TETRAHYDROQUINOLINE (THQ) COUMPOUNDS
20240287025 · 2024-08-29
Inventors
- Zuzana MACEK JILKOVA (GRENOBLE, FR)
- J?r?me GOVIN (EYBENS, FR)
- Anouk EMADALI (GRENOBLE, FR)
- Carlo PETOSA (GRENOBLE, FR)
- Yung-Sing WONG (SAINT MARTIN D’HERES, FR)
Cpc classification
C07D401/12
CHEMISTRY; METALLURGY
A61P29/00
HUMAN NECESSITIES
C07F11/00
CHEMISTRY; METALLURGY
A61K31/4709
HUMAN NECESSITIES
A61K31/506
HUMAN NECESSITIES
C07D215/48
CHEMISTRY; METALLURGY
C07D401/04
CHEMISTRY; METALLURGY
International classification
C07D401/12
CHEMISTRY; METALLURGY
C07D215/48
CHEMISTRY; METALLURGY
C07F7/18
CHEMISTRY; METALLURGY
C07F11/00
CHEMISTRY; METALLURGY
C07D401/04
CHEMISTRY; METALLURGY
A61K31/4709
HUMAN NECESSITIES
A61K31/506
HUMAN NECESSITIES
A61K31/4706
HUMAN NECESSITIES
Abstract
The present invention relates to new tetrahydroquinoline (THQ) compounds and new methods for synthetizing such compounds.
The present invention relates to the applications thereof, in particular in therapeutic treatment.
The present invention relates in particular to compound having the following structure:
##STR00001##
wherein R, R, R.sub.A, Nu, R1, R2, R3, and R4 are each independently an atom or a chemical group of atoms.
Claims
1. A compound having the following structure: ##STR00152## wherein R, R, R.sub.A, Nu, R1, R2, R3, and R4 are each independently an atom or a chemical group of atoms.
2. The compound of claim 1, wherein said compound has the following structure: ##STR00153## wherein R represents an alkyl group, wherein R1, R2, R3, R4, R7 and R8 are each independently an atom or a chemical group of atoms, wherein -Nu represents a group of atoms, preferably selected from the group consisting of N.sub.3, OR.sub.5, SR.sub.5, SeR.sub.5 and ##STR00154## wherein N is linked to the heterocycle and wherein the covalent bonds between N and R5, and N and R6 represent single or double bonds with R5 or R6, and wherein R5 and R6 represent each independently an atom or a chemical group of atoms and may form together a heterocycle, optionally substituted, or -Nu together with R form an heterocyle, for example thereby forming a hexahydropyrroloquinoline.
3. The compound of claim 1, wherein R1, R2 and R4 are hydrogen atoms.
4. The compound of claim 1, wherein R is CH.sub.3.
5. The compound of claim 2, wherein R8 is CH.sub.3.
6. The compound of claim 1, wherein R5 and R6 are each independently selected from the group consisting of H, C(O)OR.sup.9, an aryl or heteroaryl ring optionally substituted, wherein R9 is an alkyl group.
7. The compound of claim 1, wherein R5 and R6 form together an heteroaryl of the following structure: ##STR00155## wherein Ra and Rb are each independently an atom or a chemical group of atoms, preferably selected from the group consisting of H, a halogen atom (Br, Cl, F), an alkyl group optionally comprising one or more heteroatoms (O, N, S), an optionally substituted aryl or heteroaryl, for example an optionally substituted phenyl ring, and wherein Ra and Rb may form together a cycle or heterocycle, optionally substituted.
8. The compound of claim 1, wherein said compound has the following structure: ##STR00156## wherein ?linker? represents a group of atoms; or ##STR00157## or a corresponding cis-2,3 and trans-3,4 enantiomer thereof: ##STR00158## or the corresponding cis-2,3 and trans-3,4 enantiomer thereof: ##STR00159## wherein the spacer link is a covalent link comprising several atoms.
9. The compound of claim 1, wherein said compound is selected from the group consisting of the following compounds: ##STR00160## ##STR00161## ##STR00162## ##STR00163## ##STR00164## ##STR00165## ##STR00166## ##STR00167## ##STR00168## ##STR00169## ##STR00170## or the corresponding cis-2,3 and trans-3,4 enantiomer thereof.
10. A method for selective production of tetrahydroquinone, said method comprising reacting reactive compounds in the presence of (i) L-Proline and/or D-Proline and/or (S) silyl prolinol and/or (R) silyl prolinol and (ii) a Lewis acid to provide a tetrahydroquinone compound.
11. The method of claim 10 wherein said method comprises the following reaction: ##STR00171## wherein R1, R2, R3, R4, R, and Nu are each independently an atom or a chemical group of atoms, and wherein Rc is a group of atoms, typically an alkyl group, for example an ethyl group.
12. The method of claim 10, wherein said method comprises the following reaction: ##STR00172##
13. The method of claim 10, wherein said Lewis acid is BF.sub.3OEt.sub.2.
14. A compound as claimed in claim 1, for use as a selective BET inhibitor.
15. A composition comprising a compound as claimed in claim 1.
16. A pharmaceutical composition comprising a compound as claimed in claim 1.
17. A compound as claimed in claim 1, for use in a method for treating an inflammation or a cancer, preferably a cancer involving BET over-expression.
Description
ON THE FIGURES
[0139]
[0140]
[0141]
[0142]
[0143]
[0144]
[0145]
[0146]
EXAMPLES
(2S,3S,4R)-Ethyl-4-azido-6-methoxy-3-pentyl-1,2,3,4-tetrahydroquinoline-2-carboxylate (7)
[0147] ##STR00048##
Method A
[0148] To a solution of ethyl (E)-2-((4-methoxyphenyl)imino)acetate 2 (300.0 mg, 1.45 mmol) and freshly distilled heptanal (248.0 mg, 2.17 mmol) in anhydrous dioxane (10 mL) was added L-proline (26.4 mg, 0.21 mmol) at rt. The reaction mixture was stirred for 48 h at the same temperature. After the reaction was complete, TMSN.sub.3 (216.0 mg, 1.88 mmol) and BF.sub.3.Math.Et.sub.2O (90 ?L, 0.73 mmol) were added and the mixture was stirred at rt for 1 h. The reaction was quenched with NaOH (2 N) until neutralization, extracted with EtOAc, dried by MgSO.sub.4, filtered off and concentrated by vacuum. After flash chromatography (silica gel, 5% EtOAc/cyclohexane), the product 7 was isolated as an oil (333.0 mg, 66.4%); R.sub.f=0.27 (10% EtOAc/cyclohexane); [?].sub.D.sup.20=+126.6 (c=1.03, CHCl.sub.3); IR v.sub.max (thin film, CH.sub.2Cl.sub.2) 3393, 2954, 2927, 2091, 1734, 1622, 1501, 1463, 1224 cm.sup.?1; UV: 208, 245, 325; .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.84 (t, J=6.9 Hz, 3H), 0.94-1.29 (m, 8H), 1.32 (t, J=7.1 Hz, 3H), 2.24 (m, 1H), 3.76 (s, 3H), 4.19 (m, 1H), 4.26 (m, 1H), 4.29 (m, 1H), 4.40 (d, J=2.4 Hz, 1H), 6.64 (d, J=8.8 Hz, 1H), 6.68 (d, J=2.8 Hz, 1H), 6.81 (dd, J=8.8, 2.8 Hz, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 14.1 (CH.sub.3), 14.4 (CH.sub.3), 22.6 (CH.sub.2), 26.4 (CH.sub.2), 27.0 (CH.sub.2), 31.8 (CH.sub.2), 38.6 (CH), 53.5 (CH), 56.0 (CH.sub.3), 61.4 (CH), 61.6 (CH.sub.2), 115.6 (CH), 115.8 (C), 116.3 (CH), 117.1 (CH), 136.8 (C), 151.9 (C), 172.5 (C); LRMS (ESI+) m/z (%) 347 (20) [M+H].sup.+, 304 (100); HRMS (ESI+) m/z calc. for C.sub.18H.sub.27N.sub.4O.sub.3 347.2078, found 347.2077.
(2S,3S,4R)-Ethyl-6-methoxy-3-pentyl-4-(phenylthio)-1,2,3,4-tetrahydroquinoline-2-carboxylate (8)
[0149] ##STR00049##
[0150] From imine 2 (300.0 mg, 1.45 mmol), freshly distilled heptanal (248.0 mg, 2.17 mmol) and thiophenol (206.0 mg, 1.88 mmol) in dioxane (10 mL), and using method A, the product was obtained after flash chromatography (silica gel, 5% EtOAc/cyclohexane) to give 8 (329.0 mg, 55%); R.sub.f=0.17 (5% EtOAc/cyclohexane); [?].sub.D.sup.20=+110 (c=1.08, CHCl.sub.3); IR v.sub.max (thin film, CH.sub.2Cl.sub.2) 3393, 2900, 1731, 1504, 1463, 1215, 1150 cm.sup.?1; UV: 206, 223, 245, 328; .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.76 (J=7.3 Hz, 3H), 0.93-1.21 (m, 8H), 1.28 (t, J=7.1 Hz, 3H), 2.30 (m, 1H), 3.69 (s, 3H), 4.17-4.28 (m, 2H), 4.28 (d, J=1.8 Hz, 1H), 4.68 (d, J=2.8 Hz, 1H), 6.57 (d, J=8.6 Hz, 1H), 6.70 (dd, J=8.6, 2.8 Hz, 1H), 6.73 (d, J=2.8 Hz, 1H), 7.28-7.38 (m, 3H), 7.53 (dd, J=8.1, 1.4 Hz, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 14.1 (CH.sub.3), 14.3 (CH.sub.3), 22.6 (CH.sub.2), 26.5 (CH.sub.2), 27.3 (CH.sub.2), 31.4 (CH.sub.2), 37.8 (CH), 50.5 (CH), 53.5 (CH), 55.9 (CH.sub.3), 61.3 (CH.sub.2), 115.9 (CH), 116.2 (2?CH), 118.0 (C), 127.9 (CH), 129.2 (2?CH), 133.4 (2?CH), 134.9 (C), 137.1 (C), 152.0 (C), 173.1 (C); LRMS (ESI+) m/z (%) 414 (20) [M+H].sup.+, 304 (100); HRMS (ESI+) m/z calc. for C.sub.24H.sub.32NO.sub.3S 414.2097, found 414.2093.
(2S,3S,4R)-Ethyl-6-methoxy-3-pentyl-4-(phenylselanyl)-1,2,3,4-tetrahydroquinoline-2-carboxylate (9)
[0151] ##STR00050##
[0152] From imine 2 (300.0 mg, 1.45 mmol), freshly distilled heptanal (248.0 mg, 2.17 mmol) and benzeneselenol (296.0 mg, 1.88 mmol), and using method A, the product was obtained after flash chromatography (silica gel, 5% EtOAc/cyclohexane) to give 9 (220.0 mg, 33%); R.sub.f=0.23 (5% EtOAc/cyclohexane); [?].sub.D.sup.20=+135 (c=1.01, CHCl.sub.3); IR v.sub.max (thin film, CH.sub.2Cl.sub.2) 3398, 2926, 1733, 1505, 1467, 1213, 1036 cm.sup.?1; UV: 206, 226, 335; .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.75 (J=7.3 Hz, 3H), 0.86-1.18 (m, 8H), 1.29 (t, J=7.1 Hz, 3H), 2.30 (m, 1H), 3.70 (s, 3H), 4.17-4.30 (m, 2H), 4.52 (d, J=1.6 Hz, 1H), 4.79 (d, J=2.8 Hz, 1H), 6.54 (d, J=8.7 Hz, 1H), 6.67 (dd, J=8.7, 2.9 Hz, 1H), 6.72 (d, J=2.8 Hz, 1H), 7.29-7.37 (m, 3H), 7.65 (m, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 14.1 (CH.sub.3), 14.4 (CH.sub.3), 22.6 (CH.sub.2), 26.5 (CH.sub.2), 27.4 (CH.sub.2), 31.3 (CH.sub.2), 38.3 (CH), 46.2 (CH), 54.2 (CH), 55.9 (CH.sub.3), 61.4 (CH.sub.2), 115.6 (CH), 155.9 (CH), 116.2 (CH), 118.9 (C), 128.3 (CH), 129.3 (2?CH), 130.3 (C), 135.8 (2?CH), 136.9 (C), 152.0 (C), 173.2 (C); LRMS (ESI+) m/z (%) 462 (15) [M+H].sup.+, 304 (100); HRMS (ESI+) m/z calc. for C.sub.24H.sub.32NO.sub.3Se 462.1543, found 462.1542.
(2S,3R,4R)-Ethyl-4-((4-chlorophenyl)amino)-6-methoxy-3-pentyl-1,2,3,4-tetrahydroquinoline-2-carboxylate (10a)
[0153] ##STR00051##
[0154] From imine 2 (300.0 mg, 1.45 mmol), freshly distilled heptanal (248.0 mg, 2.17 mmol) and 4-chloroaniline (221.0 mg, 1.74 mmol), and using method A, the product was obtained after flash chromatography (silica gel neutralized by Et.sub.3N, 5% EtOAc/cyclohexane) to give 10a (315.0 mg, 50.5%) and 10b (31.0 mg, 5%);
[0155] 10a: R.sub.f=0.23 (10% EtOAc/cyclohexane); [?].sub.D.sup.20=+80.2 (c=1.03, CHCl.sub.3); IR v.sub.max (thin film, CH.sub.2Cl.sub.2) 3393, 2954, 2924, 1725, 1595, 1501, 1460, 1212, 1150 cm.sup.?1; UV: 206, 258, 315; .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.88 (t, J=7.0 Hz, 3H), 1.09 (m, 1H), 1.15-1.35 (m, 7H), 1.27 (t, J=7.1 Hz, 3H), 2.41 (m, 1H), 3.68 (s, 3H), 4.10 (bs, 1H), 4.14-4.31 (m, 2H), 4.36 (bs, 1H), 6.57-6.61 (m, 3H), 6.70 (d, J=2.8 Hz, 1H), 6.75 (dd, J=8.8, 2.8 Hz, 1H), 7.16 (d, J=8.8 Hz, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 14.2 (CH.sub.3), 14.4 (CH.sub.3), 22.7 (CH.sub.2), 26.9 (CH.sub.2), 27.3 (CH.sub.2), 32.2 (CH.sub.2), 37.9 (CH), 53.7 (CH), 54.4 (CH), 55.9 (CH.sub.3), 61.5 (CH.sub.2), 113.8 (2?CH), 115.6 (CH), 116.3 (CH), 116.6 (CH), 119.6 (C), 122.1 (C), 129.4 (2?CH), 136.8 (C), 145.1 (C), 152.3 (C), 173.3 (C); HRMS (ESI?) m/z calc. for C.sub.24H.sub.30N.sub.2O.sub.3Cl 429.1950, found 429.1949.
(2S,3R,4S)-Ethyl-4-((4-chlorophenyl)amino)-6-methoxy-3-pentyl-1,2,3,4-tetrahydroquinoline-2-carboxylate (10b)
[0156] ##STR00052##
[0157] 10b: R.sub.f=0.20 (10% EtOAc/cyclohexane); [?].sub.D.sup.20=+1.02 (c=0.89, CHCl.sub.3); IR v.sub.max (thin film, CH.sub.2Cl.sub.2) 3390, 2954, 2927, 2853, 2087, 1725, 1595, 1507, 1203, 1033 cm.sup.?1; UV: 206, 258, 315; .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.86 (t, J=7.1 Hz, 3H), 0.91 (t, J=6.8 Hz, 3H), 1.24-1.56 (m, 8H), 2.80 (m, 1H), 3.71 (s, 3H), 3.76 (m, 1H), 3.95 (m, 1H), 4.09 (d, J=4.2 Hz, 1H), 4.19 (bs, 1H), 6.45 (d, J=8.8 Hz, 2H), 6.63 (d, J=2.8 Hz, 1H), 6.64 (d, J=8.8 Hz, 1H), 6.78 (dd, J=8.8, 2.8 Hz, 1H), 7.13 (d, J=8.8 Hz, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 13.9 (CH.sub.3), 14.3 (CH.sub.3), 22.8 (CH.sub.2), 27.4 (CH.sub.2), 31.2 (CH.sub.2), 32.1 (CH.sub.2), 36.7 (CH), 54.0 (CH), 54.5 (CH), 56.0 (CH.sub.3), 61.3 (CH.sub.2), 113.3 (2?CH), 115.5 (CH), 116.4 (CH), 116.6 (CH), 119.8 (C), 121.8 (C), 129.3 (2?CH), 136.6 (C), 145.1 (C), 152.5 (C), 175.6 (C); HRMS (ESI?) m/z calc. for C.sub.24H.sub.30N.sub.2O.sub.3Cl 429.1950, found 429.1945.
(2S,3S,4R)-ethyl 4-{[(R)-2-acetamido-3-methoxy-3-oxopropyl]thio}-6-methoxy-3-pentyl-1,2,3,4-tetrahydroquinoline-2-carboxylate (11)
[0158] ##STR00053##
[0159] From imine 2 (300.0 mg, 1.45 mmol), freshly distilled heptanal (248.0 mg, 2.17 mmol) and methyl acetyl-L-cysteinate (281.0 mg, 1.59 mmol), and using method A, the product was obtained after flash chromatography (silica gel, 40% EtOAc/cyclohexane) to give 11 (320.6 mg, 46%); R.sub.f=0.29 (50% EtOAc/cyclohexane); [?].sub.D.sup.20=?11.6 (c=1.19, CHCl.sub.3); IR v.sub.max (thin film, CH.sub.2Cl.sub.2) 3385, 2929, 1730, 1656, 1505, 1370, 1216, 1153 cm.sup.?1; UV: 205, 246, 330; .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.85 (t, J=7.0 Hz, 3H), 1.08 (m, 1H), 1.14-1.29 (m, 7H), 1.34 (t, J=7.1 Hz, 3H), 2.07 (s, 3H), 2.31 (m, 1H), 2.94 (dd, J=13.7, 6.3 Hz, 1H), 3.23 (dd, J=13.7, 4.5 Hz, 1H), 3.75 (s, 3H), 3.79 (s, 3H), 3.93 (d, J=1.6 Hz, 1H), 4.22-4.37 (m, 2H), 4.50 (m, 1H), 4.94 (ddd, J=7.6, 6.3, 4.5 Hz, 1H), 6.54 (d, J=8.7 Hz, 1H), 6.69 (dd, J=8.7, 2.8 Hz, 1H), 6.73 (d, J=2.8 Hz, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 14.2 (CH.sub.3), 14.5 (CH.sub.3), 22.7 (CH.sub.2), 23.4 (CH.sub.3), 27.1 (CH.sub.2), 27.7 (CH.sub.2), 31.9 (CH.sub.2), 33.8 (CH.sub.2), 39.0 (CH), 46.2 (CH), 52.1 (CH.sub.3), 53.0 (CH), 53.7 (CH), 55.9 (CH.sub.3), 61.6 (CH.sub.2), 115.9 (CH), 116.0 (CH), 116.1 (CH), 118.2 (C), 136.7 (C), 152.0 (C), 170.1 (C), 171.4 (C), 173.1 (C); LRMS (ESI+) m/z (%) 481 (1) [M+H].sup.+, 302 (100); HRMS (ESI+) m/z calc. for C.sub.24H.sub.37N.sub.2O.sub.6S 481.2367, found 481.2357.
