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DOI: 10.1055/s-2006-926263
Synthesis of the C1-C5 and C6-C24 Fragments of the RNA Polymerase Inhibitors Ripostatin A and B
Publication History
Publication Date:
06 February 2006 (online)
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Abstract
The enantioselective synthesis of the C1-C5 and C6-C24 fragments of the ripostatins utilize a Negishi coupling, two Nagao acetate aldol reactions followed by a Denmark vinylogous aldol reaction and Stille couplings as key C-C bond forming steps.
Key words
natural product synthesis - antibiotics - RNA polymerase inhibitors - vinylogous aldol reaction - Nagao aldol reaction
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1a
Irschik H.Augustiniak H.Gerth K.Höfle G.Reichenbach H. J. Antibiot. 1995, 48: 787 -
1b
Augustiniak H.Irschik H.Reichenbach H.Höfle G. Liebigs Ann. 1996, 1657 - 2
O’Neill A.Oliva B.Storey C.Hoyle A.Fishwick C.Chopra I. Antimicrob. Agents Chemother. 2000, 44: 3163 - 3
Wipf P.Lim S. Angew. Chem. 1993, 105: 1095 -
4a
Nagao Y.Hagiwara Y.Kumagai T.Ochiai M. J. Org. Chem. 1986, 51: 2391 -
4b
Nagao Y.Hagiwara Y.Kumagai T.Ochiai M. J. Org. Chem. 1986, 51: 2391 - 5
Denmark SE.Beutner GL. J. Am. Chem. Soc. 2003, 125: 7800 -
7a The configuration of the newly formed stereogenic center was further proven for acetonide 17 according to Rychnovsky et al. Acetonide 17 was prepared after DIBAL-H reduction of 8 followed by protection of the 1,3-diol moiety (Figure 2). See:
Rychnovsky SD.Rogers BN.Richardson TI. Acc. Chem. Res. 1998, 31: 9 -
7b
Experimental Procedure.
DIBAL-H (50 µL, 1 M) in hexane (0.05 mmol) was added to a stirred solution of ethyl ester 8 (3 mg, 0.005 mmol) in abs. CH2Cl2 (1 mL) at -78 °C. After 20 min sat. Na,K-tartrate solution (5 mL) was added and stirred rapidly at r.t. for 1 h. The aqueous phase was extracted several times with CH2Cl2. The combined organic phases were dried with MgSO4 and concentrated in vacuo to yield 2.5 mg of the triol which was used without further purification for the next step.
The crude product was dissolved in 2,2-dimethoxypropane (1 mL) and PPTS (1 mg, 4 µmol) was added. After stirring for 1 h at r.t. aq phosphate buffer solution (pH = 7, 5 mL) was added. The aqueous phase was extracted several times with CH2Cl2. The combined organic phases were dried with MgSO4, concentrated in vacuo and purified by flash chromatography (PE-EtOAc, 10:1 to 2:1) to yield acetonide 17 (1 mg, 2 µmol, 40% yield). 1H NMR (400 MHz, CDCl3): δ = 0.04 (s, 3 H, TBS), 0.05 (s, 3 H, TBS), 0.88 (s, 9 H, TBS), 1.25 (s, 3 H, H-20), 1.35 (s, 3 H, H-22), 1.42 (s, 3 H, H-23), 1.42-1.73 (m, 6 H, H-6, H-8, H-10), 1.70 (s, 3 H, H-19), 2.00-2.05 (m, 2 H, H-11), 2.07 (dd, J = 13.7, 6.3 Hz, 1 H, H-4), 2.26 (dd, J = 13.7, 6.3 Hz, 1 H, H-4), 3.35 (d, J = 7.3 Hz, 2 H, H-14), 3.88-4.01 (m, 3 H, H-5, H-7, H-9), 4.16 (d, J = 6.8 Hz, 1 H, H-1), 4.17 (d, J = 6.8 Hz, 1 H, H-1), 5.33 (t, J = 7.3 Hz, 1 H, H-13), 5.45 (t, J = 6.8 Hz, 1 H, H-2), 7.14-7.20 (m, 3 H, Ph), 7.23-7.30 (m, 2 H, Ph) ppm. 13C NMR (100 MHz, CDCl3): δ = -4.5, -4.0, 16.3, 16.9, 18.1, 20.1, 25.9, 30.3, 34.1, 34.3, 36.5, 37.5, 44.3, 46.3, 59.3, 65.7, 67.4, 68.1, 98.4, 123.1, 125.7, 125.8, 2 × 128.3, 136.0, 136.4, 141.7 ppm. - 10
Ma S.Lu X. J. Chem. Soc., Chem. Commun. 1990, 1643
References and Notes
The pivaloate protection was beneficial for high diastereo-selectivity (dr = 93:7). In contrast, the corresponding TBS-protected aldehyde gave the vinylogous aldol product in only 4:1 dr.
