JP3924282B2 - Process for catalytic asymmetric dihydroxylation of olefins - Google Patents

Abstract

Osmium-catalyzed methods of addition to an olefin are discussed. In the method of asymmetric dihydroxylation of the present invention, an olefin, a chiral ligand, an organic solvent, water, an oxidant and an osmium-containing compound are combined. In the method of asymmetric oxyamination of the present invention, an olefin, a chiral ligand, an organic solvent, water, a metallochloramine derivative, an osmium-containing compound and, optionally, a tetraalkyl ammonium compound are combined. In the method of asymmetric diamination of the present invention, an olefin, a chiral ligand, an organic solvent, a metallo-chloramine derivative, an amine and an osmium-containing compound are combined. In one embodiment, an olefin, a chiral ligand which is a polymeric dihydroquinidine derivative or a dihydroquinine derivative, acetone, water, a base, an oxidant and osmium tetroxide are combined to effect asymmetric dihydroxylation of the olefin.

Description

  The present invention relates to a process for asymmetric addition of olefins catalyzed by osmium, in particular asymmetric dihydroxylation.

  In nature, organic components of animals, microorganisms, and plants are made from chiral molecules, ie, molecules that exhibit antipodal properties. Enantiomers are stereoisomers or chiral molecules whose configurations (configuration of component atoms) are mirror images that do not overlap with each other, and the absolute configuration at the chiral center is determined by a set of rules and is therefore preferred Sex is given for each substituent and is labeled R and S. The physical properties of the enantiomers are the same except that they rotate the chiral, one enantiomer rotates the plane-chiral to the right and the other enantiomer rotates it to the left. However, the degree of rotation caused by each is the same.

  The chemical properties of enantiomers are the same except for their interaction with optically active reagents. Optically active reagents interact with enantiomers at different rates, reaction rates vary widely, and in some cases interact at different rates such that no reaction with one enantiomer or isomer occurs. . This is particularly evident in biological systems where stereochemical specificity is common since enzymes (biological catalysts) and the substrates on which they act are optically active.

  A mixture containing equal amounts of two enantiomers is a racemate (or racemic variant). As a result of the fact that the rotation of polarized light caused by one isomeric molecule is equal to or opposite to that caused by its enantiomeric molecule, the racemate is optically inactive. Racemates, compounds that are not optically active, are the products of many synthetic steps. Because of the identity of the many physical properties of enantiomers, they are, for example, fractional distillation (because they have the same boiling point), fractional crystallization (equivalent in solvents unless they are optically active) Cannot be separated by commonly used methods such as chromatography (since they are optically active and because they are equally firmly held on certain adsorbents). As a result, resolution of racemic mixtures into enantiomers cannot be easily performed and can be costly and time consuming.

  In recent years there has been an increasing demand for complex organic molecules with high optical purity, such as insect hormones and pheromones, prostaglandins, antitumor compounds, and other drugs, in the synthesis of chiral compounds. Interest is increasing. In an ecosystem, events often occur where one enantiomeric function works effectively but the other enantiomer does not have biological activity and / or does not interfere with the biological activity of the first enantiomer. This interest, for example, is a particularly important consideration with regard to pharmaceuticals.

  In nature, the enzyme catalyst involved in a chemical reaction ensures that the reaction proceeds asymmetrically to produce only the correct enantiomer (ie, the biologically or physiologically functional enantiomer). However, this is not done in laboratory synthesis, and despite the interest and energy expended in developing a method that allows asymmetric production of the desired chiral molecule (eg, of the selected enantiomer). Limited success has been achieved.

  In addition to resolving the desired molecule from the racemate of the two enantiomers, it is also possible to produce asymmetric molecules selected, for example, by chiral pool or template methods, where the selected asymmetric molecule Is produced from existing naturally occurring asymmetric molecules. Asymmetric heterogeneous hydrogenation and asymmetric epoxidation have also been used to produce chiral molecules. Asymmetric hydrogenation to mimic the naturally occurring asymmetric reaction is regarded as the first artificial reaction. Sharpless, KB, Chemistry in Britain, January 1986, pp. 38-44, Mosher, HS and JD Morrison Science, 221: 1013-1019 (1983), Maugh, TH, Science, 221: 351-354 (1983), Stinson, S., Chemistry and • Chemistry and Engineering News, 24 (6/2/86).

  However, currently available asymmetric synthesis methods are limited in their application. Effective catalytic asymmetric synthesis reactions are very rare and they usually require an indicator group, thus limiting the substrate. Since such reactions are rare and chirality can be particularly important in pharmaceuticals, pheromones and other biologically functional compositions, asymmetric dihydroxylation contact methods are of great value. There will be. In addition, many naturally occurring products are dihydroxylated and can be easily derived from many corresponding proximate diol derivatives.

  Olefins or alkenes, with or without adjacent heteroatom-containing functional groups, are asymmetrically dihydroxylated using the osmium-catalyzed process that is the subject of the present invention. , Oxyaminated or diaminated. Chiral ligands, particularly dihydroquinidine derivatives or dihydroquinine derivatives or salts thereof, which are novel alkaloid derivatives useful in the method of the present invention, are also the subject of the present invention. Derivatives of the parent compound, alkaloids such as quinidine or quinine, or their salts can also be used, but the rate of catalysis is slightly slower.

  In one aspect of the invention, the chiral ligand is motion-inhibited or added into the polymer. Both monomeric and polymeric ligands can be kinetically inhibited or added to the polymer. Repetitive use of the complex, with the kinetically restrained or added ligand forming a complex with the osmium catalyst during the reaction, resulting in an effective catalytic action that the complex is retained after the reaction. Can do. Alternatively, pre-manufactured osmium-ligand complexes can be used in the reaction and recovered.

  In the asymmetric modification or addition process of the present invention, olefins, selected chiral ligands, organic solvents, water, oxidants, osmium sources and optionally additives that promote hydrolysis of the osmic acid intermediate product. Are combined under conditions suitable for the reaction to take place. The ligand-promoted catalysis method of the present invention is useful for performing asymmetric dihydroxylation, asymmetric oxyamination, and asymmetric diamination of the olefin. A special advantage of the catalytic asymmetry method is that only a small amount of osmium catalyst is required.

  Asymmetric epoxidation has been the subject of much research for over a decade. Initial research has shown that the titanium tartrate epoxidation catalyst is actually a complex mixture of epoxidation catalysts in mechanical equilibrium with each other and that the major types present (ie, 2: 2 structures) are best. It is shown to be a catalyst (ie about 6 times more active than titanium isopropoxide without tartrate). This study also shows that this rate advantage is essential to the success of the process, since the catalysis has been developed with a class having chiral ligands.

The reaction of osmium tetroxide (OsO ₄ ) with olefins is a highly selective and reliable organic conversion method. It has long been known that this reaction is promoted by nucleophilic ligands. Kriegiee, R. Justus Liebigs Ann. Chem. 522: 75 (1936), Criegee, R. et al., Justus Liebigs Anerlen del Hemy (Justus Liebigs Ann. Chem.), 550: 99 (1942), Van Rheenen et al., Tetrahedron Lett., 1973 (1976). It has been shown previously that highly effective osmium catalyzed methods can be used to modify previously known methods such as, for example, stoichiometric asymmetric osmylation methods. Hentges, S.G. and K. B. Sharpless, Journal of the American Chemical Society, 102: 4263 (1980). The method of the present invention leads to asymmetry induction and reaction rate enhancement by the binding of selected ligands. Asymmetric dihydroxylation, asymmetric diamination or asymmetric oxyamination can be carried out by using the ligand-promoted contact method of the present invention.

  As a result of this method, two hydroxyl groups are added stereospecifically (embedded) in the hydrocarbon backbone, resulting in cis-proximal dihydroxylation. The novel contact method of the present invention provides a substantially improved speed and turnover number (as compared to previously available methods) and a useful level of asymmetry induction. Moreover, because of the improved reaction rate and turnover number, the process of the present invention requires less osmium catalyst than previously known processes. As a result, the costs and possible toxicity problems associated with previously known methods are reduced. Furthermore, the present invention allows for the recovery and reuse of osmium, which also reduces the cost of the process.

The process of the present invention is described below, in which E-stilbene (C ₆ H ₅ CH: CHC ₆ H ₅ ) and its in asymmetric dihydroxylation of trans-3-hexene (CH ₃ CH ₂ CH: CHCH ₂ CH ₃ ) Illustrated with particular reference to use. The method can generally be described as indicated below, and the description and the following examples illustrate the dramatic and unexpected results of ligand-promoted catalysis As well as the simplicity and effectiveness of the method.

The asymmetric dihydroxylation process of the present invention is schematically represented in FIG. According to the method of the present invention, selected olefins are selected under appropriate conditions with a selected chiral ligand (which will generally be a chiral substituted quinuclidine), an organic solvent, water, an oxidant and tetraoxidation. Combined with osmium and optionally a compound that promotes hydrolysis of the product from osmium. Acids or bases can be used for this purpose. In one aspect, the selected olefin, chiral ligand, organic solvent, water and oxidant are combined and the OsO ₄ is added after the olefin and other components are combined. On the one hand, the olefin, organic solvent, chiral ligand, water and OsO ₄ are combined and an oxidizing agent is added to the resulting combination. These additions can be made very close in time (ie, sequentially or simultaneously).

In one embodiment of the invention, the components of the reaction mixture are combined to form the initial reaction combination, and the olefin is generally slowly added to it with frequent or constant stirring such as stirring. In this embodiment, labeled “slow addition” method, the organic solvent, chiral ligand, water, OsO ₄ and oxidizing agent are combined. The olefin can then be slowly added to the other reactants. It is important to apply agitation, preferably agitation, during the olefin addition. Surprisingly, for many, if not most, olefins, the slow addition of olefins to the initial combination is much better than the above method (ie, all olefins are present at the start of the reaction). This results in an enantiomeric excess (ee) and a fast reaction rate. The advantageous effect of slow olefin addition (ie relatively high ee) is shown in Table 5 (column 6). A particular advantage of this slow addition method is that it greatly expands the range of olefin types to which asymmetric dihydroxylation can be applied. That is, it can be applied to simple hydrocarbon olefins that do not have aromatic substituents or other functional groups. In this method, olefin is added slowly (eg, over time) as needed to maximize ee. This method is particularly valuable because it results in a relatively high ee and a relatively fast reaction time.

In another embodiment of the method, the chiral ligand is kinetically inhibited or added into the polymer, thereby inhibiting the kinetics of the ligand. Both the alkaloid ligand monomer and polymer can be inhibited. The kinetically inhibited ligand forms a complex with the osmium catalyst, which produces an osmium catalyst complex that can be recovered after the reaction. The OsO ₄ -polymer complex is recoverable and can be used for repeated processes without washing or other treatment. The complex can be recovered, for example, by filtration or centrifugation. By using alkaloid derivatives, heterogeneous catalytic asymmetric dihydroxylation with good to excellent enantioselectivity in the dihydroxylation of olefins is obtained.

  On the other hand, an alkaloid polymer can also be used as a ligand. Alkaloid polymers that can be used are, for example, Kobayashi and Iwai, Tetrahedron Letters, 21: 2167-2170 (1980) and Polymer Journal, 13 (3): 263-271 (1981), von Herman and Wynberg, Helvet. Chim. Acta, 60: 2208-2212 (1977), and Hodge et al., The Chemical Society Perkin Trans., I, (1983), pages 2205-2209. As used herein, the term “polymeric” refers to a single alkaloid ligand that is either chemically bonded or linked to the polymer support and the ligand remains linked under the reaction conditions. Is it a polymer or polymer, or a ligand that produces a copolymer that is copolymerized with one or more monomers (eg, acrylonitrile) and alkaloids are added to the polymer, or is the motion inhibited? Or it is meant to encompass alkaloid polymers as described above that are not copolymerized with another polymer or other carrier.

Industrial scale synthesis of optically active proximity diols using polymeric ligands is possible. The simplicity and economy of the method is increased by recycling the alkaloid-OsO ₄ complex. This aspect of the method allows for effective heterogeneous asymmetric dihydroxylation utilizing polymeric or motion-inhibited quinaalkaloid derivatives.

  The polymeric quinaalkaloids that can be used in the present method can be prepared by techniques known in the art. For example, Grubhofer and Schleith, Naturwissenschaften, 40: 508 (1953), Yamauchi et al., Bulletin of the Chemical Society of Japan (Bull. Chem. Soc. Jpn.), 44: 3186 (1971), Yamauchi et al., J. Macromal. Sci. Chem., A10: 981 (1976). Numerous different types of polymers incorporating dihydroquinidine or dihydroquinine derivatives can be used in this method. These polymers include (a) copolymers of quinaalkaloid derivatives and copolymerization reagents such as vinyl chloride, styrene, acrylamide, acrylonitrile, or acrylic acid or methacrylates, (b) quinaalkaloid derivatives And polymers cross-linked with a cross-linking reagent such as 1,4-divinylbenzene, ethylene glycol bismethacrylate, and (c) quinaalkaloid derivatives covalently bonded to polysiloxanes. The point of attachment of the polymer backbone with the alkaloid derivative is C (10), C (11), C (9) -O, N (1 ') as shown below for both quinidine and quinine derivatives. Or it can be C (6 ')-O. Table 3 shows examples of monomeric alkaloid derivatives that can be added to the polymer system.

