* 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.
A mixture of triphenylphosphine (131 g, 0.500 mol) and imidazole (34 g, 0.50 mol) in DCM (600 mL) was cooled to 0 °C and iodide (127 g, 0.50 mol) was added in small portions over 0.5 h. The cooling bath was removed and the mixture was stirred for 0.5 h. After the mixture was re-cooled to 0 °C, a solution of (5)-methyl 2-((tert- butoxycarbonyl)amino)-3-hydroxypropanoate (73 g, 0.33 mol) in DCM (300 mL) was added dropwise. After the addition, the cooling bath was removed and the mixture was allowed to warm to ambient temperature and stirred for 1.5 h. The mixture was filtered and the filtrate was concentrated to remove most of the solvent. MTBE (400 mL) was added to the residue and the mixture was filtered to remove triphenylphosphine oxide. The filtrate was concentrated and the residue was purified by flash column chromatography on silica gel to afford (i?)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (74.0 g, 68percent yield) as a colorless solid.
67%
Stage #1: With methyltriphenoxyphosphonium iodide In N,N-dimethyl-formamide at 0℃; for 0.5 h; Stage #2: With sodium hydrogencarbonate In water; N,N-dimethyl-formamide for 0.25 h;
Triphenylphosphite methiodide (Fieser and Fieser, Reagents for Organic Synthesis, Vol. 4, p557; 34Og, 753 mmol, 1.4 equiv.) was added in one portion to a solution of (S)-2- rert-butyloxycarbonylamino-3-hydroxypropionic acid methyl ester (118g, 538 mmol) in dry N,N-dimethylformamide (1.1 L) at 0°C. After 30 minutes at O0C solid sodium bicarbonate (27Og) was added followed by water (1. IL). The resulting mixture was stirred vigorously for 15 minutes and then extracted with 1:1 diethylether/hexanes (3 x 80OmL). The combined organic extracts were washed with 0.5M sodium hydroxide (5 x IL) and brine (2 x IL), dried over magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting orange oil was loaded onto a SiO2 plug (2" x 7") and eluted with 5percent EtOAc/hexanes to afford (R)-methyl 2-(tert-butoxycarbonylamino)-3-iodopropanoate as a pinkish oil, which solidified (118.5g, 67percent) 1H NMR (CDC13; 400MHz): δppm 5.32 (m, IH), 4.51 (m, IH), 3.81 (s, 3H), 3.58 (m, 2H), 1.45 (s, 9H).
65%
With 1H-imidazole; iodine; triphenylphosphine In dichloromethane at 0 - 20℃; for 3 h; Inert atmosphere
Triphenylphosphine (66.0 g, 0.250 mol) and imidazole (17.1 g, 0.250 mol) were dissolved in methylene chloride (900 ml). After cooling to 0° C., iodine (64.0 g, 0.250 mol) was added thereto, and the temperature was gradually raised from 0° C. to room temperature in the presence of nitrogen gas, followed by stirring for 10 minutes. After cooling to 0° C., a methylene chloride solution (100 of methyl N-(tert-butoxycarbonyl)-L-serinate (45.0 g, 0.200 mol) was slowly added dropwise over one hour, followed by stirring at room temperature for 2 hours. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1:1 to 1:2) to obtain the title compound (43.8 g, 65percent). [0585] 1H NMR (CDCl3, 400 MHz): δ 5.36-5.34 (m, 1H), 4.53-4.51 (m, 1H), 3.80 (s, 3H), 3.61-3.53 (m, 2H), 1.46 (s, 9H)
Reference：
[1] Journal of Organic Chemistry, 2009, vol. 74, # 17, p. 6792 - 6796
[2] Organic Letters, 2003, vol. 5, # 24, p. 4599 - 4602
[3] Organic Letters, 2011, vol. 13, # 10, p. 2614 - 2617
[4] Tetrahedron, 2017, vol. 73, # 42, p. 6085 - 6091
[5] Tetrahedron Letters, 2007, vol. 48, # 16, p. 2857 - 2859
[6] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 12, p. 1199 - 1203
[7] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4427 - 4431
[8] Patent: WO2014/152127, 2014, A1, . Location in patent: Paragraph 00319; 00322
[9] Patent: WO2010/56877, 2010, A2, . Location in patent: Page/Page column 53
[10] Patent: US2015/51395, 2015, A1, . Location in patent: Paragraph 0584-0585
[11] Journal of the Chemical Society, Dalton Transactions, 2001, # 18, p. 2655 - 2662
[12] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 1, p. 191 - 195
[13] Phosphorus, Sulfur and Silicon and the Related Elements, 1998, vol. 136, p. 611 - 616
[14] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 16, p. 2443 - 2447
[15] Synlett, 1997, vol. 1997, # 2, p. 169 - 170
[16] Tetrahedron Letters, 1994, vol. 35, # 4, p. 551 - 554
[17] Tetrahedron, 1985, vol. 41, # 10, p. 1833 - 1845
[18] Journal of the American Chemical Society, 2014, vol. 136, # 35, p. 12469 - 12478
[19] RSC Advances, 2015, vol. 5, # 64, p. 51807 - 51811
[20] Patent: US2016/185821, 2016, A1, . Location in patent: Paragraph 0383; 0384; 0385
[21] Arkivoc, 2016, vol. 2017, # 2, p. 260 - 271
[22] Organic Syntheses, 2005, vol. 81, p. 77 - 88
[23] Patent: WO2007/144379, 2007, A1, . Location in patent: Page/Page column 34
2
[ 56926-94-4 ]
[ 93267-04-0 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 16, p. 2443 - 2447
[2] Organic Syntheses, 2005, vol. 81, p. 77 - 88
[3] Tetrahedron, 1985, vol. 41, # 10, p. 1833 - 1845
[4] Tetrahedron Letters, 1984, vol. 25, # 26, p. 2759 - 2762
[5] Tetrahedron Letters, 1994, vol. 35, # 4, p. 551 - 554
[6] Phosphorus, Sulfur and Silicon and the Related Elements, 1998, vol. 136, p. 611 - 616
3
[ 2766-43-0 ]
[ 55477-80-0 ]
[ 93267-04-0 ]
Reference：
[1] Organic Syntheses, 2016, vol. 92, p. 103 - 116
[2] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4427 - 4431
With sodium iodide; In acetone; for 22h;Inert atmosphere;
The entire following procedure was performed in the dark. A 2-liter round bottom flask covered in foil was charged with the tosylate of BOC-L-serine methyl ester 2a (0.40 mol) and acetone (855 mL) under an atmosphere of nitrogen. While stirring, sodium iodide (1.0 mol) was added in one portion and allowed to stir for 22 h, at which time the reaction was complete by thin layer chromatography (30% ethyl acetate in heptane, KMnC stain, disappearance of 2a). The reaction mixture was added slowly over 1 h to 0-5 C water (3 L) and stirred for 2 h at that temperature. The crude solids were filtered using a fritted funnel, washed with water (3x50 mL), then deliquored for 16 h. A 1-liter round bottom flask was charged with the crude solids and heptane (225 mL). The mixture was warmed to 35-40 C at which point all of the solids had dissolved. A phase separation was performed and the lower aqueous layer was drained and discarded. The organic layer was cooled to -15 C and stirred for 2 h. The solids were filtered using a fritted funnel and rinsed twice with the filtrate, then with clean, 0 C, heptane (20 mL). The solids were dried in a vacuum drying oven at ambient temperature for 24 h, providing pure iodo- intermediate 3a in 80% yield.
Boc-homoallyl glycine (9b) was synthesized using a three-step protocol from commercially available Boc-Ser-OMe (S2). In a typical procedure, a flask was charged with Boc-Ser-OMe (2.0 g, 9.1 mmol) and triphenylphosphine (3.6 g, 13.7 mmol, 1.5 eq.) under Ar(g). To this was added THF (20 mL) and the solution cooled to 0 C. by immersion in an ice bath. Pyridine (1.5 mL, 18.2 mmol, 2 eq.) was added dropwise, followed by solid iodine (3.5 g, 13.7 mmol, 1.5 eq.) in three portions at 0 C. The ice bath was removed and stirring was continued for 4 h at room temperature. The mixture was extracted with Et2O (3*20 mL). The combined organic layers were washed with 1M HCl (3*20 mL), 1M Na2S2O3 (2*20 mL), brine (2*20 mL) and dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was of sufficient purity to be used in the next step without further purification. The iodopropanoate S3 was dissolved in DMF (5 mL) and added dropwise to a flask containing activated zinc (2.4 g, 36.4 mmol, 4 eq.) at 0 C. under Ar(g). The reaction mixture was removed from the ice bath and allowed to stir at room temperature for 3 h, upon which TLC (4:1 petroleum ether: EtOAc) indicated loss of starting material and formation of a lower Rf spot. At this point, the reaction mixture was stopped to let the solid settle to the bottom. The supernatant was then carefully transferred by syringe to a suspension of copper (I) bromide (0.26 g, 1.8 mmol) in DMF (mL) at -15 C. that also contained allyl chloride (1.3 mL, 15.5 mmol, 1.7 eq.). After complete addition, the cooling bath was removed and stirring was continued overnight. At this point, EtOAc (20 mL) was added to the reaction mixture and stirring was continued for 15 min. To the mixture was added H2O (20 mL), the organic layer was removed and successively washed with 1M Na2S2O3 (2*20 mL), H2O (2*20 mL), brine (2*20 mL), and dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 8:1 petroleum ether:EtOAc) to afford 2.0 g (90%) of (9b) as a colorless oil. 1H NMR (500 MHz, CDCl3) delta 5.72 (ddt, J=16.9, 10.2, 6.6 Hz, 1H), 5.18-5.07 (m, 1H), 5.01-4.90 (m, 2H), 4.26-4.23 (m, 1H), 3.67 (s, 3H), 2.08-2.01 (m, 2H), 1.88-1.79 (m, 1H), 1.70-1.61 (m, 1H), 1.37 (s, 9H); 13C NMR (126 MHz, CDCl3) delta 173.11, 155.23, 136.87, 115.50, 79.64, 52.09, 51.99, 31.85, 29.39, 28.21 (3C). HRMS (ESI) m/z calcd for C12H21NO4 [M+H]+: 244.1471. found 244.1474.
(S)-methyl 2-(tert-butoxycarbonylamino)-3-(2-nitrophenyl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
General procedure: A 1 M stock of the zincate was prepared as follows: To a suspension of zinc powder (196 mg, 2.0 equiv, based on the iodoserine, dried under vacuum using a heat gun) was added DMF (0.7 mL) and catalytic iodine (50 mg, 0.19 mmol). The reaction mixture turned from colorless to red to colorless again in ?2 min. After the return to colorless a DMF solution (1.9 mL) of the iodoserine was added followed by additional iodine (50 mg). The reaction turned from pale yellow to red, and back to colorless with an associated exotherm. The solution was stirred until the exotherm subsided, was cooled to room temp (?25 min) and was stirred until the iodoserine disappeared as monitored by TLC. The zincate solution was syringed away from the excess zinc and was added to a separate flask containing Pd(OAc)2 (4 mg, 0.018 mmol), X-Phos (15 mg, 0.032 mmol), and the aryl bromide (1.88 mmol) in DMF (0.5 mL). The resulting mixture was stirred at room temperature overnight. Upon completion as indicated by TLC, the reaction was quenched with satd NH4Cl (10 mL), poured into H2O (50 mL) and extracted with EtOAc (2 × 50 mL). The organic layers were washed with H2O (2 × 100 mL), brine (1 × 100 mL), dried over MgSO4, filtered, and concentrated to a crude oil. The desired material was isolated via flash chromatography.
(S)-methyl 2-((tert-butoxycarbonyl)amino)-4-oxopentanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1: 39%
2: 7%
Stage #1: N-(tert-butoxycarbonyl)-L-3-iodoalanine methyl ester With chloro-trimethyl-silane; ethylene dibromide; zinc In tetrahydrofuran at 45℃; for 1.45h;
Stage #2: ethyl thioacetate In tetrahydrofuran at 45℃; for 4.5h;
Stage #1: N-(tert-butoxycarbonyl)-L-3-iodoalanine methyl ester With chloro-trimethyl-silane; ethylene dibromide; zinc In tetrahydrofuran at 45℃; for 1.45h;
Stage #2: Sphenyl N-benzyloxycarbonylaminoethanothioate With tris-(o-tolyl)phosphine In tetrahydrofuran at 45℃; for 4.5h;
With 1H-imidazole; iodine; triphenylphosphine; In dichloromethane; at 0℃; for 1.5h;Inert atmosphere;
Triphenylphosphine (30.7g, 117mmol, 1.25eq.) was dissolved in anhydrous CH2Cl2 (390mL), cooled to 0C and imidazole (7.96g, 117mmol, 1.25eq.) was added. Iodine (29.7g, 117mmol, 1.25eq.) was added in portions and the resulting reaction mixture was stirred 5min at 0C and additional 10min at ambient temperature. The reaction was cooled to 0C and a solution of alcohol 64 22 (20.5g, 93.6mmol, 1.0eq.) in anhydrous 69 CH2Cl2 (90mL) was added over 10min. The reaction mixture was stirred 90min at 0C (monitored by TLC), then filtered over a plug of Celite. The filtride was washed with pentane-ether 1:1 (500mL). The filtrate was concentrated in vacuo and dissolved in CH2Cl2, silica was added and all volatiles were removed in vacuo to complete dryness. The residue was subjected to flash column chromatography (pentane-ether, 100:3?6:1) to obtain iodide as pale yellow solid (25.8g, 78.4mmol, 84% yield) which was stored at -20C. Rf=0.19 (pentane-ether, 20:1), stains dark blue with vanillin. 1H NMR (400MHz, CDCl3) delta 5.35 (d, J=7.8Hz, 1H), 4.52 (dt, J=7.9, 3.9Hz, 1H), 3.80 (s, 3H), 3.64-3.50 (m, 2H), 1.46 (s, 9H). 13C NMR (101MHz, CDCl3) delta 170.1, 154.8, 80.5, 53.7, 53.0, 28.3, 7.9. HRMS (ESI): calcd. for C9H16INO4 [M+Na]+ 352.0022, found 352.0022. [alpha]25D [alpha]D25 +40.3 (c 1.07, CHCl3).
68%
With 1H-imidazole; iodine; triphenylphosphine; at 0 - 20℃; for 1.5h;
A mixture of triphenylphosphine (131 g, 0.500 mol) and imidazole (34 g, 0.50 mol) in DCM (600 mL) was cooled to 0 C and iodide (127 g, 0.50 mol) was added in small portions over 0.5 h. The cooling bath was removed and the mixture was stirred for 0.5 h. After the mixture was re-cooled to 0 C, a solution of (5)-methyl 2-((tert- butoxycarbonyl)amino)-3-hydroxypropanoate (73 g, 0.33 mol) in DCM (300 mL) was added dropwise. After the addition, the cooling bath was removed and the mixture was allowed to warm to ambient temperature and stirred for 1.5 h. The mixture was filtered and the filtrate was concentrated to remove most of the solvent. MTBE (400 mL) was added to the residue and the mixture was filtered to remove triphenylphosphine oxide. The filtrate was concentrated and the residue was purified by flash column chromatography on silica gel to afford (i?)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (74.0 g, 68% yield) as a colorless solid.
67%
Triphenylphosphite methiodide (Fieser and Fieser, Reagents for Organic Synthesis, Vol. 4, p557; 34Og, 753 mmol, 1.4 equiv.) was added in one portion to a solution of (S)-2- rert-butyloxycarbonylamino-3-hydroxypropionic acid methyl ester (118g, 538 mmol) in dry N,N-dimethylformamide (1.1 L) at 0C. After 30 minutes at O0C solid sodium bicarbonate (27Og) was added followed by water (1. IL). The resulting mixture was stirred vigorously for 15 minutes and then extracted with 1:1 diethylether/hexanes (3 x 80OmL). The combined organic extracts were washed with 0.5M sodium hydroxide (5 x IL) and brine (2 x IL), dried over magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting orange oil was loaded onto a SiO2 plug (2" x 7") and eluted with 5% EtOAc/hexanes to afford (R)-methyl 2-(tert-butoxycarbonylamino)-3-iodopropanoate as a pinkish oil, which solidified (118.5g, 67%) 1H NMR (CDC13; 400MHz): deltappm 5.32 (m, IH), 4.51 (m, IH), 3.81 (s, 3H), 3.58 (m, 2H), 1.45 (s, 9H).
