Substituted lactones of amino acids

Novel substituted lactones of amino acids in all their possible stereoisomeric forms or mixtures thereof of the formula ##STR1## wherein A is a hydrocarbon chain of 1 to 10 chain members containing one or more heteroatoms and one or more unsaturations and the chain members being a mono- or polycyclic system or comprises a system of spiro or endo type and may contain one or more chiral atoms or the lactone copula can present a supplementary chirality due to the asymetric spatial configuration of the molecule make up and R is selected from the group consisting of: ##STR2## wherein Z is the organic remainder of an amino acid of the formula: ##STR3## Y is derived from a primary, secondary or tertiary alcohol of the formula Y-OH and B is the remainder of a heterocycle amino acid of 3 to 6 carbon atoms of the formula: ##STR4## and their preparation and their use for the resolution of amino acids.

STATE OF THE ART 
Related compounds are described in German Pat. Nos. 2,510,714 and 1,081,471 
and copending, commonly assigned U.S. patent application Ser. No. 021,833 
filed Mar. 19, 1979. 
OBJECTS OF THE INVENTION 
It is an object of the invention to provide the novel lactones of formula I 
and a novel process for their preparation. 
It is another object of the invention to provide a novel process for the 
resolution of amino acids. 
These and other objects and advantages of the invention will become obvious 
from the following detailed description. 
THE INVENTION 
The novel lactones of the invention are substituted lactones of amino acids 
in all their possible stereoisomeric forms or mixtures thereof of the 
formula: 
##STR5## 
wherein A is a hydrocarbon chain of 1 to 10 chain members containing one 
or more heteroatoms and one or more unsaturations and the chain members 
being a mono- or polycyclic sytem or comprises a system of spiro or endo 
type and may contain one or more chiral atoms or the lactone copula can 
present a supplementary chirality due to the asymetric spatial 
configuration of the molecule make up and R is selected from the group 
consisting of: 
##STR6## 
wherein Z is the organic remainder of an amino acid of the formula: 
##STR7## 
Y is derived from a primary, secondary or tertiary alcohol of the formula 
Y-OH and B is the remainder of a heterocycle amino acid of 3 to 6 carbon 
atoms of the formula: 
##STR8## 
The esters of amino acids of the formula 
##STR9## 
are denominated herein as formula III.sub.A and esters of cyclic amino 
acids of the formula: 
##STR10## 
are denominated as formula III.sub.B. The amino acids of formula: 
##STR11## 
include the naturally occuring amino acids, notably those listed in Chem. 
Abs., Vol. 76, p. 901 and also include synthetic amino acids, especially 
those listed in "Amino acids, peptides and proteins," Vol. 2, page 10, 
Specialist Periodic Reports and The Chemical Society, Burlington House, 
London W1 VOBN 1970 Edition or Vol. 1, p. 13, 1969 edition. 
Among the preferred compounds of formula I are those wherein the A chain 
contains at least one asymetric carbon atom and in which the 2 atoms or 
different radicals which substitute the atom of asymetric carbon are 
independently selected from one or other of the following groups: (a) 
groups are hydrogen, halogens, nitro, alkyl of 1 to 10 carbon atoms, 
cycloalkyl of 3 to 6 carbon atoms, phenyl, phenyl substituted with at 
least one member of the group consisting of halogen, alkyl of 1 to 6 
carbon atoms, carboxyl, --CN, --CHO, acyl of an organic carboxylic acid of 
1 to 6 carbon atoms, 
##STR12## 
and alkylthio and alkoxy of 1 to 6 carbon atoms; (b) a group selected from 
the group consisting of 
##STR13## 
where ALK is alkyl of 1 to 6 carbon atoms and --NH--X.sub.1 where X.sub.1 
is hydrogen alkyl of 1 to 6 carbon atoms, (c) the group of the formula 
##STR14## 
where X.sub.2 and X.sub.3 are individually alkyl of 1 to 6 carbon atoms or 
taken together with the nitrogen atom form a heterocycle of 6 atoms or 
X.sub.3 is benzyl and X.sub.2 is carboxyl. 
Other preferred compounds of formula I are those wherein A is an aliphatic 
hydrocarbon of 2 to 3 carbon atoms, those wherein A is an aliphatic 
hydrocarbon interrupted by one or more heteroatoms, those wherein A is an 
aliphatic hydrocarbon containing a double bond, those wherein A is a 
monocyclic hydrocarbon of 3 to 6 carbon atoms optionally containing one 
unsaturation, those wherein A is a bicyclic hydrocarbon containing 5 to 10 
carbon atoms optionally containing one unsaturation, those wherein A is 
##STR15## 
those wherein A is 
##STR16## 
and X.sub.4 and X.sub.5 are individually selected from the group 
consisting of hydrogen, fluorine, chlorine, bromine and alkyl of 2 to 6 
carbon atoms or taken together with the carbon atoms to which they are 
attached from a carbon homocycle of 3 to 7 carbon atoms and those wherein 
A is 
##STR17## 
wherein R.sub.3 is selected from group consisting of --O--, --S--, --NH-- 
and --NR.sub.4 -- and R.sub.4 is alkyl of 1 to 6 carbon atoms. 
