On the Ability of Formaldehyde to Act as a Tethering Catalyst in Water.

The low concentration issue is a fundamental challenge when it comes to prebiotic chemistry, as macromolecular systems need to be assembled via intermolecular reactions, and this is inherently difficult in dilute solutions. This is especially true when the reactions are challenging, and reactions that proceeded more rapidly could have dictated chemical evolution. Herein we establish that formaldehyde is capable of catalyzing, via temporary intramolecularity, a challenging reaction in water at low concentrations, thus providing an alternative to other approaches that can either lead to higher concentrations or higher effective molarities.

Inhibition of Ice Recrystallization by Nylon-3 Polymers.

Nontoxic cryoprotectants are needed for storage of tissues and food preservation. Frozen tissue is particularly susceptible to damage caused by formation of large ice crystals during the thawing process. The current practice of using 5 wt % DMSO for cryopreservation does not produce 100% cell viability post-thaw, at least in part because of DMSO toxicity that is manifested during the freezing and thawing stages of the process. Recently, poly(vinyl alcohol) (PVA) has shown promise in inhibiting ice recrystallization, an activity that is critical for cryoprotection. Inspired by this discovery, we have evaluated nylon-3 polymers for ice recrystallization inhibition activity and for toxicity toward mammalian cells. A survey of homo- and heteropolymers, with side chains bearing variable functionality, has identified new nylon-3 materials that display excellent ice recrystallization inhibition activity and low toxicity.

Evaluation of the Ser-His Dipeptide, a Putative Catalyst of Amide and Ester Hydrolysis.

Efficient hydrolysis of amide bonds has long been a reaction of interest for organic chemists. The rate constants of proteases are unmatched by those of any synthetic catalyst. It has been proposed that a dipeptide containing serine and histidine is an effective catalyst of amide hydrolysis, based on an apparent ability to degrade a protein. The capacity of the Ser-His dipeptide to catalyze the hydrolysis of several discrete ester and amide substrates is investigated using previously described conditions. This dipeptide does not catalyze the hydrolysis of amide or unactivated ester groups in any of the substrates under the conditions evaluated.

Formaldehyde as Tethering Organocatalyst: Highly Diastereoselective Hydroaminations of Allylic Amines.

Catalysts possessing sufficient activity to achieve intermolecular alkene hydroaminations under mild conditions are rare, and this likely accounts for the scarcity of asymmetric variants of this reaction. Herein, highly diastereoselective hydroaminations of allylic amines utilizing hydroxylamines as reagents and formaldehyde as catalyst are reported. This catalyst induces temporary intramolecularity, which results in high rate accelerations, and high diastereocontrol with either chiral allylic amines or chiral hydroxylamines. The reaction scope includes internal alkenes. Overall this work provides a new, stereocontrolled route to form complex vicinal diamines.

Catalysis through temporary intramolecularity: mechanistic investigations on aldehyde-catalyzed Cope-type hydroamination lead to the discovery of a more efficient tethering catalyst.

Mechanistic investigations on the aldehyde-catalyzed intermolecular hydroamination of allylic amines using N-alkylhydroxylamines are presented. Under the reaction conditions, the presence of a specific aldehyde catalyst allows formation of a mixed aminal intermediate, which permits intramolecular Cope-type hydroamination. The reaction was determined to be first-order in both the aldehyde catalyst (α-benzyloxyacetaldehyde) and the allylic amine. However, the reaction displays an inverse order behavior in benzylhydroxylamine, which reveals a significant off-cycle pathway and highlights the importance of an aldehyde catalyst that promotes a reversible aminal formation. Kinetic isotope effect experiments suggest that hydroamination is the rate-limiting step of this catalytic cycle. Overall, these results enabled the elaboration of a more accurate catalytic cycle and led to the development of a more efficient catalytic system for alkene hydroamination. The use of 5-10 mol % of paraformaldehyde proved more effective than the use of 20 mol % of α-benzyloxyacetaldehyde, leading to high yields of intermolecular hydroamination products within 24 h at 30 °C.

A catalytic tethering strategy: simple aldehydes catalyze intermolecular alkene hydroaminations.

Herein we describe a catalytic tethering strategy in which simple aldehyde precatalysts enable, through temporary intramolecularity, room-temperature intermolecular hydroamination reactivity and the synthesis of vicinal diamines. The catalyst allows the formation of a mixed aminal from an allylic amine and a hydroxylamine, resulting in a facile intramolecular hydroamination event. The promising enantioselectivities obtained with a chiral aldehyde also highlight the potential of this catalytic tethering approach in asymmetric catalysis and demonstrate that efficient enantioinduction relying only on temporary intramolecularity is possible.