Cinchona alkaloids, Sharpless asymmetric

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. 

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... 

Other functionalized supports that are able to serve in the asymmetric dihydroxylation of alkenes were reported by the groups of Sharpless (catalyst 25) [88], Sal-vadori (catalyst 26) [89-91] and Cmdden (catalyst 27) (Scheme 4.13) [92]. Commonly, the oxidations were carried out using K3Fe(CN)g as secondary oxidant in acetone/water or tert-butyl alcohol/water as solvents. For reasons of comparison, the dihydroxylation of trons-stilbene is depicted in Scheme 4.13. The polymeric catalysts could be reused but had to be regenerated after each experiment by treatment with small amounts of osmium tetroxide. A systematic study on the role of the polymeric support and the influence of the alkoxy or aryloxy group in the C-9 position of the immobilized cinchona alkaloids was conducted by Salvadori and coworkers [89-91]. Co-polymerization of a dihydroquinidine phthalazine derivative with hydroxyethylmethacrylate and ethylene glycol dimethacrylate afforded a functionalized polymer (26) with better swelling properties in polar solvents and hence improved performance in the dihydroxylation process [90]. 

An asymmetric osmylation method has been developed by Sharpless and coworkers. 0s04 modified by a dihydroquinidine auxiliary (cinchona alkaloid derivatives)449,455 158 or chiral diamines449,457 160 such as 59 and 60 used in stoichiometric oxidation may yield cis diols with excellent optical purity 460... 

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]. 

The highest enantioselectivity (up to >99%) yet achieved in the addition of S-nucleophiles to enones was reported in 2002 by Deng et al. [59]. By systematic screening of monomeric and dimeric cinchona alkaloid derivatives they identified the dihydroquinidine-pyrimidine conjugate (DHQD PYR (72, Scheme 4.35) as the most effective catalyst. This material is frequently used in the Sharpless asymmetric dihydroxylation and is commercially available. Screening of several aromatic thiols resulted in the identification of 2-thionaphthol as the nucleophile giving best yields and enantioselectivity. Examples for the (DHQD PYR-catalyzed addition of 2-thionaphthol to enones are summarized in Scheme 4.35. 

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... 

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. 

The Sharpless asymmetric epoxidation of allyl alcohol gives the glycidol derivative 61 in 90% ee after in situ tosylation of 60 [63]. This process is working on a multiton-a-year scale (Arco Co., USA), facilitating the synthesis of a variety of /0-blockers. Asymmetric dihydroxylation of the allyl ether 63 catalyzed by a combined system of OSO4 and the cinchona alkaloid-based ligand 65 allows the commercial synthesis of the propranolol intermediate 64 in 91 % (Sepracor Co., USA) [64]. 

Arrington, M. P., Bennani, Y. L., Gobel, T., Walsh, P., Zhao, S. H., Sharpless, K. B. Modified cinchona alkaloid ligands improved selectivities in the osmium tetroxide catalyzed asymmetric dihydroxylation (AD) of terminal olefins. Tetrahedron Lett. 1993, 34, 7375-7378. 

A variation of the Sharpless asymmetric epoxidation is to employ chiral hydroperoxides. The chiral iminium salt 89 has moderate enantiocontrol for epoxidation. Quatemized cinchona alkaloids can serve as chiral catalyst and phase-transfer agents in epoxidation of enones with NaOCl. Enones are also epoxidized by oxygen in the presence of diethylzinc and A-methylpseudoephedrine, whereas IZj-enones are submitted to enantioselective epoxidation by t-BuOOH-O-PrO),Yb and the BINOL 90. 

Sharpless bis-cinchona alkaloids such as [DHQD]2PYR (163a) have proved to serve as highly efficient catalysts for the asymmetric vinylogous Michael addition of the electron-deficient vinyl malonitriles 164 as the nucleophilic species to nitroole-fins 124 [50], This process exhibited exclusive y-regioselectivity and high diastereo-and enantioselectivity. Only the anti-products 165 were observed in all reactions (Scheme 9.57). Of note, 1-tetralone did not react with nitroolefins under these... 

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]. 

Catalytic asymmetric aminohydroxylation using Os(VIII) and Sharpless cinchona alkaloid ligand has been applied to a,p- and P,Y-unsaturated phosphonate substrates (Scheme 48). The reaction only works for the aryl substituted examples (287) and although initial e.e. s are sometimes low, they can be increased to >90% by a single recrystallisation. The phosphonic acid analogue... 

Two classes of ligands have been successfully used in asymmetric osmylation of prochiral olefins chiral diamines and cinchona alkaloids. The diamines have been developed mainly by Corey, Koga and Tomioka, Hirama and their coworkers [559, 750, 754, 755, 756], and cinchona alkaloids have been designed and implemented by Sharpless and coworkers [750, 753-756],... 

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