CA1238051A - Intermediate compounds useful in the preparation of n-(l-aspartyl)-n'-(2,2,5,5- tetramethylcyclopentanecarbonyl)-r-1,1- diaminoethane - Google Patents

Abstract

ABSTRACT
The invention relates to novel intermediate compounds useful in the preparation of N-(L-aspartyl)-N'-(2,2,5,5-tetramethylcyclopentanecarbonyl)-R-1,1-diiaminoethane which is a potent sweetener free from undesirable flavor qualities. These intermediate compounds are 2,2,5,5-tetra-methylcyclopentanone, 1,2,2,5,5-pentamethylcyclopentanol;
1-methylene-2,2,5,5-tetramethylcyclopentane; 2,2,5,5-tetra-methylcyclopentylmethanol; and 2,2,5,5-tetramethylcyclopen-tanecarboxylic acid.

Description

L

This is a divisional application of Canadian application No. 455,761 filed June 4, 1984 which relates to novel gem-diaminoalkanes, their preparation and their use as sweeteners.
The search for new sweeteners which are many times sweeter than sucrose and which are'also non-caloric and non-cariogenic has been a continuing search for many years. In particular the search has been to provide new sweeteners which are not only many times sweeter than sucro~e but which are free of the'bitter aftertaste particularly associated with such artificial sweeteners as saccharine, and which in addition do not break down into products which are physiologic~lly harmful and also which remain stable in aqueous systems and upon expo-sure to heat, for example during cooking.
U.S. Patent No. 3,492,131 describes certain lower alkyl esters of L-aspartyl-L-phenylalanine which are up to 200 times as sweet as sucrose and which are free of bitter aftertaste. These compounds, however, possess only limited solubility in aqueous systems and are unstahle due to diketopi-perazine formation and hydrolysis especially in the neutral toacid pH range of most food systems (the diketopiperazine forms more slowly under acidic conditions).
European Patent Application ~o. 0034876, published September 2, 1981, describes branched amides of L-aspartyl-D-~,~ amino acid dipeptides as sweeteners. These compounds are stated as being free of undesirable flavor qualities at conven-tional use levels and as having high stability both in solid ; form and in aqueous systems. The breakdown products thereof are not given so that the final possible uses of these sweet-eners are not yet known.

The parent application proposed a new series of , ~3~

derivatives of gem-diaminoalkanes of the formula:

H3N+ - CH - CO - NH - C - NII - CO - R" (I) (f ~)n R' wherein n is 0 or l, R is lower alkyl (substituted or unsubstituted), R' is H or lower alkyl, and R" is a branched alkyl, alkyl-cycloalkyl, cycloalkyl, polycycloalkyl (poly = 2 or more, fused or non-fused), phenyl or alkyl-substituted phenyl, and physiologically acceptable cationic and acid addition salts thereof, which possess a high degree of sweet-ness, without undesirable flavor notes, and in addition possess significant advantages as compared to known sweeteners.
~; In particular, these new gem-diaminoalkane derived sweeteners possess a high degree of stability in all types of aqueous systems and even upon cooking, and break down only into compounds which are physiologically compatible with the body.
; 20 In the above formula ~I), R is lower alkyl, such as methyl, ethyl, n-propyl, isopropyl, isobutyl, etc~, or substi-tuted lowex alkyl, such as hydroxymethyl, methyl thiomethyl, etc.' R' is H or lower alkyl, preferably methyl or ethyl, and R" is a branched alkyl group, preferably of 3-lO carbon atoms, e.g.

- C ~ R2 where Rl is H or lower alkyl, preferably methyl or ethyl, R2 and R3 are H or lower alkyl such as methyl, ethyl, n-propyl, isopropyl, isobutyl, t-butyl, etc.' R" may also be allcylcyclo-al~yl or dicycloalkyl, i.e.

~1~3~

R4 ~5 ~8 ~ c~l2~n ( (CI12)n ' where R4 and R8 are H or methyl, R5, R6 and R7 are H or lower alkyl, preferably methyl, ethyl or isopropyl, and n and n~ =
0, 1 or 2, R" may also be cycloalkyl, preferably of 3-7 carbon atoms, most preferably of 5-6 carbon atoms, or substituted cycloalkyl, the cycloalkyl group most preferably being of 4-6 carbon atoms and substituted by 1-4 alkyl groups, e.g.

/
Rg / C \

-C \ ~ 2)x /c \
R12 R~

; where Rg is H or methyl, Rlo, Rl1, R12 and R13 are H or lower alkyl, such as methyl, ethyl, isopropyl, isobutyl, t-butyl, etc., and x = 0, 1, 2 or 3, R" may also be h~terocycloalkyl or alkyl-substituted heterocycloalkyl, where the heteroatom is oxygen, nltrogen or sulfur and the preferred ring size is 4-7 atoms, e.g.

¦ R 15 R 16 . ~ \C/

(CH2)y -C C ~ CH2)Z

~ / \

~3~$~

where R14 is H or methyl, R15, R16, R17 and R18 are H or lower alkyl, such as methyl, ethyl, isopropyl, isobutyl, t-butyl, etc., y and z = O, ~ or 2, and Q is-O, .NH, S, SO or S02, R" may also be polycycloalkyl, such as norbornyl, -fenchyl, C~3 : or-l- or-2-adamantyl : ~ ~ ~

or phenyl~or alkyl-su~stituted~pherly-l, the alky~ yroup~s) preferably being lower alkyl, e.g.
Rlg ~ :: >=, where R19 and R20 are H, lower alkyl such as rnethyl, ethyl, 3n isopropyl, etc.

~2;:~8~

The preferred sweeteners are those wherein R" is cycloalkyl or alkyl s~bstituted cycloalkyl substi-tuted by 1-5 alkyl groups, -the alXyl preferably being lower alkyl.
Exa~ples of the most valuable compourld3 of the formula (I) are those wherein Rl' is:
tetramethylcyclopentyl, ; cyclopentyl, methylcyclohexyl, dicyclopropylmethyl, dimethylcyclopentyl, trimethylcyclopentyl, ~imethylcyclohexyl, trimethylcyclohe~yl, t-butylcyclohexyl.
The invention of the parent application also provides compositions for sweetening edible materials comprising a : sweetening effective amount of a compound of the formula (I) along with a nontoxic carrier, for example lactose, dextrose or sucrose, as well as sweetened edible compositions which . 20 comprise an edible material plus a sweetening effective amount of a compound of the formula ~I) .
The invention of the parent application further provides compositions for sweetening edible materials compri-sing a sweetening amount of a mixture of a compound of the ~: formula (I) with another artificial sweetener such as saccha-:
rine or a physiologically acceptable salt thereof, cyclamate ::~ or a physiological.ly compatible salt thereof, aspartame, acesulfame-K or thaumatin.
The physiologically acceptable salts of saccharine and of cyclama-te are the salts thereof with physiolog.ically acceptable cations such as sodium, potassium, calcillm or ammonium.
The physiologically acceptable cationic salts of the compounds of formula (I) are the salts thereof formed by neutralization of the carboxylic acid group of the compounds of formula (I) by bases of physiologically acceptable metals, such as sodium and potassium, ammonia and amines such as N-methyl glucamine and ethanol-amine.
The physiologically acceptable acid addition salts are those formed of physiologically acceptable acids such as acetic acid, benzoic acid, hydrobromic acid, hydrochloric acid, citric acid, fumaric acid, gluconic acid, lactic acid, maleic acld, malic acid, nitric, phosphoric, saccharic, succinic and tartaric acid.
The present divisional application is directed to novel intermediate compounds useful in the preparation of a specific gem-diaminoalkane of the formule (I), i.e.,N-(L-aspartyl)-N'-~2,2,5,5-tetramethylcyclopentanecarbonyl)-R-l,l-diaminoethane. These intermediate compounds are thylcyclopentanol, l-methylene-2,2,5,5-tetramethylcyclopen-tane, 2,2,5,5-tetramethylcyclopentylmethanol, and 2,2/S,5-tetramethylcyclopentanecarboxylic acid~
The following is a general scheme for the production ol the gem-diaminoalkane sweetener~ of the formula (I3:

:~;
~:

~3~

X-NH-CH-COOH 1. Activation> X-NH-CH-CO-NH-C COOZ
(C 2)r~ ~ (CH2)n R~
¦ 2. H2~-C-COO~ l COOY I COOY
R' (II) (III) (IV) Deprotection ( -Z) R~ R
X-NH-fH-CO-~H-f-CONH2 ~1 Activation X-~H-fH-CO-NH-f-COOH
(fH2)n R ~f 2)n COOY COOY
; (VI) (V) Rearrangement ~ R R
X-~H-CH-CO-~H-I-NH3 A R''COC1/base> X-~H-fH-CO-~H-f-NH-COR"
' IH2)n Ri 'f 2)n COOY /COOY
(VII) / (VIII) : 20 ~ eprotect ~ (I) :~ Scheme 1 The sweeteners (I) may be synthesized by the general route outlined in Scheme 1 above. In this route, a protected aminomalonic acid derivative (II, n = 0) or aspartic acid derivative (II, n = 1) is employed as starting rnaterial. The amine protecting group X may be any of the groups which are commonly employed for this purpose, as described by Bodanszky et al, in "Peptide Synthesis", Wiley-Interscience, New York (1976), pp. 18 48. Particularly preferred groups are benzyloxycarbonyl, t-butylo~ycarbonyl and 9-fluorenylmethyl-~3~

oxycarbonyl. The carboxyl-protecting group, Y, may be any of the groups which are normally used for this purpose, as described by Bodanszky et al. in "Peptide Synthesis", pp.
49-57. Preferred groups include benzyl, t-butyl or lower alkyl, such as methyl or ethyl. ~ particularly preferred corr~ination of protecting groups for the protection of the amine and carboxyl functions in (II) is benzyloxycarbonyl/
benzyl, since these groups may be removed selectively by hydrogen-olysis under mild conditions. When use of this deprotection method is precluded, for example in compounds containing sulfur, the combination of t-butyloxycarbonyl/
t-butyl, which are removable under acidic conditions, may be employed. Alternatively, the combination of 9-fluorenyl~
methyloxycarbonyl/benzyl or alkyl, which are cleaved simultaneously under basic conditions, may be used.
In the first step of the synthesis, the carboxyl component (II) is activated by a suitable method and coupled with an amino acid derivative (III). Any of the methods commonly used for the formation of amide bonds, as described by Bodanszky et al. in "Peptide Synthesis", pp. 85-128, may be used. However, a particularly preferred method is the mixed carboxylic-carbonic anhydride method, using isobutyl or ethyl chloroformate. The amino acid derivative (III) may be a free amino acid (i.e. Z = H) or may be a derivative in which the carbox~1 group is protected by a suitable protecting group Z which may be cleaved selectively in the presence of the other protecting groups, X and Y, in the protected deriva-tive (IV). A particularly preferred method of protection involved -the use of trialkylsilyl esters (i.e. Z - trialkyl-silyl), such as trimethylsilyl~ since these groups may be removed under aqueous acidic conditions. In this case, ~3~

removal of this protecting group may be effected during the work-up procedure, following the coupling of the carboxyl component (II) with the amino acid derivative (III), so that the partially deprotected product (IV) may be isolated di-rectly, without the necessity for a separate deprotection step. The product (IV) may be purified, if necessary, by conventional methods, such as recrystallization or column chromatography.
The key step in the synthesis of the novel, gem-diaminoalkane-derived sweeteners of the invention involves the transformation of the carboxylic acid derivatives (V) to the monoacylated gem-diaminoalkane salts (VII). This may be accomplished by one of several standard methods, such as the Curtius rearrangement or the Schmidt rearrangement. Alter-natively, the carboxylic acid derivative may first be trans-formed to the amide (VI) by acti~ation and condensation with ammonia. In a preferred method, the dipeptide (V) is activa~
ted via the mixed carboxylic-carbonic anhydride at low tempe-rature and condensed with the ammonium salt of l-hydroxyben-zotriazole. The amide (VI) may then be transformed to thegem-diaminoalkane salt (VII~ via the Hofmann rearrangement using sodium hypobromite. Alternatively, a preferred reagent for effecting this transformation is iodobenzene bis (tri-fluoroacetate), as descxibed by Radhakrishna et al., J. Org.
Chem. 44, 1746-1747 (1979).
The monoacylated gem-diaminoalkane salt (VII) is acylated by the appropriate acid chloride R"COC1 under basic ; conditions to provide the protected sweetener derivative (VIII).
~his reaction may be carried out under a variety of conditions, for example in a mixture of an organic solvent such as aceto-nitrile and aqueous potassium bicarbonate. Alternatlvely, ~3~

the coupling reaction may be carried out in an anhydrous organic solvent, such as tetrahydrofuran, in the presence of an equivalent of an organic base such as triethylarnine. The protected sweetener derivative (VIII) may be purified if required by conventional techniques, such as recrystalliza-tion or column chromatography.
In the final step of the synthesis, the protected sweetener (VIII) is deprotected under appropriate conditions to give the final gem-diaminoalkane-derived sweetener (I).
The conditions used for deprotection will depend upon the nature of the protecting groups used, i. 2. X and Y. As outlined above, when the preferred combination of benzyloxy-carbonyl and benzyl protecting groups is used, deprotection may be effected by hydrogenolysis at pressures of 1-10 atmos pheres in the presence of a noble metal catalyst such as palladium or platinum. In the event that the molecule contains sulfur and an alternate combination of p~otecting groups is used, hydrolytic methods must be used for their cleavage.
For example, if 9-fluorenylmethyloxycarbonyl and benzyl are used, the protecting groups may be cleaved simultaneously by basic hydrolysis, for example by treatment with excess potas-sium hydroxide in anhydrous methanol. While the final sweet-ener (I), obtained by these techniques, may be substantially pure, further purification, for example by recrystallization, is desirable.
In an al~ernate route (Scheme 2), the gem-diamino-alkane derivatives (I) may be prepared by first treating the amino acid derivative (III) with the appropriate acid chloride RCOCl. As described above, the amino acid derivative (III) may be a free amino acid (i.e. Z = F~) or may be ~3~

