Novel antibacterial class: A series of tetracyclic derivatives

Article abstract of DOI:10.1021/jm060010w

We describe the synthesis and antibacterial activity of a series of tetracyclic naphthyridones. The members of this series act primarily via inhibition of bacterial translation and belong to the class of novel ribosome inhibitors (NRIs). In this paper we

Full text of DOI:10.1021/jm060010w

4842
J. Med. Chem. 2006, 49, 4842-4856
Novel Antibacterial Class: A Series of Tetracyclic Derivatives
Mira M. Hinman,* Teresa A. Rosenberg, Darlene Balli, Candace Black-Schaefer, Linda E. Chovan, Douglas Kalvin,
Philip J. Merta, Angela M. Nilius, Steve D. Pratt, Niru B. Soni, Frank L. Wagenaar, Moshe Weitzberg, Rolf Wagner, and
Bruce A. Beutel
Infectious Diseases Research, Abbott Laboratories, 200 Abbott Park Road, Abbott Park, Illinois 60064-6217
ReceiVed January 5, 2006
We describe the synthesis and antibacterial activity of a series of tetracyclic naphthyridones. The members
of this series act primarily via inhibition of bacterial translation and belong to the class of novel ribosome
inhibitors (NRIs). In this paper we explore the structure-activity relationships (SAR) of these compounds
to measure their ability both to inhibit bacterial translation and also to inhibit the growth of bacterial cells
in culture. The most active of these compounds inhibit Streptococcus pneumoniae translation at concentrations
of <5 µM and have minimum inhibitory concentrations (MICs) of <8 µg/mL against clinically relevant
strains of bacteria.
Introduction
Bacteria resistant to known therapies are a growing threat
across the globe. An increasing fraction of bacterial isolates
show reduced susceptibility to our most trusted antibiotics.1,3,4
Figure 1. General structure of the novel ribosome inhibitors (NRIs).
Although it was once believed that we had conquered bacteria
and that they no longer posed a threat to human health,2 the
shortsightedness of that belief is now clear. An unavoidable
consequence of the length of the bacterial life cycle compared
with the length of our own is that bacteria can adapt to their
environment vastly faster than humans. The antibiotics that
seemed infallible 30 years ago are much less effective today
and will become even less effective in the future. Our best
weapon against this threat is continually to develop new
antibiotics against which bacteria have not yet developed
resistance.
topoisomerases II and IV.7 These two mechanisms are not
mutually exclusive. A compound could be a potent inhibitor of
either or both pathways. What we have observed in our work
is a series of compounds that act predominantly via translation
inhibition. A thorough study was performed to prove this point
for two lead compounds in this series.6 The topic of this paper
is a series of NRIs with substitution linking the 6- and the
7-positions.
Results and Discussion
Nowhere is the rise in resistant strains of bacteria more
evident than in the treatment of respiratory tract infections.
Respiratory infections are responsible for millions of deaths each
year. Streptococcus pneumoniae is the most commonly identified
pathogen associated with community-acquired pneumonia, and
resistance in S. pneumoniae to traditional therapies continues
to increase.3,4 Overall rates of resistance in S. pneumoniae are
as high as 36% for penicillin and 31% for the macrolide
antibiotics.1 The rates of resistance toward fluoroquinolones are
still quite low; however, they too are rising.5 A new class of
antimicrobial agent that is not cross-resistant to drug-resistant
strains of S. pneumoniae would be a powerful tool to treat
community-acquired respiratory infections.
Synthesis of Tetracyclic NRIs. A general synthesis is
outlined in Scheme 1. The protected 7-chloronaphthyridine, 10
or 11, was reacted with an unprotected prolinol with optional
substitution. The substitution on the prolinol greatly affected
the difficulty of this reaction. Unsubstituted prolinol reacted
readily with the core (10) in acetonitrile in the presence of
diisopropylethylamine at room temperature over the course of
2 days to afford the desired compound (1b) in 88% yield. In
contrast, compound 22 (R3 ) allyl, R4 ) R5 ) H, n ) 1) reacted
with the core (11) only very slowly in dimethylacetamide
(DMA) with diisopropylethylamine at 110 °C, affording the
desired products, compounds 19a and 20a, in only 20% yield
after 6 days.
The goal of our research for the past several years has been
the discovery of a new class of antibiotic to treat community-
acquired respiratory infections. The traits of this new drug should
ideally include efficacy against a variety of relevant bacterial
strains and a mechanism of action different from those employed
by known therapies. Toward this end, we have discovered the
novel ribosome inhibitors (NRIs; Figure 1).6
The NRIs are a class of compounds with a core structure
similar to quinolone antibiotics, but they function predominantly
by a different cellular mechanism than quinolones. The NRIs
inhibit translation in bacterial cells by interacting with the
ribosome. In contrast, the quinolone antibiotics inhibit bacterial
The next step in the sequence is closure of the fourth ring.
While this reaction generally does not work with the C-3 ester
in place, initial hydrolysis of the ester followed by cyclization
afforded the desired products cleanly.10 The esters could be
hydrolyzed with lithium hydroxide in a mixture of ethanol and
water. The ring closure was effected by the addition of sodium
hydride to a solution of the acid in N,N-dimethylformamide
(DMF), followed by heating to afford the cyclized products (1c,
4c-6c, and 14c-22c).
To complete the synthesis, the N-1 protecting group was
removed. For the cleavage of the 2,4-dimethoxybenzyl and tert-
butyl groups, the protected intermediates were dissolved in
trifluoroacetic acid and warmed as necessary. This reaction was
greatly accelerated by the addition of a catalytic amount of
concentrated sulfuric acid.
* Corresponding author: phone 847-935-2527; fax 847-938-2756; e-mail
Mira.Hinman@abbott.com.
10.1021/jm060010w CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/11/2006

NoVel Antibacterial Class: Tetracyclic DeriVatiVes
Scheme 1. Synthesis of Tetracyclic NRIsa
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 16 4843
a (a) R3N, CH3CN; (b) LiOH, EtOH; (c) NaH, DMF, ∆; (d) TFA.
Scheme 2. Synthesis of Tricyclic NRIsa
a (a) R3N, CH3CN; (b) LiOH, EtOH; (c) NaH, DMF, ∆; (d) TFA.
Synthesis of Tricyclic NRIs. Synthesis of the tricyclic
analogues was similar to that of the tetracycles. In general, the
cyclization chemistry was more difficult but could ultimately
be accomplished as shown in Scheme 2. When R3 was hydrogen,
cyclization was not successful, even with prolonged heating.
To obviate this difficulty, we used a 2,4-dimethoxybenzyl
protecting group at R3. The cyclization proceeded and the
protecting group was removed in the final step.
Synthesis of Amino Tetracyclic NRIs. Synthesis of the
nitrogen analogues of the tetracycles is shown in Scheme 3.
The primary difference in the synthesis came in the cyclization
reaction. While in the synthesis of compound 1 and its analogues
it was necessary to deprotonate the alcohol to effect cyclization,
deprotonation of amine 23 resulted in a slower and less clean
cyclization reaction. As with the oxygen analogue, these
reactions were performed on the carboxylate, not on the acid.

4844 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 16
Scheme 3. Synthesis of Amino Tetracyclic NRIsa
Hinman et al.
a (a) R3N, CH3CN; (b) LiOH, EtOH; (c) NaH, DMF, ∆; (d) TFA, cat. H2SO4; Ac2O, Et3N; (e) NaH, MeI; TFA, cat. H2SO4.
Table 1. SAR of N-1 Alkyl and N-1 H in Quinolones and NRIs
For best results, the monodeprotonated amino acid was slurried
in DMF and warmed to 100 °C overnight. After cyclization,
substituents could be installed on the nitrogen by deprotonation
of the nitrogen followed by its reaction with an electrophile.
This procedure worked for most substituents; however, acyl
groups proved to be unstable to the subsequent deprotection
conditions and these groups were best installed after deprotec-
tion.
Biochemical and Antibacterial Activity of Tetracyclic and
Tricyclic NRIs. Three primary assays were used to evaluate
the compounds in this series. The compounds were tested in a
cell-free, uncoupled S. pneumoniae translation assay to deter-
mine their biochemical potency as inhibitors of bacterial
translation. This assay is sensitive only to compounds that inhibit
bacterial translation and not to those that inhibit transcription.
The assay used mRNA encoding the luciferase gene to monitor
translation. Test compounds were dried in 96-well plates and
treated with a cell-free S30 extract, mRNA encoding luciferase
protein, and a complete amino acid mix. The reactions were
incubated to allow for translation and then stopped by the
addition of kanamycin. Finally, luciferin reagent was added and
the wells were read by flash luminescence. A complete
description of the assay procedure can be found in an earlier
paper in this series.6 In addition to cell-free biochemical potency,
we were interested in the antimicrobial activities of the
compounds. To assess this activity, we used minimum inhibitory
concentrations (MICs) to evaluate the compounds’ ability to
inhibit bacterial growth in vitro. MICs were determined by the
broth microdilution method as described by the National
Committee for Clinical Laboratory Standards.11 In this paper,
we present data for three clinically relevant bacterial strains
associated with community-acquired pneumonia. Two strains
of S. pneumoniae are included. S. pneumo 6303 is quinolone-
susceptible and S. pneumo 7257 is resistant to inhibition
by quinolone antibiotics. Haemophilus influenzae 1435 is a
quinolone-susceptible strain. Data for H. influenzae are presented
to demonstrate that the NRIs not only inhibit Gram-positive
organisms but also can inhibit the growth of a clinically relevant,
Gram-negative organism. The final assay we employed was a
Jijoye B-cell cytotoxicity assay. The procedure for the toxicity
assay is also described in detail elsewhere.6
The compounds presented in this paper follow the structure-
activity relationship (SAR) pattern of the NRIs and not the
pattern common to quinolones. A hallmark of the quinolones
is the importance to activity of an alkyl substituent at the
1-position. A comparison of compounds 27 and 28 illustrates
this point. Compound 28, ciprofloxacin, shows a typical pattern
of minimum inhibitory concentrations (MICs). The quinolone-
susceptible strain of S. pneumoniae (S. pneumo 6303) is inhibited
at a concentration of 2 µg/mL. In contrast, the quinolone-
resistant strain of S. pneumomoniae (S. pneumo 7257) requires
a concentration of 16 µg/mL to achieve inhibition. S. pneumo

NoVel Antibacterial Class: Tetracyclic DeriVatiVes
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 16 4845
Table 3. SAR of Substitution at the N-1 Position of Tetracyclic NRI’s
Figure 2. Compound 1.
Table 2. SAR of Tetracyclic NRIs
1 and 29 affords a parallel comparison. Compound 29 has an
alkyl group favored for the quinolones at the 1-position but is
not very active as a quinolone. According to the precedent from
quinolone SAR, removal of the cyclopropyl group should result
in an even less active antimicrobial compound.8 In fact, removal
of the cyclopropyl group affords compound 1, which shows
significantly improved MICs in both susceptible (S. pneumo
6303) and resistant (S. pneumo 7257) strains of S. pneumoniae.
This increase in activity against S. pneumoniae is accompanied
by improved inhibition of S. pneumoniae translation, measured
in a cell-free, biochemical assay. Compound 1 has an IC50 of
5.7 µM against S. pneumoniae translation and also shows
antibacterial activity with MICs of 1 µg/mL for the quinolone-
resistant (7257) and 4 µg/mL for the quinolone-susceptible
(6303) strains of S. pneumoniae. Furthermore, as one might
expect from a mechanism unrelated to topoisomerase II in-
hibition, the quinolone-resistant strain of S. pneumoniae (7257)
is no longer resistant. In fact, the quinolone-resistant strain
(7257) is actually more susceptible to this series of compounds.
One possible explanation for the greater susceptibility of the
quinolone-resistant strain of S. pneumoniae (7257) is that this
strain could be intrinsically less hardy and thus its growth is
more easily inhibited by mechanisms not relying on topo-
isomerase II inhibition. Although it is possible, and even likely,
that the NRIs retain some inhibition of topoisomerase II, this
activity is weak compared with quinolone antibiotics and the
data point to bacterial translation inhibition as the primary
mechanism of antimicrobial activity in Steptococcus pneumoniae
by the NRIs.
a Value for a transcription/translation coupled assay.
7257 is a strain with mutant topoisomerase II and IV that
demonstrates reduced susceptibility to quinolones. Removal of
the cyclopropyl group at the 1-position of ciprofloxacin affords
compound 27. From the data shown in Table 1, we see a
profound effect upon removing the alkyl substitution at the
1-position of ciprofloxicin. The overall ability of the compound
to inhibit bacterial growth is significantly compromised. MICs
for compound 27 are greater than 64 µg/mL for both resistant
and susceptible strains of S. pneumoniae. This observation is
well-precedented in the quinolone literature.8 When the pre-
dominant cause of bacterial growth inhibition is topoisomerase
II inhibition, as we see with the quinolones, removal of the alkyl
group at the 1-position results in less inhibition of bacterial
growth and higher MICs. In contrast, when the driving force
for bacterial growth inhibition is inhibition of bacterial transla-
tion, removal of the alkyl group at the 1-position gives greater
bacterial growth inhibition and lower MICs. This pattern is
common to the NRIs and we see it when we compare compound
1 with compound 29 (Table 1).6,9 Examination of compounds
The general structure of this class of NRI has four rings that
can be labeled A-D as shown in Figure 2. This group of

4846 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 16
Table 4. Substitution SAR of Tetracyclic NRIs
Hinman et al.
compounds is distinct from the greater class of NRIs by the
presence of the C-ring.9 To highlight the effect of the C-ring, a
direct comparison of compound 1 with an analogue lacking the
C-ring (compound 3) is shown in Table 2. When compounds 1
and 3 are compared, the C-ring offers a modest but still
significant improvement. It appears to be critical to have the
pyrrolidine ring in, or nearly in, the plane of the core. In fact,
the slight improvement in activity seen in compound 1 over
compound 3 may be the result of the C-ring locking the
pyrrolidine and the core into an almost coplanar conformation.
Further supporting this theory are the data for compound 2.
Compound 2 has a hydroxymethyl group similar to compound
1, but its pyrrolidine ring is most likely locked out of plane
with the A,B-rings for steric reasons, and it has no activity at
the highest concentration tested. Changes in the D-ring also have
a noticeable effect on activity. Compounds lacking the D-ring
are markedly less active analogues. Further, the size of the
D-ring has an effect on activity. While four- and five-membered
rings are both tolerated, the six-membered ring is 10-fold less
active. The stereochemistry at the C,D-ring juncture has little
effect on activity. From these data, we can conclude that the
presence of both the C- and D-rings is advantageous and that,
for optimum activity, the D-ring should be either a four- or a
five-membered ring.
One of the earliest trends that we observed with the NRIs is
that substitution on the nitrogen at the 1-position significantly
reduces both biochemical potency and antibacterial activity9
(Table 3). This trend holds true for the tetracycles. We have
direct comparisons with tert-butyl and 2,4-dimethoxybenzyl
groups at N-1 compared to the N-1 H analogues. Substitution
reduces biochemical activity in the translation assay by more
than 10-fold, and this reduction usually translates to weaker
antibacterial activity.
We were interested to see the effect of substitution on the
B-, C-, and D-rings (Table 4). In general, substitution on the
C-ring, R to the oxygen, with groups larger than a methyl group
resulted in a loss of activity. Furthermore, the stereochemical
configuration of this site affected activity. Compound 17 shows
good biochemical activity with little loss in antibacterial activity
compared with compound 1. In contrast, diastereoisomer 18

