Cyclic oxonitriles: stereodivergent grignard addition-alkylations

Area of Science:

• Organic Chemistry
• Synthetic Methodology
• Stereoselective Synthesis

Background:

• Grignard reagents are versatile organometallic compounds widely used in organic synthesis.
• Cyclic nitriles are important structural motifs found in pharmaceuticals and natural products.
• Controlling stereochemistry in the synthesis of cyclic compounds remains a significant challenge.

Purpose of the Study:

• To develop an efficient method for synthesizing highly substituted cyclic nitriles.
• To investigate the influence of carbocyclic ring size on the diastereoselectivity of alkylation reactions.
• To explore strategies for reversing or controlling stereochemical outcomes in nitrile synthesis.

Main Methods:

• Sequential carbonyl addition-conjugate addition of Grignard reagents to cyclic oxoalkenenitriles.
• Alkylation of generated cyclic magnesiated nitriles.
• Conversion of C-magnesiated nitriles to N-metalated nitriles to alter selectivity.

Main Results:

• Efficient generation of cyclic magnesiated nitriles from 5-7 membered oxoalkenenitriles.
• Diastereoselectivity of alkylation is dictated by ring size: steric control in 5-membered rings, stereoelectronic control in 6-7 membered rings.
• Reversal of selectivity in 6-membered rings achieved via N-metalation, demonstrating steric control.

Conclusions:

• The study presents a novel and efficient route to complex cyclic nitriles with controlled stereochemistry.
• Ring size plays a critical role in determining the stereochemical outcome of Grignard reagent additions and subsequent alkylations.
• The developed methodology allows for selective access to diastereomers, particularly at the quaternary nitrile-bearing carbon.