Endiandric acid C, isolated from the tree '' Endiandra introrsa'', is a well characterized

chemical compound A chemical compound is a chemical substance composed of many identical molecules (or molecular entities) containing atoms from more than one chemical element held together by chemical bonds. A molecule consisting of atoms of only one element ...

. Endiadric acid C is reported to have better

antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...

activity than

ampicillin Ampicillin is an antibiotic used to prevent and treat a number of bacterial infections, such as respiratory tract infections, urinary tract infections, meningitis, salmonellosis, and endocarditis. It may also be used to prevent group B strepto ...

. This genus of trees is in the family

Lauraceae Lauraceae, or the laurels, is a plant family that includes the true laurel and its closest relatives. This family comprises about 2850 known species in about 45 genera worldwide (Christenhusz & Byng 2016 ). They are dicotyledons, and occur ma ...

. These trees are found in the north-eastern Australian

rainforest Rainforests are characterized by a closed and continuous tree canopy, moisture-dependent vegetation, the presence of epiphytes and lianas and the absence of wildfire. Rainforest can be classified as tropical rainforest or temperate rainfores ...

s and other

tropical The tropics are the regions of Earth surrounding the Equator. They are defined in latitude by the Tropic of Cancer in the Northern Hemisphere at N and the Tropic of Capricorn in the Southern Hemisphere at S. The tropics are also referred to ...

and

subtropical The subtropical zones or subtropics are geographical zone, geographical and Köppen climate classification, climate zones to the Northern Hemisphere, north and Southern Hemisphere, south of the tropics. Geographically part of the Geographical z ...

regions. However, they are also found in southern

Canada Canada is a country in North America. Its ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, covering over , making it the world's second-largest country by tot ...

and in

Chile Chile, officially the Republic of Chile, is a country in the western part of South America. It is the southernmost country in the world, and the closest to Antarctica, occupying a long and narrow strip of land between the Andes to the east a ...

. Endiandric acid C is also isolated from the species ''E. xanthocarpa''. Endiandric acids are also found in ''

Beilschmiedia ''Beilschmiedia'' is a genus of trees and shrubs in family Lauraceae. Most of its species grow in tropical climates, but a few of them are native to temperate regions, and they are widespread in tropical Asia, Africa, Madagascar, Australia, N ...

'' trees, which were categorized under the genus ''Endiandra'', but moved to their own genus as they found in cold, high

latitude In geography, latitude is a coordinate that specifies the north– south position of a point on the surface of the Earth or another celestial body. Latitude is given as an angle that ranges from –90° at the south pole to 90° at the north pol ...

areas, and even in

New Zealand New Zealand ( mi, Aotearoa ) is an island country in the southwestern Pacific Ocean. It consists of two main landmasses—the North Island () and the South Island ()—and over 700 smaller islands. It is the sixth-largest island count ...

. Other endiandric acids are found in ''B. oligandra'' and ''B. anacardioides'', which are found in the Western Province of

Cameroon Cameroon (; french: Cameroun, ff, Kamerun), officially the Republic of Cameroon (french: République du Cameroun, links=no), is a country in west-central Africa. It is bordered by Nigeria to the west and north; Chad to the northeast; the C ...

Bioactivity

This compound has the best antibacterial activity of Endiandrianic acid A-G compounds. Endiandric acid C was tested towards five strains of

bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...

, which included ''

Bacillus subtilis ''Bacillus subtilis'', known also as the hay bacillus or grass bacillus, is a Gram-positive, catalase-positive bacterium, found in soil and the gastrointestinal tract of ruminants, humans and marine sponges. As a member of the genus ''Bacillu ...

'', '' Micococcus luteus'', ''

Streptococcus faecalis ''Enterococcus faecalis'' – formerly classified as part of the group D ''Streptococcus'' system – is a Gram-positive, commensal bacterium inhabiting the gastrointestinal tracts of humans. Like other species in the genus ''Enterococcus'', ''E ...

'', '' Pseudomonas palida'', and ''

Escherichia coli ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...

'' through examining zone inhibition and minimum concentration, which was found to range between 0.24 µg/mL and 500 µg/mL. Endiandric acid C has also been used to cure uterine tumors,

rubella Rubella, also known as German measles or three-day measles, is an infection caused by the rubella virus. This disease is often mild, with half of people not realizing that they are infected. A rash may start around two weeks after exposure and ...

, and female genital infections, and

rheumatism Rheumatism or rheumatic disorders are conditions causing chronic, often intermittent pain affecting the joints or connective tissue. Rheumatism does not designate any specific disorder, but covers at least 200 different conditions, including art ...

