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Solid-phase Synthesis of [4.4] Spirocyclic Oximes
Published on: February 6, 2019
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Synthetic studies towards putative yuremamine using an iterative C(sp(3))-H arylation strategy
Matthew B Calvert1, Jonathan Sperry
1School of Chemical Sciences, University of Auckland, 23 Symonds Street, Auckland, New Zealand. j.sperry@auckland.ac.nz.
Organic & Biomolecular Chemistry
|February 19, 2016
Summary
This study explores 8-aminoquinoline-directed C(sp(3))-H arylation for synthesizing pyrroloindoles. Key findings involve protecting group strategies and challenges in achieving the target yuremamine structure via C-H functionalization.
Area of Science:
- Organic Chemistry
- Synthetic Chemistry
- Catalysis
Background:
- Pyrroloindole alkaloids, like yuremamine, are complex natural products with potential biological activities.
- Directed C(sp(3))-H arylation offers a powerful strategy for constructing complex molecular architectures, including those found in alkaloids.
- The development of efficient and selective C-H functionalization methods is crucial for modern organic synthesis.
Purpose of the Study:
- To investigate an iterative 8-aminoquinoline (AQ)-directed C(sp(3))-H arylation strategy for accessing the pyrroloindole core structure.
- To explore the synthesis of the alkaloid yuremamine and related diarylated pyrroloindoles.
- To identify challenges and develop solutions for regioselective C(sp(3))-H arylation in complex heterocyclic systems.
Main Methods:
- Utilized 8-aminoquinoline (AQ) as a directing group for palladium-catalyzed C(sp(3))-H arylation reactions.
- Employed model indane systems to optimize reaction conditions and evaluate different protecting groups (MOM vs. dimethyl ether).
- Applied the developed methodology to pyrroloindole scaffolds, including C9-substituted variants, to achieve iterative diarylation.
Main Results:
- Identified MOM as a superior protecting group for iodoresorcinol, stabilizing key palladium intermediates and improving yields.
- Achieved 1,3-cis-diarylation on a model yuremamine system using sequential C(sp(3))-H arylations with iodoresorcinol and iodopyrogallol.
- Encountered competing C(sp(2))-H arylation at C9 and steric hindrance issues with tryptamine side chains in pyrroloindole systems.
- Observed undesired 1,3-trans-diarylation and epimerization at C1 in a C9-methyl pyrroloindole system, hindering the synthesis of yuremamine.
Conclusions:
- The 8-aminoquinoline-directed C(sp(3))-H arylation strategy shows promise for pyrroloindole synthesis but requires careful consideration of substrate substitution and regioselectivity.
- Optimized protecting group strategies are essential for successful C(sp(3))-H arylation of specific aryl partners.
- Further research is needed to overcome challenges related to competing C-H activation and stereochemical control in complex systems, contributing to the broader field of C-H functionalization.
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