Studies toward the synthesis of menogaril: Synthesis of a-ring precursors and their conversion to the tetracyclic core via the benzannulation reaction

Article abstract of DOI:10.1055/s-1999-3402

A model study for the synthesis of menogaril is reported which involves the benzannulation reaction of a Fischer carbene complex with an alkyne that contains the A-ring of the tetracyclic core of menogaril. The synthesis of methoxy and benzyloxy derivatives of this alkyne are reported as well as the reaction of the methoxy derivative with an o-methoxyphenyl carbene complex to generate a tricyclic naphthol containing three of the four rings of menogaril core. Completion of the model study and the synthesis of the tetracyclic anthracyclinone core of menogaril was accomplished by an intramolecular Friedel-Crafts cyclization.

Full text of DOI:10.1055/s-1999-3402

PAPER
415
Studies Toward the Synthesis of Menogaril: Synthesis of A-Ring Precursors
and Their Conversion to the Tetracyclic Core via the Benzannulation
Reaction
William D. Wulff,* Jing Su, Peng-Cho Tang, Yao-Chang Xu
Department of Chemistry, Searle Chemistry Laboratory, The University of Chicago,Chicago, IL 60637, USA
Fax +(773)7080805; E-mail: wulff@rainbow.uchicago.edu
Received 31 July 1998
date for the development of out-patient chemotherapy of
Abstract: A model study for the synthesis of menogaril is reported
lymphoma and myeloma.7a
which involves the benzannulation reaction of a Fischer carbene
complex with an alkyne that contains the A-ring of the tetracyclic
core of menogaril. The synthesis of methoxy and benzyloxy deriv-
atives of this alkyne are reported as well as the reaction of the meth-
oxy derivative with an o-methoxyphenyl carbene complex to
complexes.9 These efforts, as well as those of others, have
generate a tricyclic naphthol containing three of the four rings of
menogaril core. Completion of the model study and the synthesis of
Our interest in the synthesis of anthracyclines8 lies in the
development of a general approach to anthracyclines uti-
lizing the benzannulation reaction of Fischer carbene
resulted in the synthesis of several anthracyclinones uti-
lizing Fischer carbene complexes.9 Herein we describe
the tetracyclic anthracyclinone core of menogaril was accomplished
our initial results directed to the development of a strategy
for the synthesis of menogaril (3). The syntheses of the
methoxy and benzyloxy derivatives of alkyne 6 are report-
ed along with the synthesis of the tetracyclic intermediate
4 via the reaction of these alkynes with the carbene com-
plex 5 in a model study of the strategy for the construction
of the fully functionalized tetracyclic core of menogaril
(3). The retrosynthetic strategy is shown in Scheme 1.
by an intramolecular FriedelÐCrafts cyclization.
Key words: benzannulation reaction, Fischer carbene complex,
FriedelÐCrafts cyclization, anthracyclinones, menogaril
Daunorubicin (1) and adriamycin (2) belong to the anthra-
cycline family of antitumor antibiotics and are isolated
from Streptomyces species. Ever since the recognition of
their pharmacological activities in the 1960s,1,2 dauno-
rubicin (1) and adriamycin (2) have emerged as among the
most widely used compounds in the treatment of cancers
such as acute leukemia, breast cancer, HodgkinÕs disease,
non-Hodgkin's lymphomas and sarcomas.3Ð4 Menogaril
(3) is a semi-synthetic derivative of the natural product
nogalamycin and its activity is somewhat superior to that
of adriamycin (2) and in addition it is several fold less car-
diotoxic.5 Recent studies have shown that menogaril (3) is
unique among anthracyclines in that it binds to the major
rather than the minor groove of DNA6 and that it is active
after oral administration, thus extravasion is not a side ef-
fect.7 As an orally active drug, menogaril (3) is a candi-
Scheme 1
Commercially available ketone 7 was treated with meth-
yllithium or methylmagnesium bromide to give the ter-
tiary alcohol 8 in 75% yield with a 25% recovery of the
starting material. The reaction could not be driven to com-
pletion under more forcing conditions. However, pretreat-
ment of the Grignard reagent with CeCl3 significantly
improved the yield to 96%.10 Exposure of the alcohol to
sodium hydride and iodomethane followed by deprotec-
tion of the ketal gave the desired ketone 9 in 85% yield.
The propargylation of ketones is often problematic and
ketone 9 proved no exception. Allenic by products are of-
ten observed11 and it has been reported that the propargyl-
ation reaction could be effected in fair to good yields and
with little allene formation if the C-terminus is substituted
with a trimethylsilyl group.12 However, reaction of ketone
9 with LDA and then 3-bromo-1-(trimethylsilyl)prop-1-
yne in the presence of two equivalents of HMPA afforded
the propargylated product 10 in only 30Ð35% yield. The
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416
W. D. Wulff et al.
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starting material was recovered in 10Ð20% yield and at thioacetals to acids is accomplished by the use of mercuric
least two side products were observed which were tenta- oxide.20 However, these reaction conditions would not be
tively assigned as dialkylated products. On some occa- compatible with 12b which has an alkynyl group. Instead,
sions, the desilylated product was isolated in 5% yield. a two-step procedure was developed which involved acid
This was disappointing since the use of HMPA has been hydrolysis of the ketene thioacetal21 followed by basic hy-
reported to increase the amount of monoalkylation of car- drolysis of the crude reaction mixture containing the S-
bonyls.13 Other methods that have been reported to sup- thioester22 which was found to be facilitated by oxidation
press polyalkylation failed to give improved results with hydrogen peroxide. The trimethylsilyl group was lost
including triethanolamine borate (TEAB),14 dimethyl during this base hydrolysis producing the acid 13b. Ester-
zinc15 and the dicobalt hexacarbonyl complexation.16 The ification gave the alkyne 14b in 73% yield for the three
best conditions that were found gave 10 in 44% yield as a steps from 12b.
1.7:1 mixture of diastereomers. This reaction was con-
ducted by generating the enolate of 9 by LDA at Ð78oC in
THF and then treatment with 3-bromo-1-(trimethyl-
silyl)prop-1-yne for one hour (Scheme 2).
Scheme 3
Scheme 2
The synthesis of the alkyne 18b follows from the strategy
developed for 14b discussed above. It was anticipated that
the benzyl protecting group would be stable to strongly
acidic and basic conditions that will be required for the
synthesis of the tetracyclic carbon core intermediate of
menogaril (3). The synthesis of alkyne 18b begins from
the same ketone 7 that was used in the synthesis of alkyne
14b. The alcohol 8 was then isolated and subsequently
treated with sodium hydride and benzyl bromide. Depro-
tection of the ketal afforded the desired ketone 15 in 80%
yield. It was pleasing to find that propargylation of 15
gave both a higher yield and a better stereoselectivity than
the corresponding propargylation of ketone 9 (Scheme 4).
