Scheme 4.

Total synthesis of SNAC ester 16 and seco acid 17^[a] and feeding experiments with 16 towards deschloro-desmethoxy AP3 18.

^[a] Reagents and conditions: (a) Boc₂O, Et₃N, dioxane/ H₂O (2.5:1), rt, 12 h, (82 %); (b) PPh₃, CBr₄, CH₂Cl₂, rt, 1 h (83 %); (c) Pd(dppf)Cl₂, THF, 65 °C, 4 h (98%); (d) TBAF*3H₂O, THF, -20 °C, 1 h (88%); (e) i. AlMe₃, Cp₂ZrCl₂, (CH₂Cl)₂, rt, 1 h, then addition of 11^[13] at 0°C rt, 72 h, ii. I₂, THF, -30 °C to 0 °C, 1.5 h (53%); (f) TeocCl, NaHCO₃, CH₂Cl₂, rt, 10 min (91%); (g) 14, Pd(OAc)₂, CsCO₃, Bu₄NBr, NEt₃, DMF, rt, 2 h (68 %); (h) DMSO, (COCl)₂, -60 °C, 1 h then Et₃N, -40°C (90%); (i) NaClO₂, NaH₂PO₄ H₂O, t-BuOH, 2-methyl-2-butene, 0 °C to rt, 30 min (85%); (j) AcHN(CH₂)₂SH, DIC, DMAP, CH₂Cl₂, rt, 2 h (56%); (k) HF*pyr (70% HF) / THF, rt, 24 h (62 %); (l) ZnCl₂, MeNO₂, ultrasound, rt, 80 min (63 %; towards 17: 11%). (TMS= trimethylsilyl Boc= tert-butyloxycarbonyl; dppf= bis(diphenylphosphino) ferrocene, TBAF= tetra-n-butylammonium fluoride; DIC= diisopropyl carbodiimide, DMAP= 4-dimethylamino pyridine