* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Organic Chemistry, 2003, vol. 68, # 26, p. 9899 - 9906
2
[ 73-32-5 ]
[ 24424-99-5 ]
[ 13139-16-7 ]
Yield
Reaction Conditions
Operation in experiment
95%
With sodium hydroxide In 1,4-dioxane at 20℃; for 24 h; Cooling with ice
A solution of L-Isoleucine (1.31 g, 10 mmol, 1.0 equiv.) in 20.5 mL 1M NaOH was cooled in an ice-bath and Boc2O (2.62 g, 12 mmol, 1.2 equiv., dissolved in 7 mL dioxane) was added slowly. The reaction was stirred at ambient tempe-rature for one day. After adjusting the pH to 10 with 1M NaOH, diethyl ether was added and the phases were separated. The aqueous layer was acidified to pH 2 with 1M HCl and extracted with EtOAc. The combined EtOAc layers were washed with brine and dried over Na2SO4. Removal of the volatiles left the title compound as a colourless oil (2.20 g, 95percent). IR 3292 (w), 2967 (m), 2934 (w), 2880 (w), 1713 (s), 1661 (m), 1504 (m), 1465 (w), 1394 (m), 1368 (s), 1242 (m), 1159 (s), 1121 (m), 1046 (m), 1019 (w), 857 (w), 778 (w), 657 (w). 1H NMR (500 MHz, CDCl3) δ 0.94 (t, J = 7.3 Hz, 3H, H-6), 0.98 (d, J = 7 Hz, 3H, H-4), 1.15-1.29 (m, 1H, H-5a), 1.46 (s, 9H, H-9/10/11), 1.46-1.54 (m, partially overlapped, 1H, H-5b), 1.83-1.99 (m, 1H, H-3), 4.30 (dd, J = 8.9, 4.6 Hz, 1H, H-2), 5.02 (d, J = 8.9 Hz, 1H, NH). 13C NMR (125 MHz, CDCl3) δ 11.8 (C-6), 15.7 (C-4), 25.0 (C-5), 28.5 (C-9/10/11), 37.9 (C-3), 58.0 (C-2), 80.2 (C-8), 155.9 (C-7), 177.2 (C-1). HRMS (ESI) m/z [M-H]- calcd for C11H20NO4- 230.13868, found 230.13926. [α]20D +3.6 (c 2.00, CH3OH) (Lit[3]: [α]25D +3.8 (c 1.01, CH3OH)).
88.7%
With sodium hydroxide In 1,4-dioxane; water at 20℃; for 18 h;
3.00 mg (22.87 mmol) of L-isoleucine (S)-11 is introduced in a 300 ml egg plant type flask and dissolved by adding 21 ml of 1N-NaOH, Furthermore, 15 ml of water, 15 ml of dioxane and 5.49 mg (25.15 mmol) of Boc2O are added and stirred at room temperature for 5 hours, and additional 2.70 mg (12.37 mmol) of Boc2O are added and stirred at room temperature for 13 hours. The reaction solution is washed for three times with 30 ml of ether, pH is adjusted to 2-3 by adding citric acid to an aqueous layer in an ice bath, and thereafter it is washed twice with 50 ml of diethyl ether, extracted twice with 30 ml of ethyl acetate, washed for 5 times with 20 ml of water, dried with sodium sulfate and distilled off the solvent, to obtain 4.69 g (yield; 88.7percent) of a Boc form (S)-12 of L-isoleucine as colorless oil.
78.8%
With sodium hydroxide In tetrahydrofuran; water at 0 - 20℃; for 24 h;
General procedure: l-lysine, l-alanine, l-leucine, l-isoleucine, l-phenylalanine, l-threonine (5g, 1 equiv) was dissolved in H2O (100mL), and to it NaOH (3 equiv) was added and stirred. To this, di-tert-butyl dicarbonate (Boc2O) (2.4 equiv) in 50mL of tetrahydrofuran (THF) was added at 0°C [39]. Then the reaction mixture was stirred at room temperature for 24h. At the end of the reaction, THF was removed under reduced pressure and the aqueous layer was washed with diethyl ether to remove organic impurities. Then the aqueous layer was acidified to pH 4–5 using 1M H2SO4 aqueous solution. The aqueous layer was then extracted with dichloromethane (DCM). The organic layer was then washed with brine and dried over anhydrous Na2SO4. The organic layer was removed under reduced pressure to obtain the compound.
Reference：
[1] Tetrahedron Letters, 2005, vol. 46, # 38, p. 6537 - 6540
[2] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 17, p. 6340 - 6350
[3] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 14, p. 3573 - 3586
[4] Tetrahedron, 1992, vol. 48, # 37, p. 8007 - 8022
[5] Tetrahedron, 2006, vol. 62, # 31, p. 7274 - 7283
[6] Tetrahedron, 2018, vol. 74, # 38, p. 5138 - 5142
[7] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2007, vol. 46, # 7, p. 1137 - 1142
[8] Journal of Medicinal Chemistry, 2011, vol. 54, # 8, p. 2823 - 2838
[9] Patent: US6348484, 2002, B1, . Location in patent: Page column 30
[10] RSC Advances, 2015, vol. 5, # 24, p. 18751 - 18760
[11] Organic and Biomolecular Chemistry, 2016, vol. 14, # 4, p. 1450 - 1454
[12] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1995, vol. 34, # 1, p. 45 - 47
[13] Organic Syntheses, 1985, vol. 63, p. 160 - 160
[14] European Journal of Medicinal Chemistry, 2018, vol. 143, p. 1489 - 1509
[15] Chemistry of Natural Compounds, 1979, vol. 15, p. 471 - 476[16] Khimiya Prirodnykh Soedinenii, 1979, vol. 15, p. 543 - 548
[17] Angewandte Chemie - International Edition, 2000, vol. 39, # 15, p. 2752 - 2754
[18] Bioorganic and medicinal chemistry letters, 2004, vol. 14, # 1, p. 275 - 278
[19] Chemistry - A European Journal, 2001, vol. 7, # 5, p. 1014 - 1027
[20] Chemistry - A European Journal, 2006, vol. 12, # 25, p. 6572 - 6584
[21] Tetrahedron, 2010, vol. 66, # 29, p. 5384 - 5395
[22] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 6, p. 1832 - 1837
[23] Chemical Communications, 2011, vol. 47, # 29, p. 8337 - 8339
[24] European Journal of Medicinal Chemistry, 2011, vol. 46, # 11, p. 5387 - 5397
[25] Chinese Chemical Letters, 2012, vol. 23, # 3, p. 297 - 300
[26] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2012, vol. 67, # 7, p. 731 - 746
[27] RSC Advances, 2013, vol. 3, # 43, p. 21106 - 21109
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[29] Molecules, 2014, vol. 19, # 5, p. 6822 - 6837
[30] Journal of Natural Products, 2014, vol. 77, # 8, p. 1871 - 1880
[31] Acta Chimica Slovenica, 2016, vol. 63, # 2, p. 344 - 350
[32] Patent: CN103980341, 2016, B, . Location in patent: Paragraph 0125
[33] Chemical Biology and Drug Design, 2018, vol. 92, # 2, p. 1576 - 1580
[34] Tetrahedron, 2018, vol. 74, # 52, p. 7485 - 7494
3
[ 1070-19-5 ]
[ 73-32-5 ]
[ 13139-16-7 ]
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[1] Tetrahedron, 2007, vol. 63, # 41, p. 10282 - 10289
[2] Justus Liebigs Annalen der Chemie, 1967, vol. 702, p. 188 - 196
[3] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1977, vol. 15, p. 80 - 81