NoVel Antibacterial Class: Tetracyclic DeriVatiVes
Table 5. SAR of Amino Tetracyclic NRIs
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 16 4847
loses much biochemical and antibacterial activity. We observe
a similar correlation between stereochemical configuration and
activity in another set of diastereoisomers, 19 and 20. Substitu-
tion at the C-D ring juncture, even with just a methyl group
(21), causes an almost complete loss of activity.
potency but loses all antibacterial activity. As discussed for
compound 14 earlier, physiochemical properties may explain
the lack of antibacterial activity observed for compound 12.
From our results, it is evident that the nitrogen-containing
tetracycles are likely to be a promising area for future research.
Our research will focus on expanding our understanding of this
chemistry as well as that of the oxygen-containing tetracycles.
Conclusion. We have reported a series of tri- and tetracyclic
antibacterial compounds with surprising activity. While structur-
ally similar to the quinolone antibiotics, they behave very
differently. These compounds are more active in strains of
bacteria resistant to quinolones and their SAR runs contrary to
trends common to all quinolones. Further, their antimicrobial
activity tracks with their ability to inhibit bacterial translation.
These data show these compounds to be novel ribosome
inhibitors (NRIs).6 The series of NRIs presented in this paper
contain four rings. These compounds give improved activity
relative to the parent compounds that lack the fourth ring.9 The
improvement is seen both in a cell-free, biochemical assay to
assess translation inhibition and in experiments measuring
antibacterial activity in intact cells (MIC). This series of
compounds shows translation inhibitions ranging from <1 µM
to >100 µM. The MICs of this series of compounds range from
1 µg/mL to >64 µg/mL. The most active compound in this
series is slightly less active than ciprofloxacin in the quinolone-
susceptible strain of S. pneumoniae (S. pneumo 6303) and
significantly more active than ciprofloxacin against the
quinolone-resistant strain of S. pneumoniae (S. pneumo 7257).
Interestingly, the change that resulted in the best biochemical
activity did not translate into improved MIC’s. Compound 14
has excellent biochemical activity, but has little antibacterial
activity in intact cells. This observation may be the result of
the physiochemical properties of this particular compound. One
possibility is that compound 14 may not cross the cell membrane
as readily as other compounds, and this feature would have
caused its intracellular concentration to be lower than other
compounds, resulting in lower activity. Alternatively, compound
14 may be less soluble in aqueous media than other compounds
and thus the bacterial cells may have been exposed to a lower
effective concentration of compound 14 than of other com-
pounds. To determine the exact reason for the lack of agreement
between biochemical activity and MIC’s in compound 14 and
others like it, further experiments will be required.
We also made a small set of compounds that contained two
nitrogen atoms in the C-ring. The results from this set are
summarized in Table 5. The simple substitution of a nitrogen
atom for an oxygen atom (compare compound 1 with compound
23) resulted in a modest loss of activity. The addition of a methyl
group on the C-ring nitrogen (24) gave a compound with
improved biochemical activity but without the corresponding
improvement in antibacterial activity. Acylation of the amine
gave a compound (25) with similar biochemical activity and
weaker antibacterial activity. The addition of larger groups on
the nitrogen (26) appeared detrimental, although the set of
nitrogen-substituted analogues is small. Finally, acylation of the
nitrogen by oxidizing the R carbon in the C-ring affords a
compound (12) that maintains relatively good biochemical
Experimental Section
Synthetic Materials and Methods. Unless otherwise specified,
reactions were performed under an inert atmosphere of nitrogen
and monitored by thin-layer chromatography (TLC) or by liquid
chromatography-mass spectrometry (LC-MS). All reagents were

4848 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 16
Hinman et al.
purchased from commercial suppliers and used as provided. Flash
column chromatography was performed either on a Biotage Flash
40 system using 50 or 90 g prepacked silica columns or on an
Alltech Extract-Clean vacuum manifold with 5 and 10 g prepacked
silica cartridges with HPLC-grade solvents. Analytical LC-MS was
performed on a Agilent Series 1100 HPLC system equipped with
an autosampler and coupled to a Finnegan Thermoquest atmospheric
pressure chemical ionization (APCI) mass spectrometer. Peak
detection was by ultraviolet absorption at 220 and 254 nm and by
evaporative light scattering (ELS) detection. Proton nuclear mag-
netic resonance (1H NMR) spectra were recorded on a Bruker ARX
spectrometer (300 MHz) or on a Varian Inova Spectrometer (500
MHz), are given in parts per million (ppm), and are referenced to
residual solvent peaks (DMSO-d6, δ 2.50 ppm) or to an internal
standard of tetramethylsilane (TMS, δ 0.00 ppm). 1H-1H couplings
are assumed to be first-order, and peak multiplicity is reported as
s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br
(broad). Electrospray ionization (ESI) and desorption chemical
ionization (DCI) mass spectrometry were performed on Finnigan
SSQ700 single-quadrupole mass spectrometers. Elemental analyses
were performed by Roberston Microlit Laboratories (Madison, NJ)
and by Qualitative Technologies Inc. (Whitehouse, NJ). All of the
compounds reported were analyzed by LC-MS, 1H NMR, and mass
spectrometry and are consistent with the proposed structures in each
case. Purity (>99% for all compounds reported) was assessed by
analytical LC-MS on a Agilent 1100-Finnigan Navigator HPLC-
MS system with ELS detection (Sedere Sedex 75), on a Phenom-
enex Luna C8(2) column (2.0 × 30 mm, 5 µM, 100 Å) by either
method A (linear gradient 10-100% MeCN with 0.1% TFA over
3 min + 1 min hold at 100% MeCN, at 1.5 mL/min) or method B
(linear gradient 10-100% MeCN with 10 mM NH4OAc over 3
min + 1 min hold at 100% MeCN, at 1.5 mL/min).
filtration. The crude product could be purified by column chroma-
tography (5-10% methanol in CH2Cl2) and also by trituration with
a variety of standard, organic solvents.
General Procedure for the Deprotection of the tert-Butyl
Protecting Group. The tert-butyl-protected substrate was dissolved
in TFA (0.05 M), treated with several drops of concentrated sulfuric
acid, stirred at room temperature for 2-4 h, and concentrated in
vacuo. The crude product could be purified by column chroma-
tography (5-10% methanol in CH2Cl2) and also by trituration with
a variety of standard, organic solvents.
1-(2,4-Dimethoxybenzyl)-6-fluoro-7-[(S)-2-hydroxymethyl-
pyrrolidin-1-yl]-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic
Acid Ethyl Ester (1a). Compound 1a was prepared according to
the general procedure from chloride 10 and (S)-2-hydroxy-
1
methylpyrrolidine (7 mmol scale) in 91% yield. H NMR (300
MHz, DMSO-d6) δ 1.26 (t, J ) 7.12 Hz, 3H), 1.90 (m, 2H), 2.04
(m, 2H), 3.29 (m, 1H), 3.39 (m, 1H), 3.52 (m, 1H), 3.63 (m, 1H),
3.74 (m, 3H), 3.80 (m, 3H), 4.19 (q, J ) 7.12 Hz, 2H), 4.37 (m,
1H), 4.81 (t, J ) 5.76 Hz, 1H), 5.38 (m, 2H), 6.48 (dd, J ) 8.14,
2.37 Hz, 1H), 6.60 (m, 1H), 7.12 (d, J ) 8.14 Hz, 1H), 7.83 (d, J
) 13.6 Hz, 1H), 8.62 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ
14.3, 22.5, 27.0, 48.8, 49.2, 55.2, 55.4, 59.6, 60.5, 61.2, 98.5, 104.7,
109.96, 113.3, 116.1, 118.8 (d, J ) 21 Hz), 130.4, 144.9, 145.1 (d,
J ) 256 Hz), 147.7 (d, J ) 12 Hz), 148.2, 158.3, 160.5, 164.3,
171.9. Anal. (C25H28FN3O3) C, H, N, F.
1-(2,4-Dimethoxybenzyl)-6-fluoro-7-[(S)-2-hydroxymethyl-
pyrrolidin-1-yl]-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic
Acid (1b). Carboxylic acid 1b was prepared from ethyl ester 1a
according to the general procedure (4 mmol scale) in 100% yield.
1H NMR (300 MHz, DMSO-d6) δ 1.92 (m, 2H), 2.08 (m, 2H),
3.42 (m, 1H), 3.54 (m, 1H), 3.67 (m, 1H), 3.74 (m, 3H), 3.76 (m,
3H), 3.85 (m, 1H), 4.41 (m, 1H), 4.86 (m, 1H), 5.51 (m, 2H), 6.51
(dd, J ) 8.48, 2.37 Hz, 1H), 6.60 (d, J ) 2.37 Hz, 1H), 7.16 (d, J
) 8.48 Hz, 1H), 7.96 (d, J ) 13.22 Hz, 1H), 8.81 (m, 1H), 15.44
(m, 1H); 13C NMR (75 MHz, DMSO-d6) δ 22.5, 27.0, 49.3, 49.4,
49.8, 55.3, 55.5, 60.9, 98.6, 104.9, 107.3, 110.8, 115.3, 117.6 (d, J
) 22 Hz), 130.8, 145.8, 145.8 (d, J ) 259 Hz), 147.5, 148.6 (d, J
) 12 Hz), 158.4, 160.8, 166, 176.1. Anal. (C23H24FN3O3) C, H, N,
F.
General Procedure for Displacement of the Chloride of
Naphthyridine 10 or 11 with Prolinols. Compound 10 was
partially dissolved in CH3CN (0.1 M). To this mixture was added
the prolinol (1.2 equiv), producing a mixture that turned bright
i
orange. Addition of Pr2EtN (3.3 equiv) provided a solution that
was stirred at room temperature for 3 days before being diluted
with water. If the product precipitated, it was collected by filtration.
If the product did not precipitate, the mixture was extracted with
CH2Cl2 and the organic phase was washed with 1 N HCl, saturated
aqueous NaHCO3, and H2O, and concentrated in vacuo to give a
yellow semisolid. The crude material was taken up in hot CH3CN
and water was added until the product precipitated. The product
was collected by filtration.
General Procedure for the Hydrolysis of Ethyl Esters. The
ethyl ester was dissolved in ethanol (∼0.05 M). To this solution
was added aqueous LiOH (0.1 M in water, 2 equiv). The mixture
was stirred for 1 day and then brought to pH 3 by the addition of
1 N HCl. Generally, a white precipitate formed and was collected
by filtration.
10-(2,4-Dimethoxybenzyl)-7-oxo-2,3,(S)-3a,4,7,10-hexa-
hydro-1H-5-oxa-10,11,11b-triazacyclopenta[a]anthracene-8-car-
boxylic Acid (1c). Compound 1c was prepared from 1b according
to the general displacement conditions (3 mmol scale) in 100%
1
yield. H NMR (300 MHz, DMSO-d6) δ 0.81 (m, 1H), 1.54 (m,
1H), 1.97 (m, 1H), 2.15 (m, 2H), 3.63 (m, 2H), 3.73 (m, 3H), 3.77
(m, 3H), 3.84 (m, 1H), 4.64 (dd, J ) 10.51, 3.73 Hz, 1H), 5.52
(m, 2H), 6.54 (m, 2H), 7.34 (d, J ) 8.48 Hz, 1H), 7.53 (m, 1H),
8.86 (m, 1H), 15.86 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ
22.2, 27.5, 46.0, 49.6, 54.9, 55.1, 55.2, 67.3, 98.5, 105.0, 106.9,
111.1, 113, 115.4, 131.2, 137.9, 143.3, 145.6, 148.0, 158.4, 160.6,
165.8, 175.7. Anal. (C23H23N3O3) C, H, N, F.
General Procedure for the Cyclization of the C-ring by
Displacement of Fluorine by the Hydroxyl Group of a Substi-
tuted Prolinol. The alcohol was dissolved in DMF (0.04 M) and
cooled to 0 °C. Sodium hydride (60% in oil, 2.6 equiv) was added.
After 30 min at room temperature, the mixture was warmed to 90
°C. The mixture was kept between 90 and 115 °C until the reaction
was complete (generally 1 h-3 days). The mixture was cooled to
room temperature, diluted with one solvent volume of H2O, and
brought to pH 3 with aqueous 1 N HCl. A precipitate formed and
was collected by filtration. If a precipitate did not form, the product
could be isolated by standard organic extraction. The crude product
could be further purified by column chromatography or trituration
with a variety of standard, organic solvents.
General Procedure for the Deprotection of the Dimethoxy-
benzyl Protecting Group. The 2,4-dimethoxybenzyl-protected
substrate was dissolved or slurried in trifluoroacetic acid (0.05 M)
and the mixture was warmed to 70 °C. The mixture became a clear,
purple solution. After 3 h at 70 °C, the mixture was cooled and
concentrated. The purple residue was taken up in CH3CN and
treated with H2O. A gray precipitate formed and was collected by
7-Oxo-2,3,(S)-3a,4,7,10-hexahydro-1H-5-oxa-10,11,11b-triaza-
cyclopenta[a]anthacene-8-carboxylic Acid (1). Compound 1 was
prepared from 2,4-dimethoxybenzyl-protected 1c according to the
1
general procedure (0.6 mmol scale) in 52% yield. H NMR (500
MHz, DMSO-d6) δ 1.56 (m, 1H), 2.00 (m, 1H), 2.10 (m, 1H), 2.19
(m, 1H), 3.58 (m, 1H), 3.68 (m, 2H), 3.84 (m, 1H), 4.63 (dd, J )
10.99, 3.66 Hz, 1H), 7.50 (m, 1H), 8.34 (m, 1H), 12.67 (br s, 1H),
15.67 (m, 1H); 13C NMR (125 MHz, DMSO-d6) δ 22.22, 27.49,
45.88, 55.12, 67.35, 107.21, 110.42, 112.47, 138.12, 141.15, 145.72,
148.82, 165.88, 176.26. Anal. (C14H13N3O4) C, H, calcd for N 14.63,
found 13.49. HPLC [retention time (RT) given in minutes] (method
A) RT ) 1.24, (method B) RT ) 1.19.
6-Fluoro-7-(2-hydroxymethylpyrrolidin-1-yl)-4-oxo-1,4-dihy-
dro-[1,8]naphthyridine-3-carboxylic Acid (2). Compound 2 was
prepared from compound 1b according to the general procedure
1
(0.23 mmol scale) in 10% yield. H NMR (300 MHz, DMSO-d6)
δ 1.99 (m, 4H), 3.55 (m, 2H), 3.76 (m, 2H), 4.42 (m, 1H), 4.85 (t,
J ) 5.1 Hz, 1H), 7.95 (d, J ) 13.2 Hz, 1H), 8.47 (s, 1H), 13.18 (s,
1H), 15.52 (s, 1H). Anal. (C14H14FN3O4‚0.5H2O) C, H, N. HPLC
(method A) RT ) 1.45, (method B) RT ) 0.59.

