Oxazolidinone antibacterial agents. An enantioselective synthesis of the [6,5,5] tricyclic fused oxazolidinone ring system and application to the synthesis of a rigid DuP 721 analogue

Full text of DOI:10.1021/jo960945s

6470
J . Org. Chem. 1996, 61, 6470-6474
Sch em e 1
Oxa zolid in on e An tiba cter ia l Agen ts. An
En a n tioselective Syn th esis of th e [6,5,5]
Tr icyclic F u sed Oxa zolid in on e Rin g System
a n d Ap p lica tion to th e Syn th esis of a Rigid
Du P 721 An a logu e
D. Mark Gleave* and Steven J . Brickner†
Sch em e 2
Medicinal Chemistry Research, Pharmacia & Upjohn, Inc.,
Kalamazoo, Michigan 49001
Received May 22, 1996
Oxazolidinones represent an exciting new class of
synthetic antibacterial agents.1,2 Key oxazolidinones
synthesized to date include DuPont’s seminal compound
DuP 721 (1)2 and Pharmacia & Upjohn’s current clinical
Sch em e 3a
candidates U-100592 (2) and U-100766 (3).1a These
compounds show potent in vitro and in vivo activity
against multiple antibiotic resistant strains of Gram-
positive bacteria.
A number of rigid, tricyclic fused oxazolidinone anti-
bacterial agents have been previously synthesized in
racemic form.3 A goal of this work was to gain an
understanding of the importance of the spatial relation-
ship and torsional angle between the aryl and oxazoli-
dinone rings with regard to antibacterial activity. Among
the more active compounds synthesized were several
racemic [6,5,5] tricyclic fused oxazolidinones.3a,b A num-
ber of aryl analogues (5) were synthesized directly from
the parent 4, via bromination and Suzuki-type coupling
(Scheme 1).4 Only the trans compounds showed activity.
In all cases tested, the corresponding cis isomers were
inactive.
a
Reagents: (a) BH3‚DMS, THF then PCC, CH2Cl2; (b)
(CF3CH2O)2P(O)CH2CO2Me, KHMDS, 18-crown-6, THF, -78 °C,
43%; (c) DIBALH, PhCH3, 0 °C, 100%; (d) SnCl2‚2H2O, EtOH, 96%;
(e) CBZCl, NaHCO3, acetone, H2O, 100%; (f) racemic series:
m-CPBA, CHCl3, 96%; asymmetric series: Ti(i-PrO)4, L-(-)-DET,
t-BuOOH, molecular sieves, CH2Cl2, 84% yield, >95% ee.
A key reaction in the synthesis of optically active 5(R)-
(hydroxymethyl)-3-aryl-2-oxazolidinones is the previously
reported aryl N-lithiocarbamate cyclization with (R)-
(-)-glycidyl butyrate.3a We anticipated that an intra-
molecular version of this reaction might be employed to
construct both five-membered rings of 4 in one step from
the epoxy carbamate 6 (Scheme 2). The requisite epoxide
would be best derived from the cis-olefin 7 using a
Sharpless asymmetric epoxidation.5
Given the high synthetic utility of the parent [6,5,5]
tricyclic fused template 4 for constructing other poten-
tially active tricyclic analogues, an asymmetric synthesis
of this molecule was targeted.
2-Nitrophenyl acetaldehyde 96 (Scheme 3) was consid-
ered an appropriate starting material; however, it was
found to be unstable and difficult to purify. Decomposi-
tion occurred upon silica gel and also during attempted
distillation. We found it most advantageous to purify 9
by immediately converting it to the ethylene acetal, which
was readily purified by chromatography. Hydrolysis
(AcOH/H2O) then gave 9 in a high state of purity, suitable
for carrying into the following Horner-Wadsorth-Em-
mons reaction. Using the Still conditions7 with methyl
bis(trifluoroethyl) phosphonoacetate and 5 equiv of 18-
crown-6, 10 was obtained with a Z:E ratio of 15:1. In
the absence of crown ether, the selectivity was only 4:1.
The methyl acrylate isomers could be easily separated
* Phone: (616) 385-5499. Fax: (616) 833-2516. E-mail: dmgleav$@
pwinet.upj.com.
† Current address: Central Research, Pfizer, Inc., Groton, CT 06340.
(1) (a) Brickner, S. J .; Hutchinson, D. K.; Barbachyn, M. R.;
Manninen, P. R.; Ulanowitcz, D. A.; Garmon, S. A.; Grega, K. C.;
Hendges, S. K.; Toops, D. S.; Zurenko, G. E.; Ford, C. W. J . Med. Chem.
1996, 39, 673. (b) Barbachyn, M. R..; Hutchinson, D. K.; Brickner, S.
J .; Cynamon, M. H.; Kilburn, J . O.; Klemens, S. P.; Glickman, S. E.;
Grega, K. C.; Hendges, S. K.; Toops, D. S.; Ford, C. W.; Zurenko, G. E.
J . Med. Chem. 1996, 39, 680. (c) Grega, K. C.; Barbachyn, M. R.;
Brickner, S. J .; Miszak, S. A. J . Org. Chem. 1995, 60, 5255.
(2) (a) Slee, A. M.; Wunonola, M. A.; McRipley, R. J .; Zajac, I.;
Zawada, M. J .; Bartholomew, P. T.; Gregory, W. A.; Forbes, M.
Antimicrob. Agents Chemother. 1987, 31, 1791. (b) Wang, C-L. J .;
Gregory, W. A.; Wuonola, M. A. Tetrahedron 1989, 45, 1323. (c) Park,
C-H.; Brittelli, D. R.; Wang, C. L-J .; Marsh, F. D.; Gregory, W. A.;
Wuonola, M. A.; McRipley, R. J .; Eberly, V. S.; Slee, A. M.; Forbes, M.
