Resolution and reduction of physostigmine intermediates and derivatives

One aspect of the present invention provides for the separation of a racemic mixture or a mixture enriched with one or other enantiomer, said mixture comprising the enantiomers of the compound of the formula: ##STR1## wherein R is CN or CONHR' where R' is a C.sub.1 -C.sub.6 alkyl, hydrogen, or benzyl, and R.sub.1 is C.sub.1 -C.sub.6 alkyl or benzyl. Another aspect of the present invention provides a method of preparing a compound of the formula: ##STR2## wherein R is H, C.sub.1 -C.sub.6 alkyl or benzyl, and wherein R.sub.2, R.sub.3, and R.sub.4 are C.sub.1 -C.sub.6 alkyl or benzyl.

TECHNICAL FIELD OF THE INVENTION 
The present invention generally relates to methods for preparing 
physostigmine derivatives, as well as to the separation of racemic 
mixtures obtained during their preparation. 
BACKGROUND OF THE INVENTION 
Physostigmine, represented by the formula I below, 
##STR3## 
is a naturally-occurring, optically-active compound which has shown 
encouraging responses in treating Alzheimer's disease, due to its 
anticholinesterase activity. However, as in the case of many 
pharmaceuticals, one of the enantiomers of this compound i.e., the (3aS) 
enantiomer, demonstrates significantly greater efficacy as compared to the 
other. 
The (3aS) enantiomer of physostigmine is presently extracted from Calabar 
beans, which are of West African origin. However, the limited availability 
of these beans has resulted in a scarcity of physostigmine, and what 
little is available is relatively expensive. These factors have caused the 
pharmaceutical industry and academia to devise alternate routes to 
synthetically obtain the (3aS) enantiomer of physostigmine. 
In order to synthesize the (3aS) enantiomer of physostigmine, it is 
necessary to provide an optically-pure intermediate, (3aS-cis)-esermethole 
(II). 
##STR4## 
Methods for the preparation of this optically-pure intermediate are well 
known, e.g., Julian et al., J. Am. Chem. Soc., 57, 563-566 (1935) ("Julian 
et al. I"); Julian et al., J. Am. Chem. Soc., 57, 755-757 (1935) ("Julian 
et al. II"); Kobayashi, Liebigs Ann. Chem., 536, 143 et seq. (1935); and 
Dale et al., J. Pharm. Pharmacol., 22, 889-896 (1970). These methods 
comprise a synthesis in which 1,3-dimethoxy-5-ethoxy oxindole (III) 
##STR5## 
is 3-cyanoalkylated using chloroacetonitrile, with the resulting nitrile 
(IV) 
##STR6## 
being reduced to a racemic mixture of the amine (V) 
##STR7## 
The racemic mixture is subsequently separated into its enantiomers by a 
chemical process. This chemical process requires that the racemic amine 
mixture be successively treated with camphorsulfonic acid and tartaric 
acid. Each acid functions to crystallize one of the enantiomers (the 
tartaric acid crystallizing the desirable (3aS) enantiomer), thereby 
providing for their separation. After separation, the desired (3aS) 
enantiomer is then cyclized using a reducing agent comprising sodium and 
ethanol. 
Others have modified the foregoing method of cyanoalkylation so that the 
racemic amine mixture contains the (3aS) enantiomer in excess (about 73%). 
Lee et al., J. Org. Chem., 56, 872-875 (1991) ("Lee et al. I"). The 
separation of this enantiomer from the racemic amine mixture, however, was 
also accomplished by treating the mixture with tartaric acid. Pallavicini 
et al., Tetrahedron: Asymmetry, 5, 111 et. seq. (1994). 
While the foregoing separations of the (3aS) enantiomer using chemical 
methods, e.g., crystallization using tartaric acid, are operable, there 
are certain drawbacks to the use of such methods. One of these is the 
relatively low yields obtainable thereby, this being due to the several 
steps that are required to be executed to effect such separation. These 
methods may also employ the use of caustic chemicals. 
