Note: Descriptions are shown in the official language in which they were submitted.
~2~4~335
L-AMINODICARBOXYLIC ACID A~IIDES
.... _
FIELD OF THE INVE~TION
This invention relates to a novel group of
10 compounds and more particularly to a novel group of
compounds particularly well suited as sweeteners in
edible foodstuff.
DESCRIPTION OF THE PRIOR ART
Sweetness is one of the primary taste cravings
15 of both animals and humans. Thus, the utilization
of sweetening agents in foods in order to satisfy
this sensory desire is well established.
Naturally occuring carbohydrate sweeteners
such as sucrose, are still the most widely used
20 sweetening agents. While thse naturally occurring
carbohydrates, i.e., sugars, generally fulfill the
requirements of sweet taste, the abundant usage
thereof does not occur without deleterious conse-
~uence, e.g., high caloric intake and nutritional
25 imbalance. In fact, oftentimes the level of these
sweeteners required in foodstuffs is far greater
than the level of the sweetener that is desired for
economic, dietetic or other functional consideration.
3o
.
.
.
-2- ~2~835
1 In an attempt to eliminate the disadvantages
concomitant with natural sweeteners, considerable
research and expense have been devoted to the
production of artificial sweeteners, such as for
5 example, saccharin, cyclamate, dihydrochalcone,
aspartame, etc. While some of these artificial
sweeteners satisfy the requirements of sweet taste
without caloric input, and have met with considerable
commercial success, they are not, however, without
10 their own inherent disadvantages. For example, many
of these artificial sweeteners have the disadvan-
tages of high cost, as well as delay in the percep-
tion of the sweet taste, persisten~ lingering of the
sweet taste, and very objectionable bitter, metallic
15 aftertaste when used in food products.
Since it is believed that many disadvantages
of artificial sweeteners, particularly aftertaste, is a
function of the concentration of the sweetener, it
has been previously suggested that these effects could
20 be reduced or eliminated by combining artificial
sweeteners such as saccharin, with other ingredients
such as aspartame or natural sugars, such as sorbitol,
dextrose, maltose, etc. These combined products,
however, have not been entirely satisfactory either.
Some U.S. Patents which disclose sweetener mixtures
include for example, U.S. Patent No. 4,228,198; U.S.
Patent No. 4,158,068; U.S. Patent No. 4,1S4,862; and
U.S. Patent No. 3,717,477.
3o
-3~ 35
Accordingly, much work has continued in an
a~tempt to develop and identify compounds that have a
sweet taste and which will satisfy the need for better
lower calorie sweeteners. Search continues for sweeteners
that have intense sweetness, that is, deliver a sweet
taste at low use levels and which will also produce enough
sweetness at low levels to act as sole sweetener for most
sweetener applications. Furthermore, the sweeteners sought
must have good temporal and sensory qualities. Sweeteners
with good temporal qualities produce a time-intensity
sweetness response similar to natural sweeteners without
lingering. Sweeteners with good sensory qualities lack
undersirable off tastes and aftertaste. Furthermore,
these compounds mubt be economical and safe to use.
In U.S. Patent No. 3,798,204, L-aspartyl-O-t-
butyl-L-serine methyl ester and L-aspartyl-O-t-amyl-L-
serine methyl ester are described as sweet compounds
having significant sweetness.
In U.S. Patent No. 4,448,716 metal complex
salts of dipeptide sweeteners are disclosed. In the back-
ground of this patent a generic formula is described as
an attempt to represent dipeptide sweeteners disclosed
in five prior patents: U.S. Patent No. 3,475,403; U.S.
Patent No. 3,492,131; Republic of South Africa Patent
No. 695,083 published July 10, 1969; Republic of South
Africa Patent No. 695,910 published August 14, 1969; and
German Patent No. 2,054,554. The general formula
attempting to represent these patents is as follows:
.
- _ 4_ ~ 83~
H2N - CH - CONH - :fH- COOR
CH2COOH (CH2) nR
L L
Wherein R represents the lower alkyls, lowex
alkylaryls and cycloalkyls, n stands for integers O
through 5, Rl represents (a) phenyl group, (b) lower
alkyls, (c) cycloalkyls, (d) R2.
Where R2 is hydroxy, lower alkoxy, lower alkyl,
halogen, (e) (S()m (lower alkyl) where m is O, 1 or 2
and pro~ided n is 1 or 2, (f) R3.
Where R3 represents an hydroxy or alkoxy and
(g) single or double unsaturated cycloalkyls with up to
eight carbons. These compounds also are not entirely
satisfactory in producing a high quality sweetness or
in producing a sweet response at lower levels of sweetener.
Dipeptides of aspartyl-cysteine and aspartyl-
methionine methyl esters are disclosed by Brussel, Peer
and Van der Heijden in Chemical Senses and Flavour, 4,
141-152 (1979? and in ~. Levensm. Untersuch-Forsch., 159,
337-343 (1975). The authors disclose the following
dipeptides:
G~-L-Asp-L-Cys(Me)-OMe
C~-L-Asp L-Cys(Et)-OMe
C~-L-Asp-L-Cys(Pr)-OMe
c~-L-Asp-L-Cys(i-Pr)-OMe
C~-L-Asp-L-Cys(t-But)-OMe
C~-L Asp-L-Met-OMe
~ .
:
.
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-4a- ~44~35
In U.S. Patent No. 4,399,163 to Brennan et al.,
sweeteners having the following formulas are disclosed:
NH
COOH - CH2 - CH / NH Ra
" CHCONHR
and physiologically acceptable cationic and acid addition
salts thereof wherein
R is CH20H or CH20CH3;
R is a branched member selected from the group
consisting of fenchyl, diisopropylcarbinyl, d-methyl-t-
butylcarbinyl, d-ethyl-t-butyl-carbinyl, 2-methylthio-2,
4-dimethyl-pentan-3-yl, di-t-butyl-carbinyl,
Rl R 1 R~
CH
--~S~ (CHl)~ CH
R~ R~
R2 r~
(C~t)~
~ ~r
L (CHI)~ ~
~ jH2h
0~
R~
~ ~C~
~ OH
.'
3 0 ~ IL Ri-
.
.
~ -5- 1~835
European Patent Application 34,876 describes
amides of L-aspartyl-D-amino acid dipeptides of the formula:
NH2
CH2 CH NH Ra
COOH / \ C / \ 1
'' CHCONHR
wherein Ra is methyl, ethyl, n-propyl or isopropyl and
R is a branched aliphatic, alicyclic or heterocyclic
member which is branched at the alpha carbon atom and also
branched again at one or both of the beta carbon atoms.
These compounds are indicated to be of significant
sweetness.
In the Journal of Medicinal Chemistry, 1984,
Vol. 27, No. 12, pp. 1663-8, are described various
sweetener dipeptide esters, including L-aspartyl-OC-
aminocycloalkane methyl esters.
The various dipeptide esters of the prior art
have been characterized as lacking significant stability
at low pH values and/or thermal stability. These charac-
~o terstics have limited the scope of use of these sweeteners
in food products which are of low pH values or are
prepared or served at elevated temperatures.
Accordingly, it is desired to find compoundsthat provide quality sweetness when added to foodstuffs
or phamaceuticals~at low levels and thus eliminate or
greatly diminish the aforesaid disadvantages associated
with prior art sweeteners.
SUMMARY OF THE INVENTION
_
The present new compounds are amides of certain
* Published September 2, 1981
-: :
,
` -6- 1~835
cY~ -aminodicarboxylic acids and B-aminoethers which are
low calorie sweeteners that possess a high order of
sweetness with pleasing taste and higher stability at
acid pH and elevated temperatures compared to known
dipeptide sweeteners.
This invention provides new sweetening
compounds represented by the formula:
L
H2N - CH - CONH - C(A')A
(fH2)m CHOY (I)
CO2H R5
wherein
A is hydrogen, alkyl eontaining 1-3 carbon atoms,
hydroxyalkyl containing 1-3 earbon atoms or alkoxymethyl
wherein the alkoxy eontains 1-3 earbon atoms;
A' is hydrogen or alkyl containing 1-3 earbon
atoms; alternatively
A and A' taken together with the carbon atom to
whieh they are attaehed form eycloalkyl containing 3-4
earbon atoms;
Y is - (CHR2)n-Rl or CHR3R4;
Rl is eyeloalkyl, eyeloalkenyl, lower alkyl
substituted cyeloalkyl or cycloalkenyl, bicyeloalkyl,
bieyeloalkenyl or tricyeloalkyl eontaining up to 10 ring
earbon atoms and up to a total of 12 earbon atoms;
R2 and R5 are eaeh H or alkyl eontaining 1-4
earbon atoms;
R3 and R4 are eaeh eyeloalkyl eontaining 3-4 ring
earbon atoms;
n = 0 or 1; and
m = 0 or 1;
I and food-aeeeptable salts thereof.
