Enantioselective Synthesis of (−)-Gilbertine via a Cationic Cascade Cyclization

Abstract

Described is the first enantioselective synthesis of (-)-gilbertine (2), a member of the uleine-type family, and the determination of the absolute configuration of this natural product is reported. The key step employs a cationic cascade reaction for a tetrahydropyrane and piperidine ring formation and the construction of the pentacyclic framework in one step. The synthetic strategy utilizes the Shibasaki reaction to build up the first stereogenic center. A formylation reaction of a 3-substituted cyclohexanone derivative was achieved, giving only the desired regioisomer. The Japp-Klingemann Fischer indole protocol was used successfully as a convergent synthetic approach for the construction of the desired tetrahydrocarbazole (20). Furthermore, an unexpected behavior of this 2,3-disubstituted cyclohexanone derivative during an epimerization process was investigated, resulting in different chemical behavior of the enantiomers and the racemate. The diastereomeric resolution was achieved via the cationic cascade reaction, demonstrating the versatility of this approach. Significantly, the synthetic 17-step sequence was easy to execute, giving (-)-gilbertine in 5.5% overall yield.

Studies toward the AB ring system of the tetrapetalone natural products

“…Thus, 18a was decarbalkoxylated, 21 and methylated to furnish indanone 19 (Scheme 4). This material was then globally deprotected with TBAF, chemoselectively protected at the less hindered hydroxyl group, and then treated with triflic anhydride and pyridine to furnish aryl triflate 20 .…”

Studies on the synthesis of 4‐oxo‐2,3,4,9‐tetrahydrocarbazole derivatives

“…For the synthesis of 4‐oxotetrahyrocarbazole derivatives, we started from the diastereomers 1 , which were reported previously [1]. Diastereomers like 1‐oxo‐2‐substituted‐2,3,4,9‐tetrahydrocarbazole were converted into the racemic trans form by treatment with sodium methoxide [6, 7]. However, the diastereomer of 1 was transformed into the racemic trans keto acid 2 by using 15% potassium hydroxide in methanol‐water (3:1) at room temperature (Scheme ).…”

Synthesis of (±)‐Tetrapetalone A‐Me Aglycon

“…Next, 15 was subjected to a modified Krapcho decarboxylation in the presence of 1,4‐diazabicyclo[2.2.2]octane (DABCO)17 to furnish the indanone 16 in 91 % yield (Scheme ). Ketone α‐methylation was completely diastereoselective, thus occurring anti to the isopropenyl group on the B ring.…”