Synthetic and mechanistic studies on the azabicyclo[7.3.1]enediyne core and naphtho[2,3-h]quinoline portions of dynemicin A

Article abstract of DOI:10.1021/ja970435v

The synthesis of the 13-keto-10-azabicyclo[7.3.1]enediyne core structure of dynemicin A has been achieved by two routes, Schemes 4 and 6. The chemistry of the 13-keto core structure is dominated by the unusually facile bridgehead enolization. Comparison of the rates of cycloaromatization of a variety of enediynes revealed that substantial rate differences occurred even though the distance between the bonding acetylenes was virtually identical. A non-radical cycloaromatization pathway, initiated by thiol addition to the enediyne system, was discovered, and the simple core amine 26 exhibits modest in vitro and in vivo antitumor activity. Finally, two methods for the synthesis of the naphtho[2,3-h]quinoline portion of dynemicin A are described, and both these compounds also exhibit antitumor activity.

Full text of DOI:10.1021/ja970435v

J. Am. Chem. Soc. 1997, 119, 5591-5605
5591
Synthetic and Mechanistic Studies on the
Azabicyclo[7.3.1]enediyne Core and Naphtho[2,3-h]quinoline
Portions of Dynemicin A
Philip Magnus,* Shane A. Eisenbeis, Robin A. Fairhurst, Theodore Iliadis,
Nicholas A. Magnus, and David Parry
Contribution from the Department of Chemistry and Biochemistry, UniVersity of Texas at Austin,
Austin, Texas 78712
ReceiVed February 10, 1997X
Abstract: The synthesis of the 13-keto-10-azabicyclo[7.3.1]enediyne core structure of dynemicin A has been achieved
by two routes, Schemes 4 and 6. The chemistry of the 13-keto core structure is dominated by the unusually facile
bridgehead enolization. Comparison of the rates of cycloaromatization of a variety of enediynes revealed that
substantial rate differences occurred even though the distance between the bonding acetylenes was virtually identical.
A non-radical cycloaromatization pathway, initiated by thiol addition to the enediyne system, was discovered, and
the simple core amine 26 exhibits modest in Vitro and in ViVo antitumor activity. Finally, two methods for the
synthesis of the naphtho[2,3-h]quinoline portion of dynemicin A are described, and both these compounds also
exhibit antitumor activity.
Introduction
In 1990, Semmelhack10 speculated that dynemicin A under-
goes bioreductive activation with concomitant epoxide ring
opening to give the extended quinone methide 1a. Hydration
and oxidation of 1a followed by Bergman cycloaromatization
of the diol 1b lead to the diyl 1c which can hydrogen abstract
to provide the adduct 1d.11 Consequently if dynemicin A or
one of the subsequent adducts is bound to DNA,12 the diyl is
fully capable of backbone scission, Scheme 2. Generally, it is
thought that, prior to bioreduction, dynemicin forms an inter-
calation complex with the DNA. A model for this complex
has been constructed (using energy minimization and molecular
dynamics techniques), and appeared to be consistent with the
available experimental data.4
The isolation and structural elucidation of dynemicin A 1 (R
) H) was reported in 1989.1 It was the first enediyne antitumor
agent whose structure 1 (R ) Ac) was confirmed by X-ray
crystallography, Scheme 1.2,3 The source of 1 was the
fermentation broth of a new Micromonospora strain, isolated
from a soil sample collected in Gujarat State, India, and
identified as Micromonospora chersina sp. nov. no. M956-1.
Dynemicin A was found to exhibit strong growth inhibition of
Gram-positive bacteria, especially of recombination-deficient
mutants such as Bacilus subtillis M45 strain. Most importantly,
both dynemicin A and its triacetate show potent in ViVo
antitumor activity. Dynemicin A is a member of the family of
antitumor antibiotics commonly known as the enediyne natural
products;4 this group includes the calicheamicins, esperamicins,5
neocarzinostatin,6 kedarcidin,7 C-1027,8 and maduropeptin.9
Studies to design models that mimic dynemicin A have been
based upon this working hypothesis.13 It has been generally
assumed that the formation of a diradical intermediate is a
prerequisite for biological activity. The diradical (p-benzyne)
intermediates in simple prototype enediynes were proposed by
Bergman in 1972.14 There have been many reports of different
strategies for the synthesis of the core structure of dynemicin
A,15 and recently the Myers16 and Danishefsky17 groups have
completed its total synthesis.
X Abstract published in AdVance ACS Abstracts, May 15, 1997.
(1) Konishi, M.; Ohkuma, H.; Matsumoto, K.; Tsuno, T.; Kamei, H.;
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1989, 42, 1449. Konishi, M.; Ohkuma, H.; Matsumoto, K.; Saitoh, K.;
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Chem. Soc. 1991, 113, 3106.
S0002-7863(97)00435-6 CCC: $14.00 © 1997 American Chemical Society

5592 J. Am. Chem. Soc., Vol. 119, No. 24, 1997
Magnus et al.
Scheme 1
Scheme 2
Retrosynthetic Analysis (X ) H or OR)
enediyne section can be constructed from a 3-(silyloxy)-
quinolinium intermediate, 7, leading directly to 6.
In Scheme 1 dynemicin A is drawn in two ways. The first
emphasizes the enediyne (F-ring), and is a particularly good
representation for illustrating the diradical mechanism, Scheme
2. The second drawing more readily shows the bicyclo[7.3.1]-
enediyne core in relation to calicheamicinone (2). A third way
of drawing dynemicin A is shown in Scheme 3 that lends itself
to providing a clear picture of our retrosynthetic analysis. The
enediyne bisects the two fused six-membered rings, providing
a pseudo-axis of symmetry. While this may seem to be a mute
point, the structural relationships between compounds and the
subsequent analysis of possible pathways for their synthesis can
frequently be strongly influenced by how the compounds are
drawn.
As an extension of our research on esperamicin and cali-
cheamicin,18 we have applied the key η2Co2(CO)6-propargyl
cation cyclization strategy for the synthesis of cyclic ten-
membered ring enediynes to the synthesis of the azabicyclo-
[7.3.1]enediyne core structure 3, Scheme 3.19
We considered that the core structure 3 should be a stable
molecule with respect to cycloaromatization at ambient tem-
peratures, and could be derived from 4, which in turn should
be available from a cobalt-mediated cyclization of 5. The
Synthesis of the Azabicyclo[7.3.1]enediyne Core
The protected enediyne 9 was prepared using two consecutive
palladium(0)-catalyzed acetylenic coupling reactions. Coupling
(15) Wood, J. L.; Porco, Jr. J. A.; Taunton, J.; Lee, A. Y.; Clardy, J.;
Schreiber, S. L. J. Am. Chem. Soc. 1992, 114, 5898. Porco, Jr. J. A.;
Schoenen, F. J.; Stout, T. J.; Clardy, J.; Schreiber, S. L. J. Am. Chem. Soc.
1990, 112, 7410. Taunton, J.; Wood, J. L.; Schreiber, S. L. J. Am. Chem.
Soc. 1993, 115, 10378. Nicolaou, K. C.; Hwang, C.-K.; Smith, A. L.;
Wendeborn, S. V. J. Am. Chem. Soc. 1990, 112, 7416. Nicolaou, K. C.;
Maligres, P.; Suzuki, T.; Wendeborn, S. V.; Dai, W.-M.; Chadha, R. K. J.
Am. Chem. Soc. 1992, 114, 8890. Nicolaou, K. C.; Hong, Y.-P.; Torisawa.
Y.; Tsay, S.-C.; Dai, W.-M. J. Am. Chem. Soc. 1991, 113, 9878. Nicolaou,
K. C.; Dai, W.-M.; Tsay, S.-C.; Estevez, V. A.; Wrasidlo, W. Science 1992,
256, 1172. Nicolaou, K. C.; Dai, W.-M. J. Am. Chem. Soc. 1992, 114, 8908.
Dai, W.-M. J. Org. Chem. 1993, 58, 7581. Shair, M. D.; Yoon, T.;
Danishefsky, S. J.J. Org. Chem. 1994, 59, 3755. Shair, M. D.; Yoon, T.;
Chou, T.-C.; Danishefsky, S. J. Angew. Chem., Int. Ed. Engl. 1994, 33,
2477. Nishikawa, T.; Isobe, M.; Goto, T. Synlett 1991, 393. Nishikawa, T.;
Isobe, M. Tetrahedron 1994, 50, 5621. Maier, M. E.; Abel, U. Synlett 1994,
38. Wender, P. A.; Beckham, S.; Mohler, D. L. Tetrahedron Lett. 1995,
36, 209. Wender, P. A.; Zercher, C. K.; Beckham, S.; Haubold, E.-M. J.
Org. Chem. 1993, 58, 5867. Wender, P. A.; Beckham, S.; O’Leary, J. O.
Synthesis 1994, 1278. Nishikawa, T.; Ino, A.; Isobe, M.; Goto, T. Chem.
Lett. 1991, 1271. Nishikawa, T.; Yoshikai, M.; Obi, K.; Isobe, M.
Tetrahedron Lett. 1994, 35, 7997. Nishikawa, T.; Ino, A.; Isobe, M.
Tetrahedron 1994, 50, 1449. Nishikawa, T.; Isobe, M.; Goto, T. Synlett
1991, 99. Sakamoto, Y.; Takahashi, T. Synlett 1995, 513. Takahashi, T.;
Sakamoto, Y.; Yamada, H.; Usui, S.; Fukazawa, Y. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1345.
(14) Jones, R. R.; Bergman, R. G. J. Am. Chem. Soc. 1972, 94, 660.
Bergman, R. G. Acc. Chem. Res. 1973, 6, 25. Lockhart, T. P.; Comita, P.
B.; Bergman, R. G. J. Am. Chem. Soc. 1981, 103, 4082. Lockhart, T. P.;
Bergman, R. G. J. Am. Chem. Soc. 1981, 103, 4091. For biradical activity,
see: Chapman, O. L.; Chang, C. V. C.; Kole, J. J. Am. Chem. Soc. 1976,
98, 5703. Darby, N; Kim, C. U.; Salaun, J. A.; Shelton, K. W.; Takeda, S.;
Masamune, S. J. Chem. Soc. 1971, 1516. Wong, H. N. C.; Sondheimer, F.
Tetrahedron Lett. 1980, 21, 217.
(16) Myers, A. G.; Fraley, M. E.; Tom, N. J.; Cohen, S. B.; Madar, D.
J. Chem. Biol. 1995, 2, 33. Myers, A. G.; Fraley, M. E.; Tom, N. J. J. Am.
Chem. Soc. 1994, 116, 11556.

Synthetic and Mechanistic Studies of Dynemicin A
J. Am. Chem. Soc., Vol. 119, No. 24, 1997 5593
Scheme 3
Scheme 4a
a Conditions: (a) HCCCH2OTHP/THF/n-BuNH2/Pd(PPh3)4 (2.5 mol %)/CuI (5 mol %), 8 (72%). (b) HCCSiMe3/THF/n-BuNH2/Pd(PPh3)4 (2.5
mol %)/CuI (5 mol%), 9 (90%). (c) TBAF‚H2O/Et2O, 10 (100%). (d) 10/EtMgBr/THF, followed by 11 or 12 and AdOCOCl, 13 (64%), 14 (75%).
(e) p-TsOH‚H2O/EtOH, 15 (87%), pyridinium tosylate/EtOH, 16 (86%). (f) Co2(CO)8/EtOAc, 17 (60%), Co2(CO)8/THF, 18 (59%) and 20 (33%).
(g) Ce(NH4)2(NO2)6/acetone/2,6-di-tert-butyl-4-methylpyridine, 16 (76%). (h) Tf2O/2-nitropropane/2,6-di-tert-butyl-4-methylpyridine at -10 °C
for 15 min, followed by Ce(NH4)2(NO2)6/acetone, 23 (55%), 24 (53%). (i) TFA/CH2Cl2, 25 (81%), 26 (78%).
of propargyl O-THP ether, with cis-1,2-dichloroethylene gave
8 (72%), Scheme 4.20 (Trimethylsilyl)acetylene was coupled
to 8 to give the enediyne tetrahydropyranyl ether 9 (90%).
Treatment of 9 with tetrabutylammonium fluoride (or, alterna-
tively, lithium hydroxide in aqueous THF) gave the terminal
acetylene 10 in quantitative yield. This sequence provides large
quantities of 10 (70 g), which was used immediately since it is
difficult to store without extensive decomposition.
Initially, we used 3-hydroxyquinoline to test the viability of
the strategy, and we also experimented with several chlorofor-
mates to convert 10 and 11 into 13. Eventually, it was found
that the most suitable carbamate derivative that could be readily
removed to provide access to the unprotected aniline derivatives
was the adamantyl carbamate adduct, Scheme 4.21 Treatment
of 1122 with the magnesioacetylide salt of 10 in the presence of
(17) Shair, M. D.; Yoon, T. Y.; Mosny, K. K.; Chou, T. C.; Danishefsky,
S. J. J. Am. Chem. Soc. 1996, 118, 9509. Shair, M. D.; Danishefsky, S. J.
J. Org. Chem. 1996, 61, 16. Shair, M. D.; Yoon, T. Y.; Danishefsky, S. J.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1721.
(18) Magnus, P. Tetrahedron 1994, 50, 1397.
(20) Stephens, R. D.; Castro, C. E. J. Org. Chem. 1963, 28, 3313.
Ratovelomanana, V.; Linstrumelle, G. Tetrahedron Lett. 1984, 25, 6001.
Guillerm, D.; Linstrumelle, G. Tetrahedron Lett. 1985, 26, 3811. Coste, J.;
Frerot, E.; Jouin, P.; Castro, B. Tetrahedron Lett. 1991, 32, 1967.
Sonogashira, K.; Tohda, Y.; Hashigara, N. Tetrahedron Lett. 1975, 16, 4467.
(19) Preliminary communications: Magnus, P., Fortt, S. M. J. Chem.
Soc., Chem. Commun. 1991, 544. Magnus, P.; Parry, D.; Illiadis, T.;
Eisenbeis, S. A.; Fairhurst, R. A. J. Chem. Soc., Chem. Commun. 1994,
1543.

