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Reflections on a Half Century of Flavor Chemistry
SFC 50th Anniversary Flavor Symposium
October 7, 2004
John C. LeffingwellLeffingwell & Associates
Or is it???
Mold
Dicoumarol (Coumadin)
Coumarin
Major metabolite in man
Is it hepatoxic?
1954 – FDA BANS COUMARIN
O O
O OHO O O
OHOO
OH
O O
OH
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 Instrumentation1952 First publication on gas chromatography (James & Martin)1952 Bloch and Purcell awarded the Nobel Prize for NMR1952 Varian sells first NMR to Humble Oil1954 E.J. Corey solves first structure problem with NMR1955 Perkin-Elmer - first commercial GC1956 First demonstration of GC/MS (Bendix Corporation) 1958 M. Golay develops capillary columns1959 Flame ionization detector introduced 1976 HP introduces world’s first benchtop GC/MS 1977 Wozniak & Jobs introduce the Apple II computer1978 NBS releases 25,000 MS spectra1981 The IBM Personal computer & Bill Gates1984 HP introduces the 5890, the best-selling GC in history1988 NIST MS database1991 Wiley MS database1994 HP introduces the ChemStation software1996 NIST releases AMDIS deconvolution program
Volatile Chemicals Identified in Foodstuffs
01000
20003000
40005000
60007000
8000
Thou
ssan
ds.
0123456
PPM
Major Advances in Instrumentation - NMR
Gas Chromatography – Mass Spectrometry
12.00 14.00 16.00 18.00 20.00 22.00 24.00 26.00 28.00 30.00 32.00 34.00 36.000
2000000
4000000
6000000
8000000
1e+07
1.2e+07
1.4e+07
1.6e+07
Time-->
Abundance
GC-MS Analysis of a Meat Flavor
Peak Identified as Furfuryl MercaptanPowerful Coffee Aroma
Peaks are 2-Methyl-2,3-dihydrofuran-3-thiol isomersPowerful meat-like aroma
O
SH
CH3 O
SH
CH3
O
SH
Major Advances in Instrumentation
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-lactonesBy the mid-50’s margarine was poised to overtakebutter as the table spread of choice
About 1955 it was recognized that delta-dodecalactonewas an important butter flavor and combinations ofdelta-decalactone & delta-dodecalactone would soon be the key to improved acceptability
O OC5H11O OC7H15
• 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 MaterialsPyrazines
Advances in Flavoring Materials
Green, Bell pepper,Galbanum
Roasted peanut,hazelnut
Popcorn, nutty,bready
Cocoa, dark chocolate,nutty
Earthy, raw potato; aroma of damp black
earth
Nutty, brown, roasted, earthy and musty
1950’s –1960’s - Pyrazines
Today about 60 different pyrazines are employed in flavor creation
N
N OCH3
N
N O
CH3
CH3
N
N
O
N
N
N
N N
N
Advances in Flavoring Materials
2-acetylthiazoleNutty, popcorn, bread,
toasted cereal
2-isobutylthiazoleGreen tomato aroma and taste;
tomato leaf aroma
Sulfurolmeaty-beef like with nutty note
2,4-Dimethyl-5-vinylthiazoleNutty, meat like notes
1950’s – 1970’s – Thiazoles
Today about 45 different thiazoles are employed in flavor creation.
N
S OH
S
N
S
N
O
S
N
Advances in Flavoring Materials1950’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.
(R)
HO H
(S)
OHH
Natural mushroom odor,slightly fruity
Herbaceous, green, musty
Today, we know that the racemates odor is dominated by theolfactively more powerful (-)-(R)- enantiomer.
Advances in Flavoring Materials
beta-Pinene
Myrcene
Linalool
Geraniol Citronellol Citronellal
MentholLinalyl Acetate
1959 – Bain & Webb – Turpentine into Fragrance & Flavor
CH3CH3
C H2
C H 2
CH 3 C H3
C H2
CH 3
CH3 C H3
C H2
O H
CH 3
CH 3 CH 3
O H
C H3
CH3 C H3
O H
C H 3
CH 3 CH3
O
C H 3
CH 3 CH 3
O H
CH3
CH 3 CH 3
CH 2
O
OCH 3
1959 – Roche Process for Linalool & Citral via AcetyleneAdvances in Flavoring Materials
O
OH
OH
CHO
Linalool
Citral
Advances in Flavoring Materials1959 – Discovery of Methyl Dihydrojasmonate
Hedione®
1996 - First synthesis of pure "(+)-cis-Hedione®" the olfactively most active stereoisomer of Hedione®
1971 – Introduction of Hedione®"
O
O
O
O
O
O
Advances in Flavoring Materials
1959 – Discovery of Rose Oxide
1960 – Safrole BannedRoot 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.
