Synthesis of β-boswellic acid analogues with a carboxyl group at c-17 isolated from the bark of Schefflera octophylla

Full text of DOI:10.1021/jo0008688

6278
J . Org. Chem. 2000, 65, 6278-6282
6 from commercially available ursolic acid (5). Our work
also confirms the structures proposed for these com-
pounds.
Syn th esis of â-Bosw ellic Acid An a logu es
w ith a Ca r boxyl Gr ou p a t C-17 Isola ted
fr om th e Ba r k of Sch effler a octoph ylla
Lothar Bore,† Tadashi Honda, and Gordon W. Gribble*
Department of Chemistry, Dartmouth College,
Hanover, New Hampshire 03755-3564
Grib@Dartmouth.edu
Received J une 7, 2000
â-Boswellic acid (1) and its analogues, 2 and 3, having
a â-carboxyl group at C-4 and an R-hydroxyl group at
C-3 in ring A as structural features, are reported to have
interesting biological, pharmacological, and medicinal
activities, such as antiinflammatory activity, anti-brain
tumor activity, inhibition of human leukocyte elastase,
anti-complementary activity, and 5-lipoxygenase inhibi-
tory activity.1 In connection with our triterpenoid project
involving the design and synthesis of various oleanane
and ursane triterpenoids to discover new structures with
high potency against inflammation and/or carcinogen-
esis,2 we found that 3-epi-ursolic acid (4) inhibits produc-
tion of nitric oxide (NO) induced by interferon-γ in mouse
macrophages2g and suppresses the inducible cyclooxyge-
nase (COX-2) gene,2b although ursolic acid (5) does not
show such activity in either assay. Therefore, to further
discern structure-activity relationships, we designed
â-boswellic acid analogues with a carboxyl group at C-17
having the general structural formula I based on struc-
tures of both â-boswellic acid (1) and 3-epi-ursolic acid
(4). Our literature survey of these structures disclosed
3R-hydroxyurs-12-ene-23,28-dioic acid (6), a naturally
occurring triterpene isolated from the bark of Schefflera
octophylla, and its derivatives 7-9.3 We herein describe
the first synthesis of the 28-methyl ester 7 and the 23,-
28-dimethyl ester 9 of this naturally occurring triterpene
Resu lts a n d Discu ssion
Functionalization of the hindered C-4 equatorial meth-
yl group of ursolic acid (5) was achieved by Baldwin’s
method, which involves cyclopalladation of the methyl
group at C-4 from a 3-one oxime functionality.4 Dimeric
organopalladium complex 11 was prepared in 98% yield
from methyl ursonate oxime (10),5 which was prepared
in three steps from 5 according to a known method, with
Na2PdCl4 and NaOAc in AcOH. Acetylation of 11 with
Ac2O in the presence of Et3N and DMAP in CH2Cl2 gave
an unstable acetate, 12, which was immediately oxidized
with Pb(OAc)4 and pyridinium acetate in THF, followed
by reductive workup with NaBH4 to afford diacetate 13
(81% yield from 11). Deacetylation of 13 with Na2CO3 in
MeOH gave oxime 14 (98% yield), which was hydrolyzed
with TiCl3 in aqueous THF to give ketol 156 in 88% yield.
Transformation of 15 into the target compounds 7 and
9 has the following three problems. First, because 15 has
an R-hydroxymethyl-ketone functionality in ring A, the
hydroxymethyl group is readily cleaved via a retro-aldol
reaction under basic conditions. Second, if an intermedi-
ate that is derived from 15 has a â-keto-carboxylic acid
functionality in ring A, decarboxylation readily occurs
under both basic and acidic conditions. Third, conversion
of a carbonyl group at C-3 into an R-hydroxyl group by
* To whom correspondence should be addressed. Phone: 603-646-
3118. Fax: 603-646-3946.
† Present address: Ciba Specialty Chemicals Schweizerhalle Inc.,
Postfach 1130, CH-4133 Pratteln, Switzerland.
(1) (a) Simmet, T.; Ammon, H. P. T. German Patent, DE 4445728
A1, 1996; Chem. Abstr. 1996, 125, 67823. (b) Safayhi, H.; Rall, B.; Sailer
E. R.; Ammon, H. P. T. J . Pharmacol. Exp. Ther. 1997, 281, 460. (c)
Knaus, U.; Wagner, H. Phytomedicine 1996, 3, 77. (d) Safayhi, H.;
Sailer, E. R.; Ammon, H. P. T. Phytomedicine 1996, 3, 71. (e) Sailer,
E. R.; Hoernlein, R. F.; Subramanian, L. R.; Ammon, H. P. T.; Safayhi,
H. Arch. Pharm. (Weinheim, Ger.) 1996, 329, 54.
(2) (a) Honda, T.; Finlay, H. J .; Gribble, G. W.; Suh, N.; Sporn, M.
B. Bioorg. Med. Chem. Lett. 1997, 7, 1623. (b) Finlay, H. J .; Honda,
T.; Gribble, G. W.; Danielpour, D.; Benoit, N. E.; Suh, N.; Williams,
C.; Sporn, M. B. Bioorg. Med. Chem. Lett. 1997, 7, 1769. (c) Suh, N.;
Honda, T.; Finlay, H. J .; Barchowsky, A.; Williams, C.; Benoit, N. E.;
Xie, Q.; Nathan, C.; Gribble, G. W.; Sporn, M. B. Cancer Res. 1998,
58, 717. (d) Honda, T.; Rounds, B. V.; Gribble, G. W.; Suh, N.; Wang,
Y.; Sporn, M. B. Bioorg. Med. Chem. Lett. 1998, 8, 2711. (e) Suh, N.;
Wang, Y.; Honda, T.; Gribble, G. W.; Dmitrovsky, E.; Hickey, W. F.;
Maue, R. A.; Place, A. E.; Porter D. M.; Spinella, M. J .; Williams, C.
