X. Eric Hu

Enantioselective synthesis of phosphinyl peptidomimetics via an asymmetric Michael reaction of phosphinic acids with acrylate derivatives

Abstract Asymmetric Michael reaction of phosphinic or aminophosphinic acids with acrylate derivatives afforded phosphinyl dipeptidomimetics in excellent yields (>90%). Chiral induction of substituents at the α-position of acrylate derivatives of Evans oxazolidinone type auxiliaries was obtained in moderate to excellent diastereomeric and enantiomeric excesses (50–98%). Pure diastereomers and enantiomers of phosphinyl dipeptidomimetics 16 – 19 were also successfully separated by HPLC.

Lewis acid promoted regio- and stereoselective hetero nucleophilic addition to a piperidinyl aziridine. Synthesis of trans 3-amino-4-substituted piperidines

Abstract A piperidinyl aziridine underwent alcoholic nucleophilic addition with alcohols to result in corresponding trans 3-amino-4-substituted piperidines. The addition reaction was catalyzed by BF3·OEt2 in excellent regio- and stereoselectivity. The application of this method was extended to the addition of thiols, acids and halogens with sustained regio- and stereoselectivity.

Regio- and stereo-controlled copper organometallic addition to a piperidinyl aziridine: synthesis of trans 3-amino-4-alkyl-piperidines

Abstract 3,4-Piperidinyl aziridine N -phosphonate underwent ring opening in Grignard addition catalyzed by a copper reagent to yield trans 3-amino-4-alkyl-piperidines. The nucleophilic addition occurred trans to the aziridine group and regioselectively at C-4 position of the piperidine ring. The high regioselectivity was rationalized by steric argument based on conformational analysis.

Synthesis and biological testing of non-Fluorinated analogues of levofloxacin

Quinolones without the usual 6-fluorine substituent have been recently described as potent antibacterial agents. A series of non-fluorinated analogues of the antibacterial quinolone Levofloxacin were synthesized and tested.

Expansion of First-in-Class Drug Candidates That Sequester Toxic All-Trans-Retinal and Prevent Light-Induced Retinal Degeneration

All-trans-retinal, a retinoid metabolite naturally produced upon photoreceptor light activation, is cytotoxic when present at elevated levels in the retina. To lower its toxicity, two experimentally validated methods have been developed involving inhibition of the retinoid cycle and sequestration of excess of all-trans-retinal by drugs containing a primary amine group. We identified the first-in-class drug candidates that transiently sequester this metabolite or slow down its production by inhibiting regeneration of the visual chromophore, 11-cis-retinal. Two enzymes are critical for retinoid recycling in the eye. Lecithin:retinol acyltransferase (LRAT) is the enzyme that traps vitamin A (all-trans-retinol) from the circulation and photoreceptor cells to produce the esterified substrate for retinoid isomerase (RPE65), which converts all-trans-retinyl ester into 11-cis-retinol. Here we investigated retinylamine and its derivatives to assess their inhibitor/substrate specificities for RPE65 and LRAT, mechanisms of action, potency, retention in the eye, and protection against acute light-induced retinal degeneration in mice. We correlated levels of visual cycle inhibition with retinal protective effects and outlined chemical boundaries for LRAT substrates and RPE65 inhibitors to obtain critical insights into therapeutic properties needed for retinal preservation.

Ketopiperazines: Conformationally Constrained Peptidomimetic of Arginine Amides

Abstract We have synthesized guanidine‐containing ketopiperazines designed to be conformational mimics of peptidomimetic arginine amides. D‐Allylglycine was converted by an efficient approach to give enantiopure ketopiperazines in which the trans stereochemistry of the C‐substituents resulted from stereospecific enolate alkylation.