Method for asymmetric epoxidation

Methods and compositions are provided for asymmetrically donating an oxygen atom to a pair of electrons to produce an asymmetric product. Specifically, a metal alkoxide is used as a catalyst, where the metal has a coordination number of at least four, and at least one, usually two, of the alkoxide groups bonded to the metal are bonded to asymmetric carbon atoms. The metal catalyst is employed in conjunction with a hydroperoxide and an alkanol having a functionality with a pair of electrons capable of accepting an oxygen atom. The resulting product is enriched in one enantiomer due to the enantioselective introduction of an asymmetric center or an enhanced rate of reaction of one of the enantiomers of a chiral alkanol.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The ability to introduce a chiral center stereospecifically or resolve a 
racemic mixture has broad industrial applications. Natural products having 
chiral centers are normally stereoisomeric, with only one of the 
stereoisomers being physiologically active. Where synthesizing or 
modifying a natural product involving the formation of a stereoisomeric 
center, the ability to introduce the functionality asymmetrically is of 
extreme economic importance. Where only one enantiometer is active, not 
only is half of a racemic product inactive, but where it is required to 
separate the inactive product, the recovery of the desired stereoisomer 
results in further losses of the desired product. In synthetic procedures 
involving a number of steps, an intermediate or final step resulting in a 
yield less than 50% will seriously affect the economics of the synthetic 
approach. 
Furthermore, with polymers, stereoregularity can provide for greatly 
enhanced physical properties. Because asymmetric compounds other than 
naturally occurring compounds are frequently costly, stereoregular 
polymers of asymmetric monomers have not found extensive use. 
There has been, therefore, a continuing interest in being able to prepare 
compounds by asymmetric induction to provide a product having enhanced 
amounts of a particular stereoisomer. 
2. Description of the Prior Art 
Methods of asymmetric synthesis may be found in J. D. Morrison and H. S. 
Mosher, "Asymmetric Organic Reactions," Prentice-Hall, Englewood Cliffs, 
N.J., 1971 258-62; S. Yamada et al. J. Am. Chem. Soc., 99, 1988 (1977); R. 
C. Michaelson et al. ibid., 99 1990 (1977); H. B. Kagen et al. Angew. 
Chem. Int. Ed. Eng., 18 45 (1979) K. Tani et al., Tetrahedron Lett., 3017 
(1979); and H. Wynberg and B. Marsman, J. Org. Chem., 45 158 (1980); K. B. 
Sharpless and T. R. Verhoeven, Aldrichimica Acta, 12 63 (1979). Tani et 
al., Tetra. Letters 32, 3017-3020 (1979) describe the use of molybdenum 
catalysts to symmetrically epoxidize olefinic hydrocarbons in the presence 
of chiral diols. 
SUMMARY OF THE INVENTION 
Methods and compositions are provided for asymmetric transfer of oxygen 
from a hydroperoxide to a functionality having a pair of electrons capable 
of accepting an oxygen atom to form a covalent bond to provide oxides 
(includes epoxides) and for kinetic resolution to high optical purity. The 
method employs a metal alkoxide catalyst where the metal has a 
coordination number of at least four, and at least one of the alkoxides 
bonded to the metal is asymmetric. The catalyst, substrate and 
hydroperoxide are combined in an inert medium under mild conditions for a 
time sufficient to oxidize the substrate and the asymmetrically oxidized 
product and/or unreacted starting material isolated or further transformed 
as desired.

DESCRIPTION OF THE SPECIFIC EMBODIMENTS 
Method and compositions are provided for asymmetric induction involving 
transfer of an oxygen atom from a peroxide to a functionality in an 
alkanol having a pair of electrons capable of accepting the oxygen atom to 
form a bond, usually stable. The primary constituents of the method are 
the metal catalyst having an asymmetric alkoxide as a ligand; the alkanol, 
and the peroxide. In discussing the subject invention, the components 
indicated above will first be described, followed by a description of the 
method, setting forth any other components and conditions employed in the 
method. 
COMPOSITIONS 
Catalysts 
The catalysts employed in the subject method involve metal alkoxides, where 
the metal has a coordination number of at least four, usually six, and 
wherein at least one of the alkoxides bonded to the metal is asymmetric. 
The metal will be a metal of Groups 4b to 6b of atomic number 22 to 74, 
particularly those metals of groups 4b to 5b of atomic number 22 to 73 of 
the Periodic Chart. (Handbook of Chemistry and Physics, 44th ed. Chemical 
Rubber Publishing Co., pp. 448-9). The metals of interest include 
titanium, tantalum, zirconium, hafnium, niobium, vanadium, and molybdenum, 
particularly the first four metals indicated and more particularly 
titanium and tantalum. 
The asymmetric alkoxide can be a monool or a diol, particularly a vicinal 
diol or 1,3-diol. That is, the hydroxyl groups will be separated by from 
two to three carbon atoms. Normally, in the diols, both of the hydroxyls 
will be enantiomeric and usually of the same configuration, rather than 
opposite configuration. That is, both of the chiral centers will be R or 
S, rather than one being R and the other being S. The asymmetric alkoxide 
may be water soluble or insoluble. 
The remaining portion of the asymmetric alkoxide molecule, particularly of 
the glycol, may be hydrocarbon, which includes aliphatic particularly 
alkyl, alicyclic, aromatic, or combinations thereof; substituted 
hydrocarbon, where the substituent can be of a wide variety of groups, 
since the substituent will normally not play a critical role in the 
reaction, but must not be a reactive group which interferes with the role 
of the catalyst, so that any inert (unreactive) substituent may be 
employed; or a functionality, which is unreactive, and desirably has an 
oxygen and/or neutral nitrogen bonded to carbon. The significant factor in 
all of the substituents is that the functionalities present, if any, must 
not react with the reactants in the medium to interfere with the transfer 
of the oxygen atom, nor to provide a product which results in the 
formation of water. 
