Automated solid-phase organic synthesis in micro-plate wells. Synthesis of n-(alkoxy-acyl)amino alcohols

Bioorganic and Medicinal Chemistry Letters

Volumn 7, Issue 8, 1997, Pages 1013-1016

  Krchňák, Viktor ^a   Weichsel, Aleksandra S ^a   Lebl, Michal ^a   Felder, Stephen ^a  

^a Selectide Corporation   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMINOALCOHOL;

ARTICLE; AUTOMATION; DRUG SYNTHESIS; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; METHODOLOGY; TECHNIQUE;

EID: 0343471491     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(97)00146-7     Document Type: Article

References (12)

1. Presented as a poster at the Symposium "Combinatorial Library and Drug Discovery Methods for Basic Research". Tucson, December 1995.
2. Present address: Houghten Pharmaceuticals Inc., 3550 General Atomics Court, San Diego, CA 92121.
3. Krchnak, V.; Cabel, D.; Lebl, M. Peptide Res. 1996, 9, 45.
4. Schnorrenberg, G.; Gerhardt, H. Tetrahedron Lett. 1989, 45, 7759.
5. Meyers, H.V.; Dilley, G.J.; Durgin, T.L.; Powers, T.S.; Winssinger, N.A.; Zhu, H.; Pavia, M.R. Mol. Diversity 1995, 1, 13.
6. Krchnak, V.;. Weichsel, A.S.; Cabel, D.; Flegelova, Z.; Lebl, M. Mol. Diversity 1996, 1, 149.
7. 6 Fmoc groups were removed by piperidine and quantified. Substitution of 0.18 mmol/g was found.
8. The esterified resin was distributed into 96 deep-well polypropylene micro-titer plate by the pipetting station. The resin (400 mg) was suspended in DMF (total volume 8 mL) and 200 μL of stirred suspension was pipetted and delivered, i.e., each well contained 50 μL of settled resin slurry (ca. 2 μmol). Fmoc-tyrosinol and Fmoc-glycinol derivatized resins were each distributed into 40 wells A1-H5, A6-H10 respectively. No compounds were synthesized in columns 11 and 12. Building block distribution is schematically shown in Figure 2.
9. Polymer-supported amino groups were acylated by 4 different aromatic hydroxy acids: p-hydroxybenzoic, p-hydroxycinnamic, 2-(4-hydroxyphenoxy)propionic, and 3-hydroxy-4-methoxybenzoic acids. 0.1 mL of 0.5 M solution of acid and HOBt was added to each well, followed by addition of 200 μL of 0.25 M DIC in DMF (total volume of liquid per well was 350 μL, final concentration of acid was ca 0.15 mM, the excess was 50 μmol/2 μmol, i.e., 25-fold). The plate was shaken on a IKA-Schutter MTS 4 Vibrax shaker for 3 h at rt, washed 6 x with DMF and stored overnight in DMF containing 1% of HOBt.
10. 3 in THF was added to each well (final concentration of alcohol was 0.65 mM, the excess was 125-fold), immediately followed by the addition of 62 μL of 2 M solution of DIAD in THF (added in two portions 2 × 31 μL) at rt. The plate was left overnight and then washed 6x with THF. No etherification was done in columns 5 and 10.
11. The tBu side-chain protecting groups were cleaved (rows 1-5 only) by TFA. The resin was washed 5 × with methyl-t-butyl ether (500 μL per well), then 200 μL of a 70% TFA in DCM containing 5% of p-cresol was added and left for 1 h at rt. The resin was washed 5 × with methyl-t-butyl ether, 5 × with DMF, 5 × with MeOH, 5 × with methyl-t-butyl ether and then dried in dessicator for 2 h.
12. The compounds were released from the resin by NaOH. 200 μL of 0.5% NaOH in 50% MeCN was added to each well. After 3 h the solution was neutralized with 200 μL of 20% aqueous AcOH.