10.1002/cmdc.201700614
ChemMedChem
FULL PAPER
20.3. LRMS-ESI (m/z): 577.2 [M+H]+, 599.3 [M+Na]+; HRMS-ESI
(m/z) [M+Na]+ calculated for C29H40N2O8SNa 599.2404, found
599.2408. HPLC analysis: Chiralpak IA-3 column, 10%
isopropanol in n-hexane, flow = 1 mL/min, t = 24 °C, λ = 254 nm,
rt = 32.1 min, dr 98:2.
steps). 1H NMR (500 MHz, CDCl3) δ 8.17 (d, J = 8.5 Hz, 2H), 7.86
(d, J = 8.6 Hz, 2H), 7.73 (s, 1H), 7.36 – 7.11 (m, 5H), 5.64 (d, J =
5.2 Hz, 1H), 5.01 (dd, J = 14.2, 6.3 Hz, 1H), 4.94 (d, J = 8.5 Hz,
1H), 4.70 (s, 2H), 3.96 (dd, J = 9.6, 6.3 Hz, 1H), 3.94 – 3.77 (m,
3H), 3.78 – 3.61 (m, 3H), 3.56 (s, 1H), 3.20 (dd, J = 15.2, 8.4 Hz,
1H), 3.14 – 2.98 (m, 3H), 2.96 – 2.84 (m, 2H), 2.84 – 2.74 (m, 1H),
1.91 – 1.79 (m, 1H), 1.71 – 1.53 (m, 1H), 1.52 – 1.41 (m, 1H),
0.98 – 0.84 (m, 6H). 13C NMR (125 MHz, CDCl3) δ 160.5, 155.7,
142.4, 139.9, 137.7, 136.4, 131.4, 129.5, 128.8, 128.1, 127.2,
126.9, 109.5, 73.7, 72.9, 70.9, 69.8, 58.8, 57.3, 55.4, 53.7, 45.5,
35.8, 27.4, 26.0, 20.3, 20.1. LRMS-ESI (m/z): 630.3 [M+H]+, 652.2
[M+Na]+.
(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl
hydroxy-4-((4-((S)-1-hydroxyethyl)-N-
((2S,3R)-3-
isobutylphenyl)sulfonamido)-1-phenylbutan-2-yl)carbamate
(3f): Compound 3f was obtained from 3d following the same
procedure described for compound 3e employing RuCl(p-
cymene)[(S,S)-Ts-DPEN] as the catalyst. Compound 3f was
obtained in 98% yield. 1H NMR (500 MHz, CDCl3) δ 7.81 (d, J =
8.2 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.41 – 7.18 (m, 5H), 5.70 (d,
J = 5.2 Hz, 1H), 5.10 – 4.90 (m, 3H), 4.04 – 3.97 (m, 1H), 3.97 –
3.87 (m, 3H), 3.79 – 3.64 (m, 3H), 3.23 (dd, J = 15.1, 8.5 Hz, 1H),
3.14 (dd, J = 14.2, 3.8 Hz, 1H), 3.11 – 3.02 (m, 2H), 3.00 – 2.93
(m, 1H), 2.92 – 2.80 (m, 2H), 2.20 (br, 1H), 1.96 – 1.85 (m, 1H),
