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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... Shikimic acid was purified as a amorphous white solid from the water extract of the soft hulls with a high yield (14.86%) and its chemical structure was characterized by FTIR, 1 H-NMR, 13 C-NMR, 1D-and 2D-MR spectroscopy. It is an intermediate metabolite in the synthesis of phenolic compounds in plants and microorganisms [41][42][43]. The plants contain varying amounts of shikimic acid, however the best source for shikimic acid isolation is star anise (Illicium sp.) [41][42][43][44][45]. Shikimic acid is commonly used in the synthesis of the antiviral drug agent, oseltamivir [43][44][45]. ...
... It is an intermediate metabolite in the synthesis of phenolic compounds in plants and microorganisms [41][42][43]. The plants contain varying amounts of shikimic acid, however the best source for shikimic acid isolation is star anise (Illicium sp.) [41][42][43][44][45]. Shikimic acid is commonly used in the synthesis of the antiviral drug agent, oseltamivir [43][44][45]. ...
Article
Pistachio (Pistacia vera L.) is an important cultivated plant in the Southeastern Anatolia region and its fruits are widely used in the food industry. The previous studies mostly focused on the food minerals and components. However, there is no study on chemical components and biological activity of the soft hulls of the pistachio fruits. In this study, it was focused on the acetone and water extracts of the soft hulls of pistachio fruits. Hence, the acetone extract was subjected to sephadex LH-20 column chromatography and fractioned into five fractions (Frs. A-E) according to molecular weight of components. A triterpen compound isolated from the Fr. B by crystallation method and its chemical structure was characterized as masticadienonic acid by spectroscopic methods. The fractions contain a mixture of the anacardic acids 13:1, 15:2, 15:1 and 17:1 and their derivatives according to their spectroscopic data and GC-MS analysis. Shikimic acid used in the synthesis of the oseltamivir, antiviral agent was also purified at high yield (14.36%) from the water extract of the soft hulls of pistachio fruits. In order to explore the antidiabetic properties of the pure compounds, the extracts and the fractions, their inhibition effects were determined on the activities of digestive enzymes (α-glucosidase and α-amylase). All of the extracts, masticadienonic acid and the fractions containing the anacardic acids strongly inhibited the α-glucosidase activity much more than acarbose. However, all applications exhibited much weaker inhibitory properties againts α-amylase, as compaired to the inhibition effect of the acarbose. Furthermore, the treatments of mesocarps of Pistachio fruits acted as much weaker inhibitors against AChE, whereas the acetone extract and its fractions containing different rates of anacardic acids were powerful agents against BChE as strong as neostigmine and galantamine. The cytotoxic activities of the extracts and the compounds against HUVEC, A549 and H1299 cells were also determined using the MTT analysis method and it was determined that the acetone extract and the compounds, masticadienonic and shikimic acids showed cytotoxic effects on the cells
... 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 [4][5][6][7][8]. In the pharmaceutical industry, lack of supply of shikimic acid has become the bottle neck for making the drug to meet the increasing social needs [6,[9][10][11]]. An excellent alternative to the isolation of shikimic acid from fruits of the Illicium plant is the fermentative production by metabolic engineered microorganisms [5]. ...
... Whereas, chemical synthesis process and microbial fermentation technology for producing shikimic acid both involve complex procedures which are results in high cost. Thus extraction of the compound from plants seems to be an affordable way to solve the supply problem [8,[10][11][12][13]. ...
Article
Shikimic acid is an important intermediate to oseltamivir phosphate which is the most effective drug for treating bird flu disease. This study was performed to determine the shikimic acid distribution of Illicium lanceolatum which was affected by its age, light condition and ecotype. The results indicated that the age of trees had an optimal effect on its content of leaves and it maintained at the highest level as trees grew. Whereas the content in root and branch declined with increasing age. The 50% light condition promoted accumulation of schikimic acid and the leaf contained the highest level of that regardless of the light conditions. The Wu’ning ecotype produced the largest amount of that in all organs. The result that the shikimic acid content in the leaves was higher than in the root indicated that the leaves can substitute for the root which was a traditional medicinal part. Possible mechanisms for the enhanced content are discussed. Findings from this study have provided the scientific bases for promoting shikimic acid industry, and developing a high efficiency artificial cultivation system of I.lanceolatum.
