Chiral catalysts and catalytic epoxidation catalyzed thereby

Methods of using chiral catalysts for enantioselectively epoxidizing a prochiral olefin and for enantioselectively oxidizing a prochiral sulfide are disclosed. In accordance with one aspect of the invention, the catalyst used is a salen derivative which has the following general structure: ##STR1## In accordance with another aspect of the present invention is a method of producing an epoxychroman using a chiral catalyst. In accordance with this method, a chromene derivative, an oxygen atom source, and a chiral catalyst are reacted under such conditions and for such time as is needed to epoxidize said chromene derivative. In accordance with yet another aspect of this invention is a method of enantioselectively epoxidizing a cis-cinnamate derivative to make taxol or an analog thereof. In accordance with another aspect a method of disproportionation of hydrogen peroxide using the catalysts of the present invention is disclosed.

BACKGROUND OF THE INVENTION 
Chiral Catalysts and Catalysis 
The present invention relates to the field of asymmetric catalysis. More 
particularly, the invention relates to the field of organometallic 
catalysts useful for enantioselectively epoxidizing prochiral olefins. 
Several advances in catalysis of asymmetric group transfer have occurred in 
recent years. One such advance has been the discovery by K. B. Sharpless 
et al. of the epoxidation of allylic alcohols which provides access to 
enantiomerically pure synthetic building blocks. Unfortunately, Sharpless 
catalysis requires the presence of a specific functional group, namely an 
allylic alcohol, on the olefin to be epoxidized. Naturally, this 
requirement severely limits the variety of olefins which can be so 
epoxidized. 
Some success has been achieved in asymmetric catalysis of unfunctionalized 
olefins. For example, K. B. Sharpless reported in 1988 that certain 
cinchona alkaloid derivatives were effective ligands in the 
osmium-catalyzed asymmetric dihydroxylation of trans-stilbene and various 
other olefins. This method provides a practical route to certain chiral 
diols, although cis olefins afford poor results. 
Aside from the catalysts disclosed herein, it is believed that there 
currently exists no practical catalytic method for the asymmetric 
epoxidation of unfunctionalized olefins. Some progress has been made in 
this area through the use of chiral porphyrin complexes. In particular, J. 
T. Groves et al. reported in 1983 the asymmetric epoxidation of styrene by 
a chiral iron porphyrin catalyst. Unfortunately, the Groves system suffers 
several disadvantages, namely, the porphyrin catalyst is relatively 
difficult to prepare, oxidant proceeds to low substrate conversion, is 
limited to styrene derivatives, and achieves enantiomeric excess (ee) 
values of less than about 50 percent. 
Epoxychroman Synthesis 
Given the broad synthetic utility of epoxides, a simple, reliable, and 
practical procedure for asymmetric epoxidation of simple olefins is 
clearly desirable. One class of chiral epoxide with synthetic utility is 
the group of compounds generally known as epoxychromans, or epoxides of 
derivatives of chromene. For example, the epoxide of 
6-cyano-2,2-dimethylchromene has been found to be useful in the synthesis 
of a compound known as cromakalim. Two variations of cromakalim are shown 
in FIGS. 12 and 13. Both of these are believed to be potassium channel 
activators and have shown considerable promise as antihypertensive drugs. 
As can be seen in FIGS. 12 and 13, the cromakalim compounds have two 
enantiomers. It is currently believed that only one of these enantiomers, 
namely the 3S, 4R enantiomer, possesses the antihypertensive activity. 
Consequently, a method of making a more enantiomerically pure epoxide of 
the precursor chromene derivative is highly desirable. 
Taxol Synthesis 
Taxol has emerged as a promising anti-cancer drug in preliminary clinical 
trials. However, taxol is a highly complex molecule which has not been 
fully synthesized and remains in short supply. Taxol may be considered to 
have two basic structural units, an N-benzoyl-3-phenyl-isoserine side 
chain and a highly functionalized diterpene nucleus. The tetracyclic ring 
structure of the nucleus represents by far the greater synthetic 
challenge, one that has as yet not been met despite the concerted efforts 
of several leading laboratories. 
Consequently, a number of research groups are seeking semisynthetic routes 
of making taxol or analogs with taxol-like activity. Some of the new 
strategies involve side-chain synthesis and linkage to a naturally derived 
diterpene nucleus, or taxol congener. 
A ready source of the taxol congener 10-deacetyl baccatin III (10-DB III) 
has been found. Chauviere, G., Guenard, D.; Picot, F.; Senilh, V.; Potier, 
P. C. R.: Seances Acad. Sci., Ser. 2, 293: 501-03, 1981. Denis et al. (J. 
Amer. Chem. Soc. 110:5417, 1988) developed a method of converting 10-DB 
III to taxol which utilizes, for the taxol C13 side chain, the protected 
form (2R,3S)-N-benzoyl-O-(1-ethoxyethyl)-3-phenyl-isoserine. Denis, J. 
-N.; Greene, A. E.; Serra, A. A.; Luche, M. -J. J. Org. Chem. 51: 46-50, 
1986. 
A more efficient method of synthesizing an optically pure C13 side chain of 
taxol is desirable. 
Chiral Catalysts and Oxidation of Sulfides 
The present invention also relates to the field of organometallic catalysts 
useful for enantioselectively oxidizing sulfides to sulfoxides. Given the 
broad synthetic utility of sulfoxides, a simple, reliable, and practical 
procedure for asymmetric oxidation of sulfides is clearly desirable. 
Asymmetric sulfide oxidation and olefin epoxidation strategies utilizing 
chiral oxaziridine derivatives have been developed with good to excellent 
success by Davis et al. Enantioselective catalysis of these reactions (and 
of asymmetric stoichiometric epoxidation) constitutes among the most 
interesting challenges in modem synthetic chemistry. To date, the only 
well-established and broadly successful methods for both these processes 
employ closely related Ti-tartrate-based catalysts with alkyl 
hydroperoxides as the terminal oxidant. Also, several chiral porphyrin 
complexes have been reported to catalyze both types of oxidation processes 
with modest selectivity using iodosylarenes as terminal oxidants. 
Catalytic Disproportionation of Hydrogen Peroxide 
The enzyme catalase, which occurs in blood and a variety of tissues 
decomposes hydrogen peroxide into oxygen gas and water very rapidly. This 
catalytic disproportionation of hydrogen peroxide (also known as the 
catalytic reaction) protects aerobic cells from oxidative stress and 
therefore is a biologically important process. Thus, it is desirable to 
find compounds which can function like catalase. 
SUMMARY OF THE INVENTION 
Briefly stated, the present invention is a chiral catalyst as well as a 
method of using said catalyst for enantioselectively epoxidizing a 
prochiral olefin. 
In accordance with a first aspect of the invention, the chiral catalyst has 
the following structure: 
##STR2## 
wherein M is a transition metal ion, A is an union, and n is either 0, 1, 
or 2. At least one of X1 or X2 is selected from the group consisting of 
silyls, aryls, secondary alkyls and tertiary alkyls; and at least one of 
X3 or X4 is selected from the same group. Y1, Y2, Y3, Y4, Y5, and Y6 are 
independently selected from the group consisting of hydrogen, halides, 
alkyls, aryl groups, silyl groups, and alkyl groups bearing hereto-atoms 
such as alkoxy and halide. Also, at least one of R1, R2, R3 and R4 is 
selected from a first group consisting of H, CH.sub.3, C.sub.2 H.sub.5, 
and primary alkyls. Furthermore, if R1 is selected from said first group, 
then R2 and R3 are selected from a second group consisting of aryl groups, 
heteroatom-bearing aromatic groups, secondary alkyls and tertiary alkyls. 
If R2 is selected from said first group, then R1 and R4 are selected from 
said second group. If R3 is selected from said first group, then R1 and R4 
are selected from said second group. If R4 is selected from said first 
group, then R2 and R3 are selected from said second group. 
In accordance with a second aspect of the invention, the chiral catalyst 
has the following structure: 
##STR3## 
wherein M is a transition metal ion and A is an anion; where at least one 
of X1 or X2 is selected from the group consisting of aryls, primary 
alkyls, secondary alkyls, tertiary alkyls, and hetero atoms; where at 
least one of X3 or X4 is selected from the group consisting of aryls, 
primary alkyls, secondary alkyls, tertiary alkyls, and hetero atoms; and 
where Y1, Y2, Y3, Y4, Y5, Y6, Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9, Z10, 
Z11, and Z12 are independently selected from the group consisting of 
hydrogen, halides, alkyls, aryls, and alkyl groups bearing hetero atoms. 
In accordance with a third aspect of the invention, the chiral catalyst has 
the following structure: 
##STR4## 
where M is a transition metal ion and A is an anion; where n is either 0, 
1, or 2; where at least one of X1 or X2 is selected from the group 
consisting of aryls, primary alkyls, secondary alkyls, tertiary alkyls, 
and hetero atoms; where at least one of X3 or X4 is selected from the 
group consisting of aryls, primary alkyls, secondary alkyls, tertiary 
alkyls, and hetero atoms; where at least one of Y1 or Y2 is selected from 
the group consisting of aryls, primary alkyls, secondary alkyls, tertiary 
alkyls, and hereto atoms; where at least one of Y4 or Y5 is selected from 
the group consisting of aryls, primary alkyls, secondary alkyls, tertiary 
alkyls, and hetero atoms; where Y3 and Y6 are independently selected from 
the group consisting of hydrogen and primary alkyl groups; where either 
one or two of R1, R2, R3 and R4 is hydrogen; where, if R1 is hydrogen, 
then R3 is a primary alkyl; where, if R2 is hydrogen, then R4 is a primary 
alkyl; where, if R3 is hydrogen, then R1 is a primary alkyl; and where, if 
R4 is hydrogen, then R2 is a primary alkyl. 
In accordance with a fourth aspect of the invention, chiral catalyst has 
the following structure: 
##STR5## 
where M is a transition metal ion and A is an anion; where n is either 3, 
4, 5 or 6; where at least one of X1 or X2 is selected from the group 
consisting of aryls, primary alkyls, secondary alkyls, tertiary alkyls, 
and hetero atoms; where at least one of X3 or X4 is selected from the 
group consisting of aryls, primary alkyls, secondary alkyls, tertiary 
alkyls, and hetero atoms; where at least one of Y1 or Y2 is selected from 
the group consisting of aryls, primary alkyls, secondary alkyls, tertiary 
alkyls, NO.sub.2, and hetero atoms; where at least one of Y4 or Y5 is 
selected from the group consisting of aryls, primary alkyls, secondary 
alkyls, tertiary alkyls, NO.sub.2, and hetero atoms; where Y3, and Y6 are 
independently selected from the group consisting of hydrogen and primary 
alkyl groups; where R1 and R4 are trans to each other and at least one of 
R1 and R4 is selected from the group consisting of primary alkyls and 
hydrogen; and where the carbons in the (C).sub.n portion have substituents 
selected from the group consisting of hydrogen, alkyl, aryl, and 
heteroatoms. 
In accordance with the method aspect of the invention, a prochiral olefin, 
an oxygen atom source, and the chiral catalyst of one of the four aspects 
of the invention are reacted under such conditions and for such time as is 
needed to epoxidize said olefin. 
In accordance with an alternate method aspect of this invention, a 
pyridine-N-oxide derivative is used. Preferably, 4-phenylpyridine-N-oxide 
or 4-t-butylpyridine-N-oxide is used. More preferably, 
4-phenylpyridine-N-oxide is used. 
The present invention of chiral catalysts and catalysis has provided 
certain advantages. First, the catalysts of the present invention provide 
a means for catalyzing the enantioselective epoxidation of mono, di, and 
tri-substituted olefins without the need for a specialized functional 
group on the olefin to interact with the catalyst. In other words, the 
catalysts of the present invention are particularly suited for catalyzing 
the asymmetric epoxidation of unfunctionalized olefins. This is in 
contrast to the prior art catalysts, such as the Sharpless catalyst, 
referred to above. 
Second, the preferred catalysts of the invention show remarkable 
enantioselectivity in catalyzing the epoxidation of cis, disubstituted 
olefins. See Example 1 below, where an ee of 85% was obtained with 
cis-.beta.-methylstyrene when catalyzed with the most preferred embodiment 
of the first aspect. See also, the ee values for Example 12 which uses the 
most preferred catalyst of the fourth aspect of the present invention. As 
noted above, prior art catalysts have not provided ee values over 40% for 
cis, disubstituted olefins. 
Third, the catalysts of the present invention are relatively easy to 
synthesize, particularly as compared to the porphyrin systems disclosed in 
the prior art. 
Briefly stated, yet another embodiment of the present invention is a method 
of producing an epoxychroman using a chiral catalyst. In accordance with 
this method, a chromene derivative, an oxygen atom source, and a chiral 
catalyst from those described below are reacted under such conditions and 
for such time as is needed to epoxidize said chromene derivative. 
The chromene derivative used in the present method has the following 
structure: 
##STR6## 
wherein R1, R2, R3, R4, X1, X2, X3, and X4 are each selected from the 
group consisting of hydrogen, aryls, primary alkyls, secondary alkyls, 
tertiary alkyls, and hetero atoms, and wherein no more than one of R1 and 
R2 are hydrogen. 
The enantioselective method of producing an epoxychroman has provided 
certain advantages. First, the preferred catalysts of the invention show 
remarkable enantioselectivity in catalyzing the epoxidation of chromene 
derivatives. See Example 17 below, where an ee of 97% was obtained with 
the 6-cyano-2,2-dimethylchromene and the most preferred catalyst shown 
below. As noted above, prior art catalysts have not provided ee values 
over 40% for cis, disubstituted olefins. 
