Ulf Berg

The Quantitative Analysis of Steric Effects in Heteroaromatics

Publisher Summary This chapter describes the quantitative analysis of steric effects in heteroaromatics. This chapter illustrates that, important progress in the quantitative analysis of steric effects in heteroaromatics has been made recently by linear free energy relationships (LFER), geometrical, and theoretical methods. Heterocycles have been used to propose and exemplify new concepts and new parameters in physical organic chemistry. This chapter is concerned with the importance of steric effects in rationalizing the reactivity and dynamic stereochemistry of heteroaromatics and with recent attempts to bridge the gap between them. There has been a decisive evolution in the treatment of steric effects in heteroaromatic chemistry. A better knowledge of static and dynamic stereochemistry has helped greatly in understanding not only intramolecular but also intermolecular steric effects associated with rates and equilibria. Quantum and molecular mechanics calculations will certainly be used in the future to a greater extent. Heteroaromatics have features in common with aromatic hydrocarbons. However, the variety of geometrical situations, the number of heteroatoms and their associated reactivity, and the ease of monitoring stereochemistry often associated with the presence of heteroatoms all have made, and continues to make, heterocycles exceptional probes for better understanding of reactivity, structures, and the relations between them.

Synthesis and conformational studies of a Leu-enkephalin amide analogue containing a ferrocene substructure

Solution phase synthesis of a constrained Leu(5)-enkephalin amide analogue 10 is reported, in which the cyclic ferrocenyl containing subunit 7 was introduced as a mimetic of the tetrapeptide Tyr-Gly-Gly-Phe unit. Temperature dependence of the chemical shift of the amide protons of 10 indicated a hydrogen bond between the same amino acid residues as observed for the natural Leu-enkepalin in the single-bend conformation. The rotational barrier (DeltaG(c)(not equal)=16.8 kcal/mol) of the C-terminal amide group, which was determined by DNMR spectroscopy, and NOESY experiments indicated that the two termini were more distant as compared to the single-bend conformation of natural Leu-enkephalin amide

Stereochemistry of colchicinoids. Enantiomeric stability and binding to tubulin of desacetamidocolchicine and desacetamidoisocolchicine

Abstract Desacetamidocolchicine (3) and desacetamidoisocolchicine (4) have been chromatographically resolved into enantiomers. Thermal racemization gives inversion barriers of 22.1 and 23.4 kcal mol−1, respectively, for rotation around the bond joining the two aromatic rings. Kinetic binding experiments show that the enantiomer of 3 with the same helicity as native colchicine binds approximately 62 times as fast as colchicine to tubulin whereas the other enantiomer and both enantiomers of 4 do not bind. With molecular mechanics computations both the structures and the rotational barriers are reproduced, provided that the MM2(1985) force field, which gives stiffer aromatic rings than earlier force fields, is used.

Gear effect—10: Conformational aspects of the positive or negative buttressing effects of methyl groups: polymethylpyridines

Abstract The effect of the shape of a methyl group on reactivity, which cannot be accounted for by considering a methyl group as a spherical substituent with the appropriate van der Waals radius, was considered in kinetics of alkylalion of substituted pyridines and barriers to rotation and ground state conformations of an isopropyl group attached to a planar framework. The perturbation of a methyl group by an o-methyl group is accounted for by a unique conformational explanation which involves the polyhedral shape of the methyl group.

Spirobicyclo[2.2.2]octane derivatives: mimetics of baccatin III and paclitaxel (Taxol)

The formylated spirobyclic alcohol was computer modeled to be a mimetic of paclitaxel. In this model, the formyl group was used as a truncated paclitaxel side chain in order to reduce the computational work. Compound , carrying the paclitaxel side chain, was synthesized in six steps from optically active 1,3-diketone . Microtubule stabilization was not observed for , indicating that the model needs to be adjusted.

