Revisiting the Kinnel-Scheuer hypothesis for the biosynthesis of palau'amine

Abstract

We propose herein an alternative biosynthetic pathway for palau'amine in order to resolve the stereochemical issue from the original Kinnel-Scheuer hypothesis. Furthermore, we use this revised hypothesis as a guide toward the laboratory synthesis of palau'amine.

Scheme 1

The original (top) and revised (bottom) Kinnel–Scheuer biosynthesis of palau’amine.

Scheme 2

The synthesis of 20, a close analog of the Kinnel–Scheuer intermediate. (a) NaH, BOMCl, DMF, 23 °C, then NaH, CuCl₂, O₂, 23 °C, then POCl₃, 23 °C; 68%. (b) Ph₃P=CHCOOMe, benzene, 23 °C; 95%. (c) DIBAL, THF, 0 °C. (d) Cbz-β-Ala-OH, DCC, CH₂Cl₂, 23 °C. (e) LiHMDS, THF, −78 °C; 79% over three steps. (f) Dess–Martin periodinane, H₂O, CH₂Cl₂, 23 °C. (g) Mn(OAc)₃, HOAc, 60 °C; 36% over two steps. (h) LiOH, THF, H₂O, 23 °C. (i) (PhO)₂P(O)N₃, DEAD, PPh₃, THF, 23 °C; 42% over two steps. (j) LiHMDS, THF, then HOAc, −78→0 °C. (k) Ca(BH₄)₂, THF, 0 °C, then NaBH₃CN, HOAc, 50 °C. (l) TFA, CH₂Cl₂, 0 °C. (m) Dess–Martin periodinane, H₂O, CH₂Cl₂, 23 °C. (n) HCl, MeOH, H₂O, 40 °C, then o-(HO₂C)C₆H₄(CO₂K), NaOH, KOCN, 110 °C. (o) PPh₃, H₂O, THF, 80 °C; 7–10% over 6 steps. (p) (Br₂-Pyrrole)COCCl₃, NEt₃, DMF, 70 °C; 33%. (q) PhIO, Na₂CO₃, TFE, 23 °C. (r) DMSO, 50 °C; 20% over two steps.