65%
With 1H-imidazole; iodine; triphenylphosphine; In dichloromethane; at 0 - 20℃; for 3h;Inert atmosphere;
Triphenylphosphine (66.0 g, 0.250 mol) and imidazole (17.1 g, 0.250 mol) were dissolved in methylene chloride (900 ml). After cooling to 0 C., iodine (64.0 g, 0.250 mol) was added thereto, and the temperature was gradually raised from 0 C. to room temperature in the presence of nitrogen gas, followed by stirring for 10 minutes. After cooling to 0 C., a methylene chloride solution (100 of methyl N-(tert-butoxycarbonyl)-L-serinate (45.0 g, 0.200 mol) was slowly added dropwise over one hour, followed by stirring at room temperature for 2 hours. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1:1 to 1:2) to obtain the title compound (43.8 g, 65%). [0585] 1H NMR (CDCl3, 400 MHz): delta 5.36-5.34 (m, 1H), 4.53-4.51 (m, 1H), 3.80 (s, 3H), 3.61-3.53 (m, 2H), 1.46 (s, 9H)
With pyridine; iodine; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 4h;Inert atmosphere;
Boc-homoallyl glycine (9b) was synthesized using a three-step protocol from commercially available Boc-Ser-OMe (S2). In a typical procedure, a flask was charged with Boc-Ser-OMe (2.0 g, 9.1 mmol) and triphenylphosphine (3.6 g, 13.7 mmol, 1.5 eq.) under Ar(g). To this was added THF (20 mL) and the solution cooled to 0 C. by immersion in an ice bath. Pyridine (1.5 mL, 18.2 mmol, 2 eq.) was added dropwise, followed by solid iodine (3.5 g, 13.7 mmol, 1.5 eq.) in three portions at 0 C. The ice bath was removed and stirring was continued for 4 h at room temperature. The mixture was extracted with Et2O (3*20 mL). The combined organic layers were washed with 1M HCl (3*20 mL), 1M Na2S2O3 (2*20 mL), brine (2*20 mL) and dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was of sufficient purity to be used in the next step without further purification. The iodopropanoate S3 was dissolved in DMF (5 mL) and added dropwise to a flask containing activated zinc (2.4 g, 36.4 mmol, 4 eq.) at 0 C. under Ar(g). The reaction mixture was removed from the ice bath and allowed to stir at room temperature for 3 h, upon which TLC (4:1 petroleum ether: EtOAc) indicated loss of starting material and formation of a lower Rf spot. At this point, the reaction mixture was stopped to let the solid settle to the bottom. The supernatant was then carefully transferred by syringe to a suspension of copper (I) bromide (0.26 g, 1.8 mmol) in DMF (mL) at -15 C. that also contained allyl chloride (1.3 mL, 15.5 mmol, 1.7 eq.). After complete addition, the cooling bath was removed and stirring was continued overnight. At this point, EtOAc (20 mL) was added to the reaction mixture and stirring was continued for 15 min. To the mixture was added H2O (20 mL), the organic layer was removed and successively washed with 1M Na2S2O3 (2*20 mL), H2O (2*20 mL), brine (2*20 mL), and dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 8:1 petroleum ether:EtOAc) to afford 2.0 g (90%) of (9b) as a colorless oil. 1H NMR (500 MHz, CDCl3) delta 5.72 (ddt, J=16.9, 10.2, 6.6 Hz, 1H), 5.18-5.07 (m, 1H), 5.01-4.90 (m, 2H), 4.26-4.23 (m, 1H), 3.67 (s, 3H), 2.08-2.01 (m, 2H), 1.88-1.79 (m, 1H), 1.70-1.61 (m, 1H), 1.37 (s, 9H); 13C NMR (126 MHz, CDCl3) delta 173.11, 155.23, 136.87, 115.50, 79.64, 52.09, 51.99, 31.85, 29.39, 28.21 (3C). HRMS (ESI) m/z calcd for C12H21NO4 [M+H]+: 244.1471. found 244.1474.
With 1H-imidazole; iodine; triphenylphosphine; In dichloromethane; at 0℃; for 2h;Inert atmosphere;
Under nitrogen atmosphere, triphenyl phosphine (911 mg, 3.5 mmol) andimidazole (237 mg, 3.5 mmol) were dissolved in dry dichloromethane (12 mL). To this solution cooled on an icebath was added iodine (899 mg, 3.5 mmol). The mixture was stirred at rt for 10 min and then cooled on an icebath again. To the resulting yellow suspension was added a solution of 5 (507 mg, 2.3 mmol) in drydichloromethane (8 mL). After stirring for 2 h on an ice bath, the reaction mixture (a yellow suspension) waspassed through a short silica gel column (hexane:Et2O = 1:1) to remove the precipitates. The eluent wasevaporated to give crude 8 as an orange oil. Obtained 8 and bis-(p-methylbenzyl) diselenide (385 mg, 1.1mmol) were dissolved in a mixture of MeOH (8 mL) and Et2O (12 mL). The solution was cooled on an ice bathand then added with sodium borohydride until the solution color disappeared. After stirring for 1 h, water wasadded to the resulting solution, and the mixture was extracted with EtOAc. The organic layer was washed withbrine, dried over MgSO4, and evaporated. The obtained crude product (a yellow oil) was purified by silica gelcolumn chromatography (hexane:EtOAc = 4:1) to give 7 as a pale yellow oil (741 mg, 83% from 5). When crude8 was purified by silica gel column chromatography, the yield of 7 was decreased to 75% from 5. Identity andpurity of 831 were confirmed by 1H NMR.
With 1H-imidazole; iodine; triphenylphosphine; In dichloromethane; at 0℃; for 2.33333h;
lambda/-(terf-butoxycarbonyl)-3-iodo-L-alanine methyl ester; Iodine (1.25 eq., 70.70 mmol, 17.94 g) was added portionwise to a mixture of PPh3 (1.25 eq., 70.70 mmol, 18.54 g) and imidazole (1.25 eq., 70.70 mmol, 4.81 g) in DCM (250 ml) at 0 deg C over 15 minutes. The cooling bath was removed and the mixture was stirred for 20 minutes. A solution of Boc-Ser-OMe (1 eq., 56.6 mmol, 12.40 g) in DCM (50 ml) was then added dropwise over 45 minutes at 0 deg C. The mixture was stirred at this temperature for a further 1 hour then warmed to room temperature. The mixture was filtered through silica (50% tBuOMe in ihexane eluant) then concentrated. 50% tBuOMe in ihexane was added and the precipitate formed was filtered off. The solution was concentrated and the residue purified by column <n="36"/>(silica, 15% -> 50% tBuOMe in ihexane) to give the product as a pale yellow oil which solidified on standing. The compound was stored in the dark until ready for use.1H NMR (400 MHz, CDCI3) delta; 5.38 (brd, 1 H), 4.50-4.56 (m, 1 H), 3.79 (s, 3H), 3.50-3.60 (m, 2H), 1.43 (s, 9H).
With 1H-imidazole; iodine; triphenylphosphine; In dichloromethane;
Starting from Boc-Ser-OMe, 6a was synthesized in 3 steps following the similar procedure reported for the synthesis of Boc-Sec(MPM)-OH.[S1] In brief, Boc-Ser-OMe was iodized with iodine, triphenylphosphine, and imidazole in DCM. The obtained crude product was reacted with di(benzhydryl) diselenide and sodium borohydride in a mixture solvent of MeOH and Et2O (2:3). The product was purified by silica gel column chromatography (EtOA-hexane 1:3). Obtained Boc-Sec(Bzh)-OMe was then saponified under a basic condition to give 6a as colorless crystals in 90% total yield. Product 6a was used for subsequent reactions after recrystallization from Et2O-hexane.
Zinc dust (1.18 g, 18 mmol, 3 eqv) was added to a flame dried nitrogen purged side arm round bottom flask. DMF (6 mL) was added via syringe followed by a sub-stoichiometric amount of iodine (240 mg, 0.9 mmol). Once the reaction mixture had turned colourless N(tert-Butoxycarbonyl)-3-iodo-L-alanine methyl ester (1 .97 g, 6 mmol, 1 eqv) was added. The reaction mixture was stirred at room temperature and gave a noticeable exotherm. Once the reaction mixture had cooled Pd(PPh3)2C12 (211 mg, 0.3 mmol, 0.05 eqv), and 2, 5, dibromopyridine (1 .848 g, 7.8 mmol, 1 .3 eqv) were added to the flask. The reaction was heated to 50 00 and left stirring overnight, under a positive pressure of nitrogen. Thereaction mixture was then partitioned between EtOAc and Brine, followed by extraction of the aqueous layer with EtOAc (2x). The organic layers were then combined, dried with MgSO4, and concentrated under reduced pressure. The crude compound was then purified by silica gel column using 15% EtOAc / 85% 40-60 petroleum ether to afford the desired compound 4 (1 .38 g, 3.84 mmol, 64% yield).Thick yellow oil; OH (400 MHz, ODd3) 1.44 (5, 9H), 3.25 (dd, J = 5.5, 15.0 Hz, 1H), 3.31(dd, J = 5.5, 15.0 Hz, 1H), 3.72 (5, 3H), 4.70 (td, J = 5.5, 8.5 Hz, 1H), 5.72 (d, J = 8.5 Hz,1H), 7.07 (d, J = 8.5 Hz, 1H), 7.75 (dd, J = 2.5, 8.5 Hz, 1H), 8.58 (d, J = 2.5 Hz, 1H); O(101 MHz, ODd3) 28.3, 38.8, 52.3, 52.7, 79.8, 119.0, 125.0, 139.1, 150.0, 155.2, 155.7,172.0; [ciD22 -12 (c 0.9, Acetone), [ciD22 +29 (c 1.0, CHCI3), lit, value [ciD17 -13.3 (c 0.9,Acetone). Proton and carbon NMR in agreement with the literature (Synthetic Communications 2009, 39, 523).
54%
The methyl N-(tert-butoxycarbonyl)-3-(5-hydroxypyridin-2-yl)-L-alaninate used as 5 the starting material is known and may be prepared as described below: Zinc dust (148.2 g, 2.28 M) was added to a 4 litre, 3 necked round-bottomed flask, purged with nitrogen and heated with a heat-gun for 10 minutes under vacuum. The slurry was cooled to room temperature and a solution of 1,2-dibromoethane (9.78 ml, 114 mmol) in DMF (500 ml) was added dropwise over a period of 10 minutes. The resulting suspension was heated at o 900C for 30 minutes and cooled to room temperature. Chlorotrimethylsilane (2.9 ml, 22.8 mmol) was added and the suspension was stirred for a further 30 minutes at room temperature. A solution of Boc-beta-iodo- AIa-OMe (125 g, 379.9 mmol) in DMF (800 ml) <n="152"/>was added dropwise over a period of 10 minutes and the resulting suspension was heated at 350C for 2 hours. The reaction mixture was cooled to room temperature and 2,5- dibromopyridine (117.1 g, 494 mmol) was added followed by (Ph3P)2PdCl2 (13.3 g, 19 mmol). The resulting suspension was heated at 680C for 2 hours, cooled to room5 temperature, filtered to remove the excess of zinc and the filtrate was partitioned between a mixture of water (2 liters) and ether (1 liter). The phases were separated and the aqueous phase was re-extracted with ether (2 x 500 ml), the organic phases were combined, dried (MgSO4), filtered and concentrated to afford a yellow oil. The yellow oil was purified by flash chromatography (petroleum ether /AcOEt 75/25) to afford methyl 3-(5- o bromopyridin-2-yl)-N-(ter?-butoxycarbonyl)-L-alaninate (3) (73.7 g, 54%) as a pale yellow solid; 1H NMR Spectrum: (CDCl3) delta 1.42 (9H, s), 3.19-3,35 (2H, m), 3.70 (3H, s), 4.64- 4.74 (IH, m), 5.67 (IH, d), 7.05 (IH, d), 7.73 (IH, dd), 8.57 (IH, d); Mass spectrum [M+H]+ 359, 361.
54%
An operation in which zinc (24.0 g, 0.360 mol) was heated at 200 C. for 30 minutes and cooled to room temperature was repeated three times, and then an N,N?-dimethylformamide solution (50 ml) of dibromoethane (3.40 g, 18.2 mmol) was added thereto. An operation in which the obtained reaction mixture was heated to 90 C. and then cooled to room temperature was repeated twice, and then chlorotrimethylsilane (0.400 g, 3.64 mmol) was added to the reaction mixture, followed by stirring at room temperature for 30 minutes. An N,N?-dimethylformamide solution (70 ml) of methyl N-(tert-butoxycarbonyl)-3-iodo-L-alaninate (20.0 g, 60.7 mmol) was added dropwise, followed by stirring at 35 C. for 2.5 hours. Then, 2,5-dibromopyridine (19.0 g, 80.7 mmol) and bis(triphenylphosphine)palladium(II) chloride (2.30 g, 3.30 mmol) were further added to the reaction solution, followed by stirring at 70 C. for 2 hours. After cooling to room temperature, the reaction solution was diluted with water, followed by extraction with ethyl acetate (200 ml×3). The extraction liquids were combined, washed with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. Then, the solvent was removed. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1:1 to 1:2) to obtain the title compound (11.7 g, 54%). [0588] 1H NMR (CDCl3, 400 MHz): delta 8.61 (s, 1H), 7.98-7.96 (m, 1H), 7.29-7.25 (m, 2H), 4.45-4.39 (m, 1H), 3.60 (s, 3H), 3.12-2.97 (m, 2H), 1.32 (s, 9H)
(2S)-2-tert-butoxycarbonylamino-3-cyclopent-1'-enyl-propanoic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
To a suspension of zinc (123 g, 1.90 mol) in DMF (500 mL) was added TMSC1 (46 mL) dropwise. The mixture was stirred at ambient temperature for 45 min. The upper clear liquid was drained out and the residue was washed with DMF (2x200 mL). The resulting solid was re-suspended in DMF (200 mL) and the mixture was cooled to 0 C. A solution of (i?)-methyl 2-((fert-butoxycarbonyl)amino)-3-iodopropanoate (104 g, 0.32 mol) in DMF (300 mL) was added. The mixture was stirred at 0 C under nitrogen for 20 min. The upper clear liquid was drained out and added dropwise to a solution of cyclopent-l-en-l-yl trifluoromethanesulfonate (90 g, 0.37 mol) and Pd(dppf)Cl2 (3.9 g, 4.7 mmol) in DMF (500 mL). After addition, the reaction mixture was stirred at 50 C under nitrogen overnight then cooled to ambient temperature. Brine (500 mL) was added and the resulting mixture was extracted with MTBE (3><300 mL). The organic layers were combined, washed with brine, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 100: 1 to 40: 1) to afford (S)-methyl 2-((tert- butoxycarbonyl)amino)-3-(cyclopent-l-en-l-yl)propanoate as a viscous oil (62 g, 72% yield).
Stage #1: N-(tert-butoxycarbonyl)-L-3-iodoalanine methyl ester With iodine; zinc In N,N-dimethyl-formamide at 20℃; Inert atmosphere;
Stage #2: bromobenzene With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0) In N,N-dimethyl-formamide at 50℃; for 3h; Inert atmosphere;
60%
Stage #1: N-(tert-butoxycarbonyl)-L-3-iodoalanine methyl ester With iodine; zinc In N,N-dimethyl-formamide for 0.0833333h;
Stage #2: bromobenzene With tris-(o-tolyl)phosphine In N,N-dimethyl-formamide at 50℃; for 2h; Further stages.;
To an amberized flask containing activated Zn dust (0.349 g, 5.51 mmol) under Ar is added THF (2 mL) and 1,2-dibromoethane (0.018 mL, 0.21 mmol). The suspension is brought to reflux for several minutes, cooled to approximately 30 C., and TMSCl (0.17 mL of a 1 M solution in THF) is added. The reaction mixture is stirred at 40+/-5 C. for 30 min and then is cooled to below rt. A solution of N-[(1,1-dimethylethoxy)carbonyl]-3-iodo-L-alanine methyl ester [93267-04-0] (1.81 g, 5.50 mmol) in 11:7 dimethylacetamide/THF (9.0 mL) is added, and the resulting reaction mixture is stirred at 45 C. for 5 h. The reaction mixture is cooled to below rt, and solid PdCl2(PPh3)2 (0.192 g) is added, followed immediately by addition of a degassed solution of the iodopyridine (0.936 g, 2.76 mmol) in 1:1 THF/dimethylacetamide (5.6 mL). This reaction mixture is stirred for 4 h at 45 C. It is cooled to 0 C., quenched with sat'd aq NH4Cl, and extracted with EtOAc. The combined EtOAc portions are washed with sat'd aq NH4Cl and brine. The EtOAc solution is dried, filtered and concentrated to give a green-yellow colored foam, that upon purification by silica flash chromatography (7:3 hexanes/EtOAc) gives 0.879 g (1.85 mmol, 60%) of the title product: TLC (7:3 hexanes/EtOAc) Rf 0.21; 1H NMR (CDCl3, 300 MHz) d 7.39 (1H), 7.00 (1H), 5.46 (1H), 4.61 (1H), 4.13 (1H), 3.80 (3H), 3.62 (1H), 3.20 (1H), 2.13-1.53 (6H), 1.42 (9H).
(S)-Methyl 2-(tert-butoxycarbonylammo)-3-(6-(trifluoromethyl)pyridin-3-yl)propanoate: To a 250 mL round-bottomed flask was added zinc, nanosize activated powder (0.75 mL, 82 mmol, Aldrich), and DMF (14 mL, 177 mmol). The mixture was stirred and treated dropwise with 1 ,2-dibromoethane (0.35 mL, 4.1 mmol, Aldrich). The resulting mixture was then stirred at 90 0C for 30 minutes. After cooling, chlorotrimethylsilane (0.10 mL, 0.82 mmol, Aldrich) was added, and the mixture was stirred at room temperature for 30 minutes. To this stirred mixture, Boc-3-iodo-L-alanine methyl ester (4.5 g, 14 mmol, Aldrich) in 10 mL DMF was added dropwise via an addition funnel. After addition, the combined mixture was stirred at room temperature for 4 hours. To this mixture was then added dichlorobis(triphenylphosphine)palladium(0) (0.48 g, 0.68 mmol, Aldrich) and a 10 mL DMF solution of 5-bromo-2- (trifluoromethyl)pyridine (4.0 g, 18 mmol, Aldrich). The resulting mixture was stirred at 25 0C overnight. The reaction mixture was filtered through Celite brand filter aid, diluted with NH4Cl and water (70 mL each), and diluted with EtOAc (200 mL). The aqueous layer was extracted with EtOAc (2 x 100 mL), and the combined organic layers were then washed with saturated sodium chloride (1 x 50 mL), and water (1 x 5 mL), and then dried over Na2SO4, filtered, and concentrated in vacuo. The remaining residue was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient (5 - 50 % EtOAc in hexane) to provide (S)-methyl 2-(tert-butoxycarbonylamino)-3-(6-(trifluoromethyl)pyridin-3-yl)propanoate (4.39 g, 93 %): LCMS (API-ES) m/z (%): 349.3 (100 %, M++H).