Another separation method used to effect the separation of racemates which 
attempts to overcome the drawbacks associated with the aforesaid chemical 
separation methods involves the use of a separation column. These columns 
typically include a material therein, referred to as a stationary phase, 
which functions to cause each enantiomer of a racemic mixture to move 
through the column at a different rate. Thus, upon operation, when a 
mobile phase is passed through a column in which the racemic mixture in 
transiently entrained, one of the enantiomers will elute more rapidly than 
the other. This allows one to obtain optically-pure solutions of 
enantiomers by collecting the eluant at different times. This type of 
one-step separation process is not only easier to complete as compared to 
the aforementioned multi-step chemical separation processes, but also 
provides a relatively greater yield of the desired enantiomer. 
Articles which relate to the analytical separation of certain physostigmine 
intermediates into their respective enantiomers using such a column 
include Lee et al. I and Lee et al., J. Chromatography, 523, 317-320 
(1990) ("Lee et al. II"). Lee et al. II describes the use of relatively 
expensive columns (Chiracel OD/OJ) which contain a benzoylor 
carbamate-derivatized cellulose-coated stationary phase in the analysis of 
racemic mixtures, e.g., of (3aS) and (3aR) enantiomers of 
1,3-dimethyl-3-cyanomethyl-5-methoxyoxindole (VI) 
##STR8## 
using isopropanol-hexane (10:90) as the mobile phase, wherein the (3aR) 
enantiomer is the first to elute out of the column. 
The work reported in Lee et al. II provides an assay for the intermediates, 
as opposed to providing a preparative separation method. Moreover, the 
process disclosed in this article appears to be relatively unpredictable, 
and highly compound-specific, in that the carbamate (--CH.sub.2 --CH.sub.2 
--NH--COOCH.sub.3) and dinitrobenzoyl (--CH.sub.2 --CH.sub.2 
--NH--CO--3,5--(NO.sub.2).sub.2 --Ph) amide intermediates disclosed 
therein are said to be separable in the column, but, surprisingly, the 
acetamide (--CH.sub.2 --CH.sub.2 --NH--COCH.sub.3) and benzoylamide 
(--CH2--CH2--NH--CO--Ph) intermediates were not found to be separable 
thereby. Lee et al. I also discloses an analytical method directed to the 
assay of the optical purity of the cyanomethyl and the aminoethyl 
physostigmine intermediates, and of esermethole, using the aforementioned 
Chiracel columns. 
Once one has obtained a physostigmine intermediate, e.g., 
1,3-dimethyl-3-cyanomethyl-5-methoxyoxindole (VI), in optically-pure form, 
by any known process, its efficient conversion into the closed-ring 
structure of physostigmine and derivatives thereof is of great interest. 
Several methods for effecting the conversion of the intermediate into the 
desired closed-ring structure have been used. One of these methods, 
disclosed in Julian et al. I and II, and U.S. Pat. No. 4,791,107 to Hamer 
et al., uses a two-step procedure for the preparation of the physostigmine 
closed-ring structure starting from (3aS) 
1,3-dimethyl-3-cyanomethyl-5-ethoxyoxindole (IV). In the first step, the 
cyanomethyl group is reduced by palladium/hydrogen to the aminoethyl 
group, which is then reduced in the second step by sodium in ethanol to 
obtain the closed-ring structure. In the case of this starting material, a 
further step, i.e, methylation of the closed-ring thus formed, or 
alternatively methylation of the aminoethyl group, is required to obtain 
(3aS) physostigmine. 
A second method, set forth in Yu et al., Heterocycles, 36 (6), 1279-1285 
(1993); Yu et al., Heterocycles, 27 (7), 1709-1712 (1988); and Lee et al. 
II, comprises a one-step method for effecting the aforesaid cyclization. 
This method provides for the reduction of the cyanomethyl derivative in a 
single step using the reducing agent lithium aluminum hydride. This 
reducing agent, however, is very hazardous due its extreme flammability. 
