FOR CATALYTIC ASYMMETRIC

DIHYDROXYLATION OF OLEFINS

Background In nature, the organic constituents of animals, microorganisms and plants are made up of chiral molecules, or molecules which exhibit handedness. Enantiomers are stereoisomers or chiral molecules whose configurations (arrangements of constituent atoms) are nonsuperimposed mirror images of each other; absolute configurations at chiral centers are determined by a set of rules by which a priority is assigned to each substituent and are designated R and S. The physical properties of enantiomers are identical, except for the direction in which they rotate the plane of polarized light: one enantiomer rotates plane-polarized light to the right and the other enantiomer rotates it to the left. However, the magnitude of the rotation caused by each is the same.

The chemical properties of enantiomers are also identical, with the exception of their interactions with optically active reagents. Optically active reagents interact with enantiomers at different rates , resulting in reaction rates which may vary greatly and, in some cases, at such different rates that reaction with one enantiomer or isomer does not occur. This is partic¬ ularly evident in biological systems, in which stereo- chemical specificity is the rule because enzymes (bio- logical catalysts) and most of the substrates on which they act are optically active.

A mixture which includes equal quantities of both enantiomers is a racemate (or racemic modification) . A racemate is optically inactive, as a result of the fact that the rotation of polarized light caused by a molecule of one isomer is equal to and in the opposite direction from the rotation caused by a molecule of its enantiomer. Racemates, not optically active compounds, are the products of most synthetic procedures. Because of the identity of most physical characteristics of enantiomers, they cannot be separated by such commonly used methods as fractional distillation (because they have identical boiling points), fractional crystallization (because they are equally soluble in a solvent, unless it is optically active) and chromatography (because they are held equally tightly on a given adsorbent, unless it is optically active). As a result, resolution of a racemic mixture into enantiomers is not easily accomplished and can be costly and time consuming. Recently, there has been growing interest in the synthesis of chiral compounds because of the growing demand for complex organic molecules of high optical

purity, such as insect hormones and pheromones, prostaglandins , antitumor compounds, and other drugs. This is a particularly critical consideration, for example, for drugs, because in living systems, it often happens that one enantiomer functions effectively and the other enantiomer has no biological activity and/or interferes with the biological function of the first enantiomer .

In nature, the enzyme catalyst involved in a given chemical reaction ensures that the reaction proceeds asymmetrically, producing only the correct enantiomer (i.e. , the enantiomer which is biologically or physio¬ logically functional). This is not the case in labor¬ atory synthesis, however, and, despite the interest in and energy expended in developing methods by which asymmetric production of a desired chiral molecule (e.g. , of a selected enantiomer) can be carried out, there has been only limited success.

In addition to resolving the desired molecule from a racemate of the two enantiomers, it is possible, for example, to produce selected asymmetric molecules by the chiral pool or template method, in which the selected asymmetric molecule is "built" from pre-existing, naturally-occurring asymmetric molecules. Asymmetric homogeneous hydrogenation and asymmetric epoxidation have also been used to produce chiral molecules. Asymmetric hydrogenation is seen as the first manmade reaction to mimic naturally-occurring asymmetric reactions. Sharpless, K.B. , __h<_,__;ϊ_i__;r__in_B__,i__,a__,I_> January 1986, pp 38-44; Mosher, H.S. and J.D. Morrison, S_ci.ence ,

221:1013-1019 (1983) ; Maugh , T.H. , Science, 221:351-354

(1983 ) ; Stinson , S . , Ch__mis try_ and Engineering__News , : 24 ( 6/2/86 ) .

Presently-available methods of asymmetric synthesis are limited in their applicability, however. Efficient catalytic asymmetric synthesis reactions are very rare; and they usually require a directing group and thus are substrate limited. Because such reactions are rare and chirality can be exceptionally important in drugs , pheromones and other biologically functional compositions, a catalytic method of asymmetric dihydroxylation would be very valuable. In addition, many naturally-occurring products are dihydroxylated or can be easily derived from a corresponding vicinal diol derivative.

Summary of the Invention

Olefins or alkenes with or without proximal heteroatom-containing functional groups, are asym¬ metrically dihydroxylated, oxyaminated or diaminated using an osmium-catalyzed process which is the subject of the present invention. Chiral ligands which are novel alkaloid derivatives , particularly dihydroquinidine derivatives or dihydroquinine derivatives or salts thereof, useful in the method of the present invention are also the subject of the present invention. Derivatives of the parent alkaloids, e.g. quinidine or quinine, or salts thereof can also be used, but the rate of catalysis is slightly slower.

In one embodiment of the present invention, the chiral ligand is immobilized to or incorporated within a polymer. Both monomeric and polymeric ligands can be immobilized to or incorporated into the polymer. The

immobilized or incorporated ligands form a complex with the osmium catalyst during the reaction, resulting in efficient catalysis in which the complex can be preserved after the reaction, allowing repetitive use of the complex. Alternatively, a preformed osmium-ligand complex can be used in the reaction, and recovered.

In the method of asymmetric modification or addition of the present invention, an olefin, a selected chiral ligand, an organic solvent, water, an oxidant, an osmium source and, optionally, an additive which accelerates hydrolysis of the osmate intermediate are combined, under conditions appropriate for reaction to occur. The method of ligand-accelerated catalysis of the present invention is useful to effect asymmetric dihydroxylation, asymmetric oxyamination and asymmetric diamination of an olefin of interest. A particular advantage of the catalytic asymmetric method is that only small quantities of osmium catalyst are required.

___-i£-_-__-_ι££_-_-E__i£2_£_-____2;_l__-Σ___-iS-_ __ Figure 1 is a schematic representation of asymmetric dihydroxylation via ligand-accelerated catalysis which is carried out by the method of the present invention.

Figure 2 is a schematic representation of asymmetric catalytic oxyamination of stilbene which is carried out by the method of the present invention.

Figure 3 is a plot of amine concentration vs_ second- order-rate constant k for the catalytic £i_s_-dihydroxy¬ lation of styrene. At point a, no amine has been added. Point a thus represents the rate of the catalytic process in the absence of added amine ligands. Line b represents the rate of the catalytic process in the presence of

varying amounts of quinuclidine , a ligand which sub¬ stantially retards catalysis. Line c represents the rate of the catalytic process in the presence of the di- hydroquinidine benzoate derivative 1 represented in Figure 1. K is defined as K . /[OsO, ] where rate — -d[styrene]/dt - K , [styrene] . Conditions: 25 C, [OsO ] - 4 x 10 ^"4 M, [NM0] _Q - 0.2M [styrene] _Q - 0.1M.

Figure 4 is a schematic representation of a proposed mechanism of catalytic olefin dihydroxylation. This scheme shows two diol-producing cycles believed to be involved in the ligand-accelerated catalysis of the present invention. Formula 1 represents an alkaloid- osmium complex; formula 2 represents a monoglycolate ester; formula 3 represents an osmium(VIII) triox- oglycolate complex; formula 4 represents a bisglycolate osmium ester; and formula 5 represents a dioxobisglycolate .

___-____ii-__ϊ____-__£____E__i£--_£__-__l-__-_SZ_iI__ ___£S

Asymmetric epoxidation has been the subject of much research for more than ten years . Earlier work demon¬ strated that the titanium-tartrate epoxidation catalyst is actually a complex mixture of epoxidation catalysts in dynamic equilibrium with each other and that the main species present (i.e. , the 2:2 structure) is the best catalyst (i.e. , about six times more active than titanium isopropoxide bearing no tartrate) . This work also showed that this rate advantage is essential to the method's success because it ensures that the catalysis is chan¬ neled through a chiral ligand-bearing species . The reaction of osmium tetroxide (OsO, ) with olefins is a highly selective and reliable organic transforma-

tion. It has long been known that this reaction is accelerated by nucleophilic ligands. Criegee, R. Justus __i_--_i_--___-_lS--__-2_l______. 122:75 (1936); Criegee, R. et al . ,

-LHS__H_-_Li____i_-_L___I-____-__l______' 119. -' " (1942); VanRheenen et al. , Tetrahedron_Lett_ _LI 1973 (1976). It has now been shown that a highly effective osmium-catalyzed process can be used to replace previously known methods, such as the stoichiometric asymmetric osmylation method. Hentges, S.G. and K.B. Sharpless, Journal. £_______ __£__i£_________ __i£__I_._.££i ___-> ____2:4263 (1980). The method of the present invention results in asymmetric induction and enhancement of reaction rate by binding of a selected ligand. Through the use of the ligand- ccelerated catalytic method of the present invention, asymmetric dihydroxylation, asymmetric diamination or asymmetric oxyamination can be effected.

As a result of this method, two hydroxyl groups are stereospecifically introduced into (imbedded in) a hydrocarbon framework, resulting in c_i_s_ vicinal di- hydroxylation. The new catalytic method of the present invention achieves substantially improved rates and turnover numbers (when compared with previously-available methods) , as well as useful levels of asymmetric induc¬ tion. In addition, because of the improved reaction rates and turnover numbers, less osmium catalyst is needed in the method of the present invention than in previously-known methods. As a result, the expense and the possible toxicity problem associated with previously- known methods are reduced. Furthermore, the invention allows the recovery and reuse of osmium, which reduces the cost of the process.

The method of the present invention is exemplified below with particular reference to its use in the asym¬ metric dihydroxylation of E-stilbene (Cg^CH: CHC _g H ₅ ) and trans-3-hexene (CH ₃ CH ₂ CH:CHCH ₂ CH ₃ ) . The method can be generally described as presented below and that descrip¬ tion and subsequent exemplification not only demonstrate the dramatic and unexpected results of ligand-accelerated catalysis, but also make evident the simplicity and effectiveness of the method. The asymmetric dihydroxylation method of the present invention is represented by the scheme illustrated in Figure 1. According to the method of the present in¬ vention, asymmetric dihydroxylation of a selected olefin is effected as a result of ligand-accelerated catalysis. That is, according to the method, a selected olefin is combined, under appropriate conditions, with a selected chiral ligand (which in general will be a chiral sub¬ stituted quinuclidine) , an organic solvent, water, an oxidant and osmium tetroxide and, optionally, a compound which promotes hydrolysis of the products from the osmium. Acids or bases can be used for this purpose. In one embodiment, a selected olefin, a chiral ligand, an organic solvent, water and an oxidant are combined; after the olefin and other components are combined, OsO, is added. The resulting combination is maintained under conditions (e.g. , temperature, agitation, etc.) conducive for dihydroxylation of the olefin to occur. Alter¬ natively, the olefin, organic solvent, chiral ligand, water and OsO, are combined and the oxidant added to the resulting combination. These additions can occur very close in time (i.e. , sequentially or simultaneously).

In one embodiment of the present invention, components of the reaction mixture are combined, to form an initial reaction combination, and olefin is added slowly to it, generally with frequent or constant agi- tation, such as stirring. In this embodiment, designated the "slow addition" method, organic solvent, chiral ligand, water, OsO, and the oxidant are combined. The olefin can then be slowly added to the other reactants. It is important that agitation, preferably stirring, be applied during the olefin addition. Surprisingly, for many, if not most olefins, slow addition of the olefin to the initial combination results in much better enantio- meric excess (ee), and a faster rate of reaction than the above-described method (i.e. , that in which all the olefin is present at the beginning of the reaction) . The beneficial effects (i.e. , higher ee's) of slow olefin addition are shown in Table 5 (Column 6) . A particular advantage of this slow-addition method is that the scope of the types of olefins to which the asymmetric dihydroxylation method can be applied is greatly broadened. That is, it can be applied to simple hydrocarbon olefins bearing no aromatic substituents , or other functional groups. In this process, the olefin is added slowly (e.g. , over time), as necessary to maximize ee. This method is particularly valuable because it results in higher ee's and faster reaction times.

In another embodiment of the present method, the chiral ligands are immobilized or incorporated into a polymer, thereby immobilizing the ligands. Both monomers and polymers of alkaloid ligands can be immobilized. The immobilized ligands form a complex with the osmium catalyst, which results in formation of an osmium

catalyst complex which can be recovered after the reaction. The OsO, -polymer complex is recoverable and can be used for iterative processes without washing or other treatment. The complex can be recovered, for example, by filtration or centrifugation. By employing 05 alkaloid derivatives, heterogeneous catalytic asymmetric dihydroxylation is achieved with good to excellent enantioselectivities in the dihydroxylation of olefins.

Alternatively, alkaloid polymers can be used as ligands. Alkaloid polymers which can be used are des- 10 cribed, for example, by Kobayashi and Iwai in Tetrahedron _- ___--__--_ _> 21:2167-2170 (1980) and Po______er_Journal,

13(3) :263-271 (1981); by vonHermann and Wynberg in Helvetica Chimica Acta, 6_0: 2208-2212 (1977); and by Hodge et a1. , J _Chem _Spc. Perkin Trans_. I, (1983) pp. 2205- 152209. Both alkaloid polymer ligands and immobilized ligands form a complex with the osmium iri situ. The term "polymeric", as used herein is meant to include monomers or polymers of alkaloid ligands which are chemically bonded or attached to a polymer carrier, such that the 0 ligand remains attached under the conditions of the reaction, or ligands which are copolymerized with one or more monomers (e.g. , acrylonitrile) to form a co-polymer in which the alkaloid is incorporated into the polymer, or alkaloid polymers as described above, which are not 5 immobilized or copolymerized with another polymer or other carrier.

Industrial scale syntheses of optically active vicinal diols are possible using polymeric ligands. The convenience and economy of the process is enhanced by 0 recycling the alkaloid-OsO, complex. This embodiment of the present method allows efficient heterogeneous

asymmetric dihydroxylation utilizing polymeric or immobilized cinchona alkaloid derivatives.

