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Mini-Reviews in Medicinal Chemistry, 2012, 12, 1443-1454 1443
A Short Overview on the Medicinal Chemistry of (—)-Shikimic Acid
Amalia M. Estévez and Ramón J. Estévez*
Departamento de Química Orgánica (Facultade de Química) and Centro Singular de Investigación en Química
Biolóxica e Materiais Moleculares, Campus Vida, Universidade de Santiago de Compostela, Jenaro de la Fuente s/n,
15782, Santiago de Compostela, Spain
Abstract: Shikimic acid, a natural compound is a key intermediate in the biosynthesis of amino acids. Consequently, this
derivative is widely present in many plants and has interesting biological properties. But besides the pharmacological
relevance of shikimic acid itself, it is also an intermediate in the synthesis of many drugs, being the most relev ant the
antiviral agent oseltamivir (T amifluTM). Here we present a short overview on recent natural, biotechnological and
synthetical sources of shikimic acid, togheter with pharmacological applications of this compound and a selection of
derivatives, including oseltamivir (TamifluTM).
Keywords: Shikimic acid, natural products, biotechnology, Oseltamivir (TamifluTM), neuraminidase inhibitors.
1. INTRODUCTION
Shikimic acid (Fig. 1) [1], first isolated in 1885 by
Eykman from the fruit of Illicium religiosum [2], is a
hydroaromatic intermediate in the common pathway of
aromatic amino acid biosynthesis which is widely spread in
leaves of fruit of many plants and also in microorganisms
(bacteria and fungi), but in limited quantities [3].
CO
2
H
HO
OH
OH
Fig. (1). (-)-Shikimic acid.
Shikimic acid is a key hydroaromatic intermediate in the
biosynthetic shikimate pathway (Scheme 1) of essential
aromatic amino acids (L-phenylalanine, L-tyrosine and L-
tryptophan), lignin and most of the alkaloids of plants and
microorganisms [4]. It plays also a principal role as
precursor of cinnamic acids and flavonoids, such as flavones,
antocyanidins, flavonols and tanins [5]. Moreover, it is also
required for the assimilation of folic acid, alkaloids and
vitamins in those organisms.
*Address correspondence to this author at the Departamento de Química
Orgánica (Facultade de Química) and Centro Singular de Investigación en
Química Biolóxica e Materiais Moleculares, Campus Vida, Universidade de
Santiago de Compostela, Jenaro de la Fuente s/n, 15782, Santiago de
Compostela, Spain; Tel:/Fax: +34 881 815 704;
E-mail: ramon.estevez@usc.es
Taking into account that the shikimate pathway is not
present in mammals, there is great potential for the design
and synthesis of enzyme inhibitors, which may selectively
block specific enzyme-catalysed transformations along this
pathway. Accordingly, intensive work was developed aimed
at the design, synthesis and evaluation of antibacterial,
herbicidal and antifungal agents of low environmental
impact that may interfere specific transformations along this
pathway, without a negative effect towards mammals [6]. An
example is the commercial broad spectrum herbicide
Roundup® which contains the active ingredient glyphosate
(N-phosphonomethyl glycine), a specific inhibitor of the
enzyme 5-enolpyruvylshikimate-3-phosphate synthase in
that pathway [7].
Shikimic acid has interesting biological properties,
displaying activity as antioxidant, anticoagulant and
antithrombotic, antibacterial, antiinflamatory and analgesic
agent. However, besides being important itself from the
pharmacological point of view, shikimic acid has also a key
role in the synthesis of a number of relevant compounds in
the pharmacological industry and there are reports on the
shikimic acid-based synthesis of anticancer agents,
antibacterials, hormones or herbicides.
