Switching the Stereochemical Outcome of 6-Endo-Trig Cyclizations; Synthesis of 2,6-Cis-6-Substituted 4-Oxopipecolic Acids

Abstract

A base-mediated 6-endo-trig cyclization of readily accessible enone-derived α-amino acids has been developed for the direct synthesis of novel 2,6-cis-6substituted-4-oxo-L-pipecolic acids. A range of aliphatic and aryl side chains were tolerated by this mild procedure to give the target compounds in good overall yields. Molecular modeling of the 6-endo-trig cyclization allowed some insight as to how these compounds were formed, with the enolate intermediate generated via an equilibrium process, followed by irreversible tautomerization/neutralization providing the driving force for product formation. Stereoselective reduction and deprotection of the resulting 2,6-cis-6-substituted 4-oxo-L-pipecolic acids to the corresponding 4-hydroxy-L-pipecolic acids was also performed.

Synthesis and Fluorescent Properties of β-Pyridyl α-Amino Acids

“…Following protection of the amino and carboxylic acid groups, the key step involved the highly regioselective reaction of the anion of dimethyl methylphosphonate with the sterically accessible β-methyl ester of 2 to give phosphonate ester 3 . Horner–Wadsworth–Emmons reaction of 3 with a wide range of aldehydes under mild conditions gave enones 4a – j , exclusively as the E -isomers. , The focus of this project was to prepare aryl substituted pyridyl side chains, and therefore, benzaldehyde derivatives were mainly used to explore the scope of this reaction. As expected, the majority of these gave high yields of the E -enones (66–95%), although highly electron-rich aldehydes required longer reaction times (120 h) and gave more moderate yields (e.g., 4e ).…”

Efficient synthesis of β’-amino-α,β-unsaturated ketones

“…Over the years, many examples of base-promoted Horner–Wadsworth–Emmons (HWE) reactions have been reported in the literature, and various combinations of bases and solvents (K 2 CO 3 /CH 3 CN[23], DBU/THF[25], NaH/THF[29], Et 3 N/LiCl/CH 3 CN[30] or Ba(OH) 2 /(THF/H 2 O)[31]) have been used. We subjected our substrate 13a to three of those mild sets of conditions (Scheme 7, Table 2), which, after reaction with the benzaldehyde, will furnish the chiral amino ketone 15a .…”

The endo-aza-Michael addition in the synthesis of piperidines and pyrrolidines

“…27 On the other hand, treatment of the trityl protected amine 67 with acid, followed by base yielded the cis isomer 68b as the major product with a ratio of isomers of 75:25. 28 In the former case, it is likely that the nucleophilic species is the imine 69, with an N-substituent that is sterically demanding due to sp 2 -hybridisation. In the latter case it is likely that the nucleophilic species is the sterically undemanding primary amine 70.…”