5594 J. Am. Chem. Soc., Vol. 119, No. 24, 1997
Magnus et al.
adamantyl chloroformate (Ad ) adamantyl) gave, in a com-
pletely regiospecific reaction,23 the dihydroquinoline 13 (64%).
Selective deprotection of the THP ether 13 to give 15 (87%)
was accomplished using p-TsOH‚H2O.
Scheme 5a
Complexation of 15 with Co2(CO)8 gave 17 (60%) along with
some complexation at the other acetylene 19 (ca. 15%) and small
amounts (<5%) of biscomplexation. In this series the minor
regioisomer was not recycled. When the alcohol 17 was
exposed to triflic anhydride/2,6-di-tert-butyl-4-methylpyridine
(DBMP) in CH2Cl2 at -10 °C, a rapid transformation took place
to give a symmetrical ether (69%).24 None of the desired adduct
21 could be detected. We reasoned that the alcohol 17 could
be intermolecularly hydrogen bonded, and as a consequence
ionization of the hydroxyl group to the η2-Co2(CO)6-propargylic
cation takes place when it is solvated by un-ionized molecules
of 17 (in CH2Cl2).25 This solvate collapses to the ether faster
than intramolecular enol ether trapping to give 21. This simple
notion predicts that a cation-solvating solvent might stabilize
the η2-Co2(CO)6-propargylic cation long enough to be trapped
by the TBS enol ether. Treatment of 17 with triflic anhydride/
DBMP in (Me)2CHNO2 (ꢀ 35.9)/CH2Cl2 (ꢀ 8.9) (1:2) at -10
°C gave the cyclized product 21, and none of the ether. The
cobalt-complexed cyclization product 21 was quite unstable and
could not be readily purified without extensive decomposition,
and therefore it was immediately oxidatively decomplexed using
ceric ammonium nitrate (CAN) to give 23 (55% from 17).
Treatment of the newly generated enediyne core 23 with
trifluoroacetic acid in dichloromethane cleanly generated the
sec-amine 25 (81%).
a Conditions: (a) p-MeOC6H4NH3Cl/AcOH/PhSH (catalytic), reflux,
12b (48%). (b) SnCl2/HCl, 12c (86%). (c) NaNO2/H2SO4, 12d (95%).
(d) t-BuMe2SiCl/DMF, 12e (91%).
mucobromic acid with NaOH)27 was condensed with p-anisidine
to give the vinylogous enamide 12a. Treatment of 12a with
p-anisidine hydrochloride/AcOH in the presence of a catalytic
amount of thiophenol gave 12b. The function of thiophenol
(it clearly accelerates the reaction) is presumably to equilibrate
the E/Z-isomers of 12a, thus facilitating cyclization into 12b.
Reduction, diazotization, and hydrolysis of 12b gave 12d, Via
12c. Standard silylation conditions gave 12e.
Following the same reaction protocols 12e was converted
into 14 and then into 16.28 Complexation of 16 with Co2(CO)8
in tetrahydrofuran gave 18 (59%) along with some complexation
at the other acetylene 20 (33%) and traces of biscomplexation.
The undesired regioisomer 20 was recycled by ceric ammonium
nitrate oxidation to give 16 (76%). All attempts to make this
complexation more selective did not improve the above ratio
(1.8:1). The uncomplexed propargyl alcohol 16, and the η2-
Co2(CO)6 isomer 20 do not cyclize to the dynemicin core
structure using the conditions described below.
Treatment of the cobalt adduct 18 with triflic anhydride/
DBMP in (Me)2CHNO2 at -10 °C for 30 min gave 22. Direct
oxidative workup by ceric ammonium nitrate oxidation gave
the cyclized enediyne 24 (53%, for the two steps). The structure
of 24 was confirmed by X-ray crystallography.29 The adamantyl
carbamate was removed by treatment of 24 with trifluoroacetic
acid in dichloromethane to give the amine 26 (78%). While
the route to the azabicyclo[7.3.1]enediyne core structure 24 is
short (five steps from 12, overall 15% yield), the 3-(silyloxy)-
quinoline 12 is tedious to make, and lacks flexibility for more
substituted systems.
The next stage required the synthesis of 3-hydroxy-6-
methoxyquinoline (12d), which despite its apparent simplicity
proved to be a tedious compound to synthesize, especially on a
large scale. The classical sequence shown in Scheme 5 proved
to be the most practical.26
O-Sodionitromalonodialdehyde (27) (made by treatment of
(21) Haas, W. L.; Krumkalns, E. V.; Gerzon, K. J. Am. Chem. Soc. 1966,
88, 1988.
(22) Organic Syntheses; Baumgarten, H. E., Ed.; Wiley: New York,
1973; Collect. Vol. V, p 635.
(23) Yamaguchi, R.; Nakazono, Y.; Kawanisi, M. Tetrahedron Lett. 1983,
24, 1801.
(24) For examples of η2-Co2(CO)6-propargylic cation reactions and
cyclizations, see: Nicholas, K. M.; Pettit, R. Tetrahedron Lett. 1971, 3475.
Nicholas, K. M.; Nestle, M. O.; Seyferth, D. In Transition Metal Organo-
metallics in Organic Synthesis; Alper, H., Ed.; Academic Press: New York,
1978; Vol. 2. Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207. Nicholas, K.
M.; Mulraney, M.; Bayer, M. J. Am. Chem. Soc. 1980, 102, 2508. Schreiber,
S. L.; Sammakia, T.; Crowe, W. E. J. Am. Chem. Soc. 1986, 108, 3128.
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109, 5749. Montana, A. M.; Nicholas, K. M.; Khan, M. A. J. Org. Chem.
1988, 22, 5193. The symmetrical ether is formulated as i, and is a mixture
of diastereomers.
Alternative Synthesis of the Azabicyclo[7.3.1]enediyne
Core
Commercially available 6-hydroxyquinoline, was treated with
triisopropylsilyl trifluoromethanesulfonate and 2,6-lutidine to
give 28 in >95% yield, Scheme 6. Treatment of the quinoline
28 with the magnesioacetylide salt of 10 resulted in exclusive
1,2-addition, affording 29. When 29 was treated with MCPBA
(25) For general discussions of the effects of solvent polarity on reaction
rates see: SolVents and SolVent Effects in Organic Chemistry; Reichardt,
C., Ed.; VCH: Weinheim, Germany, 1988. Kinetics and Mechanism. A
Study of Homogeneous Chemical Reactions; Frost, A. A., Pearson, R. G.,
Eds.; Wiley: New York, 1963. Mechanism in Organic Chemistry; Alder,
R. W., Baker, R., Brown, J. M., Eds.; Wiley: New York, 1975.
(26) Weissberg, A.; Taylor, E. C. The Chemistry of Heterocyclic
Compounds. Quinoline. Parts I-III; Jones, G., Ed.; Interscience Publications,
John Wiley & Sons: London, 1977; Vol. 32. Van der Plas, H. C.;
Yamaguchi, T. Recl. TraV. Chim. Pays-Bas. 1977, 96, 89. Cho, I.; Gong,
L.; Muchowski, J. M. J. Org. Chem. 1991, 56, 7288. Stanetty, P.; Koller,
H.; Mihovilovic, M. J. Org. Chem. 1992, 57, 6833. Arnold, Z. Collect.
Czech. Chem. Commun. 1973, 38, 1168. Lloyd, D.; McNab, H. Angew.
Chem., Int. Ed. Engl. 1976, 15, 459.
(27) Uhle, F. C.; Jacobs, W. A. J. Org. Chem. 1945, 10, 76. Morley, J.
S.; Simpson, J. S. C. J. Chem. Soc. 1948, 2024. Fanta, P. E. Organic
Syntheses; Wiley: New York, 1963; Collect. Vol. IV, p 844.
(28) Miyashita, N.; Yoshikoshi, A.; Grieco, P. A. J. Org. Chem. 1977,
42, 3772.
(29) Lynch, V. M.; Iliadis, T.; Fairhurst, R.; Magnus, P.; Davis, B. E.
Acta Crystallogr., Sect. C 1995, C51, 782.

Synthetic and Mechanistic Studies of Dynemicin A
J. Am. Chem. Soc., Vol. 119, No. 24, 1997 5595
Scheme 6a
a Conditions: (a) 10/EtMgBr/THF, followed by 28 and AdOCOCl. (b) MCPBA/CH2Cl2/NaHCO3, 30 (100%). (c) (PhSe)2/EtOH/NaBH4, 31
(64%). (d) t-BuMe2SiCl/DMF/imidazole, 32 (95%). (e) MCPBA/CH2Cl2, followed by pyridine, reflux, 33 (95%). (f) Pyridinium tosylate/EtOH, 34
(95%). (g) Co2(CO)8/EtOAc, 35 (60%). (h) Tf2O/2-nitropropane/2,6-di-tert-butyl-4-methylpyridine at -10 °C for 15 min, followed by Ce(NH4)2(NO2)6/
acetone, 36 (55%). (i) CsF/MeCN/H2O, 37 (95%).
in dichloromethane, a 1:1 mixture of epoxides was formed in
low yield, whereas exposure of 29 to MCPBA in the presence
of aqueous sodium bicarbonate gave 30 as a single stereoisomer,
presumably with the stereochemistry as shown. Treatment of
diphenyl diselenide with sodium borohydride resulted in a
selenyl/borate complex which when added to 30 generated the
anti-adduct 31.30 The hydroxyl group was protected as the tert-
butyldimethylsilyl ether 32 under standard conditions, and
oxidation with MCPBA generated the selenoxide, which upon
warming in the presence of excess pyridine undergoes syn-
elimination to produce the dihydroquinoline 33 (>95%). This
alternative synthesis is efficient, with 33 being produced in good
overall yield (ca. 40%). Conversion of 33 into 36 proceeded
without complications. Treatment of 36 with cesium fluoride
in wet acetonitrile afforded the desired phenol 37 in 97% yield.
The phenol 37 is only moderately stable at room temperature,
and slowly decomposes due to air oxidation.
39b. The formation of the iminoquinomethide intermediate 39a
is completely analogous to the chemistry exhibited by dyne-
micin, and speculated to be an intermediate formed from
opening of the epoxide in 1.
Direct oxidation of the enolate 24a with dibenzoyl peroxide
gave the bridgehead benzoate 43. The enolate 24a was readily
alkylated; for example, treatment of 24a with chloromethyl
methyl ether gave 44 in excellent yield. Quite surprisingly,
attempts to form the enol triflate in tetrahydrofuran by treatment
with a variety of triflating reagents only resulted in the C-triflate
45 with small amounts of the desired O-triflate 46.32 Eventually,
it was found that the O-triflate 46 became the major product if
toluene was used as the solvent, but the yield is a modest 33%.
While 46 underwent PdII-catalyzed carboxymethylation to give
47,33 which potentially allows access to the E-ring of dynemicin,
the low yields did not make it practical for further investigation.
Rates of Cycloaromatization
Bridgehead Enolate Reactivity
We have found that, for a series of enediynes where the
bonding distance between the acetylenes (r, 3, 8) is virtually
identical, their relative rates of cycloaromatization are dramati-
cally different, Scheme 8.34 Measuring the rate of cycloaro-
matization of 24 (r ) 3.4 Å, X-ray) to give 48 (68%) in 3,6-
dihydrotoluene from 65 to 114 °C gave the thermodynamic
parameters. The data were extrapolated to 37 °C (Table 1),
and clearly show that 24 is very stable under physiological
conditions. There is a modest solvent effect on the rate of
cyclization of 24 to 48, t1/2(cyclohexadiene, 81 °C) ) 10.9 h
versus t1/2(3,6-dihydrotoluene, 81 °C) ) 35.0 h and t1/2(THF,
67 °C) ) 114.9 h versus t1/2(3,6-dihydrotoluene, 67 °C) ) 167.4
h.35
Having established a concise route to gram quantities of the
core structure, we examined some of the chemistry of 24. The
bridged ketone 24 was readily enolized using LiN(TMS)2/THF/
-78 °C, and quenching with PhSeBr gave the bridgehead
selenide 38 (93%), Scheme 7.31 The X-ray structure of 24
shows that the bridgehead proton is in the plane of the π-orbitals
of the carbonyl group, and therefore ideally aligned for
enolization. Oxidation of 38 (MCPBA) gave the selenoxide
39 which was sufficiently stable to be isolated. Heating 39 at
40 °C resulted in rearrangement to the selenite ester 40, and
eventually the alcohol 41 (68%). If 39 is heated in the presence
of the trimethylsilyl enol ether of acetone, the bridgehead
acetonyl compound 42 is formed. These transformations
indicate that the iminoquinomethide 39a is formed from 39,
and does not lose a proton to form the R,â-unsaturated ketone
The bridgehead alkylated adduct 44 undergoes cycloaroma-
tization to give 50 (>95%), in an exceptionally clean reaction
(32) Stang, P. J.; Treptow, W. Synthesis 1980, 283.
(33) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1985, 26, 1109.
(34) Magnus, P.; Fairhurst, R. A. J. Chem. Soc., Chem. Commun. 1994,
1541.
(30) Liotta, D.; Markiewicz, W.; Santiesteban, H. Tetrahedron Lett. 1977,
4365.
(31) Magnus, P.; Carter, P.; Elliot, J.; Lewis, R.; Harling, J.; Pitterna,
T.; Bauta, W. E.; Fortt, S. J. Am. Chem. Soc. 1992, 114, 2544. Magnus, P.;
Lewis, R.; Bennett, F. J. Am. Chem. Soc. 1992, 114, 2560.
(35) While the t1/2 differ by a factor of 3.2, this represents a very small
change in ∆Gq.

5596 J. Am. Chem. Soc., Vol. 119, No. 24, 1997
Magnus et al.
Scheme 7a
a Conditions: (a) Li(TMS)2/THF/-78 °C. (b) PhSeBr, 38 (93%). (c) MCPBA/CH2Cl2/-78 °C. (d) 1-[(Trimethylsilyl)oxy]-1-methylethylene
followed by TMSOTf, 41 (22%) and 42 (51%), dimethyldioxirane/acetone, 41 (68%). (e) (PhCO)2O2, 43 (55%), ClCH2OMe, 44 (81%). (f) LiN(TMS)2/
PhMe/Tf2O/-78 °C, 45 (10%) and 46 (33%). (g) Pd(OAc)2/DMF/PPh3/MeOH/Et3N/CO at 25 °C, 47 (55%).
Scheme 8a
a Conditions: (a) NaBH4/THF/MeOH, 52 (43%). (b) n-BuLi/(EtO)2P(O)CH2CN/THF, 53 (85%).
compared to 24. The thermodynamic parameters are very
similar to those of 24, and indicate that it is more resistant to
cycloaromatization even though the distance between the two
bonding acetylene carbon atoms (r) must be virtually the same.
The amine 26 was heated in THF at temperatures from 51 to
67 °C to give 49 (72%). The most notable feature is that the
rate of cycloaromatization of 26 increases more rapidly with
increasing temperature than that of the carbamates 24 and 44.
At 37 °C 26 cycloaromatizes 1.6 times faster than 24, and at
65 °C the difference increases to 20 times (∆Gq ) 29 and 28.1,
respectively). The origin of this difference lies in the T∆Sq
term.36
The remarkable change in entropy (26, ∆Sq ) +28.3
cal‚mol-1, 24, ∆Sq ) -9.3 cal‚mol-1) appears to be caused by

