Total Synthesis of ( - )-Baimuxifuranic Acid

Article abstract of DOI:10.1039/a704440b

The first total synthesis of ( - )-baimuxifuranic acid (1) starting from ( - )-carvone is described: in our studies a surprising allylic oxidation was found in the oxidation of an α,β-unsaturated aldehyde 5 with silver oxide.

Full text of DOI:10.1039/a704440b

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472 J. CHEM. RESEARCH (S), 1997
J. Chem. Research (S),
1997, 472–473†
Total Synthesis of (ꢀ)-Baimuxifuranic Acid†
Yonggang Chen, Zhaoming Xiong, Jiong Yang and Yulin Li*
National Laboratory of Applied Organic Chemistry and Institute of Organic Chemistry,
Lanzhou Univesity, Lanzhou 730000, P. R. China
The first total synthesis of (ꢀ)-baimuxifuranic acid (1) starting from (ꢀ)-carvone is described: in our studies a surprising
allylic oxidation was found in the oxidation of an a,b-unsaturated aldehyde 5 with silver oxide.
Recently, Yang et al.1 isolated (ꢀ)-baimuxifuranic acid (1)
from the volatile oil of Chen-Xiang, determined its structure
by spectroscopic methods and reduced it to the known com-
pound isobaimuxinol. Compound 1 is the first carboxylic acid
with a dihydroagarofuran skeleton to be isolated from
natural sources. Herein we report the first total synthesis of 1
from (ꢀ)-carvone 2. During our studies we also found a
surprising allylic oxidation of an a,b-unsaturated aldehyde
with silver oxide.
reducing a,b-unsaturated aldehydes to saturated aldehydes.6
In our studies, after several failures at converting the allylic
aldehyde 5 into the saturated aldehydes 6 or 7 by reported
methods,7 we found that 5 could be hydrogenated by addition
of a small amount (10%) of triethylamine to the H2–Pd/C
system,5 affording the desired aldehydes 6 and 7 in the ratio
4:1 (determined by GC) and in a combined yield of 44%; no
carbonyl-group-reduced compounds were detected. The con-
figuration at C-4 in compounds 6 and 7 was determined from
the 1H NMR spectra. Thus the 4b-proton of 6 appeared at d
2.30 as a broad doublet (J3eq,4eq 4.9 Hz)‡ while the 4a-proton
of 7 appeared at d 2.34 as a doublet triplet (J3ax,4ax 13.3 Hz,
J3eq,4ax,4ax,12 4.3 Hz). In this reduction, 20 mol% of Pd in the
form of 10% Pd–C was needed. Steric effects might be
responsible for these results. Because of the steric hindrance
between the 10a-methyl group and the tetrahydrofuran ring,
it is difficult to hydrogenate the C-3–C-4 bond, especially
from the a-side. In the presence of anhydrous K2CO3 in meth-
anol, 6 was easily transformed into the more stable isomer 7.
Aldehyde 7 was treated with KMnO4 in tert-butyl alcohol–
aqueous NaH2PO4 to give the title compound 1 in quantita-
tive yield.9 The spectral data of the synthetic product are fully
consistent with structure 1 and identical with literature data1
for the natural product.
Using a published method,2 a-agarofuran (3) was prepared
from 2 in six steps with an overall yield of 40% (Scheme 1).
Previously we have reported2b the regiospecific oxidation of 3
at C-12 with selenium dioxide supported on silica gel,3 use of
this system as a regioselective allylic oxidizing agent having
first been reported by Shirahama and co-workers.3 Although
the regioselectivity is very good, the preparation of this
reagent, involving evaporation of a methanol–water suspen-
sion of selenium dioxide and silica gel, has some operational
drawbacks owing to the subliming property and toxicity of
selenium dioxide. We found that this reagent can be pre-
pared by simply stirring4 a mixture of selenium dioxide pow-
der and silica gel without solvent for 24 h at room tempera-
ture. The resulting selenium dioxide (5 wt%) adsorbed on
silica gel is also effective for the regiospecific allylic oxidation
of a-agarofuran (3), giving a result similar to that previously
reported.2b The alcohol 4 was oxidized to the allylic aldehyde
5 with MnO2 in 90% yield.
In an early stage of our studies, we wished to synthesize 1
by oxidation of 5 to the allylic acid 8 and subsequent hydro-
genation of the double bond. When we treated 5 with silver
oxide in aqueous ethanol, the enonic acid 9 was surprisingly
obtained instead of the normal carboxylic acid 8 (Scheme 2).
Silver oxide has been widely used10 for conversion of alde-
hydes to carboxylic acids but its use for this kind of allylic
oxidation has not been reported previously. Catalytic hydro-
genation of 9 with Pd–C in ethanol afforded stereospecifi-
ically the carboxylic acid 10 in excellent yield. The structures
of both 9 and 10 were confirmed by their 1H and 13C NMR, IR
and mass spectra. The configuration of C-4 in 10 was estab-
lished by the appearance of the 4a-proton at d 3.13 as a
13
9
6
1
4
i
ii
2
3
10
8
7
+
5
14
15
O
11
O
O
12 O
OHC
HO
2
3
4
29%
5 50%
iii
iv
vi
1
double doublet (J 13.4 and 5.0 Hz) in its H NMR spec-
5
7
+
trum.
O
O
O
OHC
OHC
HO2C
Experimental
6
4 : 1
v
7
1
Mps are uncorrected. IR spectra were recorded on a Nicolet
FT-170SX spectrometer as liquid films. H and 13C NMR spectra
1
were measured on Bruker AM-400 spectrometers with Me4Si as an
internal standard and CDCl3 as solvent. Mass spectra were deter-
mined on a V.G. ZAB-HS spectrometer (EI, 70 eV).
Scheme 1 Reagents: i, Ref. 2; ii, SeO2–SiO2, dioxane; iii, MnO2,
CH2Cl2; iv, H2, Pd–C (10%), Et3N, MeOH; v, K2CO3, MeOH; vi,
KMnO4, ButOH, aq. NaH2PO4
Regioselective reduction of a,b-unsaturated carbonyl com-
pounds is an important and challenging transformation in
organic synthesis.5 Although many methods can be used for
such reductions, there are few methods for regioselectively
i
5
O
i
HO2C
8
*To receive any correspondence (e-mail: liyl@lzu.edu.cn).
†This is a Short Paper as defined in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1997, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).
‡In the 1H NMR spectrum of 6, 12-H appeared at d 9.78 as a singlet,
indicating there is no coupling between this proton and 4-H, and the
coupling constant between 3ax-H and 4eq-H was near zero, which is
consistent with a slightly distorted chair conformation for ring A in
which the dehedral angle between 3ax-H and 4eq-H is close to 90°.
The configuration at C-4 in 6 was also confirmed by conversion of 6
into 7 in the presence of K2CO3.
O
O
ii
O
O
HO2C
HO2C
9
10
Scheme 2 Reagents: i, AgNO3, KOH, EtOH–H2O; ii, H2, Pd–C
(10%), EtOH

