Practical Synthesis of (R,R)- and (S,S)-Bis[2,6-bis(1-ethoxyethyl)phenyl] Diselenide.

Abstract

We recently reported the synthesis of a new chiral C2 symmetrical organoselenium reagent, 1a, and showed its usefulness in the asymmetric selenomethoxylation of olefins1a and in the preparation of enantiomerically enriched heterocycles via asymmetric ring closure reactions.1b However, in order for this new reagent to be more synthetically useful, a facile and economical access to both enantiomers was highly desirable. Although our original synthesis was highly enantioselective, it was, nevertheless, lengthy, and the chiral reagents involved were somewhat expensive. We now report a more practical enantioselective synthesis of (R,R)and (S,S)-1 featuring a dual asymmetric reduction of the diketone intermediate 3 (Scheme 1). Our original synthesis involved the sequential conversion of each carboxylic acid in 2 to the desired chiral ethoxyethyl moiety. Clearly, it would be more efficient if we could convert both carboxylic acids simultaneously. However, attempts to prepare the diketone 3 by adding methyl organometallic reagents to activated acyl derivatives of the bromophthalic acid 2 turned out to be problematic. Loss of the bromine atom was a major side reaction, and the separation of 3 from the resultant complex mixture was difficult. We have now found that condensation of the diacyl chloride of 2 with the sodium salt of dimethyl malonate followed by hydrolysis and decarboxylation2 afforded the desired diketone 3 in 75% yield after distillation. In our original synthesis, we achieved the stepwise enantioselective reduction of the two carbonyls via the oxazaborolidine-catalyzed borane reaction.3 We thus attempted to use this reagent for the dual asymmetric reduction of 3 to give 4. However, in our hands, this method gave irreproducible yields and enantioselectivities. We obtained more reproducible results including high enantioselectivities using commercially available (+)or (-)-B-chlorodiisopinocampheylborane (DIP-chloride).4 Thus treating 3 with 2.2 equiv of (+)-DIP-chloride in THF at -25 °C afforded the desired R,R diol 4a in 81% yield and with an enantiomeric purity >99% (measured by chiral HPLC).5 The S,S diol 4b (>99% ee) was similarly obtained from (-)-DIP-chloride in 82% yield. It should be noted that both (+)and (-)DIP-chloride, even used in stoichiometric amounts, are less expensive than the R,R-diphenyl-2-pyrrolidinemethanol used in the oxazaborolidine-catalyzed borane reduction. Treatment of the diols 4a,b with ethyl iodide and sodium hydride gave the diethyl ethers 5a,b in 83% yield. As previously described, the diselenides 1a,b were prepared by lithiation of 5a,b with 2 equiv of tert-BuLi in THF at low temperature followed by the addition of elemental selenium. Air oxidation of the crude product in the presence of a catalytic amount of sodium hydroxide and crystallization from methanol afforded the desired diselenide 1a,b in 70-76% yield with an enantiomeric purity >99%. In summary we have developed a short and highly enantioselective synthesis of the C2 symmetrical R,R and S,S diselenides 1. This new synthetic route relies on the efficient and reproducible asymmetric reduction of the diketone 3 with (+)or (-)-B-chlorodiisopinocampheylborane.