structural properties of these peptides by NMR spectroscopy and X-ray diffraction revealed that attachment of even small substituents in the 6 position of the pipe-colic acid results in efficient syn-proline analogs like 1 in Scheme 1.2.1 [19].

The stereochemistry of these substituted cyclic amino acids is important, however, because 2,6-trans-substituted analogs 1 strongly favor the syn rotamer (> 99% syn isomer in methanol and DMSO), whereas 2,6-cis-substituted pipecolic acids like 3 do not favor the syn isomer (43% syn isomer in water) as demonstrated for a model bisamide incorporating 6-tert-butylpipecolic acid 3 [20]. The reason for these findings is the pseudo allylic 1,3-interaction of substituents attached to C2 and C6 of the piperidine ring. In 2,6-trans-substituted piperidines like 1 the smaller substituent (in this case the methyl group attached to C6) is in an equatorial position. Steric interactions between this substituent and the adjacent amino acid are therefore maximized. In 2,6-cis-substituted analogs like 3, in contrast, both substituents at C2 and C6 prefer an axial position to avoid 1,3-allylic interactions with the neighboring amide bond. Consequently, steric interactions between the bulky tert-butyl group in 3 and the adjacent amino acid are minimized and induction of the syn rotamer is relatively weak. Evidence for this hypothesis can be drawn from NMR spectroscopic investigations and X-ray crystal structures for a range of different 2,6-substituted piperidines [19, 20].

Surprisingly, some 2,3,6-substituted pipecolic acid derivatives like 2 favor exclusively the anti amide isomer [19]. The anti preference of 2 has been demonstrated by NMR spectroscopy in solution (methanol and DMSO) and X-ray analysis in the solid state. The reason for this unexpected finding is the special arrangement of substituents on the pipecolic heterocycle. In contrast to compounds like 1, the additional bulky substituent attached to C3 forces the carboxy group at C2 into an equatorial position and the substituent at C6 into an axial position.

The preferred geometry of the N-terminal peptide bond in pipecolic acids can therefore be triggered by choice of substituents attached to the heterocycle and their relative configuration.

2,3,6-Substituted piperidines like 2 were initially also synthesized in the racemic form by use of the multicomponent reaction mentioned above. A recently estab-

Ph N^Me


CO2Et 72 h at rt


3. NaBH4

Baby Sleeping

Baby Sleeping

Everything You Need To Know About Baby Sleeping. Your baby is going to be sleeping a lot. During the first few months, your baby will sleep for most of theday. You may not get any real interaction, or reactions other than sleep and crying.

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