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

Abstract

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.

Kinetics and thermochemistry of the unusual [2π + 2σ + 2σ]‐cycloaddition of quadricyclane with some dienophiles

“…The synthetic potential of such cycloadditions is still to be explored. Recently, 1 has been used as a starting point in the total synthesis of a potent antifungal agent—hippolachnin A . The parent molecule of norbornadiene reacts with electrophilic olefins via the different, [2π + 2π + 2π] (homo Diels‐Alder)–cycloaddition mechanism with much smaller reaction rates (Scheme ) .…”

Recent Applications of Rh‐ and Pd‐Catalyzed C(sp3)–H Functionalization in Natural Product Total Synthesis

“…In 2016, the Wood and Brown groups jointly reported their independent syntheses of (±)‐hippolachnin A ( 53 ; Scheme ) . In addition, the two groups forged a partnership to utilize the best features of their routes to accomplish a more efficient collaborative total synthesis of 53 .…”

Efficient Synthetic Routes to (±)‐Hippolachnin A, (±)‐Gracilioethers E and F and the Alleged Structure of (±)‐Gracilioether I

“…Carreira also completed the first synthesis of (±)‐glacilioether E ( 8 , along with gracilioether F 5 ) later in the same year. Another synthesis of (±)‐glacilioether F by Wong and (±)‐hippolachnin A by Wood and Brown appeared in early 2016. As for gracilioether B (along with gracilioether C, structure not shown in Figure ), it was synthesized for the first time in early 2015 by Perkins, and co‐workers.…”

“…A more efficient formal synthesis of 7 was achieved later: Irradiation of 1 with UV light with PhCOPh as the sensitizer gave the tricyclic species 23 (an advanced intermediate in Wood‐Brown's synthesis of hippolachinin A) in 63 % yield within 6 h. Besides, the yield for this photocycloaddition remained unchanged even if the reaction was performed on a gram scale.…”