Michael Reggelin

Catalysis of allylic substitutions by Pd complexes of oxazolines containing an additional P, S, or Se Center. X-ray crystal structures and solution structures of chiral π-allyl palladium complexes of phosphinoaryloxazolines

Allylic alkylations with Pd complexes of chiral oxazolines with an additional donor P, S, or Se center are reported. Crystal and solution structures of palladium π-allyl complexes of phosphinoaryloxazolines were determined by X-ray crystallography and cross relaxation experiments, respectively. From the results conclusions concerning the steric course of allylic substitutions are drawn.

Direct Determination of Absolute Molecular Stereochemistry in Gas Phase by Coulomb Explosion Imaging

Absolute Images Molecules are held together by a balance of charge between negative electrons and positive nuclei. When multiple electrons are expelled by laser irradiation, the remaining, mutually repulsive nuclei fly apart in a Coulomb explosion. Instead of traditional x-ray diffraction methods that require crystalline samples, Pitzer et al. (p. 1096) show that by tracking the fragment trajectories from laser-induced Coulomb explosions of relatively simple gas phase molecules, they can determine the absolute stereochemical configuration of enantiomers (mirror-image isomers). A simple molecule’s three-dimensional structure can be ascertained from the fragment trajectories when it is blown apart. Bijvoet’s method, which makes use of anomalous x-ray diffraction or dispersion, is the standard means of directly determining the absolute (stereochemical) configuration of molecules, but it requires crystalline samples and often proves challenging in structures exclusively comprising light atoms. Herein, we demonstrate a mass spectrometry approach that directly images the absolute configuration of individual molecules in the gas phase by cold target recoil ion momentum spectroscopy after laser ionization–induced Coulomb explosion. This technique is applied to the prototypical chiral molecule bromochlorofluoromethane and the isotopically chiral methane derivative bromodichloromethane.

(Phosphanyloxazoline)palladium Complexes, Part I: (η3-1,3-Dialkylallyl)(phosphanyloxazoline)palladium Complexes: X-Ray Crystallographic Studies, NMR Investigations, and Quantum-Chemical Calculations

A series of systematically varied (eta3-1,3-dialkylallyl)palladium complexes of (4S)-[2-(2-diphenylphosphanyl)phenyl]-4,5-dihydrooxazole (PHOX) ligands were characterized by X-ray crystal structure analysis and NMR spectroscopy. Complexes with identical substituents in the 1,3-positions of the allyl group can form eight stereoisomers. In solution four to six isomers were observed and their conformations assigned with the aid of NOE experiments. The dynamic behavior of the complexes was analyzed. In addition, quantum-chemical calculations (restricted Hartree-Fock (HF), density functional theory (DFT)) were carried out and gave satisfactory agreement with experimental findings.

Towards polyketide libraries: Iterative, asymmetric aldol reactions on a solid support

Abstract A polymer bound aldehydr obtained from the oxidation of Wangs resin can be used as starter unit for iterative, asymmetric aldol reactions. The synthetic protocol relies on the boron enolate chemistry of D. A. Evans, the N-methoxy substituted amides of S. M. Weinreb and entails the opportunity for the generation of polyketide libraries.

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

Is Enantiomer Assignment Possible by NMR Spectroscopy Using Residual Dipolar Couplings from Chiral Nonracemic Alignment Media?—A Critical Assessment

