Andrey P. Antonchick

Highly enantioselective synthesis and cellular evaluation of spirooxindoles inspired by natural products

In biology-oriented synthesis the underlying scaffold classes of natural products selected in evolution are used to define biologically relevant starting points in chemical structure space for the synthesis of compound collections with focused structural diversity. Here we describe a highly enantioselective synthesis of natural-product-inspired 3,3′-pyrrolidinyl spirooxindoles—which contain an all-carbon quaternary centre and three tertiary stereocentres. This synthesis takes place by means of an asymmetric Lewis acid-catalysed 1,3-dipolar cycloaddition of an azomethine ylide to a substituted 3-methylene-2-oxindole using 1–3 mol% of a chiral catalyst formed from a N,P-ferrocenyl ligand and CuPF6(CH3CN)4. Cellular evaluation has identified a molecule that arrests mitosis, induces multiple microtubule organizing centres and multipolar spindles, causes chromosome congression defects during mitosis and inhibits tubulin regrowth in cells. Our findings support the concept that compound collections based on natural-product-inspired scaffolds constructed with complex stereochemistry will be a rich source of compounds with diverse bioactivity. A Lewis-acid-catalysed 1,3-dipolar cycloaddition provides rapid access to a variety of substituted spirooxindoles. Initial cellular evaluations supports the view that compound collections based on natural-product-inspired scaffolds constructed with complex stereochemistry, and decorated with assorted substituents, will be a rich source of compounds with diverse bioactivity.

The Pictet-Spengler Reaction in Nature and in Organic Chemistry

Alkaloids are an important class of natural products that are widely distributed in nature and produced by a large variety of organisms. They have a wide spectrum of biological activity and for many years were used in folk medicine. These days, alkaloids also have numerous applications in medicine as therapeutic agents. The importance of these natural products in inspiring drug discovery programs is proven and, therefore, their continued synthesis is of significant interest. The condensation discovered by Pictet and Spengler is the most important method for the synthesis of alkaloid scaffolds. The power of this synthesis method has been convincingly proven in the construction of stereochemicaly and structurally complex alkaloids.

Catalytic enantioselective 1,3-dipolar cycloadditions of azomethine ylides for biology-oriented synthesis

Conspectus Cycloaddition reactions are among the most powerful methods for the synthesis of complex compounds. In particular, the development and application of the 1,3-dipolar cycloaddition, an important member of this reaction class, has grown immensely due to its powerful ability to efficiently build various five-membered heterocycles. Azomethine ylides are commonly used as dipoles for the synthesis of the pyrrolidine scaffold, which is an important motif in natural products, pharmaceuticals, and biological probes. The reaction between azomethine ylides and cyclic dipolarophiles allows access to polycyclic products with considerable complexity. The extensive application of the 1,3-dipolar cycloaddition is based on the fact that the desired products can be obtained with high yield in a regio- and stereocontrolled manner. The most attractive feature of the 1,3-dipolar cycloaddition of azomethine ylides is the possibility to generate pyrrolidines with multiple stereocenters in a single step. The development of enantioselective cycloadditions became a subject of intensive and impressive studies in recent years. Among many modes of stereoinduction, the application of chiral metal–ligand complexes has emerged as the most viable option for control of enantioselectivity. In chemical biology research based on the principle of biology-oriented synthesis (BIOS), compound collections are prepared inspired by natural product scaffolds. In BIOS, biological relevance is employed as the key criterion to generate hypotheses for the design and synthesis of focused compound libraries. In particular, the underlying scaffolds of natural product classes provide inspiration for BIOS because they define the areas of chemical space explored by nature, and therefore, they can be regarded as “privileged”. The scaffolds of natural products are frequently complex and rich in stereocenters, which necessitates the development of efficient enantioselective methodologies. This Account highlights examples, mostly from our work, of the application of 1,3-dipolar cycloaddition reactions of azomethine ylides for the catalytic enantioselective synthesis of complex products. We successfully applied the 1,3-dipolar cycloaddition in the synthesis of spiro-compounds such as spirooxindoles, for kinetic resolution of racemic compounds in the synthesis of an iridoid inspired compound collection and in the synthesis of a nitrogen-bridged bicyclic tropane scaffold by application of 1,3-fused azomethine ylides. Furthermore, we performed the synthesis of complex molecules with eight stereocenters using tandem cycloadditions. In a programmable sequential double cycloaddition, we demonstrated the synthesis of both enantiomers of complex products by simple changes in the order of addition of chemicals. Complex products were obtained using enantioselective higher order [6 + 3] cycloaddition of azomethine ylides with fulvenes followed by Diels–Alder reaction. The bioactivity of these compound collections is also discussed.

