Preparation of a 24-nor-1,4-dien-3-one triterpene derivative from betulin: A new route to 24-nortriterpene analogues

Article abstract of DOI:10.1021/jo010929h

A new route to 24-nortriterpene derivatives with 2-hydroxy-δ^1,4-cyclohexadieny-3-one A-rings from triterpene precursors has been demonstrated beginning with betulin to prepare derivatives of betulinic acid. The key steps in the transformation are a Suarez cleavage of the A-ring with a subsequent SM1₂-mediated pinacol-type coupling to reclose the A-ring following removal of the C-24 carbon by oxidative cleavage.

Full text of DOI:10.1021/jo010929h

2864
J . Org. Chem. 2002, 67, 2864-2873
P r ep a r a tion of a 24-Nor -1,4-d ien -3-on e Tr iter p en e Der iva tive fr om
Betu lin : A New Rou te to 24-Nor tr iter p en e An a logu es1
Yonghong Deng and J ohn K. Snyder*
Department of Chemistry, Boston University, 590 Commonwealth Avenue, Boston, Massachusetts 02215
jsnyder@chem.bu.edu
Received September 17, 2001
A new route to 24-nortriterpene derivatives with 2-hydroxy-∆1,4-cyclohexadien-3-one A-rings from
triterpene precursors has been demonstrated beginning with betulin to prepare derivatives of
betulinic acid. The key steps in the transformation are a Sua´rez cleavage of the A-ring with a
subsequent SmI2-mediated pinacol-type coupling to reclose the A-ring following removal of the C-24
carbon by oxidative cleavage.
In tr od u ction
We recently reported the isolation and structure of the
cytotoxic remangilones A- D (1-4), from the Madagascar
plant Physena madagascariensis, which have the 24,28-
bisnoroleanane skeleton, with 1 and 2 possessing 2-hy-
droxy-∆1,4-cyclohexadien-3-one A-rings.2 The cytotoxicity
of the remangilones led us to consider the possibility of
converting readily available polycyclic triterpenes into 24-
noranalogues with similar A-rings and examining these
derivatives for biological activity. The ready availability
of the triterpene betulin (5) from local collections (betulin
comprises up to 30% of the outer bark of the white-barked
birches, Betula spp.)3 suggested an abundant source of
material to test this possibility. Furthermore, the recent
discovery of the highly selective anticancer activity of
betulinic acid (6)4 against human melanoma,5 as well as
its value as an anti-HIV agent,6 and the ease with which
betulin can be converted into betulinic acid7 suggested 7
as a target (Scheme 1). This conversion would also
require the generation of the C-28 carboxylic acid, which
has been suggested to be essential for the anticancer
activity of betulinic acid.8 Indeed, modifications of bio-
logically active triterpenoid carboxylic acids,9 including
betulinic acid,10 are well-known to enhance both the anti-
HIV and anticancer activities.
Sch em e 1
* To whom correspondence should be addressed. Phone: 617/353-
2621 (353-2575). Fax: 617/353-6466.
(1) Deng, Y. Ph.D. Dissertation, Boston University, Boston, MA,
2001.
(2) (a) For the isolation and structure determination of the remang-
ilones A-C, see: Deng, Y.; J iang, T.-Y.; Sheng, S.; Tianasoa-Rama-
monjy, M.; Snyder, J . K. J . Nat. Prod. 1999, 62, 471-476. (b) For the
isolation and structure determination of remangilone D, see: Deng,
Y.; Tianasoa-Ramamonjy, M.; Snyder, J . K. Z. Naturforsch. B 2001,
56B, 1079-1083.
(3) (a) J a¨a¨skela¨inen, P. Pap. Puu 1981, 63, 599-603. (b) Eckerman,
C.; Ekman, R. Pap. Puu 1985, 67, 100-106. (c) Hayek, E. W. H.; J ordis,
U.; Moche, W.; Sauter, F. Phytochemistry 1989, 28, 2229-2242. (d)
O’Connell, M. M.; Bentley, M. D.; Campbell, C. S.; Cole, B. J . W.
Phytochemistry 1988, 27, 2175-2176.
(4) For initial reports on the anticancer activity of betulin, see: (a)
Sheth, K.; J olad, S.; Wiedhopf, R.; Cole, J . R. J . Pharm. Sci. 1972, 61,
1819. (b) Trumbull, E. R.; Bianchi, E.; Eckert, D. J .; Wiedhopf, R. M.;
Cole, J . R. J . Pharm. Sci. 1976, 65, 1407-1408. (c) Kingston, D. G. I.;
Munjal, R. C. Lloydia 1978, 41, 499-500.
(5) (a) Pisha, E.; Chai, H.; Lee, I.-S.; Chagwedera, T. E.; Farnsworth,
N. R.; Cordell, G. A.; Beecher, C. W. W.; Fong, H. H. S.; Kinghorn, A.
D.; Brown, D. M.; Wani, M. C.; Wall, M. E.; Hieken, T. J .; Das Gupta,
T. K.; Pezzuto, J . M. Nature Med. 1995, 1, 1046-1051. (b) Fulda, S.;
Friesen, C.; Los, M.; Scaffidi, C.; Mier, W.; Benedict, M.; Nun˜ez, G.;
Krammer, P. H.; Peter, M. E.; Debatin, K.-M. Cancer Res. 1997, 57,
4956-4964.
Conversions of sterols into derivatives with 1,4-cyclo-
hexadien-3-one A-rings,11 and of triterpenes into both 24-
nor-12 and 23,24-bisnortriterpenes,13 have long been es-
(7) (a) Kim, D. S. H. L.; Chen, Z.; Nguyen, v. T.; Pezzuto, J . M.;
Qiu, S.; Lu, Z.-Z. Synth. Commun. 1997, 27, 1607-1612. For earlier
conversions of betulin to betulinic acid, see: (b) Ruzicka, L.; Lamberton,
A. H.; Christie, E. W. Helv. Chim. Acta 1938, 21, 1706-1717. (c)
Robertson, A.; Soliman, G.; Owen, E. C. J . Chem. Soc. 1939, 1267-
1273.
(8) (a) Chatterjee, P.; Pezzuto, J . M.; Kouzi, S. A. J . Nat. Prod. 1999,
62, 761-763. (b) Kim, D. S. H. L.; Pezzuto, J . M.; Pisha, E. Bioorg.
Med. Chem. Lett. 1998, 8, 1707-1712.
(6) (a) Fujioka, T.; Kashiwada, Y.; Kilkuskie, R. E.; Cosentino, L.
M.; Ballas, L. M.; J iang, J . B.; J anzen, W. P.; Chen, I.-S.; Lee, K.-H. J .
Nat. Prod. 1994, 57, 243-247. (b) Lee, K.-H.; Morris-Natschke, S. L.
Pure Appl. Chem. 1999, 71, 1045-1051.
10.1021/jo010929h CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/11/2002

A New Route to 24-Nortriterpene Analogues
J . Org. Chem., Vol. 67, No. 9, 2002 2865
Sch em e 2
tablished, though strategies that also allow for incorpora-
tion of a C-2 hydroxyl group in a ∆1,4-dien-3-one system
(∆4-2,3-diketones in enol tautomer) are less well-known.14
The conversions of triterpenes into 24-nor and 23,24-
bisnor derivatives typically feature A-ring cleavage under
relatively harsh conditions followed by removal of the
unwanted carbon(s) and A-ring reclosure. Approaches
proceeding through selective oxidation and subsequent
removal of a C-4 methyl group via decarboxylation have
also been reported,15 though these are less attractive from
a synthetic viewpoint. We felt a more efficient route to
oxidized 24-nor A-rings, as targeted in 7, from 3-hydroxy-
triterpenes such as 5 could begin with a Sua´rez cleavage16
and proceed through formation of a terminal olefin from
C-4/C-24 of the original triterpene (Scheme 2). Oxidative
(9) For some recent examples, see: (a) Honda, T.; Finlay, H. J .;
Gribble, G. W.; Suh, N.; Sporn, M. B. Bioorg. Med. Chem. Lett. 1997,
7, 1623-1628. (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, 1769-1772. (c) Honda, T.; Rounds, B. V.; Gribble,
G. W.; Suh, N.; Wang, Y.; Sporn, M. B. Bioorg. Med. Chem. Lett. 1998,
8, 2711-2714. (d) Kashiwada, Y.; Wang, H.-K.; Nagao, T.; Kitanaka,
S.; Yasuda, I.; Fujioka, T.; Yamagishi, T.; Cosentino, L. M.; Kozuka,
M.; Okabe, H.; Ikeshiro, Y.; Hu, C.-Q.; Yeh, E.; Lee, K.-H. J . Nat. Prod.
1998, 61, 1090-1095. (e) Assefa, H.; Nimrod, A.; Walker, L.; Sindelar,
R. Bioorg. Med. Chem. Lett. 1999, 9, 1889-1894. (f) Kashiwada, Y.;
Nagao, T.; Hashimoto, A.; Ikeshiro, Y.; Okabe, H.; Cosentino, L. M.;
Lee, K.-H. J . Nat. Prod. 2000, 63, 1619-1622.
olefin cleavage and subsequent pinacol-type coupling to
reclose the A-ring would then form the 24-norskeleton,
with further transformations ultimately giving the target
7. To avoid complications arising from the introduction
of the methyl ketone at C-20 from the oxidative olefin
cleavage, the 20,29-dihydro derivative was the final
target. We now report the fruition of this work culminat-
ing in the efficient conversion of 5 into 7.
Resu lts a n d Discu ssion
(10) For some recent examples, see: (a) Mayaux, J .-F.; Bousseau,
A.; Pauwels, R.; Huet, T.; He´nin, Y.; Dereu, N.; Evers, M.; Soler, F.;
Poujade, C.; de Clercq, E.; le Pecq, J .-B. Proc. Natl. Acad. Sci. U.S.A.
1994, 91, 3564-3568. (b) Kashiwada, Y.; Hashimoto, F.; Cosentino,
L. M.; Chen, C.-H.; Garrett, P. E.; Lee, K.-H. J . Med. Chem. 1996, 39,
1016-1017. (c) Sun, I.-C.; Shen, J .-K.; Wang, H.-K.; Cosentino, L. M.;
Lee, K.-H. Bioorg. Med. Chem. Lett. 1998, 8, 1267-1272. (d) Hash-
imoto, F.; Kashiwada, Y.; Cosentino, L. M.; Chen, C.-H.; Garrett, P.
E.; Lee, K.-H. Bioorg. Med. Chem. 1997, 5, 2133-2143. (e) Lee, S.-S.;
Chen, W.-C.; Huang, C.-F.; Su, Y. J . Nat. Prod. 1998, 61, 1343-1347.
(f) Sun, I.-C.; Wang, H.-K.; Kashiwada, Y.; Shen, J .-K.; Cosentino, L.
M.; Chen, C.-H.; Yang, L.-M.; Lee, K.-H. J . Med. Chem. 1998, 41, 4648-
4657. (g) J eong, H.-J .; Chai, H.-B.; Park, S.-Y.; Kim, D. S. H. L. Bioorg.
Med. Chem. Lett. 1999, 9, 1201-1204. (h) Kouzi, S. A.; Chatterjee, P.;
Pezzuto, J . M.; Hamann, M. T. J . Nat. Prod. 2000, 63, 1653-1657.
(11) (a) Djerassi, C.; Scholz, C. R. J . Am. Chem. Soc. 1947, 69, 2404-
2410. (b) Ringold, H. J .; Rosenkranz, G.; Sondheimer, F. J . Org. Chem.
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1989, 45, 6409-6426. (d) Mateos, A. F.; Barrueco, O. F.; de Pascual
Teresa, J .; Gonza´lez, R. R. Tetrahedron 1991, 47, 4375-4382. (e) van
Leusen, D.; van Leusen, A. M. J . Org. Chem. 1994, 59, 7534-7538. (f)
Abul-Hajj, Y. J .; Liu, X.-P.; Hedge, M. Steroids 1995, 60, 423-427.
