©WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
One Hundred Years of Vitamins—A
Success Story of the Natural Sciences
Essential: The discovery of vitamins was
a scientific breakthrough that changed the
world! The synthesis of vitamins on
a commercial scale and their application
in diets had a dramatically positive impact
on human and animal health as well as
economic development. The key achieve-
ments in research of vitamins are high-
lighted in this Review, starting from the
first industrial synthesis of l-ascorbic acid
up to modern catalytic methods.
M. Eggersdorfer, D. Laudert, U. Ltinois,
T. McClymont, J. Medlock, T. Netscher,
W. Bonrath* 12960 – 12990
Keywords: catalysis · fine chemicals ·
nutrition · synthesis methods · vitamins
2012 – 51/52
ACIEFS 51 (52) 12899–13180 (2012) · ISSN 1433–7851 · Vol. 51 · No. 52
From Supramolecular to Systems Chemistry
Editorial by J. F. Stoddart
One Hundred Years of Vitamins
Review by W. Bonrath et al.
William Lawrence Bragg
Essay by J. M. Thomas
Highlights: Silicon Stereocenters · Gold(III) Monohydride
Vitamins DOI: 10.1002/anie.201205886
One Hundred Years of Vitamins—A Success Story of the
Manfred Eggersdorfer, Dietmar Laudert, Ulla Ltinois, Tom McClymont,
Jonathan Medlock, Thomas Netscher, and Werner Bonrath*
catalysis · fine chemicals · nutrition ·
synthesis methods · vitamins
Reviews W. Bonrath et al.
12960 www.angewandte.org 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2012,51, 12960 – 12990
Vitamins are essential organic compounds which are
either not synthesized in the human or animal organism, or
are formed in insufficient amounts, and therefore must be
taken up with the diet as such or as a precursor.
In 1906 Frederick Gowland Hopkins (Figure 1) indicated
that “no animal can live on a mixture of pure protein, fat,
carbohydrate, salts, and water”. This started the search for
“growth factors” in food. It was the Dutch physician
Christiaan Eijkman who found that a constituent of rice
bran can prevent a beriberi-like disease in chickens. The
credit for being the first scientist to adopt the deficiency
theory for the etiology of this disease belongs to Gerrit Gijns.
He stated that the disease breaks out when a substance
necessary for the metabolism is lacking in the food.
In 1912 the Polish biochemist Casimir Funk (Figure 2)
isolated a bioactive substance from rice bran which was at first
given the name “vita-amine” (later “aneurin” for “anti-
neuritic vitamin” and eventually “thiamin”). Funk realized
that this substance could cure chickens and humans of
beriberi. He published a landmark paper “The etiology of
the deficiency diseases” and stated that all deficiency
“diseases can be prevented and cured by the addition of
certain preventive substances, the deficient substances”, for
which he proposed the name “vitamins”.
In 1916 the American biochemist Elmer McCollum
(Figure 3) introduced the capital letters A–D to differentiate
between vitamins. Later, vitamins E and K were added, and
it was realized that vitamin B can contain more than one
factor, so a further differentiation into vitamins B1,B
2, and so
on was made.
These observations and findings greatly facilitated exper-
imental research in the following years. The next three
The discovery of vitamins as essential factors in the diet was a scientific
breakthrough that changed the world. Diseases such as scurvy, rickets,
beriberi, and pellagra were recognized to be curable with an adequate
diet. These diseases had been prevalent for thousands of years and had
a dramatic impact on societies as well as on economic development.
This Review highlights the key achievements in the development of
industrial processes for the manufacture of eight of the 13 vitamins.
From the Contents
1. Introduction 12961
2. l-Ascorbic Acid (Vitamin C) 12965
3. Thiamin (Vitamin B1)12967
4. Riboflavin (Vitamin B2)12970
5. Pyridoxine (Vitamin B6)12973
6. Pantothenic Acid (Vitamin B5)12975
7. Biotin (Vitamin B7, Vitamin H)12975
8. Vitamin A (Retinol) 12978
9. Vitamin E (a-Tocopherol) 12982
10. Conclusions 12986
Figure 1. Frederick Gowland Hopkins (source: Roche Historical
Figure 2. Casimir Funk (source: Roche Historical Archive).
[*] Dr. M. Eggersdorfer, Dr. D. Laudert, Dr. U. Ltinois, Dr. T. McClymont,
Dr. J. Medlock, Dr. T. Netscher, Priv.-Doz. Dr. W. Bonrath
Research and Development, DSM Nutritional Products Ltd.
P.O. Box 2676, CH-4002 Basel (Switzerland)
Homepage: http ://www.dsmnutritionalproducts.com
One Hundred Years of Vitamins Angewandte
12961Angew. Chem. Int. Ed. 2012,51, 12960 – 12990 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
decades were full of scientific breakthroughs in understanding
the role of vitamins, and by 1941 all 13 vitamins had been
identified, their structures characterized, and their role for
humans and animals defined. A summary of the discovery,
isolation, and assignment of the chemical structure and first
production of the individual vitamins is given in Table 1 (see
also Figure 4).
These scientific breakthroughs were honored with 12
Nobel Prizes to 20 laureates. The first Nobel Prize in
chemistry relating to vitamins was given to Adolf Windaus for
his studies on the constitution of sterols and their connection
with the vitamins. This was followed by the Nobel Prize in
Medicine and Physiology in 1929 jointly to Christiaan Eijk-
man, for the discovery of the anti-neuritic vitamin, and to Sir
Frederick Gowland Hopkins, for the discovery of the growth-
The understanding that micronutrients are essential for
human and animal growth and health was a major stimulus for
nutritional science. It subsequently became clear that break-
throughs in production, formulation, and application would
have to be achieved to allow vitamins to be given to humans
and animals. This inspired scientists in universities and
companies to develop synthetic routes and production
technologies. The first commercialized vitamin was ascorbic
acid/vitamin C from Merck (Cebion), which was isolated from
plant leaves, and became available in 1933. The first
industrial-scale chemical production was also of vitamin C
and was achieved by F. Hoffmann–La Roche (Roche) in
1934, and was based on a combined fermentation and
chemical process developed by Tadeus Reichstein
(Figure 5). To commemorate this, the Swiss Chemical
Society selected vitamin C for the 100 Rappen Swiss postage
stamp for the International Year of Chemistry in 2011
In the following years, all of the vitamins became available
through chemical synthesis, fermentation, or extraction from
natural materials (Table 1), and it was not until 1987 that all
the vitamins were accessible by industrial processes. Today,
Manfred Eggersdorfer completed his PhD at
the Technical University Munich. After post-
doctoral research at Stanford University,
working with Carl Djerassi on the isolation
and characterization of sterols from marine
origin, he joined BASF, Ludwigshafen and
worked in different positions including Head
of R&D Fine Chemicals. He joined Roche in
1999 as Head of R&D Vitamins and Fine
Chemicals, which was acquired by DSM. He
is an active member of the Advisory Board
of the Johns Hopkins Bloomberg School of
Public Health and the Strategy Board of the
Institute of Food Science University Ham-
Dietmar Laudert studied biology and com-
pleted his PhD in Plant Physiology at the
University Bochum, Germany. He started
his industrial career at Scinet Bioproducts
GmbH, working as Scientist and project
manager on molecular biology contract
research. He joined Roche Vitamins/DSM
Nutritional Products in 2001, where he has
been engaged in several strain and process
development activities for the production of
water-soluble vitamins such as riboflavin and
ascorbic acid. He is currently a Senior Scien-
tist and competence team coordinator in the
Biotech Department at DSM Nutritional
Ulla Ltinois studied chemistry at the Uni-
versity of Oldenburg, Germany and at the
University Champagne-Ardennes, France.
After a PhD in organic synthesis and spec-
troscopy under the co-direction of Stefan
Berger (University of Leipzig, Germany) and
Patrick Pale (University of Strasbourg,
France), and postdoctoral research with
Jean-Pierre Sauvage and Bernard Meunier
(Toulouse, France) in 2005 she started work-
ing in Basel, Switzerland as a laboratory
head in DSM Nutritional Products in Pro-
Jonathan Medlock studied natural science
(chemistry) at the University of Cambridge,
UK and stayed there to complete a PhD in
organic synthesis with Stuart Warren in
2000. After postdoctoral research in asym-
metric catalysis with Andreas Pfaltz (Univer-
sity of Basel) he returned to Cambridge to
work for the ‘Catalysis and Chiral Technolo-
gies’ group of Johnson Matthey. In 2009 he
moved to the Process R&D department of
DSM Nutritional Products in Basel, Switzer-
land, where he is currently a Senior Scientist
and Laboratory Head. His interests cover all
aspects of catalysis, especially hydrogenation
Figure 3. Elmer McCollum (source: Roche Historical Archive).
Reviews W. Bonrath et al.
12962 www.angewandte.org 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2012,51, 12960 – 12990
chemical synthesis is still the dominant method on a commer-
1.1. Vitamin Production
Vitamins are organic molecules with complex and quite
different chemical structures. The development of industrial
production processes required a broad array of scientific and
manufacturing expertise. The development of synthetic
routes for vitamins was a pioneering phase in chemistry and
process development, and the development of industrial
Tom McClymont graduated in chemistry
from Glasgow University in 1966. He com-
pleted his PhD at Hatfield Polytechnic in
1972, partly on aspects of the Lindlar hydro-
genation in the vitamin A synthesis. He
joined Roche in 1966 and worked for ten
years in vitamins process research (England),
then in chemical production and site man-
agement (Scotland), and finally in technol-
ogy strategy (Switzerland) until his retire-
ment from DSM Nutritional Products at the
end of 2009.
Thomas Netscher studied chemistry at the
Universities of Constance and Freiburg i.Br.,
Germany, where he completed his PhD with
Horst Prinzbach. In 1987 he joined F. Hoff-
mann–La Roche, now DSM Nutritional
Products, in Basel (with a stay at the Roche
Research Center in Nutley, USA in 1991/
92), where he is now a Principal Scientist
responsible for isoprenoid chemistry.
Together with colleagues from DSM and
Solvias he received the Sandmeyer Award
2008, held the Roche Lecture in 1997/98, is
currently Lehrbeauftragter of the University
of Freiburg i.Br. , and a member of the German, the Swiss, and the
American Chemical Societies.
Werner Bonrath studied chemistry in Bonn
and Mnster (Diploma 1985) and com-
pleted his PhD in 1988 at the MPI, Ml-
heim, with Gnther Wilke. He joined Hoff-
mann–La Roche in 1989 and worked in the
field of catalysis for fine chemicals, especially
vitamins and carotenoids. In 2007 he com-
pleted his habilitation at the University Jena,
and is a lecturer at the Universities of Jena
and Basel. Since the integration of Roche
Vitamins into DSM, he is Competence Man-
ager, Heterogeneous Catalysis at DSM
Nutritional Products in Kaiseraugst, Switzer-
land. His interests cover all aspects of catalysis, especially Lindlar-type
hydrogenation and ethynylation.
Table 1: Vitamins and their discovery, synthesis, and main biological function.
