Synthesis of a xylo-Puromycin Analogue

Abstract

N ⁶-Bis-demethylated xylo-puromycin analogue 2 was synthesized over six steps in 56% yield from adenosine 3, involving a Mattocks bromoacetylation, a regio- and stereoselective ribo-epoxide ring opening with sodium azide and an efficient Staudinger-Vilarrasa reaction to couple the amino acid to an azide precursor.

coupling - epoxides - nucleosides - amides - malaria

References and Notes

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9-(3′-Azido-5′- O - tert -butyldiphenylsilyl-3′-deoxy-β- d -xylofuranos-1-yl)adenine (6): To a stirred solution of 5 (52 mg, 0.11 mmol) in DMF (1 mL), were added NaN₃ (42 mg, 0.69 mmol) and H₂O (0.3 mL). The reaction mixture was precisely warmed to 78-80 ˚C for 20 h, then quenched with sat. NaHCO₃ solution and diluted with EtOAc. The layers were separated and the aqueous portion was washed with EtOAc (3 ×). The combined organic extracts were washed with 10% aq LiCl (3 ×) to remove the residual DMF, washed once with brine, dried over anhyd MgSO₄, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (EtOAc-toluene, 1:1, 3:1, 5:1, 7:1; EtOAc-toluene-MeOH, 7:1:0.5) to afford 6 as a white solid (47 mg, 80%); mp 181 ˚C (uncorrected); R _f 0.40 (EtOAc-toluene, 4:1). ^¹H NMR (300 MHz, DMSO-d ₆): δ = 0.99 (s, 9 H, Si-t-Bu), 3.88 (dd, 1 H, ^² J = 11.0 Hz, ^³ J = 4.5 Hz, H_A5′), 4.00 (dd, 1 H, ^² J = 11.0 Hz, ^³ J = 3.9 Hz, H_B5′), 4.46 (m, 1 H, H3′), 4.48 (m, 1 H, H4′), 4.82 (q ‘ddd’, 1 H, ^³ J = 3.9, 4.5 Hz, H2′), 5.91 (d, 1 H, ^³ J = 4.5 Hz, H1′), 6.36 (d, 1 H, ^³ J = 5.1 Hz, OH), 7.33 (br s, 2 H, NH₂), 7.36-7.46 (m, 6 H, H-m-Ar, H-p-Ar), 7.61-7.66 (m, 4 H, H-o-Ar), 8.13 (s, 1 H, H8), 8.15 (s, 1 H, H2). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 18.8 (SiCMe₃), 26.6 [3 × C, SiCMe ₃], 63.0 (C5′), 66.0 (C3′), 77.0 (C2′), 79.3 (C4′), 87.6 (C1′), 118.9 (C5), 127.9, 128.0 (4 × C, C-m-SiPh), 130.0 (2 × C, C-p-SiPh), 132.5, 132.8 (2 × C, C-i-SiPh), 135.0, 135.1 (4 × C, C-o-SiPh), 138.9 (C8), 149.4 (C4), 152.8 (C2), 156.0 (C6). HRMS (ESI⁺): m/z [M + H]⁺ calcd for C₂₆H₃₀N₈O₃Si (530.65): 531.2288; found: 531.2285.