The chiral alkanols (including glycols) will be monomeric or polymeric, 
when monomeric will be of at least three carbon atoms, usually at least 
four carbon atoms, having one or more alkanolic hydroxyl groups, usually 
not more than three hydroxyl groups, preferably two hydroxyl groups, which 
are separated by two to three carbon atoms and will generally have not 
more than about 30 carbon atoms, more usually not more than about 20 
carbon atoms, and most usually not more than about 10 carbon atoms. The 
number of heteroatoms other than the oxygens of the hydroxyls will be from 
0 to 12, more usually from 0 to 10, preferably from 2 to 10, and more 
preferably from 2 to 6. The heteroatoms will for the most part be 
chalcogen, nitrogen and halogen. 
Functionalities will include oxygen as oxo:oxocarbonyl, and 
non-oxo-carbonyl; and oxy bonded solely to carbon and such other 
functionalities which will be described subsequently; sulfur, bonded 
solely to carbon, nitrogen and chalcogen (sulfur and oxygen), which sulfur 
when present as thioether, under the conditions of the reaction, will 
normally be oxidized to sulfoxide or sulfone, which groups are also 
included, sulfonate ester and sulfonamide; nitrogen, normally as non-basic 
amino, particularly tertiary, or amide; halogen, normally as aryl halogen, 
usually of atomic number 9 to 17. The chiral alkoxide is desirably free of 
ethylenic unsaturation, since under the conditions of the reaction such 
ethylenic bonds could be oxidized. Preferably the chiral alkoxide will be 
a secondary alkoxide. 
As for other heterofunctionalities, except for those alpha to the carbinol 
group, since they will normally not participate in the reaction, they will 
only be chosen where they provide some advantage in isolation, solubility, 
or the like. 
The polymeric chiral carbinol can be an addition or condensation polymer 
having side chains coming within the monomeric chiral alkanol definition. 
The number of chiral carbinols bonded to the metal will be at least one, 
normally two and may be more, although optimum results are obtained with 
two chiral centers bonded to the metal. The catalyst may have from one to 
two metal atoms in a molecule. 
The non-chiral alkoxides bonded to the metal may be any hydroxyl 
functionality free of interfering groups, but will conveniently be 
aliphatic alcohols, generally of from 1 to 12, more usually of from 1 to 6 
carbon atoms. Preferably, the alkoxides will be relatively bulky, having 
from 3 to 6 carbon atoms, preferably being branched at the alpha carbon 
atom, normally one to two branches. Particularly preferred is isopropoxide 
and tert.-butoxide. It should be clearly understood, that the alkanols are 
solely chosen for convenience and any carbinol may be employed, so long as 
the substituents on the carbinol do not interfere with the course of the 
reaction. As to all of the components of the reaction mixture, acidic 
groups e.g. carboxylic and sulfonic acids, and basic amino groups should 
be avoided. Illustrative alkoxides include methoxide, ethoxide, propoxide, 
isopropoxide, butoxide, tert.-butoxide, hexoxide, and the like. 
The preparation of the catalyst is conventional and can be performed in 
situ. The alkoxide substituted dihalo metal may be combined with the 
chiral alkoxide of an appropriate metal e.g. lithium or sodium, in an 
inert polar solvent, and the product separated from the inorganic salt. 
More conveniently, the polyalkoxide of the metal may be combined with the 
chiral alkoxide in approximately stoichiometric amounts in an inert 
solvent. There is no requirement that the alcohol which is formed be 
removed. 
Compounds which are illustrative of the chiral carbinols are as follows: 
TABLE I 
1,2-propylene glycol 
2,3-butanediol 
3,4,-dimethyl-3,4-hexanediol 
4,5-octandiol 
2,3,-hexandiol 
1,3-di(p-nitrophenyl)propan-1,2-diol 
2,4-pentanediol 
dimethyl tartrate 
diisopropyl tartrate 
distearyl tartrate 
diphenyl tartrate 
tartaric acid diamide 
N,N-dimethyl tartaric acid diamide 
trans-1,2-cyclopentandiol 
diethyl 1,2-cyclohexandiol-1,2-dicarboxylate 
dimethyl 2,4-dihydroxyglutarate 
ethyl N,N-diethyl tartrate monoamide 
2,5-dioxo-3,4-octandiol 
1,2-bis-acetylethylene glycol 
bis-2,2'-(2-hydroxycaprolactone) 
Of particular interest as catalyst are compounds combining di(alpha-oxo 
substituted) vicinal glycols in combination with titanium, where the ratio 
is one glycol and two alkoxides per titanium. For the most part, the 
catalyst will have the following unit formula: 
##STR1## 
wherein: 
R is a non-interfering group, conveniently alkyl of from 1 to 8 carbon 
atoms, usually of from 1 to 6 carbon atoms, more usually of from 2 to 4 
carbon atoms and particularly as described previously for the non-chiral 
carbinol; 
the two Ds are the same or different and are hydrogen, alkyl of from 1 to 
6, more usually 1 to 4, preferably 1 to 2 carbon atoms or two Ds may be 
taken together to form a ring with the carbons to which they are attached 
of from 4 to 8, usually from 5 to 6 carbon atoms, preferably hydrogen; 
* intends an asymmetric carbon bonded to the other asymmetric carbon to 
define a vicinal glycol. 
A is saturated hydrocarbyloxy of from 1 to 12, more usually of from 1 to 6, 
preferably of from 1 to 4 carbon atoms, usually aliphatic and free of 
aliphatic unsaturation, hydrocarbyl of from 1 to 12, usually of from 1 to 
6, more usually of from 1 to 4 carbon atoms, particularly alkyl, amino, 
alkylamino and dialkylamino, where each of the alkyl groups is of from 1 
to 6, more usually of 1 to 4 carbon atoms, or the two As may be taken 
together to form a carbocyclic ring of from 5 to 7 carbon atoms; the two 
As may be the same or different and where one of the As is amino, it is 
preferred that the As be different. 
Based on evidence of the results with the use of mixtures of chiral 
alkoxides with titanium it is believed that the catalyst is oligomeric, 
particularly dimeric. The dimeric catalyst will for the most part have the 
following formula: 
##STR2## 
where the symbols have all been defined previously. 
