Total Synthesis of Puberuline C

Area of Science:

• Organic Chemistry
• Total Synthesis
• Natural Product Chemistry

Background:

• Puberuline C (1) is a C19-diterpenoid alkaloid characterized by a complex hexacyclic (ABCDEF) ring system.
• It features a unique ring fusion pattern, one tertiary amine, six oxygen functionalities, and 12 contiguous stereocenters, including three quaternary ones.
• The structural complexity of Puberuline C presents a significant challenge for chemical synthesis.

Purpose of the Study:

• To achieve the first total synthesis of the architecturally complex natural product Puberuline C (1).
• To develop and demonstrate a novel synthetic strategy for assembling highly complex molecules.

Main Methods:

• The synthesis commenced from 2-cyclohexenone (9), employing a strategy integrating radical cascade and Mukaiyama aldol reactions.
• Key steps included a double Mannich reaction for A- and E-ring fusion, Sonogashira coupling for C-ring attachment, and a radical cascade for simultaneous B- and F-ring cyclization.
• An intramolecular Mukaiyama aldol reaction formed the D-ring, followed by functionalization to yield Puberuline C.

Main Results:

• The first total synthesis of Puberuline C (1) was accomplished in 32 steps from 2-cyclohexenone (9).
• A radical cascade process efficiently installed five contiguous stereocenters, including two quaternary carbons, into the B- and F-rings.
• The strategy successfully navigated the assembly of the complex hexacyclic core with multiple stereocenters and polar functionalities.

Conclusions:

• The study demonstrates the power of radical cascade reactions in streamlining the synthesis of highly complex molecular architectures.
• This novel synthetic route provides an efficient pathway to Puberuline C and showcases a versatile strategy for natural product synthesis.