 | |
| Identifiers | |
|---|---|
| |
| CAS Number | |
| PubChem CID | |
| ChemSpider | |
| UNII | |
| CompTox Dashboard (EPA) | |
| Chemical and physical data | |
| Formula | C14H15NO8 |
| Molar mass | 325.273 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
| (verify) | |
Pancratistatin (PST) is a natural compound initially extracted from spider lily, [1] a Hawaiian native plant of the family Amaryllidaceae [2] (AMD).
Pancratistatin occurs naturally in Hawaiian spider lily, a flowering plant within the family Amaryllidaceae. Pancratistatin is mostly found in the bulb tissues of spider lilies. It has been shown that the enrichment of atmospheric CO2 can enhance the production of antiviral secondary metabolites, including pancratistatin, in these plants. [3] Pancratistatin can be isolated from the tropical bulbs of Hymenocallis littoralis in the order of 100 to 150 mg/kg when bulbs are obtained from the wild type in Hawaii. However, the compound has to be commercially extracted from field- and greenhouse-grown bulbs or from tissue cultures cultivated, for example, in Arizona, which generate lower levels of pancratistatin (a maximum of 22 mg/kg) even in the peak month of October. After October, when the bulb becomes dormant, levels of pancratistatin drop, down to only 4 mg/kg by May. Field-grown bulbs, which show monthly changes in pancratistatin content, generate somewhat smaller amounts (2–5 mg/kg) compared to those grown in greenhouses cultivated over the same period. [4] There are about 40 different spider lily species worldwide and they are mainly native to the Andes of South America.
Pancratistatin is thought to have potential as a basis for the development of new pharmaceuticals, [5] particularly in the field of cancer treatment. [6]
Although there may not be a precise elucidation of pancratistatin biological synthesis, there have been speculations on biosynthesis of narciclasine and lycoricidine that are very similar to pancratistatin in terms of structure. The biosynthesis is accomplished via synthesis from O-methylnorbelladine by para-para phenol coupling to obtain vittatine as an intermediate. Subsequent elimination of two carbon atoms and hydroxylations of vittatine then leads to narciclasine. [7]
The first total synthesis [8] of racemic (+/-)-pancratistatin was reported by Samuel Danishefsky and Joung Yon Lee, which involved a very complex and long (40 steps) total synthesis. According to Danishefsky and Joung, there were several weak steps in this synthesis that gave rise to a disappointing low synthetic yield. Amongst the most challenging issues, the Moffatt transposition and the orthoamide problem, which required a blocking maneuver to regiospecifically distinguish the C, hydroxyl group for rearrangement were considered to be the severe cases. However, both Danishevsky and Yon Lee stated that their approach towards the PST total synthesis was not without merit and believed that their work would interest other medicinal scientists to construct a much more practical and efficient way for PST total synthesis. [9] [10]
The work of Danishevsky and Joung provided the foundation for another total synthesis of PST, which was propounded by Li, M. in 2006. This method employed a more sophisticated approach, starting out with pinitol that has stereocenters which are exactly the same as the ones in the C-ring of pancratistatin. [11] Protection of the diol functions of compound 30 gave compound 31. The free hydroxyl of this was subsequently substituted by an azide to give 32. After removal of the silyl function, a cyclic sulfate was installed to obtain product 33. The Staudinger reaction gave the free amine 34 from azide 33. The coupling reaction between 34 and 35 gave compound 36 with a moderate yield. Methoxymethyl protection of both the amide and the free phenol gave compound 37. Treatment of this latter product with t-BuLi followed by addition of cerium chloride gave compound 38. Full deprotection of 38 by BBr3 and methanol afforded pancratistatin 3 in 12 steps from commercially available pinitol with an overall yield of 2.3% 20. [12]
The most recent and shortest synthesis of pancratistatin was accomplished by David Sarlah and co workers, completing the asymmetric synthesis of (+)-pancratistatin and (+)-7-deoxypancratistatin in 7 and 6 steps respectively. [13] The key step of this synthesis was the Nickel catalyzed dearomatization of benzene which directly installed the amine and catachol ring in 98:2 er. Epoxidation then dihydroxylation of the resulting diene afforded the 4 hydroxyl groups. The synthesis was completed by deprotection of the amine and a Cobalt catalyzed CO insertion to furnish the lactam. (+)-7-deoxypancratistatin can then be directly oxidized in a 62% yield to give (+)-pancratistatin. This synthesis yielded multiple grams of the final product which may be essential in the biological evaluation of pancratistatin and analogues.
A very recent approach to a stereocontrolled pancratistatin synthesis was accomplished by Sanghee Kim from the National University of Seoul, in which Claisen rearrangement of dihydropyranethlyene and a cyclic sulfate elimination reaction were employed 21.
