Stereoselectivity Friedel-Crafts alkylation

Stereoselective Friedel-Crafts alkylation. 4 Alkylation of benzene with methyl (S)-2-(mesyloxy)propionate, derived from (S)-lactic acid, under Friedel-Crafts conditions (2 equiv. of A1C13) affords methyl (S)-phenylpropionate in 50-80% chemical yield and as high as 97% optical yield. Unfortunately extension to other aromatics results in mixtures of isomeric products. 

Bandini, M., Melloni, A., Umani-Ronchi, A. New catalytic approaches in the stereoselective Friedel-Crafts alkylation reaction. Angew. Chem., Int. Ed. Engl. 2004, 43, 550-556. 

New catalytic approaches in the stereoselective Friedel-Crafts alkylation reaction 04AG(E)550. 

New Catalytic Approaches in the Stereoselective Friedel-Crafts Alkylation Reaction ... 

Friedel-Crafts alkylation 606-629, 676 Brpnsted acid catalyzed 612 Lewis acid catalyzed 607-611 solid acid catalyzed 612-621 stereoselective 621-626 under supercritical conditions 621 Fries rearrangement 472-478, 631, 685, 773, 774, 776, 778... 

The next step is a simple electrophilic attack by another molecule of formaldehyde on the alkene - in other words a simple Prins reaction 215 - showing the regioselectivity we expect to produce the secondary benzylic cation 216. The second molecule of formaldehyde has added onto the opposite side from the first. The resulting cation is perfectly placed for an intramolecular Friedel-Crafts alkylation 216 of the benzene ring. This is again a stereoselective reaction giving the more stable anti diastereoisomer 214. This sequence involves three successive C-C bondforming reactions and the stereochemistry is simply controlled by the preference for the more stable anti product. 

Friedel—Crafts alkylation of benzene with mesyl lactates under nonracemizing reaction conditions affords methyl or ethyl (5)-2-phenylpropionate (182) in high chemical yield and 97% optical yield [67,68]. The excellent stereoselectivity results from the ability of the Lewis acid to form a complex with 156 prior to the back-side attack of benzene with net inversion of configuration. Analogous reaction with isobutylbenzene produces a mixture of regioisomeric products from which (5)-ibuprofen is isolated. 

The approach to haplophytine proposed by Fukuyama and Tokuyama et al. did not rely on the synthesis of aspidophytine previously reported [75]. One of the main synthetic problems was the connection of the left-hand segment to the indole moiety of aspidophytine. Retrosynthetically, Fischer indole synthesis of the fully elaborated left-hand fragment 186 and the tricychc ketone 187 gave haplophytine. 186 was generated through oxidative skeletal rearrangement from precursor 188, which was accessible from indole 189 by Friedel-Crafts alkylation. Optically active ketone 187 was assembled through a stereoselective intramolecular Mannich reaction from aldehyde 190 (Scheme 33). 

Polysubstituted 3,4-dihydro-3-nitro-2ff-chromans are obtained from the enantioselective Michael—Michael cascade reaction of chalcone enolates and nitromethane catalyzed by bifunctional thiourea 19 (Scheme 31) (13JOC6488) and tandem Friedel—Crafts alkylation—Michael addition reaction of nitroolefin enoates and 1-methylindole promoted by Zn(OTf)2 (13S601).A squaramide-tertiary amine catalyst promotes the asymmetric sulfa-Michael—Michael cascade reaction of thiosalicylates with nitroalkene enoates which leads to polysubstituted chromans in high yields with excellent stereoselectivities (13OL1190). 

Cyclopenta[h]indoles can be synthesized in a multistep, one-pot procedure (Scheme 6.32). The reaction proceeds via an a-alkylation, which is catalyzed by a primary amine-substituted thiourea and two consecutive Brpnsted acid-catalyzed Friedel-Crafts alkylation reactions. Stmcturally diverse cyclopenta[ ]indoles can be obtained in high yields with excellent diastereo and enantioselectivities in this operation. Also, the cyclopenta[h]indoles can be converted into cyclopenta-[f>]indolines without loss of stereoselectivity. The potentially useful bisindole units are present in many natural and pharmaceutical products including yuehchukene. It is noteworthy... 

Podophyllum peltatumJLinum flavum by Lewis and coworkers [13a] using radiolabeled substrates, whereas (-)-matairesinol (45) that serves as a biosynthetic precursor for (-)-podophyllotoxin (39) had been also determined earlier by Dewick and coworkers [13b]. These late-stage transformations include modifications of two aryl rings and subsequent Friedel-Crafts alkylation of the resultant yatein (46) just like that described from 36 to 37 (Scheme 10.5). Finally, the regio- and stereoselective hydroxylation of (-)-deoxypodophyllotoxin (47) completes the biosynthesis of (-)-podophyllotoxin (39). 

Asymmetric Friedel-Crafts alkylations of indoles with a,p-unsaturated carbonyl compounds have been and continue to be of significant interests in synthesizing chiral indole alkaloids. Following the very successful iminium-catalysis with enals by MacMillan s catalyst [47], Chen and Melchiorre have independently reported asymmetric Friedel-Crafts alkylation of indoles with a,P-unsaturated aryl ketones [48] using similar cinchona-alkaloid derived catalysts 77 and 91, respectively (Scheme 5.24) [49]. In both cases, the proper choice of an acidic additive has been shown to be essential for catalytic activity and stereoselectivity. 

The carbon-carbon bond may be formed when a carbon nucleophile is used in the combination system. The most representative examples include the Friedel-Crafts-type alkylation of aromatics (Scheme XI, equation 1) (18) and the acid-catalyzed Diels-Alder reaction (Scheme XI, equation 2). The reaction of a combination system consisting of aluminum chloride and 1,3-dienes leading to regio- and stereoselective functionalization of 1,3-dienes via the thienium cation Diels-Alder reaction (19) (Scheme XI, equation 3) is described here. 

On the other hand, 2-naphthols have been used with different success as Michael donors in conjugate Friedel Crafts reactions with nitroalkenes and related substrates (Scheme 4.53). For example, cinchonine-derived thiourea 72b was identified as an excellent promoter for the reaction of a wide variety of 2-naphthols and nitroolefins, providing excellent yields and enantioselectivities. Remarkably, the more challenging p-alkyl substituted nitroalkenes were also found to undergo the reaction in a highly stereoselective way and with comparable yields to those obtained when nitrostyrene derivatives were employed. 

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