A powerful o-quinone dimethide strategy for intermolecular Diels-Alder cycloadditions

Article abstract of DOI:10.1021/ja993627u

Conrotatory thermal fragmentation of trans-1,2- disilyloxybenzocyclobutenes generates o-quinone dimethides at remarkably low temperatures. Smooth stereoselective Diels-Alder cycloaddition with a range of dienophiles provides hydronaphthalene derivatives in excellent yield. Direct oxidative desilylation of the adducts affords the corresponding naphthoquinones. Substitution of the benzene nucleus with an electron- releasing methoxyl group directs the cycloaddition to give good control of regioselectivity in the expected direction. A short synthesis of the aglycon of the anticancer antibiotic idarubicin is presented.

Full text of DOI:10.1021/ja993627u

J. Am. Chem. Soc. 2000, 122, 571-575
571
A Powerful o-Quinone Dimethide Strategy for Intermolecular
Diels-Alder Cycloadditions
John G. Allen,† Martin F. Hentemann,† and Samuel J. Danishefsky*,†,‡
Contribution from the Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer
Research, 1275 York AVenue, New York, New York 10021, and the Department of Chemistry,
Columbia UniVersity, New York, New York 10027
ReceiVed October 8, 1999
Abstract: Conrotatory thermal fragmentation of trans-1,2-disilyloxybenzocyclobutenes generates o-quinone
dimethides at remarkably low temperatures. Smooth stereoselective Diels-Alder cycloaddition with a range
of dienophiles provides hydronaphthalene derivatives in excellent yield. Direct oxidative desilylation of the
adducts affords the corresponding naphthoquinones. Substitution of the benzene nucleus with an electron-
releasing methoxyl group directs the cycloaddition to give good control of regioselectivity in the expected
direction. A short synthesis of the aglycon of the anticancer antibiotic idarubicin is presented.
The influence of the Diels-Alder reaction in classical and
contemporary organic synthesis can hardly be overstated.1 For
many years, our laboratory has been interested in highly
functionalized dienes, capable of imparting to their cycloaddition
products functionality implements, which would facilitate
progression to complex targets.2 An already well recognized
opportunity in this regard is represented by o-quinone dimethides
of the type 2 (Scheme 1).3 Cycloaddition of 2 with dienophiles
creates tetrahydro- or dihydronaphthalenes. Novel sequences
based on 1,4-elimination of complementary bis(benzyl) sub-
stituents,4 cheleotropic eliminations,5 or photoenolizations6 have
been used to generate o-quinone dimethides. However, the most
widely practiced method for reaching 2 has been via fragmenta-
tion of benzocyclobutenes (cf. 1).7
Scheme 1
a pendant site of dienophilicity. We note that the widely
practiced IMDA reactions of 2 have been directed to the
synthesis of constellations associated with hydrophenanthroid
targets (cf. steroids, diterpenes, alkaloids).9
The purposes of our research can be summarized along the
following lines. We wished to develop quinodimethide precursor
types that would give rise to type 2 systems under conditions
that are sufficiently general to permit classical intermolecular
Diels-Alder reactions with a range of dienophiles. We wanted
the type 2 structure, so generated, to be capable of incorporating
an oxygen-based functionality at both of its termini (see structure
3, Scheme 2). Furthermore, we hoped to create protocols such
that the benzylic oxygens in adduct 4 could be exploited via
oxidation (cf. 5). To be particularly valuable, the oxidation when
needed would have to take clear precedence over elimination
reactions leading to aromatization (cf. 6). For certain targets,
protocols for clean elimination would be desirable. Our orienting
While there certainly are ample instances of intermolecular
Diels-Alder (DA) reactions based on the use of type 1 systems
as precursors of type 2 dienes,8 the bulk of the important
teachings in this regard arise from intramolecular Diels-Alder
(IMDA) reactions of 1, generated from analogues of 2 bearing
† Sloan-Kettering Institute for Cancer Research.
‡ Columbia University.
(1) Oppolzer, W. Intramolecular Diels-Alder Reactions. In Compre-
hensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: New York, 1991; Vol. 5, p 315.
(2) (a) Danishefsky, S. J.; Kitahara, T. J. Am. Chem. Soc. 1974, 96, 7807.
(b) Danishefsky, S. J.; Kitahara, T. J. Org. Chem. 1975, 40, 538.
(3) (a) Michellys, P.-Y.; Pellissier, H.; Santelli, M. Org. Prep. Proc. Int.
1996, 28, 545. (b) Funk, R. L.; Vollhardt, K. P. C. Chem. Soc. ReV. 1980,
9, 41. (c) McCullough, J. J. Acc. Chem. Res. 1980, 13, 270. (d) Charlton,
J. L.; Alauddin, M. M. Tetrahedron 1987, 43, 2873.
(4) (a) Han, B.-H.; Boudjouk, P. J. Org. Chem. 1982, 47, 751. (b)
Rubottom, G. M.; Wey, J. E. Synth. Commun. 1984, 14, 507. (c) Inaba, S.;
Wehmeyer, R. M.; Forkner, M. W.; Rieke, R. D. J. Org. Chem. 1988, 53,
339. (d) Schiess, P. Thermochim. Acta 1987, 112, 31. (e) See also: Troll,
T.; Schmid, K. Tetrahedron Lett. 1984, 25, 2981.