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J. CHEM. RESEARCH (S), 1997 473
Allylic Oxidation of a-Agarofuran 3.sA mixture of 3 (110 mg, 0.5
mmol) in dioxane (18 mL) and freshly prepared 5% SeO2 absorbed
on silica gel (1.1 g, 0.5 mmol) was refluxed under argon for 12 h.
After usual work-up, purification by column chromatography
afforded 5 (59 mg, 50%) followed by 4 (34 mg, 29%). The spectral
properties of 4 and 5 were identical with those reported,3b and in
order to ensure that no 2-oxo product was formed, the 13C NMR
spectrum of 5 was also determined: dC 21.7, 22.9, 24.15, 24.24, 29.9,
30.9, 31.7, 33.9, 37.0, 44.1, 82.0, 82.5, 139.3, 157.6, 194.3.
Oxidation of Compound 4 to 5.sTo a well stirred solution of 4
(34 mg, 0.144 mmol) in CH2Cl2 (1.5 mL) was added active MnO2
(125 mg, 1.44 mmol) and the mixture was stirred at room tempera-
ture (r.t.) for 10 h. After usual work-up, the crude product was
purified by column chromatography to yield 5 (30 mg, 90%).
Hydrogenation of Allylic Aldehyde 5.sA solution of the allylic
aldehyde 5 (36 mg, 0.154 mmol) and 10% palladium–charcoal (28
mg) in MeOH–Et3N (10:1, 2 mL) was stirred under a hydrogen
atmosphere at r.t. for 30 min. After usual work-up, column
chromatography afforded 6 and 7 both as light yellow oils. 6: 12.8
mg (35%); vmax/cmꢀ1 1719, 1458, 1018; m/z 237 (Mǹ ǹ1, 60%), 236
(Mǹ, 5), 221 (16), 219 (40), 190 (100), 147 (93), 123 (29); dH 0.82 (s,
3 H, 10-Me), 1.21 (s, 3 H, 11-Me), 1.39 (s, 3 H, 11-Me), 2.30 (d, J
4.9 Hz, 4-H), 9.78 (s, 1 H, 14-H) [Found: m/z, 221.1441 (Mǹ ꢀ15).
C14H21O2 requires m/z,221.1541]. 7: 3.3 mg (9%); [a]1D5 ꢀ78 (c 0.86,
CHCl3); vmax/cmꢀ1 1719, 1459, 1136, 889; m/z 237 (Mǹ ǹ1, 0.15%),
236 (Mǹ, 0.1), 221 (2), 190 (77), 175 (28), 147 (100), 135 (27), 95
(26); dH 0.98 (s, 3 H, 10-Me), 1.10 (s, 3 H, 11-Me), 1.39 (s, 3 H,
11-Me), 2.34 (td, J 4.3, 13.3 Hz, 4-H), 9.68 (d, J 4.2 Hz, 1 H,
4-H).
a,b-unsaturated aldehyde 5 (30 mg, 0.128 mmol) in ethanol (1 mL)
under stirring. Then, aq. KOH solution (1.15 mL; 2.1 g of KOH
dissolved in 35 mL of H2O) was added in drops to the mixture and
stirring was continued at r.t. for 8 h. After usual work-up, column
chromatography yielded 9 (17 mg, 50%); [a]1D5 ꢀ100 (c 0.70,
CHCl3), mp 157–158 °C; vmax/cmꢀ1 3383 br, 1717, 1685; m/z 264
(Mǹ, 5), 249 (13), 231 (11), 189 (33), 161 (15), 133 (9), 123 (30), 124
(75), 81 (100); dH 1.10 (s, 3 H, 10-Me), 1.37 (s, 3 H, 11-Me), 1.45 (s,
3 H, 11-Me), 6.59 (s, 1 H, 3-H); dC 22.8, 23.5, 24.0, 30.1, 33.7, 34.0,
41.0, 44.3, 49.4, 82.8, 84.2, 134.1, 146.1, 169.7, 199.4 [Found: m/z,
249.1159 (Mǹ ꢀ15). C14H17O4 requires m/z 249.1127].
(ꢀ)-2-Oxobaimuxifuranic Acid (10).sA mixture of 9 (17 mg,
