Asymmetric Tsuji allylation

Palladium-Catalyzed Asymmetric Tsuji Allylation of Allyl Enol Carbonates... 

Table 2 Non-PHOX ligands synthesized and tested in the asymmetric Tsuji allylation...

Computational simulation of asymmetric Tsuji allylation involving prochiral nucleophiles and nonprochiral allyl fragments has proved to be consistent with experimental findings (Scheme 182). " ... 

Thus, [HRh(C0)(TPPTS)3]/H20/silica (TPPTS = sodium salt of tri(m-sulfophenyl)phopshine) catalyzes the hydroformylation of heavy and functionalized olefins,118-122 the selective hydrogenation of a,/3-unsaturated aldehydes,84 and the asymmetric hydrogenation of 2-(6 -methoxy-2 -naphthyl)acrylic add (a precursor of naproxen).123,124 More recently, this methodology was tested for the palladium-catalyzed Trost Tsuji (allylic substitution) and Heck (olefin arylation) reactions.125-127... 

The enantioselectivity associated with quaternary allylation is connected with scenario 5 above (one of the five points associated in the catalytic cycles shown by Schemes 12.10a and b where chirality could be induced), which is where enantioselection of one of two faces of the nucleophile (the enolate ion) occurs. Theoretical studies of the transformation using the PHOX ligand have shown support for an inner sphere mechanism, where nucleophilic attack of the enolate onto the rf-allyl ligand occurs from the Pd-bound enolate and not from an external nucleophile.74 These studies have not been able to definitively determine the step that defines the enantioselectivity of the reaction, and it is not clear how these results would carry over to reactions involving the Trost ligands. At this time, selection of which ligand one should use not only to induce enantioselectivity but also to predict the sense of absolute configuration of any asymmetric Tsuji-Trost allylation is mostly based on empirical results. Work continues on this... 

Asymmetric Induction on the Nucleophile The use of the tBu-PHOX ligand led to the first catalytic enantioselective Tsuji allylations of simple alkanone enol derivatives 62. These mild, operationally straightforward and stereoselective reactions described by Stoltz et al. [52] produce chiral cycloalkanones 63 with quaternary stereocenters at the a-position with high enantiopurities and in excellent chemical yields (Scheme 12.31). Mechanistic studies showed the incorporation of an O-bound enolate in the intermediate Pd-allyl complex [53]. Further investigations on the substrate scope led to several applications in the synthesis of natural products [54]. Recently, a similar approach was used to afford enantiopure quaternary lactams 65 that intercept synthetic intermediates previously used in the synthesis of the Aspidospcrma alkaloids quebrachamine and rhazinilam, but that were previously only available by chiral-auxiliary-assisted approaches or as racemic mixtures (Scheme 12.32) [55],... 

Tsuji Allylation A significant contribution to the field of asymmetric ketone alkylation is the Tsuji allylation. This method represents one of the only catalytic methods for asymmetric alkylation that has been suitably successful for application in the context of complex natural products. Significantly, this method also allows for the formation of all carbon quaternary stereocenters. 

The formation of chromane derivatives has also been realised in the palladium catalyzed intramolecular nucleophilic substitution of allyl carbonates (Tsuji-Trost reaction). In most cases the reaction is accompanied by the formation of a new centre of chirality. Using Trost s chiral ligand the ring closure was carried out in an enantioselective manner. The asymmetric allylation of the phenol derivative shown in 4.20. was achieved both in good yield and with excellent selectivity.23... 

Enol carbonates react with alkylating agents in the presence of a palladium catalyst. The decarboxylative alkylation of allyl enol carbonates to the corresponding aUylcyclohexanone derivatives is known as the Tsuji alkylation. An asymmetric version of this reaction has been reported. The same reaction can be done using enolate anion and aUylic acetates with a palladium catalyst. ... 

Pd-catalyzed allylic substitutions such as the Tsuji-Trost reaction have been investigated widely, essentially in their asymmetric version [44]. This represents a valuable tool in organic synthesis since the catalyst can accommodate various functionalities on the substrate and it is possible to tune the coordination sphere through the electronic and steric effects of the ligands. Those which contain a sulfur atom are based on an oxazoline backbone, and an ee as high as 96 % has been... 

