Enantioselective allylic alkylations additions

Another major contribution of polydentate ligands is the creation of a chiral pocket around the catalytic center providing, an appropriate chiral environment. The chiral pocket concept has been introduced by Trost for catalytic enantioselective allylic alkylation with the tetradentate aminophosphine ligand 33 [133]. The nucleophile fits into the chiral environment created by the chiral ligand and the allyl Pd intermediate. As a result, the enantiocontrol of the newly formed chiral center is very effective. In addition, the chiral control is likely to be efficient even at positions remote from the chiral ligand. That auxiliary has been widely... 

The catalytic enantioselective addition of vinylmetals to activated alkenes is a potentially versatile but undeveloped class of transformations. Compared to processes with arylmetals and, particularly alkylmetals, processes with the corresponding vinylic reagents are of higher synthetic utility but remain scarce, and the relatively few reported examples are Rh-catalysed conjugate additions. In this context, Hoveyda et al. reported very recently an efficient method for catalytic asymmetric allylic alkylations with vinylaluminum reagents that were prepared and used in Thus, stereoselective reactions... 

A formal asymmetric nucleophilic addition to carbonyl compounds is achieved by Trost and his co-workers in the allylic alkylation of acylals of alkenals. An excellent enantioselectivity is observed in this alkylation. The starting acylals are easily prepared by the Lewis-acid catalyzed addition of acid anhydrides to aldehydes, by use of Trost s ligand 118 (Scheme 13), where various carbon-centered nucleophiles are available (Scheme l4),101,101a-10lc Asymmetric synthesis of some natural products is achieved according to this procedure. 

Catalytic enantioselective conjugate addition and allylic alkylation reactions using Grignard reagents... 

As recently highlighted by Woodward, enantioselective Sf/2 allylic substitution reactions are mechanistically related to conjugate addition reactions . Theoretical studies carried out by Nakamura and coworkers for the conjugate addition and allylic alkylation using Gilman s cuprates revealed profound mechanistic similarities between these two processes . ... 

A study of the synthesis of chromans from allylic carbonates involving Pd-catalysed asymmetric allylic alkylation has established that the addition of acetic acid results in a pronounced increase in enantioselectivity. Furthermore, (E) allylic carbonates afford (R) chromans and the (Z) substrates the (S) heterocycle (Scheme 13) <03JA9276>. This approach to chromans has been combined with a radical epoxide cyclisation in a total synthesis of (-)-siccanin <03AG(E)3943>. 

In 1999 Trost and Schroder reported on the first asymmetric allylic alkylation of nonstabilized ketone enolates of 2-substituted cyclohexanone derivatives, e.g. 2-methyl-1-tetralone (45), by using a catalytic amount of a chiral palladium complex formed from TT-allylpaUadium chloride dimer and the chiral cyclohexyldiamine derivative 47 (equation 14). The addition of tin chloride helped to soften the lithium enolate by transmetala-tion and a slight increase in enantioselectivity and yield for the alkylated product 46 was observed. Besides allyl acetate also linearly substituted or 1,3-dialkyl substituted allylic carbonates functioned well as electrophiles. A variety of cyclohexanones or cyclopen-tanones could be employed as nucleophiles with comparable results . Hon, Dai and coworkers reported comparable results for 45, using ferrocene-modified chiral ligands similar to 47. Their results were comparable to those obtained by Trost. 

Several enantioselective approaches to vitamin E (1), based on resolution of the products, the use of enantiopure natural building blocks, auxiliary controlled reactions and asymmetric oxidations have been described. In addition, a palladium-catalyzed asymmetric allylic alkylation reaction to build up the chiral chroman framework has been employed by Trost. Tietze and coworkers have developed asymmetric syntheses of the chiral chroman moiety using either the selective ally-lation of an alkyl methyl ketone or a Sharpless dihydroxylation as the key step. However, none of these methods is efficient enough for an industrial approach. ... 

Spectacular enantioselection has been observed in hydrogenation (cf. Section 2.2) [3] and hydrometallation of unsaturated compounds (cf. Section 2.6) [4], olefin epoxidation (cf Section 2.4.3) [5] and dihydroxylation (cf Section 3.3.2) [6], hydrovinylation (cf Section 3.3.3) [7], hydroformylation (cf Section 2.1.1) [4a, 8], carbene reactions [9] (cf Section 3.1.10), olefin isomerization (cf Section 3.2.14) [10], olefin oligomerization (cf Section 2.3.1.1) [11], organometallic addition to aldehydes [12], allylic alkylation [13], Grignard coupling reactions [14], aldol-type reactions [15], Diels-Alder reactions [12a, 16], and ene reactions [17], among others. This chapter presents several selected examples of practical significance. 

Allylation of ketones is a fundamental and important transformation, and therefore, efficient catalysts promoting addition of allylstannanes to ketones have been investigated [89]. Enantioselective allylation of ketones is a very challenging topic. It has been disclosed that asymmetric allylation of ketones with allylstannanes was promoted by addition of BINOL/TiCl2(OiPr)2 catalyst [90] or by premixing of BINOL with tetraallyltin [91]. In these reactions, however, enantioselectivity was not sufficient for practical purposes (acetophenone <65% ee). It was recently discovered that acetophenone was allylated by a mixture of tetraallyltin and an alkyl-triallyltin in the presence of monothiobinaphthol to furnish the desired chiral homoallyl alcohol with high enantioselectivity (Scheme 12.35) [92]. 

Based on our earlier success in developing heterogeneous catalysts for allylic alkylation (10), we took up the task of developing a polymer-based heterogeneous catalytic system for the enantioselective addition of diethylzinc to an aldehyde. We herein report the results from our investigation in this area. 

Chen and coworkers employed the cinchona alkaloid-derived catalyst 26 to direct Mannich additions of 3-methyloxindole 24 to the A-tosylimine 25 to afford the all-carbon quaternary center of oxindole 27 with good enantioselectivity (84% ee) [22]. The outcome of this Mannich reaction is notable in that it provided very good selectivity for the anti diastereomer (anti/syn 94 6). The mechanism of asymmetric induction has been suggested to involve a hydrogen bonding network between the cinchona alkaloid 26, the oxindole enolate of 24, and the imine electrophile 25 (Scheme 7). Asymmetric allylic alkylation of oxindoles with Morita-Baylis-Hillman carbonates has been reported by the same group [23]. 

The most common nucleophiles employed in the allylic alkylation are soft species such as malonate esters. However, Trost and Schroeder have discovered that high ees can be achieved in the addition of cyclic lithium enolates using ligand (10.54) with one equivalent of trimethyltin chloride, which may act to soften the nucleophilic species by transmetaUation to the tin enolate. Enantioselective additions of nonstabilised ketone enolates can also be achieved using an alternate palladium-catalysed decarboxylation protocol. In this approach an allyl 3-ketoester (10.72) or allyl vinyl carbonate (10.73) undergoes decarboxylation in the presence of Pd(0) to... 

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