P-ketoesters, cyclic

Claisen reaction. As we have seen previously (see Section 7.9.1), intramolecular reactions are favoured over intermolecular reactions when the reaction is carried out at high dilution, conditions that minimize the interaction of two separate molecules. A simple example involving the transformation of diethyl adipate into a cyclic P-ketoester is shown. 

The reverse Claisen reaction is common, especially with cyclic P-ketoesters, such as one gets from the Dieckmann reaction (see Section 10.8). If one only wants to hydrolyse the ester, it thus becomes necessary to use the rather less effective acid-catalysed hydrolysis method (see Section 7.9.2). 

The scope of electrophiles was explored with malonates and p-ketoesters, providing chiral amine adducts in high yield and enantioselectivities (Scheme 57) [109]. Addition of cyclic P-ketoesters was also explored with hydrazines, providing cyclic and bicyclic chiral amines with quaternary centers in high enantiomeric ratios (Scheme 58). 

Enders et al.173) transformed open chain and cyclic P-ketoesters into the corresponding SAMP-hydrazones. Metalation with n-butyllithium, followed by trapping of the intermediate anions with alkyhalides generates esterhydrazones which upon cleavage by ozonolysis finally leads to optically active p-ketoesters. While the overall chemical yields are good, the enantiomeric excesses of 18-60% are relatively low. 

The asymmetric a-substitution of carbonyl derivatives including imines of a-amino esters, achiral enolizable carbonyls, and cyclic P-ketoesters in the presence of chiral... 

Scheme 7.23 Muzart/Henin s palladium-catalyzed tandem debenzylation/EDP of cyclic p-ketoesters [29].

When the Michael donors have a sufficiently low pKa, the Michael addition can be catalyzed by a base. The first catalytic asymmetric conjugate addition was achieved by Wynberg et al. in 1975 using cinchona bases [la]. They performed the reaction of cyclic P-ketoesters such as 1 with methyl vinyl ketone in the presence of quinine and... 

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). 

In 2007, Jorgensen and coworkers also reported the anti-Michael reaction of the cyclic P-ketoesters 53 with the sulfone group-substituted acrylonitrile 54 under PTC conditions (52 (6mol%), CHC13, aq Cs2C03 or K3P04) [15]. As depicted in Scheme 9.18, the sulfone group of the acceptor directed the nucleophile and then is removed to afford the anti-Michael (a-addition Morita-Baylis-Hillman-like) adducts 55 in variable yields (42-90%) and ee values (60-94% ee) (Scheme 9.18). 

The reaction did not require dry solvents or inert atmosphere and afforded the desired adducts in 42-98% yield. As expected, the more reactive acrolein and methyl vinyl ketone gave very good results with both acyclic and cyclic p-ketoesters and p-diketones and, surprisingly, acrylonitrile and methyl acrylate, reported to be totally inactive under Lewis acid catalysis, " afforded the corresponding adducts with a-acetylbutyrolactone in high yield (77 and 98% respectively). In the reaction with crotonaldehyde, a 1 1 mixture of... 

In a modified Biginelli reaction, cyclic p-ketoester 281 with urea and an aldehyde (1 2 molar ratio) gave spiro heterobicyclic aliphatic 282 (Scheme 110) (00MI3) with substituents exclusively in the as configuration. Likewise, a pseudo four-component reaction of an aldehyde and urea (2 1 molar ratio) and a cyclic p-diester or p-diamide 283 (1 equiv), using microwave irradiation under solvent-free conditions, furnished spiro-fused 284 (Scheme 110) (04TL2575). 

Another efficient iVA -dioxide organocatalyst system was also developed for the asymmetric a-chlorination of cyclic p-ketoesters using NCS to provide a series of optically active a-chloro-/3-ketoesters in excellent yields with 90-98% ee. ... 

There is also one example in which a chiral phosphoric acid has been employed as catalyst in the reaction. In particular, the addition of several cyclic p-ketoesters to methyl vinyl ketone was found to occur smoothly in the presence of several chiral phosphoric acids (Scheme 4.35). As mentioned earlier, a key feature of the chiral phosphoric acid catalyst is the backbone binaphthyl axial chirality together with the incorporation of bulky substituents at the 2 positions. In this case, 60b was identified as an appropriate promoter of the reaction leading to the corresponding Michael adducts in excellent yields, although with moderate enantioselectivity. In addition, the authors succeeded in applying this reaction to a procedure to carry out a subsequent Robinson-type annulation. 