(7) (a) Jensen, F.; Coleman, W. E. J. Am. Chem. Soc. 1958, 80, 6149.
(b) Wong, H. N. C.; Lan, K.-L.; Tam, D. F. Top. Curr. Chem.1986, 133,
124-130. (c) Arnold, B. J.; Sammes, P. G.; Wallace, T. W. J. Chem. Soc.,
Perkin Trans. 1 1974, 401. (d) Macdonald, D. I.; Durst, T. J. Org. Chem.
1986, 51, 4750. (e) Franck, R. W.; John, T. V.; Olejniczak, K. J. Am. Chem.
Soc. 1982, 104, 1106. (f) Jung, M. E.; Lam, P. Y.-S.; Mansuri, M.; Speltz,
L. M. J. Org. Chem. 1985, 50, 1087.
(5) (a) Cava, M. P.; Deana, A. A. J. Am. Chem. Soc. 1959, 81, 4266. (b)
Jung, F.; Molin, M.; Van Den Dlzen, R.; Durst, T. J. Am. Chem. Soc. 1974,
96, 935. (c) Durst, T.; Tetreault-Ryan, L. Tetrahedron Lett. 1978, 2353.
(d) Charlton, J. L. Can. J. Chem. 1985, 64, 723.
(6) (a) Jung, M. E.; Lowe, J. A. J. Org. Chem. 1977, 42, 2371. (b) Krohn,
K.; Rieger, H.; Broser, E.; Schiess, P.; Chen, S.; Strubin, T. Liebigs Ann.
Chem. 1988, 943. (c) Krohn, K. Angew. Chem., Int. Ed. Engl. 1986, 25,
790. (d) Kessar, S. V.; Mankotia, A. K. S.; Agnihotri, K. R. J. Chem. Soc.,
Chem. Commun. 1993, 598. (e) Sammes, P. G. Tetrahedron 1976, 32, 405.
(f) Coll, G.; Costa, A.; Deya´, P. M.; Flexas, F.; Rotger, C.; Saa´, J. M. J.
Org. Chem. 1992, 57, 6222.
(8) (a) LaDuranty, J.; Lepage, L.; Lepage, Y. Can. J. Chem. 1980, 1161.
(b) Amaro, A.; Carreno, M. C.; Farina, F. Tetrahedron Lett. 1979, 3983.
(c) Moss, R. J.; Rickborn, B. J. Org. Chem. 1984, 49, 3694. (d) Kametani,
T.; Toya, T.; Ueda, K.; Tsubuki, M.; Honda, T. J. Chem. Soc., Perkin Trans.
1 1988, 2433.
(9) (a) Oppolzer, W. Synthesis 1978, 793. (b) Kametani, T. Pure Appl.
Chem. 1979, 51, 747. (c) Kametani, T.; Nemoto, H. Tetrahedron 1981, 37,
3. (d) Magnus, P.; Gallagher, T.; Brown, P.; Pappalardo, P. Acc. Chem.
Res. 1984, 17, 35. (e) Ito, Y.; Nakatsuka, M.; Saegusa, T. J. Am. Chem.
Soc. 1982, 104, 7609. (f) Oppolzer, W. Heterocycles 1980, 14, 1615. (g)
Nemoto, H.; Fukumoto, K. Tetrahedron 1998, 54, 5425.
10.1021/ja993627u CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/19/2000

572 J. Am. Chem. Soc., Vol. 122, No. 4, 2000
Allen et al.
Scheme 2
Scheme 5a
Scheme 3
Scheme 4a
a All reactions (90-95%) performed in benzene at 40 °C, 1-2 h
with: (a) benzo-1,4-quinone; (b) maleic anhydride; (c) 5-hydroxynaph-
tho-1,4-quinone; (d) cyclohexen-2-one; (e) dimethylacetylene dicar-
boxylate; (f) for 18, methyl vinyl ketone; for 19 and 20, methyl
methacrylate at 50 °C (19:20 ) 9:1).
cis ) 6:1).15 Interestingly, the trans diol had not been known.
This mixture was silylated, as shown, to generate 11 or 12.
Although trans-11 could be purified, 12 was used as a mixture
of trans and nonreactive cis isomers. Reactions of either 11 or
12 were carried out with various potential dienophiles in
benzene-d6 or toluene-d8. Uncatalyzed cycloadditions occurred
under remarkably mild conditions. A particularly impressive
case is seen in the formation of 13 (Scheme 5). Although
cyclohexen-2-one is a notoriously sluggish dienophile in non-
catalyzed Diels-Alder reactions,16 13 is formed in near-
quantitative yield at 40°!
