Silyl ethers, diarylprolinol

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... 

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. 

Diarylprolinol silyl ether catalyst was able to promote enantioselective allqrlations of a,p-unsaturated aldehydes with stabilised carbcations as electrophiles. Dienamine intermediates were trapped by the electrophile in two positions. The y-disubstituted aldehydes were not good substrates for y-substitution. However, linear unbranched and p-substituted a,p-unsaturated aldehydes preferred y-substitution. ot-Substituted aldehydes were unreactive under secondary amine catalysis (Scheme 8.45). 

Scheme 11.45 Organocatalytic asymmetric transformations catalysed by conformationally constrained bicyclic diarylprolinol silyl ethers 44.

Together with the diarylprolinol silyl ethers (Jprgensen-Hayashi catalysts) [54] shown in the first row of Figure 2.3, the chiral imidazolidinones devised by MacMillan are the most usual catalysts for iminium activation. Some representative examples are shown in Figure 2.16. 

FIGURE 2.19. Seebach-Uchimam model for the reactive conformation of diarylprolinol silyl ether iminium cations. 

SCHEME 5.2. Reusable diarylprolinol silyl ether organocatalysts. 

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]. 

Specific protocols based on the use of diarylprolinol silyl ethers as catalysts have been employed in the synthesis of certain molecules of biological interest such as INCB018424 [72] and Maraviroc (UK-427,857) [73]. 

Chiral tetrahydrothiophenes are compounds displaying important biological activities. They were obtained also through an enantioselective domino sulfa-Michael-Michael process of a,(3-unsaturated aldehydes with ethyl 4-mercapto-2-butenoate [47]. While catalyst 17a turned out to be ineffective, the diarylprolinol silyl ether 17b afforded cyclic products with high to excellent enantio- and diastereoselectivity (Scheme 14.16a). A closely related sulfa-Michael aldol process was developed by using 3-mercapto a-carbonyl esters as reaction partners. The best stereoselectivity and yield were obtained with diaryl prolinol 17c in the presence of small amounts of H2O (Scheme 14.16b) [48]. 

SCHEME 14.16. Enantioselective synthesis of tetrahydrothiophenes through cascade processes of a,p-unsaturated aldehydes with 4-mercapto-2-butenoate and 3-mercapto a-carbonyl esters, promoted by diarylprolinol silyl ethers 17b,c. 

Scheme 1.68 Aza-Michael reactions catalysed by diarylprolinol silyl ether.

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). 

Finally, Kim reported the asymmetric conjugate addition of organoboronic acids to y-hydroxy a,p-unsaturated aldehydes catalysed by diarylprolinol silyl ethers, which afforded the corresponding p-substituted y-lactols in good yields. High enantioselectivities of up to 91% ee were obtained in the case of... 

In 2009, a wide range of optically active chromans and tetrahydroquinolines were synthesised by Xiao et al. on the basis of the first enantioselective organo-catalytic intramolecular hydroarylations of phenol- and aniline-derived enals. Good yields combined with good to high enantioselectivities of up to 96% ee were obtained for the Michael adducts generated by catalysis with a diarylprolinol silyl ether (Scheme 1.83). 

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. 

In 2009, a diarylprolinol silyl ether was involved as an organocatalyst in an asymmetric domino aldol-oxa-Michael reaction occurring between salicy-laldehyde and senecialdehyde. As shown in Scheme 2.28, this process generated the corresponding chiral tricyclic systems in good yields and high enantioselectivities of up to 98% ee. One of these products could be further converted into 4-dehydroxydiversonol. 

On the other hand, a diarylprolinol silyl ether salt was demonstrated by Hayashi et al. to be an efficient organocatalyst for the enantioselective Diels-Alder reaction of cyclopentadiene with a,p-unsaturated aldehydes performed in water. Under these solvent-free conditions, the cycloadducts were obtained in high yields with good exo selectivities and excellent enantioselectivities of up to 99% ee (Scheme 6.5). The authors have examined the role of water and demonstrated that it accelerated the reaction and increased the enantioselectivity. 

An A-Boc sulfone derivative has been used for in situ generation of an a-keto imine, which undergoes an asymmetric Mannich reaction, using a diarylprolinol silyl ether (17) as organocatalyst." 0... 

The diarylprolinol silyl ether system was initially applied for the asymmetric a-sulfenylation of aldehydes. Since then, it has proven its usefulness in combination with a large number of heteroatom- and carbon-based electrophiles for asymmetric a-functionalizations of aldehydes (Scheme 2.3) [2, 3, 9]. 

Complementary to the enamine-based reactions, the diarylprolinol silyl ether catalysts can be applied for activation of a,p-unsaturated aldehydes toward conjugate additions through iminium-ion-induced processes. Mechanistically, this conceptually different activation mode draws close parallels to the enamine chemistry (Scheme 2.4) [5]. The secondary aminocatalyst condenses with the enal to form... 

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