Adrian L. Schwan

Palladium catalyzed cross-coupling reactions for phosphorus–carbon bond formation

Underappreciated in the realm of palladium catalyzed cross-coupling chemistry is the formation of phosphorous-carbon bonds. This tutorial review summarises a collection of important contributions in the area, providing a flavour of the many types of phosphorus species that are participants in palladium catalyzed phosphorus-carbon bond formation. Recent developments include the usage of the cross-coupling reaction for preparation of phosphine ligands and the involvement of low molecular weight phosphinic acid derivatives for the synthesis of unsaturated phosphinic and phosphonic acid derivatives. Mechanistic cycles are offered in some instances. Stereochemical issues are addressed where applicable. The literature is covered to mid 2003.

Exotoxin A–eEF2 complex structure indicates ADP ribosylation by ribosome mimicry

The bacteria causing diphtheria, whooping cough, cholera and other diseases secrete mono-ADP-ribosylating toxins that modify intracellular proteins. Here, we describe four structures of a catalytically active complex between a fragment of Pseudomonas aeruginosa exotoxin A (ETA) and its protein substrate, translation elongation factor 2 (eEF2). The target residue in eEF2, diphthamide (a modified histidine), spans across a cleft and faces the two phosphates and a ribose of the non-hydrolysable NAD+ analogue, βTAD. This suggests that the diphthamide is involved in triggering NAD+ cleavage and interacting with the proposed oxacarbenium intermediate during the nucleophilic substitution reaction, explaining the requirement of diphthamide for ADP ribosylation. Diphtheria toxin may recognize eEF2 in a manner similar to ETA. Notably, the toxin-bound βTAD phosphates mimic the phosphate backbone of two nucleotides in a conformational switch of 18S rRNA, thereby achieving universal recognition of eEF2 by ETA.

In Situ PM-IRRAS Studies of an Archaea Analogue Thiolipid Assembled on a Au(111) Electrode Surface

Polarization modulation infrared reflection absorption spectroscopy (PM-IRRAS) has been applied to determine the conformation, orientation, and hydration of a monolayer of 2,3-di-O-phytanyl-sn-glycerol-1-tetraethylene glycol-dl-alpha-lipoic acid ester (DPTL) self-assembled at a gold electrode surface. This Archaea analogue thiolipid has been recently employed to build tethered lipid bilayers. By synthesizing DPT(d16)L, a DPTL molecule with a deuterium substituted tetraethylene glycol spacer, it was possible to differentiate the C-H stretch vibrations of the phytanyl chains from the tetraethylene glycol spacer and acquire the characteristic IR spectra for the chains, spacer, and lipoic acid headgroup separately. Our results show that the structure of the monolayer displays remarkable stability in a broad range of electrode potentials and that the phytanyl chains remain in a liquid crystalline state. The tetraethylene glycol chains are coiled, and the IR spectrum for this region shows that it is in the disordered state. The most significant result of this study is the information that in contrast to expectations the spacer region is poorly hydrated. Our results have implications for the design of a tethered lipid membrane based on this thiolipid.

Generation, structure and reactions of sulfenic acid anions

A comprehensive review of recent chemistry of sulfenate anions is presented. Compound structure, methods of generation and reaction of sulfenates are all addressed. Topical areas including asymmetric alkylation, sulfinyl zinc species and bio-organic mechanisms are covered.

Dynamic Surface Activity of a Fully Synthetic Phospholipase-Resistant Lipid/Peptide Lung Surfactant