_7~ ~ 35
1 DESCRIPTION OF THE PREFERRED EMBODIMENTS
In accordance with the present invention,
the preferred compounds are those in ~Jhich R1 is
an alkyl-substituted cycloalkyl or bicycloalkyl
5 containing 5 - 7 ring carbon atoms and up to a
total of 10 carbon atoms. Especially preferred
are cycloalkyl substituted with at least one methyl
group on the B and/or ~ ' carbon atoms of the
cycloalkyl ring. Particularly preferred cycloalkyls
include cyclopropyl, cyclopentyl, and cyclohexyl
and the preferred bicycloalkyl is fenchyl.
Also preferred are those compounds in
which R5 = H and n = 0. In those compounds in
which n = 1, Rl is preferably a cyclopropyl group
and R2 is preferably tertiary butyl or iso-
propyl.
The ether groups representative of Y
in the present new compounds include such groups
as cycloalkyl, e.g., cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, etc.; alkyl-substituted
cycloalkyls, e.g., l-methylcyclopentyl, l-methyl-
cyclohexyl, 1-methylcyclobutyl, l-methylcycloheptyl,
~5
3o
-8- ~ 835
l-ethylcyclobutyl, l-ethylcyclopentyl, 1 ethylcycloheptil,
l-ethylcyclohexyl, l-isopropylcyclobutyl, l-isopropyl-
cyclopentyl, l-isopropylcyclohexyl, l-siopropylcycloheptyl,
1,2-dimethylcyclohexyl, 1,2-dimethylcyclopentyl, 1,2-
dimethylcycloheptyl, 1,3-dimethylcyclohexyl, 1,3-
dimethylcyclopentyl, 1,3-dimethylcycloheptyl, 1,4-dimethyl-
cyclohexyl, 1,4-dimethylcycloheptyl, 2,3-dimethylcyclo-
pentyl, 2,3-dimethylcyclohexyl, 2,3-dimethylcycloheptyl,
2,4-dimethylcyclopentyl, 2,4-dimethylcyclohexyl,
2,4-dimethylcycloheptyl, 2,5-dimethylcyclopentyl,
2,5-dimethylcyclohexyl, 2,5-dimethylcycloheptyl,
2,6-dimethylcyclohexyl, 2,6-dimethylcycloheptyl,
2,7-dimethylcycloheptyl, 3,4-dimethylcyclopentyl,
3,4-dimethylcyclohexyl, 3,4-dimethylcycloheptyl,
3,5-dimethylcyclopentyl, 3,5-dimenthylcyclohexyl,
3,5-dimethylcycloheptyl, 4,5-dimethylcyclopentyl/ 4,5-
dimethylcyclohexyl, 4,5-dimethylcycloheptyl, 3,6-dimethyl-
cyclohexyl, 3,6-dimethylcycloheptyl, 3,7-dimethylcycloheptyl,
4,6-dimethylcycloheptyl,-4,:6-dimethycyc10hexyl, 4,7-
dimethylcycloheptyl, 5,6-dimethylcyclohexyl, 5,6-
dimethylcyclohexyl, 5,6-dimethylcycloheptyl, 5,7-
dimethylcycloheptyl, 6,7-dimethylcycloheptyl, 2,2-
dimethylcyclopentyl, 2,2-dimethylcyclohexyl, 2,2-
dimethylcycloheptyl, 3,3- dimethylcyclopentyl, 3,3-
dimethylcyclohexyl, 3,3- dimethylcycloheptyl, 4,4-
dimethylcyclohexyl, 4,4-dimethylcycloheptyl, 2,2,3-
trimethylcyclopentyl, 2,2,3-trimethylcyclohexyl, 2,2,3-
trimethylcycloheptyl, 2j2,4-trimethylcyclopentyl, 2,2,4-
trimethylcyclohexyl, 2,2,4-trimethylcycloheptyl,
~ .
: ,
.
-9- ~2~835
2~2,5-trimethylcyclopentyl~ 2,2,5-trimethylcyclohexyl, 2,2,
5-trimethylcycloheptyl, 2,2,6-trimethylcyclohexyl, 2,2,6-
trimethylcyclohepty 2,2,7-trimethylcycloheptyl, 1,2,2-trim-
ethylcyclopentyl, 1,2,2-trimethylcyclohexyl, 1,2,2-
trimethylcycloheptyl, 1,3,3--trimethylcyclopentyl, 1,3,3-
trimethylcyclohexyl, 1,3,3-trimethylcycloheptyl, 1,4,4-
trimethylcyclohexyl, 1,4,4-trimethylcyclopentyl, 3,3,4-
trimethylcyclopentyl, 3,3,4-trimethylcyclohexyl, 3,3,4-
trimethylcycloheptyl, 2,3,3-trimethylcyclopentyl, 2,3,3-
trimathylcyclohexyl, 2,3,3-trimethylcycloheptyl, 2,4,4-
trimethylcyclopentyl, 2,4,4-trimethylcyclohexyl, 2,4,4-
trimethylcycloheptyl, 1,2,3-trimethylcyclopentyl, 1,2,3-
trimethylcyclohexyl, 1,2,3-trimethylcycloheptyl, 1,2,4-
trimethylcyclopentyl, 1,2,4-trimethylcyclohexyl, 1,2,4-
trimethylcycloheptyl, 1,2,5-trimethylcyclopentyl, 1,2,5-
trimethylcyclohexyl, 1,2,5-trimethycycloheptyl, 1,2,6-
trimethylcyclohexyl, 1,2,6-trimethylcycloheptyl, 1,2,7-
trimethylcycloheptyl, 2,3,4-trimethylcyclopentyl, 2,3,4-
trimethylcyclohexyl, 2,3,4-trimethylcycloheptyl, 2,3,5-
trimethylcyclopentyl, 2,3,5-trimethylcyclohexyl, 2,3,5-
trimethylcycloheptyl, 2,3,6-trimethylcyclohexyl, 2,3,6-
trimethylcycloheptyl, 2,3,7-trimethylcycloheptyl, 3,4,4-
trimethylcyclohexyl, 3,4,4-trimethylcyclopentyl, 2,2,5,5
tetramethylcyclopentyl, 2,2,5,5-tetramethylcyclohexyl,
2,2,5,5-tetramethylcycloheptyl, 2,2,6,6- tetramethyl-
cyclohexyl, 2,2,6,6-tetramethylcycloheptyl, 2,2,7.7-
tetramethylcycloheptyl, 2,2,4,4-tetramethylcyclopentyl,
2,2,4,4-tetramethylcyclohexyl, 2,2,4,4-tetramethylcyclo-
heptyl, 2,2,3,3-tetramethylcyclopentyl, 2,2,3,3-
tetramethylcycloheptyl, 3,3,4,4-tetramethylcyclopentyl,
1~4~335
--10-
3,3,4,4-tetramethylcyclohexyl, 3,3,4,4-tetramethylcycloheptyl,
3,3,5,5-tetramethylcyclohexyl, 3,3,5,5-te~ramethylcycloheptyl,
1,2,3,4-tetramethylcyclopentyl, 1,2,3,4-tetramethylcyclohexyl,
1,2,3,4-tetramethylcycloheptyl, 1,2,3,5-tetramethylcyclopentyl,
1,2,3,5-tetramethylcyclohexyl, 1,2,3,5-tetramethylcyclyoheptyl,
1,2,3,6-tetramethylcyclohexyl, 1,2,3,6-tetramethylcycloheptyl,
2,3,4,5-tetramethylcyclopentyl, 2,3,4,5-tetramethylcyclohexyl,
2,3,4,5-tetramethylcycloheptyl, 2,3,4,6-tetramethylcycloheptyl,
2,3,4,6-tetramethylcyclohexyl, 2,3,4,7-tetramethylcycloheptyl,
1~ 2,2,3,4-tetramethylcyclopentyl, 2,2,3,4-tetramethylcyclohexyl,
2,2,3,4-tetramethylcycloheptyl, 2,2,3,5-tetramethylcyclopentyl,
2,2,3,5-tetramethylcyclohexyl, 2,2,3,5-tetramethylcycloheptyl,
2,2,3,6-tetramethylcyclohexyl, 2,2,3,6-tetramethylcycloheptyl,
2,2,3,7-tetramethylcycloheptyl, 2,3,3,4-tetramethylcyclohexyl,
2,3,3,4-tetramethlycyclopently, 2,3,3,4-tetramethylcycloheptyl,
2,3,3,5-tetramethylcyclopently, 2,2,3,5-tetramethylcyclohexyl,
2,3,3,5-tetramethylcycloheptyl, 2,3,3,6-tetramethylcyclohexyl,
2,3,3,6-tetramethylcycloheptyl, 2,3,3,7-tetramethylcycloheptyl,
2,2,3,4-tetramethylcyclopentyl, 2,2,3,4-tetramethylcyclohexyl,
~ 2,3,3,4-tetramethylcycloheptyl, 2,2,3,5-tetramethylcyclopentyl,
2,2,3,5-tetramethylcyclohexyl, 2,2,3,6-tetramethylcyclohexyl,
2,2,3,6-tetramethylcycloheptyl, 2,2,3,7-tetramethylcycloheptyl,
2,2,4,5-tetramethylcyclopentyl, 2,2,4,5-tetramethylcyclohexyl,
2,2,4,5-tetramethylcycloheptyl, 2,2j4,6-tetramethylcyclohexyl,
2,2,4,6-tetramethylcycloheptyl, 2,2,4,7-tetramethylcycloheptyl,
4-methyl-cyclohexylisopropyl, 4-methylcycloheptylisopropyl, 3-
methylcyclopentylisopropyl, 3-methylcyclohexylisopropyl,
dicyclopropylmethyl, t-butylcyclopropylmethyl, t-butylcyclo-
pentylmethyl, 2-isopropylcyclopentyl, 2-t-butylcyclopentyl,
2-isopropylcyclohexyl, 2-t-butylcyclopentyl, 2-isopropylcyclo-
hexyl, 2-t-butylcyclohexyl, 2-t-amylcyclopentyl, t-amylcyclo-
propylmethyl, dicyclobutyImethyl, t-butylcyclobutylmethyl,
. .
