29 apr 2025

Improved Chemical Synthesis of Avenanthramides Family and its Analogs by Mixed Anhydride Method

Abstract

Amides derived from common hydroxycinnamic acids — including 4-hydroxycinnamic acid, 3-methoxy-4-hydroxycinnamic acid, 3,4-dihydroxycinnamic acid, 3,4-dimethoxycinnamic acid, and 3,4,5-trimethoxycinnamic acid — along with various free aminobenzoic acids, such as 5-hydroxy-2-aminobenzoic acid, a key component of the avenanthramide family, have been rapidly synthesized using an innovative, environmentally friendly synthetic methodology. This approach, grounded in traditional chemistry, utilizes mixed anhydrides to simultaneously protect and activate hydroxycinnamic acids through the actions of triethylamine and isobutyl chloroformate while employing acetone as a green solvent. The resulting amides, formed from the coupling with free aromatic amino acids, are constructed as O-carbonate-protected derivatives with high yields and purity, isolated directly via crystallization, thus eliminating chromatographic or HPLC purifications. Furthermore, free phenols can be conveniently released on demand using morpholine in methanol. Under these conditions, C-protected aromatic amino acids remain unacylated. This synthetic strategy represents a significant advancement over conventional acyl chloride methodologies, which often rely on toxic reagents and solvents and entail time-consuming and complex procedures. It enhances the production of important phytochemicals such as Avenanthramides and opens doors to various analogs, paving the way for potential pharmacological applications.




Research Article
Open Access

First published: 16 April 2025
 

Sustainable Chemical Derivatization of Hydroxycinnamic Acids

Graphical Abstract

Hydroxycinnamic acids have been derivatized in ethyl acetate using N-methyl morpholine and an alkyl chloroformate to protect and activate them. Amines were added to produce O-carbonate-protected amides, and DMAP was used as a catalyst to add alcohols, resulting in protected esters. The related acylated derivatives were obtained by activating the compounds in acetone and adding nucleophiles in water, such as free amino acids, sodium azide, or sodium hydroxide.


Description unavailable

Abstract

Green solvents like ethyl acetate and acetone convert hydroxycinnamic acids into natural and unnatural derivatives such as amides, esters, and other valuable synthetic intermediates. Employing as protection-activation a system based on an alkyl chloroformate and N-methyl morpholine, ethyl acetate emerges as an excellent solvent for coupling O-carbonate-protected mixed anhydrides in acylation reactions of C-protected amino acids, amines, and catalyzed acylation of alcohols. This results in high yields of O-protected phenolic amides and esters. Acetone is preferred for acyl nucleophilic substitution reactions involving ionic species like free amino acids, sodium azide, and sodium hydroxide, all added in water. This approach releases the resultant O-protected acylation products. Free phenolic compounds are promptly obtained on demand through carbonate deprotection. This synthetic method offers a simplified procedure and employs low-cost reagents to prepare natural and unnatural hydroxycinnamic acid derivatives.



First published: 13 March 2024
 

Research Activities




6 mag 2020

Hydroxycinnamic amides and N-Hydroxycinnamoyl-amino acids

doi.org/10.1002/slct.202000176

z Sustainable Chemistry

Protection and Activation of Hydroxycinnamic Acids in Water

Marina DellaGreca and Luigi Longobardo*[a]

Hydroxycinnamic acids such as p-coumaric, ferulic, sinapic and caffeic acids were protected as carbonates and activated as mixed carbonic anhydrides in water at RT by adding a base and isobutyl chloroformate. These anhydrides were used for amine and C-protected α-amino acid acylation to give O-carbonate protected phenolic amides. Acylation of free α-amino acids was performed in acetone-water in high yields producing the O- carbonate protected N-hydroxycinnamoyl-α-amino acids. Pure derivatives were obtained in many cases directly by crystallization. Free phenolic compounds were rapidly obtained by carbonate deprotection with piperidine. The method offers a novel route for amide bond formation in water and the direct functionalization of hydroxycinnamic acid families with free α- amino acids, providing a facile preparation of precious natural bioactive derivatives.

