Objective

To synthesize nine Ugi products via a 4 component Ugi Reaction. The diamides were ranked with in the top 20 list of Sortase inhibitors, from the docking experiment D-EXP016 , spreadsheet D-Exp016-A

UCExp231-4A :N-butyl-2-[(2-methoxyacetyl)-[(5-methyl-2-furyl)methyl]amino]-2-[‚Äč4-(trifluoromethyl)phenyl]acetamide; C22H27F3N2O4; 1H NMR (external image delta.gif ppm, CDCl3) 0.903 (t, 3H J 7.3Hz),1.24-1.36 (m, 2H), 1.4-1.5 (m, 2H), 2.13 (s, 3H), 3.15-3.32 (m, 2H), 3.47 (s, 3H), 4.33 (s, 2H), 4.2-4.6 (m, 2H), 5.73 (s, 2H), 5.89 (s, 1H), 6.23 (bs, 1H), 7.4(d, 2H, J 8Hz) 7.53 (m, 2H, ); 13C NMR (external image delta.gif ppm, CDCl3) ppm, 13.3, 13.6, 19.9, 31.3, 39.5, 42.9, 59.2, 62.2, 71.4, 106.3, 109.4, 125.2, 125.3, 129.5, 130.1(q), 138.9, 147.5, 151.9, 168.5, 170.6; yield 4% (31mg)

Results

UCExp231 Spreadsheet
IMG-UCExp231-1
IMG-UCExp231-2
IMG-UCExp231-3
IMG-UCExp231-4


UCExp231-4A
HNMR
CNMR
DEPT- IMG
All protonated Carbons



Discussion

The Ugi product UCExp231-4 was ranked 6 in the sortase inhibitor library. The target ugi product had a 'high electrostatic score' in the docking runs for the Sortase inhibitor library D-EXP016 , spreadsheet D-Exp016-A
UCExp231-4A HNMR assignments

