HOME

TheInfoList



OR:

The Saegusa–Ito oxidation is a
chemical reaction A chemical reaction is a process that leads to the chemistry, chemical transformation of one set of chemical substances to another. When chemical reactions occur, the atoms are rearranged and the reaction is accompanied by an Gibbs free energy, ...
used in
organic chemistry Organic chemistry is a subdiscipline within chemistry involving the science, scientific study of the structure, properties, and reactions of organic compounds and organic matter, organic materials, i.e., matter in its various forms that contain ...
. It was discovered in 1978 by Takeo Saegusa and Yoshihiko Ito as a method to introduce α-β unsaturation in
carbonyl compound In organic chemistry, a carbonyl group is a functional group with the formula , composed of a carbon atom double-bonded to an oxygen atom, and it is divalent at the C atom. It is common to several classes of organic compounds (such as aldehydes, ...
s. The reaction as originally reported involved formation of a
silyl enol ether In organosilicon chemistry, silyl enol ethers are a class of organic compounds that share the common functional group , composed of an enolate () bonded to a silane () through its oxygen end and an ethene group () as its carbon end. They are i ...
followed by treatment with
palladium(II) acetate Palladium is a chemical element; it has symbol Pd and atomic number 46. It is a rare and lustrous silvery-white metal discovered in 1802 by the English chemist William Hyde Wollaston. He named it after the asteroid Pallas (formally 2 Pallas), wh ...
and
benzoquinone Benzoquinone (C6H4O2) is a quinone with a single benzene ring. There are 2 (out of 3 hypothetical) benzoquinones: * 1,4-Benzoquinone, most commonly, right image (also ''para''-benzoquinone, ''p''-benzoquinone, ''para''-quinone, or just quinone) * ...
to yield the corresponding enone. The original publication noted its utility for regeneration of unsaturation following 1,4-addition with
nucleophile In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...
s such as organocuprates. For acyclic substrates the reaction yields the
thermodynamic Thermodynamics is a branch of physics that deals with heat, work, and temperature, and their relation to energy, entropy, and the physical properties of matter and radiation. The behavior of these quantities is governed by the four laws of th ...
E-olefin product exclusively. This discovery was preceded nearly eight years earlier by a report that treatment of unactivated
ketone In organic chemistry, a ketone is an organic compound with the structure , where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group (a carbon-oxygen double bond C=O). The simplest ketone is acetone ( ...
s with palladium acetate yielded the same products in low yields. The major improvement provided by Saegusa and Ito was the recognition that the
enol In organic chemistry, enols are a type of functional group or intermediate in organic chemistry containing a group with the formula (R = many substituents). The term ''enol'' is an abbreviation of ''alkenol'', a portmanteau deriving from "-ene ...
form was the reactive species, developing a method based on silyl enol ethers. Benzoquinone is used as a sacrificial oxidant to regenerate palladium(II) from its reduced form palladium(0), so that a smaller amount of expensive palladium(II) acetate is required at the beginning. The reaction conditions and purifications could be simplified by using excess
palladium(II) acetate Palladium is a chemical element; it has symbol Pd and atomic number 46. It is a rare and lustrous silvery-white metal discovered in 1802 by the English chemist William Hyde Wollaston. He named it after the asteroid Pallas (formally 2 Pallas), wh ...
without benzoquinone. Since the reaction typically employs near-
stoichiometric Stoichiometry () is the relationships between the masses of reactants and products before, during, and following chemical reactions. Stoichiometry is based on the law of conservation of mass; the total mass of reactants must equal the total m ...
amounts of palladium and is therefore often considered too expensive for industrial usage, some progress has been made in the development of
catalytic Catalysis () is the increase in reaction rate, rate of a chemical reaction due to an added substance known as a catalyst (). Catalysts are not consumed by the reaction and remain unchanged after it. If the reaction is rapid and the catalyst ...
variants. Despite this shortcoming, the Saegusa oxidation has been used in a number of syntheses as a mild, late-stage method for introduction of functionality in complex molecules.


