In the investigation of efficient chemical transformations, the carbon-carbon bond-forming reactions play an outstanding role. In this context, organocatalytic processes have achieved considerable attention. 1 Beside their facile reaction course, selectivity, and environmental friendliness, new synthetic strategies are made possible. Particularly, the inversion of the classical reactivity (Umpolung) opens up new synthetic pathways. 2 In nature, the coenzyme thiamine (vitamin B1), a natural thiazolium salt, utilizes a catalytic variant of this concept in biochemical processes as nucleophilic acylations. 3 The catalytically active species is a nucleophilic carbene. 4

Organocatalysis by N-Heterocyclic Carbenes

Fluorine in medicinal chemistry: Recent therapeutic applications of fluorinated small molecules

The Methylation Effect in Medicinal Chemistry Eliezer J. Barreiro,* Arthur E. K€ummerle, and Carlos A. M. Fraga Laborat orio de Avaliac-~ao e Síntese de Subst̂ancias Bioativas (LASSBio), Faculdade de Farm acia, Universidade Federal do Rio de Janeiro, CCS, Cidade Universit aria, CP 68.006, 21941-902 Rio de Janeiro, RJ, Brazil Programa de P os-Graduac-~ao em Farmacologia e Química Medicinal, Instituto de Cîencias Biom edicas, Universidade Federal do Rio de Janeiro, Cidade Universit aria, Ilha do Fund~ao, Rio de Janeiro, RJ, Brazil Programa de P os-Graduac-~ao em Química, Instituto de Química, Universidade Federal do Rio de Janeiro, Cidade Universit aria, Ilha do Fund~ao, Rio de Janeiro, RJ, Brazil

The methylation effect in medicinal chemistry.

[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-((1-­methylethyl)-3-phenyl-4-[(phenylamino)-carbonyl]-1H-­pyrrole-1-heptanoic acid or (2R-trans)-5-(4-fluorophenyl)-­2-(1-methylethyl-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-­oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide; a process for their preparation and pharmaceutically acceptable salts thereof.

(R-(R*R*))-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl-3-phenyl-4((phenylamino)-carbonyl)-1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof

Green Chemistry or Sustainable Chemistry is defined by the Environmental Protection Agency as “the design of chemical products that reduce or eliminate the use of hazardous substances” In recent years there is a greater societal expectation that chemists and chemical engineers should produce greener and more sustainable chemical processes and it is likely that this trend will continue to grow over the next few decades. This tutorial review gives information on solvents and solvent selection, basic environmental metrics collection and three industrial case histories. All three case histories involve enzymatic chemistry. Pregabalin (Lyrica®) is produced using a lipase based resolution and is extremely unusual in that all four manufacturing steps to make pregabalin are performed in water. Sitagliptin (Januvia®) uses a transaminase in the final chemical step. Finally a rosuvastatin (Crestor®) intermediate is produced using a deoxy ribose aldolase (DERA) enzyme in which two carbon–carbon bonds and two chiral centres are formed in the same process step.

The importance of Green Chemistry in Process Research and Development

The convergent synthesis of CI-981, an optically active, highly potent, tissue selective inhibitor of HMG-CoA reductase

The synthesis of (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate, a key intermediate for the preparation of CI-981, a highly potent, tissue selective inhibitor of HMG-CoA reductase

An improved process for the preparation of trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-ones by a novel synthesis is described where 1,6-heptadien4-ol is converted in eight operations to the desired products, as well as an improved process for the preparation of (2R-trans) and trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3carboxamide by a novel synthesis where 4-methyl-3-oxoN-phenylpentanamide is converted in eight operations to the desired product or alternatively 4-fluoro-α-[2methyl-1-oxopropyl]-γ-oxo-N,β-diphenylbenzenebutaneamide is converted in one step to the desired product, and additionally, a process for preparing (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1Hpyrrole-3-carboxamide from (R)-4-cyano-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]butanoic acid, as well as other valuable intermediates used in the processes.

Process for trans-6-[12-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis

An improved process for the preparation of trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-ones by a novel synthesis is described where 1,6-heptadien-4-ol is converted in eight operations to the desired products, as well as an improved process for the preparation of (2R-trans) and trans-(U)-5-(4-fluoro-phenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide by a novel synthesis where 4-methyl-3-oxo-N-phenylpentanamide is converted in eight operations to the desired product or alternatively 4-fluoro-alpha-[2-methyl-1-oxopropyl]-gamma-oxo-N,beta-diphenylbenzenebutaneamide is converted in one step to the desired product, and additionally, a process for preparing (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide from (R)-4-cyano-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]butanoic acid, as well as other valuable intermediates used in the processes.

Novel process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis

An improved process for the preparation of a cyclic amino acid by a novel synthesis is described where benzonitrile is treated with an alkali metal and an amine under Birch reduction conditions to generate in situ an anionic intermediate which is alkylated with an α-haloacetic acid moiety which is subsequently converted to the desired product, as well as valuable intermediates used in the process.

Carl Francis Deering

Papers

The convergent synthesis of CI-981, an optically active, highly potent, tissue selective inhibitor of HMG-CoA reductase

The synthesis of (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate, a key intermediate for the preparation of CI-981, a highly potent, tissue selective inhibitor of HMG-CoA reductase

Process for trans-6-[12-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis

Novel process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis

Process for preparing a cyclic amino acid anticonvulsant compound