Ethyl-DuPHOS

Form Supplied in colorless oil commercially available. Analysis of Reagent Purity optical rotation NMR spectroscopy. Preparative Methods the preparation of (5, 5)-ethyl-DuPHOS is based on (3R,61 )-octane-3,6-diol as an enantiomerically pure starting compound. The latter is synthesized by a three-step procedure starting from methyl 3-oxopentanoate, which is transformed to methyl (l )-3-hydroxypentanoate (99% ee) by enantioselective hydrogenation with a Ru-(R)-BINAP catalyst, followed by hydrolysis to the hydroxy acid. The subsequent electrochemical Kolbe coupling reaction leads to (3R,6R)-octane-3,6-diol in a protocol that can be scaled up to multigram quantities (eq 1). ... 

The chiral octanediol in turn is converted into the corresponding cyclic sulfate by reaction with thionyl chloride and subsequent oxidation with sodium periodate and a catalytic amount of ruthenium(ni) chloride (0.1 mol%) (eq 2). In the final step, 1,2-diphosphinobenzene is lithiated by treatment with n-butyllithium (n-BuLi 2 equiv, 1.6 mol% in hexane) followed by the addition of the (3R,6R)-octane-3,6-diol cyclic sulfate (2 equiv) and a further addition of 2.2 equiv of n-BuLi. (5,5)-Ethyl-DuPHOS is obtained in a yield of over 70% [78% yield was described for the (R,R)-enantiomer by an analogous method ]. In addition to (5,5)-ethyl-DuPHOS, a variety of related bisphospholanes either linked by an ethylene bridge, or bearing other 2,5-alkyl substituents, or with opposite configuration have been prepared by this methodology. ... 

Cationic rhodium(I) complexes such as Rh[(5,5)-ethyl-DuPHOS](cod) +X- (X=OTf, PFe, BF4, SbFe) are usually employed as precatalysts for enantioselective hydrogenation " or hydrosilylation reactions. The precatalysts can be prepared from the chiral ligand and [Rh(cod)2] X -complexes by a standard method. The corresponding Rh[(5, 5)-ethyl-DuPHOS](nbd) complex can be accessed equally well by the method of Schrock and Osborne or by exchange of cod in the relevant rhodium complex by norbornadiene (nbd). ... 

In these hydrogenations, less than 2% of the y,( -double bond was reduced. This feature indicates the ethyl-DuPHOS ligand to be superior in comparison to related DuPHOS/BPE-ligands or... 

Diastereoselective hydrogenation of a bis(dehydroamino acid) derivative, recognized to be important for the syntheses of isotyrosine, in the presence of Rh[(5, S)-ethyl-DuPHOS](cod) +OTl as catalyst yielded excellent results (eq 5). ... 

Table 2 Enantioselective hydrogenation of dehydroamino alcohols and dehydro-a-amino aldoximes with Rh[(,S,S)-ethyl-DuPHOS](cod) OTf ...

Enol acetates and corresponding derivatives constitute another class of unsaturated compounds that can advantageously be hydrogenated with high enantiomeric excess. This reaction is related to the enantioselective reduction of ketones. Acylated enol carboxy-lates (as an equivalent of a-keto carboxylic acid) can likewise be successfully reduced with rhodium(I) catalysts based on (5,5)-ethyl-DuPHOS (eq 8). Subsequent deprotection of the hydroxyl group or reduction of the carboxylic acid derivatives so obtained deliver chiral a-hydroxy carboxylates and 1,2-diols, respectively. 

Burk et al. showed that the Rh-(5,5)-ethyl-DuPHOS complex is able to reduce acylated a-hydroxy carboxylates with high enantiomeric excess independently of the E Z ratio of the alkene substrate (Table 3). However, the reaction failed when substrates branched in p-position were tested. 

Finally, several examples of the enantioselective hydrogenation of unsaturated substrates without any heteroatom attached to the olefinic double bond are noteworthy. Of particular relevance to the production of pharmaceutics, agrochemicals, flavors and aroma stuffs is the formation of the chiral 2-substituted succinates based on relevant itaconic acid derivatives. Burk et al. demonstrated that a rhodium(I) catalyst derived from (5,5)-ethyl-DuPHOS is able to hydrogenate aryl- or alkyl-substituted itaconic... 

A catalyst based on ethyl-DuPHOS also showed its high potential in the enantioselective hydrogenation of a sodium glutarate as the pivotal intermediate in the multi-step synthesis of candoxatril (eq 10). ... 

By application of the relevant Rh-(5,5)-ethyl-DuPHOS catalyst, no isomerization of the starting material to the enol ether occurred by migration of the double bond. This side reaction operates in the presence of the corresponding ruthenium catalysts. When (5,5)-ethyl-DuPHOS was applied as ligand the R-enantiomer was formed instead of the desired 5-enantiomer, necessary for the synthesis of candoxatril. 

Another example of the synthesis of a compound with pharmaceutical relevance is the chemical transformation of rac-warfarin into enantiomerically pure (R)- or (5)-warfarin. In the first step, rac-warfarin is oxidized to the corresponding ot,p-unsaturated ketone. The latter can be easily hydrogenated to the desired enantiomer by application of the appropriate DuPHOS-catalyst (eq 11). Prior transformation of dehydrowarfarin into the sodium salt or its methyl ether improved the yield and suppressed side reactions. Simultaneously, the enantioselectivity of the hydrogenation product was enhanced. The (5,5)-ethyl-DuPHOS-complex leads to R-configured warfarin. 

The enantioselective reduction of a C=N double bond is an interesting alternative for the production of chiral amines by hydrogenation of enamides. Required imines or oximes can be prepared by reaction of ketones with amines or hydroxylamines. However, to date, trials to reduce these substrates with ethyl-DuPHOS catalysts gave no satisfying results. Therefore, transformation of ketones or a-keto acids into acylhydrazones and subsequent enantioselective hydrogenation has proven advantageous (eq 12, Table 5). ... 

Table 5 Enantioselective hydrogenation of benzoylhydrazones with Rh[(5,5)-ethyl-DuPHOS](cod) +OTf catalyst (i-PrOH, 0.4 MPa Ha, S/C = 500 1) ...

The reactions were preferentially carried out by employment of (R,/f)-ethyl-DuPHOS giving rise to the S-configurated product. However, as Burk et al. pointed out, the antipodal (S,S)-configurated ligand gave same yields and ena-tiomeric excess, but products with R-configuration. 

Ethyl-DuPHOS has been employed mainly for enantioselective hydrogenation. Several types of reaction can be run very successfully. In other enantioselective reactions, this ligand has... 

It is likely that several results obtained with the homologous ligands of R-DuPHOS (R=Me, Pr) or their opposite enantiomers can be related also to (X5)-ethyl-DuPHOS. Recently, Burk has published a review about the application of phospholane ligands in asymmetric catalysis, which gives a good survey of the use of DuPHOS- and BPE-ligands. ... 

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