C2-Symmetric Pyrrolidines

Waldmann in Organic Synthesis Highlights //(Ed. H. Waldmann), VCH, Weinheim (1995) 49. 

Yamamoto, J. Hoshino, Y. Fujimoto, J. Ohmoto, S. Sawada, Synthesis (1993) 298. 

Defoin, A. Brouillard-Piochet, J. Streith, Helv. Chim. Acta 74 (1991) 103. T. K. M. Shing, Tetrahedron 44 (1988) 7261. 

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Very recently, the same group proposed an access to a-amino P-ketoesters from chiral P-enamino esters [12e]. The animation reaction was performed with sulfonyl-oxycarbamate 6e (1 to 3 equiv.) in dichloromethane without base over two days, using chiral p-enamino ester derived from C2 symmetric pyrrolidines 24 or (/ )-1-phenylethylamine 26 (Scheme 10). 

Finally, the C2-symmetric pyrrolidine 8, obtained from D-mannitol, affords the tricyclic dienophile 9 which reacts with cyclohexadiene to give, in 90 % yield and > 99% de, a dihydro-1, 2-oxazine derivative 10 in which the newly formed bicyclic system has the (15,4/ ) configuration, as determined by comparison with known compounds107. 

As indicated by Entry 5 in Table 6.2, the lithium enolates of pyrrolidine amides show excellent simple diastereoselectivity, and rearrange in excellent yields [69]. These amides also show a slight dependence of selectivity on the structure of the amide base used [69]. Monosubstituted pyrrolidine amides were poor auxiliaries for this reaction (<76% ds) [69], but C2-symmetric pyrrolidines are highly selective, as shown in Scheme 6.22 [90]. The Si facial selectivity of the lithium enolate and the illustrated zirconium enolate were comparable, but only the zirconium enolate also showed a high preference for the ul topicity illustrated. The two views of the transition structure rationalize both the topicity and the absolute configuration of the product. The enolate Si face is favored because the closer of the two pyrrolidine stereocenters blocks the Re face. The ul topicity is favored because when the enolate moiety is on the concave face of the cyclopentane envelope, a severe interaction between a pseudoaxial hydrogen and a cyclopentadiene is avoided cf. Scheme 6.14 a for another illustration). 

Treatment of 762 with allyl bromide and sodium hydride provides in 82% yield the C2-symmetric pyrrolidine 776. Chemoselective N-oxidation with er butylhydroperoxide in the presence of vanadyl acetylacetonate affords in 75% yield the N-oxide 111 which, when treated with LDA, forms a benzylideneazomethine ylid (having the Z-configuration) that undergoes an intramolecular 1,3-dipolar cycloaddition to afford the e isolable product in 35% yield (Scheme 170). 

C2-Symmetric pyrrolidines have been employed as chiral auxiliaries effectively. Intramolecular cycloadditions of keteniminium salts as well as reactions with imines furnishing 3-lactams have been reported in the literature. ... 

Cycloadditions of chiral A -acylnitroso compounds have been widely studied. These heterodienophiles are accessible e.g. by oxidation of hydroxamic acid derivatives with periodate. C2-symmetric pyrrolidines lead to high selectivities. 1,2-Oxazines are useful precursors of amino alcohols and aza sugars. 

The use of C2-symmetric chiral auxiliaries attached to the nitrogen atom of amine iV-oxides can obviate the need for synthesizing substrates bearing an allylic amine stereocenter for stereoselective [2,3]-Meisenheimer rearrangements. For exanple, Enders and Kenpen developed a C2-symmetric pyrrolidine auxiliary 82 that guided the selective formation of the... 

The C2-symmetric pyrrolidine-containing selenyl bromide 268 has been described as a reagent for enantioselective methoxyselenation of styrene derivatives in 50-60% d.e., leading, after oxidative elimination, to 1-arylallyl methyl ethers of predominantly R configuration (Schone 55). 

Rawal efficiently utilized the C2-symmetric pyrrolidine derivative 458 to induce facial control as 459 rearranged to thioamide 462 in excellent yield and high diastereoselection. ... 

A C2-symmetric pyrrolidine-based tetraamine promotes additions of ketones to nitroolefins and chalkones with respective yields of <99% and <91% and relative ee values of <91% and <93%. Excellent enantioselectivities have been reported for conjugate addition of ketones to nitroalkenes catalysed by chiral pyrrolidine sulfamides incorporation of an additional chiral centre in the side-chain is of negligible advantage. Additions of ketones to nitroolefins have also been promoted by a chiral amino-naphthalene-derived prolinamide. " ... 

Independently, Alexakis and coworkers reported that 2,2 -bipyrrolidine catalyst 28 showed excellent catalytic activity in several types of asymmetric Michael addition reactions [143]. It has been postulated that the isopropyl group on one of the C2-symmetric pyrrolidine rings should block not only the back face against the approach of Michael acceptors but also shift the equiUbrium towards one of the two rotamers. Since then, closely related catalysts have also been reported [144]. Furthermore, different types of catalysts such as 29 have been shown to be useful in asymmetric Michael addition reactions [145-148]. 

Use of the valine derived (4S )-3-acetyl-4-isopropyl-1,3-oxazolidine (8)92, the C2-symmetric reagents (2.5,55)-l-acetyl-2,5-bissubstituted pyrrolidine 994, or the doubly deprotonated acetyl urea /V-acetyl- V..V -bis[(.S)-l-phcnylethyl]urea (10), also does not lead to sufficient induced stereoselectivity combined with acceptable chemical yield. When the acetyl urea enolate is reacted with aliphatic and aromatic aldehydes, the diastereomeric adducts (ratios ranging from 1 1 to 3 1) may be separated by column chromatography to give ultimately both enantiomers of the 3-hydroxy acids in 99% ee110. 

