Efficient Synthesis of α- and β-2′-Deoxy-heteroaryl-C-nucleosides

Marie Spadafora; Alain Burger; Rachid Benhida

doi:10.1055/s-2008-1072589

LETTER

Efficient Synthesis of α- and β-2′-Deoxy-heteroaryl-C-nucleosides

Marie Spadafora, Alain Burger*, Rachid Benhida*
Laboratoire de Chimie des Molécules Bioactives et des Arômes, UMR 6001 CNRS, Institut de Chimie de Nice, Université de Nice-Sophia Antipolis, 28 Avenue de Valrose, 06108 Nice Cedex 2, France
Fax: +33(4)92076151; e-Mail: benhida@unice.fr;

Abstract

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Abstract

A short and efficient method for the synthesis of a series of 2′-deoxy-heteroaryl-C-nucleosides has been developed by the application of aryl-aldol condensation followed by p-toluenesulfonic acid (PTSA)-mediated isopropylidene cleavage and subsequent cycloetherification.

Key words

C-nucleosides - aryl-aldol condensation - cycloetherification

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References

References and Notes

For recent reviews on the chemistry of C-glycoside analogues, see:

<A NAME="RG04008ST-1A">1a</A> Wu Q. Simons C. Synthesis 2004, 1533

<A NAME="RG04008ST-1B">1b</A> Bililign T. Griffith BR. Thorson JS. Nat. Prod. Rep. 2005, 22: 742

<A NAME="RG04008ST-1C">1c</A> Lee DYW. He MS. Curr. Top. Med. Chem. 2005, 5: 1333

For a brief overview of the biological and clinical impact of tiazofurin, see:

<A NAME="RG04008ST-2A">2a</A> For pyrazofurin and formycin, see: Grifantini M. Curr. Opin. Investig. Drugs 2000, 1: 257

<A NAME="RG04008ST-2B">2b</A> Shaban MAE. Nasr AZ. In Advances in Heterocyclic Chemistry Vol. 68: Katritzky AR. Academic Press; San Diego: 1997. p.259

<A NAME="RG04008ST-2C">2c</A> For showdomycin, see: Shaban MAE. Nasr AZ. In Advances in Heterocyclic Chemistry Vol. 70: Katritzky AR. Academic Press; San Diego: 1998. p.230

<A NAME="RG04008ST-2D">2d</A> Nishimura H. Mayama M. Komatsu Y. Kato H. Shimsoka N. Tanaka Y. J. Antibiot., Ser. A 1964, 17: 148

<A NAME="RG04008ST-2E">2e</A> Rabinovitz M. Uehara Y. Vistica DT. Science 1979, 206: 1085

<A NAME="RG04008ST-2F">2f</A> Barett AGM. Broughton HB. J. Org. Chem. 1986, 51: 495

<A NAME="RG04008ST-3A">3a</A> Adamo MFA. Adlington RM. Baldwin JE. Day AL. Tetrahedron 2004, 60: 841

<A NAME="RG04008ST-3B">3b</A> Hashmi IA. Ali FI. Feist H. Michalik M. Reinke H. Peseke K. Synthesis 2007, 2819

<A NAME="RG04008ST-3C">3c</A> Oda H. Hanami T. Iwashita T. Kojima M. Itoh M. Hayashizaki Y. Tetrahedron 2007, 63: 11021

<A NAME="RG04008ST-3D">3d</A> Hainke S. Singh I. Hemmings J. Seitz O. J. Org. Chem. 2007, 72: 8811

<A NAME="RG04008ST-4A">4a</A> Kool ET. Acc. Chem. Res. 2002, 35: 936

<A NAME="RG04008ST-4B">4b</A> Sismour AM. Benner SA. Nucleic Acids Res. 2005, 33: 5640

<A NAME="RG04008ST-4C">4c</A> Leconte AM. Matsuda S. Hwang GT. Romesberg FE. Angew. Chem. Int. Ed. 2006, 45: 4326

See, for example:

