This Review compiles the evolution, mechanistic understanding, and more recent advances in enantioselective Pd-catalyzed allylic substitution and decarboxylative and oxidative allylic substitutions. For each reaction, the catalytic data, as well as examples of their application to the synthesis of more complex molecules, are collected. Sections in which we discuss key mechanistic aspects for high selectivity and a comparison with other metals (with advantages and disadvantages) are also included. For Pd-catalyzed asymmetric allylic substitution, the catalytic data are grouped according to the type of nucleophile employed. Because of the prominent position of the use of stabilized carbon nucleophiles and heteronucleophiles, many chiral ligands have been developed. To better compare the results, they are presented grouped by ligand types. Pd-catalyzed asymmetric decarboxylative reactions are mainly promoted by PHOX or Trost ligands, which justifies organizing this section in chronological order. For asymmetric oxidative allylic substitution the results are grouped according to the type of nucleophile used.

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The completion of the Saccharomyces cerevisiae genome project in 1996 showed that almost 60% of the potential open reading frames of the genome had no experimentally determined function. Using a conserved sequence motif present in the zinc-containing mediumchain alcohol dehydrogenases, we found several potential alcohol dehydrogenase genes with no defined function. One of these, YAL060W, was overexpressed using a multicopy inducible vector, and its protein product was purified to homogeneity. The enzyme was found to be a homodimer that, in the presence of NAD ؉ , but not of NADP, could catalyze the stereospecific oxidation of (2R,3R)-2,3-butanediol (K m ‫؍‬ 14 mM, k cat ‫؍‬ 78,000 min ؊1 ) and meso-butanediol (K m ‫؍‬ 65 mM, k cat ‫؍‬ 46,000 min ؊1 ) to (3R)-acetoin and (3S)-acetoin, respectively. It was unable, however, to further oxidize these acetoins to diacetyl. In the presence of NADH, it could catalyze the stereospecific reduction of racemic acetoin ((3R/3S)-acetoin; K m ‫؍‬ 4.5 mM, k cat ‫؍‬ 98,000 min ؊1 ) to (2R,3R)-2,3-butanediol and meso-butanediol, respectively. The substrate stereospecificity was determined by analysis of products by gas-liquid chromatography. The YAL060W gene product can therefore be classified as an NAD-dependent (2R,3R)-2,3-butanediol dehydrogenase (BDH). S. cerevisiae could grow on 2,3-butanediol as the sole carbon and energy source. Under these conditions, a 3.5-fold increase in (2R,3R)-2,3-butanediol dehydrogenase activity was observed in the total cell extracts. The isoelectric focusing pattern of the induced enzyme coincided with that of the pure BDH (pI 6.9). The disruption of the YAL060W gene was not lethal for the yeast under laboratory conditions. The disrupted strain could also grow on 2,3-butanediol, although attaining a lesser cell density than the wild-type strain. Taking into consideration the substrate specificity of the YAL060W gene product, we propose the name of BDH for this gene. The corresponding enzyme is the first eukaryotic (2R,3R)-2,3-butanediol dehydrogenase characterized of the medium-chain dehydrogenase/reductase family.

A large number of therapeutic roles have been proposed for sigma(1) receptors but the involvement of sigma(1) receptor in non-acute pain had not been well explored up to now. sigma(1) receptor knock-out mice became available offering us the possibility to study the role of sigma(1) receptor in nociception, particularly in models where central sensitization processes play a significant role. Given the attractive therapeutic potential, we have developed a chemical program aimed at the discovery of novel and selective sigma(1) ligands. Herein we discuss the rational basis of this approach and report preliminary pharmacological results of several chemical series and aspects of their structure-activity relationship on sigma(1) receptor. Functional data in pain models are presented mainly on one series that provide evidence to consider selective sigma(1) receptor antagonists an innovative and alternative approach for treating neuropathic pain.

Here we report the use of 2-piperidino-1,2,2-triphenylethanol (5) as an outstanding catalyst for the ligand-catalyzed arylation of aldehydes. The use of 5 and a 2/1 mixture of Et(2)Zn/Ph(2)Zn provided the corresponding chiral diarylcarbinols with enantiomeric excess of up to 99% ee. The effect of temperature on the reaction enantioselectivity was studied and the inversion temperature (T(inv)) was determined to be 10 degrees C for reaction with p-tolylaldehyde. Most remarkably, lowering the amount of catalyst (5) to 0.5 mol % still afforded excellent levels of enantiocontrol (93.7% ee). Kinetics of the catalyzed and uncatalyzed arylation of aldehydes was studied by means of in situ FT-IR. The background uncatalyzed addition rates to p-tolylaldehyde when using pure Ph(2)Zn and Et(2)Zn/Ph(2)Zn (2/1) suggest that in the latter case a mixed zinc species forms (EtPhZn) minimizing the undesired nonselective addition. Formation of EtPhZn was modeled at the DFT calculation level. A four-center TS (TS-V) corresponding to the Et/Ph scrambling was localized along with two dimers (D-IV and D-VI). The model supports the hypothesis that Et/Ph exchange is a kinetically facile process. Gas evolution experiments during the formation of the active catalyst showed that the formation of an active site with a ONZn-Et (10) moiety is kinetically favored over ONZn-Ph (11). Finally, the phenyl transfer to benzaldehyde was modeled at the PM3(tm) level through anti and syn 5/4/4 tricyclic TS structures for both 10 and 11. The model could correctly predict the sense and selectivity of the overall process and predicted that 11 should be more selective than 10.

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The lithium perchlorate-induced ring opening of (S)-triphenylethylene oxide (3) with secondary amines (piperidine (a), N-methylpiperazine (b), N-phenylpiperazine (c) and morpholine (d)) takes place in a stereospecific and completely regioselective manner to afford (R)-2-(dialkylamino)-1,1,2-triphenylethanols (4a-d). These amino alcohols catalytically induce the addition of diethylzinc to benzaldehyde with high enantioselectivity at 0 degrees C and at room temperature. Ligand 4a, which provides the highest enantioselectivity at 0 degrees C, has been studied in the addition of Et(2)Zn to a family of 20 representative aliphatic and aromatic aldehydes 5a-t. For a 17-membered set of alpha-substituted substrates (5a-m,q-t), including ortho-, meta-, and para-substituted benzaldehydes, the naphthaldehydes, alpha,beta-unsaturated and aliphatic (cyclic and acyclic) aldehydes, the mean enantiomeric excess of the resulting alcohols 6a-m,q-t is 97%, whereas for three alpha-unsubstituted specimens (5n-p) the addition takes place with an enantioselectivity of 92-93%.