Ralph F. Hirschmann award address 2009: Merger of organic chemistry with peptide diversity

Abstract

A huge unleashed potential lies hidden in the large and diverse pool of encoded and particularly nonencoded chiral alpha-, beta-, and gamma-amino acids available today. Although these have been extensively exploited in peptide science, the community of organic chemistry has only used this source of diversity in a quite focused and targeted manner. The properties and behavior of peptides as functional molecules in biology are well documented and based on the ability of peptides to adapt a range of discrete conformers at a minimal entropic penalty and therefore ideally fitting their endogenous targets. The development of new organic reactions and chemistries that in a general and quantitative way transform peptides into new functional molecules, preferably on solid support, is a source of completely new classes of molecules with important and advantageous functional properties. The peptide diversity and the ability to perform chemistry on solid support add tremendously to the combinatorial scope of such reactions in pharmaceutical and materials screening scenario. In recent years, the need for "click" reactions to shape complex molecular architecture has been realized mainly with a basis in the world of peptides and DNA, and in polymer chemistry where connection of highly functionalized biologically active substances or property bearing fragments are assembled as molecular LEGO using quantitative and orthogonal click chemistries. In this article, three such new reactions originating in the Carlsberg Laboratory over the last decade taking advantage of organic transformations in the peptide framework is presented. Initially, the click reaction between azide and terminal alkynes catalyzed by Cu(1) (CuAAC-reaction) is described. This CuAAC "click" reaction was observed first at Carlsberg Laboratory in reactions of azido acid chlorides with alkynes on solid support. Second, the Electrophilic Aromatic Substitution Cyclization-Intramolecular Click-Cascade (EASCy-ICC) reaction will be presented. This quantitative stereo-selective cascade reaction provides a highly diverse set of interesting novel scaffolds from peptides. Finally, we describe the preparation of solid phase peptide phosphine- and carbene-based green catalysts (organozymes), which upon complex formation with transition metal perform with high turnovers under aqueous conditions. These catalysts thrive from the peptide folding and diversity, while phosphines and carbenes in the backbone provide for bidental complex formation with transition metals in a format providing an excellent entry into combinatorial catalyst chemistry.

Recent Advances in Recoverable Systems for the Copper-Catalyzed Azide-Alkyne Cycloaddition Reaction (CuAAC)

“…With applications ranging from material science to medicinal chemistry it is not surprising that investigations connected with the CuAAC topic, or just making use of this technique, are appearing with impressive and increasingly high frequency in the literature. As shown in Figure 1, these advancements comprise long-standing topics and some incompletely settled aspects like, e.g., the reaction mechanism, as well as new trends and examples of use of CuAAC in unprecedented directions [6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61].…”

Dihydroquinazolinones via A3‐Type Reactions of N‐Carbamoyliminium Ions

“…Previous studies of INCIC reactions have predominantly been conducted on solid‐support, which provide simple product isolation [31, 32] . Hence, the INCIC/A 3 methodology was explored by solid‐phase chemistry in combination with peptide synthesis.…”

“…Previous studies of INCIC reactions have predominantly been conducted on solid-support, which provide simple product isolation. [31,32] Hence, the INCIC/A 3 methodology was explored by solid-phasec hemistry in combinationw ith peptide synthesis. For this purpose, urea 7 was generated by coupling of Box-protected amino aldehyde buildingblock 1 to the N-terminus of the model tripeptide, Ala-Phe-Gly,a ttachedt oap olyethylene glycol polyacrylamide copolymer (PEGA) resin using an 4-hydroxymethylbenzoic acid (HMBA) linker.…”

Diversity‐Oriented Syntheses by Combining CuAAC and Stereoselective INCIC Reactions with Peptides

“…The THC and THIQ scaffolds are commonly obtained by Pictet–Spengler type reactions through iminium species . We introduced the related intramolecular N ‐carbamoyl iminium cascade (INCIC) reactions, which quantitatively yields elaborate scaffolds, including THC and THIQ, generated with extraordinary reactivity and diastereoselectivity (see, for example, 5 and 6 , Figure ) …”