Merrilactone A
Encyclopedia
Merrilactone A is one of the four sesquiterpene
s that were newly discovered from the fruit of Illicium merrillianum in 2000. Members of the genus Illicium
include Chinese star anise, widely used as a spice for flavouring food and beverages, and also poisonous plants such as Japanese star anise
. Chemical studies of Illicium have developed rapidly over the last 20 years, and merrilactone A has been shown to have neurotrophic activity in fetal rat cortical
neuron
cultures. This has led researchers to believe that Merrilactone A may hold therapeutic potential in the treatment of neuro-degenerative diseases such as Alzheimer’s disease and Parkinson's disease
.
. The genus Illicium belongs to the family Illiciaceae
and is an evergreen shrub or tree. Approximately 40 species are disjunctively distributed in eastern North America
, Mexico
, the West Indies, and eastern Asia. The highest concentration of species is in northern Myanmar
and southern China, where nearly 35 species have been described. The fruits of the Illicium species are distinctive star-shaped follicle
s that have a characteristic refreshing flavour. The fruits of Illicium merrillianum also have an aromatic odor, bland taste and cause numbness of the tongue when chewed.
The only economically important product from this genus is the fruit of Illicium verum, or Chinese star anise, which is widely used as a spice for flavouring food and beverages. In contrast, the fruit of Japanese star anise
, Illicium anisatum, have been known to be very toxic for several centuries.
outgrowth in the primary cultures of fetal rat cortical
neuron
s at concentrations from 10 to 0.1 μmol/L. It was also found that this compound had a property of neuroprotection
at same concentration.
. Three DMAPPs, or one DMAPP and two isopentenyl diphosphate (IPP), are made into a farnesyl diphosphate (FPP), which is the fundamental precursor of sesquiterpene
, and then sesquiterpene cyclise enzymes cause it a cyclization. The synthesis up to here is well known, though process after the first cyclization was unclear.
Anislactone-type sesquiterpenes which merrilactone A belongs to has been thought to be biosynthezised from majucin since they have γ-lactone. However, this pathway has trouble to elucidate some configuration
s and other feature they have. The biosynthesis
shown in the figure was newly proposed and solved these problems.
The point of this pathway is that seco-prezizaane, anislactone and tashironin group which are all found in Illicium are all derived from the same intermediate 6. This is expected to be able to give all characteristic sequiterpenes in Illicium plants a reasonable explanation of biosynthesis.
body, and two produce natural enantiomer
. The following part will introduce the latest one.
The synthesis of the ring on the back side starting from the alcohol
5 is relatively easy to accomplish and high yield. Since the strategy of this synthesis is using a Lewis acid
to perform Nazarov cyclization, the next target is to make the substrate, which is 20 here.
The distinguishing point is that this synthesis uses the Lewis acid
-catalyzed Nazarov cyclization (20 to 22 in the figure). The Nazarov cyclization is a 4π electrocyclization typically involving the conversion
of divinyl ketone
s to cyclopentenone
s by activation with a Lewis acid
. The Lewis acid catalyst 21 used here is shown below.
This synthesis has least number of step and generally gives high yield at every process, though the total yield could not be found.
Sesquiterpene
Sesquiterpenes are a class of terpenes that consist of three isoprene units and have the molecular formula C15H24. Like monoterpenes, sesquiterpenes may be acyclic or contain rings, including many unique combinations...
s that were newly discovered from the fruit of Illicium merrillianum in 2000. Members of the genus Illicium
Illicium
Illicium is a genus of flowering plants containing 42 species of evergreen shrubs and small trees, in family Schisandraceae. The species are native to the tropical and subtropical regions of eastern and southeastern Asia, southeastern North America, and the West Indies.Selected species*Illicium...
include Chinese star anise, widely used as a spice for flavouring food and beverages, and also poisonous plants such as Japanese star anise
Japanese star anise
Illicium anisatum, commonly known as the Japanese star anise, is a tree similar to Chinese star anise. It is highly toxic, therefore it is not edible; instead, it has been burned as incense in Japan, where it is known as...
. Chemical studies of Illicium have developed rapidly over the last 20 years, and merrilactone A has been shown to have neurotrophic activity in fetal rat cortical
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
cultures. This has led researchers to believe that Merrilactone A may hold therapeutic potential in the treatment of neuro-degenerative diseases such as Alzheimer’s disease and Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
.
Occurrence
Merrilactone A occurs naturally in Illicium merrillianum, a plant indigenous to southern China and MyanmarMyanmar
Burma , officially the Republic of the Union of Myanmar , is a country in Southeast Asia. Burma is bordered by China on the northeast, Laos on the east, Thailand on the southeast, Bangladesh on the west, India on the northwest, the Bay of Bengal to the southwest, and the Andaman Sea on the south....
. The genus Illicium belongs to the family Illiciaceae
Illiciaceae
Illiciaceae is the botanical name of a family of flowering plants. The family has been recognized by most taxonomists, at least for the past several decades....
and is an evergreen shrub or tree. Approximately 40 species are disjunctively distributed in eastern North America
North America
North America is a continent wholly within the Northern Hemisphere and almost wholly within the Western Hemisphere. It is also considered a northern subcontinent of the Americas...
, Mexico
Mexico
The United Mexican States , commonly known as Mexico , is a federal constitutional republic in North America. It is bordered on the north by the United States; on the south and west by the Pacific Ocean; on the southeast by Guatemala, Belize, and the Caribbean Sea; and on the east by the Gulf of...
