Stereodivergent synthesis of sulfoxide-containing oxazolidinone antibiotics

Article abstract of DOI:10.1016/S0040-4039(00)00631-6

Carbamate 5 was prepared under mild conditions via a novel metal-halogen exchange procedure without competing benzyne formation. Selection of an appropriate oxidation/reduction sequence afforded access to either the cis- or trans-1-oxo-4-aryltetrahydrothi

Full text of DOI:10.1016/S0040-4039(00)00631-6

Tetrahedron Letters 41 (2000) 4301±4305
Stereodivergent synthesis of sulfoxide-containing
oxazolidinone antibiotics
James R. Gage,* William R. Perrault, Toni-Jo Poel and Richard C. Thomas
Pharmacia & Upjohn, Inc., 7000 Portage Rd, Kalamazoo, MI 49001, USA
Received 13 March 2000; revised 4 April 2000; accepted 5 April 2000
Abstract
Carbamate 5 was prepared under mild conditions via a novel metal±halogen exchange procedure without
competing benzyne formation. Selection of an appropriate oxidation/reduction sequence a€orded access to
either the cis- or trans-1-oxo-4-aryltetrahydrothiopyran system, important intermediates in the synthesis of
a new class of oxazolidinone antibiotics. # 2000 Elsevier Science Ltd. All rights reserved.
Oxazolidinones are a new class of synthetic antibacterial agents having activity against impor-
tant human pathogens including S. aureus, S. pneumoniae, E. faecalis, and H. in¯uenzae.1 Sig-
ni®cantly, these new agents show activity against multiple-drug resistant strains of the Gram-
positive organisms. A New Drug Application has been ®led with the US FDA for linezolid, the
lead development compound, for treatment of respiratory tract, skin, and soft tissue infections.
Recently, we had occasion to prepare some 1-oxo-4-aryltetrahydrothiopyran-substituted oxa-
zolidinones represented by structures 1 and 2 (Scheme 1). The major synthetic challenges involved
in approaching these compounds were ecient construction of the carbon±carbon bond linking
the ¯uorinated aromatic ring to the sulfur heterocycle and control of the stereochemistry at sulfur
to obtain either the cis or trans sulfoxide relative to the aromatic linker. Solutions to both problems
are described below.
Scheme 1.
* Corresponding author. Fax: 616-833-9282; e-mail: james.r.gage@am.pnu.com
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00631-6

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3-Fluoroaniline was chosen as the starting material (Scheme 2). Acylation with isobutyl-
chloroformate under Schotten±Baumann conditions proceeded smoothly. The carbamate solution
was reacted without puri®cation with 1,3-dibromo-5,5-dimethylhydantoin to give an 87:13
mixture of carbamate 3 and a regioisomer derived from bromination para to the ¯uorine.2 Pure 3
was obtained following crystallization from heptane. Because lithium/halogen exchange reactions
are often times fast enough to su€er reprotonation by unreacted acidic functional groups,3 3 was
normally treated with a base to deprotonate the carbamate moiety before addition of butyl-
lithium. In the course of reaction optimization, it was found that the o-¯uoroarylmetal inter-
mediate was stable to relatively high temperatures when magnesium was chosen as the counterion
to the base. The stability toward decomposition via a benzyne pathway presumably stemmed
from transmetallation of the initially formed aryllithium with the magnesium carbamate. In the
optimized procedure, a solution of 3 in THF at ^20ꢀC was treated ®rst with EtMgBr and then
nBuLi. The resulting solution was treated with a slurry of MgBrCl (conveniently prepared from
EtMgBr and TMSCl)4 before reacting with ketone 4 to obtain the tertiary alcohol 5 in high
yield.5 The added magnesium salt helped to suppress undesired enolization of ketone 4.
Scheme 2. Reagents and conditions: (a) isobutylchloroformate, K2CO3, CH2Cl2/water, 1,3-dibromo-5,5-dimethyl-
hydantoin; (b) EtMgBr, n-BuLi, MgBrCl, THF, then 4; (c) TFA, CH2Cl2, NaIO4, MeOH/water; (d) 5% Pt/C, H2,
DMF; (e) (Me3Si)2O, PMHS, pTSA, toluene; (f) Ti(OiPr)4, d-diisopropyl tartrate, tBuOOH, CH2Cl2
With the key bond in hand, attention was turned next to elaborating the tetrahydrothiopyran.
