Proline derivatives prolinols

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. 

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. 

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... 

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... 

A number of alternatives to oxazolines based on other diamine or amino alcohol derivatives have been proposed, and in several cases good control over planar stereoselectivity can be achievecL The earliest, published before any work on fer-rocenyloxazolines, drew on Nozaki s early studies [3,39] on stereoselective lithiation of aminomethylferrocenes, and made use of the proline-derived amino ether 45 (Scheme 13) [40]. Substitution of 44 gave 46, whose lithiation proceeded with 93 7 stereoselectivity with w-BuLi in ether at -78°C and with 99 1 stereoselectivity with s-BuIi in ether at -78°C. Reaction of 47 with ClPPh2 gave 48 the enantiomer is available by silylation, re-lithiation, phosphination and deprotection in the manner of Scheme 9. Removal of the prolinol auxihary is achieved by acetylation and hydrolysis to 49 [41]. 

An alternative catalyst design consists of the introduction of bulky groups at the pyrrolidine ring, which would exert their stereochemical influence via steric shielding of one of the diastereotopic faces of the enamine intermediate. In this context, a wide variety of different proline derivatives have been employed in this transformation, including prolinol silyl ether homoprolinol silyl... 

The TIPS-protected L-prolinol derivative A (see Chapter 8) gave superior enantioinduction however, only 44% enantiomeric excess was still obtainable. Tetrazole-derived catalyst B (see Chapter 9) gave the highest yield (98% yield). Figure 5.9 illustrates the difference in reactivity and enantioselectivities between L-proline, and proline-derived catalysts A and B. 

In 2006, the same group reported the synthesis of other chiral A-aminoethyl prolinol derivatives on the basis of a DKR of A-(a-bromo-a-phenylacetyl)-proline methyl ester in asymmetric nucleophilic substitution and subsequent reduction (Scheme 1.17). These peptide-derived prolinols were tested as chiral... 

Finally, a remarkable four-component tandem Michael-aza-Henry-hemi-aminalisation-dehydration tandem reaction was recently developed by Lin and co-workers on the basis of a dual organocatalysis involving a chiral diaryl prolinol trimethylsilyl ether and a chiral cinchona alkaloid." As shown in Scheme 2.37, the reaction began with the Michael addition of an aldehyde to a nitroalkene catalysed by the L-proline-derived catalyst, giving the corresponding intermediate aldehyde. The latter intermediate... 

Other proline-derived catalysts promoting the selective formation of the fl/iti-diastereomer have been developed, for example, by the groups of Maruoka (axially chiral amino sulfonamides 98, symmetric chiral pyrrolidine-based amino sulfonamides 99) [66, 67] and Cdrdova (diaryl-prolinols 100) [68], among others, involving Coulombic or steric interactions (or both) as well to lock the transition state in the conformation required for stereoselective catalysis (Figure 11.3). 

Proline and proline derivatives have been utilized extensively as chiral catalysts for a wide range of asymmetric transformations [40, 132]. Gelman has documented a remarkable case in which enolizable aldehydes undergo selective Michael additions to enone acceptors (Equation 28) [133]. Diphenylpro-linol methyl ether (165) proved superior to other prolinol derivatives in terms of enantioselectivity and reactivity. As an example, the addition of oc-tanal (163) to ethyl vinyl ketone (164) in the presence of 5 mol% of 165 was carried out without solvent to furnish 166 in 87% yield and >95% ee. 

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). 

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... 

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. 

The mesitylylene-bridged tris(NAH) derivative of 5-prolin-amide and the p-xylylene-bridged bis(NAH) derivative of 5-prolinol switched the steric course of reduction so as to give the enantiomeric 5-mandelate in lower e.e. 

Among the ethers of prolinol, (5)-2-methoxymethylpyrrolidinc [SMP, (S)-10] has found most applications. It is readily prepared from prolinol by the normal sodium hydride/iodo-methane technique9,13 (sec also Section 2.3. for O-alkylations of other amino alcohols) and is also commercially available. An improved synthesis from proline avoids the isolation of intermediates and gives the product (which is highly soluble in water) by continuous extraction14. SMP has been used as the lithium salt in deprotonation and elimination reactions (Section C.) and as an auxiliary for the formation of chiral amides with carboxylic acids, which in turn can undergo carbanionic reactions (Sections D.l.3.1.4., D.l. 1.1.2.. D.l. 1.1.3.1., in the latter experimental procedures for the formation of amides can be found). Other important derivatives are the enamines of SMP which are frequently used for further alkylation reactions via enolates (Sections D.l.1.2.2.. where experimental procedures for the formation of enamines are... 

In the past Lewis acid-catalyzed [4+2] cycloaddition reactions of chiral alkyl acrylates have been systematically studied. Chiral auxiliaries derived from camphor, menthol and amino acids or from carbohydrates have been developed. Stereochemical and theoretical aspects of these chiral inductors have been intensively reviewed (see. Chapter 6). Asymmetric Diels-Alder reactions of chiral acrylamides derived from Ca-symmetrical secondary amines lead selectively to the cycloadducts in the presence of Lewis acids such as AICI3. In reactions of chiral auxiliaries derived from (iS)-proline and (iS)-prolinol excellent endo/exo selectivities and diastereoselectivities were obtained in the presence of catalytic amounts of Et2AlCl or TiCL. Cycloadducts of chiral crotonoyl derivatives derived from oxazolidinones 62, sultam 63 or for example (S)-lactate IS were obtained with high selectivities in the presence of Lewis acids such as Et2AICl. 

Modified diaiyl prolinols at the aryl rings or the proline scaffold " were subsequently reported as successful promoters in the asymmetric epoxidation of disubstituted tra/zs-enones. Zhao and coworkers studied the possibility of using recyclable diaiyl prolinols in this process. Dendrimeric catalyst If and fluoro-derivative Ig/ were synthesised and used at 30 mol% loading in tetrachloromethane as solvent in the epoxidation of a variety of fra/zs-enones (Scheme 7.4). 

Besides proline and MacMillan et al. s imidazolidi-nones, prolinol derivatives (Scheme 10.10) and corresponding diamines have been employed as catalysts in aldol reactions. 

---