But the reason why shikimic acid has found itself thrust
under the spotlight in the recent years is because it is
generally used as a starting material for industrial synthesis
of the antiviral oseltamivir, a drug against the H5N1
influenza virus [8]. As fears spread about a potential flu
pandemic, the current supply of of tamiflu is thought to
cover just 2% of the world population. Health officials and
researchers around the word are now working against the
clock in creating enough supplies of shikimic acid to prepare
large amounts of the antiviral drug, which could help to
control an eventual outbreak of bird flu until a vaccine can
be developed. Accordingly, studies on the presence of
shikimic acid and new techniques for its isolation from
/12 $58.00+.00 © 2012 Bentham Science Publishers
1444 Mini-Reviews in Medicinal Chemistry, 2012, Vol. 12, No. 14 Estévez and Estévez
known and novel sources are topics of current interest.
However, limited availability from plants has led to the
discovery of other synthetic and biosynthetic means to obtain
shikimic acid. Many synthetic strategies have been
developed for the multigram preparation of shikimic acid
and recently it has been also reported the obtention of
shikimic acid from microbial fermentation of glucose, using
recombinant Escherichia coli.
To sum up, shikimic acid has become a compound of
enormous interest in medicinal chemistry due to its key role
in the preparation of antivirals. Different procedures have
been employed for the access to shikimic acid: isolation
from natural sources, biotecnological procedures or chemical
synthesis.
The main aim of this review is to present a compendium
on the recent approaches to obtain shikimic acid, as well as
the most relevant aspects of the medical application of this
compound and relevant derivatives.
2. ISOLATION OF SHIKIMIC ACID FROM
NATURAL SOURCES.
Although shikimic acid is present in most autotrophic
organisms, it is a biosynthetic intermediate generally found
in very low concentrations.
Currently most of the shikimic acid required by the
pharmaceutical industry for production of oseltamivir
(TamifluTM) arises from the chinese star anise (Illicium
verum) [9]. The fruits of this tree are reported to yield 2 to
7% of shikimic acid, the higher concentration found in
plants. But, as the cultivation of this tree is difficult, it is
unlikely that I. verum source alone could satisfy its growing
market demand. This is the reason why there is a continuous
search for alternate plant sources of shikimic acid, as well as
attempts to explore novel tecnologies for more efficient
isolation [10]. Here we include a compendium of plants from
where shikimic acid was isolated since 2005 and of different
methods of extraction, which were subsequently developed.
CO
2
H
HO
OH
OH
(-)-Shikimic acid
Glucose
CO
2
H
OPO
3
H
2
Phosphoenolpyruvic
acid
H
2
O
3
PO H
OOH
OH
D
-Erythose-4-phosphate
O
OH
OH
OH
3-Deoxy-
D
-arabino
heptulosonic acid
phosphate
OPO
3
H
2
HO CO
2
H
OOH
OH
OH
3-Dehydroquinic acid
HO CO
2
H
CO
2
H
O
OH
OH
3-Dehydroshikimic
acid
CO
2
H
H
2
O
3
PO
OH
OH
Shikimate
3-phosphate
CO
2
H
H
2
O
3
PO
OH
O
5-Enolpyruvil
shikimate-3-phosphate
CO
2
H
CO
2
H
OH
O
Chlorismate
CO
2
H
L-Phenylalanine
L-Tyrosine
L-Tryptophan
Isoprenoid quinones
Folates
Scheme (1). The shikimate pathw ay.