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J . Chem. Soc., Chem. Commun. 1969, 945-946. (b) Barton, D. H. R.;
Kumari, D. Liebigs Ann. Chem. 1970, 737, 108-118. (c) Pettit, G. R.;
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Kazlauskas, R.; Pinhey, J . T. J . Chem. Soc., Perkin Trans. 1 1973,
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1991, 69, 570-577.
(13) (a) Voser, W.; White, D. E.; Heusser, H.; J eger, O.; Ruzicka, L.
Helv. Chim. Acta 1952, 35, 830-837. (b) Voser, W.; Heusser, H.; J eger,
O.; Ruzicka, L. Helv. Chim. Acta 1953, 36, 299-301. (c) Barton, D. H.
R.; Ives, D. A.; Thomas, B. R. J . Chem. Soc. 1954, 903-907. (d) Crabbe´,
P.; Ourisson, G.; Takahashi, T. Tetrahedron 1958, 3, 279-302. (e)
Pettit, G. R.; Hofer, P. Helv. Chim. Acta 1963, 46, 2142-2146. (f) Pettit,
G. R.; Dias, J . R. Can. J . Chem. 1969, 47, 1091-1092. (g) Shoppee, C.
W.; Hughes, N. W.; Lack, R. E.; Pinhey, J . T. J . Chem. Soc. C 1970,
1443-1447. (h) Hase, T. A.; Huikko, R. Acta Chem. Scan. B 1978, 32,
467-468. (i) Uusvuori, R.; Hase, T. A. Synth. Commun. 1982, 12,
1081-1088. (j) Wolff, G. A.; Trendel, J . M.; Albrecht, P. Tetrahedron
1989, 45, 6721-6728. (k) Honda, T.; Gribble, G. W. J . Org. Chem. 1998,
63, 4846-4849.
Monoacetylation of betulin (5) resulted in selective
acylation of the primary alcohol to give 8 (60-72%
depending upon the scale, Scheme 3). Selective protection
of the C-28 alcohol in 5 with TBSCl or TBSOTf was
unsuccessful presumably due to the relatively hindered
nature of this neopentyl-type primary alcohol, invariably
resulting in a mixture of mono- and disilylated products.
Further transformations were carried out initially on 8
to optimize procedures and then subsequently on 20,29-
dihydro derivative 9, quantitatively prepared from 8 by
hydrogenation, though only the dihydro derivative 9 was
completely transformed into the desired oxidized A-ring.
Sua´rez cleavage16,17 of 8 and 9 produced aldehydes 10a
and 10b, respectively (63% crude yield of 10a and 55%
yield of 10b after purification). Similar olefin production
has been previously noted in the â-fragmentations of
alkoxy radicals photolytically generated from hypoiodites,
particularly when a tertiary radical is produced, and has
been proposed to proceed by oxidation of the radical to
the tertiary carbocation with subsequent olefin formation
or through an intermediate tertiary iodide followed by
in situ HI elimination (Scheme 4).16,18
As aldehydes 10a and 10b were not robust, slowly
decomposing upon standing on the benchtop over the
course of a few days, they were immediately protected
as the dimethyl acetals 11a and 11b, respectively (55%
yield over two steps for 11a from 8 and 91% yield of 11b
from 10b), with trimethyl orthoformate.19 Originally, the
ethylene glycol acetal was prepared from 10a ; however,
subsequent removal of the protecting group to regenerate
(14) (a) Baran, J . S. J . Am. Chem. Soc. 1958, 80, 1687-1691. (b)
Clarke, R. L. J . Am. Chem. Soc. 1960, 82, 4629-4631. (c) Frimer, A.
A.; Hameiri-Buch, J .; Ripshtos, S.; Gilinsky-Sharon, P. Tetrahedron
1986, 42, 5693-5706.
(15) (a) Dasai, M. C.; Singh, C.; Chawla, H. P. S.; Dev, S. Tetrahe-
dron 1982, 38, 201-208. (b) Carr, K.; Saxton, H. M.; Sutherland, J .
K. J . Chem. Soc., Perkin Trans. 1 1988, 1599-1601.
(16) For a review, see: (a) Sua´rez, E.; Rodr´ıguez, M. S. In Radicals
in Organic Synthesis; Renaud, P., Sibi, M. B., Eds.; Wiley: New York,
2001; Vol. 2, pp 440-454. For a study of the mechanism, see: (b)
Courtneidge, J . L.; Lusztyk, J .; Page´, D. Tetrahedron Lett. 1994, 35,
1003-1006.
(17) Boto, A.; Freire, R.; Herna´ndez, R.; Sua´rez, E.; Rodriguez, M.
S. J . Org. Chem. 1997, 62, 2975-2981.
(18) (a) Lorenc, L.; Bondarenko, L.; Rajkovic, M.; Milovanovic, A.;
Mihalovic, M. Lj. Tetrahedron 1983, 39, 3609-3614. (b) Suginome, H.;
Yamada, S. Bull. Chem. Soc. J pn. 1985, 58, 3055-3056. (c) Suginome,
H.; Yamada, S. Tetrahedron, 1987, 43, 3371-3386. (d) Arencibia, M.
T.; Freire, R.; Perales, A.; Rodriguez, M. S.; Sua´rez, E. J . Chem. Soc.,
Perkin Trans. 1 1991, 3349-3360.
(19) Wenkert, E.; Goodwin, T. E. Synth. Commun. 1977, 7, 409-
415.

2866 J . Org. Chem., Vol. 67, No. 9, 2002
Deng and Snyder
Sch em e 3
Sch em e 4
respectively, in good yields, both as mixtures of R- and
â-oriented cis vicinal diols (R:â ) 10.7:1 for 14a and 10:1
for 14b; Scheme 5, Eq 1). While these diols proved to be
extremely difficult to separate by chromatography, the
diols of 14a were ultimately purified, whereas only the
major diol of 14b could be obtained in pure form.
The stereochemistry of the major diol R14a was as-
signed on the basis of extensive NMR experiments. The
proton at δ 3.52 (br s, W1/2 ) 6.3 Hz with the correspond-
ing carbon identified in the HMQC spectrum at δ 73.8)
showed long-range heteronuclear coupling in the HMBC
spectrum with C-1 (δ 32.3), C-2 (δ 21.8), C-4 (δ 73.2), and
C-5 (δ 49.8) and was assigned as H-3. The relatively
narrow line width indicated the proton was â-oriented
since a W1/2 of 6.3 Hz indicates an equatorial proton with
vicinal couplings e 3 Hz (H-3 has two vicinal partners).
The methyl resonance (1H/13C, δ 1.09/21.1), which showed
long-range heteronuclear coupling with C-3, C-4, and C-5,
was assigned to the C-24 methyl group. Another methyl
resonance (1H/13C, δ 0.77/14.9), which showed long-range
heteronuclear coupling with C-1, C-5, and C-10 (δ 37.5),
must therefore be the C-25 methyl group. Irradiation of
this methyl group (C-25) resulted in enhancements of the
C-24 methyl signal as well as another methyl singlet (δ
0.993), which therefore must be the C-26 methyl group,
indicating that the C-24 methyl group lies on the â-face
and both hydroxyl groups must be in a cis relationship
and R-oriented.
the aldehyde proved to be surprisingly troublesome,20 so
the more labile dimethyl acetals were used. Oxidative
cleavage of the olefins with stoichiometric RuO2/NaIO4
21
gave diketone 12a from 11a (75%) and monoketone 12b
from 11b (85%). The use of catalytic [RuO4]22 resulted in
significantly more sluggish reactions and lower yields,
while ozonolysis also gave considerably lower yields of
11a and 11b contaminated with over-oxidized products.
Deprotection of the aldehydes (PPTS/wet acetone) gave
keto aldehydes 13a (92%) and 13b (88%), respectively,
setting the stage for the pinacol coupling to reclose the
A-ring with a C-4 methyl group now removed.
Initial efforts attempting to utilize McMurry couplings
with 13a were unsuccessful.23 Samarium diiodide reduc-
tive coupling of 13a and 13b in THF in the presence of
tert-BuOH as a proton source (2 equiv),24 however,
provided the desired diols 14a (77%) and 14b (87%),
The stereochemistry of the minor diol â14a was
similarly defined. Thus, the proton resonance at δ 3.20
(dd, J ) 7.9, 7.9 Hz, corresponding carbon at δ 75.3 from
the HMQC spectrum), which showed long-range hetero-
nuclear couplings in the HMBC spectrum with C-1 (δ
37.7), C-2 (δ 27.5), and C-4 (δ 74.1), was assigned as H-3.
The methyl singlet (1H/13C, δ 1.21/25.1), which showed
long-range heteronuclear couplings with C-3, C-4, and
C-5 (δ 53.4), was assigned as the C-23 methyl group,
while the proton resonance at δ 0.73 (dd, J ) 2.1, 11.9
Hz, 1H), correlating to C-5 in the HMQC spectrum, was
assigned as H-5. Nuclear Overhauser enhancements
(20) For similar difficulties in an ethylene glycol acetal deprotection,
see: Masse, C. E.; Yang, M.; Solomon, J .; Panek, J . S. J . Am. Chem.
Soc. 1998, 120, 4123-4134.
(21) (a) Nakata, H. Tetrahedron 1963, 19, 1959-1963. (b) Piccialli,
V.; Smaldone, D. M. A.; Sica, D. Tetrahedron 1993, 49, 4211-4228.
(22) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J . Org. Chem. 1981, 46, 3936-3938.
(23) Pinacol coupling procedures attempted: (a) Mukaiyama, T.;
Sato, T.; Hanna, J . Chem. Lett. 1973, 1041-1044. (b) Kato, N.;
Takeshita, H.; Kataoka, H.; Ohbuchi, S.; Tanaka, S. J . Chem. Soc.,
Perkin Trans. 1 1989, 165-174. (c) McMurry, J . E.; Rico, J . G.
Tetrahedron Lett. 1989, 30, 1169-1172. For
a review, see: (d)
McMurry, J . E. Chem. Rev. 1989, 89, 1513-1524.
(24) (a) Namy, J . L.; Souppe, J .; Kagan, H. B. Tetrahedron Lett.
1983, 24, 765-766. (b) Souppe, J .; Danon, L.; Namy, J . L.; Kagan, H.
B. J . Organomet. Chem. 1983, 250, 227-236. (c) Molander, G. A.;
Kenny, C. J . Org. Chem. 1988, 53, 2132-2134. (d) Molander, G. A.;
Kenny, C. J . Am. Chem. Soc. 1989, 111, 8236-8246. (e) Kagan, H. B.
New J . Chem. 1990, 14, 453-460. (f) Hoffman, H. M. R.; Mu¨nnich, I.;
Nowitzki, O.; Stucke, H.; Williams, D. H. Tetrahedron 1996, 52, 11783-
11798. (g) Nowitzki, O.; Mu¨nnich, I.; Stucke, H.; Hoffman, H. M. R.
Tetrahedron 1996, 52, 11799-11810. For a review, see: (h) Molander,
G. A. Chem. Rev. 1992, 92, 29-68.

A New Route to 24-Nortriterpene Analogues
J . Org. Chem., Vol. 67, No. 9, 2002 2867
Sch em e 5
(NOEs) of H-5 with H-3 and H-23 indicated that these
protons were on the R-face of the molecule; thus, the
hydroxyl groups are cis and â-oriented. Similar experi-
ments established the stereochemistry of the major
diastereomer of 14b as R14b.
sluggish, gave the R,â-unsaturated ketones 16a (73%, 48
h) and 16b (73%, 48 h), respectively. While these dehy-
drations were performed on the mixtures of R- and
â-ketols, presumably only the major R-ketols undergo
dehydration since the Burgess reagent functions by syn
elimination. Thus, the dominant R-diol stereoselectivity
in the SmI2-coupling was critical to the success of this
later Burgess elimination.
