Total Synthesis of (±)-Veadeiroic Acid

Article abstract of DOI:10.1039/a801895b

The synthesis of the diterpene veadeiroic acid (9) from the phenol 1 is described.

Full text of DOI:10.1039/a801895b

View Article Online / Journal Homepage / Table of Contents for this issue
380 J. CHEM. RESEARCH (S), 1998
J. Chem. Research (S),
1998, 380±381$
Total Synthesis of (2)-Veadeiroic Acid$
Ajoy K. Banerjee* and Elvia V. Cabrera
Centro de Quõmica, IVIC, Apartado 21827, Caracas 1020-A, Venezuela
The synthesis of the diterpene veadeiroic acid (9) from the phenol 1 is described.
Nagata et al.1 reported an interesting method for the
introduction of the hydroxymethylene group at the ortho
position of phenols which consisted in treatment of the
phenol with phenylboronic acid and a catalytic amount of
propionic acid followed by addition of paraformaldehyde
and propane-1,3-diol. This observation encouraged us to
study hydroxymethylation of the already reported2 phenol 1
by the published procedure1 to obtain the diol 3 aiming at
its further transformation to veadeiroic acid 9, a diterpene
with the rare cleistanthane skeleton whose ®rst total syn-
thesis was reported by Saha and Nasipuri.3 The present
paper records the results of our e€orts towards the synthesis
of veadeiroic acid 9.
The phenol 1 on treatment with phenylboronic acid
(Aldrich) and paraformaldehyde in the presence of a
catalytic amount of propionic acid yielded boron
a
complex 2 which exhibited almost total disappearance of the
hydroxy group in the IR spectrum. In the mass spectrum
‡
it presented a peak at m/z 242 [M PhBH2CO]. The pro-
duct 2 without puri®cation was converted into the diol 3 by
heating under re¯ux with benzene and propylene glycol.
Its structure was con®rmed by spectroscropic properties.
The diol 3 on heating with 2,3-dichloro-5,6-dicyanobenzo-
quinone (DDQ) in 1,4-dioxane4 a€orded the aldehyde 4 in
‡
74% yield. It had a strong peak at m/z 272 (M ) in the
mass spectrum and a signal at d 9.02 (CHO) in the 1H
NMR spectrum. The aldehyde 4 on oxidation5 with nickel
peroxide in aqueous alkaline solution yielded the acid 5 in
60% yield. It exhibited strong IR absorptions, at 3240 and
1
1710 cm and a peak at m/z in the mass spectrum. These
1
absorptions at 3240 and 1710 cm and a peak at m/z 243
in the mass spectrum. These spectroscopic data lent strong
support to the structure of the acid 5 which was methylated
with an excess of dimethyl sulfate in the presence of potass-
ium carbonate to ester 6. This exhibited a molecular ion at
‡
‡
m/z 316 (M ) and a peak at m/z 256 (M MeCOOH) in
1
the mass spectrum and absorption at 1720 cm in the IR
spectrum.
In order to achieve the total synthesis of veadeiroic acid
9, the ester 6 was hydrolysed with potassium tert-butoxide
and dimethyl sulfoxide6 to obtain the acidic material. Its
acid chloride, prepared by treatment with thionyl chloride,
on treatment3 with 2-amino-2-methylpropanol followed by
preparative chromatographic puri®cation yielded oxazole
derivative 7 as a thick liquid yellow material which though
not homogeneous in TLC was almost free from the refer-
ence material. The crude product was treated with ethyl-
lithium, prepared by the published procedure,3 at 40 8C,
hydrolysed with 10% methanolic hydrochloric acid to
obtain the acidic material and esteri®ed with diazomethane
to obtain the already reported3 methyl veadeiroate 8 whose
mp and spectrosciopic data were identical with those
reported.3 This was converted by heating with dimethyl sulf-
oxide and potassium tert-butoxide6 into the already reported
Scheme 1
veadeiroic acid 9 whose mp and spectroscopic properties
were identical with those reported.
Experimental
For general methods see Ref. 7.
1-Hydroxy-2-hydroxymethyl-4b,8,8-trimethyl-trans-4b,5,6,7,8,8a,9,10-
octahydrophenanthrene 3.ÐA solution of phenol 1 (2.46 g), phenyl-
boronic acid (2.61 g) and propionic acid (408 mg) in dry benzene
(150 ml) was re¯uxed with azeotropic removal of water. During
re¯uxing paraformaldehyde (4 g) was added over 1.5 h and after 3 h
phenylboronic acid (2.04 g) was added and the re¯uxing continued
for 6 h. The usual work-up a€orded product 2, mp 48±53 8C, m/z
*To receive any correspondence.
$This is a Short Paper as de®ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).
‡
242 [M PhBH2CO].

