Structure-Activity Relationship Studies of Illudins: Analogues Possessing a Spiro-cyclobutane Ring

Article abstract of DOI:10.1021/jo0346499

Bicyclic and tricyclic analogues of anticancer sesquiterpene illudin S have been synthesized. These contain a spiro-cyclobutane instead of spiro-cyclopropane structure. The cytotoxicity of the former is less than that of the corresponding cyclopropane-containing compounds.

Full text of DOI:10.1021/jo0346499

Str u ctu r e-Activity Rela tion sh ip Stu d ies of Illu d in s: An a logu es
P ossessin g a Sp ir o-cyclobu ta n e Rin g
Trevor C. McMorris,*,† Qiang Cong,† and Michael J . Kelner‡
Department of Chemistry and Biochemistry, University of California, San Diego, La J olla, California
92093-0506, and Department of Pathology, UCSD Medical School, San Diego, California 92103-8320
tmcmorris@ucsd.edu
Received May 15, 2003
Bicyclic and tricyclic analogues of anticancer sesquiterpene illudin S have been synthesized. These
contain a spiro-cyclobutane instead of spiro-cyclopropane structure. The cytotoxicity of the former
is less than that of the corresponding cyclopropane-containing compounds.
SCHEME 1. Mech a n ism of Toxicity a n d
An titu m or Activity of Illu d in s
In tr od u ction
Illudins S (1a ) and M (1b) are highly cytotoxic ses-
quiterpenes produced by the basidiomycete Omphalotus
illudens (Omphalotus olearius, formerly Clitocybeillu-
dens).1-4 The toxicity and antitumor activity of these
compounds can be explained by their behavior as alkyl-
ating agents. As shown in Scheme 1, Michael-type
addition to the R,â-unsaturated ketone gives a highly
reactive cyclohexadiene intermediate that undergoes
cyclopropane ring opening with attack by nucleophiles
(protein, DNA, H2O). The driving force in this reaction
is relief of ring strain when the cyclopropane opens. The
stable aromatic structure that results is also a factor.5,6
Earlier SAR studies of illudins revealed that oxidation
of illudin M to dehydroilludin M (2) resulted in lower
toxicity but enhanced efficacy.9,10 Also, treatment of
illudin S with dilute H2SO4 gave acylfulvene (3), which
was even less toxic than 2 and had superior efficacy.11-13
Compounds 2 and 3 react with nucleophiles in the same
way as Illudin S or M (cf. Scheme 1).
The increase in efficacy parallels reduction in reactivity
of the compounds to thiols at neutral pH. Thus by
modulating the reactivity it might be possible to prepare
further useful analogues. Among the changes to the
structure, we considered replacing the spiro-cyclopropane
by a spiro-cyclobutane group, giving structures such as
4a and 4b. The cyclobutane would be expected to exhibit
much less angle strain than the cyclopropane and would
be less easily opened.14 If a similar mechanism as in
The nucleophile in the Michael reaction can be a thiol
such as cysteine or glutathione or the thiol group of a
protein. It has also been found that reduction by cytosolic
NADH- and NADPH-dependent enzymes can lead to
similar aromatic products.7,8
(8) McMorris, T. C.; Elayadi, A. N.; Yu, J .; Hu, Y.; Kelner, M. J .
Drug Metab. Dispos. 1999, 27, 983-985.
* Corresponding author.
† Department of Chemistry and Biochemistry.
(9) McMorris, T. C.; Kelner, M. J .; Wang, W.; Estes, L. A.; Montoya,
M. A.; Taetle, R. J . Org. Chem. 1992, 57, 6876-6883.
(10) Kelner, M. J .; McMorris, T. C.; Taetle, R. Anticancer Res. 1995,
15, 873-878.
‡ Department of Pathology.
(1) McMorris, T. C.; Anchel, M. J . Am. Chem. Soc. 1965, 87, 1594-
600.
(2) McMorris, T. C.; Anchel, M. J . Am. Chem. Soc. 1963, 85, 831-
832.
(11) Kelner, M. J .; McMorris, T. C.; Estes, L.; Starr, R. J .; Ruther-
ford, M.; Montoya, M.; Samson, K. M.; Taetle, R. Cancer Res. 1995,
55, 4936-4940.
(3) Anchel, M.; Hervey, A.; Robbins, W. J . Proc. Natl. Acad. Sci.
U.S.A. 1950, 36, 300-305.
(12) McMorris, T. C.; Kelner, M. J .; Wang, W.; Diaz, M. A.; Estes,
L. A.; Taetle, R. Experientia 1996, 52, 75-80.
(4) Anchel, M.; Hervey, A.; Robbins, W. J . Proc. Natl. Acad. Sci.
U.S.A. 1952, 38, 927-928.
(13) Weinreb, S. M.; McMorris, T. C.; Anchel, M. Tetrahedron Lett.
1971, 3489-3491.
(5) McMorris, T. C.; Kelner, M. J .; Wang, W.; Moon, S.; Taetle, R.
Chem. Res. Toxicol. 1990, 3, 574-579.
(14) Cyclopropanes and cyclobutanes are known to have similar
enthalpies of reations in the gas phase. Howerer, cyclobutane is
essentially inert toward eletrophiles, whereas cyclopropane has moder-
ate activity; see: Wiberg, K. B.; Kass, S. R. J . Am. Chem. Soc. 1985,
107, 988-995.
(6) McMorris, T. C.; Kelner, M. J .; Chadha, R. K.; Siegel, J . S.; Moon,
S. S.; Moya, M. M. Tetrahedron 1989, 45, 5433-5440.
(7) Tanaka, K.; Inoue, T.; Kadota, S.; Kikuchi, T. Xenobiotica 1992,
22, 33-39.