NoVel Antibacterial Class: Tetracyclic DeriVatiVes
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 16 4849
1
1-(2,4-Dimethoxybenzyl)-6-fluoro-4-oxo-7-pyrrolidin-1-yl-1,4-
dihydro-[1,8]naphthyridine-3-carboxylic Acid Ethyl Ester (3a).
To a suspension of chloride 10 (30 g, 71 mmol) in 750 mL of
acetonitrile was added potassium carbonate (25 g, 181 mmol)
followed by pyrrolidine (15.2 g, 214 mmol). The reaction mixture
was stirred at room temperature for 2 days and then the solvent
was concentrated to ca. 1/4 volume. The concentrated mixture was
treated with CH2Cl2 and water, and the phases were separated. The
organic phase was washed twice with 10% aqueous citric acid,
water, and brine. The organic phase was dried over MgSO4, filtered,
and concentrated in vacuo. The produce was crystallized from a
mixture of CH2Cl2/Et2O/hexanes to afford a yellow solid (85%
yield). 1H NMR (300 MHz, chloroform-d) δ 1.39 (t, J ) 7.12 Hz,
3H), 1.94-2.05 (m, 4H), 3.72-3.81 (m, 5H), 3.79 (s, 3H), 3.84
(s, 3H), 4.36 (q, J ) 7.12 Hz, 2H), 5.37 (s, 2H), 6.41 (dd, J )
8.14, 2.37 Hz, 1H), 6.47 (d, J ) 2.37 Hz, 1H), 7.21 (d, J ) 8.48
Hz, 1H), 8.05 (d, J ) 12.89 Hz, 1H), 8.63 (s, 1H).
1-(2,4-Dimethoxybenzyl)-6-fluoro-4-oxo-7-pyrrolidin-1-yl-1,4-
dihydro-[1,8]naphthyridine-3-carboxylic Acid (3b). To a suspen-
sion of compound 3a (17.9 g, 39 mmol) in 750 mL of tetrahydro-
furan (THF) was added a solution of 1 N aqueous LiOH (196 mL,
196 mmol). After 5 min, the reaction mixture was treated with 80
mL of methanol. After 1.5 h, the precipitate was filtered and washed
with THF and THF/water to afford the lithium salt of the product
(16.6 g, 98%). The lithium salt was suspended in 30 mL of a 1:2
mixture of water and CH2Cl2 and treated with 1 N aqueous HCl.
After 15 min, the phases were separated, and the organic phase
was washed with water, dried over MgSO4, and concentrated in
vacuo to afford a white solid (702 mg, 92%). 1H NMR (300 MHz,
chloroform-d) δ 2.0-2.11 (m, 4H), 3.79 (s, 3H), 3.80-3.89 (m,
4H), 3.84 (s, 3H), 5.45 (s, 2H), 6.40-6.48 (m, 2H), 7.23 (d, J )
8.14 Hz, 1H), 7.99 (d, J ) 12.89 Hz, 1H), 8.84 (s, 1H).
yield. H NMR (300 MHz, DMSO-d6) δ 0.81 (m, 1H), 1.54 (m,
1H), 1.97 (m, 1H), 2.15 (m, 2H), 3.63 (m, 2H), 3.73 (m, 3H), 3.77
(m, 3H), 3.84 (m, 1H), 4.64 (dd, J ) 10.51, 3.73 Hz, 1H), 5.52
(m, 2H), 6.54 (m, 2H), 7.34 (d, J ) 8.48 Hz, 1H), 7.53 (m, 1H),
8.86 (m, 1H), 15.86 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ
22.2, 27.5, 46.0, 49.6, 54.9, 55.1, 55.2, 67.3, 98.5, 105.0, 106.9,
111.1, 113, 115.4, 131.2, 137.9, 143.3, 145.6, 148.0, 158.4, 160.6,
165.8, 175.7. Anal. (C23H23N3O3) C, H, N, F.
7-Oxo-2,3,(R)-3a,4,7,10-hexahydro-1H-5-oxa-10,11,11b-triaza-
cyclopenta[a]anthacene-8-carboxylic Acid (4). Compound 4 was
prepared from 2,4-dimethoxybenzyl-protected 4c according to the
1
general procedure (0.6 mmol scale) in 52% yield. H NMR (500
MHz, DMSO-d6) δ 1.56 (m, 1H), 2.00 (m, 1H), 2.10 (m, 1H), 2.19
(m, 1H), 3.58 (m, 1H), 3.68 (m, 2H), 3.84 (m, 1H), 4.63 (dd, J )
10.99, 3.66 Hz, 1H), 7.50 (m, 1H), 8.34 (m, 1H), 12.67 (br s, 1H),
15.67 (m, 1H); 13C NMR (125 MHz, DMSO-d6) δ 22.22, 27.5,
45.9, 55.1, 67.4, 107.2, 110.4, 112.5, 138.1, 141.2, 145.7, 148.8,
165.9, 176.3. Anal. (C14H13N3O4) C, H, calcd for N 14.63, found
13.22. HPLC (method A) RT ) 1.27, (method B) RT ) 0.96.
1-(2,4-Dimethoxybenzyl)-6-fluoro-7-[2-(S)-hydroxymethylazet-
idin-1-yl]-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic Acid
Ethyl Ester (5a). N-tert-Butoxycarbonyl-2-hydroxymethylazetidine
(1.0 g, 5.4 mmol) was dissolved in 3 mL of CH2Cl2 and added
dropwise to 25 mL of 4 N HCl in dioxane that had been cooled to
0 °C. The cooling bath was removed, and after 1 h the mixture
was concentrated. Chloride 10 (1.6 g, 3.8 mmol) was mostly
dissolved in 25 mL of acetonitrile. In a separate flask, the 2-(S)-
hydroxymethylazetidine hydrochloride was dissolved in 20 mL of
acetonitrile, treated with diisopropylethylamine (4 mL, 23 mmol),
and added to the solution of 10 in CH3CN. After 3 days, the mixture
was diluted with 350 mL of H2O and filtered to afford a white
solid, which was purified by column chromatography (3% MeOH
in CH2Cl2) to give the desired product (1.0 g, 58%). 1H NMR (300
MHz, DMSO-d6) δ 1.27 (t, J ) 7.12 Hz, 3H), 2.35 (m, 2H), 3.64
(m, 1H), 3.74 (s, 3H), 3.79 (s, 3H), 3.85 (m, 1H), 4.21 (q, J )
7.12 Hz, 2H), 4.21 (m, 2H), 4.59 (m, 1H), 4.92 (t, J ) 5.76 Hz,
1H), 5.34 (m, 2H), 6.49 (m, 1H), 6.58 (m, 1H), 7.15 (d, J ) 8.14
Hz, 1H), 7.80 (d, J ) 11.87 Hz, 1H), 8.64 (s, 1H); 13C NMR (75
MHz, DMSO-d6) δ 14.3, 19.8, 49.2, 50.0, 55.2, 55.5, 59.6, 61.6,
65.2, 98.5, 104.7, 109.9, 113.7, 116.0, 117.9 (d, J ) 16 Hz), 130.9,
145.3, 145.4 (d, J ) 255 Hz), 148.3, 149.6 (d, J ) 14 Hz), 158.4,
160.5, 164.3, 172.0. Anal. (C24H26FN3O6) C, H, N, F.
6-Fluoro-4-oxo-7-pyrrolidin-1-yl-1,4-dihydro-[1,8]naphthyri-
dine-3-carboxylic Acid (3). Compound 3 was prepared from 2,4-
dimethoxybenzyl-protected 3b according to the general procedure
(6.0 mmol scale) in 96% yield. 1H NMR (300 MHz, DMSO-d6) δ
1.93-1.98 (m, 4H), 3.60-3.83 (m, 4H), 7.92 (d, J ) 13.2 Hz,
1H), 8.43 (s, 1H), 15.52 (br s, 1H). Anal. (C13H12FN3O3) C, H, N,
F.
1-(2,4-Dimethoxybenzyl)-6-fluoro-7-[(R)-2-hydroxymethylpyr-
rolidin-1-yl]-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxyl-
ic Acid Ethyl Ester (4a). Compound 4a was prepared according
to the general procedure from compound 10 (7 mmol scale) in 88%
yield. 1H NMR (300 MHz, DMSO-d6) δ 1.26 (t, J ) 7.12 Hz, 3H),
1.90 (m, 2H), 2.04 (m, 2H), 3.29 (m, 1H), 3.39 (m, 1H), 3.52 (m,
1H), 3.63 (m, 1H), 3.74 (m, 3H), 3.80 (m, 3H), 4.19 (q, J ) 7.12
Hz, 2H), 4.37 (m, 1H), 4.81 (t, J ) 5.76 Hz, 1H), 5.38 (m, 2H),
6.48 (dd, J ) 8.14, 2.37 Hz, 1H), 6.60 (m, 1H), 7.12 (d, J ) 8.14
Hz, 1H), 7.83 (d, J ) 13.56 Hz, 1H), 8.62 (m, 1H); 13C NMR (75
MHz, DMSO-d6) δ 14.3, 22.5, 27.0, 48.8, 49.2, 55.2, 55.4, 59.6,
60.5, 61.2, 98.5, 104.7, 109.96, 113.3, 116.1, 118.8 (d, J ) 21 Hz),
130.4, 144.9, 145.1 (d, J ) 256 Hz), 147.7 (d, J ) 12 Hz), 148.2,
158.3, 160.5, 164.3, 171.9. Anal. (C25H28FN3O3) C, H, N, F.
1-(2,4-Dimethoxybenzyl)-6-fluoro-7-[(R)-2-hydroxymethylpyr-
rolidin-1-yl]-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxyl-
ic Acid (4b). Carboxylic acid 4b was prepared from ethyl ester 4a
according to the general procedure (4 mmol scale) in 94% yield.
1H NMR (300 MHz, DMSO-d6) δ 1.92 (m, 2H), 2.08 (m, 2H),
3.42 (m, 1H), 3.54 (m, 1H), 3.67 (m, 1H), 3.74 (m, 3H), 3.76 (m,
3H), 3.85 (m, 1H), 4.41 (m, 1H), 4.86 (m, 1H), 5.51 (m, 2H), 6.51
(dd, J ) 8.48, 2.37 Hz, 1H), 6.60 (d, J ) 2.37 Hz, 1H), 7.16 (d, J
) 8.48 Hz, 1H), 7.96 (d, J ) 13.22 Hz, 1H), 8.81 (m, 1H), 15.44
(m, 1H); 13C NMR (75 MHz, DMSO-d6) δ 22.5, 27.0, 49.3, 49.4,
49.8, 55.3, 55.5, 60.9, 98.6, 104.9, 107.3, 110.8, 115.3, 117.6 (d, J
) 22 Hz), 130.8, 145.8, 145.8 (d, J ) 259 Hz), 147.5, 148.6 (d, J
) 12 Hz), 158.4, 160.8, 166, 176.1. Anal. (C23H24FN3O3) C, H, N,
F.
1-(2,4-Dimethoxybenzyl)-6-fluoro-7-(2-(S)-hydroxymethylazet-
idin-1-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic Acid
(5b). Carboxylic acid 5b was prepared from ethyl ester 5a according
1
to the general procedure (2 mmol scale) in 97% yield. H NMR
(300 MHz, DMSO-d6) δ 2.37 (m, 2H), 3.64 (m, 1H), 3.75 (s, 3H),
3.76 (s, 3H), 3.89 (m, 1H), 4.27 (m, 2H), 4.65 (m, 1H), 4.98 (m,
1H), 5.48 (m, 2H), 6.54 (m, 2H), 7.19 (m, 1H), 7.94 (d, J ) 11.87
Hz, 1H), 8.85 (s, 1H), 15.45 (s, 1H). Anal. (C22H22FN3O6) C (calcd
for 59.59, found 59.03), H, N, F.
9-(2,4-Dimethoxybenzyl)-6-oxo-1,2,(S)-2a,3,6,9-hexahydro-4-
oxa-9,10,10b-triazacyclobuta[a]anthracene-7-carboxylic Acid
(5c). Compound 5c was prepared from compound 5b according to
the general displacement conditions (2 mmol scale) in 93% yield.
1H NMR (300 MHz, DMSO-d6) δ 2.51 (m, 2H), 3.62 (m, 1H),
3.72 (s, 3H), 3.75 (s, 3H), 4.28 (m, 1H), 4.52 (m, 2H), 4.78 (m,
1H), 5.44 (m, 2H), 6.51 (m, 2H), 7.33 (d, J ) 8.09 Hz, 1H), 7.58
(s, 1H), 8.84 (s, 1H), 15.59 (s, 1H); 13C NMR (75 MHz, DMSO-
d6) δ 22.0, 50.7, 53.6, 55.2, 55.5, 60.1, 66.4, 98.4, 104.8, 106.7,
112.9, 115.2, 116.0, 132.4, 140.0, 145.2, 147.0, 151.5, 158.9, 160.8,
166.3, 176.5.
Sodium 6-Oxo-1,2,(S)-2a,3,6,9-hexahydro-4-oxa-9,10,10b-tri-
azacyclobuta[a]anthracene-7-carboxylate (5). Compound 5 was
prepared from 2,4-dimethoxybenzyl-protected 5c according to the
general procedure (0.6 mmol scale) in 74% yield. The parent
compound was converted to the sodium salt: acid 5 (91 mg, 0.33
mmol) was slurried in 60 mL of H2O. To this mixture was added
sodium hydroxide (300 µL, 1.037 M, 0.31 mmol). The mixture
had a pH of 7.0-7.5 and was filtered through a 0.45 µM filter.
The clear solution was lyophilized to afford the sodium salt (80
10-(2,4-Dimethoxybenzyl)-7-oxo-2,3,(R)-3a,4,7,10-hexa-
hydro-1H-5-oxa-10,11,11b-triazacyclopenta[a]anthracene-8-car-
boxylic Acid (4c). Compound 4c was prepared from 4b according
to the general displacement conditions (3 mmol scale) in 100%