View Article Online
J. CHEM. RESEARCH (S), 1998 381
To crude product 2 (3.82 g) dissolved in dry benzene (60 ml) was
added propylene glycol (35.25 g) and re¯uxed for 12 h. The usual
work-up followed by chromatographic puri®cation on silica gel
(eluent diethyl ether±hexane 8:2) yielded the oily diol 3 (1.92 g,
70%), m/z 256 (M H2O) and 241 (M H2O-Me), ꢀ~max/cm 3450
(OH); d 0.92 (3 H, s), 1.03 (3 H, s), 1.16 (3 H, s), 4b,8,8-Me) 4.62
(2 H, s, CH2OH), 5.85 (s, 1 H, OH) (very weak), 6.68 (1 H, s)
and 6.82 (1 H, s) (aromatic protons) (Found: C, 78.84; H, 9.58.
dark oily material which was treated with thionyl chloride (3 ml),
stirred for 30 min and ether (50 ml), added and stirred. After decan-
tation of the ether, the gummy material was treated with aqueous
sodium hydroxide solution (10%, 30 ml). The usual work-up
a€orded a viscous oil which was placed on a silica gel plate (2 mm,
PF254, Merck) and eluted with 45% ethyl acetate±hexane to a€ord
‡
‡
1
‡
1
the oxazolinone derivative 7 (457 mg), m/z 343 (M ), ꢀ~max/cm
1650. To the derivative 7 (455 mg) in tetrahydrofuran (15 ml) was
added an excess of ethyllithium in hexane (4 ml) under nitrogen.
The mixture was stirred at 45 8C for 3 h and then at room
temperature for 18 h. Work-up a€orded an oily material which
showed a very weak 1H NMR signal of the methoxy group.
C18H26O2 requires C, 78.79; H, 9.55%).
2-Formyl-1-hydroxy-4b,8,8-trimethyl-trans-4b,5,6,7,8,8a,9,10-octa-
hydrophenanthrene 4.ÐTo a solution of the diol 3 (1.82 g) in dry
1,4-dioxane (50 ml) was added DDQ (2.32 g) and stirred at room
temperature for 16 h. The work-up a€orded a brown solid which on
crystallization a€orded the aldehyde 4 (1.33 g, 74%), mp 119±
The crude compound was hydrolysed with hydrochloric acid
(10%, 25 ml) by heating for 1 h and then further re¯uxing with
methanolic hydroxide (10%, 40 ml) for 1 h. Work-up, esteri®cation
with diazomethane followed by chromatographic puri®cation
(hexane: 1:1) a€orded methyl vadeiroate 8 (179 mg, 30%), mp
‡
‡
1
120 8C, m/z 272 (M ) and 2.57 (M Me), ꢀ~max/cm 1720 (CO);
ꢁ 0.94 (3 H, s), 1.08 (3 H, s), 1.18 (3 H, s, 4b,8,8-Me), 5.82 (s, 1 H,
OH) (very weak), 6.64 (1 H, s), 6.68 (1 H, s) (aromatic protons),
9.02 (CHO) (Found: C, 79.41; H, 8.91. C18H24O2 requires C, 79.37;
H, 8.88%).
‡
78±81 8C (from aqueous acetone) (lit.,3 78±80 8C), m/z 314 (M ),
1
ꢀ~max/cm 1720 (CO), d 0.96 (3 H, s), 0.98 (3 H, s), 1.21 (3 H, s),
2-Carboxyl-1-hydroxy-4b,8,8-trimethyl-trans-4b,5,6,7,8,8a,9,10-octa-
hydrophenanthrene 5.ÐTo a solution of the aldehyde 4 (1.31 g) and
sodium hydroxide (2.2 g) in water (50 ml) was added nickel peroxide
(7.22 g) and stirred for 2 h at room temperature under nitrogen.
The work-up yielded a gummy material which on crystallization
with ether a€orded the acid 5 (828 mg, 60%), mp 210±212 8C
4b,8,8-Me), 1.22 (3 H, t, J ˆ 6, ArCH2Me), 2.84±3.08 (4 H, m,
2 ÂArCH2), 3.68 (3 H, s, OMe), 7.23 (1 H, d, J ˆ 8) and 7.60 (1 H,