Synthetic and Mechanistic Studies of Dynemicin A
J. Am. Chem. Soc., Vol. 119, No. 24, 1997 5597
Table 1.
substrate
∆Gq (kcal‚mol-1
)
∆Hq (kcal‚mol-1
)
∆Sq (cal‚mol-1‚K-1
)
Ea (kcal‚mol-1
)
rate (s-1) (37 °C)
t1/2
24
26
53
44
29.0
28.1
25.1
30.2
26.1
36.9
21.7
26.1
-9.3
28.3
-10.9
-9.3
26.8
37.6
22.2
33.0
2.48 × 10-8
4.10 × 10-8
1.26 × 10-5
3.50 × 10-9
324 d
196 d
15.3 h
6.28 y
Scheme 9a
a Conditions: (a) Heating in 2,5-dihydrotoluene (air leakage). (b) MCPBA/CH2Cl2, 55 (59%), 56 (82%). (c) Heating in 2,5-dihydrotoluene at
140 °C, 57 (15%).
hydrogen bonding. Both the NH and CdO infrared bands of
26 change as a function of concentration, indicating intermo-
lecular hydrogen bonding. Variable concentration 1H NMR also
confirmed this phenomenon. The degree of intermolecular
hydrogen bonding (aggregation) is a function of temperature,
and therefore causes the entropy of activation to increase and
become positive (dissociation).
The ketone 24 reacted with (EtO)2P(O)CH2CN/n-BuLi to give
53 (85%) as a single stereoisomer. While the distance (r)
between the bonding acetylenic carbon atoms in 24 and 53 is
virtually the same, and the hybridization at the bridging carbon
atom is trigonal in both compounds, 53 cycloaromatizes to give
54 (X-ray) 500 times faster than 24 at 37 °C! An even more
dramatic change in rate occurs when the bridging trigonal carbon
atom is made tetrahedral. Reduction of 24 with sodium
borohydride in methanol at 25 °C gave directly the cycloaro-
matized alcohol 52 (43%). We could not detect the intermediate
enediyne 51. Using a conservative estimate, the alcohol 51
cycloaromatizes 106 times faster than 24 at 37°C!
While the above cycloaromatization rate studies were con-
ducted with the exclusion of air, for the slower reactions, for
example, 24 to 48 at 65 °C, it was found that a new product
slowly accumulated as air leaked into the reaction. The new
compound turned out to be the cycloaromatized lactone 55, and
an authentic sample was made by treating 48 with m-chloro-
peroxybenzoic acid, Scheme 9. Surprisingly, when 24 was
exposed to m-chloroperoxybenzoic acid, the amide-acetal 56
(82%) was the only isolable product.37 Even if less than 1 equiv
of oxidant was used, 56 and 24 were the only materials present.
Apparently, the further Baeyer-Villiger oxidation of the
presumed intermediate 24b (in the open iminium ion form) is
faster than 24! When 56 was heated at 140 °C, it extruded
carbon dioxide, cycloaromatized, and eliminated water to give
the indole derivative 57 (15%).
Quantitative investigations indicate that the overall change
in strain energy from enediyne to cycloaromatized adduct
provides the closure driving force. We have presented com-
putational evidence that factors controlling the ease of cycloaro-
matization are directly related to strain energy in the transition
state rather than to proximity of the acetylenic carbon atoms
(r) in the ground state.38 The experimental data reported above
support the strain hypothesis, but the relative rates are not
predicted by computational methods that worked in the espe-
ramicin/calicheamicin core compound(s).39 It therefore appears
that the small changes in ∆Gq, which are manifested in
substantial rate differences, are difficult to match by computa-
tional methods.
Non-Radical Cycloaromatization Pathway for the
Azabicyclo[7.3.1]enediyne Core Structure Initiated by
Thiolate Addition
It has been assumed that the formation of a diradical
intermediate is a prerequisite for biological activity.4 The simple
azabicyclo[7.3.1]enediyne dynemicin core analogue 23 under-
goes cycloaromatization Via a polar non-radical pathway, and
exhibits both in Vitro and in ViVo antitumor activity.40
Treatment of 23 with sodium 3,5-dimethylthiophenolate/THF
at 0 °C gave a mixture of two compounds, 58 (ca. 1:1), which
(38) For calculations concerning the rate of diyl formation, see: Snyder,
J. P.; Tipword, G. E. J. Am. Chem. Soc. 1990, 112, 4040 3. Snyder, J. P.
J. Am. Chem. Soc. 1989, 111, 7630. Snyder, J. P. J. Am. Chem. Soc. 1990,
112, 5367. Magnus, P.; Fortt, S. M.; Pitterna, T.; Snyder, J. P. J. Am. Chem.
Soc. 1990, 112, 4986. Semmelhack, M. F.; Gallagher, J.; Minami, T.; T.
Date, T. J. Am. Chem. Soc. 1993, 115, 11618.
(36) Isaacs, N. S. Physical Organic Chemistry; Longman Scientific &
Technical: Birmingham, AL, 1987.
(37) The double Baeyer-Villiger oxidation of diethyl ketals gives a
mixture of orthocarbonates and carbonate. Bailey, W. F.; Shih, M.-J. J.
Am. Chem. Soc. 1982, 104, 1769.
(39) Dr. David Langley (Bristol-Myers Squibb) is thanked for his efforts
to match the relative ∆Gq values by computational methods.
(40) Magnus, P.; Eisenbeis, S. A. J. Am. Chem. Soc. 1993, 115, 12627.

5598 J. Am. Chem. Soc., Vol. 119, No. 24, 1997
Magnus et al.
Scheme 10a
a Conditions: (a) 3,5-Dimethylthiophenol/NaH/THF/0 °C, 58 (73%). (b) TFA/CH2Cl2, 59 (25%). (c) NaH/THF/25 °C, 60 (72%). (d) NaH/THF/
MeOD.
Scheme 11
upon deprotection (TFA) gave a single completely aromatized
adduct, 59 (structure by X-ray), Scheme 10. Conducting the
above reaction in THF-d8 did not result in any deuterium
incorporation into 58 or 59, thus precluding a radical intermedi-
ate in the conversion of 23 into 58. Treatment of 23 with
sodium 3,5-dimethylthiophenolate/THF/excess NaH at 0 °C gave
the naphthol 60 (72%). Carrying out the same transformation
in the presence of MeOD gave 23a with the incorporation of
two deuterium atoms in the positions shown. Excess NaH
converted 58 into 60 (72%). Irradiation of 23 in the presence
of PhSSPh/benzene resulted in slow decomposition to an
intractable mixture.
trapped by THF-d8.41 It has been shown by Saito that there is
a second pathway available for the cycloaromatization of
neocarzinostatin. Under physiological conditions (D2O/buffered
2-mercaptoethanol) neocarzinostatin cycloaromatizes with the
incorporation of one deuterium atom (80%) in the aromatic
ring.42 This duality of cycloaromatization mechanisms, diradical
and polar, has not been seen in any other enediynes. This study
shows that the dynemicin core analogue 23 can undergo
cycloaromatization to 23e Via the “normal” thermal (97 °C)
diradical cycloaromatization pathway, and in the presence of
thiolate (0 °C), a polar cycloaromatization pathway intervenes
to give 58/60.43
A plausible mechanistic explanation for this unprecedented
reaction involves thiolate addition to the enediyne 23 to give
the cumulene 23b, which can undergo further thiolate addition
resulting in the enolate 23c. Enolate anion ring closure to 23d
followed by protonation and tautomerism results in 58, which
gives 60. It should be noted that 23 does not undergo the normal
Bergman cycloaromatization to give 23e at an appreciable rate
until it is heated to at least 97 °C (t1/2 ) 8.26 h). The mechanism
shown in Scheme 11 is consistent with the MeOD experiment,
and it is probable that the deuterium para to the -OH was
introduced by base-catalyzed exchange after elimination of
ArS-.
Naphtho[2,3-h]quinoline Portion of Dynemicin
The biological activity of anthraquinones and methods for
their synthesis have been the subject of numerous reviews.44
A
number of anthraquinones exhibit in Vitro activity versus murine
L1210 leukemia cell lines, as well as in ViVo activity against
P388 leukemia cell lines.45 This raises the intriguing possibility
(41) Myers, A. G. Tetrahedron Lett. 1987, 28, 4493. Myers, A. G.;
Dragovich, P. S. J. Am. Chem. Soc. 1989, 111, 9130. Myers, A. G.; Proteau,
P. J. J. Am. Chem. Soc. 1989, 111, 1146. Nicolaou, K. C.; Skokotas, G.;
Furuya, S.; Suemune, H.; Nicolaou, C. Angew. Chem., Int. Ed. Engl. 1990,
1064.
(42) Sugiyama, H.; Yamashita, K.; Nishi, M.; Saito, Tetrahedron Lett.
1992, 33, 515. Hirama, M.; Fujiwara, K.; Shigematu, K.; Fukazawa, Y. J.
Am. Chem. Soc. 1989, 111, 4120. Fujiwara, K.; Kurisaki, A.; Hirama, M.
Tetrahedron Lett. 1990, 31, 4329.
Myers has shown that neocarzinostatin chromophore under-
goes thiol addition to trigger cycloaromatization. The actual
cycloaromatization reaction involves a diradical which has been

Synthetic and Mechanistic Studies of Dynemicin A
J. Am. Chem. Soc., Vol. 119, No. 24, 1997 5599
Scheme 12a
a Conditions: (a) (i) PPh3/CBr4, (72%). (ii) LiN(TMS)2/THF followed by n-BuLi and ClCO2Me, 62 (95%). (b) 4,7-Dimethoxyisobenzofuran/
PhH/reflux for 18 h, 63 (100%). (c) TBSOTf/2,6-lutidine/CH2Cl2, 64 (99.6%). (d) LDA/THF/25 °C, followed by PivCl/py, 65 (72%). (e) AgIIO/
dioxane HNO3, 66 (72%). (f) HBr/AcOH/reflux followed by Ac2O/py, 68 (68%).
that the anthraquinone portion of dynemicin could have
antitumor activity, rather than simply serving as a DNA
intercalating partner.46,47
it was found to be extremely insoluble in the majority of organic
solvents, thus making characterization difficult. Acetylation of
67 gave the triacetate 68 (68% from 66). Due to the instability
of the triacetate 68 (deacetylation), and the inability to purify
the trihydroxyanthraquinone 67, neither were submitted for
biological evaluation. However, 66 showed promising results.
The in Vitro assays against HCT-116 cell lines provided an IC50
value of 500 ng/mL. Comparisons to dynemicin A and its
triacetate reveal that 66 is less active in Vitro, with dynemicin
A 1 (R ) H) and its triacetate 1 (R ) Ac) having IC50 values
of 0.28 and 0.18 ng/mL, respectively, in HCT-116 cell lines.43
An alternative synthesis of the naphtho[2,3-h]quinoline core
structure was examined that avoided the construction of 4,7-
dimethoxyisobenzofuran, and is regiospecific, Scheme 13.
ortho Lithiation of 2,5-dimethoxybenzyl alcohol using n-
butyllithium in tetrahydrofuran at reflux, followed by quenching
the resulting dianion with carbon dioxide and acidification, gave
the lactone 70 (80%). Addition of the lactone 70 to a solution
of lithium diisopropylamide in tetrahydrofuran, followed by
ethyl 3-(3-methylpyrid-2-yl)propenoate gave the adduct 71 (and
stereoisomer) in excellent yield.
The aldehyde 6148 was converted into the alkyne 62 using
standard methodology,49 and heated with 4,7-dimethoxyisoben-
zofuran in benzene at reflux to afford the adduct 63 in
quantitative yield, Scheme 12.50 The bridging ether in 63 was
cleaved with tert-butyldimethylsilyl trifluoromethanesulfonate,
affording a 5:1 ratio of (tert-butyldimethylsilyl)oxy-protected
phenols 64 (only one regioisomer shown). Treatment of 64 with
lithium diisopropylamide in tetrahydrofuran, followed by piv-
aloyl chloride, gave 65.51 The mixture of 65 (and regioisomer)
was readily oxidized to the anthraquinone 66 (72%, AgIIO,
HNO3/dioxane).52 The minor regioisomer was destroyed under
these conditions. Deprotection of the anthraquinone 66 proved
to be quite difficult; however, warming 66 with 48% aqueous
HBr/AcOH gave 67. Although the triol 67 could be isolated,
(43) The core azabicyclo[7.3.1]enediyne compounds 25 showed in ViVo
potency and activity (efficacy, T/C > 125%) in P388 leukemia assays using
CDF1 mice (2 mg/kg gave T/C values of 175% and 170%, respectively.
Kedarcidin gave a T/C of 175% at 2.4 mg/kg. In a distal solid tumor model,
which measured delay in tumor growth of a subcutaneous M109 lung
carcinoma, 26 was active (T - C ) 7.5 days) when administered
intervenously every two days beginning on the day of tumor implant for a
total of five doses of 1.2 (mg/kg)/dose. Using the same model and schedule,
25 was found to be marginally active (T - C ) 3.0 days) while esperamicin
(T - C ) 11.0 days at 0.05 (mg/kg)/dose) and neocarzinostatin (T - C )
19.3 days at 0.6 (mg/kg)/dose) were more active. In Vitro cytotoxicity,
assessed in HCT116 human colon carcinoma cells, showed that 25 was
350 times more potent than 23 (IC50 values of 0.21 and 75 µM, respectively).
Dr.’s William C. Rose, Nada Zein, and Wyle Solomon, Bristol-Myers
Squibb, Pharmaceutical Research Institute, Oncology Drug Discovery, P.O.
Box 4000, Princeton, NJ 08543.
Exposure of 71 to p-toluenesulfonic acid in chloroform at
40 °C resulted in clean aromatization to give, after pivaloylation,
the naphthalene derivative 72. When the derived pivaloyl ester
derivative 72 was treated with lithium diisopropylamide in
tetrahydrofuran at -70 to +26 °C, it was converted into 73
(50) 4,7-Dimethoxyisobenzofuran (iv) was made by treatment of ii with
the tetrazine iii.
(44) Kelly, T. R. Tetrahedron 1984, 40, 4537.
(45) (45) Showalter, H. D. H.; Johnson, J. L.; Hoftiezer, J. M. J.
Heterocycl. Chem. 1986, 23, 1491. Showalter, H. D. H.; Johnson, J. L.;
Hoftiezer, J. M.; Turner, W. R.; Werbel, L. M.; Leopold, W. R.; Shillis, J.
L.; Jackson, R. C.; Elslager, E. F. J. Med. Chem. 1987, 30, 121.
(46) Magnus, P.; Eisenbeis, S. A.; Magnus, N. J. Chem. Soc., Chem.
Commun. 1994, 1545.
(47) Chikashita, H.; J. A. Porco. J. A. Jr.; Stout, T. J.; Clardy, J.;
Schreiber, S. L. J. Org. Chem. 1991, 56, 1692. Nicolaou, K. C.; Gross, J.
L.; Kerr, M. A.; Lemus, R. H.; Ikeda, K.; Ohe, K. Angew. Chem., Int. Ed.
Eng. 1994, 33, 781. Okita, T.; Isobe, M. Tetrahedron, 1994, 50, 11143.
Okita, T.; Isobe, M. Tetrahedron 1995, 51, 3737. Okita, T.; Isobe, M. Synlett
1994, 589.
(48) Ochiai, E. J. Org. Chem. 1953, 18, 534. Boekelheide, V.; Lynn,
W. J. J. Am. Chem. Soc. 1954, 76, 1286. Ginsburg, S.; Wilson, I. J. Am.
Chem. Soc. 1957, 79, 481. Mathes, W.; Sauermilch, W. Chem. Ber. 1957,
90, 758. Jones, G.; Mouat, D. J.; Tonkinson, D. J. J. Chem. Soc., Perkin
Trans. 1 1985, 2719.
(49) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
McIntosh, M.; Weinreb, S. J. Org. Chem. 1993, 58, 4823.
While iv has been reported as an intermediate in various [2 + 4]
cycloaddition reactions, it has not been previously isolated presumably
because of its assumed instability. For the synthesis of ii see: Cragg, G.
M. L.; Giles, R. G. F.; Roos, G. P. H. J. Chem. Soc. Perkin Trans. 1 1975,
1339. iii: Geldard,J. F.; Lions, F. J. Org. Chem. 1965, 30, 318. Lynch, V.
M.; Fairhurst, R.; Magnus, P.; Davis, B. E. Acta Crystallogr., Sect. C 1995,
C51, 780-782. Warrener, R. N. J. Org. Chem. 1971, 93, 2346. Priestly,
G. M.; Warrener, R. N. Tetrahedron Lett. 1972, 13, 4295. Recently
Danishefsky has reported the in situ use of 4,7-dimethoxyisobenzofuran
for the synthesis of dynemicin analogs; see: Shair, M. D.; Yoon, T.; Chou,
T.-C.; Danishefsky, S. J. Angew. Chem., Int. Ed. Engl. 1994, 33, 2477.
(51) Branda˜o, M. A. F.; de Oliveira, A. B.; Snieckus, V. Tetrahedron
Lett. 1993, 34, 2437.
(52) Snyder, C. D.; Rapoport, H. J. Am. Chem. Soc. 1972, 94, 227.

