Total syntheses of (+)-chloropuupehenone and (+)-chloropuupehenol and their analogues and evaluation of their bioactivities

Article abstract of DOI:10.1021/jo0491399

Tetracyclic pyrans (+)-chloropuupehenone (1) and (+)-chloropuupehenol (5) and its C8-R-isomer (+)-3 were synthesized via a one-pot condensation of 1-chloro-2-lithio-3,5,6-tris(tert-butyldimethylsilyloxy)benzene (8) with (4aS,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2,5,5,8a-tetramethylnaphthalene-1- carboxaldehyde (7). The major condensation product, (4aS,6aR,12bS)-2H-9,10- bis(tert-butyldimethylsilyloxy)-11-chloro-1,3,4,4a,5,6,6a,12b-octahydro-4,4,6a, 12b-tetramethyl-benzo[a]xanthene (4), after desilylation provided tetracyclic pyran (+)-(4aS,6aR,12bS)-2H-11-chloro-1,3,4,4a,5,6,6a,12b-octahydro-4,4,6a,12b- tetramethyl-benzo[a]xanthene-9,10-diol (3). At a dosage of 42 mg/rat over 8 h, pyran diol 3 inhibited the intestinal absorption of cholesterol by 71% in rats. Tetracyclic pyran 4 was also converted to o-quinone 28, which inhibited cholesteryl ester transfer protein (CETP) activity and L1210 leukemic cell viability with IC₅₀ values of 31 and 2.4 μM, respectively. Diol (+)-5 inhibited CETP activity with an IC₅₀ value of 16 μM. The minor condensation product, (4aS,6aS,12bS)-2H-9,10-bis(tert- butyldimethylsilyloxy)-11-chloro-1,3,4,4a,5,6,6a,12b-octahydro-4,4,6a, 12b-tetramethyl-benzo[a]xanthene (6), was transformed into (+)-5 and (+)-1. A stepwise stereoselective synthesis of (+)-1 was also developed utilizing an oxyselenylation ring-closure reaction. The synthetic sequence also produced four biologically active naturally occurring drimanic sesquiterpenes, (+)-drimane-8α,11-diol (34), (-)-drimenol (38), (+)-albicanol (39), and (-)-albicanal (31) as intermediates.

Full text of DOI:10.1021/jo0491399

Tota l Syn th eses of (+)-Ch lor op u u p eh en on e a n d
(+)-Ch lor op u u p eh en ol a n d Th eir An a logu es a n d Eva lu a tion of
Th eir Bioa ctivities
Duy H. Hua,*,† Xiaodong Huang,† Yi Chen,† Srinivas K. Battina,† Masafumi Tamura,†
,‡
Sang K. Noh,‡,| Sung I. Koo, Ichiji Namatame,§ Hiroshi Tomoda,§
Elisabeth M. Perchellet,# and J ean-Pierre Perchellet#
Departments of Chemistry, Biology, and Human Nutrition, Kansas State University,
Manhattan, Kansas 66506, and Kitasato Institute for Life Sciences, Kitasato University, 5-9-1, Shirokane,
Minato-Ku, Tokyo, 108-8642 J apan
duy@ksu.edu
Received May 21, 2004
Tetracyclic pyrans (+)-chloropuupehenone (1) and (+)-chloropuupehenol (5) and its C8-R-isomer
(+)-3 were synthesized via a one-pot condensation of 1-chloro-2-lithio-3,5,6-tris(tert-butyldimeth-
ylsilyloxy)benzene (8) with (4aS,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2,5,5,8a-tetramethylnaphthalene-
1-carboxaldehyde (7). The major condensation product, (4aS,6aR,12bS)-2H-9,10-bis(tert-butyldi-
methylsilyloxy)-11-chloro-1,3,4,4a,5,6,6a,12b-octahydro-4,4,6a,12b-tetramethyl-benzo[a]xanthene (4),
after desilylation provided tetracyclic pyran (+)-(4aS,6aR,12bS)-2H-11-chloro-1,3,4,4a,5,6,6a,12b-
octahydro-4,4,6a,12b-tetramethyl-benzo[a]xanthene-9,10-diol (3). At a dosage of 42 mg/rat over 8
h, pyran diol 3 inhibited the intestinal absorption of cholesterol by 71% in rats. Tetracyclic pyran
4 was also converted to o-quinone 28, which inhibited cholesteryl ester transfer protein (CETP)
activity and L1210 leukemic cell viability with IC50 values of 31 and 2.4 µM, respectively. Diol
(+)-5 inhibited CETP activity with an IC50 value of 16 µM. The minor condensation product,
(4aS,6aS,12bS)-2H-9,10-bis(tert-butyldimethylsilyloxy)-11-chloro-1,3,4,4a,5,6,6a,12b-octahydro-
4,4,6a,12b-tetramethyl-benzo[a]xanthene (6), was transformed into (+)-5 and (+)-1. A stepwise
stereoselective synthesis of (+)-1 was also developed utilizing an oxyselenylation ring-closure
reaction. The synthetic sequence also produced four biologically active naturally occurring drimanic
sesquiterpenes, (+)-drimane-8R,11-diol (34), (-)-drimenol (38), (+)-albicanol (39), and (-)-albicanal
(31) as intermediates.
I. In tr od u ction
protein (LDL). Low levels of HDL cholesterol and high
levels of LDL cholesterol are found in patients with
atherosclerosis.5 Inhibition of CETP may improve lipid
parameters of HDL, LDL, and triglyceride blood levels
and prevent the formation of more atherogenic lipopro-
tein particles in certain patient populations.5d The inhibi-
As part of our studies of the syntheses of pyranopy-
rones1 and their related bioactive compounds,2 the total
synthesis of pyranomethine quinone natural products
was undertaken. (+)-Chloropuupehenone (1; Figure 1),
a pyranomethine quinone, isolated from marine sponges3
in Hawaii, strongly inhibits the effect of cholesteryl ester
transfer protein (CETP; IC50 ) 0.3 µM) and possesses
other bioactivity.4 CETP, a hydrophobic neutral glyco-
protein, mediates the net transfer of cholesteryl ester
from high-density lipoprotein (HDL) to low-density lipo-
(3) Isolation of chloropuupehenone, bromopuupehenone, and puu-
pehenone: (a) Ravi, B. N.; Perzanowski, H. P.; Ross, R. A.; Erdman,
T. R.; Scheuer, P. J . Pure Appl. Chem. 1979, 51, 1893-1900. (b) Amade,
P.; Chevelot, L.; Perzanowski, H. P.; Scheuer, P. J . Helv. Chim. Acta
1983, 66, 1672-1675. (c) Hamann, M. T.; Scheuer, P. J . Tetrahedron
Lett. 1991, 32, 5671-5672. Isolation of chloropuupehenone and its
metabolites: (d) Hamann, M. T.; Scheuer, P. J . J . Org. Chem. 1993,
58, 6565-6569. Puupehenone-related metabolites: (e) Nasu, S. S.;
Yeung, B. K. S.; Hamann, M. T.; Scheuer, P. J .; Kelly-Borges, M.;
Goins, K. J . Org. Chem. 1995, 60, 7290-7292. Absolute stereochem-
istry of puupehenone and related metabolites: (f) Urban, S.; Capon,
R. J . J . Nat. Prod. 1996, 59, 900-901.
(4) CETP inhibition: (a) Coval, S. J .; Conover, M. A.; Mierzwa, R.;
King, A.; Puar, M. S.; Phife, D. W.; Pai, J .-K.; Burrier, R. E.; Ahn,
H.-S.; Boykow, G. C.; Patel, M.; Pomponi, S. A. Bioorg. Med. Chem.
Lett. 1995, 5, 605-610. Antimicrobial and cytotoxic activity of puu-
pehenone and chloropuupehenone: (b) Popov, A. M.; Stekhova, S. I.;
Utkina, N. K.; Rebachuk, N. M. Pharm. Chem. J . 1999, 33, 71-73.
Antimalarial activity: (c) El Sayed, K. A.; Dunbar, D. C.; Goins, D.
K.; Cordova, C. R.; Perry, T. L.; Wesson, K. J .; Sanders, S. C.; J anus,
S. A.; Hamann, M. T. J . Nat. Toxins 1996, 5, 261-285. Anti-
tuberculosis: (d) El Sayed, K. A.; Bartyzel, P.; Shen, X. D.; Perry, T.
L.; Zjawiony, J . K.; Hamann, M. T. Tetrahedron 2000, 56, 949-953.
† Department of Chemistry, Kansas State University.
‡ Department of Human Nutrition, Kansas State University.
| Current address: Department of Food and Nutrition, Changwon
National University, Changwon, Kyongnam, 641-773, Korea.
Current address: Department of Nutritional Sciences, University
of Connecticut, Storrs, CT 06269-4017.
§ Kitasato Institute for Life Sciences, Kitasato University, 5-9-1,
Shirokane, Minato-Ku, Tokyo, 108-8642 J apan.
#
Department of Biology, Kansas State University.
(1) Hua, D. H.; Chen, Y.; Sin, H.-S.; Maroto, M. J .; Robinson, P. D.;
Newell, S. W.; Perchellet, E. M.; Ladesich, J . B.; Freeman, J . A.;
Perchellet, J .-P.; Chiang, P. K. J . Org. Chem. 1997, 62, 6888-6896.
(2) Hua, D. H.; Huang, X.; Tamura, M.; Chen, Y.; Woltkamp, M.;
J in, L.-W.; Perchellet, E. M.; Perchellet, J .-P.; Chiang, P. K.; Tomoda,
H. Tetrahedron 2003, 59, 4795-4803.
10.1021/jo0491399 CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/07/2004
J . Org. Chem. 2004, 69, 6065-6078
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Hua et al.
F IGURE 1. Retroanalysis.
tion of CETP should increase HDL and decrease LDL
levels.5 Although various syntheses of puupehenone (2),6
a natural analogue of 1, have been reported, the synthesis
of 1 itself has not appeared. Our goals were to synthesize
(+)-1 and its analogues and to evaluate their CETP
activities and the inhibition of lymphatic absorption of
cholesterol.7a Analogues include stereoisomers at C8 (the
natural product’s numbering system is used). Lipid
lowering by targeting CETP and other cholesterol regula-
tors has been studied,7b and CETP inhibitors such as
torcetrapib7d are reportedly lipid-lowering agents. Herein,
we describe two methods leading to (+)-1, (+)-chloro-
puupehenol (5),3e its C8-R-isomer (+)-3, and the inhibi-
tion of CETP and lymphatic absorption of cholesterol. A
new and facile two-bond forming reaction for the coupling
of the A-B and the D ring fragments is discussed.
Beside these approaches, a ring opening of a C8,9 epoxide
from a C17 hydroxyl group was utilized in the construc-
tion of two related p-methine quinone natural products,
UPA0043 and UPA0044.8 We envision that tetracyclic
pyran 5, a precursor of 1, and its C8 epimer 3 could be
assembled in one pot by tandem formation of C15-C16
and C8-O22 bonds from (4aS,8aS)-carboxaldehyde 7 and
aryllithium 8, as illustrated in Figure 1. The one-pot
cyclization would utilize the ease of displacing the
resulting benzylic allylic alcohol resulting from 7 and 8
and would not produce a stereoselective formation at C8
but would provide different stereoisomers for bioevalu-
ation. Indeed, compound 3 is the most active compound
in the inhibition of lymphatic cholesterol absorption (vide
infra). In the following section, we describe a one-pot
cyclization of aryllithium 8 and enal 7 via a benzylic
allylic alcohol intermediate, followed by a second method
involving a stereoselective ring closure reaction.
II. Resu lts a n d Discu ssion
(a ) Syn th esis of Ald eh yd e 7. Compound 7 was
previously prepared9a,b from (-)-sclareol and (+)-sclar-
eolide (9).9c Our synthesis of 7, starting from 3aR-(+)-
sclareolide (9), which is less expensive than sclareol, was
accomplished in four steps via a strategy similar to that
reported in wiedendiol A synthesis,9c but with different
reagents (Scheme 1). Hence, hydroxylation of lactone 9
with LDA in THF at -78 °C, followed by MoO5‚pyridine‚
HMPA10 complex gave R-hydroxylactone 10 (65.6% yield)
and â-isomer 11 (12.4% yield) with 20% recovery of
starting material 9. Compounds 10 and 11 were readily
separated by silica gel column chromatography. The
absoluate configuration at C1 of 10 and 11 were tenta-
1. Syn th esis. Two approaches to the synthesis of
puupehenone (2) have been reported. The first involves
a cationic cyclization of a C17 hydroxyl group with C7,8
and C8,13 double bonds,6a-c and the second incorporates
a ring closure by the attack of C8 hydroxyl group onto
the oxidatively activated 1,2-dihydroxyphenyl moiety.6d
(5) For reviews of CETP and atherosclerosis: (a) Ross, R. Nature
1993, 362, 801-809. (b) Tall, A. R. J . Lipid Res. 1993, 34, 1255-1274.
(c) Lagrost, L. Biochim. Biophys. Acta 1994, 1215, 209-236. (d) Wang,
J .; Qiang, H.; Zhang, C. D.; Zhuang, Y. Clin. Chim. Acta 2002, 322,
85-90.
(6) Synthesis of puupehenone: (a) Trammell, G. I. Tetrahedron Lett.
1978, 18, 1525-1528. (b) Barrero, A. F.; Alvarez-Manzaneda, E. J .;
Chahboun, R. Tetrahedron Lett. 1997, 38, 2325-2328. (c) Barrero, A.
F.; Manzaneda, E. J . A.; Chahboun, R.; Cortes, M.; Armstrong, V.
Tetrahedron 1999, 55, 15181-15208. (d) Quideau, S.; Lebon, M.;
Lamidey, A.-M. Org. Lett. 2002, 4, 3975-3978. Synthesis of 15-
oxopuupehenonol: (e) Arjona, O.; Garranzo, M.; Mahugo, J .; Maroto,
E.; Plumet, J .; Saez, B. Tetrahedron Lett. 1997, 38, 7249-7252.
Synthesis of 8-epipuupehenone: (f) Armstrong, V.; Barrero, A. F.;
Alvarez-Manzaneda, E. J .; Cortes, M.; Sepulveda, B. J . Nat. Prod.
2003, 66, 1382-1383.
1
tively assigned on the basis of the H J values of C1-H’s.
The J value of C1-H of 10 is 12 Hz (axial-axial
coupling); the J value of C1H of 11 is 3.2 Hz (axial-
(8) Takao, K.; Sasaki, T.; Kozaki, T.; Yanagisawa, Y.; Tadano, K.;
Kawashima, A.; Shinonaga, H. Org. Lett. 2001, 3, 4291-4294.
(9) (a) Barrero, A. F.; Manzaneda, E. A.; Chahboun, R. Tetrahedron
Lett. 1997, 38, 8101-8104 and references therein. (b) Barreoro, A. F.;
Manzaneda, E. A.; Chahboun, R. Tetrahedron 1998, 54, 5635-5650.
(c) Chackalamannil, S.; Wang, Y.; Xia, Y.; Czarniecki, M. Tetrahedron
Lett. 1995, 36, 5315-5318.
(7) (a) Loest, H. B.; Noh, S. K.; Koo, S. I. J . Nutr. 2002, 132, 1282-
1288. For reviews: (b) Bays, H.; Stein, E. A. Expert Opin. Pharmaco-
ther. 2003, 4, 1901-1938. (c) Wierzbicki, A. S. Expert Opin. Emerg.
Drugs 2003, 8, 365-376. (d) Curatolo, W. J .; Sutton, S. C.; Appel, L.
E. PCT Int. Appl. 2003063868, 2003; 176 pp.
(10) Vedejs, E.; Engler, D. A.; Telschow, J . E. J . Org. Chem. 1978,
43, 188-196.
6066 J . Org. Chem., Vol. 69, No. 18, 2004

