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DOI: 10.1055/sos-SD-202-00157

Ramón, D. J.; Yus, M.Science of Synthesis: Stereoselective Synthesis, (20112371.

Various chiral carbonyl compounds have been used in the Darzens reaction to obtain the corresponding chiral epoxides 38. The reaction can produce four different isomers: two cis-epoxides and two trans-epoxides, with the trans-epoxides being the only ones displayed in Table 19. Initial studies were carried out using haloacetate derivatives (R1=alkoxy in 37), where it was found that the trans/cis isomer ratio was greatly affected by the nature of the halogen atom, with chloride giving practically the same amount of all possible isomers but bromine yielding mainly the cis-epoxide.[‌155‌] The nature of the ester moiety has little impact on the diastereoselectivity found for either trans- or cis-isomers, being never higher than 60% (entries 14). The use of a two-step sequence to afford the corresponding epoxides does not produce any significant improvement (entry 5).[‌156‌] The Darzens reaction with a ketone derivative, however, gives better results (entry 6).[‌157‌] Although the reaction with aromatic aldehydes gives, in all tested cases, essentially only one of the four possible diastereomers with excellent results, the reaction with aliphatic starting materials is more disappointing. The final product (trans,Si)-38 can be easily transformed into the corresponding α,β-epoxy acid derivatives by treatment with ammonium cerium(IV) nitrate. Density functional theory calculations show that the process proceeds via the two expected steps: an aldol-type reaction and epoxide formation, with the hydroxy group of the starting ketone playing a fundamental role in the stereoselectivity.[‌158‌] The above-mentioned menthyl[‌159‌] and 8-phenylmenthyl esters[‌160‌] have also been used in the Darzens reaction with various ketones, but with modest results.

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Meeee M8 M8 M Meeeeeeeee Meeee (eeeee/eee) Meeee (%) ee (eeeee,Me)-88 Meeee (%) ee (eeeee,Me)-88 Mee
8 Me Me e-MeMM (888eee%), Me8M, 88 ee 8°M, 88e 8.88:8 88 88 [‌888‌]
8 Me Me e-MeMM (888eee%), Me8M, 88 ee 8°M, 88e 8.88:8 8 8 [‌888‌]
8 Me Me e-MeMM (888eee%), Me8M, 88 ee 8°M, 88e 8.8:8 88e 88e [‌888‌]
8 Me Me e-MeMM (888eee%), Me8M, 88 ee 8°M, 88e 8.88:8 8e 8e [‌888‌]
8 eMe Me 8. MeMe8 (888eee%), eMe8MMe (888eee%), 88°M, 8e
8. M8MM8, MeMM, 88°M
8:8 8 88 [‌888‌]
8 Me Me MMM (888eee%), Me8M, 88°M, 8e 88:8 <8 88 [‌888‌]

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