10.1021/jo0346499 CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/13/2003
9648
J . Org. Chem. 2003, 68, 9648-9653

Structure-Activity Studies of Illudins
SCHEME 2. Syn th esis of 5a
SCHEME 3. Syn th esis of 14a
a
Reagents and conditions: (a) KOH, EtOH, 0 °C, 94%; (b) (i)
SOCl2, 50 °C, (ii) MeLi, CuI, -25 °C, THF, 70% for two steps; (c)
KOH, EtOH, 0 °C, 92%; (d) (i) ClCO2CH3, K2CO3, CH2Cl2, 0 °C,
(ii) CH2N2, -10 °C, 64% for two steps; (e) Rh2(OAc)4, MS (4 Å),
chlorobenzene, rt, 65%; (f) MeLi, ether, -78 to -0 °C, 62%; (g)
IBX, DMSO, THF 43%.
a
Reagents and conditions: (a) Rh2(OAc)4, chlorobenzene, rt,
37%; (b) TMSCl, CH2Cl2, ethylene glycol, rt, 77%; (c) KOH,
CH3OH, 53 °C, 75%; (d) TESCl, pyridine, 60 °C, 92%; (e) (i) TMSCl,
LDA, Et3N, THF, -78 °C, (ii) Pd(OAc)2, CH3CN, THF, rt, 65% for
two steps; (f) (i) DIBALH, THF, -78 °C, (ii) HCl, CHCl3, rt; (g) (i)
TBAF, HOAc, THF, 0 °C, (ii) PDC, CH2Cl2, 0 °C, 51% for two steps.
Scheme 1 is assumed for alkylation by 4a , reaction should
be less favorable and might lead to enhanced efficacy.
The compound was employed in a 1,3-dipolar cycload-
dition reaction with propargyl chloride following es-
sentially the procedure of Padwa.20 The oxabicyclo[2,2,1]-
heptane (12) was obtained in 65% yield from diazoketone
(11) in the reaction catalyzed by Rh2(OAc)4 and carried
out in chlorobenzene at room temperature. There was no
indication of any regioisomer formation.
Treatment of 12 with 3 equiv of MeLi gave the diol
(13) resulting from attack at the ketone and also allylic
proton abstraction and oxo-bridge opening. The exocyclic
double bond is assigned the E configuration on the basis
of NMR data (NOESY). Finally, oxidation of diol (13) with
2-iodoxybenzoic acid (IBX) gave the target compound (5)
in 43% yield. The cyclopropane analogue (6) was also
prepared according to Kinder et al.’s procedure,16 for
comparison of cytotoxicity.
Two acylfulvene analogues containing a cyclobutane
ring were also synthesized. From our experience with
acylfulvenes the most readily accessible target appeared
to be spirocyclobutane (14) as shown in Scheme 3. In
addition, the cyclopropane analogue 15 had previously
been prepared and found to have biological activity
similar to that of acylfulvene.15 The synthesis of 14
involved the same diazoketone (11) that on cycloaddition
reaction with 2-cyclopentenone afforded the tetracyclic
adduct 16 though only in modest yield. An X-ray crystal-
lographic analysis of 16 (see Figure 1) indicated the
relative stereochemistry of the oxo-bridge and cyclopen-
tanone ring fusion. Only the exo-isomer was isolated,
although the endo-product may have been formed as well.
Selective ketalization of 16 was achieved with ethylene
glycol and TMSCl in dichloromethane at room temper-
ature. The oxo-bridge in 17 was then readily cleaved with
Resu lts a n d Discu ssion
The approach to synthesis of 4a follows that used for
synthesis of acylfulvenes.15 However we focused first on
a simpler target molecule (i.e., 5), because synthesis of
the spiro-cyclopropane analogue (6) has been reported by
Kinder et al.16 and is straightforward. Moreover 6 was
found to have IC50 values comparable to those of adria-
mycin in human tumor cell lines.
Synthesis of 5 is outlined in Scheme 2. Commercially
available cyclobutane-1,1-dicarboxylic acid diethyl ester
(7) on partial hydrolysis afforded the monoester carboxyl-
ic acid (8).17 The latter was converted to the acid chloride,
which on reaction with methyllithium and cuprous iodide
afforded the ketoester (9) in high yield.18 Hydrolysis of
the ester and then reaction of the corresponding acid (10)
with methyl chloroformate and K2CO3 in dichloromethane,
followed by treatment with an ether solution of diazo-
methane, gave diazoketone (11) in 64% yield.19
(15) McMorris, T. C.; Yu, J .; Hu, Y.; Estes, L. A.; Kelner, M. J . J .
Org. Chem. 1997, 62, 3015-3018.
(16) Kinder, F. R., J r.; Wang, R.-M.; Bauta, W. E.; Bair, K. W.
Bioorg. Med. Chem. Lett. 1996, 6, 1029-1034.
(17) Miyadera, A.; Satoh, K.; Imura, A. Chem. Pharm. Bull. 2000,
48, 563-565.
(18) Takemura, M.; Kimura, Y.; Takahashi, H.; Kimura, K.; Miyau-
chi, S.; Ohki, H.; Sugita, K.; Miyauchi, R. U.S. Patent 6,121,285, 2000.
(19) Miller, R. D.; Theis, W. Tetrahedron Lett. 1986, 27, 2447-2450.
(20) Padwa, A.; Sandanayaka, V. P.; Curtis, E. A. J . Am. Chem. Soc.
1994, 116, 2667-2668.
J . Org. Chem, Vol. 68, No. 25, 2003 9649

McMorris et al.
alcohol (23) (90%) after removal of the acetal protecting
group. Treatment of 23 with KOH in methanol opened
the oxo bridge, yielding unsaturated alcohol (24).
To form the fulvene ring, the secondary alcohol in 24
was protected as the triethylsilyl derivative and the
compound 25 was treated with trimethylsilyl chloride
and LDA (THF, -78 °C) followed by Pd(0Ac)2 in CH3-
CN, THF at room temperature, giving the cross-conju-
gated ketone (26).21 Reduction of the latter with DIBALH
(THF, -78 °C) and 1,4-elimination of the resulting
alcohol yielded fulvene (27). The triethylsilyl protecting
group was then removed (TBAF, HOAC and THF, room
temperature) and oxidation of the resulting secondary
alcohol (PDC, CH2Cl2) gave target acylfulvene (28) in
overall yield of 7% from 16.
F IGURE 1. ORTEP view of X-ray molecular structure of 16.
Bicyclic analogues 5 and 6 were first tested and were
found to possess similar cytotoxicity (see Table 1) against
several cell lines: MV 522 (lung adenocarcinoma), HL60
(human myeloid leukemia), 8392 (B cell lymphoma/
leukemia), CHRF 2881 (normal megakaryocyte cell line).