4850 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 16
Hinman et al.
1
mg, 74% yield). H NMR (300 MHz, DMSO-d6) δ 2.37 (m, 1H),
1-(2,4-Dimethoxybenzyl)-6-fluoro-7-[(2-hydroxyethyl)methyl-
amino]-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic Acid
(7b). Acid 7b was prepared from ester 7a (4.6 mmol scale)
2.60 (m, 1H), 3.66 (t, J ) 10.51 Hz, 1H), 4.21 (m, 1H), 4.38 (m,
2H), 4.65 (m, 1H), 7.57 (s, 1H), 8.61 (s, 1H); 13C NMR (75 MHz,
DMSO-d6) δ 21.4, 53.2, 59.8, 66.7, 106.3, 112.6, 115.6, 139.1,
151.9, 151.9, 155.4, 170.4, 173.2. HPLC (method A) RT ) 1.08,
(method B) RT ) 0.96.
1
according to the general procedure in 92% yield. H NMR (300
MHz, DMSO-d6) δ 3.29 (d, J ) 3.05 Hz, 3H), 3.61 (q, J ) 5.65
Hz, 2H), 3.74 (s, 3H), 3.74 (m, 2H), 3.76 (s, 3H), 4.81 (t, J ) 5.26
Hz, 1H), 5.53 (s, 2H), 6.49 (dd, J ) 8.14, 2.37 Hz, 1H), 6.60 (d,
J ) 2.37 Hz, 1H), 7.10 (d, J ) 8.48 Hz, 1H), 7.98 (d, J ) 13.90
Hz, 1H), 8.86 (s, 1H), 15.39 (s, 1H); 13C NMR (75 MHz, DMSO-
d6) δ 39.4 (d, J ) 6 Hz), 49.8, 54.3 (d, J ) 7 Hz), 55.2, 55.5, 58.8,
98.6, 104.8, 107.3, 111.2, 115.4, 118.3 (d, J ) 22 Hz), 130.3, 145.3,
146.2 (d, J ) 237 Hz), 147.7, 150.1 (d, J ) 10 Hz), 158.2, 160.7,
166.0, 176.1. IR (microscopy) 3481, 1698, 1629 cm-1. Anal.
(C21H22FN3O6) C, H, N, F.
1-(2,4-Dimethoxybenzyl)-6-fluoro-7-(2-hydroxymethylpiperi-
din-1-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic Acid
(6b). Chloride 10 (2.15 g, 5.1 mmol) was slurried in 50 mL of
acetonitrile. To this mixture was added 2-hydroxymethylpiperidine
(890 mg, 7.7 mmol) and diisopropylethylamine (2.5 mL, 14 mmol).
After 20 h at room temperature, the mixture was warmed to 75 °C
for 5 days and then cooled and diluted with 200 mL of H2O. The
mixture was extracted with 200 mL of CH2Cl2, and the organic
phase was washed with H2O, 1 N HCl, and H2O and concentrated
in vacuo. The crude material was taken up in 110 mL of EtOH
and lithium hydroxide (90 mL, 0.1 M, 9 mmol) was added. After
16 h, the pH was adjusted to 3 and the mixture was extracted with
CH2Cl2. The organic phase was concentrated in vacuo. The crude
material was recrystallized from EtOAc/hexanes to afford the
desired material as pale crystals (1.62 g, 74%). 1H NMR (300 MHz,
DMSO-d6) δ 1.63 (m, 6H), 3.17 (m, 2H), 3.62 (m, 1H), 3.75 (s,
3H), 3.76 (s, 3H), 4.30 (m, 1H), 4.64 (m, 1H), 4.78 (t, J ) 5.43
Hz, 1H), 5.53 (m, 2H), 6.49 (m, 1H), 6.59 (m, 1H), 7.16 (d, J )
8.48 Hz, 1H), 7.99 (d, J ) 13.90 Hz, 1H), 8.86 (s, 1H), 15.35 (s,
1H); 13C NMR (75 MHz, DMSO-d6) δ 18.7, 25.1, 41.8, 41.9, 49.9,
55.3, 55.5, 59.2, 98.5, 104.9, 107.3, 111.9, 115.3, 118.6, 118.8 (d,
J ) 23 Hz), 118.9, 130.7, 145.2, 147.8, 149.8 (d, J ) 182 Hz),
150.9, 158.3, 160.7, 166.0, 176.1. Anal. (C24H26FN3O6) C, H, N,
F.
11-(2,4-Dimethoxybenzyl)-8-oxo-1,2,3,4,4a,5,8,11-octahydro-
6-oxa-11,12,12b-triazabenzo[a]anthracene-9-carboxylic Acid (6c).
Compound 6c was prepared according to the general procedure from
alcohol 6b (2.1 mmol scale). The crude material was recrystallized
from 900 mL of EtOAc to give the desired product in 68% yield.
1H NMR (300 MHz, DMSO-d6) δ 1.52 (m, 6H), 2.84 (m, 1H),
3.59 (m, 1H), 3.73 (s, 3H), 3.78 (s, 3H), 3.97 (dd, J ) 11.19, 6.78
Hz, 1H), 4.33 (dd, J ) 11.53, 3.73 Hz, 1H), 4.83 (m, 1H), 5.54
(m, 2H), 6.52 (m, 2H), 7.15 (d, J ) 8.48 Hz, 1H), 7.50 (s, 1H),
8.86 (s, 1H), 15.73 (s, 1H).
Sodium 8-Oxo-1,2,3,4,4a,5,8,11-octahydro-6-oxa-11,12,12b-
triazabenzo[a]anthracene-9-carboxylate (6). Acid 6c (217 mg,
0.48 mmol) was dissolved in 10 mL of TFA. After 16 h at room
temperature, the solution was concentrated in vacuo. The purple
residue was slurried in acetone and the solvent was decanted. This
process was repeated with CH2Cl2. The crude product was isolated
as a gray solid. The gray solid (113 mg, 0.38 mmol) was slurried
in 100 mL of H2O. To this mixture was added sodium hydroxide
(290 µL, 1.002 M in H2O, 0.29 mmol) and the mixture was
sonicated for 2 h. The cloudy solution was filtered through a 0.45
µM filter and lyophilized to give the desired product as a fluffy,
white solid (110 mg, 91%). 1H NMR (300 MHz, DMSO-d6) δ 1.22
(m, 1H), 1.47 (m, 2H), 1.78 (m, 3H), 2.68 (m, 1H), 3.42 (m, 1H),
3.91 (dd, J ) 11.03, 7.72 Hz, 1H), 4.26 (dd, J ) 11.03, 3.31 Hz,
1H), 4.83 (m, 1H), 7.42 (s, 1H), 8.57 (s, 1H); 13C NMR (75 MHz,
DMSO-d6) δ 22.8, 24.3, 26.9, 43.1, 52.3, 68.2, 106.4, 111.5, 113.8,
138.3, 149.4, 151.5, 154.6, 170.5, 172.4. HPLC (method A) RT )
1.47, (method B) RT ) 1.42.
5-(2,4-Dimethoxybenzyl)-4-methyl-8-oxo-3,4,5,8-tetrahydro-
2H-1-oxa-4,5,10-triazaanthracene-7-carboxylic Acid (7c). Com-
pound 7c was prepared from compound 7b (2.3 mmol scale)
1
according to the general procedure in 30% yield. H NMR (300
MHz, DMSO-d6) δ 3.25 (s, 3H), 3.66 (t, J ) 4.78 Hz, 2H), 3.74
(s, 3H), 3.77 (s, 3H), 4.26 (t, J ) 4.78 Hz, 2H), 5.55 (s, 2H), 6.50
(dd, J ) 8.27, 2.39 Hz, 1H), 6.59 (d, J ) 2.57 Hz, 1H), 7.21 (d, J
) 8.46 Hz, 1H), 7.47 (s, 1H), 8.83 (s, 1H), 15.81 (s, 1H).
4-Methyl-8-oxo-3,4,5,8-tetrahydro-2H-1-oxa-4,5,10-triaza-
anthracene-7-carboxylic Acid (7). Compound 7 was prepared from
compound 7c according to the general procedure (0.7 mmol scale)
in 38% yield. 1H NMR (300 MHz, DMSO-d6) δ 3.23 (s, 3H), 3.66
(dd, J ) 5.15, 4.41 Hz, 2H), 4.27 (dd, J ) 4.41, 4.41 Hz, 2H),
7.44 (s, 1H), 8.39 (d, J ) 6.99 Hz, 1H), 13.07 (d, J ) 5.15 Hz,
1H), 15.87 (s, 1H); 13C NMR (125 MHz, CF3COOD) δ 40.3, 51.2,
66.3, 107.2, 112.7, 114.8, 145.7, 145.9, 150.1, 155.8, 172.4, 173.0.
Anal. (C12H11N3O4) C, H, N.
1-(2,4-Dimethoxybenzyl)-7-[ethyl(2-hydroxyethyl)amino]-6-
fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic Acid
Ethyl Ester (8a). A solution of chloride 10 (2 g, 4.75 mmol),
2-(ethylamino)ethanol (556 µL, 5.7 mmol), and triethylamine (1.98
mL, 14.25 mmol) in acetonitrile (47.5 mL) at 25 °C was stirred
for 18 h, treated with more 2-(ethylamino)ethanol (556 µL, 5.7
mmol), heated at 55-75 °C for 4 days, cooled to 25 °C, and filtered
1
with acetonitrile rinsing to give a white solid (1.96 g, 87%). H
NMR (300 MHz, DMSO-d6) δ 1.12 (t, J ) 6.95 Hz, 3H), 1.26 (t,
J ) 7.12 Hz, 3H), 3.60 (m, 6H), 3.73 (s, 3H), 3.80 (s, 3H), 4.19
(q, J ) 7.12 Hz, 2H), 4.78 (m, 1H), 5.38 (s, 2H), 6.47 (dd, J )
8.14, 2.37 Hz, 1H), 6.61 (d, J ) 2.37 Hz, 1H), 6.93 (d, J ) 8.48
Hz, 1H), 7.84 (d, J ) 13.90 Hz, 1H), 8.62 (s, 1H).
1-(2,4-Dimethoxybenzyl)-7-[ethyl(2-hydroxyethyl)amino]-6-
fluoro-4-oxo-1 ,4-dihydro-[1,8]naphthyridine-3-carboxylic Acid
(8b). Acid 8b was prepared from ester 8a according to the general
1
procedure (4.2 mmol scale) in 100% yield. H NMR (300 MHz,
DMSO-d6) δ 1.14 (t, J ) 6.95 Hz, 3H), 3.68 (m, 6H), 3.74 (s,
3H), 3.77 (s, 3H), 4.82 (m, 1H), 5.52 (s, 2H), 6.48 (dd, J ) 8.48,
2.37 Hz, 1H), 6.61 (d, J ) 2.37 Hz, 1H), 6.97 (d, J ) 8.48 Hz,
1H), 8.00 (d, J ) 14.24 Hz, 1H), 8.83 (s, 1H), 15.39 (s, 1H); 13C
NMR (75 MHz, DMSO-d6) δ 12.9, 46.2 (d, J ) 4.89 Hz), 49.7,
52.2 (d, J ) 7.3 Hz), 55.3, 55.5, 59.1, 98.6, 104.8, 107.5, 111.2 (d,
J ) 2.4 Hz), 115.5, 118.6 (d, J ) 12.9 Hz), 129.6, 145.5, 146.1 (d,
J ) 258.8 Hz), 147.7, 149.4 (d, J ) 9.7 Hz), 158, 160.6, 166,
176.2. Anal. (C22H24N3O) C, H, N.
5-(2,4-Dimethoxybenzyl)-4-ethyl-8-oxo-3,4,5,8-tetrahydro-2H-
1-oxa-4,5,10-triazaanthracene-7-carboxylic Acid (8c). A solution
of 8b (1.14 g, 2.56 mmol) in DMF (45 mL) at 25 °C was treated
with 60% oily sodium hydride (215 mg, 5.37 mmol), stirred for 4
h, heated at 100 °C for 2 days, cooled to 25 °C, treated with more
60% oily sodium hydride (100 mg, 2.50 mmol), stirred for 4 h,
heated at 100 °C for 2 days, cooled to 25 °C, treated with water,
adjusted to pH 3.5 with 1 M HCl, and filtered; the filtrant was
purified by flash chromatography on silica gel with 0-4%
methanol/dichloromethane to give a white solid (498 mg, 46%).
1H NMR (300 MHz, DMSO-d6) δ 1.11 (t, J ) 6.99 Hz, 3H), 3.69
(m, 4H), 3.73 (s, 3H), 3.78 (s, 3H), 4.24 (t, J ) 4.60 Hz, 2H), 5.54
1-(2,4-Dimethoxybenzyl)-6-fluoro-7-[(2-hydroxyethyl)methyl-
amino]-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic Acid
Ethyl Ester (7a). A solution of chloride 10 (2 g, 4.75 mmol),
N-methylaminoethanol (572 µL, 7.13 mmol), and triethylamine (2
mL, 14.25 mmol) in acetonitrile (50 mL) was stirred at 25 °C for
18 h and then filtered. The solid was washed with acetonitrile and
1
air-dried to give off-white crystals (2.09 g, 96%). H NMR (300
MHz, DMSO-d6) δ 1.26 (t, J ) 7.12 Hz, 3H), 3.24 (d, J ) 3.05
Hz, 3H), 3.60 (m, 2H), 3.67 (m, 2H), 3.74 (s, 3H), 3.80 (s, 3H),
4.20 (q, J ) 7.12 Hz, 2H), 4.77 (t, J ) 5.43 Hz, 1H), 5.38 (s, 2H),
6.48 (dd, J ) 8.31, 2.54 Hz, 1H), 6.60 (d, J ) 2.37 Hz, 1H), 7.06
(d, J ) 8.14 Hz, 1H), 7.83 (d, J ) 13.90 Hz, 1H), 8.65 (s, 1H).