5600 J. Am. Chem. Soc., Vol. 119, No. 24, 1997
Magnus et al.
Scheme 13a
a Conditions: (a) n-BuLi/THF/reflux, followed by CO2, 70 (80%). (b) LDA/THF/70, followed by ethyl 3-(3-methylpyrid-2-yl)propenoate/-78
°C, 71 (96%). (c) p-TsOH/CHCl3, followed by PivCl/Et3N/DMAP/CH2Cl2, 72 (87%). (d) LDA/THF/-70 to +26 °C, 73 (95%). (e) Ce(NH4)2(NO2)6/
MeCN/H2O, 74 (74%).
spectra were recorded on General Electric QE-300 (75 MHz) instrument
(95%). Presumably, the origin of the ethyl ether 73 is Via the
as solutions in CDCl3 unless otherwise indicated. Chemical shifts are
reported in parts per million (ppm, δ) downfield from TMS and are
referenced to the center line of CDCl3 (77.0 ppm) as internal standard.
IR spectra were recorded either neat on sodium chloride plates or as
solutions in solvent as indicated using a Perkin-Elmer 1600 FT-IR
spectrometer, and are reported in wavenumbers (cm-1). Low-resolution
chemical ionization (CI) mass spectra were obtained on a TSQ 70
instrument, and the exact mass determinations were obtained on a VG
Analytical ZAB2-E instrument.
intermediate ortho ester 72a, which prefers to eliminate pivaloate
anion rather than ethoxide anion, thus providing in situ
protection of the newly formed anthracene 73.
Oxidation of 73 with ceric ammonium nitrate in acetonitrile-
water gave the anthraquinone 74 as an orange crystalline solid
(74%).53 Tests for cytotoxicity and DNA cleavage were
conducted using etoposide (UP-16) as the reference. The
inhibitory concentration (IC50) of anthraquinone 74 was 2.8 ×
10-3 mg/mL, while the reference had an IC50 of 1.5 × 10-3
mg/mL.43
Routine monitoring of reactions was performed using Merck
Alufolien Kieselgel 60 F254 silica gel and aluminum-backed TLC plates.
Flash chromatography was performed using silica gel Merck Kieselgel
60H F254 and Florisil 100-200 mesh with the solvent indicated.
Summary
In all of the η2Co2(CO)6-acetylene-mediated cyclizations, the
blank reaction without the cobalt metallocycle was unsuccessful.
This strategy has provided short synthetic routes to the core
structures of the other enediyne antitumor agents.54 The rate
studies clearly show that ring strain and conformational factors
control the ease of cycloaromatization. This information should
assist the design of non-natural enediynes with potential
antitumor activity.
N-[(Adamantyloxy)carbonyl]-1,2-dihydro-2-[(Z)-7-[(tetrahydro)-
pyranyloxy]hept-3-ene-1,5-diynyl]-3-[(tert-butyldimethylsilyl)oxy]-
quinoline (13). Ethylmagnesium bromide (36.0 mL, 1 M, 0.036 mol)
was added to a cooled solution of 10 (5.7 g, 0.030 mol) in tetrahy-
drofuran (45 mL), and the mixture was stirred for 20 min followed by
addition of 11 (7.00 g, 0.027 mol) in tetrahydrofuran (30 mL).
Adamantyl chloroformate (7.31 g, 0.034 mol) was slowly added over
a period of 2 h and the mixture stirred for 15 h and poured into saturated
aqueous NH4Cl (100 mL), the layers were separated, and the aqueous
layer was extracted with Et2O (3 × 100 mL). The extracts were dried
(MgSO4) and concentrated in Vacuo. The crude product was chro-
matographed over silica gel eluting with 5% Et2O/pentane to give the
product 13 (10.4 g, 64%) as a pale yellow foam: IR (CDCl3) 2973,
Experimental Section
Unless noted otherwise, all starting materials were obtained from
commercial suppliers and were used without further purification.
Diethyl ether (Et2O) and tetrahydrofuran (THF) were distilled from
sodium/benzophenone under nitrogen prior to use. N,N-Dimethylform-
amide (DMF), hexane, and benzene were distilled from calcium hydride.
Methanol (MeOH) was distilled from magnesium methoxide and stored
over 3 Å molecular sieves under argon. Triethylamine was distilled
from calcium hydride and stored under argon. All reactions involving
organometallic reagents or other moisture sensitive reactants were
executed under an atmosphere of dry nitrogen or argon using oven-
dried and/or flame-dried glassware.
1
2956, 2196, 1702, 1655 cm-1; H NMR (300 MHz, CDCl3) δ 7.56-
7.55 (1H, m), 7.09-6.97 (3H, m), 5.76-5.68 (4H, m), 4.75 (1H, bs),
4.35-4.19 (2H, q), 3.87 (1H, m), 3.57 (1H, m), 2.17 (9H, s), 1.83-
1.52 (12H, m), 0.97 (9H, s), 0.26 (3H, s), 0.25 (3H, s); 13C NMR (75
MHz, CDCl3) δ 151.9, 150.1, 131.6, 129.0, 127.7, 126.9, 125.2, 124.9,
124.8, 124.3, 119.5, 119.3, 103.5, 96.9, 93.1, 92.9, 82.7, 81.9, 80.2,
61.9, 54.7, 48.9, 41.5, 36.2, 31.0, 30.1, 25.6, 19.1, -4.4, -4.7; HRMS
(CI) calcd for C38H49NO5Si (M+) 627.338, found 627.338.
N-[(Adamantyloxy)carbonyl]-1,2-dihydro-2-[(Z)-7-hydroxyhept-
3-ene-1,5-diynyl]-3-[(tert-butyldimethylsilyl)oxy]quinoline (15). A
solution of 13 (1.34 g, 2.64 mmol) and p-TsOH‚H2O (0.15 g) in ethanol
(30 mL) was stirred at 55 °C for 10 h. The mixture was concentrated
in Vacuo, dissolved in Et2O (50 mL), washed with saturated aqueous
NaHCO3 (20 mL) and brine, dried (MgSO4), and filtered. The filtrate
was concentrated in Vacuo, and the residue chromatographed over silica
gel eluting with 40% Et2O/pentane to give 15 (0.98 g, 87%): IR
Melting points were determined on a Thomas-Hoover melting point
apparatus and are uncorrected. 1H NMR spectra were recorded on a
General Electric QE-300 (300 MHz) spectrometer as solutions in
deuteriochloroform (CDCl3), unless otherwise indicated. Chemical
shifts are expressed in parts per million (ppm, δ) downfield from
tetramethylsilane (TMS) and are referenced to CDCl3 (7.24 ppm) as
internal standard. Coupling constants are given in hertz (Hz). 13C NMR
1
(CHCl3) 3460, 2918, 1689 cm-1; H NMR (300 MHz, CDCl3) δ 7.58
(53) Ho, T.-L.; Hall, T.-W.; Wong, C. M. Synthesis 1973, 206.
(54) Magnus, P. The Use of η2Co2(CO)6-Acetylene Complexes for the
Synthesis of Enediyne Antitumor Antibiotics; SmithKline Beecham Research
Symposium, Organometallic Reagents in Organic Synthesis; Academic Press
Ltd.: New York, 1994; Chapter 1, p 1. Magnus, P.; Carter, R.; Davies, M.;
Elliott, J.; Pitterna, T. Tetrahedron 1996, 52, 6283.
(1H, br s), 7.11-6.98 (3H, m), 5.78-5.69 (3H, m), 4.25 (2H, s), 2.61
(9H, s), 2.17 (6H, s), 0.97 (9H, s), 0.27 (3H, s), 0.26 (3H, s); 13C NMR
(75 MHz, CDCl3) δ 168.2, 131.6, 127.7, 125.3, 124.3, 119.9, 119.8,
119.0, 103.5, 95.2, 93.2, 82.6, 82.2, 80.3, 51.4, 48.9, 41.5, 36.1, 30.9,

Synthetic and Mechanistic Studies of Dynemicin A
J. Am. Chem. Soc., Vol. 119, No. 24, 1997 5601
25.6, 18.2, -4.4, -4.67; HRMS (CI) calcd for C33H42NO4Si (M+ + 1)
gave 14 (16.11 g, 75%): IR (CHCl3) 1687 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.43 (1H, s), 6.62 (1H, dd, J ) 8.8, 2.8 Hz), 6.52 (1H, d, J
) 2.8 Hz), 5.74 (1H, dd, J ) 11.0, 1.4 Hz), 5.68-5.79 (1H, s), 5.67
(1H, d, J ) 11.0 Hz), 5.62 (1H, s), 4.75 (1H, s), 4.31 (1H, dd, J )
16.0, 1.4 Hz), 4.23 (1H, dd, J ) 16.0, 1.4 Hz), 3.77-3.89 (1H, m),
3.76 (3H, s), 3.46-3.58 (1H, m), 2.15 (9H, s), 1.64 (6H, s), 1.45-
1.89 (6H, m), 0.96 (9H, s), 0.25 (3H, s), 0.24 (3H, s); 13C NMR (75
MHz, CDCl3) δ 156.3, 152.0, 128.9, 125.5, 124.8, 119.5, 119.3, 110.5,
109.9, 103.5, 96.8, 93.1, 92.8, 82.7, 81.6, 80.1, 61.9, 55.3, 54.7, 48.8,
41.5, 36.1, 30.9, 30.2, 25.5, 25.3, 19.0, 18.1, -4.3, -4.7; HRMS (FAB)
calcd for C39H51NO6Si (M+) 657.349, found 657.351.
544.288, found 544.288.
N-[(Adamantyloxy)carbonyl]-1,2-dihydro-2-[(Z)-7-hydroxy(5,6-
η2-hexacarbonyldicobaltio)hept-3-ene-1,5-diynyl]-3-[(tert-butyldi-
methylsilyl)oxy]quinoline (17). To a solution of 15 (1.0 g, 2.36 mmol)
in EtOAc (50 mL) at 0 °C was added Co2(CO)8 (0.89 g, 1.1 equiv) as
a solid. Immediate evolution of gas was observed. The mixture was
stirred for 15 min, and concentrated to dryness. The crude product
was chromatographed over silica gel (200 times the original weight of
starting material) and eluted with 20% Et2O/pentane (60% yield): IR
1
(CHCl3) 3215, 2863, 2605, 2030, 1963, 1685, 1650 cm-1; H NMR
(300 MHz, CDCl3) δ 7.61-7.54 (1H, br d), 7.19-7.02 (3H, m), 6.71
(1H, d, J ) 9.2 Hz), 5.83 (1H, s), 5.76 (1H, s), 5.63 (1H, dd, J ) 9.2,
2.3 Hz), 4.82-4.60 (2H, m), 2.17 (9H, s), 1.72 (6H, s), 0.97 (9H, s),
0.27 (3H, s), 0.26 (3H, s); 13C NMR (75 MHz, CDCl3) δ 199.0-198.8,
151.9, 149.9, 138.2, 131.4, 127.6, 125.5, 125.1, 124.4, 124.3, 110.0,
103.6, 97.6, 95.9, 82.3, 81.7, 81.3, 64.1, 49.0, 41.4, 36.1, 30.9, (25.5),
18.1, -4.4, -4.7. This compound was used directly in the next step.
N-[(Adamantyloxy)carbonyl]-1,2-dihydro-2-[(Z)-7-hydroxyhept-
3-ene-1,5-diynyl]-3-[(tert-butyldimethylsilyl)oxy]-6-methoxyquino-
line (16). Pyridinium p-toluenesulfonate (1.23 g, 4.9 mmol) was added
to a solution of 14 (16.1 g, 24.5 mmol) in ethanol (320 mL) at 25 °C
and the solution heated at reflux for 18 h. After the solution was cooled
to 25 °C, the solvent was evaporated in Vacuo, and water (150 mL)
added to the residue. The mixture was extracted with Et2O (200 mL
and 2 × 100 mL), dried (MgSO4), and evaporated to give the crude
product. Flash chromatography over silica gel eluting with 3:2 pentane/
Et2O gave 16 (12.58 g, 89%). Alternatively 16 can be obtained from
the crude product by crystallization from 4:1 pentane/Et2O (50 mL)
N-[(Adamantyloxy)carbonyl]-15-oxobenzo[10a,14a]bicyclo[7.3.1]-
trideca-3,7-diyn-5-ene (23). To a solution of 17 (0.913 g, 1.10 mmol)
in 2-nitropropane (39.0 mL) and 2,6-di-tert-butyl-4-methylpyridine
(DBMP) (1.13 g, 5.50 mmol) at -10 °C was rapidly added triflic
anhydride (Tf2O) (0.56 mL, 3.30 mmol). The mixture was stirred at
-10 °C for 15 min followed by the addition of saturated aqueous
NaHCO3 (20 mL). The layers were separated, and the aqueous layer
was extracted with 2-nitropropane (3 × 10 mL) and dried (MgSO4).
The extracts were filtered and diluted with acetone (70 mL) and cooled
to -10 °C, followed by the addition of ceric ammonium nitrate (CAN)
(4.82 g, 8.80 mmol) in three portions (over 5 min). The mixture was
stirred for an additional 15 min with rapid evolution of gas occurring.
Addition of NEtiPr2 (4.80 mL, 27.5 mmol) resulted in the formation of
a brown precipitate. The mixture was poured onto a column of silica
(50 g) and eluted with EtOAc (500 mL). The organic layers were
concentrated, and the crude product was chromatographed over silica
gel eluting with dichloromethane to give 23 (0.25 g, 55%): IR (CHCl3)
1
(12.15 g, 86%): IR (CHCl3) 3474, 1685, 1653 cm-1; H NMR (300
MHz, CDCl3) δ 7.44 (1H, s), 6.63 (1H, dd, J ) 8.9, 2.7 Hz), 6.52 (1H,
d, J ) 2.7 Hz), 5.77 (1H, m), 5.70-5.80 (1H, m), 5.68 (1H, m), 5.64
(1H, s), 4.27 (2H, s), 3.77 (3H, s), 2.15 (9H, s), 1.64 (6H, s), 0.96 (3H,
s), 0.26 (3H, s), 0.25 (3H, s); 13C NMR (75 MHz, CDCl3) δ 156.3,
152.2, 128.9, 125.3, 124.8, 119.9, 119.6, 110.5, 109.9, 103.6, 95.3,
93.2, 82.5, 81.9, 80.2, 55.3, 51.3, 48.9, 41.5, 36.1, 30.9, 25.5, 18.1,
-4.33, -4.71; HRMS (FAB) calcd for C34H43NO5Si (M+) 579.291,
found 573.290.
N-[(Adamantyloxy)carbonyl]-1,2-dihydro-2-[(Z)-7-hydroxy(5,6-
η2-hexacarbonyldicobaltio)hept-3-ene-1,5-diynyl]-3-[(tert-butyldi-
methylsilyl)oxy]-6-methoxyquinoline (18). A solution of dicobalt
octacarbonyl (2.67 g, 7.81 mmol) in tetrahydrofuran (60 mL) was added
rapidly in a single portion to a stirred solution of 16 (4.27 g, 7.44 mmol)
in tetrahydrofuran (80 mL) at 25 °C. After the initial evolution of gas
the mixture was stirred at 25 °C for 40 min, and evaporated to give a
viscous brown oil. Flash column chromatography over silica gel eluting
with 9:1 pentane/Et2O gave a trace of the biscobalt complex as a black
amorphous solid, followed by 18 (3.77 g, 59%) as a red-brown
amorphous solid. Further elution with 7:3 pentane/Et2O gave 20 (2.02
g, 33%) as a red brown amorphous solid. Finally, elution with 3:2
pentane/Et2O gave 16 (0.25 g, 6%). Data for 18: IR (CHCl3) 2092,
2056, 2026, 1687, 1655 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.4 (1H,
s), 6.6-6.72 (2H, m), 6.54 (1H, d, J ) 2.8 Hz), 5.80 (1H, s), 5.66
(1H, s), 5.62 (1H, dd, J ) 10.5, 2.0 Hz), 4.82 (1H, m), 4.70 (1H, d, J
) 14.5 Hz), 3.77 (3H, s), 2.16 (9H, s), 1.65 (6H, s), 0.95 (9H, s), 0.25
(3H, s), 0.24 (3H, s); 13C NMR (75 MHz, CDCl3) δ 156.5, 152.3, 138.2,
128.9, 125.4, 124.6, 110.7, 110.1, 103.7, 97.7, 96.0, 82.1, 81.8, 81.2,
64.1, 64.0, 55.4, 41.5, 36.1, 30.9, 25.5, 18.1, -4.3, -4.7. This
compound was used directly in the next step.
1
3013, 2917, 2341, 1736, 1698 cm-1; H NMR (300 MHz, CDCl3) δ
7.55 (1H, d, J ) 7.31 Hz), 7.29-7.21 (3H, m), 5.82 (1H, s), 5.75 (1H,
d, J ) 9.3 Hz), 5.63 (1H, d, J ) 9.6 Hz), 3.71 (1H, br s), 3.54-3.50
(1H, m), 3.48-3.20 (1H, dd, J ) 14.5, 3.0 Hz), 2.15 (9H, s), 1.66
(6H, s); 13C NMR (75 MHz, CDCl3) δ 198.9, 151.7, 136.1, 128.2, 127.2,
126.3, 126.2, 125.8, 125.6, 121.2, 99.3, 91.4, 89.7, 83.3, 82.7, 49.1,
41.4, 36.2, 36.0, 30.9, 21.5; HRMS (CI) calcd for C27H25NO3 (M+)
411.183, found 411.183.
15-Oxo-10-azabenzo[10a,14a]bicyclo[7.3.1]trideca-3,7-diyn-5-
ene (25). To a solution of 23 (0.247 g, 0.60 mmol) in dichloromethane
(10 mL) was added trifluoroacetic acid (2.31 mL, 30.0 mmol), and the
mixture was stirred at 25 °C for 2 h. The mixture was quenched by
the addition of solid NaHCO3 (5.0 g), and extracted with dichlo-
romethane (3 × 25 mL). The extracts were dried (MgSO4), filtered,
concentrated in Vacuo, and chromatographed over silica gel eluting with
dichloromethane to give 25 (0.14 g, 81%): IR (CH2Cl2) 3379, 2986,
2305, 1733 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.25-7.22 (1H, d, J
) 9.7 Hz), 7.15 (1H, t, J ) 7.5 Hz), 6.95 (1H, t, J ) 7.5 Hz), 6.74
(1H, d, J ) 7.9 Hz), 5.73 (2H, q, J ) 22.4, 9.1 Hz), 4.62 (1H, s), 4.23
(1H, br s), 3.63 (1H, t, J ) 4.1 Hz), 3.51 (1H, dd, J ) 2.9 Hz), 3.39
(1H, qd, J ) 17.7, 4.8, 1.7 Hz); 13C NMR (75 MHz, CDCl3) δ 199.6,
142.4, 127.9, 126.6, 125.8, 122.3, 121.3, 120.9, 116.5, 100.1, 92.7,
90.0, 83.0, 54.0, 53.4, 21.7; HRMS (CI) calcd for C16H11NO (M+)
233.084, found 233.083.
Recycling Incorrect Cobalt Regioisomer 20. Ceric ammonium
nitrate (5.15 g, 9.40 mmol) was added portionwise over 3-4 min to a
solution of 20 (2.02 g, 2.35 mmol) and 2,6-di-tert-butyl-4-methylpyr-
idine (3.86 g, 18.8 mmol) in acetone (24 mL) at -10 °C. After an
initial evolution of gas the mixture was stirred for 20 min at -10 °C
and quenched with N,N-diisopropylethylamine (6.07 g, 47.0 mmol).
The resulting dark brown slurry was eluted through a short column of
silica gel with 1:1 Et2O/dichloromethane to give a viscous brown oil.
Flash column chromatography over silica gel eluting with 3:2 pentane/
Et2O gave 16 (1.03 g, 76%).
N-[(Adamantyloxy)carbonyl]-1,2-dihydro-2-[(Z)-7-[(tetrahydro-
pyranyl)oxy]hept-3-ene-1,5-diynyl]-3-[(tert-butyldimethylsilyl)oxy]-
6-methoxyquinoline (14). A solution of ethylmagnesium bromide in
tetrahydrofuran (43 mL, 1 M solution, 43 mmol) was added to a solution
of 10 (6.89 g, 36.2 mmol) and 12 (9.41 g, 32.5 mmol) in tetrahydrofuran
(210 mL) at 0 °C. After the initial evolution of gas, the mixture was
stirred for 20 min at 0 °C, and a solution of adamantyl chloroformate
(11.51 g, 53.6 mmol) in tetrahydrofuran (40 mL) was added Via syringe
pump over 90 min, maintaining the temperature at 0 °C. The mixture
was allowed to warm to 25 °C, stirred for 18 h, and quenched with
saturated aqueous NaHCO3 (60 mL). The resulting mixture was
extracted with Et2O (300 mL and 2 × 150 mL), and the combined
extracts were dried (MgSO4) and evaporated to give a brown oil. Flash
column chromatography over silica gel eluting with 4:1 pentane/Et2O
N-[(Adamantyloxy)carbonyl]-15-oxo-13-methoxy-10-azabenzo-
[10a,14a]bicyclo[7.3.1]trideca-3,7-diyn-5-ene (24). Trifluoromethane-
sulfonic anhydride (1.71 mL, 10.2 mmol) was added rapidly in a single
portion to a stirred solution of 18 (2.18 g, 2.54 mmol) and 2,6-di-tert-
butyl-4-methylpyridine (3.13 g, 15.2 mmol) in 2-nitropropane (55 mL)
at -10 °C. After being stirred for 30 min at -10 °C, the mixture was
quenched with saturated aqueous NaHCO3 (20 mL), and the layers were
separated. The aqueous layer was extracted with 2-nitropropane (15
mL), and the combined extracts were dried (MgSO4), filtered, and
diluted with acetone (80 mL) to give an opaque red-brown solution.
After cooling to -10 °C, ceric ammonium nitrate (13.93 g, 25.4 mmol)