Substrate 
The substrate employed for the above described catalyst is characterized by 
having a carbinol group, which may or may not be asymmetric, being chiral 
or prochiral, and a functionality having a pair of electrons which is 
capable of accepting an oxygen atom to form a covalent bond. The chirality 
may be at the carbinol or at some other site in the molecule, usually not 
too remote from the carbinol preferably within about ten atoms. The oxygen 
accepting functionality will be separated from the carbinol carbon by from 
0 to 2, usually 0 to 1 carbon atoms. Where the functionality is an 
aliphatically unsaturated group i.e. a double or triple bond, the multiple 
bond will normally be separated by from 0 to 2 atoms, usually 0 to 1 atom, 
preferably being bonded to the carbinol carbon. Where the functionality is 
other than the multiple bond, the functionality will normally be separated 
from the carbinol by from 1 to 3 atoms. The separating atoms are normally 
carbon atoms. 
The atom separation indicated is directed to a spatial relationship between 
the hydroxyl of the carbinol and the oxygen accepting functionality. There 
will be instances where the hydroxyl of the carbinol and the oxygen 
accepting functionality will be separated by many more atoms than 
specified above, but within the spatial requirements for asymmetric 
transfer of oxygen to the oxygen accepting functionality, the unbonded 
distance will fulfill the spatial requirement. Because these compounds 
will be a relatively narrow class of compounds and normally have special 
constraints, there is no simple way to describe them, but it should be 
understood that they could be employed in the subject invention, although 
outside the literal limitations indicated above. 
Substrates will be employed for two purposes. The first purpose will be 
enantioselective epoxidation. Usually, with a chiral carbinol, one 
enantiomer of the erythro diasteriomer results. The second purpose will be 
to resolve a racemic mixture of a chiral carbinol by preferential 
oxidation of one of the enantiomers to provide optically active product 
and optically active starting material of the opposite configuration. 
The functionalities which may be present for the oxidation to produce the 
enantiomer will normally be nitrogen or third row elements of atomic 
number 15 to 16, which elements are capable of accepting an oxygen atom to 
form a stable covalent bond. For the most part, these elements will be 
phosphorus and sulfur. These atoms should be free of functionalities which 
would react adversely either with catalyst or the hydroperoxide. That is, 
the atoms should be free of readily oxidizable hydrogen and carbon bonds. 
Particular, sulfur is the preferred functionality i.e. thioether. 
Usually the oxygen accepting atom will be bonded solely to carbon, nitrogen 
and oxygen. 
The substrates may be of from 3 to any number of carbon atoms since 
monomers, oligomers and polymers may be employed. Where monomeric 
compounds are involved, the monomers will be from about 3 to 60 carbon 
atoms, more usually from about 3 to 50 carbon atoms, and generally from 
about 4 to 40 carbon atoms. Higher yields are frequently obtained where 
the product is water insoluble, that is, having a solubility of less than 
about 1 gram per 100 ml at 20.degree. C. Therefore, when feasible, where 
small molecules are involved as a substrate, to enhance the yield, the 
compound may be modified to reduce its water solubility. This can be 
achieved by introducing a removable functionality at a site remote from 
the oxidizable functionality. 
The allylic groups may be mono-, di-, tri-, or tetra-substituted with 
aliphatic, alicyclic or aromatic groups, particularly aliphatic and 
alicyclic groups, and the olefin may be exocyclic or endocyclic. The 
olefin should be allylic, homoallylic or bishomoallylic, particularly 
allylic. The propargyl group may be mono- or disubstituted. 
Where a heteroatom is involved, it will be desirable that the heteroatom be 
bonded stably by non-oxidizable bonds to its substituents. For example, 
phosphorus should be present as phosphite or phosphinite, sulfur would be 
bonded to carbon and from zero to one oxygen or nitrogen. Nitrogen will 
normally be amino and bonded solely to carbon. The functionality may 
therefore be bonded directly to carbon or bonded through an oxygen to 
carbon. 
For the most part, the substrates will have the following partial formula: 
##STR3## 
wherein: 
where one of the atoms bonded to the carbinol carbon will usually be 
hydrogen, 
n is 0 to 3 being 0 to 2 when G is an olefin and 1 to 3 when G is other 
than an olefin; 
T can be any inert group, free of active functionalities such as basic 
amines and acidic groups; and 
G is a group having a functionality having a pair of electrons capable of 
accepting an oxygen atom to form a bond and will normally be of at least 
one carbon atom and may be 60 carbon atoms or more, more usually not more 
than about 30 carbon atoms and has as the group having an oxygen accepting 
pair of electrons, a functionality such as alkene, alkyne, or a 
heterofunctionality having phosphorus or sulfur. 
In view of the enormous diversity of carbinols, which may be employed as 
substrates, only various classes of products of interest can be suggested 
as useful in the subject process, either for synthesis of the particular 
product or for modification of an existing product, particularly a natural 
product. 
The subject invention can be used in organic syntheses of enantiomers both 
for introduction of a variety of functionalities in a synthetic procedure 
and optical resolution of an enantiomer from a racemic mixture. The sole 
requirements for use of the subject invention in syntheses and/or 
resolution are the presence of (1) an hydroxyl group; (2) normally a 
chiral or prochiral center, which may or may not involve the hydroxyl, and 
(3) a functionality capable of accepting an oxygen atom to form a covalent 
bond, particularly aliphatic unsaturation, more particularly, ethylenic 
unsaturation. 
General classes of compounds of interest include steroids, lipids, 
prostaglandins, terpenoids, hormones, saccharides, CNS drugs, .alpha.- and 
.beta.-andrenergic blocking agents, antiarrythmic drugs, vasodilator 
drugs, analgesics, antibiotics, amino acids, and the like. 
