2280 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 9
Lin et al.
35.5, 29.7, 26.8, 22.7, 22.1, 20.1, 14.7, 9.6; LRMS (APIMS) m/z
1028 (MH+), 1046 (M + NH4+).
3 H), 1.45 (s, 3 H), 1.21 (s, 3 H), 1.17 (s, 3 H); 13C NMR (CDCl3)
δ 201.9, 169.7, 169.6, 168.7, 167.4, 167.2, 166.9, 153.2, 140.9,
136.4, 133.7, 133.5, 132.7, 132.0, 130.2 129.2, 129.1, 128.7,
128.6, 127.1, 126.6, 93.8, 83.9, 80.9, 78.6, 77.5, 77.2, 76.3, 75.2,
74.5, 72.3, 71.6, 56.0, 52.7, 50.2, 46.9, 43.3, 41.7, 35.3, 33.4,
32.9, 32.3, 26.4, 22.6, 21.2, 20.7, 14.4, 10.9; LRMS (APIMS)
m/z 1161 (M + NH4+). Anal. (C55H60NO17SCl3) C, H, N.
3-Me t h yl-3-(2,4,6-t r im e t h oxyp h e n ylm e t h ylt h io)b u -
tyr ic Acid (3). To a solution of 3-mercapto-3-methylbutyric
acid14 (4.6 g, 34 mmol) in dichloromethane (250 mL) under
nitrogen and cooled over ice/salt to 5 °C (internal temperature)
was added trifluoroacetic acid (82 g, 0.72 mol). To this was
then added dropwise a solution of 2,4,6-trimethoxybenzyl
alcohol15 (6.45 g, 32 mmol) in dichloromethane (150 mL) such
that the reaction temperature did not rise above 5 °C. After
the addition was complete, the mixture was stirred for an
additional 5 min at 5 °C and the volatiles were removed in
vacuo. The residue was partitioned between diethyl ether and
water, and the organic phase was dried over anhydrous sodium
sulfate and filtered, and the volatile material was removed in
vacuo. The residue was treated with activated charcoal and
recrystallized from diethyl ether/hexane to give the title
7-(3-Meth yl-3-su lfa n ylbu tyr yl)p a clita xel (6). To com-
pound 5 (1.2353 g, 1.0784 mmol) in methanol/acetic acid (9:1,
80 mL) was added zinc dust (4.5349 g, 69.352 mmol). The
reaction suspension was stirred at room temperature for 20
min. The zinc dust was removed by filtration. The filtrate was
concentrated to dryness, treated with dichloromethane, and
washed with water and brine. The organic phase was dried
(sodium sulfate), concentrated, and purified by chromatogra-
phy (silica gel, ethyl acetate/hexane 1:3, then ethyl acetate/
hexane 8:17) to give the title compound 6 (1.0353 g, 1.0672
1
1
compound 3 (7 g, 70%): mp 103-105 °C; H NMR (CDCl3) δ
mmol, 99%): mp 161-166 °C; H NMR (CDCl3) δ 8.13-8.10
10.5 (broad s, 1 H), 6.12 (s, 2 H), 3.80-3.85 (m, 11 H), 2.74 (s,
2 H), 1.47 (s, 6 H); 13C NMR (CDCl3) δ 173.9, 160.6, 158.6,
105.6, 90.5, 55.7, 55.3, 45.9, 43.6, 28.4, 21.0. Anal. (C15H22O5S)
C, H.
(m, 2 H), 7.78-7.75 (m, 2 H), 7.62 (m, 1 H), 7.53-7.48 (m, 3
H), 7.44-7.34 (m, 7 H), 7.07 (d, J ) 8.9 Hz, 1 H), 6.21 (s, 1 H),
618 (t, J ) 9.3 Hz, 1 H), 5.81 (dd, J ) 2.1 and 9.0 Hz, 1 H),
5.67 (d, J ) 6.8 Hz, 1 H), 5.59 (dd, J ) 7.2 and 10.0 Hz, 1 H),
4.95 (d, J ) 8.7 Hz, 1 H), 4.79 (d, J ) 2.5 Hz, 1 H), 4.32 (d, J
) 8.4 Hz, 1 H), 4.19 (d, J ) 8.4 Hz, 1 H), 3.93 (d, J ) 6.8 Hz,
1 H), 3.62 (broad s, 1 H), 2.64 (m, 3 H), 2.38 (s, 3 H), 2.34 (m,
2 H), 2.16 (s, 3 H), 1.89 (m, 1 H), 1.85 (s, 3 H), 1.83 (s, 3 H),
1.76 (broad s, 1 H), 1.67 (broad s, 1 H), 1.49 (s, 3 H), 1.45 (s,
3 H), 1.20 (s, 3 H), 1.17 (s, 3 H); 13C NMR (CDCl3) δ 201.8,
172.4, 170.4, 169.9, 168.8, 166.9, 140.4, 138.0, 133.8, 133.7,
133.0, 131.9, 130.2, 129.1, 129.0, 128.7, 128.3, 127.1, 127.0,
83.9, 81.1, 78.5, 77.2, 75.3, 74.3, 73.3, 72.2, 71.7, 56.1, 54.9,
50.3, 47.1, 43.2, 41.8, 35.6, 33.5, 33.0, 32.4, 26.6, 22.5, 20.8,
14.7, 10.9; LRMS (APIMS) m/z 970 (MH+), 987 (M + NH4+),
992 (M + Na+). Anal. (C52H59NO15S) C, H, N.
