title: Studies toward the unique pederin family member psymberin: full structure elucidation, two alternative total syntheses, and analogs.
abstract: Two synthetic approaches to psymberin have been accomplished. A highly convergent first generation synthesis led to the complete stereochemical assignment and demonstrated that psymberin and irciniastatin A are identical compounds. This synthesis featured a diastereoselective aldol coupling between the aryl fragment and a central tetrahydropyran core and a novel one-pot procedure to convert an amide, via intermediacy of a sensitive methyl imidate, to the N-acyl aminal reminiscent of psymberin. The highlights of the second generation synthesis include an efficient iridium-catalyzed enantioselective bisallylation of neopentyl glycol and a stepwise Sonogashira coupling/cycloisomerization/reduction sequence to construct the dihydroisocoumarin unit. The two synthetic avenues were achieved in 17-18 steps (longest linear sequence, ~14-15 isolations) from 3 fragments prepared in 7-8 (first generation) and 3-8 (second generation) steps each. This convergent approach allowed for the preparation of sufficient amounts of psymberin (~ 0.5 g) for follow-up biological studies. Meanwhile, our highly flexible strategy enabled the design and synthesis of multiple analogs, including a psymberin-pederin hybrid, termed psympederin, that proved crucial to a comprehensive understanding of the chemical biology of psymberin and related compounds that will be described in a subsequent manuscript.
authors.affiliation: Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Feng
authors.forename: Xin
authors.initials: X
authors.lastname: Jiang
authors.forename: Jef K
authors.initials: JK
authors.lastname: De Brabander
mesh_terms: D003374:Coumarins; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D015394:Molecular Structure; D011714:Pyrans / Q000737:chemistry*; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry*
chemical_list: D003374:Coumarins; D011714:Pyrans; D011753:Pyrones; C498383:psymberin; C100127:pederin