Synthesis of the tetracyclic carbon core of menogaril utilizing the benzannulation reaction of a Fischer carbene complex and an alkyne

Article abstract of DOI:10.1021/jo981481w

The synthesis of the 2-bromoanthracyclinone 3 containing the tetracyclic core of menogaril is achieved with a strategy that is formulated around the benzannulation reaction of a Fischer carbone complex and an alkyne. This benzannulation requires a 2,5-dimethoxyphenyl carbene complex that bears an additional functional group at the 4-position that is the nascent 2-bromo substituent in 3. The evaluation of 4-bromo- and 4-trimethysilyl-substituted complexes with 1-pentyne revealed that the benzannulation was more efficient with the silyl complex. The synthesis of 3 is achieved with methoxy and acetoxy substituents at the C-9 position, which begins with the methoxy- and benzyloxy-substituted alkynes 14 and 30 that contain the A ring of the menogaril core. The closure of the last ring is accomplished by a Friedel- Crafts reaction on an in situ generated acid chloride. Adjustment of the oxidation states of the B and C rings failed according to procedures that had been developed in model studies. This was accomplished in an unexpected fashion with novel bromination reactions that occurred at a benzylic position with the C-9 methoxyl derivative and alpha to a ketone in the C-9 acetoxy derivative.

Full text of DOI:10.1021/jo981481w

8440
J . Org. Chem. 1998, 63, 8440-8447
Syn th esis of th e Tetr a cyclic Ca r bon Cor e of Men oga r il Utilizin g
th e Ben za n n u la tion Rea ction of a F isch er Ca r ben e Com p lex a n d
a n Alk yn e
J ing Su and William D. Wulff*
Department of Chemistry, Searle Chemistry Laboratory, The University of Chicago,
Chicago, Illinois 60637
Richard G. Ball
Merck Research Laboratories, Division of Merck and Company, Inc., Box 2000,
Rahway, New J ersey 07065-0900
Received J uly 27, 1998
The synthesis of the 2-bromoanthracyclinone 3 containing the tetracyclic core of menogaril is
achieved with a strategy that is formulated around the benzannulation reaction of a Fischer carbene
complex and an alkyne. This benzannulation requires a 2,5-dimethoxyphenyl carbene complex
that bears an additional functional group at the 4-position that is the nascent 2-bromo substituent
in 3. The evaluation of 4-bromo- and 4-trimethysilyl-substituted complexes with 1-pentyne revealed
that the benzannulation was more efficient with the silyl complex. The synthesis of 3 is achieved
with methoxy and acetoxy substituents at the C-9 position, which begins with the methoxy- and
benzyloxy-substituted alkynes 14 and 30 that contain the A ring of the menogaril core. The closure
of the last ring is accomplished by a Friedel-Crafts reaction on an in situ generated acid chloride.
Adjustment of the oxidation states of the B and C rings failed according to procedures that had
been developed in model studies. This was accomplished in an unexpected fashion with novel
bromination reactions that occurred at a benzylic position with the C-9 methoxyl derivative and
alpha to a ketone in the C-9 acetoxy derivative.
In tr od u ction
is supported by the finding that the combination of
cyclophosphamide, menogaril, and 5-fluorouracil is su-
perior to the first choice in breast cancer chemotherapy
of cyclophosphamide, adriamycin, and 5-fluorouracil as
measured by activity against human breast cancer xe-
nographs in mice.6
The anthracycline antitumor antibiotics are among the
most important clinical agents used in cancer chemo-
therapy.1 Menogaril is a semisynthetic derivative of the
natural product nogalamycin and has activity against
tumor systems that is substantially greater than nogala-
mycin.2 The activity of menogaril is somewhat superior
to that of adriamycin, the most widely used anthracy-
cline, and at the same time is much less cardiotoxic than
adriamycin. Recent studies have revealed that menogaril
has unique aspects as a member of the anthracycline
family. Menogaril has been shown to bind in the major
groove of DNA, whereas all other anthracyclines have
been found to bind in the minor groove.3 Menogaril has
been shown to poison topoisomerase II but not topo-
isomerase I, while its parent, nogalamycin, poisons
topoisomerase I but not II.4 Recently it has been reported
that menogaril is different from other anthracyclines in
that it is active after oral administration.5 Oral treat-
ment with menogaril is expected to be useful for outpa-
tient treatment of lymphoma and breast cancer, and this
The biological activity of menogaril has stimulated the
development of various strategies for the synthesis of
menogaril and analogues. There have been two total
syntheses of menogaril reported7 along with a number
of other synthetic studies.8 Our approach to the synthe-
sis of menogaril involves the bromoanthracyclinone 3 as
an advanced intermediate which contains the tetracyclic
core of menogaril. Introduction of the sugar unit is
planned by a Grignard addition, and introduction of the
C-9 methoxyl group will be accomplished as previously
described.7 In this paper, we report the utilization of the
benzannulation of the highly functionalized carbene
complex 4 with alkyne 5 as the key step in the synthesis
of 25 and 40, the methyl and acetoxy analogues of 3,
respectively (Scheme 1).
(6) Yoshida, M.; Fujioka, A.; Nakano, K.; Kobunai, T.; Saito, H.;
Toko, T.; Takeda, S.; Unemi, N. Anticancer Res. 1996, 16, 1155.
(7) (a) Kawasaki, M.; Matsuda, F.; Terashima, S. Tetrahedron 1988,
44, 5727. (b) Matsuda, F.; Kawasaki, M.; Ohsaki, M.; Yamada, K.;
Terashima, S. Tetrahedron 1988, 44, 5745. (c) Hauser, F. M.; Chakra-
pani, S.; Ellenberger, W. P. J . Org. Chem. 1991, 56, 5248.
(8) (a) Bates, M. A.; Sammes, P. G. J . Chem. Soc., Chem. Commun.
1983, 896. (b) J oyce, R. P.; Parvez, M.; Weinreb, S. M. Tetrahedron
Lett. 1986, 27, 4885. (c) Smith, T. H.; Wu.; H. Y. J . Org. Chem. 1987,
52, 3566. (d) DeShong, P.; Li, W.; Kennington, J . W., J r..; Ammon, H.
L. J . Org. Chem. 1991, 56, 1364. (e) Yin H.; Frank, R. W.; Chen, S.-L.;
Quigley, G. J .; Todaro, L., J . Org. Chem. 1992, 57, 644. (f) Semmelhack,
M. F.; J eong, N. Tetrahedron Lett. 1990, 31, 605. (g) Semmelhack, M.
R.; J eong, N.; Lee, G. R. Tetrahedron Lett. 1990, 31, 609.
(1) (a) Wiley, P. F. Anthracycline Antibiotics; El Khadem, H. S., Ed.;
Academic Press: New York, 1982. (b) Anthracycline Antibiotics; El
Khadem, H. S., Ed.; Academic Press: New York, 1982. (c) Anthracy-
cline Antibiotics; Priebe, W., Ed.; American Chemical Society: Wash-
ington, DC, 1995.
(2) (a) See page 97 in ref 1a. (b) Eckle, E.; Stezowski, J . J .; Wiley,
P. F. Tetrahedron Lett. 1980, 507.
(3) Chen, H.; Patel, D. J . J . Am. Chem. Soc. 1995, 117, 5901.
(4) Sim, S.-P.; Gatto, B.; Yu, C.; Liu, A. A.; Li, T.-K.; Pilch, D. S.;
LaVoie, E. J .; Liu, L. F., Biochemistry 1997, 36, 13285.
(5) (a) Ueda, Takanori,; Fukushima, T. Expert Opin. Invest. Drugs
1996, 5, 1639. (b) Yoshida, M.; Fujioka, A.; Nakano, K.; Yuasa, C.; Toko,
T.; Takeda, S.; Unemi, N. Anticancer Res. 1996, 16, 2875.
