Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~3(~716~3
84-P~02~6
METHOD OF MAKING A DIASTEREOMERIC MIXTURE
CONTAINING TWO DIASTFREOMERIC N-ACYL-AMINO ACID EST~RS
Thls lnvent~on relates to a process for mak~ng an optlcally
actlve mlxture of an N-acyl-amlno acld ester conta~n~ng at least two
chlral centers.
The separatlon of enant~omers by physlcal means such as
fractlonal d~stlllatlon or fractlonal crystalllzatlon and the llke ~s
known to be hlghly dlfflcult ln general.
It ~s an ob~ect of the lnvent~on to prov~de a process to produce
a reactlon mlxture contalnlng certain ~-carboxy am~des (N-acyl-amlno acld
esters) having two (at least) chlral centers whlch mlxture contains two
of four posslble optlcal conflguratlons and contalns substantlally no
enantlomerlc palrs.
Other ob~ects as well as features aspects and advantages of
the lnventlon wlll become apparent from a study of the speclflcatlon
lncludlng the examples and the clalms.
We have now concelved a process for maklng such a mlxture.
Thus ln accordance wlth the present lnventlon we have provlded
a process for maklng a separable reactlon mlxture contalnlng
dlastereomerlc N-acyl-a-amlno acld esters havlng at least two chlral
centers whlch process comprlses hydrocarboxylatlng an a-enam~de wlth
1. ~
~3~iL768
84-P-0246
carbon monoxide and an organ~c hydroxyl compound having a chlral carbon
atom, sald organic hydroxyl compound be~ng essentially only in either the
L conflguratlon or the D conf~guration, to produce a reactlon mlxture of
d~astereomeric N-acyl-a-amlno acld esters having two chiral centers,
which mixture contains essent~ally no enantlomerlc pairs.
Further, in accordance w~th the present inventlon, there ls
prov1ded a process wh~ch comprlses hydrocarboxylatlng an a-enamide
accord~ng to the equation:
1 2 3 4 CORs ~ C0 + R60H ~ RlR2cHc~R3)N(R4)coR5(cooR6)
to produce an essent~ally diastereomeric mlxture of two stereo~somerlc
N-acyl-a-am~no acid esters havlng at least two ch~ral carbons, where~n
(A) the carbon bonded to R3 in the product ls chiral, (B) R3 is not
the same as -CHRlR2, -COOR6, or -N(R4)COR5,~(C) each of Rl,
R2, R3, R4, R5, and R6 contalns no ethylen~c or acetylenic
unsaturation, (D) eaeh of Rl, R2, R3, R4, and R5 contain zero
to 15 carbon atoms and is independently selected from:
(1) H, a hydrocarbyl group, an acyl group;
(2) a hydrocarbyl group substituted wlth acylamino,
acyl-(N-hydrocarbyl) amlno, formylamino and
formyl-(N-hydrocarbyl) amino, hydrocarbyloxy,
hydrocarbylthio, acyloxy, acylthio, carboxyl, hydrocarbyl
carboxyl, hydrocarbyl th~ocarboxyl, hydrocarbyl amino,
dihydrocarbyl amino, hydrocarbonyl, hydrocarbyl carbonyl,
3-indolyl, carbamoyl, hydrocarboxylcarbamoyl,
d~hydrocarbylcarbamoyl, 5-im~dazolyl, 2-guanidinoyl and
halo groups, wlth the proviso that
~3~L7~8
84-P-0246
~3) Rl and R2 can addlt~onally be selected lndependently
from acylamlno acyl-(N-hydrocarbyl) amlno formylamlno and
formyl-~N-hydrocarbyl) amlno hydrocarbyloxy
hydrocarbylthlo hydrocarbyl amlno dlhydrocarbyl amlno
acy10xy acylth10 carboxyl hydrocarbyl carboxyl
hydrocarbyl thlocarboxyl hydrocarbonyl hydrocarbyl
carbonyl ~-lndolyl carbamoyl hydrocarbylcarbamoyl
dlhydrocarbylcarbamoyl 5-1m1dazolyl 2-guanld1noyl and
halo groups;
(E) Rl and R2 Rl and R3 or R2 and R3 can be llnked to form
a rlng and R~ can be 11nked w1th Rl or R2 or R5 to form a r1ng
(F) R6 conta1ns l to 15 carbon atoms and ~s lndependently selected from
hydrocarbyl hydrocarbyl substltuted w~th one or more hydroxy
subst1tuents and one of the (2) groups above with the prov1so that R6
conta1ns a chlral carbon atom.
~ hen the R60H reactant ls essentlally all L the reactlon
product mlxture contalns the dlastereomerlc N-acyl-a-amino acid esters of
the conf~gurat10ns DL and LL where the flrst des19natlon ls the
conflguratlon at the alpha carbon atom and the second ls the
conf1guratlon of the chlral center ln R6. If the startlng materlal
R60H 1s essentially all D optlcal lsomer the d1astereomerlc react10n
product mlxture contalns the d1astereomerlc N-acyl-a-amlno acld esters of
the conf1gurations DD and LD.
1~O i 7 6~ 84-P-02~6
Speclfic examples of optically pure R60H reactants useful ~n
the present process ~nclude D- or L-3-metho~y-l butanol D- or
L-2-octanol L-menthol D- or L-2-butanol and L-menthoxyethanol.
In most instances R4 is H or acyl in the practice of the
present inventlon.
