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.

Molecular recognition of DNA by rigid [N]-polynorbornane-derived bifunctional intercalators: synthesis and evaluation of their binding properties.

We have exploited the concept of multivalency in the context of DNA recognition, using novel chemistry to synthesize a new type of bis-intercalator with unusual sequence-selectivity. Bis-intercalation has been observed previously, but design principles for de novo construction of such molecules are not known. Our compounds feature two aromatic moieties projecting from a rigid, polynorbornane-based scaffold. The length and character of the backbone as well as the identity of the intercalators were varied, resulting in mono- or divalent recognition of the double helix with varying affinity. Our lead compound proved to be a moderately sequence-selective bis-intercalator with an unwinding angle of 27 degrees and a binding constant of about 8 microM. 9-aminoacridine rings were preferred over acridine carboxamides or naphthalimides, and a rigid [3]-polynorbornane scaffold was superior to a [5]-polynorbornane. The flexibility of the linker connecting the rings to the scaffold, although less influential, could affect the strength and character of the DNA binding.

Porphyrin-containing molecular capsules: metal mediated dimerization of a bis-porphyrin cavity.

[reaction] A self-complementary V-shaped bis-porphyrin cavity has been synthesized that is capable of dimerization to form a capsule structure. Self-assembly of the dimer occurs via metal ion coordination and produces an internal volume for guest encapsulation.

Probing the dimensions of semi-rigid inner functionalised U-shaped bis-porphyrin cavities.

The synthesis of a series of open U-shaped bis-porphyrin cavity molecules is described, with bridged bicyclic backbones to confer rigidity, and a pendant substituted aromatic probe unit suspended on the inside of the cavity. The dimensions and flexibility of the bis-zincporphyrin cavity were probed using several different techniques. Initially the molecular ruler concept was employed, using flexible bidentate ligands as guests with a range of possible linear dimensions. Secondly, NMR methods were employed with rigid bidentate ligand guests of fixed lengths, and thirdly diffusion based NMR methods were utilised. The range of inter-porphyrin distances estimated by these methods suggests that these types of open-cavity systems have a surprising degree of flexibility.

Pyramidalized olefins: a DFT study of the homosesquinorbornene and sesquibicyclo[2.2.2]octene nuclei.

Density functional theory (B3LYP/6-31G*) was used to study a series of homosesquinorbornenes and sesquibicyclo[2.2.2]octenes. The compounds in which the two faces of the double bond are different are predicted to have a pyramidal double bond with butterfly bendings (psi) ranging from 1.8 to 17.9 degrees. The degree of pyramidalization of these central double bonds is greater in the homosesquinorbornenes than in the sesquibicyclo[2.2.2]octenes.

Diels-Alder reactivity of benzannulated isobenzofurans as assessed by density functional theory.

Density functional theory (DFT) calculations at the B3LYP/6-31G* level for isobenzofuran1 and eleven benzannulated derivatives of types2 and3 have been performed in order to compare their relative reactivities as dienes in Diels-Alder reactions. The transition state (TS) energies for their reactions with ethylene have been determined and shown to form a linear correlation between activation energies and structure count (SC) ratios. TS energies as a method for comparison of diene reactivities can be applied to IBFs bearing substituents on the ring as well as those containing heteroatoms, for which the SC ratio method failed. Different measures of aromaticity of benzannulated IBFs indicated a decrease in aromaticity going from 4 to 14, which is also reflected in their reactivity as a dienes in Diels-Alder reaction.

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, E(complexation), which relies on the calculation of AM1 heats of formation for host, guest, and hemicarceplex. If E(complexation) 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 E(complexation) 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.

Cycloadditions of isobenzofuran to a constrained template bearing neighboring dienophiles.

A high yielding synthesis of the pentacyclic diene-dione 1 has enabled investigation of its reactivity as a double dienophile in Diels-Alder [4+2] cycloadditions with isobenzofuran, leading to novel and highly symmetrical three-sided cavitands 3 and 4.