George C. Morton

Novel safety-catch linker and its application with a Ugi/De- BOC/cyclization (UDC) strategy to access carboxylic acids, 1,4- benzodiazepines, diketopiperazines, ketopiperazines and dihydroquinoxalinones

Abstract This communication reveals the synthesis and application of a novel resin bound isonitrile. The resin is an example of a novel safety-catch linker which upon BOC-activation can be resin cleaved with a variety of nucleophiles. Use of this polymer supported isonitrile in the Ugi multi-component reaction (MCR), followed by resin clipping and cyclization allows access to diverse arrays of 1,4-benzodiazepine-2,5-diones, diketopiperazines and ketopiperazines respectively. The methoxide safety-catch clipping strategy and subsequent solution phase cyclization offers similar advantages to a traceless linker.

Novel applications of carbon dioxide/MeOH for the synthesis of hydantoins and cyclic ureas via the Ugi reaction

Abstract This communication reveals novel applications of the CO 2 /MeOH reagent combination coupled with the UDC (Ugi/DeBOC/Cyclize) strategy. The Ugi five component condensation (5CC) affords carbamate protected amino-amides in good yield. When one of the supporting reagents employed in the Ugi reaction possesses a tethered amino-BOC protected functional group, subsequent acid treatment and proton scavenging results in rapid cyclization to cyclic ureas. Additionally, treatment of the 5CC product with base affords hydantoins in good yield, representing a novel and short approach to this class of molecule.

Novel applications of convertible isonitriles for the synthesis of mono and bicyclic γ-lactams via a UDC strategy

This communication reveals a novel application of the so-called convertible isonitriles for the solution/solid phase generation of γ-lactam analogues. Use of tethered N-BOC aldehydes in the Ugi multi-component reaction (MCR), followed by BOC removal and base treatment (a ‘3-step, 1-pot procedure’) affords γ-lactams in good yield. The UDC (Ugi/De-BOC/Cyclize) strategy, coupled with a convertible isonitrile, is now feasible from all three substitution sites of the Ugi product. A conceptually novel approach, combining a bi-functional precursor with a post-condensation modification to give fused lactam-ketopiperazines, is also revealed.

Novel solid-phase synthesis of 1,5-benzothiazepine-4-one derivatives

Abstract A new solid-phase efficient route to 1,5-benzothiazepine-4-one derivatives is reported. The synthesis exploits the variety of halo-nitrobenzene derivatives available and the facile substitution of the benzamide nitrogen. A wide range of derivatives can be obtained in excellent purity.

Directed Sorting Approach for the Synthesis of Large Combinatorial Libraries of Discrete Compounds

Publisher Summary This chapter reviews the principle of directed sorting and presents two detailed examples of its application in drug discovery: (1) the synthesis of piperazine-2 carboxamide derivatives and (2) the synthesis of benzothiazepine derivatives. The directed sorting approach (or mix-and-sort approach) uses small synthetic objects, called microreactors that are equipped with a readable encoding system. Typically the synthetic objects can be resin beads placed in a semi-porous container, a grafted polymer surface, or large plugs of resin beads. The coding system can be a radiofrequency tag (RF-Tag), a two-dimensional (2D) optical bar code, a color scheme, or a spatial array. Several types of equipment can be used to prepare combinatorial libraries through the directed sorting technique. The Accutag system is well suited to prepare libraries of 10-10,000 compounds, whereas the Nanokan system is useful for 10,000-100,000 member libraries. For small libraries, the color-coded MicroKans can be used.

Synthesis and diversity analysis of lead discovery piperazine-2-carboxamide libraries

A Lead Discovery Library ofpiperazine-2-carboxamide derivatives was produced forgeneral screening. This paper discloses two novelsolid phase synthetic routes used to produce 15 000single compounds via the Irori directed sortingtechnique. Computational methods such as reagentclustering and library profiling were used to maximizereagent diversity and optimize pharmacokineticparameters. The results of a four center pharmacophoreanalysis revealed the added diversity gained by usingtwo independent synthetic routes.