Petasis reaction
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The Petasis reaction (alternatively called the Petasis borono–Mannich (PBM) reaction) is the
multi-component reaction In chemistry, a multi-component reaction (or MCR), sometimes referred to as a "Multi-component Assembly Process" (or MCAP), is a chemical reaction where three or more compounds react to form a single product. By definition, multicomponent reaction ...
of an
amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituen ...
, a
carbonyl In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containing a ...
, and a
vinyl Vinyl may refer to: Chemistry * Polyvinyl chloride (PVC), a particular vinyl polymer * Vinyl cation, a type of carbocation * Vinyl group, a broad class of organic molecules in chemistry * Vinyl polymer, a group of polymers derived from vinyl m ...
- or
aryl In organic chemistry, an aryl is any functional group or substituent derived from an aromatic ring, usually an aromatic hydrocarbon, such as phenyl and naphthyl. "Aryl" is used for the sake of abbreviation or generalization, and "Ar" is used as ...
-
boronic acid A boronic acid is an organic compound related to boric acid () in which one of the three hydroxyl groups () is replaced by an alkyl or aryl group (represented by R in the general formula ). As a compound containing a carbon–boron bond, membe ...
to form substituted amines. Reported in 1993 by Nicos Petasis as a practical method towards the synthesis of a geometrically pure antifungal agent,
naftifine Naftifine hydrochloride (brand names include Exoderil and Naftin) is an allylamine antifungal drug for the topical treatment of tinea pedis, tinea cruris, and tinea corporis (topical fungal infections). Naftifine was invented at the Sandoz Researc ...
. In the Petasis reaction, the vinyl group of the organoboronic acid serves as the nucleophile. In comparison to other methods of generating allyl amines, the Petasis reaction tolerates a multifunctional scaffold, with a variety of amines and organoboronic acids as potential starting materials. Additionally, the reaction does not require anhydrous or inert conditions. As a mild, selective synthesis, the Petasis reaction is useful in generating α-amino acids, and is utilized in
combinatorial chemistry Combinatorial chemistry comprises chemical synthetic methods that make it possible to prepare a large number (tens to thousands or even millions) of compounds in a single process. These compound libraries can be made as mixtures, sets of individua ...
and
drug discovery In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered. Historically, drugs were discovered by identifying the active ingredient from traditional remedies or by ...
.


Reaction scope and synthetic applications

The amine is condensed with the carbonyl followed by addition of the boronic acid . One of the most attractive features of the Petasis reaction is the stability of the vinyl boronic acids. With the advent of the
Suzuki coupling The Suzuki reaction is an organic reaction, classified as a cross-coupling reaction, where the coupling partners are a boronic acid and an organohalide and the catalyst is a palladium(0) complex. It was first published in 1979 by Akira Suzuki, a ...
, many are commercially available. Other methods of generating boronic acids were also reported. A wide variety of functional groups including alcohols, carboxylic acids, and amines are tolerated in the Petasis Reaction. Known substrates that are compatible with reaction conditions include vinylboronate esters, arylboronate esters, and potassium
organotrifluoroborate Organotrifluoroborates are organoboron compounds that contain an anion with the general formula BF3sup>−. They can be thought of as protected boronic acids, or as adducts of carbanions and boron trifluoride. Organotrifluoroborates are toleran ...
s. Additionally, a variety of substituted amines can be used other than secondary amines. Tertiary
aromatic amines In organic chemistry, an aromatic amine is an organic compound consisting of an aromatic ring attached to an amine. It is a broad class of compounds that encompasses anilines, but also many more complex aromatic rings and many amine substituents ...
,
hydrazines Hydrazines (R2N−NR2) are a class of chemical compounds with two nitrogen atoms linked via a covalent bond and which carry from one up to four alkyl or aryl substituents. Hydrazines can be considered as derivatives of the inorganic hydrazine (H ...
, hydroxylamines,
sulfonamide In organic chemistry, the sulfonamide functional group (also spelled sulphonamide) is an organosulfur group with the structure . It consists of a sulfonyl group () connected to an amine group (). Relatively speaking this group is unreactive. ...
s, and
indoles Indole is an aromatic heterocyclic organic compound with the formula C8 H7 N. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indole is widely distributed in the natural environment ...
have all been reported.


