Sweetness and Sweeteners - American Chemical Society

Chapter 34

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Recent Developments in Structure-Taste Studies of Sulfamates William J. Spillane*, Damien P. Kelly, Jean-Baptiste Malaubier, Gary G. Hanniffy, Brendan G. Feeney, Catherine C. Coyle, Lorraine M. Kelly, Emer F. Thompson, Danny G. Concagh, and Maryanne B. Sheahan Department of Chemistry, National University of Ireland, University Road, Galway, Ireland

The effect of sulfamation on known tastants has been investigated using several series o f compounds containing a primary amine function namely, nitroanilines, phenylureas and -thioureas and amino acids and peptides. Profund changes in taste took place on sulfamation. The effect of chirality on the taste portfolios of various sulfamates has also been examined by preparing sets of enantiomeric pairs from aliphatic, aliphatic/aromatic and alicyclic/aromatic precursor amines and aminoalcohols. Some interesting taste differences have emerged, though these are not as great as observed in the first study.

530

© 2008 American Chemical Society

In Sweetness and Sweeteners; Weerasinghe, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2008.

531

Introduction For some years we have been synthesizing sodium sulfamates R N H S 0 N a , where R may be aliphatic (straight chain or branched), alicyclic, aromatic and hetero- (open chain and cyclic) and developing both quantitative and semiquantitative structure-taste (SAR) relationships (7-3). The SARs developed have involved the use of various spatial, electronic and other parameters and the use of a number of techniques, such as linear and quadratic discriminant analysis {4,5) and more recently classification and regression (CART) analysis {6,7). The derived relationships generally have good predictive ability in the sense that i f a large training set is used they can usually predict the predominant tastes of most of the members of a small test set correctly. Secondly they have faired quite well in correctly predicting the tastes of compounds that at the time had not been synthesized. Thirdly, because steric or volume parameters are always involved in the SARs constructed, a reasonable estimate can be made of the 'opening' dimensions of the receptor site. Apart from seeking quantitative structure-taste relationships qualitative ones have also been sought by examining the effects of changes in the - N H S 0 " N a portion of the sulfamate moiety. Thus, replacement of the amino hydrogen by an alkyl group destroys sweetness'(8) but the replacement of the negative charge on the sulfamate anion does not and sulfamate esters R N H S 0 R ' tend to be strongly sweet with concomitant bitterness (P). However, we have not produced a new highly potent sulfamate (cyclamate) sweetener and the sweetest known sodium sulfamate, sodium exonorbornylsulfamate with a relative sweetness (RS) ~ 76 (5) has been known for more than twenty years (70). Now in two fresh approaches (i) known (usually) sweet tastants have been sulfamated and the taste portfolios of the products examined and (ii) the effect of chirality on sulfamate tastes has been looked at.


3

3

+

3

Sulfamation of Known Tastants One could list a variety of ways of trying to induce sweetness or prepare new sweet compounds. They would include: (i) (ii) (iii)

use of templates such as suosan, aspartame etc. (77), use of the Nofre and Tinti Multicomponent Attachment Theory ( M C A ) (72) or other structure-taste relationships {6,13,14), the identification of atoms, groups or molecules known to be sweet taste potentiators and the introduction of these into other molecules U5).


532


A n interesting early example of (iii) is shown in Figure 1 where an attempt was made to prepare a new sweet molecule(s) by combining two known sweeteners, namely, dulcin and saccharin (16).

