Malonate enantioselective 1,4-addition

Simple bis(oxazoline) ligands, especially azabis(oxazolines), can catalyse the addition of indoles to benzylidene malonates in up to 99% ee, provided that excess of the chiral ligand is avoided.166 The paradigm followed in many asymmetric catalytic reactions that an excess of the chiral ligand with respect to the metal should improve enantioselectivity because the background reaction catalysed by a free metal is suppressed, was shown not to be applicable here,166 which might call for revisiting some of the many copper(II)-bis(oxazoline)-catalysed processes known. Enantioselective additions of pyrroles and indoles to ,/9-unsaturated 2-acylimidazoles catalysed by the bis(oxazolinyl)pyridine-scandium(III) triflate complex have been accomplished.167... 

The catalytic enantioselective addition of aromatic C - H bonds to alkenes would provide a simple and attractive method for the formation of optically active aryl substituted compounds from easily available starting materials. The first catalytic, highly enantioselective Michael addition of indoles was reported by Jorgensen and coworkers. The reactions used a,fl-unsaturated a-ketoesters and alkylidene malonates as Michael acceptors catalyzed by the chiral bisoxazoline (BOX)-metal(II) complexes as described in Scheme 27 [98,99]. 

The push toward enantiomerically-pure carbocyclic intermediates has led to the development of new methods for the enantiodifferentiation of inexpensive prochiral cyclic starting materials. For instance, Robert H. Morris of the University of Toronto recently reported (Organic Lett. 2005, 7, 1757) that a family of enantiomerically-pure Ru complexes originally developed for asymmetric transfer hydrogenation also mediate the enantioselective addition of malonate to cyclohexenone. 

The most common nucleophiles employed in the allylic alkylation are soft species such as malonate esters. However, Trost and Schroeder have discovered that high ees can be achieved in the addition of cyclic lithium enolates using ligand (10.54) with one equivalent of trimethyltin chloride, which may act to soften the nucleophilic species by transmetaUation to the tin enolate. Enantioselective additions of nonstabilised ketone enolates can also be achieved using an alternate palladium-catalysed decarboxylation protocol. In this approach an allyl 3-ketoester (10.72) or allyl vinyl carbonate (10.73) undergoes decarboxylation in the presence of Pd(0) to... 

The enantioselective addition of carbon nucleophiles to a,p-unsaturated carbonyls is one of the most studied organic reactions. The diamine catalyst, (S)-l-(2-pyrrolidinylmethyl)pyrrolidine la is effective for conjugate additions. The addition of cyclic ketones to allgrlidene malonate and frans-p-nitroslyrene was demonstrated (Scheme 9.11). Comparable stereochemical results were obtained when the reaction was catalysed by (S)-proline. 

Li, H. Wang, Y. Tang, L. Deng, L. Highly Enantioselective Addition of Malonate and 3-Ketoester to Nitroalkenes Asymmetric C-C Bond Formation with New Bifunctional Organic Catalysts Based on Chinchona Alkaloids. /. Am. Chem. Soc. 2004,126, 9906-9907. 

Schaus et al. employed (15a) as a catalyst for the enantioselective addition of stabilized nucleophiles such as nitroethane and malonates to N-acyl aldimines [109]. P-Nitroamines were obtained in good yields with 90-97% enantioselectivities and up to 97% diastereoselectivities (Scheme 2.53). 

Takemoto and coworkers [32] elaborated bifunctional catalyst 27, which was found, after this initial report, to be highly versatile in promoting a large variety of transformations. The combination of a thiourea and a tertiary amine separated by a chiral scaffold, (R,l )-l,2-cyclohexyldiamine, was studied to build a new type of organocatalyst. Aminothiourea 27 was first examined as catalyst for the enantioselective addition of malonate to nitroaUcenes (Scheme 34.5). The thiourea moiety of catalyst 27 guides and activates the nitroolefin while the tertiary amine part deprotonates the malonate. 

The utilization of copper complexes (47) based on bisisoxazolines allows various silyl enol ethers to be added to aldehydes and ketones which possess an adjacent heteroatom e.g. pyruvate esters. An example is shown is Scheme 43[126]. C2-Symmetric Cu(II) complexes have also been used as chiral Lewis acids for the catalysis of enantioselective Michael additions of silylketene acetals to alkylidene malonates[127]. 

When cyclic enones were used as Michael acceptors, both malonates and acetoacetates gave impressive yields and enantioselectivities of the desired Michael addition products (Scheme 5.2Q) NMR spectra and single-crystal X-ray data supported the following ruthenium intermediate (Scheme 5.21) and transition state (Figure 5.8). 

Highly enantioselective organocatalytic Mannich reactions of aldehydes and ketones have been extensively stndied with chiral secondary amine catalysts. These secondary amines employ chiral prolines, pyrrolidines, and imidazoles to generate a highly active enamine or imininm intermediate species [44], Cinchona alkaloids were previonsly shown to be active catalysts in malonate additions. The conjngate addition of malonates and other 1,3-dicarbonyls to imines, however, is relatively nnexplored. Snbseqnently, Schans et al. [45] employed the nse of Cinchona alkaloids in the conjngate addition of P-ketoesters to iV-acyl aldimines. Highly enantioselective mnltifnnctional secondary amine prodncts were obtained with 10 mol% cinchonine (Scheme 5). 

Dicarbonyl donors bearing a thioester has been applied in the Mannich reaction to A -tosyl imines. Ricci presented an enantioselective decarboxylative addition of malonic half thioester 37 to imine 38. In the Mannich-type addition, catalyst 36 deprotonates the malonic acid thioester followed by decarboxylation to generate a stabilized thioacetate enolate. This stabilized anion reacts with facial selectivity to the imine due to steric-tuning from 36 [47] (Scheme 8). 

The scope of electrophiles was explored with malonates and p-ketoesters, providing chiral amine adducts in high yield and enantioselectivities (Scheme 57) [109]. Addition of cyclic P-ketoesters was also explored with hydrazines, providing cyclic and bicyclic chiral amines with quaternary centers in high enantiomeric ratios (Scheme 58). 

Tan and co-workers reported the Michael reactions of di-thiomalonates and P-keto-thioesters to a range of acceptors, including maleimides, cyclic enones, furanones and acyclic dioxobutenes [129]. Unlike dimethyl malonate, additions with acidic thioesters proceeded in higher yields, and overall better enantioselectivities (Scheme 74). 

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