For example, polymer-bound dihydroquinidine is prepared by copolymerizing 9- (10-undecenoyl) dihydroquinidine in the presence of acrylonitrile (5 equivalents) to give a 13% yield and 4% alkaloid. Indicates the participation rate. This polymer, ie acrylonitrile copolymer of 9- (10-undecenoyl) -10,11-dihydroquinidine, is shown as polymer 4 in Table 1 below. Three other polymers, 9- (4-chlorobenzoyloxy) quinine (polymer 1, Table 3), 11- [2-acryloyloxy) ethylsulfinyl] -9- (4-chlorobenzoyloxy)- 10,11-dihydroquinine (polymer 2, Table 1) and 11- [2-acryloyloxy) ethylsulfonyl] -9- (N, N-dimethylcarbamoyl) -10,11-dihydroquinidine (polymer 3, table) 1) was prepared according to Inaguki et al.'S other process or a modified version of this known method. See Inaguki et al., Bulletin of Chemical Society of Japan (Bull. Chem. Soc. Jpn.), 60: 4121 (1987). These polymers were used to perform asymmetric dihydroxylation of trans-stilbene. The results are summarized in Table 1. Good to excellent asymmetry induction and reasonable reaction rates were observed. As shown in Table 1, the reaction with polymer 2 showed the highest asymmetry induction. The OsO ₄ -polymer complex is retained after the reaction, and the complex can be used repeatedly. This reaction can be carried out with terminally substituted and aliphatically substituted olefins and has good yields and enantioselectivities (eg, those of styrene and polymer 2, 60% ee, 68% yield and that of ethyl trans-2-octoate and polymer 3, 60% ee, 85% yield), and the same process can be applied to a variety of different olefins.

In another aspect of the method, an additive that promotes hydrolysis of the osmate intermediate product can optionally be added to the reaction combination. These additives can be, for example, acids or bases. Bases are suitable for this purpose. For example, soluble carboxylates having an organic soluble counterion (eg, tetraalkylammonium ion) are useful. Suitable carboxylates in this reaction are soluble in organic media and in organic / aqueous cosolvent systems. For example, tetraethylammonium acetate has been shown to promote the reaction rate and ee of certain olefins (Table 5). The additive does not replace the alkaloid in the reaction. Compounds that can be used include benzyltrimethylammonium acetate, tetramethylammonium acetate and tetraethylammonium acetate. However, other oxyanion compounds (eg sulfonates, carbonates, borates or phosphates) can also be used in the hydrolysis of the osmate intermediate product. Prior to olefin addition, the compound can be added to the reaction combination with organic solvent, chiral ligand, water and OsO ₄ in a reaction vessel. Additives can also be added to the reaction combination described above, where all of the olefin is added at the beginning of the reaction. In one aspect, the amount of additive is generally about 2 equivalents, and generally about 1 to about 4 equivalents will be used.

In another embodiment of the invention, the process can be carried out in an organic nonpolar solvent such as toluene. This embodiment is particularly useful in the slow addition method. Preferably, a carboxylic acid ester compound (eg, tetraethyl acetate or tetramethyl ammonium acetate) is added that promotes hydrolysis of the osmate intermediate product. This embodiment is denoted as the “phase transition” method. In this embodiment, olefins that are not soluble or have limited solubility in acetone / water or acetonitrile / water are dissolved in toluene and then slowly dissolved in a mixture of organic solvent, chiral ligand, water and OsO _4. Added. Carboxylate has the dual function of solubilizing acetate ions in the organic phase to promote hydrolysis of osmate esters and carrying the water associated with it, which is essential for hydrolysis, to the organic phase.

In another aspect of the invention, boric acid or a boric acid derivative (R—B (OH) ₂ , R = alkyl, aryl or OH), such as boric acid itself (ie, B (OH) ₃ ) or phenylboric acid (ie, , Ph-B (OH) ₂ ) can be added to the reaction mixture. In the slow addition method, boric acid is added to the ligand-organic solvent-OsO ₄ mixture before the olefin addition. The amount of boric acid added is sufficient to produce a borate ester of diol produced during the reaction. Without wishing to be bound by theory, it is believed that boric acid hydrolyzes the osmate and destroys the diol generated during the reaction. In this reaction, water or a soluble carboxylic acid ester such as tetraalkylammonium carboxylate is not required to hydrolyze the osmic acid ester. The addition of boric acid facilitates the isolation of these diols because the presence of water can make it difficult to isolate and recover the water-soluble diols. In particular, in the case of aryl or alkylboric acids, it is easy because the product becomes a cyclic borate instead of a diol, which can then be hydrolyzed to a diol. Iwasawa et al., Chemistry Letters, 1721-1724 (1988). The addition of boric acid is particularly useful as a slow addition method.

In another embodiment of the process, an oxidizing agent such as potassium hexacyanoferrate (III) (potassium ferricyanide, K ₃ Fe (CN) ₆ ) is added to the reaction as a reoxidant. In a preferred embodiment, at least 2 equivalents of oxidizing agent (based on the olefin substrate) is added to the reaction. It is preferred to add an equal amount of base, such as potassium carbonate (K ₂ CO ₃ ), along with the reoxidant. Catalytic asymmetric dihydroxylation using K ₃ Fe (CN) ₆ as a reoxidant provides high enantioselectivity.

The use of potassium ferricyanide in the asymmetric osmium-catalyzed dihydroxylation of olefins has been described by Minato, Yamamoto and Tsuji, The Journal of the Organic Chemistry (J Org. Chem.) 55: 766 (1990). The addition of K ₃ Fe (CN) ₆ (with base) is a ligand that strongly inhibits catalysis when using other oxidants such as N-methylmorpholine-N-oxide (NMO). Even in the presence of some quinuclidine, it results in improved turnover capability of the azalea catalyst system. In this embodiment, potassium ferricyanide and potassium carbonate were added to the asymmetric dihydroxylation method based on this quinaalkaloid, and this result was unexpected (ie, reoxidizing osmium with a difficult substrate and And / or quite different from other methods to get a good turnover). As shown in Table 2, the use of potassium ferricyanide / potassium carbonate instead of NMO results in an overall increase in the level of asymmetry induction for most olefins. The first two terms of the data shown in Table 2 relate to the results of using NMO with or without “slow addition” of olefin, respectively. The results so far (shown in Table 2) were obtained at 0 ° C., but the improvement in enantioselectivity is significant, as evidenced by the fact that the ferricyanide experiment was performed at room temperature. However, the ferricyanide reaction can be carried out at a range of temperatures depending on the substrate.

  In all cases, the isolated yield was 85% -95%.

  The amount of water added to the reaction mixture is an important factor in the process. The optimal amount of water added can be determined experimentally and should generally be that which gives the maximum ee. In general, about 10-16 equivalents, preferably 13-14 equivalents, of water can be added.

  The olefin can be asymmetrically dihydroxylated according to the present invention. For example, a hydrocarbon containing at least one carbon-carbon bond as a functional group can be asymmetrically dihydroxylated according to the method. The process is applicable to the olefins and in particular asymmetrically dihydroxylates prochiral olefins [olefins that can be converted to products that exhibit chirality or handedness]. Well suited for. If the polarizing olefin is asymmetrically dihydroxylated using the process of the present invention, one enantiomer will be more reactive than the other. As a result, optical enantiomers can be separated or kinetically resolved. That is, by use of appropriately selected reactants, the asymmetrically dihydroxylated product can be separated from unreacted starting material, and both the product and recovered starting material are enantiomerically It will be excessive.

  Chiral ligands used in asymmetric dihydroxylation will generally be alkaloids or nitrogen-based organic compounds that are usually heterocyclic. The chiral ligand can be a naturally occurring compound, a pure synthetic compound or a salt thereof, such as a hydrochloride salt. The optimum derivative used can be determined based on the process conditions for each reaction. Examples of alkaloids that can be used as chiral ligands in asymmetric dihydroxylation methods include quina alkaloids such as quinine, quinidine, cinchonine, and cinchonidine. Examples of alkaloid derivatives useful in the method of the present invention are shown in Table 3. As described in detail below, the two alkaloids, quinine and quinidine, act much more like enantiomers in the formula shown in FIG. 1 than the similar diastereomers.

  As shown in FIG. 1 and as shown by the results in Table 4, dihydroquinidi derivatives (designated DHQD) and dihydroquinine derivatives (designated DHQ) are used in this method. Has a pseudo-enantiomeric relationship (DHQD and DHQ are effectively diastereomers). That is, they exhibit the opposite enantioface selectivity. Such derivatives can be, for example, esters or ethers, but other forms can also be used. The choice of derivative depends on the process. When dihydroquinidine is used as the ligand, the distribution of the two hydroxyl groups arises from the top or top surface (shown in FIG. 1) of the olefin to be dihydroxylated. That is, in this case, a direct attack of the re- or re, re-plane occurs. In contrast, when a dihydroquinine derivative is the ligand used, the two hydroxyl groups are also located on the bottom or bottom face (si- or si, si-face), as also shown in FIG. Derived from. This is best explained by reference to numbers 1, 2 and 5 in Table 4. As shown, the diol generated when using DHQD (dihydroquinidine esters) has the R or R, R configuration, and the diol generated when using ligand 2 (dihydroquinine esters) is S or S, S configuration.

The following examples are phosphoryl derivatives and are therefore different from the carboxylic acid ester derivatives described above. The phosphorus atom is directly bonded to the alkaloid oxygen atom.
Ph ₂ P (O) Diphenylphosphinic acid 69 97.5
ester

^a All stoichiometric reactions were carried out in acetone-water, 10: 1 volume / volume, at 0 ° C. and at a concentration of 0.15 M in each reagent.

^b All reactions were performed at 0 ° C. according to the original procedure reported in reference number 1 (a).

^c All reactions were performed exactly as reported in reference number 1 (a) except that 2 equivalents of Et ₄ NOAc · 4H ₂ O were present (ie not slow addition)
It was implemented.

^d All reactions were carried out at 0 ° C. using an alkaloid concentration of 0.25M as described in 2 for trans-3-hexene. The period of slow olefin addition is shown in parentheses. When dihydroquinidine p-chlorobenzoate was used as a ligand, ee shown in the table was obtained. Under the same conditions, the pseudoenantiomer dihydroquinine p-chlorobenzoate gave a product with 5-10% lower ee. In all cases, the isolated yield was 85-95%.

^e This reaction took 7 days to complete.

^{f After a} 16 hour addition period, 63 and 65% ee were obtained at 0 ° C. and 20 ° C., respectively, and the slow addition over 16 hours at 0 ° C. combined with the presence of 1 equivalent of Et ₄ N OAc.4H ₂ O 81% ee was achieved.

^g This reaction took 5 days to complete.

^{h When the} reaction was carried out at 20 ° C. and the olefin was added over 24 hours, 59% ee was obtained.

  Because of this face selection principle or phenomenon, the absolute configuration of the dihydroxylated product can be predetermined by the use of the present invention and a suitable polarizing ligand.

  As shown in Table 4, asymmetric dihydroxylation of various olefins has been successfully performed according to the present invention. Each described embodiment results in asymmetric dihydroxylation, and the “slow addition” method is particularly useful for this purpose. In each case shown in the table where absolute positioning is established, the face selection “principle” (explained with reference to the orientation shown in FIG. 1) applies and uses DHQD This results in attack or dihydroxylation resulting from the top or top surface, and DHQ results in attack or dihydroxylation resulting from the bottom or bottom surface of the olefin. This yields a product having the R or R, R configuration and a product having the S or S, S configuration, respectively.

  In a preferred embodiment of the process, aromatic ethers of various quina alkaloids are used as ligands. The term “aromatic ethers” includes aryl ethers and heterocyclic ethers. The use of dihydroquinidine or aromatic ethers of dihydroquinine as the ligand provides a high level of asymmetry induction. For example, aromatic ethers having the following formula are particularly useful.

[Where:
R is phenyl, naphthyl, or o-methoxyphenyl]
Stoichiometric asymmetric dihydroxylation of various dialkyl-substituted olefins was performed using phenyl ether derivatives of dihydroquinidine. The results are shown in Table 6.

The reaction is performed by adding 1 equivalent of olefin to a 1: 1 mixture of OsO ₄ and ligand in dry toluene (0.1 M), followed by a reducing treatment using lithium aluminum hydride (LiAlH ₄ ). (R, R) -diol is produced in good to excellent enantiomeric excess in 60-95% yield. Reactions with α, β-unsaturated esters, using this ligand, resulted in a much improved enantio- and diastereoselectivity (≧ 90% as shown in Tables 7 and 8). ) By reducing the reaction temperature to −78 ° C., the reaction with linear dialkyl-substituted olefins has very high enantioselectivity (≧ 93% as shown in Tables 2, 4, and 6). Progressed. In the several cases plotted, the variation in ee with temperature was very in accordance with the Arrhenius relationship.

  Several dihydroquinidine aromatic ether derivatives were tested as chiral ligands for asymmetric dihydroxylation of (E) -3-hexene, as shown in Table 7 below. Reactions with all aromatic ether derivatives tested showed higher enantioselectivity than the corresponding reaction with dihydroquinidine p-chlorobenzoate. The highest enantioselectivity was obtained using 9-O- (2'-methoxyphenyl) -dihydroquinidine (No. 2, Table 7).

In one aspect of the method, an aromatic ether ligand was used in the catalytic asymmetric dihydroxylation of (E) -3-hexene. The results for this embodiment are shown in Table 8. Catalytic asymmetric dihydroxylation reaction (Nos. 1-3, Table 8) was carried out in phenyl-ether dihydroquinidine (0.25 equivalent), N-methylmorpholine at 0 ° C. in acetone-water (10/1, volume / volume). This is done by slowly adding (E) -3-hexene to a mixture of N-oxide (NMO, 1.5 eq) and OsO ₄ (0.004 eq), followed by treatment with Na ₂ S ₂ O _5. . The reaction proceeded relatively quickly when tetraethylammonium acetate (2 eq) was added to the reaction mixture (No. 4, Table 8). Potassium ferricyanide was added as a side oxidant (numbers 5 and 6, Table 8). In these cases, the slow addition of olefin was not necessary. (E) -3-hexene (1 equivalent), aromatic ether of dihydroquinidine (0.25 equivalent), K ₃ Fe (CN) _{6 in} tertiary-butyl alcohol-water (1/1, volume / volume) To a mixture of (3 eq) and potassium carbonate (K ₂ CO ₃ , 3 eq) was added OsO ₄ (0.0125 eq) and the resulting mixture was stirred at room temperature for 20 h. (Using _Na 2 SO ₃₎ by reductive treatment, diol was given in 85-90% of those obtained in a stoichiometric reaction yield essentially the same ee.

