Gerhard Raabe

Control of four stereocentres in a triple cascade organocatalytic reaction

Efficient and elegant syntheses of complex organic molecules with multiple stereogenic centres continue to be important in both academic and industrial laboratories. In particular, catalytic asymmetric multi-component ‘domino’ reactions, used during total syntheses of natural products and synthetic building blocks, are highly desirable. These reactions avoid time-consuming and costly processes, including the purification of intermediates and steps involving the protection and deprotection of functional groups, and they are environmentally friendly and often proceed with excellent stereoselectivities. Therefore, the design of new catalytic and stereoselective cascade reactions is a continuing challenge at the forefront of synthetic chemistry. In addition, catalytic cascade reactions can be described as biomimetic, as they are reminiscent of tandem reactions that may occur during biosyntheses of complex natural products. Here we report the development of an asymmetric organocatalytic triple cascade reaction for the synthesis of tetra-substituted cyclohexene carbaldehydes. This three-component domino reaction proceeds by way of a catalysed Michael/Michael/aldol condensation sequence affording the products with good to moderate yields (25–58 per cent). During this sequence, four stereogenic centres are formed with high diastereoselectivity and complete enantioselectivity. In addition, variation of the starting materials can be used to obtain diverse polyfunctional cyclohexene derivatives, which can be used as building blocks in organic synthesis.

N-heterocyclic carbene catalysed asymmetric cross-benzoin reactions of heteroaromatic aldehydes with trifluoromethyl ketones

A new triazolium salt derived N-heterocyclic carbene catalyses an asymmetric cross-benzoin-type reaction of heteroaromatic aldehydes and various trifluoromethyl ketones in good to excellent yields (69-96%) and moderate to good enantioselectivities (ee = 39-85%). Up to 99% ee can be achieved by recrystallisation.

Merging Organocatalysis and Gold Catalysis: Enantioselective Synthesis of Tetracyclic Indole Derivatives through a Sequential Double Friedel–Crafts Type Reaction

Annulated indoles, fused at the C2and C3-position, are chemically and biologically interesting as key structural motifs in many natural products and as pharmaceutically active substances. Furthermore, annulated, tetracyclic indoles containing a seven-membered ring, such as in 1 (Scheme 1), have shown anticancer activities on leukemia and colon cell lines, as well as antiproliferative activities through DNA intercalation. However, accessing such seven-membered-ring-containing polycycles is synthetically challenging owing to the preferential six-membered-ring formation in the cyclisation step. The reactivities of the indole C3and C2-position, as well as the indole nitrogen, provide many opportunities to access enantiopure, annulated indole derivatives. This can be achieved, for example, with an intramolecular Friedel–Crafts type reaction or an aza-Michael addition of the indolic nitrogen on a suitable acceptor. While reports on the enantioselective synthesis of polycyclic indoles using various catalytic activation modes, especially in the fields of organocatalysis and gold catalysis, are numerous, most of such synthetic strategies required substrates containing a prefunctionalised indole, either on the C3or the C2-position (Scheme 1). In view of limited precedence for the synthesis of annulated indoles from C3,C2-unsubstituted indoles 2, we hypothesised that chiral, polycyclic indoles could be accessed enantioselectively through a single-pot tandem operation. To the best of our knowledge, an enantioselective variant of such a transformation is not yet known. Moreover, we envisioned that the recent surge in utilising one-pot, multicatalytic, tandem reactions combining distinct organocatalytic and transition-metal cycles could be used as a viable strategy to obtain enantiopure, annulated indoles. This emerging area has also spurred some efforts in utilising indole as a key substrate in enantioselective, sequential reactions. In our synthetic planning, we were interested in combining both organocatalysis and gold catalysis, especially the latter to access nonconventional molecular frameworks through domino and rearrangement reactions. It is worth noting that the pioneering studies on gold catalysis by Echavarren et al. and Zhang et al., as well as very recent reports, allowed complex functionalisations of indole substrates containing an intramolecular tethered alkyne. We now wish to report an efficient and highly enantioselective one-pot, multicatalytic, C2/C3-annulation of indoles, giving rise to tetracyclic, seven-membered-ring-containing derivatives 1. The new protocol utilises the bifunctional ortho-alkyne-substituted nitrostyrenes 3 as substrates, allowing two sequential Friedel–Crafts type reactions. The nitroalkene moiety is activated through hydrogen-bonding organocatalysis, to incorporate the stereochemical information in the first Friedel–Crafts reaction,and the alkyne functionality provides access to gold catalysis and its alkynophilicity, to effect the second Friedel–Crafts/ring expansion cascade. [a] C. C. J. Loh, J. Badorrek, Prof. Dr. G. Raabe, Prof. Dr. D. Enders Institute of Organic Chemistry RWTH Aachen University Landoltweg 1, 52074 Aachen (Germany) Fax: (+49) 241-809-2127 E-mail : enders@rwth-aachen.de Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201102793. Scheme 1. Strategy comparison between current work and known methods.