8
Analytical Data for Compounds 8 and 16:
Compound 8: Aldehyde 6 (17 mg, 36 µmol) was dissolved in CH2Cl2 (0.3 mL) under nitrogen. Bisphosphoramide (R,R)-12 (3 mg, 3.5 µmol), TBAI (5 mg, 13.5 µmol) and DIPEA (5 µL, 30 µmol) were added and the solution was cooled to -78 °C. Then, 1 M SiCl4 in CH2Cl2 (100 µL, 100 µmol) was added. Ketene acetal 11 (50 µL, 0.2 mmol) was added dropwise. The solution was stirred at -40 °C for 4 d and then poured into a rapidly stirring 1:1 sat. aq KF-KH2PO4 (1.0 M) solution (10 mL). This biphasic mixture was stirred vigorously for 2 h at r.t. The aqueous phase was extracted several times with CH2Cl2. The combined organic phases were dried with MgSO4, concentrated in vacuo and purified by flash column chromatography (PE-EtOAc, 10:1 to 7:1) to yield aldol product 8 (10 mg, 16.6 µmol, 46% yield). [α]D
20 -13.0 (c 1,CHCl3). 1H NMR (400 MHz, CDCl3, TMS = 0 ppm): δ = 0.02 (s, 3 H, TBS), 0.03 (s, 3 H, TBS), 0.88 (s, 9 H, TBS), 1.18 (s, 9 H, Piv), 1.27 (t, J = 7.2 Hz, 3 H, OEt), 1.52-1.84 (m, 6 H, H-6, H-8, H-10), 1.71 (d, J = 0.8 Hz, 3 H, H-19), 1.96-2.12 (m, 2 H, H-11), 2.17 (d, J = 1.0 Hz, 3 H, H-20), 2.22 (dd, J = 13.3, 8.2 Hz, 1 H, H-4), 2.33 (dd, J = 13.3, 4.1 Hz, 1 H, H′-4), 3.35 (d, J = 7.1 Hz, 2 H, H-14), 3.70 (m, 1 H, H-9), 3.86 (dddd, J = 12.3, 8.2, 4.1, 4.1 Hz, 1 H, H-5), 4.14 (q, J = 7.2 Hz, 2 H, OEt), 5.01 (m, 1 H, H-7), 5.35 (tq, J = 7.1, 0.8 Hz, 1 H, H-13), 5.71 (d, J = 1.0 Hz, 1 H, H-2), 7.14-7.21 (m, 3 H, Ph), 7.24-7.31 (m, 2 H, Ph) ppm. 13C NMR (100 MHz, CDCl3, CDCl3 = 77 ppm): δ = -4.7, -4.1, 14.2, 16.3, 18.0, 18.8, 25.9, 27.1, 34.2, 34.7, 36.4, 38.8, 42.3, 42.9, 49.0, 59.6, 66.8, 68.8, 69.8, 118.4, 123.1, 125.7, 2 × 128.3, 135.9, 141.6, 155.9, 166.4, 178.4 ppm. HRMS: m/z calcd for C35H59O6Si [M + H]+: 603.4081; found: 603.4110.
Compound 16: Allyl tributyltin (2.65 mL, 8 mmol, 1.1 equiv) and Pd(PPh3)4 (356 mg, 0.3 mmol, 0.04 equiv) were added to a solution of crude vinyliodide (3.24 g, 7.0 mmol, 1 equiv) in benzene (70 mL) and stirred overnight at 70 °C. After cooling to r.t. acetone (10 mL) and a sat. KF solution (20 mL) were added and stirring was continued for additional 2 h. The precipitate was removed by filtration through CeliteTM and the filtrate was washed with sat. NH4Cl solution. Drying (MgSO4), evaporation and flash column chromatograpghy (PE-EtOAc, 25:1) yielded diene 15 (2.40 g, 6.3 mmol, 90%).
