Wilhelm A. Eger

Enantioselective total synthesis of the mexicanolides: khayasin, proceranolide, and mexicanolide.

The enantioselective total synthesis of the limonoids khayasin, proceranolide and mexicanolide was achieved via a convergent strategy utilizing a tactic aimed at incorporating natural products as advanced intermediates. This extended biomimetically inspired approach additionally achieved the enantioselective total synthesis of the intermediates azedaralide and cipadonoid B.

A Mechanistic Investigation into the Zinc Carbenoid-Mediated Homologation Reaction by DFT Methods: Is a Classical Donor—Acceptor Cyclopropane Intermediate Involved?

An extensive density functional theory (DFT, M05-2X) investigation has been performed on the zinc carbenoid-mediated homologation reaction of β-keto esters. The mechanistic existence of a classical donor-acceptor cyclopropane intermediate was probed to test the traditional school of thought regarding these systems. Calculations of the carbenoid insertion step, following enolate formation, unmasked two possible pathways. Pathway B was shown to explain the proposed, but spectroscopically unobservable donor-acceptor cyclopropane intermediate, while the second (pathway A) reveals an alternative to the classical intermediate in that a cyclopropane transition state leads to product.

Metal-Mediated Reaction Modeled on Nature: The Activation of Isothiocyanates Initiated by Zinc Thiolate Complexes

On the basis of detailed theoretical studies of the mode of action of carbonic anhydrase (CA) and models resembling only its reactive core, a complete computational pathway analysis of the reaction between several isothiocyanates and methyl mercaptan activated by a thiolate-bearing model complex [Zn(NH(3))(3)SMe](+) was performed at a high level of density functional theory (DFT). Furthermore, model reactions have been studied in the experiment using relatively stable zinc complexes and have been investigated by gas chromatography/mass spectrometry and Raman spectroscopy. The model complexes used in the experiment are based upon the well-known azamacrocyclic ligand family ([12]aneN(4), [14]aneN(4), i-[14]aneN(4), and [15]aneN(4)) and are commonly formulated as ([Zn([X]aneN(4))(SBn)]ClO(4). As predicted by our DFT calculations, all of these complexes are capable of insertion into the heterocumulene system. Raman spectroscopic investigations indicate that aryl-substituted isothiocyanates predominantly add to the C═N bond and that the size of the ring-shaped ligands of the zinc complex also has a very significant influence on the selectivity and on the reactivity as well. Unfortunately, the activated isothiocyanate is not able to add to the thiolate-corresponding mercaptan to invoke a CA analogous catalytic cycle. However, more reactive compounds such as methyl iodide can be incorporated. This work gives new insight into the mode of action and reaction path variants derived from the CA principles. Further, aspects of the reliability of DFT calculations concerning the prediction of the selectivity and reactivity are discussed. In addition, the presented synthetic pathways can offer a completely new access to a variety of dithiocarbamates.

Allene as the Parent Substrate in Zinc-Mediated Biomimetic Hydration Reactions of Cumulenes†

The aim of our present investigation is to unravel the general mode of biomimetic activation of a wide variety of cumulenes by carbonic anhydrase (CA) models. Carbonic anhydrases allow the specific recognition, activation and transfer not only of CO2 but also of heteroallenes X=C=Y such as the polar or polarizable examples COS, CS2, H2CCO, and RNCS. Therefore, this enzyme class fulfils the requirements of excellent catalysts with a wide variety of important applications. Can this be extended to the isoelectronic but less reactive allene molecule, H2C=C=CH2 and extremely simplified models as mimetic concept for active center of the carbonic anhydrase? Allene is a waste product in the refinery, i.e. the C3-cut of the naphtha distillation; therefore, any addition product that can be obtained from allene in high yields will be of significant value. We investigated the complete catalytic cycle of a very simple model reaction, the hydration of allene, using density functional theory. Additionally, calculations were performed for the uncatalyzed reaction. There are two possible ways for the nucleophilic attack leading to different products. The zinc hydroxide complex and the water molecule can react at the central or the terminal carbon atoms (positional selectivity), the resulting products are 2-propen-1-ol and propen-2-ol, respectively, acetone. The calculations indicate a significant lower energy barrier for the rate determining step of the formation of propen-2-ol and therefore a well-expressed regioselectivity for the addition of such small molecules. The zinc complex has a pronounced catalytic effect and lowers the activation barrier from 262.5 to 123.9 kJ/mol compared with the uncatalyzed reaction. This work suggests the most probable paths for this reaction and discloses the necessity for the development of novel catalysts.