NoVel Antibacterial Class: Tetracyclic DeriVatiVes
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 16 4851
(s, 2H), 6.48 (dd, J ) 8.46, 2.21 Hz, 1H), 6.60 (d, J ) 2.21 Hz,
1H), 7.05 (d, J ) 8.46 Hz, 1H), 7.48 (s, 1H), 8.84 (s, 1H), 15.83
(s, 1H).
with 60% oily sodium hydride (112.0 mg, 2.79 mmol), stirred for
2 h, heated at 100-130 °C for 6 days, cooled to 25 °C, treated
with water, adjusted to pH 3.5 with 1 M HCl, and filtered. The
crude material was purified by silica gel chromatography and eluted
with 0-10% methanol in dichloromethane to give a white solid
Sodium 4-Ethyl-8-oxo-3,4,5,8-tetrahydro-2H-1-oxa-4,5,10-tri-
azaanthracene-7-carboxylate (8). A solution of 8c (498 mg, 1.17
mmol) in TFA (20 mL) was stirred at 25 °C for 18 h and
concentrated; the concentrate was azeotroped with toluene, con-
centrated, and triturated first with acetone and then with methanol
to give the crude product as a white powder (498 mg). To a
suspension of the crude material (200 mg) in water (200 mL) was
added 1.002 N NaOH solution (412.5 µL), and the mixture was
sonicated and heated for 6 h. The resulting pH 7.5 suspension was
filtered through a 0.45 µM syringe filter and the filtrate was
lyophilized to give the sodium salt (89.3 mg, 63%). 1H NMR (300
MHz, DMSO-d6) δ 1.16 (t, J ) 7.17 Hz, 3H), 3.56 (m, 2H), 3.72
1
(111 mg, 23%). H NMR (300 MHz, DMSO-d6) δ 1.89 (s, 9H),
2.03 (m, 3H), 2.30 (m, 1H), 3.76 (m, 2H), 4.45 (m, 1H), 7.66 (s,
1H), 8.78 (s, 1H), 10.99 (s, 1H), 15.76 (s, 1H). Anal. (C14H13N3O5‚
0.25H2O) C, H, N.
4,7-Dioxo-1,2,3,3a,4,5,7,10-octahydro-5,10,11,11b-tetraazacyclo-
penta[a]anthracene-8-carboxylic Acid (12). Compound 12 was
prepared from compound 12c according to the general procedure
(0.3 mmol scale) in 64% yield. 1H NMR (300 MHz, 1:1 CF3COOD/
DMSO-d6) δ 15.93 (s, 1H), 8.42 (s, 1H), 7.61 (s, 1H), 4.42 (m,
1H), 3.77 (m, 1H), 3.65 (m, 1H), 2.32 (m, 1H), 2.03 (m, 3H). HPLC
(method A) RT ) 0.44 min, (method B) RT ) 0.30 min.
1-(2,4-Dimethoxybenzyl)-6-fluoro-7-[(R)-4-hydroxy-(S)-2-hy-
droxymethylpyrrolidin-1-yl]-4-oxo-1,4-dihydro-[1,8]naphthyri-
dine-3-carboxylic Acid Ethyl ester (16a). Compound 16a was
prepared from chloride 10 and (S)-5-hydroxymethylpyrrolidin-(R)-
3-ol12 according to the general procedure (5.4 mmol scale) in 42%
(q, J ) 7.11 Hz, 2H), 4.20 (m, 2H), 7.40 (s, 1H), 8.56 (s, 1H); 13
C
NMR (75 MHz, DMSO-d6) δ 11.6, 41.8, 44.5, 63.4, 106.2, 110.7,
113.3, 137.8, 148.5, 151.3, 155.0, 170.6, 172.2. Anal. (C13H12N3-
NaO4) C, H, N, Na.
7-Chloro-1-(2,4-dimethoxybenzyl)-6-fluoro-4-oxo-1,4-dihydro-
[1,8]naphthyridine-3-carboxylic Acid Ethyl Ester (10). Com-
mercially available 3-(2,6-dichloro-5-fluoropyridin-3-yl)-3-oxo-
propionic acid ethyl ester [CAS 96568-04-6] (40 g, 143 mmol) was
slurried in 100 mL of acetic anhydride, treated with triethylortho-
formate (27 mL, 163 mmoL), and heated to reflux for 14 h. The
mixture was cooled and concentrated in vacuo to afford a brown
oil. The oil was dissolved in 500 mL of CH2Cl2, and the flask was
placed in an ice bath. The mixture was treated with 2,4-dimethoxy-
benzylamine (22 mL, 147 mmol), stirred at room temperature for
1 h, and concentrated in vacuo. The residue was dissolved in 250
mL of acetonitrile and treated with potassium carbonate (40 g, 289
mmol), heated to reflux for 14 h, and cooled. The solution was
diluted with EtOAc, washed with H2O and 10% aqueous citric acid,
dried over Na2SO4, and concentrated in vacuo. The crude material
was recrystallized from 300 mL of EtOAc to afford an off-white
powder (19 g, 32% yield). 1H NMR (300 MHz, DMSO-d6) δ 1.29
(t, J ) 7.1 Hz, 3H), 3.74 (s, 3H), 3.80 (s, 3H), 4.25 (q, J ) 7.1 Hz,
2H), 5.43 (s, 2H), 6.51 (dd, J ) 8.5, 2.4 Hz, 1H), 6.59 (d, J ) 2.4
Hz, 1H), 7.28 (d, J ) 8.1 Hz, 1H), 8.43 (d, J ) 7.8 Hz, 1H), 8.89
(s, 1H).
1-tert-Butyl-7-chloro-6-fluoro-4-oxo-1,4-dihydro-[1,8]naph-
thyridine-3-carboxylic Acid Ethyl Ester (11). Compound 11 was
synthesized as described for compound 10 (143 mmol scale), with
tert-butyl amine (15 mL, 143 mmol) in place of 2,4-dimethoxy-
benzylamine to afford the product as a white solid (17.6 g, 38%
yield). 1H NMR (300 MHz, DMSO-d6) δ 1.29 (t, J ) 7.1 Hz, 3H),
1.83 (s, 9H), 4.25 (q, J ) 7.1 Hz, 2H), 8.47 (d, J ) 8.1 Hz, 1H),
8.83 (s, 1H).
1-tert-Butyl-7-(2-carbamoylpyrrolidin-1-yl)-6-fluoro-4-oxo-
1,4-dihydroquinoline-3-carboxylic Acid Ethyl Ester (12a). Com-
pound 12a was prepared from chloride 10 and L-prolinamide
according to the general procedure (12.2 mmol scale) in 75% yield.
1H NMR (300 MHz, DMSO-d6) δ 1.27 (t, J ) 7.17 Hz, 3H), 1.81
(s, 9H), 1.84 (m, 1H), 1.97 (m, 2H), 2.26 (m, 1H), 3.75 (m, 1H),
3.94 (m, 1H), 4.21 (q, J ) 7.23 Hz, 2H), 4.66 (m, 1H), 7.08 (s,
1H), 7.51 (s, 1H), 7.89 (d, J ) 13.24 Hz, 1H), 8.68 (s, 1H). Anal.
(C20H25FN4O4) C, H, N, F.
1
yield. H NMR (300 MHz, DMSO-d6) δ 1.25 (t, J ) 10.51 Hz,
3H), 1.91(m, 1H), 2.16 (m, 1H), 3.48 (m, 3H), 3.74 (s, 3H), 3.72
(s, 3H), 3.85 (m, 1H), 4.10 (q, J ) 10.51 Hz, 2H), 4.44 (m, 2H),
4.72 (t, J ) 5.76 Hz, 1H), 4.99 (d, 4.07 Hz, 1H), 5.39 (m, 2H),
6.48 (dd, J ) 8.48, 2.37 Hz, 1H), 6.60 (d, J ) 2.03 Hz, 1H), 7.05
(d, J ) 8.48 Hz, 1H), 7.85 (d, J ) 13.22 Hz, 1H), 8.63 (s, 1H).
1-(2,4-Dimethoxybenzyl)-6-fluoro-7-[(R)-4-hydroxy-(S)-2-hy-
droxymethylpyrrolidin-1-yl]-4-oxo-1,4-dihydro-[1,8]naphthyri-
dine-3-carboxylic Acid Ethyl Ester (16b). A suspension of the
ethyl ester 16a (0.698 g, 1.39 mmol) and 1 M NaOH (4.2 mL) in
ethanol (35 mL) was stirred for 18 h. Water (20 mL) was added
and the mixture heated at 50 °C for 5 h. More water (20 mL) was
added, and the solution adjusted to pH 3 with 1 M HCl and then
extracted with dichloromethane (3 × 50 mL). The organic extracts
were dried and concentrated to give a yellow solid (578 mg, 88%).
1H NMR (300 MHz, DMSO-d6) δ 1.94 (m, 1H), 2.18 (m, 1H),
3.45 (m, 1H), 3.64 (m, 2H), 3.75 (s, 3H), 3.76 (s, 3H), 3.83 (m,
1H), 4.46 (m, 2H), 4.76 (s, 1H), 5.02 (s, 1H), 5.52 (dd, J ) 21.33,
14.34 Hz, 2H), 6.50 (dd, J ) 8.46, 2.21 Hz, 1H), 6.61 (d, J ) 2.57
Hz, 1H), 7.10 (d, J ) 8.46 Hz, 1H), 8.01 (d, J ) 12.87 Hz, 1H),
8.80 (s, 1H), 15.44 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 49.7,
55.3, 55.5, 58.0 (d, J ) 9 Hz), 60.0, 98.6, 104.9, 107.4, 111.0,
115.3, 117.7 (d, J ) 22 Hz), 130.5, 146.1 (d, J ) 243 Hz), 145.7,
149.1 (d, J ) 7 Hz), 158.3, 160.8, 166.0, 176.1. Anal. (C23H24-
FN3O7) C, H, N, F.
10-(2,4-Dimethoxybenzyl)-(R)-2-hydroxy-7-oxo-2,3,(S)-3a,4,7,10-
hexahydro-1H-5-oxa-10,11,11b-triazacyclopenta[a]anthracene-
8-carboxylic Acid (16c). Compound 16c was prepared from
compound 16b (1.1 mmol scale) according to the general procedure
in 55% yield. This reaction required an unusually long heating time
1
to effect cyclization. H NMR (300 MHz, DMSO-d6) δ 1.67 (m,
1H), 2.06 (dd, J ) 12.32, 5.33 Hz, 1H), 3.61 (m, 2H), 3.74 (s,
3H), 3.77 (s, 3H), 3.82 (m, 1H), 4.05 (m, 1H), 4.53 (m, 1H), 4.66
(dd, J ) 10.66, 3.68 Hz, 1H), 5.25 (d, J ) 3.31 Hz, 1H), 5.53 (dd,
J ) 14.34, 2.57 Hz, 2H), 6.51 (dd, J ) 8.27, 2.39 Hz, 1H), 6.58
(d, J ) 2.57 Hz, 1H), 7.32 (d, J ) 8.09 Hz, 1H), 7.54 (s, 1H), 8.86
(s, 1H), 15.85 (s, 1H).
1-tert-Butyl-7-(2-carbamoylpyrrolidin-1-yl)-6-fluoro-4-oxo-
1,4-dihydroquinoline-3-carboxylic Acid (12b). Compound 12b
was prepared from ester 12a according to the general procedure (5
mmol scale) in 89% yield. 1H NMR (300 MHz, DMSO-d6) δ 1.86
(s, 9H), 2.00 (m, 3H), 2.27 (m, 1H), 3.83 (m, 1H), 3.97 (m, 1H),
4.74 (m, 1H), 7.13 (s, 1H), 7.56 (s, 1H), 8.02 (d, J ) 12.87 Hz,
1H), 8.85 (s, 1H), 15.37 (s, 1H); 13C NMR (75 MHz, DMSO-d6)
δ 22.0 (br), 28.9, 32.0 (br), 50.6 (br), 62.5 (br), 65.5, 106.7, 113,
117.6 (d, J ) 20.8 Hz), 144.6, 145.7 (d, J ) 258.8 Hz), 146.5,
148.0 (d, J ) 11.0 Hz), 166.3, 173.4, 175.8. Anal. (C18H21FN4O4)
C, H, N, F.
10-(2,4-Dimethoxybenzyl)-(S)-2-amino-7-oxo-2,3,(S)-3a,4,7,10-
hexahydro-1H-5-oxa-10,11,11b-triazacyclopenta[a]anthracene-
8-carboxylic acid (14c). To a solution of 16c (519 mg, 1.15 mmol)
and triethylamine (398.5 µL, 2.88 mmol) in dichloromethane (5
mL) at 0 °C was added dropwise mesyl chloride (177.4 µL, 2.3
mmol). The mixture was stirred at 0 °C for 1 h and then at room
temperature for 18 h. The reaction was diluted with dichloromethane
(15 mL) and the organic phase was washed with aqueous saturated
NaHCO3, dried (Na2SO4), filtered, and concentrated in vacuo. To
a solution of the crude mesylate in DMF (14 mL) was added sodium
azide (724.8 mg, 11.5 mmol). The resulting gelatinous mixture was
stirred at 65 °C for 18 h. The mixture was cooled to room
temperature and diluted with water (100 mL), and the resulting
10-tert-Butyl-4,7-dioxo-1,2,3,3a,4,5,7,10-octahydro-5,10,11b-
triazacyclopenta[a]anthracene-8-carboxylic Acid (12c). A solu-
tion of 12b (500 mg, 1.33 mmol) in DMF (20 mL) was treated

4852 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 16
Hinman et al.
1
solid was collected by vacuum filtration. The solid was washed
with water and dried to give the crude azide. To a solution of the
crude azide (147.3 mg) in THF (3 mL) and water (100 µL) was
added triphenylphosphine (97 mg, 0.37 mmol). The solution was
stirred at 50 °C for 18 h. The mixture was cooled to room
temperature and concentrated in vacuo, and the residue was
triturated with ether (three portions) to give a pale yellow solid,
which was further purified by reversed phase (RP) HPLC (100 mg,
Data for diastereomer B (18a): H NMR (300 MHz, DMSO-
d6) δ 1.07 (d, J ) 6.3 Hz, 3H), 1.27 (t, J ) 7.0 Hz, 3H), 1.82 (s,
9H), 1.89 (m, 2H), 2.10 (m, 2H), 3.78 (m, 2H), 4.03 (m, 1H), 4.21
(q, J ) 7.2 Hz, 2H), 4.28 (m, 1H), 4.73 (d, J ) 5.2 Hz, 1H), 7.90
(d, J ) 13.6 Hz, 1H), 8.67 (s, 1H). Anal. (C21H28FN3O4) C, H, N,
F.
1-tert-Butyl-6-fluoro-7-[(S)-2-[(S)-1-hydroxyethyl]pyrrolidin-
1-yl]-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic Acid
(17b). Compound 17b (3:1 mixture of diastereomers) was prepared
from 17a according to the general procedure (1.2 mmol scale) in
95% yield. 1H NMR (300 MHz, DMSO-d6) δ 1.07 (d, J ) 5.9 Hz,
3H), 1.89 (s, 9H), 1.97 (m, 4H), 3.78 (m, 3H), 4.47 (m, 1H), 4.85
(d, J ) 4.4 Hz, 1H), 7.95 (d, J ) 13.2 Hz, 1H), 8.83 (s, 1H), 15.46
(s, 1H).
1-tert-Butyl-6-fluoro-7-[(S)-2-[(R)-1-hydroxyethyl]pyrrolidin-
1-yl]-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic Acid
(18b). Compound 18b (9:1 mixture of diastereomers) was prepared
from 18a according to the general procedure (1.4 mmol scale) in
75% yield. 1H NMR (300 MHz, DMSO-d6) δ 1.08 (d, J ) 6.6 Hz,
3H), 1.87 (s, 9H), 1.93 (m, 2H), 2.15 (m, 2H), 3.83 (m, 2H), 4.05
(m, 1H), 4.34 (m, 1H), 4.79 (d, J ) 4.8 Hz, 1H), 8.04 (d, J ) 13.2
Hz, 1H), 8.84 (s, 1H), 15.40 (s, 1H).
10-tert-Butyl-(S)-4-methyl-7-oxo-2,3,3a,4,7,10-hexahydro-1H-
5-oxa-10,11,11b-triazacyclopenta[a]anthracene-8-carboxylic Acid
(17c). Compound 17c (3:1 mixture of diastereomers) was prepared
from 17b according to the general procedure (0.9 mmol scale) in
121% yield (contaminated with mineral oil) as a 4:1 mixture of
diastereomers. 1H NMR (300 MHz, DMSO-d6) δ 1.42 (d, J ) 5.9
Hz, 3H), 1.59 (m, 1H), 1.90 (s, 9H), 2.00 (m, 1H), 2.16 (m, 2H),
3.51 (m, 1H), 3.76 (m, 3H), 7.57 (s, 1H), 8.78 (s, 1H), 15.85 (s,
1H).
10-tert-Butyl-(R)-4-methyl-7-oxo-2,3,3a,4,7,10-hexahydro-1H-
5-oxa-10,11,11b-triazacyclopenta[a]anthracene-8-carboxylic Acid
(18c). Compound 18c (15:1 mixture of diastereomers) was prepared
from 18b according to the general procedure (1 mmol scale) in
127% yield (contaminated with mineral oil) as a 15:1 mixture of
diastereomers. 1H NMR (300 MHz, DMSO-d6) δ 1.06 (d, J ) 6.6
Hz, 3H), 1.61 (m, 1H), 1.90 (s, 9H), 1.99 (m, 1H), 2.15 (m, 2H),
3.68 (m, 1H), 3.83 (m, 1H), 4.00 (m, 1H), 4.83 (m, 1H), 7.58 (s,
1H), 8.78 (s, 1H), 15.87 (s, 1H).
1
15%). H NMR [of free amine] (300 MHz, DMSO-d6) δ 8.85 (s,
1H), 7.50 (s, 1H), 7.30 (d, J ) 8.46 Hz, 1H), 6.58 (d, J ) 2.21 Hz,
1H), 6.51 (dd, J ) 8.46, 2.21 Hz, 1H), 5.51 (dd, J ) 14.34, 1.84
Hz, 2H), 4.58 (dd, J ) 10.30, 3.68 Hz, 1H), 3.88 (m, 2H), 3.78 (s,
3H), 3.74 (s, 3H), 3.69 (m, 2H), 2.24 (m, 1H), 1.40 (m, 1H); 13C
NMR (75 MHz, 5% CH3OD in DMSO-d6) δ 37.8, 49.9, 50.7, 53.8,
55.2, 67.7, 98.3, 104.3, 107.1, 112.4, 114.9, 132.3, 138.5, 145.4,
145.9, 146.0, 148.0, 159.0, 161.3, 168.1, 176.4. Anal. (C23H24N4O6‚
1.5CF3COOH) C, H, N.
(S)-2-Amino-7-oxo-2,3,(S)-3a,4,7,10-hexahydro-1H-5-oxa-
10,11,11b-triazacyclopenta[a]anthracene-8-carboxylic Acid (14).
A solution of crude 14c (65 mg, 0.14 mmol) in TFA (10 mL) was
stirred for 3 days and then concentrated. The concentrate was
azeotroped with acetonitrile (3×). The residue was suspended in
water (100 mL) and the suspension was washed with ether. The
aqueous layer was filtered through a 0.45 µM syringe filter and
then lyophilized to give a white powder, which was further purified
by RP HPLC (23.6 mg, 39%): 1H NMR (300 MHz, DMSO-d6) δ
15.8 (br s, 1H), 8.44 (s, 1H), 8.23 (br s, 2H), 7.58 (s, 1H), 4.67
(dd, J ) 10.66 Hz, 3.68 Hz, 1H), 4.13-3.85 (m, 3H), 3.80-3.64
(m, 2H), 2.52 (m, 1H), 1.72 (m, 1H); 13C NMR (75 MHz, DMSO-
d6) δ 32.5, 47.7, 49.4, 54.0, 67.2, 107.4, 111.2, 113.5, 138.4, 142.0,
145.8, 148.4, 166.4, 176.7; Anal. (C14H14N4O4‚1.75 CF3COOH)
C, H, N, F.
(R)-2-Hydroxy-7-oxo-2,3,(S)-3a,4,7,10-hexahydro-1H-5-oxa-
10,11,11b-triazacyclopenta[a]anthracene-8-carboxylic Acid (16).
A solution of 16c (267 mg, 0.59 mmol) in TFA (5 mL) was heated
at 55 °C for 1 h, cooled to 25 °C, stirred for 18 h, and concentrated.
The concentrate was azeotroped with toluene, sonicated for 2 h in
water (300 mL) and 1 M NaOH (1.36 mL, 1.35 mmol), washed
with diethyl ether, adjusted to pH 3.5 with 1 M HCl, and filtered.
The crude material was triturated with acetone and then further
purified by RP HPLC (44.4 mg, 25%). 1H NMR (300 MHz, DMSO-
d6) δ 13.16 (m, 1H), 8.37 (d, J ) 4.07 Hz, 2H), 7.53 (m, 1H), 4.67
(dd, J ) 10.51, 3.73 Hz, 1H), 4.49 (m, 1H), 4.08 (m, 1H), 3.68
(m, 4H), 2.07 (dd, J ) 12.55, 5.09 Hz, 1H), 1.67 (m, 1H); 13C
NMR (75 MHz, DMSO-d6) δ 37.0, 54.0, 55.7, 67.5, 67.8, 107.3,
110.7, 112.9, 138.6, 141.6, 146.1, 149.2, 166.6, 176.6. Anal.
(C14H13N3O5‚0.4H2O) C, H, N.
(S)-4-Methyl-7-oxo-2,3,3a,4,7,10-hexahydro-1H-5-oxa-10,11,11b-
triazacyclopenta[a]anthracene-8-carboxylic Acid (17). Com-
pound 17 was prepared from compound 17c (4:1 mixture of
diastereomers) according to the general procedure (0.9 mmol scale)
1
in 68% yield (94:6 ratio of diastereomers). H NMR (500 MHz,
1:1 CF3CO2D/DMSO-d6) δ 1.52 (d, J ) 7.0 Hz, 3H), 1.68 (m,
1H), 2.12 (m, 1H), 2.25 (m, 1H), 2.31 (m, 1H), 3.59 (m, 1H), 3.78
(m, 1H), 3.92 (m, 1H), 7.64 (s, 1H), 8.87 (s, 1H); 13C NMR (125
MHz, DMSO-d6) δ 17.6, 22.8, 29.0, 46.3, 61.1, 74.3, 106.3, 110.4,
112.6, 137.5, 148.1, 151.1, 155.4, 170.6, 172.5. HPLC (method
A) RT ) 1.42 min, (method B) RT ) 1.32 min.
(R)-4-Methyl-7-oxo-2,3,3a,4,7,10-hexahydro-1H-5-oxa-
10,11,11b-triazacyclopenta[a]anthracene-8-carboxylic Acid (18).
Compound 18 was prepared from compound 18c (95:5 mixture of
diastereomers) according to the general procedure (1 mmol scale)
1-tert-Butyl-6-fluoro-7-[2-(1-hydroxyethyl)pyrrolidin-1-yl]-4-
oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic Acid Ethyl Es-
ter (17a, 18a). A solution of 2-(1-hydroxyethyl)pyrrolidine-1-
carboxylic acid tert-butyl ester13 (0.94 g, 4.37 mmol) and
p-toluenesulfonic acid monohydrate (1.25 g, 6.58 mmol) in aceto-
nitrile (10 mL) was refluxed for 2 h and cooled to room temperature,
and the solution was used in the next reaction.
1
A solution of 11 (0.952 g, 2.92 mmol), crude 1-pyrrolidin-2-
ylethanol p-toluenesulfonate salt (approximately 4.37 mmol in 10
mL of acetonitrile), and triethylamine (1.62 mL, 11.6 mmol) in
acetonitrile (15 mL) at 55 °C was stirred for 3 days, adsorbed onto
silica gel and eluted with 0-10% methanol/dichloromethane. This
gave diastereomer A as a 3:1 mixture (0.486 g, 41%) and
diastereomer B as a 9:1 mixture (0.55 g, 47%).
in 62% yield (>95:5 mixture of diastereomers). H NMR (300
MHz, DMSO-d6) δ 1.05 (d, J ) 6.6 Hz, 3H), 1.59 (m, 1H), 2.04
(m, 3H), 3.63 (m, 1H), 3.75 (m, 1H), 3.98 (m, 1H), 4.80 (m, 1H),
7.49 (s, 1H), 8.36 (d, J ) 6.6 Hz, 1H), 13.17 (d, J ) 6.6 Hz, 1H);
13C NMR (125 MHz, DMSO-d6) δ 13.0, 22.8, 28.0, 46.5, 58.0,
69.9, 107.3, 110.9, 113.7, 136.3, 141.5, 146.0, 148.9, 166.6, 176.4.
HPLC (method A) RT ) 1.34 min, (method B) RT ) 1.22 min.
1-tert-Butyl-6-fluoro-7-[(S)-2-(1-hydroxybut-3-enyl)pyrrolidin-
1-yl]-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic Acid
Ethyl Ester (19a and 20a). N-(tert-Butoxycarbonyl)-L-prolinal (5.0
g, 25 mmol)was dissolved in 100 mL of THF and cooled to -78
°C. Allylmagnesium bromide (30 mL, 1.0 M in Et2O, 30 mmol)
was added, and the mixture was stirred for 2 h at -78 °C and for
1 h at room temperature. The reaction was quenched by the addition
of saturated aqueous NH4Cl and the mixture was extracted with
EtOAc. The organic phases were washed with H2O, dried over
1
Data for diastereomer A (17a): H NMR (300 MHz, DMSO-
d6) δ 1.03 (d, J ) 6.3 Hz, 3H), 1.27 (t, J ) 7.0 Hz, 3H), 1.83 (s,
9H), 1.95 (m, 4H), 3.75 (m, 3H), 4.21 (q, J ) 7.1 Hz, 3H), 4.45
(m, J ) 3.7 Hz, 1H), 4.77 (d, J ) 4.8 Hz, 1H), 7.84 (d, J ) 13.6
Hz, 1H), 8.67 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ 14.3,
19.1, 22.2, 26.2, 29.0, 45.5, 49.5, 59.7, 63.2 (d, J ) 7.3 Hz,), 63.6,
67.2, 109.3, 115.5, 118.6 (d, J ) 20.8 Hz), 144.6 (d, J ) 236.8
Hz), 144.9, 145.6, 147.5 (d, J ) 9.7 Hz), 165.0, 171.6. Anal.
(C21H28FN3O4) C, H, N, F.

