Petasis reaction

The amine is condensed with the carbonyl followed by addition of the boronic acid .

Image:Alphaaminoacidsynthesis.png

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, many are commercially available.

Image:Organoboronic acid synthesis.png

Other methods of generating boronic acids were also reported.{{citation |author1=Hoffmann. R.W. |author2=Dresely, S. | journal=Synthesis| year = 1988 | volume=1988 | issue=2| pages = 103–106 | title = Preparation of 3-substituted (E)-1-alkenylboronic esters | doi=10.1055/s-1988-27480}}{{citation |author1=Brown, H.C. |author2=Bhat, N.G. |author3=Iyer, R.R. | journal=Tetrahedron Lett.| year = 1991 | volume=32 | issue=30| pages = 3655–3658 | title = A novel route to 1,3-dienyl-2-boronic esters providing simple syntheses of conjugated (E,E)-dienes and conjugated (E)-alkenones | doi=10.1016/s0040-4039(00)79758-9}}

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.{{citation |author1=Petasis, N.A. |author2=Goodman, A., Zavialov, I.A. |journal=Tetrahedron|year=1997 | volume=53 |issue=48 | pages=16463–16470 | doi = 10.1016/S0040-4020(97)01028-4 | title = A new synthesis of α-arylglycines from aryl boronic acids}}{{citation |author1=Kabalka, G.W. |author2=Venkataiah, B. |author3=Dong, G. | journal = Tetrahedron Lett. | year=2004 | volume=45 |issue=4 | pages= 729–731 | doi = 10.1016/j.tetlet.2003.11.049 | title = The use of potassium alkynyltrifluoroborates in Mannich reactions}}{{citation |author1=Tremblay-Morin, J.-P. |author2=Raeppel, S. |author3=Gaudette, F. | journal = Tetrahedron Lett. | year=2004 | volume=45 |issue=17 | pages=3471–3474 | doi = 10.1016/j.tetlet.2004.03.014 | title = Lewis acid-catalyzed Mannich type reactions with potassium organotrifluoroborate}} 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.{{citation |author1=Portlock, D.E. |author2=Naskar, D. |author3=West, L. |author4=Li, M. | journal = Tetrahedron Lett. | year=2002 | volume=43 |issue=38 | pages= 6845–6847 | doi = 10.1016/S0040-4039(02)01511-3 | title = Petasis boronic acid-Mannich Reactions of substituted hydrazines: synthesis of α-hydrazino carboxylic acids}}{{citation | author = Naskar, D., Roy, A., Seibel, W.L., Portlock, D.E. | journal = Tetrahedron Lett. | year=2003 | volume=44 | issue = 49 | pages= 8865–8868 | doi = 10.1016/j.tetlet.2003.09.179 | title = Hydroxylamines and sulfinamide as amine components in the Petasis boronic acid–Mannich reaction: synthesis of N-hydroxy or alkoxy-α-aminocarboxylicacids and N-(tert-butyl sulfinyl)-α-amino carboxylicacids}}{{citation |author1=Naskar, D. |author2=Roy, A. |author3=Seibel, W.L., Portlock, D.E. | journal = Tetrahedron Lett. | year=2003 | volume=44 | issue = 31 | pages= 5819–5821 | doi = 10.1016/S0040-4039(03)01405-9 | title = Novel Petasis Boronic Acid—Mannich Reactions with Tertiary Aromatic Amines}}{{citation |author1=Naskar, D. |author2=Neogi, S. |author3=Roy, A. |author4=Mandal, A.B. | journal = Tetrahedron Lett. | year=2008 | volume=49 | issue = 48 | pages= 6762–6764 | doi = 10.1016/j.tetlet.2008.08.029 | title = Novel Petasis boronic acid reactions with indoles: synthesis of indol-3-yl-aryl-acetic acids}}

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:

Image:E-Allylamines.png

This reaction was used to synthesize naftifine

Image:Petasis-naftifine.png

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.{{cite journal|last=Jourdan|first=H.|author2=Gouhier, G.; Van Hijfte, L.; Angibaud, P.; Piettre, S. R.|journal=Tetrahedron Lett.|year=2005|volume=46|issue=46|pages=8027–8031|doi=10.1016/j.tetlet.2005.09.060|title=On the use of boronates in the Petasis reaction}}

Image:Generic rxn 1 HFIP.png

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.

Image:Aryl glycine rxn scheme.png

Racemic Clopidogrel, an antiplatelet agent, was synthesized in two steps using Petasis reaction.{{cite journal|last=Kalinski|first=C.|author2=Lemoine, H. |author3=Schmidt, J. |author4=Burdack, C. |author5=Kolb, J. |author6=Umkehrer, M. |author7= Ross, G. |journal=Synthesis|year=2008|pages=4007–4011|doi=10.1055/s-0028-1083239 |volume=2008 |issue=24|title=Multicomponent Reactions as a Powerful Tool for Generic Drug Synthesis}}

Image:Clopidogrel synthesis.png

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.

Image:Diastereoselectivealphaaminoacids.png

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.