The monoalkylation product 16 was isolated as a 10:1
mixture of diastereomers in 54% yield, favoring the trans
isomer 16b. Also observed was a 14% yield of a dialkyl-
ated product and a 26% recovery of the starting material
15. The relative stereochemistry of 16b was assigned as
trans by a correlation of the chemical shifts of the methine
proton and the methyl group with those of the 10a and
10b. Compound 16a was not separated from 16b and the
mixture of 16 was converted to the ketene acetal 17 which
was also produced as approximately a 10:1 mixture of
diastereomers. The major isomer 17b was purified and sub-
jected to acidic hydrolysis, oxidative basic hydrolysis and
esterification to give the desired ester 18b in 63% yield.
The relative stereochemistry of 10b was initially assigned
as trans and this was subsequently confirmed by an X-ray
structure on a compound derived from 10b.17 Interesting-
ly, the cis and trans isomers have quite distinct 1H NMR
spectra. As indicated in the Figure, there is a 0.30 ppm dif-
ference between the axial methine proton of the two dia-
stereomers with the more downfield shifted methine
proton in the axial position in the trans isomer.18 The more
downfield shifted methyl group is observed for the cis iso-
mer where the methyl is in an axial position.
Figure. 1H NMR Data of Ha and CH3 Protons of Conformers 10a
and 10b
Although the propargylation of ketone 9 produced a mix-
ture of diastereomers, this did not limit the synthetic via-
bility of this intermediate since the new chiral center
would be destroyed eventually when the B-ring is aroma-
tized. The synthesis of alkyne 14 was carried out with the
purified major isomer 10b for the convenience of charac-
terization of intermediates, however, it was shown that the
minor isomer 10a could be converted to the diastereomer-
ic alkyne 14. The Peterson olefination of 10b indicated in
Scheme 3 worked well to afford the ketene thioacetal 12b
in 96% yield.19 Most commonly, the conversion of ketene
The benzannulation of carbene complex 5 with alkyne
14b was carried out under a few different conditions
(Scheme 5) and the results are summarized in the Table.
Polar and nonpolar solvents can have very different ef-
fects on the benzannulation reaction but in this particular
case changing the solvent from acetonitrile to benzene has
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Studies Toward the Synthesis of Menogaril
417
Scheme 4
very little effect on the yield of the phenol product 19.23 The phenol function in 19 was protected as its methyl
The furan product 20 was isolated as a minor product in ether in preparation for the FriedelÐCrafts ring closure.
two cases. In the optimal case, the naphthol 19 was ob- This was accomplished in 98% yield with methyl iodide
tained in 60% yield and the furan in 10% yield from the and potassium carbonate in refluxing acetone. Hydrolysis
reaction in benzene. An account of the remainder of the of the methyl ester with sodium hydroxide provided the
mass balance in this reaction was not made. The furan acid 22. The FriedelÐCrafts closure of 22 with strong acid
could be readily separated by silica gel chromatography to such as trifluoroacetic acid can give varying amounts of
provide naphthol 19 in pure form.
elimination of methanol from the tertiary ether. In order to
minimize the amount of acid present and the elimination
of methanol, the acid 22 was treated with one equivalent
of aqueous sodium hydroxide and then lyophilized under
reduced pressure to give the dry sodium carboxylate. This
salt was converted to the acid chloride by addition of
pyridine and oxalyl chloride. Addition of tin tetrachloride
induced the closure of the B-ring to form the tetracyclic
intermediate 23 in 71% overall yield from 21 (Scheme 6).
The oxidation of the C-ring to a quinone was unsuccessful
with cerium (IV) ammonium nitrate and with iodine. Both
reactions gave a complicated mixture of products. Oxida-
tion with lead(IV) tetraacetate resulted in a mixture of two
compounds one of which was found to be the desired
quinone 24. The successful oxidation of 23 was finally
achieved cleanly with excess silver oxide. The quinone 24
could be obtained by treatment with AgO in acetone for a
few minutes. Nitric acid is necessary for the reaction to go
to completion. The oxidative aromatization of 24 by mo-
lecular oxygen in DMF was quite efficient giving the tar-
get anthracyclinone 25 in 93% yield. Occasionally this
reaction will produce the over oxidation product 26 in
small amounts along with two other unidentified com-
pounds (Scheme 5). It was not possible to isolate 26 in
pure form away from the product 25 since they coelute on
Table. Benzannulation of Complex 5 with Alkyne 14
Mole Ratio
of 5:14b
Solvent
Yield (%)
Major
Minor
Product 19 Product 20
1.00:0.85
1.00:0.85
1.00:0.85
1.00:1.20
MeCN
53
34
54
60
not detected
not detected
9
10
hexane
benzene
benzene
Scheme 5
Reagent and conditions: a) MeI/K2CO3; b) 2 N NaOH c) NaOH (1 equiv); d) (COCl)2/pyridine; e) SnCl4; f) AgO/HNO3; g) O2/DMF
Scheme 6
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418
W. D. Wulff et al.
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then MeI (11 mL, 174.16 mmol, 4 equiv) and Me4NBr (1.65 g,
10.88 mmol, 0.25 equiv) were quickly added and the solution was
stirred under N2 overnight. The reaction was quenched by the addi-
tion of a pH 7 buffer (50 mL). The solvent was removed in vacuo
and the residue was extracted with Et2O. The organic layer was
washed with brine and stripped of the solvent to give a yellow oil
which was treated with conc. HCl (8.4 mL), acetone (48 mL) and
H2O (70 mL). After the mixture was stirred at r. t. for 2 h, it was neu-
tralized with solid K2CO3. The volume was reduced to one half fol-
lowed by extraction with a large excess of Et2O. The organic layer
was washed with brine and dried (MgSO4) and filtered through
Celite. Removal of the solvent gave 5.24 g of the ketone 9 as yellow
oil in 85% yield; Rf 0.37 (Et2O/CH2Cl2/hexane, 1:1:1).
silica gel with a number of different solvent systems. In a
control experiment, it was shown that a pure sample of 25
could not be oxidized to 26 under the reaction conditions.
Since 25 could not be separated from 26, it was desirable
to find reliable conditions for the efficient oxidation of 24.