835
3-methylcycloheptylisopropyl, 2-methylcycloheptylisopropyl, 2-
methylcyclohexylisopropyl, 2-methylcyclopentylisopropyl, etc,;
cycloalkenes, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl,
etc.; al~yl-substituted cysloalkenes, e.g., l-methyl-3-
cyclopentenyl, l-methyl-3-cyclohexenyl, 1-methyl-3-cyclo-
heptenyl, l-methyl-4-cycloheptenyl, 3-cyclopentenylisopropyl,
3-cyclohexenylisopropyl, 3-cycloheptenylisopropyl, 4-cyclo-
heptenylisopropyl, 3-cyclopentenylmethyl, 3-cyclopentenylethyl,
3-cyclohexenylpropyl, 3-cyclohexenylethyl, 3-cycloheptenyl-
propyl r 3-cycloheptenylethyl, 4-cycloheptenylmethyl, 4-cyclo-
heptenylethyl, 2-methyl-3-cyclohexenyl r 2-methyl-3-cyclo-
pentenyl, 2-methyl-3-cycloheptenyl r 2-methyl-4-cycloheptenyl r
3-methyl-3-cyclohexenyl r 3-methyl-3-cyclopentenyl r 3-methyl-3-
cycloheptenyl r 4-methyl-3-cycloheptenyl r 4-methyl-3-cyclo-
hexenyl r 4-methyl-3-cyclopentenyl r 5-methyl-3-cyclopentenyl r 5~
methyl-3-cyclohexenyl, 5-methyl-3-cycloheptenyl, 6-methyl-3-
cyclohexenyl r 6-methyl-3-cycloheptenyl r 2-methyl-2-
cyclopentenyl r 2-methyl-2-cyclohexenyl r 2-methyl-2-cyclo-
heptenyl r 2-methyl-2-cyclopentenyl r 3-methyl-2-cyclohexenyl r 3-
methyl-2-cycloheptenyl, 1-methyl-2-cyclopentenyl r 1-methyl-2-
cyclohexenyl r l-methyl-2-cysloheptenyl, 5-methyl-2-cyclo-
hexenyl r 4-methyl-2-cyclopentenyl, 4-methyl-2-cycloheptenyl, 5-
methyl-2-cyclohexenyl r 5-methyl-2-cycloheptenyl r 6-methyl-2-
cyclohexenyl, 6-methyl-2-cycloheptenyl, 7-methyl-2-cyclo-
heptenyl r 2 r 3-dimethyl-2-cyclopentenyl, 2,3-dimethyl-2-cyclo-
hexenyl, 2,4-dimethyl-2-cyclopentenyl, 2,4-dimethyl-2-cyclo-
hexenyl, 2,5-dimethyl-2-cyclohexenyl, 2,5-dimethyl-2-cyclo-
heptenyl, 2,6-dimethyl-2-cyclohexenyl r2r 6-dimethyl-
~'
-12-
3-cyclohexenyl, 2,5-dimethyl-3-cyclohexenyl, 2,5-dimethyl-2-
cyclopentenyl, 2,4-dimethyl-3-cyclopentenyl, 2,4-dimethyl-3-
cyclohexenyl, 3,3-dimethyl-3-cyclopentenyl, 3,3-dimethyl-3-
cyclohexenyl, 3,4-dimethyl-3-cyclopentenyl, 3,4-dimethyl-3-
cyclohexenyl, 4,5-dimethylcyclo-3-pentenyl, 4,5-dimethyl-3-
cyclo-3-hexenyl, 5,5-dimethyl-3-cyclohexenyl, 5,5-dimethyl-3-
cyclopentenyl, 5,5-dimethyl-3-cycloheptenyl, 6,6-dimethyl-3-
cyclohexenyl, 1,2-dimethly-3-cyclopentenyl, 1,2-dimethyl-3-
cyclohexenyl, 1,3-dimethyl-3-cyclopentenyl, 1,3-dimethly-3-
1~ cyclohexenyl, 1,3-dimethyl-3 cycloheptenyl, 1,4-dimethyl-3-
cyclopentenyl, 1,4-dimethyl-3-cyclohexenyl, 1,4-dimethyl-3-
cyclohexenyl, 1,5-dimethyl-3-cyclopentenyl, 1,5-dimethyl-3-
cyclohexenyl, 1,5-dimethyl-3-cycloheptenyl, 2,2,6-trimethyl-3-
cyclohexenyl, 2,2,5-trimethyl-3-cyclohexenyl, 2,5,5-trimethyl-
3-cyclohexeneyl, 2,5,5-trimethyl-3-cyclopentenyl, 2,7,7-
trimethyl-3-cycloheptenyl, 2,7,7-trimethyl-4-cycloheptenyl,
2,2,7-trimethyl-3-cycloheptenyl, 2,2,7-trimethyl-4-
cycloheptenyl, 2,3,6-trimethyl-3-cyclohexenyl, 2,3,7-trimethyl-
3-cyclo-heptenyl, 2,3,5-trimethyl-3-cyclo-pentenyl, 2,2,6,6-
~0 tetramethyl-3-cyclohexenyl, 2,2,5,5-tetra-methyl-3-
cyclopentenyl, 2,2,7,7-tetramethyl-3-cycloheptenyl, 2,3,5,5-
tetramethyl-3-cyclopentenyl, 2,3,6,6-tetramethyl-3-
cyclohexenyl, 2,3,7,7-tetramethyl-3-cycloheptenyl, 2,3,6,6-
tetramethyl-3-cycloheptenyl, 2,3,5,5-tetramethyl-3-cyclo-
hexenyl, 2,3,4,5-tetramethyl-3-cyclopentenyl, 2,3,4,5-
tetramethyl-3-cyclohexenyl, t4-ethylcyclohex-3-enyl)isopropyl,
(4-propylcyclohex-3-enyl)isopropyl, (4-methylcyclohex-3-
enyl)ethyl, (3-methylcyclohex-3-enyl)isopropyl, (4-ethylcyclo-
pent-3-enyl)isopropyl, (4-propylcyclopent-3-enyl)isopropyl, (4-
3Q methylcyclopent-3-enyl)isopropyl,
335
-13-
(4-methyleyclopent-3-enyl)ethyl, (3-me-thyleyelopent-3-
enyl)isopropyl, (2-methyleyelohex-3-enyl)isopropyl, (2-
methyleyelopent-3-enyl)isopropyl, ete; bieyelic compounds, sueh
as norbornyl, norcaranyl, norpinanyl, bicyclo [2.2.2] oetyl,
ete.; alkyl substituted bieyelie eompounds, e.g., 6,6-
dimethyl-bieyelo [3.1.1] heptyl, 6,7,7-trimethylnorbornyl
(bornyl or eamphanyl), pinanyl, thujanyl, earanyl, fenehyl, 2-
norbornylmethyl, 2-norbornylethyl, 2-norbornypropyl, 3-
norbornylpropyl, ete.; unsubstituted and alkyl-substituted
la bieyeloalkenes sueh as norborenyl, norpinenyl, norearenyl, 2-
(4-norborenyl)ethyl, pinenyl, carenyl, fenehenyl, ete.; and
trieyelo eompounds sueh as adamantyl and alkyl-substituted
adamantyl, ete.