(2R,3R,4S)-ethyl 4-{[(R)-2-acetamido-3-methoxy-3-oxopropyl]thio}-6-methoxy-3-pentyl-1,2,3,4-tetrahydroquinoline-2-carboxylate (12)
[0160] ##STR00054##
[0161] From 2 (300.0 mg, 1.45 mmol), freshly distilled heptanal (248.0 mg, 2.17 mmol) and methyl acetyl-L-cysteinate (281.0 mg, 1.59 mmol), and using the method A and D-proline as catalyst, the product was obtained after flash chromatography (silica gel, 40% EtOAc/cyclohexane) to give 12 (346.4 mg, 50%); R.sub.f=0.27 (50% EtOAc/cyclohexane); [?].sub.D.sup.20=+123.8 (c=1.00, CHCl.sub.3); IR v.sub.max(thin film, CH.sub.2Cl.sub.2) 3303, 2954, 2927, 2863, 1739, 1655, 1503, 1467, 1290, 1230 cm.sup.?1; UV: 206, 247, 333; .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.85 (t, J=7.0 Hz, 3H), 1.06 (m, 1H), 1.13-1.30 (m, 7H), 1.33 (t, J=7.1 Hz, 3H), 2.05 (s, 3H), 2.30 (m, 1H), 3.08 (dd, J=13.9, 4.9 Hz, 1H), 3.14 (dd, J=13.9, 4.7 Hz, 1H), 3.75 (s, 3H), 3.80 (s, 3H), 3.85 (d, J=1.7 Hz, 1H), 4.31-4.36 (m, 2H), 4.51 (d, J=2.9 Hz, 1H), 4.95 (dt, J=7.8, 4.8 Hz, 1H), 6.54 (dd, J=7.8, 1.2 Hz, 1H), 6.67-6.70 (m, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 14.1 (CH.sub.3), 14.5 (CH.sub.3), 22.6 (CH.sub.2), 23.3 (CH.sub.3), 27.1 (CH.sub.2), 27.7 (CH.sub.2), 31.9 (CH.sub.2), 34.1 (CH.sub.2), 39.7 (CH), 47.0 (CH), 52.2 (CH.sub.3), 52.8 (CH), 53.6 (CH), 55.9 (CH.sub.3), 61.6 (CH.sub.2), 115.8 (CH), 116.0 (CH), 116.1 (CH), 118.2 (C), 136.7 (C), 152.0 (C), 170.0 (C), 171.4 (C), 173.0 (C); HRMS (ESI+) m/z calc. for C.sub.24H.sub.37N.sub.2O.sub.6S 481.2367, found 481.2361.
Ethyl-(2S,3S,4R)-4-(((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxy)-6-methoxy-3-pentyl-1,2,3,4-tetrahydroquinoline-2-carboxylate (13)
[0162] ##STR00055##
[0163] From imine 2 (300.0 mg, 1.45 mmol), freshly distilled heptanal (248.0 mg, 2.17 mmol) and (?)-menthol (295.0 mg, 1.88 mmol), and using method A, the product was obtained after flash chromatography (silica gel, 5% EtOAc/cyclohexane) to give 13 (217.0 mg, 32.6%); R.sub.f=0.29 (5% EtOAc/cyclohexane); [?].sub.D.sup.20=+24.6 (c=1.58, CHCl.sub.3); IR v.sub.max (thin film, CH.sub.2Cl.sub.2) 3404, 2920, 1733, 1503, 1460, 1366, 1213, 1154, 1040 cm.sup.?1; UV:226, 246; .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.82-0.91 (m, 9H), 0.98 (d, J=6.6 Hz, 3H), 1.02-1.34 (m, 13H), 1.32 (t, J=7.1 Hz, 3H), 1.42 (m, 1H), 1.63-1.72 (m, 2H), 2.26-2.35 (m, 3H), 3.31 (td, J=10.4, 4.1 Hz, 1H), 4.17 (d, J=1.9 Hz, 1H), 4.23 (m, 1H), 4.23-4.30 (m, 2H), 6.60 (m, 1H), 6.71-6.75 (m, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 14.2 (CH.sub.3), 14.4 (CH.sub.3), 16.0 (CH.sub.3), 21.6 (CH.sub.3), 22.6 (CH.sub.3, CH.sub.2), 23.1 (CH.sub.2), 25.2 (CH), 25.8 (CH.sub.2), 27.4 (CH.sub.2), 31.9 (CH), 32.0 (CH.sub.2), 34.7 (CH.sub.2), 38.6 (CH), 41.7 (CH.sub.2), 48.2 (CH), 53.7 (CH), 56.0 (CH.sub.3), 61.3 (CH.sub.2), 73.5 (CH), 76.9 (CH), 115.9 (CH), 116.2 (CH), 116.8 (CH), 120.2 (C), 137.3 (C), 152.3 (C), 173.5 (C); HRMS (ESI+) m/z calc. for C.sub.28H.sub.46NO.sub.4 460.3421, found 460.3419.
Ethyl-(2R,3R,4S)-4-(((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxy)-6-methoxy-3-pentyl-1,2,3,4-tetrahydroquinoline-2-carboxylate (14)
[0164] ##STR00056##
[0165] From imine 2 (300.0 mg, 1.45 mmol), freshly distilled heptanal (248.0 mg, 2.17 mmol) and (?)-menthol (295 mg, 1.88 mmol), and using method A and D-proline as catalyst, the product was obtained after flash chromatography (silica gel, 5% EtOAc/cyclohexane) to give 14 (232.5 mg, 35%); R.sub.f=0.4 (5% EtOAc/cyclohexane); [?].sub.D.sup.20=?108.6 (c=0.89, CHCl.sub.3); IR v.sub.max (thin film, CH.sub.2Cl.sub.2) 3402, 2930, 2089, 1505, 1463, 1250 cm.sup.?1; UV: 225, 246; .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.42 (d, J=6.9 Hz, 3H), 0.80 (d, J=7.1 Hz, 3H), 0.84 (t, J=7.0 Hz, 3H), 0.96 (d, J=6.6 Hz, 3H), 1.01-1.32 (m, 13H), 1.33 (t, J=7.1 Hz, 3H), 1.42 (m, 1H), 1.54-1.68 (m, 2H), 2.10 (m, 1H), 2.25 (m, 1H), 2.33 (m, 1H), 3.32 (td, J=10.5, 4.0 Hz, 1H), 3.74 (s, 3H), 4.20-4.32 (m, 2H), 4.29 (m, 1H), 4.41 (m, 1H), 6.58 (d, J=8.7 Hz, 1H), 6.65 (d, J=2.8 Hz, 1H), 6.74 (dd, J=8.7, 2.8 Hz, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 14.2 (CH.sub.3), 14.5 (CH.sub.3), 15.5 (CH.sub.3), 21.3 (CH.sub.3), 22.6 (CH), 22.7 (CH.sub.3), 23.2 (CH.sub.2), 25.4 (CH), 26.1 (CH.sub.2), 27.3 (CH.sub.2), 31.9 (CH), 32.0 (CH.sub.2), 34.8 (CH), 38.8 (CH), 41.6 (CH.sub.2), 48.9 (CH), 53.4 (CH), 56.1 (CH.sub.3), 61.3 (CH.sub.2), 73.8 (CH), 75.5 (CH), 115.7 (CH), 115.9 (CH), 117.0 (CH), 118.8 (C), 137.4 (C), 151.3 (C), 173.9 (C); HRMS (ESI+) m/z calc. for C.sub.28H.sub.46NO.sub.4 460.3421, found 460.3426.
(2S,3S,4R)-Ethyl 4-hydroxy-6-methoxy-3-pentyl-1,2,3,4-tetrahydroquinoline-2-carboxylate (15)
[0166] ##STR00057##
[0167] From imine 2 (300.0 mg, 1.45 mmol), freshly distilled heptanal (248.0 mg, 2.17 mmol) and water (34.0 mg, 1.88 mmol), and using method A, the product was obtained after flash chromatography (silica gel, 10% to 15% EtOAc/cyclohexane) to give 15 (125.6 mg, 27%); R.sub.f=0.33 (20% EtOAc/cyclohexane); [?].sub.D.sup.20=+33.3 (c=1.00, CHCl.sub.3); IR v.sub.max (thin film, CH.sub.2Cl.sub.2) 3395, 2956, 2923, 2851, 1730, 1503, 1461, 1284, 1227, 1153, 1027 cm.sup.?1; UV: 208, 246, 322; .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.84 (t, J=6.9 Hz, 3H), 0.85-1.31 (m, 8H), 1.32 (t, J=7.1 Hz, 3H), 2.31 (m, 1H), 4.22-4.32 (m, 2H), 4.25 (d, J=3.2 Hz, 1H), 4.52 (d, J=2.4 Hz, 1H), 6.62 (m, 1H), 6.76-6.79 (m, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 14.1 (CH.sub.3), 14.4 (CH.sub.3), 22.6 (CH.sub.2), 26.0 (CH.sub.2), 27.2 (CH.sub.2), 31.9 (CH.sub.2), 40.5 (CH), 53.0 (CH), 55.9 (CH.sub.3), 61.4 (CH.sub.2), 69.6 (CH), 115.5 (CH), 116.1 (CH), 116.6 (CH), 121.1 (C), 136.8 (C), 152.1 (C), 173.4 (C); LRMS (ESI+) m/z (%) 322 (60) [M+H].sup.+, 304 (100); HRMS (ESI+) m/z calc. for C.sub.18H.sub.28NO.sub.4 322.2013, found 322.2013.
(2S,3S,4S)-Ethyl-4-azido-3-pentyl-1,2,3,4-tetrahydroquinoline-2-carboxylate (16)
[0168] ##STR00058##
[0169] To a solution of aniline (108.0 mg, 1.16 mmol) and ethylglyoxylate (0.28 mL, 1.39 mmol, 50% in toluene) in toluene was added MgSO.sub.4 (87.0 mg, 0.72 mmol) at rt. The reaction mixture was stirred at 110? C. for 1 h. After cooling rt, the reaction was filtered off and co-evaporated with toluene two times. The mixture was diluted in dioxane (8 mL) and freshly distilled heptanal (199.0 mg, 1.74 mmol) and L-proline (20.0 mg, 0.17 mmol) were added at rt. The reaction mixture was stirred at this temperature for 48 h. After the reaction was complete TMSN.sub.3 (213.0 mg, 1.51 mmol) and BF.sub.3.Math.Et.sub.2O (54 ?L, 0.58 mmol) were added at rt and the reaction was stirred at this temperature for 1 h30. The reaction was quenched by NaOH (2 N), extracted with EtOAc, dried by MgSO.sub.4, filtered off and concentrated in vacuum. The product was obtained after flash chromatography (silica gel, 5% EtOAc/cyclohexane) to give 16 (140.0 mg, 38%); R.sub.f=0.21 (5% EtOAc/cyclohexane); [?].sub.D.sup.20=+151.3 (c=1.10, CHCl.sub.3); IR v.sub.max (thin film, CH.sub.2Cl.sub.2) 3427, 2932, 2857, 2093, 1732, 1620, 1496, 1259, 1220 cm.sup.?1; UV: 225, 252; .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.84 (t, J=6.9 Hz, 3H), 1.02 (m, 1H), 1.08-1.29 (m, 7H), 1.33 (t, J=7.1 Hz, 1H), 2.24 (m, 1H), 4.21-4.35 (m, 3H), 4.44 (d, J=2.5 Hz, 1H), 6.66 (d, J=8.1 Hz, 1H), 6.71 (td, J=7.4, 1.1 Hz, 1H), 7.10 (dd, J=7.4, 1.1 Hz, 1H), 7.16 (ddd, J=8.1, 7.4, 1.5 Hz, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 14.1 (CH.sub.3), 14.4 (CH.sub.3), 22.6 (CH.sub.2), 26.4 (CH.sub.2), 27.0 (CH.sub.2), 31.8 (CH.sub.2), 38.2 (CH), 53.2 (CH), 61.2 (CH), 61.7 (CH.sub.2), 114.8 (C), 114.9 (CH), 117.4 (CH), 130.2 (CH), 131.2 (CH), 142.7 (C), 172.5 (C); HRMS (ESI+) m/z calc. for CO.sub.17H.sub.24O.sub.2N.sub.4Li 323.2054, found 323.2047.
(2S,3S,4R)-Ethyl-4-azido-6-methoxy-3-methyl-1,2,3,4-tetrahydroquinoline-2-carboxylate (17)
[0170] ##STR00059##
[0171] From imine 2 (450.0 mg, 2.17 mmol), recently purchased propioaldehyde (189.0 mg, 3.26 mmol) and TMSN.sub.3 (275.0 mg, 2.82 mmol), and using method A, the product was obtained after flash chromatography (silica gel, 4% EtOAc/cyclohexane) to give 17 as an oil (373.0 mg, 59.5%); R.sub.f=0.48 (7% EtOAc/cyclohexane); [?].sub.D.sup.20=+126.1 (c=1.00, CHCl.sub.3); IR v.sub.max (thin film, CH.sub.2Cl.sub.2) 3384, 2933, 2090, 1731, 1501, 1463, 1251 cm.sup.?1; UV: 205, 249, 326; .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.76 (d, J=7.0 Hz, 3H), 1.32 (t, J=7.1 Hz, 3H), 2.40 (m, 1H), 3.76 (s, 3H), 4.18 (dd, J=2.9, 2.3 Hz, 1H), 4.24-4.34 (m, 3H), 6.65 (d, J=8.8 Hz, 1H), 6.68 (d, J=2.8 Hz, 1H), 6.81 (dd, J=8.8, 2.9 Hz, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 12.0 (CH.sub.3), 14.4 (CH.sub.3), 33.3 (CH), 53.2 (CH), 56.0 (CH.sub.3), 61.7 (CH.sub.2), 63.4 (CH), 115.4 (C), 115.6 (CH), 116.4 (CH), 117.2 (CH), 136.4 (C), 151.9 (C), 172.4 (C); HRMS (ESI+) m/z calc. for C.sub.14H.sub.19N.sub.4O.sub.3 291.1452, found 291.1447.
(2S,3S,4R)-tert-Butyl-4-azido-6-methoxy-3-methyl-1,2,3,4-tetrahydroquinoline-2-carboxylate (18)
[0172] ##STR00060##
[0173] From tert-butyl (E)-2-((4-methoxyphenyl)imino)acetate.sup.1 (341.0 mg, 1.45 mmol), recently purchased propioaldehyde (126.0 mg, 2.17 mmol) and TMSN.sub.3 (218.0 mg, 1.88 mmol), and using method A, the product was obtained after flash chromatography (silica gel, 5% to 10% EtOAc/cyclohexane) to give 18 (221.0 mg, 48%); R.sub.f=0.37 (5% EtOAc/cyclohexane); [?].sub.D.sup.20=+145.2 (c=1.11, CHCl.sub.3); IR v.sub.max (thin film, CH.sub.2Cl.sub.2) 3398, 2977, 2090, 1725, 1503, 1366, 1240, 1157, 1040 cm.sup.?1; UV: 247; .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.76 (d, J=7.0 Hz, 3H), 1.51 (s, 9H), 2.35 (m, 1H), 3.75 (s, 3H), 4.06 (d, J=3.1 Hz, 1H), 4.22 (d, J=2.4 Hz, 1H), 6.63 (d, J=8.8 Hz, 1H), 6.67 (d, J=2.8 Hz, 1H), 6.80 (dd, J=8.8, 2.8 Hz, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 11.8 (CH.sub.3), 28.2 (3?CH.sub.3), 33.2 (CH), 53.4 (CH), 56.0 (CH.sub.3), 63.6 (CH), 82.3 (C), 115.3 (C), 115.6 (CH), 116.3 (CH), 117.3 (CH), 136.6 (C), 151.8 (C), 171.6 (C); LRMS (ESI+) m/z (%) 319 (10) [M+H]+, 220 (100); HRMS (ESI+) m/z calc. for C.sub.16H.sub.23N.sub.4O.sub.3 319.1770, found 319.1764.
(2S,3S,4R)-Ethyl-4-azido-3-(4-((tert-butyldimethylsilyl)oxy)benzyl)-6-methoxy-1,2,3,4-tetrahydroquinoline-2-carboxylate (19)
[0174] ##STR00061##
[0175] From imine 2 (300.0 mg, 1.45 mmol), 3-(4-((tert-butyldimethylsilyl)oxy)phenyl)propanal.sup.2 (574.0 mg, 2.17 mmol) and TMSN.sub.3 (216.0 mg, 1.88 mmol), and using the method A, the product was obtained after flash chromatography (silica gel, 5% EtOAc/cyclohexane) to give 19 as a white solid (485.0 mg, 67.5%); R.sub.f=0.38 (5% EtOAc/cyclohexane); [?].sub.D.sup.20=+40.5 (c=1.00, CHCl.sub.3); IR v.sub.max (thin film, CH.sub.2Cl.sub.2) 3406, 2956, 2934, 2854, 2094, 1737, 1605, 1509, 1466, 1257, 1229 cm.sup.?1; UV: 205, 249, 326; .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.19 (s, 6H), 0.98 (s, 9H), 1.30 (t, J=7.1 Hz, 3H), 2.18 (dd, J=14.0, 10.2 Hz, 1H), 2.47 (dd, J=14.0, 4.8 Hz, 1H), 2.52 (m, 1H), 3.75 (s, 3H), 4.14-4.21 (m, 2H), 4.22 (d, J=2.3 Hz, 1H), 4.25 (dd, J=2.8, 1.9 Hz, 1H), 6.63 (d, J=2.8 Hz, 1H), 6.68 (d, J=8.8 Hz, 1H), 6.74 (d, J=8.5 Hz, 2H), 6.84 (dd, J=8.8, 2.8 Hz, 1H), 6.88 (d, J=8.5 Hz, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 14.4 (CH.sub.3), 18.3 (C), 25.8 (3?CH.sub.3), 32.0 (CH.sub.2), 40.3 (CH), 53.1 (CH), 55.9 (CH.sub.3), 60.4 (CH), 61.6 (CH.sub.2), 115.4 (C), 115.5 (CH), 116.3 (CH), 117.2 (CH), 120.1 (2?CH), 130.2 (2?CH), 131.3 (C), 136.7 (C), 151.9 (C), 154.4 (C), 172.1 (C); LRMS (ESI+) m/z (%) 497 (100) [M+H].sup.+, 454 (35); HRMS (ESI+) m/z calc. for C.sub.26H.sub.37N.sub.4O.sub.4Si 497.2579, found 497.2581.
