Enols aldol cyclization

A proposed simplified mechanism for the conjugate addition/aldol cyclization, as depicted in Scheme 2.25, is based on detailed mechanistic studies performed on related Rh-catalyzed enone conjugate additions [45]. A model accounting for the observed relative stereochemistry invokes the intermediacy of a (Z)-enolate and a Zimmerman-Traxler-type transition state as shown in 2-110 to give 2-111. 

Cyclopentenones. 1,3-Dicarbonyl compounds add to enol ethers or esters (terminal) in the presence of Mn30(OAc)7 (excess) to form l-alkoxy-l,2-dihydro-furans. These can be converted to a 1,4-diketone, which undergoes aldol cyclization to fused (or spiro) cyclopentenones.1... 

This method can also be applied to silyl enol ethers of homologous unsaturated ketones as well as of unsaturated aldehydes or esters [85-87]. While unmodified unsaturated esters give only the corresponding aldehydes without cyclization under tandem hydroformylation/aldol reaction conditions, the corresponding silylated ester enolates smoothly cyclize in a tandem hy-droformylation/ Mukaiyama aldol reaction (Scheme 32) [85-87]. 

The method involves a regioselective, trans-diastereoselective, and enantioselective three-component coupling, as shown in Scheme 7.26. In this case, the zinc enolate resulting from the 1,4-addition is trapped in a palladium-catalyzed allyla-tion [64] to afford trans-2,3-disubstituted cyclohexanone 96. Subsequent palladium-catalyzed Wacker oxidation [82] yields the methylketone 97, which in the presence of t-BuOK undergoes an aldol cyclization. This catalytic sequence provides the 5,6-(98) and 5,7- (99) annulated structures with ees of 96%. 

Michael addition of tin(II) dienolates.1 The tin(II) dienolates of (3,y-enones undergo y-selective addition to acyclic ot,(3-enones to give frans-l,7-enediones. If the reaction is carried out at high dilution, the intermediate tin(II) enolate can undergo an intramolecular aldol cyclization to give a cyclohexenol. 

The Michael reaction is the conjugate addition of a soft enolate, commonly derived from a P-dicarbonyl compound 24, to an acceptor-activated alkene such as enone 41a, resulting in a 1,5-dioxo constituted product 42 (Scheme 8.14) [52]. Traditionally, these reactions are catalyzed by Bronsted bases such as tertiary amines and alkali metal alkoxides and hydroxides. However, the strongly basic conditions are often a limiting factor since they can cause undesirable side- and subsequent reactions, such as aldol cyclizations and retro-Claisen-type decompositions. To address this issue, acid- [53] and metal-catalyzed [54] Michael reactions have been developed in order to carry out the reactions under milder conditions. 

It has been demonstrated that optically active oxetanes can be formed from oxazolidinone 92, a crotonic acid moiety functionalized with Evans chiral auxiliary (Scheme 18) <1997JOC5048>. In this two-step aldol-cyclization sequence, the use of 92 in a deconjugative aldol reaction, with boron enolates and ethanal, led to formation of the syn-aldol 93. This product was then converted to the corresponding oxetanes, 94a and 94b, via a cyclization with iodine and sodium hydrogencarbonate. This reaction sequence was explored with other aldehydes to yield optically active oxetanes in similar yields. Unlike previous experiments using the methyl ester of crotonic acid, in an analogous reaction sequence rather than the oxazolidinone, there was no competing THF formation. 

Enolization can be part of an aldol condensation. We examined the aldol cyclization of compound 52 to 53 catalyzed by the bis-imidazole cyclodextrin artificial enzymes, and again saw that the A,D isomer was the preferred catalyst [139]. This was not an obvious result the rate-limiting step in this case is cyclization of the enol, which is... 

One enol can cyclize through an eight-membered cyclic transition state and the other through a six-membered ring. In each case the product would first be formed as an aldol but would dehydrate to the cyclic enone having the same ring size as the transition state, In practice, only the less strained six-membered ring is formed and the enone can be isolated in 85% yield. 

The product of Michael addition of an enolate to an a,p-unsaturated carbonyl compound will normally be a 1,5-dicarbonyl compound. The two reactive carbonyl groups separated from one another by three carbon atoms present the opportunity for ring formation by intramolecular aldol condensation. If one of the carbonyls acts as an electrophile while the other forms a nucleophilic enolate, this cyclization gives a six-membered ring. 

Aldol cyclization. Although the keto aldehyde 1 is resistant to aldol cyclization under normal, alkaline conditions, this reaction can be accomplished by a method originally developed by Raphael et Reduction of the enol lactone (2), derived from 1, with DIBAH produces a bridged ketol, which is oxidized to 3 with chromic add. This diketone was employed as an intermediate in a synthesis of the sesquiterpene gymnomitrol (4). 

The mechanism is a conjugate addition of the central enolate of the keto-ester to the enal fcw- il5 by an aldol cyclization of the ketone enolate on to the aldehyde and dehydration. 

The aldol cyclization step and the dehydration are sometimes separated from the conjugate addition and from each other and sometimes not. It depends to some extent on the conditions. Very mild conditions in this example allowed each step to be performed separately and in good yield but notice the exceptionally mild conditions for the conjugate addition (just mix in water ) which are possible only because of the two carbonyl groups in the enol component. 

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