Synthetic Studies on the Kinamycin Family of Antibiotics: Synthesis of 2-(Diazobenzyl)-p-naphthoquinone, 1,7-Dideoxy-3-demethylprekinamycin, and 1-Deoxy-3-demethylprekinamycin

Article abstract of DOI:10.1021/jo9700484

2-(Diazobenzyl)-p-naphthoquinone was synthesized from 2-benzyl-1,4-dimethoxynaphthalene by cerric ammonium nitrate oxidation to 2-benzyl-p-naphthoquinone followed by diazo transfer with tosyl azide. 1,7-Dideoxy-3-demethylprekinamycin was prepared from 1,4-dimethoxynaphthalene by bromination, lithiation, and condensation with acetanthranil to give 2-(2′-N-acetaminobenzoyl)-1,4-dimethoxynaphthalene, which, following deacylation, was subjected to Pschorr cyclization to give 1,3,7-trihydro-O,O-dimethylkinafluorenone. This was then demethylated, subjected to hydrazinolysis, and then oxidized with Fetizon's reagent to complete the synthesis. 1-Deoxy-3-demethylprekinamycin was synthesized from 3-bromo-1,5-dimethoxy-4-naphthol by an identical route.

Full text of DOI:10.1021/jo9700484

4364
J . Org. Chem. 1997, 62, 4364-4369
Syn th etic Stu d ies on th e Kin a m ycin F a m ily of An tibiotics:
Syn th esis of 2-(Dia zoben zyl)-p-n a p h th oqu in on e,
1,7-Did eoxy-3-d em eth ylp r ek in a m ycin , a n d
1-Deoxy-3-d em eth ylp r ek in a m ycin
William Williams, Xin Sun, and David J ebaratnam*
Department of Chemistry, Northeastern University, Boston, Massachusetts 02115
Received J anuary 7, 1997X
2-(Diazobenzyl)-p-naphthoquinone was synthesized from 2-benzyl-1,4-dimethoxynaphthalene by
cerric ammonium nitrate oxidation to 2-benzyl-p-naphthoquinone followed by diazo transfer with
tosyl azide. 1,7-Dideoxy-3-demethylprekinamycin was prepared from 1,4-dimethoxynaphthalene
by bromination, lithiation, and condensation with acetanthranil to give 2-(2′-N-acetaminobenzoyl)-
1,4-dimethoxynaphthalene, which, following deacylation, was subjected to Pschorr cyclization to
give 1,3,7-trihydro-O,O-dimethylkinafluorenone. This was then demethylated, subjected to hy-
drazinolysis, and then oxidized with Fetizon’s reagent to complete the synthesis. 1-Deoxy-3-
demethylprekinamycin was synthesized from 3-bromo-1,5-dimethoxy-4-naphthol by an identical
route.
In tr od u ction
Pursuant to our goals of studying the DNA cleaving
and/or alkylating properties of the kinamycin family of
antibiotics and within the context of our previous work
on the design of novel DNA cleaving reagents,1,2 we wish
to report the synthesis of a number of prekinamycin
analogues. These were chosen with an eye toward the
simplification of our synthetic strategy while preserving
essential functionality in the target molecule.
The kinamycin antibiotics were first isolated from
Streptomyces murayamaensis3,4 and originally character-
ized by Omura and co-workers as being benzo[b]carbazole
cyanamides 1 (Figure 1). They have been shown to
possess activity against Gram-positive, and to a lesser
extent, Gram-negative bacteria, as well as against Ehr-
lich ascites carcinoma and sarcoma-180.4 Their struc-
tures were later revised by Gould5 using spectroscopic
methods to be 5-diazobenzo[b]fluorenes 2. Additionally,
the cyanocarbazole prekinamycin structure 3 was regi-
oselectively synthesized by Dmitrienko6 and used to
demonstrate by IR and NMR spectroscopy that authentic
kinamycins do not possess the cyanamide functionality.
The 5-diazobenzo[b]fluorene structure remains to date
X Abstract published in Advance ACS Abstracts, May 15, 1997.
(1) (a) J ebaratnam, D. J .; Kugabalasooriar, S.; Chen, H.; Arya, D.
P. Tetrahedron Lett. 1995, 36, 3123-3126. (b) J ebaratnam, D. J .; Arya,
D. P.; Chen, H.; Kugabalasooriar, S.; Vo, D. BioMed. Chem. Lett. 1995,
5, 1191-1196. (c) Arya, D. P.; Warner, P. M.; J ebaratnam, D. J .
Tetrahedron Lett. 1993, 34, 7823. (d) Arya, D. P.; J ebaratnam, D. J .
Tetrahedron Lett. 1995, 36, 4369-4372.
F igu r e 1.
the best fit to experimental data, although Hauser7
recently completed the synthesis of prekinamycin 4 and
found it to not be identical to the fraction previously
characterized by Gould8 as prekinamycin. Subsequently,
Gould9 has identified a S. murayamaensis metabolite
identical to the compound synthesized by Hauser and
named it prekinamycin, while leaving the structure of
the original choice an open question.
(2) Arya, D. P.; J ebaratnam, D. J . J . Org. Chem. 1995, 60, 3268-
3269.
(3) (a) Ito, S.; Matsuya, T.; Omura, S.; Otani, M.; Nakagawa, A.;
Takeshikma, H.; Iwai, Y.; Ohtani, M.; Hata, T. J . Antibiot. 1970, 23,
315-317. (b) Omura, S.; Nakagawa, A.; Yamada, H.; Hata, T.;
Furusaki, A.; Watanabe, T. Chem. Pharm. Bull. 1971, 19, 2428-2430.
(c) Furusaki, A.; Matsui, M.; Watanabe, T.; Omura, S.; Nakagawa, A.;
Hata, T. Isr. J . Chem. 1972, 10, 173-187. (d) Omura, S.; Nakagawa,
A.; Yamada, H.; Hata, T.; Furusaki, A.; Watanabe, T. Chem. Pharm.