Alcohol 5 was readily dehydrated by treatment with tri¯uoroacetic acid. Oxidation with NaIO4
a€orded sulfoxide 7. Remarkably, Pt/C-catalyzed hydrogenation gave exclusively the cis-sulfoxide
8 in which hydrogen had been added to the face opposite the oxygen atom. Palladium catalysts
reacted with the same stereoselectivity but with unsatisfactory chemoselectivity; deoxygenation of
the sulfoxide competed with saturation of the alkene, thereby amplifying a catalyst deactivation
problem as well.6 No conditions were found for the reduction of 7 to the trans-sulfoxide 10.
In order to obtain access to compounds in the trans series, recourse was made to selective oxidation
of the saturated tetrahydrothiopyran, an avenue pioneered by Johnson in 1965.7 Tertiary alcohol
5 was subjected to a silane reduction using poly(methylhydrosiloxane) (PMHS) as the hydride
donor to a€ord 9, the oxidation substrate. Under these conditions, a very fast elimination to the

4303
alkene 6 is followed by a slower reduction step. Of the various oxidants surveyed in the Johnson
paper, the highest selectivity for trans-1-oxo-4-aryltetrahydrothiopyrans was obtained using
ozone. Unfortunately, in our hands the yield of the desired sulfoxide was unacceptably low due to
competing overoxidation to the sulfone 11. Better, more reproducible results were obtained by
the application of Kagan's conditions for asymmetric oxidation of sul®des.8 Thus, reaction with
t-butylhydroperoxide, Ti(OiPr)4, and diisopropyl d-tartrate in CH2Cl2 at ^20ꢀC a€orded 8, 10,
and 11 in yields (HPLC) of 17.9, 77.5, and 1.3%, respectively. Trans-sulfoxide 10 was still the
major product at 71.5% without the chiral tartrate ligand.9 It was isolated in sucient purity for
use in the subsequent chemistry by a single crystallization from methanol. Although about 6% of
the cis diastereomer 8 was present at this stage as an impurity, the level could be reduced if
desired to less than 1% by one or more high-yielding recrystallizations from ethyl acetate.
Both 8 and 10 were converted to their respective end targets by the application of chemistry
developed for the synthesis of linezolid (Scheme 3).10 Thus, carbamate lithiation and reaction
with glycidol generated in situ from (S)-3-chloro-1,2-propanediol a€orded the oxazolidinone
alcohols 12 and 14. Sulfonylation proceeded smoothly in both series. Because the m-nitobenzene
sulfonate in the cis series was an oil, the crystalline 2,5-dichlorobenzene sulfonate was prepared
instead as a suitably activated substrate for the next reaction. Ammonolysis followed by acylation
of the intermediate amines gave 1 and 2.11 It is important to note that no equilibration of
sulfoxide diastereomers or other unwanted sulfoxide chemistry occurred during this sequence.
Scheme 3. Reagents and conditions: (a) lithium t-amylate, (S)-3-chloro-1,2-propanediol, DMF; (b) 2,5-dichloro-
benzenesulfonyl chloride, Et3N, CH2Cl2; (c) NH4OH, MeOH, CH3CN, Ac2O; (d) 3-nitrobenzenesulfonyl chloride,
Et3N, CH2Cl2; (e) NH4OH, MeOH, CH3CN, propionic anhydride
In conclusion, a versatile synthesis of 1-oxo-4-aryltetrahydrothiopyran-substituted oxazolidinones
has been developed. Key features are a robust method to form the carbon±carbon bond between
rings via a Mg/Li dianion and the ability to access the diastereomeric sulfoxides by choosing an
appropriate oxidation/reduction sequence.
References
1. Brickner, S. J.; Hutchinson, D. K.; Barbachyn, M. R.; Manninen, P. R.; Ulanowicz, D. A.; Garmon, S. A.; Grega,
K. C.; Hendges, S. K.; Toops, D. S.; Ford, C. W.; Zurenko, G. E. J. Med. Chem. 1996, 39, 673±679.
2. Gray, G. W.; Hird, M.; Toyne, K. J. Mol. Cryst. Liq. Cryst. 1991, 204, 43±64.
3. Beak, P.; Musick, T. J.; Chen, C. W. J. Am. Chem. Soc. 1988, 110, 3538±3542.

