Enantiopure ethyl 2,3‐dibromopropionate: Enantioselective synthesis vs preparative HPLC enantioseparation of racemate on multigram scale

Abstract

Racemic ethyl 2,3-dibromopropionate, commercially available at low price, is a key intermediate used in the synthesis of several heterocycle fragments, which are present in many biologically active compounds. Surprisingly, the enantiomers are not commercially available and have never been described in the literature. In this work, we undertook two different strategies to obtain these enantiomers, which are enantioselective synthesis and preparative HPLC enantioseparation of commercially available racemate on multigram scale. The first strategy has proved inadequate because racemization occurred during the synthesis (ee ≈ 9-50%). Conversely, the second strategy produced a very good enantioseparation of commercially available racemate (ee > 99.5% for both enantiomers) on multigram scale.

Multigram‐scale HPLC enantioseparation as a rescue pathway for circumventing racemization problem during enantioselective synthesis of ethyl 3,4‐dihydro‐2H‐1,4‐benzoxazine‐2‐carboxylate

“…2-Aminophenol (99%, 109.13 g/mol) and ethyl 2,3-dibromopropionate racemate rac-2 (≥ 98%, 259.92 g/mol) were purchased from Sigma-Aldrich. (R)-Ethyl 2,3-dibromopropionate (R)-2 (ee > 99.5%, [α] D 25 = + 12 (CH 2 Cl 2 , c = 3.29)) was obtained previously by our team 41 through preparative HPLC enantioseparation of commercially available rac-2 on multigram scale. Ethanol, heptane, and acetonitrile were HPLC grade and were purchased from VWR.…”

“…The racemic synthesis of rac-1 on multigram scale (83% yield) is carried out by a mainly used procedure using 2-aminophenol and rac-2 with anhydrous K 2 CO 3 in refluxed dry acetone during 16 h (Scheme 1). The first enantioselective version of this reaction (85% yield, synthesis performed twice) is also achieved using (R)-2 ([α] D 25 = + 12 (CH 2 Cl 2 , c = 3.29), which was recently isolated for the first time by our team 41 (Scheme 1). This reaction should normally be performed through a double S N 2 process and afforded (R)-1 from (R)-2.…”

“…First, both enantiomers of 2 have been just recently isolated by our team through a preparative HPLC enantioseparation of racemate on multigram scale. 41 Second, this reaction should be proceeded via a…”