Biosynthesis

Many

biochemist Biochemists are scientists who are trained in biochemistry. They study chemical processes and chemical transformations in living organisms. Biochemists study DNA, proteins and Cell (biology), cell parts. The word "biochemist" is a portmanteau of ...

s predicted when examining

K. C. Nicolaou Kyriacos Costa Nicolaou ( el, Κυριάκος Κ. Νικολάου; born July 5, 1946) is a Cypriot-American chemist known for his research in the area of natural products total synthesis. He is currently Harry C. and Olga K. Wiess Professor of ...

biomimetic synthesis Biomimetic synthesis is an area of organic chemical synthesis that is specifically biologically inspired. The term encompasses both the testing of a "biogenetic hypothesis" (''conjectured'' course of a biosynthesis in nature) through execution of ...

of the endiandric acid cascade that

enzymes Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...

aided this

reaction Reaction may refer to a process or to a response to an action, event, or exposure: Physics and chemistry *Chemical reaction *Nuclear reaction *Reaction (physics), as defined by Newton's third law *Chain reaction (disambiguation). Biology and me ...

in the

biosynthesis Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. ...

. The biomimetic series determined that this process took place synthetically through a series of Diels-Alder cyclization reactions and therefore led researches to believe that Diels-Alderase assisted the formation of endiandric acid C. Although it has been discovered since then that many famous cyclization reactions like that of

lovastatin Lovastatin, sold under the brand name Mevacor among others, is a statin medication, to treat hypercholesterolemia, high blood cholesterol and reduce the risk of cardiovascular disease. Its use is recommended together with lifestyle changes. It ...

do result from the Diels-Alderase they have determine that the endiandric acid cascade does not involve enzymes but rather spontaneously undergoes ring formation from a derivative of bisnoryangonin 5, which results from both the

shikimate Shikimic acid, more commonly known as its anionic form shikimate, is a cyclohexene, a cyclitol and a cyclohexanecarboxylic acid. It is an important biochemical metabolite in plants and microorganisms. Its name comes from the Japanese flower ''sh ...

and acetic pathways. The 4-hydroxycinnamoyl-CoA, compound 2, is the precursor that comes from the shikimate pathway. Two units of

malonyl CoA Malonyl-CoA is a coenzyme A derivative of malonic acid. Functions It plays a key role in chain elongation in fatty acid biosynthesis and polyketide biosynthesis. Fatty acid biosynthesis Malonyl-CoA provides 2-carbon units to fatty acids and commi ...

are then added to through the acetate pathway 3. Compound 3 is then reduced to the di-

enol In organic chemistry, alkenols (shortened to enols) are a type of reactive structure or intermediate in organic chemistry that is represented as an alkene ( olefin) with a hydroxyl group attached to one end of the alkene double bond (). The te ...

form that tautomerizes to give the bisnoryangonin 5. A small amount of compound 5 can be isolated, however ''S''-adenosyl methionine methylates most of it and gives

yangonin Yangonin is one of the six major kavalactones found in the kava plant. It has been shown to possess binding affinity for the cannabinoid receptor CB1 (Ki = 0.72 μM), and selectivity vs. the CB2 receptor (Ki >10 μM) where it behaves as an ago ...

6. It has been proposed that a bisnoryangonin derivative 7, is then reduced by

dehydrogenase A dehydrogenase is an enzyme belonging to the group of oxidoreductases that oxidizes a substrate by reducing an electron acceptor, usually NAD+/NADP+ or a flavin coenzyme such as FAD or FMN. Like all catalysts, they catalyze reverse as well as f ...

to give the

polyene In organic chemistry, polyenes are poly- unsaturated, organic compounds that contain at least three alternating double () and single () carbon–carbon bonds. These carbon–carbon double bonds interact in a process known as conjugation, resultin ...

precursor 8, that goes through spontaneous 8π conrotatory, 6π disrotatory, and +2cyclization reactions to form endiandric acid C. This proposal is supported by the fact that endiandric acids naturally occur as racemic mixtures and not in an enantiomerically pure form, which should happen if enzymes mediate this process. The Diels-Alder reaction itself is a powerful reaction that can give cyclic compounds with many stereogenic centers. Biosynthesis of yangonin numbered

Biomimetic total synthesis

K. C. Nicolaou's group successfully synthesized endiandric acid, 1, in 1982 as a test of Black's biosynthetic conjecture,W.M. Bandaranayake, J.E. Banfield & D.St.C. Black, 1980, Postulated electrocyclic reactions leading to endiandric acid and related natural products, ''J. Chem Soc. Chem. Commun.'' 1980:902-903, se

accessed 6 June 2014. using a biomimetic synthesis, biomimetic strategy involving series of stereocontrolled

electrocyclic reaction In organic chemistry, an electrocyclic reaction is a type of pericyclic rearrangement where the net result is one pi bond being converted into one sigma bond or vice versa. These reactions are usually categorized by the following criteria: * React ...

