Joon Hee Hong

Efficient synthesis of novel carbocyclic nucleosides via sequential Claisen rearrangement and ring-closing metathesis

Abstract Very efficient synthetic route to novel 4′α- C -hydroxymethyl branched carbocyclic nucleosides was described. The stereocontrolled synthesis of target nucleosides was successfully achieved by Johnson orthoester–Claisen rearrangement, ring-closing metathesis (RCM) starting from a simple acyclic precursor 1,3-dihydoxy acetone 1 . Nucleosidic bases (adenine and cytosine) were coupled by Pd(0)-catalyzed allylic alkylation in a highly regiocontrolled manner.

Enhanced cellular uptake of Ara-C via a peptidomimetic prodrug, L-valyl-ara-C in Caco-2 cells

This study aimed to investigate the gastrointestinal stability and the cellular uptake characteristics of l‐valyl‐ara‐C, a peptidomimetic prodrug of ara‐C (cytarabine). After the synthesis of l‐valyl‐ara‐C via the incorporation of l‐valine into the N4‐amino group of the cytosine ring in ara‐C, the gastrointestinal stability of l‐valyl‐ara‐C was examined using artificial gastric juice and artificial intestinal fluids. The cellular uptake characteristics of l‐valyl‐ara‐C were also examined in Caco‐2 cells. The disappearance half‐life of l‐valyl‐ara‐C was 2.2 h in artificial gastric juice, while the degradation of l‐valyl‐ara‐C was negligible in artificial intestinal fluid and also in the supernatant above the Caco‐2 cell monolayer during the 2‐h incubation. The cellular accumulation of l‐valyl‐ara‐C was 5‐fold higher than that of ara‐C in Caco‐2 cells. Furthermore, the cellular uptake of l‐valyl‐ara‐C did not increase proportionally to the increase in drug concentration. The cellular accumulation of l‐valyl‐ara‐C was significantly reduced in the presence of uridine, p‐aminohippurate, tetraethylammonium and small dipeptides, while it was not changed in the presence of l‐valine and benzoic acid, suggesting that l‐valyl‐ara‐C could interact with multiple uptake transporters, including peptide transporters, organic anion and cation transporters and nucleoside transporters, but might not interact with amino acid transporters. In conclusion, l‐valyl‐ara‐C could be effective to improve the oral absorption of ara‐C via the carrier‐mediated transport pathway.

Stereocontrolled synthesis of novel 6′(α)-hydroxy carbovir analogues

Abstract This paper describes the racemic and stereoselective synthetic route for a novel 6′(α)-hydroxy-carbovir from a simple acyclic precursor, Solketal. The relative stereochemistry of the target nucleosides was successfully controlled by a sequential stereoselective glycolate Claisen rearrangement followed by a ring-closing metathesis (RCM). Adenine and cytosine were coupled using a Pd(0) catalyzed allylic alkylation strategy in a high regio- and stereoselective manner.

Short Synthesis and Antiviral Activity of Acyclic Phosphonic Acid Nucleoside Analogues

An efficient route for synthesizing novel allylic and cyclopropanoid phosphonic acid nucleoside analogues is described. The condensation of the bromine derivatives 6 and 18 with nucleoside bases (A, U, T, C, G) under standard nucleophilic substitution and deprotection conditions, afforded the target phosphonic acid nucleoside analogues. These compounds were evaluated for their antiviral properties against various viruses. Cyclopropanoid phosphonic adenine nucleoside analogue 23 showed significant anti-HIV activity.

Synthesis and anti-HCMV activity of novel cyclopropyl phosphonic acid nucleosides.

A simple synthetic route for novel acyclic phosphonate nucleosides is described. The characteristic cyclopropyl moiety 8 was constructed employing the Simmons-Smith reaction as key step starting from simple acyclic 2-butene-1,4-diol. The condensation of the mesylate 11 with natural nucleosidic bases (A,C,T,U) under nucleophilic substitution conditions (K2CO3, 18-Crown-6, DMF) and hydrolysis afforded the target nucleosides 16, 17, 18, and 19. In addition, the antiviral evaluations against various viruses were performed.