... 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. ...
... 0.17% and 0.02%, respectively [11,12]. The SAC in the dried needles of P. sylvestris was 1.60% [34]. The extractable shikimic acid was estimated as 3.79% in Calophyllum brasiliense leaves [35]. ...
Article
Full-text available
Liquidambar formosana is a multipurpose tree species native to China. There has been increasing interest in L. formosana due to its leaves being rich in shikimic acid, which plays a key role in the synthesis of the antiviral drug oseltamivir phosphate. Here, shikimic acid content (SAC) and other breeding traits, including tree height (HT), diameter at breast height (DBH), height to crown base (HCB), individual tree volume (VOL), leaf color (LC) and stem straightness degree (SSD), for 387 families of 19 provenances were evaluated in a provenance–family trial of L. formosana to estimate genetic parameters and reveal geographical variation patterns and, ultimately, screen out superior provenances and families. Differences among provenances and families were significant for all tested traits, indicating a high potential for selective breeding. Broad-sense heritabilities of provenance (hp2 = 0.19–0.57) and family (hf2 = 0.16–0.31) were moderate for most traits. Moderate to strong genetic correlations were found among HT, DBH, VOL, HCB and LC (rA = 0.339–0.982), while adverse correlations (rA = −0.494 to −0.816) were observed between SAC and growth traits. All target traits, excluding SSD, exhibited clinal variation in response to latitudinal gradients, and a clustering heatmap divided the 19 provenances into three groups. For single-trait selection, SAC persistently had the highest genetic gains (85.14%–163.57%). A weighted index based on breeding values was used to concomitantly improve SAC, HT and DBH. At a selection rate of 25%, the genetic gains at the provenance and family levels for SAC were 36.42% and 73.52%, and those for core growth traits ranged from −2.29% to 3.49% and 4.05% to 4.47%, respectively. As far as we know, this is the first study in L. formosana to explore the inheritance of SAC and its correlations with other traditional breeding traits. The genetic parameter estimations contribute to a better understanding of the genetic basis of SAC, and the superior provenances and families obtained lay a material foundation for the development of new varieties rich in shikimic acid, thereby promoting the in-depth exploitation and utilization of germplasm resources of L. formosana.
... 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
... 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] 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. ...
... 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.
... 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.
... 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)).
... 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.
... 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] 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.
... 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.
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Sustainable development goals require a reduction in the existing heavy reliance on fossil resources. Forestry can be considered a key resource for the bioeconomy, providing timber, energy, chemicals (including fine chemicals), and various other products. Besides the main product, timber, forestry generates significant amounts of different biomass side streams. Considering the unique and highly complex chemical composition of coniferous needle/greenery biomass, biorefinery strategies can be considered as prospective possibilities to address top segments of the bio-based value pyramid, addressing coniferous biomass side streams as a source of diverse chemical substances with applications as the replacement of fossil material-based chemicals, building blocks, food, and feed and applications as fine chemicals. This study reviews biorefinery methods for coniferous tree forestry biomass side streams, exploring the production of value-added products. Additionally, it discusses the potential for developing further biorefinery strategies to obtain products with enhanced value.