4
[ 73-32-5 ]
[ 98015-52-2 ]
[ 13139-16-7 ]
Reference：
[1] Synthesis, 1986, # 8, p. 627 - 632
5
[ 73-32-5 ]
[ 13139-16-7 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1989, vol. 62, # 10, p. 3103 - 3108
6
[ 73-32-5 ]
[ 75844-68-7 ]
[ 13139-16-7 ]
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[1] Chemical and Pharmaceutical Bulletin, 1984, vol. 32, # 6, p. 2174 - 2181
7
[ 73-32-5 ]
[ 13303-10-1 ]
[ 13139-16-7 ]
Reference：
[1] Journal of the American Chemical Society, 1957, vol. 79, p. 6180,6181
8
[ 73-32-5 ]
[ 13139-16-7 ]
Reference：
[1] Journal of Organic Chemistry, 1992, vol. 57, # 11, p. 3007 - 3013
9
[ 73-32-5 ]
[ 50739-44-1 ]
[ 13139-16-7 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1983, vol. 56, # 10, p. 2974 - 2980
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[1] Justus Liebigs Annalen der Chemie, 1968, vol. 716, p. 175 - 185
12
[ 73-32-5 ]
[ 16965-08-5 ]
[ 13139-16-7 ]
Reference：
[1] Journal of the Chemical Society [Section] C: Organic, 1967, p. 2632 - 2636
13
[ 73-32-5 ]
[ 81616-10-6 ]
[ 13139-16-7 ]
Reference：
[1] Journal of Organic Chemistry, 1982, vol. 47, # 14, p. 2697 - 2700
14
[ 2280-44-6 ]
[ 73-32-5 ]
[ 56-86-0 ]
[ 657-27-2 ]
[ 60-18-4 ]
Reference：
[1] Agricultural and Biological Chemistry, 1990, vol. 54, # 12, p. 3275 - 3282
15
[ 67-56-1 ]
[ 73-32-5 ]
[ 18598-74-8 ]
Yield
Reaction Conditions
Operation in experiment
97.5%
Stage #1: at 0℃; for 0.5 h; Stage #2: at 0℃;
General procedure: To 5 mL of ice-bath cooled methanol was added dropwise 1 mL of SOCl2, the resulting mixture was stirred for 0.5 h and 1.01 g (8.55 mmol) of l-Valine was added. The stirring was continued overnight, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatograph (eluent: methanol/ether = 1/5, v/v) to afford a colorless pinch-like crystal. Yield 98.8percent. The spectral data were consistent with that reported in the literature.8
86%
at 20℃; Cooling with ice
General procedure: This compound has previously been described5 and can be purchased from Toronto Research. To a round bottom flask containing MeOH (50 mL) and cooled in an ice bath was added SOCl2(6.1 mL, 84 mmol) dropwise over 5 min. L-Leucine 1e (5.0 g, 38) was then added and the mixture was left to stir overnight at rt. The reaction mixture was concentrated on the rotovap using MeOH (2 x 50 mL) to chase away excess thionyl chloride. Diethyl ether (50 mL) was added to the resulting solids and followed by a combination of scratching and sonication to produce a white solid which was filtered, rinsing with diethyl ether (3 x 10 mL). Product was further purified by recrystallization by partially dissolving solids in hot EtOAc (50 mL) followed by cooling to rt and filtration. Yield: 3.9 g (56percent). [α]D24 +18.8° (c 0.50, MeOH). >98percent pure by NMR. 1H NMR ((CD3)2SO) δ 8.61 (br s, 3H), 3.95 (t, J = 7, 1H), 3.74 (s, 3H), 1.75 (m, 1H), 1.65 (m, 2H), 0.89 (d, J = 7, 6H).
Reference：
[1] Organic and Biomolecular Chemistry, 2017, vol. 15, # 44, p. 9372 - 9378
[2] Angewandte Chemie, 1992, vol. 104, # 1, p. 97 - 99
[3] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 8, p. 2747 - 2761
[4] Bulletin des Societes Chimiques Belges, 1991, vol. 100, # 1, p. 63 - 77
[5] Angewandte Chemie - International Edition, 2018, vol. 57, # 36, p. 11683 - 11687[6] Angew. Chem., 2018, vol. 130, # 36, p. 11857 - 11861,5
[7] Synthetic Communications, 2010, vol. 40, # 8, p. 1161 - 1179
[8] Journal of Organometallic Chemistry, 1986, vol. 317, p. 93 - 104
[9] Tetrahedron Asymmetry, 2000, vol. 11, # 6, p. 1367 - 1374
[10] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 20, p. 5000 - 5006
[11] Journal of Biological Chemistry, 1946, vol. 164, p. 753,754, 756
[12] Journal of Biological Chemistry, 1952, vol. 199, p. 801,808
[13] Heterocycles, 1991, vol. 32, # 10, p. 1879 - 1895
[14] Phytochemistry (Elsevier), 1988, vol. 27, # 1, p. 77 - 84
[15] Synthetic Communications, 1995, vol. 25, # 4, p. 561 - 568
[16] Tetrahedron Letters, 2002, vol. 43, # 21, p. 3935 - 3937
[17] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 6, p. 1629 - 1632
[18] Journal of Organic Chemistry, 2003, vol. 68, # 26, p. 9899 - 9906
[19] Journal of Medicinal Chemistry, 2006, vol. 49, # 24, p. 7215 - 7226
[20] Tetrahedron, 2008, vol. 64, # 30-31, p. 7353 - 7361
[21] Synlett, 2009, # 8, p. 1227 - 1232
[22] European Journal of Medicinal Chemistry, 2009, vol. 44, # 7, p. 2796 - 2806
[23] Arkivoc, 2010, vol. 2010, # 2, p. 31 - 48
[24] Synthetic Communications, 2011, vol. 41, # 23, p. 3485 - 3490
[25] Letters in Organic Chemistry, 2011, vol. 8, # 5, p. 358 - 360
[26] Journal of Organic Chemistry, 2012, vol. 77, # 1, p. 317 - 331
[27] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 12, p. 3807 - 3815
[28] Asian Journal of Chemistry, 2012, vol. 24, # 3, p. 1227 - 1236
[29] Journal of Enzyme Inhibition and Medicinal Chemistry, 2013, vol. 28, # 4, p. 717 - 726
[30] Tetrahedron Letters, 2013, vol. 54, # 35, p. 4637 - 4640
[31] Journal of Natural Products, 2013, vol. 76, # 7, p. 1388 - 1391
[32] Medicinal Chemistry Research, 2015, vol. 24, # 7, p. 2825 - 2837
[33] Organic Syntheses, 1988, vol. 66, p. 151 - 151
16
[ 73-32-5 ]
[ 75-36-5 ]
[ 18598-74-8 ]
Reference：
[1] European Journal of Organic Chemistry, 2013, # 26, p. 5838 - 5847
17
[ 73-32-5 ]
[ 71989-23-6 ]
Yield
Reaction Conditions
Operation in experiment
88%
With potassium carbonate In acetonitrile at 20℃; for 2 h;
General procedure: To a solution of H-Phe-OH (100 mg, 60.5 mmol) in 50 percent MeCN (6.1 mL)were added Fmoc-OPhth (233 mg, 60.5 mmol) and K2CO3 (167 mg, 121 mmol) and stirred at room temperature. After 2 h of stirring saturated sodium bicarbonate solution and H2O were added and the resulting solution was washed with diethyl ether. The aqueous phase is acidified to pH 1 with 1M HCl and extracted with diethyl ether. The organic phase was washed with 1 M HCl, H2O, brine, dried over MgSO4. The filtrate was evaporatedevaporated under reduced pressure to give yellow solid as crude product.