"Saccharin-6-dulcin" (Tasteless)

"Saccharin 2-/?-ethoxyformani 1 ide" (Tasteless)

Figure 1. Combining the known sweeteners Dulcin and Saccharin

A more or less similar strategy has been tried with the sweet dihydrochalcone (DHC) shown in Figure 2 which was sulfamated to give a sulfamate with the same level of sweetness (17). This latter example shows one can try to induce additional sweetness by introducing a 'sweet-conferring entity' into a known sweet molecule. Probably the reason that the taste did not change is because the crucial 'receptor' sites of the D H C molecule were not interfered with as a result of sulfamation at the relatively distant - N H position. 2

A dihydrochalcone (DHC)

A dihydrochalcone-sulfamate

Figure 2. Effect of sulfamation on taste of a dihydochalcone (DHC)


533 This is the kernel of our approach in this part of our work but in order to proceed we have to (i) identify molecules with a primary amine function (suitable 'sulfamatable' site - the molecule must retain a hydrogen atom on the sulfamate nitrogen after sulfamation (vide infra) to have the possibility of being sweet and (ii) have available taste data in the literature for these molecules (see Figure 3). Suitable SO, Downloaded by MICHIGAN STATE UNIV on February 18, 2015 | http://pubs.acs.org Publication Date: March 4, 2008 | doi: 10.1021/bk-2008-0979.ch034

NH

NHSO3

2

Not suitable R-NH

S0 — —

3

S0 R'R'TM

•

R'NS0

3

3

— R ' R " N . S 0

3

Requirements: 1) Primary amine function 2) Taste data already available in the literature Figure 3. Criteria for suitable molecules for sulfamation

Fortunately the, mostly older, literature contains large amounts of taste data since there was a tendency then to include tasting of a new compound together with a plethora of other determinations such as solubility, mp/bp, Kjeldahl analysis for nitrogen (when appropriate) and various additional physical measurements. Several extensive compilations of systematic taste data are available (18-21). The molecules that we have chosen for sulfamation are shown schematically by class in Figure 4. At the top left of the Figure anilines (mostly nitroanilines) are shown and moving anti-clockwise through the Figure are phenylureas, phenylthioureas, amino acids and dipeptides.

Anilines Anilines were either available commercially or synthesized as shown in Figure 5 with separation by flash chromatography and/or recrystallization. A l l sulfamates irrespective of precursor were synthesized by the procedures illustrated in Figure 6. In the third vertical column in Table I the literature tastes of the parent anilines are reported and most of these can be obtained from two major listings


534

NH

R

2

R

NaO.C-C-N-^pC-NH, H RI Anilines \ ^

OH Dipeptides

/

NHCONH

2

Na0 C-C-NH 2

NHCSNH,

2

H


Amino acids

Phenylthioureas

Figure 4. Molecules of known tastants which possess a "sulfamatable" site

Preparation of reagent in situ α-Pic

CISO3H

+

a-Pic.S0

3

+

a-Pic.HCl

Sulfamation

J

+

a-Pic.S0

3

Recrystallization from aqueous EtOH Tests for CI, S0 ,-NHS0 * Characterization by H and C NMR, IR and C, Η and Ν analysis 2

a-Pic

4

-

a Ν

3

1

Me

1 3

Figure 6. Synthesis ofsulfamates


535 Table I. Comparative taste studies of various mono- and disubstituted anilines and their sulfamates Aniline R R QH3NH2 R

1

Predominant taste(s)* & lesser taste(s) of sulfamates R'R^eHjNHSOjNa

Tasteless Sweet Almost Tasteless Sweet Sweet Sweet Sweet Sweet Sweet Sweet Sweet Sweet

Very bitter Bitter Sour Sweet Bitter/Sweet a. V. bitter V. bitter Bitter/Sweet Sweet/Bitter Sweet/Sour Sweet/Bitter Sour

2

R H H H H 5-CFj 5-CFj 5-CFj 5-N0 5-N0

2-NO2 3-NO2 Downloaded by MICHIGAN STATE UNIV on February 18, 2015 | http://pubs.acs.org Publication Date: March 4, 2008 | doi: 10.1021/bk-2008-0979.ch034

Lit. taste of Anilines

4-NOz 3-CN 2-C1 2-Br 2-F 2-Pr"0 2-F 2-C1 2-Me 2-MeO

c

2

2

5-NO2 5-NO2 4-NO2

a

b

b

c

Bold font indicates predominant taste. Sweet a. means sweet aftertaste. Synthesised in 34% yield.

