Synthesis of the 2‐ethyl‐3‐methylsuccinic acidsviaa stereospecific malonic ester alkylation

Abstract

Synthesis of the 2-ethyl-3-nzethylsuccinic acids0-and p-Halogenoanilines Slarlinq from 0-or p-arsanilic acid'. Recrystallized arsanilic acid (30 mg) was dissolved in 1 ml of 7.2 N H,S04. After addition of the 1311 or the '"At activity and 5 mg of K1 the reaction mixture was heated at 60°C for 30 min. After cooling to OOC, 1 ml of diethyl ether was added and under vigorous stirring of the solution the pH was brought to 11.5 by addition of solid Na,CO,. The aniline were purified on SiO, with CH,CI, as eluent.Starring from (ch1oromercuri)anilines. This reaction is described elsewhere in detail'. m-Halogenoaniline m-(Ch1oromercuri)nitrobenzene was prepared as described by Klapprofh et al.'. To a suspension of 10 mg of this compound in 1 ml of 0.4 N H,SO,, 5 PI of 1 M K1, together with the 13'1 or 'llAt activity were added and the reaction mixture was stirred for 30 minutes. The precipitated Hgl, was dissolved by addition of an excess of K1. The halogenonitrobenzene was extracted with CH,CI, and the CH,Cl, layer was washed with a 1 mM aqueous Na,SO, solution. After removal of the CH,CI, in uacw the residue was dissolved in 2 ml of 6 N HCI and 15 mg of SnC1,.2 H,O were added. The reaction mixture was heated to 55OC for 2 h and subsequently cooled to 0°C. Diethyl ether (2 ml) was added and under vigorous stirring the pH of the solution was brought to 11.5 by addition of Na,CO,. The ethereal layer was separated and washed with aqueous Na,SO, and chromatographed on SiO, (eluent CH,CI,). 0-and p-HalogenophenolsA mixture of 0-and p-(ch1oromercuri)phenols was prepared as described by Dimrorh". These compounds were converted into the corresponding halogenophenols as described earlier'. The phenols were isolated by chromatography on SiO, (eluent CH,CI,). m-Halogenophenol m-Astatoaniline (or ['311]-tn-iodoaniline) was diazotized in 2 ml of 0.4 N H,SO, at -5°C with NaNO, (3 mg). After stirring for 30 minutes the excess NaNO, was destroyed by addition of urea. Heptane (2 ml) was added and under vigorous stirring the reaction mixture was slowly heated to 45OC and kept at this temperature for 2 h. The heptane layer was isolated and washed with a Na,SO, solution and chromatographed on SiO, (eluent CH,CI,). 5-HalogenouracilThe halogenouracil was synthesized from the 5-chloromercuri derivative as described elsewhere*. The product was isolated by chromatography on SiO, using the organic phase of a mixture of benzeneln-butanollwater (5/3/4) as eluent. pK, measurementsThe ?"At or 1311 compound was dissolved in heptane (except for the halogenouracils, which were dissolved in benzene). Two ml of this solution was thoroughly shaken at 0°C with 2 ml of an aqueous buffer of different pH values (in steps of 0.1-0.25 pH units). After standing at 0°C for $ h 1 ml of each layer was pipetted quickly and counted. Each p& measurement was carried out at least six times. The following buffer systems were used: halogenobenzoic acids citrate buffer pH 2-45 halogenoanilines citrate buffer pH 2.24.9 halogenophenols borax buffer pH 8.0-9.0 halogenouracils ...

Stereocontrolled synthesis of andrimid and a structural requirement for the activity

“…The first problem was solved by a two-step homologation of the chain by mimicking an expected biosynthetic pathway;y addition of a protected acetamide C2-unit to activated Boc-L-valine to form a P-ketoamide (3),** then the addition of the (2s)propionyl unit. However, at the second alkylation step with benzyl 2-bromopropionate(4) , 9 which was derived from L-alanine with retention of stereochemistry10 in 84% enantiomeric excess (48% yield), a column chromatographically separable diastereoisomeric product was also formed in the 3 : 1 ratio.?? The second point, ring closure of tt Formation of a rather higher amount of the diastereoisomer could be due to the partial racemization of the unreacted alkyl bromide (4) by the action of the bromide ions released during the SN2 alkylation reaction, which in the case of secondary bromide is quite slow compared to the reaction with primary alkyl bromide.…”