10.1002/cmdc.202000807
ChemMedChem
FULL PAPER
(1H, dd, J 8.0, 2.1 Hz, H6), 3.80 (2H, t, J 6.8 Hz, H8), 2.76 (2H,
t, J 6.7 Hz, H7), 1.02 and 1.01 (18H, s, (CH3)3CSiOAr), 0.23 and
0.22 (12H, s, (CH3)2SiOAr). 13C NMR (100 MHz, CDCl3): δ 146.8,
145.5, 131.3, 121.9, 121.8, 121.0, 63.8, 38.5, 25.9, 18.4, 4.0,
4.1. MS (ESI+): calcd. for C20H39O3Si2 [M+H]+ 383.24, found
383.55.
molecular sieves. After a few min, each mixture was added to
suitable phosphoramidite 10 (11 or 12, 0.70 mmol) dissolved in 1
mL of DCM and the solution was stirred for 3 h. Once the reaction
appeared to be complete by TLC (Hexane/AcOEt 80:20, v/v), 150
µL (0.82 mmol) of a TBHP solution in decane (5.5 M) was added
to the mixture, and after 1 h, the solvent was removed under
vacuum. The crude material was then purified by column
chromatography (Hexane/AcOEt 70:30 to 50:50 v/v) afforded
desired compound 13 (14 or 15) in good yields.
Syntheses of phosphoramidites 10 12: general procedure
To TBDMS ether 7 (8 or 9; 0.93 mmol) dissolved in anhydrous
DCM (7 mL), DIEA (516 µL, 3.70 mmol) and then
2cyanoethylN,Ndiisopropylaminochlorophosphoramidite
(250 µL, 0.39 mmol) were added. Reaction progress was
monitored by TLC (Hexane/AcOEt 80:20 v/v). After 1 h, the
solution was diluted with AcOEt, and the organic phase was
washed twice with brine and then concentrated. Column
chromatography of the residue (Hexane/AcOEt 80:20, v/v with 1%
TEA) afforded desired compound 10 (11 or 12; 0.24 mmol) in
good yields.
1
Compound 13 (338.0 mg, 0.55 mmol, 78% yield) H NMR (400
MHz, CDCl3): δ 7.07 (4H, d, J 8.6 Hz, H2, H2’, H6 and H6’),
6.78 (4H, d, J 8.5 Hz, H3, H3’, H5 and H5’), 4.17 (4H, q, J
7.0 Hz, H8 and H8’), 4.01 (1H, t, J 6.2 Hz, CNCH2CH2OP), 3.99
(1H, t, J 6.2 Hz, CNCH2CH2OP), 2.89 (4H, t, J 7.5 Hz, H7 and
H7’) 2.58 (2H, t, J 6.2 Hz, CNCH2CH2OP), 0.99 (18H, s,
(CH3)3CSiOAr), 0.19 (12H, s, (CH3)2SiOAr). 13C NMR (100 MHz,
CDCl3): δ 154.5, 130.0, 129.5, 120.1, 116.5, 68.7, 68.6, 61.6, 61.5,
35.8, 35.7, 25.7, 19.6, 19.5, 18.2, 4.4. 31P NMR (161.98 MHz,
CDCl3): δ 2.1. MS (ESI+): calcd. for C31H51NO6PSi2 [M+H]+
620.30, found 620.88.
1
Compound 10 (309.0 mg, 0.66mmol, 72% yield) H NMR (400
MHz, CDCl3): δ 7.09 (2H, d, J 8.5 Hz, H2 and H6), 6.78 (2H, d,
J 8.5 Hz, H3 and H5), 3.913.76 (4H, m, CNCH2CH2OP and
1
Compound 14 (372.5 mg, 0.57 mmol, 82% yield) H NMR (400
H8), 3.653.56 (2H, m, [(CH3)2CH]2N), 2.87 (2H, t, J 7.0 Hz, H7), MHz, CDCl3): δ 7.05 (2H, d, J 8.6 Hz, H2’ and H6’), 6.77 (3H,
2.60 (2H, t, J 6.6 Hz, CNCH2CH2OP), 1.20 (6H, d, J 6.7 Hz,
[(CH3)2CH]2N), 1.17 (6H, d, J 6.7 Hz, [(CH3)2CH]2N), 1.00 (9H, s,
(CH3)3CSiOAr), 0.20 (6H, s, (CH3)2SiOAr). 13C NMR (100 MHz,
d, J 8.6 Hz, H5, H3’ and H5’), 6.71 (1H, d, J 2.0 Hz, H2), 6.65
(1H, dd, 8.0, 2.0 Hz, H6), 4.18 (4H, m, H8 and H8’), 3.99 (2H,
q, J 6.3 Hz, CNCH2CH2OP), 3.77 (3H, s, OCH3), 2.88 (4H, t, J 6.4
CDCl3): δ 154.1, 131.3, 129.9, 119.9, 117.6, 64.6, 64.5, 58.4, 58.2, Hz, H7 and H7’), 2.58 (2H, t, J 6.3 Hz, CNCH2CH2OP), 1.00
43.1, 43.0, 37.1, 37.0, 25.7, 24.8, 24.7, 24.6, 24.5, 20.4, 20.3,
18.2, 4.4. 31P NMR (161.98 MHz, CDCl3): δ 147.3. MS (ESI+):
calcd. for C23H42N2O3PSi [M+H]+ 453.27, found 453.39.
