Transcript Reflections on a Half Century of Flavor Chemistry

Reflections on a Half Century
of Flavor Chemistry
SFC 50th Anniversary Flavor Symposium
October 7, 2004
John C. Leffingwell
Leffingwell & Associates
1954 – FDA BANS COUMARIN
Is it hepatoxic?
Or is it???
OH
Mold
O
Coumarin
O
O
O
O
O
OH
OH
HO
O
O
Major metabolite in man
O
O
Dicoumarol (Coumadin)
Reflections on a Half Century of Flavor Chemistry
1954 - television screens were small
round and black & white
1954 – the first transistor radio (The
Regency) is introduced in October 1954
(transistors were developed at Bell Labs
in 1948 by Shockley, Brattain & Bardeen
for which they received the Nobel Prize in
Physics 1956)
Tom Watson, Jr., at IBM gave Regency
radios to his engineers and told them to
put transistors in computers.
By 1954 over a million people a year were deserting
the big cities for affordable homes in suburbia
Major Advances in Instrumentation
1952
1952
1952
1954
1955
1956
1958
1959
1976
1977
1978
1981
1984
1988
1991
1994
1996
First publication on gas chromatography (James & Martin)
Bloch and Purcell awarded the Nobel Prize for NMR
Varian sells first NMR to Humble Oil
E.J. Corey solves first structure problem with NMR
Perkin-Elmer - first commercial GC
First demonstration of GC/MS (Bendix Corporation)
M. Golay develops capillary columns
Flame ionization detector introduced
HP introduces world’s first benchtop GC/MS
Wozniak & Jobs introduce the Apple II computer
NBS releases 25,000 MS spectra
The IBM Personal computer & Bill Gates
HP introduces the 5890, the best-selling GC in history
NIST MS database
Wiley MS database
HP introduces the ChemStation software
NIST releases AMDIS deconvolution program
Volatile Chemicals Identified in
Foodstuffs
8000
6000
5000
4000
3000
2000
1000
19
99
19
94
19
89
19
84
19
79
19
74
19
69
0
19
63
Thoussands.
7000
Major Advances in Instrumentation - NMR
6
5
4
PPM
3
2
1
0
Major Advances in Instrumentation

Gas Chromatography – Mass Spectrometry
GC-MS Analysis of a Meat Flavor
Abundance
Peak Identified as Furfuryl Mercaptan
Powerful Coffee Aroma
1.6e+07
1.4e+07
SH
O
Peaks are 2-Methyl-2,3-dihydrofuran-3-thiol isomers
Powerful meat-like aroma
1.2e+07
SH
SH
1e+07
8000000
O
6000000
CH3
CH3
O
4000000
2000000
0
12.00
Time-->
14.00
16.00
18.00
20.00
22.00
24.00
26.00
28.00
30.00
32.00
34.00
36.00
1958 – Food Additives Amendment
Food Additives Amendment enacted, requiring
manufacturers of food additives to establish safety.
FEMA begins process for establishment of a GRAS list
for flavorings in cooperation with the FDA.
1960 – FEMA publishes first “tentative” list of GRAS
flavorants.
1961 – FEMA publishes first “expert committee peer
reviewed” list of GRAS flavorants (662 items).
1965 – FEMA publishes expanded GRAS list (1124
items).
2004 – FEMA GRAS lists now contain ~2066 items
1955 - Butter Flavor and the delta-lactones
By the mid-50’s margarine was poised to overtake
butter as the table spread of choice
C7H15
O
O
C5H11
O
About 1955 it was recognized that delta-dodecalactone
was an important butter flavor and combinations of
delta-decalactone & delta-dodecalactone would soon be
the key to improved acceptability
O
Advances in Flavoring Materials
Pyrazines
• In 1926, Reichstein & Staudinger patented the use of furfuryl
mercaptan and other coffee isolates including a series of alkyl
pyrazines for use in artificial coffee flavor
• But the value of pyrazines as flavorants was overlooked until
the mid 50’s when they were rediscovered as important
contributors to cocoa by Dietrich, et al., at Firmenich.
