Divergent Synthesis of C5‐Heteroatom Substituted Oxazoles

5‐Oxazoyl‐sulfamates have been profiled as versatile building blocks for modifications of oxazoles with various nucleophiles. The unified approach provides a diversification platform to directly access 5‐amino‐oxazoles, 5‐oxazolyl‐sulfides, and 5‐oxazoyl‐aryl ethers from a single precursor

Temperature-sensitive protein–DNA dimerizers

Programmable DNA-binding polyamides coupled to short peptides have led to the creation of synthetic artificial transcription factors. A hairpin polyamide-YPWM tetrapeptide conjugate facilitates the binding of a natural transcription factor Exd to an adjacent DNA site. Such small molecules function as protein-DNA dimerizers that stabilize complexes at composite DNA binding sites. Here we investigate the role of the linker that connects the polyamide to the peptide. We find that a substantial degree of variability in the linker length is tolerated at lower temperatures. At physiological temperatures, the longest linker tested confers a "switch"-like property on the protein-DNA dimerizer, in that it abolishes the ability of the YPWM moiety to recruit the natural transcription factor to DNA. These observations provide design principles for future artificial transcription factors that can be externally regulated and can function in concert with the cellular regulatory circuitry

Stereoselective Total Synthesis of (−)‐Thallusin for Bioactivity Profiling

Chemical mediators are key compounds for controlling symbiotic interactions in the environment. Here, we disclose a fully stereoselective total synthesis of the algae differentiation factor (−)‐thallusin that utilizes sophisticated 6‐ endo ‐cyclization chemistry and effective late‐stage sp 2 –sp 2 ‐couplings using non‐toxic reagents. An EC 50 of 4.8 pM was determined by quantitative phenotype profiling in the green seaweed Ulva mutabilis (Chlorophyte), underscoring this potent mediator‘s enormous, pan‐species bioactivity produced by symbiotic bacteria. SAR investigations indicate that (−)‐thallusin triggers at least two different pathways in Ulva that may be separated by chemical editing of the mediator compound structure

Minimization of a Protein−DNA Dimerizer

A protein−DNA dimerizer constructed from a DNA-binding polyamide and the peptide FYPWMKG facilitates the binding of a natural transcription factor Exd to an adjacent DNA site. The Exd binding domain can be reduced to a dipeptide WM attached to the polyamide through an ε-aminohexanoic acid linker with retention of protein−DNA dimerizer activity. Screening a library of analogues indicated that the tryptophan indole moiety is more important than methionine's side chain or the N-terminal acetamide. Remarkably, switching the stereochemistry of the tryptophan residue (l to d) stabilizes the dimerizer•Exd•DNA ternary complex at 37 °C. These observations provide design principles for artificial transcription factors that may function in concert with the cellular regulatory circuitry

Cornforth–Evans Transition States in Stereocontrolled Allylborations of Epoxy Aldehydes

Allylboration reactions rank among the most reliable tools in organic synthesis. Herein, we report a general synthesis of trifunctionalized allylboronates and systematic investigations of their stereocontrolled transformations with substituted aldehyde substrates, in order to efficiently access diverse, highly substituted target substrates. A peculiar transition in stereocontrol was observed from the polar Felkin–Anh (PFA) to the Cornforth–Evans (CE) model for alkoxy‐ and epoxy‐substituted aldehydes. CE‐type transition states were uniformly identified as minima in advanced, DFT‐based computational studies of allylboration reactions of epoxy aldehydes, conforming well to the experimental data, and highlighting the underestimated relevance of this model. Furthermore, a mechanism‐based rationale for the substitution pattern of the epoxide was delineated that ensures high levels of stereocontrol and renders α,β‐epoxy aldehydes generally applicable substrates for target synthesis

(Z)-Methyl 2-methoxy­imino-3-oxo­butanoate

The title compound, C6H9NO4, was prepared stereoselectively as a precursor for 1-aza­dienes in a study of hetero-Diels–Alder reactions. The configuration of the C=N double bond was found to be Z, corroborating earlier assignments of similar compounds based only on NMR and IR spectroscopic analysis

Toward artificial developmental regulators

A polyamide-peptide conjugate is designed which recruits sequence specifically the developmental regulator Exd to a cognate DNA site. In particular, an eight-ring hairpin polyamide (Im-Im-Py(C3H6NHR)-Py-gamma-Im-Py-Py-Py-beta-Dp) with a heptapeptide (R = Ac-Phe-Tyr-Pro-Trp-Met-Lys-Gly-) attached on a central ring was shown to induce cooperative binding of the Drosophila Hox protein cofactor Exd with a Kd of 4.4 nM in vitro, an order of magnitude more efficient than the natural Hox protein partner Ubx. The conjugate joins two sequence specific domains, one for DNA and one for the protein. This small molecule thus serves as a cooperative protein-DNA dimerizer, which mimics the natural Hox family of developmental regulators

Stereoselektive Totalsynthese von (−)‐Thallusin zur Bioaktivitätsprofilierung

Chemische Mediatoren sind Schlüsselverbindungen zur Kontrolle von Symbiosen in unserer Umwelt. Hier berichten wir über eine völlig stereoselektive Totalsynthese des Algendifferenzierungsfaktors (−)‐Thallusin, die sich durchdachter 6‐ endo ‐Zyklisierungschemie und effektiver sp 2 –sp 2 ‐Kupplungen mittels Zinn‐freier Reagenzien auf späten Stufen bedient. Durch quantitative phänotypische Profilierung wurde für die weit verbreitete Grünalge Ulva mutabilis (Chlorophyta) ein EC 50 ‐Wert von 4.8 pM ermittelt, was die enorme artenübergreifende Bioaktivität dieses von symbiotischen Bakterien produzierten Mediators aufzeigt. SAR‐Untersuchungen weisen darauf hin, dass (−)‐Thallusin mindestens zwei unterschiedliche Signalwege in Ulva auslöst, die durch chemische Editierung der Mediatorstruktur separiert werden können

Minimization of a Protein−DNA Dimerizer

A protein−DNA dimerizer constructed from a DNA-binding polyamide and the peptide FYPWMKG facilitates the binding of a natural transcription factor Exd to an adjacent DNA site. The Exd binding domain can be reduced to a dipeptide WM attached to the polyamide through an ε-aminohexanoic acid linker with retention of protein−DNA dimerizer activity. Screening a library of analogues indicated that the tryptophan indole moiety is more important than methionine's side chain or the N-terminal acetamide. Remarkably, switching the stereochemistry of the tryptophan residue (l to d) stabilizes the dimerizer•Exd•DNA ternary complex at 37 °C. These observations provide design principles for artificial transcription factors that may function in concert with the cellular regulatory circuitry