Hydroxylamines: From Synthetic Intermediates to Synthetic Targets.

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Medicinal Chemistry

Background:

• The synergy between university teaching and research can foster innovative synthetic strategies.
• Hydroxylamines offer a unique approach as "tethered nitrogen" synthons for C-N bond formation.
• Developing efficient methods for synthesizing N,O-heterocycles is crucial for accessing natural products.

Purpose of the Study:

• To explore novel synthetic methodologies for constructing isoxazolidines and related N,O-heterocycles.
• To apply these methods to the total synthesis of complex alkaloids and natural products.
• To achieve high stereo- and regiochemical control in C-N bond formation.

Main Methods:

• Development of palladium-catalyzed cyclocarbonylation and silver-catalyzed allene cyclization for heterocycle synthesis.
• Application of intramolecular aza-Michael addition and cross-metathesis for isoxazolidine and tetrahydro-1,2-oxazine synthesis.
• Integration of allene cyclization with iminium ion chemistry and allylation reactions for complex alkaloid synthesis.

Main Results:

• Successful synthesis of sedamine, Nuphar alkaloids, monomorine, porantheridine, and sedinine using the developed methods.
• Stereocontrolled synthesis of cis-3,5-disubstituted isoxazolidines and trans-3,6-disubstituted tetrahydro-1,2-oxazines.
• Access to complementary trans-isoxazolidines and cis-oxazines, and synthesis of 5-hydroxysedamine and the antibiotic negamycin.

Conclusions:

• The "tethered nitrogen" concept using hydroxylamines provides a versatile platform for alkaloid synthesis.
• Novel cyclization strategies offer efficient and stereocontrolled routes to diverse N,O-heterocycles.
• These synthetic approaches confirm the structures of natural products like raistrickindole A and preisomide.