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Synlett 2010(7): 1055-1058  
DOI: 10.1055/s-0029-1219436
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of a Deoxyxylopuromycin Analogue

Kollappillil S. Krishnakumar, Peter Strazewski*
Laboratoire de Synthèse de Biomolécules (UMR 5246, ICBMS), Bâtiment Eugène Chevreul (5ème étage), Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
Fax: +33(4)72431323; e-Mail: strazewski@univ-lyon1.fr;
Further Information

Publication History

Received 16 January 2010
Publication Date:
23 February 2010 (online)

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Abstract

N6-Bis-demethylated deoxyxylopuromycin was synthesized over six steps in 56% overall yield. The key steps are Mitsunobu­ reaction with DPPA and a Staudinger-Vilarrasa coupling.

Key words

Antibiotic - ribosome - azide - Mitsunobu - Staudinger-Vilarrasa

    References and Notes

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18

5′- O -( tert -Butyldiphenylsilyl)-2′-deoxyadenosine (6) TBDPSCl (1.6 g, 5.7 mmol) was added to 5 (1.2 g, 4.8 mmol) in dry pyridine (24 mL), and the solution was stirred for 18 h at r.t. under N2. H2O (2 mL) was added, stirring was continued for 30 min, and the volatiles were evaporated. The residue was partitioned (H2O-EtOAc), and the organic phase was washed with H2O (2 × 50 mL) and brine, then dried (Na2SO4). The volatiles were evaporated, and the residue was column chromatographed (step gradient from EtOAc-cyclohexane = 1:1 to 1:0 and then to EtOAc-MeOH = 95:5) to yield 6 (2.0 g, 88%). R f = 0.33 (EtOAc-MeOH = 9:1). ¹H NMR (300 MHz, CDCl3): δ = 1.06 [s, 9 H, SiC(CH3)3], 2.53 (ddd, 1 H, J = 13.4, 6.2, 4.0 Hz, HA2′), 2.75 (td, 1 H, J = 13.1, 6.4 Hz, HB2′), 3.79-3.98 (m, 2 H, H5′5′′), 4.71-4.75 (m, 1 H, H3′), 5.84 (s, 2 H, NH2), 6.46 (t, 1 H, J = 6.5 Hz, H1′), 7.31-7.45 (m, 6 H, ar), 7.62-7.65 (m, 4 H, ar), 8.02 (s, 1 H, H2), 8.29 (s, 1 H, H8). ¹³C NMR (70 MHz, CDCl3 + CD3OD): δ = 18.7 (SiC), 26.3 [(CH3)3], 40.6 (C2′), 63.4 (C5′5′′), 70.6 (C3′), 84.0 (C1′), 87.1 (C4′), 118.8 (C5), 127.3 (p-ar), 129.4, 129.4 (o-ar), 132.1, 132.4 (i-ar), 134.9, 135.1 (m-ar), 138.2 (C2), 148.4 (C4), 152.1 (C6), 155.1 (C8). MS (ESI+): m/z = 490.1 [MH]+ 6- N -[(di- n -Butylamino)methylene]-5′- O -( tert -butyl-diphenylsilyl)-2′-deoxyadenosine (7) Compound 6 (600 mg, 1.3 mmol) was dissolved in MeOH (5 