Synthesis of the C19-C28 Segment of Rifamycin S
J. Am. Chem. Soc., Vol. 119, No. 42, 1997 10039
(3R,4R,5S,6S)-6-[(Benzyloxy)methoxy]-7-(tert-butyldiphenyl-
silanyloxy)-4-methoxymethoxy-3,5-dimethylheptanoic Acid Methyl
Ester (6). To a suspension of CuI (4.17 g, 21.9 mmol) in THF (150
mL) was added MeLi‚LiBr (1.5 M in ether, 29.2 mL, 43.8 mmol) at
-15 °C, and the mixture was allowed to warm up to 0 °C over 30 min
and then cooled to -78 °C. To the resulting mixture were added Me3-
SiCl (11.1 mL, 87.2 mmol) and a solution of 5 (4.4 g, 7.3 mmol) in
THF (20 mL). The reaction was continued for 3 h at -78 °C and
quenched with saturated NH4Cl, and the mixture was diluted with
AcOEt and concentrated NH4OH. The aqueous layer was extracted
with AcOEt, and the combined organic extracts were washed with
saturated NH4Cl-NH4OH (1:1), saturated NH4Cl, and brine and then
dried over Na2SO4. The crude product was purified by chromatography
saturated NaHCO3, saturated NH4Cl, and brine and then dried over
Na2SO4. The product was purified by chromatography to afford the
diol as an oil (495 mg, 82%): [R]D -9.1° (c 1.8, CHCl3); H-NMR:
1
δ (ppm) ) 7.73-7.66 (m, 4H), 7.47-7.26 (m, 11H), 4.86 (d, J ) 6.94
Hz, 1H), 4.79 (dd, J ) 4.4, 6.4 Hz, 2H), 4.70 (d, J ) 11.9 Hz, 1H),
4.57 (dd, J ) 6.3, 13.4 Hz, 2H), 4.10 (m, 1H), 3.86-3.64 (m, 4H),
3.59-3.47 (m, 2H), 3.34 (s, 3H), 2.15-2.10 (m, 1H), 1.77-1.71 (m,
1H), 1.07 (s, 9H), 0.90 (d, J ) 6.9 Hz, 3H), 0.87 (d, J ) 7.1 Hz, 3H);
13C-NMR: δ (ppm) ) 137.66 (0), 135.61, 135.59, 135.56, 133.26 (0),
133.25 (0), 129.69, 128.33, 127.71, 127.66, 127.63, 127.59, 98.89,
94.66, 82.08, 80.58, 70.80, 70.01(0), 65.17 (0),64.06 (0), 56.02, 37.97,
37.03, 26.78, 19.16 (0), 10.54, 10.26; IR: 3460 (br), 1960, 1890, 1830,
1730, 1590 cm-1; HRMS: C35H50O7SiNa, calcd: 633.3223, found:
633.3197.
1
to afford 6 as an oil (3.8 g, 85%): [R]D -14.8° (c 1.0, CHCl3); H-
NMR: δ (ppm) ) 7.72-7.68 (m, 4H), 7.44-7.26 (m, 11H), 4.88 (d,
J ) 6.8 Hz, 1H), 4.83 (d, J ) 6.8 Hz, 1H), 4.67-4.54 (m, 4H), 3.90-
3.86 (dd, J ) 3.2, 11.2 Hz, 1H), 3.78-3.73 (dd, J ) 4.5, 11.2 Hz, 1H),
3.68-3.56 (s, m, 5H), 3.34 (s, 3H), 2.64-2.58 (dd, J ) 4.1, 14.7 Hz,
1H), 2.30-2.05 (m, 3H), 1.08 (s, 9H), 0.97 (d, J ) 6.5 Hz, 3H), 0.89
(d, J ) 7.0 Hz, 3H); 13C-NMR: δ (ppm) ) 173.64, 137.83, 135.81,
135.50, 135.46, 133.26, 129.51, 128.13, 127.79, 127.51, 127.47, 127.31,
98.24, 94.83, 82.86, 80.60, 69.62, 64.10, 55.61, 51.15, 37.85, 36.53,
33.83, 26.67, 19.08, 16.89, 10.14; IR (neat): 2950, 2890, 1740, 1430,
1115, 1040 cm-1; HRMS: C36H50O7SiNa, calcd: 645.3223, found:
645.3252.