10.1021/jo981481w CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/29/1998

Tetracyclic Carbon Core of Menogaril
J . Org. Chem., Vol. 63, No. 23, 1998 8441
Sch em e 1
Sch em e 2
Syn th esis of Men oga r il Cor e 25
From the systematic studies by our group and others
it is known that the product distribution of the benzan-
nulation reaction depends on many factors.9-11 One of
these factors is the electronic nature of the substituents
on the arene ring of the carbene complex. Therefore, in
an initial consideration of options for the synthesis of 3
via a benzannulation reaction, a model study was per-
formed that evaluated the reaction of 1-pentyne with the
carbene complexes 4, 6, and 9, which contain a trimeth-
ylsilyl, hydrogen, or bromine substituent para to the
carbene carbon, respectively. Interestingly, it was found
that for carbene complex 6 (R ) H) the yield of the phenol
product increased as the polarity of the solvent increased.
The highest yield of 76% was obtained in acetonitrile,
and the yield dropped to 14% in hexane. Other products
were observed by TLC and NMR, but no attempt was
made to characterize them. The benzannulation reaction
has been extensively studied by several groups over the
last twenty years and, with only two known exceptions,9,11c
higher yields of phenol products are found in nonpolar
solvents such as hexane and benzene. At this time it is
not known why the presence of the 2,5-dimethoxy sub-
stituents in complex give rise to the third known example
of this effect.12 An increase in the yield of the phenol
product was also seen for the reaction of complex 4
bearing the para trimethylsilyl group upon going from
hexane to THF but not from THF to acetonitrile. In the
case of the reaction with carbene complex 9, the naphthol
product was oxidized to the quinone 10 due to the
difficulties in purifying the naphthol. The reaction of the
para-bromo complex 9 in THF gave a much lower yield
than the para-trimethylsilyl complex 4 (24 vs 46%). One
of the side products in the reaction of complex 9 was the
keto ester 11, which is indicative of furan formation
(Scheme 2).9-11 On the basis of the above results, it was
decided to pursue the synthesis of 3 with the para-
trimethylsilyl complex 4.
Sch em e 3
higher yield than did the model study with 1-pentyne.
In this reaction, acetonitrile was the superior solvent
giving the desired naphthol product 15 in 66% yield along
with two other products, which were not characterized.
The same reaction in THF gave the phenol 15 in only
46% yield. Since the unprotected naphthol was not
compatible with Friedel-Crafts reaction conditions,14 the
naphthol 15 was methylated with potassium hydroxide
and methyl iodide in DMSO at room temperature to give
16 in 94% isolated yield.15 Hydrolysis of compound 16
under the conditions in Scheme 3 gave a quantitative
conversion to the acid 17 in preparation for the Friedel-
Crafts reaction. However, due to the acid-sensitive TMS
and tertiary methyl ether groups, standard Friedel-
Crafts cyclization conditions were not successful. In
addition, acid 17 could not be directly converted to the
acid chloride in a clean fashion. The acid chloride was
generated by treatment of the acid with 1 equiv of NaOH
followed by addition of oxalyl chloride. A variety of Lewis
acids were screened for the Friedel-Crafts cyclization on
this in situ generated acid chloride (FeCl3,TiCl4, ZnCl2,
It was satisfying to find that the benzannulation of the
para-trimethylsilyl complex 4 with alkyne 1413 gave a
(9) Wulff, W. D.; Bax, B. M.; Brandvold, T. A.; Chan, K. S.; Gilbert,
A. M.; Hsung, R. P.; Mitchell, J . M.; Clardy, J . Organometallics 1994,
13, 102.
(10) Bos, M. E.; Wulff, W. D.; Miller, R. A.; Chamberlin, S.;
Brandvold, T. A. J . Am. Chem. Soc, 1991, 113, 9293.
(11) (a) Do¨tz, K. H.; Pruskil, I.; Mu¨hlemeier, J . Chem. Ber. 1982,
115, 1278. (b) Do¨tz, K. H.; Kuhn, W. Angew. Chem., Int. Ed. Engl. 1983,
22, 732. (c) Do¨tz, K. H. J . Organomet. Chem. 1977, 140, 177.
(12) The benzannulation of the 2,5-dimethoxy complex 6 has been
previously reported, but only in THF solvent.10
(14) Parker, K. A.; Tallman, E. A. Tetrahedron 1984, 40, 4781.
(15) J ohnstone, R. A. W.; Rose, M. E. Tetrahedron 1979, 35, 2169.
(13) Wulff, W. D.; Su, J .; Xu, Y.; Tang, P. C. Synthesis, submitted.

8442 J . Org. Chem., Vol. 63, No. 23, 1998
Su et al.
Sch em e 4
Sch em e 5
density on this ring, which results from the presence of
two methoxyl and one trimethylsilyl group. If this is
correct, then it may be possible to direct the oxidation of
18 by decreasing the electron density of the D ring by
exchanging the trimethylsilyl group for a bromide. This
exchange reaction was already designed into the ret-
rosynthetic plan to provide a functional handle for the
installation of the amino sugar subunit at a later step,
and therefore, this change in the synthesis would not
increase the number of synthetic steps. The reaction of
bromine with compound 18 in CH2Cl2 at -78 °C gave
the desired product 24 in 66% yield (Scheme 5).22 The
oxidation of 24 with AgO/HNO3 indeed only took place
at the C ring. Subsequent air oxidation of this quinone
gave the desired product 25 along with the inseparable
overoxidation product 26 (35% yield, 1:1). In the syn-
thesis of a similar model compound this overoxidation
could be avoided by performing the air oxidation without
solvent,13 but unfortunately it was not possible to mini-
mize the side product 26 by this procedure.
(CF3CO)2O, HgCl2, AlCl3, TMSOTf), but unfortunately all
of the yields were in the range 20-40%. Milder reagents
such as polyphosphorus ester (PPE) afforded only 10%
of the desired product 18.16 All of the side products that
were isolated had lost the tertiary methyl ether, and this
is believed to be due to elimination under the reaction
conditions. It was finally found that the cyclization
product 18 could be obtained in 65-70% yield by using
SnCl4 on the in situ generated acid chloride if a non-
aqueous workup was employed.
Finishing the synthesis of the tetracyclic core of
menogaril 25 from the intermediate 18 required an
adjustment of the oxidation states of the B and C rings.
This was initially attempted by a two-step approach that
had been successful in model studies.13 The first step
involved the oxidation of the C ring with silver oxide in
nitric acid.17 This gave a 58% yield of a compound that
was expected to be the quinone 19. This product was
originally assigned the structure 19; however, it was
surprising to find that the second oxidation of the B ring
was quite difficult. This oxidative aromatization by
molecular oxygen18 gave more than five products, and the
desired product was obtained in only 10% yield. Other
Despite the fact that the oxidation of 24 occurred at
the C ring, the overall conversion of 18 to 25 (11%) was
not synthetically viable. This problem was solved by the
following discovery. It was found that the reaction of 2
equiv of bromine with compound 18 in a nonpolar solvent
such as pentane at 0 °C gave the benzylic bromination
product 27 in 51% yield, while the same reaction of 18
with bromine in polar solvent such as CH2Cl2 or HOAc
at 0 °C gave the dibromo product 28 in 60-70% yield
(Scheme 6). This dibromo compound 28 could be gener-
ated from 18 by either of the two methods outlined in
Scheme 6 in which each bromine was introduced in a
single step and in either order. The best method for the
synthesis of compound 28 involved the two-step protocol.