Therefore, a need exists for a relatively high efficiency, low cost, 
separation process which is able to separate racemic mixtures of a 
relatively wider variety of physostigmine intermediates and derivatives 
thereof as compared to existing separation methods. Of course, a process 
which operates more quickly than existing processes, and which is able to 
provide for such separation on a preparative (as opposed to analytic) 
scale, would also be of great interest. 
A further need exists for a safe and efficient method of effecting 
cyclization of physostigmine intermediates and derivatives thereof. 
These and other objects and advantages of the present invention, as well as 
additional inventive features, will be apparent from the description of 
the invention provided herein. 
SUMMARY OF THE INVENTION 
One aspect of the present invention provides for the separation of a 
racemic mixture or a mixture enriched with one or other enantiomer, said 
mixture comprising the enantiomers of the compound of the formula: 
##STR9## 
wherein R is CN or CONHR' where R' is a C.sub.1 --C.sub.6 alkyl, hydrogen, 
or benzyl, and R.sub.1 is C.sub.1 -C.sub.6 alkyl or benzyl. The method 
comprises contacting the racemic mixture with a cellulosic solid phase 
material, eluting said mixture in contact with the solid phase material 
with an eluant comprising at least 50 vol. % C.sub.1 -C.sub.6 alcohol, and 
recovering an eluted product having an enantiomeric excess greater than 
that of said mixture. 
The method of the present invention provides a means by which the 
separation of a relatively broad range of physostigmine intermediates and 
derivatives thereof may be successfully completed. In addition to its 
relatively broad applicability, the method. provides excellent separation 
efficiencies--it provides products having a high level of optical purity 
(up to about 100% enantiomeric excess), at high yields. The method may 
further be completed faster than known separation methods, and is 
excellent for preparative synthesis. In addition, all of the foregoing 
advantages are achieved while using relatively inexpensive components, 
e.g., the method uses alcohol (e.g., at least 50 vol. %) in the mobile 
phase, which alcohol may be industrial grade. 
Another aspect of the present invention provides a method of preparing a 
compound of the formula: 
##STR10## 
wherein R is H, C.sub.1 -C.sub.6 alkyl, or benzyl, and wherein R.sub.2, 
R.sub.3, and R.sub.4 are C.sub.1 -C.sub.6 alkyl or benzyl. This method 
comprises contacting a compound of the formula: 
##STR11## 
wherein R is CN or CONHR' where R' is a C.sub.1 -C.sub.6 alkyl, hydrogen, 
or benzyl, and wherein R.sub.2, R.sub.3, and R.sub.4 are C.sub.1 -C.sub.6 
alkyl or benzyl, with sodium dihydrido-bis(2-methoxyethoxy)-aluminate. 
This method provides a safe and efficient (single-step) method of 
effecting cyclization of physostigmine intermediates and derivatives 
thereof in that it does not require the use of lithium aluminum hydride, 
which is extremely flammable. 
The invention may best be understood with reference to the following 
detailed description of the preferred embodiments. 
DESCRIPTION OF THE PREFERRED EMBODIMENTS 
One aspect of the present invention is a method which provides for the 
efficient separation of a relatively wide variety of physostigmine 
intermediates and derivatives thereof. Surprisingly, it was found that 
such separations could be effected in a more cost effective manner by 
using alcohol, and even industrial grade alcohol if desired, (as opposed 
to the relatively more expensive hexane which must be used in known 
methods) in the eluant in an amount of at least about 50 vol. %, and up to 
100 vol. %, without any substantial loss in efficiency or yield. In fact, 
the method of the present invention provides further surprising results in 
that separations were able to be completed quicker, and, as mentioned 
previously, the method is able to separate a relatively broader range of 
physostigmine intermediates and derivatives, as compared to known methods, 
in both preparative and analytical separations. 