The exclusive production of cis vicinal diols in the
intramolecular pinacol coupling promoted by SmI2 ob-
served in these reactions parallels results noted by
Molander,24c,d Hanessian,25 and others24f,26 in intramo-
lecular SmI2-mediated pinacolic cyclizations. Presumably,
the stereoselectivity favoring the R-diols 14 results from
the greater steric interactions between the samarium
ligands of the chelated ketyl24c,d,27 and the C-25 angular
methyl group in the transition state leading to the â-diols
in comparison to the analogous interactions between the
C-24 and C-25 methyl groups in the transition state
leading to the R-diols (Figure 1). Since the dienone A-ring
of the target lacks stereochemical identity at C-3 and C-4,
further transformations of the diols could be accom-
plished on the mixtures of the diastereomers.
Oxidation of the secondary alcohol to the C-3 ketone
was accomplished with the Swern protocol28 yielding
ketones 15a (73%) and 15b (79%) from 14a and 14b,
respectively (Scheme 5, Eq 1). Oxidations employing
PCC29 or the Dess-Martin reagent,30 both potential
chelating oxidants, were also examined with 14a , but in
these cases, significant amounts of diol cleavage ac-
companied the formation of 15a , regenerating the diketo
aldehyde 13a (Scheme 5, Eq 2). Subsequent dehydration
of 15a and 15b with the Burgess reagent,31 though
With the 3-keto-∆4-nor-24 A-ring construction com-
plete, all that remained was oxidation of C-2 in the A-ring
as well as oxidation of C-28 to the carboxylic acid. Since
oxidation of the kinetic enolate was envisioned as a
straightforward means to establish the 2-hydroxy-∆1,4
-
dien-3-one A-ring from 16b, and complications were
anticipated from the second enolizable ketone at C-20 of
16a following this strategy, a second model 17c, easily
prepared from betulin (5) by hydrogenation (>99%) and
a J ones oxidation (62%),7a served to optimize the proce-
dures for manipulation of the carboxylic acid during the
A-ring oxidation (Scheme 6). Since considerable material
was lost during the isolation of 17c by chromatography,
the crude product mixture from the J ones oxidation was
converted to the methyl ester 18c to enable optimal
purification. Classic esterification procedures (MeOH/H+,
SOCl2/MeOH) failed, presumably due to the hindered
tertiary nature of the carboxylic R-position,7c,32 but simple
nucleophilic substitution by the carboxylate anion (MeI/
CsF)33 was successful, providing 18c in 87% yield.
(25) Chiara, J . L.; Cabri, W.; Hanessian, S. Tetrahedron Lett. 1991,
32, 1125-1128.
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M.; Ito, S.; Matsuda, F.; Shirahama, H. J . Org. Chem. 1994, 59, 5532-
5534.
(27) Corey, E. J .; Danheiser, R. L.; Chandrasekaran, S. J . Org.
Chem. 1976, 41, 260-265.
(28) (a) Mancuso, A. J .; Huang, S.-L.; Swern, D. J . Org. Chem. 1978,
43, 2480-2482. (b) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651-
1660. (c) Mancuso, A. J .; Swern, D. Synthesis 1981, 165-185. (d) Marx,
M.; Tidwell, T. T. J . Org. Chem. 1984, 49, 788-793. For a study of
Swern oxidation of vicinal diols, see: (e) Amon, C. M.; Banwell, M. G.;
Gravatt, G. L. J . Org. Chem. 1987, 52, 4851-4855.
(29) (a) Corey, E. J .; Suggs, J . W. Tetrahedron Lett. 1975, 2647-
2650. For a review, see: (b) Piancatelli, G.; Scettri, A.; D’Auria, M.
Synthesis 1982, 245-258.
(30) (a) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155-
4156. (b) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277-
7287.
(31) (a) Burgess, E. M.; Penton, H. R., J r.; Taylor, E. A. J . Am. Chem.
Soc. 1970, 92, 5224-5226. (b) Burgess, E. M.; Penton, H. R., J r.; Taylor,
E. A. J . Org. Chem. 1973, 38, 26-31.
F igu r e 1. SmI2-promoted pinacol coupling of ketoaldehydes
13a and 13b favoring R-diols due to diaxial interactions
between samarium ligands and the C-25 methyl group in the
closure leading to â-diols.

2868 J . Org. Chem., Vol. 67, No. 9, 2002
Deng and Snyder
Sch em e 6
Sch em e 7
R-Oxidation of the ketone enolate of 18c at C-2 was then
achieved under modified Rubottom conditons34 (Et3N/
TMSCl and then m-CPBA)35 to give the silylated R-hy-
droxyketone 19c (74%). The large, transdiaxial coupling
observed for H-2 (δ 4.55, dd, J ) 6.4, 12.4 Hz) indicated
that the silyl ether is R-oriented. Other R-oxidation
procedures (LDA/TMSCl/m-CPBA34 and KHMDS/3-phen-
yl-2-(phenylsulfonyl)oxaziridine36) were less successful.
Swern oxidation of 19c (84%) and demethylation (Me2S/
AlBr3, 77%)37 yielded the model 20c.38 Other attempts
to demethylate the methyl ester by basic hydrolysis
(NaOH, LiOH, LiOH/H2O2, tert-BuOK) all failed, again
illustrating the hindered nature of this neopentyl-type
carbonyl.39
With the model studies completed, methyl ester 18b
was prepared from 16b following the same protocols
employed in the model study with 18c (Scheme 7):
methanolysis gave the primary alcohol (95%) followed by
J ones oxidation (85%) and esterification (85%) yielding
18b. Thus, only the A-ring oxidation of 18b remained to
be undertaken. Originally, it was anticipated that C-2
enolate formation would be favored under kinetic condi-
tions, which would minimize or avoid formation of the
thermodynamically favored enolate at C-6.14c,40 However,
treatment of 18b with a variety of hindered bases at low
temperatures (HMDS, KHMDS, LDA, Hu¨nig’s base,
LTMP, and proton sponge) to form the kinetic enolate,
followed by oxidation with 2-(phenylsulfonyl)-3-phenyl-
oxaziridine36,41 or by a TMSCl quench and then m-CPBA,
invariably produced a mixture of C-2 and C-6 oxidized
products. For example, Hu¨nig’s base (iPr2NEt) followed
by TMSCl/mCPBA gave a 1.1:1 mixture of C-2 and C-6
keto alcohols 21 and 22 in 71% combined yield, each as
single diastereomers (Scheme 7, Eq 1). Selective C-2
oxidation was finally achieved with benzeneseleninic
anhydride/KOtBu42 to produce the desired 23 in 52% yield
(with 30% recovered starting material, Scheme 6, Eq 2).
The target 7 was completed by the Me2S/AlBr3 demeth-
ylation of the ester (74%) as described in the model
studies.
Bioa ctivity. Both the target compound 7 and model
20c were submitted to NCI for anticancer screening.
Overall, both compounds were slightly less active than
betulinic acid as evidenced by the GI50, TGI, and LC50
values averaged over all 60 cell lines (see Supporting
Information). Notable in the activity of 7, however, was
a GI50 of <10 nM against SK-OV-3 ovarian cancer cells
(TGI ) 363 nM), far exceeding the activity observed with
any other cell line. Betulinic acid derivative 20c with the
C-4 gem-dimethyl group intact also showed significant
activity against all six leukemia cell lines screened (GI50
) 2-7 µM).
(32) 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, 3429-3434.
(33) Sato, T.; Otera, J .; Nozaki, H. J . Org. Chem. 1992, 57, 2166-
2169.
(34) (a) Rubottom, G. M.; Vazquez, M. A.; Pelegrina, D. R. Tetra-
hedron Lett. 1974, 4319-4322. (b) Brook, A. G.; Macrae, D. M. J .
Organomet. Chem. 1974, 77, C19-C21. (c) Hassner, A.; Reuss, R. H.;
Pinnick, H. W. J . Org. Chem. 1975, 40, 3427-3429.
(35) VanderRoest, J . M.; Grieco, P. A. J . Org. Chem. 1996, 61, 5316-
5325.
(36) Davis, F. A.; Vishwakarma, L. C.; Billmers, J . M.; Finn, J . J .
Org. Chem. 1984, 49, 3241-3243.
(37) (a) Node, M.; Nishide, K.; Sai, M.; Fuji, K.; Fujita, E. J . Org.
Chem. 1981, 46, 1991-1993. For a review, see: (b) Salomon, C. J .;
Mata, E. G.; Mascaretti, O. A. Tetrahedron 1993, 49, 3691-3734.
(38) Lehn, J .-M.; Ourisson, G. Bull. Soc. Chim. Fr. 1962, 1133-
1136.
(40) (a) Camerino, B.; Patelli, B.; Sciaky, R. Tetrahedron Lett. 1961,
554-559. (b) D’Angelo, J . Tetrahedron 1976, 32, 2979-2990.
(41) For a review, see: Davis, F. A.; Chen, B.-C. Chem. Rev. 1992,
92, 919-934.
(42) (a) Ayrey, G.; Barnard, D.; Woodbridge, D. T. J . Chem. Soc.
1962 2089-2099. (b) Barton, D. H. R.; Ley, S. V.; Magnus, P. D.;
Rosenfeld, M. N. J . Chem. Soc., Perkin Trans. 1 1977, 567-572. For
recent, similar applications, see: (c) Holton, R. A.; Kim, H.-B.; Somoza,
C.; Liang, F.; Biediger, R. J .; Boatman, P. D.; Shindo, M.; Smith, C.
C.; Kim, S.; Nadizadeh, H.; Suzuki, Y.; Tao, C.; Vu, P.; Tang, S.; Zhang,
P.; Murthi, K. K.; Gentile, L. N.; Liu, J . H. J . Am. Chem. Soc. 1994,
116, 1599-1600. (d) Danishefsky, S. J .; Masters, J . J .; Young, W. B.;
Link, J . T.; Snyder, L. B.; Magee, T. V.; J ung, D. K.; Isaacs, R. C. A.;
Bornmann, W. G.; Alaimo, C. A.; Coburn, C. A.; Di Grandi, M. J . J .
Am. Chem. Soc. 1996, 118, 2843-2859.
(39) (a) Honda, T.; Rounds, B. V.; Gribble, G. W.; Suh, N.; Wang,
Y.; Sporn, M. B. Bioorg. Med. Chem. Lett. 1998, 8, 2711-2714. (b)
Kashiwada, Y.; Chiyo, J .; Ikeshiro, Y.; Nagao, T.; Okabe, H.; Cosentino,
L. M.; Fowke, K.; Morris-Natschke, S. L.; Lee, K. H. Chem. Pharm.
Bull. 2000, 48, 1387-1390.

A New Route to 24-Nortriterpene Analogues
J . Org. Chem., Vol. 67, No. 9, 2002 2869
NaHCO3 solution, and then saturated brine and then dried
(Na2SO4). Removal of the solvent in vacuo and flash chroma-
tography of the crude product on silica gel (85:15 hexanes:
EtOAc) afforded 8 (2.59 g, 60%) as a white solid, accompanied
by 3,28-diacetate10f (290 mg, 6%) and recovered betulin (651.9
mg, 16%): mp 217-219 °C; 1H NMR (400 MHz, CDCl3) δ 0.72
(s, 3H), 0.79 (s, 3H), 0.93 (s, 3H), 0.94 (s, 3H), 0.99 (s, 3H),
1.64 (s, 3H), 2.04 (s, 3H), 2.41 (ddd, J ) 6.0, 11.2, 11.2 Hz,
1H), 3.15 (dd, J ) 5.2, 11.6 Hz, 1H), 3.82 (d, J ) 11.2 Hz, 1H),
4.21 (dd, J ) 1.2, 11.2 Hz, 1H), 4.55 (br s, 1H), 4.65 (d, J ) 1.6
Hz, 1H); 13C NMR (67.5 MHz, CDCl3) δ 14.7, 15.3, 15.95, 16.04,
18.2, 19.0, 20.7, 21.0, 25.1, 27.0, 27.3, 27.9, 29.5, 29.7, 34.1,
34.5, 37.1, 37.5, 38.6, 38.8, 40.8, 42.6, 46.2, 47.6, 48.7, 50.3,
55.2, 62.7, 78.9, 109.8, 150.1, 171.6.
