Article

Separation of Shikimic Acid from Pine Needles

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Abstract

Shikimic acid is used as a precursor for the synthesis of oseltamivir phosphate (Tamiflu®), which is used as an anti-viral for the H5N1 strain. As concern for this virus increases, demand for medicinal products capable of treating it increases, while shikimic acid resources remain limited. In this study, for the first time shikimic acid is extracted from pine needles using water at relatively low temperature. After the subsequent evaporation, column adsorption/desorption and crystallization processes, shikimic acid crystals with a purity of over 98 % are obtained. A total recovery of approximately 85 % is reached, with the highlights of the method being simplicity, low cost and industrial practicality.

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... Whereas obtaining pure shikimic acid involves relatively simple and low-cost processes (Sui, 2008), the use of reduced rates of glyphosate can be an interesting strategy for accumulating this acid for further industrial use. The process shown here may be of interest to the pharmaceutical industry, in search of options to supplement the meager supply of shikimic acid. ...
... Endogenous shikimic acid concentrations in the control plants are close to those determined in needles of Pinus spp. and seeds of Liquidambar styraciflua (Enhrich et al., 2008;Sui, 2008;Martin et al., 2010) and within the range expected for angiosperms (Hattori et al, 1954;Sambanthamurthi et al., 2010). ...
Article
Full-text available
Oseltamivir phosphate is a potent viral inhibitor produced from shikimic acid extracted from seeds of Ilicium verum, the most important natural source. With the site of action 5-enolpyruvylshikimate-3-phosphate synthase (EPSP), glyphosate is the only compound capable of inhibiting its activity with the consequent accumulation of shikimic acid in plants. Corn and soybean plants were sprayed with reduced rates of glyphosate (0.0 to 230.4ga.i.ha1) and shikimic acid content in the dry mass was determined by HPLC 3, 7 and 10days after application. Results showed shikimic acid accumulation in dry mass with increases of up to 969% in corn and 33,000% on soybeans, with peak concentrations 3days after treatment (DAT). Industrial feasibility for shikimic acid production, combined with favorable climatic conditions for growing corn and soybean in virtually all over Brazil, favor the use of reduced rates of glyphosate in shikimic acid biosynthesis, with potential for use as an inducer in exploration of alternative sources for production of oseltamivir phosphate with low environmental impact.
... Several varieties of pine, fir and spruce are known to produce shikimic acid. A hot water (45-75°C) extraction of the needles of Scots pine (Pinus sylvestris) yielded around 1.6% (w/w) shikimic acid (Sui, 2008). Extraction from the needles of the pine Pinus elliottii has been described (Xie et al., 2010). ...
... Shikimic acid is highly soluble in water (180 g/L at 20°C), but not in non-polar solvents. Therefore, a hot water extraction of the plant tissue is used as the primary extraction step (Ohira et al., 2009;Sui, 2008;Xie et al., 2010;Ye et al., 2007). Shikimic acid content in the plant tissue varies depending on the source of the tissue, the time of harvest and other possible factors. ...
... The first method, being the most popular one, is the extraction and purification of SA from plant tissues. In this method, polar solvent such as water, methanol and ethanol are used to extract the SA from plants such as Chinese star anise (Edmonds and Payne, 2005), certain varieties of pine, fir and spruce (Sui, 2008) and leaves of several varieties of sweetgum tree (Enrich et al., 2008;Martin et al., 2010). Although the production of SA via this extraction method seems simple, the separation and purification of SA from the crude extract is tedious and involve several steps before a product with acceptable quality is produced. ...
Article
Full-text available
Shikimic acid is an important component in the production of several important drugs particularly the anti-influenza drug, Oseltamivir. Commercially, shikimic acid is extracted from the Chinese star anise or produced through the fermentation process by modified strain of E. coli. Regardless of the method of production, shikimic acid needs to be purified before it can be used for the intended purpose. Conventional method in the purification of shikimic acid usually involves the use of non-specific adsorbents that are less effective in isolating the shikimic acid. Molecularly imprinted polymer, being one of the latest adsorbents in separation science, offers an alternative technique that is more selective and specific than the conventional adsorption methods. This article is the exploratory work done to optimise the formulation for the preparation of molecular imprinted polymer for shikimic acid that is 100% compatible with aqueous systems. It emphasises particularly on the effects of various template: monomer: cross-linker ratios (TMX) on the performance of final polymer, including the preliminary evaluation results of the polymer performance.
