Issue in Honor of Prof. Rod Rickards ARKIVOC 2004 (x) 118-133
5-Bromo-1-pentanol 14 was prepared according to a literature procedure,20 and protected using triisopropylsilyl chloride and imidazole in DMF to give bromide 15. This underwent coupling with deprotonated methallyl alcohol satisfactorily in the presence of TMEDA to give allyl alcohol 16. This was epoxidised under modified Sharpless conditions using L-(+)-diethyl tartrate as the ligand to give compound 17a, D-(-)-diethyl tartrate to give the (R) enantiomer 17b (not pictured), or mCPBA to give racemate 17c (not pictured). Enantiomeric purity (e.e. =96 %) was again proved by the formation of (R)-Mosher esters as above (not pictured, compounds 18a and 18b for the (S) and (R) enantiomers respectively in the experimental section).
Epoxy alcohol 17a was oxidised and esterified under the same conditions which yielded Etomoxir 3a to give ester 19, and the protecting group was removed using tetrabutylammonium fluoride (TBAF) in THF to give alcohol 20. This alcohol should be used promptly as it appears to go off on standing.
The final step was the coupling of 20 with a source of the 2,4-dinitrophenoxy group to yield the target compound 4a. To achieve this, two approaches were examined: nucleophilic aromatic substitution with 2,4-dinitrofluorobenzene, and Mitsunobu reaction21 with 2,4-dinitrophenol. The Mitsunobu reaction, which has been used in the synthesis of 2-substituted-oxirane-2carboxylates previously,15,22 was the better of the two, 2,4-dinitrofluorobenzene giving difficultto- reproduce results and sometimes yielding compound 4a contaminated with an unidentified impurity difficult to remove by chromatography.
Overall, this route is slightly longer than the route which yielded Etomoxir 3a, but has the advantage that the use of the Mitsunobu reaction allows for the dereferal of the coupling of the aromatic group until after the formation of the oxirane-carboxylate portion of the molecule. This opens up the possibility of the synthesis of a wide variety of chemically sensitive or nonphenolic analogues.
Conclusions
In conclusion, we have developed a versatile and efficient route to 2-substituted oxirane-2carboxylates, which should allow the synthesis of a broad range of analogues in enantiomerically pure form. In doing so, we have developed the shortest synthesis yet published of Etomoxir.
Experimental Section
General Procedures. Anhydrous solvents were purchased from Fluka, and n-butyllithium from Sigma-Aldrich. TMEDA and methallyl alcohol were distilled immediately before use. tert-Butyl hydrogen peroxide in anhydrous toluene was prepared according to the method of Sharpless.23 All other reagents were used as received. Column chromatography on silica refers to medium
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