Illustrative compounds of interest for applying the subject invention in 
their synthesis and/or resolution include the acetonide of 
2-methyl-1,3,4-trihydroxybutane, propanolol, 4-amino-3-hydroxybutyric 
acid, bestatin, .alpha.-methyldopa, propoxyphene, sphingosine, muscarine, 
ipsdienol, frontalin, acosamine, daunosamine, 4-deoxydaunosamine, 
ristosamine, vancosamine, epivancosamine, sibrosamine, gulono-1,4-lactone, 
cerulenin, spectinomycin, erythromycin, N-acetyl galactosamine, N-acetyl 
muramic acid, N-acetyl neuraminic acid, perillyl alcohol, methyl 
tetradeca-2,4,5-trienoate, disparlure, etc. 
The following are a few synthetic procedures illustrating preparation of 
compounds employing the subject invention. Where the reagents involved are 
conventional, they are frequently omitted. The step(s) involving the 
subject invention is indicated by an asterisk. 
##STR4## 
Hydroperoxide 
The hydroperoxides will usually be aliphatic hydroperoxides. The 
hydroperoxides may be mono- or polyhydroperoxides, usually having not more 
than two hydroperoxide groups. For the most part, the hydroperoxides will 
be monohydroperoxides. The hydroperoxides will be from about 1 to 20 
carbon atoms, more usually from 1 to 12 carbon atoms, particularly alkyl 
hydroperoxides having acceptable thermal stability, which for the most 
part will be secondary or tertiary hydroperoxides. 
Illustrative hydroperoxides include tert.-butyl hydroperoxide, alpha, 
alpha-dimethylheptylhydroperoxide, bis-diisobutyl-2,5-dihydroperoxide, 
1-methylcyclohexylhydroperoxide, cumene hydroperoxide, and cyclohexyl 
hydroperoxide. 
Method 
As the reaction medium, inert solvents will be employed, particularly 
halohydrocarbon solvents. The solvent should be relatively free of 
reactive protons, (particularly acidic) such as are present in alcohols, 
mercaptans, acids, or the like, but ethers can find use. The solvent 
should also be anhydrous, care being taken to remove substantially all of 
water to avoid catalyst hydrolysis. 
Mild conditions will normally be employed, with temperatures below about 
80.degree. C., usually below about 30.degree. C., and generally in the 
range of about -100.degree. to 20.degree. C., more usually in the range of 
about -50.degree. to 10.degree. C. The reaction is preferably carried out 
under an inert atmosphere, conveniently nitrogen. 
The catalyst can be preprepared or conveniently prepared in situ. In 
preparing the catalyst, the metal alkoxide may be combined with the chiral 
alcohol, in a dry inert solvent at a temperature below 30.degree. C. and 
in about stoichiometric proportions, although small excesses, generally 
less than about 50 mol % of the chiral carbinol may be employed. The 
reaction is then allowed to proceed for a sufficient time for the catalyst 
to form. 
The catalyst can be preprepared by combining the metal alkoxide e.g. 
titanium tetralkoxide, the chiral alcohol e.g. tartrate ester, amide or 
half-ester amide, in at least stoichiometric proportions, generally not 
more than 50 mol % excess of the chiral alcohol, in an inert solvent and 
distilling off the alcohol from the alkoxide to drive the reaction to 
completion and remove the alcohol which appears to have an adverse effect. 
Usually, the reaction forming the catalyst is complete in less than 30 min, 
more usually less than about 15 min. This will depend to some degree on 
the size of the reaction mixture, the concentrations employed, as well as 
the particular reactants. The time is not critical and will be optimized 
for a particular set of conditions and materials. 
The amount of catalyst which is prepared in relation to the substrate may 
be varied widely, depending upon the nature of the substrate, the rate of 
reaction desired, the conditions under which the reaction is carried out, 
the concentrations employed, and the economics. Normally, there will be 
from about 0.001 to 1.5, more usually about 0.01 to 1 mole of catalyst per 
mole of substrate. 
After a sufficient time for the catalyst to form, the substrate is added, 
while maintaining the temperature. After the addition of the substrate, 
the hydroperoxide is normally added in at least stoichiometric amount, and 
preferably in significant excess, usually at least 25% excess, more 
usually at least 50% excess, and not more than about 500% excess, usually 
not more than about 300% excess. That is, about 1 to 3 equivalents, 
preferably about 2 to 3 equivalents of the hydroperoxide will be used per 
equivalent of functionality to be oxidized. 
The concentrations of the various materials may be varied widely, the 
catalyst normally being from about 0.005 to about 2M, preferably being 
from about 0.05 to 1M. The concentrations of the other reactions will be 
related accordingly. 
After all the reactants have been combined in the inert medium, the 
reaction is continued until the substrate has been transformed to the 
desired degree. For a kinetic resolution, this may vary depending on 
whether the product or reactant is desired. The rate of the reaction 
varies depending upon the conditions and the amount of material involved, 
and may vary from a few minutes to a few days. 
After completion of the reaction, the catalyst is destroyed using a mildly 
acidic aqueous solution, and where the oxidized substrate is in the 
organic layer, the organic layer isolated, dried and the product isolated. 
For water soluble products, salting out, extraction or chromatography may 
be required. Purification of the product may then be carried out in 
accordance with conventional means. 
For water soluble substrates, conveniently an inorganic salt saturated 
aqueous solution e.g. saturated aqueous sodium sulfate, is added at a 
ratio of about 1 ml per mmole of substrate to the mixture, to effect 
destruction of the catalyst, in combination with a polar organic solvent 
e.g. diethyl ether, tetrahydrofuran, acetonitrile, etc., in about 1-2 ml 
per mmole of substrate. Temperature will generally range from about 
0.degree. C. to ambient. After filtration, the organic solvent can then be 
dried and the product isolated. 
The following examples are offered by way of illustration and not by way of 
limitation. 
EXPERIMENTAL 
A typical procedure is provided with comments (as appropriate) indicating 
the function of the particular condition, so that with other reactants, 
conditions can be varied accordingly. 
