Michael J. Stocks

Molybdenum-Mediated Carbonylation of Aryl Halides with Nucleophiles Using Microwave Irradiation

A new, efficient, and practical molybdenum-mediated carbonylation of aryl and heteroaryl halides with a variety of nucleophiles is described using microwave irradiation. A range of reactions illustrating the wide scope of this chemistry were carried out and proceeded in good to excellent yields.

Synthesis and evaluation of dual domain macrocyclic FKBP12 ligands.

Abstract A number of dual domain, macrocyclic FKBP12 ligands were synthesised in which the FK506 effector domain was fused to simplified FKBP12 bindings domains. The resulting macrocyclic compounds possessed moderate binding affinities for FKBP12 but showed no activity in an assay for FKBP12 dependent calcineurin inhibition.

A synthesis of the C(1)-C(15) segment of tsukubaenolide (FK 506).

Abstract A synthesis of the C(1)-C(15) segment ( 4 ) of Tsukubaenolide ( 1 ) from Tri-O-acetyl-D-glucal and (S)-Pipecolinic acid methyl ester is described.

The contribution to binding of the pyranoside substituents in the excised binding domain of FK-506

Abstract The contributions of the C-11 methyl and C-13 / C-15 methoxy substituents to the affinity of FK-506 for the immunophilin FKBP-12 were investigated. Substraction of the C-11 methyl group led to a 400-fold drop in affinity. Removal of the C-13 and C-15 methoxy substituents led to a much smaller drop in affinity.

Synthetic FKBP12 ligands. Design and synthesis of pyranose replacements.

Abstract A number of FKBP12 ligands were designed and synthesised and their affinity for FKBP12 assessed. In these ligands the pyranose ring of FK506 was replaced by other more synthetically accessible groups. The preparation of suitable intermediates for the synthesis of “dual domain” inhibitors (compounds 6a–c, 15 and 22) is also described.

A novel rearrangement reaction conversion of 3-(chloromethyl)azetidin-2-ones to azetidine-3-carboxylic acid esters

Abstract Transformation of 3-(chloromethyl)azetidin-2-ones to azetidine-3-carboxylic acid esters is described. The readily available 3-(chloromethyl)azetidin-2-ones rearranged in good yields to azetidine-3-carboxylic acid esters on treatment with alkoxides. An alternative ring opening - ring closure procedure is also identified.

Organocatalytic Enantioselective One‐Pot Four‐Component Ugi‐Type Multicomponent Reaction for the Synthesis of Epoxy‐tetrahydropyrrolo[3,4‐b]pyridin‐5‐ones

Enantioselective multicomponent reaction: in the presence of a catalytic amount of chiral BINOL-derived phosphoric acid (TRIP), the reaction of an α-isocyanoacetate 1, an aldehyde 2, and an aniline 3, followed by addition of a toluene solution of α,β-unsaturated acyl chloride 4 afforded the oxa-bridged tricycle 5 in excellent yield, diastereoselectivity, and enantioselectivity. Six chemical bonds, five stereogenic centers, and three cycles were formed in this one-pot four-component reaction.

Macrocyclic ring closures employing the Intramolecular Heck reaction

Abstract Intramolecular Heck reactions have been employed for the final ring closure step in the construction of a series of macrocyclic compounds.

Synthesis of FK506-Cyclosporin hybrid macrocycles

Abstract An attempt was made to synthesise calcineurin inhibitors using dual domain macrocyclic compounds that incorporated a FKBP12 binding domain together with a calcineurin recognition domain which had been designed by consideration of the relevant features of both FK506 and Cyclosporin A.

A Practical Method for Targeted Library Design Balancing Lead-like Properties with Diversity

Choosing the right compounds to synthesise from large virtual combinatorial libraries is a current challenge for the pharmaceutical industry. Herein we describe a highly optimised method that aligns lead‐like properties with compound diversity. The methods are illustrated by considering a two‐dimensional library based on the interesting spirocyclic bis‐azetidine template.