s. Specifically,K. C. Nicolaou, N. A. Petasis, R. E. Zipkin, 1982, The endiandric acid cascade. Electrocyclizations in organic synthesis. 4. Biomimetic approach to endiandric acids A-G. Total synthesis and thermal studies, ''J. Am. Chem. Soc.'' 104(20):5560–5562, DOI: 10.1021/ja00384a080, se

accessed 6 June 2014. they observed that the natural products endiandric acids A and C could have arisen from a common precursor, via slightly different 6π s+2scycloaddition ( Diels-Alder) reactions. This key precursor was in turn accessible biosynthetically via two further thermally allowed sequential 6π electron and 8π electron

electrocyclization In organic chemistry, an electrocyclic reaction is a type of pericyclic rearrangement where the net result is one pi bond being converted into one sigma bond or vice versa. These reactions are usually categorized by the following criteria: * React ...

s. The Nicolaou group therefore sought to synthesize endiandric acid C from an acyclic symmetric diacetylenic diol precursor, 14 (as shown); they began with "mild hydrogenation" in the presence of

Lindlar catalyst A Lindlar catalyst is a heterogeneous catalyst that consists of palladium deposited on calcium carbonate or barium sulfate which is then poisoned with various forms of lead or sulfur. It is used for the hydrogenation of alkynes to alkenes (i.e. ...

and quinoline, anticipating tetraene diol 15, cyclooctatriene 16, or the fully cyclized bicyclo .2.0ctadiene (bicyclic diol) 17. Remarkably, following this 3-6 hour, 25 °C process, a 45-55% yield of bicyclic diol 17 could be isolated. Hence, it was not necessary to do anything specific to promote the required sequence of 8π

conrotatory An electrocyclic reaction can either be classified as conrotatory or disrotatory based on the rotation at each end of the molecule. In conrotatory mode, both atomic orbitals of the end groups turn in the same direction (such as both atomic orbital ...

and 6π

disrotatory An electrocyclic reaction can either be classified as conrotatory or disrotatory based on the rotation at each end of the molecule. In conrotatory mode, both atomic orbitals of the end groups turn in the same direction (such as both atomic orbital ...

cyclizations (further highlighted in supplementary image); they occurred spontaneously on generation of tetraene-diol 15. Protection of a single alcohol moiety (as TBDPS) was accomplished using the silyl chloride via the corresponding tricyclic iodoether intermediate (not shown), with the internally masked remaining

hydroxyl group In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy g ...

being released on treatment with zinc dust in acetic acid (giving 18 in 70-80% yield). Bromination of the alcohol under Appel conditions followed by its displacement on treatment with

sodium cyanide Sodium cyanide is a poisonous compound with the formula Na C N. It is a white, water-soluble solid. Cyanide has a high affinity for metals, which leads to the high toxicity of this salt. Its main application, in gold mining, also exploits its hi ...

HMPA Hexamethylphosphoramide, often abbreviated HMPA, is a phosphoramide (an amide of phosphoric acid) with the formula This colorless liquid is a useful reagent in organic synthesis. Structure and reactivity HMPA is the oxide of the highly basic ter ...

gave ''nitrile 20, the key intermediate in all of this group's endiandric acid syntheses.'' The title compound was then pursued via

DIBAL Diisobutylaluminium hydride (DIBALH, DIBAL, DIBAL-H or DIBAH) is a reducing agent with the formula (''i''-Bu2AlH)2, where ''i''-Bu represents isobutyl (-CH2CH(CH3)2). This organoaluminium compound is a reagent in organic synthesis. Properties Lik ...

reduction of the nitrile at low temperature, followed by mild acidic hydrolysis to release

aldehyde In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl grou ...

21. A series of 7 further steps—condensation to form trans-butenoate 22, thermal intramolecular Diels-Alder reaction to create the tetracyclic endiantric core structure 23, desilylation to unmask alcohol 24, bromination and nitrile formation (as described above) to give 25 and 26, respectively, then hydrolysis of the methyl ester and repeat of the earlier DIBAL/acid hydrolysis sequence—generated the endiantric core structure with pendant aldehyde, 28, that was poised for the final step. Its treatment with diethyl cinnamylphosphonate and

LDA LDA may refer to: Aviation *Localizer type directional aid, an instrument approach to an airport *Landing distance available, the length of runway that is available for the ground run of an airplane landing Law *Legal document assistant, a non-la ...

at low temperature in

THF Tetrahydrofuran (THF), or oxolane, is an organic compound with the formula (CH2)4O. The compound is classified as heterocyclic compound, specifically a cyclic ether. It is a colorless, water- miscible organic liquid with low viscosity. It is ...

(generating en route the anionic olefination reagent) formed the desired diene in good yield in a "geometrically controlled manner", thus providing the desired endiandric acid C product. ElectrocyclizationInEndrianicAcidSynth

Bioactivity

Biosynthesis

Biomimetic total synthesis

References

Further reading