A 500 ml, 1-necked round-bottomed flask equipped with a Teflon-coated 
magnetic stirring bar was oven-dried, then fitted with a serum cap and 
flushed with nitrogen. The flask was charged with 200 ml of dry (distilled 
from CaH.sub.2) reagent grade dichloromethane and cooled by stirring in a 
-23.degree. C. bath (dry-ice/CCl.sub.4).sup.(a) Then the following liquids 
were added sequentially via syringe while stirring in the cooling bath: 
5.94 ml (5.68 g, 20 mmol) titanium tetraisopropoxide (Aldrich); 3.43 ml 
(4.12 g, 20 mmol).sup.(b) L(+)-diethyltartrate stirred five minutes before 
next addition; 3.47 ml (3.08 g, 20 mmol) of geraniol; and, finally, ca. 11 
ml of dichloromethane solution (3.67M in TBHP) containing ca. 40 mmol (2 
equiv) of anhydrous tert-butyl hydroperoxide (TBHP). [One can just as well 
use dichloroethane, carbon tetrachloride or hexane solutions of anhydrous 
TBHP. Complete experimental details for preparing these anhydrous TBHP 
solutions are given in Sharpless and Verhoeven supra.] 
The resulting homogeneous solution was then stored overnight (ca. 18 hrs) 
in the freezer at ca. -20.degree. C. in the sealed (serum cap) reaction 
vessel [The progress of the epoxidation can be monitored by TLC]. Then the 
flask was placed in a -23.degree. C. bath (dry ice/CCl.sub.4) and 50 ml of 
10% aqueous tartaric acid solution was added while stirring; the aqueous 
layer solidified. After 30 minutes the cooling bath was removed and 
stirring was continued at room temperature for 1 hr or until the aqueous 
layer became clear. After separation of the aqueous layer, the organic 
layer was washed once with water, dried (Na.sub.2 SO.sub.4), and 
concentrated to afford a colorless oil with an odor revealing 
contamination by TBHP. 
This oil was diluted with 150 ml of ether and the resulting solution was 
cooled in an ice-bath, then 60 ml of 1N sodium hydroxide solution was 
added. This produced a two-phase mixture which was stirred at 0.degree. C. 
for 1/2 hr..sup.(c) The ether phase was washed with brine, dried (Na.sub.2 
SO.sub.4) and concentrated to give 4.24 g of a clear oil. Chromatography 
on silica gel afforded 2.6 g (77%) of 2(S),3(S)-epoxygeraniol, 
[.alpha.].sup.24.sub.D -6.36.degree. (cl.5, CHCl.sub.3). Analysis of this 
material as the MTPA ester.sup.(d) gave an enantiomeric excess of &gt;95%. 
Whereas, analysis of the derived expoxyacetate using Eu(hfbc).sub.3 chiral 
shift reagent gave 94% e.e. 
(a) Cooling serves two purposes. The obvious one of optimizing 
enantioselectivity, and the less obvious one of minimizing 
transesterification processes. Titanium alkoxides are excellent 
transesterification catalysts, and there is an extensive patent literature 
on this subject. We have now found that the rate of transesterification is 
substantially accelerated by an .alpha.-hydroxy substituent. Thus, in the 
presence of Ti(OiPr).sub.4 methyl mandelate transesterifies much faster 
than methyl phenylacetate. As .alpha.-hydroxy esters, the tartrates also 
undergo rather facile transesterification in our reaction system at room 
temperature. This produces tartrate esters which incorporate i-propanol 
and also the allylic alcohol substrate, and can give rise to problems at 
the product isolation stage. Fortunately, transesterification is slow at 
-20.degree. and running the reactions near that temperature has so far 
proved a viable solution to the problem. 
(b) It is important to have at least one mole of tartrate per mole of 
Ti(OR).sub.4. Excess tartrate does not seem to matter, so a small excess 
(10 to 20 mole %) is added. In kinetic resolutions an excess of 20 mole 
percent or more is commonly added. 
(c) Do not expose the reaction mixture to this base treatment for longer 
than 1/2 hr as base-catalyzed rearrangements of the epoxyalcohol may occur 
[G. B. Payne, J. Org. Chem., 27, 3819 (1962)]. Alternatively 1N NaOH in 
saturated brine may be employed. Diethyl tartrate is fairly soluble in 
water and hydrolyzes readily under these conditions. We have found that 
(+)-dimethyl tartrate (Aldrich) is as effective (&gt;95% e.e.) as the ethyl 
ester for epoxidation of 4a. The methyl ester is much more water soluble 
and may prove advantageous when the hydrolysis step is unacceptable. The 
i-propyl ester also works well and is the tartrate of choice for kinetic 
resolutions. 
(d) J. A. Dale, D. L. Dull, and H. S. Mosher, J. Org. Chem., 34, 2543 
(1969). We used MTPA-chloride and DMAP in CH.sub.2 Cl.sub.2. 
TABLE II 
__________________________________________________________________________ 
Asymmetric Epoxidation of Allylic Alcohols 
Allylic Alcohol Epoxyalcohol % Yield.sup.b 
% e.e.sup.c 
Configuration.sup.d 
__________________________________________________________________________ 
##STR5## 
##STR6## 77 95 (Eu,M) 
2(S), 3(S) 
##STR7## 
##STR8## 79 94 (Eu,M) 
2(S), 3(R) 
##STR9## 
##STR10## 70.sup.g 
&gt;95 (Eu) 
6(S), 7(S) 
##STR11## 
##STR12## 87 &gt;95 (Eu) 
2(S), 3(S) 
##STR13## 
##STR14## 79 &gt;95 (M) 
2(S), 3(S) 
##STR15## 
##STR16## 82 90 (M) 
2(S), 3(R) 
##STR17## 
##STR18## 80 90 (M) 
2(R), 3(S) 
##STR19## 
##STR20## 81 &gt;95 (M) 
2(S).sup.o 
##STR21## 
##STR22## 38 64 3(R) 
__________________________________________________________________________ 
.sup.a Unless otherwise noted, all reactions were performed as described 
in detail for 
geraniol (1a). In most cases the scale was smaller (ca. 2 mmol). 
.sup. b Isolated yields. All new compounds gave appropriate analytical 
and spectral data. 
