Note: Descriptions are shown in the official language in which they were submitted.
43-4257A
1094094
"
ASYMMETRIC CATALYSIS
This invention relates to new catalytic asymmetric
hydrogenation processes. More specifically, this invention is
directed to a hydrogenation process which provides outstanding
levels of optical purity.
Homogeneous catalysis, i.e., those catalyzed reactions
that are conducted where both reactants and catalysts are soluble
in the reaction mass, have been found to be particularly useful
in processes wherein an asymmetric result is obtained. For in-
stance, it has been found that when an olefin, which is capableof forming a racemic mixture is hydrogenated in the presence of
a homogeneous, optically active catalyst, one or the other of the
possible optical enantiomorphs is obtained in a ma;or amount with
the other optical enantiomorph being obtained in minor amounts.
Furthermore, it has been found that certain such olefinic sub-
strates, for instance, precursors of c~~-amino acids containing
~-acylamido and carboxylic acids, salts, esters or amides
substituents, are particularly amenable to hydrogenation with
homogeneous, optically active catalysts. Such catalytic asymmet-
ric hydrogenation processes have resulted in the production oflarge amounts of the desired optical enantiomorph. It has more
recently been found that certain homogeneous, optically active
catalysts containing optically active bis phosphine ligands pro-
vide outstanding levels of optical purity, i.e., reaching 80%
and higher with such cC-amino acid precursors. Other olefinic
substrates which would provide such outstanding levels of optical
purity of optical enantiomorphs leading to o~`-amino acids, upon
hydrogenation, are particularly desirable.
It is an object of the present invention to provide
such olefinic substrates.
It is a further ob~ect to provide novel catalytic
asymmetric hydrogenation processes which produce large amounts
of the desired optical enantiomorph. ~
` 43-4257A
1094094
These and other objects, aspects and advantages of
this invention will become apparent from a consideration of the
accompanying specification and claims.
Summary of the Invention
In accordance with the above ob~ects, the present inven-
tion provides catalytic asymmetric hydrogenation of the Z geomet-
ric isomer of a compound o~ the formula
Rl ,R2
R~ C = C~NH R3
wherein R and Rl each independently represent substituents as
desired in the hydrogenation product or its derivatives, R2
0 R4 O
represents -CN,-C-N~ 5 or -C-0-R6 wherein R4 and R5 each indepen-
dently represent hydrogen, alkyl having from 1 to 5 carbon atomsor aryl, R6 represents hydrogen, alkyl having from 1 to 5 carbon
atoms, aryl or an alkali metal and R3 represents -C-o-R7 or
-C-R8 wherein R7 and R8 each independently represent alkyl having
from 1 to 5 carbon atoms or aryl; provided that, when R3 is
0 0 o R4
-C-R8, R2 cannot be -C-0-R6 or -C-N~ 5 , in the presence of a
homogeneous, coordination complex catalyst comprising rhodium,
iridium or ruthenium in combination with an optically active bis
phosphine ligand. This process provides outstanding levels of
optical purity of desired optical enantiomorphs.
Description of the Preferred Embodiments
The hydrogenation reaction is illustrated by the
following equation:
~ C = C ~ +H2 > ~ CH-CH
R ~NH-R3 optically R NH-R3
active
catalyst
shows one or both carbon atoms are asymmetric
43-4257A
1094094
.
wherein R, Rl, R2 and R3 have the same meaning as described above.
It has been found that the geometric stereochemistry of
the olefinic substrate being hydrogenated effects the results ob-
tained. In general, it is necessary to utilize the Z geometric
isomer to realize the outstanding levels of optical purity with
the olefinic substrates of this inventlon. The E and Z geometric
isomer nomenclature is described in detail in The Journal of
Organic Chemistry, Vol. 35, No. 9, September 1970, pp 2849-2867.
It has been found that either the E or Z geometric isomer will,
upon hydrogenation, produce the same optical enantiomorph when
using the same catalyst but at different levels of optical purity.
R, Rl, R4, R5, R6, R7, and R8 can be exemplified by alkyl
groups such as methyl, ethyl, propyl, etc. and by aryl groups such
as phenyl. Those skilled in the art will recognize that the sub-
stituents on the olefinic substrate can be selected from a large
number of groups and that this is limited only by the optical
enantiomorph that is the desired end-product. Furthermore, it
may occur that such substituent groups are themselves precursors
of substituents that are desired substituents. For instance, if
the desired substituent is hydroxyl the unsaturated precursor
o
might contain the substituents -O-C-CH3 or -0-CH3 which would pro-
vide the hydroxyl by simple hydrolysis after the catalytic asym-
metric hydrogenation.