Polymeric cinchona alkaloids which are useful in the present method can be prepared by art-recognized tech- niques. __££ _ι for example, Grubhofer and Schleith, Naturwi_ssenschaften, 40:508 (1953); Yamauchi et al . , BH_ _: I_._-:ll_i!-_._S££_._JE-!_.. 44:3186 (1971); Yamauchi et al . , _L____l-_£Σ£S_-I-___i£_____---l£----> ______: 981 (1976). A number of different types of polymers that incorporate dihydro- quinidine or dihydroquinine derivatives can be used in this process. These polymers include: (a) co-polymers of cinchona alkaloid derivatives with co-polymerizing reagents, such as vinyl chloride, styrene, acrylamide, acrylonitrile , or acrylic or methacrylic acid esters; (b) cross-linked polymers of cinchona alkaloid derivatives with cross-linking reagents, such as 1 , -divinylbenzene , ethylene glycol bismethacrylate ; and (c) cinchona alkaloid derivatives covalently linked to polysiloxanes . The connecting point of the polymer backbone to the alkaloid derivative can be at C(10) , C(ll) , C(9) -0 ,N(1 ' ) , or C(6')-0 as shown below for both quinidine and quinine derivatives. Table 3 shows the examples of the monomeric alkaloid derivatives which can be incorporated in the polymer system. For example, a polymer binding dihydroquinidine was prepared by copolymerizing 9-(10-undecenoyl)dihydro- quinidine in the presence of acrylonitrile (5 eq) ; a 13% yield was obtained exhibiting 4% alkaloid incorporation. This polymer, an acrylonitrile co-polymer of 9- (10- undecenoyl) -10 , 11-dihydroquinidine , is shown as polymer 4 in Table 1, below. Three other polymers, an acrylonitrile co-polymer of 9- (4-chlorobenzoyloxy) quinine , (polymer 1,

Table 3) an acrylonitrile co-polymer of 11- [2- acryloyloxy)ethylsulfinyl] -9- (4-chlorobenzoyloxy) -- 10, 11-dihydroquinine (polymer 2, Table 1) and an acrylo¬ nitrile co-polymer of 11- [2-acryloyloxy) -ethylsulfonyl] - 9- (N,N-dimethylcarbamoyl) -10 , 11-dihydroquinidine, (polymer 3, Table 1) were prepared according to the procedures of Inaguki et al. , or slightly modified versions of this procedure. _______ Inaguki et al. , Bull .

Chem. Soc. Jpn. , 60:4121 (1987). Using these polymers, the asymmetric dihydroxylation of trans-stilbene was carried out. The results are summarized in Table 1. Good to excellent asymmetric induction and reasonable reaction rates were observed. As shown in Table 1, reaction with polymer 2 exhibited the highest degree of asymmetric induction. The activity of the OsO, -polymer complex is preserved after the reaction, thus allowing repetitive use of the complex. This reaction can be carried out with terminal and aliphatically substituted olefins to show good yields and enantioselectivities (for example, styrene with polymer 2, 60% ee , 68% yield, and ethyltrans-2-octenoate with polymer 3, 60% ee, 85% yield) and the same process can be applied to a variety of different olefins.

Table 1. Heterogeneous Catalytic Asymmetric

Dihydroxylation of trans-Stilbene Using Various Polymeric Alkaloids

alkaloid polymer (0-2 255 eq), cat Os secondary oxidant „, solvent*

Secondary Reaction Reaction

Entry Polymers OsCq Oxidant Temp Time Yield (%) ee(%)

General procedure is set out in detail in Example 14. With N-methylmorpholine-N-oxide (NMO) acetone/water

(10/1, v/v) was the solvent and ferricyanide tert-butyl alcohol/water (1/1, v/v) was used as solvent. Results ^v ary _c slightly depending on different batches of polymer

2. Reaction was carried out with polymer 2 which had been used in entry 3 without further addition of 0 0 s 4 '

In another embodiment of the present method, an additive which accelerates hydrolysis of the osmate ester intermediates can, optionally, be added to the reaction combination. These additives can be acids or bases, for 5 example. Bases are preferred for this purpose. For example, soluble, carboxylic acid salts with organic- solubilizing counter-ions (e.g., tetraalkyl ammonium ions) are useful. Carboxylate salts which are preferred in the present reaction are soluble in organic media and in organic/aqueous co-solvent systems. For example, tetraethyl ammonium acetate has been shown to enhance the reaction rate and ee of some olefins (Table 5) . The additive does not replace the alkaloid in the reaction. Compounds which can be used include benzyltrimethyl- ammoniumacetate, tetramethylammonium acetate and tetraethylammonium acetate. However, other oxyanion compounds (e.g. , sulfonates, carbonates, borates or phosphates) may also be useful in hydrolyzing the osmate ester intermediates. The compound can be added to the reaction combination of organic solvent, chiral ligand, water and OsO, in a reaction vessel, before olefin addition. It is important to agitate (e.g., by stirring) the reaction combination during olefin addition. The additive can also be added to the reaction combination, described above, wherein all of the olefin is added at the beginning of the reaction. In one embodiment, the amount of additive is generally approximately 2 equiva¬ lents; in general from about 1 to about 4 equivalents will be used. In another embodiment of the present invention, the process can be run in an organic non-polar solvent such

as toluene. This embodiment is particularly useful in the slow addition method.. Preferably, a carboxylate compound which accelerates hydrolysis of the osmate ester intermediates (e.g. , tetraethyl- or tetramethyl ammonium acetate) is added. This embodiment is designated the "phase transfer" method. In this embodiment olefins which are not soluble, or have limited solubility, in mixtures of acetone/water or acetonitrile/water, are dissolved in toluene and then added slowly a mixture of organic solvent, chiral ligand, water and OsO, . The carboxylate salt serves the dual function of solubilizing the acetate ion in the organic phase where it can promote hydrolysis of the osmate ester, and carrying water associated with it into the organic phase, which is essential for hydrolysis. Higher ee's are obtained with many substrates using this method.

In a further embodiment of the present invention, a boric acid or a boric acid derivative (R-B(OH)-,, R-alkyl, aryl or OH), such as boric acid itself (i.e. , B(OH)_) or phenylboric acid (i.e. , Ph-B(OH)-), can be added to the reaction mixture. In the slow addition method, the boric acid is added to the ligand - organic solvent - OsO, mixture prior to the addition of the olefin. The amount of boric acid added is an amount sufficient to form the borate ester of the diol produced in the reaction.

Without wishing to be bound by theory, it is believed that the boric, acid hydrolyzes the osmium ester and captures the diols which are generated in the reaction. Neither water nor a soluble carboxylate such as tetra- alkyl ammonium carboxylate, is required to hydrolyze the osmium ester in the present reactions. Because the presence of water can make the isolation and recovery oξ _,

water-soluble diols difficult, the addition of a boric acid makes isolation of these diols easier. Especially, in the case of an aryl or alkyl boric acid, it is easy because, in place of the diol, the product is the cyclic 05borate ester which can be subsequently hydrolyzed to the diol. Iwasawa et al., Chemistry _, Letters , pp. 1721-1724 (1988) . The addition of a boric acid is particularly useful in the slow addition method.

In another embodiment of the present method, lOoxidants such as potassium hexacyanoferrate (III) (potassium ferricyanide, K_Fe(CN) _β ) is added to the reaction as a reoxidant. In a preferred embodiment, at least two equivalents of the oxidant (based on the amount of olefin substrate) is added to the reaction. It is 5also preferable that an equivalent amount of a base, such as potassium carbonate (K-CO,), is added in conjunction with the reoxidant. High enantioselectivities are obtained in catalytic asymmetric dihydroxylations using K,Fe(CN) _Λ as the reoxidant. 0 The use of potassium ferricyanide in a stoichio- metric amount as an oxidant for non-asymmetric osmium- catalyzed dihydroxylation of olefins .was reported by Mina o , Yamamoto and Tsuj i, in ________________________, 55:766

(1990). The addition of K.-Fe(CN) ₆ (in conjunction with 5the base) results in an improvement in the ability of the Tsuji's catalytic system to turn over, even in the presence of quinuclidine, a ligand which strongly inhibits catalysis when other oxidants are used, e.g. N-methylmorpholine-N-oxide (NMO) . In the present embodiment, potassium ferricyanide and potassium carbonate were added to the present cinchona alkaloid- based asymmetric dihydroxylation process and the outcome.

was unexpected (i.e. not just another way to reoxidize the osmium and/or achieve better turnover with difficult substrates) . As shown in Table 2, the use of potassium ferricyanide/potassium carbonate in place of NMO leads to across-the-board increases in the level of asymmetric induction for most olefins. The first two columns of data shown in Table 2 are for results employing NMO with and without "slow addition" of olefin, respectively. The third column reveals the results obtained using K,Fe(CN), with the same substrates and without "slow addition" of the olefin. The improvements of enantioselectivity are great as evidenced by the fact that the previous results (shown in Table 2) were obtained at 0°C while the ferricyanide experiments were performed at room temperature. The ferricyanide reactions can be run at a range of temperatures, however, dependin .upon the substrate .

Table 2. Percentage enantiomeric excesses of diols obtained in the asymmetric dihydroxylation of olefins under different catalytic conditions using dihydroquinidine p-chlorobenzoate as the chiral ligand.

OH

OH

NMO" K3Fe(CN ⁾ 6 ^b entry olefins ee(%) ee(%) ee(%)

(slow addition) (no slow addition) (no slow addition)

Reactions were carried out in acetone-water, 10:1 v/v, at 0°C. Reactions were carried out in tert-butyl alcohol-water 1:1 v/v, at ambient temperature. In all cases the isolated yield was 85%-95%

The amount of water added to the reaction mixture is an important factor in the present method. The optimum amount of water to be added can be determined empirically and, in general, should be that amount which results in maximum ee . Generally, approximately 10 to 16 equivalents of water can be added, preferably 13 to 14 equivalents should be used.

An olefin of interest can undergo asymmetric dihydroxylation according to the present invention. For

example, any hydrocarbon containing at least one carbon- carbon double bond as a functional group can be asym¬ metrically dihydroxylated according to the subject method. The method is applicable to any olefin of interest and is particularly well suited to effecting asymmetric dihydroxylation of prochiral olefins (i.e. , olefins which can be converted to products exhibiting chirality or handedness). In the case in which the method of the present invention is used to asymmetrically dihydroxylate a chiral olefin, one enantiomer will be more reactive than the other. As a result, it is pos¬ sible to separate or kinetically resolve the enantio- morphs . That is, through use of appropriately-selected reactants, it is possible to separate the asymmetrically dihydroxylated product from the unreacted starting material and both the product and the recovered starting material will be enantiomerically enriched.

The chiral ligand used in the asymmetric dihydroxyl¬ ation method will generally be an alkaloid, or a basic nitrogenous organic compound, which is generally heterocyclic . The chiral ligand can be a naturally occurring compound, a purely synthetic compound or a salt thereof, such as a hydrochloride salt. The optimum derivative which is used can be determined based upon the process conditions for each reaction. Examples of alkaloids which can be used as the chiral ligand in the asymmetric dihydroxylation method include cinchona 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 cinchona alkaloids quinine and quinidine act more like enantiomers than l _^ 'ke diastereomers in the scheme represented in Figure 1.

As represented in Figure 1, and as shown by the results in Table 4, dihydroquinidine derivatives (repre¬ sented as DHQD) and dihydroquinine derivatives (repre¬ sented as DHQ) have a pseudo-enantiomeric relationship in the present method (DHQD and DHQ are actually diastereo- mers) . That is, they exhibit opposite enantiofacial selection. Such derivatives can be, for example, esters or ethers, although other forms can be used. The choice of derivative depends upon the process. When dihydro¬ quinidine is used as the ligand, delivery of the two hydroxyl groups takes place from the top or upper face

(as represented in Figure 1) of the olefin which is being dihydroxylated. That is, in this case direct attack of the re- or re, re- face occurs. In contrast, when the dihydroquinine derivative is the ligand used, the two hydroxyl groups are delivered from the bottom or lower (si- or si, si-face) face of the olefin, again as repre¬ sented in Figure 1. This is best illustrated by reference to entries 1, 2 and 5 of Table 4. As shown, when DHQD (dihydroquinidine esters) is used, the re- suiting diol has an R or R,R configuration and when ligand 2 (dihydroquinine esters) is used, the resulting diol has an S or S,S configuration.

T ble 3 Alkaloid Derivatives

%ee

96-5

96

96.7

98.6

91

96

92

97.6 99

94.4 93

98

The example below is a phosphoryl derivative and therefore differs from the carboxylic add ester derivatives shown above: the phosphorus atom is directly bound to the oxygen atom of the alkaloid.

Ph ₂ P(0) diphenylphosphinic 69 97.5 ester

Table 4 ligand; ee*;

Olefins confgn. of diol

OHQD; 20%, (70%, 10h); RR DHQ; (60%, 16h); SS

cr OHQD; 46%, (50%, 20h); R

CI *^ ^cι OHQD; 35%, (40%, 12h)

Enaπtiomeric excesses in parentheses were obtained with slow addition of olefin over a period of ti indicated and with stirring at 0°C except otherwise staled. Telraethylammonium acetate tetrahydr were added in some cases as indicated.

Table 4 cont . ligand; ee';

Olefins confgn. of diol

cr DHQD; 56%, (61%, 5h); R DHQ; 54%; S

cr DHQD; 53%

* Enaπtiomerie excesses in parentheses were obtained with slow addition of olefin over a period of indicated and with stirring at 0°C except otherwise stated. Tetraethyiammonium acetate tetrahy were added in some cases as indicated.

Table 4 cont ligand; ee*;

O ^{^} OAc

DHQD; 76%; RR

® ⁰ ^ OHQD; 34%

DHQD; 27%

indicated and with stirring at 0°C except otherwise stated. Tetraethylammonium acetate tetrahy were added in some cases as indicated.