Among the particularly preferred compounds of the invention of formula I 
are those wherein Y is derived from a primary aliphatic alcohol of 1 to 12 
carbon atoms, those wherein Y is derived from a primary cycloaliphatic 
alcohol of 4 to 8 carbon atoms, those wherein Y is derived from benzyl 
alcohol, those wherein R is derived from an ester of a natural amino acid, 
those wherein R is derived from an ester of a natural amino acid of the 
group consisting of leucine, proline, phenylalanine and methionine and 
those wherein R is derived from an ester of a synthetic amino acid. 
Among the specific compounds of formula I are the various possible 
stereoisomeric forms and mixtures thereof of benzyl 
(.alpha.R,3R,3aR,4S,7R,7aS).alpha.-[(1-oxo-3a,4,7,7a-tetrahydro-1H, 
3H-4,7-methanoisobenzofuran-3-yl)-amino]-isohexanoate, benzyl 
(.alpha.S,3S,3aS,4R,7S,7aR) .alpha.-[(1-oxo-3a,4,7,7a-tetrahydro-1H, 
3H-4,7-methanoisobenzofuran-3-yl)-amino]-isohexanoate, benzyl 
(.alpha.R,3S,3aS,4R,7S,7aR).alpha.-(1-oxo-3a,4,7,7a-tetrahydro-1H, 
3H-4,7-methanoisobenzofuran-3-yl)-D prolinate, benzyl 
(.alpha.R,3R,3aR,4S,7R,7aS) .alpha.-(1-oxo-3a,4,7,7a-tetrahydro-1H, 
3H-4,7-methanoisobenzofuran-3-yl)-L-prolinate, methyl 
(.alpha.R,3R,3aR,4S,7R,7aS).alpha.-[(1-oxo-3a,4,7,7a-tetrahydro-1H,3H-4,7- 
methanoisobenzofuran-3-yl)-amino]-phenylpropanoate, methyl 
(.alpha.S,3S,3aS,4R,7S,7aR).alpha.-[(1-oxo 3a,4,7,7a-tetrahydro-1H, 3H- 
4,7-methanoisobenzofuran-3-yl)-amino]-phenylpropanoate, methyl 
(3S,3aS,4R,7S,7aR).alpha.-(1-oxo-3a,4,7,7a-tetrahydro-1H, 
3H-4,7-methanoisobenzofuran-3-yl)-L-methioninate and methyl 
(3R,3aR,4S,7R,7aS).alpha.-(1-oxo-3a,4,7,7a-tetrahydro-1H, 
3H,4,7-methanoisobenzofuran-3yl)-L-methioninate. 
The novel process of the invention for the preparation of compounds of 
formula I comprises reacting a compound of the formula: 
##STR18## 
wherein A has the above definition with an ester of an amino acid of 
formula III.sub.A or III.sub.B to obtain the corresponding compound of 
formula I or otherwise denominated as formula I.sub.A where the chiral 
atoms possess a well defined configuration when the lactonic copula and 
the ester of the amino acid possess one or more chiral atom of well 
defined configuration or otherwise denominated as formula I.sub.B where it 
acts as a mixture of diastereoisomers, the lactone being a well defined 
optical isomer and the chiral center or centers of the ester of the amino 
acid not having an univocal configuration or otherwise denominated as 
formula I.sub.C when it acts as a mixture of diastereoisomers, the ester 
of the amino acid being a well defined optical isomer and the chiral atoms 
of the lactonic copula not having all of an univocal configuration, then, 
if necessary separating by a physical method the diastereoisomeric 
compounds contained either in the mixtures of type I.sub.B or in the 
mixtures of type I.sub.C wherein the chiral centers are all of an univocal 
configuration. 
A preferred form of the process of the invention for the preparation of the 
compounds of formula I comprises reacting the ester of an amino acid of 
formula III.sub.A and the lactone of formula II while removing the water 
of reaction by physical means, especially by azeotropic distillation with 
a solvent selected from the group consisting of chlorinated solvents, 
aromatic hydrocarbons, aliphatic hydrocarbons and ethers, more especially 
by distillation under reduced pressure. The separation of the 
diastereoisomeric compounds is preferably effected by crystallization or 
chromatography. 
The lactonic compounds of formula II are preferably selected from the group 
consisting of (1R,5S) 6,6-dimethyl-4(R)-hydroxy-3-oxabicyclo (3,1,0) 
hexan-2-one, (1S,5R) 6,6-dimethyl-4(S)-hydroxy-3-oxabicyclo (3,1,0) 
hexan-2-one, (3R,3aR,4S,7R,7aS) 
3-hydroxy-tetrahydro-4,7-methanoisobenzofuran-1-one and (3S,3aS,4R,7S,7aR) 
3-hydroxy-tetrahydro-4,7-methanoisobenzofuran-1-one. 
If the chiral atom or atoms of the lactonic copula of formula II are each 
of (R) or (S) determined steric configuration when the asymetric carbon 
atom or atoms of the ester of the amino acid of formula III.sub.A or 
III.sub.B are individually of (R) or (S) determined steric configuration, 
the compounds of formula I.sub.A are directly obtained with retention of 
the configurations. When the esters of the amino acids of formula 
III.sub.A or III.sub.B possessing one or more unresolved asymetric carbon 
atom are used in the process of the invention, a mixture of 
diastereoisomeric compounds of formula I denominated as formula I.sub.B 
are obtained which can be separated by a physical treatment, especially by 
chromatography or by crystallization from a solvent, with the latter being 
especially interesting. 