<A NAME="RG04008ST-5A">5a</A> Tanaka K. Shinoya M. J. Org. Chem. 1999, 64: 5002

<A NAME="RG04008ST-5B">5b</A> Seela F. Debelak H. J. Org. Chem. 2001, 66: 3303

See, for example:

<A NAME="RG04008ST-6A">6a</A> Chen D.-W. Beuscher AE. Stevens RC. Wirsching P. Lerner RA. Janada KD. J. Org. Chem. 2001, 66: 1725

<A NAME="RG04008ST-6B">6b</A> Griesang N. Richert C. Tetrahedron Lett. 2002, 43: 8755

<A NAME="RG04008ST-6C">6c</A> Aketani S. Tanaka K. Yamamoto K. Ishihama A. Cao H. Tengeiji A. Hiraoka S. Shiro M. Shionoya M. J. Med. Chem. 2002, 45: 5594

<A NAME="RG04008ST-7A">7a</A> For the synthesis of aryl C-glycosides via the Heck reaction, see: Wellington KW. Benner SA. Nucleosides, Nucleotides Nucleic Acids 2005, 1309 ; (review)

<A NAME="RG04008ST-7B">7b</A> Oda H. Hanami T. Iwashita T. Kojima M. Itoh M. Hayashizaki Y. Tetrahedron 2007, 63: 12747

<A NAME="RG04008ST-8A">8a</A> Guianvarc’h D. Benhida R. Fourrey J.-L. Maurisse R. Sun J.-S. Chem. Commun. 2001, 1814

<A NAME="RG04008ST-8B">8b</A> Guianvarc’h D. Fourrey J.-L. Sun J.-S. Maurisse R. Benhida R. Bioorg. Med. Chem. 2003, 11: 2751

<A NAME="RG04008ST-8C">8c</A> Guianvarc’h D. Fourrey J.-L. Tran Huu Dau M.-E. Guérineau V. Benhida R. J. Org. Chem. 2002, 67: 3724

<A NAME="RG04008ST-8D">8d</A> Guianvarc’h D. Fourrey J.-L. Maurisse R. Sun J.-S. Benhida R. Org. Lett. 2002, 4: 4209

<A NAME="RG04008ST-9">9</A> Ratiometric fluorescent probes will be used (unpublished results). For classical fluorescent nucleosides, see: Wilson JN. Kool ET. Org. Biomol. Chem. 2006, 4: 4265

<A NAME="RG04008ST-10A">10a</A> Joos PE. Esmans EL. Domise RA. De Bruyn A. Balzarini JM. De Clercq ED. Helv. Chim. Acta 1992, 75: 613

Aldehyde 1 was obatined from 2′-deoxyribose in four steps and 62% overall yield.