Finally, it was found that compound 25 could be repro-
ducibly obtained in 85Ð92% yield from 23 if the quinone
24 was coated on the inside of a flask and heated at 100¡C
in the presence of air in the absence of solvent. This reac-
tion is very clean and in no case could the byproduct 26 be
detected.
1H NMR (CDCl3): d = 1.23 (s, 3 H), 1.69 (dt, 2 H, J = 4.6, 13.5 Hz),
2.10Ð2.22 (m, 4 H), 2.58 (dt, 2H, J = 6.1, 14.3 Hz), 3.28 (s, 3 H).
13C NMR (CDCl3): d = 22.97, 35.02, 36.44, 48.71, 71.46, 211.22.
In summary, a synthesis of the alkyne 6 has been devel-
oped which is to serve as the A-ring precursor in the syn-
thesis of menogaril (3) via the benzannulation of this
alkyne with an aryl Fischer carbene complex. The methyl
and benzyl derivatives 14b and 18b were prepared in
eight steps from the commercially available ketone 7 in
25% and 24% overall yields, respectively. In a model
study for the synthesis of 3, alkyne 14b was reacted with
carbene complex 5 to give the naphthol 19 in 60% yield.
The success of this model study followed from subsequent
FriedelÐCrafts ring closure of the B-ring in 71% yield and
the oxidation of the C and B-rings in 93% yield. The target
tetracyclic intermediate 25 was thus achieved in 38%
overall yield from alkyne 14b. The viability of the use of
the benzannulation reaction in the synthesis of menogaril
(3) is established and further studies directed to this goal
will be reported in due course.
IR (neat): n = 2967 s, 2940 s, 2827 m, 1715 s, 1467 m, 1374 m, 1312
m, 1137 s, 1122 m, 1078 s, 862 m cmÐ1.
MS: m/z (% rel. intensity) = 142 (M+, 25), 127 (10), 116 (4), 110 (7),
99 (5), 97 (7), 95 (17).
Anal calcd for C8H14O2: C, 67.57; H, 9.92. Found: C, 67.71; H,
10.22.
4-Methoxy-4-methyl-2-(3-trimethylsilylprop-2-yn-1-yl)cyclo-
hexanone (10)
Lithium diisopropylamide was freshly prepared by treatment of dis-
tilled (i-Pr)2NH (4.34 mL, 30.99 mmol, 1.1 equiv) with BuLi
(19.37 mL, 1.6 M, 30.99 mmol, 1.1 equiv) in THF (32 mL) at
Ð78¡C under N2 for 15 min. The ketone 9 (4.0 g, 28.17 mmol) was
transferred neat by dropwise addition via cannula to the LDA solu-
tion at Ð78¡C. After 10 min the dry ice/acetone bath was replaced
by an ice bath and the mixture was stirred for 30 min before it was
recooled to Ð78¡C. After dropwise addition of neat 3-bromo-1-(tri-
methylsilyl)prop-1-yne (5.92 g, 30.99 mmol, 1.1 equiv) via syringe
to the enolate solution at Ð78¡C, the solution was stirred for 30 min
and then warmed up to 0¡C and stirred for 1 h. The solution was
warmed to r.t. and stirred for 20 min before it was quenched with
H2O (20 mL). The solvent was removed and the residue extracted
with Et2O. The organic layer was washed with aq sat. NaHCO3 so-
lution and brine, dried (MgSO4) and filtered through Celite. After
removal of the solvent the residue was chromatographed over silica
gel (Et2O/CH2Cl2/hexane, 1:1:4) to give 1.97 g of 10b and 1.15 g of
10a as yellow oils in a total of 44% yield.
Unless otherwise stated, all chemicals were obtained from commer-
cial suppliers and were used without further purification. THF, ben-
zene and Et2O were distilled from sodium benzophenone ketyl
immediately prior to use. CH2Cl2, diisopropylamine and HMPA
were distilled from CaH2. Elemental analyses were carried out by
Galbraith Labs., Inc. Routine proton NMR spectra were recorded on
either a DS-1000 500MHz spectrometer or a GE-300 MHz instru-
ment in CDCl3. The 13C NMR data were obtained on the QE-300 or
W-500 spectrometer. IR spectra were taken on a Nicolet 20SX
FTIR spectrometer. Low resolution mass spectra were recorded on
a Finnigan 1015 mass spectrometer. High resolution mass spectra
were recorded on a VG 70Ð250 instrument or obtained from the
Midwest Center for Mass Spectrometry in Lincoln, Nebraska. Ele-
mental analysis were done by Galbraith Laboratories in Knoxville,
Tennessee.
10a: Rf 0.20 (Et2O/CH2Cl2/hexane, 1:1:4).
1H NMR (CDCl3): d = 0.17 (s, 9 H), 1.44 (s, 3 H), 1.75 (t, 1 H, J =
12.6 Hz), 1.95Ð1.97 (m, 2 H), 2.25Ð2.34 (m, 3 H), 2.44Ð2.55 (m, 2
H), 2.70 (dd, 1 H, J = 4.4, 17.2 Hz), 3.27 (s, 3 H).
13C NMR (CDCl3): d = 0.68, 21.12, 22.20, 35.97, 37.49, 41.31,
4-Methoxy-4-methylcyclohexanone (9)
46.03, 49.75, 73.88, 86.80, 105.38, 210.71.
A sample of CeCl3¥7 H2O (17.91 g, 48.06 mmol, 1.25 equiv) was
heated under vacuum (0.5 Torr) in a 500 mL flask at 130¡C for 2 h.
This flask was cooled to 0¡C, filled with argon and then THF
(100 mL) and MeMgBr (16 mL, 3.0 M, 48.06 mmol, 1.25 equiv)
were added and stirred for 1 h. A solution of ketone 7 (5.0 g,
32.05 mmol, 1 equiv) in THF (30 mL) was transferred to the above
solution. The mixture was stirred at 0¡C for 2.5 h and then
quenched with a pH 7 buffer (30 mL). Extraction with excess Et2O
(8 × 50 mL), drying (MgSO4), filtration through Celite and removal
of the solvent gave 6.4 g white solid 8 in 96% yield.
IR (neat): n = 2945 vs, 2905 vs, 2838 s, 2175 vs, 1717 vs, 1425 s,
1377 s, 1249 vs, 1138 vs, 1071 vs, 844 vs cmÐ1.
MS: m/z (% rel. intensity) = 252 (M+, 1), 237 (4), 220 (31), 205
(44), 192 (6), 165 (12), 141 (8), 131 (14), 85 (44), 73 (100).