The cells were subjected to short exposure (2 h) and long
exposure (48 h) to the compounds. (It is known that
certain cells, e.g., MV522 and HL60, are sensitive to short
exposure because of energy-dependent cellular accumula-
tion.)22,23
SCHEME 4. Syn th esis of 28a
Acylfulvene analogue 14 was found to be far less
cytotoxic than the cyclopropane analogue 15 (Table 1),
which had been prepared previously.15 Because of the
poor solubility of 14 we were unable to obtain an accurate
measure of its efficacy. This led us to synthesize target
28, which we hoped would be more soluble. Acylfulvene
28 had cytotoxicity similar to that found for acylfulvene
14, except that 28 was more cytotoxic to MV522 cells in
the 48 h assay. If a similar mechanism applies to both
cyclopropyl and cyclobutyl compounds 14, 15, and 28, it
is possible that more facile ring opening in highly
strained 15 will contribute to its greater cytotoxicity.
Overall the results indicate that replacement of the
cyclopropane by a cyclobutane moiety reduced the high
cytotoxicity of acylfulvenes. Xenograft trials are now
being carried out to test the efficacy of these compounds.
a
Reagents and conditions: (a) TMSCl, CH2Cl2, ethylene glycol,
-6 °C, 71%; (b) (i) MeLi, THF, -78 °C, (ii) TSA, acetone, reflux,
92% for two steps; (c) KOH, CH3OH, 60 °C, 32%, (d) TESCl,
pyridine, 80 °C, 90%; (e) (i) TMSCl, LDA, Et3N, THF, -78 °C, (ii)
Pd(OAc)2, CH3CN, THF, rt, 65% for two steps; (f) (i) DIBALH,
THF, -78 °C, (ii) HCl, CHCl3, 70% for two steps; (g) (i) TBAF,
HOAc, THF, 0 °C, (ii) IBX, CH2Cl2, DMSO, rt, 77% for two steps.
Exp er im en ta l Section
Acid (8). An aqueous solution of KOH (360 mL, 0.648 mol,
1.8 M) was added to diester 7 (126.0 g, 0.630 mol), which was
dissolved in 550 mL of EtOH at 0 °C. After 40 h, most of the
EtOH was removed by evaporation, H2O was added to dissolve
all solids, then the solution was washed with 150 mL of ether,
and the pH was carefully adjusted to 2 at 0 °C. The aqueous
solution was extracted with EtOAc three times. The organic
extracts were combined, washed with brine, dried, and evapo-
rated to give 8 (101.8 g, 94%) as a colorless liquid. IR (neat):
KOH-methanol at 53 °C. Protection of the alcohol (18)
as the triethylsilyl derivative (19) followed by formation
of the trimethylsilyl ether and then treatment with
palladium acetate in CH3CN at room temperature21 gave
the unsaturated ketone (20) in good overall yield from
18.
1,2-Reduction of key intermediate 20 with DIBALH in
THF (-78 °C) gave an unstable alcohol, which on
elimination of H2O afforded the fulvene (21). Removal of
the protecting TES group and oxidation of the resulting
alcohol with pyridinium dichromate (PDC) in dichlor-
omethane yielded target acylfulvene (14). The overall
yield of 14 from 11 was 5%.
3189, 1729,1709 cm-1 1H NMR (CDCl3, 400 MHz): δ 10.91
.
(1H, br s), 4.23 (2H, q, J ) 6.8 Hz), 2.58 (4H, t, J ) 8.0 Hz),
2.24-1.78 (2H, m), 1.27 (3H, t, J ) 6.8 Hz). 13C NMR (CDCl3,
100 MHz): δ 177.7, 171.5, 61.9, 52.7, 29.0, 16.4, 14.3. HRMS
(MALDI) (m/z) [M + Na]+ calcd for C8H12O4Na, 195.0628,
found 195.0629.
Ketoester (9). SOCl2 (50 mL, 0.685 mol) was added to 8
(50.5 g, 0.293 mol) at room temperature. The solution was
heated gradually, bubbling started at 50 °C, and the solution
The tricyclic acylfulvene analogue (28) was synthesized
as follows (Scheme 4). Selective ketalization of intermedi-
ate 16 at -6 °C (TMSCl, CH2Cl2) yielded the unstable
monoacetal (22). The latter was immediately treated with
methyllithium in THF at -78 °C to give the tertiary
(22) Kelner, M. J .; McMorris, T. C.; Taetle, R. J . Natl. Cancer Inst.
1990, 82, 1562-1565.
(23) Kelner, M. J .; McMorris, T. C.; Beck, W. T.; Zamora, J . M.;
Taetle, R. Cancer Res. 1987, 47, 3186-3189.
(21) Ito, Y.; Hirao, T.; Saegusa, T. J . Org. Chem. 1978, 43, 1011.
9650 J . Org. Chem., Vol. 68, No. 25, 2003

Structure-Activity Studies of Illudins
TABLE 1. An a logu e Cytotoxicity (IC50, µM) in Select Cell Lin esa
MV522 lung
HL60 myeloid
8392 B cell
CHRF-2881 megakaryocyte
2 h
48 h
2 h
48 h
2 h
48 h
2 h
48 h
5
6
14
15
28
58.8 ( 6.6
50.6 ( 6.0
>400
10.0 ( 1.1
>140
15.8 ( 2.6
28.0 ( 0.4
>123
4.6 ( 0.2
49 ( 13
12.8 ( 1.8
13.7 ( 0.9
126 ( 4
nt
2.9 ( 0.4
5.3 ( 0.2
24 ( 1
12.0 ( 2.3
43.9 ( 5.1
350 ( 20
29.9 ( 3.3
>140
2.7 ( 0.4
8.5 ( 2.0
13.1 ( 1.6
nt
15.9 ( 1.6
11.7 ( 2.4
4.2 ( 1.2
5.0 ( 0.8
nt
nt
nt
nt
nt
nt
nt
>140
24.0 ( 4.0
15.0 ( 4.0
a
IC50 is the concentration of the compound at which 50% inhibition of colony formation occurs (in the 48-h assay) or 50% inhibition of
tritiated thymidine into genomic DNA occurs (in the 2-h assay). Values are reported as the mean ( standard deviation for 3-5
experiments.22,23
was kept at this temperature for 3 h until the bubbling ceased
and there was no further decrease in volume. A simple
distillation (50-125 °C, 10 mmHg) gave 95 mL of the corre-
sponding acid chloride as a yellow liquid. An ether solution of
MeLi (137 mL, 191.8 mmol, 1.4M) was added to CuI (37.4 g,
196 mmol) in 400 mL THF at -25 °C. After 1 h, half of the
acid chloride in 50 mL THF was added to the yellow solution
of MeCu. After 1.5 h the mixture was warmed to room
temperature. After a further 0.5 h, 300 mL aqueous citric acid
(10%) was added to quench the reaction. Following evaporation
of most of the THF, the liquid was filtered and the filtrate
was extracted three times with EtOAc. The combined organic
phase was washed successively with Na2S2O3 (15%) solution
and brine, then dried and evaporated. The procedure was
repeated for the remainder of acid chloride. Fractional distil-
lation (71-73 °C, 0.9 mmHg) of the residue gave 9 (34.68 g,
70%) as a colorless liquid. IR (neat): 1735, 1711 cm-1. 1H NMR
(CDCl3, 300 MHz): δ 4.21 (2H, q, J ) 7.2 Hz), 2.47 (4H, t, J )
7.9 Hz), 2.13 (3H, s), 2.05-1.74 (2H, m), 1.27 (3H, t, J ) 7.2
Hz). 13C NMR (CDCl3, 100 MHz): δ 203.1, 172.2, 61.6, 59.4,
27.8, 25.4, 15.7, 14.3. HRMS (CI) (m/z): [M + H]+ calcd for
C9H15O3 171.1014, found 171.1021.
