From Intriguing Reactivity
of 2-Bromothiophene to the First Synthesis of C1′-Disubstituted C-Nucleosides

Corinne Peyron; Rachid Benhida

doi:10.1055/s-0028-1087537

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Synlett 2009(3): 472-476
DOI: 10.1055/s-0028-1087537

LETTER

From Intriguing Reactivity of 2-Bromothiophene to the First Synthesis of C1′-Disubstituted C-Nucleosides

Corinne Peyron, 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;

Further Information

Publication History

Received 24 October 2008
Publication Date:
21 January 2009 (online)

Abstract
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Abstract

A two-step approach to a family of C1′-disubstituted C-nucleosides is described. It relies on a double aryl condensation on ribonolactone 1 to give the desired disubstituted diols 2c, 6c and 7c. The cycloetherification of these diols followed by protecting group cleavage gave high yields of C-nucleosides 2d, 6d and 7d, respectively, featuring two hydrophobic aryl groups as nucleobase surrogates.

Key words

C-nucleosides - double aryl-aldol condensation - cycloetherification

References and Notes

For pyrazofurin and formycin, see:
1a Shaban MAE. Nasr AZ. In Advances in Heterocyclic Chemistry Vol. 68: Katritzky AR. Academic Press; San Diego: 1997. p.259

Google Scholar
1b Shaban MAE. Nasr AZ. In Advances in Heterocyclic Chemistry Vol. 70: Katritzky AR. Academic Press; San Diego: 1998. p.230

Google Scholar
1c For showdomycin, see: Nishimura H. Mayama M. Komatsu Y. Kato H. Shimsoka N. Tanaka Y. J. Antibiot., Ser. A 1964, 17: 148

Google Scholar
1d Rabinovitz M. Uehara Y. Vistica DT. Science 1979, 206: 1085

Google Scholar
1e Barett AGM. Broughton HB. J. Org. Chem. 1986, 51: 495

Google Scholar
2 Grifantini M. Curr. Opin. Invest. Drugs 2000, 1: 257

Google Scholar
3a For recent articles, see: For a review, see: Maden BEH. Nature (London) 1997, 389: 129

Google Scholar
3b Chang Y.-C. Herath J. Wang TH.-H. Chow CS. Bioorg. Med. Chem. 2008, 16: 2676

Google Scholar
3c Hamma T. Ferré-D’Amaré AR. Chem. Biol. 2006, 13: 1125

Google Scholar
4a Kool ET. Acc. Chem. Res. 2002, 35: 936

Google Scholar
4b Haberli A. Leumann CJ. Org. Lett. 2002, 4: 3275

Google Scholar
4c Guianvarc’h D. Fourrey J.-L. Maurisse R. Sun J.-S. Benhida R. Org. Lett. 2002, 4: 4209

Google Scholar
4d Guianvarc’h D. Fourrey J.-L. Sun J.-S. Maurisse R. Benhida R. Bioorg. Med. Chem. 2003, 11: 2751

Google Scholar
4e Leconte AM. Matsuda S. Hwang GT. Romesberg FE. Angew. Chem. Int. Ed. 2006, 45: 4326

Google Scholar
For recent reviews on the chemistry of C-glycoside analogues, see:
5a Wu Q. Simons C. Synthesis 2004, 1533

Google Scholar
5b Lee DYW. He MS. Curr. Top. Med. Chem. 2005, 5: 1333

Google Scholar
5c For recent articles, see: Wellington KW. Benner SA. Nucleosides, Nucleotides Nucleic Acids 2005, 1309

Google Scholar
5d Guianvarc’h D. Fourrey J.-L. Tran Huu Dau M.-E. Guérineau V. Benhida R. J. Org. Chem. 2002, 67: 3724

Google Scholar
5e Urban M. Pohl R. Klepetarova B. Hocek M. J. Org. Chem. 2006, 71: 7322

Google Scholar
5f Joubert N. Pohl R. Klepetarova B. Hocek M. J. Org. Chem. 2007, 72: 6797

Google Scholar
6a Kodama T. Shuto S. Ichikawa S. Matsuda A. J. Org. Chem. 2002, 67: 7706

Google Scholar
6b Haraguchi K. Kubota Y. Tanaka H. J. Org. Chem. 2004, 69: 1831

Google Scholar
6c Ogamino J. Mizunuma H. Kumamoto H. Takeda S. Haraguchi K. Nakamura KT. Sugiyama H. Tanaka H. J. Org. Chem. 2005, 70: 1684