(2S,3S,4R)-Ethyl-3-allyl-4-azido-6-methoxy-1,2,3,4-tetrahydroquinoline-2-carboxylate (20)
[0176] ##STR00062##
[0177] From imine 2 (300.0 mg, 1.45 mmol), recently purchased 4-pentenal (187.0 mg, 2.17 mmol) and TMSN.sub.3 (217.0 mg, 1.88 mmol), and using method A, the product was obtained after flash chromatography (silica gel, 5% EtOAc/cyclohexane) to give 20 (266.0 mg, 58%); R.sub.f=0.29 (5% EtOAc/cyclohexane); [?].sub.D.sup.20=+188.6 (c=1.00, CHCl.sub.3); IR v.sub.max (thin film, CH.sub.2Cl.sub.2) 3405, 2936, 2091, 1729, 1503, 1226, 1153, 1035 cm.sup.?1; UV: 226, 245; .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 1.31 (t, J=7.1 Hz, 3H), 1.76 (m, 1H), 1.97 (m, 1H), 2.34 (m, 1H), 3.74 (s, 3H), 4.20 (m, 1H), 4.20-4.31 (m, 2H), 4.40 (d, J=2.3 Hz, 1H), 4.92 (dd, J=17.0, 1.4 Hz, 1H), 5.00 (d, J=10.1 Hz, 1H), 5.70 (m, 1H), 6.64 (d, J=8.8 Hz, 1H), 6.67 (d, J=2.8 Hz, 1H), 6.81 (dd, J=8.8, 2.8 Hz, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 14.3 (CH.sub.3), 31.0 (CH.sub.2), 38.0 (CH), 52.9 (CH), 55.9 (CH.sub.3), 60.8 (CH), 61.5 (CH.sub.2), 115.3 (C), 115.4 (CH), 116.2 (CH), 117.1 (CH), 117.7 (CH.sub.2), 135.2 (CH), 137.0 (C), 151.9 (C), 172.0 (C); LRMS (ESI+) m/z (%) 317 (12) [M+H].sup.+, 274 (100); HRMS (ESI+) m/z calc. for C.sub.16H.sub.21N.sub.4O.sub.3 317.1608, found 317.1600.
(2S,3S,4R)-Ethyl-3-allyl-4-(allyloxy)-6-methoxy-1,2,3,4-tetrahydroquinoline-2-carboxylate (21)
[0178] ##STR00063##
[0179] From imine 2 (300.0 mg, 1.45 mmol), recently purchased 2-pentenal (187.0 mg, 2.17 mmol) and 2-propen-1-ol (109.0 mg, 1.88 mmol), and using method A, the product was obtained after flash chromatography (silica gel, 5% EtOAc/cyclohexane) to give 21 (182.8 mg, 38%); R.sub.f=0.21 (5% EtOAc/cyclohexane); [?].sub.D.sup.20=+104.7 (c=1.02, CHCl.sub.3); IR v.sub.max (thin film, CH.sub.2Cl.sub.2) 3408, 2936, 1730, 1638, 1505, 1495, 1210, 1153 cm.sup.?1; UV: 245; .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 1.32 (t, J=7.1 Hz, 3H), 1.65 (m, 1H), 1.91 (m, 1H), 2.56 (m, 1H), 3.74 (s, 3H), 4.10 (m, 1H), 4.11 (m, 1H), 4.15 (d, J=2.6 Hz, 1H), 4.19-4.32 (m, 2H), 4.33 (dd, J=3.1, 2.1 Hz, 1H), 4.90 (ddd, J=17.0, 3.2, 1.6 Hz, 1H), 4.96 (m, 1H), 5.19 (ddd, J=10.4, 3.0, 1.3 Hz, 1H), 5.30 (ddd, J=17.0, 1.6, 1.6 Hz, 1H), 5.72 (dddd, J=17.0, 10.4, 7.8, 6.4 Hz, 1H), 5.95 (dddd, J=17.0, 10.4, 5.6, 5.6 Hz, 1H), 6.61 (d, J=8.7 Hz, 1H), 6.68 (d, J=2.9 Hz, 1H), 6.77 (dd, J=8.7, 2.9 Hz, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 14.3 (CH.sub.3), 30.6 (CH.sub.2), 37.4 (CH), 53.0 (CH), 56.0 (CH.sub.3), 61.3 (CH.sub.2), 69.0 (CH.sub.2), 75.4 (CH), 115.8 (CH), 116.3 (CH), 116.8 (CH), 117.0 (CH), 117.1 (CH), 118.0 (C), 135.4 (CH), 135.9 (CH), 137.1 (C), 151.6 (C), 173.0 (C); LRMS (ESI+) m/z (%) 332 (24) [M+H].sup.+, 274 (100); HRMS (ESI+) m/z calc. for C.sub.19H.sub.26NO.sub.4 332.1856, found 332.1858.
(2S,3S,4R)-Ethyl-3-allyl-6-methoxy-4-(prop-2-yn-1-yloxy)-1,2,3,4-tetrahydroquinoline-2-carboxylate (22)
[0180] ##STR00064##
[0181] From imine 2 (300.0 mg, 1.45 mmol), recently purchased 2-pentenal (187.0 mg, 2.17 mmol) and propargyl alcohol (106.0 mg, 1.88 mmol), and using method A, the product was obtained after flash chromatography (silica gel, 5% EtOAc/cyclohexane) to give 22 (191.0 mg, 40%); R.sub.f=0.21 (5% EtOAc/cyclohexane); [?].sub.D.sup.20=+162.2 (c=1.06, CHCl.sub.3); IR v.sub.max (thin film, CH.sub.2Cl.sub.2) 3284, 2942, 1729, 1505, 1229, 1207, 1155 cm.sup.?1; UV: 248, 324, 322; .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 1.32 (t, J=7.1 Hz, 3H), 1.68 (m, 1H), 1.91 (m, 1H), 2.50 (t, J=2.4 Hz, 1H), 2.52 (m, 1H), 3.76 (s, 3H), 4.18 (dd, J=16.0, 2.4 Hz, 1H), 4.18-4.30 (m, 4H), 4.42 (d, J=2.6 Hz, 1H), 4.91 (ddd, J=17.0, 3.2, 1.5 Hz, 1H), 4.98 (m, 1H), 5.73 (m, 1H), 6.63 (d, J=8.1 Hz, 1H), 6.77-6.81 (m, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 14.4 (CH.sub.3), 30.7 (CH.sub.2), 37.3 (CH), 52.9 (CH), 54.9 (CH.sub.2), 56.1 (CH3), 61.4 (CH.sub.2), 74.5 (CH), 74.8 (C), 80.4 (CH), 116.0 (CH), 116.7 (C), 116.8 (C), 117.2 (CH), 135.7 (CH), 137.2 (C), 151.7 (C), 173.0 (C); LRMS (ESI+) m/z (%) 329 (45), 274 (100); HRMS (ESI+) m/z calc. for C.sub.19H.sub.24NO.sub.4 330.1700, found 330.1704.
(2S,3S,4R)-Ethyl-4-((3-mercaptopropyl)thio)-6-methoxy-3-pentyl-1,2,3,4-tetrahydroquinoline-2-carboxylate (23)
[0182] ##STR00065##
[0183] Chemical Formula: C.sub.21H.sub.33NO.sub.3S.sub.2
[0184] Molecular Weight: 411.6216
[0185] From imine 2 (300.0 mg, 1.45 mmol), freshly distilled heptanal (248.0 mg, 2.17 mmol) and 1,3 propanedithiol (235.0 mg, 2.17 mmol), and using method A, the product was obtained after flash chromatography (silica gel, 5% EtOAc/cyclohexane) to give 23 (208.5 mg, 35%); R.sub.f=0.32 (10% EtOAc/cyclohexane); [?].sub.D.sup.20=+51.9 (c=1.03, CHCl.sub.3); IR v.sub.max (thin film, CH.sub.2Cl.sub.2) 3398, 2955, 2923, 2850, 1732, 1503, 1467, 1213, 1150, 1039 cm.sup.?1; UV: 205, 245, 325; .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.85 (t, J=6.9 Hz, 3H), 1.10 (m, 1H), 1.15-1.39 (m, 7H), 1.33 (t, J=7.1 Hz, 3H), 1.96 (m, 2H), 2.34 (m, 1H), 2.64-2.85 (m, 4H), 3.74 (s, 3H), 3.89 (d, J=1.7 Hz, 1H), 4.21-4.36 (m, 2H), 4.57 (d, J=2.8 Hz, 1H), 6.55 (d, J=8.0 Hz, 1H), 6.68 (dd, J=8.0, 2.8 Hz, 1H), 6.69 (d, J=2.8 Hz, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 14.1 (CH.sub.3), 14.5 (CH.sub.3), 22.6 (CH.sub.2), 23.6 (CH.sub.2), 27.7 (CH.sub.2), 30.1 (CH.sub.2), 31.9 (CH.sub.2), 33.6 (CH.sub.2), 39.0 (CH), 46.2 (CH), 53.7 (CH), 55.9 (CH.sub.3), 61.5 (CH.sub.2), 115.5 (CH), 116.0 (CH), 116.1 (CH), 118.9 (C), 136.7 (C), 152.0 (C), 173.2 (C); LRMS (ESI+) m/z (%) 412 (5) [M+H].sup.+, 304 (100); HRMS (ESI+) m/z calc. for C.sub.21H.sub.34NO.sub.3S.sub.2 412.1974, found 412.1966.
Methyl-(2S,3R,4S)-4-azido-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (26)
[0186] ##STR00066##
[0187] To a solution of methyl-4-aminobenzoate (1.02 g, 6.75 mmol) and propionaldehyde (1.95 g, 33.1 mmol) at ?20? C., D-proline (228.5 mg, 1.985 mmol) was added at ?20? C. The reaction mixture was stirred for 20 min at ?20? C. and kept at the same temperature for two days. Dioxane was added (50 mL) and TMSN.sub.3 (1.3 mL, 9.92 mmol) and then BF.sub.3.Math.Et.sub.2O (0.6 mL, 4.72 mmol) were added at rt and the reaction mixture was stirred at this temperature for 25 min. The reaction was quenched by NaOH (1 N), extracted with EtOAc, dried by MgSO.sub.4, filtered off and concentrated in vacuo. After flash chromatography (silica gel, 10% EtOAc/cyclohexane), the product 26 was isolated (1.52 g, 82%) as a yellow solid. The product is recrystallized in CH.sub.2Cl.sub.2/heptane to obtain 814 mg (44%) with an enantiomeric excess >99%; R.sub.f=0.27 (10% EtOAc in cyclohexane); [?].sub.D.sup.20=?128.3 (c=0.93, CHCl.sub.3); IR v.sub.max (thin film, CH.sub.2Cl.sub.2): 3427, 3053, 2969, 2093, 1704, 1613, 1436, 1265 cm.sup.?1; .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.74 (d, J=7.1 Hz, 3H), 1.03 (t, J=7.5 Hz, 3H), 1.53-1.62 (m, 2H), 1.97 (m, 1H), 3.42 (m, 1H), 3.85 (s, 3H), 4.27 (d, J=2.7 Hz, 1H), 6.52 (d, J=8.5 Hz, 1H), 7.80 (dd, J=8.5, 2.0 Hz, 1H), 7.83 (d, J=2.0 Hz, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 10.4 (CH.sub.3), 10.5 (CH.sub.3), 25.3 (CH.sub.2), 33.2 (CH), 51.1 (CH.sub.3), 51.8 (CH), 63.8 (CH), 113.5 (CH), 114.5 (C), 118.1 (C), 131.8 (CH), 133.6 (CH), 148.1 (C), 167.2 (C); LMRS (ESI+) m/z (%) 297 (100) [M+Na].sup.+; HRMS (ESI+) m/z calc. for C.sub.14H.sub.18N.sub.4O.sub.2Li [M+Li].sup.+281.1584, found 281.1585.
Methyl-(2S,3R,4S)-1-acetyl-4-azido-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (27)
[0188] ##STR00067##
[0189] To a stirred solution of tetrahydroquinoline 26 (437.0 mg, 1.59 mmol) in dry CH.sub.2Cl.sub.2 under argon atmosphere was added dry pyridine (0.39 mL, 4.78 mmol). Acetyl chloride (0.23 mL, 3.18 mmol) was added dropwise at 0? C. The mixture was stirred at room temperature overnight. The same procedure was repeated (dry pyridine (0.39 mL, 4.78 mmol) and acetyl chloride (0.23 mL, 3.18 mmol) added at 0? C.) and the mixture was stirred overnight at room temperature until completion.
[0190] The solvent was removed and EtOAc was added. The organic layer was washed with brine, dried over MgSO.sub.4 and the solvent was removed in vacuum. The product was obtained after flash chromatography (silica gel, 20% EtOAc/cyclohexane) to give 27 (479.9 mg, 95%); R.sub.f=0.29 (20% EtOAc/cyclohexane); [?].sub.D.sup.20=+307.8 (c=0.96, CHCl.sub.3); IR v.sub.max (thin film, CH.sub.2Cl.sub.2): 1461, 2967, 2936, 2877, 2095, 1710, 1609, 1497, 1125 cm.sup.?1; .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.85 (t, J=7.2 Hz, 3H), 1.07 (m, 1H), 1.24 (d, J=6.9 Hz, 3H), 1.61 (m, 1H), 2.30 (s, 3H), 2.31 (m, 1H), 3.94 (s, 3H), 4.10 (d, J=10.3 Hz, 1H), 4.68 (m, 1H), 7.35 (d, J=8.5 Hz, 1H), 7.97 (dd, J=8.5, 2.0 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 10.7 (CH.sub.3), 16.8 (CH.sub.3), 18.5 (CH.sub.2), 23.8 (CH.sub.3), 39.1 (CH), 52.5 (CH.sub.3), 59.0 (CH), 63.7 (CH), 125.5 (CH), 127.3 (C), 128.2 (C), 129.8 (CH), 130.8 (CH), 141.0 (C), 166.2 (C), 170.1 (C); LRMS (ESI+) m/z (%) 317 (30) [M+H].sup.+, 232 (100); HRMS (ESI+) m/z calc. for. C.sub.16H.sub.21N.sub.4O.sub.3 317.1614, found 317.1608.
Methyl-(2S,3R,4S)-1-acetyl-2-ethyl-3-methyl-4-(4-phenyl-1H-1,2,3-triazol-1-yl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (28)
[0191] ##STR00068##
Method B
[0192] To a solution of 6-a (300.0 mg, 0.67 mmol) and phenylacetylene (138.0 mg, 1.35 mmol) in CH.sub.2Cl.sub.2 (1 mL) was added Amberlyst CuI.Math.Et.sub.3N.sup.[3] (40.0 mg) at rt. The reaction mixture was stirred at this temperature for 24 h. After completion, the reaction was filtered off, the supported catalyst was washed with CH.sub.2Cl.sub.2 (2 mL), and the solvent was concentrated under vacuum. After flash chromatography (silica gel, 25% EtOAc/cyclohexane), the product 28 was isolated (318.3 mg, 86%) as a white solid; R.sub.f=0.12 (30% EtOAc/cyclohexane); [?].sub.D.sup.20=+189.9 (c=1.00, CHCl.sub.3); IR v.sub.max (thin film, CH.sub.2Cl.sub.2): 3478, 3128, 2966, 2877, 2094, 1719, 1664, 1260 cm.sup.?1; .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.95 (t, J=7.2 Hz, 3H), 1.09 (d, J=6.7 Hz, 2H), 1.20-1.33 (m, 2H), 1.76 (m, 1H), 2.41 (s, 3H), 2.65 (m, 1H), 3.81 (s, 3H), 5.66 (d, J=11.2 Hz, 1H), 7.33 (t, J=7.4 Hz, 1H), 7.41 (t, J=7.4 Hz, 2H), 7.54 (bs, 1H), 7.64 (d, J=1.9 Hz, 1H), 7.67 (s, 1H), 7.83 (d, J=7.4 Hz, 2H), 7.99 (dd, J=8.6, 1.9 Hz, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 10.8 (CH.sub.3), 16.1 (CH.sub.3), 18.5 (CH.sub.2), 24.1 (CH.sub.3), 40.6 (CH), 52.4 (CH.sub.3), 60.6 (CH), 63.1 (CH), 117.9 (CH), 125.9 (2?CH), 126.9 (CH), 127.6 (2?C), 128.6 (CH), 129.1 (2?CH), 130.1 (CH), 130.3 (CH), 130.4 (C), 140.5 (C), 149.0 (C), 165.9 (C), 170.1 (C); LRMS (ESI+) m/z (%) 441 (100) [M+Na].sup.+, 419 (10) [M+H].sup.+; HRMS (ESI+) m/z calc. for C.sub.24H.sub.26N.sub.4O.sub.3Na 441.1903, found 441.1901.
Methyl-(2S,3S,4R)-4-azido-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (29)
[0193] ##STR00069##
[0194] A solution of methyl-4-benzoate (100.0 mg, 0.66 mmol), (S)-(?)-?,?-diphenyl-2-pyrrolidine methanol trimethylsilyl ether (44.0 mg, 0.13 mmol) and 4-nitrophenyl acetic acid (24 mg, 0.13 mmol) in MTBE (1.5 mL) was stirred for 10 min at ?10? C. Then propionaldehyde (0.65 mL, 8.61 mmol) was added and stirred for 48 h at ?10? C. After the reaction was complete, TMSN.sub.3 (0.13 mL, 0.99 mmol) and BF.sub.3.Math.Et.sub.2O (180 ?L, 1.39 mmol) were added at ?10? C. and the mixture was stirred at rt for 4 h. The reaction was quenched with NaOH (2 N) until neutralization, extracted with EtOAc, dried by MgSO.sub.4, filtered off and concentrated by vacuum. After flash chromatography (silica gel, 5% EtOAc/cyclohexane), the product 29 was isolated (106.4 mg, 58.6%); R.sub.f=0.35 (10% EtOAc/cyclohexane); .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.98 (t, J=7.5 Hz, 3H), 1.08 (d, J=6.7 Hz, 3H), 1.53 (m, 1H), 1.72 (m, 1H), 1.84 (m, 1H), 3.24 (ddd, J=10.3, 7.0, 3.3 Hz, 1H), 3.85 (s, 3H), 4.39 (d, J=3.1 Hz, 1H), 6.52 (d, J=9.1 Hz, 1H), 7.79 (d, J=2.0 Hz, 1H), 7.80 (dd, J=9.1, 2.0 Hz, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 8.6 (CH.sub.3), 14.3 (CH.sub.3), 25.7 (CH.sub.2), 34.5 (CH), 51.8 (CH.sub.3), 52.9 (CH), 63.7 (CH), 113.5 (CH), 116.7 (C), 117.7 (C), 131.9 (CH), 132.0 (CH), 148.3 (C), 167.2 (C); HRMS (ESI+) m/z calc. for C.sub.14H.sub.18N.sub.4O.sub.2Li [M+Li].sup.+281.1584, found 281.1585.
