 494.2880), and yielded compound 9 (120.5mg, 48.2%) having [α]D −82.6
a hydroxyl group appeared at 3550cm−1 in the IR spectrum. (MeOH) and a molecular formula of C22H32O3+Na at m/z
The 1H-NMR spectrum (in pyridine-d5) displayed signals 367.2252 (Calcd: 367.2249), as revealed by positive HR-FAB-
1
due to H3-21 (d, J=6.7Hz) at δ 0.73, H3-18 (s) at δ 0.99, H3- MS. The H-NMR spectrum of 9 showed two tertiary methyl
19 (s) at δ 1.02, H3-27 (d, J=6.7Hz) at δ 1.18, Hax-26 (t-like, groups at δ 0.90 (3H, s, H3-18) and 0.95 (3H, s, H3-19); one
J=11.0Hz) at δ 3.46, Heq-26 (m) at δ 3.54, H-3 (m) at δ 3.82, secondary methyl group at δ 1.23 (3H, d, J=7.5Hz, H3-21);
H-16 (dd, J=7.6, 15.6Hz) at δ 4.64, H-6 (m) at δ 5.36, and two oxygen-bearing methine protons at δ 3.46 (1H, m, H-3)
H-23 (dd, J=4.5, 11.3Hz) at δ 3.82. Their coupling constants and 4.89 (1H, m, H-16); and one olefinic proton at δ 5.31 (1H,
indicated that the hydroxyl group was oriented equatorially m, H-6). The 13C-NMR spectrum displayed a total of 22 car-
(S). In the 13C-NMR spectrum (in pyridine-d5), one hydroxyl bon signals including two oxygen-bearing carbons at δ 71.7
Chart 2. Introduction of Oxygen Function into C-23

152
Vol. 60, No. 1
Chart 3. Reaction of Solasodine
and 82.9; one trisubstituted double bond at δ 121.3 and 141.0; 1H-NMR spectrum (in CDCl3) δ: 0.79 (3H, s, H3-18), 1.02 (3H,
and one lactone carbonyl carbon at δ 181.5. This compound s, H3-19), 0.93 (6H, d, J=6.7Hz, H3-21, H3-27), 3.59, 3.78 (1H,
was coincident with vespertilin.7)
m, and 1H, t-like, J=11.3Hz, Heq-26 and Hax-26, respec-
Consequently, in the reaction of solasodine with NaNO2 and tively), 3.51 (1H, m, H-3), 4.61 (1H, dd, J=6.8, 15.7Hz, H-16),
13
—
BF3, the results when only AcOH was used in suspension state 5.34 (1H, m, H-6). C-NMR spectrum (in CDCl3): C-1 C-27,
as a solvent differed from those obtained when AcOH and δ 37.3, 29.7, 71.8, 43.5, 141.0, 121.2, 31.7, 31.5, 50.1, 36.7, 20.8,
CHCl3 were used in solution state, thus they would depend on 39.6, 40.8, 56.7, 31.7, 83.4, 61.8, 16.0, 19.4, 34.8, 14.4, 109.9,
the solubility.
201.8, 43.9, 35.8, 65.7, 17.1.
°
We are currently preparing tomatidine produced from the
aerial part of Solanum lycopersicum.