Bull. 1973, 21, 931-940.
(4) Hata, T.; Omura, S.; Iwai, Y.; Nakagawa, A.; Otani, M. J .
Antibiot. 1971, 24, 353-359.
(5) Gould, S. J .; Tamayo, N.; Melville, C. R.; Cone, M. C. J . Am.
Chem. Soc. 1994, 116, 2207-2208.
(7) Hauser, F. M.; Zhou, M. J . Org. Chem. 1996, 61, 5722.
(8) Seaton, P. J .; Gould, S. J . J . Antibiot. 1989, 42, 189-197.
(9) Gould, S. J .; Chen, J .; Cone, M. C.; Gore, M. P.; Melville, C. R.;
Tamayo, N. J . Org. Chem. 1996, 61, 5720-5721.
(6) Mithani, S.; Weeratunga, G.; Taylor, N. J .; Dmitrienko, G. I. J .
Am. Chem. Soc. 1994, 116, 2209-2210.
S0022-3263(97)00048-0 CCC: $14.00 © 1997 American Chemical Society

Studies on the Kinamycin Family of Antibiotics
J . Org. Chem., Vol. 62, No. 13, 1997 4365
Sch em e 1
Sch em e 2
seemed that compounds 8 should be readily accessible
through Friedel-Crafts acylation of naphthalenes 6 with
electrophiles 7 (Scheme 1), all of which are commercially
available or readily accessible.13-15 The analogous com-
pound 5a (Figure 1) had been synthesized previously by
Gould,16 but only as a side product en route to a different
synthetic goal. Kinafluorenone 5b had been identified
as a S. murayamaensis metabolite,17 and kinobscurinone
5c had been shown to be a biosynthetic precursor of
kinamycin.18 1,7-Dideoxy-3-demethyl-O,O- dimethylkin-
afluorenone (11a ) (Scheme 3) has since been synthesized
by Mal and Hazra19 as well.
Syn th esis of 2-(Dia zoben zyl)-p-n a p h th oqu in on e
(Sch em e 2). Our initial investigations were into the
facile synthesis of 10 (Scheme 2), an open-chain analogue
of prekinamycin 4. In this manner, we could both rapidly
establish the viability of our synthetic strategy and obtain
a compound that retains only the diazo and quinone
functionalities of kinamycin. This could in principal be
accomplished from the known and easily accessible
2-benzyl-1,4- dimethoxynaphthalene20 (8a ) by cerric am-
monium nitrate oxidative demethylation21 to give 2-ben-
zyl-p-naphthoquinone (9a ) followed by a diazotransfer
reaction with tosyl azide11 in the presence of triethy-
lamine (Scheme 2). This sequence indeed proceeded as
desired, with the initial oxidative demethylation giving
a single product in 91% yield and the subsequent diaz-
otransfer also giving a single significant product 10,
The goal of our current research is the development of
easily accessible prekinamycin analogs that will be useful
for future mechanistic and biological studies. The un-
usual diazo functionality and benzo[b]fluorene structure5
offer intriguing possibilities in this regard.
Resu lts a n d Discu ssion
Retr osyn th etic An a lysis (Sch em e 1). In our strat-
egy for the synthesis of kinamycin analogs, we sought to
utilize a unified approach, so as to develop several
compounds from a single synthesis. As we were inter-
ested in both the open (2-diazobenzyl-p-naphthoquinone
(10)) and closed (prekinamycins 12) forms, we chose to
make our primary disconnection at the phenyl-phenyl
bond of the C-ring10 (Scheme 1). Additionally, due to the
likely reactivity of the diazo functionality, it seemed
prudent to introduce it at the last step of the synthesis,
either by hydrazinolysis/oxidation of ketone forms of 11
(Scheme 1) or by diazotransfer11 from the methylene
quinones 9a (Scheme 2) and 15 (Scheme 4). Formation
of the phenyl-phenyl bond could, in principal, be ac-
complished by photolysis of the aryl iodide 8, by a Pd-
catalyzed Heck reaction of 8 or 9, by a reductive free-
radical addition, or by a Pschorr coupling of 8 (Scheme
1).12 We thus identified compounds 8 or 9 and 11 as key
intermediates offering potential access to a wide array
of open and closed kinamycin analogs. Furthermore, it
(12) (a) Duclos, R. I.; Tung, J . S.; Rapoport, H. J . Org. Chem. 1984,
49, 5243-5246. (b) Wassmundt, F. W.; Kiesman, W. F. J . Org. Chem.
1995, 60, 196-201.
(13) (a) Fieser, L. F. J . Am. Chem. Soc. 1948, 70, 3165-3174. (b)
Kometani, T.; Takeuchi, Y.; Yoshii, E. J . Chem. Soc., Perkin Trans. 1
1981, 1197-1202.
(14) (a) Bogert, M. T.; Gortner, R. A.; Amend, C. G. J . Am. Chem.
Soc. 1911, 33, 949-962. (b) Tomioka, H.; Kawasaki, H.; Kobayashi,
N.; Hirai, K. J . Am. Chem. Soc. 1995, 117, 4483-4498.
(15) Hannan, R. L.; Barker, R. B.; Rapoport J . Org. Chem. 1979,
44, 2153.
(16) (a) Gore, M. P.; Gould, S. J .; Weller, D. D. J . Org. Chem. 1991,
56, 2289-2291. (b) Gore, M. P.; Gould, S. J .; Weller, D. D. J . Org. Chem.
1992, 57, 2774-2783.
(17) Cone, M. C.; Melville, C. R.; Gore, M. P.; Gould, S. J . J . Org.
Chem. 1993, 58, 1058-1061.
(18) Gould, S. J .; Melville, C. R. Bioorg. Med. Chem. Lett. 1994, 5,
51-54.