... Miles et al. [30] used alcohol additives and mild temperature swing (23–54 @BULLET C) to recover shikimic acid from natural products. Sui [31] used water at temperatures from 45 to 75 @BULLET C to extract shikimic acid from pine needles. Ye et al. [32] proposed the use water and alkali solutions to separate shikimic acid from agricultural sources. ...
Article
Shikimic acid can be rapidly separated (ca. 5 min) from Chinese star anise with hot water extraction at temperatures of 120 °C or higher to obtain recoveries of 100%. Extraction recoveries of shikimic acid close to 97% can be obtained with water at 70 °C using slightly longer extraction times (ca. 10 min) than those at 120 °C. A semi-batch flow apparatus was used to study the effect of temperature, average particle size, water flow rate, and extraction time on the experimental recoveries. For 0.5 g Chinese star anise raw material that contained ca. 8% shikimic acid, 100% recoveries of shikimic acid could be obtained with 60 g water at 150 °C at 15 MPa in 4 min for star anise material having a particle size range from 355 to 600 μm. A one-site kinetic model was found to provide good correlation of the data and the kinetic parameters of the model could be written in terms of linearized contributions in temperature, average particle diameter and flow rate.
... A total recovery of approx. 85 % is reached [75]. ...
Article
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 relevant the antiviral agent oseltamivir (Tamiflu (TM)). 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 (Tamiflu (TM)).
... Pine trees have been the research focus of scientists, academicians, industrialists at the national and international level, almost every part of this valuable tree is of several uses. For instance, pine needles are good source of Shikimic acid [3], Abietic acid [4] Vitamins A and C [5] etc...Its bark is used for medical purpose, for example, in treatment of cold, cough, influenza [6][7]. Varieties of ink and adhesives are used in various kinds of paints mainly a product of pine trees [8]. ...
Article
Full-text available
Deforestation, forest fire hazard and exploitation of forest have been warning threats to our environment and ecosystem globally. Uttarakhand is a hilly state of India situated in the lap of Central Himalayas and Chir pine forest is the foremost species of this state. In this state, 65% area is covered mainly by forest and population wise, about 70% of its total population inhibit in its rural areas. Pine forest is found enormously in several districts of the Uttarakhand state. One of the prime means of survival hood of rural there is collection of hay stuff for cattle and growing tendrils for vegetables etc. For this purpose every year, villagers need a number of poles as a support to hay stuff and tendrils. Pine trees, bearing a pole kind of structure, are the most victims for this reason as it is easily available to the villagers. Pine has been a valuable asset internationally for many applications e.g. medicine, drugs, expensive chemicals, etc. It has been a research focus of many scientists and industrialists. It's under usage for hay and tendril purpose is, however, hardly noticed. The present study deals with estimation of poles, required for hay and tendril purpose in various districts of the Uttarakhand. A field survey is conducted to observe and estimate pine deforestation by individual family. The findings of present survey indicate: (i) pine deforestation by villages needs to be noticed and avoided (ii) villages may be provided an alternative solution (iii) instead, pine trees should be preserved and used for enhancing social, environmental and economic measures. The alternate for hay and tendril poles is discussed. The benefits of preserving pine trees and its scope is thoroughly studied. Harmful effects of pine forest degradation are highlighted.
... Studies have found that shikimic acid is present both in Christmas trees and pine trees, and particularly in pine needles. Recent research has examined ways to separate shikimic acid from pine needles (Sui 2008). ...
... The test results were found to be zero bacterial growth in presence of water extract confirming the prospective hypothesis of potential antiseptic activity present in the plant. [63][64] f. Antispasmatic had investigated the antispasmodic activity in the wood of Cedrus deodara and found Himachalol as the major antispasmodic constituent. ...
