Dihydroquinidine , alkene

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 ... 

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. 

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. 

Air or dioxygen can be used as an oxidant with non-chiral DABCO to give a low cost catalyst for dihydroxylation of alkenes into racemic mixtures dihydroquinidine modified catalysts with the air variant give lower e.e. s than the AD-mix catalysts [26],... 

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). 

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]. 

Optically active ds.vic-diofa.1 It is known that pyridine catalyzes the hydroxyl-ation of alkenes with Os04 and that the osmate ester intermediates form an isolable complex with pyridine (1, 760-761). Hentges and Sharpless reasoned that a similar chiral amine could induce chirality in the diol. And indeed addition of 1 equivalent of 1 or of the C8-diastereoisomer, dihydroquinidine acetate (2), does result in vic-diols in fair to high enantiomeric excess, particularly in reactions performed in toluene at —78°. Opposite stereoselectivities are exhibited by 1 and 2. Optical yields range from 25 to 85%. Use of an amine in which the chiral center is two carbon atoms removed from the coordination site lowers the optical yield to 3 18%. 

L = (S,S)-JV V -bis(2,4,6-trimethylbenzylidene)-l,2-diphenyl-l,2-diamine 393 catalytic asymmetric cis dihydoxylation of alkenes L = dihydroquinidine or dihydroquinine 4-nitrobenzoate catalytic 394... 

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. 

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). 

X-ray crystallographic structures of the cw-dioxo osmium(VI) esters derived from dihy-droquinine-4-chlorobcnzoate/Os04/( )-2,2,5,5-tetramethyl-3-hexene and dihydroquinidine 4-chlorobenzoate/Os04/(i )-2,5-dimethyl-3-hexene have also been reported 22. Inspection of these sixteen-electron complexes reveals that, despite the considerable distance between the ligand stereocenters and the reacting site, the 4-chlorobenzoyl moieties effectively shield one of the two possible modes of alkene approach. 

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. 

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. 

Predict the absolute configuration of the diols obtained from each of the following alkenes using either a dihydroquinidine or a dihydroquinine type dihydroxylation catalysts. 

Quinidine [3, (9S)-6 -methoxy-9-cinchonanol] is mostly applied for the same purposes as quinine, such as the addition of zinc alkyls to carbonyl compounds (Section D 1.3.1.4.), or addition of thiophenol to acrylic derivatives (Section D.2.I.). An important technical synthesis of malic acid is based on the quinidine catalyzed enantioselective [2 + 2] cycloaddition of ketene to chloral (see Section D. 1.6.1.3.). Esters and ethers of dihydroquinidine (4) (just like the corresponding derivatives of dihydroquinine) have been used as chiral ligands in osmium tetroxide catalyzed dihydroxylations of alkenes (Section D.4.4.). 

Asymmetric dihydroxylation of the side-chain of Z-1-(4-meth-oxyphenyl)-1-(tert-butyldimethylsiloxy)-1-propene to give (R)-l-hydroxyethyl 4-methoxyphenyl ketone in 94% yield (99% e.e.) was effected by addition of the alkene to a stirred mixture of osmium tetroxide, potassium ferricyanide, potassium carbonate, a 9-0-(9 -phenanthryl)ether(PHN) of dihydroquinidine and 1 mole of methanesulphonamide in aqueous tert-butanol (1 1), with reaction during 16 hours at ambient temperature. Then treatment with sodium sulphite prior to work-up to gave the product (ref. 130). Other best ligands were the 9-0-(4 -methyl-2 -quinolyl) ethers (MEQ) of dihydroquinine. 

However, the use of these dihydroquinidine and dihydroquinine phthalazine ligands does not improve the enantioselectivity of c/5-disubstituted alkenes. The problem in this case can be solved by use of carbamate ligands such as (9-0-indolinylcarbamoyl)dihydroquinidine, DHQO-IND (1). 

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