R.; Wu, G.; Dannenberg, A. J .; Flanders, K. C.; Letterio, J . J .;
Mangelsdorf, D. J .; Nathan, C. F.; Nguyen, L.; Porter, W. W.; Ren, R.
F.; Roberts, A. B.; Roche, N. S.; Subbaramaiah, K.; Sporn, M. B. Cancer
Res. 1999, 59, 336. (f) Honda, T.; Rounds, B. V.; Bore, L.; Favaloro, F.
G., J r.; Gribble, G. W.; Suh, N.; Wang, Y.; Sporn, M. B. Bioorg. Med.
Chem. Lett. 1999, 9, 3429. (g) Honda, T.; Gribble, G. W.; Suh, N.;
Finlay, H. J .; Rounds, B. V.; Bore, L.; Favaloro, F. G., J r.; Wang, Y.;
Sporn, M. B. J . Med. Chem. 2000, 43, 1866.
(4) (a) Baldwin, J . E.; J ones, R. H.; Najera, C.; Yus, M. Tetrahedron
1985, 41, 699. (b) Carr, K.; Saxton, H. M.; Sutherland, J . K. J . Chem.
Soc., Perkin Trans. 1 1988, 1599. (c) Peakman, T. M.; Lo ten Haven,
H.; Rullko¨tter, J .; Tetrahedron 1991, 47, 3779.
(5) Yasue, M.; Sakakibara, J .; Kaiya, T. J . Pharm. Soc. J pn.
(Yakugaku Zasshi) 1973, 93, 296, and references therein.
(6) Triterpene acid corresponding to this methyl ester 15 is a
naturally occurring triterpene isolated from twigs and leaves of
Cussonia natalensis: Fourie, T. G.; Matthee, E.; Snyckers, F. O.
Phytochemistry 1989, 28, 2851. This conversion of ursolic acid (5) into
15 is also the first synthesis of this natural product.
(3) Sung, T. V.; Lavaud, C.; Porzel, A.; Steglich, W.; Adam, G.
Phytochemistry 1992, 31, 227.
10.1021/jo0008688 CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/30/2000

Notes
J . Org. Chem., Vol. 65, No. 19, 2000 6279
Sch em e 1a
a
Key: (a) CH2N2, Et2O, THF; (b) J ones, acetone; (c) NH2OH‚HCl, NaOAc, MeOH, CH2Cl2; (d) Na2PdCl4, NaOAc, AcOH; (e) Ac2O,
Et3N, DMAP, CH2Cl2; (f) Pb(OAc)4, pyr., AcOH, THF; NaBH4, NaOH (aq); (g) Na2CO3, MeOH; (h) TiCl3, NH4OAc, H2O, THF.
Sch em e 2a
a
Key: (a) ethylene glycol, PPTS, benzene; (b) BnBr, KH, n-Bu4NI, THF; (c) p-TsOH, PPTS, acetone; (d) Al(i-PrO)3, i-PrOH; (e) TBSCl,
KH, 18-crown-6, THF; (f) H2, 10% Pd/C, THF; (g) RuO2‚xH2O, NaIO4, H2O, CH3CN, CCl4; (h) 48% aq HF, CH3CN; (i) CH2N2, Et2O, THF.
reducing agents was initially considered to be difficult
because the â-face of the C-3 carbonyl group of 15 is
sterically hindered. However, our literature survey re-
vealed that Meerwein-Ponndorf reduction of 3-oxours-
12-en-28-oic acid (ursonic acid)7 gives 3-epi-ursolic acid
(4) predominantly.8,9 Therefore, in considering these
problems, we adopted the synthetic route shown in
Scheme 2. Because direct benzylation of 15 did not give
benzyl ether 18 due to a retro-aldol reaction as expected,
we attempted to synthesize 18 via ethylene ketal 16.
Ketalization of 15 with ethylene glycol in the presence
of PPTS in benzene gave 16 in 99% yield. Benzylation of
16 with benzyl bromide in the presence of KH and n-Bu4-
NI in THF afforded benzyl ether 17 in 94% yield. Ketone
18 was obtained in 91% yield by deketalization of 17 with
p-TsOH and PPTS in acetone. Pleasingly, as we initially
expected, Meerwein-Ponndorf reduction of 18 gave the
desired R-alcohol 19 as the major product and â-alcohol
20 as the minor product (72% and 28% yield, respec-
(7) Kuwada, S.; Matsukawa, T. J . Pharm. Soc. J pn. (Yakugaku
Zasshi) 1933, 53, 593.
(8) Huneck, S.; Snatzke, G. Chem. Ber. 1965, 98, 120.
1
tively). Structures of both alcohols were assigned by H
NMR. Each proton at C-3 of 19 and 20 is observed at δ
3.70 ppm (1H, t, J ) 2.3 Hz) and δ 3.64 ppm (1H, dd, J
) 4.5, 10.5 Hz), respectively. Protection of the C-3
hydroxyl group of 19 with tert-butylchlorodimethylsilane
(9) Because our preliminary work disclosed that
a Mitsunobu
reaction10 does not give methyl 3R-hydroxyurs-12-en-28-oate (methyl
3-epi-ursolate) from methyl 3â-hydroxyurs-12-en-28-oate (methyl ur-
solate) due to steric hindrance of the C-3 â-hydroxyl group (Honda, T.
