Synthesis and structure-activity studies of antibacterial oxazolidinones containing dihydrothiopyran or dihydrothiazine C-rings

Article abstract of DOI:10.1016/j.bmcl.2006.03.104

A new series of antimicrobial oxazolidinones bearing unsaturated heterocyclic C-rings is described. Dihydrothiopyran derivatives were prepared from the saturated tetrahydrothiopyran sulfoxides via a Pummerer-rearrangement/elimination sequence. Two new syn

Full text of DOI:10.1016/j.bmcl.2006.03.104

Bioorganic & Medicinal Chemistry Letters 16 (2006) 3475–3478
Synthesis and structure–activity studies of antibacterial
oxazolidinones containing dihydrothiopyran
or dihydrothiazine C-rings
a
a
b
a
Adam R. Renslo,a, Gary W. Luehr, Stuart Lam, Neil E. Westlund, Marcela Gomez,
*
´
Corrine J. Hackbarth,a Dinesh V. Patela and Mikhail F. Gordeeva
aPfizer Global Research and Development, 34790 Ardentech Ct. Fremont, CA 94555, USA
bPfizer Global Research and Development, 2800 Plymouth Rd. Ann Arbor, MI 48105, USA
Received 15 March 2006; accepted 30 March 2006
Available online 27 April 2006
Abstract—A new series of antimicrobial oxazolidinones bearing unsaturated heterocyclic C-rings is described. Dihydrothiopyran
derivatives were prepared from the saturated tetrahydrothiopyran sulfoxides via a Pummerer-rearrangement/elimination sequence.
Two new synthetic approaches to the dihydrothiazine ring system were explored, the first involving a novel trifluoroacetylative-det-
rifluoroacetylative Pummerer-type reaction sequence and the second involving direct dehydrogenation of tetrahydrothiopyran S,S-
dioxide intermediates. Final analogs such as 4 and 13 represent oxidized congeners of recent pre-clinical and clinical oxazolidinones.
Ó 2006 Elsevier Ltd. All rights reserved.
The oxazolidinones, exemplified by linezolid, comprise a
promising new class of antibacterial protein synthesis
inhibitors with activity against methicillin-resistant
Staphylococcus aureus (MRSA) and Staphylococcus
epidermidis (MRSE).1 The clinical and commercial
success of linezolid has inspired the search for second-
generation oxazolidinones with improved antibacterial
potency and/or spectrum. Oxazolidinone analogs 1 and
2 exemplify this new generation of oxazolidinones and
have been the subject of pre-clinical and clinical studies.2
These new oxazolidinones substitute sulfur-containing
heterocycles for the morpholine ring of linezolid and,
in the case of 2, introduce an additional fluorine atom
in the B-ring.
Structure–activity studies of these new C-ring types
included the examination of oxidized congeners (i.e.,
analogs bearing dihydrothiopyran or dihydrothiazine
ring systems). We considered that these unsaturated
C-ring structures might confer improved activity against
fastidious Gram-negative bacteria as is often observed
for fully unsaturated (i.e., aromatic and heteroaromatic)
C-ring oxazolidinone analogs.3 Here, we describe the
synthesis and antibacterial activity of oxidized conge-
ners of 1 and 2, including a systematic exploration of
B-ring and C-5 SAR. We also report new synthetic
methods to access the dihydrothiazine ring system.
We prepared dihydrothiopyran and dihydrothiazine
ring systems from the saturated precursors using Pum-
merer-type reaction sequence (Schemes 1 and 2).4 The
synthesis of dihydrothiopyran analogs 4a–c began from
O
S
O
S
F
F
C Z
X
Z
X
O
O
O
O
B
N
N
O
S
A O
O
O
S
Y
Y
NHAc
NH
O
R
O
O
1
2
Z = CH
Z = N
PNU-141659 (X = H)
PNU-288034 (X = F)
a, b
Q
X
N
X
N
O
O
3a-c
4a-c
NHAc
NHAc
Keywords:
Antibacterials;
Oxazolidinones;
Dihydrothiazine;
a X, Y = H; b X = F; Y = H; c X, Y = F
Dihydrothiopyran.
*
Scheme 1. Reagents and conditions: (a) (CF3CO)2O, N-methylmor-
pholine, CH2Cl2, rt, 20 h; (b) AcOOH, THF, rt (60–80% overall).
Corresponding author. Tel.: +1 415 514 9698; fax: +1 415 514
4507; e-mail: adam.renslo@ucsf.edu
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.03.104

