Synthesis of the C(7)–C(22) Sector of (+)-Acutiphycin via O‑Directed Double Free Radical Alkyne Hydrostannation with Ph₃SnH/Et₃B, Double I–Sn Exchange, and Double Stille Coupling

Herein a new double O-directed free radical hydrostannation reaction is reported on the structurally complex dialkyldiyne <b>11</b>. Through our use of a conformation-restraining acetal to help prevent stereocenter-compromising 1,5-H-atom abstraction reactions by vinyl radical intermediates, the two vinyl­stannanes of <b>10</b> were concurrently constructed with high stereocontrol using Ph₃SnH/Et₃B/O₂. Distannane <b>10</b> was thereafter elaborated into the bis-vinyl iodide <b>9</b> via O-silylation and double I–Sn exchange; double Stille coupling of <b>9</b>, O-desilylation, and oxidation thereafter furnished <b>8</b>

The Absolute Configuration for Inthomycin C: Revision of Previously Published Work with a Reinstatement of the (3<i>R</i>)‑Configuration for (−)-Inthomycin C

Stereochemical evidence is presented to demonstrate that (−)-inthomycin C has (3<i>R</i>)- and not (3<i>S</i>)-stereochemistry. Careful reappraisal of the previously published work− now indicates that the Hatakeyama, Hale, Ryu, and Taylor teams <i>all</i> have synthesized (−)-(3<i>R</i>)-inthomycin C. The newly measured [α]_D of pure (−)-(3<i>R</i>)-inthomycin C (98% ee) is −7.9 (<i>c</i> 0.33, CHCl₃) and not −41.5 (<i>c</i> 0.1, CHCl₃) as was previously reported in 2012

Biosynthetic Chlorination of the Piperazate Residue in Kutzneride Biosynthesis by KthP

Kutznerides 2 and 8 of the cyclic hexadepsipeptide family of antifungal natural products from the soil actinomycete <i>Kutzneria</i> sp. 744 contain two sets of chlorinated residues, a 6,7-dichlorohexahydropyrroloindole moiety derived from dichlorotryptophan and a 5-chloropiperazate moiety, as well as a methylcyclopropylglycine residue that may arise from isoleucine via a cryptic chlorination pathway. Previous studies identified KtzD, KtzQ, and KtzR as three halogenases in the kutzneride pathway but left no candidate for installing the C5 chlorine on piperazate. On the basis of analysis of the complete genome sequence of <i>Kutzneria</i>, we now identify a fourth halogenase in the pathway whose gene is separated from the defined kutzneride cluster by 12 open reading frames. KthP (kutzneride halogenase for piperazate) is a mononuclear nonheme iron halogenase that acts on the piperazyl ring tethered by a thioester linkage to the holo forms of thiolation domains. MS analysis of the protein-bound product confirmed chlorination of the piperazate framework from the (3<i>S</i>)- but not the (3<i>R</i>)-piperazyl-S-pantetheinyl thiolation proteins. After thioesterase-mediated release, nuclear magnetic resonance was used to assign the free imino acid as (3<i>S</i>,5<i>S</i>)-5-chloropiperazate, distinct from the 3<i>S</i>,5<i>R</i> stereoisomer reported in the mature kutznerides. These results demonstrate that a fourth halogenase, KthP, is active in the kutzneride biosynthetic pathway and suggest further processing of the (3<i>S</i>,5<i>S</i>)-5-chloropiperazate during subsequent incorporation into the kutzneride depsipeptide frameworks