Background This study examines the surface activity and resistance to phospholipase degradation of a fully-synthetic lung surfactant containing a novel diether phosphonolipid (DEPN-8) plus a 34 amino acid peptide (Mini-B) related to native surfactant protein (SP)-B. Activity studies used adsorption, pulsating bubble, and captive bubble methods to assess a range of surface behaviors, supplemented by molecular studies using Fourier transform infrared (FTIR) spectroscopy, circular dichroism (CD), and plasmon resonance. Calf lung surfactant extract (CLSE) was used as a positive control. Results DEPN-8+1.5% (by wt.) Mini-B was fully resistant to degradation by phospholipase A2 (PLA2) in vitro, while CLSE was severely degraded by this enzyme. Mini-B interacted with DEPN-8 at the molecular level based on FTIR spectroscopy, and had significant plasmon resonance binding affinity for DEPN-8. DEPN-8+1.5% Mini-B had greatly increased adsorption compared to DEPN-8 alone, but did not fully equal the very high adsorption of CLSE. In pulsating bubble studies at a low phospholipid concentration of 0.5 mg/ml, DEPN-8+1.5% Mini-B and CLSE both reached minimum surface tensions <1 mN/m after 10 min of cycling. DEPN-8 (2.5 mg/ml)+1.5% Mini-B and CLSE (2.5 mg/ml) also reached minimum surface tensions <1 mN/m at 10 min of pulsation in the presence of serum albumin (3 mg/ml) on the pulsating bubble. In captive bubble studies, DEPN-8+1.5% Mini-B and CLSE both generated minimum surface tensions <1 mN/m on 10 successive cycles of compression/expansion at quasi-static and dynamic rates. Conclusions These results show that DEPN-8 and 1.5% Mini-B form an interactive binary molecular mixture with very high surface activity and the ability to resist degradation by phospholipases in inflammatory lung injury. These characteristics are promising for the development of related fully-synthetic lipid/peptide exogenous surfactants for treating diseases of surfactant deficiency or dysfunction.

Novel Phospholipase-Resistant Lipid/Peptide Synthetic Lung Surfactants

Animal-derived drugs are currently widely-used to treat clinical lung surfactant deficiency, but synthetic surfactants have significant advantages as pharmaceutical agents. This article examines exogenous surfactants containing novel synthetic phospholipase-resistant lipids of extremely high surface activity. Mixtures of these lipid analogs with purified native surfactant apoproteins are detailed as a proof of concept for related fully-synthetic surfactants containing laboratory-produced peptides. The chemistry and biophysics of relevant lipid analogs and peptides are reviewed in the context of developing new synthetic drugs of utility for patients with surfactant deficiency or lung injury-related surfactant dysfunction.

β-Sulfinyl acrylate esters as a convenient source of alkane- and arenesulfenate anions

Methyl acrylate esters bearing alkane- and arenesulfinyl units on the 2-carbon liberate sulfenate anions upon nucleophilic attack. The sulfenates are readily captured through sulfur alkylation. When a sulfenate derived from R-cysteine is generated, diastereoselective benzylation is observed.

1,2-Dibromotetrachloroethane: An Ozone-Friendly Reagent for the in Situ Ramberg–Bäcklund Rearrangement and Its Use in the Formal Synthesis of E-Resveratrol

Dibromotetrachloroethane (C(2)Br(2)Cl(4)) is demonstrated as a halogenating reagent for the one-pot conversion of sulfones to alkenes by way of the Ramberg-Bäcklund rearrangement. Dibromotetrachloroethane successfully replaces known ozone depleting agents CCl(4), CBr(2)F(2) and C(2)Br(2)F(4). A formal synthesis of E-resveratrol is demonstrated using C(2)Br(2)Cl(4).

Diastereoselective Alkylations of a Protected Cysteinesulfenate

To further understand stereoselection in the alkylation of sulfenate anions, a protected cysteinesulfenate was generated in THF solution at low temperature. Introduction of a reactive alkylating agent brings about a cysteinyl sulfoxide in 51-75% yield, with diastereomeric ratios at the sulfinyl group ranging from 83:17 to 95:5. An internally complexed lithium counterion is proposed to account for the stereoselectivity.

A novel base-induced cyclization of selected benzyl alkynyl sulfides for the synthesis of 2-aryl-2,3-dihydrothiophenes

2-Halobenzyl 1-alkynyl sulfides undergo an unprecedented dihydrothiophene formation when treated with 2 equiv. of KOtBu in CH3CN. The reaction, believed to proceed via a 5-endo-dig cyclization, is sluggish or non-existent in the absence of the halogen.