CATALYTIC CASCADE REACTIONS

Advanced Synthesis & Catalysis

-unsaturated aldehydes have been traditionally used in LUMO lowering asymmetric aminocatalysis (iminium catalysis), while the use of saturated aldehydes as substrates in this type of catalysis has been elusive, until recently. Herein, we demonstrate that organic, single-electron oxidants in the presence of diarylprolinol silylether type catalysts serve as effective tools for the transformation of electron rich enamines to iminium ions which partake in a subsequent Diels-Alder reaction. This enantioselective one-pot transformation represents the first example of saturated aldehydes being used in domino Diels-Alder reaction processes and demonstrates the power of this protocol for construction of stereo-defined chiral compounds and building blocks.

ChemCatChem, 2015

New Opportunities in Enantioselective Organocatalysis A revelation: Enamine activation of abranched b-ketocarbonyl compounds is actually possible, very efficient, and highly enantioselective with a bifunctional primary amine/tertiary ammonium triflate salt catalyst. This covalent HOMO activation mode competes with existing strategies for the enantioselective activation of b-ketocarbonyls and their analogues. E = Electrophile; X = CH 2 , O, NR; OTf= Triflate.

Tetrahedron, 1998

The reactions of a series of enamines generated from a range of cyclic ketones with chloromethyl and iodomethyl vinyl ketone have been studied. The principal products are bridged ring diketones. The four carbon bridge, bearing a 2-oxobutyl function, spans the α and α′ carbons of the original cyclanone. Presumptive evidence as to the pathway of this novel one step bridging annulation is provided.Reaction of enamines (cf. 1) with iodomethylvinylketone Box 106, New York, N.Y. 10021, USA and cThe (cf. 15) commences with Michael addition and culminates Department of Chemistry, Butler University, 4600 Sunset in a one step α,α′-annulation leading to a bridged product Avenue, Indianapolis, IA 46208. (cf. 11).

Angewandte Chemie International Edition, 2006

The Journal of Organic Chemistry, 2007

Nineteen chiral amines and their derivatives were prepared and investigated as organocatalytic Lewis bases in the R-amination of ethyl R-phenyl-R-cyanoacetate. For comparison purposes, a few natural products were also examined as catalysts in this study. Among the results obtained, (R)-N-benzyl-N-(1-phenylethyl)-amine and (R,R)-N,N′-bis(1-phenylethyl)-propane-1,3-diamine as the catalysts afforded the amination products in excellent yields and with up to 84% ee. By contrast, under comparable conditions the two derivatives of natural products (DHQ) 2 PYR and (DHQD) 2 PYR provided the product of amination with lower than 10% enantiomeric excess.

Angewandte Chemie International Edition, 2013

Domino and cascade reactions that give access to multiple CÀ C bonds and multiple contiguous stereocenters with high chemo-and stereoselectivity are important for chemical synthesis and are performed in nature by multi-enzymatic pathways. [1] Cascade reactions enable the synthesis of complex molecules in a minimal number of synthetic steps and with lower amounts of waste and solvents (green chemistry). [2] Catalytic asymmetric cascade transformations are most commonly catalyzed by single metal complexes. However, recently the use of organic catalysts has resulted in important advances in this research field. The concept of using a transition metal catalyst together with a metal-free catalyst in one flask ("organo/metal cooperative catalysis") is gaining increasing interest. [6][7] The reactivity and advantages of both metal and organic catalyst systems are combined and thereby can result in unique reactivity. However, this research field is still in its infancy with challenges such as incompatibility between the transition metal and organocatalyst (e.g. catalyst inhibition and different optimal reaction conditions). In 2006, we disclosed the merging of transition metal and aminocatalysis for the aallylic alkylation of aldehydes. [6a] Since disclosure of this synergistic catalysis strategy there has been increasing number of reports on the development of the concept of organo/metal cooperative catalysis. [6][7] The construction of quaternary carbon stereocenters with high enantioselectivity is important and challenging goal in organic synthesis. In this context, new methods for the catalytic construction of polysubstituted carbocycles with contiguous stereocenters, including an all-carbon stereocen-ter, are desirable but difficult to achieve. Based on our previous research on organo/metal cooperative catalysis, [6] we envisioned a novel dynamic catalytic asymmetric Michael/aallylic alkylation cascade reaction between compounds 1 and enals 2 mediated by a combination of Pd and chiral amine 5 catalysts (Scheme 1). Thus, initial reversible conjugate addition via an iminium intermediate I would give the corresponding enamine intermediate II, which upon hydrolysis would provide Michael adduct 3. This process is reversible, however, oxidative addition of the Pd catalyst to intermediate II would generate p-allyl intermediate III, ready for intramolecular nucleophilic stereoselective attack by its enamine moiety. Subsequent CÀC bond formation, hydrolysis, and protonation would deliver polysubstituted carbocycles 4 as well as regenerate the amine and Pd catalysts. However, there are a few main challenges to address. For example, chemoselectivity issues, as substrates 1 could undergo a Pd-catalyzed intermolecular Tsuji-Trost reaction, polymerization, or Nalkylation with amine 5 instead of the desired pathway. We also know from our previous research that the Pd/amine cocatalyzed conjugate additions can deliver racemic Michael products. [6g-i] Thus, the reaction via enamine intermediate II has to occur at a higher rate compared to the that via IIa. Moreover, the equilibration between ent-3 and 3 (racemization) must be faster than the carbocyclization for this reaction to become a dynamic kinetic transformation (DYKAT). If no racemization occurred, the overall process would have a maximum theoretical yield of 50 % (kinetic resolution). With respect to the construction of carbocycles 4 (E ¼ 6 E 1 ), the cascade transformation is also complex and difficult to control as Michael adducts (3 having 2 stereocenters) are formed as four stereoisomers. Herein, we disclose a novel highly enantioselective dynamic Michael/a-allylic alkylation cascade transformation that gives polysubstituted cyclopentanes and cyclohexanes, which have a quaternary carbon stereocenter, in high yields with excellent enantiomeric ratios (99.5:0.5! 99:0.5 e.r.).