10b: Rf 0.28 (Et2O/CH2Cl2/hexane, 1:1:4).
1H NMR (CDCl3): d = 0.14 (s, 9 H), 1.23 (s, 3 H), 1.42 (t, 1 H, J =
13.5 Hz), 1.71 (dt, 1 H, J = 4.5, 13.8 Hz), 2.13Ð2.26 (m, 3 H), 2.52Ð
2.60 (m, 1 H), 2.63Ð2.71 (m, 2 H), 2.76Ð2.83 (m, 1 H), 3.32(s, 3 H).
A dispersion of NaH in mineral oil (60% by weight, 3.48 g,
87.00 mmol, 2 equiv) was washed with hexane three times before
use. The hexane was removed by a pipette and the flask was flushed
with N2 and THF (20 mL) was added. A solution of the tertiary al-
cohol 8 (7.49 g, 43.54 mmol, 1 equiv) in THF (80 mL) was added
by cannula at r.t. The mixture was stirred under N2 for 30 min and
13C NMR (CDCl3): d = Ð0.01, 19.37, 23.34, 36.78, 36.98, 40.68,
43.85, 48.87, 72.48, 85.74, 105.06, 210.82.
IR (neat): n = 2963Ð2901brs, 2827 m, 2176 s, 1715 s, 1467 m, 1374
m, 1250 s, 1142 m, 1098 m, 1072 m, 1044 m, 843 m cmÐ1.
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Studies Toward the Synthesis of Menogaril
419
MS-CI: m/z (% rel. intensity) = 253 (M+1)+ (50), 221 (100), 220
(20), 210 (33), 205 (18).
IR (neat): n = 3292 s, 2967 s, 2938 s, 2826 s, 1732 s, 1464 m, 1435
s, 1374 m, 1332 s, 1263 s, 1242 s, 1193 s, 1169 s, 1138 m, 1080 s,
1029 m cmÐ1.
MS: m/z (% rel. intensity) = 224 (M+, 1), 209 (48), 185 (100), 169
Anal calcd for C14H24O2Si: C, 66.61; H, 9.58. Found: C, 66.32; H,
9.75.
(13), 149 (18), 123 (70), 93 (42), 85 (81), 72 (73).
2-[4-Methoxy-4-methyl-2-(3-trimethylsilylprop-2-yn-1-yl)]cy-
clohexylidene-1,3-dithiane (12b)
Anal calcd for C13H20O3: C, 69.61; H, 8.99. Found: C, 69.61; H,
9.13.
Freshly distilled 2-trimethylsilyl-1,3-dithiane (3.17 g, 16.47 mmol,
1.4 equiv) was dissolved in THF (12 mL) and treated with BuLi
(10.3 mL, 1.6 M, 16.48 mmol, 1.4 equiv) under N2 at 0¡C for
40 min. A solution of 10b (2.97 g, 11.78 mmol) in THF (10 mL)
was transferred dropwise to the above solution and the resulting
mixture was stirred for 3 h at 0¡C before it was quenched with H2O
(20 mL). The solvent was removed in vacuo and the residue was ex-
tracted with Et2O. The organic layer was dried (MgSO4), filtered
through Celite and stripped of the solvent. Purification of the prod-
uct by chromatography on silica gel (Et2O/CH2Cl2/hexane, 1:1:10)
gave 4.00 g of 12b as a colorless oil in 96% yield; Rf 0.20 (Et2O/
CH2Cl2/hexane, 1:1:10).
1H NMR (CDCl3): d = 0.18 (s, 9 H), 1.30 (s, 3 H), 1.60 (dt, 1 H, J
= 5.3, 12.8 Hz), 1.64Ð1.73 (m, 1 H), 1.79 (dd, 1 H, J = 6.9, 13.9 Hz),
2.02Ð2.10 (m, 2 H), 2.11Ð2.18 (m, 2 H), 2.34 (dd, 1 H, J = 9.7,
14.0 Hz), 2.38 (dd, 1 H, J = 6.2, 14.0 Hz), 2.78Ð3.18 (m, 5 H), 3.20
(s, 3 H), 3.38Ð3.41 (m, 1 H).
4-Benzyloxy-4-methylcyclohexanone (15)
NaH (60% in dispersion, 2.46 g, 61.6 mmol, 2 equiv) was washed
three times with hexane and then a solution of alcohol 8 (5.3 g,
30.8 mmol, 1 equiv) in THF (120 mL) was slowly added under N2
at 0¡C. After stirring for 1 h at r.t. benzyl bromide (7.5 mL, 2 eq)
and Bu4NBr (2.48 g, 0.25 eq) were added. The mixture was refluxed
at 80¡C under N2 overnight and carefully quenched by H2O. After
removal of solvent, H2O (10 mL) was added and the mixture was
extracted with Et2O (2 × 60 mL). The solvent was removed and the
residue was treated with conc. HCl (6.7 mL), H2O (60 mL) and ace-
tone (40 mL). After stirring for 2 h the volume of the solution was
reduced to half. Extraction with Et2O (4 × 60 mL) followed by re-
moval of the solvent gave a yellow residue. The product was puri-
fied by chromatography (Et2O/CH2Cl2/hexane, 1:1:6) on a silica gel
column (4 × 20 cm) to give the ketone 15 (5.4 g) in 80% yield; yel-
low liquid; Rf 0.25 (Et2O/CH2Cl2/hexane, 1:1:6).
13C NMR (CDCl3): d = 0.04, 23.47, 24.35, 25.01, 25.16, 30.29,
1H NMR (CDCl3): d = 1.39 (s, 3 H), 1.79 (dt, 2 H, J = 5.9, 13.5 Hz),
2.22Ð2.32 (m, 4 H), 2.70 (dt, 2 H, J = 5.7, 13.5 Hz), 4.54 (s, 2 H),
7.20Ð7.35 (m, 5 H).
13C NMR (CDCl3): d = 24.46, 36.09, 37.18, 63.82, 72.67, 127.57,
127.30, 128.59, 139.17, 211.00.
35.82, 36.46, 37.50, 48.60, 73.45, 86.48, 105.29, 119.87, 143.14.
IR (CH2Cl2): n = 2956Ð2933 brs, 2172 s, 1422 m, 1249 s, 1104 m,
1075 s, 1039 m, 910 s, 843 vs, 759 s cmÐ1.
MS: m/z (% rel. intensity) = 354 (M+ , 2), 322 (5), 243 (88), 211
(30), 171 (100), 97 (15), 73 (15).