The preferred Rl is cycloalkyl or bicycloalkyl or
alkyl-substituted cycloalkyl or bieycloalkyl, especially where
the alkyl group is in the ~ or ~' positions. Further,
preference exists for compounds in which Rl is a cycloalkyl
with two~ three or four alkly groups in the ~, B' positions
sueh as ~ '-tetraalkyl-substituted cyclopentyl,
~a eyelobutyl, eyelohexyl, and eycloheptyl, as well as ~
trialkyl substituted cyelobutyl, cyclopropyl, cyclohexyl,
eyelopentyl, and cyeloheptyl, and fenchyl. Also preferred are
~-alkyleyeloalkyls in whieh the alkyl group is isopropyl or
tertiary butyl.
~r~
835
-14-
These novel compounds are eEfective sweetness agents
when used alone or in combination with other sweeteners in an
ingesta, e.g., foodstuffs or pharmaceuticals. For example,
other natural and/or artificial sweeteners which may be used
with the novel compounds of the present invention include
sucrose, fructose, corn syrup solids, dextrose, xylitol,
sorbitol, mannitol, acetosulfam, thaumatin, invert sugar,
saccharin, thiophene saccharin, meta-aminobenzoic acid, meta-
hydroxybenzoic acid, cyclamate, chlorosucrose, dihydro-
chalcone, hydrogenated glucose syrups, aspartame (L-aspartyl-L-
phenylalanine methyl ester) and other dipeptides, glycyrrhizin
and stevioside and the like. These sweeteners when employed
with the sweetness agents of the present invention, it is
believed, could produce synergistic sweetness responses.
3Q
~Z~8~5
15-
Furthermorev when the sweetness agents of the present
invention are added to ingesta, the sweetness agents may be
added alone or with nontoxic carriers such as the above-
mentioned sweeteners or other food ingredients such as
acidulants and natural and artificial gums. Typical
foods-tuffs, and pharmaceutical preparations, in which the
sweetness agents of the present invention may be used are, for
example, beverages including soft drinks, carbonated beverages,
ready to mix beverages and the like, infused foods (e.g.
vegetables or fruits), sauces, condiments, salad dressings,
juices, syrups, desserts, including puddings, gelatin and
frozen desserts, like ice creams, sherbets, icings and flavored
frozen desserts on sticks, confections, toothpaste) mouthwash,
chewing gum, cereals, baked goods, intermediate moisture foods
(e.g. dog food) and the like.
In order to achieve the effects of the present
invention, the compounds described herein are generally added
to the food product at a level which is effective to perceive
sweetness in the foodstuff and suitably is in an amount in the
2~ range of from about 0.0005 to 2~ by weight based on the
consumed product. Greater amounts are operable but not
practical. Preferred amounts are in the range of from about
0.001 to about 1% of the foodstuff. Generally, the sweetening
effect provided by the present compounds are experienced over a
wide pH range, e.g. 2 to 10 preferably 3 to 7 and in buffered
and unbuffered formulations.
'`~i
....~. ~
~ -16- ~Z~35
It is desired that when the sweetness agents of
this invention are employed alone or in combination
with another sweetner, the sweetener or combination
of sweeteners provide a sucrose equivalent ln the
5 range of from about 2 weight percent to about 40
weight percent and more preferably from about 3
weight percent to about 15 weight percent in the
foodstuff or pharmaceutical.
A taste procedure for determination of sweetness
lO merely involves the determination of sucrose equiva-
lency. Sucrose equivalence for sweeteners are
readily determined. The amount of a sweetener that
is equivalent to a given weight percent sucrose can
be determined by having a pnel of tasters taste
15 solutions of a sweetener at known concentrations and
match its sweetness to standard solutions of sucrose.
In order to prepare compounds of the present
invention several reaction schemes may be employed.
In one reaction scheme compounds of the general
2~ rormula II (protected CC-aminodicarboxylic acid) and
III (etherified hydroxy amino compound) are condensed
to form compounds of the general formula IV. Sub-
sequent removal of protecting groups A and B from
compounds of general formula IV give the desired
compounds of general formula I.
~Z~335
-17-
L A'
A - NH - CH, - COOH + NH2 - C - A
(CH2)mCOOB CHOY >
R5
II III
L A'
A
- HN -
In these, group A is an amino protecting group, B is a
carboxyl protecting group and the remaining groups have the
same meaning as previously described. A variety of protecting
groups known in the art may be employed. Examples of many of
these possible groups may be found in "Protective Groups in
Organic Synthesis" by T.W. Green, John Wiley and Sons, 1981.
Among the preferred groups that may be employed are benzyloxy-
carbonyl for A and benzyl for B. When A includes a free
hydroxy group suitable protecting groups can be employed as
known in the art.
Coupling of compounds with general formula II to
compounds having general formula III employs established amide-
forming techniques. One such technique uses dicyclohexyl-
carbodiimide (DCC) as the coupling agent. The DCC method may
be employed with~or without additives such as 4-dimethyl-
3Q aminopyridine or copper~II). The DCC coupling reaction
generally proceeds at room temperature, however, it may be
:
,: : : :
~0 ~ ~
:
83~
-18-
carried out from about -20 to 50C. in variety of solvents
inert to the reactants. Thus suitable solvents include, but
are not limited to, N,N-dimethylformamide, methylene chloride,
toluene and the like. Preferably the reaction is carried out
under an inert atmosphere such as argon or nitrogen. Coupling
usually is complete within 2 hours but may take as long as 24
hours depending on reactants.
Various other amide-forming methods can be employed to
prepare the desired compounds using suitable derivatives of the
~ree-carboxy group in compounds of structure II, e.g., acid
halide, mixed anhydride with acetic acid and similar
derivatives. The following illustrates such methods using
aspartic acid as the amino dicarboxylic acid.
One such method utilizes the reaction of N-protected
aspartic anhydrides with the selected amino compound of formula
III. Thus compounds of formula III can be reacted directly in
inert organic solvents with L-aspartic anhydride having its
amino group protected by a formyl, carbobenzloxy, or p-methoxy-
carbobenzloxy group which is subsequently removed after
coupling to give compounds of general formula I. The N-acyl-L-
aspartic anhydrides are prepared by reacting the corresponding
acids with acetic anhydride in amounts of 1.0 - 1.2 moles per
mole of the N-acyl-L-aspartic acid at 0 to 60C. in an inert
solvent. The N-acyl-L-aspartic anhydrides are reacted with
preferably l to 2 moles of compounds
3Q
~i
335
--19--
of formula III in an organic solvent capable of dissolving both
and inert to the same. Representative solvents are ethyl
acetate, methyl propionate, tetra-hydrofuran, dioxane, e-thyl
ether, N,N-dimethylformamide and benzene. The reaction
proceeds smoothly at 0 to 30C. The N-acyl group is removed
after coupling by catalytic hydrogenation with palladium on
carbon or with Hsr or HCl in a conven-tional manner. U.S.
Patent 3,879,372 discloses that this coupling method can also
be performed in an aqueous solvent at a temperature of -10 to
50C. and at a pH of 4-12~
Compounds of formula III are prepared by art-recognized
procedures from known compounds or readily preparable
intermediates. For example, the cycloalkanol can be reacted
with the appropriate nitroalkene in an inert solvent. As in
any organic reaction, solvents can be employed such as
methylene chloride, ether, tetrahydrofuran, dioxane, chloroform
and the like. The reaction is normally effected at 0C., but
temperatures ranging from -78C. to 100C. can be employed.
Usually an inert atmosphere of nitrogen or argon is supplied.
The nitro group of the formed product is then reduced by
catalytic hydrogenation, e.g., H2/Pd or H2/Nickel.
Compound III can be prepared from the reaction of an
cycloalkanol and the appropriate N-protected alkyl aziridine in
an inert solvent. Inert solvents include methylene chloride,
ether, tetrahydrofuran, dioxane, chloroform and the like. The
reaction is normally effected at cold temperatures, e.g., 0C.
but temperatures ranging from -78C. to -100C. can be
employed. Usually an inert atmosphere of nitrogen or argon is
employed.
835
-20-
Compounds of general Eormula III may be synthesized
from N-protec-ted ethanolamine compounds by employing a variety
of etheriEication methods known in the art. Some of these
methods may be found in "Modern Synthetic Reactions", 2nd ed.,
by H.O. House, W.A. Benjamin, Inc., 1972; "Advanced Organic
Chemistry", 2nd ed., by J. March McGraw-Hill, 1977, and
"Compend-ium of Organic Synthetic Methods", Vol. 1 and 2, by
I.T. Harrison and S. Harrison, Wiley-Interscience, 1971 & 1974.