(10) Sato, Y.; Gould, S. J . J . Am. Chem. Soc. 1986, 108, 4625-4631.
(11) (a) Davies, H. M. L.; Cantrell, W. R.; Romines, K. R.; Baum, J .
S. In Organic Syntheses; Meyers, A. I., Ed.; J ohn Wiley & Sons, Inc.:
New York, 1992; Vol. 70, pp 93-95. (b) Regitz, M.; Hocker, J .;
Liedhegener, A. In Organic Syntheses; Baumgarten, H. E., Ed.; J ohn
Wiley & Sons, Inc.: New York, 1973; Collect. Vol. V, pp 179-183.
(19) Mal, D.; Hazra, N. K. Tetrahedron Lett. 1996, 37, 2641-2642.
(20) J oshi, B. S.; J iang, Q.; Rho, T.; Pelletier, S. W. J . Org. Chem.
1994, 59, 8220-8232.
(21) Tanoue, Y.; Terada, A. Bull. Chem. Soc. J pn. 1988, 61, 2039-
2045.

4366 J . Org. Chem., Vol. 62, No. 13, 1997
Williams et al.
Sch em e 3
Sch em e 4
basic hydrolysis with KOH in n-PrOH/H2O to give the
deacylated product 8c in 80% yield. Ring closure was
accomplished by a hydroquinone-catalyzed Pschorr reac-
tion12 with isoamyl nitrite in AcOH to give 1,7-dideoxy-
3-demethyl-O,O-dimethylkinafluorenone (11a ) in 42%
yield.
With the dimethylkinafluorenone 11a in hand, we
attempted the synthesis of our second target molecule,
5-diazo-1,7-dideoxy-3-demethyl-O,O-dimethylkinafluo-
rene (11c) (Scheme 4). Hydrazinolysis in EtOH followed
by oxidation with HgO in Et2O, however, gave instead
the kinafluorenone 14 (Scheme 3). This, we postulate,
resulted from an unusual nucleophilic attack of hydrazine
at the 6-position instead of the expected 5-position,
followed by elimination of methanol to give the aryl
hydrazide 13, which upon oxidation gave 14. Our results
in this regard are in concurrence with those of Gould.9
We then considered the use of our proven diazotransfer
methodology for introduction of the diazo functionality.
Triethylsilane reduction of the ketone 11a proceed
smoothly (Scheme 4), but all attempts to selectively
oxidize the hydroquinone to quinone, either by oxidative
demethylation21 or by demethylation followed by oxida-
tion (HgO, O2, NO+), while retaining the methylene
group, failed. We were also unable to effect diazotransfer
on 1,7-dideoxy-3- demethylkinafluorene (11d ) to give 11c,
utilizing t-BuLi and TsN3 in Et2O.
albeit in only 36% yield. The poor mass recovery during
purification may well be due to decomposition on the
column.
Syn th esis of 1,7-Did eoxy-3-d em eth ylp r ek in a m y-
cin (Sch em e 3). Encouraged by our success, we set out
on the synthesis of our primary target 11a (Scheme 3).
Our initial strategy for the construction of the kinamycin
ring system sought to exploit the easy accessability of
compounds of the form 8 (Scheme 1) through Friedel-
Crafts acylation of dimethoxynaphthalene (6a )13 followed
by reduction with triethylsilane.20 All attempts, however,
to close the C-ring, utilizing various nonamino derivatives
of 8, failed, while the 2′-amino series proved inaccessible
through Friedel-Crafts methodology. We therefore turned
to an anionic coupling of 2-bromo-1,4-dimethoxynaph-
thalene (6b) with acetanthranil14 (7a ) to form ketone 8b22
followed by use of the Pschorr reaction to close the C-ring
(Scheme 3). The synthesis of 11a thus proceeded as
follows: Regioselective bromination of 1,4-dimethox-
ynaphthalene (6a ) with bromine in methylene chloride
yielded 2-bromo-1,4-dimethoxynaphthalene (6b) in 93%
yield. The bromide 6b was then lithiated in Et2O at -78
°C and quenched in a reverse addition to acetanthranil14
(7a ) to give 2-(2′-acetaminobenzoyl)-1,4-dimethoxynaph-
thalene (8b) in 78% yield. This was then subjected to
At this point, we determined that the best course of
action was to return to our original strategy, despite the
discouraging results of the hydrazinolysis of ketone 11a
(Schemes 3 and 4). To this end, we demethylated 11a
with BBr3 in CH2Cl2 in quantitative yield (Scheme 3) to
give 1,7-dideoxy-3-demethylkinafluorenone (11b). The
related compound, kinobscurinone, had been synthesized
by Gould18 as the quinone and found to be an NMR silent
species related to the stealthins.23 Compound 11b gave
no detectable 13C NMR signal in nonacidic solvents
1
(acetone-d6, DMSO-d6, methanol-d4), while the H spec-
trum in these solvents showed extensive band broadening
(22) Directed lithiation of 1,4-dimethoxynaphthalene (6a ) followed
by quenching with acetanthranil (7a ) produced a complex mixture and
low yield.
(23) Shin-ya, K.; Furihata, K.; Teshima, Y.; Hayakawa, Y.; Seto, H.
Tetrahedron Lett. 1992, 33, 7025-7028.

Studies on the Kinamycin Family of Antibiotics
J . Org. Chem., Vol. 62, No. 13, 1997 4367
Sch em e 5
utilized in the future and current work on the mode of
action of the kinamycin antibiotics. This is postulated
to be either bioreductive alkylation of DNA nucleotides26
leading to cross-linking, or possibly radical or carbene
cleavage of the sugar backbone, demonstrated by us for
9-diazofluorene and â-naphthylphenyldiazomethane un-
der oxidative conditions.2 The role of the quinone moiety
in the bioreductive alkylation26 of both prekinamycin (4)
and kinamycin (2) is of particular interest.
