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Total synthesis of (+)-macquarimicin A
Ryosuke Munakata1, Hironori Katakai, Tatsuo Ueki
1Department of Applied Chemistry, Keio University, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan.
Journal of the American Chemical Society
|December 4, 2003
Summary
The first total synthesis of (+)-macquarimicin A, an anti-inflammatory drug, was achieved. This study also determined its absolute configuration and revised its geometry, paving the way for new therapeutic developments.
Area of Science:
- Organic Chemistry
- Medicinal Chemistry
- Chemical Synthesis
Background:
- Macquarimicin A is a novel neutral sphingomyelinase (N-SMase) inhibitor.
- N-SMase inhibitors have potential anti-inflammatory activity.
- The total synthesis and absolute configuration of macquarimicin A were previously unknown.
Purpose of the Study:
- To achieve the first total synthesis of (+)-macquarimicin A.
- To determine the absolute configuration of (+)-macquarimicin A.
- To revise the C(2)-C(3) geometry of (+)-macquarimicin A.
Main Methods:
- A convergent and efficient synthetic pathway was designed.
- A transannular Diels-Alder reaction was employed to construct the tetracyclic framework.
- Stereoselective synthesis was utilized to control the molecule's configuration.
Main Results:
- The first total synthesis of (+)-macquarimicin A was successfully accomplished.
- The absolute configuration of (+)-macquarimicin A was determined.
- The C(2)-C(3) geometry was revised to Z.
- The synthesis was completed in 27 steps with a 9.9% overall yield.
Conclusions:
- The total synthesis provides access to (+)-macquarimicin A for further biological evaluation.
- The established synthetic route and determined configuration offer a foundation for developing N-SMase inhibitors.
- This work contributes to the understanding of macquarimicin A's structure-activity relationship and its potential as an anti-inflammatory agent.
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