Total Synthesis of Rifamycin S
FULL PAPER
pTsOH·H2O (21 mg, 0.11 mmol, 0.05 equiv) was added to a solution of
the crude diol (ꢀ)-35 (1.25 g) in dimethoxypropane (20 mL) at room
temperature. The reaction mixture was stirred for 2 h at room tempera-
ture, neutralized with solid NaHCO3, filtered, and evaporated. The resi-
due was purified by FC (PE/EtOAc 20:1). Yield 1.09 g 79% of (ꢀ)-36
(over 2 steps). Colorless oil; Rf =0.8(PE/EtOAc 9:1); [a]2D5 =ꢀ11, (c=
0.34 in CHCl3); 1H NMR (CDCl3, 400 MHz): d=7.33–7.29, 7.24–7.19
(2 m, 5H; arom), 5.22 (q, J=7.0 Hz, 1H; H-C(2)), 4.54 (d, J=6.4 Hz,
1H; H-C(2’)), 3.72 (dd, J=5.8, 1.3 Hz, 1H; H-C(5)), 3.56 (d, J=3.8 Hz,
2H; H-C(11)), 3.51 (dd, J=10.9, 3.8 Hz, 1H; H-C(9)), 2.82 (t, J=7.0 Hz,
1H; H-C(7)), 2.65 (sept, J=7.0 Hz, 1H; (CH3)2CHCOO-C(1)), 2.62 (dq,
J=7.0, 6.4 Hz, 1H; H-C(4)), 1.68 (dq, J=7.0, 6.4 Hz, 1H; H-C(6)), 1.63–
1.56 (m, 2H; H-C(8), H-C(10)), 1.17 (d, J=6.4 Hz, 3H; H-C(1)), 1.34 (d,
J=6.4 Hz, 3H; H-C(2’)), 1.27, 1.26 (2d, J=7.0 Hz, 6H; (CH3)2CHCOO-
C(1)), 1.18 (s, 3H; CH3-(Cacetonide)), 1.04 (d, J=7.0 Hz, 3H; CH3-C(4)),
0.93 (s+d, J=7.0, 6H; CH3-(Cacetonide), CH3-(C6)), 0.89 (s, 9H; TBSO-
C(11)), 0.83 (d, J=7.0 Hz, 3H; CH3-C(10)), 0.70 (d, J=7.0 Hz, 3H; CH3-
C(8)), 0.02, 0.01 ppm (2s, 6H; TBSO-C(11)); 13C NMR (CDCl3,
100.6 MHz): d=174.7, 150.5, 145.5, 128.2, 127.1, 126.4, 111.6, 100.1, 76.7
(3 signals), 69.4, 64.4, 42.5, 38.7, 35.5, 35.3, 34.4, 26.0, 25.6, 24.5, 23.6,
19.3, 19.2, 18.4, 13.1, 12.9, 12.5, 10.9, 10.8, ꢀ5.4, ꢀ5.5 ppm; IR (film): n˜ =
(CDCl3, 396 MHz): d=ꢀ71.87 ppm; HRMS (MALDI-TOF): m/z calcd
for C40H61F3O7SiNa+: 761.4036; found: 761.4046.
