Journal of Medicinal Chemistry
ARTICLE
1H NMR (400 MHz, CD3OD): δ 7.94 (m, 1H, CHdCHꢀN), 7.38ꢀ7.24
(m,4H,aromatic),6.10(d,J= 8.0 Hz, 1H, CHdCHꢀN), 4.68 (ddd, J=13.8,
13.8, 2.8 Hz, 0.8H, CHaHbO (SP)), 4.61ꢀ4.52 (m, 1.2H, CHaHbO (RP) and
CHaHbO), 4.47 (dd, J = 14.8, 7.6 Hz, 0.8H, CHaHbP (SP)), 4.44ꢀ4.35 (m,
1.2H, CHaHbP(RP) andCHNH2), 4.32ꢀ4.23 (m, 2H, CHO, CHaHbP(SP)
and CHaHbN (RP)), 4.19ꢀ4.13 (m, 1H, CHaHbP (RP) and CHaHbN (SP)),
4.10 (dd, J = 14.5, 8.0 Hz, 0.8H, CHaHbN (SP)), 3.86 (s, 0.6H, OCH3 (RP)),
3.85 (s, 2.4H, OCH3 (SP)), 3.84 (m, 0.2H, CHaHbN (RP)), 3.30 (m, 1H,
CHaHb (Tyr)), 3.21 (m, 1H, CHaHb (Tyr)). 31P NMR (162 MHz,
CD3OD): δ 12.01 (0.79P (SP)), 10.39 (0.21P (RP)). HRMS: m/z calcd
439.1387 (M + H)+, found 439.1378 (M + H)+. HPLC: tR, 24.05 min.
Methyl O-[(5S)-5-[(4-Amino-2-oxopyrimidin-1(2H)-yl)methyl]-
2-oxido-1,4,2-dioxaphosphinan-2-yl]-(D)-tyrosinate (7). Yield 50%.
Obtained as a hydrochloride salt; mixture of two diastereomers (SP/RP, 2.7:1).
1H NMR (400 MHz, CD3OD): δ 7.89 (d, J = 7.6 Hz, 0.7H, CHdCHꢀN,
(SP)), 7.86 (d, J = 8.4 Hz, 0.3H, CHdCHꢀN (RP)), 7.37ꢀ7.23 (m, 4H,
aromatic), 6.08 (d, J = 7.6 Hz, 1H, CHdCHꢀN), 4.68 (ddd, J = 12.4, 12.4,
2.4 Hz, 0.7H, CHaHbO (SP)), 4.63ꢀ4.50 (m, 1.3H, CHaHbO (RP) and
CHaHbO), 4.47 (dd, J = 15.2, 8.0 Hz, 0.7H, CHaHbP (Sp)), 4.36 (m, 1.3H,
CHaHbP (Rp) and CHNH2), 4.30ꢀ4.24 (m, 2H, CHO, CHaHbP (SP) and
CHaHbN (RP)), 4.24ꢀ4.13 (m, 1H, CHaHbP (RP) and CHaHbN (SP)),
4.08 (dd, J = 14.4, 7.6 Hz, 0.7H, CHaHbN (SP)), 3.85 (s, 0.9H, OCH3
(RP)), 3.84 (s, 2.1H, OCH3 (SP)), 3.83 (dd, J = 13.9, 8.1 Hz, 0.3H,
CHaHbN (RP)), 3.28 (m, 1H, CHaHb (Tyr)), 3.20 (m, 1H, CHaHb
(Tyr)). 31P NMR (162 MHz, CD3OD): δ 11.97 (0.73P (SP)), 10.39
(0.27P (RP)). HRMS: m/z calcd 439.1377 (M + H)+, found 439.1387
(M + H)+. HPLC: tR, 24.13 min (RP), 24.54 min (SP).