Typical Procedure To a solution of benzofuran (2 mmol) in anhyd THF (6 mL) was added dropwise n-BuLi (1.6 M in hexane, 2 mmol) at 0 °C. The mixture was stirred for 30 min and aldehyde 1 (412 mg, 1 equiv) in anhyd THF (2 mL) was slowly added. The reaction was stirred during 90 min and warmed slowly to r.t., then quenched with a cold solution of NH₄Cl and extracted with CH₂Cl₂ (3 × 40 mL). The combined organic layers were dried (MgSO₄) and evaporated under reduced pressure to give a crude oil. Silica gel column chroma-tography purification using gradient elution [cyclohexane (100%) to EtOAc-cyclohexane (8:92)] afforded (S)-2a and (R)-2a as yellow oils (440 mg, 83%, R/S = 35:65).
Compound (S)-2a: TLC (cyclohexane-EtOAc, 7:3). R _f = 0.49. ¹H NMR (200 MHz, CDCl₃): δ = 0.95 (s, 9 H, t-Bu), 1.28 (s, 3 H, CH₃), 1.37 (s, 3 H, CH₃), 2.06-2.27 (m, 1 H, H-2′), 2.37-2.47 (m, 1 H, H-2′), 3.72 (d, 2 H, J = 6.3 Hz, 2 × H-5′), 4.30 (q, 1 H, J = 6.2 Hz, H-4′), 4.42-4.52 (m, 1 H, H-3′), 5.12 (dd, 1 H, J = 3.8, 8.7 Hz, H-1′), 6.67 (s, 1 H, H-furan), 7.26 (m, 2 H, 2 × H-Ar), 7.36 (m, 7 H, 6 × H-Ph and 1 × H-Ar), 7.55 (m, 1 H, H-Ar), 7.64 (m, 4 H, 4 × H-Ph) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 19.10 (Me₃ C), 25.44 (Me ₂C), 26.75 (Me ₃C), 27.91 (Me ₂C), 35.36 (C-2′), 62.19 (C-5′), 68.14 (C-1′), 76.85 (C-3′), 77.51 (C-4′), 102.49 (C-3), 108.78 (Me₂ C), 111.15 (C-7), 120.96 (C-4), 122.63 (C-5), 123.92 (C-6), 127.70 (C-Ph), 127.72 (C-Ar), 129.77, 132.90, and 135.51 (C-Ph), 154.75 (C-Ar), 158.64 (C-2) ppm. MS (ESI⁺): m/z = 568.5 [MK⁺], 552.6 [MNa⁺].
Compound (R)-2a: TLC (cyclohexane-EtOAc, 7:3). R _f = 0.40. ¹H NMR (200 MHz, CDCl₃): δ = 1.00 (s, 9 H, t-Bu), 1.26 (s, 3 H, CH₃), 1.38 (s, 3 H, CH₃), 2.22-2.45 (m, 2 H, 2 × H-2′), 3.69-3.74 (m, 2 H, 2 × H-5′), 4.20-4.29 (m, 1 H, H-4′), 4.42-4.52 (m, 1 H, H-3′), 5.08-5.16 (m, 1 H, H-1′), 6.65 (s, 1 H, H-furan), 7.26 (m, 2 H, 2 × H-Ar), 7.36 (m, 7 H, 6 × H-Ph and 1 × H-Ar), 7.55 (m, 1 H, H-Ar), 7.64 (m, 4 H, 4 × H-Ph) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 19.19 (Me₃ C), 25.54 (Me ₂C), 26.86 (Me ₃C), 28.08 (Me ₂C), 34.12 (C-2′), 62.36 (C-5′), 66.52 (C-1′), 74.52 (C-3′), 77.48 (C-4′), 102.69 (C-3), 108.35 (Me₂ C), 111.21 (C-7), 120.99 (C-4), 122.75 (C-5), 123.97 (C-6), 127.79 (C-Ph), 128.30 (C-Ar), 129.87, 133.04, and 135.62 (C-Ph), 154.90 (C-Ar), 159.56 (C-2) ppm. MS (ESI⁺): m/z = 552.6 [MNa⁺], 450.7.