The B ring of the phenanthridone (three-membered nitrogen heterocyclic ring) is formed using the Bischler-Napieralski reaction. The n precursor 3 with its stereocenters in the C ring is stereoselectively synthesized from the cis-disubstituted cyclohexene 4. The presence of unsaturated carbonyl in compound 4 suggested the use of a Claisen rearrangement of 3,4-dihydro-2H-pyranylethylene. [14]
The synthesis starts with the treatment of 6 with excess trimethyl phosphate. This reaction provides phosphate 7 in 97% yield. Using the Horner-Wadsworth-Emmons reaction between 7 and acrolein dimmer 8 in the presence of LHMDS in THF forms (E)-olefin 5 with very high stereoselectivity in 60% yield. Only less than 1% of (Z)-olefin was detected in the final product. The Claisen rearrangement of dihydropyranethylene forms the cis-distributed cyclohexene as a single isomer in 78% yield.
The next step of the synthesis involves the oxidation of aldehyde of compound 4 using NaClO2 to the corresponding carboxylic acid 9 in 90% yield. Iodolactonization of 9 and subsequent treatment with DBU in refluxing benzene gives rise to the bicyclic lacytone in 78% yield. Methanolysis of lactone 10 with NaOMe forms a mixture of hydroxyl ester 11 and its C-4a epimer (pancratistatin numbering). Saponification of the methyl ester 11 with LiOH was followed by a Curtius rearrangement of the resulting acid 12 with diphenylphosphoryl azide in refluxing toluene to afford an isocyanate intermediate, treatment of which with NaOMe/MeOH forms the corresponding carbamate 13 in 82% yield.
The next steps of the synthesis involve the regioselective elimination of the C-3 hydroxyl group and subsequent unsaturation achieved by cyclic sulfate elimination. Diol 16 needs to be treated with thionyl chloride and further oxidation with RuCl3 provides the cyclic sulfate 17 in 83% yield. [15] Treatment of cyclic sulfate with DBU yields the desired allylic alcohol 18 (67% yield).
Reaction with OsO4 forms the single isomer 19 in 88% yield. Peracetylation of 19 (77% yield) accompanied by Banwell’s modified Bischler-Napieralski reaction forms the compound 20 with a small amount of isomer 21 ( 7:1 regioselectivity). The removal of protecting groups with NaOMe/MeOH forms pancratistatin in 83%.
The Beckmann rearrangement, named after the German chemist Ernst Otto Beckmann (1853–1923), is a rearrangement of an oxime functional group to substituted amides. The rearrangement has also been successfully performed on haloimines and nitrones. Cyclic oximes and haloimines yield lactams.
A protecting group or protective group is introduced into a molecule by chemical modification of a functional group to obtain chemoselectivity in a subsequent chemical reaction. It plays an important role in multistep organic synthesis.
A sigmatropic reaction in organic chemistry is a pericyclic reaction wherein the net result is one σ-bond is changed to another σ-bond in an uncatalyzed intramolecular reaction. The name sigmatropic is the result of a compounding of the long-established sigma designation from single carbon–carbon bonds and the Greek word tropos, meaning turn. In this type of rearrangement reaction, a substituent moves from one part of a π-bonded system to another part in an intramolecular reaction with simultaneous rearrangement of the π system. True sigmatropic reactions are usually uncatalyzed, although Lewis acid catalysis is possible. Sigmatropic reactions often have transition-metal catalysts that form intermediates in analogous reactions. The most well-known of the sigmatropic rearrangements are the [3,3] Cope rearrangement, Claisen rearrangement, Carroll rearrangement, and the Fischer indole synthesis.
The Bamford–Stevens reaction is a chemical reaction whereby treatment of tosylhydrazones with strong base gives alkenes. It is named for the British chemist William Randall Bamford and the Scottish chemist Thomas Stevens Stevens (1900–2000). The usage of aprotic solvents gives predominantly Z-alkenes, while protic solvent gives a mixture of E- and Z-alkenes. As an alkene-generating transformation, the Bamford–Stevens reaction has broad utility in synthetic methodology and complex molecule synthesis.
The Claisen rearrangement is a powerful carbon–carbon bond-forming chemical reaction discovered by Rainer Ludwig Claisen. The heating of an allyl vinyl ether will initiate a [3,3]-sigmatropic rearrangement to give a γ,δ-unsaturated carbonyl, driven by exergonically favored carbonyl CO bond formation (Δ = −327 kcal/mol.
The Reformatsky reaction is an organic reaction which condenses aldehydes or ketones with α-halo esters using metallic zinc to form β-hydroxy-esters:
In stereochemistry, a chiral auxiliary is a stereogenic group or unit that is temporarily incorporated into an organic compound in order to control the stereochemical outcome of the synthesis. The chirality present in the auxiliary can bias the stereoselectivity of one or more subsequent reactions. The auxiliary can then be typically recovered for future use.