J . Med. Chem. 1992, 35, 1156.
(3) (a) Brickner, S. J .; Manninen, P. R.; Ulanowicz, D. A.; Lovasz,
K. D.; Rohrer, D. C. 206th ACS National Meeting, Chicago, Il., August
22-27, 1993. Abst. Pap. Am. Chem. Soc. 206 (1-2). (b) Brickner, S. J .
U. S. Patent 5,231,188, J ul 27, 1993. (c) Brickner, S. J . U.S. Patent
5,247,090, Sep 21, 1993.
(5) (a) J ohnson, R. A.; Sharpless, K. B. in Comprehensive Organic
Synthesis ed. Trost, B. M. Pergamon Press: New York, 1991; Vol. 7,
Chapter 3.2. (b) Hanson, R. M.; Sharpless, K. B. J . Am. Chem. Soc.
1986, 51, 1922.
(6) Ishii, H.; Murakami, K.; Sakurada, E.; Hosoya, K.; Murakami,
Y. J . Chem. Soc. Perkin Trans. 1 1988, 2377.
(4) The most active aryl analog was that having
a 3-pyridyl
appendage. This compound was equipotent to vancomycin in vivo.
(7) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
S0022-3263(96)00945-0 CCC: $12.00 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 18, 1996 6471
Sch em e 4
Sch em e 5a
a
Reagents: (a) TBDMSCl, imidazole, CH2Cl2, 74%; (b) LHMDS,
THF, -78 °C to rt, 100%; (c) n-Bu4NF, THF, 73%; (d) MsCl, Et3N,
CH2Cl2, 100%; (e) NaN3 DMF, 100%; (f) H2, Pd/C, MeOH, 98%;
(g) Ac2O, pyr, 82%; (h) Ac2O, MsOH, Ms2O, 75%.
glycidyl butyrate.3a Using lithium hexamethyldisilazane
(LiHMDS) as base, the major product was the undesired
[6,5,6] isomer 1614 (38% isolated yield). Only a small
amount of the desired [6,5,5] isomer 18 (11%) was
observed, together with the ring-opened product 17
(14%). The fact that the undesired [6,5,6] product was
being formed implied that the butyrate protecting group
of intermediate 15 was either cleaved or migrated to the
adjacent oxygen atom. This would liberate a terminal
alkoxide which could attack the carbamate carbonyl to
generate the unwanted six-membered ring. Both NaH-
MDS and KHMDS were tried as alternative bases; their
use led to a decrease in the amount of 16 and an increase
in the amount of 17. The desired oxazolidinone 18 was
again formed only in very low yield (<10%). Not surpris-
ingly, when the cyclization was attempted on the unpro-
tected alcohol 13 using 2 equiv of LiHMDS, the undesired
16 was formed as the major product in 46% isolated yield.
It became clear that the terminal hydroxy group would
require a nonlabile protecting group which would pre-
clude formation of the six-membered tetrahydrooxazinone
ring in 16. The (tert-butyldimethyl)silyl protecting group
proved suitable. The cyclization reaction with 20 ran
smoothly using LiHMDS as base (Scheme 5).15 The
desired (crude) silyl-protected oxazolidinone 21 was
produced in quantitative yield. Deprotection of the
silylated oxazolidinone with Bu4NF furnished the free
alcohol 18 (73%). In the asymmetric series, 18 was
converted to the Mosher ester and the ee was shown to
be g95% (1H and 19F NMR). The remaining steps in the
synthesis (conversion of ROH to RNHAc) were performed
using methodology similar to that described previously.1
Alcohol 18 was converted to mesylate 22, which was
readily displaced with sodium azide at 70 °C. Hydrogen-
ation of azide 23 followed by acylation furnished the
target acetamide 4 in good overall yield (73%) from the
alcohol 18. In the asymmetric series the ee of 4 was
determined by chiral HPLC to be 98.8%.16
by chromatography.8 The desired isomer 10Z was then
reduced with DIBALH9 to give the allylic alcohol 11.
Reduction of the nitro group with stannous chloride10
gave the aniline 12, which was protected as the benzyl
carbamate using standard Schotten-Baumann condi-
tions to give intermediate 7 in 78% overall yield from
10Z.
Treatment of 7 with m-CPBA gave epoxide 13 in 96%
yield. Initial attempts to perform an asymmetric Sharp-
less epoxidation of 7, using 10, 20 or 50 mol % of the
Ti(Oi-Pr)4 and L-(+)-diethyl tartrate reagents in the
presence of 4 Å molecular sieves,5b gave very low yields
of 13. The reaction was successful when a stoichiometric
amount of the reagents were used at -20 °C in the
presence of molecular sieves,11 giving optically active
epoxide 13 in 84% yield. An ee of g95% was consistently
achieved over a number of runs, as measured by 19F and
1H NMR of the corresponding Mosher ester.12
The new cyclization reaction was initially examined
using racemic, rather than optically active, epoxide 13
for the following reasons: (i) to demonstrate proof of
concept, (ii) to provide both enantiomers to facilitate
analysis of the ee in the asymmetric synthesis, and (iii)
to optimize reaction conditions. Opening of the epoxide
to form the desired five-membered ring (5-exo vs 6-endo
closure) was expected.13 The cyclization reaction was
first performed with the hydroxy group of 13 protected
as the butyrate ester 14 (Scheme 4), in direct analogy to
the intermolecular version of the cyclization which uses
(8) Isolated yields of the cis olefin 10Z were often only 40-50%. This
was due to partial isomerization of the olefin upon silica gel or on
prolonged storage. It isomerized fairly readily to an inseparable
mixture, presumed to be the trans R,â-unsaturated ester and the trans-
styrene. To circumvent this, the ester 10 was immediately reduced to
11 with DIBALH.