Synthesis of allyl amines

Vinyl boronic acids react with the adducts of secondary amines and paraformaldehyde to give tertiary allylamines. The geometry of the double bond of the starting vinyl boronic acid is retained in the final product: This reaction was use to synthesize naftifine


Synthesis of amino acids

β,γ-unsaturated, N-substituted amino acids are prepared through the condensation of organoboronic acids, boronates, or boronic esters with amines and glyoxylic acids. The highly polar protic solvents Hexafluoroisopropanol (HFIP) can shorten reaction time and improve yield. Apart from vinyl boronic acids, aryl boronic acids and other heterocyclic derivatives can also be used in Petasis multicomponent coupling. Possible substrate scope includes thienyl, pyridyl, furyl, and benzofuranyl, 1-naphthyl, and aryl groups with either electron-donating or electron-withdrawing substituent. Racemic Clopidogrel, an antiplatelet agent, was synthesized in two steps using Petasis reaction. The Petasis reaction exhibits high degrees of stereocontrol when a chiral amine or aldehyde is used as a substrate. When certain chiral amines, such as (S)-2-phenylglycinol, are mixed with an α-keto acid and vinyl boronic acid at room temperature, the corresponding allylamine is formed as a single diastereomer. Furthermore, enantiomeric purity can be achieved by hydrogenation of the diastereoselective product.


Unconventional synthesis of carboxylic acids

Apart from amino-acids, PBM reaction can also be used to prepare carboxylic acids, albeit with unconventional mechanisms. In the case of ''N''-substituted indoles as amine equivalent, the reaction begins with the nucleophilic attack of the 3-position of the "N"-substituted indole to electrophilic aldehyde, followed by formation of "ate complex" 1 via the reaction of boronic acid with the carboxylic acid. The intermediate then undergoes dehydration, followed by migration of boronate-alkyl group to furnish the final carboxylic acid product. A wide range of aryl boronic acids is tolerated, while the usage of vinyl boronic acids is not reported. "N"-unsubstituted indoles react very sluggishly under normal reaction conditions, thus confirming the mechanism below.
Tertiary aromatic amines can be used in the Petasis reaction as another equivalent of amine nucleophile. The mechanism is similar to the N-substituted indole case. The reaction is carried out under harsh conditions (24-hr reflux in 1,4-dioxane), but the resultant carboxylic acid is obtained in reasonable yield. Usage of α-ketoacids instead of glyoxylic acid does not diminish yields. 1,3,5-trioxygenated benzene derivatives can also be used in lieu of tertiary aromatic amines.


Synthesis of iminodicarboxylic acid derivatives


When used as nitrogen nucleophiles, amino acids can furnish various iminodicarboxylic acid derivatives. High diastereoselectivity is usually observed, and the newly formed stereocenter usually share the same configuration with the starting amino acid. This reaction works well in highly polar solvents (ex. water, ethanol, etc.). Peptides with unprotected nitrogen terminal can also be used as a nitrogen nucleophile equivalent. Petasis and coworkers prepared Enalaprilat, an ACE inhibitor, with this method.


Synthesis of peptidomimetic heterocycles

When diamines are used in PBM reactions, heterocycles of various structures, such as piperazinones, benzopiperazinones, and benzodiazepinones, are efficiently prepared. Lactamization reactions are commonly employed to form the heterocycles, usually under strongly acidic conditions.


Synthesis of amino alcohols

When a α-hydroxy aldehyde is used as a substrate in the synthesis of β-amino alcohols, a single diastereomer is generated. This reaction forms exclusively anti-product, confirmed by 1H NMR spectroscopy. The product does not undergo racemization, and when enantiomerically pure α-hydroxy aldehydes are used, enantiomeric excess can be achieved. It is believed that the boronic acid first reacted with the chiral hydroxyl group, furnishing a nucleophilic alkenyl boronate, followed by face selective, intramolecular migration of the alkenyl group into the electrophilic iminium carbon, forming the desired C-C bond irreversibly. Diastereoselectivity may arise from the reaction of the more stable (and, in this case, more reactive) conformation of the ate complex, where 1,3 allylic strain is minimized. With dihydroxyacetone, a somewhat unconventional aldehyde equivalent, Petasis reaction give the core structure of FTY720, a potent immunosuppressive agent.