The method of the present invention is able to separate from a racemic 
mixture or a mixture enriched with one or the other enantiomer of a 
physostigmine intermediate or derivative thereof, an enantiomer of the 
formula (VII) wherein R is CN or CONHR' where R' is a C.sub.1 -C.sub.6 
alkyl, hydrogen, or benzyl, and R.sub.1 is C.sub.1 -C.sub.6 alkyl or 
benzyl. The method comprises contacting that racemic mixture with a 
cellulosic solid phase material, eluting said mixture in contact with said 
material with an eluant comprising at least 50 vol. % C.sub.1 -C.sub.6 
alcohol, and recovering an eluted product having an enantiomeric excess 
greater than that of said mixture. 
Advantageous results in separation efficiencies as compared to known 
separation processes have been obtained in respect to a certain group of 
the compounds of formula VII, e.g., wherein R is CN, CONHCH.sub.2 C.sub.6 
H.sub.5, or CONHCH.sub.3, and R.sub.1 is CH.sub.3. These efficiencies 
include, but are not limited to, the time required to effect the 
separation, the separation yield, and material cost. 
The amount of one enantiomer in a mixture of enantiomers, be it a product 
or starting mixture, is typically described in terms of enantiomeric 
excess ("ee"). The enantiomeric excess in regard to a particular 
enantiomer in relatively greater concentration (ee.sub.1) may be 
calculated as follows: 
EQU ee.sub.1 =(E.sub.1 -E.sub.2)/(E.sub.1 +E.sub.2).times.100 
wherein E.sub.1 and E.sub.2 are the weight (or moles) of the higher and 
lower concentration enantiomers, respectively. Advantageous results in the 
form of separation efficiencies, e.g., high optical purity levels in the 
product, have been observed when racemic mixtures possessing little or no 
enantiomeric excess as well as possessing enantiomeric excesses of from 
about 60-80% are separated in accordance with the method of the present 
invention. 
When a separation is conducted in accordance with the present invention, 
the method provides the eluted product in an enantiomeric excess of at 
least about 80%.-+.5% preferably at least about 95-100% and most 
preferably substantially 100% (i.e., a substantially pure enantiomer). 
The eluant used in the inventive method comprises at least 50 vol. % of an 
alcohol. The alcohol is advantageously an alkanol and, more 
advantageously, is selected from the group consisting of methanol, 
ethanol, propanol, isopropanol, n-butanol, sec-butanol, t-butanol, and 
mixtures thereof. Ethanol is preferably used alone as the alcohol 
component of the eluant because it provides the greatest separation 
efficiency compound to the pure methanol, although the precise reason for 
this is not fully understood at present. 
The eluant may further comprise water. The inclusion of small amounts of 
water in the eluant, below about 10 vol. %, as is typically found in 
industrial grade alcohols, has been found to have no substantial 
deleterious effects upon the separation efficiencies. Therefore, one is 
able to use such relatively low cost industrial grade alcohols without a 
corresponding loss in separation efficiency. 
Advantageously, then, the aqueous eluant may comprise at least about 70 
vol. % of said alcohol, and preferably at least about 90 vol. % of said 
alcohol. 
When methanol is used as the sole alcohol component in the eluant, however, 
the inclusion of water in the eluant, up to about 30 vol. %, actually 
improved certain of the separation efficiencies as compared to using only 
methanol as the eluent, e.g., the resolution factor and separation factor. 
The reasons for this phenomenon are not fully understood at present. 
The solid phase material used in the separation of the present invention, 
which is typically packed within a chromatography column, may comprise any 
commercially available cellulosic material, i.e., any material which 
includes cellulose or a cellulose derivative. Advantageously, the 
cellulosic solid phase material is selected from the group consisting of 
cellulose triacetate, cellulose diacetate, cellulose p-methylbenzoate, 
cellulose 3,5-dimethylphenylcarbamate, and combinations thereof. These 
materials were found to provide products having high optical purity and 
yield in the context of the present invention. 