  Enantioselectivity in the dihydroxylation of dialkyl-substituted olefins, which was previously possible only through the use of stoichiometric reagents at low temperatures, is a catalytic asymmetry using these aromatic ether ligands at room temperature. Obtained now in dihydroxylation. Disclosed herein are two ligands that are particularly useful in the present methods, 9-O- (9'phenanthryl) of dihydroquinidine (1a and 1b below) and dihydroquinine (2a and 2b below). ) Ethers and 9-O- (4'-methyl-2'-quinolyl) ethers.

  The R group can include other benzenoid hydrocarbons. The aromatic moiety may be modified with substituents such as lower alkyl, alkoxy or halogen groups.

  Other effective heterocyclic ligands include

Is included.

  The improvements obtained with these novel ligands are best seen by the results shown in Table 9. A particularly important advantage is that terminal olefins (numbers 1-7, Table 9) were initially in the “useful” ee-range.

HPLC of ^a bis -MTPA esters, GC or enantiomeric excess as determined by ¹ H-NMR analysis, (see supplements for details of the analysis).

^b All reactions were carried out essentially as described in Example 20 with minor modifications: (1) 1-1.25 mol% OsO ₄ or K ₂ OsO ₂ (OH) ₄ , (2)
2-25 mol% ligand, (3) 0.067-0.10 M in olefin, (4) 18
-24 hours reaction time. In all cases, the isolated yield of diol was 75-95%.

All olefins other than ^c number 6 and 7 are commercially available. The absolute configuration of the diols is based on their optical rotation with the literature values (Nos. 1, 3-5, 8, 10-13) or (R)-(−)-2-phenyl-1, which is a sure diol. Measured by comparing with 2-propanediol (No. 6) or by comparing with ORD (No. 9). The remaining two (numbers 2, 7) were tentatively assigned in a similar manner from the optical rotation of very relevant diols and the retention time of bisMTPA esters on HPLC.

^e Reaction was performed at room temperature.

  The data for the novel ligands 1a and 1b were compared with the results for another ligand, ρ-chlorobenzoate 1c (final term in Table 9). In addition, it should be noted that the highest enantioselectivity for each substrate is highlighted by parentheses, and that the parentheses are very small in the section below ligand 1c. Clearly, ligands 1a and 1b also gave significant ee gains for trans-substituted olefins, especially those lacking aromatic substituents (numbers 8 and 9).

  Six possible substitution schemes for olefins are:

It is.

  Four of these types are displayed in Table 9. This success with mono- and gem-di-substituted forms doubled the range of catalytic ADH compared to diol production when using ligands other than aromatic ether ligands.

The results for dihydroquinine ligand analogs (ie 2a, 2b and 2c) are not significantly present in Table 9. The quinidine and quinine homologues of these novel ligands also gave very good results using the same olefin types as shown in Table 9. Original ρ-chlorobenzoate ligand comparison (1c vs. 2c) Similar to ^2b , the quinine ether systems gave somewhat lower ee than their dihydroquinidine partners (1a vs. 2a and 1b vs. 2b). For example, compared to the R-diol at 93% ee recorded in Table 9 using 1a, vinylcyclooctane (number 2) gave S-diol at 8.8% ee using 2a. .

  Detailed general steps for catalytic ADH are shown in annotation example 20 using ligand 1a and vinylcyclooctane as substrate. Note the experimental simplicity of the method. It is carried out at ambient or ice bath temperature in the presence of air and water. Another advantage is that the most expensive component, the ligand, can be easily recovered in> 80% yield.

It should also be noted that K ₂ OsO ₂ (OH) ₄ , a solid non-volatile osmium (VI) salt, was used in place of osmium tetroxide. This new scheme should be useful in all catalytic oxidations including OsO ₄ to avoid the risk of exposure to volatile osmium species.

  Other olefin types can be asymmetrically dihydroxylated when using O-carbamoyl-, p-chlorobenzoate- or O-phenanthrolene-substituents of DHQD or DHQ ligands in the process of the present invention. This type is a cis-disubstituted form of olefin. Table 10 shows the ee and% yields for various substrates when using these ligands. Methods for making these ligands and performing ADH are shown in Examples 23 and 24.

Here, the ligands are denoted as dimethylcarbamoyl (DMC), methylphenylcarbamoyl (MPC), diphenylcarbamoyl (DPC), p-chlorobenzoate (PCB), phenanthryl (PHN) and phenylcarbamoyl (PhC). This is an ether-linked substituent of DHQD.

  A relatively large ee is obtained when using O-carbamoyl-DHQD ligands, which are attractive ligands for cis-disubstituted asymmetric dihydroxylation of olefins of this class. It shows that there is. These results also show that reasonable good yields and ee are obtained for this olefin type, and that five of the six olefins can be successfully asymmetrically dihydroxylated here. .

  In general, the concentration of chiral ligand used will range from about 0.001M or less to -2.0M. In one embodiment illustrated below, the solution is 0.261 M in Alkaloid 1 (dihydroquinidine derivative). In one embodiment of the method performed at room temperature, the concentration of each alkaloid displayed in FIG. 1 is 0.25M. This method maximizes the enantiomeric excess produced under the conditions used. The amount of chiral ligand required for the process of the present invention can be varied as the temperature at which the reaction occurs varies. For example, the amount of alkaloid (or other chiral ligand) used can be reduced as the temperature at which the reaction occurs changes. For example, if it is performed at 0 ° C. with a dihydroquinidine derivative, the alkaloid concentration can be 0.15M. In another embodiment performed at 0 ° C, the alkaloid concentration was 0.0625M.

Many oxidants (ie, essentially any source of oxygen) can be used. For example, amine oxides (eg, trimethylamine oxides), tertiary-butyl hydroperoxide, hydrogen peroxide, and oxygen + metal catalysts (eg, copper (Cu ⁺ -Cu ⁺⁺ / O ₂ ), platinum (Pt / O ₂ ), palladium (Pd / O ₂ ) can be used, while NaOCl, KIO ₄ , KBrO ₃ or KClO ₃ can be used.In one aspect of the invention, N-methylmorpholine N— Oxide (NMO) is used as the oxidizing agent, which is commercially available (Aldrich Chemicals, 97% NMO anhydrous, or in 60% aqueous solution), and further, as described above, potassium ferricyanide is amine oxidized. Potassium ferricyanide is an effective oxidizing agent in the process.

Osmium is generally provided in the process of the present invention in the form of osmium tetroxide (OsO ₄ ) or potassium osmate VI dihydrate, but other sources (eg, anhydrous osmium trichloride, osmium trichloride hydrate) ) Can also be used. OsO ₄ can be added in solid form or in solution.

The osmium catalyst used in the process of the present invention can be recycled for reuse in subsequent reactions. This not only reduces process costs, but also makes it possible to recover toxic osmium catalysts. For example, an osmium catalyst can be recycled as follows: A reducing catalyst (eg, Pd-C) is used to reduce and adsorb osmium VIII species onto the reducing catalyst. The resulting solid is filtered and resuspended. When NMO (ie, oxidant), alkaloid and substrate (olefin) are added, the osmium associated with the Pd / C solid is reoxidized to OsO ₄ , and when the solution is added again, it is used to produce the desired diol. Play a useful catalytic role. This step (shown below) is performed in several cycles, so that the osmium species can be reused. Palladium or carbon can be deterred, for example in a fixed bed or in a cartridge.

In one embodiment, for example, recrystallized trans - stilbene _{(C 6 H 5 CH: CHC} 6 H 5) such olefins chiral ligand (e.g., p- chlorobenzoyl hydroquinidine), acetone, water and NMO let's do it together. The classification can be added sequentially or simultaneously, and the order in which they are brought together can be changed. In this embodiment, after combining the components, the resulting combination is cooled (eg, to about 0 ° C. in the case of trans-stilbene), where cooling can be accomplished using an ice-water bath. OsO ₄ is then added in the form of a solution of OsO _{4 in} an organic solvent (eg in toluene) (eg by injection). After the addition of OsO ₄ , the resulting combination is kept under conditions suitable for the dihydroxylation reaction to proceed.

In another preferred embodiment, a chiral ligand (eg, dihydroquinidine 4-chlorobenzoate), NMO, acetone, water and OsO ₄ (5M in toluene) are combined. The classifications can be added sequentially or simultaneously, and the order in which they are brought together can be changed. In this embodiment, after combining the components, the resulting combination is cooled (eg, to about 0 ° C. in the case of trans-stilbene), where cooling can be accomplished using an ice-water bath. It is particularly preferred to stir (eg stir) the combination. To this well stirred mixture, olefin (eg trans-3-hexene) is slowly added (eg by injection). The optimum rate of addition (ie to give maximum ee) will vary depending on the nature of the olefinic substrate. In the case of trans-3-hexene, the olefin is added over a period of about 16-20 hours. After the olefin addition, the mixture can be stirred for an additional hour at low temperature (1 hour in the case of trans-3-hexene). A slow addition method is preferred because it produces a relatively good ee and a relatively fast reaction rate.

  In another aspect, compounds that promote the hydrolysis of osmate intermediates (eg, soluble carboxylic esters, such as tetraethylammonium acetate) are coupled with chiral ligands, water, solvents, oxidants and osmium catalysts and olefins. It can be added to the mixture or, if a slow addition of olefin is used, can be added before the addition of olefin.

  A schematic of the diol-production mechanism that appears to occur when using the slow olefin addition method is shown in FIG. According to the proposed mechanism, there are at least two diol-production cycles. As shown in FIG. 4, only the first cycle appears to produce a high ee. An important intermediate product is the osmium (VIII) trioxoglycolate complex, shown as Formula 3 in FIG. 4, which has the following general formula:

Where L is a chiral ligand and R ₁ , R ₂ , R ₃ and R ₄ are organic functional groups corresponding to olefins. For example, R ₁ , R ₂ , R ₃ and R ₄ are alkyl, alkoxy, aryloxy or other organic functional groups that are compatible with the reaction process. Examples of olefins that can be used and their functional groups are shown in Table 4 above.

  This complex occupies the rotational position of the binding site between two cycles and determines how the diol production is split between cycles.

  By discovering that the event in FIG. 4 can be mimicked by performing the method in a stepwise manner under stoichiometric conditions, the osmium (VIII) trioxoglycolate complex (Formula 3, FIG. 4) ) Proves an intermediate generation tendency. These experiments were performed in toluene under anhydrous conditions. In the method shown in FIG. 4, one equivalent of an alkaloid osmium complex (shown in Formula 1, FIG. 4) is reacted with an olefin to produce an emerald green monoglycolate ester (Formula 2, FIG. 4). give. When another olefin is then added followed by an equivalent amount of anhydrous amine N-oxide, rapid formation of the bisglycolate ester (Formula 4, FIG. 4) is observed. Exactly one equivalent of each diol is liberated during the reductive hydrolysis of the bisglycolate ester. These experiments show that the second cycle, possibly via an osmium trioxoglycolate complex, is as effective as the first cycle in the production of diols from olefins. It is also possible to use the same olefin in both stages in order to carry out this parallel addition process. When this was done using 1-phenylcyclohexene as the olefin, the ee for the first stage was 81% and the ee for the second stage was 7% in the reverse direction (ie, a small amount of enantiomeric tendency in the first stage). Met). Thus, for this substrate, the second cycle invasion was particularly damaged and under the original contact conditions 1-phenylcyclohexene gave only 8% ee (number 3, Table 5).

  The reduced ee is just the reverse productivity part of the second cycle turning, and the reduced turnover is another confidence factor. Bisosmates (Formula 4, FIG. 4) tend to immobilize the catalyst because they are usually slowly reoxidized and hydrolyzed. For example, 1-phenylcyclohexene takes 7 days to fully reach the original conditions (8% ee quoted above). With the slow addition of olefins, the oxidation was complete in 1 day and gave the diol in 95% yield and 73% ee (number 3, Table 5).

  The most important prediction arising from the mechanism diagram shown in FIG. 4 is the minimization of the second cycle when the olefin is added slowly. The slow addition of the olefin gives sufficient time for the osmium (VIII) acid intermediate product of the trioxoglycolate to hydrolyze so that the osmium catalyst is not retained by reacting with the olefin during the second cycle. To repeat, the second cycle not only exacerbates ee but also hinders turnover, since some of the contained complex is slowly reoxidized and / or hydrolyzed. The optimum feed rate depends on the olefin, which can be determined experimentally as described herein.

  The maximum ee obtained by the contact method is determined by the addition of the alkaloid osmium complex (Formula 1, FIG. 4) to the olefin (ie, first term in Table 5). Thus, stoichiometric addition can be used to determine the ee-maximum, which performs hydrolysis of 3 (FIG. 4) to govern the alternating reaction of olefins with the second molecule 4 (FIG. 4). ) Can reach or approach the contact method. In the case of styrene (Table 5), which is a terminal olefin, trioxyglycolate esters hydrolyze rapidly due to slow addition, or the effect of osmate ester hydrolysis additive is minimal on ee Only give an increase. However, most olefins benefit greatly from modifications that speed up the hydrolysis of the osmate intermediate product (3, FIG. 4) (No. 2-5, Table 5), and in extreme cases the osmate ester The influence of hydrolysis additives or slow addition is not sufficient. Diisopropylethylene (No. 4, Table 5) reaches the highest ee only when both effects are used together while slow addition is performed in the presence of acetate. The other numbers in the table reach their optimal ee only by slow addition, but even in these cases the addition time can be substantially reduced if a compound such as a tetraalkylammonium acetate is present. it can.

  In many cases, temperature also affects ee. When ee is reduced by the second cycle, ee can often be increased by increasing temperature. This occurs especially when NMO is used as a secondary oxidant. For example, diisopropylethylene gives 46% ee at 0 ° C. and 59% ee at 25 ° C. (24 hours slow addition time in both cases). The hydrolysis rate of the osmium trioxoglycolate intermediate product is clearly more temperature dependent than the rate of its reaction with olefins. This temperature effect is easily theorized by the anticipated desire to dissociate the chiral ligand from the osmium complex (3) to bind water and initiate hydrolysis, but the addition of olefins It is not necessary for the ligand to dissociate to occur (in fact, this second cycle olefin addition step also appears to be facilitated by the ligand).