Given the reasonable assumption that conrotatory opening
of 11 produces, torquospecifically,11 the outside-outside dienes,
all cycloadditions would have occurred in a highly endo-
selective fashion.17 In fact, of the group of dienophiles surveyed
to date with the diene derived from 11, the sole exo product
we have observed has been 20, which is the minor product (∼1:
9) accompanying 19.
We next turned to the matter of post-Diels-Alder survival
of the adducts and their amenability to oxidative desilylation.
For this purpose we utilized the bis(trimethylsilyloxy) system
12 as the o-quinone dimethide precursor. Our focus at this stage
was on direct oxidation-desilylation, a reaction type earlier
described by Jung.18 While we have not studied the scope of
this reaction in detail, we have found that, at least in simple
cases, dicyanodichlorobenzoquinone19 (DDQ) accomplishes
direct oxidation smoothly (see products 21, 22, and 23; Scheme
6).
a (a) NaBH4, MeOH; (b) TMSCl, HMDS or TBSOTf, Et3N (50-
70%, two steps).
target structures for this opening phase of the inquiry would be
anthracycline-based systems of high biological interest.
It seemed that a benzocyclobutene of type 7 (Scheme 3), with
two trans-disposed silyloxy functions could be of considerable
value in reaching our goals. Following the calculations and
chemistry of Houk,10 we expected the two â-donating OSiR3
groups to facilitate conrotatory ring opening of the cyclobutene
thereby generating the (E,E)-quinone dimethide (see torquoi-
somer 8).11 Remarkably, while diacyloxy12 and dimethoxy13
versions of 3 had been prepared and evaluated, the bis(silyloxy)
compounds were unknown. Such compounds were foreseen to
have several potential advantages, particularly as regards the
projected post-Diels-Alder phase of the sequence.
The known14 dione 9 (Scheme 4), upon reduction with sodium
borohydride in methanol afforded 10 as the major product (trans:
(10) (a) Dolbier, W. R.; Koroniak, H.; Houk, K. N.; Sheu, C. Acc. Chem.
Res. 1996, 29, 471. (b) KirMSe, W.; Rondan, N. G.; Houk, K. N. J. Am.
Chem. Soc. 1984, 106, 7989. (c) Niwayama, S.; Kallel, E. A.; Sheu, C.;
Houk, K. M. J. Org. Chem. 1996, 61, 2517. (d) Niwayama, S.; Kallel, E.
A.; Spellmeyer, D. C.; Sheu, C.; Houk, K. M. J. Org. Chem. 1996, 61,
2813.
(11) (a) Rudolf, K.; Spellmeyer, D. C.; Houk, K. N. J. Org. Chem. 1987,
52, 3708. (b) Houk, K. N.; Spellmeyer, D. C.; Jefford, C. W.; Rimbault, C.
G.; Wang, Y.; Miller, R. D. J. Org. Chem. 1988, 53, 2125. (c) Nakamura,
K.; Houk, K. N. J. Org. Chem. 1995, 60, 686.
(12) trans-Diacyloxy-substituted benzocyclobutenes of type 3 give
Diels-Alder products with 42 at 80 °C. Elaboration into the naphthoquinone
was not possible, and in practice, thermal elimination of the diacetoxy groups
gave the corresponding anthracene: (a) Hassall, C. H.; Broadhurst, M. J.;
Thomas, G. J. J. Chem. Soc., Perkin Trans. 1 1982, 2239. (b) Broadhurst,
M. J.; Hassall, C. H.; Thomas, G. J. Tetrahedron 1984, 40, 4649.
(13) trans-Dimethoxybenzocyclobutenes of type 3 give Diels-Alder
products with maleic anhydride: Arnold, B. J.; Sammes, P. G.; Wallace,
T. W. J. Chem. Soc., Perkin Trans. 1 1974, 415.
(14) (a) Liebeskind, L. S.; Lescosky, L. J.; McSwain, C. M., Jr. J. Org.
Chem. 1989, 54, 1435. (b) Du¨rr, H.; Nickels, H. J. Org. Chem. 1980, 45,
973. (c) Abou-Teim, O.; Goodland, M. C.; McOmie, F. W. J. Chem. Soc.,
Perkin Trans. 1 1983, 2659. (d) Liebeskind, L. S.; South, M. S. J. Org.
Chem. 1982, 47, 3815. Silyloxy-substituted benzocyclobutenes have also
been prepared by Suzuki: (e) Hosoya, T.; Hasegawa, T.; Kuriyama, Y.;
Suzuki, K. Tetrahedron Lett. 1995, 36, 3377. (f) Hosoya, T.; Hasegawa,
T.; Kuriyama, Y.; Matsumoto, T.; Suzuki, K. Synlett 1995, 177. (g)
Matsumoto, T.; Hamura, T.; Kuriyama, Y.; Suzuki, K. Tetrahedron Lett.
1997, 38, 8985.
(15) Bis(trimethylsilyloxy) derivatives 11 and 33 were obtained in 4:1-
6:1 trans/cis ratios. The bis(tert-butyldimethylsilyloxy) derivatives 12 and
27 were obtained in 6:1-9:1 trans/cis ratios. The difference was possibly
due to partial decompostion of the trans isomer during preparation of 11
and 33.
