Exploiting Orthogonally Reactive Functionality: Synthesis and Stereochemical Assignment of (−)-Ushikulide A

Abstract

In spite of the tremendous advances in modern spectroscopic methods, organic synthesis continues to play a pivotal role in elucidating the full structures of complex natural products. This method has the advantage that even in the absence of a firm structural assignment, a combination of logic and spectroscopic comparison can arrive at the correct structure. Herein, we report execution of this strategy with respect to ushikulide A, a newly isolated and previously stereochemically-undefined member of the oligomycin-rutamycin family. To maximize synthetic efficiency, we envisioned chemoselective manipulation of orthogonally reactive functional groups, notably alkenes and alkynes as surrogates for certain carbonyl and hydroxyl functionalities. This approach has the dual effect of minimizing the number of steps and protecting groups required for our synthetic route. This strategy culminated in the efficient synthesis and stereochemical assignment of ushikulide A.

Thionium Ion Initiated Medium-Sized Ring Formation: The Total Synthesis of Asteriscunolide D

“…11 The chiral propargylic alcohol could be obtained using a chemoselective Zn-ProPhenol catalyzed asymmetric methyl propiolate addition to the keto aldehyde 10 . 12,13 …”

Studies Towards the Stereoselective Total Synthesis of 7‐O‐methylnigrosporolide

“…At this stage, we have two fragments, alkyne 14 and aldehyde 18 , which have to couple to yield a key intermediate. Deprotanation of terminal alkyne ( 14 ) with n ‐BuLi, followed by addition of aldehyde fragment ( 18 ) in anhydrous THF at −78 °C, to achieve, the racemic propargylic alcohol 19 in excellent yields and this mixture was oxidized with IBX in DMSO at r.t., to give, ( S , Z )‐9‐[( tert ‐butyldimethyl silyl)oxy]‐1‐[( S )‐2,2‐dimethyl‐1,3‐dioxolan‐4‐yl]dec‐1‐en‐4‐yn‐3‐one ( 20 ) in (80%) yield.…”

Synthesis of the Spiroketal Fragment of (–)‐Ushikulide A

“…Protection of the secondary alcohol in 14 as its TBS ether with tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) and 2,6-lutidine in CH 2 Cl 2 produced 19 in 92 % yield. [8] After the successful synthesis of the two iodohydrin derivatives 4 and 6, the next task was dialkylation of 4 and 6 with tosylmethyl isocyanide. [19] Removal of the benzyl group in 20 with Li/Naphthalene in THF at -20°C afforded primary alcohol 21 in 90 % yield.…”

“…IUK-102 by Takahashi and co-workers ( Figure 1). [8] Intrigued by its excellent biological activity and interesting molecular architecture, we became interested in the synthesis of (-)-ushikulide A by using Prins cyclization as a key step. [3,4] Ushikulide A is related to the Oligomycin family [5] in which 26-membered lactones Oligomycin F [6] and 41-demethylhomooligomycin B [7] are known to possess immunosuppressive activities.…”