Con clu sion s
A new route to 24-nortriterpene derivatives with
oxidized A-rings from triterpene precursors has been
demonstrated beginning with betulin to prepare deriva-
tives of betulinic acid. The key steps in the transforma-
tion are a Sua´rez cleavage of the A-ring with a subse-
quent SmI2-mediated pinacol-type coupling to reclose the
A-ring following removal of the C-24 carbon by oxidative
cleavage. Further applications of this chemistry are
underway to prepare other derivatives of betulin for
anticancer screening.
28-O-Acetyl-3-lu p a n ol (9). A solution of 8 (2.56 g, 5.48
mmol) in a mixture of THF:MeOH (1:2, v/v, 55 mL) was
hydrogenated under H2 (40 psi) over 10% Pd/C (0.768 g, 30 wt
%) with shaking for 22 h and then filtered. Removal of the
solvent in vacuo afforded 946 (2.57 g, 99+%) as a white solid.
No further purification was necessary: mp 243-245 °C; 1H
NMR (400 MHz, CDCl3) δ 0.739 (d, J ) 6.4 Hz, 3H), 0.741 (s,
3H), 0.81 (s, 3H), 0.82 (d, J ) 6.4 Hz, 3H), 0.93 (s, 3H), 0.95
(s, 3H), 1.01 (s, 3H), 2.04 (s, 3H), 3.17 (dd, J ) 5.2, 11.6 Hz,
1H), 3.80 (d, J ) 11.2 Hz, 1H), 4.21 (dd, J ) 1.6, 11.2 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 14.6, 14.8, 15.4, 16.0 (2C), 18.2,
20.7, 21.0, 21.5, 22.9, 26.9, 26.9, 27.3, 27.9, 29.4, 29.8, 34.2,
34.6, 37.05, 37.08, 38.6, 38.8, 40.8, 42.8, 44.4, 46.4, 48.0, 50.0,
55.2, 62.8, 78.9, 171.6; HRMS (EI, 70 eV) m/z calcd for C32H54O3
486.4073, found 486.4099 ([M]+, 1.8%).
Su a´r ez Clea va ge of 8: seco-Dim eth yla ceta l 11a . A
solution of 8 (2 g, 4.13 mmol) in dry hexanes (142 mL),
containing diacetoxyiodobenzene (DIB, 1.996 g, 6.20 mmol) and
I2 (1.050 g, 4.13 mmol), was irradiated with a 425 W sunlamp
for 4 h at 25 °C. The reaction mixture was then poured into
saturated aqueous sodium thiosulfate solution (70 mL) and
then extracted with CH2Cl2 (3 × 70 mL). The combined organic
extracts were washed with saturated brine and dried (Na2-
SO4), and the solvent was removed in vacuo to give crude 11a ,
which was used in the next step without further purification.
A small sample of the crude product could be purified by flash
chromatography on silica gel (95:5 hexanes:EtOAc) to give a
sample of pure 10a as a colorless oil (Rf ) 0.4, 9:1 hexanes:
EtOAc) for characterization: 1H NMR (400 MHz, CDCl3) δ 0.84
(s, 3H), 0.97 (s, 3H), 1.06 (s, 3H), 1.67 (s, 3H), 1.69 (s, 3H),
2.05 (s, 3H), 2.18-2.28 (m, 1H), 2.36-2.47 (m, 2H), 3.84 (d, J
) 11.0 Hz, 1H), 4.23 (dd, J ) 1.8, 11.0 Hz, 1H), 4.58 (br s,
1H), 4.59 (d, J ) 1.8 Hz, 1H), 4.67 (d, J ) 1.8 Hz, 1H), 4.81
(br s, 1H), 9.69 (dd, J ) 2.1, 2.1 Hz, 1H); 13C NMR (67.5 MHz,
CDCl3) δ 14.6, 16.0, 19.1, 20.2, 21.1, 21.3, 22.9, 24.4, 25.0, 27.6,
29.5, 29.6, 31.0, 32.6, 34.5, 37.6, 38.2, 39.0, 40.6, 40.8, 43.1,
46.3, 47.6, 48.7, 50.5, 62.7, 110.0, 113.4, 147.6, 150.0, 171.6,
202.9; HRMS (EI, 70 eV) m/z calcd for C32H50O3 482.3760,
found 482.3758 ([M]+, 16%).
Exp er im en ta l Section
Gen er a l Meth od s. 1H and 13C NMR spectra were recorded
at 93.94 kG (1H NMR 400 MHz, 13C NMR 100 MHz), 70.50
kG (1H NMR 300 MHz, 13C NMR 75 MHz), or 63.41 kG (1H
NMR 270 MHz, 13C NMR 67.5 MHz) at ambient temperature
in the solvents as indicated. Chemical shifts (in parts per
million) are relative to an internal reference using the residual
protio solvent for the proton reference and the center line of
the solvent multiplet for the carbon reference (1H/13C (CDCl3)
7.24/77.0, (C6D6) 7.16/128.0). Unless otherwise noted, each
carbon resonance represents a single carbon (relative inten-
sity); intensities of more than a single carbon were established
from integration of spectra acquired under inverse-gated
decoupled conditions (delay between transients of 10 s). All
OH proton assignments were confirmed by D2O exchange.
Only distinctive resonances from the proton spectra of the
triterpenoid derivatives are given; in all spectra, considerable
overlap of the nonmethyl resonances exists between δ 1.0-
2.0. Mass spectra (HRMS) were recorded in either CI (140 eV)
or EI (70 eV) mode as noted. Infrared spectra were recorded
on NaCl plates; solid samples were prepared by depositing a
solution of the sample (typically in CDCl3) on the plate and
allowing the solvent to evaporate prior to recording the spectra.
All reaction solvents were dried and distilled immediately
prior to use (THF and Et2O over sodium/benzophenone, CH2-
Cl2 over CaH2);43 chromatography solvents were distilled prior
to use. Commercially available reagents were used without
further purification; all reactions were carried out in oven-
dried (105 °C) glassware. Dry ice-acetone baths were used to
maintain reactions at -78 °C and dry ice-50% aqueous
acetone baths to maintain reactions at -30 °C. Flash chro-
matography was performed using silica gel 60 (43-60 µm);
TLC was performed on silica gel plates, with visualization
accomplished by either UV illumination or staining with acidic
vanillin solution (2 g of vanillin in 2 mL of concd H2SO4 per
100 mL of 95% EtOH).
Betu lin (5). The bark of the white birch (Betula papyrifera,
∼1 kg), collected in Harvard, MA, was cut into small pieces
and soaked in acetone with 0.5% MeOH for 2 days. The
extraction was filtered and the solvent removed in vacuo to
produce a dark yellow solid residue (239 g). A portion of this
crude extract (80 g) was dissolved in MeOH/CHCl3 (1:1, 300
mL), and the solution was briefly refluxed and then allowed
to stand overnight at room temperature. The crystals that
formed were collected to give betulin (5, 9 g) that was 95%
Crude 10a was dissolved in dry MeOH (40 mL), then treated
with p-TsOH monohydrate (35.6 mg, 0.187 mmol, 4.5 mol %),
and trimethyl orthoformate (3.6 mL, 33.0 mmol). The reaction
mixture was refluxed for 1 h and then the solvent removed in
vacuo. The residue was partitioned between EtOAc (50 mL)
and saturated aqueous NaHCO3 solution (50 mL). The organic
layer was washed with saturated brine and dried (Na2SO4),
and the solvent was removed in vacuo. Flash chromatography
of the crude product on silica gel (98:2 hexanes:EtOAc) afforded
11a (1.20 g, 55% for two steps, Rf ) 0.42, 9:1 hexanes:EtOAc)
as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.76 (s, 3H),
0.94 (s, 3H), 1.02 (s, 3H), 1.64 (s, 3H), 1.68 (s, 3H), 2.03 (s,
3H), 2.41 (ddd, J ) 5.8, 11.0, 11.0 Hz, 1H), 3.28 (s, 3H), 3.30
pure by H NMR44 and used without further purification.
1
28-O-Acetyl-20(29)-lu p en -3-ol (8).45 The yield of this
reaction varied with the scale (60-72%), with highest yields
obtained at smaller scales (200 mg of 5). In a larger-scale
reaction, to a solution of betulin (5, 4 g, 9.04 mmol), 4-(di-
methylamino)pyridine (DMAP, 0.4 g, 1% w/w), and pyridine
(6 mL, 25.2 mmol) in CH2Cl2 (36 mL) was added acetic
anhydride (0.90 mL, 9.53 mmol), and the resulting mixture
was stirred at room temperature for 18 h. The reaction mixture
was washed with 10% aqueous HCl, water, saturated aqueous
(45) Other procedures for the monoacetylation of betulin: (a) Tietze,
L. F.; Heinzen, H.; Moyna, P.; Rischer, M.; Neunaber, H. Liebigs Ann.
Chem. 1991, 1245-1249. (b) Breton, G. W. J . Org. Chem. 1997, 62,
8952-8954.
(46) Previous references on 9 do not give any spectroscopic data:
(a) Protiva, J .; Lepsˇa, L.; Klinotova´, E.; Klinot, J .; Krecek, V.; Vystrcil,
A. Collect. Czech. Chem. Commun. 1981, 46, 2734-2741. (b) Sejbal,
J .; Klinot, J .; Budeˇsˇ´ınsky´, M.; Protive, J . Collect. Czech. Chem.
Commun. 1991, 56, 2936-2949.
(43) Perrin, D. D.; Armarego, W. L. F.; Perrin, D. R. Purification of
Laboratory Chemicals, 2nd ed.; Pergamon Press: New York, 1980.
(44) Siddiqui, S.; Hafeez, F.; Begum, S.; Siddiqui, B. S. J . Nat. Prod.
1988, 51, 229-233.

2870 J . Org. Chem., Vol. 67, No. 9, 2002
Deng and Snyder
(s, 3H), 3.82 (d, J ) 11.0 Hz, 1H), 4.16-4.22 (m, 2H), 4.55 (br
s, 1H), 4.61 (d, J ) 2.0 Hz, 1H), 4.64 (d, J ) 2.0 Hz, 1H), 4.78
(br s, 1H); 13C NMR (67.5 MHz, CDCl3) δ 14.6, 15.9, 19.0, 20.4,
21.0, 21.3, 23.0, 24.6, 25.0, 26.3, 27.0, 29.5, 29.6, 32.6, 33.9,
34.4, 37.5, 39.0, 40.4, 40.5, 43.0, 46.2, 47.6, 48.6, 50.4, 52.9,
53.6, 62.7, 105.8, 109.8, 112.9, 148.0, 150.0, 171.5; IR (NaCl)
1740 cm-1; HRMS (EI, 70 eV) m/z calcd for C34H56O4 528.4178,
found 528.4132 ([M]+, 0.05%).
Su a´r ez Clea va ge of 9: seco-Ald eh yd e 10b. Prepared as
described above for 10a from 9 (2 g, 4.11 mmol). Flash
chromatography of the crude product on silica gel (98:2
hexanes:EtOAc) gave 10b (1.10 g, 55%, Rf ) 0.48, 9:1 hexanes:
EtOAc) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.73
(d, J ) 6.4 Hz, 3H), 0.80 (d, J ) 7.0 Hz, 3H), 0.83 (s, 3H), 0.93
(s, 3H), 1.05 (s, 3H), 1.67 (s, 3H), 1.91 (dd, 1.8, 12.6 Hz, 1H),
2.02 (s, 3H), 2.18-2.27 (m, 1H), 2.36-2.44 (m, 1H), 3.78 (d, J
) 11.0 Hz, 1H), 4.20 (d, J ) 11.0 Hz, 1H), 4.58 (s, 1H), 4.79 (s,
1H), 9.68 (s, 1H); 13C NMR (67.5 MHz, CDCl3) δ 14.4, 14.8,
16.0, 20.1, 21.0, 21.3, 21.5, 22.8, 22.9, 24.3, 26.6, 26.9, 29.4,
29.7, 30.9, 32.7, 34.6, 37.1, 38.2, 38.9, 40.4, 40.6, 43.2, 44.4,
46.4, 48.0, 50.4, 62.7, 113.4, 147.5, 171.5, 202.6; IR (NaCl) 1738
cm-1; HRMS (EI, 70 eV) m/z calcd for C32H52O3 484.3916, found
484.3933 ([M]+, 10.1%).