37%
(S)-Methyl 2-(tert-butoxycarbonylamino)-3-(6-(trifluoromethyl)pyridin-3-yl)propanoate. Zinc (12 g, 186 mmol) and methylene dibromide (1.6 g, 9.3 mmol) were stirred in DMF (45 mL) at 90C for 30 minutes. After cooling to room temperature, trimethylsilyl chloride (0.24 mL, 1.9 mmol) was added, and the mixture was stirred at room temperature 30 minutes. Boc-3-iodo-l-alanine methyl ester (13 g, 40 mmol)(commercially available from 3B Scientific Corporation Product List (Order Number 3 B3 -063312)) in 15 mL DMF was added in one portion. After stirring at room <n="197"/>temperature for 4 hours, dichlorobis(triphenyl-phosphine)palladium (ii) (1.2 g, 1.7 mmol) and 5-bromo-2-(trifluoromethyl)pyridine (7.0 g, 31.0 mmol)(commercially available from 3B Scientific Product List (Order Number 3B3-009312)) in 20 mL DMF were added. The reaction mixture was stirred at room temperature 16 hours. The reaction mixture was filtered through a pad of Celite and washed with EtOAc (3 x). The solvent was evaporated. The residue was taken up in EtOAc and the organic layer was washed with saturated ammonium chloride (300 mL) and brine, dried over sodium sulfate, and evaporated. The residue was purified by chromatography on silica gel (20 % EtOAc in hexane) to provide the product as a tan solid (4.0 g, 37 %). LCMS (API-ES) m/z (%): 349.1 (100%, M+H+).
37%
[00367] (S)-Methyl 2-(tert-butoxycarbony lamino)-3 -(6-(trifluoromethy l)pyridin-3-yl)propanoate. Zinc (12 g, 186 mmol) and methylene dibromide (1.6 g, 9.3 mmol) were stirred in DMF (45 mL) at 9O0C for 30 minutes. After cooling to room temperature, trimethylsilyl chloride (0.24 mL, 1.9 mmol) was added, and the mixture was stirred at room temperature 30 minutes. Boc-3-iodo-l-alanine methyl ester (13 g, 40 mmol)(commercially available from 3B Scientific Corporation Product List (Order Number 3B3-063312)) in 15 mL DMF was added in one portion. After stirring at room temperature for 4 hours, dichlorobis(triphenyl-phosphine)palladium (ii) (1.2 g, 1.7 mmol) and 5-bromo-2-(trif.uoromethyl)pyridine (7.0 g, 31.0 mmol)(commercially available from 3B Scientific Product List (Order Number 3B3-009312)) in 20 mL DMF were added. The reaction mixture was stirred at room temperature 16 hours. The reaction mixture was filtered through a pad of Celite and washed with EtOAc (3 x). The solvent was evaporated. The residue was taken up in EtOAc and the organic layer was washed with saturated ammonium chloride (300 mL) and brine, dried over sodium sulfate, and evaporated. The residue was purified by chromatography on silica gel (20 % EtOAc in hexane) to provide the product as a tan solid (4.0 g, 37 %). LCMS (API-ES) m/z (%): 349.1 (100%, M+Ff).
Stage #1: N-(tert-butoxycarbonyl)-L-3-iodoalanine methyl ester With iodine; zinc In N,N-dimethyl-formamide at 0 - 20℃; for 0.5h;
Stage #2: 1-bromo-4-(phenylsulphonyl)benzene In N,N-dimethyl-formamide at 0 - 65℃; for 15h;
102.a
a) (S)-Methyl 2-(tert-butoxycarbony lamino)-3 -(4-(phenylsulfonyl)phenyl)propanoateZinc dust (<10 micron particle size) (0.271 g) and iodine (0.016 g) were weighed into a 3- neck 10OmL round bottomed flask with a magnetic stirrer. The flask was heated with a heat gun for 10 min, then evacuated and flushed with nitrogen three times and allowed to cool to RT. Dry DMF (0.5 mL) followed by a solution of (R)-methyl 2-(te/t-butoxycarbonylamino)- 3-iodopropanoate (1.05 g) in DMF (7 mL) were added via syringe to the well-stirred suspension of zinc dust, and the mixture was cooled to 0 0C and stirred for 30 min. The ice bath was removed before l-bromo-4-(phenylsulfonyl)benzene (0.948 g) and dichlorobis(triphenylphosphine)-palladium(II) (0.090 g) were added, and then the mixture was heated at 65 0C for 15 h. The cooled mixture was poured into a 2% w/v citric acid solution and this was extracted thrice with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo to leave an orange oil. This was purified by flash silica chromatography, eluting with 1 : 4 to 1 : 3 ethyl acetate / isohexane, to give the subtitle compound (0.72 g) as a pale brown gum. 1H NMR (299.946 MHz, CDCl3) δ 7.94 (d, J = 8.3 Hz, 2H), 7.87 (d, J = 8.7 Hz, 2H), 7.60 - 7.47 (m, 4H), 7.31 - 7.25 (m, IH), 5.03 - 4.93 (m, IH), 4.63 - 4.53 (m, IH), 3.69 (s, 3H), 3.19 (dd, J = 13.6, 5.7 Hz, IH), 3.10 - 2.98 (m, IH), 1.36 (s, 9H).
tert-Butyl (at)(3.5(at)-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3-y11 carbamate; To a cooled oven dried flask under nitrogen was added zinc dust (2.45 g, 7.44 mmol) followed by anhydrous DMF (9.1 ml) and chlorotrimethylsilane (1.25 ml, 9.89 mmol). The suspension was stirred vigorously for 10 mins, allowed to stand for 40 mins, the solvent was removed via a syringe and the residue heated under vacuum with a heat gun for 5 mins and allowed to cool. A solution of methyl N-(tert-butoxycarbonyl)-3-iodo-L-alaninate (2.45 g, 7.44 mmol) in anhydrous DMF (9.1 ml) was added and the suspension was stirred vigorously for 30 mins. Dichlorobis (triphenylphosphine)palladium mgs, 0.401 mmol) and 3-amino- 2-bromopyridine (1.71 g, 9.90 mmol) were added and the reaction mixture was allowed to stir at ambient temperature for 48 hrs. The mixture was filtered through a pad of celite, washed with EtOAc (2 x 200 ml), the filtrate was washed with brine (2 x 100ml), the organic extract was dried (MgS04) and concentrated to leave crude product. The residue was purified on a 120g Redisep silica cartridge (Isco CompanionNo.; eluting with 30-80% EtOAc-isohexane) to provide the title compound as a solid (1.04 g, 54%) ; ¹H NMR (CDC13) 1.49 (s, 9H), 3.09 (t, 1 H), 3 .62 - 3 .70 (dd, 1 H), 4.47 - 4.57 (m, 1 H), 5.41 (d, 1 H), 7.10 - 7.15 (m, 2H), 8.25 - 8.27 (m, 1 H), 8.3 8 (brs, 1 H) ; MS 286 (M+Na)+, 264 (MH)+.
Stage #1: N-(tert-butoxycarbonyl)-L-3-iodoalanine methyl ester With chloro-trimethyl-silane; zinc In N,N-dimethyl-formamide at 20 - 50℃; for 0.420833h; Inert atmosphere;
Stage #2: 5,6-dihydro-4-trifluoromethylsulfonyloxy-2H-pyran In N,N-dimethyl-formamide at 50℃; Inert atmosphere;
38
Intermediate: (f?)-methyl 2-(te/t-butoxycarbonyl)-3-(3,6-dihydro-2/-/-pyran-4- yl)propanoate (38b).(38b)In rigorously anaerobic conditions, zinc dust (72.7 g, 1.11 mol) was suspended in anhydrous DMF (100 ml_), and to the stirred solution, trimethylsilyl chloride (23 ml_ 0.18 mol) was added (exotherm to 55°C). The mixture was stirred for 20 minutes, during which time the supernatant became brown in color. The mixture was allowed to settle, and the supernatant decanted off using vacuum. The activated zinc powder was washed with DMF (4 x 50 ml_), until the supernatant solvent became colorless. (f?)-methyl 2-(tert-butoxycarbonylamino)-3-iodopropanoate (85 g, 0.26 mol) was dissolved in DMF under argon, added in one portion to the activated zinc powder and stirred briskly. After approximately 5 minutes, the mixture self heated rapidly (21 -300C over about 15 seconds). The stirring was stopped and the cooling bath immediately applied, allowing the exothermic reaction to be ceased at 500C. As the temperature subsided, the cooling bath was removed and the mixture stirred at ambient temperature for 20 minutes and allowed to settle. The supernatant was syringed into a pre-prepared solution of Intermediate (38a) (60 g, 0.26 mol) and PdCI2(PPh3^ (5.44 g, 7.75 mmol). The metallic solids were washed with DMF (30 ml_) and the washings added to the thflate/catalyst mixture, which was stirred at 50°C overnight. The solution was concentrated under reduced pressure and the crude product slurried in water (500 ml_) and 20% ethyl acetate in hexane (500 ml_). The mixture was filtered and partitioned, and the aqueous layer re-extracted with 20% ethyl acetate in hexane (500 ml_). The combined organic phases were washed with brine (500 ml_), dried over MgSO4, and concentrated under reduced pressure. The semi-crude product was obtained as a free running red-brown oil (81 g), which was purified twice by dry-flash chromatography (SiO2, ethyl acetate and hexanes, 0 to 100%) followed by carbon treatment in 10% ethyl acetate/hexane to afford (38b): 1H NMR (CDCI3, 300 MHz): δ 5.50 (1 H), 4.95 (1 H), 4.40 (1 H), 4.10 (2H), 3.77 (2H), 3.73 ( 3H), 2.50 (1 H), 2.31 (1 H), 2.07 (2H), 1.43 (9H).
Stage #1: N-(tert-butoxycarbonyl)-L-3-iodoalanine methyl ester With chloro-trimethyl-silane; N,N-dimethyl-formamide; zinc at 20 - 30℃; Inert atmosphere;
Stage #2: 5,6-dihydro-4-trifluoromethylsulfonyloxy-2H-pyran With bis-triphenylphosphine-palladium(II) chloride In N,N-dimethyl-formamide
In rigorously anaerobic conditions, zinc dust (72.7 g, 1.11 mol) was suspended in anhydrous Λ/,Λ/-dimethylformamide (100 ml_), and to the stirred solution, trimethylsilyl chloride (23 ml_ 0.18 mol) was added (exotherm to 55°C). The mixture was stirred for 20 minutes, during which time the supernatant became brown in color. The mixture was allowed to settle, and the supernatant decanted off using vacuum. The activated zinc powder was washed with /V,/V-dimethylfornnannide (4 x 5OmL), until the supernatant solvent became colorless.(R)-methyl 2-(tert-butoxycarbonylamino)-3-iodopropanoate (Oakwood Products, West Columbia, SC) (85 g, 0.26 mol) was dissolved in Λ/,Λ/-dimethylformamide under argon, added in one portion to the activated zinc powder and stirred briskly. After approximately 5 minutes, the mixture self heated rapidly (21-300C over about 15 seconds). The stirring was stopped and the cooling bath immediately applied, allowing the exothermic reaction to be ceased at 500C. As the temperature subsided, the cooling bath was removed and the mixture stirred at ambient temperature for 20 minutes and allowed to settle. The supernatant was syringed into a pre-prepared solution of (l-10a) (60 g, 0.26 mol) and PdCI2(PPh3^ (5.44 g, 7.75 mmol). The metallic solids were washed with Λ/,Λ/-dimethylformamide (30 ml_) and the washings added to the triflate/catalyst mixture, which was stirred at 50°C overnight. The solution was concentrated under reduced pressure and the crude product slurried in water (500 ml_) and 20% ethyl acetate in hexane (500 ml_). The mixture was filtered and partitioned, and the aqueous layer re-extracted with 20% ethyl acetate in hexane (500 ml_). The combined organic phases were washed with brine (500 ml_), dried over MgSO4, and concentrated under reduced pressure. The semi-crude product was obtained as a free running red-brown oil (81 g), which was purified twice by dry-flash chromatography (SiO2, ethyl acetate and Hexanes, 2 to 20%) followed by carbon treatment in 10% ethyl acetate/hexane to afford (l-10b): 1H NMR (CDCI3, 300 MHz): δ 5.50 (1 H), 4.95 (1 H), 4.40 (1 H), 4.10 (2H), 3.77 (2H), 3.73 ( 3H), 2.50 (1 H), 2.31 (1 H), 2.07 (2H), 1.43 (9H).
Stage #1: N-(tert-butoxycarbonyl)-L-3-iodoalanine methyl ester With chloro-trimethyl-silane; zinc In N,N-dimethyl-formamide at 20 - 50℃;
Stage #2: 5,6-dihydro-4-trifluoromethylsulfonyloxy-2H-pyran In N,N-dimethyl-formamide at 50℃;
Intermediate (1b): (R)-methyl 2-(tert-butoxycarbonyl)-3-(3,6-dihydro-2H-pyran-4-yl)propanoate; In rigorously anaerobic conditions, zinc dust (72.7 g, 1.11 mol) was suspended in anhydrous N,N-dimethylformamide (100 mL), and to the stirred solution, trimethylsilyl chloride (23 mL 0.18 mol) was added (exotherm to 55° C.). The mixture was stirred for 20 minutes, during which time the supernatant became brown in color. The mixture was allowed to settle, and the supernatant decanted off using vacuum. The activated zinc powder was washed with N,N-dimethylformamide (4×50 mL), until the supernatant solvent became colorless.(R)-methyl 2-(tert-butoxycarbonylamino)-3-iodopropanoate (85 g, 0.26 mol) (Sigma-Aldrich, Milwaukee, Wis.) was dissolved in N,N-dimethylformamide under argon, added in one portion to the activated zinc powder and stirred briskly. After approximately 5 minutes, the mixture self heated rapidly (21-30° C. over about 15 seconds). The stirring was stopped and the cooling bath immediately applied, allowing the exothermic reaction to be ceased at 50° C. As the temperature subsided, the cooling bath was removed and the mixture stirred at ambient temperature for 20 minutes and allowed to settle. The supernatant was syringed into a pre-prepared solution of Intermediate (1a) (60 g, 0.26 mol) and PdCl2(PPh3)2 (5.44 g, 7.75 mmol). The metallic solids were washed with N,N-dimethylformamide (30 mL) and the washings added to the triflate/catalyst mixture, which was stirred at 50° C. overnight. The solution was concentrated under reduced pressure and the crude product slurried in water (500 mL) and 20% ethyl acetate in hexane (500 mL). The mixture was filtered and partitioned, and the aqueous layer re-extracted with 20% ethyl acetate in hexane (500 mL). The combined organic phases were washed with brine (500 mL), dried over MgSO4, and concentrated under reduced pressure. The semi-crude product was obtained as a free running red-brown oil (81 g), which was purified twice by dry-flash chromatography (SiO2, ethyl acetate and hexanes, 0 to 100%) followed by carbon treatment in 10% ethyl acetate/hexane to afford Intermediate (1b): 1H NMR (CDCl3, 300 MHz): δ 5.50 (1H), 4.95 (1H), 4.40 (1H), 4.10 (2H), 3.77 (2H), 3.73 (3H), 2.50 (1H), 2.31 (1H), 2.07 (2H), 1.43 (9H).
To a stirred suspension of zinc powder (2.1 g, 32.3 mmol) in anhydrous N,N-d m ethyl form a ide (10 mL) under nitrogen was added iodine (170 mg). After 5min, a solution of methyl (i?)-2-((/er/-butoxycarbonyl)amino)-3-iodopropanoate (4.2 g, 12.8 mmol) in A( A'-di m ethyl form a i de (10 mL) was added slowly over lOmin. The mixture was stirred at rt for 30min. A suspension of <strong>[75344-77-3]4-bromo-3,5-dimethylbenzonitrile</strong> (2.5 g, 12 mmol), Pd2(dba)3 (205 mg, 0.22 mmol), and 2-dicyclohexylphosphino-2',6'- dimethoxybiphenyl (Sphos, 210 mg, 0.51 mmol) in A( A-di m eth yl form am i de (10 mL) was added into the zinc reagent mixture. The reaction mixture was heated at 50C and stirred overnight. After cooling, the reaction mixture was quenched with water, diluted with EtOAc and filtered through Celite. The filter cake was washed with EtOAc and the filtrate was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography over silica gel (0-20% EtOAc/CH2Cl2) to afford the desired product as a white solid (2.0 g, 50%). LC-MS: 355.2 [M+Na]+; 1H NMR (400MHz, CDCl3) d 7.30 (s, 2H), 5.13 (d, 1H, J = 8.8 Hz), 4.56 (q, 1H, J = 8.0 Hz), 3.67 (s, 3H), 3.15-3.00 (m, 2H), 2.38 (s, 6H), 1.35 (s, 9H).
