René Peters

Enantioselective Bimetallic Catalysis of Michael Additions Forming Quaternary Stereocenters

Direct conjugate additions of a-carbonyl-stabilized nucleophiles to activated olefins are among the most attractive reactions for C C bond constructions owing to their ideal atom economy and the versatility of the activating functional groups involved. For catalytic asymmetric versions, a high level of efficiency has been demonstrated with 1,3-dicarbonylbased nucleophiles. In contrast, the realization of a general, practical, highly active, and highly enantioselective catalyst for the conjugate addition of a-cyanoacetates to enones remains elusive. This might be explained by the fact that acyanoacetates are incapable of two-point binding to a Lewis acid. In this study we were particularly interested in the direct Michael addition of trisubstituted a-cyanoacetates to enones, in light of the demand for efficient catalytic asymmetric C C bond-forming methods that create substituted quaternary stereocenters and thus provide access to broadly useful multifunctional chiral building blocks. Enolate formation by deprotonation of trisubstituted acyanoacetates with a Brønsted base such as a tertiary amine can trigger the conjugate addition to enones, but the basic conditions might also induce various side reactions with basesensitive functionalities. To obtain synthetically useful enantioselectivities and yields, low-temperature reaction techniques, high catalyst loadings, and extended reaction times are usually required. In their seminal study in 1992, Ito and coworkers reported that a Rh complex bearing a trans-chelating diphosphine ligand is able to catalyze the addition of acyanopropionate to vinyl ketones with high enantioselectivity in the absence of a base. Unfortunately, a substituents bulkier than Me impeded valuable enantioselectivities. Subsequently, Richards et al. found that Pd–pincer complexes also promote the same reaction utilizing iPr2NEt as cocatalyst, but with low enantioselectivity. With a sterically demanding Pd–pincer complex, Uozumi et al. later achieved good enantioselectivity under similar reaction conditions yet found the same limitation with a-Me substituents. A conceptually different approach was developed by Jacobsen et al., who employed a dimeric O-bridged Al–salen complex. In contrast to the soft Lewis acid catalysts, this catalyst tolerated an a-phenyl-substituted a-cyanoacetate. The application of a variety of a-aryland a-amino-substituted acyanoacetates was described for the addition to a,b-unsaturated imides without the necessity of an additional base. The use of unsubstituted vinyl acceptors was not mentioned in this study. Herein we report the application of the bispalladacycle complex FBIP-Cl which exploits the principal advantages of soft Lewis acids like high catalytic activity as a consequence of low oxophilicity, resulting in negligible product inhibition, and overcomes the narrow structural restrictions for the previously reported late-transition-metal catalysts. The rationale behind this development was that a soft bimetallic complex capable of simultaneously activating both substrates would not only lead to superior catalytic activity, but also to an enhanced level of stereocontrol as a result of the highly organized transition state: the a-cyanoacetate should be activated by enolization promoted by coordination of the nitrile moiety to one Pd center, while the enone should be activated as an electrophile by coordination of the olefinic double bond to the carbophilic Lewis acid. Cooperative reactivity between two metal centers has been suggested for enzymatic systems and is emerging as an intriguing design principle for artificial catalysts. Bispalladacycle FBIP-OTs, which was generated in situ from FBIP-Cl by treatment with AgOTs, was indeed able to smoothly catalyze the addition of a-phenyl-substituted cyanoacetate 1Aa (R = Me) to methyl vinyl ketone (MVK) (precatalyst loading 0.5 mol%), albeit with poor enantioselectivity (Table 1, entry 1). 15] The enantioselectivity was considerably increased by use of bulky ester groups, though at the expense the reaction rate (Table 1, entries 2 and 4; initial reaction rates at c = 0.20 mol L : 1Ab : 40.6 mmol L 1 h ; 1Ad : 18.4 mmol L 1 h ). To increase the reactivity of the tertbutyl ester 1 Ad, various solvents were screened. The reaction medium was found to have a strong influence: the enantioselectivity decreased in all solvents tested relative to the selectivity in CH2Cl2, while a significantly enhanced reaction rate was noticed in cyclohexane, Et2O, diglyme, and EtOH (Table 1, entries 7, 8, 11, and 13). Whereas in the protic solvent EtOH, nearly racemic product was formed, the reaction in in diglyme showed promising selectivity, which [*] S. Jautze, Prof. Dr. R. Peters Laboratory of Organic Chemistry, ETH Z rich Wolfgang-Pauli-Strasse 10, H nggerberg HCI E 111 8093 Z rich (Switzerland)