In this context, there is a relevant example of a newly designed cinchona-alkaloid derived bis-ammonium salt 105 employed as catalyst in the Michael reaction of cyclic p-ketoesters with methyl vinyl ketone (Scheme 5.12). Excellent yields and moderate enantioselectivities of the corresponding Michael adducts were obtained under the best reaction conditions, which also allowed the use of an organic base (Hiinig base) for the deprotonation of the p-ketoester. However, perhaps the most relevant feature associated to the use of this catalyst is the fact that it can be easily separated from the reaction medium by precipitation in ether, which allowed its recycling for further uses without loss of activity. 

Scheme 5.12 Enantioselective Michael reaction of cyclic P-ketoesters with methyl vinyl ketone using bis-quinidinium salt 105 as catalyst.

In a much more recent report, conveniently O-protected a-hydroxymethyl aryl ketones were also successfully employed as Michael donors in the conjugate addition to methyl acrylate and acrylonitrile using a cinchonine-based ammonium salt as catalyst. Bis-quinidine-based ammonium salt 105 has also shown to be useful in the reaction of cyclic p-ketoesters to methyl and ethyl acrylate. ... 

A first approach described the use of catalyst 106a in the Michael reaction of a cyclic p-ketoester with acrolein (Scheme 5.28). ° The reaction proceeded satisfactorily, furnishing quantitatively the desired conjugate addition product in excellent enantioselectivity, requiring the in situ protection of the formyl moiety as the corresponding cyclic acetal derivative. However, the authors reported the need of a 9-fluorenyl ester Michael donor and the reaction was not studied further, with no data reported about the scope and limitations of the methodology. 

Scheme 5.28 Enantioselective Michael reaction of a cyclic P-ketoester with acrolein catalyzed by 106a.

Finally, it should also be pointed out that the dimeric quinidine-based bis-ammonium salt 105 developed by Najera has also been shown to perform quite well in the reaction of cyclic p-ketoesters with acrolein, furnishing the corresponding adducts in good yields and enantioselectivities (Seheme 5.30). As was pointed out earlier, one of the main advantages associated with the use of this catalyst is the possibility of its recycling for further uses in other reaetions without loss of activity after precipitation with diethyl ether. 

Lattanzi and coworkers disclosed that L-diaiyl prolinols served as suitable catalysts in one of the most popular Michael addition reaction, i.e. the reaction of malonate esters and cyclic p-ketoesters to nitroalkenes to generate functionalised products amenable to further manipulation (Scheme 7.7). 

Earlier on, Kim et al. reported results wherein similar reagents were investigated [44]. Excellent results were obtained by using the bifunctional urea catalyst 69 to facilitate the reaction of the cyclic P-ketoesters 70 with Al-Boc-aldimines 23. The downside of this method was that the reactions took several days to reach completion. Very high ee s (>95%) and superb diastereoselectivities were reported in those reactions (Scheme 5.33). 

In addition to the presented Sjj/Michael transformations, a twofold domino Sn/Sn cycloalkylation of stabilized carbanions from cyclic P-ketoesters with 1,4-dibromobut-2-yne yielding annulated 2-vinyHdenehydrofurans has been reported... 

Scheme 14.5 Asymmetric Michael addition of cyclic p-ketoesters to nitroalkenes catalysed by BnO-CPN under solvent-free, grinding conditions.

Jorgensen et al. described a highly enantioselective amination of a-substituted a-cyanoacetates with di-tert-butyl-azodicarboxylate (DEAD) catalysed by the quinidine-derived constrained alkaloid, p-isocupreidine (p-ICPD). ° Products were isolated in excellent yield and enantioselectivity (up to >98%). The generality of the method was demonstrated by the reaction on both open-chain and cyclic p-ketoesters. Products were again obtained in up to 99% yield, but in somewhat lower ee (up to 90%). Deng... 

Recently, in 2008, Dixon and co-workers [96] developed highly efficient enantioselective a-alkylation of cyclic p-ketoesters with o-(trifiuoromethane)benzene-sulfonyl aziridine 39 under phase-transfer catalysis with (9-adamantoyl derivative LII (up to 85% yield and 97% ee). Moreover, the corresponding products 40 were obtained with high diastereoselectivity when PTC aziridine ring-opening of single enantiomeric aziridines was performed. In this work, also formation of diastereomerically pure tricyclic compounds via one-pot alkylation/desulfonation/ cyclization sequence was described. 

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