When K ₃ Fe (CN) ₆ is used as a secondary oxidant, the effect of temperature on ee is opposite to the effect when NMO is used as a secondary oxidant. That is, when potassium ferricide is used as a secondary oxidant, a decrease in temperature can often increase ee. Also, the olefin need not be added slowly to the mixture, and in fact can be added all at once instead of potassium ferricyanide as a by-oxidant. These effects and conditions clearly occur because the second cycle is suppressed when using this secondary oxidant. When the secondary oxidant is potassium ferricyanide, the second cycle reaction does not appreciably contribute to the formation of diols.

The following is a description of how to determine the optimum conditions for a specific olefin. To optimize asymmetric dihydroxylation catalyzed by osmium,
1) If in doubt from the known examples what the maximum ee is, determine it by performing stoichiometric osmylation in acetone / water at 0 ° C. with 1 equivalent of OsO ₄ -alkaloid complex. be able to.
2) Slow addition at 0 ° C .: Addition time taking into account the constant temperature at which each olefin has its own “fastest” addition rate, beyond which ee decreases to move to the second cycle The last term in Table 3 can be used as a guide for selecting. When the olefin addition rate is sufficiently slow, the reaction mixture remains yellow-orange (1 color, FIG. 4), and if the rate is too fast, the solution becomes blackish and dark brown to black bisglycolate complex The body (4, FIG. 4) has been generated.
3) If the maximum ee is not reached after steps 1 and 2, a slow addition at 0 ° C. and a tetraalkylammonium acetate (or other compound that assists in hydrolysis of the osmate intermediate product) can also be used. . For all these variants, it is preferred to stir (eg stir) the mixture for the entire reaction period.

  The process of the invention can be carried out over a wide temperature range, and the limits of the range will be determined, for example, by the limits of the organic solvent used. The method can be performed, for example, at a temperature range of about 40 ° C to about -30 ° C. The concentration of individual reactants (eg, chiral ligand, oxidant, etc.) can be varied according to the temperature at which the process of the present invention is performed. The saturation point (eg, the concentration of chiral ligand that results in the maximum) is temperature-dependent. As explained above, for example, when the method is carried out at a relatively low temperature, the amount of alkaloid used can be reduced.

  The organic solvent used in the present method is, for example, acetone, acetonitrile, THF, DME, cyclohexane, hexane, pinacolone, tertiary-butanol, toluene or a mixture of two or more organic solvents. These solvents are particularly suitable when NMO is used as a secondary oxidant.

When potassium ferricyanide (K ₃ Fe (CN ₆ )) is a by-oxidizer, it is advantageous to use a combination of solvents that separate the organic and aqueous phases. The process of the present invention can also be carried out using the organic solvent of the previous section using potassium ferricyanide as a side oxidant, but using a separable organic and aqueous solvent layer that causes asymmetric dihydroxylation. Ee is less than time.

  Yields and ee for various organic solvents mixed with water and various substrates are shown in Tables 11-12. Table 11 shows the yield and ee for several organic solvents (with water) for a specific substrate. The ligand is DHQD-p-chlorobenzoate (PCB) or DHQD-naphthyl ether. Table 12 shows the ee for various substrates for t-butanol or cyclohexane as the organic phase. From these tables it is clear that suitable organic phase solvents include cyclohexane, hexane, ethyl ether and t-butyl methyl ether. A preferred aqueous solvent is water.

b) Effect of solvent on hexenediol using DHQD-PCB ligand Reaction time = 24 hours

c) Effect of solvent on decenediol using DHQD-PCB ligand Reaction time = 24 hours

d) Effect of solvent on hexenediol using DHQD naphthyl ether ligand Reaction time = 24 hours

e) Effect of solvent on decenediol using DHQD naphthyl ether ligand Reaction time = 24 hours

Yield (%) ee (%)
tBuOH 40.7 94
* 5 ml of t-Bu-O-Me was added to dissolve all ligands.
** 6 ml of t-Bu-O-Me was added to dissolve all ligands.

In another aspect of the invention, styrene is combined with a chiral ligand (DHQD), acetone, water and NMO and OsO ₄ . A plot of amine concentration versus second order rate constant K for catalytic cis-dihydroxylation is displayed in FIG. The rate data in FIG. 2 clearly shows the dramatic effect of ligand-promoted catalysis obtained by using the method of the present invention. Point a in FIG. 2 represents the speed of the contact method in the absence of amine ligand (t1 / 2 = 108 minutes). Line b shows the rate of the process in the presence of quinuclidine, a varying amount of the ligand that substantially delays catalysis (for quinuclidine greater than 0.1M, t1 / 2 is greater than 30 hours. Is). Due to the observed delayed effect of quinuclidine (ligand-retarded catalysis), the results represented by line C are unexpected. That is, when the process occurs in the presence of dihydroquinidine benzoate derivative 1 (see FIG. 1), the alkaloid moiety potentiates the contact process at all concentrations despite the presence of the quinuclidine moiety in its structure. (Ligand 1 = 0.4M, t1 / 2 = 4.5 minutes).

The stoichiometric reaction rates of styrene and osmium tetroxide and the corresponding contact method rates were compared. The comparison shows that both have the same rate coefficient [K stoichiometric = (5.1 ± 0.1) × 10 ² M ⁻¹ min− ¹ and K catalyst = (4.9 ± 0.4) × 10 ² M ⁻¹ min ⁻¹ ] and that they received the same rate enhancement with the addition of ligand 1. Hydrolysis and reoxidation of reduced osmium species, the stage of catalyst turnover, is not kinetically significant in the catalytic process using styrene. It was concluded that the limiting step was the same for both methods and included an initial addition reaction that produced an osmate (2, FIG. 1). Detailed mechanistic studies indicate that the rate enhancement observed with the added ligand 1 is due to the formation of osmium tetroxide-alkaloid complexes, which in the case of styrene is 23 times more reactive than free osmium tetroxide. Was shown to be great. The rate reached a maximum and reached a constant value above the (about) 0.25 M concentration of ligand 1. This onset of rate saturation corresponds to a pre-equilibrium between DHQD and osmium tetroxide with a rather weak coupling constant (K equivalent = 18 ± 2 M ⁻¹ ). Increasing the concentration of DHQD to above 0.25 M does not result in a corresponding increase in enantiomeric excess of product diol. In fact, because of the ligand-promoting effect, the ee of the process reaches its maximum much faster than reaching the maximum rate, which means that an optimal ee is obtained at rather low alkaloid concentrations. is doing.

  At least in the case of styrene, the rate enhancement in the presence of alkaloids is compensated by the acceleration of the initial osmylation stage. The exact opposite effect of quinuclidine and DHQD on catalysis also promotes the addition of osmium tetroxide to olefins, but it is too strongly bound to the resulting osmium (VI) ester intermediate product and cycle hydrolysis / regeneration. This may be related to the fact that catalyst turnover is improved by delaying oxidation. In contrast, alkaloids appear to give a balanced action, which plays almost perfect role as a promoter of dihydroxylation catalysis. It binds strong enough to facilitate the addition of olefins, but not so tightly that it interferes with subsequent stages of the catalytic cycle. Chelating tertiary-amines [eg, 2,2'-bipyridine and (-)-(R, R) -N, N, N'N'-tetramethyl-1,2-cyclohexanediamine] The catalyst action is completely suppressed at 2M. Pyridine has the same effect at 0.2M.

  As indicated in Table 4, the process of the present invention applies to various olefins. In each case, it is shown that the above face selection principle applies (see olefin orientation displayed in FIG. 1). That is, in the case of an asymmetric dihydroxylation reaction in which the dihydroquindine derivative is a chiral ligand, attack occurs on the re- or re, re-plane, and when the dihydroquinine derivative is a chiral ligand. Attacks occur on the si- or si, si- plane. Thus, as shown by the data displayed in Table 2, the process of the present invention is effective in carrying out catalytic asymmetric dihydroxylation, with diol yields of 80-95% in all cases. With certain and slow addition variants, most olefins give ee in the range of 40-90%.

  The method can be used to synthesize chiral intermediate products that are important building blocks for biologically active chiral molecules such as drugs. In one aspect, the method is used to produce an optically pure intermediate used in the synthesis of the drug diltiazem (also known as cardizem). The reaction is shown by the following reaction formula.

  The process of the present invention is also useful for performing asymmetric proximity oxyamination of olefins and is also useful for asymmetric proximity diamination. In the case of substitution of two nitrogens or nitrogen and oxygen, amino derivatives are used as aminotransfer agents and oxidants. For example, the olefin to be modified, organic solvent, water, chiral ligand, amino derivative and osmium-containing compound are combined and the combination is kept under conditions suitable for the reaction to take place. The amino derivative can be, for example, N-chlorocarbamic acid ester or chloroamine T. Asymmetric catalytic oxyamination of recrystallized transstilbene according to the method of the present invention is displayed in FIG.

  In another embodiment, the method was used to produce intermediate products for the synthesis of homobrassinolide and 24-epibrassinolide known to exhibit the same biological activity as brassinolide. These brassinosteroids show very effective plant growth activity at the hormonal level, and large quantities of these compounds can only be obtained by synthetic means.

  In another aspect of the process, a highly optically active diol was prepared from asymmetric dihydroxylation of ethyl trans-2-octenoate. The diol can be converted to an optically pure β-lactam structure that is well known for their antibiotic activity.

Example 1 Asymmetric Dihydroxylation of Stilbene The following were placed sequentially in a 2 liter bottle (or flask): 180.2 g (1.0 M) of recrystallized trans stilbene (Aldrich 96%), 180 0.2 g (0.134 mol, 0.134 equivalent) of p-chlorobenzoic acid ester of hydroquinidine (1), 450 ml of acetone, 86 ml of water (solution was 0.261 M in alkaloid 1) and 187. 2 g (1.6 mol, 1.6 eq) solid N-methylmorpholine N-oxide (NMO, Aldrich 97%). The bottle was capped, shaken for 30 seconds, and cooled to 0-4 ° C. using an ice water bath. OsO ₄ (0.120 g OsO ₄ / ml toluene, 0.002 mol%, 0.002 equiv) was injected. The bottle was shaken and placed in a refrigerator at about 4 ° C. with occasional shaking. A dark purple color appeared and slowly changed to deep orange, the heterogeneous reaction mixture gradually became homogeneous and a clear orange solution was obtained at the end of the reaction. The reaction was easily monitored by TLC (silica gel, CH ₂ Cl ₂ , disappearance of starting material at defined Rf). After 17 hours, 100 g of solid sodium bisulfite (Na ₂ S ₂ O ₅ ) was added, the reaction mixture was shaken (1 minute) and left at 20 ° C. for 15 minutes. The reaction mixture was then diluted with an equal volume of CH ₂ Cl ₂ and anhydrous Na ₂ SO ₄ was added (100 g). After an additional 15 minutes, the solid was removed by filtration through a pad of celite, diluted 3 times with a 250 ml portion of CH ₂ Cl ₂ and the solvent was evaporated under vacuum (rotary-evaporator, bath temperature = 30− 35 ° C.).

The crude oil was dissolved in ethyl acetate (750 ml), extracted with 500 ml portions of 2.0 M HCl three times, 2.0 M NaOH once, dried over Na ₂ SO ₄ and concentrated in vacuo. 190 g (89%) of the crude diol remained as a pale yellow solid. The enantiomeric excess of crude R, R-diol was determined to be 78% by HPLC analysis of the derived bis-acetate (Pilcle 1A column using a 5% isopropanol / hexane mixture as eluent). Retention times were t1 = 18.9 minutes and t2 = 19.7 minutes. Recrystallization from about 1000 ml of CH ₂ Cl ₂ gave 150 g (70%) of pure diol (ee = 90%). A second recrystallization gave 115 g of 99% e diol (55% yield). ee (enantiomeric excess) is the relation (eg for the R enantiomer):
Percentage ee = [(R) − (S) / [(R) + (S)] × 100
Calculated from

The aqueous layer was cooled to 0 ° C. and treated with 2.0 M NaOH until pH = 7. Methylene chloride (500 ml) was added and the pH was adjusted to 10-11 using a further 2.0 M NaOH (ca. 500 ml). The aqueous layer was separated, extracted twice with methylene chloride (2 × 300 ml), and the combined organic layers were dried over Na ₂ SO ₄ . The solvent was removed in vacuo to give the alkaloid in the form of a yellow foam. The crude alkaloid was dissolved in ether (1000 ml), cooled to 0 ° C. (ice bath), and treated with dry HCl until acidic pH (about 1-2). A pale yellow precipitate of p-chlorobenzoylhydroquinidine hydrochloride was collected by filtration and dried under high vacuum (0.01 mmHg).

