Pyrrolidines conformation

An interesting study of conformationally mobile systems involves iodo-methylation of nicotine derivatives 47, where steric effects of substituents at position-2 and -6 modify the alkylation rate at the pyridine nitrogen and at the two nitrogens (N trans and N cis) of the pyrrolidine conformers (80JA7741 81JOC3040) (Scheme 26b). 

That the methyl group in the pyrrolidine enamine of 2-methylcyclo-hexanone (7) is in fact axial was demonstrated by Johnson and Whitehead (8). They found that careful hydrolysis of the pyrrolidine enamine of the conformationally more stable system, i.e., 2-methyI-4-t-butylcyclohexanone (13), led to a 1 4 mixture of cis and trans isomers of the ketone (14 and 15), showing that the methyl group in the enamine is largely in the axial orientation. 

With the amide 8 (R1 = C 11,) derived from 2-oxopropanoic acid and amine E, the (2 R)-diastereomer is predominantly formed, regardless of the solvent, through chelation-controlled Re-side attack of the organometal14. Presumably, the weaker steric interaction between the pyrrolidine moiety and the methyl substituent of the amide (R1 = CH3) compared to the phenyl substituent (R1 = C6H5) facilitates the preferential formation of the chelated conformer S-m-8. 

As well as the disubstituted C2-symmelrie pyrrolidines E and F, the monosubstituted (f> )-2-(mcthoxymethyl)pyrrolidine G can be used as chiral auxiliary for the diastereoselecti ve addition of organomctallic reagents to a-oxo amides16. As with the phenylglyoxylic acid derivatives derived from amines E and F. methyllithium or methylmagnesium bromide in diethyl ether preferentially attack the (,S)-mms-conformer 11 (R = ( 6H5), leading to predominant formation of the (2 S)-diastercomer by Re-side attack. 

After 19 hours, no reaction between the zinc chelate 2 and benzaldehyde can be detected at 20 °C. However, 10 mol % of the zinc chelate effectively catalyzes theenantioselective addition of diethylzinc to aromatic aldehydes. The predominant formation of the S-configurated products, effected by this conformationally unambiguous catalyst, can be explained by a six-mem-bered cyclic transition state assembly17. The fact that the zinc chelate formed from ligand M is an equally effective catalyst clearly demonstrates that activation of the aldehyde moiety does not occur as a consequence of hydrogen bond formation between the ammonium proton of the pyrrolidine unit and the aldehydic oxygen. 

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. 

The enamines derived from cyclohexanones are of particular interest. The pyrrolidine enamine is most frequently used for synthetic applications. The enamine mixture formed from pyrrolidine and 2-methylcyclohexanone is predominantly isomer 17.106 A steric effect is responsible for this preference. Conjugation between the nitrogen atom and the tt orbitals of the double bond favors coplanarity of the bonds that are darkened in the structures. In isomer 17 the methyl group adopts a quasi-axial conformation to avoid steric interaction with the amine substituents.107 A serious nonbonded repulsion (A1,3 strain) in 18 destabilizes this isomer. 

The preferred TS is a chair with the enolate oriented syn to the bulky pyrrolidine substituent. It was suggested that the syn acylation occurs through an envelope conformation of the pyrrolidine ring with the nitrogen electron pair oriented axially. 

Sequential pyrrolidine and hydantoin ring-forming reactions via intramolecular [2+3] cycloaddition have been applied to the stereoselective solid-phase synthesis of conformationally constrained tricyclic triazacyclopenta [C]pentalene scaffold 43 < 1999JOC8342>. These novel compounds 43 share the structural complexity characteristic of certain alkaloid natural products, angular triquinanes. The retrosynthetic analysis is shown in Scheme 87. 

Not much information is available for the five-membered ring pyrrolidine (4). MM2 calculations predicted that the 2-half-chair form is preferred over a host of other conformers by an average of 0.3 kealmol-1 with a 4.37 kealmol-1 barrier to planarity. The equatorial hydrogen is calculated to be favored by AE = 0.20 kealmol-1 over the axial one. 

Claisen rearrangement presumably was the boat-like form 156 (bj0) with minimized 1,3 repulsive interactions resulting in the lactams 157. However, the 2,4-as disubstituted pyrrolidine 159 (R =OTBS, R, R =H) gave the expected lactam diastereomer 158 via a chair-like transition state conformation 160 (entry 16, Table 8) (Scheme 31). 

Peptide bonds involving a-amino acid residues have been shown to be in the trans conformation but for Pro-containing and A-methylglycine peptides the bond may be cis or trans. When isomerization of Pro-Pro peptide bond occurs, the a and 6 protons of the pyrrolidine ring change positions with respect to the carbonyl group. ... 

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