The outer cell wall of the Gram-negative bacteria is a crucial barrier for antibiotics to reach their target. Here, we show that the chemical stability of the widely used antibiotic ampicillin is a major factor in the permeation across OmpF to reach the target in the periplasm. Using planar lipid bilayers we investigated the interactions and permeation of OmpF with ampicillin, its basic pH-induced primary degradation product (penicilloic acid), and the chemically more stable benzylpenicillin. We found that the solute-induced ion current fluctuation is 10 times higher with penicilloic acid than with ampicillin. Furthermore, we also found that ampicillin can easily permeate through OmpF, at an ampicillin gradient of 10 μm and a conductance of ≅ 3.8 fS, with a flux rate of roughly 237 molecules/s of ampicillin at = 10 mV. The structurally related benzylpenicillin yields a lower conductance of ≅ 2 fS, corresponding to a flux rate of ≈120 molecules/s. In contrast, the similar sized penicilloic acid was nearly unable to permeate through OmpF. MD calculations show that, besides their charge difference, the main differences between ampicillin and penicilloic acid are the shape of the molecules, and the strength and direction of the dipole vector. Our results show that OmpF can impose selective permeation on similar sized molecules based on their structure and their dipolar properties.

Aldol reaction chemoselectivity, racemic or enantioselective, has not been previously demonstrated in the presence of Knoevenagel active functional groups. Here, we show that unhindered β-diketones remain unreacted while a ketone moiety undergoes a highly enantioselective aldol desymmetrization resulting in three new stereogenic centers using in water reaction conditions. A mechanistic hypothesis for the chemoselective formation of either aldol or Knoevenagel products is presented. It elucidates how these amino acid catalyzed reactions completely suppress formation of the expected Knoevenagel product under in water (heterogeneous) reaction conditions, but not when water is present as a dissolved cosolvent (homogeneous). Finally, the developed hypothesis reinforces and expands the role of water at an organic-water interface.

An extensive introduction is provided for the non-expert regarding enantioselective, amine catalyzed, aldol reactions (Sections 1-3). There, a broad perspective is provided regarding: methodology limitations, mechanism, in-water versus on-water definitions and their theoretical basis, small-and large-scale physical-mechanical aspects, solid versus liquid starting material considerations, reproducibility, ball milling, diketone substrates, etc. The thematic emphasis then turns to practical outcomes for the reaction of nineteen aliphatic, cyclic, and aromatic ketones with 4-nitrobenzaldehyde and benzaldehyde prior to 2021. In doing so, 172 catalysts are highlighted. The ketone substrates are listed in the Table of Contents (Section 4) and their structures are shown in Figure 1. Each ketone is summarized by a: (i) schematic, (ii) text summary, (iii) catalyst Figures, and (iv) tabular reaction/ product data. Individual ketone summaries, at times, represent the distillation of over six hundred and fifty research articles, and the data refinement and its tabular reconstitution is not reproducible using a chemical database search with filters. In the review's broadest use, the Figure 1 ketone structures serve as templates to extrapolate to hypothetical substrates holding more functionality, but of related steric and electronic similarity. This pseudo matching permits a rapid answer to, "Does this methodology suit the ketone substrate at hand or not?" In a positive outcome, the best reaction conditions (stoichiometry, catalyst structure and loading, solvent, time, etc.) to affect aldol product formation (yield, dr, and ee) are delineated. A second envisioned use, allows the directed construction of diketone substrates (after viewing the tabularized data of Section 4) capable of undergoing regioselective mono-aldol product formation. This ketone regioselectivity tactic, reacting one carbonyl moiety while the other remains unreacted, avoids ketone protection-deprotection, and is demonstrated for the advantageous synthesis of an Alzheimer drug candidate.

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.