The free base was liberated by suspending the salt in ethyl acetate (500 ml), cooling to 0 ° C. and adding 28% NH ₄ OH until pH = 11 was reached. After separation, the aqueous layer was extracted twice with ethyl acetate, the combined organic layers were dried over Na ₂ SO ₄ and the solvent was removed in vacuo to give the free base in the form of a white foam.
Example 2 Asymmetric dihydroxylation of stilbene A 3-liter, 3-necked round bottom flask equipped with a mechanical stirrer and two glass stoppers at room temperature was E-1,2-diphenylethene (trans-stilbene) ( 180.25 g, 1.0 mol, 1.0 eq), 4-methylmorpholine N-oxide (260 ml of a 60 wt% aqueous solution (1.5 mol, 1.5 eq), dihydroquinidine 4-chlorobenzoate (23 0.25 g, 0.05 mol, 0.05 eq.), 375 ml of acetone and 7.5 ml of H ₂ O were added, the solution was 0.1 M in olefin in alkaloid M, and the solvent was 25% water / 75 % Acetone (volume / volume) The flask was immersed in a cooling bath at 0 ° C. and stirred for 1 hour Osmium tetroxide (1.0 g, 4.0 mmol, 4.0 × 10 ^{− 3} equivalents) was added in one portion, resulting in a milky brown yellow suspension The reaction mixture was then stirred at 0 ° C. for 24 hours and silica TLC (3: 1 CH ₂ Cl ₂ Et ₂ O capacity / volume). At this point, sodium metabisulfite (285 g, 1.5 mol) was added and the mixture was diluted 3 times with 500 ml of CH ₂ Cl ₂ , warmed to room temperature and stirred at room temperature for 1 hour. Anhydrous sodium sulfate (50 g) was added and stirred overnight at room temperature, the suspension was filtered through a 20 cm Buchner funnel, the filtrate was rinsed thoroughly with acetone (3 × 250 ml), and the filtrate was heated slightly on a rotary evaporator. Concentrate (bath temperature 30-40 ° C.) to a brown paste, which is dissolved in 3.5 liters of EtOAc, transferred to a 6 liter separatory funnel and Washed with H ₂ O (2 × 500 ml) and brine (1 × 500 ml) The initial aqueous wash was kept separate from the subsequent acidic wash retained for alkaloid recovery. Na ₂ SO ₄ ) and the solvent was evaporated under vacuum (rotary-evaporator, bath temperature = 30-35 ° C.).

The crude oil was dissolved in ethyl acetate (750 ml), extracted with 500 ml portions of 2.0 M HCl three times, 2.0 M NaOH once, dried over Na ₂ SO ₄ and concentrated in vacuo. 190 g (89%) of the crude diol remained as a pale yellow solid. The enantiomeric excess of crude R, R-diol was determined to be 78% by HPLC analysis of the derived bis-acetate (Pilcle 1A column using a 5% isopropanol / hexane mixture as eluent). Retention times were t1 = 18.9 minutes and t2 = 19.7 minutes. Recrystallization from about 1000 ml of CH ₂ Cl ₂ gave 150 g (70%) of pure diol (ee = 90%). A second recrystallization gave 115 g of 99% e diol (55% yield). ee (enantiomeric excess) is the relation (eg for the R enantiomer):
Percentage ee = [(R) − (S) / [(R) + (S)] × 100
Calculated from

The aqueous layer was cooled to 0 ° C. and treated with 2.0 M NaOH until pH = 7. Methylene chloride (500 ml) was added and the pH was adjusted to 10-11 using a further 2.0 M NaOH (ca. 500 ml). The aqueous layer was separated, extracted twice with methylene chloride (2 × 300 ml), and the combined organic layers were dried over Na ₂ SO ₄ . The solvent was removed in vacuo to give the alkaloid in the form of a yellow foam. The crude alkaloid was dissolved in ether (1000 ml), cooled to 0 ° C. (ice bath), and treated with dry HCl until acidic pH (about 1-2). A pale yellow precipitate of p-chlorobenzoylhydroquinidine hydrochloride was collected by filtration and dried under high vacuum (0.01 mmHg).

The free base was liberated by suspending the salt in ethyl acetate (500 ml), cooling to 0 ° C. and adding 28% NH ₄ OH until pH = 11 was reached. After separation, the aqueous layer was extracted twice with ethyl acetate, the combined organic layers were dried over Na ₂ SO ₄ and the solvent was removed in vacuo to give the free base in the form of a white foam.
Example 3 Asymmetric dihydroxylation of stilbene Asymmetric dihydroxylation of stilbene was performed as described in Example 1 except that 1.2 equivalents of NMO was used.
Example 4 Asymmetric dihydroxylation of stilbene Asymmetric dihydroxylation of stilbene was performed as described in Example 1 except that 1.2 equivalents of NMO was used as a 62 wt% aqueous solution. .
Example 5 Preparation of dihydroquinidine derivatives
Preparation of dihydroquinidine by catalytic reduction of quinidine To a solution of 16.2 g quinidine (0.05 mol) in 150 ml 10% H ₂ SO ₄ (15 g concentrated H ₂ SO _{4 in} 150 ml H ₂ O) .2 g of PdCl ₂ (0.022 equivalent, 0.0001 mol) was added. The reaction mixture was hydrogenated in a Parshaker at 50 psi pressure. After 2 hours, the catalyst was removed by filtration through a pad of celite and washed with 150 ml of water. The pale yellow solution thus obtained was slowly added to a stirred aqueous NaOH solution (15 g NaOH in 150 ml H ₂ O). A white precipitate formed immediately and the solution was brought to 10-11 by addition of excess aqueous 15% NaOH. The precipitate was collected by filtration, compressed to dryness and suspended in ethanol (175 ml). When the boiling solution was rapidly filtered and cooled to room temperature, white needles crystallized. The crystals were collected and dried overnight under vacuum (90 ° C., 0.05 mmHg). This gave 8.6 g (52.8%) of pure dihydroquinidine. Melting point = 169.5-170 ° C. The mother liquor was placed in a refrigerator at -15 ° C overnight. After filtration and drying of the crystals, another 4.2 g (21.4%) of pure material was obtained, increasing the total amount of dihydroquinidine to 12.8 g (74.1%).
Preparation of dihydroquinidine p-chlorobenzoate (ligand 1) from dihydroquinidine hydrochloride (Aldrich) 100 g of dihydroquinidine hydrochloride (0.275 mol) cooled in 300 ml of dry CH ₂ Cl ₂ ( To the suspension was added 115 ml Et ₃ N (0.826 eq, 3 eq) dissolved in 50 ml CH ₂ Cl ₂ with efficient stirring over 30 minutes. The addition funnel was rinsed with an additional 20 ml of CH ₂ Cl ₂ . After stirring for 30 minutes at 0 ° C., 42 ml of p-chlorobenzoyl chloride (0.33 mol, 57.8 g, 1.2 eq) were added dropwise over 2 hours. The heterogeneous reaction mixture was then stirred at 0 ° C. for 30 minutes and at room temperature for 1 hour, and then 700 ml of 3.0 M NaOH solution was added slowly until pH = 10-11 was obtained. After partitioning, the aqueous layer was extracted 3 times with 100 ml portions of CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and the solvent was removed in vacuo (rotary evaporator). The crude oil was dissolved in 1 liter of ether, cooled to 0 ° C. and treated with HCl until the ether solution gave a pH of about 2 with wet pH paper. A slightly yellow precipitate was collected and dried under vacuum to give 126 g (91.5%) of dihydroquinidine p-chlorobenzoate.

The salt was suspended in 500 ml of ethyl acetate, cooled to 0 ° C. and treated with 28% NH ₄ OH until pH = 11 was reached. The combined organic layers were dried over Na ₂ SO ₄ and the solvent removed under vacuum leaving the free base 1 in a white foam (112 g, 88% total). This material could be used without further purification, or it could be recrystallized from a minimal amount of hot acetonitrile, giving colorless crystals with about 70-80% recovery. Melting point 102-104 ° C,
^{[] 25 D-76.5 ° c1.11} , EtOH);
IR (CH ₂ Cl ₂ ) 2940, 2860, 1720, 1620, 1595, 1520, 1115, 1105, 1095, 1020 cm ⁻¹ ; ¹ H NMR (CDCl ₃ ) 8.72 (d, 1H, J = 5 Hz), 8 0.05 (wide d, 3H, J = 9.7 Hz), 7.4 (m, 5H), 6.72 (d, 1H, J = 7.2 Hz), 3.97 (s, 3H), 3. 42 (dd, 1H, J = 9, 19.5 Hz), 2.9-2.7 (m, 4H), 1.87 (m, 1H), 1.75 (wide s, 1H), 1.6 -1.45 (m, 6H), 0.92 (t, 3H, J = 7 Hz).
Analysis for C ₂₇ H ₂₉ ClN ₂ O ₃ ,
Calculated: C, 69.74; H, 6.28; Cl, 7.62; N, 6.02.
Found: C, 69.95; H, 6.23; Cl, 7.81; N, 5.95.
To a solution of dihydroquinidine from 1.22 g dihydroquinidine (0.0035 mol) in 30 ml CH ₂ Cl ₂ at 0 ° C. was added 0.78 ml Et ₃ N (0.000056 mol, 1.5 eq), then p- chlorobenzoyl (0.005 mol, 1.2 eq) chloride 0.71ml of _CH 2 Cl ₂ 1ml was added. After stirring at 0 ° C. for 30 minutes and at room temperature for 1 hour, the reaction was captured by addition of 10% Na ₂ CO ₃ (20 ml). After separation, the aqueous layer was extracted 3 times with 10 ml portions of CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and the solvent was removed in vacuo. The crude product was purified as described above. Dihydroquinidine p-chlorobenzoate (1) was obtained in a white foam in 91% yield (1.5 g).
The recovered aqueous acidic extracts of dihydroquinidine p-chlorobenzoate (see Example 1) were combined, cooled to 0 ° C., and treated with 2.0 M NaOH solution (500 ml) until pH = 7 was obtained. Methylene chloride (500 ml) was added and the pH was adjusted to 10-11 using a further 2.0 M NaOH solution. The aqueous layer was separated and extracted twice with 300 ml portions of CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated to leave the crude alkaloid in a yellow foam. Crude p-chlorobenzoic acid dihydroquinidine (1) is dissolved in 1 liter of ether, cooled to 0 ° C. and HCl gas is bubbled into the solution until a pH of 1-2 is obtained with wet pH paper. It was. One pale yellow precipitate as the hydrochloride salt was collected by filtration and dried under high vacuum (0.01 mmHg). The free base is liberated by suspending the salt in 500 ml ethyl acetate, cooling the heterogeneous mixture to 0 ° C. and adding 28% NH ₄ OH (or 15% NaOH) until pH = 11 is obtained. I let you. After separation, the aqueous layer was extracted twice with 100 ml portions of ethyl acetate, the combined organic layers were dried over Na ₂ SO ₄ and the solvent was removed in vacuo to yield 56 g (91% recovery) of pure Dihydroquinidine p-chlorobenzoate (1) was given in the form of a white foam.
Example 6 Preparation of dihydroquinine derivatives
Preparation of p-chlorobenzoate dihydroquinine. Catalytic hydrogenation and p-chlorobenzoylation were performed as described for dihydroquinidine p-chlorobenzoate to obtain a white amorphous solid at 85-90% yield. Given by rate. This solid could be used without further purification, or it could be recrystallized from a minimum amount of hot acetonitrile to give colorless crystals. Melting point: 130-133 ° C.
[A] ²⁵ D + 150 [deg.] (C 1.0, EtOH). The physical properties of the solid before recrystallization (ie, “white amorphous solid”) were as follows:
[] ²⁵ + 142.1 ° c = 1, EtOH);
IR (CH ₂ Cl ₂ ) 2940, 2860, 1720, 1620, 1595, 1520, 1115, 1105, 1095, 1020 cm ⁻¹ ;
¹ H NMR (CDCl ₃ ) 8.72 (d, 1H, J = 5 Hz), 8.05 (wide d, 3H, J = 8 Hz), 7.4 (m, 5H), 6.7 (d, 1H) , J = 8 Hz), 4.0 (s, 3 H), 3.48 (dd, 1 H, J = 8, 15.8 Hz), 3.08 (dd, 1 H, J = 11, 15 Hz), 2.69 (Ddd, 1H, J = 5, 12, 15.8 Hz), 2.4 (dt, 1H, J = 2.4, 15.8 Hz), 1.85-1.3 (m, 8H), 0.8 87 (t, 3H, J = Hz).
Analysis for C ₂₇ H ₂₉ ClN ₂ O ₃ ,
Calculated: C, 69.74; H, 6.28; Cl, 7.62; N, 6.02.
Found: C, 69.85; H, 6.42; Cl, 7.82; N, 5.98.
The recovery process for p-chlorobenzoate dihydroquinine was identical to that described above for 1 recovery.
Example 7 0.465 g (1 mmol, 0.25 equivalent = 0.25 M in liter) of dihydroquinidine 4-chlorobenzoate for the asymmetric dihydroxylation of trans-3-hexene under “addition” conditions (Aldrich, 98%), 0.7 g (6 mmol, 1.5 eq) of N-methylmorpholine N-oxide (Aldrich, 97%), and 32 liters of osmium tetroxide (16 mol, 4 × 10 ^−3). Equivalent) of 4 ml acetone-water mixture (10: 1 volume / volume) to a well-stirred mixture at 0 ° C. consisting of a 0.5 M toluene solution was added pure 0.5 ml (0.34 g, 4 mmol). Trans-3-hexene (Willie, 99.9%) was added through a gas-tight syringe controlled by an infusion pump and while dipping the tip of the infusion needle into the reaction mixture. Slowly added over time. The mixture gradually changed from heterogeneous to homogeneous. After the addition was complete, the resulting clear orange solution was stirred at 0 ° C. for an additional hour. Solid sodium metabisulfite (Na ₂ S ₂ O ₅ , 1.2 g) was added and the mixture was stirred for 5 minutes, then diluted with dichloromethane (8 ml) and dried (Na ₂ SO ₄ ). The solid was removed by filtration and washed 3 times with dichloromethane. The combined filtrates are concentrated and the residual oil is subjected to flash column chromatography on silica gel (25 g, elution with diethyl ether-dichloromethane 2: 3 volume / volume, Rf 0.33) and the corresponding fraction classification is 30-0.32 g (85-92% yield) of hexanediol was provided. The enantiomeric excess of the diol was 70% as determined by GLC analysis of the derived bis-Mosher ester (5% phenyl-methyl silicone, 0.25 m film, 0317 mm diameter, 29 m length).

The above reaction was repeated with 1.2 ml (6 mmol, 1.5 eq) of 60% aqueous NMO (Aldrich) in 4 ml of acetone to give 71% ee. That is, this aqueous NMO gave comparable results and it was about 20 times cheaper than the 97% solids grade. Using an alkaloid concentration of 0.1 M (ie 0.186 g) and using an olefin addition time of 20 hours at 0 ° C., the ee was 65%. Thus, the small sacrifice of ee resulted in a great savings in alkaloids. At 0 ° C., both trans-hexene and trans-methylstyrene reached their maximum ee values of alkaloid concentrations between 0.20 and 0.25M.
Example 8 Asymmetrical dihydroxylated 1-phenylcyclohexene using Et ₄ NOAc-4H ₂ O Except that the trans-stilbene was replaced with 1-phenylcyclohexene (1.0 M). The process was repeated. The reaction was allowed to proceed for 3 days, after which only 40% conversion to diol was obtained (8% ee).