Exp er im en ta l Section
Gen er a l P r oced u r e. NMR peak frequencies were re-
corded on a 300 MHz 1H/75 MHz 13C spectrometer and
reported in ppm from TMS. IR spectra were recorded using
KBr pellets or in CCl4 at a resolution of 4 cm-1 with peak
frequencies reported in cm-1. Elemental analyses were per-
formed at Desert Analytics of Tucson, AZ, or at Galbraith
Laboratories of Knoxville, TN.
Compounds 8a ,20 6a ,15 were prepared by known procedures.
Ma ter ia ls. Flash chromatography was carried out utilizing
silica gel-60, 230-400 mesh (EM-9385). Dry solvents were
distilled from CaH2 and N2, except for Et2O, which was
distilled from Na/benzophenone.
2-Ben zyl-1,4-n a p h t h oq u in on e (9a ). 2-Benzyl-1,4-di-
methoxynaphthalene (8a )20 (1.31 g, 4.71 mmol) was dissolved
in 10 mL of acetonitrile and 2 mL of chloroform. Cerric
ammonium nitrate (3 equiv, 7.75 g, 14.1 mmol) in 10 mL of
H2O was added dropwise with stirring and the mixture stirred
for 15 min at room temperature. The reaction mixture was
extracted into ethyl acetate, washed with saturated NaHCO3
(aq) and brine, and then dried over anhydrous Na2SO4. The
solvent was removed under vacuum to give 9a (1.06 g, 4.27
mmol, 91%) as a yellow powder that was used without further
purification: mp 97-99 °C; IR (KBr) 3033, 2960, 1678 (vs);
1H NMR (CDCl3) δ 8.08 (1H, m), 8.02 (1H, m), 7.70 (2H, m),
7.33 (2H, m), 7.26 (3H, m), 6.60 (1H, s), 3.89 (2H, s); 13C NMR
(CDCl3) δ 185.09, 184.95, 150.88, 136.76, 135.65, 133.75,
133.69, 132.17, 132.08, 129.46, 128.88, 127.10, 126.66, 126.11,
35.74. Anal. Calcd for C17H12O2: C, 82.24; H, 4.87. Found:
C, 81.88; H, 5.01.
of the aromatic region. This behavior appears to be
characteristic of 5-hetero-substituted benzo[b]fluorene
hydroquinones, as reported by Seto,23 with whom our
results are in concurrence. We were, however, able to
obtain both 13C and 1H spectra of 11b in DMSO-d6
containing 20% TFA-d1-DMSO-d6.24 Hydrazinolysis of
the crude product followed by HgO (EtOH/KOH) oxida-
tion produced a complex product mixture. Hydrazinoly-
sis followed by oxidation with Fetizon’s reagent,25
however, produced the desired product, 1,7-dideoxy-3-
demethylprekinamycin (12a ) in 50% overall yield from
11a .
Syn th esis of 1-Deoxy-3-d em eth ylp r ek in a m ycin
(12b) Sch em e 5). Our final goal was the synthesis of a
prekinamycin analog retaining the A-ring hydroxyl
(Scheme 5). The synthetic sequence followed that of 1,7-
dideoxy-3-demethylprekinamycin (12a ), beginning with
O-methylation of the known 3-bromo-1,5-dimethoxy-4-
naphthol (6c)15 to give 6d (62%). This was followed by
lithiation and condensation by reverse addition to acet-
anthranil14 7a , giving amide 8d in 50% yield. The amide
was then subjected to basic hydrolysis with KOH in
methanol to give aniline 8e quantitatively and then
diazotized in situ with isoamyl nitrite in AcOH and
cyclized reductively with hydroquinone12 to give 1-deoxy-
3-demethyl-O,O-dimethylkinafluorenone (11e) in 72%
yield. This material was then demethylated with BBr3
and the crude product subjected to hydrazinolysis and
then oxidized with Fetizon’s reagent25 to give 1-deoxy-
3-demethylprekinamycin (12b) in 70% overall yield from
11e.
2-(Dia zoben zyl)-p-n a p h th oqu in on e (10). 2-Benzyl-1,4-
naphthoquinone (9a ) (0.10 g, 0.403 mmol) and p-toluenesulfo-
nyl azide (0.08 g, 0.403 mmol) were dissolved in 4.0 mL of dry
CH3CN under N2 at 0 °C. This was cannulated at 0 °C into
Et3N (3.0 equiv, 0.17 mL) in 1.0 mL of CH3CN and stirred
overnight, warming to room temperature. The product mix-
ture was extracted into EtOAc, washed with 1 g of NaOH in
40 mL of H2O and then brine, and dried over anhydrous Na2-
SO4. The crude product was purified by flash chromatography
with 98% hexanes/2% EtOAc and crystallized from MeOH,
yielding 10 (0.04 g, 0.146 mmol, 36%) as golden needles: IR
1
(KBr) 3033, 2095 (vs), 1684 (s); H NMR (CDCl3) δ 8.28 (1H,
d, J ) 6.9 Hz), 8.24 (1H, d, J ) 7.2 Hz), 7.92 (1H, s), 7.76 (2H,
t, J ) 7.2 Hz), 7.41 (2H, m), 7.34 (3H, m); 13C NMR (CDCl3) δ
180.94, 178.58, 134.47, 134.29, 134.00, 133.84, 133.61, 131.20,
129.29, 129.15, 128.33, 128.12, 126.27, 120.14. 77.27 (buried
in CDCl3 peak, but visible). Note: elemental analysis of
compound 10 was not performed due to its apparent instabil-
ity.