Vitamin[a] Discovery Isolation Structural
Main biological function
vitamin A 1916 1931 1931 1947 retinal, the oxidized metabolite of retinol, is required for the process of vision
vitamin D 1918 1932 1936 1959 bone mineralization, control of cell proliferation, and differentiation, regulation of
calcium and phosphate blood levels; modulation of immune system
vitamin E 1922 1936 1938 1938 fat-soluble antioxidant, cell signaling, regulation of gene expression.
vitamin K 1929 1939 1939 1939 blood coagulation, bone metabolism
vitamin B11912 1926 1936 1936 cofactor in energy metabolism and pentose metabolism, nerve impulse conduction,
and muscle action
vitamin B21920 1933 1935 1935 precursor for biosynthesis FMN or FAD, cofactors involved in redox reactions
1936 1936 1937 1994 precursor for biosynthesis of NAD and NADP, cofactors involved in redox reactions
1931 1938 1940 1940 pantothenic acid, as a constituent of coenzyme A, is involved in metabolism of
carbohydrates, proteins, and fats
vitamin B61934 1938 1938 1939 cofactor involved in neurotransmitter biosynthesis
1931 1935 1942 1943 cofactor involved in the metabolism of lipids, proteins and, carbohydrates
1941 1941 1946 1946 cofactor involved in amino acid metabolism and synthesis of nucleic acids
vitamin B12 1926 1948 1956 1972 necessary for the formation of blood cells, nerve sheaths, and various proteins;
involved in fat and carbohydrate metabolism
vitamin C 1912 1928 1933 1933 involved in collagen synthesis, antioxidant
[a] Vitamins A, D, E, and K represent the subgroup of lipid-soluble vitamins, the others belong to the water-soluble ones. For the sake of clarity only one
representative of each class is given in Figure 4.
One Hundred Years of Vitamins Angewandte
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processes for the production of vitamins can roughly be
divided into four phases:
-The pioneering days from 1930 to 1950;
-the scaling-up and engineering phase from 1950 to 1970;
-the period of worldwide production plants followed by
consolidation from 1970 to 1990; and
-the period of the rise of new technologies from the 1990s to
the present day.
The first phase was characterized by laboratory-scale
syntheses to confirm their structures and to provide enough of
the bioactive to perform animal and human studies. Practical
manufacturing routes for small-scale production were then
developed. This was often done in close cooperation between
academic and industrial research groups. Examples are the
cooperation of Roche Basel with Tadeus Reichstein (ETH
Zurich, vitamin C) and Paul Karrer (University of Zurich,
vitamins A and E), as well as of Georg Wittig with BASF
(vitamin A). This was followed by the construction of small
production plants in several countries to enable market
development on a local or regional basis.
The growth of the vitamin market continued and required
the production of larger volumes, so scaling up and engineer-
ing factors characterized the second phase. This presented
new challenges, such as recycling of solvents, improving
yields, and for the larger volume products even moving from
batch to continuous processes. New routes or improved
processes were developed at universities as well as in
companies. The concept of larger plants triggered a rational
process R&D from the laboratory via pilot plants and finally
to production. The resulting “economy of scale” enabled
Figure 5. Tadeus Reichstein (source: Roche Historical Archive).
Figure 6. Stamp issued on the occasion of the International Year of
Chemistry 2011, depicting a molecule of vitamin C as a symbol of
innovation that originated from Swiss chemical research. ( Die
Figure 4. Representative structures of the 13 vitamins.
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12964 www.angewandte.org 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2012,51, 12960 – 12990
production costs to be reduced significantly. The large
companies—especially Hoffmann–La Roche and BASF,
who were market leaders—built several plants in different
regions for security of supply. The number of companies
producing and selling vitamins grew: especially European and
Japanese pharmaceutical companies as well as a few chemical
companies, such as BASF and Lonza, which had the benefit of
backward integration in key raw materials.
The third phase was characterized by an even higher
growth in volume, based in particular on market development
in animal nutrition. This resulted in the rationalization of
production into one single plant. This philosophy was
especially promoted by the Vitamins Division of Hoff-
mann–La Roche (now DSM Nutritional Products). This
strategy required a reliable and stable operation of the
plant, because a shutdown would have had a major impact on
the global supply of the vitamin. Process development
became a key competence and differentiating factor. Building
a pilot plant was too costly, so “miniplants” were developed
which simulated the complete production concept, including
recycling of solvents and recovered precursors. A change in
the competitive environment also became evident in this
phase: China defined supplying its population with vitamins
as a key strategy and stimulated local companies to enter the
The fourth phase in vitamin production was characterized
by the rise of new technologies and by a dramatic change in
the competitive environment. The benefits of “economy of
scale” for major producers made smaller producers leave the
market. The number of Chinese producers initially increased
and then declined because of the increasing role of environ-
mental factors and quality issues. In parallel, general
economic trends such as the increase in raw material and
energy costs, sustainability, and quality influenced production
and required major investments. The number of companies
active in vitamin production and marketing changed, and left
DSM as the only Western producer with a complete portfolio,
BASF with a strong position in vitamins A and E, and
a reasonable number of Chinese companies, none of them
complete portfolio providers.
Fermentation technology started to gain in importance:
vitamin B12 is only produced by fermentation, the production
of vitamin B2shifted from chemical to fermentation technol-
ogy in the last decade, and promising approaches are in
development for the other water-soluble vitamins. We are also
experiencing the early phase of a new technology: the over-
expression of vitamins in plants by using traditional breeding
or genetically modified plants. The first studies on the sweet
potato or yellow corn with an increased level of b-carotene
(pro-vitamin A) obtained by traditional breeding are in being
tested in Africa. A project called “golden rice”, involving
a genetically modified plant with higher b-carotene, has been
announced for the start of 2013.
1.2. Nutritional Role of Vitamins
The World Banks assessment of fortification of food
products such as milk, flour, and juice was: “probably no other
technology available today offers as large an opportunity to
improve lives and accelerate development at such low cost and
in such a short time”. The synthesis and industrial
production of vitamins has resulted in their worldwide
availability. Authorities had started to establish dietary
standards and nutrient requirements for the optimal and
safe intake of vitamins depending on age, gender, and risk
groups as early as the 1940s. A number of countries
implemented fortification programs of staple food to secure
a sufficient intake of vitamins for the full population; today
this has been established in more than 50 countries.
Today, as a consequence of results from many human
studies, there is a general consensus by scientists about the
biological function of vitamins and their impact on health and
healthy aging. In addition, new data from national intake
surveys reveal that, even in industrialized countries in
Europe, US, and others parts of the globe, some segments
of the population have a vitamin deficiency, for example, of
vitamin D, folate, or vitamin E. Triggered by the analysis of
the human genome and building on new science, a renaissance
in vitamin research started this century: it allows nutrient–
gene interactions to be studied, and the discovery of
polymorphism (individual differences in the genome in
populations) has allowed specific requirements for vitamins
to be identified.
This Review provides an overview of the development of
industrial synthetic processes for manufacturing a selected
number of vitamins. These examples have been chosen
because they represent typical characteristics of the history
of science and technical development from identification and
characterization to industrial production.
We start with the first industrially synthesized vitamin
(vitamin C) and then continue with other members of the
water-soluble vitamins group (vitamin B1,B
acid, biotin) and conclude with two lipid-soluble vitamins (A
2. l-Ascorbic Acid (Vitamin C)
2.1. Physiological Functions
Vitamin C is a water-soluble vitamin that is essential for
the biosynthesis of collagen, carnitine, and catecholamines. It
is also a strong antioxidant that protects molecules from
oxidative damage. Vitamin C serves as an electron donor for
enzymes involved in the synthesis of collagen, carnitine, and
norepinephrine. It is also involved in the metabolism of
tyrosine. The clinical syndrome of vitamin C deficiency is
scurvy, a condition characterized by bleeding and impaired
Scurvy was a common disease among mariners and
discoverers until the beginning of the 19th century, with
serious symptoms such as collagen instability causing loss of
teeth, bleeding of mucous membranes, anemia, and even-
One Hundred Years of Vitamins Angewandte
12965Angew. Chem. Int. Ed. 2012,51, 12960 – 12990 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org
tually death. Medical studies by ships
doctors such as Lind (1717–1794) and
Blane (1749–1834) proved that scurvy
results from the lack of a nutritional
factor in the human diet. This was first
designated as the antiscorbutic factor, later
l-ascorbic acid or vitamin C. Vitamin C
was isolated from plant tissues as well as
the adrenal glands of guinea pigs suffering
from scurvy, and crystallized by Szent-Gyçrgyi in 1931. Its
chemical structure (Figure 7) was elucidated in 1933 and
confirmed by a synthetic route developed by Walter Norman
Haworth. Shortly after the structural confirmation of l-
ascorbic acid and its first synthesis, an industrial process for its
manufacture was established by Reichstein, Grssner, and
Oppenauer. l-Ascorbic acid (1) was the first industrially
produced vitamin. Several processes for the production of
vitamin C have since been established.
2.3. First Syntheses
Several overviews on l-ascorbic acid syntheses have been
published over the last 50 years. In general, polyhydroxy
compounds were used as the starting materials in all the
efficient syntheses. Chemical synthesis can start from differ-
ent sugars, depending on the reaction pathway chosen,
whereas biotechnological approaches only use glucose as
the starting material.
In Haworths first synthesis of vitamin C, l-xylosone (2)
was synthesized from the pentose xylose. The C1chain
extension was then achieved using potassium cyanide. Lacto-
nization and enolization of the l-xylonitrile (3) under acidic
conditions resulted in a yield of l-ascorbic acid of around
40% (Scheme 1).[25a] This procedure was never of commercial
interest, since the starting materials are too expensive. A
similar synthesis starting from arabinose also found no
The principle of l-ascorbic acid preparation includes
either an acid-catalyzed cyclization of 2-keto-l-gulonic acid
(2-KGA, 4) or a base-catalyzed cyclization of the correspond-
ing methyl ester (Scheme 2). These aspects are discussed in
more detail below.
2.4. Industrial Processes
The first industrial preparation of l-ascorbic acid used the
Reichstein–Grssner process. In the classical process d-
glucose (5; Scheme 3) is hydrogenated over a nickel-alloy
catalyst to afford sorbitol (6). Microbiological oxidation with
Gluconobacter oxydans results in the formation of l-sorbose
(7). An acid-catalyzed reaction with acetone results in the
formation of 2,3,4,6-di-O-isopropylidene-a-l-sorbofuranose
(8), which is oxidized in high yield and selectivity to di-O-
isopropylidene-2-ketogulonic acid. Acid treatment removes
the acetal protecting groups and the resulting 2-ketogulonic
acid rearranges to l-ascorbic acid.[27a] The base-catalyzed
rearrangement has also been described, and the advantages
and disadvantages have been discussed. The oxidation of 8
can be effected by treatment with hypochlorite in presence of
a nickel salt, by electrochemistry, or by air-oxidation cata-
lyzed by palladium or platinum on a carrier.
A further attractive approach to l-ascorbic acid is the
synthesis of 2-ketogulonic acid (2-KGA, 4) by direct oxida-
tion of l-sorbose (7). This reaction was investigated by
several research groups with little success (Scheme 4). The
gold-catalyzed oxidation of carbohydrates shows interesting
results. Problems in the selectivity of the sorbose oxidation
may be solved by these catalysts in the future.
2.5. Biotechnological Production of l-Ascorbic Acid
A two-stage microbial fermentation process developed in
China in the late 1960s and early 1970s is generally
employed to produce 4by a biotechnological approach.
Figure 7. Vita-
min C (1).
Scheme 1. Synthesis of l-ascorbic acid from xylosone.
Scheme 2. Principle of l-ascorbic acid synthesis through rearrange-
Scheme 3. Reichstein–Grssner process for the manufacture of l-
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Similar to the Reichstein–Grssner process described above,
l-sorbose (7) is generated by the Gluconobacter-mediated
oxidation of d-sorbitol (6). However, in contrast to the
chemical oxidation, the biochemical oxidation is carried out
in a second fermentation step with Ketogulonicigenium
strains, and 4is obtained by oxidation of the intermediate l-
sorbosone. Efficient fermentation of Ketogulonicigenium
requires co-cultivation of a helper strain, for example,
Bacillus megaterium. The underlying supportive mechanism,
however, is not understood. For process control, the 2-KGA
fermentation process must be separated into two sequential
steps, keeping Ketogulonicigenium apart from d-sorbitol. In
contrast to Gluconobacter,Ketogulonicigenium would medi-
ate the oxidation of d-sorbitol to glucose, gluconate, 2-
ketogluconate, and other oxidation products, which would
result in a lower yield of 4. As in the Reichstein–Grssner
process, 4is eventually converted by an acid-catalyzed
reaction via its methyl ester into l-ascorbic acid. The
described two-stage microbial fermentation process is very
efficient and can produce up to 130 g L14with a yield of over
80% based on d-sorbitol. Compared to the Reichstein–
Grssner process, the 2-KGA fermentation process provides
a clear cost benefit, since it requires not only less chemicals
and energy, but also significantly less investment in produc-
tion equipment because of the simpler process requirements.