Synthesis of amino polyols and amino sugars

Petasis and coworkers reported the usage of unprotected carbohydrates as the carbonyl component in PBM reactions. It is used as the equivalent of α-hydroxyl aldehydes with pre-existing chirality, and the aminopolyol product is usually furnished with moderate to good yield, with excellent selectivity. A wide variety of carbohydrates, as well as nitrogen nucleophiles (ex. amino acids), can be used to furnish highly stereochemically-enriched products. The aminopolyol products can then undergo further reactions to prepare aminosugars. Petasis used this reaction to prepare Boc-protected mannosamine from D-arabinose.


Applications in enantioselective synthesis


With chiral amine nucleophile

Generally speaking, when chiral amine is used in Petasis coupling, the stereochemical outcome of Petasis reaction is strongly correlated to the chirality of the amine, and high to excellent diastereoselectivity is observed even without the usage of bulky chiral inducing groups. Chiral benzyl amines, 2-substituted pyrrolidines, and 5-substituted 2-morpholinones have been shown to induce good to excellent diastereomeric excess under different Petasis reaction conditions.


With chiral N-acyliminium ions

Chiral N-acyliminium ion "starting materials" are generally prepared by in-situ dehydration of cyclic hemiaminal. They also carry a chiral hydroxyl group that is in proximity with the iminium carbon; boronic acids react with such chiral hydroxyl groups to form a chiral and electron-rich boronate species, followed by side-selective and intramolecular boronate vinyl/aryl transfer into the iminium carbon. Hence, the reaction is highly diastereoselective, with cis- boronate aryl/vinyl transfer being the predominant pathway. Hydroxypyrrolidines and Hydroxy-γ- and δ-lactams have been shown to react very diastereoselectively, with good to excellent yield. However, such procedures are limited to the usage of vinyl- or electron-rich aryl- boronic acids only. (±)-6-Deoxycastanospermine was prepared in 7 steps from the vinyl boronic ester. The key acyclic precursor to deoxycastanospermine (A) is formed first by condensing vinyl boronic ester 1 with Cbz-protected hydroxy-pyrrolidine 2 with a PBM coupling, followed by dihydroxylation and TBS protection. A then undergo intramolecular cyclization via a one-pot imine formation and reduction sequel, followed by TBS deprotection, to afford (±)-6-deoxycastanospermine.


With thiourea catalyst

Enantioselective Petasis-type reaction transform quinolines into respective chiral 1,2-dihydroquinolines (product) using alkenyl boronic acids and chiral thiourea catalyst: Chloroformates are required as electrophilic activating agents. Also, a 1,2-amino alcohol functionality is required on the catalyst for the reaction to proceed stereoselectively.