• Subsequently many hundreds of publications have appeared
on the flavor properties of pyrazines. In coffee, cocoa and tea
alone, 100 monocyclic pyrazines, 15 bicyclic pyrazines and 12
quinoxalines have been identified.
Advances in Flavoring Materials
1950’s –1960’s - Pyrazines
O
N
N
O
O
CH3
N
CH3
N
Green, Bell pepper,
Galbanum
N
CH3
Roasted peanut,
hazelnut
N
Popcorn, nutty,
bready
N
N
N
N
N
N
Cocoa, dark chocolate,
nutty
Earthy, raw potato;
aroma of damp black
earth
Nutty, brown, roasted,
earthy and musty
Today about 60 different pyrazines are employed in flavor creation
Advances in Flavoring Materials
1950’s – 1970’s – Thiazoles
S
OH
S
N
N
Sulfurol
meaty-beef like with nutty note
2,4-Dimethyl-5-vinylthiazole
Nutty, meat like notes
O
S
N
2-isobutylthiazole
Green tomato aroma and taste;
tomato leaf aroma
S
N
2-acetylthiazole
Nutty, popcorn, bread,
toasted cereal
Today about 45 different thiazoles are employed in flavor creation.
Advances in Flavoring Materials
1950’s – Mushroom alcohol (1-octen-3-ol)
Although first isolated from Armillaria matsutake in 1937 and
Later (in 1944) from lavender, this material was virtually
unknown to most Flavorists until the late 1950’s.
HO
H
(R)
Natural mushroom odor,
slightly fruity
OH
H
(S)
Herbaceous, green, musty
Today, we know that the racemates odor is dominated by the
olfactively more powerful (-)-(R)- enantiomer.
Advances in Flavoring Materials
1959 – Bain & Webb – Turpentine into Fragrance & Flavor
O
H3C
CH
3
CH
2
H C
3
H3C
OH
H3C
CH2
CH2
beta-Pinene
H3C
CH2
Linalool
CH2
H3C
CH3
CH3
O
H3C
CH3
Linalyl Acetate
OH
H3C
Menthol
CH3
CH3
CH3
CH3
CH3
Myrcene
OH
OH
H3C
CH3
Geraniol
H3C
CH3
Citronellol
O
H3C
CH3
Citronellal
Advances in Flavoring Materials
1959 – Roche Process for Linalool & Citral via Acetylene
OH
OH
O
Linalool
CHO
Citral
Advances in Flavoring Materials
1959 – Discovery of Methyl Dihydrojasmonate
Hedione®
O
O
O
O
O
O
1971 – Introduction of Hedione®"
1996 - First synthesis of pure "(+)-cis-Hedione®" the
olfactively most active stereoisomer of Hedione®
Advances in Flavoring Materials
1959 – Discovery of Rose Oxide
1960 – Safrole Banned
Root Beer manufacturers shudder. Key ingredient
banned.
Manufacturers and flavor companies scramble to
reformulate.
Solution: Methyl salicylate with other items such as
methyl chavicol and anethole.
O
O
HO
Safrole
O
O
O
O
Methyl salicylate
Methyl chavicol
Anethole
Advances in Flavoring Materials
Leaf Alcohol
Although the exact structure of leaf alcohol was
established in 1938, it was not widely available until
Bedoukian’s process in 1961.