1.76 – 1.64 (m, 1H), 1.58 (d, J = 6.5 Hz, 3H), 1.55 – 1.46 (m, 1H),
0.98 (dd, J = 24.1, 6.6 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ
155.9, 151.6, 138.0, 137.3, 129.8, 129.0, 128.0, 127.1, 126.6,
109.7, 73.9, 73.3, 71.3, 70.0, 59.4, 55.6, 54.3, 45.8, 36.1, 28.3,
27.8, 26.3, 25.9, 20.6, 20.3. LRMS-ESI (m/z): 577.2 [M+H]+, 599.2
(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl
((2S,3R)-3-
hydroxy-4-((N-isobutyl-4-(oxazol-5-yl)phenyl)sulfonamido)-
1-phenylbutan-2-yl)carbamate (3i): Compound 3i was obtained
from compound 10 and activated bis-THF derivative 6 following
the same procedure described for compound 3c (47% over 2
steps). 1H NMR (500 MHz, CDCl3) δ 8.00 (s, 1H), 7.84 (d, J = 8.7
Hz, 2H), 7.80 (d, J = 8.6 Hz, 2H), 7.52 (s, 1H), 7.33 – 7.26 (m,
2H), 7.25 – 7.17 (m, 3H), 5.64 (d, J = 5.2 Hz, 1H), 5.09 – 4.95 (m,
2H), 4.01 – 3.79 (m, 4H), 3.79 – 3.54 (m, 3H), 3.20 (dd, J = 15.1,
8.4 Hz, 1H), 3.14 – 2.96 (m, 3H), 2.96 – 2.87 (m, 2H), 2.86 – 2.70
(m, 1H), 1.93 – 1.78 (m, 1H), 1.74 – 1.56 (m, 1H), 1.50 – 1.39 (m,
1H), 0.90 (dd, J = 22.2, 6.6 Hz, 6H). 13C NMR (125 MHz, CDCl3)
δ 155.4, 151.4, 149.6, 137.7, 137.4, 131.7, 129.2, 128.5, 128.0,
126.5, 124.7, 123.9, 109.2, 73.4, 72.7, 70.7, 69.5, 58.5, 55.1,
53.5, 45.3, 35.5, 27.1, 25.7, 20.0, 19.7. LRMS-ESI (m/z): 600.3
[M+H]+, 622.2 [M+Na]+; HRMS-ESI (m/z) [M+Na]+ calculated for
C30H37N3O8SNa 622.2199, found 622.2205.
[M+Na]+;
HRMS-ESI
(m/z)
[M+Na]+
calculated
for
C29H40N2O8SNa 599.2404, found 599.2408. HPLC analysis:
Chiralpak IA-3 column, 10% isopropanol in n-hexane, flow = 1
mL/min, t = 24 °C, λ = 254 nm, rt = 34.6 min, dr 98:2.
Methyl
2-(4-(N-((2R,3S)-3-(((((3R,3aS,6aR)-
hexahydrofuro[2,3-b]furan-3-yl)oxy)carbonyl)amino)-2-
hydroxy-4-phenylbutyl)-N-
isobutylsulfamoyl)phenyl)oxazole-4-carboxylate
(3g):
