5098 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 16
Stephenson et al.
(m, 5H), 7.15 (ddd, J ) 7.8 Hz, J ) 7.8 Hz, J ) 4.6 Hz, 1H), 6.79
(d, J ) 7.5 Hz, 1H), 6.70-6.63 (m, 2H), 4.80-4.76 (m, 1H),
4.60-4.43 (m, 2H), 4.23-4.18 (m, 1H), 4.10-3.97 (m, 2H),
3.71-3.65 (m, 1H), 3.57-3.48 (m, 3H), 2.32-2.31 (2 × S, 3H),
1.22 (d, J ) 7.0 Hz, 3H). 13C NMR (CDCl3, 100 MHz) δ: 158.4,
157.4(8), 157.4(3), 139.9(4), 139.8(9), 138.2(1), 138.1(4), 129.5(5),
129.5(3), 128.6(9), 128.6(5), 128.0, 127.9(3), 127.9(1), 127.8(8),
122.6(0), 122.5(6), 115.6(5), 115.6(3), 111.6(4), 111.6(0), 73.2(3),
73.2(0), 71.7(1), 71.6(6), 71.3(0), 71.2(8), 68.3(4), 68.3(3), 48.6(7),
48.6(2), 43.8(9), 43.6(6), 21.7, 14.6(9), 14.6(5).
mixture was subsequently diluted with additional CH2Cl2 (75 mL),
washed with H2O (3 × 75 mL), brine (1 × 75 mL), dried over
Na2SO4, filtered, and concentrated to yield a colorless oil. The Boc-
protected intermediate of 11 was then dissolved in 35 mL of
anhydrous toluene. Sodium hydride (60%, 17.06 mmol) was added
and the heterogeneous mixture heated to 80 °C for 3 h. The mixture
was then cooled to room temperature, diluted with 100 mL of
EtOAc, washed with H2O (3 × 75 mL), brine (1 × 75 mL), dried
over Na2SO4, filtered, and concentrated to yield a colorless oil. The
product was isolated in 85% yield (from 11) as unresolved
diastereomers via flash column chromatography (20:80 (v/v),
(5S)-3-(1-Hydroxypropan-2-yl)-5-(m-tolyloxymethyl)oxazolidin-
2-one (9). Compound 8 (0.70 mmol) was dissolved in 2 mL of
MeOH and 2 mL of CH2Cl2. Pd(OH)2 (30 mg) and 10% Pd/C (30
mg) were added followed by a balloon of H2 gas. The heterogeneous
mixture was stirred rapidly at room temperature for 1 h and then
filtered over diatomaceous earth (Celite 545) and concentrated. The
products, as diastereomers, were inseparable as a clear colorless
1
EtOAc/hexanes). H NMR (CDCl3, 300 MHz) δ: 7.32-7.20 (m,
5H), 4.55-4.38 (m, 3H), 4.17-4.05 (m, 1H), 3.75-3.61 (m, 2H),
3.53-3.38 (m, 4H), 1.22-1.11 (m, 3H), 0.84-0.82 (m, 9H),
0.02-0.01 (m, 6H).
((R)-3-(1-(Benzyloxy)propan-2-yl)-2-oxooxazolidin-5-yl)methyl
4-Methylbenzenesulfonate (13). Compound 12 (2.5 mmol) was
dissolved in 13 mL of CH2Cl2 and cooled to 0 °C. TBAF (1.0 M
in THF, 5.08 mmol) was then added dropwise and stirred for 60
min. The mixture was then diluted with an additional 60 mL of
CH2Cl2, washed with H2O (3 × 75 mL), brine (1 × 75 mL), dried
over Na2SO4, filtered, and concentrated to yield a colorless oil. The
OTBS deprotected product was isolated in 90% yield via flash
column chromatography (80:20 (v/v), EtOAc/hexanes) as an oil
and used immediately in the next step.
All of the isolated OTBS deprotected 12 was dissolved in 11
mL of anhydrous CH2Cl2 and cooled to 0 °C. Triethylamine (6.5
mmol), catalytic 4-(dimethylamine)pyridine (5 mg), and p-tolu-
enesulfonyl chloride (4.5 mmol) were added, and the resultant
mixture was stirred at room temperature for 1.5 h. The solution
was then diluted with 75 mL of additional CH2Cl2, washed with
H2O (3 × 100 mL), brine (1 × 100 mL), dried over Na2SO4,
filtered, and concentrated to yield a colorless oil. The products (as
diastereomers) were isolated together via flash column chromatog-
raphy (50:50 (v/v), EtOAc/hexanes) in 86% yield. 1H NMR (CDCl3,
300 MHz) δ: 7.79-7.73 (m, 2H), 7.37-7.28 (m, 7H), 4.66-4.59
(m, 1H), 4.55 (dd, J ) 12.0 Hz, J ) 2.9 Hz, 1H), 4.44 (dd, J )
12.0 Hz, J ) 5.0 Hz, 1H), 4.16-4.07 (m, 3H), 3.62 (dd, J ) 16.0
Hz, J ) 8.9 Hz, 1H), 3.54-3.36 (m, 3H), 2.45-2.44 (m, 3H),
1.20-1.14 (m, 3H).
