Volker Schmidts

On the Treatment of Conformational Flexibility when Using Residual Dipolar Couplings for Structure Determination

Mission possible! The motional averaging of NMR spectroscopic data complicates the determination of conformation and relative configuration in flexible organic molecules. Two alternative routes are discussed for the treatment of conformational equilibrium in a moderately flexible compound (see the superposition of the two conformers of the butyrolactone studied) when residual dipolar couplings are used.

Polyacetylenes as Enantiodifferentiating Alignment Media

The availability of residual dipolar couplings (RDCs) measured in weakly aligned media has had a major impact on the structural characterization of dissolved (chiral) molecules by NMR spectroscopy. This has been and still is especially true for biomacromolecules but more recently, the field has seen a rapidly increasing interest in the application of RDCs to solve structural problems for small molecules, too. 3] This, at first sight surprising fact, is by no means a back-extension, because the molecules under investigation pose problems being absent in the above-mentioned biopolymers. In contradiction to the latter many small molecules contain stereogenic units of unknown relative and absolute configuration. Given the fact that configurational analysis is always a problem of conformational analysis at the same time, the simultaneous treatment of both structural aspects is a necessity to solve the stereochemical problem exhaustively. With the advent of RDCs as a new NMR parameter containing distance and angle information the scope of NMRbased stereochemical analysis has been broadened considerably. This is mainly because of the fact that RDCs deliver conformationally relevant information without the need for parametrization as is the case for the evaluation of scalar couplings. Moreover, RDCs are global parameters not relying on short-range interactions like cross-relaxation (nuclear Overhauser effect, NOE) or cross-correlated relaxation. A precondition for the measurement of RDCs, as anisotropic NMR parameters, is to partially orient the analyte with respect to the magnetic field (weak alignment: RDC amounts approximately 10 3 of the maximum dipolar coupling). This can be done either by stretched polymer gels (SAG = strain-induced alignment in a gel) or by dissolving the compound in a lyotropic liquid-crystalline (LLC) phase. In the last years considerable progress has been made in the field of these orienting or alignment media especially for typical organic molecules being insoluble in water. On the other hand if the determination of the absolute configuration of a chiral, nonracemic water-insoluble compound is the goal of the investigation, it is necessary to orient the analyte in an enantiodifferentiating manner. This in turn is possible only if the alignment medium is itself chiral and of uniform configuration. The number of media fulfilling these criteria is still extraordinary small. As far as chiral LLC phases are concerned, only the homopolypeptide-based LLC phases derived from poly-g-benzyl-l/d-glutamate (PBLG/PBDG), poly-g-ethyl-l-glutamate (PELG/PEDG), and poly-e-carboxybenzoyl-l/d-lysin (PCBLL/PCBDL) as well as a recently introduced polyguanidine are known to meet the described needs. Moreover, Luy and co-workers have shown that gelatin cross-linked by accelerated electrons (e -gelatin) allows for the distinction of enantiomers in DMSO and DMSO/D2O mixtures at temperatures up to 60 8C. Despite our encouraging results with the polyguanidines, we decided to look for alternative helically chiral polymers capable of forming LLC phases. This decision was driven by a number of drawbacks associated with the polyguanidines. First of all the linewidths of the NMR signals from the analyte are rather large which hampers a precise determination of RDCs. Furthermore, the induced alignment is too strong which may lead to strong coupling artifacts. Finally, the purification of the noncrystalline carbodiimide monomers suffers from decomposition during chromatography. Within the family of helically chiral polymers 12] the amino-acid-stabilized polyisocyanides and polyacetylenes look most promising. Both polymer types are known to form LLC phases 14f,g,h] in a number of organic solvents and they are characterized by large persistence lengths 14h] (depending on the solvent) which should reduce the critical concentration for the phase transition. Moreover, the synthesis of the corresponding monomers is straightforward and their transition-metal-induced polymerization works efficiently with a high tolerance for functional groups. 16] In this contribution we would like to describe the suitability of the valine-derived polyacetylene p1 and its enantiomer p2 as alignment media. The synthesis of monomer 1 was achieved in three steps starting from 4-iodobenzoic acid ethyl ester 2 and valine 3 (Scheme 1; for a detailed description see the Supporting Information). According to the work of Okoshi and Yashima 18] the polymerization of 1 was initiated by [Rh(nbd)Cl]2 delivering polymer p1 as a yellow solid (nbd = norbornadiene). This polymerization reaction was repeated three times whereby a total of four different polymer samples (p1 a, p1 b, p1c, and [*] Dipl.-Chem. N.-C. Meyer, Dipl.-Ing. A. Krupp, Dipl.-Ing. V. Schmidts, Prof. Dr. C. M. Thiele, Prof. Dr. M. Reggelin Technische Universit t Darmstadt Clemens Schçpf Institut f r Organische Chemie und Biochemie Petersenstrasse 22, 64287 Darmstadt (Germany) E-mail: re@punk.oc.chemie.tu.darmstadt.de Homepage: deepthought.oc.chemie.tu-darmstadt.de

