Petasis Reaction - Reaction Scope and Synthetic Applications

Reaction Scope and Synthetic Applications

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.

Synthesis of allyl amines
Petasis and coworkers proposed, in their seminal study, that vinyl boronic acids can 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 completely retained in the final product. Yield is typically in the good to excellent range. The following reaction is particularly effective, hitting a yield of 96%:

Petasis and coworkers used this reaction to synthesize naftifine, a very potent topical antimycotic, in one step in 82% yield. Other compounds with related structure include terbinafine and NB598.

Synthesis of amino acids
β,γ-unsaturated, N-substituted amino acids are conveniently prepared through the condensation of organoboronic acids, boronates, or boronic esters with amines and glyoxylic acids. Yields are typically in the range of 60-80%, and a wide variety of polar or non-polar solvents can be employed (although DCM and MeOH is typically used). Free amino acids that do not have N-substitutions can be prepared by using trityl amine or bis-(4-methoxyphenyl)methyl amine, followed by deprotection under aciic conditions. Piettre and coworkers found out that the usage of highly-polar protic solvents like Hexafluoroisopropanol (HFIP) can shorten reaction time and improve yield. Microwave irradiation was also be used to promote the reaction in methanol.

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.

Clopidogrel, an antiplatelet agent, was racemically synthesized by Kalinski and coworkers in two steps, using Petasis reaction as the key strategy. Acid-catalyzed esterification immediately following the multicomponent coupling steps to afford Clopidogrel in 44% overall yield.

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. In the reaction with (S)-2-phenylglycinol, (R)-2-phenylglycinol is generated in 76% yield.

Unconventional Synthesis of Carboxylic acids
Apart from amino-acids, Petasis borono-Mannich reaction can also be used to prepare carboxylic acids, albeit with unconventional mechanisms. Naskar et al. reported the use of N-substituted indoles as amine equivalent. The mechanism 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. The yield is in the moderate to good range (40-70%). A wide range of aryl boronic acids is tolerated, while the usage of vinyl boronic acids is not reported. It is interesting to note that "N"-unsubstituted indoles react very sluggishly under normal reaction conditions, thus confirming the mechanism below.

Naskar et al. also proposed the usage of tertiary aromatic amines in 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 (41-54% yield). Note that the 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. In the reaction of enantiomerically pure glyceraldehydes, the corresponding 3-amino 1,2-diol product is formed in 70% yield and greater than 99% ee.

Pyne and coworkers suggested that diastereoselectivity arises 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.

Using dihydroxyacetone, a somewhat unconventional aldehyde equivalent, Sugiyama et al. is able to use Petasis reaction to assemble the core structure of FTY720 (a potent immunosuppressive agent) in 40% yield. A straight forward hydrogenation then follows to afford the product via a one-step benzyl-group removal and C-C double bond hydrogenation.

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.