Friedel-Crafts alkylations diastereoselective

The concept of a diastereoselective Friedel-Crafts alkylation of a-chiral benzyl alcohols was first examined by Bach and coworkers [62, 63]. The initial protocol required stoichiometric amounts of strong Brpnsted acids like HBF4 and was followed by a more valuable methodology in which catalytic amounts of AuC L were employed for the diastereoselective functionalization of chiral benzyl alcohols [64], Beside arenes, allyl silanes, 2,4-pentanediones and silyl enol ethers have been used as nucleophiles. Depending on the diastereodiscriminating group and on the catalyst (Brpnsted or Lewis acid), the authors observed either the syn or the anti diastereoisomer as the major product. 

Only recently, the diastereoselective synthesis and preparative separation of the enantiomers of galaxolide (Givaudan) have been described. [169] The titanium tetrachloride-catalysed Friedel-Crafts alkylation of 1,1,2,3,3-pentamethylin-dane with (S)-propylene oxide produces two epimeric alcohols (whereby no racemisation is observed) with paraformaldehyde and catalytic amounts of sulfuric acid, these are converted into the desired isochroman diastereomers. The separation of the epimers is accomplished by means of the corresponding chro-... 

The diastereoselective [4 + 3] cycloaddition between 2,5-disubstituted furans and vinylthionium ions was achieved (140L4476). The vinylthio-nium ion was generated either from a ort/io-phenylethynylbenzoyl allylic ester in the presence of a gold catalyst or from the allylic alcohol with a Bronsted acid. However, using 2-substituted furans led predominantly to the formation of Friedel-Crafts alkylated products. 

Xiao et al. developed a highly enantioselective, copper-catalyzed Friedel-Crafts alkylation/A7-hemiacetalization cascade reaction of indoles. Indole 184 was allowed to react with ester 185 to furnish fused indole 186 in excellent yield, diastereoselectivity, and enantioselectivity. Indole 186 was further elaborated to complete a formal synthesis of analogs of flinderoles B and C (13AG(I)3250). 

Wang elegantly demonstrated the potentiality of chiral diarylprolinol ether 54 in the synthesis of chromanes 56 via enantioselective Michael-type Friedel-Crafts alkylation/cychzation cascade synthetic sequence between 5a and a,p-unsaturated aldehydes 37a [30a]. Under optimal conditions, moderate diastereoselectivity and high enantioselectivity were obtained. Differently, phenol was found unreactive (Scheme 5.17a). The same team years later documented also the activity of a rosin-derived tertiary amine-thiourea 55 in similar process involving 1- and 2-naphthols and P,y-unsaturated a-ketoesters 25 (Scheme 5.17b) [30b]. A proposed model of the enantiodiscrimi-nating step of the reaction is also provided by the authors (58). 

Scheme 27 Diastereoselective Friedel-Crafts alkylation of 2-methylthiophene [48]...

This mild Friedel-Crafts alkylation was expeditiously extended to highly regio- and diastereoselective intramolecular version at elevated temperature by the same research group [39], thus allowing an easy access to tetralin and indane skeletons in good yields (Scheme 10.21). This reaction starts... 

SCHEME 10.23 Diastereoselective intennolecular Friedel-Crafts alkylation via chiral a-branched benzyUc carbocations. 

Besides performing diastereoselective reactions using chiral staring materials, optically active catalyst-controlled enantioselective Friedel-Crafts alkylation [31] can also be served as an alternative to provide chiral products. Great advances have been demonstrated in this hot field within the last decade. Generally, three strategies have been success-fnlly ntilized to achieve catalytic asymmetric Friedel-Crafts alkylation. The first one involves the nse of chiral Lewis acids, where a chiral ligand is coordinated to the Lewis acid. 

Methylthiophene undergoes diastereoselective Friedel-Crafts-type alkylation with l-(2, 2, 3, 3 -tetramethylcyclopropyl)-aIkan-l-ols under Brdnsted acid catalysis [47]. Tetramethylcyclopropy[-substituted carbocations formed under the reaction conditions underwent a fast ring opening which led to the formation of allylic cations, which by reaction with thiophene gave the products (Scheme 26) [47]. 

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