(2R,3R,4R,5S,6S)-6-[(Benzyloxy)methoxy]-7-[(tert-butyldiphenyl-
silanyl)oxy]-2-hydroxy-4-methoxymethoxy-5-methylheptanoic Acid
Methyl Ester (7). To a solution of 6 (3.58 g, 5.76 mmol) in THF
(100 mL) was added KHMDS (0.5 M in toluene, 16.1 mL, 8.0 mmol)
at -78 °C. The resulting mixture was stirred for 30 min, and a solution
of the Davis oxaziridine reagent7b (3.0 g, 115 mmol) in THF (20 mL)
was added. The reaction was continued for 3 h at -78 °C and quenched
with saturated NH4Cl. The mixture was extracted with AcOEt, and
the combined organic extracts were washed with saturated NH4Cl and
brine and then dried over Na2SO4. The crude product was purified by
chromatography to give 7 as an oil (3.0 g, 80%): [R]D -17.2° (c 1.1,
CHCl3); 1H-NMR: δ (ppm) ) 7.70-7.66 (m, 4H), 7.43-7.27 (m, 11H),
4.87 (d, J ) 6.9 Hz, 1H), 4.82 (d, J ) 6.9 Hz, 1H), 4.76 (d, J ) 6.3
Hz, 1H), 4.68 (d, J ) 6.3 Hz, 1H), 4.67 (d, J ) 11.0 Hz, 1H), 4.64 (d,
J ) 11.0 Hz, 1H), 4.53 (d, J ) 2.2 Hz, 1H), 3.93-3.88 (m, 2H), 3.80-
3.72 (s, m, 4H), 3.61-3.58 (m, 1H), 3.32 (s, 3H), 2.17-2.05 (m, 2H),
1.06 (s, 9H), 0.87 (d, J ) 7.1 Hz, 3H), 0.84 (d, J ) 6.9 Hz, 3H);
13C-NMR: δ (ppm) ) 175.38, 137.78, 135.51, 133.30, 129.55, 128.18,
127.63, 127.56, 127.51, 127.39, 98.86, 94.89, 80.66, 80.62, 70.58, 69.89,
64.32, 55.71, 52.17, 39.38, 36.45, 26.71, 19.14, 10.60, 9.53; IR (neat):
3520, 2950, 1738, 1430, 1150, 1120, 1040 cm-1; HRMS: C36H50O8-
SiNa, calcd: 661.3172, found: 661.3202.
To a solution of the above diol (495 mg, 0.81 mmol) in CH2Cl2 (15
mL) was added trityl-4-dimethylaminopyridium chloride (649 mg, 2
equiv), and the resulting mixture was refluxed for 7 h. After removing
solvent, the residue was purified by chromatography to give the trityl
ether as an oil (418 mg, 60%) and starting material diol (109 mg,
1
22%): [R]D -0.5° (c 1.2, CHCl3); H-NMR: δ (ppm) ) 7.71-7.68
(m, 4H), 7.51-7.22 (m, 26H), 4.89 (d, J ) 6.9 Hz, 1H), 4.80 (t, J )
6.7 Hz, 2H), 4.69 (d, J ) 12.1 Hz, 1H), 4.66 (d, J ) 6.3 Hz, 1H), 4.55
(d, J ) 12.0 Hz, 1H), 4.32 (br, 1H), 3.90-3.83 (m, 2H), 3.76 (dd, J )
4.8, 11.2 Hz, 1H), 3.63-3.61 (m, 1H), 3.38 (s, 3H), 3.37-3.31 (m,
1H), 3.23 (d, J ) 3.6 Hz, 1H), 3.00 (dd, J ) 6.0, 8.9 Hz, 1H), 2.13 (m,
1H), 1.87 (m, 1H), 1.08 (s, 9H), 0.90 (d, J ) 7.0 Hz, 3H), 0.74 (d, J
) 6.8 Hz, 3H); 13C-NMR: δ (ppm) ) 144.14 (0), 137.88 (0), 135.64,
135.61, 133. 39 (0), 133.37, 129.63, 128.70, 128.30, 127.76, 127.73,
127.67, 127.63, 127.50, 126.88, 98.95 (-), 94.85 (-), 86.45 (0), 82.11,
80.81, 69.92 (-), 69.05 (-), 65.84 (-), 64.39, 55.96, 37.91, 37.18,
26.82, 19.20 (0), 10.20, 9.98; IR: 3460 (br), 2950, 1960, 1890, 1830,
1730, 1590 cm-1; HRMS: C54H64O7SiNa, calcd: 875.4318, found:
875.4321.