R R
ZOOC-C-N~I2 + R"COCl Base~ ZOOC-C-NH-COR"
R' R' (III) (IX) ¦ Depro~ec~ion i 1. Activation H2~-CO-C-~rI-COR~ -- HOOC-C~ COR"

2. ~I
R' 3 (XI ) (X,~
Rearrangement R ~ (fH2)~r--COOY R
+ I X-NH-CH-COOH (II) A H3N - IC-NH-cOR" ~ X-NH-fH-CO-NH-f-~I-COR"
R ' Condensation (CH2)N R' (XII)~ COOY
(VIII~
COOH Deprotection (IH2)n (I) fH c;o ~ X
\C /
0 (XIII) , ~ Scheme ~
:~ carboxyl-protected. A preferred carboxyl-protecting group is the trialkylsilyl ester group, such as the trimethylsilyl : group, which may be removed by aqueous acid, as described above. The next step, the key transformation of the acylated amino acid derivative (X) to the monoacylated gem-diamino-30 alkane salt (XII), may be accompl.ished by any of the methods discussed above, although the preferred route involves -transformation to the primary amide derivative (XI) and rearrangement using iodobenzene bis(trifluoroacetate). Con-densation of this diaminoalkane derivative (XII) with a protected aminomalonic acid or aspartic acid derivative (II) by tec~miques described above results in the same, fully protected sweetener derivative ~VIII) as that obtained in Scheme 1. Deprotection and purification may be effected by the same techniques as those described previously.
In a preferred method, the amine salt (XII) is acylated by a cyclic derivative of aminomalonic acid or aspartic acid, such as the N-carboxyanhydride or the thio-carhoxyanhydride (XIII, X = O or S). Use of these interme-diates avoid the need for protection of the aminomalonic or aspartic acid residues. In yet another variation, partially protected aspartic acid derivatives, such as ~-formyl aspartic anhydride, may also be used to acylate the amine salt (XII).
In this case, cleavage of the formyl protecting group may be effected by treatment with aqueous acid.
The carboxylic acid chlorides R"COCl used for the synthesis of these sweeteners may be commercially available or may be synthesized by standard techniques. A preferred route for the synthesis of the carboxylic acid precursors utilizes ketones as the starting materials, as described by Martin, ~y~ (1979), 633-664 and is outlined in Scheme 3. By this route, the ketone (XIV) is first converted to the alXene (XVI). Several possible methods may be used for this purpose.
Use of the Wittig method, involving treatment of the ketone with methylene triphenylphosphorane, results in the alkene directly. An alternate procedure, useful for ketones in which R21 and R22 contain tertiary carbon atoms adjacent to the ketone, ~3~

~C=o ~22 (XIV) ~
\-Ph3P=cH2 ~¦, CH3MgBr <~ SOC12 ;21 C=CH
R22 OH pyridineR22 (XV) (XVI) ¦ 1. BH3 ~ ~. NaOH/H202 R21 Oxidation R21 ~CH--C2H ~ ~CH-CH20H

: (XVIII) (~II) Scheme 3 ~:~ involves the two-step treatment of thé ketone with methyl magnesium bromide, to give the methyl carbinol (XV), followed :~ by dehydration with thionyl chloride in the presence of excess pyridine. The alkene (XVI) is next transformed to the alcohol (XVII) by hydroboration ~treatment with borane, followed by aqueous sodium hydroxide and hydrogen peroxide). Finally, the alcohol is oxidized to the carboxylic acid (XVIII) by one of many standard techniques, such as treatment with sodium dichromate in concentrated sulfuric acid. The carboxylic acid may be transformed to the acid chloride form required for the synthesis described above by one of several standarcl techniques, such as treat~ent with thionyl chloride or phosphorus penta-chloride.
The requigite ketone precursors for the carboxylic ac.ids required for the invention are either commercia:lly available, known in the prior art, or may be prepared by - 13 ~

~:3~

known methods. For example, the cycloalkanones and heterocy-cloalkanones of the general formula (XIX) and (XX), ~here 10 R13, "~, ~, CH 2 ) z (XIX) (XX) R15-R18, x, y, z and Q are as defined above, may be prepared by alkylation of the corresponding ketones in which Rlo-R13 and R15-R18 are hydroyen. Alkylation may be effected by treatment with a strong base, such as sodium hydride, sodium amide or sodium amylate, in the presence of an alkylating agent such as an alkyl halide or dialkyl sulfate.
The methods described above are provided for the purpose of illustrating the invention but in no way are meant to limit the scope of the invention. Alternate methods, obvious to those skilled in the art, may be substituted at any stage of the syntheses described.
~; The degree of sweetness of the compounds of the formula (I) is dependent on a number o~ factors. The most important of these is the nature of the acylating group, R", derived from the carboxylic acid precursor~ In general, branched, bulky, hydrophobic groups are preferred, but, more specifically, cycloalkyl and heterocycloalkyl yroups contai-ning alkyl substituent groups adjacent to the carbonyl group are preferred. Thus, for example, a cyclopentyl group con-taining geminal dimethyl substituents in the 2- and 5-positions on the ring is particularly preferred (see l'able 1).

Substitution in the 3- and 4- positions on the ring does not yenerally lead to high levels of sweetness.

-- 1~ --~38~5~

Sweetness Data for Gem-Diaminoalkane Derived Sweeteners R
H3N - Cll - CO - NH - C - ~1 - CO - R"
Cll2 R' R - R' R" Sweetnessb_ ~H3 ~ C(C'~3)3 75 100 IC(c1~3)2 50-75 CH2-CH(CH3)2 ~I C
" " 3 ~ 10-25 '~ ~
C~ ~ 500-700 , " " ~ 5-20 " ll ~ 50-75 " " H3 ~ 35-50 ~13C ~
150~20t) f~~
" " ~ 150-2t~t~
~I3)3 ~

~2~

TABLE 1 (Continued) R R' R" Sweetness _ _ _ _ , H3C ~
" " ~ 300-400 1 0 ~
Il , ~ 800-~ oon H3C CH c " I~ " 600-800 CH2CH3 " ~ 200-300 CH2OH '` 400-500

3 X 3 CH3 " ~ S 150-200 ~13C C~13 - " " ~ ~5-100 ~ 3 ~ 50-100 Sweeteners derived from L-aspartyl-R-gem-diaminoalkarles, unless otherwise noted. bRelative to sucrose. CDerived from L-aspartyl-S-l,l-diaminoethane.

A further aspect of the invention relates to the stereo-chemistry of the two primary chiral centers. The chirality of the first center (aspartic acid or aminomalonic acid) is important. In the case of aspartic acid-containing sweeteners (i.e. I, n = 1~, it is preferred that the amino acid of the L-configuration be used, although use of racemic (i.e. D,L-) aspartic acid still results in useful sweeteners.
However, incorporation of a D-aspartic acid moiety does not lead to useful sweeteners. In the case of aminomalonic acid-containing sweeteners (i.e. I, n = 0), the R-enantiomer is preferred, although the racemic, R,S-mixture is most often used in order to avoid the difficult problem of resolution of diastereomers.
The chemistry at the second chiral center (i.e. the gem-diaminoalkane moiety) in the sweeteners is less critical.
Thus, while diaminoalkanes of the R-configuration (i.e. those derived from the D-amino acid amides when the sweeteners are ; synthesized via Scheme 1, or from L-amino acid amides when prepared via Scheme 2) are ~enerally preferred, S-diamino-alkanes may also be used with only minimal loss of sweetness.
This result is surprising since in other classes of amino acid-derived sweeteners known in the prior art, chirality at the second center is extremely critical. L-Aspartyl-L-phenylalani-ne methyl ester, for example, is extremely sweet, while L-aspartyl-D-phenylalanine methyl ester is bitter. This novel discovery is of considerable economic signi-Eicance since the sweeteners of the formula (I) may be derived from racemic amino acids, such as alanine, serine, etc., which are much cheaper than their optically pure counterparts. The sweete-ners of the formula (I) may also be derived from amino acidswhich are achiral, such as ~-aminoisobutyric acid (I, R = R' =
C~3, or from unnatural, optically active amino acids, such as ~3~

~-methylserine (I, R = CH20H, R' = C~3).
As noted above, a most important, novel aspect of the invention relates -to the use of gem-diaminoalkane derivatives for the preparation of useful sweeteners. However, the placement of this diaminoalkane residue in the molecules is also extremely critical. In other words, if the other amide bond in the rnolecule is reversed to give structures of the type:

R
H3N -- fH -- NH - CO -- C - NH - CO - R"

(fl~2~ n CO
the compounds are not useful as sweeteners.
~ Thus, the invention is characterized by a number of 1~ important features, which include the nature of the substituent group, R", the inclusion of -the diaminoalkane moiety and its position in the molecule and also the stereochemistry of the chlral centers in the molecule. The proper combination of these features provides for optimum sweetness in these mole-cules.
Whlle the degree of sweetness of the compounds of ~; formula (I), as compared to sucrose on a weight to weight basis varies considerably depending upon the substituent R", all of these compounds provide considerable advantages as sweetening agents due to the fact that the breakdown products thereof are all compatible to the human physiology, e.g.

acetic acid and arnino acids, and further due to the high stability thereof in both solid form and in solution form.
Still further, the compounds of the formula ~I) when used with other sweeteners such as saccharine help to avoid the ~38~

undesired bitter aftertaste of the other sweete~ers.
Consequently, the compounds of the formula (I) canbe used for the sweetening of edible materials of all types, such as foods, prepared food items, chewing gum, beverages, etc.
The compounds of the formula (I) can be prepared in many forms suitable for use as sweetening agents, such as powders, tablets, granules, solutio~s, suspensions, syrups, etc.
Thus, sweetened edible compositions may comprise an edible material and a sweetening amount of the compound of formula (I) either alone or in combination with another sweetening agent such as saccharine. There is actually no limitation as to the edible materials that can be sweetened with such compositions, including fruits, vegetables, juices, meats, eg~ products, gelatins, jam, jellies, preser~es, milk products such as ice cream, sherbert, syrups, beverages such : ~
as coffee, tea, carbonated soft drinks, non-carbonated soft drinks, wines, liquors, confections such as candies, etc.
The compounds of the formula (I), in addition to providing a high degree of sweetness, are of particular inte-rest because these compounds are actually amino acid deriva-~`~ tives rather than peptides. As a ~onsequence, the degree of safety provided ~y the compounds of the formula (I) is much greater than with any of the known synthetic sweeteners. Thus, ; the compounds of the formula (I) are highly stable, do not form diketopiperazines, and the safety of these compounds is implicit in the fact that the compounds are formed from natural amino acids and are formed into stable molecules.
30 Any possible breakdown products of the compounds of the formula (I) are likely to be either easily metabolized or in ~3~5~

the pathway of normal ingredients of intermediary metabolism.
Still further, the compounds can be used over a much wider p~ range than compounds such as L-aspartyl-L-phenyl-alanine methyl ester and related dipeptide sweeteners and the compounds also remain stable under conditions of high tempe-rature.
The compounds of the formula (I) are non-caloric in the amount which would be used for sweetening purposes, are non-cariogenic and are safe.
The following non-limiting examples are given to further illustrate the inventions of both the parent and present divisional applications.