(+)-Chloropuupehenone and (+)-Chloropuupehenol
SCHEME 1
DMF (70% yield) followed by silylation with tert-bu-
tyldimethylsilyl chloride (99% yield) (Scheme 2). The
regiochemistry of aryl bromides 15 and 22 was initially
based only on the 1H NMR chemical shifts of the aromatic
hydrogen atoms but later was confirmed through the
transformation of compound 15 to (+)-chloropuupe-
1
henone (vide infra). The H NMR resonace of the only
aromatic H of 15 (H-5), δ 6.41 ppm, is affected by a
greater electron-donating effect from two adjacent sily-
loxy groups than is H-5 of 22, δ 6.54 ppm, which is
flanked by a silyloxy group and a chlorine.
(c) On e-P ot Syn th esis of Tetr a cyclic P yr a n es 4
a n d 6. The reaction of aryllithium 8 with aldehyde 7
turned out to be a one-pot synthesis of tetracyclic pyranes
4 and 6. Thus, treatment of bromide 15 with 2 equiv of
t-BuLi in diethyl ether at -78 °C followed by aldehyde 7
afforded a mixture of two stereoisomers at C6a (IUPAC
numbering system), 4 (45% yield) and 6 (9.1% yield)
(Scheme 3). Apparently, attack by lithiated arene 8 on
the aldehyde function of 7 produced a mixture of two
diastereoisomeric alcohols 24. Both alcohols underwent
an intramolecular ring closure by an elimination of the
benzylic allylic hydroxyl group during aqueous workup
to form a carbocation intermediate, 25A or 25B, followed
by ring closure from the attack of C7 oxygen and the
release of the tert-butyldimethylsilyl group with water.
The C7 oxygen attacks the carbocation preferentially
from the opposite side of the C12b methyl (less hindered
face) to give 4 as the predominant product and isomer 6
as minor product. Removal of the silyl ether protecting
groups of 4 and 6 separately gave 6aR-diol 3 (82% yield)
and (+)-chloropuupehenol (5) (81.4% yield),3e respectively.
The stereochemistry at C6a of pyrans 4 and 6 was
established by 2D NOESY spectroscopy. Compound 4
exhibited NOE correlation between C6a and C12b
methyls, while compound 6 exhibited no NOE correlation.
equatorial coupling). Because the stereocenter at C1 of
10 and 11 would be destroyed later in the synthesis, a
mixture of 10 and 11 was used. Reduction of 10 and 11
with lithium aluminum hydride (LAH) in THF at room
temperature produced triol 12 (70% yield) and lactol 13
(30% yield), the latter being further reduced to triol 12
(91% yield). Oxidative cleavage of triol 12 with lead
tetraacetate in benzene at 25 °C provided â-hydroxyal-
dehyde 14 (90% yield),9c which on dehydration with
p-toluenesulfonic acid in refluxing toluene for 2 h fur-
nished enal 7 (78% yield).9
(b) Syn th esis of Ar yl Br om id e 15, P r ecu r sor of
Lith iu m 8. Scheme 2 outlines a practical synthesis of
D-ring fragment 15, a precursor of lithium 8, in six steps
from 3-chlorovanillin (16), readily prepared by the chlo-
rination of vanillin with chlorine in acetic acid (85%
yield).11Demethylation12 of 16 with BBr3 in CH2Cl2 (94%
yield) followed by protection of the resulting diol, 17, with
tert-butyldimethylsilyl chloride, triethylamine, and 4-(dim-
ethylamino)pyridine (DMAP) gave aldehyde 18 (93%
yield). Baeyer-Villiger oxidation13 of 18 with m-chloro-
perbenzoic acid (MCPBA) in methylene chloride (70%
yield) followed by removal of the resulting formyl ester
function by treatment with potassium carbonate (90%
yield) and silylation of the phenolic hydroxyl group of 20
with tert-butyldimethylsilyl chloride (83% yield) afforded
trisilyl ether 21. Selective bromination of 21 at C4 (less
hindered site than C6) with N-bromosuccinimde (NBS)
in N,N-dimethylformamide (DMF) at 25 °C gave 15 (67%
yield) as the only product. It is important to note that
although no C6 isomer 22 was detected in the bromina-
tion at 25 °C, when carried out at 50 °C, a 2:1 ratio of 22
to 15 was obtained, and these products were separated
by column chromatography.
To synthesize (+)-chloropuupehenone and its ana-
logues, reduction of the C12-12a double bond followed
by oxidation of the substituted catachol functionality to
the methine quinone are needed. Therefore, tetracyclic
pyranes 4 and 6 were stereoselectively hydrogenated with
hydrogen and palladium/carbon in ethanol to give 26 and
29, respectively (Scheme 4). The palladium hydrogens
approach the C12-C12a double bond of 4 and 6 from the
less hindered R-face (opposite to the two angular meth-
yls). Desilylation of C6a-R-26 with tetra-n-butylammo-
nium fluoride in THF (83% yield) followed by oxidation
with pyridinium chlorochromate (PCC) provided a 77%
yield of o-quinone 28. No methine quinone was detected.
Attempts with other oxidizing reagents, viz., pyridinium
dichromate (PDC), 2,3-dichloro-5,6-dicyano-1,4-quinone
(DDQ), and KOH-O2 failed to provide methine quinone;
only o-quinone 28 was obtained.
Contrary to the oxidation of C6a-R-27, the C6a-S
isomer, 29, after desilylation with tetra-n-butylammo-
nium fluoride, was successfully oxidized to the methine
quinone (+)-chloropuupehenone (1) (73% yield). The
methine quinone structure of 1 was readily ascertained
by 1H NMR spectroscopy, in which the C12-olefinic H
appears as a doublet at δ 7.14; o-quinone 28 does not
possess an olefinic H. It is apparent that only the cis-
annulate pyran (the C ring of the tetracyclic structure),
Alternatively, a higher yield of bromide 15 was ob-
tained from the bromination of phenol 20 with NBS in
(11) Hann, R. M.; Spencer, G. C. J . Am. Chem. Soc. 1927, 49, 535-
7.
(12) J ong, T. T.; Williard, P. G.; Porwoll, J . P. J . Org. Chem. 1984,
49, 735-6.
(13) Godfrey, I. M.; Sargent, M. V.; Elis, J . A. J . Chem. Soc., Perkin
Trans. 1974, 1, 1353.
J . Org. Chem, Vol. 69, No. 18, 2004 6067

Hua et al.
SCHEME 2
SCHEME 3
30, produced methine quinone upon oxidation; oxidation
of the trans-annulate pyran, 27, produced only the
o-quinone.
It should be noted that tetracyclic pyran diol 3 effected
a complete inhibition of lymphatic cholesterol absorption
in mice (vide infra).
(d ) Step w ise Ster eoselective Syn th esis of (+)-
Ch lor op u u p eh en on e [(+)-1]. The above synthetic route
produced (+)-1 as the minor product. To synthesize (+)-1
stereoselectively, a stepwise synthetic route was inves-
tigated starting with nonconjugated aldehyde 31 or 32
(Scheme 5). We also found that the silyl ether protecting
group of aryl halide 23 is incompatible to the reaction
conditions after the coupling of 23 with aldehyde 31 or
32, and hence a benzyl ether protecting group, i.e., aryl
bromide 33, was used in the synthesis (Scheme 6).
First, in the synthesis of aldehydes 31 and 32, elimina-
tion of the C2-hydroxyl group of 14 is required. Hence,
reduction of 14 with lithium aluminum hydride in ether
at 0 °C gave drimane-8R,11-diol (34)14 (97% yield), which
upon selective protection of its primary hydroxyl function
by reaction with tert-butyldimethylsilyl chloride and
imidazole (98% yield), followed by elimination when
(14) (a) Hlubucek, J . R.; Aasen, A. J .; Almqvist, S.-O.; Enzell, C. R.
Acta Chem. Scand.
B 1974, 28, 289-294. (b) Kuchkova, K. I.;
Chumakov, Y. M.; Simonov, Y. A.; Bocelli, G.; Panasenko, A. A.; Vlad,
P. F. Synthesis 1997, 1045-1046. (c) Shishido, K.; Omodani, T.;
Shibuya, M. J . Chem. Soc., Perkin Trans. 1 1991, 2285-2287.
6068 J . Org. Chem., Vol. 69, No. 18, 2004

(+)-Chloropuupehenone and (+)-Chloropuupehenol
SCHEME 4
SCHEME 5
SCHEME 6
treated with methanesulfonyl chloride and triethylamine,
afforded a 1:1 ratio of alkene 36 and 37 (90% yield;
Scheme 5). Bicyclic alkene 36 and 37 were separated by
silica gel column chromatography. Desilylation of alkene
36 with tetra-n-butylammonium fluoride gave (-)-
drimenol3f (38) (92% yield), which was oxidized with
Dess-Martin periodinane to aldehyde 32 (90% yield). Via
a similar sequence of reactions, desilylation of exo-bicyclic
alkene 37 gave (+)-albicanol (39)15a (93% yield); subse-
quent oxidation provided (-)-albicanal (31)15b-d (91%
yield).
The benzyl-protected aryl bromide 33 was synthesized
via a similar method used to prepare the silyl-protected
bromide 15 (Scheme 6). Hence, benzylation of catachol
17 with benzyl bromide, potassium iodide, and potassium
carbonate provided aldehyde 40 (78% yield). Baeyer-
Villiger oxidation of 40 with MCPBA in dichloromethane,
followed by hydrolysis with potassium carbonate in
methanol, and silylation with tert-butyldimethylsilyl
chloride and triethylamine afforded aryl chloride 43 in
73% overall yield (from 40). Regioselective oxidation of
43 with NBS in dichloromethane provided bromide 33
(96% yield); no p-bromochloro isomer was detected.
(15) (a) Toshima, H.; Oikawa, H.; Toyomasu, T.; Sassa, T. Biosci.
Biotechnol. Biochem. 2001, 65, 1244-1247. (b) Poigny, S.; Huor, T.;
Guyot, M.; Samadi, M. J . Org. Chem. 1999, 64, 9318-9320. Isolation
of (-)-albicanal and (+)-albicanol: (c) Toyota, M.; Ooiso, Y.; Kusuyama,
T.; Asakawa, Y. Phytochemistry 1994, 35, 1263-1265. (d) Weyerstahl,
P.; Marschall, H.; Schneider, S. Flavour Fragrance J . 1995, 10, 179-
185.
Coupling of bromide 33 with aldehyde 31 was carried
out like that of 15 with 7. Treatment of bromide 33 with
1.1 equiv of tert-butyllithium in ether at -78 °C, followed
by exo-cycloalkenal 31 (89% yield), and desilylation with
n-Bu4NF in THF (93% yield) afforded diol 45 as a mixture
J . Org. Chem, Vol. 69, No. 18, 2004 6069

Hua et al.
SCHEME 7
SCHEME 8
of two isomers at the newly created stereogenic center
(Scheme 7). Because this stereocenter will be removed
in later steps, both isomers were used in the subsequent
reaction. Oxyselenylation16 of diol 45 with 1.1 equiv of
N-phenylselenophthalimide (N-PSP; 46) and 0.1 equiv of
tin tetrachloride in dichloromethane at 25 °C gave selenyl
pyran 47 (38% yield) and unsaturated pyran 48 (56%
yield), which were separated by column chromatography.
Compound 48 apparently was formed from the dehydra-
tion of alcohol 47 catalyzed by either tin tetrachloride or
HCl (generated from the hydroxyl moiety and tin tetra-
chloride). The stereochemistry at C6a of 47 and 48 were
revealed after conversion of these two compounds to
tetracyclic pyran 30 (vide infra). Most likely, the phen-
ylselenyl reagent approaches the exo double bond of 45
from the opposite face (R face) of C12a side chain and
C12b methyl, and O7-phenolic oxygen attacks C6a anti16
from the phenylselenyl group providing 47. Acetylation
of 47 with acetic anhydride and pyridine (94% yield)
followed by 2,2′-azobisisobutyronitrile (AIBN) and tri-n-
butyltin hydride in refluxing toluene furnished pyran 50
(91% yield). Removal of the benzyl ether and benzylic
acetate groups of 50 with 10% palladium on activated
carbon in methanol afforded 30 (97% yield). Similarly to
that described in Scheme 4, oxidation of 30 with PDC
gave (+)-1.
Selenide 48, likewise deselenylated with AIBN and tri-
n-butyltin hydride followed hydrogenation with H2-Pd/C
in methanol produced 30 (83% overall yield).
endo-Bicyclic alkenal 32, similarly treated with the
aryllithium generated from bromide 33, gave adduct 51
(77% yield) as a mixture of two stereoisomers at the
hydroxyl carbon (Scheme 8). As described above, because
this stereocenter will be destroyed in later steps, they
were used in subsequent reactions without separating
the isomers. Attempted cyclization of 51 with (+)-
camphorsulfonic acid6e in dichloromethane at 25 °C gave
diol 52 (73% yield) along with intractable materials. No
cyclized tetracyclic pyran (such as 53) was detected.6e Diol
52 was independently synthesized from the reaction of
51 and n-Bu4NF in THF. Contrary to the reaction of diol
45, reaction of 52 with N-PSP and a catalytic amount of
tin tetrachloride produced tetracyclic pyran 53 (51%
yield), but no selenylated products were detected. Instead
of tin tetrachloride, other additives such as p-TsOH, (+)-
camphorsulfonic acid, and BF3‚ether were tried, but
again no selenylated products were observed. It is pos-
sible that hydrochloric acid was formed from the alcohol
52 and tin tetrachloride, which catalyzed a cationic
cyclization whose rate was faster than that of the reaction
of the bicyclic alkene with N-PSP. Hydrogenation of 53
with H2-Pd/C in methanol afforded tetracyclic pyran 27.
It is noteworthy that oxyselenylation of exo-bicyclic
alkene 45 took place readily, although no oxyselenylation
was observed with the endo-bicyclic alkene 52. This may
(16) Nicolaou, K. C.; Claremon, D. A.; Barnette, W. E.; Seitz, S. P.
J . Am. Chem. Soc. 1979, 101, 3704-3706.
6070 J . Org. Chem., Vol. 69, No. 18, 2004

