Enamines enantioselective reactions

The optically active Schiff bases containing intramolecular hydrogen bonds are of major interest because of their use as ligands for complexes employed as catalysts in enantioselective reactions or model compounds in studies of enzymatic reactions. In the studies of intramolecularly hydrogen bonded Schiff bases, the NMR spectroscopy is widely used and allows detection of the presence of proton transfer equilibrium and determination of the mole fraction of tautomers [21]. Literature gives a few names of tautomers in equilibrium. The OH-tautomer has been also known as OH-, enol- or imine-form, while NH tautomer as NH-, keto-, enamine-, or proton-transferred form. More detail information concerning the application of NMR spectroscopy for investigation of proton transfer equilibrium in Schiff bases is presented in reviews.42-44... 

Enantioselective -Functionalization of Aldehydes and Ketones The direct and enantiosective functionalization of enolates or enolate equivalents with carbon-, nitrogen-, oxygen-, sulfur- or halogen-centered electrophiles represents a powerful transformation of chemical synthesis and of fundamental importance to modem practitioners of asymmetric molecule constmction. Independent studies from List, J0rgensen, Cordova, Hayashi, and MacMiUan have demonstrated the power of enamine catalysis, developing catalytic enantioselective reactions such as... 

Abstract The reversible reaction of primary or secondary amines with enolizable aldehydes or ketones affords nncleophilic intermediates, enamines. With chiral amines, catalytic enantioselective reactions via enamine intermediates become possible. In this review, structure-activity relationships and the scope as well as cnrrent limitations of enamine catalysis are discnssed. 

Momiyama and Yamamoto have recently demonstrated that acid cocatalysts can even influence the outcome of enamine-mediated reactions [63]. In their studies of the acid-catalyzed O- and A-nitroso aldol reaction, they found that the nature of the acid catalyst dictates the regioselectivity of the reaction between preformed enamine species A carboxylic acid catalyst promoted the 0-nitroso aldol reaction whereas a hydrogen bonding catalyst catalyzed the formation of an A-adduct, both in high enantioselectivities(Scheme 10). 

In a first approach to an enantioselective version of this method, we employed19 chiral enamines derived from praline,20 (see 1-3 in Scheme 1). In this stoichiometric, enantioselective reaction, the valuable auxiliary used has to be recovered (i.e., recycled) in preparative-scale applications.21... 

Keywords Aldol, Direct, Ketone, Asymmetric catalysis, Enantioselective reaction, Diastereo-selectivity, 1,2-Diol, Aldehyde, Enamine, Lewis acid, Bronsted base, Organocatalysis, Bimetal-... 

Enantioselective reactions have also been reported for the hydrolysis of enamines containing a chiral amine moiety via protonation or of prochiral enamines by the use of a chiral acid. Other asymmetric reactions are summarized in an excellent review by Seebach and coworkers179 and by Oare and Heathcock193. 

A new diastereoselective and enantioselective synthesis of a-amino-y-oxo acid esters has been reported involving the alkylation of enamines with acyliminoacetates (78). The stereocontrol is attributed to formation of a Diels-Alder like transition state (79). Ring opening of the adduct leads to a zwitterion or alkylated enamine, hydrolysis of which gives the single diastereoisomer (80 de > 96%)174 (Scheme 71). The use of a chiral ester [R = ( + )- or ( —)-menthyl or (—)-8-phenylmenthyl] converted this process into an enantioselective reaction (de and ee 24-67%). Since the reaction proceeds with complete anti-diastereoselectivity the two stereoisomers, enantiomeric at the two new stereogenic centres, could readily be separated by fractional crystallization. The main isomer of 80 (X = CH2), obtained in 80% yield, was shown to have the (l S, 2R)-configuration174. 

An enantioselective aryloxylation of aldehydes is based on their prior conversion to an enamine through reaction with a chiral secondary amine catalyst. A subsequent inverse HDA reaction with o-quinones leads to 3-alkyl-2-hydroxy-l,4-benzodioxins with ee ca. 80% (Scheme 47). Manipulation allows the synthesis of (S)-2-alkyl-2,3-dihydro-l,4-benzodioxins <07TL1605>. In like manner, racemic nitidanin, which possesses antimalarial properties, has been synthesised through a regioselective cycloaddition of an o-quinone with a protected 3-arylpropen-l-ol <07TL771>. 

The enamine geometry 32 is cmcial for the stereocontrol in organocatalytic aldehyde-aldehyde couplings amines of type 31 are convenient catalysts for enantioselective enamine-aldol reactions. Examples are shown in Scheme 24 [126,131,132,133,134,135]. 