~-(L-Aspartyl)-N'-Cyclopentanecarbonyl-R-l,l-Diaminoethane [Formula I, R - C~3, R' = H, R" = cyclopentyl]
A. D-Alanine (20 g, 0.225 mole) was dissolved in dimethylformamide (400 ml), treated with chlorotrimethylsilane (26.8 g, 0.250 mole) and the mixture stirred at room tempera-ture until a homogeneous solution was obtained (approx. 45 minutes)O Meanwhile, ~-benzyloxycarbonyl-~-benzyl-L-aspartic acid (72 g, 0.200 mole) was dis~solved in a 1:1 mixture of - dimethylformamide and tetrahydrofuran (880 ml), cooled to a ~; -15C and treated with ~-methylmorpholine (2204 ml, 0.200 `~ mole~ and isobutyl chloroformate (26.2 ml, 0.200 mole). After 8 minutesl activation at -15C the precooled solution of D-alanine silyl ester from above was added, followed by the dropwise addition of ~-methylmorpholine (22.4 ml, 0.200 mole), ensuring that the temperature of the reaction mixture was maint.ained at -15~. The solution was allowed to warm to room temperature slowly and stirred for several hours before acidi~ying to pH 1-2 (with cooling) using aqueous hydrochloric ~3~3Q~i~

acid. Chloroform was added, the phases separated and the aqueous layer re-extracted with chloroform. The combined ; organic extracts were washed with 1 N hydrochloric acid (3 x), saturated aqueous sodium chloride and dr:ied (MgSO4). After evaporation of the solvent under reduced pressure, the oily residue was triturated with ether. The resulting solid was filtered and dried in vacuo to give N~-benzyloxycarbonyl-~-benzyl-L-aspartyl-D-alanine (67 g), m.p. 158-159~C, which was homogeneous by TLC.
B. The product from Part A (64 g, 0.150 mole) was dissolved in dimethylformamide (600 ml), cooled to -15~C and treated with N-methylmorpholine (16.5 ml, 0.150 mole) and isobutyl chloroformate (19.5 ml, 0.150 mole). After 5 minutes t activation at -lSC, l-hydroxybenzotriazole ammonium salt (34 g, 0.225 mole) was added as a solid, and the mixture stirred at -15C for 15 minutes. After warming slowly to room temperature over 4 hours, chloroform and water were added, the phases separated and the aqueous phase re-extracted with chloroform. The combined organic extracts were washed with 1 N hydrochloric acid (3 x), saturated aqueous sodium bicarbo-nate (3 x ), saturated sodium chloride and dried (MgS04). The solvent was evaporated under reduced pressure and the solid residue recrystalllzed from ethyl acetate-hexanes to give N~ benzyloxycarbonyl-~-benzyl-L-aspartyl-D-alanyl amide ~50 ~), m.p. 170-171C, which was homogeneous by TLC.
C. q`he product from Part B ~2.2 g 5.1 mmole) was dissolved in acetonitrile (50 ml) and the solution diluted with an equal volume of water. Iodobenzene bis(trifluoroacetate) (2.4 g, 5.6 mmole) was then added and the reaction mixture stirred at room temperature for 4 hours ~clear solution after approximately 2 hours). The solution was evaporatecl and the :~X3~

residue redlssolved in aqueous ~Cl and lyophilized, to give N-(N~-benzyloxycarbonyl-~-benzyl-L-aspartyl~-R--l,l-diamino-ethane hydrochloride in quantitative yield, which was used without further purification.
. The product from Part C, (2.95 g, 5.1 mmole) was dissolved in tetrahydrofuran (50 ml), cyclopentanecarbonyl chloride (1.5 g, 10.6 mmole) added, followed by potassium bicarbonate (2.5 g, 25 mmole) and water (50 ml) and the mixture stirred at room temperature. After 2.5 hours, a clear solution was obtained but TLC indicated that reaction was incomplete and second portions of cyclopentanecarbonyl chloride (1.5 g, 10.6 mmole3 and potassium bicarbonate (2 g, 20 mmole) were therefore added. The process was repeated 15 minutes later. After 20 minutes, ethyl acetat0 and water were added, the phases separated and the aqueous phase extracted with ethyl acetate. The combined organic phases were washed with lM sodium bicarbonate (2 x), 2N hydrochloric acid (3 x), again with lM sodium bicarbonate (2 x) and finally with satu-rated sodium chloride and dried (MgS04). The solution was filtered, evaporated under reduced pressure and the residue triturated with ether to provide ~-(N~-benzyloxycarbonyl-~-benzyl-L-aspartyl)-N'-cyclopentanecarbonyl-R-l,l-diaminoethane (1.5 g) as a crystalline solid which was homogeneous by TLC.
I'he nmr spectrum of the product was consistent with the assi-gned structure.
E. The product from Part D tl.5 g, 3.03 mmole) was hydrogenated in glacial acetic acid (50 ml) over 10% palladium on carbon (approx. 0.2 g) at 40 p.s.i. overnight. The catalyst was filtered, washed with glacial acetic acid and the filtrate lyophilized. The resultant powder was redissolved in water and relyophilized (twice) to give N-(L-aspartyl)-N'-cyclo-~3~

pentanecarbonyl~ diaminoethane in ~uantitative yield, m.p. 220C dec.
Sweetness = 75-100 x sucrose N-~L-Aspartyl)-~'-Trimethylacetyl-R-l,l-Diaminoethane [Formula I, R = C~3, ~' = H, R" = C(CH3)3~
; A. N-(N~-Benzyloxycarbonyl-~-ben~yl-L-aspartyl)-R-l, l-diaminoethane hydrochloride (5.2 g, 12 mmole), prepared as described in Example 1, Part C, was suspended in water (50 ml) at room temperature. Potassium bicarbonate (6 g, 60 mmole) was added, followed by pivaloyl chloride (1.5 ml, 12 mmole) dissolved in acetonitrile (50 ml). The homogeneous reaction mixture was stirred at room ternperature for 3 hours when TLC
showed incomplete reaction. Further aliquots of the acid chloride ~0.8 ml) and potassium bicarbonate ~5 g) were there-fore added and the reaction mixture stirred for a further 1 hour. The solution was then diluted with ethyl acetate ~500 ml) and extracted with lN hydrochloric acid ~3 x), saturated aqueous sodium bicarbonate ~3 x) and saturated sodium chloride ~1 x). The organic phase was dried (MgS04), filtered and evaporated to dryness under reduced pressure. The residue was crystallized from ethyl acetate/hexanes to provide ~ N~-benzyloxycarbonyl-~~benzyl-L-aspartyl-N'-trimethyl-acetyl-R-l,l-diaminoethane ~4.8 g) which was homogeneous by LC, m.p. 66 69C. The nmr spectrum of the product was con-sistent with the assigned structure.
B. The product from Part A (4 g) was dissolved in glacial acetic acid (150 ml) and hydrogenated overnight at 40 p.s.i. over 10% palladium on carbon (approx. 0.5 g). The catalyst was filtered, washed with glacial acetic acid and the filtrate lyophilized. The resultant powcler was redlssolved ~3~

in water and relyophilized (twice) to give N-(L-aspartyl)-Nt-trimethylacetyl-R-l,l-diaminoethane in quantitative yield, m.p. 150C.
Sweetness = 75-100 x sucrose EXAMæLE 3 N (I,Aspartyl)-N'-Cyclohexanecarbonyl-R~ Diamimoethane ~Formula I, R = CH3, R' = H, R" = cyclohexyl]
A. N-(N~-Benzyloxycarbonyl-~-benzyl-L-aspartyl)-R-l, l-diaminoethane hydrochloride (Example 1, Part C) (5.2 g, 12 mmole) was treated with cyclohexanecarbonyl chloride (1.75 ml, 12 mmole) and potassium bicarbonate (6 g, 60 mmole), as described in Exarnple 2, Part A. A second aliquot oE the acid chloride (0.8 ml) and potassium bicarbonate (5 g) were added after 3 hours. The product precipitated and was collected by filtration, dried, triturated with hexane and dried in vacuo to give N-(N~-benzyloxycarbonyl-~-benzyl-L-aspartyl)-NI-cyclo-hexanecarbonyl-R-l,l-diaminoethane (5.8 g) which was homogen-eous by TLC, m.p. 178-180C. The nmr spectrum of the product was consistent with the assigned structure.
B. The product from Part A (S g) was hydrogenated ; in the usual manner in glacial acetic acid (150 ml) over ~; palladium on carbon. After lyophilization several tlmes from water, ~-(L,aspartyl)-N'-cyclohexanecarbonyl-R-l,l-diamino-ethane was obtained in quantitative yield.
Sweetness = 50-75 x sucrose N-(L-Aspartyl)-N'-Benzoyl-R-l,l-Diaminoethane [Formula I, R = CH3, R' = H, R" = phenyl]
A. N-(N~-Benzyloxycarbonyl-~-benzyl-L-aspartyl)-R-l, l-diaminoethane hydrochloride (Example 1, Part C) (5.2 g, 12 mmole) was dissolved in tetrahydrofuran (100 ml) at room ~L~3B~

temperature. Triethylamine (1.6~ ml, 12 mmole~ was added, ~ollowed by benzoyl chloride (1.62 g, 12 mmole) and a second equivalent of triethylamine (1.68 ml) and the mixture stirred at room temperature. After 3 hours reaction was incomple-te by TLC and another aliquot of triethylamine (1.15 rnl) was therefore added and the mixture stirred at room temperature for a further 1 hour. The reaction mixture was then evapo-rated to dryness, the residue redissolved in ethyl acetate (approx. 1000 ml), and extracted in the usual manner. (This procedure proved to be difficult because of the formation o~
emulsions and precipitates). After drying (MgSO~) the organic phase was evaporated to dryness under reduced pressure and the residue crystallized ~rom ethyl acetate/hexanes -to give N-(N~-benzyloxycarbonyl-~-benzyl-L-aspartyl)-N'-benzoyl-R-l, l-diaminoethane (1.5 g) which was homogeneous by TLC. The nmr spectrum of the product was consistent with the assigned ~; structure.
B. The product ~rom Part A (1 g) was hydrogenated in the usual manner in glacial acetic acid (50 ml) over 10%
~ 20 palladium on carbon. Lyophilization several times ~rom water ; gave N-(L-aspartyl)-N'-benzoyl-R-l,l-diaminoethane in quanti-tative yield.
Sweetness = 5-20 x sucrose.

(N-(L-As~artyl)-N'-(2-Norbornanecarbonyl)-R-l,l-Diaminoethane [Formula I, R = CH3, R' = H, R" = 2 norbornyl]
A. N~-Benzyloxycarbonyl-~-benzyl-L-aspartyl-D~alanyl amide (Example 1, Part B) ~10.7 g, 25 mmole) was suspended in 1:1 acetonitrile:water (200 ml) and iodobenzene bis (trifluo-roacetate) (12 9, 28 mmole) added. The reaction mixture was stirred at room temperature ~or 4 hours (a homogeneous ~2~

solution was obtained after 2 hours) and then trea-ted with norbornane-2-carboxyl chloride (10 g, 63 mmole) and potassium bicarbonate (12 g, 120 mmole). After stirring for 2 hours at room temperature, TLC showed complete reaction and the product was extracted and worked up in the usual manner. After drying (MgS04), the organic phase was evaporatecl to dryness under reduced pressure and the residue crystallized from ethyl acetate~hexanes to give N-(N~-benzyloxycarbonyl-~-benzyl-L-aspartyl)-N1-(2-norbornanecarbonyl)-R-l,l-diatninoethane (10.3 g), m~p. 127-130C, which was homogeneous by TLC. The nmr spectrum of the product was consistent with the assigned structure.
B. ~he product from Part A (9 g) was hydrogenated in the usual manner in glacial acetic acid (200 ml) over 10%
palladium on carbon. After lyophilization several times from water, ~-(L-aspartyl)~ (2-norbornanecarbonyl)-R-l, l-diaminoethane was obtained in quantitative yield, m.p.
177-178C.
Sweetness = 75-100 x sucrose, N-(L-Aspa ~ necarbonyl)=R-l,l-Diaminoethane [Formula I, R = CH3, R' = H, R" = l-adamantyl]
A. N~-Benzyloxycarbonyl-~-benzyl-L-aspartyl-D-alanyl amide (Example 1, Part B) (8.54 g, 20 mmole) was treated with iodobenzene bis~trifluoroacetate) using the procedure described in Example 5, Part A. The resulting solution was treated with l-adamantanecarbonyl chloride (6 g, 30 mmole) and potassium bicarbonate (15 g, 150 mmole) and stirred at room temperature for 4 hours. After the usual work-up, the crude product was obtained as an oil which was purified by chromatogl-aphy on silica gel, eluting with chloroform:hexane (3:1, v~v)~