The discovery of Jean-Baptiste Biot in 1815 that optical activity is not a property bound to a certain aggregation state of matter but a property of the constituting molecules themselves, has had an enormous influence on the structural models that chemists developed at the end of the 19th century, long before the description of the chemical bond was based on quantum mechanics. Pasteur achieved the first separation of enantiomers in 1847, namely by crystallization of a racemic tartrate mixture that separated the two enantiomers into enantiomorphic crystals, solutions of which rotated the plane of linearly polarized light in opposite directions. Not until 1951, when Bijvoet used anomalous X-ray diffraction, it was possible to assign the absolute configuration to a specific enantiomer. However, anomalous X-ray diffraction has not put the problem of assigning absolute configurations to rest, because many chemical compounds cannot be crystallized. Moreover, anomalous X-ray diffraction of molecules that consist exclusively of lightweight atoms commonly lacks the needed accuracy to allow unambiguous assignment of absolute configurations. An alternative method for resolving enantiomers is to convert them to diastereoisomers, either by chemical derivatization with chiral nonracemic moieties or by intermolecular coordination with chiral nonracemic reagents. In this way it is possible to determine absolute configuration from NMR observables, most commonly chemical shifts. The use of chiroptical spectroscopies such as optical rotatory dispersion, and electronic or vibrational circular dichroism is well established, sometimes in combination with ab initio calculations. Further methods are conceivable but impractical momentarily. Yet, there is currently not a simple and universally applicable approach to determine the absolute configuration of molecules with few stereogenic centers. Two recent papers published in 2007 and 2011 have therefore created a lot of excitement in the chemistry and NMR spectroscopy communities. Their titles are: “Stereochemical Identification of (R)and (S)-Ibuprofen Using Residual Dipolar Couplings, NMR, and Modeling”, henceforth called “article 1”, and more recently: “Spin-Selective Correlation Experiment for Measurement of Long-Range J Couplings and for Assignment of (R/S) Enantiomers from the Residual Dipolar Couplings and DFT”, henceforth called “article 2”. Both articles describe the assignment of the absolute configuration of the chiral molecules, ibuprofen 1 (article 1) and 4-methyl-1,3-dioxolan-2-one 2 (article 2), using NMR spectroscopy in chiral nonracemic alignment media (Figure 1). Under chiral nonracemic conditions, the authors measured residual dipolar couplings (RDCs), a NMR parameter only visible in oriented samples, such as in liquid crystals, but not in isotropic solvents. The interaction of the enantiomers with the chiral nonracemic alignment medium gives rise to diastereomorphic associates for which reason the authors indeed found different sets of anisotropic parameters for each enantiomer, in total

Towards polyketide libraries — II: Synthesis of chiral aracemic di- and triketides on a solid support

Abstract A new fluoride ion cleavable linker serves as starter unit for iterative asymmetric aldol reactions on a solid support. The synthetic protocol relies on the boron enolate chemistry of D. A. Evans and a cyclic reestablishment of key functionalities. It entails the opportunity for the generation of di- and triketide libraries.

Structure Determination of a Key Intermediate of the Enantioselective Pd Complex Catalyzed Allylic Substitution Reaction

The structure of a catalytic intermediate with important implications for the interpretation of the stereochemical outcome of the palladium complex catalyzed allylic substitution with phosphino-oxazoline (PHOX) ligands is determined by liquid state NMR. The complex displays a novel structure that is highly distorted compared with other palladium eta2-olefin complexes known so far. The structure has been determined from nuclear overhauser data (NOE), scalar coupling constants, and long range projection angle restraints derived from dipole dipole cross-correlated relaxation of multiple quantum coherence. The latter restraints have been implemented into a distance geometry protocol. The projection angle restraints yield a higher precision in the determination of the relative orientation of the two molecular moieties and are essential to provide an exact structural definition of the olefinic part of the catalytic intermediate with respect to the ligand.

One-pot synthesis of (S)-4-isopropyl-2-p-toluene-4,5-dihydro-[1.2λ6,3]oxathiazole 2-Oxides: Efficient precursors of optically active sulfoximines

Abstract The title compounds were prepared from p-toluenesulfinyl chloride and (S)-O-trimethylsilyl valinol without isolation of intermediates. Key step in the synthesis is the fluoride-induced cyclisation of sulfonimidoyl chlorides yielding the crystalline sulfonimidates 4 and 5 as a mixture of enantiomerically pure diastereomers which were easily separable by column chromatography or just simple crystallisation. Their reactions with either organolithium or Grignard reagents offer a convenient entry to enantiomerically pure sulfoximines in high yields.

[2,3]-Sigmatropic Rearrangements of Allylic Sulfur Compounds

Nine variations of [2,3]-sigmatropic rearrangements of allylic sulfur compounds are reviewedwith particular emphasis on newer developments and applications in target molecule oriented research.