5602 J. Am. Chem. Soc., Vol. 119, No. 24, 1997
Magnus et al.
was added portionwise over 3-4 min. After the initial gas evolution,
the mixture was stirred for 20 min, and quenched with N,N-diisopro-
pylethylamine (8.85 mL, 50.8 mmol). Elution of the mixture through
a short column of silica gel with 1:1 Et2O/dichloromethane gave a
viscous brown oil. Flash column chromatography over silica gel eluting
with dichloromethane gave 24 (0.59 g, 53%). Recrystallization from
Et2O/dichloromethane gave small white prisms: mp 115-119 °C dec
N-[(Adamantyloxy)carbonyl]-1,2-dihydro-2-[(Z)-7-[(tetrahydro-
pyranyl)oxy]hept-3-ene-1,5-diynyl]-3,4-dihydro-3-[(tert-butyldimeth-
ylsilyl)oxy]-4-(phenylseleno)-6-[(triisopropylsilyl)oxy]quinoline (32).
A solution of 31 (18.3 g, 21.9 mmol) in DMF (200 mL) was treated
with tert-butyldimethylsilyl chloride (18.0 g) and imidazole (18.0 g).
The mixture was stirred for 24 h, quenched with water (1.0 L), and
extracted with Et2O (3 × 100 mL). The combined extracts were dried
(MgSO4), concentrated in Vacuo, and heated (50 °C) under reduced
pressure to give 32 (20.9 g, >95% yield): IR (CHCl3) 3059, 2927,
1687, 1610 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.75 (2H, m), 7.40-
7.25 (4H, m), 7.03 (1H, d, J ) 2.2 Hz), 6.70 (1H, br d, J ) 8.9 Hz),
5.76 (2H, dd, J ) 11.1, 7.0 Hz), 5.55 (1H, br s), 4.82 (1H, br s), 4.67
(1H, br s), 4.39 (2H, m), 4.24 (1H, s), 3.82 (1H, m), 3.56 (1H, m),
2.14 (9H, s), 1.85-1.47 (12H, m), 1.24-1.15 (5H, m), 1.06 (12H, s),
1.04 (6H, s), 0.75 (9H, s), -0.03 (3H, s), -0.11 (3H, s); 13C NMR (75
MHz, CDCl3) δ 152.8, 151.8, 134.4, 132.1, 129.2, 129.1, 128.7, 128.6,
127.7, 121.0, 119.2, 119.1, 118.8, 96.7, 93.3, 92.8, 83.2, 83.0, 81.0,
74.6, 61.8, 54.7, 54.6, 46.9, 41.5, 36.1, 30.8, 30.2, 25.7, 25.3, 18.9,
17.8, 12.4, -4.9, -5.2; HRMS (CI) calcd for C53H75NO6Si2Se (M+)
957.430, found 957.434.
(rapid heating in sealed capillary tube); IR (CHCl3) 1733, 1696 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.44 (1H, d, J ) 8 Hz), 6.81 (1H, dd,
J ) 2.4, 8.9 Hz), 6.76 (1H, s), 5.77 (1H, s), 5.75 (1H, d, J ) 9.5 Hz),
5.62 (1H, d, J ) 9.5 Hz), 3.79 (3H, s), 3.68 (1H, X of ABX), 3.47
(1H, A of ABX), 3.19 (1H, B of ABX), 2.13 (9H, s), 1.64 (6H, s); 13
C
NMR (75 MHz, CDCl3) δ 198.5, 157.1, 151.8, 129.5, 129.3, 126.8,
126.3, 121.1, 112.3, 111.6, 99.1, 91.5, 90.0, 83.3, 82.3, 55.4, 54.2, 49.2,
41.4, 36.0, 30.9, 21.5; HRMS (CI) calcd for C28H28NO4 (M+ + 1)
442.201, found 442.201.
15-Oxo-13-methoxy-10-azabenzo[10a,14a]bicyclo[7.3.1]trideca-
3,7-diyn-5-ene (26). Trifluoroacetic acid (2.1 mL, 27.3 mmol) was
added dropwise to a stirred solution of 24 (481 mg, 1.09 mmol) in
dichloromethane (22 mL) at 0 °C. The mixture was warmed to room
temperature, and after 1.5 h the mixture was quenched with saturated
aqueous NaHCO3 (20 mL). The mixture was extracted with dichlo-
romethane (3 × 15 mL), dried (MgSO4), and evaporated in Vacuo to
give a brown amorphous solid. Chromatography over silica gel eluting
with 9:1 dichloromethane/Et2O gave 26 (224 mg, 78%) as a white
amorphous solid: mp 101-105 °C dec (rapid heating in sealed capillary
tube); 1H NMR (300 MHz, CDCl3) δ 6.6-6.8 (3H, m), 5.78 (1H, d, J
) 9.2 Hz), 5.66 (1H, d, J ) 9.2 Hz), 4.58 (1H, s), 3.76 (3H, s), 3.59
(1H, X of ABX), 3.55 (1H, A of ABX), 3.22 (1H, B of ABX); 13C
NMR (75 MHz, CDCl3) δ 199.6, 153.9, 136.3, 125.6, 123.5, 121.2,
117.0, 112.9, 112.4, 99.9, 93.2, 89.9, 82.9, 55.5, 54.2, 48.6, 21.6; HRMS
(CI) calcd for C17H14NO2 (M+ + 1) 264.102, found 264.102.
N-[(Adamantyloxy)carbonyl]-1,2-dihydro-2-[(Z)-7-[(tetrahydro-
pyranyl)oxy]hept-3-ene-1,5-diynyl]-3-[(tert-butyldimethylsilyl)oxy]-
6-[(triisopropylsilyl)oxy]quinoline (33). A solution of 32 (6.92 g, 7.24
mmol) in dichloromethane (250 mL) was cooled to 0 °C, followed by
addition of m-chloroperoxybenzoic acid (1.50 g, 8.68 mmol) in small
portions. After 1 h the mixture was warmed to 25 °C, pyridine (2.93
mL, 36.2 mmol) added, and the mixture heated at reflux for 5 h. The
reaction was quenched by the addition of saturated aqueous NaHCO3
(250 mL) and extracted with dichloromethane (3 × 100 mL). The
combined extracts were dried (MgSO4) and concentrated in Vacuo, and
the residue was purified by chromatography over silica gel eluting with
1:1 Et2O/pentane to give 33 (5.8 g, >95% yield): IR (CDCl3) 2929,
1
2360, 1688, 1655 cm-1; H NMR (300 MHz, CDCl3) δ 7.38 (1H, br
N-[(Adamantyloxy)carbonyl]-1,2-dihydro-2-[(Z)-7-[(tetrahydro-
pyranyl)oxy]hept-3-ene-1,5-diynyl]-3,4-dihydro-3,4-epoxy-6-[(triiso-
propylsilyl)oxy]quinoline (30). A solution of 29 (7.7 g, 11.5 mmol),
water (850 mL), and saturated NaHCO3 (850 mL) in dichloromethane
(850 mL) was treated with m-chloroperoxybenzoic acid (7.94 g, 46.0
mmol). After 10 min the mixture was diluted with dichloromethane
(850 mL). After 24 h the reaction mixture was quenched with 1-pentene
(200 mL) and extracted with dichloromethane (3 × 150 mL). The
extracts were dried (MgSO4) and concentrated in Vacuo to give 30 (7.87
g, 100%), which was used directly in the next step: IR (CDCl3) 2944,
s), 6.59 (1H, d, J ) 8.7 Hz), 6.50 (1H, d, J ) 2.4 Hz), 5.74 (1H, d, J
) 10.9 Hz), 5.66 (1H, d, J ) 10.9 Hz), 5.59 (1H, s), 4.79 (1H, s), 4.32
(2H, m), 3.83 (1H, m), 3.57 (1H, m), 2.15 (9H, s), 1.89-1.40 (12H,
m), 1.25 (5H, m), 1.09 (12H, s), 1.07 (6H, s), 0.96 (9H, s), 0.09 (3H,
s), 0.00 (3H, s); 13C NMR (75 MHz, CDCl3) δ 152.4, 134.9, 131.2,
130.6, 128.9, 128.6, 127.5, 125.0, 119.1, 115.9, 103.5, 96.5, 93.0, 82.5,
81.2, 79.9, 61.6, 54.4, 41.3, 36.0, 30.7, 30.0, 25.4, 25.2, 18.8, 17.9,
17.7, 12.4, -3.13, -4.5; HRMS (CI) calcd for C47H69NO6Si2 (M+)
799.466, found 799.466.
N-[(Adamantyloxy)carbonyl]-13-hydroxy-15-oxo-10-azabenzo-
[10a,14a]bicyclo[7.3.1]trideca-3,7-diyn-5-ene (37). To a solution of
36 (10.0 mg, 0.017 mmol) in CH3CN (10 mL) at 0 °C was added CsF
(3.0 equiv), and the mixture was stirred for 4 h at 0 °C. The mixture
was warmed to 25 °C for 2 h, poured onto saturated aqueous NaHCO3
(30 mL), and extracted with Et2O (3 × 15 mL). The combined extracts
were dried (MgSO4), concentrated in Vacuo, and chromatographed over
silica gel eluting with 1:1 EtOAc/hexane to give 37 (7.1 mg, 95%):
IR (CDCl3) 3596, 2917, 1735, 1701, 1697 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.40 (1H, d, J ) 8.8 Hz), 6.74 (2H, m), 5.80 (2H, m), 5.63
(1H, d, J ) 8.8 Hz), 5.11 (1H, br s), 3.67 (1H, m), 3.65 (1H, m), 3.15
(1H, m), 2.17 (9H, br s), 1.63 (6H, s); 13C NMR (75 MHz, CDCl3) δ
198.5, 153.3, 152.0, 129.8, 129.3, 127.1, 126.4, 121.2, 114.6, 112.7,
99.1, 91.6, 89.9, 83.3, 82.6, 65.9, 49.1, 41.5, 36.0, 30.9, 21.5; HRMS
(CI) calcd for C27H25NO4 (M+ + 1) 428.186, found 428.187.
N-[(Adamantyloxy)carbonyl]-1-(phenylseleneno)-15-oxo-13-meth-
oxy-10-azabenzo[10a,14a]bicyclo[7.3.1]trideca-3,7-diyn-5-ene (38).
A solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.0
M, 0.48 mL, 0.48 mmol) was added dropwise to a cold (-78 °C)
solution of 24 (192 mg, 0.435 mmol) in tetrahydrofuran (3.5 mL). The
resulting yellow solution was stirred under argon for 20 min and
quenched by dropwise addition of a solution of phenylselenenyl bromide
(140 mg, 0.58 mmol) in tetrahydrofuran (0.25 mL). The mixture was
stirred at -78 °C, the cooling bath was removed, and saturated aqueous
NH4Cl (2.0 mL) was added. The mixture was diluted with Et2O (8.0
mL), the phases were separated, and the aqueous phase was extracted
with Et2O (2 × 6 mL). The combined extracts were dried (MgSO4)
and filtered, and the solvent was evaporated in Vacuo to give the crude
product (310 mg). Flash chromatography over silica gel eluting with
Et2O/pentane (1:4) gave 38 (241 mg, 93%) as a pale yellow amorphous
solid: IR (CDCl3) 2913, 1721, 1697 cm-1; 1H NMR (300 MHz, CDCl3)
1
1693, 1614 cm-1; H NMR (300 MHz, CDCl3) δ 7.20 (1H, s), 6.88
(1H, m), 6.81 (1H, d, J ) 5.6 Hz), 5.91 (1H, br s), 5.76 (1H, d, J )
10.9 Hz), 5.62 (1H, d, J ) 10.9 Hz), 4.84 (1H, m), 4.40 (2H, m), 4.0
(1H, m), 3.85-3.8 (2H, m), 3.60-3.50 (1H, m), 2.20-2.00 (9H, br
d), 1.90-1.40 (14H, m), 1.30-1.20 (3H, m), 1.09 (12H, s), 1.07 (6H,
s); 13C NMR (75 MHz, CDCl3) δ 152.7, 126.2, 119.9, 119.8, 118.7,
96.3, 96.2, 93.0, 92.9, 90.8, 82.5, 82.4, 81.9, 81.2, 81.1, 61.6, 61.5,
61.0, 54.3, 50.6, 41.2, 35.9, 30.7, 30.0, 25.2, 18.7, 17.7, 12.4; HRMS
(CI) calcd for C41H44NO6Si (M+) 685.380, found 685.378.
N-[(Adamantyloxy)carbonyl]-1,2-dihydro-2-[(Z)-7-[(tetrahydro-
pyranyl)oxy]hept-3-ene-1,5-diynyl]-3,4-dihydro-3-hydroxy-4-
(phenylseleno)-6-[(triisopropylsilyl)oxy]quinoline (31). To a slurry
of diphenyl diselenide (31.9 g, 102.1 mmol) in EtOH (735 mL) was
added NaBH4 (3.22 g, 85.1 mmol) in small portions. The slurry was
stirred for 1 h followed by slow addition (ca. 30 min) of 30 (23.3 g,
34.0 mmol) dissolved in tetrahydrofuran (365 mL). The mixture was
stirred for 4 h and quenched with water (2 L). The mixture was
extracted with Et2O (3 × 200 mL), dried (MgSO4), and evaporated in
Vacuo, and the crude material was purified by chromatography over
silica gel eluting with 10% Et2O/pentane to give 31 (18.3 g, 64%) as
a yellow oil: IR (CDCl3) 3399, 2944, 1693 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.60 (2H, m), 7.43 (1H, d, J ) 8.5 Hz), 7.32-7.25 (3H, m),
7.13 (1H, d, J ) 3.9 Hz), 6.73 (1H, dd, J ) 8.9, 2.8 Hz), 5.78 (2H, s),
5.38 (1H, s), 4.90 (1H, dt, J ) 10.3, 3.1 Hz), 4.40-4.25 (3H, m), 3.80
(1H, m), 3.57 (3H, m), 3.18 (1H, m), 2.15 (9H, s), 1.8-1.57 (12H, m),
1.19 (5H, m), 1.06 (12H, s), 1.04 (6H, s); 13C NMR (75 MHz, CDCl3)
δ 153.1, 152.5, 132.6, 131.6, 129.3, 129.1, 128.7, 127.1, 126.0, 120.4,
119.4, 119.3, 119.2, 118.9, 96.1, 93.8, 92.5, 83.0, 82.1, 81.4, 75.5, 61.5,
54.5, 47.0, 41.3, 36.0, 30.7, 29.9, 25.2, 18.6, 17.8, 12.4; HRMS (CI)
calcd for C47H61NO6SiSe (M+) 843.343, found 843.342.

