1. High energy intermediates

Enzymes can often be blocked by substances that are similar to the transition state of the natural substrate but chemically stable. According to the Hammond postulate high energy intermediates (HEI), present in non-enzymatic reactions, are good proximisations to these enzyme bound transition states.

The HEI that is simulated by the substances synthesised in this work ocurrs in the delta 8-delta 7-sterol isomerase, a key enzyme of the ergosterol biosynthesis pathway. It is common to replace the unstable carbocation of the HEI by nitrogen that can form a stable ammonium cation. The HEI and one of my main basic structures can be seen in the figure below.

2. Synthetic strategies

My model belongs to the 2-azabicyclo[5.3.0]decanes. As it has many features of a steroid it can also be called a des-A,B-C-azahomosteroid.

It is chemically derived from cholecalciferole (vitamin D₃), a secosteroid that is available commercially at reasonable cost and already features all of the stereochemical requirements.

The initial step is an ozonisation, immediately followed by the formation of an oxime as ketone 6 is stereochemically unstable. Oxime 7 (which is the last substance described elsewhere) can be submitted to a Beckmann rearrangement to form lactame 8, activated to give the highly reactive oxime mesylate 9 or reduced to give amine 10 , a substance that already has considerable antifungal potency.

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