(S)-MTPA ester of (ꢀ)-37: 1H NMR (CDCl3, 400 MHz): d=7.58–7.56
(m, 2H; arom), 7.43–7.41 (m, 3H; arom), 7.30–7.28 (m, 4H; arom), 7.25–
7.21 (m, 51H; arom), 4.60 (dd, J=10.1, 4.3 Hz, Ha-C(1)), 4.51 (q, J=
6.8 Hz, H-C(1’)), 4.30 (dd, J=11.1, 6.5 Hz, Hb-C(1)), 3.70–3.68, 3.61–3.49
(2 m, 4H; H-C(3), H-C(7), H-C(9)), 2.80 (dd, J=9.2, 6.2 Hz, 1H; H-
C(5)), 2.07 (dq, J=7.7, 6.8 Hz, 1H; H-C(2)), 1.66 (quint, J=7.4 Hz, 1H;
H-C(4)), 1.63–1.53 (m, 2H; H-C(8), H-C(6)), 1.36 (d, J=6.2 Hz, 3H; H-
C(2’)), 1.18 (s, 3H; CH3-(Cacetonide)), 1.00 (s, 3H; CH3-(Cacetonide)), 0.98 (d,
J=6.8 Hz, 3H; CH3-C(4)), 0.89 (s, 9H; TBSO-C(9)), 0.87 (d, J=6.8 Hz,
3H; CH3-C(2)), 0.82, 0.70 (2d, J=6.8 Hz, 6H; CH3-C(8), CH3-C(6)),
0.03, 0.02 ppm (2 s, 6H; TBSO-C(9)); 19F NMR (CDCl3, 396 MHz): d=
ꢀ71.87 ppm; HRMS (MALDI-TOF): m/z calcd for C40H61F3O7SiNa+:
761.4036; found: 761.4033. The ee was determined by comparing integral
of the dd signal of the (S)-ester at 4.60 ppm (1H) with the total integral
from signals 4.47, 4.43, 4.40 ppm (3H) in the (R)-ester. A signal at
4.60 ppm was not observed at all in the spectrum of the (R)-ester. Con-
clusion: ee^99%.
Diacetonide (+)-38: A solution of diol (ꢀ)-35 (0.41 g, 0.71 mmol) in
AcOH (15 mL) was diluted with water (8 mL) and heated at +658C for
3 h. The solvent was evaporated in vacuo, and the residue redissolved in
MeOH (30 mL). Pd(OH)2 (10% on activated charcol, 0.20 g) was added
and the resulting suspension was stirred at room temperature under H2
atmosphere (1 bar) for 1 h. The solution was saturated with N2, filtered
through Celite, and evaporated in vacuo. The resulting tetrol was dis-
solved in CH2Cl2 (10 mL) and cooled to 58C. Dimethoxypropane (5 mL)
was added, followed by pTsOH·H2O (7 mg, 0.037 mmol, ~5 mol% of
(+)-35)). After 2 h at 08C the reaction mixture was quenched by a satu-
rated aqueous solution of NaHCO3 (15 mL) and extracted with CH2Cl2
(3ꢃ20 mL). The combined organic layers were washed with brine
(30 mL), dried (Na2SO4), and evaporated in vacuo. The residue was puri-
fied by FC (hexane/EtOAc 9:1). Yield: 0.234 g, 75%, over three steps.
Colorless oil; Rf =0.58 (hexane/EtOAc 8:2); [a]2D5 =+10.5 (c=0.2 in
CHCl3); 1H NMR (CDCl3, 400 MHz): d=5.16 (q, J=7.0 Hz, 1H; H-
C(1’)), 3.86 (dd, J=10.5, 2.2 Hz, 1H; H-C(7)), 3.70 (dd, J=11.4, 4.9 Hz,
1H; Ha-C(9)), 3.66 (dd, J=10.5, 3.7 Hz, 1H; H-C(3)), 3.52 (t, J=
11.4 Hz, 1H; Hb-C(9)), 3.27 (dd, J=9.6, 6.5 Hz, 1H; H-C(5)), 2.71 (sept,
J=7.0 Hz, 1H; (CH3)2CHCOO-C(1)), 2.34 (dq, J=10.8, 7.0 Hz, 1H; H-
C(2)), 1.85 (ddt, J=11.1, 7.1, 4.9 Hz, 1H; H-C(8)), 1.79–1.68 (m, 2H; H-
C(6), H-C(4)), 1.43 (d, J=6.8 Hz, 3H; H-C(2’)), 1.39, 1.35, (2 s, 6H;
CH3-(Cacetonide 7,9)), 1.28 (s, 6H; CH3-(Cacetonide 3,5)), 1.27, 1.26 (2d, J=
7.1 Hz, 6H; (CH3)2CHCOO-C(1)), 0.92 (d, J=7.1 Hz, 3H; CH3-C(2)),
0.89, 0.87 (2d, J=6.8, 7.1 Hz, 6H; CH3-C(4), CH3-C(6)), 0.71 ppm (d, J=
6.8 Hz, 3H; CH3-C(8)); 13C NMR (CDCl3, 100.6 MHz): d=174.5, 149.7,
111.1, 100.6, 98.1, 74.3, 72.9, 70.5, 66.7, 39.6, 39.3, 36.4, 34.3, 30.5, 29.9,
25.7, 23.6, 19.4, 19.3, 19.1, 14.2, 12.7, 12.2, 11.0, 7.9 ppm; IR (film): n˜ =
2970, 2930, 2855, 1750, 1695, 1470, 1375, 1250, 1220, 1135, 1085 cmꢀ1
;
HRMS (MALDI-TOF): m/z calcd for C36H62O6SiNa+: 641.4213; found:
641.4239; elemental analysis calcd (%) for C36H62O6Si (618.96): C 69.86,
H 10.10; found: C 69.86, H 10.04.