... The test results were found to be zero bacterial growth in presence of water extract confirming the prospective hypothesis of potential antiseptic activity present in the plant. [63][64] x Antispasmatic: had investigated the antispasmodic activity in the wood of Cedrus deodara and found Himachalol as the major antispasmodic constituent. The antispasmodic activity was similar to that of pipavarine. ...
Article
The first record of practice of traditional medicine by humans comes from the tablet around 2600 B.C. old. The tablet mentions the significance and use of oils from Cedrus species (Cedar), Cupressus sempervirens (cypress), Glycyrrhiza glabra (licorice), etc.vital plants of that time. In recent times change in behavior of industry seems to take place, where they are now reverting back towards in traditional medicines and herbs. A quick show up of the present scenario indicates a surge in, the Global herbal supplements and remedies market, reaching to Rs. 9315 crores, comparatively in lead is the Indian Herbal Market with extreme growth expectations to Rs. 14,500 crore (2015). Herbal exports project market size of Rs. 9000 crores by 2015. However, Chinese herbal medicinal market poses big threat, so urgent need is required to build regulated traditional medicine practice in par with international standards. Realizing this fact, the review puts light on traditional system of medicine scenario in India, hurdles and ways to overcome them, along with description upon two essential herbs Cedrus deodara and Operculina turpethum, as an example to justify potential and expertise India could achieve in Drug Industry in coming future.
... It has been reported that the pine needles comprise about 1.5-2.5% shikimic acid, although a little change with season and age has also been observed. The studies carried out in available literature confirm that few pine species contain a good enough amount of a key precursor which is used in the production of Tamiflu®, an antiviral drug used in the treatment of H5N1 flu (Xie et al. 2012;Sui 2008). Chen et al. (2014) achieved about a 6% yield of shikimic acid from Masson pine needles, which is possibly the highest extracted yield from any pine species till now (Chen et al. 2014). ...
Chapter
Full-text available
Essential oils from pine species have been utilized for numerous applications since centuries. This chapter discusses major aspects of pines’ essential oils, such as their composition, global availability, and medical as well as industrial applications. It has been observed that there are 40 major pine species with availability across the different continents/regions, which has been identified. Though there are a number of contributors in pine essential oils and their respective yields from different species, in the present chapter, 20 major contributors with their yields have been discussed. Further, in last few decades, several extraction techniques have been developed to intensify the extraction of essential oils from different pine species, which are discussed in brief. A few of the emerging techniques are based on ultra-sonication and microwave-assisted irradiations, which take very less time (almost less than 6–10 times) as compared to conventional extraction techniques. Also, major plant pathways dedicated to shikimate and terpenoids have been discussed which are readily found in pine species.
... The test results were found to be zero bacterial growth in presence of water extract confirming the prospective hypothesis of potential antiseptic activity present in the plant. [63][64] x Antispasmatic: had investigated the antispasmodic activity in the wood of Cedrus deodara and found Himachalol as the major antispasmodic constituent. The antispasmodic activity was similar to that of pipavarine. ...
... The test results were found to be zero bacterial growth in presence of water extract confirming the prospective hypothesis of potential antiseptic activity present in the plant. [63][64] x Antispasmatic: had investigated the antispasmodic activity in the wood of Cedrus deodara and found Himachalol as the major antispasmodic constituent. The antispasmodic activity was similar to that of pipavarine. ...
... The test results were found to be zero bacterial growth in presence of water extract confirming the prospective hypothesis of potential antiseptic activity present in the plant. [63][64] x Antispasmatic: had investigated the antispasmodic activity in the wood of Cedrus deodara and found Himachalol as the major antispasmodic constituent. The antispasmodic activity was similar to that of pipavarine. ...
... The test results were found to be zero bacterial growth in presence of water extract confirming the prospective hypothesis of potential antiseptic activity present in the plant. [63][64] f. Antispasmatic had investigated the antispasmodic activity in the wood of Cedrus deodara and found Himachalol as the major antispasmodic constituent. ...