Compound 11 (481.7 mg, 0.63, 68% yield) H NMR (400 MHz,
CDCl3): δ 6.78 (1H, d, J 8.1 Hz, H5), 6.74 (1H, d, J 1.8 Hz, H2),
(9H, s, (CH3)3CSiOAr), 0.98 (9H, s, (CH3)3CSiOAr), 0.17 (6H, s,
(CH3)2SiOAr), 0.13 (6H, s, (CH3)2SiOAr). 13C NMR (100 MHz,
CDCl3): δ 154.5, 150.8, 143.8, 130.3, 130.0, 129.9, 129.5, 121.2,
120.8, 120.1, 116.5, 113.0, 68.7, 68.5, 61.6, 61.5, 55.5, 36.3, 36.2,
35.8, 25.7, 25.6, 19.5, 18.5, 4.4, 4.6. 31P NMR (161.98 MHz,
CDCl3): δ -2.0. MS (ESI+): calcd. for C33H55NO8PSi2 [M+H]+
680.32, found 680.55.
1
6.68 (1H, dd,
J 8.0, 1.9 Hz, H6), 3.923.72 (4H, m,
CNCH2CH2OP and H8), 3.81 (3H, s, OCH3), 3.653.56 (2H, m,
[(CH3)2CH]2N), 2.87 (2H, t, J 7.0 Hz, H7), 2.60 (2H, t J 6.6 Hz,
CNCH2CH2OP), 1.19 (6H, d, J 6.7 Hz, [(CH3)2CH]2N), 1.16 (6H, d,
J 6.7 Hz, [(CH3)2CH]2N), 1.01 (9H, s, (CH3)3CSiOAr), 0.16 (6H, s,
(CH3)2SiOAr). 13C NMR (100 MHz, CDCl3): δ 150.7, 143.4, 132.0,
1
Compound 15 (361.2 mg, 0.53 mmol, 76% yield) H NMR (400
MHz, CDCl3): δ 6.76 (2H, d, J 8.0 Hz, H5 and H5’), 6.70 (2H, d,
J 1.9 Hz, H2 and H2’), 6.64 (2H, dd, J 8.0, 1.9 Hz, H6 and
H6’), 4.19 (4H, q, J 7.1 Hz, H8 and H8’), 3.99 (1H, q, J 6.1 Hz,
121.2, 120.7, 117.7, 113.1, 64.7, 64.5, 58.4, 58.2, 55.5, 43.1, 43.0, CNCH2CH2OP), 3.97 (1H, q, J 6.1 Hz, CNCH2CH2OP), 2.90 (4H,
37.5, 37.4, 25.7, 24.7, 24.6, 24.5, 20.4, 20.3, 18.4, 4.6. 31P NMR
(161.98 MHz, CDCl3): δ 147.3. MS (ESI+): calcd. for MS (ESI+):
calcd. for C24H44N2O4PSi [M+H]+ 483.28, found 483.37.