Unpublished data), we excluded this reaction from our synthetic route.

6280 J . Org. Chem., Vol. 65, No. 19, 2000
Notes
in the presence of KH and 18-crown-6 in THF11 yielded
silyl ether 21 quantitatively. Debenzylation of 21 was
achieved by hydrogenolysis in the presence of 10% Pd/C
at atmospheric pressure to give alcohol 22 quantitatively.
After several attempts using various oxidizing agents,
we found that oxidation of 22 with RuO4 (catalytic
amount) in CH3CN, CCl4 and water12 gives acid 23 and
aldehyde 24 in 65% and 9% yield, respectively. Depro-
tection of 23 with 48% aqueous HF solution in CH3CN13
afforded the target compound 7 in 99% yield, which was
converted to the second target compound, dimethyl ester
9, with ethereal CH2N2 in 91% yield. The structures of
Met h yl 23-H yd r oxy-3-h yd r oxyim in ou r s-12-en -28-oa t e
(14). A solution of 13 (1.92 g, 3.3 mmol) and Na2CO3 (1.23 g,
14.8 mmol) in MeOH (185 mL) was stirred at room temperature
for 16 h. After removal of MeOH in vacuo, the resultant colorless
solid was dissolved in Et2O (50 mL) and 1 N aqueous HCl
solution (50 mL). The organic layer was washed with saturated
aqueous NaHCO3 solution (three times), dried over MgSO4,
filtered, and evaporated in vacuo to give a solid. The solid was
purified by flash column chromatography [hexanes-EtOAc (2:
1)] to give 14 as an amorphous solid (1.61 g, 98%): TLC
[hexanes/EtOAc (2:1)] Rf 0.34; IR (KBr) 3392, 2971, 2907, 1725
cm-1; 1H NMR (CDCl3) δ 5.26 (1H, t, J ) 3.5 Hz), 3.63 (1H, d, J
) 11.5 Hz), 3.62 (3H, s), 3.52 (1H, d, J ) 11.5 Hz), 3.13 (1H, m),
2.24 (1H, d, J ) 11.0 Hz), 1.08 (6H, s), 1.05 (3H, s), 0.94, 0.86
(each 3H, d, J ) 6.5 Hz), 0.79 (3H, s); 13C NMR (CDCl3) δ 178.3,
167.0, 138.5, 125.5, 67.8, 53.1, 51.7, 50.0, 48.3, 47.1, 45.0, 42.3,
39.7, 39.2, 39.1, 38.2, 37.0, 36.8, 32.7, 30.8, 28.2, 24.4, 23.8, 23.6,
21.4, 19.1, 18.8, 17.7, 17.3, 15.5; CIMS m/z 500 [M + H]+;
HRCIMS calcd for C31H49NO4+H 500.3740, found 500.3740.
Anal. Calcd for C31H49NO4: C, 74.51; H, 9.88; N, 2.80. Found:
C, 74.23; H, 9.79; N, 2.85.
1
both compounds 7 and 9 are fully characterized by H
and 13C NMR, low- and high-resolution mass spectra, IR
spectra, and elemental analyses.14 Studies on the biologi-
cal properties of both compounds are in progress.
Exp er im en ta l Section
Meth yl 23-Hyd r oxy-3-oxou r s-12-en -28-oa te (15). To a
buffered solution of TiCl3 (1.31 mL of 20% aqueous HCl solution
containing 19% TiCl3) and NH4OAc (750 mg, 9.7 mmol) in water
(28 mL) was added a solution of 14 (180 mg, 0.36 mmol) in THF
(26.5 mL). The mixture was stirred at room temperature for 4
h. It was extracted with Et2O (three times). The extract was
washed with saturated aqueous NaHCO3 solution (three times),
dried over MgSO4, filtered, and evaporated in vacuo to give a
solid. The solid was purified by flash column chromatography
[hexanes-EtOAc (2:1)] to give 15 as an amorphous solid (154
mg, 88%): TLC [hexanes/EtOAc (2:1)] Rf 0.43; [R]24D +67° (c 0.39,
Gen er a l P r oced u r es. Elemental microanalysis was per-
formed by Atlantic Microlab Inc. TLC was fulfilled with Merck
precoated TLC plates silica gel 60 F254. Flash column chroma-
tography was done with Select Scientific silica gel (230-400
mesh). All experiments were performed under N2 atmosphere
unless otherwise stated.
Meth yl 3-Acetoxyim in o-23-acetoxyu r s-12-en -28-oate (13).
