Asymmetric Total Synthesis of (−)‐Englerin A through Catalytic Diastereo‐ and Enantioselective Carbonyl Ylide Cycloaddition

Abstract

An asymmetric total synthesis of the guaiane sesquiterpene (−)‐englerin A, a potent and selective inhibitor of the growth of renal cancer cell lines, was accomplished. The basis of the approach is a highly diastereo‐ and enantioselective carbonyl ylide cycloaddition with an ethyl vinyl ether dipolarophile under catalysis by dirhodium(II) tetrakis[N‐tetrachlorophthaloyl‐(S)‐tert‐leucinate], [Rh2(S‐TCPTTL)4], to construct the oxabicyclo[3.2.1]octane framework with concomitant introduction of the oxygen substituent at C9 on the exo‐face. Another notable feature of the synthesis is ruthenium tetraoxide‐catalyzed chemoselective oxidative conversion of C9 ethyl ether to C9 acetate.

Navigating the Chiral Pool in the Total Synthesis of Complex Terpene Natural Products

“…137 This natural product immediately attracted the attention of both chemists and biologists due its high potency and selectivity toward renal cancer cell lines (GI 50 values = 1–87 nM). Not surprisingly, myriad synthetic groups have pursued syntheses of this target, 138 and in the eight years since its isolation, total and formal syntheses have already been reported by the groups of Christmann, 139 Nicolaou, 140 Theodorakis, 141 Ma, 142 Echavarran, 143 Chain, 144 Hatakeyama, 145 Parker, 146 Cook, 147 Metz, 148 Sun and Lin, 149 Shen, 150 Hashimoto and Anada, 151 Iwasawa, 152 and Mascareñas. 153 Among these works, five have utilized chiral pool terpenes: Christmann’s synthesis using cis,trans -nepetalactone, 139 Ma’s synthesis employing citronellal, 142 Chain’s synthesis from citronellal, 144 Metz’s synthesis from isopulegol, 148 and Shen’s carvone-based route.…”

Total Synthesis of (±)‐Englerin A Using An Intermolecular [3+2] Cycloaddition Reaction of Platinum‐Containing Carbonyl Ylide

“…However, these zwitterionic species preferentially react with electron‐deficient dipolarophiles such as acrylate or propiolate esters, and thus, further functional‐group manipulations are consequently required to introduce the C9‐oxygen functionality of 1 , as depicted in Figure . Very recently, the group of Hashimoto and Anada reported the total synthesis of 1 on the basis of a Rh‐catalyzed cycloaddition of a carbonyl ylide derived from an α‐diazo‐β‐ketoester . The introduction of an electron‐withdrawing ester group onto a carbenoid precursor enabled cycloaddition of the corresponding ylide with a vinyl ether, thereby furnishing a 8‐oxabicyclo[3.2.1]octane derivative with a C9‐oxygen functionality .…”

“…Very recently, the group of Hashimoto and Anada reported the total synthesis of 1 on the basis of a Rh‐catalyzed cycloaddition of a carbonyl ylide derived from an α‐diazo‐β‐ketoester . The introduction of an electron‐withdrawing ester group onto a carbenoid precursor enabled cycloaddition of the corresponding ylide with a vinyl ether, thereby furnishing a 8‐oxabicyclo[3.2.1]octane derivative with a C9‐oxygen functionality . Nevertheless, several synthetic operations were still required for conversion of the ester functionality to the C15‐methyl group of 1 .…”

Englerins: A Comprehensive Review

“…36 While not particularly step- or yield-efficient (25 steps, 5.2% yield), this approach may provide entry to a particular class of analogues. A [3+2] cycloaddition was used by Iwasawa’s group to prepare racemic englerin A with good yield (16.2%) and in only 14 steps.…”