9-(3′-Azido-5′- O - tert -butyldiphenylsilyl-3′-deoxy-β- d -xylofuranos-1-yl)-6- N -(di- n -butylamino)methylene-adenine (7): Beforehand co-evaporated with toluene (3 × 2 mL), the azido compound 6 (243 mg, 0.46 mmol) was dissolved in anhyd MeOH (1.2 mL). N,N-Di-n-butylformamide dimethylacetal [5z] (196 mg, 0.96 mmol) was added and the reaction mixture was slightly warmed for a few seconds with a heat gun every 15 min and stirred for 1 h. The volatiles were removed under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc-cyclohexanes, 1:1, 2:1, 3:1, 4:1, 5:1) to yield 7 (301 mg, 98%) as a colorless oil; R _f 0.63 (EtOAc-cyclohexanes, 5:1). ^¹H NMR (300 MHz, CDCl₃): δ = 0.94-0.97 [m, 6 H, N(CH₂CH₂CH₂CH ₃)₂], 0.96 (s, 9 H, Si-t-Bu), 1.30-1.46 [m, 4 H, N(CH₂CH₂CH ₂CH₃)₂], 1.59-1.72 [m, 4 H, N(CH₂CH ₂CH₂CH₃)₂], 3.40 [t, 2 H, ^³ J = 7.4 Hz, N(CH ₂CH₂CH₂CH₃)₂], 3.61-3.79 [m, 2 H, N(CH ₂CH₂CH₂CH₃)₂], 3.87 (dd, 1 H, ^² J = 10.8 Hz, ^³ J = 4.8 Hz, H_A5′), 3.94 (dd, 1 H, ^² J = 10.8 Hz, ^³ J = 5.4 Hz, H_B5′), 4.37 (dd, 1 H, ^³ J = 4.7, 5.1 Hz, H3′), 4.54 (pseudo q ‘ddd’, 1 H, ^³ J = 4.8, 5.1, 5.4 Hz, H4′), 4.81 (pseudo t, 1 H, ^³ J = 4.1, 4.7 Hz, H2′), 5.91 (d, 1 H, ^³ J = 4.1 Hz, H1′), 6.46 (br s, 1 H, OH), 7.32-7.42 (m, 6 H, H-m-Ar, H-p-Ar), 7.62-7.65 (m, 4 H, H-o-Ar), 8.05 (s, 1 H, H8), 8.41 (s, 1 H, H2), 9.01 (s, 1 H, N=CHNBu₂). ^¹³C NMR (75 MHz, CDCl₃): δ = 13.6, 13.9 [2 × C, N(CH₂CH₂CH₂ CH₃)₂], 19.0 (SiCMe₃), 19.7, 20.1 [2 × C, N(CH₂CH₂ CH₂CH₃)₂], 26.7 (3 × C, SiCMe ₃), 29.2, 30.9 [2 × C, N(CH₂ CH₂CH₂CH₃)₂], 45.3, 52.0 [2 × C, N(CH₂CH₂CH₂CH₃)₂], 62.1 (C5′), 66.2 (C3′), 79.5 (C2′), 81.3 (C4′), 90.9 (C1′), 125.8 (C5), 127.7 (4 ¥ C, C-m-SiPh), 129.8 (2 × C, C-p-SiPh), 132.7 (2 × C, C-i-SiPh), 135.5 (4 × C, C-o-SiPh), 139.5 (C8), 150.4 (C4), 152.0 (C2), 158.8 (N=CHNBu₂), 159.9 (C6). HRMS (ESI⁺): m/z [M + H]⁺ calcd for C₃₅H₄₇N₉O₃Si (669.89): 670.3644; found: 670.3649.
9-[5′- O - tert -Butyldiphenylsilyl-3′- N -(α- N -fluorenyl-methoxycarbonyl- p -methoxy- l -phenylalanyl)amido-3′-deoxy-β- d -xylofuranos-1-yl]-6- N -(di- n -butyl-amino)methyleneadenine (8): N-Fmoc-O-Me-l-Tyr (114 mg, 0.282 mmol) and HOBt (45 mg, 0.282 mmol) were co-evaporated from anhyd THF (3 × 3 mL). The mixture was dissolved in anhyd THF (2 mL) and the solution was cooled to 0 ˚C under N₂ for 10 min. Then, DIC (38.3 µL, 0.242 mmol) was added and the reaction mixture was stirred for 10 min at the same temperature. PMe₃ (1 M in THF, 303 µL, 0.303 mmol) was added to a solution of 7 (135 mg, 0.202 mmol) in THF (2 mL), and the mixture was