.sup.c The enantiomeric excesses were determined by .sup.1 H NMR on the 
corresponding 
epoxyacetates (pyridines/Ac.sub.2 O) in the presence of Eu(hfbc).sub.3 
and/or 
by conversion to the MTPA ester followed by .sup.1 H or .sup.19 F NMR 
analysis. The technique(s) 
used is inidicated in parentheses. When both methods were employed, the % 
e.e. reported was 
an average of the two values. 
.sup.d All absolute configurations were proven by chemical correlation as 
indicated for each case. 
All of the epoxyalcohols in the Table gave a negative rotation in 
CHCl.sub.3 except for 4b and 6c. 
.sup.e The enantiomer of 1b has been correlated with (R)(-)-linalool..sup. 
1b 
.sup.f The enantiomer of 2b has been correlated with (S)(+)-linalool..sup. 
1b 
.sup.g Alkaline hydrolysis step was omitted in this case; the diethyl 
tartrate was removed by 
chromatography. 6(S),7(S)(-)-3b was correlated with (S)(-)-6, 
7-epoxygeraniol [S. Yamada, N. Oh-hashi and K. Achiwa, Tetrahedron Lett., 
2557 (1976)]. 
The 8-hydroxyl group of 3b was replaced by hydrogen via the following 
reaction sequence: 
TsCl/pyridine; NaI/acetone; NaH.sub.3 BCN/HMPA; LiOH/CH.sub.3 OH, H.sub.2 
O. 
.sup.h Epoxidation was performed at 0.degree. C. and was completed in 
less than 30 min. 
.sup.i 4b was correlated with methyl-(S)(+)-2,3-diphenyl-2-hydroxypropiona 
te (ii) 
[H. R. Sullivan, J. R. Beck and A. Pohland, J. Org. Chem., 28, 2381 
(1963); see also E. Bye, 
Acta Chem. Scand., 27, 3403 (1973)]. Epoxyalcohol 4b was transformed to i 
by the following steps: 
RuO.sub.4 /CCl.sub.4, CH.sub.3 CN, H.sub.2 O; CH.sub.2 N.sub.2 Et.sub.2 
O; W-2 Raney nickel, H.sub.2 /absolute EtOH. 
.sup.j 5b was correlated with (R)(-)-tridecan-3-ol [K. Freudenberg, 
Stereochemie. 
Eine Zusammenfassung der Ergebnisse, Grundlagen und Probleme, p. 696, Ed. 
Franz 
Deuticke, Leipzig und Wien] by the following sequence: 
TsCl/pyridine; NaI/acetone; Zn/HOAc; H.sub.2 PtO.sub.2. 
.sup.k These results were obtained during enantioselective syntheses of 
both natural-(+)- and unnatural-(-)-disparlure. 
.sup.l 6b was was correlated with unnatural-(-)-disparture. -.sup.m In 
this case D-(-)-diethyl tartrate (the unnatural enentiomer) was used. 
6c was correlated with natural-(+)-disparlure. 
.sup.n This epoxidation was run for 40 hrs at -20.degree. C. and a trace 
of 7a still remained. 
.sup.o 7b was correlated with (R)(-)-2-cyclohexyl-2-butanol [D. J. Cram 
and J. Tadanier, 
J. Am. Chem. Soc., 81, 2737 (1959)] through the following steps: 
LiAlH.sub.4 /Et.sub.2 O; TsCl/pyridine; LiCuMe.sub.2 /Et.sub.2 O. 
.sup.p The alcohol is homoallylic and water soluble. Therefore the workup 
employed the saturated 
Some additional commentary is worthwhile concerning the reaction procedure. 
Water soluble compounds are only difficultly isolated so that the 
technique described previously should be employed. 
While the exemplary preparation described above employed a 1:1 molar ratio 
of catalyst to substrate, substantially smaller amounts may be employed 
with reactive allylic alcohols, for examples 1a, 2a, 3a, and 4a in Table 
II, where 0.1 equivalent of both titanium isopropoxide and diethyltartrate 
suffice. Under these conditions, the yields of 1b, 2b and 4b were 
comparable to or somewhat better than those with one equivalent of the 
catalytic materials and product isolations were cleaner and easier. 
However, the enantiomeric excess was somewhat poorer for 1b (91%) e.e. and 
2b (84%) e.e. but was still greater than 95% e.e. for 4b. For less 
reactive substrates, 5a, 6a, and 7a of Table II, in order to obtain 
reasonable rates under the above conditions, the one equivalent was 
desirable. In employing the one equivalent with 7a, almost two days were 
required for completion. 
The following study was made with a variety of chiral carbinols using the 
following procedure. A 0.5-1 mmol scale was employed. Freshly distilled 
anhydrous dichloromethane (10 ml) was cooled under nitrogen in an ice/salt 
bath and one eq. titanium isopropoxide added, followed by the addition of 
the chiral carbinol. After stirring for 5 min, 1 eq. of 
alpha-phenylcinnamyl alcohol (Table II, 4a) was added and after a 10 min 
interval, 2 eq. of t-butylhydroperoxide (solution in dichloromethane) was 
added. The progress of the reaction was monitored by tlc. At completion, 5 
ml of a 10% tartaric acid solution was added and the mixture stirred until 
hydrolysis was complete as indicated by the appearance of two clear 
layers. The organic phase was separated, dried over magnesium sulphate and 
concentrated. The crude product was acetylated with acetic 
anhydride/pyridine and the acetate purified by tlc. Chiral shift studies 
were done in CDCl.sub.3 at 60 MHz using Eu(hfbc).sub.3. Optical yields 
were confirmed by rotation. The following table indicates the results. 
TABLE III 
______________________________________ 
Chiral Carbinol (CC) 
##STR23## 
CC/Ti 
e.e. %, 
mole 
A B C D E Config. 