2-Br om o-1,4-d im et h oxyn a p h t h a len e (6b ). To 1,4-di-
methoxynaphthalene (6a )13 (2.00 g, 7.49 mmol) in 20 mL of
dry CH2Cl2 under N2 at 0 °C was added dropwise with stirring
Br2 (1.1 equiv, 1.87 g, 8.23 mmol) in 1 mL of CH2Cl2. The
reaction mixture was stirred for 15 min at 0 °C and then
extracted into CH2Cl2 and washed with saturated NaHCO3
(aqueous), saturated Na2S2O5 (aqueous), and brine. The
organic phase was dried over anhydrous Na2SO4 and the
solvent removed under vacuum, yielding a light brown oil. The
crude product was purified by flash chromatography with 95%
hexanes/5% ethyl acetate to yield 6b (2.63 g, 6.97 mmol, 93%)
as a colorless oil that crystallized from MeOH to give a white
Con clu sion
This work offers rapid routes to a series of both open-
and closed-chain prekinamycin analogues that will be
(24) The lack of any 13C NMR signals within the region character-
istic of a quinone allows unambiguous assignment to 11b of the
hydroquinone oxidation state. Further, an exchangeable peak was
visible at ∼3.35 ppm in the acetone-d6 1H NMR spectrum, and the IR
spectrum has a broad peak at 3364 cm-1. Elemental analysis and mass
spectroscopy also favor the hydroquinone. See the Experimental
Section and Supporing Information.
(25) (a) Balogh, V.; Fe´tizon, M.; Golfier, M. J . Org. Chem. 1971, 36,
1339-1341. (b) Fe´tizon, M.; Golfier, M.; Milcent, R.; Papadakis, I.
Tetrahedron 1975, 31, 165-170.
(26) Moore, H. W. Science 1977, 197, 527-532.

4368 J . Org. Chem., Vol. 62, No. 13, 1997
Williams et al.
powder. Note: A very small amount of inseparable material
thought to be the 5-bromo isomer was also present in the
product (detected by TLC and NMR), but purity appeared to
be sufficient for synthetic purposes: mp 54-58 °C; IR (CCl4)
2938, 2844, 1589; 1H NMR (CDCl3) δ 8.22 (1H, d, J ) 7.2 Hz),
8.08 (1H, d, J ) 6.6 Hz), 7.60-7.49 (2H, m), 6.90 (1H, s), 3.972
and 3.969 (6H, 2s); 13C NMR (CDCl3) δ 152.25, 146.67, 128.94,
127.35, 125.82, 122.80, 122.62, 121.86, 111.94, 107.82, 61.46,
55.92.
127.01, 125.65, 124.42, 124.04, 122.60, 119.60, 63.20, 61.33.
Anal. Calcd for C19H14O3: C, 78.61; H, 4.86. Found: C, 78.45;
H, 4.97.
1,7-Did eoxy-3-d em eth ylk in a flu or en on e (11b). Com-
pound 11a (0.50 g, 1.72 mmol) was dissolved in 40 mL of dry
CH2Cl2 under N2 and brought to -78 °C. BBr3 (1 M in CH2-
Cl2, 3.0 equiv, 5.16 mmol, 5.2 mL) was added dropwise with
stirring and the reaction mixture stirred overnight, warming
to room temperature. The reaction mixture was then poured
into H2O, washed with saturated NaHCO3 (aqueous) and then
saturated Na2S2O5 (aqueous), and dried over anhydrous Na2-
SO4. The solvent was removed under vacuum, yielding 11b
(0.46g, 1.72 mmol, 100%) as a brown-red solid, which was
judged pure enough by TLC to be used in subsequent steps
without further purification. A small portion of material was
recrystallized from chloroform and used for spectroscopic
purposes, as NMR spectra of this compound proved to be
difficult to obtain: mp 257-258 °C; IR (KBr) 3364 (br, vs),
2-(2′-N -Ace t a m in ob e n zoyl)-1,4-d im e t h oxyn a p h t h a -
len e (8b). 2-Bromo-1,4-dimethoxynaphthalene (6b ) (4.00g,
11.4 mmol) was dissolved in 30 mL of dry Et2O under N2 and
then brought to -78 °C. t-Bu Li (1.7 M in pentane, 1.2 equiv,
10.57 mL) was then added dropwise with stirring, and after 5
min the mixture was cannulated rapidly into acetanthranil14
(7a ) (1.2 eq, 2.90 g, 13.7 mmol) in 50 mL of dry Et2O, N2, -78
°C. The reaction mixture was stirred overnight, warming to
room temperature. The product mixture was extracted into
ethyl acetate, washed with saturated NH4Cl (aqueous) and
dried over anhydrous Na2SO4 and the solvent removed under
vacuum. The product was purified by flash chromatography
with 90% hexanes/10% ethyl acetate to give 8b (4.07 g, 8.89
mmol, 78% yield) as a light yellow powder: mp 168-169 °C;
1
1667 (vs), 1619 (vs); H NMR (acetone-d6) δ 8.24 (br, d, J )
7.8 Hz), 7.69 (br, t, J ) 7.2 Hz), ∼3.35 (vbr); 1H NMR (DMSO-
d6/20% TFA-d1): δ 8.29 (1H, d, J ) 9.1 Hz), 8.23 (1H, d, J )
8.4 Hz), 8.14 (1H, d, J ) 7.3 Hz), 7.66 (2H, m), 7.61 (1H, t, J
) 7.7 Hz), 7.54 (1H, t, J ) 6.9 Hz), 7.32 (1H, t, J ) 7.7 Hz);
13C NMR (DMSO-d6/20% TFA-d1) δ 193.66, 149.59, 144.19,
142.23, 135.63, 135.11, 133.22, 129.86, 127.99, 127.16, 125.35,
124.91, 123.89, 123.76, 118.82, 113.14; MS (rel int) m/z 263
(M + H)+; CID of 263 m/ z 263 ([M + H]+, 100), 262 (M+, 71),
189 (80). Anal. Calcd for C17H10O3: C, 77.86; H, 3.84.
Found: C, 76.48; H, 3.89. See ref 24.