mL). N,N-Di-n-butylformamide dimethylacetal (600 mg, 2.6 mmol) was added, and the solution was stirred for 2 h at r.t. The volatiles were removed under reduced pressure, and the residue was purified using silica gel column chromatog-raphy (EtOAc-MeOH = 100:0 to 95:5 step gradient) to yield 7 (750 mg, 98%). R f = 0.45 (CH2Cl2-MeOH = 9.5:0.5). ¹H NMR (300 MHz, CDCl3): δ = 0.82-0.88 (m, 6 H, 2 × NCH2CH2CH2CH3), 0.96 [(s, 9 H, SiC(CH3)3], 1.23-133 (m, 4 H, 2 × NCH2CH2CH2CH3), 1.49-1.62 (m, 4 H, 2 × NCH2CH2CH2CH3), 2.46 (ddd, J = 13.2, 6.0, 3.5 Hz, 1 H, HA2′), 2.57-2.66 (m, 1 H, HB2′), 3.28-3.34 (m, 2 H, NCH2CH2CH2CH3), 3.59-3.65 (m, 2 H, NCH2CH2CH2CH3), 3.72-3.85 (m, 2 H, H5′5′′), 4.05-4.09 (m, 1 H, H4′), 4.64-4.68 (m, 1 H, H3′), 6.44 (t, J = 6.6 Hz, 1 H, H1′), 7.25-7.32 (m, 6 H, ar), 7.53-7.58 (m, 4 H, ar), 8.02 (s, 1 H, H2), 8.41 (s, 1 H, H8), 8.91 (s, 1 H, CH=N). ¹³C NMR (70 MHz, CDCl3): δ = 13.6 (NCH2CH2CH2CH3), 13.8 (NCH2CH2CH2CH3), 19.1 (SiC), 19.6 (NCH2CH2CH2CH3), 20.1 (NCH2CH2CH2CH3), 26.8 [(CH3)3], 29.1 (NCH2CH2CH2CH3), 30.9 (NCH2CH2CH2CH3), 40.6 (C2′), 45.1 (NCH2CH2CH2CH3), 51.7 (NCH2CH2CH2CH3), 64.0 (C5′5′′), 71.7 (C3′), 84.01 (C1′), 87.0 (C4′), 126.1 (C5), 127.7, 129.7, 129.8, 132.7, 132.8, 135.4, 135.4 (Ar), 139.7 (C2), 151.0 (C4), 152.3 (C6), 158.3 (C8), 159.9 (CH=N). HRMS (ESI+): m/z calcd: 629.3635 [MH]+; found: 629.3636.
9-[3′-Azido-5′- O -( tert -butyldiphenylsilyl)-2′,3′-dideoxy-β- d -xylofuranosyl)-6- N -[(di- n -butylamino)methylene]-adenine (8)
To a THF (1.9 mL) solution of 7 (69 mg, 0.11 mmol) and Ph3P (90 mg, 0.33 mmol), a mixture of DIAD (71 µL, 0.33 mmol) and DPPA (65 µL, 0.33 mmol) in THF (500 µL) was added dropwise at 0 ˚C under Ar. After 7 h of stirring at r.t., EtOH (1 mL) was added, and the solution was stirred for 30 min. After evaporation of all the volatiles, the oily residue was purified by silica gel column chromatography (EtOAc-cyclohexane = 3:7 to 8:2 step gradient). Ph3PO contained in the chromatographed product was removed by precipitation from cold Et2O (3 h, 4 ˚C). After the second precipitation the filtrate was evaporated to yield 8 (61 mg, 85%). R f = 0.4 (CH2Cl2-MeOH = 9.5:0.5). ¹H NMR (300 MHz, CDCl3): δ = 0.94 (2 t, J = 7.3, 7.3 Hz, 6 H, 2 × NCH2CH2CH2CH3), 1.09 [s, 9 H, SiC(CH3)3], 1.21-1.45 (m, 4 H, 2 × NCH2CH2CH2CH3), 1.58-1.71 (m, 4 H, 2 × NCH2CH2CH2CH3), 2.54 (dd, J = 14.8, 0.9 Hz, 