Asymmetric hydrocarboxylation

Ojima, I. Eguchi, M. Tzamarioudaki, M. Transition Metal Hydrides Hydrocarboxylation, Hydroformylation, and Asymmetric Hydrogenation. In Wilkinson, G. Stone, F. B. A. Abel, E. W., Eds., Comprehensive Organometallic Chemistry 2, Vol. 12, Pergamon, Oxford, 1995, Chapter 2. 

Since the discovery and development of highly efficient Rh catalysts with chiral diphosphites and phosphine-phosphites in the 1990s, the enantioselectivity of asymmetric hydroformylation has reached the equivalent level to that of asymmetric hydrogenation for several substrates. Nevertheless, there still exist substrates that require even further development of more efficient chiral ligands, catalyst systems, and reaction conditions. Diastereoselective hydroformylation is expected to find many applications in the total synthesis of complex natural products as well as the syntheses of biologically active compounds of medicinal and agrochemical interests in the near future. Advances in asymmetric hydrocarboxylation has been much slower than that of asymmetric hydroformylation in spite of its high potential in the syntheses of fine chemicals. 

Gonsidering that the chiral aldehydes obtained by asymmetric hydroformylation of vinylarenes are often oxidized to give the corresponding acids that exhibit biological activities, asymmetric hydrocarboxylation and its related reactions naturally attract much attention. Unfortunately, however, less successful work has not been reported on this subject than on the hydroformylation. Palladium(ii) is most commonly used for this purpose. Styrene and other vinylaromatics are most widely examined and the data for representative examples are summarized in Table 14. The products are of... 

Styrene characteristically yields the branched acid in the presence of palladium and monodentate phosphine ligands,132 142 and in the [Fe(CO)5]-promoted process.143 Palladium with certain bidentate phosphines, in turn, produces more linear acid.142 Asymmetric hydrocarboxylations with palladium complexes and chiral ligands with enantiomeric excesses up to 84% have been reported.144 145... 

Advance in asymmetric hydrocarboxylation has been much slower than that of asymmetric hydroformylation in spite of its high potential in the syntheses of fine chemicals. However, some very encouraging results have recently been reported, and thus much improvements in this reaction can be expected in the next decade. 

Asymmetric hydrocarboxylation of styrenes.1 Use of (S)- or (R)-l as a chiral ligand in the palladium-catalyzed hydrocarboxylation of p-isobutylstyrene (2) results in (S)- or (R)-2 (ibuprofen) in 83-84% ee. Similar enantioselectivity obtains in hydrocarboxylation of a 2-vinylnaphthalene to form naproxen. 

Other approaches that have been suggested include catalytic asymmetric hydroformylation of 2-methoxy-6-vinylnaphthalene (6) using a rhodium catalyst on BINAPHOS ligand followed by oxidation of the resultant aldehyde 7 to yield 5-naproxen (Scheme 6.3).22 However, the tendency of the aldehyde to racemize and the co-generation of the linear aldehyde isomer make the process less attractive. Other modifications related to this process include catalytic asymmetric hydroesterification,23 hydrocarboxylation,24 and hydrocyanation.25... 

Other asymmetric synthetic processes used for the manufacturing of (S)-(+)-naproxen can also be applied to the production of (S)-(+)-ibuprofen these include the Rh-phosphite catalyzed hydro-formylation,37 hydrocyanation,25 and hydrocarboxylation reactions.24... 

Hydrocarboxylation. The cyclic phosphate resolved according to eq 2 can be used as the chiral ligand in the palladium(II) catalyzed asymmetric hydrocarboxylation of arylethylenes. The 1-arylpropanoic acid is obtained regiospecifically with high enan-tioselectivity (91% ee) (eq 4). 

Chiral Ligand for Asymmetric Catalysts. (5)-(+)- and (R)-(—)-BNPPA are efficient chiral ligands for the Pd-catalyzed hydrocarboxylation of alkenes. Naproxen can be obtained re-gioselectively in 91% ee (eq 2). 

Asymmetric Hydrocarboxylation. The title reagent was used in the first example of an asymmetric hydrocarboxylation (eq 1). With the a-methylstyrene, the straight chain isomer was formed. The regiospecificity was much less pronounced, however, for other alkenic substrates. The influence of some reaction variables on the reaction shown in eq 1 was studied. For example, the presence of a solvent such as THF or benzene, the alcohol source, the effect of CO pressure, the effect of substitution on the phenyl ring, the PdC /DIOP molar ratio, or the presence of PPha along with DIOP, were varied to improve the optical yield. ... 

Scheme 5. Asymmetric synthesis of profens by hydrocarboxylation of aryl olefins.

Traditionally carbonylation reactions are underestimated in fine chemical business. Due to an abundance of starting materials and relatively inexpensive carbon monoxide or syn gas carbonylations will be enq>loyed more often to synthesize interesting building blocks amino acids via amidocarbonylation, profenes by asymmetric hydroformylations or hydrocarboxylations, reductive and oxidative carbonylations towards urethanes and ureas, etc. 