(16) (a) Fringuelli, F.; Taticchi, A.; Wenkert, E. Org. Prep. Proc. Int.
1990, 22, 131. (b) Bartlett, P. D.; Woods, G. F. J. Am. Chem. Soc. 1940,
62, 2933. (c) Friguelli, F.; Pizzo, F.; Taticchi, A.; Halls, T. D. J.; Wenkert,
E. J. Org. Chem. 1982, 47, 5057.
(17) Relative configuration of the adducts were determined by 2-D and
NOE NMR experiments. All product ratios were determined by integration
in the NMR spectra.
(18) Using TrBF4: (a) Jung, M. E. J. Org. Chem. 1976, 41, 1479. See
also: (b) Muzart, J. Synthesis 1993, 11.
(19) (a) Paterson, I.; Cowden, C. J.; Rahn, V.; Woodrow, M. D. Synlett
1998, 915. (b) Piva, O.; Amougay, A.; Pete, J. Tetrahedron Lett. 1991, 32,
3993. (c) Jung, M. E.; Pan, Y.-G.; Rathke, M. W.; Sullivan, D. F.;
Woodbury, R. P. J. Org. Chem. 1977, 42, 3961.

o-Quinone Dimethide Use for Diels-Alder Additions
J. Am. Chem. Soc., Vol. 122, No. 4, 2000 573
Scheme 6a
Scheme 8a
a R ) TMS; (a) benzo-1,4-quinone, 80 °C, 3 h, and then DDQ, THF,
22 °C, 12 h (36:37 ) 7:1, 80%); (b) methyl vinyl ketone 120 °C, 4 h
and then DDQ, THF, 22 °C, 12 h (38:39:39a ) 1:1:1, 80%); (c)
dimethylacetylene dicarboxylate 120 °C, 3 h and then DDQ, THF, 22
°C, 4 h (92%).
a (a) DDQ, THF, 22 °C, 12 h.
Scheme 7a
there were isolated two products, 30 and 31, in a ratio of 1:6,
each corresponding to the expected regiochemical outcome. The
reasons for apparent regiospecificity when cyclohexen-2-one
was the dienophile as opposed to methyl vinyl ketone are not
yet known. Interestingly, in the cyclohexen-2-one case, the major
product 31 apparently arose from position-specific elimination
of the silyloxy group peri to the methoxyl function. The
â-elimination of this particular silyloxy function can readily be
rationalized by steric and electronic effects exerted by the
methoxyl.
We have investigated, though not in great detail, the oxidation
of the Diels-Alder product in the peri-methoxyl series. For this
purpose, as above, we turned to the bis(trimethylsilyloxy)
benzocyclobutene derivative, 32 (Scheme 8), readily synthesized
from 24. Oxidations of the Diels-Alder adducts 33, 34, and
35 were again conducted with DDQ. With 33, the major product
was 36;21 however, this compound was accompanied by 15%
of 37. Again regioselective elimination of the silyloxy group
peri to the methoxyl had occurred to a small extent competitively
with oxidation. With adduct 34, treatment with DDQ provided
3822 and the product of only partial oxidation, 39. Its recovery
was complicated by hydrolysis of the silyl group (see 39a).
Oxidation of 35 occurred smoothly to produce 40. Thus with
our present protocols, the peri-methoxyl does tend to complicate
the ready exploitation of the silyloxy groups for structural
development through oxidation. It clearly facilitates elimination
of its peri silyloxy group, and perhaps hinders its oxidation.
However, the basic capability has been demonstrated.
a R ) TBS; (a) benzo-1,4-quinone, 80 °C, 3 h (95%); (b) methyl
vinyl ketone, 120 °C, 4 h (2820:29 ) 7:1, 95%); (c) cyclohexen-2-one,
120 °C, 24 h (30:31 ) 1:6, 70%).
We next probed the adaptability of the reaction to ortho-
substituted versions of trans-disilyloxybenzocyclobutenes. Of
particular interest was the question of the degree of regiochemi-
cal control exercised by a “peri” methoxyl group in cycload-
ditions with biased dienophiles. Reduction of diketone 24
(Scheme 7) as before afforded a mixture of trans- (25) and cis-
diols with the former being predominant (∼8:1). Silylation of
25 provided 26. It was soon found that 26 was much less
reactive than the desmethoxyl analogue 11 vis a` vis cycload-
dition. This large difference presumably reflects the relative
facility of cyclobutene fragmentation. It might have been
expected that the methoxyl function would stabilize the radi-
caloid character of the fragmenting bis(silyloxy) δ-bond en route
to the quinone dimethide.10 In retrospect, overall loss of
reactivity of 26 relative to 11 may well be a consequence of
serious hindrance imposed by the peri-methoxyl group to
conrotatory opening in the preferred “outside-outside” torquo
mode.11 Thus, it was found that Diels-Alder reaction of 26
with 1,4-benzoquinone required temperatures of ∼80 °C to occur
at a reasonable rate. Compound 27 was obtained in 95% yield.