All products gave satisfactory spectral data. Data for selected products are given here.
Compound (R,S)-2b: TLC (cyclohexane-EtOAc, 7:3): R _f = 0.70-0.75. ¹H NMR (200 MHz, CDCl₃): δ = 1.04 (s, 9 H, t-Bu), 1.34 (s, 3 H, CH₃), 1.41 (s, 3 H, CH₃), 1.50-2.2 (m, 2 H, H-2′), 3.68-3.71 (m, 2 H, 2 × H-5′), 4.21-4.42 (m, 2 H, H-4′, H-3′), 4.88-4.95 (m, 1 H, H-1′), 6.25-6.26 (m, 2 H, 2 × H-Ar), 7.38-7.41 (m, 7 H, 6 × H-Ph, 1 × H-Ar), 7.62-7.66 (m, 4 H, 4 × H-Ph) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 19.29 (Me₃ C), 25.66 (Me ₂C), 26.93 (Me ₃C), 28.14 (Me ₂C), 35.40 (C-2′), 62.43 (C-5′), 67.64-65.66 (C-1′), 76.54-74.36 (C-3′), 77.18 (C-4′), 106.01-108.69 (C-Ar), 108.83 (Me₂ C), 110.26-111.95 (C-Ar), 127.91, 129.96, 133.17, 135.70, 142.03 (C-Ph and C-Ar) ppm. MS (ESI⁺):
m/z = 503.2 [MNa⁺].
Compound (R,S)-2e: TLC (cyclohexane-EtOAc, 7:3). R _f = 0.50-0.53. ¹H NMR (200 MHz, CDCl₃): δ = 0.96 (s, 9 H, t-Bu), 1.27 (s, 3 H, CH₃), 1.31 (s, 3 H, CH₃), 1.50-2.11 (m, 2 H, H-2′), 3.59-3.65 (m, 2 H, 2 × H-5′), 4.12-4.22 (m, 1 H, H-4′), 4.30-4.37 (m, 1 H, H-3′), 5.00-5.10 (m, 0.4 H, H-1′), 5.11-5.20 (m, 0.6 H, H-1′), 6.80-6.89 (m, 2 H, 2 × H-Ar), 7.20-7.26 (m, 1 H, H-Ar), 7.30-7.40 (m, 6 H, 6 × H-Ph), 7.52-7.58 (m, 4 H, 4 × H-Ph) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 19.29 (Me₃ C), 25.63 (Me ₂C), 26.98 (Me ₃C), 28.17 (Me ₂C), 37.91 (C-2′), 62.54 (C-5′), 68.01 (C-1′), 77.37 (C-3′), 77.62 (C-4′), 108.42 (Me₂ C), 123.27, 124.43, 126.85, 127.88, 129.96, 133.10, 135.69, 149.07 (C-Ph and C-Ar) ppm. MS (ESI⁺): m/z = 534.6 [MK⁺], 518.7 [MNa⁺], 497.6 [MH⁺].

<A NAME="RG04008ST-13">13</A> Jiang YL. Stivers JT. Tetrahedron Lett. 2003, 44: 4051

General Procedure
To a solution of 2a (R or S, 1 mmol) in toluene (25 mL) was added PTSA (0.2 mmol, 0.2 equiv). The mixture was stirred at 50 °C for 4 h then quenched with a sat. soln of NaHCO₃ and extracted with CH₂Cl₂ (3 × 30 mL). The combined organic layers were dried over MgSO₄ and evaporated under reduced pressure to give a crude oil. Silica gel column chromatography purification using gradient elution [cyclohexane (100%) to EtOAc-cyclohexane (20:80)] afforded 3a as a yellow oil.
Compound α-3a: TLC (cyclohexane-EtOAc, 7:3). R _f = 0.43. ¹H NMR (200 MHz, CDCl₃): δ = 1.08 (s, 9 H, t-Bu), 2.27-2.39 (m, 1 H, H-2′), 2.66-2.80 (m, 1 H, H-2′), 3.69-3.88 (m, 2 H, 2 × H-5′), 4.16-4.20 (m, 1 H, H-4′), 4.52-4.59 (m, 1 H, H-3′), 5.24-5.31 (dd, 1 H, J = 8.0, 5.3 Hz, H-1′), 6.69 (s, 1 H, H-furan), 7.39-7.66 (m, 10 H, 6 × H-Ph and 4 × H-Ar), 7.67-7.71 (m, 4 H, 4 × H-Ph) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 19.40 (Me₃ C), 27.05 (Me ₃C), 39.40 (C-2′), 64.98 (C-5′), 74.04 and 74.78 (C3′, C-1′), 86.53 (C-4′), 103.95, 111.48, 121.31, 123.03, 124.54, 127.97, 129.99, 135.75, 156.72 (C-Ph and C-Ar) ppm. MS (ESI⁺): m/z = 510.8 [MK⁺], 495.1 [MNa⁺].
Compound β-3a: TLC (cyclohexane-EtOAc, 7:3): R _f = 0.26. ¹H NMR (200 MHz, CDCl₃): δ = 1.07 (s, 9 H, t-Bu), 2.20-2.42 (m, 1 H, H-2′), 2.47-2.56 (m, 1 H, H-2′), 3.68-4.01 (m, 2 H, 2 × H-5′), 4.02-4.07 (m, 1 H, H-4′), 4.62-4.67 (m, 1 H, H-3′), 5.30 (dd, 1 H, J = 9.3, 6.2 Hz, H-1′), 6.63 (s, 1 H, H-furan), 7.31-7.60 (m, 10 H, 6 × H-Ph and 4 × H-Ar), 7.62-7.79 (m, 4 H, 4 × H-Ph) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 19.40 (Me₃ C), 27.05 (Me ₃C), 39.56 (C-2′), 64.77 (C-5′), 73.82 (C-1′), 74.40 (C-3′), 87.22 (C-4′), 104.08, 111.43, 121.16, 122.81, 124.34, 127.90, 129.96, 135.74, 156.72 (C-Ph and C-Ar) ppm. MS (ESI⁺):
m/z = 510.8 [MK⁺], 495.1 [MNa⁺].

