Ausgeprägte Methyleffekte in der Wirkstoff‐Forschung und der Bedarf an neuen C‐H‐Methylierungsreaktionen

Abstract

Die Methylgruppe gehört zu den häufigsten Kohlenstoffbausteinen in niedermolekularen Wirkstoffen. Dieser einfachste Alkylrest kommt in mehr als 67 % der 2011 meistverkauften Wirkstoffe vor und kann die biologischen und physikalischen Eigenschaften einer Verbindung in bedeutendem Maß modulieren. Den Schwerpunkt dieses Aufsatzes bildet der so genannte magische Methyleffekt auf das Bindungsvermögen, bei dem der scheinbar banale Wechsel von der C‐H‐ zur C‐Me‐Gruppe den IC50‐Wert eines potenziellen Wirkstoffs um mehr als das 100fache verbessert. Anschließend an diese Diskussion folgt ein Überblick über Fortschritte in der Synthesechemie, die eine direkte Methylierung von sp2‐ und sp3‐C‐H‐Bindungen ermöglichen. Wir hoffen, dass die hier besprochene Bedeutung der einfachen Methylgruppe für die Wirkstoff‐Forschung zu Berichten über neue und umfassende C‐H‐Methylierungsreaktionen anregt.

Re2O7‐Mediated Dehydrative Cyclization Reactions: Total Synthesis of Herboxidiene and Its 12‐Desmethyl Analogue

“…This is illustrated by structure 37 in Figure 1. [35] 1 HNMR analysis again supports this hypothesis,w ith the coupling constants of the C12 and C13 hydrogen atoms in 36 being 5.6 and 8.1 Hz, which correlates with at ime-averaged conformational ensemble. 1 HNMR data support this analysis.T he C13 hydrogen atoms of 22 have coupling constants of 4.8 and 10.8 Hz to the C12 hydrogen atom, indicating ad ominant conformation.…”

“…Removal of the C12 methyl group eliminates the energetic penalty for the syn-pentane interaction, thereby making several additional conformations available through rotation around the C12À C13 and C11ÀC12 bonds. [35] 1 HNMR analysis again supports this hypothesis,w ith the coupling constants of the C12 and C13 hydrogen atoms in 36 being 5.6 and 8.1 Hz, which correlates with at ime-averaged conformational ensemble. We postulate that 37 represents the binding conformation and removing the methyl group leads to asignificant reduction in the population of conformers that interact with the spliceosome.…”

Re2O7‐Mediated Dehydrative Cyclization Reactions: Total Synthesis of Herboxidiene and Its 12‐Desmethyl Analogue

“…Removal of the C12 methyl group eliminates the energetic penalty for the syn -pentane interaction, thereby making several additional conformations avaliable through rotation around the C12–13 and C11–C12 bonds. [35] 1 H NMR analysis again supports this hypothesis, with the coupling constants of the C12 and C13 hydrogens in 36 being 5.6 and 8.1 Hz, which correlates with a time averaged conformational ensemble. We postulate that 37 represents the binding conformation and removing the methyl group leads to a significant reduction in the population of conformers that interact with the spliceosome.…”

Cobalt‐Catalyzed C(sp2)−H Methylation by using Dicumyl Peroxide as both the Methylating Reagent and Hydrogen Acceptor

“…The metal-catalyzed CÀHm ethylation in principle meets these requirements because of its inherents implicity and potential abbreviation of synthetic procedures. [4] Reactions of this sort have been lesse xplored, [5][6][7][8][9] indeed most of these reactions rely on the use of the expensive 4d transition-metal catalyst palladium [6][7][8] together with MeI [6a-j] or its equivalents [6k-m] as the electrophilic methylating reagents under basic conditions, or with organometallic compoundsasn ucleophilic methylating reagents under oxidativec onditions. [7] Recently,t he CÀHm ethylation catalyzed by first-row transition metals has attractedm uch attention because of the ready availability,low cost, relatively low toxicity, and unique catalytic abilitieso ft hese metal agents (Scheme 1A).…”