Example 2; Preparation of (S)-2-tert-Butoxvcarbonvlamino-3-(4-cvano-2,6-dimethvl- phenvD-propionic acid methyl esterA 5OmL three-necked round bottom flask equipped with an addition funnel, magnetic stirrer, heating mantel, and thermocouple was charged under nitrogen dry DMAc (2mL), I2 (38.1 mg, 0.15mmol) and zinc powder activated (washed with 10% HCI, rinsed with H2O and acetone) (393 mg, 6 mmol). The resulting mixture was stirred at 23C until the red color of I2 disappeared (2 minutes). A solution of Boc-beta-iodo-L-alanine methyl ester (1 g, 3mmol) in DMAc (2 ml.) was added slowly, (temperature change from 210C to 29C) and the resulting mixture was stirred at 8O0C for 0.5-1 hour, then co cooled to 35C. To the resulting mixture were added, successively, 4-bromo-3,5-dimethyl- benzonithle (315 mg, 1.5mmol) in DMAc (6ml_), P(o-tol)3 (36.5 mg, 0.12 mmol) and Pd2(dba)3 (55 mg, O.Odeltammol). The resulting mixture was heated to 700C, with stirring for 1 hour, then cooled to ambient temperature. The resulting mixture was diluted with EtOAc (15ml_) and filtered with STAND SUPER-CEL 815520. The EtOAc solution was quenched with 1 N HCI (4OmL) and extracted with ethyl acetate (2OmL). The combined organic phases were washed with H2O (2 x 5OmL) and then with 50% brine, dried over Na2SO4 , filtered and evaporated to dryness in vacuo to yield a brown solid. The title compound was crystallized from EtOAc (5mL) and heptane (4OmL) to yield a white solid.
(S)-Methyl 2-(tert-butoxycarbonylamino)-3-(5-chloro-6-fluoropyridin-3- yl)propanoate: To a stirred suspension of zinc (0.89 mL, 96 mmol, Aldrich) in DMF (15 mL, 195 mmol) was added dibromomethane (0.33 mL, 4.8 mmol, Aldrich). The resulting mixture was then heated at 90 0C for 30 minutes. The mixture was then cooled, trimethylsilyl chloride (0.12 mL, 0.96 mmol, Aldrich) was added, and stirring was continued at room temperature for 30 minutes. Boc-3-iodo-l-alanine methyl ester (7.9 g, 24 mmol, Fluka) in DMF (15 mL) was added, and the mixture was stirred at room temperature for 4 hours prior to the introduction of Pd(PPh3)2Cl2 (0.56 g, 0.80 mmol, Aldrich) and a solution of <strong>[38185-56-7]5-bromo-3-chloro-2-fluoropyridine</strong> (3.38 g, 16 mmol) in DMF (15 mL). The resulting mixture was stirred at room temperature 16 hours and then was passed through a short path of Celite brand filter aid. The filter cake was washed with EtOAc (30 mL x 3) and the combined organic layers were washed with NH4Cl(aq), water, and brine successively. The solvent was evaporated and the residue was purified by flash column chromatography (ISCO Combiflash system, pure hexanes - 50 % EtOAc in hexanes) to provide the desired product (S)-methyl 2-(tert-butoxycarbonylamino)-3-(5- chloro-6-fluoropyridin-3-yl)propanoate (0.80 g, 15 %). LCMS (API-ES) m/z (%): 333.8 (100 %, M++H).
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;
(S)-Methyl 2-(tert-butoxycarbonylamino)-3-(4-(trifluoromethyl)- IH- imidazol-l-yl)propanoate: A 100 mL round-bottomed flask was charged with A- (trifluoromethyl)-lH-imidazole (1.75 g, 12.9 mmol), (R)-methyl 2-(tert- butoxycarbonylamino)-3-iodopropanoate (4.23 g, 12.9 mmol, Fluka catalog number 15126), cesium carbonate (4.82 g, 14.8 mmol, Aldrich), and 20 mL of DMF. The resulting mixture was stirred at room temperature for 12 hours and then was diluted with water and extracted with ether. The organic layers were washed with water (2 x 100 mL), dried (MgSO4), filtered, and concentrated to provide an oil. Purification via chromatography on silica gel (10 - 70 % EtOAc/hexane) gave (S)-methyl 2-(tert- butoxycarbonylamino)-3-(4-(trifluoromethyl)-lH-imidazol-l-yl)propanoate (3.00 g, 69 %) as a colorless oil. 1H NMR (CDCl3) delta 7.46 (s, IH), 7.19 (s, IH), 5.24 (br, IH), 4.64- 4.38 (m, 3H), 3.83 (s, 3H), 1.49 (s, 9H).
Methyl N-(tert-butoxycarbonyl)-3-(2-nitro-5-phenoxypyridin-3-yl)-L-alaninate (65); Trimethylsilyl chloride (0.348 ml, 2.74 mmol) was added to a stirring suspension of zinc dust (989 mg, 13.7 mmol) in dry DMF (1 mL) and the mixture was stirred for 30 min. The stirring was stopped, and the solids were allowed to settle for 10 min, at which time the supernatant was removed via syringe. The activated zinc was washed with DMF and the solvent was again removed with a syringe; the zinc was then dried under vacuum using a heat gun. A solution of methyl N-(tert-butoxycarbonyl)-3-iodo-L-alaninate (prepared according to S. van Zutphen et al., Tetrahedron Lett. 2007, 48, 2857-2859) (1.81 g, 5.49 mmol) in DMF (1.0 M) was added to the dry activated zinc, and the resulting suspension was stirred for 30 min at RT. The zincate solution was transferred via syringe into a dry flask under nitrogen. To this was sequentially added 3-bromo-2-nitro-5-phenoxypyridine (64) (1.35 g, 4.58 mmol), palladium(II) acetate (51.4 mg, 0.229 mmol) and then X-Phos (dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine, 218 mg, 0.458 mmol). The resulting solution was stirred at RT for 18 h. The reaction mixture was diluted with Et2O (100 mL), washed with water (5×20 mL), dried over Mg2SO4, filtered and concentrated in vacuo. Purification via silica gel chromatography (Eluants: 10% EtOAc in heptane, then 15%, then 20%) afforded the product as a yellow oil (297 mg, 16% yield). LCMS m/z 418.1 (M+1). 1H NMR (400 MHz, CDCl3) delta 1.38 (br s, 9H), 3.14-3.21 (m, 1H), 3.5 (m, 1H, assumed; obscured by residual Et2O), 3.74 (s, 3H), 4.62-4.68 (m, 1H), 5.19 (br d, J=8 Hz, 1H), 7.09-7.13 (m, 2H), 7.27-7.32 (m, 2H), 7.47 (br dd, J=8, 8 Hz, 2H), 8.15 (br s, 1H).
Methyl N-(tert-butoxycarbonyl)-2-nitro-5-phenoxy-L-phenylalaninate (91); Freshly distilled DMF (45 mL) was added to Zn powder (20.0 g, 306 mmol) under N2.Trimethylsilyl chloride (8.0 mL, 0.2 eq.) was added at RT and the resulting suspension was stirred vigorously for 35 min. The resulting pale orange supernatant was removed via syringe. The activated Zn was washed with DMF (2×30 mL). After removal of the DMF, the activated zinc was dried under vacuum using a heat gun. Methyl N-(tert-butoxycarbonyl)-3-iodo-L-alaninate (37.0 g, 112 mmol) was freshly recrystallized from petroleum ether, dried in vacuo, and dissolved in freshly distilled DMF (93 mL), and the solution was added to the activated zinc at 0 C. After 5 min, the cooling bath was removed. The reaction mixture was stirred for 20 min in a RT water bath, at which time TLC analysis indicated disappearance of the starting iodide. The grayish supernatant was transferred via syringe into a dry flask under N2, and the remaining zinc metal was washed with DMF (20 mL). To the flask containing the combined DMF fractions was added sequentially a solution of 2-bromo-1-nitro-4-phenoxybenzene (90) (30.0 g, 102 mmol) in DMF (18 mL), Pd(OAc)2 (1.1 g, 5.1 mmol), then dicyclohexylphosphino-2',4',6%-triisopropyl-1,1'-biphenyl (4.9 g, 10.2 mmol). The resulting brown solution was stirred at RT, and the solution turned red within 1 h. The reaction mixture was maintained at RT for 16 h. The reaction mixture was poured into EtOAc (400 mL), and the resulting suspension was filtered through Celite. The filtrate was washed with water (2×400 mL) and saturated aqueous sodium chloride solution (400 mL), and the separated aqueous phase was washed with EtOAc (2×150 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (Gradient: 0% to 25% EtOAc in heptane) to provide the title compound as a pale yellow solid (27.9 g, 66%). LCMS m/z 415.1 (M-1). 1H NMR (500 MHz, CDCl3) delta 1.38 (s, 9H), 3.21 (dd, J=13, 9 Hz, 1H), 3.57 (dd, J=13.3, 5.2 Hz, 1H), 3.73 (s, 3H), 4.65-4.72 (m, 1H), 5.17 (br d, J=8 Hz, 1H), 6.87-6.92 (m, 2H), 7.07-7.10 (m, 2H), 7.24-7.27 (m, 1H), 7.44 (dd, J=7.9, 7.9 Hz, 2H), 8.03 (d, J=8.8 Hz, 1H).tert-Butyl [(3S)-1-hydroxy-2-oxo-6-phenoxy-1,2,3,4-tetrahydroquinolin-3-yl]carbamate (92) In three equal batches, methyl N-(tert-butoxycarbonyl)-2-nitro-5-phenoxy-L-phenylalaninate (91) (9.33 g, 22.3 mmol) was dissolved in pyridine (250 mL) in a Parr bottle and Pt/C (5% w/w dry catalyst, 4.4 g, 1.1 mmol) was added. The reaction mixture was placed under H2 atmosphere (30 psi) and shaken for 3 h. The combined reaction mixtures were filtered through Celite with EtOAc washing. The filtrate was concentrated in vacuo and the crude residue was purified by silica gel chromatography (Gradient: 20% to 50% EtOAc in heptane) to provide the title compound as a solid (19.2 g, 77%). LCMS m/z 369.1 (M-1). 1H NMR (400 MHz, CD3OD) delta 1.47 (s, 9H), 2.96-3.06 (m, 2H), 4.39 (dd, J=12, 8 Hz, 1H), 6.89-6.99 (m, 4H), 7.09 (tt, J=7.4, 1.1 Hz, 1H), 7.31-7.37 (m, 3H).
Step a) (S)- Methyl 2-(tert-butoxycarbonylamino)-3-(3-oxocvclopent-l-env0propanoate (BB10- a)Boc- -Iodo-Ala-OMe (1.0 g, 3 mmol) was added to a slurry of zinc dust (0.596 g, 9 mmol) and I2 (0.2 mg) in 3 ml DMF under N2. The mixture was stirred for 1 h then Pd2dba3 (0.070 g, 0.076 mmol), SPhos ligand (0.062 g, 0.15 mmol), and 1,3-cyclopentanedione (0.63 g, 3.9 mmol) were added. The reaction mixture was stirred over night. Purification by flash chromatography (0- 100% EtOAc in iso-hexane) gave compound the title compound (0.468 g) in 70% yield.[M+H]+: 284.
Degassed anhydrous DMF (42 mL) was added to zinc (13.72 g, 209.8 mmol) under a flow of argon. Chlorotrimethylsilane (5.30 mL, 42.0 mmol) was added and the mixture stirred vigorously for 30 min. Stirring was stopped and the zinc was allowed to settle. The supernatant was decanted under a flow of argon and the zinc washed with degassed DMF (2 × 20 mL). A solution of Boc-3-iodoalanine methyl ester (29.9 g, 90.9 mmol) in degassed DMF (75 mL) was added to the zinc. Upon addition an exotherm was observed. The cloudy gray solution was stirred for 30 min at room temperature and then the zinc was allowed to settle. This was repeated for a second batch of zincate. The two batches of zincate were combined by decanting the supernatant into a clean flask under a flow of argon. A solution of bromide 8 (40.0 g, 140 mmol) in degassed DMF (120 mL), palladium acetate (1.57 g, 6.99 mmol), and X-Phos (6.67 g, 14.0 mmol) were added sequentially. The reaction was heated at 40 C. After 16 h the reaction mixture was poured into water (400 mL) and ethyl acetate (250 mL) was added. The mixture was filtered through a pad of celite, washing the filter cake with ethyl acetate (2 × 50 mL). The layers were separated, the aqueous extracted with ethyl acetate (100 mL) and the organics combined. The organics were then washed with brine (5 × 400 mL), dried (MgSO4), and concentrated in vacuo. The resulting residue was purified by dry flash chromatography (2% ethyl acetate in heptane to 20%) to give compound 9 as a brown solid (35.95 g, 63%).1H NMR (400 MHz, CDCl3): 7.84 (s, 1H), 7.47-7.36 (m, 2H), 5.22-5.14 (m, 1H), 4.72-4.63 (m, 1H), 3.74 (s, 3H), 3.57 (dd, 1H), 3.25-3.15 (m, 1H), 1.33 (s, 9H).
General procedure: A 1 M stock of the zincate was prepared as follows: To a suspension of zinc powder (196 mg, 2.0 equiv, based on the iodoserine, dried under vacuum using a heat gun) was added DMF (0.7 mL) and catalytic iodine (50 mg, 0.19 mmol). The reaction mixture turned from colorless to red to colorless again in ?2 min. After the return to colorless a DMF solution (1.9 mL) of the iodoserine was added followed by additional iodine (50 mg). The reaction turned from pale yellow to red, and back to colorless with an associated exotherm. The solution was stirred until the exotherm subsided, was cooled to room temp (?25 min) and was stirred until the iodoserine disappeared as monitored by TLC. The zincate solution was syringed away from the excess zinc and was added to a separate flask containing Pd(OAc)2 (4 mg, 0.018 mmol), X-Phos (15 mg, 0.032 mmol), and the aryl bromide (1.88 mmol) in DMF (0.5 mL). The resulting mixture was stirred at room temperature overnight. Upon completion as indicated by TLC, the reaction was quenched with satd NH4Cl (10 mL), poured into H2O (50 mL) and extracted with EtOAc (2 × 50 mL). The organic layers were washed with H2O (2 × 100 mL), brine (1 × 100 mL), dried over MgSO4, filtered, and concentrated to a crude oil. The desired material was isolated via flash chromatography.
General procedure: A 1 M stock of the zincate was prepared as follows: To a suspension of zinc powder (196 mg, 2.0 equiv, based on the iodoserine, dried under vacuum using a heat gun) was added DMF (0.7 mL) and catalytic iodine (50 mg, 0.19 mmol). The reaction mixture turned from colorless to red to colorless again in ?2 min. After the return to colorless a DMF solution (1.9 mL) of the iodoserine was added followed by additional iodine (50 mg). The reaction turned from pale yellow to red, and back to colorless with an associated exotherm. The solution was stirred until the exotherm subsided, was cooled to room temp (?25 min) and was stirred until the iodoserine disappeared as monitored by TLC. The zincate solution was syringed away from the excess zinc and was added to a separate flask containing Pd(OAc)2 (4 mg, 0.018 mmol), X-Phos (15 mg, 0.032 mmol), and the aryl bromide (1.88 mmol) in DMF (0.5 mL). The resulting mixture was stirred at room temperature overnight. Upon completion as indicated by TLC, the reaction was quenched with satd NH4Cl (10 mL), poured into H2O (50 mL) and extracted with EtOAc (2 × 50 mL). The organic layers were washed with H2O (2 × 100 mL), brine (1 × 100 mL), dried over MgSO4, filtered, and concentrated to a crude oil. The desired material was isolated via flash chromatography.
General procedure: A 1 M stock of the zincate was prepared as follows: To a suspension of zinc powder (196 mg, 2.0 equiv, based on the iodoserine, dried under vacuum using a heat gun) was added DMF (0.7 mL) and catalytic iodine (50 mg, 0.19 mmol). The reaction mixture turned from colorless to red to colorless again in ?2 min. After the return to colorless a DMF solution (1.9 mL) of the iodoserine was added followed by additional iodine (50 mg). The reaction turned from pale yellow to red, and back to colorless with an associated exotherm. The solution was stirred until the exotherm subsided, was cooled to room temp (?25 min) and was stirred until the iodoserine disappeared as monitored by TLC. The zincate solution was syringed away from the excess zinc and was added to a separate flask containing Pd(OAc)2 (4 mg, 0.018 mmol), X-Phos (15 mg, 0.032 mmol), and the aryl bromide (1.88 mmol) in DMF (0.5 mL). The resulting mixture was stirred at room temperature overnight. Upon completion as indicated by TLC, the reaction was quenched with satd NH4Cl (10 mL), poured into H2O (50 mL) and extracted with EtOAc (2 × 50 mL). The organic layers were washed with H2O (2 × 100 mL), brine (1 × 100 mL), dried over MgSO4, filtered, and concentrated to a crude oil. The desired material was isolated via flash chromatography.
General procedure: A 1 M stock of the zincate was prepared as follows: To a suspension of zinc powder (196 mg, 2.0 equiv, based on the iodoserine, dried under vacuum using a heat gun) was added DMF (0.7 mL) and catalytic iodine (50 mg, 0.19 mmol). The reaction mixture turned from colorless to red to colorless again in ?2 min. After the return to colorless a DMF solution (1.9 mL) of the iodoserine was added followed by additional iodine (50 mg). The reaction turned from pale yellow to red, and back to colorless with an associated exotherm. The solution was stirred until the exotherm subsided, was cooled to room temp (?25 min) and was stirred until the iodoserine disappeared as monitored by TLC. The zincate solution was syringed away from the excess zinc and was added to a separate flask containing Pd(OAc)2 (4 mg, 0.018 mmol), X-Phos (15 mg, 0.032 mmol), and the aryl bromide (1.88 mmol) in DMF (0.5 mL). The resulting mixture was stirred at room temperature overnight. Upon completion as indicated by TLC, the reaction was quenched with satd NH4Cl (10 mL), poured into H2O (50 mL) and extracted with EtOAc (2 × 50 mL). The organic layers were washed with H2O (2 × 100 mL), brine (1 × 100 mL), dried over MgSO4, filtered, and concentrated to a crude oil. The desired material was isolated via flash chromatography.
methyl N-(tert-butoxycarbonyl)-3-fluoro-6-nitro-L-phenylalaninate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
General procedure: A 1 M stock of the zincate was prepared as follows: To a suspension of zinc powder (196 mg, 2.0 equiv, based on the iodoserine, dried under vacuum using a heat gun) was added DMF (0.7 mL) and catalytic iodine (50 mg, 0.19 mmol). The reaction mixture turned from colorless to red to colorless again in ?2 min. After the return to colorless a DMF solution (1.9 mL) of the iodoserine was added followed by additional iodine (50 mg). The reaction turned from pale yellow to red, and back to colorless with an associated exotherm. The solution was stirred until the exotherm subsided, was cooled to room temp (?25 min) and was stirred until the iodoserine disappeared as monitored by TLC. The zincate solution was syringed away from the excess zinc and was added to a separate flask containing Pd(OAc)2 (4 mg, 0.018 mmol), X-Phos (15 mg, 0.032 mmol), and the aryl bromide (1.88 mmol) in DMF (0.5 mL). The resulting mixture was stirred at room temperature overnight. Upon completion as indicated by TLC, the reaction was quenched with satd NH4Cl (10 mL), poured into H2O (50 mL) and extracted with EtOAc (2 × 50 mL). The organic layers were washed with H2O (2 × 100 mL), brine (1 × 100 mL), dried over MgSO4, filtered, and concentrated to a crude oil. The desired material was isolated via flash chromatography.