Second, the present invention provides an effective and concise route to 
epoxychromans with very high enantioselectivity. Enantiomerically enriched 
epoxychromans are valuable intermediates for the synthesis of chiral 
3,4-disubstituted chromans. 
Third, the method is effective with a wide variety of substituted chromene 
derivatives. 
Fourth, the catalysts of the present invention are relatively easy to 
synthesize, particularly as compared to the porphyrin systems disclosed in 
the prior art. 
Yet another embodiment of the present invention is the method of 
enantioselectively producing a cis-epoxide of a cinnamate derivative using 
a chiral catalyst. In accordance with this method, a cis-cinnamate 
derivative, an oxygen atom source, and a chiral catalyst selected from 
those described below are reacted under such conditions and for such time 
as needed to epoxidize said cis-cinnamate derivative. Even more 
preferably, the reaction takes place in the presence of a pyridine-N-oxide 
derivative. 
The cis-cinnamate derivative used in the present method has the following 
structure: 
##STR7## 
wherein A1-A5 are selected from the group consisting of hydrogen, aryls, 
primary alkyls, secondary alkyls, tertiary alkyls, hydroxyl, alkoxy 
groups, F, Cl, Br, I, and amines. 
Still another embodiment of the present invention is the method of making a 
side chain of taxol or an analog thereof using a chiral catalyst. In 
accordance with this method, a cis-cinnamate derivative, an oxygen atom 
source, and a chiral catalyst selected from those described below are 
reacted under such conditions and for such time as needed to 
enantioselectively epoxidize said cis-cinnamate derivative. Even more 
preferably, the reaction takes place in the presence of a pyridine-N-oxide 
derivative. The cis-cinnamate derivative has the same structure as shown 
above. 
The epoxide of the cis-cinnamate derivative is then regioselectively opened 
(i.e., preferentially breaking one particular oxygen bond) to produce 
3-phenyl isoserinamide derivative. This 3-phenyl isoserinamide derivative 
is hydrolyzed to produce a 3-phenyl-isoserine derivative, which in turn is 
reacted with benzoyl chloride to form N-benzoyl-3-phenyl-isoserine 
derivative. 
In yet another embodiment of this invention, taxol is synthesized using a 
chiral catalyst. In accordance with this method, an ethyl phenylpropiolate 
is partially hydrogenated to produce a cis-ethyl cinnamate. Then, the 
cis-ethyl cinnamate, an oxygen atom source, and a chiral catalyst selected 
from those described below are reacted under such conditions and for such 
time as needed to enantioselectively epoxidize said cis-ethyl cinnamate. 
Even more preferably, the reaction takes place in the presence of a 
pyridine-N-oxide derivative. 
The epoxide of the cis-cinnamate is then regioselectively opened to produce 
3-phenyl isoserinamide. This 3-phenyl isoserinamide is hydrolyzed to 
produce 3-phenyl-isoserine, which in turn is reacted with benzoyl chloride 
to form N-benzoyl-3-phenyl-isoserine. Next, the 
N-benzoyl-3-phenyl-isoserine is reacted with 1-chloroethyl ether and a 
tertiary amine in methylene chloride to form 
N-benzoyl-O-(1-ethoxyethyl)-3-phenyl-isoserine. Then, 
N-benzoyl-O-(1-ethoxyethyl)-3-phenyl-isoserine is reacted with the alcohol 
shown below: 
##STR8## 
This resulting intermediate is converted to taxol by hydrolytically 
removing the 1-ethoxyethyl and triethylsilyl protecting groups. 
The present method of enantioselectively synthesizing the side chain of 
taxol has certain advantages. The preferred catalysts of the invention 
show remarkable enantioselectivity in catalyzing the epoxidation of 
cis-cinnamate derivatives. The synthesis may begin with relatively 
inexpensive ethyl phenylpropiolate. In particular, the addition of a 
pyridine-N-oxide derivative also increases the specificity and completion 
of the epoxidation. 
Briefly stated, yet another embodiment of the present invention is a method 
of enantioselectively oxidizing sulfides using a chiral catalyst. In 
accordance with this method a sulfide, an oxygen atom source, and a chiral 
catalyst from those described below are reacted under such conditions and 
for such time as is needed to oxidize said sulfide. Preferably, the 
sulfide has the formula R1-S-R2 wherein R1 is any aromatic group and R2 is 
any alkyl group. Preferably, a cosolvent such as tetrahydrofuran, acetone 
or acetronitrile is employed. Also preferably, the oxygen atom source is 
either hydrogen peroxide or iodosylbenzene. 
Still another embodiment of the invention is a method of catalytic 
disproponionation of hydrogen peroxide using a catalyst of the present 
invention. In accordance with this method, hydrogen peroxide and a 
catalyst selected from those described below are reacted under such 
conditions and for such time as is needed to disproportionate the hydrogen 
peroxide to dioxygen and water. Preferably, the catalyst is a monometallic 
(salen)Mn complex. Also preferably, the catalyst is mixed with a solvent 
such as EtOH, acetone, CH.sub.2 Cl.sub.2, or H.sub.2 O.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
As noted above, the present invention is a chiral catalyst as well as 
methods of using said those catalysts for enantioselectively epoxidizing 
prochiral olefins, chromene derivatives and cis-cinnamate derivatives. 
The entire disclosures of U.S. patent application Ser. No. 809,446 filed 
Dec. 16, 1991 and U.S. patent application Ser. No. 749,460 filed Aug. 26, 
1991, and of U.S. patent application Ser. No. 673,208 filed Mar. 21, 1991 
which application was in turn a continuation-in-part of U.S. patent 
application Ser. No. 496,992 filed Mar. 21, 1990 are incorporated herein 
by reference. 
The First Catalyst of the Invention 
FIG. 1 shows the structure of the first aspect of the present invention 
preferred chiral catalyst. 
The preferred catalysts of the present invention are salen derivative-based 
complexes of a metal ion. The term "salen" is used herein to refer to 
those ligands typically formed through a condensation reaction of two 
molecules of a salicylaldehyde derivative with one molecule of a diamine 
derivative. While salen ligands are formed from ethylenediamine 
derivatives, propyl and butyl diamines may also be used to give analogous 
salpn and salbn derivatives. Salen derivatives are preferred and their 
general structure is shown in FIG. 1. A salen derivative where n is 0 is 
shown in FIG. 2. 
As seen in FIG. 1, the two nitrogens and the two oxygens are oriented 
toward the center of the salen ligand and thus provide a complexing site 
for the transition metal ion M. Preferably, this metal ion is selected 
from the group consisting of Mn, Cr, Fe, Ni, Co, Ti, V, Ru, and Os. More 
preferably, the transition metal ion is selected from the group consisting 
of Mn, Cr, Fe, Ni, and Co. Most preferably, the metal ion is Mn. 
The selection of the anion, A, is not seen to be critical to the 
performance of the catalyst. Preferably, the anion is selected from the 
group consisting of PF.sub.6, (aryl).sub.4, BF.sub.4, B(aryl).sub.4, 
halide, acetate, triflate, tosylate, with halide or PF.sub.6 being more 
preferred, and chloride being most preferred. 
FIG. 1 also shows the many sites available for substitution on the salen 
ligand. Of these sites, it is believed that R1, R2, R3, R4, and X1, X2, 
X3, X4, Y3 and Y6 are the most important in this first catalyst. 
According to the first aspect of the invention, at least one of the X1 and 
X2 sites, and at least one of the X3 and X4 sites include a substituent 
selected from the group consisting of secondary or tertiary alkyl groups, 
aryl groups, silyl groups, and alkyl groups bearing heteroatom 
substituents such as alkoxy or halide. For reasons to be discussed below, 
these will be referred to as "blocking" substituents. Preferably, it is 
the X1 and X3 sites which bear one of these blocking substituents. More 
preferably, X1 and X3 bear the same substituent, which substituent is most 
preferably a tertiary alkyl group, such as tertiary butyl. Preferably, 
when X1 and X3 bear the blocking substituent, then X2 and X4 can be 
selected from a group of non-blocking substituents such as H, CH.sub.3, 
C.sub.2 H.sub.5, and primary alkyls, most preferably, H. Alternatively, 
either three or four of X1, X2, X3, and X4 can be selected from the group 
of blocking substituents. 
According to this first aspect of the invention, at least one and no more 
than two of R1, R2, R3 and R4 are selected from a group consisting of H, 
CH.sub.3, C.sub.2 H.sub.5, and primary alkyls. For convenience, and 
consistent with the present theory to be discussed below, this group will 
be referred to as the non-blocking group. If R1 is selected from the 
non-blocking group, then R2 and R3 are selected from the blocking group. 
If R2 is selected from the non-blocking group, then R1 and R4 are selected 
from the blocking group. Likewise, if R3 is selected from the non-blocking 
group, then R1 and R4 are selected from the blocking group. Finally, if R4 
is selected from the non-blocking group, then R2 and R3 are selected from 
the blocking group. 
Stated in other terms, this first aspect of the invention requires that, of 
the four sites available for substitution on the two carbon atoms adjacent 
to nitrogen, either one or two of these will include a substituent from 
the non-blocking group. The invention also requires that the remaining 
sites include a substituent from the blocking group. In addition, it is a 
requirement that there not be two non-blocking substituents on the same 
carbon, and that there not be two non-blocking substituents on the same 
side on the two different carbons, i.e. not cis across the nitrogen. 
Stated in yet another way, if there is only one non-blocking substituent, 
that non-blocking substituent can be on any one of the four substitution 
sites, R1, R2, R3, and R4, and the other three sites must include a 
blocking substituent. If, on the other hand, there are two non-blocking 
substituents, then they must be on different carbon atoms, and they must 
be trans to each other. 
Preferably, the non-blocking substituent is either hydrogen or methyl, but 
most preferably, hydrogen. Preferably, the blocking substituent is either 
a phenyl group or a tertiary butyl group, but most preferably a phenyl 
group. 
The substituents on the Y3 and Y6 sites affect the conformation of the 
ligand and thus have an influence on enantioselectivity in the 
epoxidation. Preferably, Y3 and Y6 are hydrogen, methyl, alkyl, or aryl. 
More preferably, they are hydrogen or methyl. Most preferably, they are 
hydrogen. 
The Y1, Y2, Y4, and Y5 sites are seen to be less critical. Preferably, 
these sites are occupied by hydrogen, although these sites may also be 
occupied by substituents independently selected from the group consisting 
of hydrogen, halides, alkyls, aryls, alkoxy groups, nitro groups. 
FIG. 2 shows the structure of the most preferred embodiment of this first 
aspect of the present invention catalyst. As can be seen, the most 
preferred substituent at X1 and X3 is a t-butyl group. Also, it is most 
preferred for the R1 and R4 sites to have the same blocking group, namely 
a phenyl group. In addition, it is most preferred to have the R2 and R3 
sites occupied by a hydrogen. Finally, it is most preferred that the X2, 
X4, Y1, Y2, Y3, Y4, Y5, and Y6 sites are also all occupied by a hydrogen. 
While not wishing to be bound by any particular theory, the following 
mechanism has been proposed to explain the remarkable enantioselectivity 
of the first aspect of the present invention catalyst. Referring to FIG. 
4, which is a 3-dimensional view of the R,R enantiomer of the most 
preferred catalyst in its proposed oxo-intermediate state, it is seen 
that, with important exceptions, the salen ligand assumes a generally 
planar conformation with the oxygen atom 11 being complexed with the 
Manganese ion 13 and aligned on an axis generally perpendicular to this 
plane. The exceptions are the tert-butyl blocking groups attached at the 
X1 and X3 sites 15 and 17 respectively, and the phenyl blocking groups 
attached at the R1 and R3 sites 21 and 23, respectively. Although hard to 
depict in two dimensions, the phenyl blocking group 23 at R4 is behind the 
phenyl blocking group 21 at R1, while the R4 phenyl blocking group 23 is 
substantially above the plane of the catalyst and the R1 phenyl blocking 
group 21 is substantially below the plane of the catalyst. 
FIGS. 5A-5C show the different transition orientations possible for a 
cis-disubstituted olefin, namely cis-methylstyrene, which are possible 
during epoxidation of the double bond. 
FIG. 5A shows the favored orientation, i.e. the orientation with the least 
steric hindrance between the olefin and the blocking groups of the 
catalyst. This orientation results when the double bond approaches the 
oxygen atom from the front (as shown). This orientation results in the 
formation of the 1R,2S enantiomer of the cis-.beta.-methylstyreneoxide. 
FIG. 5B shows an orientation wherein methylstyrene has been rotated 180 
degrees thus bringing the phenyl group of the styrene closer to the 
t-butyl groups 15 and 17 at the X1 and X3 positions. It is expected that 
steric hindrance between the phenyl group of the styrene 25 and the 
t-butyl groups 15 and 17 would disfavor this orientation. 
FIG. 5C shows an orientation resulting from the double bond approaching the 
oxygen atom from behind (as shown). This orientation results in the 
formation of the 1S,2R enantiomer of the cis-.beta.-methylstyrene oxide. 
In this orientation the phenyl group of the styrene 25 is closer to the 
phenyl group 23 on the R4 site. Steric hindrance between these two phenyl 
groups would thus disfavor this approach from behind the oxygen atom, and 
thus disfavor synthesis of the 1S,2R enantiomer. 
In contrast, the orientation shown in FIG. 5A results from an approach from 
the front, i.e. the side where the R1 phenyl group 21 is below the plane 
of the catalyst, and thus not in the way. For this reason, the approach 
depicted in FIG. 5A is sterically favored, and thus synthesis of the 1R,2S 
enantiomer is favored. 
It should be borne in mind that, although the above-described mechanism 
accurately predicts the high degree of enantioselectivity observed in the 
catalysts of the present invention, the mechanism is at present only a 
theory. As such, the proposed mechanism should in no way limit the scope 
of the present invention as defined by the appended claims. 