Department of Chemical Science University of Napoli Federico II Via Cinthia 4 - 80126 Napoli - Italy E-mail: luilongo@unina.it

Supporting information for this article is available on the WWW under https://doi.org/10.1002/slct.202000176

ChemistrySelect 2020, 5, 4588 – 4591



5 mag 2020

Hydroxycinnamyl Alcohols



A Facile Preparation of Hydroxycinnamyl Alcohols with Simultaneous Protection of Phenol Groups as Carbonate

Lucia Panzella, Marina DellaGreca, and Luigi Longobardo*[a]

A novel procedure for reduction and simultaneous protection of phenol groups of hydroxycinnamic acids to the related alcohols has been developed. During the formation of mixed anhydrides from the acids and an alkyl chloroformate, the phenol was protected as carbonate, and the mixed anhydrides were reduced with an aqueous solution of sodium borohydride. Free phenols were obtained by deprotection under mild conditions with 30% aq. NH4OH in methanol. O-protected phenolic alcohols can be converted by standard methods into orthogonally protected derivatives. This rapid and efficient synthetic method offers a simple and high-yield preparation of these important fine chemicals, overcoming the tedious and costly procedures associate with the use of strong reducing agents such as LiAlHand DIBALH.

ChemistrySelect 2018, 3, 10637 –10640

 © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim


3 mar 2018

Novel thiol- and thioether-containing amino acids: cystathionine and homocysteine families


Abstract 

Natural L-homocysteine and L,L-cystathionine, along with a series of unnatural analogues, have been prepared from L-aspartic and L-glutamic acid. Manipulation of the protected derivatives provided x-iodoamino acids, which were used in thioalkylation reactions of sulfur nucleophiles, such as the ester of L-cysteine and potassium thioacetate.







2 mar 2018

A practical route to β2,3-amino acids with alkyl side chains


Longobardo et al. SpringerPlus (2015) 4:553DOI 10.1186/s40064-015-1351-6
RESEARCH
A practical route to β2,3-amino acids with alkyl side chains

Luigi Longobardo1*, Marina DellaGreca1 and Ivan de Paola2



*Correspondence: luilongo@unina.itDipartimento di Scienze Chimiche, Università degli Studi di Napoli Federico II, Via Cinthia 4, 80126 Naples, Italy

Full list of author information is available at the end of the articleOp



Abstract
en Access
Enantiopure N(Boc)-β3-amino nitriles, valuable synthetic intermediates in the multistep homologation of α-amino acids, were alkylated using n-BuLi as base. 

Alkylations afforded easily separable, almost equimolecular mixtures of diastereomeric N(Boc)-protected syn and anti β2,3-amino nitriles. 

Suitable manipulations of both cyano and amino groups eventually led to enantiopure N- and/or C-protected β2,3-amino acids. 

For example, methanolysis using conc. HCl gas in MeOH, provides C-protected β2,3 amino acids in excellent yields. 
This methodology is applied to the synthesis of a series N(Boc)-β2,3-dialkyl amino nitriles derived from L-phenylalanine, D-phenylalanine, L-valine and one C-protected β2,3 amino acid. 

We demonstrate an efficient procedure for the preparation of anti and syn β2,3-amino acids with alkyl side chains, from α-amino acids in reasonable yields.




Keywords: Beta-amino acids, Beta-amino nitriles, Alkylation, Homologation, Carbanions








7 mag 2013

Esami CHIMICA ORGANICA BPM 2013



I prossimi appelli della sessione estiva 2013 per sostenere gli esami di Chimica Organica  per BIOLOGIA DELLE PRODUZIONI MARINE
si svolgeranno:
  • Mercoledì 12 giugno 2013 alle ore 10 a MSA
  • Mercoledi 17 luglio 2013 alle ore 10 a MSA
Inviare una e-mail di prenotazione a: luilongo@gmail.com

28 feb 2013

Immaginarie fasce della docenza universitaria




Sulle Immaginarie Fasce della Docenza Universitaria


Abstract: This report concern on unreality of teaching level in italian university. The simple analysis of a real case show that the rules applied for teaching assignments are based on pure imaginary considerations, and are quite distant from real experimental data. These rules indirectly generate resources dissipation, associated with a low quality of teaching activity. 


L’attuale sistema di reclutamento dei professori universitari, secondo quanto stabilito dai regolamenti ANVUR, è basato quasi esclusivamente su degli indicatori che misurano la presunta qualità e quantita della produzione scientifica dei singoli candidati, ma curiosamente non fa alcun riferimento a precedenti esperienze di insegnamento maturate dai candidati.