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Cellulose acetate membrane (CAM) has become one of the most widely used membrane materials by virtue of stability and hydrophilicity. In this work, to achieve the aim of selective recognition and separation of drug molecule shikimic acid (SA), an effective recognition tactics was proposed by combining boron affinity technology with surface imprinting strategy based on cellulose acetate membrane with low price and biocompatibility. The supporting CAM material was prepared through the phase inversion technique by continuous adjustment of different factors including solvent type and kinds of pore-forming agents, and the optimal CAM with multistage structure and highly porosity was applied for the imprinting of SA. Then the imprinted polymer membrane (MIPs-CAM) was developed via boron affinity surface imprinting polymerization. Various methods (FT-IR, UV-vis, SEM, XPS, AFM and TGA) were used to characterize the structure, morphology, elemental composition, surface roughness and thermal property of the obtained membrane. The as-prepared MIPs-CAM showed homogeneous and abundant imprinted layer, good thermal stability. The batch adsorption results showed that the MIPs-CAM had fast adsorption kinetics, specific recognition ability, and the adsorption capacity could obtain 63.598 mg g⁻¹, which was two times higher than that of non-imprinted membrane (NIPs-CAM). The adsorption isotherms conformed to the Langmuir isotherm and the adsorption processes were spontaneous and endothermic. Additionally, the adsorption capacity of MIPs-CAM still reached 85% of the initial result after five cycles. The experimental results revealed that the molecularly imprinted membrane possessed the advantages of high selectivity and easy recovery compared with the traditional molecular imprinted polymers for SA separation. These results indicate that boron affinity MIPs-CAM with high performance will provide a promising platform for the separation and purification of other cis-diol drug molecules from environmental resources.
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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.
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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 dimensional (2D) ¹H NMR technique.
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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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Efficient and highly stereoselective syntheses of (+)-proto-quercitol and (−)-gala-quercitol starting from the naturally abundant (−)-shikimic acid were described in this article. (−)-Shikimic acid was first converted to the key intermediate by eight steps in 53% yield. It was then converted to (+)-proto-quercitol by three steps in 78% yield and was also converted to (−)-gala-quercitol by five steps in 63% yield. In summary, (+)-proto-quercitol and (−)-gala-quercitol were synthesized from (−)-shikimic acid by 11 and 13 steps in 41 and 33% overall yields, respectively.
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N-Octyl-β-valienamine (NOV) 1 and N-octyl-4-epi-β-valienamine (NOEV) 2 are potent chemical chaperone drug candidates for the therapy of lysosomal storage disorders. Novel stereoselective syntheses of NOV 1 and NOEV 2 starting from naturally abundant (−)-shikimic acid are described in this article. The common key intermediate compound 5 was first synthesized from readily available (−)-shikimic acid via 9 steps in 50% yield. Compound 5 was then converted to NOV 1 via 5 steps in 61% yield, and it was also converted to NOEV 2 via 8 steps in 38% yield. In summary, NOV 1 was synthesized via 14 steps in 31% overall yield; and NOEV 2 was synthesized via 17 steps in 19% overall yield.
Chapter
This chapter contains sections titled: Introduction Shikimic Acid Applications of Shikimic Acid Conclusion
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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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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 the critical precursor to manufacture the antiviral drug Oseltamivir phosphate, also known as Tamiflu. Current sources of shikimic acid feedstock have been strained during pandemic influenza outbreaks. This article proposes an alternative process to produce shikimic acid feedstock through the bioenhancement of graminoid crops using glyphosate. To demonstrate, a Gulf cultivar of Italian annual ryegrass ( Lolium multiflorum Lam.) was grown in controlled greenhouse conditions and Yamhill winter wheat ( Triticum aestivum L.) was grown in a field trial. Plants were treated with a range of glyphosate doses and harvested between 48 and 298 h following application. Samples were dried, extracted, and analyzed by high performance liquid chromatography. Shikimic acid levels increased up to four‐fold in glyphosate‐treated Gulf annual ryegrass, a plant with high native shikimic acid. Concentrations of shikimic acid in Yamhill winter wheat, a plant low in native shikimic acid, increased from below method detection limits (<19 mg kg ⁻¹ ) in the control groups to >2000 mg kg ⁻¹ in treatment groups harvested after 169 h post application. Estimated biomass accumulation of shikimic acid were projected using concentrations observed in these trials for annual ryegrass, alfalfa ( Medicago sativa L.), and winter wheat based on published biomass yields resulted in 21.1 to 299 kg of potential shikimic acid production per hectare, which meet or exceed current feedstocks. This study provides evidence that glyphosate can be used to bioenhance graminoid forage crops to produce elevated shikimic acid levels throughout the entire plant biomass, resulting in a substantially greater yield of shikimic acid than current botanical sources on a per‐hectare basis.
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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.