An improved version of the fermentation process to
generate 4involves three oxidation reactions from d-sorbitol
to 2-KGA (4) in a single process step that is facilitated by
a mixed culture of Gluconobacter suboxydans IFO3255 and
Ketogulonicigenium vulgare. Gluconobacter can substitute for
the Bacillus helper strain, thus facilitating Ketogulonicige-
nium growth. It also mediates the oxidation of sorbitol to
sorbose at a sufficient rate without allowing Ketogulonicige-
nium to oxidize the sorbitol to glucose and other undesired
oxidation products. A single-strain process for 2-keto-l-
gulonic acid based on an intensively mutagenized G. oxydans
strain was developed, but never commercially exploited,
probably because of inferior space–time yields.
Alternative microbial routes to 2-keto-l-gulonic acid (4)
starting from d-glucose via 2,5-diketo-d-gluconate have been
developed by employing Erwinia and Corynebacterium
species in a two-step process or by employing genetically
engineered Erwinia species expressing a gene for a Coryne-
bacterium 2,5-diketoreductase. However, as a consequence
of poor performance, these processes were not used industri-
All of the l-ascorbic acid bioprocesses developed to an
industrial stage so far result in the formation of the precursor
compound 2-KGA (4), which is converted in a costly final
chemical rearrangement step into ascorbate. Numerous
attempts have been made to further reduce the production
costs associated with ascorbate and to design microbial routes
that directly form l-ascorbic acid. Microalgae such as
Chlorella species that synthesize l-ascorbic acid in an
analogous manner to the plant pathway yielded up to
1of the vitamin, although it was mainly associated
with the biomass. Although d-glucose (5) was used as the
fermentation substrate, the reported low productivity ren-
dered a commercial application nonviable.
Another approach tried to utilize the biosynthetic
capacity of Saccharomyces cerevisiae (bakers yeast), which
can synthesize the C5l-ascorbic acid analogue d-erythroas-
corbic acid in nature. Characterization of the S. cerevisiae
pathway revealed that cells incubated with l-galactose, l-
galactono-1,4-lactone, and l-gulono-1,4-lactone led to the
direct formation of l-ascorbic acid. The results suggest that
the pathway could be exploited for the direct production of
ascorbate by a single fermentation step, but so far no
commercial process has been established.
Another promising direct route to l-ascorbic acid has
been identified by the discovery of dehydrogenases present in
Ketogulonicigenium sp. and Gluconobacter species that con-
vert l-sorbosone, the partially oxidized biosynthetic inter-
mediate of the microbial 2-KGA processes, directly into
3. Thiamin (Vitamin B1)
3.1. Physiological Functions
Thiamin (9, Figure 8) is a water-soluble vitamin that plays
an essential role in the metabolism of carbohydrates and
branched-chain amino acids. Thiamin, in the form of thiamin
pyrophosphate, acts as co-enzyme in the oxidative phosphor-
ylation of a-ketoacids and in transketolase reactions, two
processes important to the metabolism of carbohydrates and
lipids. Thiamin deficiency is characterized by beriberi,
a syndrome that occurs in two principle forms—dry (paralytic
peripheral neuropathy) and wet (heart abnormalities and
failure)—and by the Wernicke–Korsakoff syndrome.
Vitamin B1or thiamin (9) played a very important part in
the early history of the synthesis and commercial manufacture
of vitamins. From the end of the 19th century there was
intense scientific and medical debate in Europe, Asia, and the
USA about the real cause of the wasting disease known as
Scheme 4. Direct oxidation of l-sorbose (7).
Figure 8. Thiamin (9).
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beriberi. Causes ranging from bacteria, parasites, toxins, to—
the ultimately correct—nutritional deficiency were postulated
and heatedly defended. In Japan and the Dutch East Indies,
the introduction of white (“polished”) rice prepared by
mechanically removing the outer layers of the grain coincided
sometimes with major outbreaks of beriberi. In 1897 Christian
Eijkman, a Dutch physician working in Batavia (todays
Jakarta), showed that polyneuritis in birds and the related
beriberi in humans could be induced by a diet restricted to
polished rice, and that this could be reversed by feeding
unpolished rice or the “polishings” which had been removed
in the processing. Eijkman believed that the harmful
component (a bacterium or toxin) was in the rice kernel,
and that somehow the husks prevented the disease.
In 1901 Gerrit Grijns, Eijkmans assistant in Java,
proposed the correct interpretation: that polyneuritis and
beriberi were caused by a deficiency of a nutrient found in the
rice husks. In 1911 the Polish chemist Casimir Funk,
working at the Lister Institute in London, isolated an impure
substance from rice bran that prevented polyneuritis or
beriberi, and soon after he coined the term “vita-amine”. In
1926, working in Eijkmans institute in Jakarta, the Dutch
biochemists Barend Jansen and Willem Donath isolated a tiny
amount of pure crystalline substance from several hundred
kilograms of rice polishings. Eijkman showed that this
substance could cure polyneuritis at a concentration of only
2 ppm. Elucidation of the structure of the molecule proved to
be difficult, not least because of the tiny amounts which were
available. A major step forward was made by Adolf Windaus
in Gçttingen in 1932, who first recognized that the molecule
contained sulfur and who also correctly proposed
C12H18N4OSCl2as the molecular formula of the thiamin
chloride hydrochloride salt. Working from his fortuitous
discovery that the molecule could be quantitatively split into
two components—a pyrimidine and a thiazol ring—by treat-
ment with sodium sulfite, the American chemist Robert R.
Williams proposed the correct molecular structure 9for the
vitamin in 1934 and later the now-accepted name “thia-
min”. The correct structure of the pyrimidine component
was clearly shown by the work of Rudolf Grewe in
Gçttingen. Several syntheses followed in quick succession
in 1936–1937, for example, by Hans Andersag and Kurt
Westphal (IG-Farben, Elberfeld); Robert R. Williams and
Joseph K. Cline (Bell Labs/Merck, USA); Alexander Todd
and Franz Bergel (Univ. Edinburgh/Lister Institute,
A characteristic of this pioneering research into thiamin
was the speed with which these successful syntheses followed
the isolation and structure elucidation. There was intense
competition among the various research groups, driven in part
by the certain knowledge that the scourge of beriberi,
widespread in some countries, could be cured by enrichment
of foodstuffs with the vitamin, which implied a ready market
for the newly named “thiamin”. In contrast, scurvy, known to
be curable by l-ascorbic acid (vitamin C), was a relatively
Of the synthetic routes to thiamin, the most practical for
developing to an industrial scale were those of Williams and
Cline (Scheme 5) and of Todd and Bergel (Scheme 6). The
pioneering work of Williams had been generously supported
by Merck & Co, and it was natural that the exclusive rights to
his synthesis were readily granted to that company, which first
produced thiamin in Rahway, New Jersey in 1937. F. Hoff-
mann–La Roche (Basel) had supported Todd and Bergel,
through the friendship of their head of research Markus
Guggenheim with Prof. George Barger of Edinburgh Uni-
versity. Roche quickly developed the Todd–Bergel route into
a process which could be operated on a scale that would allow
the annual production of some hundreds of kilograms.
Mercks industrial-scale version of the Williams synthesis
consisted firstly of the production of both the required 4-
amino-5-bromomethyl-2-methylpyrimidine (10) and the thia-
zole component 11. Condensation gave thiamin bromide
hydrobromide which was converted by silver chloride or ion
exchange into the required thiamin chloride hydrochloride
(9·HCl, Scheme 5). The Todd–Bergel route (Scheme 6)
depended on the formation of a thioformyl derivative 13 of
diamine 12 (generally known as “Grewe diamine”), which
was condensed with an open-chain chloroketone 14 to give
the required thiazole.
This process was eventually replaced by a much more
efficient route (Scheme 7), in which Grewe diamine 12 reacts
with carbon disulfide and the chloroketone 14 to give
a ketodithiocarbamate 15 and then thiothiamin 16, which is
oxidized and transformed to 9·HCl. Chloroketone 14 can
also be replaced by a mercaptoketone 17, which is then
treated, not with 12, but with dehydrated, bicyclic N-formyl
Grewe diamine 18 (Scheme 8).
Scheme 5. Synthesis of thiamin by Williams and Cline.
Scheme 6. Synthesis of thiamin by Todd and Bergel.
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In the years immediately before and during World War II,
Roche operated small thiamin plants in Basel, Nutley (USA),
Welwyn Garden City (UK), and Grenzach (Germany). After
1950, intensive efforts were made by Roche and Merck to
improve their processes. The complexity of the multistep
synthesis and the many chemical options theoretically avail-
able offered great opportunities for significant improvements
in the process. Moreover, the rapid progress made by
Nathan C. Hindley in improving the yield was the main
driving force for the early introduction of process research as
a highly regarded discipline within Roche.
3.3. Current Syntheses
All industrially relevant syntheses of 9use Grewe diamine
12 as the key building block. The common starting materials
(C3units) for the synthesis of 12 are acrylonitrile or
malononitrile. Malononitrile is transformed with orthofor-
mate into the related aminomethylene malononitrile, which is
condensed with an activated acetonitrile, methyl acetimidate,
and leads to the 5-cyanopyrimidine (Scheme 9).
Malononitrile is a key cost determinant in the synthesis of
12. Many routes starting from the cheaper acrylonitrile were
investigated over the years to improve the cost efficiency of
the process, and several options were developed by the
leading manufacturers. Acrylonitrile is functionalized with
ammonia to give aminopropionitrile[54a] or with formamide to
give N-formylaminopropionitrile,[54b,c] which is reacted to
form the corresponding metal enolate 19. The highly sensitive
enolate 19 is converted into an enamine (usually using o-
chloroaniline; Scheme 10), to an enol alkyl ether
(Scheme 11), or to a dialkylacetal (not shown). Both
derivatives are condensed with acetamidine to afford 12.
The latter two processes have the disadvantage that highly
carcinogenic reactants such as o-chloroaniline and dimethyl
sulfate are used. The derivatization with dimethyl sulfate
leads to stoichiometric amounts of sodium methylsulfate
waste. o-Chloroaniline is recycled, but traces may possibly be
found in the final product 9. Acetamidine is commercially
available as the hydrochloride salt, the free base being not
very stable. In both syntheses, acetamidine hydrochloride has
to be reacted with a strong base, which leads to additional
amounts of salt waste.
Very recent Grewe diamine syntheses involve even
shorter routes, which conveniently use metal enolate 19
directly in a Lewis acid catalyzed condensation with acet-
amidine hydrochloride (Scheme 12). Biphasic hydrolysis of
Scheme 7. An industrial synthesis of 9.
Scheme 8. Coupling of mercaptoketone 17 to 9·HCl.
Scheme 9. Synthesis of 12 starting from malononitrile.
Scheme 10. Synthesis of 12 via an enamine by using o-chloroaniline as
a derivatizing agent.