Na
O
OH
OH
or
Cl
OH
Leaf alcohol was essential for the development of
many fruit flavors, especially strawberry
The esters are important in many tropical flavors
Advances in Flavoring Materials
Discovered in 1937, the First Publication on
Raspberry Ketone appears in 1961
O
HO
Advances in Flavoring Materials
1962 – First publications appear on Methyl Jasmonate &
Methyl Dihydrojasmonate
O
O
3
4
H
H
2
(R)
1
(R)
5
(Z)
CO2CH3
H
1R,2R-(-)-Z-methyl jasmonate
(Z)
(S)
H3CO2C
H
1S,2S-(+)-Z-methyl jasmonate
O
O
H
H
(S)
(Z)
(Z)
CO2CH3
1R,2S-(+)-Z-methyl epijasmonate
(R)
(S)
(R)
H
(S)
H3CO2C
H
1S,2R-(-)-Z-methyl epijasmonate
Methyl Jasmonate – odorant, insect pheromone, plant growth regulator
Advances in Flavoring Materials
Chirality & Odor - Methyl Jasmonate & Methyl
Dihydrojasmonate
Configuration
Methyl jasmonates
1R,2R-(-)1S,2S-(+)1S,2R-(-)-epi1R,2S-(+)-epi-
Odor Description
Odor Threshold (in PPB)
Weak odor
Odorless
Odorless
Strong odor; floral, true jasmin-like
>70*
Odorless
Odorless
3*
Ref: T.E. Acree et. al., J.Agric.Food.Chem. 1985
Methyl dihydrojasmonates
1R,2R-(-)Floral, sweet, jasminelike
240**
1S,2S-(+)Floral, fatty, cis-jasmone, hay character,
15,360**
tea note, slightly lemon peellike (weak)
1S,2R-(-)-epiHerbal, fatty, tea-like, tobacco,
12,500**
β-damascone, cis-jasmone
1R,2S-(+)-epiIntensely floral, jasmine-like, bright, cis15**
jasmone, slightly fatty, woody,
β-ionone-like, extremely long lasting
Ref: Werkhoff, P., et. al., Food Reviews International, 2002
* detection threshold
**recognition threshold
Advances in Flavoring Materials
1964 – Introduction of Furaneol®
OH
O
O
1965 – First publications on isolation of Furaneol®
from strawberry and pineapple
Advances in Flavoring Materials
1965-66 – α- & β- Sinensal isolated from orange oil
CHO
CHO
Advances in Flavoring Materials
O
1. NOCl
2. H3O+
(R)
(-)-(4R)-carvone
(l-carvone)
Odor: Spearmint
(R)
Mirror Images
1950’s - 60’s – Synthetic Carvones
(+)-(4R)-limonene
(d-Limonene)
O
1. NOCl
2. H3O+
(S)
(-)-(4S)-limonene
(l-Limonene)
(S)
(+)-(4S)-carvone
(d-carvone)
Odor: Caraway
• By 1957 a commercially viable route to l-carvone was
available and in the 1960’s both synthetic l-carvone and
d-carvone were items of commerce.
• But only in 1971 was it unequivocally proven that the odor
differences were due to the enantioselective odor perception
of the differing chiral forms.
Advances in Flavoring Materials
1960’s – Nootkatone
First isolated in 1962, it’s importance to citrus flavor
was unknown until it’s isolation from grapefruit by
Mcleod in 1964.
In 1966, Coca-Cola introduced Fresca. By 1970,
Nootkatone was GRAS and became a key ingredient in
Fresca. Coca-Cola manufactured Nootkatone for many
years and soon made it available to the flavor industry.
O
(-)-Nootkatone
weak woody (vetiver note);
no grapefruit character;
virtually no taste
Threshold:
60,000 ppb
O
(+)-Nootkatone
strong grapefruit odor,
bitter in taste
800 ppb
Advances in Flavoring Materials
1968 – Pfizer patents Ethyl maltol
O
OH
O
Ethyl maltol (Veltol Plus®) was touted to be about 6X
stronger than maltol and an important substitute for
Coumarin. Well, at least it is stronger than maltol.
Advances in Flavoring Materials
1960’s-80’s – Important meaty compounds
SH
SH
O
O
2-methylfuran-3-thiol 2-methyl-4,5-dihydrofuran-3-thiol
Cooked meat
Cooked meat
SH
SH
S
2-methylthiophene-3-thiol
Cooked meat
CHO
Decadienal
Meat & poultry fat
Ortho-toluenthiol
Meaty, liver
N
2-pentylpyridine
Tallow flavor
Advances in Flavoring Materials
1970’s-80’s – Other Furanones
Sotolon (caramel furanone) & Maple furanone
identified in cane sugar – powerful caramel maple
notes
HO
O
HO
O
Sotolon
Threshold: 0.003 ppb
O
O
Maple Furanone (Abhexone)
0.00005 ppb
Sotolon – key flavorant of fenugreek, sake, sherry wine
Advances in Flavoring Materials
1970 – Discovery Damascenone & β-Damascone
O
O
O
1975 - Introduction of α-Damascone and β-Damascone
1982 – Introduction of Damascenone
Advances in Flavoring Materials
1973 - Haarmann & Reimer (-)-Menthol Synthesis
1965 – Haarmann & Reimer begins study on synthesis of
(-)-menthol from m-cresol/thymol
1973 – H&R menthol plant begins production in Holzminden
1978 – H&R’s Bushy Park, SC menthol plant on stream
H2
OH
OH
Resolution
via benzoate
OH
OH
Advances in Flavoring Materials
1974 – Thiomenthones identified in Buchu oil
O
HS
O
HS
Key component for black currant and
the “fuzzy” peach skin note
Advances in Flavoring Materials
1970’s - Wilkinson Sword’s - “Cool without Menthol”
In the 1970's Wilkinson Sword Ltd. designed and evaluated
about 1200 compounds for their cooling activity.