The preferred cellulosic solid phase material is cellulose triacetate 
because it appears to interact with the alcohol-containing eluant in a 
manner which provides excellent separation properties, while being 
relatively inexpensive. The rationale underlying this interaction is 
unknown. The use of those two components in the method provides superior 
results, particularly when the eluant comprises 96 vol. % ethanol and 4 
vol. % water. 
While the cellulosic solid phase materials are available in a variety of 
forms, it is preferable to use micronized materials in the separations of 
the present invention. The particles which comprise those materials should 
preferably range from about 10 .mu.m to about 40 .mu.m in average 
diameter, and most preferably from about 15 .mu.m to about 25 .mu.m in 
average diameter. It was determined that such micronization of the 
cellulosic solid phase material provided optimal separation efficiencies 
in the inventive method. An example of the preferred cellulosic solid 
phase material is microcrystalline cellulose triacetate prepared by the 
heterogeneous acetylation of native microcrystalline cellulose. 
Microcrystalline cellulose triacetate is available from E. Merck of 
Darmstadt, Germany in a 15 .mu.m to 25 .mu.m particle size, and from Fluka 
Chemical Co. of Ronkonkoma, N.Y. 
The present inventive method may be undertaken with the cellulosic solid 
phase material packed within any type of suitable chromatography column, 
including columns constructed of glass, stainless steel, or other inert 
material. The selection and preparation of an appropriate column which 
would be suitable to effect the separations of the present invention is 
well within the skill of an ordinary worker. 
A second aspect of the present invention is a method for preparing a 
compound of the formula VIII, wherein wherein R is H, C.sub.1 -C.sub.6 
alkyl, or benzyl, and R.sub.2, R.sub.3, and R.sub.4 are C.sub.1 -C.sub.6 
alkyl or benzyl. This method comprises contacting a compound of the 
formula (IX), wherein R is CN or CONHR' where R' is a C.sub.1 -C.sub.6 
alkyl, hydrogen, or benzyl, and wherein R.sub.2, R.sub.3, and R.sub.4 are 
C.sub.1 -C.sub.6 alkyl or benzyl, with a solution comprising sodium 
dihydrido-bis(2-methoxyethoxy)-aluminate. This method provides an 
efficient (single-step) method of effecting cyclization of the foregoing 
physostigmine intermediates and derivatives thereof, and, in addition, 
avoids the use of lithium aluminum hydride, an extremely flammable 
compound, as a reducing agent. 
The method is particularly useful when one desires to cyclize certain 
physostigmine intermediates, e.g., those of formula (IX) wherein R is CN, 
CONHCH.sub.2 C.sub.6 H.sub.5, or CONHCH.sub.3, and R.sub.2, R.sub.3, and 
R.sub.4 are CH.sub.3. When R is CONHCH.sub.2 C.sub.6 H.sub.5, the 
resulting compound has a benzyl group at the N.sup.1 position. Since 
benzyl groups are known as good leaving groups, the cyclized compound 
having a benzyl group at the N.sup.1 position provides a further advantage 
in that the benzyl group can be subsequently easily replaced by other 
desirable functional groups. For example, the benzyl group can be replaced 
by hydrogen by catalytic hydrogenation. 
In the cyclization method of the present invention, the reducing agent is 
advantageously provided in an amount which is sufficient to effect the 
reductive cyclization of the total amount of the compound of formula (IX) 
which is present in the reaction mixture. This amount will typically range 
from about 0.5 mol % to about 2.0 mol %. 
The aforesaid reductive cyclization is advantageously conducted while the 
reactive components are in solution. Most advantageously, the solution may 
comprise an inert solvent, the selection of such inert solvents being well 
within the skill of the ordinary worker. Examples of preferred solvents 
include benzene, toluene, xylene, and cyclohexane. 
During the reductive cyclization, it is preferred that such be conducted in 
an inert atmosphere, most preferably in a nitrogen, argon, or helium 
atmosphere. If oxygen and/or moisture is present during the cyclization, 
destruction of the reducing agent can occur. 