Tab le 4 cont

Oiefins ligand; ee*;

πCisHs.

^^CO_Et OHQD; 47.4%, (67%, 31h) n-CsH _t1

)

OAc, rt)

* Enantfomeric excesses in parentheses were obtained with stow addition of olefin over a period of t indicated and with stirring at 0°C except otherwise stated. Teiraethy1arnmor_υm acetate tetrahyd

Table 4 cont

Olefins ligand; ee*;

OEt

DHQD; 27%, (31%, 13h)

OEt

DHQD; (56%, 20h)

^, _s ^^ ⁰ ^ (66%, 20h OAC)

Me n-C ₅ Hf|" OHQD; (46%, 18h) (50%, 18h 4 OAC)

OMe OMe OHQD; (75%, 18h) (83%, 18h 4 OAc)

Me

OHQD; (60%, 10h) (89%, 10h 4 OAC)

* Enaπtiomeric excesses in parentheses were obtained with stow addition of olefin over a period of tim indicated and with stirring at O ^β C except otherwise staled. Tetraethylammonium acetate tetrahydrat were added in some cases as indicated.

- 28 -

Tab le 5 Enant-omeric excesses obtained in the asyznmetric dihydroxylation of olefins under different conditions ^• catalytic* catalytic catalytic* entrv olefin stoichiometric* (original) (acetate) (slow addition)

'AH stofchioxnetric reactions were carried out in acetone-water, 10:1 v/v, at 0 *C and at a concentration of 0.15 M in each reagent *AI1 reactions were carried out at 0 *C according to the original procedure reported in ref. 1(a). AD reaction- were carried out exactly as described in ref. 1(a) (Le. without slow addition) except that 2 eq of Et< NOAc- r_2θ were present. ' ll reactions were carried out at 0 *C as described in note 2 for frcns-3-hexene with an alkaloid concentration of ⁽ -25 M. The period for slow addition of the olefin is indicated in parentheses. The ee's shown in the Table were obtained with dihydroquinidine p-ch-orober-zoate as the ligand. Under the same conditions, the pseudoenantiomer, dihyc_Oquinine p-chbrobenzoate, provides products with ee's 5- 30% lower. In all cases the isolated yield was 85-95%. This reaction took 7 days to complete. ΛVith an addition period of 16 h, ee's of 63 and 65% were obtained at 0 *C and 20 ^« respectively; with the comb-nation of alow addition over a period of 16 h ai-J the presence of 1 eq of E-ιNOAc-H ₂ 0 at C° an ee of 81% was realized ^, fϊhis reaction took 5 days to complete. *When the reaction was carried out at 20 °C and the olefin was added over a period of 2. fa, an ee of 5?% was obtained.

Because of this face selection rule or phenomenon, it is possible, through use of the present method and the appropriate chiral ligand, to pre-determine the absolute configuration of the dihydroxylation product. As is also evident in Table 4, asymmetric di¬ hydroxylation of a wide variety of olefins has been successfully carried out by means of the present in¬ vention. Each of the embodiments described results in asymmetric dihydroxylation, and the "slow addition" method is particularly useful for this purpose. In each of the cases represented in the Table in which absolute configuration was established, the face selection "rule" (as interpreted with reference to the orientation represented in Figure 1) applied: use of DHQD resulted in attack or dihydroxylation occurring from the top or upper face and use of DHQ resulted in attack or dihydroxylation occurring from the bottom or lower face of the olefin. This resulted, respectively, in formation of products having an R or R,R configuration and products having an S or S,S configuration.

In a preferred embodiment of the present method, aromatic ethers of various cinchona alkaloids are used as ligands. The term "aromatic ethers" includes aryl ethers and heterocyclic ethers . A high level of asymmetric induction can be obtained using aromatic ethers of dihydroquinidine or dihydroquinine as ligands. For example, aromatic ethers having the following formula are particularly useful:

wherein R is phenyl, naphthyl, or o-methoxyphenyl . The stoichiometric asymmetric dihydroxylation of various dialkyl substituted olefins was performed using the phenyl ether derivative of dihydroquinidine. The results are shown in Table 6.

Table 6. Stoichiometric Asymmetric Dihydroxylation Phenyl Ether Dihydroquinidine

I) leq0s0 ₄ O OHH V .R ¹ . ^le ^ ¹ ' ^{in toluene} jp

R ¹ / 2) LiAlH ₄

OH

Entry Olefins Reaction temp % * *ee* with 3

(XT) (for comparison)

1 71

2

3 73

4

Enantiomeric excess was determined by GLC or HPLC annalysis of the bis-Mosher ester derivatives. Th reaction was worked up with NaHSO in H-0-THF. Diastereomeric excess.

The reaction was performed by adding 1 eq of olefin to a 1:1 mixture of 0s0 ₄ and the ligand in dry toluene (0.1M) followed by a reductive work-up using lithium aluminum hydride (LiAlH ₄ ) to yield the (R.R)-diol in

60-95% yield with good to excellent enantiomeric excess. Reactions with α, 3-unsaturated esters also proceeded with much improved enantio- and diastereoselectivities (>90%, as shown in entries 7 and 8, Table 6) using this ligand. B lowering the reaction temperature to -78 ^β C, the reaction with straight chain dialkyl substituted olefins proceeded with very high enantioselectivities (>93%, as shown in entries 2, 4 and 6 of Table 6). In the several cases which were plotted the variance in ee with temper- ature closely followed the Arrhenius relationship.

Several dihydroquinidine aromatic ether derivatives were examined as chiral ligands for the asymmetric dihydroxylation of (E) -3-hexene , as shown in Table 7, below. Reactions with all of the aromatic ether derivatives tried exhibited higher enantioselectivities than the corresponding reaction with p-chlorobenzoate dihydroquinidine. The highest enantioselectivity was obtained with 9-0-(2 ' -methoxyphenyl)-dihydroquinidine (entry 2 , Table 7) .

32 -

Table 7. Stoichiometric Asymmetric Hydroxylation of (E) -3-hexene

In one embodiment of the present method, aromatic ether ligands were used in the catalytic asymmetric dihydroxylation of (E) -3-hexene . In this embodiment, the results are summarized in Table 8. The catalytic asymmetric dihydroxylation reactions (entries 1-3, Table 8) were carried out by slow addition of (E) -3-hexene (1 eq) to a mixture of phenyl ether dihydroquinidine (0.25 eq) , N-methylmorpholine N-oxide (NMO, 1.5 eq) and OsO, (0.004 eq) in acetone-water (10/1, v/v) at 0°C. followed by work-up with Na_S-0_. The reaction proceeded faster

upon addition of tetraethylammonium acetate (2 eq) to the reaction mixture (entry 4, Table 8). Potassium ferricyanide was added as the secondary oxidant (entries 5 and 6, Table 8) . In these cases, slow addition of olefin was not required. To a mixture of (E) -3-hexane (1 eq) , aromatic ether of dihydroquinidine (0.25 eq) , K,Fe(CN), (3eq) and potassium carbonate (K„C0„ 3 eq) in tert-butyl alcohol-water (1/1, v/v) was added OsO, (0.0125 eq) ; the resulting mixture was stirred at room temperature for 20 hours. Reductive work-up (with

Na_S0 ₃ ) gave the diol in 85-90% yield with essentially the same ee as that obtained in the stoichiometric reaction.

Table 8. Catalytic Asymmetric Dihydroxylation of (E)-3-hexene

Enantioselectivities in the dihydroxylation of dialkyl substituted olefins, which were previously only possible through the use of stoichiometric reagents at low temperature, can now be obtained in the catalytic asymmetric dihydroxylation using these aromatic ether ligands at room temperature. Disclosed here are two ligands which are particularly useful in the present method: the 9-0- (9 'phenanthryl) ethers and the 9-0- (4 ' -methyl-2 ' -quinolyl) ethers of dihydroquinidine (la and lb below) and dihydroquinine (2a and 2b below) .

The R group can include other benzenoid hydrocarbons. The aromatic moieties also can be modified by substitutions such as by lower alkyl, alkoxy or halogen radical groups.

Additional effective heterocyclic aromatic ligands include :

The improvements achieved with these new ligands are best appreciated through the results shown in Table 9. A particularly important advantage is that the terminal olefins (entries 1-7, Table 9) , have moved into the "useful" ee-range for the first time.

Table 9. Ee (%)- ^a of the Diols Resulting rom Catalytic

Asymmetric Dihydroxylation

clefir. temp, ^ l ζPHN) lb (MEQ) lc (PCB) configr olefin «"**

8 _fr8u ^' ⁿ * ^ϋ 79 R,R

R» 9 ^ _t ^^ ^∞ ^ ^{i ri} 67 2S-3R

IP^- ^* '

10 _ph s cp_M _β 91 2S,3R 11 R,R

R» 12 74 R tf^*

13 . X ⁾ 151 R,R

/ ;

Enantiomeric excess as were determined_,by HPLC, GC , or

H-NMR analysis of the bis-MTPA esters (see supplementary materials for details of analyses). All reactions were performed essentially as described in Example 20 with some variations: (1) 1-1.25 mol % OsO or

K-OsO (OH), ; (2) 2-25 mol.% ligand, (3) 0.067-0.10 M in olefin; (4) 18-24 h reaction time. In all cases the isolated yield of the diol was 75-95% . ^C A11 olefins are commercially available except entries 6 and 7. The absolute configurations of the diols were determined by comparison of their optical rotations with literature values (entries 1, 3-5, 8, 10-13), or with an authentic diol (R)-(-) -2-phenyl- 1, 2 -propanediol (entry 6) , or by comparison of ORD (entry 9). The remaining two (entries 2,7) are tentatively assigned by analogy from optical rotations of closely related diols and the retention times of the bis MTPA esters on HPLC (see supplementary material for details), Reaction was carried out at room temperature.

The data for the new ligands la and lb has been compared to the results for another ligand, the p-chloro- benzoate lc (last column of Table 9). Note further that the highest enantioselectivities for each substrate have been highlighted by bracketing, and that this bracketing is conspicuously sparse in the column under ligand lc. Clearly, ligands la and lb also deliver a significant ee enhancement for trans-substituted olefins, especially those lacking aromatic substituents (entries •_ and 9) .

The six possible substitution patterns for olefins are :

mono- ge_mat.--ddJi- ns-dl- *r«r«πs-dl- _ tri-

Four of these classes are represented in Table 9. The present success with the mono- and gem-disubstituted types has essentially doubled the scope of the catalytic ADH when compared to diol production when ligands other. than aromatic ether ligands are used.

Strikingly absent from Table 9 are the results for the dihydroquinine ligand analogs (i.e. , 2a, 2b and 2c). The quinidine and quinine analogs of these new ligands also give very good results with the same olefin classes shown in Table 9. Like the original p-chlorobenzoate

9" ligand comparison (lc vs 2c) , the quinine ether series gives somewhat lower ee's than their dihydroquinidine counterparts (la vs 2a and lb vs 2b). For example, vinyl cyclooctane (entry 2) gives the S-diol in 8.8% ee using 2a compared with the R-diol in 93% ee recorded in Table 9 using la.

The detailed general procedure for the catalytic ADH is given in note Example 20, using ligand la and vinyl cyclooctane as the substrate. Note the experimental simplicity of the process. I is performed in the presence of air and water at either ambient or ice bath temperature. A further advantage is that the most expensive component, the ligand, can be easily recovered in >80% yield. Note also that the solid and nonvolatile osmium (VI) salt, K-OsO-, (OH) , , is used in place of osmium tetroxide. This innovation should be useful in all catalytic oxidations involving OsO, since it avoids the risk of exposure to volatile osmium species. Another olefin class can be asymmetrically dihydroxylated when 0-carbamoyl- ,p-chlorobenzoate- or 0- phenanthrolene- substitutions of DHQD or DHQ ligands are used in the method of the present invention. This class is the cis-disubstit ted typ ^e of olefin. Table 10 shows the ee's and % yields for a variety of substrates when these ligands were used. Procedures for producing these ligands and for carrying out the ADH are illustrated in_ Examples 23 and 2 .

Table 10: Enantiomeric Excesses (ee's) Obtained for ci_s_- Olefins with Various Dihydroquinidine Ligands; ee (% yield)

where the ligands are ether linked substituents of DHQD designated as dimethyl carbamoyl (DMC) , methyl phenyl carbomoyl (MPC) , diphenylcarba oyl (DPC) , p-chlorobenzoate (PCB) , phenanthryl (PHN) and phenyl carbomoyl (PhC) .

The greatest ee's were obtained when O-carbamoyl-DHQD ligands were employed which indicates that this class of compound is an attractive ligand for asymmetric dihydroxylation of the cis-disubstituted type of olefin. These results also demonstrate that reasonably good yields and ee's can be obtained for this

olefin class and that, now, five of the six classes of olefins can successfully be asymmetrically dihydroxylated.

In general, the concentration of the chiral ligand used will range from approximately 0.001 M or less to 2.0 M. In one embodiment, exemplified below, the solution is 0.261M in alkaloid 1 (the dihydroquinidine derivative). In one embodiment of the method, carried out at room temperature, the concentrations of each alkaloid represented in Figure 1 is at 0.25M. In this way, the enantiomeric excess resulting under the conditions used is maximized. The amount of chiral ligand necessary for the method of the present invention can be varied as the temperature at which the reaction occurs varies. For example, it is possible to reduce the amount of alkaloid (or other chiral ligand) used as the temperature at which the reaction is carried out is changed. For example, if it is carried out, using the dihydroquinidine derivative, at 0 C , the alkaloid concentration can be 0.15M. In another embodiment, carried out at 0 C, the alkaloid concentration was 0.0625M.

