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Encyclopedia > Oseltamivir total synthesis
Oseltamivir

Oseltamivir total synthesis concerns the total synthesis of the antiinfluenza drug oseltamivir marketed by Hoffmann-La Roche under the trade name Tamiflu. Its commercial production starts from the biomolecule shikimic acid harvested from Chinese star anise with a limited worldwide supply. Therefore the hunt is on for alternative synthetic routes preferably skipping shikimic acid and to date several such routes have been published. Control of stereochemistry is important: the molecule has three stereocenters and the sought-after isomer is only 1 of 8 stereoisomers. Image File history File links Size of this preview: 722 × 599 pixel Image in higher resolution (1100 × 913 pixel, file size: 195 KB, MIME type: image/png) File links The following pages on the English Wikipedia link to this file (pages on other projects are not listed): Oseltamivir Oseltamivir total... A total synthesis is the complete chemical synthesis of complex organic molecules from simple, commercially available (petrochemical) precursors. ... Oseltamivir (INN) (IPA: ) is an antiviral drug that is used in the treatment and prophylaxis of both Influenzavirus A and Influenzavirus B. Like zanamivir, oseltamivir is a neuraminidase inhibitor. ... Hoffmann-La Roche, Ltd. ... A trade name, also known as a trading name or a business name, is the legal name of a business, or the name which a business trades under for commercial purposes. ... ... Shikimic acid, more commonly known as its anionic form shikimate, is an important biochemical intermediate in plants and microorganisms. ... Binomial name Illicium verum Hook. ... A stereocenter in organic chemistry generally refers to a carbon atom in a chemical compound that has four different types of atoms or groups of atoms attached to it. ...

Contents

Commercial production

The current production method is based on research by Gilead Sciences [1] [2] starting from naturally occurring quinic acid and that of Hoffmann-La Roche [3] starting from shikimic acid. Gilead Sciences NASDAQ: GILD is a biopharmaceutical company that discovers, develops and commercializes therapeutics to advance the care of patients suffering from life-threatening diseases, principally HIV, hepatitis B and influenza. ... Quinic acid, C7H12O6 is a crystalline acid obtained from cinchona bark, coffee beans, and other plant products and made synthetically by hydrolysis of chlorogenic acid. ... Hoffmann-La Roche, Ltd. ... Shikimic acid, more commonly known as its anionic form shikimate, is an important biochemical intermediate in plants and microorganisms. ...


Karpf / Trussardi synthesis

The current production method includes two reaction steps with potentially hazardous azides. A reported azide-free Roche synthesis of tamiflu is summarised graphically below [4]: An azide is the N3- anion, the anion of hydrazoic acid or a reactive group in organic chemistry where a carbon substituent is attached as RN3. ...

