Prolines Prolinol

Heterofunctionalisation of carbonyl compounds in the a-position has become an important facet of oiganocatalytic enamine-mediated reactions. In 2005, the Jorgensen group described asymmetric a-sulfenylation of aliphatic aldehydes using TMS-protected prolinol catalysts. The best sulfenylating agent was M-benzylsulfanyl-1,2,4-triazole. Other catalysts, such as proline, prolinol, prolinamide or other secondary amide were less effective. The catalyst with bulkier aromatic groups (C2a) afforded the most enantioselective reaction (Scheme 8.39). 

General procedure for the production of Boc-protected a,a-diaryl-L-prolinols (6). To 100 mL of a 0.42 M solution of ArMgBr in THF (0.042 mol) at 0°C was added N- t- BOC)-L-proline methyl ester (5) (3.0 mL, 0.014 mol) dropwise via syringe over a five-minute period. The solution was stirred for at least 4 h at 25°C and then cooled to 0°C. After slow addition of 3 mL of water, the solution was slowly warmed to ft with stirring. The mixture was decanted and the solid was washed with 100 mL of ethyl ether. The organics were pooled and washed with brine, dried with sodium sulfate and evaporated to yield the final compound. 

As with the above pyrrolidine, proline-type chiral auxiliaries also show different behaviors toward zirconium or lithium enolate mediated aldol reactions. Evans found that lithium enolates derived from prolinol amides exhibit excellent diastereofacial selectivities in alkylation reactions (see Section 2.2.32), while the lithium enolates of proline amides are unsuccessful in aldol condensations. Effective chiral reagents were zirconium enolates, which can be obtained from the corresponding lithium enolates via metal exchange with Cp2ZrCl2. For example, excellent levels of asymmetric induction in the aldol process with synj anti selectivity of 96-98% and diastereofacial selectivity of 50-200 116a can be achieved in the Zr-enolate-mediated aldol reaction (see Scheme 3-10). 

There are several reports dealing with the use of tetrahydropyrrolo[l,4]oxazinones derived from natural proline or prolinol as chiral auxiliaries for the synthesis of enantiomerically pure compounds. The preparation of the heterocycle is described in Scheme 33 (Section 11.11.7.4). The presence of a rigid bicyclic skeleton allows stereoselective introduction of different substituents. The final ring opening of the system (generally by hydrolysis) provides enantiomerically pure compounds with the possibility of recycling the starting chiral auxiliary. 

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. 

Chiral pyrrolidine derivatives, proline, and amino acid-derived imidazolidinones mediate the asymmetric epoxidation of ,/i-unsalurated aldehydes. Protected a,a-diphenyl-2-prolinol catalyses the asymmetric formation of 2-epoxyaldehydes, with hydrogen peroxide or sodium percarbonate as the oxygen sources, with 81-95% conversion with up to 96 4 dr and 98% ee.204... 

Kurokawa et al81 reported the enzyme-catalyzed kinetic resolution of racemic N-carbamoyl, A-Boc, N-Cbz proline esters and prolinols using protease and Candida antarctica lipase B. The latter was efficient in the enantioselctive hydrolysis of both N-Boc and N-Cbz proline derivatives with E > 100. 

In the pioneering studies of Melchiorre and Jorgensen and colleagues, a variety of pyrrolidine-derived catalysts was tested (Scheme 2.51) [40]. Whilst modest selectivity was obtained with proline, and unhindered prolinol derivatives, (S)-2-(bis(phenyl)methyl)pyrrolidine derivative, 45c, allowed good conversion and enantio selectivity in the addition of linear aldehydes to methyl-vinyl ketone (MVK) (revalues up to 85%). Cyclic enones as well as -substituted enones afforded no, or perhaps poor, results. 

Chiral Amines with C2 Symmetry, trans-2,5-Dimethylpyrrolidine (1) was the first chiral amine possessing C2 symmetry used as a chiral auxiliary in asymmetric synthesis. Since that time a number of related systems have been developed including the title compound (2) and (4). These amines were developed as C2-symmetric analogs to the commercially available prolinol derivative (5). While proline-derived chiral auxiliaries have been widely used in asymmetric synthesis, the C2-symmetric chiral auxiliaries often give enhanced stereoselectivity when compared directly to the prolinol derivatives. Unfortunately the preparation of the C2-symmetric compounds is more tedious and, at the time of writing, none are commercially available. For example, the standard route to chiral pyrrolidines (2) and (3) involves the resolution of tranf-N-benzylpyrrolidine-2,5-dicarboxylic acid, although other preparations have been... 

The diacid corresponding to 114 is callosobruchic acid (115), and forms part of the copulation release pheromone of the azuki bean weevil, Callosobruchus chinensis Both chiral isomers have been synthesized by Mori et al. from methyl geranate epoxide (123). After scission of the epoxide group, the iodide 124 was made conventionally, then the chiral group was introduced using the Evans (R)- or (5)-prolinol propionamide enolate anion (125) (made with lithium diethylamide in tetrahydrofuran on the amide). Removal of the proline group... 

Prolinol methyl ether 31 is used in Enders s SAMP and RAMP chiral auxiliaries (chapter 27) and (S)-()-SAMP 32 can be made in 50-58% overall yield from (S)-L-(—) -proline on a 75 g scale.12... 

Analogous additions were later reported by Ito and co-workers (Scheme 9) (20). The enamines for these additions were prepared from the corresponding aminals using a mild base in the presence of trimethylsilyl chloride. In turn, the aminals used are available from (— )-ephedrine and (S)-prolinol. The byproduct amine hydrochloride was removed either by distillation or by precipitation from a benzene solution. Enamines prepared by this method were found to be unreactive toward unsaturated carbonyl compounds in a variety of solvents. Importantly, it was found that use of a mild Lewis acid such as anhydrous MgCl2 or ZnCl2 in THF promoted the reactions. Thus, the addition of enamines 9.1 and 9.2 to methyl acrylate is achieved. Of the two enamines, the proline-derived 9.1 is the more effective auxiliary. The... 

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