Acylpyrrolidines, synthesis

The intramolecular Mannich reaction has been combined with the facile [3,3] sigmatropic rearrangement of iminium cations to provide a versatile synthesis of 3-acylpyrrolidines and other more complex ring systems containing this subunit.In the simplest case, a homoallylic amine with alkoxy or hydroxy substitution at the allylic site is allowed to react with an aldehyde in the presence of an equivalent or less of acid to yield substituted 3-acylpyrrolidine products (Scheme 50). The mild conditions of this transformation—which occurs at near ambient temperature and neutral pH—are apparent in the success of this sequence with labile aldehydes such as furfural. Ketones can be employed also in this case a two-step... 

Asym. synthesis of carboxylic acids via C-alkylation of N-acylpyrrolidines... 

As mentioned in an earlier section in this Report, free-radical carbon-carbon bond-forming processes are becoming increasingly important in synthesis, and this year they have proved themselves particularly useful for the synthesis of pyrrolizidine alkaloids. Thus, Hart and his group have now applied their intramolecular tin hydride generated ot-acylamino radical to alkyne cyclization [viz. (97) - (98)] and to the synthesis of (-)-dehydrohastanecine (99), (+)-heliotridene (100), and (+)-hastanecine (101). In addition, free radical in mechanism is the photochemical cyclization of the -acylpyrrolidine (102) to the pyrrolizidene (103), a key intermediate in a synthesis of ( )-isoretronecanol (104). 

The Overman pyrrolidine synthesis is a tandem reaction, or cascade, used to generate acylpyrrolidine derivatives. This process begins with condensation of an allylic alcohol/ether-containing secondary homoallylic amine with an aldehyde, followed by an aza-Cope rearrangement and subsequent Mannich reaction. Commonly, this reaction is run in refluxing benzene with an acidic additive, such as c/-10-camphorsulfonic acid (CSA). 

Application of transition metal catalysts as Lewis adds provides yet another mechanistic paradigm for lactone synthesis. Kanemasa used Ni(II) with a bisoxazoline ligand for the synthesis of hexahydrobenzopyranones from a, J-unsaturated N-acylpyrrolidines and Meldrum s acid. An asymmetric variant was later reported (Scheme 2.63) [120, 121]. 

Let us turn to experiments that probe in more detail the mechanism of this tetrahydrofuran synthesis. Three mechanistic possibilities are suggested in Figure 7 and these parallel mechanisms we recently considered for the formation of 3-acylpyrrolidines from protic acid-catalyzed rearrangement of 5-vinyloxazolidines (Figure 2, X = NR). [8] The first two possibilities seem to us most likely and one approach to probing these is to examine the stereochemical outcome of the... 

---