Note: Descriptions are shown in the official language in which they were submitted.
43-4253A
`
~6~1
ASYMMETRIC CAT~L~SIS
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
instance, it has been found that when an olefin, which is capable
of 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 major amount
with the other optical enantiomorph being obtained in minor
amounts. ~urthermore, it has been found that certain such ole-
finic substrates, for instance, precursors of ~ -amino acids
containing ~-acylamido substituents, are particularly amenable
to hydrogenation with homogeneous, optically active catalysts.
~- Such catalytic asymmetric hydrogenation processes have resulted
in the production of large amounts of the desired optical
enantlomorph. It has more recently been found that certain
homogeneous, optically active catalysts containing optically
active bis phosphine ligands provide outstanding levels of
optical purity, i.e., reaching 80% and higher with such ~C-amino `
acid precursors. Other olefinic substrates which would provide
such outstanding levels of optical purity, upon hydrogenation,
are partloularly desirable.
It is an ob~ect of the present invention to provide
such olefinic~substrates.
lt is a further object to provide novel catalytic
asymmetric hydrogenation processes which produce large amounts
of the desired optical enantiomorph.
,
.. ~ , .. ,. . :. . ~ , . - .
43-4253A
~86~
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 obJects, the present in-
vention provides catalytic asymmetric hydrogenation of the Z
geometric isomer of a compound of the formulae
C = C.~
R'~ ~C~O :
: R
and
R3 o :
o~ G C ~COOR
R~ ~ Rl . .-
wherein~R, R1 and R2 each independently~represent hydrogen,
substituted or unsubstituted alkyl having from 1 to 5 carbon :~.
: atoms or substituted or unsubstituted aryl, and R3 represents
substituted or unsubstituted alkyl having from 1 to 5 carbon
atoms or substituted or unsubstituted aryl, 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 purlty of desired optical enantiomorphs.
Description of the Preferred Embodiments
The hydrogenation reaction is illustrated by the
following equation: :
: R~ ~ `o~ ~o +H Rl * ~COOR2
2 ~ or
3 ~ optically 3 0
`` : G~ active R~ ~ :::
R~ ~Rl ~CH-CH 1
~ ,.
-3- ~ :
43-11253A
16)~i36~
shows one or both carbon atoms are asymmetric
wherein R, R1, 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
obtained. In general, it is necessary to utilize the Z geometric
isomer to reali~e the outstanding levels of optical purity with
the olefinic substrates of this invention. 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.
R, Rl, R2 and R3 can be exempli~ied by alkyl groups
such as methyl, ethyl~ propyl, etc. and by aryl groups such as
phenyl, 4-chlorophenyl, 3,4-dihydroxyphenyl, 4-methylphenyl, etc.
Those skilled in the art will recognize that such substituents
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 was
hydroxyl the unsaturated precursor might contain the substituent
"
-O-C-CH3 which would provide the hydroxyl by simple hydrolysis
after the catalytic asymmetric hydrogenation.
The optical enantiomorphs resulting fro~ the process
of this invention are particularly desirable in that optical
activity is a characteristic of compounds which are biologically
active, i.e. normally only one or the other optical enantiomorphs
is useful in living organisms. For instance, those optical
enantiomorphs resulting from this process which have an dC-
hydroxy (resulting from simple hydrolysis) substituent on a
carboxylic acid are recognized as replacements for ~ -amino
acids.
-4-
.~ :
43-L1253A
~)86'771
The compounds represented by the following structural
formula provide excellent results with the process of this in-
vention and there~ore represent compounds particularly amenable
to the hydrogenation process of this invention
Rl ~ COOR2
~C = C~
R 0 ~ ~O
C~R3
wherein R, Rl, R2 and R3 have the same meaning as described above.
Particularly preferred embodiments of this invention
are the catalytic asymmetric hydrogenation of (Z)-ethyl 2-
(acetyloxy)-3-phenyl-2-propenoate~ (Z)-methyl 2-(acetyloxy)-2-
propenoate and (~)-ethyl 2-(acetyloxy)-2-propenoate.
The L enantiomorphs of phenyllactic acid and lactic
acid can be readily obtained by 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 conditions of this reaction, can be used. The
preferred solvents are alcohols particularly methanol, ethanol
and 2-propanol, for instance, those alcohols corresponding to
the ester group in the olefinic substrate being hydrogenated
are particularly desirable.
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 there-
fore referred to as "homogeneous" catalysts.