Image:N-sub indole Petasis-acid formation.png

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.

Image:Petasis with tri-substituted aromatic amine.png

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.{{cite book|title=Multicomponent Reactions|url=https://archive.org/details/multicomponentre00zhuj|url-access=limited|year=2005|publisher=Wiley-VCH|pages=[https://archive.org/details/multicomponentre00zhuj/page/n214 199]–223|doi=10.1002/3527605118.ch7|author=Petasis, N.A.|editor1=Zhu, J. |editor2=Bienayme, H. |chapter=Multicomponent Reactions with Organoboron Compounds|isbn=9783527605118}}

Image:Enalaprilat scheme.png

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.

Image:Piperazinones, benzopiperazinones, and benzodiazepinones.png

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.

Image:StereocontrolofBaminoalcohols.png

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.{{cite journal|last=Davis|first=A.S.|author2=Pyne, S. G. |author3=Skelton, B. W. |author4= White, A. H. |journal=J. Org. Chem.|year=2004|volume=69|issue=9|pages=3139–43|pmid=15104453|title=Synthesis of putative uniflorine A|doi=10.1021/jo049806y}}{{cite journal|last=Au|first=C. W. G.|author2=Pyne, S.G.|journal=J. Org. Chem.|year=2006|volume=71|issue=18|pages=7097–9|pmid=16930074|title=Asymmetric synthesis of anti-1,2-amino alcohols via the Borono-Mannich reaction: A formal synthesis of (−)-swainsonine|doi=10.1021/jo0610661|url=https://ro.uow.edu.au/scipapers/1191 }}{{cite journal|last=Pyne|first=S.G.|author2=Au, C. W. G. |author3=Davis, A. S. |author4=Morgan, I. R. |author5=Ritthiwigrom, T. |author6= Yazici, A. |journal=Pure Appl. Chem.|year=2008|volume=80|issue=4|pages=751–762|doi=10.1351/pac200880040751 |title=Exploiting the borono-Mannich reaction in bioactive alkaloid synthesis|doi-access=free}}

Image:Stereocontrol mechanism of amino alcohol.png

With dihydroxyacetone, a somewhat unconventional aldehyde equivalent, Petasis reaction give the core structure of FTY720, a potent immunosuppressive agent.{{cite journal|last=Sugiyama|first=S.|author2=Arai, S. |author3=Kiriyama, M. |author4= Ishii, K. |journal=Chem. Pharm. Bull.|year=2005|volume=53|issue=1|pages=100–2|pmid=15635240|title=A convenient synthesis of immunosuppressive agent FTY720 using the petasis reaction |doi=10.1248/cpb.53.100|doi-access=free}}

Image:FTY720 synthesis.png

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.

Image:Mannosamine synthesis.png

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,{{cite journal|last=Jiang|first=B.|author2=Yang, C.-G. |author3=Gu, X.-H. |journal=Tetrahedron Lett.|year=2001|volume=42|issue=13|pages=2545–2547|doi=10.1016/s0040-4039(01)00229-5|title=A highly stereoselective synthesis of indolyl N-substituted glycines}} 2-substituted pyrrolidines,{{cite journal|last=Nanda|first=K.K.|author2=Trotter, B.W.|journal=Tetrahedron Lett.|year=2005|volume=46|issue=12|pages=2025–8|doi=10.1016/j.tetlet.2005.01.151|title=Diastereoselective Petasis Mannich reactions accelerated by hexafluoroisopropanol: a pyrrolidine-derived arylglycine synthesis}} and 5-substituted 2-morpholinones{{cite journal|last=Harwood|first=L.M.|author2=Currie, G. S. |author3=Drew, M. G. B. |author4= Luke, R. W. A. |journal=Chem. Commun.|issue=16|year=1996|pages=1953| doi = 10.1039/cc9960001953 |title=Asymmetry in the boronic acid Mannich reaction: diastereocontrolled addition to chiral iminium species derived from aldehydes and (S)-5-phenylmorpholin-2-one}}{{cite journal|last=Currie|first=G.S.|author2=Drew, M. G. B. |author3=Harwood, L. M. |author4=Hughes, D. J. |author5=Luke, R. W. A. |author6= Vickers, R. J. |journal=J. Chem. Soc., Perkin Trans. 1|issue=17|year=2000|pages=2982–2990|doi=10.1039/B003067H|title=Chirally templated boronic acid Mannich reaction in the synthesis of optically active α-amino acids}} have been shown to induce good to excellent diastereomeric excess under different Petasis reaction conditions.

Image:Diastereoselective synthesis w- chiral amine.png

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{{cite journal|last=Batey|first=R.A.|author2=MacKay, D. B. |author3=Santhakumar, V. |journal=J. Am. Chem. Soc.|year=1999|volume=121|issue=21|pages=5075–5076|doi=10.1021/ja983801z|title=Alkenyl and Aryl BoronatesMild Nucleophiles for the Stereoselective Formation of Functionalized N -Heterocycles}} and Hydroxy-γ- and δ-lactams{{cite journal|last=Morgan|first=I.R.|author2=Yazici, A. |author3=Pyne, S. G. |journal=Tetrahedron|year=2008|volume=64|issue=7|pages=1409–1419|doi=10.1016/j.tet.2007.11.046|title=Diastereoselective borono-Mannich reactions on cyclic N-acyliminium ions}} 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.