~3~
N ~N~-benzyloxycarbonyl-~-benzyl-L-aspartyl)-N~ -adamantane-carbonyl)-R-l,l-didminoethane was obtained as an oil (2.5 g) which was homogeneous by TLC. The nmr spectrum of the product was consistent with the assigned structure.
B. The product from Part A (2.0 g) was hydrogenated in the usual manner in glacial acetic (50 ml) over 10%
palladium on carbon. After lyophilization several times from water, N-(L-aspartyl)-N'-(l-adamantanecarbonyl)-R-l,l-diamino-ethane was obtained in quantitative yield, m.p. 174-175C.
Sweetness = 5-15 x sucrose.
X~MPLE 7 N-(L-Aspartyl)-N~-(2-Methylcyclohexanecarbonyl)-R-l,l-Diaminoethane [Formula I, R = CH3, Rl - H, R" = 2-methylcyclohexyl]
A. Ethyl 2-methylcyclohexanecarboxylate (50 g, 0.295 mmole) was added to a solution of potassiu~ hydroxide (27 g, 0.48 mole) in anhydrous methanol (300 ml). The mixture was stirred overnight at room temperature and then evaporated -~ ~ to dryness under reduced pressure. The residue was redissol-ved in water and the solution extracted with ether (3 x 200 ml), then acidified (pH <2), and re-extracted with ether (3 x 200 ml).
The final, combined organic extracts were washed with water, dried (MgSO4) and evaporated under reduced pressure to yield 2-methylcyclohexanecarboxylic acid. The crude product was converted to the acid chloride by treatment with excess :
thionyl chloride (100 ml) at room temperature for 30 minutes.
The thionyl chloride was evaporated under reduced pressure and the residue distilled in vacuo to give 2-methylcyclohexane-carboxyl chloride (33 g).
B. N~-Benzyloxycarbonyl-~-benzyl-L-aspartyl-D-alanyl amide (Example 1, Part B) (10.7 g, 25 mmole) was treated with iodobenzene bis(tri~luoroacetate) using the procedure described 3~

in Example 5, Part A. The resulting solution was treated with potassium blcarbonate (20 g, 200 mmole), followed by 2-methyl-cyclohexanecarboxyl chloride (5.5 g, 35 ~nole). The reaction was followed by TLC. Addition of two further aliquots (3 g each) of the acid chloride was required for complete reaction.
The reaction mixture was worked up in the usual manner and the product crystallized from ethyl acetate~hexanes (yield = 10.0 g) and then chromatographed on silica gel, eluting with 5% metha-nol in chloroform, to give N-(N~-benzyloxycarbonyl-~-benzyl-L-aspartyl)-N'-~2-methylcyclohexanecarbonyl)-R-l,l-diaminoethane ~8.0 g) which was homogeneous by TLC. The nmr spectrum of the product was consistent with the assigned structure.
C. The product from Part ~ (8.0 g) was hydrogenated in the usual manner in glacial acetic acid (~00 ml) over 10%
palladium on carbon. After lyophilization from water several times ~-(L-aspartyl)-~'-(2-methylcyclohexanecarbonyl)-~-1, l-diaminoethane was obtained in quantitative yield, m.p.
203-204C.
Sweetness = 150-250 x sucrose.

N-(L-AsDartvl)-N'-(l--Methylc~clohexanecar~onyl)-R-l,1-Diaminoethane [Formula I, R = CH3, R' = H, R" = l-methylcyclohexyl]
A. l-Methylcyclohexanecarboxylic acid (5~ g, 350 rnmole) was converted to the acid chloride by treatment with an excess of thionyl chloride (75 ml) at room temperature. The excess thionyl chloride was evaporated under reduced pressure and the residue distilled 1 acuo to provide 1 methylcyclohexanecarboxyl chlorid~ (49 g).
B. N~-Benzyloxycarbonyl-~-benzyl-L-aspartyl-D-alanyl amide (E~ample ~1, Part B) (10.7 g,25 mmole) was treated with iodobenzene bis(trifluoroacetate) using the procedure described ~3~

in Exemple 5, Part A. The resulting solution was treated with potassium bicarbonate (20 g, 200 mmole), followed by l-methylcyclohexanecarboxyl chloride (5.5 g, 35 mmole), and two further aliquots (3 g each) over 3 hours. When reaction was complete by TLC, the reaction mixture was worked up in the usual manner and the crude product purified by chromatography on silica gel, eluting with 5% methanol in chloroform to give N-(N~-benzyloxycarbonyl-~-benzyl-L-aspartyl)-N'-(l-methyl-cyclohexanecarbonyl)-R-l,l-diaminoethane (8.2 g) which was homogeneous by TLC. The nmr spectrum of the product was consistent with the assigned structure.
C. The product from Part B (8.2 g) was hydrogenated in the usual manner in glacial acetic acid (200 ml) over 10%
palladium on carbon. After lyophilization several times from waterl N-(L-aspartyl)-N'-(1-methylcyclohexanecarbonyl)-~-1, ; l-diaminoethane was obtained in quantitative yield, m.p.
- 142-143~C.
Sweetness = 35-S0 x sucrose.
~XAMPLE 9 Nl L-Aspartyl~-N'-~l-Methylcyclopropanecarbonyl)-R
Diaminoethane ~Formula I, R = CH3, R' = H, Rl' = l-methylcyclopropyl]
A. N~-Benzyloxycarbonyl-~-benzyl-I,-aspartyl-D-alanyl amide (Rxample 8, Part B) (10.7 g, 25 mmole~ was treated with iodo~enzene bis(trifluoroacetate) using the procedure descri-bed in Example 5, Part A. The resulting solution was treated with potassium bicarbonate (20 g, 200 mmole), followed by l-methylcyclopropanecarboxyl chloride (3.65 g, 35 mmole), and two further aliquots (2 g each) over 3 hours. When reac-tion was complete by TLC the reaction mixture was worked up in the usual manner and the product crystallized from ethyl acetate~hexanes to give N-(N~-benzylo~ycarbonyl-~-benzyl-L-~ 29 -3L~3~

aspartyl~-N'-(l-methylcyclopropanecarbonyl)-R-l,l-diamino-ethane (8 g) which ~as homogeneous by TLC, m.p. 120-123C.
The nmr spectrum of the product was consistent with the assi-gnecl structure.
s. The product from Part A (7 g) was hydrogenated in the usual manner in glacial acetic acid (200 ml) over l~/o palladium on carbon~ After lyophilization from water several times N-(L-aspartyl)-N'-(l-methylcyclopropanecarbonyl)-R-l, l-diaminoethane was obtained in quantitative yield, m.p.
134-135C.
Sweetness = 10-25 x sucrose.

. . _ N-(L-Aspartyl)-N'-(2,2,4-trimethylpentanoyl)-R-l,l-Diaminoethane [Formula I, R = CH3, R' = H, R" = 1,1,3-trimethylbutyl~
A. 2,4-Dimethyl-3-pentanol (29 g, 0.25 mole), dissolved in formic acid (9~/O~ 46 g, 1 mole), was added drop-wise over one hour to a rapidly-stirred, ice-cooled mixture of formic acid (9~0, 3 ml) and concentrated sulfuric acid (270 ml).
During the addition the reaction mixture foamed vigorously and was stirred for a further one hour at 10-20C. The mixture was poured on to ice (1 kg) and the resulting solution extrac-ted with hexanes ( 3 x 200 ml). The combined organic phases were extracted with 2~ potassium hydroxide (2 x 200 ml) plus ice (S0 g~ and the aqueous extracts washed with hexanes ~100 ml).
The aqueous phase was then acidified ~pH 2) and the product extracted into hexanes (3 x 200 ml). A~ter washing with saturated sodium chloride and drying ~MgS04), the solution was evaporated under reduced pressure and the residue distilled to give 2,2,4-trimethylpentanoic acid (36 g).
B. The product from Part A (36 g) was treated with an exces.s of thionyl chloride (50 ml) and the mixture stirred at - 30 ~

3L23~@3~L

room temperature overnight. The thionyl chloride was evaporated under reduced pressure and the product distilled in vacuo to give 2,2,4-trimethylpentanoyl chloride (35 g).
CO N~-Benzyloxycarbonyl-~-benzyl-L-aspartyl-D-alanyl amide (Example 1, Part B) (10.7 g, 25 mmole~ was treated with iodobenzene bis(trifluoroacetate) using the procedure descri-bed in Example 5, Part A. The resulting solution was treated with potassium bicarbonate (20 g, 200 mmole) followed by 2,2,4-trimethylpentanoyl chloride (5.4 g, 30 mrnole) and a second portion (2.7 g, 15 mmole) after 30 minutes. The reac-tion mixture was stirred at room temperature for a further 1~5 hours, when reaction was completed by TLC. The reaction mixture was worked up in the usual manner and the product crystallized from ethyl acetate/hexanes to give N-(N~-benzyl-oxycarbonyl-~-benzyl-L-aspartyl)-N'-(2,2,4-trimethylpentanoyl)-R-l,l-diaminoethane (9.4 g), which was homogeneous by TLC, m.p. 98-101C. The nmr spectrum of the product was consistent with the assigned structure.
D. The product from Part C (9.0 g) was hydrogenated in the usual manner in glacial acetic acid (200 ml) over 10%
palladium on carbon. After lyophilization ~rom water several times N-(L-aspartyl)-N'-~2,2,4-trimethylpentanoyl)-1,1-diami-noethane was obtained in quantitative yield, m.p. 120C dec.
Sweetness = 50-75 x sucrose.

N-~L-Aspartyl)-Nl-(Trimeth~lcyclohexanecarbonyl)-R
Diaminoethane [Formula I, R = CH3, R' = H, R" = trimethylcyclohexyl]
A. A solution of 2,6-dimethylcyclohexanone (35 g, 0.277 rnole) in ether (200 ml) was cooled to -78C and treated with a 2-fold excess of a solution of methyl magnesium bromide in ether ~2.8M, 198 ml). After stirring at -78C for 3 hours , the reaction mixture was warmed to 0C and quenched carefully with water and brine. The organic layer was separated, dried (MgS04) and the ether evaporated under reduced pressure to give 1,2,6-trimethylcyclohexanol (32.2 g)~
B. A solution of 1,2,6-trimethylcyclohexanol ~32.2 g, 0.226 mole) in formic acid (9~/O~ ~6 g, 1 mole) was added drop-wise to an ice-cooled mixture o-f formic acid (90%, 3 ml) and sulfuric acid (9~/O~ 270 ml, ~.86 mole). The solution foamed vigorously during the addition. After stirring for a further one hour the reaction mixture was poured on ~o crushed ice (2 kg) and worked up as described for Example 10, Part A.
Yield of trimethylcyclohexanecarboxylic acid was 29.9 g.
C. The product from Part B (29.9 g, 0.176 mole) was added carefully to excess thionyl chloride (65 ml) and the mixture stirred at room temperature overnight. The thionyl chloride was evaporated under reduced pressure to give trimethylcyclohexanecarboxyl chloride (25.5 g) which was used without further purification.
D. N~-Benzyloxycarbonyl-~-benzyl-L-aspartyl-D-alanyl amide (Example 1, Part B) (10.7 g, 25 mmole) was treated with iodobenzene bis(trifluoroacetate) using the procedure descri-bed in Example 5, Part A. The resulting solution was treated with potassium bicarbonate (20 g, 200 mrnole~ and trimethylcy-clohe~anecarbo~yl chloride ~6.15 g, 30 r~nole), followed by a second portion (3 g) after 30 minutes. After 3 hours, when TLC showed that the reaction was complete, the reaction mix-ture was worked up in the usual manner. The product was crystallized from ethyl acetate/hexanes to give ~-(N~-benzyl-oxycarbonyl-~-benzyl-L-aspartyl)-N'-(trimethylcyclohexane-carbonyl~-R-l,l-diaminoethane (8.6 g) which was homogeneous by TI.C. I'he nrnr spectrum of the product was consistent with - 3~ -~31~

the assigned structure.
E. The product from Part D (8 g) was hydrogenated in the usual manner in glacial acetic acid (200 ml) over 10%
palladium on carbon. After lyophilization frorn water several times N-(L-aspartyl)-Nt-trimethylcyclohexanecarbonyl-R
l-diaminoethane was obtained in quantitative yield.
Sweetness = 25-50 x sucrose.
- ExAMæLE 12 N-_L-Aspartyl)-N -(l,l-Dicyclopropylacetyl)-R-l,l-D_aminoethane [Formula I, R = CH3, R' = H, R" = dicyclopropylmethyl]
A. Methyltriphenylphosphonium bromide (116 g, 0.325 mole) was suspended in dry ether (600 ml), cooled to -10C and treated with a solution of n-butyllithium in hexane (2.2M, 175 ml). The mixture was stirred for 5 minutes ~efore adding a solut:Lon of dicyclopropyl ketone (35.6 g, 0.325 mole) m ether (100 ml) which had been precooled to 0C. The suspension was allowed to warm to room temperature and then stirred for a further 2 hours. Water (1000 ml) was then added, in small portions at first, and the mixture stirred until the precipitate dissolved. The organic layer was separated, washed with water, dried (MgS04) and the solvent evaporated under reduced pressure. The residue contained a solid (triphenylphosphine oxide) which was separated from the oil, washed with a little ether and the combined etheral/
organic residues were fractionated to yield dicyclopropyl ethylene (6.5 g), b.p. 130C/760 mm, which was pure by GC.
B. Dicyclopropyl ethylene (19 g, Q.176 mole) was dissolved in dry tetrahydrofuran ~100 ml) in a three-neck flask under nitrogen and treated with borane-tetrahydrofuran in tetrahydrofuran (lM, 210 m].). ~he mixture was stirred at room temperature for 4 hours before adding cautiously - ~.23~

(foaming occurs) 3N sodium hydroxide (60 ml). After addition was complete, aqueous hydrogen peroxide (3~/O~ 60 ml) was added dropwise at a rate sufficient to maintain reflux. When addition was complete, the mixture was refluxed for a further 30 minutes, cooled and the aqueous layer saturated with sodium chloride. The layers were separated, the organic layer dried (MgS04) and evaporated under reduced pressure to give a quantitative yiel~ of 2,2-dicyclopropylethanol which was pure by GC. (The product could also be distilled, b.p.
99C~25mm).
C. The product from Part B (16 g, 0.127 mole) was dissolved in ether (300 ml) and the solution added to a mixture of potassium dichromate (60 g) dissolved in concen-trated sulfuric acid (120 ml) and ice-water (600 ml~. The reaction mixture, which ir~mediately became dark, was stirred at room temperature for one hour. The organic layer was then separated, washed with water (3 x), dried (MgS04) and the ether evaporated under reduced pressure. The residue was distilled to give l,l-dicyclopropylacetic acid (10.3 g), b.p.
130-141QC~25 mm, which was pure by GC.
D. The product from Part C (10 g, 0.071 mole) was dissolved in dry tetrahydrofuran (25 ml) and treated with e~cess thionyl chloride (25 ml). After stirring the mixture at room temperature for one hour, conversion to the acid chloride was complete by GC. The solvent and excess thionyl chloride were evaporated under reduced pressure to giYe l~l-dicyclopropylacetyl chloride in quantitative yield, which was used without further purification.