1 H, HA2′), 2.83 (ddd, J = 14.0, 7.9, 6.0 Hz, 1 H, HB2′′), 3.38 (t, J = 7.3 Hz, 2 H, NCH2CH2CH2CH3), 3.67-3.75 (m, 2 H, NCH2CH2CH2CH3), 3.96-4.07 (m, 2 H, H5′5′′), 4.19-4.24 (m, 1 H, H4′), 4.41-4.44 (m, 1 H, H3′), 6.41 (dd, J = 7.9, 2.1 Hz, 1 H, H1′), 7.42-7.70 (m, 10 H, ar), 8.19 (s, 1 H, H2), 8.52 (s, 1 H, H8), 9.02 (s, 1 H, CH=N). ¹³C NMR (70 MHz, CDCl3): δ = 13.6 (NCH2CH2CH2CH3), 13.9 (NCH2CH2CH2CH3), 19.1 (SiC), 19.7 (NCH2CH2CH2CH3), 20.1 (NCH2CH2CH2CH3), 26.8 [(CH3)3], 29.2 (NCH2CH2CH2CH3), 30.9 (NCH2CH2CH2CH3), 39.0 (C2′), 45.1 (NCH2CH2CH2CH3), 51.8 (NCH2CH2CH2CH3), 61.5 (C3′), 61.9 (C5′5′′), 83.1 (C1′), 83.1 (C4′), 125.8 (C5), 125.8, 127.8, 128.3, 131.8, 131.9, 132.0, 135.4 (ar), 139.8 (C2), 151.0 (C4), 156.6 (C6), 157.3 (C8), 158.4 (CH=N). HRMS (ESI+): m/z calcd: 654.3700 [MH]+; found: 654.3700.
9-[ 5 ′ -O- ( tert -Butyldiphenylsilyl)-3′-[ N -(9-fluorenyl)-methoxycarbonyl- O -methyl- l -tyrosyl]amido - 2′,3′-dideoxy-β- d -xylofuranosyl)-6- N -[(di- n -butylamino)-methylene]adenine (9)
N-Fmoc-O-Me-l-Tyr (45 mg, 0.11 mmol) and HOBt (18 mg, 0.11 mmol) were co-evaporated with anhyd THF (3 × 1 mL). The mixture was dissolved in anhyd THF (1 mL) and cooled down to 0 ˚C under N2 for 10 min. Diisopropylcarbodiimide (16 µL, 0.10 mmol) was added, and the reaction mixture was stirred at the same temperature for 15 min and then 10 min at r.t. Me3P (1 M in THF, 160 µL, 0.16 mmol) was added to 8 (52.6 mg, 0.08 mmol) in THF (1 mL) and stirred at r.t. for 5 min. The amino acid solution was added to the iminophosphorane solution and stirred for 4 h at r.t. The reaction mixture was concentrated under reduced pressure and dissolved in EtOAc (20 mL) and then washed with sat. aq NaHCO3 solution (15 mL) and H2O (2 × 20 mL). The organic layer was dried over Na2SO4, evaporated, and the residue was purified by silica gel column chromatog-raphy (CH2Cl2-MeOH = 99.5: 0.5 to 98:2 step gradient) to yield 9 (70 mg, 85%). R f = 0.45 (CH2Cl2-MeOH = 9.5:0.5). ¹H NMR (300 MHz, CDCl3): δ = 0.81-0.91 (m, 6 H, 2 × NCH2CH2CH2CH3), 1.06, 1.07 [2 s, 9 H, SiC(CH3)3], 1.22-1.39 (m, 4 H, 2 × NCH2CH2CH2CH3), 1.52-1.72 (m, 4 H, 2 × NCH2CH2CH2CH3), 1.93 (dd, J = 15.0, 2.9 Hz, 1 H, HA2′), 2.72-2.74 (m, 1 H, HB2′), 1.88 (d, J = 6.1 Hz, 1 H, Hβ), 3.36 (t, J = 7.3 Hz, 2 H, NCH2CH2CH2CH3), 3.56-3.59 (m, 2 H, NCH2CH2CH2CH3), 3.66-3.71 (m, 2 H, H5′′), 3.89 (dd, J = 11.1, 