Synthesis of the C1-C5 and C6-C24 Fragments of the RNA Polymerase Inhibitors Ripostatin A and B

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

References and Notes

• 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 

6

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 Celite^TM 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 Celite^TM 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, CH_trans H _cisCH), 5.11 (dd, J = 1.6, 17.1 Hz, 1 H, CH _transH_cisCH), 5.78 (br s, 1 H, CHCO₂), 5.81 (tdd, J = 6.8, 10.2, 17.0 Hz, 1 H, CH_transH_cisCH), 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.

9

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.