Scheme 11. Synthesis of 12 by using dimethyl sulfate as a derivatizing
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the N-formyl Grewe diamine allows for easy separation and
purification of 12. The compound can be prepared in
a three-step synthesis from acrylonitrile. Another recent
synthesis avoids the use of acetamidine hydrochloride, but
makes use of the primary enamine 20, which reacts directly
with acetonitrile in a base-catalyzed reaction to give 12
Even today, 12 remains of interest to current process
research groups still trying to develop novel routes to highly
pure thiamin (9). Although cost was always a main driver
for process research, developing a process that would reliably
produce thiamin of sufficient excellent pharmaceutical qual-
ity proved to be a very challenging task. Since the synthesis is
complex, there are many opportunities for the formation of
by-products which can carry through to the final product.
Every process change brings with it the chance that the
impurity profile will also change. This aspect of the thiamin
synthesis was key to the rapid acceptance of chromatographic
techniques (GC, paper, thin-layer, later HPLC etc.) by the
In addition to the challenge of chemical purity, thiamin
chloride hydrochloride sets the chemist, whether in develop-
ment, production, or formulation, a particular physicochem-
ical challenge in that it exists in several crystal forms. This
property was already noted by the early investigators. The
normal commercial form is the (nonstoichiometric) mono-
hydrate. This can convert into the thermodynamically pre-
ferred hemihydrate, which can then set to a concrete-like
mass on liberation of the water.
The main commercially available product forms are
thiamin chloride hydrochloride and thiamin mononitrate.
Thiamin pyrophosphate (cocarboxylase) was earlier pro-
duced as a specialty product, but today plays no significant
part in the global thiamin market.
Today, since thiamin is widely used in human nutrition,
deficiency is very much less prevalent, but it can still occur in
particular groups, for example in patients with congestive
heart failure, in those who abuse alcohol, and in famine
4. Riboflavin (Vitamin B2)
4.1. Physiological Functions
Riboflavin (21) is a water-soluble vitamin that is an
essential coenzyme for redox reactions in many different
metabolic pathways. It is the precursor to the flavoenzymes
flavin mononucleotide (FMN) and flavin adenine dinucleo-
tide (FAD), and is found in nature also in the free form and as
the 5’-phosphate derivative (Figure 9). FAD is part of the
respiratory chain and is central to energy production.
Flavoenzymes are involved in one-electron transfers, dehy-
drogenase reactions, hydroxylations, oxidative decarboxyla-
tions, and dioxygenations.
In the past, Vitamin B2was often called lactoflavin,
ovoflavin, lyochrome, heptoflavin, or uroflavin. Riboflavin
is found in all plant and animal cells. In culture media of fungi
or bacteria, for example, Ashbya gossypii,Eremothecium
ashbyii,orBacillus subtilis, riboflavin can be accumulated at
concentrations over 10 gL1.
Riboflavin had already been isolated around 1880 as the
yellow pigment from whey by the English chemist Blyth.
Scheme 12. Lewis acid catalyzed coupling of enolate 11 with acetami-
Scheme 13. Base-catalyzed enamine–acetonitrile coupling to 12.
Figure 9. Riboflavin derivatives in nature.
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However, he did not recognize its nutritional function. The
vitamin B complex was initially discovered in 1917 in extracts
of brewers yeast, and nutritional scientists distinguished two
components of the complex: vitamin B1or the antineuritic
factor and vitamin B2or the rat antipellagra factor. Whereas
vitamin B1turned out to be a unique chemical entity, that is,
thiamin 9, vitamin B2consisted of several different compo-
nents including a yellow, intensively fluorescing compound
designated riboflavin. Kuhn, Gyçrgy, and Wagner-Jauregg
isolated pure 21 from egg yolk and determined its function as
a vitamin. Karrer and Schçpp later isolated 21 from liver
and vegetables. The structure of riboflavin was proven by
chemical synthesis in the mid-1930s.[70,71] Since the 1950s, the
biochemical aspects of flavin research have been the main
focus. For a more detailed summary and an insight into the
chemistry and biochemistry of flavoenzymes the reader is
referred to comprehensive reviews.[72,73]
Chemical production processes were established at
Merck, Roche, BASF, ADM, and Takeda in the first decades
of vitamin B2production. The industrial production process
was switched from chemistry to biotechnology around 2000.
In a similar way to other water-soluble vitamins, competitors
from Asia entered the market around 1990, and applied
chemical and biotechnological production procedures to
manufacture 21. Today, DSM Nutritional Products manufac-
tures the vitamin in a plant in Southern Germany, with
Bacillus subtilis employed in the fermentation process. BASF
moved their riboflavin production process based on Ashbya
gossipii from Germany to Gunsan, South Korea some years
ago. The main Chinese producer is Hubei Guangji Pharma-
ceutical Co. Ltd. of Hubei Province, who also uses Bacillus
subtilis for the fermentation. The total quantity of riboflavin
produced at present by fermentation is more than 4000 t each
year. About 70% is used as a feed additive in the form of
spray-dried granules, and 30% is required for the fortification
of foods and in pharmaceutical applications.
4.3. Chemical Production of Riboflavin
The first chemical synthesis of riboflavin was accom-
plished by the research groups of Kuhn and Karrer in 1934
and 1935.[70,71] The procedure of Kuhn et al. involved a reduc-
tive condensation of 6-nitro-3,4-xylidine with d-ribose, and
the resulting nitro compound was reduced catalytically to the
phenylenediamine, which was treated with alloxane under
acid conditions. The yield was 16% based on ribose. Karrer
et al. also obtained 21 starting from d-ribose. Treatment with
2-(ethoxycarbonylamino)-4,5-dimethylaniline was followed
by hydrogenation under basic conditions and condensation
with alloxane to give riboflavin in 15 % yield (Sche-
The yield was increased by employing a modification of
the route used by Karrer et al., whereby 3,4-xylidine was
condensed with d-ribose or its tetraacetate to give N-d-
ribityl-3,4-xylidine, which was coupled with a diazonium salt.
This compound could be reduced and treated with alloxane to
4.4. Technical Processes to Riboflavin
Since 1934 many variations and refinements have been
introduced to the general syntheses developed by the research
groups of Kuhn and Karrer to adapt them to large-scale
manufacture. An important step forward in riboflavin syn-
thesis was the direct condensation of barbituric acid with an
azo dye in acetic acid. This so-called Tishler reaction gives 21
in 48 % yield based on ribose (Scheme 15).
All subsequent chemical routes to riboflavin followed this
principle. In the technical processes d-ribose, ribitylxylidine,
and barbituric acid were used as the starting materials. d-
Ribose was first synthesized by Emil Fischer and is nowadays
produced by microbiological methods from glucose with
Bacillus pumilis or Bacillus subtilis.[78,79] The annual produc-
tion of d-ribose by using this method is several thousand tons.
The key intermediate ribitylxylidine (22) is produced from d-
ribose and xylidine in high yield, with xylidine itself manu-
factured from 4-bromo-o-xylene and ammonia in the pres-
ence of cuprous chloride.[80,81] An alternative method for the
synthesis of 22 consists of coupling ribonolactone with
xylidine, then converting the resulting anilide into the
Scheme 14. Synthesis of riboflavin by Karrer, Kuhn et al.
Scheme 15. Riboflavin synthesis by a Tishler reaction.
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chloroimine, which is reduced to ribitylxylidine. The
reductive coupling of ribonolactone and 3,4-xylidine and
a subsequent dehydration of ribonamide to ribonitrile are
followed by condensation with barbituric acid. The product
arising from the condensation of ribose and xylidine, after
hydrogenation over a nickel-alloy catalyst at a hydrogen
pressure of 25–60 bar, is ribitylxylidine 22. The synthesis of
barbituric acid is described in detail in the literature.[86,87]
As mentioned in the previous section, another key
intermediate in riboflavin synthesis is the so-called azo dye
23. The reaction of ribitylxylidine and an aryl diazonium salt
(aryl =phenyl or nitrophenyl) was first described by Karrer
et al.[10,76] A modified synthesis of 23 from ribitylxylidine and
substituted amines, e.g. o-anisidine, was described in
a patent. Chemical processes for the manufacture of
riboflavin may be summarized as shown in Scheme 16.
The purification of crude riboflavin by using mineral acids
was first patented in 1943. Alternative approaches for
purification under basic conditions were not industrialized.
4.5. Biosynthesis of Riboflavin in Microorganisms
Of the water-soluble vitamins, the biosynthetic pathway
leading to riboflavin was the most intensively studied.
Ground-breaking findings for the elucidation of riboflavin
biosynthesis were contributed in the 1950s by the research
group of Plaut, and since the 1970s by the research group of
Bacher. For more detailed insights into the biocatalytic
mechanism of riboflavin biosynthesis the reader is referred
to excellent comprehensive reviews.[91,92] The synthetic path-
way to 21 in microorganisms has been studied in detail and
has been reviewed in detail.
4.6. Biotechnological Production of Riboflavin
The first microbial production processes for riboflavin
that were developed in the 1940s used natural overproducing
yeast strains such as Candida famata,Eremothecium ashbyi,
and Ashbya gossypi. Another riboflavin production process
based on the fermentation of the Gram-negative bacterium
Corynebacterium ammoniagenes was developed at Kyowa
Hakko of Japan. However, despite attractive published
productivities, the C. ammoniagenes production strains were
probably never employed for the commercial manufacture of
riboflavin. In the early 1970s Merck Sharp and Dohme, USA,
developed a riboflavin production process based on an
A. gossypii which was later purchased by BASF, who imple-
mented it on an industrial scale. After several years of the
chemical and microbial processes being used in parallel, the
chemical route was abandoned. Over the years steady
improvements in the production capabilities of the A. gossypii
host strain were obtained by classical mutagenesis and
selection as well as metabolic engineering.
The riboflavin process based on A. gossypii uses vegetable
oils as the fermentation feedstock, thus necessitating b-
oxidation of fatty acids and subsequent efficient utilization of
the acetyl-CoA (CoA =coenzyme A) produced. The meta-
bolic flux through the riboflavin biosynthetic pathway was
improved by a rational approach and additional copies of the
genes encoding riboflavin biosynthetic enzymes were intro-
duced into the genome of A. gossypii.[94–96] A. gossypii depos-
its riboflavin in its vacuole by an active transport process, and
intracellular crystals are formed at elevated concentrations.
Riboflavin is released into the medium by heat-induced
lysis of the biomass after completion of the fermentation run.
Controlled cooling of the fermentation broth promotes
growth of the riboflavin crystals and enables separation of
the crystals from the biomass by decantation. Further
purification of riboflavin is achieved by recrystallization.
A high-performing riboflavin production strain based on
B. subtilis was developed at Roche and is similar to the
production strain developed at the Russian Institute for
Genetics and Selection of Industrial Microorganisms.[97,98] A
B. subtilis mutant designated RB50 was isolated that con-
tained purine-analogue-resistant mutations designed to
deregulate the purine pathway and a riboflavin-analogue-
resistant mutation in the riboflavin kinase that deregulates
the riboflavin biosynthetic pathway. The mutation in the
riboflavin kinase resulted in drastically reduced levels of
FMN formed, thus leading to low FMN levels in the cell.