The synthesis commences from naturally available (−)-shikimic acid. The 3,4-pentylidene acetal mesylate is prepared in three steps: esterification with ethanol and thionyl chloride; ketalization with p-toluenesulfonic acid and 3-pentanone; and mesylation with triethylamine and methanesulfonyl chloride. Reductive opening of the ketal under modified Hunter conditions (JOC 1993, 58, 6756) in dichloromethane yields an inseparable mixture of isomeric mesylates. The corresponding epoxide is formed under basic conditions with potassium bicarbonate. Using the inexpensive Lewis acid magnesium bromide diethyl etherate (commonly prepared fresh by the addition of magnesium turnings to 1,2-dibromoethane in benzene:diethyl ether), the epoxide is opened with allyl amine to yield the corresponding 1,2-amino alcohol. The water-immiscible solvents methyl tert-butyl ether and acetonitrile are used to simplify the workup procedure, which involved stirring with 1 M aqueous ammonium sulfate. Reduction on palladium, promoted by ethanolamine, followed by acidic workup yielded the deprotected 1,2-aminoalcohol. The aminoalcohol was converted directly to the corresponding allyl-diamine in an interesting cascade sequence that commences with the unselective imination of benzaldehyde with azeotropic water removal in methyl tert-butyl ether. Mesylation, followed by removal of the solid byproduct triethylamine hydrochloride, results in an intermediate that was poised to undergo aziridination upon transimination with another equivalent of allylamine. With the librated methanesulfonic acid, the aziridine opens cleanly to yield a diamine that immediately undergoes a second transimination. Acidic hydrolysis then removed the imine. Selective acylation with acetic anhydride (under buffered conditions, the 5-amino group is protonated owing to a considerable difference in pKa, 4.2 vs 7.9, preventing acetylation) yields the desired N-acetylated product in crystalline form upon extractive workup. Finally, deallylation as above, yielded the freebase of oseltamivir, which was converted to the desired oseltamivir phosphate by treatment with phosphoric acid. The final product is obtained in high purity (99.7%) and an overall yield of 17-22% from (−)-shikimic acid. It is noted that the synthesis avoids the use of potentially explosive azide reagents and intermediates; however, the synthesis actually used by Roche uses azides. Roche has other routes to oseltamivir that do not involve the use of (−)-shikimic acid as a chiral pool starting material, such as a Diels-Alder route involving furan and ethyl acrylate or an isophthalic acid route, which involves catalytic hydrogenation and enzymatic desymmetrization. Image File history File links Download high resolution version (695x1015, 39 KB) Summary redrawn by me from references Licensing Patented Material is not for commercial uses. ... Shikimic acid, more commonly known as its anionic form shikimate, is an important biochemical intermediate in plants and microorganisms. ... In chemistry, mesylate is salt (or seldom an ester) of methanesulfonic acid CH3SO3H. In salts is present as CH3SO3- anion, which is also called mesylate. ... Esterification is the general name for a chemical reaction in which two chemicals (typically an alcohol and an acid) form an ester as the reaction product. ... Ethanol, also known as ethyl alcohol, drinking alcohol or grain alcohol, is a flammable, colorless, slightly toxic chemical compound with a distinctive perfume-like odor, and is the alcohol found in alcoholic beverages. ... R-phrases , , , S-phrases , , , Flash point non flammable Supplementary data page Structure and properties n, εr, etc. ... An ketal is a functional group or molecule containing the functional group of a carbon bonded to two -OR groups. ... Tosyl Group with a generic R Group attached (where R can be anything, typically a carbon). ... 