Diels−Alder Reactions of Amino Acid-Derived Trienes

Abstract

Triene precursors (1a−e, 2a−k) were constructed for substrate-controlled asymmetric Diels−Alder reactions. Boc-l-phenylalanal and Boc-l-valinal were condensed with triethyl phosphonoacetate or 2-phosphonopropionate to generate the α,β-unsaturated esters as dienophiles. Removal of the Boc group to give free amines 4a−d, which after, or without N-benzylation, were treated with 3,5-hexadienoyl chloride to give 1a−e, or with 2,4-hexadienoyl chloride to afford 2a−f. The trienes 2g−i were prepared via reductive alkylation of amines 4a−i with 2,4-hexadienal. The secondary amide triene 1a failed to yield any Diels−Alder product when heated at 170 °C. The tertiary amide trienes 1b−e produced in refluxing toluene the major cycloaddition products that were cis-fused and derived from the exo transition states. Trienes 2a−k underwent surprisingly facile Diels−Alder reactions to produce the major trans-fused isomers that were derived from the endo transition states. For trienes 2b−h and 2j,k, Diels−Alder reactions proceeded at room temperature. For the primary amide 2a, the Diels−Alder reaction proceeded smoothly in refluxing toluene. The tertiary amide triene 22 was constructed to have two electron-withdrawing ester substituents at the termini of the triene. The Diels−Alder reaction of 22 took place spontaneously at room temperature upon benzoylation of the secondary amine 21 and produced a single isomer derived from the endo transition state. 1,3-Allylic strain is discussed as an important factor in control of the diastereoselectivity.