Synthetic and Mechanistic Studies of Dynemicin A
J. Am. Chem. Soc., Vol. 119, No. 24, 1997 5603
δ 7.15-7.50 (6H, m), 6.74 (1H, dd, J ) 2.7, 10.0 Hz), 6.28 (1H, d, J
) 2.7 Hz), 5.96 (1H, m), 5.69 (1H, d, J ) 9.6 Hz), 5.60 (1H, d, J )
9.6 Hz), 3.66 (1H, d, J ) 17.4 Hz), 3.59 (3H, s), 3.31 (1H, d, J ) 17.4
Hz), 2.19 (9H, s), 1.67 (6H, s); 13C NMR (75 MHz, CDCl3) δ 195.1,
156.9, 156.9, 151.9, 138.4, 130.5, 129.8, 129.1, 128.8, 128.8, 127.9,
127.6, 125.8, 120.8, 113.5, 110.9, 98.5, 92.6, 89.9, 84.3, 82.1, 55.3,
55.2, 41.5, 36.1, 30.9, 27.9; HRMS (FAB) calcd for C34H31NO4Se (M+)
597.142, found 597.140.
3.42 (3H, s), 3.37 (1H, A of AB, J ) 16.1 Hz), 3.24 (1H, B of AB, J
) 16.1 Hz), 2.21 (9H, s), 1.68 (6H, s); 13C NMR (75 MHz, CDCl3) δ
204.0, 156.5, 152.2, 135.4, 134.1, 129.7, 129.1, 128.7, 128.1, 127.3,
124.7, 112.6, 111.4, 82.1, 72.7, 60.5, 59.6, 55.3, 53.9, 46.3, 41.6, 36.1,
31.0, one quaternary resonance not detected; HRMS (CI) calcd for
C30H33NO5 (M+) 487.236, found 487.235.
Cycloaromatized Adduct 52. Sodium borohydride (2.0 mg, 51.6
µmol) was added to a solution of 24 (22.8 mg, 51.6 µmol) in
tetrahydrofuran (500 µL) and MeOH (500 µL). After 30 min an
additional 1 equiv of sodium borohydride was added and the mixture
stirred at 25 °C for 1.5 h. The reaction mixture was treated with 2 N
HCl (1 mL) and neutralized with aqueous NaHCO3 solution. The
mixture was extracted with dichloromethane (3 × 10 mL), dried
(MgSO4), and evaporated in Vacuo to give a residue which was purified
by chromatography over silica gel eluting with dichloromethane/EtOAc
(3:1) to give 52 (9.9 mg, 43%): mp 210-212 °C (from EtOAc); IR
N-[(Adamantyloxy)carbonyl]-1-(2-oxopropyl)-15-oxo-13-methoxy-
10-azabenzo[10a,14a]bicyclo[7.3.1]trideca-3,7-diyn-5-ene (42).
A
solution of m-chloroperoxybenzoic acid (23.2 mg, 0.134 mmol) in
dichloromethane (0.2 mL) was added dropwise to a stirred solution of
38 (59.0 mg, 0.1 mmol), in dichloromethane (0.67 mL), under argon
at -78 °C. The mixture was stirred at -78 °C for 45 min and treated
with 1-[(trimethylsilyl)oxy]-1-methylethylene (200 mg, 1.54 mmol)
followed by trimethylsilyl trifluoromethanesulfonate (33.4 mg, 0.15
mmol). After 10 min at -78 °C, the mixture was warmed to 0 °C,
aqueous saturated NaHCO3 (4.0 mL) was added, the mixture was diluted
with dichloromethane (4.0 mL), and the phases were separated. The
organic phase was washed with saturated aqueous NaHCO3 (2.0 mL),
dried (MgSO4), and filtered, and the solvent evaporated in Vacuo to
give the crude product (79.3 mg). Purification by chromatography on
a silica gel plate (1.0 mm, 1:1 Et2O/pentane) gave 42 (25 mg, 51%)
and 41 (10 mg, 22%). Data for 42: 1H NMR (300 MHz, CDCl3) δ
7.22 (1H, m), 6.82 (1H, dd, J ) 2.7, 8.9 Hz), 6.70 (1H, d, J ) 2.7 Hz),
6.11 (1H, m), 5.75 (1H, d, J ) 9.6 Hz), 5.67 (1H, d, J ) 9.6 Hz), 3.80
(3H, s), 3.25 (1H, d, J ) 24 Hz), 3.20 (1H, d, J ) 24 Hz), 3.0 (2H,
m), 2.18 (9H, s), 1.86 (3H, s), 1.65 (6H, s); 13C NMR (75 MHz, CDCl3)
δ 202.6, 157.4, 153.4, 133.3, 130.8, 130.8, 128.9, 127.1, 122.1, 118.9,
112.8, 112.0, 99.9, 93.8, 89.9, 84.2, 82.1, 58.2, 56.5,53.5, 41.8, 36.4,
32.3, 32.2, 30.1; HRMS (FAB) calcd for C31H31NO5 (M+) 497.220,
found 497.222.
1
(CHCl3) 3457, 1698, 1679 cm-1; H NMR (300 MHz, CDCl3) δ 7.58
(1H, s), 7.43 (1H, d, J ) 6.8 Hz), 7.19-7.06 (2H, m), 6.96 (1H, d, br,
J ) 6.9 Hz), 6.66 (1H, d, J ) 2.9 Hz), 6.60 (1H, dd, J ) 9.1, 2.9 Hz),
5.68-5.60 (1H, m), 4.47-4.39 (1H, m), 3.73 (3H, s), 3.51 (1H, dd, J
) 15.8, 4.7 Hz), 3.39-3.31 (1H, m), 2.73 (1H, d, J ) 15.8 Hz), 2.23
(9H, s), 1.95 (1H, d, D2O exchangeable) 1.69 (6H, s); 13C NMR (75
MHz, CDCl3) δ 155.5, 152.8, 134.2, 132.7, 132.0, 131.0, 128.9, 128.7,
127.9, 126.7, 124.3, 113.7, 112.5, 81.5, 66.4, 65.9, 55.4, 54.5, 41.7,
38.7, 36.2, 33.7, 31.0; HRMS (CI) calcd for C28H31NO4 (M+) 445.225,
found 445.225.
(E)-Nitrile 53. A 2.5 M solution of n-butyllithium in hexanes (41
mL, 103 mmol, 1.05 equiv) was added dropwise to a stirred solution
of diethyl (cyanomethyl)phosphonate (17 mL, 108 mmol, 1.10 equiv)
in anhydrous tetrahydrofuran (0.5 mL) at 25 °C. After being stirred
for 40 min at 25 °C, the colorless solution was added dropwise to a
solution of 24 (43.2 mg, 98 mmol, 1.00 equiv) in tetrahydrofuran (1.5
mL) at 0 °C. The clear orange solution was stirred at 0 °C for 20 min,
eluted with dichloromethane through a short column of silica gel, and
evaporated to give a viscous brown oil. Purification of the crude
product by chromatography over silica gel eluting with dichloromethane
gave 53 as a white amorphous solid (45.6 mg, 85%): IR (CHCl3) 2223,
1694 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.28-7.42 (1H, m), 6.70-
6.80 (2H, m), 5.91 (1H, s), 5.78 (1H, d, J ) 9.4 Hz), 5.67 (1H, d, J )
9.4 Hz), 5.54 (1H, s), 4.22 (1H, X of ABX), 3.79 (3H, s), 3.56-3.38
(2H, AB of ABX), 2.17 (3H, s), 2.10 (6H, s), 1.64 (6H, s); 13C NMR
(75 MHz, CDCl3) δ 160.5, 157.0, 151.7, 129.5, 129.3, 127.2, 126.5,
121.7, 115.3, 112.4, 111.26, 100.2, 97.3, 94.0, 88.8, 83.0, 82.3, 55.4,
49.4, 41.5, 40.3, 36.0, 30.8, 24.9. HRMS (CI) calcd for C30H28N2O3
(M+) 464.210, found 464.211.
Cycloaromatized Adduct 48. A solution of 24 (35 mg, 79.3 µmol)
in 3,6-dihydrotoluene (4 mL) under an argon atmosphere was heated
in an oil bath at 114 °C, and aliquots were removed after 20 (88%,
24), 40 (69%, 24), 60 (53%, 24), 90 (42%, 24), 150 (27%, 24), and
210 (14%, 24) min for 1H NMR analysis. The combined aliquots were
purified by PLC eluting with Et2O to give 48 (23.8 mg, 68%): mp
126-129 °C (from EtOAc); IR (CHCl3) 1743, 1698 cm-1; UV (CH2Cl2)
1
λmax (ꢀ) 247.5 (9.32 × 103), 295.5 (2.09 × 103) nm; H NMR (300
MHz, CDCl3) δ 7.51 (1H, d, br, J ) 9.2 Hz), 7.37 (1H, dd, J ) 6.9,
1.9 Hz), 7.13-7.25 (2H, m), 6.98 (1H, d, J ) 6.9 Hz), 6.65 (1H, dd,
J ) 9.2, 2.9 Hz), 6.59 (1H, d, J ) 2.9 Hz), 5.79 (X of ABX), 3.73
(3H, s), 3.64-3.55 (B of ABX), 3.39-3.30 (A of ABX), 2.22 (9H, s),
1.68 (6H, s); 13C NMR (75 MHz, CDCl3) δ 204.8, 156.4, 152.4, 135.6,
133.5, 131.8, 130.1, 128.8, 128.7, 128.3, 127.4, 124.8, 113.0, 112.3,
82.2, 60.6, 55.4, 49.9, 43.9, 41.6, 36.1, 31.0; HRMS (CI) calcd for
C28H29NO4 (M+) 443.210, found 443.210. The same experiment was
carried out at 98, 81, and 65 °C to provide the data for an Arrhenius
plot, Table 1. Prolonged reactions gave rise to by-product 52 (see
below).
Cycloaromatized Adduct 54. A solution of 53 (11.6 mg, 25 µmol)
in tetrahydrofuran-d8 (1 mL) under an argon atmosphere was heated
in an oil bath at 60 °C, and aliquots were removed for 1H NMR analysis.
The combined aliquots were purified by PLC eluting with 10% Et2O/
dichloromethane to give 54 (5.4 mg, 47%): mp 224-225 °C (from
EtOAc); IR (CHCl3) 2224, 1683 cm-1; 1H NMR (300 MHz, CDCl3) δ
7.50-7.30 (2H, m), 7.21-7.10 (2H, m), 6.95 (1H, d, J ) 2.8 Hz),
6.68 (1H, d, J ) 2.9 Hz), 6.62 (1H, dd, J ) 9.0, 2.9 Hz), 6.13 (1H, s),
5.46 (1H, s), 4.34 (1H, s), 3.74 (3H, s), 3.38 (1H, dd, J ) 6.1, 4.3 Hz),
3.20 (1H, dd, J ) 16.1, 2.2 Hz), 2.20 (9H, s), 1.68 (6H, s); 13C NMR
(75 MHz, CDCl3) δ 160.2, 156.5, 152.6, 134.9, 133.9, 130.9, 129.4,
129.0, 128.7, 128.6, 127.3, 125.4, 115.5, 113.2, 112.4, 91.5, 82.2, 56.3,
55.5, 43.1, 41.9, 41.1, 36.3, 31.1; HRMS (CI) C30H30N2O3 (M+) calcd
for 466.226, found 466.227.
Cycloaromatized Adduct 49. A solution of 26 (13 mg, 49 µmol)
in 3,6-dihydrotoluene (2 mL) under an argon atmosphere was heated
1
in an oil bath at 114 °C, and aliquots were removed as above for H
NMR analysis. The combined aliquots were purified by PLC eluting
with 10% Et2O/dichloromethane to give 49 (9.3 mg, 72%): mp 218-
220 °C (from dichloromethane); IR (CHCl3) 3392, 1740 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.29-7.16 (3H, m), 7.06 (1H, d, J ) 7.1 Hz),
6.65-6.53 (2H, m), 6.47 (1H, d, J ) 8.6 Hz), 4.39 (1H, s), 3.71 (3H,
s), 3.76-3.62 (2H, m), 3.45 (1H, d, J ) 14.4 Hz); 13C NMR (75 MHz,
CDCl3) δ 207.0, 153.8, 138.6, 134.8, 133.1, 128.9, 128.6, 128.4, 127.5,
126.7, 117.12, 114.4, 113.4, 61.1, 55.7, 49.4, 44.7; HRMS (FAB) calcd
for C17H15NO2 (M+) 265.110, found 265.110.
Cycloaromatized Adduct 55. To a solution of 48 (23.8 mg, 53.7
µmol) in dichloromethane (1 mL) was added m-chloroperoxybenzoic
acid (18.5 mg, 53.7 mmol), and the mixture stirred at 25 °C for 1.5 h.
Saturated aqueous NaHCO3 (2 mL) was added, and the mixture
extracted with dichloromethane (3 × 10 mL), dried (MgSO4), and
evaporated in Vacuo. The residue was purified by PLC eluting with
1:1 pentane/Et2O to give 55 (14.5 mg, 59%): mp 193-195 °C (from
EtOAc); IR (CHCl3) 1746, 1709 cm-1; 1H NMR (300 MHz, CDCl3) δ
7.34 (1H, s), 7.29-7.14 (3H, m), 7.08-6.98 (2H, m), 6.64 (1H, dd, J
) 8.9, 2.8 Hz), 6.58 (1H, d, J ) 2.8 Hz), 4.38 (1H, X of ABX), 3.76
(3H, s), 3.72 (1H, A of ABX), 3.16 (1H, B of ABX), 2.20 (9H, s),
1.69 (6H, s); 13C NMR (75 MHz, CDCl3) δ 173.6, 157.5, 152.5, 134.9,
131.7, 130.4, 129.6, 129.2, 129.0, 126.8, 113.0, 112.8, 85.3, 83.0, 55.4,
Cycloaromatized Adduct 50. A solution of 44 (42.3 mg, 87.1
µmol) in 3,6-dihydrotoluene (4 mL) under an argon atmosphere was
heated in an oil bath at 114 °C, and aliquots were removed as above
1
for H NMR analysis. The combined aliquots were purified by PLC
eluting with 10% Et2O/dichloromethane to give 50 (44.4 mg, >95%)
1
as a viscous pale yellow oil: IR (CHCl3) 1742, 1697 cm-1; H NMR
(300 MHz, CDCl3) δ 7.46 (1H, d, J ) 9.1 Hz), 7.34 (1H, dd, J ) 1.3,
6.9 Hz), 7.22-7.10 (2H, m), 7.09 (1H, d, J ) 2.8 Hz), 6.93 (1H, d, J
) 7.1 Hz), 6.64 (1H, dd, J ) 2.8, 9.1 Hz), 5.83 (1H, s), 4.02 (1H, A
of AB, J ) 9.9 Hz), 3.97 (1H, B of AB, J ) 9.9 Hz), 3.72 (3H, s),

