Douglas N. Butler

New and improved ‘LEGO’ BLOCK protocols for the direct synthesis of hydrophilic ribbon molecules with acid, ester or peptide functionality

Abstract Hydrophilic ribbon molecules are produced directly from the reaction of cyclobutene epoxide BLOCKs with norbornene dipolarophiles or indirectly by chemical modification of substituents in preformed lipophilic ribbon molecules. The formation of di- and tetra-acid chloride epoxides holds the key to the formation of ester, acid and amide BLOCKs which are active in 1,3-dipolar cycloadditions with norbornene dipolarophiles, thereby delivering a wide range of substituents into the ribbon molecules and opening up combinatorial opportunities at each step.

syn-Facial hetero-bridged [n]polynorbornanes: a new class of polarofacial framework molecules composed of fused 7-oxa- and 7-azanorbornanes

Abstract New oxygen-bridged norbornane-fused cyclobutene epoxides and bis-(cyclobutene epoxides) are described and shown to react stereoselectively with 7-azanorbornenes to produce syn-facial N,O-bridged polynorbornanes and stereorandomly with 7-oxanorbornenes to produce O,O-bridged polynorbornanes as mixtures of syn-facial and anti-facial products. 1 Polarofacial systems containing up to six syn-facial norbornane bridges are described, while systems with seven co-facial oxygen atoms have been prepared by incorporating terminal epoxide rings to O5-[5]polynorbornanes. Ester-substituted 1,3,4-oxadiazoles are shown to be useful reagents for coupling 7-oxanorbornanes and produce predominantly syn-facial O-bridged polarofacial systems together with their anti-facial isomers.

Molecular topology: The synthesis of a new class of rigid arc-shaped spacer molecules based on syn-facially fused norbornanes and 7-heteronorbornanes in which heterobridges are used to govern backbone curvature

Abstract Norbornadienes and 7-heteronorbornadienes are reacted with 7-oxa (or carba or aza) norbornene-fused cyclobutene epoxides (or aziridines) to produce hetero-bridged polynorbornane cycloadducts containing syn -facially arranged N,O (or C,N or C,O) bridges. New dual cyclobutene epoxides and dual cyclobutene aziridines are used to prepare multi-fused norbornanes having curved topology in which the heteroatoms modify the curvature in a predictable way C>N>O; AM1 modelling of representative [9]polynorbornanes is prosented.

Incorporation of a molecular hinge into molecular tweezers by using tandem cycloadditions onto 5,6-dimethylenenorbornene.

Site-selective 1,3-dipolar coupling at the norbornene pi-bond of 5,6-dimethylenenorbornene 1 yields cycloadducts with an end-fused 1,3-diene system which have been reacted with N=N (or C=C) dienophiles to produce ribbon molecules, in which the internal diazacyclohexene (or cyclohexene) subunits are capable of acting as conformational hinges. Direct coupling of 5,6-dimethylenenorbornene with 1,3,4-oxadiazoles or dual coupling with bis(cyclobutene epoxides) afforded bis(1,3-dienes) that diastereoselectively react with dienophiles to produce new, conformationally mobile, molecular tweezers.

Alicyclophanes: a new range of cyclophanes containing rigid alicyclic subunits in place of the aromatic rings

Norbornenosuccinimides have been coupled stereoselectively with 2,5-bis(trifluoromethyl-1,3,4-oxadiazole to prepare alicyclic scaffolds 5 and 20 . Alkylations of the terminal succinimido-nitrogens of 5 with bis-alkylating agents have produced macrocyclic compounds in a short, high-yielding procedure. Alicyclophanes containing one scaffold subunit were obtained from 1,6-dibromohexane, 1,5-dichloro-3-oxapentane, 1,11-dibromo-3,6,9-trioxaundecane and 9,10-bis(chloromethyl)anthracene. Larger alicyclophanes incorporating two spacer subunits were formed by intermolecular cyclisation of 5 with 1,2-dibromoethane or 19 with m - or p -xylylene dibromide. Reaction of 5 with propargyl bromide, followed by oxidative coupling (CuCl) of the pendant acetylenes provided bis-acetylenic alicyclophane 13 .

