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Synlett 2009(3): 472-476  
DOI: 10.1055/s-0028-1087537
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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)

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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

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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 (CPh), 127.93 (CPh), 129.28 (C3), 130.05 (CPh), 133.41 (CPh), 134.95 (CPh), 135.71 (CPh), 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 (CPh), 129.94 (CPh), 131.39 (C4), 133.10 (CPh), 135.23 (C3), 135.70 (CPh), 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 (CPh), 129.25-129.63 (C3), 130.24-130.29 (CPh), 135.91 (CPh), 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 (CHAr), 127.84 (CPh), 129.15 (CHAr), 129.82 (CHAr), 130.19 (CPh), 130.39 (CHAr), 131.22 (CPh), 135.62-135.81 (CPh), 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 (CPh), 128.44 (C2), 130.19-130.35 (CPh), 131.60 (C1), 132.22-132.32 (CPh), 135.78-135.95 (CPh), 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 (CPh), 129.77 (C2), 131.44-131.94 (CPh), 135.46-135.58 (CPh), 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 (CPh), 128.83-129.79 (C3), 133.51 (CPhl), 135.8-135.89 (CPh), 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 (CPh), 129.89-129.95 (CPh), 135.59-135.77 (CPh), 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, HTh), 6.87 (d, 1 H, J = 3.9 Hz, HTh), 7.01-7.08 (m, 2 H, HTh). 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.