5604 J. Am. Chem. Soc., Vol. 119, No. 24, 1997
Magnus et al.
52.2, 41.3, 39.2, 36.1, 30.9, two aromatic resonances not detected;
HRMS (CI) calcd for C28H29NO5 (M+) 459.205, found 459.204.
Lactone 56. To a solution of 24 (45.9 mg, 104 µmol) in
dichloromethane (4 mL) was added m-chloroperoxybenzoic acid (71.8
mg, 416 µmol), and the mixture stirred at 25 °C for 20 h. Workup
(CDCl3) 3424, 3188, 2915, 1719 cm-1; 1H NMR (300 MHz, CDCl3) δ
10.7 (1H, s), 8.00 (1H, bd, J ) 7.5 Hz), 7.94 (1H, dd, J ) 8.0, 1.2
Hz), 7.72 (1H, dd, J ) 7.4, 1.2 Hz), 7.53 (1H, d, J ) 8.4 Hz), 7.47
(1H, dd, J ) 8.0, 7.4 Hz), 7.38 (1H, d, J ) 8.4 Hz), 7.36 (1H, dt, J )
7.5, 2.0 Hz), 7.24 (1H, dd, 7.7, 2.0 Hz), 7.12 (1H, dt, J ) 7.7, 1.3 Hz),
6.79 (2H, s), 6.74 (1H, s), 2.19 (6H, s), 2.11 (3H, s), 2.03 (6H, s), 1.61
(6H, s); HRMS (CI) calcd for C35H35NO3S 549.233, found 549.234.
as for 55 gave 56 (39.2 mg, 82%): IR (CHCl3) 3200, 1757, 1721 cm-1
;
1H NMR (500 MHz, CDCl3) δ 7.11 (1H, d, J ) 8.6 Hz), 6.81 (1H, d,
J ) 2.4 Hz), 6.78 (1H, dd, J ) 8.6, 2.4 Hz), 5.76 (1H, d, J ) 10.1
Hz), 5.66 (1H, d, J ) 10.1 Hz), 4.10-4.03 (1H, X of ABX), 3.74 (3H,
s), 3.26-3.16 (1H, B of ABX,), 3.13-2.95 (1H, A of ABX), 2.09 (3H,
s), 2.07 (6H, s), 1.57 (6H, s); 13C NMR (125 MHz, CDCl3, 323K) δ
173.4, 160.8, 152.8, 152.6, 136.3, 131.5, 130.9, 126.8, 118.2, 114.6,
114.1, 98.6, 91.9, 89.2, 85.6, 80.9, 55.6, 44.6, 41.2, 36.1, 31.1, 23.7;
MS (FAB) base peak 135, no M + 1 detected.
1
23a is missing signals at δ 7.72 and 7.53 in the H NMR spectrum.
1,4-Dihydro-1,4-epoxy-2-(methoxycarbonyl)-3-(3-methylpyrid-2-
yl)-5,8-dimethoxynaphthalene (63). A mixture of 4,7-dimethoxy-
isobenzofuran (0.99 g, 5.50 mmol) and 62 (1.02 g, 5.80 mmol) in
benzene (30 mL) was heated at reflux for 18 h. The mixture was cooled
to room temperature and concentrated in Vacuo. The crude product
was purified by chromatography over silica gel eluting with EtOAc to
give 63 (1.95 g, 100%): IR (CHCl3) 2954, 1719 cm-1; 1H NMR (300
MHz, CDCl3) δ 8.43 (1H, d, J ) 4.4 Hz), 7.48 (1H, d, J ) 7.7 Hz),
7.13 (1H, dd, J ) 7.7, 4.4 Hz), 6.62 (2H, s), 6.31 (1H, d, J ) 1.0 Hz),
6.06 (1H, d, J ) 1.0 Hz), 3.86 (3H, s), 3.72 (3H, s), 3.62 (3H, s), 2.02
(3H, s); 13C NMR (75 MHz, CDCl3) δ 163.4, 151.7, 148.6, 148.4, 146.7,
142.6, 137.5, 135.5, 135.0, 132.0, 122.9, 113.67, 113.4, 85.7, 82.0,
56.7, 56.8, 51.6, 18.2; HRMS (CI) calcd for C20H20NO5 (M+ + 1)
354.134, found 354.133.
Indole 57. A solution of 56 (38.0 mg, 80.2 µmol) in 3,6-
dihydrotoluene (8 mL) was heated in a sealed tube at 140 °C for 20 h.
The mixture was evaporated in Vacuo and the residue purified by
chromatography over silica gel eluting with dichloromethane to give
57 (5.0 mg, 15%): mp 206-207 °C (from dichloromethane/Et2O); IR
1
(CHCl3) 1786, 1762, 1723 cm-1; H NMR (300 MHz, CDCl3) δ 7.84
(1H, d, J ) 8.9 Hz), 7.79 (1H, d, J ) 7.7 Hz), 7.72-7.65 (1H, m),
7.58 (1H, d, J ) 7.6 Hz), 7.50-7.41 (1H, m), 6.83 (1H, dd, J ) 9.0,
2.7 Hz), 6.43 (1H, d, J ) 2.7 Hz), 3.85 (1H, B of AB, J ) 17.4 Hz),
3.70 (3H, s), 3.41 (1H, A of AB, J ) 17.4 Hz), 2.26 (6H, s), 2.22 (3H,
s), 1.69 (6H, s); 13C NMR (126 MHz, CDCl3) δ 198.7, 173.2, 157.1,
153.5, 148.4, 135.9, 134.4, 134.2, 129.9, 128.4, 126.5, 125.7, 116.6,
113.6, 108.4, 84.5, 55.7, 41.4, 38.7, 36.1, 31.0; HRMS (CI) calcd for
C27H27NO3 (M+) 413.200, found 413.199.
2-(Methoxycarbonyl)-3-(3-methylpyrid-2-yl)-4-[(tert-butyldimeth-
ylsilyl)oxy]-5,8-dimethoxynaphthalene (64). To a mixture of 2,6-
lutidine (0.66 mL, 5.66 mmol) and 63 (0.10 g, 0.28 mmol) in
dichloromethane (10 mL) at -78 °C was added tert-butyldimethylsilyl
trifluoromethanesulfonate (0.325 mL, 1.42 mmol). The mixture was
stirred at room temperature for 18 h, quenched with water (10 mL),
and extracted with dichloromethane (3 × 5 mL). The extracts were
dried (MgSO4), concentrated in Vacuo, and purified by chromatography
over silica eluting with EtOAc to give 64 (0.132 g, 99.6%) as a pale
yellow foam: IR (CHCl3) 2955, 2898, 1723 cm-1; 1H NMR (300 MHz,
CDCl3) δ 8.48 (1H, s), 8.44 (1H, d, J ) 4.7 Hz), 7.50 (1H, d, J ) 7.5
Hz), 7.13 (1H, dd, J ) 7.5, 4.7 Hz), 6.75 (2H, q, J ) 8.5 Hz), 3.95
(3H, s), 3.80 (3H, s), 3.60 (3H, s), 2.33 (3H, s), 0.75 (9H, s), -0.23
(3H, s), -0.54 (3H, s); 13C NMR (75 MHz, CDCl3) δ 168.4, 158.8,
150.7, 149.8, 149.2, 145.9, 136.9, 133.9, 130.6, 128.6, 127.4, 122.1,
121.9, 118.5, 107.6, 104.7, 55.8, 55.7, 51.9, 25.9, 19.2, 18.3, -3.9,
-4.3; HRMS (CI) calcd for C26H33NO5Si (M+) 467.213, found 467.214.
[2-[N-(Adamantoxycarbonyl)amino]phenyl]-1,2,3,4-tetrahydro-
1-oxo-4,8-bis(3,5-dimethylphenyl)thio]naphthalene (58). A slurry of
NaH (4 equiv) in tetrahydrofuran (10 mL) was treated with 3,5-
dimethylthiophenol (3 0 equiv). The mixture was stirred for 15 min
at 0 °C, followed by dropwise addition of 23 (0.60 g) in tetrahydrofuran
(5 mL). After 10 min, the cooling bath was removed and the mixture
was stirred for 4 h. The mixture was quenched with water (10 mL)
and extracted with EtOAc (3 × 10 mL). The extract was dried
(MgSO4), filtered, and concentrated in Vacuo. The crude mixture was
purified by chromatography over silica gel to give 58 (0.73 g, 73%):
IR (CHCl3) δ 3413, 2916, 1712, 1663 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 7.78 (1H, d, J ) 7.7 Hz), 7.57 (1H, br d, J ) 7.7 Hz), 7.31-
7.00 (8H, m), 6.90 (1H, s), 6.80 (2H, m), 4.75 (1H, m), 4.05 (1H, X of
ABX), 2.82-2.63 (2H, AB of ABX), 2.32 (6H, s), 2.29 (6H, s), 2.11
(9H, br s), 1.64 (6H, br s); 13C NMR (75 MHz, CDCl3) δ 197.6, 153.6,
146.5, 144.7, 139.3, 138.7, 136.5, 133.4, 133.3, 132.5, 131.7, 131.1,
130.7, 129.9, 129.4, 129.3, 127.9, 127.6, 126.4, 126.2, 125.3, 124.0,
80.0, 79.8, 48.5, 48.0, 41.4, 36.0, 30.7, 21.1, 21.0; HRMS (CI) calcd
for C43H46NO3S2 (M+ + 1) 688.290, found 688.292.
8,11-Dimethoxy-12-hydroxy-6-[(tert-butylcarbonyl)oxy]naphtho-
[2,3-h]quinoline (65). A solution of tetrahydrofuran (2 mL) and
diisopropylamine (0.18 mL, 1.28 mmol) was cooled to 0 °C followed
by addition of n-BuLi (2.5 M, 0.43 mL, 1.07 mmol). After 30 min,
64 (0.10 g, 0.21 mmol) in tetrahydrofuran (3 mL) was added. The
mixture was warmed to room temperature for 2 h and quenched with
saturated aqueous NH4Cl (10 mL) and the aqueous layer extracted with
dichloromethane (3 × 5 mL). The extracts were dried (MgSO4),
concentrated in Vacuo, and dissolved in dichloromethane (10 mL)
containing pyridine (0.70 mL, 8.56 mmol) and pivaloyl chloride (0.52
mL, 4.28 mmol). The mixture was stirred overnight, concentrated in
Vacuo, and purified by chromatography over silica gel eluting with
EtOAc to give 65 (0.62 g, 72%) as a pale yellow powder: IR (CHCl3)
1-[(3,5-Dimethylphenyl)thio]-11H-benzo[a]carbazole (59). A so-
lution of 58 (650 mg, 1.18 mmol) in dichloromethane (10.0 mL) was
treated with trifluoroacetic acid (5.18 mL, 59.1 mmol) at 25 °C. The
mixture was stirred for 1.5 h, quenched with saturated aqueous NaHCO3
(10 mL), and extracted with EtOAc (3 × 5 mL). The extracts were
dried (MgSO4), filtered, and concentrated in Vacuo. The crude material
was purified by chromatography over silica gel eluting with dichlo-
romethane to give 59 (100 mg, 24%): IR (CHCl3) 3397, 2921, 1601
1
2935, 1752, 1624, 1604 cm-1; H NMR (300 MHz, CDCl3) δ 8.71
(1H, dd, J ) 4.8, 1.4 Hz), 8.20 (1H, s), 8.14 (1H, dd, J ) 7.9, 1.4 Hz),
7.52 (1H, dd, J ) 7.9, 4.8 Hz), 7.30 (1H, s), 6.85 (1H, d, J ) 8.5 Hz),
6.81 (1H, d, J ) 8.5 Hz), 4.07 (3H, s), 4.00 (3H, s), 1.57 (9H, s); 13C
NMR (75 MHz, CDCl3) δ 175.1, 159.7, 152.4, 149.3, 148.5, 147.4,
143.1, 135.7, 128.5, 126.6, 126.0, 120.8, 115.9, 115.2, 111.2, 104.8,
104.5, 104.2, 56.8, 56.0, 40.3, 27.4; HRMS (CI) calcd for C24H23NO5
(M+) 405.158, found 405.158.
1
cm-1; H NMR (500 MHz, acetone-d6) δ 11.53 (1H, br s), 8.31 (1H,
d, J ) 8.5 Hz), 8.19 (1H, dd, J ) 8.1 Hz), 8.16 (1H, dd, J ) 8.1, 1.1
Hz), 7.84 (1H, dd, J ) 7.2, 1.1 Hz), 7.77 (1H, d, J ) 8.5 Hz), 7.76
(1H, dd, J ) 8.1 Hz), 7.56 (1H, dd, J ) 8.1 Hz), 7.40 (1H, dt), 7.25
(1H, dt), 6.88 (2H, br s), 6.77 (1H, s), 2.12 (6H, s); 13C NMR (125
MHz, CDCl3) δ 139.0, 137.9, 137.0, 136.3, 134.6, 134.2, 131.0, 128.3,
126.5, 125.3, 125.0, 124.8, 124.7, 123.1, 122.7, 120.6, 120.1, 119.9,
119.6, 111.3, 21.2; HRMS (CI) calcd for C24H19NS (M+) 353.123, found
353.124.
[2-[N-(Adamantoxycarbonyl)amino]phenyl]-1-hydroxy-8-[(3,5-
dimethylphenyl)thio]naphthalene (60). To a slurry of NaH (9.0 mg,
0.364 mmol) in tetrahydrofuran (3 mL) was added a solution of 58
(20 mg, 0.036 mmol) in tetrahydrofuran (3 mL). The mixture was
stirred for 5 h followed by the addition of water (3 mL). The aqueous
phase was extracted with EtOAc (3 × 5 mL). The combined extracts
were dried (MgSO4), filtered, and concentrated in Vacuo. The crude
product was purified by chromatography over silica gel eluting with
20% Et2O/pentane to give 60 (11.4 mg, 72%) as a yellow solid: IR
8,11-Dimethoxy-7,12-dioxo-6-[(tert-butylcarbonyl)oxy]naphtho-
[2,3-h]quinoline (66). To a slurry (sonicated for 5 min) of AgIIO (12.2
mg, 98.8 mmol), 65 (10.0 mg, 24.7 mmol), and dioxane (0.75 mL,
freshly distilled over sodium) was added 6 M HNO3 (0.05 mL). The
mixture rapidly changed from a green-yellow color to an intense red
color. The mixture was stirred for 3 min and quenched with a mixture
of chloroform and water (4:1, 5 mL). The aqueous layer was extracted
with chloroform (3 × 5 mL), and the extracts were dried (Na2SO4),
filtered, and concentrated in Vacuo. The crude material was purified
by preparative plate chromatography eluting with EtOAc to give 66
(7.5 mg, 72%) as an orange-yellow solid: IR (CHCl3) 2934, 1752,
1
1685, 1602 cm-1; H NMR (300 MHz, CDCl3) δ 9.22 (1H, dd, J )
4.2, 1.0 Hz), 8.12 (1H, dd, J ) 8.3, 1.0 Hz), 7.65 (1H, s), 7.51 (1H,

