875668-29-4

Upstream product

• 104523-60-6 (2S)-2-benzyloxycarbonylamino-4-phenylselenyl-butyric acid methyl ester 
• 501-53-1 benzyl chloroformate 
• 75266-39-6 methyl (S)-2-<<(benzyloxy)carbonyl>amino>-4-(methylsulfinyl)butanoate 
• 5621-44-3 dimethyl 2-methylenepentanedioate 
• 864682-69-9 (S)-2-benzyloxycarbonylamino-4-hydroxyphosphinoyl-butyric acid methyl ester 
• 75266-40-9 N-benzyloxycarbonyl-L-α-vinylglycine methyl ester 
• 15159-67-8 (2S)-2-benzyloxycarbonylamino-4-bromo-butyric acid methyl ester 

Downstream Products

• 864683-01-2 (S)-2-[(3-benzyloxycarbonylamino-3-methoxycarbonyl-propyl)-methoxy-phosphinoylmethyl]-pentanedioic acid dimethyl ester 

Relevant academic research and scientific papers

Prodrug forms of N-[(4-deoxy-4-amino-10-methyl)pteroyl]glutamate-γ- [ψP(O)(OH)]-glutarate, a potent inhibitor of folylpoly-γ-glutamate synthetase: Synthesis and hydrolytic stability

Ester prodrugs of the phosphinate pseudopeptide N-[(4-deoxy-4-amino-10- methyl)pteroyl]glutamate-γ-[ψP-(O)(OH)]-glutarate (1a) were synthesized. H-phosphinic acids derived from N-Cbz vinyl glycine esters were converted to the desired pseudopeptides by Michael addition to α-methyleneglutarate esters. Pivaloyloxymethyl (POM) ester moieties were incorporated in both the N-terminal and C-terminal fragments prior to formation of either C-P bond, N-Alkylation of the corresponding amides derived from N-(N-methyl)aminobenzoic acid with 2,4-diamino-6-(bromomethyl)pteridine gave the target compounds. POM esters of methotrexate and the corresponding γ-glutamyl conjugate were also synthesized using the same strategy. All prodrugs were evaluated in Chinese hamster ovary cells. Although the pseudopeptide prodrugs were ineffective, prodrugs of methotrexate and the corresponding γ-glutamyl conjugate were equipotent with the parent compounds. Stability of the prodrugs was investigated in both phosphate buffer and cell line medium to provide a rationale for the observed biological data.

A stereoselective synthesis of phosphinic acid phosphapeptides corresponding to glutamyl-γ-glutamate and incorporation into potent inhibitors of folylpoly-γ-glutamyl synthetase

Radical addition of H3PO2 to N-/C-protected vinyl glycine led to the corresponding H-phosphinic acid in excellent yield. The non-nucleophilic H-phosphinic acid was converted to a nucleophilic P III species, RP(OTMS)2, which was used in two approaches to the target phosphinic acid containing pseudopeptide. New methodology was developed that led to excellent yields in the reaction of RP(OTMS)2 with unactivated electrophiles, including an acyclic homoallylic bromide. However, en route to the target pseudopeptide, Arbuzov reaction of RP(OTMS) 2 with a cyclic homoallylic bromide, (R)-3-(bromomethyl)-cyclopent-1- ene, led to a rearranged allylic phosphinic acid rather than the desired homoallylic derivative, a putative glutarate surrogate. Conjugate addition of RP(OTMS)2 to α-methylene glutarate containing a chiral auxiliary resulted in only modest diastereoselectivity. Purification by flash chromatography provided protected derivatives of both diastereomers of the pseudopeptide. Following global deprotection, coupling of (S)-H-Glu-γ- [Ψ(P(O)(OH)(CH2))]-(S)-Glu-OH and (S)-H-Glu-γ-[Ψ(P(O) (OH)(CH2))]-(R)-Glu-OH to (4-amino-4-deoxy-10-methyl)pteroyl azide led to the target compounds for biochemical study as inhibitors of the ATP-dependent ligase, folylpoly-γ-glutamate synthetase.