Dennis Worgull

Reductive C–C Bond Formation after Epoxide Opening via Electron Transfer

This review presents a description of the C–C bond-forming reactions that have emerged in the field of titanocene mediated or catalyzed epoxide opening over the last 5 years or so. The powerful tandem sequences for polycylization will be especially emphasized.

Enantioselective One-Pot Synthesis of α-Amino Esters by a Phosphine-Catalyzed [3+2]-Cycloaddition Reaction

Phosphine-catalyzed [3+2]-cycloaddition reactions of electron-deficient allenes and alkynes with α,β-unsaturated carbonyl compounds can give access to important highly functionalized cyclopentenes.1 The seminal example of such a transformation was first reported by Lu et al. in 1995,2 and its asymmetric version in 1997 by the group of Zhang.3 However, it took another ten years before the potential of this annulation strategy using chiral phosphine catalysts was studied more intensively.4 The last decade has witnessed considerable progress in the development of suitable new chiral phosphine catalysts and their application in asymmetric [3+2]-cycloaddition reactions.5

An Asymmetric Organocatalytic One‐Pot Strategy to Octahydroacridines

A major focus of organocatalysis has been the development of domino, cascade, and one-pot reactions. These classes of reactions enable the construction of molecules with great structural complexity with a minimum of manual operations, thereby saving time, effort, and production cost. Moreover, given the current focus on the development of more environmental-friendly procedures, these reactions, with their fewer purification steps, are useful alternatives to the classical stepwise approaches. Recently, the aza-Diels–Alder reaction between an N-aryl imine and an olefin moiety (the Povarov reaction) has attracted considerable attention, 5] as this reaction provides a simple route to a variety of nitrogen-containing polycyclic structures. In general, N heterocycles are of broad interest due to their vast abundance in natural and pharmaceutical compounds, and for instance tetrahydroquinolines have shown biological activity in numerous examples. However, though they possess a tetrahydroquinoline core structure, suggesting potentially interesting biological properties, the class of octahydroacridines remains virtually unexplored due to their limited availability. This type of compounds may be accessed through an intramolecular Povarov reaction, in which an e,z-unsaturated aldehyde upon condensation with an aryl amine, subsequently undergoes a formal cycloaddition and re-aromatization, affording the final product. However, access to optically active octahydroacridines has so far exclusively been based on a chiral pool approach and, furthermore, limited diastereomeric control is often observed. To the best of our knowledge, no catalytic asymmetric approaches to these interesting N-heterocyclic structures have been described to date. We imagined a route (Scheme 1), in which the addition of malononitrile derivatives to an a,b-unsaturated aldehyde employing aminocatalysis would furnish a suitable intermediate, which could be trapped in a following condensation/ cyclization cascade by an aniline derivative. Optimally, the stereocenter of the initial addition step would direct the subsequent cycloaddition, hereby controlling the formation of the optically active octahydroacridines with high diastereoselectivity. Herein, we describe a protocol for the preparation of a series of octahydroacridines having four stereocenters with excellent enantioand diastereomeric control. A rationale for the stereochemical outcome of the reaction is proposed, and further derivatizations of the products are demonstrated, such as the selective hydrolysis of one of the nitrile functionalities, leading to octahydroacridines with five stereocenters. In order to reach an efficient one-pot protocol, the initial organocatalytic addition step was first investigated. At the outset, slightly modified conditions to those previously reported were applied. Accordingly, with malononitrile 2a, 2 equiv of hex-2-enal (1a), and 10 mol% of (S)-2-[bis(3,5bistrifluoromethylphenyl)trimethylsilyloxymethyl]pyrrolidine (3) as the catalyst in CH2Cl2, full and clean conversion to the desired Michael addition intermediate was observed. Consequently, the anticipated condensation/Povarov cascade was attempted, and, gratifyingly, the addition of 1.5 equiv of 4-nitroaniline (4a) and 2 equiv of trifluoroacetic acid (TFA) to the diluted reaction mixture at 30 8C gave clean conversion to the proposed product with excellent diastereomeric control. With these conditions in hand, the scope of the reaction was examined by varying the a,b-unsaturated aldehyde 1, malononitrile 2, and aniline 4 (Table 1). The developed reaction concept showed great tolerance towards a variety of aliphatic a,b-unsaturated aldehydes 1. Saturated and unsaturated side chains of different length were successfully applied (Table 1, entries 1–5, 18) and, furthermore, benzyl ether and homobenzyl functionalities were tolerated (entries 6 and 7). Generally, high yields (59 to 93 %), taking into account the multiple reaction steps being involved, were observed with excellent stereocontrol (89 to 99% ee and > 20:1 d.r. in all examples). Interestingly, no Scheme 1. Synthetic outline for the formation of octahydroacridines. TMS= trimethylsilyl.