The zinc complex catalyzed hydration of alkyl isothiocyanates

AbstractBased upon our preceding studies of the hydration of CO2, COS and CS2, accelerated by the carbonic anhydrase (CA) using simplified [ZnL3OH]+ complexes as model catalysts, we calculated the hydration mechanisms of both the uncatalyzed and the [ZnL3OH]+-catalyzed reactions (L = NH3) of isothiocyanates RNCS on the B3LYP/6-311+G(d,p) level of theory. Interestingly, the transition state for the favored metal mediated reaction with the lowest Gibbs free energy is only slightly higher than in the case of CO2 (depending on the attacking atom (N or S). Calculations under inclusion of solvent corrections show a reduction of the selectivity and a slight decrease of the Gibbs free energy in the rate-determining steps. The most plausible pathway prefers the mechanism via a Lindskog proton-shift transition state leading to the thermodynamically most stable product, the carbamatic-S-acid. Furthermore, powerful electron withdrawing substituents R of the cumulenic substrates influence the selectivity of the reaction to a significant extent. Especially the CF3-group in trifluoromethylisothiocyanate reverses the selectivity. This investigation demonstrates that reaction principles developed by nature can be translated to develop efficient catalytic methods, in this case presumably for the transformation of a wide variety of heterocumulenes aside from CO2, COS and CS2. FigureCompeting transition structures for the [ZnL3OH]+-mediated activation of isothiocyanates

A combined DFT and NMR investigation of the zinc organometallic intermediate proposed in the syn-selective tandem chain extension-aldol reaction of β-keto esters

The tandem chain extension-aldol (TCA) reaction of β-keto esters provides an α-substituted γ-keto ester with an average syn:anti selectivity of 10:1. It is proposed that the reaction proceeds via a carbon-zinc bound organometallic intermediate potentially bearing mechanistic similarity to the Reformatsky reaction. Evidence, derived from control Reformatsky reactions and a study of the structure of the TCA intermediate utilizing DFT methods and NMR spectroscopy, suggests the γ-keto group of the TCA intermediate plays a significant role in diastereoselectivity observed in this reaction. Such coordination effects have design implications for future zinc mediated reactions.

Push-Pull-Allenes: The Influences of Substituents on the Activation of Allenes by Biomimetic Zinc Complexes

The influence of substituents at the allene skeleton on the rate-determining step of the reaction with nucleophiles catalyzed by biomimetic zinc complexes was investigated with quantum chemical (especially DFT) methods. Additional examinations were applied to derivatives of the zinc hydroxide complex modeled in analogy to the catalytic center of carbonic anhydrase. Especially suitable substituents in the allene moiety can lead to a significant lowering of the activation barrier. Further we demonstrate that by the application of this principle of a bioanalogous enhancement of reactivity other nucleophiles instead of the biological substrate can also be reactants in completely closed catalytic reaction cycles. Graphical Abstract Push-Pull-Allenes: The Influences of Substituents on the Activation of Allenes by Biomimetic Zinc Complexes

Mechanistic aspects of the lycopodine Michael-Claisen domino cyclization.

The Michael-Claisen domino (MCD) cyclization used in the lycopodine synthesis by Stork, was evaluated mechanistically using DFT calculations. Calculations suggest that a dianion is not formed, which conforms to classical dianion formation normally requiring strong kinetic bases. Instead ethoxide in ethanol produces a monoanionic species driving the MCD cyclization. This endeavor has opened up potential to expand the scope of this unique reaction and provide educational clarity.

The Carbonic Anhydrase as a Paragon: Theoretical and Experimental Investigation of Biomimetic Zinc-Catalyzed Activation of Cumulenes

Biomimetics as an interdisciplinary concept involves learning from and imitating of nature using appropriate models. The mimicry of biological models does not only consist of the construction of engineering systems and modern technology, furthermore, it is able to be a guide for designing and architecturing in the complete range of natural sciences. In particular, the actual development of novel and uncommon chemical reactions is aimed to apply high optimized, biochemical processes to laboratory and industrially usable syntheses. Especially enzymes stand in the visual focus as highly efficient and almost extreme specialized catalysts, as nature has had a long time to develop and optimize a wide diversity of life. Nearly every organism owns different tissues, motion types, sensoring functions and surviving instincts and the basis for all of these properties are highly efficient catalyzed chemical reactions. Organisms have not only to synthesize huge biopolymers for growth, but also to provide small molecules for signal transduction, energy transfers or regulation processes. Therefore, it is obvious that the study of those reactions not only gives insights in important biochemical processes, but also suggests new chemical pathways to use in synthesis or other related appliances. The possibilities of biomimetics in chemistry are outlined on the basis of the enzyme carbonic anhydrase. As this enzyme is one of the most efficient catalysts originated by nature, the investigation of such a catalytical active protein enriches not only the knowledge of biological and biochemical mechanisms and their mode of action, but also gives detailed information about the active center inside of the enzyme. In that way, one can fathom out important factors for the growth and development as well as for the investigation of diseases and glitches. In this chapter we describe the enzymatic metal mediated reaction of the cumulene system carbon dioxide with water and its extention to the bio-analogue activation of further isoelectronic cumulenes (carbonyl sulfide, isothiocyanate and allene).