It is noted that synthesis of the 1S,2R enantiomer of the 
cis-.beta.-methylstyrene oxide is favored by using the S,S enantiomer of 
the catalyst. 
It is also noted that this most preferred catalyst has C.sub.2 symmetry, 
i.e. it is identical when rotated 180 degrees. Consequently, whether the 
oxygen atom is aligned on the top of the catalyst as shown, or the bottom 
of the catalyst, the result is exactly the same. 
In alternative embodiments, the catalyst has only approximate C.sub.2 
symmetry. In particular, as per the rules described above, the groups are 
positioned on R1-R4 so that when rotated 180.degree., the blocking groups 
are in the same place and the non-blocking groups are in the same place. 
Consequently, the enantioselectivity of the catalyst is maintained because 
the oxygen can be complexed to either side of the catalyst while achieving 
roughly the same steric hindrances which favor the approach of the 
prochiral olefin from one side. 
In other alternative embodiments, the catalyst has only one non-blocking 
group. As a result, there is a favored approach only when the oxygen is 
aligned on one side of the catalyst. Thus, the enantioselectivity of the 
catalyst is maintained. 
The Second Aspect of the Invention 
In accordance with the second aspect of the present invention, the chiral 
catalyst is made with a binaphthyl diamine and has the following general 
structure (see also FIG. 3): 
##STR9## 
In this binaphthyl embodiment, the transition metal ion M and the anion A 
are preferably selected from the same group as that discussed above with 
FIG. 1. Also as above, it is required that at least one of X1 and X2 
together with at least one of X3 and X4 are occupied by a group selected 
group of blocking substituents consisting of secondary or tertiary alkyl 
groups, aryl groups, silyl groups, and alkyl groups beating heteroatom 
substituents such as alkoxy or halide. Preferably, it is the X1 and X3 
sites which bear one of these substituents. More preferably, X1 and X3 
bear the same substituent, which substituent is most preferably a tertiary 
alkyl group, such as tertiary butyl. 
The substituents on the Y3 and Y6 sites affect the conformation of the 
ligand and thus have an influence on enantioselectivity in the 
epoxidation. Preferably, Y3 and Y6 are hydrogen, methyl, alkyl, or aryl. 
More preferably, they are hydrogen or methyl. Most preferably, they are 
hydrogen. 
The substituents Z1 and Z2 affect the differentiation between the faces of 
the proposed metal oxo and thus have an influence on enantioselectivity in 
the epoxidation. Preferably, Z1 and Z2 are hydrogen, ethyl, alkyl, silyl, 
or aryl. More preferably, they are alkyl or aryl groups. 
The Y1, Y2, Y4, and Y5 sites on the catalyst of this second aspect are also 
seen to be less critical. As above, these sites are preferably occupied by 
hydrogen, although these sites may also be occupied by substituents 
independently selected from the group consisting of hydrogen, halides, 
alkyls, aryls, alkoxy groups, nitro groups. 
As can be visualized, this binaphthyl alternative embodiment effects the 
same enantioselectivity as that of the preferred catalysts shown in the 
other figures. In particular, the configuration of the binaphthyl ligand 
provides for one of the naphthyl groups to be above the plane of the 
catalyst and the other naphthyl group to be below the plane of the 
catalyst, thereby favoring approach to the oxygen atom from one side. 
The Third Aspect of the Invention 
FIG. 6 shows the structure of the third aspect of the present invention. In 
accordance with this aspect, the chiral catalyst has the following 
structure: 
##STR10## 
As with the first and second aspects, M is a transition metal ion selected 
from the group mentioned above, with Mn being the most preferred. 
Likewise, A is an anion selected from the group mentioned above, with Cl 
being most preferred. 
Also, n can be 0, 1, or 2, but 0 is the most preferred. 
As with the first and second aspects, there is a blocking substituent on 
either X1 or X2 or on both. This blocking substituent is selected from the 
group consisting of aryls, primary alkyls, secondary alkyls, tertiary 
alkyls, and hetero atoms. There is also a blocking substituent selected 
from the same group on either X3 or X4 or on both. Preferably, the 
blocking substituents are at X1 and X3. More preferably they are the same 
group, and most preferably the blocking substituents are tert-butyl. 
As a point of difference with the first aspect, the third aspect requires a 
blocking substituent located at the following positions: at least one of 
Y1 and Y2, and at least one of Y4 and Y5. These blocking substituents are 
selected from the group as those for X1-X4, namely the group consisting of 
aryls, primary alkyls, secondary alkyls, tertiary alkyls, and hetero 
atoms. The importance of these "side" blocking substituents will be 
discussed below. 
In this third aspect, substituents Y3 and Y6 are independently selected 
from the group consisting of hydrogen and primary alkyl groups. 
Preferably, Y3 and Y6 are hydrogen. 
Also in this third aspect, at least one of R1, R2, R3 and R4 is hydrogen. 
Where R1 is hydrogen, R3 is a primary alkyl. Where R2 is hydrogen, R4 is a 
primary alkyl. Where R3 is hydrogen, R1 is a primary alkyl. Finally, where 
R4 is hydrogen, R2 is a primary alkyl. Preferably, R1 and R4 are both 
hydrogen and R2 and R3 are primary alkyls. Most preferably, R2 and R3 are 
methyl groups. 
As can be seen, the catalyst of this third aspect is similar to the 
catalyst of the first aspect with the exception that the third aspect 
requires blocking substituents at the side positions of the catalyst, i.e. 
on the Y1 and/or Y2, and Y4 and/or Y5 sites. Also, either one or two of 
R1, R2, R3 and R4 is required to be an hydrogen, with the remaining 
substituents at the R sites required to be primary alkyls in the defined 
arrangement. The importance of this configuration and the proposed 
mechanism for the second catalyst are discussed below in connection with 
FIG. 10. 
The Fourth Aspect of the Invention 
FIG. 7 shows the structure of a catalyst of the fourth aspect of the 
invention. This catalyst has the following structure: 
##STR11## 
In this embodiment, the transition metal, M, and the anion, A, are selected 
from the same groups as above, with the same preferences. 
Likewise, the substituents at X1, X2, X3, X4, Y1, Y2, Y4, and Y5 are 
selected from the same groups as in the second catalyst described above 
with the same preferences. In other words, this embodiment requires 
blocking substituents at the "bottom" and "sides" as does the second 
catalyst. Most preferably, X1, X3, Y1, and Y4 are all t-butyl. 
The requirements and preferences for Y3 and Y6 are the same as with the 
third aspect. Preferably, Y3 and Y6 are hydrogen. 
As can be seen, this catalyst of the fourth aspect of the invention 
includes a ring attached to the two nitrogen atoms, which ring is n+2 
carbons long. In this catalyst, n can be 3, 4, 5 or 6. The carbons in the 
"C.sub.n " portion can have substituents selected from hydrogen, alkyl, 
aryl, and hetero atoms. Preferably, the substituents on the carbons in the 
"C.sub.n " portion are hydrogen. 
In this fourth aspect, R1 and R4 are configured so as to be trans to each 
other. Also, R1 and R4 are selected from the group consisting of primary 
alkyls and hydrogen. Preferably, R1 and R4 are the same. Most preferably, 
both R1 and R4 are hydrogen. Most preferably, this catalyst is used to 
epoxidize cis-cinnamate derivatives (see below). 
Conceptually, the carbons in the ring which are adjacent the carbons which 
in turn are adjacent the nitrogen atoms are attached to what were shown as 
the R2 and R3 sites in the third aspect (FIG. 6). Thus, this fourth aspect 
is, in some respects, a subset of the third aspect with the two ends of 
the n carbon chain (a primary alkyl) being attached to the R2 and R3 
sites. 
One distinction between the third and fourth aspects is that the catalyst 
of the fourth aspect has R1 and R4 which can be either hydrogen or a 
primary alkyl. 
FIG. 8 shows a preferred embodiment of this fourth aspect of the invention. 
As can be seen in this embodiment, the ring is six-membered, that is, n=4. 
Also, R1 and R4, which are trans to each other, are hydrogen. X1, X3, Y1, 
and Y4 are all t-butyl. All other substituents are hydrogen. 
FIGS. 9 and 10 illustrate the distinction between the mechanism proposed 
for the first and second aspects of the invention and the proposed 
mechanism for the third and fourth aspects. 
FIG. 9, representing the first and second aspects, shows the proposed 
favored approach of the prochiral olefin. Approach c is believed to be 
disfavored by the bulky t-butyl groups. Approach d is similarly 
unfavorable, due to the steric bulk of the phenyl groups on the catalyst. 
Approaches a and b are differentiated by the dissymmetry of the catalyst. 
As shown in the depicted embodiment, because the phenyl to the left is 
below the page and the phenyl to the right is above the page, it is 
predicted that approach b will be less favorable due to steric 
interactions between the olefin and the phenyl group. In the context of 
the more favored approach from the left (approach a), it is predicted that 
the more favorable approach of the olefin to the oxo group is such that 
the larger substituent on the olefin is oriented away from the t-butyl 
groups on the catalyst. 
FIG. 10, representing the third and fourth aspects of the invention, shows 
the proposed favored approach of the olefin when the catalyst has side 
blocking groups. It is believed that, because of the side t-butyl groups 
at Y1 and Y4, the approaches a from the left and b from the right are 
disfavored. Likewise, because of the bottom blocking groups at X1 and X3, 
the approach c from the bottom is also disfavored. Thus, approach d from 
the top is favored. In addition, because of the chirality of the catalyst, 
the orientation of the prochiral olefin is also influenced. As shown in 
this depicted embodiment, because of greater steric hindrance on the 
right, the olefin is predicted to orient itself with the larger group on 
the left. 
Because approach d is theorized to be the favored approach, the groups at 
R1 and R4 are limited to hydrogen and primary alkyls. In other words, it 
is believed that larger groups would block the approach d. 
It should be noted that, although the above discussion is consistent with 
the observed results, the proposed mechanism for all four aspects of the 
invention is only theorized at this point. Consequently, the explanation 
is not to be viewed as limiting the scope of the invention as defined in 
the appended claims. 
The preferred route to prepare the chiral catalysts of the present 
invention is a condensation reaction with the substituted salicylaldehyde 
and the substituted diamine. In general, quantities of these compounds are 
reacted in a 2 to 1 molar ratio in absolute ethanol. The solutions are 
refluxed typically for 1 hour, and the salen ligand is either precipitated 
in analytically pure form by addition of water, or the metal complex is 
generated directly by addition of the metal as its acetate, halide, or 
triflate salt. 
The following procedure is general for the preparation of: 
##STR12## 
The salen ligand is redissolved in hot absolute ethanol to give a 0.1M 
solution. Solid Mn(OAc).sub.2 .multidot.4H.sub.2 O (2.0 equivalents) is 
added in one portion and the solution is refluxed for 1 h. Approximately 3 
equivalents of solid LiCl are then added and the mixture is heated to 
reflux for an additional 0.5 h. Cooling the mixture to 0.degree. C. 
affords the Mn(III) complex 1 as dark brown crystals which are washed 
thoroughly with H.sub.2 O and isolated by filtration in .apprxeq.75% 
yield. An additional crop of material can be obtained by dropwise addition 
of H.sub.2 O to the mother liquor. Combined yields of catalyst are 89-96% 
for this step, and 81-93% overall from the optically pure 
1,2-diphenylethylene aliamine. Acceptable C, H, N, Cl, and Mn analyses of 
each of the catalysts have been obtained (.+-.0.4%), although these vary 
according to the extent of water and ethanol incorporation in the powdery 
product. Enantioselectivities in the epoxidation reactions did not vary 
among different batches of a given catalyst, indicating that the solvent 
content of the catalysts does not influence its effectiveness. 
Another example of the method of preparing the catalyst is described as 
follows: Most preferably, the starting diamine is R,R- or 
S,S-1,2-diamino-1,2-diphenylethane and the starting salicylaldehyde is 
3-tert-butylsalicylaldehyde. 
A solution of 2.0 mmol of 3-tert-butylsalicylaldehyde in 3 ml of absolute 
ethanol is added dropwise to a solution of 1.0 mmol of 
(R,R)-1,2-diamino-1,2-diphenylethane in 5 ml of ethanol. The reaction 
mixture is heated to reflux for 1 h and then 1.0 mmol of Mn(OAc).sub.2 
.multidot.4H.sub.2 O is added in one portion to the hot (60.degree. C.) 
solution. The color of the solution immediately turns from yellow to brown 
upon addition. It is refluxed for an additional 30 min and then cooled to 
room temperature. A solution of 10% NaCl (5 ml) is then added dropwise and 
the mixture stirred for 0.5 h. The solvents are then removed in vacuo and 
the residue is triturated with 50 ml of CH.sub.2 Cl.sub.2 and 50 ml of 
H.sub.2 O. The organic layer is separated and the brown solution was 
washed with saturated NaCl. Separation of the organic phase and removal of 
solvent resulted in a crude material which was recrystallized from C.sub.6 
H.sub.6 /C.sub.6 H.sub.14 to give 0.938 mmol of the (R,R)-catalyst shown 
above (93.8%). 
In accordance with the epoxidation method aspect of the invention, the 
prochiral olefin, an oxygen atom source, and the chiral catalyst are 
reacted under such conditions and for such time as is needed to epoxidize 
said olefin. 
The prochiral olefin can be selected from mono-substituted, 
1,1-disubstituted, cis-1,2-disubstituted, trans-1,2-disubstituted, 
trisubstituted, and tetrasubstituted. Of these, the monosubstituted and 
cis-1,2-disubstituted have shown the highest ee values. 