Synthetic and Mechanistic Studies of Dynemicin A
J. Am. Chem. Soc., Vol. 119, No. 24, 1997 5605
dd, J ) 8.3, 4.2 Hz), 7.20 (1H, d, J ) 9.3 Hz), 7.17 (1H, d, J ) 9.3
Hz), 3.95 (3H, s), 3.89 (3H, s), 1.47 (9H, s); 13C NMR (75 MHz, CDCl3)
δ 184.1, 182.7, 177.3, 153.0, 151.9, 151.8, 144.9, 142.6, 135.4, 134.4,
131.2, 131.0, 125.4, 125.2, 124.1, 123.1, 118.9, 118.7, 57.1, 56.3, 39.25,
27.1; HRMS (CI) calcd for C24H21NO6 (M+) 419.137, found 419.137.
6,8,11-Triacetoxy-7,12-dioxonaphtho[2,3-h]quinoline (68). A so-
lution of 66 (20.0 mg, 47.7 mmol) in 5:1 aqueous hydrogen bromide
(48%)/glacial acetic acid was heated at reflux for 4 h. The mixture
was concentrated to dryness in Vacuo followed by addition of acetic
anhydride (3 mL) and pyridine (2 mL). The reaction mixture was
stirred for 12 h and concentrated to dryness in Vacuo. The product
was purified by preparative plate chromatography eluting with EtOAc
to give 68 (14.1 mg, 68%) as an orange-yellow solid: mp >175 °C
colorless solid (6.90 g, 96%): IR (CHCl3) 3340, 2941, 1733, 1612,
1
1369, 1254 cm-1; H NMR (300 MHz, CDCl3) δ 11.30 (1H, s), 8.43
(1H, d, J ) 4.3 Hz), 8.43 (1H, d, J ) 4.3 Hz), 7.62 (1H, s), 7.52 (1H,
d, J ) 7.5 Hz), 7.15 (1H, dd, J ) 4.8, 7.5 Hz), 6.77 (2H, s), 3.89-
4.05 (5H, m), 3.87 (3H, s), 2.19 (3H, s), 0.84 (3H, t, J ) 7.1 Hz). To
a stirred solution of the above compound (1.88 g, 5.12 mmol) in dry
dichloromethane (20 mL) at 26 °C was added Et3N (5.18 g 51.23 mmol)
followed by a catalytic amount of 4-(dimethylamino)pyridine. Pivaloyl
chloride (3.71 g, 30.74 mmol) was added over 0.5 h. After an additional
1.0 h, the dichloromethane and excess pivaloyl chloride were removed
in Vacuo. The resulting residue was chromatographed over silica gel
eluting with EtOAc/petroleum ether (2:3). The product 72 (2.10 g,
87%) was crystallized from hexanes/EtOAc to give needles: mp 123-
1
1
dec; IR (CDCl3) 2985, 1771, 1686, 1643 cm-1; H NMR (300 MHz,
125 °C; IR (thin film) 2981, 2936, 1756, 1736 cm-1; H NMR (300
CDCl3) δ 9.23 (1H, dd, J ) 4.8, 2.3 Hz), 8.16 (1H, dd, J ) 8.0, 2.3
Hz), 7.77 (1H, s), 7.55 (1H, dd, J ) 8.0, 4.8 Hz), 7.38 (1H, d, J ) 8.2
Hz), 7.33 (1H, d, J ) 8.2 Hz), 2.51 (3H, s), 2.46 (3H, s), 2.42 (3H, s);
13C NMR (75 MHz, CDCl3) δ 184.3, 183.6 169.6, 169.1, 169.1, 157.6,
153.6, 146.5, 146.1, 143.3, 135.6, 131.9, 131.3, 130.3, 129.3, 128.4,
127.2, 126.4, 125.2, 121.7, 21.2, 21.0, 21.0; HRMS (CI) calcd for
C23H16NO8 (M+ + 1) 434.088, found 434.089.
2,5-Dimethoxyphthalide (70). To a stirred solution of 69 (8.86 g,
52.72 mmol) in dry tetrahydrofuran (180 mL) at -78 °C was added
dropwise a solution of 2.5 M n-butyllithium in hexanes (42 mL, 105.55
mmol). The mixture was slowly warmed to 70 °C, allowed to stir for
2.0 h, and then cooled to 0 °C. Dry carbon dioxide was bubbled through
the solution for 0.25 h, followed by addition of an excess of 2 M
hydrochloric acid. Phthalide 70 precipitated as a colorless crystalline
solid (4.32 g, 42%) which was collected Via vacuum filtration, and
rinsed with hexanes. The mother liquors were extracted with chloro-
form (3 × 100 mL). The combined extracts were dried (Na2SO4), and
the solvent was evaporated in Vacuo. Purification by chromatography
over silica gel eluting with petroleum ether/EtOAc (4:1) gave a further
quantity of 70 (3.87 g, 38%), total yield 80%: mp 167-168 °C (from
EtOAc/hexanes); IR (thin film) 1762, 1606 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.02 (1H, d, J ) 8.77 Hz), 6.84 (1H, d, J ) 8.77 Hz), 5.16
(2H, s), 3.91 (3H, s), 3.83 (3H, s); HRMS (CI) calcd for C10H11O4
(M+ + 1) 195.066, found 195.066.
2r-Carbethoxy-3â-(3-methylpyrid-2-yl)-4â-hydroxy-5,8-dimethoxy-
3,4-dihydro-1(2H)-naphthenone (71). To a stirred solution of diiso-
propylamine (2.09 g, 20.62 mmol) in dry tetrahydrofuran (80 mL) at
-60 °C was added n-butyllithium (1.32 g, 20.62 mmol) in hexanes
(6.31 mL). After 0.75 h, 70 (2.00 g, 10.31 mmol) was added to the
mixture, and the mixture was allowed to stir for 1 h. Ethyl 3-(3-
methylpyrid-2-yl)propenoate (1.97 g, 10.31 mmol) was added to the
mixture, and after 0.5 h at -78 °C the mixture was quenched with
saturated aqueous NH4Cl (20 mL) and diluted with distilled water (100
mL), and the resulting solution extracted with chloroform (3 × 100
mL). The combined extracts were washed with water (3 × 50 mL),
dried (MgSO4), and evaporated in Vacuo to give 71 as a colorless solid
(3.80 g, 96%) and a mixture of diastereomers: IR (thin film) 3292,
2965, 1715, 1684 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.38 (1H, d, J
) 3.9 Hz), 7.50 (1H, d, J ) 6.9 Hz), 7.11-7.15 (2H, m), 7.11-7.15
(2H, m), 6.96-6.99 (1H, d, J ) 9.02 Hz), 6.30-6.38 (1H, br s, -OH),
5.40 (1H, d, J ) 1.9 Hz), 4.60 (1H, d, J ) 12.5 Hz), 3.87-4.07 (2H,
m), 3.84 (3H, s), 3.81 (3H, s), 2.37 (3H, s), 1.06 (3H, t, J ) 7.2 Hz);
HRMS (CI) calcd for C21H24NO6 (M+ + 1) 386.160, found 386.160.
Ethyl 1-(Pivaloyloxy)-3-(3-methylpyrid-2-yl)-5,8-dimethoxy-2-
naphthoate (72). To a stirred solution of 71 (7.50 g, 19.48 mmol) in
chloroform (500 mL) at 40 °C was added p-toluenesulfonic acid
monohydrate (20.00 g), and the mixture was allowed to stir for 15.0 h.
The mixture was made basic with saturated aqueous NaHCO3 (500
mL), and the chloroform layer separated. The aqueous phase was
extracted with chloroform (3 × 100 mL). The combined extracts were
dried (MgSO4) and evaporated in Vacuo to give a moderately stable
MHz, CDCl3) δ 8.44 (1H, d, J ) 4.6 Hz), 8.14 (1H, s), 7.55 (1H, d, J
) 7.6 Hz), 7.16 (1H, dd, J ) 4.8, 7.6 Hz), 6.77 (2H, s), 3.95 (2H, q,
J ) 7.1 Hz), 3.89 (3H, s), 3.85 (3H, s), 2.27 (3H, s), 1.38 (9H, s), 0.86
(3H, t, J ) 7.1 Hz); HRMS (CI) calcd for C26H30NO6 (M+ + 1)
452.206, found 452.207.
6-Ethoxy-7-hydroxy-8,11-dimethoxynaphtho[2,3-h]quinoline (73).
To a stirred solution of diisopropylamine (0.225 g, 2.22 mmol) in dry
tetrahydrofuran (8 mL) at -78 °C was added dropwise a solution of
n-butyllithium (0.142 g, 2.22 mmol) in dry hexanes (0.734 mL). After
0.75 h, 72 (0.200 g, 0.443 mmol) was added to the solution. The
mixture was warmed to 26 °C, after 0.5 h, saturated aqueous NH4Cl
(5 mL) was added to the mixture, and the resulting solution was
extracted with chloroform (3 × 50 mL). The combined extracts were
dried (Na2SO4), and the solvent was evaporated in Vacuo. Chroma-
tography over silica gel eluting with EtOAc/hexanes (2:3) gave 73 as
a yellow solid (0.143 g, 95%): mp 205-210 °C (from hexanes/EtOAc,
yellow needles); IR (thin film) 3333, 2966, 1621 cm-1; 1H NMR (300
MHz, CDCl3) δ 11.01 (1H, s), 9.67 (1H, s), 8.81 (1H, dd, J ) 1.5, 4.4
Hz), 7.89 (1H, dd, J ) 1.5, 7.9 Hz), 7.40 (1H, d, J ) 4.4, 7.9 Hz),
6.73-6.75 (2H, m), 6.69 (1H, s), 4.39 (2H, q, J ) 6.9 Hz), 4.04 (3H,
s), 4.03 (3H, s), 1.65 (3H, t, J ) 6.9 Hz); HRMS (CI) calcd for C21H20-
NO4 (M+ + 1) 350.138, found 350.139.
6-Ethoxy-7,12-dioxo-8,11-dimethoxynaphtho[2,3-h]quinoline (74).
To a stirred solution of 73 (1.65 g, 4.876 mmol) in acetonitrile (150
mL) at -10 °C was added dropwise a solution of ceric ammonium
nitrate (5.33 g, 9.734 mmol) in distilled water (10 mL) over 0.25 h.
After 1.0 h, the mixture was filtered through a short plug of silica gel
eluting with EtOAc to give 74 (1.3 g, 74%): mp softens at 248 °C and
decomposed at 281 °C (from hexanes/EtOAc, dark orange needles);
IR (Nujol) 1685, 1594 cm-1; 1H NMR (300 MHz, CDCl3) δ 9.07 (1H,
dd, J ) 1.4, 3.6 Hz), 8.00 (1H, dd, J ) 1.5, 8.5 Hz), 7.42 (1H, dd, J
) 3.8, 8.6 Hz), 7.23 (1H, s), 7.15 (2H, s), 4.28 (2H, q, J ) 6.8 Hz),
3.94 (3H, s), 3.93 (3H, s), 1.60 (3H, t, J ) 7.2 Hz); HRMS (CI) calcd
for C21H18NO5 (M+ + 1) 364.119, found 364.118.
Acknowledgment. The National Institutes of Health (Grant
CA 50512) and National Science Foundation are thanked for
their support of this research. Dr. Vince Lynch (University of
Texas at Austin) is thanked for the X-ray crystal structure of
54. Bristol-Myers Squibb is thanked for the bioassays and
financial support.
Supporting Information Available: Complete experimental
details and spectral information for compounds 8-12, 12b, 12c,
12d, 12, 23e, 28, 29, 34-36, 41, 43-47, 62, and ethyl 3-(3-
methylpyrid-2-yl)propenoate and X-ray spectral data for struc-
ture 54 (33 pages). See any current masthead page for ordering
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