Article
Pine needle extract (PE) and fermented pine needle extract (FPE) have been reported to show various biological and pharmacological activities such as antioxidant, anti-inflammatory, anti-bacterial, anti-cholesterol, gastrointestinal motility control, and fibrinolytic effect. The aims of our research were to isolate fibrinolytic compounds from PE and FPE and evaluate their antithrombotic activity in vitro and in vivo. Protocatechuic (1) and shikimic (2) acids were isolated and identified from FPE. 1 and 2 not only have fibrinolysis activity but also inhibit fibrin formation similar to aspirin. Lysis of fibrin clots by 1 and 2 occurred completely at pH 2–4. Results of SDS-PAGE showed that fibrin polypeptide chains (Aα, Bβ, γ) lysed by 1 and 2 were intact. The antithrombotic effects of 1 and 2 were confirmed by models of carrageenan-induced tail thrombosis, collagen and epinephrine-induced pulmonary thromboembolism in mice, and FeCl3-induced carotid arterial thrombus. Moreover, 1 and 2 did not induce hemorrhage in the tail veins of mice, unlike common antithrombotic compounds. We also measured changes in the quantities of 1 and 2 obtained from FPE. As fermentation progressed, we demonstrated that the quantity of 1 steadily increased, while the quantity of 2 did not significantly change. We therefore demonstrated that FPE is an excellent resource for 1 and 2 and can be produced inexpensively in sufficient quantities for industrial-scale extraction.
Article
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.
Article
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.
Article
Shikimic acid (SA) is the drug lead of oseltamivir phosphate (Tamiflu (R)). The pharmaceutical industry has great demand for SA to match the production of the drug. This article describes the development of an integrated expanded-bed adsorption chromatography (EBAC) system and its application in SA extraction and separation. The hydrodynamic behavior of an expanded-bed ion exchange resin, D293, was investigated to show that D293 resin is able to act as an adsorbent for recovery of SA from Illicium verum. SA was extracted from 8 g of I. verum in 150 mL of deionized water at an expansion ratio of 1.4 via integrated EBAC at 40 degrees C. The SA was then eluted in 200 mL of a 2% NaCl solution. The recovery rate of SA was 96.7% and its purity was 59.6%. Different methods were compared, and the results indicated that the method developed in this article is promising for the recovery of SA from I. verum. The process efficiency of the integrated method was 2.6 times higher than that of the conventional method, while its energy efficiency was about 6 times of that of the conventional method.
Article
All of the four stereoisomers of methyl 4,5‐epoxy‐3‐hydroxy‐cyclohex‐1‐ene‐carboxylate (1a–1d) are useful chiral building blocks. Novel and efficient syntheses of these four epoxy chiral building blocks from naturally abundant (−)‐shikimic acid (2) via cyclic sulfite intermediates are described in this article. The targeted compound (3R,4R,5S)‐1a was synthesized via four steps from (−)‐shikimic acid in 79% overall yield. The other three targeted compounds (3S,4R,5S)‐1b, (3S,4S,5R)‐1c and (3R,4S,5R)‐1d were synthesized via seven steps from (−)‐shikimic acid in 56%, 64% and 65% overall yields, respectively.
Article
Total syntheses of (+)-valiolamine (1) and (–)-1-epi-valiolamine (2) from the naturally abundant (–)-shikimic acid are described. Ethyl 3-epi-5-O-methylsulfonyl-shikimate (3), as the key common intermediate, was first synthesized in five steps in 74 % overall yield, and then converted into the targets 1 and 2 in seven steps in 48 and 41 % overall yield, respectively.
Article
A novel azide-free asymmetric synthesis of oseltamivir phosphate 1 (Tamiflu®) starting from Roche’s epoxide is described. Roche epoxide 2 was converted into N-acetyl aminoalcohol 3 in 95% yield via a BF3·OEt2-catalyzed epoxide-opening with acetonitrile as a nucleophile. Compound 3 was then transformed into a methanesulfonate 4 in 98% yield. Compound 4 was converted into aziridine 5 in 91% yield. Aziridine 5 was subsequently converted into oseltamivir phosphate 1 via two paths (a and b). In the path a, compound 5 underwent aziridine-opening with diallylamine as a nucleophile to afford compound 7 in 93% yield; compound 7 could then be converted into oseltamivir phosphate 1 in 88% yield. In path b, compound 5 underwent aziridine-opening with isopropyl 2,2,2-trichloroacetimidate as a nucleophile to afford compound 8 in 94% yield, which was then converted into oseltamivir phosphate 1 in 82% yield.
