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A. J. Cocuzza et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1389–1392
The difficulty in separating the 3-alkyl-4,1-benzox-
azepinone diastereomers led us to investigate a stereo-
selective synthesis. By carefully monitoring the sodium
hydride-mediated cyclization reaction depicted in
Scheme 2 by TLC and NMR we found that one dia-
stereomeric 2-bromoamide 7 cyclized much faster than
the other. If the reaction was not allowed to proceed to
completion the more potent benzoxazepinone 1f, in
which the 3-methyl is cis to the 5-trifluoromethyl group,
formed in preference to the trans isomer 1g. Since this
strategy could at best afford a 50% yield of 1f, we
sought reaction conditions which would promote the
conversion of both diastereomeric bromoamides 7 into
the desired cis-benzoxazepinone 1f. In particular, reac-
tion conditions which caused the two diastereomeric
bromoamides to interconvert at a rate faster than the
cyclization step could funnel both bromoamide inter-
mediates into the desired cis isomer. Such a fast inter-
conversion of haloamides could possibly be effected by
tandem SN2 reactions promoted by the addition of
excess bromide or iodide. 2-Bromopropionamide 7 was
subjected to a number of such conditions, one of which
proved particularly effective in promoting a diastereo-
selective transformation. Treatment of 7 with cesium
carbonate (1.5 equiv) and lithium iodide (2 equiv) in
DMF at room temperature afforded a 93:7 ratio of the
cis-benzoxazepinone 1f to the trans-benzoxazepinone
1g.11 The structure of 1f was confirmed by X-ray crys-
tallography, while the relative stereochemistry of later
analogues could be determined by the 19F NMR reso-
nance of the trifluoromethyl group (À79 d for the cis-
benzoxazepinones, À74.5 d for the trans in CDCl3). The
procedures described above were used to synthesize a
number of 3-alkylbenzoxazepinones. The sodium
hydride cyclization procedure was initially used to pre-
pare mixtures of the two diastereomeric 3-alkyl-ben-
zoxazepinones, and once the trans isomers were found
less potent, the cesium carbonate/lithium iodide cycli-
zation conditions were used to prepare stereoselectively
the cis-4,1-benzoxazepinones (Table 1).
The ability of 4,1-benzoxazepinones to inhibit HIV-1
reverse transcriptase in an in vitro enzyme assay
(enzyme IC50) and to inhibit the wild-type RF strain of
HIV-1 (wild-type IC90) in a whole cell assay is repre-
sented in Table 1. In addition, most compounds were
examined for their ability to inhibit a virus containing
the clinically relevant K103N mutation (K103N IC90).
Aromatic substitutions which had proven optimal in
other series were investigated and compounds with
potent activity were found in 7-chloro, 7-fluoro, and
6,7-difluoro substituted compounds. Compounds in
which the acetylene or olefin side chain was terminally
substituted with ethyl, isopropyl, or cyclopropyl groups
(1b, 1c, and 1e) were potent antivirals, however, acet-
ylenes substituted with larger phenyl (1a) or 3-furanyl
(1d) groups resulted in some loss of activity. 3-Unsub-
stituted benzoxazepinones 1b, 1c, 1e, and 2e demon-
strated potency against wild-type virus, but their ability
to inhibit replication of the K103N mutant was poor.
When a 3-methyl or 3-ethyl group was introduced cis to
the trifluoromethyl group, benzoxazepinones with
potent antiviral activity against both wild-type and the
K103N mutant viruses were obtained. The antiviral
potency of 1f, 2f, and 2h is comparable to quinazoli-
nones DPC 961 and DPC 083. The introduction of lar-
ger 3-alkyl groups (1i, 1j, and 1k) resulted in some loss
of wild-type activity. When compared to their cis-ste-
reoisomers, benzoxazepinones in which the 3-alkyl is
trans to the trifluoromethyl group suffered loss in wild-
type or K103N potency. For example, 1g exhibited far
less potency against the mutant virus than its isomer
1f.15
Scheme 1. Reagents and conditions: (a) n-BuLi, alkylacetylene, THF,
0 ꢀC, 15 min; (b) LAH, THF, rt, 16 h; (c) concd HCl, MeOH, rt, 30
min; (d) 2-bromoacyl bromide, pyridine, ether, 1 h; (e) NaH, DMF, rt,
3–24 h.
Two benzoxazepinone NNRTIs, acetylene 1f and its
olefin analogue 2f were selected for in vivo evaluation.
Rhesus monkeys were given either a single oral 10 mg/kg
Scheme 2.
Cocuzza, Anthony J.