The above steps were repeated except that 2 equivalents of tetraethylammonium acetate (Et ₄ NOAc-4H ₂ O) was added to the reaction mixture at the start of the reaction. Using this process, 52% ee was obtained and the reaction was complete in about 1 day.
Example 9 Asymmetric dihydroxylation of trans-stilbene under “phase-transition” conditions in toluene 58.2 mg (0.125 mmol, 0.25 equiv) of p-chlorobenzoic acid ester of hydroquinidine, 1 ml Of toluene, 88 mg (0.75 mmol, 1.5 eq) N-methyl-morpholine N-oxide, 181 mg (1 mmol, 2 eq) tetramethylammonium hydroxide pentahydrate, 57 μl (2 mmol, 2 eq) ) Acetic acid, 0.1 ml water, and OsO ₄ (121 mg OsO ₄ / ml solution made with toluene, 0.004 mol%, 0.004 equiv.) Into a well-stirred mixture. At room temperature, 90 mg (0.4 mmol) of trans-stilbene in toluene (1 ml) was gas-sealed as controlled by the infusion pump. Using a syringe and the tip of the injection needle is immersed in the reaction mixture was added slowly over a period of 24 hours. After the addition was complete, 10% NaHSO ₃ solution (2.5 ml) was added to the mixture and the resulting mixture was stirred for 1 hour. The organic material was extracted with ethyl acetate and the combined extracts were washed with brine and dried over Na ₂ SO ₄ . The solvent was evaporated under reduced pressure and the residual oil was subjected to column chromatography on silica gel (5 g, eluted with hexane-ethyl acetate, 2: 1 volume / volume, Rf 0.17) to give 67.3 mg (63%) of diol. Gave. Enantiomeric excess of diol was determined by HPLC analysis of derived bis-acetate (Pilcle 1A column using 5% isopropanol / hexane mixture as eluent. Retention times were t ₁ = 22.6 minutes, t ₂ = 23.4 minutes. ) To be 94%.
Example 10 Asymmetric dihydroxylation of trans-methyl-4-methoxycinnamate under phase-transition conditions in toluene 116.3 mg (0.25 equivalents) of p-chlorobenzoic acid ester of hydroquinidine, 2 ml Of toluene, 175.8 mg (1.5 mmol, 1.5 eq) N-methyl-morpholine N-oxide, 522 mg (2 mmol, 2 eq) tetramethylammonium acetate tetrahydrate, 0.2 ml water, and _OsO 4 (solution prepared by using _OsO 4 / ml of toluene 121 mg, 0.004 mol%, 0.004 equiv) at room temperature to a well stirred mixture is composed of, transformer 192 mg (1 mmol) A gas-tight injector in which a toluene solution of methyl-4-methoxycinnamate (1 ml) is regulated by an infusion pump And then the tip of the injector needle immersed in the reaction mixture using, was added slowly over a period of 24 hours. After the addition was complete, 10% NaHSO ₃ solution (5 ml) was added to the mixture and the resulting mixture was stirred for 1 hour. The organic material was extracted with ethyl acetate and the combined extracts were washed with brine and dried over Na ₂ SO ₄ . The solvent was evaporated under reduced pressure and the residual oil was subjected to column chromatography on silica gel (10 g, eluted with hexane-ethyl acetate, 2: 1 volume / volume, Rf 0.09) to give 118.8 mg (53%) of diol. Gave. Enantiomeric excess of diol was determined by HPLC analysis of derived bis-acetate (Pilcle 1A column using 10% isopropanol / hexane mixture as eluent. Retention times were t ₁ = 25.9 minutes, t ₂ = 26.7 minutes ) To be 84%.
Example 11 Asymmetric dihydroxylation of trans-stilbene in the presence of boric acid 58.2 mg (0.125 mmol, 0.25 equiv) of hydroquinidine p-chlorobenzoate, 70 mg (0.6 mmol) 1.2 eq) N-methyl-morpholine N-oxide, 37 mg (0.6 mmol, 1.2 eq) boric acid, 0.5 ml dichloromethane, and OsO ₄ (121 mg OsO ₄ / ml toluene) 90 mg (0.4 mmol) of a trans-stilbene solution in toluene (at room temperature) was added to a well-stirred mixture consisting of 4.2 μl of a solution prepared using 0.04 mol%, 0.004 equiv. 1 ml) is immersed in the reaction mixture using a gas tight syringe controlled by an infusion pump and the tip of the syringe needle is immersed in the 24 hour period. It was added slowly over a period of. After the addition was complete, 10% NaHSO ₃ solution (2.5 ml) was added to the mixture and the resulting mixture was stirred for 1 hour. The organic material was extracted with ethyl acetate and the combined extracts were washed with brine and dried over Na ₂ SO ₄ . The solvent was evaporated under reduced pressure and the residual oil was subjected to column chromatography on silica gel (5 g, eluted with hexane-ethyl acetate, 2: 1 volume / volume, Rf 0.17) to give 78.3 mg (73%) of diol. Gave. The enantiomeric excess of the diol was determined to be 94% by ¹ H NMR analysis of the derived bis-Mosher ester.
Example 12 Asymmetric dihydroxylation of methyl trans-4-methoxycinnamate in the presence of boric acid 116.3 mg (0.25 mmol, 0.25 equiv) of p-chlorobenzoic acid ester of hydroquinidine, 175 0.8 mg (1.5 mmol, 1.5 eq) N-methyl-morpholine N-oxide, 74.4 mg (1.2 mmol, 1.2 eq) boric acid, 1 ml dichloromethane, and OsO ₄ (121 mg 192 mg (1 mmol) of trans- at room temperature to a well-stirred mixture consisting of 8.4 μl of a solution prepared with ₄ ml of OsO ₄ / ml of toluene, 0.004 mol%, 0.004 eq. Mix methyl methoxycinnamate in dichloromethane (1 ml) using a gas tight syringe controlled by an infusion pump and the tip of the injection needle. Is immersed in the object, it was added slowly over a period of 24 hours. After the addition was complete, 10% NaHSO ₃ solution (5 ml) was added to the mixture and the resulting mixture was stirred for 1 hour. The organic material was extracted with ethyl acetate and the combined extracts were washed with brine and dried over Na ₂ SO ₄ . The solvent was evaporated under reduced pressure and the residual oil was subjected to column chromatography on silica gel (10 g, eluted with hexane-ethyl acetate, 2: 1 volume / volume, Rf 0.09) to give 151.1 mg (67%) of diol. Gave. Enantiomeric excess of diol was determined by HPLC analysis of derived bis-acetate (Pilcle 1A column using 10% isopropanol / hexane mixture as eluent. Retention times t ₁ = 24.0 min, t ₂ = 24.7 min ) To be 76%.
Example 13 Asymmetric dihydroxylation of trans-β-methylstyrene in the presence of boric acid 58.2 mg (0.125 mmol, 0.25 equiv) hydroquinidine p-chlorobenzoate, 70 mg (0 0.6 mmol, 1.2 eq) N-methyl-morpholine N-oxide, 72 mg (0.6 mmol, 1.2 eq) phenylboric acid, 0.5 ml dichloromethane, and OsO ₄ (121 mg OsO ₄ / 65 μl (0.5 mmol) at room temperature to a well-stirred mixture consisting of 4.2 μl of a solution prepared with ml toluene, 0.004 mol%, 0.004 eq) (0.5 ml) Of trans-methylstyrene was immersed in the reaction mixture using a gas tight syringe controlled by an infusion pump and the tip of the infusion needle was immersed in the reaction mixture for 24 hours. It was added slowly over a period of time. After the addition was complete, 10% NaHSO ₃ solution (2.5 ml) was added to the mixture and the resulting mixture was stirred for 1 hour. The organic material was extracted with ethyl acetate and the combined extracts were washed with brine and dried over Na ₂ SO ₄ . The solvent was evaporated under reduced pressure and the residual oil was column chromatographed on silica gel (5 g, eluted with hexane-ethyl acetate, 2: 1 volume / volume, Rf 0.62) to give 109 mg (91%) of phenylborate ester. Gave. The phenylborate ester was dissolved in acetone (3 ml) and 1,3-propanediol (0.5 ml) and the resulting mixture was left at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the residual oil was subjected to column chromatography on silica gel (5 g, hexane-ethyl acetate, eluted at 2: 1 volume / volume, Rf 0.10) to give 48.6 mg (70%) of diol. Gave. Enantiomeric excess of diol was determined by HPLC analysis of derived bis-acetate (Pilcle 1A column using 0.5% isopropanol / hexane mixture as eluent. Retention times t ₁ = 17.1 minutes, t ₂ = 18.1. Was 73%).
Example 14 A General Method for Asymmetric Dihydroxylation of Trans-Stilbene Using Polymeric Alkaloid Ligands Alkaloid Copolymers (eg Polymer 2-4, Table 1; Based on Added Alkaloids) 0.25 equivalent), NMO (1.5 equivalent), and magnetically stirred consisting of tetraethylammonium acetate tetrahydrate (1.0 equivalent) in acetone-water (10/1, volume / volume). To the suspension was added a solution of OsO ₄ (0.01 eq) in toluene or acetonitrile. After stirring for 10-30 minutes, trans-stilbene (1.0 eq) was added, the reaction mixture was stirred for a period of time and monitored by silica gel TLC (hexane-EtOAc 2/1, volume / volume). The concentration of olefin in the reaction mixture was 0.3-0.4M. After the reaction was complete, the mixture was diluted with acetone, water, hexane or ether, and the polymer was separated from the reaction mixture by centrifugation or filtration. The supernatant is then processed as described by Jacobsen et al., The Journal of the American Chemical Society, 110; 1968 (1988). did.
Example 15 A-symmetrical dihydroxylated alkaloid copolymer of trans-stilbene using polymeric alkaloid ligand and potassium ferricyanide (0.05 mmol based on added alkaloid), potassium ferricyanide (0 .198 g, 0.6 mmol) and a well-stirred suspension of potassium carbonate in tertiary-butanol (1.5 ml) and water (1.5 ml) was added to an OsO ₄ solution (0 .0025 mmol) was added. After stirring for 10 minutes, trans-stilbene (36 mg, 0.2 mmol) was added and the reaction mixture was stirred for a period of time and monitored by silica gel TLC. When the reaction was complete, water (3.0 ml) was added and the mixture was filtered. The filtrate was extracted with dichloromethane (5 ml × 2). The organic layer was stirred with excess sodium metabisulfite and sodium sulfate for 1 hour. The suspension was filtered and the filtrate was concentrated to give the crude diol, which was purified on a silica gel column.
EXAMPLE 16 Asymmetrical dihydroxylation of olefins in the presence of potassium ferricyanide General procedure for asymmetrical dihydroxylation of olefins using potassium ferricyanide 0.465 g (1 mmol, 0.5 eq = coordination) 0.033M in ligand, dihydroquinidine p-chlorobenzoate (Aldrich, 98%), 1.980 g (6 mmol, 3.0 eq) potassium ferricyanide, 0.980 g (6 mmol, 3.0 eq) ) Of potassium carbonate and 0.5 ml of osmium tetroxide (0.025 mmol, 0.0125 equivalent) in 30 ml of tertiary-butyl alcohol-water mixture (1: 1, volume / volume). To a well-stirred mixture of Lee-butyl alcohol solution, olefin (2 mmol) at a time at room temperature. I was painting. The reaction mixture was stirred at room temperature for 24 hours. Solid sodium sulfite (Na ₂ SO ₃ , 1.5 g) was added and the mixture was stirred for an additional hour. The resulting solution was concentrated to dryness under reduced pressure and the residue was extracted with 3 portions of ether. The combined extracts were dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by column chromatography (silica gel, dichloromethane-ether).
Example 17 Preparation of 9-O-phenyldihydroquinidine To a suspension of dihydroquinidine (4.0 g) in THF (40 ml) was added η-BuLi (2.5 M in hexane, 4.95 ml) at 0 ° C. The ice bath was removed and the reaction mixture was left at room temperature for 10 minutes. Solid cuprous chloride (1.2 g) was added to the resulting yellow solution. After standing for 30 minutes, pyridine (30 ml) and HMPA (1 ml) were added. After stirring for 5 minutes, phenyl iodide (1.37 ml) was added and the mixture was stirred at reflux for 36 hours. To the resulting mixture was added aqueous NH ₄ OH and the mixture was extracted with ethyl ether. The extract was dried over MgSO _4. The solvent was evaporated under reduced pressure and the residue was subjected to column chromatography on silica gel (100 g, ethyl acetate-ethanol, eluting with 9: 1 volume / volume, Rf 0.23) 1.77 g (36% yield) of 9 -O-phenyldihydroquinidine was provided.
¹ H NMR (CDCl ₃ ) δ 8/68 ( ¹ H, d, J = 4.5 Hz), 8.08 (1 H, d, J = 9 Hz), 7.3-7.5 (3 H, m), 7. 17 (2H, t, J = 8 Hz), 6.89 (1 H, t, J = 8 Hz), 6.78 (2H, d, J = 8 Hz), 6.02 (1H, d, J = 3 Hz), 4.00 (3H, s), 2.7-3.3 (5H, m), 2.2-2.4 (1H, m), 1.4-1.9 (6H, m), 1. 1-1.3 (1 H, m), 0.97 (3 H, t, J = 7 Hz).
Example 18 Asymmetric dihydroxylation of trans-3-hexene with 9-O-phenyldihydroquinidine and potassium ferricyanide 46 mg 9-O-phenyldihydroquinidine, 396 mg potassium ferricyanide, 166 mg potassium carbonate and 8 μl To a well-stirred mixture consisting of a solution of 0.63 M toluene in 6 ml of t-butyl alcohol-water (1: 1, volume / volume) of potassium tetroxide at room temperature is added 50 μl of trans-3-hexene all at once. It was. The reaction mixture was stirred at room temperature for 20 hours. Solid sodium sulfite was added and the mixture was stirred for 3 hours. The solid was removed by filtration and the filtrate was extracted with ethyl ether. The extract was dried over MgSO _4. The solvent was evaporated under reduced pressure and the residue was subjected to column chromatography on silica gel (eluted with hexane-ethyl acetate, 2: 1 volume / volume) to give 40.5 mg (85% yield) of diol. The enantiomeric excess of the diol was determined to be 83% by GLC analysis of the derived bis-Mosher ester (5% phenyl-methylsilicone, 0.25 m film, 0.317 mm diameter, 29 m length, retention time is t ₁ = 15.6 minutes, t ₂ = 16.0 minutes).
Example 19 Asymmetric oxyamination of trans-stilbene with N-chloro-N-sodio-t-butylcarbamate 81 mg trans-stilbene, 122 mg N-chloro-N-sodio-t-butylcarbamate, 95 mg chloride To a well-stirred mixture consisting of 2,209 mg of mercury, dihydroquinidine p-chlorobenzoate and 370 μl of water acetonitrile (5 ml) was added 9 μl of a 0.5 M toluene solution of osmium tetroxide. The mixture was stirred overnight at room temperature. Solid sodium sulfite and water were added and the solid mixture was stirred at 60 ° C. for 1 hour. The mixture was extracted with dichloromethane and the extract was dried over MgSO ₄ . The solvent was evaporated under reduced pressure and the residue was subjected to column chromatography on silica gel (elution with hexane-ethyl acetate, 4: 1 volume / volume, Rf 0.13) to give 131 mg (93% yield) of diol. It was. Enantiomeric excess of aminoalcohol was determined by HPLC analysis of derived bis-Mosher ester (Pilcle Covalent Phenyl Glycine column using 10% isopropanol / hexane mixture as eluent, retention time t ₁ = 12.7 min, t ₂ = 15.2 minutes).
¹ H NMR (CDCl ₃ ) δ 7.1-7.4 (10H, m), 5.3-5.4 (1H, m), 4.95 (1H, d, J = 3.5 Hz), 4. 8-5.0 (1H, m), 2.6-2.7 (1H, m), 1.34 (9H,).
Example 20 Preparation and Properties of Asymmetric Dihydroxylated Ligands Using Heterocyclic Chiral Ligands 1a: Room temperature suspension of DHQD (48.9 g, 0.15 mol) in dry DMSO (600 ml) NaH (4.0 g, 0.17 mmol), pyridine (12.1 ml, 0.15 mol), CuI (28.6 g, 0.15 mol), and then 9-phenanthryl iodide (45.6 g). 0.15 mol) was added under argon. After 70 hours of reaction at 120 ° C., 1a was obtained in 73% yield (55.0 g). See also Lindley, J. Tetrahedron, 1984, 40, 1433 and references therein.
Mp 98-100 ° C. ¹ H NMR (250 MHz, CDCl ₃ ):
δ = 8.7 (m, 1), 8.07 (d, 1), 7.57 (d, 1), 7.4 (m, 6), 6.63 (s, 1), 6.63 (D, 1), 4.03 (s, 3), 3.38 (m, 1), 3.16 (m, 1), 2.97 (m, 2), 2.78 (m, 1) 2.55 (s, wide, 1), 2.39 (t, 1), 1.81 (s, 1), 1.6 (m, 6), 0.98 (t, 3).
¹³ C NMR (75 MHz, CDCI ₃ ): δ = 158.2, 150.4, 147.5, 144.6, 143.7, 132.3, 132.0, 131.5, 127.4, 127. 2, 126.7, 126.6, 126.4, 124.5, 122.8, 122.2, 121.9, 118.1, 104.8, 100.9, 78.8, 60.3, 55.8, 51.0, 50.1, 37.4, 27.1, 26.6, 25.2, 21.7, 11.8.
IR (KBr): υ = 1622, 1508, 1452 and 1227 cm ⁻¹ .
[Α] D ²³ = −281.3 (CHCI ₃ , c = 1.12 gml ⁻¹ ).
1b: To a suspension of room temperature DHQD (65.2 g, 0.20 mol) in DMF (300 ml) was added NaH (6.06 g, 0.24 mol) followed by 2-chloro-4-methylquinoline (42 0.6 g, 0.24 mol) was added. After stirring at room temperature for 24 hours, 2a was obtained in 82% yield (76.3 g).
Mp 151-153 ° C. ¹ H NMR (250 MHz, CDCl ₃ ):
δ = 0.93 (3H, t, J = 7.2 Hz), 1.4-1.7 (6H, m), 1.76 (1H, s), 2.12 (1H, t, J = 10) 0.0Hz), 2.61 (3H, s), 2.7-3.0 (4H, H), 3.43 (1H, dd, J = 6.4, 8.8Hz), 3.94 (3H , s, 6.82 (1H, s), 7.2-7.6 (6H, m), 7.73 (1H, d, J = 2.5 Hz), 7.81 (1H, d, J = 8.0 Hz), 7.98 (1 H, d, J = 9.2 Hz), 8.67 (1 H, d, J = 4.6 Hz).
¹³ C NMR (CDCI ₃ ): δ = 11.8, 18.4, 22.9, 25.8, 27.1, 37.2, 49.8, 50.6, 55.4, 59.2, 73.1, 101.7, 112.5, 118.5, 121.4, 123.3, 123.7, 125.2, 127.5, 129.0, 131.3, 144.5, 145. 8, 147.3, 157.4, 160.4.
IR (KBr): 1608, 1573, 1508, 1466, 1228, 1182, 1039, 848, 758 cm ⁻¹ .
[Α] D ²¹ = −194.7 ° (EtOH, c = 1.0).
2a and 2b could be synthesized in a similar manner. Similar to p-chlorobenzoate derivatives, these two new types of ligands are now available from Aldrich.
Typical steps for catalytic ADH (vinylcyclooctane) DHQD-PHN1a (100 mg, 0.2 mmol, 0.02 equiv), K ₃ Fe (CN) ₆ (9.88 g, 30 mmol, 3 equiv) and K Potassium (IV) osmate to a well-stirred mixture in a tertiary-BuOH-H ₂ O mixture (100 ml, 1/1, volume / volume) of ₂ CO ₃ (4.15 g, 30 mmol, 3 eq) Dihydrate (7.4 mg, 0.02 mmol, 0.002 equiv) was added. The resulting yellow solution was cooled to 0 ° C. and vinylcyclooctane (1.65 ml, 10 mmol) was added. The reaction mixture was stirred at 0 ° C. for 18 hours. Na ₂ SO ₃ (7.5 g) was added and the resulting mixture was stirred for 30 minutes. The two phases were separated and then the aqueous phase was extracted with CH ₂ Cl ₂ . The combined organic solution was evaporated and the residue was diluted with ethyl acetate, washed with 1 MH ₂ SO ₄ , aqueous NaHCO ₃ and brine and dried. Concentration and flash chromatography gave 1.63 g (95%) of cyclooctylethanediol as a colorless oil. [α] D ²² = −4.1 ° (EtOH, c = 1.0). The ee of the diol was determined to be 93% by HPLC analysis of the derivatized bis-MTPA. The alkaloid ligand was recovered in 82% yield by adjusting the acidic aqueous wash to pH 11 with Na ₂ CO ₃ and extracting with CH ₂ Cl ₂ .
Example 21 Asymmetric dihydroxylation of olefins using 9-O-phenanthryl and 9-O-naphthyl dihydroquinidine ligands This example is an enantioselectivity of 9-O-aryl DHQD ligands-ligands It describes the structure and explains the advantages of these novel ligands.