E. N~-Benzyloxycarbonyl-~-benzyl-L-aspartyl-D-alanyl amide ~Example 1, Part B) (8.54 g, 20 r~mole) was treated with iodobenzene bis~trifluoroacetate~ using the procedure described in Example S, Part A. The resultirlg solution was treated with 5~

potassium bicarbonate (16 g, 160 mmole), followed by drop-wise addition of l,l-dicyclopropylacetyl chloride (4.7 g, 30 mmole~. A precipitate formed almost immediately and the reaction mixture was stirred at room temperature for one hour.
Water and chloroform were then added, the phases separated and the organic layer washed with saturated aqueous sodium bicarbonate (3 x), 3N aqueous hydrochloric acid and saturated sodium chloride. After drying (~a2SO4) the solvent was evapo-rated under reduced pressure and the solid residue recrystal-lized from ethyl acetate to give N~ benzyloxycarbonyl-~-benzyl-L-aspartyl)-N'-(l,l-dicyclopropylacetyl)-R-l,l-diami-noethane (6.5 g), which was homogeneous by TLC, m.p. 200-201C.
The nmr spectrum of the product was consistent with the assigned structure.
F. The product from Part E (4 g) was hydrogenated in the usual manner in glacial acetic acid (200 ml) over 10%
palladium on charcoal. After lyophilization several times from water, the residue was crystallized from ethanol/water to give ~-(L-aspartyl)-N'-(l,l-dicyclopropylacetyl)-R-l,l-diami-noethane (1.0 g), m.p. 209-210C.
Sweetness = 500 - 700 x sucrose.
EX~MPLE 13 -(L-Aspa_tyl)-N'-(2,5-Dimethylcyclopentanecarbonyl)~R-l,l=
' Di~a`~mnoethane ~Formula I, R = CH3, R' = H, R" = 2,5-dimethylcyclopentyl]
A. Sodium metal (16 g, 0~7 mole3 was dissolved in absolute ethanol (500 ml) under argon with cooling as necessa-ry to maintain a temperature of ~70C. The solution was cooled and redistilled diethyl malonate (54.3 g, 0.362 mole) was added dropwise, with cooling as necessary, followed by 2,5-dibromohexane (85 g, 0.348 mole) in a single poltion. rrhe ~ ~3~

reaction mixture was stirred overnight at room temperature and then refluxed -for 2 hours. The mixture was then concen-trated to approximately half the volume under reduced pressure, water (500 ml) added and the mixture extracted with ether (3 x 200 ml). The combined extracts were dried (Na2S04), filtered, and evaporated under reduced pressure. rrhe residue was fractionated in vacuo to yield diethyl 2,5-dime-thylcyclo-. _ pentane-l,l-dicarboxylate (35 g), which was homogeneous by GC.
s. The product from Part A (35 g, 0.145 mole) was added to a solution of potassium hydroxide (55 g) in absolute ethanol (300 ml) and the mixture refluxed overnight. The reaction mixture was evaporated under reduced pressure and the residue dissolved in water (500 ml). The aqueous solution was extracted with ethyl acetate (200 ml), acidified to p~I 1 (conc. HCl) and extracted with ether (3 x 200 ml). The com-bined extracts were washed with lN hydrochlorid acid and dried (~a2SO4). The solution was evaporated under reduced pressure and the residual oil triturated with pentane to induce crystallization. The product was filtered and dried in vacuo to give 2,5-dimethylcyclopentane-1,1-dicarboxylic acid (10.5 g) which was homogeneous by GC.
C. The product from Part B (10.5 g, 56 mmole) was heated to 230C in a stream or argon for 1.25 hour. The residue was dissolved in tetrahydrofuran, decolorized (~ORIT A, trade mark), and the solvent evaporated under reduced pressure.
The residual oil crystallized on standing to give 2,5-dimethyl-c~vclopentanecarboxylic acid ~6.3 g), m.p. 45C, which was pure by GC.
D. The product from Part C (6.3 g, 48 mmole) was dissolved in tetrahydrofuran/thionyl chloride (1 1, v~v, 100 ml) and the mixture stirred at room temperature for one ~3~

hour. The solution was evaporated under reduced pressure to give a quantative yield of 2,5-dimethylcyclopentanecarbonyl chloride which was used without fur-ther purification.
E. N~-senzyloxycarbonyl-~-benzyl-L-aspartyl-D-alanyl amide (Example 1, Part s) (8.6 g, 20 mmole) was treated with iodobenzene bis(trifluoroacetate) using the procedure descri-bed in Example 5, Part A. The resulting solution was treated with potassium bicarbonate (20 g, 200 mmole) followed by 2,5-dimethylcyclopentanecarboxyl chloride (4.8 g, 30 mmole), ; 10 added dropwise over 5 minutes. The product precipitated almost immediately and stirring was continued for a further 2 hours at room temperature. The reaction mixture was worked up in the usual manner, except that the product crystallized during the drying of the final extracts over Na2S04. The solution was therefore heated to boiling, filtered hot and the Na2S0~ washed with ethyl acetate. The filtrate was evapo-rated under reduced pressure and the residue crystallized from ethyl acetate~hexanes to give N-(N~-benzyloxycarbonyl-~-benzyl-L-aspartyl)-N'-(2,5-dimethylcyclopentanecarbonyl~-1,1-diamino-ethane, (6.1 g) which was homogeneous by TLC, m.p. 193-195C.
The nmr spectrum of the product was consistent with the assigned structure.
F. The product from Part E (5.5 g) was hydrogenated in the usual manner in glacial acetic acid (200 ml) over 10%
palladium on carbon. After lyophilization several times from water, the solid residue was recrystallized from ethanol/water to giv~ N-(L-aspartyl)-N'-(2,5-dimethylcyclopentanecarbonyl)-R-l,l-diaminoethane (2.6 g), m.p. 208-209C.
Sweetness = 300-400 x sucrose.

_ 37 ~3~

EXAMPLE 14N-(L-Aspartyl)-N'-(2,2,5,5-Tetramethylcyclopentanecarbonyl)-R-l,l-Diaminoethane [Formula I, R = CH3, R' = H, R" = 2,2,5,5-tetramethylcyclopentyl~
A. Sodium hydride (50% dispersion in oil, 1~4 g, 3.0 mole) was added to a 3-liter, 3-neck flask fitted with a reflux condenser, a mechanical stirrer and a nitrogen inlet.
A moderate stream of nitrogen was passed through the flask and dry tetrahydrofuran (1.5 1) added. Solutions of cyclo-pentanone (53.6 g, 0.64 mole) in dry tetrahydro~uran (350 ml) and dimethyl sulfate (285 ml, 3.0 mole) in the s~me solvent (120 ml) were added simultaneously in small portions (20-40 ml) to the stirred suspension, so as to maintain a gentle evo-lution of hydroyen~ The reaction mixture was cooled as ; necessary to maintain a temperature of <40C. When addition was complete (several hours) the reaction mixture was refluxed for 2 hours. After cooling, t-butanol (100 ml) was added slowly to destroy excess hydride, followed ~y water (1 1), cautiously at first. The reaction mixture was then refluxed 2 hours to destroy excess dimethyl sulfate. On cooling, the layers were separated and the organic phase washed with satu-rated sodium chloride and dried (~a2SO4). The solvent was evaporated under reduced pressure and the residue fractionated ~ in vacuo to give 2,2,5,5-tetramethylcyclopentanone (59 g), b.p.
; 55C/20 mm.
B~ A solution of 2,2,5,S-tetramethylcyclopentanone (30 g, 0.215 mole) in ether (50 ml) was treated, under nitro gen, with a 3M solution o~ methyl magnesium bromide in ether (100 ml). The reaction mi~ture was ~tirred overnight at room temperature and saturated aqueous ammonium chloride (65 ml) then added dropwise. The mixture was stirred for 10 minutes, ~3~

the ether solution decanted and the solid residue triturated with ether. The ether extra~ts were dried (Na2SO4) and evaporated under reduced pressure to give crude 1,2,2,5,5-pentamethylcyclopentanol (3~ g) which was used without furtner purification.
C. The crude product from Part B (30 g) was dissolved in pyridine (150 ml), the solution cooled to O~C and treated (dropwise) with thionyl chloride (20 ml, 0.28 mole), maintai-ning a temperature of <5C. The reaction mixture was stirred overnight, filtered and ether and water added. The phases were separated and the organic phase washed with water ( 2 x 200 ml) and dried (Na2S04). The solvent was evaporated under reduced pressure to give l-methylene-2,2,5,5-tetramethylcy-clopentane (10.8 g) which was pure by GC.
D. The product from Part C (10.~3 g, 78 mmole) was dissolved in dry tetrahydrofuran (100 ml) and treated under nitrogen with lM borane-tetrahydrofuran in tetrahydrofuran (100 ml). The reaction mixture was stirred overnight at room temperature and treated with 3N aqueous sodium hydroxide (40 ml), followed by dropwise addition of 30/O aqueous hydrogen peroxide (40 ml) at a rate sufficient to maintain a gentle reflux. The mi~t~re was refluxed for a fur-ther one hour, sodium chloride added to saturation, and the mixture cooled to room temperature with stirring. The phases were separated, the organic phase dried (Na2S04) and evaporated under reduced pressure to give a quantitative yield of crude 2,2,5,5-tetra-methylcyclopentylmethanol which was used without further purification.
E. The product from Part D was dissolved in ether (300 rnl) and added to a solution of potassium dichromate (45 g, O.lS mole) in concentrated slllfuric acid (90 ml, 1.7 mole) and 3~

water (450 ml). The mixture was stirred at room -temperature for 3 hours. The pha~es were then separated, the organic phase washed with saturated sodium chloride and dried (Na2S04).
The solvent was evaporated under reduced pressure and the residue distilled in vacuo to give 2,2,5,5-tetramethylcyclo-pentanecarboxylic acid (6.6 g) which was homogeneous by GC.
F. The product from Part E (6.5 g, 38 mmole) was dissolved in tetrahydrofuran (100 ml) and treated dropwise with excess thionyl chloride (20 ml, 270 mmole). The solution was refluxed for two hours, evaporated under reduced pressure and the residue distilled in vacuo to give 2,2,5,5--tetramethyl-cyclopentanecarboxyl chloride (4.8 g), b.p. 65-75C/4mm.
G. N~-Benzyloxycarbonyl-~-benzyl-L-aspartyl-D-alanyl amide (Example 1, Part B) (10.7 g, 25 mmole) ~as treated with iodobenzene bis(trifluoroacetate) as described in Example 5, Part A. The resulting solution was evaporated to near dryness under reduced pressure, water and a large excess of concentrated hydrochloric acid added, and the mixture re-evaporated to dry-ness. The solid residue was dissolved in 4.4M HCl/dioxane (20 ml), the solution evaporated to dryness, and the residue redissolved in dioxane (lOQ ml) and lyophilized to give N-(N~-benzyloxycarbonyl-~-benzyl-L-aspartyl)-R-l,l-diaminoethane hydrochloride (10.2 g), which was homogeneous by TLC.
M. The product from Part G (6.6 g, 15 mmole) was dissolved in dry tetrahydrofuran (150 ml) and treated with 2,2,5,5-tetramethylcylopentanecarboxyl chloride (from Part F, 3rl g~ 15 mmole~ followed by triethylamine (4.2 ml, 30 mmole~.
The reaction mixture was stirred at room temperature for one hour, ethyl acetate added, and the product worked up in the usual manner. Crystallization from ethyl acetateJhexanes gave N~(N~-benzyloxycarbonyl-~-benzyl-L-aspartyl)-N'-~2,2,5,5-.
_ 40 -~3~35~

tetramethylcyclopentanecarbonyl)-R-l,l-diaminoethane (6.0 g), whlch was homogeneous by TLC, m.p. 122-125C. The nmr spectrum was consistent with the assigned structure.
I. The product from Par~ H (5.5 g) was hydrogenated in the usual manner in glacial acetic acid (200 ml) over 10%
palladium on carbon. After lyophilization from water several times, the solid residue was crystallized from ethanol~hexanes to give N-(L-aspartyl)-N'~~2,2,5,5~tetramethylcyclopentane-carbonyl)-R-l,l-diaminoethane (2.0 g), m.p. 171-172C. The compound was homogeneous by high pressure liquid chromatography (HPLC) (Conditions: LICHROSORB RP-18, trade mark, linear gradient of 24-33% acetonitrile in 0.01 M triethyla~onium phosphate, pE 4.5, flow rate = 1 ml/min., retention time =
12.31 ~in.).
Sweetness = 800-1000 x sucrose.