One possible etherification method is the acid
catalyzed reaction of N-protected ethanolamine compounds with
an appropriate olefinic precursor of the desired Y moiety. For
example when Y is Rl, N-carbobenzyloxy ethanolamine is reacted
with methylenecyclopentane to obtain the N-protected
intermediate of general formula III in which Rl represents 1-
methylcyclopentane. This intermediate is then deprotected to
give a compound of formula III having Rl equal to l~methyl
cyclopentane. When cycloalkadienes are used, the product is a
cycloalkenyl ether. As illustrative examples, the following R
olefinic precursors can be utilized to give the corresponding
R1 group:
3Q
~l2~835
-21-
1 Precursor 1 Group
methylenecyclobutane l-methylcyclobutyl
l-methyl-l-cyclobutene l-methylcyclobutyl
l-methyl-l-cyclopentene l-methylcyclopentyl
l-methyl-l-cyclohexene l-methylcyclohexyl
methylenecyclohexane l-methylcyclohexyl
1,2-dimethyl-1-cyclohexene 1,2-dimethylcyclohexyl
l-methyl-l-cycloheptene l-methylcycloheptyl
l-ethyl-l-cyclohexene l-ethylcyclohexyl
l-ethyl-l-cyclopentene l-ethylcyclopentyl
1,3-cyclopentadiene 2-cyclopentenyl
l-methyl-1,4-cyclohexadiene 1-methyl-1-cyclohex-3-enyl
d-limonene l,l-dimethyl-l-(4'-methylcyclo-
hex-3'-enyl)methyl
The reaction of an appropriate olefinic Rl precursor
with an N-protected ethanolamine compound is preferably carried
out in the presence of an acid catalyst. Any acid is
employable but a mineral acid such as sulfuric acid is
advantageous. Usually an excess of from 1.2 to 50 moles of the
olefin precursor is utilized. Reaction temperatures are in the
range of -10 to 40C. and reaction times range from 2 to 48
hours. The reaction is carried out in a solvent that will
dissolve both reactants and is inert to both as well. Solvents
include, but are not limited to methylene chloride, toluene,
tetrahydrofuran, chloroform and the like. Usually an inert
atmosphere of nitrogen or argon is supplied.
~.
`
835
-22-
Another possible etherification method is the base, or
other catalyst, promoted reaction of N-protected ethanolamine
compound with Y-X, where X is an organic leaving group such as
halide, tosylate or mesylate. Any base normally employed to
deprotonate an alcohol may be used, such as sodium hydride,
sodium hydroxide, triethylamine, or diisopropyl ethylamine.
Reaction temperatures are in the range of -78 to 100C., and
the reaction times vary from 2 to 48 hours. The reaction is
carried out in a solvent that will dissolve both reactants and
is inert to both as well. Solvents include, but are not
limited to, diethyl ether, tetrahydrofuran, N,N-dimethyl-
formamide, dimethylsulfoxide, and the like. Vsually an inert
atmosphere of nitrogen or argon is supplied.
Alternatively, a neutral catalyst such as mercury (II)
salts or nickel (II) 2,4-pentanedionate may be employed in this
reaction. These reactions are also carried out in inert
solvents at room temperature or above. The intermediate formed
in this reaction is deprotected to yield compounds of formula
III.
A third method is the solvomercuration-demercuration
reaction of the appropriate olefinic precursor of Rl with an N-
protected ethanolamine compound. This reaction is carried out
in the presence of mercuric acetate or mercury trifluoroacetate
at a reaction temperature oE -10 to 100C. in a solvent which
will dissolve both reactants and is inert to both. Solvents
include, but are not limited to, diethyl
3Q
.
335
-23-
ether, tetrahydrofuran, methylene chloride, and the like.
Reaction times vary ~rom 5 minutes to 24 hours. The resulting
organomercury intermediate is reduced ln situ with basic
aqueous sodium borohydride, or other reducing ayen-ts, to remove
the mercury, followed by deprotection to yield compounds of
general formula III.
A further method of etherification is the reaction of
an N-protected compound of the formula
NH2 ~ C(A) (A') - CH (R5) X
where X is halide, tosylate, mesylate or other leaving groups,
with Y - OH using a base or other catalyst. Any base normally
employed to deprotonate an alcohol may be used, including
sodium hydride, sodium hydroxide, triethylamine, or diisopropyl
ethylamine. The reaction may be run either with or without
additives, for example, copper salts. Reaction temperatures
are in the range of -78C. to 100C., and reaction times vary
from 2 to 48 hours. The reaction is carried out in a solvent
that will dissolve both reactants and is inert to both.
Solvents include, but are not limited to, diethyl ether,
~ tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, and
the like. Usually an inert atmosphere of nitrogen or argon is
supplied.
Alternatively, a neutral catalyst such as mercury (II)
salts or nickel (II) 2,4-pentanedionate may be employed in this
reaction. These are also carried out in inert solvents at room
temperature or above. This product is then deprotected to
yield compounds of general formula III.
835
With regard to the removal of protecting groups from
compounds of formula IV and N-protected precursors of formula
III, a number of deprotecting techniques are known in the art
and can be utilized to advantage depending on the na-ture of the
protecting groups. Among such techniques is catalytic
hydrogenation utilizing palladium on carbon or transfer
hydrogenation with 1,4-cyclohexadiene. Generally the reaction
is carried at room temperature but may be conducted from 5 to
65C. Usually the reaction is carried out in the presence of a
suitable solvent which my include, but are not limited to
water, methanol, ethanol, dioxane, tetrahydrofuran, acetic
acid, t-butyl alcohol, isopropanol or mixtures thereof. The
reacti.on is usually run at a positive hydrogen pressure of 50
psi but can be conducted over the range of 20 to 250 psi.
Reactions are generally quantitative taking 1 to 24 hours for
completion.
In any of the previous synthetic methods the desired
products are preferably recovered from reaction mixtures by
crystallization. Alternatively, normal or reverse-phase
chromatography may be utilized as well as liquid/liquid
extraction or other means.
The desired compounds of formula I are usually obtained
in the free acid form; they may also be recovered as their
physiologically acceptable salts, i.e., the corresponding amino
salts such as hydrochloride, sulfate, hydrosulfate, nitrate,
hydrobromide, hydroiodide, phosphate or hydrophosphate; or the
alkali metal salts such as the sodium, potassium, lithium, or
the alkaline earth metal salts such as calcium or magnesium, as
well as aluminum, zinc and like salts.
-25-
Conversion of the present new compounds of formula I
into their physiologically acceptable salts is carried out by
conventional means, as for example, bringing the compounds of
formula I into contact with a mineral acid, an alkali metal
hydroxide, an alkali metal oxide or carbonate or an alkaline
earth metal hydroxide, oxide, carbonate or other complexed
form.
These physiologically acceptable salts can also be
utilized as sweetness agents usually having increased
solubility and stability over their free forms.
It is known to those skilled in the art that the
compounds of the present invention having asymmetric carbon
atoms may exist in racemic or optically active forms. All of
these forms are contemplated within the scope of the invention.
The compounds of the present invention have one
asymmetric site, which is designated by an asterik
(*) in the formula below, and two pseudoasymmetric sites which
are designated by a double asterik (**): COOH
I
(CH )m A'
1 2
H2N - CH - CONH **f A
**CHOY
R4
Whenever A is identical to A' and R4 is hydrogen, the compounds
oE the present invention have only one asymmetric site,
designated by the asterik, in the dicarboxylic acid moiety.
~2~835
-26-
Although both the D and L forms are possible; the preferred
compounds are those in which the dicarboxylic acid group is in
the L-configuration. Whenever, the groups A' and A are
different and R4 is not hydrogen, the carbon atoms designated
by the double asteriks become asymmetric centers and the
compounds of the present invention will contain at ]east three
asymmetric centers. If only A is different from A' or R4 is
not hydrogen, then the compounds of the present invention
contain at least two asymme-tric centers. Regardless, the
configuration around each of the asymmetric sites, whenever
present, may exist in either the D or L forms, and all possible
stereoisomers are contemplated to be within the scope of the
present invention. Since the aspartyl group is in the L-
configuration, whenever an asymmetric center is present at
either of the other two carbon sites, the compounds of the
present invention are diastereomers, which can be separated, if
desired, by art-recognized techniques, as, for example,
chromatography. However, mixtures of at least any two
stereoisomers exhibit sweetness properties and are useful as
sweeteners.
The following examples further illustrate the
invention.