IR (neat): n = 2984 s, 1713 s, 1497 m, 1452 s, 1383 s, 1313 s, 1263
s, 1126 s, 1028 s, 887 s, 723 s cmÐ1.
Anal calcd for C18H30OSi: C, 60.96; H, 8.53. Found: C, 60.46; H,
9.17.
MS: m/z (% rel intensity) = 218 M+, 7), 160 (5), 112 (77), 104 (61),
99 (28), 91 (100), 77 (20), 71 (54), 65 (39).
Methyl 4-Methoxy-4-methyl-2-(prop-2-yn-1-yl)-1-cyclohexane
carboxylate (14b)
Anal calcd for C14H18O2: C, 77.03; H, 8.31. Found: C, 76.56, H
8.41.
Compound 12b (4.0 g, 11.30 mmol) was treated with CF3CO2H
(12.3 mL, 14.14 equiv) in MeCN (123, mL) and H2O (37 mL). The
mixture was stirred at r.t. for 20 h. The solvent (and CF3CO2H) was
completely removed in vacuo at 70¡C. The crude mixture was ex-
tracted with Et2O/pentane (1:1, 150 mL). After separation, the or-
ganic layer was washed with H2O (3 × 10 mL) until the odor of
CF3CO2H was no longer present in the organic layer. After removal
of the solvent, the yellow oil was treated with a mixture of THF
(74 mL), EtOH (31 mL) and 2 N NaOH (30.8 mL, 5.4 equiv) and
then 30% H2O2 (9.85 mL, 8.5 equiv) was added. The mixture was
stirred at r.t. for 3 h and/or until TLC showed only one spot (Rf 0,
Et2O/CH2Cl2/hexane, 1:1:4). If more than one spot was present,
then 1 equiv of NaOH was added and stirred for another hour and
repeated until they were gone. After neutralization with conc. HCl,
the solvent was removed and the residue was extracted with Et2O.
The organic layer was washed with brine, dried (MgSO4) and fil-
tered through Celite. The solvent was removed and resulting yellow
oil was dissolved in acetone (128 mL) and treated with MeI (14 mL,
large excess) and K2CO3 (15.63 g). The mixture was refluxed under
N2 at 70¡C for 5 h before it was cooled down to r.t. Filtration
through Celite removed the excess solid K2CO3. The solvent was re-
moved to give essentially pure 14b (1.85 g, 73%) as judged by 1H
NMR; colorless oil; Rf 0.37 (Et2O/CH2Cl2/hexane, 1:1:4).
4-Benzyloxy-4-methyl-2-(3-trimethylsilylprop-2-yn-1-yl)cyclo-
hexanone (16)
To a solution of (i-Pr)2NH (3.78 mL, 26.99 mmol, 1.1 equiv) in
THF (36 mL) cooled to 0¡C was added dropwise BuLi (10.8 mL,
2.5 M, 26.99 mmol, 1.1 equiv). The mixture was stirred for 15 min
and then cooled to Ð78¡C and treated with a solution of the ketone
15 (5.35 g, 24.54 mmol, 1 equiv) in THF (89 mL) which was slowly
transferred via cannula. After 10 min the mixture was warmed to
0¡C for 30 min before it was recooled to Ð78¡C. 3-Bromo-1-(tri-
methylsilyl)prop-1-yne (4.79 g, 24.54 mmol, 1 equiv) in THF
(18 mL) was added slowly and after 30 min the mixture was
warmed to 0¡C for 48 h. The reaction was quenched by addition of
brine (10 mL). The solvent was removed and the residue was ex-
tracted with Et2O. The combined organic layers were dried
(MgSO4) and filtered through Celite. Removal of the solvent gave
a mixture of three compounds which were separated by column
chromatography on silica gel (Et2O/CH2Cl2/hexane, 1:1:6) to give
4.35g of the desired product 16 in 54% yield (diastereomeric ratio,
10:1) along with a 26% recovery of the ketone 15 and a 14% yield
of the dialkylated product.
Major isomer 16b: Yellow oil; Rf 0.40 (Et2O/CH2Cl2/hexane,
1:1:6).
1H NMR (CDCl3): d = 1.12 (s, 3 H), 1.14Ð1.28 (m, 2 H), 1.70Ð1.74
(m, 1 H), 1.75Ð1.83 (m, 1 H), 1.86Ð1.92 (m, 1 H), 1.97Ð2.03 (m, 2
H), 2.12Ð2.23 (m, 4 H), 3.15 (s, 3 H), 3.68 (s, 3 H).
13C NMR (CDCl3): d = 23.73, 25.09, 25.53, 33.18, 34.84, 40.24,
47.60, 48.96, 52.00, 70.71, 73.00, 82.09, 176.23.
1H NMR (CDCl3): d = 0.14 (s, 9 H), 1.35 (s, 3 H), 1.48 (t, 1 H, J =
13.5 Hz), 1.73 (dt, 1 H, J = 4.4, 14.1 Hz), 2.15Ð2.26 (m, 3 H), 2.62Ð
2.75 (m, 3 H), 2.83Ð2.88 (m, 1 H), 4.50 (s, 2 H), 7.21Ð7.34 (m, 5 H).
13C NMR (CDCl3): d = 0.32, 19.67, 24.54, 37.22, 37.83, 41.38,
44.29, 63.77, 73.31, 86.14, 105.46, 127.48, 127.61, 128.58, 139.10,
210.97.
Synthesis 1999, No. 3, 415–422 ISSN 0039-7881 © Thieme Stuttgart · New York

420
W. D. Wulff et al.
PAPER
IR (neat): n = 2962 s, 2175 s, 1715 vs, 1249 s, 1144 s, 1097 s, 1060
1H NMR (CDCl3): d = 1.29 (s, 3 H), 1.30Ð1.34 (m, 2 H), 1.77Ð1.80
(m, 1 H), 1.94Ð2.05 (m, 4 H), 2.11Ð2.27 (m, 1 H), 2.30Ð2.45 (m, 3
H), 3.69 (s, 3 H), 4.40 (s, 2 H), 7.22Ð7.37 (m, 5 H).
13C NMR (CDCl3): d = 23.50, 25.49, 25.69, 32.94, 35.08, 40.03,
47.24, 51.74, 63.15, 70.56, 73.31, 81.85, 127.33, 127.39, 128.49,
139.62, 175.94.
s, 842 s, 732 s cmÐ1.
MS: m/z (% rel intensity) = 328 (M+, 2), 237 (24), 220 (95), 205
(85), 181 (8), 165 (20), 151 (16), 99 (41), 91 (100), 73 (83), 65 (38).