A Short Overview on the Medicinal Chemistry of (—)-Shikimic Acid Mini-Reviews in Medicinal Chemistry, 2012, Vol. 12, No. 14 1445
Natural sources from which shikimic acid has been
isolated include: seeds and pericarps from Illiciun griffithii
(12-18%) [11], star anise (Illicium verum) (3-7%) [12], sweet
gum (Liquidambar Styraciflue) (1-5%) [13], needles and
branches from Cedrus deodara (From 1.66% to 4.11%) [14],
Rhizoma Smilacis Glabrae (RSG) [15], leaves of the Malian
medicinal tree Terminalia macroptera [16], ginkgo biloba
leaves [17], stems and leaves of I. Simonsii [18], herbal plant
Dendrobium huoshanense (traditional Chinese medicine)
[19], fermentation broth and mycelia of strain PRE-5 (Strain
PRE-5 was isolated from the root of the herbal plant Panax
notoginseng) [20], needles of Pinus densiflora (a
representative pinus species that grows in Korea) [21],
platycladus orientalis [22], leaves of Dipteronia dyeriana
[23], pine needles of Pinus elliottii [24], pericarp of Illicium
macranthum [25], leaves of Ficus carica [26], Pinus
massoniana [27], Illicium simonsii [28], Linaria vulgaris
(Scrophulariaceae) infusion [29], bark of Pseudolarix
kaempferi [30], stems and leaves of Calophyllum inophyllum
L [31], young fronds of the bracken fern Pteridium
aquilinum [32], leaves of Taxodium distichum L [33], leaves
of Sapium sebiferum [34], leaves of Alnus formosana [35],
Schinus polygamus [36], berries of Juniperus phoenicea
[37], fruits of Chaenomeles lagenaria [38], seeds of Cydonia
oblonga [39], leaves of the big tree from american tropical
rain forests Calophyllum brasiliense (Clusiaceae) [40], plant
Rhus tripartitum [41], Selaginella tamariscina (Beauv.) [42],
aerial parts of Hypericum monogynum [43], fruits of T,
chebula Retz [44], pine needles of Pinus massoniana [45],
and roots of Codonopsis lanceolada [46] and Cleistopholis
patens [47].
The extraction of shikimic acid from natural sources is a
very complex process. Roche, the company that
manufactures oseltamivir, starts with dried star anise
(Illicium verum). It is harvested by local farmers in four
chinese provinces between March and May and the shikimic
acid is extracted at the start of a 10-stage manufacturing
process which takes a year. Moreover, huge amounts of
seeds are needed to isolate shikimic acid and the 90% of the
production is already used by Roche for the preparation of
oseltamivir (TamifluTM). In addition to the efforts made to
find alternative sources for shikimic acid, many efforts have
also been made for improved methods for its extraction.
Some of the recent methods developed for the detection and
isolation of shikimic acid are the following:
• Detection by spectrophotometric and high-pressure
liquid chromatography (HPLC) methods [48].
• Capillary electrophoresis (DAD fingerprint method)
[49].
• Methanol extraction [50].
• Extraction with the ionic liqu id 1-butyl-3-methylimidazolium
chloride ([bmim]Cl), which dissolves cellulose [51].
• Extraction with ethanol. Then, the ethanol extract was
dispersed in water and extracted with petroleum,
chloroform and butanol, successively. The organic
fractions were isolated and purified by column
chromatography [52].
• Fractionation of the water soluble part of D. huoshanense
by repeated chromatography [53].
• Extraction of the dried pine needle of Cedrus deodara
with ethanol. The alcohol is dispersed in water, followed
by washing with petroleum ether. The remained aqueous
solution is extracted with ethyl acetate, evaporated and
mixed with silica gel. Elution afforded crude shikimic
acid, which is dissolved in methanol and precipitated
with dichloromethane to obtain the final pure product
[54].
• Pulverization of Illicium verum, extraction with water,
filtration through microporous filtering film and through
hyperfiltration membrane, and purification of the filtrate
via ion resin column chromatography, eluting with 5 %
sodium hydroxide afforded, after crystallization in
methanol, the pure product [55].
• Extraction at 100°C during of 80 min. with 10-folds
water and precipitation with ethanol [56].
• Decompressing inner ebullition method [57].
• Ultrasonic extraction technology [58].
• Dilute acid pretreatment [59].
• Water extraction and ethanol precipitation, followed
with macroporous adsorptive resin decolorization and
ion-exchange resin purification [60].
• Extraction of aniseed oil from Illicium verum with
supercritic CO2 fluid, immersing the treated Illicium
verum in water, concentrate via reverse osmosis
membrane and crystallization [61].
• Microwave assisted extraction process of shikimic acid
by response surface analisys methodology [62].