Compound α-4a: TLC (CH₂Cl₂-MeOH, 98:2). R _f = 0.3. ¹H NMR (500 MHz, CDCl₃): δ = 2.33-2.37 (m, 1 H, H-2′), 2.61-2.64 (m, 1 H, H-2′), 3.73-3.76 (m, 2 H, 2 × H-5′), 4.01-4.04 (q, 1 H, J = 4.7 Hz, H-4′), 4.43-4.45 (q, 1 H, J = 5.7 Hz, H-3′), 5.21 (t, 1 H, J = 6.9 Hz, H-1′), 6.67 (s, 1 H, H-furan), 7.16-7.20 (t, 1 H, J = 7.2 Hz, H-Ar), 7.22-7.25 (m, 1 H, H-Ar), 7.42 (d, 1 H, J = 8.2 Hz, H-Ar), 7.50 (d, 1 H, J = 7.6 Hz, H-Ar) ppm. ¹³C NMR (CDCl₃, 125 MHz): δ = 39.23 (C-2′), 58.74 (C-5′), 62.74 (C-3′), 73.23 (C-1′), 85.69 (C-4′), 103.95 (C-3), 111.35 (C-7), 121.85 (C-4), 122.87 (C-5), 124. (C-6), 128.15 (C-Ar), 154.75 (C-Ar), 157.30 (C-2) ppm. MS (ESI⁺): m/z = 256.7 [MNa⁺], 241.9 [MLi⁺], 214.7 [M⁺ - H₂O].
Compound β-4a: TLC (CH₂Cl₂-MeOH, 98:2). R _f = 0.28. ¹H NMR (500 MHz, CDCl₃): δ = 2.17-2.30 (m, 1 H, H-2′), 2.45-2.51 (m, 1 H, H-2′), 3.75 (d, 2 H, J = 4.4 Hz, 2 × H-5′), 4.05 (m, 1 H, H-4′), 4.56 (m, 1 H, H-3′), 5.30 (dd, 1 H, J = 6.6, 8.8 Hz, H-1′), 6.67 (s, 1 H, H-furan), 7.18-7.21 (m, 1 H, H-Ar), 7.22-7.25 (m, 1 H, H-Ar), 7.45 (d, 1 H, J = 8.3 Hz, H-Ar), 7.52 (d, 1 H, J = 7.8 Hz, H-Ar) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 39.91 (C-2′), 58.82 (C-5′), 63.54 (C-3′), 73.78 (C-1′), 87.73 (C-4′), 104.23 (C-3), 111.45 (C-7), 121.12 (C-4), 122.89 (C-5), 124.46 (C-6), 128.15 (C-Ar), 155.18 (C-Ar), 156.81 (C-2) ppm. MS (ESI⁺): m/z = 256.7 [MNa⁺], 241.9 [MLi⁺], 214.7 [M⁺ - H₂O].