These catalysks contain optically active bis phosphine
~0 compounds of general formulae I and II below. These bis phosphine
-5-
4 3 Ll253
~()86
compounds are characterized by the structural formula
A - P - CH2CH2 - P - A
B B
wherein A and B each independently represent substituted and
unsubstituted alkyl of from 1 to 12 carbon atoms, substituted
and unsubstituted cycloalkyl having from 4 to 7 carbon atoms,
substituted and unsubstituted aryl; provided that such substi-
. tuents provide no significant inter~erence with the steric re-
quirements 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 pre-
ferred, particularly those wherein one such aryl group has an
alkoxy substituent at the.ortho position. :
More preferred bis phosphine compounds useful in the
... present invention are t.he optically active bis phosphines
~ characterized by the structural formula
`'., X - P - CH2CH2 - P - X
II ;
wherein X represents substituted and unsubstituted phenyl,
Y represents substituted and unsubs~tituted 2-alkoxyphenyl ; .
wherein the alkoxy has from 1 to 6 carbon atoms; pro-
vlded 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 hydro-
genation react.ions of khis invention.
Still more particularly preferred optically active
' ~ bis phosphine compounds useful in the present invention are
characterized by the structural formula
CH2CH2 P M
N N III
-. ~ -6-
.. . . . .
,
13-42531~
;77~
wherein M represen~s
R"'O~_
N represents
~` ,
R' and R" each independently represent hydrogen, halogen~
alkyl having from l to 6 carbon atoms and alkoxy having
from l to 6 carbon atoms, and :
. Rl'i represents normal alkyl having from l 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 com- .
: " . .
pounds 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-bisC(2-methoxy-5-bromophenyl)-phenylphosphino] ethane :: .
1,2-bis(2-ethoxyphenylphenylphosphino) ethane .:
1,2-bisCo-anisyl-(_-phenylphenyl)phosphino] ethane
1,2-blsC(2-methoxy-4-methylphenyl)-phenylphosphino] ethane
1~2~bis(2-ethoxyphenyl-4-chlorophenylphosphino) ethane
1,2-bis(o-anisyl-2-methylphenylphosphino) ethane
1,2-bis(o-anisyl-4-ethylphenylphosphino) ethane
1,2-bis(o-anisDl-3-ethylphenylphosphino) ethane
1,2-bis(o-anisyl-3-phenylphenylphosphino) ethane .
For these bis phosphine compounds to be useful in
:
~, .
43-4253A
6~7~
asymmetric hydrogenation reactions they must be utilized as the
optically active enantiomorph and not in the meso ~orm.
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.
Illustrative coordination metal complexes can be
represented by the ~ormula MeTL wherein Me is a transition metal
selected ~rom the group consisting of rhodium, iridium and ruthen-
ium; T is selected ~rom the group consisting of hydrogen, fluorine,bromine, chlorine and iodine; L is the optically active bis
phosphine ligand as previously de~ined.
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 o~ a metal
selected ~rom the group consisting of rhodium, iridium and ru-
thenium, 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 adding a soluble metal compound to the
reaction mass together with the addition of the proper amount of
the optically active bis phosphine ligand to the reaction mass
either before or during hydrogenation.
~,:
--8--
113-~1253.~
~llDI!~67~ -
The preferred metal ror use in this process is rhodium.
Soluble rhodium compounds that can be utilized include rhodium
trichloride hydrate, rhodium tribromide hydrate, rhodium sul~ate,
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 ~orm bidentate
ligands, or an active ~orm o~ metallic rhodium that is readily
solubilized.
It has been found that a preferred embodiment of this
invention is the hydrogenation process where the optically active
bls phosphine ligand is present in a ratio of about 0.5 to about
-` 2.0, preferablg, 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 ~ound that outstanding results can be obtained with
solid, cationic coordination metal complexes.
Catlonic coordination metal complexes containing one
mole of the optlcally active bis phosphine ligand per mole of :
metal and a chelating bis olefin represent a pre~erred form of
the oatalysts 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 rhodium complex in an alcohol, such as ethanol, adding
one mole per mole of rhodium of the optically active bis phos-
phine compound 8G that an ionic solution is formed, followed by
the addition of a suitable anion, such as, for instance, tetra-
fluoroborate, tetraphenylborate or any other anion that will
result in the preclpltation 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-anisylphenylphosphina) ethane]
':'' - .
_g_
.. , : - : . . - -
43-4253A
6~7~
rhodium tetrafluoroborate, cyclooctadiene-1,5-[1,2-bls(o-anisyl-
phenylphosphino) ethane] rhodium tetraphenyl borate and bicyclo-
2.2.1-hepta-2,5-diene-[1,2-bis(o-anisylphenylphosphino) ethane]
rhodium tetrafluoroborate.