4‐exo Cyclizations by Template Catalysis

The cyclobutane ring is an important structural motif in many natural products. A number of synthetic approaches to fourmembered rings have been described, but none of them is general. This is also the case for radical cyclizations, even though they are in principle amongst the most powerful reactions for the construction of carbocyclic rings. Difficulties encountered in the preparation of cyclobutanes are caused by their inherent strain and by the low rate constant of the cyclization of the archetypal pentenyl radical. Therefore, the few efficient examples of 4-exo cyclizations in classical free radical chemistry, and in metal-mediated and metal-catalyzed radical reactions using SmI2 [3] and titanocene(III) reagents have to rely on special structural features. In these cases, the presence of gem-dialkyl or gemdialkoxyl substitution adjacent to the radical center or the incorporation of the cyclization into transannular tandem sequences was necessary for obtaining useful yields of the desired products. A general access to cyclobutanes by the 4-exo cyclization is still elusive. Herein, we address this issue by using cationic functionalized titanocenes as template catalysts for such reactions. In these complexes the pendant amide ligand as well as the chloride ligand can be replaced by polar groups. For a suitably substituted radical this results in an energetically favorable two-point binding to the template in which the radical center and radical acceptor are forced into close spatial proximity. As a consequence, the 4-exo cyclization becomes a transannular transformation, which is thermodynamically and kinetically more favorable. With careful adjustment of the steric interactions this template effect can lead to highly ordered intermediates and transition states, and hence to a stereoselective cyclization (Scheme 1). We have realized the two-point binding with unsaturated epoxides as radical precursors. Reductive electron transfer to the epoxide generates a radical which is covalently attached to titanium through a Ti O bond. The pivotal second binding can be enforced by a donor group displacing the amide ligand. To this end, we chose 1 as the substrate, because a,bunsaturated carbonyl groups usually constitute better ligands than the corresponding saturated carbonyl groups. The reaction of a tertiary radical renders the process thermodynamically unfavorable. Our results of the first 4-exo cyclization without gem disubstitution are summarized in Scheme 2 and Table 1 (Coll = collidine = 2,4,6-trimethylpyridine).

Asymmetric organocatalytic monofluorovinylations.

The development of highly enantio- and diastereoselective organocatalytic monofluorovinylations is presented. Based on the application of α-fluoro-β-keto-benzothiazolesulfones, the formal addition of a monofluorovinylic anion synthon to a range of acyclic and cyclic enones, as well as imines, is shown. These procedures give selective access to both E- and Z-isomers of the monofluorovinylated products, which are isolated as the pure diastereoisomers in good to excellent yields with up to 99% ee. Furthermore, the application of this concept for the formation of highly enantioenriched bicylic compounds containing a monofluorovinyl moiety is also described. In addition, a mechanistic rationale for the observed E:Z-selectivities is presented.

Carbonyl-Substituted Titanocenes: A Novel Class of Cytostatic Compounds with High Antitumor and Antileukemic Activity

The outstanding success of cisplatin [cis-Pt ACHTUNGTRENNUNG(NH3)2Cl2], one of the most broadly used chemotherapeutic agents, has sparked tremendous interest in the development of related metal compounds with similar properties. Currently, complexes of platinum, iron, ruthenium and titanium are in the center of attention. Of the titanium compounds derivatives of titanocene dichloride [Cp2TiCl2] have emerged as the most promising candidates for further investigations. However, the progress of this fascinating field of research has been severely hampered by the lack of a general approach to structurally and functionally diverse complexes. Thus, the highly desirable screening of wide regions of chemical space could not be realized. Recently, we have described the first modular approach to exactly these compounds, that relies on the use of titanocenes with pending carboxylic acid chlorides. In this manner oxygen and nitrogen nucleophiles could be acylated to yield a large number of structurally and functionally diverse titanocene complexes possessing ester and amide functionality. Besides the possibility to vary the nucleophile another crucial issue for the biological activity of the titanocenes can be addressed. Due to coordination of the carbonyl group, the amide complexes are soluble and stable in water or DMSO. Here, we report on the first synthesis of ketonesubstituted titanocenes and the activity of our complexes against a variety of malignant cells. As in the case of the amides our synthetic targets were cationic and water soluble complexes. However, ketones are noticeably weaker ligands than amides. Thus, we looked for a synthetic sequence that allows the conversion of the carboxylic acid chloride to electron-rich ketones as well as the abstraction of one chloride ligand of titanium. Thus, a general access to a large number of cationic complexes can be envisioned. All complexes discussed here were obtained as racemates, only one enantiomer is shown. Friedel–Crafts acylations of donor-substituted arenes in the presence of ZnCl2 emerged as especially well-suited for our purposes. The desired complexes could be isolated in satisfactory to high yields as the tetrachloro zincates (Table 1). An example of the coordination of the ketone at the cationic titanium center is depicted in Figure 1. In addition to the variation of the aryl substituents and the straightforward modification of the gem-dialkyl group attached to the upper cyclopentadienyl ligand our synthesis of the carboxylates allows the alteration of the distance of the keto group from this ligand and the introduction of the substituents at the lower cyclopentadienyl ligand. A single additional methylene group prevents coordination of the ketone in 2 f as the result of the highly unfavorable formation of a strained ring. The structural modifications (Table 1, Scheme 1) should be essential for the biological activity of the complexes for three reasons. First, the polarity of the compounds can be tailored. Second, the electronic and steric properties of all substituents will have an influence on the exact coordination geometry of titanium. Third, the overall three-dimensional shape of the titanocenes can be varied in a straightforward manner. This can turn out to be crucial regarding the binding ability to enzymes and receptors. To understand the biological activity of our titanocenes, we investigated a broad spectrum of both solid tumors and leukemia cell lines. These include BJAB cells (lymphoma), [a] Prof. Dr. A. Gans;uer, I. Winkler, D. Worgull, Dr. T. Lauterbach, Dr. D. Franke Kekul?-Institut f@r Organische Chemie und Biochemie Universit;t Bonn, Gerhard-Domagk-Str. 1 53121 Bonn (Germany) Fax: (+49)228-734760 E-mail : andreas.gansaeuer@uni-bonn.de [b] A. Selig, L. Wagner, Dr. A. Prokop Department of Pediatric Oncology/Hematology University Medical Center Charit? Berlin, 13353 Berlin (Germany) Fax: (+49)450-559999 E-mail : aram.prokop@charite.de Supporting information for this article is available on the WWW under http://www.chemistry.org or from the author.