stirred for 1 min at r.t. The amino acid solution was warmed to r.t. during 1 min, and then added to the iminophosphorane solution. The reaction mixture was stirred at r.t. overnight, concentrated under reduced pressure and co-evaporated from CHCl₃ (2 × 3 mL), then dissolved in EtOAc (30 mL) and quenched with sat. NaHCO₃ (15 mL). The organic layer was extracted with EtOAc (2 ×) and washed with H₂O (2 × 10 mL), dried over anhyd MgSO₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc-toluene, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, EtOAc-toluene-MeOH, 3:1:0.25) to yield 8 (175 mg, 83%). ^¹H NMR (300 MHz, CDCl₃): δ = 0.92 (s, 9 H, Si-t-Bu), 0.96 [t, 6 H, ^³ J = 6.9 Hz, N(CH₂CH₂CH₂CH ₃)₂], 1.31-1.47 [m, 4 H, N(CH₂CH₂CH ₂CH₃)₂], 1.60-1.73 [m, 4 H, N(CH₂CH ₂CH₂CH₃)₂], 2.81-2.98 (m, 2 H, Hβ), 3.41 [t, 2 H, ^³ J = 7.2 Hz, N(CH ₂CH₂CH₂CH₃)₂], 3.61 (s, 3 H, OMe), 3.65-3.81 [m, 3 H, N(CH ₂CH₂CH₂CH₃)₂, H_A5′], 3.92 (dd, 1 H, ^² J = 11.3 Hz, ^³ J = 4.1 Hz, H_B5′), 4.15 (pseudo t, 1 H, ^³ J = 6.0, 6.9 Hz, H aliph. Fl.), 4.24-4.30 (m, 2 H, Hα, CH ₂Fl.), 4.38-4.47 (m, 3 H, H4′, H2′, CH ₂Fl.), 4.71-4.77 (m, 1 H, H3′), 5.43 (d, 1 H, ^³ J = 6.9 Hz, NHFmoc), 5.43 (br s, 1 H, OH), 5.74 (d, 1 H, ^³ J = 3.6 Hz, H1′), 6.63 [d, 2 H, ^³ J = 8.1 Hz, H-o-Ph(OMe)], 6.99 [d, 2 H, ^³ J = 8.1 Hz, H-m-Ph(OMe)], 7.20-7.30 (m, 8 H, H-m ^²-Fl., H-m-SiPh, H-p-SiPh), 7.32-7.40 (m, 2 H, H-p ^³-Fl.), 7.48-7.55 (m, 6 H, H-o ^¹-Fl., H-o-SiPh), 7.73 (t ‘2¥d’, 2 H, ^³ J = 7.2, 7.5 Hz, H-m ⁴-Fl.), 7.97 (s, 1 H, H8), 8.46 (s, 1 H, H2), 8.54 (d, 1 H, ^³ J = 7.8 Hz, 3′-NH), 9.02 (s, 1 H, N=CHNBu₂). ^¹³C NMR (75 MHz, CDCl₃): δ = 13.7, 13.9 [2 ¥ C, N(CH₂CH₂CH₂ CH₃)₂], 19.0 [SiCMe₃], 19.7, 20.2 [2 ¥ C, N(CH₂CH₂ CH₂CH₃)₂], 26.7 (3 ¥ C, SiCMe ₃), 29.2, 30.9 [2 ¥ C, N(CH₂ CH₂CH₂CH₃)₂], 38.4 (Cβ), 45.4 [N(CH₂CH₂CH₂CH₃)₂], 47.1 (CH aliph. Fl.), 52.0 [N(CH₂CH₂CH₂CH₃)₂], 55.0 (OMe), 56.7 (C3′), 57.2 (Cα), 62.6 (C5′), 66.9 (CH₂Fl.), 80.3 (C2′), 80.3 (C4′), 91.6 (C1′), 113.8 [2 ¥ C, C-o-Ph(OMe)], 119.9 (2 ¥ C, C-m ⁴-Fl.), 125.0 (2 ¥ C, C-o ^¹-Fl.), 126.7 (C5), 127.0 (2 ¥ C, C-m ^²-Fl.), 127.6 (2 ¥ C, C-p ^³-Fl.), 127.7 (4 ¥ C, C-m-SiPh), 127.8 [C-p-Ph(OMe)], 129.8 (2 ¥ C, C-p-SiPh), 130.3 [2 ¥ C, C-m-Ph(OMe)], 132.6, 132.7 (2 ¥ C, C-i-SiPh), 135.5 (4 ¥ C, C-o-SiPh), 141.2 (2 ¥ C, C8), 141.2 (2 ¥ C, C-o ⁵-Fl.), 143.7, (2 ¥ C, C-i-Fl.), 150.0 (C2), 151.9 (C4), 155.6 (N=CHNBu₂), 158.4 (C6), 158.5 [C-i-Ph(OMe)], 162.3 [RC(O)OCH₂Fl.], 171.4 [3′-NHC(O)R′]. HRMS (ESI⁺): m/z [M + H]⁺ calcd for C₆₀H₇₀N₈O₇Si (1043.36): 1043.5215; found: 1043.5211.