HO
O
O
Methyl salicylate AnetholeMethyl chavicol
Safrole
OO
O
O
Leaf AlcoholAlthough the exact structure of leaf alcohol was established in 1938, it was not widely available until Bedoukian’s process in 1961.
Leaf alcohol was essential for the development of many fruit flavors, especially strawberryThe esters are important in many tropical flavors
OOH
OHor
OHCl
Na
Advances in Flavoring Materials
Discovered in 1937, the First Publication on Raspberry Ketone appears in 1961
O
HO
Advances in Flavoring Materials
Advances in Flavoring Materials1962 – First publications appear on Methyl Jasmonate &
Methyl Dihydrojasmonate
1R,2R-(-)-Z-methyl jasmonate 1S,2S-(+)-Z-methyl jasmonate
4
5
1(R)
2 (R)
3
O
(Z)
CO2CH3
H
H
(S)(S)
O
(Z)
H3CO2C
H
H
(R)(S)
O
(Z)
CO2CH3
H
H
(S)(R)
O
(Z)
H3CO2C
H
H
1R,2S-(+)-Z-methyl epijasmonate 1S,2R-(-)-Z-methyl epijasmonate
Methyl Jasmonate – odorant, insect pheromone, plant growth regulator
Advances in Flavoring MaterialsChirality & Odor - Methyl Jasmonate & Methyl
DihydrojasmonateConfiguration Odor Description Odor Threshold (in PPB)
Methyl jasmonates1R,2R-(-)- Weak odor >70*1S,2S-(+)- Odorless Odorless1S,2R-(-)-epi- Odorless Odorless1R,2S-(+)-epi- Strong odor; floral, true jasmin-like 3*Ref: T.E. Acree et. al., J.Agric.Food.Chem. 1985Methyl dihydrojasmonates1R,2R-(-)- Floral, sweet, jasminelike 240**1S,2S-(+)- Floral, fatty, cis-jasmone, hay character, 15,360**
tea note, slightly lemon peellike (weak)1S,2R-(-)-epi- Herbal, fatty, tea-like, tobacco, 12,500**
β-damascone, cis-jasmone1R,2S-(+)-epi- Intensely floral, jasmine-like, bright, cis- 15**
jasmone, slightly fatty, woody, β-ionone-like, extremely long lasting
Ref: Werkhoff, P., et. al., Food Reviews International, 2002* detection threshold**recognition threshold
1964 – Introduction of Furaneol®
1965 – First publications on isolation of Furaneol®from strawberry and pineapple
Advances in Flavoring Materials
O
O OH
O
O OH
1965-66 – α- & β- Sinensal isolated from orange oil
CHO
CHO
Advances in Flavoring Materials
1950’s - 60’s – Synthetic Carvones
Advances in Flavoring Materials
• 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.
(R)
(+)-(4R)-limonene(d-Limonene)
(R)
O
(-)-(4S)-limonene (l-Limonene)
(S)
O1. NOCl
2. H3O+
(-)-(4R)-carvone(l-carvone)
Odor: Spearmint
(+)-(4S)-carvone(d-carvone)
Odor: Caraway
1. NOCl
2. H3O+
(S)
Mirr
or Im
ages
Advances in Flavoring Materials1960’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.
OO
(+)-Nootkatonestrong grapefruit odor,
bitter in taste
(-)-Nootkatoneweak woody (vetiver note);
no grapefruit character; virtually no taste
Threshold: 60,000 ppb 800 ppb
1968 – Pfizer patents Ethyl maltol
O
OH
O
Ethyl maltol (Veltol Plus®) was touted to be about 6Xstronger than maltol and an important substitute for Coumarin. Well, at least it is stronger than maltol.
Advances in Flavoring Materials
Advances in Flavoring Materials1960’s-80’s – Important meaty compounds
O
SH
O
SH
S
SHSH
CHO N
2-methylthiophene-3-thiolCooked meat
Ortho-toluenthiolMeaty, liver
2-methylfuran-3-thiolCooked meat
2-methyl-4,5-dihydrofuran-3-thiolCooked meat
DecadienalMeat & poultry fat
2-pentylpyridineTallow flavor
Advances in Flavoring Materials
1970’s-80’s – Other Furanones
Sotolon (caramel furanone) & Maple furanone identified in cane sugar – powerful caramel maple notes
O
HO
OO
HO
O
Sotolon Maple Furanone (Abhexone)
Threshold: 0.003 ppb 0.00005 ppb
Sotolon – key flavorant of fenugreek, sake, sherry wine
Advances in Flavoring Materials
1975 - Introduction of α-Damascone and β-Damascone
1982 – Introduction of Damascenone
1970 – Discovery Damascenone & β-Damascone
OO O
Advances in Flavoring Materials
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
OH OH OH OH
H2 Resolution
via benzoate
1973 - Haarmann & Reimer (-)-Menthol Synthesis
Advances in Flavoring Materials
1974 – Thiomenthones identified in Buchu oil
OHS
OHS
Key component for black currant and the “fuzzy” peach skin note
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
C2H5
O
O
HN CH3
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).