Compound 12 (487.0 mg, 0.84, 90% yield) H NMR (400 MHz,
CDCl3): δ 6.76 (1H, d, J 8.1 Hz, H5), 6.70 (1H, d, J 1.9 Hz, H2),
t, J 7.1 Hz, H7 and H7’), 2.58 (2H, t, J 6.0 Hz, CNCH2CH2OP),
0.98 (18H, s, (CH3)3CSiOAr), 0.13 (12H, s, (CH3)2SiOAr). 13C
NMR (100 MHz, CDCl3): δ 150.9, 143.8, 130.2, 121.2, 120.8,
116.5, 113.0, 68.6, 68.5, 61.6, 61.5, 55.5, 36.3, 36.2, 25.7, 18.4,
4.6. 31P NMR (161.98 MHz, CDCl3): δ 2.0. MS (ESI+): calcd. for
C31H51NO6PSi2 [M+H]+ 620.30, found 620.36.
1
6.67 (1H, dd,
J 8.0, 2.1 Hz, H6), 3.883.70 (4H, m,
1
CNCH2CH2OP and H8), 3.663.56 (2H, m, [(CH3)2CH]2N), 2.82
(2H, t, J 7.3 Hz, H7), 2.62 and 2.61 (2H, t, J 6.6 and 6.4 Hz,
CNCH2CH2OP), 1.20 (6H, d, J 6.8 Hz, [(CH3)2CH]2N), 1.17 (6H, d,
J 6.8 Hz, [(CH3)2CH]2N), 1.01 (9H, s, (CH3)3CSiOAr), 1.00 (9H, s,
(CH3)3CSiOAr), 0.21 (6H, s, (CH3)2SiOAr), 0.20 (6H, s,
(CH3)2SiOAr). 13C NMR (100 MHz, CDCl3): δ 146.5, 145.3, 131.5,
Compound 16 (361.3 mg, 0.45 mmol, 65% yield) H NMR (400
MHz, CDCl3): δ 7.07 (2H, d, J 8.5 Hz, H2’ and H6’), 6.79 (2H,
d, J 8.4 Hz, H3’ and H5’), 6.77 (1H, d, J 7.5 Hz, H5), 6.70 (1H,
d, J 2.1 Hz, H2), 6.66 (1H, dd, 8.0, 2.2 Hz, H6), 4.19 (4H, q, J
7.4 Hz, H8 and H8’), 4.05 (1H, t, J 6.3 Hz, CNCH2CH2OP), 4.03
(1H, t, J 6.3 Hz, CNCH2CH2OP), 2.91 (2H, t, J 7.0 Hz, H7’), 2.86
121.9, 121.8, 120.8, 117.6, 64.6, 64.4, 58.5, 58.3, 43.1, 43.0, 37.2, (2H, t, J 7.1 Hz, H7) 2.62 (2H, t, J 6.2 Hz, CNCH2CH2OP), 1.00,
37.1, 26.0, 24.7, 24.6, 24.5, 24.4, 20.4, 20.3, 18.5, 18.4, 4.1. 31
P
0.99, 0.98 (27H, s, (CH3)3CSiOAr), 0.21, 0.20, 0.19 (18H, s,
(CH3)3CSiOAr). 13C NMR (100 MHz, CDCl3): δ 154.5, 146.7,
145.7, 130.0, 129.8, 129.4, 121.9, 121.8, 121.0, 120.1, 116.4,
68.8, 68.7, 61.6, 61.5, 36.9, 35.9, 25.9, 25.7, 19.6, 19.5, 18.4,
18.2, 4.1, 4.4. 31P NMR (161.98 MHz, CDCl3): δ 2.0. MS
(ESI+): calcd. for C37H65NO7PSi3 [M+H]+ 750.38, found 750.44.
NMR (161.98 MHz, CDCl3): δ 147.2. MS (ESI+): calcd. for
C29H56N2O4PSi2 [M+H]+ 583.35, found 583.43.
Syntheses of Phosphotriester-linked Tyrosol dimers (13
15): general coupling procedure
The coupling reactions between the phosphoramidites (10 12)
and the appropriately protected tyrosol building blocks (7 9)
were carried out by suspending derivative 7 (8 or 9, 0.76 mmol)
in a 0.25 M solution of DCI in ACN (4.5 mL 1.12 mmol) with 3Å
1
Compound 17 (420.0 mg, 0.54 mmol, 77% yield) H NMR (400
MHz, CDCl3): δ 66.79, 6.77 (2H, d, J 8.0 Hz, H5 and H5’), 6.72,
6.69 (2H, d, J 2.1 Hz, H2 and H2’), 6.68, 6.66 (2H, dd, J 8.3,
2.2 Hz, H6 and H6’), 4.19 (4H, m, H8 and H8’), 4.05 (1H, t, J
9
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