9-[3′-Deoxy- 3′ - N -( p -methoxy- l -phenylalanyl)amido-β- d -xylofuranos-1-yl]adenine (2): Compound 9 (25 mg, 0.027 mmol) (or 8) was dissolved in 33% MeNH₂-EtOH (5 mL). The reaction mixture was stirred at r.t. overnight in a closed vessel. The solution was concentrated under reduced pressure and co-evaporated from CHCl₃ (2 × 4 mL). The oily residue was dissolved in MeOH (1 mL) and then ammonium fluoride (5.2 mg, 0.138 mmol) was added to the solution. The reaction mixture was warmed to 50-55 ˚C for 4 h, and monitored by TLC. The volatiles were removed under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc-MeOH-H₂O, 14:1:0.5, 12:1: 0.5, 10:1:0.5, 8:1:0.5, 6:1:0.5, 4:1:0.5) to yield after evaporation the target compound 2 as a fluffy white solid (12 mg, 98% from 9). ^¹H NMR (300 MHz, CD₃OD): δ = 2.90 (dd, 1 H, ^² J = 13.5 Hz, ^³ J = 6.3 Hz, Hβ1), 2.97 (dd, 1 H, ^² J = 13.5 Hz, ^³ J = 7.5 Hz, Hβ2), 3.53 (dd, 1 H, ^² J = 12.6 Hz, ^³ J = 4.2 Hz, H_A5′), 3.64 (s, 3 H, OMe), 3.68-3.70 (m, 1 H, Hα), 3.75 (dd, 1 H, ^² J = 12.6 Hz, ^³ J = 3.3 Hz, H_B5′), 4.34 (‘ddd’, 1 H, ^³ J = 3.3, 3.6, 6.9 Hz, H4′), 4.43 (t, 1 H, ^³ J = 5.1 Hz, H2′), 4.60 (dd, 1 H, ^³ J = 5.4, 5.7 Hz, H3′), 5.79 (d, 1 H, ^³ J = 4.8 Hz, H1′), 6.73 [d, 2 H, ^³ J = 8.7 Hz, H-o-Ph(OMe)], 7.11 [d, 2 H, ^³ J = 8.7 Hz, H-m-Ph(OMe)], 8.18 (s, 1 H, H8), 8.22 (s, 1 H, H2). ^¹³C NMR (125 MHz, CD₃OD): δ = 40.9 (Cβ), 55.6 (OMe), 57.6 (C3′), 58.6 (Cα), 62.1 (C5′), 79.4 (C2′), 81.4 (C4′), 92.5 (C1′), 115.0 [2 ¥ C, C-o-Ph(OMe)], 121.3 (C5), 129.8 [C-p-Ph(OMe)], 131.6 [2 ¥ C, C-m-Ph(OMe)], 142.5 (C8), 149.4 (C4), 153.6 (C2), 157.7 (C6), 160.2 [C-i-Ph(OMe)], 175.2 [3′-NHC(O)R′]. HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₂₀H₂₅N₇O₅: 466.1815; found: 466.1817.
The supporting information for this article contains protocols and experimental details for the syntheses of 4, 5, 9, and 10, as well as the ^¹H NMR, DEPT, ^¹³C NMR, ^¹H-^¹H COSY, ^¹H-^¹³C HSQC, and (in part) ^¹H-^¹³C HMBC spectra of all compounds.