Allyl keto esters

One intramolecular Diels-Alder cycloaddition which does not involve a ring as a starting point has been described. The sequence commences with allylic / -keto ester derivatives (201) and ends with the formation of the highly reduced furopyridazine (202 R = 2,4-dinitrophenyl or benzoyl) (Equation (70)) <89JCS(P1)353>. 

Ring expansion (1, 369-370 6, 252-253). The ring expansion of ketones to the next higher homolog with ethyl diazoacetate requires hydrolysis and decarboxylation of the intermediate 8-keto ester, a step that is sometimes troublesome. Baldwin and Landmesser have used benzyl diazoacetate and allyl diazoacetate as alternative reagents. The benzyl jS-keto esters are cleaved and decarboxylated on hydrogenation both benzyl and allyl keto esters are reduced by sodium in liquid ammonia to ketones. 

Hydrolysis of the dialkylated jS-keto esters and malonates is not easy, and usually harsh conditions are required. Also decarboxylation occurs only at high temperature. On the other hand, hydrolysis and decarboxylation reactions of substituted allyl -keto esters and allyl malonates using Et3N-HC02H proceed at room temperature under neutral conditions. THP-protected allyl jS-keto ester 597 was converted to 598 at room temperature without deprotection of THP [213]. The free mono-carboxylic acid 600 was obtained smoothly from the disubstituted diallyl malonate 599 [214]. 

An interesting strategy for convergent steroid synthesis has been reported by Deslongchamps based on Pd-catalyzed decarboxylation-Michael addition of allyl -keto ester (bicyclic Nazarov reagent) 605 to cyclohexanone 604. The first intermolecular Michael addition of the Pd-enolate, generated from 605, to 604 afforded 606. Further intramolecular Michael addition constructed the steroid skeleton 607, and the tetracycle 608 was obtained by jS-H elimination [218]. 

Other Methods. - One of the most important and flexible approaches to ketone synthesis involves the manipulation of 6-keto-esters. Tsuji et al. have reported that the use of allyl keto-esters, which are prepared from ketones and diallyl carbonate or allyl chloroformate, offer advantages over more common esters in that the ester hydrolysis/decarboxylation step... 

Pd(0) species can catalyse the decarboxylation of allyl -keto-esters e.g. 48) to give ketones (49). The reactions are efficient for cyclohexanones but much less so with acyclic esters. Examples with other ring sizes were not reported. 

No 0-allylation is observed in formation of the six-membered ring compound 79 by intramolecular allylation of the /3-keto ester 78(15,57]. Intramolecular allylation is useful for lactone fonnation. On the other hand, exclusive formation of the eight-membered ring lactone 81 from 80 may be in part derived from the preference for the nucleophile to attack the less substituted terminus of the allyl system[58]. 

The 1.3-allylic diacetate 135 can be used for the formation of the methy-lenecyclopentane 137 with the dianionic compound 136(86]. The cyclohexa-none-2-carboxylate 138 itself undergoes a similar annulation with the 1,3-allylic diacetate 135 to form the methylenecyclohexane derivative 139(90]. The reaction was applied as a key step in the synthesis of huperzin A[91]. On the other hand. C- and 0-allylations of simple J-dikctones or. 1-keto esters take place, yielding a dihydropyran 140(92]. 

The four-membered vinyloxetane 280 is cleaved with Pd(0j and used for allylation a homoallylic alcohol unit can be introduced into the keto ester 281 as a nucleophile with this reagent to form 282[168],... 

The decarboxylation of allyl /3-keto carboxylates generates 7r-allylpalladium enolates. Aldol condensation and Michael addition are typical reactions for metal enolates. Actually Pd enolates undergo intramolecular aldol condensation and Michael addition. When an aldehyde group is present in the allyl fi-keto ester 738, intramolecular aldol condensation takes place yielding the cyclic aldol 739 as a main product[463]. At the same time, the diketone 740 is formed as a minor product by /3-eIimination. This is Pd-catalyzed aldol condensation under neutral conditions. The reaction proceeds even in the presence of water, showing that the Pd enolate is not decomposed with water. The spiro-aldol 742 is obtained from 741. Allyl acetates with other EWGs such as allyl malonate, cyanoacetate 743, and sulfonylacetate undergo similar aldol-type cycliza-tions[464]. 

The Pd enolates also undergo intramolecular Michael addition when an enone of suitable size is present in the allyl d-keto ester 744[465]. The main product is the saturated ketone 745, hut the unsaturated ketone 746 and ally-lated product 747 are also obtained as byproducts. The Pd-catalyzed Michael... 

An example for synthesis of the chiral [l-keto ester 69 is illustrated in equation 64. It involves conjugate addition of the dipotassium / -keto ester 68 to vinyl sulfone 67 followed by in situ quenching with allyl bromide54. The method provides a new procedure to sevenring annulation product 70 that is a potential precursor for (l)-(-)-cytochalasin C. 

Yang12 has effected an intramolecular asymmetric carbonyl-ene reaction between an alkene and an a-keto ester. Reaction optimization studies were performed by changing the Lewis acid, solvent, and chiral ligand. Ligand-accelerated catalysis was observed for Sc(OTf)3, Cu(OTf)2, and Zn(OTf)2 (Equation (6)). The resulting optically active m-l-hydroxyl-2-allyl esters provide an entry into multiple natural products. 

Reduction of vinyloxiranes The substrates are reduced rapidly by Sml2 to (E)-allylic alcohols without effect on keto, ester, or nitrile groups. Chiral substrates are reduced to optically active alcohols with complete retention of stereochemistry. 

Alkylation of P-dicarbonyl compounds and p-keto esters occurs preferentially on the carbon atom, whereas acylation produces the 0-acyl derivatives (see Chapter 3). There are indications that C- and 0-alkylated products are produced with simple haloalkanes and benzyl halides, but only C-alkylated derivatives are formed with propargyl and allyl halides [e.g. 90]. Di-C-alkylation frequently occurs and it has been reported that the use of tetra-alkylammonium 2-oxopyrrolidinyl salts are more effective catalysts (in place of aqueous sodium hydroxide and quaternary ammonium salt) for selective (-90%) mono-C-alkylation of p-dicarbonyl compounds [91]. 

Scheme 9.11 Allylic substitutions with 2-substituted malonates and P-keto-esters as pronucleophiles.

Trost and his co-workers succeeded in the allylic alkylation of prochiral carbon-centered nucleophiles in the presence of Trost s ligand 118 and obtained the corresponding allylated compounds with an excellent enantioselec-tivity. A variety of prochiral carbon-centered nucleophiles such as / -keto esters, a-substituted ketones, and 3-aryl oxindoles are available for this asymmetric reaction (Scheme jg) Il3,ll3a-ll3g Q jjg recently, highly enantioselective allylation of acyclic ketones such as acetophenone derivatives has been reported by Hou and his co-workers, Trost and and Stoltz and Behenna - (Scheme 18-1). On the other hand, Ito and Kuwano... 

Retrosynthetic considerations reveal an approach (Scheme 1.2.6) in the first step based on disconnections of the C -Cy and C12-C13 double bonds. Those can be built up using highly B-selective Wittig olefinations between allyltributylphos-phorous ylides derived from the corresponding allylic bromides 29 and 31 [31]. The aldehyde 30 is accessible from the keto ester 33, which can be prepared in high enantiomeric purity by a biocatalytic enantioselective reduction of a... 

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