Angewandte Chemie International Edition, 2008

Control of relative and absolute stereochemistry with stepeconomy [1, 2] presents a continuing challenge in organic synthesis. [3] Asymmetric crossed aldols have historically involved chiral auxiliaries or O-trapped organometallic intermediates; the latter operate by either a Zimmerman-Traxler or an open transition-state model. [4] However, auxiliaries lengthen syntheses, and organometallics typically require careful control of reaction conditions and have limited functional-group tolerance. Enamines, however, predominantly react at the Cterminus, and generally deliver products under ambient reaction conditions. [3] The C 2-symmetric trans-2,5-dimethylpyrrolidine reagent is used in asymmetric enamine reactions. However, it suffers from poor efficacy and is scarce. Although several asymmetric syntheses exist for the preparation of this reagent, [5] its limited commercial availability suggests that these lengthy protocols have not impacted supply. [6] This problem has been somewhat alleviated by prolinederived organocatalysts, which have been under intense investigation in recent years and discussed in reports from the groups of Yamamoto [7] and Miller. [8] Reactions of supported (both hetero-and homogeneous) [9] and nonsupported [10] organocatalysts have been reviewed. When applied to aldol condensations, heterogeneous supported organocatalysts often require high catalyst loading [11] and long reaction times, [12] while delivering varied enantioselectivities. [11-13] Non-supported organocatalysts often require extended reaction times, [14] have strict solvent requirements, [15] and produce variable yields. [16]

Synlett, 2011

Angewandte Chemie International Edition, 2009

In the past decade, asymmetric aminocatalysis has become a fundamental synthetic strategy for the stereoselective construction of chiral molecules. The extraordinary pace of innovation and progress in aminocatalysis has been dictated mainly by the discovery of distinct catalytic activation modes which have enabled previously inaccessible transformations. To the same extent, the design of novel structural classes of organic catalysts has also ignited the field, enabling the activation of challenging types of carbonyl substrates. Whereas chiral secondary amines have proven invaluable for the asymmetric functionalization of aldehydes, primary amine catalysis has offered the unique possibility of participating in processes between sterically demanding partners. Therefore it overcomes the inherent difficulties of chiral secondary amines in generating congested covalent intermediates. Chiral primary amine based catalysts have been successfully used for the enamine activation of challenging substrates, such as a,a-disubstituted aldehydes and ketones. In 2005, Ishihara and Nakano [6a] additionally extended the potential of chiral primary amines to include the iminium ion activation of a-acyloxy-acroleins toward a stereoselective Diels-Alder process. [6] However, the use of a,b-disubstituted unsaturated aldehydes still represents an elusive and fundamental target for asymmetric aminocatalysis. This is particularly true when considering that an alternative asymmetric metal-catalyzed strategy for the functionalization of this compound class is also lacking. Herein we show that the chiral primary amine catalyst 1 provides an efficient solution to this longstanding and sought after issue, activating a,b-disubstituted enals toward a welldefined iminium/enamine tandem sequence (Scheme 1). Specifically, we developed organocascade reactions which combine two intermolecular and stereoselective steps involving a Michael addition/amination pathway. The described olefin aryl-amination and thio-amination processes afford straightforward access to valuable precursors of a-amino acids which have two adjacent stereogenic centers, one of which is quaternary, with very high optical purity.

Tetrahedron Letters, 2007