(9) Yoon, N. M.; Gyoung, Y. S. J . Org. Chem. 1985, 50, 2443.
(10) Bellamy, F. D.; Ou, K. Tetrahedron Lett. 1984, 25, 839.
(11) For a successful Sharpless asymmetric epoxidation performed
on a related system, see: Sharpless, K. B. et al., Pure Appl. Chem 1983,
55, 589 (cis-PhCH2CHdCHCH2OH, 83% yield, 91% ee).
(12) Ward, D. E.; Rhee, C. K. Tetrahedron Lett. 1991, 49, 7165.
(13) Baldwin, J . E. J . Chem. Soc. Chem. Commun. 1976, 734.
(14) The structure of the [6,5,6] isomer 16 was confirmed by X-ray
crystallography (W. Watt and F. Han, Pharmacia & Upjohn, Inc.).
(15) The reaction was unsuccessful when KHMDS was used as base.
Less than 10% of the desired oxazolidinone was observed. Isolated
reaction products seemed to indicate that 6-endo cyclization of the
epoxide had occurred.

6472 J . Org. Chem., Vol. 61, No. 18, 1996
Notes
Hz, 1H), 6.40 (dt, J ) 11.4, J ′ ) 7.3 Hz, 1H), 5.9 (d, J ) 11.4 Hz,
1H), 4.32 (d, J ) 7.3 Hz, 2H), 3.78 (s, 3H). 13C NMR (CDCl3,
100.6 MHz) δ: 166.9, 149.4, 146.1, 134.8, 133.7, 132.7, 128.0,
125.1, 120.9, 51.6, 32.6. Anal. Calcd for C11H11NO4: C, 59.73;
H, 5.01; N, 6.33. Found: C, 59.63; H, 5.09; N, 6.17.
As a demonstration of the synthetic utility of the
parent tricyclic oxazolidinone 4, it was converted in one
step to 25,17 the tricyclic analogue of DuP 721, by
Friedel-Crafts acylation.2b,3c
In summary, a novel intramolecular version of the aryl
N-lithiocarbamate-epoxide cyclization has been demon-
strated in the synthesis of [6,5,5] tricyclic fused oxa-
zolidinones 4 and 25. In this reaction both five-
membered rings are constructed in one step with com-
plete regiochemical control. High enantioselectivity was
achieved through the use of an asymmetric Sharpless
epoxidation, which furnished product of 98.8% ee. The
parent 4 is a useful intermediate for the potential
synthesis of a large number of novel oxazolidinone
antibiotics.3a
(Z)-4-(2-Nitr op h en yl)bu t-2-en ol (11). To a solution of ester
10Z (3.527 g, 15.9 mmol) in dry toluene at 0 °C was added,
dropwise, a solution of DIBALH (35.1 mL of a 1 M solution in
toluene). After stirring for 1 h at 0 °C, the reaction was
quenched with MeOH (15 mL) and 1 N HCl (15 mL). The
solution was warmed to rt and an additional 150 mL of 1 N HCl
was added to dissolve the precipitated aluminum salts. The
mixture was extracted with CH2Cl2 (3 × 75 mL), and the
combined organics were washed with brine. Drying over MgSO4
followed by removal of solvents in vacuo yielded 3.072 g (100%)
of 10Z as an orange oil which was of sufficient purity to be used
in the next reaction. An analytically pure sample was obtained
by bulb-to-bulb distillation (0.1 mmHg, 150-175 °C): 1H NMR
(CDCl3, 400 MHz) δ: 7.93 (d, J ) 8.2 Hz, 1H), 7.55 (dd, J ) 7.5
Hz, J ′ ) 7.0 Hz, 1H), 7.39 (d + dd, J ) 8.2 Hz, J ′ ) 7.5 Hz, J ′′
) 7.0 Hz, 2H), 5.80 (m, 1H), 5.62 (m, 1H), 4.32 (d, J ) 6.6 Hz,
2H), 3.76 (d, J ) 7.3 Hz, 2H), 1.51 (br s, 1H). 13C NMR (CDCl3,
100.6 MHz) δ: 149.6, 135.5, 133.6, 132.0, 131.3, 128.5, 127.8,
125.1, 58.8, 31.4. Anal. Calcd for C10H11NO3: C, 62.17; H, 5.74;
N, 7.25. Found: C, 61.78; H, 5.88; N, 7.22.
(Z)-4-(2-An ilin o)bu t-2-en ol (12). To a solution of aryl nitro
compound 11 (3.00 g, 15.5 mmol) in EtOH (30 mL) was added
SnCl2‚2H2O (17.52 g, 77.6 mmol). The mixture was heated to
80 °C. After 40 min, the solution was cooled to rt and poured
onto 65 g of ice. Water (100 mL) was added, followed by the
careful addition of solid NaHCO3 (13 g, 155 mmol) until the
solution tested basic. The mixture was then extracted with
EtOAc (5 × 150 mL). The combined organics were washed with
brine and dried (sodium sulfate). Removal of solvents yielded
2.44 g (96%) of the aniline as an orange oil. The material was
used without further purification in the next step of the
synthesis. An analytically pure sample was obtained by chro-
matography (SiO2; EtOAc/hexane 20 f 50%) which gave a yellow
solid. Mp: 38-39 °C. 1H NMR (CDCl3, 400 MHz) δ: 7.10-
7.03 (m, 2H), 6.77 (dd, J ) 7.5 Hz, J ′ ) 7.2 Hz, 1H), 6.68 (d, J
) 7.7 Hz, 1H), 5.79 (m, 1H), 5.66 (m, 1H), 4.29 (d, J ) 6.7 Hz,
2H), 4.0-2.8 (br s, 3H) 3.33 (d, J ) 7.2 Hz, 2H. 13C NMR (CDCl3,
100.6 MHz) δ: 144.8, 130.7, 130.0 (2C), 127.9, 125.1, 119.5,
116.5, 58.4, 30.5. Anal. Calcd for C10H13NO: C, 73.59; H, 8.03;
N, 8.58. Found: C, 73.42; H, 8.19; N, 8.47.