We investigated the case of methyl vinyl ketone to probe
issues of regiochemistry in o-quinone dimethides where the
perturbing element is in the “benzo” section. In this reaction,
compounds 2820 and 29 were obtained in a 7:1 ratio as shown.
Cycloaddition with cyclohexen-2-one required temperatures of
120 °C and was conducted over 24 h. At the end of this period,
A pleasing application of this Diels-Alder strategy described
herein was accomplished in the context of a highly concise and
efficient total synthesis of the important anthracycline drug
precursor idarubicinone (43).23 Cycloaddition of 12 and 4112
occurred smoothly to produce the endo-adduct 42 (Scheme 9).
(20) Compound 28 was obtained as a 4:3 mixture of endo and exo
diastereomers.
(21) (a) Bosshard, D.; Fumagalli, S.; Good, R.; Treub, W.; Philipsborn,
W. V.; Eugster, C. H. HelV. Chim. Acta 1964, 47, 769. (b) Uno, H. J. Org.
Chem. 1986, 51, 350.
(22) Kessler, H.; Mu¨ller, A. Liebigs Ann. Chem. 1986, 1687.
(23) Idarubicin (Idamycin) was approved in 1990 for use in the United
States for treatment of acute nonlymphocytic and lymphoblastic leukemia.
It has been shown to have superior therapeutic efficacy and reduced
cardiotoxicity and to provide longer duration of survival compared to
Daunorubicin: (a) Hollingshead, L. M.; Faulds, D. Drugs 1991, 42, 690.
(b) Cersosimo, R. J. Clin. Pharm. 1992, 11, 152. Idarubicin is produced,
with some difficulty, by semisynthesis from Daunomycin: Penco, S. Chim.
Ind. Milan 1993, 75, 369; EP 0 337 665 B1.

574 J. Am. Chem. Soc., Vol. 122, No. 4, 2000
Allen et al.
Scheme 9a
(2.1 equiv) as a solid at 25 °C, and the resulting solution stirred for an
additional 12 h, at which point it was diluted with a 2-fold excess of
methylene chloride and washed twice with saturated NaHCO3 solution.
After drying over MgSO4 the material was purified by column
chromatography (80:20 hexanes/ethyl acetate) to give pure compound.
Naphthoquinone 21. Red solid (mp 187-188 °C) after chroma-
tography (82%): FTIR (film) 1627, 1585, 1454, 1226 cm-1; 1H NMR
(400 MHz, CDCl3) δ 12.94 (s, 2H, exch. with D2O), 8.41 (m, 2H),
7.91 (m, 2H), 7.27 (s, 2H); 13C (100 MHz, CDCl3) δ 187.0, 157.8,
134.5, 133.5, 129.4, 127.1, 112.8; HRMS (DEI) for [C14H8O4]+, m/z
calcd 240.0423, found 240.0423.
a (a) 50 °C, 2 h and then DDQ, THF 22 °C, 10 h; (b) H2O2, NaOH,
THF; (c) TsOH, acetone; 65% three steps.
Oxidative desilylation of 42 followed by sequential cleavage
of the borate and ketal blocking groups delivered idarubicinone
(43). The overall yield for the four-step total synthesis of 43
was 65%. This sequence attempted with methoxyl-substituted
benzocyclobutene 32 resulted in a 1:1 mixture of regioisomers
due to the low polarization of dienophile 41.
In summary, the major goals of the project have been realized,
though some difficulties can arise in the oxidative desilylation
step, particularly in the case of the Diels-Alder adducts bearing
a peri-methoxyl function. Obviously these interesting results
raise issues of mechanism, scope, possibilities for catalysis, and
feasibility in attaining enantiocontrol in the cycloaddition step.
Such matters are under current investigation and will be
disclosed in due course.
trans-Bis(tert-butyldimethylsilyloxy)-3-methoxybenzocyclo-
butene (26). 3-Methoxybenzocyclobutendione (200 mg, 1.23 mmol)
was dissolved in methanol (10 mL), cooled to 0 °C, and sodium
borohydride (33 mg, 0.87 mmol) was added. After 1 h, the solvent
was removed at 0 °C, the residue was passed through a plug of silica
with cold ethyl acetate, and the filtrate was concentrated. The residue
was dissolved with CH2Cl2 (10 mL), the mixture cooled to -78 °C,
and TBSOTf (1.13 mL, 4.92 mmol) and Et3N (0.68 mL, 4.92 mmol)
were added. After 2 h, methanol (1 mL) was added. The organic solution
was washed with NH4Cl(aq) and NaCl(aq), dried (MgSO4), and evaporated.
