P,y-unsaturated a-ketoesters

The excellent chemoselectivity achieved with catalyst 153r may be attributed to its steric properties the bulky 3,3 -silyl substituents (R = SiPhj) ensure an effective shielding of the carbonyl group and thus prevent 1,2-addition. In the presence of catalyst 153r (5 mol%), the reaction of A-methylindoles 151 and p,y-unsaturated a-ketoesters 152 furnished the 1,4-addition products 155 in moderate to good yields and enantioselectivities (43-88%, 80-92% ee) (Scheme 64). 

SELECTIVE REDUCTION OF CARBONYL GROUP IN p,y-UNSATURATED a-KETOESTERS BY TRANSFER HYDROGENATION WITH Ru(P-CYMENE)(TsDPEN)... 

The HDA reaction between chiral P-substituted A-vinyl-1,3-oxazolklin-2-ones and p,y-unsaturated a-ketoesters shows both high endo and facial selectivity. However, the stereochemistry of the resulting dihydropyrans is controlled by the choice of Lewis acid catalyst (Scheme 9) <07OL211>. 

Enol ethers have often been used as the olefinic component in inverse electron demand Diels Alder reactions. De Meijere and co-workers reported a novel approach to the synthesis of racemic 2-deoxy-z rz2Z,z o-hexopyranoside skeleton by a pressure-promoted hetero-Diels Alder reaction between the cyclopropa-nated enol ether 61 and p,Y-unsaturated a-ketoesters 62 (Scheme 7.14). 

Scheme 4.56 Enantioselective conjugate Friedel-Crafts reaction of indoles with p,y-unsaturated-a-ketoesters.

It was based on an enantioselective domino Michael/hemiketalization reaction of ethyl 4,4,4-trifluoroacetoacetate and other trifluoromethyl-substituted nucleophiles with p,y-unsaturated a-ketoesters catalyzed by a chiral quinine-derived thiourea. 

For instance, an early example by Jorgensen relates to p,y-unsaturated a-ketoesters 169, which served as acceptors for indoles, furanes and electron-rich arenes [135]. The same catalyst system, a combination of Cu(OTf)2 and tert-butyl-substituted bisoxazoline 173, was employed by Palomo in the highly enantioselective addition of indoles and pyrroles to a -hydroxy enones 170 (Figures 8.11 and 12) [136]. 

In 2011, the group successfully introduced p,y-unsaturated a-ketoesters as the homoenolate acceptors for the annulation reaction of enals. In the presence of the Lewis acid Ti(OiPr)4 substituted cyclopentanes 71 were obtained in moderate to good yields with good to excellent diastereo- and enantioselectivity (Scheme 20.34). 

SCHEME 3.27. P,"y-Unsaturated a-ketoesters as acceptors in the aldol reaction [165],... 

The groups headed by Wang [32] and Cao [33] simultaneously demonstrated that cyclic 1,3-dicarbonyl compounds could efficiently react with p,-y-unsaturated a-ketoesters under hydrogen-bonding catalysis, affording chiral coumarins in excellent yields and enantioselectivities following a Michael addition/hemiacetal formation (Scheme 16.15). The relative configurations of the hemiacetals were not determined. 

Synthetic Routes to Chromanes Chromanes are important structural motifs in organic synthesis and have been found as core structural elements commonly present in many bioactive compounds. J0rgensen et al. [32] have developed a tandem reaction that involves a Lewis acid-catalyzed oxa-Michael addition of phenols 208 to p,y-unsaturated a-ketoesters 209, followed by an intramolecular FC alkylation to form chromanes 211 (Scheme 2.29). The reaction proceeds under the influence of a Mg-BOX (210) catalyst to give diastereomerically pure chromanes with enanti-oselectivities up to 81% and excellent yields. The best results were obtained with m-methoxyphenol, while m-A(Al-dimethylaminophenol afforded the corresponding chromane as single diastereomer in excellent yield but with low enantioselectivity (<20% ee). 

On the other hand, Yang etal. [33] have developed an organocatalyzed enantioselective FC-type addition reaction of 2-naphthol 212 with p,y-unsaturated a-ketoesters 209 using a cinchona alkaloid-derived thiourea catalyst 213 (Scheme 2.30). The resulting product 214 is in rapid equilibrium with the cyclic hemiketal 215, which was dehydrated with a catalytic amount of concentrated H SO in a one-pot fashion, providing the naphthopyran derivatives 216 with moderate to good yields (51-91%) and enantioselectivities (57-90% ee). 

SCHEME 2.30 Organocatalytic asymmetric FC alkylation/cyclization cascade reaction of 2-naphthols with P,y-unsaturated a-ketoesters. 

Later, the same group [35] disclosed the synthesis of various potential bioactive chiral functionalized chromanes 222 with high levels of enantio- and diastereoselectivity (up to 76% ee and >20 1 dr) via the rosin-derived tertiary amine-thiourea 221 catalyzed enantioselective FC alkylation/cyclization cascade of 1-naphthol 217 with a variety of p,y-unsaturated a-ketoesters 209 (Scheme 2.32). 