(Z)-4-(2-((B e n zy lo x y c a r b o n y l)a m in o )p h e n y l)b u t -2-
en ol (7). To a solution of the aniline 12 (2.166 g, 13.3 mmol)
and NaHCO3 (2.230 g, 26.5 mmol) in 2:1 acetone:water (90 mL),
at 0 °C, was added, dropwise, benzyl chloroformate (2.27 mL,
15.9 mmol). The solution was allowed to slowly warm to rt and
stirred overnight. The acetone was removed in vacuo, an
additional 50 mL of water was added, and the aqueous solution
was extracted with EtOAc (3 × 50 mL). The combined organics
were washed with brine and dried over sodium sulfate. The
solvent was removed in vacuo to yield 3.959 g (100%) of a cream
colored solid. Mp: 82-83 °C. 1H NMR (CDCl3, 400 MHz) δ:
7.78 (br s, NH), 7.45-7.30 (m, 6H), 7.27 (dd, J ) 8.2, J ′ ) 6.3,
1H), 7.18 (d, J ) 6.3 Hz, 1H), 7.10 (dd, J ) 7.5 Hz, J ′ ) 7.1 Hz,
1H), 5.76 (m, 1H), 5.61 (m, 1H), 5.20 (s, 2H), 4.29 (dd, J ) 5.9
Hz, J ′ ) 5.8 Hz, 2H), 3.44 (d, J ) 7.4 Hz, 2H), 1.70 (t, J ) 5.9
Hz, OH). 13C NMR (CDCl3, 100.6 MHz) δ: 155.1, 136.7, 136.3,
130.5, 130.1, 129.9, 129.0 (2C), 128.8, 128.7, 127.7, 125.5, 123.7,
67.4, 58.5, 30.9. Anal. Calcd for C18H19NO3: C, 72.71; H, 6.44;
N, 4.71. Found: C, 72.48; H, 6.39; N, 4.55.
Exp er im en ta l Section
2-Nitr op h en yla ceta ld eh yd e (9). To a solution of 2-nitro-
phenylacetic acid (8) (27.173 g, 150 mmol) in THF (150 mL) was
added dropwise, via addition funnel, borane-methyl sulfide
complex (77.5 mL of a 2.0 M solution in diethyl ether). The
mixture was heated to reflux for 1 h. After cooling to rt the
THF was removed in vacuo. The intermediate borane was then
dissolved in CH2Cl2 (75 mL) and was added dropwise to a
suspension of PCC (48.501 g, 225 mmol) in CH2Cl2 (200 mL).
The mixture was heated to reflux for 1 h. After cooling to rt,
Et2O (300 mL) was added and the suspension stirred for 20 min.
The mixture was filtered through diatomaceous earth (an
additional 3 × 200 mL of Et2O was passed through the filter
pad). Removal of solvents in vacuo gave 18.68 g (75%) of crude
2-nitrophenylacetaldehyde (9). This procedure provides material
of about 80% purity. Attempts to purify by distillation or
chromatography led to significant decomposition. To a solution
of crude 9 (18.68 g, 113 mmol) in toluene (400 mL) were added
PPTS (5.680 g, 22.6 mmol) and ethylene glycol (15.75 mL, 283
mmol). The mixture was heated to reflux in the presence of a
Dean-Stark trap. After 2 h the mixture was cooled to rt and
washed with saturated NaHCO3 solution and brine and then
dried (sodium sulfate). Removal of the solvents in vacuo yielded
24.21 g of a dark orange oil. Chromatography (SiO2, 10% f 20%
EtOAc/hexane) gave 12.033 g (51%) of the intermediate 2-nitro-
phenylacetaldehyde ethylene acetal as a yellow oil. 1H NMR
(CDCl3, 400 MHz) δ: 7.89 (d, J ) 8.1 Hz, 1H), 7.54 (t, J ) 7.6
Hz, 1H), 7.39 (m, 2H), 5.18 (t, J ) 4.5 Hz, 1H), 3.84 (m, 4H),
3.35 (d, J ) 4.5 Hz, 2H). A solution of the acetal (6.904 g, 33.0
mmol) in acetic acid (30 mL) and water (7 mL) was heated in
an oil bath to 80 °C for 42 h. After cooling to rt, water (200 mL)
was added and the mixture was extracted with CH2Cl2 (3 × 100
mL). The combined organics were then washed with saturated
aqueous NaHCO3 (3 × 200 mL, Ca u tion ! CO2 evolution).