To a solution of methyl 3-hydroxyiminours-12-en-28-oate (10)5
(2.00 g, 4.1 mmol) in AcOH (220 mL) were added NaOAc (0.37
g, 4.5 mmol) and Na2PdCl4 (1.34 g, 4.6 mmol). The solution was
stirred for 72 h, and then ice water (300 mL) was added to give
a yellow precipitate. The precipitate was filtered and dried in
vacuo at 60 °C for 24 h to give palladium complex 11 (2.53 g,
98%), which was used for the next reaction without further
purification. To a solution of 11 in dry CH2Cl2 (180 mL) were
added DMAP (10 mg), Et3N (0.82 mL), and Ac2O (0.6 mL). The
mixture was stirred at room temperature for 45 min. It was
washed with water (twice), dried over MgSO4, filtered, and
evaporated in vacuo to afford 12 as an oil. A solution of 12 and
pyridine (0.3 mL) in THF (150 mL) was stirred at room
temperature for 15 min. To the solution was added a solution of
Pb(OAc)4 (1.85 g, 4.2 mmol) in AcOH (62 mL) in a dry ice-
acetone bath. The solution was stirred at room temperature for
16 h. To remove remaining Pd salts, a solution of NaBH4 (164
mg) in 1 N aqueous NaOH solution (60 mL) was added to the
reaction mixture. The mixture was stirred for 10 min. After the
mixture was filtered, the filtrate was diluted with CH2Cl2 (300
mL), which was washed with saturated aqueous NaHCO3
solution (until the AcOH was completely removed), dried over
MgSO4, filtered, and evaporated in vacuo to give a solid. The
solid was purified by flash column chromatography [hexanes-
EtOAc (2:1)] to give 13 as an amorphous solid (1.92 g, 81% from
11): TLC [hexanes/EtOAc (2:1)] Rf 0.68; IR (KBr) 2976, 2932,
1
CHCl3); IR (KBr) 3478, 2950, 2917, 1725, 1676 cm-1; H NMR
(CDCl3) δ 5.27 (1H, t, J ) 3.8 Hz), 3.65 (1H, d, J ) 11.5 Hz),
3.62 (3H, s), 3.43 (1H, d, J ) 11.5 Hz), 2.63 (1H, m), 2.28 (1H,
m), 2.25 (1H, d, J ) 12.5 Hz), 1.15, 1.10, 1.03 (each 3H, s), 0.95
(3H, d, J ) 6.0 Hz), 0.87 (3H, d, J ) 7.0 Hz), 0.82 (3H, s); 13C
NMR (CDCl3) δ 219.4, 178.3, 138.7, 125.4, 67.2, 53.1, 52.6, 51.7,
49.4, 48.3, 46.9, 42.4, 39.7, 39.3, 39.2, 39.1, 36.8, 36.7, 35.5, 32.6,
30.9, 28.3, 24.4, 23.8, 23.7, 21.4, 19.4, 17.29, 17.25, 17.1, 15.6;
CIMS m/z 485 [M + H]+; HRCIMS calcd for C31H48O4+H
485.3631, found 485.3629. Anal. Calcd for C31H48O4‚H2O: C,
74.06; H, 10.02. Found: C, 73.69; H, 9.69.
Meth yl 3,3-Eth ylen ed ioxy-23-h yd r oxyu r s-12-en -28-oa te
(16). A mixture of 15 (130 mg, 0.27 mmol), ethylene glycol (1.3
mL, 23 mmol), and PPTS (24 mg, 0.095 mmol) in benzene (13
mL) was heated under reflux with a Dean-Stark apparatus
filled with molecular sieves for 20 h. It was diluted with a
mixture of Et2O and CH2Cl2 (2:1) (20 mL). It was washed with
water (four times), dried over MgSO4, filtered, and evaporated
in vacuo to give a solid. The solid was purified by flash column
chromatography [hexanes-EtOAc (5:1)] to give 16 as an amor-
phous solid (140 mg, 99%): TLC [hexanes/EtOAc (5:1)] Rf 0.26;
1
IR (KBr) 3511, 2960, 2906, 1725 cm-1; H NMR (CDCl3) δ 5.22
(1H, t, J ) 3.3 Hz), 4.00 (2H, m), 3.93 (2H, m), 3.63 (1H, d, J )
11.5 Hz), 3.57 (3H, s), 3.15 (1H, d, J ) 11.5 Hz), 2.20 (1H, d, J
) 11.0 Hz), 1.08, 0.97 (each 3H, s), 0.92 (3H, d, J ) 6.0 Hz),
0.83 (3H, d, J ) 6.5 Hz), 0.73 (6H, s); 13C NMR (CDCl3) δ 178.0,
138.3, 125.4, 115.4, 65.7, 64.6, 63.9, 53.1, 51.6, 48.3, 47.7, 46.2,
44.5, 42.3, 39.7, 39.2, 39.1, 37.0, 36.8, 36.6, 32.7, 30.9, 28.2, 26.5,
24.4, 23.9, 23.5, 21.4, 18.4, 17.2, 17.1, 16.9, 15.8; CIMS m/z 529
[M + H]+; HRCIMS calcd for C33H52O5+H 529.3893, found
529.3894. Anal. Calcd for C33H52O5: C, 74.96; H, 9.91. Found:
C, 74.91; H, 10.27.
1769, 1736 cm-1 1H NMR (CDCl3) δ 5.27 (1H, t, J ) 3.5 Hz),
;
4.19 (1H, d, J ) 10.6 Hz), 4.13 (1H, d, J ) 10.6 Hz), 3.60 (3H,
s), 2.75 (1H, m), 2.53 (1H, m), 2.24 (1H, d, J ) 11.0 Hz), 2.17,
2.05, 1.17, 1.07, 0.98 (each 3H, s), 0.94 (3H, d, J ) 6.0 Hz), 0.85
(3H, d, J ) 6.5 Hz), 0.78 (3H, s); 13C NMR (CDCl3) δ 178.2, 171.1,
170.7, 169.9, 138.5, 125.5, 68.5, 53.2, 51.7, 48.6, 48.3, 46.8, 44.0,
42.3, 39.6, 39.2, 39.0, 37.3, 37.1, 36.8, 36.6, 32.4, 30.8, 28.1, 24.4,
23.7, 23.6, 21.3, 21.1, 20.5, 20.2, 19.5, 17.2, 17.1, 15.6; CIMS
m/z 584 [M + H]+; HRCIMS calcd for C35H53NO6+H 584.3951,
found 584.3949. Anal. Calcd for C35H53NO6: C, 72.01; H, 9.15;
N, 2.40. Found: C, 71.75; H, 9.27; N, 2.22.