Book
Endeavor to Research World-By Devansh Mehta.pdf
... The test results were found to be zero bacterial growth in presence of water extract confirming the prospective hypothesis of potential antiseptic activity present in the plant. [63][64] f. Antispasmatic had investigated the antispasmodic activity in the wood of Cedrus deodara and found Himachalol as the major antispasmodic constituent. ...
Book
Research compilation book - By Devansh.pdf
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Shikimic acid properties and its available analytical techniques are discussed. Plants having the highest content of shikimic acid are shown. The existing isolation methods are analyzed and the most optimal approaches to extracting this acid from natural sources (plants and microorganisms) are considered.
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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 relevant the antiviral agent oseltamivir (tamiflu). 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 selections of derivatives, including Oseltamivir (Tamiflu™).
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Deforestation, forest fire hazard and exploitation of forest have been warning threats to our environment and ecosystem globally. Uttarakhand is a hilly state of India situated in the lap of Central Himalayas and Chir pine forest is the foremost species of this state. In this state, 65% area is covered mainly by forest and population wise, about 70% of its total population inhibit in its rural areas. Pine forest is found enormously in several districts of the Uttarakhand state. One of the prime means of survival hood of rural there is collection of hay stuff for cattle and growing tendrils for vegetables etc. For this purpose every year, villagers need a number of poles as a support to hay stuff and tendrils. Pine trees, bearing a pole kind of structure, are the most victims for this reason as it is easily available to the villagers. Pine has been a valuable asset internationally for many applications e.g. medicine, drugs, expensive chemicals, etc. It has been a research focus of many scientists and industrialists. It's under usage for hay and tendril purpose is, however, hardly noticed. The present study deals with estimation of poles, required for hay and tendril purpose in various districts of the Uttarakhand. A field survey is conducted to observe and estimate pine deforestation by individual family. The findings of present survey indicate: (i) pine deforestation by villages needs to be noticed and avoided (ii) villages may be provided an alternative solution (iii) instead, pine trees should be preserved and used for enhancing social, environmental and economic measures. The alternate for hay and tendril poles is discussed. The benefits of preserving pine trees and its scope is thoroughly studied. Harmful effects of pine forest degradation are highlighted.
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Oseltamivir phosphate is a potent viral inhibitor produced from shikimic acid extracted from seeds of Ilicium verum, the most important natural source. With the site of action 5-enolpyruvylshikimate-3-phosphate synthase (EPSP), glyphosate is the only compound capable of inhibiting its activity with the consequent accumulation of shikimic acid in plants. Corn and soybean plants were sprayed with reduced rates of glyphosate (0.0 to 230.4 g a.i. ha-1) and shikimic acid content in the dry mass was determined by HPLC 3, 7 and 10 days after application. Results showed shikimic acid accumulation in dry mass with increases of up to 969% in corn and 33,000% on soybeans, with peak concentrations 3 days after treatment (DAT). Industrial feasibility for shikimic acid production, combined with favorable climatic conditions for growing corn and soybean in virtually all over Brazil, favor the use of reduced rates of glyphosate in shikimic acid biosynthesis, with potential for use as an inducer in exploration of alternative sources for production of oseltamivir phosphate with low environmental impact. © 2014, Sociedade Brasileira da Ciencia das Plantas Daninha. All rights reserved.
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Shikimic acid (SA) is widely found in higher plants and microbial shikimic acid pathway intermediates, with anti-tumor and cardiovascular and cerebrovascular system effects. SA can be used as anti-avian influenza drugs osmium phosphate Wei (trade name Tamiflu) and dithromycin, glyoxal inhibitors and other anti-tumor drug synthesis of raw materials. In addition, in biosynthesis also play an important role, such as phenylpropanoids, aromatic amino acids, flavonoids and so on are generated through the shikimic acid pathway. Shikimic acid production of raw materials mainly from plants, of which magnolia plants star anise in the content of high. During the outbreak of the avian flu virus, the market price of shikimic acid soared to 5 000 yuan / kg, the main raw material star anise prices have doubled. In order to develop and investegate the shikimic acid resources, the author summarizes the recent research situation of shikimic acid, hoping to provide reference for the development of shikimic acid resources.
