RESUMO
Pyrrolidine-2,4-diones have been identified as a novel starting point for the synthesis of peptide analogues. This paper describes a method for the efficient and diastereoselective incorporation of this moiety into peptide chains to furnish di- and tripeptide analogs. The stability of these pyrrolidinone modified di- and tripeptides was found to be markedly improved when compared to that of a natural peptide. In addition, solid phase peptide synthesis employing a pyrrolidinone containing tripeptide is demonstrated.
Assuntos
Oligopeptídeos/química , Oligopeptídeos/síntese química , Pirrolidinonas/química , Estabilidade de Medicamentos , Conformação Proteica , EstereoisomerismoRESUMO
The pyrrolidine-2,4-diones have been identified as a convenient starting point for the synthesis of peptide analogues. Herein we describe an optimized two-step reductive amination procedure, which provides a small library of pyrrolidinone-containing dipeptide analogues in high yield and excellent diastereoselectivity.
Assuntos
Dipeptídeos/síntese química , Pirrolidinonas/química , Aminoácidos/química , Dipeptídeos/química , Modelos Moleculares , EstereoisomerismoRESUMO
The total synthesis of hippadine by a tandem metalation/cross-coupling/lactamization strategy was investigated starting from either 7-bromoindole or a 6-halogenated methyl piperonate. The Kumada and Negishi cross-coupling reactions failed to provide any of the desired product. However, the Stille and Suzuki reactions furnished hippadine in low yields starting from the electron-deficient methyl 6-iodo- and 6-bromopiperonate, respectively. Starting from the metalated indole, only the Suzuki reaction occurred, affording hippadine in 67-74% and pratosine in 62% isolated yield.
Assuntos
Alcaloides/síntese química , Alcaloides de Amaryllidaceae/síntese química , Alcaloides/química , Alcaloides de Amaryllidaceae/química , Catálise , Estrutura Molecular , OxirreduçãoRESUMO
[reaction: see text] Pyrrolidine-2,4-diones (1) are naturally occurring analogues of amino acids. We herein present a facile synthesis of N-acylated, O-alkylated pyrrolin-2-ones (2) in high yield and excellent enantiopurity. Molecular mechanics calculations suggest that the resulting dipeptide analogues adopt a linear, extended conformation.
Assuntos
Dipeptídeos/síntese química , Pirróis/química , Pirróis/síntese química , Pirrolidinonas/síntese química , Aminoácidos/química , Dipeptídeos/química , Conformação Molecular , Estrutura Molecular , Pirrolidinonas/química , TermodinâmicaRESUMO
Copper mediated allylic substitutions and conjugate additions to geranyl, cinnamyl and allylic indole compounds have been investigated with the aim of finding a method for the creation of the all-carbon quaternary centre present in the natural product lyngbyatoxin A. Reaction conditions have been found giving a 68% SN2' selectivity in the copper mediated addition of PhMgBr to geranyl chloride, as well as 99% and 95% SN2' selectivity in the copper catalysed addition of EtMgBr to cinnamyl chloride and acetate, respectively. When the optimised reaction conditions were applied to the corresponding allylic compounds containing a 7-substituted indole moiety, the regioselectivity was reversed giving only the SN2 product. The allylic indole-containing substrates were also found to be unproductive in Pd- or Mo-catalysed SN2'-type substitution reactions. In related studies, copper catalysed conjugate addition of EtMgBr to the tricyclic lactam 6-methyl-pyrrolo[3,2,1-ij]quinolin-4-one gave a maximum of 20% of the 1,4-addition product.
Assuntos
Compostos Heterocíclicos com 3 Anéis/síntese química , Indóis/química , Toxinas de Lyngbya/síntese química , Cinamatos/química , Cobre/química , Ciclização , Compostos Heterocíclicos com 3 Anéis/química , Lactamas/química , Cloreto de Lítio/química , Espectroscopia de Ressonância Magnética , Conformação Molecular , Estrutura Molecular , Molibdênio/química , Compostos Organometálicos/química , Paládio/química , Solventes/química , Temperatura , Terpenos/químicaRESUMO
The reaction of stabilized Peterson reagents (alpha-silyl ester enolates) with ketones has been studied theoretically and experimentally. Enolate geometry was studied by trapping experiments and NMR spectroscopy and was found to differ markedly with the nature of the base (LiHMDS vs LDA vs KHMDS). The chelating effect of the lithium counterion was found to be critical for the reaction. For the two ketones studied, the combined weight of experimental and computational data assigns geometrical selectivity to the initial addition transition state, though in general there appears to be a fine balance between three possible choices for the rate-determining step.