(+)-Chloropuupehenone and (+)-Chloropuupehenol
capillaries located adjacent to the blood vessels. The
lymphatic system transports nutrients to the cells and
collects waste products. Hence, diol 3 may serve as a
cholesterol-lowering drug.
o-Quinone 28 inhibited the viability of L1210 leukemic
cells with an IC50 value of 2.4 µM after 4 days in culture.
The antileukemic activity agrees with the finding by
Popov et al.,4b in that sesquiterpenequinones possess
cytotoxic activity against Ehrlich ascites tumor cells. The
activity probably contributes from the o-quinone func-
tionality.20
III. Con clu sion s
Two synthetic routes were investigated in the total
syntheses of (+)-chloropuupehenone (1), (+)-chloropuu-
pehenol, and their stereoisomers. A one-pot addition
followed by cyclization of aryllithium 8 and bicyclic
alkenal 7 was found. The major product of this one-pot
condensation reaction was desilylated to give tetracyclic
pyran 3, which possesses strong inhibitory of cholesterol
absorption in rats. This facile cyclization reaction can be
used in the synthesis of other pyran natural products.21
Compound 3 and its analogues are being investigated as
cholesterol-lowering drugs. An oxyselenylation reaction
was utilized in a stepwise stereoselective synthesis of (+)-
1, and only the exo-bicyclic alkenal, 45, provided the
expected product. Such results can be used in planning
future synthesis involving oxyselenylation. Four biologi-
cally active naturally occurring drimanic sesquiterpenes,
(+)-drimane-8R,11-diol (34), (-)-drimenol (38), (+)-albi-
canol (39), and (-)-albicanal (31), were also produced as
synthetic intermediates in the total synthesis.
F IGURE 2. Hourly rates of lymphatic absorption of 14C-
labeled cholesterol (14C-CH) in rats for 8 h during intraduode-
nal infusion of lipid emulsion containing compound 3 (5.25 mg/
h), respective to lipid emulsion containing no compound 3
(control; CT). Values are expressed as means ( SD, n ) 5.
Asterisk denotes a significant difference from rats infused with
compound 3 at each time, P < 0.05.
TABLE 1. Tota l Lym p h a tic Absor p tion of
14C-Ch olester ol (14C-CH), Ou tp u t of Oleic Acid , a n d
Lym p h Volu m e in Ra ts In fu sed w ith Lip id Em u lsion
Con ta in in g Com p ou n d 3, Resp ective to Th a t Con ta in in g
No Com p ou n d 3 (con tr ol)a
lymph lipids
control
compound 3
14C-CH (% dose/8 h)
oleic acid (µmol/8 h)
lymph (mL/8 h)
37.7 ( 1.8
596.5 ( 61.3
18.3 ( 2.4
10.9 ( 3.3*
229.2 ( 45.7*
16.6 ( 4.2
a
Means ( SD, n ) 5. Asterisk denotes a significant difference
from control group (P < 0.05).
IV. Exp er im en ta l Section
attribute to the rapid reaction of exo-terminal alkenes
with N-PSP16 and a slower reaction from endo-trisubsti-
tuted alkenes with N-PSP.
Gen er a l Meth od s. Unless otherwise indicated, NMR spec-
tra were obtained at 400 MHz for 1H and 100 MHz for 13C in
CDCl3 and reported in ppm. Infrared spectra are reported in
wavenumbers (cm-1). High-resolution mass spectra were taken
using 2,5-dihydroxybenzoic acid as a matrix. Tetrahydrofuran
and diethyl ether were distilled over sodium and benzophenone
before use. Methylene chloride was distilled over CaH2, and
toluene and benzene were distilled over LiAlH4.
2. Bioa ctivities. The inhibition of CETP17 with com-
pounds 28, 50, (+)-1, and (+)-5 were examined, and IC50
values are 31, >100, 28, and 16 µM, respectively. Under
our CETP assay conditions, the IC50 value of (+)-1 is
much higher than that reported.4a The iron-containing
o-iminoquinone ferroverdin A18 exhibits an IC50 value of
20 µM under similar CETP assay conditions. This
observation prompted us to examine their effect on
another potential role of these compounds in cholesterol
metabolism, i.e., intestinal cholesterol absorption,19 as
they are structurally related to cholesterol. Interestingly,
pyran diol 3 inhibits the intestinal absorption of choles-
terol by 71% in rats with a dosage of 42 mg/rat over 8 h.
Interestingly, it also inhibits the absorption of fat by 62%.
The hourly rates of cholesterol absorption, as affected by
this compound, are shown by Figure 2, and the cumula-
tive absorptions of cholesterol and fat over 8 h are
summarized in Table 1. No apparent toxicity was ob-
served after this treatment and all internal organs were
normal, including intestine. Similar to the blood circula-
tion system, the lymphatic system is composed of fine
(1S,3aR,5aS,9aS,9bR)-1-Hydr oxy-dodecah ydr o-3a,6,6,9a-
tetr a m eth yln a p h th o-[2,1-b]fu r a n -2-on e (10) a n d (1R,3a R,
5a S,9a S,9b R)-1-H yd r oxy-d od eca h yd r o-3a ,6,6,9a -t et r a -
m eth yln a p h th o[2,1-b]fu r a n -2-on e (11). To a cold (-78 °C)
solution of 1.02 mL (7.79 mmol) of diisopropylamine in 40 mL
of THF under argon was added 6.36 mL (7.19 mmol) of n-BuLi
(1.6 M in hexane). The solution was stirred at -78 °C for 1 h,
and a solution of 1.50 g (5.99 mmol) of (+)-sclareolide (9) in
20 mL of THF was added via cannula dropwise. The solution
was stirred at -78 °C for 1 h, added to 5.10 g (0.012 mol) of
MoO5‚pyridine‚HMPA, and stirred for 30 min. The mixture
was diluted with saturated aqueous Na2SO3 and extracted
three times with ethyl acetate, and the organic layer was
washed with water and brine, dried (Na2SO4), concentrated,
and column chromatographed on silica gel using a mixture of
hexane/ether (9:1) as an eluent to give 1.05 g (65.6% yield) of
compound 10 and 0.20 g (12% yield) of compound 11 along
with 0.296 g (20% recovery) of 9. Compound 10:9c [R]22
)
D
(20) Gutierrez, P. L. Front. Biosci. 2000, 5, D629-638; electronic
publication.
(21) For a review, see: Vilella, D.; Sanchez, M.; Platas, G.; Salazar,
O.; Genilloud, O.; Royo, I.; Cascales, C.; Martin, I.; Diez, T.; Silverman,
K. C.; Lingham, R. B.; Singh, S. B.; J ayasuriya, H.; Pelaez, F. J . Ind.
Microbiol. Biotechnol. 2000, 25, 315-327.
(17) Tomoda, H.; Tabata, N.; Masuma, R.; Si, S.-Y.; Omura, S. J .
Antibiot. 1998, 51, 618-623.
(18) Tomoda, H.; Tabata, N.; Shinose, M.; Takahashi, Y.; Woodruff,
H. B.; Omura, S. J . Antibiot. 1999, 52, 1101-1107.
(19) Noh, S. K.; Koo, S. I.; J iang, Y. Nutraceut. Food 2003, 8, 1-6.
J . Org. Chem, Vol. 69, No. 18, 2004 6071

Hua et al.
1
+97.1° (c 1.0, CHCl3); MS (electrospray) m/z 267 (M + 1); H
72.9, 71.4, 55.3, 42.9, 41.8, 39.9, 37.5, 33.5, 30.5, 25.4, 21.5,
20.0, 18.3, 17.7.
NMR δ 4.48 (d, J ) 12 Hz, 1 H, CHO, axial), 2.06 (d, J ) 12
Hz, 1 H, C9b-axial H), 1.95-1.06 (m, 11 H), 1.38 (s, 3 H, Me),
1.03 (s, 3 H, Me), 0.88 (s, 3 H, Me), 0.84 (s, 3 H, Me); 13C NMR
δ 179.0 (s, CdO), 83.5, 68.7, 64.2, 56.4, 42.3, 39.4, 39.3, 36.9,
(4a S,8a S)-3,4,4a ,5,6,7,8,8a -Oct a h yd r o-2,5,5,8a -t e t r a -
m et h yln a p h t h a len e-1-ca r b oxa ld eh yd e (7). To a flask
equipped with a Dean-Stark apparatus under argon were
added 10 mg (42 µmol) of aldehyde 14, 10 mL of toluene, and
3 mg (17 µmol) of p-toluenesulfonic acid. After the solution
was reflux for 2 h, the solution was cooled to 25 °C, diluted
with saturated aqueous sodium bicarbonate, and extracted
three times with ethyl acetate. The combined extracts were
washed with brine, dried (MgSO4), concentrated, and column
chromatographed on silica gel using a gradient mixture of
hexane and ethyl acetate as an eluent to give 7.2 mg (78%
yield) of aldehyde 7.9c In a larger-scale synthesis of 7, the
product was distilled under reduced pressure to give colorless
oil, bp 60 °C/3 mmHg (to eliminate trace amount of water),
and the distilled product was used in next step: [R]22D ) +52°
(c 1, CHCl3), lit.9c +46.2 (c 0.65, CHCl3); MS (electrospray) m/z
33.4, 33.2, 23.5, 21.1, 20.7, 18.1, 15.9. Compound 11:9c [R]22
D
) -19.1° (c 1.0, CHCl3); MS (electrospray) m/z 267 (M + 1);
1H NMR δ 4.37 (dd, J ) 5.6, 3.2 Hz, 1 H, CHO, equatorial),
2.32 (d, J ) 3.2 Hz, 1 H, OH), 2.06 (d, J ) 12 Hz, 1 H), 1.89-
0.98 (m, 10 H), 1.69 (s, 3 H, Me), 1.21 (s, 3 H, Me), 0.87 (s, 3
H, Me), 0.85 (s, 3 H, Me); 13C NMR δ 177.6 (s, CdO), 88.8,
70.2, 62.6, 57.8, 42.4, 39.8, 38.7, 37.3, 27.1, 25.2, 21.1, 20.8,
18.3, 17.3.
1-[(1′S) a n d (1′R)-1,2-Dih yd r oxyet h yl)]-(1R,2R,4a S,
8aS)-decah ydr o-2,5,5,8a-tetr am eth yl-n aph th alen -2-ol (12)
a n d
(3a R,5a S,9a S,9b R)-Dod eca h yd r o-3a ,6,6,9a -t et r a -
m eth yln a p h th o[2,1-b]fu r a n -1,2-d iol (13). To a solution of
0.90 g (3.4 mmol) of 10 in 20 mL of THF under argon was
added 0.66 g (17.3 mmol) of LiAlH4, and the mixture was
stirred for 4 h at 25 °C. To it, 60 mL of water and 16 mL of 1
N HCl were added, and the solution was extracted with diethyl
ether three times (50 mL each). The combined ether extracts
were washed with brine, dried (MgSO4), concentrated, and
column chromatographed on silica gel using a gradient mixture
of hexane and ethyl acetate as an eluent to give 0.65 g (71%
yield) of triol 12 and 0.27 g (30% yield) of lactol 13. Two
stereoisomers (1:1) at C1′ of 12 were separated from the above
1
221 (M + 1); H NMR δ 10.04 (s, 1 H, CHO), 2.55 (d, J ) 13
Hz, 1 H), 2.26 (dd, J ) 8, 4 Hz, 1 H), 2.03 (s, 2 H, Me), 1.70-
1.40 (m, 6 H), 1.18 (s, 3 H, Me), 1.17-0.91 (m, 2 H), 0.90 (s, 3
H, Me), 0.86 (s, 3 H, Me); 13C NMR δ 192.8 (CdO), 153.7 (Cd
C), 143.9 (CdC), 51.8, 41.8, 37.8, 36.7, 36.4, 33.6, 33.5, 33.2,
21.8, 20.4, 19.1, 18.5.
3-Ch lor o-4-h yd r oxy-5-m eth oxyben za ld eh yd e (16).11 To
a solution of 2.50 g (16.4 mmol) of vanillin in 15 mL of glacial
acetic acid was added chlorine gas through a glass tubing over
30 min (with a slow gas flow) at 25 °C. White solid product
was collected by filtration, washed with 50 mL of hexane, and
dried in vacuo to give 2.03 g of 16. The acetic acid filtrate was
again treated with chlorine gas as above for 30 min to give
another 0.66 g of 16. A total of 2.69 g (88% yield) of 16 was
obtained. The white solids were used in next step without
purification: 1H NMR δ 10.04 (s, 1 H, OH), 9.76 (s, 1 H, CHO),
7.56 (d, J ) 1.6 Hz, 1 H, Ar), 7.37 (d, J ) 1.6 Hz, 1 H, Ar),
3.91 (s, 3 H, OMe); 13C NMR δ 190.5 (CdO), 149.0 (s, 2 C),
128.2 (s), 125.6 (d), 120.1 (s), 109.2 (d), 56.3 (q).
5-Ch lor o-3,4-d ih yd r oxyben za ld eh yd e (17).12 To a solu-
tion 2.00 g (10.7 mmol) of aldehyde 16 in 20 mL of dichlo-
romethane under argon at 0 °C was added 1.20 mL (11.8
mmol) of boron tribromide. The solution was stirred at 0 °C
for 0.3 h and 25 °C for 4 h and diluted with 40 mL of methanol,
and the solvents were removed on a rotary evaporator (tri-
methyborate was removed). To it was added 40 mL of
methanol, and methanol and trimethyl borate were removed
by evaporation on a rotary evaporator; this process was
repeated three times. The residue was diluted with dichlo-
romethane and filtered and washed with a small amount of
dichloromethane to give 1.72 g (94% yield) of pure 17.12 This
material was used in next step without purification: 1H NMR
δ 10.43 (s, 2 H, OH), 9.70 (s, 1 H, CHO), 7.42 (d, J ) 2.0 Hz,
1 H, C6-H), 7.22 (d, J ) 2.0 Hz, 1 H, C2-H); 13C NMR (DMSO-
d6) δ 190.6 (CdO), 148.3 (s), 146.9 (s), 128.4 (d), 124.2 (d), 120.3
(s), 112.5 (s).
3,4-Bis(ter t-bu tyld im eth ylsilyloxy)-5-ch lor oben za ld e-
h yd e (18). To a solution of 1.68 g (9.70 mmol) of 17 and 0.21
g (2.80 mmol) of 4-(dimethylamino)pyridine (DMAP) in 20 mL
of dichloromethane under argon at 0 °C were added 9.80 mL
(68.0 mmol) of distilled triethylamine and 4.40 g (59.2 mmol)
of tert-butyldimethylsilyl chloride. The reaction mixture was
stirred at 0 °C for 1 h and 25 °C for 3 h, 100 mL of saturated
aqueous NH4Cl was added, and the mixture was extracted
three times with diethyl ether (80 mL each). The combined
extracts were washed with 60 mL of brine, dried (MgSO4),
concentrated, and column chromatographed on silica gel using
a gradient mixture of hexane and diethyl ether as an eluent
to give 3.64 g (93% yield) of 18: 1H NMR δ 9.77 (s, 1 H, CHO),
7.50 (d, J ) 2.0 Hz, 1 H, C6-H), 7.27 (d, J ) 2.0 Hz, 1 H, C2-
H), 1.04 (s, 9 H, t-Bu), 0.98 (s, 9 H, t-Bu), 0.26 (s, 6 H, Me),
0.23 (s, 6 H, Me); 13C NMR δ 189.3 (CdO), 149.5 (s), 149.2 (s),
130.3 (s), 127.8 (s), 125.7 (d), 118.8 (d), 26.1 (q, 3 C, t-Bu), 26.0
(q, 3 C, t-Bu), 18.7 (s, 2 C, t-Bu), -3.4 (q, 2 C, Me), -3.6 (q, 2
column chromatography. Compound 12 (the less polar isomer):
9c
[R]22 ) -7.2° (c 0.8, CH3OH); MS (electrospray) m/z 271
D
1
(M + 1); H NMR δ 4.53 (m, 1 H, CHO), 4.08 (dd, J ) 10, 8
Hz, 1 H, CH2O), 3.64 (dd, J ) 10, 4 Hz, 1 H, CH2O), 1.95 (d,
J ) 4 Hz, 1 H), 1.70-1.01 (m, 11 H), 1.43 (s, 3 H, Me), 1.10 (s,
3 H, Me), 0.90 (s, 3 H, Me), 0.82 (s, 3 H, Me); 13C NMR δ 82.9,
75.2, 71.8, 68.8, 48.7, 42.4, 38.4, 36.3, 34.9, 33.7, 33.2, 28.3,
23.0, 21.9, 20.0, 18.5. Compound 12 (the more polar isomer):
1
MS (electrospray) m/z 271 (M + 1); H NMR δ 3.87 (m, 1 H,
CHO), 3.68 (dd, J ) 11, 3 Hz, 1 H, CH2O), 3.42 (dd, J ) 11, 8
Hz, 1 H, CH2O), 3.15 (broad s, 3 H, OH), 1.80-0.8 (m, 12 H),
1.54 (s, 3 H, Me), 0.99 (s, 3 H, Me), 0.87 (s, 3 H, Me), 0.81 (s,
3 H, Me). Compound 13 (as a mixture of 4 diastereomers at
1
C1 and C2): MS (electrospray) m/z 269 (M + 1); H NMR δ
5.38, 5.32 (broad s, 1 H), 5.33, 5.22 (s, 1 H), 4.36, 4.35 (t, J )
5 Hz, 1 H), 2.8, 2.5 (broad s, 1 H, OH), 1.9-0.9 (m, 12 H),
1.49, 1.34 (s, 3 H, Me), 1.19, 1.16 (s, 3 H, Me), 0.97, 0.86 (s, 3
H, Me), 0.87, 0.84, 0.83 (s, 3 H, Me); 13C NMR δ 94.5, 79.2,
73.1, 70.8, 64.3, 62.9, 60.6, 57.1, 56.9, 42.5, 40.8, 40.4, 39.9,
37.0, 36.8, 33.8, 33.3, 25.3, 25.2, 24.6, 21.6, 21.3, 20.8, 18.4,
16.4, 16.2.
Com p ou n d 12 fr om Red u ction of 13. To a solution of 20
mg (75 µmol) of 13 in 2 mL of THF under argon was added 9
mg (0.23 mmol) of lithium aluminum hydride. After the
mixture was stirred for 3 h, aqueous NH4Cl was added, and
the mixture was extracted three times with ethyl acetate. The
combined organic layer was washed with brine, dried (MgSO4),
concentrated, and column chromatographed on silica gel using
hexane/ethyl acetate (1:1) as an eluant to give 19 mg (91%
yield) of 12.
(1R,2R,4a S,8a S)-Deca h yd r o-2-h yd r oxy-2,5,5,8a -t et r a -
m et h yln a p h t h a len e-1-ca r b oxa ld eh yd e (14) fr om Tr iol
12. To a solution of 0.65 g (2.4 mmol) of triol 12 in 25 mL of
benzene under argon was added 1.3 g (2.9 mmol) of lead
tetraacetate. After stirring at 25 °C for 4 h, the mixture was
diluted with diethyl ether, and the organic layer was washed
with water and brine, dried (MgSO4), concentrated, and
column chromatographed on silica gel using a gradient mixture
of hexane and diethyl ether as an eluent to give 0.52 g (90%
yield) of aldehyde 14:9c [R]22 ) +31.9° (c 0.75, CHCl3); MS
D
(electrospray) m/z 239 (M + 1); 1H NMR δ 10.06 (d, J ) 3 Hz,
1 H, CHO), 2.93 (broad s, 1 H, OH), 2.15 (d, J ) 3 Hz, 1 H,
C1-H), 1.8-0.9 (a series of m, 11 H), 1.20 (s, 3 H, Me), 1.17 (s,
3 H, Me), 0.90 (s, 3 H, Me), 0.86 (s, 3 H, Me); 13C NMR δ 208.3,
6072 J . Org. Chem., Vol. 69, No. 18, 2004