Ratio 
______________________________________ 
Me Me OH H H 40,2S 1:1 
.phi. .phi. OH H H 0 1:1 
CO.sub.2 H 
CO.sub.2 H OH H H 8,2S 1:1 
CO.sub.2 C.sub.3 H.sub.6 OEt 
CO.sub.2 C.sub.3 H.sub.6 OEt 
OH H H 93,2S 1:1 
CO.sub.2 Et 
CO.sub.2 Et 
OH Me Me 13,2S 1:1 
CO.sub.2 Et 
H H H H 10,2S 2:1 
CO.sub.2 Et 
CO.sub.2 Et 
H H H 0 1:1 
CO.sub.2 Et 
H OH H H 65,2S 1:1 
##STR24## 
##STR25## OH H H 0 
CONEt.sub.2 
CONEt.sub.2 
OH H H 15,2R 1:1 
CONH.sub.2 
CONH.sub.2 OH H H 15,2R 1:1 
CO.sub.2 Et 
CONHCH.sub.2 .phi. 
OH H H 60-80, 
1:1 
2R 
##STR26## OH H H 15,2S 2:1 
CO.sub.2 C.sub.18.sup.a 
CO.sub.2 C.sub.18 
OH H H &gt;95,2S 
b b OH H H 10,2R 
1:1 Mixtures 
CO.sub.2 Et 
CO.sub.2 Et 
OH H H &gt;90,2S 
CO.sub.2 Et 
CONH.sub.2 OH H H 
CO.sub.2 Et 
CO.sub.2 Et 
OH H H &gt;90,2S 
CONH.sub.2 
CONH.sub.2 OH H H 
CO.sub.2 Et 
CO.sub.2 Et 
OH H H 0 
______________________________________ 
a C.sub.18 = Stearyl 
##STR27## 
c Mixture of tartrate enantiomers 
It is evident from the above table, that while a variety of different 
chiral carbinols can be used, with certain carbinols no asymmetric 
induction was observed. In some instances, both shown and not shown, the 
complex precipitated. This was observed with the acid and certain cyclic 
imides, not shown. While the tartaric acid derivatives appeared to provide 
optimal results, numerous variations can be made and asymmetric induction 
observed. 
In the next system, a number of different metals were employed as 
catalysts. No effort was made to optimize the results with each of the 
metals and some negative results were observed. The procedure described 
previously was employed using the alpha-phenylcinnamyl alcohol as the 
allylic alcohol. The following table indicates the results. 
TABLE IV 
__________________________________________________________________________ 
Chiral CC/CP 
Catalyst Carbi- mole Temp 
Time 
Yield 
% ee 
Precursor(CP).sup.c 
nol(CC).sup.d 
ratio 
.degree.C. 
hr % nmr.sup.a 
__________________________________________________________________________ 
Ti(OiPr).sub.4 
(+)DET 1.11 0 .ltoreq.0.5 
87 &gt;95 
Zr(OiPr).sub.4 iPrOH 
(+)DET 1.11 0 .about.0.5 
86 10.sup.b 
VO(OiPr).sub.3 
(+)DET 1.17 0 .about.0.2 
100 
17.sup.b 
Nb(OEt).sub.5 
(+)DET 1.11 20 &lt;24 .about.71 
0 
Ta(OEt).sub.5 
(+)DET 1.12 0 .about.7 
.about.90 
.about.50.sup.b 
MoO.sub.2 (acac).sub.2 
(+)DiPrT 
2.0 20 10 days 
.about.88 
.about.15.sup.b 
__________________________________________________________________________ 
.sup.a As the acetate. 
.sup.b Reverse configurations from the titanium product 
.sup.c iPr isopropyl 
Et ethyl 
acac acetylacetone 
.sup.d DET diethyl tartrate 
DiPrT diisopropyl tartrate 
It is evident from the above results that a number of different metals can 
provide asymmetric induction. While titanium provides the highest 
asymmetric induction, vanadium has been found to be faster in its 
catalytic effect, while also providing some asymmetric induction. 
The next aspect to be considered is a general procedure devised for 
asymmetric epoxidation of homoallylic alcohols. 
Into a dry N.sub.2 purged flask is added with stirring 10 mmol of 
homoallylic alcohol, 11 mmol of (+) diethyl tartrate and 30 ml of dry 
dichloromethane and while maintaining the flask under a positive pressure, 
the flask is cooled to about -50.degree. C. Titanium isopropoxide (10 
mmol) is syringed into the flask and after a 5 minute interval, 20 mmol of 
an anhydrous solution of t-butylhydroperoxide is syringed in and the 
mixture stirred for 5-30 min. After removing the flask from the cooling 
bath, it is put into a refrigerator and maintained at -20.degree. to 
-18.degree. C. After from about 1-7 days, while monitoring by tlc and glc, 
when the reaction appears to have terminated, the mixture is worked up by 
adding about 50 ml of diethyl ether and 10 ml saturated aqueous sodium 
sulphate and stirring the mixture vigorously for 30-60 min. 
The mixture is filtered through a cake of celite, the precipitate washed 
with diethyl ether, any aqueous phase in the filtrate removed, the organic 
phase dried and the product isolated. 
In addition to the above allylic alcohols, (+)Disparlure, the gypsy moth 
sex attractant was prepared in accordance with the following synthetic 
procedure. 
##STR28## 
The same system which is selective for the maiden introduction of chirality 
by epoxidation is also very sensitive to pre-existing chirality in an 
alcohol substrate having a nearby functionality capable of accepting an 
oxygen atom. Thus, when a racemic carbinol capable of accepting an oxygen 
atom is exposed to the chiral oxidation system, one of the enantiomers is 
oxidized much more rapidly than the other. 
A reaction was carried out employing a racemic mixture of 3-hydroxy-4 
methylpentene-1 with titanium isopropoxide, L-(+)-diethyl tartrate and 
TBHP in methylene dichloride at 0.degree. C., in accordance with the 
conditions described above. When epoxidation was carried to 70% 
completion, the recovered allylic alcohol was greater than &gt;99.99% 
optically pure. When the reaction was carried to 45% completion, the epoxy 
alcohol formed was almost pure erythro and was &gt;95% optically pure. The 
titanium tartrate expoxidation catalyst greatly favors production of 
erythro epoxyalcohols. It is much more erythro selective than any other 
known catalyst. 