The optical enantiomorphs resulting from the process of
this invention are particularly desirable in that optical activity
is a desirable characteristic of C~-amino acids, i.e. normally only
one or the other optical enantiomorphs is useful in living organ-
isms. For instance, those optical enantiomorphs of c~-amino acids
resulting from this process which have phenyl or substituted phenyl
substituents on the ~ position lead to desirable L-phenylalanines.
The compounds represented by the following structural
formula provide excellent results with the process of this
43-4257A 1094094
invention and therefore represent compounds particularly amenable
to the hydrogenation process of this invention
~ C = C~ 3
R ~ NH-R
wherein R, Rl and R3 have the same meaning as described above.
Particularly preferred embodiments of this invention
are the catalytic asymmetric hydrogenation of (Z)-ethyl-2-(N-
ethoxycarbonylamino)-3-phenyl-2-propenoate and (Z)-2-benzamido-3-
- phenyl-2-propenenitr~le.
The L enantiomorph of phenylalanine can be readily
derived from such procedures.
Such hydrogenation reactions are usually conducted in
a solvent, such as benzene, ethanol, 2-propanol, toluene, cyclo-
hexane, and mixtures of these solvents. Almost any aromatic or
saturated alkane or cycloalkane solvent, which is inactive to
the hydrogenation condltions of this reaction, can be used. The
preferred solvents are alcohols particularly methanol, ethanol
and 2-propanol.
The homogeneous, optically active catalysts useful in
this invention are soluble coordination complexes comprising a
metal which is rhodium, iridium or ruthenium in combination with
at least one optically active bis phosphine ligand, preferably
at least about 0.5 moles of bis phosphine ligand per mole of
metal. These catalysts are soluble in the reaction mass and are
therefore referred to as "homogeneous" catalysts.
These catalysts contain optically active bis phosphine
compounds of general formulae I and II below. These bis phos-
phine compounds are characterized by the structural formula
A ~ P ~ CH2CH2 ~ P - A
B B
wherein A and B each independently represent substituted and un-
substituted alkyl of from 1 to 12 carbon atoms, substituted and
_c~ _
43-4257A
1094094
unsubstltuted cycloalkyl having from 4 to 7 carbon atoms, substi-
tutued and unsubstituted aryl; provided that such substituents
provide no significant interference with the steric requirements
around the phosphorus atom and A and B are different.
Among such bis phosphine compounds, those having two
dissimilar aryl groups on each phosphorus atom are also preferred,
particularly those wherein one such aryl group has an alkoxy sub-
stituent at the ortho position.
More preferred bis phosphine compounds useful in the
present invention are the optically active bis phosphines charac-
terized by the structural formula
, 2C 2 P X II
Y Y
wherein X represents substituted and unsubstituted phenyl,
Y represents substituted and unsubstituted 2-alkoxyphenyl
wherein the alkoxy has from 1 to 6 carbon atoms; pro-
vided that such substituents provide no significant
interference with the steric requirements around the
phosphorus atom and X and Y are different.
The catalysts prepared utilizing those optically active
bis phosphine compounds of more specific formula III, below, are
more particularly preferred in the catalytic asymmetric hydrogena-
tion reactions of this invention.
Still more particularly preferred optically active bis
phosphine compounds useful in the present invention are charac-
terized by the structural formula
M ~ P ~ CH2CH2 ~ P - M III
N N
~ R'
wherein M represents
R"'0
N represents ~
--6--
43_4257A ~094094
R' and R" each independently represent hydrogen, halogen,
alkyl having from 1 to 6 carbon atoms and alkoxy having
from 1 to 6 carbon atoms, and
R"' represents normal alkyl having from 1 to 6 carbon
atoms;
provided that M and N are different.
A particularly preferred optically active bis phosphine
compound useful in the present invention is 1,2-bis(o-anisyl-
phenylphosphino) ethane.