General procedure: A 1 M stock of the zincate was prepared as follows: To a suspension of zinc powder (196 mg, 2.0 equiv, based on the iodoserine, dried under vacuum using a heat gun) was added DMF (0.7 mL) and catalytic iodine (50 mg, 0.19 mmol). The reaction mixture turned from colorless to red to colorless again in ?2 min. After the return to colorless a DMF solution (1.9 mL) of the iodoserine was added followed by additional iodine (50 mg). The reaction turned from pale yellow to red, and back to colorless with an associated exotherm. The solution was stirred until the exotherm subsided, was cooled to room temp (?25 min) and was stirred until the iodoserine disappeared as monitored by TLC. The zincate solution was syringed away from the excess zinc and was added to a separate flask containing Pd(OAc)2 (4 mg, 0.018 mmol), X-Phos (15 mg, 0.032 mmol), and the aryl bromide (1.88 mmol) in DMF (0.5 mL). The resulting mixture was stirred at room temperature overnight. Upon completion as indicated by TLC, the reaction was quenched with satd NH4Cl (10 mL), poured into H2O (50 mL) and extracted with EtOAc (2 × 50 mL). The organic layers were washed with H2O (2 × 100 mL), brine (1 × 100 mL), dried over MgSO4, filtered, and concentrated to a crude oil. The desired material was isolated via flash chromatography.
(S)-methyl 2-(tert-butoxycarbonylamino)-3-(2-nitrophenyl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
General procedure: A 1 M stock of the zincate was prepared as follows: To a suspension of zinc powder (196 mg, 2.0 equiv, based on the iodoserine, dried under vacuum using a heat gun) was added DMF (0.7 mL) and catalytic iodine (50 mg, 0.19 mmol). The reaction mixture turned from colorless to red to colorless again in ?2 min. After the return to colorless a DMF solution (1.9 mL) of the iodoserine was added followed by additional iodine (50 mg). The reaction turned from pale yellow to red, and back to colorless with an associated exotherm. The solution was stirred until the exotherm subsided, was cooled to room temp (?25 min) and was stirred until the iodoserine disappeared as monitored by TLC. The zincate solution was syringed away from the excess zinc and was added to a separate flask containing Pd(OAc)2 (4 mg, 0.018 mmol), X-Phos (15 mg, 0.032 mmol), and the aryl bromide (1.88 mmol) in DMF (0.5 mL). The resulting mixture was stirred at room temperature overnight. Upon completion as indicated by TLC, the reaction was quenched with satd NH4Cl (10 mL), poured into H2O (50 mL) and extracted with EtOAc (2 × 50 mL). The organic layers were washed with H2O (2 × 100 mL), brine (1 × 100 mL), dried over MgSO4, filtered, and concentrated to a crude oil. The desired material was isolated via flash chromatography.
General procedure: A 1 M stock of the zincate was prepared as follows: To a suspension of zinc powder (196 mg, 2.0 equiv, based on the iodoserine, dried under vacuum using a heat gun) was added DMF (0.7 mL) and catalytic iodine (50 mg, 0.19 mmol). The reaction mixture turned from colorless to red to colorless again in ?2 min. After the return to colorless a DMF solution (1.9 mL) of the iodoserine was added followed by additional iodine (50 mg). The reaction turned from pale yellow to red, and back to colorless with an associated exotherm. The solution was stirred until the exotherm subsided, was cooled to room temp (?25 min) and was stirred until the iodoserine disappeared as monitored by TLC. The zincate solution was syringed away from the excess zinc and was added to a separate flask containing Pd(OAc)2 (4 mg, 0.018 mmol), X-Phos (15 mg, 0.032 mmol), and the aryl bromide (1.88 mmol) in DMF (0.5 mL). The resulting mixture was stirred at room temperature overnight. Upon completion as indicated by TLC, the reaction was quenched with satd NH4Cl (10 mL), poured into H2O (50 mL) and extracted with EtOAc (2 × 50 mL). The organic layers were washed with H2O (2 × 100 mL), brine (1 × 100 mL), dried over MgSO4, filtered, and concentrated to a crude oil. The desired material was isolated via flash chromatography.
General procedure: In a dried Schlenk vessel activated zinc dust (200mg, 3.05mmol) suspended in dry DMF (1mL) was stirred with TMSCl (0.04mL, 0.31mmol) under argon at r.t. for 30min. The mixture was cooled to 0C and Boc-l-Ala(I)-OMe (21) (330mg, 1.00mmol) dissolved in dry DMF (1mL) was added. The mixture was stirred at r.t. until the starting material was transformed completely (about 1h, DC monitoring). In a second dried Schlenk vessel a copper(I)-bromide-dimethyl sulfide complex (31mg, 0.15mmol) was carefully heated under vacuum using a heat gun until the greenish color of CuBr appeared. The vessel was flushed with argon and 2-fluoroprop-2-enyltosylate (300mg, 1.30mmol) in dry DMF (1mL) was added. The mixture was cooled to -15C. Using a syringe the supernatant liquid of the first Schlenk vessel was added to the second vessel. Under argon, the solid residue in the first vessel was stirred with dry DMF (0.5mL) and after precipitation the supernatant liquid was also transferred to the second vessel using a syringe. The reaction mixture was stirred at -15C for 30min and subsequently overnight allowing warm up to r.t. Then ethyl acetate (5mL) was added and stirred for 10min. The mixture was diluted with ethyl acetate (80ml) and washed with 5% sodium thiosulfate solution (50mL), water (50mL) and brine (50mL). After drying over MgSO4 the solvent was removed in vacuo and the crude product was purified by column chromatography (silica gel, cyclohexane/ethyl acetate, 3:1) to give the title compound 22a as a colorless oil.
Preparation of the Compound (S)-Methyl 2-(Tert-Butoxycarbonylamino)Hex-5-Enoate (IX) In an anhydrous DMF solution (28 mL) containing zinc powder (2.48 g, 37.9 mmol) 1, 2-dibromoethane (0.17 mL) is injected under argon. The solution is stirred for 20 min at room temperature. TMSCI (50 muL) is injected and the solution is heated with stirring to 60 C. for 30 min. (R)-methyl 2-(tert-butoxycarbonylamino)-3-iodopropanoate (VIII) (2.0 g, 6.08 mmol) in DMF (8 mL) is added drop wise. The solution is then stirred for 20 min at 60 C. LiCl (587 mg, 13.8 mmol) and CuCN (619 mg, 6.9 mmol) in DMF (6.5 mL) are injected at -55 C. and the solution is placed at 0 C. for 10 min. The latter is again placed at -55 C. and allyl bromide (1.05 mL, 12 mmol) is injected. After 5 min, the solution is placed at 0 C. and stirred for 2 hours at this temperature. The zinc which has not reacted is removed by filtration on celite and the filtrate is treated with a saturated NH4Cl solution. The product is extracted with ethyl acetate (EtOAc). The collected organic phases are washed with a saturated NaCl solution, and then dried on MgSO4 and evaporated. After flash chromatography (silica gel, 8% EtOAc/cyclohexane), the product (IX) (1.38 g, 93%) is isolated as a colorless oil.Rf=0.25 (10% EtOAc/cyclohexane); [alpha]D=+20.5 (c=1, CHCl3); IR vmax (film, CH2Cl2) 3358, 2978, 1745, 1716, 1518, 1453, 1366, 1249, 1163, 914 cm-1; 1H NMR (400 MHz, CDCl3) delta ppm 1.45 (s, 9H), 1.74 (m, 1 H), 1.90 (m, 1 H), 2.12 (m, 2 H), 3.74 (s, 3 H), 4.32 (m, 1 H), 5.00 (bd, J=10.3 Hz, 1 H), 5.05 (bd, J=17.0, 1 H), 5.18 (bd, J=7.2 Hz, NH), 5.79 (m, 1 H); 13C NMR (100 MHz, CDCl3) delta ppm 28.4 (3×CH3), 29.6 (CH2), 32.0 (CH2), 52.3 (CH3), 53.0 (CH), 79.8 (C), 115.7 (CH2), 137.0 (CH), 155.4 (C), 173.4 (C); Mass (ESI+) m/z (%) 266 (100) [M+Na]+, 210 (43), 166 (38).
methyl 2-[(tert-butoxycarbonyl)amino]-4-(4-chlorophenyl)-5-oxohexanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 4h;
A
Intermediate 9 tert-Butyl [(3S,5S,6R)-6-methyl-2-oxo-5-phenylpiperidin-3-yl]carbamate; Step A: Methyl 2-[(tert-butoxycarbonyl)amino]-4-(4-chlorophenyl)-5-oxohexanoate; To a solution of methyl N-(tert-butoxycarbonyl)-3-iodo-L-alaninate (215 g, 652 mmol) and 4-chlorophenylacetone (100 g, 593 mmol) in N,N-dimethylformamide (1.5 L) was added cesium carbonate (483 g, 1.48 mol) at room temperature. After 4 h, the mixture was then added to a stirring solution of pH 7 buffer and EtOAc. The aqueous layer was extracted with EtOAc and the combined organics were washed with pH 7 buffer, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (10% ethyl acetate/heptane→30% ethyl acetate/heptane) to provide the title compound as a mixture of diastereomers. MS: m/z=392.1 (M+Na).
150 g
With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 4h;
1.25.A Step A: Methyl 2-[ifert-butoxycarbonyl)amino1-4-(4-c3iIorophenyl)-5-oxohexanoate
Example 1.25 f6SVN-r(5i;,6£8Sy5-Methyl-6-phen^ a] pyridin- 8-yll -2'-oxo- Γ,2' .5 J-tetrahydro spiro [cyclopenta[&1 pyridine-6,3 '-pyrrolo [2,3- >1pyridinel-3-carboxamide Step A: Methyl 2-[ifert-butoxycarbonyl)amino1-4-(4-c3iIorophenyl)-5-oxohexanoate To a solution of methyl N-(/er/-butoxycarbonyl)-3-iodo-L-alaninate (215 g, 652 mmol) and 4-chlorophenylacetone (100 g, 593 mmol) in dry N,N- dimethylformamide (1.5 L) was added cesium carbonate (483 g, 1483 mmol) at room temperature. After 4 h, the mixture was then added to a stirring solution of pH 7 buffer and EtOAc. The aqeuous layer was extracted with EtOAc and the combined organics were washed with pH 7 buffer, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (10% ethyl acetate/ heptane→ 30% ethyl acetate/ heptane) to provide the title compound as a mixture of diastereomers (150 g). MS 392.1 (M+Na).
Step 1 . Synthesis of methyl N-(te/t-butoxycarbonyl)-4-cvano-2-nitro-L- phenylalaninate (CD. A 3-necked, 2-liter round-bottomed flask equipped with a mechanical stirrer and temperature probe was charged with zinc powder (86.41 g, 1 .32 mol). Lambda/,/V-Dimethylformamide (500 ml_) was added and the flask was cooled in a water bath at 10 to 12 C. Trimethylsilyl chloride (62.73 ml_, 493.4 mmol) was added drop-wise while the internal temperature was held at 20 to 25 C, and the resulting suspension was stirred at 18 to 22 C for 30 minutes. The stirring was stopped and the solids were allowed to settle; the dark yellow supernatant was removed via cannula using suction and then was discarded. To the solid was added Lambda/,/V-dimethylformamide (250 ml_) and the suspension was stirred for 5 minutes. The stirring was stopped and the supernatant was again removed via cannula. This wash process was carried out twice more under identical conditions. N,N- Dimethylformamide (100 ml_) was added to the flask to give a suspension of activated zinc.A solution of methyl N-(ter/-butoxycarbonyl)-3-iodo-L-alaninate (which may be prepared according to S. van Zutphen et al., Tetrahedron Lett. 2007, 48, 2857-2859) (173.98 g, 528.59 mmol) in Lambda/,/V-dimethylformamide (500 ml_) was added drop-wise via addition funnel to the activated zincsuspension, while cooling the flask in a water bath at 8 to 10 C. The internal temperature was held below 25 C during the addition. The cooling bath was removed and the mixture was stirred at 20 to 25 C for 30 minutes. Analysis by thin layer chromatography (4:1 heptane/EtOAc) showed complete conversion of the starting material to the zincate. The stirring was stopped and, after the solids had settled, the organozinc solution was transferred via cannula, using nitrogen gas pressure, into an addition funnel while leaving the solid zinc behind. Lambda/,/V-Dimethylformamide (100 ml_) was added to the zinc residue and the mixture was stirred for 5 minutes. The stirring was stopped and the supernatant was transferred to the addition funnel via cannula in the same manner.A 4-necked, 5-liter round-bottomed flask equipped with a mechanical stirrer, an addition funnel and a temperature probe was charged with a solution of <strong>[89642-49-9]4-bromo-3-nitrobenzonitrile</strong> (100 g, 440.5 mmol) in N,N- dimethylformamide (1 L). 2-Dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl (XPhos) (21 .0 g, 44.0 mmol) and palladium(ll) acetate (4.94 g, 22.0 mmol) were added and the flask was cooled in a water bath at 14 to 16 C. The zincate solution that had been transferred to an addition funnel was added as a small stream while the internal temperature was held at 18 to 20 C. The resulting mixture was stirred at 20 C for 16 hours, at which time EtOAc (1 L) was added and the mixture was filtered through Celite. The Celite pad was washed with EtOAc (500 ml_) and to the filtrates were added EtOAc (1 L) and te/t-butyl methyl ether (500 ml_). The organic phase was washed with 20% brine (3 x 1 L) and then concentrated to give a dark orange oil. The oil was dissolved in te/t-butyl methyl ether (500 ml_), filtered through Celite, and the Celite pad was washed with te/t-butyl methyl ether (2 x 100 mL). The filtrates were concentrated to dryness to give a dark brown oil, which was chromatographed on silica (heptane/EtOAc gradient elution) to give a beige solid (178 g), which was slurried in heptane (900 mL) for 16 hours. The solid was filtered, washed with heptane (2 x 100 mL) and dried under vacuum at 30 C for 4 hours to provide C1 as an off-white solid. Yield: 94.67 g, 271 .0 mmol, 62% yield. 1H NMR (400 MHz, CDCI3) delta 1 .34 (s, 9H), 3.25 (dd, J=13.4, 8.8 Hz, 1 H), 3.65 (dd, J=13.4, 5.5 Hz, 1 H), 3.75 (s, 3H), 4.63-4.72 (m, 1 H), 5.24 (br d, J=7.9 Hz, 1 H), 7.57 (d, J=8.0 Hz, 1 H), 7.81 (br d, J=8.0 Hz, 1 H), 8.26 (br s, 1 H).
