Pyrrolidine diastereoselectivity

Ring closure is expected for a radical precursor set with an unsaturation four bonds away when such a compound is treated with BusSnH-AIBN. The versatility of such cyclizations is derived from allowance of many varieties of substitution patterns and heteroatoms between the reactive centers. Furthermore, as shown in a synthesis of 2,4-disubstituted pyrrolidines, diastereoselectivity may be controlled in certain cases. 

Diastereoselective synthesis of pyrrolidine derivatives using chiral and non-racemic A-cyanomethyloxazolidines 99CSR383. 

Chiral and nonracemic A-cyanomethyloxazolidines in diastereoselective synthesis, particularly of pyrrolidine and piperidine derivatives 99CSR383. 

Imines with an electron-withdrawing group at the nitrogen atom are excellent acceptors for the acetate (1) or the carbonate (13) [36]. Thus, N-tosylimines (84) gave very good yields of pyrrolidines (85) under typical conditions. The strained cyclic imine (86) and a,/ -unsaturated imine (87) both participated smoothly in the cydoadditions. The hindered nitrimine (88) also reacts well with (1) (but not with 13) to produce the pyrrolidine (89) with a 17 1 diastereoselectivity. However, the unhindered nitrimines from cyclohexanone and 2-nonanone failed to react presumably due to enolization (Scheme 2.24). 

Ideal starting materials for the preparation of. svn-aldols are ketones that can be readily deprotonated to give (Z)-enolates which are known to give predominantly yyu-adducts. Thus, when (5,)-1-(4-methylphenyl)sulfonyl-2-(l-oxopropyl)pyrrolidine is treated with dibutylboryl triflate in the presence of diisopropylethylamine, predominant generation of the corresponding (Z)-boron enolate occurs. The addition of this unpurified enolate to 2-methylpropanal displays not only simple diastereoselectivity, as indicated by a synjanti ratio of 91 9, but also high induced stereoselectivity, since the ratio of syn- a/.vyn-lb is >97 3. 

Optically active 2-allylpiperidines and -pyrrolidines arc obtained by treating hydroxylactams containing the l-[(S)-l-arylethyl]substituent as an auxiliary (see Appendix) with tin(IV) chloride and trimethyl(2-propenyl)silane46. Interestingly, the moderate diastereoselection when the aryl group is phenyl decreases when 2-chlorophenyl is used, whereas the sense of the stereoselectivity reverses for 2,6-dichlorophenyl or pentachlorophcnyl. These results are rationalized by application of molecular orbital theory and substrate conformational preferences46. 

Hepatite Virus NS3/4A having the pyrrolidine-5,5-trans-lactam skeleton [83], starting from (R)- and (S)-methionine, respectively. The key step is the addition of the proper silyl ketene acetal to an iminium ion, e.g., that generated by treatment of the intermediate 177 with boron trifluoride, which provided the adduct 178 with better diastereoselectivity than other Lewis acids. Inhibitors of hepatitis C virus NS3/4A were efficiently prepared by a similar route from (S)-methionine [83]. The addition of indole to a chiral (z-amino iminium ion was a completely diastereoselective step in a reported synthesis of tilivalline, a natural molecule which displays strong cytotoxicity towards mouse leukemia L 1210 [84]. 

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. 

An enantioselective variant of the diene cydization reaction has been developed by application of chiral zirconocene derivatives, such as Brintzinger s catalyst (12) [10]. Mori and co-workers demonstrated that substituted dial-lylbenzylamine 25 could be cyclized to pyrrolidines 26 and 27 in a 2 1 ratio using chiral complex 12 in up to 79% yield with up to 95% ee (Eq. 4) [ 17,18]. This reaction was similarly applied to 2-substituted 1,6-dienes, which provided the analogous cyclopentane derivatives in up to 99% ee with similar diastereoselectivities [19]. When cyclic, internal olefins were used, spirocyclic compounds were isolated. The enantioselection in these reactions is thought to derive from either the ate or the transmetallation step. The stereoselectivity of this reaction has been extended to the selective reaction of enantiotopic olefin compounds to form bicyclic products such as 28, in 24% yield and 59% ee after deprotection (Eq. 5) [20]. 

