Abstract
While elucidating the inhibitory mechanism of a hydrolytic enzyme
by aldehyde-containing natural products, we discovered a reaction
involving a rapid 6π-azaelectrocyclization of azatrienes
generated from aldehyde with lysine residues. The electrocyclic
reaction of the 1-azatriene system, a cyclization precursor, exhibited
a substituent effect. Structure-reactivity studies showed that
azaelectrocyclization, which usually proceeds in low yield at high
temperatures, produced a quantitative yield in less than 5 minutes
at room temperature. Asymmetric chiral piperidine synthesis and
a one-pot library synthesis of pyridines on solid supports were applied
to synthesize pyridine/indole alkaloid-type natural products.
Additionally, we developed lysine-based labeling and engineering
of biomolecules and living cells based on the rapid 6π-azaelectrocyclization.
Both 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)
as a metal chelating agent and fluorescent groups, as
well as oligosaccharide structures were introduced efficiently and
selectively into surface lysines within 10 minutes at concentrations
as low as 10-8 M. The DOTA-labeled somatostatin
and glycoproteins were then radiometallated with 68 Ga;
the receptor-mediated accumulation of somatostatin in pancreas and
the oligosaccharide-dependent circulatory residence of glycoproteins
were visualized by microPET for the first time. Furthermore, we
succeeded to image the trafficking of the fluorescence-labeled lymphocytes
noninvasively, while the N -glycan-engineered
lymphocytes targeted the colon carcinoma in tumor mouse model; the
tumor-targeting cells were thus synthesized using our 6π-azaelectrocyclization.
1 Introduction
2 Discovery of Smooth 6π-Azaelectrocyclization: Inhibitory Mechanism
of Bovine Pancreatic Phospholipase A2 by Unsaturated
Aldehyde Terpenoids
3 Renaissance of 6π-Azaelectrocyclization: Remarkable
Acceleration by Substituent Effects
3.1 Synthesis of 3-cis -1-Azatriene
Derivatives and Their Reactivities toward Azaelectrocyclization
3.2 Rationale for Acceleration of 6π-Azaelectrocyclization
by Computational Analysis
4. 6π-Azaelectrocyclization as a New Strategy for
Natural Products Synthesis
4.1 One-Pot Pyridine Synthesis: Formal Synthesis of the Ocular Age
Pigment A2-E
4.2 Library-Directed One-Pot Solution and Solid-Phase Synthesis
of 2,4-Disubstituted Pyridines
4.3 Highly Stereoselective Asymmetric 6π-Azaelectrocyclization
4.4 Application to Natural Alkaloid Synthesis: Formal Synthesis
of 20-Epiuleine
5 6π-Azaelectrocyclization-Based Microgram-Scale Labeling
of Peptides and Proteins: Biomolecule-Based In Vivo Imaging
5.1 Development of Non-Destructive Lys-Labeling Kit ‘Stella
+
’ by
6π-Azaelectrocyclization
5.2 Positron Emission Tomography (PET) of Biomolecules: First
Visualization of Somatostatin Accumulation to Pancreas and Sialic
Acid Dependent Circulatory Residence of Glycoproteins
6 Labeling and Engineering of Living Cells by Azaelectrocyclization
6.1 Fluorescence Labeling of Living Cell Surfaces
6.2 Chemical Engineering of Cell Surfaces by Functional Molecules
6.3 In Vivo Fluorescence Imaging of Lymphocytes and Effects of
Cell Surface Engineering by N -Glycan
7 Site-Selective and Non-Destructive Protein Labeling via Azaelectrocyclization-Induced
Cascade Reactions
8 Conclusion
Keywords
synthetic (chemical) biology - 6π-azaelectrocyclization - enzyme inhibition - lysine - natural products
synthesis - chiral piperidine - pyridine - labeling - PET (positron emission tomography) - fluorescence - glycoproteins - lymphocytes - cell surface
engineering - tumor targeting