Met h yl 23-Ben zyloxy-3,3-et h ylen ed ioxyu r s-12-en -28-
oa te (17). A mixture of 16 (140 mg, 0.27 mmol), benzyl bromide
(0.2 mL, 1.6 mmol), KH (35% in mineral oil) (0.2 mL), and n-Bu4-
NI (10 mg, 0.027 mmol) in THF (3 mL) was heated under reflux
for 28 h. After it was cooled in an ice bath, i-PrOH (1 mL) was
carefully added to decompose unreacted KH. The mixture was
diluted with a mixture of Et2O and CH2Cl2 (2:1) (20 mL). It was
washed with water (three times), dried over MgSO4, filtered, and
evaporated in vacuo to give a solid. The solid was purified by
flash column chromatography [hexanes-EtOAc (5:1)] to give 17
as an amorphous solid (155 mg, 94%): TLC [hexanes/EtOAc (5:
1)] Rf 0.61; IR (KBr) 2955, 2860, 1719 cm-1; 1H NMR (CDCl3) δ
7.35 (5H, m), 5.26 (1H, t, J ) 3.5 Hz), 4.51 (1H, d, J ) 12.5 Hz),
(10) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Hughes, D. L. In
Organic Reactions, Vol. 42; Paquette, L. A. et al., Eds.; J ohn Wiley &
Sons: New York, 1992; pp 335-656.
(11) Braish, T. F.; Fuchs, P. L. Synth. Commum. 1986, 16, 111.
(12) Carlsen, P. J .; Katsuki, T.; Martin, V. S.; Sharpless K. B. J .
Org. Chem. 1981, 46, 3936.
(13) Newton, R. F.; Reynolds, D. P.; Finch, M. A. W.; Kelly, D. R.;
Roberts, S. M. Tetrahedron Lett. 1979, 3981.
(14) Unfortunately, because we were unable to obtain authentic
samples and spectral data from the authors,3 we could not compare
our synthetic analogues with the natural products directly.

Notes
J . Org. Chem., Vol. 65, No. 19, 2000 6281
4.47 (1H, d, J ) 12.5 Hz), 3.92 (4H, m), 3.62 (3H, s), 3.37 (1H,
d, J ) 9.5 Hz), 3.13 (1H, d, J ) 9.5 Hz), 2.24 (1H, d, J ) 11.0
Hz), 1.15, 1.01 (each 3H, s), 0.98 (3H, d, J ) 6.0 Hz), 0.92 (3H,
s), 0.90 (3H, d, J ) 6.5 Hz), 0.78 (3H, s); 13C NMR (CDCl3) δ
178.3, 139.1, 138.4, 128.3, 127.8, 127.4, 125.6, 113.3, 74.1, 73.6,
64.8, 64.6, 53.1, 51.6, 49.7, 48.2, 47.4, 45.6, 42.3, 39.7, 39.2, 39.0,
36.9, 36.8, 32.7, 30.9, 28.2, 27.4, 24.4, 24.1, 23.5, 21.4, 19.0, 17.2,
17.1, 17.0, 15.8; CIMS m/z 619 [M + H]+; HRCIMS calcd for
dried over MgSO4, filtered, and evaporated in vacuo to give a
solid. The solid was purified by flash column chromatography
[hexanes-EtOAc (10:1)] to give 21 as an amorphous solid (669
mg, 100%): TLC [hexanes/EtOAc (10:1)] Rf 0.57; IR (KBr) 2954,
2921, 1730 cm-1; 1H NMR (CDCl3) δ 7.30 (5H, m), 5.28 (1H, t, J
) 3.3 Hz), 4.54 (1H, d, J ) 12.3 Hz), 4.36 (1H, d, J ) 12.3 Hz),
3.77 (1H, s), 3.62 (3H, s), 3.38 (1H, d, J ) 8.0 Hz), 3.21 (1H, d,
J ) 8.0 Hz), 2.25 (1H, d, J ) 11.5 Hz), 1.10 (3H, s), 0.97 (3H, d,
J ) 4.5 Hz), 0.96 (3H, s), 0.92 (9H, s), 0.90 (3H, d, J ) 4.5 Hz),
0.89, 0.75, 0.04, -0.01 (each 3H, s); 13C NMR (CDCl3) δ 178.3,
139.4, 138.3, 128.3, 127.5, 127.3, 126.0, 77.9, 73.2, 71.9, 53.1,
51.7, 48.3, 47.7, 46.5, 42.1, 42.0, 39.6, 39.3, 39.1, 37.1, 36.9, 33.3,
33.1, 30.9, 28.2, 26.3, 25.2, 24.5, 23.6, 23.5, 21.4, 18.6, 18.5, 17.44,
17.38, 17.1, 16.1, -3.9, -4.9; CIMS m/z 691 [M + H]+; HRCIMS
calcd for C44H70O4Si+H 691.5122, found 691.5121. Anal. Calcd
for C44H70O4Si‚1/3H2O: C, 75.81; H, 10.22. Found: C, 75.89; H,
10.38.
C
40H58O5+H 619.4363, found 619.4354. Anal. Calcd for
C40H58O5: C, 77.63; H, 9.45. Found: C, 77.57; H, 9.33.