Many oxidants (i.e. , essentially any source of oxygen) can be used in the present method. For example, amine oxides (e.g., trimethyl amine oxides), tert-butyl hydroperoxide, hydrogen peroxide, and oxygen plus metal

+ ++ catalysts (e.g. , copper (Cu -Cu /0_), platinum (Pt/0.), palladium (Pd/0.) can be used. Alternatively, NaOCl, IO, , KBrO_ or KC10_ can be used. In one embodiment of the invention, N-methylmorpholine N-oxide (NMO) is used as the oxidant. NMO is available commercially (e.g. , Aldrich Chemicals, 97% NMO anhydrous, or as a 60%

solution in water). In addition, as stated above, potassium ferricyanide can be used in lieu of the amine oxide. Potassium ferricyanide is an efficient oxidant in the present method.

Osmium will generally be provided in the method of the present invention in the form of osmium tetroxide (OsO.) or potassium osmate VI dihydrate , although other sources (e.g. , osmium trichloride anhydrous, osmium trichloride hydrate) can be used. OsO, can be added as a solid or in solution.

The osmium catalyst used in the method of the present invention can be recycled, for re-use in sub¬ sequent reactions. This makes it possible not only to reduce the expense of the procedure, but also to recover the toxic osmium catalyst. For example, the osmium catalyst can be recycled as follows: Using reduction catalysts (e.g. , Pd-C), the osmium VIII species is reduced and adsorbed onto the reduction catalyst. The resulting solid is filtered and resuspended. NMO (or an oxidant) , the alkaloid and the substrate (olefin) are added, with the result that the osmium which is bound to the Pd/C solid is reoxidized to OsO. and re-enters

4 solution and plays its usual catalytic role in formation of the desired diol. This procedure (represented below) can be carried out through several cycles, thus re-using the osmium species. The palladium or carbon can be immobilized, for example, in a fixed bed or in a car¬ tridge .

-42-

H ₂ /Pd-C

t

oxidant/alkaloid

In one embodiment an olefin, such as recrystallised trans-stilbene (C,H_CH: CHC,H _C ) , is combined with a chiral

6 5 6 5 ligand (e.g. , p-chlorobenzoyl hydroquinidine) , acetone, water and NMO. The components can be added sequentially or simultaneously and the order in which they are com¬ bined can vary. In this embodiment, after the components are combined, the resulting combination is cooled (e.g. , to approximately 0 C in the case of trans-stilbene) ; cooling can be carried out using an ice-water bath. OsO, is then added (e.g. , by injection), in the form of a solution of OsO, in an organic solvent (e.g. , in toluene). After addition of OsO , the resulting com¬ bination is maintained under conditions appropriate for the dihydroxylation reaction to proceed. In another preferred embodiment, a chiral ligand

(e.g. , dihydroquinidine 4-chlorobenzoate) , NMO, acetone, water and OsO, (as a 5M toluene solution) are combined. The components can be added sequentially or simul¬ taneously and the order in which they are combined can vary. In this embodiment, after the components are combined, the resulting combination is cooled (e.g. , to approximately 0 ^β C) ; cooling can be carried out using an ice-water bath. It is particularly preferred that the combination is agitated (e.g. , stirred). To this well- stirred mixture, an olefin (e.g. , trans- 3 -hexene) is added slowly (e.g. , by injection) . The optimum rate of addition (i.e. , giving maximum ee) , will vary depending on the nature of the olefinic substrate. In the case of trans - 3-hexene , the olefin was added over a period of about 16-20 hours. After olefin addition, the mixture can be stirred for an additional period of time at the

low temperature (1 hour in the case of trans-3-hexene) . The slow-addition method is preferred as it results in better ee and faster reaction times.

In another embodiment, a compound which accelerates hydrolysis of the osmate ester intermediates (e.g. , a soluble carboxylate salt, such as tetraethylammonium acetate) is added to the reaction mixture. The compound (approximately 1-4 equiv.) can be added to the mixture of chiral ligand, water, solvent, oxidant and osmium catalyst and olefin, or prior to the addition of olefin, if the olefin slow-addition method is used.

The diol-producing mechanistic scheme which is thought to operate when the slow-addition of olefin method is used is represented in Figure 4. According to the proposed mechanism, at least two diol-producing cycles exist. As shown in Figure 4, only the first cycle appears to result in high ee. The key intermediate is the osmium (VIII) trioxoglycolate complex, shown as formula 3 in Figure 4, which has the following general formula:

wherein L is a chiral ligand and wherein R_ , R , R and R, are organic functional groups corresponding to the olefin. For example, R_ , R R and could be alkyl,

aryl, alkoxy aryloxy or other organic functional groups compatible with the reaction process. Examples of olefins which can be used, and their functional groups, are shown on Table 4 hereinabove. This complex occupies the pivotal position at the junction between the two cycles, and determines how diol production is divided between the cycles.

Evidence in favor of the intermediacy of the osmium (VIII) trioxoglycolate complex (formula 3, Figure 4) is provided by the finding that the events in Figure 4 can be replicated by performing the process in a stepwise manner under stoichiometric conditions. These experi¬ ments were performed under anhydrous conditions in toluene. In the process shown in Figure 4, one equiva- lent of the alkaloid osmium complex (shown as formula 1, Figure 4) is allowed to react with an olefin to give the emerald green monoglycolate ester (formula 2, Figure 4) . A different olefin is then added, followed by an equiva¬ lent of an anhydrous amine N-oxide, and rapid formation of the bisglycolate ester (formula 4, Figure 4) is observed. Upon reductive hydrolysis of the bisglycolate ester, precisely one equivalent of each diol is liberat¬ ed. These experiments indicate that a second cycle, presumably via the osmium trioxoglycolate complex, is as efficient as the first in producing diols from olefins. One can also use the same olefin in both steps to run this tandem addition sequence. When this was done using 1-phenylcyclohexene as the olefin, the ee for the first step was 81% and the ee for the second step was 7% in the opposite direction (i.e. , in favor of the minor enantiomer in the first step) . Thus, for this substrate

any intrusion of the second cycle is particularly damag¬ ing, and under the original catalytic conditions 1- phenylcyclohexene only gave 8% ee (entry 3, Table 5).

Reduced ee is just part of the counterproductivity of turning on the second cycle; reduced turnover is the other liability. The bisosmate esters (formula 4, Figure 4) are usually slow to reoxidize and hydrolyze, and therefore tend to tie up the catalyst. For example, 1-phenylcyclohexene took 7 ^" days to reach completion under the original conditions (the 8% ee cited above) . With slow addition of the olefin, the oxidation was complete in one day and gave the diol in 95% yield and 78% ee (entry 3, Table 5) .

The most important prediction arising from the mechanistic scheme shown in Figure 4 is the minimization of the second cycle if the olefin is added slowly. Slow addition of the olefin presumably gives the osmium (VIII) trioxoglycolate intermediate sufficient time to hydrolyze so that the osmium catalyst does not get trapped into the second cycle by reacting with olefin. To reiterate, the second cycle not only ruins the ee but also impedes turnover, since some of the complexes involved are slow to reoxidize and/or hydrolyze. The optimum feed rate depends on the olefin; it can be determined empirically, as described herein. The maximum ee obtainable in the catalytic process is determined by the addition of the alkaloid osmium complex (formula 1, Figure 4) to the olefin (i.e. , the first column in Table 5). Thus, stoichiometric additions can be used to enable one to determine the ee-ceiling which can be reached or approached in the catalytic

• 47 -

process if the hydrolysis of 3 (Figure 4) can be made to dominate the alternative reaction with a second molecule of olefin to give 4 (Figure 4) . In the case of terminal olefins, styrene (Table 5), the trioxoglycolate esters hydrolyze rapidly, since slow addition, or the effect of the osmate ester hydrolytic additive give only a slight increase in the ee. However, most olefins benefit greatly from any modification which speeds hydrolysis of the osmate ester intermediate (3, Figure 4) (entries 2-5, Table 5), and in extreme cases neither the effect of the osmate ester-hydrolytic additive nor slow addition is sufficient alone. Diisopropyl ethylene (entry 4, Table 5) approaches its ceiling-ee only when both effects are used in concert, with slow addition carried out in the presence of acetate. The other entries in the Table reach their optimum ee's through slow addition alone, but even in these cases the addition times can be sub¬ stantially shortened if a compound, such as a tetraalkyl ammonium acetate, is present. I ¹¹ many cases, temperature also affects the ee .

When the ee is reduced by the second cycle, raising the temperature can often increase it. This occurs, in particular, when NMO is used as the secondary oxidant. For example, diisopropyl ethylene gave 46% ee at 0°C and 59% ee at 25°C (24h slow addition time in both cases) . The rate of hydrolysis of the osmium trioxoglycolate intermediate is apparently more temperature dependent than the rate of its reaction with olefin. This temperature effect is easily rationalized by the expected need to dissociate the chiral ligand from the osmium complex (3) in order to ligate water and initiate

- 48 -

hydrolysis, but the ligand need not dissociate for addition of olefin to occur (in fact this second cycle olefin addition step is also likely to be ligand-accelerated) . 5 When K,Fe(CN) _fi is used as the secondary oxidant, the effect of temperature on the ee is opposite the effect when NMO is the secondary oxidant. That is, lowering the temperature can often increase the ee when potassium ferricyanide is the secondary oxidant. Also, the olefin I _Q need not be slowly added to the mixture but can, instead, be added all at once when potassium ferricyanide is the secondary oxidant. These effects and conditions apparently occur because the second cycle is suppressed when this secondary oxidant is used. The reactions of _j e the second cycle do not appreciably contribute to the formation of diols when the secondary oxidant is potassium ferricyanide.

The following is a description of how optimum conditions for a particular olefin can be determined. To

20 optimize the osmium-catalyzed asymmetric dihydroxylation: 1) If from the known examples there is doubt about what the ceiling-ee is likely to be, it can be determined by performing the stoichiometric osmylation in acetone/water at 0 ^β C using one equivalent of the OsO, - alkaloid

25 complex; 2) Slow addition at 0°C: the last column in Table 3 can be used as a guide for choosing the addition time, bearing in mind that at a given temperature each olefin has its own "fastest" addition rate, beyond which the ee suffers as the second cycle turns on. When the 30 olefin addition rate is slow enough, the reaction mixture remains yellow-orange (color of 1, Figure 4); when the

rate is too fast, the solution takes on a blackish tint, indicating that the dark-brown-to-black bisglycolate complex (4, Figure 4) is being generated; 3) If the ceiling ee is not reached after steps 1 and 2, slow addition plus tetraalkyl ammonium acetate (or other compound which assists hydrolysis of the osmate ester intermediate) at 0°C can be used; 4) slow addition plus a soluble carboxylate salt, such as tetraalkyl ammonium acetate at room temperature can also be used. For all these variations, it is preferable that the mixtures is agitated (e.g. , stirred) for the entire reaction period. The method of the present invention can be carried out over a wide temperature range and the limits of that range will be determined, for example, by the limit of the organic solvent used. The method can be carried out, for example, in a temperature range from about 40°C to about -30°C. Concentrations of individual reactants (e.g. , chiral ligand, oxidant, etc.) can be varied as the temperature at which the method of the present invention i carried out. The saturation point (e.g. , the concen¬ tration of chiral ligand at which results are maximized) is temperature-dependant . As explained previously, for example, it is possible to reduce the amount of alkaloid used when the method is carried out at lower temperatures.

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

When potassium ferricyanide (K_Fe(CNg) is the secondary oxidant, it is advantageous to use a combination of solvents that separate into organic and aqueous phases. Although the method of the present invention can be carried out with potassium ferricyanide as the secondary oxidant using the organic solvents of the preceding paragraph, asymmetric dihydroxylation does occur but the ee's are less than when separable organic and aqueous solvent phases are employed.

The yields and ee's for a variety of organic solvents, mixed with water and a variety of substrates are shown in Tables 11-12. Table 11 shows yields and ee's for several organic solvents (with water) for a specific substrate. The ligand is either

DHQD-p-chlorobenzoate (PCB) or DHQD-napthyl ether. Table 12 shows the ee's for a veriety of substrates for either t-butanol or cyclohexane as the organic phase. It is apparent from these Tables that preferred organic phase solvents include cyclohexane, hexane, ethyl ether and t-butyl methyl ether. The preferred aqueous solvent is water.

Table 11. Solvent Study of Catalytic ADH using K ₃ Fe(CN) ₆

a) Solvent Effects on Styrene Diol using DHQD-PCB Ligand Reaction Time - 4 hours

b) Solvent Effects on Hexene Diol using DHQD-PCB Ligand Reaction Time — 24 hours

Solvent Yie!d(%) ee(%)

Cyclohexane

Hexane* t-BuOH t-Bu-O-Me

Et_O

ElOAc

Toluene

CH _j CN

CH ₂ σ ₂

Chlorobenzene THF

c) Solvent Effects on Decene Diol using DHQD-PCB Ligand Reaction Time — 24 hours

d) Solvent Effects on Hexene Diol using DHQD Napthyl Ether Ligand Reaction Time - 24 hours

e) Solvent Effects on Decene Diol usin _j DHQD Napthyl Ether Ligand Reaction Time - 24 hours

* 5ml of t-Bu-O-Me were added to dissolve all the ligand ** 6ml of t-Bu-O-Me were added to dissolve all the ligand

Table 12. Ee's of Various Substrates in the Catalytic ADH

DHQD-PCB , cat. O-O ₄ . r.l.

^{,/ N/} K_Fe.CN), . K_C0_ , Solv nl / H.O

Substrate f- BuOH Cyclohexane

,^^Et 74 ⁷⁴

In another embodiment of the present invention, styrene was combined with a chiral ligand (DHQD) , acetone, water and NMO and OsO, . The plot of amine concentration vs second-order-rate-constant K for the

catalytic cis-dihydroxylation of styrene is represented in Figure 2. The kinetic data of Figure 2 clearly shows the dramatic effect of ligand-accelerated catalysis achieved by use of the method of the present invention. Point a in Figure 2 represents the rate of the catalytic process in the absence of amine ligands (tl/2 - 108 minutes). Line b shows the rates of the process in the presence of varying amounts of quinuclidine , a ligand which substantially retards catalysis (at greater than 0.1M quinuclidine, tl/2 is greater than 30 hours).

