Synthesis of MK-0476 Metabolic Oxidation Products
J . Org. Chem., Vol. 61, No. 24, 1996 8525
97.0, 119.0, 125.6, ,126.3, 126.4, 126..7, 127.3, 127.4 , 128.6,
128.7, 129.0, 131.6, 131.7, 135.5, 136.5, 136.6, 140.5, 141.6,
129.4, 129.5, 129.7, 130.3, 132.3, 135.6, 135.9, 137.2, 137.5,
141.5, 144.1, 144.9, 149.5, 158.0, and 172.7; HRMS (FAB) m/z
calcd for C35H36ClNO4S 602.2131, found 602.2129. Anal.
Calcd for C35H36ClNO4S: C, 69.81; H, 6.02; N, 2.32. Found:
C, 69.92; H, 5.92; N, 2.40.
143.4, 157.0, and 174.6; HRMS (FAB) m/z calcd for C37H40
-
ClNO5S 646.2394, found 646.2393. Anal. Calcd for
C37H40ClNO5S: C, 68.76; H, 6.23; N, 2.16. Found: C, 68.80;
H, 6.35; N, 2.14.
(R,S or R)-1-[((1-[3-(2-(7-Ch lor o-2-qu in olin yl)-(E)-eth e-
n yl)p h en yl]-3-(2-(1,2-d ih yd r oxy-1-m eth yleth yl)p h en yl)-
p r op yl)th io)m eth yl]cyclop r op a n ea cetic a cid (4). To a
solution of compound 26b (162 mg, 0.270 mmol) in 0.50 mL of
ethanol was added 0.52 mL of aqueous NaOH (1 N). The
mixture was stirred at 60 °C for 4 h, and then cooled and
acidified with 20 µL of AcOH to pH 5, and finally diluted with
1 mL of H2O and 2 mL of EtOAc. The organic extracts were
dried over Na2SO4, filtered, and concentrated. Flash chroma-
tography (silicic acid, hexanes/EtOAc 50:50) afforded 110 g
(70%) of the title compound 4: [R]D ) +51.2° (c ) 0.25, CHCl3);
IR (neat) 3450, 2920, 1710, and 1605 cm-1; NMR (400 MHz) δ
0.39-0.55 (m, 4H), 1.51 (s, 3H), 2.16-2.30 (m, 2H), 2.44 (s,
2H), 2.60 (s, 2H), 2.80-2.88 (m, 1H), 3.10-3.17 (m, 1H), 3.63
(d, J ) 10.8 Hz, 1H), 3.76 (d, J ) 10.8 Hz, 1H), 4.08 (t, J ) 7.8
Hz, 1H), 7.04-7.19 (m, 4H), 7.39-7.60 (m, 5H), 7.80-8.02 (m,
5H), and 8.33 (d, J ) 8.6 Hz, 1H); 13C NMR (100 MHz) δ 12.6,
12.8, 17.6, 27.1, 33.6, 39.6, 40.1, 40.9, 50.9, 51.4, 70.6, 76.2,
121.1, 126.1, 126.7, 126.8, 127.5, 127.6, 127.8, 128.6, 129.4,
129.5, 129.7, 130.3, 132.3, 135.6, 135.9, 137.2, 137.5, 141.5,
144.1, 144.9, 149.5, 158.0, and 172.7; HRMS (FAB) m/z calcd
for C35H36ClNO4S 602.2131, found 602.2129. Anal. Calcd for
C35H36ClNO4S: C, 69.81; H, 6.02; N, 2.32. Found: C, 69.72;
H, 6.10; N, 2.30.
MK-0476 Su lfoxid e 5 a n d 6. To a suspension of the
sodium salt of MK-0476 (1.57 g, 2.58 mmol) in 50 mL of dry
CH2Cl2 at -22 °C was added TFA (400 µL, 5.39 mmol). To
the resulting yellow solution was cannulated a solution of
m-CPBA (543 mg, 3.12 mmol) dropwise, and the resulting
mixture was stirred at -22 °C for 2 h. It was poured into 100
mL of citrate buffer (0.5 M) at pH 4.75 and extracted with
CH2Cl2 (2 × 100 mL). The combined organic extracts were
dried over Na2SO4, filtered, and concentrated. Flash chroma-
tography (SiO2, toluene/acetone/AcOH 80:20:1) or HPLC using
a Prep Nova-Pak® HR C18 columm (CH3CN/H2O/AcOH 60:
39:1) afforded 192 mg (12%) of the desired diastereomeric
sulfoxide 5: [R]D ) -22.5° (c ) 0.10, CHCl3); 1H NMR (400
MHz) δ 0.51-0.66 (m, 4H), 1.56 (s, 3H), 1.58 (s, 3H), 2.25 (d,
J ) 15.8 Hz, 1H), 2.34 (d, J ) 13.6 Hz, 1H), 2.46-2.54 (m,
2H), 2.67 (d, J ) 15.9 Hz, 1H), 2.70 (d, J ) 13.8 Hz, 1H), 3.02-
3.05 (m, 1H), 3.16-3.19 (m, 1H), 3.94 (dd, J ) 9.2 and 6.0 Hz,
1H), 7.10 (td, J ) 7.4 and 1.6 Hz, 1H), 7.15 (td, J ) 7.4 and
1.5 Hz, 1H), 7.22 (dd, J ) 7.5 and 1.6 Hz, 1H), 7.39 (dd, J )
7.8 and 1.5 Hz, 1H), 7.41-7.55 (m, 4H), 7.73 (d, J ) 7.6 Hz,
1H), 7.78 (s, 1H), 7.87 (d, J ) 8.6 Hz, 1H), 7.94 (d, J ) 16.3
Hz, 1H), 7.96 (d, J ) 8.7 Hz, 1H), 8.02 (d, J ) 1.5 Hz, 1H),
and 8.35 (d, J ) 8.5 Hz, 1H); 13C NMR (125 MHz, DMSO-d6)
δ 10.7, 12.2, 31.0, 31.4, 31.4, 32.1, 40.0, 56.5, 56.6, 63.9, 71.4,
119.9, 125.0, 125.0, 125.3, 126.1, 126.3, 126.4, 126.9, 128.1,
128.3, 128.4, 129.5, 129.7, 131.0, 134.1, 134.7, 134.8, 135.6,
136.3, 139.3, 146.4, 147.7, 156.6, and 172.4; HRMS (FAB) m/z
calcd for C35H36ClNO4S 602.21295, found 602.21295. Further
elution afforded 801 mg (50%) of the diastereomeric sulfoxide
6: [R]D ) +97.9° (c ) 0.14, CHCl3); 1H NMR (400 MHz) δ 0.40-
0.68 (m, 4H), 1.52 (s, 6H), 2.22 (d, J ) 16.1 Hz, 1H), 2.31-
2.36 (m, 1H), 2.58 (d, J ) 13.7 Hz, 1H), 2.61-2.67 (m, 1H),
2.72 (d, J ) 16.2 Hz, 1H), 2.87 (d, J ) 13.9 Hz, 1H), 2.91-
2.94 (m, 1H), 3.07-3.13 (m, 1H), 4.07 (dd, J ) 11.0 and 4.3
Hz, 1H), 7.12-7.19 (m, 3H), 7.39 (dd, J ) 7.7 and 1.5 Hz, 1H),
7.42 (d, J ) 7.7 Hz, 1H), 7.47-7.56 (m, 3H), 7.32 (d, J ) 7.7
Hz, 1H), 7.81 (s, 1H), 7.86 (d, J ) 8.6 Hz, 1H), 7.93 (d, J )
17.5 Hz, 1H), 7.96 (d, J ) 8.8 Hz, 1H), 8.01 (d, J ) 1.4 Hz,
1H) and 8.35 (d, J ) 8.6 Hz, 1H); 13C NMR (125 MHz, DMSO-
d6) δ 10.5, 12.1, 30.6, 31.1, 31.3, 31.3, 39.8, 56.5, 56.7, 66.2,
71.2, 120.0, 125.0, 125.0, 125.3, 126.1, 126.4, 126.6, 126.9,
127.6, 128.5, 129.0, 129.0, 129.5, 130.9, 134.1, 134.5, 135.7,
136.3, 136.4, 139.3, 146.4, 147.7, 156.5 and 172.4; HRMS (FAB)
m/z calcd for C35H36ClNO4S 602.21295, found 602.21295.
Meth yl (R,R or S)-1-[((1-[3-(2-(7-Ch lor o-2-qu in olin yl)-
(E)-eth en yl)p h en yl]-3-(2-(1,2-d ih yd r oxy-1-m eth yleth yl)-
p h en yl)p r op yl)th io)m eth yl]cyclop r op a n ea ceta te (26a ,b).
To a solution of the acids 25 (1.00 g, 1.55 mmol) in 10 mL of
Et2O was added
a solution of diazomethane until total
consumption of starting material by TLC. The mixture was
evaporated to dryness and was then dissolved in 35 mL of tert-
butyl alcohol. PPTS (3.89 g, 15.5 mmol) was added and the
mixture was refluxed for 12 h. The reaction mixture was
poured into 250 mL of aqueous NH4OAc (25%) and extracted
with 100 mL of Et2O. The organic phase was washed with
100 mL of water, dried over Na2SO4, filtered, and concentrated.