20
oxidizing agents such as DDQ19 or SeO2 failed to
improve the yield. This failure was surprising given the
ease with which the B ring in the model compound 22
could be oxidized.13 Furthermore, dehydrogenation with
Pd-C was attempted under many different conditions,
but in each case only the starting material was recov-
ered.19,21 All of these results taken together led to the
suspicion that the structural assignment for the oxidation
product of 18 may not have been made correctly. A single
crystal of this compound was grown in pentane, and an
X-ray diffraction study gave an unexpected but perhaps
not surprising result: the oxidation of 18 occurred at the
D ring instead of the C ring to give the quinone 20
(Scheme 4).
The reaction of bromine with compound 18 in pentane
at 0 °C provided 27, which, without purification, was
treated immediately with bromine in CH2Cl2 at -78 °C
to provide the product 28 in overall 70% yield. Oxidation
of compound 28 with AgO in HNO3 gave the quinone 29,
which could not be isolated and subsequently eliminated
HBr to afforded the final product 25 in 69% yield from
28. Apparently, the elimination is driven by the ther-
modynamic favorability of the aromatic B ring, which is
apparently greater than that for 28. No overoxidation
product was observed for this reaction. The discovery of
the benzylic bromination obviates the final aromatization
step in 24, which requires more forcing reaction condi-
tions and therefore provides a more efficient synthesis
of the target tetracycle 25.
The selective oxidation of intermediate 18 at the D ring
presumably occurred as a result of the high electron
(16) Kanaka, Y.; Yonemitsu, O.; Tanizawa, K.; Ban, Y. Chem.
Pharm. Bull. 1965, 13, 1065.
(17) Snyder, C. D.; Rapoport, H. J . Am. Chem. Soc. 1972, 94, 277.
(18) Hauser, F. M.; Mal. D. J . Am. Chem. Soc. 1983, 105, 5688.
(19) (a) Fu, P. P.; Harvey, R. G. Chem. Rev. 1978, 78, 317. (b) Fu,
P. P.; Lee, H. M.; Harvey, R. G. Tetrahedron Lett. 1978, 551.
(20) Yadav, J .; Corey, P.; Hsu, C.; Perlman, K.; Sih, C. J . Tetrahe-
dron Lett. 1981, 811.
(21) (a) Mosettig, E.; Duvall, H. M. J . Am. Chem. Soc. 1937, 59, 387.
(b) Newman, M. S.; Blum, J . J . Am. Chem. Soc. 1964, 86, 503.
(22) Chan, T. H.; Fleming, I. Synthesis 1979, 761.

Tetracyclic Carbon Core of Menogaril
J . Org. Chem., Vol. 63, No. 23, 1998 8443
Sch em e 6
Sch em e 8
occasions. The diol 35 could be oxidized to 36 by the
Dess-Martin reaction, and by so doing the tertiary
alcohol 36 could be prepared in 76% yield. The use of
hydrogen transfer hydrogenations (such as ammonium
formate)23 did not improve the total yield from 34. The
diol 35 was always observed when 34 was treated with
ammonium formate (15-32 equiv) on Pd/C in MeOH at
90 °C for 1-2 h. It was surprising to encounter difficulty
in the acylation of the alcohol 36 with DMAP/pyridine
or (iPr)2NEt/Ac2O.24 When a catalytic amount of DMAP
was used, only the starting material was recovered after
chromatography. Even with a large excess of DMAP (4
equiv), this reaction could not be driven to completion:
the acetate 37 was isolated in 54% yield and 46% of 36
was recovered. However, when this starting material
was recycled, efficient throughput to the acetate 37 could
be achieved (Scheme 8).
Sch em e 7
Syn th esis of Men oga r il P r ecu r sor 40
Completion of the synthesis of the target tetracycle 40
from intermediate 37 requires only the oxidation of the
B ring and the substitution of silicon with bromine.
Given the success in effecting both steps via bromination
in the synthesis of 25 from 18, this was the first and only
approach we investigated for 37. In principle, this
dibromination could be carried out on either the alcohol
36 or the acetate 37. However, attempts to dibrominate
the alcohol 36 ended with the formation of a complex
mixture of products. Hence, the focus of the dibromina-
tion became the acetate 37. Given the experience gained
in the bromination of 18, it was expected that the
treatment of 37 with bromine in pentane at 0 °C and then
with bromine in methylene chloride at -78 °C should
provide the dibromide 41. However, the crude reaction
mixture was found to contain a mixture of compounds
none of which were the desired product 41 nor the
starting material. Nonetheless, when this mixture was
subjected to oxidation with AgO/HNO3, the target tetra-
cyclic compound 40 was isolated in 48% overall yield from
37 (Scheme 9). The mixture of isomers obtained from
the bromination of 37 in CH2Cl2 is tentatively assigned
as 39 where bromination of the ketone function in 37
occurred. Since the bromine in 39 can be eliminated to
form the aromatic B ring, this bromination of the ketone,
like the benzylic bromination of 18 (Scheme 6), serves to
avoid the difficult aromatization step that was encoun-
tered in the synthesis of 24 by oxidative methods (Scheme
5).
The reaction of carbene complex 4 and alkyne 3013 in
acetonitrile, like the same reaction with alkyne 14, gave
the desired benzannulation product in good yields. Over
a number of runs the yields of naphthol 31 varied from
59 to 68%. Two byproducts were isolated, and their
spectroscopic data showed that they were likely alkyne
oligomers. The naphthol 31 was protected as the methyl
ether by using the same method as developed for naph-
thol 15. Hydrolysis of ester 32 took much longer than
for the analogous ester 16. After 32 was refluxed in
NaOH and MeOH at 80 °C for 36 h and neutralized with
concentrated HCl, the corresponding acid was obtained
in near quantitative yield. The Friedel-Crafts cycliza-
tion reaction proceeded very smoothly utilizing the condi-
tions optimized for 17 and provided the tetracyclic
intermediate 34 in 86% yield (Scheme 7). Whereas
methoxyl elimination products were observed as side
products in the Friedel-Crafts reaction of 17, products
resulting from the elimination of the benzyloxy group
were not detected in the reaction of 33.
The benzyl protecting group was removed prior to the
oxidation of the B ring since it was found that if these
steps were reversed, the benzyl group could not be
removed without substantial decompositon of the starting
material. Thus, compound 34 was treated with Pd-C
under H2, which was found to give the desired alcohol
36. If the mixture was stirred too long (12 h), a
significant amount of the reduced product 38 was isolated
(64%). Shortening the reaction time to 1 h eliminated
38; however, even with a 1 h reaction time, the desired
product 36 was accompanied by the diol 35 on some
(23) Bieg, T.; Szeja, W. Synthesis 1985, 76.
(24) Hauser, F. M.; Prasanna, S. Tetrahedron 1984, 40, 4711.

8444 J . Org. Chem., Vol. 63, No. 23, 1998
Su et al.
cannula to a solution of Cr(CO)6 (4.66 g, 21.18 mmol, 1 equiv)
in 100 mL of THF at room temperature and stirred for 1.5 h.
The solvent was removed, and 100 mL of dichloromethane was
added at 0 °C. Methyl triflate (2.64 mL, 23.30 mmol, 1.1 equiv)
was added, and the solution was stirred for 10 min. The
reaction was quenched with H2O and extracted with dichlo-
romethane. The organic layer was washed with brine. After
removal of the solvent, the residue was chromatographed with
a 1:1:30 mixture of ether/dichloromethane/hexane as eluent
to give 7.15 g (76%) of 4 as a red solid. Spectral data for 4:
1H NMR (CDCl3) δ 0.30 (s, 9 H), 3.77 (s, 3 H), 3.79 (s, 3 H),
4.20 (br s, 3 H), 6.26 (s, 1 H), 6.86 (s, 1 H); 13C NMR (CDCl3)
δ -0.31, 56.42, 66.16, 104.15, 118.18, 130.27, 142.30, 158.99,
216.82, 225.81, 354.58; IR (neat) 1930 vs cm-1; mass spectrum
m/z (% rel intensity) 444 M+ (6), 416 (7), 388 (15), 360 (6), 332
(66), 304 (100). Anal. Calcd for C18H20CrO8Si: C, 48.65; H,
4.54. Found: C, 48.33; H, 4.57. Red solid, mp 75-76 °C (dec).
Rf ) 0.27 (ether/dichloromethane/hexane ) 1:1:30).