Purification by column chromatography (hexanes f 95:5 hexanes/
EtOAc) gave pure trans-26 (338 mg, 70%) as a colorless oil: FTIR
(film) 2927, 2855, 1606, 1584, 1482 cm-1; 1H (400 MHz, toluene-d8)
δ 7.24 (dd, J ) 7.70 Hz, 1H), 6.95 (d, J ) 7.17 Hz, 1H), 6.87 (d, J )
8.25 Hz, 1H), 5.18 (s, 1H), 5.09 (s, 1H), 3.78 (s, 1H), 1.15 (s, 9H),
Experimental Section24
1.11 (s, 9H), 0.38 (s, 3H), 0.32 (s, 3H), 0.30 (s, 3H), 0.26 (s, 3H); 13
C
(100 MHz, CDCl3) δ 155.6, 145.9, 131.0, 127.6, 115.2, 115.1, 79.3,
79.0, 56.9, 25.8, 18.0, -3.9, -4.5, -4.7, -5.1; HRMS (NH3/CI) for
[C21H38O3Si2]+, m/z calcd 394.2359, found 394.2346.
trans-Bis(tert-butyldimethylsilyloxy)benzocyclobutene (11). So-
dium borohydride (125 mg, 3.29 mmol) was added to a 0 °C solution
of benzocyclobutenedione 914 (400 mg, 3.28 mmol) dissolved in
methanol (16 mL). The resulting solution was stirred for 30 min or
until TLC showed complete consumption of starting material, at which
time excess borohydride was quenched with acetone (1 mL). The
solvent was removed at 0 °C via rotary evaporation and the residue
passed through a plug of silica gel and rinsed with ethyl acetate. The
filtrate was concentrated at 0 °C, redissolved in CH2Cl2 (20 mL), and
cooled to -78 °C. To the solution was added TBSOTf (0.90 mL, 3.94
mmol) and NEt3 (0.68 mL, 4.92 mmol), and the resulting solution stirred
for 1.5 h at which time it was diluted with Et2O (20 mL), washed once
each with water and brine, and then dried over MgSO4. Purification
by column chromatography (97:3 hexanes/ethyl acetate) gave pure trans
11 (675 mg, 58%): FTIR (film) 2955, 2929, 2857, 1256, 1114, 835,
777 cm-1, 1H NMR (400 MHz, CDCl3) δ 7.02-7.14 (m, 4H), 4.73 (s,
2H), 0.77 (s, 18H), 0.02 (s, 12H), 0.01 (s, 12H); 13C (100 MHz, CDCl3)
δ 144.3, 129.4, 122.8, 79.6, 25.7, 17.7, -4.8 (2); MS for [C20H36O2Si2
+ Na]+, m/z 387.
Benzoquinone Diels-Alder Adduct 27. Benzo-1,4-quinone (8 mg,
74 µmol) was heated in toluene-d8 (1 mL) with 26 (15 mg, 38 µmol)
at 80 °C 3 h, when quantitative conversion was observed by 1H.
Attempted purification by column chromatography caused partial
enolization of the adduct. Pure 27 was obtained as a colorless oil: FTIR
(film) 2928, 2855, 1674, 1472, 1253 cm-1; 1H (400 MHz, toluene-d8)
δ 7.02 (dd, J ) 7.93 Hz, 1H), 6.87 (d, J ) 7.48 Hz, 1H), 6.39 (d, J )
7.56 Hz, 1H), 6.27 (s, 2H), 5.85 (d, J ) 5.40 Hz, 1H), 5.12 (d, J )
5.39 Hz), 3.31 (s, 3H), 2.67 (dd, J ) 5.36 Hz, 9.98 Hz, 1H), 2.55 (dd,
J ) 5.03 Hz, 10.0 Hz, 1H), 0.89 (s, 9H), 0.84 (s, 9H), 0.22 (s, 3H),
0.14 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H); 13C (100 MHz, toluene-d8) δ
197.6, 196.7, 156.4, 141.5, 141.0, 140.1, 135.6, 126.6, 121.0, 110.1,
71.4, 64.0, 54.2, 49.4, 48.6, 26.7, 26.6, -4.1, -4.2, -4.4, -4.6; HRMS
(DCI) for [C27H43O5Si2]+, m/z calcd 503.2649, found 503.2634.
trans-Bis(trimethylsilyloxy)-3-methoxybenzocyclobutene (32).
3-Methoxybenzocyclobutendione (500 mg, 3.09 mmol) was dissolved
in methanol (18 mL), cooled to 0 °C, and sodium borohydride (81 mg,
2.16 mmol) was added. After 1 h, the solvent was removed at 0 °C,
the residue was passed through a plug of silica with cold ethyl acetate,
and the filtrate was concentrated. The residue was dissolved with CH2-
Cl2 (10 mL), the mixture cooled to 0 °C, and HMDS (3.90 mL, 12.4
mmol) and TMSCl (2.35 mL, 12.4 mmol) were added. After 12 h,
volatiles were evaporated and the residue was passed with n-pentane
through Celite, and the filtrate was evaporated to give 6:1 mixture of
trans- and cis-32 (0.68 g, 60%) as a colorless oil: FTIR (film) 2957,
General Procedure for the Diels-Alder Reaction with 11.
Dienophile (2.0 equiv) and disilyloxybenzocyclobutene 11 were
combined in benzene-d6 and heated at 45 °C until quantitative
conversion was observed by 1H NMR (typically 1.5-2.5 h). Removal
of the solvent followed by column chromatography yielded compounds
13-20.