Two of these, WS-3 and WS-23 were commercialized with
limited success.
HN
H
N
CH3
O
C2H5
O
WS-3
WS-23
Upon expiration of the Wilkinson Sword patents in the late 90’s,
a flurry of activity resulted in expanded interest in these and
related “sensate” compounds (such as Takasago’s Coolant
Agent 10 and Symrise’s Frescolat® series).
Advances in Flavoring Materials
1980 – Patent on Oxane®
1977 - Winter identifies 2-methyl-4-propyl-1,3-oxathiane as
a character impact compound in Passionfruit
1984 – Pickenhagen determines that (-)- cis- 2-methyl-4propyl-1,3-oxathiane is the important diastereomer
O
H
O
H
S
H
H
S
(-)-(2R,4S)-2-methyl-4-propyl-1,3-oxathiane
(+)-(2S,4R)-2-methyl-4-propyl-1,3-oxathiane
• Odor: powerful sulfury, tropical fruit
• Odor: flat, estery, camphoraceous,
floral, less sulfury
• Threshold: 2 ppb
• Threshold:4 ppb
Advances in Flavoring Materials
1981 – BASF Citral Plant comes on stream
Isomerization
OH
OH
O
Oxidation
O
O
O
Citral
2004 – BASF opens new
continuous process citral plant
with 40,000 metric tons capacity
Advances in Flavoring Materials
1982 – 1-p-Menthene-8-thiol
Demole identifies 1-p-Menthene-8-thiol as a character impact
compound in Grapefruit Juice
S
SH
Very powerful with an odor threshold of 0.0001 ppb, it also
requires stabilization as it tends to rapidly cyclize to the thio
analog of dihydropinol.
Advances in Flavoring Materials
1983 – Takasago’s new Enantioselective Method
For producing (-)-menthol
CH2
CH3
H
CH3
CH2
Li
(S)-BINAP-Ru
NH(C 2H5)2
H3C
N(C 2H5)2
H3C
CH3
N(C 2H5)2
H3C
CH3
CH3
H 3O
H
CH3
H
CH3
H2
CH3
CH3
ZnBr 2
OH
H3C
H
+
O
OH
H3C
CH2
H3C
CH3
Advances in Flavoring Materials
1986 – H&R Patents Filbertone
The Character Impact Compound of Hazelnut
O
H
(S)
(+)-(E,S)-Filbertone - hazelnut,
metallic, fatty, pyidine, stronger impact
(at 25 ppb in water)
Odor Threshold of (+)-(E,S)-Filbertone
is about 10 times lower than for (-)(E,R)-Filbertone
O
H
(R)
(-)-(E,R)-Filbertone - hazelnut,
soft, butter, chocolate, metallic,
weaker impact (at 25 ppb in water)
Odor Threshold of (-)-(E,R)-Filbertone
is about 10 times higher than for (+)(E,S)-Filbertone
Advances in Flavoring Materials
2000 – The 3-mercapto-2-methyl-pentane-1-ols
HO
HS
3-mercapto-2-methyl-pentane-1-ol diastereosomers
broth-like, sweaty, leek-like
Advances in Flavoring Materials
2001 - 2,4,6-trithiaheptane
S
S
S
Character impact compound of white truffles
Odor: Leek, onion, cress, horseradish;
mushroom-like, earthy, green tinge
Advances in Flavoring Materials
2001 – Takasago’s Professor Ryoji Noyori wins
the 2001 Nobel Prize for Chemistry
OH
HO
Advances in Flavoring Materials
Advances in an Ambergris Compound Synthesis
O
H
1950 – Synthesis of (-)-Ambrox® from Sclareol via Sclareolide
(~90% (-)-Ambrox)
1988 – Introduction of DL-Ambrox (purely synthetic) (>50%
(+/-)-Ambrox + <50% diastereomers)
1993 – Intoduction of Cetalox® (purely synthetic) (~96%
(+/-)-Ambrox)
2004 – Introduction of (-)-Cetalox Leavo (purely synthetic)
(99% (-)-Ambrox) presumably via resolution of racemic
Sclareolide acid with a pseudoephedrine enantiomer
Advances in Flavoring Materials
Coumarinic p-Menthane Lactones
O
O
O
O
O
O
Wine lactone (1996)
GRAS No.