• Soaking raw material (Illicium verum fruit, Illicium
simonsii fruit, or Illicium lanceolatum fruit) with water
for 1-3 h, decocting twice each for 2-3 h under mildly
boiling, merging the decoctions, cooling, filtering,
adjusting the filtrate to pH 8-10 with base, purifying on
macroporous adsorbent resin column eluting with
diluted acid concentrate, crystallize at 0-4°C, dehydrate
by high-speed centrifugation, dissolve with pure water,
decolorize with macroporous adsorbent resin (such as
AB-8) or activated carbon, concentrate, recrystallize at
0-4°C, dehydrate by high-speed centrifugation, and
freeze dry to obtain shikimic acid [63].
• Recovery of the shikimic acid product from aqueous
process streams utilizing membrane separation techniques
[64].
• Rapid separation of shikimic acid from chinese star
anise (Illicium verum) with hot water extraction [65].
• Isolation from Illicium verum by extraction with ethanol
and water, basic anion resin chromatography and
recrystallization [66].
• Extraction with n-butanol from the bark of Pseudolarix
kaempferi [67].
1446 Mini-Reviews in Medicinal Chemistry, 2012, Vol. 12, No. 14 Estévez and Estévez
• Extraction and purification by repeated silica gel and
sephadex LH-20 chromatography [68].
• A simple and rapid capillary zone electrophoresis
method using phosphate-borate mixture as running
electrolyte with direct UV detection was developed for
the analyzation of shikimic acid [69].
• Pulverizing dry Illicium verum fruit, desorbing with an
apolar solvent, drying, extracting with industrial grade
ethanol, combining the extracts and concentrating,
dissolving with hot water, precipitating, blotter-treating,
and filtering, concentrating, introducing to neutral
macroporous absorbent resin to remove impurities, then
introducing to a basic anion exchange resin to purify,
volatilizing solvent, dissolving in hot water, adding
acetone, freeze-crystallizing, and recrystallizing [70].
• Extraction from Illicium verum with organic solvent
under reflux, filtering, concentrate, add water,
decolorize with activated carbon, concentrate, centrifuge
and filter to obtain crude solid. Crystallization to obtain
pure shikimic acid [71].
• Response surface analisys methodology (RSM) was
used for optimizing the extraction process of shikimic
acid from Illicium verum. Based on single-factor
experiments, three independent variables (extraction
time, solvent-solid ratio and ultrasound power) were
selected as affecting factors during extraction [72].
• Grinding Illicium verum fruit, extracting with alcohol
twice under reflux, combining both extracts, concentrate,
dissolve in water, filter, adsorb the supernatant on basic
anionic resin column (D201-D296), wash with water,
alcohol solution, elute with glacial acetic acid precipitate
and recrystallize in alcohol twice to obtain pure shikimic
acid as a white powdery crystal [73].
• Simultaneous extraction of shikimic acid and essential
oil from Illicium verum fruit [74].
• Extraction from pine needles using water at relatively
low temperature. After the subsequent evaporation,
column adsorption/desorption and crystallization
afforded shikimic acid crystals with a purity of over
98%. A total recovery of approx. 85 % is reached [75].
• Extraction from star anis seeds employing aqueous
isopropanol. [12a]
• Pulverization of Illicium verum and extraction with
water. Microfilter to remove water-soluble proteins,
pectin and suspended substances, ultra-filter to separate
shikimic acid, nano-filter to concentrate untill 1/10 the
volume and recrystallize in acetone to obtain shikimic
acid [76].
• Extraction with water, methanol, ethanol, acetone or n-
butanol, removing impurity, purifying on ion exchange
chromatography column, decoloring and recrystallizing
[12b].
• Ultrasonic wave extraction of shikimic acid in Illicium
verum was achieved using water as solvent in a solute
ratio 1:15 and extracting twice 40 min [12c].
• Pulverization of Illicium verum dry fruits, extraction
with supercrit. CO2 at 40-45, 25-35 MPa, CO2 flow
speed of 15-20 kg/h for 1-2 h, reflux with methanol and
extraction with ethyl acetate. Evaporation and
crystallization of the crude product with chloroform and
methanol [77].