1
IR (KBr) 3255, 2938, 1705 (s); H NMR (CDCl3) δ 11.59 (1H,
br, s), 8.77 (1H, d, J ) 9.3 Hz), 8.31 (1H, m), 8.15 (1H, m),
7.63-7.56 (4H, m), 7.01 (4H, t, J ) 7.2 Hz), 6.67 (1H, s), 3.97
(3H, s), 3.80 (3H, s), 2.31 (3H, s); 13C NMR (CDCl3) δ 200.75,
169.54, 151.72, 147.97, 141.34, 135.36, 134.89, 128.46, 127.76,
127.62, 127.36, 127.20, 122.77, 122.57, 122.48, 122.30, 120.61,
102.42, 63.68, 55.86, 25.57. Anal. Calcd for C21H19NO4: C,
72.19; H, 5.48; N, 4.01. Found: C, 71.85; H, 5.61; N, 3.97.
1,7-Dideoxy-3-dem eth ylpr ekin am ycin (12a). Compound
11b (0.10 g, 0.381 mmol) was dissolved in 16 mL of 100% EtOH
and anhydrous hydrazine (0.878 mL, 70 equiv) added at once.
The reaction mixture was refluxed for 0.5 h and then cooled
to room temperature, and the solvent was removed under
vacuum. The solids were dissolved again in anhydrous EtOH,
which was again removed under vacuum to remove traces of
hydrazine. The 0.108 g of crude hydrazone was then sus-
pended in 10 mL of dry CH2Cl2 under N2 with 1.03 mL of Et3N,
and Fetizon’s reagent (2.83 g, ∼4.97 mmol Ag2CO3, ∼13 equiv)
added at once with stirring. The reaction mixture was stirred
for 5 min, then the solids were removed by gravity filtration
and washed with CH2Cl2. The solvent was removed under
vacuum and the crude product purified by flash chromatog-
raphy with 65% hexanes/35% CH2Cl2, yielding 12b (0.063 g,
0.191 mmol, 50%) as a bright red solid: mp 168 °C dec; IR
2-(2′-Am in ob en zoyl)-1,4-d im et h oxyn a p h t h a len e (8c).
Compound 8b (5.37g, 17.5 mmol) was dissolved in 80 mL of
n-propanol at reflux. KOH, 3.45 g in 30 mL of H2O, was added
dropwise with stirring and the reaction mixture refluxed for
3 h under N2. The product mixture was poured into H2O,
extracted into ethyl acetate, and dried over anhydrous Na2-
SO4. The solvent was then removed under vacuum and the
crude product crystallized from MeOH to give 8c (3.79 g, 14.0
mmol, 80%) as light yellow crystals: mp 145-147 °C; IR (KBr)
3455, 3339, 1610 (vs); 1H NMR (CDCl3) δ 8.31 (1H, d, J ) 7.2
Hz), 8.17 (1H, d, J ) 7.2 Hz), 7.59 (2H, m), 7.40 (1H, d, J )
8.7 Hz), 7.29 (1H, t, J ) 8.1 Hz), 6.75 (1H, d, J ) 8.4 Hz), 6.70
(1H, s), 6.55 (1H, t, J ) 7.5 Hz), 6.47 (2H, s, br), 3.98 (3H, s),
3.84 (3H, s); 13C NMR (CDCl3): δ 199.08, 151.63, 150.80,
146.83, 135.20, 134.93, 128.67, 128.51, 127.20, 127.06, 126.57,
122.61, 122.43, 118.50, 116.94, 116.05, 102.76, 63.37, 55.82.
Anal. Calcd for C19H16NO2: C, 74.25; H, 5.58; N, 4.56.
Found: C, 74.06; H, 5.42; N, 4.53.
1
(KBr) 2966, 2097 (vs), 1656 (s); H NMR (CDCl3) δ 8.44 (1H,
m), 8.16 (1H, d, J ) 7.5 Hz), 8.06 (1H, d, J ) 7.8 Hz), 7.68
(2H, m), 7.45 (1H, m), 7.38 (2H, m); 13C NMR (CDCl3) δ 180.69,
180.05, 134.41, 134.26, 133.93, 133.89, 133.21, 132.88, 130.38,
127.28, 126.84, 126.76, 126.68, 126.09, 125.92, 118.44, 77.25
(buried in CDCl3 peak, but visible); MS (rel int) m/ z 273, (M
+ H)+; CID of 273 m/ z 272 (M+, 57), 40 (100). Anal. Calcd
for C17H8N2O2: C, 75.00; H, 2.96; N, 10.29. Found: C, 74.44;
H, 3.07; N, 9.76.
1 , 7 -D i d e o x y -3 -d e m e t h y l -O , O -d i m e t h y l k i n a -
flu or en on e (11a ). Compound 8c (1.06 g, 3.45 mmol) was
dissolved by warming in 150 mL of acetic acid with stirring,
under N2, and then cooled to ∼15 °C. Isoamyl nitrite (2 equiv,
6.90 mmol, 0.93 mL) was then added at once with rapid
stirring. The deep red reaction mixture was stirred for 0.5 h
covered with aluminum foil at ∼15 °C, under N2, and then
hydroquinone (1.2 equiv, 0.46 g) in 10 mL of acetone was added
dropwise. N2 gas evolved, and the reaction mixture became
clear. The reaction was stirred overnight and the solvent
removed under vacuum. The solids were then extracted into
ethyl acetate, washed with saturated NaHCO3 (aqueous) and
then with brine, and dried over anhydrous Na2SO4, and the
solvent was again removed under vacuum. The product was
purified by flash chromatography with 99% hexanes/1% ethyl
acetate and then crystallized from MeOH. The unresolved
fraction from chromatography was combined with filtrate from
the crystallization, rechromatographed with same solvent, and
then recrystallized from MeOH to yield 11a (0.42 g, 1.45 mmol,
42%) as brilliant yellow spars: mp 173-174 °C; IR (KBr) 2949,
3-Br om o-1,4,5-tr im eth oxyn a p h th a len e (6d ). 3-Bromo-
1,5-dimethoxy-4-naphthol (6c)15 (800 mg, 2.827 mmol) was
dissolved in 150 mL of 14% aqueous sodium hydroxide solution
and 1 mL of EtOH added. Dimethyl sulfate (2.64 mL) was
added in five portions over a 24 h period. The reaction solution
was extracted into two volumes (250 mL) of CH2Cl2 The
.
organic phases were combined and washed with two 250 mL
volumes of 14% aqueous sodium hydroxide solution and then
twice with 250 mL of water and twice with 250 mL of brine.