Enamine-mediated aldolizations offer much better prospects for a stereo-controlled process. The famous enantioselective proline-catalyzed triketone cyclization to the Wieland-Miescher ketone 43 [56], as well as the chemistry of type I aldolase enzymes [57],provide ample precedents for stereo- and enantioselective enamine-mediated reactions. 

The story of the development of the lab-scale reaction into a 1000 ton per year process has been told in several reviews, and detailed information on the mechanism of the reaction has been published previously. The initially formed enamine (12.02) is converted into citronellal (12.03) by hydrolysis, with subsequent cyclisation to isopulegol (12.04) and reduction to menthol (12.05). The whole process is performed by Takasago International Corporation, and represents the biggest application (so far) of an enantioselective reaction catalysed by a transition metal complex. Interestingly, the alternative geometry of starting material (the (Z)-isomer) affords the opposite enantiomer of product. 

Heterofunctionalisation of carbonyl compounds in the a-position has become an important facet of oiganocatalytic enamine-mediated reactions. In 2005, the Jorgensen group described asymmetric a-sulfenylation of aliphatic aldehydes using TMS-protected prolinol catalysts. The best sulfenylating agent was M-benzylsulfanyl-1,2,4-triazole. Other catalysts, such as proline, prolinol, prolinamide or other secondary amide were less effective. The catalyst with bulkier aromatic groups (C2a) afforded the most enantioselective reaction (Scheme 8.39). 

Chen and co-workers [72] reported an asymmetric quadruple amino catalytic domino reaction catalyzed by secondary amines. The reaction consists of a quadruple iminium-enamine-iminium-enamine cascade reaction initiated by a Michael addition of oxindole 114 to the enal and a subsequent intramolecular Michael reaction between the enamine formed in the previous step and the unsaturated oxindole to yield intermediate 116. Next, this intermediate reacts with another molecule of enal via a Michael addition of the oxindole to the enal. The sequence ends with an intramolecular aldol reaction between the preformed enamine and the aldehyde. This organocascade reaction affords highly complex spirooxindoles 118 bearing six contiguous chiral centers in excellent yields and with excellent diastereo- and enantioselectivities (Scheme 10.31). 

Further appUcations of this catalyst class as Br0nsted acids were shown by Maruoka and coworkers in various enantioselective reactions, such as addition of aza-enamines and vinylogous aza-enamines to imines (178,179), addition of diazo compounds to in situ generated acyclic azomethine imines (Scheme 10.72) [180], and 1,3-dipolar cydoaddition reactions of cyclic azomethine imines with enol ethers and vinylogous aza-enamines (Scheme 10.73) (181). 

In 2000, List and co-workers reported on the asymmetric aldol reaction catalyzed with proUne (Scheme 8.47). The reaction of acetone 291 with 4-nitrobenzaldehyde 292 was promoted by using proUne 280 (30mol%) at room temperature to give aldol adduct 294 in good yield and ee. In contrast, Northmp and MacMillan found that proline catalyzed the direct and enantioselective reaction of aldehydes (Scheme 8.48). Substituted aldehyde 295 was converted into enamine 296, which reacted with the other aldehyde to give anti adduct 298 stereoselectively. Enamine... 

On using enamine activation, nucleophiles were limited to aldehydes and ketones but the emergence of H-bonding activation [31] has expanded considerably this scope. With this mode of activation other carbon-centered nucleophiles and also heteroatom-centered nucleophiles could be considered. During the period 2003-2012, growing interest was focused on the ability to perform catalytic enantioselective reactions with small organic molecules able to produce such weak interactions. 

Reactions with Active Methylene Compounds. Enolates of ketones," esters," enediolates," 1,3-dicarbonyl compounds," amides and lactams," as well as nitrile-stabilized carbanions," can be alkylated with benzyl bromide. Cyclohexanone may be benzylated in 92% ee using a chiral amide base." Amide bases as well as alkoxides have been employed in the case of nitrile alkylations." Benzylation of metalloenamines may be achieved and enantioselective reactions are possible using a chiral imine (eq 3). However, reactions between benzyl bromide and enamines proceed in low yield. The benzylation of a ketone via its enol silyl ether, promoted by fluoride, has been observed. ... 

Diastereoselective and enantioselective [3C+2S] carbocyclisations have been recently developed by Barluenga et al. by the reaction of tungsten alkenylcarbene complexes and enamines derived from chiral amines. Interestingly, the regio-chemistry of the final products is different for enamines derived from aldehydes and those derived from ketones. The use of chiral non-racemic enamines allows the asymmetric synthesis of substituted cyclopentenone derivatives [77] (Scheme 30). 

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