  The enantiomeric excess obtained from the catalytic ADH reaction of various olefins using 9-O-aryl DHQD is summarized in Table 13. As described below, these 9-O-aryl DHQD ligands have moderate to good yields (52-) in one step from commercially available hydroquinidine, NaH, CuI, and the corresponding aryl halides. 70%) and could be easily manufactured. Compared to DHQDρ-chlorobenzoate 1, 9-O-phenyl DHQD2 is clearly a better ligand for aliphatic olefins than for aromatic olefins. In contrast, 9-O-naphthyl 3 and in particular 9-O-phenanthryl DHQD4 showed much higher enantioselectivities for both aromatic and aliphatic olefins.

^a All reactions, except that 25 mole% of ligand was used, Kwong, HL et al., Tetrahedron Lett., 30: 2041 (198
It was done as described in 9). The reaction was performed at room temperature. In all cases, the isolated yield of diol was 75-95%.

^b Diol is converted to the corresponding bisesters of (R)-(+)-α-methoxytrifluoromethylphenylacetic acid and GLC, HPLC, and / or ¹ H NM
By measuring the ratio of diastereomers by R, the enantiomeric excess was determined.

Various 9-O-substituted DHQD derivatives were then tested to obtain information regarding the relationship between ligand structure and enantioselectivity in ADH. The structure of the 9-O-substituents of these DHQD derivatives and their enantioselectivities for typical aliphatic and aromatic olefins, trans-5-decene and trans-stilbene are shown in Table 14. Since each structure in Table 14 is depicted with its expected spatial orientation in the reaction intermediate product osmate, the relatively large sterically hindered 6-methoxyquinoline moiety is on the left side of structure ^11. is there.

  In group A, all derivatives having a second benzene ring on the right side (1, 3 and 4) are higher with respect to stilbene (99%) than without the second benzene ring (94%) (2) gave ee. Furthermore, the naphthyl derivative (3) gave a higher ee for decene (94%) than the phenyl derivative (2) (88%). These two results suggest that the benzene ring on the right side is important for high enantioselectivity with both aliphatic and aromatic olefins. On the other hand, the derivatives (2-4) are related to decene (88-96%), and the p-chlorobenzoate derivative (1) (79%) is important for the aromatic ring on the left side with respect to the aliphatic olefins. It gave a much higher ee than shown.

  Next, the o-position of phenyl derivatives was tested (2, 5-7, group B). The phenyl-derivative (2) and the 2-methylphenyl derivative (6) give considerably higher ee with respect to decene (88, 91%), but the 2-pyridyl (5) and 2-methylphenyl (7) derivatives (71 50%) does not give satisfactory enantioselectivity. This indicates that the left o-position of the phenyl derivative needs to be C—H for high enantioselectivity. The effect on the m- and p-positions can be understood by comparing the derivatives of groups C and D. These results indicate that both m- and p-positions need to be CH or higher for high ee with aliphatic olefins.

Steps for the synthesis of 9-O-aryl DHQDs (3) and (4) In a 100 ml 3-neck round bottom flask, 2.00 g (6.12 mmol) of dihydroquinidine (註: addition and reaction of all reagents) Was carried out under argon) and 0.160 g (6.73 mmol) of NaH was dissolved in 20 ml of dimethyl sulfoxide. After stirring for about 10 minutes, the reaction mixture began to become a clear orange-yellow solution. At this point 1.17 g (6.12 mmol) of copper (I) iodide and 0.50 ml (6.12 mmol) of pyridine and 6.12 mmol of 1-naphthyl iodide or phenanthryl bromide, respectively, were added. And the reaction mixture was heated to 120 ° C. for 3 days. The reaction mixture was then naturally cooled to room temperature and dichloromethane (30 ml) and water (30 ml) were added. Next, 10 ml of concentrated ammonium hydroxide was slowly added to the reaction mixture. After stirring for 15 minutes, the two phases were separated. The aqueous phase was extracted twice with dichloromethane (20 ml). The organic phases were combined, washed with water (10 ml) and evaporated. The resulting residue was then purified by column chromatography (silica gel, using 5% methanol / ethyl acetate as eluent) to give 9-O-naphthyl DHQD (3) (yield: 70%) or 9-, respectively. O-phenanthryl DHQD (4) (yield: 52%) slightly yellow crystals were produced.
(3): Melting point 75-77 ° C.
¹ H NMR (250 MHz, CDCI ₃ ): δ = 8.60 (dd, 2), 8.05 (dd, 1), 7.80 (d, 1), 7.4 (m, 5), 7. 07 (t, 1), 6.42 (d, 1), 6.24 (d, 1), 3.99 (s, 3), 3.31 (dt, 1), 3.17 (dd, 1 ), 2.92 (dd, 2), 2.78 (m, 1), 2.37 (m, 2), 1.79 (s, wide, 1), 1.6 (m, 6), 0 .96 (t, 3).
¹³ C NMR (75 MHz, CDCI ₃ ): δ = 158.2, 150.4, 147.5, 132.3, 132.0, 131.5, 127.4, 127.2, 126.6, 126. 4, 124.5, 122.8, 122.2, 121.9, 118.1, 104.8, 100.9, 78.8, 60.3, 55.8, 51.0, 50.1, 37.4, 27.1, 26.6, 25.2, 21.7, 11.8.
IR (KBr): v = 1622, 1508, 1452 and 1227 cm ⁻¹ .
[Α] D ²³ = −281.3 (CHCI ₃ , c = 1.12 gml ⁻¹ ).

9-O-aryl DHQDs (3) and (4) were prepared according to the Ullman phenyl ether synthesis: Lindy, Journal of Tetrahedron, 40: 1433 (1984) and references therein.
All these 9-O-substituted DHQD derivatives (5), (9) and (10) were synthesized at room temperature except for copper (I) iodide.
EXAMPLE 22 Asymmetric dihydroxylation of olefins using dihydroquinine aryl ethers A high level of asymmetry induction occurs in asymmetric dihydroxylation of a wide range of olefins using 9-O-aryl dihydroquinines as ligands Obtained. (B. Lohray et al., Tetrahedron Lett., 30: 2041 (1989))
Asymmetric dihydroxylation using catalytic amounts of osmium tetroxide and quinaalkaloid derivatives is a combination of high levels of enantioselectivity, good to excellent yields, simple and mild experimental conditions for a wide range of substrates. It is one of several examples. Another point to emphasize is the availability of the necessary quina alkaloids. The two enantiomers of diols are obtained by selecting dihydroquinine (DHQ) or dihydroquinidine (DHQD) derivatives.