Meth yl 23-Ben zyloxy-3-oxou r s-12-en -28-oa te (18). A mix-
ture of 17 (1.17 g, 18.9 mmol), p-TsOH (50 mg, 0.26 mmol), and
PPTS (50 mg, 0.20 mmol) in acetone (350 mL) was stirred at
room temperature for 48 h. After removal of acetone, the
resultant residue was dissolved in CH2Cl2 (25 mL). The solution
was washed with water (three times), dried over MgSO4, filtered,
and evaporated in vacuo to give a solid. The solid was purified
by flash column chromatography [hexanes-EtOAc (5:1)] to give
18 as an amorphous solid (986 mg, 91%): TLC [hexanes/EtOAc
Meth yl 3r-(ter t-Bu tyld im eth yl)silyloxy-23-h yd r oxyu r s-
12-en -28-oa te (22). A mixture of 21 (669 mg, 0.97 mmol) and
10% Pd/C (a catalytic amount) in THF (20 mL) was stirred at
room temperature under H2 at atmospheric pressure for 3 h.
After insoluble matter was removed through Celite, the filtrate
was evaporated in vacuo to give a solid. The solid was purified
by flash column chromatography [hexanes-EtOAc (5:1)] to give
22 as an amorphous solid (581 mg, 100%): TLC [hexanes/EtOAc
(5:1)] Rf 0.54; IR (KBr) 2960, 2863, 1720, 1698 cm-1 1H NMR
;
(CDCl3) δ 7.31 (5H, m), 5.30 (1H, t, J ) 3.0 Hz), 4.55 (1H, d, J
) 12.5 Hz), 4.38 (1H, d, J ) 12.5 Hz), 3.62 (3H, s), 3.53 (1H, d,
J ) 8.5 Hz), 3.23 (1H, d, J ) 8.5 Hz), 2.47 (2H, dd, J ) 5.5, 9.0
Hz), 2.27 (1H, d, J ) 11.0 Hz), 1.14, 1.00 (each 3H, s), 0.97 (3H,
d, J ) 6.0 Hz), 0.93 (3H,s), 0.89 (3H, d, J ) 6.0 Hz), 0.82 (3H, s);
13C NMR (CDCl3) δ 217.4, 178.8, 139.3, 139.0, 129.0, 128.2,
128.1, 126.3, 75.9, 73.8, 53.8, 52.2, 51.9, 48.9, 47.9, 46.8, 43.0,
40.2, 39.8, 39.6, 38.2, 37.4, 36.9, 36.4, 32.9, 31.4, 28.8, 25.0, 24.3,
24.2, 21.9, 20.3, 18.7, 17.8, 17.7, 16.0; CIMS m/z 575 [M + H]+;
HRCIMS calcd for C38H54O4+H 575.4100, found 575.4101. Anal.
Calcd for C38H54O4: C, 79.40; H, 9.47. Found: C, 79.17; H, 9.36.
Meth yl 23-Ben zyloxy-3r-h yd r oxyu r s-12-en -28-oa te (19)
an d Meth yl 23-Ben zyloxy-3â-h ydr oxyu r s-12-en -28-oate (20).
A mixture of 18 (193 mg, 0.34 mmol) and Al(i-PrO)3 (206 mg,
1.0 mmol) in i-PrOH (4 mL) was heated under reflux for 10 h.
After the mixture was diluted with a mixture of Et2O and CH2-
Cl2 (2:1) (20 mL), it was washed with 5% aqueous HCl solution
(twice) and saturated aqueous NaHCO3 solution (twice), dried
over MgSO4, filtered, and evaporated in vacuo to give a solid.
The solid was purified by flash column chromatography [hex-
anes-EtOAc (5:1)] to give 19 as an amorphous solid (139 mg,
72%) and 20 as an amorphous solid (53 mg, 28%). 19: TLC
[hexanes/EtOAc (5:1)] Rf 0.49; IR (KBr) 3450, 2917, 2863, 1720
cm-1; 1H NMR (CDCl3) δ 7.37 (5H, m), 5.30 (1H, t, J ) 3.5 Hz),
4.61 (1H, d, J ) 11.8 Hz), 4.48 (1H, d, J ) 11.8 Hz), 3.70 (1H, t,
J ) 2.3 Hz), 3.65 (3H, s), 3.50 (1H, d, J ) 9.5 Hz), 3.29 (1H, d,
J ) 9.5 Hz), 2.28 (1H, d, J ) 11.0 Hz), 1.16 (3H, s), 0.99 (3H, d,
J ) 8.0 Hz), 0.98 (3H,s), 0.90 (3H, d, J ) 7.0 Hz), 0.79 (6H, s);
13C NMR (CDCl3) δ 178.2, 138.2, 137.9, 128.6, 128.0, 127.7,
125.8, 78.5, 75.3, 73.6, 53.1, 51.6, 48.3, 47.5, 43.4, 42.2, 40.8,
39.7, 39.2, 39.0, 37.0, 36.8, 33.1, 32.7, 30.9, 28.2, 25.0, 24.4, 23.8,
23.3, 21.4, 18.4, 18.1, 17.2, 17.1, 15.9; CIMS m/z 577 [M + H]+;
HRCIMS calcd for C38H56O4+H 577.4257, found 577.4259. Anal.
