Asymmetric dihydroxylation dihydroquinidine

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 major breakthrough in the catalytic asymmetric dihydroxylation reactions of olefins was reported by Jacobsen et al.55 in 1988. Combining 9-acetoxy dihydroquinidine as the chiral auxiliary with /V-methylmorphine TV-oxide as the secondary oxidant in aqueous acetone produced optically active diols in excellent yields, along with efficient catalytic turnover. 

Also fifteen years of painstaking work and the gradual improvement of the system, the Sharpless team announced that asymmetric dihydroxylation (AD) of nearly every type of alkene can be accomplished using osmium tetraoxide, a co-oxidant such as potassium ferricyanide, the crucial chiral ligand based on a dihydroquinidine (DHQD) (21) or dihydroquinine (DHQ) (22) and metha-nesulfonamide to increase the rate of hydrolysis of intermediate osmate esters 1811. 

Asymmetric catalytic osmylation.s Chiral cinchona bases are known to effect asymmetric dihydroxylation with 0s04 as a stoichiometric reagent (10, 291). Significant but opposite stereoselectivity is shown by esters of dihydroquinine (1) and of dihydroquinidine (2), even though these bases are diastereomers rather than enantiomers. 

Recently, effective chiral ligands for the enantioselective dihydroxylation of olefins have been intensively investigated. Among the reported asymmetric dihydroxylation systems, the superiority of an H20/f-Bu0H-K3Fe(CN)6/K2C03 system with chiral ligands, that is, dihydroquinidine (DHQD) and/or a dihydroquinine (DHQ) derivative, has been mentioned (see Sect. 15.2.4.7) [476]. 

After the "asymmetric epoxidation" of allylic alcohols at the very beginning of the 80 s, at the end of the same decade (1988) Sharpless again surprised the chemical community with a new procedure for the "asymmetric dihydroxylation" of alkenes [30]. The procedure involves the dihydroxylation of simple alkenes with N-methylmorpholine A -oxide and catalytic amounts of osmium tetroxide in acetone-water as solvent at 0 to 4 °C, in the presence of either dihydroquinine or dihydroquinidine p-chlorobenzoate (DHQ-pClBz or DHQD-pClBz) as the chiral ligands (Scheme 10.3). 

Janda, Bolm and Zhang generated soluble polymer-bound catalysts for the asymmetric dihydroxylation by attaching cinchona alkaloid derivatives to polyethylene glycol monomethyl ether (MeO-PEG) [84—87]. Since these polymeric catalysts like (24) are soluble in many common solvents they are often as effective as their small homogenous counterparts. Janda et al. prepared catalyst (24) in which two dihydroquinidine (DHQD) units were linked together by phthalazine and finally were attached to MeO-PEG via one of the bicyclic ring system moieties (Scheme... 

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]. 

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. 

The chiral ligand consists of a diphenylpyrimidine (PYR) 39, which is connected to two dihydroquinidine (DHQD) molecules 40. Dihydroquinidine (DHQD) 40 and dihydroquinine (DHQ) 41 are diastereomers. However, in the asymmetric dihydroxylation, they behave like pseudo-enantiomers, giving diols of opposite configuration. 

Catalytic asymmetric dihydroxylation (14, 237-239 15, 240-241). Complete details are now available for this reaction with a solid substrate, ftms-stilbene, in acetone/water (3 1, v/v) with dihydroquinidine 4-chlorobenzoate as catalyst.1 4... 

With this aim, the group of Norrby developed a transition state force field for the study of the asymmetric dihydroxylation reaction [91]. This force field is purely developed from quantum mechanical reference data [92]. In their studies they use different ligands from the first generation (where the amine ligands are the alkaloids dihydroquine or dihydroquinidine) and second generation (where a symmetric linker couples two alkaloid units), and several alkenes. The calculated ee s are in very good agreement with experiment. 

This collection begins with a series of three procedures illustrating important new methods for preparation of enantiomerically pure substances via asymmetric catalysis. The preparation of 3-[(1S)-1,2-DIHYDROXYETHYL]-1,5-DIHYDRO-3H-2.4-BENZODIOXEPINE describes, in detail, the use of dihydroquinidine 9-0-(9 -phenanthryl) ether as a chiral ligand in the asymmetric dihydroxylation reaction which is broadly applicable for the preparation of chiral dlols from monosubstituted olefins. The product, an acetal of (S)-glyceralcfehyde, is itself a potentially valuable synthetic intermediate. The assembly of a chiral rhodium catalyst from methyl 2-pyrrolidone 5(R)-carboxylate and its use in the intramolecular asymmetric cyclopropanation of an allyl diazoacetate is illustrated in the preparation of (1R.5S)-()-6,6-DIMETHYL-3-OXABICYCLO[3.1. OJHEXAN-2-ONE. Another important general method for asymmetric synthesis involves the desymmetrization of bifunctional meso compounds as is described for the enantioselective enzymatic hydrolysis of cis-3,5-diacetoxycyclopentene to (1R,4S)-(+)-4-HYDROXY-2-CYCLOPENTENYL ACETATE. This intermediate is especially valuable as a precursor of both antipodes (4R) (+)- and (4S)-(-)-tert-BUTYLDIMETHYLSILOXY-2-CYCLOPENTEN-1-ONE, important intermediates in the synthesis of enantiomerically pure prostanoid derivatives and other classes of natural substances, whose preparation is detailed in accompanying procedures. 