3476
A. R. Renslo et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3475–3478
O
S
CF3
O
S
O
S
Y
Y
Y
O
N
X
N
X
N
X
b, c
a
O
O
O
N
N
N
O
O
O
5a-b
6a-b
7a-c
NHBoc
NHBoc
NHBoc
e
O
S
O
S
F
F
O
O
d
N
F
N
F
O
O
N
O
N
O
H
H
8
9
Scheme 2. Reagents and conditions: (a) (CF3CO)2O, N-methylmorpholine, CH2Cl2, rt; (b) mCPBA, CH2Cl2; (c) K2CO3, MeOH, CH3CN, reflux
(30–45% for three steps); (d) DDQ, dioxane, reflux, 22 h (35%); (e) 2.5 equiv LiOt-Bu, 1.3 equiv (S)-ClCH2CH(OH)CH2NHBoc, DMF (71%).
the sulfoxide analogs 3a–c, which were prepared as
described elsewhere.5 Reaction of 3a–c with trifluoro-
acetic anhydride in the presence of N-methylmorpholine
produced the dihydrothiopyran ring system in a single
step. This conversion presumably proceeds via initial
Pummerer rearrangement followed by elimination of
trifluoroacetic acid from the a-trifluoroacetoxy sulfide
intermediate.6 Oxidation with peracetic acid in THF
then provided sulfone analogs 4a–c. When thiomorpho-
line sulfoxide analogs 5a–b5 were subjected to similar
reaction conditions, the unexpected trifluoroacetyl-
substituted compounds 6a–b were obtained (Scheme 2).
In this case, the initially formed dihydrothiazine interme-
diate reacts with excess trifluoroacetic anhydride in the
reaction mixture, thus generating 6a–b. The trifluoroace-
tyl group in 6a–b could be removed under surprisingly
mild conditions (K2CO3 in refluxing MeOH–MeCN). A
final oxidation step then provided the desired dihydrothi-
azine S,S-dioxide intermediates 7a–b. For the bis-fluoro
B-ring series (i.e., 7c) an alternative protocol was em-
ployed. Thiomorpholine intermediate 85 was oxidized
with DDQ in refluxing dioxane to afford the dihydrothi-
azine 9 directly in modest yield along with recovered 8.
This protocol was only effective with bis-fluorinated inter-
mediates such as 8. The desired bis-fluoro oxazolidinone
intermediate 7c was prepared from 9 using established
procedures.7
12a–k bearing dichloroacetamide, difluoroacetamide,
or difluorothioacetamide8 functionality at C-5.
The synthesis of dihydrothiazine analogs 13a–k pro-
ceeded similarly, starting from Boc-protected amino-
methyl oxazolidinones 7a–c. Removal of the Boc
group in 7a–c was accomplished with TMSOTf in
2,6-lutidine,9 after we discovered that the dihydrothi-
azine ring in 7a–c was sensitive to typical acidic Boc
cleavage conditions. The resulting amines 11a–c were
then converted to dihydrothiazine analogs 13a–k as de-
scribed above for 12a–k (Scheme 3).
The new oxazolidinone analogs were tested against a
panel of Gram-positive and fastidious Gram-negative
bacteria. Minimum inhibitory concentration (MIC, in
lg/mL) values were determined using standard broth
microdilution methods.10 The activities of dihydrothio-
pyran analogs are summarized in Table 1 and those for
the dihydrothiazine analogs are presented in Table 2.
MIC data for the progenitor analogs 1 and 2 are provided
for comparison.
The in vitro activity of dihydrothiopyran analogs was
similar to that of the parent tetrahydrothiopyran analog
1. The acetamides 4a–c had similar Gram-positive activity
as 1 but were generally less active against the Gram-
negative pathogen Haemophilus influenzae. Surprisingly,
the degree of B-ring fluorination had little impact on
overall potency, although a mono-fluoro B-ring does
appear optimal for activity against H. influenzae and
Moraxella catarrhalis. Among the C-5 side chains exam-
ined, the dichloroacetamide variant (e.g., 12a, 12e, and
12i) consistently produced the bestGram-negative activity,
The synthesis of analogs of various C-5 side-chain type
was accomplished as shown in Scheme 3, starting from
compounds 4a–c or 7a–c. The C-5 acetamide in 4a–c
was cleaved via acid hydrolysis and the resulting amines
10a–c acylated with anhydride or ester reagents. This
two-step protocol provided dihydrothiopyran analogs
O
S
O
S
O
S
Y
Y
Y
O
O
O
Z
X
Z
X
Z
X
a
b or c
O
O
O
N
N
N
O
O
O
NH2
12a-k
13a-k
NH
4a-c
NH
Z = CH
Z = N
10a-c
11a-c
Z = CH; R = CH3
7a-c Z = N; R = Ot-Bu
Z = CH
Z = N
R
R
Q
O
R = CH3, CHF2, CHCl2
Q = O, S
a X, Y = H; b X = F; Y = H; c X, Y = F
Scheme 3. Reagents and conditions: (a) for 4a–c: HCl, MeOH, 75 °C, 20 h; for 7a–c: TMS-OTf, 2,6-lutidine, CH2Cl2, rt, 1 h, then MeOH, 30 min;
(b) (RC@O)2O, Py, CH2Cl2 (80% overall); (c) CHF2C(O)OEt or Ph2CHCH2CH2OC(S)CHF2, Et3N, MeOH (40–80% overall).