In addition to nitrones, azomethine ylides are also valuable 1,3-dipoles for five-membered heterocycles [415], which have found useful applications in the synthesis of for example, alkaloids [416]. Again, the groups of both Grigg [417] and Risch [418] have contributed to this field. As reported by the latter group, the treatment of secondary amines 2-824 with benzaldehyde and an appropriate dipolarophile leads to the formation of either substituted pyrrolidines 2-823, 2-825 and 2-826 or oxa-zolidines 2-828 with the 1,3-dipole 2-827 as intermediate (Scheme 2.184). However, the yields and the diastereoselectivities are not always satisfactory. 

Recently, the research groups of Enders (Eq. 8.38)61 and Barluenga (Eq. 8.39)62 reported on the cycloaddition of chiral 2-aminobutadiene and described elegant solutions to the stereochemistry problems (regio-, diastereo-, and enantioselectivity). The reaction of 2-[(5)-2-methoxymethyl]pyrrolidin-l-yl]buta-l,3-diene with various 2-aryl-1-nitroethenes produces after hydrolysis 5-aryl-2-methyl-substituted 4-nitrocyclohexanones in excellent enantiomeric purity (ee = 75-95%) and with high diastereoselectivity (ds = 75-95%).61... 

A highly diastereoselective exchange reaction between a variety of bis(dimethy-lamino)arylphosphines and (S)-2-(anilinomethyl)pyrrolidine (197a) and its SV-aryl analogues constituted a key step in the synthesis of a series of substituted monodonor diazaphospholidine ligands, 213-220 [90, 91] (Figure 1). 

The reaction of nitrones with 3-butenylmagnesium bromide was used in the diastereoselective synthesis of cis -2,5-disubstituted pyrrolidines, arising from a Cope retro-elimination (Scheme 2.145) (Table 2.11) (201, 572). 

In the study of Weber et al.,41 a series of proline-derived hydrazones were prepared, and the reactions of the hydrazones with organocerium reagents were examined. It is clear from the table in Scheme 2 24 that the diastereoselectivity of the examined reactions depends on the nature of the side chain. (S )-l-amino-2-(2-methoxyethoxymethyl) pyrrolidine (40) gave the highest selectivity for various nucleophiles. 

Pyrrolo[l,2- ][l,2]oxazines are a class of compounds with very few references regarding synthesis and reactivity. An interesting preparation has been described by intramolecular cyclization of IV-hydroxy pyrrolidines carrying a methoxyallene substituent at C-2 (242, Scheme 32). These compounds were obtained by addition of a lithiated allene to chiral cyclic nitrones 241. Cyclization occurred spontaneously after some days at relatively high dilution (0.05 M). Compounds 243 (obtained with excellent diastereoselectivity) can be submitted to further elaboration of the double bond or to hydrogenolysis of the N-O bond to form chiral pyrrolidine derivatives (Section 11.11.6.1) <2003EJ01153>. 

Enantioselective a-hydroxylotion of carbonyl compounds. The lithium enolates of the SAMP-hydrazones of ketones undergo facile and diastereoselective oxidation with 2-phenylsulfonyl-3-phenyloxaziridine (13, 23-24) to provide, after ozonolysis, (R)-a-hydroxy ketones in about 95% ee. High enantioselectivity in hydroxylation of aldehydes requires a more demanding side chain on the pyrrolidine ring such as —QCjHOjOCH, which also results in reversal of the configuration. 