Article
A novel and high-yielding asymmetric synthesis of oseltamivir phosphate 1 (Tamiflu®) is described. The target compound 1 was obtained in 55% overall yield via an 11-step asymmetric synthesis starting from the naturally abundant (−)-shikimic acid. The present synthesis is characterized by some advantages such as the easy separation of intermediate 6 from triphenylphosphine oxide by using its large water-solubility, the use of inexpensive reagents throughout the synthesis, the lack of toxic heavy metals, mild reaction conditions and high yields for all steps. The stereochemical structure of the key intermediate 6 was unequivocally confirmed by X-ray crystallographic analysis.
Article
Shikimic acid is an industrially important chiral compound used as a key ingredient in formulation of drug Oseltamivir phosphate (Tamiflu) for the treatment of swine/avian flu. The high cost and limited availability of shikimic acid isolated from plants has detained the use of this valuable building block of the drug. It is a versatile compound having many characteristic properties for many synthetic reactions particularly in pharmaceuticals and cosmetic industries. By virtue of being a natural product, the relevant biochemical pathway in microorganisms can be harnessed into fermentation processes to produce shikimic acid. This is an excellent alternative for the sustainable and efficient production of shikimic acid over the tedious and cumbersome process of plant based extraction methods. Various strategies of shikimic acid production are reviewed and an account of comparison of their challenges, promises and restraint is presented. Furthermore, present review attempts to focus on the market trend of shikimic acid due to its high demand with particular emphasis laid on the pandemics of swine flu. This review not only covers the recent advances in shikimic acid production but also highlights the versatile applications and its market scenario. The concluding remarks and its potential as a commercial bulk chemical are discussed in the light of current research.
Article
Shikimic acid has wide use in pharmaceuticals due to its application in the synthesis of drug Tamiflu used in the treatment of Swine flu. The high cost and limited availability of shikimic acid isolated from plants has impeded the use of this valuable building block of the drug. In this context, fermentation route to produce shikimic acid from renewable resources has become increasingly attractive. The present study was embarked upon isolation of wild-type microorganisms able to produce shikimic acid. Out of the 42 isolates obtained from the soil, isolate GR-21 was selected as the best with initial production of 0.54 g/L shikimic acid and later identified as Citrobacter sp. The process optimization resulted in 14-fold increase in the shikimic acid production, thereby claiming this process to be a sustainable alternative for the production of this important biomolecule. The process was further scaled up to 14 L bioreactor to validate the production of shikimic acid. Further, the product formed is shikimic acid was confirmed by FTIR analysis. The current studies suggest that the selected isolate could be used as a promising agent to fulfill the worldwide demand of shikimic acid.
Article
Full-text available
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™).
Article
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.
Article
The antibacterial activity of water-soluble extract from pine needles of Cedrus deodara (WEC) was evaluated on five food-borne bacteria, and its related mechanism was investigated by transmission electron microscope. In vitro antibacterial assay showed that WEC possesses a remarkable antibacterial activity against tested food-borne bacteria including Escherichia coli, Proteus vulgaris, Staphylococcus aureus, Bacillus subtilis and Bacillus cereus, with the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values in the ranges of 0.78-12.5 mg/ml and 1.56-25mg/ml, respectively. In a food system of fresh-squeezed tomato juice, WEC was observed to possess an effective capacity to control the total counts of viable bacteria. Shikimic acid was isolated from WEC and identified as the main antibacterial compound. All results of our study suggested that WEC might be a new potential source of natural antibacterial agents applicable to food.
Article
An alternative biomass-based route to benzoic acid from the renewable starting materials quinic acid and shikimic acid is described. Benzoic acid is obtained selectively using a highly efficient, one-step formic acid-mediated deoxygenation method.
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.
Article
Full-text available
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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