3-Pentanone, also known as diethyl ketone, is a colorless liquid ketone with an odor like that of acetone. ... Triethylamine, also known as N,N-diethylethanamine, TEN or N,N,N-Triethylamine, is a colorless, volatile liquid with a strong, unpleasant and fishy smell reminiscent of ammonia. ... An ketal is a functional group or molecule containing the functional group of a carbon bonded to two -OR groups. ... Dichloromethane or Methylene chloride is a chemical compound widely used as a solvent for organic materials. ... In chemistry, isomers are molecules with the same chemical formula and often with the same kinds of bonds between atoms, but in which the atoms are arranged differently. ... An epoxide is a cyclic ether with only three ring atoms. ... Potassium bicarbonate (also known as potassium hydrogen carbonate or potassium acid carbonate), is a colorless, odorless, slightly basic, salty substance. ... In chemistry, a Lewis acid can accept a pair of electrons and form a coordinate covalent bond, after the American chemist Gilbert Lewis. ... General Name, Symbol, Number magnesium, Mg, 12 Chemical series alkaline earth metals Group, Period, Block 2, 3, s Appearance silvery white Atomic mass 24. ... 1,2-Dibromoethane is a manufactured chemical. ... Benzene, also known as benzol, is an organic chemical compound with the formula C6H6. ... Diethyl ether, also known as ether and ethoxyethane, is a clear, colorless, and highly flammable liquid with a low boiling point and a characteristic smell. ... Allylamine (also known as 3-aminopropene, 3-aminopropylene, monoallylamine, 2-propenamine, 2-propen-1-amine, or allyl amine) is an organic amine with the molecular formula C3H7N. It is a highly toxic and flammable colorless liquid. ... For other uses, see Solvent (disambiguation). ... MTBE is highly flammable and is widely used as an oxygenate. ... Acetonitrile is an organic molecule, often used as a solvent, with the chemical formula of CH3CN. Also known as methyl cyanide, it is the simplest of the organic nitriles. ... Ammonium sulphate, [NH4]2[SO4] contains 21% nitrogen as ammonia and 24% sulfur as sulfate. ... General Name, Symbol, Number palladium, Pd, 46 Chemical series transition metals Group, Period, Block 10, 5, d Appearance silvery white metallic Atomic mass 106. ... Ethanolamine, or 2-Amino ethanol, is a toxic flammable corrosive colorless viscous liquid with an odor similar to ammonia. ... The chemical compound benzaldehyde (C6H5CHO) consists of a benzene ring with an aldehyde group attached to one carbon. ... An azeotrope is a liquid mixture of two or more components which has a unique constant boiling point. ... Triethylamine, also known as N,N-diethylethanamine, TEN or N,N,N-Triethylamine, is a colorless, volatile liquid with a strong, unpleasant and fishy smell reminiscent of ammonia. ... In chemistry, hydrochlorides are salts resulting, or regarded as resulting, from the reaction of hydrochloric acid with an organic base (mostly amines). ... It has been suggested that Sulfonic acid/Temp be merged into this article or section. ... Aziridine parent compound Aziridines are a group of organic compounds sharing the aziridine functional group which is a three membered heterocycle with one amine group and two methylene groups 1,2. ... Hydrolysis is a chemical reaction or process in which a molecule is split into two parts by reacting with a molecule of water, which has the chemical formula H2O. One of the parts gets an OH- from the water molecule and the other part gets an H+ from the water. ... An imine is a functional group or chemical compound containing a carbon-nitrogen double bond. ... In chemistry, acylation is the process of adding an acyl group to a compound. ... Acetic anhydride, also known as ethanoic anhydride, is one of the simplest of acid anhydrides. ... Acids and bases: Acid-base reaction theories pH Self-ionization of water Buffer solutions Systematic naming Electrochemistry Acids: Strong acids Weak acids Bases: Strong bases Weak bases edit Buffer solutions are solutions which resist change in hydronium ion and the hydroxide ion concentration (and consequent pH) upon addition of small... Protonation is the addition of a proton (H+) to an atom, molecule, or ion. ... In chemistry and biochemistry, the acid dissociation constant, the acidity constant, or the acid-ionization constant (Ka) is a specific type of equilibrium constant that indicates the extent of dissociation of hydronium ions from an acid. ... Acetylation describes a reaction, usually with acetic acid, that introduces an acetyl functional group into an organic compound. ... Freebase refers to the standalone basic form of an alkaloid, as opposed to its water-soluble salt form. ... Phosphoric acid, also known as orthophosphoric acid or phosphoric(V) acid, is an inorganic mineral acid having the chemical formula H3PO4. ... An azide is the N3- anion, the anion of hydrazoic acid or a reactive group in organic chemistry where a carbon substituent is attached as RN3. ...