.~
~L2~35
-27-
EXAMPLE 1
N-(L-Aspartyl)-1-(2-aminopropoxy)-2,2,5,5-tetramethyl-
cyclopentane
Method A:
2,2,5,5-Tetramethyl-l-cyclopentanol is added to a dry
flask under argon at 0C. Dry tetrahydrofuran is added with a
syringe. Sodium hydride (60% dispersion in oil) is added
quickly in one portion and the contents of the flask are
stirred for one hour at room temperature. A 10 mM solution of
18-crown-6-ether in acetonitrile is added with a syringe and
the flask cooled to 0C. A tetrahydrofuran solution of 2-
nitropropene is added with vigorous stirring over a 10 minute
period. After completion of -the reaction as judged by thin
layer chromatography, it is quenched with saturated ammonium
chloride and extracted with ethyl acetate. The organic layer
is dried over MgSO4 and evaporated to yield 1-(2-nitropropoxy)-
2,2,5,5-tetramethylcyclopentane.
l-t2-Nitropropoxy)-2,2,5,5-tetramethylcyclopentane is
dissolved in methanol and hydrogenated at 50 psi with Raney
nickel T-l as a catalyst. The reaction mixture is filtered
through Celite and evaporated to yield 1-(2-aminopropoxy)-
2,2,5,5-tetramethylcyclopentane.
Method B:
2-Methyl aziridine is dissolved in CH2C12 and
triethylamine under argon at 0C. Benzylchloroformate is added
and the contents of the flask are at room temperature
overnight. The mixtu~e is poured
* Trade Mark
..~
835
-28-
into 10% citric acid and is extracted with CHC13. The
organic layer is washed with dilute aqueous NaHC03 and dried
over MgS04. The solution is evaporated to yield N-Cbz-2-
methyl aziridine.
N-Cbz-2-Methyl aziridine and 2,2,5,5-tetramethyl-1-
cyclopentanol are dissolved in CH2C12 at 0C. under argon.
Boron trifluoride etherate is added and the flask is stirred
overnight. The contents are poured into saturated NaHC03 and
are extracted with ethyl acetate. The organic layer is dried
over MgS04 and evaporated to yield N-Cbz-1-(2~aminopropoxy)-
2,2,5,5~tetramethylcyclopentane.
N-Cbz-1-(2-Aminopropoxy)-2,2,3,5-tetramethylcyclo-
pentane is dissolved in CH30M hydrogenated over 5~ Pd/C
in a Parr hydrogenation apparatus. When the reaction is
complete the mixture is filtered through Celite and
concentrated to yield l-(2-amino-propoxy)-2,2,5,5-tetramethyl-
cyclopentane.
To a magnetically stirred solution of 1-(2-aminopropoxy)-
2,2,5,5-tetramethylcyclopentane in dry dimethylformamide at
0C. under argon atmosphere is added N-Cbz-L-aspartic acid
_eta-benzyl ester followed by copper (II) chloride and
dicyclohexyl carbodiimide. This is stirred for 18 hours, after
which the reaction mixture is poured into 0.1 N HC1 and
extracted with ethyl acetate. The organic phase is washed with
saturated NaHC03 and then water, and dried over MgS04.
Evaporation of the solvent yielded N-(N'-Cbz-L-aspartyl beta-
benzyl ester)-l-(2-aminopropoxy)-2,2,5,5-tetramethylcyclo-
pentane.
3Q
X ~ '
.
,
.
lZ~835
~29-
N-(N'-Cbz-L-aspartyl beta-benzyl ester)-1-(2-aminopropoxy)-
2,2,5,5-tetramethylcyclopentane is dissolved in CH30H and
hydrogenated over 5~ Pd/C in a Parr apparatus. Upon completion
of the reaction the mixture is filtered and concentrated to
yield
N- (L-aspartyl)-1-(2-aminopropoxy)-2,2,5,5-tetramethylcyclo-
pentane.
Similarly, by using the appropriate starting materials,
the following compounds are also prepared:
N-(_-Aspartyl)-1-(2-aminopropoxy)-2 t 2,5-trimethylcyclopentane;
N-(_-Aspartyl)-1-(2-aminopropoxy)-2,5-dimethylcyclopentane;
N- (_-Aspartyl)-1-(2-aminopropoxy)-dicyclopropylmethane;
N-(L-Aspartyl)-1-(2-aminopropoxy)-fenchane;
N-( -Aspartyl)-1-(2-aminopropoxy)-1-t-butylcyclopropylmethane;
N-(L-Aspartyl)-1-(2-aminopropoxy)-1-isopropyl-1-cyclopropyl-
methane;
N- (_-Aspartyl)-1-(2-aminopropyl)-2-t-butylcyclopentane.
3t)
4835
-30-
EXAMPLE 2
N-(L-Aspartyl)-1-(2-amino-2-meth~lpropoxy)-2,2,5,5-
tetramethylcyclopentane
Method ~-
-
2,2,5,5-Tetramethyl-l-cyclopentanol is added to a dry
flask under argon at 0C. Dry tetrahydrofuran was added with a
syringe. Sodium hydride (60% dispersion in oil) is added
quickly in one portion and the contents of the flask are
stirred for one hour at room temperature. A 10 mM solution of
18-crown-6-ether in acetonitrile is added with a syringe and
the flask cooled to 0C. A tetrahydrofuran solution of 2-
nitropropene is added with vigorous stirring over a 10 minute
period. After completion of the reaction, as judged by thin
layer chromatography, it is quenched with dimethyl sulfate,
poured into saturated ammonium chloride and extracted with
ethyl acetate. The organic layer is dried over MgSO4 and
evaporated to yield l-(2-nitro-2-methylpropoxy)- 2,2,5,5-
tetramethylcyclopentane.
1-(2-Nitro-2-methylpropoxy)- ,2,5,5-tetramethyl-
cyclopentane is dissolved in methanol and hydrogenated at 50
psi with Raney nickel T-l as a catalyst.
The reaction mixture is filtered through Celite and evaporated
to yield l-t2-amino-2-methylpropoxy)-2,2,5,5~tetramethyl-
cyclopentane.
_ethod B:
2,2-Dimethyl aziridine is dissolved in CH2C12 and tri-
ethylamine under argon at 0C. Benzylchloroformate is added
and the contents of the flask are stirred at room temperature
overnight. The mixture is poured into 10% citric acid and
3Q extracted with
~r
~2~835
CHC13. The organic layer is washed with dilute aqueous NaHC03
and dried over MgS04. The solution is evaporated to yield N-
Cbz-2,2-dimethylaziridine.
N-Cbz-2,2-Dimethyl aziridine and 2,2,5,5-tetramethyl-1-
cyclopentanol are dissolved in CH2C12 at 0C. under argon.
Boron trifluoride etherate is added and the flask is stirred
overnight. The contents are poured into saturated NaHC03 and
extracted with ethyl acetate. The organic layer is dried over
MgS04 and evaporated to yield N-Cbz-1-(2-amino-2-methyl-
propoxy)-2,2,5,5-tetramethylcyclopentane.
N-Cbz-1-(2-amino-2-methylpropoxy)-2,2,5,5-cyclopentane
is dissolved in CH30H and hydrogenated over 5~ Pd/C in a Parr
hydrogenation apparatus. When the reaction is complete the
mixture is ~iltered through Celite and concentrated to yield 1-
(2-amino-2-methylpropoxy)-2,2,5,5-tetramethylcyclopentane.
~ethod C:
2-Methyl-2-aminopropanol is dissolved in saturated
aqueous NaHC03 at room temperature. Di-tert-butyldicarbonate
is added in tert-butanol. The contents are stirred overnight
and then extracted with ethyl acetate. The organic layer is
dried over MgS04 and filtered. The filtrate is evaporated to
give N-Boc-2-amino-2-methylpropanol.
N-Boc-2-Amino-2-methylpropanol is dissolved in tri-
ethylamine under argon at 0C. Methanesulfonyl chloride is
added and the mixture is stirred overnight. The solution is
poured into 10% aqueous citric acid and extracted with ethyl
acetate. The organic layer is dried over MgS04, filtered and
evaporated to give N-Boc-2-amino-2-methyl-1-propyl mesylate.
., ~ ~
B35
2,2,5,5-Tetramethyl-l-cyclopentanol is added to a dry
flask under argon at 0C. Dry tetrahydrofuran is added with a
syringe. Sodium hydride (60% dispersion in oil) is added
quickly in one portion and the contents of the flask are
stirred for one hour at room temperature. A 10 mM solution of
18-crown-6-ether in acetonitrile is added with a syringe and
the flask cooled to 0C. A tetrahydrofuran solution of N-Boc-
2-amino-2-methyl-1-propyl mesylate is added with vigorous
stirring over a 10 minute period. After completion of the
reaction, as judged by thin layer chromatography, it is
quenched with dimethyl sulfate, poured into saturated ammonium
chloride and extracted with ethyl acetate. The organic layer
is dried over MgSO4 and evaporated to yield N-Boc-l-t2-amino-2-
methylpropoxy)-tetramethyl-2,2,5,5-cyclopentane.