Since FMN, but not riboflavin, acts as an effector compound
that triggers the riboswitch-based riboflavin repression
system in B. subtilis, the mutants overproduce and secrete
riboflavin. Genetic engineering was applied to further
enhance expression of the rib gene by making use of strong,
constitutive promoters and by increasing the dosage of the rib
gene. This procedure was optimized, and a production strain
was established. Riboflavin accumulates during the fer-
mentation and crystallizes in the fermentation broth. The long
needle-shaped crystals can be easily recovered and separated
from the biomass by decanting. Treatment of the recovered
riboflavin crystals with acid at elevated temperatures fol-
lowed by intensive washing resulted in isolation of a 96%
pure product. Food/pharma-grade riboflavin of over 99%
purity can be obtained by recrystallization. Since 2000, DSM
Nutritional Products has been producing riboflavin exclu-
sively by the microbial process based on B. subtilis. For more
details on the microbial production of riboflavin the reader is
referred to an excellent review by Hohmann and Stah-
Scheme 16. Industrial manufacture of riboflavin by chemical process-
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5. Pyridoxine (Vitamin B6)
5.1. Physiological Functions
Vitamin B6consists of pyridoxal (PL), pyridoxine (PN),
pyridoxamine (PM), and their 5’-phosphate derivatives (PLP,
PNP, and PMP, respectively). PLP is involved in many
different enzymatic reactions in the body that affect
immune function, erythrocyte metabolism, gluconeogenesis,
formation of niacin, and hormone modulation. Vitamin B6
deficiency is characterized by nonspecific findings of sebor-
rheic dermatitis, microcytic anemia, convulsions, and depres-
The six chemically closely related compounds of the
vitamin B6complex were identified by Gyçrgy and Birch, and
called adermin. Their isolation from rice bran and yeast as
well as their structural confirmation were achieved in 1938
independently by several research groups. Two syntheses
of pyridoxine, in the hydrochloride form, were published in
1939. They are similar in the structural element 2-methyl-
3-hydroxypyridine, only the substituents in positions 4 and 5
are different (Figure 10). It was demonstrated by micro-
biological methods that the six compounds with vitamin B6
activity are interconvertible.
5.3. Principal Methods for the Synthesis of Pyridoxine
Up to now, five principally different routes have been
developed for the synthesis of pyridoxine. Several variants of
all of those schemes exist. Review articles summarizing these
developments have been published.[107,108] Pyridoxine was
synthesized for the first time starting from substituted
isoquinolines or quinolines, for example, 2-methyl-3-meth-
oxyisoquinoline, by degradation (Scheme 17).[105b] The main
disadvantages of this procedure are the limited availability of
the starting materials and the expensive methods for reducing
the intermediate diacid 26 into the diol 24.
The first commercial process for the preparation of 24
started from aliphatic precursors such as ethyl acetylacetate
(27) and cyanoacetamide (28) or malononitrile (Sche-
me 18).[105a,109, 110] The advantage of this route was the easy
availability of the starting materials. The disadvantages of this
sequence are a high number of reaction steps including
problems with the yields of individual transformations and
the rather low overall yield. Several approaches following this
concept were described over many years. The N-acetyl
compound 29 was synthesized from furan in a multistep
reaction sequence and then further transformed into pyr-
idoxine by an anodic electrolytic oxidation in methanol
followed by a saponification (Scheme 19). However, the
overall yield of the process is low and not competitive with
Kondrateva demonstrated the potential of oxazoles in the
synthesis of pyridine rings by Diels–Alder reactions. Based on
this fundamental study, the synthesis of pyridoxine was
realized. This concept resulted in a considerable number
of patent applications on this topic. A real breakthrough was
the introduction of a leaving group in position 5 of the
methyloxazole. The diene compound in the industrial
production of pyridoxine is 5-cyano-4-methyloxazole or 5-
ethoxy-4-methyloxazole. Commercial syntheses of pyri-
doxine carried out by Takeda, Merck, Daiichi, BASF, and
Roche followed this Diels–Alder concept, but differed in the
type of diene used (Scheme 20).
Several routes are known for the production of 5-ethoxy-
4-methyloxazole (30, Scheme 21). The starting material is
d,l-alanine ethyl ester, which is formylated and dehydrated in
Figure 10. Compounds with a vitamin B6function.
Scheme 17. Pyridoxine from isoquinolines.
Scheme 18. Synthesis of pyridoxine by a Knoevenagel reaction.
Scheme 19. Furan approach to pyridoxine.
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the presence of phosphorus pentoxide. Alternative routes
to alkoxyoxazoles start from maleic anhydride, which is
transformed by treatment with ammonia to d,l-aspartic acid,
followed by N-formylation, dehydration, saponification, and
decarboxylation. Furthermore, oxalic ester derivatives of d,l-
alanine can be transformed to oxazole derivatives. During
recent years, several modifications of this approach hav been
established by changing the reaction sequence and applying
basic conditions. This has led to lower waste formation and an
increased yield. An alternative synthesis of alkoxyoxazole
derivatives is based on isonitriles, produced from alanine by
formylation, dehydration, and thermal treatment, but has not
been industrialized up to now.
Since ethoxyoxazoles are very expensive from an indus-
trial viewpoint, alternative oxazole derivatives from cheaper
starting materials are of great interest. Moreover, oxazoles
with an improved thermal stability would be beneficial.
Therefore, 4-methyl-5-cyanooxazole (31) is a useful diene for
the Diels–Alder reaction. For example, 4-methyl-5-carb-
oxyoxazol esters are available starting from ethyl acetoace-
tate (from ethanol and diketene) by chlorination and reaction
with formamide. Treatment of the ester with ammonia and
dehydration form the 4-methyl-5-cyanoxazole. The dehy-
dration is carried out in the presence of phosphorus pent-
oxide/quinoline. Several other dehydration methods which
are more environmentally friendly have been described,[108,121]
for example, using cyanuric chloride, sulfur trioxide amine
complexes, silicon tetrachloride, or gas-phase reactions.
The following general statements can be made about the
dienophiles which can be used in the Diels–Alder reaction
leading to pyridines: derivatives of maleic and fumaric acid
are rather reactive in this reaction. Their disadvantage is that
the reduction of the carboxylic acid functionality needs costly
hydride reagents. None of the vitamin B6syntheses presently
in operation makes use of it. The theoretically ideal reaction
partner of 4-methyloxazoles would be (Z)-butynediol. This
dienophile, however, reacts in the presence of oxazoles in an
alternative reaction pathway with formation of furans in good
yields. The best dienophiles reported so far are cyclic
acetals of (Z)-butenediol.[114b] In general, the oxazole com-
pound in this cycloaddition reaction should have rather little
steric hindrance and high thermal stability to achieve good
results. Today, more than 60 years after Kondratevas first
publication on the synthesis of pyridines by a Diels–Alder
reaction with oxazoles as dienes, it can be stated with a very
high degree of certainty that all present-day industrial
vitamin B6syntheses use this basic reaction in their key step.
A different approach to the synthesis of pyridine deriv-
atives by employing a cobalt-catalyzed [2
was established by Parnell and Vollhard as well as by
Geiger et al. (Scheme 22). Acetonitrile and a,w-diynes
could be transformed into pyridoxine. However, the selectiv-
ity of this reaction was moderate due to competitive
formation of carbocycles. The replacement of the trimethyl-
silyl group by an aromatic OH group limited the yield (only
17% for this step), thus resulting in a disappointingly low
overall yield of 3–7%. The moderate selectivity of the cobalt-
2] cycloaddition could be enhanced by
applying a modified Co catalyst under irradiation, whereas
the introduction of the OH group can be achieved in an
acceptable yield by using a different silicon protecting
In contrast to the situation of other water-soluble
vitamins, DSM (formerly Roche) is the only one of the
early companies still producing vitamin B6. Since the 1990s
the picture has changed in such a manner that producers from
Asia (in particular China) have entered the market and
increased their production volumes. Since the 1960s all
producers of pyridoxine have been using the Diels–Alder
approach. Whereas the producers in Asia use ethoxyoxazole
as the diene component, those in Europe use cyanooxazole.
Scheme 20. The Diels–Alder approach for the synthesis of a pyridox-
Scheme 21. Synthesis of oxazole derivatives.
Scheme 22. Cobalt-catalyzed [2
2] cycloaddition on the way to
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6. Pantothenic Acid (Vitamin B5)
6.1. History and Physiological Functions
Pantothenic acid (vitamin B5,33 ; Figure 11) was identi-
fied in 1931 as a growth factor and isolated in 1938 from
sheeps liver. This factor prevents chicken dermatitis and
was essential for the growth of rats. Pantothenic acid is
widely distributed in foods, thus pantothenic acid deficiency is
Pantothenic acid is an acid- and a base-sensitive hygro-
scopic oil, and thus it is sold commercially as its calcium or
sodium salts or as the primary alcohol derivative panthenol
(34). In nature, pantothenic acid is part of coenzyme A and is
found, for example, in the liver, kidney, corn, yeast, and green
plants. The ubiquitous distribution of 33 is also reflected in its
name pantothenic acid, which comes from Greek and means
everywhere. Lipman recognized co-enzyme A as a cofactor
of the enzymatic acyl transferase reaction. A pantothenic
acid unit was also identified in pantetheine, a secondary
growth factor in lactic acid bacteria. The biosynthesis of 33
starts from pyruvic acid, which is transformed in a complex
pathway to vitamin B5. Pantothenic acid and also panto-
lactone (35), the key intermediate of its synthesis, occur in
nature in the Rconfiguration. Therefore, a milestone in the
history of pantothenic acid was the determination of its
absolute configuration by Hill and Chan. The X-ray
analysis of calcium–pantothenate complexes was described
6.2. Synthesis of Pantothenic Acid
One stereogenic center, an w-peptide linkage, a carboxylic
moiety, and a primary as well as a secondary hydroxy group
are found in pantothenic acid. The synthesis of 33 and of most
of its derivatives starts from (R)-pantolactone ((R)-35).
Pantolactone is synthesized in racemic form from isobutyr-
aldehyde and is later resolved to give the Risomer. The (S)-
pantolactone is separated, transformed into the sodium salt,
and racemized. Condensation of 35 with alanine or deriva-
tives thereof affords pantothenic acid or derivatives
The synthesis of the racemic pantolactone involves the
aldol condensation of isobutyraldehyde and formaldehyde,
followed by treatment with hydrogen cyanide under acidic
conditions. The intermediates are not isolated and rac-35 can
be obtained after extraction and distillation in a yield of
around 90%. Several methods are known for the reso-
lution of rac-35. The resolution is carried out on an industrial
scale by treatment of rac-35 with quinine in methanol. The
(R)-35 salt is less soluble then the (S)-35 salt and can be
isolated by crystallization. Alternative methods make use
of strong bases derived from cinchona alkaloids. Efficient
separation of (R)-35 can also be achieved with chiral amines
such as dehydroabietylamine (from pine resin) or (
aminoethylpinane (from ()-a-pinene). Alternative pro-
cedures for the synthesis of (R)-35 starting from 2-oxopanto-
lactone, synthesized by oxidation of rac-35, and enantiose-
lective hydrogenation in the presence of a chiral rhodium
catalyst or microbiological methods have been reported, but
not scaled-up into production.[31a,138]
A different concept follows the oxynitrilase-catalyzed
synthesis of cyanohydrin. Aldehydes, for example, 3-hydroxy-
3,3-dimethylpropanal, are treated with hydrocyanic acid in
the presence of such an enzyme and then hydrolyzed to give
(R)-35 in high optical purity.
Calcium and sodium pantothenates are manufactured by
the addition of calcium or sodium b-alaninate to (R)-35 in
methanol. Depending on the reaction conditions, products
are obtained in different forms as a result of polymorph-
7. Biotin (Vitamin B7, Vitamin H)
7.1. Physiological Functions
)-Biotin (vitamin H or vitamin B7;36) is a member of
the water-soluble B vitamins. It functions as a coenzyme in
bicarbonate-dependent carboxylation reactions in lactate and
pyruvate metabolism, leucine degradation, and propionate
metabolism. Biotin deficiency, described in individuals on
a prolonged diet of raw egg whites and in those on total
parenteral nutrition that lacks biotin supplementation, is
Figure 11. Pantothenic acid and derivatives.
Scheme 23. Synthesis of pantothenic acid.
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characterized by dermatitis, conjunc-
tivitis, alopecia, and central nervous
system abnormalities. An adult
human needs about 0.03–0.1 mg
)-biotin per day. Biotin possesses
three stereogenic cen-
ters. The only isomer
exhibiting full biolog-
ical activity is the one with the configuration
3aS,4S,6aR, namely d-(+
7.2. Introduction to the Chemistry and Overview
of the Industrial Production of (
The history of biotin starts with the publi-
cations of the first total synthesis of racemic
biotin and its subsequent optical resolution by
Harris, Folkers et al. at Merck in 1943.