(+)-Chloropuupehenone and (+)-Chloropuupehenol
C, Me). Anal. Calcd for C19H33ClO3Si2: C, 56.90; H, 8.29.
Found: C, 56.62; H, 8.41.
ether (40 mL each), and the combined extracts were washed
with brine (30 mL), dried (MgSO4), and concentrated to give
42 mg (70% yield) of 23. This material was used in next step
without purification: 1H NMR δ 6.53 (s, 1 H, Ar, C6-H), 1.03
(s, 9 H, t-Bu), 0.96 (s, 9 H, t-Bu), 0.22 (s, 6 H, Me), 0.17 (s, 6
H, Me); 13C NMR δ 148.3 (s), 147.4 (s), 138.8 (s), 127.0 (s),
106.9 (d), 102.9 (s), 26.2 (q, t-Bu), 18.8 (s), -3.3 (q, Me), -3.5
(q, Me). HRMS calcd for C18H32BrClSi2O3 (M + H) 471.0791,
found 471.0780.
P r ep a r a tion of 15 fr om Silyla tion of 23. To a mixture
of 42 mg (90 µmol) of 23, 16 mg (0.11 mmol) of tert-
butyldimethylsilyl chloride, and 3 mg (10 µmol) of DMAP in 2
mL of dichloromethane under argon at 25 °C was added 50
µL (0.26 mmol) of triethylamine. The reaction mixture was
stirred for 3 h, diluted with 30 mL of water, and extracted
three times with diethyl ether (30 mL each). The combined
ether extracts were with 30 mL of brine, dried (MgSO4), and
concentrated to give 51 mg (99% yield) of 15.
2-Br om o-5-ch lor o-1,3,4-tr is(ter t-bu tyldim eth ylsilyloxy)-
ben zen e (22). A solution of 0.10 g (0.20 mmol) of 21 and 0.035
g (0.20 mmol) of NBS in 2 mL of DMF under argon was stirred
at 50 °C for 2 day. The solution was diluted with 30 mL of
water and extracted three times with diethyl ether (30 mL
each), and the combined extracts were washed with brine,
dried (MgSO4), concentrated, and column chromatographed on
silica gel using a mixture of hexane and diethyl ether (100:1)
as an eluent to give 31 mg (27% yield) of 15 and 63 mg (54%
yield) of 22. Compound 22: 1H NMR δ 6.54 (s, 1 H, Ar, C6-H),
1.03 (s, 18 H, t-Bu), 0.97 (s, 9 H, t-Bu), 0.23 (s, 12 H, Me), 0.17
(s, 6 H, Me). Anal. Calcd for C24H46BrClO3Si3: C, 49.51; H,
7.96. Found: C, 49.73; H, 8.07.
3,4-Bis(ter t-bu tyldim eth ylsilyloxy)-5-ch lor oph en yl For -
m a te (19). To a solution of 1.73 g (4.30 mmol) of 18 in 15 mL
of dichloromethane under argon was added 2.03 g (6.50 mmol)
of 55% m-chloroperbenzoic acid (MCPBA). After refluxing for
10 h, the solution was diluted with 30 mL of water and
extracted three times with diethyl ether (50 mL each). The
combined extracts were washed twice with saturated aqueous
NaHCO3 (30 mL each), 30 mL of water, and 30 mL of brine,
dried (MgSO4), concentrated, and column chromatographed on
silica gel using hexane as an eluent to give 1.24 g (70% yield)
of 19: 1H NMR δ 8.22 (s, 1 H, CHO), 6.79 (d, J ) 3.2 Hz, 1 H),
6.58 (d, J ) 3.2 Hz, 1 H), 1.03 (s, 9 H, t-Bu), 0.96 (s, 9 H, t-Bu),
0.22 (s, 6 H, Me), 0.19 (s, 6 H, Me); 13C NMR δ 159.0 (s, CdO),
148.8 (s), 143.0 (s), 142.4 (s), 127.1 (s), 115.5 (d), 113.1 (d),
26.2 (q, 6 C, t-Bu), 18.8 (s, 2 C, t-Bu), -3.3 (q, 2 C, Me), -3.6
(q, 2 C, Me). Anal. Calcd for C19H33ClO4Si2: C, 54.71; H, 7.97.
Found: C, 54.90; H, 8.13.
3,4-Bis(ter t-bu tyldim eth ylsilyloxy)-5-ch lor oph en ol (20).
To a solution of 1.24 g (2.97 mmol) of 19 in 10 mL of methanol
was added 2.05 g (15.0 mmol) of potassium carbonate at 25
°C. The solution was stirred for 30 min, diluted with 35 mL of
water, and extracted three times with diethyl ether (50 mL
each). The combined extracts were washed with brine, dried
(MgSO4), and concentrated to give 1.03 g (90% yield) of 20: 1H
NMR δ 6.45 (d, J ) 2.8 Hz, 1 H), 6.31 (d, J ) 2.8 Hz, 1 H),
1.00 (s, 9 H, t-Bu), 0.93 (s, 9 H, t-Bu), 0.18 (s, 6 H, Me), 0.15
(s, 6 H, Me); 13C NMR δ 149.7 (s), 148.9 (s), 137.7 (s), 126.9
(s), 109.8 (d), 107.8 (d), 26.3 (q, 3 C), 26.2 (q, 3 C), -3.6 (q, 2
C, Me), -3.4 (q, 2 C, Me). Anal. Calcd for C18H33ClO3Si2: C,
55.57; H, 8.55. Found: C, 55.39; H, 8.87.
(4a S,6a R,12b S)-2H -9,10-Bis(ter t-b u t yld im et h ylsilyl-
oxy)-11-chloro-1,3,4,4a,5,6,6a,12b-octahydro-4,4,6a,12b-tetra-
m eth yl-ben zo[a ]xa n th en e (4) a n d (4a S,6a S,12bS)-2H-
9 ,1 0 -B i s ( t e r t -b u t y l d i m e t h y l s i l y l o x y ) -1 1 -c h l o r o -
1,3,4,4a ,5,6,6a ,12b-octa h yd r o-4,4,6a ,12b-tetr a m eth yl-ben -
zo[a ]xa n th en e (6). In a dried flask was placed 2.60 g (4.5
mmol) of bromide 15,which was dried by adding 1 mL of
freshly distilled toluene (distilled over sodium) followed by
evaporation under vacuum. This addition-evaporation of tolu-
ene process was repeated and maintained under argon. To it
was added 25 mL of dried diethyl ether, cooled to -78 °C, and
2.7 mL (4.50 mmol) of t-BuLi (1.7 M in pentane) was added
via syringe. After 0.5 h of stirring at -78 °C, a solution of 0.82
g (3.7 mmol) of aldehyde 7 in 10 mL of diethyl ether (-78 °C)
was added via cannula, and the resulting solution was stirred
at -78 °C for 10 min and 25 °C for 1 h (the reaction was
monitored by TLC). The reaction solution was diluted with 10
mL of saturated aqueous NH4Cl and extracted three times
with diethyl ether, and the combined extracts were washed
with water and brine, dried (MgSO4), concentrated, and
column chromatographed on silica gel using a gradient mixture
of hexane and toluene and then hexane and ether as eluents
to give 0.98 g (45% yield) of 4 and 0.20 g (9.1% yield) of 6.
3-Ch lor o-1,2,5-t r is(t er t -b u t yld im e t h ylsilyloxy)b e n -
zen e (21). To a mixture of 1.03 g (2.65 mmol) of 20, 0.60 g
(4.00 mmol) of tert-butyldimethylsilyl chloride, and 48 mg (0.40
mmol) of 4-(dimethylamino)pyridine in 10 mL of dichlo-
romethane under argon at 25 °C was added 1.30 mL (9.3
mmol) of triethylamine. After stirring at 25 °C for 10 h, the
mixture was diluted with 30 mL of water and extracted three
times with diethyl ether (50 mL each). The combined extracts
were washed with 30 mL of brine, dried (MgSO4), concentrated,
and column chromatographed on silica gel using a gradient
mixture of hexane and diethyl ether as an eluent to give 1.10
g (83% yield) of 21: 1H NMR δ 6.49 (d, J ) 2.8 Hz, 1 H, Ar,
C4-H), 6.30 (d, J ) 2.8 Hz, 1 H, C6-H), 1.04-0.97 (broad s, 27
H, t-Bu), 0.18 (s, 6 H, Me), 0.175 (s, 12 H, Me); 13C NMR δ
149.3 (s), 148.6 (s), 138.6 (s), 126.8 (s), 114.6 (d), 112.1 (d),
26.3 (q, t-Bu), 25.9 (q, t-Bu), 18.9 (s), 8.8 (s), -3.5 (q, 2 C, Me),
-3.4 (q, 2 C, Me), -4.3 (q, 2 C, Me). Anal. Calcd for C24H47
-
ClO3Si3: C, 57.27; H, 9.41. Found: C, 57.37; H, 9.55.
5-Br om o-6-ch lor o-1,2,4-tr is(ter t-bu tyldim eth ylsilyloxy)-
ben zen e (15). A mixture of 0.65 g (1.3 mmol) of 21 and 0.28
g (1.6 mmol) of N-bromosuccinimide in 10 mL of DMF under
argon was stirred at 25 °C for 5 days. The reaction mixture
was diluted with 30 mL of water, extracted three times with
diethyl ether (50 mL each), and the combined extracts were
washed with 30 mL of water, and 30 mL of brine, dried
(MgSO4), concentrated, and column chromatographed on silica
gel using a gradient mixture of hexane and diethyl ether as
an eluent gave 0.51 g (67% yield) of 15: 1H NMR δ 6.41 (s, 1
H, Ar, C3-H), 1.03 (s, 9 H, t-Bu), 1.02 (s, 9 H, t-Bu), 0.97 (s, 9
H, t-Bu), 0.23 (s, 6 H, Me), 0.22 (s, 6 H, Me), 0.18 (s, 6 H, Me);
13C NMR δ 147.3 (s), 147.2 (s), 139.4 (s), 128.3 (s), 111.1 (d),
108.4 (s), 29.9 (q, t-Bu), 26.3 (q, t-Bu), 26.2 (q), 26, 18.9 (s),
18.6 (s), -3.3 (q, Me), -3.4 (q, Me), -3.5 (q, Me), -4.0 (q). Anal.
Calcd for C24H46BrClO3Si3: C, 49.51; H, 7.96. Found: C, 49.78;
H, 8.11.
Compound 4: [R]22 ) +56° (c 3.3, CHCl3); 1H NMR δ 6.43 (s,
D
1 H, C8-H), 6.28 (s, 1 H, C12-H), 2.18 (d, J ) 12 Hz, 1 H), 2.02
(d, J ) 12 Hz, 1 H), 1.90-1.00 (a series of m, 9 H), 1.37 (s, 3
H, Me), 1.16 (s, 3 H, Me), 1.03 (s, 9 H, t-BuSi), 0.95 (s, 9 H,
t-BuSi), 0.92 (s, 3 H, Me), 0.87 (s, 3 H, Me), 0.21 (s, 3 H, MeSi),
0.20 (s, 3 H, MeSi), 0.17 (s, 9 H, MeSi), 0.16 (s, 3 H, MeSi);
13C NMR δ 151.3, 147.3, 146.1, 138.1, 123.6, 115.7, 111.7,
107.9, 78.0, 52.4, 41.8, 41.7, 39.5, 38.2, 33.8, 33.6, 26.4 (3 C,
t-Bu), 26.3 (3 C, t-Bu), 26.1, 23.7, 21.9, 19.5, 19.1, 18.9, -3.2,
-3.46, -3.49, -3.6. Anal. Calcd for C33H55ClO3Si2: C, 67.02;
H, 9.37. Found: C, 67.15; H, 9.53. Compound 6: white solids,
mp 83-85 °C; [R]22 ) +50° (c 1.8, CHCl3); 1H NMR δ 6.39 (s,
D
1 H, C8-H), 6.31 (s, 1 H, C12-H), 2.20-0.90 (m, 11 H), 1.31 (s,
3 H, Me), 1.23 (s, 3 H, Me), 1.03 (s, 9 H, t-Bu), 0.96 (s, 9 H,
t-Bu), 0.95 (s, 3 H, Me), 0.86 (s, 3 H, Me), 0.21 (s, 3 H, MeSi),
0.20 (s, 3 H, Me), 0.18 (s, 3 H, Me), 0.15 (s, 3 H, Me); 13C NMR
δ 151.9, 147.5, 146.0, 138.0, 123.8, 116.5, 111.9, 108.0, 78.0,
52.2, 44.1, 42.3, 39.4, 39.1, 34.0, 33.0, 31.1, 26.4 (3 C, t-Bu),
2-Br om o-3-ch lor o-4,5-b is(ter t-b u t yld im et h ylsilyoxy)-
p h en ol (23). A solution of 50 mg (0.12 mmol) of 20 and 23
mg (0.12 mmol) of NBS in 2 mL of DMF under argon was
stirred at 25 °C for 1 day. The reaction mixture was diluted
with 30 mL of water and extracted three times with diethyl
J . Org. Chem, Vol. 69, No. 18, 2004 6073