Preferably, the prochiral olefin to be epoxidized is selected from the 
group consisting of cis-disubstituted olefins, including cyclic olefins, 
bearing a sterically demanding substituent on one end and a smaller 
substituent on the other end. More preferably, the prochiral olefin is a 
cis disubstituted olefin with a primary substituent on one side of the 
double bond and a secondary, tertiary, or aryl substituent on the other 
side. 
The prochiral olefin can also be selected from the group consisting of 
enamines, enols, and alpha, beta-unsaturated carbonyls. More preferably, 
the prochiral olefin is selected from the group consisting of 
cis-.beta.-methyl-styrene, dihydronaphthalene, 
2-cyclohexenyl-1,1-dioxolane, propylene, styrene and 2,2-dimethylchromene. 
Most preferably, the prochiral olefin is cis-.beta.-methylstyrene. 
The oxygen atom source used in the epoxidation reaction should be an 
oxidant which is relatively unreactive toward olefins under mild 
conditions. Preferably, the oxygen atom source is selected from the group 
consisting of NaOCl, iodosylmesitylene, NaIO.sub.4, NBu.sub.4 IO.sub.4, 
potassium peroxymonosulfate, magnesium monoperoxyphthalate, and 
hexacyanoferrate ion. More preferably, the oxygen atom source is selected 
from the group consisting of NaOCl and iodosylmesitylene. For economic 
reasons, the most preferred oxygen atom source is NaOCl. 
A preferred method uses NaOCl as the oxygen atom source. For convenience 
this method will be designated METHOD A. The details of METHOD A are as 
follows: 
A solution of 0.05M Na.sub.2 B.sub.4 O.sub.7 10H.sub.2 O (1.0 ml) is added 
to a 2.5 ml solution of undiluted commercial household bleach (Chlorox). 
The pH of the resulting buffered solution is approximately 9.5, and it is 
adjusted to a pH of about 10.5 by addition of a few drops of 1M NaOH 
solution. To this solution is added a solution of 0.02 mmol of the 
preferred catalyst and 1.0 mmol of cis B methylstyrene in 2.0 ml of 
CH.sub.2 Cl.sub.2. The two-phase mixture is stirred at room temperature 
and the reaction progress is monitored by capillary gas chromatography. 
After approximately 3 hours, 10 ml of CH.sub.2 Cl.sub.2 is added to the 
mixture and the brown organic phase is separated, washed twice with 10 ml 
H.sub.2 O and once with 10 ml saturated NaCl solution, and then dried for 
15 minutes over anhydrous Na.sub.2 SO.sub.4. The solution is filtered and 
solvent is removed under vacuum. The residue is purified by flash 
chromatography on silica gel using a 20:80 mixture of CH.sub.2 Cl.sub.2 
:hexane as the eluting solvent. Pure epoxide is isolated as a colorless 
liquid in 70% yield (0.70 mmol) by combination of the product-containing 
fractions and removal of solvent under vacuum. The optical purity of this 
material is determined to be 85% ee by the method described below. 
In a slightly less preferred embodiment, iodosylmesitylene is used as the 
oxygen atom source. For convenience, this method is designated as METHOD B 
and has the following preferred details: A solution of 1.0 mmol of olefin, 
8 ml CH.sub.2 Cl.sub.2 and 0.04 mmol of the catalyst are stirred at room 
temperature as solid iodosomesitylene is added in 0.3 mmol portions at 
15-30 minute intervals. Disappearance of starting olefin is complete after 
addition of 6 portions (1.8 mmol) of total iodosylmesitylene. Solvent is 
removed in vacuo, the residue is extracted with hexane, and the mixture 
was filtered through Celite to remove catalyst and other solids. Pure 
epoxide was obtained by flash chromatography (10 g SiO.sub.2, CH.sub.2 
Cl.sub.2 /hexane 20:80 eluent). Enantiomeric excesses are determined by 1H 
NMR using Eu(hfc).sub.3 as a chiral shift reagent, or in the case of 
stilbene oxide by direct separation by HPLC on a commercial (Regis) 
covalently-bound leucine Pirkle column. Absolute configurations were 
assigned by comparison of .alpha.D with accepted literature values. 
An alternative method also uses a pyridine-N-oxide derivative as a 
coordinating ligand, in addition to NaOCl as the oxygen source. More 
preferably, 4-phenylpyridine-N-oxide or 4-t-butylpyridine-N-oxide is used. 
Even more preferably, 4-phenylpyridine-N-oxide is used. 
The trans-epoxide is a significant (about 25%) by-product of the 
epoxidation reaction. Preferably, the mixture of diastereomeric products 
is enriched in the desired cis- form by flash chromatography. Even more 
preferably, for large scale batches, no chromatography is not performed. 
The next steps are shown in Scheme 2. 
##STR13## 
The epoxide mixture is reacted with ammonia in ethanol, which results in 
regioselective ting-opening to the desired 3-phenyl-isoserine amide 
derivative. Preferably, very little regioisomer is detected in the crude 
amide mixture by .sup.1 H NMR. Next, diastereomerically pure 
3-phenyl-isoserinamide is isolated by recrystallization of the crude 
product mixture. For convenience this method will be designated METHOD C. 
The details of METHOD C are as follows: 
A solution of 0.05M Na.sub.2 B.sub.4 O.sub.7 .multidot.10H.sub.2 O (1.0 ml) 
or other suitable buyer such as phosphate is added to a 2.5 ml solution of 
undiluted commercial household bleach (Chlorox.RTM.). The pH of the 
resulting buffered solution is approximately 9.5, and it is adjusted to a 
pH of about 10.5-11.5 by addition of a few drops of 1M NaOH solution and 
cooled in an ice bath to about 0.degree.-4.degree. C. A separate solution 
of 10 mmol of alkene and 2.0 mmol (or 20 mol %) of a pyridine-N-oxide 
derivative are dissolved in 10 ml of CH.sub.2 Cl.sub.2. Next, 0.05-0.6 
mmol (0.5-6 mol %) of catalyst 1 or 2 were added to the alkene solution 
and 
##STR14## 
cooled separately in an ice bath. When the two solutions were at 
0.degree.-4.degree. C., they were combined, and the two-phase mixture was 
stirred. The reaction progress was monitored by capillary gas 
chromatography. After about one to five hours, 200 ml of hexane was added 
to the mixture and the organic phase was separated, washed twice with 100 
ml H.sub.2 O and once with 100 ml saturated NaCl solution, and then dried 
for 15 minutes over anhydrous Na.sub.2 SO.sub.4. The solution is filtered 
and solvent is removed under vacuum. The residue is purified by 
chromatography, distillation or crystallization. Pure epoxides were 
isolated, and the optical purity of the materials were determined as 
described in more detail below. 
Method of Chromene Lipoxidation 
As noted above, the present invention is a method of using a chiral 
catalyst to epoxidize a chromene derivative, thus producing an 
epoxychroman. The structure of the chromene derivative is as follows: 
##STR15## 
wherein R1, R2, R3, R4, X1, X2, X3, and X4 are each selected from the 
group consisting of hydrogen, aryls, primary alkyls, secondary alkyls, 
tertiary alkyls, and hetero atoms, and wherein no more than one of R1 and 
R2 are hydrogen. 
It has been found that when both R1 and R2 are hydrogen, i.e. when the 
chromene is not substituted at the R1 and R2 locations, the epoxide is not 
formed (see Example 24 below). 
Preferably, R1 and R2 are the same group. In this situation, the chromene 
derivative is prochiral. 
Also, the chromene derivative preferably includes an alkyl group at both R1 
and R2. More preferably, the chromene derivative includes a methyl group 
at R1 and R2. Most preferably, the chromene derivative is 
6-cyano-2,2-dimethylchromene, namely the precursor for making cromakalim. 
As mentioned above, this most preferred chromene derivative can be 
epoxidized with a remarkably high degree of enantioselectivity to the 
epoxychroman useful in producing enantiomerically pure cromakalim (see 
Example 17 below). 
As noted above, this embodiment of the present invention has been found to 
produce remarkable enantioselectivity in the epoxidation of chromene 
derivatives. In addition, the catalysts of the present invention have been 
found to provide remarkably high yields (See Examples 17-23, and 25 
below). The catalyst of the fourth aspect (FIG. 8) above is the most 
preferred catalyst used in the present method. Experiments have shown that 
when a racemic mixture of the chiral catalysts are used in the reaction 
that relatively high yields of a racemic mixture of the epoxychromans are 
achieved. Consequently, in accordance with a less preferred embodiment of 
the invention, when a racemic mixture of the epoxychromans is desirable or 
acceptable, a racemic mixture of the chiral catalyst is used with the 
chromene derivatives. Nevertheless, because enantiomerically pure 
epoxychromans are typically highly desirable, particularly as synthetic 
precursors, enantiomerically pure chiral catalysts are clearly preferred. 
In accordance with the epoxychroman synthetic method of the present 
invention, the chromene derivative, an oxygen atom source, and the chiral 
catalyst are reacted under such conditions and for such time as is needed 
to epoxidize said chromene derivative. Alternatively, a pyridine-N-oxide 
derivative is added to the reaction mixture. 
The oxygen atom source used in the epoxidation reaction should be an 
oxidant which is relatively unreactive toward olefins under mild 
conditions. Preferably, the oxygen atom source is selected from the group 
consisting of NaOCl, iodosylmesitylene, NaIO.sub.4, NBu.sub.4 IO.sub.4, 
potassium peroxymonosulfate, magnesium monoperoxyphthalate, H.sub.2 
O.sub.2, peroxybenzoic acid derivatives, and hexacyanoferrate ion. More 
preferably, the oxygen atom source is selected from the group consisting 
of NaOCl and iodosylmesitylene. For economic reasons, the most preferred 
oxygen atom source is NaOCl. 
In the most preferred method for chromene epoxidation, NaOCl is the oxygen 
atom source, as described above for METHOD A. In a slightly less preferred 
embodiment, iodosylmesitylene is used as the oxygen atom source, as 
described above for METHOD B. Alternatively, a pyridine-N-oxide derivative 
and NaOCl are used, as described in METHOD C. 
Method of Epoxidation of cis-Cinnamate Derivatives and Preparation of Taxol 
Intermediates and Analogs 
As a first step in the synthesis of the C-13 side chain of taxol, 
commercially available ethyl phenylpropiolate is partially hydrogenated to 
cis-ethyl cinnamate over commercial Lindlar's catalyst (Scheme 1 below). 
Because the reaction was observed to be more enantioselective, ethyl 
phenylpropiolate is preferred over methyl phenylpropiolate as a starting 
material. 
##STR16## 
The cis-ethyl cinnamate thus obtained has been observed to contain small 
amounts (about 5%) of overreduced material and starting alkyne. However, 
these impurities do not appear to interfere with subsequent steps and are 
easily removed later in the synthetic sequence. 
Next, cis-ethyl cinnamate is epoxidized with commercial bleach in the 
presence of one of the chiral catalysts discussed above as the first, 
second third and fourth embodiments of the invention. Most preferably, the 
fourth embodiment of the invention (the (R,R) 5 catalyst of FIG. 8) is 
employed and is shown below: 
##STR17## 
In the presence of this enantioselective catalyst, the cis-ethyl cinnamate 
was observed to epoxidize to the (R,R)-(+) enantiomer of the cis-epoxide. 
Preferably, 4-phenylpyridine-N-oxide is added to the epoxidation mixture. 
This coordinating ligand appears to markedly enhance reaction completion 
and enantioselectivity. With the use of 4-phenylpyridine-N-oxide, the 
(R,R)-(+)- enantiomer of cis-ethyl cinnamate epoxide was in excess of 
96-97%. Either a less preferred pyridine-N-oxide derivative, or 
4-t-butylpyridine-N-oxide may be used, but 4-phenylpyridine-N-oxide is 
preferred. 
The trans-epoxide is a significant (about 25%) by-product of the 
epoxidation reaction. Preferably, the mixture of diastereomeric products 
is enriched in the desired cis- form by flash chromatography. Even more 
preferably, for large scale batches, no chromatography is not performed. 
The next steps are shown in Scheme 2 below. 
##STR18## 
The epoxide mixture is reacted with ammonia in ethanol, which results in 
regioselective ring-opening to the desired 3-phenyl-isoserine amide 
derivative. Very little regioisomer has been detected in the crude amide 
mixture by .sup.1 H NMR. Next, diastereomerically pure 
3-phenyl-isoserinamide was isolated by recrystallization of the crude 
product mixture. 
The 3-phenyl-isoserinamide is hydrolyzed to remove the amide group. 
Preferably, the hydrolysis is effected without epimerization. Even more 
preferably, the hydrolysis is effected by using Ba(OH).sub.2 in water. 
Next, the hydrolyzing salt is acidified and precipitated. Preferably, if 
Ba(OH).sub.2 salt is used for hydrolysis, it is next precipitated out of 
the solution by addition of sulfuric acid. 
Next, 3-phenyl-isoserine is obtained directly by crystallization of the 
product mixture. This enantiomerically enriched 3-phenyl-isoserine is used 
to prepare a wide variety of taxol analogs. Preferably, the taxol side 
chain benzoyl derivative is prepared from 3-phenyl-isoserine. 
The taxol side chain is prepared by adding to the 3-phenyl-isoserine formed 
above benzoyl chloride and sodium bicarbonate in an acid two-phase 
reaction. Subsequently, the benzoic acid by-product is extractively 
removed by stirring the solid product mixture with ether and ethanol. 
Finally, pure N-benzoyl-3-phenyl-isoserine is collected by filtration. The 
material thus obtained was determined by polarimetry to have an ee of more 
than 97% and to have the same absolute configuration as the side chain 
from natural taxol. 