4304
4. Sommer, L. H.; Kerr, G. T.; Whitmore, F. C. J. Am. Chem. Soc. 1948, 70, 434±435.
5. To EtMgBr (348.13 mmol, 1.18 equiv. in THF (530 ml) was added chlorotrimethylsilane (35.4 g, 325.85 mmol,
1.11 equiv.) with an exotherm from 22 to 43ꢀC. The resultant MgBrCl solution was then cooled to give a slurry at
^30ꢀC. To a solution of 3 (85.00 g, 292.97 mmol) and 1,10-phenanthroline monohydrate (0.580 g, 2.93 mmol,
0.010 equiv.) in TMEDA (103.76 g, 892.9 mmol, 3.05 equiv.) and THF (1.15 l) was added EtMgBr in THF (243.2
g at 1.36 mol; 332 mmol; 1.13 equiv.) to the colorless to pink endpoint. The resultant solution was cooled to ^26ꢀC
and butyllithium in hexane (163 g at 23.8 wt%, 590 mmol, 2.01 equiv.) was added over 1.5 h while maintaining ^26
to ^23ꢀC. The MgBrCl slurry was added to the resultant dianion slurry while maintaining ^25 to ^19ꢀC. A
solution of tetrahydrothiopyran-4-one (44.39 g, 382 mmol, 1.30 equiv.) in THF (252 ml) was then added while
maintaining ^26 to ^23ꢀC. The reaction solution was then added to a solution of acetic acid (115 g, 1.92 mol, 6.54
equiv.) in water (570 ml) while maintaining 0 to 10ꢀC. The phases were separated and the lower aqueous phase was
back extracted with a mixture of MTBE (568 ml) and branched octanes (220 ml). The organics were washed with a
mixture composed of aqueous ammonia (29.3 wt%, 43 g), ammonium chloride (43 g), and water (570 ml) and then
washed with water (570 ml). The organics were combined and concentrated in vacuo to 1500 ml. A constant
volume vacuum distillation was then performed while maintaining 1500 ml and adding branched octanes (3000
ml). Branched octanes (400 ml) were added and the slurry cooled to 3ꢀC. The product was collected by vacuum
®ltration, washed with 3ꢀC branched octanes (570 ml) and dried in a nitrogen stream to a€ord a white solid, 5
(86.20 g, 89.9%).
6. Other heterogeneous catalyst systems based on ruthenium, cobalt, or nickel all failed to react with the desired
chemoselectivity if at all. No reaction was observed with diimide, and deoxygenation predominated with silanes.
7. Johnson, C. J.; McCants Jr., D. J. Am. Chem. Soc. 1965, 87, 1109^1114.
8. Zhao, S. H.; Samuel, O.; Kagan, H. B. Tetrahedron 1987, 43, 5135±5144.
9. A trend toward equatorial attack (leading to the trans product) and decreasing reaction rate was observed with
increasing steric demand of the oxidant. In practice, the conditions reported here a€orded the most acceptable
trade-o€ between the two.
10. Pearlman, B. A.; Perrault, W. R.; Barbachyn, M. R.; Manninen, P. R.; Toops, D. S.; Houser, D. J.; Fleck, T. J.
PCT Int. Appl. WO 9737980 A1, 1997.
11. Compound 3: 1H NMR (CDCl3, 400 MHz) ꢀ 7.41 (2H, J=8.4), 6.96 (1H, J=2.0, 8.4), 6.87 (1H), 3.96 (2H,
J=6.4), 1.97 (1H, J=13.5), 0.96 (6H, J=6.6); 13C NMR (CDCl3, 75 MHz) ꢀ 159.2 (JC F=245.5), 153.4, 139.0
(JC F=10.1), 133.3, 115.1, 107.1 (JC F=28.2), 102.0 (JC F=21.1), 71.8, 27.9, 19.0; anal calcd for C11H13BrFNO2:
1
C, 45.54; H, 4.52; N, 4.83; found: C, 45.40; H, 4.54; N, 4.86. Compound 5: H NMR (CDCl3, 400 MHz) ꢀ 7.38
(1H, J=8.8), 7.32 (1H, J=14.4), 7.00 (1H, J=1.6, 8.4), 6.74 (1H), 3.96 (2H, J=6.4), 3.23 (2H, J=12.8), 2.44 (2H,
J=14.0), 2.37 (2H, J=3.6, 13.6), 2.05 (2H, J=14.4), 1.96 (1H, J=6.8), 0.96 (6H, J=6.8); 13C NMR (CDCl3, 100
MHz) ꢀ 160.3 (JC F=243.0), 153.5, 138.7 (JC
(JC F=29.4), 71.6, 71.2 (JC F=4.0), 37.7, 37.6, 27.9, 23.9, 19.0; anal calcd for C16H22FNO3S: C, 58.69; H, 6.77;
=12.0), 129.9 (JC F=44), 126.7 (JC F=6), 113.8, 107.0
F
1
N, 4.28; found: C, 58.39; H, 6.68; N, 4.27. Compound 8: H NMR (DMSO-d6, 500 MHz) ꢀ 9.76 (1H), 7.35 (1H,
J=13), 7.26±7.20 (2H), 3.88 (2H, J=6.6), 3.31 (1H), 3.02±2.89 (3H), 2.81 (2H, J=14), 2.51 (1H), 2.33 (2H,
J=13), 1.92 (1H, J=6.7), 1.66 (2H, J=12), 0.93 (2H, J=6.7); 13C NMR (DMSO-d6, 125 MHz) ꢀ 159.5
(JC F=241), 153.5, 139.0 (JC F=11) 127.7 (JC F=6.3), 125.8 (JC F=15), 114.1, 105.0 (JC F=29), 70.1, 44.9,
34.2, 27.5, 21.3, 18.8; anal calcd for C16H22FNO3S: C, 58.69; H, 6.77; N, 4.28; found: C, 58.56; H, 6.59; N, 4.19.