Static and dynamic stereochemistry of alkyl and analogous groups

Publisher Summary This chapter discusses the static and dynamic stereochemistry of alkyl and analogous groups. It discusses the forces that determine the conformations of organic molecules and the experimental and theoretical methods that are available for use in conformational analysis. The experimental and theoretical material is organized with respect to the central bonds, sp3-sp3 or sp2-sp3, and also with respect to the atoms involved. The selection of examples is not intended to be exhaustive, but is governed by a wish to display typical trends and by the bias created by our own research experience. The chapter discusses an example, provided by the tri-t-butyl-methanes, -silanes and -phosphines, where the same type of energy minima (C3) and the same exchange processes occur in spite of considerably different bond lengths. Two isopropyl groups bound to an sp2 hybridized atom or to vicinal atoms in a planar five-membered ring comprise another structural element with similar behavior in several different environments. This entity also illustrates the dangers of reliance on simple and rigid mechanical models. Concerted rotation is a rarer occurrence than might be expected, although this mechanism is implied by molecular mechanics calculations for tri-t-butylmethane and analogs, and is convincingly demonstrated by experiments for the ditriptycyl derivatives.

Inter- and intramolecular potential for the N-formylglycinamide-water system. A comparison between theoretical modeling and empirical force fields

An intramolecular NEMO potential is presented for the N‐formylglycinamide molecule together with an intermolecular potential for the N‐formylglycinamide‐water system. The intramolecular N‐formylglycinamide potential can be used as a building block for the backbone of polypeptides and proteins. Two intramolecular minima have been obtained. One, denoted as C5, is stabilized by a hydrogen bonded five member ring, and the other, denoted as C7, corresponds to a seven membered ring. The interaction between one water molecule and the N‐formylglycinamide system is also studied and compared with Hartree‐Fock SCF calculations and with the results obtained for some of the more commonly used force fields. The agreement between the NEMO and SCF energies for the complexes is in general superior to that of the other force fields. In the C7 region the surfaces obtained from the intramolecular part of the commonly used force fields are too flat compared to the NEMO potential and the ab initio calculations. We further analyze the possibility of using a charge distribution obtained from one conformation to describe the charge distribution of other conformations. We have found that the use of polarizabilities and generic dipoles can model most of the changes in charge density due to the different geometry of the new conformations, but that one can expect additional errors in the interaction energies that are of the order of 1 kcal/mol.

Synthesis and conformational studies of a 1,1′-ferrocenophane lactam mimetic of substance P

Abstract The synthesis of a bis-phenylalanine mimetic 6 and its incorporation into Substance P (SP), giving a conformationally constrained organometallic SP analogue 8 , is described. The lactam 6 was synthesized in five steps, via a HWE olefination reaction, enantioselective hydrogenation with [Rh(I)(COD)(( S , S )Et-DuPHOS)] + OTf − and intramolecular cyclization with PyAOP as a coupling reagent. Comparative CD studies of 8 with native SP indicated that the flexibility around the amide bond of Phe(7)–Phe(8) sequence is crucial for the C-terminal (from residue Gln(4)) to adopt an α-helical conformation in the micellar environment created by SDS or in methanol.

Endocyclic cleavage of glycosides. VI. Substituent effects of the alkylative endocyclic cleavage of glycosides

Abstract A number of pentopyranoside derivatives were treated with Me 3 Al in order to investigate the influence of structural parameters on the methyl group transfer in the endocyclic alkylative cleavage reaction of these substrates. A cyclic CH…O hydrogen bonded model is suggested as an intermediate, which is used to explain the stereoselectivities for different substrates. In several cases the diastereoselectivities were better than 9:1.

Enantiomers of polarized alkenes: chromatographic enrichment and thermal interconversion

Abstract (+)- and (−)- 1 as well as (+)- and (−)- 2 were partially separated by liquid chromatography on triacetylcellulose; racemizations resulted in the barriers (Table 2) to rotation via planarized transition states.