Calcd for C38H56O4‚3/4H2O: C, 77.31; H, 9.82. Found: C, 77.10;
H, 9.56. 20: TLC [hexanes/EtOAc (5:1)] Rf 0.32; IR (KBr) 3522,
(5:1)] Rf 0.60; IR (KBr) 3545, 2951, 2855, 1718 cm-1 1H NMR
;
(CDCl3) δ 5.26 (1H, t, J ) 3.5 Hz), 3.62 (1H, t, J ) 3.0 Hz), 3.61
(3H, s), 3.42 (1H, d, J ) 11.8 Hz), 3.27 (1H, d, J ) 11.8 Hz),
2.24 (1H, d, J ) 11.0 Hz), 1.11, 0.95 (each 3H, s), 0.94 (3H, d, J
) 6.3 Hz), 0.93 (9H, s), 0.89 (3H, d, J ) 6.5 Hz), 0.76, 0.67, 0.14,
0.13 (each 3H, s); 13C NMR (CDCl3) δ 178.3, 138.5, 125.8, 78.9,
71.4, 53.1, 51.6, 48.3, 47.7, 42.9, 42.2, 41.0, 39.8, 39.2, 39.1, 36.9,
36.7, 33.4, 32.7, 31.8, 30.9, 28.2, 26.2, 26.0, 24.5, 23.8, 23.5, 22.9,
21.4, 18.5, 18.2, 17.4, 17.2, 15.9, 14.3, -3.9, -4.7; CIMS m/z 601
[M + H]+; HRCIMS calcd for C37H64O4Si+H 601.4652, found
601.4654. Anal. Calcd for C37H64O4Si: C, 73.95; H, 10.73.
Found: C, 73.83; H, 10.74.
3r-(ter t-Bu tyldim eth yl)silyloxyu r s-12-en e-23,28-dioic Acid
28-Meth yl Ester (23) a n d Meth yl 3r-(ter t-Bu tyld im eth yl)-
silyloxy-23-oxou r s-12-en -28-oa te (24). A mixture of 22 (45 mg,
0.074 mmol), RuO2‚xH2O (25 mg), and NaIO4 (62 mg, 0.29 mmol)
in CCl4 (0.5 mL), CH3CN (0.5 mL), and water (0.75 mL) was
stirred at room temperature for 5.5 h. To the mixture was added
CH2Cl2 (8 mL). The aqueous layer was extracted with CH2Cl2
(10 mL) (three times). The combined organic layers were dried
over MgSO4, filtered, and evaporated in vacuo to give a solid.
The solid was purified by flash column chromatography [hex-
anes-EtOAc (5:1)] to give 23 as an amorphous solid (30 mg, 65%)
and 24 as an amorphous solid (4 mg, 9%). 23: TLC [hexanes/
EtOAc (5:1)] Rf 0.38; IR (KBr) 3314, 2943, 2856, 1725, 1698 cm-1
;
1H NMR (CDCl3) δ 5.27 (1H, t, J ) 3.5 Hz), 3.88 (1H, s), 3.62
(3H, s), 2.25 (1H, d, J ) 11.5 Hz), 1.17, 0.97 (each 3H, s), 0.96,
0.91 (each 3H, d, J ) 6.5 Hz), 0.90 (3H, s), 0.88 (9H, s), 0.77,
0.06, 0.01 (each 3H, s); 13C NMR (CDCl3) δ 182.1, 178.3, 138.7,
125.6, 74.5, 53.1, 52.2, 51.7, 48.3, 47.8, 43.9, 42.3, 40.2, 39.2,
39.1, 36.9, 36.8, 32.8, 32.5, 31.8, 30.8, 28.2, 26.0, 25.2, 24.5, 23.9,
23.5, 22.9, 21.4, 21.2, 18.2, 17.42, 17.38, 16.1, 14.4, -3.9, -5.3;
CIMS m/z 613 [M - H]+; HRCIMS calcd for C37H62O5Si-H
613.4288, found 613.4288. Anal. Calcd for C37H62O5Si: C, 72.26;
H, 10.16. Found: C, 71.98; H, 10.27. 24: TLC [hexanes/EtOAc
(5:1)] Rf 0.59; IR (KBr) 2954, 2856, 1723 cm-1; 1H NMR (CDCl3)
δ 9.49 (1H, s), 5.27 (1H, t, J ) 3.5 Hz), 3.72 (1H, s), 3.60 (3H, s),
2.24 (1H, d, J ) 11.5 Hz), 1.14 (3H, s), 0.95 (6H, s), 0.94 (3H, d,
J ) 6.0 Hz), 0.89 (3H, d, J ) 6.5 Hz), 0.87 (9H, s), 0.76, 0.02,
-0.05 (each 3H, s); 13C NMR (CDCl3) δ 210.1, 178.2, 138.5, 125.6,
74.5, 53.1, 52.3, 51.6, 48.3, 47.5, 43.8, 42.2, 40.3, 39.2, 39.0, 36.8,
36.3, 32.9, 32.8, 30.8, 28.1, 26.0, 25.8, 24.4, 23.7, 23.4, 21.4, 20.7,
18.2, 17.3, 17.2, 15.8, 14.5, -4.1, -5.2; CIMS m/z 599 [M + H]+;
HRCIMS calcd for C37H62O4Si+H 599.4496, found 599.4497.