The process of the invention for making the diastereomeric
mixture containing two (or more) stereoisomeric N-acyl-a-amino acid
esters ~s of importance ln providing a source for relatlvely easily
obtaining a part1cular stereoisomeric configurat~on of a given -amino
acld separated from any other stereo~somer thereof. Thus the m~xture
made according to the present invention can be resolved by ordinary
measures. Thus the two diastereomers are separated physically by well
known physical means such as fractional crystallization fractiona
absorption on solid absorbents countercurrent solvent extraction
fractional d~stillat~on where feas~ble or other phys~cal means.
Thereafter the product fractions are separately hydrolyzed in the
presence of an acid or base in the conventional manner to obtain the
corresponding a-aminO acids and the chiral optically active (L or D)
alcohol. This is especially useful because it allows an overall process
involving recycle of the chiral alcohol. Thus in this aspect of the
invention the organic hydroxyl compound which ~s regenerated during the
hydrolysis ~s recycled at least in part to the step of
hydrocarboxylating thus allowing repeated use of R60H.
The present inventlon is of considerable value ~n providlng a
route for making of the L form or the D form of amino ac~ds occurring in
nature. In thls aspect of the invention the product is a diastereomeric
m~xture containing N-acyl-~-am~no ac~d esters that are hydrolyzable to
~.
~3~i7~i8
~4-P-0246
naturally occurrlng amlno ac~ds. The present lnventlon is of
conslderable advantage when compared to present methods. Thus optlcally
pure amlno aclds are produced lndustrially by the followlng methods:
1) fermentat1On
2) hydrolys~s of plant anlmal or single cell prote~n
3) chemisal synthesls followed by enant~omer~c resolutlon of a
subsequently prepared der~vat~ve
a) enzymatlc enantloselective hydrolysls
b) chemlcal or physlcal separat~on of diastereomers
Each of these methods has dlstlnct d~sadvantages which make them costly
to operate. Fermentatlon methods are often quite slow requ~re rig~dly
controlled cond~tlons and hlghly dilute aqueous reactlon medla and
usually produce a mlxture of products from whlch lsolatlon and
purif7cation of the deslred chiral amlno ac~d is la~orious and
expenslve. Hydrolysls of naturally occurrlng proteln ~s saddled wlth
laborious separation problems and ls lim~ted by the intrinslc
concentration of the deslred amlno acld(s) In the proteln. Chemlcal
am~no ac~d syntheses produce racemic mlxtures of products ln additlon to
their use of expensive chemlcal feedstocks such as expenslve and toxlc
HCN.
In these syntheses the enantlomerlc resolution Is accomplished
by derlvatlzatlon of the amino ac~d racemlc m~xture followed by
enantloselective hydrolysls wlth an enzyme catalyst and separatlon of
the L-amlno acld from the D-amlno acld derlvative and racemization and
recycle of the D-derivative (or optlonally chemical hydrolysls of the D
derivative when the D-amino acid is desired); or followed by physical
5.
3(~L~ 3
84-P-0246
separatlon when the derlvatlzatlon ls performed wlth a chlral reagent.
These procedures add steps to the overall processes and are expenslve and
tlme and labor consumlng.
Among the advantages of the present lnventlon are:
(1) Lower cost startlng materlals;
(2) Inltlal formatlon of d~astereomerlc products as a
result of the amlno acld formlng reactlon, not a
subsequent step;
(3) Fewer process steps.
In a partlcularly advantageous aspect of the lnvent70n we have
provlded a process whlch comprlses (1~ hydrocarboxylatlng an a-enamlde
wlth carbon monoxlde and an organlc hydroxyl compound havlng a chlral
carbon atom, sald organlc hydroxyl compound belng essentlally only ln
elther the L conflguratlon or the D configuratlon to produce a reactlon
mlxture of dlastereomerlc N-acyl-a-amlno acld esters havlng two chlral
centers, whlch mlxture contalns essentlally no enantlomerlc palrs, (2
separatlng the dlastereomers by physlcal means, (3) hydrolyzlng each
dlastereomer to make the L and D -amlno aclds, plus sald organlc
hydroxyl compound, and ~4) recycllng at least a part of sald hydroxyl
compound to step ~
In European patent appllcatlon no. 84 307,683.7, publlshed June
19, 1985, under Publlcatlon No. 0145,265, ls dlsclosed the detalls of how
to hydrocarboxylate alpha enamldes wlth carbon monoxlde and an organlc
hydroxyl compound.
~3(~7~
The above referenced ~uropean patent application i.s
directed to the ma]cing of ~-amino acids or their
precursors through addition of CO and a hydroxyl compound
across the double bond of an enamide. The processing
thus includes a hydrocarboxylation process which involves
reactin~ an enamide with water or an oryanic hydroxyl
compound according to the equation
2 P
/ ~ ~ 5 R6H
R1 R3R4
~G
C=O
~CJI - C- N - C - R
Rl R3R4
wherein each of R1, R2, R3, R4, R5 and R6 contain no
ethylenic or acetylenic unsaturation, contain zero to 15
carbon atoms and are independently selected ~rom:
(1) H or a hydrocarbyl group
(2) a hydrocarbyl yroup substituted with acylamino,
acyl-(N-hydrocarbyl) amino, formylamino and formyl-(N-
hydrocarbyl) amino, hydrocarbyloxy, hydrocarbylthio,
acyloxy, acylthio, carboxyl, hydrocarbyl carboxyl, hydro-
carbyl thiocarboxyl, hydrocarbyl amino, dihydrocarbyl
amino, hydrocarbonyl, hydrocarbyl carbonyl, 3-indolyl,
carbamoyl, hydrocarbylcarbamoyl, dihydrocarbylcarbamoyl,
5-imidazolyl, 2-guanidinoyl and halo groups, and wherein
(3) Rl and R2 can additionally be selected
independently from acylamino, acyl~(N-hydrocarbyl) amino,
formylamino and formyl-(N-hydrocarbyl) amino,
hydrocarbyloxy, hydrocarbylthio, hydrocarbyl amino,
dihydrocarbyl amino, acyloxy, acylthio, carboxyl,
6a.