A more traveled route to the absolute configuration represented by cyclohexa-1,4-diene 8 involves Birch reduction-alkylation of benzoxazepinone 9.2.5 heterocycle is best prepared by the base-induced cyclization of the amide obtained from 2-fiuorobenzoyl chloride and (5)-pyrrolidine-2-metha-nol. o The molecular shape of enolate 10 is such that the hydrogen at the stereogenic center provides some shielding of the a-face of the enolate double bond. Thus, alkylation occurs primarily at the 3-face of 10 to give 11 as the major diastereomer. The diastereoselectivity for alkylation with methyl iodide is only 85 15, but with more sterically demanding alkyl halides such as ethyl iodide, allyl bromide, 4-bromobut-1-ene etc., diastereoselectivities are greater than 98 2. 

Photoinduced electron transfer promoted cyclization reactions of a-silyl-methyl amines have been described by two groups. The group of Pandey cyclized amines of type 135 obtaining pyrrolidines and piperidines 139 in high yields [148]. The cyclization of the a-silylated amine 140 leads to a 1 1 mixture of the isomers 141 and 142 [149]. The absence of diastereoselectivity in comparison to analogous 3-substituted-5-hexenyl radical carbocyclization stereochemistry [9] supports the notion that a reaction pathway via a free radical is unlikely in this photocyclization. The proposed mechanism involves delocalized a-silylmethyl amine radical cations as reactive intermediates. For stereochemical purposes, Pandey has investigated the cyclization reaction of 143, yielding... 

A chair-like amino-zinc-enolate transition state has been used to explain how substituents on the ring affect the diastereoselective and enantioselective formation of polysubstituted pyrrolidines during intramolecular amino-zinc-enolate carbometalla-tion reactions. ... 

Trons-divinyl-pyrrolidines and -piperidines were prepared by sequential intermolecular and intramolecular aminations of bis-allylic carbonates (Scheme 9.21) [22aj. Due to double stereoselection, these reactions proceeded with high diastereoselectivity and enantioselectivity. 

Aminomethylferrocene 338, this time without further methoxy substituents, also lithi-ates diastereoselectively (Scheme 150) , and similar results may be obtained with simple chiral pyrrolidines. Treatment of 322 with the binaphthylamine 337 yields 338. Lithiation generates a 9 1 mixture of diastereoisomeric organoUthiums, which give the phosphine 339 (Scheme 150) Attempts to obtain reversed planar diastereoselectivity by using silylation to block the more reactive lithiation site failed. 

Dihydro-4//-l,3-thiazines 231 are conveniently prepared by the iodocyclization of A -homoallyl thioamides 230 in the presence of triethylamine (Scheme 28) <2004CL508>. The selectivity of the reaction was dependent on the groups attached to the thioamide, and high diastereoselectivities are achieved with the 1-naphthyl or the 2-methoxyphenyl groups giving the major product 233 with the aryl group in the equatorial position rather than 234. Treatment of thiazines 231 with pyrrolidine resulted in the formation of 6-alkylidene-5,6-dihydro-4//-l,3-thiazines 232. 

Chiral aziridines having the chiral moiety attached to the nitrogen atom have also been applied for diastereoselective formation of optically active pyrrolidine derivatives. In the first example, aziridines were used as precursors for azomethine ylides (90-95). Photolysis of the aziridine 57 produced the azomethine ylide 58, which was found to add smoothly to methyl acrylate (Scheme 12.20) (91,93-95). The 1,3-dipolar cycloaddition proceeded with little or no de, but this was not surprising, as the chiral center in 58 is somewhat remote from the reacting centers... 

The enantiomerically pure l-[(benzyl(dimethyl)silyl)methyl]pyrrolidine, obtained from ben-zyl(chloro)(dimethyl)silane and (5,)-2-(methoxymethyl)pyrrolidine , afforded after deprotonation and subsequent alkylation the diastereomerically pure (by NMR spectroscopy) (a-alkylben-zyl)silanes2. To obtain this high degree of diastereoselectivity, the alkylation had to be performed in the weakly complexing solvent diethyl ether. In THF a diastereomeric ratio of only 3 1 was found with iodomethane as alkylating agent. 

Cyclization of the pyrrolidine derivative 5 diastereoselectively gave isomer 6, the thermodynamically more stable of the two possible ethyl pyrrolizidinecarboxylates, as the only product106. 

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