of the tastes of organic compounds (18,20) and some tastes can be found in Verkade (21) and Blanksma and van der Weyden (22). There are some interesting anilines listed in Table I. For example, 3nitroaniline (R = 3 - N 0 , R = H) is believed to be the earliest sweet compound reported in the literature in 1846 (23) and 2-n-propoxy-5-nitroaniline, known as P-4000, was the sweetest compound known (24) until the discovery of the hyperpotent sweeteners about 20 years ago. Comparsion of the literature taste data for the anilines in column 3 of Table I with that for the sulfamated anilines in column 4 shows that sweetness is frequently retained on sulfamation though it is often tempered with bitterness or sourness. The literature tastes for the anilines are qualitative but probably reliable and in a few cases different groups have reported the same taste. For example, 2-chloro-5-nitroaniline (R = 2-C1, R = 5N 0 ) is reported to be sweet by Wheeler in 1895 (25) and by Blanksma in 1946 (26). 1

2

2

1

2

2

Phenylureas and -thioureas About half of the phenylureas needed were available commercially and the others were synthesized by the methods (27,28) outlined in Figure 7.


536 ArNH

+ 2

Dil. CH C0 H 3

2

HNCO

ArNHCONH

2

35°C

ArNH

2

+ SCHNCOC H 6

Heat 5

ArNHCSNHCOC H 6

5

Debenzoylation ArNHCSNH Downloaded by MICHIGAN STATE UNIV on February 18, 2015 | http://pubs.acs.org Publication Date: March 4, 2008 | doi: 10.1021/bk-2008-0979.ch034

2

Figure 7. Synthesis of phenylureas andphenylthioureas

The % yields of those synthesized are given in Table II. The third and fourth columns in the Table record the literature tastes (18-21) and the tastes found by us for the parent ureas and generally there is good agreement where comparsion is possible. The sulfamation of the ureas was carried out as for the anilines above (see Figure 6). The last column contains the tastes recorded for the resulting phenylureasulfonates and there are a number of interesting changes. 2Fluorophenylurea ( X = 2-F) a bitter compound becomes predominantly sweet on sulfonation, 3-methylphenylurea ( X = 3-Me) has some slight sweetness introduced and 4-methoxyphenylurea ( X = 4-MeO) retains substantial sweetness. The former well known commercial sweetener Dulcin, 4ethoxyphenylurea ( X = 4-EtO) used in the U S in the fifties for a time, retains a little sweetness after sulfonation. The final compound on the list is 2methylphenylthiourea which retains its bitterness on sulfamation. One issue which arises in the case of the ureas is the possibility of various products forming. These are shown in Figure 8. Disulfamation occurs readily with some ureas and thus (A) and (B) are possible products of the sulfamation reaction. The expected and desired monosubstituted product would be (C) but (D) could also form. Formation of (A) and (B) can be inhibited by using less pyridine sulfur trioxide adduct in the sulfamation. Proton N M R analysis of the product shows i f (A) or (B) are present since some or all of the Hs on the two nitrogens N and N will be missing. Similarly if (C) forms the two Hs on N and N respectively can be seen and i f (D) is present the Ν H is missing and the N Hs can be clearly discerned (29). 1

2

2

1

1

2

Amino acids and dipeptides In Table III literature tastes for a series of amino acids and dipeptides are brought together. The first seven amino acid tastes in column 2 have been reported by Birch and Kemp (30) and the taste of L-phenylalanine is given by


537

Table II. Comparison of tastes of various phenylureas, thioureas and their sulfonates Phenylurea/thiourea XC H NHCYNH a


6

4

% yield

Lit. taste

Taste(s) of sulfonates XC H NHCYNHS0 Na

Found taste

6

2

4-Br H 2-Me 3-Me 4-Me 2-MeO 4-MeO 2-EtO 3-EtO 4-EtO 2-F 4-F 2-Me

85

38

53 46 83

17

Sweet Bitter Tasteless Bitter Sweet Tasteless Sweet

a

c

b

Y = 0 for the first 12 compounds, Y = S for the last entry. Bold font indicates predominant taste and normal font indicates lesser tastes. a. means aftertaste. c