The reductive cyclization may be carried out at any suitable temperature, 
although improved yields are obtained when the reaction mixture has a 
temperature of between about 0.degree. C. to about 60.degree. C. Optimal 
results are obtained when the temperature of the mixture is maintained at 
ambient temperatures, e.g., about 20.degree.-25.degree. C. 
The reaction should generally be left to proceed to completion, which may 
range in duration from about fifteen minutes to about 6 hours. 
Advantageously, substantial completion may be obtained within about 3 
hours after the initiation of the reductive cyclization. 
The following examples further illustrate the present invention but, of 
course, should not be construed as in any way limiting its scope. 
The formulas of some of the compounds described in the illustrative 
examples are set forth below. 
##STR12## 
Further, all of the isolated enantiomers in the examples are at 100% ee.

EXAMPLE 1 
A glass column (65 cm.times.2.5 cm ID) was slurry packed with 80 g of the 
solid phase material, cellulose triacetate, which had been pre-swollen in 
200 ml of 95% ethanol solvent at 75.degree. C. for 20 min. After removing 
the excess solvent, the solid phase material was washed by pumping through 
it 200 ml of 95% ethanol at a flow rate 0.5 ml/min. 
166 mg of the racemic 1,3-dimethyl-3-cyanomethyl-5-methoxyoxindole (VI) was 
dissolved in 0.5 mL of the ethanol solvent and injected into the packed 
column. The mobile phase eluant was 95% ethanol and pumped at a flow rate 
of 0.5 ml/min. 3 ml fractions of the eluant eluting from the column were 
collected. Optical purity of the various fractions were checked by HPLC 
using a Chiracel OD column (25 cm.times.0.46 cm ID), hexane/isopropanol 
(80/20) as the mobile phase at a flow rate of 1.0 ml/min, and a UV 
detector. 
The 3aR enantiomer eluted first. Fractions having pure enantiomers were 
combined separately, and the pure enantiomers were recovered after 
evaporation of solvent under reduced pressure. 81 mg of the 3aR enantiomer 
was obtained as colorless gum: [.alpha.].sub.D -50.5.degree. (c=0.54, 
CHCl.sub.3) in 49% yield. 80 mg of the 3aS enantiomer was obtained as 
colorless gum, [.alpha.].sub.D +50.6.degree. (c=0.74, CHCl.sub.3) in 48% 
yield. Certain fractions had enantiomeric mixtures. But the amounts of 
enantiomers present in these fractions were relatively small. These 
fractions were combined, and the solvent was evaporated to obtain 3.5 mg 
of mixture as a colorless gum. An analysis of all three products using a 
TLC plate (silica gel, CH.sub.2 Cl.sub.2 with 2% MeOH) confirmed that the 
enantiomers were not damaged by the separation process. 
EXAMPLE 2 
270 mg of an optically active nitrile (VI) having a 64% ee of the 3aS 
enantiomer prepared by the asymmetric cyanoalkylation procedure reported 
in Lee et al. I was separated on the same column and under the same 
conditions as in Example 1 to obtain 40 mg of the 3aR enantiomer, which 
eluted first, as a colorless gum: [.alpha.].sub.D -50.5.degree. (c=0.54, 
CHCl.sub.3) in 15% yield, and 215 mg of the 3aS enantiomer as a colorless 
gum: [.alpha.].sub.D +50.6.degree. (c=0.74, CHCl.sub.3) in 80% yield, and 
15 mg of mixture as a colorless gum. An analysis of all three products 
using TLC plate (silica gel, CH.sub.2 Cl.sub.2 with 2% MeOH) and infrared 
and NMR spectral data, confirmed that the enantiomers were not damaged by 
the process. 