N-(L-Aspartyl)-N'-(2,6-Dlmethylcyclohexanecarbonyl)-R-1,1-Diaminoethane [Formula I, R = CH3, R' = H, R" = 2,6-dimethylcyclohexyl]
A~ Methyltriphenylphosphonium bromide (286 g, 0.80 mole) was suspended in ether 11500 ml) and treated with n-butyllithium (1.6 M in ether, 500 ml, 0.80 mole~, followed by 2,6~dimethylcyclohexanone (50.4 g, 0.40 mole), following the ::
procedure described in Example 12, Part A. The crude product was distilled to give l-methylene-2,6-dimethylcyclohexane (24 g), b.p. 146-154C/760 mm.
B. The product from Part A (24 g, 0.10 mole) was dissolved in dry tetrahydrofuran (50 ml) and treated under ; nitrogen with lM ~orane-tetrahydrofuran in tetrahydrofuran (250 ml). ~he reaction mixture was stirred overnight at room temperature and treated with 3N aqueous sodium hydroxide (20 ml) ~3~

dropwise (foaming occurs), followed, dropwise, by 30% aqueous hydrogen peroxide (20 ml). The mixture was refluxed for 30 minutes, sodium chloride added to saturation and the mixture cooled to room temperature with stirring. The phases were separated and the organic phase dried (Na2SO4) and evaporated under reduced pressure to give a quantitative yield of 2,6-di-methylcyclohexylmethanol. The product was purified by frac-tionation in vacuo b.p. 187-210C/760 mm.
C. The product from Part B (20 g, 0.14 mole) was dissolved in ether (300 ml) and added to a solution of potassium dichromate (90 g, 0.30 mole) in concentrated sulfuric acid (175 ml) and water (900 ml) in an ice bath. The mixture was warmed to room temperature and stirred for 2 days. The phases were separated, the organic phase washed with water, dried (MgS04) and evaporated under reduced pressure. The residue was fractionated to give 2,6-dimethylcyclohexanecarboxylic acid (16.7 g), which was pure by GC, b.p. 145-148C.
D. The product from Part C (16.7 g) was dissolved in tetrahydrofuran (100 ml~ and treated with excess thionyl chlo-ride (30 ml) at room temperature. After stirring at room tem-perature for one hour, the solvent and excess thionyl chloride were evaporated under reduced pressure to provide a quantitative yield of 2,6-dimethylcyclohexanecarboxyl chloride which was used without further purification.
E. N~-Benzyloxycarbonyl-~-benzyl-L-aspartyl-D-alarlyl amide (E~ample 1, Part B) (10.7 g, 25 mmole) was treated with iodobenzene bis(trifluoroacetate) using the procedure described in Example 5, Part A. The resulting solution was treated with potassium bicarbonate ~20 g, 200 mmole), followed by 2,6-dime-thylcyclo~lexanecarboxyl chloride (6.1 g, 35 mmole) added drop-wise over 2 minutes. The reaction mixture was stirred for 3 ~%~ 5~

hour~s at room temperature, and then worked up in the usual manner, except that the product crystalliæed during drying of the final extracts over Na2~4. The solution was therefore heated to boiling, filtered hot and the Na2S04 washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue recrystallized from ethyl acetate to give N (N~-benzyloxycarbonyl-~-benzyl-L-aspartyl)-N'-(2,6-di-methylcyclohexanecarbonyl)-~-l,l-diaminoethane ~4.5 g) which was homogeneous by TLC, m.p. 146-150C. The nmr spectrum of the product was consistent with the assigned structure.
F. The product from Part E (4 g) was hydrogenated in the usual manner in glacial acetic acid (150 ml) over 10%
palladium on carbon. After lyophilization from water several times, the solid residue was crystallized from ethanol/water to give N-(L-aspartyl)-NI-(2,6-dimethylcyclohexanecarbonyl)-R-l,l-diaminoethane (0.8 g)~
Sweetness - 150-200 x sucrose.

-(L-Aspartyl)-N'-(2-t-Butylcyclohexanecarbonyl)-R
Diaminoethane [Formula I, R = CH3, Rl = H, R" = 2-t-butylcyclohexyl]
A. Methyltriphenylphosphonium bromide (346 g, 0.97 mole) was suspended in ether (1500 ml) and treated with n-butyllithium (2.5M in ether; 388 ml, 0.97 mole) followed by 2-t-butylcyclohexanone (50 g, 0~324 mole), following the procedure described in Example 12, Part A. The reaction mix-ture was heated under reflux for 2 days and then worked up in the usual manner. The crude product was fractionated to provi-de methylene-2-t-butylcyclohexane (22 g), which was pure by GC.
B. The product from Part A (22 g, 0.146 mole) was dissolved in dry tetrahydrofuran (50 ml) and treated under !

~3~

nitrogen with boranetetrahydrofuran in tetrahydrofuran (lM, 160 ml, 0.16 mole~. The reaction mixture was sti.rred at room temperature for 2 days and treated with 4N aqueous sodium hydroxide (40 ml) dropwise (foaming occurs), followed by 30/O
aqueous hydrogen peroxide (40 ml). The reaction mixture was refluxed overnight and then quenched with ice water, extracted with ether and the combined extracts dried (MgS04). The solvent was evaporated under reduced pressure to give 2-t-bu-tylcyclohexylmethanol (17 g) which was used without further purification.
C The product from Part B (15 g, 0.088 mole) was added to a solution of potassium dichromate (51.8 g, 0.176 mole) in sulfuric acid (102 ml) and water (600 ml). The reaction mixture was stirred at room temperature until all of the starting material had disappeared by GC. The reaction was quenched with water, extracted with ether and the combined extracts dried (MgSO4). The solvent was evaporated under reduced pressure to give 2-t-butylcyclohexanecarboxylic acid (10 g) which was used without further purification.
D. The product from Part C (10 g, 0.054 mole) was dissolved in pyridine:ether (1:1, 100 ml) and treated with an excess of thionyl chloride (12 ml, 0.162 mole). The reaction mixture was stirred at room temperature for 12 hours and then evaporated under reduced pressure. The residue was fractiona ted to give 2-t-butylcyclohexanecarboxyl chloride (7 g)~
E. N-(N~-Benzyloxycarbonyl-~benzyl L-aspartyl)-R-l,l~
diaminoethane hydrochloride (8.52 g, 20 n~ole~, prepared as described in Example 14, Part G, was dissolved in dry -tetra-hydrofuran (200 ml) and treated with 2-t-butylcyclohex~necar-boxyl chloride (from Part D, 4.05 g, 20 mmole), followed by triethylamine (5.6 ml, ~0 mmole). The reaction mixture was - ~4 -~L~3~3~5~

stirred at room temperature for 3 hours, ethyl acetate added and the product worked up in the usual manner. Crystalliza-tion from ethyl acetate~hexanes gave N-(N~-benzyloxycarbonyl-~-benzyl-L-aspartyl)N'(2-t-butylcyclohexanecarbonyl)-1,1-diaminoethane (4.5 ~), which was-homogeneous by TLC, m.p.
165-166C. The nmr spectrum of the product was consistent with the assigned structure.
FA The product from Part E (4 g~ was hydrogenated in the usual manner in glacial acetic acid (150 ml) over 10%
palladium on carbon. After lyophilization several times from water, the solid residue was crystallized from isopro-panol/water to give N-(L-aspartyl)-N'-(2-t-butylcyclohexane-carbonyl)-R-l,l-diaminoethane (1.5 g), m.p. 195-198C.
Sweetness = 150-200 x sucrose.

N-(L-Aspar ~ ramethylcyclopentanecarbonyl ? -R-l,l Diam o-2-Hydroxyethane [Formula I, R = CH20H, R' = H, R~ = 2,2,5,5-tetramethylcyclopentyl]
A. 0-Benzyl-D-serine (5.0 g, 25.6 mmole) was dissolved in dimethylformamide (50 ml), treated with chloro-trlmethylsilane (3.053 g, 28.1 mmole) and the mixture stirred ~ ~ at room temperature until a homo~eneous solution was obtained ;~ (approx. 1 hour). Meanwhile, N-benzyloxycarbonyl-~-benzyl-L-:
aspartic acid (9.14 g, 25.6 mmole) was dissolved in a 1:1 mixture of dimethylformamide and tetrahydrofuran, cooled to -15C and treated with N methylmorpholine (2.81 ml, 25.6 mmole), followed by isobutyl chloroformate (3.32 ml, 25.6 ~ole). After 10 minutes' activation, the precooled solution of 0-benzyl-D-serine silyl ester was added, followed hy dropwise addition of N-methylmorpholine (2.81 ml, 25.6 mmole), ~3~3~i~

ensuring that the temperature o~ the reaction mix~ure was maintained at -15C. The solution was allowed to warm to room temperature slowly and stirred for ~ hours before acidi-~ying to pH 1-2 (with cooling) using aqueous hydrochloric acid~ Chloroform was added, the phases separated and the aqueous layer re-extracted with chloroform. The combined organic extracts were washed with lN hydrochloric acid (3 x) and with saturated sodium chloride and dried (MgS04). The solvent was evaporated under reduced pressure and the solid residue crystallized from ethyl acetate/hexanes to give N~-benzyloxycarbonyl-~-benzyl-L-aspartyl-0-benzyl-D-serine (11.0 g), m.p. 107-108C, which was homogeneous by TLC. The nmr spectrum of the product was consistent with the assigned structure.
B. The product from Part A (10.0 g, 18.7~ mmole) was dissolved in dimethylformamide (100 ml), cooled to -15C and treated with N--methylmorpholine (2.05 ml, 18.72 mmole~
; followed by isobutyl chloroformate (2.43 ml, 18.72 mmole).
After 4 minutes' activation at -15C, 1-hydroxybenzotriazole ammonium salt (3.13 g, 20.5 mmole), was added as a solid and the mixture stirred at -15C for 30 minutes. A~ter warming to room temperature with stirring over 4 hours, chloroform and ; water were added, the phases separated and the aqueous phase re-extracted with chloroform. The combined organic phases were washed with 1~ hydrochloric acid (3 x), saturated aqueous sodium bicarbonate (3 x), saturated sodium chloride and dried (MgSO4). The solvent was evaporated under reduced pressure and t~e solid residue recrystallized from ethyl acetate~hexanes to give N~-benzyloxycarbonyl-~-benzyl-L-aspartyl-0-benzyl-D-seryl amide (7.4 g), m.p. 150C which was homogeneous by TLC. The nmr spectrum of t~e pxoduct was ~3~

consistent with the assigned structure~
C. The product from Part B ~5.33 g, 10 mmole) was dissolved in acetonitrile (50 ml) and the solution diluted with an equal volume of water. Iodobenzene bis(trifluoro-acetate) (4.8 g, 11.2 mmole) was then added and the reaction mixture stirred at room temperature for 5 hours. The solution was evaporated u~der reduced pressure and the residue redis-solved in anhydrous HCl/dioxane (4N) and the solution lyo-philized to give N-(N~-benzyloxycarbonyl-~-benzyl-L-aspartyl)-R-l,l-diamino-2-hydroxyethane hydrochloride in quantitative yield which was used without further purification.
D. The product from Part C was dissolved in tetrahy-drofuran (50 ml), N-methylmorpholine (3.30 ml, 30 mmole) added, followed by 2,2,5,5-tetramethylcyclopentanecar~onyl chloride (3.1 g, 16 mmole) and the mixture stirred at room temperature for 4 hours. Ethyl acetate and water were added, the phases separated and the aqueous phase re~extracted with ethyl acetate. The combined organic phases were washed with lM sodium bicarbonate (2 x), 2~ hydrochloric acid (3 x), again with lM sodium bicarbonate (2 x), finally with saturated sodium chloride and dried (MgSO4). The solution was filtered, the filtrate evaporated under reduced pressure and the residue crystallized from ethyl acetate~hexanes to give N-(N~-benzyl-oxycarbonyl-~benzyl-L-aspartyl)-N'-2,2,5,5-tetramethylcyclo-pentanecarbonyl-l,l-diamino-2-hydroxyethane ~4.0 g), m.p.
90-93C, which was homogeneous by TLC. The nmr spectrum of the product was consistent with the assigned structure.
E. ~he product from Part D (3.8 g) was hydrogenated in the usual manner in glacial acetic acid (150 ml) over 10%
palladium on carbon. After lyophilization and relyophiliza-tion from water several times, N-(L-aspartyl)--N'-(2,2,'i,5-tetramethylcyclopentanecarbonyl)-R-l,l-diamino-2-hydroxye-thane was obtained in quantitative yield, m.p. 174-176C dec.
Sweetness = 400-500 x sucrose.