Compound 10: 1H NMR (DMSO-d6, 400 MHz) ꢀ 9.88 (1H), 7.44 (1H, J=12.8), 7.38±7.27 (2H), 3.98 (2H, J=6.6),
3.49±3.41 (2H), 3.14±3.08 (1H), 2.90 (1H, J=11.0), 2.62 (2H), 2.10±1.91 (5H), 1.04 (6H, J=6.7); 13C NMR
(DMSO-d6, 100 MHz) ꢀ 160.0 (JC F=241.1), 153.9, 143.5, 128.4 (JC F=6.0), 124.8 (JC F=15.1), 114.4, 105.4
(JC F=27.2), 70.6, 51.5, 34.6, 29.1, 27.9, 19.2; anal calcd for C16H22FNO3S: C, 58.69; H, 6.77; N, 4.28; found: C,
58.46; H, 6.83; N, 4.23. Compound 12: 1H NMR (DMSO-d6, 500 MHz) ꢀ 7.51 (1H, J=2.0, 13.2), 7.36 (1H,
J=8.5), 7.30 (1H, J=2.1, 8.6), 5.21 (1H, J=5.6), 4.71 (1H, J=3.5, 9.3), 4.08 (1H, J=9.0), 3.83 (1H, J=6.2, 8.8),
3.69±3.66 (1H), 3.59±3.56 (1H), 3.05 (1H, J=12.5), 2.95 (2H, J=12.4), 2.82 (2H, J=13.4), 2.51 (1H), 2.35 (2H,
J=12.9), 1.68 (2H, J=12.0); 13C NMR (DMSO-d6, 125 MHz) ꢀ 159.5 (JC F=241), 154.3, 138.2 (JC F=11.3),
127.9 (JC F=6.3), 126.9 (J=15.1), 113.6, 104.9 (J=28), 73.2, 61.6, 45.9, 44.8, 34.2, 21.3, 21.3; anal calcd for
C15H18FNO4S: C, 55.03; H, 5.54; N, 4.28; found: C, 55.01; H, 5.57; N, 4.36. Compound 13: 1H NMR (DMSO-d6,
400 MHz) ꢀ 8.03 (1H, J=2.4), 7.88 (1H, J=2.4, 8.4), 7.79 (1H, J=8.4), 7.44 (1H, J=1.2, 13.2), 7.37 (1H, J=8.4),
7.23 (1H, J=2.4, 8.8), 4.99±4.96 (1H), 4.56±4.49 (2H), 4.16 (1H, J=9.6), 3.77 (1H, J=6.0, 9.2), 3.06 (1H,
J=12.0), 2.96 (2H, J=12.8), 2.83 (2H, J=2.8, 13.6), 2.51 (1H, J=1.6), 2.36 (2H, J=12.0), 1.69 (2H, J=12.0);
13C NMR (DMSO-d6, 100 MHz) ꢀ 159.5 (JC F=242.5), 153.3, 137.7 (JC F=12.1), 135.6, 134.1 (JC F=17), 134.0,

4305
132.5, 130.8, 130.3, 128.0 (JC F=7.0), 127.3 (JC F=15.1), 113.8, 105.1 (JC F=29.2), 71.6, 69.7, 45.6, 44.8, 34.2,
21.3; anal calcd for C21H20Cl2FNO6S2: C, 47.02; H, 3.76; N, 2.61; found: C, 46.90; H, 3.55; N, 2.77. Compound
14: 1H NMR (DMSO-d6, 400 MHz) ꢀ 7.69 (1H, J=2.2, 13.3), 7.54 (1H, J=8.6), 7.47 (1H, J=2.2, 8.6), 5.40 (1H,
J=5.5), 4.26 (1H, J=9.0), 4.01 (1H, J=6.2, 8.9), 3.89±3.85 (1H), 3.78±3.74 (1H), 3.59±3.56 (2H), 3.54 (1H), 3.25±
3.22 (1H), 3.01 (2H, J=10.8), 2.71 (1H, J=1.7), 2.20 (2H, J=12.8), 2.08 (2H, J=13.0); 13C NMR (DMSO-d6, 100
