Asymmetric a-alkylation reactions

SCHEME 10.71 WAcylated sugar-derived chiral oxazolidinones are substrates for asymmetric a-alkylation reactions. 

The paramount importance of Michael additions as versatile C-C bond forming transformations was discussed in some detail earlier in this volume. Thus, it is not surprising that, besides the use of chiral PTCs in asymmetric a-alkylation reactions, their use for stereoselective Michael additions is one of the most carefully investigated reactions in asymmetric phase-transfer catalysis (328, 329). Accordingly, the additional use of this methodology in asymmetric total synthesis has been reported on several occasions. 

Early investigations have demonstrated that aldehydes and ketones can be enantioselectiveiy a-alkyl-ated via Michael reactions of the corresponding enamines, prepared from proline-derived secondary amines.149-156 However, optical purities of the products were generally low and never exceeded 59% ee.iS1 This kind of asymmetric a-alkylation could later be improved, allowing for example the preparation of compound (141) with high ee (Scheme 51).156-160... 

As many endeavors in transition-metal catalysis, the design, synthesis and screening of chiral ligands have played a pivotal role in the development of the asymmetric allylic alkylation reaction. A series of C2-symmetric diphosphines such as DiPAMP, chiraphos, DIOP. and BINAP,... 

The asymmetric a-alkylation of carbonyl compounds is a fundamental reaction. Under PTC conditions, acidic substrates such as phenylketone derivatives can be used to create chiral stereogenic centers. Andrus demonstrated asymmetric glycolate alkylation with up to 90% ee using various electrophiles and its application to the synthesis of (-)-ragaglitazar in six steps (Scheme 3.16) [37-39]. 

Raluy E, Dieguez M, Pamies O (2007) Sugar-based diphosphoroamidite as a promising new class of ligands in Pd-catalyzed asymmetric allylic alkylation reactions. J Org Chem 72 2842-2850... 

The report includes details for asymmetric a-alkylation of a symmetrical ketone (97% ee) via the SAMP hydrazone and references to other stereoselective reactions of SAMP (or RAMP) hydrazones. Under standard conditions (LDA, 0°), deprotonation takes place regioselectively at the less substituted a-position with uniform dia.stereoface differentiation. 

The obtained amino functionalised imidazolium salts could be used to generate the corresponding palladium(ll) carbene complexes using the silver(l) complexes as carbene transfer agents. Application of these palladium(ll) complexes (predominantly in situ) in asymmetric allylic alkylation reactions between ( )-l,3-diphenylprop-3-enyl acetate and dimethyl malonate (a standard reaction for this catalytic process [145]) gave up to 80% ee,... 

There are a number of metal-ligand systems that will provide the proper activation for nucleophile coupling, but the Pd system is by far the most well developed and useful. In recent years, asymmetric allylic alkylation reactions have received the most interest for organic synthesis apphcations (see Asymmetric Synthesis by Homogeneous Catalysis). Metals other than Pd have also received some additional attention. 

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. ... 

Asymmetric a-alkylation of amines was achieved applying an immobilized chiral sulfonamide (Scheme 12.29) [13, 40]. To synthesize auxiliary 76, a tertiary alcohol (73) was converted into Grignard reagent 74. Addition of sulfur dioxide and subsequent chlorination furnished the sulfinyl chloride 75. Reaction with (S)-2-amino-l,l,2-triphenylethanol, followed by reduction, hydroboration and... 

Owens, T.D., Souers, A.J. and Ellman, J.A. (2003) The preparation and utility of bis(sulfinyl) imidoamidine ligands for the copper-catalysed Diels-Alder reaction. The Journal of Organic Chemistry, 68, 3-10 Kochi, T. and Ellman, J.A. (2004) Asymmetric a-alkylation of N -tert-butanesulfinyl amidines. Application to the total synthesis of (6R,75)-7-amino-7,8-dihydro-a-bisabolene. Journal of the American Chemical Society, 126, 15652-15653. 

L-proline and derivatives function as effective catalysts in the a-fimctionahsation of aldehydes with a range of heteroatomic species (see Section 5.3) and Vignola and List have attempted to apply this methodology to the asymmetric a-alkylation. While the intermolecular reaction has proved unsuccessful, high ees in the cycli-sation of aldehydes such as (12.53) have been achieved using (S)-a-methylproline (12.52). 

The ABC-ring system of (—)-galanthamine has also been constructed using intramolecular Heck reactions with a particularly notable and early example being described by Trost et al. Specifically, they showed (Scheme 2) that on exposure to 15 mol% Pd(OAc)2, 15 mol% of the ligand diphenylphosphinopropane (dppp), and 3 mol equivalents of AgaCOs, the allylic ether 5, itself the product of an asymmetric allylic alkylation reaction, was converted into compound 6. This was then carried forward over a further four steps into (—)-galanthamine. 

In 2004 List and Vignola proposed the use of 7a to tackle the challenging asymmetric a-alkylation of aliphatic aldehydes. The transformation itself is complicated by the possibility of many side reactions, among which are self-aldolisation and N-alkylation of the amine catalyst, producing a cataly-tically inactive tertiary ammonium salt. Thus, when the proline-catalysed reaction between cyclohexanone or propanal and benzylbromide was tested, only the products of proline benzylation were identified. Luckily, the intramolecular a-allg lation worked successfully and after a screening of several proline derivatives and different amines, 7a was identified as the catalyst of choice (Scheme 11.6). Bromides and iodides may be used efficiently in these reactions, whereas tosylates gave particularly slow reactions. 

Eneouraged hy Bandini s pioneering studies, You and co-workers introduced indolyl carbonates 180 into Ir-catalyzed intramolecular asymmetric allylic alkylation reactions. Interestingly, spiroindolenine derivatives 181 are obtained in 50-98% yields with up to >99/1 dr and 97% ee (Scheme 6.83). Chiral phosphoramidite ligand (/ ,/ a)-170d (Me-THQphos), newly developed by the You group, was responsible for excellent reactivity, diastereo- and enantioselectivity of this process. 

MBH diene adducts have also been employed successfully in a palladium-catalyzed asymmetric allylic alkylation reactions with various phenols in good regio- and enantioselectivity. These high enantioselectivities are even more substantial considering the ambiguity introduced by the additional double bond in the allylic system (Scheme 3.139). ... 

The intramolecular organocatalytic asymmetric a-alkylation of aldehydes was developed by Vignola and List in 2004 [34]. Experimentally, it was found that 2-methylproline was a much better catalyst than proline itself, and Methylamine accelerated the reaction. A subsequent theoretical study by Fu, List, and Thiel [35] concluded that the reaction proceeds via an enamine displacement of the halogen. Triethylamine was found to provide a salt bridge between the carboxylic acid and the departing halide, and the stereoselectivity of the reaction was shown to arise from preferred cyclization (by 1 kcal/mol) of an a ri-enamine relative to that of the syn-enamine (Figure 2.12). The calculations also indicated that the enhanced enantio-selectivity of the 2-methylproline catalyzed aldol reaction compared with the proline-catalyzed process is due to the inherently larger steric interactions between the methyl and the aldehyde substituent in the syn transition state. 

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