Metal-free cross-dehydrogenative coupling of heterocycles with aldehydes.

The direct transformation of nonfunctionalized C H bonds into C C bonds is a fundamental challenge in organic chemistry and offers substantial benefits. The synthetic method to generate C C bonds directly from two different C H bonds under oxidative conditions, termed cross-dehydrogenative coupling (CDC), represents the state-of-art in C C bond-forming reactions. 2] Such a coupling allows the use of simple nonfunctionalized substrates, thus making syntheses shorter and more efficient. Two issues with CDC methods are low reactivity and selectivity, owing to the highenergy of dissociation and the ubiquity of C H bonds in organic molecules, respectively. The development of new and efficient CDC reactions is a fundamental and important challenge in organic synthesis. Nitrogen-containing heterocycles are abundant in nature and have extensive applications in chemistry and biology. Numerous methods for the de novo synthesis of electrondeficient heterocycles have been described, but their functionalization by cross-dehydrogenative coupling is far less studied. In contrast to the acylation of electron-rich aromatic compounds (Friedel–Crafts reaction), very few methods are available for the acylation of electron-deficient heterocycles. Among these methods, the addition of nucleophilic acyl radicals to electron-deficient heterocyclic aromatic bases, that is, the Minisci reaction, is a commonly used approach. But, this reaction has been underutilized because of harsh reaction conditions, such as heating in the presence of peroxy compounds and metals. Additional reported issues include low site selectivity, incomplete conversion of starting materials, limited substrate scope, and the use of metals in up to stoichiometric amounts. Direct acylation of heterocycles with aldehydes is difficult owing to the electron-deficient nature of both partners, and because the products of radical acylation can be more susceptible to radical attack than the starting material. Based on previous reported acylations, we hypothesized that the generation of nucleophilic acyl radicals under mild reaction conditions could be key to eliminating the difficulties in direct acylations. 5] Herein, we describe an unprecedented metal-free, cross-dehydrogenative coupling of heterocycles with aldehydes at ambient temperature. Furthermore, this method was used for the synthesis of natural products in one step. In connection to our continued interest in developing efficient metal-free C H functionalization strategies, we decided to investigate the use of hypervalent iodine reagents for the direct acylation of N-heterocycles with aldehydes. Initially, we evaluated numerous reaction conditions for the direct coupling of isoquinoline (1a) and benzaldehyde (2a). To our delight, the cross-coupling occurred in presence of (bis(trifluoroacetoxy)iodo)benzene (PhI(OCOCF3)2) and sodium azide at ambient temperature in ethylacetate to form product 3 a in 47 % yield (Table 1, entry 1). Notably, functionalization of isoquinoline (1a) occurred selectively at the C1-position to give only one regioisomer of 3a. Product 3a was not formed in the absence of either PhI(OCOCF3)2 or NaN3. A variety of polar and nonpolar solvents were successfully employed (Table 1, entries 1-4 and the Supporting Information). The best yield (52 % of 3a) was achieved for the reaction with benzene as the solvent. Next, we examined the influence of various oxidants in the cross-dehydrogenative coupling (Table 1, entries 4–11). A number of other hypervalent iodine based oxidants were screened, and only the use of Koser s reagent and (bis(trifluoroacetoxy)iodo)pentafluorobenzene (Table 1, entries 7 and 8) provided product 3a, although in lower yield than with PhI(OCOCF3)2. Other oxidizing agents, such as tBuOOH and mCPBA, did not promote the desired transformation (Table 1, entries 9–11, and Supporting Information). With PhI(OCOCF3)2 as the obvious choice of oxidant, we tested different additives. Changing the additive from NaN3 to TMSN3 resulted in a dramatic rise of the yield to 90% (Table 1, entry 12). The use of other sources of azide and iodine did not lead to formation of the product (Table 1, entries 13–15). With the optimized oxidant and additive established, we looked into the relative ratio of reactants (Table 1, entries 16–21 and Supporting Information). Decreasing the amount of aldehyde from 4 equivalents to 3 and 1.5 equivalents led to a drop in yield to 70% and 26 %, respectively, and lowering the amount of oxidant and/or additive to 1 equivalent did not prove beneficial. Equipped with a set of optimized conditions (Table 1, entry 16), we explored the scope of this cross-coupling reaction by investigating the reaction between isoquinoline (1a) and various aldehydes (Scheme 1). The scope turned out to be very broad, and various aliphatic, aromatic and heteroaromatic aldehydes, including those with electron[*] Dr. K. Matcha, Dr. A. P. Antonchick Max-Planck-Institut f r Molekulare Physiologie Abteilung Chemische Biologie Otto-Hahn-Strasse 11, 44227 Dortmund (Germany) E-mail: andrey.antonchick@mpi-dortmund.mpg.de