A. R. Renslo et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3475–3478
3477
Table 1. Minimum inhibitory concentrations (MICs, lg/mL) for dihydrothiopyran analogs 4a–c and 12a–k against Gram-positive and fastidious
Gram-negative bacteriaa
Compound
X
Y
R
Q
S. a. MIC
S. p. MIC
E. f. MIC
H. i. MIC
M. c. MIC
—
Linezolid
PNU-141659
CH3
4
1
4
2
4
2
4
2
2
2
2
1
2
2
2
2
16
8
1
4a
2–4
4–8
2–4
4–8
2–4
4
0.5
1–2
0.5
1
4–8
8–16
4
2–4
8
H
H
H
H
H
H
H
H
F
H
H
H
H
F
F
F
F
F
F
F
F
O
O
O
S
12a
12b
12c
4b
CHCl2
CHCF2
CHCF2
CH3
4
8–16
8–16
8
4–8
4
0.5–1
1
O
O
O
S
2
12e
12f
12g
4c
CHCl2
CHCF2
CHCF2
CH3
2–4
2–4
2
0.5
1
4
2–4
4–8
2–4
8
4–8
8–16
8–16
8
0.5
1
O
O
O
S
4
12i
12j
12k
F
CHCl2
CHCF2
CHCF2
2
0.5–1
1
0.5
4
F
2
1–2
8–16
16
8
F
4
a Strains: S. a. Staphylococcus aureus UC12673, UC9213, ATCC29213, and UC9271; S. p. Streptococcus pneumoniae ATCC6305 and 31573; E. f.
Enterococcus faecium UC12712, vancomycin-resistant; H. i. Haemophilus influenzae 30063 and ATCC31517; M. c. Moraxella catarrhalis 30607 and
30603.
Table 2. Minimum inhibitory concentrations (MICs, lg/mL) for dihydrothiazine analogs 13a–k against Gram-positive and fastidious Gram-negative
bacteriaa
Compound
X
Y
R
Q
S. a. MIC
S. p. MIC
E. f. MIC
H. i. MIC
M. c. MIC
—
2
Linezolid
PNU-288034
CHCl2
4
1
4
16
8
2
1
2
4–8
2–4
8–16
4–8
4
4
13a
13b
13c
13d
13e
13f
13g
13h
13i
13j
13k
H
H
H
H
H
H
H
F
H
H
H
F
F
F
F
F
F
F
F
O
O
S
4
0.5–1
1
0.5
2
2–4
4–8
4–8
2–4
2–4
4
CHCF2
CHCF2
CH3
4–8
2
2
1
O
O
O
S
4
0.5
0.5
2
CHCl2
2–4
4
1–2
2
2–4
4
CHCF2
CHCF2
CH3
0.5–1
0.5
1–2
2–4
4
1
4
4–8
4–8
4
O
O
O
S
0.5–1
0.5–1
0.5–1
0.25
1–2
1
8
F
CHCl2
CHCF2
CHCF2
4–8
4–8
4–8
F
4
1–2
1
0.25
4
2–4
F
a Strains: see Table 1.
while retaining good activity against the rest of the panel.
The novel C-5 difluorothioacetamide analogs 12c, 12g,
and 12k exhibited excellent activity against the Gram-posi-
tive strains, although H. influenzae activity suffered
somewhat.
In summary, novel oxazolidinones featuring dihydrothi-
opyran and dihydrothiazine heterocyclic C-rings were
prepared and evaluated for antimicrobial activity.
En route to the dihydrothiazine derivatives, two new
synthetic approaches to this unusual heterocyclic ring
system were explored. These novel unsaturated C-ring
analogs exhibit in vitro antibacterial activity similar
and in some cases superior to that of fully saturated pro-
genitors 1 and 2, and of linezolid. More notable
improvements in potency and spectrum can be realized
through the introduction of various halogenated amide
and thioamide C-5 side-chain moieties.
Dihydrothiazine analogs 13a–k displayed antibacterial
activity comparable or slightly better than the thiomorph-
oline progenitor 2 (Table 2). In comparison to dihydrothi-
opyrans 12a–k, the dihydrothiazine analogs 13a–k were
somewhat more potent in general, and in particular
against H. influenzae strains. The mono-fluoro B-ring
type was optimal with respect to both activity and
spectrum. As in the dihydrothiopyran series, the dichloro-
acetamide side chain provided the best Gram-negative
activity (13a, 13e, and 13i), while the difluorothioaceta-
mide C-5 moiety conferred excellent Gram-positive
activity. For example, the difluorothioacetamide analog
13k was 4- to 8-fold more potent than the saturated
thiomorpholine analog 2 against Streptococcus pneumo-
niae and Enterococcus faecium strains. In total,
five dihydrothiazine analogs displayed improved
Gram-negative activity as compared to the thiomorpho-
line oxazolidinone PNU-288034 (2).
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