N-Boc-1-(2-amino-2-methylpropoxy)-2,2,5,5-tetramethyl
cyclopentane is dissolved in tri~luoroacetic acid and stirred
overnight. The solution is poured into water and neutralized
with 20~ aqueous KOH. The mixture is extracted with ethyl
acetate, dried over MgSO4, filtered and evaporated to give 1-
~0 (2-amino-2-methyl-propoxy)-2,2,5,5-tetramethylcyclopentane.
To a magnetically stirred solution of 1-(2-amino-2-
methylpropoxy)-2,2,5,5-tetramethylcyclopentane in dry
dimethylformamide at 0C. under argon atmosphere is added N-
Cbz-L-aspartic acid beta-benzyl ester followed by copper (II)
chloride and dicyclohexylcarbodiimide. This is stirred for 18
hours, after which the reaction mixture is poured into 0.1 N
HCl and extracted with ethyl acetate. The organic phase is
335
washed with satura-~ed NaHC03 and then water, and dried
over MgS04. Evaporation of the solvent yields N-(N'-Cbz-L-
aspartyl beta-benzyl ester)-l-(2-amino-2-methylpropoxy)-
2,2,5,5-tetramethylcyclopentane.
N- ( N ' -Cbz-L-aspartyl beta-benzyl ester)-1-(2-amino-2-
methylpropoxy)-2,2,5,5-tetramethylcyclopentane is dissolved in
CH30H and hydrogenated over 5% Pd/C in a Parr apparatus. Upon
completion of the reaction the mixture is filtered and
concentrated to yield N- (L-Aspartyl)-1-(2-amino-2-methyl-
propoxy)-2,2,5,5-tetramethylcyclopentane.
Similarly, by using the appropriate starting materials,
the following compounds are also prepared:
N-(L-Aspartyl)-1-(2-amino-2-methylpropoxy)-2,2,5-tri-
methylcyclopentane.
N- ( L-Aspartyl)-1-(2-amino-2-methylpropoxy)-2,5-
dimethyl-cyclopentane.
N- ( L-Aspartyl)-1-(2-amino-2-methylpropoxy)-dicyclo-
propylmethane.
N-(L-Aspartyl)-1-(2-amino-2-methylpropoxy)-fenchane.
N-(L-Aspartyl)-1-(2-amino-2-methylpropoxy)-1-t-butyl-
cyclopropylmethane.
N-(L-Aspartyl)-1-(2-amino-2-methylpropoxy)-1-iso-
propyl-l-cyclopropylmethane.
N-(L-Aspartyl)-1-(2-amino-2-methylpropoxy)-2-t-butyl-
cyclopentane.
~Z~835
-34-
EXAMPLE 3
l-(N-(Aspartyl)amino)-1-[(2,2,5,5-tetramethylcyclopentoxy)
_ethyl]cyclopropane
To a suspension of 1-amino-1-cyclopropane carboxylic
acid in dry diethyl ether under argon at OC. is slowly added 1
M borane in tetrahydrofuran with vigorous stirring. The
contents are stirred overnight and then water is added dropwise
to destroy the remainder of the borane. The mixture is acidi-
fied with 2 N HC1 and then brought to approximately pH 11 with
20% KOH and saturated with NaCl. The product is extracted with
ethyl acetate and the organic layer dried over MgSO4.
Filtration and evaporation of the solvent yields l-amino-l-
hydroxymethylcyclopropane.
l-Amino-l-hydroxymethylcyclopropane is dissolved in
saturated aqueous NaHCO3 at room temperature. Di-tert-
butyldicarbonate is added in tert-butanol. The contents are
stirred overnight and then extracted with ethyl acetate. The
organic layer is dried over MgSO4 and filtered. The filtrate
is evaporated to give N-Boc-l-amino-l-hydroxymethylcyclo-
propane.
~0 N-Boc-l-amino-l-hydroxymethylcyclopropane is dissolved
in triethylamine under argon at OC. Methanesulfonyl chloride
is added with a syringe and the contents stirred at room
temperature overnight. The solution is poured into 10~ aqueous
citric acid and extracted with ethyl acetate. The organic
layer is dried over MgSO4 filtered and evaporated to give N-
Boc-l-amino-l-hydroxymethylcyclopropane mesylate.
.~ ,
1~9L835
2,2,5,5-Tetramethyl-1-cyclopentanol is added to a dry
flask under argon at 0C~ Dry tetrahydrofuran is added with a
syringe. Sodium hydride (60% dispersion in oil) is added
quickly in one portion and the contents of the flask are
stirred for one hour at room temperature. A 10 mM solution of
18-crown-6-ether in acetonitrile is added with a syringe and
the flask cooled to 0C. A tetrahydrofuran solution of N-Boc-
l-amino-l-hydroxymethylcyclopropane mesylate i9 added with
vigorous stirring over a 10 minute period. After completion of
the reaction, as judged by thin layer chromatography, it is
quenched with dimethyl sulfate, poured into saturated ammonium
chloride and extracted with ethyl acetate. The organic layer
is dried over MgS04 and evaporated to yield N-Boc-0-(2,2,5,5-
tetramethyl-l-cyclopentyl)-l-amino-l-hydroxymethyl-
cyclopropane.
N-Boc-0-(2,2,5,5-tetramethyl-1-cyclopentyl)-1-amino-1-
hydroxymethylcyclopropane is dissolved in trifluoroacetic acid
and stirred overnight. The solution is poured into water and
neutralized with 20~ aqueous KOH. The mixture is extracted
with ethyl aceta-te, dried over MgS04, filtered and evaporated
to give 0-(2,2,5,5-tetramethyl-1-cyclopentyl)-1-amino-1-
hydroxymethylcyclopropane.
To a magnetically stirred solution of 0-(2,2,5,5-
tetramethyl-l-cyclopentyl)-l-amino-l-hydroxy-methylcyclo-
propane in dry dimethylformamide at 0C. under argon atmosphere
is added N-Cbz-L-aspartyl acid beta-benzyl ester followed by
copper (II) chloride and dicyclohexylcarbodiimide. This is
stirred for 18 hours
~L2~835
-36-
after which the reaction mixture is poured into 0.1
N HCl and extracted with ethyl acetate. The organic phase
is washed with saturated NaHCO3 and then water, and dried over
MgSO4. Evaporation of the solvent yields N-(N'-Cbz-L-aspartyl
beta-benzyl ester)-0-(2,2,5,5-tetramethyl-1-cyclopentyl)-1-
amino-l-hydroxymethylcyclopropane.
N-(N'-Cbz-L-Aspartyl beta-benzyl ester)-0-(2,2,5,5-
tetramethyl-l-cyclopentyl)-1-amino-1-hydroxymethylcyclopropane
is dissolved in CH3CH and hydrogenated over 5% Pd/C in a Parr
apparatus. Upon completion of the reaction the mixture is
filtered and concentrated to yield N-(L-aspartyl)-0-(2,2,5,5-
tetramethyl-l-cyclopentyl)-l-amino-l-hydroxymethylcyclopropane.
Similarly, by using the appropriate cycloalkanol, the
following compounds are also prepared:
l-(N-(L-Aspartyl)amino)-1-[(2,2,5-trimethylcyclopentoxy)-
methyl~cyclopropane;
l-(N-(_-Aspartyl)amino)-1-[(2,5-dimethylcyclopentoxy)methyl~-
cyclopropane;
l-(N-( -Aspartyl)amino)-l-(dicyclopropylmethoxymethyl)-
cyclopropane;
l-(N-(L-Aspertyl)amino)-l-(fenchoxymethyl)cyclopropane;
l-(N-(_-Aspartyl)amino)-1-[(2-t-butylcyclopentoxymethyl)]cyclo-
propane;
l-(N-(L-Aspartyl)amino)-l-[(l-t-butyl-l-cyclopropylmethyl)-
oxymethyl]cyclopxopane.
l-(N-(L-Aspartyl)amino)-l-[(l-isopropyl-l-cyclopropylmethyl)-
oxymethyl)cyclopropane.
~ r
~2~335
EXAMPLE 4
N-(L-Aspartyl)-1-(2-amino-3-hydroxypropoxy)-2,2,5,5-tetra-
methyl cyclopropane
A. L-N-Triphenylmethyl serine methyl ester
A solution of L-serine methyl ester hydrochloride (100
g), triphenylmethylchloride (179.3 g) and triethylamine (197
ml) is stirred at 0C. for 2 hours, then allowed to warm to
room temperature overnight. The solution is then washed
successively with 10~ aqueous citric acid and water, dried over
magnesium sulfate, and the solvent evaporated to yield the
product.