2′-(2,2,2-Tr ich lor oeth oxyca r bon yl)-7-[3-m eth yl-3-(2,4,6-
tr im eth oxyp h en ylm eth ylsu lfa n yl)bu tyr yl]p a clita xel (4).
To compound 2 (2.3804 g, 2.3126 mmol) in dichloromethane
(50 mL) was added 3 (2.4110 g, 7.6686 mmol), 4-(dimethyl-
amino)pyridine (509.7 mg, 4.172 mmol), and then 1-[3-(di-
methylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.4583
g, 7.6072 mmol) at room temperature. The reaction mixture
was stirred overnight and washed with water, saturated
sodium bicarbonate, 0.2 M citric acid, saturated sodium
bicarbonate, and brine. The organic phase was dried (sodium
sulfate), concentrated, and purified by chromatography twice
(silica gel, ethyl acetate/hexane 1:3, and silica gel, methanol/
dichloromethane 1:99) to give the title compound 4 (2.0752 g,
7-(3-Meth yl-3-n itr osoth iobu tyr yl)p a clita xel (7). To com-
pound 6 (659.2 mg, 0.6795 mmol) in dichloromethane (8.5 mL)
was added tert-butyl nitrite (120 µL, 104 mg, 1.01 mmol) at
room temperature. The reaction mixture was stirred at room
temperature for 15 min, concentrated to dryness, and dissolved
in dichloromethane. The dichloromethane solution was washed
with water and brine. The organic phase was dried (sodium
sulfate), concentrated, dried in a vacuum, and purified by
chromatography (silica gel, ethyl acetate/hexane 1:3, then ethyl
acetate/hexane 1:2) to give the title compound 7 (602.5 mg,
0.6030 mmol, 89%) as a green solid: mp 165-170 °C (melt to
1
1.5653 mmol, 67%): mp 129-138 °C; H NMR (CDCl3-D2O)
δ 8.15-8.12 (m, 2 H), 7.77-7.74 (m, 2 H), 7.61 (m, 1 H), 7.54-
7.49 (m, 3 H), 7.42-7.38 (m, 7 H), 6.94 (d, J ) 9.3 Hz, 1 H),
6.28 (s, 1 H), 6.26 (t, J ) 9.3 Hz, 1 H), 6.10 (s, 2 H), 6.05 (dd,
J ) 2.6 and 9.3 Hz, 1 H), 5.68 (m, 2 H), 5.56 (d, J ) 2.8 Hz, 1
H), 4.97 (d, J ) 8.2 Hz, 1 H), 4.78 (AB q, J ) 11.9 Hz, ∆νAB
)
17.8 Hz, 2 H), 4.34 (d, J ) 8.4 Hz, 1 H), 4.29 (d, J ) 8.4 Hz, 1
H), 3.98 (d, J ) 6.8 Hz, 1 H), 3.82 (s, 6 H), 3.79 (s, 2 H) 3.78
(s, 3 H), 2.71 (s, 2 H), 2.67 (m, 1 H), 2.47 (s, 3 H), 2.42 (m, 1
H), 2.22 (m, 1 H), 2.14 (s, 3 H), 2.00 (s, 3 H), 1.92 (m, 1 H),
1.83 (s, 3 H), 1.47 (s, 3 H), 1.41 (s, 3 H), 1.21 (s, 3 H), 1.17 (s,
3 H); 13C NMR (CDCl3) δ 201.9, 170.0, 169.6, 168.6, 167.4,
167.0, 166.9, 160.2, 158.6, 153.2, 140.9, 136.4, 133.7, 133.5,
132.7, 132.0, 130.2, 129.2, 129.1, 128.7, 128.6, 127.1, 126.6,
107.7, 93.9, 90.7, 84.1, 81.0, 78.6, 77.5, 77.2, 76.3, 75.2, 74.6,
72.3, 71.4, 56.0, 55.7, 55.3, 52.8, 47.0, 46.6, 43.8, 43.3, 35.3,
33.2, 28.7, 28.0, 26.5, 22.7, 21.2, 20.8, 20.6, 14.5, 10.9; LRMS
(APIMS) m/z 1341 (M + NH4+).
