The cyclic depsipeptide skyllamycin A is a potent inhibitor of the platelet-derived growth factor (PDGF) signaling pathway by inhibiting binding of homodimeric PDGF BB to the PDGF β-receptor. Its structure contains a cinnamoyl side chain and shows a high amount of β-hydroxylated amino acids as well as an unusual α-hydroxyglycine moiety as a rare structural modification. The skyllamycin biosynthetic gene cluster was cloned and sequenced from Streptomyces sp. Acta 2897. Its analysis revealed the presence of open reading frames encoding proteins for fatty acid precursor biosynthesis, non-ribosomal peptide synthetases, regulators, and transporters along with other modifying enzymes. Specific in-frame mutagenesis of these tailoring enzymes resulted in the production of novel skyllamycin derivatives revealing that β-hydroxy groups in skyllamycin A are introduced by a promiscuous cytochrome P450 monooxygenase, whereas a two-component flavin-dependent monooxygenase is involved in α-hydroxylation.
The discovery of single-bond activation at transition-metal centers has led to a plethora of catalytic transformations, which highlights the power of organometallic chemistry. Recently, main-group systems, [1] such as B/P-based frustrated Lewis pairs (FLPs) [2] and singlet carbenes, [3] possessing a lone pair of electrons and a vacant orbital were also shown to be able to split chemical bonds. Yet, despite this major advancement in main-group chemistry, the transfer of an activated fragment to a substrate remains challenging. The difficulty lies in regenerating the active species, which is a necessity for catalytic turnover. So far, FLP catalysis is only known with covalent H À H [4] and Si À H [5,6] bonds and sodium hydride. [7] We were keen to extend this series. [8] Because the heterolytic BÀH [9] and NÀH [10] bond activation of boranes and amines by FLPs has received little attention, we investigated the formation of the activated species 2,3A versus the adducts 2,3B (Scheme 1). For this, we reacted the readily accessible geminal phosphorus/aluminumbased FLP 1 [11] with BH 3 ·THF, ammonia (NH 3 ), and amineboranes H 3 B·NR 2 H [12] (R = H and Me). The potential of the B/N adduct as hydrogen carrier was revealed in the transition-
Helpful frustration: The geminal phosphorus/aluminum‐based frustrated Lewis pair (Mes2P)(tBu2Al)CC(H)Ph (Mes=2,4,6‐Me3C6H2) forms stable adducts with alkali metal hydrides (LiH, NaH, KH). These molecular hydride complexes display enhanced reactivity, which was demonstrated by the catalytic transformation of chlorotriphenylsilane to the corresponding hydride through a frontside SN2‐f@Si pathway.
Hydroalumination of aryldialkynylphosphines RP(C≡C-(t)Bu)(2) (R = Ph, Mes) with equimolar quantities of diethylaluminum hydride afforded mixed alkenyl-alkynyl cyclic dimers in which the dative aluminum-phosphorus bonds are geminal to the exocyclic alkenyl groups. Addition of triethylaluminum to isolated 1 (R = Ph) or to the in situ generated species (R = Mes) caused diethylaluminum ethynide elimination to yield the arylethylphosphorus dimers 2 and 3. These possess a chair-like Al(2)C(2)P(2) heterocycle with intermolecular Al-P interactions. The boat conformation (4) was obtained by the reaction of (t)Bu-P(C≡C-(t)Bu)(2) with di(tert-butyl)aluminum hydride. Despite being dimeric, 2 behaves as a frustrated Lewis pair and activates small molecules. The reaction with carbon dioxide gave cis/trans isomeric AlPC(2)O heterocycles that differ only by the configuration of the exocyclic alkenyl unit. Four isomers resulted from the reaction with phenyl isocyanate. This is caused by cis/trans isomerization of the initial C=O adduct and subsequent rearrangement to the AlPC(2)N heterocycle, being the C=N adduct.
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