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Shikimic acid (SA) is a key precursor for synthesis of drug against H5N1 virus. The demand for this compound is met from plant resources, especially from the fruits of Chinese star anise (Ilichium vernum L.). Present study expounds understanding on distribution of SA in various plant species collected from Western Ghats using RP-UFLC analysis. The area under curve obtained after RP-UFLC run were used to comprehend on possible natural groupings and correlations. 14 out of 58 samples yielded SA in an excess of 1 mg/g and Mammea suriga (Buch.-Ham. ex Roxb.) Kosterm (29.34 mg/g) being the highest among all. Probably, this is the first report of M. suriga to be accounted for SA content. Higher yielding samples grouped together in hierarchical clustering analysis.
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Shikimic acid is a natural product of industrial importance utilized as a precursor of the antiviral Tamiflu. It is nowadays produced in multihundred ton amounts from the extraction of star anise ( Illicium verum) or by fermentation processes. Apart from the production of Tamiflu, shikimic acid has gathered particular notoriety as its useful carbon backbone and inherent chirality provide extensive use as a versatile chiral precursor in organic synthesis. This review provides an overview of the main synthetic and microbial methods for production of shikimic acid and highlights selected methods for isolation from available plant sources. Furthermore, we have attempted to demonstrate the synthetic utility of shikimic acid by covering the most important synthetic modifications and related applications, namely, synthesis of Tamiflu and derivatives, synthetic manipulations of the main functional groups, and its use as biorenewable material and in total synthesis. Given its rich chemistry and availability, shikimic acid is undoubtedly a promising platform molecule for further exploration. Therefore, in the end, we outline some challenges and promising future directions.
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This chapter contains sections titled: Introduction Shikimic Acid Applications of Shikimic Acid Conclusion
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Oseltamivir phosphate (OSP), marketed under the brand name of Tamiflu®, is a potent inhibitor of viral neuraminidase, a glycoside hydrolase enzyme essential for viral replication. OSP is also important to control influenza virus (H1N1) and is produced mainly from shikimic acid (SA) extracted from plants. The main source of SA is from seeds of I. verum. Alternatives to meet the worldwide demand are necessary. One of this is Cryptomeria japonica. In this study, we found a content of 56.36 mg.kg-1 of SA in dried biomass for C. japonica, while for I.verum, the traditional source, was 96.57 mg.kg-1. Due to the fact of C. japonica is a tree, exploited for commercial production, it can be a renewable and reliable source SA for OSP production.
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Novel stereodivergent total syntheses of all the seven stereoisomers of (‒)‐shikimic acid [(−)‐SA 1 ] have been systematically performed. (+)‐ ent ‐SA ent ‐ 1 was synthesized from (−)‐SA 1 via 9 steps in 31% overall yield; (‒)‐3‐ epi ‐SA 2 was synthesized from (−)‐SA 1 via 5 steps in 66% overall yield; (+)‐3‐ epi ‐ ent ‐SA ent ‐ 2 was synthesized from (−)‐SA 1 via 7 steps in 43% overall yield; (‒)‐4‐ epi ‐SA 3 was synthesized from (−)‐SA 1 via 11 steps in 32% overall yield; (+)‐4‐ epi ‐ ent ‐SA ent ‐ 3 was synthesized from (−)‐SA 1 via 7 steps in 42% overall yield; (‒)‐5‐ epi ‐SA 4 was synthesized from (−)‐SA 1 via 6 steps in 56% overall yield; and (+)‐5‐ epi ‐ ent ‐SA ent ‐ 4 was synthesized from (−)‐SA 1 via 12 steps in 29% overall yield. The stereochemistry of all the above seven stereoisomers of (−)‐SA 1 were further studied by two dimentional (2D) 1 H NMR technique.