After separation of diastereoisomers of formula I.sub.B, for example, after 
separation of formula I.sub.A, a simple hydrolysis permits the obtaining 
of esters of amino acids of formula III.sub.A or III.sub.B resolved about 
the racemic asymetric carbon atoms which are initially present. When the 
ester of amino acids of formula III.sub.A or III.sub.B possess m 
nonresolved chiral centers, it forms 2 m analogous diastereoisomers of 
formula I.sub.A which can eventually separated into the individual ones. 
Otherwise, one recovers the lactonic compounds of formula II used of which 
the chiral atoms have the (R) or (S) determined steric configuration which 
exists in the starting compound. It is understood that the preceding 
considerations apply in the same manner to the esters of the amino acids 
of formula III.sub.A and III.sub.B. 
When the lactonic copula has the (RS) racemic configuration due to one or 
more unresolved chiral centers, one obtains a mixture of diastereoisomeric 
compounds of formula I denominated as formula I.sub.C which can be 
separated by a physical treatment, especially by chromatography or 
crystallization from a solvent, preferably the latter. 
After separation of diastereoisomers of formula I into formula I.sub.C, for 
example after separation of formula I.sub.A, a simple hydrolysis permits 
the obtaining of resolved lactonic compounds due to (RS) racemic 
configuration of chiral atoms which are initially present. When the 
lactonic copula possesses n non-resolved chiral centers, it forms 2 n 
diastereoisomers of formula I.sub.A which eventually can be separated into 
the individual ones. 
Otherwise, one recovers the ester of amino acids of formula III.sub.A or 
III.sub.B due to the asymetric carbon atoms of (R) or (S) determined 
configuration which exists in the starting amino acids of formulae 
III.sub.1 or III.sub.2. It is understood that the preceding considerations 
concerning the esters of amino acids of formula I.sub.A are equally 
applicable to the esters of formula III.sub.B. 
In all of the preceding discussion, the presence of at least one resolved 
or unresolved chiral center in the compounds of formulae II, III.sub.1 or 
III.sub.2 implies the following different possibilities: either the chiral 
centers do not possess an univocal configuration of (R) or (S) and the 
compound of formula I is a mixture of racemates of enantiomers or one part 
of the chiral centers possesses an univocal (R) or (S) configuration and 
the compound of formula I is a mixture of diastereoisomers or all the 
chiral centers have an univocal (R) or (S) configuration and the compound 
of formula I are of well defined optical isomers. 
It is to be emphasized that a single chiral atom of the indispensable 
lactonic compound to resolve amino acids (in the ester form) or to resolve 
the lactone itself is the one that is situated in the .alpha.-position to 
the endocyclic oxygen, the other supplementary chiral carbon atoms can 
exist in the lateral chain A and aren't indispensable for effecting the 
resolutions. 
In a particularly preferred embodiment of the process of the invention, the 
lactonic compound is (3R,3aR,4S,7R,7aS) 
3-hydroxy-tetrahydro-4,7-methanoisobenzofuran-1-one or (3S,3aS,4R,7S,7aR) 
3-hydroxy-tetrahydro-4,7-methano-isobenzofuran-1-one and the compounds of 
formula I are esters of amino acids selected from the group consisting of 
benzyl leucinate, benzyl prolinate, methyl phenylalaninate and methyl 
methioninate. 
The novel process for the invention for the resolution of compounds of 
formula II or compounds of formula III comprises subjecting the 
diastereoisomeric compounds isolated from mixtures of formula I.sub.C or 
I.sub.B to acid hydrolysis in an aqueous medium to either recover 
compounds of formula II with asymetric carbon atoms of an univocal 
configuration or subjecting the resulting ester of an amino acid of 
formula III to the action of a hydrolysis agent to hydrolyze the ester 
group and recovering the desired amino acid with asymetric carbon atoms of 
an univocal configuration. 
In this process, the ester of the amino acid possesses an unresolved 
asymetric center and the lactone of formula II possesses at least one 
chiral center of the (R) or (S) defined configuration. The two said 
compounds are reacted to form a mixture of the two diastereoisomers of 
formula I.sub.A (I.sub.D and I.sub.E) which is then separated by physical 
means such as chromatography or crystallization. The individual isomers of 
formula I.sub.D and I.sub.E are then subjected to hydrolysis to obtain the 
corresponding isomer of the ester of the amino acid of formula III.sub.A 
or III.sub.B which is then subjected to hydrolysis to remove the ester 
group resulting in obtaining the individual isomer of the amino acid in 
the (R) or (S)antipodes. 
If the hydrolysis of the esters of formula III.sub.A or III.sub.B is 
effected with an alkaline agent in an aqueous medium, the amino acid of 
formula III.sub.1 or III.sub.2 is recovered in the form of its salt. The 
removal of the ester group may also be effected by hydrogenolysis with 
hydrogen in the presence of a catalyst. Other classical methods may also 
be used. 
In a similar manner, the starting lactone of formula II has chiral centers 
presenting the configuration corresponding to a racemate and is reacted 
with a prefectly defined optical isomer of an ester of an amino acid of 
formula III.sub.A or III.sub.B to obtain 2 compounds of formula I.sub.A 
(I.sub.F and I.sub.G) which are separated by physical methods such as 
chromatography or crystallization. The individual isomers of formula 
I.sub.F or I.sub.G have an antipodal configuration and are then subjected 
to acid hydrolysis to obtain the resolved lactone of formula II in its 
antipodal form. 
