Stereoselective Tandem Synthesis of Pyrrolidine Derivatives under Gold Catalysis: An Asymmetric Synthesis of (−)-Lepadiformine A

Abstract

A Au-catalyzed tandem alkyne hydroamination/iminium ion formation/allylation reaction was developed for expedient access to pyrrolidine derivatives bearing a tetrasubstituted carbon stereocenter. The tandem reaction was successfully applied to a 12-step asymmetric synthesis of (−)-lepadiformine A, a marine cytotoxic tricyclic alkaloid.

Collective Asymmetric Total Synthesis of Cylindricines

“…The synthesis of cylindricines A–H ( 1 – 8 ) and the proposed structures of cylindricines I and J ( 9 and 10 ) is summarized in Scheme . As described previously, oxidative cleavage of the double bond of 13 gave aldehyde 18 . Nozaki–Hiyama–Kishi reaction of 18 with iodoolefin 19a (NiCl 2 , CrCl 2 , DMSO) proceeded cleanly to deliver allylic alcohol 20a in 77% yield as a single diastereomer.…”

“…We have recently described an asymmetric total synthesis of lepadiformine A (11) by means of a tandem Au-catalyzed alkyne hydroamination/iminium formation/allylation reaction of 12 (Figure 1a). 9 The resultant spirocyclic pyrrolidine 13 was transformed into 11 over seven steps via the formation of the piperidine ring. In this work, we envisioned that 13 should serve as a pluripotent intermediate toward collective synthesis of 1−10.…”

t-BuOK-Catalyzed Regio- and Stereoselective Intramolecular Hydroamination Reaction Leading to Phthalazinoquinazolinone Derivatives

“…Alkyne hydroamination reactions proved to be one of the most powerful tools for the construction of a wide range of enamine/imine-containing N -heterocyclic skeletons . For example, metal-catalyzed and/or base-mediated intramolecular hydroamination of alkynes has been widely used for the direct synthesis of numerous fused N -heterocyclic compounds with five/six/seven-membered ring systems, especially for natural products and biologically active organic compounds . Despite the significant achievements, to the best of our knowledge, the base-catalyzed intramolecular hydroamination reaction of functionalized quinazolinones for the synthesis of new 2,3-fused phthalazino-quinazolinone derivatives has not been disclosed up to now.…”

Collective Asymmetric Total Synthesis of Cylindricines

“…We have recently described an asymmetric total synthesis of lepadiformine A ( 11) by means of a tandem Au-catalyzed alkyne hydroamination/iminium formation/allylation reaction of 12 (Figure 1a). 9 The resultant spirocyclic pyrrolidine 13 was transformed into 11 over seven steps via the formation of the piperidine ring. In this work, we envisioned that 13 should serve as a pluripotent intermediate toward collective synthesis of 1-10.…”