Chiral compounds asymmetric hydroformylation

Considerable advances in asymmetric hydroformylation, a process which, among other things, provides a potential route to enantiomericaHy pure biologically active compounds, have occurred. Of particular interest are preparations of nonsteroidal antiinflammatory (NSAI) pharmaceuticals such as Naproxen (8) and Ibuprofen (9), where the represents a chiral center. 

Chiral bis-(binaphthophosphole) (bis(BNP)) ligands have been used in the asymmetric hydroformylation of styrene. In solution, the free diphospholes display fluxional behavior. Consistent with their structure, the reaction of the bis(BNP) compounds with platinum(II) derivatives gives either cis chelate mononuclear complexes or trans phosphorus-bridged polynuclear derivatives. Coordination to platinum enhances the conformational stability of bis(BNP)s and diastereomeric complexes can be detected in solution. In the presence of SnCl2, the platinum complexes give rise to catalysts that exhibit remarkable activity in the hydroformylation of styrene. Under optimum conditions, reaction takes place with high branched selectivity (80-85%) and moderate enantio-selectivity (up to 45% ee). 

Rhodium complexes with chiral dithiolato and dithiother ligands have been studied in rhodium-catalyzed asymmetric hydroformylation. In all instances, enantioselectivities were low.391-393 Catalysis with compounds containing thiolate ligands has been reviewed.394... 

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. 

Through asymmetric hydroformylation a broad variety of chiral molecules are accessible which are valuable precursors for pharmaceuticals and agrochemicals. The potential market for synthetic chiral products in bulk form at the beginning of the 21st century is estimated to be more than US 2 billion [70], In order to obtain pure compounds, high regioselectivity and high enantioselectivity have to be combined. The desired product is the branched compound with an asymmetric carbon atom (eq. (3)). 

Some heterocyclic systems such as tetrahydrofuxan, tetrahydropyran, thiophene, and pyrrolidine are foimd in a wide range of biologically active compounds. Hydroformylation of these heterocyclic olefins provides a potential synthetic route for the synthesis of these targets (Scheme 11) [93,94]. Asymmetric hydroformylation of a-methylene-y-butyrolactone using the cationic Rh(I)-(l )-BINAP complex as a catalyst is also reported to give an aldehydic lactone containing a quaternary chiral center in up to 37% ee [95]. 

Carboxylic acids and their derivatives, esters, amides, anhydrides, and acyl halides, are formally synthesized from olefins, carbon monoxide, and compounds represented with HX where X- equals OR-, NR2-, etc (see Scheme 1). Considering that the chiral aldehydes obtained by asymmetric hydroformylation of viny-larenes are often oxidized in order to exhibit biological activities, asymmetric hydrocarboxylation and its related reactions naturally attract much attention. Unfortunately, however, as yet only less successful work has been reported on this subject than on hydroformylation. Palladium(II) is most commonly used for this purpose. Asymmetric hydrocarboxylation of olefins was first reported in 1973 by Pino using PdCl2 and (-)-DIOP [105]. Chiusoh reached 52% ee in the... 

The asymmetric hydroformylation of alkenes is an exceptionally atom-efficient method for the synthesis of enantiomerically-pure carbonyl-containing compounds.[1] The hydroformylation of vinylacetate, in particular, represents an excellent method for the preparation of ot-alkoxy aldehydes and, through their reduction, homochiral 1,2-diols. The use of the novel chiral ligand, ESPHOS (1),[2] in a rhodium(I) complex, results in hydroformylation of vinyl acetate in high branched linear selectivity and exceptional ee (Figure 12.1).[3]... 

Optically-active aldehydes are very important as precursors not only for biologically active compounds but also for new materials. Asymmetric hydroformylation is an attractive catalytic approach to the synthesis of a large number of chiral aldehydes. With the platinum precursor (Pt(PhCN)2Cl2), anhydrous tin(II) chloride was used as cocatalyst (SnCl2/Pt 1), which is essential for catalytic activity. In case of rhodium systems an excess amount (P/Rh = 4) of diphosphite ligand was always added to the catalyst precursor to exclude the formation of HRh(CO)4, which is an active achiral hydroformylation catalyst. 