The therapeutic potential of phosphatase inhibitors

Protein phosphatases (PPs) constitute a large family of enzymes, which are crucial modulators of cellular phosphorylation events. Malfunction in PP activity has been associated with human diseases, including diabetes, obesity, cancer, and neurodegenerative and autoimmune disorders, and makes this class of enzymes attractive targets for chemical biology and medicinal chemistry research. A number of strategies are currently explored for the identification and development of various classes of PP modulators and have resulted in a plethora of chemically distinct inhibitors. Limited selectivity and adverse pharmacological properties of PP inhibitors are still major bottlenecks for further clinical development and resulted in only a few molecular entities currently in clinical trials.

Organocatalytic, Oxidative, Intermolecular Amination and Hydrazination of Simple Arenes at Ambient Temperature

New atom-economical, environmental friendly, direct oxidative intermolecular processes of amination and hydrazination of nonprefunctionalized arenes were developed. The products were formed in a good regioselective manner under organocatalytic conditions at ambient temperature.

Brønsted-Acid-Catalyzed Activation of Nitroalkanes: A Direct Enantioselective Aza-Henry Reaction

A direct asymmetric organocatalytic aza-Henry reaction has been developed in which a new bifunctional Brønsted-acid-catalyzed activation of nitroalkanes provides an efficient access to alpha,beta-diamino acids with high dia- and enantioselectivities under mild and base-free reaction conditions.

A Highly Enantioselective Brønsted Acid Catalyzed Reaction Cascade

Enantioselective domino reactions have emerged as powerful methods for the rapid synthesis and construction of complex target molecules starting from simple and readily available precursors. Asymmetric organocatalytic cascade reactions represent an important and promising area in organic synthesis, providing direct access to enantioenriched compounds under mild and environmentally friendly reaction conditions. Generally these organocascades are based on biomimetic principles, and often aminocatalytic activation is the key for successful execution. Over the past few years Brønsted acid catalysts, including chiral phosphoric acids, have been applied in asymmetric synthesis, whereby the chiral phosphate counterion formed as a intermediate induces high enantioselectivities. As part of our studies we have recently demonstrated that chiral Brønsted acids can serve as powerful catalysts for the enantioselective activation of imines and carbonyl functionalities. Here we report a new asymmetric organocatalytic cascade reaction in which multiple steps are catalyzed by a chiral Brønsted acid catalyst and which provides valuable tetrahydropyridines and azadecalinones with high enantioselectivities [Eq. (1)].

Asymmetric Synthesis of Indolines by Catalytic Enantioselective Reduction of 3H-Indoles

A highly enantioselective metal-free reduction of 3H-indoles has been developed. This Brønsted acid catalyzed transfer hydrogenation of indole derivatives with Hantzsch dihydropyridine as the hydrogen source constitutes an efficient method for the synthesis of various optically active indolines with high enantioselectivities.

A framework for identification of actionable cancer genome dependencies in small cell lung cancer

Small cell lung cancer (SCLC) accounts for about 15% of all lung cancers. The prognosis of SCLC patients is devastating and no biologically targeted therapeutics are active in this tumor type. To develop a framework for development of specific SCLC-targeted drugs we conducted a combined genomic and pharmacological vulnerability screen in SCLC cell lines. We show that SCLC cell lines capture the genomic landscape of primary SCLC tumors and provide genetic predictors for activity of clinically relevant inhibitors by screening 267 compounds across 44 of these cell lines. We show Aurora kinase inhibitors are effective in SCLC cell lines bearing MYC amplification, which occur in 3–7% of SCLC patients. In MYC-amplified SCLC cells Aurora kinase inhibition associates with G2/M-arrest, inactivation of PI3-kinase (PI3K) signaling, and induction of apoptosis. Aurora dependency in SCLC primarily involved Aurora B, required its kinase activity, and was independent of depletion of cytoplasmic levels of MYC. Our study suggests that a fraction of SCLC patients may benefit from therapeutic inhibition of Aurora B. Thus, thorough chemical and genomic exploration of SCLC cell lines may provide starting points for further development of rational targeted therapeutic intervention in this deadly tumor type.