~-(L-As artyl)-N'-(2,2,5,5-Tetramethylcyclopentanecarbonyl)--- P __ S-l,l-Diaminoethane [Formula I, R = H, R' = CH3, R" = 2,2,5,5-tetramethylcyclopentyl]
A. N~-benzyloxycarbonyl-~-benzyl-L-aspartic acid (1.70 g, 5 mmole) was dissolved in tetrahydrofuran (100 ml), the solution cooled to -15C and treated with N~methylmorpho-line (0.55 ml, 5 mmole). Arter 10 minutes' activation at -15~, a precooled solution of L-alanineamide hydrochloride (0.75 g, 6 mmole) in dimethylformamide (50 ml) was added, followed by~N-methylmorpholine (O.66 ml, 6 mmole). The solution was allowed to warm to room temperature and stirred overnight. Chloroform and water were then added, the phases separated and the aqueous phase re-extracted with chloroform.
The combined organic phases were washed with lN hydrochloric acid (3 x), saturated sodium chloride and dried (MgS04). The solution was filtered, the filtrate evaporated under reduced pressure and the residue crystallized from ethyl acetate/he-xanes to give ~-benzyloxycarbonyl-~benzyl-L-aspartyl-L-alanyl amide (2.0 g3, m.p. 180-180.5C which was homogeneous by TLC. The nmr spectrum of the product was consistent with ~ the assigned structure.
; B. The product from Part A (1.0 ~, 4.4 mmole) was dissolved in acetonitrile (25 ml), diluted with an equal volume of water and treated with iodobenzene bis(trifluoro-acetate) (2.13 g, 5 mmole). After stirring the solution at room temperature for 5-hours the product was worked up as described in Example 17, Part C, to give N-(N~-benzyloxy-~X38~

carbonyl-~-benzyl-L-aspartyl)-S-l,l~diaminoethane hydrochlo-ride in quantitative yield, which was used without further purification.
C. The product from Part B was dissolved in tetra-hydrofuran (100 ml), N-methylmorpholine ~1.1 ml, 10 mmole) added, followed by 2,2,5,5-tetramethylcyclopentanecarbonyl chloride (1.25 g, 6.5 mmole) and the mixture stirred at room temperature for 5 hours. Ethyl acetate and water were then added, the phases separated and the aqueous phase re-extracted with ethyl acetate. The combined organic phases were washed with lM sodium bicarbonate (2 x), 2N hydrochloric acid (3 x), again with lM sodium bicarbonate (2 x), ~inally with satu-rated sodium chloride and dried (MgS04). The solution was filtered, the filtrate evaporated under reduced pressure and the residue crystallized from ethyl acetate/hexanes to give -benzyloxycarbonyl-~-benzyl-L-aspartyl)-~'-(2,2,5,5-te-tramethylcyclopentanecarbonyl)-S-l,l-diaminoethane (1.3 g), m.p. 129-131C which was homogeneous by TLC. The nmr spec-trum of the product was consistent with the assigned struc-ture.
D. The product from Part C was hydrogenated in the usual manner in glacial acetic acid ~50 ml) over 10% palla-dium on carbon. A~ter lyophilization and relyophilization ~ from water several times, N-(L-aspartyl)-N'-(2,2,5,5-tetra-; methylcyclopentanecarbonyl)-S-l,l-diaminoethane was obtained in quantitative yield, m.p. 174-176C dec. The compound was homogeneous by HPLC (Conditions: see Example 14, retention time - 10.27 min.).
Sweetness = 600-800 x sucrose.

~L~31~)5~L

(L-Aspartyl)-N'-(2,2,5,5-Tetramethylthietane-3-carbonyl)-R-l,1-Diaminoethane [ Formula I, R = CH3, R' - ~
R" = 2,2,4,4-tetramethylthietane-3-yl]
A. A solution of 1,3-dithiane (25.0 g, 0.208 mole) in tetrahydro~uran (200 ml) was cooled to -30C and treated with a solution of n-butyllithium in hexane (2.5 M, 83.17 ml, - 0.208 mole). The reaction mixture was stirred at this tempe-rature for one hour, the bath lowered to -78C and chlorotri-methylsilane (26.4 ml, 0~208 mole) added dropwise. The reac-tion mixture was stirred at -78C for two hours and then quenched at 0C with water. The mixture was then extracted twice with ether, the organic extracts corribined, dried (MgS04) and evaporated under reduced pressure to give tri-methylsilyldithiane (38.0 g) as a pale yellow oil. The product was > 95% pure by GC and was used without further pu-rification.
:~
B. The product from Part A ~27.08 g, 0.174 mole) was dlssolved in tetrahydrofuran (150 ml), cooled to -78C and treated dropwise with a solution of n-butyllithium in hexane (2.5 M, 69.44 ml, 0.174 mole). The reaction mixture was stirred at this temperature for one hour and then treated with a solution of 3-oxo-2,2,4,4-tetramethylthiet'ane (25.0 g, 0.174 mole) in tetrahydrofuran (200 ml). The reaction mixture : ~ :
; ~ was stirred at -78C for two hours, warmed to room temperature and stirred for a further two hours when reaction was 75%
complete by GC. A further aliquot of lithio trimethylsilyl-dithiane (9.61 g, 0.062 mole~ was added to complete the reaction. ~fter stirring overnight at room temperature the reaction mixture was quenched with water, extracted with ~ 50 ~

~1.23~

ether (2 x), the organic extracts dried ~MgS0~3 and evaporated under reduced pressure. The residue was recrystallized from methanol to give 2,2,4,4-tetramethylthietane-3-ketene thioa-cetal (39.0 g), m.p. 10~-105C, which was homogeneous by GC.
The nmr spectrum of -the product was consistent with the assigned structure.
C. The product from Part B (39.0 g, 0.159 mole) was dissolved in a~ueous methanol (1:2, v~v, 150 ml), dilllted with tetrahydrofuran (50 ml) and treated with p-toluenesulfonic acid (150.7 g, 0.79 mole). The solution was heated under reflux until reaction was complete (disappearance of ketene thioacetal) by GC. The solution was cooled, diluted with water, extracted with ether (2 x), the organic extracts dried (MgS04) and evaporated under reduced pressure. The solid residue contained 1,3-propanedithio-2,2,4,4-tetramethylthie-tane-3-carboxylate (29.0 g), m.p. 133-136C, which was pure ; by GC. The nmr spectrum of the product was consistent with the assigned structure.
D. The product from Part C (29.0 g, 0.110 mole) was dissolved in aqueous methanol (1:2l v~v, 150 ml), diluted with tetrahydrofuran (50 ml) and solid potassium hydroxide (61.8 g, 1.10 mole) added. The solution was heated under reflux until reaction was complete (disappearance of the thioester~ by GC. The solution was cooled, ether and water added and the phases separated. The ether layer was extracted wlth water (3 x) and the aqueous phases combined, acidified and re~extracted with ether (3 x) and hexanes (3 x). The combined organic extracts were washed with water, dried ~MgS04) and evaporated under reduced pressure. The residue was recrystallized from methanol to give 2,2,4,4-tetramethyl~
thietane-3-carboxylic acid (12.1 g), m.p. 149-151C which was ~:3~

pure by GC. The nmr spectrum of the product was consistent with the assigned structure.
E. The product from Part D (10 g, 0.057 mole) was dissolved in tetrahydrofuran (50 ml) and treated with excess thionyl chloride (25 ml). The reaction mixture was stirred at room temperature for 5 hours and then evaporated ~mder reduced pressure to give 2,2,4,4-tetramethylthietane-3-carboxyl chloride in quantitative yield which was used without further purification.
F. D-Alanine (5 g, 0.056 mole) was dissolved in dimethylformamide (100 ml) and treated with chloro-trimethyl-silane (6.7 g, 0.063 mole). The reaction mixture was stirred at room temperature until homo~eneous (approx. 1 hour).
Meanwhile, N~-9-fluorenylmethyloxycarbonyl-~-benzyl-L-aspartic acid (22~3 g, 0.050 mole) was dissolved in dimethylformamide~
tetrahydrofuran (1:1, v~v, 200 ml), cooled to -15C and treated with ~-methylmorpholine (5.5 ml, 0.050 mole) and isobutyl chloroformate (6.5 mo, 0.050 mole). After 10 minu-tes' acti~ation at -15C, the precooled solution of D-alanine silyl ester ~rom above was added, followed by a second equivalent of N-methylmorpholine (5.5 ml, O.050 mole). The reaction mixture was allowed to warm to room temperature, stirred ~or 3 hours and then acidified (pH 1-2) using aqueous ; hydrochloric acid. The reaction mixture was stirred for 30 minutes and ethyl acetate added and the phases separated.
The aqueous phase was re-extracted with ethyl acetate and the combined organic extracts washed with 1 N hydrochloric acid (3 x) and dried (M~S04). After evaporation of the sclvent under reduced pressure the residue was crystallized from ethyl acetate/hexanes to ~ive N~-9 fluorenylmethyloxy--carbonyl-~-hen~yl-L-aspartyl-D-alanine (22.5 ~), m.p. 11~-116C

- ~.2;3B051 which was homogeneous by TLC. The nmr spectrum of the product was consistent with the assigned structure.
G. The product from Part F (20.6 g, 0.040 mole~
was dissolved in dimethylformamide (150 ml), cooled to -15C
and treated ~ith N-methylmorpholine (4.4 ml, 0.040 mole) and ; isobutyl chloroformate (5.2 ml, 0.040 mole). After 4 minutes~
activation at -15C, l-hydroxybenzotriazole ammonium salt (9.1 g, 0.060 mole) was added and the mixture stirred at -15C
for 15 minutes. After warming to room temperature the mix-ture was stirred for a further 4 hours. Chloroform (large amounts were required because of emulsion formation) and water were added, the phases separated and the oryanic layer ; washed with saturated aqueous sodium bicarbonate (3 x), 2 N
hydrochloric acid (3 x) and dried (MgS04). After evaporation of the solvent under reduced pressure the solid residue was recrystallized from ethyl acetate to give N~-9-fluorenyl-methyloxycarbonyl-~-benzyl-L-aspartyl-D-alanyl amide (5.6 g) m.p. 200-204C, which was homogeneous by TLC. The nmr spec-trum of the product was consistent with the assigned structure.
H. The product from Part G (2 g, 3.0 mmole~ was dissolved in acetonitrileJwater (1:1, v/v, 500 ml) and trea-ted with iodobenzene bis(,trifluoroacetate~ (1.9 g, 4.4 mmole).
The reaction mixture was stirred overnight at xoom temperature, evaporated to dryness and the product dissolved in HCl/dioxane ~' (4j~) and re-evaporated. The process was repeated and the ~ product finally redissolved in dioxane and lyophilized to - give N-(N~-9-fluorenylmethyloxycarborlyl-~-benzyl-L-aspartyl)-R-l,l~diaminoethane hydrochloride in quantitative y:ield which was used without further purification.
I. The product from Part H was dissolved in tetra-hydrofurarl (50 rnl) and treated with 2,2,4,4-tetrarnethyl thietane-3-carboxyl chloride (from Part E, 1.35 g, 7 mmole) followed by N-methylmorpholine (1.32 ml, 12 mmole). The reaction mixture was stirred for a further 20 minutes. Ethyl acetate was then added, the phases separated and the organic phase washed with 2 N HCl (3 x), saturated aqueous sodium ~icarbonate (3 x) and dried (MgS04). The solvent was evapo-rated under reduced pressure and the residue crystallized from ethyl acetateJhexanes to ~ive N-(N~-9-fluorenylmethyl-oxycarbonyl-~-benzyl-L-aspartyl)-N'-(2,2,4,4-tetramethyl-thietane-3-carbonyl)-R-l,l-diaminoethane (1.5 g) which was homogeneous by TLC. The nmr spectrum of the product was consistent with the assigned structure.
J. The product from Part I was dissolved in a mixtu-re of methanol (20 ml) and aqueous potassium hydroxide (1 N, ; 20 ml). A precipitate formed immediately which partially dissolved on addition of tetrahydrofuran (10 ml). The mix-ture was stirred at room temperature for 5 hours and then acidified (pH 5) with acetic acid. After stirring for several hours at room temperature, the mixture was concentrated under reduce~ pressure and the solution filtered. The filtrate was lyophilized and the residue recrystalliæed from ethanol/
hexanes to give N-(L-aspar-tyl)-N'-(2,2,4,4-tetramethylthie-tane-3-carbonyl)-R-l,l-diaminoethane (0.4 g), m.p. 158-161C, which was homogeneous by TLC. The nmr spectrum of the pro-- duct was consistent w~th the assigned structure.
Sweetness - 150-200 x sucrose.