MHz) ꢀ 160.1 (JC F=242.5), 154.7, 138.7 (JC F=12.1), 128.6 (JC F=6.0), 125.9 (JC F=14.1), 113.9 (JC F=2.0),
105.3 (JC F=28.2), 73.6, 62.0, 51.4, 46.3, 34.6, 29.0; anal calcd for C15H18FNO4S: C, 55.03; H, 5.54; N, 4.28;
found: C, 54.95; H, 5.56; N, 4.32. Compound 15: 1H NMR (DMSO-d6, 400 MHz) ꢀ 8.82 (1H, J=8.2), 8.75 (1H),
8.57 (1H, J=7.9), 8.19 (1H, J=8.1), 7.61 (1H, J=10.5), 7.53 (1H, J=8.6), 7.38±7.32 (1H), 4.76±4.68 (2H), 4.31
(1H, J=9.4), 3.91 (1H, J=5.9, 9.2), 3.58 (2H, J=11.6), 3.55 (1H), 3.25 (1H, J=11.9), 3.01 (2H, J=12.2), 2.71
(1H), 2.21 (2H, J=13.2), 2.08 (2H, J=13.0); 13C NMR (DMSO-d6, 100 MHz) ꢀ 160.0 (JC F=242.5), 153.7, 148.4,
138.1 (JC F=11.1), 136.6, 133.9, 132.3, 129.4, 126.3 (JC F=15.1), 1223.0, 114.0, 105.5 (JC F=29.2), 71.7, 70.1,
51.4, 46.0, 34.6, 29.0; anal calcd for C21H21FN2O8S2: C, 49.21; H, 4.13; N, 5.47; found: C, 48.98; H, 4.05; N, 5.44.
Compound 1: 1H NMR (CDCl3, 400 MHz) ꢀ 7.45 (1H, J=2.0, 12.4), 7.29 (1H, J=8.4), 7.15±7.11 (2H), 4.83±4.78
(1H), 4.06 (1H, J=8.8), 3.82 (1H, J=6.8, 9.2), 3.66 (2H, J=4.8), 3.14 (2H, J=12.8), 3.04 (1H, J=12.0), 2.62 (2H,
J=12.8), 2.55 (1H, J=4.4, 13.2), 2.03 (3H), 1.83±1.80 (2H); 13C NMR (CDCl3, 100 MHz) ꢀ 171.5, 160.1
(JC F=244.5), 154.4, 137.8 (JC F=11.1), 127.8 (JC F=6.0), 127.6 (JC F=15.1), 113.7 (JC F=3.0), 106.0
(JC F=28.2), 72.1, 47.5, 46.0, 41.8, 34.8, 23.0, 21.5, 21.5; anal calcd for C17H21FN2O4S: C, 55.42; H, 5.75; N,
1
7.60; found: C, 55.40; H, 5.71; N, 7.55. Compound 2: H NMR (DMSO-d6, 400 MHz) ꢀ 8.15 (1H, J=6.0), 7.45
(1H, J=2.4, 13.2), 7.35 (1H, J=8.8), 7.24 (1H, J=2.0, 8.4), 4.10 (1H, J=9.2), 3.74 (1H, J=6.0, 9.2), 3.43±3.34
(3H), 3.32 (1H), 3.08±3.02 (1H), 2.81 (2H, J=10.8), 2.51 (1H), 2.10 (2H, J=7.6), 2.00 (2H, J=12.8), 1.88 (2H,
J=13.2), 0.96 (3H, J=7.6); 13C NMR (DMSO-d6, 100 MHz) ꢀ 173.7, 159.6 (JC F=242.5), 153.9, 138.2
(JC F=11.1), 128.2 (JC F=7.0), 125.7 (JC F=15.1), 113.7 (JC F=3.0), 105.1 (JC F=28.2), 71.6, 51.0, 47.1, 41.3,
34.2, 28.6, 28.3, 9.8; anal calcd for C18H23FN2O4S. H2O: C, 53.99; H, 6.29; N, 6.99; S, 8.01; found: C, 53.85; H,
6.24; N, 6.90; S, 7.91.