• Solvent extraction using an extractant/diluent system
was evaluated for the recovery of shikimic and quinic
acids. Tridodecylamine (TDA) was used as the extractant,
and 1-heptanol as the diluent [78].
3. BIOTECHNOLOGICAL PREPARATION OF
SHIKIMIC ACID
Fermentation is an alternative way to produce shikimic
acid and Roche already uses engineered E. coli bacteria to
boost shikimic acid production [79]. Today, around two
thirds of the shikimic acid used for oseltamivir are gained
from star anise and the remaining shikimic acid is obtained
through fermentation [80]. Fermentation is as an alternative
to isolation that allows independece from events such as bad
harvests and could also allow to ramp up production if
needed.
There is another advantage to using fermentation:
microbes could be engineered to make variations on the
structure of shikimic acid and so allow production of analogues
of Oseltamivir with slightly different pharmacological
properties that could potentially target emerging strains other
than H5N1. Should a pandemic hit, it might be valuable to
focus on accelerating the biological evaluation of such
analogues.
Some recent advances in the production of shikimic acid
via biosynthetic pathways are the following:
• Escherichia coli for production of shikimic acid [81].
• Metabolic engineering approaches were employed to
produce shikimic acid in Escherichia coli strains
derived from an evolved strain (PB12) lacking the
phosphoenolpyruvate [82].
• Biological fermentation method for expressing and
manufacturing shikimic acid, and constructed
engineering bacteria [83].
• Fermentation for producing shikimic acid using
Brevibacterium lactofermentu [84].
• Method for constructing bacterial strain capable of
producing shikimic acid [85].
• Production of shikimic acid from glyphosphate in
recombinant microorganisms [86].
• Shikimate production from quinate with two enzymatic
systems of acetic acid bacteria [87].
• Shikimic acid production by a modified strain of E. coli
(W3110.shik1) under phosphate-limited and carbon
limited conditions [88].
A Short Overview on the Medicinal Chemistry of (—)-Shikimic Acid Mini-Reviews in Medicinal Chemistry, 2012, Vol. 12, No. 14 1447
• Metabolic engineering for microbial production of
shikimic acid [89].
• Shikimic acid production by a modified strain of E. coli
K-12 upon increased availability of phosphoenolpyruvate
[90].
• Shikimic acid is preparation with the coenzyme PQQ-
and quinate dehydrogenase-producing acetic acid bacteria
which has deficient TCA cycle [91].
• Bioengineered synthesis of shikimic acid from a carbon
source [92].
• Increase in transketolase activity and production of
shikimic acid from cloned Citrobacter freundii strain
HSK10 [93].
• Low-cost extracellular manuf acturation of shikimic acid
using a mutant U-5 strain of Citrobacter freundii [94].
• Biocatalytic synthesis of shikimic acid in genetically
engineered Escherichia coli [95].
• Shikimic acid is produced by cultivating a bacterium
belonging to the genus Bacillus [96].
• Shikimic acid production by using a microorganism
mutant, which belongs to the genus Citrobacter and is
capable of secreting shikimic acid [97].
• Shikimic acid manufacturation with microorganism such
as Citrobacter freundii that secretes extracellularly
shikimic acid in the presence of a transition metal [98].
• A fed-batch fermentor cultivation of a genetically
engineered Escherichia coli resulted in the synthesis of
27.2 g/L of shikimic acid [99].
4. SYNTHESIS OF SHIKIMIC ACID
There are several methods available for the chemical
synthesis of shikimic acid and its analogues from simple
starting materials, which have been revised in 1998 [100].
We include here a brief compilation of some of the methods
developed since then.
• Regioselective transformation of (-)-quinic acid to (-)-
shikimic acid via direct conversion of a 1,2-diol into
allyl sulfide [101].
• Transformation of (-)-quinic acid into (-)-shikimic acid
in a route involving dehydration with Martin's sulfurane
[102].
• Synthesis of (-)-shikimic acid from carbohydrates in a
route involving as key steps a Barbier allylation and a
ring-closing metathesis reaction [103].