Enantioselective Organocatalytic Synthesis of Quaternary α-Amino Acids Bearing a CF3 Moiety

A highly enantioselective Friedel-Crafts reaction catalyzed by a chiral phosphoric acid was developed. N-Boc-protected ethyl trifluoropyruvate imine was activated by 6 mol % of catalyst and reacted with a wide variety of indole derivatives to afford quaternary α-amino acids in excellent yields (up to 99%) and high enantioselectivities (up to 98:2 er).

Synthesis of iridium complexes with novel planar chiral chelating imidazolylidene ligands

Abstract New planar chiral imidazolium salts such as ( S p )-1-[4-(4,4-dimethyl-4,5-dihydrooxazolyl)[2.2]paracyclophane-12-ylmethyl]-3-methyl imidazolium bromide ( S p )- 8a have been synthesized starting from enantiopure 4,12-dibromo[2.2]paracyclophane ( S p )- 4 . Deprotonation of these salts followed by reaction with [Ir(COD)Cl] 2 yielded chelating iridium imidazolylidene complexes 9a – c , which were applied in asymmetric hydrogenations of alkenes. The solid state structure of ( S p )- 9c was determined by single-crystal X-ray structure analysis.

Streocontrolled Construction of Six Vicinal Stereogenic Centers on Spiropyrazolones via Organocascade Michael/Michael/1,2-Addition Reactions

A highly stereoselective one-pot procedure for the synthesis of spiropyrazolone derivatives bearing six contiguous stereogenic centers including two tetrasubstituted carbons has been developed. Under sequential catalysis by two organocatalysts, a cinchona-derived aminosquaramide and DBU, a series of diversely functionalized spiropyrazolones are obtained in good yields (47-62%) and excellent stereoselectivities (up to >25:1 dr and 98-99% ee). The opposite enantiomers of the spiropyrazolones are also accessible by employing a pseudoenantiomeric aminosquaramide catalyst.

A Branched Domino Reaction: Asymmetric Organocatalytic Two‐Component Four‐Step Synthesis of Polyfunctionalized Cyclohexene Derivatives

Traditionally, domino reactions are defined as processes of two or more bond-forming reactions, in which the subsequent transformation takes place at the functionalities obtained in the former transformation under identical reaction conditions. 2] In linear domino reactions, the progress of the former step will always affect that of the next steps (Figure 1a). Among the domino/cascade reactions, organocata-

C1-Symmetric Aminosulfoximines in Copper-Catalyzed Asymmetric Vinylogous Mukaiyama Aldol Reactions

Vinylogous Mukaiyama-type aldol reactions have been catalyzed by a combination of Cu(OTf)2 and readily available C1-symmetric aminosulfoximines. After a fine-tuning of the reaction conditions and an optimization of the modularly assembled ligand structure, high stereoselectivities and excellent yields have been achieved in catalyzed reactions involving various electrophile/nucleophile combinations. The relative and absolute configurations of two products were assigned by X-ray single crystal structure analysis and a comparison of calculated and experimental CD spectra.

Regioselective palladation of 2-oxazolinyl-[2.2]paracyclophanes.: Synthesis of planar-chiral phosphines

Abstract Palladations of the diastereomeric 4-(4- tert -butyl-2-oxazolinyl)-[2.2]paracyclophanes ( S , R p )- 3 and ( S , S p )- 3 have been investigated. Exclusive ortho -palladation occurs, when ( S , R p )- 3 is treated with Pd(OAc) 2 in glacial acetic acid. In contrast, ( S , S p )- 3 affords products from either metallation in the ortho or the benzylic position of the [2.2]paracyclophane skeleton depending on the reaction conditions. Upon treatment of the resulting complexes with LiCl followed by addition of PPh 3 mononuclear chloro{4-(2-oxazolinyl)-[2.2]paracyclophane,5- C ,3- N }(triphenylphosphine)palladium(II) complexes ( S , S p )- 7 , ( S , R p )- 7 , and ( S , S p )- 9 have been obtained. The solid state structures of ( S , S p )- 7 and ( S , R p )- 7 have been determined by X-ray diffraction analysis. Reaction of ortho -palladated complexes ( S , S p )- 7 and ( S , R p )- 7 with KPPh 2 gives the corresponding planar-chiral phosphines ( S , S p )- 11 and ( S , R p )- 11 , respectively. From benzyl substituted complex ( S , S p )- 9 bromo derivative ( S , S p )- 12 was obtained.

Asymmetric Synthesis of Novel Ferrocenyl Ligands with Planar and Central Chirality

A stereogenic center at the position beta to the metallocene backbone is present in ferrocenyl ligands 2, which are interesting for asymmetric catalysis. These planar-chiral compounds are accessible for the first time by a highly diastereoselective and enantioselective synthesis (de=93-97 %; ee>/=96 %) from the ferrocenyl ketones 1. A variety of donor groups (E(1)=Ph(2)P small middle dotBH(3), SMe, SiPr; E(2)=SMe, STol, SePh, Ph(2)P small middle dotBH(3), iPr(2)P small middle dotBH(3)) can be introduced as electrophiles. Tol=tolyl=CH(3)C(6)H(4).