To a solution of the above compound (411 mg, 0.48 mmol) in DMF
(4 mL) at 0 °C were added sodium hydride (60% in mineral oil, 191
mg, 10 equiv) and then methyl iodide (0.45 mL, 7.2 mmol). The
reaction was continued for 1 h at room temperature and quenched with
MeOH. The product was directly purified by chromatography to afford
9 as an oil (408 mg, 97%): [R]D -13.1° (c 1.9, CHCl3); 1H-NMR: δ
(ppm) ) 7.73-7.68 (m, 4H), 7.50-7.22 (m, 26H), 4.87 (dd, J ) 6.1,
7.4 Hz, 2H), 4.75 (d, J ) 6.3 Hz, 1H), 4.70 (d, J ) 6.4 Hz, 1H), 4.66
(d, J ) 12.4 Hz, 1H), 4.57 (m, 2H), 3.94 (dd, J ) 2.7, 11.3 Hz, 1H),
3.86 (d, J ) 9.3 Hz, 1H), 3.79-3.74 (m, 2H), 3.68-3.64 (m, 1H),
3.39 (s, 3H), 3.38 (s, 3H), 3.10 (dd, J ) 5.5, 9.5 Hz, 1H), 2.03 (m,
1H), 1.89 (m, 1H), 1.08 (s, 9H), 0.84 (d, J ) 7.1 Hz, 3H), 0.72 (d, J
) 7.0 Hz, 3H); 13C-NMR: δ (ppm) ) 144.12, 138.14, 135.66, 135.62,
133.56, 129.57, 129.54, 128.68, 128.19, 127.70, 127.61, 127.59, 127.53,
127.31, 126.86, 98.67, 95.18, 86.70, 81.38, 81.16, 79.24, 69.67, 64.85,
58.19, 55.57, 38.38, 36.46, 26.80, 19.23, 10.21, 9.54; IR: 2930, 1960,
1890, 1830, 1730, 1600 cm-1; MS: 889 (M + 23), 867 (M + 1).