Compound 5, an amorphous powder, [α]D −99.6 (c=0.5,
CHCl3), IR νmax 1730cm−1 (carbonyl carbon). HR-FAB-MS
1
(m/z): 540.2935 (C29H43NO7+Na, Calcd: 540.2937). H-NMR
spectrum (CDCl3) δ: 0.76 (3H, s, H3-18), 1.02 (3H, s, H3-19),
Experimental
General Procedure Optical rotations were measured 0.93 (3H, d, J=4.3Hz, H3-27), 0.94 (3H, d, J=4.3Hz, H3-21),
with a JASCO P-1020 (l=0.5) automatic digital polarimeter. 2.17 (3H, s, acetyl signal), 3.77 (1H, m, H-3), 3.77 (1H, t-like,
FAB-MS were obtained with a glycerol matrix in the positive J=11.2Hz, Heq-26), 4.51 (1H, m, H-16). 13C-NMR spectrum
—
ion mode using a JEOL JMS-DX300 and a JMS-DX 303 HF (CDCl3): C-1 C-27, δ 38.9, 29.8, 68.0, 45.6, 87.1, 178.0, 33.7,
1
spectrometer. The H- and 13C-NMR spectra were measured 34.5, 55.1, 36.9, 21.2, 39.7, 42.2, 56.7, 32.7, 83.5, 61.9, 15.8,
in pyridine-d5 with JEOL α-500 spectrometer, and chemical 17.3, 34.6, 14.6, 109.9, 201.6, 45.2, 35.9, 65.6, 17.1, acetyl
shifts are given on a δ (ppm) scale with tetramethylsilane group, 169.5, 18.2.
(TMS) as the internal standard. Column chromatographies
Reaction of Compound 4 with NaBH4 Compound 4
were carried out on a Diaion HP-20 (Mitsubishi Chemical (250mg) was reduced with NaBH4 (200mg) in MeOH (6mL)
—
Ind.), and silica gel 60 (230 400 mesh, Merck). TLC was for 30min at rt. After addition of a small amount of AcOH,
performed on silica gel plates (Kieselgel 60 F254, Merck) and its reaction mixture was evaporated to give a residue, which
RP C18 silica gel plates (Merck). The spots on TLC were was then chromatographed on silica gel with n-hexane–ace-
—
visualized by UV light (254/366nm) and sprayed with 10% tone=4:1 3:1 to provide compound 6 (160mg, 64.0%).
—
°
H2SO4, followed by heating.
Compound 6 exhibited colorless needles, mp 212 214 C,
Reaction of Diosgenin with NaNO2 and BF3-Ethelate in [α]D −112.4 (c=0.5, CHCl3), IR νmax 3550cm−1 (hydrox-
AcOH Firstly, to a solution of diosgenin (3, 1g) in acetic yl). HR-FAB-MS (m/z): 467.3017 (C27H42NO4+Na, Calcd:
°
1
acid (40mL), NaNO2 (3.0g) and BF3·Et2O (4.5mL) was gradu- 467.3012). H-NMR spectrum (in pyridine-d5) δ: 0.73 (3H, d,
ally added with stirring for 1h at rt. After 1.5h, the reaction J=6.7Hz, H3-21), 0.99 (3H, s, H3-18), 1.02 (3H, s, H3-19), 1.18
mixture was treated in an usual manner to give the product (3H, d, J=6.7Hz, H3-27), 3.46 (1H, t-like, J=11.0Hz, Hax-26),
which was chromatographed on silica gel with n-hexane–ace- 3.54 (1H, m, Heq-26), 3.82 (1H, m, H-3), 3.82 (1H, dd, J=4.5,
→
tone=4:1 3:1 to give compounds 4 (349mg, 33.8%) and 5 11.3Hz, H-23), 4.64 (1H, dd, J=7.6, 15.6Hz, H-16), 5.36 (1H,
13
—
m, H-6). C-NMR spectrum (in pyridine-d5): C-1 C-27, δ
(137mg, 11.9%).
—
°
Compound 4, colorless needles, mp 199 202 C, [α]D 37.8, 29.8, 71.2, 43.4, 142.0, 120.9, 33.7, 31.7, 50.5, 37.0, 21.2,
−84.4 (c=0.5, CHCl3), IR νmax 1732cm−1 (carbonyl carbon). 40.3, 41.0, 56.8, 32.7, 81.6, 62.5, 35.8, 14.7, 111.7, 67.4, 38.8,
°
HR-FAB-MS (m/z): 451.2826 [C27H40O4+Na, Calcd: 451.2824]. 31.7, 65.2, 16.9.

