C 2-Symmetric bis(oxazolinyl)pyridine (pybox)−Cu(II) complexes have been shown to catalyze enantioselective Mukaiyama aldol reactions between (benzyloxy)acetaldehyde and a variety of silylketene acetals. The aldol products are generated in high yields and in 92−99% enantiomeric excess using as little as 0.5 mol % of chiral catalyst [Cu((S,S)-Ph-pybox)](SbF6)2. With substituted silylketene acetals, syn reaction diastereoselection ranging from 95:5 to 97:3 and enantioselectivities ≥95% are observed. Investigation into the reaction mechanism utilizing doubly labeled silylketene acetals indicates that the silyl-transfer step is intermolecular. Further mechanistic studies revealed a significant positive nonlinear effect, proposed to arise from the selective formation of the [Cu((S,S)-Ph-pybox)((R,R)-Ph-pybox)](SbF6)2 2:1 ligand:metal complex. A stereochemical model is presented in which chelation of (benzyloxy)acetaldehyde to the metal center to form a square pyramidal copper intermediate accounts for the observed sense of induction. Support for this proposal has been obtained from double stereodifferentiating reactions, EPR spectroscopy, ESI spectrometry, and, ultimately, the X-ray crystal structure of the aldehyde bound to the catalyst. The C 2-symmetric bis(oxazolinyl)−Cu(II) complex [Cu((S,S)-tert-Bu-box)](OTf)2 is also an efficient catalyst for the aldol reaction, but the scope with this system is not as broad.

Recent efforts in the field of thrombin inhibitor research have focused on the identification of compounds with good oral bioavailability and pharmacokinetics. In this manuscript we describe a metabolism-based approach to the optimization of the 3-(2-phenethylamino)-6-methylpyrazinone acetamide template (e.g., 1) which resulted in the modification of each of the three principal components (i.e., P1, P2, P3) comprising this series. As a result of these studies, several potent thrombin inhibitors (e.g., 20, 24, 25) were identified which exhibit high levels of oral bioavailability and long plasma half-lives.

Calcitonin gene-related peptide (CGRP) is a potent neuropeptide that plays a key role in the pathophysiology of migraine headache. CGRP levels in the cranial circulation are increased during a migraine attack, and CGRP itself has been shown to trigger migraine-like headache. The correlation between CGRP release and migraine headache points to the potential utility of CGRP receptor antagonists as novel therapeutics in the treatment of migraine. Indeed, clinical proof-of-concept in the acute treatment of migraine was demonstrated with an intravenous formulation of the CGRP receptor antagonist BIBN4096BS (olcegepant). Here we report on the pharmacological characterization of the first orally bioavailable CGRP receptor antagonist in clinical development, MK-MK-0974 is a potent antagonist of the human (K i ϭ 0.77 nM) and rhesus (K i ϭ 1.2 nM) CGRP receptors but displays Ͼ1500-fold lower affinity for the canine and rat receptors as determined via 125 I-human CGRP competition binding assays. A rhesus pharmacodynamic assay measuring capsaicin-induced changes in forearm dermal blood flow via laser Doppler imaging was utilized to determine the in vivo activity of CGRP receptor antagonism. MK-0974 produced a concentration-dependent inhibition of dermal vasodilation, generated by capsaicininduced release of endogenous CGRP, with plasma concentrations of 127 and 994 nM required to block 50 and 90% of the blood flow increase, respectively. In conclusion, MK-0974 is a highly potent, selective, and orally bioavailable CGRP receptor antagonist, which may be valuable in the acute treatment of migraine.CGRP is a 37 amino acid neuropeptide produced by tissuespecific alternative mRNA splicing of the calcitonin gene (Amara et al., 1982) and is a member of the calcitonin family of peptides, which includes calcitonin, amylin, and adrenomedullin. CGRP activity is mediated by the coexpression of a G-protein-coupled receptor, calcitonin receptor-like receptor, a single transmembrane-spanning protein designated receptor activity-modifying protein (RAMP) 1 (McLatchie et al., 1998), and an intracellular protein, receptor component proArticle, publication date, and citation information can be found at

The C 2-symmetric (S,S)-tert-butyl-bis(oxazolinyl)Cu(OTf)2 complex (1a) has been shown to catalyze the enantioselective aldol reaction between α-keto esters and silylketene acetals or enolsilanes with enantioselectivities ranging from 93 to 99%. With substituted silylketene acetals, syn reaction diastereoselection ranging from 90:10 to 98:2 and enantioselectivities ranging from 93 to 98% are observed. High levels of carbonyl regioselectivity (98:2), diastereoselectivity (93:7), and enantioselectivity (97% ee) are also observed in the aldol addition to 2,3-pentanedione. In all instances, the aldol adducts are generated in high yield and in excellent enantiomeric excess using as little as 1 mol % of the chiral complex 1a. Mechanistic insight into the pyruvate aldol reaction has also been gained. Silyl crossover experiments demonstrate that the silyl-transfer step is intermolecular. Based upon these results, TMSOTf has been identified as an addend to accelerate these reactions. Furthermore, solvent was shown to have a dramatic impact on the rates of addition and catalyst turnover in the pyruvate aldol reaction. Crystallographic structures and semiempirical calculations provide insight into the mode of asymmetric induction, allowing the construction of a model in which chelation of the pyruvate ester through a square planar Cu(II) complex accounts for the observed sense of asymmetric induction. Two other Cu(II) complexes, [Cu((S,S-i-Pr-pybox)](SbF6)2 and bis(imine) complex 26, have also been evaluated as enantioselective catalysts for the pyruvate aldol reaction; however, the scope of the process with these systems is more limited.

The C 2 -symmetric complexes [Cu(S,S)-tert-butylbis(oxazolinyl)](SbF6)2 (2a), its bis(aquo) counterpart [Cu(S,S)-tert-butylbis(oxazolinyl)(H2O)2](SbF6)2 (4), and [Cu(S,S)-phenylbis(oxazolinyl)](OTf)2 (1c) have been shown to catalyze the enantioselective ene reaction between glyoxylate esters and various olefins. Monosubstituted, disubstituted, and trisubstituted olefins each react with ethyl glyoxylate in the presence of 0.2−10 mol % of catalysts 1, 2, and 4 to afford the ene products in good yield and enantioselectivity. Complex 2a has also been shown to catalyze the addition of 1,1-disubstituted olefins to methyl pyruvate in good yields (76−95%) and excellent enantioselectivies (≥98% ee). The synthetic utility of the glyoxylate−ene reaction was demonstrated by conversion of the resulting α-hydroxy ester into the corresponding methyl ester, free acid, Weinreb amide, and α-azido ester, all with no detectable racemization.