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). 

In the Friedel-Crafts realm, Lou and coworkers reported on the activity of Mg-phosphoric acid-based binary catalyst in the alkylation of free phenols via Michael addition of p,y-unsaturated a-ketoesters 25 [41], Despite the real structure of the binary organometallic catalytic species is still unknown, excellent levels of chemical and optical outcomes were achieved in the titled process (Scheme 5.24). To be mentioned that neither the BA nor MgF alone could promote the model reaction at any extents, proving the formation of a concertedly activated catalytic aggregate between the two acids. 

Other similar Rh-catalyzed 1,2-addition of oxonium ylides to aldehydes or imines have been described [163]. Moreover, this methodology has been applied to the 1,2-addition of oxonium ylides to isatins [164a], p,y-unsaturated a-ketoesters [164b], and azetidine-2,3-diones [164c]. 

SCHEME 3.74 Iron-catalyzed 1,2-addition of ammonium ylides to P,y-unsaturated a-ketoesters. 

Arylalkylketenes undergo stereoselective cy do additions using chiral Lewis acid catalysts LI and L2, forming P-lactones with isatins (Eqn (4.98)), and y-lactones with P,y-unsaturated a-ketoesters (Eqn (4.99)). ... 

The scope of this protocol was extended by these authors to homoenolate addition to p,y-unsaturated a-ketoesters, which afforded the corresponding chiral highly substituted and functionalisable cyclopentanols in good yields, moderate to high diastereoselectivities of up to 90% de, and excellent enantioselectivities of up to 98% ee, as shown in Scheme 7.15. ... 

Interestingly, the y-aryl-P,y-unsaturated a-ketoesters 107 show a reversal of the regio-chemistry established above when reacted with primary aromatic amines in TFA [179] instead of the expected quinoline-4-carboxylates 106, quinoline-4-carboxylates 108 are obtained ... 

In 2012, Hu and coworkers developed a three-component, tandem 1,4-conjugated addition-cyclization reaction of diazoacetophenones 107 with anilines 108 and p,y-unsaturated a-ketoesters 109 (Scheme 2.28). This reaction performed well over a broad range of substrates to give the multisubstituted pyrrolidine products 110 in moderate to high yields (up to 84%) with high diastereoselectivities [43]. 

Lewis acid-activated, NHC-catalyzed addition of homoenolates to p,y-unsaturated a-ketoesters enables the rapid assembly of highly substituted and functionalizable cyclopentanols (Scheme 6.17). The use of Ii(0 Pr)4 as a mild Lewis acid compatible with optically active NHC-triazolium catalyst is essential for activation of the electrophile and promotion of the conjugate addition with very good enantiomeric excess [21]. 

Ma and coworkers reported a similar reaction for the synthesis of spiro-3,4-dihydropyranes [44]. The reaction between cyclic p-oxo aldehydes and aromatic p,Y-unsaturated a-ketoesters catalyzed by the cinchona alkaloid derivatives afforded the corresponding spirocyclic compounds in good yields and moderate to good enantioselectivities. 

On the other hand, 22a bearing sterically demanding aromatic substituents on the binaphthyl unit and the small methyl group on the guanidine nitrogen turned out to be a catalyst of choice for the [4-e2] cycloaddition of azlactone to P.y-unsaturated a-ketoesters, which proceeded through three consecutive transformations to afford a-amino-8-lactone derivatives with high diastereo- and enanti-oselectivities (Scheme 7.40) [64]. 

Chiral phosphoric acid analogs as catalysts in the F-C alkylation reaction of indoles with a,(l-unsaturated aromatic enones were also devised [53]. p,y-Unsaturated a-ketoesters were also used as electrophiles in organocatalyzed F-C alkylations of indoles and 2-naphthols. With indoles, chiral acidic N-triflylphos-phoramide was successfully employed (Scheme 35.4) [28], whereas in the presence of 2-naphthols a thiourea-based catalyst showed better capacity to mediate a sequential F-C/cycUzation process, giving naphthopyran scaffolds in moderate yields and selectivities (up to 90% ee) [54]. Recently, a,P-unsaturated acyl phos-phonates were effectively used as hydrogen bond acceptors for F-C alkylations of indole derivatives in the presence of thiourea catalyst ent-19 [55]. 

Scheme 35.4 Selected example of P.y-unsaturated a-ketoesters as electrophile...

The natural cinchona alkaloids were shown also to catalyze conjugate addition followed by an oxa-nucleophilic rearrangement in the reaction of 2-(l-hydroxy-3-arylaUylidenejmalonates with p,y-unsaturated a-ketoesters (Scheme 6.5) [20]. Alkaloid 1 gave the best yields and enantioselectivities compared to other natural cinchona alkaloids and C9 ethers derivatives while a C9 phenyl substituted derivative of quinine appeared to be unreactive. 

---