MHz, CDCl3) δ 0.72 (d, J ) 6.8 Hz, 3H), 0.79 (d, J ) 6.8 Hz,
3H), 0.87 (s, 3H), 0.90 (s, 3H), 1.05 (s, 3H), 2.01 (s, 3H), 2.10
(s, 3H), 2.39 (dd, J ) 2.7, 12.9 Hz, 1H), 3.29 (s, 3H), 3.31 (s,
3H), 3.77 (d, J ) 11.4 Hz, 1H), 4.19 (d, J ) 11.4 Hz, 1H), 4.22
(dd, J ) 5.4, 5.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 14.5,
14.8, 15.9, 19.9, 20.6, 21.0, 21.5, 21.8, 22.8, 26.5 (2C), 26.9,
29.3, 29.6, 31.5, 31.8, 34.5, 34.6, 37.1, 38.5, 40.0, 40.3, 43.2,
44.3, 46.3, 47.9, 53.0, 53.8, 56.2, 62.6 105.5, 171.5, 212.8; IR
(NaCl) 1738, 1707 cm-1; HRMS (CI, CH4, 140 eV) m/z calcd
for C33H56O5 532.4128, found 532.4082 ([M]+, 0.08%).
Dep r otection of 12a : Dik eto Ald eh yd e 13a . A solution
of 12a (260 mg, 0.488 mmol) in wet acetone (50 mL, 10:1
distilled acetone:distilled H2O), containing pyridinium p-
toluenesulfonate (PPTS, 365 mg, 1.46 mmol), was refluxed for
1 h. After removing the solvents in vacuo, the residue was
partitioned between CH2Cl2 and saturated aqueous NaHCO3
solution (25 mL each); then, the organic layer was washed with
saturated brine and dried (Na2SO4) and the solvent removed
in vacuo. Flash chromatography of the crude product on silica
gel (8:2 hexanes:EtOAc) gave 13a (218 mg, 92%, Rf ) 0.21,
7:3 hexanes:EtOAc) as a colorless oil: 1H NMR (400 MHz,
CDCl3) δ 0.91 (s, 3H), 0.97 (s, 3H), 1.04 (s, 3H), 2.03 (s, 3H),
2.06 (s, 3H), 2.12 (s, 3H), 2.24 (m, 1H), 2.27 (dd, J ) 2.6, 13.2
Hz, 1H), 2.52 (ddd, J ) 4.1, 11.7, 16.3 Hz, 1H), 2.62 (ddd, J )
5.9, 11.7, 11.7 Hz, 1H), 3.73 (d, J ) 11.1 Hz, 1H), 4.15 (d, J )
11.1 Hz, 1H), 9.72 (s, 1H); 13C NMR (67.5 MHz, CDCl3) δ 14.5,
15.8, 19.7, 20.6, 20.9, 21.6, 26.87, 26.93, 27.4, 29.1, 29.9, 31.0,
31.4, 31.6, 34.2, 36.2, 38.0, 38.4, 40.2, 40.4, 42.9, 46.1, 48.8,
51.2, 56.4, 62.2, 171.4, 201.8, 211.5, 212.0; IR (NaCl) 1734,
1710 cm-1; HRMS (EI, 70 eV) m/z calcd for C30H46O5 486.3345,
found 486.3383 ([M]+, 1.8%).
seco-Dim eth yla ceta l 11b. A solution of 10b (1.05 g, 2.17
mmol) in dry MeOH (21.7 mL, 0.1 mM), containing pyridinium
p-toluenesulfonate (PPTS, 1.26 g, 5.02 mmol) and trimethyl
orthoformate (2.37 mL, 21.7 mmol), was stirred for 48 h at
room temperature. The solvent was removed in vacuo, and the
residue was partitioned between EtOAc and saturated aqueous
NaHCO3 solution (25 mL each). The organic solution was
washed with saturated brine and dried (Na2SO4), and the
solvent was removed in vacuo. Flash chromatography of the
crude product on silica gel (99:1:0.5 hexanes:EtOAc:Et3N)
afforded 11b (1.05 g, 91%, Rf ) 0.52, 9:1 hexanes:EtOAc) as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.74 (d, J ) 6.4
Hz, 3H), 0.79 (s, 3H), 0.81 (d, J ) 7.0 Hz, 3H), 0.93 (s, 3H),
1.04 (s, 3H), 1.70 (s, 3H), 1.96 (dd, J ) 2.1, 12.9 Hz, 1H), 2.03
(s, 3H), 3.29 (s, 3H), 3.31 (s, 3H), 3.80 (d, J ) 10.7 Hz, 1H),
4.18-4.23 (m, 2H), 4.62 (d, J ) 1.6 Hz, 1H), 4.79 (s, 1H); 13C
NMR (67.5 MHz, CDCl3) δ 14.6, 14.8, 16.0, 20.4, 21.0, 21.3,
21.5, 22.8, 23.1, 24.6, 26.2, 26.7, 26.9, 29.3, 29.7, 32.7, 33.9,
34.6, 37.1, 39.0, 40.2, 40.5, 43.2, 44.4, 46.4, 48.0, 50.4, 52.6,
Dep r otection of 12b: Keto Ald eh yd e 13b. Prepared as
described above for 13a from 12b (820 mg, 1.54 mmol). Flash
column chromatography of the crude product on silica gel (85:
15 hexanes:EtOAc) gave 13b (660 mg, 88%, Rf ) 0.3, 8:2
hexanes:EtOAc) as a colorless oil: 1H NMR (400 MHz, CDCl3)
δ 0.74 (d, J ) 6.7 Hz, 3H), 0.82 (d, J ) 6.7 Hz, 3H), 0.94 (s,
3H), 0.95 (s, 3H), 1.09 (s, 3H), 2.04 (s, 3H), 2.09 (s, 3H), 2.28
(m, 2H), 2.56 (dddd, J ) 1.2, 4.5, 11.8, 15.0 Hz, 1H), 3.79 (d,
J ) 11.1 Hz, 1H), 4.22 (dd, J ) 1.5, 11.1 Hz, 1H), 9.74 (dd, J
) 1.5, 2.1 Hz, 1H); 13C NMR (67.5 MHz, CDCl3) δ 14.4, 14.8,
16.0, 19.8, 20.6, 21.0, 21.5, 21.7, 22.8, 26.5, 26.9, 29.4, 29.7,
30.9, 31.5, 31.8, 34.6, 37.0, 38.2, 38.5, 40.3, 40.4, 43.3, 44.4,
53.6, 62.8, 105.7, 113.0, 148.1, 171.6; IR (NaCl) 1740 cm-1
;
HRMS (CI, CH4, 140 eV) m/z calcd for C34H58O4 530.4335,
46.4, 47.9, 56.7, 62.6, 171.6, 202.3, 212.3; IR (NaCl) 1737 cm-1
;
found 530.4339 ([M]+, 1.1%).
HRMS (EI, 70 eV) m/z calcd for C31H56O4 486.3709, found
Oxid a tive Clea va ge of 11a : Dik etoa ceta l 12a . To a
stirred suspension of ruthenium dioxide hydrate (1.308 g, 7.72
mmol) in CCl4 (196 mL) was added a solution of sodium
metaperiodate (16.83 g, 78.6 mmol) in water (155 mL) at 0
°C. After the mixture was stirred for 1 h at this temperature,
the lower yellow layer (RuO4) was separated and added to a
solution of 11a (1.238 g, 2.34 mmol) in a mixture of CCl4 (52
mL) and water (32 mL). The mixture was stirred at room
temperature for 4 h; then, the water layer was removed, and
2-propanol (5 mL) was added to the reaction mixture. The
solution was filtered twice, the second time through Celite.
The filtrate was dried (Na2SO4) and the solvent removed in
vacuo; the crude product was purified by flash chromatography
on silica gel (8:2 hexanes:EtOAc) to give 12a (932 mg, 75%, Rf
) 0.10, 8:2 hexanes:EtOAc) as a colorless oil: 1H NMR (400
MHz, CDCl3) δ 0.88 (s, 3H), 0.98 (s, 3H), 1.05 (s, 3H), 2.05 (s,
3H), 2.13 (s, 3H), 2.15 (s, 3H), 2.42 (dd, J ) 2.9, 12.9 Hz, 1H),
2.64 (ddd, J ) 5.9, 11.1, 11.1 Hz, 1H), 3.30 (s, 3H), 3.32 (s,
3H), 3.76 (d, J ) 12.2 Hz, 1H), 4.17 (d, J ) 12.2 Hz, 1H), 4.23
(dd, J ) 5.3, 5.3 Hz, 1H); 13C NMR (67.5 MHz, CDCl3) δ 14.5,
15.8, 19.8, 20.6, 20.9, 21.7, 26.4, 26.9, 27.0, 27.4, 29.1, 29.8,
31.6, 31.7, 34.2, 34.6, 36.3, 38.5, 40.2 (2C), 42.8, 46.2, 49.0,
51.4, 53.0, 53.5, 56.0, 62.3, 105.2, 171.4, 211.5, 212.6; IR (NaCl)
1736, 1708 cm-1; HRMS (EI, 70 eV) m/z calcd for C32H52O6
532.3764, found 532.3776 ([M]+, 0.17%).
486.3717 ([M]+, 6.8%).
28-O-Acetyl-3r,4r-dih ydr oxy-24-n or lu pan -20-on e (r14a)
a n d
28-O-Acet yl-3â,4â-d ih yd r oxy-24-n or lu p a n -20-on e
(â14a ). A solution of 1,2-diiodoethane (668 mg, 2.37 mmol) in
anhydrous THF (24 mL) was added to samarium (427 mg, 2.84
mmol) under argon. The reaction mixture was stirred at room
temperature for 1 h, and to the resulting deep blue solution
was added a mixture of 13a (288 mg, 0.59 mmol) and t-BuOH
(113 µL, 1.18 mmol) in anhydrous THF (16 mL) over a period
of 1 h. The mixture was stirred overnight at room temperature,
and then saturated aqueous NaHCO3 solution (15 mL) was
added. The organic layer was separated; the aqueous phase
was extracted with Et2O (3 × 15 mL), and the combined
organic extracts were washed with saturated aqueous sodium
thiosulfate solution and saturated brine and dried (Na2SO4).
Evaporation of the solvent and flash chromatography of the
crude product on silica gel (7:3 hexanes:EtOAc) afforded pure
R14a (203 mg, 70.4%, Rf ) 0.25, 6:4 hexanes:EtOAc) as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.77 (s, 3H), 0.987
(s, 3H), 0.993 (s, 3H), 1.08 (s, 3H), 2.05 (s, 3H), 2.14 (s, 3H),
2.40 (br s, OH), 2.63 (ddd, J ) 5.9, 11.7, 11.7 Hz, 1H), 3.52 (br
s, 1H), 3.76 (d, J ) 11.1 Hz, 1H), 4.17 (d, J ) 11.1 Hz, 1H);
13C NMR (67.5 MHz, CDCl3) δ 14.7, 14.9, 15.9, 17.2, 20.8, 21.0,
21.9, 25.3, 26.8, 27.2, 27.5, 29.3, 29.7, 32.3, 33.4, 34.4, 36.4,
37.5, 40.9, 42.6, 46.3, 49.3, 49.7, 49.9, 51.6, 62.5, 73.2, 73.8,
171.6, 211.8; IR (NaCl) 3454, 1736, 1712 cm-1; HRMS (EI, 70
eV) m/z calcd for C30H48O45488.3502, found 488.3535 ([M]+,
13.3%); and â14a (19 mg, 6.6%, Rf ) 0.28, 6:4 hexanes:EtOAc)
as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.73 (dd, J )
2.1, 11.9 Hz, 1H), 0.84 (m, 1H), 0.91 (s, 3H), 0.95 (s, 3H), 1.02
Oxid a tive Clea va ge of 11b: Ketoa ceta l 12b. Prepared
as described above for 12a from 11b (991.5 mg, 1.87 mmol).
