Aldehydes enantioselective organocatalytic

L2909>. An organocatalytic addition of 2-trimethylsilyloxyfuran to aldehydes using 10 mol% of l,3-bis(3-(trifluoromethyl)phenyl)urea provided adducts with modest threo selectivity <06TL8507>. A syn-selective, enantioselective, organocatalytic vinylogous Mukaiyama-Michael addition of 2-trimethylsilyloxyfuran to (E)-3-... 

An enantioselective organocatalytic 1,3-DC reaction, based on the activation of a,fi-unsaturated aldehydes through the reversible formation of iminium ions with chiral imidazolidinones 100, was described. Good levels of asymmetric induction and diastereocontrol were achieved (up to 94% ee and 94 6 dr) <00JA9874>. 

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). 

The first report of an enantioselective organocatalytic [3+2] cycloaddition between nitrones and a,P-nnsaturated aldehydes was reported by MacMillan and co-workers who showed that iminium ion activation was effective in this reaction (Scheme 8) [64], After a survey of seven catalysts the imidazolidinonium salt 12 HC10 emerged as the most efficient system. The reactions were conducted in a mixture of nitromethane and water at -20 °C in the presence of 20 mol% catalyst... 

A key step in the total synthesis of the marine metabolite (—)-solanopyrone D (161) is the enantioselective organocatalytic intramolecular Diels-Alder reaction of the trienal (158) to the decalin aldehyde (160) in the presence of the imidazolidinone catalyst (159) (Scheme 45).187 Protonated 1,2-diamino-1,2-diphenylethane has been... 

Enantioselective organocatalytic (with tetrahydro-4//-imidazol-4-one-based catalysts of type 102nHX) 2-alkylation of pyrroles by, -unsaturated aldehydes generates 3-(pyrrol-2-yl) aldehydes 103 (Scheme 46) <2001JA4370, 2002JA1172, 200SJA1S0S1 and references therein>. 

Beeson TD, MacMillan DWC (2005) Enantioselective organocatalytic alpha-fluorination of aldehydes. J Am Chem Soc 127 8826-8828 Berkessel A, Groger H (2005) Asymmetric organocatalysis. Wiley-VCH, Weinheim... 

Brochu MP, Brown SP, MacMillan DWC (2004) Direct and enantioselective organocatalytic alpha-chlorination of aldehydes. J Am Chem Soc 126 4108-4109... 

Itoh T, Nagata K, Miyazaki M, Ishikawa H, Kurihara A, Ohsawa A (2004) A selective reductive amination of aldehydes by the use of Hantzsch dihydropy-ridines as reductant. Tetrahedron 60 6649-6655 Jen WS, Wiener JJM, MacMillan DWC (2000) New strategies for organic catalysis The first enantioselective organocatalytic 1,3-dipolar cycloaddition. J Am Chem Soc 122 9874-9875... 

Kunz RK, MacMillan DWC (2005) Enantioselective organocatalytic cyclopro-panations. The identification of a new class of iminium catalyst based upon directed electrostatic activation. J Am Chem Soc 127 3240-3241 Lacour J, Hebbe-Viton V (2003) Recent developments in chiral anion mediated asymmetric chemistry. Chem Soc Rev 32 373-382 Li X, List B (2007) Catalytic asymmetric hydrogenation of aldehydes. Chem Commun 17 1739-1741... 

Paras NA, MacMillan DWC (2002) The enantioselective organocatalytic 1,4-addition of electron-rich benzenes to alpha,beta-unsaturated aldehydes. J Am Chem Soc 124 7894-7895... 

Peelen TJ, Chi Y, Gellman SH (2005) Enantioselective organocatalytic Michael additions of aldehydes to enones with imidazolidinones cocatalyst effects and evidence for an enamine intermediate. J Am Chem Soc 127 11598— 11599... 

Enantioselective organocatalytic conjugate addition of benzo[A] furan-2-boronic acid to ap-unsaturated aldehydes was utilized to synthesize 2-substituted benzo[Z>]furan with a chiral side chain as illustrated below <07JA15438>. Asymmetric syntheses of 2,2-disubstituted dihydrobcnzo b furans were also achieved by a palladium(II)-catalyzed cyclization of 2-allylphenols in the presence of chiral bisoxazolines <07TL4083 07TL4179>. 

The first enantioselective organocatalytic 1,3-dipolar cycloaddition of acyclic nitrones with acrolein and crotonal-dehyde has been reported <2000JA9874>. In particular, the reversible formation of iminium ions from a,/3-unsatu-rated aldehydes and the enantiopure imidazolidinone 535 provided ( A-4-formylisoxazolidines in high yields and ees (Equation 86). A polymer-supported version of catalyst 535 was also prepared <2004EJ0567>. The catalytic performance of various chiral pyrrolidinium salts in the cycloaddition of 1-cycloalkene-l-carboxaldehydes was also evaluated <2003EJO2782>. 