NoVel Antibacterial Class: Tetracyclic DeriVatiVes
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 16 4853
Na2SO4, and concentrated to afford a clear oil (6.3 g). A portion
of this crude material (3.45 g, 14.3 mmol) was dissolved in 40 mL
of ethanol and treated with p-toluenesulfonic acid (4.1 g, 22 mmol),
and the mixture was warmed to 60 °C for 2 h. Because the reaction
was not complete, an additional aliquot of p-toluenesulfonic acid
(510 mg, 2.7 mmol) was added and the mixture was warmed to 80
°C for 1 h. The solution was concentrated to afford the p-
toluenesulfonic acid salt of 1-pyrrolidin-2-ylbut-3-en-1-ol, and this
material was used without further purification.
1-Pyrrolidin-2-ylbut-3-en-1-ol p-toluenesulfonic acid salt (4.5 g,
14.3 mmol) was slurried in CH3CN and treated with chloride 11
(4.0 g, 12.2 mmol) and triethylamine (7 mL, 50 mmol). After 2 h
at room temperature, the mixture was warmed to 50 °C for 1 day.
The mixture was cooled and diluted with 150 mL of H2O. A
precipitate formed and was collected by filtration. This solid was
a 2:1 mixture of diastereomers with diastereomer A predominating.
This material could be recrystallized from EtOAc to afford
analytically clean material, still as a 2:1 mixture of diastereomers.
Diastereomer A (R Configuration at the Alcohol Center): 1-
tert-Butyl-6-fluoro-7-{(S)-2-[(R)-1-hydroxybut-3-enyl)]pyrroli-
din-1-yl}-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic Acid
Ethyl Ester (20a). 1H NMR (300 MHz, DMSO-d6) δ 1.27 (t, J )
7.35 Hz, 3H), 1.82 (s, 9H), 1.94 (m, 2H), 2.14 (m, 4H), 3.76 (m,
2H), 3.92 (m, 1H), 4.21 (q, J ) 7.35 Hz, 2H), 4.34 (m, 1H), 4.87
(d, J ) 5.52 Hz, 1H), 5.03 (m, 2H), 5.83 (m, 1H), 7.91 (d, J )
13.60 Hz, 1H), 8.66 (s, 1H). Anal. (C23H30N3O4) C, H, N.
The filtrate from the above procedure was extracted with EtOAc
and the organic phase was concentrated. This material was
recrystallized from EtOAc and hexanes to afford clean desired
compound as a 1:3 mixture of diastereomers, now with diastereomer
B predominating.
(S)-4-Allyl-10-tert-butyl-7-oxo-2,3,(S)-3a,4,7,10-hexahydro-
1H-5-oxa-10,11,11b-triazacyclopenta[a]anthracene-8-carbox-
ylic Acid (19c). Compound 19c was prepared from 19b according
to the general procedure (2.3 mmol scale) to afford a 28% yield of
a 3:1 mixture of diastereomers favoring 19c. 1H NMR (300 MHz,
DMSO-d6) δ 1.64 (m, 2H), 1.89 (s, 9H), 2.00 (m, 1H), 2.16 (m,
2H), 2.62 (m, 1H), 3.70 (m, 4H), 5.22 (m, 2H), 5.97 (m, 1H), 7.57
(s, 1H), 8.78 (s, 1H), 15.85 (s, 1H).
(R)-4-Allyl-7-oxo-2,3,(S)-3a,4,7,10-hexahydro-1H-5-oxa-
10,11,11b-triazacyclopenta[a]anthracene-8-carboxylic Acid (20).
Compound 20 was prepared from compound 20c (0.19 mmol scale)
to afford a 66% yield of a 10:1 mixture of diastereomers, favoring
20. 1H NMR (500 MHz, DMSO-d6) δ 1.68 (m, 1H), 1.92 (m, 2H),
2.04 (m, 1H), 2.13 (m, 1H), 2.30 (m, 1H), 3.60 (m, 1H), 3.72 (m,
1H), 4.01 (m, 1H), 4.65 (dt, J ) 10.38, 3.66 Hz, 1H), 4.96 (m,
2H), 5.80 (m, 1H), 7.46 (s, 1H), 8.40 (s, 1H); 13C NMR (100 MHz,
DMSO-d6) δ 22.8, 27.7, 31.1, 46.4, 57.9, 72.5, 107.3, 111.0, 113.9,
117.7, 133.5, 136.1, 141.6, 146.1, 149.1, 166.5, 176.4.
(S)-4-Allyl-7-oxo-2,3,(S)-3a,4,7,10-hexahydro-1H-5-oxa-
10,11,11b-triazacyclopenta[a]anthracene-8-carboxylic Acid (19).
Compound 19 was prepared from compound 19c (0.2 mmol scale)
to afford a 100% yield of a 10:1 mixture of diastereomers, favoring
19. 1H NMR (300 MHz, DMSO-d6) δ 1.57 (m, 1H), 1.98 (m, 1H),
2.14 (m, 2H), 2.43 (m, 1H), 2.61 (m, 1H), 3.56 (m, 2H), 3.72 (m,
2H), 5.22 (m, 2H), 5.97 (m, 1H), 7.48 (s, 1H), 8.40 (s, 1H), 16.14
(s, 1H); 13C (125 MHz, DMSO-d6 with TFA-d) δ 25.5, 31.7, 38.7,
50.7, 64.0, 81.4, 107.5, 112.2, 114.1, 121.5, 134.5, 145.2, 145.7,
149.8, 153.2, 172.3, 172.6.
1-tert-Butyl-6-fluoro-7-(2-hydroxymethyl-2-methylpyrrolidin-
1-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic Acid
Ethyl Ester (21a). N-(tert-Butoxycarbonyl)-DL-proline methyl ester
(3.0 g, 13.0 mmol) was dissolved in 50 mL of THF and cooled to
-78 °C. To this solution was added lithium diisopropylamide (8.5
mL, 2.0 M in heptane, 17 mmol). After 3 h at -78 °C, methyl
iodide (1.6 mL, 25.7 mmol) was added and the mixture was warmed
to 0 °C. After 2.5 h at 0 °C, the reaction was quenched by the
addition of H2O and the mixture was extracted with EtOAc. The
organic phase was washed with 1 N HCl and H2O, dried over
Na2SO4, and concentrated to afford an amber oil (3.4 g). The crude
material was dissolved in 50 mL of THF and cooled to -78 °C.
To this solution was added DiBAl (32 mL, 1.0 M in toluene, 32
mmol). After 15 min, the cooling bath was removed and the mixture
was stirred at room temperature for 2.5 h. The reaction was
quenched by the addition of H2O and saturated aqueous Rochelle’s
salt. The mixture was extracted with EtOAc, and the organic phase
was washed with H2O and concentrated to afford an orange oil
(2.8 g). The crude material (1.5 g, 7.0 mmol) was dissolved in 20
mL of ethanol, and p-toluenesulfonic acid (1.8 g, 9.4 mmol) was
added. The mixture was warmed to 60 °C for 3 h, and the mixture
was then treated with an additional aliquot of p-toluenesulfonic acid
(220 mg, 1.1 mmol). The mixture was left at 60 °C for 2 h, cooled,
and concentrated to afford (2-methylpyrrolidin-2-yl)methanol as the
p-toluenesulfonic acid salt.
Diastereomer B: (S Configuration at the Alcohol Center):
1-tert-Butyl-6-fluoro-7-{(S)-2-[(S)-1-hydroxybut-3-enyl)]pyr-
rolidin-1-yl}-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic
1
Acid Ethyl Ester (19a). H NMR (300 MHz, DMSO-d6) δ 1.27
(t, J ) 6.99 Hz, 3H), 1.83 (s, 9H), 1.94 (m, 4H), 2.14 (m, 2H),
3.75 (m, 3H), 4.20 (q, J ) 6.99 Hz, 2H), 4.49 (m, 1H), 4.91 (d, J
) 5.15 Hz, 1H), 5.03 (m, 2H), 5.83 (m, 1H), 7.83 (d, J ) 13.24
Hz, 1H), 8.67 (s, 1H).
1-tert-Butyl-6-fluoro-7-{(S)-2-[(R)-1-hydroxybut-3-enyl)]pyr-
rolidin-1-yl}-4 -oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic
Acid (20b). Carboxylic acid 20b was prepared from ethyl ester
20a according to the general procedure (2.8 mmol scale) to afford
1
an 89% yield of a 4:1 mixture of diastereomers, favoring 20b. H
NMR (300 MHz, DMSO-d6) δ 1.85 (s, 9H), 1.95 (m, 2H), 2.15
(m, 4H), 3.82 (m, 3H), 4.38 (m, 1H), 4.91 (d, J ) 5.52 Hz, 1H),
5.04 (m, 2H), 5.82 (m, 1H), 8.00 (d, J ) 13.24 Hz, 1H), 8.81 (s,
1H), 15.36 (s, 1H). Anal. (C21H26N3O4) C, H, N.
1-tert-Butyl-6-fluoro-7-{(S)-2-[(S)-1-hydroxybut-3-enyl)]pyr-
rolidin-1-yl}-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic
Acid (19b). Carboxylic acid 19b was prepared from ethyl ester
19a according to the general procedure (2.7 mmol scale) to afford
a 95% yield of a 1.5:1 mixture of diastereomers, favoring 19b. 1H
NMR [major diastereomer] (300 MHz, DMSO-d6) δ 1.87 (s, 9H),
2.11 (m, 6H), 3.70 (m, 3H), 4.52 (m, 1H), 5.01 (m, 3H), 5.84 (m,
1H), 7.94 (d, J ) 13.24 Hz, 1H), 8.82 (s, 1H), 15.47 (s, 1H). Anal.
(C21H26FN3O4) C, H, N.
Chloride 11 (2.0 g, 6.12 mmol) was dissolved in 20 mL of DMA,
and the toluenesulfonic acid of (2-methylpyrrolidin-2-yl)methanol
(2.0 g, 7 mmol) and diisopropylethylamine (4.5 mL, 26 mmol) were
added. The mixture was warmed to 110 °C for 6 days. The mixture
was cooled and diluted with H2O, and a white precipitate formed.
The precipitate was collected by filtration and chromatographed
on SiO2 with 1-4% MeOH in CH2Cl2 to afford the desired product
(R)-4-Allyl-10-tert-butyl-7-oxo-2,3,(S)-3a,4,7,10-hexahydro-
1H-5-oxa-10,11,11b-triazacyclopenta[a]anthracene-8-carbox-
ylic Acid (20c). Compound 20c was prepared from 20b according
to the general procedure (2.3 mmol scale) to afford an 81% yield
of a 6:1 mixture of diastereomers favoring 20c. The material could
further be recrystallized from EtOAc and hexanes to give analyti-
1
(1.0 g, 40%). H NMR (300 MHz, DMSO-d6) δ 1.27 (t, J ) 7.35
Hz, 3H), 1.38 (d, J ) 2.21 Hz, 3H), 1.70 (m, 1H), 1.82 (s, 9H),
1.95 (m, 2H), 2.37 (m, 1H), 3.57 (m, 1H), 3.77 (m, 3H), 4.21 (q,
J ) 6.99 Hz, 2H), 4.86 (t, J ) 5.52 Hz, 1H), 7.93 (d, J ) 13.97
Hz, 1H), 8.70 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 14.3, 21.7,
22.9, 28.9, 38.6, 53.5, 59.7, 63.5, 64.7, 66.9, 109.2, 116.2, 119.7
(d, J ) 23 Hz), 145.4, 145.5, 145.1 (d, J ) 255 Hz), 147.1 (d, J )
12 Hz), 164.9, 171.6. Anal. (C21H28FN3O6) C, H, N, F.
1
cally pure desired compound. H NMR (300 MHz, DMSO-d6) δ
1.74 (m, 1H), 1.90 (s, 9H), 1.99 (m, 2H), 2.14 (m, 2H), 2.38 (m,
1H), 3.68 (m, 1H), 3.81 (m, 1H), 4.05 (m, 1H), 4.73 (dt, J ) 10.30,
4.04 Hz, 1H), 5.03 (m, 2H), 5.85 (m, 1H), 7.55 (s, 1H), 8.78 (s,
1H), 15.84 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 22.8, 27.8,
29.0, 31.2, 46.7, 57.8, 65.4, 72.8, 106.5, 113.0, 114.6, 117.7, 133.5,
135.3, 142.7, 146.0, 147.0, 166.7, 175.5. Anal. (C21H25N3O4) C,
H, N.
1-tert-Butyl-6-fluoro-7-(2-hydroxymethyl-2-methylpyrrolidin-
1-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic Acid
(21b). Carboxylic acid 21b was prepared from ethyl ester 21a