~3~ 8
hydrocarbyl carboxyl, hydrocarbyl thiocarboxyl,
hydrocarbonyl, hydrocarbyl carbonyl, 3-indolyl,
carbamoyl, hydrocarbylcarbamoyl, dihydrocarbylcarbamoyl,
5-imidazolyl, 2-guanidinoyl and halo groups, and wherein
R6 can additionally be a hydrocarbyl group having one or
more hydroxy substituents, and
wherein Rl and R2, R1 and R3, or R2 and R3 can be
linked to ~orm a rin~, and wherein ~4 can be linked with
Rl or R2 to form a ring.
The hydrocarboxylation reaction is carried out
catalytically and can be effected continuously or in a
batch operation in the liquid phase, or in the vapor
phase where feasible at the reaction temperatures noted
hereinafter. Usually it is effected in a batch
operation in a solvent under pressure. The reactant
concentration can vary widely and are not critical. For
convenience, the ratio of the hydrocarboxylation reactant
R60H to the enamide should be no greater than 100/1 on a
molar basis and is preferably at least 1/1. The amount
of carbon monoxide can vary widely but it is usual to
carry out the reaction under a carbon monoxide pressure
of zero to 3500 psig, more usually 250 to 2500 psig. The
amount of catalyst can also vary widely. Most
conveniently, the amount of catalyst is between 0.001 and
100 mole percent based on the enamide, more usually 0.1
to 10 mole percent.
Usually, the reaction is carried out with a solvent.
The solvent should be inert under the reaction
conditions and preferably dissolve the active catalyst
species as well as the reactants but not necessarily all
of the C0. Suitable solvents found to date include
tetrahydrofuran, benzene, CH3CN and CH2C12, CHC13,
CH3Cl, CC14, toluene, ethyl ether and dimethyl~ormamide.
The now preferred solvent is tetrahydrofuran,
particularly when using (~3P)2PdC12 catalyst, or other
palladium compounds. Usually, the amount of solvent in
6b
13~ 8
the system will be such that the enamide concentration is
at least about 0.01 weight percent in the solution, but
not over 70 weight percent.
The reaction is normally carried out at a
temperature of 0 to 250C, preEerably 20 to 150C.
However, the reaction temperature can be below or above
this if desired. Reaction times on the order of 0.1 to
250 hours can be employed, with reaction times on the
order of 2 to 100 hours being more convenient.
Catalyst useful are generally transition metal
catalyst compounds, particularly coordination complexes
of such metals. Palladium coordination complexes are
effective, especially those complexed with phosphine such
as P~3. However, many known transition metal catalyst
complexes for hydrocarboxylation of alkenes, or for
hydroformylation for enol ethers or enol acetates (U.S.
Patent 3,888,880; B. Fell, M. Barl. J. Mol. Catal., 1977,
2, 301-6; Tinker, Harold B. (Monsanto) Ger. Offen.
2,623,673; U.S. 4,072,709, are not eff7active in the
present hydrocarboxylation. Especially useful Pd
complexes are (~3P)2PdC12 and (~3P)4Pd while HCl is a co-
catalyst. When (~3P)2PdC12 is the catalyst, the now
preferred reaction solvent is tetrahydrofuran.
Once the hydrocarboxylation reaction is completed,
the product amino acid or ester can be recovered from the
reaction system in a conventional manner, such as for
example, by vacuum distillation or crystallization.
The following examples are illustrative of the
hydrocarboxylation reaction.
EXAMPLE _
A 70 mL stainless steel high pressure reactor having
a Pyrex glass liner and a magnetic stir bar was charged
6c
~,
130~76~
with 5 mL of tetrahydrofuran, 0.5 mmol oE m-xylene
internal standard, 2.5 mmol of methanol, 36 mg. of
(P~3)2PdC12 and 0.5 mmol of 9~.5 percent puriky N ~-
styrylbenzamide, and was pressurized to 1000 psig with
C0 at room temperature. This reaction mixture was
stirred for ~8 hours at 100C. Thereafter, the reaction
was cooled to room temperature and vented to atmospheric
pressure. the reactor product was analyzed by gas
chromatography and mass spectrometry and the analysis
indicated a 77 percent conversion of the styrylbenzamide
and a 15 percent selectivity to N-benzolphenylalanine
methyl ester.
EXAMPLES B-W
In the following Examples B-W, the enamides shown
in the left column of Table 1 are reacted exactly as
given in Example A, but substituting the respective
enamide mole for mole for the N-~-styrylbenzamide of
that example, the other reactants and the conditions of
time, temperature, C0 pressure, catalyst and mole ratios
being the same. The hydrocarboxylation reaction in each
instance produces the compounds as shown in the right
column.
6d
~3~17E88
'~
r ~ ~1 t~l ~ N r~ ~ t`~ ~ ~ ~ ~`1 ~ ~`J N
r-l ~ q 3~
r H
.~ ~ ~ N ~ ~ N
Z ,i ~I r~l ,1 ,-1 ~ r l ~1 ~I Z Z ~ d'
m ~ H 1~ K :1 ~ z O
6e
.. . ... .. .