The triple Michael/Michael/aldol sequence developed by Enders shown in Scheme 7.8 can probably be considered as one of the most impressive demonstrations of the ability and power of enantioselective organocatalytic cascade reactions for the generation of molecular complexity from very simple and cheap starting materials." In this reaction, a nitroalkene, an enolizable aldehyde and an a,p-unsaturated aldehyde reacted with each other in the... 

The constrained tricyclic chiral secondary amine 43 was proposed hy Loh et al. in 2011 for the highly enantioselective organocatalytic Michael addition of aliphatic aldehydes to vinyl sulfones (Scheme 11.44). DFT calculations revealed that only 42-derived sy -enamine is formed due to steric congestions and that the naphthyl ring is puckered in the chiral pocket of the tricyclic system, efficiently shielding only one of the diastereotopic faces of the reactive enamine. ... 

One of the most interesting developments in recent years is the non-enzy-matic, enantioselective, organocatalytic addition of hydrogen cyanide to aldehydes. This reaction is, for example, very efficiently catalysed by optically pure diketopiperazines, such as cydo-(f )-Phe-(i )-His), which are readily accessible from the corresponding amino acids. [114-116]... 

In 2005, MacMillan reported an enantioselective organocatalytic intramolecular Diels-Alder reaction (IMDA) of a,p-unsaturated aldehyde and diene, as well as the application in the asymmetric synthesis of solanapyrone D (6), Scheme 3.1 [5]. Later, Danishefsky and Christmann individually reported the total synthesis of UCS1025A (9) by coupling reaction with MacMillan aldehyde (8) [6]. The malim-ide analogue 10 of the telomerase inhibitor UCS1025A (9) was also prepared by Christmann et al. by modified MacMillan s conditions (10 mol% catalyst loading in nitromethane, affording 74% yield and >99% ee after a sequence of recrystallization and oxidation). Scheme 3.2 [7]. 

In 2000, MacMillan and his co-workers presented the first enantioselective organocatalytic 1,3-dipolar cycloaddition of nitrones 187 and a,p-unsaturated aldehydes 28 (dipolarphiles) to afford the e do-(45)-isoxazolidine adducts 188, Scheme 3.59 [75]. With the LUMO-lowering activation of a,p-unsaturated aldehydes 28 and enforced formation of (fi)-iminium isomer, the HClO -salt of catalyst 30 effectively promote cycloaddition of the dipolarphile. In addition, e do-cycloaddition effectively alleviated nonbonding interaction between the nitrone phenyl group and the neopentyl methyl substituent on the catalyst framework. Later, in 2002, Karlsson and Hbgberg reported the organocatalytic enantioselective 1,3-dipolar cycloaddition of... 

Scheme 3.67 Enantioselective organocatalytic [3+2] reaction between 2-acylaminomalonates and a, 3-unsaturated aldehydes...

Enantioselective organocatalytic a-chlorination of aldehydes, via enamine catalysis, was independently reported by the groups of MacMillan and Jprgensen in 2004 (Scheme 13.20) [46, 47]. MacMillan utilized his imidazolidinone catalyst and a perchlorinated quinone as the chlorine source, to obtain the S-enantiomer of the a-chloroaldehyde products. Jprgensen employed NCS as the chlorine source, and either a prolinamide catalyst to access the / -enantiomer of the a-chloroaldehyde products, or a Ci-symmetric amine catalyst to access the 5-enantiomer. A recyclable fluorous pyrrolidine-thiourea bifunctional organocatalyst was later employed as an enamine catalyst in this transformation [48]. 

Zu L, Xie H, Li H, Wang H, Wang W (2007) Highly Enantioselective Organocatalytic Conjugate Addition of Nitromethane to a,P-Unsaturated Aldehydes Three-Step Synthesis of Optically Active Baclofen. Adv Synth Catal 349 2660... 

Hong BC, Wu MF, Tseng HC, Liao JH (2006) Enantioselective Organocatalytic Formal [3-l-3]-Cycloaddition of a,P-Unsaturated Aldehydes and Application to the Asymmetric Synthesis of (-)-Isopulegol Hydrate and (-)-Cubebaol. Org Lett 8 2217... 

Brown SP, Brochu MP, Sinz CJ, MacMillan DWC (2003) The Direct and Enantioselective Organocatalytic a-Oxidation of Aldehydes. J Am Chem Soc 125 10808... 

Peelen TJ, Chi YG, Gelhnan SH (2005) Enantioselective Organocatalytic Micltae/ Additions of Aldehydes to Enones with Imidazolidinones Cocatalyst Effects and Evidence for an Enamine Intermediate. J Am Chem Soc 127 11598... 

Gong and coworkers reported the first enantioselective organocatalytic Biginelli reaction (Scheme 9.8) [44]. Thus, chiral phosphoric acid 29 efficiently activated the process between an aldehyde 10, a thiourea 24 or urea 11,... 

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