Na0 S> 3

•A*

.SCXNa

^S0 Na 3

Ar

Ar

S0 Na 3

Ο

Ο

/S0 Na Ν Ν I I Ar Η 3

C

Na0 S^, Ν 3

I Ar

3

Bitter Sour Bitter/Sour Bitter/Sour/Sweet a. Sour Tasteless/Bitter Bitter/Sweet a. Bitter Bitter Bitter/Sweet a. Sweet Sour Bitter

c

Sour/Sweet a. Bitter Tasteless Bitter Sweet Bitter Sweet Tasteless Tasteless Sweet Sweet Bitter Bitter Tasteless/Bitter a.

4

Ν I Η

D

Figure 8. Possible phenylureasulfonate products


a

538 Table III. Tastes of amino acids and dipeptides and of their sulfamates Amino acids

Lit. taste

Glycine

Sweet

L-alanine

Sweet

Sulfamates R N H S 0 N a R=

Predominant taste(s) & lesser taste(s) Salty

3

a

NaCLC—C— H '

Bitter N a O2X — C — C H3,


H

L-methionine

Sweet/Sour

Bitter Na0 C—C—(CH )5—S—CH H 2

L-valine

2

Sweet/Sour

Sweet/Bitter Na0 C—C—CH-(CH ) H 2

L-glutamic acid

3

3

2

Salty/Sour

Sour N a 0 C — C — ( C H ^ C0 Na H 2

L-aspartic acid

2

Sour

Sour HCLC—C—C—C0 H H H 2 2

2

2

L-aspartic acid

Salty

Sour NaCLC—C—C—CCLNa H H 2

2

2

L-phenylalanine

Sour/Salty

Bitter HO,C—C—C—GIL H H 2

6

5

2

L-phenyl-Lphenylalanine methyl ester

Bitter

Bitter Q

Ç0 Me 2

>

H L-aspartyl-Lphenylalanine methyl ester (Aspartame)

Sweet

Ç0 HO

XT

Na a

+

"0 S"%

Sour

C0 Me

2

2

Tl

>

*

H

3

Bold font indicates predominant taste.


539


Solms, Vuataz and Egli (31). The tastes of the two dipeptides are reported by Mazur, Schlatter and Goldkamp (32). There are some features of interest in Table III, which records the literature tastes in column 2 and then in the final column the taste assessments of the 'sulfamated amino acids and dipeptides'. Glycine and L-alanine lose sweetness on being sulfamated, however sweetness is induced in L-methionine and retained in L-valine. Less change may be noted in the other amino acids when sulfamated. L-aspartic acid can retain its sourness in the monosodium salt but becomes salty when it is isolated as the trisodium salt. Sulfamation of the first dipeptide produces no change but sulfamation of aspartame destroys sweetness producing a sour compound.

Effect of Stereoisomerism on Sulfamate Taste There have been some studies on the tastes of structural isomers of sodium sulfamates (1,6) and some of these are illustrated in Figure 9, where it is clear that the position of a particular group or atom or of the sulfamate grouping can have a major effect on taste.

Sweet

Me

Very sweet

Ci

Nonsweet /sweet

Bitter, sweet aftertaste

Figure 9. Tastes of structural isomers ofsulfamates


540 For the sulfamates the effect of geometrical isomerism (Figure 10) has been examined, particularly by Unterhalt and Boschemeyer in a series of papers (5555) and de Nardo, Runti and Ulian (70) have shown that sodium endonorbornylsulfamate is tasteless and the exo-isomer is 'molto dolce and is the sweetest sulfamate synthesized to date. The RS values for the two compounds are 9 and 70 respectively (5). In the second part o f our current work we have been examining the effect on taste of the stereoisomerism of pairs of sodium sulfamate (R)- and (S)isomers. For the ten pairs of compounds shown in Table IV only minor differences have been observed, though some sweetness has been introduced into sodium 1 -( 1 S)-( 1,2,3,4)-tetrahydro-1 -naphthalenylsulfamate compared to the (R)-isomer (see entry 8) and removed in sodium l-(lS)-(3-methoxypheriyl)ethylsulfamate as compared to the (R )-isomer (see entry 2).