~3~
~ -D
, ~
I l ~ .~
~ ~ ~ 3
~. I
6f
~l30~7~
In general, starting material enamides can be
prepared by reacting the corresponding aldehyde and the
corresponding amide to form an ethylidinebisamide which
is then converted to the enamide by thermolysis. See R.
Giger and D. Ben Ishai, Isr. ~. Chem. 5, 253-9 (1967).
For instance, the enamide for Example 1 was so prepared,
by reacting phenylacetaldehyde and benzamide to make 0.28
g. of ~-phenylethylidinebisbenzamide. This was heated in
a sublimator to 265C at 10 mm Hg for 25 minutes. A
yellow-white solid (0.21 g.) was deposited in the
coldfinger and was collected by careful scraping. Five
additional runs were made and the crude yellow-white
solids combined with the 0.21 g. from the first run. The
combined crude products were recrystallized from ethanol-
water to yield a pale yellow solid which was shown by NMR
spectroscopy to be a 6.6/91.9 mixture of cis- and krans-
N-~-styrylbenzamide of 98.5 percent purity (0.97 g., 52
percent yield) M.P. 161-164C.
Other methods for making enamides are shown in
Hickmott, Tetrahedron, 38, No. 1~, pp. 1975 to 2050,
1982; in Lenz, Synthesis, pp. ~89-518, 1978; and in the
book The_ Chemistry of Amides edited by Zabicky,
Interscience Publishers, New York, 1970.
6~
!`~
`. ' g
ll7~8
84-P-0246
It should be noted that ln such a hydrocarboxylatlon, the alpha
carbon atom ln the hydrocarboxylatlon product ls chlral. Therefore, the
N-acyl-a-amlno acld ester produGed ls a racemlc mlxture of the L and D
forms. If one wants elther the L form or the D form wlthout lts
enantlomer, the separatlon is d~fflcult and expenslve.
The crux of the broadest aspect of the present lnvent10n ls the
concept of employing an organlc hydroxyl compound starting material ln
the foregolng reactlon that ls essentlally all L or all D so that when
the reactlon ls carrled out, the product wlll contaln essentlally no
enantlomerlc palrs, as prevlously dlscussed. Slnce the product mlxture
has no enantlomerlc palrs, the stereolsomers can be more easily separated
by physlcal means than can a reactlon mlxture contalnlng enantlomerlc
palrs.
The dlastereomerlc N-acyl--amlno acld ester mixtures of the
lnventlon are all useful, as noted, to make optlcally actlve a-aminO
aclds by hydrolysls. The amlno aclds are all useful to make peptldes by
known methods, and these can be converted to protelns to make anlmal feed
supplements, for lnstance. The amlno aclds can also be converted to
useful solld polyamldes by conventlonal condensatlon technlques, useful
for thermoplastlc molding of solld shapes, such as structural parts,
plates, tumblers, etc.
The hydrocarboxylatlon reactlon ls carrled out catalytlcally and
can be effected continuously or ln a batch operatlon ln the llquid phase,
or ln the vapor phase where feaslble at the reactlon temperatures noted
hereafter. Usually lt ls effected ln a batch operatlon ln a solvent
under pressure.
6~3
~4_P-0246
The reactant concentratlons can vary w~dely and are not
crlt~cal. For convenience, the rat~o of the hydrocarboxylat~on reactant
R60H to the enamlde should be no greater than 10/1 on a molar basls and
~s preferably at least 1/1. The amount of carbon monox~de can vary
w~dely, but it is usual to carry out the reaction under a carbon monoxide
pressure of zero to 3500 ps~, more usually 250 to 2500 psig. The amount
of catalyst can also vary w~dely. Most conveniently, the amount of
catalyst ls between 0.001 and 100 mole percent based on the enam~de, more
usually 0.1 to 10 mole percent.
Usually, the reaction ls carr~ed out w~th a solvent. The
solvent should be ~nert under the react~on conditlons and preferably
d~ssolve the active catalyst spec~es as well as the reactants but not
necessarily all of the C0. Su~table solvents found to date include
tetrahydrofuran, benzene, CH3CN and CH2C12, CHC13, CH3Cl,
CC14, toluene, ethyl ether and d~methylformamlde. The now preferred
solvent ~s tetrahydrofuran, part~cularly when us~ng (~3P)2PdC12
catalyst, or other palladium compounds~ Usually, the amount of solvent
in the system w~ll be such that the enamide concentrat~on is at least
about 0.01 we~ght percent in the solution, but not over 70 we~ght percent.
The react~on is normally carried out at a temperature of 0 to
250C, preferably 20 to 150C. However, the reactlon temperature can be
below or above this if des~red. React~on times on the order of 0.1 to
250 hours can be employed, wlth react~on t~mes on the order of 2 to 100
hours being more conven~ent.
Catalysts useful in the hydrocarboxylat~on reaction are
generally trans~t~on metal catalyst compounds, particularly coordinat~on
~31~1'76E~
~-P-0246
comp1exes of such metals. Palladium coordlnatlon complexes are
effect~ve, especlally those complexed wlth phosph~ne such as P~3.
Cobalt coordlnatlon complexes are also effectlve, such as Co2(CO)8
and lts phosphlne- or phosphlte-subst~tuted derlvat~ves. When Co
complexes are used it ~s advantageous to ~ncorporate hydrogen and a
tert~ary am~ne, pyridine or a pyrldine der~vat~ve ~nto the reaction
ml~ture to enhance catalyt~c actlv~ty.