The N-benzoyl-3-phenyl-isoserine is reacted to produce 
N-benzoyl-O-(1-ethoxyethyl)-3-phenyl-isoserine, which in turn is reacted 
with a tertiary amine activating agent and 7-triethylsilyl baccatin III to 
form a C-2', C-7-protected taxol derivative. This derivative is treated 
with acid in ethanol to produce taxol. 
While not wishing to be bound by this theory, it appears that 
4-phenylpyridine-N-oxide effectively increases the success of the 
enantiomerically selection and complete epoxidation of cis-ethyl cinnamate 
to the (R,R)-(+)-enantiomer of the cis-epoxide. In the absence of 
4-phenyl-pyridine-N-oxide, epoxidation is 10-15% less selective and is 
less complete, even when 15-20 mol % more catalyst is used. Control 
experiments indicated that the pyridine-N-oxide derivative did not act as 
the oxygen-atom source, but rather as a coordinating ligand. It appears 
that coordination of pyridine-N-oxide derivative to the mildly Lewis 
acidic Mn(BI) and/or Mn(V) oxo intermediate helps prevent the metallic 
center from remaining complexed with the carbonyl functionality on the 
substrate in a non-product coordination mode. Thus, the pyridine-N-oxide 
derivative appears to prevent decomposition reactions and improve catalyst 
stability with certain olefins, although not all olefins. 
The enantioselectivity of the reaction was also found to be quite sensitive 
to the identity of the ester group on the starting material, with 
cis-methyl cinnamate being epoxidized under similar conditions as 
cis-ethyl cinnamate, but in only 87-89% enantiomeric excess. 
The advantages of this synthetic method are that it begins with 
commercially available ethyl phenylpropiolate and employs hydrogen gas, 
household bleach, ammonia and barium salts as stoichiometric reagents. 
Another advantage is the high optical and chemical purity of 
N-benzoyl-3-phenyl-isoserine. As will become apparent in the examples 29 
to 39 below, the yields of each of the individual steps are acceptable for 
a commercially feasible process, even though they have not yet been 
completely optimized. The catalytic specificity, procedural simplicity, 
inexpensive reagents and avoidance of preparative chromatographic 
separations renders this synthetic method a most practical route to 
enantiomerically pure 3-phenyl-isoserine derivatives. 
Method of Sulfide Oxidation 
As noted above, the present invention is a method of using a chiral 
catalyst to enantioselectively oxidize a sulfide to a sulfoxide. The 
method involves reacting a sulfide, an oxygen atom source, and a chiral 
catalyst under the proper conditions to oxidize the sulfide. Preferably 
the sulfide has the formula R1-S-R2 where R1 is any aromatic group and R2 
is any alkyl group. Preferably, the oxygen atom source is hydrogen 
peroxide or iodosylbenzene and preferably, a cosolvent such as 
tetrahydrofuran, acetone, or acetonitrile is used. 
As described above, for enantioselective epoxidation by the (salen)Mn 
catalysts, aqueous sodium hypochlorite was used as the stoichiometric 
oxidant. However, the reaction between sulfides and sodium hypochlorite 
was too rapid for this oxidant be useful for enantioselective sulfide 
oxidation reactions. Iodosylbenzene was tried because iodosylarenes react 
slowly with sulfides. It was found that iodosylbenzene did indeed serve as 
an effective oxygen atom source. However, iodosylarenes are impracticable 
as stoichiometric oxidants due to their instability in the solid state, 
their lack of solubility, their relatively high cost and the high 
molecular weight of the byproduct of oxygen transfer, an iodoarene. 
Hydrogen peroxide was determined to be a good oxidant for sulfide 
oxidation. Hydrogen peroxide gave higher yields of sulfoxide, minimal 
overoxidation to sulfone and identical enantioselectivities to those 
observed with iodosylbenzene. This suggests that both oxidants generate a 
common Mn(V) oxo reactive intermediate. 
To facilitate the reaction, a cosolvent was used. The cosolvent minimized 
the catalase-decomposition of hydrogen peroxide by the catalysts and a 
complete conversion of sulfide was accomplished with less than 6 
equivalents of oxidant. 
Generally, catalysts derived from 1,2-diaminocyclohexane and 
1,2-diphenylethylene diamine were more selective than those prepared from 
other synthetically less accessible diamines. FIGS. 19 and 20 show the 
structures of the preferred catalysts. Specific catalysts based on these, 
were tested for asymmetric sulfide oxidation and Example 40 lists the 
results of the tests. 
Catalytic Disproportionation of Hydrogen Peroxide 
As mentioned above, the decomposition of hydrogen peroxide into oxygen and 
water is a biologically important process. All of the catalysts described 
so far are useful in the catalytic disproportionation of hydrogen 
peroxide. However, for this particular reaction, the catalysts do not have 
to be chiral. Thus, any catalyst having the following formula will 
function in the decomposition reaction: 
##STR19## 
wherein M is a transition ion, A is an anion, n is either 0, 1, or 2 and 
X1 through X14 are independently selected from the group consisting of 
hydrogen, halides, alkyls, aryls and alkyl groups bearing hetero atoms. 
The catalysts of the present invention are stable, easy to synthesize, have 
a low molecular weight and a high catalytic activity. In fact their 
catalytic activity is comparable to any synthetic catalase mimic developed 
to date. The preferred catalysts are the monometallic (salen)Mn complexes 
shown in FIGS. 22 and 23. 
To carry out the disproportionation reaction, the catalyst is mixed with a 
solvent such as EtOH, acetone, CH.sub.2 Cl.sub.2, or H.sub.2 O and then 
hydrogen peroxide is added. 
EXAMPLES 
The following examples are provided by way of explanation and illustration. 
As such, these examples are not to be viewed as limiting the scope of the 
invention as defined by the appended claims. 
Preparation of the Catalysts 
Procedures for the Preparation of Chiral Salen Based Catalysts 
Preparation of: 
##STR20## 
(R,R)-1,2-Diphenyl-1,2-bis(3-tert-butylsalicylideamino)ethane (2). 
A solution of 360.5 mg (2.0 mmol) of 3-tert-butylsalicylaldehyde in 3 ml of 
EtOH was added dropwise to a solution of 212.3 mg (1.0 mmol) of 
(R,R)-1,2-diamino-1,2-diphenylethane in 5 ml of EtOH. The reaction mixture 
was heated to reflux for 1 h and water (5 ml) was added. The oil that 
separated solidified upon standing. Recrystallization from MeOH/H.sub.2 O 
gave 485.8 mg (91%) of yellow powder, mp 73.degree.-74.degree. C. .sup.1 H 
NMR (CDCl.sub.3) .delta. 1.42 (s, 18H, CH.sub.3), 4.72 (s, 2H, CHN.dbd.C), 
6.67-7.27 (m, 16H, ArH), 8.35 (s, 2H, CH.dbd.N), 13.79 (s, 2H, ArOH) ppm; 
13C NMR (CDCl.sub.3) .delta. 29.3, 34.8, 80.1, 117.8, 118.5, 127.5, 128.0, 
128.3, 129.6, 130.1, 137.1, 139.5, 160.2, 166.8 ppm. Anal. Calcd. for 
C.sub.36 H.sub.40 N.sub.2 O.sub.2. C, 81.17; H, 7.57; N, 5.26. Found: C, 
81.17; H, 7.60; N, 5.25. 
((R,R)-1,2-Diphenyl-1,2-bis(3-tert-butylsalicylideamino)ethane)manganese(II 
) Complex (3). 
Under strictly air-free conditions, a solution of 64.0 mg (1.6 mmol) of 
NaOH in 2 ml of MeOH was added dropwise to a solution of 426.1 mg (0.8 
mmol) of (2) in 5 ml of EtOH with stirring under an atmosphere of 
nitrogen. A solution of 196.1 mg (0.8 mmol) of Mn(OAc).sub.2 
.multidot.4H.sub.2 O in 3 ml of MeOH was added rapidly and the orange 
mixture was stirred for 24 hr. The solvent was removed in vacuo and the 
residue was stirred with 5 ml of benzene and filtered to remove NaOAc. The 
filtrate was concentrated to about 1 ml and 3 ml of hexane was added. The 
mixture was cooled to -30.degree. C. and the precipitate was collected by 
filtration to give 410.2 mg (87%) of orange powder. Anal. Calcd. for 
C.sub.36 H.sub.38 MnN.sub.2 O.sub.2 -(CH.sub.3 OH) 0.5; C, 72.86; H, 6.70; 
N, 4.66. Found: C, 73.05; H, 6.76; N, 4.39. 
((R,R)-1,2-Diphenyl-1,2-bis(3-tert-butylsalicylideamino)ethane)manganese(II 
I) Hexafluorophosphate ((R,R)-1). 
A solution of 165.5 mg (0.5 mmol) of ferrocenium hexafluorophosphate in 2 
ml of CH.sub.3 CN was added dropwise to a solution of 292.8 mg (0.5 mmol) 
of (3) in 3 ml of CH.sub.3 CN under N.sub.2. The reaction mixture was 
stirred for 30 min and the solvent was removed in vacuo. The residue was 
triturated with 5 ml of hexane and filtered. The solid was then washed 
with hexane until the filtrate was colorless and dried under vacuum to 
give 360.5 mg (93%) of (1) as a brown powder. IR (CH.sub.2 Cl.sub.2) 2955, 
1611, 1593, 1545, 1416, 1389, 1198, 841 cm.sup.-1. Anal. Calcd. for 
C.sub.36 H.sub.38 F.sub.6 MnN.sub.2 O.sub.2 P.multidot.(H.sub.2 
O)1.5.multidot.(CH.sub.3 CN)0.5: C, 56.93; II, 5.30; N, 4.57. Found: C, 
57.11; H, 5.50; N, 4.50. 
Preparation of: 
##STR21## 
The salicylaldehyde derivative (4) was prepared by the following sequence 
using well-established procedures in each step: 
##STR22## 
(R,R)-1,2-Diphenyl-1,2-bis(3-diphenylmethylsilylsalicylideamino)ethane (5). 
A solution of 348.3 mg (1.09 mmol) of (4) and 116.0 mg (0.546 mmol) of 
(R,R)-1,2-diamino-1,2-diphenylethane in 5 ml of ethanol was heated to 
reflux for 0.5 h. A bright yellow oil separated from the solution and it 
solidified upon standing. The mixture was faltered and the yellow solid 
was washed with 2.times.5 ml ethanol. The isolated yield of product pure 
by .sup.1 H NMR analysis was 416 mg (97%). .sup.1 H NMR (CDCl.sub.3) 80.95 
(s, 3H), 4.68 (s, 2H), 6.72-7.55 (m, 36H, ArH), 8.37 (s, 2H), 13.34 (s, 
2H) ppm. 
((R,R)-1,2-Diphenyl-1,2-bis(3-diphenylmethylsilylsalicylideamino)ethane)man 
ganese(II) Complex (6). 
Under strictly air-free conditions, a solution of 32.0 mg (0.48 mmol) of 
KOH in 2 ml of ethanol was added dropwise to a suspension of 195 mg (0.24 
mmol) of (5) in 3 ml of ethanol with stirring. The heterogeneous mixture 
was stirred for 20 min, and a solution of 51.5 mg (0.24 mmol) of 
Mn(OAc).sub.2 .multidot.4H.sub.2 O in 3 ml of MeOH was then added rapidly. 
The yellow-orange mixture was stirred for 8 hr. at room temperature, then 
refluxed under N.sub.2 for 4 hr. The solvent was removed in vacuo and the 
residue was washed with 5 ml of methanol, 5 ml of ethanol, and isolated by 
filtration. The yield of orange product was 188 mg (90%). This material 
was used in the next step without any further purification or analysis. 
((R,R)-1,2-Diphenyl-1,2-bis(3-diphenylmethylsilylsalicylideamino)ethane) 
manganese(III) Hexafluorophosphate ((R,R)-1(7). 
A solution of 72 mg (0.217 mmol) of ferrocenium hexafluorophosphate in 2 ml 
of CH.sub.3 CN was added dropwise to a solution of 188 mg (0.217 mml) of 
(6) in 3 ml of CH.sub.3 CN under N.sub.2. The reaction mixture was stirred 
for 30 min and the solvent was removed in vacuo. The solid residue was 
then washed with hexane until the filtrate was colorless. The brown powder 
was dried under vacuum to give 201.3 mg (92%) of (7). Anal. Calcd. for 
C.sub.54 H.sub.46 F.sub.6 MnN.sub.2 O.sub.2 PSi.sub.2 .multidot.(CH.sub.3 
CN)1.5.multidot.(H.sub.2 O): C, 62.77; H, 4.85; N, 4.50. Found: C, 62.89; 
H, 4.47; N, 4.57. 
Preparation of: 
##STR23## 
2,2'-Bis(3-tert-Butylsalicylideamino)-1,1'-Binaphthyl. 
A solution of 725 mg (4.0 mmol) of 3-tert-butyl-salicylaldehyde in 6 ml of 
EtOH was added dropwise to a solution of 569 mg (2.0 mmol) of 
(+)-2,2'-diamino-1,1-binaphthyl in 5 ml of EtOH. The reaction mixture was 
heated to reflux for 8 h and then volatile materials were removed under 
vacuum. The residue was purified by flash chromatography on 80 g SiO2, 
using 20% CH.sub.2 Cl.sub.2 in hexane as eluent. The mobile yellow 
fraction was collected and solvents were removed under vacuum to give 725 
mg (1.20 mmol, 59% yield) of the diamine as a yellow powder. 
1,1'-Binaphthyl-2,2'-bis(3-tert-Butylsalicylideamino)-manganese(II) 
Complex. 
