Pyrrolidine cycloadducts

Hou and coworkers have developed a remarkable methodology for highly enantioselective cycloaddition of azomethine ylides (349) with nitroalkenes (353) [109]. CuC104/ligand (354) or (357) complexes both provide the desired pyrrolidine cycloadducts (355) or (358) excellent enantioselectivities. However, CuCl04/(354)... 

The enamines derived from cyclic ketones give the normal alkylated products, although there is some evidence that unstable cycloadducts are initially formed (55b). Thus the enamine (28) derived from cyclohexanone and pyrrolidine on reaction with acrylonitrile, acrylate esters, or phenyl vinyl sulfone gave the 2-alkylated cyclohexanones (63) on hydrolysis of the intermediates (31,32,55,56). These additions are sensitive to the polarity of the solvent. Thus (28) in benzene or dioxane gave an 80% yield of the... 

In practice, the [2 + 2] cycloadduct of 3-(pyrrolidin-l-yl)-l-benzothiophene (3) and dimethyl acetylenedicarboxylate isomerizes at 40°C to give the 3,4,5-trisubstituted 1-benzothiepin 5.12 In this synthesis cycloadduct 4 is not isolated. 

A family of interesting polycychc systems 106 related to pyrrolidines was obtained in a one-pot double intermolecular 1,3-dipolar cycloaddition, irradiating derivatives of o-allyl-sahcylaldehydes with microwaves in toluene for 10 min in presence of the TEA salt of glycine esters [71]. A very similar approach was previously proposed by Bashiardes and co-workers to obtain a one-pot multicomponent synthesis of benzopyrano-pyrrolidines 107 and pyrrole products 108 (Scheme 37). The latter cycloadducts were obtained when o-propargylic benzaldehydes were utihzed instead of o-allyhc benzalde-hydes, followed by in situ oxidation [72]. 

Increasing the steric hindrance of the ester was found to suppress completely the undesired lactamization. Thus, C-5-/-butoxycarbonyl cycloadducts 54a-e were reduced in near quantitative yield (NaBH3CN, 2M HC1, THF) to the A-substituted pyrrolidines 55a-e with, in some cases, the formation of the C-4 epimers 56c and 56d in low yield (Equation 6) <1996TL1711>. 

Thus, derivatives of structure 84 were treated with iV-methylmaleinide to give the cycloadducts 85 in high yields. In accordance with the concerted nature of this process, the pyrazoles and pyrrolidine-dione had a rxr-fusion. Similar cycloaddition was also experienced with dimethyl acetylenedicarboxylate (DMAD) to afford 86 containing the partially unsaturated pyrazole ring. 

The generation of an 1,2-oxazine 4-1 by hetero Diels-Alder reaction is a transformation which opens a versatile array of highly functionalised acyclic and cyclic structures. Thus, pyrrolidine derivatives 4-2, amino alcohols 4-3 and aza sugars 4-4 are easily available from these cycloadducts. Cyclic dienes, e.g. 4-5 are converted into bicyclic adducts 4-6 representing straightforward intermediates for aminocyclitols 4-7 (Fig. 4-1). 

Cyclic nitrones generated by [4+ 2]-cycloaddition of nitroalkenes undergo various, synthetically very valuable reactions. Thus, Denmark et al. have developed an elegant access to different enantiopure, 3- and 3,4-substituted pyrrolidine derivatives by reductive ring contraction of the cyclic nitrone resulting from a hetero Diels-Alder reaction [389,390]. Upon reaction of -2-nitrostyrene 4-51 with the chiral enol ether 4-52 in the presence of the bulky Lewis acid MAPh (4-53), three diastereomeric cycloadducts 4-54, 4-55 and 4-56 were formed. Hydrogenolysis of the main product 4-54 yielded the desired pyrrolidine 4-57 in excellent optical purity and allowed nearly quantitative recovery of the chiral auxiliary (Fig. 4-12) [391]. It is noteworthy that the nature of the Lewis acid catalyst, especially its steric demand, decisively influences the stereochemical course of such cycloadditions [392]. 

In the dipole cascade reaction, a proton must be removed from the a-carbon atom in order to generate the azomethine ylide. When the a-position of the pyrrolidine ring was blocked by a benzyl group, formation of the azomethine ylide dipole could not occur. In fact, treatment of diazoketone 186 with rhodium(II) acetate in the presence of dimethyl acetylenedicarboxylate afforded only the carbonyl ylide-derived cycloadduct 187 in 95% yield [117]. 

Ring expansion of dichlorocarbene cycloadducts may be followed by further carbene cycloaddition to give 70 and 71 (R2N = morphcjJino) (Scheme 36). In the case of the pyrrolidine enamine, the reaction stops at the eniminium salt stage (69) to give structures such as 72 and 73 on hydrolysis59,60. 

The reaction of the N-(5,5-dimethyl-3-oxo-l-cyclohexenyl)-N -arylcarbodiimides 41 with l-(L-pyrrolidino)cyclohexene affords a mixture of the [2+4] cycloadduct 42 (46 %) and the pyrrolidine adduct to the starting carbodiimide 43 (41 %). 

When reacted with 1-aryl-3,3,3-trifluoropropynes, azomethine ylide 14, generated from the aziridine, provides pyrrolines in high yield, with no rcgioseleclivily. These cycloadducts can be converted into the corresponding pyrroles or pyrrolidines. ... 

A -Benzyl-C-glycosyl nitrones reacted with acrylate to give glycosyl isoxazolidines which were easily converted to glycosyl pyrrolidines by reduction of the N-0 bond with Zn in acetic acid. The best result was obtained with pyranosyl nitrone 88 which quantitatively afforded the cycloadduct 89 with complete regio- and stereoselectivity <03TA3731>. 

Cycloaddition Reactions. Chiral acrylamides derived from pyrrolidines (2) or (3) undergo stereoselective [4 + 2] cycloaddition reactions with a variety of cyclic dienes. Similarly, nitroso compounds derivatized with pyrrolidine (2) and generated in situ give cycloadducts with a high degree of stereoselectivity (eq 6). Intramolecular [2 + 2] cycloadditions involving pyrrolidine-derived keteniminium salts have been shown to produce chiral cyclobutanones. ... 

Carbamoyl nitroso dienophiles, derived from chiral pyrrolidines, have been generated and their reactivity with cyclohexa-diene investigated. Using (—)-fra/w-2,5-dimethylpyirolidine as the auxiliary, the [4 + 2] cycloadduct is isolated in 82% yield and with 98% diastereomeric excess (eq 10). Similarly, chiral ynamine dienophiles have been utilized in asymmetric [4 + 2] cycloadditions with a,p-unsaturated nitroalkenes to afford cyclic nitronic esters. The resulting esters subsequently undergo a rapid [1,31-rearrangement to afford chiral cyclic nitrones in moderate yield and high diastereoselectivity (eq 11)-... 

Pyrrolidine Synthesis. The lithium (Z)-enolate of methyl iV-benzylideneglycinate undergoes a cycloaddition rapidly at —78°C with methyl (4J ,5R)-( )-3-( 1,3-dimethyl-4,5-diphenyl-2-imidazolidinyl)propenoate (1) to give pyrrolidine-2,4-dicarboxylate in quantitative yield and as a single stereoisomer (eq 1). Removal of the chiral auxiliary from the cycloadduct can be readily performed by treatment with cone Sulfuric Acid in MeOH at rt to produce the optically pure pyrrolidine-2,4-dicarboxylate bearing an acetal substituent at the 3-position. 

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