• Using a chiral building block having a 6,8-
dioxabicyclo[3.2.1]octane framework as starting
material for a diastereocontrolled synthesis of (-)-
shikimic acid by employing a ring-closing metathesis as
the key step [104].
• Synthesis of (-)-shikimic acid from a synthetic
equivalent of (R)-4-hydroxycyclohex-2-enone via either
a retro-Diels Alder reaction [105] or a palladium-
mediated elimination reaction [106].
5. BIOLOGICAL ACTIVITY OF SHIKIMIC ACID
Shikimic acid and its derivatives displays a number of
interesting biological properties. For example, shikimic acid
presents high antioxidant activity [107]. It has been reported
to be active against DPPH and nitric oxide radicals in a
concentration-dependent way and presented capacity to
scavenge superoxide radical [108]. Shikimic acid can
decrease triglycerides (TG), total cholesterol (TC), low-d.
lipoprotein (LDL), hemotocrit, and blood viscosity, and
increase high-d. lipoprotein (HDL) of atherosclerosis
suffering rats, thus being a promising candidate in the search
for therapeutics for atherosclerosis [109] and for the control
of biliary stone [110]. The application of shikimic acid to
prepare medicines for treating ulcerative colitis was also
described, obtaining promising results in animal tests [111].
Shikimic acid has inhibitory effects of on platelet
aggregation and blood coagulation [112], and it shows
antagonistic effects of shikimic acid against focal cerebral
ischemia injury in rats subjected to middle cerebral artery
thrombosis [113].
On other hand, it has been reported that shikimic acid
displays antipyretic, antiinflammatory and analgesic activity
[114], as well as antibacterial activity [115]. Some
derivatives of shikimic acid also have interesting biological
properties. For example, the triacyl derivatives of shikimic
acid can inhibit blood platelet assembling and thrombosis by
affecting the metabolism of arachidonic acid [116]. There are
also data available on the synthesis of monopalmityloxy
shikimic acid possessing anticoagulant activity and being
capable of reducing blood coagulability when injected
intramuscularly [117]. Other derivative, the 3,4-oxo-
isopropylidene-shikimic acid (ISA), have an interestin g
biological profile. This derivative has anti-thrombosis effect,
increasing the PGI2 release [118] and inhibiting anti-
platelet-aggregation [119]. ISA have some protective effect
on focal cerebral ischemia, decreasing the the size of
cerebral infarction and the brain edema [120] and improving
the abilities of learning and memory [121]. ISA also have
significan t antiinflammatory effects which might be related
to reducing the production of PGE2 and inhibiting free
radical oxidation [122].
6. SHIKIMIC ACID DERIVATIVES
Over recent years, there has been ex tensive interest in the
efficient preparation of analogues of (-)-shikimic acid, which
have been targeted as likely inhibitors of enzymes on the
shikimic acid pathway and which are of relev ance as
potential antifungal, antibacterial and antiparasitic agents.
6.1. Oseltamivir (TamifluTM) and Related Compounds
The arsenal of antiviral therapeutic agents is relatively
modest, as compared to antibacterials and antifungals. In the
recent years, the emergence and worldwide spread of the
avian influenza A virus subtype H5N1 has raised concerns of
possible easy human-to-human transmission, which calls for
the need to develop more potent antiviral drugs to be used
for the prophylaxis and treatment of influenza, a viral
infection of the respiratoy system that affects around 20% of
the worldwide poblation and results in ca. 500.000 deaths
[123].
1448 Mini-Reviews in Medicinal Chemistry, 2012, Vol. 12, No. 14 Estévez and Estévez
Neuraminidase (NA), a membrane glycoprotein of the
influenza virus which is required for the release of budding
virions from the host cell, is one of the potential drug targets
of antiviral agents. Neuraminidase is an external
glycoprotein that accelerates the breaking of the connection
of sialic acid end and neighboring sugar half which causes
subsequent respiratory infection via various mechanisms.
Probably the discharge of virus from infected cells initiates
and stimulates the penetration of virus into respiratory
epithelial cells which was initially caused by neuraminid ase.