Hua et al.
26.3 (3 C, t-Bu), 26.1, 25.6, 25.1, 23.7, 21.4, 19.2, 18.9, 18.8,
17.6, -3.3, -3.4, -3.5, -3.6. Anal. Calcd for C33H55ClO3Si2:
C, 67.02; H, 9.37. Found: C, 67.11; H, 9.16.
2D NOESY spectra were obtained, and in compound 4, C6a
methyl and C12b methyl have NOE connectivity; however, in
compound 6, C6a methyl and C12b methyl have no NOE
connectivity.
(4aS,6aR,12bS)-2H-11-Ch lor o-1,3,4,4a,5,6,6a,12b-octah y-
dr o-4,4,6a,12b-tetr am eth yl-ben zo[a ]xan th en e-9,10-diol (3).
To a solution of 0.16 g (0.27 mmol) of 4 in 3 mL of THF under
argon at 25 °C was added 0.58 mL (0.60 mmol) of tetra-n-
butylammonium fluoride (1.0 M in THF). After 5 min of
stirring at 25 °C, 0.30 mL of acetic acid was added, and the
resulting solution was concentrated on a rotary evaporator and
column chromatographed on silica gel using a gradient mixture
2.61 (d, J ) 17 Hz, 1 H, C12H), 2.34 (m, 1 H, C12H), 2.02 (m,
1 H), 1.80-0.90 (a series of m, 11 H), 1.14 (s, 3 H, Me), 0.91
(s, 6 H, Me), 0.85 (s, 3 H, Me); when the proton NMR spectrum
was measured in benzene-d6 solvent, all methyl groups are
separated, δ 0.99 (s, 3 H, Me), 0.77 (s, 3 H, Me), 0.71 (s, 3 H,
Me), 0.61 (s, 3 H, Me); 13C NMR (C6D6) δ 149.1, 144.0, 134.5,
120.4, 111.3, 104.7, 76.6, 55.9, 51.9, 41.9, 41.0, 39.0, 36.8, 33.4,
33.1, 30.0, 21.6, 19.8, 19.1, 18.7, 14.7; HRMS calcd for C21H30
-
ClO3 (M + H) 365.1885, found 365.1901.
(4a S,6a R,12a R,12bS)-2H-11-Ch lor o-1,3,4,4a ,5,6,6a ,9,10,
12,12a ,12b-d od eca h yd r o-4,4,6a ,12b-tetr a m eth yl-ben zo[a ]-
xa n th en e-9,10-d ion e (28). To a solution of 10 mg (0.027
mmol) of diol 27 in 1 mL of dichloromethane under argon at
25 °C was added 3 mg of pyridinium dichromate (PDC). After
stirring for 2 h, the mixture was diluted with a small amount
of dichloromethane, filtered through Celite, concentrated, and
column chromatographed on silica gel using a gradient mixture
of hexane and ethyl acetate as an eluent to give 7.7 mg (77%
of hexane and ethyl acetate as an eluent to give 0.08 g (82%
1
yield) of 3: [R]22 ) +0.11° (c 1.8, CH2Cl2); H NMR δ 6.42-
D
6.20 (broad s, 3 H, C8H, C12H, and OH), 5.8 (broad s, 1 H,
OH), 2.18 (d, J ) 12 Hz, 1 H), 2.01 (d, J ) 12 Hz, 1 H), 1.86-
0.90 (a series of m, 9 H), 1.42 (s, 3 H, Me), 1.15 (s, 3 H, Me),
0.92 (s, 3 H, Me), 0.87 (s, 3 H, Me); 13C NMR δ 151.3, 147.3,
146.1, 138.1, 123.6, 115.7, 111.7, 107.9, 78.0, 42.3, 41.8, 38.2,
34.0, 33.9, 33.5, 33.0, 21.9, 21.4, 20.9, 19.5, 19.1. Anal. Calcd
for C21H27ClO3: C, 69.51; H, 7.50. Found: C, 69.28; H, 7.32.
yield) of 28: [R]22 ) +16° (c 0.03, CHCl3); 1H NMR δ 5.80 (s,
D
1 H, C8H), 2.84 (dd, J ) 20, 5 Hz, 1 H, C12H), 2.50 (dd, J )
20, 13 Hz, 1 H, C12H), 2.11 (dt, J ) 13, 3 Hz, 1 H), 2.22-0.90
(a series of m, 11 H), 1.33 (s, 3 H), 0.93 (s, 3 H), 0.92 (s, 3 H),
0.85 (s, 3 H); 13C NMR δ 178.3, 177.2, 163.8, 155.3, 127.6,
107.2, 75.0, 56.0, 51.0, 41.8, 41.1, 40.5, 38.7, 33.5, 29.9, 21.6,
20.9, 19.8, 19.5, 18.4, 14.8; HRMS calcd for C21H28ClO3 (M +
H) 363.1728, found 363.1722.
(+)-Ch lor op u u p eh en ol (5). To a solution of 60 mg (0.10
mmol) of 6 in 2 mL of THF under argon at 25 °C was added
0.22 mL (0.22 mmol) of tetra-n-butylammonium fluoride (1.0
M in THF). After 10 min of stirring at 25 °C, 0.10 mL of acetic
acid was added, the solution was concentrated on a rotary
evaporator, and the residue was column chromatographed on
silica gel using a gradient mixture of hexane and ethyl acetate
(4a S,6a S,12a R,12bS)-2H-9,10-Bis(ter t-bu tyld im eth ylsi-
lyloxy)-11-ch lor o-1,3,4,4a ,5,6,6a ,12,12a ,12b -d eca h yd r o-
4,4,6a ,12b-tetr a m eth yl-ben zo[a ]xa n th en e (29). A mixture
of 60 mg (0.1 mmol) of compound 6 and 80 mg of 10%
palladium/carbon in 2 mL of distilled ethanol was charged with
1 atm of hydrogen gas (by the use of a hydrogen balloon), and
the mixture was stirred at 25 °C for 2 h. The reaction mixture
was filtered through Celite and washed with dichloromethane,
and the combined filtrate was concentrated and column
chromatographed on silica gel using a gradient mixture of
hexane and toluene as an eluent to give 54 mg (90% yield) of
as an eluent to give 30 mg (81.4% yield) of 5:3e [R]22 ) +105°
D
(c 0.3, CH3OH), lit.3e +112° (c 0.35, MeOH); MS m/z 363 (M +
1); 1H NMR δ 6.38 (s, 1 H, C8H), 6.31 (s, 1 H, C12H), 5.36
(broad s, 1 H, OH), 5.03 (broad s, 1 H, OH), 2.20-1.05 (a series
of m, 11 H), 1.44 (s, 3 H, Me), 1.23 (s, 3 H, Me), 0.96 (s, 3 H,
Me), 0.87 (s, 3 H, Me); 13C NMR δ 151.3, 148.5, 146.1, 133.6,
123.6, 116.5, 110.6, 103.0, 78.0, 43.8, 42.0, 39.1, 33.8, 32.7, 30.8,
30.3, 25.0, 21.2, 20.5, 18.9, 17.2.
compound 29 as white solids: mp 67-69 °C; [R]22 ) -35° (c
D
0.7, CHCl3); 1H NMR δ 6.21 (s, 1 H, C8H), 2.75 (d, J ) 18 Hz,
1 H, C12H), 2.64 (dd, J ) 18, 8 Hz, 1 H, C12H), 2.10 (d, J )
11 Hz, 1 H), 1.85 (d, J ) 12 Hz, 1 H), 1.62-1.10 (a series of m,
10 H), 1.11 (s, 3 H, Me), 1.03 (s, 9 H, t-Bu), 0.95 (s, 9 H, t-Bu),
0.89 (s, 3 H, Me), 0.81 (s, 3 H, Me), 0.64 (s, 3 H, Me), 0.20 (s,
3 H, MeSi), 0.18 (s, 3 H, MeSi), 0.16 (s, 3 H, MeSi), 0.157 (s,
3 H, MeSi); 13C NMR δ 148.9, 146.3, 137.3, 126.0, 114.6, 108.4,
75.4, 55.5, 49.7, 42.1, 40.7, 40.3, 38.6, 33.9, 33.5, 27.1, 26.4 (3
C, t-Bu), 26.3 (3 C, t-Bu), 22.1, 21.9, 18.9, 18.7, 18.5, 14.1, -3.3
(2 C, MeSi), -3.5, -3.6. Anal. Calcd for C33H57ClO3Si2: C,
66.79; H, 9.68. Found: C, 66.92; H, 9.78.
(4a S,6a R,12a R,12bS)-2H-9,10-Bis(ter t-bu tyld im eth ylsi-
lyloxy)-11-ch lor o-1,3,4,4a ,5,6,6a ,12,12a ,12b -d eca h yd r o-
4,4,6a ,12b-tetr a m eth yl-ben zo[a ]xa n th en e (26). A mixture
of 0.18 g (0.30 mmol) of compound 4 and 0.40 g of 10%
palladium/carbon in 7 mL of distilled ethanol was charged with
1 atm of hydrogen gas (by the use of a hydrogen balloon), and
the mixture was stirred at 25 °C for 2 h. The reaction mixture
was filtered through a short Celite column, the column was
washed with ethanol, and the combined filtrate was concen-
trated and column chromatographed on silica gel using a
gradient mixture of hexane and toluene as an eluent to give
(4a S,6a S,12a R ,12b S)-2H -11-Ch lor o-1,3,4,4a ,5,6,6a ,12,
12a ,12b-d eca h yd r o-4,4,6a ,12b-tetr a m eth yl-ben zo[a ]xa n -
th en e-9,10-d iol (30). To a solution of 50 mg (84 µmol) of 29
in 2 mL of THF under argon at 25 °C was added 0.25 mL (0.25
mmol) of tetra-n-butylammonium fluoride (1 M in THF). The
solution was stirred for 15 min, 1 drop of acetic acid was added,
and the resulting red solution was concentrated to dryness and
column chromatographed on silica gel using a gradient mixture
0.18 g (99% yield) of 26: [R]22 ) +35.6° (c 0.8, CHCl3); 1H
D
NMR δ 6.23 (s, 1 H, C8H), 2.64 (dd, J ) 17, 5 Hz, 1 H, C12H),
2.33 (dd, J ) 17, 12 Hz, 1 H, C12H), 2.02 (dt, J ) 12, 3 Hz, 1
H), 1.80-1.15 (a series of m, 11 H), 1.12 (s, 3 H, Me), 1.03 (s,
9 H, t-Bu), 0.95 (s, 9 H, t-Bu), 0.90 (s, 6 H, Me), 0.85 (s, 3 H,
Me), 0.194 (s, 3 H, MeSi), 0.191 (s, 3 H, MeSi), 0.17 (s, 3 H,
MeSi), 0.15 (s, 3 H, MeSi); 13C NMR δ 147.4, 146.5, 137.4,
126.8, 114.4, 108.2, 76.8, 56.4, 52.2, 42.1, 41.1, 39.4, 37.1, 33.7,
33.4, 26.4 (3 C, t-Bu), 26.3 (3 C, t-Bu), 25.2, 24.1, 21.8, 20.7,
20.0, 18.9, 18.7, 15.0-3.2 (MeSi), -3.4, -3.5 (2 C). Anal. Calcd
for C33H57ClO3Si2: C, 66.79; H, 9.68. Found: C, 67.15; H, 9.45.
of hexane and ethyl acetate as an eluent to give 10 mg (50%
1
yield) of diol 30: [R]22 ) -38.7° (c 0.45, CHCl3); H NMR δ
D
6.33 (s, 1 H, C8H), 5.24 (broad s, 1 H, OH), 5.01 (bs, 1 H, OH),
2.72 (d, J ) 17 Hz, 1 H, C12H), 2.64 (dd, J ) 17, 7 Hz, 1 H,
C12H), 1.84 (d, J ) 13 Hz, 1 H), 1.60-0.90 (a series of m, 11
H), 1.12 (s, 3 H, Me), 0.89 (s, 3 H, Me), 0.81 (s, 3 H, Me), 0.67
(s, 3 H, Me); 13C NMR δ 149.1, 143.1, 133.3, 119.1, 112.4, 103.3,
75.7, 68.2, 55.4, 49.4, 42.1, 40.6, 40.3, 38.5, 33.9, 33.4, 27.1,
22.1, 18.7, 18.4, 14.3; HRMS calcd for C21H30ClO3 (M + H)
365.1885, found 365.1890.
(4a S,6a R,12a R ,12b S)-2H -11-Ch lor o-1,3,4,4a ,5,6,6a ,12,
12a ,12b-d eca h yd r o-4,4,6a ,12b-tetr a m eth yl-ben zo[a ]xa n -
th en e-9,10-d iol (27). To a solution of 39 mg (66 µmol) of 26
in 2 mL of THF under argon at 25 °C was added 0.20 mL (0.20
mmol) of tetra-n-butylammonium fluoride (1 M in THF). The
solution was stirred for 30 min, 1 drop of acetic acid was added,
and the resulting red solution was concentrated to dryness and
column chromatographed on silica gel using a gradient mixture
of hexane and ethyl acetate as an eluent to give 20 mg (83%
yield) of diol 27: [R]22D ) +5.6° (c 2.0, CHCl3); 1H NMR δ 6.35
(s, 1 H, C8H), 5.33 (broad s, 1 H, OH), 5.06 (broad s, 1 H, OH),
(+)-Ch lor op u u p eh en on e (1). To a solution of 6 mg (16
µmol) of 30 in 1 mL of dichloromethane under argon at 25 °C
was added 12 mg (32 µmol) of PDC. After stirring for 15 min,
the solution was filtered through Celite, rinsed with diethyl
ether, concentrated, and column chromatographed on silica gel
6074 J . Org. Chem., Vol. 69, No. 18, 2004

