The purpose of this perspective is to indicate the range of chemistries used in the manufacture of drug candidate molecules and to highlight certain gaps in current technologies. To do this a survey was carried out of chemical syntheses within the Process Chemistry R&D departments of GlaxoSmithKline, AstraZeneca and Pfizer.

Analysis of the reactions used for the preparation of drug candidate molecules.

Separation of enantiomers: needs, challenges, perspectives☆

Cu-catalysed arylation reactions devoted to the formation of C–C and C–heteroatom bonds (Ullmann-type couplings) have acquired great importance in the last decade. This review discusses the history and development of coupling reactions between aryl halides and various classes of nucleophiles, focusing mostly on the different mechanisms proposed through the years. Selected mechanistic investigations are treated more in depth than others. For example, evidence in favour or against radical mechanisms is discussed. Cu(I) and Cu(III) complexes involved in the Ullmann reaction and N/O selectivity in aminoalcohol arylation are discussed. A separate section has been dedicated to the synthesis of heterocyclic rings through intramolecular couplings. Finally, recent developments in green chemistry for these reactions, such as reactions in aqueous media and heterogeneous catalysis, have also been reviewed.

https://pubs.rsc.org/en/content/getauthorversionpdf/C3CS60289C

Copper catalysed Ullmann type chemistry: From mechanistic aspects to modern development

TADDOLs, which contain two adjacent diarylhydroxymethyl groups in a trans relationship on a 1,3-dioxolane ring, can be prepared from acetals or ketals of tartrate esters by reaction of the latter with aromatic Grignard reagents. They are extraordinarily versatile chiral auxiliaries. Here, a historical review of the subject is followed by discussion of the preparation of TADDOLs and analogous systems, including TADDOLs with N-, P-, O-, and S-heteroatom ligands appropriate for metals. Crystal structure analysis reveals that the heteroatoms on the diarylmethyl groups are almost always in close proximity to each other, joined together by H-bonds, and predisposed to form chelate complexes in which the metallic centers reside in propeller-like chiral environments. Applications of TADDOL derivatives in enantioselective synthesis extend from utilization as stoichiometric chiral reagents or in Lewis acid mediated reactions, to roles in catalytic hydrogenation and stereoregular metathesis polymerization. Derivatives and complexes based on the following metals have so far been investigated: Li, B, Mg, Al, Si, Cu, Zn, Ce, Ti, Zr, Mo, Rh, Ir, Pd, Pt. The number of stereoselective reactions already accomplished with TADDOLs is correspondingly large. It is also easy to prepare TADDOL derivatives that are readily polymerizable and graftable, and to transform them into immobilized solid-phase catalysts. The result is catalysts, simply or dendritically immobilized in polystyrene or on silica gel and characterized by unexpected stability even after multiple use in titanium TADDOLate mediated reactions. TADDOLs show further unusual characteristics that make them useful for applications in material science and supramolecular chemistry: they are the most effective doping agents known for phase transformations of achiral (nematic) into chiral (cholesteric) liquid crystals. The TADDOL OH group that is not involved in intramolecular H-bonding shows a strong tendency to associate intermolecularly with H-bond acceptors. In the process of crystallization this leads, enantioselectively, to the formation of inclusion compounds that lend themselves to the separation of racemic mixtures not otherwise suited to the classical method of crystallization through diastereomeric salts. The high melting points of TADDOLs even make possible the resolution of racemates by distillation! Host-guest compounds formed between TADDOLs and achiral partners can serve as platforms for enantioselective photoreactions. It seems safe to predict that many more applications will be discovered for the TADDOLs and their derivatives. Supporting information for this article is available on the WWW under http://www.angewandte.com or from the author.

/pdf/taddols-their-derivatives-and-taddol-analogues-versatile-3khxc7t5en.pdf

TADDOLs, Their Derivatives, and TADDOL Analogues: Versatile Chiral Auxiliaries

on the use ofmicrowaveirradiationto“accelerate”organicchemicaltrans-formations, there has been considerable speculation anddiscussion of this effect. Much of the debate has centeredaround the question whether the observed effects can in allinstances be rationalized by purely thermal/kinetic phenom-ena (thermal microwave effects) arising from the rapidheating and high bulk reaction temperatures attained withmicrowave dielectric heating, or whether some effects areconnected to so-called specific or nonthermal microwaveeffects.

Microwave Effects in Organic Synthesis: Myth or Reality?

The resolution of racemates is revolutionized with the method presented here, in which mixtures ("families") of structurally and stereochemically related resolving agents are used to precipitate salts of acidic or basic racemates rapidly and dependably. The racemate is usually separated in a single operation into enantiomers-the enantiomeric excesses and yields are good to excellent. Reagent mixtures with racemic or achiral components have also been developed.

/pdf/the-family-approach-to-the-resolution-of-racemates-37bnd9up50.pdf

The Family Approach to the Resolution of Racemates

https://www.cell.com/trends/biotechnology/pdf/0167-7799(88)90057-1.pdf

Lipases in the preparation of β-blockers

/pdf/the-role-of-nucleation-inhibition-in-optical-resolutions-4pj5busq8i.pdf

The Role of Nucleation Inhibition in Optical Resolutions with Families of Resolving Agents

The mechanism of the oxidation of benzyl alcohol by iron(III)nitrate: conventional versus microwave heating

Die Racematspaltung revolutionieren konnte das hier vorgestellte kombinatorische Verfahren, bei dem Gemische („Familien”) strukturell und stereochemisch verwandter Reagentien mit den zu trennenden racemischen Sauren oder Basen umgesetzt werden. Die in ublicherweise einem Schritt gebildeten diastereomeren Salze fallen fast immer rasch aus, Ausbeuten und Enantiomerenuberschusse sind gut bis hervorragend. Auch Reagensgemische mit racemischen oder achiralen Komponenten wurden entwickelt.

Lumbertus A. Hulshof

Papers

The Family Approach to the Resolution of Racemates

Lipases in the preparation of β-blockers

The Role of Nucleation Inhibition in Optical Resolutions with Families of Resolving Agents

The mechanism of the oxidation of benzyl alcohol by iron(III)nitrate: conventional versus microwave heating

Racematspaltungen mit Substanzfamilien