Dihydroquinidines

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. 

Hydrocupreidine (Dihydrocupreidine), C19H24O2N2. a H20. This base, isomeric with the foregoing, is made by demethylating dihydroquinidine, and was first definitely obtained by Heidelberger and Jacobs. It forms glistening, cream-tinted, hexagonal plates, m.p. 195° (dec.), -(- 227-2°... 

On catalytic hydrogenation it furnishes mainly dihydroquinidine. Benzoyl chloride converts it into the enol benzoate, m.p. 114-5°, and on interaction with magnesium alkyl halides it forms alkylquinidines, e.g., methylquinidine, 2H2O, m.p, 105-12°, [a] ° -(- 168° (EtOH),... 

Using the (— )-Aowocincholoipon produced as described, Rabe and Schultze, by the same sequence of reactions, have produced (—)-dihydro-quininone (m.p. 98-9[a]f, ° — 70-0° (final value EtOH)), which on hydrogenation in presence of palladium gave a mixture of bases, of which (—)-dihydroquinidine and (-j-)-dihydroquinine were isolated. The characters of these mirror-image isomerides of dihydroquinidine and dihydroquinine respectively have been given already with the directions of rotation at the centres of asymmetry C , C , C , C (see table, p. 446). 

As found in commerce, the cinchona alkaloids are not necessarily pure quinidine, for example, may contain up to 30 per cent, of dihydroquinidine. Working with carefully pmdfied specimens of the four chief cinchona alkaloids and their dihydro-derivatives, Buttle, Henry and Trevan found the results recorded in the table (p. 471) in tests with malaria in canaries. The figures in brackets represent the dose of quinine necessary to produce the same degree of protection as unit dose of the alkaloid named. To the results are also added the data found later by the same authors, with Solomon and Gibbs, for some of the transformation products (p. 449) of quinine and quinidine. The Roman numeral at the head of each column refers to the type formula on p. 470. 

On these results the primary cinchona alkaloids and their dihydroderivatives arrange themselves in the following descending order of activity (1) dihydroquinine, (2) quinine, (3) dihydroquinidine, (4) cincho-nidine and quinidine, (5) cinchonine, dihydrocinchonidine and dihydrocinchonine. 

Of the other cinchona bases, the dextrorotatory forms cinchonine and quinidine have been used as anti-malarial drugs in cases of idiosyncrasy to quinine, a subject to which Dawson has given much attention. Quinidine is used to eontrol auricular fibrillation, and its value for this purpose in comparison with dihydroquinidine has been investigated by several workers. Dawes has recently devised a method of testing... 

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 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 ... 

Palacios et al. utilized the modified Neber reaction for the preparation of 2ff-azirine-2-phosphonates 33 as shown in Scheme 18 [28 a]. The use of quini-dine and dihydroquinidine as the chiral base resulted in moderate chirality transfer (20-52% ee). Similarly, 2-phosphinoyl-2H-azirines could be obtained by the Neber 1,3-elimination reaction [28bj. 

Osmium tetroxide oxidations can be highly enantioselective in the presence of chiral ligands. The most highly developed ligands are derived from the cinchona alkaloids dihydroquinine (DHQ) and dihydroquinidine (DHQD).45 The most effective... 

The 1,2-diol is liberated easily from cyclic osmate ester by either reductive or oxidative hydrolysis.213 Importantly, the ligand acceleration has been utilized extensively for the production of chiral 1,2-diols from (achiral) olefins using optically active amine bases (such as L = dihydroquinidine, dihydroquinine and various chiral diamine ligands).215... 

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... 

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. 

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. 

DHQ)PHN and (DHQ)2PHAL are the respective abbreviations of dihydroquinine 9-phenan-thryl ether and of dihydroquinidine 1,4-phthalazinediyl diether. 

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. 

In Figure 14.14 we have depicted the most striking result from the 1980 paper involving /rara-stilbenc as the substrate and dihydroquinine acetate. After addition the osmate ester was decomposed by reduction with UAIH4, a common procedure in the early days, to give the threo-dio. A diastereomer of the ligand, dihydroquinidine acetate, gave similar e.e. but the opposite enantiomer. The enantioselectivity was 83%. 

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],... 

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]. 

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