(4R,5R,6S,7S,8R)-4-[(Benzyloxy)methoxy]-8-methoxy-6-meth-
oxymethoxy-5,7-dimethyl-9-trityloxynon-2-enoic Acid Methyl Ester
(10). To a solution of 9 (404 mg, 0.47 mmol) in THF (4 mL) was
added TBAF (1.0 M in THF, 0.93 mL, 2 equiv) at room temperature,
and the reaction was continued for 4.5 h. The product was purified by
chromatography to afford the alcohol as an oil (283 mg, 96%): [R]D
-0.9° (c 1.56, CHCl3); 1H-NMR: δ (ppm) ) 7.48-7.46 (m, 6H),
7.37-7.22 (m, 14H), 4.90 (dd, J ) 7.0, 15.8 Hz, 2H), 4.78 (d, J )
11.8 Hz, 1H), 4.69 (dd, J ) 6.5, 15.2 Hz, 2H), 4.60 (d, J ) 11.9 Hz,
1H), 3.86 (br, 1H), 3.76 (d, J ) 9.4 Hz, 1H), 3.67 (m, 1H), 3.61-3.44
(m, 2H), 3.41-3.59 (s, s, m, 8H), 3.10 (dd, J ) 5.6, 9.6 Hz, 1H),
1.92-1.86 (m, 1H), 1.86-1.76 (m, 1H), 0.89 (d, J ) 7.0 Hz, 3H),
0.67 (d, J ) 6.9 Hz, 3H); 13C-NMR: δ (ppm) ) 144.04 (0), 137.18
(0), 128.64, 128.47, 127.86, 127.73, 127.91, 98.76 (-), 95.64 (-), 86.74
(0), 84.97, 81.47, 79.18, 70.14 (-), 64.56 (-), 64.09 (-), 58.05, 55.67,
(3R,4R,5S)-5-[(1R, 2S)-3-(tert-Butyldiphenylsilanyloxy)-2-hydroxy-
1-(methylpropyl)]-3-hydroxy-4-methyldihydrofuran-2-one (8). To
a solution of 7 (36 mg, 0.056 mmol) in dry dichloromethane (1 mL) at
-40 °C was added TMSBr (75 µL, 0.56 mmol). The resulting mixture
was stirred for 2 h, and the temperature was allowed to rise to 0 °C.
The reaction was quenched with saturated NH4Cl, and the mixture was
diluted with AcOEt, washed with saturated NaHCO3 and brine, and
then dried over Na2SO4. The product was purified by chromatography
to give 8 as a crystalline solid, mp 122-124 °C (18.5 mg, 72%): [R]D
-8.5° (c 0.9, CHCl3); 1H-NMR: δ (ppm) ) 7.67-7.64 (m, 4H), 7.47-
7.38 (m, 6H), 4.56 (d, J ) 10.4 Hz, 1H), 4.08 (d, J ) 10.7 Hz, 1H),
3.83 (dd, J ) 3.1, 10.2 Hz, 1H), 3.69-3.65 (m, 1H), 3.60-3.56 (m,
1H), 2.29-2.22 (m, 1H), 1.84-1.80 (m, 1H), 1.20 (d, J ) 6.5 Hz,
3H), 1.07 (s, 9H), 0.73 (d, J ) 7.0 Hz, 3H); 13C-NMR: δ (ppm) )
176.72 (0), 135.40, 135.37,132.72 (0), 132.61 (0), 129.89, 129.88,
127.78, 127.76. 81.29, 74.57, 72.34, 65.86(-), 40.47, 35.93, 26.73,
19.14 (0), 13.81, 8.22; IR: 3580, 2940, 2870,1780, 1595 cm-1
HRMS: C25H34O5SiNa, calcd: 465.2073, found: 465.2088.
;
38.11, 36.13, 10.16, 9.85; IR: 3440 (br), 2950, 1960, 1830, 1600 cm-1
HRMS: C39H49O7, calcd: 629.3478, found: 629.3473.
;
(2R,3S,4R,5S,6S)-6-[(Benzyloxy)methoxy]-6-[(tert-butyldiphenyl-
silanyl)oxy]-2-methoxy-4-methoxymethoxy-3,5-dimethyl-1-trityloxy-
heptane (9). To a solution of 7 (632 mg, 1.0 mmol) in THF-H2O (10
mL, 4:1) was added NaBH4 (510 mg, 15 equiv), and the resulting
mixture was stirred for 72 h at room temperature. The reaction was
carefully quenched with 2% HCl, and the reaction mixture was extracted
with AcOEt. The combined organic extracts were washed with
To a solution of oxalyl chloride (28 mL, 0.32 mmol) in CH2Cl2 (0.5
mL) at -70 °C was added DMSO (45 mL, 0.62 mmol), and the
resulting mixture was stirred for 15 min during which time the
temperature was allowed to rise to -55 °C, and then a solution of the
above alcohol (34 mg, 0.54 mmol) in CH2Cl2 (1 mL) was added. The