Flash chromatography (SiO2, toluene/EtOAc 67:33) afforded
550 mg (58%) of the title compounds, along with 302 mg of
the methyl ester intermediate. The two diastereoisomers were
separated by HPLC on a preparative column (CHIRALPAK
AD) using ethanol as the eluent. From 550 mg of the
diastereomeric mixture was obtained 191 mg of the title
compound 26a , with a retention time of 14 min: IR (neat)
3450, 2910, 1730, and 1605 cm-1; 1H NMR (400 MHz) δ 0.38-
0.53 (m, 4H), 1.51 (s, 3H), 2.23 (dd, J ) 16.3 and 7.6 Hz, 2H),
2.39 (d, J ) 15.9 Hz, 1H), 2.46 (d, J ) 15.9 Hz, 1H), 2.55 (s,
2H), 2.85-2.92 (m, 1H), 3.05-3.11 (m, 1H), 3.57 (s, 3H), 3.63
(d, J ) 10.8 Hz, 1H), 3.89 (d, J ) 10.8 Hz, 1H), 4.05 (t, J ) 7.4
Hz, 1H), 7.06-7.17 (m, 3H), 7.39-7.44 (m, 3H), 7.52-7.56 (m,
2H), 7.62-7.64 (m, 1H), 7.79 (s, 1H), 7.87-7.96 (m, 3H), 8.04
(s, 1H), and 8.35 (d, J ) 8.6 Hz, 1H); 13C NMR (100 MHz) δ
12.6, 12.8, 17.6, 27.0, 33.6, 39.6, 40.1, 40.9, 50.9, 51.4, 70.6,
76.2, 121.1, 126.1,126.7, 126.8, 127.5, 127.6, 127.8, 128.6,
128.6, 129.4, 129.5, 129.7, 130.3, 132.3, 135.6, 135.9, 137.2,
137.5, 141.5, 144.1, 144.9, 149.5, 158.0, and 172.7; HRMS
(FAB) m/z calcd for C36H38ClNO4S 616.2285, found 616.2285.
Anal. Calcd for C36H38ClNO4S: C, 70.17; H, 6.21; N, 2.27.
Found: C, 70.22; H, 6.25; N, 2.11. The column was further
eluted to give 162 mg of diastereoisomer 26b, with a retention
time of 26 min: IR (neat) 3450, 2920, 1730, and 1605 cm-1
;
1H NMR (400 MHz) δ 0.38-0.53 (m, 4H), 1.51 (s, 3H), 2.20-
2.29 (m, 2H), 2.39 (d, J ) 15.8 Hz, 1H), 2.46 (d, J ) 15.8 Hz,
1H), 2.55 (s, 2H), 2.81-2.88 (m, 1H), 3.09-3.12 (m, 1H), 3.57
(s, 3H), 3.63 (d, J ) 10.8 Hz, 1H), 3.76 (s, J ) 10.8 Hz, 1H),
4.05 (t, J ) 6.6 Hz, 1H), 7.06-7.16 (m, 3H), 7.39-7.43 (m, 3H),
7.53-7.57 (m, 2H), 7.62-7.64 (m, 1H), 7.80 (s, 1H), 7.88-7.97
(m, 3H), 8.05 (s, 1H), and 8.35 (d, J ) 8.6 Hz, 1H); 13C NMR
(100 MHz) δ 12.6, 12.8, 17.6, 27.0, 33.6, 39.6, 40.1, 40.9, 50.9,
51.4, 70.6, 76.2, 121.1, 126.1,126.7, 126.8, 127.5, 127.6, 127.8,
128.6, 128.6, 129.4, 129.5, 129.7, 130.3, 132.3, 135.6, 135.9,
137.2, 137.5, 141.5, 144.1, 144.9, 149.5, 158.0, and 172.7;
HRMS (FAB) m/z calcd for C36H38ClNO4S 616.2285, found
616.2288. Anal. Calcd for C36H38ClNO4S: C, 70.17; H, 6.21;
N, 2.27. Found: C, 70.12; H, 6.15; N, 2.37.
(R,R or S)-1-[((1-[3-(2-(7-Ch lor o-2-qu in olin yl)-(E)-eth e-
n yl)p h en yl]-3-(2-(1,2-d ih yd r oxy-1-m eth yleth yl)p h en yl)-
p r op yl)th io)m eth yl]cyclop r op a n ea cetic a cid (3). To a
solution of the ester 26a (191 mg, 0.316 mmol) in 0.50 mL of
ethanol was added 0.61 mL of aqueous LiOH (1 N). The
mixture was stirred at 60 °C for 4 h and then cooled and
acidified with 20 µL of AcOH to pH 5, and finally diluted with
1 mL of H2O and 2 mL of EtOAc. The organic extracts were
dried over Na2SO4, filtered, and concentrated. Flash chroma-
tography (silicic acid, hexanes/EtOAc 50:50) afforded 0.14 g
(73%) of the title compound: [R]D ) +75.2° (c ) 0.25, CHCl3);
IR (neat) 3450, 2910, 1710, and 1605 cm-1; 1H NMR (400 MHz)
δ 0.38-0.56 (m, 4H), 1.51 (s, 3H), 2.19-2.27 (m, 2H), 2.44 (s,
2H), 2.60 (s, 2H), 2.83-2.97 (m, 1H), 3.08-3.15 (m, 1H), 3.63
(d, J ) 10.8 Hz, 1H), 3.76 (d, J ) 10.8 Hz, 1H), 4.08 (t, J )
7.35 Hz, 1H), 7.05-7.19 (m, 4H), 7.39-7.62 (m, 5H), 7.80-
8.02 (m, 5H), and 8.33 (d, J ) 8.6 Hz, 1H); 13C NMR (100 MHz)
δ 12.6, 12.8, 17.6, 27.1, 33.6, 39.6, 40.1, 40.9, 50.9, 51.4, 70.6,
76.2, 121.1, 126.1,126.7, 126.8, 127.5, 127.6, 127.8, 128.6,
J O9615817