Other exemplary optically active bis phosphine compounds
useful in this invention are:
1,2-bis(o-anisyl-4-methylphenylphosphino) ethane
1,2-bis(o-anisyl-4-chlorophenylphosphino) ethane
1,2-bis(o-anisyl-3-chlorophenylphosphino) ethane
1,2-bis(o-anisyl-4-bromophenylphosphino) ethane
1,2-bis[(2-methoxy-5-chlorophenyl)-phenylphosphino] ethane
1,2-bis[(2-methoxy-5-bromophenyl)-phenylphosphino] ethane
1,2-bis(2-ethoxyphenylphenylphosphino) ethane
1,2-bis[o-anisyl-~-phenylphenyl)phosphino] ethane
1,2-bis[(2-methoxy-4-methylphenyl)-phenylphosphino] ethane
1,2-bis(2-ethoxyphenyl-4-chlorophenylphosphino) ethane
i,2-bis(o-anisyl-2-methylphenylphosphino) ethane
1,2-bis(o-anisyl-4-ethylphenylphosphino) ethane
1,2-bis(o-anisyl-3-ethylphenylphosphino) ethane
1,2-bis(o-anisyl-3-phenylphenylphosphino) ethane
For these bis phosphine compounds to be useful in
asymmetric hydrogenation reactions they must be utilized as the
optically active enantiomorph and not in the meso form.
Optical activity of the coordinated complex catalysts
useful in this invention resides in the bis phosphine ligand.
This optical activity results from having two different groups,
in addition to the ethane bridge, on the phosphorus atom.
43-4257A 1094094
Illustrative coordination metal complexes can be repre-
sented by the formula MeTL wherein Me is a transition metal selec-
ted from the group consisting of rhodium, iridium and ruthenium;
T is selected from the group consisting of hydrogen, fluorine,
bromine, chlorine and iodine; L is the optically active bis phos-
phine ligand as previously defined.
It has been found that outstanding levels of optical
purity of the desired optical enantiomorphs can be achieved not
only with the above-described catalysts represented by the formula
MeTL, which are coordination complexes of a metal selected from
the group consisting of rhodium, lridium and ruthenium, but can
also be achieved when the hydrogenation is carried out in the
presence of an in situ complex catalyst that comprises a solution
of a transition metal selected from the group consisting of
rhodium, iridium and ruthenium and at least about 0.5 moles of
the optically active bis phosphine ligand per mole of metal. For
instance, such catalysts can be prepared by dissolving a soluble
compound of the appropriate metal in a suitable solvent together
with an optically active bis phosphine compound as the ligand
wherein the ratio of ligand to metal is at least 0.5 moles of
ligand per mole of metal, preferably one mole of ligand per mole
of metal. It has been found that the catalyst is formed in situ
by addlng a soluble metal compound to the reaction mass together
with the addition of the proper amount of the optically active bis
phosphine li~and to the reaction mass either before or during
hydrogenation.
The preferred metal for use in this process is rhodium.
Soluble rhodium compounds that can be utilized include rhodium
trichloride hydrate, rhodium tribromide hydrate, rhodium sulfate,
organic rhodium complexes with ethylene, propylene, etc., and bis
olefins such as 1,5-cyclooctadiene and 1,5-hexadiene, bicyclo-
2.2.1-hepta-2,5-diene and other dienes which can form bidentate
43-4257A
~094094
ligands, or an active form of metallic rhodium that is readily
solubllized.
It has been found that a preferred embodiment of this
invention is the hydrogenation process where the optically active
bis phosphine ligand is present in a ratio of about 0.5 to about
2.0, preferably, 1.0, moles of bis phosphine ligand per mole of
metal. In practice, it is preferred to have the optically active
catalyst in a solid form for purposes of handling and storage.
It has been found that outstanding results can be obtained with
solid, cationic coordination metal complexes.
Cationic coordination metal complexes containing one
mole of the optically active bis phosphine ligand per mole of
metal and a chelating bis olefin represent a preferred form of
the catalysts useful in the present invention. For instance,
using organic rhodium complexes, as described above, one can
prepare such cationic coordination rhodium complexes by slurrying
the organic rhodlum complex in an alcohol, such as ethanol,
adding one mole per mole of rhodium of the optically active bis
phosphine compound so that an ionic solution is formed, followed
by the addition of a suitable anion, such as, for instance,
tetrafluoroborate, tetraphenylborate or any other anion that will
result in the precipitation or crystallization of a solid, cationic
coordination metal complex either directly from the solvent or
upon treatment in an appropriate solvent.
Exemplary cationic coordination metal complexes are
cyclooctadiene-1,5-~1,2-bis(o-anisylphenylphosphino) ethane]
rhodium tetrafluoroborate, cyclooctadiene-1,5-[1,2-bis(o-anisyl-
phenylphosphino) ethane] rhodium tetraphenylborate and bicyclo-
2.2.1-hepta-2,5-diene-[1,2-bis(_-anisylphenylphosphino) ethane]
rhodium tetrafluoroborate.