(+)-Chloropuupehenone and (+)-Chloropuupehenol
using a gradient mixture of hexane and diethyl ether as an
eluent to give 3 mg (50% yield) of (+)-chloropuupehenone (1).
The 1H and 13C NMR data are similar to those reported,3a,3d
and the optical rotation has not been reported previously:
trated, and column chromatographed on silica gel using a
mixture of hexane/ethyl acetate (5:1) as an eluent to give 0.304
g (92% yield) of 38:3f [R]22 ) -15° (c 1.0, CHCl3), lit.3f -14° (c
D
1
0.28, CHCl3); H NMR δ 5.54 (m, 1 H, dCH), 3.84 (ddd, 1 H,
[R]22 ) +137.5° (c 0.04, CHCl3); MS (CI) m/z 363, 362 (M + 1
J ) 11, 5.2, 3.4 Hz, 1H, CH2O), 3.75 (dt, J ) 11, 5.2 Hz, 1 H,
CH2O), 2.02-1.0 (a series of m, 10 H), 1.79 (s, 3 H, Me), 0.89
(s, 3 H, Me), 0.86 (s, 3 H, Me), 0.85 (s, 3 H, Me); 13C NMR δ
133.0, 124.3, 61.2, 57.5, 50.1, 42.4, 40.2, 36.4, 33.6, 33.2, 23.9,
22.4, 22.2, 19.1, 15.3.
D
and M+), 211, 173, 84; 1H NMR δ 7.14 (d, J ) 7 Hz, 1 H, C12H),
5.84 (s, 1 H, C8H), 2.18 (d, J ) 7 Hz, 1 H, C12aH), 1.80-0.80
(a series of m, 11 H), 1.24 (s, 3 H, Me), 0.93 (s, 3 H, Me), 0.86
(s, 3 H, Me), 0.82 (s, 3 H, Me); 13C NMR δ 180.0 (CdO), 162.7,
144.4, 141.2, 127.7, 111.1, 105.2, 79.3, 54.9, 54.0, 41.8, 41.2,
40.3, 39.2, 33.9, 33.6, 28.2, 22.2, 18.6, 18.3, 15.4.
(1S,4a S,8a S)-1,4,4a ,5,6,7,8,8a -Oct a h yd r o-2,5,5,8a -t et -
r a m eth yln a p h th a len e-1-ca r boxa ld eh yd e (32) [(+)-Dr im -
7-en -11-a l]. A mixture of 0.30 g (1.35 mmol) of alcohol 38 and
0.858 (2.0 mmol) of Dess-Martin periodinane in 5 mL of
dichloromethane under argon was stirred at 25 °C for 2 h,
diluted with aqueous Na2S2O3, and extracted with diethyl
ether three times. The combined extract was washed with
water and brine, dried (Na2SO4), concentrated, and column
chromatographed on silica gel using a mixture of hexane/ethyl
acetate/triethylamine (20:1:0.01) as an eluent to give 0.27 g
(+)- Dr im a n -8r,11-d iol [(1S,2R,4a S,8a S)-Deca h yd r o-2-
h yd r oxy-2,5,5,8a -t et r a m et h yln a p h t h a len e-1-m et h a n ol]
(34). To a cold (0 °C) solution of 80 mg (2.1 mmol) of LiAlH4
in 15 mL of diethyl ether under argon was added 1.0 g (4.2
mmol) of aldehyde 14. After stirring at room temperature for
1 h, the reaction mixture was diluted with aqueous NH4Cl and
extracted three times with dichloromethane. The organic
layers were washed with brine, dried (Na2SO4), concentrated,
and column chromatographed on silica gel using a mixture of
hexane/ethyl acetate (2:1) as an eluent to give 0.98 g (97%
yield) of 34:14 [R]20D ) +2.1° (c 0.5, CHCl3), lit.14a +1.6° (c 0.63,
(90% yield) of aldehyde 32:6e [R]22 ) +23.4° (c 1.89, CHCl3),
D
lit.6e +18.8° (c 0.32, CHCl3); 1H NMR δ 9.69 (d, J ) 5 Hz, 1 H,
CHO), 5.69 (m, 1 H, dCH), 2.59 (m, 1 H, C1-H), 2.0 (m, 2 H),
1.7-1.1 (a series of m, 7 H), 1.62 (s, 3 H, Me), 1.07 (s, 3 H,
Me), 0.92 (s, 3 H, Me), 0.87 (s, 3 H, Me); 13C NMR δ 206.9,
142.6, 125.7, 49.3, 42.2, 40.6, 37.2, 35.6, 33.5, 33.2, 23.9, 22.3,
21.8, 18.5, 15.9.
1
CHCl3); H NMR δ 3.93 (d, J ) 7 Hz, 2 H, CH2O), 1.9-0.8 (a
series of m, 12 H), 1.35 (s, 3 H, Me), 0.88 (s, 3 H, Me), 0.79 (s,
6 H, 2 Me); 13C NMR δ 75.2, 61.3, 60.7, 56.1, 44.7, 41.9, 40.2,
33.7, 33.5, 31.2, 24.5, 21.8, 20.4, 18.8, 16.2.
(1S,4a S,8a S)-3H-2-Meth ylen e-1,4,4a ,5,6,7,8,8a -octa h y-
d r o-5,5,8a -tr im eth yln a p h th a len e-1-m eth a n ol (39) [(+)-
Albica n ol]. A similar reaction procedure as that described
above (29) was followed, and a 93% yield of 39 was obtained:
[(1S,2R,4a S,8a S)-1-(ter t-Bu tyld im eth ylsilyloxym eth yl)-
d eca h yd r o-2,5,5,8a -tetr a m eth yln a p h th a len -2-ol] (35). To
a cold (0 °C) solution of 0.90 g (3.8 mmol) of diol 34 and 1.0 g
(15 mmol) of imidazole in 5.0 mL of DMF under argon was
added a solution of 0.62 g (4.1 mmol) of tert-butyldimethylsilyl
chloride in 6 mL of DMF. After stirring at 25 °C for 2 h, the
reaction mixture was diluted with water and extracted three
times with ethyl acetate. The combined ethyl acetate layer was
washed with brine, dried (Na2SO4), concentrated, and column
chromatographed on silica gel using a mixture of hexane/ethyl
[R]22 ) +14.0° (c 1.0, CHCl3), lit.15b +13.4° (c 0.84, CHCl3);
D
1H and 13C NMR spectral data are identical to those reported.15a
(1S,4a S,8a S)-3H-2-Meth ylen e-1,4,4a ,5,6,7,8,8a -octa h y-
d r o-5,5,8a -tr im eth yln a p h th a len e-1-ca r boxa ld eh yd e (31)
[(-)-Albica n a l]. A mixture of 0.30 g (1.35 mmol) of alcohol
39 and 0.858 (2.0 mmol) of Dess-Martin periodinane in 5 mL
of dichloromethane under argon was stirred at 25 °C for 2 h,
diluted with aqueous Na2S2O3, and extracted with diethyl
ether three times. The combined extract was washed with
water and brine, dried (Na2SO4), concentrated, and column
chromatographed on silica gel using a mixture of hexane:ethyl
acetate (20:1) as an eluent to give 0.27 g (91% yield) of
acetate (10:1) as an eluent to give 1.3 g (98% yield) of 35: mp
1
64-65 °C; [R]20 ) +30.1° (c 0.73, CHCl3); H NMR δ 5.06 (s,
D
1 H, OH), 3.99 (dd, J ) 10, 4 Hz, 1 H, CH2O), 3.89 (t, J ) 10
Hz, 1 H, CH2O), 1.84 (dt, J ) 12, 3 Hz, 1 H), 1.7-0.96 (a series
of m, 11 H), 1.30 (s, 3 H, Me), 0.90 (s, 9 H, t-Bu), 0.88 (s, 3 H,
Me), 0.80 (s, 3 H, Me), 0.79 (s, 3 H, Me); 13C NMR δ 73.2, 62.4,
59.3, 56.1, 43.1, 41.8, 40.4, 37.4, 33.8, 33.4, 26.0 (3 C), 25.1,
21.9, 20.0, 18.8, 18.2, 16.0, -5.4, -5.5; HRMS calcd for
aldehyde 31:15b,c [R]22 ) -68.3° (c 1.3, CHCl3), lit.15c -69.8°
D
(c 3.1, CHCl3); 1H NMR15d δ 9.87 (d, J ) 5 Hz, 1 H, CHO),
4.92 (s, 1 H, dCH), 4.50 (s, 1 H, dCH), 2.45 (m, 2 H), 2.10 (m,
1 H), 1.8-1.0 (a series of m, 9 H), 1.15 (s, 3 H, Me), 0.88 (s, 3
H, Me), 0.86 (s, 3 H, Me); 13C NMR15d δ 205.8, 145.3, 109.5,
68.1, 54.2, 42.1, 40.1, 39.2, 36.9, 33.7, 33.6, 23.3, 22.1, 18.9,
16.2.
C
21H43O2Si (M + H) 355.3034, found 355.3039.
[(1S,4a S,8a S)-1-(ter t-Bu t yld im et h ylsilyloxym et h yl)-
1,4,4a ,5,6,7,8,8a -octa h yd r o-2,5,5,8a -tetr a m eth yln a p h th a -
len e] (36) a n d [(1S,4a S,8a S)-1-(ter t-Bu tyld im eth ylsilyl-
oxym eth yl)-3H-1,4,4a ,5,6,7,8,8a -octa h yd r o-2-m eth ylen e-
5,5,8a -tr im eth yln a p h th a len e] (37). To a cold (0 °C) solution
of 1.0 g (2.8 mmol) of 35 in 5 mL of THF under argon were
added 1.4 g (14 mmol) of triethylamine and 0.48 g (4.2 mmol)
of methanesulfonyl chloride. After stirring at 25 °C for 4 h,
the reaction mixture was diluted with cold water and extracted
three times with ethyl acetate. The combined extract was
washed with water and brine, dried (Na2SO4), concentrated,
and column chromatographed on silica gel using hexane as
an eluent to give 0.42 g (45% yield) of 36 and 0.42 g (45% yield)
of 37.15 Compound 36: 1H NMR δ 5.44 (s, 1 H, dCH), 3.76
(dd, J ) 10, 3.2 Hz, 1 H, CH2O), 3.60 (t, J ) 10, 6 Hz, 1 H,
CH2O), 1.95-1.00 (a series of m, 10 H), 1.73 (s, 3 H, Me), 0.88
(s, 12 H, t-Bu & Me), 0.85 (s, 3 H, Me), 0.80 (s, 3 H, Me), 0.04
(s, 3 H, Me), 0.03 (s, 3 H, Me); 13C NMR δ 134.6, 122.7, 61.2,
57.2, 50.2, 42.4, 40.0, 36.2, 33.6, 33.2, 26.1, 23.9, 22.3, 22.2,
19.1, 18.3, 14.9, -5.2, -5.3; HRMS calcd for C21H41OSi (M +
H) 337.2928, found 337.2939. 1H and 13C NMR spectra of
compound 37 are identical with those reported.15
3,4-Diben zyloxy-5-ch lor oben za ld eh yd e (40).22 A mix-
ture of 1.00 (5.8 mmol) of 17, 2.18 g (12.7 mmol) of benzyl
bromide, 0.19 g (1.2 mmol) of KI, and 2.40 g (17.4 mmol) of
K2CO3 in 100 mL of acetone was heated under reflux for 25 h,
cooled to 25 °C, filtered through Celite, concentrated, and
column chromatographed on silica gel using a mixture of
hexane/ethyl acetate (10:1) as an eluent to give 1.60 g (78%
yield) of 40:22 1H NMR δ 9.83 (s, 1 H, CHO), 7.52 (d, J ) 2 Hz,
1 H), 7.45 - 7.30 (m, 11 H), 5.18 (s, 2 H), 5.17 (s, 2 H); 13C
NMR δ 190.1, 153.7, 150.2, 136.6, 135.9, 132.7, 129.7, 128.9,
128.8, 128.6, 128.5 (2 C), 127.8, 126.1, 111.4, 75.4, 71.5. Anal.
Calcd for C21H17ClO3: C, 71.49; H, 4.86. Found: C, 71.24; H,
5.00.
3,4-Diben zyloxy-5-ch lor op h en ol (42). A mixture of 1.6
g (4.5 mmol) of aldehyde 40 and 1.2 g (6.8 mmol) of 3-chlo-
roperoxybenzoic acid in 20 mL of dichloromethane under argon
was heated under reflux for 18 h, cooled to 25 °C, diluted with
ethyl acetate, and washed with aqueous NaHCO3, water, and
brine. The organic layer was dried (Na2SO4) and concentrated
to give formate 41, which was used in the next step without
(-)-Dr im en ol (38).3f A solution of 0.50 g (1.5 mmol) of 36
and 2.0 mL (2 mmol) of n-Bu4NF (1.0 M in THF) was stirred
under argon at 25 °C for 36 h, diluted with aqueous NH4Cl,
and extracted with ethyl acetate twice. The combined extract
was washed with water and brine, dried (Na2SO4), concen-
(22) Kaiser, C.; Colella, D. F.; Pavloff, A. M.; Wardell, J . R. J . J .
Med. Chem. 1974, 17, 1071-1075.
J . Org. Chem, Vol. 69, No. 18, 2004 6075

