Short, Tin-Free Synthesis of All Three Inthomycins

Abstract

The inthomycins are a family of structurally and biologically rich natural products isolated from Streptomyces species. Herein the implementation of a modular synthetic route is reported that has enabled the enantioselective synthesis of all three inthomycins. Key steps include Suzuki and Sonogashira cross-couplings and an enantioselective Kiyooka aldol reaction.

Keywords: inthomycin; phthoxazolin; total synthesis.

Figure 1

Inthomycin natural products.

Figure 2

Retrosynthesis of the inthomycins 1.

Scheme 1

Synthesis of dienylboronic ester 15. a) nBuLi, Me₃SiCl, THF, −78 °C then 2 m HCl, 0 °C to RT, 62 %; b) PPh₃, N‐bromosuccinimide, CH₂Cl₂, −30 °C, 81 %; c) nBuLi, iPr₃SiOTf, THF, −78 °C to RT, 82 %; d) 13, nBuLi, CuCN⋅2LiCl, THF, −78 °C then add 12, 81 %; e) Na₂S, THF:H₂O (1:1), 0 °C to RT, 85 %, after one recycle.; f) pinacol borane, (C₅H₅)₂ZrHCl, Et₃N, 60 °C, 84 %. RT=room temperature, Tf=SO₂CF₃, THF=tetrahydrofuran.

Scheme 2

Synthesis of the alkenyl iodides (Z)‐ and (E)‐17. a) MeMgBr, Cu^II, THF, −10 °C then I₂, −10 to −5 °C, 66 %; b) MnO₂, CH₂Cl₂; c) BH₃⋅THF, 18, 9, CH₂Cl₂, −78 °C then HCl, (Z)‐5, 68 % (2 steps), 89 % ee, (E)‐5, 61 % (2 steps), 89 % ee; d) Et₃SiCl, imidazole, CH₂Cl₂, 0 °C to RT, (Z)‐17 93 %, (E)‐17 91 %; e) Me₃Al, (C₅H₅)₂ZrCl₂, CH₂Cl₂, 0 °C to RT then I₂, −78 ° to RT, 61 %.

Scheme 3

Synthesis of inthomycins B and C. a) (Z)‐17 or (E)‐17, Pd(OAc)₂, PPh₃, Na₂CO₃, THF, H₂O, 19 64 %, 22 65 %; b) HF⋅pyridine, CH₃CN, 0 °C to RT, 20 80 %, 23 97 %; c) LiOH, H₂O, THF, MeOH, 0 °C to RT; d) C₆H₅OH, EDCI⋅HCl, DMAP, CH₂Cl₂, 21 80 % (2 steps), 24 87 % (2 steps); e) NH₄OH, THF, 0 °C to RT, 2 95 %, 3 94 %. EDCI=1‐ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide).

Scheme 4

Synthesis of inthomycin A. a) (Z)‐17, Pd(PPh₃)₄, Cu^II, Et₃N, 62 %; b) HF⋅pyridine, CH₃CN, 0 °C to RT, 91 %; c) Zn‐Cu‐Ag couple, MeOH, 35 °C, 80 %; d) LiOH, H₂O, THF, MeOH, 0 °C to RT; e) C₆H₅OH, EDCI⋅HCl, DMAP, CH₂Cl₂, 78 % (2 steps); f) NH₄OH, THF, 0 °C to RT, 89 %.