Science of Synthesis

Jautze, S.; Peters, R., Science of Synthesis: Stereoselective Synthesis, (2011) 3, 464.

A Lewis acid promoted, enantioselective reaction of ketenes, formed in situ from (benzyloxy)acetyl chloride and allylic amines ‌64‌, to form α,β-disubstituted γ,δ-unsaturated morpholine amides ‌66‌ has been reported (‌Scheme 18‌).[‌54‌] Morpholine amides are cost-efficient substitutes for the commonly used Weinreb amides.[‌55‌,‌56‌] The bis(4,5-dihydrooxazole) complex ‌65‌ provides a highly effective asymmetric environment for acid chlorides that can chelate with the metal complex, such as (benzyloxy)acetyl chloride. In contrast, poorly chelating substrates are not useful. Considerably lower enantioselectivity is obtained with substoichiometric Lewis acid loadings, indicating a competing thermal background reaction. Significant structural variation at the C3 (R1/R2) and C2 (R3) positions is possible without loss of enantioselectivity (‌Scheme 18‌). The high diastereoselectivity can be rationalized by the high preference for a chair-like transition state ‌67‌ in the acyl-Claisen-rearrangement step. Even all-carbon-substituted quaternary stereocenters are accessible in good yields and with excellent stereocontrol [e.g., amide ‌66‌ (R1 = CO2Et; R2 = Me)].

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References