Step 3. Synthesis of methyl A/-(te/ -butoxycarbonyl)-2-nitro-0- (triisopropylsilvD-L-tyrosinate (C5). The following zincate formation was carried out in two batches due to the exotherm observed during this reaction. Dry degassed Lambda/,/V-dimethylformamide (32 mL) was added to zinc (10.5 g, 0.161 mol) in a straight-sided vessel under argon. Trimethylsilyl chloride (4.05 mL, 31 .9 mmol) was added and the mixture was stirred vigorously for 30 minutes, at which time the stirring was stopped and the zinc was allowed to settle. The supernatant was decanted under a flow of argon, and N,N- dimethylformamide (20 mL) was added to the zinc. The mixture was stirred for 30 seconds, the zinc was allowed to settle, and the supernatant was removed as before. This procedure was repeated twice more. A solution of methyl /V-(te/t-butoxycarbonyl)-3-iodo-L-alaninate (which may be prepared according to S. van Zutphen et al., Tetrahedron Lett. 2007, 48, 2857-2859) (22.86 g, 69.46 mmol) in Lambda/,/V-dimethylformamide (55 mL) was added to the activated zinc and the mixture was stirred vigorously. After the exotherm had subsided (this was controlled with an ice bath), the reaction was stirred for an additional 30 minutes, at which time the stirring was stopped and the zinc was allowed to settle. The supernatants from both zincate formations were decanted under a flow of argon into a clean reaction flask. A solution of C4 (40.0 g, 106.9 mmol) in N,N-dimethylformamide (100 ml_), palladium(ll) acetate (1 .20 g, 5.34 mmol) and 2-dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl (XPhos) (5.10 g, 10.70 mmol) were added sequentially to the zincate. The reaction was heated at 40 C for 18 hours, then was poured into water (400 ml_); EtOAc (400 ml_) was added, and the resulting mixture was filtered through a pad of Celite and the filter cake was washed with EtOAc (2 x 100 ml_). The layers were separated and the aqueous layer was extracted with EtOAc (100 ml_); the combined organic layers were washed with brine (5 x 400 ml_), dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification using silica gel chromatography(Gradient: 2% to 10% EtOAc in heptane) afforded C5 as a pale orange oil that solidified on standing. Yield: 44.3 g, 89.2 mmol, 83%. 1H NMR (400 MHz, CDCIs) delta 1 .10 (d, J=7.2 Hz, 18H), 1 .23-1 .31 (m, 3H), 1 .37 (s, 9H), 3.19 (dd, J=13.5, 8.2 Hz, 1 H), 3.41 (dd, J=13.7, 5.8 Hz, 1 H), 3.71 (s, 3H), 4.56- 4.66 (m, 1 H), 5.18 (br d, J=8 Hz, 1 H), 7.05 (dd, J=8.4, 2.6 Hz, 1 H), 7.21 (d, J=8.5 Hz, 1 H), 7.43-7.47 (m, 1 H).
methyl (2S)-2-[(tert-butoxycarbonyl)amino]-4-(4-chlorophenyl)-5-oxohexanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 4h;
1.19.A
Example 1.19(2iO-N-{(5i?,6£8SV5-Methvl~6-phenvl-3-[l-( ^^tetrahydro[I,2,41triazolo[4,3^pyrrolo [2,3 -frlpyridinel -5-carboxamideStep A: Methyl 2-[('fert-butoxycarbonyl)amino]-4-(4-chlorophenyl)-5-oxohexanoateTo a solution of methyl iV-(tert-butoxycarbonyl)-3-iodo-L-alaninate (215 g, 652 mmol) and 4-chlorophenylacetone (100 g, 593 mmol) in dry N,N- dimethylformamide (1.5 L) was added cesium carbonate (483 g, 1483 mmol) at roomtemperature. After 4 h, the mixture was then added to a stirring solution of pH 7 buffer and EtOAc. The aqeuous layer was extracted with EtOAc and the combined organics were washed with pH 7 buffer, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (10% ethyl acetate/ heptane→ 30% ethyl acetate/ heptane) to provide the title compound as a mixture of diastereomers (150 g). MS 392.1 (M+Na).
To zinc (104 mg, 1.59 mmol) stirring in DMF (1.5 mL) was added iodine (20.2 mg, 0.08 mmol). After the color disappeared, (i?)-methyl 2-((tert- butoxycarbonyl)amino)-3-iodopropanoate (175 mg, 0.53 mmol) and further iodine (20.2 mg, 0.08 mmol) were added. After 30 min, the mixture was de-gassed by bubbling through N2 then treated with 4-(4-bromophenyl)-2-(4- (heptyloxy)phenyl)oxazole (220 mg, 0.53 mmol), Pd2dba3 (12.2 mg, 0.01 mmol) and dicyclohexyl(2',6'-dimethoxy-[l, -biphenyl]-2-yl)phosphine (10.9 mg, 0.03 mmol) followed by THF (1 mL). The reaction mixture was heated to 50C for 2 h, cooled to RT and purified by column chromatography (gradient of 15-95% EA in z'so-hexanes) to afford 188 mg (65%) of (S)-methyl 2-((fert-butoxycarbonyl)amino)-3-(4-(2-(4- (heptyloxy)phenyl)oxazol-4-yl)phenyl)propanoate. LCMS-ESI (m/z) calculated for C3iH4oN206: 536.6; found 537.0 [M+H]+, tR = 3.72 min. (Method 11).
65%
(S)-methyl 2-((tert-butoxycarbonyl)amino)-3- (4-(2- (4- (heptyloxy)phenyl)oxazol-4- yl)phenyl)propanoate [00474j To zinc (104 mg, 1.59 mmol) stirring in DMF (1.5 mL) was added iodine (20.2 mg, 0.08 mmol). After the color disappeared, (R)-methyl 2-((tert- butoxycarbonyl)amino)-3 -iodopropanoate (175 mg, 0.53 mmol) and further iodine (20.2 mg, 0.08 mmol) were added. After 30 mm, the mixture was de-gassed by bubbling through N2 then treated with 4-(4-bromophenyl)-2-(4- (heptyloxy)phenyl)oxazole (220 mg, 0.53 mmol), Pd2dba3 (12.2 mg, 0.01 mmol) and dicyclohexyl(2?,6?-dimethoxy- [1,1 ?-biphenyl] -2-yl)phosphine (10.9 mg, 0.03 mmol) followed by THF (1 mL). The reaction mixture was heated to 50C for 2 h, cooled to room temperature and purified by column chromatography (gradient of 15-95% EA in iso-hexanes) to afford 188 mg (65%) of (5)-methyl 2-((tert-butoxycarbonyl)amino)-3- (4-(2-(4-(heptyloxy)phenyl)oxazol-4-yl)phenyl)propanoate. LCMS-ESI (mlz) calculated for C31H40N206: 536.6; found 537.0 [M+H], tR = 3.72 mm. (Method 11).
65%
[005381 To zinc (104 rng, 1.59 mrnol) stirring in DMF (1.5 mL) was added iodine (20.2 rng, 0.08 nrnol). After the color disappeared, (R)-methyi 2-((tert-butoxycarbonyi)arnino)- 3-iodopropanoate (175 mg, 0.53 mrnol) and further iodine (20.2 rng, 0.08 rnrnol) were added. After 30 mm, the mixture was de-gassed by bubbling through N2 then treated with4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl)oxazole (220 mg, 0.53 mmol), Pd2dba3 (12.2 mg, 0.01 rnrnol) and dicyclohexyl(2?,6?-dimethoxy- [171 ?-biphenylj-2-yl)phosphine (10.9 mg, 0.03 mmol) followed by THF (1 rnL). The reaction mixture was heated to 50C for 2 h, cooled to room temperature and purified by column chromatography (gradient of 15- 95% EA in iso-hexanes) to afford 188 mg (65%) of (S)-methyl 2-((tert- butoxycarbonyl)amino)-3 -(4-(2-(4-(heptyloxy)phenyl)oxazol-4-yl)phenyl)propanoate.LCMS-ESI (m/z) calculated for C31H49N206: 536.6; found 537.0 [M±H], I = 3.72 mm. (Method 11).
To a stirring suspension of zinc (228 mg, 3.49 mmol) in DMF (2 mL) was added diiodine (44 mg, 0.17 mmol). When the color was discharged, (i?)-methyl 2- ((fert-butoxycarbonyl)amino)-3-iodopropanoate (382 mg, 1.16 mmol) and further diiodine (44.2 mg, 0.17 mmol) were added. After stirring at RT for 30 min, the reaction mixture was de-gassed by bubbling through N2 then 2-(4-bromophenyl)-4-(4- (heptyloxy)phenyl)thiazole (500 mg, 1.16 mmol), dicyclohexyl(2',6'-dimethoxy-[l , l'- biphenyl]-2-yl)phosphine (23.8 mg, 0.06 mmol), Pd2dba3 (26 mg, 0.03 mmol) and DMF (2 mL) were added. The reaction mixture was heated to 50 C for 3 h, cooled and purified by column chromatography (10-80% EA in z'so-hexanes) to afford 620 mg (96%) of (iS)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(4-(4-(heptyloxy) phenyl) thiazol-2-yl) phenyl propanoate. LCMS-ESI (m/z) calculated for C3iH40N2O5S: 552.3; no ion observed, tR = 3.37 min. {Method 4).
96%
(S)-Methyl 2- ((tert-butoxycarbonyl)amino)-3- (4- (4-(4- (heptyloxy)phenyl)thiazol-2- yl)phenyl)propanoate[00477j To a stirring suspension of zinc (228 mg, 3.49 mmol) in DMF (2 mL) was added diiodine (44 mg, 0.17 mmol). When the color was discharged, (R)-methyl 2- ((tert-butoxycarbonyl)amino)-3 -iodopropanoate (382 mg, 1.16 mmol) and further diiodine (44.2 mg, 0.17 mmol) were added. After stirring at room temperature for 30 mm, the reaction mixture was de-gassed by bubbling through N2 then 2-(4-bromophenyl)-4-(4-(heptyloxy)phenyl)thiazole (500 mg, 1.16 mmol),dicyclohexyl(2?,6?-dimethoxy-[ 1,1 ?-biphenyl] -2-yl)phosphine (23.8 mg, 0.06 mmol), Pd2dba3(26 mg, 0.03 mmol) and DMF (2 mL) were added. The reaction mixture was heated to 50 C for 3 h, cooled and purified by column chromatography (10-80% EA in iso-hexanes) to afford 620 mg (96%) of (5)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(4-(4-(heptyloxy)phenyl) thiazol-2-yl)phenylpropanoate. LCMS-ESI (mlz)calculated for C31H40N205S: 552.3; no ion observed, tp. = 3.37 mm. (Method 4).
96%
[005411 To a stifling suspension of zinc (228 mg, 3.49 mmol) in DMF (2 rnL) was added diiodine (44 mg, 0.17 rnrnol). When the color was discharged. (R)-rnethyl 2-((tert- butoxycarbonyl)arnino)-3-iodopropanoate (382 mg, 1.16 mrnol) and further diiodine (44.2 mg, 0.17 rnmol) were added. After stirring at room temperature for 30 mm, the reaction mixture was de-gassed by bubbling through N2 then 2-(4-bromophenyl)-4-(4- (heptyloxy)phenyl)thiazole (500 mg, 1.16 mmol), dicyclohexyl(2?,6?-dimethoxy-[ 1,1?- biphenyl]-2-yl)phosphine (23.8 mg, 0.06 rnmol), Pd2dba3 (26 mg, 0.03 mrnol) and DMF (2 mL) were added. The reaction mixture was heated to 50 C for 3 h, cooled and purified by column chromatography (10-80% EA in iso-hexanes) to afford 620 mg (96%) of (S)-methyl 2-(Qert-butoxycarbonyl)amino)-3-(4-(4-(4-(heptyloxy)phenyl) thiazol-2- yl)phenylpropanoate. LCMS-ESI (m/z) calculated for C31H40N205S: 552.3; no ion observed, tR = 3.37 mi (Method 4).
To a stirring mixture of zinc (182 mg, 2.79 mmol) in DMF (2 mL) was added diiodine (35.4 mg, 0.14 mmol). When the color was discharged, further diiodine (35.4 mg, 0.14 mmol) and (i?)-methyl 2-((tert-butoxycarbonyl)amino)-3- iodopropanoate (306 mg, 0.93 mmol) were added. After 30 min, DMF (1 mL) was added and the mixture de-gassed by bubbling through N2. To the reaction mixture were added 4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl)thiazole (400 mg, 0.93 mmol), Pd2dba3 (21 mg, 0.02 mmol) and dicyclohexyl(2',6'-dimethoxy-[l, -biphenyl]-2- yl)phosphine (19 mg, 0.05 mmol), the mixture was further de-gassed then heated to 50 C for 3 h. The reaction mixture was cooled and purified by column chromatography (10-80% EA in z'so -hexanes). The product obtained was taken into DCM (4 mL) and washed with water (20 mL) and dried through a hydrophobic frit. The organics were suspended in ACN (4 mL) and concentrated to afford 432 mg (83%) of (5)-methyl 2- ((fert-butoxycarbonyl)amino)-3-(4-(2-(4-(heptyloxy)phenyl)thiazol-4- yl)phenyl)propanoate as a yellow foam. LCMS-ESI (m/z) calculated for C3iH40N2O5S: 552.7; no ion observed, fa = 3.36 min. {Method 4).
83%
(S)-Methyl 2- ((tert-butoxycarbonyl)amino)-3- (4- (2-(4- (heptyloxy)phenyl)thiazol-4- yl)phenyl)propanoate [00481j To a stirring mixture of zinc (182 mg, 2.79 mmol) in DMF (2 mL) was added diiodine (35.4 mg, 0.14 mmol). When the color was discharged, further diiodine (35.4 mg, 0.14 mmol) and (R)-methyl 2-((tert-butoxycarbonyl)amino)-3 - iodopropanoate (306 mg, 0.93 mmol) were added. After 30 mi DMF (1 mL) was added and the mixture de-gassed by bubbling through N2. To the reaction mixture were added 4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl)thiazole (400 mg, 0.93 mmol), Pd2dba3 (21 mg, 0.02 mmol) and dicyclohexyl(2?,6?-dimethoxy- [1,1 ?-biphenyl]-2- yl)phosphine (19 mg, 0.05 mmol), the mixture was further de-gassed then heated to 50C for 3 h. The reaction mixture was cooled and purified by column chromatography (10-80% EA in iso-hexanes). The product obtained was taken into DCM (4 mL) and washed with water (20 mL) and dried through a hydrophobic fit. The organics were suspended in ACN (4 mL) and concentrated to afford 432 mg (83%) of (5)-methyl 2- ((tert-butoxycarbonyl)amino)-3 -(4-(2-(4-(heptyloxy)phenyl)thiazol-4-yl)phenyl)propanoate as a yellow foam. LCMS-ESI (mlz) calculated for C31H40N205S:552.7; no ion observed, tR = 3.36 mm. (Method 4).
83%
[005451 To a stirring mixture of zinc (182 mg, 2.79 mmol) in DMF (2 mL) was added diiodine (35.4 mg, 0.14 mrnol). When the color was discharged, further diiodine (35.4 mg, 0.14 mmol) and (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (306 mg, 0.93 mmol) were added. After 30 mm, DMF (1 rnL) was added and the mixture degassed by bubbling through N2. To the reaction mixture were added 4-(4-brornophenyl)- 2-(4-(heptyloxy)phenyl)thiazole (400 mg, 0.93 mmol), Pd2dba3 (21 mg, 0.02 rnmol) and dicyclohexyl(2?,6-dimethoxy- [1,1 ?-biphenyl]-2-yl)phosphine (19 mg, 0.05 mmol), themixture was further de-gassed then heated to 50 C for 3 h. The reaction mixture was cooled and purified by column chromatography (10-80% EA in iso-hexanes). The product obtained was taken into DCM (4 rnL) and washed with water (20 rnL) and dried through a hydrophobic fit. The organics were suspended in ACN (4 rnL) and concentrated to afford 432 mg (83%) of (S-rnethy1 2-(Qert-butoxycarbonyl)amino)-3-(4- (2-(4-(heptyloxy)phenyl)thiazol-4-yl) phenyl) propanoate as a yellow foam. LCMS-E SI (rnz) calculated for C31H40N205S: 552.7; no ion observed, 1R = 3.36 mm. (Method 4).
(R)-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)zinc(II)iodide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; Schlenk technique;
In a dry Schlenk tube zinc dust (0.98 g, 13.68 mmol) was charged and flushed withdry nitrogen. DMF (2 ml) and TMSCl (0.36 ml, 4.00 mmol) were added and thereaction mixture was stirred 15 min at room temperature. The zinc was allowed tosettle and the supernatant solution was removed. Subsequently, the zinc was dried invacuo using a heat gun. 2-tert-butoxycarbonylamino-3-iodo-propionic acid methyl ester 3a (0.74 g, 2.28mmol, 1.3 equiv) was dissolved in DMF (3 ml) under an atmosphere of dry nitrogenand transferred slowly to the previously activated zinc. The reaction mixture wasstirred at room temperature until TLC monitoring indicated complete consumption ofthe starting material. Subsequently, Pd[P(o-tol)3]2Cl2 (0.08 g, 0.05 mmol, 5.40 mol%)was added to the flask followed by dropwise addition of a solution of 9-oxo-9Hxanthen-2-yl trifluoromethanesulfonate 2 (0.60 g, 1.76 mmol) in DMF (2 ml). Theresulting mixture was heated up to 60C for 2 h and stirred over night at roomtemperature. The reaction mixture was diluted with ethyl acetate (50 ml) and filteredthrough a plug of celite. After removal of the solvent in vacuo the crude product wasobtained as yellow oil. Purification of crude material by column chromatography onsilica gel (DCM/MeCN 20:1) yielded 0.28 g (40%) of 1a as a white solid.
To zinc (1.2 g, 18.2 mmol) dried by heating with a heatgun for1 min under vacuum, DMF (1.5 mL) and 1,2-dibromoethane(0.08 mL, 0.911 mmol) were added. The reaction was heated to50 C and was stirred for 30 min. After returning to rt TMS-Cl(0.03 mL, 0.2 mmol) was added and the mixture was stirred for60 min at rt. Methyl (R)-2-(tert-butoxycarbonylamino)-3-iodopropanoate(1.00 g, 3.04 mmol) in DMF (1.5 mL) was added dropwiseand an exotermic reaction was observed after stirring for a few seconds.After 10 min the starting material was consumed (judged byTLC). The concentration of 7 was determined to approximately0.7 M using a standard titration method
methyl 2-[(tert-butoxycarbonyl)amino]-4-(3-chlorophenyl)-5-oxohexanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1 (,3 ,55',6R -3-Amino-6-methyl-5-phenyl-l-('2,2,2-trifluoroethyl piperidin-2-one Step A: Methyl 2-r(fe^butoxycarbonyl)amino1-4-(3-chlorophenyl)-5-oxohexanoate A mixture of cesium carbonate (9.80 g, 30.1 mmol) and methyl N-(tert- butoxycarbonyl)-3-iodo-D-alaninate (9.90 g, 30.1 mmol) in DMF (75 mL) was stirred at ambient temperature for 45 min before l-(3-chlorophenyl)propan-2-one (6.09 g, 36.1 mmol) and additional cesium carbonate (9.80 g, 30.1 mmol) were added. The resulting mixture was stirred for 2.5 h. The majority of the DMF was then removed under reduced pressure at a bath temperature of
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); iodine; zinc; In N,N-dimethyl-formamide; at 50℃; for 3h;Inert atmosphere;
To an oven dried 8 mL vial with teflon cap purged with N2 was added Zinc dust (298 mg, 4.56 mmol), DMF(1.5 mL), and iodine (57.8 mg, 0.228 mmol). To this mixture was added (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (500 mg, 1.519 mmol), immediately followed by iodine (57.8 mg, 0.228 mmol).Pd2(dba)3 (69.6 mg, 0.076 mmol), 2-dicyclohexylphosphino-2?6-dimethoxybiphenyl (62.4 mg, 0.152 mmol)and <strong>[60811-21-4]4-bromo-2-chloro-1-fluorobenzene</strong> (477 mg, 2.279 mmol) were then added and the reaction mixture wasallowed to stir at 50 C. for 3 hours. The crude mixture was diluted in 30 mL of EtOAc and DMF wasremoved with 4 aqueous washes. The organic phase was dried over anhydrous sodium sulfate. The solutionwas filtered and concentrated, and the crude product was purified by silica gel chromatography using 100%hexanes to 30% EtOAc/Hexanes. The desired product was obtained as a pale yellow oil, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(3-chloro-4-fluorophenyl)propanoate (0.174 g, 35%). 1H NMR (400 MHz,chloroform-d) delta 7.27 (s, 1H), 7.17 (dd, J=6.9, 1.4 Hz, 1H), 7.11-6.93 (m, 1H), 5.03 (d, J=6.8 Hz, 1H), 4.55(d, J=6.4 Hz, 1H), 3.73 (s, 3H), 3.19-3.04 (m, 1H), 2.98 (dd, J=13.9, 5.9 Hz, 1H), 1.49-1.37 (m, 10H).