Because of the observed retarding effect of quinuclidine (ligand-decelerated catalysis) the result represented by line C was unexpected. That is, when the process occurs in the presence of dihydroquinidine benzoate derivative 1 (see Figure 1) , the alkaloid moiety strongly accelerates the catalytic process at all concentrations (with ligand 1 = 0.4M, tl/2 — 4.5 minutes) , despite the presence of the quinuclidine moiety in its structure.

The rate of the stoichiometric reaction of styrene with osmium tetroxide and that of the corresponding catalytic process were compared. The comparison indi¬ cates that both have identical rate constants

[K . -(5.1 ± 0.1)xl0 ² M ^"1 min ^"1 and K -(4.9 ± stoic _ . - cat

0.4)xl0 M min ] , and that they undergo the same rate acceleration upon addition of ligand 1. Hydrolysis and reoxidation of the reduced osmium species, steps which accomplish catalyst turnover, are not kinetically sig¬ nificant in the catalytic process with styrene. It may be concluded that the limiting step is the same in both processes and consists of the initial addition reaction forming the osmate ester (2, Figure 1) . A detailed

mechanistic study reveals that the observed rate acceleration by added ligand 1 is due to formation of an osmium tetroxide-alkaloid complex which, in the case of styrene, is 23 times more reactive than free osmium tetroxide. The rate reaches a maximal and constant value beyond an (approximate) 0.25 M concentration of ligand 1.

The onset of this rate saturation corresponds to a pre-equilibrium between DHQD and osmium tetroxide with a rather weak binding constant (K — 18 ± 2 M ) . In- eq ^— creasing the concentration of DHQD above 0.25 M does not result in corresponding increases in the enantiomeric excess of the product diol. In fact, due to the ligand-acceleration effect, the ee of the process approaches its maximum value much faster than the maximum rate is reached, which means that optimum ee can be achieved at rather low alkaloid concentrations.

At least in the case of styrene, the rate accelera¬ tion in the presence of the alkaloid is accounted for by facilitation of the initial osmylation step. The strik¬ ingly opposite effects of quinuclidine and DHQD on the catalysis can be related to the fact that although quinuclidine also accelerates the addition of osmium tetroxide to olefins, it binds too strongly to the resulting osmi-um(VI) ester intermediate and inhibits catalyst turnover by retarding the hydrolvsis/reoxidation steps of the cycle. In contrast the alkaloid appears to achieve a balancing act which renders it near perfect for its role as an accelerator of the dihydroxylation catalysis. It binds strongly enough to accelerate addition to olefins, but not so tightly that it inter- feres (as does quinuclidine) with subsequent stages of the catalytic cycle. Chelating tertiary amines [e.g. ,

56 . 1 -

2,2' -bipyridine and ( - ) - (R,R) -N,N , ' ,N' -tetramethyl-1 , 2- cyclohexanediamine) at.0.2M completely inhibit the catalysis. Pyridine at 0.2 M has the same effect.

As represented in Table 4, the method of the present invention has been applied to a variety of olefins. In each case, the face selection rule described above has been shown to apply (with reference to the orientation of the olefin as represented in Figure 1). That is, in the case of the asymmetric dihydroxylation reaction in which the dihydroquinidine derivative is the chiral ligand, attack occurs on the re- or re, re- face) and in the case in which the dihydroquinine derivative is the chiral ligand, attack occurs on the si- or si, si- face. Thus, as demonstrated by the data presented in the Table 2, the method of the present invention is effective in bringing about catalytic asymmetric dihydroxylation; in all cases, the yield of the diol was 80-95%, and with the slow- addition modification, most olefins give ee's in the rage of 40-90%. The present method can be used to synthesize chiral intermediates which are important building blocks for biologically active chiral molecules, such as drugs. In one embodiment, the present method was used to produce an optically pure intermediate used in synthesizing the drug diltiazem (also known as cardizem) . The reaction is shown in the following scheme:

57

DHlIa2em / Cardi-βm

The method of the present invention is also useful to effect asymmetric vicinal oxyamination of an olefin, and may be useful for asymmetric vicinal diamination. In the case of substitution of two nitrogen or of a nitrogen and oxygen, an amino derivative is used as an amino transfer agent and as an oxidant. For example, the olefin to be modified, an organic solvent, water, a chiral ligand, an amino derivative and an osmium- containing compound are combined and the combination maintained under conditions appropriate for the reaction to occur. The amino derivative can be, for example, an N-chlorocarbamate or chloroamine T. Asymmetric catalytic oxyamination of recrystallized trans stilbene, according to the method of the present invention, is represented in Figure 2.

58-

In another embodiment, the present method was used to produce intermediates for the synthesis of homo- brassinolide and 24-epibrassinolide, which are known to exhibit the same biological activities as brassinolide. These brassinosteroids show very potent plant-growth activity at hormonal level and access to these compounds in a large quantity can only be achieved by synthetic means .

In another embodiment of the present method, highly optically active diol was produced from the asymmetric dihydroxylation of ethyl trans - 2-octenoate . This diol

• 59 -

has been converted to optically pure ^-lactam structure, which are well-known for their antibiotic activities:

U_____-E______ Agymmetric Dihydroxylation of Stilbene The following were placed sequentially in a 2L bottle (or flask): 180.2g (1.0 M) of recrystallised trans stilbene (Aldrich 96%), 62.4g (0.134 moles; 0.134 eq) of the p-chlorobenzoate of hydroquinidine (1), 450 mL of acetone, 86 mL of water (the solution is 0.261 M in alkaloid 1) and 187.2 g (1.6 mol, 1.6 eq.) of solid N-Methylmorpholine N-Oxide (NMO, Aldrich 97%). The bottle was capped, shaken for 30 seconds, cooled to 0-4 C using an ice-water bath. OsO, (4.25 mL of a solution prepared using 0.120g OsO /mL toluene; 0.002 Mol%; 0.002 eq.) was injected. The bottle was shaken and placed in a refrigerator at ca. 4 C with occasional shaking. A dark purple color developed and was slowly replaced by a deep orange one; the heterogeneous reaction mixture gradually became homogeneous and at the end of the reaction, a clear orange solution was obtained. The reaction can be conveniently monitored by TLC (silica gel; CH_C1 ^• disap¬ pearance of the starting material at a defined Rf) . After 17 hours, lOOg of solid sodium metabisulfite (Na-S_0,_) were added, the reaction mixture was shaken (1 mmiinnuuttee)) aanndd lleefftt aatt 2200 CC dduurriinngg 1155 mmiinnuutteess. The reaction mixture was then diluted by an equal volume of CH, anhydrous Na.SO, added (100 g) . After another 15

- 60 -

minutes , the solids were removed by filtration through a pad of celite, washed three times with 250 mL portions of CH-C1- and the solvent was evaporated under vacuum (rotatory-evaporator, bath temperature - 30-35 C) . The crude oil was dissolved in ethyl acetate (750 mL) , extracted thiee times with 500 ml. portions of 2.0 M HC1, once with 2.0 M NaOH , dried over N _S0 ₄ and con¬ centrated i _^ n vacuo to leave 190 g (89%) of the crude diol as a pale yellow solid. The enantiomeric excess of the crude R,R-diol was determined to be 78% by HPLC analysis of the derived bis-acetate (Pirkle 1A column using 5% isopropanol/hexane mixture as eluant. Retention times are: tl -= 18.9 minutes; t2 - 19.7 minutes. Recrystalli- zation from about 1000 ml. CH-Cl- gave 150 g (70%) of pure diol (ee — 90%) . A second recrystallization gave 115g of diol (55% yield) of 99% ee . Ee (enantiomeric excess) is calculated from the relationship (for the R enantiomer, for example) : percent e.e.-[(R)-(S)/[(R)+(S)]xl00. The aqueous layer was cooled to 0 C and treated with

2.0M NaOH (about 500 L) until pH - 7. Methylene chloride was added (500 mL) and the pH adjusted to 10-11 using more 2.0M NaOH (about 500 L) . The aqueous layer was separated, extracted twice with methylene chloride (2x300 mL) and the combined organic layers were dried over Na„S0, . The solvent was removed in vacuo to provide the alkaloid as a yellow foam. The crude alkaloid was dissolved in ether (1000 mL) , cooled to 0 C (ice-bath) and treated with ry HC1 until acidic pH (about 1-2) . The faint yellow precipitate of p-chlorobenzoylhydro- quinidine hydrochloride was collected by filtration and dried under high vacuum (0.01mm Hg) .

•61-

The free base was liberated by suspending the salt in ethyl acetate (500 mL) , cooling to 0 C and adding 28%

NH,0H until τ>H — 11 was reached. After separation, the 4 aqueous layer was extracted twice with ethyl acetate, the combined organic layers were dried over Na„S0, and the solvent removed in vacuo to give the free base as a white foam.

_______-£________ J. ^ k .— ∑^L°. ∑λ^ 2.Ω:—2.i.—^ ^ ^e .Ω^.

To a 3 L, 3-necked, round-bottomed flask equipped with a mechanical stirrer and two glass stoppers at room temperature were added E-l , 2-diphenylethene

(Trans-stilbene) (180.25 g, 1.0 mol, 1.0 eq) ,

4-methylmorpholine N-oxide (260 mL of a 60% by wt. aqueous solution (1.5 mol, 1.5 eq) dihydroquinidine 4-chlorobenzoate (23.25 g, 0.05 mol, 0.05 eq) 375 mL acetone and 7.5 mL H_0. The solution was 0.1 M in alkaloid M in olefin, and the solvent was 25% water/75% acetone (v/v). The flask was immersed in a 0 ^β C cooling bath and stirred for 1 h. Osmium tetroxide (1.0 g, 4.0

-3 mmol., 4.0 x 10 eq) was added in one portion producing a milky brown-yellow suspension. The reaction mixture was then stirred at 0°C for 24 h and monitored by silica

TLC (3:1 CH-C1 -Et 0 v/v) . At this point, sodium metabisulfite (285 g, 1.5 mol) was added, the mixture was diluted with 500 mL of CH_C1_, warmed to room temperature, and stirred at room temperature for 1 h.

Anhydrous sodium sulfate (50 g) was added and the mixture was stirred at room temperature overnight. The suspension was filtered through a 20 cm Buchner funnel,

- 62 -

the filtrand was ϊinsed thoroughly w: th acetone (3 x 250 mL) , and the filtrate was concentrati-d to a brown paste on a rotary evaporator with slight heating (bath temperature 30-40 ^β (.'). The paste was dissolved in 3.5 L of EtOAc, transferred to a 6 L separatory funnel, and washed sequentially with H„0 (2 x 500 mL) , and brine (1 x 500 mL) . The initial aqueous washes were kept separate from the subsequent acid washes which were retained for alkaloid recovery. The organic layer was dried (Na_S0,), and concentrated fo give the crude diol in quantitative yield (222.7 g, 1.04 -mol, 104%). Th ee of the crude product was deterπ ined by H NMR analysis of the derived bis-Mosher ester . c, be 90 % . One rec'-ystallization from hot 95% acueous e.hanol (3 mL/g) affcrded 172-180 g (80-84%) of enanti nmerically pure stilbene diol as a white solid, mp 1'■ . ^" > .5- 146.5°C , [α] _D ²⁵ -91.1° (c-1.209, abs EtOH) .

_____-__£.___-_._. _iiiΣ___-£_-__-_£__2i_l-_____£-iZi_-__i££__2______ii__ _lS__

Asymmetric dihydrox lation of stilbene was carried out as described in Example 1, except that 1.2 equiva¬ lents of NMO were _sed.

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Asymmetric dihydrox lation of st ilbene was carried out as described in Example 1, except that 1.2 equivalents of NMO, a s a 62% wt. solution in water, were used.

-63-

_- ^x ____E__£__- _-_- EJ_Ξ_--_-_ -_-----^^-h rp uinidine derivative

Preparation of dihydroquinidine by catalytic

__.____££____££_£___£_-_-£__-___££

To a solution of 16.2 g of quinidine (0.05mol) in

150mL of 10% H.S0 ₄ (15 g cone H-,S0 ₄ in 150mL H ₂ 0) was added 0.2 g of PdCl_ (0.022eq; O.OOllmol). The reaction mixture was hydrogenated in a Parr shaker at 50 psi pressure. After 2h, the catalyst was removed by filtra¬ tion through a pad of celite and washed with 150mL of water. The faint yellow solution so obtained was slowly, added to a stirred aqueous NaOH solution (15 g of NaOH in 150mL H-,0. A white precipitate immediately formed and the pH of the solution was brought to 10-11 by addition of excess aqueous 15% NaOH. The precipitate was col- lected by filtration, pressed dry and suspended in ethanol (175mL) . The boiling solution was quickly filtered and upon cooling to room temperature, white needles crystallized out. The crystals were collected and dried under vacuum (90 C; 0.05 mm Hg) overnight. This gave 8.6 g (52.7%) of pure dihydroquinidine mp—169.5-170 C. The mother liquor was placed in a freezer at -15 C overnight. After filtration and drying of the crystals, another 4.2 g (21.4%) of pure material was obtained, raising the total amount of dihydroquini- dine to 12.8 g (74.1%) .