sieves (1 g, 4 Å), and chlorobenzene (1 mL), was added 1 mL
of chlorobenzene solution of 11 (100 mg, 0.60 mmol) slowly at
room temperature. After half of the solution was added,
another 2 mg of Rh2(OAc)4 was added. The total addition took
2 h. After evaporation of the excess propargyl chloride, the
residue was eluted through a column of silica gel (CH2Cl2/
hexane 2:3) to give 12 (83 mg, 65%) as a colorless liquid. IR
1
(neat): 1750 cm-1. H NMR (CDCl3, 400 MHz): δ 6.43-6.30
(1H, m), 4.61 (1H, s), 4.18 (2H, s), 2.28-2.10 (3H, m), 2.08-
1.95 (1H, m), 1.95-1.83 (1H, m), 1.70 (3H, s) 1.60-1.46 (1H,
m). 13C NMR (CDCl3, 100 MHz): δ 210.7, 143.2, 139.9, 90.4,
83.9, 48.5, 38.7, 27.9, 26.3, 16.3, 15.3. HRMS (CI) (m/z): [M +
NH4]+ calcd for C11H17NO2Cl 230.0948, found 230.0947.
Diol (13). To an ether solution (2 mL) of 12 (60 mg, 0.28
mmol) was added a solution of MeLi (606 µL, 0.85 mmol, 1.4
M) in ether at -78 °C, and the temperature was raised to 0
°C after 40 min and kept there for 10 min before saturated
NH4Cl solution was added to quench the reaction. The reaction
mixture was extracted with ether three times, and the
combined organic phase was washed with brine, dried, and
evaporated. The residue was chromatographed (CH2Cl2/EtOAc
4:1) to give 13 (40 mg, 62%) as a liquid with a slight yellow
color. IR (neat): 3442 cm-1. 1H NMR (CDCl3, 400 MHz): δ 6.14
(1H, br s), 6.12-6.02 (1H, m), 4.14 (1H, d, J ) 2.0 Hz), 2.73-
2.54 (1H, m), 2.38-2.24 (1H, m), 2.23-2.14 (1H, m), 2.11 (3H,
s), 2.00-1.69 (3H, m), 0.92 (3H, s). 13C NMR (CDCl3, 100
MHz): δ 145.9, 136.6, 116.5, 111.4, 76.1, 72.4, 51.2, 27.9, 23.6,
Ketoa cid (10). An aqueous solution of KOH (20.5 mL, 36.9
mmol, 1.8M) was added to 9 (5.7 g, 33.5 mmol) in 30 mL of
EtOH at 0 °C. After 1 day, the ethanol was removed with a
rotary evaporator, and the aqueous solution was washed with
ether. The pH of the aqueous solution was carefully adjusted
to 2 with HCl (6 M) at 0 °C, and then the aqueous solution
was extracted with EtOAc three times. The combined organic
phase was washed with brine, dried, and evaporated to give
10 (4.4 g, 92%) as a colorless liquid. IR (neat): 3156, 1744,
20.8, 15.8, 15.7. HRMS (CI) (m/z): [M + NH4]+ calcd for C12H21
NO2Cl 246.1261, found 246.1265.
-
Keto Alcoh ol (5). IBX (2-iodoxybenzoic acid) (49 mg, 0.175
mmol) was added to 1 mL of DMSO. After 20 min the solution
became clear, and then 13 (20 mg, 0.087 mmol) in 1 mL of
THF was added to the IBX solution at room temperature. After
4 h, water was added to dilute the solution, and ether was
used to extract the solution three times. The combined organic
phase was washed with brine, dried, and evaporated. The
concentrate was chromatographed (hexane/EtOAc 25:1) to give
5 (8.5 mg, 43%) as a colorless liquid. IR (neat): 3496, 1698,
1559 cm-1. UV (methanol) λ nm (ꢀ): 233 (11580), 290 (7804).
1H NMR (CDCl3, 400 MHz): δ 6.99-6.82 (1H, m), 6.42-6.26
(1H, m), 4.02 (1H, s), 2.51-2.25 (3H, m), 2.23-2.21 (3H, m),
2.02-1,80 (2H, m), 1.78-1.64 (1H, m), 1.20 (3H, s). 13C NMR
(CDCl3, 100 MHz): δ 201.3, 149.7, 132.0, 124.3, 116.0, 79.1,
52.3, 29.2, 23.8, 21.8, 21.7, 16.2. HRMS (CI) (m/z): [M + NH4]+
calcd for C12H19NO2Cl 244.110, found 244.1097.
1
1710 cm-1. H NMR (CDCl3, 400 MHz): δ 10.40-8.77 (1H, br
s)), 2.54 (4H, t, J ) 8 Hz), 2.23 (3H, s), 2.14-1.97 (1H, m),
1.95-1.78 (1H, m). 13C NMR (CDCl3, 100 MHz): δ 203.0, 178.1,
59.1, 28.1, 25.7, 15.8. HRMS (MALDI) (m/z): [M + Na]+ calcd
for C7H10O3Na 165.0522, found 165.0523.
Dia zok eton e (11). ClCO2CH3 (5.9 mL, 76.36 mmol) was
added slowly to a suspension of K2CO3 (20.1 g, 145.43 mmol)
in 40 mL of CH2Cl2 at 0 °C. To the resulting suspension was
added 10 (4.4 g, 30.9 mmol) in 30 mL of CH2Cl2 at -3 °C. After
5 h, the liquid was filtered through a pad of Celite, more CH2-
Cl2 was used to wash the Celite pad, and the filtrate was
evaporated to remove the solvent and the excess ClCO2CH3.
