α-Lithioamine Synthetic Equivalents: Synthesis of Diastereoisomers from Boc Derivatives of Cyclic Amines

Article abstract of DOI:10.1021/jo00057a024

Sequences of α'-lithiations and electrophilic substitutions of Boc-pyrrolidines, Boc-piperidines, and Boc-hexahydroazepines that provide compounds which are substituted adjacent to nitrigen are reported, and the pathways of the reactions are discussed.By this methodology monosubstituted 2 and disubstituted 2,4, 2,6, and 2,5 Boc-piperidines are obtained as single or separable diastereoisomers consistent with equatorial lithiations and retentive electrophilic substitution in chair conformations.Both cis and trans 2,6-disubstituted diastereoisomers can be prepared, and control of diastereoselectivity is demonstrated by syntheses of solenopsin A, a 2,6-trans-disubstituted piperidine, and of Boc-dihydropinidine, a 2,6-cis-disubstituted piperidine.In the case of 3-methoxy-Boc-piperidine elimination of methoxide occurs upon lithiation, and with cis-2,4-disubstituted Boc-piperidines the electrophile is introduced with trans stereochemistry at C-6.These reactions are suggested to involve twist boat conformations consistent with an X-ray crystal structure of 2-methyl-6-(trimethylstannyl)-4-phenyl-N-Boc-piperidine.Boc-pyrrolidine lithiates more rapidly than Boc-piperidine, provides 2-substituted products with electrophiles, and on further lithiation-substitution gives 2,5-cis- and -trans substituted products.Boc-perhydroazepine provides 2-substituted products by the sequence and on further lithiation-substitution gives 2,7-trans-disubstituted products.