Methyl-(2S,3S,4R)-1-acetyl-4-azido-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (30)
[0195] ##STR00070##
[0196] To a stirred solution of tetrahydroquinoline 29 (85.8 mg, 0.31 mmol) in dry CH.sub.2Cl.sub.2 (1.6 mL) under argon atmosphere was added dry pyridine (76 ?L, 0.94 mmol). Acetyl chloride (45 ?L, 0.63 mmol) was added dropwise at 0? C. The mixture was stirred at room temperature overnight. The same procedure was repeated (dry pyridine (76 ?L, 0.94 mmol) and acetyl chloride (45 ?L, 0.63 mmol) added at 0? C.) and the mixture was stirred for 8 h at room temperature until completion. The solvent was removed and EtOAc was added. The organic layer was washed with brine, dried over MgSO.sub.4 and the solvent was removed in vacuum. The product was obtained after flash chromatography (silica gel, 10% EtOAc/cyclohexane) to give 30 (65.2 mg, 65.8%); R.sub.f=0.20 (10% EtOAc/cyclohexane); .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.80 (t, J=7.4 Hz, 3H), 1.24 (d, J=6.7 Hz, 3H), 1.38 (m, 1H), 1.75 (m, 1H), 1.83 (m, 1H), 2.16 (s, 3H), 3.95 (s, 3H), 4.31 (m, 1H), 4.48 (d, J=3.3 Hz, 1H), 7.30 (d, J=8.3 Hz, 1H), 7.99 (d, J=2.0 Hz, 1H), 8.07 (dd, J=8.3, 2.0 Hz, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 9.7 (CH.sub.3), 17.2 (CH.sub.3), 23.2 (CH.sub.3), 27.2 (CH.sub.2), 40.7 (CH), 52.6 (CH.sub.3), 57.4 (CH), 63.8 (CH), 126.7 (CH), 127.8 (C), 129.1 (CH), 131.0 (CH), 132.2 (C), 142.9 (C), 166.2 (C), 170.2 (C); LRMS (ESI+) m/z (%) 339 (25) [M+Na].sup.+, 317 (100) [M+H].sup.+; HRMS (ESI+) m/z calc. for C.sub.16H.sub.21O.sub.3N.sub.4 [M+H].sup.+ 317.1608, found 317.1606.
Methyl-(2S,3S,4R)-1-acetyl-2-ethyl-3-methyl-4-(4-phenyl-1H-1,2,3-triazol-1-yl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (31)
[0197] ##STR00071##
[0198] To a solution of acetyled product 30 (27.5 mg, 0.087 mmol) and phenylacetylene (18 ?L, 0.174 mmol) in dry DCM (0.1 mL) was added CuI.Math.Et.sub.3N (9 mg) according to Method B. The mixture was stirred at RT overnight. CuI.Math.Et.sub.3N (6.8 mg) and phenylacetylene were added (18 ?L, 0.174) again, and the reaction was stirring at RT overnight until completion. The reaction was filtered off and washed by DCM and concentrated in vacuo. After flash chromatography (silica gel, 20% EtOAc/cyclohexane), the product was isolated (16.4 mg, 45%).
[0199] R.sub.f=0.23 (20% EtOAc/cyclohexane); .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.90 (t, J=7.2 Hz, 3H), 0.91 (d, J=7.0 Hz, 3H), 1.53 (m, 1H), 1.72 (m, 1H), 2.25 (s, 3H), 2.47 (m, 1H), 3.81 (s, 3H), 4.39 (m, 1H), 5.94 (d, J=6.0 Hz, 1H), 7.25 (t, J=7.4 Hz, 1H), 7.34 (t, J=7.4 Hz, 2H), 7.47 (m, 1H), 7.51 (s, 1H), 7.72 (d, J=7.4 Hz, 2H), 7.82 (d, J=2.0 Hz, 1H), 7.99 (dd, J=8.5, 2.0 Hz, 1H); LRMS (ESI+) m/z (%) 441 (35) [M+Na].sup.+, 419 (100) [M+H].sup.+; HRMS (ESI+) m/z calc. for C.sub.24H.sub.27O.sub.3N.sub.4 [M+H].sup.+ 419.2078, found 419.2069.
Methyl-(2S,3S,4R)-4-(4-(2,5,8,11-tetraoxatetradec-13-yn-1-yl)-1H-1,2,3-triazol-1-yl)-1-acetyl-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (32)
[0200] ##STR00072##
[0201] Using the same protocol as 31 and starting from 30 (20.5 mg, 0.06 mmol) and dialkyne-PEG (44 mg, 0.19 mmol), and after flash chromatography (silica gel, EtOAc 100%), the compound 32 was obtained (16.2 mg, 46%):
[0202] R.sub.f=0.34 (2% MeOH/CH.sub.2Cl.sub.2); .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.92 (d, J=6.9 Hz, 3H), 0.93 (t, J=7.4 Hz, 3H), 1.56 (m, 1H), 1.79 (m, 1H), 2.29 (s, 3H), 2.42 (t, J=2.4 Hz, 1H), 2.45 (m, 1H), 3.61-3.72 (m, 12H), 3.88 (s, 3H), 4.19 (d, J=2.4 Hz, 2H), 4.43 (m, 1H), 4.67 (s, 2H), 5.91 (d, J=5.9 Hz, 1H), 7.30 (s, 1H), 7.48 (m, 1H), 7.82 (s, 1H), 8.04 (dd, J=8.5, 2.0 Hz, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 10.2 (CH.sub.3), 16.0 (CH.sub.3), 23.5 (CH.sub.3), 25.9 (CH.sub.2), 38.0 (CH), 52.5 (CH.sub.3), 58.6 (CH.sub.2), 59.8 (CH), 61.0 (CH), 64.9 (CH.sub.2), 70.0 (CH.sub.2), 70.6 (CH.sub.2), 70.7 (CH.sub.2), 70.7 (CH.sub.2), 70.8 (CH.sub.2), 70.8 (CH.sub.2), 74.7 (CH), 79.9 (C), 122.9 (CH), 126.4 (CH), 127.6 (2?C), 130.4 (CH), 130.7 (CH), 142.1 (C), 145.4 (C), 166.0 (C), 170.7 (C); LRMS (ESI+) m/z (%) 441 (35) [M+Na].sup.+, 419 (100) [M+H].sup.+; HRMS (ESI+) m/z calc. for C.sub.28H.sub.39O.sub.7N.sub.4 [M+H].sup.+ 543.2813, found 543.2793.
N-(4-amino-[1,1-biphenyl]-4-yl)hex-5-enamide (XA)
[0203] ##STR00073##
[0204] Chemical Formula: C.sub.18H.sub.20N.sub.2O
[0205] Molecular Weight: 280,3710
[0206] A solution of 5-hexenoic acid (1.3 mL, 7.246 mmol), DMAP (133.0 mg, 1.09 mmol), and benzidine (2.0 g, 10.87 mmol) in DCM (70 mL) was cooled at 0? C. DCC (2.24 g, 10.87 mmol) was solubilized in CH.sub.2Cl.sub.2 (70 mL) and this solution was added dropwise to the previous mixture. The reaction mixture was stirred overnight at rt. The mixture was filtered on and washed with HCl (1 N) then with NaHCO.sub.3 until pH=8. Organic layer was washed again with brine, dried over MgSO.sub.4, filtered on and concentrated under vacuum. The product was purified by flash chromatography (30% cyclohexane in 70% mixture of 2% EtOAc in CH.sub.2Cl.sub.2) to yield the product XA (1.32 g, 65%) as a white solid. R.sub.f=0.20 (2% EtOAc/CH.sub.2Cl.sub.2); .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 1.84 (m, 2H), 2.15 (m, 2H), 2.36 (t, J=7.5 Hz, 2H), 4.98-5.08 (m, 2H), 5.80 (m, 1H), 6.73 (d, J=8.5 Hz, 2H), 7.37 (d, J=8.5 Hz, 2H), 7.47 (d, J=8.7 Hz, 2H), 7.53 (d, J=8.7 Hz, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 24.8 (CH.sub.2), 33.3 (CH.sub.2), 37.0 (CH.sub.2), 115.6 (2?CH), 115.7 (CH.sub.2), 120.4 (2?CH), 126.9 (2?CH), 127.9 (2?CH), 131.1 (C), 136.5 (C), 137.4 (C), 138.0 (CH), 145.9 (C), 171.3 (C); LRMS (ESI+) m/z (%) 281 (100) [M+H].sup.+; HRMS (ESI+): m/z calc. for C.sub.18H.sub.21ON.sub.2 281.1648, found 281.1646.
N-(4-((2S,3R,4S)-4-azido-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)hex-5-enamide (XB)
[0207] ##STR00074##
[0208] Chemical Formula: C.sub.24H.sub.29N.sub.5O
[0209] Molecular Weight: 403.52
[0210] A solution of N-(4-amino-[1,1-biphenyl]-4-yl)hex-5-enamide XA (213.0 mg, 0.761 mmol) and D-proline (26.0 mg, 0.226 mmol) in CH.sub.3CN (20 mL) was cooled at ?40? C. Propionaldehyde (600.0 mg, 10.33 mmol) was added at ?40? C. The reaction mixture was stirred at ?40? C. for 2 h then at 0? C. overnight. TMSN.sub.3 (114.0 mg, 0.989 mmol) and then BF.sub.3.Math.Et.sub.2O (0.40 mL, 3.241 mmol) were added at rt. The reaction mixture is stirred at rt for 1 h30. The reaction is quenched with NaOH (1 N), concentrated and dissolved in EtOAc. The layer was dried over MgSO.sub.4, filtered on and concentrated under vacuum. The product was purified by flash chromatography (silica gel, 10% to 20% EtOAc/cyclohexane) to obtain XB (194.1 mg, 63%); R.sub.f=0.37 (20% EtOAc/cyclohexane); .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.79 (d, J=7.1 Hz, 3H), 1.02 (t, J=7.4 Hz, 3H), 1.55 (m, 2H), 1.84 (m, 2H), 1.95 (m, 1H), 2.14 (m, 2H), 2.36 (t, J=7.5 Hz, 2H), 3.35 (td, J=7.1, 2.6 Hz, 1H), 4.28 (d, J=2.6 Hz, 1H), 4.96-5.08 (m, 2H), 5.80 (ddt, J=16.9, 10.2, 6.7 Hz, 1H), 6.60 (d, J=8.4 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.34 (dd, J=8.4, 2.0 Hz, 1H), 7.46 (d, J=8.5 Hz, 2H), 7.53 (d, J=8.5 Hz, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 10.5 (CH.sub.3), 10.6 (CH.sub.3), 24.8 (CH.sub.2), 25.5 (CH.sub.2), 33.3 (CH.sub.2), 33.9 (CH), 37.0 (CH.sub.2), 51.1 (CH), 64.4 (CH), 114.9 (CH), 115.6 (CH.sub.2), 115.9 (C), 120.4 (2?CH), 126.8 (2?CH), 128.3 (CH), 129.3 (C), 129.4 (CH), 136.4 (C), 137.1 (C), 138.0 (CH), 143.6 (C), 171.4 (C); LRMS (ESI+) m/z (%) 361 (100) 404 (10) [M+H].sup.+; HRMS (ESI+): m/z calc. for C.sub.24H.sub.30N.sub.5O 404.2450, found 404.2439.
N-(4-((2S,3R,4S)-1-acetyl-4-azido-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phel)hex-5-enamide (XC)
[0211] ##STR00075##
[0212] To a solution of XB (191.5 mg, 0.47 mmol) and pyridine (0.11 mL, 1.43 mmol) in CH.sub.2Cl.sub.2 (6 mL) was added acetyl chloride (36 ?L, 0.50 mmol) at 0? C. The reaction mixture was stirred at 0? C. to rt for 2 h30. The reaction was concentrated under vacuum. After flash chromatography (silica gel, 30% EtOAc/cyclohexane), the product XC was isolated (117.8 mg, 84%) as a yellow solid; R.sub.f=0.20 (30% EtOAc/cyclohexane); [?].sub.D.sup.20=+247.5 (c=1.03, CHCl.sub.3); .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.86 (t, J=7.2 Hz, 3H), 1.12 (m, 1H), 1.22 (d, J=6.9 Hz, 3H), 1.60 (m, 1H), 1.86 (m, 2H), 2.16 (m, 2H), 2.31 (s, 3H), 2.33 (m, 1H), 2.40 (t, J=7.5 Hz, 2H), 4.11 (d, J=10.0 Hz, 1H), 4.74 (m, 1H), 5.01 (m, 1H), 5.06 (m, 1H), 5.81 (ddt, J=16.9, 10.0, 6.6 Hz, 1H), 7.29 (m, 1H), 7.49 (dd, J=8.4, 2.1 Hz, 1H), 7.54 (d, J=8.6 Hz, 2H), 7.61 (d, J=2.1 Hz, 1H), 7.64 (d, J=8.6 Hz, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 10.8 (CH.sub.3), 16.9 (CH.sub.3), 18.3 (CH.sub.2), 23.7 (CH.sub.3), 24.7 (CH.sub.2), 33.3 (CH.sub.2), 37.0 (CH.sub.2), 39.5 (CH), 60.6 (CH), 64.1 (CH), 115.6 (CH.sub.2), 120.4 (2?CH), 126.1 (CH), 127.0 (CH), 127.3 (CH), 127.5 (2?CH), 127.6 (C), 127.7 (C), 128.7 (C), 135.5 (C), 138.0 (CH), 138.2 (C), 170.3 (C), 171.6 (C); LMRS (ESI+) m/z (%) 359 (100) 446 (10) [M+H].sup.+; HRMS (ESI+) m/z calc. for C.sub.26H.sub.31N.sub.5O.sub.2Na 468.2375, found 468.2383.
N-(4-((2S,3R,4S)-1-acetyl-2-ethyl-3-methyl-4-(4-phenyl-1H-1,2,3-triazol-1-yl)-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)hex-5-enamide (XD)
[0213] ##STR00076##
[0214] According to method B: To a solution of XC (300.0 mg, 0.67 mmol) and phenylacetylene (138.0 mg, 1.35 mmol) in CH.sub.2Cl.sub.2 (1 mL) was added Amberlyst CuI.Math.Et.sub.3N (40.0 mg) at rt. The reaction mixture was stirred at this temperature for 24 h. After completed, the reaction was filtered off, washed with CH.sub.2Cl.sub.2 (2 mL) and concentrated under vacuum. After flash chromatography (silica gel, 50% EtOAc/cyclohexane), the product XD was isolated (318.3 mg, 86%) as a white solid; R.sub.f=0.24 (50% EtOAc/cyclohexane); [?].sub.D.sup.20=+294.1 (c=0.97, CHCl.sub.3); .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.96 (t, J=7.3 Hz, 3H), 1.09 (d, J=6.8 Hz, 3H), 1.31 (m, 1H), 1.77 (m, 1H), 1.82 (m, 2H), 2.10 (m, 2H), 2.35 (m, 2H), 2.41 (s, 3H), 2.64 (m, 1H), 4.96 (m, 1H), 5.00 (m, 2H), 5.69 (d, J=11.3 Hz, 1H), 5.76 (m, 1H), 7.12 (s, 1H), 7.27-7.59 (m, 9H), 7.76 (m, 1H), 7.78 (d, J=7.8 Hz, 2H); .sup.13C NMR (100 MHZ, CDCl.sub.3) ? ppm 10.8 (CH.sub.3), 16.1 (CH.sub.3), 18.3 (CH.sub.2), 24.0 (CH.sub.3), 24.7 (CH.sub.2), 33.2 (CH.sub.2), 37.0 (CH.sub.2), 40.9 (CH), 60.6 (CH), 63.5 (CH), 115.6 (CH.sub.2), 117.8 (CH), 120.3 (2?CH), 125.8 (2?CH), 127.4 (2?CH), 127.5 (C), 127.9 (CH), 128.6 (CH), 128.7 (CH), 128.9 (C), 129.0 (2?CH), 130.1 (C), 130.4 (CH), 134.9 (C), 138.0 (CH), 138.1 (C), 138.4 (C), 149.0 (C), 170.2 (C), 171.5 (C); LRMS (ESI+) m/z (%) 570 (100) 548 (10) [M+H].sup.+; HRMS (ESI+) m/z calc. for C.sub.34H.sub.37N.sub.5O.sub.2Na 570.2845, found 570.2842.