Without pre~udice to the present invention it is thought
that the catalyst is present actually as a catalyst precursor and
that upon contact with hydrogen the catalyst is converted to an
43-4257A
~05~4094
active form. This conversion can, of course, be carried out
during the actual hydrogenation or can be accomplished by sub-
jecting the catalyst (or precursor) to hydrogen prior to addition
to the reaction mass to be hydrogenated.
As previously noted, the catalyst can be added to the
solvent either as a compound per se or as its components which
then form the catalyst in situ. When the catalyst is added as
its components it may be added prior to or after the addition
of the olefinic substrate. Components for the preparation of
the catalyst in situ are the soluble metal compound and the
optically active bis phosphine compound. The catalyst can be
added in any effective catalytic amount and generally in the
range of about 0.001% to about 5% by weight of contained metal
based on the olefinic substrate to be hydrogenated.
Within the practical limits, means should be provided
so as to avoid contacting the catalyst or reaction mass with
oxidizing materials. In particular, care should be taken so as
to avoid contact with oxygen. It is preferred to carry out the
hydrogenation reaction preparation and actual reaction in gases
(other than H2) that are inert to both reactants and catalysts
such as, for instance, nitrogen or argon.
After addition of the reactants and catalyst to the
solvent, hydrogen is added to the mixture until about 0.5 to
about 5 times the mole quantity of the olefinic substrate present
has been added. The pressure of the system will necessarily vary
since it will be dependent upon the type of reactant, type of
catalyst, size of hydrogenation apparatus, amount of reactants
and catalyst and amount of solvent. Lower pressures, including
atmospheric and sub-atmospheric pressure can be used as well as
higher pressure.
Reaction temperatures may be in the range of about
-20C. to about 110C. Higher temperatures may be used but are
43-4257A
1094094
normally not required and may lead to an increase of side reac-
tions.
Upon completion of the reaction which, is determined by
conventional means, the product is recovered by conventional means.
Many naturally occurring products and medicaments exist
in an optically active form. In these cases only the L or D form
is usually effective. Synthetic preparation of these compounds in
the past has requlred an additional step of separating the products
into its enantlomorphs. This process is expensive and time con-
suming. The process of the present invention permits the directformation of desired optical enantiomorphs with outstanding opti-
cal purity thus eliminating much of the time consuming and expen-
sive separation of such optical enantiomorphs. Furthermore, the
process provides a hlgher yield of the desired optical enantio-
morph while concurrently decreasing the yleld of the unwanted
optical enantiomorph.
The hydrogenation process of this invention is particu-
larly desirable because of its ability to not only provide an
unusually high optical purity of the desired optical enantiomorph
but also because of its ability to afford a rapid rate of hydro-
genation at low catalyst concentrations.
The following examples will serve to illustrate certain
specific embodiments within the scope of this invention and are
not to be construed as limiting the scope thereof. In the exam-
ples, the percent optical purity is determined by the following
equation (it being understood that the optical activity, ex-
pressed as specific rotation, is measured in the same solvent):
%Opt cal = Observed optical activity of the mixture x 100
Purity Optical activity of pure optical isomer.
43-4257A 10~4094
Example 1
Preparation of
(Z)-ethyl-2-(N-ethoxycarbon~lamino)-3-phenyl-2-propenoate
To a solution of 21.0 g. (0.12 mole) of ethyl N-
(ethoxycarbonyl) glycine, 10.08 g. (0.096 mole) of benzaldehyde
and 200 ml. of ethyl ether, maintained at 5C., was added 3.0 g.
(0.13 mole) of sodium metal. The mixture was stirred 18 hours
at ambient temperature and was filtered to remove the solid pre-
cipitate. The ethereal filtrate was washed with water and dried.
The ether was stripped and the solid residue was recrystallized
from toluene. The yield was 4.9 g., m.p. 102-107. The product
was identified as (Z)-ethyl-2-(N-ethoxycarbonylamino)-3-phenyl-
2-propenoate by NMR, GLC, and W analysis.
Example 2
Preparation of ethyl-2-(N-ethoxycarbonylamino)-3-phenylpropanoate
A solution of 2.29 g. of (Z)-ethyl-2-(N-ethoxycarbonyl-
amino)-3-phenyl-2-propenoate, 0.0105 g. of cyclooctadiene-1,5-
[1,2-bis(o-anisylphenylphosphino) ethane] rhodium tetrafluoro-
borate and 30 cc. of ethanol was hydrogenated at 3 atm. and 50C.
After 2 1/2 hours, the solution was stripped on a rotary evapora-
tor. NMR analysis indicated that hydrogenation was complete.