N-(L-Aspartyl)-N~-(Cyclopentanecar~onyl) 2,2-Diaminoprol~ ne [Formula I, R = R' = CH3, R" = cyclopentyl]
A. ~-Aminoisobutyric acid (20 g, 0.194 mole) was ~ ~3~

suspended in tetrahydrofuran (400 ml), treated with a solution of phosgene in toluene (3 ~, 160 ml) and the mixture heated at 65~C overnight. The resulting clear solution was evaporated under reduced pressure, redissolved in tetrahy-drofuran and re-evaporated to give ~-aminoisobutyric acid N-carboxyanhydride as a thick oil which was used without further purification.
B. The product from Part A was dissolved in tetra-hydrofuran (200 ml), cooled to -20C and treated with excess ammonia gas. The solution was allowed to warm to room tempe-rature slowly and then evaporated to dryness under reduced pressure. The solid residue was extracted with ethyl acetate using a soxhlet extractor over 3 hours, the resultant solu-tion filtered and the product allowed to crystallize.
~-Aminoisobutyramide was obtained as a crystalline solid (10 g), m.p. 115-118C, which was homogeneous by TLC. The nmr spectrum of the product was consistent with the assigned structure.
C. N~-Benzyloxycarbonyl-~-benzyl-~-aspartic acid (24.2 g, 67 mmole) was dissolved in dry dimethylformamide (300 ml), the solution cooled to -20C and treated with dicyclohexylcarbodiimide (14.5 g, 71 mmole). After 30 minutes activation at this temperature a precooled solution of ~-ami-noisobutyramide (6.9 g, 67 mmole) in dimethylformamide (125 m1) was added and the mixture allowed to warm to room tempe-rature. After stirring for 2 days, the mixture was evaporated to dryness under reduced pressure and the residue purified by flash chromatography on silica gel, eluting with a step-wise gradien~ of chloroform~hexanes (3:1, v/v), chloroform and then chloroform~methanol ~95:5, v/v). The final product to elute was N~-benzyloxycarbonyl-~-benzyl-L-aspartyl-~-amino-isobutyramide (10.0 g) which was homogeneous by TLC. The nmr spectrum of the product was consistent with the assigned structure.
D. The product from Part C (5.0 g, 11 mmole~ was dissolved in acetonitrile (30 ml), the solution diluted with an equal volume of water and treated with iodobenzene bis-(trifluoroacetate) (5.16 g, 12 mmole). The reaction mixture was stirred at room temperature for 7 hours ~hen xeaction was complete by TLC. The solution was evaporated under reduced pressure, the residue dissolved in dioxane (100 ml) and con-ce~trated hydrochloric acid (3 ml) and lyophilized. The process was repeated to give N-(N~-benzyloxycarbonyl-~-benzyl-L-aspartyl)-2,2-diaminopropane hydrochloride in quantitative ; yield, which was used without further purification.
. ....
E. The product from Part D was dissolved in tetra-hydrofuran (100 ml) and treated with triethylamine (2.5 g, 24 mmole), followed by cyclopentanecarbonyl chloride (1.75 g, 13.2 mmole). The reaction mixture was stixred at room tempe-rature for 5 hours, filtered and the filtrate evaporated under reduced pressure. The residue was purified by chromatography on silica gel to give N-(N~-benzyloxycarbonyl-~-benzyl-L-~ aspartyl)-N'-(cyclopentanecarbonyl)-2,2-diaminopropane, which ;~ was homogeneous by TLC. ~he nmr spectrum of the product was consistent with the assigned structure.
F. The product from Part E was hydrogenated in the , :~
usual manner in glacial acetic acid (100 ml) over 10% palla-dium on carbon. After lyophilization and relyophilization from water several times, N-(L-aspartyl~-N'-(cyclopentanecar-bonyl~-2,2-diaminopropane was obtained in quantitative yield.
Sweetness = 50-100 x sucrose.

N-(L-Aspartyl~-N~-(2~2~5~5-Tetramethy~cyclopentanecarbonyl) R-l,l-Diaminopropane [Compound I, R = C~2CH3, R' = H, R" = 2,2,5,5-tetramethylcyclope~tyl]
A. D-~-Amino-n-butyric acid (5.0 g, 48.5 mmole) was dissolved in dimethylformamide (50 ml), treated with chloro-trimethylsilane (6.15 ml, 48.5 ~mole) and the mixture stirred at room temperature for 1 hour. Meanwhile, N~-benzyloxy-carbonyl-~-benzyl-L-aspartic acid (15.73 g, 45.1 mmole) was dissolved in dimethylformamide (50 ml), cooled to -15C and treated with N-methylmorpholine (4.84 ml, 44.1 mmole), follo-wed by isobutyl chloroformate (5.72 ml, 44.1 mmole). After 10 minutes' activation, the precooled solution of D-~-amino-n-butyric acid silyl ester was addedj- followed by a second equivalent of ~-methylmorpholine (4.84 ml, 44.1 mmole). The `~ solution was allowed to warm to room temperature, stirred for

4 hours and then acidified (pH 1-2) with aqueous hydrochloric acid. Chloroform was added, the phases separated and the aqueous layer re-extracted with chloroform. The combined organic phases were washed with 1~ hydrochloric acid t3 x), ;~ ; saturated sodium chloride and dried (MgSO4). The solvent was !: '-' -evaporated under reduced pressure and the residue crystallized from ethyl acetate~hexanes to give ~-benzyloxycarbonyl-~-benzyl-L-aspartyl-D-~-amino-n-butyric acid (13.3 g), m.p.
150-152C, which was homogeneous by TLC. The nmr spectrum of the product was consistent with the assigned structure.
The product from Part A (10.0 g, 22.6 mmole) was dissolved in dimethylformamide (50 ml), cooled to -15C and treated with N-methylmorpholine (2.48 ml, 22.6 mmole) followed by isobutyl chloroformate (2.93 ml, 22.6 mmole). After 4 ~.~3~
.

minutes' activation at -15~C, l-hydroxybenzotriazole ammonium salt ~3.84 g, 2~.9 mmole) was added as a solid and the mix-ture stirred at -15C for ~5 minutes. The reaction mixture was allowed to warm to room temperature slowly, stirred for 4 hours and then dil~ted with water and chloroform. The phases were separated and the aqueous phase re-extracted with chloroform. The combined organic extracts were washed with lN hydrochloric acid (3 x), saturated aqueous sodium bicarbonate (3 x), saturated sodium chloride and dried (MgS04). The solvent was evaporated under reduced pressure and the solid residue recrystallized from ethyl acetate~
hexanes to give N~-benzyloxycarbonyl-~-benzyl-T,-aspartyl-D-~-amino-n-butyramide (7.5 g), m.p. 170-171C, which was homo-geneous by TLC. The nmr spectrum of the product was consis-tent with the assigned structure.
C. The product from Part B ~5~0 g, 11.3 mmole) was dissolved in aqueous acetonitrile (1:1, v/v, 100 ml) and treated with iodobenzene bis(trifluoroacetate) (5.85 g, 13.6 mmole). The reaction mixture was stirred at room temperature for 5 hours and evaporated to dryness under reduced pressure.
The residue was redissolved in dio~ane (50 ml), excess con-centrated aqueous hydrochloric acld added, and the solution re-evaporated several times and ~inally lyophilized ~rom dioxane to give N-(~-benzyloxycarbonyl-~-benzyl-L-aspartyl)-R~ diaminopropane hydrochloride in quantitative yield which was used without further purification.
D. The product from Part C was dissolved in te-trahy-drofuran (25 ml) and treated with 2,2,5,5-tetramethylcyclo-pentanecarbonyl chloride (2.56 g, 13.6 mmole), followed by triethylamine (3.46 ~1, 24.9 mmole). The mixture was stirred at room temperature and the reaction monitored by TLC. When ~3~

reaction was complete (approximately 5 hours)/ ethyl acetate and water were added, the phases separated and the aqueous phase re-extracted with ethyl acetate. The combined organic phases were washed with IM aqueous sodium bicarbonate (2 x~, 2N hydrochloric acid (3 x), saturated sodium chloride and dried (MgSO4). The solvent was evaporated under reduced pressure and the residue recrystallized from ethyl acetate~
hexanes to give N-(N~-benzyloxycarbonyl-~-benzyl-L-aspartyl)-N'-(2,2,5,5-tetramethylcyclopentanecarbonyl)-R~ diamino-propane (4.4 g) which was homogeneous by TLC. The nmr spec-trum of the product was consistent with the assigned structure.
E. The product from Part D (4.0 g) was hydrogenated in the usual manner in glacial acetic acid (100 m:L) over 10%
palladium on carbon. After lyophilization and relyophiliza-tion from water several times, N-~L-aspartyl)-~'-(2,2,2,5-tetramethylcyclopentanecarbonyl)-R-l,l-diaminopropane was obtained in quantitative yield, m.p. 164C dec.
Sweetness = 200-300 x sucrose.

StabilitY of N-(L-AsPartyl)-N'-(2,2,5,5-Tetram thylcyclopentanecarbonyl)-R-l,l-Diamlnoethanethane Sweetener The stability of -the title sweetener (Example 14) was studied at 90C and pH 7.0 and 3.0 in 0.01M phosphate - buffer. The disappearance of the compound under these condi-tions was monitored by quantitative HPLC measurements, under the following conditions: column: LICHROSORB RP-18, flow rate: 1.5 ml/min., isocratic acetonitrile (17%) in 0.01M
triethylammonium phosphate buffer, pH 4.5. The results of these studies are summarized in Table 2.
From these data the half-life of this compound at ~:3~

both pH 3.0 and pH 7.0 is estimated to be a minimum of 20 years at room temperature (250Cj.

Stability of N-(L-Aspartyl)-N'-(2,2,5,5-Tetramethylcyclo-pentanecarbonyl)-R-l,l-Diaminoethane Sweetener at pH 7.0 and 3.0 Percent Sweetener Remaining TimepH 7.0 pH 3.0 1 hour99.6 98.9 3 hours 98.7 96.5 8 hours 97.0 92.4 1 day92.4 83.0 4 days81.0 58.2 Sweetness Evaluation The following is an outline of the "sip and spit"
method of blind evaluation used to evaluate the sweetness of the compounds of the invention.
Samples were prepared by dissolving a given amount of the sweetener (e.g. 40 mg in 100 ml) in water or coffee. The sweetener concentration was chosen on the basis of preliminary taste evaluation in which the order of magnitude of sweetness was somewhat established. In addition to the experimental sam~le, three other samples of sucrose were prepared, their concentrations being chosen to bracket the estimated sweetness of the compound being tested. Samples were presented to an expert taste panel for evaluation. The selected judges were asked to evaluate each sample for sweetness intensity by sipping the solution and spitting and to rank the samples in accordance with descending order of sweetness.
~ The average rank of the experimental sample was computed and the e~uivalent concentration of sucrose! was ~2~

estimated. The relative sweetness was calculated from this data. If the experimental product was ranked lowest or highest, the experiment was repeated using different sucrose concentrations.
In addition to being sweeteners, the compounds of the present invention are also useful as flavor potentiators.
This is confirmed by the following tests:
Flavor Potentiatinq -- Tomato Sauce To commercial spaghetti sauce, 3 ppm of the following were added:
1. Compound Example 1 2. Compound Example 14 3. Saccharin : The sauces were mixed, heated and evaluated hot by an expert panel for flavor level on a.scale of 0 =-none to 8 = very - -strong. The panel also received a blind control product (with nothing added). The results are summarized below:
Sample Flavor Level Control 6.0 Compound Example 1 6.7*
Compound Example 14 7.0*
Saccharin 5,7 : *Significant at the 95 percent confidence level.
These data clearly indicate that these compounds act as flavor - enhancers and that this property is not related to their : sweetness properties.
Flavor Potentiatinq -- Mouthwash To a co~nercial mouthwash preparation, the following compounds were added at the 1.5 ppm level:
1. Compound E~ample 1 2~ Compound Example 14 ~3~

In addition, a control (unaltered product) was included.
An expert panel was asked to gargle with the mouthwash for 15 seconds and evaluated the flavor intensity immediately and 3 minutes after gargling on a scale of O = none to 8 = very strong. The results are outlined below:
1 minute 3 minutes Control 5.7 2.2 Example 14 6.7 * 3.0 *
Example 1 6.0 3.0 *
* Significant at the 95 pexcent confidence level.
These data clearly establish the flavor enhancing properties of the compounds of the invention.
While the invention has been described with respect to particular compound and methods of producing the compounds, - it is apparent that variations and modifications of the invention can be made.

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Claims (4)

The embodiments of the invention in which an exclusive pro-perty or privilege is claimed are defined as follows:

1. The compound 1,2,2,5,5-pentamethylcyclopentanol.

2. The compound 1-methylene-2,2,5,5-tetramethylcyclo-pentane.

3. The compound 2,2,5,5-tetramethylcyclopentylmetha-nol.

4. The compound 2,2,5,5-tetramethylcyclopentanecarbo-xylic acid.