Reference：
[1] Russian Journal of Bioorganic Chemistry, 1999, vol. 25, # 5, p. 283 - 287[2] Bioorganicheskaya Khimiya, 1999, vol. 25, # 5, p. 323 - 328
[3] Synthetic Communications, 2009, vol. 39, # 11, p. 2022 - 2031
[4] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 13, p. 2980 - 2983
19
[ 73-32-5 ]
[ 28920-43-6 ]
[ 71989-23-6 ]
Reference：
[1] RSC Advances, 2015, vol. 5, # 24, p. 18751 - 18760
[2] Journal of the Chinese Chemical Society, 2011, vol. 58, # 4, p. 509 - 515
20
[ 73-32-5 ]
[ 88744-04-1 ]
[ 71989-23-6 ]
Reference：
[1] Synthesis, 1986, # 4, p. 303 - 305
21
[ 73-32-5 ]
[ 102774-86-7 ]
[ 71989-23-6 ]
Reference：
[1] Liebigs Annalen der Chemie, 1988, p. 1095 - 1098
22
[ 73-32-5 ]
[ 24629-25-2 ]
Yield
Reaction Conditions
Operation in experiment
4.5 g
With lithium aluminium tetrahydride In tetrahydrofuran for 20 h; Reflux; Inert atmosphere
L-Isoleucinol 3: L-Isoleucinol was prepared following a reported procedure61 with slight modifications. Under nitrogen, 2.5 equiv of Lithium aluminium hydride (7.2 g, 0.19 mol) was stirred in dry THF (120 mL). Then L-isoleucine (10 g, 0.08 mol) was added in portions and the suspension was refluxed for 20 h. After cooling to room temperature, ethyl acetate was added and the reaction mixture was poured carefully to concentrated sodium hydroxide solution. The organic layer was extracted with water and dried with sodium sulphate. 4.5 g of yellow liquid isoleucinol was obtained after removing the solvents. The product was used without further purification. 1H NMR (400 MHz, CDCl3): δ 0.75-0.90 (6H, m), 1.01-1.17 (1H, m), 1.22-1.36 (1H, m), 1.37-1.50 (1H, m), 2.48 (2H, br s), 2.50-2.65 (1H, m), 3.19-3.29 (1H, m), 3.57 (1H, dd, J = 3.27, 10.64 Hz) ppm.
Reference：
[1] Synthetic Communications, 1996, vol. 26, # 4, p. 703 - 706
[2] Russian Chemical Bulletin, 2008, vol. 57, # 9, p. 1981 - 1988
[3] Helvetica Chimica Acta, 2004, vol. 87, # 1, p. 90 - 105
[4] Journal of Organic Chemistry, 1993, vol. 58, # 13, p. 3568 - 3571
[5] Chemical Communications, 1997, # 12, p. 1087 - 1088
[6] Tetrahedron Asymmetry, 2006, vol. 17, # 13, p. 2028 - 2033
[7] Tetrahedron, 2006, vol. 62, # 29, p. 6782 - 6791
[8] Chemical and pharmaceutical bulletin, 1965, vol. 13, # 8, p. 995 - 1000
[9] Tetrahedron Asymmetry, 2009, vol. 20, # 18, p. 2077 - 2089
[10] Tetrahedron Letters, 2009, vol. 50, # 21, p. 2509 - 2511
[11] Heterocycles, 2009, vol. 77, # 2, p. 865 - 872
[12] Chemical Communications, 2013, vol. 49, # 46, p. 5265 - 5267
[13] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 7, p. 666 - 670
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[15] Journal of Molecular Catalysis A: Chemical, 2013, vol. 379, p. 225 - 233
[16] Chirality, 2013, vol. 25, # 2, p. 119 - 125
[17] Inorganica Chimica Acta, 2014, vol. 409, # PART B, p. 244 - 253
[18] Journal of Organic Chemistry, 2015, vol. 80, # 20, p. 9926 - 9941
[19] Chemistry - A European Journal, 2016, vol. 22, # 43, p. 15529 - 15535
[20] Tetrahedron Asymmetry, 2017, vol. 28, # 12, p. 1675 - 1685
23
[ 73-32-5 ]
[ 24629-25-2 ]
Reference：
[1] Beilstein Journal of Organic Chemistry, 2015, vol. 11, p. 524 - 529
With lithium aluminium tetrahydride; In tetrahydrofuran; for 20h;Reflux; Inert atmosphere;
L-Isoleucinol 3: L-Isoleucinol was prepared following a reported procedure61 with slight modifications. Under nitrogen, 2.5 equiv of Lithium aluminium hydride (7.2 g, 0.19 mol) was stirred in dry THF (120 mL). Then L-isoleucine (10?g, 0.08?mol) was added in portions and the suspension was refluxed for 20?h. After cooling to room temperature, ethyl acetate was added and the reaction mixture was poured carefully to concentrated sodium hydroxide solution. The organic layer was extracted with water and dried with sodium sulphate. 4.5?g of yellow liquid isoleucinol was obtained after removing the solvents. The product was used without further purification. 1H NMR (400?MHz, CDCl3): delta 0.75-0.90 (6H, m), 1.01-1.17 (1H, m), 1.22-1.36 (1H, m), 1.37-1.50 (1H, m), 2.48 (2H, br s), 2.50-2.65 (1H, m), 3.19-3.29 (1H, m), 3.57 (1H, dd, J?=?3.27, 10.64?Hz) ppm.
With water; sodium hydrogencarbonate; sodium carbonate; In acetone; at 15 - 20℃;pH 8 - 10;
General procedure: The (S)-amino acid (10.0 g) was dissolved in H2O (300 ml) and Na2CO3 (2.0 equiv) and NaHCO3 (1.0 equiv) were added at rt, with stirring, to give a clear solution. Acetone (4.0 vol, with respect to the amino acid) was added and the slightly turbid solution was cooled in an ice water bath to 15-20 C. Cbz-Cl (1.25 equiv) was added slowly, with stirring, and the reaction mixture allowed to warm to rt. After stirring for an additional 3 h at rt the mixture was extracted with Et2O (50 ml). To the aqueous phase was slowly added aqueous HCl to give a pH of 2. The resulting oil was extracted into EtOAc (150 ml) and this was washed with H2O (100 ml) and then concentrated in vacuo to give the N-Cbz amino acid as a white solid, see Table 1.