Article
Shikimic acid (SA) is a valuable compound found in water hyacinth and is a precursor for synthesis of antiviral drug oseltamivir phosphate (Tamiflu®) which is used to treat H5N1 avian influenza. In the present work, the acid was extracted from different morphological parts (stem, leaves, and roots) of water hyacinth (a notorious aquatic weed) using sonication. The parametric study has been conducted by varying sonication time (10–50 min), solvent composition (methanol + water), solvent volume (20–50 mL), amplitude of sonication (30–60%), and pulse ratio (20–50%) for improving the recovery of shikimic acid (SA), antioxidant activity (AA) and total phenolic content (TPC) of water hyacinth extract. Also, the acid was extracted conventionally as a benchmark study. The highest yield of 2.4% at 40 min and 3.1% at 30 min was observed in case of conventional and ultrasound assisted extraction (UAE), respectively for stem. Leaves showed a higher TPC value of 7.4 mg GAE/g biomass and a higher AA was observed 83.21% at 20 min for stem in case of conventional method. The highest TPC value of 11.11 mg GAE/g biomass has been observed for leaves while stem has shown the highest AA of 87.72% at 10 min of sonication time for UAE. It was possible to recover the valuable chemicals with better processing conditions in the case of UAE.
Article
Oseltamivir phosphate (1) was synthesized from (-)-shikimic acid through a short and practical synthetic route via eight steps in 47% overall yield. In addition, the highly regioselective and stereoselective nucleophilic replacement of OMs by the N(3) group in the third and seventh steps has been studied in detail, and the reaction conditions were optimized.
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Some of the general features of the pathway for l-tryptophan biosynthesis in cell cultures of Nicotiana tabccum var. Wisc. 38 have been investigated. The results of both isotope competition and direct-labeling experiments show that shikimic acid, anthranilic acid, indoleglycerol phosphate, and indole can serve as precursors to l-tryptophan in these cells, indicating that, in terms of its biochemical intermediates, the pathway is similar to that described for the bacteria and fungi.
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In 2002, the University of Wisconsin (UW) Internships in Public Science Education (IPSE) program started as a way to connect audiences of all ages to scientific expertise and cutting-edge research that might not otherwise be available to them. Graduate and undergraduate interns designed hands-on, interactive activities that use basic science concepts to explain cutting-edge nanotechnology concepts. To date, the collaboration has resulted in an innovative program using the strengths of each partner to bring cutting-edge science to the public. In the process, the interns received technical training and engaged in an iterative project development process as they gained experience in communicating science; the public developed a better understanding of and appreciation for nanoscale science, technology, and engineering.
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A laboratory experiment is outlined in which in the process of extracting shikimic acid from star aniseed exposes students to a number of important experimental techniques. The experimental procedure is designed to be carried out in a time period suitable for most undergraduate courses and is appropriate for both organic and natural product courses.
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Summary 1. The fractional and amino-acid compositions of needle proteins and of a protein-vitamin concentrate isolated from an extract have been determined. 2. The optimum conditions of the protein-extracting process have been found. The dependence of the influence of various factors on the degree of extraction of the protein from the needles has been shown. 3. The results obtained enable the protein-vitamin concentrate to be recommended as a valuable additive to fodder for agricultural animals.
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A second-generation manufacturing process from a shikimic acid-derived epoxide to oseltamivir phosphate features a magnesium chloride−amine complex-catalyzed ring opening of the epoxide by tert-butylamine, a selective O-sulfonylation of the resulting tert-butylamino alcohol, a surprisingly efficient cleavage of a tert-butyl group from an aliphatic tert-butylamide, and the isolation of oseltamivir phosphate from a palladium-catalyzed allyl transfer reaction mixture. The overall yield from the epoxide to oseltamivir phosphate has been increased from 27 to 29% or 35−38% for two previous processes, respectively, to 61%.