Preparation of dihydroquinidine p-chlorobenzoate X__i_-__£_-_ϋ

64-

__£____i_i_lΣ__£££Hi£i--i£ ___l ___-££_li£______£___-_i_--___£__._.

To a cooled (0 C) suspension of 100 g dihydroquinidine hydrochloride (0.275mol) in 300mL of dry CH-C1- was added, over 30 minutes with efficient stirring, 115mL of Et_N (0.826eq; 3eqs) dissolved in 50mL of CH-C1-. The dropping funnel was rinsed with an additional 20mL of CH-C1-. After stirring 30 minutes at 0°C, 42mL of p-chlorobenzoyl chloride (0.33mol ; 57.8g ; 1.2eq) dissolved in 120mL of CH-C1- was added dropwise over a period of 2h . The heterogeneous reaction mixture was then stirred 30 minutes at 0 C and 1 hour at room temperature; 700mL of a 3.0M NaOH solution was then slowly added until pH-10-11 was obtained. After part¬ itioning, the aqueous layer was extracted with three lOOmL portions of CH-C1-. The combined organic layers were dried over Na-SO. and the solvent removed in vacuo

2 4

(rotatory evaporator) . The crude oil was dissolved in 1L of ether, cooled to 0 C and treated with HC1 gas until the ether solution gives a pH of about 2 using wet pH paper. The slightly yellow precipitate was collected and dried under vacuum to give 126 g (91.5%) of dihydro¬ quinidine p-chlorobenzoate hydrochloride.

The salt was suspended in 500mL of ethyl acetate, cooled to 0°C and treated with 28% NH ₄ 0H until pH-11 was reached. After separation, the aqueous layer was extracted with two 200mL portions of ethyl acetate. The combined organic layers were dried over Na-SO. and the solvent removed under vacuum, leaving the free base 1 as a white foam (112g; 88% overall). This material can be used without further purification, or it can be recrystallized from a minimum volume of hot acetonitrile

- 65 -

to give an approximately 70-80% recovery of colorless crystals: mp : 102-104 ^β C, [ ] ²⁵ D-76.5° [cl .11 , EtOH) ; IR (CH CI.) 2940, 2860, 1720, 1620, 1595, 1520, 1115, 1105, 1095, 1020 cm ^"1 ; ^X H NMR (CDC1..) 8.72 (d, IH, J-5Hz), 8.05 (br d, 3H, J-9.7Hz), 7.4 (m, 5H) , 6.72 (d, IH, J-7.2Hz), 3.97 (s, 3H) , 3.42 (dd, IH, J-9 , 19.5Hz), 2.9-2.7 (m, 4H) , 1.87 (m, IH) , 1.75 (br s, IH) , 1.6-1.45 (m, 6H) , 0.92 (t, 3H, J-7Hz). Anal. Calcd for C ₂ _,H ₂₉ C1N ₂ 0 ₃ : 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.

Z__£_______l___-__£££__£______££

To a 0 C solution of 1.22g dihydroquinidine

(0.0037mol) in 30mL of CH ₂ C1 ₂ was added 0.78mL of Et N

(0.0056mol; 1.5eq), followed by 0.71mL of p-chlorobenzoyl chloride (0.005mol; 1.2eq) in ImL CH ₂ C1 After stirring 30 minutes at 0 C and 1 hour at room temperature, the reaction was quenched by the addition of 10% Na_C0_ (20mL) . After separation, the aqueous layer was ex¬ tracted with three lOmL portions of CH.C1-. The combined organic layers were dried over Na_S0 and the solvent removed under vacuum. The crude product was purified as described above. Dihydroquinidine p-chlorobenzoate (1) was obtained in 91% yield (1.5g) as a white foam.

i ££Y£ΣΪ-_£_________l_-___-£££__£______£ __E_:£_l__£Ξ££ ____£____

The aqueous acidic extracts (see EXAMPLE 1) were combined, cooled to 0 C and treated with 2.0M NaOH solution (500mL) until pH*=7 was obtained. Methylene chloride was added (500mL) and the pH was adjusted to 10-11 using more 2.0M NaOH. The aqueous layer was

- 66

separated and extracted with two 300mL portions of

CH.C1_. The combined organic layers were dried over

Na_S0, and concentrated to leave the crude alkaloid as a 2 4 yellow foam. The crude dihydroquinidine p-chlorobenzoate (1) was dissolved in 1L of ether, cooled to 0°C and HC1 gas was bubbled into the solution until a pH of 1-2 was obtained using wet pH paper. The pale yellow precipitate of 1 as the hydrochloride salt was collected by fil¬ tration and dried under high vacuum (0.01mm Hg) . The free base was liberated by suspending the salt in 500mL of ethyl acetate, cooling the heterogeneous mixture to 0°C and adding 28% NH ₄ 0H (or 15% NaOH) until pH-11 was obtained. After separation, the aqueous layer was extracted with two lOOmL portions of ethyl acetate, the combined organic layers were dried over Na_S0, and the solvent removed in vacuo to give 56g (91% recovery) of pure dihydroquinidine p-chlorobenzoate (1) as a white foam.

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_--_£E Ξ _---£E--£_I---_i-lΣ--_I£2Hi£_-££_E_l£_li£__£____£ __£____

The catalytic hydrogenation and p-chlorobenzoylation were conducted as described for the dihydroquinidine p-chlorobenzoate to give a white amorphous solid in 85-90% yield. This solid can be used without further purification, or it can be recrystallized from a minimum volume of hot acetonitrile to afford colorless crystals: Mp:130-133°C, [ a] ²⁵ D+150° (c 1.0, EtOH) . The physical properties of the solid before recrystallization (i.e. , the "white amorphous solid") are as follows: [ ] 25

- 67 -

D+142.1 (C-l, EtOH); IR (CH ₂ C1 ₂ ) 2940, 2860, 1720, 1620, 1595, 1508, 1115, 1105, 1095, 1020 cm ^"1 , ¹ R NMR (CDC1-.) d 8.72 (d, IH, J-5Hz), 8.05 (br d, 3H, J-8Hz) , 7.4 (m, 5H) , 6.7 (d, IH, J-8Hz), 4.0 (s, 3H) , 3.48 (dd, IH, J-8.5 , 15.8Hz), 3.19 (m, IH) , 3.08 (dd, IH, J-11, 15Hz), 2.69

(ddd, IH, J-5, 12, 15.8Hz), 2.4 (dt, IH, J-2.4, 15.8Hz), 1.85-1.3 (m, 8H) , 0.87 (t, 3H, J-Hz). Anal. Calcd for C ₂ -,H _2g ClN ₂ 0 ₃ : C, £9.74; H, 6.28; Cl, 7.62; N, 6.02. Found: C, 69.85; H, 6.42; Cl, 7.82; N, 5.98.

__£££Z_-ΣZ_£_--__----l----_-£ £--£--£ —E-l£-i--£--££ £--£-------- -i-l

The procedure is identical to that described above for recovery of 1.

-____-__E___-_Z Procedure for Asymmetric Dihydroxylation of Trans__ -_£-- _}--—HB__ JΓ____S_low_Addition_" __££_-___--_££_-

To a well stirred mixture of 0.465g (1 mmol, 0.25 eq=0.25M in L) dihydroquinidine 4-chlorobenzoate

(Aldrich, 98%), 0.7g (6 mmol, 1.5 eq) N-methylmorpholine

N-oxide (Aldrich, 97%) , and 32 L of a 0.5M toluene

_ solution of osmium tetroxide (16 mol, 4 x 10 equiv), in 4 mL of an -acetone-water mixture (10:1 v/v) at 0°C, neat 0.5 mL (0.34g, 4 mmol) trans-3-hexene (Wiley, 99.9%) was added slowly, via a gas tight syringe controlled by a syringe pump and with the tip of the syringe needle immersed in the reaction mixture, over a period of 16 h. 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

68 -

additional hour. Solid sodium metabisulfite Na_S ₂ 0 ₅ , 1.2g) was added and the mixture was stirred for 5 min, and then diluted with dichloromethane (8mL) and dried (Na.SO, ) . The solids were removed by filtration, and washed three times with dichloromethane. The combined filtrates were concentrated, and the residual oil was subjected to flash column chromatography on silica gel (25g, elution with diethyl ether-dichloromethane , 2:3 v/v, R- 0.33) and collection of the appropriate fractions afforded 0.30-0.32g (85-92% yield) of the hexanediol.

The enantiomeric excess of the diol was determined by GLC analysis (5% phenyl-methylsilicone, 0.25 m film, 0317 mm diameter, 29 m long) of the derived bis-Mosher ester to be 70%. When the above reaction was repeated with 1.2 mL

(6mmol, 1.5eq) 60% aqueous NMO (Aldrich) in 4 mL acetone, an ee of 71% was obtained. Thus, this aqueous NMO gives equivalent results and is almost twenty times less expensive than the 97% solid grade. With an alkaloid concentration of only 0.1M (i.e. , 0.186g) and with an olefin addition period of 20 hours at 0°C, the ee was 65%. A small sacrifice in ee thus leads to a large saving in alkaloid. At 0°C, both trans - 3 -hexene and trans- -methylstyrene reach their maximum ee value between 0.20 and 0.25M alkaloid concentration.

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__l _££_.__£Σ£_-£-l __ £ ____i£_l____r^ 0A£__.4H_^0

The procedure set out in Example 1 was followed, except that 1-phenylcyclohexene (1.0M) was substituted

69 -

for trans-stilbene. The reaction was allowed to proceed for three days, after which only 40% conversion to the diol was obtained (8% ee) .

The above procedure was repeated, with the difference that 2 equivalents of tetraethyl ammonium acetate (Et,N0Ac-4H„0) was added to the reaction mixture 4 2 at the beginning of the reaction. Fifty-two (52%) percent ee was obtained using this procedure, and the reaction was finished in about one day.

________£_______ __£Σ____ £Ξ__£______lΣ-__I£_i-_-_ £i££_£___-____£ -_i_E_____-££

££__ £—. E_- £--.£££B£U££-_—££B_-ϊ£i£B£—ϊE—-_£_-££ £ To a well-stirred mixture of 58.2 mg (0.125 mmol;

0.25 eq.) of the p-chlorobenzoate of hydroquinidine, 1 mL of toluene, 88 mg (0.75 mmol; 1.5 eq.) of N-methyl- morpholine N-oxide, 181 mg (1 mmol; 2 eq.) of tetra- methylammonium hydroxide pentahydrate , 57 /.L (2 mmol; 2 eq.) of acetic acid, 0.1 mL of water, and OsO, (4.2 μL of solution prepared using 121 mg OsO,/mL toluene; 0.004 Mol%, 0.004 eq.) at room temperature, a toluene solution (1 mL) of 90 mg (0.4 mmol) of trans-stilbene was added slowly, with a gas-tight syringe controlled by a syringe pump and with the tip of the syringe needle immersed in the reaction mixture, over a period of 24 h. After the addition was completed, 10% NaHSO- solution (2.5 mL) was added to the mixture, and the resulting mixture was stirred for 1 h. Organic materials were extracted with ethyl acetate, and the combined extracts were washed with brine and dried over Na_S0 ₄ . The solvent was evaporated under reduced pressure, and the residual oil was sub¬ jected to column chromatography on silica gel (5 g,

- 70

elution with hexane-ethyl acetate, 2:1 v/v, R_0.17) to afford 67.3 mg (63%) of the diol. The enantiomeric excess of the diol was determined by HPLC analysis of the derived bis-acetate (Pirkle 1A column using 5% isopropanol/hexane mixture as eluant. Retention times are: t. - 22.6 minutes; t- - 23.4 minutes) to be 94%.

____ __£_-£__-__- __ι _-i__-_2£__£i£___-__l--_l-_£_-Yi __-_££_-£__--___. £ _l__£___l__i

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£££_-___-i££ —--£_--£_-££££ To a well-stirred mixture of 116.3 mg (0.25 eq. ) of the p-chlorobenzoate of hydroquinidine, 2 mL of toluene,

175.8 mg (1.5 mmol; 1.5 eq . ) of N-methylmorpholine

N-oxide, 522 mg (2 mmol; 2 eq. ) of tetraethylammonium acetate tetrahydrate, 0.2 mL of water, and OsO, (8.4 μL of solution prepared using 121 mg Os0 ₄ /mL toluene; 0.004 Mol% , 0.004 eq.) at room temperature, a toluene solution (1 mL) of 192 mg (1 mmol) of trans-methyl 4- methoxycinnamate was added slowly, with a gas-tight syringe controlled by a syringe pump and with the tip of the syringe needle immersed in the reaction mixture, over a period of 24 h. After the addition was complete, 10%

NaHSO- solution (5 mL) was added to the mixture, and the resulting mixture was stirred for 1 h. Organic materials were extracted with ethyl acetate, and the combined extracts were washed with brine and dried over Na _o S0, .

2 4

The solvent was evaporated under reduced pressure, and the residual oil was subjected to column chromatography on silica gel (10 g, elution with hexane-ethyl acetate, 2:1 v/v R 0.09) to afford 118.8 mg (53%) of the diol. The enantiomeric excess of the diol was determined by

- 71 -

HPLC analysis of the derived bis-acetate (Pirkle Covalent Phenyl Glycine column using 10% isopropanol/hexane mixture as eluant. Retention times are: t_ - 25.9 minutes; t„ - 26.7 minutes) to be 84%.

Examp_le__J.3. Asymmetric _^ Dihydroxylation of_trans^Stilbene ϊ£___l —E__£ ££ _£______£_-i£—__£____

To a well-stirred mixture of 58.2 mg (0.125 mmol;

0.25 eq) of the p-chlorobenzoate of hydroquinidine, 70 mg (0.6 mmol; 1.2 eq.) of N-methylmorpholine N-oxide, 37 mg (0.6 mmol; 1.2 eq.) of boric acid, 0.5 mL of dichloro¬ methane, and 0s0 ₄ (4.2 μL of a solution prepared using 121 mg OsO /mL toluene; 0.004 Mol%, 0.004 eq.) at room temperature, a dichloromethane solution (1 mL) of 90 mg (0.5 mmol) of trans-stilbene was added slowly, with a gas-tight syringe controlled by a syringe pump and with the tip of the syringe needle immersed in the reaction mixture, over a period of 24 h. After the addition was complete, 10% NaHS0_ solution (2.5 mL) was added to the mixture, and the resulting mixture was stirred for 1 h. Organic materials were extracted with ethyl acetate, and the combined extracts were washed with brine and dried over Na-SO, . The solvent was evaporated under reduced pressure, and the residual oil was subjected to column chromatography on silica gel (5 g, elution with hexane- ethyl acetate, 2:1 v/v, 0.17) to afford 78.3 mg (73%) of the diol. The enantiomeric excess of the diol was determined by H-NMR (solvent: CDC1_) analysis of the derived bis-Mosher ester to be 94%.