Sch em e 9
Su m m a r y
A synthesis of the 2-bromoanthracyclinone 40 was
achieved in 10 steps and 8% overall yield from 2,5-
dibromo-1,4-dimethoxybenzene. The key steps are the
benzannulation of the 2,4-dimethoxy-4-p-(trimethylsilyl)-
phenyl carbene complex 4 with alkyne 30, the subsequent
Friedel-Crafts cyclization to give the tetracyclic inter-
mediate 34, and a novel bromination that provides the
proper final oxidation state of the B ring of the anthra-
cyclinone core. The results of this study demonstrate
that the benzannulation reaction of Fischer carbene
complexes can provide an attractive strategy for the
synthesis of menogaril.
P r ep a r a tion of 2-(Meth yl 4-m eth oxy-4-m eth yl-2-m e-
th ylen e-1-cycloh exa n e ca r boxyla te)-1-h yd r oxy-4,5,8-tr i-
m eth oxy-7-(tr im eth ylsilyl)n a p h th a len e (15). A mixture
of carbene complex 4 (0.8678 g, 1.95 mmol) and alkyne 1413
(0.4816 g, 2.15 mmol, 1.1 equiv) was diluted with 3.90 mL of
CH3CN to give a 0.5 M solution in carbene complex. This
solution was added to a single-necked flask in which the
ground glass joint had been replaced with a threaded high-
vacuum Teflon stopcock and deoxygenated by the freeze-thaw
method (3 cycles, -196-25 °C). The flask was sealed under
1 atm of argon at 25 °C and heated to 45 °C for 36 h. The
reaction mixture was strirred open to the air for 30 min.
Solvent was removed, and chromatography on silica gel with
ethyl acetate/petroleum ether (1:5) gave 0.65 g of 15 as a yellow
viscous oil in 66% yield. Spectral data for 15: 1H NMR (CDCl3)
δ 0.41 (s, 9 H), 1.03 (s, 3 H), 1.20-1.23 (m, 1 H), 1.70-1.73
(m, 1 H), 1.82-1.89 (m, 4 H), 2.15-2.19 (m, 1 H), 2.36-2.39
(m, 1 H), 2.65 (dd, 1 H, J ) 9.6, 13.3 Hz), 2.72 (dd, 1 H, J )
5.5, 13.3 Hz), 2.98 (s, 3 H), 3.65 (s, 3 H), 3.77 (s, 3 H), 3.88 (s,
Exp er im en ta l Section
Unless otherwise stated, all chemicals were obtained from
commercial suppliers and were used without further purifica-
tion. Tetrahydrofuran, benzene, and diethyl ether were
distilled from sodium benzophenone ketyl immediately prior
to use. Methylene chloride, diisopropylamine, and HMPA
were distilled from calcium hydride. Some of the high-
resolution mass spectra were obtained at the Midwest Center
for Mass Spectrometry in Lincoln, NE. Elemental analysis
were done by Galbraith Laboratories in Knoxville, TN.
Syn th esis of 1-Br om o-2,5-d im eth oxy-4-(tr im eth ylsilyl)-
ben zen e 13. A solution of 1,4-dibromo-2,5-benzene (7.15 g,
24.15 mmol) in 150 mL of THF was cooled to -78 °C under a
nitrogen atmosphere. This solution was treated with nBuLi
(15.9 mL, 1.6 M, 1.1 equiv) and stirred for 1 h. Freshly
distilled trimethylsilyl chloride (6.13 mL, 48.30 mmol, 2 equiv)
in 30 mL of THF was added, and the mixture was stirred at
-78 °C for 50 min. The cold bath was removed and the
solution was stirred for additional 20 min before 5 mL of H2O
was added. The solvent was removed, and the residue was
washed with brine and extracted three times with ether. The
organic layer was dried over MgSO4 and filtered through
Celite. Removal of solvent gave the desired product 13 (6.77
g, 97%), which appeared to be a single compound by 1H NMR.
However, further purification by chromatography on silica gel
with a 1:1:60 mixture of ether/dichloromethane/hexane as
eluent gave 4.50 g of pure 13 in 64% yield, a 5% yield of 1,4-
bis(trimethylsilyl)-2,5-dimethoxybenzene, and a 10% yield of
1-(trimethylsilyl)-2,5-dimethoxybenzene. Spectral data for
13: 1H NMR (CDCl3) δ 0.28 (s, 9 H), 3.76 (s, 3 H), 3.86 (s, 3
H), 6.90 (s, 1 H), 6.99 (s, 1 H); 13C NMR (CDCl3) δ -0.40, 56.60,
57.84, 114.15, 115.96, 119.60, 129.07, 150.78, 159.47; mass
spectrum m/z (% rel intensity) 290 M+ (81Br), (66), 245 (100).
Anal. Calcd for C11H17O2SiBr: C, 45.68; H, 5.92. Found: C,
45.55; H, 5.70. White solid, mp 48-49 °C. Rf ) 0.15 (ether/
dichloromethane/hexane ) 1:1:60).
3 H), 3.93 (s, 3 H), 6.71 (s, 1 H), 6.76 (s, 1 H), 9.50 (s, 1 H); 13
C
NMR (CDCl3) δ 0.87, 25.13, 25.66, 32.34, 35.02, 35.17, 37.12,
42.35, 49.15, 51.67, 57.74, 58.92, 65.52, 74.00, 111.22, 114.75,
119.59, 120.41, 122.86, 127.82, 145.35, 149.64, 153.94, 155.82,
176.01; IR (CH2Cl2) 1730 s cm-1; mass spectrum m/z (% rel
intensity) 505 (M + 1)+ (100); m/z calcd for C27H40O7Si
504.2544, measured 504.2543. Anal. Calcd for C27H40O7Si:
C, 64.26; H, 7.99. Found: C, 64.00; H, 8.08. Rf ) 0.13 (ethyl
acetate/petroleum ether ) 1:5).
P r ep a r a tion of 2-(Meth yl 4-m eth oxy-4-m eth yl-2-m e-
th ylen e-1-cycloh exan ecar boxylate)-1,4,5,8-tetr am eth oxy-
7-(tr im eth ylsilyl)n a p h th a len e (16). Powdered KOH (0.347
g, 6.196 mmol, 4 equiv) was dissolved in DMSO (3 mL) along
with compound 15 (0.78 g, 1.548 mmol) and MeI (2.3 mL, large
excess). After stirring for 5 h at room temperature, ether was
added and the resulting solution was washed four times with
water. The aqueous layer was extracted four times with CH2-
Cl2. The organic layer was combined, and the solvents were
removed. Elution with ether through a short silica gel column
gave 0.75 g of 16 as a yellow viscous oil in 94% yield. Spectral
data for 16: 1H NMR (CDCl3) δ 0.37 (s, 9 H), 0.99 (s, 3 H),
1.20-1.25 (m, 1 H), 1.74-1.90 (m, 5 H), 2.16 (td, 1 H, J )
11.0, 2.5 Hz), 2.30-2.45 (br m, 1 H), 2.68-2.97 (m, 2 H), 2.97
(s, 3 H), 3.64 (s, 3 H), 3.69 (s, 3 H), 3.70 (s, 3 H), 3.92 (s, 3 H),
3.93 (s, 3 H), 6.72 (s, 1 H), 6.82 (s, 1 H); 13C NMR (CDCl3) δ
0.58, 25.40, 26.22, 34.77, 35.85, 36.21, 39.53, 49.11, 50.12,
52.18, 57.97, 58.10, 62.60, 63.67, 73.01, 110.87, 112.60, 121.37,
123.99, 129.91, 130.26, 147.40, 153.50, 153.68, 155.71, 177.22;
IR (CH2Cl2) 1731 s cm-1; mass spectrum m/z (% rel intensity)
518 M+ (100). Anal. Calcd for C28H42O7Si: C, 64.83; H, 8.16.
Found: C, 64.74; H, 8.28. Rf ) 0.13 (ethyl acetate/petroleum
ether ) 1:5).