Google Scholar
7a Guianvarc’h D. Benhida R. Fourrey J.-L. Maurisse R. Sun J.-S. Chem. Commun. 2001, 1814

Google Scholar
7b Peyron C. Benhida R. Bories C. Loiseau P. Bioorg. Chem. 2005, 33: 439

Google Scholar
7c Spadafora M. Burger A. Benhida R. Synlett 2008, 1225

Google Scholar
7d Spadafora M. Mehiri M. Burger A. Benhida R. Tetrahedron Lett. 2008, 49: 3967

Google Scholar
8 Peyron C. Navarre JM. Dubreuil D. Vierling P. Benhida R. Tetrahedron Lett. 2008, 49: 6171

Crossref Google Scholar

9

2a _h: ^¹H NMR (200 MHz, CDCl₃): δ = 1.07-1.11 (2 × s, 9 H, Met-Bu), 1.30 (s, 3 H, Me), 1.48 (s, 3 H, Me), 3.72 (dd, 1 H, J = 3.6, 11.2 Hz, H₅ _′), 3.90 (dd, 1 H, J = 3.5, 11.3 Hz, H₅ _′), 4.36 (t, 1 H, J = 2.5 Hz, H₄ _′), 4.62 (d, 1 H, J = 5.7 Hz, H₃ _′), 4.75 (s, 1 H, OH), 4.89 (dd, 1 H, J = 1.4, 5.6 Hz, H₂ _′), 6.96 (s, 2 H, H₃, H₄), 7.37-7.46 (m, 6 H, Ph), 7.57-7.72 (m, 4 H, Ph). ^¹³C NMR (50 MHz, CD₃OD): δ = 19.79 (CMe₃), 24.44 (Me), 26.26 (Me), 26.51 (CMe₃), 66.35 (C₅ _′), 84.63 (C₂ _′), 87.19 (C₄ _′ or C₃ _′), 88.07 (C₃ _′ or C₄ _′), 106.85 (CMe₂), 113.40 (C₁ _′), 113.80 (C₂), 126.15 (C₄), 127.60 (C_Ph), 127.93 (C_Ph), 129.28 (C₃), 130.05 (C_Ph), 133.41 (C_Ph), 134.95 (C_Ph), 135.71 (C_Ph), 145.66 (C₅). MS (ESI⁺): m/z = 610.8-612.8 (100, 83) [M + Na]⁺. MS (ESI^-): m/z = 587.0-589.0 (100, 69) [M - H]^-. Anal. Calcd for C₂₈H₃₃BrO₅SSi: C, 57.04; H, 5.64. Found: C, 57.29; H, 5.87.
2a _k: ^¹H NMR (200 MHz, CDCl₃): δ = 1.05 (s, 9 H, Met-Bu), 1.34 (s, 3 H, Me), 1.44 (s, 3 H, Me), 2.81 (d, 1 H, J = 4.8 Hz, OH), 3.72-3.92 (m, 3 H, H₄ _′, H₅ _′), 4.59 (t, 1 H, J = 6.1 Hz, H₃ _′), 4.98 (d, 1 H, J = 5.5 Hz, H₂ _′), 7.12 (d, 1 H, J = 4.0 Hz, H₄), 7.33-7.44 (m, 6 H, Ph), 7.62-7.70 (m, 4 H, Ph), 7.82 (d, 1 H, J = 4.1 Hz, H₃). ^¹³C NMR (50 MHz, CDCl₃): δ = 19.41 (CMe₃), 26.25 (Me), 26.96 (CMe₃), 27.27 (Me), 64.79 (C₅ _′), 72.81 (C₄ _′), 77.41 (C₃ _′), 80.72 (C₂ _′), 111.67 (CMe₂), 124.47 (C₂), 127.90 (C_Ph), 129.94 (C_Ph), 131.39 (C₄), 133.10 (C_Ph), 135.23 (C₃), 135.70 (C_Ph), 145.66 (C₅), 190.18 (C₁ _′). MS (ESI⁺): m/z = 611.1-613.1 (93, 100) [M + Na]⁺. Anal. Calcd for C₂₈H₃₃BrO₅SSi: C, 57.04; H, 5.64. Found: C, 57.17; H, 5.73.