Wikhout prejudice to the present invention it is
thought that the catalyst is present actually as a catalyst pre-
cursor and that upon contact with hydrogen the catalyst is con-
verted to an active form. This conversion can, of course, be
carried out during the actual hydrogenation or can be accomplished
by subjecting 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 wh~ch
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
~0 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
oxidlzing 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
., : . , . . : . . ., - :
113-L1253~
:
~l~)86~77~
necessarily vary since it wlll 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
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 ~s recovered by conventional means.
Many natura].ly 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 com-
pounds in the past has required an additional step of separating
the products into its enantiomorphs. This process is expensive
and time consuming. The process of the present invention permits
the direct formation of desired optical enantiomorphs with out-
standing optical purity thus eliminating much of the time consum-
ing and expensive separation of such optical enantiomorphs.Furthermore, the process provides a higher yield of the desired
optical enantiomorph while concurrently decreasing the yield of
the unwanted optical enantiomorph.
The hydrogenation process of this invention is particu-
; larly deslrable 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 arenot to be construed as limiting the scope thereof. In the
examples, the percent optical purity is determined by the follow-
.
--11-- . -
`.' '.' ' '~ ' ' ''" ' '' '''. .
. .
L~3_ Ll 253~
~16'771
ing equation tit being understood that the optical activity, ex-
pressed as specific rotation, is measured in the same solvent):
%Optical
= Observed optical activity of the mixture x 100
Purity Optical activity o~ pure optical isomer.
Exam~le 1
Preparation of (Z)-ethyl-2-(acetyloxy)-3-phenyl-2-propenoate
A solution containing 22 g. of ethyl phenylpyruvate,
65 g. of acetic anhydride and 20 mg. of _-toluenesulfonic acid
monohydrate was refluxed for 2.5 hours. Excess acetic anhydride
was stripped from the reaction mass and the product, crude
10 (Z)-ethyl-2-(acetyloxy)-3-phenyl-2-propenoate, was distilled at
about 1.6 mm. Hg. (b.p. 120-135C.). The recovered product
crystallized on standing in refrigeration and was recovered by
filtration and recrystallized from ethanol, recovered 12.1 g.,
m.p. 41-47C.; second recrystallization, 10.5 g., m.p. 47-49C.;
third recrystallization, 9.2 g., m.p. 47-49C.
Example 2
~; Preparation of ethyl_2~(acetyloxy)-3-phenylpropanoate
(A) 1.9903 g. of (Z)-ethyl-2-(acetyloxy)-3-phenyl-2-
propenoate and 0.0175 g. of cyclooctadiene-1,5-[1,2-bis(o-
20 anisylphenylphosphino) ethane~ rhodium tetrafluoroborate in
30 cc. of ethanol was shaken in a Hoke bomb at about 27 atm. and ;
.-
50C. Hydrogen uptake was essentially complete in 2 hours. The
resulting solution was stripped of ethanol on a rotary evaporator
j and examined by NMR which confirmed the presence of the hydro-
genation product~ ethyl-2-(acetyloxy)-3-phenylpropanoate, as an
oil. The product was-recovered by vacuum distillation. 1.6 g.
o~ di.stillate, b.p. 80-83C. at 0.05 mm.Hg. were recovered. NMR ~;
`
assay shows the product to consist of 97.6% of the desired hydro-
genation product and 2.4% of the starting olefin. Gas chromato-
: ~ .
30 graphy confirmed this assay. The [~ ]20 = -6.91 (C = 6.o in
CHC13). Optical purity was 79.4%, if ad~usted for assay would
be 81.5%
~-'
-12-
43-LI253A
(B) 2.2721 g. of (Z)-ethyl-2-(acetyloxy)-3-phenyl-2-
propenoate and 0.0202 g. cyclooctadiene 1,5-[1~2-bis(_-anisyl-
phenylphosphino) ethane] rhodium tetrafluoroborate in 30 cc. of
ethanol was subjected to 3 atm. H2 pressure at 51C. The resul-
ting solution was stripped of ethanol on a rotary evaporator.
NMR shows 89% completion after 6 hours. The product~ ethyl-2-
: (acetyloxy)-3-phenylpropanoate, was recovered by flash distilla-
tion, b.p. 80-85C. at 0. 5 mm. Hg. NMR assay shows 87.o% of the
desired product. The observed rotation of the product was 0.515~ -
~o~]D = 8.27 (C=6.o in CHC13). Optical purity adjusted for
assay was 95%.