N-(4-((2S,3R,4S)-1-acetyl-2-ethyl-3-methyl-4-(4-pentyl-1H-1,2,3-triazol-1-yl)-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)hex-5-enamide (XE)
[0215] ##STR00077##
[0216] From XC (100.0 mg, 0.22 mmol), 1-heptyne (43.0 mg, 0.45 mmol), Amberlyst CuI.Math.Et.sub.3N (40.0 mg), CH.sub.2Cl.sub.2 (1 mL), and using the method B, the product was obtained after flash chromatography (silica gel 30% to 50% EtOAc/cyclohexane) to give XE (87.0 mg, 71.5%); R.sub.f=0.25 (50% EtOAc/cyclohexane); [?].sub.D.sup.20=+234.6 (c=0.68, CHCl.sub.3); .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.84 (t, J=6.8 Hz, 3H), 0.95 (t, J=7.6 Hz, 3H), 1.05 (d, J=6.8 Hz, 3H), 1.25-1.35 (m, 5H), 1.64 (m, 2H), 1.73 (m, 1H), 1.84 (m, 2H), 2.14 (m, 2H), 2.38 (m, 2H), 2.39 (s, 3H), 2.56 (m, 1H), 2.68 (m, 2H), 4.95-5.07 (m, 3H), 5.61 (d, J=11.3 Hz, 1H), 5.79 (m, 1H), 7.05 (s, 1H), 7.15 (s, 1H), 7.17 (m, 1H), 7.35 (d, J=8.5 Hz, 2H), 7.50 (dd, J=8.4, 2.0 Hz, 1H), 7.56 (d, J=8.5 Hz, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 10.8 (CH.sub.3), 14.1 (CH.sub.3), 16.1 (CH.sub.3), 18.2 (CH.sub.2), 22.5 (CH.sub.2), 23.9 (CH.sub.3), 24.7 (CH.sub.2), 26.0 (CH.sub.2), 29.1 (CH.sub.2), 31.6 (CH.sub.2), 33.3 (CH.sub.2), 37.0 (CH.sub.2), 40.8 (CH), 58.2 (CH), 63.2 (CH), 115.6 (CH.sub.2), 118.7 (CH), 120.3 (2?CH), 126.3 (CH), 127.3 (CH), 127.4 (3?CH), 127.7 (C), 135.1 (C), 138.0 (CH, C), 138.1 (C), 138.3 (C), 149.9 (C), 170.2 (C), 171.5 (C); LRMS (ESI+) m/z (%) 564 (100) 542 (40) [M+H].sup.+; HRMS (ESI+) m/z calc. for C.sub.33H.sub.44N.sub.5O.sub.2 542.3495, found 542.3489.
Methyl (2S,3R,4S)-1-acetyl-2-ethyl-3-methyl-4-(4-pentyl-1H-1,2,3-triazol-1-yl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (XF)
[0217] ##STR00078##
[0218] From 27 (100.0 mg, 0.32 mmol), 1-heptyne (61.0 mg, 0.63 mmol), Amberlyst CuI.Math.Et.sub.3N (40.0 mg), CH.sub.2Cl.sub.2 (1 mL), and using the method B, the product was obtained after flash chromatography (silica gel, 30% EtOAc/cyclohexane) to give XF (98.0 mg, 75%); R.sub.f=0.10 (30% EtOAc/cyclohexane); [?].sub.D.sup.20=+219.7 (c=0.76, CHCl.sub.3); .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.88 (t, J=7.4 Hz, 3H), 0.93 (t, J=7.2 Hz, 3H), 1.04 (d, J=6.8 Hz, 3H), 1.24 (m, 1H), 1.28-1.36 (m, 4H), 1.66 (m, 2H), 1.73 (m, 1H), 2.38 (s, 3H), 2.57 (m, 1H), 2.71 (t, J=7.6 Hz, 2H), 3.83 (s, 3H), 4.69 (bs, 1H), 5.57 (d, J=11.3 Hz, 1H), 7.14 (s, 1H), 7.49 (s, 1H), 7.57 (d, J=2.1 Hz, 1H), 7.97 (d, J=8.5, 2.1 Hz, 1H); .sup.13C NMR (125 MHz, CDCl.sub.3) ? ppm 10.8 (CH.sub.3), 14.1 (CH.sub.3), 16.1 (CH.sub.3), 18.4 (CH.sub.2), 22.5 (CH.sub.2), 24.0 (CH.sub.3), 26.0 (CH.sub.2), 29.0 (CH.sub.2), 31.6 (CH.sub.2), 40.4 (CH), 52.4 (CH.sub.3), 59.5 (CH), 62.8 (CH), 118.9 (CH), 125.8 (CH), 127.2 (C), 127.6 (C), 130.0 (CH), 130.1 (CH), 140.5 (C), 149.8 (C), 165.9 (C), 170.1 (C); LRMS (ESI+) m/z (%) 274 (100) 413 (55) [M+H].sup.+; HRMS (ESI+) m/z calc. for C.sub.23H.sub.33N.sub.4O.sub.3 413.2553, found 413.2551.
N-(4-((2S,3S,4S)-1-acetyl-4-amino-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)hex-5-enamide (XG)
[0219] ##STR00079##
[0220] To a solution of XC (300.0 mg, 0.67 mmol) in methanol (6 mL) were added Et.sub.3N (0.47 mL, 3.37 mmol) and 1,3-propanedithiol (0.34 mL, 3.37 mmol) at rt. The reaction mixture was added at this temperature for 24 h. After completion, the reaction was diluted in methanol and H.sub.2O, acidified by HCl 1 M, washed with ether. The organic layer was basified with NaOH 1 M, extracted by EtOAc four times, dried by MgSO.sub.4, filtered off and concentrated under vacuum. The product XG was obtained (240.9 mg, 85%) as a yellow solid; R.sub.f=0.24 (4% MeOH/CH.sub.2Cl.sub.2; .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.75-0.85 (t, J=7.3 Hz, 3H), 1.09 (m, 1H), 1.18 (d, J=6.9 Hz, 3H), 1.55 (m, 1H), 1.83 (m, 2H), 2.14 (m, 2H), 2.29 (s, 3H), 2.39 (m, 2H), 2.86 (m, 1H), 3.68 (d, J=10.0 Hz, 1H), 4.78 (m, 1H), 5.00 (m, 1H), 5.04 (m, 1H), 5.81 (m, 1H), 7.21 (m, 1H), 7.40 (d, J=2.0 Hz, 1H) 7.48-7.64 (m, 4H), 7.73 (m, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 10.7 (CH.sub.3), 16.8 (CH.sub.3), 18.2 (CH.sub.2), 23.7 (CH.sub.3), 24.8 (CH.sub.2), 33.3 (CH.sub.2), 36.9 (CH.sub.2), 42.1 (CH), 53.9 (CH), 58.4 (CH), 115.5 (CH.sub.2), 120.4 (2?CH), 125.7 (CH), 126.9 (CH), 127.3 (3?CH, C), 135.6 (C), 137.8 (C), 137.9 (2?C), 138.0 (CH), 170.3 (C), 171.9 (C); LRMS (ESI?) m/z (%) 454 (100) 418 (40) [M?H].sup.?; HRMS (ESI?) m/z calc. for C.sub.26H.sub.32N.sub.3O.sub.2 418.2495, found 418.2476.
Methyl-(2S,3S,4S)-1-acetyl-4-amino-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (XH)
[0221] ##STR00080##
[0222] To a solution of 27 (843.2 mg, 2.66 mmol) in ethanol (40 mL) was added Pd/C (290.0 mg, 2.66 mmol). The reaction mixture was stirred at rt under H.sub.2 for the night. The reaction was filtered off under celite, washed with ethanol and concentrated under vacuum. The product XH was isolated (744.5 mg, 96.2%); R.sub.f=0.33 (5% MeOH/CH.sub.2Cl.sub.2); .sup.1H NMR (400 MHz, CD.sub.3OD) ? ppm 0.82 (t, J=7.2 Hz, 3H), 1.01 (m, 1H), 1.30 (d, J=6.9 Hz, 3H), 1.68 (m, 1H), 2.31 (m, 1H), 2.34, (s, 3H), 3.93 (s, 3H), 4.31 (d, J=9.5 Hz, 1H), 4.66 (m, 1H), 7.64 (d, J=8.3 Hz, 1H), 8.04 (d, J=8.3, 1.6 Hz, 1H), 8.27 (d, J=1.6 Hz, 1H); .sup.13C NMR 6 ppm (100 MHz, CD.sub.3OD) 10.5 (CH.sub.3), 16.4 (CH.sub.3), 19.2 (CH.sub.2), 23.5 (CH.sub.3), 39.5 (CH), 52.9 (CH.sub.3), 54.2 (2?CH), 127.8 (CH), 128.9 (C), 131.5 (2?CH), 132.7 (C), 142.3 (C), 167.2 (C), 172.4 (C); LRMS (ESI+) m/z (%) 232 (100); HRMS (ESI+) m/z calc. for C.sub.16H.sub.22N.sub.2O.sub.3Na 313.1528, found 313.1526
Isopropyl-((2S,3S,4S)-1-acetyl-2-ethyl-6-(4-(hex-5-enamido)phenyl)-3-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate (XI)
[0223] ##STR00081##
[0224] To a solution of XG (220.0 mg, 0.52 mmol) and DIPEA (0.27 mL, 1.57 mmol) in CH.sub.2Cl.sub.2 (6 mL) under N.sub.2 at rt was added isopropyl chloroformate 2 M in toluene (0.39 mL, 0.79 mmol). The reaction mixture was stirred at this temperature for 2 h. The reaction was concentrated under vacuum. EtOAc (11 mL) and H.sub.2O (4 mL) were added and the organic layer was washed with H.sub.2O (3 mL), with saturated aqueous solution of NaCl (1.5 mL), dried over MgSO.sub.4, filtered off and concentrated under vacuum. After flash chromatography (silica gel, 20% to 50% EtOAc/cyclohexane), the product XI (188.9 mg, 71%) was isolated as a white solid. R.sub.f=0.35 (50% EtOAc/cyclohexane); [?].sub.D.sup.20=+111.3 (c=1.02, CHCl.sub.3); .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.88 (t, J=7.2 Hz, 3H), 1.15 (d, J=6.8 Hz, 3H), 1.27 (d, J=6.4 Hz, 6H), 1.28 (m, 1H), 1.65 (m, 1H), 1.86 (m, 2H), 2.06 (m, 1H), 2.17 (m, 2H), 2.30 (s, 3H), 2.39 (t, J=7.5 Hz, 2H), 4.60 (m, 1H), 4.72 (m, 1H), 4.94-5.11 (m, 3H), 5.82 (ddt, J=16.9, 10.2, 6.7 Hz, 1H), 7.21 (m, 1H), 7.43 (dd, J=8.3, 2.1 Hz, 1H), 7.51 (d, J=8.5 Hz, 2H), 7.56 (m, 1H), 7.58 (d, J=8.5 Hz, 2H); .sup.13C NMR (100 MHz, CD.sub.3OD) ? ppm 11.1 (CH.sub.3), 16.6 (CH.sub.3), 19.0 (CH.sub.2), 22.6 (2?CH.sub.3), 23.7 (CH.sub.3), 26.2 (CH.sub.2), 34.5 (CH.sub.2), 37.5 (CH.sub.2), 40.6 (CH), 54.2 (2?CH), 69.7 (CH), 115.9 (CH.sub.2), 121.6 (2?CH), 126.7 (CH), 127.3 (C), 127.5 (CH), 128.1 (3?CH), 137.0 (C), 139.2 (CH, C), 139.6 (2?C), 159.8 (C), 172.9 (C), 174.5 (C); LRMS (ESI+) m/z (%) 528 (100) 506 (10) [M+H].sup.+; HRMS (ESI+) m/z calc. for C.sub.30H.sub.39N.sub.3O.sub.4Na 528.2838, found 528.2839.
Methyl-(2S,3S,4S)-1-acetyl-2-ethyl-4-((isopropoxycarbonyl)amino)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (XJ)
[0225] ##STR00082##
[0226] Chemical formula: C.sub.20H.sub.28N.sub.2O.sub.5
[0227] Molecular weight: 376.45
[0228] To a solution of XH (70.0 mg, 0.24 mmol) and DIPEA (0.12 mL, 0.70 mmol) in CH.sub.2Cl.sub.2 (2 mL) under N.sub.2 at rt was added isopropyl chloroformate 2 M in toluene (0.18 mL, 0.36 mmol). The reaction mixture was stirred at this temperature for 24 h. The reaction was concentrated under vacuum. EtOAc (8 mL) and H.sub.2O (4 mL) were added and the organic layer was washed with H.sub.2O (3 mL), with saturated aqueous solution of NaCl (1.5 mL), dried over MgSO.sub.4, filtered off and concentrated under vacuum. The product was obtained after flash chromatography (silica gel, 20% to 30% EtOAc/cyclohexane) to give XJ (70.9 mg, 78%); R.sub.f=0.37 (50% EtOAc/cyclohexane); .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.87 (t, J=7.3 Hz, 3H), 1.13 (m, 1H), 1.14 (d, J=6.9 Hz, 3H), 1.27 (d, J=6.2 Hz, 3H), 1.31 (d, J=6.2 Hz, 3H), 1.65 (m, 1H), 2.07 (m, 1H), 2.28 (s, 3H), 3.89 (s, 3H), 4.62 (m, 1H), 4.81 (t, J=9.9 Hz, 1H), 5.0 (m, 1H), 7.34 (m, 1H), 7.89 (dd, J=8.5, 2.0 Hz, 1H), 8.05 (d, J=2.0 Hz, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 10.9 (CH.sub.3), 16.4 (CH.sub.3), 18.4 (CH.sub.2), 22.3 (2?CH.sub.3), 24.2 (CH.sub.3), 40.5 (CH), 52.4 (CH.sub.3), 52.8 (2?CH), 69.0 (CH), 125.4 (C), 127.2 (CH), 129.0 (CH), 130.6 (CH, C), 140.5 (C), 157.2 (C), 166.5 (C), 170.2 (C); LRMS (ESI+) m/z (%) 399 (100) 377 (10) [M+H].sup.+; HRMS (ESI+) m/z calc. for C.sub.20H.sub.29N.sub.2O.sub.5 377.2076, found 377.2069.
N-(4-((2S,3S,4S)-1-acetyl-4-((5-chloropyrimidin-2-yl)amino)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)hex-5-enamide (XK)
[0229] ##STR00083##
[0230] To a solution of XG (30.5 mg, 0.073 mmol) and 2,5-dichloropyrimidine (22.0 mg, 0.145 mmol) in DMSO (0.4 mL) was added DIPEA (28.0 mg, 0.218 mmol). The reaction mixture was stirred under microware at 160? C. for 1 h30. After cooling to rt EtOAc and H.sub.2O were added. The reaction was extracted by EtOAc, the organic layer was dried by MgSO.sub.4, filtered off and concentrated under vacuum. After flash chromatography (silica gel, 20% to 50% EtOAc/cyclohexane), the product XK was obtained (15.0 mg, 38.7%); R.sub.f=0.36 (50% EtOAc/cyclohexane); .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.91 (t, J=7.2 Hz, 3H), 1.11 (d, J=6.9 Hz, 3H), 1.29 (m, 1H), 1.70 (m, 1H), 1.85 (m, 2H), 2.16 (m, 2H), 2.25 (m, 1H), 2.33 (s, 3H), 2.37 (t, J=7.5 Hz, 2H), 4.86 (m, 1H), 5.01 (m, 1H), 5.05 (m, 1H), 5.15 (m, 1H), 5.81 (ddt, J=17.0, 10.0, 6.7 Hz, 1H), 7.29 (s, 1H), 7.39-7.44 (m, 3H), 7.48 (m, 1H), 7.54 (d, J=8.2 Hz, 2H), 8.18 (s, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 10.9 (CH.sub.3), 16.5 (CH.sub.2), 18.4 (CH.sub.2), 23.9 (CH.sub.3), 24.8 (CH.sub.2), 33.3 (CH.sub.2), 37.1 (CH.sub.2), 40.6 (CH), 53.4 (CH), 60.6 (CH), 115.8 (CH.sub.2), 119.5 (C), 120.3 (2?CH), 126.1 (CH), 126.7 (C), 127.6 (4?CH), 135.1 (C), 137.5 (C), 137.8 (C) 138.0 (CH, C), 156.5 (C), 161.3 (2?CH), 170.3 (C), 171.3 (C); LRMS (ESI+) m/z (%) 532 (100) [M+H].sup.+; HRMS (ESI+) m/z calc. for C.sub.30H.sub.35N.sub.5O.sub.2Cl 532.2479, found 532.2485.
Methyl (2S,3S,4S)-1-acetyl-4-((5-chloropyrimidin-2-yl)amino)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (XL)
[0231] ##STR00084##
[0232] To a solution of XH (100.0 mg, 0.34 mmol) and 2,5-dichloropyrimidine (103.0 mg, 0.69 mmol) in DMSO (1 mL) was added DIPEA (0.17, 1.0 mmol). The reaction mixture was stirred under microware at 160? C. for 1 h30. After cooling to rt EtOAc and H.sub.2O were added. The reaction was extracted by EtOAc, the organic layer was dried by MgSO.sub.4, filtered off and concentrated under vacuum. The product was obtained after flash chromatography (silica gel, 30% to 50% EtOAc/cyclohexane) to give XL (13.5 mg, 10%); R.sub.f=0.36 (50% EtOAc/cyclohexane); .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.89 (t, J=7.3 Hz, 3H), 1.10 (d, J=6.9 Hz, 3H), 1.21 (m, 1H), 1.69 (m, 1H), 2.27 (m, 1H), 2.31 (s, 3H), 3.85 (s, 3H), 4.64 (m, 1H), 5.51 (d, J=9.7 Hz, 1H), 7.34 (s, 1H), 7.89 (dd, J=8.5, 2.1 Hz, 1H), 7.99 (d, J=2.1 Hz, 1H), 8.20 (s, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 10.8 (CH.sub.3), 16.4 (CH.sub.3), 18.5 (CH.sub.2), 23.9 (CH.sub.3), 39.9 (CH), 52.3 (CH.sub.3), 53.1 (CH), 60.5 (CH), 119.7 (CH, C), 125.4 (C), 127.1 (C), 128.8 (CH), 130.2 (CH), 140.8 (C), 156.5 (2?CH), 161.1 (C), 166.5 (C), 170.2 (C); LRMS (ESI+) m/z (%) 232 (100) 403 (45) [M+H].sup.+; HRMS (ESI+) m/z calc. for C.sub.20H.sub.24N.sub.4O.sub.3Cl 403.1537, found 403.1534.
Methyl (2S,3R,4S)-1-acetyl-2-ethyl-4-(4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (XM)
[0233] ##STR00085##
[0234] From 27 (106.0 mg, 0.33 mmol), 4-ethynylanisole (89.0 mg, 0.67 mmol), Amberlyst CuI.Math.Et.sub.3N (10.0 mg), CH.sub.2Cl.sub.2 (0.4 mL), and using the method B, the product was obtained after flash chromatography (silica gel, 40% EtOAc/cyclohexane) to give XM (118.0 mg, 78.4%); R.sub.f=0.25 (40% EtOAc/cyclohexane); [?].sub.D.sup.20=+146.6 (c=1.05, CHCl.sub.3); .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.95 (t, J=7.2 Hz, 3H), 1.08 (d, J=6.8 Hz, 3H), 1.25 (m, 1H), 1.76 (m, 1H), 2.40 (s, 3H), 2.66 (m, 1H), 3.80 (s, 3H), 3.82 (s, 3H), 4.70 (m, 1H), 5.64 (d, J=11.2 Hz, 1H), 6.93 (d, J=8.8 Hz, 2H), 7.55 (m, 1H), 7.62 (s, 1H), 7.64 (s, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.98 (dd, J=8.5, 2.0 Hz, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 10.7 (CH.sub.3), 16.0 (CH.sub.3), 18.4 (CH.sub.2), 24.0 (CH.sub.3), 40.4 (CH), 52.3 (CH.sub.3), 55.4 (CH.sub.3), 60.5 (CH), 62.9 (CH), 114.4 (2?CH), 117.1 (CH), 123.1 (CH), 125.8 (CH), 126.9 (C), 127.1 (2?CH), 127.5 (C), 130.0 (CH), 130.1 (CH), 140.5 (C), 148.7 (C), 159.9 (C), 165.8 (C), 170.1 (C); LRMS (ESI+) m/z (%) 449 (100) [M+H].sup.+; HRMS (ESI+) m/z calc. for C.sub.25H.sub.29N.sub.4O.sub.4 449.2189, found 449.2190.