The chiral ligand used is based on a phthalazine (PHAL) modified by two dihydroquinidine (DHQD) substituents. Other asymmetric dihydroxylation reactions for the synthesis of pharmaceuticals have been developed at Chirex and Pharmacia/Upjohn. 

Asymmetric dihydroxylation Sharpless developed a catalytic system (AD-mix- 3 or AD-mix-a) that incorporates a chiral ligand into the oxidizing mixture which can be used for the asymmetric dihydroxylation of alkenes. The chiral ligands used in Sharpless asymmetric dihydroxylation are quinoline alkaloids, usually dihydroquinidine (DHQD) or dihydroquinine (DHQ) linked by a variety of heterocyclic rings such as 1,4-phthalhydrazine (PHAL) or pyridazine (PYR) (see section 1.6, reference 32 of Chapter 1). 

Preparative Methods the acetate is prepared from dihydroquinidine and the p-chlorobenzoate is commercially available. The phthalazine-derived bis(dihydroquinidine) ligand is commercially available. A formulation of the standard reactants for the asymmetric dihydroxylation (AD-mix-p) on the small scale has been developed and is commercially available. AD-mix-p (1 kg) consists of potassium osmate (0.52 g), the phthalazine-derived ligand (5.52 g), K3Fe(CN)6 (700 g), and powdered K2CO3 (294 g). 

As in the dihydroquinidine series, the phthalazide cinchona derivative [(DHQ)2-PHAL] (1) is the best ligand for the asymmetric dihydroxylation of terminal, trans, 1,1-disubstituted, and trisubstituted alkenes, and enol ether, whereas the DHQ-IND ligand (2) turns out to be superior for c/i-alkenes (Table 1). The addition of Methanesulfonamide to enhance the rate of osmate(VI) ester hydrolysis is recommended for all nonterminal alkenes. 

For additional examples and an extensive discussion on the use of these ligands in asymmetric dihydroxylation reactions, see Dihydroquinidine Acetate. 

Sharpless asymmetric dihydroxylation procedure was applied to the synthesis of the side chain of azinomycin A (equation Horner-Emmons condensation of phospho-nate 36 with a -aziridine substituted acrolein afforded dehydroamino acid diene 37. Treatment of the diene with catalytic amounts of an osmium reagent and dihydroquinidine (DHQD) p-chlorobenzoate resulted in asymmetric dihydroxylation, producing diol 38. Diol 38 was further converted to the naphthyl ester. 

Many other dihydroquinidine derivatives have been assayed In the catalytic, asymmetric dihydroxylation reaction (ADH)4 g d the submitters have recently found that the benzoate and 2-naphthoate esters are slightly better for aryl-substituted alkenes while certain ethers are better for other substrates. However, since the level of asymmetric Induction Is already high, there is little advantage to be gained from their use in this case. 

Soluble polymers may also serve as carriers for catalysts and other auxiliary reagents. In this form they can be easily separated from the reaction products by simple precipitation of the polymer. Thus, a Sharpless asymmetric dihydroxylation with PEG-bound (DHQD)2PHAL (bis-ether of 1,4-dihydroxyphthalazine and dihydroquinidine) of various olefins gave the corresponding diols in good yields with high enantiomeric excesses [74]. 

Bis(9-0-dihydroquinidine)-2,3-diphenylpyrazino[2,3-d]pyridazine was used as a ligand in the catalytic asymmetric dihydroxylation of allyl bromide to give cnantiomerically enriched (+)-(S)-3-bromopropane-l,2-diol.83 Furthermore, improved selectivities were... 

Figure 8.4. Representative ligands used in stoichiometric, asymmetric dihydroxylation reactions, (a) Dihydroquinidine (DHQD) and (b) dihydroquinine (DHQ) are used for stoichiometric osmylation reactions when R = H effective dihydroxylation catalysts result from appropriate modifications at this position (e.g., see Figure 8.5 below). Also, (c) [69] and (d) [70] are examples of C2 symmetrical ligands used in stoichiometric reactions.

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