Asymmetric hydrocarboxylation of a-methylstyrene was also examined, leading to 3-phenylbutanal, the normal-product. The highest enantiomeric excess is... 

Structure 2. Examples of chiral ligands used in Pd-catalyzed asymmetric hydrocarboxylations... 

In spite of its potential apphcability in fine chemical synthesis, asymmetric hydrocarboxylation seems to be waiting for a conceptual improvement to meet practical interests. 

Transition metal catalyzed asymmetric hydrocarboration reactions are addition reactions forming one C—C and one C—H bond. Prominent examples are hydrovinylation, hydroformylation, hydroacylation, hydrocarboxylation, and hydrocyanation. Various related conversions, such as hydroalkylation, hydroarylation, conjugate addition, reductive dimerization, and metal induced ene reactions are collected in Section 1.5.8.2.6. dealing with miscellaneous methods of this type. Some of these methods are not exclusively mediated by metal catalysts and therefore are also covered in other sections of this volume. 

The first examples of asymmetric hydrocarboxylation have been reported for various alkenes, converted in the presence of palladium(II) chloride and Diop, with a maximum ee of 14.2% 6 (for 2-phenylpropene). In this unsymmetrical addition reaction, similar to hydroformylation, both at- and -induction via C—C and C —H bond formation are observed. Styrene and 2-phenyl-l-propene (a-methylstyrene) are typical examples. 

While early results of asymmetric hydrocarboxylation were considered as promising developments l3, for a long time only a few examples of low-to-medium asymmetric induction were reported. This failure to achieve successful asymmetric hydrocarboxylation is attributed to the fact that high carbon monoxide pressures (359.1 —452.2 bar) are necessary8. Usually palladium ) chloride is used together with Diop-type ligands. This catalyst system, prepared in situ, requires milder reaction conditions (50 °C) than cobalt (140 °C) or other metal catalysts. 

Only recently have better results for asymmetric hydrocarboxylation and interesting applications to stereoselective organic synthesis been achieved. Earlier results are extensively reviewed together with other catalytic methods7-13 39-4,1. As in asymmetric hydroformylation a simple model can be applied to predict the prevailing antipode and regioisomer in the reaction products of asymmetric hydrocarboxylation12. 

One of the first examples of the asymmetric hydrocarboxylation of a-methylstyrene (2-phenyl-1-propene) in the presence of palladium(II) chloride and Diop was reported with a maximum enantiomeric excess of 14.2 % 6. In this case /7-induetion was achieved in the linear product via C-H bond formation. a-Induction through C.-C bond formation occurs in the branched product of styrene. Interestingly, the reaction of a-methylstyrene with different alcohols gives varying amounts of asymmetric induction. While 9.7% op is observed with ethanol, the more sterically hindered 2-propanol gives the linear product with 14.2% op6. 

The conversion of a-methylstyrene (2-phenyl- 1-propene) also serves as a model reaction in many other investigations of asymmetric hydrocarboxylation. Due to its high regioselectivity and low tendency for alkene isomerization, only the linear reaction product is formed (> 95 %) together with minor amounts of the achiral branched product. With styrene itself, and other vinyl aromatics generally lower regioselectivities are observed. The results of asymmetric hydrocarboxylation of this substrate type are compiled in Table 10. 

Asymmetric hydrocarboxylation of a-ethylstyrene (2-phenyl-l-butene) giving asymmetric induction in both regioisomers shows that regioselectivity is different for the two enantio-faces12. 

Table 10. Asymmetric Hydrocarboxylation of Styrene and Other Vinyl Aromatics... 

Many other chiral phosphane ligands are used in asymmetric hydrocarboxylation. In the presence of NMDPP and trifluoroacetic acid in methanol carbomethoxylation of vinyl aromatics. in particular styrene, with palladium(0)bis(dibenzylidcncacetone) takes place with marked asymmetric induction (up to 52% cc) and high selectivities towards the branched product (94%)20. With other chiral ligands and other acids only smaller inductions are observed using the same catalytic system. With an increase in carbon monoxide pressure the asymmetric induction decreases. Involvement of the complex PdH(PR3),OCOCF3 is presumed20. 

Asymmetric hydrocarboxylation of styrene and aliphatic alkenes with palladium(II) chloride in the presence of the steroidal phosphanes (+)-DICOL and (—)-DIOCOL (prepared from cholesterol) show remarkable catalytic activity and very high regioselectivity, but only poor stereoselectivities21, 22. Optical yields of up to 12.5% ee are obtained in asymmetric hydrocar-boxylations using DIOCOL. The results obtained with DICOL and DIOCOL have been compared with the inductions obtained with Diop. 

More effective regio- and enantiosclcctivc asymmetric synthesis of branched optically active free carboxylic acids via palladium-catalyzed hydrocarboxylation of alkenes is achieved in the presence of (-)-(/ )- or ( + )-(5)-2,2/-(l,r-binaphthyl)phosphoric acid23. 

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