Journal of Medicinal Chemistry
Article
(tt, J = 7.4, 1.2 Hz, 1H, C2O2C-p-Ph, 1H), 7.54−7.46 (m, 3H,
C2O2C-m-Ph and C3′NHCO-p-Ph), 7.44−7.35 (m, 6H, C3′-o-Ph,
C3′-m-Ph, and C3′NHCO-m-Ph), 7.28 (tt, J = 7.2, 1.3 Hz, 1H, C3′-p-
Ph), 7.22 (d, J = 8.7 Hz, 1H, C3′NH), 6.55 (s, 1H, H10), 6.23 (br dd,
J = 10, 9 Hz, 1H, H13), 5.74 (dd, J = 8.6, 3.0 Hz, 1H, H3′), 5.70 (d, J
= 7.1 Hz, 1H, H2), 4.99 (d, J = 3.0 Hz, 1H, 2′H), 4.94 (dd, J = 9.7, 1.9
Hz, 1H, H5), 4.61 (dd, J = 10.6, 6.8 Hz, 1H, H7), 4.31 (d, J = 8.4 Hz,
1H, H20α), 4.20 (d, J = 8.4 Hz, 1H, H20β), 3.86 (d, J = 7.0 Hz, 1H,
H3), 3.67 {t, J = 6.7 Hz, 6H, C7OSi[OCH2(CH2)6CH3]3}, 3.61 {t, J =
6.7 Hz, 6H, C2′OSi[OCH2(CH2)6CH3]3}, 2.65 (ddd, J = 14.7, 9.7, 6.8
Hz, 1H, H6α), 2.45 (s, 3H, C4OAc), 2.33 (dd, J = 15.3, 9.4 Hz, 1H,
H14α) 2.13 (s, 3H, C10OAc), 2.06 (d, J = 1.2 Hz, 3H, C18H3), 2.09−
2.02 (m, 1H, H14β), 1.96 (ddd, J = 14.5, 10.8, 2.2 Hz, 1H, H6β), 1.73
(s, 3H, C19H3), 1.66 (br s, 1H, C1OH), 1.56−1.44 {m, 12H,
1173, 1116, 1047, 989, 893, 839, 767, and 711. Mp = 108−113 °C.
TLC Rf (2:1 hexanes/EtOAc) = 0.55.
7-O-(Triethoxysilyl)paclitaxel (3a). Bis(triethoxy)silicate ester 2a
(99.5 mg, 0.0845 mmol, 1.0 equiv) was dissolved in acetone-d6 (1.8
mL, dried over 3 Å molecular sieves) in an NMR sample tube. A 9:1
mixture of D2O/TFA was added (200 μL), and the reaction progress
was monitored by 1H NMR spectroscopy. After 8 min at 21.4 °C, the
mixture was transferred into saturated aqueous NaHCO3 (2 mL). This
mixture was extracted with CH2Cl2 (3 × 5 mL). The combined
organic extracts were dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by MPLC (SiO2, 2:1
hexanes/EtOAc) to provide recovered starting material 2a (27.3 mg,
0.0232 mmol, 27.4%). Additional elution in 1:1 hexanes/EtOAc gave
the title compound as a white, crystalline solid [56.9 mg, 0.0560 mmol,
1
C 2 ′ O S i [ O C H 2 C H 2 ( C H 2
)
5 C H 3
]
a n d C 7 O S i -
66.3% (91.4% brsm)]. H NMR (500 MHz, CDCl3): δ 8.12 (dd, J =
3
[OCH2CH2(CH2)5CH3]3}, 1.34−1.21 {m, 63H, C17H3, C2′OSi-
[OCH2CH2(CH2)5CH3]3, and C7OSi[OCH2CH2(CH2)5CH3]3}, 1.17
(s, 3H, C16H3), and 0.88 {overlapping t’s, J = 6.8 Hz, 18H,