Article
Shikimic acid, which constitutes 1.5-2.5% of the dry matter in needles of Scots pine, was found to stimulate the growth of various litter-decomposing basidiomycetes of the genera Marasmius, Mycena and Xeromphalina in a synthetic nutrient medium. Out of eighteen litter-decomposing species, ten were stimulated by shikimic acid, wheras the eight mycorrhizal and four wood-rotting species tested were not affected. Maximal effect was obtained at a concentration of ca 2 mM. Growth experiments at varying pH-values indicated active uptake of shikimic acid. Even in the presence of aromatic amino acids, shikimic acid stimulated the growth of the fungi. In certain species the strong inhibiting effect of phenylalanine, tyrosine and tryptophan, when added simultaneously, was reversed in the presence of shikimic acid. Fungi which were stimulated by shikimic acid were also able to use this compound as their sole carbon source. Maximal stimulating effect of shikimic acid occurred when glucose had been added at optimal concentration.
Article
The effect of ozone, needle age, and season on the pH of homogenate and acid contents of Scots pine and Norway spruce needles is presented. In addition enzyme activities of cytochrome C-oxidase (cyt. C-ox), phosphoenolpyruvate-carboxylase (PEPC), shikimic acid-dehydrogenase (SHDH) and malate-dehydrogenase (MDH) were measured in Scots pine needles. In freshly sprouted spruce needles the level of quinic acid is high and the pH of the needle homogenate is low. Shikimic acid starts at low levels, increases with increasing needle age and becomes dominant, whereas the quinic acid content decreases. Malic acid has a marked seasonal trend; no trend was found in citric acid. Ozone (200 g/m3) decreased shikimic acid and quinic acid, whereas pH, malic acid and citric acid increased. Ozone (100 g/m3) had a similar effect, except in the current-year spruce needles. In Scots pine needles ozone led to increased enzymatic activities of cyt. C-ox, PEPC and SHDH, and a decrease in the activity of MDH. This effect was more pronounced in summer than in autumn, but the visible damage was greater in autumn. These effects can be found with other stresses and are not specific for ozone.
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This review covers the literature published during 2000 on the biosynthesis of compounds derived wholly or partly from intermediates on the shikimate pathway. Recent developments in the enzymology and genetics of the shikimate pathway are also described. Enzymes involved in the biogenetic pathway to the aromatic amino acids are covered initially followed by sections dedicated to metabolites derived in some part from intermediates on the pathway. These include pyrrolnitrin. violacein, indole-3-acetic acid, coumarins, lignans, lignin, tannins, melanin, flavanoids, ubiquinone, TOPA quinone, PQQ, and tropanes.
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The physicochemical properties (capacity, kinetics and selectivity) of the ion exchange resins Amberlite IRA900, IRA400, IRA96 and IRA67 were determined to evaluate their comparative suitability for lactic acid recovery. Both the kinetics of lactic acid sorption from aqueous solutions and the equilibrium were assessed using mathematical models, which provided a close interpretation of the experimental results. The best resins (Amberlite IRA96 and IRA67) were employed in further fixed-bed operation using aqueous lactic acid solutions as feed. In this set of experiments, parameters such as capacity, regenerant consumption, percentage of lactic acid recovery and product concentration were measured. Amberlite IRA67, a weak base resin, was selected for lactic acid recovery from SSF (simultaneous saccharification and fermentation) broths. Owing to the presence of nutrients and ions other than lactate, a slightly decreased capacity was determined when using SSF media instead aqueous lactic acid solutions, but quantitative lactic acid recoveries at constant capacities were obtained in four sequential load/regeneration cycles.
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Shikimic acid is a high valued compound used as a key starting material for the synthesis of the neuramidase inhibitor GS4104, which was developed under the name Tamiflu for treatment of antiviral infections. An excellent alternative to the isolation of shikimic acid from fruits of the Illicium plant is the fermentative production by metabolic engineered microorganisms. Fermentative production of shikimic acid was most successfully carried out by rational designed Escherichia coli strains by blocking the aromatic amino acid pathway after the production of shikimic acid. An alternative is to produce shikimic acid as a result of dephosphorylation of shikimate-3-phosphate. Engineering the uptake of carbon, the regulatory circuits, central metabolism and the common aromatic pathway including shikimic acid import that have all been targeted to effect higher productivities and lower by-product formation are discussed.
