The l-Alanosine Gene Cluster Encodes a Pathway for Diazeniumdiolate Biosynthesis.

N-Nitroso-containing natural products are bioactive metabolites with antibacterial and anticancer properties. In particular, compounds containing the diazeniumdiolate (N-nitrosohydroxylamine) group display a wide range of bioactivities ranging from cytotoxicity to metal chelation. Despite the importance of this structural motif, knowledge of its biosynthesis is limited. Herein we describe the discovery of a biosynthetic gene cluster in Streptomyces alanosinicus ATCC 15710 responsible for producing the diazeniumdiolate natural product l-alanosine. Gene disruption and stable isotope feeding experiments identified essential biosynthetic genes and revealed the source of the N-nitroso group. Additional biochemical characterization of the biosynthetic enzymes revealed that the non-proteinogenic amino acid l-2,3-diaminopropionic acid (l-Dap) is synthesized and loaded onto a free-standing peptidyl carrier protein (PCP) domain in l-alanosine biosynthesis, which we propose may be a mechanism of handling unstable intermediates generated en route to the diazeniumdiolate. These discoveries will facilitate efforts to determine the biochemistry of diazeniumdiolate formation.

Synthetic studies toward citrinadin A: construction of the pentacyclic core.

This manuscript describes the preparation of an advanced intermediate toward the total synthesis of citrinadin A, featuring a [3+2] cycloaddition employing in situ generation of the dipole.

Collaborative Total Synthesis: Routes to (±)-Hippolachnin A Enabled by Quadricyclane Cycloaddition and Late-Stage C-H Oxidation.

Described herein are synthetic efforts toward the synthesis of hippolachnin A. Two independently devised routes from the Brown and Wood groups allowed for the synthesis of hippolachnin A from the unusual starting material, quadricyclane, by harnessing the power of late-stage C-H oxidation. Collaborative union of the best features of the two routes allowed for preparation of the molecule with improved efficiency.

Synthetic studies toward the citrinadins: enantioselective preparation of an advanced spirooxindole intermediate.

This manuscript describes the enantioselective preparation of a spirooxindole that is suited for advancedment to either Citrinadin A or B.

An enantioselective total synthesis and stereochemical revision of (+)-citrinadin B.

This manuscript describes an enantioselective synthesis of the naturally occurring alkaloid citrinadin B. The synthetic effort revealed an anomaly in the original structural assignment that has led to the proposal of a stereochemical revision. This revision is consistent with the structures previously reported for a closely related family of alkaloids, PF1270A-C. The synthesis is convergent and employs a stereoselective intermolecular nitrone cyloaddition reaction as a key step.