(S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(3,5-dichloro-4-fluorophenyl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); iodine; zinc; In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere; Sealed tube;
To an oven dried 8 mL vial with teflon cap purged with N2 was added Zinc dust (298 mg, 4.56 mmol), DMF(1.5 mL), and iodine (57.8 mg, 0.228 mmol). To this mixture was added (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (500 mg, 1.519 mmol), immediately followed by iodine (57.8 mg, 0.228 mmol).Pd2(dba)3 (69.6 mg, 0.076 mmol), 2-dicyclohexylphosphino-2?,6?-dimethoxybiphenyl (62.4 mg, 0.152mmol), <strong>[17318-08-0]5-bromo-1,3-dichloro-2-fluorobenzene</strong> (556 mg, 2.279 mmol) and the reaction mixture was allowedto stir at rt for 16 h. The crude mixture was diluted in 30 mL of EtOAc and DMF was removed using fouraqueous washes. The organic phase was dried over anhydrous sodium sulfate. The solution was filtered andconcentrated and the crude product was purified by silica gel chromatography using 100% hexanes to 30%EtOAc/Hexanes. The desired product was obtained as a pale yellow oil, (S)-methyl 2-((tertbutoxycarbonyl)amino)-3-(3,5-dichloro-4-fluorophenyl)propanoate, 0.102 g which was taken into next stepdirectly.
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); iodine; benzoyl chloride; In N,N-dimethyl-formamide; at 20℃; for 16h;Sealed tube;
To an oven dried 8 mL vial with teflon cap purged with N2 was added Zinc dust (298 mg, 4.56 mmol), DMF(1.5 mL), and iodine (57.8 mg, 0.228 mmol). To this mixture was added (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (500 mg, 1.519 mmol), immediately followed by iodine (57.8 mg, 0.228 mmol).Pd2(dba)3 (69.6 mg, 0.076 mmol), 2-dicyclohexylphosphino-2?,6?-dimethoxybiphenyl (62.4 mg, 0.152mmol), <strong>[202982-67-0]1-chloro-2-fluoro-4-iodobenzene</strong> (584 mg, 2.279 mmol), and the reaction mixture was stirred at roomtemperature for 16 h. The crude mixture was diluted in 30 mL of EtOAc and DMF was removed using fouraqueous washes. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and thecrude product was purified by silica gel chromatography using 100% hexanes to 30% EtOAc/Hexanes. Thedesired product was obtained as a pale yellow oil, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-chloro-3-fluorophenyl)propanoate, 0.220 g; purity, 93% by LCMS analysis. Analysis LCMS condition F: rt=2.59min; ESI-MS(+) m/z 332.2 (M+H).
(S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(3,5-dichlorophenyl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.16 g
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); iodine; zinc; In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere; Sealed tube;
To an oven dried 8 mL vial with teflon cap purged with N2 was added Zinc dust (298 mg, 4.56 mmol), DMF(1.5 mL), and iodine (57.8 mg, 0.228 mmol). To this mixture was added (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (500 mg, 1.519 mmol), immediately followed by iodine (57.8 mg, 0.228 mmol).Pd2(dba)3 (69.6 mg, 0.076 mmol), 2-DICYCLOHEXYLPHOSPHINO-2?,6?-DIMETHOXYBIPHENYL(62.4 mg, 0.152 mmol), <strong>[3032-81-3]1,3-dichloro-5-iodobenzene</strong> (622 mg, 2.279 mmol) and the reaction mixture wasallowed to stir at rt for 16 h. The crude mixture was diluted in EtOAc (30 mL) and DMF was removed withfour aqueous washes. The organic phase was dried over anhydrous sodium sulfate. The solution was filteredand concentrated, and the crude was purified by silica gel chromatography using 100percent hexanes to 30percentEtOAc/Hexanes. The desired product was obtained as a pale yellow oil, (S)-methyl 2-((tertbutoxycarbonyl)amino)-3-(3,5-dichlorophenyl)propanoate, 0.160 g yield in 77percent purity by LCMS analysis.Analysis LCMS condition F: Retention time=2.84 min; ESI-MS(+) m/z 348.1 (M+H).
2-(4-bromo-2-fluorophenyl)-5-(4-(heptyloxy)phenyl)-1,3,4-thiadiazole[ No CAS ]
[ 93267-04-0 ]
(S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(3-fluoro-4-(5-(4-(heptyloxy)phenyl)-1,3,4-thiadiazol-2-yl)phenyl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
[0010981 Prepared using General Procedure 3]. To a stirring suspension of zinc (109 mg, 1.669 rnrnol) in DMF (2 mL) was added iodine (21 mg. 0.083 mmol). After the colour was observed to have been discharged, (R)-methyl 2-((tert-butoxycarbonyl)amino)-3 - iodopropanoate (183 mg, 0.556 mmol) and further iodine (21 rng, 0.083 rnmol) were charged. After a further 30 nm, the mixture was treated with 2-(4-bromo-2- fluorophenyl)-5-(4-(heptyloxy)phenyl)- 1 ,3,4-thiadiazole (250 mg, 0.556 mmol), diluted with DMF (1 mL) and de-gassed. The mixture was treated with dicyclohexyl(2?,6?- dimethoxy[1,1biphenyl]2y1)phosphine (11 mg, 0.028 mmoi) and Pd2dba3 (13 mg, 0.0 14 mmol) then heated to 5 0C. After 3 h, the mixture was allowed to cool then directly purified by column chromatography (EAliso-hexanes) to afford 238 mg (75%) of (S,)methyl 2-((tert-butoxycarbonyl)amino)-3-(3-fluoro-4-(5-(4-(heptyloxy)phenyl)- 1,3,4- thiadiazol-2-yl)phenyl)propanoate as a waxy, yellow solid. LCMS-ESI (mz) calculated for C30H8FN3O5S: 571.3; found 572.2 [M+Hj, 1R = 3.00 mm (Method ii).
methyl 2-[(tert-butoxycarbonyl)amino]-4-(3-chlorophenyl)-5-oxohexanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Step A: Methyl 2-[(tert-butoxycarbonyl)amino]-4-(3-chlorophenyl)-5-oxohexanoate (0247) A mixture of cesium carbonate (9.80 g, 30.1 mmol) and methyl N-(tert-butoxycarbonyl)-3-iodo-D-alaninate (9.90 g, 30.1 mmol) in DMF (75 mL) was stirred at 23 C. for 45 min before <strong>[14123-60-5]1-(3-chlorophenyl)propan-2-one</strong> (6.09 g, 36.1 mmol) and additional cesium carbonate (9.80 g, 30.1 mmol) were added. The resulting mixture was stirred for 2.5 h. The majority of the DMF was then removed under reduced pressure at a bath temperature of
methyl N-(tert-butoxycarbonyl)-4-(2-fluorophenyl)-5-nitrilonorvalinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Step A: Methyl N-(tert-butoxycarbonyl)-4-(2-fluorophenyl)-5-nitrilonorvalinate (0251) To a solution of methyl N-(tert-butoxycarbonyl)-3-iodo-D-alaninate (5.00 g, 15.2 mmol) in DMF (20 mL) was added cesium carbonate (5.44 g, 16.7 mmol) and the mixture was stirred at 23 C. for 2 hours. (2-Fluorophenyl)acetonitrile (5.87 mL, 45.6 mmol) and cesium carbonate (7.42 g, 22.8 mmol) were added and the resulting mixture was stirred for 1 hour. The mixture was filtered and water was added to the filtrate. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (0% ethyl acetate?50% ethyl acetate/hexane) gave the title compound as a racemic mixture of cis and trans diastereomers. MS: m/z=378.1 (M+CH3CN+1).
With sodium tetrahydroborate; In methanol; diethyl ether; at 0 - 20℃; for 1h;Inert atmosphere;
Under nitrogen atmosphere, triphenyl phosphine (911 mg, 3.5 mmol) andimidazole (237 mg, 3.5 mmol) were dissolved in dry dichloromethane (12 mL). To this solution cooled on an icebath was added iodine (899 mg, 3.5 mmol). The mixture was stirred at rt for 10 min and then cooled on an icebath again. To the resulting yellow suspension was added a solution of 5 (507 mg, 2.3 mmol) in drydichloromethane (8 mL). After stirring for 2 h on an ice bath, the reaction mixture (a yellow suspension) waspassed through a short silica gel column (hexane:Et2O = 1:1) to remove the precipitates. The eluent wasevaporated to give crude 8 as an orange oil. Obtained 8 and bis-(p-methylbenzyl) diselenide (385 mg, 1.1mmol) were dissolved in a mixture of MeOH (8 mL) and Et2O (12 mL). The solution was cooled on an ice bathand then added with sodium borohydride until the solution color disappeared. After stirring for 1 h, water wasadded to the resulting solution, and the mixture was extracted with EtOAc. The organic layer was washed withbrine, dried over MgSO4, and evaporated. The obtained crude product (a yellow oil) was purified by silica gelcolumn chromatography (hexane:EtOAc = 4:1) to give 7 as a pale yellow oil (741 mg, 83% from 5). When crude8 was purified by silica gel column chromatography, the yield of 7 was decreased to 75% from 5. Identity andpurity of 831 were confirmed by 1H NMR.
(R)-methyl 2-(tert-butoxycarbonylamino)-3-(4-methoxybenzylselanyl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With sodium tetrahydroborate; In methanol; diethyl ether; at 0 - 20℃; for 1h;Inert atmosphere;
Following similarprocedures to those for the synthesis of 7 via iodide 8 (vide supra), selenide 9 was obtained from 5 as a yellowoil in 83% yield by use of bis-(p-methoxybenzyl) diselenide instead of bis-(p-methylbenzyl) diselenide. Thespectral data of 9 were identical to the literature.19 The purity was confirmed by 1H NMR. 1H NMR (CDCl3): H1.39 (9H, s, tBu), 2.82 (2H, m, betaH), 3.68 (3H, s, p-OMe), 3.69 (2H, s, CH2), 3.72 (3H, s, OMe), 4.54 (1H, m, alphaH),5.22 (1H, d, JHH 8.0 Hz, NH) , 6.75 (2H, m, ArH) , 7.13 (2H, m, ArH). 13C NMR (CDCl3): C 25.8, 27.4, 28.3, 52.5,53.4, 55.3, 80.2, 114.0, 130.0, 130.6, 155.1, 158.6, 171.7. 77Se NMR (CDCl3): Se 216.3.
After stirring of bis-2-(trimethylsilyl)ethyl diselenide (1, 3.6mmol), NaBH4 (3.6mmol), and EtOH (9.0mmol) in DMF (2ml) at 0C for 30min, N-Boc-3-iodo-L-alanine methyl ester (2, 3.0 mmol) was added to the solution, and the reaction was continued at rt for an additional 1h. The resultant solution was poured into distilled water, partitioned with EtOAc, and washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluted with n-hexane/EtOAc (15/1) to afford 3 (89% yield) as a yellow oil; [alpha]D20+18.8 (c 1.02, CHCl3); IR (film): numax 3379, 2953, 1717cm-1; 1H NMR (400MHz, CDCl3): delta 0.00 (s, 9H, TMS), 0.92 (dd, 2H, J=7.1 and 11.2Hz, SeCH2CH2TMS), 1.44 (s, 9H, tBu), 2.62 (dt, 2H, J=3.2 and 13.8Hz, SeCH2CH2TMS), 2.99 (t, 2H, J=4.6Hz, H-beta), 3.75 (s, 3H, CO2Me), 4.63 (dt, 1H, J=4.1 and 7.8Hz, H-alpha), 5.37 (d, 1H, J=7.8Hz, NH); 13C NMR (100MHz, CDCl3): delta-1.8, 18.7, 20.3, 26.0, 28.4, 52.6, 53.6, 80.2, 155.2, 171.8; 77Se NMR (113MHz, CDCl3): delta 177.8; HRESITOFMS: m/z 406.0906 [M+Na]+ (calcd for C14H29NO4SeNa, 406.0929)
(S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(6-(trifluoromethyl)pyridin-2-yl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49.3%
To a 50-mL flask under N2 was added zinc (0.894 g, i3.67 mmol) (dust), followed by N,N-Dimethylformamide (DMF) (iO mL) and 12 (0.i74 g) . Some heat was given out and the mixture changed from dark red to a colorless suspension. After iO mm, (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (i .5 g, 4.56 mmol) and 12 (0.i74 g) were added, and the mixture was stirred at rt for 90 mi 2-bromo-6- (trifluoromethyl)pyridine (i.339 g, 5.92 mmol), Pd2(dba)3 (0.i04 g, 0.ii4 mmol) and dicyclohexyl(2,6-dimethoxy-[i ,i -biphenyl]-2-yl)phosphine (or Sphos) (0.094 g, 0.228 mmol) were added, and the mixture was stirred at 50C overnight. The reaction was diluted with EtOAc (50 mL) and filtered. The organic solution was washed with water (5 x iS mL), dried (Na2504), filtered and concentrated. The residue was purified by Combiflash automated silica gel chromatography, eluting with [EtOAcIEtOH76 :24]/Hexanes 5-40% to afford (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(6- (trifluoromethyl)pyridin-2-yl)propanoate (0.783 g, 2.248 mmol, 49.3 % yield) as a light green oil. LCMS: [M+Na]+: 37i .2.
methyl N-(tert-butoxycarbonyl)-2-fluoro-4-methyl-L-phenylalaninate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10 g
Preparation Example 6 Zinc powder (9 g) was dried with a heating gun for 15 minutes under reduced pressure and left to be cooled to room temperature. Then, N,N-dimethylformamide (50 mL) was added thereto under an argon atmosphere. Iodine (250 mg) was added thereto at room temperature, followed by stirring, and then to the reaction mixture were added iodine (250 mg) and methyl N-(tert-butoxycarbonyl)-3-iodo-L-alaninate (15.5 g) at room temperature, followed by stirring for 35 minutes. To the reaction mixture were added tris(dibenzylideneacetone)dipalladium (0) (2.2 g), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (2.0 g), and <strong>[452-74-4]1-bromo-2-fluoro-4-methylbenzene</strong> (9 mL) at room temperature, followed by stirring at 60C for 18 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by filtering through Celite. The filtrate was extracted with ethyl acetate and the organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, the insoluble materials were then separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 97:3 to 83:17), and then purified by basic silica gel column chromatography (hexane:ethyl acetate = 97:3 to 83:17) to obtain methyl N-(tert-butoxycarbonyl)-2-fluoro-4-methyl-L-phenylalaninate (10 g) as a solid.