Determination of the Conformation of the Key Intermediate in an Enantioselective Palladium-Catalyzed Allylic Substitution from Residual Dipolar Couplings†

Transition-metal-catalyzed enantioselective C C bond-forming reactions such as allylic substitution are of great importance in academic research and industrial processes. In investigating the origin of the stereoselection of such a reaction knowledge about the spatial relationships between the ligand(s), the transition metal, and the substrate is a crucial step. If an intermediate can be isolated, the spatial structure of the intermediate can in principle be obtained either by X-ray crystallography or NMR spectroscopy. However, it should be pointed out here that the equilibrium conformation of the intermediate does not necessarily lead to conclusive insights on reactivity and selectivity, since that depends on whether an early or late transition state is involved in the formation of the product. 4] Extensive studies have been devoted to probing the origin of stereoselection in allylic substitutions with bidentate ligands, of which only few can be mentioned here. For systems with monodentate ligands, as is the case in the present study (see 1), several X-ray structures of catalyst–substrate complexes exist, but to our knowledge no detailed NMR spectroscopic study in solution has yet been performed. The conformation of an intermediate complex in solution might not necessarily resemble that determined crystallographically. Furthermore, the solution conformation and in particular the dynamics of the intermediate species might be important for insight into the stereoselective step. Unfortunately, determining the predominant conformation in solution is not always straightforward, especially if organometallic species are considered. Conventional NMR parameters such as J couplings and NOEs might fail either because of missing links between spins (for both J couplings and NOEs), missing parametrizations (for J couplings especially for organometallic species), or conformational flexibility. This was also the case for the complex described herein. In contrast to the short-range information content of J couplings and NOEs, residual dipolar couplings (RDCs) provide long-range structural information and can also be used to relate non-interacting spins in biomolecular and recently also in organic compounds. The complex investigated here by means of RDCs was reported by Helmchen et al. to be a self-organizing palladium catalyst system bearing two monodentate ligands 1 and showing high activity and enantioselectivity in allylic alkylation reactions (Scheme 1). As the ligands are monodentate, considerable flexibility in the corresponding substrate– catalyst complex can be expected. It is thus very important to obtain information about the conformational behavior of the catalyst–substrate complex 2 in solution.

RDC-Based Determination of the Relative Configuration of the Fungicidal Cyclopentenone 4,6-Diacetylhygrophorone A12

The hygrophorones, a class of cyclopentenones isolated from fruiting bodies of the genus Hygrophorus (basidiomycetes), show promising antifungal activity. While the constitution of 4,6-diacetylhygrophorone A(12) (3) and the relative configuration of the stereogenic centers in the cyclopentenone ring were elucidated using standard NMR and MS techniques, the relative configuration of the exocyclic stereogenic center could not be assigned. By introducing a sample of 3 into an alignment medium and measuring anisotropic NMR parameters, namely, residual dipolar couplings, we were able to unambiguously determine the relative configuration of all three stereogenic centers in 4,6-diacetylhygrophorone A(12) simultaneously by fitting several structure proposals to the experimental data.

How different are diastereomorphous orientations of enantiomers in the liquid crystalline phases of PBLG and PBDG: a case study

The orientational properties of the two enantiomers of an example compound, namely isopinocampheol [(+)‐ and (−)‐IPC] in the two enantiomers of a liquid crystalline phase, namely Poly‐γ‐benzyl‐L/D‐glutamate (PBLG/PBDG) with the organic cosolvent CDCl3, were investigated. The interactions can be either enantiomorphous, leading to equal orientations and residual dipolar couplings (RDCs), or diastereomorphous, leading to different orientations and RDCs. The difference between the two diastereomorphous orientations was determined to be rather small (5° in the Euler angle β). Furthermore, we investigated whether one of the two diastereomorphous interactions is favored. Copyright

Perspectives in the application of residual dipolar couplings in the structure elucidation of weakly aligned small molecules

This perspective article aims to review the general methodology in the application of residual dipolar couplings (RDCs) in the structure elucidation of small molecules and give the authors view on challenges for future applications. Recent improvements in the availability of alignment media, new pulse sequences for the measurement of couplings and improvements in the analysis software have garnered widespread interest in the technique. However, further generalization is needed in order to make RDC analysis into a truly “routine” method. Copyright

Exploring the Conformational Space of Bridge‐Substituted Dithienylcyclopentenes

Stimuli responsive compounds and materials are of high interest in synthetic chemistry and materials science, with light being the most intriguing stimulus due to the possibility to remote control the physicochemical properties of a molecule or a material. There is a constant quest to design photoswitches with improved switching efficiency and especially diarylethene-type switches promise photo cyclization quantum yields up to unity. However, only limited attention has been paid towards the influence of the solution conformation on the switching efficiency. Here, we describe a detailed NMR spectroscopic investigation on the conformational distribution of bridge-substituted dithienylcyclopentenes in solution. We could discriminate between several photoactive and photoinactive as well as two diastereomorphous conformations and show that the trends observed in the switching efficiency match the conformer populations obtained from state of the art NMR parameters in solution.