In the process of the preparation of the compounds of formula I of the 
invention and in the use of the compounds, the esters of the amino acids 
of formula III.sub.A or III.sub.B and the amino acids of formula III.sub.1 
or III.sub.2 are conveniently obtained in the form of their acid addition 
salts, especially the hydrochloride. 
In summary, the aggregate of the reactions permit either the resolution of 
amino acids after transformation into their esters with the lactones of 
formula II of a well defined configuration or the resolution of the 
lactones of formula II with the ester of amino acids of a well defined 
configuration. 
The biologically used amino acids are generally used in the form of their 
optical isomers and the method of the invention permits the resolution of 
the corresponding racemic amino acids produced by synthesis. As the 
resolution of lactones of formula II is difficult to effect, it is welcome 
to find an elegant solution to the problem.

In the following examples there are described several preferred embodiments 
to illustrate the invention. However, it should be understood that the 
invention is not intended to be limited to the specific embodiments. 
EXAMPLE 1 
Benzyl (.alpha.R,3R,3aR,4S,7R,7aS).alpha.-[(1-oxo-3a,4,7,7a-tetrahydro-1H, 
3H-4,7-methano-isobenzofuran-3-yl)-amino]-isohexanoate 
STEP A: Benzyl DL leucinate 
A mixture of 3.93 g of the tosylate of benzyl DL leucinate, 25 ml of 
demineralized water, 150 ml of ether and 1.01 g of triethylamine was 
stirred at 20.degree. C. for 10 minutes and the mixture was then extracted 
with ether. The decanted organic phase was dried and evaporated to dryness 
under reduced pressure to obtain 2.2 g of benzyl DL leucinate. 
STEP B: Benzyl 
(.alpha.R,3R,3aR,4S,7R,7aS).alpha.-[(1-oxo-3a,4,7,7a-tetrahydro-1H,3H-4,7- 
methano-isobenzofuran-3-yl)-amino]-isohexanoate 
A mixture of 2.2 g of the product of Step A and 1.66 g of 
(3R,3aR,4S,7R,7aS) 3-hydroxy-tetrahydro-4,7-methano-isobenzofuran-1-one 
with a specific rotation [.alpha.].sub.D.sup.20 =+47.degree. (c=1% in 
chloroform) and 30 ml of benzene was refluxed with stirring for one hour 
while azeotropically distilling the water of reaction from the mixture and 
the mixture was then evaporated to dryness under reduced pressure. The 
residue was crystallized from about 15 ml of isopropyl ether and the 
mixture was iced and vacuum filtered at 10.degree. C. to obtain 1.4 g of 
benzyl 
(.alpha.R,3R,3aR,4S,7R,7aS).alpha.-[(1-oxo-3a,4,7,7a-tetrahydro-1H,3H-4,7- 
methano-isobenzofuran-3-yl)-amino]-isohexanoate melting at 88.degree. C. 
IR Spectrum (chloroform): Absorption at 3340 cm.sup.-1 (NH); at 1760 to 
1745 cm.sup.-1 (carbonyl, .gamma.-lactone, ester); at 1390 to 1370 
cm.sup.-1 (geminal methyls); at 698 cm.sup.-1 (phenyl). 
NMR Spectrum (CDCl.sub.3): Peaks at 6.32 ppm (5- and 6-ethylenic hydrogens 
of lactone); at 1.32-1.45 ppm and 1.58-1.72 ppm (hydrogens of 8--CH.sub.2 
of lactone); at 4.68 ppm (3-hydrogen of lactone); at 2.52 ppm (hydrogen of 
amine); at 0.85-0.93 ppm (hydrogens of geminal methyls); at 5.2 ppm 
(.alpha.-hydrogens to phenyl); at 7.42 ppm (aromatic hydrogens). 
Circular dichroism (dioxane): 
______________________________________ 
max. at 225 nm .DELTA..epsilon. = +1.9 
max. at 260 nm .DELTA..epsilon. = -0.03 
______________________________________ 
EXAMPLE 2 
Benzyl 
(.alpha.S,3S,3aS,4R,7S,7aR).alpha.-[(1-oxo-3a,4,7,7a-tetrahydro-1H,3H-4,7- 
methano-isobenzofuran-3-yl)-amino]-isohexanoate 
Using the procedure of Step B of Example 1, a mixture of 2.2 g of benzyl DL 
leucinate, 1.66 g of 
(3S,3aS,4R,7S,7aR)-3-hydroxy-tetrahydro-4,7-methano-isobenzofuran-1-one 
with a specific rotation of [.alpha.].sub.D.sup.20 =-47.degree. (c=1% in 
chloroform) and 30 ml of benzene was refluxed for 2 hours to obtain 1.4 g 
of benzyl 
(.alpha.S,3S,3aS,4R,7S,7aR(.alpha.[(1-oxo-3a,4,7,7a-tetrahydro-1H,3H-4,7-m 
ethano-isobenzofuran-3-yl)-amino]-isohexanoate melting at 88.degree. C. 