In the laboratory of B.M. Trost, the second generation asymmetric synthesis of the potent glycosidase inhibitor (-)-cyclophellitol was completed using a Tsuji-Trost allylation as the key step. The synthetic plan called for the conversion of the a-nitrosulfone allylation product to the corresponding carboxylic acid or ester. Numerous oxidative Nef reaction conditions were tested, but most of them caused extensive decomposition of the starting material or no reaction at all. Luckily, the nitrosulfone could be efficiently oxidized with dimethyidioxirane under basic conditions (TMG) to afford the desired carboxylic acid in high yield. 

It was not long after the original work on the Trost-Tsuji reaction that asymmetric examples were reported.60 In recent years, numerous cases have appeared where this reaction was used to create chiral substituted allylic compounds in high % ee. Enhancement of chirality in allyl substrates is challenging because chemistry on the allylic ligand occurs remotely from the chiral ligand also attached to the metal. There are several different points in the catalytic cycles depicted in Schemes 12.10a and b where asymmetric induction could occur.61 These scenarios include the following ... 

The asymmetric alkylation of allylic systems by means of palladium catalysis, the so-called Tsuji-Trost reaction, is one of the most investigated asymmetric catalytic reactions [34,35]. It is therefore no surprise that it has also caused interest in the area of ACTC ligands. 

In contrast to the processes based on the external attack of a nucleophile on the coordinated CO or olefin ligands on Pd(II) species, where re-oxidation of the Pd(0) produced to reactive Pd(II) presents a considerable problem, no such problem is involved in reaction of a Pd(0) complex with allylic substrates. As we have already discussed in Schemes 1.9 and 1.10, allylic compounds such as allylic acetates or carbonates readily oxidatively add to Pd(0) species to form 7 -allyl palladium(II) complexes that are susceptible to nucleophilic attack. The catalytic process converting allylic substrates to produce allylation products of nucleophiles has found extensive uses in organic synthesis, notably in the work of Tsuji and Trost. Employment of a chiral ligand in the catalytic allylation of nucleophiles allows catalytic asymmetric synthesis of allylation... 

The use of palladium(II) 7i-allyl complexes in organic chemistry has a rich history. These complexes were the first examples of a C-M bond to be used as an electrophile [1-3]. At the dawn of the era of asymmetric catalysis, the use of chiral phosphines in palladium-catalyzed allylic alkylation reactions provided key early successes in asymmetric C-C bond formation that were an important validation of the usefulness of the field [4]. No researchers were more important to these innovations than Prof. B.M. Trost and Prof. J. Tsuji [5-10]. While most of the early discoveries in this field provided access to tertiary (3°) stereocenters formed on a prochiral electrophile [Eq. (1)] (Scheme 1), our interest focused on making quaternary (4°) stereocenters on prochiral enolates [Eq. (2)]. Recently, we have described decarboxylative asymmetric allylic alkylation reactions involving prochiral enolates that provide access to enantioenriched ot-quatemary carbonyl compounds [11-13]. We found that a range of substrates (e.g., allyl enol carbonates,... 

Allylic alkylation, also known as the Tsuji-Trost reaction, operates via a unique mechanism that exploits the electrophihcity of 7t-allyl Pd complexes. It is a versatile transformation in asymmetric synthesis, and new catalysts are generally tested in this benchmark reaction. The investigation of functionalised NHC ligands containing electronically dissimilar groups has met limited success. Actually, allylic alkylation is one of the rare transformations in which phosphines still outperform NHCs. 

In 1977, Trost published the first example of an asymmetric variant of the Tsuji-Trost reaction, termed the asymmetric allylic alkylation reaction (AAA). Much of the subsequent development of the AAA reaction can be attributed to the dedicated work of Trost and co-workers.There was a substantial time lag however, in the development of processes where high enantioselectivities were realized in a predictable fashion. This was due, in part, to the fact that chiral, asymmetrically pure ligands must create a chiral environment on the opposite face of the allyl fragment to the metal centre (a stereoelectronic requirement, vide infra)P This obviously represents a significant design challenge in the production of effective ligand systems. 

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