Site selectivity, differentiating instances of the same functional group type on one substrate, represents a forward-looking theme within chemistry: reduced dependence on protection/deprotection protocols for increased overall yield and step-efficiency. Despite these potential benefits and the expanded tactical advantages afforded to synthetic design, site selectivity remains elusive and especially so for ketone-based substrates. Herein, site-selective intermolecular mono-aldolization has been demonstrated for an array of prochiral 4-keto-substituted cyclohexanones with concomitant regio-, diastereo-, and enantiocontrol. Importantly, the aldol products allow rapid access to molecularly complex ketolactones or keto-1,3-diols, respectively containing three and four stereogenic centers. The reaction conditions are of immediate practical value and general enough to be applicable to other reaction types. These findings are applied in the first enantioselective, formal, synthesis of a leading Alzheimer's research drug, a γ-secretase modulator (GSM), in the highest known yield.

We report broad guidance on how to catalyze enantioselective aldehyde additionst on itroalkene or maleimide Michael electrophiles in the presence of unprotected acidic spectator groups,e .g.,c arboxylic acids,a cetamides,p henols,c atechols,a nd maleimide NH groups.R emarkably,t hese l-threonine and l-serine potassium salt-catalyzedr eactions proceedevenwhen the nucleophilic and electrophilic Michaelp artners simultaneously contain acidics pectator groups.T hese findings begin to address the historical non-compatibility of enantioselective catalytic reactions in the presenceo fa cidic moieties and simultaneously encroach on the spectator group toler-ances normallya ssociated with cellular environments.Ac arboxylate salt bridge,f rom the catalyst enabled enamine to the Michaele lectrophile,i s thought to facilitate the expanded Michaels ubstrate profile.Apractical outcome of these endeavours is a new synthetic route to (R)-Pristiq, (À)-O-desmethylvenlafaxine,a na ntidepressant, in the highest yield known to date because no protecting groups are required.Keywords: carboxylate salt bridge;m aleimide;M ichael reaction; nitroalkenes;o rganocatalysis;p eracetic acid para-based phenolic alcohol substrates and involve the addition of acetaldehyde, [4] propanal, [5] or isobutyraldehyde. [6] Scheme1.Enantioselective aldehyde additions to b-nitrostyrenes containing acidic moieties.

Site-selectivity, differentiating members of the same functional group type on one substrate, is an emerging tactic for shortened advanced building block and biomolecule synthesis. Despite its potential, site-selectivity remains less studied and especially so for ketone-based substrates. During this work ketone site-selectivity has been coupled with the chiral amine-catalyzed aldol desymmetrization of 4-keto-substituted cyclohexanones, allowing three stereogenic centers to form in the aldol product while leaving the acyclic ketone unreacted. Unique here, compared to all previous 4-substituted cyclohexanone desymmetrizations, is the first access to synthetically useful quantities of an epimeric (remote stereogenic center) aldol product. To demonstrate the value of these aldol products, we show their elaboration into eight keto-acetonide and one keto-lactone products. All compounds were isolated as single diastereomers and in high ee (! 96%). These efforts represent the first full characterization of aldol products with type III, Figure 2, relative stereochemistry, regardless of the enantiomer formed.

Common limitations of Protein A affinity chromatography include high adsorbent costs, ligand instability and possible ligand leakage. In this study, a short peptide with affinity for IgG was synthesized chemically and subsequently immobilized on a megaporous support. The support was prepared utilising the cryogel technique while the peptide-ligand was covalently immobilised via thiol-epoxy click chemistry. The cryogel support was chemically grafted to increase the number of reaction sites. This adsorbent was designated as "MP-Pep". Adsorption isotherms were employed to evaluate protein binding capacity. A maximum static binding capacity within the range of 30-60 mg/mL was observed for hIgG. This parameter compares well with other commercial and non-commercial adsorbents, as reported in the literature. As a control material, a Protein A grafted megaporous cryogel was synthesized. Dynamic binding capacity values were obtained by breakthrough analysis. The peptide cryogel showed a dynamic capacity value 9.0 mg/mL in comparison to 9.7 mg/mL in the case of the Protein A based adsorbent. The ratio of dynamic binding capacity to static binding capacity was 20%, indicating suboptimal product capture. However, the advantage of MP-Pep lies in its cost-effective preparations while maintaining a reasonable binding capacity for the targeted product. The presence of cooperative effects during protein binding could also represent an advantage during the processing of a feedstock containing a product in high concentration.