8.5, 1.3 Hz, 2H, C2O2C-o-Ph), 7.75 (dd, J = 8.5, 1.4 Hz, 2H,
C3′NHCO-o-Ph), 7.61 (tt, J = 7.5, 1.2 Hz, 1H, C2O2C-p-Ph, 1H),
7.53−7.46 (m, 5H, C2O2C-m-Ph, C3′NHCO-p-Ph, and C3′-o-Ph,),
7.43−7.37 (m, 4H, C3′-m-Ph and C3′NHCO-m-Ph), 7.34 (tt, J = 7.3,
1.2 Hz, 1H, C3′-p-Ph), 7.09 (d, J = 9.0 Hz, 1H, C3′NH), 6.56 (s, 1H,
H10), 6.18 (br dd, J = 9, 9 Hz, 1H, H13), 5.80 (dd, J = 6.9, 2.5 Hz, 1H,
H3′), 5.69 (d, J = 6.9 Hz, 1H, H2), 4.93 (dd, J = 9.6, 1.7 Hz, 1H, H5),
4.78 (dd, J = 4.9, 2.7 Hz, 1H, 2′H), 4.57 (dd, J = 10.5, 6.9 Hz, 1H,
H7), 4.30 (d, J = 8.4 Hz, 1H, H20α), 4.19 (dd, J = 8.3, 0.9 Hz, 1H,
H20β), 3.83 (d, J = 6.9 Hz, 1H, H3), 3.76 [q, J = 7.0 Hz, 6H,
C7OSi(OCH2CH3)3], 3.69 (br s, 1H, C2′OH), 2.65 (ddd, J = 14.7,
9.7, 6.9 Hz, 1H, H6α), 2.37 (s, 3H, C4OAc), 2.35−2.25 (m, 2H, H14α
and H14β), 2.15 (s, 3H, C10OAc), 1.95 (ddd, J =14.6, 10.7, 2.1 Hz,
1H, H6β), 1.93 (d, J = 1.3 Hz, 3H, C18H3), 1.76 (br s, 1H, C1OH),
1.73 (s, 3H, C19H3), 1.23 (s, 3H, C17H3), 1.19 [t, J = 7.0 Hz, 9H,
C7OSi(OCH2CH3)3], and 1.16 (s, 3H, C16H3). 13C NMR (125 MHz,
CDCl3): δ 202.4, 172.6, 170.4, 169.0, 167.2, 167.1, 140.1, 138.2, 133.9,
133.8, 132.1, 130.3, 129.4, 129.1, 128.89, 128.87, 128.5, 127.3, 127.24,
127.23, 84.4, 81.5, 78.8, 76.8, 76.1, 74.8, 73.4, 72.5, 72.1, 59.5, 58.6,
55.0, 47.0, 43.4, 36.7, 35.6, 26.8, 22.9, 21.1, 21.0, 18.2, 14.5, and 10.3.
HRMS (ESI) calcd for C53H65NNaO17Si [M + Na]+ 1038.3914, found
1038.3914. IR (thin film) 3500 (br), 2975, 2898, 1724, 1653, 1602,
1580, 1515, 1485, 1451, 1394, 1370, 1314, 1266, 1240, 1172, 1079,
1025, 969, 913, 888, 839, 797, and 712 cm−1. Mp = 141−146 °C. TLC
Rf (1:1 hexanes/EtOAc) = 0.5.
C 2 ′ O S i [ O C H 2 C H 2 ( C H 2
)
5 C H 3
]
a n d C 7 O S i -
3
[OCH2CH2(CH2)5CH3]3}. 13C NMR (75 MHz, CDCl3): δ 202.4,
170.9, 169.8, 168.7, 167.3, 167.2, 140.9, 138.3, 134.3, 133.8, 133.3,
131.9, 130.4, 129.4, 128.91, 128.89, 128.8, 128.1, 127.3, 126.8, 84.6,
81.2, 79.0, 76.8, 75.8, 75.1, 74.9, 72.0, 71.5, 64.1, 63.9, 58.3, 55.5, 46.8,
43.5, 36.6, 35.6, 32.5, 32.4, 32.1, 32.0, 29.6, 29.63, 29.60, 29.57, 26.7,
25.92, 25.89, 23.0, 22.91, 22.90, 21.6, 21.1, 14.3 (×2), 14.1, and 10.4.