Solvents were removed to provide 5.53 g (100%) of 2-nitro-
phenylacetaldehyde (9) (>90% purity) as an orange oil. Spectral
data were identical to that previously reported.6
(Z)-Meth yl 4-(2-n itr op h en yl)bu t-2-en oa te (10Z). To a
solution of bis(2,2,2-trifluoroethyl ((methoxycarbonyl)methyl)
phosphonate (0.66 mL, 3.1 mmol) in THF (60 mL) at -78 °C
was added KHMDS (6.2 mL of a 0.5 M solution in toluene)
dropwise. After 5 min a solution of 2-nitrophenylacetaldehyde
(9) (0.51 g) in THF (2 mL) was added dropwise, at which point
the solution turned purple. After 2 h the reaction was quenched
with saturated NH4Cl solution (20 mL) and allowed to warm to
rt. The mixture was extracted with EtOAc (2 × 20 mL), and
the organics were then washed with brine. After drying (sodium
sulfate) and removal of solvents, the crude product was chro-
matographed (SiO2, 5% ethyl acetate/hexane) to give 238 mg
(43%) of the cis-olefin 10Z as a yellow oil: 1H NMR (CDCl3, 400
MHz) δ: 7.97 (d, J ) 9.3 Hz, 1H), 7.56 (dd, J ) 8.0 Hz, J ′ ) 6.3
Hz, 1H), 7.49 (d, J ) 6.4 Hz, 1H), 7.42 (dd, J ) 7.7 Hz, J ′ ) 7.0
Intermediates in the asymmetric synthesis follow.
(-)-(2S,3R)-4-(2-((Ben zyloxyca r b on yl)a m in o)p h en yl)-
2,3-ep oxybu ta n ol (-)-13). To a suspension of powdered,
activated 4 Å molecular sieves (350 mg) in dry CH2Cl2 (13 mL)
at -10 °C was added a solution of (L)-(+)-diethyl tartrate (509
mg; 2.47 mmol) in CH2Cl2 (2 mL + 1mL rinse) followed by Ti(Oi-
Pr)4 (0.69 mL, 2.35 mmol). The reaction mixture was then cooled
to -22 °C and a solution of t-BuOOH (1.03 mL of a 5-6 M
solution in decane) was added. After stirring for 1 h (aging the
reagent) a solution of allylic alcohol 7 (700 mg) in CH2Cl2 (7 mL
+ 2 mL rinse) was added dropwise over 10 min. Stirring was
continued at -22 °C for 20 h before quenching with 10% aqueous
tartaric acid (7 mL). The mixture was allowed to warm to rt
and stirred for an additional 1 h. Brine (30 mL) was added and
(16) HPLC was performed on an (R,R) Whelk-01, 0.46 × 25 cm
column, (Regis Technologies, Morton Grove, Il). The running conditions
were 40% i-PrOH/hexane (v/v) at 1.0 mL/min, with the monitor set at
236 nm. Observed tR ) 12.0 and 15.4 min.
(17) Compound 25 exhibits strong antibacterial activity. It is
approximately 2-fold less active than DuP 721.

Notes
J . Org. Chem., Vol. 61, No. 18, 1996 6473
the mixture was extracted with EtOAc (3 × 20 mL). The
combined organics were dried (sodium sulfate) and solvents
removed to give 1.310 g of a yellow oil comprising the desired
epoxide (-)-13, together with diethyl tartrate. The crude oil
was dissolved in Et2O (20 mL) and cooled in an ice bath. 1 N
NaOH (7 mL) was added to hydrolyze the tartrate ester. After
stirring for 30 min, the organic phase was removed and washed
with brine. Drying (sodium sulfate) followed by removal of
solvent yielded 621 mg (84%) of (-)-13 as a waxlike solid, which
was of sufficient purity for the next reaction. An analytically
pure sample was prepared by recrystallizing from EtOAc/
were removed in vacuo and the resulting brown oil was purified
by chromatography (SiO2, MeOH/CH2Cl2 0% f 3%) to give a
colorless oil (108 mg; 62%) which slowly crystallized upon
standing to give (-)-18 as colorless needles. Mp: 99-102 °C.
[R]25 ) -77.6° (c ) 1, CHCl3). 1H NMR (CDCl3, 400 MHz) δ:
D
7.43 (d, J ) 7.8 Hz, 1H), 7.26 (t, J ) 6.8 Hz, 1H), 7.22 (d, J )
8.2, 1H), 7.10 (t, J ) 7.5 Hz, 1H), 4.75 (m, 1H), 4.59 (m, 1H),
4.05 (br d, J ) 12 Hz, 1H), 3.87 (br d, J ) 12 Hz, 1H), 3.27 (dd,
J ) 15.8 Hz, J ′ ) 9.0 Hz, 1H), 3.12 (dd, J ) 15.8 Hz, J ′ ) 9.3
Hz, 1H), 2.76 (br s, OH). 13C NMR (CDCl3, 75.5 MHz) δ: 156.5,
140.2, 132.3, 128.0, 125.2, 124.8, 115.2, 84.0, 62.0, 60.6, 34.9.
Anal. Calcd for C11H11NO3: C, 64.39; H, 5.40; N, 6.83. Found:
C, 64.72; H, 5.36; N, 6.78.
hexanes: Mp: 43-45 °C. [R]25 ) -7.07° (c 10.0, CH2Cl2). 1H
D
NMR (CDCl3, 400 MHz) δ: 7.80 (br s, 1H), 7.45-7.27 (m, 7H),
7.22 (d, J ) 7.3 Hz, 1H), 7.10 (dd, J ) 7.5 Hz, J ′ ) 7.3 Hz, 1H),
5.22 (2 x d, J ) 12.3 Hz, 2H), 3.96 (m, 2H), 3.27 (dd, J ) 9.7 Hz,
J ′ ) 4.9 Hz, 1H), 3.21 (m, 1H), 2.98 (dd, J ) 14.9 Hz, J ′ ) 4.1
Hz, 1H), 2.90 (dd, J ) 14.9 Hz, J ′ ) 8.1 Hz, 1H), 1.85 (br s, OH).