Goldberg and Sternbach of Hoffmann–La Ro-
che applied for patents on the first commer-
cially applicable biotin synthesis in 1946 (pub-
lication in 1949). Since then, the optimum
total synthesis of biotin (or, alternatively,
a biotechnological method) has attracted the
interest of many industrial and academic
research laboratories. Companies who made
considerable developments in this field were
Merck & Co. (Research Laboratory, Rahway)
and Merck (Darmstadt), Hoffmann–La Roche
(with several research groups in Nutley, Paris,
and Basel), Lonza, Sumitomo Chemical Co.,
Takeda Chemical Industries, BASF, Lederle Laboratories
(Pearl River), Parke–Davis, Syntex Research (Palo Alto), and
Pfizer Central Research.
The general production method still applied today is
a multistep chemical synthesis. The world market for 36 is
about 100 t per year. Since several companies stopped
production, the current manufacturers of (+
)-biotin (36) are
DSM and several Chinese producers.
From a chemical and, in particular, from a production
point of view, the following general problems accompanied
with efficient routes to 36 have to be solved in an econom-
ically and ecologically satisfactory manner: The introduction
of nitrogen and sulfur functionalities to form the highly
functionalized bi-heterocycle, introduction of the C5side
chain, and generation of the three stereogenic centers of the
all-cis-thiophane ring. Excellent reviews on approaches to
biotin, covering about 40 original full total syntheses with
discussion and comparison of synthetic strategies, were
published by De Clercq and Seki.
7.3. Commercial Routes to (
)-Biotin: The Goldberg–Sternbach
Although the Goldberg–Sternbach concept described in
the patents dates back to 1946 (publication in 1949), this
lactone–thiolactone approach is still valuable today. The
cyclic anhydride 42 was obtained by starting from readily
available fumaric acid (37) via the meso compounds 38–40
(Scheme 24). After several functional-group transformations
with racemic thiolactone rac-41 as an intermediate, rac-43 was
transformed to the racemic sulfonium salt rac-44. The early
optical resolution (on the racemic sulfonium salt rac-44) was
desirable and not a drawback, since the “wrong” isomer was
used as a pharmaceutically active compound for another
product stream at that time. (
)-Biotin (36) was produced by
2elongation (!46) and decarboxylation sequence. Optical
resolution by use of d-camphorsulfonic acid delivered the
chiral salt 45.
This concept is undoubtedly the origin of commercial
production by total synthesis. Several features are contained
in this scheme, which were used in later synthesis sequences
developed by other research groups: the thiolactone inter-
mediate, the generation of the all-cis configuration by
catalytic hydrogenation of an exocyclic olefin, and the use
of the N-benzyl protective groups and their removal by
hydrogen bromide. Thus, this process has been designated “a
landmark accomplishment in the context of biotin synthesis”
by De Clercq.
7.4. Further Developments and Other Total Syntheses
The original Goldberg–Sternbach concept was improved
significantly by Gerecke, Zimmermann, and Aschwanden.
They found that (chiral) lactone 47 can be directly converted
with potassium thioacetate into (chiral) thiolactone 41
Figure 12. (
Scheme 24. The Goldberg–Sternbach concept.
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(Scheme 25). The optical resolution step, which takes place
advantageously at a relatively late stage, delivered d-lactone
47 after reduction and cyclization of the crystalline ephedrine
salt of the diastereomeric half-ester intermediate. The unde-
sired enantiomer was recycled by acid hydrolysis back to
diacid 40. This procedure was operated on a commercial scale
until the 1990s.
A further improvement was made by Pauling and Wehrli.
They used a diastereoselective ring opening of anhydride 42
with a chiral alcohol (Scheme 26) to replace the optical-
resolution step. d-Lactone 47 was thus obtained by reduction
of the selectively formed diastereoisomeric half-ester by
treatment with a complex hydride and ring closure.
One central question has to be answered in all commer-
cially attractive synthesis schemes: At which stage should
chirality be introduced? Classical optical resolution and the
use of chiral auxiliaries (including enzymes) have been
evaluated as methods to achieve this (Scheme 27). Routes
involving chiral starting materials available from natural
sources were also investigated thoroughly.[146,147] Particularly
attractive were cheap carbohydrates such as d-mannose and
d-glucose which had been selectively derivatized to introduce
the nitrogen and sulfur functionalities. Of the other carbohy-
drates, l-cysteine (l-cystine) was studied extensively for its
suitability in industrially feasible routes. Up to now,
however, none of the approaches starting from chiral pool
materials could be transferred to large-scale production. The
advantage of even very cheap stereochemically defined chiral
starting materials is often lost by lengthy sequences, requiring
protection and deprotection transformations because of the
high degree of functionalization in the respective intermedi-
An analysis of processes generating (+
operated on an industrial scale (see Scheme 27, upper part)
clearly shows that d-lactone 47 (or its equivalent 50)
is the most commonly used chiral intermediate. That
is, transformations yielding 47 are the most preferred
methods for the introduction of chirality. Several
reaction sequences have been used in the past to
-Ring opening of anhydride 42 by (achiral) alkanols
delivers half-esters 53 (R1or R2=H), which are
resolved by the formation of diastereoisomeric
salts with chiral amines such as d-ephedrine (see
-diastereoselective ring opening with chiral alcohols yields
diastereoisomeric esters (see Scheme 26) ;
-derivatization to chiral imides is also described;
-lipase-catalyzed esterification of diacid 40 as well as the
hydrolysis of diesters 53 (R1and R2=alkyl) have been
-diastereoisomeric acetals formed from hydroxylactones 52
give d-lactone 47 after reduction and cyclization.
All these routes to d-lactone 47 have, unfortunately, the
common disadvantage that several steps are required from
the precursors 40 or 42, and recycling of the undesired
stereoisomer(s) and/or the (expensive) chiral auxiliary is
Scheme 25. The improved Goldberg–Sternbach concept: Direct conversion of a lactone
into a thiolactone and late optical resolution.
Scheme 26. The Pauling–Wehrli concept of diastereoselective ring opening.
Scheme 27. Selected strategies used for the introduction of opti-
cal activity in routes to (
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7.5. Latest Developments Based on Catalytic Asymmetric
A highly diastereoselective RhI-catalyzed asymmetric
hydrogenation was the key step in a very short route to
)-biotin developed by researchers at Lonza together with
colleagues from the catalysis group of the former Ciba–
Geigy.[150, 151] Tetronic acid (48, Scheme 27), prepared from
diketene, served as a cheap starting material. The selectivity
of the heterogeneous diastereoselective hydrogenation of
intermediate 49 could be improved to >99:1 when the
diphosphane josiphos2 was used as a ligand. The production
of biotin via lactone 50 and thiolactone 51 was performed on
multiton scale, but had to be terminated due to a severe
drawback with this approach: the final deprotection step
involving hydrogenation of an intermediate olefin followed
by HBr treatment destroys the chirality of the (expensive)
auxiliary used for protection of the nitrogen atom, thus
leading to a dramatic increase in the overall production cost.
Nonetheless, the potential of asymmetric catalysis has
been further exploited. When analyzing the key steps
described in the preceding paragraphs, the following con-
clusion can be drawn: Based on the easy availability of cyclic
anhydride 42 as a precursor and the use of d-lactone 47 as
a preferred chiral intermediate, it becomes apparent that
a direct reductive transformation of cyclic meso-anhydride 42
to d-lactone 47 in a catalytic enantioselective manner
(Scheme 28, upper part) would be a further breakthrough.
An alternative would be the reduction of thioanhydride 54 to
Despite the rapid development of organic synthesis
methods, however, environmentally friendly and efficient
protocols for some functional-group transformations are still
lacking. Such an example is the direct reduction of cyclic
meso-anhydrides to optically active lactones. Only a few
studies on this topic are reported in the literature. Matsuki
et al. have described the stereoselective reduction of 42 to 47
with Noyoris binal-H (Scheme 29, upper part). Over-
stoichiometric amounts of the expensive chiral reagent,
however, had to be used at low temperature (78
achieve acceptable results (76 % yield, 90% ee). Although the
direct highly enantioselective reduction and concomitant
desymmetrization could be achieved in a single step for the
first time, a large-scale application is problematic and costly
due to the extensive use of the chiral auxiliary. The method
has, however, been applied successfully to the (laboratory-
scale) reduction of thioanhydride 54 to d-thiolactone 41.
The overall synthesis of (+
)-biotin based on the original
Goldberg–Sternbach approach, which had already been
assessed as being highly efficient, could also be improved
considerably by using the tools of todays highly sophisticated
asymmetric catalysis: In an intercompany collaboration
between DSM Nutritional Products and Solvias, the dream
reaction depicted in Scheme 29 (lower part) could be
achieved with high chemoselectivity and optical induction
(>95% ee) at full conversion.[154, 155] Furthermore, this
method can be applied to the preparation of a variety of
(achiral) lactones, which are valuable materials in the fine
8. Vitamin A (Retinol)
8.1. History and Physiological Functions
Vitamin A (55), or retinol, is a lipid-soluble diterpene; it is
one of a family of compounds called the retinoids, which all
have similar biological activity. Other members of the family
include the corresponding aldehyde (retinal) and acid (reti-
noic acid), and they are only found in animal tissue.
Vitamin A plays an important role in the process of vision.
Vitamin A deficiency affects an estimated 190 million pre-
school children in developing countries worldwide and
accounts for a large proportion of morbidity, mortality, and
blindness in young children in these countries. The related
compounds in plants are the carotenoids, especially b-
carotene (56, provitamin A), which can be oxidatively
degraded in the animal to give vitamin A and its deriva-
tives. Although it was originally isolated from liver oil,
almost all of the vitamin A produced nowadays is derived
from chemical synthesis. Since vitamin A itself is unstable,
the major commercial product is vitamin A acetate (57), with
the propionate 58 and palmitate 59 being used for specialist
applications (Figure 13).
The use of certain foods rich in vitamin A (e.g. liver) has
been known since Egyptian times to cure night blindness.
Vitamin A was part of the vital lipid-soluble substances
Scheme 28. Preferred direct key steps for introducing chirality into
Scheme 29. Direct reduction of cyclic anhydride 42 to d-lactone 47 by
a stoichiometric transformation and by catalytic asymmetric hydro-
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isolated from milk by Stepp in 1909, and was differentiated
into “fat-soluble A” by McCollum and Kennedy in 1916 and
later into vitamin A.[7a] In 1931 Karrer and co-workers
isolated almost pure retinol from the liver oil of mackerel,
and Karrer was awarded the Nobel Prize in 1937 for his work.
8.2. First Synthesis of Vitamin A
Vitamin A can be isolated from the liver oils of a number
of different marine animals, and this was the main method of
production in the 1930s and 1940s. However, the amount of
vitamin A present varied from animal to animal, and being
from natural sources had supply constraints. The first syn-
thesis of vitamin A was reported by Kuhn and Morris in 1937
(Scheme 30). Starting from b-ionone (60), a C2extension
gave the C15 aldehyde 61, which was then condensed with 3-
methylcrotonaldehyde (62), to give vitamin A aldehyde (63).
A Meerwein–Ponndorf–Verley reduction with isopropanol
gave a yellow oil that had a vitamin A content of 7.5%.
Despite the low yield, the preparation of synthetic
vitamin A had been demonstrated, and this provided the
incentive for other academic and industrial laboratories to
start or continue work in this area. Several unsuccessful
attempts were made to repeat the Kuhn synthesis.[163,164] It
would be another ten years before vitamin A was synthesized
again, although the outbreak of the Second World War almost
certainly interfered with progress. The key building block for
the synthesis by Kuhn and Morris, as well as all future
vitamin A syntheses, is b-ionone (60). Therefore, it is worth-
while considering its synthesis before continuing with the
preparation of vitamin A.