Hua et al.
purification. It hydrolyzed on silica gel column to give phenol
42. Formate 41: 1H NMR δ 8.24 (s, 1 H), 7.48-7.28 (m, 10
H), 6.85 (d, J ) 2.5 Hz, 1 H), 6.73 (d, J ) 2.5 Hz, 1 H), 5.09 (s,
2 H), 5.03 (s, 2 H); 13C NMR δ 158.8, 153.6, 145.7, 140.0, 137.0,
136.0, 129.3, 128.8, 128.7, 128.6, 128.5, 128.3, 127.7, 115.1,
106.8, 75.3, 71.6. A solution of crude formate 41 and 0.50 g
(3.62 mmol) of K2CO3 in 10 mL of methanol was stirred at 0
°C for 1 h, diluted with ethyl acetate, and washed with water
and brine. The organic layer was dried (Na2SO4) and concen-
trated to give phenol 42: 1H NMR δ 7.43-7.30 (m, 10 H), 6.47
(d, J ) 2.5 Hz, 1 H, Ar), 6.41 (d, J ) 2.5 Hz, 1 H, Ar), 5.06 (s,
2 H), 5.00 (bs, 1 H, OH), 4.97 (s, 2 H); 13C NMR δ 153.7, 152.3,
138.9, 137.2, 136.5, 129.1, 128.9, 128.8, 128.5, 128.3, 128.1,
127.6, 108.8, 101.5, 75.5, 71.2. This material was used in the
next step without purification. A small amount of the com-
pound was purified on silica gel column using a gradient
mixture of hexane and ethyl acetate as an eluent to give an
analytical sample. Anal. Calcd for C20H17ClO3: C, 70.49; H,
5.03. Found: C, 70.13; H, 5.11.
0.86 (s, 3 H), 0.85 (s, 3 H), 0.17 (s, 3 H), 0.15 (s, 3 H); 13C NMR
δ 151.4, 150.4, 149.2, 137.3, 136.5, 129.7, 129.0, 128.7, 128.4,
128.2, 127.9, 127.6, 127.4, 126.7, 126.4, 125.4, 108.7, 107.9,
105.6, 105.4, 75.0, 71.1, 66.8, 55.2, 40.9, 38.1, 33.9, 33.6, 26.0,
25.9, 25.3, 21.7, 21.6, 19.5, 18.3, 15.8, 15.7, -4.1, -4.2. Anal.
Calcd for C41H55ClO4Si: C, 72.91; H, 8.21. Found: C, 73.15;
H, 8.02. The more polar isomer: [R]22D ) -39.8° (c 1.3, CHCl3);
1H NMR δ 7.51 (m, 2 H), 7.38-7.31 (m, 8 H), 6.30 (s, 1 H, Ar),
5.44 (d, J ) 10 Hz, 1 H, CHO), 5.10 (s, 2 H), 5.08 (s, 1 H, d
CH), 4.99 (s, 2 H), 4.86 (s, 1 H, dCH), 3.11 (d, J ) 10 Hz, 1
H), 2.57 (m, 1 H), 2.44 (dt, J ) 11, 4 Hz, 1 H), 2.04 (m, 1 H),
1.78 (m, 1 H), 1.4-1.0 (m, 6 H), 0.99 (s, 9 H, t-Bu), 0.87 (s, 3
H), 0.83 (s, 3 H), 0.75 (s, 3 H), 0.18 (s, 3 H), 0.13 (s, 3 H); 13C
NMR δ 151.4, 150.9, 149.1, 147.9, 137.2, 136.5, 136.4, 129.6,
128.6, 128.2, 128.1, 128.0, 127.9, 127.5, 127.4, 127.0, 125.4,
108.0, 105.5, 104.9, 74.9, 71.1, 61.9, 42.5, 41.9, 40.9, 33.9, 33.7,
33.6, 26.0, 25.9, 22.0, 21.6, 19.4, 18.3, 15.7, 15.6, -4.0, -4.1.
A mixture of the two diastereomers was used in the following
experiment.
1,2-Diben zyloxy-3-ch lor o-5-(ter t-bu tyldim eth ylsilyloxy)-
ben zen e (43). The above crude phenol 42 was dissolved in
15 mL of dichloromethane under argon. To it were added 1.5
g (14 mmol) of triethylamine, 50 mg (0.41 mmol) of 4-(dim-
ethylamino)pyridine, and a solution of 70 mg (4.6 mmol) of
tert-butyldimethylsilyl chloride in 6 mL of dichloromethane.
The mixture was stirred at 25 °C for 8 h, diluted with water,
and extracted three times with ethyl acetate. The combined
extracts were washed with water and brine, dried (Na2SO4),
concentrated, and column chromatographed on silica gel using
a mixture of hexane/ethyl acetate (20:1) as an eluent to give
1.49 g (73% overall yield from compound 40) of 43: 1H NMR
δ 7.45-7.30 (m, 10 H), 6.48 (d, J ) 2.5 Hz, 1 H, Ar), 6.37 (d,
J ) 2.5 Hz, 1 H, Ar), 5.07 (s, 2 H), 5.00 (s, 2 H), 0.95 (s, 9 H),
0.14 (s, 6 H); 13C NMR δ 153.3, 152.1, 139.7, 137.5, 136.7,
128.8, 128.6, 128.4, 128.2, 128.1, 127.5, 126.2, 113.6, 106.2,
(1S,4a S,8a S)-1-[(3,4-Diben zyloxy-2-ch lor o-6-h yd r oxy-
p h en yl)-h yd r oxym et h yl]-3H -2-m et h ylen e-1,4,4a ,5,6,7,8,
8a -octa h yd r o-5,5,8a -tr im eth yln a p h th a len e (45). To a cold
(0 °C) solution of 0.45 g (0.67 mmol) of 44 in 5 mL of THF
under argon was added 0.8 mL (0.8 mmol) of n-Bu4NF (1.0 M
in THF). After stirring at 0 °C for 4 h, the solution was diluted
with diethyl ether, washed with water and brine, dried (Na2-
SO4), concentrated, and column chromatographed on silica gel
using a mixture of hexane/ethyl acetate (5:1) as an eluent to
give 0.35 g (93% yield) of 45 as a mixture of two diastereomers
at C15: [R]22D ) -56.1° (c 3.1, CHCl3); 1H NMR δ 8.15 (s, 1 H,
OH), 7.45-7.3 (m, 10 H), 6.51 (s, 1 H, Ar), 5.60 (d, J ) 9 Hz,
1 H, CHO), 5.12 (d, J ) 12 Hz, 1 H), 5.10 (s, 1 H, dCH), 5.07
(d, J ) 12 Hz, 1 H), 4.93 (d, J ) 10 Hz, 1 H), 4.88 (d, J ) 10
Hz, 1 H), 4.87 (s, 1 H, dCH), 2.74 (d, J ) 9 Hz, 1 H), 2.46 (m,
1 H), 2.08 (m, 1 H), 1.80 (m, 1 H), 1.43-0.7 (m, 8 H), 0.95 (s,
3 H), 0.83 (s, 3 H), 0.76 (s, 3 H); 13C NMR δ 153.1, 151.9, 147.8,
136.9, 136.5, 128.8, 128.6, 128.5, 128.2, 128.0, 127.6, 127.5,
118.6, 110.5, 101.8, 75.0, 73.7, 70.7, 60.2, 51.3, 42.2, 42.0, 40.1,
75.2, 71.3, 26.1, 25.8 (3 C), -4.4 (2 C). Anal. Calcd for C26H31
ClO3Si: C, 68.62; H, 6.87. Found: C, 68.43; H, 7.00.
-
4-Br om o-3-ch lor o-1,2-d iben zyloxy-5-(ter t-bu tyld im eth -
ylsilyoxy)ben zen e (33). To a solution of 1.40 g (3.08 mmol)
of 43 in 20 mL of dichloromethane under argon was added
0.64 mg (3.60 mmol) NBS. The solution was stirred at 25 °C
for 8 h, diluted with ethyl acetate, washed with water and
brine, dried (Na2SO4), concentrated, and column chromato-
graphed on silica gel using a mixture of hexane/ethyl acetate
(20:1) to give 1.59 g (96% yield) of 33: 1H NMR (CDCl3) δ 7.50
(m, 2 H), 7.4-7.30 (m, 8 H), 6.42 (s, 1 H, Ar), 5.08 (s, 2 H),
5.00 (s, 2 H), 1.00 (s, 9 H), 0.14 (s, 6 H); 13C NMR δ 151.9,
149.9, 141.6, 140.6, 137.2, 136.4, 130.4, 128.8, 128.7, 128.5,
128.3, 128.2, 127.3, 105.9, 75.3, 71.5, 26.1, 25.9 (3 C), -4.1 (2
C). Anal. Calcd for C26H30BrClO3Si: C, 58.48; H, 5.66. Found:
C, 58.81; H, 5.74.
33.6, 33.5, 33.4, 25.6, 23.0, 22.3, 19.1. Anal. Calcd for C35H41
ClO4: C, 74.91; H, 7.36. Found: C, 74.85; H, 7.41.
-
(4a S,6a S,12a S,12b S)-2H -9,10-Dib en zyloxy-11-ch lor o-
1,3,4,4a ,5,6,6a ,12,12a ,12b-d eca h yd r o-6a -[(p h en ylselen o)-
m eth yl]-4,4,12b-tr im eth yl-ben zo[a ]xan th en -12-ol (47) an d
(4aS,6aS,12bS)-2H-9,10-Diben zyloxy-11-ch lor o-1,3,4,4a,5,6,
6a ,12b-octa h yd r o-6a -[(p h en ylselen o)m eth yl]-4,4,12b-tr i-
m eth yl-ben zo[a ]xa n th en e (48). To a cold (-78 °C) solution
of 122 mg (0.22 mmol) of diol 45 in 1 mL of dichloromethane
under agon were added 76 mg (0.25 mmol) of N-(phenylseleno)-
phthalimide (46) and 0.1 mL (0.023 mmol) of a solution of
SnCl4 (0.23 M) in dichloromethane. After stirring for 4 h, the
solution was warmed to 0 °C, diluted with aqueous NaHCO3,
and extracted with diethyl ether three times. The combined
extracts were washed with water and brine, dried (Na2SO4),
concentrated, and column chromatographed on silica gel using
a mixture of hexane/ethyl acetate (15:1) to give 62 mg (38%
(1S,4a S,8a S)-1-[(3,4-Diben zyloxy-6-ter t-bu tyld im eth yl-
silyloxy-2-ch lor op h en yl)-h yd r oxym eth yl]-3H-2-m eth yl-
en e-1,4,4a ,5,6,7,8,8a -octa h yd r o-5,5,8a -tr im eth yln a p h th a -
len e (44). To a cold (-78 °C) solution of 0.83 g (1.55 mmol) of
bromide 33 in 5 mL of diethyl ether under argon was added
0.88 mL (1.50 mmol) of t-BuLi (1.7 M in n-pentane). After the
solution was stirred for 30 min, a solution of 0.30 g (1.36 mmol)
of (-)-albicanal (31) in 2 mL of diethyl ether was added via
cannula. The solution was stirred at -78 °C for 2 h, diluted
with aqueous NH4Cl, and extracted with diethyl ether three
times. The combined extracts were washed with water and
brine, dried (Na2SO4), concentrated, and column chromato-
graphed on silica gel using a mixture of hexane/ethyl acetate
(20:1) as an eluent to give a total of 0.82 g (89% yield) of 44 as
a mixture of two isomers at C15 (follows chloropuupehenone’s
numbering system). A partial separation was achieved from
yield) of 47 and 90 mg (56% yield) of 48. Compound 47: [R]22
D
1
) -42.3° (c 1.25, CHCl3); H NMR δ 7.42 - 7.16 (m, 15 H),
6.35 (s, 1 H, Ar), 4.99 (s, 2 H), 4.97 (s, 2 H), 4.82 (d, J ) 3 Hz,
1 H), 3.48 (d, J ) 13 Hz, 1 H, CHSe), 3.29 (d, J ) 13 Hz, 1 H,
CHSe), 2.77 (d, J ) 3 Hz, 1 H), 2.29 (d, J ) 15 Hz, 1 H), 2.0-
1.0 (a series of m, 10 H), 0.91 (s, 3 H), 0.80 (s, 3 H), 0.58 (s, 3
H); 13C NMR δ 138.0, 137.4, 136.5, 132.5, 129.1, 128.8, 128.7,
128.5, 128.3, 128.2, 127.8, 126.6, 124.1, 120.4, 117.6, 115.8,
108.3, 101.9, 75.4, 71.0, 62.3, 55.1, 54.8, 41.9, 39.9, 38.6, 37.7,
37.6, 33.9, 33.5, 29.9, 22.2, 18.6, 18.1, 14.7. Anal. Calcd for
C
41H45ClO4Se: C, 68.76; H, 6.33. Found: C, 69.02; H, 6.07.
Compound 48: 1H NMR δ 7.50-7.15 (m, 15 H), 6.53 (s, 1 H,
dCH), 6.28 (s, 1 H, Ar), 4.98 (d, J ) 11 Hz, 1 H), 4.95 (s, 2 H),
4.92 (d, J ) 11 Hz, 1 H), 3.50 (d, J ) 13 Hz, 1 H, CHSe), 3.26
(d, J ) 13 Hz, 1 H, CHSe), 2.83 (bd, J ) 12 Hz, 1 H), 2.06 (bd,
J ) 12 Hz, 1 H), 1.80-1.10 (a series of m, 9 H), 1.18 (s, 3 H),
0.91 (s, 3 H), 0.84 (s, 3 H); 13C NMR δ 152.3, 149.2, 147.8,
the above chromatography. The less polar isomer: [R]22
)
D
-17.1° (c 1.6, CHCl3); 1H NMR δ 7.46 (m, 2 H), 7.40-7.30 (m,
8 H), 6.27 (s, 1 H, Ar), 5.35 (t, J ) 8 Hz, 1 H, CHO), 5.06 (dd,
J ) 7, 6 Hz, 2 H), 4.96 (s, 2 H), 4.41 (s, 1 H, dCH), 3.83 (s, 1
H, dCH), 2.3-0.9 (m, 12 H), 0.98 (s, 9 H, t-Bu), 0.98 (s, 3 H),
6076 J . Org. Chem., Vol. 69, No. 18, 2004