N-tert-butyloxycarbonyl-3-iodopropargylamine[ No CAS ]
[ 93267-04-0 ]
methyl (S)-2,6-bis[(tert-butoxycarbonyl)amino]hex-4-ynoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
a) Zinc Insertion1,2-Dibromoethane (57.8 muL, 126 mg, 0.67 mmol) was added to a suspension of Zn dust (727 mg, 11.1 mmol) in THF (2.0 mL). The reactionmixture was heated to reflux and cooled down to r.t. 4 times. Afterwards,TMSCl (19.1 muL, 16.3 mg, 0.15 mmol) was added followed bystirring at r.t. for 15 min. Iodoalanine (1.45 g, 4.41 mmol) in THF (9.0mL) was then added to the preactivated Zn dust and the reaction mixturewas stirred at 35-40 C for 70 min. b) Transmetallation and C-C CouplingThe zinc solution was added at -10 C to a solution of flame driedCuCN (349 mg, 3.90 mmol) and LiCl (355 mg, 8.37 mmol) in THF (9.0mL) and the suspension was stirred at 0 C for 15 min. Afterwards, 3c(869 mg, 3.09 mmol) in THF (11.0 mL) was added at -20 C and thereaction mixture was stirred at this temperature for 16 h. The mixturewas then hydrolysed with sat. aq NH4Cl and extracted withEtOAc. The combined organic layers were dried (anhyd Na2SO4), concentrated,and the crude product was purified by flash chromatography(silica gel, PE/EtOAc 9:1 to 6:4). Alkyne 4b was isolated as a colourlessresin; yield: 631 mg (1.77 mmol, 57%); Rf = 0.09 (PE/EtOAc8:2);
3-iodo-4-methoxy-2-methyl-1-(phenylsulfonyl)-1H-indole[ No CAS ]
[ 93267-04-0 ]
methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-methoxy-2-methyl-1-(phenylsulfonyl)-1H-indol-3-yl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
Activated zinc dust20 (872mg, 13.3mmol, 3.0eq.) was placed in a flame-dried Schlenk tube and heated to 100C under high vacuum for 1min. The flask was cooled to ambient temperature and anhydrous 75 DMF (4.5mL) was added under an argon atmosphere. 68 Iodine (170mg, 667mumol, 15mol%) was added in one portion (color change to dark orange) and the reaction mixture was stirred vigorously until the color disappeared (?30s). At this point, iodoalanine 70 17 (1.46g, 4.45mmol, 1.0eq.) was added in one portion followed by iodine (170mg, 667mumol, 15mol%). Once again, the reaction mixture turned dark orange and the color disappeared after?30s. The reaction mixture was stirred vigorously at 35C for 45min (monitored by TLC). After full formation of the zincate the reaction mixture was cooled to ambient temperature. SPhos (91.3mg, 222mumol, 5mol%) was added in one portion followed by Pd2dba3·CHCl3 (115mg, 111mumol, 2.5mol%) and iodoindole 16 (1.90g, 4.45mmol, 1.0eq.). The reaction mixture was stirred at ambient temperature for 4h. The reaction mixture was diluted with 1n HCl and EtOAc, the layers were separated and the aqueous layer was extracted one additional time with EtOAc. The combined organic layers were dried over Na2SO4 and all volatiles were removed under reduced pressure. The crude material was subjected to flash column chromatography (cyclohexane-EtOAc, 6:1?3:1) to obtain title compound 91 23 as pale yellow foam (1.97g, 3.92mmol, 88% yield). Rf=0.3 (cyclohexane-EtOAc, 4:1). 1H NMR (400MHz, CDCl3) delta 7.81 (d, J=8.4Hz, 1H), 7.72 (d, J=7.8Hz, 2H), 7.56-7.48 (m, 1H), 7.46-7.37 (m, 2H), 7.17 (t, J=8.3Hz, 1H), 6.67 (d, J=8.1Hz, 1H), 5.36 (d, J=8.2Hz, 1H), 4.39 (q, J=7.6Hz, 1H), 3.90 (s, 3H), 3.55 (s, 3H), 3.19 (d, J=7.2Hz, 2H), 2.52 (s, 3H), 1.29 (s, 9H). 13C NMR (101MHz, CDCl3) delta 173.0, 153.1, 139.4, 137.8, 133.7, 133.3, 129.4, 126.4, 124.9, 115.4, 108.0, 104.3, 77.4, 55.4, 54.7, 52.2, 28.3, 24.0, 12.7. HRMS (ESI): calcd. for C25H30N2O7S [M+H]+ 525.1671 found 525.1668. [alpha]20D [alpha]D20 =-12.9 (c 0.92, CHCl3).
Multi-step reaction with 2 steps
1.1: zinc / N,N-dimethyl-formamide / 2 h / 20 °C / Inert atmosphere
1.2: 12 h / 50 °C / Inert atmosphere
2.1: (butylcarbamoyl)-L-tryptophan / methanol; water / 20 °C
5-bromo-1-(phenylsulfonyl)-1H-pyrazolo[3,4-c]pyridine[ No CAS ]
[ 93267-04-0 ]
methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(1-(phenylsulfonyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
To a stirred suspension of Zinc powder (2.3g, 1 1.83 mmole) in DMF (20 mL) was added iodine (0.3 g, 1.18 mmole). After stirring for 10 minutes, methyl (R)- 2- ((/er/-butoxycarbonyl)amino)-3-iodopropanoate (4.67 g, 14.2 mmole) was added, followed by iodine (0.3 g, 1.18 mmole). The resulting mixture was stirred for 2h. The mixture was then added to the mixture of 5-bromo- l -(phenyl sulfonyl)- l//-pyrazolo[3, 4- cjpyridine (4.0 g, 11.83 mmole), S-Phos (0.24 g, 0.6 mmole), and Pd2(dba)3 (0.21 g, 0.23 mmole) in DMF (10 mL). After the addition was completed, the reaction mixture was heated to 40C in l6h. The reaction mixture was cooled, diluted with EtOAc, filtered through the pad of Celite. The filtrate was concentrated to dryness, and purified by ISCO (0-50% EtO Ac/Hexanes) to give the title compound (5.14 g, 94%). LC-MS (+ESI) M+H: 461.3.
To a stirred suspension of Zinc powder (9.4 g, 143 mmol) in dimethylformamide (50 mL) was added iodine (1.1 g, 4.3 mmol) After stirring for 10 minutes, methyl (i?)-2-((/er/-butoxycarbonyl)amino)-3-iodopropanoate (17.1 g, 52 mmol) was added, followed by iodine (1.1 g, 4.3 mmol). The resulting mixture was stirred at RT for lh. The mixture was then added to a stirred mixture of Int-5B (10.5 g, 43 mmol), S-Phos (1.8 g, 4.3 mmole), and Pd2(dba)3 (2.0 g, 2.2 mmol) in DMF (20 mL) and then heated to 80C for l6h. After cooling to room temperature, the suspension was diluted with ethyl acetate and filtered through packed celite. The filtrate was washed with water and the organic layer was dried and concentrated to half its original volume. The precipitated solids were collected by filtration to give the product as a white powder (6.1 g, 40%). The filtrate was concentrated, and the residue was purified on Combiflash using hexanes / ethyl acetate gradient to give additional product (6.0 g, 38%). Total yield (12.1 g, 78%). 1H NMR (400 MHz, CHLOROFORM-^/) d ppm 7.33 (s, 2 H) 6.00 - 6.16 (m, 1 H) 5.05 (br d, =8.80 Hz, 1 H) 4.46 (q, =8.07 Hz, 1 H) 3.56 (s, 3 H), 3.02 - 3.04 (m, 2 H), 2.91 (d, J = 8.80 Hz, 3 H) 2.30 (s, 6 H), 1.29 (s, 9 H)
methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(2-chloro-4-hydroxyphenyl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
To a stirred suspension of zinc powder (2 g, 31 mmol) in anhydrous N,N-d m ethyl form amide (10 mL) under nitrogen was added iodine (250 mg). After 5min, a solution of methyl (i?)-2-((/er/-butoxycarbonyl)amino)-3-iodopropanoate (4.0 g, 12 mmol) in A( A-di m ethyl form ami de (10 mL) was slowly added over lOmin. Then additional iodine (250 mg) was added. The mixture was stirred at rt for 30min. A suspension of <strong>[13631-21-5]4-<strong>[13631-21-5]bromo-3-chlorophenol</strong></strong> (2.0 g, 10 mmol), Pd2(dba)3 (230 mg, 0.25 mmol), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (Sphos, 210 mg, 0.5 mmol) in N, A-di m eth yl form am i de (10 mL) was added into the zinc reagent mixture. The reaction mixture was heated at 40C and stirred overnight. After cooling, the reaction mixture was quenched with water, diluted with EtOAc and filtered through Celite. The filter cake was washed with EtOAc and the filtrate was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography over silica gel (0-50% EtOAc/hexane) to afford the desired product as brown foam (2.7 g, 83%). LC-MS: 352.1 [M+Na]+; 1H NMR (400MHz, CDCI3) (rotamers) d 7.04 (d, 1H, J = 8.3 Hz), 6.86 (s, 1H), 6.65 (d, 1H, J = 7.5 Hz), 5.96 (br s, 0.2H), 5.41 (s, 0.7H), 5.07 (d, 0.8H, J = 8.2 Hz), 4.83 (br s, 0.2H), 4.56 (m, 1H), 3.73 (s, 3H), 3.21 (dd, 1H, J = 14.0, 6.0 Hz), 3.02 (dd, 0.8H, J = 13.6, 7.6 Hz), 2.80 (m, 0.2H), 1.39 and 1.33 (s, 9H).
methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(2-chloro-4-hydroxyphenyl)propanoate[ No CAS ]
1-(tert-butyl) 2-methyl (S)-6-hydroxyindoline-1,2-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25%
To a stirred suspension of zinc powder (3 g, 46 mmol) in anhydrous A( Af-di ethyl aceta i de (10 mL) under nitrogen was added iodine (400 mg). After 5min, a solution of methyl (f?)-2-((/er/-butoxycarbonyl)amino)-3-iodopropanoate (5.0 g, 15.2 mmol) in N, A-di m eth y 1 acetam i de (10 mL) was added slowly over lOmin. The mixture was heated at 50C for 30min, and then a suspension of 4-bromo-3- chlorophenol (3.0 g, 15 mmol), Pd2(dba)3 (750 mg), and 2-dicyclohexylphosphino-2',6'- dimethoxybiphenyl (Sphos, 675 mg) in /V,/V-dimethylacetamide (10 mL) was added into the zinc reagent mixture. The reaction mixture was heated at 95C and stirred overnight. After cooling, the reaction mixture was quenched with water, diluted with EtOAc and filtered through Celite. The filter cake was washed with EtOAc and the filtrate was washed with 1N aq. HC1 and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography over silica gel (0-50% EtOAc/hexane) to isolate 1 -(/tvV-butyl) 2-methyl (5)-6-hydroxyindoline-l,2- dicarboxylate as a light brown solid (1.1 g, 25%) and methyl ( S)-2-((tert - butoxycarbonyl)amino)-3-(2-chloro-4-hydroxyphenyl)propanoate as a light brown foam (2 g, contaminated with some des-chloro side product). l-(/er/-butyl) 2-methyl fV)-6-hydroxyindoline- l ,2-di carboxyl ate: LC- MS: 316.1 [M+Na]+; 1H NMR (400MHz, CDCl3) (rotamers) d 7.47 (s, 0.75H), 7.02 (br s, 0.25H), 6.94 (d, 1H, J = 8.8 Hz), 6.45 (m, 1H), 5.14 (s, 0.75H), 5.00-4.80 (m, 1.25H), 3.75 (s, 3H), 3.43 (m, 1H), 3.02 (d, 1H, J = 11.6 Hz), 1.61 and 1.49 (s, 9H).
methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-fluoro-4-(methylcarbamoyl)phenyl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
To a stirred suspension of zinc powder (2.5 g, 38.5 mmol) in anhydrous N,N-d m ethyl form a ide (10 mL) under nitrogen was added iodine (200 mg). After 5 min, a solution of methyl (f?)-2-((/er/-butoxycarbonyl)amino)-3-iodopropanoate (5.0 g, 15.2 mmol) in A( A'-di m ethyl form a i de (10 mL) was added slowly over lOmin. The mixture was stirred at rt for 30min. A suspension of 4-bromo-2-fluoro-Af- methylbenzamide (2.8 g, 12 mmol), Pd2(dba)3 (280 mg, 0.3 mmol), and 2- dicyclohexylphosphino-2',6'-dimethoxybiphenyl (Sphos, 250 mg, 0.6 mmol) in /V,/V- dimethylformamide (10 mL) was added into the zinc reagent mixture. The reaction mixture was heated at 50C and stirred overnight. After cooling, the reaction mixture was quenched with water, diluted with EtOAc and filtered through Celite. The filter cake was washed with EtOAc and the filtrate was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography over silica gel (0-80% EtO Ac/hexane) to afford the desired product as a beige solid (4.0 g, 94%). LC-MS: 377.1 [M+Na]+; 1H NMR (400MHz, CDCl3) d 8.04 (t, 1H, J = 8.1 Hz), 7.02 (d, 1H, J = 8.0 Hz), 6.91 (d, 1H, J = 12.8 Hz), 6.70 (m, 1H), 5.02 (d, 1H, J = 8.0 Hz), 4.60 (m, 1H), 3.73 (s, 3H), 3.18 (dd, 1H, J = 13.8, 5.4 Hz), 3.07 (m, 1H), 3.03 (d, 3H, J = 4.6 Hz), 1.43 (s, 9H).
To a stirred suspension of Zinc powder (7.9 g, 120.92 mmole) in DMF (40 mL) was added iodine (1.02 g, 4.03 mmole) After stirring for 10 minutes, methyl (f?)-2-((/er/-butoxycarbonyl)amino)-3-iodopropanoate (19.9 g, 60.46 mmole) was added, followed by another iodine (1.02 g, 4.03 mmole). The resulting mixture was stirred at RT for 2h. The mixture was then added to a stirred mixture of 4-bromo-3,5- dimethylphenol (10 g, 40.31 mmole), S-Phos (1.65 g, 4.03 mmole), and Pd2(dba)3 in DMF (20 mL). The reaction mixture was then heated to 60C for l6h, cooled to RT, diluted with EtOAc, filtered the a pad of Celite, washed with EtOAc. The filtrate was concentrated to dryness, and purified by ISCO (0-40% EtO Ac/hexanes) to give Int-IA (11.5 g, 88%). LC-MS (+ESI) M+H: 346.2.
Stage #1: N-(tert-butoxycarbonyl)-L-3-iodoalanine methyl ester With iodine; zinc In N,N-dimethyl-formamide at 50℃; for 0.333333h; Inert atmosphere;
Stage #2: With 3-bromofurane; tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene at 25 - 50℃; for 25h; Inert atmosphere;
Stage #1: N-(tert-butoxycarbonyl)-L-3-iodoalanine methyl ester With iodine; zinc In N,N-dimethyl-formamide at 50℃; for 0.333333h; Inert atmosphere;
Stage #2: With 3-bromofurane; 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0) at 25 - 50℃; for 25h; Inert atmosphere;
N-tert-butyloxycarbonyl 3-furanylalanine methyl ester[ No CAS ]
[ 28875-17-4 ]
Yield
Reaction Conditions
Operation in experiment
1: 74%
2: 14%
Stage #1: N-(tert-butoxycarbonyl)-L-3-iodoalanine methyl ester With iodine; zinc In N,N-dimethyl-formamide at 50℃; for 0.333333h; Inert atmosphere;
Stage #2: 3-bromofurane With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0) at 25 - 50℃; for 25h; Inert atmosphere;
N-tert-butyloxycarbonyl 3-furanylalanine methyl ester[ No CAS ]
[ 28875-17-4 ]
[ 55477-80-0 ]
Yield
Reaction Conditions
Operation in experiment
1: 71%
2: 22%
3: 7%
Stage #1: N-(tert-butoxycarbonyl)-L-3-iodoalanine methyl ester With iodine; zinc In N,N-dimethyl-formamide at 50℃; for 0.333333h; Inert atmosphere;
Stage #2: 3-bromofurane With tris-(dibenzylideneacetone)dipalladium(0); XPhos In N,N-dimethyl-formamide at 25 - 50℃; for 25h; Inert atmosphere; chemoselective reaction;
Activated zinc dust (4.00 g, 60.8 mmol, 4.0 eq.) was heated under vacuum for 20 min, then the flask wasfilled with argon and cooled down to 70 °C. Anhydrous DMF (15 mL) and I2 (389 mg, 1.52 mmol, 0.1 eq.)were added and the resulting light grey suspension was stirred at 70 °C for a further 20 min. The reactionmixture was cooled to 50 °C and then added a solution of iodoalanine 3 (5.00 g, 15.2 mmol, 1.0 equiv.) inDMF (12 mL). The mixture was stirred under argon for another 20 min. and then treated sequentially with3-bromofuran (4.47 g, 45.6 mmol, 3.0 eq.), Pd2(dba)3 (1.37 g, 1.52 mmol, 0.1 eq.) and XPhos (2.86g, 6.08mmol, 0.40 eq.). The reaction mixture was stirred for 5 h at 50 °C, and for 20 h at room temperature priorto be filtered through a pad of celite. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (EtOAc/hexanes =1: 25) to provide 4 (2.91 g, 71%) as a yellow oil.
1: 66%
2: 20%
3: 14%
Stage #1: N-(tert-butoxycarbonyl)-L-3-iodoalanine methyl ester With iodine; zinc In N,N-dimethyl-formamide at 50℃; for 0.333333h; Inert atmosphere;
Stage #2: 3-bromofurane With tris-(dibenzylideneacetone)dipalladium(0); tert-butyl XPhos at 25 - 50℃; for 25h; Inert atmosphere;
1: 58%
2: 17%
3: 17%
Stage #1: N-(tert-butoxycarbonyl)-L-3-iodoalanine methyl ester With iodine; zinc In N,N-dimethyl-formamide at 50℃; for 0.333333h; Inert atmosphere;
Stage #2: 3-bromofurane With tris-(dibenzylideneacetone)dipalladium(0); ruphos at 25 - 50℃; for 25h; Inert atmosphere;
1: 30%
2: 30%
3: 41%
Stage #1: N-(tert-butoxycarbonyl)-L-3-iodoalanine methyl ester With iodine; zinc In N,N-dimethyl-formamide at 50℃; for 0.333333h; Inert atmosphere;
Stage #2: 3-bromofurane With tris-(dibenzylideneacetone)dipalladium(0); dicyclohexyl-(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine at 25 - 50℃; for 25h; Inert atmosphere;
1: 40%
2: 33%
3: 20%
Stage #1: N-(tert-butoxycarbonyl)-L-3-iodoalanine methyl ester With iodine; zinc In N,N-dimethyl-formamide at 50℃; for 0.333333h; Inert atmosphere;
Stage #2: 3-bromofurane With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0) at 50℃; for 25h; Inert atmosphere;
1: 34%
2: 18%
3: 15%
Stage #1: N-(tert-butoxycarbonyl)-L-3-iodoalanine methyl ester With iodine; zinc In N,N-dimethyl-formamide at 50℃; for 0.333333h; Inert atmosphere;
Stage #2: 3-bromofurane With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0) at 25℃; for 25h; Inert atmosphere;
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