Реакция Петасиса: многокомпонентный синтез замещенных аминов и кислот.

The Petasis reaction (alternatively called the Petasis borono–Mannich (PBM) reaction) is the multi component reaction of an amine, a carbonyl, and a vinyl or aryl boronic acid to form substituted amines. Reported in 1993 by Nicos Petasis as a practical method towards the synthesis of a geometrically pure antifungal agent, naftifine. 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 and drug discovery.

The amine is condensed with the carbonyl followed by addition of the boronic acid
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 organotrifluoroborates. Additionally, a variety of substituted amines can be used other than secondary amines. Tertiary aromatic amines, hydrazines, hydroxylamines, sulfonamides, and indoles have all been reported.

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:

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. 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.

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.

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. With dihydroxyacetone, a somewhat unconventional aldehyde equivalent, Petasis reaction give the core structure of FTY720, a potent immunosuppressive agent.

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. 2 substituted pyrrolidines, and 5 substituted 2 morpholinones have been shown to induce good to excellent diastereomeric excess under different Petasis reaction conditions.

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. [[Image:Deoxycastanospermine synthesis. png|center|600px|Deoxycastanospermine synthesis. center|500px|Takemoto et al. 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. center|575px|Takemoto et al. transition state