title: Asymmetric syntheses of sceptrin and massadine and evidence for biosynthetic enantiodivergence.
abstract: Cycloaddition is an essential tool in chemical synthesis. Instead of using light or heat as a driving force, marine sponges promote cycloaddition with a more versatile but poorly understood mechanism in producing pyrrole-imidazole alkaloids sceptrin, massadine, and ageliferin. Through de novo synthesis of sceptrin and massadine, we show that sponges may use single-electron oxidation as a central mechanism to promote three different types of cycloaddition. Additionally, we provide surprising evidence that, in contrast to previous reports, sceptrin, massadine, and ageliferin have mismatched chirality. Therefore, massadine cannot be an oxidative rearrangement product of sceptrin or ageliferin, as is commonly believed. Taken together, our results demonstrate unconventional chemical approaches to achieving cycloaddition reactions in synthesis and uncover enantiodivergence as a new biosynthetic paradigm for natural products.
authors.affiliation: Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Rodriguez
authors.affiliation: Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Curtis E
authors.initials: CE
authors.lastname: Moore
authors.affiliation: Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Shuanhu
authors.initials: S
authors.lastname: Gao
authors.affiliation: Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Xianghui
authors.initials: X
authors.lastname: Tan
authors.affiliation: Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Yuyong
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Arnold L
authors.initials: AL
authors.lastname: Rheingold
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Phil S
authors.initials: PS
authors.lastname: Baran
authors.affiliation: Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. chuo.chen@utsouthwestern.edu.
authors.forename: Chuo
authors.initials: C
authors.lastname: Chen
mesh_terms: D000818:Animals; D053898:Biosynthetic Pathways; D061565:Cycloaddition Reaction; D015394:Molecular Structure; D011161:Porifera / Q000378:metabolism*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D011758:Pyrroles; C478874:massadine; C077210:sceptrin