2-pyrrolidinemethanol

The methyltitanium reagents 37 modified by the chiral 2-pyrrolidinemethanols 36 also did not show satisfactory enantioselectivities in addition reactions to aromatic aldehydes35. Noteworthy, however, is the fact that the enantioselectivity substantially increases with the change from A-methyl to A-acyl substituents. 

Enolates from l-acyl-2-pyrrolidinemethanols (A -acylprolinols) and their ethers are alkylated diastereoselectively, usually providing products in good to excellent diastereomeric ratios1-4. The most commonly employed auxiliaries are (S)-2-pyrrolidinemethanol (L-prolinol, 1), (S)-a,a-dimethyl-2-pyrrolidinemethanol (2) and (S)-2-(alkoxymethyl)pyrrolidines 3. For the preparation of these and the corresponding A -acyl derivatives, see Appendix. 

The opportunity for chelation in the various enolate intermediates offers a possible explanation for the observed diastereoselectivities. In the dianions derived from l-acyl-2-pyrrolidinemethanols strong chelation of both of the lithium cations should lead to a rigid enolate structure 9. It is reasonable to assume that the pyrrolidine ring is locked in one conformation. Since, according to models, it is difficult to attribute the observed high diastereoselectivity to steric hindrance, it is probable that the lone pair on the nitrogen directs the facial selectivity of electrophilic attack (see Section 1.1.1.3.3.1.) to one side of the enolate a-carbon. 

Table 5. 2-Alkylalkanoic Acids and a-Alkyl Lactones by Alkylation of Enolates from l-Acyl-2-pyrrolidinemethanols and Their Ethers, Followed by Hydrolysis...

An interesting example exists of variation of diastereoselectivity, due both to the nature and sense of chirality of the electrophile, and to the configuration of the 2-pyrrolidinemethanol auxiliary6. Thus, the use of epoxide 16 as electrophile leads to an unexpected reversal of the diastereoselectivity relative to that observed when the corresponding O-protected iodohydrin 10 is employed. Both of the electrophiles are chiral and therefore reaction of each with the enantiomers of 1-(l-oxopropyl)-2-pyrrolidinemethanol leads to different diastereoselectivities due to the fact that there is a matched and a mismatched pair of reactions. 

The alkylation of enolates from 1-acyl-2-pyrrolidinemethanols is not limited to compounds carrying two a-hydrogens. An example of an interesting type of dianion is that derived from the a-oxoamide 17, which is then alkylated with iodomethane to give a 87 13 ratio of diastereomers, as determined by NMR7. 

A variation of the procedure for alkylation of l-acyl-2-pyrrolidinemethanols (see Section 1.1.1.3.3.4.1.2.1.) relies on increasing the steric bulk of the chiral auxiliary by exchanging the primary alcohol function for a tertiary alcohol19 23. The resulting 1-acyl-a,a-dimethyl-2-pyrro-lidinemethanols 1 can be alkylated in a manner similar to the l-acyl-2-pyrrolidinemethanols. 

For the preparation of l-acyl-a,a-dimethyl-2-pyrrolidinemethanols 1 via two routes starting from the methyl ester of proline, see Appendix. 

AIkylalkanoic Acids 4 General Procedure for the Hydrolysis of l-(2-Alkyl-l-oxoalkyl)-z,a-diincthyl-2-pyrrolidinemethanols 21 ... 

Birch Reduction—Alkylation of Derivatives of l-Aroyl-2-pyrrolidinemethanol and l-Aroyl-2-pyrrolidinecarboxylic Acids... 

The combined Birch reduction alkylation of chiral, enantiomerically pure aroyl amides of 2-pyrrolidinemethanol (prolinol) or 2-pyrrolidinecarboxylic acid (proline) gives chiral, non-racemic, 1,1-disubstituted 2,5-cyclohexadienes 1 or 2-cyclohexenes 2, respectively, in high diastereomeric ratios. These reactions are useful for the preparation of valuable chiral synthetic intermediates 3 25 29-31-36. 

Acylation of 2-pyrrolidinemethanol with benzoyl or substituted benzoyl chlorides gives chiral l-aroyl-2-pyrrolidinemethanols while condensation of 2-pyrrolidinecarboxylic acid with 2 H-3,l-benzoxazinc-2,4-(l 7/)-diones results in pyrrolobenzodiazepinediones25. 

Acylation of (S)-2-pyrrolidinemethanol (1) with aroyl chlorides provides amides 2 which, when treated with base and iodomethane or chloro(methoxy)methane, furnish the corresponding methyl or methoxymethyl ethers 3. 

Table6. 1,1-Dialkylated 2,5-Cyclohexadienes by Birch Reduction-Alkylation of l-Aroyl-2-pyrrolidinemethanol Derivatives32 3, 38,3y 1. k/nh3/thf...

Several methods are available for removal of the 2-pyrrolidinemethanol unit from the products of Birch reduction-alkylation28,29. The most straightforward consists of refluxing with aqueous mineral acid and the chiral auxiliary can be recovered from the aqueous phase. However, under these conditions, one of the remaining double bonds of the alkylation product can undergo protiolactonization. 

A polymer-bound 2-pyrrolidinemethanol 47 was prepared and used as a chiral ligand in the reaction of diethylzinc with benzaldehyde. The alcohols were formed with 100% conversion and 89% enantiomeric excess (equation 19).69 The same results were obtained using 2 or 5 mol % of the catalyst. 

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