The crude product was purified by flash chromatography on
silica gel (85:15 hexanes:EtOAc) to give 12b (846 mg, 85%, Rf
) 0.19, 9:1 hexanes:EtOAc) as a colorless oil: 1H NMR (400

A New Route to 24-Nortriterpene Analogues
J . Org. Chem., Vol. 67, No. 9, 2002 2871
(s, 3H), 1.20 (s, 3H), 2.04 (s, 3H), 2.13 (s, 3H), 2.63 (ddd, J )
5.8, 11.3, 11.3 Hz, 1H), 3.20 (br dd, J ) 7.9, 7.9 Hz, 1H), 3.74
(d, J ) 11.2 Hz, 1H), 4.17 (dd, J ) 1.2, 11.2 Hz, 1H); 13C NMR
(67.5 MHz, CDCl3) δ 14.6, 15.3, 16.2, 17.7, 20.6, 21.0, 25.1,
26.9 (2C), 27.2, 27.5, 29.3, 29.9, 33.8, 34.4, 36.3, 36.8, 37.7,
40.6, 42.6, 46.3, 49.2, 49.3, 51.5, 53.4, 62.5, 74.1, 75.3, 171.5,
211.8; IR (NaCl) 3481, 1734, 1716 cm-1; HRMS (EI, 70 eV)
m/z calcd for C30H48O45 488.3502, found 488.3511 ([M]+, 19.1%).
28-O-Acetyl-24-n or lu p a n e-3r,4r-d iol (r14b) a n d 28-O-
Acetyl-24-n or lu p a n e-3â,4â-d iol (â14b). Prepared as de-
scribed above for R14a and â14a from 13b (0.643 g, 1.32
mmol). Flash chromatography of the crude product on silica
gel (8:2 hexanes:EtOAc) afforded pure R14b (143 mg) and a
mixture of R14b and â14b (417 mg, combined yield 87%, 10.7:
1, Rf ) 0.15, 8:2 hexanes:EtOAc) as a colorless oil. 28-O-
Acetyl-24-n or lu p a n e-3R,4R-d iol (R14b): 1H NMR (400 MHz,
CDCl3) δ 0.74 (d, J ) 7.0 Hz, 3H), 0.78 (s, 3H), 0.81 (d, J ) 7.0
Hz, 3H), 0.94 (s, 3H), 1.02 (s, 3H), 1.10 (s, 3H), 1.97 (s, OH),
2.04 (s, 3H), 2.43 (s, OH), 3.53 (br d, J ) 2.7 Hz, 1H), 3.80 (d,
J ) 10.5 Hz, 1H), 4.21 (d, J ) 10.5 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 14.7, 14.86, 14.90, 16.0, 17.3, 20.9, 21.1, 21.6,
22.0, 22.9, 25.3, 26.77, 26.83, 29.4, 29.8, 32.4, 33.5, 34.6, 37.1,
37.5, 41.1, 43.0, 44.5, 46.4, 48.0, 49.6, 49.8, 62.8, 73.3, 73.9,
171.1; IR (NaCl) 3435, 1741 cm-1; HRMS (EI, 70 eV) m/z calcd
for C31H52O4 488.3865, found 488.3884 ([M]+, 22.9%).
28-O-Acetyl-4r-h yd r oxy-24-n or lu p a n e-3,20-d ion e (15a ).
To a stirred solution of oxalyl chloride (49.1 µL, 0.56 mmol) in
CH2Cl2 (1.0 mL) was added a solution of DMSO (80.6 µL, 1.13
mmol) in CH2Cl2 (0.5 mL) at -78 °C. The reaction mixture
was stirred at this temperature for 30 min, and then a solution
of R14a (106 mg, 0.217 mmol) in CH2Cl2 (2.5 mL) was added
and stirring continued for an additional 45 min. Triethylamine
(300 µL, 2.15 mmol) was added with subsequent stirring for
15 min, and then the reaction mixture was allowed to warm
to room temperature. Water (3 mL) was added; the layers were
separated, and the aqueous layer was extracted with CH2Cl2
(5 mL). The combined organic extracts were washed with
saturated brine and dried (Na2SO4). Evaporation of the solvent
and flash chromatography of the crude product on silica gel
(7:3 hexanes:EtOAc) gave 15a (77 mg, 73%, Rf ) 0.30, 7:3
hexanes:EtOAc) as a colorless oil: 1H NMR (400 MHz, CDCl3)
δ 0.96 (s, 3H), 1.04 (s, 6H), 1.23 (s, 3H), 2.06 (s, 3H), 2.14 (s,
3H), 2.34 (ddd, J ) 2.4, 4.0, 14.6 Hz, 1H), 2.64 (ddd, J ) 5.8,
11.6, 11.6 Hz, 1H), 2.67 (ddd, J ) 6.1, 14.3, 14.6 Hz, 1H), 3.76
(d, J ) 11.3 Hz, 1H), 3.90 (s, OH), 4.17 (d, J ) 11.3 Hz, 1H);
13C NMR (67.5 MHz, CDCl3) δ 14.6, 14.8, 15.9, 18.1, 21.0, 21.2,
22.0, 26.9, 27.1, 27.4, 29.3, 29.7, 33.2, 33.6, 34.4, 36.4, 37.1,
40.9, 41.0, 42.6, 46.2, 49.2, 49.7, 51.6, 58.8, 62.4, 76.8, 171.6,
211.6, 215.4; IR (NaCl) 3427, 1738, 1712 cm-1; HRMS (EI, 70
eV) m/z calcd for C30H46O5 486.3345, found 486.3343 ([M]+,
8.2%).
lized methyl (carboxysulfamoyl)triethylammonium hydroxide
inner salt47 (Burgess’ reagent, 100 mg, 0.42 mmol). The
reaction mixture was refluxed for 46 h, and then the reaction
was quenched by adding water (3 mL). The aqueous layer was
extracted with EtOAc (3 × 3 mL); the combined organic
extracts were washed with saturated brine and dried (Na2-
SO4), and the solvent was removed in vacuo. Flash chroma-
tography of the crude product on silica gel (75:25 hexanes:
EtOAc) gave 16a (37 mg, 73%, Rf ) 0.35, 7:3 hexanes:EtOAc)
as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.94 (s, 3H),
1.08 (s, 3H), 1.19 (s, 3H), 1.75 (s, 3H), 2.06 (s, 3H), 2.14 (s,
3H), 2.30 (ddd, J ) 2.9, 5.0, 17.1 Hz, 1H), 2.40 (ddd, J ) 5.3,
15.2, 17.1 Hz, 1H), 2.62 (ddd, J ) 3.5, 3.5, 14.6 Hz, 1H), 2.66
(ddd, J ) 5.9, 11.7, 11.7 Hz, 1H), 3.76 (d, J ) 11.1 Hz, 1H),
4.21 (dd, J ) 1.2, 11.1 Hz, 1H); 13C NMR (67.5 MHz, CDCl3)
δ 11.0, 14.4, 15.4, 18.1, 21.0, 21.5, 24.5, 26.9, 27.3, 27.4, 29.1,
29.8, 32.5, 33.2, 34.3, 36.4, 36.5, 39.3, 40.3, 42.8, 46.3, 48.8,
49.1, 51.4, 62.4, 128.1, 164.1, 171.5, 198.8, 211.5; IR (NaCl)
1736, 1715, 1664 cm-1; HRMS (EI, 70 eV) m/z calcd for
C
30H44O4 468.3239, found 468.3215 ([M]+, 3.6%).
28-O-Acet yl-24-n or lu p -4-en -3-on e (16b). Prepared as
described above for 15a from a mixture of 15b C-4 epimers
(147 mg, 0.302 mmol). Flash chromatography of the crude
product on silica gel (93:7 hexanes:EtOAc) gave 16b (102 mg,
73%, Rf ) 0.59, 8:2 hexanes:EtOAc) as a colorless oil: 1H NMR
(400 MHz, CDCl3) δ 0.74 (d, J ) 6.4 Hz, 3H), 0.82 (d, J ) 6.8
Hz, 3H), 0.89 (s, 3H), 1.10 (s, 3H), 1.22 (s, 3H), 1.76 (s, 3H),
2.04 (s, 3H), 2.24 (ddd, J ) 6.4, 15.0, 15.0 Hz, 1H), 2.30 (ddd,
J ) 2.7, 4.8, 17.0 Hz, 1H), 2.42 (ddd, J ) 5.4, 14.9, 17.0 Hz,
1H), 2.60 (ddd, J ) 3.2, 3.2, 15.0 Hz, 1H), 3.80 (d, J ) 11.3
Hz, 1H), 4.24 (dd, J ) 1.6, 11.3 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 11.0, 14.3, 14.8, 15.6, 18.1, 21.0, 21.51, 21.54, 22.9,
24.6, 26.84, 26.86, 29.4, 29.6, 32.8, 33.3, 34.6, 36.5, 37.3, 39.3,
40.5, 43.1, 44.4, 46.5, 47.8, 49.0, 62.7, 128.0, 164.4, 171.7, 198.9;
IR (NaCl) 1739, 1668 cm-1; HRMS (EI, 70 eV) m/z calcd for
C
31H48O3 468.3603, found 468.3581 ([M]+, 100%).
3-Oxo-28-lu p a n oic Acid (17c). A solution of betulin (5,
3.46 g, 7.82 mmol) in a mixture of THF and methanol (1:2,
v/v, 156 mL) was hydrogenated under 40 psi of H2 over 10%
Pd/C (1.04 g, 30 wt %) overnight and then filtered. Removal
of the solvent in vacuo afforded lupane-3â,28-diol10f as a white
solid (3.48 g, 100%). No further purification was necessary:
mp 276-278 °C; 1H NMR (400 MHz, CDCl3) δ 0.74 (d, J ) 6.4
Hz, 3H), 0.74 (s, 3H), 0.81 (s, 3H), 0.82 (d, J ) 6.4 Hz, 3H),
0.94 (s, 3H), 0.95 (s, 3H), 1.00 (s, 3H), 3.18 (dd, J ) 5.4, 11.3
Hz, 1H), 3.28 (d, J ) 10.7 Hz, 1H), 3.75 (dd, J ) 1.1, 10.7 Hz,
1H); 13C NMR (67.5 MHz, CDCl3) δ 14.6, 14.9, 15.4, 15.9, 16.0,
18.3, 20.8, 21.7, 22.9, 26.8 (2C), 27.3, 28.0, 29.3, 29.5, 34.0,
34.2, 36.8, 37.1, 38.6, 38.8, 40.9, 42.8, 44.5, 47.9, 48.0, 50.0,
55.2, 60.6, 79.0; HRMS (EI, 70 eV) m/z calcd for C30H52O2
444.3967, found 444.3953 ([M]+, 8.1%).