WS-3 WS-23
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-4-propyl-1,3-oxathiane is the important diastereomer
Advances in Flavoring Materials
O
S
H H
(-)-(2R,4S)-2-methyl-4-propyl-1,3-oxathiane
• Odor: powerful sulfury, tropical fruit• Threshold: 2 ppb
O
S
HH
(+)-(2S,4R)-2-methyl-4-propyl-1,3-oxathiane
• Odor: flat, estery, camphoraceous, floral, less sulfury • Threshold:4 ppb
Advances in Flavoring Materials1981 – BASF Citral Plant comes on stream
2004 – BASF opens new continuous process citral plant with 40,000 metric tons capacity
OH
OH
OOxidation
Isomerization
OCitral
O O
SH
S
1982 – 1-p-Menthene-8-thiol
Demole identifies 1-p-Menthene-8-thiol as a character impact compound in Grapefruit Juice
Very powerful with an odor threshold of 0.0001 ppb, it alsorequires stabilization as it tends to rapidly cyclize to the thio analog of dihydropinol.
Advances in Flavoring Materials
Advances in Flavoring Materials1983 – Takasago’s new Enantioselective Method
For producing (-)-menthol
CH3CH3
CH2
CH2
CH3H
OH
CH3 CH2
CH3CH3
CH3
N(C2H5)2
CH3CH3
CH3
N(C2H5)2
H
CH3CH3
CH3
O
HCH3H
OH
CH3 CH3
NH(C2H5)2
Li (S)-BINAP-Ru
H3O+
ZnBr2H2
Advances in Flavoring Materials
1986 – H&R Patents Filbertone
(S)
OH
(R)
OH
The Character Impact Compound of Hazelnut
(-)-(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
(+)-(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
Advances in Flavoring Materials
3-mercapto-2-methyl-pentane-1-ol diastereosomersbroth-like, sweaty, leek-like
HO
HS
2000 – The 3-mercapto-2-methyl-pentane-1-ols
Advances in Flavoring Materials
2001 - 2,4,6-trithiaheptane
Character impact compound of white truffles
Odor: Leek, onion, cress, horseradish; mushroom-like, earthy, green tinge
SSS
Advances in Flavoring Materials
2001 – Takasago’s Professor Ryoji Noyori wins the 2001 Nobel Prize for Chemistry
HOOH
Advances in Flavoring Materials
H
O
Advances in an Ambergris Compound Synthesis
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
O
O
O
O
O
O
Mintlactone (1983) Dihydromintlactone (1995)Wine lactone (1996)
GRAS No. -- 3764 4032Odor: Vinous, lactonic Minty, coumarinic, Coumarinic, hay,
(coconut) tenacious lactonic, tonkaFlavor: Lactonic, sweet, herbal Coumarinic, fatty, Coumarinic,
herbal lactonic, coconutThreshold*: 0.0000016ppb 0.00012 ppb 0.000039 ppb*In airRef: Frerot, et. al., Flavour Fragr. J., 2002; 17: 218–226; Gaudin, Tetrahedron, 2000, 56: 4769-4776
Coumarinic p-Menthane Lactones
A 5th taste sensation called “Umami” (aka Umani) is now accepted. Most common example is MSG (Monosodium glutamate) which enhances meat & savory flavors.
The Fifth TasteUntil 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
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.
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])
Biotechnology & the Future
86
7169
68
6564
42
28.328
2322
21
15inactiveinactive
0 10 20 30 40 50 60 70 80 90 100
% icilin responseAdapted from Behrendt, et .al, Brit. J. Pharm., 141:737-745 (2004)
icilin
WS-3
(-)menthol
Frescolat MGA
(+)menthol
Cooling Agent 10
Frescolat ML
Coolact P
WS-23
geraniol
PMD 38
eucalyptol
linalool
hydroxycitronellal
eugenol
citral
Efficacy of TRPM8 agonists[Ca2+]i responses were measured as maximal increases in fluorescence, expressed as percentages
of the maximum icilin response.
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.