Anal calcd for C20H28O2Si: C, 73.12; H, 8.59. Found: C, 72.63; H,
8.95.
IR (neat): n = 3304 s, 2933 s, 2100 w, 1729 s, 1451 s, 1435 s, 1382
m, 1331 s, 1265 s, 1169 s, 697 s cmÐ1.
2-[4-Benzyloxy-4-methyl-2-(3-trimethylsilylprop-2-ynyl)]cyclo-
hexylidene-1,3-dithiane (17)
MS: m/z (% rel intensity) = 300 (M+, 2), 285 (2), 269 (4), 261 (6),
194 (100), 177 (7), 153 (28), 133 (25), 105 (22), 91 (100), 77 (22),
65 (31).
Freshly distilled 2-(trimethylsilyl)-1,3-dithiane (5.73 mL,
29.88 mmol, 1.4 eq) was dissolved in THF (32 mL) and cooled to
0¡C. BuLi (1.87 mL, 1.6 M, 29.88 mmol, 1.4 equiv) was added and
the mixture was stirred under N2 for 40 min. A solution of the ke-
tone 16 (7.0 g, 21.34 mmol, diastereomeric ratio 10:1) in THF
(96 mL) was transferred to the above solution and the ice bath re-
moved. The mixture was stirred for 3 h before it was quenched with
aq satd NH4Cl solution (10 mL). The solvent was removed and the
residue extracted with Et2O. After removal of the solvent, the crude
product was loaded onto a silica gel column (4 × 20 cm) and eluted
with a 1:1:25 mixture of Et2O/CH2Cl2/hexane to give the unreacted
2-(trimethylsilyl)-1,3-dithiane and then with a 1:1:20 mixture to
give 8.40 g (92%, diastereomeric ratio, 10:1) of 17 as a yellow oil.
Major isomer Rf 0.35 (Et2O/CH2Cl2/hexane, 1:1:16).
Anal calcd for C19H24O3: C, 75.97; H, 8.05. Found: C, 75.50, H,
8.27.
Annulation of the Carbene Complex 5 with Acetylene 14b
A solution of the complex 5 (0.166 g, 0.48 mmol) and the acetylene
14b (0.135 g, 0.60 mmol) in benzene (6 mL) was deoxygenated by
the freeze-thaw method (3 cycles) and then stirred at 50¡C for 48 h.
The mixture was stirred in air for 1 h and then concentrated and
loaded onto a silica gel column and eluted with a 1:1:1 mixture of
Et2O/CH2Cl2/hexane to give the naphthol 19 as foamy solid in 60%
yield (0.116 g, 0.29 mmol, Rf 0.36) along with the furan product 20
as a viscous oil in 10% yield (0.020 g, 0.05 mmol, Rf 0.52).
17b
1H NMR (CDCl3): d = 0.18 (s, 9 H), 1.38 (s, 3 H), 1.73Ð1.80 (m, 1
H), 1.81Ð1.84 (m, 1 H), 2.01 (d, 2 H, J = 6.1 Hz), 2.06Ð2.16 (m, 3 H),
2.32Ð2.42 (m, 2 H), 2.72Ð2.78 (m, 1 H), 2.80Ð2.90 (m, 3 H), 2.99Ð
3.05 (m, 1 H), 3.39Ð3.45 (m, 1 H), 4.42 (s, 2 H), 7.21Ð7.31 (m, 5 H).
19
1H NMR (CDCl3): d = 0.95Ð1.05 (m, 1 H), 1.05 (s, 3 H), 1.22Ð1.32
(m, 1 H), 1.70Ð1.80 (m, 3 H), 2.00Ð2.25 (m, 4 H), 2.82 (s, 3 H),
2.90Ð2.96 (m, 1 H), 3.78 (s, 3 H), 3.89 (s, 3 H), 3.96 (s, 3 H), 6.56
(s, 1 H), 6.81 (d, 1 H, J = 8.0 Hz), 7.30 (s, 1 H), 7.33 (t, 1 H, J =
8.0 Hz), 7.89 (d, 1 H, J = 8.0 Hz).
13C NMR (CDCl3): d = 0.34, 24.86, 25.11, 25.28, 25.46, 30.33,
30.45, 35.78, 36.44, 38.52, 63.49, 74.37, 86.60, 105.62, 119.76,
127.22, 127.43, 128.36, 139.88, 143.57.
IR (neat): n = 3407s, 2935s, 2829w, 1732s, 1706s, 1601s, 1464s,
1388s, 1378s, 1337m, 1292s, 1270s, 1211m, 1129s, 1075s, 1027m,
981m, 754m, 731m cmÐ1.
MS: m/z (% rel. intensity) = 402 (M+, 55), 370 (60), 338 (32), 310
(6), 244 (5), 218 (22), 217 (100), 216 (15), 203 (8), 189 (8), 175(5),
155 (6), 121 (24), 93 (11), 85 (10).
IR (neat): n = 2931 s, 2172 s, 1452 m, 1429 m, 1380 m, 1248 s, 1103
s, 843 s, 734 s cmÐ1.
MS: m/z (% rel intensity) = 430 (M+, 8), 319 (21), 261 (23), 213
(100), 171 (22), 91 (95), 73 (45), 65 (13).
Anal calcd for C24H34OS2Si: C,66.92; H, 7.96. Found: C, 65.91; H,
8.21.
HRMS: m/z calcd for C23H30O6 402.2042, found 402.2082.
20
1H NMR (CDCl3): d = 1.05Ð1.28 (m, 2 H), 1.07 (s, 3 H), 1.65Ð1.94
(m, 4 H), 2.05Ð2.22 (m, 3 H), 2.30Ð2.36 (m, 1 H), 3.09 (s, 3 H), 3.67
(s, 3 H), 3.91 (s, 3 H), 3.94 (s, 3 H), 6.71 (s, 1 H), 6.89 (d, 1 H, J =
7.8 Hz), 6.95 (t, 1 H, J = 7.7 Hz), 7.13 (t, 1 H, J = 7.6 Hz), 7.65 (d,
1 H, J = 7.7 Hz).
Methyl 4-Benzyloxy-4-methyl-2-(prop-2-ynyl)cyclohexanecar-
boxylate (18b)
Compound 17b (2.96 g, 6.89 mmol) was dissolved in MeCN
(75 mL) and treated with H2O (23 mL) and CF3CO2H (7.5 mL,
14.14 equiv). The mixture was stirred in the air at r.t. for 20 h. The
solvent was completely removed in vacuo. The residue was taken
up in pentane (60 mL) and Et2O (60 mL) and the solution was
washed with H2O (3 × 5 mL). The solvent and CF3CO2H were re-
moved in vacuo at 70¡C. The crude residue was cooled to 0¡C and
treated with THF (55 mL), EtOH (23 mL), NaOH (23.7 mL, 2 N,
6.9 equiv) and H2O2 (7.38 mL, 30%, 10.5 equiv). The mixture was
stirred at r.t. for several hours and with addition of extra 2 N NaOH
as necessary until the TLC indicated that all compounds had been
converted to the desired acid at Rf 0.10 (Et2O/CH2Cl2/hexane, 1:1:6).
