Asymmetric allylation prochiral nucleophiles

Whereas preparation of a-amino acid derivatives by asymmetric allylation of an acyclic iminoglycinate gave a modest enantioselectivity (62% ee) in an early investigation [189], the use of conformationally constrained nucleophiles in an analogous alkylation resulted in high selectivities (Scheme 8E.43) [190], With 2-cyclohexenyl acetate, the alkylation of azlactones occurred with good diastereomeric ratios as well as excellent enantioselectivities. This method provides very facile access to a variety of a-alkylamino acids, which are difficult to synthesize by other methods. When a series of azlactones were alkylated with a prochiral gem-diacetate, excellent enantioselectivities were uniformly obtained for both the major and minor diastereom-ers (Eq. 8E.20 and Table 8E.12). 

Transition metal (such as Pd, Ir, Mo and W)-catalyzed asymmetric allylic substitutions with various nucleophiles are widely employed in organic synthesis and played an important role in the area of asymmetric C-C bond formation. Trost, Helmchen, Pfaltz and others have focused primarily on the direct allylation of malonates by prochiral electrophiles ... 

Having demonstrated the potential of artificial metalloenzymes for the reduction of V-protected dehydroaminoacids, we turned our attention towards organometallic-catalyzed reactions where the enantiodiscrimination step occurs without coordination of one of the reactants to the metal centre. We anticipated that incorporation of the metal complex within a protein enviromnent may steer the enantioselection without requiring transient coordination to the metal. In this context, we selected the palladium-catalyzed asymmetric allylic alkylation, the ruthenium-catalyzed transfer hydrogenation as well as the vanadyl-catalyzed sulfoxidation reaction. Indeed, these reactions are believed to proceed without prior coordination of the soft nucleophile, the prochiral ketone or the prochiral sulfide respectively. Figure 13.5. 

A-(Diphenylmethylene)glycine t-butyl ester (t-butyl glycinate-benzophenone Schiff base) (171) is a reactive prochiral nucleophile and a-allyl-a-amino acids can be prepared by allylation and hydrolysis of the allylated product. Asymmetric allylation of 171 with cinnamyl acetate (41) afforded 172 regioselec-tively with high % ee when the reaction was carried out in presence of achiral phosphite P(OPh)3, and a ehiral phase-transfer catalyst of alkaloid [0-allyl-(9-anthracenylmethyOcinchonidinium iodide] [65,66]. 

Scheme 12.78 Mo-catalyzed asymmetric allylic alkylations with prochiral nucleophiles [173, 179].

The use of a prochiral nucleophile in allylic substitution reactions provides an additional opportunity for asymmetric indnction. Allyl acetate itself can be used as the electrophilic partner and the new stereogenic center is positioned further away from the allyl group (Scheme 28). 

A comprehensive review of asymmetric allylic alkylation since our initial publication would be beyond the scope of this accotmt. Instead, we will highlight the use of prochiral nucleophiles in asymmetric allylic alkylation reactions. Unlike the majority of asymmetric allylic alkylation reactions, reactions involving prochiral nucleophiles generate a stereocenter on the nucleophile. Major advances have occurred with regard to the classes of prochiral nucleophiles that can be used in these reactions. 

Scheme 17 Non-ketone derived prochiral nucleophiles in asymmetric allylic alkylation...

The asymmetric Pd-catalyzed allylation of prochiral nucleophiles such a-acetoamido- 8-keto esters in toluene at —30 °C has been reported. The reaction with (/ )-BINAP provided an optically active a -allyl-Q -acetamido- 8-keto ester with high enantioselectiv-ity (eq 58). ... 

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

Sulfoxides (R1—SO—R2), which are tricoordinate sulfur compounds, are chiral when R1 and R2 are different, and a-sulfmyl carbanions derived from optically active sulfoxides are known to retain the chirality. Therefore, these chiral carbanions usually give products which are rich in one diastereomer upon treatment with some prochiral reagents. Thus, optically active sulfoxides have been used as versatile reagents for asymmetric syntheses of many naturally occurring products116, since optically active a-sulfinyl carbanions can cause asymmetric induction in the C—C bond formation due to their close vicinity. In the following four subsections various reactions of a-sulfinyl carbanions are described (A) alkylation and acylation, (B) addition to unsaturated bonds such as C=0, C=N or C= N, (C) nucleophilic addition to a, /5-unsaturated sulfoxides, and (D) reactions of allylic sulfoxides. 

Trost and his co-workers succeeded in the allylic alkylation of prochiral carbon-centered nucleophiles in the presence of Trost s ligand 118 and obtained the corresponding allylated compounds with an excellent enantioselec-tivity. A variety of prochiral carbon-centered nucleophiles such as / -keto esters, a-substituted ketones, and 3-aryl oxindoles are available for this asymmetric reaction (Scheme jg) Il3,ll3a-ll3g Q jjg recently, highly enantioselective allylation of acyclic ketones such as acetophenone derivatives has been reported by Hou and his co-workers, Trost and and Stoltz and Behenna - (Scheme 18-1). On the other hand, Ito and Kuwano... 

An interesting use of the nickel-catalyzed allylic alkylation has prochiral allylic ketals as substrate (Scheme 8E.47) [206]. In contrast to the previous kinetic-resolution process, the enantioselectivity achieved in the ionization step is directly reflected in the stereochemical outcome of the reaction. Thus, the commonly observed variation of the enantioselectivity with respect to the structure of the nucleophile is avoided in this type of reaction. Depending on the method of isolation, the regio- and enantioselective substitution gives an asymmetric Michael adduct or an enol ether in quite good enantioselectivity to provide further synthetic flexibility. 

Besides the transition-metal-catalyzed asymmetric addition reactions to prochiral olefins, the substitution reaction of a carbon nucleophile to allylic esters has been investigated using a variety of chiral transition-metal catalysts. Using the aforementioned sugar diphosphites... 

Alcohols can be obtained from many other classes of compounds such as alkyl halides, amines, al-kenes, epoxides and carbonyl compounds. The addition of nucleophiles to carbonyl compounds is a versatile and convenient methc for the the preparation of alcohols. Regioselective oxirane ring opening of epoxides by nucleophiles is another important route for the synthesis of alcohols. However, stereospe-cific oxirane ring formation is prerequisite to the use of epoxides in organic synthesis. The chemistry of epoxides has been extensively studied in this decade and the development of the diastereoselective oxidations of alkenic alcohols makes epoxy alcohols with definite configurations readily available. Recently developed asymmetric epoxidation of prochiral allylic alcohols allows the enantioselective synthesis of 2,3-epoxy alcohols. 

In another example, Shibasaki and co-workers applied an asymmetric Heck reaction/anion-capture cascade process to the total synthesis of marine sesquiterpenes capnellenols 14 and capnellene 17 (Schemes 13.5 and 13.6). The cascade involved the use of prochiral cyclo-pentadienyl systems for the generation of bicyclic 71-allyl-palladium species, which were then trapped by a suitable nucleophile. Initial studies in the total synthesis of capnellenols described the trapping of the 71-allylpalladium... 

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