Diastereoselective Synthesis of 2-Amino-4-phosphonobutanoic Acids by Electrophilic Substitution and Tin−Peterson Olefination of Bis-lactim Ethers Derived from cyclo-[l-AP4-d-Val]

• Published in: Journal of organic chemistry 2006-09, Vol.71 (18), p.6958-6974
• Main Authors: Fernández, María C, Díaz, Aniana, Guillín, Juan J, Blanco, Olga, Ruiz, María, Ojea, Vicente
• Format: Article
• Language: English
• Subjects: Alkenes - chemistry; Aminobutyrates - chemical synthesis; Aminobutyrates - chemistry; Chemistry; Chemistry, Organic - methods; Ethers - chemistry; Exact sciences and technology; Lactams - chemistry; Models, Molecular; Organic chemistry; Stereoisomerism; Valine - chemistry
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo061072x

Electrophilic substitutions on lithiated Schöllkopf's bis-lactim ethers derived from cyclo-[l-AP4-d-Val] take place regio- and stereoselectively at the α-position of the phosphonate ester. Subsequent olefination of α-silyl-, α-phosphoryl-, and α-stannyl-stabilized phosphonate carbanions give rise exclusively to vinylphosphonates. Both processes allow a direct and stereoselective access to a variety of 4-substituted and 3,4-disubstituted 2-amino-4-phosphonobutanoic acids (AP4 derivatives) in enantiomerically pure form that may be useful tools for characterizing the molecular pharmacology of metabotropic glutamate receptors (mGluRs) of group III. The relative stereochemistry was assigned from X-ray diffraction analyses or NMR studies of 1,2-oxaphosphorinane and other cyclic derivatives. In accordance to density functional theory (DFT) calculations, the syn-selectivity in the electrophilic substitutions may originate from the intervention of seven- and eight-membered chelate structures in which the bis-lactim ether moiety shields one of the faces of the phosphonate carbanion. DFT calculations for the tin−Peterson olefination of α-stannyl stabilized phosphonate carbanions indicate that rate and selectivity are determined in the initial carbon−carbon bond formation step where the unlike transition structures leading to (Z)-vinylphosphonates are favored both in the gas phase and in THF solution.