The residue was redissolved in 40 mL of CH2Cl2, to it was
added 200 mL of an ether solution of diazomethane (61.2
mmol, 1 M) at -10 °C, and the mixture was kept for 12 h
without stirring. (Caution! Diazomethane should be handled
in an efficient fume hood behind a protection shield because
of its toxicity and the possibility of explosions.) The liquid was
then filtered, and the filtrate was evaporated to remove excess
diazomethane and solvent. The residue was chromatographed
(hexane/EtOAc 4:1) to give 11 (3.28 g, 64%) as a yellow liquid.
Dik eton e (16). A solution of 11 (2.83 g, 17.03 mmol) in 30
mL of chlorobenzene was added dropwise to 2-cyclopentenone
(5 g, 60.9 mmol) dissolved in 3 mL of chlorobenzene with Rh2-
(OAc)4 (26.5 mg, 0.06 mmol) at room temperature during 12
h. After 1 h, the solvent and the excess 2-cyclopentenone were
evaporated off at 50 °C. The residue was chromatographed
(hexane/EtOAc 5:1-5:2) to give compound 16 (1.37 g, 37%) as
1
IR (neat): 2107, 1709, 1633 cm-1. H NMR (CDCl3, 400 MHz)
a white solid: mp 111-113 °C. IR (KBr): 1756, 1737 cm-1
.
δ 5.17 (1H, br s), 2.70-2.34 (4H, m), 2.08 (3H, s), 1.95-1.62
(2H, m). 13C NMR (CDCl3, 100 MHz): δ 204.5, 191.4, 65.6,
53.2, 27.9, 25.1, 15.5. HRMS (CI) (m/z): [M + H]+ calcd for
C8H11N2O2 167.0821, found 167.0820.
Cycloa d d u ct (12). To a mixture of propargyl chloride (332
µL, 4.59 mmol), Rh2(OAc)4 (2 mg, 0.005 mmol), molecular
1H NMR (CDCl3, 400 MHz): δ 4.30 (1H, s), 2.75-2.55 (1H, dt,
J ) 4.4 Hz, 8.4 Hz), 2.42-2.27 (2H, m), 2.27-2.13 (3H, m),
2.12-2.02 (2H, m), 2.02-1.91 (2H, m), 1.90-1.75 (2H, m), 1.52
(3H, s). 13C NMR (CDCl3, 100 MHz): δ 217.4, 214.8, 90.7, 87.0,
56.1, 53.2, 42.0, 39.6, 26.0, 25.5, 25.2, 15.1, 14.0. HRMS (CI)
(m/z) [M + H]+ calcd for C13H17O3 221.1178, found 221.1177.
J . Org. Chem, Vol. 68, No. 25, 2003 9651

McMorris et al.
Keton e (17). Ethylene glycol (25 mL) was added to a CH2-
Cl2 (10 mL) solution of 16 (1.5 g, 6.90 mmol), and to this
solution was added TMSCl (6.6 mL, 52.0 mmol) at 0 °C. The
temperature was then raised to room temperature and kept
for 27 h. The solution was poured into an aqueous solution of
NaHCO3 (150 mL, 0.63M) at 0 °C. The product was extracted
with CH2Cl2 three times, and the combined organic phase was
washed with brine and dried. After evaporation, the residue
was chromatographed (hexane/EtOAc 5:2) to give 17 (1.4 g,
77%) as a white solid: mp 119-120 °C. IR (dry film): 1726
HRMS (MALDI) (m/z) [M + H]+ calcd for C21H33O4Si 377.2143,
found 377.2151.
F u lven e (21). A toluene solution of DIBALH (532 µL, 0.798
mmol, 1.5M) was added to a solution of 20 (200 mg, 0.51 mmol)
in THF (5 mL) at -78 °C. After 3.5 h, CH3OH (1 mL) was
added, and the solution was warmed to room temperature.
After 10 min sodium potassium tartrate solution (10 mL, 1
M) was added. The solution was filtered, and the residue was
washed with chloroform. The organic phases were combined,
and a few drops of HCl (1.5%) were added. After stirring for a
few hours, the solution was evaporated, and the residue
chromatographed (hexane/EtOAc 5:0.4) to give 21 (160 mg,
87%) as a yellow oil. The proton and carbon NMR spectra
indicated that it was a mixture of two isomers in a ratio of
1:0.24. At high temperatures the peaks on the proton spectrum
coalesced, and at low temperature they separated. Major
isomer: 1H NMR (CD2Cl2, 500 MHz, -15 °C): δ 6.40-6.32
(1H, m), 6.31-6.27 (1H, m), 6.12-6.08 (1H, m), 4.76 (1H, d, J
) 2.0 Hz), 4.28-4.20 (1H, m) 4.19-4.03 (2H, m), 3.99-3.92
(1H, m) 2.68-2.56 (1H, m), 2.32 (3H, s), 2.30-2.22 (1H, m),
2.22-2.08 (1H, m), 2.01-1.80 (3H, m), 0.97 (9H, t, J ) 8.0
Hz), 0.73-0.62 (6H, m). 13C NMR (CD2Cl2, 125 MHz, -15 °C):
δ 154.4, 138.4, 136.9, 131.5, 123.2, 117.9, 116.0, 71.4, 67.6, 67.4,
52.2, 28.9, 23.4, 17.9, 15.9, 7.0, 4.9. HRMS(CI) (m/z) [M + H]+
calcd for C21H33O3Si 361.2199, found 361.2195.
1
cm-1. H NMR (CDCl3, 400 MHz): δ 4.06 (1H, m), 4.01-3.88
(4H, m), 2.95-2.86 (1H, m), 2.35-2.19 (3H, m), 2.18-1.91 (4H,
m), 1.89-1.52 (4H, m), 1.39 (3H, s). 13C NMR (CDCl3, 100
MHz): δ 220.1, 113.5, 91.0, 87.7, 65.6, 65.0, 55.4, 53.3, 39.8,
39.6, 25.5, 25.5, 23.0, 15.5, 14.5. HRMS (CI) (m/z) [M + H]+
calcd for C15H21O4 265.1440, found 265.1434.
