exp021

=Objective= To accomplish the Ugi Synthesis and cyclization to a diketopiperazine using [|3,4-dihydroxybenzaldehyde], [|5-methylfurfurylamine], [|Boc-Gly-OH], and [|benzylisocyanide] using the protocol described [|here], with the modification that THF will be used instead of 1,2-dichloroethane in the cyclization step. The [|target diketopiperazine] is not predicted to be active but is a close analog of the [|product] that we wish to make once the [|catechol aldehyde] is obtained.

=Procedure= To a 50ml Erlenmeyer flask added methanol (25ml), [|3,4-dihydroxybenzaldehyde] (80.23mg, 0.58mmol), [|5-methylfurfurylamine] (65µl, 0.58mmol) by micropipette, [|benzylisocyanide] (70µl, 0.58mmol) by 500µl GE syringe, and [|Boc-Gly-OH] (101.41mg, 0.58mmol). Vacuumed of solvent and performed chromatotron chromatography.

=Results=

Characterization of 21A (after Ugi)
[|TLC1: 21A]

Characterization of 21B (after Ugi and vac)
[|HMR] [|TCL2: 21B]
 * 302.5 mg**

Characterization of 21B Fractions 1-5
[|TLC of all fractions]
 * 21B-F1(NMR, 174.6mg)** [|NMR of Fraction#1]
 * 21B-F2(NMR, 11.8mg)** [|NMR of Fraction#2]
 * 21B-F3(NMR, 25mg)** [|NMR of Fraction #3]
 * 21B-F4(NMR, 13.8mg)** [|NMRs of fraction 4]
 * 21B-F5(NMR, 3.2mg)** [|NMR of fraction 5]

Characterization of 21C (after cyclization)
[|HMR of 21C] [|TLC of the top layer and the bottom layer].
 * 19 mg**

=Discussion= Based on the HMR of 21B, there is no peak in the 9.7-9.8 region that would suggest an aldehyde. A cluster of peaks in the 4.4-4.6 region may suggest some benzylisocyanide is still present. The sharp peak at 3.8 may suggest that there is also some acid but it may be misleading as the CH2 group between the N and carboxyl group may lead that peak anywhere. The NH on the amine can be anywhere on the spectrum so it can not be determined readily. The NMR of Fractions 1&2 are virtually identical and have peaks in the 4-5 region that may suggest benzylisocyanide of the uncyclized product is present along with the 5.8 region where the furan protons would be present. The tert-butyl group of the amino acid is present in the 1.3-1.4 region and lastly there is a peak that can integrate to about 5 protons at 7.2. The H-NMR for 21B-F1 is consistent with what would be expected from the Ugi product. We need the C-NMR to confirm the assignment. The HMR of 21C shows no amine peaks. Due to this either the aqueous layer maybe looked at again since it did spot more than the bottom layer.

=Conclusion= The HMR of 21C shows no methylfurfuryl peaks in the 5.8 region and therefore must be considered a failure.

=Log=

2006-08-8
1. 9:30] Started stirring of Ugi solution with yellowish color **[|Video]**

2006-08-9
2. 12:30] Stopped stirring of Ugi solution and noticed reddish color (Sample 21A) [|Video] 3. Performed TLC of 21A after 22 hours vs the starting acid and benzylisocyanide in 1:1 methylene chloride hexanes and the starting aldehyde in 7:1 methylene chloride methanol [|PIC] 4. Put on rotovap which was previously used for Exp020 so the bath was already at 60C. Methanol evaporated within 10 minutes.

2006-08-10
5. 20:30] Put on High Vac with an average pressure of 1.5mmHg for 1 hr(21B). Solution bubbled and dried to give weight=302.5mg

2006-08-14
6. TLC of 21B vs 21A and starting materials. Amine and benzylisocyanide were done in 1:1 methylenechloride hexanes. Aldehyde was done in 7:1 methylene chloride methanol. [|PIC] 7. Performed chromatotron on 21B. Collections #1-4 are 1:1 methylene chloride hexanes, #5-8 are pure DCM, #9-27 are 7:1 methylene chloride methanol, #28 & #29 are hexanes and #30 is methanol.

2006-08-15
8. Performed TLCs on all fractions with 21B as standard. [|PIC1-6] [|PIC7-12] [|PIC13-18] [|PIC19-24] [|PIC25-30]

2006-08-16
9. Combined collections #9-13 to make a complete fraction1, #14 is fraction2, #15&16 is fraction3 and collections #17 and #18 are fractions 4 and 5 respectively. [|TLC of combined fractions1-3] in 10:1 methylene chloride methanol. A [|TLC of 3,4-dihydroxybenzaldehyde] in pure DCM was done to confirm that a polar solvent such as methanol is needed to pull catechols up the TLC plate.

2006-08-18
10. Put Fractions 1 and 2 on high vac with average pressure of 1mmHg by manometer. Wt of fraction#1 is 174.6mg. Wt of fraction#2 is 11.8mg.

2006-08-21
11. Put fraction 3 on high vac with an average pressure of 0.9mmHg. Wt of fraction#3= 25mg 12. [|NMR of Fraction#1] [|NMR of Fraction#2] [|NMR of Fraction #3]

2006-08-22
13. Put fractions 4 &5 on high vacuum. Thin layer of film usually forms that prevents all of the solvent to be evaporated however it has been avoided but tilting the round bottom flask slightly as the vacuum begins. This does however produce some spattering in the flask. Wt of fraction#4 is 13.8mg. Wt of fraction#5 is 3.2mg. [|NMRs of fraction 4] [|NMR of fraction 5]. After the respective solvents were vacuumed off a [|TLC of all fractions] was done.

2006-08-29
14. After trying to get a C13MR with D2O and Acetone-d6, only 60mg of 21B-F1 remain. 21:10] This amount was added to 10%TFA in 1,2-dichloroethane and left stirring over night.

2006-08-30
15. 15:45] TFA solution was washed with DI Water (80mL x 3) pH was brought to 6-7. Bottom layer was cloudy and red/pink in color 16. Dried with magnesium sulfate 17. Put on rotovap and high vacuum to obtain about 19mg **21C** 18.[|TLC of the top layer and the bottom layer].

2006-08-31
19. Took [|HMR of 21C] =Tags= [|Benzylisocyanide] [|InChI=1/C8H7N/c1-9-7-8-5-3-2-4-6-8/h2-6H,7H2] [|3,4-dihydroxybenzaldehyde] [|InChI=1/C7H6O3/c8-4-5-1-2-6(9)7(10)3-5/h1-4,9-10H] [|Boc-Gly-OH] [|InChI=1/C7H13NO4/c1-7(2,3)12-6(11)8-4-5(9)10/h4H2,1-3H3,(H,8,11)(H,9,10)] [|5-methylfurfurylamine] [|InChI=1/C6H9NO/c1-5-2-3-6(4-7)8-5/h2-3H,4,7H2,1H3] ugi018: [|InChI=1/C29H35N3O6/c1-19-10-11-21(14-19)18-32(25(35)17-31-28(37)38-29(2,3)4)26(22-12-13-23(33)24(34)15-22)27(36)30-16-20-8-6-5-7-9-20/h5-13,15,26,33-34H,14,16-18H2,1-4H3,(H,30,36)(H,31,37)] [|DKP018] [|InChI=1/C17H18N2O4/c1-10-2-3-11(6-10)9-19-15(22)8-18-17(23)16(19)12-4-5-13(20)14(21)7-12/h2-5,7,16,20-21H,6,8-9H2,1H3,(H,18,23)]

media type="custom" key="4479"