With sodium borohydrid; acetic acid; In tetrahydrofuran; water;
Example 2 A mixture of L-isoleucine (289 mg), sodium borohydride (76 mg) and tetrahydrofuran (15 ml) is refluxed under nitrogen atmosphere for three hours. The mixture is cooled to -20 C., and thereto is added 2-(4-methoxyphenyl)-1,5-benzothiazepine-3,4(2H,5H)-dione (299 mg), and the mixture is stirred at the same temperature for 20 hours. To the reaction solution is added acetic acid (600 mg), and the mixture is stirred for two hours, and then evaporated under reduced pressure to remove the solvent. Water is added to the residue, and the precipitated crystal is collected by filtration, washed with water, and dried to give (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (263 mg). Yield: 87.4%. Optical purity of the cis-compound: 61% e.e. Content of the trans-compound: 12%.
EXAMPLE 16 L-Isoleucine, N-Methyl-N-[1-(2-Phenyl-2-Oxoethyl)-L-Prolyl] Benzylamide Using the procedure described in example 5, 56 mg (0.17 mmol) of L-proline-L-(N-methyl)-isoleucine benzylamide (prepared from N-alpha-t-Boc-N-methyl-L-isoleucine (Schweizerhall, Piscataway, N.J.) using the procedure described in examples 2, 3, and 4) was treated with sodium carbonate (41 mg, 0.40 mmol), and 2-bromoacetophenone (52 mg, 0.26 mmol, 1.5 eq) in methanol (5 mL). A sample of the crude mixture was purified by preparative TLC to provide 2.2 mg of L-Isoleucine, N-Methyl-N-[1-(2-phenyl-2-oxoethyl)-L-prolyl] benzylamide. Rf (20% ethyl acetate in dichloromethane)=0.24 HRMS calcd for (M+H)+ ?(C27 H36 N3 O3 +H)+! ion 450.6057; found 450.2760
EXAMPLE 27 L-Isoleucine, N-[1-(2-(2,5-Dimethoxyphenyl)-2-Oxoethyl)-L-Prolyl] Benzylamide Using the procedure described in Example 5, treatment of a solution of L-proline-L-isoleucine benzylamide (51 mg, 0.16 mmol), with triethylamine (113 uL, 0.81 mmol, 5.0 eq), and 2-bromo-2'-5'-dimethoxyacetophenone (50 mg, 0.19 mmol, 1.2 eq) in THF (5 mL), provided 60 mg (75%) of L-isoleucine, N-[1-(2-(2,5-dimethoxyphenyl)-2-oxoethyl)-L-prolyl] benzylamide as a colorless oil. Rf (50% dichloromethane in ethyl acetate)=0.36 HRMS calcd for (M+H)+ ?(C28 H38 N3 O5 +H)+! ion 496.6307; found 496.2813
In tetrahydrofuran; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; ethyl acetate;
EXAMPLE 3 N Z-N-Methyl-(S,S)-Isoleucinol A solution of Z-(S,S)-isoleucine (10 g, 37.7 mmol) and methyl iodide (18.8 ml, 302 mmol) in tetrahydrofuran (150 ml) was cooled to 0 C. and stirred under argon. Sodium hydride (60% dispersion, 5.42 g, 113 mmol) was carefully added. The suspension was stirred at room temperature for 36 hours. Ethyl acetate (100 ml) was added followed by ice water (300 ml). The aqueous layer was washed with ether (2*200 ml), acidified with concentrated HCl at 0 C. and extracted with ethyl acetate (3*400 ml). The latter extract was washed with water, dried and solvent removed to give N-Me-isoleucine (83% yield See: McDermott et al, Can. J. Cham, 1973, 51, 1915) as a chromatographically homogeneous viscous oil.
Peptide Synthesis. All the peptides were synthesised by solid phase synthesis on a MultiSynTech Syro (Witten, Germany), using Fmoc/tBu chemistry. Coupling activation was carried out by HOBt/DIPEA/HBTU (1/2/0.9) in DMF and the Fmoc-protection on amine was removed employing 40% piperidine in NMP. Side chain protecting groups were: tert-butyl ester for Glu and Asp; trityl for His, Gln and Asn; 2,2,4,6,7-pentamethyldihydro-benzofuran-5-sulfonyl (Pbf) for Arg; tent-butyl ether for Ser, Thr and Tyr; tert-butyloxycarbonyl (Boc) for Lys, Pro and Trp. Fmoc-Lys(Fmoc)-OH was the amino acid used to synthesize dimeric and tetrameric peptides. Fmoc-5-amino valeric acid (5-Ava) and Fmoc-8-amino octanoic acid (8-Aoa) were used to carry out lipidation at N- and/or C-terminus both on linear and dimeric peptides. Tetrameric, dimeric and linear peptides were prepared on Rink amide 4-benzhydrylamine resin (MBNA), evaluating by spectrophotometric measurements the final loading in free amino groups, while acid peptides were prepared on a 2-chlorotrityl chloride resin. All peptides were cleaved from the resins and deprotected by treatment with trifluoroacetic acid, water and triisopropylsilane (TIPS, 95:2.5:2.5). The crude peptides, obtained by precipitation in diethyl ether, were purified by Waters HPLC-UV (Milford, Mass.) on a C12 Phenomenex column and characterized by Bruker MALDI-TOF spectrometry (Billerica, Mass.). The peptide synthesis was performed as described above. Six linear acid peptides, having the general sequence H-Q-X1-KIRVRLSA-OH with X1F, I, L, V, W, Y, were synthesized and combined in equimolar amounts. The crude peptide mixture was purified as reported in the Example I. MS (LC-MS ESI/Ion Trap): (ID8) calcd for C55H96N18O13(X1F) is (M) 1216, found is 1217 (M+H); (ID9) calcd for C53H101N18O13(X1I) is (M) 1197, found is 1198 (M+H); (ID10) calcd for C52H96N18O13 (X1=L) is (M) 1182, found is 1183 (M+H); (ID11) calcd for C51H96N18O13 (X1V) is (M) 1168, found is 1169 (M+H); (ID12) calcd for C57H97N19O13 (X1W) is (M) 1255, found is 1256 (M+H); (ID13) calcd for C55H96N18O14(X1Y) is (M) 1232, found is 1233 (M+H).