Alcoh ol (18). Compound 17 (2.57 g, 9.72 mmol) was
dissolved in a methanol solution of KOH (100 mL, 6%) at 53
°C. After 3 h the solvent was evaporated at 30 °C. The residue
was partitioned between water and CH2Cl2. After separation,
the aqueous phase was extracted with CH2Cl2, and the
combined extracts were dried and evaporated. The residue was
chromatographed (CH2Cl2/EtOAc 5:1) to give 18 (1.93 g, 75%)
as a white solid: mp 178-180 °C. IR (dry film): 3442 (br),
1700, 1621 cm-1. 1H NMR (CDCl3, 400 MHz): δ 4.32-4.22 (1H,
m), 4.16-4.00 (3H, m), 3.82 (1H, d, J ) 3.6 Hz), 3.07-2.94
(1H, m), 2.80-2.67 (1H, m), 2.45 (3H, d, J ) 2.8 Hz), 2.41-
2.19 (3H, m), 2.19-2.07 (1H, m), 2.06-1.92 (3H, m,), 1.92-
1.82 (3H, m). 13C NMR (CDCl3, 100 MHz): δ 206.9, 150.1,
127.0, 110.9, 68.8, 66.8, 64.7, 49.3, 42.5, 39.7, 29.4, 23.5, 21.2,
17.1, 13.9. HRMS (CI) (m/z) [M + H]+ calcd for C15H21O4
265.1434, found 265,1432.
Keton e (14). HOAc (50 µL) was added to a THF solution
of TBAF (1 mL, 1 M). The solution was in turn added to a
solution of 21 (210 mg, 0.58 mmol) in THF (9 mL) at 0 °C.
After 3 days, 50 mL of EtOAc was added, and the solution
was washed with brine and saturated NaHCO3. Then it was
dried and evaporated. The residue was chromatographed (CH2-
Cl2/EtOAc 8:1-5:1) to give a yellow oil. Pyridinium dichromate
(90 mg, 0.24 mmol) was added to a solution of 30 mg of the
yellow oil in CH2Cl2 (3 mL) at 0 °C. After 18 h, 10 mL of CH2-
Cl2 was added, and the solution was filtered through a pad of
Celite. The filtrate was evaporated, and the residue was
chromatographed (CH2Cl2/EtOAc 5:0.15-5:0.20) to give 14 (24
mg, 51% in two steps) as a yellow oil. IR (dry film): 1681, 1622
Keton e (19). TESCl (10.1 mL, 60.2 mmol) was added to a
pyridine (90 mL) solution of 18 (1.6 g, 6.05 mmol) at 0 °C. The
solution was heated to 60 °C and kept there for 2 h. After
cooling to room temperature, it was poured into an aqueous
solution of NaHCO3 (150 mL, 0.7 M) at 0 °C. This solution
was extracted with CH2Cl2 three times. The combined organic
phase was dried and evaporated. The residue was chromato-
graphed (hexane/EtOAc 5:1-4:1) to give 19 (2.1 g, 92%) as a
1
cm-1. UV (methanol) λ nm (ꢀ): 317 (5847). H NMR (CDCl3,
300 MHz): δ 7.40-7.31 (1H, m), 6.84-6.74 (1H, dd, J ) 4.8,
1.5 Hz), 6.70-6.61 (1H, dd, J ) 4.8, 2.4 Hz), 4.32-4.09 (4H,
m), 2.56 (3H, s), 2.48-2.33 (2H, m) 2.32-2.21 (2H, m), 2.21-
2.05 (1H, m), 2.02-1.88 (1H, m). 13C NMR (CDCl3, 100 MHz):
δ 188.4, 162.1, 139.0, 135.1, 132.3, 128.2, 125.5, 109.7, 66.6,
53.7, 27.7, 19.3, 16.4. HRMS (MALDI) (m/z) [M + H]+ calcd
for C15H17O3 245.1172, found 245.1175.
white solid: mp 120-122 °C. IR (dry film): 1697, 1625 cm-1
.
1H NMR (CDCl3, 400 MHz): δ 4.37-4.20 (1H, m), 4.17-3.90
(3H, m), 3.80 (1H, d, J ) 4.0 Hz), 3.06-2.90 (1H, m), 2.89-
2.72 (1H, m), 2.46 (3H, d, J ) 2.8 Hz), 2.41-2.18 (3H, m),
2.18-2.02 (1H, m), 2.01-1.85 (3H, m,), 1.85-1.64 (2H, m) 0.94
(9H, t, J ) 7.8 Hz), 0.74-0.46 (6H, m). 13C NMR (CDCl3, 100
MHz): δ 207.1, 150.6, 127.5, 111.3, 69.6, 66.5, 64.7, 49.8, 44.1,
40.0, 29.7, 23.5, 22.2, 17.1, 13.9, 7.3, 5.3. HRMS (MALDI) (m/
z) [M + H]+ calcd for C21H35O4Si 379.2299, found 379.2299.
Ketoa ceta l (22). Diketone 16 (2.88 g, 13.08 mmol) was
dissolved in a cooled solution (-6 °C) of CH2Cl2 (15 mL) and
ethylene glycol (25 mL), to which TMSCl (16.50 mL, 130.0
mmol) was added. After 4.5 h the mixture was poured into an
aqueous solution of NaHCO3 (100 mL, 4.7 M) at 0 °C. The
mixture was stirred for 0.5 h and extracted with CH2Cl2 three
times, and the combined organic phase was washed with brine,
dried, and evaporated. The residue was chromatographed
(hexane/ether 5:2-5:4) to give 22 (2.45 g, 71%) as a liquid. IR
Cr oss Con ju ga ted Keton e (20). TMSCl (400 µL, 3.15
mmol) was added to a solution of 19 (600 mg, 1.58 mmol) in
THF (6 mL) at -78 °C. To this solution was added a solution
of LDA (2.38 mmol, 2 M) in THF (1.19 mL). After 10 min, the
solution was warmed to 0 °C for 15 min, and then it was cooled
to -78 °C. After addition of Et3N (1.5 mL), the solution was
poured into 5 mL of saturated NaHCO3 solution. The mixture
was extracted with ether three times, and the combined
organic phase was washed with aqueous citric acid (10%) until
the pH of the aqueous phase became 4.5, washed with brine,
dried, and evaporated. The residue was dissolved in mixed
solution of CH3CN and THF (8 mL, 5:3), to which Pd(OAc)2
(356.2 mg, 1.59 mmol) was added. After 3 h, the suspension
was filtered, and the filtrate was evaporated. The residue was
chromatographed (hexane/EtOAc 5:1) to give recovered 19 (96
mg, 16%) and 20 (400 mg, 65%) as an oil. IR (dry film): 1688,
1
(neat): 1753 cm-1. H NMR (CD2Cl2, 400 MHz): δ 4.04 (1H,
s), 4.00-3.89 (2H, m), 3.88-3.76 (2H, m), 2.41-2.15 (2H, m),
2.06-1.69 (8H, m), 1.62 (3H, s), 1.61-1.53 (2H, m). 13C NMR
(CDCl3, 100 MHz): δ 216.4, 118.4, 88.8, 86.4, 65.7, 63.1, 56.8,
49.7, 43.3, 35.5, 27.5, 25.6, 25.1, 14.9, 13.7. HRMS (MALDI)
(m/z): [M + Na]+ calcd for C15H20O4Na 287.1254, found
287.1266.