E’ come si cercasse un autista di autobus, ma non gli viene chiesto se ha la patente. Questa ulteriore, fastidiosa condizione dovrebbe essere accertata piuttosto da una commissione locale. E’ un impianto basato sulla convinzione che chi fa una buona ricerca, di per   abbia anche il talento di offrire buone prestazioni didattiche.  

Certo si è verificato molte volte nelle aule universitarie, come molti di noi ricordano con vero piacere, ma sono delle notabili eccezioni, non la norma. Fare una buona ricerca significa soprattutto studiare il lavoro degli altri, avere una delicata relazione con gli apparati sperimentali e con le sostanze che si manipolano. Con questi attrezzi ci si può misurare con la realtà delle entità materiali oggetto di studio, cioè si possono organizzare degli esperimenti nei quali si interroga il mondo reale. Le risposte ottenute molto spesso non soddisfano completamente le nostre curiosità, ma aprono nuovi e insospettabili scenari, che spingono a pensare a nuovi esperimenti.

Fare una buona didattica significa tutta una altra cosa, significa in primo luogo non fornire agli studenti banalmente una massa di nozioni, ma entrare direttamente nella loro testa, insegnando loro soprattutto a ragionare su come usare correttamente le nozioni acquisite. 

Mi sembrano in effetti due attività abbastanza diverse, l’una concernente i colleghi, i libri, le tecnologia e le molecole, l’altra solo il cervello di tanti giovani umani. E’ chiaro che essere dei buoni ricercatori non implica automaticamente essere anche dei buoni docenti. Una delicata relazione con gli apparati sperimentali non è sufficiente ad avere una corretta relazione con giovani umani. Essere dei buoni docenti significa infine essere necessariamente anche dei buoni ricercatori, perché bisogna fornire agli studenti nozioni "aggiornate".

Dunque, non sarebbe necessario soprattutto valutare le capacità didattiche dei candidati, che di solito hanno molti anni di attività di insegnamento alle spalle?  E’ un mistero.

Ma a pensarci bene, cosa rappresentano le tre fasce della docenza universitaria F1, F2 e F3 che plasmano la vita dei nostri atenei?

La dimostrazione che la legge F1 > F2 > F3 , che definisce prestazioni e retribuzioni delle fasce della docenza, è falsa, è molto semplice.

Qualunque legge, infatti, o è vera o è falsa. Non può essere entrambe le cose.
Per verificare se una legge è vera o è falsa bisogna fare degli esperimenti. Cioè bisogna calare la legge nella realtà. In questo modo si ottengono dei dati sperimentali, dei numeri, che ci dicono se la legge è vera o è falsa. 

Calando la  F1 > F2 > F3 nelle aule universitarie, si ottengono i seguenti set di dati sperimentali:

  A.   F1 > F2 > F3 
 B-     F1 > F3 > F2 
 C-     F2 > F1 > F3 
 D-    F2 > F3 > F1 
 E-     F3 > F1 > F2 
 F-     F3 > F2 > F1 


I dati ci dicono che effettivamente il caso A esiste nella realtà, ma esistono anche tutti gli altri casi. 

La quantificazione dei casi è ovviamente possibile solo conoscendo il peso relativo di ciascun caso, ma occorrerebbe conoscere le valutazioni della didattica, in tutte le realtà in cui essa viene svolta. 

Il risultato non potrebbe che dimostrare che la legge è falsa, cioè nella realtà la legge è sbagliata. In verità per dimostrarlo basta anche un solo caso compreso tra B e F.

La legge A.  F1 > F2 > F3  rimane valida nelle casse degli uffici stipendi.

31 gen 2013

Dottorato in Scienze Chimiche


Amino Acids Chemistry 

Programma del corso:

  • Chemistry and Biology. Chirality. alpha-World 
  • Secondary structures of alpha-peptides 
  • Protecting groups chemistry. Peptide coupling reagents 
  • Solid-phase synthesis: Supports and Linkers 
  • beta-amino acids and higher homologues of alpha-amino acids 
  • Homologation of alpha-amino acids 
  • Secondary structures of beta and gamma-peptides. Foldamers 
  • Synthetic applications of homologation intermediates
  • N-protected beta-Iodoamines 
  • Methionine metabolism 
  • Sulfur and Selenium containing natural and unnatural amino acids 
  • Cystathionine and Homocysteine families 
  • Proline based unnatural amino acids 
  • Peptidomimetics Chemistry 
  • Chemical synthesis of Protein. Chemical Ligation

Le lezioni sono  scaricabili dal link:

Amino Acids Chemistry