Cinchona chiral ligands

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 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 use of diazodicarboxylates has been recently explored in Cinchona alkaloid catalyzed asymmetric reactions. Jprgensen [50] reported the synthesis of non-biaryl atropisomers via dihydroquinine (DHQ) catalyzed asymmetric Friedel-Crafts ami-nation. Atropisomers are compounds where the chirality is attributed to restricted rotation along a chiral axis rather than stereogenic centers. They are useful key moieties in chiral ligands but syntheses of these substrates are tedious. 

A solid-phase sulfur oxidation catalyst has been described in which the chiral ligand is structurally related to Schiff-base type compounds (see also below). A 72% ee was found using Ti(OPr-i)4, aqueous H2O2 and solid-supported hgand 91 . More recently, a heterogeneous catalytic system based on WO3, 30% H2O2 and cinchona alkaloids has been reported for the asymmetric oxidation of sulfides to sulfoxides and kinetic resolution of racemic sulfoxides. In this latter case 90% ee was obtained in the presence of 92 as chiral mediator. ... 

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. 

Certain tertiary amines such as pyridine or a-quinuclidine accelerate the stoichiometric reaction between osmium tetroxide and olefins (86). An asymmetric olefin osmylation using stoichiometric amounts of cinchona alkaloids as the chiral ligands was described in 1980 (87a). Optical yields of up to 90% were attained with frans-stilbene as substrate. 

Although the use of cinchona alkaloids as chiral ligands does provide high asymmetric induction with a number of types of alkene, the search for better systems has resulted in better catalysts (Scheme 9.21).15/W58... 

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-... 

Though the mechanism of even the simple reaction of osmium tetroxide with an olefin remains uncertain, there has been considerable controversy over the mechanism of the process when a chiral cinchona alkaloid ligand is also involved . K.B. Sharpless et al., J. Org. Chem. 1996, <57, 7978. 

Sharpless and co-workers first reported the aminohydroxyIation of alkenes in 1975 and have subsequently extended the reaction into an efficient one-step catalytic asymmetric aminohydroxylation. This reaction uses an osmium catalyst [K20s02(OH)4], chloramine salt (such as chloramine T see Chapter 7, section 7.6) as the oxidant and cinchona alkaloid 1.71 or 1.72 as the chiral ligand. For example, asymmetric aminohydroxylation of styrene (1.73) could produce two regioisomeric amino alcohols 1.74 and 1.75. Using Sharpless asymmetric aminohydroxylation, (IR)-N-ethoxycarbonyl-l-phenyl-2-hydroxyethylamine (1.74) was obtained by O Brien et al as the major product and with high enantiomeric excess than its regioisomeric counterpart (R)-N-ethoxycarbonyl-2-phenyl-2-hydroxyethylamine (1.75). The corresponding free amino alcohols were obtained by deprotection of ethyl carbamate (urethane) derivatives. 

In contrast to the aforementioned fullerenes, C76 is a chiral molecule containing 30 different types of carbon-carbon bond. In this molecule five different pyracylene-type carbon-carbon bonds repeat to form chrysene-shaped units. Kinetic resolution of this fullerene has been achieved via asymmetric osmylation in the presence of a cinchona based chiral ligand (see Section 4.4.4.1.1., ligand 1 d/2 d, Table 5). The calculated enantiomeric excess of the recovered material (after 95% conversion) is >97%, whereas the regenerated C76, formed by tin(II) chloride reduction of the osmylated material (after 33 % conversion), is enriched in the opposite enantiomer. Analysis of the local curvature of the C76 molecule indicates that Os04 should selectively add to two of the 30 types of bonds86. 

Reagent-Induced Enantioface Differentiating Osmylations 4.4.4.1. Chiral Ligands for Catalytic Osmylations 4.4.4.I.I. Cinchona Alkaloid Derivatives as Chiral Ligands... 

Cinchona alkaloids have been extensively studied as chiral ligands for catalytic osmylations. This method, which has been much improved since its introduction, makes use of a complex generated in situ between 0s04 and a suitably 0-protected dihydroquinidine or dihydroquinine derivative using catalytic amounts of both these reagents at 0 or 25 °C1,2. 

In summary, the asymmetric osmylation of alkenes catalyzed by derivatives of cinchona alkaloids represents a very elegant method which enables the enantioselective cis dihydroxylation of several types of alkenes in high enantiomeric excess and with predictable selectivities. The design of specific chiral ligands for substrates that still do not afford enantiomeric excesses over 90% would be desirable for the near future. 

Besides the above mentioned cinchona based system, to date only a few nitrogen-based chiral ligands have been reported to work under catalytic conditions70-72. The C2-symmetrical l,4-diazabicyclo[2.2.2]octane (DABCO) derivative l70 and the isoxazolidines 2 and 371 are examples. The main problem with most of the other amines tested stems from the formation of ligand-osmate ester complexes which are too stable. Although with these ligands the levels of enantiomeric excess are still not satisfactory, the successful osmium turnover gives hope for future improvements. 

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. ... 

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