Concise Enantiospecific Total Synthesis of Tubingensin A

Abstract

We report the enantiospecific total synthesis of (+)-tubingensin A. Our synthesis features an aryne cyclization to efficiently introduce the vicinal quaternary stereocenters of the natural product and proceeds in only nine steps (longest linear sequence) from known compounds.

Leveraging Fleeting Strained Intermediates to Access Complex Scaffolds

“…Following our initial total synthesis of (+)-tubingensin A ( 70 ), 137 we were well-poised to address the more complex family member, (−)-tubingensin B ( 71 ). As summarized in Figure 13 , (+)-dihydrocarvone ( 74 ), an abundant chiral terpene building block, and 2-hydroxycarbazole ( 75 ) were used as starting materials and elaborated to give carbazolyne precursor 76 .…”

Total synthesis of (–)-tubingensin B enabled by the strategic use of an aryne cyclization

“…It should be noted that arynes, despite once being controversial and overlooked by the synthetic community, have recently gained traction in chemical synthesis 5,6 . However, their use as building blocks for the formation of vicinal quaternary stereocentres is limited to one example from our laboratory involving the assembly of a cyclohexyl ring present in tubingensin A 4 . Moreover, aryne cyclizations to form seven-membered rings are kinetically disfavoured and rare 6 .…”

“…3a). The known bromotriflate 8 (prepared in three steps 4 ) was treated with propargyl alcohol in the presence of catalytic Pd(PPh 3 ) 4 and CuI to effect Sonogashira coupling 9 . The resulting product, alkynol 9, was obtained in 84% yield.…”

“…3b). Olefin (−)-11, which is readily accessible from (+)-dihydrocarvone in four steps 4,13 , underwent hydroboration to furnish alkyl boron derivative 12. This adduct was directly subjected to Pd-catalysed Suzuki-Miyaura coupling with dihalocarbazole 7 to afford desired product 13 in 76% yield.…”

Enantioselective synthesis of decalin structures with all-carbon quaternary centers via one-pot sequential Cope/Rauhut–Currier reaction

“…Decalin cores with quaternary stereocenters can be found at the heart of many bioactive natural product classes, including most notably terpenoid compounds. Some recent literature examples of bioactive natural produts with a decalin core include crotonolides 23 , kauranes 24 , crotogoudin 25 , walsucochin B 26 , cafestol 27 , and tubingensin A 28 .…”