Mechanism

The
mechanism Mechanism may refer to: *Mechanism (economics), a set of rules for a game designed to achieve a certain outcome **Mechanism design, the study of such mechanisms *Mechanism (engineering), rigid bodies connected by joints in order to accomplish a ...
of the Saegusa–Ito oxidation involves coordination of palladium to the enol olefin followed by loss of the silyl group and formation of an oxoallyl-palladium complex. β-hydride elimination yields the palladium hydride enone complex which upon
reductive elimination Reductive elimination is an elementary step in organometallic chemistry in which the oxidation state of the metal center decreases while forming a new covalent bond between two ligands. It is the microscopic reverse of oxidative addition, and is ...
yields the product along with
acetic acid Acetic acid , systematically named ethanoic acid , is an acidic, colourless liquid and organic compound with the chemical formula (also written as , , or ). Vinegar is at least 4% acetic acid by volume, making acetic acid the main compone ...
and Pd0.Oxidation
, Chem 215 lecture notes
The reversibility of the elimination step allows equilibration, leading to the
thermodynamic Thermodynamics is a branch of physics that deals with heat, work, and temperature, and their relation to energy, entropy, and the physical properties of matter and radiation. The behavior of these quantities is governed by the four laws of th ...
E-selectivity in acyclic substrates. It has been shown that the product can form a stable Pd0-olefin complex, which may be responsible for the difficulty with re-oxidation seen in catalytic variants of the reaction.


Scope

The wide applicability of the Saegusa–Ito oxidation is exemplified by its use in several classic syntheses of complex molecules. The synthesis of
morphine Morphine, formerly also called morphia, is an opiate that is found naturally in opium, a dark brown resin produced by drying the latex of opium poppies (''Papaver somniferum''). It is mainly used as an analgesic (pain medication). There are ...
by
Tohru Fukuyama is a Japanese organic chemist and Professor of Chemistry at University of Tokyo in Japan. He discovered the Fukuyama coupling in 1998. Biography Fukuyama studied chemistry at Nagoya University with degrees Bachelor's (1971) and Master's (1973) ...
in 2006 is one such example, in which the transformation tolerates the presence of
carbamate In organic chemistry, a carbamate is a category of organic compounds with the general Chemical formula, formula and Chemical structure, structure , which are formally Derivative (chemistry), derived from carbamic acid (). The term includes orga ...
and
ether In organic chemistry, ethers are a class of compounds that contain an ether group, a single oxygen atom bonded to two separate carbon atoms, each part of an organyl group (e.g., alkyl or aryl). They have the general formula , where R and R� ...
substituents. Samuel J. Danishefsky's synthesis of both (+) and (-) peribysin began with a Saegusa–Ito oxidation of the Diels-Alder adduct of
carvone Carvone is a member of a family of chemicals called terpenoids. Carvone is found naturally in many essential oils, but is most abundant in the oils from seeds of caraway (''Carum carvi''), spearmint (''Mentha spicata''), and dill. Uses Food appli ...
and 3-trimethylsilyloxy-1,3-butadiene to yield the enone below. In this case the oxidation tolerated the presence of
alkene In organic chemistry, an alkene, or olefin, is a hydrocarbon containing a carbon–carbon double bond. The double bond may be internal or at the terminal position. Terminal alkenes are also known as Alpha-olefin, α-olefins. The Internationa ...
and
carbonyl In organic chemistry, a carbonyl group is a functional group with the formula , composed of a carbon atom double bond, double-bonded to an oxygen atom, and it is divalent at the C atom. It is common to several classes of organic compounds (such a ...
moieties. Yong Qiang Tu's synthesis of the
Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
medication
galantamine Galantamine is a type of acetylcholinesterase inhibitor. It is an alkaloid extracted from the bulbs and flowers of ''Galanthus nivalis'' (common snowdrop), '' Galanthus caucasicus'' (Caucasian snowdrop), '' Galanthus woronowii'' (Voronov's snow ...
likewise used this reaction in the presence of an acid-sensitive
acetal In organic chemistry, an acetal is a functional group with the connectivity . Here, the R groups can be organic fragments (a carbon atom, with arbitrary other atoms attached to that) or hydrogen, while the R' groups must be organic fragments n ...
group.
Larry E. Overman 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 Unive ...
's synthesis of laurenyne utilizes a one-pot oxidation with
pyridinium chlorochromate Pyridinium chlorochromate (PCC) is a yellow-orange salt (chemistry), salt with the chemical formula, formula 5H5NH rO3Cl��. It is a reagent in organic synthesis used primarily for organic redox reaction, oxidation of Alcohol (chemistry), al ...
followed by a Saegusa oxidation, tolerating the presence of a
halogen The halogens () are a group in the periodic table consisting of six chemically related elements: fluorine (F), chlorine (Cl), bromine (Br), iodine (I), and the radioactive elements astatine (At) and tennessine (Ts), though some authors would ...
and a
sulfonate In organosulfur chemistry, a sulfonate is a salt, anion or ester of a sulfonic acid. Its formula is , containing the functional group , where R is typically an organyl group, amino group or a halogen atom. Sulfonates are the conjugate bases of ...
. The synthesis of sambutoxin reported by David Williams uses a novel Saegusa–Ito oxidation involving an unprotected
enol In organic chemistry, enols are a type of functional group or intermediate in organic chemistry containing a group with the formula (R = many substituents). The term ''enol'' is an abbreviation of ''alkenol'', a portmanteau deriving from "-ene ...
moiety. The enone product cyclized ''in situ'' to regenerate the enol and form the
tetrahydropyran Tetrahydropyran (THP) is the organic compound consisting of a saturated six-membered ring containing five carbon atoms and one oxygen atom. It is named by reference to pyran, which contains two double bonds, and may be produced from it by addin ...
ring. Subsequent
deprotection 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. In man ...
of the methoxymethyl group furnished the
natural product A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical s ...
.