This trichloroethyl ester 15 (43 mg, 0.11 mmol) was dissolved in glacial AcOH (5 mL). Zinc (75 mg, 1.14 mmol) and H2O (2 drops) were added and the resulting suspension was sonicated for 30 min. After stirring for 3 d at 60 °C the suspension was cooled to r.t., filtered through a pad of CeliteTM and washed several times with MTBE. The solvent was removed and the crude product was azeotropically dried several times with toluene. Acid 16 was obtained after flash column chromatography (PE-EtOAc, 4:1) in 73% yield (20 mg, 0.08 mmol). 1H NMR (400 MHz, CDCl3, CDCl3 = 7.26 ppm): δ = 2.50 (dt, J = 0.9, 6.6 Hz, 2 H, CH
2CH2), 3.45 (d, J = 6.7 Hz, 2 H, CCH
2CH), 3.64 (t, J = 6.6 Hz, 2 H, CH2OBn), 4.51 (s, 2 H, CH2Ar), 5.07 (dd, J = 1.6, 10.1 Hz, 1 H, CHtrans
H
cisCH), 5.11 (dd, J = 1.6, 17.1 Hz, 1 H, CH
transHcisCH), 5.78 (br s, 1 H, CHCO2), 5.81 (tdd, J = 6.8, 10.2, 17.0 Hz, 1 H, CHtransHcisCH), 7.27-7.39 (m, 5 H, Ar) ppm. 13C NMR (100 MHz, CDCl3, CDCl3 = 77.0 ppm): δ = 36.9, 38.0, 67.7, 73.0, 2 × 116.8, 2 × 127.7, 128.4, 134.6, 138.0, 160.5, 171.1 ppm. HRMS: m/z calcd for C15H18O3 [M - H]-: 245.1178; found: 245.1176.
Analytical Data for Compound 10.
[α]D
20 -7.3 (c 0.4, CHCl3). 1H NMR (400 MHz, CDCl3, TMS = 0 ppm): δ = 0.07 (s, 3 H, TBS), 0.09 (s, 3 H, TBS), 0.90 (s, 9 H, TBS), 1.03 (s, 9 H, TBDPS), 1.15 (d, J = 0.8 Hz, 3 H, 22-H), 1.43-1.50 (m, 2 H, 12-H), 1.53-1.68 (m, 4 H, 8-H, 10-H), 1.70 (s, 3 H, 21-H), 1.94-2.16 (m, 4 H, 6-H, 13-H), 2.60 (t, J = 6.7 Hz, 2 H, 3-H), 3.35 (d, J = 7.2 Hz, 2 H, 16-H), 3.50 (s, 1 H, OH), 3.90-4.02 (m, 2 H, 7-H, 11-H), 4.07 (m, 1 H, 9-H), 4.88 (dd, J = 10.2, 1.7 Hz, 1 H, 1-H), 4.91 (dd, J = 17.0, 1.7 Hz, 1 H, 1-H′), 5.02 (tq, J = 6.7, 0.8 Hz, 1 H, 4-H), 5.33 (t, J = 7.2 Hz, 1 H, 15-H), 5.68 (ddt, J = 17.0, 10.2, 6.7 Hz, 1 H, 2-H), 7.14-7.21 (m, 3 H, Ph), 7.23-7.32 (m, 2 H, Ph), 7.32-7.45 (m, 6 H, TBDPS), 7.66-7.76 (m, 4 H, TBDPS) ppm. 13C NMR (100 MHz, CDCl3, CDCl3 = 77 ppm): δ = -4.6, -4.4, 15.7, 16.2, 18.1, 19.2, 25.9, 26.9, 32.2, 34.2, 35.4, 35.6, 43.2, 44.8, 48.2, 66.7, 70.2, 72.0, 114.3, 123.0, 124.8, 125.7, 127.4, 127.7, 2 × 128.3, 129.5, 129.8, 132.9, 133.5, 134.2, 135.9, 136.0, 136.1, 137.0, 141.7 ppm. HRMS: m/z calcd for C46H67O3Si2 [M - H]-: 723.4629; found: 723.4622.