Critical parameters affecting the stereoselective amination of (hetero)aromatic ketones using transaminases have been studied such as temperature, pH, substrate concentration, cosolvent and source and percentage of amino donor, to further optimize the production of enantiopure amines using both (S)-and (R)-selective biocatalysts from commercial suppliers.Interesting enantiopure amino building blocks have been obtained overcoming some limitations of traditional chemical synthetic methods. Representative processes were scaled-up affording halogenated and heteroaromatic amines in enantiomerically pure form and good isolated yields.

The asymmetric synthesis and biological activity of (2S,1'S,2'S,3'R)-2-(2'-carboxy-3'-methylcyclopropyl) glycine 7 and its epimer at the C3' center 6 are described. Compound 7 is a highly potent and selective agonist for group 2 metabotropric glutamate receptors (mGluRs). It is also systemically 4 orders of magnitude more active in the fear-potentiated startle model of anxiety in rats than the rigid constrained bicyclic system LY354740. Therefore, we have shown that high molecular complexity of conformationally constrained bicyclic systems is not a requirement to achieve highly selective and potent group 2 mGluRs agonists.

(+)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (1), also known as LY354740, is a highly potent and selective agonist for group II metabotropic glutamate receptors (mGlu receptors 2 and 3) tested in clinical trials. It has been shown to block anxiety in the fear-potentiated startle model. Its relatively low bioavailability in different animal species drove the need for an effective prodrug form that would produce a therapeutic response at lower doses for the treatment of anxiety disorders. We have investigated the increase of intestinal absorption of this compound by targeting the human peptide transporter hPepT1 for active transport of di- and tripeptides derived from 1. We have found that oral administration of an N dipeptide derivative of 1 (12a) in rats shows up to an 8-fold increase in drug absorption and a 300-fold increase in potency in the fear-potentiated startle model in rats when compared with the parent drug 1.

A total synthesis of natural levorotatory spinosyn A (1) has been achieved. The first objective, to confirm the absolute configurational assignment of tricyclic ketone 2 prepared earlier, was accomplished by oxidative degradation of the macrocyclic lactone ring in 1. The route began with the implementation of a four-step one-pot process that resulted in the efficient conversion of 6 into 18. A combination of periodate cleavage and peracid oxidation events then led to 2. In the reconstruction phase, a Pd-catalyzed coupling of a vinylstannane with an acid chloride reestablished the great majority of the structure in an enantiocontrolled manner. Once macrolactonization had been effected, the 2,3,4-tri-O-methylrhamnose unit was introduced first with exceptionally good stereocontrol. The final glycosidation, which involved a 2-mercaptopyrimidine derivative of d-forosamine, was met with an expectedly diminished percentage of the desired β-anomer.

Enantiomerically pure (2S,4R)-4-substituted glutamic acids were prepared and tested for homomeric GluR5 and GluR6 kainate subtype receptor affinity. Some of the 4-cinnamyl analogues showed high selectivity and potency (K(i) < 25 nM) for the GluR5 receptors. The greatest selectivity and potency were achieved with the 3-(2-naphthyl)prop-2-enyl compound. This compound, LY339434, has negligible activity at the AMPA and kainate receptors GluR1, -2, -4 and -6. Although, LY339434 shows agonist activity at NMDA receptors in cultural hippocampal neurons (approximate EC(50) of 2.5 microM), we consider that LY339434 should be a useful pharmacological tool for the investigation of the functional role of GluR5 kainate receptors.