Conjugate Additions of 1-Propenylphosphonates to Metalated Schöllkopf's Bis-lactim Ether:  Stereocontrolled Access to 2-Amino-3-methyl-4-phosphonobutanoic Acids

Abstract

Diastereoselectivity in the conjugate addition of metalated Schöllkopf's bis-lactim ethers 5a-e to (E)- and (Z)-1-propenylphosphonates 4a,b was studied experimentally and theoretically and utilized to achieve a direct and stereocontrolled synthesis of all four diastereoisomers of 2-amino-3-methyl-4-phosphonobutanoic acid, 6a,b and their enantiomers. The relative stereochemistry was assigned from an NMR study of cyclic derivatives 13a,b. According to semiempirical calculations, both in vacuo (PM3) or a dielectric continuum (PM3/COSMO), initial lithium-phosphoryl coordination, without an energy barrier, to form a solvated chelate complex is followed by the rate-determining reorganization to the 1,4-addition product through an eight-membered transition state. The translation of the Z,E geometry into a syn, anti configuration at the adducts originates from an orientational preference in the transition state for a compact disposition of the reaction partners.

Solid-State Structures and Racemization of Lithiated Schllkopf's Bis[Lactim Ether]

“…These bond lengths are typical for distorted tetrahedral arrangements at the Li center. As expected, and in agreement with calculated structures of monomeric 1 ¥ Li coordinated to three donor atoms [3], the i-Pr group is located on the opposite side of the pyrazine ring relative to the metal, and the Li center is not in close bonding distance with the nearest O-atom (Li(1)ÀO(1) 2.568 ä). However, the Li-atom does not lie symmetrically between C(1) and C(4), but is angled towards O(1), thereby protruding by 14.78 from the plane defined by C(1)ÀN(1)ÀC(4), which minimizes steric interactions.…”

“…However, HMPA complexes are also interesting targets for two reasons. First, the HMPA PO bond is similar to the phosphonate systems we are interested in, second, the addition of HMPA to the lithiated bis[lactim ether] in its conjugate to prop-1-enyl phosphonates generally gives rise to a negligible diastereoisomeric excess [3].…”

“…More recent, however, is their application in the formation of phosphobutanoic acids by conjugate addition to propenylphosphonates [3]. Highly stereoselective reactions of this type are strongly affected by the presence of varying Lewis donors that allow the formation of different aggregation states in solution.…”

“…± Lithiated Schˆllkopf×s bis[lactim ethers] have proved invaluable reagents in the synthesis of many biologically active compounds [1] and of nonproteinogenic amino acids [2]. More recent, however, is their application in the formation of phosphobutanoic acids by conjugate addition to propenylphosphonates [3]. Highly stereoselective reactions of this type are strongly affected by the presence of varying Lewis donors that allow the formation of different aggregation states in solution.…”

Asymmetric Synthesis of (S)‐(‐)‐Acromelobic Acid.

“…General Remarks: The bis(lactim) ether of cyclo(--Val-Gly-) (8) was prepared according to a literature method. [17] Infrared (IR) spectra were obtained using a PerkinϪElmer 1600 spectrometer.…”