Conclusion

One Ugi product synthesized

Log

2009-06-01
13:30 Obtained a new micropipettor (100-1000uL) Checked the calibration by dispensing 1mL of water in to a beaker set on a top loading balance tared to Zero. Weight of 1000uL of water dispensed by the new micropipettor was recorded to be 1000.3uL]
14:00 Labeled nine 1 dram vials 231-1, 231-2, 231-3, 231-4, 231-5, 231-6, 231-7, 231-8 and 231-9.
14:50 Pipetted out "Total extra solvent added" (uL) [see spreadsheet] the following volumes of the reaction solvent in each vial.
Vial 231-1 - acetonitrile 1031uL --> later added 200uL more, final volume of acetonitrile added -1231uL
Vial 231-2 THF 525.6uL
Vial 231-3 THF 314.2uL
Vial 231-4 methanol 120.73uL
Vial 231-5 methanol 1158uL
Vial 231-6 THF 1043.1uL
Vial 231-7 THF 993.2uL
Vial 231-8 THF 643.5uL
Vial 231-9 THF 367.9uL
15:00 Pipetted-out added p-tolualdehyde (4mmol, 471.6uL) in vial 231-1, followed by benzylamine (4mmol, 436.9uL), the solution was vortexed for 30s, when it warmed-up.
15:10 Added formic acid (4mmol, 150.9uL) to the same vial, vortexed it for another 30s.
15:15 Weighed out TOSMIC (4mmol, 781.4mg) and added it to the vial 231-1, the solid did not go in to the solution immediately, therefore another 200uL of acetonitrile was added to this vial, and vortexed again for 1min. A clear and homogenous solution was obtained. The vial was capped, parafilmed and left undisturbed on the bench.
15:30 To the vial labeled 231-2, containing THF (314.2uL) phenanthrene-9-carboxaldehyde (1mmol, 206.5mg), the solution was vortexed for 30s when a clear solution was obtained. Then benzylamine (1mmol, 109uL) was transferred in to the vial. The solution was vortexed for 30s to obtain a clear solution. Then crotonic acid (1mmol, 86.1mg) was added to the solution..it dissolved in easily when vortrexed for 30s. Finally t-butylisocyanide (1mmol, 113.1uL)
was transferred to it and again vortexed for 30s. The vial was capped, parafilmed and left undisturbed on the bench.
16: 20 To vial 231-3 containing THF (314uL), 2-naphthaldehyde (1mmol, 156.3mg) was added, the solution was vortexed for 30s and a clear solution was obtained. Then methylamine (1mmol, 500uL 2M THF Solution) [~ about 1mL of which was previously transferred in to clean vial] was added to the vial, the solution was vortexed for 30s. Then 1-pyrenebutyric acid (1mmol, 288.3mg) was added to the solution. The solution was initally vortexed for 30s, was unable to acheive complete dissolution of the acid added, when the solution was further vortexed for another 1min, at a certain point while vortexing the solid disappeared in a flash. Then a brown, homogeneous solution was obtained. Finally t-butylisocyanide (1mmol, 113.1uL) was pipetted out in to the vial, the solution was vortexed for 30s, the vial was capped, parafilmed and left on the bench.
16:55 To the vial labeled 231-4 containing THF (120.73uL) , 4-(Trifluoromethyl)benzaldehyde (2mmol, 273.1uL) was pipetted in, then 5-methylfurfurylamine (2mmol, 222.8uL) was added, the solution warmed-up substantially, the solution was vortexed for 30s. Then methoxyacetic acid (2mmol, 153.4uL) was pipetted in to it and vortexed again for 30s. Finally n-butylisocyanide (2mmol, 209.1uL) was added to the solution, and then vortexed for 30s. The vial was capped, parafimed and left on the bench
17:20 4,7-dimethoxy-1-naphthaldehyde (1mmol, 216.2mg) was not avialable, therefore reactions involving them were aborted; ie. vial 231-5 and 231-6.
17:45 To vial labeled 231-7, containing THF, 2-furaldehyde (1mmol , 82.8uL) and furfurylamine (1mmol, 88.4uL) were added, the solution was vortexed for 30s, then 1-pyrenebutyric acid (1mmol, 288.3mg) was added to it. The solution was vortexed for 1min and a clear solution was obtained. Finally n-butylisocyanide (1mmol, 113uL) was added to it and vortexed once again for 30s. The vial was capped, parafilmed and left on the bench undisturbed.
18:15 To vial labeled 231-8 containing THF (643.5uL) ,a green crystalline solid 2-methoxy-1-naphthaldehyde (1mmol, 186.2mg) was added, the solution was vortexed for 1min. A deep green solution was obtained. Then heptylamine (1mmol, 148.3uL) was pipetted in to the solution, again vortexed it for 30s, interestingly the deep green color of the solution turned to a oily yellow color. Then glycolic acid (1mmol, 76.0mg) was added, the solution was vortexed for 30s. Then TOSMIC (1mmol, 195.2mg) was added to the reaction vial. The solution was vortexed for 1min. A clear solution was obtained. The vial was capped and parafilmed.
18:45 To vial labeled 231-9, containing THF (367.94uL), phenanthrene-9-carboxaldehyde (1mmol, 206.2mg) was added, the solution was vortexed for 30s, unable to obtain a clear solution. However t-butylamine (1mmol, 105uL) was added, vortexed for 30s. The solution turned remained a little cloudy, not withstanding this phenylacetic acid (1mmol, 136.1mg) was added to the vial. As soon as the acid was added, the solution turned in to white paste....therefore extra THF (200uL) was added to it, and vortexed for 1min. The ppt did not dissolve...added another 200uL of THF and vortexed for 1min, the ppt still did not dissolve. Therefore this reaction is also aborted. Obtained a picture of the white ppt in the vial. IMG-UCExp231-2
19:20 Obtained a picture of the reaction vials IMG-UCExp231-1
2009-06-02
19:30 Obtained a picture of the solutions - IMG-UCExp231-3; none of the solution developed any precipitates
2009-06-03
11:00 The vials were lifted-up to check precipitate development, none of the vials had any, however vial UCExp231-4, which looked like a thick reddish gel, started developing solid....and with in a few minutes, the entire solution turned in to a solid mass...obtained a picture of the vial- IMG-UCExp231-4
Vial UCExp231-4 contained 4-(Trifluoromethyl)benzaldehyde (2mmol, 273.1uL), 5-methylfurfurylamine (2mmol, 222.8uL), methoxyacetic acid (2mmol, 153.4uL), n-butylisocyanide (2mmol, 209.1uL).
11:10 All the remaining vials were vortexed for 25s.
18:00 To the solid in vial UCExp231-4, methanol (500uL) added and vortexed for 30s, however the solid had hardened at the bottom of the vial, there as it was scratched with a spatula to loosen it up. It was revortexed for another 30s, this time it formed a very thick yellow paste, therefore another 500uL of methanol was added, revortexed for 30s and then centrifuged.
18:25 The supernatant was transferred to small (5mL) beaker, labeled 231-4B,.
18:35 Added methanol (500uL) again to UCExp231-4, vortexed for 30s, some how this time a lot of solid appeared to have dissolved in methanol. The solution was centrifuged, the superntatnt was added to 231-4B, to the residue (a small amount) more methanol (500uL) was added and vortexed again....this time almost all of the solid appeared to have dissolved in methanol...well therefore all of it was transferrd in to the beaker 231-4B, parafiled and left in the hood..for crystallization.
2009-06-04
12:00 Some solid had formed in the beaker, so the supernatant was decanted and the residue was washed with methanol (500uL), still the solid seems to be relatively more soluble than other Ugi product in the past. However after adding methanol, the solution was swirled around in the beaker so as to take-up any undesired material in the ppt..the supernatant was then decanted...the residue obtained was further washed similarly with methanol (500uL x 2), the residue obtained was dried in a vacuum desicattor. The mother liquor 231-4C was collected in a vial and left in the hood.
13:30 Obtained 31mg of, the now called UCExp231-4A...A couple of nice and sharp needle like crystals were found in UCExp231-4A..
13:45 Obtained HNMR of UCExp231-4A, by dissolving all of the remaining solid in CDCl3; on a 300MHz Varian instrument...
13:55 An overnight C13-run was set-up on the sample.
2009-06-05**
14:20 Obtained a CNMR of 231-4A; set-up for a DEPT run