Once the hydrocarboxylat~on reactlon ls completed, the product
N-acyl--amlno ac~d ester d~astereomers can be recovered from the
react~on system ln a conventlonal manner, such as for example, by vacuum
dlst~llatlon or crystall~zat~on.
As noted, the opt~cally actlve a-amlno ac~ds have numerous
uses. The naturally occurring amino acids have known uses. In
partlcular, phenylalanlne can be used to make the sweetner aspartame ~n a
known manner. See U.S. patent 3,492,131, ~ssued January 27, 1970.
The follow~ng examples are illustratlve only and are not to be
consldered ~n any way l~mltlng.
~ 3(~
EXample 1
A 70 ml stainless steel high pressure reactor fitted with a Pyrex* glass liner
and magnetic stir k~ar is charged with THF (5 mI,), Lr3-methoxy-l-butanol (0.5
mmol), (PPh3)2PdC12 (36 mg, 0.05 mmol), and N-~-styrylbenzamide (0.5 mmol). The
reactor is æaled, pressurized to 1000 psig with C0, and stirred for 24 hours at
100C. The product mixture, isolated after removal of gas from the reactor
vessel, contains a mlxture of two diastereomeric phenylalanine derivatives, N-
benzoyl-Lrphenylalanine Lr3-methoxy-1-butyl ester and N-benzoyl-D~phenylalanine
Lr3-methoxy-1-butyl ester. These diastereomers are separated by column
chromatography on silica gel with benzene-ethyl acetate eluent and are
separately hydrolyzed by heating to 100C in lN HCl for 2 hours to give pure Lr
and D-phenylalanine, benzoic acid, and Lr3-methoxy-1-butanol, which is
thereafter recycled to a repeat of the foregoing hydrocarboxylation reaction.
Example 2
A 70 mL stainless steel high pressure reactor fitted with a Pyrex glass liner
and magnetic stir bar is Gharged with THF (5 mL), Lr2-octanol (0.5 mmol),
C02(CO)8(0.05 mmol), pyridine (0.25 mmol), and N-acetyl-2-pyrroline (0.5 mmol).
The reactor is sealed, pressurized to 1500 psig with 15:1 CO:H2 and stirred for
24 hours at 100C. The product mixture, isolated after removal of gas from the
reactor vessel, contains a mixture of two diasterecmeric proline derivatives, N-
acetyl-Lrproline Lr2-octyl ester and N-acetyl-D-proline Lr2-octyl ester. These
diasterecmers are separated by column chromatography on silic~ gel with benzene-
ethyl acetate eluent and are separately hydrolyzed by heating to 100C in lN ~ICl
for 2 hours to give pure Lr and D-proline, acetic
*Trademark
--10--
~ 3~76~3
acid, and L-2-octanol, which is thereafter recycled to a repeat of the
foregoing hydrocarboxylation r~action.
Example 3
0.10 mol of isobutyraldehyde and 0.20 mot of benzamide ~re heat~d together at
100C with stirring, and the product solid is heated in a sublimator at 250t
and 1 mm Hg until formation of the enamide l-benzoylamino-2-methylpropene is
complete. A 70 mL stainless steel high pressure reactor fitted with a Pyrex
glass liner and magnetic stir bar is charged with THF (5 mL~, L-menthol (9.5
mmol), Co2(C0)8 tO.05 mmol), pyridine (0.25 mmol), and 1-benzoylamino-2-
methylpropene (0.5 mmol). The reactor is sealed, pressurized to 1500 psig
with 15:1 CO:H2 and stirred for 24 hours at 100C. The product mixture,
isolated after removal of gas from the reactor vessel, conta ns a mixture of
two diastereomeric valine derivatives, N-benzoyl-L-valine L-menthyl ester and
N-benzoyl-D-valine L-menthyl ester. These diastereomers are separated by
column chromatography on silica gel with benzene-ethyl acetate ~luent and are
separately hydrolyzed by heating to 100C in lN HCI for 2 hours to give pure
L- and D-valine, benzoic acid, and L-menthol, which is thereafter recycled to
a repeat of the foregoing hydrocarboxylation reaction.
Example 4
A 70 mL stainless steel high pressure reactor fitted with a Pyrex glass liner
and magnetic stir bar is charged with THF ~5 mL), L-menthoxyethanol (O.S
mmol), Co2(CO)8 (0.05 mmol), pyridine (0.25 mmol), and N-vinylsuccinimide (0.5
mmol). The reactor is sealed, pressurized to 1500 psig with 15:1 CO:H2, and
stirred for 24 hours at 100C. The product mixture, isolated after removal of
~ .3C3~76~3
gas from th~ roactor vessel, contains a mixturo of two diastereomeric alanine
derivatives, N-succinyl-L-alanine L-menthoxyethyl ~ster and N-succinyl-D-
alanine L-menthoxyethyl ester. These diasteroom0rs ~re separatHd by column
chromatography on silica gel with benzsne-ethyl acatate eluent and are
separately hydrolyzed by heating to 1~0C in lN HCI for 2 hours to give pure
L- and D-alanine, succinic acid, and L-menthoxyethanol, which is thereafter
recycled to a repeat o~ the foregoing hydrocarboxylation reaction.
