Fundamental Principles of BLOCK Design and Assembly in the Production of Large, Rigid Molecules with Functional Units (Effectors) Precisely Located on a Carbocyclic Framework

Abstract

IntroductionThere have been immense changes in chemistry and related sciences in the last decade, a period which has seen the emergence of supramolecular chemistry, a quantum jump in the sophistication of host-guest chemistry and the advent of molecular modelling and computational techniques for the working chemist. Combined with this, has been the breaking down of traditional subject barriers, the growth of new ones and a more interdisciplinary approach to science, especially at the research level. The increased range and sophistication of instrumentation, especially NMR has also made its mark.A key player in this new era of science at the molecular level has been the Molecular Architect (Engineer). This person needs to appreciate function in molecular terms, as well as being able to work at the supramolecular level and to be involved in design at the most advanced molecular levels. Self assembly, self replicating systems and nanotechnology are some of the emerging areas where this can be expressed and certainly fall within the bailiwick of the Molecular Architect.Our interest in rigid 3D organic structures had facets of several of the above mentioned topics, but we approached the synthesis of such systems as builders of molecules. We drew on a strong background in organic synthesis and took on board the tenets of good design, including the concepts of retrosynthesis and convergency of approach. In addition, the methods of natural synthesis and the part that enzymes play in protein and nucleic acid synthesis were factored in as instructive role models.The emergence of robotic procedures in chemistry and the upsurge of combinatorial methodology have also impacted on our quest for a new modular approach to supramolecular systems. We appreciated that we required strongly focussed goals and selected systems based on fused rings (alicyclic, aromatic or heterocyclic) with a strong bias towards fused alicyclic systems as our rigid molecular framework (molracs 5 ).The building blocks of our youth such as LEGO ® , Meccano ® and Tinkertoys ® to name a few, had left their mark for modular assembly and this was indeed, a good starting point. We envisaged collecting a kit of small molecules which could be assembled into large rigid molecular systems using stereospecific bond-forming (linking) techniques. The elements of shape and functionality would be addressed in the assembly process which should be simple and able to be achieved by non-specialist organic chemists. The longer term goal was to provide an automated procedure where individual BLOCKs could be called up by computer and assembled as required by the client. This final point highlights a service and advisory role for the Molecular Architect, where strong client interface is paramount.Within this background, the BLOCK concept 6 had its foundation and we set up a program to develop:• the design and synthesis of building BLOCKs • assembly procedures• protocols for attaching the effectors.Abstract: New cycloaddition reactions have been developed to regiospecifically c...

Strategies and methods for the attachment of amino acids and peptides to chiral [n]polynorbornane templates

“…Such technology offers a versatile method for the synthesis of polynorbornane based frameworks of various geometries, both linear and bent. 6 As polynorbornyl scaffolds inherently possess a high degree of structural rigidity they are ideally suited for use as molecular templates. Additionally, polynorbornyl templates offer, depending upon their design, the capacity to be chiral and hence may be synthesised as enantiomerically pure compounds.…”

Conformationally preorganised hosts for anions using norbornane and fused [n]polynorbornane frameworks

“…9 Examples of preorganised tripods and macrocycle. 39,41,43 Several cycloaddition strategies have been developed to access these fused polynorbornane structures [44][45][46][47][48][49][50][51][52][53][54][55] and inventive descriptions such as LEGO 48 are used to describe their construction. Other monikers including 'molecular glue' have been used to describe oxadiazole coupling 54 and also BLOCK as an acronym for 'bonzer little organic construction kit'.…”

“…Other monikers including 'molecular glue' have been used to describe oxadiazole coupling 54 and also BLOCK as an acronym for 'bonzer little organic construction kit'. 55 All such terminology hints at the modular nature of the various approaches to the ready assembly of these large molecular architectures. The terminology also clearly conveys the 'no atoms wasted' advantage inherent with a cycloaddition approach.…”

7-(1-Acetoxymethylidene)Benzonorbornadiene: A Versatile Reagent for the Synthesis of 7-Formyl and 7-Hydroxymethyl Benzonorbornadienes

“…A special feature of the different isomers of the 7-hydroxymethyl-benzonorbornadienes $red\mathbf{6}$ and $red\mathbf{9}$ as substrates for BLOCK coupling reactions [12], is the accessibility of the π-bond for reagent attack at the exo -face. This difference is attributed to the screening effect of the hydroxymethyl group when it is on the same side as the π-bond (the anti -isomer $red\mathbf{9}$) thereby precluding attack at that dienophilic centre.…”