3r-Hyd r oxyu r s-12-en e-23,28-d ioic Acid 28-Meth yl Ester
(7). A solution of 23 (56 mg, 0.091 mmol) in a mixture of 48%
aqueous HF solution and CH3CN (1:9) (3 mL) was stirred at
room temperature for 16 h. After the mixture was diluted with
a mixture of Et2O and CH2Cl2 (2:1) (10 mL), it was washed with
water (four times) and saturated aqueous NaHCO3 solution
(twice), dried over MgSO4, filtered, and evaporated in vacuo to
give 7 as an amorphous solid (45 mg, 99%): TLC [hexanes/EtOAc
2928, 2863, 1725 cm-1 1H NMR (CDCl3) δ 7.35 (5H, m), 5.26
;
(1H, t, J ) 3.5 Hz), 4.56 (1H, d, J ) 12.0 Hz), 4.50 (1H, d, J )
12.0 Hz), 3.64 (1H, dd, J ) 4.5, 10.5 Hz), 3.62 (3H, s), 3.57 (1H,
d, J ) 8.5 Hz), 3.26 (1H, d, J ) 8.5 Hz), 2.25 (1H, d, J ) 11.5
Hz), 1.09, 0.97 (each 3H, s), 0.96 (3H, d, J ) 6.0 Hz), 0.94 (3H,
s), 0.87 (3H, d, J ) 6.5 Hz), 0.75 (3H, s); 13C NMR (CDCl3) δ
178.3, 138.3, 128.7, 127.9, 127.7, 125.8, 81.0, 76.8, 73.8, 53.1,
51.7, 50.6, 48.3, 47.8, 42.2, 42.0, 39.7, 39.3, 39.1, 38.4, 37.0, 36.8,
32.9, 32.1, 30.9, 28.2, 26.2, 24.4, 23.8, 23.5, 21.4, 18.9, 17.2, 17.1,
15.9, 14.3, 12.4; CIMS m/z 575 [M - H]+; HRCIMS calcd for
C
38H56O4-H 575.4100, found 575.4101. Anal. Calcd for C38H56O4‚
1/2H2O: C, 77.90; H, 9.81. Found: C, 78.13; H, 9.93.
Meth yl 23-Ben zyloxy-3r-(ter t-bu tyldim eth yl)silyloxyu r s-
12-en -28-oa te (21). A mixture of 19 (559 mg, 0.97 mmol), tert-
butylchlorodimethylsilane (603 mg, 4.0 mmol), KH (35% in
mineral oil, 3 mL), whose oil was removed by washing with
hexanes, and 18-crown-6 (10 mg, 0.038 mmol) in THF (30 mL)
was heated under reflux for 3 h. To the mixture was added
i-PrOH (2 mL) carefully to decompose unreacted KH in an ice
bath. After the mixture was diluted with a mixture of Et2O and
CH2Cl2 (2:1) (50 mL), it was washed with 5% aqueous HCl
solution (twice) and saturated aqueous NaHCO3 solution (twice),

6282 J . Org. Chem., Vol. 65, No. 19, 2000
Notes
(2:1)] Rf 0.09; [R]24D +35° (c 0.27, acetone); IR (KBr) 3448, 2931,
Hz), 3.70 (3H, s), 3.60 (3H, s), 2.23 (1H, d, J ) 11.5 Hz), 1.19,
1.13, 0.97 (each 3H, s), 0.94 (3H, d, J ) 6.0 Hz), 0.86 (3H, d, J
) 6.5 Hz), 0.75 (3H, s); 13C NMR (CDCl3) δ 178.34, 178.30, 138.4,
125.4, 72.7, 53.1, 52.2, 51.7, 51.6, 48.3, 47.8, 45.1, 42.3, 40.1,
39.2, 39.1, 36.9, 36.8, 32.8, 32.3, 30.8, 28.1, 24.9, 24.4, 24.0, 23.3,
21.5, 21.4, 17.24, 17.21, 17.19, 16.0; CIMS m/z 515 [M + H]+;
HRCIMS calcd for C32H50O5+H 515.3737, found 515.3735. Anal.
Calcd for C32H50O5: C, 74.67; H, 9.79. Found: C, 74.81; H, 9.87.
2861, 1719 cm-1 1H NMR (acetone-d6) δ 5.20 (1H, t, J ) 3.5
;
Hz), 3.78 (1H, t, J ) 2.5 Hz), 3.54 (3H, s), 2.21 (1H, d, J ) 11.0
Hz), 1.15, 1.12, 0.97 (each 3H, s), 0.92 (3H, d, J ) 5.5 Hz), 0.86
(3H, d, J ) 6.5 Hz), 0.75 (3H, s); 13C NMR (acetone-d6) δ 178.6,
178.3, 139.8, 126.8, 73.5, 54.4, 52.14, 52.06, 49.2, 48.9, 45.4, 43.4,
41.3, 40.4, 40.2, 37.94, 37.91, 34.0, 33.4, 31.8, 29.2, 26.3, 25.5,
24.7, 24.4, 22.2, 22.0, 18.4, 18.2, 18.1, 16.6; CIMS m/z 501 [M +
H]+; HRCIMS calcd for C31H48O5+H 501.3580, found 501.3582.
Anal. Calcd for C31H48O5‚1/3H2O: C, 73.48; H, 9.68. Found: C,
73.50; H, 9.75.
Ack n ow led gm en t . This investigation was sup-
ported by funds from the Norris Cotton Cancer Center.
We thank Dr. Steven Mullen (University of Illinois) for
the mass spectra and Professor David A. Evans, Mr.
Brett D. Allison (Harvard University), and Mr. Frank
G. Favaloro, J r. (Dartmouth College) for the optical
rotation measurements.
Dim eth yl 3r-Hyd r oxyu r s-12-en e-23,28-d ioa te (9). To a
solution of 7 (42 mg, 0.084 mmol) in THF (5 mL) was added
ethereal CH2N2 (10 mL). The solution was stirred at room
temperature for 1 h and then evaporated in vacuo to give a solid.
The solid was purified by flash column chromatography [hex-
anes-EtOAc (2:1)] to give 9 as an amorphous solid (39 mg,
91%): TLC [hexanes/EtOAc (2:1)] Rf 0.52; [R]24 +41° (c 0.38,
D
CHCl3); IR (KBr) 3519, 2979, 2948, 2924, 2871, 1726 cm-1; H
1
NMR (CDCl3) δ 5.25 (1H, t, J ) 3.5 Hz), 3.78 (1H, t, J ) 2.5
J O0008688