Example 5
0.10 mol of isovaleraldehyde and 0.20 mol of succinimide are heated together
at 100C with stirring, and the product solid is heated in a sublimator at
250C and 1 mm Hg until formation of the enamiJe 1-succinimido-3-methyl-1-
butene is complete. A 70 mL stainless st~el high pressure reactor fitted with
a Pyrex glass liner and magnetic stir bar is charged with THF (~ mL), L-2-
butanol (0.5 mmol), Co2(C0)8 (0.05 mmol), pyridine (0.25 mmol), and 1-
succinimido-3-methyl-1-butene (O.S mmol). The reactor is sealed, pressurized
to 1500 psig with 15:1 CO:H2, and stirred for 24 hours at 100C. The product
mixture, isolated after removal of gas from the reactor vessei, contains a
mixture of two diastereomeric leucine derivatives, N-succinyl-L-leucine L-2-
butyl ester and N-succinyl-D leucine L-2-butyl ester. These diastereomer~ are
separated by column chromatography on silica gel with benzene ethyl acetate
eluent and are separately hydrolyzed by heating to 100C in lN HCI for 2 hours
to give pure L- and D-leucine, succinic acid, and L-2-butanol, which is
thereafter recycled to a repeat of the foregoing hydrocarboxylation reaction.
~ 3~
txample 6
0.10 mol of methoxyacetaldehyde and 0.20 mol of acetamide are h~ated together
at 100C ~ith stirring, and the product solid is heated in a sublimator at
250C and 1 mm Hg until formation of the enamide l-acetamido-2-methoxyethylene
is complete. A 70 mL stainless steel high pressure reaotor fitted with a
Pyrex glass liner and magnetic stir bar is charged with THF (5 mL), D-3-
methoxy-l-butanol (0.5 mmol), (PPh3)2PdCI2 (36 mg, 0.05 mmol), and 1-
acetamido-2-methoxyethylene (0.5 mmol). The reactor is sealed, pressurized to
1000 psig with C0, and stirred for 24 hours at 100C. The product ~;xture,
isolated after removal of gas from the reactor vessel, contains a mixture of
two diastereomeric serine derivatives, N-acetyl-L-serine D-3-methoxy-1-butyl
ester and N-acetyl-D-serine D-3-methoxy-1-butyl est~r. These diastereomers
are separated by column chromatography on silica gel with benzene-ethyl
acetate eluent and are separately hydrolyzed by heating to 100C in lN HCI for
2 hours to give pure L- and D-serine, acetic acid, and D-3-methoxy 1-butanol,
which is thereafter recycled to a r~peat of the foregoing hydrocarboxylation
reaction.
xample 7
0.10 mol of 3-(D-2-octyloxycarbonyl)acetaldehyde and 0.20 mol of acetamide are
heated tvgether at 100C with stirring, and the product solid is heated in a
sublimator at 250C and 1 mm Hg until formation of the enamide D-2-octyl-2-
acetamidoacrylate is complete. A 70 mL stainless steel high pressure reactor
fitted with a Pyrex glass liner and magnetic stir bar is charged with THF ~5
mL), D-2-octanol (0.5 mmol), (PPh3)2PdCI2 (36 mg, 0.05 mmol), and D-2-octyl-2-
acetamidoacrylate (0.5 mmol). The reactor is sealed, pressuri7ed to 1000 psig
/3
17~8
~ith C0, and stirrcd for 24 hours at 100C. The product mixture, isolated
after removal of gas from the reactor vessel, contains ~ mixture of two
diastersomeric aspartic acid derivatives, N-acetyl-L-aspartic acid di(D-2-
octyl3 ester and N-acetyi-D-aspartic acid di~D-2-octyl) est~r. These
diastereomers are separated by column chromatography on silica gei ~ith
benzene-ethyl acetate eluent and are separately hydrolyzed by heating to 100C
in lN ~CI for 2 hours to give pure L- and D-aspartic acid, acetic acid, and D-
?-octanol, which is ther~after recycled tc a repeat of the for~going
hydrocarboxyiation reaction.
Example 8
0.10 mol of 2-(benzylthio)acetaldehyde and 0.20 mol of acetamide are heated
together at 100C with stirring, and the product solid is heated in a
sublimator at 250C and 1 mm Hg until formation of the enamide 1-acetamido-2-
~enzylthioethene is complete. A 70 mL stainless steel high pressure reactor
fitted with a Pyrex glass liner and magnetic stir bar is charged with THF (5
mL), D-menthol (0.5 mmol), (PPh3)2PdCI2 (36 mg, 0.05 mmol), and 1-acetamido-2-
benzylthioethene (0.5 mmol). The reactor is sealed, pressurized to 1000 psig
with Cû, and stirred for 24 hours at 100C. The product mixture, isolated
after removal of gas from the reactor vessel, contains a mixture of two
diastereomeric cysteine derivatives, N-acetyl-L-benzylcysteine D-menthyl ester
and N-acetyl-D-benzylcysteine D-menthyl ester. These diastereomers are
separated by column chromatography on silica gel with benzene-ethyl acetate
eluent and are separately hydrolyzed by heating to 100C in lN HCI for 2 hours
to give pure L- and D-cysteine, benzyl alcohol, acetic acid, and D-menthol,
which is thereafter recycled to a repeat of tha foregoing hydrocarboxylation
reaction.
