Cinchona-osmium complexes

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). 

A vincinal amino alcohol grouping is present in a fair number of natural products which possess useful biological activity, such as antibiotics122. Such a functionality has been produced from alkenes via osmium-mediated aminohydroxylation (equation 22)123. The reaction proceeds in 40-97% yield and is enantioselective if chiral osmium-Cinchona alkaloid complexes are used to mediate the reaction. 

X-ray analysis of osmium tetroxide-cinchona alkaloid complexes [37] demonstrated that the chiral center in the alkaloid ligand is quite remote from the 0x0 ligand. Therefore it is unlikely that the complex itself is responsible for the... 

In order to study the reaction, they defined all the different pathways for approaching the olefin to the catalyst. They are depicted in Fig. 5a. There are three ways of approaching the olefin to the osmium tetroxide, each one directed to one of the equatorial oxygens. Thus, the different isomers of the oxetane complex can be created from the osmium tetraoxide-cinchona ligand complex by adding the olefin in a [2+2] fashion, therefore distorting an equatorial oxo... 

Chem., 54, 2263 (1989). On the Structure of Osmium Tetraoxide-Cinchona Alkaloid Complexes. 

A catalytic enantio- and diastereoselective dihydroxylation procedure without the assistance of a directing functional group (like the allylic alcohol group in the Sharpless epox-idation) has also been developed by K.B. Sharpless (E.N. Jacobsen, 1988 H.-L. Kwong, 1990 B.M. Kim, 1990 H. Waldmann, 1992). It uses osmium tetroxide as a catalytic oxidant (as little as 20 ppm to date) and two readily available cinchona alkaloid diastereomeis, namely the 4-chlorobenzoate esters or bulky aryl ethers of dihydroquinine and dihydroquinidine (cf. p. 290% as stereosteering reagents (structures of the Os complexes see R.M. Pearlstein, 1990). The transformation lacks the high asymmetric inductions of the Sharpless epoxidation, but it is broadly applicable and insensitive to air and water. Further improvements are to be expected. 

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 ... 

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. 

To improve the position selectivity in the AD of oligoprenyl compounds bis-cinchona alkaloid ligand 8 was introduced by Corey 15,6]. Its design was based on the [3+2]-cycloaddition model for the AD mechanism, which will be discussed in Section 6E. 1.2. The two 4-heptyl ether substituents of the quinolines are supposed to assist fixation of the substrate in the binding cleft. Additionally, the jV-methylquinuclidinium unit and the linking naphthopyridazine were introduced to rigidify the osmium tetroxide complex of 8 [6],... 

A stoichiometric procedure for the osmium-mediated, enantioselective aminohydrox-ylation of traws-alkenes RCH=CHR (R = Ph, Et, Pr1) has been developed employing chiral complexes between tert-butylirnidoosmium (BufN=0s03) and derivatives of cinchona alkaloids. The success of the reaction is dependent on a ligand acceleration effect corresponding diols are the by-products. The e.e. varies between 40 and 90%486,487. 

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. 

The cinchona alkaloids have opened up the field of asymmetric oxidations of alkenes without the need for a functional group within the substrate to form a complex with the metal. Current methodology is limited to osmium-based oxidations. The power of the asymmetric dihydroxylation reaction is exemplified by the thousands (literally) of examples for the use of this reaction to establish stereogenic centers in target molecule synthesis. The usefulness of the AD reaction is augmented by the bountiful chemistry of cyclic sulfates and sulfites derived from the resultant 1,2-diols. 

Other approaches to immobilization have included the use of macroporous resins and functionalized silica solids that contain residual vinyl groups which can be dihydroxylated as a means of anchoring the transition metal to the solid support the resulting osmium(VI) complexes are then reoxidized in situ. The AD reaction has also been investigated with polymeric versions of Sharpless chiral cinchona based ligands. ... 

An asymmetric version of this reaction would be of great interest, since it would complement the asymmetric epoxidation. This has in fact been achieved by Sharpless. The source of asymmetry this time is a chiral tertiary amine, which forms a complex with osmium tetroxide. Taking their cue from the work of Wynberg (see section 6.1.1) Sharpless and co-workers discovered once again that chiral amines (66) and (67) derived from the cinchona alkaloids quinine and quinidine respectively performed well, affording enantiomeric excesses of 50-90%. 

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