, the West Indies, and eastern Asia. The highest concentration of species is in northern Myanmar
Myanmar
Burma , officially the Republic of the Union of Myanmar , is a country in Southeast Asia. Burma is bordered by China on the northeast, Laos on the east, Thailand on the southeast, Bangladesh on the west, India on the northwest, the Bay of Bengal to the southwest, and the Andaman Sea on the south....
and southern China, where nearly 35 species have been described. The fruits of the Illicium species are distinctive star-shaped follicle
Follicle (fruit)
In botany, a follicle is a dry unilocular many-seeded fruit formed from one carpel and dehiscing by the ventral suture in order to release seeds, such as in larkspur, magnolia, banksia, peony and milkweed....
s that have a characteristic refreshing flavour. The fruits of Illicium merrillianum also have an aromatic odor, bland taste and cause numbness of the tongue when chewed.
The only economically important product from this genus is the fruit of Illicium verum, or Chinese star anise, which is widely used as a spice for flavouring food and beverages. In contrast, the fruit of Japanese star anise
Japanese star anise
Illicium anisatum, commonly known as the Japanese star anise, is a tree similar to Chinese star anise. It is highly toxic, therefore it is not edible; instead, it has been burned as incense in Japan, where it is known as...
, Illicium anisatum, have been known to be very toxic for several centuries.
Biological activity
Merrilactone A was found to exhibit a significant neurotrophic activity, such as greatly promoting neuriteNeurite
A neurite refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in culture, because it can be difficult to tell axons from dendrites before...
outgrowth in the primary cultures of fetal rat cortical
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s at concentrations from 10 to 0.1 μmol/L. It was also found that this compound had a property of neuroprotection
Neuroprotection
Neuroprotection within the nervous system protects neurons from apoptosis or degeneration, for example following a brain injury or as a result of chronic neurodegenerative diseases....
at same concentration.
Biosynthesis
This compound is originated from mevalonic acid pathway which produce dimethylallyl diphosphate (DMAPP) from acetyl-CoAAcetyl-CoA
Acetyl coenzyme A or acetyl-CoA is an important molecule in metabolism, used in many biochemical reactions. Its main function is to convey the carbon atoms within the acetyl group to the citric acid cycle to be oxidized for energy production. In chemical structure, acetyl-CoA is the thioester...
. Three DMAPPs, or one DMAPP and two isopentenyl diphosphate (IPP), are made into a farnesyl diphosphate (FPP), which is the fundamental precursor of sesquiterpene
Sesquiterpene
Sesquiterpenes are a class of terpenes that consist of three isoprene units and have the molecular formula C15H24. Like monoterpenes, sesquiterpenes may be acyclic or contain rings, including many unique combinations...
, and then sesquiterpene cyclise enzymes cause it a cyclization. The synthesis up to here is well known, though process after the first cyclization was unclear.
Anislactone-type sesquiterpenes which merrilactone A belongs to has been thought to be biosynthezised from majucin since they have γ-lactone. However, this pathway has trouble to elucidate some configuration
Molecular configuration
The configuration of a molecule is the permanent geometry that results from the spatial arrangement of its bonds. The ability of the same set of atoms to form two or more molecules with different configurations is stereoisomerism...
s and other feature they have. The biosynthesis
Biosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
shown in the figure was newly proposed and solved these problems.
The point of this pathway is that seco-prezizaane, anislactone and tashironin group which are all found in Illicium are all derived from the same intermediate 6. This is expected to be able to give all characteristic sequiterpenes in Illicium plants a reasonable explanation of biosynthesis.
Total synthesis
Since the discovery of merrilactone A, many methods of total synthesis have been proposed, of which four produce racemicRacemic
In chemistry, a racemic mixture, or racemate , is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule. The first known racemic mixture was "racemic acid", which Louis Pasteur found to be a mixture of the two enantiomeric isomers of tartaric acid.- Nomenclature :A...
body, and two produce natural enantiomer
Enantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
. The following part will introduce the latest one.
The synthesis of the ring on the back side starting from the alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
5 is relatively easy to accomplish and high yield. Since the strategy of this synthesis is using a Lewis acid
Lewis acid
]The term Lewis acid refers to a definition of acid published by Gilbert N. Lewis in 1923, specifically: An acid substance is one which can employ a lone pair from another molecule in completing the stable group of one of its own atoms. Thus, H+ is a Lewis acid, since it can accept a lone pair,...
to perform Nazarov cyclization, the next target is to make the substrate, which is 20 here.
The distinguishing point is that this synthesis uses the Lewis acid
Lewis acid
]The term Lewis acid refers to a definition of acid published by Gilbert N. Lewis in 1923, specifically: An acid substance is one which can employ a lone pair from another molecule in completing the stable group of one of its own atoms. Thus, H+ is a Lewis acid, since it can accept a lone pair,...
-catalyzed Nazarov cyclization (20 to 22 in the figure). The Nazarov cyclization is a 4π electrocyclization typically involving the conversion
Chemical reaction
A chemical reaction is a process that leads to the transformation of one set of chemical substances to another. Chemical reactions can be either spontaneous, requiring no input of energy, or non-spontaneous, typically following the input of some type of energy, such as heat, light or electricity...
of divinyl ketone
Ketone
In organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...
s to cyclopentenone
Cyclopentenone
Cyclopentenone is a hydrocarbon with chemical formula 56 and CAS number 930-30-3. It is structurally similar to cyclopentanone, with the additional feature of α-β unsaturation in the ring system. Cyclopentenone belongs to the cycloalkene class of compounds and is also a ketone...
s by activation with a Lewis acid
Lewis acid
]The term Lewis acid refers to a definition of acid published by Gilbert N. Lewis in 1923, specifically: An acid substance is one which can employ a lone pair from another molecule in completing the stable group of one of its own atoms. Thus, H+ is a Lewis acid, since it can accept a lone pair,...
. The Lewis acid catalyst 21 used here is shown below.
This synthesis has least number of step and generally gives high yield at every process, though the total yield could not be found.