(+)-Chloropuupehenone and (+)-Chloropuupehenol
139.3, 137.3, 128.9, 128.7, 128.5, 128.4, 128.1, 127.8, 127.6,
114.1, 112.8, 101.5, 101.3, 75.1, 70.8, 52.4, 41.4, 39.3, 38.1, 37.2,
33.6, 33.2, 29.6, 23.8, 22.7, 21.6, 20.6, 18.8. Anal. Calcd for
(1S,4a S,8a S)-1-[(3,4-Diben zyloxy-6-ter t-bu tyld im eth yl-
silyloxy-2-ch lor op h en yl)-h yd r oxym et h yl]-1,4,4a ,5,6,7,8,
8a -octa h yd r o-2,5,5,8a -tetr a m eth yln a p h th a len e (51). To a
cold (-78 °C) solution of 0.900 g (1.69 mmol) of bromide 33 in
8 mL of diethyl ether under argon was added 0.96 mL (1.60
mmol) of t-BuLi (1.7 M in n-pentane). After the solution was
stirred for 1 h, a solution of 0.326 g (1.48 mmol) of aldehyde
32 in 2 mL of diethyl ether was added via cannula. The
solution was stirred at -78 °C for 2 h and 0 °C for 30 min,
diluted with aqueous NH4Cl, and extracted with diethyl ether
three times. The combined extracts were washed with water
and brine, dried (Na2SO4), concentrated, and column chro-
matographed on silica gel using a mixture of hexane/ethyl
acetate (20:1) as an eluent to give 0.770 g (77% yield) of 51 as
a mixture two stereoisomers at C15 (follows chloropuupe-
henone’s numbering system): [R]22D ) -169° (c 0.055, CHCl3);
MS (electrospray) m/z 657.20 (M - H2O + H)+; 1H NMR δ 7.50
(m, 4 H), 7.39-7.30 (m, 6 H), 6.27 (s, 1 H, Ar), 5.57 (m, 1 H,
dCH), 5.18 (dd, J ) 10, 7 Hz, 1 H, CHO), 5.10 (s, 2 H), 5.01
(d, J ) 10 Hz, 1 H), 4.97 (d, J ) 10 Hz, 1 H), 3.52 (d, J ) 10
Hz, 1 H, OH), 2.73 (m, 1 H), 1.92 (m, 1 H), 1.90 (s, 3 H), 1.40-
0.90 (a series of m, 8 H), 0.98 (s, 9 H), 0.89 (s, 3 H), 0.83 (s, 3
H), 0.82 (s, 3 H), 0.16 (s, 3 H), 0.15 (s, 3 H); 13C NMR δ 151.4,
150.9, 149.1, 147.9, 137.2, 136.5, 136.4, 128.6, 128.2, 128.0,
127.9, 127.0, 125.4, 108.0, 105.5, 104.9, 74.9, 71.1, 71.0, 61.9,
60.3, 55.2, 42.5, 41.9, 40.9, 33.7, 33.6, 26.0, 25.9, 22.0, 21.6,
19.4, 15.6, -4.0, -4.1. Anal. Calcd for C41H55ClO4Si: C, 72.91;
H, 8.21. Found: C, 73.16; H, 8.37.
C
41H43ClO3Se: C, 70.53; H, 6.21. Found: C, 70.39; H, 6.05.
(4a S ,6a S ,12a S,12b S )-2H -12-Ace t oxy-9,10-d ib e n zyl-
oxy-11-ch lor o-1,3,4,4a ,5,6,6a ,12,12a ,12b -d eca h yd r o-6a -
[(p h en ylselen o)m eth yl]-4,4,12b-tr im eth yl-ben zo[a ]xa n -
th en e (49). A solution of 50 mg (70 µmol) of 47, 11 mg (0.11
mmol) of acetic anhydride, 2.0 mg (20 µmol) of 4-(dimethyl-
amino)pyridine, and 22 mg (0.28 mmol) of pyridine in 2 mL of
dichloromethane was stirred under argon at 25 °C for 18 h,
diluted with water, and extracted three times with ethyl
acetate. The combined extracts were washed with 10% aqueous
HCl, NaHCO3, water, and brine, dried (Na2SO4), concentrated,
and column chromatographed on silica gel using a mixture of
hexane/ethyl acetate (10:1) as an eluent to give 50 mg (94%
yield) of 49: [R]22 ) -28.2° (c 0.55, CHCl3); 1H NMR δ 7.48-
D
7.20 (m, 15 H), 6.38 (s, 1 H, Ar), 6.03 (s, 1 H, CHO), 5.03 (s, 2
H), 4.96 (s, 2 H), 3.49 (d, J ) 13 Hz, 1 H, CHSe), 3.10 (d, J )
13 Hz, 1 H, CHSe), 2.24 (m, 1 H), 2.06 (s, 3 H), 1.9-0.8 (a
series of m, 11 H), 0.89 (s, 3 H), 0.80 (s, 3 H), 0.64 (s, 3 H); 13
C
NMR δ 169.7, 153.8, 151.3, 139.1, 137.2, 136.2, 132.0, 131.4,
129.4, 129.1, 128.6, 128.5, 128.2, 128.1, 128.0, 127.5, 126.7,
111.5, 101.3, 78.4, 75.0, 70.8, 64.8, 54.3, 52.8, 41.6, 39.9, 38.0,
37.9, 37.1, 33.8, 33.3, 29.7, 22.0, 21.4, 18.4, 14.7. Anal. Calcd
for C43H47ClO5Se: C, 68.11; H, 6.25. Found: C, 67.96; H, 6.65.
(4a S,6a S,12a S,12bS)-2H-12-Acetoxy-9,10-d iben zyloxy-
11-ch lor o-1,3,4,4a ,5,6,6a ,12,12a ,12b-d eca h yd r o-4,4,6a ,12b-
tetr a m eth yl-ben zo[a ]xa n th en e (50). A solution of 30 mg
(40 µmol) of 49, 3.3 mg (20 µmol) of AIBN, and 11 mg (40 µmol)
of n-Bu3SnH in 3 mL of toluene was heated under reflux for
15 h, cooled to 25 °C, diluted with ethyl acetate, and washed
with water and brine. The organic layer was dried (Na2SO4),
concentrated, and column chromatographed on silica gel using
(1S,4a S,8a S)-1-[(3,4-Diben zyloxy-2-ch lor o-6-h yd r oxy-
phenyl)-hydroxymethyl]-1,4,4a,5,6,7,8,8a-octahydro-2,5,5,8a-
tetr a m eth yln a p h th a len e (52). A solution of 0.62 g (0.95
mmol) of 51 and 0.22 g (0.95 mmol) of (+)-10-camphorsulfonic
acid in 2.5 mL of dichloromethane was stirred at 25 °C for 0.5
h, diluted with aqueous NaHCO3, and extracted with ethyl
acetate three times. The combined extracts were washed with
brine, dried (Na2SO4), concentrated, and column chromato-
graphed on silica gel using a gradient mixture of hexane and
a mixture of hexane/ethyl acetate (20:1) as an eluent to give
1
22 mg (91% yield) of 50: [R]22 ) -68.8° (c 0.25, CHCl3); H
D
NMR δ 7.44-7.26 (m, 10 H), 6.44 (s, 1 H, Ar), 6.02 (s, 1 H,
CHO), 5.06 (s, 2 H), 4.98 (s, 2 H), 2.20 (m, 1 H), 2.12 (m, 1 H),
2.04 (s, 3 H), 1.65-1.05 (a series of m, 10 H), 1.31 (s, 3 H),
0.89 (s, 3 H), 0.81 (s, 3 H), 0.64 (s, 3 H); 13C NMR δ 169.0,
153.0, 151.0, 138.4, 137.3, 136.3, 128.5, 128.2, 128.1, 128.0,
127.5, 127.2, 115.7, 101.6, 75.5, 75.1, 70.8, 62.6, 57.1, 54.8, 41.7,
40.6, 39.6, 37.2, 33.7, 33.3, 27.7, 21.9, 18.4, 18.2, 14.4. Anal.
Calcd for C37H43ClO5: C, 72.67; H, 7.19. Found: C, 72.88; H,
7.34.
ethyl acetate as an eluent to give 0.372 g (73% yield) of diol
1
52: [R]22 ) -110° (c 0.04, CHCl3); H NMR δ 10.30 (s, 1 H,
D
OH; exchanged with D2O), 7.50-7.25 (m, 10 H), 6.33 (s, 1 H,
Ar), 5.64 (m, 1 H, dCH), 5.40 (bs, 1 H, CHO), 5.04 (s, 2 H),
4.91 (s, 2 H), 3.02 (bs, 1 H, OH; exchanged with D2O), 2.72
(bs, 1 H), 2.20-1.10 (a series of m, 9 H), 1.65 (s, 3 H), 0.98 (s,
3 H), 0.88 (s, 3 H), 0.85 (s, 3 H); 13C NMR δ 154.5, 151.8, 136.9,
136.6, 136.4, 132.0, 128.9, 128.5, 128.3, 128.1, 128.0, 127.6,
127.3, 126.2, 116.4, 102.2, 75.2, 73.5, 70.5, 58.2, 50.2, 42.0, 40.2,
38.7, 33.7, 33.1, 23.4, 22.6, 21.6, 18.8, 16.2. Anal. Calcd for
Con ver sion of Com p ou n d 50 to Tetr a cyclic P yr a n Diol
30. A mixture of 20 mg (33 µmol) of compound 50 and 20 mg
of 10% Pd/C in methanol under 1 atm of hydrogen was stirred
at 25 °C for 10 h, diluted with ethanol, filtered through Celite,
concentrated, and column chromatographed on silica gel using
a mixture of hexane/ethyl acetate (10:1) as an eluent to give
11.6 mg (97% yield) of diol 30. Spectral data and optical
rotation were identical with those described above.
Con ver sion of Com p ou n d 48 to P yr a n Diol 30. A
solution of 50 mg (72 µmol) of compound 48, 5.9 mg (36 µmol)
of AIBN, and 23 mg (79 µmol) of n-Bu3SnH in 3 mL of toluene
was heated under reflux for 15 h, cooled to 25 °C, concentrated
to dryness, and column chromatographed on silica gel using a
mixture of hexane/ethyl acetate (10:1) as an eluent to give 36
mg (92% yield) of (4aS,6aS,12bS)-2H-9,10-dibenzyloxy-11-
chloro-1,3,4,4a,5,6,6a,12b-octahydro-4,4,6a,12b-tetramethyl-
benzo[a]xanthene (54): 1H NMR δ 7.50-7.30 (m, 10 H), 6.44
(s, 2 H, Ar, dCH), 5.07 (d, J ) 12 Hz, 1 H), 5.02 (d, J ) 12 Hz,
1 H), 4.95 (s, 2 H), 2.10-0.90 (a series of m, 11 H), 1.00 (s, 3
H), 0.91 (s, 3 H), 0.85 (s, 3 H); HRMS calcd for C35H40ClO3 (M
+ H) 543.2668, found 543.2701. A mixture of 25 mg (46 mmol)
of 54 and 20 mg of 10% Pd/C in 1.5 mL of methanol was stirred
under 1 atm of hydrogen at 25 °C for 10 h, diluted with
ethanol, filtered through Celite, concentrated, and column
chromatographed on silica gel using a mixture of hexane/ethyl
acetate (10:1) as an eluent to give 15 mg (89.5% yield) of diol
30.
C
35H41ClO4: C, 74.91; H, 7.36. Found: C, 74.85; H, 7.41.
Tr a n for m a tion of Com p ou n d 52 to 27. To a cold (-78
°C) solution of 60 mg (0.11 mmol) diol 52 in 1 mL of
dichloromethane under agon were added 41 mg (0.14 mmol)
of N-(phenylseleno)phthalimide (46) and 55 µL (0.011 mmol)
of a solution of SnCl4 (0.20 M) in dichloromethane. After
stirring for 4 h, the solution was warmed to 0 °C, diluted with
aqueous NaHCO3, and extracted with diethyl ether three
times. The combined extracts were washed with water and
brine, dried (Na2SO4), concentrated, and column chromato-
graphed on silica gel using a mixture of hexane/ethyl acetate
(15:1) to give 30 mg (51% yield) of (4aS,6aR,12bS)-2H-
9,10-dibenzyloxy-11-chloro-1,3,4,4a,5,6,6a,12b-octahydro-
4,4,6a,12b-tetramethyl-benzo[a]xanthene (53): [R]22D ) +40.6°
(c 0.19, CHCl3); 1H NMR δ 7.47-7.31 (m, 10 H), 6.53 (s, 1 H),
6.47 (s, 1 H), 5.10 (d, J ) 12 Hz, 1 H, CH2O), 5.06 (d, J ) 12
Hz, 1 H, CH2O), 4.97 (s, 2 H), 2.02 (m, 2 H), 1.80-1.24 (a
serious of m, 9 H), 1.41 (s, 3 H), 1.17 (s, 3 H), 0.94 (s, 3 H),
0.88 (s, 3 H); 13C NMR δ 149.3, 147.6, 137.5, 136.0, 128.8,
128.7, 128.4, 128.3, 128.2, 127.6, 112.6, 109.9, 109.4, 101.8,
95.6, 80.7, 75.3, 73.3, 71.3, 45.5, 43.1, 41.7, 39.1, 37.8, 33.3,
33.2, 25.4, 25.2, 23.6, 21.9, 19.0. Anal. Calcd for C35H39ClO3:
C, 77.40; H, 7.24. Found: C, 77.28; H, 6.95.
A mixture of 20 mg (37 µmol) of 53 and 20 mg of 10% Pd/C
in 2 mL of methanol was stirred at 25 °C under 1 atm of
J . Org. Chem, Vol. 69, No. 18, 2004 6077

Hua et al.
TABLE 2. Com p osition of Lip id Em u lsion in 24 m L of
hydrogen for 10 h, diluted with ethanol, filtered through Celite,
concentrated, and column chromatographed on silica gel using
a mixture of hexane/ethyl acetate (10:1) as an eluent to give
11 mg (83% yield) of 27.
Biologica l Stu d ies. The reported procedures for the in-
hibitory activities of CETP23a and L1210 leukemic cells23b were
followed.
P BS Bu ffer (p H, 6.7)
ingredients
amount (µmol/rat/8 h)
cholesterol labeled with 14C (14C-CH)a
triolein (oleic acid)
R-tocopherol
sodium taurocholate
compound 3
20.7
451.8
3.6
396.0
114.9
Stu d ies of Ch olester ol Absor p tion . An im a ls a n d Diet.
Ten male Sprague-Dawley rats (Harlan Sprague Dawley, Inc.,
Indianapolis, IN) weighing 274.3 ( 7.8 were housed individu-
ally in plastic cages in an environmentally controlled room of
illumination (12:12-h light/dark cycle with the dark period
from 0330 to 1530), humidity (60-70%), and temperature (22-
25 °C) throughout the study. Rats had free access to deionized
water and a nutritionally adequate diet containing soybean
oil as the fat source and egg white as the protein source. The
diet was formulated according to the AIN-93G recommenda-
tions.24,25 Animals were cared for in an animal care facility
accredited by the American Association for the Accreditation
of Laboratory Animal Care. Rats were maintained in ac-
cordance with the policies and guidelines for animal care and
use procedures of the Kansas State University Institutional
Animal Care and Use Committee.
Mesen ter ic Lym p h Du ct Ca n n u la tion . At 6 weeks, rats
were starved overnight for 17 h but allowed water ad libitum
prior to the surgical placement of a lymph cannula and
duodenal infusion catheter. The mesenteric lymph duct was
cannulated as described previously.26 Briefly, while rats were
under anesthesia (2.0% halothane in 2.0 L O2/min delivered
via a halothane vaporizer), a midline abdominal incision was
made. The superior mesenteric lymph duct was cannulated
with polyethylene tubing (SV.31 tubing, i.d. 0.50 mm, o.d. 0.80
mm; Dural Plastics, Auburn, Australia). The cannula was fixed
in place with ethyl cyanoacrylate glue (Elmer’s Products,
Columbus, OH) and externalized through the right flank. An
indwelling infusion catheter (Silastic laboratory tubing, i.d.
1.0 mm, o.d. 2.2 mm; Dow Corning, Midland, MI) was
introduced via the gastric fundus into the upper duodenum
and secured in place with a purse-string suture (4-0 silk,
Ethicon, Somerville, NJ ) around the fundic incision. The
infusion catheter was exteriorized alongside the lymph can-
nula. After the abdominal incision was closed, the rats were
placed in restraining cages and housed in a recovery chamber
at 30 °C for postoperative recovery for 22-24 h. During the
recovery period, rats were infused continuously with glucose
in phosphate-buffered saline (PBS) (in mmol/L: 277 glucose,
6.75 Na2HPO4, 16.5 NaH2PO4, 115 NaCl, and 5 KCl; pH 6.7)
via the infusion catheter at 3.0 mL/h by a syringe pump
(Harvard Apparatus, model 935, South Natick, MA) to ensure
adequate hydration and nutritional status of the animals.
Deter m in a tion of Lym p h a tic 14C-Ch olester ol Absor p -
tion . After postoperative recovery, each rat was infused with
a lipid emulsion containing compound 3 at 3 mL/h for 8 h via
the duodenal catheter in subdued light. The lipid emulsion
a
Results of the inhibition of cholesterol absorption are sum-
marized in Figure 2.
consisted of 451.8 µmol of triolein (95%, Sigma Chemical, St.
Louis, MO), 33.3 kBq [4-14C]-cholesterol (14C-CH; specific
activity, 1.85 GBq/mmol, American Radiolabeled Chemicals,
St. Louis, MO), 20.7 µmol of cholesterol, 3.1 µmol of R-toco-
pherol (all-rac-dl-R-tocopherol, 97%, Aldrich Chemical, Mil-
waukee, WI) as an antioxidant, and 396.0 µmol of sodium
taurocholate (Sigma Chemical, St. Louis, MO) in 24 mL of PBS
buffer with or without 114.9 µmol of compound 3 (41.9 mg)
(Table 2). Lipid emulsion was prepared under a gentle N2
stream and subdued light for 55 min using a microprocessor-
controlled untrasonicator equipped with a microtip (XL-2020
Ultrasonic Liquid Processor, Misonix, Farmingdale, NY).
During the duodenal infusion of lipid infusion, the lymph
samples were collected hourly in preweighed ice-chilled cen-
trifuge tubes containing 4 mg of Na2-EDTA and 30 µg of
n-propyl gallate (Sigma Chemical, St. Louis, MO) as antioxi-
dants. The hourly lymph samples (100 µL) were mixed with
scintillation liquid (ScintiVerse; Fisher Scientific, Fair Lawn,
NJ ) and counted by scintillation spectrometry (Beckman LS-
6500; Beckman Instruments, Fullerton, CA). The total 14C-
radioactivity appearing in hourly lymph volume (the hourly
rates of 14C-CH absorption) was expressed as a percentage of
the total radioactivity infused (% dose). All samples were ice
chilled and handled in subdued light.
F a tty Acid An a lysis. For oleic acid analysis, total lipids
from lymph were extracted with a chloroform/methanol mix-
ture. Then the lipid extracts were hydrolyzed with methanolic
NaOH, and fatty acids were saponified and methylated
simultaneously with BF3-methanol.
The fatty acid methyl esters (FAME) were analyzed by
capillary gas chromatography (Hewlett-Packard, Model 6890,
Palo Alto, CA) using a HP-INNOWax cross-linked poly-
(ethylene glycol) phase capillary column (15 m, i.d. 0.53 mm;
Resteck Corp., Bellefonte, PA).
Sta tistica l An a lysis. All statistical analyses were per-
formed using PC SAS (SAS Institute, Cary, NC). Repeated
measures ANOVA and the least significance difference were
used to compare group means. The level of significance was
determined at P < 0.05.
Ack n ow led gm en t. D.H.H. gratefully acknowledges
financial support from the American Heart Association,
Heartland Affiliate (0350652Z), the National Science
Foundation (CHE-0078921), National Institutes of Health
(National Cancer Institute, CA86842 and Kansas Bio-
medical Research Infrastructure Network, RR16475),
NASA-BioServe Space Technologies (NAGW-1197), and
J ohnson Cancer Center.
(23) (a) Tomoda, H.; Tabata, N.; Masuma, R.; Si, S.-Y.; Omura, S.
J . Antibiot. 1998, 51, 618-623. (b) Perchellet, E. M.; Ladesich, J . B.;
Magill, M. J .; Chen, Y.; Hua, D. H.; Perchellet, J . P. Anti-Cancer Drugs
1999, 10, 489-504.
(24) Reeves, P. G.; Nielsen, F. H.; Fahey, G. C., J r. J . Nutr. 1993,
123, 1939-1951.
(25) Reeves, P. G. In Trace Elements in Laboratory Rodents; Watson,
R. R., Ed.; CRC Press: Boca Raton, FL, 1996; pp 3-37.
(26) Koo, S. I.; Noh, S. K. J . Nutr. 2001, 131, 717-722.
J O0491399
6078 J . Org. Chem., Vol. 69, No. 18, 2004