Unsaturated p-ketoesters

Scheme 6.59 Typical 4-nitrocyclohexanone derivatives prepared from the thiourea 12/TMC-catalyzed enantio- and diastereoselective double Michael addition of y,5-unsaturated P-ketoesters to frans-P-nitrostyrene.

Scheme 6.62 Double Michael addition of a y,5-unsaturated P-ketoester to trarrs-P-nitrostyrene catalyzed by PEG-bound thiourea 62.

Conjugated ketenes. a-Diazo-y.S-unsaturated P-ketoesters undergo rearrangement to ketenes which enter Diels-Alder reactions as dienes toward electron-rich alkenes. Substituted phenols are acquired. 3-Acyloxy-2-chloro-2-cyclohexenones are formed when 2-diazocyclohexane-l,3-diones are treated with acid chlorides in the presence of Rh COAc),. ... 

Phenols have been condensed with alkenoylesters to give chromans by an oxa-Michael addition/electrophilic aromatic addition sequence with magnesium(II)- or copper(II)-bis-oxazoline complexes as chiral Lewis acid catalysts (Scheme 17b) [97]. This reaction may be initiated by an oxa-Michael reaction, followed by a hydroarylation of a carbonyl group. The authors suggest that the initial stereodetermining oxa-Michael addition is followed by a fast diastereoselective aromatic substimtion [97]. A nickel Lewis acid, derived from Ni(hfacac)2 (hfacac = 1,LL5,5,5-hexafluoro-3,5-dioxopentane enolate) and chiral Al-oxide ligands, catalyzes the enantioselective oxa-Michael cyclization of 2-tert-butyloxycarbonyl-2 -hydroxy-chalcones to 3-ferf-butoxycarbonyl flavanones, which can be decarboxylated to flavanons in a separate step (Scheme 17c) [98]. A Lewis acid activation of the unsaturated p-ketoester unit can be assumed. 

Iridoids represent a class of highly oxygenated monoterpenes characterized by a c/s-fiised cyclopentapyran ring system. In principle, synthesis of such systems could be achieved by a photoreductive cyclization of S,e-unsaturated p-ketoesters. Unfortunately, unsaturated p-ketoester 101 did not lead to the ex-... 

In a similar context, y,5-unsaturated p-ketoesters (Nazarov reagents) have also been employed as suitable functionalized Michael donor substrates for a Michael/Michael cascade reaction with nitroalkenes using, in this case, Takemoto s catalyst 68a (Scheme 7.65). This reaction proceeded in a tandem... 

Chiral cyclohexene derivatives were also constructed by an asymmetric four-component quadruple domino reaction initiated by oxa-Michael addition of alcohols to acrolein. The other two components were another equivalent of acrolein and a nitroalkene. Enders has shown that cyclohexene derivatives can also be assembled by a domino reaction of y-nitroketones and enals. Domino Michael/aldol condensation of 5-oxoalkanals and a,p-unsaturated aldehydes afforded densely functionalised cyclohexenes. Combination of unsaturated aldehydes with unsaturated p-ketoesters resulted in the formation of chiral cyclohexene derivatives via a Michael/ Morita-Baylis-Hillman sequence (Scheme 8.21). ... 

Unsaturated P-ketoesters and P-diketones are also suitable starting materials for intramolecular ene reactions (Scheme 6.14). Their stronger enolic character enables reactions to proceed at lower temperatures. 

Themial WolfF rearrangement of a-diazo-p-ketoesters gives acylketene intermediates which react with enol ethers giving Y.S-unsaturated p-ketoesters by nucleophilic attack of the enol ether and rearrangement of the intermediate zwitterion (Scheme 4.39). ... 

Scheme 4.39 Y/8-Unsaturated p-ketoester formation by enol ether addition to...

Recently, the asymmetric aldol reaction between the benzyl ether of hydroxyac-etone and p.y-unsaturated-P-ketoesters was reported to be effectively catalyzed by 39 in the presence of TFA, providing the products in high yields, low to moderate diastereoselectivity, and high ee for major diastereomer (Scheme 6.50) [106]. 

Hoashi Y, Yabuta T, Takemoto Y. Bifunctional thiourea-catalyzed enantioselective double Michael reaction of y,8-unsaturated p-ketoester to nitroalkene asymmetric synthesis of (—)-epihatidine. Tetrahedron Lett. 5004 45 (50) 9185-9188. 

The first organocatalyzed conjugate addition of a-substituted p-ketoester to a,P-unsaturated ketones was presented by Deng et al. [42] (Scheme 3). Although traditional Cinchona alkaloids were efficient catalysts for conjugate addition of carbon nucleophiles to nitroalkenes and sulfones, replacement of the C(9)-OH with an ester group (Q-7b) showed great improvement in stereoselectivity. The reaction is applicable to a variety of cyclic and acyclic enones (16,18). 

The potential application of this catalytic system was illustrated by Takemoto in the application to a tandem conjugate addition towards the asymmetric synthesis of (-)-epibatidine, a biologically active natural product [100, 101], The authors designed an enantioselective double Michael addition of an unsaturated functionalized P-ketoester to a p-aryl nitro-olefm. The asymmetric synthesis of the 4-nitro-cyclohexanones was achieved in both high diastereoselectivity and enantioselectivity, with the natural product precursor synthesized in 90% yield and 87.5 12.5 er (Scheme 49). The target (-)-epibatidine was subsequently achieved in six steps. 

Application of this work to a domino process using 51 involves Michael addition of P-ketoesters [91], p-diketones or P-ketosulfones [92] to a,P-unsaturated ketones followed by an intramolecular aldol reaction provides highly functionalised cyclohexanone building blocks with up to four contiguous chiral centres. Gryko has also reported examples of this domino Michael/intramolecular aldol reaction in the coupling of 1,3-diketones and methyl vinyl ketone using L-proUne as catalyst [93],... 

The scope was illustrated with 35 examples using various P-ketoesters as well as acetylacetone as 1,3-dicarbonyl compound. The use of aliphatic a,P-unsaturated aldehydes resulted in low yield and inferior enantioselectivity. Transformation of the DHP products into other optically active heterocyclic... 

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>. 

The transformation of P-ketoester 20 into a,P-unsaturated ester 21 requires the reduction of the ketone chemoselectively in the presence of the ester. Sodium borohydride (NaBH4) is the standard reagent for this type of transformation. Subsequent reaction of the sterically hindered secondary alcohol with benzoyl triflate " provides a good leaving group in P-position to the ester moiety. Elimination under basic conditions provides the a,p-unsaturated ester 21 in 50 % yield over three steps. 

Very recently, the use of the electron-deficient allenic esters and ketones 50 as acceptors was also reported by the same group [14], Under PTC conditions (42a (3mol%), o-xylene/CHCl3, K2C03 aq), the cyclic P-ketoester 49 underwent an addition to the electron-deficient allenic esters and ketones 50, giving the corresponding p,y-unsaturated (isolated alkene) carbonyl compounds 51 with excellent enantioselectivity (up to 96% ee, Scheme 9.16). The Michael adduct 51 could be transformed into the optically active hexahydrobenzopyranone 51a and 51b with a 2 1 (51a 51b) diasteromeric ratio via a simple one-step procedure (Scheme 9.17). 

---