-Odor:
Vinous, lactonic
(coconut)
Flavor:
Mintlactone (1983)
3764
Minty, coumarinic,
tenacious
Lactonic, sweet, herbal Coumarinic, fatty,
herbal
Threshold*: 0.0000016ppb
0.00012 ppb
*In air
Ref: Frerot, et. al., Flavour Fragr. J., 2002; 17: 218–226;
Gaudin, Tetrahedron, 2000, 56: 4769-4776
Dihydromintlactone (1995)
4032
Coumarinic, hay,
lactonic, tonka
Coumarinic,
lactonic, coconut
0.000039 ppb
The Fifth Taste
Until 1999-2000 only 4 taste sensations were generally
recognized:
• Sweet – e.g. Sucrose, Aspartame
• Sour – e.g. Citric acid, Phosphoric acid (H+ ions)
• Bitter – e.g. Quinine
• Salty – Sodium Chloride
A 5th taste sensation called “Umami” (aka Umani) is now
accepted. Most common example is MSG (Monosodium
glutamate) which enhances meat & savory flavors.
Biotechnology & the Future
In 1955, Artificial flavorings comprised the vast majority of
flavors produced.
As consumer marketing became more important, a dramatic
shift to “natural” flavorings occurred requiring new and
improved methods for the production of natural flavor
chemicals. Biotechnology in the production of many materials
is now commonplace.
But, this was only the beginning.
The Future is upon us.
Biotechnology & the Future
2000/2001 – Identification of complete set of human olfactory
genes (Lancet, et. al. [Weizmann Institute] & Zozulya et. al. [Senomyx])
March 2002 - cloning and characterization of TRPM8 & CMR1
(cold and menthol receptors) (McKemy et. al. [UCSF] & Peier
et. al. [Novartis])
2002/2003 – characterization of heterodimeric receptors
T1R2/T1R3 (sweet receptors) and T1R1/T1R3 (umami receptors)
(Li et. al. [Senomyx])
2004 – Efficacy and Potency of cooling sensates demonstrated
with TRMP8 cold receptor using the (FLIPR) assay
(Behrendt et. al. [Grünenthal])
Efficacy of TRPM8 agonists
[Ca2+]i responses were measured as maximal increases in fluorescence, expressed as percentages
of the maximum icilin response.
citral
inactive
eugenol
inactive
15
hydroxycitronellal
linalool
21
eucalyptol
22
23
PMD 38
28
geraniol
28.3
WS-23
42
Coolact P
64
Frescolat ML
65
Cooling Agent 10
(+)menthol
68
Frescolat MGA
69
71
(-)menthol
86
WS-3
icilin
0
10
20
30
40
50
60
70
80
90
% icilin response
Adapted from Behrendt, et .al, Brit. J. Pharm., 141:737-745 (2004)
100
Biotechnology & the Future
WATCH
Identifying Taste Enhancers by taste receptor
screening of lead compounds
Savory – Sweet – Salt
Biotechnology & the Future
• October 4, 2004 - Richard Axel and Linda
Buck honored with the 2004 Nobel Prize in
Physiology or Medicine for pioneering
studies that clarify how the olfactory system
works.