Elaboration of Peptidomimetics Derived from a PADAM Approach: Synthesis of Polyfunctionalised 2(1H)-Pyrazinones via an Unexpected Aromatisation

Abstract

When the PADAM (Passerini reaction-amine deprotection-acyl migration) strategy is applied to N-Boc amino acids, the resulting β-acylamino-α-hydroxyamides can be elaborated by secondary-alcohol oxidation, Boc deprotection, and intramolecular ­cyclisation. When TFA is employed to cleave the Boc group a spontaneous aromatisation to 2(1H)-pyrazinones is observed.

Passerini multicomponent reaction - isocyanides - heterocycles - ring closure - protecting groups - aromatisation

References and Notes

<A NAME="RS02811ST-1">1</A>

Present address: P. Tosatti, School of Chemistry, University of Leeds, Leeds LS2 9JT, UK.

<A NAME="RS02811ST-2">2</A> Multicomponent Reactions   Zhu J. Bienaymé H. Wiley-VCH; Weinheim: 2005. 

<A NAME="RS02811ST-3">3</A> Dömling A. Chem. Rev.  2006,  106:  17 

<A NAME="RS02811ST-4A">4a</A> Zhu J. Eur. J. Org. Chem.  2003,  1133 

<A NAME="RS02811ST-4B">4b</A> Banfi L. Basso A. Riva R. Synlett  2010,  23 

<A NAME="RS02811ST-5">5</A> Banfi L. Guanti G. Riva R. Chem. Commun.  2000,  985 

<A NAME="RS02811ST-6A">6a</A> Banfi L. Guanti G. Riva R. Basso A. Calcagno E. Tetrahedron Lett.  2002,  43:  4067 

<A NAME="RS02811ST-6B">6b</A> Basso A. Banfi L. Riva R. Piaggio P. Guanti G. Tetrahedron Lett.  2003,  44:  2367 

<A NAME="RS02811ST-6C">6c</A> Banfi L. Basso A. Guanti G. Riva R. Mol. Diversity  2003,  6:  227 

<A NAME="RS02811ST-7A">7a</A> Semple JE. Owens TD. Nguyen K. Levy OE. Org. Lett.  2000,  2:  2769 

<A NAME="RS02811ST-7B">7b</A> Faure F. Hjelmgaard T. Roche SP. Aitken DJ. Org. Lett.  2009,  11:  1167 

<A NAME="RS02811ST-8">8</A> De Moliner F. Crosignani S. Banfi L. Riva R. Basso A. J. Comb. Chem.  2010,  12:  613 

<A NAME="RS02811ST-9">9</A>

We have already applied this concept using the same PG for the α-amino aldehyde and the α-amino acid (ref. 6a).

<A NAME="RS02811ST-10A">10a</A> For the synthesis of 7a-c, see: Wen JJ. Crews CM. Tetrahedron: Asymmetry  1998,  7:  1855 

<A NAME="RS02811ST-10B">10b</A>

The absence
of racemisation was checked by NMR analysis of the corresponding Mosher esters obtained by aldehyde reduction with NaBH₄ and subsequent reaction with (R)-Mosher’s chloride. We found that when the reduction with LiAlH₄ was performed in THF partial racemisation (5-10%) occurred, whilst complete retention of configuration was observed in Et₂O.

<A NAME="RS02811ST-11">11</A> Banfi L. Riva R. In Organic Reactions   Overman LE. Wiley-VCH; Weinheim: 2005.  p.1 

<A NAME="RS02811ST-12A">12a</A> Abellan T. Chinchilla R. Galindo N. Guillena G. Najera C. Sansano JM. Eur. J. Org. Chem.  2000,  2689 

<A NAME="RS02811ST-12B">12b</A> Najera C. Abellan T. Sansano JM. Eur. J. Org. Chem.  2000,  2809 

<A NAME="RS02811ST-12C">12c</A> Abellan T. Mancheno B. Najera C. Sansano JM. Tetrahedron  2001,  57:  6627 