d, J ˆ 9 Hz) (aromatic protons) (Found: C, 80.04; H, 9.74.
C
21H30O2 requires C, 80.21; H, 9.62%).
(2)-Veadeiroic Acid 9.ÐThe ester 8 (150 mg) in dimethyl sulf-
oxide (4 ml) was treated with potassium tert-butoxide (100 mg) and
heated for 40 min at 90 8C. Work-up followed by crystallization
a€orded veadeiroic acid 9 (80 mg, 56%), mp 204±206 8C (aqueous
‡
‡
(From Et2O), m/z 243 (M COOH) and 228 (M COOH-Me),
1
ꢀ~max/cm 3425 (OH) 1710 (CO); ꢁ 0.98 (3 H, s), 1.03 (3 H, s), 1.12
‡
‡
(3 H, s, 4b,8,8-Me), 5.48 (1 H, s, OH) (very weak), 7.48 (1 H, s),
7.68 (1 H, s) (aromatic protons) (Found: C, 75.02; H, 8.43.
C18H24O3 requires C, 74.97; H, 8.39%).
acetone), (lit.,3 204±205 8C), m/z 300 (M ) and 285 (M Me);
1
ꢀ~max/cm 3442±2845 (br); ꢁ 0.94 (3 H, s), 0.98 (3 H, s), 1.21 (3 H,
s), 1.24 (1 H, t, J ˆ 8, ArCH2Me), 286±3.02 (4 H, m, 2 ÂArCH2),
3.56 (3 H, s, OMe), 7.23 (1 H, d, J ˆ 8) and 7.60 (1 d, d, J ˆ 8 Hz)
(aromatic protons) (Found: C, 79.82; H, 9.52. C20H28O2 requires
C, 79.95; II, 9.39%).
1-Methoxy-2-methoxycarbonyl-4b,8,8-trimethyl-trans-4b,5,6,7,8,8a,9,10-
octahydrophenanthrene 6.ÐTo a solution of the acid 5 (800 mg) in
acetone (10 ml) was added anhydrous potassium carbonate (208 mg)
and dimethyl sulfate (1.12 g) and then re¯uxed for 12 h. Work-up
followed by chromatographic puri®cation (diethyl ether±hexane 6:4)
a€orded the ester 6 (614 mg, 70%), mp 165±166 8C (from Et2O), m/z
Received, 9th March 1998; Accepted, 12th March 1998
Paper E/8/01895B
‡
‡
1
316 (M ) and 256 (M MeCOOH), ꢀ~max/cm 1730 (CO), ꢁ 0.96 (3 H,
s), 1.05 (3 H, s), 1.14 (3 H, s, 4b,8,8-Me), 3.58 (3 H, s), 3.62 (s, 3 H)
(1,2-OMe), 7.02 (1 H, d), 7.08 (1 H, d) (each J ˆ 8 Hz) (aromatic pro-
tons) (Found: C, 75.95; H, 8.95. C20H28O3 requires C, 75.91; H,
8.92%).
References
(2)-Methyl Veadeiroate 8.ÐTo a solution of the ester 6 (602 mg)
in dimethyl sulfoxide (5 ml) was added freshly prepared potassium
tert-butoxide (300 mg) and heated in an oil-bath (90 8C) for 40 min.
Work-up a€orded an acidic material (550 mg), mp 158±164 8C,
1 W. Nagata, K. Okada and T. Aoki, Synthesis, 1979, 365.
2 R. E. Ireland and P. W. Schiess, J. Org. Chem., 1963, 28, 7.
3 A. Saha and D. Nasipuri, J. Chem. Soc., Perkin Trans. 1, 1993, 1,
2223.
4 H. D. Becker, A. Bjork and E. Adler, J. Org. Chem., 1980, 45,
1596.
5 K. Nakagawa, S. Mineo and S. Kawamura, Chem. Pharm. Bull.,
1978, 26, 299.
6 F. C. Chang and N. F. Wood, Tetrahedron Lett., 1964, 2964.
7 A. K. Banerjee and M. Laya, Synth. Commun., 1995, 25, 1035.
1
ꢀ~max/cm 3260 (OH) and 1710 (CO). To the crude acid material
dissolves in chloroform (20 ml) was added thionyl chloride (5 ml)
and stirred for 17 h. Work-up a€orded the chloride derivative which
was dissolved in dichloromethane (10 ml), added to 2-amino-2-
methylpropan-1-ol (5 ml) in dichloromethane (10 ml) in an ice-bath
and then stirred at room temperature for 5 h. Work-up a€orded a