Article
Shikimic acid is one of several industrially interesting chiral starting materials formed in the aromatic amino acid pathway of plants and microorganisms. In this study, the physiology of a shikimic acid producing strain of Escherichia coli (derived from W3110) deleted in aroL (shikimic acid kinase II gene), was compared to that of a corresponding control strain (W3110) under carbon- and phosphate-limited conditions. For the shikimic acid producing strain (referred to as W3110.shik1), phosphate limitation resulted in a higher yield of shikimic acid (0.059 +/- 0.012 vs. 0.024 +/- 0.005 c-mol/c-mol) and a lower yield of by-products from the shikimate pathway, when compared to carbon-limited condition. The yield of the by-product 3-dehydroshikimic acid (DHS) decreased from 0.076 +/- 0.028 to 0.022 +/- 0.001 c-mol/c-mol. Several other by-products were only detected under carbon-limited conditions. The latter group included 3-dehydroquinic acid (0.021 +/- 0.021 c-mol/c-mol), quinic acid (0.012 +/- 0.005 c-mol/c-mol), and gallic acid (0.002 +/- 0.001 c-mol/c-mol). For both strains, more acetate was produced under phosphate than the carbon-limited case. Considerable cell lysis was found for both strains but was higher for W3110.shik1, and increased for both strains under phosphate limitation. The advantages of the latter condition in terms of an increased shikimic acid yield was thus counteracted by an increased cell lysis, which may make downstream processing more difficult.
Article
An integrated system of simultaneous fermentation-adsorption for the production and recovery of fumaric acid from glucose by Rhizopus oryzae was investigated. The system was constructed such that growing Rhizopus mycelia were self-immobilized on the plastic discs of a rotary biofilm contactor during the nitrogen-rich growth phase. During the nongrowth, production phase, the biofilm was alternately exposed to liquid medium and air upon rotation of the discs in the horizontal fermentation vessel. The product of fermentation, fumaric acid, was removed simultaneously and continuously by a coupled adsorption column, thereby moderating inhibition, enhancing the fermentation rate, and sustaining cell viability. Another beneficial effect of the removal of fumaric acid is release of hydroxyl ions from a polyvinyl pyridine adsorbent into the circulating fermentation broth. This moderates the decrease in pH that would otherwise occur. Polyvinyl pyridine and IRA-900 gave the highest loading for this type of fermentation. This fermentation system is capable of producing fumaric acid with an average yield of 85 g/liter from 100 g of glucose per liter within 20 h under repetitive fed-batch cycles. On a weight yield basis, 91% of the theoretical maximum was obtained with a productivity of 4.25 g/liter/h. This is in contrast to stirred-tank fermentation supplemented with calcium carbonate, whose average weight yield was 65% after 72 h with a productivity of 0.9 g/liter/h. The immobilized reactor was operated repetitively for 2 weeks without loss of biological activity.
Article
An asymmetric ring-opening reaction of meso-aziridines with TMSN3 was developed using a catalyst prepared from Y(OiPr)3 and chiral ligand 2 in a 1:2 ratio. Excellent enantioselectivity was realized from a wide range of substrates with a practical catalyst loading. The products were efficiently converted to enantiomerically enriched 1,2-diamines, which are versatile chiral building blocks for pharmaceuticals and chiral ligands. This reaction was applied to a catalytic asymmetric synthesis of Tamiflu, a very important anti-influenza drug containing a chiral 1,2-diamino functionality.
Article
A short synthetic pathway has been developed for the synthesis of oseltamivir (1) or the enantiomer (ent-1). The intermediates and conditions for this process are summarized in Scheme 1. The synthesis provides a number of advantages: (1) use of inexpensive and abundant starting materials; (2) complete enantio-, regio-, and diastereocontrol; (3) avoidance of explosive, azide-type intermediates; (4) good overall yield (ca. 30%, still not completely optimized); and (5) scalability.