50 Years of Flavor Chemistry

Reflections on a Half Century of Flavor Chemistry

SFC 50th Anniversary Flavor Symposium

October 7, 2004

John C. Leffingwell

Leffingwell & 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

0

1000

2000

3000

4000

5000

6000

7000

8000

Th

ou

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-lactones

By 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 Materials

Pyrazines


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


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


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.

(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.


beta-Pinene

Myrcene

Linalool

Geraniol Citronellol Citronellal

MentholLinalyl Acetate

1959 – Bain & Webb – Turpentine into Fragrance & Flavor

CH3CH3

CH2

CH2

CH3 CH3

CH2

CH3

CH3 CH3

CH2

O H

CH3

CH3 CH3

O H

CH3

CH3 CH3

O H

CH3

CH3 CH3

O

CH3

CH3 CH3

O H

CH3

CH3 CH3

CH2

O

OCH3

1959 – Roche Process for Linalool & Citral via Acetylene


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


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.

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 strawberry

The esters are important in many tropical flavors

OOH

OHor

OHCl

Na


Discovered in 1937, the First Publication on Raspberry Ketone appears in 1961

O

HO


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

Dihydrojasmonate

Configuration 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. 1985

Methyl 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


O

O OH

O

O OH

1965-66 – α- & β- Sinensal isolated from orange oil

CHO

CHO


1950’s - 60’s – Synthetic Carvones


• 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)

Mir

ror

Imag

es


1960’s – NootkatoneFirst 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.



1960’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


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


1975 - Introduction of α-Damascone and β-Damascone

1982 – Introduction of Damascenone

1970 – Discovery Damascenone & β-Damascone

OO O


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


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


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


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


1981 – BASF Citral Plant comes on stream

2004 – BASF opens new continuous process citral plant with 40,000 metric tons capacity

OH

OH

OOxidation

Isomerization

O

Citral

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.



1983 – 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


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


3-mercapto-2-methyl-pentane-1-ol diastereosomersbroth-like, sweaty, leek-like

HO

HS

2000 – The 3-mercapto-2-methyl-pentane-1-ols


2001 - 2,4,6-trithiaheptane

Character impact compound of white truffles

Odor: Leek, onion, cress, horseradish; mushroom-like, earthy, green tinge

SSS


2001 – Takasago’s Professor Ryoji Noyori wins the 2001 Nobel Prize for Chemistry

HOOH


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


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, tonka

Flavor: Lactonic, sweet, herbal Coumarinic, fatty, Coumarinic, herbal lactonic, coconut

Threshold*: 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 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

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])


86

71

69

68

65

64

42

28.3

28

23

22

21

15

inactive

inactive

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.


WATCH

Identifying Taste Enhancers by taste receptor screening of lead compounds

Savory – Sweet – Salt


• 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.

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50 Years of Flavor Chemistry

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