EXAMPLE 3 
160 mg of the 3aS enantiomer of the nitrile (VI) prepared as in Example 1 
was dissolved in 5 ml of toluene, and 0.4 ml of a 70% toluene solution of 
sodium dihydrido bis-(2-methoxyethoxy)-aluminate (Vitride) was added. The 
mixture was stirred at ambient temperature under a nitrogen atmosphere for 
3 hours. The reaction mixture was then quenched with 8 mL of 5% sodium 
hydroxide solution. The toluene layer was separated out, and the aqueous 
layer was extracted with ether (2.times.10 mL). The combined organic 
layers were dried over anhydrous sodium sulfate and then evaporated in 
vacuo. The residue obtained by evaporation was dissolved in 2 mL of ether, 
and then a saturated ethanolic solution containing 95 mg of fumaric acid 
was added to give on standing the fumarate salt of (3aS)-N.sup.1 
-noresermethole (X): mp 199.degree.-200.degree. C. [.alpha.].sub.D 
-73.0.degree. (c=0.7, MeOH). The product and a standard sample were 
identical when analyzed using a TLC plate (silica gel, CH.sub.2 Cl.sub.2 
with 5% MeOH). 
EXAMPLE 4 
0.9 g (2.7 mmol) of the fumarate salt of compound (X) prepared as in 
Example 3, was dissolved in 15 mL of methanol and 0.9 mL of triethylamine, 
with 1.35 mL of 37% formaldehyde solution being added thereto. The mixture 
was stirred at ambient temperature under a nitrogen atmosphere for 3 
hours. The reaction mixture was then cooled to 0.degree. C., and 0.41 g of 
sodium borohydride was added slowly in small portions. The mixture was 
stirred for another 0.5 hour. After the evaporation of solvent, the 
residue was dissolved in 15 mL of 1N HCl and washed with ether (10 mL), 
made basic by 10% NaHCO.sub.3, and extracted with ether (3.times.20 mL). 
The combined ether layers were dried over Na.sub.2 SO.sub.4 and evaporated 
in vacuo. The residue was passed through a short silica gel column to 
obtain 0.555 mg of (3aS)-esermethole (II) in 89% yield as a colorless oil: 
[.alpha.].sub.D -88.0.degree. (c=1.2, CHCl.sub.3). The product and a 
standard sample were identical when analyzed using a TLC plate (silica 
gel, CH.sub.2 Cl.sub.2 with 5% MeOH). 
EXAMPLE 5 
An aqueous solution of the fumarate salt of compound (X) was treated with a 
10% NaHCO.sub.3 solution, and the free base was extracted with ether, and 
the ether solution was evaporated to obtain the free base. The free base 
was then dissolved in 30 mL of CH.sub.3 CN and 50 mg of dry K.sub.2 
CO.sub.3 and 2 g of benzylbromide were added. The reaction mixture was 
stirred at ambient temperature for 1 hour. After evaporation of solvent, 
the residue was chromatographed through a short silica gel column to 
obtain 1.3 g of the (3aS)-N.sup.1 -benzylnoresermethole (XI), in 70% yield 
as an oil: [.alpha.].sub.D -51.4.degree. (c=1.5, CHCl.sub.3). The product 
was identical with a standard sample when analyzed using a TLC plate 
(silica gel, CH.sub.2 Cl.sub.2 with 1% MeOH). 
EXAMPLE 6 
528 mg of 1,3-dimethyl-3-carboxymethylmethyl-5-methoxyoxindole (XII) were 
heated with 8 mL of a 30% methylamine aqueous solution in a sealed tube in 
an oil bath held at 100.degree. C. for 24 h. After the reaction mixture 
was cooled to room temperature, 80 mL of 2N HCl was added and the mixture 
was extracted with CH.sub.2 Cl.sub.2 (3.times.80 mL). The combined 
extracts were washed with brine (100 mL), dried over Na.sub.2 SO.sub.4, 
and evaporated in vacuo. The residue was passed through a short silica gel 
column to obtain 440 mg of 
1,3-dimethyl-3-methylamidomethyl-5-methoxyoxindole (XIII) in 84% yield as 
crystals, mp 148.degree.-149.degree. C. The product and a standard sample 
were identical when analyzed using a TLC plate (silica gel, CH.sub.2 
Cl.sub.2 with 5% MeOH). 