<A NAME="RS02811ST-13A">13a</A> Wright AE. Pomponi SS. Cross SS. McCarthy P. J. Org. Chem.  1992,  57:  4772 

<A NAME="RS02811ST-13B">13b</A> Capon RJ. Rooney F. Murray LM. Collins E. Sim ATR. Rostas JAP. Butler MS. Carroll AR. J. Nat. Prod.  1998,  61:  660 

<A NAME="RS02811ST-13C">13c</A> Wright AE, Pomponi SA, and Jacobs RS. inventors; WO  9942092.  ; Chem. Abstr. 1999, 131, 175081

<A NAME="RS02811ST-13D">13d</A> Cutignano A. Bifulco G. Bruno I. Casapullo A. Gomez-Paloma L. Riccio R. Tetrahedron  2000,  56:  3743 

<A NAME="RS02811ST-14">14</A> Hirano K. Kubota T. Tsuda M. Watanabe K. Fromontc J. Kobayashi J. Tetrahedron  2000,  56:  8107 

<A NAME="RS02811ST-15A">15a</A> Loosen PK. Tutonda MG. Khorasani MF. Compernolle F. Hoornaert GJ. Tetrahedron  1991,  47:  9259 

<A NAME="RS02811ST-15B">15b</A> Loosen PK. Khorasani MF. Toppet SM. Hoornaert SM. Tetrahedron  1991,  47:  9269 

<A NAME="RS02811ST-15C">15c</A> Rombouts FJR. De Borggraeve W. Toppet SM. Compernolle F. Hoornaert GJ. Tetrahedron Lett.  2001,  42:  7397 

<A NAME="RS02811ST-15D">15d</A> Pawar VG. De Borggraeve WM. Synthesis  2006,  2799 

<A NAME="RS02811ST-15E">15e</A> Singh BK. Appukkuttan P. Claerhout S. Parmar VS. Van der Eycken E. Org. Lett.  2006,  8:  1863 

<A NAME="RS02811ST-15F">15f</A> Garella D. Tagliapietra S. Mehta VP. Van der Eycken E. Cravotto G. Synthesis  2010,  136 

For selected examples of bioactive compounds containing the 2(1H)-pyrazinone moiety, see:

<A NAME="RS02811ST-16A">16a</A> Janssen PAJ, Van Aken KJA, Lewi PJ, Koymans LMH, De Jonge MR, Heeres J, Daeyaert FFD, Hoornaert GJC, Compernolle FJC, and Kilonda A. inventors; WO  02078708.  ; Chem. Abstr. 2002, 137, 294978

<A NAME="RS02811ST-16B">16b</A> Jinsmaa Y. Miyazaki A. Fujita Y. Li T. Fujisawa Y. Shiotani K. Tsuda Y. Yokoi T. Ambo A. Sasaki Y. Bryant SD. Lazarus LH. Okada Y. J. Med. Chem.  2004,  47:  2599 

<A NAME="RS02811ST-16C">16c</A> Heeres J. de Jonge MR. Koymans LMH. Daeyaert FFD. Vinkers M. Van Aken KJA. Arnold E. Das K. Kilonda A. Hoornaert GJ. Compernolle F. Cegla M. Azzam RA. Andries K. de Béthune M.-P. Azijn H. Pauwels R. Lewi PJ. Janssen PAJ. J. Med. Chem.  2005,  48:  1910 

<A NAME="RS02811ST-16D">16d</A> Ainge D, Chapman D, Lindsjoe M, Loenn H, Lundkvist M, Munck af Rosenschöld M, Nikitidis A, and Pavey J. inventors; WO  2009061271.  ; Chem. Abstr. 2009, 150, 515208

<A NAME="RS02811ST-16E">16e</A> Lu T. Markotan T. Ballentine SK. Giardino EC. Spurlino J. Brown K. Maryanoff BE. Tomczuk BE. Damiano BP. Shukla U. End D. Andrade-Gordon P. Bone RF. Player MR. J. Med. Chem.  2010,  53:  1843