Under strictly air-free conditions, a solution of 2 mmol of KOH in 2 ml of 
MeOH is added dropwise to a solution of 1 mmol of 
2,2'-bis(3-tert-butylsalicylideamino)-1,1'-binaphthyl in 5 ml of EtOH with 
stirring under an atmosphere of nitrogen. A solution of 1 mmol of 
Mn(OAc).sub.2 .multidot.4H.sub.2 O in 3 ml of MeOH is added rapidly and 
the orange mixture is stirred for 24 hr. The solvent is removed in vacuo 
and the residue was stirred with 5 ml of benzene and faltered to remove 
KOAc. The filtrate is concentrated to dryness to afford the Mn(II) complex 
as an orange powder. 
1,1'-Binaphthyl-2,2'-bis(3-tert-Butylsalicylideamino)-manganese(III) 
Hexafluorophosphate. 
A solution of 165.5 mg (0.5 mmol) of ferrocenium hexafluorophosphate in 2 
ml of CH.sub.3 CN is added dropwise to a solution of 0.5 mmol of 
1,1'-binaphthyl-2,2'-bis(3-tert-butylsalicylideamino)-manganese(II) 
complex in 3 ml of CH.sub.3 CN under N.sub.2. The reaction mixture is 
stirred for 30 min and the solvent is removed in vacuo. The residue is 
triturated with 5 ml of hexane and filtered. The solid is then washed with 
hexane until the filtrate is colorless and dried under vacuum to give the 
Mn(III) salt as a deep green powder. 
Preparation of: 
##STR24## 
No precautions to exclude air or moisture were necessary in this procedure. 
A solution of 360.5 mg (2.0 mmol) of 3-tert-butylsalicylaldehyde in 3 ml 
of absolute ethanol was added dropwise to a solution of 212.3 mg (1.0 
mmol) of (R,R)-1,2-diamino-1,2-diphenylethane in 5 ml of ethanol. The 
reaction mixture was heated to reflux for 1 h and then 245.1 mg (1.0 mmol) 
of Mn(OAc).sub.2 .multidot.4H.sub.2 O was added in one portion to the hot 
(60.degree. C.) solution. Upon addition, the color of the solution 
immediately turned from yellow to brown. It was refluxed for an additional 
30 min and then cooled to room temperature. A solution of 10% NaCl (5 ml) 
was then added dropwise and the mixture stirred for 0.5 h. The solvent was 
then removed in vacuo and the residue was triturated with 50 ml of 
CH.sub.2 Cl.sub.2 and 50 ml of H.sub.2 O. The organic layer was separated 
and the brown solution was washed with saturated NaCl. Separation of the 
organic phase and removal of solvent afforded crude material which was 
recrystallized from C.sub.6 H.sub.6 /C.sub.6 H.sub.14 to give 591 mg 
(0.938 mmol) of the chloride salt of (1) (94%). Anal. Calcd. for C.sub.36 
H.sub.38 ClMnN.sub.2 O.sub.2 .multidot.(H.sub.2 O)0.5: C, 68.63; H, 6.24; 
N, 4.45. Found: C, 69.01; H, 6.26; N, 4.38. 
Procedure for the Preparation of the Most Preferred Catalyst of the Fourth 
Aspect of the Invention 
(R,R)- and (S,S)-1,2,-bis(3,5-di-tert-butylsalicylide-amino)cyclohexane 
##STR25## 
3,5-Di-t-butylsalicylaldehyde (2.0 equivalents) was added as a solid to a 
0.2M solution of (R,R) or (S,S) 1,2-diaminocyclohexane (1.0 equivalent) in 
absolute ethanol. The mixture was heated to reflux for 1 hr. and then 
H.sub.2 O was added dropwise to the cooled bright yellow solution. The 
resulting yellow crystalline solid was collected by filtration and washed 
with a small portion of 95% ethanol. The yield of analytically pure salen 
ligand obtained in this manner was 90-97%. 
Spectroscopic and analytical data for the salen ligand: .sup.1 H NMR 
(CDCl.sub.3) .delta. 13.72 (s, 1H), 8.30 (S, 1H), 7.30 (d, J=2.3 Hz, 1H), 
6.98 (d, J=2.3 Hz, 1H), 3.32 (m, 1H), 2.0-1.8 (m, 2H), 1.8-1.65 (m, 1H), 
1.45 (m, 1H), 1.41 (s, 9H), 1.24 (s, 9H). .sup.13 C NMR (CDCl.sub.3): 
.delta. 165.8, 158.0, 139.8, 136.3, 126.0, 117.8, 72.4, 34.9, 33.0, 31.4, 
29.4, 24.3. Anal. Calcd for C.sub.36 H.sub.54 N.sub.2 O.sub.2 : C, 79.07; 
H, 9.95; N, 5.12. Found: C, 79.12; H, 9.97; N, 5.12. 
(R,R)- and 
(S,S)-[1,2-bis(3,5-di-tert-butylsalicylide-amino)cyclohexane]manganese(III 
) Chloride. 
The salen ligand immediately above is redissolved in hot absolute ethanol 
to give a 0.1M solution. Solid Mn(OAc).sub.2 .multidot.4H.sub.2 O(2.5 
equivalents) is added in one portion and the solution is refluxed for 1 
hr. Approximately 5 equivalents of solid LiCl are then added and the 
mixture is heated to reflux for an additional 0.5 hr. Cooling the mixture 
to 0.degree. C. and addition of a volume of water equal to the volume of 
the brown ethanolic solution to afford the Mn(III) complex as a dark brown 
powder which are washed thoroughly with H.sub.2 O, and isolated by 
filtration in 81-93% yield. Acceptable C, H, N, Cl, and Mn analyses of the 
catalyst have been obtained (.+-.0.4%), but these vary according to the 
extent of water and ethanol incorporation in the powdery product. 
Enantioselectivities in the epoxidation reactions are invariant with 
different batches of a given catalyst, indicating that the solvent content 
of the catalyst does not influence its effectiveness. 
Analytical data for this catalyst: Anal. Calcd for C.sub.36 H.sub.52 
ClMnN.sub.2 O.sub.2 .multidot.C.sub.2 H.sub.5 OH: C, 67.19; H, 8.31; Cl, 
5.22; Mn, 8.09; N, 4.12: Observed: C, 67.05; H, 8.34; Cl, 5.48; Mn, 8.31; 
N, 4.28. 
Procedures for the Asymmetric Epoxidation of Chromene Derivatives 
Method A (NaOCl as oxygen atom source): 
A solution of 0.05M Na.sub.2 B.sub.4 O.sub.7 .multidot.10H.sub.2 O (1.0 ml) 
was added to a 2.5 ml solution of undiluted commercial household bleach 
(Clorox.RTM.). The pH of the resulting buffered solution was approximately 
9.5, and it was adjusted to a pH of 10.5 by addition of a few drops of 1M 
NaOH solution. To this solution was added a solution of about 0.005 to 
0.02 mmol of the catalyst and about 1.0 mmol of olefin in 2.0 ml of 
CH.sub.2 Cl.sub.2. The two-phase mixture was stirred at room temperature 
and the reaction progress was monitored by capillary gas chromatography. 
Reactions were complete within approximately 1-5 hours. After the reaction 
was complete, 10 ml of CH.sub.2 Cl.sub.2 was added to the mixture and the 
brown organic phase was separated, washed twice with 10 ml H.sub.2 O and 
once with 10 ml saturated NaCl solution, and then dried for 15 min over 
anhydrous Na.sub.2 SO.sub.4. The solution was filtered and solvent was 
removed under vacuum. The residue was purified by standard procedures 
using flash chromatography on 10 g of silica gel using a mixture of 
CH.sub.2 Cl.sub.2 /hexane as the eluting solvent. Pure epoxide was 
isolated by combination of the product-containing fractions and removal of 
solvent under vacuum. Enantiomeric excesses were determined by .sup.1 H 
NMR Using Eu(hfc).sub.3 as a chiral shift reagent, or in the case of 
stilbene oxide by direct separation by HPLC on a commercial (Regis) 
covalently-bound leucine Pirkle column. Absolute configurations were 
assigned by comparison of [.alpha.]D with accepted literature values. 
Method B (iodosylmesitylene as oxygen atom source) 
A solution of 1.0 mmol of olefin, 8 ml CH.sub.2 Cl.sub.2 and 0.04-0.08 mmol 
of the catalyst was stirred at room temperature as solid iodosomesitylene 
was added in 0.3 mmol portions at 15-30 minute intervals. Disappearance of 
starting olefin was complete after addition of 4-10 portions (1.2 to 3 
equivalents) of total iodosylmesitylene. Solvent was removed in vacuo, the 
residue was extracted with hexane, and the mixture was filtered through 
Celite diatomaceous earth to remove catalyst and other solids. Pure 
epoxide was obtained by flash chromatography (10 g SiO.sub.2, CH.sub.2 
Cl.sub.2 /hexane eluent). The optical purity of this material was 
determined by the method described above. 
Asymmetric Epoxidation of Representative Olefins with the Most Preferred 
Embodiment of the First Aspect 
EXAMPLES 1-7 
______________________________________ 
Yield.sup.b Config- 
Entry Olefin.sup.a 
Catalyst (%) ee(%) uration.sup.c 
Method 
______________________________________ 
1 (R,R)-1 50 59 1R,2S-( ) 
B 
2 (R,R)-1d 75 57 R-(+) A 
3 (R,R)-1d 72 67 (+).sup.e 
B 
4 (R,R)-1 52 93 (-).sup.e 
B 
5 (R,R)-1 70 85 1R,2S-(-) 
A 
6 (R,R)-1.sup.d 
72 78 1R,2S-(+) 
B 
7 (R,R)-1 36 30 R-(+) B 
______________________________________ 
.sup.a Reactions were run at 25.degree. C. unless otherwise noted. 
.sup.b Isolated yields based on olefin. 
.sup.c The sign corresponds to that of [.alpha.]D. 
.sup.d Reaction run at 5.degree. C. 
.sup.e Absolute configuration not known. 
The table above shows that the highest enantiomeric excess (ee) values were 
observed with Examples 4, 5, and 6, i.e. cis disubstituted olefins. In 
contrast, Example 7, a 1,1 disubstituted olefin, had the lowest ee values. 
Example 1, a trans disubstituted olefin, and Examples 2 and 3, 
monosubstituted olefins, had intermediate ee values. 
Asymmetric Epoxidation of Representative Olefins with Catalysts from the 
First and Fourth Aspects of the Invention 
EXAMPLES 8-16 
The following Examples 8-16 were run the same as Examples 1-7, except that 
different catalysts were used. The key to the catalyst numbering system is 
found in FIG. 11. As can be seen, Example 8 was made according to the most 
preferred embodiment of the first aspect. Examples 9-16 were made 
according to the fourth aspect, with the catalyst used in Examples 12-16 
being the most preferred embodiment of the fourth aspect. It is also noted 
that all of Examples 8-16 were run with method B described above. 
TABLE II 
__________________________________________________________________________ 
##STR26## 
Entry 
Olefin.sup.a 
Catalyst 
Yield.sup.b (%) 
ee.sup.c (%) 
Configuration.sup.d 
__________________________________________________________________________ 
##STR27## (R,R)-1 
70 85 1R,2S-(-) 
9 (S,S)-2 
75 49 1S,2R-(+) 
10 (S,S)-3 80 1S,2R-(+) 
11 (S,S)-4 55 1S,2R-(+) 
12 (S,S)-5 
82 92 1S,2R-(+) 
13 
##STR28## (S,S)-5 
74 94 
14 
##STR29## (S,S)-5 
87 97 n.d. 
15 
##STR30## (S,S)-5 
53 94 R,R-(+) 
16 
##STR31## (S,S)-5 
74 75 S,S-(-) 
__________________________________________________________________________ 
.sup.a Reactions were run at 0.degree. C. 
.sup.b Isolated yields based on olefin. 
.sup.c Determined by .sup.1 H NMR analysis in the presence of 
Eu(hfc).sub.3 and by capillary GC using a commercial shiral column (J & W 
Scientific CyclodexB column, 30 m .times. 0.25 mm I.D., 0.25 .mu.m film). 
.sup.d All reactions were run in duplicate with both enantiomers of each 
catalyst. Reactions carried out with (R,R)5 afforded epoxides with 
absolute configurations opposite to those in the table and with the same 
ee's (.+-.2%). The sign corresponds to that of [.alpha.]D. 
As shown in Examples 12-15, the most preferred catalyst of the fourth 
embodiment catalyzes the epoxidation of cis-disubstituted olefins with 
excellent enantioselectivity. 
EXAMPLES 17-24 
Epoxidation of Chromene Derivatives 
The following Examples 17-24 were carded out to show the effectiveness of 
the present method to enantioselectively epoxidize various chromene 
derivatives. The catalyst used in these examples is the R,R enantiomer 
shown in FIG. 8. The method described above as Method A was used for these 
examples: 
The results are shown in Table III. It is noted that the unsubstituted 
chromene in Example 24 did not produce an epoxychroman. 
TABLE III 
__________________________________________________________________________ 
Example Isolated 
Absolute 
No. Olefin.sup.a Major Product(s) ee (%).sup.b 
Yield (%).sup.c 
Configuration 
__________________________________________________________________________ 
17 
##STR32## 
##STR33## 97 96 (3R,4R)-(+).sup.d 
18 
##STR34## 
##STR35## 94 76 (3R,4R)-(+).sup.e 
19 
##STR36## 
##STR37## 96 87 (3R,4R)-(+).sup.e 
20 
##STR38## 
##STR39## 96.sup.f 
75 (3R,4R)-(+).sup.e 
21 
##STR40## 
##STR41## 97.sup.f 
51 (3R,4R)-(+).sup.e 
22 
##STR42## 
##STR43## &gt;96 82 (3R,4R)-(+).sup.g 
23 
##STR44## 
##STR45## 
##STR46## 
38.sup.h 
not determined 
24 
##STR47## 
##STR48## -- 49 
__________________________________________________________________________ 
.sup.a Epoxidations carried out with (S,S)4 afforded products of opposite 
configuration. 