IR Spectrum (chloroform): Absorption at 3340 cm.sup.-1 (NH); at 1760 to 
1745 cm.sup.-1 (carbonyl, .gamma.lactone, ester); at 1390-1370 cm.sup.-1 
(geminal --CH.sub.3 s); at 698 cm.sup.-1 (phenyl). 
NMR Spectrum (CDCl.sub.3): Peaks at 6.18 ppm (5- and 6-ethylenic hydrogens 
of lactone); at 1.32-1.45 ppm and 1.57-1.7 ppm (hydrogens of 8--CH.sub.2 
of lactone); at 4.6 ppm (3-hydrogen of lactone); at 2.25 ppm (hydrogen of 
amine); at 0.83-0.95 ppm (hydrogens of geminal methyls); at 5.1 ppm 
(hydrogens .alpha. to phenyl); at 7.35 ppm (aromatic hydrogens). 
Circular dichroism (dioxane): 
______________________________________ 
max. at 226 nm .DELTA..epsilon. = -1.86 
max. towards 260 nm .DELTA..epsilon. .perspectiveto. +0.01 
______________________________________ 
EXAMPLE 3 
Benzyl 
(.alpha.S,3S,3aS,4R,7S,7aR).alpha.-(1-oxo-3a,4,7,7a-tetrahydro-1H,3H-4,7-m 
ethano-isobenzofuran-3-yl)-D-prolinate 
A mixture of 3.18 g of benzyl DL-prolinate hydrochloride, 3 ml of 
demineralized water, 25 ml of benzene and 1.34 g of triethylamine was 
stirred at 20.degree. C. for one hour and the decanted organic phase was 
washed with water, dried and evaporated to dryness to obtain 2.6 g of 
benzyl DL-prolinate in the form of a colorless oil. 
A mixture of 2.6 g of the said product, 2.2 g of (3S,3aS,4R,7S,7aR) 
3-hydroxy-tetrahydro-4,7-methano-isobenzofuran-1-one with a specific 
rotation of [.alpha.].sub.D.sup.20 =-47.degree. (c=1% in chloroform) and 
25 ml of anhydrous benzene was stirred for 21/2 hours at reflux while 
azeotropically distilling off the water of reaction formed. The mixture 
was evaporated to dryness under reduced pressure and the residue was 
crystallized from isopropyl ether to obtain 1.5 g of benzyl 
(.alpha.S,3S,3aS,4R,7S,7aR) 
.alpha.-(1-oxo-3a,4,7,7a-tetrahydro-1H,3H-7-methano-isobenzofuran-3-yl)-D- 
prolinate melting at 105.degree. C. 
IR Spectrum (CHCl.sub.3): 
Absorption at 1760.sup.-1 and 1740 cm.sup.-1 (carbonyl); at 1588 and 1495 
cm.sup.-1 (aromatic-presence of C--O--C); at 696 cm.sup.-1 (phenyl). 
Circular dichroism (dioxane): 
______________________________________ 
max. .about. 223 nm .DELTA..epsilon. = -2.7 
max. at 248 nm .DELTA..epsilon. = +0.13 
max. at 252 nm .DELTA..epsilon. = +0.13 
______________________________________ 
NMR Spectrum (deuterochloroform): Peaks at 6.07-6.4 ppm (5- and 6-ethylenic 
hydrogens of lactone); at 1.33-1.48 ppm and 1.58-1.73 ppm (hydrogens of 
8--CH.sub.2 of lactone); at 5.04 ppm (3-hydrogen of lactone); at 
3.75-3.87-3.98 ppm (2-hydrogens of proline); at 5.22 ppm (hydrogens 
.alpha.-to phenyl); at 7.37 ppm aromatic hydrogens). 
EXAMPLE 4 
Benzyl (.alpha.R,3R,3aR,4S,7R,7aS) 
.alpha.-(1-oxo-3a,4,7,7a-tetrahydro-1H,3H-4,7-methano-isobenzofuran-3-yl)- 
L-prolinate 
A mixture of 2.4 g of benzyl DL-prolinate hydrochloride, 25 ml of benzene, 
5 ml of demineralized water and 1.01 g of triethylamine was stirred at 
20.degree. C. for one hour and the decanted organic phase was washed with 
water, dried and evaporated to dryness under reduced pressure to obtain 
2.1 g of benzyl DL prolinate. 
A mixture of 2.1 g of latter product, 1.66 of (3R, 3aR,4S,7R,7aS) 
3-hydroxy-tetrahydro-4,7-methano-isobenzofuran-1-one with a specific 
rotation of [.alpha.].sub.D.sup.20 =+47.degree. (c=1% in CHCl.sub.3) and 
20 ml of benzene was refluxed with stirring for 21/2 hours while 
azeotropically distilling off the water of reaction formed and the mixture 
was evaporated to dryness under reduced pressure. The residue was 
crystallized from isopropyl ether to obtain 1.2 g of benzyl 
(.alpha.R,3R,3aR,4S,7R,7aS).alpha.-(1-oxo-3a,4,7,7a-tetrahydro-1H,3H-4,7-m 
ethano-isobenzofuran-3-yl)L-prolinate with a melting point of 105.degree. 
C. 
IR Spectrum (CHCl.sub.3): Absorption at 1760 cm.sup.-1 -1740cm.sup.-1 
(carbonyl); at 1588 cm.sup.-1 1495 cm.sup.-1 (aromatics--presence of 
C--O--C); at 696 cm.sup.-1 (phenyl). 
