Solid-phase parallel synthesis of natural product-like diaza-bridged heterocycles through Pictet-Spengler intramolecular cyclization.
A multistep, practical solid-phase strategy for the synthesis of natural product-like diaza-bridged heterocycles was developed. A key step in the library synthesis is tandem acidolytic cleavage with subsequent in situ iminium formation followed by the Pictet-Spengler intramolecular cyclization. The Pictet-Spengler-type intramolecular cyclization step was regioselective and diastereoselective to give final products as single diastereomers in exceptional yields and purities, which was confirmed by NMR structural study and LC/MS analysis. This approach is exemplified by the preparation of a 384-member library of 3,9-diazabicyclo[3.3.1]non-6-en-2-one skeletons, fused with indole and dihydroxybenzene and diversified at two bridging nitrogen atoms, using the solid-phase parallel synthetic methodology without further purification. In this pilot library, two diastereomerically enriched diaza-bridged core skeletons were modified by amide and urea bond formation on bridging nitrogen atoms, and this scheme exhibits the potential for expansion to obtain further diversification.
Lee
Sung-Chan
SC
School of Chemistry, Seoul National University, Seoul 151-742, Korea.
Park
Seung Bum
SB
D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D003500:Cyclization; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D013237:Stereoisomerism
D001372:Aza Compounds; D001952:Bridged-Ring Compounds