With chiral biphenols

Chiral α-amino acids with various functionalities are conveniently furnished by mixing alkenyl diethyl boronates, secondary amines, glyoxylates, and chiral biphenol catalyst in toluene in one-pot: This reaction tolerates a wide range of functionalities, both on the sides of alkenyl boronates and the secondary amine: the electron-richness of the substrates does not affect the yield and enantioselectivity, and sterically demanding substrates (dialkylsubstituted alkenyl boronates and amines with α-stereocenter) only compromise enantioselectivity slightly. Reaction rates do vary on a case-by-case basis. Under the reported condition, boronic acids substrates failed to give any enantioselectivity. Also, 3Å molecular sieve is used in the reaction system. While the authors did not provide the reason for such usage in the paper, it was speculated that 3Å molecular sieves act as water scavenger and prevent the decomposition of alkenyl diethyl boronates into their respective boronic acids. The catalyst could be recycled from the reaction and reused without compromising yield or enantioselectivity. More recently, Yuan with coworkers from Chengdu Institute of Organic Chemistry, Chinese Academy of Science combined both approaches (chiral thiourea catalyst and chiral biphenol) in a single catalyst, reporting for the first time the catalytic system that is capable of performing enantioselective Petasis reaction between salicylaldehydes, cyclic secondary amines and aryl- or alkenylboronic acids: In one application the Petasis reaction is used for quick access to a multifunctional scaffold for
divergent synthesis In chemistry a divergent synthesis is a strategy with the aim to improve the efficiency of chemical synthesis. It is often an alternative to convergent synthesis or linear synthesis. In one strategy divergent synthesis aims to generate a library ...
. The reactants are the
lactol In organic chemistry, a lactol is the cyclic equivalent of a hemiacetal or a hemiketal. The compound is formed by the intramolecular nucleophilic addition of a hydroxyl group to the carbonyl group of an aldehyde or a ketone. A lactol is often ...
derived from L-phenyl-lactic acid and
acetone Acetone (2-propanone or dimethyl ketone), is an organic compound with the formula . It is the simplest and smallest ketone (). It is a colorless, highly volatile and flammable liquid with a characteristic pungent odour. Acetone is miscib ...
, l-phenylalanine methyl ester and a
boronic acid A boronic acid is an organic compound related to boric acid () in which one of the three hydroxyl groups () is replaced by an alkyl or aryl group (represented by R in the general formula ). As a compound containing a carbon–boron bond, membe ...
. The reaction takes place in ethanol at room temperature to give the product, an anti-1,2-amino alcohol with a high
diastereomeric excess In stereochemistry, enantiomeric excess (ee) is a measurement of purity used for chiral substances. It reflects the degree to which a sample contains one enantiomer in greater amounts than the other. A racemic mixture has an ee of 0%, while a sing ...
. Notice that the authors cannot assess syn-1,2-amino alcohol with this method due to intrinsic mechanistic selectivity, and the authors argue that such intrinsic selectivity hampers their ability to access the full matrix of stereoisomeric products for the usage of small molecule screening. In a recent report, Schaus and co-workers reported that syn amino alcohol can be obtained with the following reaction condition, using a chiral dibromo-biphenol catalyst their group developed: Although the syn vs. anti diastereomeric ratio ranges from mediocre to good (1.5:1 to 7.5:1), the substrate scope for such reactions remain rather limited, and the diastereoselectivity is found to be dependent on the stereogenic center on the amine starting material.


Petasis reaction and total synthesis

Beau and coworkers assembled the core dihydropyran framework of zanamivir congeners via a combination of PBM reaction and Iron(III)-promoted deprotection-cyclization sequence. A stereochemically-defined α-hydroxyaldehyde 2, diallylamine and a dimethylketal-protected boronic acid 1 is coupled to form the acyclic, stereochemically-defined amino-alcohol 3, which then undergoes an Iron(III)-promoted cyclization to form a bicyclic dihydropyran 4. Selective opening of the oxazoline portion of the dihydropyran intermediate 4 with water or timethylsilyl azide then furnish downstream products that have structures resembling the Zanamivir family members. Wong and coworkers prepared N-acetylneuraminic acid with a PBM coupling, followed by nitrone- +2cycloaddition. Vinylboronic acid is first coupled with L-arabinose 1 and Bis(4-methoxyphenyl)methanamine 2 to form an stereochemically-defined allyl amine 3. Afterwards, the sequence of dipolar cycloaddition, base-mediated N-O bond breakage and hydrolysis then complete the synthesis of N-acetylneuraminic acid.


See also

*
Mannich reaction In organic chemistry, the Mannich reaction is a three-component organic reaction that involves the amino alkylation of an acidic proton next to a carbonyl () functional group by formaldehyde () and a primary or secondary amine () or ammonia (). ...
*
Reductive amination Reductive amination (also known as reductive alkylation) is a form of amination that involves the conversion of a carbonyl group to an amine via an intermediate imine. The carbonyl group is most commonly a ketone or an aldehyde. It is considered ...
*
Suzuki reaction The Suzuki reaction is an organic reaction, classified as a cross-coupling reaction, where the coupling partners are a boronic acid and an organohalide and the catalyst is a palladium(0) complex. It was first published in 1979 by Akira Suzuki, ...


References

{{Reflist Multiple component reactions Substitution reactions Name reactions Chemical synthesis of amino acids