Diels-Alder reactions of amino acid-derived trienes

Triene precursors (1a-e, 2a-k) were constructed for substrate-controlled as ymmetric Diels-Alder reactions. Boc-L-phenylalanal and Boc-L-valinal were c ondensed with triethyl phosphonoacetate or 2-phosphonopropionate to generat e the alpha,beta-unsaturated esters as dienophiles. Removal of the Boc grou p to give free amines 4a-d, which after, or without N-benzylation, were tre ated with 3,5-hexadienoyl chloride to give 1a-e, or with 2,4-hexadienoyl ch loride to afford 2a-f. The trienes 2g-i were prepared via reductive alkylat ion of amines 4a-i with 2,4-hexadienal. The secondary amide triene la faile d to yield any Diels-Alder product when heated at 170 degrees C. The tertia ry amide trienes 1b-e produced in refluxing toluene the major cycloaddition products that were cia-fused and derived from the exo transition states. T rienes 2a-k underwent surprisingly facile Diels-Alder reactions to produce the major trans-fused isomers that Were derived from the endo transition st ates. For trienes 2b-h and 2j,k, Diels-Alder reactions proceeded at room te mperature. For the primary amide 2a, the Diels-Alder reaction proceeded smo othly in refluxing toluene. The tertiary amide triene 22 was constructed to have two electron-withdrawing ester substituents at the termini of the tri ene. The Diels-Alder reaction of 22 took place spontaneously at room temper ature upon benzoylation of the secondary amine 21 and produced a single iso mer derived from the endo transition state. 1,3-Allylic strain is discussed as an important factor in control of the diastereoselectivity.