The following examples are illustrative of kinetic resolutions of beta, 
gamma-unsaturated alcohols. The first resolution is of 
3-hydroxy-5-phenylpentene-1. 
Into a nitrogen flushed flask fitted with a serum cap was introduced dry 
dichloromethane (10 ml/mmol of alcohol) and cooled to about -23.degree. C. 
To the solvent is added sequentially by syringe 1 eq. titanium 
tetraisopropoxide, 1.2 eq. L-(+)-diisopropyl tartrate and after stirring 
for 5 min, 1 eq. of the alcohol, followed by 0.7 eq. of anhydrous 
t-butylhydroperoxide (ca. 4-6M in CH.sub.2 Cl.sub.2). The resulting 
homogeneous solution was then stored 12 days at -20.degree. C. in a sealed 
vessel. 
The reaction mixture was worked up by pouring it into a 10% aqueous 
tartaric acid solution (2 ml/mmol of alcohol) while stirring at room 
temperature and the stirring continuing for one hour. The two layers were 
clear. The aqueous layer was separated and the organic layer washed with 
water and concentrated to a yellow oil. 
The oil was diluted with diethyl ether (2 ml/mmol of alcohol) and the 
resulting solution cooled in an ice bath, 10% aqueous sodium hydroxide 
added (2 ml/mmol of alcohol) and the mixture stirred at 0.degree. for one 
hour. The ether phase was washed with water and concentrated to give a 
yellow oil. The oil was combined at room temperature with isopropylamine 
(0.5 ml/mmol of alcohol) and water (0.1 ml/mmol of alcohol). After 
stirring for three days at room temperature, the mixture was concentrated 
in vacuo, ether added (2 ml/mmol of alcohol) and the organic layer washed 
first with water and then with 20% hydrochloric acid. After drying 
(MgSO.sub.4), the organic layer was concentrated and distilled. The 
optically pure product distilled at 90.degree. C. (0.2 mmHg) and gave a 
38% yield (76% based on available enantiomer). [.alpha.].sup.23.sub.D 
-1.28 [c14.1, ethanol]. The aqueous phase was stirred with 10% sodium 
hydroxide (10 min., 0.1 ml/mmol of alcohol) and extracted with ether. The 
ether solution was washed with water, dried over MgSO.sub.4, concentrated 
in vacuo and the crude product recrystallized from an ether-petroleum 
ether mixture, yielding a solid product m.p. 72.degree. C. The product was 
N-isopropyl 2R,3S-dihydroxy-5-phenylpentylamine-1. [.alpha.].sup.23.sub.D 
-22.7 [c2.55, ethanol]. 
The next resolution involved a propargyl alcohol, namely 
3-hydroxyundecine-4. Into the reaction flask was introduced 1 eq. of 
titanium tetraisopropoxide, 1.2 eg of L-(+)-diisopropyl tartrate, 1 eq. of 
the alcohol and dry dichloromethane (10 ml/mmol of alcohol) at room 
temperature. To the mixture with stirring was added 4 eq. of anhydrous 
t-butylhydroperoxide (ca 4-6M in dichloromethane) and the homogeneous 
mixture maintained at room temperature for 7 days, while the course of the 
reaction was followed by GC to 53% conversion. The reaction mixture was 
then poured into about two volumes (based on volume of reaction mixture) 
of acetone containing water (ml of H.sub.2 O equal to ml of titanium 
isopropoxide). After stirring at room temperature, the mixture was 
filtered, concentrated and chromatographed providing the 3R-acetylene 
compound in 82% yield (based on available enantiomer). 
[.alpha.].sup.24.sub.D +2.68 [c4.43, ethanol]. The product was correlated 
with the ethylenic analog by reduction using the Lindler catalyst 
indicating 21% ee. 
The next resolution was of ipsdienol which involved combining a mixture of 
L-(+)-diisopropyl tartrate (2.93 g, 12.5 mmol), titanium isopropoxide (3 
ml, 10 mmol) and 100 ml of dry dichloromethane under nitrogen at 0.degree. 
with stirring for 15 min. Commercial dl-ipsdienol (1.68 g, 10 mmol) and 
0.6 ml of n-pentadecane (as glc internal standard) in 20 ml of 
dichloromethane were added, the mixture cooled to -45.degree. C. and 1.2 
ml of anhydrous t-butylhydroperoxide (ca 6.54M in dichloromethane) was 
added by syringe and the mixture stirred at -45.degree. C. for 21 hours. 
The mixture was then poured into 120 ml of acetone containing 10 ml of 
water, and the resulting mixture stirred at room temperature for 1.5 hour. 
After filtration and concentration, glc analysis indicated 60% of the 
starting alcohol was consumed. The residue was taken up in 80 ml of 
diethyl ether and stirred with 30 ml of 1N sodium hydroxide at 0.degree. 
C. for 0.5 hr to hydrolyse and remove the tartrate. The ether layer was 
separated, the aqueous layer was extracted with 20 ml of ether and the 
combined organic solutions washed once with 30 ml of brine and dried over 
sodium sulfate. After concentration, the crude residue is purified on 
basic aluminum oxide (Baker, pH8) eluted with 5% acetone/ether to yield 
0.6 g of the resolved alcohol as a clear oil. [.alpha.].sup.23.sub.D -12.0 
[c1.64, ethanol] e.e. &gt;95%. After further treatment as described above 
with 0.4 eq. of t-butylhydroperoxide at - 50.degree. C. for another 22 
hrs., 0.35 g of (-)-R-ipsdienol was obtained with approximately 100% ee. 
It is evident from the above results that an extremely potent reaction 
system is provided for producing optically active compounds, either by 
introducing an epoxide asymmetrically, or by reacting with one of two 
enantiomers, so as to provide optically active starting material, as well 
as optically active product. The reaction is simple, can employ readily 
available and inexpensive materials, and can be used for a wide variety of 
applications. 
Although the foregoing invention has been described in some detail by way 
of illustration and example for purposes of clarity of understanding, it 
will be obvious that certain changes and modifications may be practiced 
within the scope of the appended claims.