Phenols intramolecular cyclization, carbonyl

An efficient synthetic methodology was developed in which the palladium-mediated intramolecular carbonylative annulation of o-alkynylphenols was employed to construct benzo[l>]furo[3,4-d]furan-l-ones by a tandem reaction. Several densely functionalized alkynyl- phenols were cyclized into their respective substituted benzo[fc]furo[3,4-d]furan-l-ones in good yields under conditions of a combination of PdCljfPPh,), dppp and CsOAc in acetonitrile at 55°C under a balloon pressure of CO. An example is depicted below <01OL1387>. 

Early examples of this reaction involved cyclizations of 4-substituted phenols tethered to alkyl sulfonates and halides [3]. CycMzalions involving carbonyl electrophiles (aldehydes, ketones) and imines have been reported as well, but esters are not sufiSciently electrophilic to react [2]. Subsequent studies established that the facility of these so-called Ai-n cyclizations was strongly affected by the size of the newly formed ring in the order 3>5>6 >4. Since the vast majority of alkylative dearomatizations involve intramolecular cyclizations (thereby avoiding competitive 0-aDcylation reactions), stereoelectronic effects operative in the transition states (resembling the TS of an Sjj2 reaction) are crucially important. These sometimes subtle effects can result in differential reactivity of structurally similar substrates [4]. 

The proposed mechanism is given in Scheme 15. Initially the dissociation of water, maybe trapped by the molecular sieve, initiates the catalytic cycle. The substrate binds to the palladium followed by intramolecular deprotonation of the alcohol. The alkoxide then reacts by /i-hydride elimination and sets the carbonyl product free. Reductive elimination of HOAc from the hydride species followed by reoxidation of the intermediate with dioxygen reforms the catalytically active species. The structure of 13 could be confirmed by a solid-state structure [90]. A similar system was used in the cyclization reaction of suitable phenols to dihydrobenzofuranes [92]. The mechanism of the aerobic alcohol oxidation with palladium catalyst systems was also studied theoretically [93-96]. 

Phenols add intramolecularly to Michael acceptors. " Under acidic conditions, a one-pot sequence starts with initial electrophilic acetylation of the activated aromatic ring and is followed by cyclization." With an appropriate leaving group in the /f-position (OMe. or other amines such as in the unsaturated carbonyl compound (e.g., 4) is formed. Other approaches to pyroncs include the self-condensation of protected //-hydroxy acrylates,intramolecular aldol reactions followed by condensation,thermal cycli-zations of unsaturated ()-chloro esters,and an iodo-cyclization-elimination sequence w th Michael acceptors.Oxymercuration of an unsaturated alcohol is an alternative cyclization approach to tetrahydropyrans. 

Figure 13.43. Two-step prodrugs of peptides derivatized with coumarinic acid (49) (218). Activation occurs by enzymatic cleavage of the ester bond, followed by intramolecular nucleophilic attack by the phenolic group on the carbonyl, resulting in cyclization to coumarin and elimination of the peptide.

A mild intramolecular fluorocyclization reaction of benzylic alcohols and amines was developed, using commercially available Selectfluor to trigger electrophilic cyclizations to afford fluorinated dihydrobenzo[c]furans (14CC13928). A novel rhodium-catalyzed carbonylative [3 + 2 + 1] cycloaddition of alkylidenecyclopropanes was developed for the synthesis of phenols with benzo[c]furan species (140L4352). 

This and other information show that nine Cg units from malonyl-coenzyme A and one C3 unit from propionyl-coenzyme A condense to form the linear polyketide intermediate shown below. These units are joined by acylation reactions that are the biosynthetic equivalent of the malonic ester synthesis we studied in Section 18.7. These reactions are also similar to the acylation steps we saw in fatty acid biosynthesis (Special Topic E in WileyPLUS). Once formed, the linear polyketide cyclizes by enzymatic reactions akin to intramolecular aldol additions and dehydrations (Section 19.6). These steps form the tetracyclic core of akiavinone. Phenolic hydroxyl groups in akiavinone arise by enolization of ketone carbonyl groups present after the aldol condensation steps. Several other transformations ultimately lead to daunomycin ... 

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