Michael addition diarylprolinol ethers

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... 

In particular, as a more challenging nucleophile, acetaldehyde was also suitable for the Michael addition with nitroalkenes. Using diarylprolinol silyl ether 7 as catalyst. List and co-workers [8] and Hayashi et al. [9] independently developed the first organocatalytic Michael reaction of acetaldehyde to afford a-unsubstituted y-nitro aldehydes in moderate to good yields and with excellent enantioselectivities (Scheme 5.3). The synthetic utility of this reaction was illustrated by List and... 

SCHEME 5.12. Michael addition of aldehydes to a,p-unsaturated his(sulfones) catalyzed by diarylprolinol silyl ether. 

Furthermore, the asymmetric PS reaction has been applied as a key step in the cascade reaction to build up chiral polycyclic compounds. In 2009, Dixon and coworkers [71] developed a chiral phosphoric acid 8f-catalyzed cyclization cascade between tryptamines and enol lactones, leading to the products in good yields and with good to excellent enantioselectivities. This was further extended to the reaction of tryptamines and ketoacids, which were more readily available than enol lactones [72]. By using diarylprolinol silyl ether as catalyst, the other cascade transformations involving Michael addition, iminium formation and PS cyclization were also efficiently realized [73]. 

SCHEME 11.18. Enantioselective aza-Michael additions to enals catalyzed by enantiopure diarylprolinol TMS ether 12. 

In 2009, Lin et al. reported an enantioselective synthesis of an important Janus kinase inhibitor, INCBO18424, the key step of which was an asymmetric aza-Michael addition of pyrazoles to an a,p-unsaturated aldehyde catalysed by a chiral diarylprolinol silyl ether. The use of benzoic acid or 4-nitrobenzoic acid as an additive was shown to increase the reaction rate. The highest enantioselectivities of up to 93% ee were observed for the reactions using the more sterically hindered organocatalysts (Scheme 1.68). 

In a same area, an efficient and simple method for the enantioselective synthesis of indolines, isoindolines, tetrahydroquinolines and tetraisoquino-lines was achieved by means of the organocatalytic intramolecular aza-Michael reaction of the corresponding aniline and benzylamine derivatives. " This process was catalysed by a diarylprolinol silyl ether used in the presence of benzoic acid as an additive, which provided the Michael adducts in good yields and excellent enantioselectivities of up to 99% ee (Scheme 1.85). This methodology was applied to the synthesis of the biologically active tetra-hydroquinoline alkaloid (-l-)-angustureine. 

---