Diarylprolinols

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). 

The [3+2] cycloaddition has also been shown to be effective in the reaction of azomethine imines 32 with a,P-unsaturated aldehydes by Chen and co-workers [70], A survey of seven catalysts revealed some interesting trends, with the diarylprolinol derivative 31 giving the highest yields and selectivities (40-95% yield endo. exo 1 4.3-1 49 77-96% ee for exo) with short reaction times (5-24 h) and low catalyst loading (10 mol%) (Scheme 11). The reaction was particularly sensitive to the amount of water present in the reaction medium and the choice of co-acid. This phenomenon is a reoccurring theme in many of the publications in the area of iminium ion catalysis and, as yet, no general explanation has been proposed to account for these observations. 

A final class of dipole shown to be effective in iminium ion catalysed [3+2] cycloadditions are azomethine ylides derived from 35 [71] (Scheme 12). Vicario showed that 20 mol% of diarylprolinol 33 catalysed the cycloaddition between a,P-unsaturated aldehydes 34 and imines 35 (THE, 4 °C, 72 h) to give the densely... 

An unexpected and potentially useful mode of reactivity was observed in the reaction of cinnamaldehyde and cyclopentadiene catalysed by diarylprolinol silyl ether 39 [73]. Rather than observing a Diels-Alder adduct, the products resulting from an ene reaction were isolated in excellent yield. The transformation was found to be general for a series of P-aryl acroleins (40) with routinely excellent levels of... 

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...

J0rgensen [111] and Vicario [112] independently described the conjugate addition of both triazole and tetrazole based nucleophiles to a,P-unsaturated aldehyde substrates as an alternative method for C-N bond formation. These reactions were catalysed by the diarylprolinol and imidazolidinone scaffolds with equal efficiency showing the complementarity and efficacy of both these catalyst architectures. In addition, Jprgensen has also shown succinimide to be an effective Michael donor (see Sect. 2.3.5 Scheme 49 for further details) [113]. 

However, formation of this bond through the conjugate addition of a soft sulfur nucleophile to a,P-unsaturated aldehydes is efficiently catalysed using iminium ion catalysis [116], Using diarylprolinol silyl ether 55 the addition of a series of sulfur based nucleophiles to a variety of a,P-unsaturated aldehydes was shown to be effective (73-87% yield 89-97% ee). The products were isolated as their p-hydroxy sulfide derivatives 73 after in situ reduction of the products (Scheme 33). 

Simultaneous publication of the iminium ion catalysed hydrophosphination of a,p-unsaturated aldehydes by Melchiorre and Cordova showed diarylprolinol silyl ether 55 was effective in the conjugate addition of diphenylphosphine 74 [117, 118], Direct transformation of the products allowed for one-pot methods for the preparation of P-phosphine alcohols 75 (72-85% yield 90-98% ee), P-phosphine oxide acids 76 (65% yield 92% ee) and 3-amino phosphines 77 (71% yield 87% ee) (Scheme 34). These reports represent the first examples of the addition of P-centred nucleophiles and the resulting highly functionalised products may well have further use in asymmetric catalysis. 

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. 

It is worth noting that use of unprotected diarylprolinol 33 provides an effective platform for the epoxidation of a,P-unsaturated ketones [148, 149]. Within these reports it was proposed that an alternative mode of activation of the substrate could be taking place. Hydrogen bonding catalysis, rather than iminium ion formation, could explain the results and would be consistent with the non-polar reaction medium adopted within these reactions. 

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). 

A new class of chiral 4-A,A-dialkylaminopyridine acyl-transfer catalysts has been developed that are capable of exploiting both van der Waals (jt) and H-bonding interactions to allow remote chiral information to control stereochemically the kinetic resolutions of secondary alcohols with moderate to excellent selectivity (S = 6-30). Catalysts derived from (.S )- , -diarylprolinol (89 Ar = Ph, 2-naphthyl) in combination with isobutyric anhydride were found to possess high activity and selectivity across a broad range of substrates 89... 

A simple route to 1,2-diols by organocatalytic enantioselective a-oxidation of aldehydes with singlet molecular oxygen, catalysed by protected diarylprolinols, has been reported. The oxidation produced (/-hydroxy ketones, which are reduced with boro-hydride to the diols. The 1,2-diols were isolated in high yields with up to 98% ee. The oxidant was photo or chemically generated 102.242... 

The first highly regio-, chemo-, diastereo-, and enantio-selective vinylogous Michael addition of oqa-dicyanoalkenes to oq/S-unsaturated aldehydes employs salts of a,a-diarylprolinol (103) (20 mol%) as organocatalysts. The reaction presumably involves the formation of an iminium species from the aldehyde as the first step of the cascade.153... 

Diphenylprolinol (4) itself is now commercially available at scale, or it can be prepared several ways (Scheme 16.2) Direct addition of an aryl Grignard reagent to a proline ester leads to the diarylprolinol with a low yield in the range of 20-25%.33 A more efficient route is based on an... 

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). ... 

The Michael-type addition of thiols to a,p-unsaturated aldehydes has been reported to proceed very efficiently using O-TMS protected diarylprolinol 31c as catalyst (Scheme 3.32). The low configurational stability of the adducts at r.t. led the authors to modify the reaction conditions, which finally involved carrying out the reaction at -24 °C and reducing the adducts in situ, furnishing the corresponding y-thio alcohols in excellent yields and enantioselectivities. Both alkyl- and aryl-substituted enals could be used as suitable Michael... 

Finally, diarylprolinol 48c has also been employed as catalyst in the enantioselective p-peroxydation of nitroalkenes with tert-butyl hydroperoxide (Scheme 4.65). The catalyst is proposed to engage in a bifunctional activation mode, which on one hand assists the deprotonation of the hydroperoxide and on the other activates the nitroalkene by the formation of one H-bond with the nitro group. Under the optimized conditions, moderate yields and enan-tioselectivities around 85% ee were achieved for a variety of nitrostyrene derivatives. 

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