Silyl ethers are a group of chemical compounds which contain a silicon atom covalently bonded to an alkoxy group. The general structure is R1R2R3Si−O−R4 where R4 is an alkyl group or an aryl group. Silyl ethers are usually used as protecting groups for alcohols in organic synthesis. Since R1R2R3 can be combinations of differing groups which can be varied in order to provide a number of silyl ethers, this group of chemical compounds provides a wide spectrum of selectivity for protecting group chemistry. Common silyl ethers are: trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS/TBDMS) and triisopropylsilyl (TIPS). They are particularly useful because they can be installed and removed very selectively under mild conditions.
The Danishefsky Taxol total synthesis in organic chemistry is an important third Taxol synthesis published by the group of Samuel Danishefsky in 1996 two years after the first two efforts described in the Holton Taxol total synthesis and the Nicolaou Taxol total synthesis. Combined they provide a good insight in the application of organic chemistry in total synthesis.
The Holton Taxol total synthesis, published by Robert A. Holton and his group at Florida State University in 1994, was the first total synthesis of Taxol.
The article concerns the total synthesis of galanthamine, a drug used for the treatment of mild to moderate Alzheimer's disease.
The Rubottom oxidation is a useful, high-yielding chemical reaction between silyl enol ethers and peroxyacids to give the corresponding α-hydroxy carbonyl product. The mechanism of the reaction was proposed in its original disclosure by A.G. Brook with further evidence later supplied by George M. Rubottom. After a Prilezhaev-type oxidation of the silyl enol ether with the peroxyacid to form the siloxy oxirane intermediate, acid-catalyzed ring-opening yields an oxocarbenium ion. This intermediate then participates in a 1,4-silyl migration to give an α-siloxy carbonyl derivative that can be readily converted to the α-hydroxy carbonyl compound in the presence of acid, base, or a fluoride source.
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 and from recombinant E. coli. Control of stereochemistry is important: the molecule has three stereocenters and the sought-after isomer is only 1 of 8 stereoisomers.
NanoPutians are a series of organic molecules whose structural formulae resemble human forms. James Tour's research group designed and synthesized these compounds in 2003 as a part of a sequence on chemical education for young students. The compounds consist of two benzene rings connected via a few carbon atoms as the body, four acetylene units each carrying an alkyl group at their ends which represents the hands and legs, and a 1,3-dioxolane ring as the head. Tour and his team at Rice University used the NanoPutians in their NanoKids educational outreach program. The goal of this program was to educate children in the sciences in an effective and enjoyable manner. They have made several videos featuring the NanoPutians as anthropomorphic animated characters.
Larry E. Overman is Distinguished Professor of Chemistry at the University of California, Irvine. He was born in Chicago in 1943. Overman obtained a B.A. degree from Earlham College in 1965, and he completed his Ph.D. in chemistry from the University of Wisconsin–Madison in 1969, under Howard Whitlock Jr. Professor Overman is a member of the United States National Academy of Sciences and the American Academy of Arts and Sciences. He was the recipient of the Arthur C. Cope Award in 2003, and he was awarded the Tetrahedron Prize for Creativity in Organic Chemistry for 2008.
The Fleming–Tamao oxidation, or Tamao–Kumada–Fleming oxidation, converts a carbon–silicon bond to a carbon–oxygen bond with a peroxy acid or hydrogen peroxide. Fleming–Tamao oxidation refers to two slightly different conditions developed concurrently in the early 1980s by the Kohei Tamao and Ian Fleming research groups.
Strychnine total synthesis in chemistry describes the total synthesis of the complex biomolecule strychnine. The first reported method by the group of Robert Burns Woodward in 1954 is considered a classic in this research field.
RTI(-4229)-274, or 2β-( methyl)-3α-(4-fluorophenyl)
2-Cyclopentenone is the organic compound with the chemical formula (CH2)2(CH)2CO. 2-Cyclopentenone contains two functional groups, a ketone and an alkene. It is a colorless liquid. Its isomer, 3-cyclopentenone is less commonly encountered.
Rearrangements, especially those that can participate in cascade reactions, such as the aza-Cope rearrangements, are of high practical as well as conceptual importance in organic chemistry, due to their ability to quickly build structural complexity out of simple starting materials. The aza-Cope rearrangements are examples of heteroatom versions of the Cope rearrangement, which is a [3,3]-sigmatropic rearrangement that shifts single and double bonds between two allylic components. In accordance with the Woodward-Hoffman rules, thermal aza-Cope rearrangements proceed suprafacially. Aza-Cope rearrangements are generally classified by the position of the nitrogen in the molecule :