The peptide synthesis was performed on a 2-chlorotrityl chloride resin, as described above. Six linear acid peptides, having the general sequence H-X1-KKIRVRLSA-OH with X1F, I, L, V, W, Y, were synthesized and combined in equimolar amounts. The resulting crude peptide mixture was purified on C12 HPLC column, in order to remove salts and scavengers coming from cleavage, and analysed by LC-MS (ESI/Ion Trap) coupled with a HPLC system (Agilent Technologies, Santa Clara, Calif.), eluting components with a gradient mode (B 5 - 95% in 20 min; A 0.1% TFA in water, B 0.1% TFA in acetonitrile) at a flow rate of 1.0 ml/min. MS (LC-MS ESI/Ion Trap): (ID2) calcd for C56H100N18O12 (X1F) is (M) 1216, found is 1217 (M+H); (ID3) calcd for C53H102N18O12 (X1I) is (M) 1182, found is 1183 (M+H); (ID4) calcd for C53H102N18O12 (X1=L) is (M) 1182, found is 1183 (M+H); (ID5) calcd for C52H100N18O12 (X1V) is (M) 1168, found is 1169 (M+H); (ID6) calcd for C58H101N19O12 (X1W) is (M) 1255, found is 1256 (M+H); (ID7) calcd for C56H100N18O13 (X1Y) is (M) 1232, found is 1233 (M+H). Peptide Synthesis. All the peptides were synthesised by solid phase synthesis on a MultiSynTech Syro (Witten, Germany), using Fmoc/tBu chemistry. Coupling activation was carried out by HOBt/DIPEA/HBTU (1/2/0.9) in DMF and the Fmoc-protection on amine was removed employing 40% piperidine in NMP. Side chain protecting groups were: tert-butyl ester for Glu and Asp; trityl for His, Gln and Asn; 2,2,4,6,7-pentamethyldihydro-benzofuran-5-sulfonyl (Pbf) for Arg; tent-butyl ether for Ser, Thr and Tyr; tert-butyloxycarbonyl (Boc) for Lys, Pro and Trp. Fmoc-Lys(Fmoc)-OH was the amino acid used to synthesize dimeric and tetrameric peptides. Fmoc-5-amino valeric acid (5-Ava) and Fmoc-8-amino octanoic acid (8-Aoa) were used to carry out lipidation at N- and/or C-terminus both on linear and dimeric peptides. Tetrameric, dimeric and linear peptides were prepared on Rink amide 4-benzhydrylamine resin (MBNA), evaluating by spectrophotometric measurements the final loading in free amino groups, while acid peptides were prepared on a 2-chlorotrityl chloride resin. All peptides were cleaved from the resins and deprotected by treatment with trifluoroacetic acid, water and triisopropylsilane (TIPS, 95:2.5:2.5). The crude peptides, obtained by precipitation in diethyl ether, were purified by Waters HPLC-UV (Milford, Mass.) on a C12 Phenomenex column and characterized by Bruker MALDI-TOF spectrometry (Billerica, Mass.).
(2S)-2-amino-3-(1-tert-butoxycarbonylindol-3-yl)propanoic acid[ No CAS ]
[ 126631-93-4 ]
C66H117N21O12[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Peptide Synthesis. All the peptides were synthesised by solid phase synthesis on a MultiSynTech Syro (Witten, Germany), using Fmoc/tBu chemistry. Coupling activation was carried out by HOBt/DIPEA/HBTU (1/2/0.9) in DMF and the Fmoc-protection on amine was removed employing 40% piperidine in NMP. Side chain protecting groups were: tert-butyl ester for Glu and Asp; trityl for His, Gln and Asn; 2,2,4,6,7-pentamethyldihydro-benzofuran-5-sulfonyl (Pbf) for Arg; tent-butyl ether for Ser, Thr and Tyr; tert-butyloxycarbonyl (Boc) for Lys, Pro and Trp. Fmoc-Lys(Fmoc)-OH was the amino acid used to synthesize dimeric and tetrameric peptides. Fmoc-5-amino valeric acid (5-Ava) and Fmoc-8-amino octanoic acid (8-Aoa) were used to carry out lipidation at N- and/or C-terminus both on linear and dimeric peptides. Tetrameric, dimeric and linear peptides were prepared on Rink amide 4-benzhydrylamine resin (MBNA), evaluating by spectrophotometric measurements the final loading in free amino groups, while acid peptides were prepared on a 2-chlorotrityl chloride resin. All peptides were cleaved from the resins and deprotected by treatment with trifluoroacetic acid, water and triisopropylsilane (TIPS, 95:2.5:2.5). The crude peptides, obtained by precipitation in diethyl ether, were purified by Waters HPLC-UV (Milford, Mass.) on a C12 Phenomenex column and characterized by Bruker MALDI-TOF spectrometry (Billerica, Mass.). The amido peptide synthesis was performed on a Rink amide resin, as described above in Peptide Synthesis paragraph. After synthesis, the crude peptides were purified by HPLC-UV and characterized by MALDI-TOF, as reported in the Example I. The mass values (M+H) were: (ID15) calcd is (M) 1395, found is 1397 (M+H); (ID16) calcd is (M) 1395, found is 1397 (M+H); (ID17) calcd is (M) 1337), found is 1339 (M+H).
Peptide Synthesis. All the peptides were synthesised by solid phase synthesis on a MultiSynTech Syro (Witten, Germany), using Fmoc/tBu chemistry. Coupling activation was carried out by HOBt/DIPEA/HBTU (1/2/0.9) in DMF and the Fmoc-protection on amine was removed employing 40% piperidine in NMP. Side chain protecting groups were: tert-butyl ester for Glu and Asp; trityl for His, Gln and Asn; 2,2,4,6,7-pentamethyldihydro-benzofuran-5-sulfonyl (Pbf) for Arg; tent-butyl ether for Ser, Thr and Tyr; tert-butyloxycarbonyl (Boc) for Lys, Pro and Trp. Fmoc-Lys(Fmoc)-OH was the amino acid used to synthesize dimeric and tetrameric peptides. Fmoc-5-amino valeric acid (5-Ava) and Fmoc-8-amino octanoic acid (8-Aoa) were used to carry out lipidation at N- and/or C-terminus both on linear and dimeric peptides. Tetrameric, dimeric and linear peptides were prepared on Rink amide 4-benzhydrylamine resin (MBNA), evaluating by spectrophotometric measurements the final loading in free amino groups, while acid peptides were prepared on a 2-chlorotrityl chloride resin. All peptides were cleaved from the resins and deprotected by treatment with trifluoroacetic acid, water and triisopropylsilane (TIPS, 95:2.5:2.5). The crude peptides, obtained by precipitation in diethyl ether, were purified by Waters HPLC-UV (Milford, Mass.) on a C12 Phenomenex column and characterized by Bruker MALDI-TOF spectrometry (Billerica, Mass.). The acid peptide synthesis was performed as described above. After synthesis, the crude peptides were purified by HPLC-UV by a gradient B 5 - 95% in 20 min and characterized by MALDI-TOF. The mass values (M+H) were: (ID1) calcd is (M) 1197, found is 1198 (M+H); (ID6) calcd is (M) 1255, found is 1256 (M+H); (ID14) calcd is (M) 1383, found is 1384 (M+H).