Corey synthesis

In 2006 the group of E.J. Corey published a novel route bypassing shikimic acid starting from butadiene and acrylic acid [5]. The inventors choose not to patent this procedure which is described below. Strictly speaking the synthesis is a formal total synthesis, as the final product to be characterized was the BOC-derivative (14 in the scheme below). Elias James Corey (born July 12, 1928) is an American organic chemist. ... Butadiene can refer to either one of two hydrocarbon chemical compounds which are alkenes that are isomers of each other. ... Acrylic acid or prop-2-enoic acid is a chemical compound with the formula C3H4O2 and structure (which is sometimes abbreviated as CH2=CHCOOH). ... A patent is a set of exclusive rights granted by a state to a patentee (the inventor or assignee) for a fixed period of time in exchange for the regulated, public disclosure of certain details of a device, method, process or composition of matter (substance) (known as an invention) which...

Butadiene 1 reacts in an asymmetric Diels-Alder reaction with the esterfication product of acrylic acid and 2,2,2-Trifluoroethanol 2 catalysed by the CBS catalyst. The ester 3 is converted into an amide in 4 by reaction with ammonia and the next step to lactam 5 is an iodolactamization with iodine initiated by trimethylsilyltriflate. The amide group is fitted with a BOC protective group by reaction with Boc anhydride in 6 and the iodine substituent is removed in an elimination reaction with DBU to the alkene 7. Bromine is introduced in 8 by an allylic bromination with NBS and the amide group is cleaved with ethanol and caesium carbonate accompanied by elimination of bromide to the diene ethyl ester 9. The newly formed double bond is functionalized with N-bromoacetamide 10 catalyzed with Tin(IV) bromide with complete control of stereochemistry. In the next step the bromine atom in 11 is displaced by the nitrogen atom in the amide group with the strong base KHMDS to the aziridine 12 which in turn is opened by reaction with 3-pentanol 13 to the ether 14. In the final step the BOC group is removed with phosphoric acid and the oseltamivir phosphate 15 is formed. Image File history File links Download high resolution version (1043x745, 18 KB) Summary Corey oseltamivir synthesis Licensing I, the creator of this work, hereby grant the permission to copy, distribute and/or modify this document under the terms of the GNU Free Documentation License, Version 1. ... Butadiene can refer to either one of two hydrocarbon chemical compounds which are alkenes that are isomers of each other. ... This article or section does not adequately cite its references or sources. ... The Diels-Alder reaction The Diels-Alder reaction is an organic chemical reaction (specifically, a cycloaddition) between a conjugated diene and a substituted alkene, commonly termed the dienophile, to form a substituted cyclohexene system. ... Esterification is the general name for a chemical reaction in that an ester is the reaction product. ... Acrylic acid or prop-2-enoic acid is a chemical compound with the formula C3H4O2 and structure (which is sometimes abbreviated as CH2=CHCOOH). ... 2,2,2-Trifluoroethanol (TFE) or trifluoroethyl alcohol is a trifluoro substituted alcohol. ... The CBS catalyst or Corey-Bakshi-Shibata catalyst is an asymmetric catalyst derived from proline. ... General formula of a carboxylate ester. ... Amide functional group In chemistry, an amide is one of two kinds of compounds: - the organic functional group characterized by a carbonyl group (C=O) linked to a nitrogen atom (N), or a compound that contains this functional group (pictured to the right); or - a particular kind of nitrogen anion. ... Ammonia is a compound with the formula NH3. ... A lactam (the noun is a portmanteau of the wods lactone + amide) is a cyclic amide. ... A lactam (the noun is a grammatical blend from lactone + amide) is a cyclic amide. ... General Name, Symbol, Number iodine, I, 53 Chemical series halogens Group, Period, Block 17, 5, p Appearance violet-dark gray, lustrous Atomic mass 126. ... A Protecting group or protective group is introduced into a molecule by chemical modification of a functional group in order to obtain chemoselectivity in a subsequent chemical reaction. ... Di-tert-butyl dicarbonate or boc anhydride is a carbonate ester and a reagent in organic chemistry. ... An elimination reaction is a type of organic reaction in which two substituents are removed from a molecule in either a one or two-step mechanism. ... DBU or 1,8-diazabicyclo(5. ... The chemical structure of ethylene, the simplest alkene. ... Flash point None R/S statement R: ? S: ? RTECS number  ? Supplementary data page Structure and properties n, εr, etc. ... Ethanol, also known as ethyl alcohol, drinking alcohol or grain alcohol, is a flammable, colorless, slightly toxic chemical compound with a distinctive perfume-like odor, and is the alcohol found in alcoholic beverages. ... Caesium carbonate (or cesium carbonate in the US) is a white crystalline solid of formula Cs2CO3. ... acetamide Acetamide (or Acetic acid amide or Ацетамид) CH3CONH2, the amide of acetic acid, is a white crystalline solid in pure form. ... The different types of isomers. ... In chemistry, nucleophilic substitution is a class of substitution reaction in which an electron-rich nucleophile attacks a molecule and replaces a group or atom, called the leaving group. ... The chemical compound sodium bis(trimethylsilyl)amide is a strong base used for deprotonation reactions or base catalyzed reaction. ... Aziridine parent compound Aziridines are a group of organic compounds sharing the aziridine functional group which is a three membered heterocycle with one amine group and two methylene groups 1,2. ... Ether is the general name for a class of chemical compounds which contain an ether group — an oxygen atom connected to two (substituted) alkyl groups. ... Phosphoric acid, also known as orthophosphoric acid or phosphoric(V) acid, is an inorganic mineral acid having the chemical formula H3PO4. ...


