Hydrazinopeptide Motifs Synthesized via the Ugi Reaction: An Insight into the Secondary Structure

Abstract

A number of N ^α-alkyl,N ^β-acylhydrazines have been synthesized via the Ugi reaction of N-acylhydrazones with an isocyanide and trifluoroacetic acid. The trifluoroacetic acid acted as a ‘silent partner’ and becomes removed upon basic workup of the reaction. These compounds have been efficiently modified further via reductive alkylation to produce N ^α,N ^α-dialkyl,N ^β-acylhydrazines. The two groups of novel hydrazinopeptide motifs have been shown by simple ^¹H NMR spectroscopic experiments to display two different secondary structure patterns. These observations were confirmed by X-ray crystallographic analysis. Combining the hydrazone and carboxylic acid moieties in one reaction precursor offers the opportunity for an ‘intramolecular’ hydrazino-Ugi reaction, which was also demonstrated.

multicomponent reactions - hydrazones - substituent effects - peptidomimetics - secondary structures

References

<A NAME="RP15009SS-1">1</A> Ugi I. Meyr R. Fitzer U. Steinbrucker C. Angew. Chem.  1959,  71:  386 

<A NAME="RP15009SS-2">2</A> Dömling A. Chem. Rev.  2006,  106:  17 

<A NAME="RP15009SS-3">3</A> El Kaim L. Grimaud L. Tetrahedron  2009,  65:  2153 

<A NAME="RP15009SS-4A">4a</A> Ugi I. Bodesheim F. Chem. Ber.  1961,  94:  2797 

<A NAME="RP15009SS-4B">4b</A> Ugi I. Bodesheim F. Justus Liebigs Ann. Chem.  1963,  666:  61 

<A NAME="RP15009SS-4C">4c</A> Zinner G. Kliegel W. Arch. Pharm. (Weinheim, Ger.)  1966,  299:  746 

<A NAME="RP15009SS-4D">4d</A> Zinner G. Bock W. Arch. Pharm. (Weinheim, Ger.)  1971,  304:  933 

<A NAME="RP15009SS-4E">4e</A> Failli A. Nelson V. Immer H. Götz M. Can. J. Chem.  1973,  51:  2769 

<A NAME="RP15009SS-4F">4f</A> Marcaccini S. Pepino R. Polo C. Pozo MC. Synthesis  2001,  85 

<A NAME="RP15009SS-5A">5a</A> Zinner G. Moderhack D. Kliegel W. Chem. Ber.  1969,  102:  2536 

<A NAME="RP15009SS-5B">5b</A> Moderhack D. Justus Liebigs Ann. Chem.  1973,  764:  359 

<A NAME="RP15009SS-5C">5c</A> Zinner G. Moderhack D. Hantelmann O. Bock W. Chem. Ber.  1974,  107:  2947 

<A NAME="RP15009SS-5D">5d</A> Basso A. Banfi L. Guanti G. Riva R. Riu A. Tetrahedron Lett.  2004,  45:  6109 

<A NAME="RP15009SS-5E">5e</A> Basso A. Banfi L. Guanti G. Riva R. Tetrahedron Lett.  2005,  46:  8003 

<A NAME="RP15009SS-6">6</A> Diaz JL. Miguel M. Lavilla R. J. Org. Chem.  2004,  69:  3550 

<A NAME="RP15009SS-7">7</A> Kiselyov AS. Tetrahedron Lett.  2005,  46:  4851 

<A NAME="RP15009SS-8">8</A> Grupe R. Baeck B. Niedrich H. J. Prakt. Chem.  1971,  314:  751 

<A NAME="RP15009SS-9">9</A> Bushkova E. Parchinsky V. Krasavin M. Mol. Diversity  2010,  in press; DOI: 10.1007/s11030-009-9200-6

<A NAME="RP15009SS-10">10</A> Lelais G. Seebach D. Helv. Chim. Acta  2003,  86:  4152 

<A NAME="RP15009SS-11">11</A> Guy L. Vidal J. Collet A. J. Med. Chem.  1998,  41:  4833 

<A NAME="RP15009SS-12">12</A> Aubury A. Mangeot J.-P. Vidal J. Collet A. Zerkout S. Marraud M. Int. J. Pept. Protein Res.  1994,  43:  305 

<A NAME="RP15009SS-13">13</A>

Efforts are currently underway in our laboratories to realize a strategy of stereochemistry relay from nonracemic partners in the hydrazino-Ugi reaction and, thus, prepare short nonracemic hydrazinopeptide compounds via diastereomeric resolution.

<A NAME="RP15009SS-14">14</A> Dömling A. Ugi I. Angew. Chem. Int. Ed.  2000,  39:  3168 

<A NAME="RP15009SS-15A">15a</A> Marcaccini S. Miguel D. Torroba T. Garcia-Valverde M. J. Org. Chem.  2003,  68:  3315 

<A NAME="RP15009SS-15B">15b</A> Marcaccini S. Pepino R. Torroba T. Miguel D. Garcia-Valverde M. Tetrahedron Lett.  2002,  43:  8591 

<A NAME="RP15009SS-15C">15c</A> Ilyin AP. Trifilenkov A. Kurashvili I. Krasavin M. Ivachtchenko AV. J. Comb. Chem.  2005,  7:  360 

<A NAME="RP15009SS-15D">15d</A> Ilyin AP. Loseva MV. Vvedensky VY. Putsykina EB. Tkachenko SE. Kravchenko DV. Khvat AV. Krasavin M. Ivachtchenko AV. J. Org. Chem.  2006,  71:  2811 

<A NAME="RP15009SS-16">16</A> Naskar D. Roy A. Seibel WL. West L. Portlock DE. Tetrahedron Lett.  2003,  44:  6297 

<A NAME="RP15009SS-17">17</A>

The ^¹H NMR spectroscopic chemical shifts showed the α-nitrogen proton in 4 as well as the analogous proton in 10 to be negligibly sensitive to the solvent change, most likely because the protons are less acidic.

<A NAME="RP15009SS-18A">18a</A> Novak P. Piculjan K. Hrenar T. Biljan T. Meic Z. J. Mol. Struct.  2009,  919:  66 

<A NAME="RP15009SS-18B">18b</A> Abraham RJ. Mobli M. Magn. Reson. Chem.  2007,  45:  865 

<A NAME="RP15009SS-18C">18c</A> Grzesiek S. Cordier F. Jaravine V. Barfield M. Prog. Nucl. Magn. Reson. Spectrosc.  2004,  45:  275 

<A NAME="RP15009SS-18D">18d</A> Samoilenko AA. Zh. Strukt. Khim.  1975,  16:  568 

<A NAME="RP15009SS-19">19</A>

All reference fragments 10 and 11 used in this work are known and commercially available compounds.

<A NAME="RP15009SS-20">20</A>

Crystallographic data (excluding structure factors) for structures 4i and 9h have been deposited with the Cambridge Crystallographic Data Centre (CCDC) as supplementary publications CCDC 743067 (4i) and CCDC 752329 (9h), respectively. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: [phone], e-mail: [e-mail]].

<A NAME="RP15009SS-21">21</A>

Molecular mechanics (MM2) calculations performed using ChemBio3D (Ultra) v11.0 demonstrated that the observed conformations for compounds 4i and 9h displayed minimized energies of 6.48 and 7.62 kcal/mol, respectively. Alternative hydrogen-bonded conformations displayed significantly higher minimized energies (14.1 and 14.0 kcal/mol, respectively).