Cyclohexenone Diels-Alder Adduct 13. Colorless oil after chro-
matography (93%): FTIR (film) 2929, 2856, 1677, 1604, 1254, 836,
1
775 cm-1; H NMR (400 MHz, CDCl3) δ 7.36 (d, J ) 6.9 Hz, 1H),
1
2897, 1606, 1586, 1482, 1252 cm-1; H (400 MHz, CDCl3) δ 7.24
7.29 (d, J ) 6.8 Hz, 1H), 7.18 (m, 2H), 4.57 (d, J ) 10.4 Hz, 1H),
4.48 (d, J ) 4.2 Hz, 1H), 3.05 (app t, J ) 7.8 Hz, 1H), 2.26 (m, 1H),
2.09 (m, 1H), 1.95 (ddd, J ) 5.9, 7.1, 12.9 Hz, 1H), 1.50 (m, 2H),
1.29 (m, 1H), 0.85 (s, 9H), 0.78 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H),
-0.03 (s, 3H), -0.06 (s, 3H); 13C (100 MHz, CDCl3) δ 212.0, 139.2,
138.0, 127.3, 127.1, 124.9, 124.5, 71.3, 65.6, 54.1, 44.0, 42.6, 26.3,
24.7, 21.9, 18.7, 18.5, -4.2 (2), -4.5, -4.6; HRMS (FAB) for
[C26H44O3Si2 + Na]+, m/z calcd 483.2727, found 483.2727.
(dd, J ) 7.68 Hz, 1H), 6.80 (d, J ) 7.30 Hz, 1H), 6.76 (d, J ) 8.36
Hz, 1H), 5.02 (s, 1H), 4.86 (s, 1H), 3.78 (s, 3H), 0.20 (s, 9H), 0.19 (s,
9H); MS for [C15H24O3Si2 + Na]+, m/z 310. Evidence for cis-33 was
as follows: 1H (400 MHz, CDCl3) δ 5.53 (d, J ) 3.84 Hz, 1H), 5.30
(d, J ) 3.80 Hz, 1H), 3.93 (s, 3H).
Naphthacene 37 and Naphthoquinone 36. Benzo-1,4-quinone (31
mg, 0.28 mmol) was heated with bis(trimethylsilyloxy)benzocy-
clobutene 32 (50 mg, 0.14 mmol) in toluene-d8 (1 mL) at 80 °C 3 h,
when conversion was observed to be complete by 1H NMR. The solvent
was evaporated and the residue taken up in THF (4 mL), and DDQ
(60 mg, mmol) was added at 0 °C. After being stirred 12 h at 22 °C,
the mixture was poured into a NaHCO3 solution. The organic layer
was washed with ice cold 1 N HCl, dried (MgSO4), and evaporated.
Column chromatography on silica gel (95:5 f 9:1 toluene/acetone)
gave first pure 37 (3.6 mg, 10%) as a red amorphous solid: FTIR (film)
General Procedure for Jung-Type Oxidation of the Diels-Alder
Adducts from 12. Dienophile (2.0 equiv) and disilyloxybenzocy-
clobutene 12 were combined in benzene-d6 and heated at 45 °C until
1
quantitative conversion was observed by H NMR (typically 1.5-2.5
h). The solvent was removed via rotary evaporation and the residue
dissolved in THF ([0.2M]) without further purification. DDQ was added
(24) Please see Supporting Information for General Methods section.

o-Quinone Dimethide Use for Diels-Alder Additions
J. Am. Chem. Soc., Vol. 122, No. 4, 2000 575
1
2920, 2849, 1720, 1664, 1480, 1261 cm-1; H (400 MHz, CDCl3) δ
for [C22H20O8 + Na]+, m/z 435. This compound was dissolved in
acetone (5 mL) and stirred in the presence of catalytic p-toluenesulfonic
acid at 25 °C for 8 h, at which point TLC indicated the reaction
complete. The solvent was removed via rotary evaporation and the
residue dissolved in 1:1 THF/diethyl ether and washed once with brine.
The organic layer was dried over Na2SO4, concentrated, and then
recrystallized from CH2Cl2 and Et2O to give idarubicinone 43 as a red
solid (12 mg 83%): mp 176-178 °C (lit.,12a 174-178 °C); FTIR (film)
3416, 1713, 1623, 1587, 1415, 1374, 1236 cm-1; 1H NMR (400 MHz,
CDCl3) δ 13.52 (s, 1H, exchange with D2O), 13.26 (s, 1H, exchange
with D2O), 8.28 (m, 2H), 7.79 (m, 2H), 5.27 (br s, 1H), 4.58 (br s, 1H,
exchange with D2O), 3.80 (br s, 1H, exchange with D2O), 3.20 (dd,
2.0, 18.6 Hz, 1H), 2.91 d, J ) 18.7 Hz, 1H), 2.47 (s, 3H), 2.36 (m,
1H), 2.20 (dd, J ) 5.0, 9.5 Hz, 1H); 13C (100 MHz, THF) δ 210.3,
186.1, 185.9, 156.1, 155.9, 136.2, 135.1, 133.7, 133.0, 132.9, 126.0,
125.9, 110.3, 109.8, 76.1, 60.5, 35.0, 32.6, 22.8; MS for [C20H16O7 +
Na]+, m/z 391. Idarubicinone was also produced in improved yield by
the preceding procedure with chromatography steps omitted. Thus, 41
(128 mg, 0.31 mmol) condensed with 12 (106 mg, 0.38 mol) yielded
43 (75 mg, 65%), which was purified by crystallization.