13C NMR (CDCl3, 100.6 MHz) δ: 155.0, 136.9, 136.8, 130.6,
129.8, 129.0, 128.6, 128.5, 128.2, 125.3, 123.8, 77.9, 67.4, 60.5,
58.0, 31.2. Anal. Calcd for C18H19NO4: C, 69.00; H, 6.11; N,
4.47. Found: C, 68.70; H, 6.21; N, 4.60.
(-)-[(1R,9a S)-(9,9a -Dih yd r o-3-oxo-1H,3H-oxa zolo[3,4-a ]-
in d ol-1-yl)m eth yl]m eth a n esu lfon a te ((-)-22). To a mixture
of the alcohol (-)-18 (89 mg; 0.43 mmol) and Et3N (0.13 mL,
0.95 mmol) in CH2Cl2 (5 mL) at 0 °C was added, dropwise, MsCl
(40.2 µL; 0.52 mmol). The mixture was allowed to slowly warm
to rt and stirred overnight. Water (6 mL) was added and the
mixture extracted with CH2Cl2 (2 × 5 mL). The combined
organics were washed with brine (10 mL) and dried (sodium
sulfate), and the solvents were removed in vacuo to give 137
mg of a colorless oil which was purified by chromatography (SiO2,
20% f 40% EtOAc/hexane) to give 122 mg (100%) of (-)-22 as
a colorless oil which solidified upon standing: Mp: 53-55 °C.
[R]25D ) -66.45° (c ) 2, CH2Cl2). 1H NMR (CDCl3, 400 MHz) δ:
7.43 (d, J ) 7.8 Hz, 1H), 7.27 (t, J ) 7.6 Hz, 1H), 7.22 (d, J )
7.4 Hz, 1H), 7.12 (t, J ) 7.5 Hz, 1H), 4.74 (m, 1H), 4.66 (m, 1H),
4.65 (dd, J ) 11.6 Hz, J ′ ) 3.7 Hz, 1H), 4.50 (dd, J ) 11.6 Hz,
J ′ ) 4.6 Hz, 1H), 3.32 (dd, J ) 15.9 Hz, J ′ ) 8.9 Hz, 1H), 3.16
(dd, J ) 15.9 Hz, J ′ ) 9.2 Hz, 1H), 3.13 (s, 3H). 13C NMR (CDCl3,
100.6 MHz) δ: 155.6, 140.5, 132.1, 128.7, 125.7, 125.6, 115.9,
80.2, 68.0, 61.5, 38.3, 35.5. Anal. Calcd for C12H13NO3S: C,
50.88; H, 4.63; N, 4.94. Found: C, 50.90; H, 4.60; N, 5.01.
(-)-(1R,9a S)-1-(Azid om eth yl)-9,9a -d ih yd r o-3-oxo-1H,3H-
oxa zolo[3,4-a ]in d ole ((-)-23). A mixture of mesylate (-)-22
(99 mg; 0.35 mmol) and sodium azide (79 mg; 1.22 mmol) in DMF
(2.5 mL) was heated to 70 °C and stirred overnight. The reaction
mixture was cooled to rt then water (10 mL) was added and the
mixture extracted with EtOAc (3 × 5 mL). The combined
organics were dried (sodium sulfate) and the solvents removed
in vacuo to yield 74 mg (91%) of a colorless oil which solidified
overnight. This material was of sufficient purity to be used in
the next step of the synthesis. An analytically pure sample of
azide (-)-23 was obtained by recrystallizing from EtOAc/hexane.
(+)-(2S,3R)-4-(2-((Ben zyloxyca r bon yl)a m in o)p h en yl)-1-
(ter t-bu tyld im eth ylsiloxy)-2,3-ep oxybu ta n e ((+)-20). To a
solution of TBDMSCl (113 mg; 0.75 mmol), DMAP (ca. 1 mg),
and imidazole (51 mg; 0.75 mmol) in DMF (0.5 mL) at 0 °C was
added a solution of glycidol (-)-13 (157 mg; 0.50 mmol) in DMF
(0.5 mL + 0.2 mL rinse). The mixture was allowed to slowly
warm to rt. After 2.5 h the mixture was poured onto water (10
mL) and extracted with hexanes (4 × 8 mL). The combined
organics were then dried (sodium sulfate) and the volatiles
removed to give 158 mg (74%) of the silylated alcohol (+)-20 as
a white solid which was of sufficient purity to be used in the
next reaction. An analytically pure sample was obtained by
recrystallizing from hexanes. Mp: 63-64 °C. [R]25D ) +11.58°
(c ) 5, CH2Cl2). 1H NMR (CDCl3, 400 MHz) δ: 7.84 (br s, NH),
7.43-7.27 (m, 7H), 7.21 (d, J ) 7.5 Hz, 1H), 7.08 (dd, J ) 7.5,
Hz, J ′ ) 6.4 Hz, 1H), 5.21 (s, 2H), 3.93 (d, J ) 5.2 Hz, 2H), 3.22
(m, 1H), 3.15 (m, 1H), 2.97 (dd, J ) 15.0 Hz, J ′ ) 3.1 Hz, 1H),
2.78 (J ) 15.0 Hz, J ′ ) 8.9 Hz, 1H), 0.91 (s, 9H), 0.08 (s, 3H),
0.07 (s, 3H). 13C NMR (CDCl3, 100.6 MHz) δ: 154.6, 137.3,
136.9, 130.6, 129.2, 128.9, 128.6, 128.5, 128.3, 124.8, 123.2, 67.2,
61.8, 58.4, 58.0, 31.9, 26.3, 18.7, -4.8, -5.0. Anal. Calcd for
C
24H33NO4Si: C, 67.42; H, 7.78; N, 3.28. Found: C, 67.07; H,
8.15; N, 3.30.
