Total Synthesis of Diterpenoid Steenkrotin A

Abstract

Aconcise and diastereoselective total synthesis of the diterpenoid (AE)-steenkrotin Ai sd escribed for the first time. The strategy mainly features three key ring formations:1 )a rhodium-catalyzed OÀHb ond insertion followed by an intramolecular carbonyl-ene reaction to build up the tetrahydrofuran subunit;2 )sequential SmI 2 -mediated Ueno-Stork and ketyl-olefin cyclizations to construct the [5,7] spirobicyclic skeleton;a nd 3) an intramolecular aldol condensation/vinylogous retro-aldol/aldol sequence to form the final six-membered ring with inversion of the relative configuration at the C7 position.

Enantioselective Total Synthesis of (+)‐Steenkrotin A and Determination of Its Absolute Configuration

“…Based on these results, the difficulty in generating the D 9,10 enolate,w hich requires deprotonation of sterically hindered H9 and would resulti nahighly strained [3,5,6,7] tetracyclic framework, became apparent and we werei nspired to develop ar eviseds trategy by constructing the quaternary carbon centera tC 9p rior to formationo ft he six-membered ring.…”

“…entries 8a nd 7), suggesting that, under these conditions, the carbonyl-ene cyclization is reversible and C7-epi-18 is the kinetic product, which could equilibrate to 18 upon warming of the reaction mixture. [20] Brønsted acids were also investigated (entries [9][10][11][12], and HF·py wase ventually foundt o be the most suitable reagent.U nder the optimized conditions (HF·py,2.0 equiv,CH 2 Cl 2 ,r t, 1h), 18 was obtained in 92 %yield.…”

“…In turn, 40 could be obtained from optically active cycloheptenone 41,w hich is ar eadily availableb uilding block. [27] In our previous approach to (AE)-steenkrotin A, [9] C11-epi-41 was employed to avoid potential difficulties with respecttothe stereochemical outcomeo ft he subsequent Ueno-Stork cyclization. However,t he preparation of C11-epi-41 suffered from low yield (up to 86 %c ombinedy ield with 41 as an inseparable 1:1 mixture), which inevitably affectedt he overall efficiency of the synthetic route.…”

“…[7] In view of foreseeable challenges lying in the cyclopropanation of highly functionalizedt ricyclic structures with dimethylcarbene, [8] we decided to install the gem-dimethylcyclopropane at an early stage,w hich finally led to the total synthesis of steenkrotin Ai nr acemic form. [9] Herein, we detail our efforts on the enantioselective total synthesis of (+ +)-steenkrotin A( 1), as well as the determination of its absolutec onfiguration. …”

Cyclopropanation Strategies in Recent Total Syntheses

“…The stereoselective introduction of the dimethylcyclopropane is an important aspect to consider in planning a synthesis of 143. Consequently, Ding and coworkers 153 envisioned reacting dimethylcarbene (146), generated in situ, with cyclic enol ether derivative 147. Importantly, the increased nucleophilicity of the enol ether was expected to lead to its chemoselective functionalization in the presence of Scheme 19.…”