Variations

The vast majority of improvements to this reaction have focused on rendering the transformation catalytic with respect to the palladium salt, primarily due to its high cost. The original conditions, though technically catalytic, still require 50 mol% of palladium(II) acetate, raising the cost to prohibitively high levels for large scale syntheses. The major advances in catalytic versions of this reaction have steered towards co-oxidants that regenerate the palladium(II) species effectively. Specifically, conditions using atmospheric oxygen as well as stoichiometric allylcarbonate have been developed. With respect to the former, the method developed by Larock in 1995 represents an environmentally and cost-attractive method as a catalytic substitute for the Saegusa–Ito oxidation. This method suffers from long reaction times and often produces significantly lower yields than the stoichiometric equivalent as showcased in the synthesis of platyphillide by Nishida. The contrast of the two methods highlights the catalytic method's shortcomings. Catalytic variants employing stoichiometric diallylcarbonate and other allylic carbonates have also been developed, primarily by Jiro Tsuji. For these the choice of solvent is essential: nitrile solvents produce the desired enones while ethereal solvents produce α-allylketones instead. This latter method has enjoyed greater success as a synthetic tool, most notably in the Shibasaki total synthesis of the famous poison
strychnine Strychnine (, , American English, US chiefly ) is a highly toxicity, toxic, colorless, bitter, crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as birds and rodents. Strychnine, when inhaled, swallowed, ...
. Despite these methods, much work remains to be done with regard to catalytic installation of α-β unsaturation.


See also

*
Silyl enol ether In organosilicon chemistry, silyl enol ethers are a class of organic compounds that share the common functional group , composed of an enolate () bonded to a silane () through its oxygen end and an ethene group () as its carbon end. They are i ...
*
Palladium(II) acetate Palladium is a chemical element; it has symbol Pd and atomic number 46. It is a rare and lustrous silvery-white metal discovered in 1802 by the English chemist William Hyde Wollaston. He named it after the asteroid Pallas (formally 2 Pallas), wh ...
*
Selenoxide elimination Selenoxide elimination (also called α-selenation) is a method for the chemical synthesis of alkenes from selenoxides. It is most commonly used to synthesize α,β-unsaturated carbonyl compounds from the corresponding saturated analogues. It is me ...
* Galantamine total synthesis * Strychnine total synthesis *


References

{{DEFAULTSORT:Saegusa-Ito oxidation Name reactions