.sup.b Ee's were determined by GC (see caption to FIG. 1) unless otherwis 
noted. 
.sup.c Isolated yields correspond to reactions carried out on 1 mmol scal 
with 4 mol % 4 and product isolation by flash chromatography. 
.sup.d Correlated with (3R,4S)(+)-2 (ref. 9b). 
.sup.e Absolute configuration assigned by analogy to 6. 
.sup.f Ee determined by .sup.1 H NMR using Eu(hfc).sub.3 as chiral shift 
reagent. 
.sup.g Personal communication from Drs. R. Gericke and J. Sombroek (E. 
Merck). 
.sup.h Isolated yield of the 2:1 mixture. 
EXAMPLE 25 
Example 25 was carried out the same as Example 19 above, with the exception 
that the catalyst shown in FIG. 2 was used. The isolated yield was found 
to be 78% and the ee was 91%. 
EXAMPLE 26 
Example 26 was carded out as a larger scale production of the epoxychroman 
produced in Example 17 above, namely 
6-cyano-2,2-dimethyl-3,4-epoxychroman. 
The pH of a solution of commercial household bleach (Clorox.RTM.) was 
buffered to pH=11.3 with 0.05M Na.sub.2 HPO.sub.4 and 1N NaOH and then 
cooled to 0.degree. C. To 500 ml of this solution (approximately 0.55M in 
NaOCl) was added a 0.degree. C. solution of 6-cyano-2,2-dimethylchromene 
and the catalyst (3.1 g, 5.0 mmol, 3.7 mol %) in 135 ml of CH.sub.2 
Cl.sub.2. The two-phase system was mechanically stirred at 0.degree. C. 
and the reaction progress was monitored by HPLC. After 9 hours, the 
heterogeneous brown mixture was filtered through a pad of Celite 
diatomaceous earth and the organic phase was separated, washed once with 
500 ml saturated NaCl solution, and then dried (Na.sub.2 SO.sub.4). The ee 
of the crude product obtained after solvent removal was determined for 
each example by GC analysis. The brown oily residue was then dissolved in 
200 ml of boiling absolute ethanol and then water (200 ml) was added 
slowly to the hot solution. A hot gravity filtration afforded a pale 
yellow solution from which the crystallized epoxychroman was isolated. 
This isolated yield was 81% and the ee was measured at 99% by GC analysis. 
EXAMPLE 27 
Example 27 was carded out to produce the cromakalin compound shown in FIG. 
13. The epoxychroman produced in Example 26, namely 
6-cyano-2,2-dimethy-3,4-epoxychroman, (1 g, 4.97 mmol), 
3-hydroxy-1-methyl-1,6-dihydropyridazin-6-one (0.652 g, 5.17 mmol) and 
pyridine (0.491 g, 6.21 mmol) were refluxed together in ethanol (10 ml) 
for 8 hours. The homogenous yellow mixture was then concentrated under 
vacuum and the residue was isolated by flash chromatography on 70 g of 
silica and ethyl acetate as eluent. The isolated yield was 1.38 g (85%). 
##STR49## 
EXAMPLE 28 
Example 28 was carded out to produce the cromakalin shown in FIG. 14. 
Sodium hydride (0.199 g of a 60% suspension in mineral oil, 4.97 mmol) was 
suspended in DMSO (1.5 ml) and 2-pyrrolidinone (0.423 g, 4.97 mmol) was 
added to the stirred mixture at room temperature under a dry nitrogen 
atmosphere. The epoxychroman from Example 26 (1 g, 4.97 mmol) was then 
added as a solid to the grey foamy mass. The mixture was stirred at room 
temperature for 10 hours. The orange-red mixture was then treated with 10 
ml of water and the resulting thick yellow precipitated was extracted 5 
times with 10 ml of ethyl acetate. Removal of solvent and chromatography 
on silica (100 g, ethyl acetate eluent) afforded pure product which was 
recrystallized from ethyl acetate. This isolated yield was 0.808 g (56%). 
##STR50## 
Synthesis of Taxol and Taxol Intermediates and Analogs 
The following general comments apply to the following examples. Melting 
points were obtained in open capillary tubes with a Laboratory Devices 
(Holliston, Mass.) Mel-Temp II melting point apparatus and are reported 
uncorrected. The boiling points are reported uncorrected. The .sup.1 H NMR 
spectra were obtained on a General Electric (Schenectady, N.Y.) QE-300 
(300 MHz) spectrometer. Low resolution EI gas chromatography/mass 
spectroscopic (GC/MS) analyses were performed on a Hewlett-Packard (Palo 
Alto, Calif.) 5970 Mass Selective Detector coupled to a Hewlett-Packard 
5890 gas chromatograph. Other mass spectra were provided by the Mass 
Spectrometry Laboratory at the University of Illinois, Urbana, Ill. 
Elemental analyses were performed by the Microanalytical Laboratory of the 
University of Illinois. 
Silica gel chromatographic purifications were performed by flash 
chromatography with Woelm silica (Aldrich Chemical Co., Milwaukee, Wis.) 
packed in 32-64 m glass columns. The weight of silica gel was 
approximately 50-100 times that of the sample unless it is noted otherwise 
below. The eluting solvent for each purification was determined by thin 
layer chromatography (TLC). Analytical TLC was conducted on Merck glass 
plates coated with 0.25 mm of silica gel 60 F.sub.254. TLC plates were 
visualized with ultraviolet light and/or in an iodine chamber unless noted 
otherwise. Gas-liquid chromatographic (GC) analyses were performed on a 
Hewlett-Packard HP 5890 gas chromatograph using the following columns: A) 
J&W Scientific (Folsom, Calif.) 0.32 mm.times.30 m DB-5 capillary column 
or B) J&W Scientific CPX-B (.beta.-cyclodextrin) capillary column, 30 m. 
Optical rotations were measured on a Jasco (Japan Spectrophotometric Co., 
Tokyo, Japan) Dip-360 digital polarimeter. 
The buffered bleach solutions employed in the epoxidation reactions were 
prepared from Clorox.RTM. bleach according to the method of Zhang W.; and 
Jacobsen, EN: J. Org. Chem. 56: 2296, 1991. Unless other noted, all 
starting materials were purchased from Aldrich and were used as received. 
EXAMPLE 29 
Preparation of Methyl 3-Phenylglycidate 
A quantity of cis-methyl cinnamate (4.5 mg, 2.5 mmol) was dissolved in 6 ml 
of CH.sub.2 Cl.sub.2. 3,5-Dimethylpyridine-N-oxide (125 mg, 40 mol %) was 
then added to the solution, followed by the addition of catalyst (S,S)-4 
(150 mg, 10 mol %). The resulting solution was cooled to 0.degree. C. and 
combined with bleach solution (15 ml at a pH of 11.25) pre-cooled to 
4.degree. C. The reaction mixture was stirred at 4.degree. C. for three 
hours. Hexane (60 ml) was then added to the reaction mixture. The organic 
phase was washed once with 30 ml water and twice with 3 ml brine and dried 
over Na.sub.2 SO.sub.4. Solvent was removed under vacuum and the residue 
was purified by chromatography (EtOAc/hexane=7:93, v/v) to provide an 
inseparable mixture of cis- and trans-methyl-3-phenylglycidate in which 
the cis:trans ratio was 4:1. The yield was 356 mg, or 80%. The assignment 
of stereoisomers and determination of ratio of stereoisomers was based on 
the literature values for .sup.1 H NMR of cis-methyl-3-phenylglycidate. 
Denis, J. N.; Greene, A. E.; Serra, A. A.; Luche, M. -J.: J. Org. Chem. 
51: 46, 1986. The ee's of the cis- and trans-epoxides were determined to 
be 87-89% and 60%, respectively, by GC analysis (using column B described 
above). 
EXAMPLE 30 
Preparation of cis-Ethyl Cinnamate 
Ethyl phenylpropiolate (10.8 g, 0.062 mol) was dissolved in hexane (540 
ml), followed by addition of quinoline (11.2 g) and palladium on calcium 
carbonate (Lindlar catalyst, 3.6 g). The resulting reaction mixture was 
stirred under hydrogen (1 atm) at room temperature, and the progress of 
the reaction was monitored closely by GC analysis. The reaction was 
stopped by displacement of the hydrogen atmosphere with nitrogen once the 
rate of absorption of hydrogen was observed to decrease abruptly. The 
resulting mixture was faltered through a pad of diatomaceous earth and the 
filtrate was dried over Na.sub.2 SO.sub.4. Solvent was removed under 
reduced pressure. Then the residue was distilled under vacuum (2.5 mm Hg, 
at 98.degree.-100.degree. C.) to provide 10.08 g of cis-ethyl cinnamate, 
for a yield of nearly 95%. By GC analysis, this product mixture was found 
to contain 5.7% over-reduced alkane and 3.5% trans-ethyl cinnamate, but 
was used without further purification. 
EXAMPLE 31 
Preparation of (2R,3R)-Ethyl-3-Phenylglycidate 
With 1.76 g or 10 mmol of cis-ethyl cinnamate prepared as described in 
Example 30, 4-phenylpyridine-N-oxide (420 mg, 2.5 mmol) was dissolved in 
CH.sub.2 Cl.sub.2 (20 ml). Catalyst (the R,R-enantiomer of FIG. 8) (360 
mg, 0.6 mmol) was added to the solution. This solution and the buffered 
bleach solution (25 ml, at pH=11.25) were cooled separately in ice bath, 
and then combined at 4.degree. C. The two-phase mixture was stirred for 
two hours, or until the disappearance of cis-ethyl cinnamate was judged to 
be complete by TLC analysis. Ethyl acetate (200 ml) was then added to the 
solution and the organic phase was separated, washed with water 
(2.times.100 ml) and brine (1.times.100 ml). Then the organic phase was 
dried over Na.sub.2 SO.sub.4. The solvent was removed under vacuum and the 
residue was subjected to GC analysis, which indicated the presence of cis- 
and trans-epoxides in a 3:1 ratio. The residue was distilled (2 mm Hg, at 
75.degree.-77.degree. C.) to provide 1.6 g (80% yield) of a crude mixture 
of 75% cis-epoxide, 18% trans-epoxide and several minor impurities, as 
determined by GC analysis. The ee of the cis-epoxide was determined to be 
96-97% by a .sup.1 H NMR shift study with Eu(hfc).sub.3 as chiral shift 
reagent. The ee of the trans-epoxide was measured to be 78% by the same 
method. The mixture was used in subsequent reactions without further 
purification. The following was obtained for cis-ethyl-3-phenylglycidate: 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.02 (t, J=7.2 Hz, 3H), 3.83 (d, J=4.8 
Hz, 1H), 3.9-4.1 (m, 2H), 4.27 (d, J=4.8 Hz, 1H), 7.2-7.5 (aromatic, 5H). 
The following was obtained for trans-ethyl-3-phenylglycidate: .sup.1 H NMR 
(CDCl.sub.3) .delta. 1.33 (t, J=7.2 Hz, 3H), 3.51 (d, J=2.1 Hz, 1H), 4.09 
(d, J=1.8 Hz, 1H), 4.2-4.4 (m, 2H), 7.2-7.5 (aromatic, 5H). 
EXAMPLE 32 
Preparation of (2R,3S)-3-Phenyl-Isoserinamide 
First, 900 mg, or 4.22 mmol, of (2R,3R)-3-phenylglycidate, prepared as 
described in Example 31, was dissolved in a solution of 20 ml of ethanol 
saturated with ammonia (prepared by passing ammonia through ethanol at 
-15.degree. C. for 15 minutes). This solution was placed in an autoclave 
and heated to 100.degree. C. for 16 hours with external agitation. After 
the solution was cooled to room temperature, agitation was continued for 
another eight hours. Solvent was removed under vacuum and the residue was 
recrystallized from ethanol. White crystalline product, weighing 540 mg, 
was isolated by filtration for a yield of 71%. The melting point was 
172.degree.-173.degree. C. The following .sup.1 H NMR (DMSO-d.sub.6 
/D.sub.2 O) data were obtained for this compound: .delta. 3.87 (d, J=3.3 
Hz, 1H), 4.08 (d, J=3.3 Hz, 1H), 7.0-7.5 (aromatic, 5H). Analytical for 
C.sub.9 H.sub.12 O.sub.2 N.sub.2 : Calculated: C, 60.00; H, 6.67; N, 
15.55. Found: C, 59.90; H, 6.71; N, 15.25. 
The corresponding racemate was synthesized by an analogous sequence with 
epoxide prepared with the (S,S) catalyst of FIG. 8. The melting point for 
the racemate was 192.degree.-193.degree. C., which compared favorably to 
the literature value of 187.degree.-188.degree. C. Kamandi, E.; Frahm, A. 
W.; and Zymalzowski, F.: Arch. Parmaz. 307: 871, 1974. 
EXAMPLE 33 
(2R,3S)-3-Phenyl-Isoserine 
(2R,3S)-3-phenyl-isoserinamide (200 mg, 1.11 mmol), as prepared in Example 
32, was combined with 354 mg (1.12 mmol) of Ba(OH).sub.2 
.multidot.8H.sub.2 O and water (2 ml). The resulting suspension was heated 
to reflux for nine hours. After the reaction mixture was cooled to 
80.degree. C., 15 ml of water was added to the solution. The temperature 
of the solution was maintained at 80.degree. C. for 20 minutes before a 
solution of 110 mg, 1.11 mmol of concentrated sulfuric acid in 1 ml of 
water was added. A white precipitate appeared in the solution which was 
determined to have a pH of between 5 and 7. Heating at 80.degree. C. was 
maintained for another 20 minutes, and the mixture was then cooled to room 
temperature. The resulting precipitate (BaSO.sub.4) was centrifuged to the 
bottom of the container, the supernatant was separated, and solvent was 
removed under vacuum. The resulting white solid was extracted with acetone 
and collected by filtration to provide 148 mg of the title compound, for a 
yield of 74%. The material melted with decomposition at 238.degree. C. The 
.sup.1 H NMR (D.sub.2 O/NaOD) data were as follows: .delta. 3.94 (d, J=3.9 
Hz, 1H), 4.01 (d, J=3.9 Hz, 1H), 7.0-7.5 (aromatic, 5H). Analytical for 
C.sub.9 H.sub.11 NO.sub.3 : Calculated: C, 59.66; H, 6.07, N, 7.73. Found: 
C, 59.10; H, 6.11; N, 7.61. 