Image:Chiral N-acyliminium Petasis reaction.png

(±)-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.{{cite journal|last=Batey|first=R.A.|author2=MacKay, D.B.|journal=Tetrahedron Lett.|year=2000|volume=41|issue=51|pages=9935–9938|doi=10.1016/s0040-4039(00)01790-1|title=Total synthesis of (±)-6-deoxycastanospermine: an application of the addition of organoboronates to N-acyliminium ions}}

Image:Deoxycastanospermine synthesis.png

Enantioselective Petasis-type reaction transform quinolines into respective chiral 1,2-dihydroquinolines (product) using alkenyl boronic acids and chiral thiourea catalyst:{{cite journal|last=Yamaoka|first=Y.|author2=Miyabe, H. |author3=Takemoto, Y. |journal=J. Am. Chem. Soc.|year=2007|volume=129|issue=21|pages=6686–7|pmid=17488015|title=Catalytic enantioselective petasis-type reaction of quinolines catalyzed by a newly designed thiourea catalyst|doi=10.1021/ja071470x}}

Image:Takemoto reaction scheme.png

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.

Image:Takemoto TS1.png

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:{{cite journal|last=Lou|first=S.|author2=Schaus, S.E.|journal=J. Am. Chem. Soc.|year=2008|volume=130|issue=22|pages=6922–6923|pmid=18459782|pmc=2440570|title=Asymmetric petasis reactions catalyzed by chiral biphenols|doi=10.1021/ja8018934}}

Image:Schaus reaction scheme.png

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:{{citation |author1=Han, W.-Y. |author2=Wu, Z.-J. |author3=Zhang, X.-M. |author4=Yuan, W.-C. | journal = Org. Lett. | year=2012 | volume=ASAP | issue = 4 | pages = 976–979 | doi = 10.1021/ol203109a |pmid=22292670 | title = Enantioselective Organocatalytic Three-Component Petasis Reaction among Salicylaldehydes, Amines, and Organoboronic Acids|s2cid=9416125 }}

Image:Yuan reaction scheme.png

In one application the Petasis reaction is used for quick access to a multifunctional scaffold for divergent synthesis. The reactants are the lactol derived from L-phenyl-lactic acid and acetone, l-phenylalanine methyl ester and a boronic acid. The reaction takes place in ethanol at room temperature to give the product, an anti-1,2-amino alcohol with a high diastereomeric excess.{{cite journal | author = Naoya Kumagai, Giovanni Muncipinto, Stuart L. Schreiber | journal = Angewandte Chemie International Edition | year = 2006 | volume = 45 | pages = 3635–3638 | doi = 10.1002/anie.200600497 | title = Short Synthesis of Skeletally and Stereochemically Diverse Small Molecules by Coupling Petasis Condensation Reactions to Cyclization Reactions | pmid = 16646101 | issue = 22| last2 = Muncipinto | last3 = Schreiber}}

Image:PetasisReaction.png

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:{{cite journal|last=Muncipinto|first=G.|author2=Moquist, P.N. |author3=Schreiber, S.L. |author4= Scahus, S.E. |journal=Angew. Chem. Int. Ed.|year=2011|volume=50|issue=35|pages=8172–8175|doi=10.1002/anie.201103271 |pmid=21751322|title=Catalytic Diastereoselective Petasis Reactions|pmc=4673970}}

Image:Schaus ACIE reaction scheme.png

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.

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.{{cite journal|last=Soule|first=J.-F.|author2=Mathieu, A. |author3=Norsikian, S. |author4= Beau, J.-M. |journal=Org. Lett.|year=2010|volume=12|issue=22|pages=5322–5325|pmid=20945892|title=Coupling the Petasis condensation to an iron(III) chloride-promoted cascade provides a short synthesis of Relenza congeners|doi=10.1021/ol102326b}}

Image:Beau et al. schemes3.png

Wong and coworkers prepared N-acetylneuraminic acid with a PBM coupling, followed by nitrone-[3+2] cycloaddition. 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.{{cite journal|last=Hong|first=Z.|author2=Liu, L. |author3=Hsu, C.-C. |author4= Wong, C,-H. |journal=Angew. Chem. Int. Ed.|year=2006|volume=45|issue=44|pages=7417–7421|doi= 10.1002/anie.200601555 |pmid=17031889|title=Three-Step Synthesis of Sialic Acids and Derivatives|url=http://ntur.lib.ntu.edu.tw/bitstream/246246/218230/-1/24.pdf}}

Image:Wong et al. scheme.png

• Mannich reaction
• Reductive amination
• Suzuki reaction

{{Reflist}}

Category:Multiple component reactions

Category:Substitution reactions

Category:Name reactions

Category:Chemical synthesis of amino acids