10

2b: ^¹H NMR (200 MHz, CDCl₃ + CD₃OD): δ = 0.95 (s, 9 H, Met-Bu), 1.24 (s, 3 H, Me), 1.36 (s, 3 H, Me), 3.26-3.39 (m, 2 H, H₅ _′), 3.62 (d, 1 H, J = 4.0 Hz, H₄ _′), 4.26 (dd, 1 H, J = 6.8, 9.8 Hz, H₃ _′), 4.65 (d, 1 H, J = 6.8 Hz, H₂ _′), 6.68 (d, 1 H, J = 3.9 Hz, H₄), 6.76 (d, 1 H, J = 3.9 Hz, H₃), 6.84 (d, 1 H, J = 3.8 Hz, H₃), 7.05 (d, 1 H, J = 3.9 Hz, H₄), 7.27-7.36 (m, 6 H, Ph), 7.45-7.62 (m, 4 H, Ph). ^¹³C NMR (50 MHz, CDCl₃ + CD₃OD): δ = 19.65 (CMe₃), 24.14 (Me), 26.54 (Me), 27.14 (Me, t-Bu), 65.68 (C₄ _′), 69.58 (C₅ _′), 76.09 (C₃ _′), 77.63 (C₁ _′), 83.83 (C₂ _′), 109.32 (CMe₂), 112.38-113.32 (C₂), 125.54-125.60 (C₄), 128.13-128.22 (C_Ph), 129.25-129.63 (C₃), 130.24-130.29 (C_Ph), 135.91 (C_Ph), 148.09-152.36 (C₅). MS (ESI⁺): m/z = 773.2, 775.1, 777.1 (49, 100, 60) [M + Na]⁺.

11

The variation of Δδ values (thiophene protons H3 and H4): Δδ = 0 for 2a _h and 0.7 for 2a _K could be explained by the possible anisotropy of the TBDPS group (aryl-TBDPS
π-stacking).

12

4a _h: ^¹H NMR (200 MHz, CDCl₃): δ = 1.07-1.12 (2 × s, 9 H, Met-Bu), 1.25 (s, 3 H, Me), 1.38 (s, 3 H, Me), 3.75 (dd, 1 H, J = 3.1, 11.2 Hz, H₅ _′), 3.95 (dd, 1 H, J = 3.0, 11.5 Hz, H₅ _′), 4.42-4.47 (m, 1 H, H₄ _′), 4.66 (d, 1 H, J = 5.7 Hz, H₂ _′), 4.87-4.95 (m, 2 H, H₃ _′, OH), 7.24-7.26 (m, 1 H, Ar), 7.37-7.71 (m, 13 H, Ph, Ar). ^¹³C NMR (50 MHz, CDCl₃): δ = 19.20 (CMe₃), 24.87 (Me), 26.37 (Me), 26.92 (CMe₃), 65.62 (C₅ _′), 82.04 (C₃ _′), 86.40 (C₄ _′), 88.36 (C₂ _′), 106.60 (C₁ _′), 112.87 (CMe₂), 121.82 (C₃), 124.59 (CH_Ar), 127.84 (C_Ph), 129.15 (CH_Ar), 129.82 (CH_Ar), 130.19 (C_Ph), 130.39 (CH_Ar), 131.22 (C_Ph), 135.62-135.81 (C_Ph), 141.37 (C₁). MS (ESI⁺): m/z = 604.6-606.5 (95, 100) [M + Na],⁺ 620.5-622.5 (95, 100) [M + K]⁺.