(s, 0.2H, NdCHꢀN (RP)), 7.34ꢀ7.24 (m, 4H, aromatic), 4.78 (ddd,
J = 12.1, 12.1, 3.0 Hz, 0.8H, CHaHbO (SP)), 4.69 (dd, J = 15.0, 8.3 Hz,
0.8H, CHaHbN (SP)), 4.61ꢀ4.34 (m, 5.4H, CHaHbO (RP), CHaHbN
(RP), CHaHbN, CHaHbO, CHaHbP, CHO and CHNH2), 4.24 (dd, J =
14.8, 4.3 Hz, 0.8H, CHaHbP (SP)), 4.12 (dd, J = 15.3, 1.3 Hz, 0.2H,
CHaHbP (RP)), 3.86 (s, 0.6H, OCH3 (RP)), 3.85 (s, 2.4H, OCH3 (SP)),
3.29 (dd, J = 14.5, 6.2 Hz, 1H, CHaHb (Tyr)), 3.18 (dd, J = 14.5, 7.4 Hz,
1H, CHaHb (Tyr)). 31P NMR (202 MHz, CD3OD):δ11.77 (0.84P (SP)),
10.19 (0.16P (RP)). HRMS: m/z calcd 463.1489 (M + H)+, found
463.1499 (M + H)+. HPLC: tR, 17.58 min (RP), 18.47 min (SP).
O-[(5S)-5-[(6-Amino-9H-purin-9-yl)methyl]-2-oxido-1,4,2-
dioxaphosphinan-2-yl]-N-(2-methylpropyl)-(L)-tyrosinamide
(11). Yield 76%. Obtained as a hydrochloride salt; mixture of two
diastereomers (SP/RP, 3.8:1). 1H NMR (400 MHz, CD3OD): diaster-
eomer SP, δ 8.42 (s, 1H, NdCHꢀN), 8.37 (s, 1H, NdCHꢀN), 7.32
(J = 8.6 Hz, 2H, aromatic), 7.19 (d, J = 8.6 Hz, 2H, aromatic), 4.76 (ddd,
J = 12.1, 12.1, 2.7 Hz, 1H, CHaHbO), 4.70 (dd, J = 14.9, 8.3 Hz, 1H,
CHaHbN), 4.60 (dd, J = 14.9, 3.5 Hz, 1H, CHaHbN), 4.54 (dd, J = 11.7,
7.4 Hz, 1H, CHaHbO), 4.49 (dd, J = 15.2, 7.0Hz, 1H, CHaHbP), 4.42 (m,
1H, CHO), 4.23 (dd, J = 14.9, 4.3 Hz, 1H, CHaHbP), 4.04 (t, J = 7.4 Hz,
1H, CHNH2), 3.17 (dd, J = 14.1, 7.6 Hz, 1H, CHaHb (Tyr)), 3.12ꢀ3.05
(m, 2H, CHaHb (Tyr) andCHaHb (i-Bu)), 2.92 (dd, J = 13.3, 7.0 Hz, 1H,
CHaHb (i-Bu)), 1.69(m, 1H, CH(CH3)2), 0.85 (d, J = 6.6Hz, 3H, CH3),
0.82 (d, J = 6.7 Hz, 3H, CH3); diastereomer RP data are summarized
in the isomerization section. 31P NMR (162 MHz, CD3OD): δ 11.69 (0.79P
(SP)), 10.10 (0.21P (RP)). HRMS: m/z calcd 504. 2119 (M + H)+, found
504.2128 (M + H)+. HPLC: tR, 17.66 min (RP), 18.32 min (SP).
Methyl (L)-Valyl-O-[(5S)-5-[(4-amino-2-oxopyrimidin-1(2H)-yl)
methyl]-2-oxido-1,4,2-dioxaphosphinan-2-yl]-(L)-tyrosinate (12).
Yield 50%. Obtained as a TFA salt; mixture of diastereomers
Isopropyl O-[(5S)-5-[(4-Amino-2-oxopyrimidin-1(2H)-yl)
methyl]-2-oxido-1,4,2-dioxaphosphinan-2-yl]-(L)-tyrosinate (8).