General Procedure: A sample of compounds 3-6 (0.1 mg each) was hydrolyzed with 6 N HCl (0.5 mL) at 110 °C for 24 h. The hydrolysate was concentrated to dryness, resuspended in H2O (100 muL), and then analyzed by chiral HPLC. Amino acid units were analyzed by HPLC/MS chiral analysis [column: Chirobiotic TAG (250 x 4.6 mm), Supelco;solvent: MeOH/10 mM NH4OAc (40:60, pH 5.6); flow rate 0.5 mL/min; detection by ESIMS in positive ion mode (MRM scan)]. The retention times (tR min; MRM ion pair, parent -> product) of the authentic amino acids were as follows: L-Pro (12.3; 116 -> 70), D-Pro (32.0), L-Val (7.7; 118 -> 72), D-Val (17.0), L-Ile (8.2;132 -> 86.1), D-Ile (20.5), L-Phe (15.1; 166.2 -> 120.2), D-Phe(22.5), N-Me-L-Phe (21.2; 180 -> 134.2), N-Me-D-Phe (37.0). The hydrolysates showed peaks corresponding to L-amino acids at tR12.3, 7.7, 8.2, 15.1 and 21.2 min. The MS parameters used were as follows: DP 32, EP 4, CE 21.8, CXP 2.8, CUR 30, CAD medium, IS 4500, TEM 700, GS1 65, and GS2 65. The absolute configurations of the alpha-hydroxy acid units were analyzed by chiral HPLC analysis under different conditions; [column: CHIRALPAK MA (+) (50 x 4.6 mm); solvent: CH3CN/2 mM CuSO4 (10:90); flow rate1 mL/min; detection by UV (254 nm)]. The retention times (tRmin) of the authentic standards were as follows: (2S,3S)-Hmpa (30.5), (2R,3R)-Hmpa (17.0), (2S,3R)-Hmpa (24.1), (2R,3S)-Hmpa (14.0), (2S)-Hiva (8.9), (2R)-Hiva (5.0). The retention times of the samples corresponded to (2S,3S)-Hmpa (30.5) in compounds 3, 4,and 6, and (2S)-Hiva (8.9) in 5.
General Procedure: A sample of compounds 3-6 (0.1 mg each) was hydrolyzed with 6 N HCl (0.5 mL) at 110 °C for 24 h. The hydrolysate was concentrated to dryness, resuspended in H2O (100 muL), and then analyzed by chiral HPLC. Amino acid units were analyzed by HPLC/MS chiral analysis [column: Chirobiotic TAG (250 x 4.6 mm), Supelco;solvent: MeOH/10 mM NH4OAc (40:60, pH 5.6); flow rate 0.5 mL/min; detection by ESIMS in positive ion mode (MRM scan)]. The retention times (tR min; MRM ion pair, parent -> product) of the authentic amino acids were as follows: L-Pro (12.3; 116 -> 70), D-Pro (32.0), L-Val (7.7; 118 -> 72), D-Val (17.0), L-Ile (8.2;132 -> 86.1), D-Ile (20.5), L-Phe (15.1; 166.2 -> 120.2), D-Phe(22.5), N-Me-L-Phe (21.2; 180 -> 134.2), N-Me-D-Phe (37.0). The hydrolysates showed peaks corresponding to L-amino acids at tR12.3, 7.7, 8.2, 15.1 and 21.2 min. The MS parameters used were as follows: DP 32, EP 4, CE 21.8, CXP 2.8, CUR 30, CAD medium, IS 4500, TEM 700, GS1 65, and GS2 65. The absolute configurations of the alpha-hydroxy acid units were analyzed by chiral HPLC analysis under different conditions; [column: CHIRALPAK MA (+) (50 x 4.6 mm); solvent: CH3CN/2 mM CuSO4 (10:90); flow rate1 mL/min; detection by UV (254 nm)]. The retention times (tRmin) of the authentic standards were as follows: (2S,3S)-Hmpa (30.5), (2R,3R)-Hmpa (17.0), (2S,3R)-Hmpa (24.1), (2R,3S)-Hmpa (14.0), (2S)-Hiva (8.9), (2R)-Hiva (5.0). The retention times of the samples corresponded to (2S,3S)-Hmpa (30.5) in compounds 3, 4,and 6, and (2S)-Hiva (8.9) in 5.
(benzohydroxamato-κ2O,O'){S-(+)-2-[(1-oxido-3-methylpentyl)iminomethyl]-3,5-dimethoxyphenolato-κ3N,O,O'}oxidovanadium(V)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
General procedure: The complexes were obtained in a following example procedure. A solution of 5mmol of S(+)-isoleucinol in absolute ethanol (10ml) was added with stirring to 5mmol of an aromatic o-hydroxyaldehyde (salicylaldehyde, 3-methoxysalicylaldehyde, 5-methoxysalicylaldehyde, 4,6-dimethoxysalicylaldehyde, 5-methylsalicylaldehyde, 5-bromosalicylaldehyde, 5-nitrosalicylaldehyde, 2,4-dihydroxybenzaldehyde) in absolute EtOH (20ml) and heated under reflux for 1h. In case of 1b-8b, benzohydroxamic acid (5mmol) in absolute EtOH (10ml) was also added with an aldehyde. Then a vanadium(V) oxytriethoxide (5mmol) in absolute EtOH (10ml) was added and stirred at room temperature for 2h. After cooling in a fridge a solid was separated and filtered off, washed several times and recrystallized from absolute EtOH.
(S)-1-((S)-2-((2S,3S)-2-((R)-3-(1H-imidazol-4-yl)-2-(3-methylbutanamido)-propanamido)-3-methylpentanamido)-3-methylbutanoyl)pyrrolidine-2-carboxamide formate salt[ No CAS ]
With lithium aluminium tetrahydride; In tetrahydrofuran;
General procedure: The compounds were prepared in a similar manner as described before9. The chiralamino acid was reduced to the amino alcohol by treatment with LiAlH4 in THF. Thereaction was quenched with water. The solid was filtered off and the filtrate was driedover anhydrous sodium sulfate. The solvent was removed under reduced pressure togive the crude product. Subsequent treatment of the crude product with TsCl andK2CO3 in MeCN afforded pure chiral aziridines.
General procedure: Approximately 0.2 mg of 1-3 and 0.1 mg of 4-5 were hydrolyzed with 6 N HCl (100 muL) at 110 C for 30 min with stirring. The hydrolysates were evaporated to dryness and then the dried hydrolysates were resuspended in H2O (100 muL). The solutions were concd under reduced pressure.
General procedure: Approximately 0.2 mg of 1-3 and 0.1 mg of 4-5 were hydrolyzed with 6 N HCl (100 muL) at 110 C for 30 min with stirring. The hydrolysates were evaporated to dryness and then the dried hydrolysates were resuspended in H2O (100 muL). The solutions were concd under reduced pressure.
With hydrogenchloride; In water; at 105℃; for 12h;
Odoamide (1, 2.5 mg) was treated with 5N HCl (0.5 mL) at 105 C for 12 h. The hydrolyzate was concentrated to dryness and partitioned between H2O-EtOAc (1:1). The aqueous layer was subjected to HPLC [Cosmosil HILIC (4.6×250 mm), MeCN/10 mM AcONH4=85:15 at 1.0 mL/min, UV detection at 215 nm] to yield N-Me-Phe, Ile, N-Me-Ala, Ala.
To the reaction vessel, in addition ODPA of 10.84g (34.93mmol), isoleucine and 20.10g of EDM of 9.17g (69.86mmol), and the mixture was stirred for 3 hours while heating at 170C . After completion of the reaction, to remove the water produced by the EDM and reaction. Subsequently, to the reaction vessel, addition of thionyl chloride in toluene and 16.69g (140.29mmol) of 40ml, the mixture was stirred for 3 hours at 70C . By removing the toluene and thionyl chloride to give the acid chloride.