Stereoheptad (ꢀ)-37: Ozone was bubbled through a solution of (ꢀ)-36
(0.19 g, 0.31 mmol, 1 equiv) in anhydrous Et2O (50 mL) at 788C until it
turned blue. Then O2 was passed through it until the disappearance of
the color. The resulting mixture was quenched by BH3·Me2S (0.23 mL,
2.45 mmol, 8 equiv) at ꢀ788C. The solution was stirred for 12 h at
ꢀ788C. The mixture diluted by additional Et2O (100 mL), washed with
brine, dried over anhydrous Na2SO4, filtered, and evaporated. The resi-
due was redissolved in anhydrous Et2O (50 mL), after which LiAlH4
(35 mg, 0.92 mmol, 3 equiv) was added at ꢀ158C. The resulting reaction
mixture was left to reach room temperature and then heated under
reflux for 30 min. It was carefully quenched by a saturated aqueous so-
lution of NH4Cl (20 mL), the layers were separated, and the aqueous
phase was additionally extracted with diethyl ether (3ꢃ20 mL). The com-
bined organic layers were washed with brine (2ꢃ10 mL), dried (Na2SO4),
and evaporated. FC gave 37 (0.122 g, 76%). Colorless oil; Rf =0.28
(CH2Cl2/EtOAc 97:3); [a]D25 =ꢀ25, (c=0.55 in CHCl3); 1H NMR (CDCl3,
400 MHz): d=7.34–7.29, 7.26–7.21 (2 m, 5H; arom), 4.53 (q, J=6.8 Hz,
1H; H-C(1’)), 3.64 (d, J=5.5 Hz, 1H; H-C(3)), 3.62–3.50 (m, 5H; H-
C(9), H-C(7), H-C(1)), 3.28 (brd, J=6.2 Hz, 1H; HO-C(1)), 2.74 (dd, J=
9.7, 6.8 Hz, 1H; H-C(5)), 2.12 (ddt, J=9.1, 7.0, 5.2 Hz, 1H; H-C(2)), 1.69
(dq, J=8.6, 7.4 Hz, 1H; H-C(4)), 1.67–1.55 (m, 2H; H-C(8), H-C(6)),
1.43 (d, J=6.2 Hz, 3H; H-C(2’)), 1.17 (s, 3H; CH3-(Cacetonide)), 0.96 (d,
J=6.8 Hz, 3H; CH3-C(4)), 0.89 (d, J=6.8 Hz, 3H; CH3-C(2)), 0.88 (s,
9H; TBSO-C(9)), 0.84 (s, 3H; CH3-(Cacetonide)), 0.83, 0.77 (2d, J=6.8 Hz,
6H; CH3-C(8), CH3-C(6)), 0.01, 0.00 ppm (2 s, 6H; TBSO-C(9));
13C NMR (CDCl3, 100.6 MHz): d=145.0, 128.4, 127.5, 126.5, 100.6, 78.5,
77.9, 76.6, 69.5, 66.2, 64.3, 39.1, 38.4, 36.4, 35.2, 26.0, 25.4, 24.1, 23.4, 18.4,
12.8, 12.7, 12.3, 10.8, ꢀ5.4, ꢀ5.5 ppm; IR (film): n˜ =3490, 2960, 2930,
2855, 1600, 1470, 1380, 1250, 1220, 1085, 1030 cmꢀ1; HRMS (MALDI-
TOF): m/z calcd for C30H54O5SiNa+: 545.3638; found: 545.3631; elemen-
tal analysis calcd (%) for C30H54O5Si (522.83): C 68.92, H 10.41; found: C
68.92, H 10.50.