Bispalladacycle-Catalyzed Brønsted Acid/Base-Promoted Asymmetric Tandem Azlactone Formation−Michael Addition

Cooperative activation by a soft bimetallic catalyst, a hard Brønsted acid, and a hard Brønsted base has allowed the formation of highly enantioenriched, diastereomerically pure masked alpha-amino acids with adjacent quaternary and tertiary stereocenters in a single reaction starting from racemic N-benzoylated amino acids. The products can, for example, be used to prepare bicyclic dipeptides.

The Asymmetric Aza‐Claisen Rearrangement: Development of Widely Applicable Pentaphenylferrocenyl Palladacycle Catalysts

Systematic studies have been performed to develop highly efficient catalysts for the asymmetric aza-Claisen rearrangement of trihaloacetimidates. Herein, we describe the stepwise development of these catalyst systems involving four different catalyst generations finally resulting in the development of a planar chiral pentaphenylferrocenyl oxazoline palladacycle. This complex is more reactive and has a broader substrate tolerance than all previously known catalyst systems for asymmetric aza-Claisen rearrangements. Our investigations also reveal that subtle changes can have a big impact on the activity. With the enhanced catalyst activity, the asymmetric aza-Claisen rearrangement has a very broad scope: the methodology not only allows the formation of highly enantioenriched primary allylic amines, but also secondary and tertiary amines; allylic amines with N-substituted quaternary stereocenters are conveniently accessible as well. The reaction conditions tolerate many important functional groups, thus providing stereoselective access to valuable functionalized building blocks, for example, for the synthesis of unnatural amino acids. Our results suggest that face-selective olefin coordination is the enantioselectivity-determining step, which is almost exclusively controlled by the element of planar chirality.

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).

Catalytic Asymmetric Synthesis of β‐Sultams as Precursors for Taurine Derivatives

Beta-sultams, biologically interesting sulfonyl analogues of beta-lactams, have been prepared by an organocatalytic asymmetric formal [2+2]-cycloaddition approach of non-nucleophilic imines with alkyl sulfonyl chlorides. In the case of very electron poor N-tosyl imines derived from chloral or ethylglyoxylate, this reaction type was catalyzed by cinchona alkaloids providing the heterocycles in high yield, with good diastereoselectivity and up to 94% ee. Mechanistic investigations suggested that the product formation proceeded via a zwitterionic imine-catalyst adduct. The scope was significantly extended by 2-pyridylsulfonyl imines derived from non-activated aromatic aldehydes employing Yb(OTf)3 as Lewis acid cocatalyst. The synthetic value of the strained enantioenriched beta-sultams was demonstrated by smooth nucleophilic ring opening reactions with O-, N- and C-nucleophiles yielding a variety of acyclic beta-aminosulfonyl (taurine) derivatives (sulfonates, sulfonamides, sulfones) without racemization or epimerization.

Bispalladacycle-Catalyzed Michael Addition of In Situ Formed Azlactones to Enones

The development and further evolution of the first catalytic asymmetric conjugate additions of azlactones as activated amino acid derivatives to enones is described. Whereas the first-generation approach started from isolated azlactones, in the second-generation approach the azlactones could be generated in situ starting from racemic N-benzoylated amino acids. The third evolution stage could make use of racemic unprotected α-amino acids to directly form highly enantioenriched and diastereomerically pure masked quaternary amino acid products bearing an additional tertiary stereocenter. The step-economic transformations were accomplished by cooperative activation by using a robust planar chiral bis-Pd catalyst, a Brønsted acid (HOAc or BzOH; Ac=acetyl, Bz=benzoyl), and a Brønsted base (NaOAc). In particular the second- and third-generation approaches provide a rapid and divergent access to biologically interesting unnatural quaternary amino acid derivatives from inexpensive bulk chemicals. In that way highly enantioenriched acyclic α-amino acids, α-alkyl proline, and α-alkyl pyroglutamic acid derivatives could be prepared in diastereomerically pure form. In addition, a unique way is presented to prepare diastereomerically pure bicyclic dipeptides in just two steps from unprotected tertiary α-amino acids.