Thus, considerable effort is necessary to achieve a wide and synthetically useful application of this method. Nevertheless, the first examples of interesting target molecules obtainable via asymmetric hydroformylation have appeared (amino acids, arylpropionic acids)180. Thus, if appropriate catalytic systems and reaction conditions can be found, even industrial applications might be realized within the near future. Thus, asymmetric hydroformylation is considered to be a powerful tool for the preparation of a large number of different chiral products to be used as precursors of several organic compounds endowed with therapeutical activity180. Examples are the essential and non-essential amino acids, 2-arylpropanoic acids, aryloxypropyl-and /1-phenylpropylamines. modified /1-phenylethylamines, pheniramines and others180. 

Asymmetric hydroformylation with participation of immobilized chiral complexes is the most promising reaction for catalytic synthesis of optically active compounds. The reaction proceeds by the scheme shown in Eq. (12-36) ... 

By appl3dng a chiral catalyst in the hydroformylation of prochiral olefins as a substrate, the ratio of enantiomers of the chiral aldehydes can be influenced. Enantioselectivities >98% have been achieved by using chiral platinum and rhodium complexes as the catalysts, providing a tool for the production of optically active compounds for pharmaceutical or agrochemical uses. For leading reviews of asymmetric hydroformylation, see Refs. (4-10). 

The most crucial precondition for the application of hydroformylation in fragrance production is ensuring a high degree of chemo- and regioselectivity, since even small amounts of byproducts can spoil the desired overall odor impression. In case of asymmetric hydroformylation, the formation of almost perfect enan-tioselectivity is aimed, since most chiral odorants are perceived by humans in a highly stereoselective manner [28]. Noteworthy, in rare cases, also naturally occurring compounds (e.g., some terpenes) may not be completely enantiomerically pure [29]. 

The Rh-catalyzed asymmetric hydroformylation was studied with trans-1-phenyl-l-propene as substrate (Scheme 6.68) [182]. Monodentate chiral phosphites with a cone angle in the range of 240-270° were used. In best cases, TOFs of 200h were noted. The 1-formyl compound was formed dominantly. 

Chiral aldehydes may be better soluble in SCCO2 than linear (achiral) aldehydes, which allows enantioenrichment of compounds with insufficient enantiomeric excess values by phase separation after the asymmetric hydroformylation [84,85]. 

Asymmetric hydroformylation of heterocyclic olefins provides potentially useful synthetic building blocks for the syntheses of biologically active compounds. The reactions of 2,5-dihy-drofuran 27a (Eq. 7), dihydropyrroles (27b, 27c, and 29) (Eqs. 7.7,7.8), and dioxepin 32 (Eq. 7.9) give the corresponding aldehydes with 47-88% ee [92]. Reaction of a-methylene-y-buty-rolactone (34) using cationic Rh-(R)-BINAP complex as the catalyst affords the formyUactone 35, bearing a quaternary chiral center, with <37% ee (Eq. 7.10) [93]. 

A number of chiral bisphosphines related to DiPAMP(l) were prepared and evaluated in asymmetric catalysis. Many variants were closely equivalent but none were superior to the parent compound. In addition, some monophosphines containing sulfone substituents were quite effective. These had the particular advantage of being usable in water solution. Several new DIOP derivatives were tried in the hydroformylation of vinyl acetate but only modest enantiomeric excesses were achieved. A 72% enantiomeric excess was achieved on dehydrovaline under relatively forcing conditions using DiCAMP(3). This result was remarkable since these phosphine ligands generally work very poorly, if at all, on tetrasubstituted olefins. 

Miscellaneous. - Several new optically active tervalent phosphorus acid derivatives have been prepared for use as ligands in asymmetric metal catalysed reactions. These include the cyclic diaminophosphines 57, the cyclic bisamino-phosphine 58, and the compounds 59, 60, 61, and 62 containing a 1,1 -binaphthalene group as the chiral inducer. A new diphosphoramidite (63) has been used for improved regioselectivity of rhodium-catalysed hydroformylations of alkenes. A new sterically hindered chiral phosphite (64) derived from glucose and a Cu(I) complex of 64 have been prepared. ... 

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