Methyl (2S,3R,4S)-1-acetyl-2-ethyl-3-methyl-4-(4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-1-yl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (XN)
[0235] ##STR00086##
[0236] From 27 (110.0 mg, 0.35 mmol), 1-ethynyl-4-(trifluoromethyl)benzene (118.0 mg, 0.70 mmol), Amberlyst CuI.Math.Et.sub.3N (10.0 mg), CH.sub.2Cl.sub.2 (0.4 mL), and using the method B, the product was obtained after flash chromatography (silica gel, 30% EtOAc/cyclohexane) to give XN (123.0 mg, 73%); R.sub.f=0.15 (30% EtOAc/cyclohexane); [?].sub.D.sup.20=+123.3 (c=1.23, CHCl.sub.3); .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.96 (t, J=7.2 Hz, 3H), 1.11 (d, J=6.8 Hz, 3H), 1.26 (m, 1H), 1.78 (m, 1H), 2.41 (s, 3H), 2.67 (m, 1H), 3.81 (s, 3H), 4.70 (m, 1H), 5.68 (d, J=11.3 Hz, 1H), 7.51 (m, 1H), 7.64 (d, J=2.0 Hz, 1H), 7.66 (d, J=8.2 Hz, 2H), 7.78 (s, 1H), 7.94 (d, J=8.2 Hz, 2H), 8.00 (dd, J=8.6, 2.0 Hz, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 10.7 (CH.sub.3), 16.1 (CH.sub.3), 18.5 (CH.sub.2), 24.0 (CH.sub.3), 40.7 (CH), 52.4 (CH.sub.3), 59.6 (CH), 63.3 (CH), 118.8 (CH), 124.2 (CF.sub.3, q, J=272 Hz), 125.9 (2?CH, q, J=4 Hz), 126.0 (2?CH), 126.7 (2?C), 127.7 (C), 130.0 (CH), 130.2 (CH), 130.3 (C, q, J=32 Hz), 133.9 (C), 140.6 (C), 147.6 (C), 165.8 (C), 170.1 (C); LRMS (ESI+) m/z (%) 487 (100) [M+H].sup.+; HRMS (ESI+) m/z calc. for C.sub.25H.sub.26N.sub.4O.sub.3F.sub.3 487.1957, found 487.1959.
Methyl-(2S,3R,4S)-1-acetyl-4-(4-cyclohexyl-1H-1,2,3-triazol-1-yl)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (XO)
[0237] ##STR00087##
[0238] From 27 (67.5 mg, 0.21 mmol), cyclohexylacetylene (46.0 mg, 0.43 mmol), Amberlyst CuI.Math.Et.sub.3N (10.0 mg), CH.sub.2Cl.sub.2 (0.4 mL), and using the method B, the product was obtained after flash chromatography (silica gel, 30% EtOAc/cyclohexane) to give XO (67.0 mg, 74%); R.sub.f=0.16 (30% EtOAc/cyclohexane); [?].sub.D.sup.20=+158.6 (c=1.20, CHCl.sub.3); .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.93 (t, J=7.2 Hz, 3H), 1.03 (d, J=6.8 Hz, 3H), 1.16-1.45 (m, 5H), 1.66-1.86 (m, 5H), 2.05 (m, 2H), 2.38 (s, 3H), 2.57 (m, 1H), 2.75 (m, 1H), 3.8 (s, 3H), 4.68 (s, 1H), 5.56 (d, J=11.3 Hz, 1H), 7.10 (s, 1H), 7.48 (m, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.97 (dd, J=8.6, 2.0 Hz, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 10.8 (CH.sub.3), 16.1 (CH.sub.3), 18.5 (CH.sub.2), 24.0 (CH.sub.3), 26.2 (CH.sub.2), 26.3 (CH.sub.2), 27.1 (CH.sub.2), 33.0 (CH.sub.2), 33.1 (CH.sub.2), 35.6 (CH), 40.5 (CH), 52.4 (CH.sub.3), 59.9 (CH), 62.8 (CH), 117.5 (CH), 125.8 (CH), 127.3 (C), 127.6 (C), 130.1 (C), 130.2 (C), 140.5 (C), 155.1 (C), 166.0 (C), 170.1 (C); LRMS (ESI+) m/z (%) 425 (100) [M+H].sup.+; HRMS (ESI+) m/z calc. for C.sub.24H.sub.33N.sub.4O.sub.3 425.2533, found 425.2562.
Methyl-(2S,3R,4S)-1-acetyl-2-ethyl-3-methyl-4-(4-((2-(prop-2-yn-1-yloxy)ethoxy)methyl)-1H-1,2,3-triazol-1-yl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (XP)
[0239] ##STR00088##
Method C
[0240] To a stirred solution of 27 (100.0 mg, 0.32 mmol), 1,2-bis(prop-2-yn-1-yloxy)ethane (131.0 mg, 0.95 mmol) in 1:1 H.sub.2O/t-BuOH (4 mL) was added CuSO.sub.4.Math.5H.sub.2O (16.0 mg, 0.06 mmol), and sodium ascorbate (63.0 mg, 0.22 mmol) and the mixture was stirred under argon at rt for 48 h. The product was extracted with EtOAc, dried (MgSO.sub.4) and the solvent was removed in vacuum. The product was obtained after flash chromatography (silica gel, 100% EtOAc) to give XP (70.2 mg, 49%); R.sub.f=0.44 (80% EtOAc/cyclohexane); .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.92 (t, J=7.2 Hz, 3H), 1.05 (d, J=6.8 Hz, 3H), 1.22 (m, 1H), 1.73 (m, 1H), 2.38 (s, 3H), 2.42 (t, J=2.4 Hz, 1H), 2.59 (m, 1H), 3.68-3.75 (m, 4H), 3.84 (s, 3H), 4.17 (d, J=2.4 Hz, 2H), 4.71 (m, 3H), 5.59 (d, J=11.3 Hz, 1H), 7.46 (s, 1H), 7.48 (m, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.97 (dd, J=8.6, 2.0 Hz, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 10.7 (CH.sub.3), 16.1 (CH.sub.3), 18.4 (CH.sub.2), 24.0 (CH.sub.3), 40.5 (CH), 52.4 (CH.sub.3), 58.6 (CH.sub.2), 59.3 (CH), 63.1 (CH), 65.1 (CH.sub.2), 69.1 (CH.sub.2), 70.0 (CH.sub.2), 74.8 (CH), 79.7 (C), 120.9 (CH), 125.8 (CH), 127.0 (C), 127.6 (C), 130.1 (CH), 130.2 (CH), 140.6 (C), 146.6 (C), 165.9 (C), 170.1 (C); LRMS (ESI+) m/z (%) 455 (100) [M+H].sup.+; HRMS (ESI+) m/z calc. for C.sub.24H.sub.31N.sub.4O.sub.5 455.2289, found 455.2282.
Dimethyl 4,4-((((oxybis(ethane-2,1-diyl))bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))(2S,2'S,3R,3R,4S,4'S)-bis(1-acetyl-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate) (XQ)
[0241] ##STR00089##
[0242] From 27 (100.0 mg, 0.32 mmol), 3-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)prop-1-yne (173.0 mg, 0.95 mmol), 1:1 H.sub.2O/t-BuOH (4 mL), CuSO.sub.4.Math.5H.sub.2O (16.0 mg, 0.06 mmol), and sodium ascorbate (63.0 mg, 0.22 mmol) and using method C, the product was obtained after flash chromatography (silica gel, 100% EtOAc) to give XQ (69.5 mg, 44%); R.sub.f=0.44 (4% MeOH/CH.sub.2Cl.sub.2); [?].sub.D.sup.20=+97.8 (c=0.92, CHCl.sub.3); IR v.sub.max (thin film, CH.sub.2Cl.sub.2) 3421, 2963, 2879, 2372, 2094, 1719, 1664, 1260 cm.sup.?1; .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.92 (t, J=7.2 Hz, 3H), 1.04 (d, J=6.8 Hz, 3H), 1.22 (m, 1H), 1.73 (m, 1H), 2.38 (s, 3H), 2.41 (t, J=2.4 Hz, 1H), 2.59 (m, 1H), 3.60-3.77 (m, 8H), 3.84 (s, 3H), 4.17 (d, J=2.4 Hz, 2H), 4.71 (m, 3H), 5.59 (d, J=11.2 Hz, 1H), 7.44 (m, 1H), 7.46 (s, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.97 (d, J=8.5, 2.0 Hz, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 10.7 (CH.sub.3), 16.1 (CH.sub.3), 18.4 (CH.sub.2), 24.0 (CH.sub.3), 40.4 (CH), 52.4 (CH.sub.3), 58.5 (CH.sub.2), 59.4 (CH), 63.1 (CH), 65.1 (CH.sub.2), 69.2 (CH.sub.2), 70.1 (CH.sub.2), 70.5 (CH.sub.2), 70.7 (CH.sub.2), 74.7 (CH), 79.8 (C), 121.0 (CH), 125.8 (CH), 127.0 (C), 127.6 (C), 130.1 (CH), 130.2 (C), 140.6 (C), 146.6 (C), 165.9 (C), 170.1 (C); LRMS (ESI+) m/z (%) 521.2 (100) [M+Na].sup.+, 499 (60) [M+H].sup.+; HRMS (ESI+) m/z calc. for C.sub.26H.sub.35N.sub.4O.sub.6 499.2551, found 499.2548.
Methyl-(2S,3R,4S)-4-(4-(2,5,8,11-tetraoxatetradec-13-yn-1-yl)-1H-1,2,3-triazol-1-yl)-1-acetyl-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (XR)
[0243] ##STR00090##
[0244] From 27 (100.0 mg, 0.32 mmol), 4,7,10,13-tetraoxahexadeca-1,15-diyne (219.0 mg, 0.95 mmol), 1:1 H.sub.2O/t-BuOH (4 mL), CuSO.sub.4.Math.5H.sub.2O (16.0 mg, 0.06 mmol), and sodium ascorbate (63.0 mg, 0.22 mmol) and using method C, the product was obtained after flash chromatography (silica, 100% EtOAc) to give XR (72.7 mg, 42%); R.sub.f=0.31 (4% MeOH/CH.sub.2Cl.sub.2); [?].sub.D.sup.20=+195.7 (c=0.44, CHCl.sub.3); .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.92 (t, J=7.2 Hz, 3H), 1.04 (d, J=6.8 Hz, 3H), 1.22 (m, 1H), 1.73 (m, 1H), 2.38 (s, 3H), 2.42 (t, J=2.4 Hz, 1H), 2.60 (m, 1H), 3.63-3.72 (m, 12H), 3.84 (s, 3H), 4.18 (d, J=2.4 Hz, 2H), 4.70 (m, 3H), 5.58 (d, J=11.3 Hz, 1H), 7.47 (m, 2H), 7.57 (d, J=2.0 Hz, 1H), 7.97 (d, J=8.6, 2.0 Hz, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 10.7 (CH.sub.3), 16.1 (CH.sub.3), 18.4 (CH.sub.2), 24.0 (CH.sub.3), 40.4 (CH), 52.4 (CH.sub.3), 58.5 (CH.sub.2), 59.4 (CH), 63.1 (CH), 65.1 (CH.sub.2), 69.2 (CH.sub.2), 70.1 (CH.sub.2), 70.5 (CH.sub.2), 70.7 (2?CH.sub.2), 70.8 (CH.sub.2), 74.7 (CH), 79.8 (C), 121.0 (CH), 125.8 (CH), 127.0 (C), 127.6 (C), 130.1 (CH), 130.2 (C), 140.6 (C), 146.6 (C), 165.9 (C), 170.1 (C); LRMS (ESI+) m/z (%) 566 (100) [M+Na].sup.+, 543 (80) [M+H].sup.+; HRMS (ESI+) m/z calc. for C.sub.28H.sub.39N.sub.4O.sub.7 543.2813, found 543.2808.
Methyl-(2S,3R,4S)-4-(4-(2,5,8,11,14-pentaoxaheptadec-16-yn-1-yl)-1H-1,2,3-triazol-1-yl)-1-acetyl-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (XS)
[0245] ##STR00091##
[0246] From 27 (100.0 mg, 0.32 mmol), 3,6,9,12,15-pentaoxaoctadec-1,17-diyne (256.0 mg, 0.95 mmol), 1:1 H.sub.2O/t-BuOH (4 mL), CuSO.sub.4.Math.5H.sub.2O (16.0 mg, 0.06 mmol), and sodium ascorbate (63.0 mg, 0.22 mmol) and using method C, the product was obtained after flash chromatography (silica, 100% EtOAc) to give XS (79.2 mg, 43%); R.sub.f=0.29 (4% MeOH/CH.sub.2Cl.sub.2); [?].sub.D.sup.20=+251.6 (c=1.11, CHCl.sub.3); .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.92 (t, J=7.2 Hz, 3H), 1.05 (d, J=6.8 Hz, 3H), 1.22 (m, 1H), 1.73 (m, 1H), 2.38 (s, 3H), 2.43 (t, J=2.4 Hz, 1H), 2.59 (m, 1H), 3.59-3.73 (m, 16H), 3.84 (s, 3H), 4.19 (d, J=2.4 Hz, 2H), 4.70 (m, 3H), 5.59 (d, J=11.3 Hz, 1H), 7.46 (m, 2H), 7.57 (d, J=2.0 Hz, 1H), 7.97 (d, J=8.6, 2.0 Hz, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 10.7 (CH.sub.3), 16.1 (CH.sub.3), 18.4 (CH.sub.2), 24.0 (CH.sub.3), 40.5 (CH), 52.4 (CH.sub.3), 58.6 (CH.sub.2), 59.2 (CH), 63.1 (CH), 65.1 (CH.sub.2), 69.3 (CH.sub.2), 70.2 (CH.sub.2), 70.6 (CH.sub.2), 70.7 (3?CH.sub.2), 70.8 (2?CH.sub.2), 74.7 (CH), 79.8 (C), 120.9 (CH), 125.8 (CH), 127.0 (C), 127.6 (C), 130.1 (CH), 130.2 (CH), 140.6 (C), 146.6 (C), 165.9 (C), 170.1 (C); LRMS (ESI+) m/z (%) 609 (100) [M+Na].sup.+, 587 (50) [M+H].sup.+; HRMS (ESI+) m/z calc. for C.sub.30H.sub.43O.sub.8N.sub.4 587.3075, found 587.3059.
Methyl-(2S,3R,4S)-4-(4-(2,5,8,11,14,17-hexaoxaicos-19-yn-1-yl)-1H-1,2,3-triazol-1-yl)-1-acetyl-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (XT)
[0247] ##STR00092##
[0248] From 27 (100.0 mg, 0.32 mmol), 4,7,10,13,16,19-hexaoxadocosa-1,21-diyne (298.0 mg, 0.95 mmol), 1:1 H.sub.2O/t-BuOH (4 mL), CuSO.sub.4.Math.5H.sub.2O (16.0 mg, 0.06 mmol), and sodium ascorbate (63.0 mg, 0.22 mmol) and using method C, the product was obtained after flash chromatography (silica, 100% EtOAc, then 100% CH.sub.2Cl.sub.2 and then gradient from 1 to 4% MeOH in CH.sub.2Cl.sub.2) to give XT (90.0 mg, 45%); R.sub.f=0.29 (4% MeOH/CH.sub.2Cl.sub.2); .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.92 (t, J=7.2 Hz, 3H), 1.04 (d, J=6.8 Hz, 3H), 1.22 (m, 1H), 1.74 (m, 1H), 2.38 (s, 3H), 2.43 (t, J=2.4 Hz, 1H), 2.59 (m, 1H), 3.58-3.74 (m, 20H), 3.84 (s, 3H), 4.20 (d, J=2.4 Hz, 2H), 4.70 (m, 3H), 5.58 (d, J=11.3 Hz, 1H), 7.46 (m, 2H), 7.57 (d, J=2.0 Hz, 1H), 7.97 (d, J=8.6, 2.0 Hz, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 10.7 (CH.sub.3), 16.1 (CH.sub.3), 18.4 (CH.sub.2), 24.0 (CH.sub.3), 40.4 (CH), 52.4 (CH.sub.3), 58.6 (CH.sub.2), 59.3 (CH), 63.2 (CH), 65.0 (CH.sub.2), 69.3 (CH.sub.2), 70.2 (CH.sub.2), 70.5 (3?CH.sub.2), 70.7 (3?CH.sub.2), 70.8 (2?CH.sub.2), 74.7 (CH), 79.8 (C), 121.2 (CH), 125.8 (CH), 127.0 (C), 127.6 (C), 130.1 (CH), 130.3 (CH), 140.5 (C), 146.4 (C), 165.9 (C), 170.2 (C); LRMS (ESI+) m/z (%) 653 (100) [M+Na].sup.+, 631 (55) [M+H].sup.+; HRMS (ESI+) m/z calc. for C.sub.32H.sub.47ON.sub.4 631.3338, found 631.3327.