Syn th esis of (Meth oxy(2,5-d im eth oxy-4-(tr im eth ylsi-
lyl))ph en ylm eth ylen e)pen tacar bon ylch r om iu m (0) (4). The
aryl bromide 13 (6.12 g, 21.18 mmol) was dissolved in 100 mL
of THF and cooled to -78 °C. A solution of nBuLi (13.90 mL,
1.6 M, 22.24 mmol, 1.05 equiv) was added, and the mixture
was stirred for 40 min. The solution was transferred via
P r ep a r a tion of 2-(4-Meth oxy-4-m eth yl-2-m eth ylen e-1-
cycloh exa n eca r boxylic a cid )-1,4,5,8-tetr a m eth oxy-7-(tr i-
m eth ylsilyl)n a p h th a len e (17). A sample of compound 16
(100 mg, 0.193 mmol) was dissolved in 8 mL of MeOH and
treated with 4 mL of 2 N aqueous NaOH, and the resulting
solution was refluxed at 80 °C for 4 h. The solution was cooled

Tetracyclic Carbon Core of Menogaril
J . Org. Chem., Vol. 63, No. 23, 1998 8445
to room temperature and neutralized with concentrated HCl.
The volatiles were removed, and the residue was extracted
with ether. The extract was stripped of solvent, and the
residue was loaded onto a short silica gel column; elution with
ether gave the desired product 17 (96 mg) as a yellow foamy
solid in quantitative yield. Spectral data for 17: 1H NMR
(CDCl3) δ 0.38 (s, 9 H), 1.01 (s, 3 H), 1.20-1.30 (m, 1 H), 1.82-
1.92 (m, 5 H), 2.18-2.22 (m, 1 H), 2.32-2.41 (m, 1 H), 2.73-
2.75 (m, 1 H), 2.83-2.86 (m, 1 H), 2.97 (s, 3 H), 3.64 (s, 3 H),
3.68 (s, 3 H), 3.91 (s, 3 H), 3.92 (s, 3 H), 6.72 (s, 1 H), 6.80 (s,
1 H); 13C NMR (CDCl3) δ 0.58, 25.37, 26.27, 34.66, 35.62, 36.16,
39.23, 49.10, 49.91, 57.99, 58.13, 62.57, 63.72, 73.10, 110.94,
112.72, 121.34, 124.03, 129.96, 130.16, 147.46, 153.48, 153.70,
atmosphere. Two equivalents of bromine (0.2879 M in CH2-
Cl2, 0.59 mL) was added dropwise. The mixture was stirred
at this temperature for 2.5 h and then filtered through a layer
of Celite and of triethylamine-treated silica gel in a sintered
glass funnel. The contents of the funnel was washed several
times with ether. After removal of the solvent, the residue
was chromatographed on silica gel with EtOAc/petroleum
ether (1:5) to give 28.1 mg of the desired product 24 in 66%
yield as a yellow solid. The other fractions collected indicated
that an equal amount of the dibromide 28 and the starting
material 18 were present (∼20% each). Spectral data for 24:
mp 107 °C (dec); Rf ) 0.09 (ethyl acetate/petroleum ether )
1:5); 1H NMR (CDCl3) δ 1.20 (s, 3 H), 1.28-1.33 (m, 2 H), 1.69-
1.72 (m, 1 H), 2.05-2.18 (m, 5 H), 2.51 (dd, 1 H, J ) 11.9,
17.1 Hz), 3.17 (s, 3 H), 3.37 (dd, 1 H, J ) 4.1, 17.2 Hz), 3.76 (s,
155.76, 183.20; IR (CH2Cl2) 3300-3200 br m, 1730 s cm-1
;
mass spectrum m/z (% rel intensity) 504 M+ (100).
P r ep a r a tion of 1,4,5,9,12-P en ta m eth oxy-9-m eth yl-2-
(tr im eth ylsilyl)-6a ,7,8,10,10a ,11-h exa h yd r on a p h th a cen -
6-on e (18). The acid 17 (74 mg, 0.1468 mmol) was treated
with 1 equiv (0.1468 mmol) of NaOH (1.48 mL of a 0.09925 N
aqueous solution), and the resultant sodium salt was dried
under high vacuum for 12 h. The salt was dissolved in 15 mL
of freshly distilled benzene, and 0.25 mL of pyridine was added
at 0 °C followed by addition of 0.16 mL of freshly distilled
oxalyl chloride (12.6 equiv). Gas evolution subsided after 10
min before 34.4 µL of SnCl4 (2 equiv) was added. The ice bath
was removed, and the solution was stirred for 15 min. The
mixture was quickly put onto a Et3N-pretreated short column
and washed with ether. A yellow solution was obtained. The
solvent was removed, and chromatography (ethyl acetate/
petroleum ether ) 1:5) gave the desired product 18 (48.0 mg)
in 67% yield: 1H NMR (CDCl3) δ 0.37 (s, 9 H), 1.18 (s, 3 H),
1.22-1.29 (m, 2 H), 1.67-1.71 (m, 1 H), 2.02-2.20 (m, 5 H),
2.48 (dd, 1 H, J ) 12.2, 17.4 Hz), 3.16 (s, 3 H), 3.36 (dd, 1 H,
J ) 3.9, 17.4 Hz), 3.683(s, 3 H), 3.685 (s, 3 H), 3.89 (s, 3 H),
3.95 (s, 3 H), 6.82 (s, 1 H); 13C NMR (CDCl3) δ 0.44, 21.88,
25.45, 31.68, 34.25, 34.45, 44.95, 49.27, 53.06, 57.97, 61.99,
63.81, 64.11, 73.14, 112.82, 124.02, 124.82, 125.99, 132.21,
133.02, 147.84, 154.64, 155.16, 156.03, 199.82; IR (CH2Cl2)
1638 s cm-1; mass spectrum m/z (% rel intensity) 486 M+ (100).
Anal. Calcd for C27H38O6Si: C, 66.63; H, 7.87. Found: C,
66.46; H, 7.95. Yellow solid, mp 170-171 °C. Rf ) 0.10 (ethyl
acetate/petroleum ether ) 1:5).