HRMS (ESI) calcd for C95H151NNaO20Si2 [M + Na]+ 1705.0260;
found 1705.0228. IR (thin film) 3500 (br), 2927, 2856, 1741, 1728,
1634, 1580, 1545, 1456, 1371, 1315, 1270, 1239, 1174, 1095, 1028,
989, 968, 924, 893, 843, 779, and 709 cm−1. TLC Rf (3:1 hexanes/
EtOAc) = 0.55.
2′,7-Di-O-(triisopropoxysilyl)paclitaxel (2c). Paclitaxel (30.1
mg, 0.0352 mmol, 1.0 equiv) was dissolved in dry THF (1.0 mL) in
an oven-dried culture tube fitted with a Teflon-lined cap and magnetic
stir bar. Pyridine (15 μL, 0.185 mmol, 5.3 equiv) was added by
Wiretrol. A 3.5:1 mixture of triisopropoxychlorosilane (5c)33/
tetraisopropoxysilane (0.0424 mg, 0.134 mmol, 2.9 equiv of
triisopropoxychlorosilane) was added. The culture tube was capped,
and a white precipitate was observed within minutes. The suspension
was stirred at room temperature for 18 h, and the mixture was filtered
through a short plug of Celite to remove the triethylammonium salt.
The filtrate was concentrated under reduced pressure, and the residue
was redissolved in a mixture of hexanes/EtOAc (2:1). Purification by
MPLC (SiO2, 2:1 hexanes/ethyl acetate) yielded the title compound
7-O-(Tri-n-octyloxysilyl)paclitaxel (3b). Bis(trioctyloxy)silicate
ester 2b (88.1 mg, 0.0523 mmol, 1.0 equiv) was dissolved in acetone-
d6 (1.8 mL, dried over 3 Å molecular sieves) in an NMR tube. A 9:1
mixture of D2O/TFA was added (200 μL), and the solution became
white and cloudy. Upon vigorous mixing for 30 s, the mixture became
homogeneous and transparent. The hydrolysis progress was monitored
1
as a white, crystalline solid (29.8 mg, 0.0236 mmol, 67.0%). H NMR
(500 MHz, CDCl3): δ 8.12 (dd, J = 8.5, 1.5 Hz, 2H, C2O2C-o-Ph),
7.80 (dd, J = 8.4, 1.5 Hz, 2H, C3′NHCO-o-Ph), 7.62 (tt, J = 7.4, 1.7
Hz, 1H, C2O2C-p-Ph, 1H), 7.55−7.46 (m, 3H, C2O2C-m-Ph and
C3′NHCO-p-Ph), 7.43−7.34 (m, 6H, C3′-o-Ph, C3′-m-Ph, and
C3′NHCO-m-Ph), 7.29−7.24 (m, 1H, C3′-p-Ph), 7.17 (d, J = 8.4
Hz, 1H, C3′NH), 6.53 (s, 1H, H10), 6.14 (br dd, J = 9, 9 Hz, 1H,
H13), 5.70 (d, J = 7.3 Hz, 1H, H2), 5.67 (dd, J = 8.4, 3.6 Hz, 1H,
H3′), 5.00 (d, J = 3.6 Hz, 1H, H2′), 4.96 (dd, J = 9.4, 2.0 Hz, 1H, H5),
4.61 (dd, J = 10.7, 6.7, Hz, 1H, H7), 4.31 (d, J = 8.8 Hz, 1H, H20α),
4.19 (d, J = 8.6 Hz, 1H, H20β), 4.13 and 4.12 {overlapping septs, J =
6.2 Hz, 6H, C2′OSi[OCH(CH3)2]3 and C7OSi[OCH(CH3)2]3}, 3.85
(d, J = 7.4 Hz, 1H, H3), 2.68 (ddd, J = 14.7, 9.7, 6.8 Hz, 1H, H6α),
2.41 (s, 3H, C4OAc), 2.30 (dd, J = 15.1, 9.3 Hz, 1H, H14α), 2.14 (s,
