The Synthesis of Novel Cyclic β-Amino Acids as Intermediates for the Preparation of Bicyclic β-Lactams

Abstract

Several derivatives of homopipecolic acid are prepared by α‐amino alkylation of malonic acid with cyclic imines 6 and 7. These are prepared on a large scale and with different substitution patterns. The β‐amino acids 8 and 9 were formed in high yield and with remarkable diastereoselectivity if chiral imines are used as starting materials. The diastereoselectivity of the amino alkylation leading to homopipecolic acid analogues is compared to those of thiazolidineacetic acids by epimerisation experiments. A method for resolution of the obtained racemic β‐amino acids by diastereomeric salt formation is described. The β‐amino acids 9 and 15 were converted into their corresponding carbacepham analogues 14 and isopenam 16. The isopenam endo‐16 was selectively epimerised by mild basic treatment of the N/S‐acetal to give an exo‐configured precursor of isopenicillin G.

Synthesis of novel pipecolic acid derivatives. Part 2. Addition of trimethylsilyl cyanide to 3,4,5,6-tetrahydropyridines

“…Recently, we reported an efficient approach to alkyl-and arylsubstituted tetrahydropyridines 1a-i. 1,21 These imines can be prepared easily and on a large scale according to a modified protocol of Zondler and Pfleiderer 22 and can be stored under nitrogen at Ϫ18 ЊC without any decomposition for several months. These reactive cyclic imines have already been demonstrated to be versatile precursors for the preparation of N-protected pipecolic acid derivatives and small peptides in high yields by using a multicomponent approach.…”

“…The product 2e (0.83 g, 100%) was obtained as a yellow liquid as a 63 : 37 mixture of racemic diastereomers, R f : 0.56 (n-hexane-ethyl acetate, 7 : 3) [Found: C, 72. 21 (2RS,6RS)-3,3-Dimethyl-6-phenylpiperidine-2-carbonitrile 2f. The title compound was prepared according to GP1 using 0.94 g (5 mmol) of rac-3,3-dimethyl-6-phenyl-3,4,5,6-tetrahydropyridine † 16 1f and 0.63 ml (5 mmol) trimethylsilyl cyanide as starting materials.…”

Structural Preorganization of Peptide Nucleic Acids: Chiral Cationic Analogues with Five- or Six-Membered Ring Structures

“…[70] The synthesis was accomplished by a simple and efficient four-component Ugi reaction and provided many previously unknown and interesting PNA monomers. Incorporation of these monomers into oligomeric structures and their DNA/RNA binding properties have not yet been reported.…”

MIRC Reactions of (E)-Chalcones with Azol-5-ones - A Diastereoselective Entry to Novel Spiro Tetrahydropyridine Derivatives

“…2 Recently, 3,4,5,6-tetrahydropyridines have successfully been used as starting materials in the preparation of bicyclic b-lactames generating a further interest in this class of compounds. 3 Nevertheless, there are few methods of synthesizing these molecules and these are of limited general applicability (high number of steps and the poor flexibility of the substitution pattern). 3,4 We have already described how isoxazol-5-olate 5 can trap selected electrophiles, namely arylaldehydes and lead, in a one-pot sequential manner, to the formation of spiroisoxazolonpyrrolines with a conjugated exocyclic double bond.…”

“…3 Nevertheless, there are few methods of synthesizing these molecules and these are of limited general applicability (high number of steps and the poor flexibility of the substitution pattern). 3,4 We have already described how isoxazol-5-olate 5 can trap selected electrophiles, namely arylaldehydes and lead, in a one-pot sequential manner, to the formation of spiroisoxazolonpyrrolines with a conjugated exocyclic double bond. 6 On the basis of this experience, we now report an efficient one-pot synthetic method for the preparation of novel tetrahydropyridines starting from chalcones 3 and azolin-5-ones 1 and 2 by tandem Michael additionaldol ring closure reactions.…”