3.9 Hz, 1 H, H5′), 4.01-4.02 (m, 1 H, H4′), 4.11-4.36 (m, 4 H, CH-Fmoc, Hα and CH2-Fmoc), 4.73 (d, J = 7.4 Hz, 1 H, H3′), 5.37 (d, J = 7.3 Hz, 1 H, NH-Fmoc), 5.88 (dd, J = 8.9, 3.5 Hz, 1 H, H1′), 6.49, 6.91 [2 d, J = 8.5 Hz, 4 H, H-o-Ph(OMe)], 7.10-7.80 [m, 18 H, ar (Fmoc and TBDPS)], 8.39 (s, 1 H, H2), 8.94 (s, 1 H, H8), 9.56 (s, 1 H, CH=N). ­¹³C NMR (70 MHz, CDCl3): δ = 13.6 (NCH2CH2CH2CH3), 13.8 (NCH2CH2CH2CH3), 19.1 (SiC), 19.7 (NCH2CH2CH2CH3), 20.1 (NCH2CH2CH2CH3), 23.4, 26.7 [(CH3)3], 29.2 (NCH2CH2CH2CH3), 30.9 (NCH2CH2CH2CH3), 38.1 (C2′), 38.7 (Cβ), 45.2 (NCH2CH2CH2CH3), 47.1 (CH-Fmoc), 48.8 (C3′), 51.8 (NCH2CH2CH2CH3), 57.1 (C5′5′′), 62.6 (OCH2 Fmoc), 66.8 (Cα), 82.7 (C4′), 84.5 (C1′), 113.6 [o-Ph(OMe)], 119.8, 125.0, 127.4, 127.5, 127.6, 128.3, 128.5, 130.2, 131.7, 131.8, 131.9, 131.9, 132.1, 133.1, 135.4, 135.5, 135.5, 141.2, 141.5, 143.7, 143.8 (Ar), 149.4 (C4), 151.8 (C2), 157.2 (C6), 157.2 (C=O), 158.3 (C8), 169.97 (CH=N). HRMS (ESI+): m/z calcd: 1049.5085 [M + Na]+; found: 1049.5084.
9-(3′- O -Methyl- l -tyrosyl)amido-2′,3′-dideoxy-β- d -xylofuranosyl)adenine (4)
Compound 9 (65 mg, 0.08 mmol) was dissolved in 33% MeNH2-EtOH (8 mL), and the mixture was stirred overnight at r.t. in a closed vessel. The solution was concentrated under reduced pressure, and the residue was dissolved in MeOH (2 mL) and then NH4F (16 mg, 0.43 mmol) was added. The reaction mixture was warmed to 50-55 ˚C for 4 h. The volatiles were evaporated, and the residue was washed with EtOAc (3×) and then purified by a preparative thin-layer column chromatography using i-PrOH-NH3-H2O (8:0.5:0.5) as the eluent to obtain 4 (24 mg, 90%). ¹H NMR (300 MHz, CD3OD): δ = 1.95-2.01 (m, 1 H, HA2′), 2.67-2.77 (m, 2 H, HB2′, Hβ), 3.44 (t, J = 7.2 Hz, 1 H, Hα), 3.49 (s, 3 H, OMe), 3.61-3.65 (m, 2 H, H5′5′′), 3.99 (dd, J = 9.7, 5.4 Hz, 1 H, H4′), 4.55-4.59 (m, 1 H, H3′), 6.03 (dd, J = 8.4, 5.1 Hz, 1 H, H1′), 6.58 [d, J = 8.6 Hz, 2 H, o-Ph(OMe)], 6.98 [d, J = 8.6 Hz, 2 H, m-Ph(OMe)], 8.05 (s, 1 H, H2), 8.11 (s, 1 H, H8). ¹³C NMR (125 MHz, CD3OD): δ = 39.4 (C2′), 39.9 (Cβ), 50.8 (C3′), 55.6 (OMe), 57.1 (Cα), 61.8 (C5′5′′), 83.3 (C4′), 86.0 (C1′), 115.1 [2 × C-o-Ph(OMe)], 122.4 (C5), 127.9 [C-p-Ph(OMe)], 131.7 [2 × C-m-Ph(OMe)], 142.6 (C2), 148.9 (C4), 153.5 (C8), 157.7 (C6), 160.5 [C-i-Ph(OMe)], 169.9 (C=O). HRMS (ESI+): m/z calcd: 428.2046 [MH]+; found: 428.2047.