(-)-(1R,9a S)-((ter t-Bu tyld im eth ylsiloxy)m eth yl)-9,9a -d i-
h yd r o-3-oxo-1H,3H-oxa zolo[3,4-a ]in d ole ((-)-21). To a solu-
tion of epoxysilane (+)-20 (408 mg; 0.95 mmol) in THF (5 mL),
at -78 °C, was added, dropwise, a solution of LHMDS (1.14 mL
of a 1M solution in hexanes). The reaction temperature was
maintained at -78 °C for 2 h. The dry ice bath was allowed to
slowly warm to ambient temperature. Stirring was continued
overnight. The solution was then cooled in an ice bath and
quenched with saturated NH4Cl solution. The reaction mixture
was extracted with EtOAc (4 × 5 mL) and the combined organics
then washed with brine. Drying over sodium sulfate and
removal of solvents yielded 304 mg (quant.) of a yellow oil which
slowly crystallized upon standing. This material was of suf-
ficient purity to be used in the next reaction. An analytically
pure sample was obtained by recrystallizing from hexane which
Mp: 90-91 °C. [R]25 ) -111.0° (c ) 1, CH2Cl2). 1H NMR
D
(CDCl3, 400 MHz) δ: 7.45 (d, J ) 7.8 Hz, 1H), 7.28 (dd {obscured
by CHCl3 peak}, 1H), 7.14 (d, J ) 7.5 Hz, 1H), 7.11 (dd, J ) 7.6
Hz, J ′ ) 7.3 Hz, 1H), 4.61 (m, 2H), 3.75 (dd, J ) 13.1 Hz, J ′ )
4.5 Hz, 1H), 3.69 (dd, J ) 13.1 Hz, J ′ ) 4.4 Hz, 1H), 3.29 (dd, J
) 15.7 Hz, 1H), 3.12 (dd, J ) 15.7 Hz, J ′ ) 8.5 Hz, 1H). 13C
NMR (CDCl3, 100.6 MHz) δ: 155.8, 140.7, 132.3, 128.6, 125.7,
125.4, 115.8, 81.7, 62.4, 52.8, 35.4; exact mass calcd for
C
11H10N4O2 230.0804, found 230.0806.
(-)-(1R,9aS)-1-(Am in om eth yl)-9,9a-dih ydr o-3-oxo-1H,3H-
oxa zolo[3,4-a ]in d ole ((-)-24). To a solution of azide (-)-23
(5.9 mg; 25.6 µmol) in MeOH (0.75 mL) was added 10% Pd/C
(1.5 mg). The mixture was stirred at rt under an atmosphere
of hydrogen (balloon). After 2 h the reaction mixture was
washed through a small plug of diatomaceous earth using an
additional 1.5 mL of MeOH. Removal of solvent yielded 5.1 mg
(98%) of (-)-24 as a white solid, which was of sufficient purity
gave white feathery crystals. Mp: 81-83 °C. [R]25 ) -47.00°
D
(c ) 2, CH2Cl2). 1H NMR (CDCl3, 400 MHz) δ: 7.45 (d, J ) 7.8
Hz, 1H), 7.27 (t, J ) 7.7 Hz, 1H), 7.21 (d, J ) 7.5 Hz, 1H), 7.10
(dd, J ) 7.3 Hz, J ′ ) 6.8 Hz, 1H), 4.68 (m, 1H), 4.50 (m, 1H),
3.98 (dd, J ) 10.9 Hz, J ′ ) 4.1 Hz, 1H), 3.93 (dd, J ) 10.9 Hz,
J ′ ) 5.4 Hz, 1H), 3.26 (dd, J ) 15.9 Hz, J ′ ) 9.1 Hz, 1H), 3.11
(dd, J ) 15.9 Hz, J ′ ) 9.3 Hz, 1H), 0.93 (s, 9H), 0.13 (2 x s, 6H).
13C NMR (CDCl3, 100.6 MHz) δ: 156.6, 141.1, 132.6, 128.5,
125.5, 125.1, 115.8, 83.6, 63.4, 62.1, 35.8, 26.1 (2C), 18.6, -5.0.
Anal. Calcd for C17H25NO3Si: C, 63.92; H, 7.89; N, 4.38.
Found: C, 63.81; H, 7.97; N, 4.36.
to be used in the next reaction. Melting point 106-108 °C. [R]25
D
) -76.1° (c ) 1, CH2Cl2). 1H NMR (CDCl3, 400 MHz) δ: 7.45
(d, J ) 7.8 Hz, 1H), 7.27 (dd obscured by CHCl3 peak, 1H), 7.21
(d, J ) 7.5 Hz, 1H), 7.11 (dd, J ) 7.6 Hz, J ′ ) 7.3 Hz, 1H), 4.60
(m, 1H), 4.51 (m, 1H), 3.27 (dd, J ) 15.8 Hz, J ′ ) 8.8 Hz, 1H),
3.18 (dd, J ) 13.6 Hz, J ′ ) 4.2 Hz, 1H), 3.13 (m, 2H), 0.93 (br s,
NH2). 13C NMR (CDCl3, 100.6 MHz) δ: 156.6, 141.0, 132.5,
128.5, 125.6, 125.2, 115.8, 85.4, 62.4, 45.0, 35.6; exact mass calcd
for C11H12N2O2 204.0899, found 204.0901.