Shibasaki Synthesis

Shibasaki Tamiflu SynthesisPart I
Shibasaki Tamiflu SynthesisPart II

Also in 2006 the group of Masakatsu Shibasaki of the University of Tokyo published a synthesis again bypassing shikimic acid [6] [7]. The University of Tokyo ), abbreviated as Todai ), is one of the leading research universities in Japan. ...



An improved method published in 2007 starts with the enantioselective desymmetrization of aziridine 1 with trimethylsilyl azide (TMSN3) and a chiral catalyst to the azide 2. The amide group is protected as a BOC group with Boc anhydride and DMAP in 3 and iodolactamization with iodine and potassium carbonate first gives the unstable intermediate 4 and then stable cyclic carbamate 5 after elimination of hydrogen iodide with DBU. In chemistry two stereoisomers are said to be enantiomers if one can be superimposed on the mirror image of the other. ... Desymmetrization in stereochemistry is the modification of a molecule which results in the loss of one or more symmetry elements, such as those which rise to chirality (a mirror plane, center of inversion, rotation-reflection axis), as in the conversion of a prochiral molecular entity into a chiral one [1... Aziridine parent compound Aziridines are a group of organic compounds sharing the aziridine functional group which is a three membered heterocycle with one amine group and two methylene groups 1,2. ... An azide is the N3- anion, the anion of hydrazoic acid or a reactive group in organic chemistry where a carbon substituent is attached as RN3. ... Amide functional group In chemistry, an amide is one of two kinds of compounds: - the organic functional group characterized by a carbonyl group (C=O) linked to a nitrogen atom (N), or a compound that contains this functional group (pictured to the right); or - a particular kind of nitrogen anion. ... Di-tert-butyl dicarbonate or boc anhydride is a carbonate ester and a reagent in organic chemistry. ... Chemical structure of DMAP 4-Dimethylaminopyridine, abbreviated as DMAP, is an acetylation catalyst with reagents such as Acetyl chloride or Acetic anhydride that is much stronger than pyridine or triethylamine . ... A lactam (the noun is a grammatical blend from lactone + amide) is a cyclic amide. ... General Name, Symbol, Number iodine, I, 53 Chemical series halogens Group, Period, Block 17, 5, p Appearance violet-dark gray, lustrous Atomic mass 126. ... Carbonate of potash redirects here. ... Carbamates are a group of organic compounds sharing a common functional group with the general structure -NH(CO)O-. More precisely the carbamate group is considered an amide group with an alkoxy or hydroxy functional group next to the carbonyl group. ... An elimination reaction is a type of organic reaction in which two substituents are removed from a molecule in either a one or two-step mechanism. ... Hydrogen iodide is a compound of hydrogen and iodine. ... DBU or 1,8-diazabicyclo(5. ...


The amide group is reprotected as BOC 6 and the azide group converted to the amide 7 by reductive acylation with thioacetic acid and 2,6-lutidine. Caesium carbonate accomplishes the hydrolysis of the carbamate group to the alcohol 8 which is subsequently oxidized to ketone 9 with Dess-Martin periodinane. Cyanophosphorylation with diethyl phosphorocyanidate (DEPC) modifies the ketone group to the cyanophosphate 10 paving the way for an intramolecular allylic rearrangement to unstable β-allyl phosphate 11 (toluene, sealed tube) which is hydrolyzed to alcohol 12 with ammonium chloride. This hydroxyl group has the wrong stereochemistry and is therefore inverted in a Mitsunobu reaction with p-nitrobenzoic acid followed by hydrolysis of the p-nitrobenzoate to 13. Caesium carbonate (or cesium carbonate in the US) is a white crystalline solid of formula Cs2CO3. ... Hydrolysis is a chemical reaction or process in which a molecule is split into two parts by reacting with a molecule of water, which has the chemical formula H2O. One of the parts gets an OH- from the water molecule and the other part gets an H+ from the water. ... Functional group of an alcohol molecule. ... Ketone group A ketone is either the functional group characterized by a carbonyl group linked to two other carbon atoms or a chemical compound that contains this functional group. ... The Dess-Martin periodinane is a chemical reagent used to oxidize alcohols to aldehydes and ketones. ... Intramolecular describes a process or characteristic limited within the structure of a single, or each molecule; a property or phenomenon limited to the extent of a single, or each molecule. ... A allylic rearrangement or allylic shift is a organic reaction in which the double bond in an allyl chemical compound shifts to the next carbon atom. ... An organophosphate (sometimes abbreviated OP) is the general name for esters of phosphoric acid and is one of the organophosphorus compounds. ... Ammonium chloride or Sal Ammoniac (chemically ammonium chloride (NH4Cl); also nushadir salt, zalmiak, sal armagnac, sal armoniac, salmiakki, salmiak and salt armoniack) is, in its pure form, a clear white water-soluble crystalline salt with a biting taste. ... The Mitsunobu reaction is an organic reaction that can convert an alcohol into a variety of functional groups, such as esters using triphenylphosphine and diethyl azodicarboxylate (DEAD). ...