8.3. Synthesis of b-Ionone
b-Ionone (60) was known in the 19th century as a compo-
nent of perfume, and could be prepared from lemongrass oil
(which is predominantly citral, 64). Condensation of 64
with acetone (65) gave pseudoionone (66), which cyclizes in
the presence of strong acid to b-ionone (60, Scheme 31).
From the 1940s onwards, synthetic routes to citral (64)
were developed by Roche and others which allowed the large-
scale production of b-ionone for the synthesis of vitamin A.
One of these routes is still used by BASF and most other
suppliers. The modern, efficient route to citral developed by
BASF and starts from isoprenal and prenol (Scheme 32).[31a]
Roche developed an efficient synthesis of pseudoionone
(66) avoiding citral by using a series of C2and C3elongations
with acetylene (67) and isopropenyl methyl ether (IPM, 68)
(Scheme 33). The route delivers methylbutenol (MBE, 69),
which then undergoes chain elongation to give methylhepte-
none (70). This process to yield pseudoionone (66) is still in
operation today.[31a, 165]
Figure 13. Vitamin A derivatives.
Scheme 30. First synthesis of vitamin A by Kuhn and Morris.
Scheme 31. Synthesis of b-ionone from citral.
Scheme 32. Synthesis of citral (64) from isoprenal and prenol.
Scheme 33. Synthesis of pseudoionone (66)byC
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8.4. Subsequent Syntheses of Vitamin A
The synthesis of vitamin A methyl ether (71, Figure 14)
was reported by Milas, who used an acetylenic Grignard
coupling to build up the polyene side chain. Although
successful, there was no method for the conversion of the
methyl ether into the alcohol, and the biological activity of 71
was found to be significantly lower than that of natural
Meanwhile, a research group at Hoffmann–La Roche in
Basel, Switzerland, led by Otto Isler (Figure 15) was trying to
develop an industrially viable route to vitamin A. In fact, the
Roche group had even prepared vitamin A methyl ether (71)
by an identical acetylenic Grignard strategy. This success-
ful “model experiment” led to further development of the
Grignard step and allowed the use of 3-methylpent-2-en-4-yn-
1-ol (73), rather than the methyl ether. Addition of the
Grignard reagent derived from 73 to the C14 aldehyde 72
resulted in the formation of diol 74, which could be partially
hydrogenated to give tetraene 75. Partial acylation to mono-
acetate 76, elimination, and isomerization gave vitamin A
acetate (57). Hydrolysis of the acetate yielded small quanti-
ties of synthetic crystalline vitamin A (55) for the first time
(Scheme 34). The C6unit 73 can be prepared in two steps
from methyl vinyl ketone (77) by addition of acetylene to give
3-methylpent-1-en-4-yn-3-ol (78), which then undergoes rear-
rangement to give the required compound 73 (Scheme 35). A
conceptually similar approach had been proposed by Heil-
bron et al. ,[163, 168] who used b-ionone, acetylene, and a pro-
tected butanone, but the planned route was not investigated
because of the unavailability of b-ionone.
Several steps of the Roche synthesis merit further
discussion. The semihydrogenation of alkyne 74 to alkene
75 was initially achieved using a poisoned palladium on
charcoal catalyst or palladium on calcium carbonate. Whilst
this process was successful, it was exceedingly difficult to
avoid over-hydrogenation, which led to impurities that were
difficult to separate. A significant improvement was made by
Lindlar who developed a lead-doped palladium on calcium
carbonate catalyst. The use of an additional catalyst poison
(usually an amine such as quinoline) allowed the hydro-
genation reaction to be easily stopped after one equivalent of
hydrogen had been consumed, thereby giving the desired
alkene in high yield.
The elimination and isomerization of monoacetate 76 is
a very sensitive step and must be carefully controlled to avoid
decomposition. It was originally performed with iodine, and
the process was improved by the use of phosphorus oxy-
chloride. However, the best procedure involves the use of
strong acid at low temperature and results in a yield of
vitamin A acetate (57) of over 90%.
Both steps in the synthesis of 73 have undergone
significant optimization (Scheme 35). The original addition
of acetylene to methyl vinyl ketone (77) resulted in moderate
yields, the formation of large amounts of waste, and high
energy usage. The optimization of the reaction conditions in
combination with improved engineering methods resulted in
a significant increase in the yield as well as to lower usage of
raw materials and less waste. The rearrangement of 3-
hydroxy-3-methyl-pent-1-yn-4-ene (78)to73 was originally
Figure 14. Vitamin A methyl ether (71).
Figure 15. Otto Isler (left) with his co-worker Gody Ryser (source:
Roche Historical Archive).
Scheme 34. Roche synthesis of vitamin A.
Scheme 35. Synthesis of C6building block 73.
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carried out with dilute sulfuric acid; more efficient
processes have recently been developed that use biphasic
conditions and heterogeneous catalysts to result in higher
yields and allow recycling of the catalyst multiple times.
The Roche synthesis described in Scheme 34 was imple-
mented on an industrial scale, initially in Roches plants in
Basel (Switzerland) and Nutley (USA; Figure 16). In 1957
a third production facility was opened in Dalry (Scotland).
Worldwide demand for vitamin A acetate increased every
year in the 1960s, and the production at Roches facilities
ended the decade six times greater than at the start. To cope
with the increased demand it was decided to consolidate the
majority of the production at one new plant in Switzerland; as
this plant came on-stream, production at other sites was
slowly wound down.
Following the successful production of vitamin A by
Roche, a number of other companies started production by
alternative routes. A series of possible disconnections of
vitamin A acetate are shown in Figure 17. The route of Kuhn
and Morris (Scheme 30) used a C15 +C5approach, forming
a carbon–carbon double bond, whereas the Roche route
(Scheme 34) used a C14 +C6approach whereby the two
subunits were coupled through formation of a carbon–carbon
single bond. Routes that have been implemented on an
industrial scale are: C15 +C5(BASF, Sumitomo, and Rhne–
Poulenc), C16 +C4(DPI, Glaxo), and C18 +C2(Philips and
AEC). Of these, the most industrially important ones are
the Roche route described above, the BASF C15 +C5route
involving a Wittig reaction, and the Rhne–Poulenc C15 +C5
route involving a Julia reaction.
In the 1950s, at the time they started work on the synthesis
of vitamin A, BASF had close contact with Georg Wittig.
They quickly realized that the use of what was to become the
“Wittig reaction” could have a significant impact on the
synthesis of polyenes such as vitamin A. However, their
first successful synthesis involved a Reformatski reaction
between the propargyl bromide 79 and b-ionone (60,
Scheme 36). Semihydrogenation of the alkyne to the alkene
and dehydration could be performed in either order and gave
the ester 80. Reduction with an aluminum hydride reagent
gave vitamin A (55) in good yield.
Greater success was achieved with the Wittig reaction;
during the course of the 1950s, BASF investigated the possible
combinations C10 +C10,C
13 +C7, and C15 +C5with either the
phosphonium salt as the C10/C13/C15 unit or as the C10/C7/C5
unit. The most successful process to date is the C15 +C5
approach with the phosphonium salt 82 and the aldehyde 83
(Scheme 37). b-Ionone (60) was converted into vinyl-b-
2extension. This extension can be done either
by direct addition of a vinyl Grignard or a two-step
addition of acetylene followed by semihydrogenation.
Vinyl-b-ionol (81) can be converted into the phosphonium
salt 79 either by treatment with triphenylphosphine and HCl
gas or direct treatment with triphenylphosphonium hydro-
Figure 16. Early production of vitamin A at Roche Nutley, USA (source:
Roche Historical Archive).
Figure 17. Synthetic strategies for the synthesis of vitamin A.
Scheme 36. First BASF route to Vitamin A.
Scheme 37. BASF route to vitamin A by using a Wittig reaction.
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chloride. A Wittig reaction with aldehyde 83 gives
vitamin A acetate (57) directly. The C5aldehyde 83 is
readily accessible from butene diacetate 85 by hydroformy-
lation. In turn, this is available by rearrangement from the
symmetrical diacetate 84 (Scheme 38).
The third industrially interesting approach to vitamin A
was developed by Rhne–Poulenc. In a similar way to BASFs
collaboration with Georg Wittig, the Rhne–Poulenc
approach used sulfone chemistry developed in collaboration
with Marc Julia for the formation of a carbon–carbon double
bond. A C15 +C5approach was also used, and the key starting
material was again vinyl-b-ionol (81), although other combi-
nations were investigated. Treatment of 81 with the anion of
phenylsulfinic acid resulted in the allylic sulfone 86
(Scheme 39).[182,183] The sulfone could be deprotonated with
a number of bases and then treated with the allyl chloride 87.
The resulting C20 sulfone 88 could then undergo elimination
to give vitamin A acetate. A wide variety of bases could be
used, but the most successful were potassium alkoxides.
Alternatively, the same sulfone condensation could be
performed with the allyl bromide 89 (Figure 18), which,
after elimination of the sulfinic acid, gave vitamin A ethyl
ester. The opposite coupling of a C5sulfone 91 and C15
halide 90 was reported by a group from Roche in 1976;
however, this route was not commercialized.
The main producers of vitamin A at present are DSM and
BASF, with lower volumes being produced by Adisseo,
Kingdomway, Zhejiang NHU, and Zhejiang Medicine Co.
Ltd. To the best of our knowledge, the current manufacturing
conditions only differ from the originally reported steps as
a result of incremental improvements in the process that have
been implemented over the past 65 years. Isler states in his
review of 1979 that “Each of the known manufacturing
procedures leaves something to be desired. The ideal synthesis,
which is not yet invented, should start of cheap reagents and use
catalytic reactions which cut down the amount of pollutants.”
Despite over 30 years having passed, this summary is still
9. Vitamin E (a-Tocopherol)
9.1. Physiological Functions and History
Vitamin E is the most important lipid-soluble antioxidant
in biological systems. The term vitamin E covers all tocol and
tocotrienol derivatives that exhibit qualitatively the biological
activity of a-tocopherol (92), which is the most relevant
compound for human health. Vitamin E functions as a chain-
breaking antioxidant that protects polyunsaturated fatty acids
in membranes and plasma lipoproteins against the propaga-
tion of free-radical reactions. Vitamin E also plays a role in
immune function as well as non-antioxidant functions in
cell signaling, gene expression, and regulation of other cell
All naturally occuring substances of this group are single-
isomer products (Figure 19). The group of a-, b-, g-, and d-
tocopherol (92–95) possess a 2R,4’R,8’Rconfiguration; the
corresponding tocotrienols (96) are found as 2R,3’E,7’E
Vitamin E was discovered by Evans and Bishop in 1922 as
a dietary factor essential for reproduction. Its isolation
from wheat germ oil enabled its structural elucidation by
Fernholz. Rich sources of active vitamin E compounds are
edible oils originating from sunflower, soybeans, and palm oil.
Vitamin E plays an essential role in the reproduction of
Scheme 38. Formation of aldehyde 83.
Scheme 39. Rhne–Poulenc synthesis of vitamin A.
Figure 18. Alternative building blocks towards vitamin A.
Figure 19. Tocopherols and tocotrienols, the naturally occuring vit-
amin E compounds.
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12982 www.angewandte.org 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2012,51, 12960 – 12990
various animal species. While RRR-92 shows the highest
specific vitamin E activity of all the stereoisomers or homo-
logues determined experimentally, the economic impor-
tance of vitamin E is based on the fact that all such
compounds differ only quantitatively in this respect. Thu,
(all-rac)-a-tocopherol ((all-rac)-92), an equimolar mixture of
all eight stereoisomers manufactured from trimethylhydro-
quinone (97) and (all-rac)-isophytol (98) (Scheme 40), is
todays industrially most relevant product.