The mixture was carefully neutralized with conc. HCl and the solvent
removed. Et2O (100 mL) was added and the aqueous layer was ex-
tracted twice more with Et2O. The combined organic layers were
dried (MgSO4) and filtered through Celite. After the solvent was re-
moved, the crude residue was treated with acetone (100 mL), MeI
(10 mL) and K2CO3 (11.84 g) and refluxed under N2 at 70¡C for 5 h.
The solvent was removed and Et2O (100 mL) was added. After filtra-
tion through Celite and washing the solid residue with several por-
tions of Et2O, the solvent was removed and the product purified by
chromatography on silica gel to give 1.292 g of 18b as a yellow oil
in 63% yield; Rf 0.36 (Et2O/CH2Cl2/hexane, 1:1:6).
IR (neat): n = 2937s, 2843Ð2825br m, 1733s, 1642m, 1498m,
1492m, 1434m, 1282m, 1263m, 1244s, 1191m, 1166s, 1137m,
1080s, 1027m, 752m cmÐ1.
MS: m/z (% rel. intensity) = 402 (M+, 68), 376 (5), 342 (6), 323 (7),
295 (5), 246 (7), 229 (11), 218 (10), 209 (57), 193 (30), 190 (47),
185 (100), 169 (12), 153 (57), 135 (28), 133 (36), 123 (69), 115
(19), 105 (16), 93 (55), 85 (90), 72 (66).
HRMS: m/z calcd for C23H30O6, found 402.2036.
The annulation reaction of 5 with 0.85 equivalent of acetylene 14b
was carried out in the same way as above. Workup and purification
of the reaction mixture provided 19 in 54% yield along with the fu-
ran 20 in 9% yield. The reactions of 5 and 14b in MeCN and hexane
were carried out according to the procedure described above. A
similar workup and purification procedure afforded a 53% yield of
the annulated product 19 in MeCN and a 34% yield of 19 in hexane.
The furan product 20 was also seen by 1H NMR in the crude reac-
tion mixture from MeCN, but it was not isolated.
Synthesis 1999, No. 3, 415–422 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Studies Toward the Synthesis of Menogaril
421
2-[(2-Methoxycarbonyl-5-methoxy-5-methyl)methylcylohex-1-
yl]-1,4,5-trimethoxynaphthalene (21)
6-Hydroxy-4,9-dimethoxy-9-methyl-7,8,9,10-tetrahydronaph-
thacen-5,12-dione (24)
A solution of compound 19 (1.362 g, 3.39 mmol) in acetone (70
mL) was refluxed with MeI (4.2 mL, 9.58 g, 67.4 mmol) and K2CO3
(4.69 g, 33.9 mmol). The product was purified by flash chromatog-
raphy on silica gel with a 1:1:2 mixture of Et2O/CH2Cl2/hexane to
give 21 in 98% yield as a viscous oil (1.382 g, 3.32 mmol, Rf 0.19).
1H NMR (CDCl3): d = 0.82Ð0.88 (m, 1 H), 0.98 (m, 3 H), 1.18Ð1.24
(m, 1 H), 1.70Ð1.76 (m, 2 H), 1.78Ð1.83 (m, 1 H), 1.88Ð1.93 (m, 1
H), 2.14Ð2.20 (m, 1 H), 2.32Ð2.41 (m, 1 H), 2.58Ð2.64 (m, 1 H),
2.70Ð2.76 (m 1 H), 2.93 (s, 3 H), 3.68 (s, 3 H), 3.79 (s, 3 H), 3.93
(s, 3 H), 3.96 (s, 3 H), 6.66 (s, 1 H), 6.82 (d, 1 H, J = 7.7 Hz), 7.37
(t, 1 H, J = 8.1 Hz), 7.63 (d, 1 H, J = 8.3 Hz).
To a solution of the naphthacenone 23 (42.7 mg, 0.11 mmol) in ac-
etone (6 mL) were added 2 N HNO3 (2.25 mL, 4.5 mmol) and AgO
(279 mg, 2.25 mmol). The resulting mixture was stirred at r.t. and
the reaction was monitored by TLC. After the starting material was
consumed, a buffer solution (pH = 7.0, 10 mL) and CH2Cl2 (30 mL)
were added. The organic phase was separated, washed with brine
and H2O, and dried (MgSO4). After removal of the solvents, the
crude quinone 24 was obtained as a orange foam.
1H NMR (CDCl3): d = 1.16 (s, 3 H), 1.20Ð1.32 (10), 3.13 (s, 3 H),
3.95 (s, 3 H), 7.27 (d, 1 H, J = 8.2 Hz), 7.60Ð7.67 (m, 2 H).
IR (neat): n = 2937s, 2826m, 1704s, 1663s, 1603m, 1586s, 1472s,
IR (neat): n = 2934s, 2840m, 1732s, 1600s, 1584s, 1463s, 1448s,
1435m, 1383s, 1269s, 1239s, 1191s, 1166s, 1150m, 1130s, 1075s,
1028m, 1008m, 840m, 756m, 736m cmÐ1.
MS: m/z (% rel. intensity) = 416 M+ (100), 402 (10), 370 (11), 338
(6), 309 (11), 277 (4), 231 (10), 217 (31), 203 (17), 185 (5), 165 (5),
153 (4), 121 (7), 93 (8), 85 (13).
1305m, 1275s, 1241m, 1074m, 729m cmÐ1.
The quinone 24 was dissolved in DMF (5 mL) and oxygen was
gently bubbled through the solution at 100¡C for 2 h. After the
DMF was removed by heating under vacuum, the orange solid was
purified by flash chromatography on silica gel with a 1:1:1 mixture
of Et2O/CH2Cl2/hexane to afford the product 25 in 93% (35.8 mg,
0.10 mmol) overall yield from 23. This reaction was conducted
many times and occasionally it gave rise to a mixture of the prod-
ucts 25 and 26. They could not be separated by chromatography.
