Cinchona-derived ligands

Most of the examples given in the preceding text relied on silver phosphine complexes as catalysts. The. Mrgensen group examined the use of cinchona-derived ligands in the silver fluoride-catalyzed reaction of aromatic iminoesters 103 with methylacrylate (27). Yields were excellent, but enantioselectivities were only in the... 

Table 6. Asymmetric Catalytic Dihydroxylation of Alkenes in the Presence of Cinchona Derived Ligands"...

Double Diastereoselection in the Dihydroxylation Reaction. The dihydroxylation reaction of chiral nonracemic substrates using the cinchona-derived ligand leads to a matched and mismatched pair (eq 6) Kinetic resolution of several racemic secondary alcohols has also been examined. ... 

During recent years, asymmetric catalysis by small organic molecules has received much attention [140]. Because these reactions proceed through intermediates that are inherently less reactive, the Friedel-Crafts reactions of electron-rich (hetero)aryls generally seem to be well suited. For instance, Deng described the use of readily accessible cinchona-derived ligand 178 to perform highly enantioselective indole additions to a-ketoesters and even simple aldehydes (Scheme 8.49) [141]. Bisindole adducts, the major side products in many Lewis acid-catalyzed reactions, were formed to only a minor extent. 

He et al. elaborated on the concept of cinchona derivatives and produced the ligands 9-amino(9-deoxy)epiquinine (96a) and epicinchonine (96b) (Scheme 4.44) [87]. The amines were tested with both Rh and Ir precursors for the ATH of ketones in PrOH/KOH. The best results were achieved using 96b as the ligand and [lr(cod)Cl]2 as the metal precursor, and for isobutyrophenone the conversion and enantioselectivity were obtained in 90 and 97% ee, respechvely. Later it was shown that the Ir complex of 9-amino(9-deoxy)epicinchonine 96b could be recovered in high yields with dilute HCl. The yields (90-94%) and enanhoselectivities of 1-phenylethanol (93-95% ee) were maintained with small variahons after six cycles [88]. 

The most promising results are offered by trifluoromethyl aminoalcohols as chiral ligands (entry 10). Cinchona alkaloids in the presence of pyridine (entry 7) and cinchona-derived surfactants (entry 6), which provide an asymmetric micellar microenvironment in aqueous solvents, are also worthy of note. 

A polymeric cinchona alkaloid-derived ligand 44 was prepared and used to catalyze the asymmetric dihydroxylation of olefins (see the diagram below).66 Both aliphatic and aromatic olefins afforded diols with good enantioselectivities. 

The development of polymeric cinchona-derived PTCs was triggered by the group of Jew and Park in 2001 [8]. The group paid particular attention to the fact that the cinchona alkaloids have demonstrated great utility in the Sharpless asymmetric dihydroxylation. Especially, it was noted that the significant improvements in both stereoselectivity and scope of the asymmetric dihydroxylation were achieved when the dimeric ligands of two independent cinchona alkaloid units attached to heterocyclic spacers were used, such as (DHQ)2-PHAL or (DHQD)2-PYR (Figure 4.4) [9]. 

Fig. 1 Different cores of Cinchona alkaloid derived ligands used in the AD process (Alk =DHQD or DHQ)...

To reduce the cost of the AD process immobilization of the chiral Cinchona alkaloid-derived ligands has attracted attention, too. Several approaches to address this problem have been reported [51]. The chiral ligand has been attached to solid supports comprising organic polymers or modified silica. After comple-... 

The phthalazide bis(cinchona) derivatives [(DHQD)2-PHAL] are the best ligands for the asymmetric dihydroxyla-tion of trans, 1,1-disubstituted, and trisubstituted alkenes, enol ethers, a,p-unsaturated ketones, and a,p- and p,y-unsaturated esters, whereas the DHQD-IND ligand turns out to be superior for c/j -alkenes (Table 1). The bis(cinchona) alkaloid-substituted pyrimidine ligand was found to be the best for monosubstituted terminal alkenes. The addition of Methanesulfonamide to enhance the rate of osmate(VI) ester hydrolysis is recommended for all nonterminal alkenes. 

Corey, E. J., Noe, M. C., Lin, S. A mechanistically designed bis-cinchona alkaloid ligand allows position- and enantioselective dihydroxylation offarnesol and other oligoprenyl derivatives at the terminal isopropylidene unit. Tetrahedron Lett. 1995, 36, 8741-8744. 

Aminohydroxylations. Several carbamates HjNCOOR (R = Et, t-Bu, CljCI ), the corresponding A-chloro-iV-sodio derivatives, and A-bromoacetamide have been employed as nitrogen source in the reaction mediated by bis-cinchona alkaloid ligand complexed osmate. The products are readily manipulated to give two pairs of chiral diamines. In one version the cinchona alkaloid derivatives are linked to silica gel surface through thiopropyl chains. ... 

Figure 3.1 Common cinchona alkaloid derived ligand systems for asymmetric oxidations.

