Tying the knot! The marriage of two-directional synthesis and tandem reactions allows access to twelve skeletally diverse scaffolds in just fifteen reactions. Two-directional synthesis yields a symmetrical linear “rope-like” keto-dienoate which is then subjected to twelve separate tandem reactions to “tie the rope in knots” thus creating twelve diverse natural product-like scaffolds containing useful functionality for further elaboration

The synthesis of (+/-)-histrionicotoxin has been achieved in just nine steps using a two-directional synthesis strategy. Key reactions include a two-directional cross-metathesis, a tandem oxime formation/Michael addition/1,4-prototopic shift/[3 + 2]-cycloaddition cascade, a selective Z,Z-bisenyne formation, and a one-pot N-O and bischloroacetylene reduction.

A short and efficient synthesis of an advanced intermediate (1) in the Clive route to halichlorine has been achieved in 12 steps and 13.2% yield by a combined two-directional synthesis/tandem reaction strategy.

Background

Two-directional cross-metathesis of a range of alpha,omega dienes with a variety of electron deficient alkenes has been accomplished. It was found that the process is quite general and gives complete selectivity for the E,E-dienes, making this a very useful and high yielding protocol for two-directional chain elongation.