28-O-Acetyl-4r-h yd r oxy-24-n or lu p a n -3-on e (15b). Pre-
pared as described above for 15a from R14b (172 mg, 0.352
mmol). Flash chromatography of the crude product on silica
gel (9:1 hexanes:EtOAc) gave 15b (135 mg, 79%, Rf ) 0.67,
8:2 hexanes:EtOAc) as a colorless oil: 1H NMR (400 MHz,
CDCl3) δ 0.73 (d, J ) 7.0 Hz, 3H), 0.81 (d, J ) 7.0 Hz, 3H),
0.91 (s, 3H), 1.06 (s, 3H), 1.07 (s, 3H), 1.24 (s, 3H), 2.04 (s,
3H), 2.34 (ddd, J ) 2.7, 4.3, 14.5 Hz, 1H), 2.69 (ddd, J ) 6.4,
14.5, 14.5 Hz, 1H), 3.80 (d, J ) 11.3 Hz, 1H), 3.90 (s, OH),
4.21 (d, J ) 11.3 Hz, 1H). Due to 13C NMR signal overlap in
CDCl3, spectra were also run in C6D6: 1H NMR (400 MHz,
C6D6) δ 0.70 (s, 3H), 0.76 (s, 3H), 0.77 (d, J ) 7.0 Hz, 3H),
0.87 (d, J ) 7.0 Hz, 3H), 0.89 (s, 3H), 1.08 (s, 3H), 1.73 (s,
3H), 1.94 (m, 3H), 2.12 (ddd, J ) 2.7, 4.3, 14.5 Hz, 1H), 2.22
(ddd, J ) 5.9, 14.5, 14.5 Hz, 1H), 3.92 (d, J ) 11.3 Hz, 1H),
4.19 (s, OH), 4.44 (dd, J ) 1.6, 11.3 Hz, 1H); 13C NMR (100
MHz, C6D6) δ 15.0, 15.1, 15.4, 16.3, 18.6, 20.9, 21.6, 22.3, 22.6,
23.4, 27.3, 27.6, 30.2, 30.6, 34.0, 34.1, 35.5, 37.4, 37.6, 41.4,
41.5, 43.4, 45.1, 47.2, 48.8, 50.0, 59.4, 63.0, 77.5, 171.0, 214.8;
IR (NaCl) 3492, 1733, 1714 cm-1; HRMS (EI, 70 eV) m/z calcd
for C31H50O4 486.3709, found 486.3663 ([M]+, 1.1%).
To a solution of lupane-3â,28-diol (1.0 g, 2.25 mmol) in
acetone (100 mL) was added freshly prepared J ones’ reagent48
dropwise at 0 °C until the color remained orange (2.2 mL).
The solution was stirred for 1.5 h at 0 °C, and the reaction
was quenched with 2-propanol (5 mL); the mixture was stirred
for 5 min, and then H2O (30 mL) was added. The organic
solvent was removed in vacuo, and the aqueous residue was
extracted with EtOAc (3 × 30 mL). The combined organic
extracts were washed with water and saturated brine and then
dried (Na2SO4). Removal of the solvent in vacuo and flash
chromatography on silica gel (85:15 hexanes:EtOAc) afforded
1749 (635 mg, 62%, Rf ) 0.55, 8:2 hexanes:EtOAc) as a white
solid: mp 244 °C dec; 1H NMR (400 MHz, CDCl3) δ 0.73 (d, J
) 7.0 Hz, 3H), 0.83 (d, J ) 7.0 Hz, 3H), 0.90 (s, 3H), 0.93 (s,
(47) Burgess, E. M.; Penton, H. R., J r.; Taylor, A. E.; Williams, W.
M. In Organic Synthesis; Noland, W. E., Ed.; J ohn Wiley & Sons: New
York, 1988; Collect. Vol. VI, pp 788-791.
(48) Bowden, K.; Heilbron, I. M.; J ones, E. R. H.; Weedon, B. C. L.
J . Chem. Soc. 1946, 39-45.
(49) Previous preparations of 17c did not report spectroscopic
data: (a) Ruzicka, L.; Frame, G. F.; Leicester, H. M.; Liguori, M.;
Bru¨ngger, H. Helv. Chim. Acta 1934, 17, 426-442. (b) Ruzicka, L.;
Bru¨ngger, H.; Gustus, E. L. Helv. Chim. Acta 1932, 15, 634-648. Also,
see ref 38. For partial data, see refs 9d and 11d.
28-O-Acetyl-24-n or lu p -4-en -3,20-d ion e (16a ). To a solu-
tion of the mixture of epimers of 15a (10.7:1, R:â-OH, 41 mg,
0.084 mmol) in benzene (5 mL) was added freshly recrystal-

2872 J . Org. Chem., Vol. 67, No. 9, 2002
Deng and Snyder
3H), 0.94 (s, 3H), 0.99 (s, 3H), 1.04 (s, 3H), 2.118-2.23 (m,
3H), 2.34-2.52 (m, 2H), 11.4 (br s, OH); 13C NMR (67.5 MHz,
CDCl3) δ 14.5, 14.6, 15.8, 15.9, 19.6, 21.0, 21.4, 22.7, 23.0, 26.6,
26.8, 29.65, 29.71, 32.0, 33.6, 34.1, 36.8, 37.4, 38.3, 39.5, 40.6,
42.6, 44.1, 47.3, 48.6, 49.6, 54.8, 56.8, 182.9, 218.2.
droxy-3-oxo-1-lupen-28-oate51 (73 mg, 84%, Rf ) 0.38, 9:1
hexanes:EtOAc) as a colorless oil: 1H NMR (400 MHz, CDCl3)
δ 0.73 (d, J ) 7.0 Hz, 3H), 0.84 (d, J ) 7.0 Hz, 3H), 0.91 (s,
3H), 0.95 (s, 3H), 1.08 (s, 3H), 1.10 (s, 3H), 1.18 (s, 3H), 2.4-
2.6 (m, 3H), 3.63 (s, 3H), 5.88 (s, 1H), 6.43 (s, OH); 13C NMR
(100 MHz, CDCl3) δ 14.6, 14.7, 16.5, 18.8, 20.2, 21.2, 21.6, 22.8,
23.0, 26.8, 27.2, 29.6, 29.8, 32.1, 34.1, 37.4, 38.3, 38.7, 41.6,
42.9, 44.0, 44.2, 45.6, 48.9, 51.2, 54.1, 57.0, 128.8, 144.0, 176.8,
201.3; IR (NaCl) 3450, 1728, 1669 cm-1; HRMS (EI, 70 eV)
m/z calcd for C31H48O4 484.3552, found 484.3563 ([M]+, 15%).
Meth yl 3-Oxo-28-lu p a n oa te (18c). To a solution of 17c
(179 mg, 0.406 mmol) in DMF (4 mL), containing cesium
fluoride (92.6 mg, 0.610 mmol), was added methyl iodide (40
µL, 0.610 mmol). The reaction mixture was stirred at room
temperature for 24 h; the reaction was quenched with satu-
rated aqueous NaHCO3 solution (20 mL), and the mixture was
extracted with EtOAc (3 × 20 mL). The combined organic
extracts were washed with saturated brine and dried (Na2-
SO4), and the solvent was removed in vacuo. Flash chroma-
tography of the crude product on silica gel (93:7 hexanes:
EtOAc) gave 1850 (156 mg, 87%, Rf ) 0.28, 9:1 hexanes:EtOAc)
as a white solid: mp 193-195 °C; 1H NMR (400 MHz, CDCl3)
δ 0.72 (d, J ) 7.0 Hz, 3H), 0.83 (d, J ) 7.0 Hz, 3H), 0.91 (s,
3H), 0.92 (s, 3H), 0.93 (s, 3H), 1.00 (s, 3H), 1.05 (s, 1H), 1.67
(m, 1H), 1.74-1.81 (m, 2H), 1.90 (ddd, J ) 4.3, 7.5, 12.4 Hz,
1H), 2.18-2.26 (m, 3H), 2.38 (ddd, J ) 4.3, 7.5, 15.6 Hz, 1H),
2.48 (ddd, J ) 7.5, 10.2, 15.6 Hz, 1H), 3.63 (s, 3H).
Meth yl 2-O-Tr im eth ylsilyl-3-oxo-28-lu p a n oa te (19c). To
a solution of 18c (183 mg, 0.389 mmol) in CH2Cl2 (8 mL) at
-78 °C under argon was added with stirring triethylamine
(0.54 mL, 3.87 mmol) followed by trimethylsilyl trifluo-
romethanesulfonate (0.352 mL, 1.95 mmol). After 1 h at -78
°C, the reaction was quenched by the addition of saturated
aqueous NaHCO3 solution (3 mL) and extracted with hexanes
(3 × 3 mL). The combined organic extracts were washed with
saturated brine and dried (Na2SO4), and the solvent was
removed in vacuo. The crude silyl enol ether (assumed to be
0.389 mmol) was dissolved in CH2Cl2 (8 mL) at 0 °C, and a
precooled solution of m-chloroperoxybenzoic acid (m-CPBA,
107 mg, 0.434 mmol) in CH2Cl2 (10 mL) was added. The
solution was stirred for 2 h; the reaction was quenched by the
addition of saturated aqueous NaHCO3 solution (5 mL), and
the mixture was extracted with CH2Cl2 (3 × 5 mL). The
combined organic extracts were washed with saturated brine
and dried (Na2SO4), and the solvent was removed in vacuo.
Flash chromatography of the crude product on silica gel (97:3
hexanes:EtOAc) gave 19c (156 mg, 74%, Rf ) 0.52, 9:1
hexanes:EtOAc) as a colorless oil: 1H NMR (400 MHz, CDCl3)
δ 0.1 (s, 9H), 0.71 (d, J ) 6.4 Hz, 3H), 0.82 (d, J ) 7.0 Hz,
3H), 0.88 (s, 3H), 0.92 (s, 3H), 1.02 (s, 3H), 1.07 (s, 3H), 1.12
(s, 3H), 1.66 (m, 1H), 1.72-1.79 (m, 2H), 2.15-2.24 (m, 4H),
3.62 (s, 3H), 4.55 (dd, J ) 6.4, 12.4 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 0.26 (3C), 14.5, 14.7, 16.1, 16.8, 19.1, 21.2, 21.6,
22.7, 23.0, 25.1, 26.7, 29.6, 29.7, 32.0, 34.1, 37.2, 38.0 (2C),
40.7, 42.6, 44.2, 48.3, 48.9, 50.0, 50.5, 51.2, 56.86, 56.93, 70.9,
176.8, 214.1; IR (NaCl) 1723 cm-1; HRMS (EI, 70 eV) m/z calcd
for C34H58SiO4 558.4104, found 558.4076 ([M]+, 5.4%).
To a stirred solution of aluminum bromide (63.3 mg, 0.237
mmol) in dimethyl sulfide (1 mL) was added a solution of
methyl 2-hydroxy-3-oxo-1-lupen-28-oate (23 mg, 0.0474 mmol)
in dimethyl sulfide (1 mL) at room temperature. The reaction
mixture was stirred at room temperature for 24 h, and the
reaction was quenched with water (2 mL); then, the mixture
was extracted with EtOAc (3 × 3 mL). The combined organic
extracts were washed with saturated brine and dried (Na2-
SO4), and the solvent was removed in vacuo. The crude product
was purified by flash chromatography on silica gel (85:15
hexanes:EtOAc), affording 20c (17.2 mg, 77%, Rf ) 0.40, 8:2
hexanes:EtOAC) as a white solid: mp 242 °C dec; 1H NMR
(400 MHz, CDCl3) δ 0.74 (d, J ) 6.6 Hz, 3H), 0.85 (d, J ) 7.0
Hz, 3H), 0.93 (s, 3H), 0.98 (s, 3H), 1.08 (s, 3H), 1.11 (s, 3H),
1.18 (s, 3H), 1.88 (dd, J ) 7.7, 12.3 Hz, 1H), 2.19-2.29 (m,
3H), 5.90 (s, 1H), 6.44 (s, OH), 10.47 (bs, OH); 13C NMR (75
MHz, CDCl3) δ 14.5, 14.6, 16.5, 18.7, 20.1, 21.2, 21.6, 22.7,
22.9, 26.7, 27.1, 29.6, 29.7, 32.0, 34.1, 37.4, 38.4, 38.6, 41.6,
42.9, 44.0, 44.1, 45.5, 48.7, 54.0, 56.8, 128.7, 143.9, 181.2, 201.1;
IR (NaCl) 3450, 1694, 1669 cm-1; HRMS (EI, 70 eV) m/z calcd
for C30H46O4 470.3396, found 470.3368 ([M]+, 6.1%).