/~
~o~
Example 9
0.10 mol of 3-(D-2-butoxycarbonyl)propi~naldehyde and 0.20 mol of acetamide
are heated together at 100C with stirring, and the product solid is heated in
a sublimator at 250C and 1 mm Hg until formation of the enamide l-acetamido-
3-(D-2-butoxycarbonyl)propene i~ complete. A 70 mL stainl~ss steel high
pressure reactor fitted with a Pyrex glass liner and magnetic stir bar is
charged with THF (5 mL), D-2-butanol ~0.5 mmol), (PPh3)2PdC12 (36 mg, 0.05
mmol), and l-acetamido-3-(D-2-butoxycarbonyl)propene (0.5 mmol). The reactor
is sealed, pressurized to 1000 p5i9 with C0, and stirred for 24 hours at
100C. The product mixture, isolated after removal of gas from the reactor
vessel, contains a mixture of two diastereomeric glutamic acid derivztives, N-
acetyl-L-glutamic acid di(D-2-butyl) esten and N-acetyl-D-glutamic acid di(D-
2-butyl) ester. These diastereomers are separated by column chromatography on
silica gel with benzene-ethyl acetate eluent and are separate3y hydrolyzed by
heating to 100C in lN HCI for 2 hours to give pure L- and D-glutamic acid,
acetic acid, and D-2-butanol, which is thereafter reGycled to a repeat of the
foregoing hydrocarboxylation reaction.
Example 10
0.10 mol of 4-oxobutyraldehyde and 0.20 mol of acetamide are heated together
at 100C with stirring, and the product solid is heated in a sublimator at
250C and 1 mm Hg until formation of the enamide 1-acetamido-3-
carbamoylpropene is complete. A 70 mL stainless steel high pressure reactor
fitted with a Pyrex glass liner and magnetic stir bar is charged with THF (5
mL), L-menthoxyethanol (0.5 mmol), (PPh3)2PdCI2 (36 mg, 0.05 mmol), and 1-
7~8
acetamido 3-carb~moylpropene (0.5 mmol). The reactor is sealed, pressurized
to 1000 psig with C0, and stirred for 24 hours ~t 100C. The product mixture,
isolated after r0moval o~ gas from the reactor vessel, contains a mixtur~ o~
two diastereomeric glutamine derivatives, N-acetyl-L-glutamine L menthoxyethyl
~ster and N-acetyl-D-glutamine L-menthoxyethyl ester. These diastereomers are
separated by cDlumn chromatography on silica gel with benzene-ethyl acetate
eluent and are separately hydrolyzed by heating to 100C in lN HCI for 2 hours
to give pure L- and D-glutamine, acetic acid, and L-menthoxyethanol, which is
therea~ter recycled to a repeat of the foregoing hydrocarboxylation reaction.
Example 11
0.10 mol of imidazole-4-acetaldehyde and 0.20 mol of acetamide are heated
together at 100C with stirring, and ~he product solid is heated in a
sublimator at 250C and 1 mm Hg until formation of the enamide l-acetamido-2-
(4-imidazolyl)ethene is complete. A 70 mL stainless steel high pressure
reactor fitted with a Pyrex glass liner and magnetic skir bar is charged with
THF (5 mL), L-2-butanol (0.5 mmol), (PPh3)2PJC12 (36 mg, 0.05 mmol), and 1-
acetamido-2-(4-imidazolyl)ethene (0.5 mmol). The reactor is sealed,
pressurized to 1000 psig with C0, and stirred for 24 hours at 100C. The
product mixture, isolated after removal of gas from the reactor vessei,
contains a mixture of two diastereomeric histidine derivatives, N-acetyi-L-
histidine L-2-butyl ester and N-acetyl-D-histidine L-2-butyl ester. These
diastereomers are separated by column chromatography on silica gel with
benzene-ethyl acetate eluent and are separately hydrolyzed by heating to 100C
in lN HCI for 2 hours to give pure L- and D-histidine, acetic acid, and L-2-
butanol, ~hich is thereafter recycled to a repeat of the foregoing
hydrocarboxylation reaction.
/~
~ L7 6
Example 12
0.10 mol of 3-methylthiopropanal and 0.20 mol of acetamide are heat*d together
at 100C with stirring, and the product soiid is heated in a sublimator at
250C and 1 mm Hg until formation of the enamide 1-acetamido-3-
methylthiopropene is complete. A 70 mL stainless steel high pressure r0actor
fitted with a Pyrex glass liner and magnetic stir bar is charged with THF (5
mL), L-3-methoxy-1-butanol (0.5 mmol), (PPh3)2PdC12 ~36 mg, 0.05 ~mol), and 1-
acetamido-3-methylthiopropene (0.5 mmol). The reactor is sealed, pressurized
to 1000 psig with C0, and stirred for 24 hours at 100C. The product mixture,
isolated after removal of gas from the reactor ve~sel, contains a mixture of
two diastereomeric methionine deriYatives, N-acetyl-L-methionine L-3-methoxy-
1-butyl est~r and N-acetyl-D-methionine L-3-methoxy-1-butyl ester. These
diastereomers are separated by column chromatography on silica gel with
benzene-ethyl acetate eluent and are separately hydrolyzed by heating to 100C
in lN HCI for 2 hours to gi~e pure L- and D-methionine, acetic acid, and L-3-
methoxy-1-butanol, which is thereafter recycled to a repeat of the foregoing
hydrocarboxylation reaction.