Yield 22%. Obtained as TFA salt; a mixture of two diastereomers (SP/RP,
1
1
(SP/RP, 5.7:1). H NMR (400 MHz, CD3OD): diastereomer SP, δ
2.6:1). H NMR (400 MHz, CD3OD): δ 7.79 (d, J = 7.2 Hz, 0.7H,
7.84 (d, J = 7.5 Hz, 1H, CHdCHꢀN), 7.26 (d, J = 8.6 Hz, 2H,
aromatic), 7.13 (d, J = 8.6 Hz, 2H, aromatic), 6.02 (d, J = 7.9 Hz, 1H,
CHdCHꢀN), 4.73 (dd, J = 8.7 Hz, 5.9 Hz, 1H, CH (Tyr)), 4.62 (ddd,
J = 13.7, 12.1, 2.8 Hz, 1H, CHaHbO), 4.48 (dd, J = 12.1, 7.5 Hz, 1H,
CHaHbO), 4.41 (dd, J = 14.5, 8.0 Hz, 1H, CHaHbP), 4.22 (dd, J = 14.8,
3.1 Hz, 1H, CHaHbP), 4.20 (m, 1H, CHO), 4.11 (dd, J = 14.5, 3.5 Hz,
1H, CHaHbN), 4.03 (dd, J = 14.5, 7.8 Hz, 1H, CHaHbN), 3.68
(s, 3H, OCH3), 3.64 (d, J = 5.5 Hz, 1H, CHNH2), 3.19 (dd, J = 14.1,
5.9 Hz, 1H, CHaHb (Tyr)), 3.01 (dd, J = 14.1, 5.9 Hz, 1H, CHaHb
(Tyr)), 2.20 (m, 1H, CH(CH3)2), 1.06 (d, J = 6.6 Hz, 3H, CH3), 1.01
(d, J = 6.7 Hz, 3H, CH3); diastereomer RP, δ 7.80 (d, J = 7.9 Hz, 1H,
CHdCHꢀN), 7.28 (d, J = 8.6 Hz, 2H, aromatic), 7.17 (d, J = 8.6 Hz,
2H, aromatic), 6.02 (d, J = 7.9 Hz, 1H, CHdCHꢀN), 4.79ꢀ3.80
(m, 8H), 3.70 (s, 3H, OCH3), 3.65 (d, J = 5.5 Hz, 1H, CHNH2), 3.19
(m, 1H, CHaHb (Tyr)), 3.01 (m, 1H, CHaHb (Tyr)), 2.20 (m, 1H,
CH(CH3)2), 1.06 (d, J = 6.6 Hz, 3H, CH3), 1.01 (d, J = 6.7 Hz, 3H,
CH3). 31P NMR (202 MHz, CD3OD): δ 11.70 (0.85P (SP)), 10.03
(0.15P (RP)). HRMS: m/z calcd 538.2061 (M + H)+, found 538.2065
(M + H)+. HPLC: tR, 16.06 min (RP), 16.43 min (SP).
Methyl (L)-Valyl-O-[(5S)-5-[(6-amino-9H-purin-9-yl)methyl]-
2-oxido-1,4,2-dioxaphosphinan-2-yl]-(L)-tyrosinate (13). Yield
54%. Obtained as a TFA salt; mixture of two diastereomers (SP/RP, 1.05:1).
1H NMR (400 MHz, CD3OD): δ 8.40 (s, 0.5H, NdCHꢀN (SP)), 8.39 (s,
0.5H, NdCHꢀN, (RP)), 8.34 (s, 0.5H, NdCHꢀN (SP)), 8.30 (s, 0.5H,
NdCHꢀN, (RP)), 7.32ꢀ7.30 (m, 2H, aromatic), 7.18ꢀ7.15 (m, 2H,
aromatic), 4.81ꢀ4.34 (m, 7H), 4.22 (dd, J = 15.1, 4.3 Hz, 0.5H, CHaHbP
(SP)), 4.11 (dd, J = 15.5, 1.6 Hz, 0.5H, CHaHbP (RP)), 3.74, 3.72 (2s, 3H,
OCH3 (SP and RP)), 3.69, 3.67 (2d, J = 5.4 Hz, 1H, CHNH2 (SP and RP)),
3.23 (m, 1H, CHaHb (Tyr)), 3.05 (m, 1H, CHaHb (Tyr)), 2.24 (m, 1H,
CH(CH3)2), 1.10, 1.09 (2d, J= 6.9 Hz, 3H, CH3), 1.05, 1.04(2d, J=7.0Hz,
3H, CH3). 31P NMR (202 MHz, CD3OD): δ 11.54 (0.50P (SP)), 9.98
(0.50P(RP)). HRMS:m/zcalcd 562.2174 (M + H)+, found 562.2180 (M +
H)+. HPLC: tR, 18.99 min (RP), 20.35 min (SP).
