ABSTRACT
A novel harringtonolide-inspired scaffold containing a cycloheptatriene ring and two fused cyclopentane rings has been synthesised from simple starting materials. The scaffold, containing a similar substitution pattern and relative stereochemistry to the complex diterpenoid, has been enumerated into a small library of derivatives. One of these library members has been converted into a sub-library of substituted triazoles using copper-catalysed azide-alkyne cycloaddition (click) chemistry. The scaffold may be useful in drug discovery or in the preparation of additional molecular probes for chemical biology.
Subject(s)
Antineoplastic Agents, Phytogenic/chemical synthesis , Chemistry, Pharmaceutical , Harringtonines/chemical synthesis , Molecular Probes/chemical synthesis , Small Molecule Libraries/chemical synthesis , Taxaceae/chemistry , Triazoles/chemical synthesis , Antineoplastic Agents, Phytogenic/analysis , Azides/chemistry , Catalysis , Click Chemistry , Copper/chemistry , Cyclopentanes/chemistry , Drug Discovery , Harringtonines/analysis , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Probes/analysis , Neoplasms/drug therapy , Plants, Medicinal/chemistry , Small Molecule Libraries/analysis , Stereoisomerism , Triazoles/analysisABSTRACT
A concise approach to the cephalotaxine CDE ring skeleton based on the intramolecular formal [5 + 2] photocycloaddition of cyclopentenyl-substituted maleimides is described. An investigation of the diastereoselectivity afforded by various protected alkoxy groups demonstrated that the best selectivity (3.5:1) was afforded by the free hydroxyl group, strongly suggesting a hydrogen-bonded excited state. Reaction: see text.
Subject(s)
Antineoplastic Agents, Phytogenic/chemical synthesis , Harringtonines/chemical synthesis , Maleimides/chemistry , Antineoplastic Agents, Phytogenic/chemistry , Harringtonines/chemistry , Homoharringtonine , Models, Molecular , Molecular Conformation , Photochemistry , Plant Leaves/chemistry , Plants, Medicinal/chemistryABSTRACT
Two new alkaloids, namely neoharringtonine (1) and anhydroharringtonine (2) with significant antileukemic activity were isolated from Cephalotaxus fortunei Hook f.. Their structures have been established by spectral analyses and semi-synthesis. Seven known alkaloids, deoxyharringtonine (3), isoharringtonine (4), isocephalotaxinone (5), acetylcephalotaxine (6), cephalotaxine (7), harringtonine (8) and homoharringtonine (9), were also isolated and identified.