Example 3
Preparation of (Z)-ethyl-3-(acetyloxy)-3-phenyl-2-propenoate
A solution of 27.8 g. (0.145 mole) of ethyl-3-oxo-3-
phenylpropanoate, 29.0 g. of 2-acetyloxy-1-propene, and 100 mg.
of _-toluenesulfonic acid monohydrate was heated to reflux for
17 hours. The reaction mass was poured into 50 ml. of a 5C.
saturated solution of NaHCO3 and the organic phase was extracted
into ethyl ether. The ether solution was dried and the solvent
was stripped off. Distillation of the residue at 0.1 mm. of Hg.
, yielded 8.3 g. of a yellow oil, b.p. 110-120C. ~he distillate ~-
was shown by GLC, NMR and W analysis to be (Z)-ethyl-3-(acetyl-
oxy)-3-phenyl-2-propenoate.
Example 4
Preparation of ethyl-3-(acetyloxy)-3-phenylpropanoate
A solution of 2.5 g. of (Z)-ethyl-3-(acetyloxy) 3-
phenyl-2-propenoate (2.65 g.) and 0.0373 g. of cyclooctadiene-
1,5-[1,2-bis(o-anisylphenylphosphino) ethane] rhodium tetrafluoro-
borate in 30 cc. of ethanol was hydrogenated at 27 atm. and 50C.
` 30 in a Hoke bomb. After 12 hours the produck was isolated by re-
moving the ethanol on a rotary evaporator. NMR analysis indicated
that the hydragenation product to olefin ratio was 89:11. In `
-13-
~: - , .
. ~ . -,
., ,~,
4 3_ L~ 2 5 3~
~ 36~7~
addition, some ethyl 3-phenylpropanoate was present, which arose
from hydrogenolysis.
2.5 g. of crude product was subjected to distillation,
a first fraction was collected, b.p. 75-87C. at 0.1 mm. of Hg.,
which was ethyl 3-phenylpropanoate. The remaining material that
distilled at 95-110C. and 0.1 mm. of Hg. was an 86:14 (NMR)
mixture o~ ethyl-3-(acetyloxy)-3-phenylpropanoate and (Z)-ethyl-
3-(acetyloxy)-3-phenyl-2-propenoate.
[C]D = ~4 74 (neat, 1=1). With correction for NMR
assay, the optical purity is 90.5%.
Example 5
Preparation of (E)-ethyl-3-(acetyloxy)-3-phenyl-2-propenoate
A solution of 5.2 g. of (Z)-ethyl-3-(acetyloxy)-3~
phenyl-2-propenoate in 60 ml. of CXC13 was irridiated with 3100 A
light for 72 hours. The solvent was removed on a rotary evapora-
tor. Distillation of the residue at 0.03 mm. of Hg. yielded 1.3
g. of yellow oil, b.p. 92-98C. The distillate was shown by ~LC,
NMR, and UV analysis to be (E)-ethyl-3-(acetyloxyj-3-phenyl-2-
propenoate of 86% purity.
Example 6
Preparation of ethyl-3-(acetyloxy)-3-phenylpropanoate
A salution of 1.1566 g. of the (E)-ethyl-3-(acetyloxy)-
3-phenyl-2-propenoate prepared in Example 5 (86% purity) and
0.027 g. of cyclooctadiene-1,5-[1,2-bis(_-anisylphenylphosphino)
; ethane] rhodium tetrafluoroborate in 30 cc. of ethanol was hy-
drogenated ~or 5 hours at 27 atm. and 50C. Ethanol was then
` stripped on a rotary evaporator and the product examined by NMR
analysis. The hydrogenation product to olefin ratio was 76:24.
This product mix was distilled at 95-120C. and 0.2 mm. of Hg.
Gas chromatography assay of the distillate indicated the ethyl-
3-(acetyloxy)-3-phenylpropanoate to (E)-ethyl-3-(acetyloxy)-3- -
phenyl-2-propenoate to ethyl 3-phenylpropanoate ratio was 64:18:18.
-14-
.. . . . . . .
. . .: ~ ~ . : , . . . : ,
,, - :. ~ .: : . . . -
43-4253A
~lO8~ 7~
This mixture had a Cc~]20 = +0.515 (neat, 1=1) with correction - -
for assay of the desired hydrogenation product the COr]D
+0.805 (neat>l=l). Optical purity is 15.4~.
While the invention has been described herein with
regard 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 o~ the invention.
.~ .
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