Hyd r oxyk eton e (23). Ketoacetal 22 (5 g, 18.92 mmol) was
dissolved in THF (40 mL) at -78 °C, to which a solution of
MeLi (16.21 mL, 22.68 mmol, 1.4 M) in ether was added. After
2 h MeOH (5 mL) was added to the mixture and saturated
ammonium chloride was used to neutralize the solution, after
it was warmed to room temperature. The mixture was then
evaporated, the residue was dissolved in EtOAc, and the
solution was washed with brine, dried, and evaporated. The
residue was added to acetone (10 mL) with toluenesulfonic acid
(pH 1) and kept overnight. A saturated NaHCO3 solution was
1
1629 cm-1. H NMR (CDCl3, 300 MHz): δ 7.37-7.20 (1H, m),
6.27 (1H, dd, J ) 6, 2.4 Hz), 4.45-4.21 (1H, m), 4.18-3.96
(4H, m), 3.75-3.54 (1H, br s), 2.93-2.67 (1H, m) 2.52 (3H, d,
J ) 0.9 Hz), 2.39-2.20 (1H, m), 2.11-2.05 (1H, m), 2.04-1.84
(3H, m,), 0.88 (9H, t, J ) 7.8 Hz) 0.53 (6H, m). 13C NMR
(CDCl3, 100 MHz): δ 197.1, 155.2, 148.5, 137.6, 126.0, 111.1,
69.7, 66.6, 64.7, 50.4, 48.0, 29.6, 23.6, 17.0, 13.3, 7.1, 5.2.
9652 J . Org. Chem., Vol. 68, No. 25, 2003

Structure-Activity Studies of Illudins
used to neutralize the mixture. It was extracted with EtOAc,
and the organic phase was washed with brine, dried, and
evaporated. The residue was chromatographed (hexane/EtOAc
5:4) to give 23 (4.1 g, 92%) as a white solid: mp 118-120 °C.
14.0, 7.2, 5.5. HRMS (MALDI) (m/z): [M + H]+ calcd for
C
20H33O3Si 349.2193, found 349.2193.
Hyd r oxyfu lven e (27). Ketone 26 (28 mg, 0.08 mmol) was
dissolved in THF (2 mL) at -78 °C, and to this solution was
added DIBALH (160.0 µL, 0.24 mmol, 1.5 M). After 15 min
methanol (0.5 mL) was added, the temperature was raised to
room temperature, and EtOAc (10 mL) and some Celite were
added. After 0.5 h the mixture was filtered, and the filtrate
was washed with brine, dried, and evaporated. The residue
was dissolved in CHCl3 (5 mL), and a few drops of 1.5% HCl
were added. After 2 h, the mixture was neutralized with
saturated NaHCO3, dried, and evaporated. The residue was
chromatographed (CH2Cl2/EtOAc 5:0.25) to give 27 (18.6 mg,
70%) as a yellow oil. IR (neat): 3599 (br), 1627, 1123, 1069,
1
IR (neat): 3448 (br), 1730 cm-1. H NMR (CDCl3, 400 MHz):
δ 3.87 (1H, s), 3.28-3.09 (1H, m), 2.34 (1H, d, J ) 7.2 Hz),
2.32-2.19 (1H, m), 2.18-1.89 (5H,m), 1.88-1.69 (2H, m),
1.68-1.49 (3H, m), 1.39 (3H, s), 1.37 (3H, s). 13C NMR (CDCl3,
100 MHz): δ 220.8, 92.1, 92.0, 78.4, 55.9, 53.6, 39.6, 39.1, 27.3,
25.9, 25.7, 25.4, 15.8, 14.9. HRMS (MALDI) (m/z): [M + H]+
calcd for C14H21O3 237.1485, found 237.1483.
Dih yd r oxyk eton e (24). Ketone 23 (50 mg, 0.21 mmol) was
dissolved in a methanolic solution of KOH (15 mL, 6%) at 60
°C for 4 h. The methanol was then removed under reduced
pressure at 40 °C. The residue was dissolved in EtOAc, and
the solution was washed with brine, dried, and evaporated.
The residue was chromatographed (hexane/EtOAc 1:1-1:3) to
give recovered 23 (25 mg, 50%) and 24 (16 mg, 32%) as a white
1
1006 cm-1. H NMR (CD2Cl2, 500 MHz): δ 6.34 (1H, dd, J )
5.0, 2.0 Hz), 6.30 (1H, d, J ) 5.0 Hz), 6.10-6.05 (1H, m), 4.64
(1H, s), 3.10-2.83 (1H, m), 2.53-2.41 (1H, m), 2.36 (3H, s),
2.32-2.20 (1H, m), 2.05 (1H, s), 2.03-1.83 (2H, m), 1.80-1.67
(1H, m), 1.01 (9H, t, J ) 8.0 Hz), 0.82 (3H, s), 0.72 (6H, q, J )
8.0 Hz). 13C NMR (CD2Cl2, 125 MHz): δ 155.5, 138.9, 137.1,
131.3, 122.6, 118.1, 80.0, 73.2, 53.9, 26.7, 23.8, 17.8, 16.3, 15.9,
7.1, 5.5). HRMS (EI) (m/z): [M]+ calcd for C20H32O2Si 332.2172,
found 323.2165.
solid: mp 184-186 °C. IR (film): 3431 (br), 1691, 1615 cm-1
.
1H NMR (CD3OD, 400 MHz): δ 3.63 (1H, d, J ) 4.0 Hz), 3.21-
2.99 (1H, m), 2.60-2.35 (5H, m), 2.35-2.13 (3H, m), 2.10-
1.89 (3H,m), 1.89-1.72 (2H, m), 1.62 (3H, s). 13C NMR
(CD3OD, 100 MHz): δ 210.1, 153.0, 128.5, 75.2, 75.1, 51.3, 42.0,
40.3, 29.6, 24.5, 23.6, 22.3, 17.2, 14.9. HRMS (MALDI) (m/z):
[M + H]+ calcd for C14H21O3 237.1485, found 237.1486.
