Ethers diarylprolinol

Type B enamine catalysts have been developed more recently. They include the diarylprolinol ethers (developed by the Hayashi and Jprgensen groups, e.g. 47 and its derivatives) [71-75] as well as the MacMillan imidazolidinone catalysts (e.g. 46) [76-78]. They excel in reactions where hydrogen bonding assistance is either not required or is not essential, such as a-halogenation reactions as well as some conjugate addition reactions (Scheme 12). 

Rueping has further developed this theme by showing that diarylprolinol ether 55 efficiently catalyses the addition of hydroxyquinones to a variety of a,P-unsatu-rated aldehydes as a method for the preparation of both 1,4- and 1,2-naphthoquinones with remarkable levels of enantioselectivity [98],... 

A synthetically more challenging C-H acid that represents a method for the glyoxylation of a,P-unsaturated aldehydes is aminonitrile 62 [104], Conjugate addition of 62 catalysed by diarylprolinol ether 30 (20 mol%) provides adducts 63. Reduction, protection and hydrolysis of these adducts leads to the glyoxylates 64 showing the impressive functional group tolerance of these transformations (Scheme 26). 

Scheme 31 Direct preparation of 5-hydroxyisoxazolidines using diarylprolinol ether 30...

Cordova has also shown hydrogen peroxide to be an effective oxidant in the epoxidation of a,P-unsatnrated aldehydes using diarylprolinol ether 30 as the catalyst (Fig. 9) [146, 147], Within these reports it was also shown that the resulting epoxy aldehydes could be used directly in either Wittig or Mannich reactions, providing synthetically useful one-pot protocols to prepare densely functionalised building blocks for further elaboration. 

Aziridines represent an important class of building block within synthesis. This structural motif is also embedded within a number of biologically significant natural products, and thus robust and efficient methods for their construction represent an important contribution to the synthetic toolkit. Cordova reported an enantiose-lective aziridination of a,P-unsaturated aldehydes catalysed by diarylprolinol ether 30 using protected hydroxylamine 91 as the nitrogen source (Scheme 38) [150]. The reaction was proposed to proceed via iminium ion formation followed by... 

Diarylprolinol ether 30 has also been used to accelerate the cyclopropanation of a,p-unsaturated aldehydes with arsonium ylides with excellent levels of asymmetric induction (95-98% ee) [157]. 

Using diarylprolinol ether 55 in conjunction with an additional base, a domino Michael/aldol/intramolecular Sj 2 process has been developed that led to highly functionalised epoxy cyclohexanones 110, with excellent control of three of the chiral centres generated (Scheme 42) [169]. Despite the apparent complexity, these reactions proceed at room temperature in less than 24 h and the products contain significant potential for a host of further transformations. 

J0rgensen has also reported a sequential Michael/Michael/aldol condensation for the three component coupling of malonitrile 111 and a,P-unsaturated aldehydes that involves two iminium ion catalysed Michael additions followed by an intramolecular aldol condensation (Scheme 43) [170]. Using diarylprolinol ether 55 (10 mol%) in a concentrated toluene solution of malonitrile 111 and 3 equivalents of a,P-unsaturated aldehyde the reaction products can be isolated in just 1 8 h (57-89% yield 97-99% ee). The atom efficiency of this three component reaction is remarkable and the ability to prepare these complex products under... 

Wang identified a series of Michael/Michael and Michael/aldol sequences catalysed by diarylprolinol ethers that led directly to densely functionalised five-mem-bered rings [172-174]. For example, highly diastereoselective and enantioselective double Michael addition reactions were achieved by treatment of a,p-unsaturated aldehydes with triester 113 catalysed by 30 (Scheme 45). Initial conjugate addition... 

Jprgensen reported the first catalytic asymmetric diamination procedure using an iminium ion/enamine method [113]. Treatment of an oc,P-unsaturated aldehyde with succinimide 122 in the presence of diarylprolinol ether 55 (10 mol%) gave the conjugate... 

An interesting alternative intramolecular cyclisation was discovered by Jprgensen and co-workers [187]. Although not strictly exploiting an enamine intermediate, the transformation represents a secondary amine catalysed Morita-Baylis-Hillman reaction leading to a series of highly functionalised cyclohexene products. Reaction of the Nazarov reagent 137 with a,P-unsaturated aldehydes in the presence of the diarylprolinol ether 30 led to the cyclohexene products 138 (49-68% yield 86-96% ee) via a tandem Michael/Morita-Baylis-Hillman reaction (Scheme 54). 

The organocatalytic, diastereo- and enantioselective Michael-Knoeve-nagel domino one-pot reaction of ethyl 4-diethoxyphosphoryl-3-oxobu-tanoate (374) with a, S-unsaturated aldehydes, catalyzed by diarylprolinol ether (375) towards highly functionalized optically active 6-substituted-3-diethoxyphosphoryl-2-oxocyclohex-3-enecarboxylates (376), have been reported by Jorgensen and co-workers (Scheme 86). ... 

Seebach, Gilmour, Ebert, and co-workers [83] have proposed a general stereochemical model to rationalize additions to a,(3-unsaturated aldehydes catalyzed either by diarylprolinol ethers or by imidazohdinones. In this model, the ( )-iminium ion intermediates are assumed to react with nucleophiles faster than the (Z)-isomers, so that the stereochemical outcome of the reaction is independent of the ( ) (Z) ratio in solution. The less stable (Z)-iminium isomers are shown to be kineticaUy favoured. The higher reactivity of the ( )-iuiinium ion is explained by the degree of steric repulsion developing between the aldehyde (3-substituent and the large substituent on the... 

Wang elegantly demonstrated the potentiality of chiral diarylprolinol ether 54 in the synthesis of chromanes 56 via enantioselective Michael-type Friedel-Crafts alkylation/cychzation cascade synthetic sequence between 5a and a,p-unsaturated aldehydes 37a [30a]. Under optimal conditions, moderate diastereoselectivity and high enantioselectivity were obtained. Differently, phenol was found unreactive (Scheme 5.17a). The same team years later documented also the activity of a rosin-derived tertiary amine-thiourea 55 in similar process involving 1- and 2-naphthols and P,y-unsaturated a-ketoesters 25 (Scheme 5.17b) [30b]. A proposed model of the enantiodiscrimi-nating step of the reaction is also provided by the authors (58). 

Another diarylprolinol ether has been used to catalyse several asymmetric domino Michael reactions. Therefore, Jorgensen et al. have demonstrated its efficiency for the asymmetric synthesis of 1,4-dihydropyridines, which are closely related to the NADH system, a biological system of utmost importance, and moreover these molecules are important drugs used in the treatment of a number of diseases, such as cardiovascular diseases and Alzheimer s disease. Thus, a series of chiral 1,4-dihydropyridines were prepared on the basis of a one-pot multicomponent reaction between a a,p-unsaturated aldehyde, a P-diketone... 

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