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

Abstract

Electrophilic substitutions on lithiated Schöllkopf's bis-lactim ethers derived from cyclo-[L-AP4-D-Val] take place regio- and stereoselectively at the alpha-position of the phosphonate ester. Subsequent olefination of alpha-silyl-, alpha-phosphoryl-, and alpha-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 alpha-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.

Phosphorus‐Bearing Lithium Compounds in Modern Synthesis

“…Although this feature is a significant drawback to the use of C α -lithiation-electrophilic quench methodology for accessing optically pure Ccentered chiral organophosphorus compounds, the feasibility of diastereo-and enantioselective C α -deprotonations has been demonstrated in a number of cases. Ruiz, Ojea, and coworkers [15] used Schöllkopf's bis-lactim ether derived from l-2-amino-4-phosphonobutanoic acid and d-valine as chiral inductor in the lithiation of phosphonate 32 with LDA. The reaction of the anion 33 formed with a range of electrophiles afforded derivatives 34 containing new carbon-carbon and carbon-heteroatom bonds in good yields.…”

ω -Phosphinyl-α -Amino Acids: Synthesis, and Development towards Use as Therapeutic Agents

“…In the same study [34], the (2S,5R)-57 analogue of cyclo-[(S)-AP4-(R)-Val] demonstrated regioselectivity and moderate asymmetric induction during 2'-substitution with a wide range of electrophilic reagents (e.g. a/ MeI, b/ HCO 2 Et, c/ Et 2 CO 3 , d/ N-fluorobenzenesulfonimide (NFSi), e/ Ph 3 SnCl and f/ Et 2 PO 3 Cl) under LDA/THF/-78 o C conditions (Scheme 8b), although some racemisation at C-2 was noted during similar azidation and silylation procedures.…”

“…The putative chelate intermediate (S-51 case shown), directing the diastereoselectivity of addition, was supported by the decrease in asymmetric induction observed on addition of the high dielectric HMPA, and the Group I ion chelator 18-crown-6, both serving to solvate the K + cation and disrupting the coordination network involving nitrogen and phosphoryl oxygen electron pairs. Chiral aminocarboxylate surrogates used in such approaches have also included the lithiated Schöllkopf's bislactim ethers R-52 and S-52 [32][33][34] (Fig. 2), derived from the corresponding valine isomers, Belokon's Ni(II)-complex with the glycine Schiff base derived from (S)-o-[(Nbenzylprolyl)amino]benzophenone (53) [35], lithiated Seebach's 1,3-imidazolidin-4-ones (2R,1'S)-54 and (2S,1'S)-54 [36,37], and oxazinone 55 [38].…”

“…Section 2.2.2) has also been generated using Schöllkopf's methodology [32]. In addition, high 2,5-trans-diastereoselectivity in the alkylation/addition of R-52 has been achieved to generate (2S,5R)-57 using an equimolar solution of O,O-diethyl bromoethylphosphonate (Component A, Scheme 8b) containing 5% of the vinylphosphonate (Component B) [34,40]. Diastereoselectivity in this case was rationalised as due to the faster rate of reaction with 'B' (>> 'A'), and continual replenishment of this component through trapping of the resulting phosphonate carbanion by 'A', leading to dehydrohalogenation.…”

“…Density function theory calculations supported the proposed origin of this stereoselectivity, from the formation of compact 7-membered (60) and 8-membered (61) lithium chelate intermediates (Scheme 8b) in the low dielectric THF environment employed, obstructing with the bis-lactim ether function the C-2'carbanion-Si-face of 60 and the Re-face of 61 respectively to electrophile approach. Hence, the corresponding 2'-methylated (a), formylated (b), carboxylated (c), fluorinated (d), stannylated (e) and phosphorylated (f) products 58/59 are accessible with retention of optical integrity at C-2, a feature exploited in Wadsworth-Horner-Emmons (cf 58/59c and 58/59f, Scheme 8b) and tin-Peterson (cf 58/59e) olefinations to effect elaboration at C-2', thereby generating structures 62 [34] on treatment with the suitable aldehyde or ketone. A stereoselective route to 4-(and also 3,4-) substituted derivatives of AP4 (4) is therefore represented.…”