Circular dichroism (dioxane): 
______________________________________ 
max. .about. 220 nm .DELTA..epsilon. .about. +2.9 
max. at 246 nm .DELTA..epsilon. = -0.19 
Inflex. towards 251 nm 
.DELTA..epsilon. = -0.18 
______________________________________ 
NMR Spectrum (deuterochloroform): Peaks at 6-6.33 ppm (5- and 6-ethylenic 
hydrogens of lactone); at 1.32-1.47 ppm and 1.58-1.73 ppm (hydrogens of 
8--CH.sub.2 of lactone); at 4.95-5 ppm (3-hydrogen of lactone); at 
3.72-3.83-3.95 ppm (2-hydrogen of proline); at 5.18 ppm (hydrogens 
.alpha.- to phenyl); at 7.4 ppm (aromatic hydrogens). 
EXAMPLE 5 
Methyl (.alpha.R,3R,3aR,4S,7R,7aS) 
.alpha.-[(1-oxo-3a,4,7,7a-tetrahydro-1H,3H-4,7-methano-isobenzofuran-1-yl) 
-amino]-phenylpropanoate 
A mixture of 4.3 g of methyl DL-aminophenylpropanoate hydrochloride, 43 ml 
of demineralized water, 86 ml of ether and 3 ml of triethylamine was 
stirred at 20.degree. C. for 10 minutes and the decanted aqueous phase was 
extracted twice with ether. The combined organic phases were dried and 
evaporated to dryness under reduced pressure to obtain 3.5 g of methyl DL 
amino-phenylpropanoate. 
A mixture of the latter product, 3.2 g of (3R,3aR,4S,7R,7aS) 
3-hydroxy-tetrahydro-4,7-methano-isobenzofuran-1-one with a specific 
rotation of [.alpha.].sub.D.sup.20 =+47.degree. (c=1% in CHCl.sub.3) and 
40 ml of benzene was refluxed with stirring for 16 hours while 
azeotropically distilling off the water of reaction formed and was then 
evaporated to dryness under reduced pressure. The residue was crystallized 
from isopropanol to obtain 2.2 g of methyl (.alpha.R,3R,3aR,4S,7R,7aS) 
.alpha.-[(1-oxo-3a,4,7,7a-tetrahydro-1H,3H-4,7-methano-isobenzofuran-1-yl) 
-amino]-phenylpropanoate melting at 120.degree. C. 
EXAMPLE 6 
Methyl (.alpha.S,3S,3aS,4R,7S,7aR) 
.alpha.-[(1-oxo-3a,4,7,7a-tetrahydro-1H,3H-4,7-methano-isobenzofuran-3-yl) 
-amino]-phenylpropanoate 
A mixture of 4.3 g of methyl DL aminophenylpropanoate hydrochloride, 43 ml 
of demineralized water, 86 ml of ether and 3 ml of triethylamine was 
stirred at 20.degree. C. for 10 minutes and the aqueous phase was 
extracted with ether. The combined ether phases were dried and evaporated 
to dryness under reduced pressure to obtain 8.3 g of methyl 
aminophenylpropanoate. 
A mixture of the 8.3 g of the latter product, 3 g of (3S,3aS,4R,7S,7aR) 
3-hydroxy-tetrahydro-4,7-methano-isobenzofuran-1-one with a specific 
rotation of [.alpha.].sub.D.sup.20 =-47.degree. (c=1% in CHCl.sub.3) and 
50 ml of anhydrous benzene was refluxed with stirring for one hour while 
azeotropically distilling off the water of reaction and was then 
evaporated to dryness under reduced pressure. The 6.7 g of residue was 
crystallized from isopropanol to obtain 2.1 g of methyl 
(.alpha.S,3S,3aS,4R,7S,7aR) 
.alpha.-[(1-oxo-3a,4,7,7a-tetrahydro-1H,3H-4,7-methano-isobenzofuran-3-yl) 
-amino]-phenylpropanoate melting at 120.degree. C. From the filtrate, 1.2 g 
of the R diastereoisomer were obtained which after recrystallization from 
isopropyl ether melted at .perspectiveto.76.degree. C. 
IR Spectrum (CHCl.sub.3): Absorption at 1743 cm.sup.-1 (carbonyl); at 3345 
cm.sup.-1 (NH). 
NMR Spectrum (deuterochloroform): Peaks at 5.83-6.25 ppm (ethylenic 
hydrogens of lactone); at 1.27-1.42 ppm and 1.52-1.67 ppm (hydrogens of 
8--CH.sub.2 of lactone); at 2.33-3.33 ppm (3a- and 7a-hydrogens of 
lactone); at 4.27-4.32 ppm (3-hydrogen of lactone); at 3.75 ppm (hydrogen 
.alpha.- to amine of phenylalanine); at 2.33-3.33 ppm (hydrogens .alpha.- 
to phenyl); at 3.67 ppm (hydrogens of CH.sub.3); at 7.35 ppm (aromatic 
hydrogens). 