Meth yl 3-Oxo-24-n or lu p -4-en -28-oa te (18b). A solution
of 16b (253 mg, 0.542 mmol) in a mixture of MeOH and THF
(1:1, v/v, 11 mL), containing NaOMe (87.8 mg, 1.63 mmol),
was refluxed for 3 h. After the solvents were removed in vacuo,
the residue was partitioned between Et2O and water (20 mL
each); the organic layer was washed with saturated brine and
dried (Na2SO4) and the solvent removed in vacuo. Flash
chromatography of the crude product on silica gel (85:15
hexanes:EtOAc) gave 28-hydroxy-24-norlup-4-en-3-one (220
mg, 95%, Rf ) 0.2, 8:2 hexanes:EtOAc) as a colorless oil: 1H
NMR (400 MHz, CDCl3) δ 0.74 (d, J ) 6.4 Hz, 3H), 0.83 (d, J
) 6.4 Hz, 3H), 0.90 (s, 3H), 1.11 (s, 3H), 1.21 (s, 3H), 1.76 (d,
J ) 1.1 Hz, 3H), 1.89 (ddd, J ) 2.2, 4.8, 13.4 Hz, 1H), 1.97
(ddd, J ) 2.7, 4.8, 12.9 Hz, 1H), 2.22 (ddd, J ) 5.9, 12.4, 14.5
Hz, 1H), 2.31 (ddd, J ) 2.7, 4.8, 17.1 Hz, 1H), 2.43 (ddd, J )
4.8, 14.9, 17.1 Hz, 1H), 2.61 (ddd, J ) 3.8, 3.8, 14.5 Hz, 1H),
3.32 (d, J ) 10.7 Hz, 1H), 3.77 (d, J ) 10.7 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 11.0, 14.3, 14.8, 15.5, 18.1, 21.6, 21.7, 22.9,
24.6, 26.8, 26.9, 29.1, 29.4, 32.8, 33.3, 34.0, 36.5, 36.9, 39.3,
40.5, 43.1, 44.4, 47.8, 47.9, 49.1, 60.5, 128.0, 164.5, 199.0; IR
(NaCl) 3444, 1666 cm-1; HRMS (EI, 70 eV) m/z calcd for
C
29H46O2 426.3498, found 426.3493 ([M]+, 14.3%).
2-Hyd r oxy-3-oxo-1-lu p en -28-oic Acid (20c). To a stirred
solution of oxalyl chloride (40.6 µL, 0.466 mmol) in CH2Cl2 (1.0
mL) was added a solution of dry DMSO (66 µL, 0.93 mmol) in
CH2Cl2 (0.5 mL) at -78 °C. The reaction mixture was stirred
at this temperature for 30 min, and a solution of 19c (100 mg,
0.179 mmol) in CH2Cl2 (3 mL) was added; stirring was
continued for an additional 45 min. Triethylamine (249 µL,
1.79 mmol) was added, and the reaction mixture was stirred
for 15 min and then allowed to warm to room temperature.
Water (3 mL) was added, and the aqueous layer was extracted
with CH2Cl2 (3 × 3 mL). The organic extracts were washed
with saturated brine and dried (Na2SO4). Evaporation of the
solvent in vacuo and flash chromatography of the crude
product on silica gel (9:1 hexanes:EtOAc) gave methyl 2-hy-
To a solution of 28-hydroxy-24-norlup-4-en-3-one (220 mg,
0.516 mmol) in acetone (15 mL) was added freshly prepared
J ones’ reagent48 dropwise until the color remained orange (0.5
mL) at 0 °C. The solution was stirred for 1.5 h at 0 °C. The
reaction was quenched with 2-propanol (1 mL), and the
mixture was stirred for an additional 5 min; H2O (5 mL) was
added. The organic solvent was removed in vacuo, and the
aqueous residue was extracted with EtOAc (3 × 5 mL). The
combined organic extracts were washed with water and then
saturated brine and dried (Na2SO4). Removal of the solvent
in vacuo and flash chromatography of the crude product on
silica gel (85:15 hexanes:EtOAc) afforded 3-oxo-24-norlup-4-
en-28-oic acid (194 mg, 85%, Rf ) 0.24, 8:2 hexanes:EtOAc)
as a white solid: 1H NMR (400 MHz, CDCl3) δ 0.74 (d, J )
7.0 Hz, 3H), 0.85 (d, J ) 7.0 Hz, 3H), 0.91 (s, 3H), 1.11 (s,
3H), 1.12 (s, 3H), 1.76 (s, 3H), 1.89 (dd, J ) 7.2, 12.3 Hz, 1H),
1.99 (ddd, J ) 2.6, 5.1, 13.2 Hz, 1H), 2.16-2.38 (m, 5H), 2.43
(ddd, J ) 5.1, 14.6, 14.6 Hz, 1H), 2.61 (ddd, J ) 3.7, 3.7, 14.6
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 11.0, 14.3, 14.6, 15.5,
18.2, 21.7, 22.7, 22.9, 24.6, 27.0, 29.7 (2C), 31.9, 33.0, 33.3,
36.6, 37.4, 38.4, 39.4, 40.4, 42.9, 44.1, 48.5, 49.4, 56.9, 128.1,
(50) Previous preparations of 18c did not report spectroscopic
data: (a) Ruzicka, L.; Brenner, M.; Rey, E. Helv. Chim. Acta 1941, 24,
515-529. (b) Mahato, S. B.; Banerjee, S. K.; Chakravarti, R. N.
Tetrahedon 1971, 27, 177-186.
(51) Previous preparations of methyl 3-hydroxy-4-oxo-1-lupen-28-
oate did not report any characterizing data: (a) Pradhan, B. P.; Ghosh,
P. Indian J . Chem., Sect. B 1993, 32B, 590-591. (b) Pradhan, B. P.;
Ghosh, P. Indian J . Chem., Sect. B 1993, 32B, 920-923.

A New Route to 24-Nortriterpene Analogues
J . Org. Chem., Vol. 67, No. 9, 2002 2873
164.3, 181.3, 198.9; IR (NaCl) 1694, 1667 cm-1; HRMS (EI, 70
eV) m/z calcd for C29H44O3 440.3290, found 440.3283 ([M]+,
61.4%).
with recovered 18b (4.5 mg, 30%): 1H NMR (400 MHz, CDCl3)
δ 0.70 (d, J ) 6.4 Hz, 3H), 0.78 (s, 3H), 0.84 (d, J ) 7.0 Hz,
3H), 1.14 (s, 3H), 1.18 (s, 3H), 1.97 (s, 3H), 2.2-2.4 (m, 4H),
2.70 (ddd, J ) 3.2, 3.2, 13.4 Hz, 1H), 3.65 (s, 3H), 6.34 (s, 1H,),
6.36 (s, OH); 13C NMR (75 MHz, CDCl3) δ 10.7, 14.2, 14.6, 16.1,
21.4, 22.8, 22.9, 23.5, 25.3, 26.8, 29.7, 29.9, 32.0, 36.0, 37.2,
38.3, 41.1, 43.4, 44.0, 44.2, 48.0, 48.7, 51.2, 57.0, 125.3, 125.9,
To a solution of 3-oxo-24-norlup-4-en-28-oic acid (179 mg,
0.406 mmol) in DMF (4 mL), containing cesium fluoride (92.6
mg, 0.610 mmol), was added methyl iodide (40 µL, 0.610
mmol). The reaction mixture was stirred at room temperature
for 24 h; the reaction was quenched with saturated aqueous
NaHCO3 solution (20 mL), and the mixture was extracted with
EtOAc (3 × 20 mL). The combined organic extracts were
washed with saturated brine and dried (Na2SO4), and the
solvent was removed in vacuo. Flash chromatography of the
crude product on silica gel (93:7 hexanes:EtOAc) gave 18b (156
mg, 85%, Rf ) 0.28, 9:1 hexanes:EtOAc) as a white solid: mp
212-214 °C; 1H NMR (400 MHz, CDCl3) δ 0.70 (d, J ) 6.8
Hz, 3H), 0.82 (d, J ) 6.8 Hz, 3H), 0.87 (s, 3H), 1.07 (s, 3H),
1.08 (s, 3H), 1.74 (s, 3H), 1.96 (ddd, J ) 2.9, 5.4, 13.2 Hz, 1H),
2.14-2.24 (m, 5H), 2.41 (ddd, J ) 4.9, 15.1, 17.0 Hz, 1H), 2.58
(ddd, J ) 3.4, 3.4, 14.6 Hz, 1H), 3.62 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 11.0, 14.3, 14.6, 15.5, 18.1, 21.7, 22.7, 22.9,
24.6, 27.0, 29.66, 29.70, 31.9, 32.9, 33.3, 36.6, 37.2, 38.2, 39.3,
40.3, 42.8, 44.1, 48.7, 49.4, 51.1, 57.0, 128.0, 164.4, 176.7, 198.8;
IR (NaCl) 1727, 1667 cm-1; HRMS (EI, 70 eV) m/z calcd for
144.4, 167.2, 176.8, 181.4; IR (NaCl) 3400, 1726, 1625 cm-1
;
HRMS (EI, 70 eV) m/z calcd for C30H44O4 468.3239, found
468.3239 ([M]+, 3.9%).
2-H yd r oxy-3-oxo-24-n or lu p a -1,4-d ien -28-oic Acid (7).
To a stirred solution of aluminum bromide (23.9 mg, 0.0897
mmol) in dimethyl sulfide (1 mL) was added a solution of 23
(8.4 mg, 0.0179 mmol) also in dimethyl sulfide (1 mL). The
reaction mixture was stirred at room temperature for 24 h;
the reaction was quenched with water (2 mL), and then the
mixture was extracted with EtOAc (3 × 3 mL). The organic
layer was washed with saturated brine and dried (Na2SO4),
and the solvent was removed in vacuo. The crude product was
purified by flash chromatography on silica gel (8:2 hexanes:
EtOAc) to afford 7 (6 mg, 74%, Rf ) 0.19, 8:2 hexanes:EtOAC)
1
as a white solid: mp 286 °C dec; H NMR (400 MHz, CDCl3)
δ 0.72 (d, J ) 6.7 Hz, 3H), 0.80 (s, 3H), 0.85 (d, J ) 7.0 Hz,
3H), 1.17 (s, 3H), 1.19 (s, 3H), 1.90 (dd, J ) 7.5, 12.4 Hz, 1H),
1.97 (s, 3H), 2.2-2.4 (m, 4H), 2.71 (ddd, J ) 3.4, 3.4, 13.4 Hz,
1H), 6.34 (s, 1H), 6.40 (br s, OH); 13C NMR (75 MHz, CDCl3)
δ 10.7, 14.1, 14.6, 16.1, 21.4, 22.7, 22.9, 23.4, 25.2, 26.7, 29.6,
29.9, 31.9, 35.9, 37.3, 38.4, 41.1, 43.4, 44.0 (2C), 47.8, 48.4,
56.7, 125.4, 126.0, 144.4, 167.0, 180.8, 181.3; IR (NaCl) 3360,
1696, 1625 cm-1; HRMS (EI, 70 eV) m/z calcd for C29H42O4
454.3083, found 454.3106 ([M]+, 8.4%).
C
30H46O3 454.3447, found 454.3433 ([M]+, 94.2%).
Meth yl 2-Hydr oxy-3-oxo-24-n or lu p-1,4-dien -28-oate (23).
A solution of 18b (15 mg, 0.033 mmol) in THF (2.2 mL) at
-78 °C was treated with tert-BuOK (0.24 M solution in THF,
0.55 mL, 0.132 mmol), and the mixture was then placed in a
-20 °C bath. After 45 min, the mixture was allowed to briefly
warm to 0 °C, and then transferred via cannula to a solution
of (PhSeO)2O (95.8 mg, 0.265 mmol) in THF (2.2 mL) also at
0 °C. After 45 min, the mixture was diluted with EtOAc (20
mL) and poured into saturated aqueous NaHCO3 solution (20
mL). The organic layer was washed with saturated aqueous
sodium thiosulfate solution and then saturated brine and dried
(Na2SO4), and the solvent was removed in vacuo. The crude
product was purified by flash chromatography on silica gel (85:
15 hexanes:Et2O), affording 23 (8 mg, 52%, 74% based on 70%
conversion, Rf ) 0.34, 8:2 hexanes:Et2O) as a white solid, along
Su p p or tin g In for m a tion Ava ila ble: 1H NMR of all
compounds and 13C NMR spectra of all compounds except the
known 18c; NOE spectra for R14a , â14a , and R14b; and
bioactivity data from NCI for 7 and 20c. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O010929H