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Synlett 2011(15): 2115-2139  
DOI: 10.1055/s-0030-1261192
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© Georg Thieme Verlag Stuttgart ˙ New York

Exploring a Unique Reactivity of 6π-Azaelectrocyclization to Enzyme Inhibition, Natural Products Synthesis, and Molecular Imaging: An Approach to Chemical Biology by Synthetic Chemists

Katsunori Tanaka*a, Koichi Fukasea, Shigeo Katsumurab
a Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka, 560-0043, Japan
Fax: +81(6)68505419; e-Mail: ktzenori@chem.sci.osaka-u.ac.jp;
b Department of Chemistry and Open Research Center on Organic Tool Molecules, School of Science and Technology, Kwansei Gakuin University, Gakuen 2-1, Sanda, Hyogo 669-1337, Japan
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Publication History

Received 23 January 2011
Publication Date:
24 August 2011 (online)

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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 68Ga; 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

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Labeling kit ‘STELLA+’ is available from Kishida Chemical Co., Ltd., http://www.kishida.co.jp/.