Total Synthesis of Leiodermatolide A via Transfer Hydrogenative Allylation, Crotylation, and Propargylation: Polyketide Construction beyond Discrete Allyl- or Allenylmetal Reagents

Abstract

The total synthesis of leiodermatolide A was accomplished in 13 steps (LLS). Transfer hydrogenative variants of three carbonyl additions that traditionally rely on premetalated reagents (allylation, crotylation, and propargylation) are deployed together in one total synthesis.

Rhodium‐Catalyzed Anti‐Markovnikov Transfer Hydroiodination of Terminal Alkynes**

“…Substrates bearing a thiophene heterocycle or a masked amine were cleanly converted to their corresponding ( Z )‐vinyl iodides 7 q and 7 r in 77 % and 95 % yield, respectively. Additionally, vinyl iodide 7 s from a TBDPS‐protected homopropargylic alcohol was obtained in 78 % yield, showcasing the potential of this method for the synthesis of polyketides [28, 29] . In all cases, the products were isolated as the exclusive anti‐Markovnikov ( Z )‐isomer.…”

“…Additionally, vinyl iodide 7 s from a TBDPS‐protected homopropargylic alcohol was obtained in 78 % yield, showcasing the potential of this method for the synthesis of polyketides. [ 28 , 29 ] In all cases, the products were isolated as the exclusive anti‐Markovnikov ( Z )‐isomer. No Markovnikov, or ( E )‐isomer was observed for any substrate.…”

Rhodium‐katalysierte Anti‐Markovnikov Hydroiodierung von Terminalen Alkinen**

“…95 % Ausbeute in die entsprechenden ( Z ) ‐ Vinyliodide 7 q und 7 r umgewandelt. Außerdem wurde Vinyliodid 7 s ausgehend von einem TBDPS‐geschützten Homopropargylalkohol in 78 % Ausbeute erhalten, was das Potenzial dieser Methode für die Anwendung in der Synthese von Polyketiden zeigt [28, 29] . In allen Fällen wurden die Produkte ausschließlich als anti‐Markovnikov ( Z ) ‐ Isomer isoliert; für kein Substrat wurde das Markovnikov oder das ( E ) ‐ Isomer beobachtet.…”

Asymmetric synthesis of aryl/vinyl alkyl carbinol estersviaNi-catalyzed reductive arylation/vinylation of 1-chloro-1-alkanol esters

“…Optically pure benzylic and allylic secondary alcohols and their derivatives represent an important class of carbinol structural units that are widely found in natural products and drug molecules (Scheme 1A), and serve as building blocks for diverse organic transformations. 1,2 Therefore, considerable efforts have been devoted to the catalytic asymmetric preparation of these chiral secondary alcohols. A typical strategy is the transformation or resolution of achiral or racemic secondary alcohols through desymmetrization, 3 dynamic kinetic/kinetic resolution, 4 and deracemisation 5 methods.…”