9

NHS0 Na 3

cis: Sweet trans: Tasteless

cis: Sweet trans: Tasteless 3 RNHSOjNa

1

R Me H H

2

R H Me H

NHS0 Na 3

3

R H H Me

cis Not sweet cis Sweet cis/trans Not sweet

R

i

M

e

H

R

2 Tasteless Tasteless

H

Me

NHS0 Na 3

/^^NHS0 Na 3

Me tram cis Some degree of sweetness" m

Tasteless RS = 9

(V

n

s

Very sweet RS = 70 NHS0 Na 3

m

d

0

NHS0 Na 3

Figure 10. Taste of geometrical isomers ofsulfamates


541

Table IV. Tastes of sulfamate stereoisomers


Entry

Z-

Sulfamate inZNHSQ Na

8

(R)

(S)

Sweet/Sour

Sweet/Bitter

Sweet/Bitter

Tasteless/ Bitter

Sweet

Tasteless/ Sweet

Salty

Salty/Bitter

Bitter/Sweet

Sweet/Bitter

Bitter/

Tasteless

Tasteless/ Bitter

Tasteless/ Sweet

Tasteless/ Sweet

3

MeO

MeO

OH

a

Bold font indicates predominant taste. Continued on next page.


542


Table IV. Continued.

a

BoId font indicates predominant taste.

Conclusions and Future Work The effect of sulfamation on the taste of anilines, arylureas, L-amino acids and dipeptides has been examined. A change in the taste portfolios has been found for about half of the compounds sulfamated. The effect on the tastes on sulfamation of a series of structural, geometrical and stereoisomers has been reviewed in outline. A series of pairs of (R)- and (S)-stereoisomers have been sulfamated and the mainly slight differences in taste between these have been noted. Future work includes further synthesis and sulfamation of ureas/thioureas and the development of structure-taste relationships (SARs) for these, synthesis of additional (R)/(S) and cis/transAsomexs and examination of some of the current results within the framework of recent taste receptor models.

References 1. 2. 3.

Spillane, W. J.; McGlinchey, G. J. Pharm.Sci.1981, 70, 933-935. Spillane, W. J.; Ryder, C. Α.; Curran, P. J.; Wall, S. N.; Kelly, L. M.; Feeney, B. G.; Newell, J. J. Chem. Soc. Perkin Trans. 2, 2000, 1369-1374. Drew, M.G.B.; Wilden, G.R.H.; Spillane, W. J.; Walsh, R. M.; Ryder, C. A.; Simmie, J. M. J.Agric.&Food Chem 1998, 46, 3016-3026.


543 4. 5. 6. 7.


8. 9. 10. 11.

12.

13.

14. 15. 16.