Synthesis and Antibacterial Activity of 1β-Methylcarbapenems Having a 2, 2-disubstituted-1, 3-Diazabicyclo[3.3.0]octan-4-one Moiety and Related Compounds. Part III

The synthesis of new series of 1β‐methylcarbapenems having a 2, 2‐disubstituted‐1, 3‐diazabicyclo[3.3.0]octan‐ and ‐[4.3.0]nonan‐4‐one moiety is described.Their in vitro antibacterial activities against both Gram‐positive and Gram‐negative bacteria were tested and the effect of the substituent of the bicyclic ring was investigated. A particular compound (16 f) bearing a hydroxymethyl group showed the most potent antibacterial activity and the compound (17 a) with a 1, 3‐diazabicyclo[4.3.0]nonane moiety exhibited excellent stability against renal dehydropeptidase‐I (DHP‐I) to Meropenem.

A convenient method for the enantiomeric separation of α-amino acid esters as benzophenone imine Schiff base derivatives

A convenient liquid chromatographic method for the separation of α-amino acid esters as benzophenone Schiff base derivatives on coated chiral stationary phases (CSPs) (Chiralcel OD-H, Chiralcel OD, Chiralpak AD-H, Chiralpak AD, and Chiralpak AS) or covalently immobilized CSPs (Chiralpak IA, Chiralpak IB, and Chiralpak IC) derived from polysaccharide derivatives is described. Benzophenone imine derivatives of α-amino acid esters were readily prepared by stirring benzophenone imine and the hydrochloride salts of α-amino acid esters in 2-propanol. The chromatographic separations were conducted at a flow rate 1.0 mL/min and a detection wavelength of 254 nm; 0.5% 2-propanol/hexane (v/v) was used on CSPs. In general, the resolution of Chiralpak IC was superior to those of the other CSPs. In addition, the resolutions of other arylimine derivatives of α-amino acid esters and the effects of different mobile phases on the enantiomeric separation of α-amino acid esters as benzophenone imine derivatives on Chiralpak IC were investigated.

Synthesis of novel 2’-methyl carbovir analogues as potent antiviral agents

In this study, the synthesis procedures of 2’-branched carbovir analogues were accomplished. The introduction of a methyl group in the requisite 2’-position was carried out by the addition of a carbonyl using isopropenyl magnesium bromide. The desired compound, cyclopentenol 10(β), was synthesizedvia ring-closing metathesis using a second-generation Grubbs’ catalyst. The nucleosidic bases (adenine, cytosine, thymine, uracil, 5-fluorouracil and 5-iodouracil) were efficiently coupled using a Pd (0) catalyst. When the synthesized compounds were examined for their activity against several viruses, including HIV-1, HSV-1, HSV-2 and HCMV, the 5-iodouracil analogue, 23, exhibited significant anti-HCMV activity.

Efficient synthesis of 4'-cyclopropylated carbovir analogues with use of ring-closing metathesis from glycolate.

The first synthetic route of novel 4′-cyclopropylated carbovir analgues is described. The construction of cyclopropylated quaternary carbon at 4′-position of carbocyclic nucleosides was successfully made via sequential Johnsons orthoester rearrangement and ring-closing metathesis (RCM) starting from ethyl glycolate. Synthesized compounds 15 and 16 showed moderate antiviral activity without any cytotoxicity up to 100 μmol.

Simple synthesis and anti-HIV activity of novel cyclopentene phosphonate nucleosides.

A very simple synthetic route for novel cyclopentene phosphonate nucleosides is described. The characteristic cyclopentene moiety 6 was constructed via a ring-closing metathesis of divinyl 5 , which could be readily prepared from diethylmalonate. The condensation of the mesylate 11 with nucleobases (A,C,T,U) under nucleophilic substitution conditions (K 2 CO 3 , 18-Crown-6, DMF) afforded the target nucleosides 12 , 13 , 14 , and 15 . In addition, the antiviral evaluations against various viruses were performed.