3H, C10OAc), 2.10 (d, J = 1.2 Hz, 3H, C18H3), 2.03 (dd, J = 15.7, 9.5
Hz, 1H, H14β), 1.95 (ddd, J = 14.6, 10.9, 2.2 Hz, 1H, H6β), 1.72 (s,
3H, C19H3), 1.61 (br s, 1H, C1OH), 1.23 (m, 3H, C17H3), and
1.18−1.10 {m, 39H, C2′OSi[OCH(CH3)a(CH3)b]3}, C2′OSi[OCH-
(CH3)a(CH3)b]3, C7OSi[OCH(CH3)a(CH3)b]3}, C7OSi[OCH-
(CH3)a(CH3)b]3, and C16H3}. 13C NMR (125 MHz, CDCl3): δ
202.6, 171.1, 169.6, 168.9, 167.3, 167.2, 141.2, 138.4, 134.4, 133.8,
133.3, 131.9, 130.4, 129.5, 128.9 (×2), 128.8, 128.1, 127.3, 127.0, 84.6,
81.2, 80.0, 76.8, 75.9, 75.2, 74.9, 72.3, 71.7, 66.6, 66.2, 58.3, 55.9, 46.8,
43.5, 36.7, 35.5, 26.8, 25.5, 25.42, 25.41, 25.38, 23.0, 21.5, 21.1, 14.7,
and 10.5. HRMS (ESI) calcd for C65H91NNaO20Si2 [M + Na]+
1284.5565, found 1284.5563. IR (thin film) 3500 (br), 2973, 2933,
1725, 1671, 1603, 1582, 1512, 1484, 1452, 1371, 1313, 1267, 1238,
1
by H NMR spectroscopy. After 30 min at room temperature, the
solution was transferred into saturated aqueous NaHCO3 (2 mL).
This mixture was extracted with CH2Cl2 (3 × 5 mL). The combined
organic layers were dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by MPLC (SiO2, 3:1
hexanes/EtOAc) to provide recovered 2b (12.9 mg, 0.0076 mmol,
27.4%). Additional elution in 2:1 hexanes/EtOAc gave the title
compound as a crystalline solid [37.3 mg, 0.0294 mmol, 56.2% (65.7%
brsm)]. 1H NMR (500 MHz, CDCl3): δ 8.12 (dd, J = 8.5, 1.3 Hz, 2H,
C2O2C-o-Ph), 7.75 (dd, J = 8.5, 1.4 Hz, 2H, C3′NHCO-o-Ph), 7.61
(tt, J = 7.4, 1.3 Hz, 1H, C2O2C-p-Ph, 1H), 7.53−7.47 (m, 5H,
C2O2C-m-Ph, C3′NHCO-p-Ph, and C3′-o-Ph,), 7.43−7.38 (m, 4H,
C3′-m-Ph and C3′NHCO-m-Ph), 7.34 (tt, J = 7.2, 1.3 Hz, 1H, C3′-p-
Ph), 7.06 (d, J = 9.0 Hz, 1H, C3′NH), 6.53 (s, 1H, H10), 6.17 (br dd,
J = 9, 9 Hz, 1H, H13), 5.81 (dd, J = 6.8, 2.4 Hz, 1H, H3′), 5.68 (d, J =
6.9 Hz, 1H, H2), 4.92 (dd, J = 9.6, 1.8 Hz, 1H, H5), 4.78 (dd, J = 4.8,
2.6 Hz, 1H, 2′H), 4.56 (dd, J = 10.5, 6.7 Hz, 1H, H7), 4.29 (d, J = 8.3
Hz, 1H, H20α), 4.19 (d, J = 8.5 Hz, 1H, H20β), 3.83 (d, J = 7.0 Hz,
1H, H3), 3.66 {t, J = 6.7 Hz, 6H, C7OSi[OCH2(CH2)6CH3]3}, 3.60
(d, J = 4.9 Hz, 1H, C2′OH), 2.64 (ddd, J = 14.7, 9.7, 6.9 Hz, 1H,
H6α), 2.37 (s, 3H, C4OAc), 2.34−2.27 (m, 2H, H14α and H14β),
2.14 (s, 3H, C10OAc), 1.97−1.90 (m, 4H, H6β and C18H3), 1.74−
1.70 (m, 4H, C1OH and C19H3), 1.52 {tt, J = 6.8, 6.8 Hz, 6H,
C7OSi[OCH2CH2(CH2)5CH3]3}, 1.34−1.22 {m, 33H, C17H3 and
2375
dx.doi.org/10.1021/jm401708f | J. Med. Chem. 2014, 57, 2368−2379