An examination of the catalytic abilities of C2-symmetric chiral A-(p-mer-captoethyl)pyrrolidines in the enantioselective addition of ZnEt2 to a variety of... 

Scheme 3.28 C2-Symmetric Al-(P-mercaptoethyl)pyrrolidine ligands for additions of ZnEt2 to aldehydes.

As another extension of this process, Davies et al. have developed highly regio-, diastereo- and enantioselective C-H insertions of methyl aryldiazoace-tates into cyclic A-Boc-protected amines catalysed by rhodium(II) S)-N- p-dodecylphenyl)sulfonylprolinate. The best results were obtained in the case of the C-H insertion of methyl aryldiazoacetates into A-Boc-pyrrolidine, which gave, in all cases, a diastereoselectivity and an enantioselectivity greater than 90% de and 90% ee respectively (Scheme 10.77). The synthetic utility of this method was demonstrated by means of a two-step asymmetric synthesis of a novel class of C2-symmetric amines. 

Having demonstrated a practical and reliable method to access 2-arylpyrrolidines in high enantioselectivity, we felt that a noteworthy extension of this methodology would lie in its application to bis-arylated products 27, providing a rapid and efficient approach to enantiopure C2-symmetric 2,5-diarylpyrrolidines, which have been identified as valuable chiral auxiliaries and chiral ligand manifolds [29]. Towards this end, substrate 26a was subjected to the standard arylation conditions, which produced 2,5-diphenyl-N-Boc-pyrrolidine 27 in a 96 4 diastereomeric ratio, and 57% isolated yield (s-BuIi/TMEDA produced 27 in lower d.r. (66 34) and yield (42%)), as depicted in Scheme 8.13. 

The reaction with N-Boc-pyrrolidine may be taken a step further by inducing a double C-H insertion sequence [27]. This results in the formation of the elaborate C2-symmetric amine 35 as a single diastereomer with control of stereochemistry at four stereogenic centers. The enantiomeric purity of 35 is higher than that obtained for the single C-H insertion products, presumably because kinetic resolution is occurring in the second C-H insertion step. 

The conjugate addition of CH3COSH to methacrylamides with chiral C2-symmetric nms -2,5-disubstituted pyrrolidines afforded the Michael addition products in excellent... 

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... 

C2 symmetric chiral pyrrolidine, useful in optically active form as a chiral auxiliary in a variety of asymmetric reactions)... 

Reduction of 1,4-Diketones. Synthetic access to C2-symmetric 1,4-diols, useful building blocks for the preparation of chiral 2,5-disubstituted pyrrolidines and phospholanes, involves reduction of the parent 2-alkane-1,4-diones, or, even better, reduction of the related ( )-alk-2-ene-1,4-diones (11) (eq 7) or 2-alkyne-1,4-diones (12) (eq 8), followed by catalytic hydrogenation. ... 

For an interesting C2-symmetrical diaza C-disaccharide of pyrrolidine character, the requisite precursor diazidocyclohexenediol 40 could be effectively obtained from racemic a fi-benzene bisepoxide [110]. Unfortunately, the... 

Comparable results are obtained in radical additions to several C2-symmetric fumaric bisamidcs. 2,5-Dimcthylpyrrolidine14,15,2°, 2,5-bis(methoxymethyl)pyrrolidine and 1,3 4,6-di-0-benzylidene-2,5-dideoxy-2,5-imino-L-idit21 are used as chiral auxiliaries. Reactions with cyclohexyl or tort-butyl radicals, generated by the mercury or the tin method, respectively, proceed with high levels of asymmetric induction, yielding essentially only one of the two possible products. 

An investigation of the influence of high pressure versus temperature on induced diastereoselectivity was performed by Eguchi et al. for the cycloaddition of the a,/ -unsaturated sulfonamide (125) bearing a C2-symmetric chiral pyrrolidine auxiliary and cyclopentadiene (126) (Scheme 8.30) [61]. The same product ratio for 127 128 of 75 25 was found after 2 h at atmospheric pressure and 80 °C and after 14 h at... 

The insertion at C-2 and C-5 of iV-Boc-pyrrolidine in the presence of Rh2[(5)-DOSP]4 gives rise to C2-symmetric compounds. On the other hand, by using Rh2[(/ )-DOSP]4 as the catalyst, the reaction leads to mixtures of diastereomers and regioisomers. 

Imides to amines. The last step of a convenient route to C2-symmetric 3,4-disubstituted pyrrolidines involves reduction of the corresponding succinimides. 

A C2-symmetrical pentacychc guanidinium salt like 16 (Figure 4.5) was used for the conjugate addition of pyrrolidine to y-crotonolactone, in which structural requirement such as the size of the cavities and substituents on tetrahydropyran rings of the guanidine catalysts is critical for asymmetric induction [23]. 

Vintonyak, V. V. and Maier, M.E. (2007) Synthesis of the core structure of cruentaren A. Organic Letters, 9, 655-658 Aggarwal, V.K., Sandrinelli, F. and Charmant, J.P.H. (2002) Synthesis of new, highly hindered C2-symmetric rranr-(25,55)-disubstituted pyrrolidines. Tetrahedron Asymmetry, 13, 87-93. 

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