4854 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 16
Hinman et al.
according to the general procedure (0.5 mmol scale) in 80% yield.
1H NMR (500 MHz, acetone-d6) δ 1.38 (m, 3H), 1.65 (m, 1H),
1.77 (s, 9H), 1.90 (m, 2H), 2.29 (m, 1H), 3.71 (m, 3H), 4.62 (m,
1H), 7.97 (m, 1H), 8.84 (m, 1H). Anal. (C19H24FN3O6) C, H, N, F.
3a-Methyl-7-oxo-2,3,3a,4,7,10-hexahydro-1H-5-oxa-10,11,11b-
triazacyclopenta[a]anthracene-8-carboxylic Acid (21). Alcohol
21b (65 mg, 0.17 mmol) was dissolved in 5 mL of DMF, and
sodium hydride (20 mg, 60% in oil, 0.5 mmol) was added. After 2
h at room temperature, the mixture was warmed to 50 °C for 18 h.
The mixture was allowed to cool and diluted to 80 mL with H2O,
and the pH was adjusted to 3 with 1 N HCl. A yellow precipitate
formed and was collected by filtration. A portion of this yellow
solid (50 mg, 0.14 mmol) was dissolved in 5 mL of TFA and a
few drops of sulfuric acid was added. After 2 h, the mixture
concentrated in vacuo and the crude product was purified by
chromatography on SiO2 with 0-5% MeOH in CH2Cl2 to afford
119.5, 133.2, 138.0, 141.7, 146.1, 148.7, 166.5, 176.6. HPLC
(method A) RT ) 1.65, (method B) RT ) 1.60.
7-(2-Aminomethylpyrrolidin-1-yl)-1-tert-butyl-6-fluoro-4-oxo-
1,4-dihydro-[1,8]naphthyridine-3-carboxylic Acid Ethyl Ester
(23a). Chloride 11 (2.72 g, 8.3 mmol) was slurried in 50 mL of
acetonitrile and cooled to 0 °C. To this mixture was added
triethylamine (3 mL, 22 mmol) and 2-(S)-(aminomethyl)pyrrolidine
(0.96 g, 9.6 mmol). The cooling bath was allowed slowly to warm
to room temperature and the mixture was stirred for 3 days. The
mixture was diluted with water and extracted with EtOAc. The
organic phase was washed with water and concentrated in vacuo
to give 2.6 g. The crude material was chromatographed with 5-8%
MeOH in CH2Cl2 to afford the desired material as an oil (22%).
1H NMR (300 MHz, DMSO-d6) δ 1.27 (t, J ) 7.0 Hz, 3H), 1.83
(s, 9H), 2.02 (m, 4H), 2.57 (m, 1H), 2.77 (m, 1H), 3.63 (m, 1H),
3.83 (m, 1H), 4.20 (q, J ) 7.0 Hz, 2H), 4.30 (m, 1H), 7.89 (d, J )
13.6 Hz, 1H), 8.66 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ
14.3, 21.7, 27.4, 29, 44, 49.6, 59.7, 61.1, 63.6, 109.4, 115.4, 119.1
(d, J ) 21 Hz), 144.8 (d, J ) 268 Hz), 145, 145.8, 146.5, 165,
171.5.
1
the desired product (18 mg, 43%). H NMR (300 MHz, DMSO-
d6) δ 1.23 (s, 3H), 1.73 (m, 1H), 1.94 (m, 1H), 2.15 (m, 2H), 3.68
(m, 3H), 4.45 (d, J ) 10.30 Hz, 1H), 7.56 (s, 1H), 8.37 (s, 1H),
13.17 (br s, 1H), 15.95 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ
21.1, 22.0, 34.4, 46.1, 59.7, 72.1, 107.2, 110.5, 112.9, 137.9, 141.7,
146.2, 148.6, 166.6, 176.5. Anal. (C15H15N3O3) C (calcd 59.79,
found 59.29), H, N.
10-tert-Butyl-7-oxo-1,2,3,3a,4,5,7,10-octahydro-5,10,11,11b-
tetraazacyclopenta[a]anthracene-8-carboxylic Acid (23c). Ester
23a (2.8 g, 7.7 mmol) was dissolved in 50 mL of ethanol and treated
with aqueous lithium hydroxide (7.5 mL, 1 M). After 2 days, an
additional aliquot of lithium hydroxide (2 mL, 1 M) was added.
After an additional 3 h, the mixture was concentrated in vacuo to
afford crude lithium carboxylate of acid 23b. The crude lithium
carboxylate of 23b (2.1 g, 5.7 mmol) was slurried in 100 mL of
DMF and warmed to 100 °C. After 20 h, the mixture was cooled,
diluted with ∼300 mL of H2O, brought to pH 4 with 1 N HCl, and
7-(2-Allyl-2-hydroxymethylpyrrolidin-1-yl)-1-tert-butyl-6-fluoro-
4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic Acid Ethyl
Ester (22a). Chloride 11 (2.0 g, 6.12 mmol) was dissolved in DMA
and treated with diisopropylethylamine (4.5 mL, 26 mmol) and (2-
allylpyrrolidin-2-yl)methanol toluenesulfonic acid salt (2.2 g, 7
mmol), and the mixture was warmed to 110 °C for 6 days. The
mixture was cooled and diluted with H2O. A precipitate formed
and was collected by filtration and washed with Et2O. The filtrate
was extracted with CH2Cl2; the organic phase was concentrated
and then taken up in EtOAc, washed with water, and concentrated
to give a brown oil. The combined crude material was chromato-
graphed on SiO2 with 0-3% MeOH in CH2Cl2 to afford the desired
1
filtered to afford the desired product as a yellow solid (48%). H
NMR (300 MHz, DMSO-d6) δ 1.23 (m, 1H), 1.62 (s, 9H), 1.81
(m, 3H), 2.48 (m, 1H), 3.40 (m, 4H), 6.29 (m, 1H), 7.01 (s, 1H),
8.38 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 22.6, 29.0, 29.8,
43.4, 46.6, 56.8, 65.0, 106.0, 107.2, 113.3, 129.7, 140.24, 144.1,
146.8, 167.4, 174.9.
1
material (247 mg, 20%). H NMR (300 MHz, DMSO-d6) δ 1.27
(t, J ) 6.99 Hz, 3H), 1.81 (s, 9H), 1.96 (m, 3H), 2.25 (m, 1H),
2.56 (m, 1H), 2.72 (m, 1H), 3.63 (m, 1H), 3.78 (m, 3H), 4.21 (q,
J ) 7.35 Hz, 2H), 4.93 (m, 3H), 5.67 (m, 1H), 7.95 (d, J ) 13.97
Hz, 1H), 8.70 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ 14.2,
21.9, 28.9, 34.6, 39.2, 53.9, 59.7, 63.5, 64.6, 64.7, 69.5, 109.3,
116.3, 118.2, 119.7 (d, J ) 22 Hz), 133.8, 145.3, 145.4, 145.5 (d,
J ) 254 Hz), 147.4 (d, J ) 12 Hz), 164.9, 171.5. Anal. (C23H30-
FN3O4) C, H, N, F.
7-Oxo-1,2,3,3a,4,5,7,10-octahydro-5,10,11,11b-tetraazacyclo-
penta[a]anthracene-8-carboxylic acid (23). Compound 23c was
deprotected to afford compound 23 according to the general
1
procedure (0.49 mmol scale) in 41% yield. H NMR (300 MHz,
DMSO-d6) δ 1.50 (m, 1H), 2.04 (m, 3H), 2.74 (m, 1H), 3.66 (m,
4H), 6.55 (s, 1H), 7.21 (s, 1H), 8.23 (d, J ) 7.0 Hz, 1H), 12.98 (d,
J ) 6.3 Hz, 1H). HPLC (method A) RT ) 1.15, (method B) RT )
0.58.
7-(2-Allyl-2-hydroxymethylpyrrolidin-1-yl)-1-tert-butyl-6-fluoro-
4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic Acid Ethyl
Ester (22b). Carboxylic acid 22b was prepared from ethyl ester
22a according to the general procedure (0.63 mmol scale) in 82%
10-tert-Butyl-5-methyl-7-oxo-1,2,3,3a,4,5,7,10-octahydro-
5,10,11,11b-tetraazacyclopenta[a]anthracene-8-carboxylic Acid
(24c). Amine 23c (150 mg, 0.44 mmol) was dissolved in 2 mL of
DMF. To this solution were added methyl iodide (100 µL, 1.6
mmol) and triethylamine (300 µL, 2.2 mmol). After 24 h at room
temperature, more methyl iodide (100 µL, 1.6 mmol) was added
and the mixture was warmed to 60 °C. After 16 h, the mixture was
cooled to room temperature and diluted with H2O. A precipitate
formed and was collected by filtration. The crude material was
chromatographed with 0-5% MeOH in CH2Cl2 to give the desired
product (92 mg, 56%). 1H NMR (300 MHz, DMSO-d6) δ 1.53 (m,
1H), 1.90 (m, 9H), 2.09 (m, 3H), 2.77 (m, 1H), 2.95 (m, 3H), 3.76
(m, 4H), 7.14 (m, 1H), 8.70 (m, 1H), 16.34 (m, 1H); 13C NMR (75
MHz, DMSO-d6) δ 24.1, 30.2, 31.5, 39.7, 49.4, 53.6, 58.5, 70.3,
103.7, 105.1, 113.0, 134.9, 141.5, 148.4, 150.6, 168.0, 171.9. HPLC
(method A) RT ) 1.34, (method B) RT ) 1.28. Anal. (C19H24N4O3‚
0.5H2O): C, H, N.
1
yield. H NMR (300 MHz, DMSO-d6) δ 1.86 (s, 9H), 2.00 (m,
3H), 2.28 (m, 1H), 2.57 (m, 1H), 2.74 (m, 1H), 3.63 (m, 1H), 3.83
(m, 3H), 4.98 (m, 3H), 5.71 (m, 1H), 8.10 (d, J ) 13.60 Hz, 1H),
8.87 (s, 1H), 15.29 (s, 1H).
3a-Allyl-10-tert-butyl-7-oxo-2,3,3a,4,7,10-hexahydro-1H-5-
oxa-10,11,11b-triaza-cyclopenta[a]anthracene-8-carboxylic Acid
(22c). Compound 22c was prepared from compound 22b according
to the general displacement conditions (0.5 mmol scale) in 82%
1
yield. H NMR (300 MHz, DMSO-d6) δ 1.65 (m, 1H), 1.90 (m,
9H), 2.20 (m, 5H), 3.59 (d, J ) 10.66 Hz, 1H), 3.79 (m, 2H), 4.55
(d, J ) 10.66 Hz, 1H), 5.15 (m, 2H), 5.88 (m, 1H), 7.65 (m, 1H),
8.79 (m, 1H), 15.81 (m, 1H); 13C (125 MHz, DMSO-d6) δ 21.0,
28.9, 31.5, 38.8, 46.9, 62.4, 65.3, 69.6, 106.4, 112.7, 113.8, 119.4,
133.1, 137.3, 142.8, 146.0, 146.6, 166.7, 175.7.
5-Methyl-7-oxo-1,2,3,3a,4,5,7,10-octahydro-5,10,11,11b-tetra-
azacyclopenta[a]anthracene-8-carboxylic Acid (24). In a 25-mL
flask, amine 24c (56 mg, 0.15 mmol) was dissolved in 3 mL of
TFA. A few drops of sulfuric acid was added. After 4 days, the
mixture was concentrated in vacuo. The crude mixture was
chromatographed on 10 g of SiO2 with 5-10% MeOH in CH2Cl2
to give a yellow film. The film was triturated and sonicated with
3a-Allyl-7-oxo-2,3,3a,4,7,10-hexahydro-1H-5-oxa-10,11,11b-
triazacyclopenta[a]anthracene-8-carboxylic Acid (22). Com-
pound 22 was prepared from compound 22c (0.14 mmol scale) in
49% yield according to the general procedure. 1H NMR (300 MHz,
DMSO-d6) δ 1.63 (m, 1H), 2.08 (m, 3H), 2.30 (m, 2H), 3.56 (d, J
) 11.03 Hz, 1H), 3.74 (m, 2H), 4.52 (d, J ) 11.03 Hz, 1H), 5.14
(m, 2H), 5.86 (m, 1H), 7.57 (s, 1H), 8.38 (d, J ) 6.62 Hz, 1H),
13.18 (d, J ) 6.62 Hz, 1H), 15.88 (s, 1H); 13C NMR (125 MHz,
DMSO-d6) δ 21.1, 31.5, 38.9, 46.6, 62.3, 69.5, 107.3, 110.7, 113.1,
1
Et2O and then with water to give the desired product (21%). H
NMR (500 MHz, DMSO-d6) δ 1.54 (m, 1H), 1.97 (m, 1H), 2.08
(m, 1H), 2.19 (m, 1H), 2.78 (m, 1H), 2.96 (s, 3H), 3.61 (dd, J )

