Asymmetric allylic substitutions

Allylic substitutions are among the most important carbon-carbon bond-forming reactions in organic synthesis. Palladium-catalyzed allylic substitutions and their asymmetric version have been extensively studied and widely used in a variety of total syntheses [78]. The palladium catalysis mostly requires soft nucleophiles such as malonate carbanions to achieve high stereo- and regioselectivity. 

In 2002, Malmstrom and coworkers attached tlie first- to fourth-generation dendritic substituents based on 2,2-bis(hydroxymethyl)propinic acid and 

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Hie use of tlie cliiral catalyst 19b for asymmetric allylic substitution of allylic substrates bas been studied in some deta d fSdieme 8.18) and, under ji-selective reaction conditions, asymmetric induction was indeed obtained [28, 34]. 

Yamano T, Taya N, Kawada M, Huang T, Imamoto T (1999) Tetrahedron Lett 40 2577 Brunner H, Nishiyama H, Itoh K (1993) Asymmetric hydrosilylation. In Ojima I (ed) Catalytic asymmetric synthesis. Wiley-VCH, New York, chap 6 Sawamura M, Kuwano R, Ito Y (1994) Angew Chem, Int Ed Engl 33 111 Kuwano R, Uemura T, Saitoh M, Ito Y (1999) Tetrahedron Lett 40 1327 Hayashi T (1993) Asymmetric allylic substitution and grignard cross-coupling. In Ojima I (ed) Catalytic asymmetric synthesis. WUey-VCH, New York, chap 7-1 Trost BM, Vranken DLV (1996) Chem Rev 96 395 Consiglio G,Waymouth RM (1989) Chem Rev 89 257... 

In 2004, Shi et al. reported Pd-catalysed asymmetric allylic substitutions using axially chiral S/S- and S/O-heterodonor ligands based on the binaphthalene backbone. The test reaction was performed in the presence of... 

In 2001, Imamoto et al. reported the preparation of novel chiral S/P-bidentate ligands containing a chirogenic centre at the phosphorus atom and their stereoinduction capability in palladium-catalysed asymmetric allylic substitution reactions (Scheme 1.14)." ... 

The catalytic enantioselective desymmetrization of meso compounds is a powerful tool for the construction of enantiomerically enriched functionalized products." Meso cyclic allylic diol derivatives are challenging substrates for the asymmetric allylic substitution reaction owing to the potential competition of several reaction pathways. In particular, S 2 and 5n2 substitutions can occur, and both with either retention or inversion of the stereochemistry. In the... 

Good fortune and design in the discovery of iridium-catalyzed asymmetric allylic substitution. 

A fourth focus of catalytic chemistry in our laboratory has been iridium-catalyzed asymmetric allylic substitution. Dr. Toshimichi Ohmura had been studying additions to rhodium and iridium allyl and benzyl complexes in hopes of developing... 

As shown in Scheme 2.20, selective lithiation of substrate 2-87 by treatment with LDA in THF at -78 °C triggers an intramolecular Michael/intermolecular aldol addition process with benzaldehyde to give a mixture of diastereomers 2-90 and 2-91. 2-91 was afterwards transformed into 2-92, which is used as a chiral ligand for Pd-catalyzed asymmetric allylic substitution reactions [29]. 

The palladium-catalyzed asymmetric allylic substitution using seven different phosphano-oxazoline ligands at various ligand-to-metal ratios was also studied.112 An aluminum block containing 27 wells was placed in a dry box in which the reactions were carried out in parallel. Analyses were performed by conventional chiral GC equipped with an autosampler. Such a setup allowed about 33 catalyst evaluations per day. Apparently, only a few dozen were carried out in the study, resulting in the identification of a catalyst showing an ee-value of 74% in the reaction of 4-acyloxy-2-pentene with malonate.112 It is not clear whether further ligand diversification would lead to catalysts more selective than the record set in this case by the Trost-catalyst (92% ee).113... 

Asymmetric allylic substitution reactions have been studied for many years because they provide valuable chiral compounds. Regardless of the alkylating agent used, there are two major goals in these reactions (i) to minimize the amount of Sn2 products, and (ii) to maximize the enantiomeric purity of the Sn2 products. Various approaches have been investigated to achieve these goals. Recently, the efforts of several research groups have been focused on the... 

The synthesis of lycorane (13) by Mori and Shiba-saki121 is breathtaking for its use of three consecutive Pd catalyzed C-C bond forming reactions. Thus, Pd-catalyzed asymmetric allylic substitution of a benzoate in meso 7 in the presence of the chiral bisphos-phine 8 leads to the regioselective formation of 10 in 40 % ee It is easy to overlook this low level of enantioselectivity when we are faced with the subsequent elegant Pd-catalyzed reactions Pd-catalyzed intramolecular animation is followed by a Pd-catalyzed Heck coupling to afford 12, which is then readily converted to the target molecule... 

The moderate ees obtained with the copper arenethiolate ligands discussed above prompted a search for new chiral ligands for use in asymmetric allylic substitution reactions. The binaphthol-derived phosphoramidite ligand 32, used successfully by Feringa et al. in copper-catalyzed 1,4-addition reactions [37], was accordingly tested in the reaction between 21 and n-BuMgl. 

Ph, 4-CF3-C6H4-, 1-naphthyl, 2-naphthyl, c-CeH-n, 3-thienyl, (Z)-(/-Pr)3SiOCH2 R = neopentyl, PhMe2SiCH2, Me3SiCH2, (+)-myrtanyl, (-)-myrtanyl Scheme 8.23. Asymmetric allylic substitution catalyzed by 39 (Ar = 2-naphthyl). 

Scheme 1 Asymmetric allylic substitution catalyzed by metaiacyciic iridium-phosphoramidite complexes...

Mechanistic studies showed that metalacycle la is competent to be a catalyst in asymmetric allylic substitution reactions. The reaction of benzylamine with methyl ciimamyl carbonate catalyzed by a mixture of LI and [Ir(COD)Cl]2 occurs with an induction period and forms product in 84% yield and 95% ee, whereas the same reaction catalyzed by a mixture of metalacycle la and [Ir(COD)Cl]2 occurs without an induction period in just 2 hours to form the substitution product in 81% yield and 97% ee. The latter reaction was conducted with added [Ir(COD)Cl]2 to trap the -bound LI after dissociation. This ligand must dissociate to provide a site for oxidative addition of the allylic carbonate. 

Asymmetric allylic substitutions are widely applied in organic synthesis, using various metal complexes, chiral ligands, nucleophiles and allyl systems [39]. Although Pd is often the metal of choice, this is not the case for monosubstituted allylic substrates, where most Pd catalysts predominantly produce the achiral linear product. In contrast. Mo, W and Ir catalysts preferentially give rise to the desired branched products and, in recent years, a number of very effective Ir catalysts for various substrates have been developed [40]. Since, to the best of our... 

I 9 Iridium-Catalyzed Asymmetric Allylic Substitutions Table 9.2 Ir-catalyzed asymmetric allylic aminations. 

I 9 Iridium-Catal fzed Asymmetric Allylic Substitutions... 

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