Mitsonobu reaction

Taking into account the close relationship to pyridines one would expect 2-pyridones to express similar type of reactivities, but in fact they are quite different. 2-Pyridones are much less basic than pyridines (pKa 0.8 and 5.2, respectively) and have more in common with electron-rich aromatics. They undergo halogenations (a. Scheme 10) [67] and other electrophilic reactions like Vilsmeier formylation (b. Scheme 10) [68,69] and Mannich reactions quite easily [70,71], with the 3 and 5 positions being favored. N-unsubstituted 2-pyridones are acidic and can be deprotonated (pJCa 11) and alkylated at nitrogen as well as oxygen, depending on the electrophile and the reaction conditions [24-26], and they have also been shown to react in Mitsonobu reactions (c. Scheme 10) [27]. 

A nucleophilic substitution of a 2-hydroxy group with 6-chloropurine via a Mitsonobu reaction has also been reported <1977CJC937>. 

Scheme 44 Application of Mitsonobu reaction and use of Sml2 for detachment...

Conversion of (D-hydroxy acids Into lactones via the Mitsonobu reaction (Scheme 6.8). Ring size and degree of oligomerisation is dependent on temperature and additives. 

Scheme 6.8 Conversion of hydroxy acids into lactones via the Mitsonobu reactions.

The catalytic process has found successful application in several natural product total syntheses. In 1996, Simon reported a synthesis of the antitumor dep-sipeptide FR-9001,228 in which the aldol addition reaction of 168 and the ethyl acetate-derived enol silane furnished a key synthetic intermediate (Eq. 23). The enantioselective aldol addition reaction of 168 was conducted with 165 and its enantiomer ent-165 to separately provide both enantiomers of the aldol adducts 169 and 170 (Scheme 14). These were then utilized in the preparation of diastereomeric seco acids 171 and 172 [101]. Macrocyhzation of 172 through a Mitsonobu reaction yielded the desired natural product 173. 

Attempts to prepare the required bicyclic azetidines by selective reduction of the C-7 carbonyl bond in penicillins failed [66, 67,68] treatment with diborane in THF gave exclusively the aminoalcohols 107 resulting from the cleavage of the four-membered ring (Scheme 34). However, 3-hydroxypropylamine derivatives can be transformed into azetidines, using for instance a modified Mitsonobu reaction [69, 70]. Nevertheless, this transformation was unsuccessful with compound 107b because cyclisation occurred onto the acylamino side-chain to yield dihydrooxazole 108 (Scheme 35). 

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