Eine verbesserte Synthese von Efavirenz durch asymmetrische Autokatalyse

Abstract

Ein Intermediat, das für sich selbst sorgt: Eine asymmetrische autokatalytische Zinkacetylid‐Addition benötigt katalytische Mengen des enantiomerenreinen Produkts als Teil einer Mischung chiraler Reagentien. Diese neue Strategie führt zu einer verbesserten Synthese einer wichtigen Efavirenz‐Vorstufe (siehe Schema).

Reactions of ZnR2 Compounds with Dibenzoyl: Characterisation of the Alkyl‐Transfer Products and a Striking Product‐Inhibition Effect

“…In contrast, employment of ZntBu 2 resulted in a full conversion of dbz upon mixing of the substrates in toluene already at À20 8C (Scheme 1). This fast reaction led to the O-alkylated product [tBuZn- (1), which was isolated with high yield after a standard work up. The NMR data are fully consistent with the anticipated formula of 1 (see the Supporting Information), which was confirmed by X-ray crystallography (see below).…”

“…To shed more light on the putative role of the zinc alkoxide product 2 in the observed course of the equimolar reaction, diffusion-ordered NMR spectroscopy (DOSY) investigations on the dibenzoyl/ZnEt 2 system were performed. 1 H DOSY measurements provide a reliable evidence of the approximate size of the species existing in solution. Very recently, it was demonstrated that the molecular weight of the species in question can be straightforwardly obtained by combining the Stokes-Einstein equation [Eq.…”

“…The solvent was removed from the resulting intensively yellow reaction mixture under reduced pressure to give the crude product 2 as a white solid. 1 H NMR (500 MHz,[D 8 ]toluene, À30 8C): d = 0.40 (2 H; Zn (1) CH 2 ), 0.60 (br s, 2 H; Zn (2) CH 2 ), 0.92 (br s, 3 H; Zn (2) 15.16, 65.84, 80.69, 133.6, 133.8, 134.3 (d), 137.4, 139.4, 139.7, 142.0, 146.6, 208.8, 209.8 ppm. Then NaHCO 3 was added to the crude product and the resulting mixture was stirred for 30 min.…”

“…The influence of a zinc alkoxide product on the rate and/or course of various reactions involving dialkylzinc reagents and carbonyl compounds is an important issue of synthetic chemistry. [1] The most spectacular example concerns the Soi autocatalytic asymmetric addition of diisopropylzinc to pyrimidinyl aldehydes, [1b,d] where both the role of the zinc alkoxide product and the structural model of the catalytic centre have been the subject of intense investigations in the last decade. [2] In the latter system, the presence of dimers and higher aggregates of the alkoxides and their adducts with diisopropylzinc have been assumed as the key molecular structures essential in the autocatalytic cycle and the amplification process.…”

“…The solution was left for crystallisation at room temperature. Colourless crystals suitable for X-ray analysis were obtained after 24 h in 75 % yield 1. H NMR (400 MHz, CDCl 3 , 208C): d = 0.85 (4 H; ZnCH 2 CH 3 ), 1.26 (6 H; ZnCH 2 CH 3 ), 1.30 (6 H; OCH 2 CH 3 ), 2.97 (m, 4 H; CH 2 CH 2 ), 3.88 (4 H; OCH 2 CH 3 ), 7.10 (m, 8 H; CH Ar ), 7.11 (m, 4 H; CH pyridyl ), 7.13 (m, 4 H; CH Ar ), 7.45 (m, 8 H; CH Ar ), 8.46 ppm (m, 4 H; CH pyridyl ).…”