Neuraminidase inhibitors also cause cellular apoptosis by
stimulating transforming growth factor beta and induce
cytokines including interleukin-1 and tumor necrosis factor.
At present, research and development of anti-influenza
drugs based on the inhibition of influenza virus
neuraminidase (sialidase) is a very active research area.
Several potent and specific inhibitors of NA have been
developed through structure-based rational dessing. However
only zanamivir (RelenzaTM) and oseltamivir phosphate
(TamifluTM) (Fig. 2) have been approved for human use and,
in practical terms, they constitute the current therapy for the
treatment of influenza [124].
CO2EtO
NH2 H3PO4
AcHN
Fig. (2). Osealtamivir phosphate (TamifluTM).
TamifluTM prodrug is hydrolized in the liver by hepatic
estearases to its active form oseltamivir carboxylate, a
compound that acts as an inhibitor of neuraminidase, one of
the proteins of the virus surface [125]. As a result of this
inhibition, the virus is unable to infect other cells.
Tamiflu is most popular due to its oral administration,
thus being the drug of reference for the therapy of avian
influenze. This resulted in a high demand for this compound
that cannot apparently be satisfied by the industrial
production, which relies on a impresive semisynthesis from
(-)-quinic acid or (-)shikimic acid, developed by Vilead and
Roche chemists [126]. This stimulated extensive efforts of
the synthetic community, with the aim of developing an
efficient total synthesis applicable on a large scale [127]. The
challenge resulted in quite a number of ingenious synthetic
approaches to this small, but densely functionalized molecule,
where a range of mechanistically different reactions were used
as key steps in syntheses [128].
Different strategies for the preparation of Tamiflu in
industrial scale have been subjected to extensive investigations
[129]. The most recent synthetic approach to oseltamivir
from (-)-shikimic acid is an efficient, nine-step route recently
reported by Karpf and Trussardi at F. Hoffmann-La Roche
Ltd. in Switzerland [129g] This and other preparations have
been addressed in a recent review on synthetic approaches to
oseltamivir phosphate reported in 2010 [127a]. Some ulterior
methods include:
• A novel asymmetric synthesis from (-)-shikimic acid via
a 3,4-cyclic sulfite intermediate [130].
• A eight-step synthesis of (-)-oseltamivir devolped by
Barry Trost [131]. Key transformations include a novel
palladium-catalyzed asymetric allylic alkylation reaction
(Pd-AAA) as well as a rhodium-catalyzed chemo-,
regio-, and stereoselective aziridination reaction.
• A enantioselective synthesis of oseltamivir phosphate
[132], including as key steps an asymmetric Diels-Alder
reaction, Mitsunobu inversion using Fukuyama modified
Weinreb reagent and carbamate directed epoxidation.
• Four generations of chemoenzymatic approaches are
surveyed [133]. The first two generations relied on the
use of cyclohexadiene-cis-diol derived enzymically
from bromobenzene. The third and fourth generation
used the corresponding diol obtained from ethyl
benzoate by fermentation with E. coli JM109 (pDTG601a).
Both of these advanced approaches benefited from
symmetry considerations and translocation of the acrylate
double bond with concomitant elimination of the C-1
hydroxyl. The syntheses are evaluated for overall
efficiency by the use of efficiency metrics and compared
with other syntheses of oseltamivir (both academic and
industrial).
Regarding pharmacological aspects of Tamiflu, a recent
review on neuraminidase inhibitors is mainly dedicate to
profile of oseltamivir: pamacokinetics, prophylasis, antiviral
chemoprophylaxis, dose adjuntment, toxicity, resistance and
drug interactions [134].
High mutation rate and emerging drug resistance to the
commercially available drugs, especially to oseltamivir, hav e
been widely reported [135]. Therefore, finding novel potent
inhibitors of NA less affected by cross-resistance as well as
identification of new drug targets is a vital goal.
