Guy Casy

The synthesis of 2,3-disubstituted cyclopentenones using the ramberg-bäcklund reaction in conjunction with organocopper chemistry

Abstract An Improved synthetic procedure is described for the preparation of 2,3-dialkylated 2,3-dihydrothiin-4-ones using organocopper chemistry. The utility of these, and the corresponding saturated compounds for the synthesis of Δ 3 - and Δ 2 -2,3-disubstituted cyclopentenones via the Ramberg-Backlund reaction is discussed. The application of this methodology to a formal total synthesis of the antimicrobial natural product tetrahydrodicranenone B is described.

An efficient route to all eight stereoisomers of a tri-functionalised cyclopentane scaffold for drug discovery

Abstract A route to all eight stereoisomers of 3-( tert -butoxycarbonylamino)-4-hydroxycyclopentanecarboxylic acid methyl ester is presented; these products should prove to be valuable scaffolds in pharmaceutical discovery.

Facile Ramberg–Bäcklund reactions for the synthesis of 2,3-disubstituted cyclopentenones; a short synthetic route to tetrahydrodicranenone B

The Ramberg–Backlund reaction has been employed to prepare protected 2,3-disubstituted cyclopent-3-enones which have been converted into cyclopent-3- and -2-enones; the α-iodosulphone precursors were obtained by a double Michael approach using a three-component coupling sequence to introduce the alkyl substituents and this methodology has been used to develop a short synthetic route to the antimicrobial natural product, tetrahydrodicranenone B (1).

Alkylation reactions of propargyl alcohol; improved routes to prostaglandin α-side chain precursors

Abstract Alkylation reactions of the dilithio derivative of propargyl alcohol and the lithio derivative of tetrahydropyranyl protected propargyl alcohol have been explored in order to develop improved synthetic routes to the key prostaglandin α-side chain precursor methyl 7-hydroxyhept-5-ynoate (5). The use of methyl 4-bromobutanoate or the lithium salt of 4-bromobutanoic acid in these reactions did not produce the required products whereas alkylation using trimethyl ortho-4-bromobutanoate (15) gave methyl 7-hydroxyhept-5-ynoate (5) or the corresponding THP ether (4) in good yield after orthoester hydrolysis. Procedures are also described for the transformation of alcohol (5) and THP (4) into methyl 7-bromohept-5-ynoate (1). Alcohol (5) can also be converted into methyl ( Z )-7-bromohept-5-enoate (2) using literature procedures.

Applications of Organocopper Reagents in Organic Synthesis

The importance of organocopper reagents in organic synthesis is highlighted and the different types of organocopper reagents available are briefly reviewed. Applications of organocopper reagents in the synthesis of natural products and related compounds of biological interest are then discussed commencing with synthetic approaches to thia-thromboxane analogues based on the organocopper conjugate addidon-enolate alkylation reaction. The extension of this methodology to the preparation of 2,3- disubstituted cyclopentenones, illustrated by the synthesis of the antimicrobial natural product, tetrahydrodicranenone B, is then discussed. Finally, synthetic applications of the organocopper alkyne addition reaction are described with emphasis on the use of double acetylene carbocupration for the stereospecific preparation of Z,Z-dienes. The use of this methodology for the synthesis of the Navel Orangeworm pheromone is discussed.

The preparation of thiathromboxane analogues and a formal total synthesis of dithiathromboxane A2 based on conjugate addition reactions of thiin-4-ones

The conjugate addition reactions of thiin-4-one and 3-methoxycarbonylthiin-4-one have been investigated. In contrast to thiin-4-one its 3-methoxycarbonyl derivative undergoes conjugate addition with a range of organocopper reagents, the most efficient being copper-catalysed Grignard reagents. The resulting adducts have been converted into 2-substituted thiin-4-ones by two procedures. This methodology has been used to prepare thiathromboxane analogues (12a), (12b), and (13) and as part of a ten step formal synthesis of dithiathromboxane A2(9).

5 Synthetic Methods for Enantiomers of Drugs

Publisher Summary This chapter provides an overview of methodologies used to make single enantiomers to assist medicinal chemists in preparing the desired single enantiomer. In addition, it reviews methods used to manufacture single enantiomers of pharmaceutical agents and emphasize the different requirements of a synthetic procedure to make the first amounts of material, and to manufacture a drug in bulk. Methodologies for single enantiomers can be divided into three basic types: (i) Chirality pool: synthetic modification of an available single-enantiomer raw material with maintenance or transfer of stereochemical integrity throughout the synthesis makes the product. (ii) Resolution: a synthetic racemic mixture is separated into its enantiomers. (iii) Asymmetric synthesis: control is at the point where the chirality is created by asymmetric modification of a prochiral substrate. All methods for providing a single enantiomer, whether chemical or biochemical can be considered as being comprised of one or more of the above. For instance, fermentation may involve a microbial strain effecting an asymmetric synthesis, etc.

Facile synthesis of (+)brefeldin A utilizing two optically active synthons prepared by different enzyme-catalysed reactions

The lactone 4a and the alcohol 6(both available in optically active form from biocatalytic processes) have been used as synthons in the preparation of (+)-brefeldin A.

The use of an altered specificity engineered enzyme for asymmetric synthesis: enantioselective reduction of 4-methyl-2-oxopent-3-enoic acid

A genetically engineered version of Bacillus stearothermophilus lactate dehydrogenase, incorporating structural motifs which serve to alter substrate specificity in favour of α-keto acids with bulky aliphatic side chains, was used to effect enantioselective reduction of 4-methyl-2-oxopent-3-enoic acid.