January 2012
153
°
Reaction of Solasodine (7) with NaNO2 and BF3 ·Et2O in −82.6 (c=1.0, MeOH). HR-positive FAB-MS (m/z): 361.2252
AcOH To a solution of solasodine (7, 307mg) in acetic acid (Calcd for, C22H32O3+Na: 361.2249). 1H-NMR spectrum
(18mL), NaNO2 (924mg) and BF3 ·Et2O (4.5mL) was gradu- (CDCl3) δ: 0.70 (3H, s, H3-18), 0.95 (3H, s, H3-19), 1.23 (3H, d,
ally added with stirring for 1h at rt. After 1.5h, the reaction J=7.5Hz, H3-21), 3.46 (1H, m, H-3), 4.89 (1H, m, H-16), 5.27
13
—
mixture was treated in the usual manner to give the product (1H, m, H-6). C-NMR spectrum (CDCl3): C-1 C-22, δ 37.3,
which was chromatographed on silica gel with n-hexane– 32.0, 71.7, 42.3, 141.0, 121.0, 31.6, 31.3, 50.2, 36.7, 20.4, 38.3,
→
acetone=4:1 3:1 to give compound 8 (184mg, 56.2%) as 41.5, 59.0, 36.5, 82.9, 61.6, 18.1, 19.5, 54.9, 13.8, 181.5.
a major product.
°
Compound 8, an amorphous powder, [α]D −98.2 (c=1.0,
References and Notes
1) Fujiwara Y., Takaki A., Uehara Y., Ikeda T., Okawa M., Yamauchi
MeOH). HR-positive FAB-MS (m/z): 465.3090 (Calcd for
C27H42N2O3+Na: 465.3093). 1H-NMR spectrum (CDCl3) δ:
0.82 (3H, s, H3-18), 0.90 (3H, d, J=6.8Hz, H3-27), 1.00 (3H,
s, H3-19), 1.17 (3H, d, J=7.5Hz, H3-21), 3.50 (1H, m, Hax-
26), 3.50 (1H, m, H-3), 3.97 (1H, m, Heq-26), 4.66 (1H, dd,
J=3.6, 13.8Hz, H-23), 5.31 (1H, m, H-6). 13C-NMR spectrum
—
K., Ono M., Yoshimitsu H., Nohara T., Tetrahedron, 60, 4915
4920 (2004).
2) Matshushiuta S., Yoshizaki M., Fujiwara Y., Ikeda T., Ono M.,
Okawara T., Nohara T., Tetrahedron Lett., 46, 3549 3551 (2005).
3) The reaction mechanism proposed on scheme 2 in ref. 2 should be
corrected as shown in Chart 1 in this report.
—
—
(CDCl3) C-1 C-27, δ 37.2, 29.7, 71.8, 42.3, 140.9, 121.4, 31.7,
—
4) Marker R. E., Rohrmann E., J. Am. Chem. Soc., 62, 518 520
31.5, 50.1, 36.7, 21.0, 39.8, 40.4, 56.5, 32.1, 83.1, 61.6, 16.4,
19.3, 44.1, 15.0, 102.1, 44.1, 42.3, 44.1, 42.3, 19.0.
(1940).
5) Barton D. H. R., Sammes P. G., Taylor M. V., Werstiuk E., J. Chem.
Reaction of Solasodine (7) with NaNO2 and BF3 ·Et2O in
AcOH and CHCl3 To a solution of solasodine (7, 304mg)
in AcOH (14mL) and CHCl3 (5mL), NaNO2 (890mg) and
BF3 ·Et2O (4.5mL) was added gradually and reft stand at rt for
2h. Usual work up gave compound 9 (120.5mg, 48.2%), [α]D
—
Soc., (C), 1977 1981 (1970).
6) Iglesias-Arteaga M. A., Gil R. P., Martinez C. S. P., Manchado F.
C., J. Chem. Soc., Perkin Trans. 1, 2001, 261 266 (2001).
7) Iglesias-Arteaga M. A., Alvarado-Nuno A. A., Tetrahedron Lett.,
—
—
47, 5351 5353 (2006).