The hydrogenation product, ethyl-2-(N-ethoxycarbonyl-
amino)-3-phenylpropanoate, was hydrolyzed to phenylalanine (with
the L enantiomorph in ma~or amount) in the following manner: To
a solution of the res~due from the above stripping in 30 cc. of
acetic acid at 75C., hydrogen bromide gas was slowly bubbled in
the resulting solution for 1 hour. After holding for several
hours, the acetic acid was removed on a rotary evaporator. The
resulting residue was added to 25 cc. of water containing 2 cc.
of 48% aqueous hydrogen bromide. The mixture was heated at re-
flux for 3 1/2 hours, cooled to 25C. and extracted with chloro-
form to remove non-hydrolyzed organics The water solution,
43-4257A
1094094
containing the phenylalanine hydrobromide salt and 1 cc. of added
acetic acid was neutralized to pH 3 with a 50% NaOH solution. The
optical rotation of the neutralized solution (100 cc.), containing
the phenylalanine was determined with a polarimeter. [OC]DO =
-27.95 (C=l in water), optical purity equals 88.7%.
Example 3
Preparation of N-benzamidoacetonitrile
Sodium carbonate (0.108 mole) was added to a solution
containing 20 g. of aminoacetonitrile hydrochloride (0.216 mole)
in 150 cc. of water. The solution was cooled to 5C. and 18.1 g.
(0.216 mole) of sodium bicarbonate was added. 30.4 g. of benzoyl
chloride (0.216 mole) was added dropwise over about 1 1/2 hours
to the cold aqueous solution and a solid formed. The resulting
mass was allowed to warm to 20C.; the solid was collected and
washed thoroughly with water. The dry weight of the recovered
material, which was crude N-benzamidoacetonitrile, was 33 g.
(96% yield) m.p. 137-139C. This material was recrystallized
from 100 cc. of methanol and 29 g. was recovered.
Example 4
Preparation of (Z)-2-benzamido-3-phenyl-2-propenenitrile
Hydrogen chloride gas was bubbled into a solution con-
taining 4 g. of benzaldehyde (0.037 mole) and 6 g. of N-benzamido-
acetonitrile (0.037 mole) in 100 cc. of diethyl ether maintained
at 0-5C. Upon holding for about 1 1/2 hours a solid precipitates;
10.4 g. of this solid was collected by filtration.
The 10.4 g. of the solid collected above was added to a
solution of 4 g. of sodium carbonate in 100 cc. of cold (0-5C.)
water. The mixture was stirred for 1 hour at 5C., then 10 cc.
of acetone was added and the resulting mass allowed ~o warm to
20C. The product, which was crude (Z)-2-benzamido-3-phenyl-2-
propenenitrile (NMR), was eollected and washed with water. The
dry weight of collected material was 8.5 g. (92% yield). The
-13-
43-4257A
1094094
8.5 g. of this material was crystalllzed from 85 cc. of ethanol.
Recovery was 6.8 g., m.p. 164-165.
Example 5
Preparation of 2-benzamido-3-phenylpropanenitrile
(A) A solution of 0.9956 g. of (Z)-2-benzamido-3-
phenyl-2-propenenitrile, .oo46 g. of cyclooctadiene-1,5-[1,2-bis
(o-anisylphenylphosphino) ethane] rhodium tetrafluoroborate and
0.5 cc. of acetic acid in 30 cc. of methanol was hydrogenated in
a Hoke bomb at 27 atm. and 50C. Hydrogenation was complete in
3 hours. The solution was diluted to 200 cc. with methanol, ob-
served rotation = -0.359, [~C]20 = -72.1. The pure enantiomorph
of 2-benzamido-3-phenylpropanenitrile in a solution of comparable
composition has a [~X~]20 = -84.3. Therefore, the optical purity
was 85.5%.
(B) A solution of 0.9924 g. of (Z)-2-benzamido-3-
phenyl-2-propenenitrile, 0.0153 g. of cyclooctadiene-1,5-[1,2-
bis(o-anisylphenylphosphino) ethane] rhodium tetrafluoroborate
and 2 drops of acetic acid in 30 cc. of methanol was subjected
to 3 atm. of hydrogen pressure at 50C. After about 24 hours,
the solution was diluted to 200 cc. with methanol. The observed
rotation was -0.372, ~]20 = _7~o. Therefore, the optical
purity was 89%.
While the invention has been described herein with re-
gard to certain specific embodiments, it is not so limited. It
is to be understood that variations and modifications thereof may
be made by those skilled in the art without departing from the
spirit and scope of the invention.