CHdCHꢀN (SP)), 7.76 (d, J = 7.6 Hz, 0.3H, CHdCHꢀN (RP)),
7.33ꢀ7.18 (m, 4H, aromatic), 6.01 (m, 1H, CHdCHꢀN), 5.03 (m, 1H,
CH(CH3)2), 4.60 (ddd, J = 12.4, 12.4, 2.8 Hz, 0.7H, CHaHbO (SP)),
4.56ꢀ4.39 (m, 1.3H, CHaHbO (RP) and CHaHbO), 4.42 (dd, J = 14.4,
7.2 Hz, 0.7H, CHaHbP (SP)), 4.37 (dd, J = 15.6, 11.2 Hz, 0.3H, CHaHbP
(RP)), 4.27ꢀ4.19 (m, 3H, CHNH2, CHO, CHaHbP (SP) and CHaHbN
(RP)), 4.13ꢀ3.99 (m, 1.7H, CHaHbP (RP), CH2N (SP)), 3.80 (dd, J =
12.4, 7.6 Hz, 0.3H, CHaHbN (RP)), 3.24ꢀ3.13 (m, 2H, CH2(Tyr)),
1.25ꢀ1.23 (m, 3H, CH3), 1.18ꢀ1.16 (m, 3H, CH3). 31P NMR (162
MHz, CD3OD): δ 11.78 (0.72P (SP)), 10.19 (0.28P (RP)). HRMS: m/z
calcd 467.1700 (M + H)+, found 467.1698 (M + H)+. HPLC: tR, 23.61
min (RP), 24.05 min (SP).
O-[(5S)-5-[(4-Amino-2-oxopyrimidin-1(2H)-yl)methyl]-2-
oxido-1,4,2-dioxaphosphinan-2-yl]-N-tert-butyl-(D)-tyrosinamide
(9). Yield 53%. Obtained as a TFA salt; mixture of two diastereomers
1
(SP/RP, 2.3:1). H NMR (400 MHz, CD3OD): δ 7.86 (d, J = 7.6 Hz,
0.7H, CHdCHꢀN (SP)), 7.84 (d, J = 8 Hz, 0.3H, CHdCHꢀN (RP)),
7.32ꢀ7.17 (m, 4H, aromatic), 6.04 (d, J = 7.6 Hz, 1H, CHdCHꢀN),
4.62 (ddd, J = 12.4, 12.4, 2.8 Hz, 0.7H, CHaHbO (SP)), 4.56 (m, 0.3H,
CHaHbO (RP)), 4.48 (m, 1H, CHaHbO), 4.41 (dd, J = 14.4, 7.6 Hz, 0.7H,
CHaHbP (SP)), 4.35 (dd, J = 15.2, 11.2 Hz, 0.3H, CHaHbP (RP))
4.24ꢀ4.16 (m, 2H, CHO, CHaHbP (Sp) and CHaHbN (RP))
4.13ꢀ4.01 (m, 1.7H, CHaHbP (RP), CH2N (SP)), 3.92 (m, 1H,
CHNH2), 3.80 (dd, J = 14.8, 8.4 Hz, 0.3H, CHaHbN (RP)), 3.11ꢀ3.00
(m, 2H, CH2(Tyr)), 1.24 (s, 2.7H, NHC(CH3)3 (RP)), 1.23 (s, 6.3H,
NHC(CH3)3 (SP)). 31P NMR (162 MHz, CD3OD): δ 11.79 (0.70P
(SP)), 10.25 (0.30P (RP)). HRMS: m/z calcd 480.2006 (M + H)+, found
480.2004 (M + H)+. HPLC: tR, 20.50 min (RP), 20.98 min (SP).
Methyl O-[(5S)-5-[(6-Amino-9H-purin-9-yl)methyl]-2-oxido-
1,4,2-dioxaphosphinan-2-yl]-(L)-tyrosinate (10). Yield 74%.
Obtained as a hydrochloride salt; mixture of two diastereomers (SP/RP,
5.4:1). 1H NMR (400 MHz, CD3OD): δ 8.41 (s, 0.8H, NdCHꢀN (SP)),
8.40 (s, 0.2H, NdCHꢀN (RP)), 8.34 (s, 0.8H, NdCHꢀN (SP)), 8.30
5689
dx.doi.org/10.1021/jm2001426 |J. Med. Chem. 2011, 54, 5680–5693