Asymmetric dihydroxylations with cinchona alkaloid ligands

Recent developments in the understanding of the mechanisms of catalytic and asymmetric dihydroxylation reactions are discussed in Section V,E,l,b. An important aspect of this work is the kinetics and thermodynamics of the formation of adducts with N heterocycles, which have an important role in promoting many reactions. The crystal structure of the [0s04] adduct with the cinchona alkaloid ligand (dimethyl-... 

Mandoli, A., Pini, D., Fiori, M. and Salvadori, P. Asymmetric dihydroxylation with recoverable cinchona alkaloid derivatives a warning note and an improved, insoluble polymer-bound ligand 5 architecture, Eur. J. Org. Chem., 2005, 1271-1282. 

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 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... 

Since Sharpless discovery of asymmetric dihydroxylation reactions of al-kenes mediated by osmium tetroxide-cinchona alkaloid complexes, continuous efforts have been made to improve the reaction. It has been accepted that the tighter binding of the ligand with osmium tetroxide will result in better stability for the complex and improved ee in the products, and a number of chiral auxiliaries have been examined in this effort. Table 4 11 (below) lists the chiral auxiliaries thus far used in asymmetric dihydroxylation of alkenes. In most cases, diamine auxiliaries provide moderate to good results (up to 90% ee). 

Asymmetric dihydroxylation can be achieved using osmium tetroxide in conjunction with a chiral nitrogen ligand. " The very successful Sharpless procedure uses the natural cinchona alkaloids dihydroquinine (DHQ) and its diastereomer dihy-droquinidine (DHQD), as exemplified in the epoxidation of imni-stilbene... 

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. 

Deng et al. later found that dimeric cinchona alkaloids such as (DHQ AQN (8, Scheme 6.6) and (DHQD PHAL (9, Scheme 6.7) - both well known as ligands in the Sharpless asymmetric dihydroxylation and commercially available - also catalyze the highly enantioselective cyanosilylation of acetal ketones with TMSCN... 

This asymmetric dihydroxylation problem was first solved by the use of cinchona alkaloid esters (16 and 17 R = p-ClC6H4) together with a catalytic amount of osmium tetroxide.142143 The alkaloid esters act as pseudoenantiomeric ligands (Scheme 9.19).144 144 They can also be supported on a... 

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. 

To explore the possibility of recycling alkaloid-Os04 complexes, several polymer-bound alkaloid derivatives have been used for heterogeneous catalytic asymmetric dihydroxylations. As chiral ligands, polymerized cinchona alkaloids or copolymers of quinine derivatives with acrylonitrile or styrene were studied [46]. In general, lower select vities and decreased rates were observed. 

Jew and Park have also utilized the dimerization effect, as observed in the development of Sharpless asymmetric dihydroxylation, where ligands with two independent cinchona alkaloid units attached to heterocyclic spacers led to a considerable increase in both the enantioselectivity and scope of the substrates, to design dimeric and trimeric cinchona alkaloid-derived phase-transfer catalysts 12 [12] and 13 [13]. These authors investigated the ideal aromatic spacer for optimal dimeric catalysts, and found that the catalyst 14 with a 2,7-bis(bromomethyl) naphthalene spacer and two cinchona alkaloid units exhibited remarkable catalytic and chiral efficiency (Scheme 11.3) [14]. 

These ligands were superseded with the development of the phthalazine (PHAL) ligands in which two cinchona alkaloid units are connected together. The two most widely used ligands are the phthalazine ligands (DHQD)2-PHAL 93 and (DHQ)2-PHAL and these are used in the two commercially available asymmetric dihydroxylation mixes - AD-mix-a and AD-mix-p. 

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