Synthesis of polycyclic natural products

Pyranonaphthoquinones show characteristic biological activities and have in common the isochromanquinone skeleton. As a consequence of their interesting structures and useful biological activities, new synthetic approaches have been developed. Our generally useful three step (Michael addition, oxidation and reduction) sequence for pyranolactone subunits represents a valuable contribution to synthetic methodology. Efforts toward the synthesis of these natural pyranonaphthoquinones led us to generate a common intermediate by which the more complex pyranonaphthoquinones can be prepared. This extremely convergent approach will permit the direct synthesis of biologically active analogues and may also aid in the structure identification of quinone natural products. In the context of extending our Diels-Alder/retro-Claisen (DARC) strategy to more complex pyranonaphthoquinones such as SCH 38519 and medermycin, a new synthesis of dialdehyde sugars using a Michael addition/aldol condensation sequence has been developed. It is complementary to previously reported methods for the production of C-glycosyl compounds;Studies on the application of functionalized bridgehead radical intermediates in natural products synthesis led us to discover a new pathway to bicyclo(3.3.0) octanes and their 3-aza counterparts by nucleophilic addition/ring contraction of bridgehead bromides. The natural product modhephene was synthesized by use of this rearrangement methodology. A new, highly efficient bridgehead radical approach to the ABDE ring skeleton of lycoctonine-type diterpenoid alkaloids has been developed. The facile carbon-carbon bond formation at the bridgehead makes this process particularly attractive for the synthesis of polycyclic diterpene alkaloid systems

ML277 specifically enhances the fully activated open state of KCNQ1 by modulating VSD-pore coupling

Upon membrane depolarization, the KCNQ1 potassium channel opens at the intermediate (IO) and activated (AO) states of the stepwise voltage-sensing domain (VSD) activation. In the heart, KCNQ1 associates with KCNE1 subunits to form

A new synthesis of aryl mono C-glycosyl derivatives of dialdehyde sugars

A new synthesis of mono C-glycosyl derivatives of dialdehyde sugars using a Michael additionlaldol condensation sequence has been developed. It is complementary to previously reported methods for the production of C-glycosyl compounds. The synthesis involves the Michael addition reaction of an enol silyl ether with acetylbenzoquinone followed by an aldol condensation and subsequent aromatization of the resulting hydroxy ketone. The aldol condensation proceeds only under select conditions and affords the unstable ketols 7 and 15

Reactions of bridgehead halides. A synthesis of modhephene, isomodhephene, and epi-modhephene

A Synthesis of modhephene has been achieved, the key feature of which is the use of a novel nucleophilic addition/rearrangement reaction to develop the carbon framework. Stereochemical control of the stereogenic center bearing the methyl group was accomplished by variation of the hydrogenation conditions. As a byproduct of this work, we have clarified structural assignments of intermediates from previous syntheses

Rearrangements of bridgehead bromides. A direct synthesis of epi-modhephene

Summary: The reaction of nucleophiles with bridgehead bromides 3 and 4 affords rearrangement products resulting from addition of the nucleophile to the carbonyl group followed by ring contraction. This rearrangement has been employed in a direct synthesis of epi-modhephene

A versatile intermediate for the synthesis of pyranoquinone antibiotics

As a result of the sophisticated detection and isolation procedures developed by Omural and others, the family of biologically active pyranoquinones continues to grow rapidly. As a consequence of their interesting structures and useful activity, several synthetic approaches have already appeared.