Adição de aliltricloroestananas a aldeidos dipeptidicos

AUTOR(ES)
DATA DE PUBLICAÇÃO

2001

RESUMO

The strategies developed for designing inhibitors active against HIV-1 protease involve the incorporation of a dipeptide isostere that resembles the tetrahedral intermediate for peptide bond hydrolysis. The hydroxy amino acid framework B, where the peptidic linkage of the sequence in A is replaced by a CH(OH)CH2 group, resulted as the core unit of potent inhibitors of HIV-1 protease. We wish to report here the first examples of allyltrichlorostannane additions to chiral N-Boc-a-aminodipeptide aldehydes. Treatment of allylsilanes with tin tetrachloride at room temperature affords allyltrichlorostannane intermediates that reacts with chiral N-Boc-a-aminodipeptide aldehydes to afford 1,2-syn homoallylic alcohols (molecules of type C) potential intermediates for the synthesis of hydroxyethylene dipeptide isosteres. The dipeptides were obtained by treatment of N-Boc-L-amino acid Phenylalanine 127 and Valine 129 and the corresponding N-deprotected-L-Weinreb amide 130-134 with HOBt, DCC and NaHCO3 in CH2CI2. The dipeptide aldehydes 147a-e were obtained in good isolated yields by LiAIH4 reduction of the corresponding Weinreb amides. The dipeptide aldehyde 151b was obtained after the following sequence: coupling between N-Boc-phenylalanine 127 and hydrochloride of serine 142 (74%), protection of 144 with TBSCI (95%), reduction with 2 M LiBH4 in THF to produce 149 (100%), followed by Swem oxidation (88%). A spectroscopic (H, C and Sn NMR) study of the reaction of chiral 99 and achiral allylsilanes 121 and 106 with SnCl4 is described. We have found that the ligand exchange between SnCl4 and allylsilane 99 is instantaneous and quantitative at room temperature as well as at -60 °C. For allylsilane 121, the metathesis is nearly complete after 60 minutes at room temperature. For allyltrimethylsilane 106 the ligand exchange reaction is nearly complete after 140 minutes at room temperature. The results of allyltrichlorostannane additions to dipeptide aldehydes 147a-e and 151b are shown below. In all cases, the major product results from a chelation controlled reaction that mainly gives the 1,2-syn isomer, showing that the (S)-a-amino dipeptide aldehydes have a preference for anti-Felkin addition (si face attack). Increased steric bulk of the R2 group (R2 = i-Pr, i-Bu) in the aldehydes gives better diastereoselection. The 1,2-syn relative stereochemistry of the major products was unambiguously established by spectroscopic analysis of the corresponding trans oxazolidines (upon irradiation of the hydrogens adjacents to Ha and Hb). Observed average coupling constants (J = 1.0 Hz) indicate that protons Ha and Hb are on opposite faces of the heterocyclic ring and, therefore, the oxazolidines are derived from 1,2-syn adducts.

ASSUNTO(S)

inibidores enzimaticos proteoliticos hiv (virus) ligantes (bioquimica)

ACESSO AO ARTIGO

Documentos Relacionados