Sp ect r a l Da t a of 5,9,12-Tr im et h oxy-9-m et h yl-2-(t r i-
methylsilyl)-6a,7,8,10,10a,11-hexahydronaphthacene-1,4,6-trione
(20). To a solution of 80 mg (0.165 mmol) of compound 18 in
21 mL of acetone was added 408 mg (20 equiv) of silver oxide
and 9.86 mL of 0.5 N aqueous HCl (30 equiv), and the resultant
mixture was stirred for 4 h at room temperature. The acetone
and water were removed by evaporation, and the residue was
extracted into ether and dried over MgSO4. The 1H NMR
spectrum of the crude reaction mixture revealed that 20 was
the major product and also the presence of a minor product,
which was tentatively identified as 19 (20:19 ) 5:1). After
removal of solvent, the residue was loaded onto a silica gel
column, and elution with ethyl acetate/hexanes (1:5) gave a
58% yield of 20 as red-brown crystals. Spectral data for 20:
Rf ) 0.09 (ethyl acetate/petroleum ether ) 1:5); 1H NMR
(CDCl3) δ 0.33 (s, 9 H), 1.18 (s, 3 H), 1.22-1.29 (m, 2 H), 1.67-
1.70 (m, 1 H), 1.94-1.98 (m, 1 H), 2.03-2.08 (m, 2 H), 2.10-
2.25 (m 2 H), 2.44 (dd, 1 H, J ) 11.3, 17.2 Hz), 3.14 (s, 3 H),
3.23 (dd, 1 H, J ) 4.1, 17.2 Hz), 3.81 (s, 3 H), 3.92 (s, 3 H),
6.89 (s, 1 H); 13C NMR (CDCl3) δ -1.64, 20.59, 24.61, 31.37,
33.15, 44.17, 48.56, 51.53, 61.65, 63.42, 72.19, 125.80, 126.22,
133.10, 146.21, 146.83, 153.31, 153.91, 156.20, 182.90, 188.00,
197.75; IR (neat) 1700 vs, 1657 vs cm-1. The structure of 20
was confirmed by X-ray diffraction. Lists of the atomic
coordinates, thermal parameters, bond distances, and bond
angles have been deposited with the Cambridge Crystal-
lographic Database, Cambridge, England.
3 H), 3.81 (s, 3 H), 3.87 (s, 3 H), 3.95 (s, 3 H), 6.94 (s, 1 H); 13
C
NMR (CDCl3) δ 21.18, 24.68, 31.01, 33.44, 33.75, 44.14, 48.51,
52.39, 56.91, 61.54, 61.59, 63.46, 72.36, 110.81, 118.38, 121.58,
124.37, 127.43, 133.50, 145.34, 147.11, 155.00, 155.66, 198.66;
IR (CH2Cl2) 1688 s cm-1; mass spectrum m/z (% rel intensity)
494 M+ (81Br) (100).
If the reaction is carried out in pentane at 0 °C with 2 equiv
of bromine for 1 h, the major product of the reaction was the
benzyl bromide 27 (51%), which was formed along with a small
amount of the dibromide 28. Spectral data for 27: yellow
viscous oil; Rf ) 0.25 (EtOAc/petroleum ether ) 1:5); 1H NMR
(CDCl3) δ 0.40 (s, 9 H), 1.25 (s, 3 H), 1.67 (t, 1 H, J ) 12.0
Hz), 1.80 (dt, 1 H, J ) 3.5, 13.7 Hz), 1.85-1.92 (m, 1 H), 2.01-
2.07 (m, 1 H), 2.13-2.22 (m, 2 H), 2.33-2.37 (m, 1 H), 2.59
(dd, 1 H, J ) 11.5, 16.5 Hz), 3.18 (s, 3 H), 3.20-3.22 (m, 1 H),
3.69 (s, 3 H), 3.70 (s, 3 H), 3.90 (s, 3 H), 3.97 (s, 3 H), 6.82 (s,
1 H); 13C NMR (CDCl3) δ 0.32, 24.83, 29.20, 31.14, 31.55, 37.30,
40.43, 49.17, 57.88, 61.74, 63.44, 63.68, 72.90, 75.45, 112.95,
122.46, 123.84, 126.05, 130.30, 133.48, 147.73, 154.57, 155.10,
158.14, 191.10; IR (CH2Cl2)1690 s cm-1; mass spectrum m/z
(% rel intensity) 566 M+ (81Br) (20), 486 (100).
P r ep a r a tion of 2,11-Dibr om o-1,4,5,9,12-p en ta m eth oxy-
9-m eth yl-6a,7,8,10,10a-pen tah ydr on aph th acen -6-on e (28).
A mixture of 12.2 mg of compound 18 (0.02510 mmol), 50 mg
of solid K2CO3, and 8 mL of pentane was cooled to 0 °C under
N2. Two equivalents of bromine (0.174 mL of a 0.2879 M
solution in CH2Cl2, 0.050 mmol) was added dropwise, followed
by addition of 0.3 mL of CH2Cl2. The mixture was stirred for
1 h and quickly filtered through a layer of Celite and of
triethylamine-treated silica gel in a sintered glass funnel. The
contents of the funnel was washed several times with ether.
All washes were combined, and the solvent was removed in
vacuo. The residue was taken up in 10 mL of CH2Cl2, and
the resulting solution was cooled to -78 °C under N2. Bromine
(0.096 mL, 0.2879 M in CH2Cl2, 0.02764 mmol, 1.1 equiv) was
added dropwise. The solution was stirred for 30 min and again
filtered through a Et3N-pretreated silica gel/Celite funnel.
After removal of the solvent, the residue was chromatographed
on silica gel with EtOAc/petroleum ether (1:5) to give 10.1 mg
of desired product 28 in 70% yield as a yellow oil. Dibromide
28 can be obtained from 27 in quantitative yield by bromina-
tion in CH2Cl2 at -78 °C and in 60-70% yield by the
bromination of 24 in pentane at 0 °C. Spectral data for 28:
1
Rf ) 0.16 (EtOAc/petroleum ether ) 1:5); H NMR (CDCl3) δ
1.25 (s, 3 H), 1.68 (t, 1 H, J ) 11.9 Hz), 1.80 (td, 1 H, J ) 13.8,
3.3 Hz), 1.84-1.91 (m, 1 H), 2.02-2.05 (m, 1 H), 2.14-2.20
(m, 2 H), 2.32-2.36 (m, 1 H), 2.64 (dd, 1 H, J ) 11.5, 17.7
Hz), 3.18 (s, 3 H), 3.21 (d, 1 H, J ) 4.6 Hz), 3.77 (s, 3 H), 3.81
(s, 3 H), 3.88 (s, 3 H), 3.96 (s, 3 H), 6.96 (s, 1 H); 13C NMR
(CDCl3) δ 24.21, 28.70, 30.50, 30.83, 36.62, 39.84, 48.60, 56.98,
61.51, 61.94, 62.88, 72.26, 74.61, 111.11, 118.82, 121.83,
122.16, 127.55, 131.65, 145.46, 147.09, 154.97, 157.75, 190.15;
IR (CH2Cl2) 1732 m, 1689 m cm-1; mass spectrum m/z (% rel
intensity) 574 M+ (81Br) (15), 492 (100).
P r ep a r a t ion of 2-Br om o-1,4,5,9,12-p en t a m et h oxy-9-
m eth yl-6a ,7,8,10,10a ,11-h exa h yd r on a p h th a cen -6-on e (24)
a n d 11-Br om o-1,4,5,9,12-p en ta m eth oxy-9-m eth yl-2-(tr i-
m e t h ylsilyl)-6a ,7,8,10,10a -p e n t a h yd r on a p h t h a ce n -6-
on e (27). Compound 18 (41.6 mg, 0.08559 mmol) was
dissolved in 10 mL of CH2Cl2 and cooled to -78 °C under a N2
P r ep a r a tion of 2-Br om o-6-h yd r oxy-1,4,9-tr im eth oxy-
9-m eth yl-7,8,10-tr ih yd r on a p h th a cen e-5,12-d ion e (25). A
mixture of compound 28 (28.0 mg, 0.04895 mmol), nitric acid
(3.4 mL, 0.5 N, 34.7 equiv), and silver oxide (140 mg, 23 equiv)
was allowed to stir for 3.5 h at room temperature in the dark
under N2. The solvent was removed, the residue was extracted

8446 J . Org. Chem., Vol. 63, No. 23, 1998
Su et al.
with ether, and the organic layer was dried over MgSO4. The
solvent was removed, and the product purified by silica gel
chromatography with EtOAc/petroleum ether (1:5) to give 15.5
mg of 25 as a red solid in 69% yield. Spectral data for 25:
mp 181-182 °C, Rf ) 0.12 (EtOAc/petroleum ether ) 1:5); 1H
NMR (CDCl3) δ 1.32 (s, 3 H), 1.72-1.78 (m, 1 H), 2.09-2.14
(m, 1 H), 2.78-2.89 (m, 3 H), 2.99 (dd, 1 H, J ) 17.3 Hz), 3.24
(s, 3 H), 3.95 (s, 3 H), 4.03 (s, 3 H), 7.41 (s, 1 H), 7.55 (s, 1 H),
12.99 (s, 1 H); 13C NMR (CDCl3) δ 20.74, 23.05, 31.03, 41.42,
49.11, 57.14, 61.77, 72.06, 113.61, 119.61, 123.30, 128.75,
130.75, 132.42, 140.58, 141.14, 144.34, 151.31, 157.06, 160.01,
181.97, 187.83; IR (CH2Cl2) 3300 br w, 1720 m, 1671 s, 1628
s cm-1; mass spectrum m/z (% rel intensity) 462 M+ (81Br) (22);
m/z calcd for C22H21O681Br 462.0501, measured 462.0501.
