Chiral phosphorous ligands

In this chapter, we will focus on the rhodium-catalyzed hydrogenation of functionalized ketones and the development of chiral phosphorous ligands for this process. Although there are other chiral phosphorous ligands which are effective for ruthenium-, iridium-, platinum-, titanium-, zirconium-, and palladium-catalyzed hydrogenation, they will not be discussed here. For details of these chemistries, the reader should refer to other chapters of this book. 

The first application of a copper-catalyzed conjugate addition of diethylzinc to 2-cyclohexenone, using chiral phosphorous ligand 12, was reported by AlexaHs (Fig. 7.1) [35]. An ee of 32% was obtained. 

The invention of efficient chiral phosphorous ligands has played a critical role in the development of asymmetric hydrogenation. To a certain extent, the development of asymmetric hydrogenation parallels that of chiral phosphorous hgands. 

Applications of Chiral Phosphorous Ligands in Rhodium-Catalyzed Asymmetric Hydrogenation... 

Several chiral phosphorous ligands with great structural diversity are effective for the rhodium-catalyzed hydrogenation of a-dehydroamino acid derivatives. Tab. 1.1 summarizes the asymmetric hydrogenation of (Z)-2-(acetamido)ciimamic acid, 2-(acetamido)acrylic acid, and their methyl ester derivatives. 

Although enol esters have a similar structure to enamides, they have proven more difficult substrates for asymmetric hydrogenation, which is evident from the significantly fewer number of examples. One possible explanation is the weaker coordinating ability of the enol ester to the metal center, as compared to the corresponding enamide. Some rhodium complexes associated with chiral phosphorous ligands such as DIPAMP [100, 101] and DuPhos [102] are effective for asymmetric hydrogenation of a-(acyloxy)acrylates. 

Amino Ketones Amino ketones and their hydrochloride salts can be effectively hydrogenated with chiral rhodium catalysts (Tab. 1.9). The rhodium precatalysts, combined with chiral phosphorous ligands such as BPPFOH [10b], MCCPM [24f-k], Cy,Cy-oxo-ProNOP [79c, e], Cp,Cp-oxoProNOP [79c, e], and IndoNOP [79g], have provided excellent enantioselectivity and reactivity for the asymmetric hydrogenation of a, yS, and y-al-kyl amino ketone hydrochloride salts. 

Asymmetric catalytic hydrogenation is unquestionably one of the most significant transformations for academic and industrial-scale synthesis. The development of tunable chiral phosphorous ligands, and of their ability to control enantioselectivity and reactivity, has allowed asymmetric catalytic hydrogenation to become a reaction of unparalleled versatility and synthetic utility. This is exemplified in the ability to prepare en-antiomerically enriched intermediates from prochiral olefins, ketones, and imines through asymmetric hydrogenation, which has been exploited in industry for the synthesis of enantiomerically enriched drugs and fine chemicals. 

With the chiral diamine (S,S)-20 as a co-catalyst full conversion was obtained in all cases, indicating that the amine has a pronounced influence on reactivity and selectivity (entries 9-14). The combination (R Rc)-4ael/(S,S)-20 afforded 18a as an almost racemic mixture (entry 9). The value of 6% ee (R) obtained in this experiment reflects two opposite contributions. On one hand, the system chiral phosphorous ligand/achiral diamine (R Rc)-4ael/19 led to 18a with 65% ee (S) (entry 1). On the other hand, an ee value of 75% (R) in the hydrogenation of 1-acetonaphthone has been reported for the system achiral phosphine (PPh3)/(S,S)-20 [41] This indicates that two inductions are canceled in an almost additive way in the mixed system. 

Figure 7.11 Chiral phosphorous ligands for asymmetric allylic substitution reactions.

In many cases, rather than synthesizing the active Rh complexes for reactions, Rh pre-catalyst systems can be treated with various additives to generate active catalyst species in situ. Chiral phosphorous ligands are used extensively in asymmetric transformations, while silver hexafluoroantimonate (AgSbFg), silver triflate (AgOTf), and silver tetrafluoroborate (AgBF4) are common additives to neutral Rh complexes to generate cationic species in situ. 

P-Amino acids have been shown to be an important class of compounds both in biomedical research and the pharmaceutical industry. These structural motifs are present in p-lactams and P-peptides and also serve as chiral templates for the synthesis of other pharmaceuticals. Perhaps the most convenient and straightforward method for the synthesis of P-amino acids is the catalytic asymmetric hydrogenation of p-(acylamino)acrylates 151. Some success has been reported for the Rh-catalyzed asymmetric hydrogenation of ( ) and (Z)- isomers of p-(acylamino)acrylates using chiral phosphorous ligands such as Me-DuPhos, DuanPhos, TangPhos, and other ligands. ... 

Methylcarbapenems are a class of (3-lactams that have been widely investigated for their biological properties, which include potent antibacterial activity and metabolic stability. " l-(3-Methylcarbapenem was synthesized via a diastereoselective hydroformylation of 4-vinyl-p-lactam catalyzed by rhodium complexes of a range of chiral phosphorous ligands (Scheme 14.20). ... 

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