9.2. The First Syntheses, Biological, and Economical Significance
The first successful chemical synthesis of a-tocopherol
was published in 1938 by Karrer et al. at the University of
Zurich. In the same year, Karrer was contracted as
a consultant by Roche. From the note added in proof in the
original publication (Figure 20) it is apparent that Isler had
identified a similar synthesis for a-tocopherol. This fruitful
collaboration between academia and industry resulted in the
launch of the acetate derivative (all-rac)-99 under the name
Ephynal in 1939. Although this was already a technical
synthesis, only a few kilograms were initially produced per
year. Interestingly, natural (optically active) phytol extracted
from hundreds of kilograms of stinging nettles was used as the
side-chain component in the synthesis on this scale, since
isophytol (98) was not yet industrially available.
9.3. Synthesis of (all-rac)-a-Tocopherol
The main producers of (all-rac)-92 today are BASF, DSM,
and some Chinese companies, while Eisai and Adisseo
(former Rhne–Poulenc) stopped production several years
ago. The large-scale industrial synthesis of this “synthetic
vitamin E” exceeds 30 000 t per year world wide, and consists
of three major parts:[31a,190, 198, 199] the preparation of the
aromatic building block (trimethylhydroquinone, 97), the
production of the side-chain component ((all-rac)-isophytol,
98, or a corresponding C20 derivative), and the condensation
reaction (Scheme 40).
Selected routes to 2,3,5-trimethylhydroquinone (97) are
shown in Scheme 41. m-Cresol (100) is catalytically methy-
lated to trimethylphenol 101, which is transformed by
oxidation to quinone 103 and subsequently reduced to
hydroquinone 97. Alternative processes start from mesitol
(102, oxidation and rearrangement), isophorones (104,105,
oxidation/hydrogenation/isomerisation sequences), snd
diethyl ketone (106, condensation reaction with methyl
vinyl ketone or crotonaldehyde).[31a,190, 200]
Scheme 40. Industrial synthesis of (all-rac)-a-tocopherol.
Figure 20. The first publication about a successful synthesis of a-
tocopherol by the Karrer research group in 1938 (copyright Verlag
Helvetica Chimica Acta). The text below the reaction scheme says:
“Note added in proof: An analogously prepared condensation product was
obtained by Dr. Isler in the laboratory of the chemical factory F.
Hoffmann–La Roche &Co. A.G., Basel, from 3-bromo-hydrophytyl bro-
mide and trimethylhydroquinone, which is not homogeneous, but the
biological testing could already be finalized in the pharmacological
laboratory of F. Hoffmann–La Roche &Co. A.G. This synthetic product
exhibits vitamin E activity.”
Scheme 41. Selected routes to 2,3,5-trimethylhydroquinone (97).
One Hundred Years of Vitamins Angewandte
12983Angew. Chem. Int. Ed. 2012,51, 12960 – 12990 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org
Various synthetic strategies are applied for the prepara-
tion of (all-rac)-isophytol (98), which is used preferentially as
the side-chain building block.[31a,190,191, 200] Representative
pathways are outlined in Scheme 42. A repeated C2+C3
homologation sequence starts from acetone (65) and acety-
lene (67) or the vinyl-Grignard compound. The C3elongation
of the isoprenoic chain is achieved by treatment of the
acetylenic alcohol with methyl acetoacetate or isopropenyl
methyl ether (68) as an activated acetone equivalent to yield
the C8unit methylheptenone (70), which is further trans-
formed to dehydrolinalool or linalool (109,110,C
10) and C13
compounds (pseudoionone, 66, which is transformed also to
vitamin A, geranylacetone (111), and hexahydropseudoio-
none (112)). Subsequent chain elongations in combination
with hydrogenation/rearrangement reactions lead to C15
(nerolidol), C18, and C20 intermediates (e.g. acetylenecarbinol
113), which finally yield (all-rac)-isophytol (98).
A different approach is the prenol–prenal route[201, 202]
starting from inexpensive isobutene (108,C
4) and formalde-
hyde (C1) to give citral (64,C
10), which is then further
processed. Myrcene (107,C
10) from natural sources has been
alkylated by a rhodium-catalyzed process in the presence of
a water-soluble phosphine ligand[173,203] to generate hexahy-
dropseudoionone (112) after subsequent decarboxylation and
Special features of this area of isoprenoid chemistry, such
as the ethynylation of ketones, the methods for C3elongation
by the acid-catalyzed Saucy–Marbet and Carroll reactions,
aldol condensation, the Prins reaction (preparation of iso-
prenol), complete hydrogenation, Lindlar-type hydrogena-
tion (which selectively reduces CC bonds to the correspond-
ing Z-configured C=C bonds), and various types of
rearrangement reactions of allylic and propargylic alcohols
(or derivatives) have become important reactions in the large-
scale production of isoprenoids.[31a,204] Multiphase catalysis is
a valuable concept towards the elaboration of efficient
(continuous) processes in such pathways.
The final step in the manufacture of (all-rac)-a-tocopherol
((all-rac)-92) by condensation of trimethylhydroquinone (97)
with isophytol (98, Scheme 40) was improved considerably by
the discovery of alternative and more-efficient Brønsted
acids. Novel acidic catalysts allowed catalyst loadings of less
than 1 mol %, thus replacing conventional reagents, such as
ZnCl2in combination with mineral acids, BF3, Fe/HCl, AlCl3,
or other reagents that have been used in stoichiometric or at
least relatively high catalytic amounts, and result in higher
selectivity and yield.[205–211]
9.4. Synthesis of (2R,4’R,8’R)-a-Tocopherol
(all-rac)-a-Tocopherol ((all-rac)-92) is industrially the
most important product. Nevertheless, the naturally occurring
stereoisomer (2R,4’R,8’R)-a-tocopherol (RRR-92; Figure 19)
exhibits the highest specific vitamin E activity. Thus, many
years ago it was already considered that this vitamin E
component should be made accessible on a large scale. The
first synthesis of RRR-92 (and of the 2S,4’R,8’Repimer) was
published by the research group of Isler in 1963
(Figure 21). Further developments will be mentioned
Today about 10 % of the total amount of vitamin E
produced industrially is isomerically pure (2R,4’R,8’R)-a-
tocopherol (RRR-92) prepared by semisynthesis for pharma
(human) applications. Soya deodorizer distillates (SDD),
a waste stream from the production of that vegetable oil, are
applied as starting materials. The mixture of the four
homologous tocopherols (“mixed tocopherols”, RRR-92 to
RRR-95, Figure 19) is isolated by a combination of several
separation methods. It is then upgraded to the biologically
more active a-tocopherol (RRR-92), of which there is only
5% in the original mixture. Permethylation reactions such as
chloro-, amino-, or hydroxymethylation reactions can be used
to achieve this.[191,213, 214] This semisynthetic approach still has
the general problem of a (given) limited availability of
starting material (SDD) from natural sources, which prevents
an increasing demand of RRR-92 from being satisfied above
a certain level. The possibility of improving the a-tocopherol
content in agricultural crops by genetically manipulating the
vitamin E biosynthetic pathway has also been investigated
Considerable efforts have been directed during the last
four decades at the development of stereoselective syntheses
of RRR-92 and of corresponding building blocks to overcome
Scheme 42. Manufacture of isophytol by various routes (E/Zisomer-
ism of olefins is omitted here).
Reviews W. Bonrath et al.
12984 www.angewandte.org 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2012,51, 12960 – 12990
the shortage of starting material from natural sour-
ces.[190,191, 199, 216–219] General routes are based on classical
optical resolution, biocatalysis (by microorganisms and iso-
lated enzymes), chiral-pool starting materials, the application
of stoichiometric and catalytic amounts of chiral auxiliaries,
and asymmetric catalysis (Figure 22). Significant efforts were
undertaken in the research centers of Roche at Basel and
Nutley, as well as in university laboratories between 1970 and
2000. Many of the methods developed, however, are not
suitable for large-scale applications because they suffer from
complexity, limited space–time yield, and formation of
excessive amounts of waste material. The goal of an economic
industrial total synthesis of RRR-92 has still not yet been
reached by any of the methods described.
In particular, industrially applica-
ble methods for the construction of
the chiral chroman bicycle and the
coupling of chroman and side-chain
building blocks are still lacking. Con-
siderable progress has been made in
key transformations by the use of
exceptionally efficient new asymmet-
ric hydrogenation techniques. Based
on the seminal work of Noyori and co-
workers in the 1980s, the homogene-
ous asymmetric hydrogenation of
allylic alcohols catalyzed by ruthe-
nium complexes was performed at
Roche in Basel on a pilot scale with
substrate/catalyst ratios of up to
150000:1 (Scheme 43). For example,
the C10 building block (E)-114 was
transformed into (R)-116 with >99%
selectivity by using (S)-MeOBIPHEP
(118,Ar=Ph, X =OCH3) as a ligand.
The hydrogenation of (E)-115 under
similar conditions with the catalyst
derived from (S)-p-Tol-BIPHEMP
(118,Ar=p-Tol, X =CH3) gave
The concomitant introduction of
two chiral centers by the reduction of
unfunctionalized trialkyl-substituted olefins in the presence
of Ir-BArFcomplexes containing chiral P,N ligands opened
the way to a completely different retrosynthetic concept
(Scheme 44). Asymmetric hydrogenation of g-tocotrienol
derivative (R,E,E)-119 with pyridyl phosphinite 120 devel-
oped in a collaboration between the Pfaltz research group and
DSM Nutritional Products furnished (all-R)-g-tocopheryl
acetate 121 with excellent stereoselectivity, and with the
formation of less than 0.5% of each of the other stereoiso-
A noteworthy approach is based on the biosynthetic
pathway of vitamin E compounds. The mechanism of the ring
closure of chromanol catalyzed by the enzyme tocopherol
cyclase from cyanobacteria has been investigated by the
Figure 21. The first synthesis of (2R,4’R,8’R)-a-tocopherol and its 2 epimer published in Helv.
Chim. Acta (copyright Verlag Helvetica Chimica Acta).
Figure 22. General strategies used in the synthesis of (2R,4’R,8’R)-a-
Scheme 43. Asymmetric hydrogenation of allylic alcohols in isoprenoid
One Hundred Years of Vitamins Angewandte
12985Angew. Chem. Int. Ed. 2012,51, 12960 – 12990 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org
Woggon research group. Tocopherol precursor E-122
yielded (2R,4’R,8’R)-g-tocopherol (RRR-94) exclusively,
while the corresponding Zisomer did not react (Scheme 45).
Biomimetic routes for chromanol cyclization have been
developed on the basis of these data.[222, 223] Organocata-
lytic and other approaches[225–228] based on new synthetic
methods have also been published in recent years, thus
showing that the synthesis of RRR-92 is still a research topic
of current interest.
Vitamins have been known now for one hundred years,
but the “history of vitamins” has still not come to an end.
Manufacturing processes continue to be improved and
completely new routes or processes are being developed.
Modern trends include the continuing shift from batch to
continuous processes and from the use of stoichiometric
amounts of reagents to catalysis. In addition, the use of
renewable raw materials as key building blocks for the
production of vitamins is of growing importance. A constantly
increasing number of studies deal with the relevance of
vitamins for long-term health and healthy aging, as well as
their importance in reducing the risk of noncommunicable
diseases. In this regard, we still have to ensure that people all
over the globe have access to sufficient vitamins. Science
continues to provide new insights into this field, and
demonstrates that the identification of the role of vitamins
was one of the most important contributions of science to
We wish to thank Klaus Krmer (DSM), Richard Semba (John
Hopkins School of Medicine), and Alexander Bieri (Curator
of the Roche Historical Collection and Archive) for their
assistance in the preparation of this article.
Received: July 24, 2012
Published online: December 3, 2012
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