The synthesis of new framework structures containing rigidly-linked pyrimidines suitable for uracil and cytosine elaboration

Abstract Fused norbornenes and tricyclo[4.2.2.1 2,5 ]undec-3,7,9-trienes containing 2,4-dichloropyrimidine and 2,4-dimethoxy pyrimidine units are coupled with norbornadiene, benzonorbornadienes and dimethoxynaphthaleno norbornadienes using s -tetrazines or ACE coupling techniques to afford framework structures where different geometrical interrelationships can be attained between the chromophores.

RIGID MOLECULAR RACKS FEATURING THE 1,10-PHENANTHROLINE LIGAND ESPECIALLY THOSE CO-FUNCTIONALISED WITH REDOX-ACTIVE GROUPS OR OTHER BIDENTATE LIGANDS

Abstract 6,7-Diazaphencyclone (DAPC), prepared for the first time, exists as a dimer in the solid state but is in thermal equilibrium with the monomer 11 in solution. DAPC is a reactive diene reacting with ring-strained and electron-deficient dienophiles with high stereospecificity. Bridged 1,10-phenanthrolines with different separation distances and ligand, ligand orientations have been prepared and mixed ligand systems are described with diazafluorene and 3,6-di(2-pyridyl)pyridazine ligand components. New diad and triad systems are reported which contain redox-active components linked to ligand centres. The rigid nature of the polyalicyclic molrac framework and the fusion method used to attach the functionality, provides molecules with exact geometric positioning and orientation of chromophores. This makes these systems key molecules for the study of electron-transfer and energy-transfer processes.

Synthesis of bis-peptides attached on poly[n]norbornene molecular scaffolds with well-defined relative positions and distances

This article describes novel synthetic approaches to polynorbornene molecular scaffolds substituted with peptides at various, well-defined positions. A library of norbornene building blocks with attached peptides was prepared. Alkene cyclobutane epoxide (ACE) coupling method was used as a key step reaction for the connection of two norbornene building blocks into bis-peptide scaffolds. Photodimerization of cyclobutene diesters offers an alternative route to polynorbornene bis-peptides. Pyrrolo-peptides were used for preparation of peptide-substituted 7-aza norbornenes. Asymmetrical bis-peptide scaffolds were prepared by ACE coupling of peptide-norbornane epoxide with another norbornene-peptide block. Chemical elaboration of bridgehead dimethyl esters of ACE products or epoxide ACE reagents was also used for peptide attachment.

THE TRAPPING OF 6,6-DIMETHYLISOBENZOFULVENE BY ITS 1,3-DIPOLAR PRECURSOR: A RARE EXAMPLE OF A DIPOLAR [6+4] CYCLOADDITION

A new route to isobenzofuran and isobenzofulvene is reported that is proposed to involve the 14e electrocyclic fragmentation of a transient 1,3-dipolar intermediate formed by ring-opening of a fused aziridinocyclobutane. 6,6-Dimethylisobenzofulvene generated in this way reacts with its 1,3-dipole precursor to form a [10π+4π] cycloadduct, the first of this type involving the participation of a 1,3-dipolar species.

The Synthesis of Geometric Variants of Rigidly-Linked Uracil-{Spacer}-Uracil and Uracil-{Spacer}-Effector Molecules Using Block Assembly Methods

Abstract Pyrimidine-containing building BLOCKs, formed from the thermal reaction of norbomadiene with 2, 4-dimethoxy-1,3-diazaanthracene, are linked together using LEGO-like assembly methods and chemically modified (hydrolysis) to form rigidly linked bis-uracils in which the pyrimidine rings can be aligned in northern or southern geometries and HH or HT variants. Similar methods are used to link pyrimidine BLOCKs to chromophore-containing BLOCKs to access rigid uracil-{spacer} - chromophore molecules which are available in a variety of different geometries.