Enantioselectivity hydroformylation

Conceptually at least, these compounds can be obtained via initial enantioselective hydroformylation of the appropriate vinyl aromatic to branched chiral aldehyde and subsequent oxidation. 

Abstract Recent advances in synthetic aspects of the rhodium-catalyzed hydroformylation of alkenes are reviewed. Emphasis is given to practical improvements, efficient new catalysts for regioselective and enantioselective hydroformylation, and to applications of the reaction in organic synthesis. Furthermore, new developments in directed hydroformylation are covered as well as new approaches toward efficient hydroformylation catalysts employing the concept of self-assembly. 

Many chiral diphosphine ligands have been evaluated with regard to inducing enantioselectivity in the course of the hydroformylation reaction [25,26]. However, a real breakthrough occurred in 1993 with the discovery of the BI-NAPHOS ligand by Takaya and Nozaki [65]. This was the first efficient and rather general catalyst for the enantioselective hydroformylation of several classes of alkenes, such as aryl alkenes, 1-heteroatom-functionalized alkenes, and substituted 1,3-dienes, and is still a benchmark in this area [66,67]. But still a major problem in this field is the simultaneous control of enantio-... 

Second generation BINAPHOS-type ligands have been developed recently. Placing 3-methoxy substituents on the aryl phosphine unit furnishes a catalyst which allows for an enantioselective hydroformylation of vinylfurans (Scheme 19) [68]. 

Chiral thioureas have been synthesized and used as ligands for the asymmetric hydroformylation of styrene catalyzed by rhodium(I) complexes. The best results were obtained with /V-phenyl-TV -OS )-(l-phenylethyl)thiourea associated with a cationic rhodium(I) precursor, and asymmetric induction of 40% was then achieved.387,388 Chiral polyether-phosphite ligands derived from (5)-binaphthol were prepared and combined with [Rh(cod)2]BF4. These systems showed high activity, chemo- and regio-selectivity for the catalytic enantioselective hydroformylation of styrene in thermoregulated phase-transfer conditions. Ee values of up to 25% were obtained and recycling was possible without loss of enantioselectivity.389... 

Keywords Aldehydes Catalysis Enantioselectivity Hydroformylation Intermediates Rhodium... 

Highly enantioselective hydroformylation catalyzed by chiral metal complexes has been obtained with only a few catalytic systems. Many chiral phosphorus ligands have been used in Pt(II) and Rh(I) systems in the asymmetric hydroformylation of styrene. The first highly enantioselective examples of the asymmetric hydroformylation of styrene were reported by Consiglio et al. in 1991 and used Pt-Sn systems. ligand 1 achieved an ee of 86% (Fig. 1) [10-12],... 

Anchoring the catalyst to polymeric materials has some advantages in easy product separation and catalyst recovery for recycling. The first example of a polymer-supported rhodium catalyst for hydroformylation was reported in 1975. Since then, many reports have been published on polymer-supported catalysts here, we focus on examples of normal-sc QcxiY or enantioselective hydroformylation. 

The potential of QUINAPHOS ligands for asymmetric catalysis was assessed in rhodium-catalyzed enantioselective hydroformylation using styrene as a benchmark substrate (Table 2.1.5.2). The catalysts were prepared in situ from [(acac)Rh(CO)2] and 4 equiv of the diastereomeric mixture or the single diaste-... 

Hydroformylation of styrene and its analogues has attracted particular attention, since this provides a general method for the preparations of optically pure arylpropionic acids. Apart from Naproxen , the drug ibuprofen is another ar-ylpropionic acid-based nonsteroidal anti-inflammatory agent. As shown by 9.9, ibuprofen may in principle be synthesized by enantioselective hydroformylation reactions followed by oxidation of the aldehydic functionality. 

Discussion Point DP7 Select a chiral pharmaceutical or agrochemical which could usefully be synthesized using an enantioselective hydroformylation procedure, and show how this might be accomplished. 

Neutral catalysts or catalyst precursors based on fluorinated ligand systems have been applied in compressed CO2 to a broad range of transformations such as Zn- and Cr-catalyzed copolymerization of epoxides and CO2 [53, 54], Mo-catalyzed olefin metathesis [9], Pd-catalyzed coupling reactions [43, 55, 56] and Pd-catalyzed hydrogen peroxide synthesis [57]. Rhodium complexes with perfluoroalkyl-substituted P ligands proved successful in hydroformylation of terminal alkenes [28, 42, 44, 58], enantioselective hydroformylation [18, 59, 60], hydrogenation [61], hydroboration [62], and polymerization of phenylacetylene... 

The enantioselective hydroformylation using BINAPHOS-based ligand systems provides a particularly illustrative example. The original catalytic system... 

Much more recently, enantiocontrol issues have been addressed in hydroformylation reactions. The first study on stereoselective biphasic hydroformylation in IL appeared in 2007, using the chiral sulfonated ligand 56 in [bmim][BF4] for the enantioselective hydroformylation of vinyl acetate and styrene (Scheme 1.26). The hydroformylation of vinyl acetate resulted in the predominant formation of 2-acetoxypropanal with ee > 50%. In the hydrophilic IL [bmim][BF4], the 56 derived catalyst showed 79% conversion with high selectivity for the branched product, while the ee was moderate at around 22%. ... 

Because of their high solubility in supercritical carbon dioxide (scCOj), similar fluorous catalyst systems have also been successfully used for enantioselective hydroformylation of olefins in this environmentally benign reaction medium [19] (Scheme 3.4). 

Scheme 3.4 Synthesis ofthe chiral fluorous (R,S)-3-H F -Binaphos (16) ligand for the rhodium-catalyzed enantioselective hydroformylation of olefins in supercritical carbon dioxide (seCOj) [19] (Rf = (CH2)2(CF2)6F).

Tab. 2 Enantioselective hydroformylation of styrene using rhodium catalysts of BINAPHOS-type ligands immobilized in scC02.

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