A second Mitsunobu reaction then forms the aziridine 14 available for ring-opening reaction with 3-pentanol catalyzed by boron trifluoride to ether 15. In the final step the BOC group is removed (HCl) and phosphoric acid added to objective 16. Aziridine parent compound Aziridines are a group of organic compounds sharing the aziridine functional group which is a three membered heterocycle with one amine group and two methylene groups 1,2. ... Boron trifluoride (BF3, trifluoroborane) is a pungent colourless toxic gas. ... Phosphoric acid, also known as orthophosphoric acid or phosphoric(V) acid, is an inorganic mineral acid having the chemical formula H3PO4. ...


References

  1. ^ Influenza Neuraminidase Inhibitors Possessing a Novel Hydrophobic Interaction in the Enzyme Active Site: Design, Synthesis, and Structural Analysis of Carbocyclic Sialic Acid Analogues with Potent Anti-Influenza Activity Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H.; Zhang, L.; Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Mendel, D. B.; Tai, C. Y.; Laver, W. G.; Stevens, R. C. J. Am. Chem. Soc.; (Article); 1997; 119(4); 681-690. DOI:10.1021/ja963036t
  2. ^ Practical Total Synthesis of the Anti-Influenza Drug GS-4104 John C. Rohloff, Kenneth M. Kent, Michael J. Postich, Mark W. Becker, Harlan H. Chapman, Daphne E. Kelly, Willard Lew, Michael S. Louie, Lawrence R. McGee, Ernest J. Prisbe, Lisa M. Schultze, Richard H. Yu, and Lijun Zhang J. Org. Chem.; 1998; 63(13) pp 4545 - 4550; (Note) DOI:10.1021/jo980330q.
  3. ^ Abrecht, S.; Harrington, P.; Iding, H.; Karpf, M.; Trussardi, R.; Wirz, B.; Zutter, U. Chimia 2004, 58, 621.
  4. ^ New, Azide-Free Transformation of Epoxides into 1,2-Diamino Compounds: Synthesis of the Anti-Influenza Neuraminidase Inhibitor Oseltamivir Phosphate (Tamiflu) Martin Karpf and René Trussardi J. Org. Chem.; 2001; 66(6) pp 2044 - 2051; (Article) DOI:10.1021/jo005702l.
  5. ^ A Short Enantioselective Pathway for the Synthesis of the Anti-Influenza Neuramidase Inhibitor Oseltamivir from 1,3-Butadiene and Acrylic Acid Ying-Yeung Yeung, Sungwoo Hong, and E. J. Corey J. Am. Chem. Soc.; 2006; 128(19) pp 6310 - 6311; (Communication) DOI:10.1021/ja0616433
  6. ^ De Novo Synthesis of Tamiflu via a Catalytic Asymmetric Ring-Opening of meso-Aziridines with TMSN3 Yuhei Fukuta, Tsuyoshi Mita, Nobuhisa Fukuda, Motomu Kanai, and Masakatsu Shibasaki J. Am. Chem. Soc.; 2006; 128(19) pp 6312 - 6313; DOI:10.1021/ja061696k
  7. ^ Second Generation Catalytic Asymmetric Synthesis of Tamiflu: Allylic Substitution Route Tsuyoshi Mita, Nobuhisa Fukuda, Francesc X. Roca, Motomu Kanai, and Masakatsu Shibasaki Org. Lett.; 2007; 9(2) pp 259 - 262; (Letter) DOI:10.1021/ol062663c

 
 

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