Uncovering Key Structural Features of an Enantioselective Peptide-Catalyzed Acylation Utilizing Advanced NMR Techniques

We report on a detailed NMR spectroscopic study of the catalyst-substrate interaction of a highly enantioselective oligopeptide catalyst that is used for the kinetic resolution of trans-cycloalkane-1,2-diols via monoacylation. The extraordinary selectivity has been rationalized by molecular dynamics as well as density functional theory (DFT) computations. Herein we describe the conformational analysis of the organocatalyst studied by a combination of nuclear Overhauser effect (NOE) and residual dipolar coupling (RDC)-based methods that resulted in an ensemble of four final conformers. To corroborate the proposed mechanism, we also investigated the catalyst in mixtures with both trans-cyclohexane-1,2-diol enantiomers separately, using advanced NMR methods such as T1 relaxation time and diffusion-ordered spectroscopy (DOSY) measurements to probe molecular aggregation. We determined intramolecular distance changes within the catalyst after diol addition from quantitative NOE data. Finally, we developed a pure shift EASY ROESY experiment using PSYCHE homodecoupling to directly observe intermolecular NOE contacts between the trans-1,2-diol and the cyclohexyl moiety of the catalyst hidden by spectral overlap in conventional spectra. All experimental NMR data support the results proposed by earlier computations including the proposed key role of dispersion interaction.

Synthesis of Poly-γ-S-2-methylbutyl-l-glutamate and Poly-γ-S-2-methylbutyl-d-glutamate and Their Use as Enantiodiscriminating Alignment Media in NMR Spectroscopy

Lyotropic liquid crystalline (LLC) phases of polyglutamic acid derivatives, such as poly-γ-benzyl-l-glutamate, are suitable alignment media for organic structure elucidation by NMR spectroscopy. Their helical structure is responsible for enantiodiscrimination. As part of our ongoing investigations concerning the alignment mechanism(s) of these systems, we considered whether an additional chiral center in the side chain could improve enantiodiscrimination relative to the helical polymer with an achiral side chain. Therefore, the diastereoisomers poly-γ-S-2-methylbutyl-l-glutamate (PSMBLG) and poly-γ-S-2-methylbutyl-d-glutamate (PSMBDG) were synthesized. These two polymers were tested for their liquid crystallinity and suitability as alignment media. The spatial structure of the solutes (-)-curcumol and isopinocampheol (IPC) were validated by the residual dipolar coupling data obtained. Additionally, enantiodiscrimination of IPC was observed in the new alignment media and compared with the enantiodiscrimination of IPC in other homopolypeptides.

The influence of electronic modifications on rotational barriers of bis-NHC-complexes as observed by dynamic NMR spectroscopy.

There has been much debate about the σ‐donor and π‐acceptor properties of N‐heterocyclic carbenes (NHCs). While a lot of synthetic modifications have been performed with the goal of optimizing properties of the catalyst to tune reactivity in various transformations (e.g. metathesis), direct methods to characterize σ‐donor and π‐acceptor properties are still few. We believe that dynamic NMR spectroscopy can improve understanding of this aspect. Thus, we investigated the intramolecular dynamics of metathesis precatalysts bearing two NHCs. We chose four systems with one identical NHC ligand (N,N′‐Bis(2,4,6‐trimethylphenyl)‐imidazolinylidene (SIMes) in all four cases) and NHCewg ligands bearing four different electron‐withdrawing groups (ewg). Both rotational barriers of the respective Ru‐NHC‐bonds change significantly when the electron density of one of the NHCs (NHCewg) is modified. Although it is certainly not possible to fully dissect σ‐donor and π‐acceptor portions of the bonding situations in the respective Ru‐NHC‐bond via dynamic NMR spectroscopy, our studies nevertheless show that the analysis of the rotation around the Ru‐SIMes‐bond can be used as a spectroscopic parameter complementary to cyclic voltammetry. Surprisingly, we observed that the rotation around the Ru‐NHCewg‐bond shows the same trend as the initiation rate of a ring‐closing metathesis of the four investigated bis‐NHC‐complexes. Copyright