0.064 mmol) and 10% Pd–C (3 mg) in ethanol (1 mL) was stirred
under a hydrogen atmosphere at r.t. for 2 h. After filtration, the
filtrate was evaporated in vacuo to give 10: 16 mg (98%); [a]D15
ꢀ73.2 (c 0.21, CHCl3), mp 168–170 °C; vmax/cmꢀ1 3092 br, 1715,
1460, 1283, 891, 732; m/z 266 (Mǹ, 3%), 251 (100), 233 (21), 205
(44), 168 (18), 167 (46), 150 (24), 123 (30), 122 (30); dH 1.01 (s, 3 H,
10-Me), 1.23 (s, 3 H, 11-Me), 1.46 (s, 3 H, 11-Me), 1.94 (dd, J 13.0,
2.3 Hz, 1 H, H-1eq), 2.42 (m), 2.45 (ddd, J 13.9, 5.0, 2.3 Hz, 1 H,
H-3eq), 2.79 (d, J 13.0 Hz, 1 H, H-1ax), 2.95 (t, J 13.9 Hz, 1 H,
H-3ax), 3.13 (dd, J 13.4, 5.0 Hz, 1 H, 4-H); dC 22.8, 23.6, 24.3, 30.1,
35.2 (2 C), 41.0, 43.3, 44.3, 47.8, 52.1, 84.2, 84.4, 174.7, 208.5
[Found: m/z, 251.1231 (Mǹ ꢀ15). C14H19O4 requires m/z
251.1283].
Received, 24th June 1997; Accepted, 3rd September 1997
Paper E/7/04440B
Isomerization of 6 to 7.sA mixture of 6 (15 mg, 0.064 mmol) in
methanol (1 mL) and anhydrous K2CO3 (8 mg) was stirred at r.t.
for 1 h. After usual work-up, the crude product was purified by
column chromatography to yield 7 (12 mg, 80%).
References
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(ꢀ)-Baimuxifuranic Acid (1).sTo a solution of aldehyde 7 (12
mg, 0.051 mmol) in ButOH (0.3 mL) and an aqueous 1.25
M
potas-
sium phosphate buffer solution (0.2 mL) was added an aqueous 1
M
KMnO4 solution (0.3 mL) at r.t., with vigorous stirring. After 5 min,
the oxidation was quenched by the addition of a saturated solution
of Na2SO3 and the mixture was acidified to pH 3 with cold dilute
HCl to dissolve the colloidal MnO2. After the usual extraction
work-up, the organic phase was concentrated to give 3: 12 mg
(98%); [a]1D5 ꢀ84.7 (c 0.28, CHCl3) (lit.,2 [a]D ꢀ83.5 (c 0.13,
CHCl3); vmax/cmꢀ1 3100 br, 1707, 1384, 1134; m/z 252 (Mǹ, 1%),
237 (100), 219 (49), 191 (61), 167 (16), 149 (30); dH 2.81 (dd, J 13.3,
4.2 Hz, 1 H, 4-H), 1.48 (s, 3 H, 11-Me), 1.30 (s, 3 H, 11-Me), 1.03 (s,
3 H, 10-Me); dC 175, 86.2, 84.4, 47.6, 43.6, 38.1, 36.6, 36.2, 35.4,
30.6, 28, 24.2, 23.2, 23.1, 20.1 [Found: m/z, 237.1515 (Mǹ ꢀ15).
C14H21O3 requires m/z 237.1491].
6 E. Keinan and N. Greenspoon, in Comprehensive Organic Synthe-
sis, ed. B. M. Trost, Pergamon, New York, 1991, vol. 8, p. 523.
7 (a) G. Mehta and A. N. Murthy, J. Org. Chem., 1987, 52, 2875; (b)
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hedron Lett., 1986, 27, 4537.
(ꢀ)-2-Oxo-3,4-didehydrobaimuxifuranic Acid (9).sTo a solu-
tion of AgNO3 (98 mg, 0.577 mmol) in H2O (0.5 mL) was added the
9 J. March, Advanced Organic Chemistry, Wiley, New York, 4th edn.,
1992, ch. 14, p. 701.