Dimethyl-4,4-(((ethane-1,2-diylbis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))(2S,2'S,3R,3R,4S,4'S)-bis(1-acetyl-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate) (XU)
[0249] ##STR00093##
[0250] From 27 (69.6 mg, 0.22 mmol), 1,2-bis(prop-2-yn-1-yloxy)ethane (13.6 mg, 0.09 mmol), Amberlyst CuI.Math.Et.sub.3N (40.0 mg), CH.sub.2Cl.sub.2 (0.4 mL), and using the method B with stirring for 72 h, the product was obtained after flash chromatography (silica gel, 100% EtOAc) to give XU (36.8 mg, 54%); R.sub.f=0.37 (4% MeOH/CH.sub.2Cl.sub.2); [?].sub.D.sup.20=+190.9 (c=0.95, CHCl.sub.3); .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.92 (t, J=7.2 Hz, 6H), 1.03 (d, J=6.9 Hz, 6H), 1.23 (m, 2H), 1.74 (m, 2H), 2.38 (s, 6H), 2.61 (m, 2H), 3.70 (s, 4H), 3.82 (s, 6H), 4.67 (m, 6H), 5.59 (d, J=11.2 Hz, 2H), 7.47 (m, 2H), 7.49 (s, 2H), 7.55 (d, J=2.0 Hz, 2H), 7.96 (dd, J=8.5, 2.0 Hz, 2H); .sup.13C NMR (125 MHz, CDCl.sub.3) ? ppm 10.8 (2?CH.sub.3), 16.1 (2?CH.sub.3), 18.4 (2?CH.sub.2), 24.1 (2?CH.sub.3), 40.4 (2?CH), 52.4 (2?CH.sub.3), 59.3 (2?CH), 63.1 (2?CH), 65.1 (2?CH.sub.2), 70.1 (2?CH.sub.2), 121.1 (2?CH), 125.8 (2?CH), 127.0 (2?C), 127.6 (2?C), 130.1 (2?CH), 130.2 (2?CH), 140.6 (2?C), 146.4 (2?C), 165.9 (2?C), 170.1 (2?C); LRMS (ESI+) m/z (%) 793 (100) [M+Na].sup.+; HRMS (ESI+) m/z calc. for C.sub.40H.sub.51N.sub.8O.sub.8 [M+H].sup.+ 771.3824, found 771.3824.
Dimethyl-4,4-((((oxybis(ethane-2,1-diyl))bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))(2S,2'S,3R,3R,4S,4'S)-bis(1-acetyl-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate) (XV)
[0251] ##STR00094##
[0252] From 27 (100.0 mg, 0.32 mmol), 3-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)prop-1-yne (23.0 mg, 0.13 mmol), Amberlyst CuI.Math.Et.sub.3N (40.0 mg), CH.sub.2Cl.sub.2 (1 mL), and using the method B with stirring for 72 h, the product was obtained after flash chromatography (silica gel, 100% EtOAc, then 100% CH.sub.2Cl.sub.2 and then gradient from 1 to 4% MeOH in CH.sub.2Cl.sub.2) to give XV (39.3 mg, 38%); [?].sub.D.sup.20=+189.6 (c=0.94, CHCl.sub.3); .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.92 (t, J=7.3 Hz, 6H), 1.03 (d, J=6.8 Hz, 6H), 1.23 (m, 2H), 1.73 (m, 2H), 2.37 (s, 6H), 2.61 (m, 2H), 3.59-3.72 (m, 8H), 3.83 (s, 6H), 4.67 (m, 6H), 5.59 (d, J=11.3 Hz, 2H), 7.47 (m, 2H), 7.50 (s, 2H), 7.56 (d, J=2.0 Hz, 2H), 7.96 (dd, J=8.6, 2.0 Hz, 2H); .sup.13C NMR (125 MHz, CDCl.sub.3) ? ppm 10.7 (2?CH.sub.3), 16.1 (2?CH.sub.3), 18.4 (2?CH.sub.2), 24.0 (2?CH.sub.3), 40.4 (2?CH), 52.4 (2?CH.sub.3), 59.4 (2?CH), 63.1 (2?CH), 65.1 (2?CH.sub.2), 70.1 (2?CH.sub.2), 70.6 (2?CH.sub.2), 121.1 (2?CH), 125.8 (2?CH), 127.0 (2?C), 127.5 (2?C), 130.1 (2?CH), 130.2 (2?CH), 140.6 (2?C), 146.5 (2?C), 165.9 (2?C), 170.1 (2?C); HRMS (ESI+) m/z calc. for C.sub.42H.sub.54N.sub.8O.sub.9 [M+H].sup.+ 815.4087, found 815.4087.
Dimethyl-4,4-((2,5,8,11-tetraoxadodecane-1,12-diyl)bis(1H-1,2,3-triazole-4,1-diyl))(2S,2S,3R,3R,4S,4S)-bis(1-acetyl-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate) (XW)
[0253] ##STR00095##
[0254] From 27 (111.0 mg, 0.35 mmol), 4,7,10,13-tetraoxahexadeca-1,15-diyne (31.6 mg, 0.14 mmol), Amberlyst CuI.Math.Et.sub.3N (40.0 mg), CH.sub.2Cl.sub.2 (1 mL), and using the method B with stirring for 72 h, the product was obtained after flash chromatography (silica gel, 100% EtOAc, then 100% CH.sub.2Cl.sub.2 and then gradient from 1 to 4% MeOH in CH.sub.2Cl.sub.2) to give XW (45.1 mg, 38%); R.sub.f=0.24 (4% MeOH/CH.sub.2Cl.sub.2); .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.92 (t, J=7.2 Hz, 6H), 1.03 (d, J=6.8 Hz, 6H), 1.22 (m, 2H), 1.73 (m, 2H), 2.37 (s, 6H), 2.60 (m, 2H), 3.61-3.70 (m, 12H), 3.83 (s, 6H), 4.67 (m, 6H), 5.58 (d, J=11.3 Hz, 2H), 7.47 (m, 4H), 7.57 (d, J=2.0 Hz, 2H), 7.96 (dd, J=8.5, 2.0 Hz, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 10.7 (2?CH.sub.3), 16.1 (2?CH.sub.3), 18.4 (2?CH.sub.2), 24.0 (2?CH.sub.3), 40.4 (2?CH), 52.4 (2?CH.sub.3), 59.3 (2?CH), 63.2 (2?CH), 65.0 (2?CH.sub.2), 63.2 (2?CH.sub.2), 70.6 (4?CH.sub.2), 121.3 (2?CH), 125.8 (2?CH), 127.0 (2?C), 127.5 (2?C), 130.1 (2?CH), 130.2 (2?CH), 140.6 (2?C), 146.2 (2?C), 165.9 (2?C), 170.1 (2?C); LRMS (ESI+) m/z (%) 881 (100) [M+Na].sup.+, 859 (85) [M+H].sup.+; HRMS (ESI+) m/z calc. for C.sub.44H.sub.59N.sub.8O.sub.10 859.4349, found 859.4344.
Dimethyl-4,4-((2,5,8,11,14-pentaoxapentadecane-1,15-diyl)bis(1H-1,2,3-triazole-4,1-diyl))(2S,2'S,3R,3R,4S,4'S)-bis(1-acetyl-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate) (XX)
[0255] ##STR00096##
[0256] From 27 (51.6 mg, 0.19 mmol), 3,6,9,12,15-pentaoxaoctadec-1,17-diyne (20.5 mg, 0.08 mmol), Amberlyst CuI.Math.Et.sub.3N (33.0 mg), CH.sub.2Cl.sub.2 (0.4 mL), and using the method B with stirring for 72 h, the product was obtained after flash chromatography (silica gel, 100% EtOAc, then 100% CH.sub.2Cl.sub.2 and then gradient from 1 to 4% MeOH in CH.sub.2Cl.sub.2) to give a mixture of monomer and dimer. This mixture was purified by flash silica chromatography (silica gel, 6% MeOH/EtOAc) to give the desired product XX (42.7 mg, 62%); R.sub.f=0.19 (6% MeOH/EtOAc); [?].sub.D.sup.20=+130.3 (c=0.58, CHCl.sub.3); IR v.sub.max (thin film, CH.sub.2Cl.sub.2) 3420, 2962, 2875, 1717, 1661, 1610, 1259 cm.sup.?1; .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.92 (t, J=7.2 Hz, 6H), 1.04 (d, J=6.8 Hz, 6H), 1.23 (m, 2H), 1.72 (m, 2H), 2.38 (s, 6H), 2.59 (m, 2H), 3.57-3.72 (m, 16H), 3.83 (s, 6H), 4.68 (s, 6H), 5.58 (d, J=11.2 Hz, 2H), 7.46 (s, 4H), 7.57 (d, J=2.0 Hz, 2H), 7.96 (dd, J=8.5, 2.0 Hz, 2H); .sup.13C NMR (125 MHz, CDCl.sub.3) ? 10.8 (2?CH.sub.3), 16.2 (2?CH.sub.3), 18.5 (2?CH.sub.2), 24.1 (2?CH.sub.3), 40.5 (2?CH), 52.5 (2?CH.sub.3), 59.3 (2?CH), 63.1 (2?CH), 65.2 (2?CH.sub.2), 70.2 (2?CH.sub.2), 70.8 (6?CH.sub.2), 121.1 (2?CH), 125.8 (2?CH), 127.1 (2?C), 127.6 (2?C), 130.2 (2?CH), 130.2 (2?CH), 140.7 (2?C), 146.7 (2?C), 165.9 (2?C), 170.1 (2?C); LRMS (ESI+) m/z (%) 925 (100) [M+Na].sup.+; HRMS (ESI+) m/z calc. for C.sub.46H.sub.63N.sub.8O.sub.11 [M+H].sup.+, 903.4611, found 903.4611.
Dimethyl-4,4-((2,5,8,11,14,17-hexaoxaoctadecane-1,18-diyl)bis(1H-1,2,3-triazole-4,1-diyl))(2S,2'S,3R,3R,4S,4'S)-bis(1-acetyl-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate) (XY)
[0257] ##STR00097##
[0258] From 27 (71.9 mg, 0.23 mmol), 4,7,10,13,16,19-hexaoxadocosa-1,21-diyne (28.8 mg, 0.09 mmol), Amberlyst CuI.Math.Et.sub.3N (40.0 mg), CH.sub.2Cl.sub.2 (0.4 mL), and using the method B with stirring for 72 h, the product was obtained after flash chromatography (silica gel, 100% EtOAc, then 100% CH.sub.2Cl.sub.2 and then gradient from 1 to 4% MeOH in CH.sub.2Cl.sub.2) to give a mixture of monomer and dimer. This mixture was purified by flash silica chromatography (silica gel, 6 to 8% MeOH/EtOAc) to give the desired product XY (29.5 mg, 26%); R.sub.f=0.14 (4% MeOH/EtOAc); [?].sub.D.sup.20=+130.3 (c=0.58, CHCl.sub.3); .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.92 (t, J=7.2 Hz, 6H), 1.04 (d, J=6.8 Hz, 6H), 1.22 (m, 2H), 1.74 (m, 2H), 2.38 (s, 6H), 2.60 (m, 2H), 3.57-3.72 (m, 20H), 3.83 (s, 6H), 4.69 (s, 6H), 5.58 (d, J=11.2 Hz, 2H), 7.47 (s, 4H), 7.57 (d, J=2.0 Hz, 2H), 7.97 (dd, J=8.5, 2.0 Hz, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 10.7 (2?CH.sub.3), 16.1 (2?CH.sub.3), 18.4 (2?CH.sub.2), 24.0 (2?CH.sub.3), 40.5 (2?CH), 52.4 (2?CH.sub.3), 59.3 (2?CH), 63.1 (2?CH), 65.2 (2?CH.sub.2), 70.2 (2?CH.sub.2), 70.6 (2?CH.sub.2), 70.7 (4?CH.sub.2), 121.0 (2?CH), 125.8 (2?CH), 127.1 (2?C), 127.6 (2?C), 130.2 (2?CH), 130.2 (2?CH), 140.6 (2?C), 146.6 (2?C), 165.9 (2?C), 170.1 (2?C); LRMS (ESI+) m/z (%) 969 (100) [M+Na].sup.+; HRMS (ESI+) m/z calc. for C.sub.43H.sub.67N.sub.8O.sub.12 [M+H].sup.+ 947.4873, found 947.4873.
Methyl-(2S,3R,4S)-1-acetyl-4-(4-(14-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2,5,8,11-tetraoxatetradec-13-yn-1-yl)-1H-1,2,3-triazol-1-yl)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (YF)
[0259] ##STR00098##
[0260] To a solution of 3-(4-iodo-1-oxoisoindolin-2-yl)piperidine-2,6-dione.sup.[4] (11 mg, 0.02 mmol) and XR (9.5 mg, 0.257 mmol) in dry DMF (1 mL) were added Pd(PPhs).sub.2Cl.sub.2 (1.4 mg, 0.00197 mmol) and CuI (0.2 mg, 0.000985 mmol) in triethylamine (40 ?L). The mixture was degazed by argon and purged many times. The reaction was stirring at 80? C. for 6 h under Argon. After cooling at room temperature, the mixture was concentrated in vacuo. After flash chromatography (silica gel, 100% EtOAC, then EtOAc/MeOH (1-4%)), the product was isolated as a yellow oil (6.3 mg, 40%).
[0261] R.sub.f=0.30 (4% MeOH/CH2Cl.sub.2); .sup.1H NMR (400 MHz, CDCl.sub.3) b ppm 0.92 (t, J=7.2 Hz, 3H), 1.04 (m, 3H), 1.23 (m, 1H), 1.74 (m, 1H), 2.24 (m, 1H), 2.37 (s, 3H), 2.44 (m, 1H), 2.62 (m, 1H), 2.84 (m, 1H), 2.92 (m, 1H), 3.55-3.80 (m, 12H), 3.84 (s, 3H), 4.40 (d, J=16.7 Hz, 1H), 4.47 (s, 2H), 4.53 (dd, J=16.7, 6.0 Hz, 1H), 4.69 (bs, 2H), 4.71 (m, 1H), 5.23 (m, 1H), 5.59 (m, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.51 (m, 2H), 7.57 (d, J=1.9 Hz, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.84 (d, J=7.6 Hz, 1H), 7.96 (dd, J=7.6, 1.9 Hz, 1H); 13C NMR (100 MHz, CDCl.sub.3) b ppm 10.8 (CH3), 16.2 (CH3), 18.5 (CH2), 23.6 (CH2), 24.1 (CH3), 31.8 (CH2), 40.5 (CH), 47.3 (CH2), 52.1 (CH), 52.5 (CH3), 59.4 (CH.sub.2), 59.6 (CH), 63.2 (CH), 65.1 (CH.sub.2), 69.5 (CH.sub.2), 70.1 (CH.sub.2), 70.5 (2?CH.sub.2), 70.6 (CH.sub.2), 70.7 (CH.sub.2), 82.1 (C), 90.8 (C), 118.4 (C), 120.1 (CH), 124.4 (CH), 125.9 (CH), 127.0 (C), 127.6 (C), 128.7 (CH), 130.1 (CH), 130.2 (CH), 132.0 (CH), 135.0 (CH), 140.6 (C), 144.1 (C), 146.5 (C), 166.0 (C), 169.0 (C), 169.7 (C), 170.2 (C), 171.3 (C); LRMS (ESI+) m/z (%) 807 (100) [M+Na].sup.+, 785 (48) [M+H].sup.+; HRMS (ESI+) m/z calc. for C.sub.41H.sub.49N.sub.6O.sub.10 [M+H].sup.+ 785.3505, found 785.3502.
Methyl-(2S,3R,4S)-1-acetyl-4-(4-((2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop-2-yn-1-yl)oxy)ethoxy)methyl)-1H-1,2,3-triazol-1-yl)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (YE)
[0262] ##STR00099##
[0263] Using the same protocol as YF, 15.0 mg of compound YE was obtained (52%); R.sub.f=0.30 (4% MeOH/CH.sub.2Cl.sub.2); .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.92 (t, J=7.2 Hz, 3H), 1.04 (m, 3H), 1.22 (m, 1H), 1.72 (m, 1H), 2.23 (m, 1H), 2.37 (s, 3H), 2.48 (m, 1H), 2.57 (m, 1H), 2.85 (m, 1H), 2.95 (m, 1H), 3.65-3.79 (m, 4H), 3.83 (s, 3H), 4.41 (dd, J=16.8, 3.4 Hz, 1H), 4.43 (s, 2H), 4.54 (dd, J=16.8, 6.1 Hz, 1H), 4.67-4.72 (m, 3H), 5.24 (dt, J=13.3, 5.3 Hz, 1H), 5.59 (m, 1H), 7.44 (s, 1H), 7.46 (t, J=7.3 Hz, 1H), 7.48 (m, 1H), 7.57 (s, 1H), 7.61 (dd, J=7.6, 1.0 Hz, 1H), 7.85 (d, J=7.6 Hz, 1H), 7.96 (m, 1H)); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 10.6 (CH.sub.3), 15.9 (CH.sub.3), 18.2 (CH.sub.2), 23.4 (CH.sub.2), 23.8 (CH.sub.3), 31.6 (CH.sub.2), 40.4 (CH), 47.1 (CH.sub.2), 51.9 (CH), 52.3 (CH.sub.3), 59.1 (CH.sub.2), 59.3 (CH), 62.9 (CH), 64.9 (CH.sub.2), 69.2 (CH.sub.2), 69.7 (CH.sub.2), 82.0 (C), 90.4 (C), 118.1 (C), 120.7 (CH), 124.7 (CH), 125.7 (CH), 126.8 (C), 127.4 (C), 128.4 (CH), 129.9 (CH), 130.0 (CH), 131.8 (CH), 134.8 (CH), 140.4 (C), 143.9 (C), 146.2 (C), 165.8 (C), 168.8 (C), 169.5 (C), 170.0 (C), 171.1 (C); LRMS (ESI+) m/z (%) 719 (100) [M+Na].sup.+, 697 (90) [M+H].sup.+; HRMS (ESI+) m/z calc. for C.sub.37H.sub.41N.sub.6O.sub.8 [M+H].sup.+ 697.2980, found 697.2978.
