Enolization cyclization

However, an even more efficient access to functionalized pyrrolidines was developed relying on a zinc enolate cyclization (see Section V.B). 

It is also worth mentioning that such cyclizations could be achieved for a-aminoesters bearing the amino group located outside of the chain. Indeed, Chemla and coworkers recently reported that the a-aminoester 421 successfully underwent a zinc-enolate cyclization, according to the standard conditions, and afforded after hydrolysis the five-membered ring tertiary amine 422 as a 80/20 mixture of diastereomers (equation 182)264. 

The zinc-enolate cyclizations are not restricted to a-aminoesters as /3-aminoesters have also been successfully involved in such reactions275. The preformed lithium enolate generated by treatment of the /J-arninoester 423 with LDA had to be added dropwise to an ethereal solution of ZnBr2 in order to avoid a competing /3-elimination reaction induced by the zinc enolate. this reverse addition protocol was respected, a smooth carbocyclization reaction occurred and provided, after hydrolysis, the substituted 3-carbomethoxypyrrolidine 424 as a 87/13 mixture of diastereomers (equation 183). 

There are acidic protons next to the cyanide, and the amide ion is strong enough to form an gnolate by the removal of one of those. The enolate cyclizes on to the benzyne to give a four-membered ring. As it happens, the nucleophile adds to the position originally occupied by the chlorine, but that is not necessary. 

Enolization occurs on the side of the ketone away from the bromine atom and the enolate cyclizes as before but the cycloprop an one intermediate is symmetrical so that the product is the same whichever C-C bond breaks after nucleophilic attack by the methoxide ion. 

The ratio of cis trans isomers was 74 26. One obvious interpretation of these results can be derived from observations of Ireland regarding the influence of HMPA on the stereoselection in the formation of ester enolates (7). Based an Ireland s work, in hexane the E-enolate would be formed preferentially and in the presence of HMPA the Z-enolate would be the major diastereomeric intermediate. It follows that E-enolates cyclize selectively to form trans cyclopropanes, and Z-enolates selectively produce cis products (Figure 5). 

A tandem aldol/intramolecular enol cyclization of epoxyaldehydes to form a-furyl carbinols, 127, has been reported <05TL5467>. Only isopropyl methyl ketones or t-butyl methyl ketones have been shown to work in this reaction. The corresponding A-Boc aziridine aldehyde 127 (X = Af-Boc) has also been used to generate an a-amino furan in excellent yield. 

Aldol reaction of a,p-aziridino- or a,p-epoxyaldehydes followed by an intramolecular enol cyclization in the presence of Bu BOTf/DIPEA provided 5-substituted-2-furylamines and carbinols in good yields. The reaction proceeded in a one-pot manner... 

Stereoselection can also occur in the intramolecular Michael addition. Factors other than those operative in the acyclic additions may influence the stereochemistry. In particular, certain stereoelectronic preferences are important in cyclizations that are not considerations in acyclic examples. In this respect, enamine and enolate cyclizations often exhibit similar behavior/... 

Diols react with 1,2-dihalo compounds under basic conditions to form 1,3-dioxolanes.504 50 Treatment of 2-chloroethyl hemiacetals with base is an alternative approach to these cyclic acetals.506 Similarly, 2-chlorocthyl ester enolates cyclize readily.M)7M>S 2-Hydroxy-509 2-phenoxy-.510 and 2-alkoxy-l, 3-dioxolanes511 are synthesized from epoxides509-51 or. viw-tel-raphenylethylene dichloride510 using trifluoroacetic acid.5"9 its silver salt,510 or alkyl trifluoro-acetates.511... 

Aromatization. a,/3 y,5-Unsaturated ketones that can be deconjugated (or enolized) cyclize and dehydrate on heating with iodine. Thus /3-ionone gives 1,1,6-trimethyltetralin in excellent yield. 

Kawase and co-workers also examined aminomalonate as a nucleophile with munchnones. In this reaction, initial attack at C-5 is followed by enolate cyclization onto the trifluoroacetyl group, leading to pyrrolidin-2-ones 100 (Fig. 4.34). The less enolic ethyl glycinate and iV-methylglycinate failed to react. 

Karoyan et al. accomplished an asymmetric synthesis of prolino-homotrypto-phan 50 via amino-zinc-ene-enolate cyclization of 47 followed by transmetalation of the cyclic zinc intermediate 48 with indolyliodide 49 [84]. The use of a Pd catalyst derived from Fu s [f-BusPHj-BFa was required to avoid the undesired p-hydride elimination. Proline chimeras such as 50 are useful tools for medicinal chemistry and/or biological applications. 

Scheme 10.16 Synthesis of dihydro-2H-pyranes through domino Michael/enolization/cyclization reaction.

Both radical and enolate cyclizations of the iodides 25 have been examined. Both conditions generate the same ring system, 26, which, in the ionic case bears a bridgehead iodine atom. The thermodynamic bisfuranolactone isomers of 25, namely 27 both generate 28 under radical conditions (Scheme 5). 

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