Synthesis of 3-Oxo-2,3-dihydropyrrole Amino Acids as Chiral Dipeptidomimics

Abstract

We describe the synthesis of a novel chiral dipeptide β-sheet mimic based on aminomethyl-3-oxo-2,3-dihydropyrrole carboxylic acids. The synthesis uses a palladium-catalyzed allylation with the chiral Trost ligand as a key step for the construction of a quaternary chiral center. This allows the enantioselective conversion of 2-carboxy-3-hydroxy-pyrrole into 3-oxo-2,3-dihydropyrrole-2-allyl-2-carboxylate. The allyl group is subsequently converted into an aldehyde or ester group. Peptide coupling of the 3-oxo-2,3-dihydropyrrole amino acid leads to more extended systems with partially constrained dipeptide units.

pyrroles - 3-oxo-2,3-dihydropyrrole - allylations - amino acids - catalysis - palladium

References

<A NAME="RZ08406SS-1">1</A> Smith AB. Akaishi R. Jones DR. Keenan TP. Guzman MC. Holcomb RC. Hirschmann R. Wood JL. Hirschmann R. Holloway MK. Biopolymers  1995,  37:  2953 

<A NAME="RZ08406SS-2">2</A> Smith AB. Hirschmann R. Pasternak A. Guzman MC. Yokoyama A. Sprengeler PA. Darke PL. Emini EA. Schleif WA. J. Am. Chem. Soc.  1995,  117:  11113 

<A NAME="RZ08406SS-3">3</A> Smith AB. Guzman MC. Sprengeler PA. Keenan TP. Holocomb RC. Wood JL. Carroll PJ. Hirschmann R. J. Am. Chem. Soc.  1994,  116:  9947 

<A NAME="RZ08406SS-4">4</A> Seebach D. Boes M. Naef R. Schweizer WB. J. Am. Chem. Soc.  1983,  105:  5390 

<A NAME="RZ08406SS-5">5</A> Bittermann H. Gmeiner P. J. Org. Chem.  2006,  71:  97 

<A NAME="RZ08406SS-6A">6a</A> Bonauer C. Zabel M. König B. Org. Lett.  2004,  6:  1349 

<A NAME="RZ08406SS-6B">6b</A> Kruppa M. Bonauer C. Michlová V. König B. J. Org. Chem.  2005,  70:  5305 

<A NAME="RZ08406SS-6C">6c</A> Bonauer C. König B. Synthesis  2005,  2367 

<A NAME="RZ08406SS-7">7</A> Trost BM. Van Vranken DL. Bingel C. J. Am. Chem. Soc.  1992,  114:  9327 

<A NAME="RZ08406SS-8">8</A> The compound was prepared according to: Bonauer C. Dissertation   Universität Regensburg; Germany: 2004. 

<A NAME="RZ08406SS-9">9</A> Momose T. Tanaka T. Yokota T. Nagamoto N. Yamada K. Chem. Pharm. Bull.  1978,  26:  3521 

<A NAME="RZ08406SS-10">10</A> Trost BM. Schroeder GM. Chem. Eur. J.  2005,  11:  174 

For examples of non-enantioselective stoichiometric related reactions, see:

<A NAME="RZ08406SS-11A">11a</A> Beyer M. Ghaffari-Tabrizi R. Jung M. Margaretha P. Helv. Chim. Acta  1984,  67:  1535 

<A NAME="RZ08406SS-11B">11b</A> Plieninger H. Herzog H. Monatsh. Chem.  1967,  98:  807 

<A NAME="RZ08406SS-12A">12a</A> Drew MGB. George AV. Isaacs NS. Rzepa HS. J. Chem. Soc., Perkin Trans. 1  1985,  1277 

<A NAME="RZ08406SS-12B">12b</A> Bennes R. Babiloni MS. Hayes W. Philip D. Tetrahedron Lett.  2001,  42:  2377 

<A NAME="RZ08406SS-12C">12c</A> Chen Z. Trudell ML. Chem. Rev.  1996,  96:  1179 

<A NAME="RZ08406SS-13">13</A> Genin ML. Johnson RL. J. Am. Chem. Soc.  1992,  114:  8778 

<A NAME="RZ08406SS-14">14</A> Zhang R. Mamai A. Madalengoitia JS. J. Org. Chem.  1999,  64:  547 

<A NAME="RZ08406SS-15">15</A>

The ¹H NMR coupling constant (³ J) between NH of the peptide bond and the α-CH shows a value of 5.9 Hz which indicates free rotation of the 3-oxo-2,3-dihydropyrrole moieties around the connecting single bond.

<A NAME="RZ08406SS-16A">16a</A> Trost BM. Schroeder GM. Kristensen J. Angew. Chem. Int Ed.  2002,  41:  3429 

<A NAME="RZ08406SS-16B">16b</A> Trost BM. Toste FD. J. Am. Chem. Soc.  1999,  121:  4545