13

7a _h: ^¹H NMR (200 MHz, CDCl₃): δ = 1.08-1.12 (2 × s, 9 H, Met-Bu), 1.26 (s, 3 H, Me), 1.40 (s, 3 H, Me), 3.71-4.01 (m, 5 H, H₅ _′, OMe), 4.38-4.52 (m, 2 H, H₄ _′, OH), 4.63 (d, 1 H, J = 5.7 Hz, H₂ _′), 4.92 (dd, 1 H, J = 1.5, 5.7 Hz, H₃ _′), 6.89 (d, 2 H, J = 8.9 Hz, H₃), 7.36-7.44 (m, 6 H, Ph), 7.54 (d, 2 H,
J = 8.8 Hz, H₂), 7.65-7.75 (m, 4 H, Ph). ^¹³C NMR (50 MHz, CDCl₃): δ = 19.39-19.49 (CMe₃), 25.14-25.20 (Me), 26.71-26.82 (Me), 27.04-27.11 (CMe₃), 55.38 (OMe), 65.88 (C₅ _′), 82.23-82.33 (C₃ _′), 86.43-86.54 (C₄ _′), 88.25 (C₂ _′), 107.30 (C₁ _′), 112.84 (CMe₂), 113.12 (C₃), 128.08-128.13 (C_Ph), 128.44 (C₂), 130.19-130.35 (C_Ph), 131.60 (C₁), 132.22-132.32 (C_Ph), 135.78-135.95 (C_Ph), 159.70 (C₄). MS (ESI⁺): m/z = 557.2 [M + Na]⁺.
7a _k: ^¹H NMR (200 MHz, CDCl₃): δ = 1.06 (s, 9 H, Met-Bu), 1.12 (s, 3 H, Me), 1.31 (s, 3 H, Me), 3.73-3.81 (m, 2 H, H₅ _′), 3.87 (s, 3 H, OMe), 4.40-4.52 (m, 2 H, H₄ _′, OH), 4.72-4.82 (m, 1 H, H₂ _′), 5.23 (d, 1 H, J = 5.5 Hz, H₃ _′), 6.98 (d, 2 H, J = 7.1 Hz, H₃), 7.33-7.44 (m, 6 H, Ph), 7.62-7.75 (m, 4 H, Ph), 8.13 (d, 2 H, J = 8.1 Hz, H₂). ^¹³C NMR (50 MHz, CDCl₃):
δ = 19.21 (CMe₃), 26.18 (Me), 26.79 (CMe₃), 27.25 (Me), 55.06-55.44 (OMe), 64.77 (C₅ _′), 68.89 (C₂ _′), 72.73 (C₃ _′), 79.35 (C₄ _′), 111.04 (CMe₂), 113.66 (C₃), 127.71-127.74 (C_Ph), 129.77 (C₂), 131.44-131.94 (C_Ph), 135.46-135.58 (C_Ph), 163.79 (C₄), 195.70 (C₁ _′). MS (ESI⁺): m/z = 557.6
[M + Na]⁺. Similar variation of Δδ was observed (H2 and H3 protons, 7a _h vs. 7a _K): Δδ = 0.65 for 7a _h and 1.15 for 7a _k.

14

2c: ^¹H NMR (200 MHz, CDCl₃): δ = 1.05 (s, 9 H, Met-Bu), 1.29 (s, 3 H, Me), 1.39 (s, 3 H, Me), 3.70-4.12 (m, 3 H, H₄ _′, H₅ _′), 4.76 (dd, 1 H, J = 2.9, 5.9 Hz, H₃ _′), 5.01 (d, 1 H, J = 5.8 Hz, H₂ _′), 6.41 (d, 1 H, J = 3.8 Hz, H₄), 6.83 (d, 1 H, J = 3.9 Hz, H₃), 6.87 (d, 1 H, J = 3.9 Hz, H₃), 6.98 (d, 1 H, J = 3.8 Hz, H₄), 7.32-7.45 (m, 6 H, Ph), 7.65-7.78 (m, 4 H, Ph). ^¹³C NMR (50 MHz, CDCl₃): δ = 19.38 (CMe₃), 24.68 (Me), 25.77 (Me), 26.94 (CMe₃), 61.83 (C₅ _′), 77.36, 78.88, 80.43, 81.37 (C₄ _′, C₃ _′, C₁ _′, C₂ _′), 112.38-113.32 (C₂), 113.36 (CMe₂), 126.13-126.27 (C₄), 127.74-127.81 (C_Ph), 128.83-129.79 (C₃), 133.51 (C_Phl), 135.8-135.89 (C_Ph), 145.13-147.38 (C₅). MS (ESI⁺): m/z = 755.0, 757.0, 759.0 (51, 100, 60) [M + Na]⁺.
7b: ^¹H NMR (200 MHz, CDCl₃): δ = 0.99 (s, 9 H, Met-Bu), 1.27 (s, 3 H, Me), 1.31 (s, 3 H, Me), 3.61-3.77 (m, 9 H, H₄ _′, H₅ _′, OMe), 4.24 (dd, 1 H, J = 5.7, 9.2 Hz, H₃ _′), 5.04 (d, 1 H, J = 5.7 Hz, H₂ _′), 6.76-6.97 (m, 4 H, H₃), 7.32-7.68 (m, 14 H, Ph, H₂). ^¹³C NMR (50 MHz, CDCl₃): δ = 19.31 (CMe₃), 24.76 (Me), 26.88 (CMe₃), 27.46 (Me), 55.20-55.23 (OMe), 65.09 (C₅ _′), 69.01 (C₃ _′, C₄ _′), 77.11 (C₁ _′), 83.05 (C₂ _′), 107.98 (CMe₂), 113.06-113.50 (C₃), 127.00-127.54 (C₂), 127.82-127.87 (C_Ph), 129.89-129.95 (C_Ph), 135.59-135.77 (C_Ph), 137.77 (C₁), 158.28 (C₄). MS (ESI⁺): m/z = 666.3 [M + Na]⁺.
7c: 1H NMR (200 MHz, CDCl3): d = 1.04 (s, 9 H, Met-Bu), 1.21 (s, 3 H, Me), 1.36 (s, 3 H, Me), 3.44 (dd, 1 H, J = 6.4, 10.6 Hz, H5’), 3.64 (dd, 1 H, J = 5.1, 10.6 Hz, H5’), 3.78 (s, 6 H, OMe), 4.46-4.54 (m, 1 H, H4’), 4.84 (dd, 1 H, J = 2.5, 6.2 Hz, H3’), 5.29 (d, 1 H, J = 6.2 Hz, H2’), 6.80 (2d, 4 H, J = 8.9 Hz, H3), 7.28-7.44 (m, 10 H, Ph, H2), 7.58-7.69 (m, 4 H, Ph).

