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DOI: 10.1055/s-0028-1087537
From Intriguing Reactivity of 2-Bromothiophene to the First Synthesis of C1′-Disubstituted C-Nucleosides
Publikationsverlauf
Publikationsdatum:
21. Januar 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
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References and Notes
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.
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]+.
11The 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).
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.
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).
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.