2.76 g (8.55 mmol) of BTDA, 2.25 g (17.11 mmol) of isoleucine and 10 ml of EDM were added to a reaction vessel and stirred at 170 ° C for 3 hours. After completion of the reaction, EDM and water generated by the reaction were removed. Subsequently, 20 ml of toluene and 4.38 g (36.81 mmol) of thionyl chloride were added to the above reaction vessel, and the mixture was stirred at 70 ° C for 3 hours. Removal of toluene and thionyl chloride gave acid chloride. In a separate reaction vessel, 2.09 g (18.00 mmol) of 3-ethyl-3-oxetane methanol, 2.35 g (23.24 mmol) of triethylamine and 20 ml of dichloromethane were mixed, and to which the previously prepared acid chloride was dropped. After completion of the dropwise addition, the mixture was further stirred for 1 hour. The reaction solution was poured into a separating funnel and washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated saline in this order. After washing, anhydrous magnesium sulfate was added and the solution was dried. After drying, anhydrous magnesium sulfate was filtered off and the solvent was removed to obtain 5.92 g of oxetane imide 2.
2.64 g (8.98 mmol) of BPDA, 2.36 g (17.97 mmol) of isoleucine and 10 ml of EDM were added to a reaction vessel and stirred at 170 ° C for 3 hours. After completion of the reaction, EDM and water generated by the reaction were removed. Subsequently, 20 ml of toluene and 3.81 g (32.01 mmol) of thionyl chloride were added to the above reaction vessel, and the mixture was stirred at 70 ° C for 3 hours. Removal of toluene and thionyl chloride gave acid chloride. In a separate reaction vessel, 2.21 g (19.05 mmol) of 3-ethyl-3-oxetane methanol, 2.18 g (21.58 mmol) of triethylamine and 20 ml of toluene were mixed, and to which the previously prepared acid chloride was dropped. After completion of the dropwise addition, the mixture was further stirred for 1 hour. The reaction solution was poured into a separating funnel and washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated saline in this order. After washing, anhydrous magnesium sulfate was added and the solution was dried. After drying, anhydrous magnesium sulfate was filtered off and the solvent was removed to obtain 6.11 g of oxetane imide 3.
3.18 g (6.94 mmol) of TAHQ, 1.82 g (13.88 mmol) of isoleucine and 11 ml of EDM were added to a reaction vessel and stirred at 170 ° C for 3 hours. After completion of the reaction, EDM and water generated by the reaction were removed. Subsequently, 20 ml of toluene and 3.51 g (29.50 mmol) of thionyl chloride were added to the above reaction vessel, and the mixture was stirred at 70 ° C for 3 hours. Removal of toluene and thionyl chloride gave acid chloride. In a separate reaction vessel, 1.76 g (15.16 mmol) of 3-ethyl-3-oxetane methanol, 2.05 g (20.28 mmol) of triethylamine and 20 ml of toluene were mixed, and to which the previously prepared acid chloride was dropped. After completion of the dropwise addition, the mixture was further stirred for 1 hour. The reaction solution was poured into a separating funnel and washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated saline in this order. After washing, anhydrous magnesium sulfate was added and the solution was dried. After drying, anhydrous magnesium sulfate was filtered off and the solvent was removed to obtain 5.80 g of oxetane imide 4.
3.33 g (6.39 mmol) of BSAA, 1.68 g (12.77 mmol) of isoleucine and 10 ml of EDM were added to a reaction vessel and stirred at 170 ° C for 3 hours. After completion of the reaction, EDM and water generated by the reaction were removed. Subsequently, 20 ml of toluene and 3.11 g (26.13 mmol) of thionyl chloride were added to the above reaction vessel, and the mixture was stirred at 70 ° C for 3 hours. Removal of toluene and thionyl chloride gave acid chloride. In a separate reaction vessel, 1.57 g (13.52 mmol) of 3-ethyl-3-oxetane methanol, 1.60 g (15.83 mmol) of triethylamine and 20 ml of toluene were mixed, and to which the previously prepared acid chloride was dropped. After completion of the dropwise addition, the mixture was further stirred for 1 hour. The reaction solution was poured into a separating funnel and washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated saline in this order. After washing, anhydrous magnesium sulfate was added and the solution was dried. After drying, anhydrous magnesium sulfate was filtered off and the solvent was removed to obtain 6.76 g of oxetane imide 5.
2.71 g (8.73 mmol) of ODPA, 2.29 g (17.47 mmol) of isoleucine and 10 ml of EDM were added to a reaction vessel and stirred at 170 C for 3 hours. After completion of the reaction, EDM and water generated by the reaction were removed. Subsequently, 20 ml of toluene and 3.69 g (31.01 mmol) of thionyl chloride were added to the above reaction vessel, and the mixture was stirred at 70 C for 3 hours. Removal of toluene and thionyl chloride gave acid chloride. In a separate reaction vessel, 2.38 g (18.24 mmol) of Diethylene glycol monovinyl ether, 2.50 g (24.75 mmol) of triethylamine and 10 ml of toluene were mixed, and to which the previously prepared acid chloride was dropped. After completion of the dropwise addition, the mixture was further stirred for 1 hour. The reaction solution was poured into a separating funnel and washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated saline in this order. After washing, anhydrous magnesium sulfate was added and the solution was dried. After drying, anhydrous magnesium sulfate was filtered off and the solvent was removed to obtain 6.44 g of vinyl imide 1.
8.13 g (26.20 mmol) of ODPA, 6.87 g (52.40 mmol) of isoleucine and 22 ml of EDM were added to a reaction vessel and stirred at 170 ° C for 3 hours. After completion of the reaction, EDM and water generated by the reaction were removed. Subsequently, 20 ml of toluene and 10.62 g (89.24 mmol) of thionyl chloride were added to the above reaction vessel, and the mixture was stirred at 70 ° C for 3 hours. Removal of toluene and thionyl chloride gave acid chloride. In a separate reaction vessel, 6.30 g (54.26 mmol) of 3-ethyl-3-oxetane methanol, 5.69 g (56.28 mmol) of triethylamine and 20 ml of toluene were mixed, and to which the previously prepared acid chloride was dropped. After completion of the dropwise addition, the mixture was further stirred for 1 hour. The reaction solution was poured into a separating funnel and washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated saline in this order. After washing, anhydrous magnesium sulfate was added and the solution was dried. After drying, anhydrous magnesium sulfate was filtered off and the solvent was removed to obtain 18.14 g of oxetane imide 1.
2.76 g (8.55 mmol) of BTDA, 2.24 g (17.11 mmol) of isoleucine and 40 ml of xylene were added to the reaction vessel, and a Dean-Stark apparatus was attached thereto to reflux for 3 hours while removing water generated by the reaction. After completion of the reaction, xylene was removed. Subsequently, 20 ml of toluene and 4.54 g (38.15 mmol) of thionyl chloride were added to the reaction vessel, and the mixture was stirred at 70 C. for 3 hours. Removal of toluene and thionyl chloride gave the acid chloride.
