Short Total Synthesis of (±)‐γ‐Lycorane by a Sequential Intramolecular Acylal Cyclisation (IAC) and Intramolecular Heck Addition Reaction

Abstract

An intramolecular acylal cyclisation (IAC) approach to the synthesis of a range of bicyclic heterocycles is reported. As an example of the utility of the IAC reaction, the methodology was applied in a protecting-group-free five-step total synthesis of (±)-γ-lycorane, incorporating a new intramolecular Heck addition reaction to generate the pentacyclic core structure of the natural product in good yield.

3D‐Printed Polypropylene Continuous‐Flow Column Reactors: Exploration of Reactor Utility in SNAr Reactions and the Synthesis of Bicyclic and Tetracyclic Heterocycles

“…As can be seen above, all IAC cyclisation precursors gave good yields of the cyclised products (34–77 %) using the 3D‐printed polypropylene reactors. Yields were comparable to the previously reported microwave conditions and were also comparable in terms of reaction time albeit at a slightly elevated temperature . Compound 40 was obtained in excellent yield and represents an important intermediate in the synthesis of the lycorane family of compounds .…”

“…Yields were comparable to the previously reported microwave conditions and were also comparable in terms of reaction time albeit at a slightly elevated temperature . Compound 40 was obtained in excellent yield and represents an important intermediate in the synthesis of the lycorane family of compounds . With the synthesis of bicyclic heterocycles in hand, we next elected to explore the synthesis of compounds related to the tetracyclic core of the erythrina alkaloid family.…”

“…As a result of the successful demonstration of the applicability of the 3D‐printed polypropylene column reactors to withstand high temperatures and polar solvents such as DMF, we next elected to explore their utility in the synthesis of heterocycles related to the core of the erythrina 5 – 7 and lycorane 8 and 9 family of natural products . We have previously described an efficient approach to the core structures of these compounds and others using microwave accelerated synthesis of the bicyclic 17 and tetracyclic cores 18 from the acylal precursors 16 using 1,2‐dichloroethane as the solvent and BF 3 as the Lewis acid in an intramolecular acylal (IAC) cyclisation approach (Scheme ) …”

“…As such, we envisaged that the column reactors would prove suitable for the synthesis of complex heterocycles related to polycyclic natural products as our previously used microwave conditions could readily be translated into continuous flow via replication of the reaction conditions in the 3D‐printed flow reactor . In the first instance, we decided to explore the synthesis of bicyclic heterocycles.…”

“…In the first instance, we decided to explore the synthesis of bicyclic heterocycles. Using the previously optimised conditions, where the IAC precursors were treated with boron trifluoride at 65 °C in the microwave for 15 min, IAC precursors were mixed with BF 3 in 1,2‐DCE and passed through the 3D‐printed flow reactor at a slightly elevated temperature of 80 °C at a flow rate of 0.1 mL/min giving a residence time of 16 min (1.6 mL internal volume), thus replicating the microwave conditions (Scheme ).…”