Sharpless observed that the choice of the particular cinchona-derived chiral ligand can invert the regioselectivity in the reaction with styrenes [96-98], Janda [96, 97] proposed that this effect might be due to steric reasons and aryl-aryl interactions [99,100] of the olefin with the aromatic linker of the ligand. Moreover, it was shown that substituents on the aromatic ring of the styrene can influence the stereoselectivity [101], which prompted Ojima [102] to propose a relation between the regioselectivity and the dipole moment of the aromatic group of the olefin. 

A ligand-independent, osmium-catalyzed aminohydroxylation of MBH adduct has been developed by Sharpless et al. (Scheme 3.202). The yield, rate and selectivity of this reaction are not affected by the addition of cinchona alkaloid ligands. The diastereoselectivity for the aminohydroxylation is influenced by the aldehyde-derived substituent, while the acrylate-derived substituent has a minimal effect. Various derivatives and close analogs of the MBH product-core failed to aminohydroxylate, emphasizing the unique reactivity of this class of olefins. 

Inspired by the positive effect of dimeric cinchona alkaloid ligands in the Sharpless asymmetric dihydroxylation [55], Jew, Park, and coworkers developed a new family of dimeric cinchona-derived catalysts. The authors first prepared a series of dimeric cinchonidinium salts 24, 25a, and 26 using a phenyl spacer (Figure 12.7)... 

Another important reaction associated with the name of Sharpless is the so-called Sharpless dihydroxylation i.e. the asymmetric dihydroxylation of alkenes upon treatment with osmium tetroxide in the presence of a cinchona alkaloid, such as dihydroquinine, dihydroquinidine or derivatives thereof, as the chiral ligand. This reaction is of wide applicability for the enantioselective dihydroxylation of alkenes, since it does not require additional functional groups in the substrate molecule ... 

The actual catalyst is a complex formed from osmium tetroxide and a chiral ligand, e.g. dihydroquinine (DHQ) 9, dihydroquinidine (DHQD), Zj -dihydroqui-nine-phthalazine 10 or the respective dihydroquinidine derivative. The expensive and toxic osmium tetroxide is employed in small amounts only, together with a less expensive co-oxidant, e.g. potassium hexacyanoferrate(lll), which is used in stoichiometric quantities. The chiral ligand is also required in small amounts only. For the bench chemist, the procedure for the asymmetric fihydroxylation has been simplified with commercially available mixtures of reagents, e.g. AD-mix-a or AD-mix-/3, ° containing the appropriate cinchona alkaloid derivative ... 

Osmium tetroxide oxidations can be highly enantioselective in the presence of chiral ligands. The most highly developed ligands are derived from the cinchona alkaloids dihydroquinine (DHQ) and dihydroquinidine (DHQD).45 The most effective... 

The most common chiral auxiliaries are diphosphines (biphep, binap and analogues, DuPhos, ferrocenyl-based ligands, etc.) and cinchona and tartaric acid-derived compounds. It is clear that the optimal chiral auxiliary is determined not only by the chiral backbone (type or family) but also by the substituents of the coordinating groups. Therefore, modular ligands with substituents that can easily be varied and tuned to the needs of a specific transformation have an inherent advantage (principle of modularity). 

The first attempt to effect the asymmetric cw-dihydroxylation of olefins with osmium tetroxide was reported in 1980 by Hentges and Sharpless.54 Taking into consideration that the rate of osmium(VI) ester formation can be accelerated by nucleophilic ligands such as pyridine, Hentges and Sharpless used 1-2-(2-menthyl)-pyridine as a chiral ligand. However, the diols obtained in this way were of low enantiomeric excess (3-18% ee only). The low ee was attributed to the instability of the osmium tetroxide chiral pyridine complexes. As a result, the naturally occurring cinchona alkaloids quinine and quinidine were derived to dihydroquinine and dihydroquinidine acetate and were selected as chiral... 

In summary, the reaction of osmium tetroxide with alkenes is a reliable and selective transformation. Chiral diamines and cinchona alkakoid are most frequently used as chiral auxiliaries. Complexes derived from osmium tetroxide with diamines do not undergo catalytic turnover, whereas dihydroquinidine and dihydroquinine derivatives have been found to be very effective catalysts for the oxidation of a variety of alkenes. OsC>4 can be used catalytically in the presence of a secondary oxygen donor (e.g., H202, TBHP, A -methylmorpholine-/V-oxide, sodium periodate, 02, sodium hypochlorite, potassium ferricyanide). Furthermore, a remarkable rate enhancement occurs with the addition of a nucleophilic ligand such as pyridine or a tertiary amine. Table 4-11 lists the preferred chiral ligands for the dihydroxylation of a variety of olefins.61 Table 4-12 lists the recommended ligands for each class of olefins. 

The first silica-supported CSP with a cinchona alkaloid-derived chromatographic ligand was described by Rosini et al. [20]. The native cinchona alkaloids quinine and quinidine were immobilized via a spacer at the vinyl group of the quinuclidine ring. A number of distinct cinchona alkaloid-based CSPs were subsequently developed by various groups, including derivatives with free C9-hydroxyl group [17,21-27] or esterified C9-hydroxyl [28,29]. All of these CSPs suffered from low enantiose-lectivities, narrow application spectra, and partly limited stability (e.g., acetylated phases). 

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