13.76 (s, 1H), 8.57 (s, 1H), 8.05 (d, J ) 8.30 Hz, 1H), 7.63 (dd, J )
8.07 Hz, 1H), 7.09 (d, J ) 7.87 Hz, 1H), 7.05 (s, 2H), 4.04 (s, 3H);
13C (100 MHz, CDCl3) δ 189.4, 184.0, 162.2, 157.5, 141.0, 139.6,
129.9, 128.8, 127.6, 126.3, 116.8, 116.5, 109.8, 55.9; HRMS (DEI)
for [C15H10O4]+, m/z calcd 254.0579, found 254.0579. Further elution
(9:1 toluene/acetone f 9:1 CH2Cl2/MeOH) gave 36 (26 mg, 70%) as
a dark orange solid (mp 240.0-240.8 °C, hexanes/ether): FTIR (CCl4)
2927, 1623, 1588, 1281 cm-1; 1H (400 MHz, CDCl3) δ 13.26 (s, 1H),
12.88 (s, 1H), 8.04 (d, J ) 8.04 Hz, 1H), 7.78 (dd, J ) 8.26 Hz, 1H),
7.39 (d, J ) 8.43 Hz, 1H), 7.30-7.20 (m, 2H), 4.08 (s, 3H); 13C (100
MHz, CDCl3) δ 187.2, 186.7, 161.0, 157.4, 157.3, 135.6, 135.5, 129.9,
128.0, 119.7, 118.3, 113.5, 56.6; HRMS (DEI) for [C15H10O5]+, m/z
calcd 270.0528, found 270.0530.
Idarubicinone (43). Crude cyclic boronate 41 (73 mg, 0.20 mmol)
was combined with disilyloxybenzocylcobutene 12 in toluene-d8 (1 mL)
and heated at 45 °C for 7 h, at which time 1H NMR indicated that the
reaction was complete. The solvent was removed and the residue taken
up in THF (1 mL), and to the resulting orange solution was added
solid DDQ (4 equiv). After stirring for 12 h at 25 °C, the solution was
diluted with CH2Cl2 (5 mL), washed twice with saturated NaHCO3
solution, and dried over Na2SO4. After removal of the solvent via rotary
evaporation, the reddish solid was dissolved in THF (1.5 mL) and
cooled to 0 °C. With rapid stirring, 30% H2O2 (1 mL) was added
followed by 1 N NaOH solution (1 mL). The resulting turbid violet
mixture was stirred for an additional 15 min, at which time the reaction
was considered complete by TLC (Rf 0.2, 1:1 hexanes/ethyl acetate).
The reaction was quenched at 0 °C by the addition of 1 mL of saturated
NaHSO3 solution, diluted with 10 mL of Et2O, and washed with brine.
The aqueous layer was washed twice with dichloromethane, and the
combined organic layers were dried over Na2SO4 and concentrated.
The reddish gum was purified by column chromatography (65:35
hexanes/ethyl acetate) to give (cis-3-[1-(1,1-ethylenedioxy)ethyl]-
1,2,3,4,6,11-hexahydro-5,12-dihydroxy-6,11-dioxonaphthacene as a
red solid (46 mg, 55%): 1H NMR (400 MHz, CDCl3) δ 13.59 (s, 1H),
13.38 (s, 1H), 8.31 (m, 2H) 7.78 (m, 2H), 5.25 (br s, 1H), 4.02 (s,
4H), 3.71 (br s, 1H), 3.19 (dd, J ) 18.2 Hz, 1H), 2.75 (d, J ) 18.5 Hz,
1H), 2.37 (m, 1H), 1.95 (dd, J ) 5.0, 9.3 Hz, 1H), 1.44 (s, 3H); MS
Acknowledgment. This work was supported by the National
Institutes of Health (AI 16943/CA 28824). Postdoctoral Fel-
lowship support is gratefully acknowledged by J.G.A. (NIH,
CA-80356) and M.F.H. (5T32 CA62948-05). We acknowledge
our earlier co-workers Tae Young Yoon, Matthew Shair, and
In-Jong Kim for relevant preliminary experiments in this area.
We are grateful to Dr. George Sukenick (NMR Core Facility,
Sloan-Kettering Institute) for NMR and mass spectral analyses.
Supporting Information Available: Characterization data
and representative spectra of 13, 14, 15, 16, 17, 18, 19, 20, 22,
23, 26, 27, 28, 29, 30, 31, 32, 36, 37, 38, 39, 40, and 43 (print/
PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
JA993627U