72-

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__£____ To a well-stirred mixture of 116.3 mg (0.25 mmol; 0.25 eq.) of the p-chlorobenzoate of hydroquinidine, 175.8 mg (1.5 mmol; 1.5 eq.) of N-methylmorpholine N-oxide, 74.4 mg (1.2 mmol; 1.2 eq.) of boric acid, 1 mL of dichloromethane, and 0s0 ₄ (8.4 μL of a solution prepared using 121 mg OsO,/mL toluene, 0.004 mol%, 0.004 eq.) at room temperature, a dichloromethane solution (lmL) of 192 mg (1 mmol) of trans-methyl 4- methoxycinnamate was added slowly, with a gas-tight syringe controlled by a syringe pump and with the tip of the syringe needle immersed in the reaction mixture, over a period of 24 h. After the addition was complete, 10% NaHSO, solution (5 mL) was added to the mixture, and the resulting mixture was stirred for 1 h. Organic materials were extracted with ethyl acetate, and the combined extracts were washed with brine and dried over Na_S0, . The solvent was evaporated under reduced pressure, and the residual oil was subjected to column chromatography on silica gel (10 g, elution with hexane-ethyl acetate, 2:1 v/v, R 0.09) to afford 151.1 mg (67%) of the diol. The enantiomeric excess of the diol was determined by HPLC analysis of the derived bis-acetate (Pirkle Covalent Phenyl Glycine column using 10% isopropanol/hexane mixture as eluant. Retention times are: t. - 24.0 minutes; t_ — 24.7 minutes) to be 76%.

_-_---__E__£_____ __: Z__ϊ_£._:___k£_____L_l__--_-£________-___££__£_______ ££ _L___ _££_2__L £Z__ E£_i£_____l£__E__ ££££__£f___£____£ Acid

73-

To a well-stirred mixture of 58.2 mg (0.125 mmol; 0.25 eq) of the p-chlorobenzoate of hydroquinidine, 70 mg (0.6 mmol; 1.2 eq) of N-methylmorpholine N-oxide, 72 mg (0.6 mmol; 1.2 eq) of phenylboric acid, 0.5 mL of dichloromethane, and 0s0 ₄ (4,2 μL [of a solution prepared using 121 mg 0s0 ₄ /mL toluene; 0.004 Mol%, 0.004 eq) at 0°C, a dichloromethane solution] (0.5 mL) , 65μL (0.5 mmol) trans- ?-methylstyrene was added slowly, with a gas-tight syringe controlled by a syringe pump and with the tip of the syringe needle immersed in the reaction mixture, over a period of 24 h. After the addition was complete, 10% NaHSO, solution (2.5 mL) was added to the mixture, and the resulting mixture was stirred for 1 h. Organic materials were extracted with ethyl acetate, and the combined extracts were washed with brine and dried over Na_,SO, . The solvent was evaporated under reduced pressure, and the residual oil was subjected to column chromatography on silica gel (5 g, elution with hexane- ethyl acetate, 2:1 v/v, R 0.62) to afford 109 mg (91%) of the phenylborate . The phenylborate was dissolved into acetone (3 mL) and 1 , 3-propandiol (0.5 mL) , and the resulting mixture was stood for 2 h at room temperature. The solvent was evaported under reduced pressure, and the residual oil was subjected to column chromatography on silica gel (5g, elution with hexaneethyl acetate, 2:1 v/v, R _f 0.10) to afford 48.6 mg (70%) of the diol. The enantiomeric excess of the diol was determined by HPLC analysis of the derived bis-acetate (Pirkle 1A column using 0.5% isopropanol/hexane mixture as eluant. Retention times are: t_ = 17.1 minutes; t. - 18.1 minutes) to be 73%.

74-

Exa.m£l_e__14 __en ral__Meth£d_f£r_th _A ymm tri_c

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__£__Σ-_£__i£__-_I-__i£_-_____i-___£-_ To a magnetically stirred suspension of the alkaloid copolymer (such as polymers 2-4, Table 1; 0.25 eq based on alkaloid incorporated), NMO (1.5 eq) , and tetraethyl¬ ammonium acetate tetrahydrate (1.0 eq) in acetone-water (10/1, v/v) a solution of 0s0 ₄ (0.01 eq) in either toluene or acetonitrile was added. After stirring for 10-30 minutes, trans-stilbene (1.0 eq) was added and the reaction mixture was stirred for the given time and monitored by silica gel TLC (hexane-EtOAc 2/1, v/v) . The concentration of olefin in the reaction mixture was 0.3-0.4 M. After the reaction was complete, the mixture was diluted with acetone, water, hexane or ether and centrifuged or filtered to separate the polymer from the reaction mixture. The supernatant was then worked up as described by Jacobsen et al . , J_, Am_. ____ __._ _§ _, ££__, 1.1_0:1968

(1988) .

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__£___-££__£S___£__£i£Σ_.£i_-£ To a well-stirred mixture of the alkaloid polymer (0.05 mmol, based on alkaloid incorporated) , potassium ferricyanide (0.198 g, 0.6 mmol) and potassium carbonate (0.83 g, 0.6 mmol) in tert-butanol (1.5 mL) and water (1.5 mL) , was added OsO solution (0.0025 mmol) in acetonitrile. After stirring for 10 min, trans-stilbene (36 mg, 0.2 mmol) was added and the mixture was stirred for the given time and monitored by silica gel TLC. When

- 75 -

the reaction was complete, water (3.0 mL) was added and the mixture was filtered. The filtrate was extracted with dichloromethane (5 mL x 2) . the organic layer was stirred for 1 h with excess sodium metabisulfite and sodium sulfate. This suspension was filtered and the filtrate was concentrated to provide crude diol, which was purified on a silica gel column.

Examp_l.e_J.6_ Asymmetric Dihydroxylation of Olefins i.n_th _Pre n£e__£f_P£ta__ __um___err__£yan__d The general procedure for asymmetric dihydroxylation of olefins using potassium ferricyanide:

To a well-stirred mixture of 0.465 g (1 mmol, 0.5 equiv — 0.033 M in ligand) dihydroquinidine p-cholorobenzoate (Aldrich, 98%), 1.980 g (6 mmol, 3.0 equiv) potassium ferricyanide, 0.830g (6 mmol, 3.0 equiv) potassium carbonate, and 0.5 mL of a 0.05 M tert-butyl alcohol solution of osmium tetroxide (0.025 mmol, 0.0125 equiv) in 30 mL of a tert-butyl alcohol-water mixture (1:1, v/v) at room temperature, olefin (2 mmol) was added t at once. The reaction mixture was stirred for 24 h at room temperature. Solid sodium sulfite (Na_S0 1.5g) was added, and the mixture was stirred for an additional hour. The solution obtained was concentrated to dryness under reduced pressure, and the residue was extracted with three portions of ether. The combined extracts were dried (Na_S0 ) and evaporated. The residue was purified by column chromatography (silica gel, dichloromethane-ether) .

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- 76 -

To a suspension of dihydroquinidine (4.0 g) in THF (40 mL) was added r _/ -BuLi (2.5 M solution in hexane, 4.95 mL) at 0°C. The ice bath was removed and the reaction mixture stood at room temperature for 10 minutes. To the resulting yellow solution, solid cuprous chloride (1.2 g) was added. After stirring 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 36h. To the resulting mixture, aqNH, OH was added and the mixture was extracted with ethyl ether. The extract was dried over MgSO, . The solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography on silica gel (100 g, elution with ethyl acetate-ethanol , 9:1 v/v, Rf 0.23) to afford 1.77 g(y. 36%) of -O-phenyldihydro- quinidine .

¹ H NMR (CDC1 ₃ ) δ 8/68 (IH, d, J - 4.5 Hz), 8.08 (IH, d, J = 9 Hz), 7.3-7.5 (3H, m) , 7.17 (2H, t, J - 8 Hz), 6.89 (IH, t, J - 8 Hz), 6.78 (2H, d, J - 8 Hz), 6.02 (IH, d, J - 3 Hz), 4.00 (3H, s), 2.7-3.3 (5H, m) , 2.2-2.4 (IH, m) , 1.4-1.9 (6H, m) , 1.1-1.3 (IH, m) , 0.97 (3H, t, J - 7 Hz).

Exam£_. _____ __ _: ΣEE£.__£l£___ _. i __ _: __£ ^x ∑i __i^

U _ln£_2^0__Phen __d__h dr£ u__n_Ld__n __and

_-£_- £i£_-_∑£_-__i£Z££_.__£ To a well-stirred mixture of 46 mg of 9-0-phenyl- dihydroquinidine , 396 mg of potassium ferricyanide, 166 mg of potassium cabonate and 8 μL of a 0.63 M toluene solution of osmium tetroxide in 6 mL of t-butyl alcohol- water (1:1, v/v) at room temperature was added 50 μL of trans-3-hexene all at once. The reaction mixture was

- 77 -

stirred for 20 h at room temperature. Solid sodium sulfite was added and the mixture was stirred for 3 h. The solid was removed by filtration and the filtrate was extracted with ethyl ether. The extract was dried over mgSO, . The solvent was evaporated under reduced pres¬ sure, and the residue was subjected to column chroma¬ tography on silica gel (elution with hexane-ethyl acetate, 2:1 v/v) to afford 40.5 mg (y. 85%) of the diol. The enantiomeric excess of the diol was determined by GLC analysis of the derived bis-Mosher ester to be 83% (5% phenyl-methylsilicone, 0.25 m film, 0.317 mm diameter, 29 m long. Retention times are = 15.6 min; t = 16.0 min. ) .

________E__£-_____ __ Σ_-_-£££_-£-____-Σ_-Ξ_-£_-.£_-££_£_-____- E _ι_i_-_-____£££

__ _-£_-__ _i-__i£££_ι_i_L_i£_-i£_ι_--l--_-__Y--£ ££ _-____ To a well-stirred mixture of 81 mg trans-stilbene,

122 mg of N-chloro-N-sodio- -butylcarbamate , 95 mg of murcuric chloride, 209 mg of 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 at room temperature overnight. Solid sodium sulfite and water were added, and the mixture was stirred at 60°C for 1 hour. The mixture was extracted with dichloromethane and the extract was dried over MgSO, . 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 v/v, Rf 0.13) to afford 131 mg (y. 93%) of the aminoalcohol . The enantiomeric excess of the

- 78 -

aminoalcohol was determined by HPLC analysis (Pirkle Covalent Phenyl Glycine column using 10% isopropanol/ hexane mixture as eluant. Retention times are: t- - 12.7 min; t„ - 15.2 min.) to be 65%. ¹ R NMR (CDC1 ₃ ) 81.1-7.4 (10H, m) , 5.3-5.4 (IH, m) , 4.95 (IH, d, J - 3.5 Hz), 4.8-5.0 (IH, m) , 2.6-2.7 (IH, m) , 1.34 (9H, ).

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ii- £-__E_-£E__Σ__-___££ __-E___EΞ£E£Ξ____£ la: To a room temperature suspension of DHQD (48.9 g, 0.15 mol) in dry DMSO (600 ml) are added NaH (4.0 g, 0.17 mmol) followed by pyridine (12.1 ml, 0.15 mol), Cul (28.6 g, 0.15 mol), and then 9-phenanthryl iodide (45.6 g, 0.15 mol) under argon. After 70 h of reaction at

120°C, la is obtained in 73% yield (55.0 g) . See also: Lindley, J. Tetrahedron, 1984, 40, 1433 and references therein. m.p. 98-100°C, ¹ H NMR (250 MHz, CDC1-): 5-8.7 (m,2), 8.38 (d,l), 8.07 (d,l), 7.75 (m,2), 7.57 (d,l), 7.4 (m,6), 6.63 (s,l), 6.63 (d,l), 4.03 (s,3), 3.38 (m,l), 3.16 (m,l), 2.97 (m,2), 2.78 (m,l), 2.55 (s,br. ,l), 2.39 (t,l), 1.81 (s,l), 1.6 (m,6), 0.98 (t,3). ¹³ C NMR (75 MHz, CDCI ₃ ): S - 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): 1622, 1508, 1452 and 1227 cm -1

[ ]D ²³ - -281.3 (CHCI c - 1.12 g ml ^"1 )

3'

79

lb: To a room temperature suspension of DHQD (65.2 g, 0.20 mol) in DMF (300 ml) are added NaH (6.06 g, 0.24 mol), followed by 2-chloro-4-methylquinoline (42.6 g, 0.24 mol). After stirring for 24 h at room temperature, 2a is obtained in 82% yield (76.3 g) . m.p. 151-153 ^β C. ¹ H NMR (250 MHz, CDCI ₃ ): 8 - 0.93 (3H,t,J

- 7.2Hz), 1.4-1.7 (6H,m), 1.76 (lH,s), 2.12 (lH.t.J - 10.0Hz), 2.61 (3H,s), 2.7-3.0 (4H,m), 3.43 (lH.dd.J - 6.4,8.8Hz), 3.94 (3H,s), 6.82 (lH.s), 7.2-7.6 (6H,m), 7.73 (lH,d,J - 2.5Hz), 7.81 (lH.d.J - 8.0Hz), 7.98(lH,d,J

- 9.2Hz), 8.67 (lH,d,J - 4.6Hz). ¹³ C NMR (CDCI ₃ ) 8 - 11.8, 18.4, 22.9, 25.2, 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 . [c_]D ²¹ - -194.7° (EtOH, c - 1.0). 2a and 2b can be synthesized in a similar fashion. Like the p-chlorobenzoate derivatives, these two new types of ligands are now available from Aldrich.