NoVel Antibacterial Class: Tetracyclic DeriVatiVes
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 16 4855
11.60, 4.27 Hz, 1H), 3.68 (m, 2H), 3.85 (m, 1H), 7.08 (s, 1H),
8.28 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ 21.9, 29.3, 38.2,
46.1, 51.9, 55.6, 104.8, 107.2, 111.0, 131.5, 139.1, 144.1, 148.9,
166.6, 175.5.
7] (20 g, 81 mmol) was slurried in 50 mL of acetic anhydride,
treated with triethylorthoformate (15 mL, 90 mmoL), and heated
to reflux for 18 h. The mixture was cooled and concentrated in
vacuo to afford an oil. The oil (1.3 g, 4 mmol) was dissolved in 5
mL of CH2Cl2. The solution was treated with 3-aminopropionitrile
(312 mg, 4.5 mmol), stirred at room temperature for 1 h, and
concentrated in vacuo. The residue (1 g, 3 mmol) was dissolved in
20 mL of THF, cooled to 0 °C, treated with sodium hydride (130
mg, 60% in oil, 3.4 mmol), stirred for 15 h, quenched by the
addition of water, and filtered to afford the desired product (655
5-Acetyl-7-oxo-1,2,3,3a,4,5,7,10-octahydro-5,10,11,11b-tetra-
azacyclopenta[a]anthracene-8-carboxylic Acid (25). Amine 23
(47 mg, 0.16 mmol) was dissolved in 1.5 mL of DMF and treated
with acetic anhydride (100 µL, 1.1 mmol) and triethylamine (150
µL, 1.1 mmol). The mixture was stirred at room temperature for 2
h, at 100 °C for 2 h, and at room temperature for 2 days. The
reaction was quenched by the addition of water, and the mixture
was extracted with 30 mL of EtOAc. The organic phase was washed
with water and concentrated in vacuo. The crude material was
chromatographed (3-10% MeOH in CH2Cl2) to afford the desired
1
mg, 70% yield). H NMR (300 MHz, CDCl3) δ 1.41 (t, J ) 7.1
Hz, 3H), 3.00 (t, J ) 6.8 Hz, 2H), 4.40 (q, J ) 7.1 Hz, 2H), 4.52
(t, J ) 6.8 Hz, 2H), 7.40 (dd, J ) 11.0, 5.9 Hz, 1H), 8.31 (dd, J
) 10.2, 8.8 Hz, 1H), 8.58 (s, 1H).
1
product (6 mg, 11%). H NMR (500 MHz, DMSO-d6) δ 2.55 (m,
7-[(4-tert-Butoxycarbonyl)piperazin-1-yl]-1-(2-cyanoethyl)-6-
fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic Acid Ethyl Ester
(27b). Compound 27a (1.0 g, 3.3 mmol) was dissolved in 10 mL
of DMSO, treated with piperazine-1-carboxylic acid tert-butyl ester
(1.8 g, 9.8 mmol), heated to 90 °C for 18 h, cooled, diluted with
Et2O, and filtered to afford the desired product (1.33 g, 85% yield).
1H NMR (300 MHz, DMSO-d6) δ 1.28 (t, J ) 7.0 Hz, 3H), 1.43
(s, 9H), 3.13 (t, J ) 6.4 Hz, 2H), 3.22 (m, 4H), 3.52 (m, J ) 4.7
Hz, 4H), 4.23 (q, J ) 7.1 Hz, 2H), 4.72 (t, J ) 6.4 Hz, 2H), 7.11
(d, J ) 7.5 Hz, 1H), 7.81 (d, J ) 13.2 Hz, 1H), 8.68 (s, 1H).
7-[(4-tert-Butoxycarbonyl)piperazin-1-yl]-6-fluoro-4-oxo-1,4-
dihydroquinoline-3-carboxylic acid (27c). Compound 27b (1.3
g, 2.8 mmol) was slurried in 50 mL of ethanol, heated to 70 °C,
treated with 1 M aqueous lithium hydroxide (8 mL, 8 mmol), stirred
for 30 min, treated with more lithium hydroxide (8 mL, 8 mmol),
heated to reflux for 4 h, cooled, and concentrated. The residue was
suspended in EtOAc, washed with 1 N HCl and H2O, and
concentrated in vacuo to afford the product (1.0 g, 97% yield). 1H
NMR (300 MHz, DMSO-d6) δ 1.43 (s, 9H), 3.20 (m, 4H), 3.53
(m, 4H), 7.24 (d, J ) 7.5 Hz, 1H), 7.85 (d, J ) 13.6 Hz, 1H), 8.81
(s, 1H), 15.48 (s, 1H).
1H), 1.95 (m, 1H), 2.05 (m, 1H), 2.15 (m, 1H), 2.75 (t, 1H), 3.28
(s, 3H), 3.7 (m, 4H), 6.55 (s, 1H), 8.22 (s, 1H).
1-(2,4-Dimethoxybenzyl)-6-fluoro-4-oxo-7-[(S)-2-phenyl-
aminomethylpyrrolidin-1-yl]-1,4-dihydro-[1,8]naphthyridine-3-car-
boxylic Acid Ethyl Ester (26a). Compound 26a was prepared
according to the general procedure from chloride 10 and (S)-
phenylpyrrolidin-2-ylmethylamine (5.3 mmol scale) in 100% yield.
1H NMR (300 MHz, DMSO-d6) δ 1.26 (t, J ) 7.12 Hz, 3H), 1.99
(m, 4H), 3.07 (m, 1H), 3.23 (m, 1H), 3.63 (m, 1H), 3.68 (s, 3H),
3.76 (s, 3H), 3.84 (m, 1H), 4.19 (q, J ) 7.12 Hz, 2H), 4.63 (m,
1H), 5.39 (m, 2H), 5.63 (m, 1H), 6.38 (m, 1H), 6.52 (m, 4H), 6.99
(t, J ) 7.46 Hz, 2H), 7.09 (d, J ) 8.48 Hz, 1H), 7.86 (d, J ) 13.22
Hz, 1H), 8.60 (s, 1H). Anal. (C31H33FN4O5) C, H, N, F.
1-(2,4-Dimethoxybenzyl)-6-fluoro-4-oxo-7-[(S)-2-phenyl-
aminomethylpyrrolidin-1-yl]-1,4-dihydro-[1,8]naphthyridine-3-car-
boxylic Acid (26b). Acid 26b was prepared according to the general
procedure from ethyl ester 26a (5.3 mmol scale) in 90% yield. 1H
NMR (300 MHz, DMSO-d6) δ 2.02 (m, 4H), 3.12 (m, 1H), 3.26
(m, 1H), 3.70 (s, 3H), 3.74 (s, 3H), 3.87 (m, 1H), 4.67 (m, 1H),
5.51 (m, 2H), 5.67 (m, 1H), 6.49 (m, 5H), 6.99 (t, J ) 7.80 Hz,
3H), 7.13 (d, J ) 8.48 Hz, 1H), 7.97 (d, J ) 12.89 Hz, 1H), 8.77
(s, 1H), 15.42 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 26.9 (br),
27.6 (v br), 49.2, 49.2, 49.6, 55.2, 55.5, 59.0, 98.6, 104.8, 107.3,
110.9, 111.9, 115.1, 115.7, 117.62 (d, J ) 21 Hz), 128.8, 130.8,
145.7, 145.8 (d, J ) 257 Hz), 148.7, 158.4, 160.8, 165.9, 176.0.
Anal. (C29H29FN4O5) C (calcd 65.40, found 64.80), H, F, N.
10-(2,4-Dimethoxybenzyl)-7-oxo-5-phenyl-1,2,3,(S)-3a,4,5,7,10-
octahydro-5,10,11,11b-tetraazacyclopenta[a]anthracene-8-car-
boxylic Acid (26c). Amine 26b (1.0 g, 1.9 mmol) was dissolved
in 50 mL of DMF. To this solution was added sodium hydride
(230 mg, 60% in oil, 5.8 mmol), and the mixture was warmed to
100 °C for 16 h. The mixture was cooled and diluted with 150 mL
of H2O, and the pH was adjusted to 4 with 1 N HCl. A brown
precipitate formed and was collected by filtration. The crude
material was recrystallized from EtOAc to afford the desired product
6-Fluoro-4-oxo-7-piperazin-1-yl-1,4-dihydroquinoline-3-car-
boxylic Acid (27). Compound 27c (95 mg, 0.24 mmol) was slurried
in 3 mL of 4 N HCl in dioxane, stirred for 1 h, and then filtered to
1
afford 27 as the hydrochloride salt. H NMR (300 MHz, DMSO-
d6) δ 3.32 (m, 4H), 3.44 (m, 4H), 7.36 (d, J ) 7.8 Hz, 1H), 7.90
(d, J ) 12.9 Hz, 1H), 8.85 (d, J ) 6.8 Hz, 1H), 9.10 (s, 2H), 13.36
(d, J ) 7.1 Hz, 1H). Anal. (C14H15FN3O3) C, H, N.
1-Cyclopropyl-6-fluoro-7-(2-hydroxymethylpyrrolidin-1-yl)-
4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic Acid Ethyl
Ester (29a). 7-Chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-
[1,8]naphthyridine-3-carboxylic acid ethyl ester14 (1.0 g, 3.4 mmoL)
was slurried in 30 mL of acetonitrile, treated with (S)-2-hydroxy-
methylpyrrolidine (0.4 mL, 4.0 mmol) and i-Pr2EtN (1.7 mL, 9.8
mmol), stirred for 2 days, treated with (S)-2-hydroxymethyl-
pyrrolidine (0.1 mL, 1 mmol), stirred for 1 day, quenched by the
slow addition of 200 mL of H2O, and filtered to afford the product
as a white solid (1.06 g, 84% yield). 1H NMR (300 MHz, DMSO-
d6) δ 0.95 (m, 1H), 1.03 (m, 1H), 1.13 (m, 2H), 1.27 (t, J ) 7.1
Hz, 3H), 1.93 (m, 2H), 2.05 (m, 2H), 3.45 (m, 1H), 3.54 (m, 1H),
3.69 (m, J ) 8.1, 4.1 Hz, 2H), 3.84 (m, 1H), 4.20 (q, J ) 7.0 Hz,
2H), 4.43 (m, 1H), 4.78 (t, J ) 5.6 Hz, 1H), 7.82 (d, J ) 13.6 Hz,
1H), 8.35 (s, 1H).
1
(800 mg, 83%). H NMR (300 MHz, DMSO-d6) δ 1.59 (m, 1H),
2.01 (m, 1H), 2.17 (m, 2H), 3.32 (m, 1H), 3.74 (m, 2H), 3.74 (s,
3H), 3.78 (s, 3H), 3.92 (m, 2H), 5.55 (m, 2H), 6.55 (m, 2H), 7.27
(m, 5H), 7.49 (m, 2H), 8.76 (s, 1H); 13C NMR (75 MHz, DMSO-
d6) δ 24.5, 31.9, 49.9, 53.2, 54.6, 56.9, 57.1, 59.5, 100.6, 105.2,
106.9, 107.1, 111.9, 116.5, 127.2, 128.8, 132.4, 134.7, 135.2, 145.9,
146.7, 148.5, 152.5, 161.8, 164.4, 168.4, 172.2.
7-Oxo-5-phenyl-1,2,3,3a,4,5,7,10-octahydro-5,10,11,11b-tetra-
azacyclopenta[a]anthracene-8-carboxylic Acid (26). Compound
26 was prepared from 2,4-dimethoxybenzyl-protected 26c according
to the general procedure (0.86 mmol scale) in 60% yield. 1H NMR
(300 MHz, DMSO-d6) δ 1.60 (m, 1H), 2.08 (m, 3H), 3.27 (m, 1H),
3.71 (m, 2H), 3.92 (m, 2H), 7.19 (s, 1H), 7.26 (m, 1H), 7.34 (m,
2H), 7.50 (m, 2H), 8.29 (s, 1H), 13.05 (s, 1H); 13C NMR (75 MHz,
DMSO-d6) δ 21.9, 29.0, 46.2, 50.4, 55.9, 107.0, 108.8, 110.4, 123.7,
124.5, 129.0, 129.2, 139.7, 144.5, 144.9, 148.9, 166.0, 175.5. Anal.
(C19H18N4O3) C, H, N (calcd 15.46, found 14.84). HPLC (method
A) RT ) 1.82 min, (method B) RT ) 1.75.
1-Cyclopropyl-6-fluoro-7-(2-hydroxymethylpyrrolidin-1-yl)-
4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic Acid (29b).
Acid 29b was prepared according to the general procedure from
ethyl ester 29a (2.7 mmol scale) in 97% yield. 1H NMR (300 MHz,
DMSO-d6) δ 1.04 (m, 1H), 1.11 (m, 1H), 1.19 (m, 2H), 1.95 (m,
2H), 2.07 (m, 2H), 3.50 (m, 1H), 3.68 (m, 2H), 3.77 (m, J ) 8.0,
3.6 Hz, 1H), 3.88 (m, J ) 6.1 Hz, 1H), 4.48 (m, 1H), 4.82 (m,
1H), 7.97 (d, J ) 13.2 Hz, 1H), 8.56 (s, 1H), 15.40 (s, 1H). Anal.
(C17H18FN3O4‚0.65H2O) C, H, N.
10-Cyclopropyl-7-oxo-2,3,(S)-3a,4,7,10-hexahydro-1H-5-oxa-
10,11,11b-triazacyclopenta[a]anthracene-8-carboxylic Acid (29).
Compound 29 was prepared from 29b according to the general
1-(2-Cyanoethyl)-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-
carboxylic Acid Ethyl Ester (27a). Commercially available 3-oxo-
3-(2,4,5-trifluorophenyl)propionic acid ethyl ester [CAS 98349-24-
1
displacement conditions (1.5 mmol scale) in 84% yield. H NMR
(300 MHz, DMSO-d6) δ 1.09 (m, 2H), 1.17 (m, 2H), 1.57 (m, 1H),

4856 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 16
Hinman et al.
(6) Dandliker, P. J.; Pratt, S. D.; Nilius, A. M.; Black-Schaefer, C.; Ruan,
X.; Towne, D. L.; Clark, R. F.; Englund, E. E.; Wagner, R.;
Weitzberg, M.; Chovan, L. E.; Hickman, R. K.; Daly, M. M.;
Kakavas, S.; Zhong, P.; Cao, Z.; David, C. A.; Xuei, X.; Lerner, C.
G.; Soni, N. B.; Bui, M.; Shen, L. L.; Cai, Y.; Merta, P. J.; Saiki, A.
Y. C.; Beutel, B. A. Novel Antibacterial Class. Antimicrob. Agents
Chemother. 2003, 47, 3831-3839.
(7) Quinolone Antimicrobial Agents; Wolfson, J. S., Hooper, D. C., Eds.;
American Society for Microbiology: Washington, DC, 1989; pp
8-10.
(8) Albrecht, R. Development of Antibacterial Agents of the Nalidixic
Acid Type. Prog. Drug Res. 1977, 21, 9-104.
2.02 (m, 1H), 2.15 (m, 2H), 3.61 (m, 1H), 3.72 (m, 3H), 3.85 (m,
1H), 4.68 (dd, J ) 10.5, 3.7 Hz, 1H), 7.53 (s, 1H), 8.49 (s, 1H),
15.82 (s, 1H). Anal. (C17H17N3O4) C, H, N.
Supporting Information Available: Tabular listing of analyti-
cal procedures performed for target compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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JM060010W