Total Synthesis of (+)-Melicolone K Enabled by a Late-Stage Programmed C-H Functionalization

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Natural Product Synthesis

Background:

• Melicolone K is a prenylated natural product with potential biological significance.
• Efficient synthetic routes to complex natural products are crucial for further study and development.

Purpose of the Study:

• To achieve the first asymmetric total synthesis of (+)-melicolone K.
• To develop a novel and efficient synthetic strategy employing late-stage C-H functionalization.

Main Methods:

• Asymmetric total synthesis of (+)-melicolone K.
• Late-stage C-H functionalization including Rh(II)-catalyzed γ-C(sp3)-H amination.
• Cyclic sulfamate ester-directed γ-C(sp3)-H prenylation via formal (4 + 2) cycloaddition/reductive ring-opening.
• Incorporation of Sharpless asymmetric dihydroxylation, Wolff ring contraction, and Ti(III)-mediated radical cyclization.

Main Results:

• Successful and concise asymmetric total synthesis of (+)-melicolone K.
• Achieved good enantio- and diastereocontrol throughout the synthesis.
• Developed a direct, single-step prenylation protocol.

Conclusions:

• The developed strategy provides efficient access to the prenylated natural product (+)-melicolone K.
• The novel prenylation protocol can streamline the synthesis of other prenylated natural products.
• This work establishes a new benchmark for the synthesis of complex prenylated compounds.