The organic phase was dried over anhydrous sodium sulfate
and the solvent removed under vacuum. The crude product
was dissolved in hexane (120 mL) and filtered to remove solids
and the solvent removed under vacuum to give 0.52 g (1.75
mmol, 62%) of 1,4,8-trimethoxy-2-bromonaphthalene (6d ),
which was judged pure enough by TLC and NMR to be used
in subsequent steps without further purification: mp 85-87
1
1
2854, 1705 (vs); H NMR (CDCl3) δ 8.30 (1H, d, J ) 8.4 Hz),
°C; IR (CCl4) 2910, 2810, 1570; H NMR (CDCl3) δ 7.83 (1H,
8.04 (1H, d, J ) 8.1 Hz), 8.00 (1H, d, J ) 7.5 Hz), 7.74 (1H, d,
J ) 7.5 Hz), 7.64-7.47 (3H, m), 7.33 (1H, t, J ) 7.5 Hz), 4.30
(3H, s), 4.00 (3H, s); 13C NMR (CDCl3) δ 190.30, 153.90, 146.99,
142.61, 136.14, 134.80, 133.64, 131.06, 129.62, 128.64, 127.70,
d, J ) 8.6 Hz), 7.38 (1H, t, J ) 8.1 Hz), 6.95 (1H, s), 6.93 (1H,
d, J ) 7.8 Hz), 3.98 (3H, s), 3.92 (3H, s), 3.87 (3H, s); 13C NMR
(CDCl3) δ 155.42, 151.76, 146.70, 128.13, 126.10, 121.20,
115.01, 114.19, 108.95, 107.93, 61.68, 56.37, 55.92; MS (rel int)

Studies on the Kinamycin Family of Antibiotics
J . Org. Chem., Vol. 62, No. 13, 1997 4369
1
m/ z 299 ([M + H]+, 30, 81Br), 297 ([M + H]+, 26, 79Br); CID of
297 m/ z 297 ([M + H]+, 57), 282 (100), 267 (99). Anal. Calcd
for C13H13Br: C, 52.50; H, 4.38; Br, 26.90. Found: C, 52.48;
H, 4.58; Br, 26.39.
yield: mp 219-220 °C; IR (CCl4) 1530, 1240, 1060; H NMR
(CDCl3) δ 7.97 (1H, d, J ) 7.8 Hz), 7.75 (1H, d, J ) 7.5 Hz),
7.69 (1H, d, J ) 8.3 Hz), 7.54 (2H, m), 7.34 (1H, t, J ) 7.1
Hz), 6.92 (1H, d, J ) 7.8 Hz), 4.08 (3H, s), 4.00 (3H, s), 3.99
(3H, s); 13C NMR (CDCl3) δ 189.20, 158.76, 154.30, 145.96,
140.81, 135.36, 133.46, 128.94, 127.63, 127.17, 123.24, 122.89,
121.14, 114.14, 107.26, 61.62, 60.06, 55.35; MS (rel int) m/ z
321 (M + H)+; CID of 321 m/z 321 ([M + H]+, 73), 306 (51),
291 (100). Anal. Calcd for C20H16O4: C, 75.00; H, 5.03.
Found: C, 72.15; H, 4.91.
1-Deoxy-3-d em et h ylp r ek in a m ycin (12b ). Compound
11e (41 mg, 0.128 mmol) was dissolved in 4 mL of dry CH2Cl2
under N2 at -78 °C. BBr3 (1 M in CH2Cl2, 3 equiv, 0.4612
mmol, 0.4612 mL) was added dropwise at -78 °C. The
reaction mixture was stirred overnight, warming to room
temperature. The product mixture was poured into water and
extracted with CH2Cl2 and the organic layer dried over
anhydrous Na2SO4. The solvent was removed under vacuum
and the crude product 11f (28.2 mg, 0.101 mmol) carried over
to the next step.
Compound 11f (28.2 mg, 0.101 mmol) was dissolved in 4.26
mL of EtOH with anhydrous hydrazine (73.5 equiv, 7.45 mmol,
0.2337 mL). The reaction mixture was refluxed for 0.5 h under
N2. The reaction was cooled to room temperature and the
solvent removed under vacuum to give the crude hydrazone
(29.2 mg, 0.0999 mmol), which was carried over into the next
step.
The crude hydrazone (29.2 mg, 0.0999 mmol) was dissolved
in 2.66 mL of CH2Cl2 with 0.274 mL of Et3N. Fetizon’s reagent
(0.753 g, ∼1.31 mmol Ag2CO3, ∼13 equiv) was added at once
and the resulting mixture stirred for 5 min at room temper-
ature. The suspension was then gravity filtered to remove
solids, which were washed with several volumes of CH2Cl2.
The solvent was removed under vacuum and the crude product
purified by flash chromatography (65% hexanes/35% CH2Cl2)
to give 12b (26 mg, 70% over three steps from 11e); mp 178
3-(2′-N-Acet a m in ob en zoyl)-1,4,5-t r im et h oxyn a p h t h a -
len e (8d ). Compound 6d (970 mg, 3.27 mmol) was dissolved
in dry ethyl ether (20 mL) and stirred under N2 at -78 °C for
30 min. t-BuLi (1.7 M in pentane, 1.55 equiv, 5.05 mmol, 2.97
mL) was slowly added, and after 15 min, the mixture was
cannulated in a reverse addition to acetanthranil14 (7a ) (1.056
g, 2 equiv, 6.534 mmol), which was dissolved in 30 mL of
diethyl ether at -78 °C. The reaction was followed by TLC.