(5R)-3-(1-(Benzyloxy)propan-2-yl)-5-(m-tolyloxymethyl)oxazo-
lidin-2-one (14). Unresolved diastereomers of 13 (0.47 mmol),
m-cresol (0.52 mmol), and K2CO3 (1.4 mmol) were combined in 3
mL of anhydrous DMF and heated to 80 °C for 4 h. The mixture
was then cooled to room temperature and poured into 100 mL of
H2O. The crude product was then extracted with CH2Cl2 (3 × 50
mL). The organic fractions were combined, washed with H2O (3
× 100 mL), brine (1 × 100 mL), dried over Na2SO4, filtered, and
concentrated to yield a colorless oil. The diastereomers were
inseparable and isolated together via PTLC (50:50 (v/v), EtOAc/
hexanes) in 62% yield. 1H NMR (CDCl3, 300 MHz) δ: 7.37-7.23
(m, 5H), 7.16 (ddd, J ) 7.7 Hz, J ) 3.5 Hz, J ) 3.4 Hz, 1H), 6.79
(d, J ) 7.5 Hz, 1H), 6.70-6.63 (m, 2H), 4.81-4.74 (m, 1H),
4.61-4.43 (m, 2H), 4.24-4.17 (m, 1H), 4.11-3.97 (m, 2H),
3.72-3.65 (m, 1H), 3.57-3.47 (m, 3H), 2.32-2.31 (2 × S, 3H),
1.22 (d, J ) 6.9 Hz, 3H). 13C NMR (CDCl3, 75 MHz) δ: 158.4,
157.4(9), 157.4(4), 139.9(4), 139.8(9), 138.2(0), 138.1(3), 129.5,
128.6(9), 128.6(5), 128.0(4), 128.0(1), 127.9(4), 127.9(1), 127.8(9),
122.6(0), 122.5(7), 115.6(4), 115.6(3), 111.6(4), 111.6(0), 73.2(3),
73.2(0), 71.7(0), 71.6(5), 71.3(0), 71.2(9), 68.3(3), 68.3(2), 48.6(8),
48.6(3), 43.9(0), 43.6(5), 21.7, 14.6(9), 14.6(7). MS (ES +ve): [M
+ H] calcd 356.4, found 356.2.
2-((R)-2-Oxo-5-(m-tolyloxymethyl)oxazolidin-3-yl)propyl 4-Me-
thylbenzenesulfonate (15). Removal of the benzyl group was
accomplished using the procedure described for the synthesis of 9
in 99% yield and used directly in the next step which followed the
method described for the preparation of 10. Compound 15 was
isolated as two diastereomers (the diastereomers are either 2R,5R
or 2R,5S and differentiated as R-DS1 and R-DS2) via PTLC (50:
50 (v/v), EtOAc/hexanes) in a combined yield of 92% (note: % de
with respect to carbon-2 assayed after radiolabeling (Figure 3)).
1
oil that did not require further purification (94% yield). H NMR
(CDCl3, 400 MHz) δ: 7.16 (dd, J ) 7.7 Hz, J ) 7.7 Hz, 1H), 6.80
(d, J ) 7.5 Hz, 1H), 6.72-6.68 (m, 2H), 4.86-4.83 (m, 1H), 4.12
(dd, J ) 9.2 Hz, J ) 4.0 Hz, 2H), 4.05-3.99 (m, 1H), 3.80-3.70
(m, 2H), 3.63-3.52 (m, 2H), 3.48 (s, 1H), 2.32 (s, 3H), 1.21-1.18
(2 × d, J ) 6.7 Hz, 3H).