Com p ou n d 25. To A pyridine solution (1 mL) of 24 (50 mg,
0.21 mmol) with DMAP (2.6 mg, 0.021 mmol) was added
molecular sieves (100 mg, 3 Å) and TESCl (350.7 µL, 2.1
mmol). The mixture was kept at 80 °C overnight and then was
cooled and poured into a saturated NaHCO3 solution (10 mL).
After filtration the mixture was extracted three times with
EtOAc, and the combined organic phase was washed with
brine, dried, and evaporated. The residue was chromato-
graphed (hexane/EtOAc 1:3) to give 25 (66 mg, 90%) as an oil.
Hyd r oxyk eton e (28). Silyl ether 27 (14 mg, 0.042 mmol)
was dissolved in THF (0.8 mL) at 0 °C. To this solution was
added a THF solution of TBAF (54.7 µL, 0.0547 mmol, 5% (v/
v) CH3COOH). The solution was kept overnight and then
dissolved in EtOAc. The organic phase was washed with brine,
dried, and evaporated to give an oily residue. The residue was
chromatographed (CH2Cl2/EtOAc 5:2) to give an oily yellow
residue. IBX (2-iodoxybenzoic acid) (22.1 mg, 0.08 mmol) was
added to DMSO (0.5 mL). After the mixture became a clear
solution, a CH2Cl2 solution (0.5 mL) of the above yellow residue
was added at room temperature. After 40 min ether was added,
and the resulting solution was washed with brine, dried ,and
evaporated. The residue was chromatographed (CH2Cl2/EtOAc
5:0.2) to give 28 (7 mg, 77%) as an oil. IR (neat): 3457 (br),
IR (neat): 3465 (br), 1704, 1627 cm-1 1H NMR (CDCl3, 400
.
MHz): δ 3.35 (1H, d, J ) 8.4 Hz), 2.86-2.70 (1H, m), 2.53-
2.40 (1H, m), 2.41 (3H, d, J ) 2.8 Hz), 2.3-2.61 (4H, m), 2.12-
1.91(5H, m), 1.43(3H, s), 1.42-1.32 (1H, m), 1.01 (9H, t, J )
8.0 Hz), 0.68 (6H, q, J ) 8.0 Hz). 13C NMR (CDCl3, 100 MHz):
δ 207.0, 151.2, 128.9, 77.5, 76.0, 52.5, 44.8, 39.5, 28.8, 26.8,
24.0, 22.4, 16.1, 15.1, 7.4, 5.7. HRMS (MALDI) (m/z): [M +
Na]+ calcd for C20H34O3Na 373.2169, found 373.2168.
1
1665, 1618 cm-1. UV (CHCl3) λ nm (ꢀ): 317 (10177). H NMR
(CD2Cl2, 400 MHz): δ 7.19 (1H, br s), 6.88-6.73 (1H, m), 6.65
(1H, dd, J ) 4.8, 2.4 Hz), 4.31 (1H, s), 2.56 (3H, s), 2.52-2.35
(3H, m), 2.08-1.87 (2H, m), 1.86-1.71 (1H, m), 1.26 (3H, s).
13C NMR (CDCl3, 100 MHz): δ 197.0, 166.3, 139.4, 133.4,
132.0, 126.0, 125.1, 81.1, 57.2, 31.8, 24.5, 24.1, 19.5, 15.9.
HRMS (MALDI) (m/z): [M + H]+ calcd for C14H17O2 217.1223,
found 217.1229.
Cr oss-Con ju ga ted Keton e (26). Unsaturated ketone 25
(80 mg, 0.228 mmol) was dissolved in THF (2 mL) at -78 °C,
to which triethylamine (0.5 mL), trimethylsilyl chloride (50.0
µL, 0.39 mmol) and a solution of LDA (0.342 mL, 0.684 mmol,
2 M) in ether were added in sequence. After 1 h a saturated
NaHCO3 solution (0.1 mL) was added, and the mixture was
brought to room temperature. Ether was added followed by
citric acid (5%) to bring down the pH of the solution to 4.5.
After separation the organic phase was washed with brine,
dried, and evaporated. The residue was dissolved in a mixture
of THF and CH3CN (1 mL, 1:1), and to this solution was added
Pd(OAc)2 (51.2 mg, 0.228 mmol) at room temperature. After 3
h CH2Cl2 was added, and the mixture was filtered through
Celite. After evaporation the residue was chromatographed
(hexane/EtOAc 3:1) to give recovered 25 (16 mg, 20%) and 26
(52 mg, 65%) as a colorless oil. IR (neat): 3446 (br), 1676, 1616
cm-1. 1H NMR (CDCl3, 400 MHz): δ 7.34 (1H, dd, J ) 6.4, 2.4
Hz), 6.28 (1H, dd, J ) 6.4, 2.4 Hz), 4.11 (1H, d J ) 3.6 Hz),
3.87-3.64 (1H, m), 2.50 (3H, d, J ) 0.8 Hz), 2.48-2.36 (1H,
m), 2.35-2.24 (1H, m), 2.23-2.10 (1H, m), 2.09-1.84 (3H, m),
1.70-1.61 (1H, br s), 1.54 (3H, s), 0.87 (9H, t, J ) 7.6 Hz),
0.61-0.42 (6H, m). 13C NMR (CDCl3, 100 MHz): δ 197.4, 155.8,
148.8, 137.4, 126.4, 75.6, 75.4, 51.1, 45.6, 29.0, 24.1, 23.6, 16.5,
Ack n ow led gm en t . This investigation was sup-
ported by MGI Pharma Inc., Bloomington, MN and by
the Cigarette and Tobacco Tax Fund of the State of
California through the Tobacco-Related Disease Re-
search Program of the University of California (award
12RT-0101). X-ray crystallographic analyses were car-
ried out by Dr. Peter K. Gantzel, Department of
Chemistry and Biochemistry, University of California,
San Diego. We also thank Michael D. Staake of this
department for providing compound 6 for biological
tests.
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of the
synthesized compounds and X-ray files of 16 and 23 in CIF
format. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O0346499
J . Org. Chem, Vol. 68, No. 25, 2003 9653