EXAMPLE 7 
Benzyl D-leucine hydrochloride 
A mixture of 2 g of the product of Example 1, 15 ml of demineralized water 
and 1.5 ml of hydrochloric acid was stirred at 20.degree. C. for one hour 
and was then heated at 60.degree. C. for one hour and then cooled to 
20.degree. C. 15 ml of water were added to the mixture and the mixture was 
extracted with methylene chloride. The organic phase was washed with 
aqueous N sodium hydroxide solution and then with water until the wash 
water was neutral, dried and evaporated to dryness under reduced pressure. 
The residue was taken up in 10 ml of ether and a current of hydrogen 
chloride was slowly bubbled through the solution,. The mixture was vacuum 
filtered to obtain 800 mg of benzyl D-leucine hydrochloride melting at 
137.degree. C. and having a specific rotation of [.alpha.].sub.D.sup.20 
=+3.5.degree. (c=1% in 0.1 N hydrochloric acid). 
Circular dichroism (dioxane): max. towards 217 nm; .DELTA..epsilon.=-0.95. 
EXAMPLE 8 
Benzyl L-leucine hydrochloride 
A mixture of 1 g of the product of Example 2, 8 ml of demineralized water 
and 0.8 ml of hydrochloric acid was stirred at 20.degree. C. for one hour 
and was then heated at 60.degree. C. for one hour and was cooled at 
20.degree. C. The mixture was diluted with 15 ml of water and was then 
extracted with methylene chloride. The organic phase was washed with 
aqueous N sodium hydroxide solution and with water until the wash water 
was neutral, dried and evaporated to dryness under reduced pressure. The 
residue was taken up in 10 ml of ether and a stream of hydrogen chloride 
was slowly bubbled therethrough. The mixture was vacuum filtered to obtain 
350 mg of benzyl L-leucine hydrochloride melting at 135.degree. C. and 
having a specific rotation of [.alpha.].sub.D.sup.20 
=-5.5.degree..+-.1.degree. (c=1% in 0.1 N hydrochloric acid). Circular 
Dichroism (dioxane): max. at 219 nm; .DELTA..epsilon.=+1.0. 
EXAMPLE 9 
Methyl D-phenylalaniate hydrochloride 
A mixture of 2.2 g of the product of Example 5, 20 ml of demineralized 
water and 1.7 ml of hydrochloric acid was stirred at 20.degree. C. for 16 
hours and the mixture was then iced and vacuum filtered. The aqueous 
filtrate was saturated with potassium carbonate and the surnagent oil was 
recovered. The aqueous phase was extracted with ether and the combined oil 
phase and ether extracts were dried and evaporated to dryness under 
reduced pressure to obtain 1.2 g of an oil. A mixture of the oil and 20 ml 
of methanol was cooled to 5.degree. to 10.degree. C. and a current of 
hydrogen chloride was slowly bubbled therethrough. The mixture was 
evaporated to dryness under reduced pressure and the thick oil was 
crystallized from ether to obtain 750 mg of methyl D-phenylalaninate 
hydrochloride melting at 160.degree. C. and having a specific rotation of 
[.alpha.].sub.D.sup.20 =.perspectiveto.28.degree..+-.1.5.degree. (c=1% in 
ethanol). 
NMR Spectrum (deuterochloroform): Peaks at 3.35-3.43 ppm (hydrogens 
.alpha.- to phenyl); at 4.42 ppm (hydrogen .beta. to phenyl); at 3.7 ppm 
(hydrogens of CH.sub.3); at 7.28 ppm (aromatic hydrogens). 
EXAMPLE 10 
Methyl L-phenyl-alaninate 
Using the procedure of Example 9, a mixture of 1.5 g of the product of 
Example 6, 5 ml of water and 1.1 ml of hydrochloric acid was reacted to 
obtain 509 mg of methyl L-phenylalaninate in the form of an oil with a 
specific rotation of [.alpha.].sub.D.sup.20 =+28.5.degree..+-.1.degree. 
(c=1.5% in ethanol). 
NMR Spectrum (CDCl.sub.3): Peaks at 2.62-3.28 ppm (hydrogens .alpha.- to 
phenyl); at 3.62-3.83 ppm (hydrogen .beta.- to phenyl); at 1.47 ppm 
(hydrogens of NH.sub.2); at 3.67 ppm (hydrogens of CH.sub.3). 
EXAMPLE 11 
Methyl (3R,3aR,4S,7R,7aS) .alpha.-(1-oxo-3a,4,7,7a-tetrahydro-1H, 
3H-4,7-methano-isobenzofuran-3-yl)-L-methioninate 
A mixture of 0.5 ml of triethylamine, 0.600 g of methyl L-methionine 
hydrochloride and 10 ml of benzene was stirred at 20.degree. C. for one 
hour and then 0.500 g of (3R,3aR,4S,7R,7aS) 
3-hydroxy-tetrahydro-4,7-methano-isobenzofuran-1-one with a specific 
rotation of [.alpha.].sub.D.sup.20 =+47.degree. (c=1% in CHCl.sub.3) were 
added thereto. The mixture was refluxed for 2 hours while azeotropically 
removing the water of reaction formed and was then cooled and filtered. 
The filtrate was evaporated to dryness under reduced pressure to obtain 
1.13 g of methyl (3R,3aR, 4S,7R,7aS) 
.alpha.-(1-oxo-3a,4,7,7a-tetrahydro-1H,3H-4,7-methanoisobenzofuran-3-yl)-L 
-methioninate. 