15

2d: mp 181-182 ˚C. ^¹H NMR (200 MHz, CDCl₃ + CD₃OD): δ = 3.47 (dd, 1 H, J = 2.8, 9.6 Hz, H₅ _′), 3.69 (dd, 1 H, J = 2.7, 7.9 Hz, H₅ _′), 3.82-3.96 (m, 2 H, H₃ _′, H₄ _′), 4.49 (d, 1 H, J = 2.8 Hz, H₂ _′), 6.54 (d, 1 H, J = 3.9 Hz, H_Th), 6.87 (d, 1 H, J = 3.9 Hz, H_Th), 7.01-7.08 (m, 2 H, H_Th). ^¹³C NMR (50 MHz, CDCl₃ + CD₃OD): δ = 62.47 (C₅ _′), 71.33 (C₃ _′), 80.42 (C₄ _′), 82.65 (C₂ _′), 88.64 (C₁ _′), 112.09-112.18 (C₂), 125.67-126.22 (C₄), 128.26-129.30 (C₃), 140.58-141.82 (C₅). MS (ESI⁺): m/z = 476.5, 478.5, 480.5 (49, 100, 54) [M + Na]⁺. Anal. Calcd for C₁₃H₁₂Br₂O₄S₂: C, 34.23; H, 2.65. Found: C, 34.48; H, 2.41.
7d: mp 90-92 ˚C. ^¹H NMR (200 MHz, CD₃OD): δ = 3.57 (dd, 1 H, J = 1.2, 12.6 Hz, H₅ _′), 3.67-3.85 (m, 8 H, H₃ _′, H₄ _′, 2 × OMe), 3.95 (dd, 1 H, J = 1.9, 12.6 Hz, H₅ _′), 4.66-4.71 (m, 1 H, H₂ _′), 6.77 (d, 2 H, J = 8.9 Hz, H₃), 6.89 (d, 2 H, J = 8.9 Hz, H₂), 7.24-7.37 (m, 4 H, H₂, H₃). ^¹³C NMR (50 MHz, CD₃OD): δ = 55.61-55.69 (Me), 67.69 (C₃ _′), 67.79 (C₅ _′), 71.35 (C₄ _′), 78.34 (C₂ _′), 84.67 (C₁ _′), 113.83-113.99 (C₃), 114.39-115.06 (C₃), 127.96-128.09 (C₂), 129.08-129.31 (C₂), 136.43-138.91 (C₁), 159.45-160.21 (C₄). MS (ESI⁺): m/z = 385.3 [M + K]⁺. MS (ESI^-): m/z = 381.8 [M + Cl]^-. Anal. Calcd for C₁₉H₂₂O₆: C, 65.88; H, 6.40. Found: C, 66.03; H, 6.29.