Spillane, W. J.; Feeney, B. G.; Coyle, C. C. Food Chemistry 2002, 79, 1522. Spillane, W.J.; Kelly, L.M.; Feeney, B.G.; Drew, M.G.B.; Hattotuwagama, C. K. ARKIVOC (Issue in honor of Prof. M. A. McKervey) 2003, 297-309. Kelly, D. P.; Spillane, W. J.; Newell, J. J. Agric. & Food Chem. 2005, 53, 6750-6758. Spillane, W. J.; Kelly, D. P.; Curran, P. J.; Feeney, B. G. J. Agric. & Food Chem. 2006, 54, in press. Audrieth, L. F.; Sveda, M. J. Org. Chem. 1944, 9, 89-101. Spillane, W. J.; Hanniffy, G. G. J. Agric. & Food Chem .2003, 51, 30563059. de Nardo, M.; Runti, C.; Ulian, F. Farmacio Ed. Sci. 1984, 39, 125-132 ; [Chem. Abs. 1984, 100, 137568] Tinti, J.-M.; Nofre, C. Design of Sweeteners - a Rational Approach In Sweeteners - Discovery, Molecular Design and Chemoreception, Walters, D. E. ; Orthoefer, F. T. ; DuBois, G. E. Ed. ACS Symposium series 450, American Chemical Society, Washington, DC, 1991; ch. 7, 88-99. Tinti, J.-M.; Nofre, C. Why Does a Sweetener Taste Sweet? - A New Model. In Sweeteners - Discovery, Molecular Design and Chemoreception, Walters, D. E . ; Orthoefer, F. T. ; DuBois, G . E . Ed.ACS Symposium series 450, American Chemical Society: Washington, D C , 1991; ch. 15, 206-213. Walters, D. E. The Rational Discovery of Sweeteners .In Sweeteners Discovery, Molecular Design and Chemoreception, Walters, D. E. ; Orthoefer, F. T. ; DuBois, G. E. Ed. A C S Symposium series 450, American Chemical Society Washington, D C , 1991; - ch. 1, 1-11. Morini, G.; Bassoli, Α.; Temussi, P. A. J. Med. Chem. 2005, 48, 5520-5529. Roy, G . Critical Reviews in Food Science 1992, 31, 59-77. Finzi, C.; Colonna, M. Atti accad. Lincei, Classe sci. fis., mat. nat. 1937, 26, 19-24 ; [Chem. Abs. 1938, 32, 3762 ]. DuBois, G. E.; Stephenson, R. A. J. Org. Chem. 1980, 45, 5371-5373. Cohn, G. Die Organischen Geschmackstoff, Franz Siemenroth: Berlin, 1914. Cohn, G. Geschmark und Konstitution bei Organischen Verbindungen, Ferdinand Enke: Stuttgart, 1916. Moncrieff, R. W. The ChemicalSenses;Leonard Hill, London, 1967. Verkade, P. E. . Farmaco Ed. Sci. 1968, 23, 248-291; [Chem. Abs. 1968, 68, 92869]. Blanksma, J. J.; Van der Weyden, P. W. N. Rec. Trav. Chim. 1940, 59, 629632. Muspratt, J. S.; Hofmann, A. W. Justus Liebigs Annalen der Chemie 1846, 57, 201-224. de Koning, A. J. J. Chem. Educ. 1976, 53, 521-522. 1

17. 18. 19. 20. 21. 22. 23. 24.



544 25. Wheeler, H. L. Amer. Chem. J. 1895, 17, 697-704. 26. Blanksma, J. J.; Van den Broek, W. J.; Hoegen, D. Rec.Trav. Chim. 1946, 65, 329-332. 27. Kurzer, F. Arylureas. I. Cyanate Method and II. Urea Method. In Coll. Org. Synthesis, Rabjohn, Ν. Ed. vol. 4, Wiley, NY 1963; 49-54. 28. Rasmussen, C. R.; Villani, F. J.; Weaner, L. E.; Reynolds, Β. E.; Hood, A. R.; Hecker, L. F.; Nortey, S. O.; Hanslin, Α.; Costanzo, M. J.; Powell, E. T.; Molinari, A. J. Synthesis 1988, 456-459. 29. Concagh, D. G. M.Sc Thesis, National University of Ireland, Galway Ireland, 1995. 30. Birch, G. G.; Kemp, S. E. Chem. Senses 1989, 14, 249-258. 31. Solms, J.; Vuataz, L.; Egli, R. H. Experientia 1965, 21, 692-694. 32. Mazur, R. H.; Schlatter, J. M.; Goldkamp, A. H. J. Amer. Chem. Soc. 1969, 91, 2684-2691. 33. Unterhalt, B.; Mollers, M. Arch. Pharm. (Weinheim, Ger.) 1991, 324, 525526. 34. Unterhalt, B.; Kerckhoff, L.; Mollers, M. Sci. Pharm. 2000, 68, 101-108. 35. Unterhalt, B.; Boschemeyer, L . Ζ. Lebensm. Unters.-Forsch. 1975, 158, 3536.


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