1. Synthesis of sulfonamides and evaluation of their histone deacetylase (HDAC) activity
Seikwan Oh, Hyung-In Moon, Il-Hong Son, Jae-Chul Jung, Mitchell A Avery Molecules. 2007 May 24;12(5):1125-35. doi: 10.3390/12051125.
A simple synthesis of sulfonamides 4-22 as novel histone deacetylase (HDAC) inhibitors is described. The key synthetic strategies involve N-sulfonylation of L-proline benzyl ester hydrochloride (2) and coupling reaction of N-sulfonyl chloride 3 with amines in high yields. It was found that several compounds showed good cellular potency with the most potent compound 20 exhibiting an IC50 = 2.8 microM in vitro.
2. Mild, orthogonal solid-phase peptide synthesis: use of N alpha-dithiasuccinoyl (Dts) amino acids and N-(iso-propyldithio)carbonylproline, together with p-alkoxybenzyl ester anchoring linkages
F Albericio, G Barany Int J Pept Protein Res. 1987 Aug;30(2):177-205. doi: 10.1111/j.1399-3011.1987.tb03327.x.
Several N alpha-dithiasuccinoyl (Dts) amino acids (1) have been esterified without racemization by use of either N,N'-dicyclohexylcarbodiimide or 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride, each in the presence of 4-dimethylaminopyridine (0.1 equiv.), to 2, 4, 5-trichlorophenyl 4'-hydroxymethylphenoxyacetate (10) or the corresponding propionate (11). The resultant handle derivatives (8,9) were purified and then quantitatively attached onto aminomethyl supports by couplings using as solvent N,N-dimethylformamide containing 1-hydroxybenzotriazole (0.1 M). This methodology facilitates anchoring of Dts-amino acids as p-alkoxybenzyl esters, which can be cleaved in good yields by trifluoroacetic acid-dichloromethane (1:1) at 25 degrees. Model experiments established that quantitative thiolytic removal (greater than 99.8%) of the Dts group occurs with (i) beta-mercaptoethanol (0.5 M)-N,N-diisopropylethylamine (0.5 M) in dichloromethane, 2 X 2 min; (ii) N-methylmercaptoacetamide (0.5 M)-N-methylmorpholine (0.5 M) in dichloromethane, 2 X 2 min; and (iii) N-methylmercaptoacetamide (0.5 M)-1-hydroxybenzotriazole (0.1 M) in N,N-dimethylformamide, 2 X 2 min. The susceptibility of the Dts functionality to nucleophiles was also defined, including demonstration of tertiary amine-catalyzed hydantoin formation from Dts-dipeptidyl units, but side reactions from these processes are entirely avoided under appropriate conditions relevant to peptide synthesis. These observations were exploited to devise efficient, racemization-free solid-phase syntheses of a number of model peptides in high yields and purities, including L-leucyl-L-alanylglycyl-L-valine, H-Gly6-Val-OH, H-Met-Ala-Gly-OH, methionine-enkephalin, and bradykinin.
3. Synthesis of ( R)-Boc-2-methylproline via a Memory of Chirality Cyclization. Application to the Synthesis of Veliparib, a Poly(ADP-ribose) Polymerase Inhibitor
Lawrence Kolaczkowski, Jufang Barkalow, David M Barnes, Anthony Haight, Wayne Pritts, Adam Schellinger J Org Chem. 2019 Apr 19;84(8):4837-4845. doi: 10.1021/acs.joc.8b02866. Epub 2019 Feb 19.
( R)-Boc-2-methylproline (3a) was synthesized in good yield with excellent stereochemical control from alanine benzyl ester hydrochloride 11. The process, which is based on a modification of one described by Kawabata, proceeds in four steps and requires no chromatography. The product ( R)-Boc-2-methylproline (3a) was then carried forward in three steps to produce veliparib 1, a poly(ADP-ribose) polymerase inhibitor.