  Recent developments in our group using potassium ferricyanide as a stoichiometric oxidant and novel aryl and heteroaromatic derivatives of dihydroquinidine and quinine have resulted in good to excellent yields for a wide variety of substrates And enantioselectivity could be obtained. (HL Kwong et al., Tetrahedron Lett., 31: 2999, M. Minato et al., The Journal of the Organic Chemistry (J. Org. Chem) .), 55: 766 (1990), T. Shibata et al., Tetrahedron Lett., 31: 3817 (1990)). In this example we report details regarding 9-O-aryl dihydroquinines 2a-4a.

  The trends for dihydroquinine and dihydroquinidine derivatives were very similar (see Table 15). As in the dihydroquinidine system, DHQ phenanthryl ether derivative 4a was far superior to la for a wide range of substrates. The improvements were particularly dramatic for trans-disubstituted aliphatic olefins such as 5-decene (No. 1) and terminal saturated olefins (No. 6 and 7) and alkyl-substituted α, β unsaturated carbonyl compounds (No. 3). It was. Little change was observed in the case of aromatic olefins (Nos. 4 and 5).

  All but the two specified reactions were performed at room temperature. In all cases, the isolated yield was 70-95%. Enantiomeric excess was determined by GC or HPLC analysis of derived bis-Mosher esters.

  Unlike the differences observed with dihydroquinidine derivatives, the difference in enantioselectivity between naphthyl-DHQ and phenanthryl-DHQ was significant (Δee = 2-10% at room temperature, DHQD derivative 1-4%). It is particularly valuable that the selectivity differences obtained with 4a and 4b are very small for all the examples in Table 12 and as a result the enantiomers of the diol are obtained with almost the same optical purity. .

  The reaction can be carried out successfully at 0 ° C., and significant improvements in enantioselectivity, especially with respect to terminal olefins (Nos. 1, 3 and 7), have been obtained.

In conclusion, we can obtain vicinal diols from various olefin substrates in excellent yields and good to excellent enantiomeric excess using dihydroquinine or dihydroquinidine.
Example 23 Synthesis of methylphenylcarbamoyl dihydroquinidine (MPC-DHQD) Dihydroquinidine (1.4 g, 4.3 mmol, 1 eq) in 15 ml CH ₂ Cl ₂ in a 3 neck 100 ml round bottom flask flask under nitrogen atmosphere. Dissolved in. At room temperature, 2 ml of triethylamine (14.4 mmol, 3.3 eq) was added to the solution and stirred for 30 minutes. N-methyl-N-phenylcarbamoyl chloride (1.6 g, 9.4 mmol, 2.2 eq) was dissolved in 6 ml of CH ₂ Cl ₂ and added dropwise to the reaction mixture via an addition funnel. The reaction mixture was stirred for 3 days under N ₂ after which the reaction was complete. 50 ml of 2N NaOH was added and the phases were separated. The CH ₂ Cl ₂ phase was stored and the aqueous phase was extracted with 50 ml of CH ₂ Cl ₂ . The CH ₂ Cl ₂ phases were combined and dried over MgSO ₄ and then concentrated to give a gummy pink material. Purification by flash chromatography (silica gel, 95.5 EtOAc / Et ₃ N, volume / volume) gave a yellow material which was then crystallized from CH ₃ CN to give white star crystals (1. 27 g, 65% yield).
Characteristic:
Melting point 119-120 ° C. High resolution mass spectrum: calculated molecular mass-458.25217 amu, found-425.2519 amu.
¹ H NMR (300 MHz, CDCl ₃ with TMS);
8.7δ (d, 1H), 8.0δ (d, 1H), 7.2-7.4δ (m, 7H), 6.4δ (d, 1H), 3.8δ (s, 3H), 3 .3.delta. (S, 3H), 3.1.delta. (1H), 2.8.delta. (Q, 1H), 2.6.delta. (M, 3H), 1.7.delta. (S, 2H), 1.3-1.4.delta. m, 7H), 0.9δ (t, 3H). ¹³ C NMR (75 MHz, CDCl ₃ with TMS): 12.1 δ, 23.9 δ, 25.3 δ, 26.2 δ, 27.3 δ, 37.5 δ, 38.2 δ, 49.8 δ, 50.7 δ, 55 .5δ, 59.7δ, 75.6δ, 101.8δ, 119.1δ, 121.8δ, 126.3δ, 126.7δ, 127.3δ, 129.1δ, 131.7δ, 143.1δ, 144.7δ 144.9δ, 147.5δ, 152.1δ, 154.8δ, 157.7δ.
Example 24 Asymmetric dihydroxylation of olefins using 9-O-carbamoyl dihydroquinidine ligands Typical steps for catalytic ADHA (cis- [beta] -methylstyrene):
DHQD-MPC (dihydroquinidine methylphenylcarbamate) (10 mg, 0.02 mmol, 0.10 equiv), K ₃ Fe (CN) ₆ (200 mg, 0.6 mmol, 3 equiv), K ₂ CO ₃ (85 mg , 0.5 mmol, 3 equivalents) of a well-stirred solution in tertiary-butanol / water solution (6 ml, 1/1, volume / volume) to an acetonitrile solution of osmium tetroxide (0.5 M, 4 μl, 0.01 equivalent) was added at room temperature. After stirring for 10 minutes, cis-β-methylstyrene (26 μl, 0.2 mmol) was added. The reaction mixture was stirred at room temperature and the progress of the reaction was monitored by thin layer chromatography. Upon completion of the reaction (within 2 hours), the phases were separated. The aqueous phase was extracted with CH ₂ Cl ₂ . Tertiary - The combined butanol and CH ₂ Cl ₂ fraction classification, and stirred for 1 h with excess sodium metabisulfite and sodium sulfate. Concentration and flash chromatography gave the diol (24.4 mg, 82% yield) as an off-white solid. The enantiomeric excess (ee) of the diol was determined by GC analysis of the bis-MPTA ester derivative.

The main features and aspects of the present invention are summarized as follows.

  1. An aromatic ether derivative of dihydroquinidine or dihydroquinine or a salt thereof, wherein the aromatic ether is covalently bonded to dihydroquinidine or dihydroquinine at an asymmetric carbon.

  2. The dihydroquinidine or dihydroquinine aromatic ether derivative according to claim 1, wherein the aromatic moiety is substituted, and the substituent is a lower alkyl, alkoxy or halogen group.

  3. An aromatic ether derivative of quinidine or quinine or a salt thereof, wherein the aromatic ether is covalently bonded to quinidine or quinine at an asymmetric carbon.

  4). The quinidine or quinine aromatic ether derivative according to claim 3, wherein the aromatic moiety is substituted, and the substituent is a lower alkyl, alkoxy or halogen group.

  5. An aryl ether derivative of dihydroquinidine or dihydroquinine or a salt thereof, wherein the aryl ether is covalently bonded to dihydroquinidine or dihydroquinine at an asymmetric carbon.

  6). 6. The dihydroquinidine or dihydroquinine aryl ether derivative of claim 5 wherein the aryl moiety is substituted and the substituent is a lower alkyl, alkoxy or halogen group.

  7). 6. The dihydroquinidine or aryl ether derivative of dihydroquinine according to claim 5 wherein the aryl moiety is phenyl, substituted phenyl, polycyclic benzenoid hydrocarbon or substituted polycyclic benzenoid hydrocarbon.

  8). Dihydroquinidine or a heterocyclic ether derivative of dihydroquinine or a salt thereof, wherein the heterocyclic ether is covalently bonded to dihydroquinidine or dihydroquinine at an asymmetric carbon.

  9. 9. The dihydroquinidine or dihydroquinine heterocyclic ether derivative according to claim 8 wherein the aryl moiety is substituted and the substituent is a lower alkyl, alkoxy or halogen group.

  10. The dihydroquinidine or the heterocyclic ether derivative of dihydroquinine according to claim 9, wherein the heterocyclic moiety is a nitrogen heterocycle.

  11. a) The dihydroquinidine derivative has the following formula:

Have
b) The dihydroquinine derivative has the following formula:

And c) R is

10) phenyl,
11) Naphthyl,
12) O-methoxyphenyl,
13) phenylcarbamoyl,
14) methylphenylcarbamoyl, or 15) diphenylcarbamoyl.
Ethers that are dihydroquinidine derivatives or dihydroquinine derivatives.

  12 formula:

Dihydroquinidine derivatives of the formula or formula:

A dihydroquinine derivative, and R is

A heterocyclic ether.

  13. formula:

Dihydroquinidine derivatives of the formula or formula:

A dihydroquinine derivative, and R is

6) Aryl ether which is O-methoxyphenyl.

  14 formula:

Dihydroquinidine derivatives of the formula or formula:

9-O-carbamoyl, wherein R is a carbamate or an N-substituted carbamate.

  15. 15. 9-O-carbamoyl according to the above 14, wherein R is phenylcarbamoyl, methylphenylcarbamoyl, or diphenylcarbamoyl.

  16. To produce an asymmetrically dihydroxylated olefin comprising a combination of an olefin, an alkaloid or alkaloid derivative chiral ligand, an organic solvent, an aqueous solution, a base, a catalyst containing osmium, and potassium ferricyanide In an osmium catalyzed process, the alkaloid is an aromatic ether derivative of dihydroquinidine or an aromatic ether derivative of dihydroquinine and the resulting combination is kept under conditions suitable for asymmetric addition to the olefin to occur .

  17. The method according to the above item 16, wherein the chiral ligand is in the form of a polymer.

  18. The process of claim 16, wherein the aromatic ether is heterocyclic.

19. a) a combination of an alkaloid or alkaloid derivative, an organic solvent, an aqueous solution, a base and potassium ferricyanide, wherein the alkaloid is an aromatic ether derivative of dihydroquinidine or an aromatic ether derivative of dihydroquinine;
b) a catalyst containing a catalytic amount of osmium is added to the reaction mixture, and c) the olefin is added to the combination prepared in (b), and the resulting combination is suitable for asymmetric addition to the olefin to occur. An osmium-catalyzed process for producing asymmetrically dihydroxylated olefins comprising maintaining under conditions.

  20. The method according to the above item 19, wherein the alkaloid or alkaloid derivative is in the form of a polymer.

  21. 20. A process according to claim 19 wherein the aryl ether is heterocyclic.

  22. 20. A process according to claim 19 wherein the osmium catalyst is osmium tetroxide or potassium osmate (IV) dihydrate.

  23. 20. The method according to the above item 19, wherein the organic solvent is cyclohexane, hexane, ethyl ether or t-butyl methyl ether.

2 is a schematic representation of a ligand-promoted catalyzed asymmetric dihydroxylation performed by the method of the present invention. 1 is a schematic representation of asymmetric catalytic oxyamination of stilbene performed by the method of the present invention. 2 is a plot of amine concentration versus second order rate constant k for catalytic cis-dihydroxylation of styrene. At point a, no amine is added. Thus, point a represents the rate of contact process in the absence of added amine ligand. Line b represents the rate of the contacting process in the presence of various amounts of quinuclidine, a ligand that substantially retards catalysis. Line c represents the speed of the contacting process in the presence of the dihydroquinidine benzoate derivative 1 displayed in FIG. K is defined as K _obs / [OsO ₄ ] _o , where rate = −d [styrene] / dt = K _obs [styrene]. Conditions: 25 ° C., [OsO ₄ ] _o = 4 × 10 ⁻⁴ M, [NMO] _o = 0.2 M [styrene] _o = 0.1 M. 1 is a schematic representation of a proposed mechanism of catalytic olefin dihydroxylation. This scheme shows two diol production cycles that are believed to be involved in the catalysis promoted by the ligands of the present invention. Formula 1 represents an alkaloid-osmium complex, Formula 2 represents a monoglycolate ester, Formula 3 represents an osmium (VIII) trioxoglycolate complex, and Formula 4 represents an osmium bisglycolate. Represents an ester, and Formula 5 represents a dioxobisglycolate.

Claims (3)

A cis-disubstituted olefin, an alkaloid or a chiral ligand that is an alkaloid derivative, an organic solvent, an aqueous solution, a base, an osmium-containing catalyst, and potassium ferricyanide, where the alkaloid is dihydroquinidine 9-O-carbamoyl (but not dimethyl). (Except carbamoyl) derivatives or 9-O-carbamoyl (except dimethylcarbamoyl) derivatives of dihydroquinine and characterized by holding the resulting combination under conditions suitable for asymmetric dihydroxylation to occur An osmium-catalyzed process for producing asymmetrically dihydroxylated oleins. combining a cis-disubstituted olefin, a polymeric chiral ligand, an organic solvent, water, an oxidant and an osmium-containing catalyst, and maintaining the combination under conditions suitable for asymmetric addition to occur; Wherein the chiral ligand is a 9-O-carbamoyl (but excluding dimethylcarbamoyl) derivative of dihydroquinidine or a 9-O-carbamoyl (but excluding dimethylcarbamoyl) derivative of dihydroquinine Osmium catalyzed process for asymmetric addition. a) cis-disubstituted olefins, cinchona alkaloid derivatives, organic solvents, water, a combination of a base and potassium ferricyanide yielding the reaction mixture, where cinchona alkaloids at a concentration of about 0.01M~ about 2.0M Present, wherein the cinchona alkaloid is a 9-O-carbamoyl (except dimethylcarbamoyl) derivative of dihydroquinidine or a 9-O-carbamoyl (but excludes dimethylcarbamoyl) derivative of dihydroquinine,
b) asymmetrically dihydroxy, characterized in that osmium tetroxide is added to the reaction mixture in a catalytic amount, and c) the product of step b) is kept under conditions suitable for dihydroxylation of the olefin to occur. An osmium-catalyzed process for the preparation of sulfonated olefins.

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