After 12 h of warming to room temperature, 20 mL of water
was added to the reaction solution, which was extracted into
methylene chloride, washed twice with water, and dried over
anhydrous sodium sulfate. The solvent was removed under
vacuum and the crude product purified by flash chromatog-
raphy (80% hexane/20% EtOAc) to yield 620 mg (50.1%) of
3-(2′-N-acetaminobenzoyl)-1,4,5-trimethoxynaphthalene: mp
141-143 °C; IR (CCl4) 3480 (br), 2920, 1570; 1H NMR (CDCl3)
δ 8.76 (1H, d, J ) 9.0 Hz), 7.92 (1H, d, J ) 8.5 Hz), 7.52 (3H,
m), 6.98 (2H, m), 6.63 (1H, s), 3.99 (3H, s), 3.94 (3H, s), 3.73
(3H, s), 2.31 (3H, s); 13C NMR (CDCl3) δ 201.35, 169.54, 156.53,
151.57, 147.39, 141.36, 135.27, 135.10, 129.96, 129.72, 127.19,
122.47, 122.35, 120.37, 114.92, 107.57, 102.77, 64.02, 56.17,
55.90, 25.61; MS (rel int) m/ z 380 (M + H+); CID of 380 m/ z
380 ([M + H]+, 36), 162 (98), 120 (100). Anal. Calcd for C22H21
-
NO5: C, 69.60; H, 5.54; N, 3.69. Found: C, 69.07; H, 5.57; N,
3.48.
3-(2′-Am in oben zoyl)-1,4,5-tr im eth oxyn a p h th a len e (8e).
Compound 8d (440 mg, 1.16 mmol) was dissolved in methanol
(39.4 mL), and 900 mg of KOH in 19.7 mL of H2O was added
to the reaction mixture, which was refluxed for 12 h and
followed by TLC. The reaction mixture was extracted twice
into methylene chloride (10 mL). The organic phases were
combined, washed twice with 10 mL of saturated aqueous
ammonium chloride, and then dried over anhydrous sodium
sulfate. The solvent was removed under vacuum to give 400
mg of 8e (100%), which was judged pure enough by TLC and
NMR to be utilized in subsequent steps without further
purification: mp 137.5-138 °C; IR (CCl4) 3460 (br), 2920, 1530;
1H NMR (CDCl3) δ 7.92 (1H, d, J ) 8.3 Hz), 7.46 (1H, t, J )
8.4 Hz), 7.34 (1H, d, J ) 8.2 Hz), 7.25 (1H, t, J ) 7.2 Hz), 6.97
(1H, d, J ) 7.8 Hz), 6.70 (1H, d, J ) 8.3 Hz), 6.67 (1H, s), 6.50
(1H, t , J ) 7.6 Hz), 6.45 (2H, br, s), 3.99 (3H, s), 3.94 (3H, s),
3.76 (3H, s); 13C NMR (CDCl3) δ 199.45, 156.46, 151.48, 150.92,
146.56, 135.37, 134.74, 131.16, 129.24, 126.52, 120.55, 118.58,
116.66, 115.93, 114.86, 107.34, 103.19, 63.86, 56.17, 55.84; MS
(rel int) m/ z 338 (M + H)+; CID of 338 m/ z 338 ([M + H]+,
12), 245 (34), 120 (100). Anal. Calcd for C20H19NO4: C, 71.20;
H, 5.60; N, 4.15. Found: C, 69.11; H, 5.35; N, 3.97.
1-Deoxy-3-dem eth yl-O,O-dim eth ylkin aflu or en on e (11e).
Compound 8e (400 mg, 1.187 mmol) was dissolved in HOAc.
Isoamyl nitrite (2 equiv, 2.374 mmol, 0.321 mL) was added
and the mixture stirred for 0.5 h. Hydroquinone (130.7 mg,
1.187 mmol) dissolved in 2 mL of acetone was added to the
red reaction mixture. The reaction mixture was stirred
overnight and then extracted twice into 15 mL of methylene
chloride. The organic phases were combined and dried over
anhydrous sodium sulfate, and the solvent was removed under
vacuum to give the crude product. After flash chromatography
(95% hexanes/5% EtOAc), 11e, 274 mg, was obtained in 72%
1
°C dec; IR (KBr) 3132 (br), 2962, 2095 (vs); H NMR (CDCl3)
δ 12.13 (1H, s), 8.53 (1H, m), 7.76 (1H, d, J )7.2 Hz), 7.63
(1H, d, J ) 8.7 Hz), 7.57 (1H, d, J ) 6.0 Hz), 7.45 (2H, m),
7.21 (1H, d, J ) 7.8 Hz); 13C NMR (CDCl3) δ 185.87, 179.56,
162.06, 136.50, 134.63, 134.25, 133.54, 130.49, 127.66, 127.00,
126.11, 123.83, 119.58, 118.56, 115.94, 115.56, 77.23 (buried
in CDCl3 peak, but visible); MS (rel int) m/ z 289 (M + H)+;
CID of 289 m/z 289 ([M + H]+, 68), 261 (80), 91 (95).
Ack n ow led gm en t. This research was supported by
the National Science Foundation (CHE-9406469). We
wish to thank Professor Paul Vorous (Northeastern
University) and his students Lisa Marzilli, J ianmei
Ding, and Eric Gangl for obtaining the mass spectral
data and Hang Chen for perfecting the methylation of
6c (Scheme 5).
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compounds 10, 6b, 11b, and 12b and a 13C NMR spectrum
for 11b (6 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O9700484