2970, 2925, 2855, 1755, 1695, 1465, 1455, 1385, 1230, 1180, 1145 cmꢀ1
;
HRMS (MALDI-TOF): m/z calcd for C25H44O6Na+: 463.3036; found:
463.3031; elemetal analysis calcd (%) for C25H44O6 (440.61): C 68.15, H
10.07; found: C 68.22 , H 9.98.
(2S)-2-((1’S,3’S,4’S,5’S,6’S)-1-Ethyl-4’,6’,8’-trimethyl-2’,9’dioxabicyclo-
[3.3.1]non-7’-en-3’-yl)propyl 3,5-dinitrobenzoate (40): A solution of diol
(ꢀ)-35 (0.14 g, 0.24 mmol, 1 equiv) in Et2O (5 mL) was added dropwise
at ꢀ788C to a solution of MeLi·LiBr (2m, 0.80 mL, 1.6 mmol, 6.6 equiv)
in Et2O (5 mL). After 4 h at ꢀ788C the reaction mixture was carefully
poured at room temperature into a saturated aqueous solution of NH4Cl
(20 mL). The layers were separated, and the aqueous phase was extracted
with EtOAc (5ꢃ20 mL). The combined organic layers were washed with
brine (10 mL), dried (Na2SO4), and evaporated. The residue was dis-
solved in 90% aqueous acetic acid (10 mL) and heated at 658C over-
night. The solvent was evaporated, and traces of acetic acid were elimi-
nated by azeotropic evaporation with toluene (2ꢃ10 mL) and pyridine
(10 mL). The resulting oil was dissolved in pyridine (10 mL), and 3,5-di-
nitrobenzoyl chloride (0.28 g, 1.21 mmol, 5 equiv) was added at 158C.
The reaction mixture was stirred for 3 h at room temperature. It was di-
luted by Et2O (100 mL), washed successively with a saturated aqueous
solution of CuSO4 (4ꢃ20 mL), water (1ꢃ20 mL), and saturated aqueous
(R)-MTPA ester of (ꢀ)-37: See the general procedure for preparing
MTPA esters of (ꢀ)-2. 1H NMR (CDCl3, 400 MHz): d=7.58–7.56 (m,
2H; arom), 7.43–7.41 (m, 3H; arom), 7.31–7.21 (m, 5H; arom), 4.47 (dd,
J=10.5, 4.1 Hz, Ha-C(1)), 4.43 (q, J=6.8 Hz, H-C(1’)), 4.40 (dd, J=10.5,
6.2 Hz, Hb-C(1)), 3.70–3.68, 3.62–3.50 (2 m, 4H; H-C(3), H-C(7), H-
C(9)), 2.77 (dd, J=9.9, 6.2 Hz, 1H; H-C(5)), 2.06 (m, 1H; H-C(2)), 1.64
(quint, J=7.4 Hz, 1H; H-C(4)), 1.61–1.52 (m, 2H; H-C(8), H-C(6)), 1.31
(d, J=6.8 Hz, 3H; H-C(2’)), 1.18 (s, 3H; CH3-(Cacetonide)), 0.99 (s, 3H;
CH3-(Cacetonide)), 0.97 (d, J=7.4 Hz, 3H; CH3-C(4)), 0.88 (s, 9H; TBSO-
C(9)), 0.86 (d, J=6.8 Hz, 3H; CH3-C(2)), 0.82, 0.77 (2d, J=6.8 Hz, 6H;
CH3-C(8), CH3-C(6)), 0.02, 0.01 ppm (2s, 6H; TBSO-C(9)); 19F NMR
Chem. Eur. J. 2005, 11, 465 – 476
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
475