Conformation Design of Hydrocarbon Backbones: A Modular Approach

Abstract

IntroductionUnbranched hydrocarbon chains have an enormous number of populated low-energy conformers. [2, 3] This number can be reduced by substituents that introduce steric strain in certain conformers. This is achieved most effectively [4] if these substituents create destabilizing syn-pentane interactions, [5] which add 7 ± 9 kJ mol À1 to the energy of a given conformer. The population of the remaining low-energy conformers is thereby increased (see Scheme 1).We are interested in defining substitution patterns on a hydrocarbon chain that would thus destabilize all but one conformer, which would remain free of syn-pentane inter- actions. This conformer would then be the only low-energy conformer and should be highly preferentially populated. If this conformer is populated to b 80 %, we call the compound or a particular segment of a compound monoconformational. [6,7] As a first step, we want to identify small segments of a hydrocarbon backbone, segments that, by virtue of their substituent pattern, have only a single low-energy conformation. As a next step we shall consider how these segments may be connected with one another to result in larger hydrocarbon backbones, which should ideally maintain the property of preferentially populating a single conformation. Discussion 1. Basic types of monoconformational skeletons: The smallest hydrocarbon segment to be considered is 2,3-dimethylbutane (2).[8] When rotating about the central 2,3-bond, 2 has three rotamers that are located at energy minima, 2 a ± c (Scheme 2). Rotamer 2 c is the lowest energy conformer. Energies of 2 a and 2 b are calculated to be slightly (ca. 1.5 kJ mol À1 ) higher, because one of the methyl groups is exposed to a double gauche interaction with two other methyl groups. To render the 2,3-dimethylbutane backbone monoconformational, two out of the three conformations of 2 have to be destabilized selectively, for example by introducing syn-pentane interactions. For instance, if it were possible to place an additional methyl group at C1 of 2, with the methyl group kept in an antiperiplanar orientation to the neighboring C2 methyl group, that is, 3, syn-pentane interactions would be created in conformers 3 b and 3 c, but not in 3 a. Likewise, if it were possible to fix the additional methyl group at C1 of 2 in a Conformation Design of Hydrocarbon Backbones: A Modular Approach** Reinhard W. Hoffmann,* Martin Stahl, Ulrich Schopfer, and Gernot Frenking* Abstract: A modular approach towards a conformation design of hydrocarbon backbones is described. The idea is to attach substituents (e.g., methyl branches) to a hydrocarbon backbone in such a manner that they create destabilizing syn-pentane interactions in all but one diamond-lattice backbone conformation. This creates a substantial (b 7 kJ mol À1 ) energy gap between the lowest energy conformer and the higher energy conformers. In consequence, the lowest energy conformer will be populated to a high extent (e.g., b 80 %). Small hydrocarbon modules that fulfil this requirement have been identified...

The Power of Hard-Sphere Models: Explaining Side-Chain Dihedral Angle Distributions of Thr and Val

“…Our modeling methods do not rely on knowledge-based and statistical approaches that overemphasize average properties of the side-chain dihedral angle distributions. There is ample precedent for this approach in studies of organic molecules (28)(29)(30)(31). Instead, we will develop a fundamental understanding of the side-chain dihedral angle distributions, which will allow us to better rank and compare individual protein designs.…”

Formal Synthesis of the Anti‐Angiogenic Polyketide (−)‐Borrelidin under Asymmetric Catalytic Control

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Conformational Design Principles in Total Synthesis

“…[11] 2) Minimal syn-pentane interac-tion:a sshown in Scheme 1b,s trong repulsion of the two spatially proximal methyl groups significantly destabilizes the syn-pentane conformer, and consequently,t here are very limited conformers that can be free of such interactions in am ultisubstituted open-chain compound. [15] Essentially,t he 1,3-allylic strain and syn-pentane interaction are Va nd er Waalsr epulsions,s ot hey are always overwhelmingly stronger than the other common stereoelectronic interactions,and thus could be regarded as safe criteria. In general, these principles can be used to destabilize undesired conformations, thereby achieving the desired stereoselectivity.…”

“…Syn-pentane interactions are widely used by nature to realize the biological function of natural products. [15] Inspired by nature,this kind of conformational-design strategy has also been widely used in the total synthesis of polyketides containing polydeoxypropionate chains,i nw hich the 2,4-dimethylpentane fragment is one of the repetitive units.I nterestingly,t he rigidity of the 2,4-dimethylpentane fragments means that they can stack with each other and form an unbroken monoconformational backbone.Avirtual diamond lattice can be used to demonstrate the conformation of the pentane module. [20] Usually,attachment of an inductor group at one end of the chain is ar eliable tactic to achieve am onoconformational backbone.T he reliability has been corroborated not only by the X-ray crystal structures of pentanecontaining natural products such as pectinatone [21] (see its monoconformational structure in Scheme 4), bourgeanic acid, [22] and TMC-151, [23] but also by calculations.…”