Paramagnetic Palladacycles with PdIII Centers Are Highly Active Catalysts for Asymmetric Aza-Claisen Rearrangements

A combination of spectroscopic and electrochemical methods--XANES, EXAFS, X-ray, (1)H NMR, EPR, Mössbauer, and cyclic voltammetry--demonstrate that the most efficient Pd catalysts for the asymmetric rearrangement of allylic trifluoroacetimidates unexpectedly possess in the activated oxidized form a Pd(III) center bound to a ferrocene core which remains unchanged (Fe(II)) during the oxidative activation. These are the first recognized Pd(III) complexes acting as enantioselective catalysts.

Asymmetric Michael additions of α-cyanoacetates by soft Lewis acid/hard Brønsted acid catalysis: stereodivergency with bi- vs. monometallic catalysts

The direct asymmetric conjugate addition of α-cyanoacetates to enones generating densely functionalized α-amino acid precursors with adjacent quaternary and tertiary stereocenters is described comparing mono- and bis-palladacycle catalysts. This edge article features the complementary value of mono- and bimetallic catalysis in a case study using related catalyst systems. Different major diastereomers of the 1,4-addition products are formed by the use of the planar chiral mono- and bimetallic catalyst systems and provide access to epimeric amino acid derivatives. Both catalyst types require the use of a Bronsted acid (HOAc) as a co-catalyst to avoid an undesired β-hydride elimination. Kinetic studies show that the C–C bond forming step takes place almost instantaneously with the bis-palladium complex after productive substrate coordination. This extraordinarily high reactivity for an elementary step generating a sterically demanding linkage of a quaternary and a tertiary stereocenter stresses the cooperativity of both metal centers.

Asymmetric Synthesis of Novel Ferrocenyl Ligands with Planar and Central Chirality and Their Application to Pd‐Catalyzed Allylic Substitutions

An efficient and flexible asymmetric synthesis of planar chiral ferrocenyl ligands bearing a stereogenic centre at the β-position to the metallocene backbone is described. A variety of donor groups can be independently introduced as electrophiles, thus allowing electronic and steric fine-tuning of the ligands, which were investigated in Pd-catalyzed enantioselective allylic substitutions. By employing a P,S ligand, the alkylation of the standard test system (±)-1,3-diphenyl-2-propenyl acetate using dimethyl malonate/BSA as the nucleophile proceeded in a quantitative yield with an ee of 97%, which is the best value reported so far in this reaction for a P∪S ligand.

Catalytic Asymmetric Formation of δ‐Lactones from Unsaturated Acyl Halides

Previously unexplored enantiopure zwitterionic ammonium dienolates have been utilized in this work as reactive intermediates that act as diene components in hetero-Diels-Alder reactions (HDAs) with aldehydes to produce optically active delta-lactones, subunits of numerous bioactive products. The dienolates were generated in situ from E/Z mixtures of alpha,beta-unsaturated acid chlorides by use of a nucleophilic quinidine derivative and Sn(OTf)(2) as co-catalyst. The latter component was not directly involved in the cycloaddition step with aldehydes and simply facilitated the formation of the reactive dienolate species. The scope of the cycloaddition was considerably improved by use of a complex formed from Er(OTf)(3) and a simple commercially available norephedrine-derived ligand that tolerated a broad range of aromatic and heteroaromatic aldehydes for a cooperative bifunctional Lewis-acid-/Lewis-base-catalyzed reaction, providing alpha,beta-unsaturated delta-lactones with excellent enantioselectivities. Mechanistic studies confirmed the formation of the dienolate intermediates for both catalytic systems. The active Er(III) complex is most likely a monomeric species. Interestingly, all lanthanides can catalyze the title reaction, but the efficiency in terms of yield and enantioselectivity depends directly on the radius of the Ln(III) ion. Similarly, use of the pseudolanthanides Sc(III) and Y(III) also resulted in product formation, whereas the larger La(III) and other transition metal salts, as well as main group metal salts, proved to be inefficient. In addition, various synthetic transformations of 6-CCl(3)- or 4-silyl-substituted alpha,beta-unsaturated delta-lactones, giving access to a number of valuable delta-lactone building blocks, were investigated.