(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl ((2S,3R)-4-((4-
(2-acetyloxazol-5-yl)-N-isobutylphenyl)sulfonamido)-3-
hydroxy-1-phenylbutan-2-yl)carbamate (3j): Compound 3j was
obtained from compound 11 and activated bis-THF derivative 6
following the same procedure described for compound 3c (80%
Compound 3g was obtained from compound 9 and activated bis-
THF derivative 6 following the same procedure described for
compound 3c (61% yield over 2 steps). 1H NMR (500 MHz,
CDCl3) δ 8.42 (s, 1H), 8.33 (d, J = 8.5 Hz, 2H), 7.95 (d, J = 8.5
Hz, 2H), 7.43 – 7.17 (m, 5H), 5.71 (d, J = 5.2 Hz, 1H), 5.09 (dd, J
= 14.2, 6.3 Hz, 1H), 5.01 (d, J = 8.4 Hz, 1H), 4.13 – 3.98 (m, 4H),
3.98 – 3.84 (m, 3H), 3.85 – 3.69 (m, 2H), 3.64 (s, 1H), 3.29 (dd, J
= 15.1, 8.3 Hz, 1H), 3.22 – 3.05 (m, 3H), 3.03 – 2.93 (m, 2H), 2.87
(dd, J = 14.0, 9.1 Hz, 1H), 1.96 – 1.81 (m, 1H), 1.78 – 1.61 (m,
1H), 1.59 – 1.45 (m, 1H), 0.96 (dd, J = 25.2, 6.6 Hz, 6H). 13C NMR
(125 MHz, CDCl3) δ 161.6, 160.9, 155.7, 144.8, 140.8, 137.7,
135.1, 130.4, 129.5, 128.8, 128.1, 127.7, 126.9, 109.5, 73.7, 72.9,
71.0, 69.8, 58.7, 55.4, 53.7, 52.7, 45.6, 35.8, 27.4, 26.0, 20.3,
20.0. LRMS-ESI (m/z): 658.2 [M+H]+, 680.3 [M+Na]+.
1
over 2 steps). H NMR (500 MHz, CDCl3) δ 7.92 (d, J = 8.4 Hz,
2H), 7.86 (d, J = 8.5 Hz, 2H), 7.66 (s, 1H), 7.35 – 7.26 (m, 3H),
7.26 – 7.17 (m, 2H), 5.64 (d, J = 5.2 Hz, 1H), 5.01 (dd, J = 14.0,
6.1 Hz, 1H), 5.00 – 4.92 (m, 1H), 4.00 – 3.80 (m, 4H), 3.75 – 3.62
(m, 2H), 3.59 (s, 1H), 3.21 (dd, J = 15.2, 8.4 Hz, 1H), 3.15 – 2.97
(m, 3H), 2.95 – 2.85 (m, 2H), 2.80 (dd, J = 13.8, 9.2 Hz, 1H), 2.72
(s, 3H), 1.85 (dt, J = 13.3, 6.8 Hz, 1H), 1.73 – 1.56 (m, 1H), 1.51
– 1.39 (m, 1H), 0.90 (dd, J = 22.9, 6.6 Hz, 6H). 13C NMR (125
MHz, CDCl3) δ 185.6, 158.0, 155.8, 152.4, 139.5, 137.6, 130.9,
129.5, 128.8, 128.4, 126.9, 126.1, 126.0, 109.5, 73.8, 72.9, 71.0,
69.8, 58.7, 55.4, 53.7, 45.6, 35.8, 27.4, 26.9, 26.0, 20.3, 20.0.
LRMS-ESI (m/z): 664.2 [M+Na]+; HRMS-ESI (m/z) [M+Na]+
calculated for C32H39N3O9SNa 664.2305, found 664.2314.
(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl
hydroxy-4-((4-(4-(hydroxymethyl)oxazol-2-yl)-N-
((2S,3R)-3-
isobutylphenyl)sulfonamido)-1-phenylbutan-2-yl)carbamate
(3h): Compound 9 (8.5 mg, 0.014 mmol) was dissolved in
absolute EtOH (3 mL) and the resulting solution was cooled to 0
°C. NaBH4 (1.6 mg, 0.042 mmol) was added and the reaction
mixture was stirred at 23 °C for 24 h. The reaction was quenched
with saturated aqueous NH4Cl and extracted with EtOAc. The
organic layers were dried over anhydrous sodium sulfate, filtered
and concentrated. The crude was purified by silica gel flash
chromatography (60% EtOAc in n-hexane) providing the
corresponding alcohol derivative (65% yield). This intermediate
underwent Boc-deprotection and coupling with the bis-THF
derivative 6 as described for compound 3c (60% yield over 2
(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl
hydroxy-4-((4-(2-((R)-1-hydroxyethyl)oxazol-5-yl)-N-
((2S,3R)-3-
isobutylphenyl)sulfonamido)-1-phenylbutan-2-yl)carbamate
(3k): Compound 3k was obtained from compound 3j following the
same procedure described for compound 3e (97% yield). 1H NMR
(400 MHz, CDCl3) δ 7.93 – 7.63 (m, 4H), 7.43 (s, 1H), 7.35 – 7.04
(m, 5H), 5.64 (d, J = 5.2 Hz, 1H), 5.13 – 4.87 (m, 3H), 4.02 – 3.75
(m, 4H), 3.76 – 3.35 (m, 4H), 3.29 – 2.95 (m, 4H), 2.96 – 2.58 (m,
4H), 1.93 – 1.81 (m, 1H), 1.69 (d, J = 6.7 Hz, 3H), 0.90 (dd, J =
15.4, 6.5 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ 166.7, 157.4,
10
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