Davor Margetić

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.

Synthesis and modelling of novel rigid rods derived from a simple pentacyclic bis-norbornene [1]

Abstract New rigid rods with 4σ, 6σ, 10σ, 12σ, and 16σ bond separations have been prepared from the pentacyclic diene 3 using ACE (alkene plus cyclobutene epoxide) and s-tetrazine coupling techniques and their shapes evaluated using AM1 calculations. The X-ray structure of the 6σ-rod 5 is reported.

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.

Use of a 9,10-dihydrofulvalene pincer cycloadduct as a cornerstone for molecular architecture

Dimethyl-3,3a,3b,4,6a,7a-hexahydro-3,4,7-metheno-7H-cyclopenta[a]pentalene-7,8-dicarboxylate (3, a 9,10-dihydrofulvalene pincer cycloadduct) was found to be a versatile building block for the synthesis of polynorbornyl scaffolds containing various end functionalities such as porphyrins, pyrimidine, and the phenanthroline ligand in the free and complexed forms. The block is stable under various cycloaddition reaction conditions and has high π-bond reactivity. Molecular modelling using a semi-empirical based method (AM1) shows that incorporation of this diene block into polynorbornyl systems has an important influence on their overall architecture. In particular, incorporation of the block results in a straightening of the curvature normally observed in polynorbornyl molecules to form almost ideally linear polycyclic rigid spacers.

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.

Thermal reaction of [3,4]-benzo-8-substituted-3Z,5Z,7E-octatetraenes and quantum-chemical study of the (8π,6π)-electrocyclisation

The first example of thermal (8π,6π)-electrocyclisation of 1,3,5,7-octatetraene with one double bond embedded in an aromatic moiety is described. By this process, [3,4]-benzo-8-substituted octatetraene derivatives, the cis,trans-1-(o-vinylphenyl)-4-(R = Me, Ph, 2-furyl)buta-1,3-dienes were transformed to a new endo-7-(R = Me, Ph, 2-furyl) and exo-7-(R = Me)-2,3-benzobicyclo[4.2.0]octa-2,4-dienes. Mechanism of reaction was also studied by DFT quantum-chemical calculations. The M06/6-311+G(d,p)//M06/6-31+G(d,p) calculations indicate that formation of the single endo-isomer in the case of phenyl and 2-furyl substituents is determined by higher activation barriers for exo-6π-electrocyclisation than for 8π-cycloreversion.

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.

Studies in the cycloproparene series: chemistry of 1-acyl-1H-cyclopropa[b]naphthalenes and synthesis of cyclopropa[b]naphthalenylidene enol ethers

Abstract The 1H-cyclopropa[b]naphthalenyl anion reacts with N,N-dimethylamides to provide C-1 acyl derivatives in good yield in what are rare examples of mono-substitution in the cycloproparene series. The availability of these acylcycloproparenes provides for subsequent benzylic proton abstraction and enolate ion interception to give O-silyl and O-phosphinate derivatives. This reaction sequence leads to the first cyclopropa[b]naphthalenylidene enol ethers and provides the only example of exocyclic alkene formation taking place in one step from the benzylic centre. Protonation of the acyl derivatives by mineral acid triggers three-membered ring opening to 2,3-disubstituted naphthalenes rather than 2-monosubstituted analogues that typically arise from protonation at the aromatic ring. Upon thermolysis ring expansion to a naphthofuran occurs.

An AM1 semiempirical study of host-guest complexation in hemicarcerand complexes.

Semiempirical AM1 calculations have been carried out on host–guest complexes of model hemicarcerands 1a and 2a. The justification for the choice of the AM1 Hamiltonian was based on a comparison between reported X‐ray data for the smaller tetrabromocavitand 4a and computational results obtained using several different Hamiltonians. The complexation behavior of hemicarcerands 1a and 2a have been compared with experimental results reported by Cram et al. for the related hemicarcerands 1b and 2b. Based on this comparison, a criterion for predicting guest encapsulation was developed, Ecomplexation, which relies on the calculation of AM1 heats of formation for host, guest, and hemicarceplex. If Ecomplexation is lower than 10 kcal/mol, then a guest will be encapsulated, while if it is greater than 30 kcal/mol, a guest will not be encapsulated. The use of constrained‐path AM1 optimizations to determine the energy barriers to guest entry and exit from the host was found to be a useful tool for examining suitable host–guest combinations when the Ecomplexation criteria does not hold. We have computed the barriers to exit of N, N‐dimethylformamide (dmf) and furan from the hemicarcerand 1a, the former has been compared with the experiment and shows excellent agreement. Based on the success of the above computational methods in predicting which host–guest combinations will form stable hemicarceplexes we have synthesized a new target hemicarceplex 1b.furan.