Synthesis of α-Heteroarylpropanoic Acid via Asymmetric Hydroformylation Catalyzed by Rh(I)-(R,S)-BINAPHOS and the Subsequent Oxidation

Abstract

The asymmetric hydroformylation of vinyl heteroarenes (vinylfurans and vinylthiophenes) was investigated by using Rh(I)-BINAPHOS derivatives as a catalyst. The hydroformylation of vinylthiophenes 1 gave the corresponding branched aldehydes 2 with high enantiopurities as major products. Oxidation of the aldehydes 2 successfully afforded alpha-heteroarylpropanoic acids 4 in good yields. In addition, the aldehydes 2 were reduced to alcohols 5 without loss of enantiomeric excess.

Highly Selective Asymmetric Rh-Catalyzed Hydroformylation of Heterocyclic Olefins

“…Asymmetric hydroformylation (AHF) is well-recognized as a powerful synthetic tool to construct a large variety of enantiomerically enriched compounds. − However, rather than chiral diphosphines, diphosphonites, or diphosphites, the most promising ligands for asymmetric hydroformylation are hybrid systems, such as phosphine-phosphite, phosphine-phosphinite, and phosphine-phosphoramidite ligands . To date, acyclic olefins and vinyl aromatics have been extensively explored in the AHF with both Rh and Pt, whereas heterocyclic olefins, such as dihydrofurans and pyrrolines, are scarcely reported, although the corresponding aldehydes are important building blocks in organic synthesis and medicinal chemistry . The carbaldehydes of dihydrofuran and pyrrolines are known to be very important precursors for the syntheses of versatile pharmaceuticals, natural products, and amino-acids. , One example is the 4-formyl derivative of cholest-4-ene, which is a valuable intermediate of potent drugs for the treatment of prostatic cancer and other androgen-dependent diseases.…”

Asymmetric Hydroformylation

“…These ligands allowed, for the first time, an increase in the scope of this process since they provided high enantioselectivity in the Rh-catalyzed asymmetric hydroformylation of several classes of monosubstituted alkenes such as vinyl arenes, 1-heteroatom-functionalised alkenes, and disubstituted 1,3-dienes (Scheme 7), and are still currently references in this area [52 and references therein; [53][54][55][56][57][58][59][60][61][62][63]. Excellent regio-and enantioselectivity were achieved with most of these substrates, although the formation of the branched product (21%) was disfavored when but-1-ene was the substrate.…”

“…The second generation of BINAPHOS-type ligands (Scheme 8) was recently developed by the introduction of 3-methoxy substituents on the aryl phosphine units 42 [53,54], and by replacement of the phosphite group by a phosphoramidite function, yielding the YANPHOS ligand (43) (Scheme 8) [67]. The Rh/42 increased the regio-and enantioselectivity in the asymmetric hydroformylation of styrene, vinylfurans, and thiophenes (Scheme 8).…”

Stereospecific Hydroformylation of 1-Substituted Cyclopent-3-en-1-ols: A Concise Access to Bridged [2, 2, 1] Bicyclic Lactones With A Quaternary Stereocenter

“…16 Therefore, the development of a concise and efficient method to produce bridged [2,2,1] bicyclic lactones is highly desirable. Asymmetric hydroformylation (AHF) represents an efficient approach for asymmetric formation of C-C bond in an atomic economic manner, 17,18,19,20,21,22,23,24,25 and the aldehyde products can be easily converted to versatile functional compounds, such as chiral alcohols, acids, amines and esters, 26,27,28,29,30,31,32,33,34 thus asymmetric hydroformylation has been widely investigated and some significant progress have been made. 35,36,37,38,39,40,41,42,43,44,45 However, asymmetric hydroformylation is very sensitive to the steric hindrance of substrate, which make it difficult to tolerate tri-or tetrasubstituted alkenes.…”