(-)-(1R,9a S)-(9,9a -Dih yd r o-3-oxo-1H,3H-oxa zolo[3,4-a ]-
in d ol-1-yl)m eth a n ol ((-)-18). To a solution of the silylated
oxazolidinone (-)-21 (270 mg; 0.85 mmol) in THF (4 mL) at 0
°C, under nitrogen, was added tetrabutylammonium fluoride
(1.54 mL of a 1.1 M solution in THF). The mixture was stirred
at 0 °C for 30 min. Water (6 mL) was added and the mixture
was extracted with EtOAc (4 × 5 mL). The combined organics
were washed with brine and dried over sodium sulfate. Solvents
(-)-(1R,9a S)-N-[(9,9a -Dih yd r o-3-oxo-1H,3H-oxa zolo[3,4-
a ]in d ol-1-yl)m eth yl]a ceta m id e ((-)-4). To a solution of
amine (-)-24 (5.0 mg; 24.5 µmol) in CH2Cl2 (0.75 mL), under
nitrogen, were added pyridine (10 µL, 123 µmol) and acetic
anhydride (6 µL, 61.3 µmol). The mixture was stirred at rt for
30 min. Solvents were removed in vacuo to yield 6.6 mg of the
crude acetamide. Purification by chromatography (SiO2; 0 f

6474 J . Org. Chem., Vol. 61, No. 18, 1996
Notes
2% MeOH/CH2Cl2) yielded 4.9 mg (82%) of acetamide (-)-4 as
1H), 3.14 (dd, J ) 16.2 Hz, J ′ ) 8.9 Hz, 1H), 2.58 (s, 3H), 2.07
(s, 3H). 13C NMR (CDCl3, 100.6 MHz) δ: 197.1, 171.3, 155.3,
144.5, 134.6, 133.3, 130.2, 125.9, 114.7, 83.6, 62.2, 41.4, 34.6,
27.0, 23.5. Anal. Calcd for C15H16N2O4: C, 62.49; H, 5.59; N,
9.72. Found: C, 62.21; H, 5.33; N, 9.72.
a colorless oil. [R]25 ) -53.48° (c ) 0.89, CH2Cl2). 1H NMR
D
(CDCl3, 400 MHz) δ: 7.40 (d, J ) 7.8 Hz, 1H), 7.24 (m, 2H),
7.10 (dd, J ) 7.5 Hz, J ′ ) 7.3 Hz, 1H), 6.29 (br s, 1H), 4.60 (m,
1H), 4.50 (m, 1H), 3.79 (ddd, J ) 14.7 Hz, J ′ ) 6.1 Hz, J ′′ ) 3.2
Hz, 1H), 3.68 (dt, J ) 14.7 Hz, J ′ ) 6.0 Hz, 1H), 3.28 (dd, J )
15.9 Hz, J ′ ) 9.0 Hz, 1H), 3.11 (dd, J ) 15.9 Hz, J ′ ) 9.2 Hz,
1H), 2.06 (s, 3H). 13C NMR (CDCl3, 100.6 MHz) δ: 171.0, 155.8,
140.1, 132.1, 128.2, 125.4, 125.0, 115.3, 82.6, 61.8, 41.4, 34.9,
23.1. Anal. Calcd for C13H14N2O3: C, 63.40; H, 5.73; N, 11.38.
Found: C, 63.59; H, 5.66; N, 11.29.
(+)-(1R ,9a S )-N -[(7-Ace t yl-9,9a -d ih yd r o-3-oxo-1H ,3H -
oxa zolo[3,4-a ]in d ol-1-yl)m eth yl]a ceta m id e ((+)-25). To a
mixture of the tricyclic parent oxazolidinone (-)-4 (11.1 mg; 45.1
µmol), Ms2O (17.8 mg; 102 µmol), and MsOH (250 µL) in CH2Cl2
(50 µL) at 0 °C was added acetic anhydride (28.4 L; 301 mol).
The temperature was maintained between 0 and 10 °C for 6 h
and then allowed to slowly warm to rt overnight. The mixture
was then added to ice-cold saturated aqueous NaHCO3 (1 mL)
and extracted with EtOAc (3 × 1 mL). The combined organics
were washed with brine and dried (Na2SO4) and the solvents
removed in vacuo to give 16.5 mg of a brown oil. The oil was
purified by chromatography (SiO2; 0 f 2% MeOH/CH2Cl2) to
give 9.8 mg (75%) of a pale yellow oil which solidified upon
standing: Mp: 171-173 °C. [R]25D ) +15.5° (c ) 0.20, CH2Cl2).
1H NMR (CDCl3, 400 MHz) δ: 7.89 (d, J ) 8.2 Hz, 1H), 7.85 (s,
1H), 7.46 (d, J ) 8.2 Hz, 1H), 6.16 (br s, NH), 4.62 (m, 1H), 4.57
(m, 1H), 3.85-3.65 (m, 2H), 3.36 (dd, J ) 16.2 Hz, J ′ ) 8.9 Hz,
Ack n ow led gm en t. The authors are grateful to the
Structural and Analytical Chemistry Department of
Pharmacia & Upjohn Inc. for elemental analyses, IR,
and mass spectral data. Gary E. Zurenko, Rhonda D.
Schaadt, and Betty H. Yagi are acknowledged for in
vitro antibacterial test results. Thanks also go to Lester
A. Dolak for chiral HPLC work. J ohn A. Tucker is
thanked for helpful discussions.
Su p p or tin g In for m a tion Ava ila ble: Additional experi-
mental data including IR and MS data for all compounds,
experimental procedures for intermediates in the racemic
synthesis, Mosher ester data and procedures and copies of 13
C
NMR for compounds 23 and 24 (10 pages). This information
is contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O960945S