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Mitsunobu Macrolactonization

Last updated

Jan 23, 2023
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- Michael addition
- Mitsunobu reaction

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The following is a standard procedure for a Mitsunobu macrolactonization.

Procedure

To a solution of the seco-acid (0.1 mmol) and PPh₃ (0.4 mmol) in PhMe (70 mL) under N₂ at -10 °C was added a solution of DIAD (0.4 mmol) in PhMe (30 mL) via syringe pump over 1 h. The resulting mixture was slowly allowed to warm to room temperature. After the disappearance of the starting material by TLC, the reaction was concentrated and the crude material was purified by flash chromatography on silica gel.

Notes:

PhMe is the most common solvent for this reaction. Other useful ones are: PhH, THF and CH₂Cl₂.
Very dilute conditions and slow addition of the diazo compound are critical to avoid formation of the diolide (dimerization of the seco-acid).
Slow addition of the seco-acid to the azo/phosphine mixture can also prevent diolide formation.
If addition of the azo compound onto the acid occurs, other diazo compounds can be used: DEAD (1972-28-7), DBAD (212-796-9), ADDP (10465-81-3) depending on the bulkiness needed.
Changing the triphenylphosphine to a less bulky phosphine (PBu₃, PMe₃) can accelerate slow reactions.

Mechanism

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