TyE_££___ __££ __£££____££_-£_i _£ _- _-∑£i£______i_ ∑i£i.Σ£Σ__£££__ £ 2

To a well-stirred mixture of DHQD-PHN la (lOOmg, 0.2 mmol. 0.02 equiv.), K-Fe(CN) , (9.88 g, 30 mmol, 3 equiv.), and K»C0- (4.1-5 g. 30 mmol, 3 equiv.) in a tert-BuOH-H-0 mixture (100 ml, 1/1, v/v) was added potassium osmate (VI) dihydrate (7.4 mg, 0.02 mmol, 0.002 equiv.). The resulting yellow solution was cooled to 0°C and vinylcyclooctane (1.65 ml, 10 mmol) was added. The reaction mixture was stirred for 18 h at 0°C. Na_ _. S0, (7.5 g) was added and the resulting mixture was stirred for 30 minutes. The two phases were separated and the

80 -

aqueous phase was then extracted with CH-C1-. The combined organic solution was evaporated and the residue was diluted with ethyl acetate, washed with 1 M H-S0 ₄ , aqueous NaHC0_ , and brine, and dried. Concentration and flash chromatography affored 1.63 g (95%) of

22 cyclooctylethanediol as a colorless oil; [α]D --4.1"

(EtOH, c-1.0). The ee of the diol was determined by HPLC analysis of the derived bis-MTPA ester to be 93%. The alkaloid ligand was recovered in 82% yield by adjusting the acidic aqueous washes to pH 11 with Na-CO., extracting with CH-C1-.

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This example describes the enantioselectivity-ligand structure relationship of the 9-0-aryl DHQD ligands which explains the advantages of these new ligands.

The enantiometric excesses obtained in the catalytic ADH reactions of various olefins using 9-0-aryl DHQD are summarized in Table 13. These 9-0-aryl DHQD ligands can be easily prepared in one step from commercially available hydroquinidine, NaH, Cul, and the corresponding aryl halide in moderate to good yields (52-70%) , as describe below. Compared to DHQD ^-chlorobenzoate 1,

- 81 -

Table 13: Catalytic Asymmetric Dihydroxylation of Olefins

a All reactions were carried out as described by Kwong, H.-L., et al. , Tetrahe r££_Let _, 10:2041 (1989), except that 25 mol. of ligand was used. Reactions were performed at room temperature. , In all cases the isolated yield of the diol was 75-95%. The enantiomeric excesses were measured by conversion of the diol into the corresponding bisesters of (R) - (+) -α-methoxytrifluoro- methylphenylacetic acid and deterajna n of the ratio of diasteromers by GLC, HPLC, and/or H

9-0-phenyl DHQD 2 is obviously a better ligand for aliphatic olefins, but not for aromatic olefins. By contrast, 9-0-naphthyl 3 and especially, 9-O-phenanthryl

DHQD 4 exhibit much higher enantioselectivities for both aromatic and aliphatic olefins.

In order to obtain information regarding the relationship between ligand structure and enantioselectivity in the ADH, various 9-0-substituted

DHQD derivatives were next examined. The structures of

82-

the 9-O-substituents of these DHQD derivatives and their enantioselectivities for the typical aliphatic and aromatic olefins, trans-5-decene and trans-stilbene are shown in Table 14. Each structure in Table 14 is drawn with its expected spatial orientation in the reaction intermediate, osmate ester such that the more sterically hindering 6-methoxyquinoline moiety is on the left side of the structure

In Group A, those derivatives having a second benzene ring on the right side (1,3 and 4) all give higher ee's for stilbene (99%) than the one (2) without that second benzene ring (94%). In addition, the naphthyl derivative (3) gives higher ee for decene (94%) than does the phenyl derivative (2) (88%) . These two results suggest that the benzene ring on the right side is important for high enantioselectivities with both aliphatic and aromatic olefins. On the other hand, the fact that derivatives (2-4) give much higher ee's for decene (88-96%) than does the p-chlorobenzoate derivative

(1) (79%) shows the importance of the aromatic ring on the left side for aliphatic olefins.

Next, the o-position of the phenyl derivatives was examined (2, 5-7, Group B). While the phenyl-derivative

(2) and the 2- ethylphenyl derivative (6) give fairly high ee's for decene (88, 91%) , the 2-pyridyl (5) and the 2 , 6 -dimethylphenyl (7) derivatives do not produce satisfactory enantioselectivities (71, 50%). This indicates that the left o-position of the phenyl derivative needs to be just C-H for high enantioselectivit . The effect at m- and p-positions can be understood by comparing the derivatives in Group C and D. These results indicate that both the m- and p-positions need to be C-H or larger for high ee's with aliphatic olefins.

-83-

Table 14

-84-

£l£££-_£I£_l£I__--l£----∑E-__l i _£l_--_l2_L£I∑I_____i_.I__ill_ E£-____tl Into a 100 ml 3-necked round-bottomed flask 2.00g

(6.12 mmol) of dihydroquinidine (Note: All addition of reagents and reaction were done under argon) and 0.160g (6.73 mmol) of NaH were dissolved in 20ml of dimethylsulfoxide . After stirring for about 10 minutes the reaction mixture became a clear orange-yellow solution. At this point, 1.17g (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

- 85 -

heated for 3 days at 120°C. Then the reaction mixture was allowed to cool down 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 two times with dichloromethane (20 ml) . The organic phases were combined, washed three times with water (10 ml) , and evaporated. The resulting residue was then purified by column chromatography (silica gel, using 5% methanol/ethyl acetate as the eluting solvent) , yielding slightly yellow crystals of 9-0-naphthyl DHQD (3) (yield: 70%) or -O-phenanthryl DHQD (4) (yield: 52%) respectively.

(3): m.p. 75-77°C. NMR (250 MHz, CDCI-,): 8 - 8.60 (dd,2), 8.05 (dd,l), 7.80 (d,l), 7.4 (m,5) , 7.07 (t,l), 6.42 (d,l), 6.24 (d,l), 3.99 (s,3), 3.31 (dt,l), 3.17 (dd.l), 2.92 (dd,2), 2.78 (m.l), 2.37 (m,2), 1.79 (s,br., 1) , 1.6 (m,6) , 0.96 (t,3). ¹³ C NMR (75 MHz, CDCI ₃ ): 8 - 158.2, 150.4, 147.5, 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) : v - 1622, 1508, 1452 and 1227 cm ^"1 . [α]D ²³ - -281.3 (CHCI.., c = 1.12g ml ^"1 ) The 9-0-aryl DHQD (3) and (4) were prepared according to the Ullmann phenyl ether synthesis: Lindley, ^J -» Tetrahedron, 40:1433 (1984) and references therein.

All these 9-0-substituted DHQD derivatives (5) , (9) and (10) were synthesized at room temperature without copper(I) iodide.

-86-

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A high level of asymmetric induction was achieved in the asymmetric dihydroxylation of a wide variety of olefins using 9-0-aryldihydroquinines as ligands. (B. Lohray, et al . , Tetrahedron_Le11__, __0:2041 (1989))

The asymmetric dihydroxylation using catalytic amounts of osmium tetroxide and cinchona alkaloid derivatives is one of the few examples of reactions combining high levels of enantioselectivity for a large range of substrates, good to excellent yields, simple and mild experimental conditions. Another point worth emphasizing, is the availability of the requisite cinchona alkaloids . Both enantiometers of the diol can be obtained choosing dihydroquinine (DHQ) or dihydroquinidine (DHQD) derivatives):

dihydroq

dihydro

1 a,b R:

- 87 '

Recent advances in our group using potassium ferricyanide as stoichiometric oxidant and new aryl and heteroaromatic derivatives of the dihydroquinindine and dihydroquininine have made it possible to obtain good to excellent yields and enantioselectivities for many different kinds of substrates. (H-L. Kwong, et al. , Tetrahedron Lett. , 21:2999; M. Minato , et al. , J. Org. ____£____ _> ____'766 (1990); T. Shibata, et al . , Tetrahedron Lett. , 3__:3817 (1990); In this example we report details about the 9-0-aryldihydroquinines 2a-4a. The trend for the dihydroquinine and dihydroquinidine derivatives are very similar (see Table 15). As in the dihydroquinidine series, the DHQ phenanthryl ether derivative 4a is greatly superior to la for a wide range of substrates. The improvement is especially dramatic for transdisubstituted aliphatic olefins such as 5-decene (entry 1) as well as for terminal saturated olefins (entries 6 and 7) and for alkyl substituted a, β unsaturated carbonyl compounds (entry 3) . The changes observed in case of aromatic olefins (entries 4 and 5) were slight.

-88

Table 15

K ₃ Fe(CN) ₆ /K ₂ C0 ₃

ee using la ee using 2a ee using 3a ee using 4a entry olefin (ee using lb) (ee using 2b) (ee using 3b) (ee using 4b)

1 ->Bu«S - _Bu 70% (79%) 75% (88%) ^' 86% (94%) 91% (96%)

[93%]0°C Ni 67% (74%) 75% (83%) 82% (92%) 85% (94%)

P ^> Ph 97% ( 99% ) 93% ( 94% ) 94% ( 99% ) 96% ( 99% )

© ^" * 66% (74%) 57% (61%) 62% (72%) 69% (73%)

₆ 1-decene 41% (45%) 44% 56% (66%) 63%

All but the three indicated reactions were carried out at room temperature. In all cases the isolated yield was 70-95%. Enantiomeric excesses were determined by GC or HPLC analysis of the derived bis-Mosher esters.

- 89

Unlike the difference observed using the dihydroquinidine derivatives , the gap in enantioselectivities between naphthyl-DHQ and phenanthryl-DHQ is significant (Δee - 2-10% at RT versus 1-4% for DHQD derivatives). Especially noteworthy is the fact that the differences of selectivities obtained using 4a and 4b is very small for all examples in Table 12 and therefore enantiomers of the diol are available in almost the same optical purity. The reaction can be successfully carried out at 0°C with a significant improvement of enantioselectivity especially for terminal olefins (entries 1,3 and 7). In conclusion, we want to point out that from a large variety of olefinic substrates, it is now possible to obtain vicinal diols in excellent yields, with good to excellent enantiomeric enrichments for both diol enantiomers using either dihydroquinine or dihydroquinidine .

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Dihydroquinidine (1.4 g, 4.3 mmol, 1 eq) was dissolved in 15 ml of CH_C1- under nitrogen atmosphere in a 3-necked 100 ml round bottom flask. 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 CH_C1_ and added to the reaction mixture dropwise via an addition funnel. The reaction mixture was stirred under N_ for three days before reaching reaction completion. 50 ml of 2N NaOH were added, and the phases were separated. The CH Cl

-90-

layer was saved, and the aqueous phase was extracted with 50 ml of CH_C1_. The CH-C1- phases were combined and dried over MgS0 ₄ before being concentrated down to afford a gummy pink material. Purification via flash chromatography (silica gel, 95.5 Et0Ac/Et-,N, v/v) afforded a yellow material which was then crystallized from CH,CN to obtain white starlike crystals (1.27 g, 65% yield) . Characterization: mp . 119-120° C. High resolution mass spec; calculated molecular mass -459.25217 amu, found-459.2519 amu. ¹ H NMR (300 MHz, CDC1 ₃ with TMS); 8.7 8 (d, IH) , 8.0 8 (d.lH) , 7.2-7.4 8 (m, 7H) 6.4 8 (d, IH) , 3.8 8 (s,3H), 3.3 8 (s,3H), 3.1 8 (IH) , 2.8 8 (q, IH) , 2.6 8 (m, 3H) , 1.7 8 (s,2H), 1.3-1.4 8 (m7H) , 0.9 8 (t, 3H) .

¹³ C NMR (75 MHz, CDC1 with TMS): 12.1 8, 23.9 8, 25.3 8, 26.2 8, 27.3 8, 37.5 8, 38.2 8, 49.8 8, 50.7 8, 55.5 8, 59.7 8, 75.6 8, 75.6 8, 101.8 8, 119.1 8, 121.8 8, 126.3 8, 126.7 8, 127.3 . , 129.1 8, 131.7 8, 143.1 5, 144.7 8, 144.9 8, 147.5 8, 152.1 8, 154.8 8, 157.7 8.

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_____- £__ Typical Procedure for the Catalytic ADH (£__s- ?- methylstyrene) :

To a well-stirred solution of DHQD-MPC (dihydroquinidine methylphenylcarbamate) (10 mg, 0.02 mmol, 0.10 equiv) , K-Fe(CN) ₆ (200 mg , 0.6 mmol, 3 equiv) , K ₂ C0 ₃ (85 mg , 0.6 mmol, 3 equiv) in a tert-butanol/water solution (6 ml, 1/1, v/v) , osmium tetroxide was added in acetonitrile

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solution (0.5 M, 4 μl, 0.01 equiv) at room temperature. After stirring for ten minutes, cis-β-methylstyrene (26 μl , 0.2 mmol) was added. The reaction mixture was stirred at room temperature, and reaction progress was monitered by thin layer chromatography. Upon reaction completion (less than two hours), the phases were separated. The aqueous phase was extracted with CH-C1-. The tert-butanol and CH-C1- fractions were combined and stirred for one hour with excess sodium metabisulfite and sodium sulfate. Concentration followed by flash chromatography afforded the diol (24.4 mg, 82% yield) as an off-white solid. Enantiomeric excess (ee) of the diol (46% ee) was determined by GC analysis of the bis-MPTA ester derivative.