IR Spectrum (chloroform): Absorption at 3348 cm.sup.-1 (NH); at 1743 
cm.sup.-1 (carbonyls); at 1654 cm.sup.-1 (--C.dbd.C-- and C--O--C). 
NMR Spectrum (deuterochloroform): Peaks at 2.1 ppm (hydrogens of methyl of 
--S--CH.sub.3); at 3.7 ppm (hydrogens of methyl of --OCH.sub.3); at 4.7 
ppm (3-hydrogen of furane ring); at 6.2 ppm (hydrogens of endocyclic 
double bond). 
EXAMPLE 12 
Methyl (3S,3aS,4R,7S,7aR) .alpha.-(1-oxo-3a,4,7,7a-tetrahydro-1H, 
3H-4,7-methano-isobenzofuran-3-yl)-L-methioninate 
A mixture of 10 ml of benzene, 0.5 ml of triethylamine and 0.600 g of 
methyl L-methionine hydrochloride was stirred at 20.degree. C. for one 
hour and then 0.500 g of (3S,3aS,4R,7S,7aR) 
3-hydroxy-tetrahydro-4,7-methano-isobenzofuran-1-one with a specific 
rotation of [.alpha.].sub.D.sup.20 =-47.degree. (c=1% in CHCl.sub.3) was 
added thereto. The mixture was refluxed for 2 hours while azeotropically 
removing the water of reaction formed and was then cooled and filtered. 
The filtrate was evaporated to dryness under reduced pressure to obtain 
1.18 g of methyl (3S,3aS,4R, 7S,7aR) 
.alpha.-(1-oxo-3a,4,7,7a-tetrahydro-1H,3H-4,7-methano-isobenzofuran-3-yl)- 
L-methioninate. 
IR Spectrum (CHCl.sub.3): Absorption at 3340 cm.sup.-1 (NH); at 1745 
cm.sup.-1 (carbonyls). 
NMR Spectrum (deuterochloroform): Peaks at 2.1 ppm (hydrogens of methyl of 
--SCH.sub.3); at 3.7 ppm (hydrogens of methyl of --OCH.sub.3); at 4.6 ppm 
(3-hydrogen of furane ring); at 6.23 ppm (hydrogens of endocyclic double 
bond). 
EXAMPLE 13 
(3S,3aS,4R,7S,7aR) 
3-hydroxy-3a,4,7,7a-tetrahydro-1H,3H-4,7-methano-isobenzofuran-1-one 
STEP A: Benzyl (.alpha.S,3S,3aS,4R,7S,7aR) 
.alpha.-[(1-oxo-3a,4,7,7a-tetrahydro-1H,3H-4,7-methano-isobenzofuran-3-yl) 
-amino]isohexanoate 
A mixture of 5.2 g of benzyl L-leucinate, 4 g of (3RS, 3aRS,4RS,7RS,7aRS) 
3-hydroxy-3a,4,7,7a-tetrahydro-1H,3H-4,7-methano-isobenzofuran-1-one and 
40 ml of anhydrous benzene was refluxed for 90 minutes while 
azeotropically distilling off the water of reaction formed and was then 
evaporated to dryness under reduced pressure. The residue was added to 
isopropyl ether and the mixture was vacuum filtered to obtain 2.3 g of 
benzyl (.alpha.S,3S,3aS,4R,7S,7aR) 
.alpha.-[(1-oxo-3a,4,7,7a-tetrahydro-1H,3H-4,7-methano-isobenzofuran-3-yl) 
-amino]isohexanoate melting at 95.degree. C. 
STEP B: (3S,3aS,4R,7S,7aR) 
3-hydroxy-3a,4,7,7a-tetrahydro-1H,3H-4,7-methano-isobenzofuran-1-one 
2.2 g of the product of Step A were added to a mixture of 1.8 ml of 
22.degree. Be hydrochloric acid in 18 ml of water and the mixture was 
heated at 55.degree. C. for 17 hours and was then cooled to 20.degree. C. 
The mixture was extracted with ethyl acetate and the organic phase was 
washed with 2 N aqueous sodium hydroxide solution. The alkaline aqueous 
phase was washed with methylene chloride, with ethyl acetate and was 
acidified to a pH of 3.5 by addition of 2 N hydrochloric acid. The mixture 
was extracted with ethyl acetate and the organic phase was washed with 
water, dried and evaporated to dryness. The residue was taken up in ether 
and the mixture was vacuum filtered to obtain 0.450 g of 
(3S,3aS,4R,7S,7aR) 3-hydroxy-3a, 
4,7,7a-tetrahydro-1H,3H-4,7-methano-isobenzofuran-1-one melting at 
133.degree. C. and having specific rotation of [.alpha.].sub.D.sup.20 
=-44.degree. (c=1% in benzene). 
EXAMPLE 14 
A mixture of 0.5 g of benzyl D-leucine hydrochloride, 20 ml of acetic acid 
and 20 ml of methanol was stirred with palladium under a hydrogen 
atmosphere until absorption ceased and the mixture was filtered. The 
filtrate was evaporated to dryness under reduced pressure and the residue 
was chromatographed over silica gel to obtain D-leucine. 
Various modifications of the products and processes of the invention may be 
made without departing from the spirit or scope thereof and it is to be 
understood that the invention is intended to be limited only as defined in 
the appended claims.