Anal. Calcd for C22H21O681Br: C, 57.28; H, 4.59. Found: C,
57.27; H, 5.22.
An attempt was made to prepare 25 by the oxidation of 24.
Treatment of 24 with nitric acid and silver oxide as described
above and then, following workup, heating the crude reaction
residue at 100 °C as a thin film exposed to air gave 25 in 17%
yield along with an equal amount of a compound tentatively
assigned as 26: 1H NMR (CDCl3) δ 1.35 (s, 3 H), 1.65-1.75
(m, 1 H), 2.08-2.15 (m, 1 H), 2.61 (d, 1 H, J ) 17.0 Hz), 2.70-
2.90 (m, 2 H), 3.15 (d, 1 H, J ) 17.0 Hz), 3.25 (s, 3 H), 3.94 (s,
3 H), 4.04 (s, 3 H), 7.55 (s, 1 H), 13.65 (s, 1 H), 13.66 (s, 1 H).
P r ep a r a tion of 2-(Meth yl 4-(ben zyloxy)-4-m eth yl-2-
m et h ylen e-1-cycloh exa n eca r boxyla t e)-1-h yd r oxy-4,5,8-
(tr im eth ylsilyl)n a p h th a len e (31). The reaction of carbene
complex 4 (0.474 g, 1.068 mmol) with alkyne 30 (0.32 g, 1.068
mmol, 1 equiv) was carried out in 1.42 mL of acetonitrile at
45 °C for 24 h according to the procedure described for the
reaction of 4 with 14. The reaction mixture was stirred open
to air for 1 h and then directly loaded onto a silica gel column,
and elution with a 1:1:6 mixture of ether/dichloromethane/
hexane gave the desired product 31 (0.384 g) in 62% yield as
NMR (CDCl3) δ 0.02, 25.62, 25.84, 34.04, 34.96, 36.02, 39.21,
49.41, 57.18, 57.62, 62.01, 62.86, 63.12, 72.94, 109.84, 112.22,
120.83, 123.48, 127.15, 128.36, 129.43, 129.56, 139.56, 146.82,
152.94, 153.20, 155.17, 212.19; IR (neat) 3200-3000 br s, 1735
m, 1701 s cm-1; mass spectrum m/z (% rel intensity) 580 M+
(100). Anal. Calcd for C33H44O7Si: C, 68.24; H, 7.64. Found:
C, 68.53; H, 7.63.
The acid 33 (155.7 mg, 0.2681 mmol) was stirred with 1
equiv of NaOH (2.72 mL of a 0.09867 N aqueous solution) for
5 min. The mixture was stripped of volatiles under vacuum
(0.5 mmHg/25 °C) for 48 h. After addition of benzene (15 mL)
and pyridine (0.46 mL, 21 equiv), the mixture was cooled to 0
°C and oxalyl chloride (0.28 mL, 12 equiv) was added. After
10 min, tin(IV) chloride (64 µL, 2 equiv) was added dropwise,
and the ice bath was removed. The mixture was stirred for
15 min before it was rapidly loaded onto a short chromatog-
raphy column filled with Et3N-pretreated silica gel. Excess
ether was used as the eluent to wash off the product, and after
removal of the solvent, the residue was rechromatographed
with a 1:1:6 mixture of ether/dichloromethane/hexane to give
34 (130 mg, 86%) as the only product. Spectral data for 34:
bright yellow solid, mp 150-151 °C; Rf ) 0.12 (ether/dichlo-
1
romethane/hexane ) 1:1:6); H NMR (CDCl3) δ 0.40 (s, 9 H),
1.32 (s, 3 H), 1.33-1.42 (m, 3 H), 1.70-1.91 (m, 1 H), 2.10-
2.22 (m, 3 H), 2.25-2.35 (m, 1 H), 2.50 (dd, 1 H, J ) 12.0,
17.0 Hz), 3.40 (dd, 1 H, J ) 4.0, 17.0 Hz), 3.68 (s, 3 H), 3.69 (s,
3 H), 3.90 (s, 3 H), 3.94 (s, 3 H), 4.39 (d, 1 H, J ) 11.1 Hz),
4.41 (d, 1 H, J ) 11.1 Hz), 6.81 (s, 1 H), 7.16-7.29 (m, 5 H);
13C NMR (CDCl3) δ 0.37, 21.23, 25.49, 30.85, 33.54, 34.21,
44.58, 52.30, 59.17, 61.15, 62.90, 62.99, 63.24, 72.83, 112.06,
123.22, 124.00, 125.17, 126.98, 127.13, 128.14, 131.38, 132.18,
139.27, 147.06, 153.82, 154.37, 155.24, 198.94; IR (CH2Cl2)
1733 s, 1687 vs cm-1; mass spectrum m/z (% rel intensity) 562
M+ (100). Anal. Calcd for C33H42O6Si: C, 70.43; H, 7.52.
Found: C, 70.64; H, 7.51.
a
yellow wax. Spectral data for 31: Rf ) 0.09 (ether/
P r ep a r a t ion of 9-Acet oxy-1,4,5,12-t et r a m et h oxy-9-
m eth yl-2-(tr im eth ylsilyl)-6a,7,8,10,10a,11-h exah ydr on aph -
th a cen -6-on e (37). A solution of benzyl ether 34 (200 mg,
0.355 mmol) in 60 mL of EtOH was exposed to 10% Pd-C (200
mg) under nitrogen. A hydrogen atmosphere was introduced
and maintained with a balloon for 1 h at 25 °C. After filtration
through Celite, the solvent was removed and the 1H NMR
spectrum of the crude reaction mixture showed a mixture of
the deprotected tertiary alcohol 36 and the diol 35 (10:1, total
146 mg). This mixture was treated with Dess-Martin reagent
(26 mg, 2 equiv wt diol 35) and pyridine (20 µL) in 10 mL of
CH2Cl2. The solution was stirred at room temperature under
nitrogen for 1.5 h. Saturated aqueous solutions of NaHCO3
and Na2S2O4 were added (1 mL each), and the mixture was
extracted with excess CH2Cl2. After removal of the solvent,
purification on silica gel with ether as eluent gave the alcohol
36 (0.128 g, 76%), which was directly taken on to the acetate
37.