Methyl-(2S,3R,4S)-1-acetyl-4-(4-(20-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2,5,8,11,14,17-hexaoxaicos-19-yn-1-yl)-1H-1,2,3-triazol-1-yl)-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (YG)
[0264] ##STR00100##
[0265] Using the same protocol as YF, 15.0 mg of compound Y was obtained (59%); R.sub.f=0.28 (4% MeOH/CH.sub.2Cl.sub.2); .sup.1H NMR (400 MHz, CDCl.sub.3) b ppm 0.92 (t, J=7.2 Hz, 3H), 1.04 (d; J=6.8 Hz, 3H), 1.22 (m, 1H), 1.73 (m, 1H), 2.23 (m, 1H), 2.38 (s, 3H), 2.48 (m, 1H), 2.65 (m, 1H), 2.84 (m, 1H), 2.92 (m, 1H), 3.59-3.80 (m, 20H), 3.84 (s, 3H), 4.44 (m, 1H), 4.48 (s, 2H), 4.55 (dd, J=16.9, 2.5 Hz, 1H), 4.71 (bs, 3H), 5.22 (m, 1H), 5.60 (d, J=11.2 Hz, 1H), 7.46 (t, J=7.7 Hz, 1H), 7.51 (bs, 2H), 7.57 (d, J=1.1 Hz, 1H), 7.62 (d, J=7.7 Hz, 1H), 7.84 (d, J=7.7, 1.1 Hz, 1H), 7.96 (d, J=7.7 Hz, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) b ppm 10.8 (CH3), 16.2 (CH3), 18.5 (CH2), 23.6 (CH2), 24.1 (CH3), 31.8 (CH2), 40.4 (CH), 47.5 (CH2), 52.2 (CH), 52.5 (CH3), 59.4 (CH2), 59.6 (CH), 63.1 (CH), 64.9 (CH.sub.2), 69.3 (CH.sub.2), 69.8 (CH.sub.2), 70.3 (6?CH.sub.2), 70.5 (2?CH.sub.2), 82.2 (C), 90.7 (C), 118.3 (C), 121.3 (CH), 124.4 (CH), 125.9 (CH), 127.0 (C), 127.5 (C), 128.6 (CH), 130.1 (CH), 130.2 (CH), 132.0 (CH), 134.8 (CH), 140.7 (C), 144.1 (C), 146.2 (C), 166.0 (C), 169.0 (C), 169.8 (C), 170.2 (C), 171.4 (C); LRMS (ESI+) m/z (%) 895 (100) [M+Na].sup.+, 873 (48) [M+H].sup.+; HRMS (ESI+) m/z calc. for C.sub.45H.sub.57N.sub.6O.sub.12 [M+H].sup.+ 873.4029, found 873.4029.
2S,3R,4S)-4-azido-2-ethyl-3-methyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline (YA)
[0266] ##STR00101##
[0267] To a solution of 4(trifluoromethyl)aniline (506.7 mg, 3.145 mmol) and propionaldehyde (41.52 g, 77.58 mmol) in CH.sub.3CN (31 mL) at ?20? C. was added D-proline (109.4 mg, 0.955 mmol). The reaction mixture was stirred for 20 min at ?20? C. and kept at ?20? C. for two days. TMSN.sub.3 (0.58 mL, 4.027 mmol) and BF.sub.3Et.sub.2O (0.28 mL, 2.201 mmol) were added at rt and the reaction mixture was stirred at this temperature for 30 min. After the reaction was complete, it was quenched by NaOH (1 N) until neutralization, extracted with EtOAc, dried by MgSO.sub.4, filtered off and concentrated under vacuum. After flash chromatoghraphy (silica gel, 1% EtOAc/5% DCM/86% cyclohexane), the product YA was isolated (710.9 mg, 80%); R.sub.f=0.32 (2% EtOAc/cyclohexane); [?].sub.D.sup.20=?207.1 (c=0.78, CHCl.sub.3); IR v.sub.max (thin film, CH.sub.2Cl.sub.2) 2970, 2090, 1622, 1520, 1330, 1109 cm.sup.?1; .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.75 (d, J=7.1 Hz, 3H), 1.02 (t, J=7.5 Hz, 3H), 1.53-1.60 (m, 2H), 1.97 (m, 1H), 3.38 (td, J=7.2, 2.8 Hz, 1H), 4.20 (s, 1H), 4.24 (d, J=2.8 Hz, 1H), 6.56 (d, J=8.1 Hz, 1H), 7.30-7.35 (m, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 10.4 (CH.sub.3), 10.5 (CH.sub.3), 25.3 (CH.sub.2), 33.2 (CH), 51.0 (CH), 63.7 (CH), 113.9 (CH), 115.0 (C), 118.4 (C, q, J=32.8 Hz), 124.9 (C, q, J=270.5 Hz), 126.9 (C, q, J=3.5 Hz), 128.6 (C, q, J=7.5 Hz), 146.8 (C); LRMS (ESI+) m/z (%) 304 (100), 278 (10) [M+Na].sup.+; HRMS (ESI?) m/z calc. for C.sub.13H.sub.15F.sub.3N.sub.4Cl [M+Cl].sup.? 319.0942, found 319.0929.
1-((2S,3R,4S)-4-azido-2-ethyl-3-methyl-6-(trifluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one (YB)
[0268] ##STR00102##
[0269] To a solution of YA (638.6 mg, 2.21 mmol) and pyridine (0.53 mL, 6.63 mmol) in CH.sub.2Cl.sub.2 (5 mL) was added acetyl chloride (0.32 mL, 4.42 mmol) at 0? C. The reaction mixture was stirred at 0? C. to rt for 2 h30 and then stirred at rt overnight. The reaction was concentrated under vacuum. After flash chromatography (silica gel, 20% EtOAc/cyclohexane), the product YB was isolated (350.1 mg, 48.5%); R.sub.f=0.12 (10% EtOAc/cyclohexane); [?].sub.D.sup.20=+145.6 (c=1, CHCl.sub.3); IR v.sub.max (thin film, CH.sub.2Cl.sub.2): 3478, 3055, 2969, 2486, 2097, 1666, 1331, 1169, 737 cm.sup.?1; .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.88 (t, J=7.2 Hz, 3H), 1.09 (m, 1H), 1.25 (d, J=6.9 Hz, 3H), 1.64 (m, 1H), 2.30 (s, 3H), 2.34 (m, 1H), 4.11 (d, J=10.4 Hz, 1H), 4.62 (bs, 1H), 7.49 (m, 1H), 7.56 (dd, J=8.5, 2.1 Hz, 1H), 7.72 (bs, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) ? ppm 10.6 (CH.sub.3), 16.7 (CH.sub.3), 18.3 (CH.sub.3), 23.6 (CH.sub.2), 38.8 (CH), 59.1 (CH), 63.3 (CH), 119.7 (CH), 122.4 (C), 125.1 (C), 125.4 (C, q, J=125.4 Hz), 125.9 (C), 126.2 (C, q, J=126.21 Hz), 127.3 (C, q, J=127.5 Hz), 128.6 (C), 139.8 (C), 169.9 (C); LRMS (ESI+) m/z (%) 242 (100) 327 (40) [M+H].sup.+; HRMS (ESI+) m/z calc. for C.sub.15H.sub.18N.sub.40F.sub.3 327.1433 found 327.1425.
1-((2S,3R,4S)-2-Ethyl-3-methyl-4-(4-phenyl-1H-1,2,3-triazol-1-yl)-6-(trifluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one (YC)
[0270] ##STR00103##
[0271] From YB (55.0 mg, 0.17 mmol), phenylacetylene (37 ?L, 0.34 mmol), Amberlyst CuI.Math.Et.sub.3N (20.0 mg), CH.sub.2Cl.sub.2 (0.5 mL), and using the method B with stirring for 72 h, the product was obtained after flash chromatography (silica, 20% to 40% EtOAc/cyclohexane) to give YC (67.7 mg, 93.5%); R.sub.f=0.26 (20% EtOAc/cyclohexane); .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.97 (t, J=7.3 Hz, 3H), 1.09 (d, J=6.9 Hz, 3H), 1.26 (m, 1H), 1.78 (m, 1H), 2.40 (s, 3H), 2.67 (m, 1H), 4.65 (m, 1H), 5.66 (d, J=11.5 Hz, 1H), 7.22 (s, 1H), 7.35 (d, J=7.5 Hz, 1H), 7.39-7.45 (m, 3H), 7.56-7.60 (m, 2H), 7.83 (d, J=7.5 Hz, 2H); LRMS (ESI+) m/z (%) 429 (100) [M+H].sup.+; HRMS (ESI+) m/z calc. for C.sub.23H.sub.24N.sub.4OF.sub.3 429.1902, found 429.1898.
1-((2S,3R,4S)-2-ethyl-3-methyl-4-(4-pentyl-1H-1,2,3-triazol-1-yl)-6-(trifluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one (YD)
[0272] ##STR00104##
[0273] From YB (100.0 mg, 0.31 mmol), 1-heptyne (59 mg, 0.61 mmol), Amberlyst CuI.Math.Et.sub.3N (40.0 mg), CH.sub.2Cl.sub.2 (1 mL), and using the method B with stirring for 48 h, the product was obtained after flash chromatography (silica, 20% to 30% EtOAc/cyclohexane) to give YD (107.5 mg, 83%); R.sub.f=0.38 (30% EtOAc/cyclohexane); .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.87 (t, J=6.8 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H), 1.04 (d, J=6.8 Hz, 3H), 1.2-1.38 (m, 5H), 1.61-1.71 (m, 3H), 1.75 (m, 1H), 2.38 (s, 3H), 2.59 (m, 1H), 2.71 (t J=7.6 Hz, 2H), 4.63 (bs, 1H), 5.57 (d, J=11.3 Hz, 1H), 7.12 (m, 1H), 7.15 (m, 1H), 7.56 (d, J=8.0 Hz, 1H); LRMS (ESI+) m/z (%) 423 (100) [M+H].sup.+; HRMS (ESI+) m/z calc. for C.sub.22H.sub.30N.sub.4OF.sub.3 423.2372, found 423.2374.
N-(4-((2S,3R,4S)-1-acetyl-4-azido-2-ethyl-3-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)-N-hydroxyoctanediamide (YH)
[0274] ##STR00105##
[0275] R.sub.f=0.22 (5% MeOH/CH.sub.2Cl.sub.2); .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.85 (d, J=7.3 Hz, 3H), 1.11 (m, 1H), 1.21 (d, J=6.9 Hz, 3H), 1.27-1.46 (m, 5H), 1.64 (m, 2H), 1.71 (m, 2H), 2.09 (t, J=7.4 Hz, 2H), 2.29 (s, 3H), 2.31 (m, 1H), 2.39 (t, J=7.4 Hz, 2H), 4.32 (d, J=9.5 Hz, 1H), 4.64 (m, 1H), 7.23 (d, J=7.9 Hz, 1H), 7.44 (m, 1H), 7.60 (d, J=8.2 Hz, 2H), 7.66 (m, 1H), 7.70 (d, J=8.2 Hz, 2H); .sup.13C NMR (100 MHz, CD.sub.3OD) ? ppm 11.0 (CH.sub.3), 16.9 (CH.sub.3), 19.5 (CH), 21.4 (CH.sub.3), 26.7 (CH.sub.2), 26.8 (CH.sub.2), 29.9 (CH.sub.2), 30.0 (CH.sub.2), 34.8 (CH.sub.2), 38.0 (CH.sub.2), 40.9 (CH), 60.4 (CH), 65.0 (CH), 121.7 (CH), 127.1 (2?CH), 127.7 (CH), 128.2 (CH), 129.9 (2?CH), 130.6 (C), 136.7 (C), 139.8 (C), 141.9 (C), 143.6 (C), 172.8 (C), 173.1 (C), 174.8 (C); LRMS (ESI+) m/z (%) 521 (30) [M+H].sup.+, 543 (100) [M+Na].sup.+; HRMS (ESI+) m/z calc. for C.sub.28H.sub.37N.sub.6O.sub.4 521.2863, found 521.2863.
Methyl-(2S,3R,4S)-1-acetyl-2-ethyl-4-(6-(hydroxymethyl)-5,5a,6,6a,7,8-hexahydrocyclopropa[5,6]cycloocta[1,2-d][1,2,3]triazol-1(4H)-yl)-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (YI)
[0276] ##STR00106##
[0277] Compound 26 (21 mg, 0.06 mmol) and bicyclo[6.1.0]non-4-yn-9-ylmethanol (BCN, 10 mg, 0.06 mmol) were dissolved in CHCl.sub.3 (1 mL) and the reaction was stirred for 2 h at room temperature. The solvent was removed in vacuo and the product was obtained after flash chromatography (silica, 4% MeOH/CH.sub.2Cl.sub.2) to give YI (13 mg, 42%);
[0278] R.sub.f=0.33 (4% MeOH/CH.sub.2Cl.sub.2); .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm 0.93 (d, J=7.2 Hz, 3H), 0.96-1.34 (m, 9H), 1.44-1.59 (m, 2H), 1.67-1.95 (m, 3H), 2.26 (m, 1H), 2.36 (s, 3H), 2.48-2.79 (m, 2H), 2.92 (m, 1H), 3.11 (m, 1H), 3.61 (m, 1H), 3.72 (m, 1H), 3.82 (s, 3H), 4.81 (m, 1H), 5.59 (m, 1H), 7.42 (m, 1H), 7.48 (m, 1H), 7.96 (m, 1H); LRMS (ESI+) m/z (%) 489 (88) [M+Na].sup.+, 467 (100) [M+H].sup.+; HRMS (ESI+) m/z calc. for C.sub.26H.sub.35N.sub.4O.sub.4 [M+H].sup.+ 467.2653, found 467.2646.
REFERENCES
[0279] [1] Hatano, M.; Yamashita, K.; Ishihara, K. Org. Lett. 2015, 17, 2412-2415 [0280] [2] Allais, F.; Ducrot, P.-H. Synthesis 2010, 1649-1653 [0281] [3] Girard, C.; ?nen, E.; Aufort, M.; Beauvi?re, S.; Samson, E.; Herscovici, J. Org. Lett. 2006, 8, 1689-1692. [0282] [4] Chong, Q.; Hu, Y. Zhou, B.; Fernandez-Salas, E.; Yang, C.-Y.; Liu, L.; McEachern, D. et al. J. Med. Chem. 2018, 61, 6685-6704.
In Vitro Experimentations
[0283] Evaluation of Cytotoxicity and Cytokine Expression after iBET/LPS Treatment
[0284] J774 mouse macrophages were cultured in DMEM 10% Fetal Calf Serum (FCS) 1% penicillin and streptomycin at 37? C. 5% CO2. 250,000 cells/ml. Cells were then seeded at 250,000 cells/ml and treated with 1 ?M, 10 ?M and 100 ?M for each iBET and, then, after 30 min, with 100 ?g/ml LPS (lipopolysaccharides, Cell Signaling Technology ref: 14011S) to induce inflammatory response. After 24 h, cytotoxicity was evaluated using CytoTox-ONE? Homogeneous Membrane Integrity Assay and/or CellTiter 96 Non-radioactive Cell Proliferation Assay (Promega) according to manufacturer's instructions. IL6 and TNF? secretion were assessed using respectively IL-6 Mouse ELISA assay and TNF? Mouse ELISA assay (Invitrogen) according to manufacturer's instructions.
[0285] Results are given on
In Vitro Evaluation of Bromodomain Inhibitors by Homogeneous Time Resolved Fluorescence
[0286] HTRF reagents and buffers were purchased from Cisbio Bioassays. The assay used a terbium (Ill) cryptate donor reagent conjugated to an anti-GST antibody (MAb anti-GST-Tb; GSTTLA), a streptavidin-conjugated acceptor reagent (streptavidin-d2) and Cisbio proprietary buffers (EPlgeneous Binding Domain Diluent and Detection buffer, respectively). GST-tagged bromodomains (BDs) were expressed in E. coli and purified using standard procedures. Incubation of GST-tagged BDs with biotinylated acetylated H.sub.4 peptide (H4K5acK8acK12acK16ac, here named H4ac4) brings the donor and acceptor into close proximity and allows for a FRET reaction. GST-tagged proteins in 25 mM Hepes pH 7.5, 150 mM NaCl, 0.5 mM DTT were assayed at a final concentration of 5 nM. Biotinylated H4ac4 peptides were used at a final concentration of 50, 600 nM in assays involving Brd4 BD1, Brd4 BD2, respectively. The antibody-conjugated donor was used at 0.5 nM and the streptavidin-conjugated acceptor was used at ? of the H4ac4 peptide concentration. Inhibitors were tested by performing an eleven-point dilution series with a maximal final concentration of 20 mM. These concentrations allowed a fixed DMSO concentration at 0.2%, critical for a Z factor ?0.8. Components were incubated at 4? C. for 4 h (BD1) or for 24 h (BD2). Experiments were performed in 384-well white plates (Greiner ref. 781080) and analyzed in a ClarioStar plate reader (BMG LABTECH, excitation at 330 nm and emission at 620 and 665 nm, corresponding to the donor and acceptor emission peaks, respectively; the 665/620 ratio is used to calculate the specific HTRF signal) with an integration delay of 60 ?s and an integration time of 400 ?s.
HTRF Results (IC50 Sur BD1 Et BD2)
[0287] Some of the HTRF results are illustrated on
TABLE-US-00001 Exam- Selec- ple tivity Product MM refer- IC50 (nM) BD2/ Molecules Reference g.mol.sup.-1 ence BD1 BD2 BD1
Evaluation of Cytotoxicity and Anti-Inflammatory Activity of BET Inhibitor Compounds
[0288] Experimental procedure: J774 mouse macrophages were cultured in DMEM 10% Fetal Calf Serum (FCS) 1% penicillin and streptomycin at 37? C. 5% CO.sub.2. Cells were seeded at 250,000 cells/mL and treated with 1 ?M, 10 ?M and 100 ?M for each iBET and, after 30 min, with 100 ?g/mL LPS (lipopolysaccharides, Cell Signaling Technology) to induce inflammatory response. After 24 h, cytotoxicity was evaluated using the Cell Proliferation Kit I (Roche) according to manufacturer's instructions. IC.sub.50 were calculated using GraphPad (Prism) using non linear regression curve fit. IL6 and TNF?? secretion was assessed using respectively IL-6 Mouse and TNF? Mouse ELISA assay (Invitrogen) on cell culture supernatants according to manufacturer's instructions. Normalized values were combined to calculate anti-inflammatory (AI) score.
[0289] As shown in
Impact of Lead BET Inhibitors Compounds on Gene Expression Profiles
[0290] Experimental procedure: RNA was extracted from 5 million of LPS-stimulated J774 mouse macrophages cells treated for 6 h with DMSO (negative control), reference iBETs (JQ1 and iBET726, 1 ?M) and lead compounds (MLE83 and JUP102, 10 ?M) using Trizol (Invitrogen) according to manufacturer's instructions. RNA sequencing was subcontracted to BGI Genomics (DNBSEQ? Sequencing Technology). FASTQ sequencing files were aligned to mouse genome (GRCm39 assembly) using STAR (v2.7.1a). Bam files were counted using HTSeq framework (v0.11.2). Reads normalization and differential analysis was performed suing SARTools and DESeq2 (v1.22.2) R packages. Genes were considered as differentially expressed when |log 2FC|>1 AND p value <0.05 between control and treated conditions. Gene Set Enrichment Analysis was performed using GSEA v4.2.1 software against the hallmark v7.5 gene sets from the Broad Institute Molecular Signature Database. A detailed description of GSEA methodology and interpretation is provided online (http://www.broadinstitute.org/gsea/doc/GSEAUserGui-deFrame.html).
[0291] As shown in
[0292] iBET-726 (reference) has the following structure:
##STR00151##