2-((S)-5-((2-Cyclohexylphenoxy)methyl)-2-oxooxazolidin-3-yl)-
propyl 4-Methylbenzenesulfonate (10). Compound 9 (0.105 mmol)
was dissolved in 1 mL of CH2Cl2. Triethylamine (0.211 mmol),
catalytic 4-(dimethylamine)pyridine (spatula tip), and p-toluene-
sulfonyl chloride (0.157 mmol) were added and the resultant mixture
stirred at room temperature for 3 h. The mixture was subsequently
diluted with CH2Cl2 (75 mL), washed with H2O (3 × 75 mL), brine
(1 × 75 mL), dried over Na2SO4, filtered, and concentrated to yield
a colorless oil. The two diastereomers were separable and isolated
via PTLC (50:50 (v/v), EtOAc/hexane) as colorless semisolids in
an overall yield of 65%. The diastereomers are either 2S,5R or 2S,5S
and arbitrarily differentiated as S-DS1 and S-DS2. The % de was
determined with respect to carbon-2 after radiolabeling. No attempts
were made to prepare authentic standards to assign the stereogenic
center on the isopropyl moiety.
1
S-DS1. H NMR (CDCl3, 300 MHz) δ: 7.79 (d, J ) 8.3 Hz,
2H), 7.36 (d, J ) 8.0 Hz, 2H), 7.16 (dd, J ) 7.8 Hz, J ) 7.7 Hz,
1H), 6.80 (d, J ) 7.6 Hz, 1H), 6.69-6.67 (m, 2H), 4.81-4.73 (m,
1H), 4.20-4.04 (m, 5H), 3.69 (dd, J ) 8.7 Hz, J ) 8.6 Hz, 1H),
3.54 (dd, J ) 8.6 Hz, J ) 6.2 Hz, 1H), 2.45 (s, 3H), 2.32 (s, 3H),
1.24 (d, J ) 6.9 Hz, 3H). 13C NMR (CDCl3, 75 MHz) δ: 158.3,
157.1, 145.5, 139.9, 132.7, 130.3, 129.6, 128.1, 122.7, 115.6, 111.6,
71.6, 71.0, 68.1, 48.2, 43.7, 21.9, 21.7, 14.1. HRMS (EI) for
C21H25NO6S: [M+] calcd 419.1403, found 419.1412.
1
S-DS2. H NMR (CDCl3, 300 MHz) δ: 7.74 (d, J ) 8.3 Hz,
2H), 7.27 (d, J ) 8.0 Hz, 2H), 7.17 (dd, J ) 7.8 Hz, J ) 7.8 Hz,
1H), 6.82 (d, J ) 7.5 Hz, 1H), 6.72-6.67 (m, 2H), 4.84-4.76 (m,
1H), 4.18-4.00 (m, 5H), 3.71 (dd, J ) 8.8 Hz, J ) 8.7 Hz, 1H),
3.53 (dd, J ) 8.6 Hz, J ) 5.6 Hz, 1H), 2.40 (s, 3H), 2.33 (s, 3H),
1.26 (d, J ) 6.7 Hz, 3H). 13C NMR (CDCl3, 75 MHz) δ: 158.3,
156.9, 145.4, 139.9, 132.7, 130.2, 129.5, 128.1, 122.7, 115.7, 111.7,
71.5, 70.8, 68.3, 48.3, 44.1, 21.9, 21.7, 14.2. HRMS (EI) for
C21H25NO6S: [M+] calcd 419.1403, found 419.1408.
(2R)-1-(1-(Benzyloxy)propan-2-ylamino)-3-(tert-butyldimethyl-
silyloxy)propan-2-ol (11). (R)-tert-Butyldimethyl(oxiran-2-ylmeth-
oxy)silane (prepared as described by Pospisil et al.,34 15.9 mmol)
and 5 (15.9 mmol) were combined in 30 mL of MeOH and stirred
at room temperature for 3 days and then heated at 50 °C for 4 h.
The solvent was removed and the product isolated via flash column
chromatography (65:35:0.1 (v/v/v), hexanes/EtOAc/TEA) as a thick
1
oil in 55% yield. H NMR (CDCl3, 300 MHz) δ: 7.37-7.26 (m,
5H), 4.52 (s, 2H), 3.73-3.54 (m, 3H), 3.43-3.28 (m, 2H),
2.94-2.58 (m, 3H), 1.05-1.02 (m, 3H), 0.90-0.88 (m, 9H),
0.08-0.05 (m, 6H).
(5R)-3-(1-(Benzyloxy)propan-2-yl)-5-((tert-butyldimethylsily-
loxy)methyl)oxazolidin-2-one (12). Compound 11 (7.92 mmol) was
dissolved in 16 mL of CH2Cl2. Di-tert-butyl dicarbonate (10.3
mmol) was added and stirred at room temperature for 1.5 h. The