Novel anti-β-functionalized γ,δ-unsaturated amino acids via a thio–Claisen rearrangement

Synthesis of γ,δ-unsaturated amino acids by Claisen rearrangement - last 25 years

“…34,35 Further investigation by Hruby led to the use of the thio-Claisen rearrangement as a key step to prepare novel optically active anti-β-substituted γ,δ-unsaturated amino acids. 36,37 The synthesis of desired compounds began with the thio-enolate, which was made by treatment of thioamide 75 with freshly prepared LDA in THF at -78 °C and then the thio-enolate was alkylated at the sulfur position with allylic bromide (Scheme 15). In this highly selective method a bulky C2-symmetric chiral auxiliary (2R,5R)-2,5-diphenylpyrrolidine 73 was used.…”

“…36 Due to the fact that nature does not use the harsh reaction conditions presented in the above-described reactions (strong base LDA), Hruby et al decided to develop a mild method to be able to obtain more structurally versatile amino acids. 37 First, the use of thioamide was found to be crucial because the resulting thioiminium ion formation should increase the acidity of the α proton in comparison to the NH proton. Hence, one equivalent of a weak base was enough to deprotonate the α proton and trigger the thio-Claisen rearrangement.…”

“…Secondly, they predicted that facilitating C-Br bond breaking should improve allylation and rearrangement yields and hence a Friedel-Crafts catalyst FeBr3 was applied (Table 13). 37 This mild reaction condition has given a chance to use the variety of functional group at the β-position. Also ester groups were successfully introduced (Table 13, entries 2 & 3).…”

“…The ester carbonyl group would form a hydrogen bond with the α-amino group, creating a second sixmembered ring to additional stabilize the transition state. 37 Table 13. Results of new method of thio-Claisen rearrangement using Friedel-Crafts alkylation type reaction.…”

“…Results of new method of thio-Claisen rearrangement using Friedel-Crafts alkylation type reaction. 37 The last step was difficult due to the ester functional groups in the molecules. An oxidationiodolactonization-reduction pathway was used to generate the target molecules (Scheme 17).…”