The formation of the undesired product 26, however, could be
avoided if the second oxidation was performed without solvent. The
crude quinone 24 was coated on the inside of the flask which was
heated opened to air at 70¡C for 24 h. Flash chromatography of the
residue on silica gel provided the product 25 in a range of 85Ð92%
yield.
HRMS: m/z calcd for C24H32O6 416.2199, found 416.2232.
4,5,9,12-Tetramethoxy-9-methyl-6,7,8,9,10,11-hexahydronaph-
thacen-6-one (23)
The methyl ester 21 (74.6 mg, 0.18 mmol) was first hydrolyzed with
NaOH solution (4 mL, 2 N) in MeOH (4 mL) at 75¡C for 4 h. After
workup, the corresponding carboxylic acid 22 was obtained as oily
residue which was subsequently treated with NaOH solution (0.1 N,
1.8 mL, 0.18 mmol). The mixture was lyophilized to dryness under
reduced pressure and then dissolved in benzene (10 mL) and pyri-
dine (0.2 mL). The mixture was cooled to 0¡C before oxalyl chlo-
ride (0.20 mL, 0.291 g, 2.29 mmol) was introduced. There was an
immediate evolution of gases. The mixture was allowed to warm to
r.t. for about 15 min. until no further evolution of gases was ob-
served. SnCl4 (0.10 mL) was slowly added and the resulting mixture
was stirred at r.t. for 20 min before addition of H2O (6 mL) and a
1:1 mixture of Et2O and CH2Cl2 (30 mL). The organic phase was
separated, washed with brine and H2O, and dried (MgSO4). After
removal of the volatiles, elution of the residue on silica gel with a
1:1:1 mixture of Et2O/CH2Cl2/hexane gave the product 23 in 72%
overall yield (48.6 mg, 0.13 mmol, Rf 0.26) along with 1.5 mg of a
yellow compound (Rf 0.44) which was not identified. The reaction
was carried out on a gram scale without a change in the yield; mp
184Ð185 ¡C.
Spectral Data for 26 (extracted from a mixture of 25 and 26)
1H NMR (CDCl3): d = 1.28 (s, 3 H), 1.55Ð1.65 (m, 1 H), 2.00Ð2.08
(m, 1 H), 2.48Ð2.55 (m, 1 H), 2.70Ð3.01 (m, 3 H), 3.18 (s, 3 H), 4.00
(s, 3 H), 7.27 (d, 1 H, J = 7.7 Hz), 7.66 (t, 1 H, J = 7.9 Hz), 7.92 (d,
1 H, J = 8.1 Hz), 13.40 (s, 1 H), 13.77 (s, 1 H).
MS: m/z (% rel. intensity) = 368 (M+, 100), 352 (40), 336 (70), 296
(30), 280 (17).
25: mp 164Ð166¡C.
1H NMR (CDCl3): d = 1.30 (s, 3 H), 1.70Ð1.78 (m, 1 H), 2.07Ð2.13
(m, 1 H), 2.77Ð2.90 (m, 3 H), 2.98Ð3.04 (m, 1 H), 3.23 (s, 3 H), 4.06
(s, 3 H), 7.32 (d, 1 H, J = 8.5 Hz), 7.49 (s, 1 H), 7.70 (t, 1 H, J =
7.8 Hz), 7.93 (d, 1 H, J = 7.6 Hz), 13.32 (s, 1 H).
13C NMR (CDCl3): d = 20.85, 23.09, 30.89, 41.35, 49.17, 56.64,
72.00, 114.07, 117.95, 119.80, 120.06, 120.92, 129.69, 133.20,
135.47, 135.96, 143.88, 160.66, 160.74, 182.81, 188.83.
1H NMR (CDCl3): d = 1.18 (s, 3 H), 1.25Ð1.33 (m, 2 H), 1.65Ð1.74
(m, 1 H), 2.02Ð2.21 (m, 5 H), 2.49 (dd, 1 H, J = 16.5 Hz, 12 Hz),
3.15 (s, 3 H), 3.28 (dd, 1 H, J = 16.5 Hz, 3.9 Hz), 3.83 (s, 3 H), 3.90
(s, 3 H), 3.97 (s, 3 H), 6.83 (d, 1 H, J = 7.7 Hz), 7.46 (t, 1 H, J =
8.1 Hz), 7.62 (d, 1 H, J = 8.4 Hz).
IR (neat): n = 3345br w, 2968m, 2926s, 2849m, 1670m, 1625s,
1586s, 1445m, 1383m, 1298m, 1273s, 1251s, 1240s, 1105m, 739m
cmÐ1.
13C NMR (CDCl3): d = 21.34, 24.73, 31.15, 33.58, 33.84, 44.19,
48.56, 52.62, 56.41, 60.82, 63.24, 72.24, 72.42, 106.44, 114.25,
120.46, 123.51, 129.01, 130.52, 133.38, 147.97, 155.93, 158.67,
198.85.
MS: m/z (% rel. intensity) = 352 (M+, 20), 337 (15), 321 (30), 320
(100), 305 (58), 293 (12), 280 (14), 262 (9).
HRMS: m/z calcd for C21H20O5 352.1310, found 352.1302.
Anal calcd for C21H20O5: C, 71.58; H, 5.72. Found: C, 71.51; H,
6.01.
IR (neat): n = 2970s, 2920s, 2842m, 1681s, 1603m, 1557s, 1457m,
1432m, 1377m, 1362s, 1329s, 1273m, 1243m, 1069s, 1042m cmÐ1.
MS: m/z (% rel. intensity) = 384 (M+,1 00), 369 (40), 337 (5), 329
(9), 305 (7), 269 (7), 255 (6), 243 (11), 225 (5), 201 (5), 181 (5), 165 Acknowledgement
(8), 152 (6), 139 (5), 128 (5), 115 (7), 105 (5), 85 (34), 72 (15).
This work was supported by the National Institute of Health (CA
HRMS: m/z calcd for C23H28O5 384.1937, found 384.1958.
33589). The Department of Education provided a predoctoral fel-
lowship to J.S. The NMR instruments used were funded in part by
the NSF Chemical Instrumentation Program.
Anal calcd for C23H28O5: C, 71.85; H, 7.34. Found C, 71.74; H,
7.48.
Synthesis 1999, No. 3, 415–422 ISSN 0039-7881 © Thieme Stuttgart · New York

422
W. D. Wulff et al.
PAPER
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