EXAMPLE 34 
N-Benzoyl-(2R,3S)-3-Phenyl-Isoserine 
First, 60 mg (0.33 mmol) of (2R,3S)-3-phenyl-isoserine, as prepared in 
Example 33, was dissolved in a 10% aqueous NaHCO.sub.3 (8 ml). The 
solution was cooled to 4.degree. C. and then 143 mg (1.0 mmol) of benzoyl 
chloride in 120 ml aqueous solution was added. This mixture was stirred 
for six hours at 4.degree. C. and then acidified to a pH of 1 by addition 
of dilute HCl solution. The resulting white precipitate was collected by 
filtration. The volume of the filtrate was reduced to 2 ml and a second 
portion of precipitate was collected and combined with the first crop. 
This material contained both desired product and benzoic acid. The benzoic 
acid was removed by stirring for six hours in ether (3 ml) containing 
several drops of ethanol. Next, 60 mg of the resulting product was 
isolated as a white solid by filtration, for a yield of 70%. This compound 
was determined by be more than 95% pure by .sup.1 H NMR. The melting point 
was 177.degree.-179.degree. C., compared to a literature value of 
167.degree.-169.degree. C. FABMS: m/e 286 (M.sup.+ +1). The .sup.1 H NMR 
(DMSO-d.sub.6) values were as follows: .delta. 4.37 (d, J=4.5 Hz, 1H), 
5.46 (dd, J=8.7 Hz and 4.5 Hz, 1H), 5.3-5.7 (b, 1H), 7.2-7.6 (m, 9H), 7.84 
(d, J=7.5 Hz, 1H), 8.58 (d, J=9.0 Hz, 1H), 12.5-13.0 (br, 1H). FABHRMS for 
C.sub.16 H.sub.16 NO.sub.4 : Calculated: 286.1079. Observed: 286.1068. 
[.alpha.].sup.25 D-35.9.degree. (c 0.565, EtOH); compared to literature 
values for the (2S,3R)-isomer of [.alpha.].sup.25 D-36.5.degree. (c 1.45, 
EtOH) and for the (2R,3S)-isomer of [.alpha.].sup.25 D-37.78.degree. (c 
0.9, EtOH). Ojima I., et al. J. Org. Chem. 56: 1681, 1991. 
EXAMPLE 35 
Taxol 
The N-benzoyl-(2R,3S)-3-phenylisoserine, as prepared in Example 34, is 
treated with 1-chloroethyl ethyl-ether in the presence of a tertiary amine 
to produce optically pure 
(2R,3S)-N-benzoyl-O-(1-ethoxyethyl)-3-phenyl-isoserine (2). 
7-tri-ethylsilyl baccatin III (1), as synthesized according to Denis et 
at. (J. Amer. Chem. Soc. 110:5417, 1988), is added to 6 equiv of optically 
pure (2R,3S)-N-benzoyl-O-(1-ethoxyethyl)-3-phenyl-isoserine (2), 6 equiv 
of di-2-pyridyl carbonate (DPC), and 2 equiv of 4-(dimethylamino) pyridine 
(DMAP) in toluene solution (0.02M). This mixture reacts at 73.degree. C. 
for 100 hours to produce the C-2', C-7-protected taxol derivative (3). 
Concomitant removal of the protecting groups at C-2' and C-7 in (3) is 
accomplished with 0.5% HCl in ethanol at 0.degree. C. for 30 hours to 
produce taxol, whose identity and purity are established via comparison 
with the melting point, rotation, and spectral (IR, MNR, FABMS) and 
chromatographic (TLC, HPLC) characteristics of the natural product. 
##STR51## 
EXAMPLES 36-39 
Effect of Pyridine-N-Oxide Derivative on Epoxidation 
The four alkenes shown in Table IV below were epoxidized with the presence 
of a pyridine-N-oxide derivative in the following manner. 
A solution of 10 mmol of an alkene and 2.0 mmol (20 mol %) of a 
pyridine-N-oxide derivative were dissolved in 10 ml of CH.sub.2 Cl.sub.2. 
Either 4-phenylpyridine-N-oxide (A in the table) or 
4-t-butylpyridine-N-oxide (B in the table) was used. 
Then, 0.08-1.0 mmol (0.8-10 mol %) of Catalyst 1 or 2 (see below) were 
added to the alkene solution. The table shows the amounts of catalyst used 
in each example. This solution and buffered bleach solution (pH=11.25) 
were cooled separately in an ice bath and then combined at 
0.degree.-4.degree. C. This two-phase mixture was stirred for one to five 
hours. Then, 200 ml of hexane was added to the solution, and the organic 
phase was separated and washed once with 100 ml water and once with 100 ml 
brine. The organic phase was then dried over Na.sub.2 SO.sub.4. The 
solvent was removed under vacuum. The residue was subjected to 
purification distillation but could also be purified by chromatography or 
crystallization. The enantiomeric compositions of the epoxide were 
established by GC on a chiral capillary column and by .sup.1 H NMR with a 
chiral shift reagent (Eu(hfc).sub.3). 
__________________________________________________________________________ 
##STR52## 
Example Major Catalyst 
N-Oxide 
No. Olefin Epoxide Product 
(mol %) 
Derivative 
Isolated Yield (%) 
ee (%) 
__________________________________________________________________________ 
36 
##STR53## 
##STR54## 1 (0.8) 
B 70 85 
37 
##STR55## 
##STR56## 1 (5) 
A 65 88 
38 
##STR57## 
##STR58## 2 (10) 
A 50 93 
39 
##STR59## 
##STR60## 2 (10) 
A 50 93 
__________________________________________________________________________ 
##STR61## 
It should be noted that, although much of the discussion has involved the 
use of salen derivatives (made from ethylenediamines), salpn derivatives 
(made from propylenediamines) and salbn derivatives (made from 
butylenediamines) are also within the scope of the present invention. 
Certainly, these are considered to lie within the scope of the invention 
as defined by the appended claims. 
Asymmetric Oxidation of Sulfides 
EXAMPLE 40 
The following catalysts were prepared using the same techniques as 
previously discussed. 
FIGS. 19 and 20, as well as Table V below, show the generalized structures 
of the catalysts. 
TABLE V 
______________________________________ 
##STR62## 
##STR63## 
##STR64## 
##STR65## 
Entry Catalyst Yield, %.sup.a 
ee, %.sup.b 
Sulfoxide confgn.sup.c 
______________________________________ 
1 (R,R)-1 90 47 S-(-) 
2 (R,R)-2 72 24 S-(-) 
3 (R,R)-3 82 0 -- 
4 (R,R)-4 74 14 S-(-) 
5 (R,R)-5 86 36 S-(-) 
6 (R,R)-6 64 34 S-(-) 
7 (R,R)-7 84 7 R-(+) 
______________________________________ 
.sup.a All yields correspond to pure products isolated by flash 
chromatography. .sup.b Ee's were determined by HPLC using a Chiralcel OD 
column. .sup.c Absolute configuration assigned by comparison of the sign 
of [.alpha.].sub.D to the literature value. 
These seven catalysts were reacted with thioanisole to measure their ee 
values. It is significant that those ligand properties that were proven to 
be important for optimal enantioselectivity in epoxidation were also 
important in sulfide oxidation. For example, the presence of bulky 
substituents on the 3,3' and 5,5' positions of the salen ligands has a 
marked effect on selectivity, indicating that these groups improve 
stereochemical communication in the transition state leading to oxo 
transfer by inducing substrate approach near the dissymmetric diamine 
bridge. An electronic effect on enantioselectively was also very 
pronounced in sulfide oxidation with (salen)Mn catalysts. As exhibited in 
the epoxidation reaction, catalysts bearing electron withdrawing 
substituents are less enantioselective than electron rich analogs (entries 
1, 3 and 4 in Table V). This effect may be attributed to the greater 
reactivity and concomitant lower selectivity, of the high valence 
intermediates bearing electron withdrawing groups. 
Catalyst 1 of Table V emerged as the most selective of the catalysts 
tested. Therefore, Catalyst 1 was used to study the asymmetric oxidation 
of prochiral sulfides. The results of these tests are shown by Table VI 
below. 
__________________________________________________________________________ 
Asymmetric Oxidation of Prochiral Sulfides Using Catalyst (R,R)-1 or 
(S,S)-1. 
##STR66## 
Entry 
Sulfide Catalyst 
Yield (%).sup.a 
ee (%).sup.b 
Sulfoxide confgn.sup.c 
__________________________________________________________________________ 
##STR67## (R,R)-1 
90 47 S-(-) 
2 
##STR68## (R,R)-1 
80 68 S-(-) 
3 
##STR69## (R,R)-1 
95 42 S-(-) 
4 
##STR70## (R,R)-1 
84 40 S-(-) 
5 
##STR71## (R,R)-1 
94 43 S-(-) 
6 
##STR72## (R,R)-1 
84 46 S-(-) 
7 
##STR73## (S,S)-1 
94 34 R-(+).sup.d 
8 
##STR74## (R,R-1 
86 66 S-(-).sup.d 
9 
##STR75## (S,S)-1 
84 63 R-(+).sup.d 
10 
##STR76## (S,S)-1 
93 56 R-(+).sup.d 
11 
##STR77## (S,S)-1 
95 65 R-(+).sup.d 
__________________________________________________________________________ 
.sup.a Isolated yields based on sulfide. Pure sulfoxides (&gt;99% by GC 
analysis) were isolated by flash chromatography, 
.sup.b Ee's were determined by HPLC using a Chiralcel OD column except fo 
entries 8,9,10 which were determined by .sup.1 H NMR in the presence of 
(R)(-)-2,2,2-trifluoro-1-(9-anthryl)ethanol. 
.sup.c Absolute configurations were established by comparison of the sign 
of [.alpha.].sub.D to literature values unless otherwise indicated. 
.sup.d Absolute configurations assigned by analogy (sign of 
[.alpha.].sub.D) to entries 1-6. 
Selectivities in these cases were moderate, although a significant 
electronic effect on substrate could be discerned. More reactive electron 
rich sulfides were oxidized with lower selectivity (e.g. entry 7, Table 
VI), while selectivities above 60% ee were obtained with substrates 
bearing halide or nitro groups (entries 2, 8-11, Table VI). The face 
selectivity in the sulfide oxidation reactions is analogous to that in the 
alkene epoxidation (see FIG. 21). This suggests that the nature of the 
transition states in the two processes may be similar. 
Catalytic Disproportionation of Hydrogen Peroxide 
EXAMPLE 41 
Preparation of: 
##STR78## 
A solution of salicylaldehyde (24.42 g, 0.200 molc) in 80 ml of EtOh was 
added to a stirred solution of ethylenediamine (6.070 g, 0.100, olc) in a 
mixture of 50 ml EtOH and 50 ml of H.sub.2 O over a period of 5 minutes. 
The reaction mixture was refluxed for 1 hour and stirred at room 
temperature overnight. The yellow crystalline product was separated by 
filtration and washed with 2.times.30 ml of cold 60% EtOh and air dried to 
yield 25.733 g (95.9%) of salen. 
Mn(OAc)2 (24.509 g, 0.100 mole) was added to a stirred solution of 13.416 g 
of salen in 1000 ml of 95% EtOH and the color immediately changed from 
yellow to dark brown. the resulting mixture was refluxed for 3 hours. The 
solvent was removed by vacuum and the resulting residue was extracted with 
1250 ml of hot water (60 degrees C.) and filtered. Solid NaCl (58.44 g, 
1.000 mole) was added to the filtrate and brown precipitate formed 
immediately. The precipitate was collected by filtration and dried. The 
crude product was recrystallized from acetone/ether to give 9.672 g of the 
product (54.2% yield). 
EXAMPLE 42 
Reaction Procedure 
A small round bottom flask equipped with a septum was charged with the 
catalyst (0.1 mol %) and 1 ml of the solvent. To this solution was added a 
buffered solution of H.sub.2 O.sub.2. The rate and conversion of the 
reaction were monitored by trapping the O.sub.2 evolved from the reaction. 
Table VII below shows the turnover values for several catalysts, whose 
generalized structures are shown in FIGS. 22 and 23. Turnovers are defined 
as moles of H.sub.2 O.sub.2 destroyed per mole of catalyst. 
TABLE VII 
__________________________________________________________________________ 
Catalyst Solvent 
Turnovers 
__________________________________________________________________________ 
##STR79## EtOH 685 
##STR80## Acetone 
316 
##STR81## CH.sub.2 Cl.sub.2 
804 
##STR82## CH.sub.2 Cl.sub.2 
608 
##STR83## CH.sub.2 Cl.sub.2 
660 
##STR84## CH.sub.2 Cl.sub.2 
741 
##STR85## CH.sub.2 Cl.sub.2 
145 
##STR86## CH.sub.2 Cl.sub.2 
211 
##STR87## EtOH 67 
##STR88## H.sub.2 O 
123 
##STR89## H.sub.2 O 
153 
##STR90## Et.sub.2 O 
38 
__________________________________________________________________________