Syntheses of racemic and non-racemic silicon- and germanium-containing α-amino acids of the formula type H2NCH(CH2ElR3)COOH (El = Si, Ge; R = organyl) and incorporation of D-H2NCH(CH2SiMe3)COOH and D-H2NCH(CH2GeMe3)COOH into biologically active decapeptides:: a study on C/Si/Ge bioisosterism

Two novel efficient methods for the synthesis of racemic silicon- and germanium-containing a-amino acids of the formula type rac-H2NCH(CH2EIR3)COOH (El = Si, Ge; R = organyl), starting from 3,6-diethoxy-2,5-dihydropyrazine, have been developed. Racemic cc-amino acids synthesized: rac-H2NCH(CH2SiMe3)COOH (rac-2), rac-H2NCH(CH2GeMe3)COOH (rac-3), rac-H2NCH(CH2SiMe2Ph)COOH (rac-4), rac-H2NCH(CH2GeMe2Ph)COOH (rac-5), and rac-H2NCH(CH2SiMe2CH=CH2)COOH (rac-6). Preparative liquid-chromatographic resolution of rac-2 and rac-3 [CHIROBIOTIC T (glycopeptide Teicoplanin covalently linked to spherical silica gel) as the stationary phase] yielded the alpha -amino acids (R)-2, (S)-2, (R)-3, and (S)-3. The (R)- and (S)-enantiomers of beta-(trimethylsilyl)alanine [(R)- and (S)-2] and beta-(trimethylgermyl)alanine I(R)- and (S)-3] are sila-analogs and germa-analogs, respectively, of the antipodes of the non-proteinogenic alpha -amino acid beta -tert-butylalanine [(S)- and (R)-H2NCH(CH2CMe3)COOH; (S)- and (R)-1]. Starting from the N-Fmoc-protected C/Si/Ge-analogous (D-configurated) alpha -amino acids (R)-1, (S)-2, and (S)-3, the C/Si/Ge-analogous decapeptides 7-9 [Ac-D-Nal(1)-4-Cl-D-Phe(2)-D-Pal(3)-Ser(4)-N-Me-Tyr(5)-D-Hci(6)- Nle(7)-Arg(8)-Pro(9)-D-Me(3)El-Ala(10)-NH2 (7, El = C; 8, El = Si; 9, El = Ge)] were prepared by sequential solid-phase synthesis. The decapeptides 7-9 were studied in vitro in a functional assay using a recombinant cell line expressing the human GnRH receptor (agonist Triptorelin). Compounds 7-9 behaved as medium-potent GnRH antagonists, the antagonistic potencies of these three C/Si/Ge analogs being very similar. (C) 2001 Elsevier Science B.V. All rights reserved.