B. L-l-Triphenylmethyl-aziridine-2-carboxylic acid methyl
ester
A mixture of compound A (212 g), methanesulfonyl
chloride (45.6 ml), and pyridine (1.76 1) is stirred at 0C.,
then allowed to warm slowly to room temperature overnight.
Ethyl acetate (1.5 1) is added, and the resulting solution
washed with 10~ aqueous citric acid and water, dried over
magnesium sulfate and the solvent removed. The residual oil is
dissolved in tetrahydrofuran (2.5 1) and triethylamine (143 ml)
is added. The mixture is heated at reflux overnight, then
cooled and most of the solvent is removed under vacuum. The
residual oil is dissolved in ethyl acetate (2 1) and the
solution is washed successively with 10% aqueous citric acid,
saturated aqueous sodium bicarbonate, and water, and then dried
over magnesium sulfate, after which the solvent is evaporated
under vacuum. The residue is dissolved in hot methanol and the
product crystallizes on cooling.
C. L-l-Benzyloxycarbon~laziridlne-2-carboxylic acid ~ y~
3Q ester
To a cold solution (0C) of compound B (17.0 g) and
methanol (100 ml) in dichloromethane (100 ml) is added con-
centrated sulfuric acid (5.0 ml). The mixture is stirred at
0C. for 10 min. Approximately half of the solvent is removed
under vacuum, and the residue is dissolved in ether. This
" 40
~Z~335
-38-
is made basic with sodium bicarbonate and extracted with di-
chloromethane (3 X 25 ml). To these combined extracts is added
triethylamine (4.63 g) and the solution is cooled to OC.
Benzyl chloroformate (7.80 g), is added, and the mixture is
allowed to warm -to room temperature overnight. The solution is
then washed successively with lM aqueous hydrochloric acid and
saturated aqueous sodium bicarbonate, dried over magnesium
sulfate, and the solvent is removed under vacuum to yield a
brown oil (7.0 g). The product is purified by column chroma-
tography on silica gel (4:1 hexanes: ethyl acetate, eluent) to
yield compound C.
D. N-Benzyloxycarbonyl-0-2,2,5,5-tetramethylcyclopentyl-L-
serine methyl ester
To a solution of compound C (1.00 g) and 2,2,5,5-tetra-
methylcyclopentanol (1.2 g) in dichloromethane (20 ml) is added
boron trifluoride diethyl etherate (15 drops). The mixture is
stirred at room temperature for 4 hours, then washed with
water, dried over magnesium sulfate and the solvent is
evaporated. The residue is purified by column chromatography
(silica gel, 10:1, hexanes: ethyl acetate, eluent) to yield
compound D.
E._ 0-2,2 ! 5,5-Tetramethylcyclopentyl-L-serine methyl ester
The product of D is dissolved in methanol in a Parr
hydrogenation bottle and purged with argon. Palladium on
carbon (5%) is added and hydrogenation carried out at 50 psi.
After cessation of hydrogen uptake, the contents of the bottle
are filtered through celite and evaporated to give the product.
F. N-(L-AsE~tyl)-1-(2-amino-3-hydroxy~ropoxy)-2,2,5,5-tetra-
_ethyl cyclopentane
The product of E is dissolved in ether and is reduced
with LiAlH4 to give 1-(2-amino-3-hydroxypropoxy)-2,2,5,5-
tetramethyl cyclopentane. To a magne-tically stirred solution
~2~335
-39-
into O.lN HCl and extracted with ethyl acetate. The organic
phase is washed with saturated NaHC03 and then water and is
dried over MgS04. The solvents evaporated off to give N-(N'-
Cbz-L-aspartyl-beta benzyl ester)-1-(2-amino-3-hydroxypropoxy)-
2,2,5,5-tetramethylcyclopentane.
This product is dissolved in CH30H and hydrogenated
over 5% Pd/C in a Parr apparatus. Nipon completion of the
reaction, the mixture is filtered and concentrated to yield the
final product.
Similarly, by utilizing the above procedure, and the
appropriate cycloalkanol, the following compounds are also
synthesized:
N-(_-Aspartyl)-1-(2-amino-3-hydroxypropoxy)-2,2,5-trimethyl-
cyclopentane;
N-(_-Aspartyl)-1-(2-amino-3-hydroxypropoxy)-2,5-dimethylcyclo-
pentane;
N-(h-Aspartyl)-1-(2-amino-3-hydroxypropoxy)-dicyclopropyl-
methane;
N-(_-Aspartyl)-1-(2-amino-3-hydroxypropoxy)-fenchane;
N-(L-Aspartyl)-1-(2-amino-3-hydroxypropoxy)-2-t-butylcyclo-
pentane;
N-(_-Aspartyl)-1-(2-amino-3-hydroxypropoxy)-1-t-butyl-1-cyclo-
propylmethane;
N-(_-Aspartyl)-1-(2-amino-3-hydroxypropoxy)-1-isopropyl-1-
cyclopropylmethane.
~L2~335
-40-
of this product in dry dimethyl formamide at OC under argon
atmosphere is added N-CB L-aspartic acid-beta-benzyl ester,
followed by Copper (II) chloride and dicyclohexylcarbodiimide.
This is stirred for 18 hours, after which the reaction mixture
is poured.
EXAMPLE 5
__
N-(L-Aspartyl~-1-(2-amino-3-methoxypropoxy)-2,2,5,5-tetra-
methylcyclopentane
To a suspension of N-Benzyloxycarbonyl-0-2,2,5,5-
tetramethylcyclopentyl-L-serine methyl ester (prepared as in
Example 4) in dry diethyl ether under argon at OC. is slowly
added l M borane in tetrahydrofuran with vigorous stirring.
The contents are stirred overnight and then water is added
dropwise to destroy the remainder of the borane. The mixture
is acidified with 2 N HCl and then brought to approximately pH
ll with 20% KOH and saturated with NaCl. The product is
extracted with ethyl acetate and the organic layer dried over
MgSO4 and filtered and the solvent is evaporated off.
The product of the preceding paragraph is dissolved in
methylene chloride and methylated with dimethylsulfate to
afford the l-(2-N-Cbz-amino-3-hydroxypropoxy)-2,2,5,5-tetra-
methylcyclopentane. This product is dissolved in methanol in a
Parr hydrogenation bottle and purged with argon. Palladium on
carbon (5%) is added and hydrogenation carried out at 50 psi.
After cessation of hydrogen uptake, the contents of the bottle
are filtered through celite and evaporated to give 1-(2-amino-
3-methoxypropoxyj-2,2,5,5-tetramethylcyclopentane.
To a magnetically stirred solution of this product in
3~ dry dimethyl formamide at OC under argon atmosphere is added
N-Cbz-L-aspartic acid beta-benzyl ester followed by copper (II)
chloride and dicyclohexyl carbodiimide. This is stirred for 18
hours, after which the reaction mixture is poured into O.lN HCl
and extracted with ethyl acetate. The organic phase is washed
~i~ 40
.
: '
:~Z~835
-40a-
with saturated NaHC03, and then water and dried over the MgS04.
The solvent is evaporated off to give N-(N-CbZ-L-aspartyl-beta-
benzyl ester)-1-(2-amino-3-methoxypropoxy)-2,2,5,5-tetra-
methylcyclopentane.
This product is dissolved in CH30H and hydrogenated
over 5% Pd/C in a Parr apparatus. Upon completion of the
reaction, the mixture is filtered and concentrated to yield the
final product.
Similarly, by utilizing the above procedure, and the
appropriate cycloalkanol, the following compounds are also
synthesized:
N-(L-Aspartyl)-1-(2-amino-3-methoxypropoxy)-2,2,5-trimethyl-
cyclopentane;
N-(L-Aspartyl)-1-(2-amino-3-methoxypropoxy)-2,5-dimethyl-
cyclopentane;
N-(L-Aspartyl)-1-(2-amino-3-methoxypropoxy)dicyclopropyl-
methane;
N-(L-Aspartyl)-1-(2-amino-3-methoxypropoxy)fenchane;
N-(L-Aspartyl)-1-(2-amino-3-methoxypropoxy)-2-t-butylcyclo-
pentane;
N-(L-Aspartyl)-1-(2-amino-3-methoxypropoxy)-1-_-butyl-1-cyclo-
propylmethane;
N-(L-Aspartyl)-1-(2-amino-3-methoxypropoxy)-1-isopropyl-1-
cyclopropylmethane.
3Q
~'