2.76 g (8.55mmol) BTDA, 2.24 g (17.11mmol) of isoleucine, and 10-ml EDM were added to the reaction container, and it flowed back for 3 hours. The water which arose at EDM and a reaction was removed after ending reaction. Continuously, a 20 ml tetrahydrofuran and a 5.26 g (44.21mmol) thionyl chloride were added to the aforementioned reaction container, and it stirred at 70 degrees C for 3 hours. The acid chloride was obtained by removing a tetrahydrofuran and a thionyl chloride.
2.64 g (8.98 mmol) of BPDA, 2.36 g (17.97 mmol) of isoleucine and 40 ml of xylene were added to the reaction vessel, a Dean-Stark apparatus was attached and reflux was carried out for 3 hours while removing water generated by the reaction. After completion of the reaction, xylene was removed. Subsequently, 20 ml of tetrahydrofuran and 4.34 g (36.47 mmol) of thionyl chloride were added to the reaction vessel, and the mixture was stirred at 70 C. for 3 hours. Removal of tetrahydrofuran and thionyl chloride gave the acid chloride.
2.64 g (8.98mmol) BPDA, 2.36 g (17.97mmol) of isoleucine, and 10-ml EDM were added to the reaction container, and it flowed back for 3 hours. The water which arose at EDM and a reaction was removed after ending reaction. Continuously, a 20 ml tetrahydrofuran and a 4.33 g (36.40mmol) thionyl chloride were added to the aforementioned reaction container, and it stirred at 70 degrees C for 3 hours. The acid chloride was obtained by removing a tetrahydrofuran and a thionyl chloride.
To the reaction vessel, 3.33 g (6.39 mmol) of BSAA, 1.68 g (12.77 mmol) of isoleucine and 40 ml of xylene were added, a Dean-Stark apparatus was attached and refluxed for 3 hours while removing water generated by the reaction. After completion of the reaction, xylene was removed. Subsequently, 20 ml of tetrahydrofuran and 2.86 g (34.62 mmol) of thionyl chloride were added to the reaction vessel, followed by stirring at 70 C. for 3 hours. Removal of toluene and thionyl chloride gave the acid chloride.
3.32 g (6.39mmol) BSAA, 1.67 g (12.77mmol) of isoleucine, and 10-ml EDM were added to the reaction container, and it flowed back for 3 hours. The water which arose at EDM and a reaction was removed after ending reaction. Continuously, 20 ml of toluene and a 4.71 g (39.59mmol) thionyl chloride were added to the aforementioned reaction container, and it stirred at 70 degrees C for 3 hours. The acid chloride was obtained by removing toluene and a thionyl chloride.
10.84 g (34.93 mmol) of ODPA, 9.17 g (69.86 mmol) of isoleucine and 40 ml of xylene were added to a reaction vessel, and a Dean-Stark apparatus was attached and refluxed for 3 hours while removing water generated by the reaction . After completion of the reaction, xylene was removed. Subsequently, 20 ml of toluene and 12.50 g (105.04 mmol) of thionyl chloride were added to the reaction vessel, and the mixture was stirred at 70 C for 3 hours. Removal of toluene and thionyl chloride gave the acid chloride.
.71 g (8.73mmol) ODPA, 2.29 g (17.47mmol) of isoleucine, and 40 ml of xylene were added to the reaction container, and it flowed back for 3 hours, removing the water which attached the Dean-Stark apparatus and arose at the reaction. Xylene was removed after ending reaction. Continuously, 20 ml of toluene and a 3.64 g (30.60mmol) thionyl chloride were added to the aforementioned reaction container, and it stirred at 70 degrees C for 3 hours. The acid chloride was obtained by removing toluene and a thionyl chloride
2.71 g (8.73 mmol) of ODPA, 2.29 g (17.47 mmol) of isoleucine and 10 ml of EDM were added to the reaction vessel, and the mixture was stirred at 170 C. for 3 hours. After completion of the reaction, water generated by EDM and reaction was removed. Subsequently, 20 ml of toluene and 3.69 g (31.01 mmol) of thionyl chloride were added to the reaction vessel, and the mixture was stirred at 70 C. for 3 hours. Removal of toluene and thionyl chloride gave the acid chloride.
a-Linolenic acid (2, 0.88 mmol, 245 mg) was dissolved in tetrahydrofuran (11 ml) with trimethylamine (0.98 mmol, 0.14 ml). Chloroformic acid ethyl ester (0.1 mmol, 0.1 ml) was added while the mixture was stirred at -10 C. After the resulting solution was stirred for 20 min, a 0.3 M aqueous NaOH solution (6.9 ml) containing Ile (1.77 mmol, 232 mg) was added to the solution and stirred for an additional 25 min at room temperature. After evaporation to remove the solvent, the obtained residue was cooled at 0 C, and poured into 1 M HCl, extracted with ethyl acetate, and dried over Mg2SO4. The extract was evaporated and purified by SiO2 gel column chromatography (Kanto Chemical, Tokyo, Japan), which was developed with a mixed solvent of acetic acid/ethyl acetate/n-hexane (1/30/70, v/v). LA-Ile (10) was obtained as a colorless oil (293.2 mg, 85%). FD-HR-MS: found m/z 392.3150 [M+H]+; calculated m/z 392.3165 for C24H42NO3; [alpha]25D +19.8 (c 0.3, CHCl3); 1H-NMR (CDCl3, 270 MHz) d: 11.03 (s, 1H), 6.44 (d, J = 8.6 Hz, 1H), 5.38-5.21 (m, 6H), 4.59 (dd, J = 4.6, 8.6 Hz, 1H), 2.77-2.73 (m, 4H), 2.22 (t, J = 8.1 Hz, 2H), 2.08-1.85 (m, 6H), 1.60-1.38 (m, 3H), 1.22-1.07 (m, 8H), 0.97-0.81 (m, 9H).
1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium-3-carboxylate (2S,3S)-2-ammonio-3-methylpentanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
In water;pH Ca. 4.6 - 4.9;Cooling with ice;
A 50 mL 1 N RBF fitted with a water condenser was charged with NaR (0.100 g, 0.392 mmol, 1 eq) and 20 ml of distilled deionised water and mixed to form a solution, a faint suspension is also ok. This solution was cooled using an ice/water bath. To this solution was then added L- isoleucine in one portion ( 0.080 g, 392 mmol, 1.0 eq). After this addition the pH was ~ 4.6-4.9 and all solids had gone into solution.The flask was then removed and the colourless solution frozen using liquid nitrogen. While the flask was frozen it was connected to the freeze dryer. This will slowly remove water. Once dried the product is rendered as a colourless solid.Yield: 147.1 mg (97 %)Melting point: 144-148 C (Corrected, degradation)Analytical data. 1 1-N i R (400 MHz, D O) 6 = 9.48 (s, 1 1 1 ). 9.18 (d, 1 1 1 ). 8.98 (d, 1 1 1). 8.21 (dd, H i). 6.24 (d, 1 1 1 ). 4.48-4.55 (m, 2H), 4.38 (t, 1H), 4.07 ( dd, 1H), 3.93 (dd, H i), 3.69 (d, H I). 2.00 (m, 1H), 1.55-1.45 (m, 1 H), 1.35-1.24 (m, 1H), 1 .04 (d, 3H), 0.95 (t, 3H) ppm
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