1
dichloromethane/hexane ) 1:1:6); H NMR (CDCl3) δ 0.37 (s,
9 H), 1.01 (t, 1 H, J ) 13.4 Hz), 1.11 (s, 3 H), 1.24-1.29 (m, 1
H), 1.71-1.74 (m, 1 H), 1.90-2.05 (m, 3 H), 2.17-2.23 (m, 1
H), 2.50-2.60 (m, 1 H), 2.61-2.69 (m, 1 H), 2.71 (dd, 1 H, J )
4.3, 13.2 Hz), 3.67 (s, 3 H), 3.71 (s, 3 H), 3.74 (s, 3 H), 3.88 (s,
3 H), 4.13 (d, 1 H, J ) 11.1 Hz), 4.17 (d, 1 H, J ) 11.1 Hz),
6.67 (s, 1 H), 6.71 (s, 1 H), 7.14-7.28 (m, 5 H), 9.45 (s, 1 H);
13C NMR (CDCl3) δ 0.32, 25.73, 25.85, 34.10, 35.09, 36.25,
39.32, 49.57, 51.58, 57.18, 58.14, 62.89, 64.89, 73.11, 110.84,
113.55, 119.02, 119.82, 121.41, 127.14, 127.29, 128.34, 139.72,
144.83, 149.22, 153.46, 155.24, 176.85; IR (neat) 3330 br m,
1730 s cm-1; mass spectrum m/z (% rel intensity) 580 M+ (100).
Anal. Calcd for C33H44O7Si: C, 68.24; H, 7.64. Found: C,
68.23; H, 7.69.
P r ep a r a tion of 9-Ben zyloxy-1,4,5,12-tetr a m eth oxy-9-
m eth yl-2-(tr im eth ylsilyl)-6a ,7,8,10,10a ,11-h exa h d r on a p h -
th a cen -6-on e (34). The naphthol 31 (1.05 g, 1.808 mmol) was
treated with powdered potassium hydroxide (0.40 g, 4 equiv),
iodomethane (1 mL, excess), and 4 mL of methyl sulfoxide.
The mixture was stirred at room temperature for 3 h. After
extraction with dichloromethane, the organic layer was washed
with water. The solvent was removed, and the residue was
quickly eluted through a short silica gel column with ether to
give the desired product 32 (0.93 g) in 86% yield. Part of this
product (0.77 g, 1.294 mmol) was treated with 15 mL of 2 N
NaOH and 40 mL of methanol. The mixture was refluxed at
80 °C for 36 h. After cooling, 100 mL of ether was added.
Neutralization with concentrated HCl was followed by removal
of solvent, which gave a yellow foamy residue, which was
extracted six times with ether. The organic layer was com-
bined, the solvent removed, and the residue eluted through a
short silica gel column to give the desired acid 33 (0.74 g) in
98% yield as a yellow foam. Spectral data for 33: 1H NMR
(CDCl3) δ 0.40 (s, 9 H), 1.05 (t, 1 H, J ) 13.0 Hz), 1.17 (s, 3
H), 1.40-1.50 (m, 1 H), 1.89-2.05 (m, 3 H), 2.07-2.16 (m, 1
H), 2.26-2.32 (m, 1 H), 2.55-2.65 (m, 1 H), 2.77-2.82 (m, 1
H), 2.89-2.92 (m, 1 H), 3.66 (s, 6 H), 3.80 (s, 3 H), 3.93 (s, 3
H), 4.18 (d, 1 H, J ) 11.1 Hz), 4.23 (d, 1 H, J ) 11.0 Hz), 6.71
The alcohol 36 (250 mg, 0.5289 mmol) was mixed with
DMAP (270 mg, 4.18 equiv), Hunig’s base (0.46 mL, 5 equiv),
and Ac2O (0.25 mL, 5 equiv) in 20 mL of CH2Cl2 and stirred
at room temperature under nitrogen for 12 h. After removal
of the solvent, the mixture was directly loaded onto a silica
gel column and eluted with pure ether to give a 46% recovery
of the starting material (117 mg) and the desired product 37
(146 mg), which was isolated in 54% yield as a yellow wax.
Spectral data for 37: Rf ) 0.045 (ether/dichloromethane/
1
hexane ) 1:1:6); H NMR (CDCl3) δ 0.40 (s, 9 H), 1.25-1.41
(m, 3 H), 1.57 (s, 3 H), 1.63-1.75 (m, 1 H), 1.98 (s, 3 H), 2.05-
2.16 (m, 2 H), 2.20 (dt, 1 H, J ) 3.8, 11.6 Hz), 2.53 (dd, 1 H,
J ) 12.2, 13.7 Hz), 2.63-2.68 (m, 1 H), 3.41 (dd, 1 H, J ) 4.0,
17.0 Hz), 3.69 (s, 3 H), 3.70 (s, 3 H), 3.90 (s, 3 H), 3.95 (s, 3 H),
6.82 (s, 1 H); 13C NMR (CDCl3) δ -0.14, 21.35, 22.47, 26.18,
30.96, 34.07, 35.67, 43.81, 52.18, 57.43, 61.47, 63.28, 63.58,
80.41, 112.38, 123.48, 124.16, 125.48, 131.24, 132.65, 147.38,
154.08, 154.63, 155.50, 170.60, 198.91; IR (CH2Cl2) 1736 s,
1687 s cm-1; mass spectrum m/z (% rel intensity) 514 M+ (100).
Anal. Calcd for C28H38O7Si: C, 65.34; H, 7.44. Found: C,
65.19; H, 7.26.
(s, 1 H), 6.82 (s, 1 H), 7.21-7.30 (m, 5 H), (-OH not seen); 13
C

Tetracyclic Carbon Core of Menogaril
J . Org. Chem., Vol. 63, No. 23, 1998 8447
P r ep a r a t ion of 9-Acet oxy-2-b r om o-6-h yd r oxy-1,4-d i-
m eth oxy-9-m eth yl-7,8,10-tr ih ydr on aph th acen e-5,12-dion e
(40). Compound 37 (88 mg, 0.1709 mmol), potassium carbon-
ate (50 mg), and bromine (1.25 mL, 0.288 N in CH2Cl2, 2.1
equiv) were combined in 20 mL of CH2Cl2 under nitrogen at 0
°C. The mixture was stirred for 2 h and filtered through a
short column packed with Et3N-pretreated silica gel. TLC of
the crude reaction mixture showed two products (Rf ) 0.38,
0.40, ether/dichloromethane/hexane ) 1:1:2). This mixture
was treated with AgO (424 mg, 20 equiv) and HNO3 (5 mL,
0.5 N) in 10 mL of acetone and stirred at room temperature
for 5 h. The solvent was removed, and the residue was
extracted with excess ether. The ether layer was dried over
MgSO4, and filtration through Celite gave a red solution.
Chromatography on silica gel with a 1:1:2 mixiture of ether/
dichloromethane/hexane gave the desired product 40 (40 mg)
as a red solid in 48% yield. Spectral data for 40: mp 152 °C;
Rf ) 0.24 (ether/dichloromethane/hexane ) 1:1:2); 1H NMR
(CDCl3) δ 1.66 (s, 3 H), 1.94 (s, 3 H), 2.52-2.60 (m, 1 H), 2.72-
2.81 (m, 1 H), 2.90-2.95 (m, 2 H), 2.94 (d, 1 H, J ) 17.7 Hz),
3.39 (d, 1 H, J ) 17.7 Hz), 3.95 (s, 3 H), 4.04 (s, 3 H), 7.40 (s,
1 H), 7.56 (s, 1 H), 12.99 (s, 1 H); 13C NMR (CDCl3) δ 20.49,
24.41, 29.66, 31.76, 41.49, 57.08, 61.77, 78.95, 113.55, 119.44,
123.04, 128.40, 128.95, 130.75, 131.65, 141.76, 143.45, 151.10,
156.95, 159.84, 170.47, 181.83, 187.79; IR (CH2Cl2) 3054 s,
1729 w cm-1; mass spectrum (CI) for C23H21O781Br m/z (% rel
intensity) 491 (M + 1)+ (55), 431 (100).
Ack n ow led gm en t. This work was supported by the
National Institutes of Health (GM 33589). The Depart-
ment of Education provided a predoctoral fellowship to
J .S. Some of the mass spectra were obtained from the
Midwest Center for Mass Spectrometry in Lincoln, NE.
J O981481W