EXAMPLE 7 
528 mg of 1,3-dimethyl-3-carboxymethylmethyl-5-methoxyoxindole (XII) were 
dissolved in 4 mL of MeOH, and 8 mL of benzylamine was added thereto. The 
reaction mixture was refluxed under nitrogen for 24 hours. The mixture was 
cooled to room temperature, and 100 mL of 2N HCl was added. The mixture 
was then extracted with CH.sub.2 Cl.sub.2 (3.times.80 mL). The combined 
extracts were washed with brine (30 mL), dried over Na.sub.2 SO.sub.4, and 
evaporated in vacuo. The residue was passed through a short silica gel 
column to obtain 600 mg of 
1,3-dimethyl-3-benzylamidomethyl-5-methoxyoxindole (XIV) in 89% yield as 
crystals, m.p. 104.degree.-105.degree. C. The product and a standard 
sample were identical on a TLC plate (silica gel, CH.sub.2 Cl.sub.2 with 
5% MeOH). 
EXAMPLE 8 
170 mg of the amide (XIII) described in Example 6 was separated on the same 
column and under the same conditions as in Example 1 to obtain 80 mg of 
the first eluted 3aS enantiomer in 47% yield as a colorless gum: 
[.alpha.].sub.D +35.8.0.degree. (c=1.03, CHCl.sub.3), 10 mg of the mixture 
as colorless gum, and 80 mg of the 3aR enantiomer in 47% yield as 
colorless gum: [.alpha.].sub.D -37.5.degree. (c=0.95, CHCl.sub.3). An 
analysis of all three products on a TLC plate (silica gel, CH.sub.2 
Cl.sub.2 with 2% MeOH) indicated that the products were identical. 
EXAMPLE 9 
300 mg of the amide (XIV) described in Example 7 was separated on the same 
column and under the same conditions as in Example 1 to obtain 147 mg of 
the first eluted 3aR enantiomer in 49% yield as a colorless gum: 
[.alpha.].sub.D -64.2.degree. (c=0.66, CHCl.sub.3), 2.3 mg of the mixture 
as a colorless crystal, m.p. 104.degree.-105.degree. C. and 145 mg of the 
3aS enantiomer in 49% yield as colorless crystal, m.p. 
104.degree.-105.degree. C.: [.alpha.].sub.D +63.1.degree. (c=0.77, 
CHCl.sub.3). An analysis of all three products using a TLC plate (silica 
gel, CH.sub.2 Cl.sub.2 with 2% MeOH) indicated that the products were 
identical. 
EXAMPLE 10 
The 3aS enantiomer of the amide (XIII) prepared as in Example 8 was reduced 
using Vitride in the manner set forth in Example 3 to obtain the 
(3aS)-esermethole (II) in 56% yield. The product and a standard sample 
were identical on a TLC plate (silica gel, CH.sub.2 Cl.sub.2 with 5% 
MeOH). 
EXAMPLE 11 
The 3aS enantiomer of the amide (XIV) prepared as described in Example 9 
was reduced using Vitride in the manner set forth in Example 3 to obtain 
the (3aS)-N.sup.1 -benzylnoresermethole (XI) in 56% yield. The product and 
a standard sample were identical on a TLC plate (silica gel, CH.sub.2 
Cl.sub.2 with 1% MeOH). 
All of the references cited herein, including patents, and publications, 
are hereby incorporated in their entireties by reference. 
While this invention has been described with an emphasis upon preferred 
embodiments, it will be obvious to those of ordinary skill in the art that 
variations of the preferred embodiments may be used and that it is 
intended that the invention may be practiced otherwise than as 
specifically described herein. Accordingly, this invention includes all 
modifications encompassed within the spirit and scope of the invention as 
defined by the following claims.