1
a brown oil, losing green color between 120 and 130 °C); H
NMR (CDCl3-D2O) δ 8.11-8.08 (m, 2 H), 7.76-7.74 (m, 2 H),
7.61 (m, 1 H), 7.52-7.46 (m, 3 H), 7.42-7.31 (m, 7 H), 7.12 (d,
J ) 8.9 Hz, 1 H), 6.19 (s, 1 H), 616 (t, J ) 8.8 Hz, 1 H), 5.79
(dd, J ) 2.0 and 8.7 Hz, 1 H), 5.65 (d, J ) 6.8 Hz, 1 H), 5.57
(dd, J ) 7.2 and 10.3 Hz, 1 H), 4.91 (d, J ) 8.7 Hz, 1 H), 4.78
(d, J ) 2.3 Hz, 1 H), 4.30 (d, J ) 8.4 Hz, 1 H), 4.17 (d, J ) 8.4
Hz, 1 H), 3.90 (d, J ) 6.7 Hz, 1 H), 3.25 (s, 2 H), 2.52 (m, 1 H),
2.36 (s, 3 H), 2.31 (m, 2 H), 2.16 (s, 3 H), 1.99 (s, 3 H), 1.95 (s,
3 H), 1.88 (m, 1 H), 1.82 (s, 3 H), 1.77 (s, 3 H), 1.19 (s, 3 H),
1.15 (s, 3 H); 13C NMR (CDCl3) δ 201.7, 172.3, 170.4, 169.2,
168.9, 167.0, 166.8, 140.4, 138.0, 133.7, 133.6, 132.9, 131.9,
130.1, 129.0, 128.9, 128.7, 128.3, 127.04, 127.02, 83.8, 81.0,
78.5, 76.4, 75.2, 74.2, 73.2, 72.1, 71.9, 56.0, 54.9, 53.6, 47.1,
47.0, 43.2, 35.5, 33.3, 29.5, 28.6, 26.5, 22.5, 20.71, 20.76, 14.6,
10.8; LRMS (APIMS) m/z 999 (MH+), 1016 (M + NH4+), 1021
(M + Na+). Anal. (C52H58N2O16S) C, H, N.
Ad a m a n ta n e-2-th ion e (9). 2-Adamantanone 8 (48.46 g,
322.6 mmol) in pyridine (300 mL) was heated to 90 °C, and
phosphorus pentasulfide (17.84 g, 40.13 mmol) was added. The
reaction mixture was stirred at 90 °C for 2 h, and heating was
turned off. The reaction mixture was set at room temperature
to cool slowly. After sitting at room temperature overnight, a
gum phase and a solution phase were formed. The pyridine
solution phase was decanted and concentrated to dryness. The
residual semisolid was treated with hexane (400 mL) to give
an orange solution containing a light-brown suspension. The
suspension was removed by filtration. The filtrate was con-
centrated to dryness to give an orange solid (50.36 g) after
2′-(2,2,2-Tr ich lor oeth oxyca r bon yl)-7-(3-m eth yl-3-su lf-
a n ylbu tyr yl)p a clita xel (5). L-Cysteine (7.21 g, 59.5 mmol)
was dissolved in formic acid (100 mL). Compound 4 (1.6357 g,
1.2338 mmol) in dichloromethane (100 mL) was added at room
temperature to give a colorless solution. The reaction mixture
was stirred at room temperature for 40 min, concentrated to
dryness, treated with ethyl acetate, and washed with saturated
sodium bicarbonate three times and brine twice. The organic
phase was dried (sodium sulfate), concentrated, and purified
by chromatography (silica gel, ethyl acetate/hexane 1:4, then
ethyl acetate/hexane 1:3) to give the title compound 5 (1.3099
g, 1.1435 mmol, 73%): mp 157-164 °C; 1H NMR (CDCl3-D2O)
δ 8.15-8.11 (m, 2 H), 7.77-7.74 (m, 2 H), 7.62 (m, 1 H), 7.54-
7.48 (m, 3 H), 7.44-7.35 (m, 7 H), 6.94 (d, J ) 9.3 Hz, 1 H),
6.26 (s, 1 H), 6.26 (t, J ) 9.3 Hz, 1 H), 6.05 (dd, J ) 2.7 and
9.3 Hz, 1 H), 5.69 (d, J ) 6.9 Hz, 1 H), 5.63 (dd, J ) 7.0 and
11.3 Hz, 1 H), 5.55 (d, J ) 2.8 Hz, 1 H), 4.96 (d, J ) 8.3 Hz, 1
H), 4.78 (AB q, J ) 11.9 Hz, ∆νAB ) 17.8 Hz, 2 H), 4.33 (d, J
) 8.4 Hz, 1 H), 4.19 (d, J ) 8.4 Hz, 1 H), 3.97 (d, J ) 6.8 Hz,
1 H), 2.64 (m, 3 H), 2.48 (s, 3 H), 2.42 (m, 1 H), 2.24 (m, 1 H),
2.15 (s, 3 H), 1.99 (s, 3 H), 1.89 (m, 1 H), 1.82 (s, 3 H), 1.49 (s,