Example 13
0.10 mol of indole-3-acetaldehyde and 0.20 mol of acetamide are heated
together at 100C with stirring, and the product solid is heated in a
sublimator at 250C and 1 mm Hg until formation of the enamide 1-acetamido-2-
~3-indolyl)ethene is complete. A 70 mL stainless steel high pressure reactor
fitted with a Pyrex glass liner and magnetic stir bar is charged with THF (5
mL), L-menthoxyethanol (0.5 mmol), (PPh3)2PdC12 (36 mg, 0.05 m~ol~, and 1-
13~17~acetamido-2-(3-indolyI)ethene (0.5 mmol). The reactor is s0aled, pressurized
to lG00 psig with C0, and stirred for 24 hours at 100C. The product mixture,
isolated ~fter removal of 935 from the reactor vessel, contains a mixture of
~wo diastereomeric tryptophan derivatives, N-acetyl-L-tryptophan L-
menthoxyathyl est0r and N-acetyl-D-tryptophan L-menthoxyethyl ester. These
diastereomers are separated by column chromatography on silica gel with
benzene-ethyi acetate eluent and are separately hydrolyzed by heating to 100C
in lN HCI for 2 hours to give pure L- and D-tryptophan, acetic acid, and L-
menthoxyethanoi, which is thereafter recycled to a repsat of the foregoing
hydrocarboxylation reaction.
Example 14
0.10 mol of p-methoxyphenylacetaldehyde and 0.20 mol of acetamide are heated
together at 100C with stirring, and the product solid is heated in a
sublimator at 250C and 1 ~m Hg until formation of the enamide 1-acetamido-2-
(4-methoxyphenyl~ethsne is complete. A 70 mL stainless steel high pr0ssure
reactor fitted with a Pyrex glass liner and magnetic stir bar is charged with
THF (5 mL), L-2-octanol, (0.5 mmol), (PPh3)2PdCI2 (36 mg, 0.05 mmol), and 1-
acetamido-2-(4-methoxyphenyl)ethene (0.5 mmol). The reactor is sealed,
pressurized to 10C0 psig with C0, and stirred for 24 hours at 100C. The
product mixture, isolated after removal of gas from the reactor vessel,
contains a mixture of two diastereomeric tyrosine deriYatives, N-acetyl-L-0-
methyltyrosine L-2-octyl ester and N-acetyl-D-0-methyltyrosine L-2-octyl
ester. These diastereomers are separated by column chromatography on sil iC3
gel with benzene-ethyl acetate eluent and are separately hydrolyzed by heating
to 100C in lN HCI for 2 hours to give pure L- and D-tyrosine, methanol,
acetic acid, and L-2-octanol, which is thereafter recycled to a repeat of the
' /~
~.3~7~
.~regoing hydrocarboxyiation reaction.
Example 15
0.10 mol of 3,4-diacetyloxyphenylacetaldehyde and 0.20 mol of acetamide are
heated togethær at 100C with stirring, and the product soiid is heated in a
sublimator at 250C and 1 mm Hg until formation of the enamide 1-ac~tamido-2-
(3,~-diacetyloxyphenyl)ethene is compiete. A 70 mL stainiess steel high
pressure reactor fitted with a Pyrex glass liner and magnetic stir bar is
charged with THF (5 mL), L-menthoxyethanol (0.5 ~mol), (PPh3)2PdC12 (36 mg,
O.05 mmol), and l-acetamido-2-(3,4-diacetyloxyphenyl)ethene (0.5 mmol~. The
reactor is sealed, pressurized to 1000 psig with C0, and stirred for 24 ho~rs
at 100C. The product mixture, isolated after removal of gas from the reactor
vessel, contains a mixture of two diastereomeric dopa derivatives, 0,O',N-
triacetyl-L-dopa L-menthoxyethyl ester and 0,O',N-triacetyl-D-dopa L-
menthoxyacetyl ester. These diastereomers are separated by column
chromatography on silica gel with benzene-ethyl acetate eluent and are
separately hydrolyzed by heating to 100C in lN HCI for 2 hours to give pure
L- and D-dopa, acetic acid, and L-menthoxyethanol, which is thereafter
recycled to a repeat of the foregoing hydrocarboxylation reaction.
Example 16
0.10 mol of 4-acetamidobutyraldehyde and 0.20 mol of acetamide are heated
together at 100C with stirring, and the product solid is heated in a
sublimator at 250C and 1 mm Hg until formation of the enamide 1,4-
diacetamido-1-butene is complete. A 70 mL stainless steel high pressure
reactor fitted with a Pyrex glass liner and magnetic stir bar is charged with
/9
8~-P-0246
THF ~5 mL), L-3-methoxy-1-butanol (0.5 ~mol), (PPh3)2PdC12 (36 mg, 0.05 mmol~,
and 1,4-diacetamido-1-buten~ (0.5 mmol). The reactor is sealed, pressuri20d
to 10~0 psig with C0, and stirred for 24 hours at 100C. Th~ product mi~ture,
i olated after r~moval of gas from the reactor v~ssel, contains a ~ix~uro of
two diast3r~0meric ornithine derivatives, N,N'-di~cetyl-L-ornithino L-3-
methoxy-l~butyl est~r ~nd N,N'-diacetyl-D-ornithine L-3-methoxy-1-but~l ester.
Thes~ diastereomers aro separatod ~y column chromatography on silica g~ h
benzen~-~thyl acetate oluent and aro ~oparately hydrolyzed by heating to 100C
in lN HCI for 2 hours to give pure L- and D-ornithine, acetic acid, ~nd L-3-
m~hoxy-1-butanol, which is thereafter recycled to a repeat of the foregoing
hydrocarbox~lation roaction.
As used here1n the term "hydroxyl" 1n the phrase "organ~c
hydroxyl compound" excludes the hydroxyl group of a carboxyllc acld
group -COOH.
As w111 be ev1dent to those sk111ed 1n the art varlous
mod1flcat10ns of th1s lnventlon can b2 made or followed 1n the l~ght of
the foregolng dlsclosure and dlscuss10n wlthout depart1ng from the sp~rlt
and scope of the dlsclosure or from the scope of the cla1ms.
20.