Regarding resistance, as an alternative to oseltamivir, the
novel neuraminidase inhibitor peramivir (RapiactaTM ) was
prepared. (Fig. 3) [136]. It failed to show statistically
significant viral inhibition due to the relatively low blood
levels obtained after oral administration [137]. But it
continues to progress through clinical trials as a potential
injectable anti-influenza drug for treating patients with life-
threatening strains of the influenza A viruses H1N1 (swine
flu) and H5N1 (bird flu) [138]. It appears to act as the long-
acting neuraminidase inhibitors, because only one injection
is required, but it needs to be administered no later than 36–
48 h after manifestation of the symptoms in order to be
effective [139].
6.2. (-)-Zeylenone
(-)-Zeylenone (Fig. 4) is a polyoxygenated cyclohexene
isolated from Uvaria grandiflora [140], which shows
antiviral, anticancer and antibiotic activities and is widely
employed as a preparation for chemotherapy of cancerous
A Short Overview on the Medicinal Chemistry of (—)-Shikimic Acid Mini-Reviews in Medicinal Chemistry, 2012, Vol. 12, No. 14 1449
diseases [141]. It was prepared for the first time in a
stereoselective synthesis from shikimic acid [142].
OH
CO
2
H
H
N
H
AcHN
NH
2
HN
Fig. (3). Peramivir (RapiactaTM).
HO
BzO
O
HO CH2OBz
Fig. (4). Zeylenone.
6.3. Haloshikimic Acids
The plethora of derivatives of shikimic acid of interest as
enzyme inhibitors include fluorinated analogues such as
(6S)-6-fluoro-shikimic acid (Fig. 5), a compound that display
in vitro antibacterial activity against a range of Escherichia
coli strains [143]. Furthermore, the 4-epi-shikimic acid
skeleton [144] is present in numerous natural products with
interesting biological properties. One example is the (6S)-6-
chloro derivative pericosine A (Fig. 5), an antitumour agent
from Periconia byssoid.
CO
2
H
HO
OH
OH
F
CO
2
H
HO
OH
OH
Cl
Fig. (5). (6R)-6-Fluoro-shikimic acid and Pericosine A.
6.4. (-)-MK7607
Carbasugars are carbocycle monosaccharides in which
the ring oxygen has been repalced by a methylene group. As
carbohydrate mimics, they are stable to enzymatic hydrolysis
in biological systems and often display a range of biological
activities, particularly as glycosidase inhibitors. (-)-MK7607
is a carbasugar isolated from the fermentation broth of
Curvularia eragrostidis D2452, which was found to have
effective herbicidal activity [145]. It was prepared from
shikimic acid in a seven-step sequence [146].
CH
2
OH
HO
OH
OH
OH
Fig. (6). (-)-MK7607.
7. CONCLUSIONS
The past several years have witnessed explosive
developments in shikimic acid chemistry and biochemistry,
targeting many biological applications. Particularly relevant
is the use of shikimik acid in the preparation of antivirals as
oseltamivir, drug or reference in the treatment of avian
influenza. Revising the existent literature on shikimic acid
and its derivatives, we can find many other pharmaceutical
applications of shikimic acid and its derivatives, as
antioxidants, antitumoral agents, antibacterials or hormones.
Thus, looking to the future, the widespread and wide field of
application of shikimic acid in medicinal chemistry, and the
emergence of increasingly sophisticated methodologies for
its synthesis and extraction, seems certain to ensure
continued interest in this derivative. We thus hope that this
review will provide a useful aid to medicinal chemists
interested in the use of shikimic acid as a base for the
development of novel pharmacologically relevant
derivatives.
CONFLICT OF INTEREST
The author(s) confirm that this article content has no
conflicts of interest.
ACKNOWLEDGEMENTS
This work was supported by the Spanish Ministry of
Science and Innovation (CTQ2009-08490) and by the Xunta
de Galicia (Research Project CN2011/037). A.M.E. thanks
the Spanish Ministry of Science and Innovation for an FPU
grant.
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Received: December 02, 2011 Revised: December 23, 2011 Accepted: December 24, 2011
