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In order to develop novel κ agonists restricted to the periphery, a diastereo- and enantioselective synthesis of (4aR,5S,8aS)-configured decahydroquinoxalines 5-8 was developed. Physicochemical and pharmacological properties were fine-tuned by structural modifications in the arylacetamide and amine part of the pharmacophore as well as in the amine part outside the pharmacophore. The decahydroquinoxalines 5-8 show single-digit nanomolar to subnanomolar κ-opioid receptor affinity, full κ agonistic activity in the [35S]GTPγS assay, and high selectivity over μ, δ, σ1, and σ2 receptors as well as the PCP binding site of the NMDA receptor. Several analogues were selective for the periphery. The anti-inflammatory activity of 5-8 after topical application was investigated in two mouse models of dermatitis. The methanesulfonamide 8a containing the (S)-configured hydroxypyrrolidine ring was identified as a potent (Ki = 0.63 nM) and highly selective κ agonist (EC50 = 1.8 nM) selective for the periphery with dose-dependent anti-inflammatory activity in acute and chronic skin inflammation.

A chemoenzymatic approach to the synthesis of functionalized α-methyl α-substituted amino acids is detailed. This involves amidase-mediated enzymatic resolution of α-methyl α-substituted side-chain ω-unsaturated amino acids followed by functionalization via cross-metathesis.

The steric influence of extended aryl substituents on 2,2′-bis(1,3-oxazoline) ligands was investigated in a series of asymmetric catalytic reactions such as Mukaiyama aldol and Michael reactions, hetero-Diels–Alder processes, and allylic alkylation reactions. 4,4′-(2-Naphthyl)- and 4,4′-(9-anthryl)-substituted isopropylidene-bridged 2,2′-bis(1,3-oxazolines) were synthesized and their enantioselective and catalytic properties in combination with different metals evaluated. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

The steric influence of extended aryl substituents on 2,2′-bis(1,3-oxazoline) ligands was investigated in a series of asymmetric catalytic reactions such as Mukaiyama aldol and Michael reactions, hetero-Diels–Alder processes, and allylic alkylation reactions. 4,4′-(2-Naphthyl)- and 4,4′-(9-anthryl)-substituted isopropylidene-bridged 2,2′-bis(1,3-oxazolines) were synthesized and their enantioselective and catalytic properties in combination with different metals evaluated. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)