3-Acylpyrrolidines

To control the equilibrium position of the rearrangement, Overman and others introduced a nucleophilic hydroxyl group at the C2 position to capture the rearranged iminium ion2 (Scheme 1.6b). Although the levels of diastereoselecti-vity for the formation of pyrrolidines 6a and 6b are low, the tandem cationic aza-Cope-Mannich cyclization provides a variety of substituted 3-acylpyrrolidines in high yields under mild reaction conditions. The first step in the reaction is the... 

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... 

Homoallylic amines containing an allylic hydroxy group rearrange in the presence of an aldehyde and an acid catalyst to yield 3-acylpyrrolidines. If the starting amino alcohol is cyclic, this transformation provides a pyrrolidine-annulated product, in which the initial ring is expanded by one member. The mechanism has been proposed to proceed via a tandem cationic aza-Cope rearrangement/Mannich cyclization1134. 

The reaction of salts of 2-alkoxy-3-butenamines with a variety of aldehydes produces 3-acylpyrrolidines, e.g., 50, in a single step1146. 

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... 

Fig. 9 A combinatorial library mixture of A-acylpyrrolidines with modest HCV NS5B activity...

Katsuki and coworkers have developed a family of salen-metal complexes capable of effecting a C—H oxidation at activated positions. meso-Tetrahydrofurans may be oxidized to the lactol in good yield and excellent enantioselectivity using iodosylbenzene as the stoichiometric oxidant and a Mn-salen complex as catalyst [Eq. (10.45)]. " Meso acylpyrrolidines behave similarly, providing slightly lower enantioselectivities using a similar catalyst [Eq. (10.46)]d ... 

In the monoanionic enolates from the ethers and other 2-substituted 1-acylpyrrolidines, chelation should be much weaker or absent, leading to less restricted rotation of the enolate moiety. Furthermore, rotation of the pyrrolidine substituent and conformational mobility of the pyrrolidine ring can lead to inversion of the nitrogen lone pair. These factors may explain the reversed and lower diastereoselectivity observed with these substrates. 

Both the (2S,5S)- and the (27 ,5/ )-enantiomers of the trans-pyrrolidine auxiliary 1 are available in high diastereomeric purity and high enantiomeric excess via resolution of traw-l-benzyl-2,5-pyrrolidinedicarboxylic acid and subsequent functional group transformation (see Appendix)7,13, 14. The chiral auxiliaries so obtained are then acylated with the appropriate acylation agent, which yields the desired /rart.v-2,5-disubstituted 1-acylpyrrolidines 2. 

The chiral irans-2,5-disubstituted 1-acylpyrrolidines have been used in many diastereoselective reactions, in particular alkylation reactions. Thus, the amide enolates have been used in the preparation of a wide variety of chiral acid derivatives, e.g., 2-alkylalkanoic acids7,8 and other 2-substituted acids, such as 2-hydroxy-9, 2-cyano-2-methyl10, and 2-aminoalkanoic acids112 and their derivatives (see Tables 7 and 8), in high chemical yield. The induced diastereoselectivity is usually very high (mostly d.r. >97.5 2.5). 

Hydrolysis of the alkylated w2.v-2,5-disubstituted 1-acylpyrrolidines 1 is usually simple and consists of refluxing with aqueous hydrochloric acid. This treatment first removes the... 

TV-acylpyrrolidine ring in S2 by a single methylene linker. This is a novel design and the candidate ligand appears to be more rigid than NAPAP, since it has a smaller number of rotatable bonds. Hence, the penalty paid for the loss in entropy upon binding should be smaller for this CCLD hit than for NAPAP. 

N-Acylpyrrolidinones. N-Acylpyrrolidines are oxidized at room temperature (10 examples, 32-81%). 

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