Synthesis and structure verification of the vaccine adjuvant QS-7-Api. Synthetic access to homogeneous Quillaja saponaria immunostimulants

Abstract

QS-7-Api is an exceedingly potent immuno-adjuvant isolated from the bark of Quillaja saponaria. It is significantly less toxic than QS-21, a related saponin that is currently the favored adjuvant in anticancer and antiviral vaccine clinical trials. Tedious isolation/purification protocols and uncertainty in its structural constitution have hindered the clinical development of QS-7. A chemical synthesis of QS-7-Api is described, providing structural verification of the adjuvant. A novel semisynthetic sequence to QS-7-Api has also been established, greatly facilitating access to QS-7 for preclinical and clinical evaluation.

Figure 1

Scheme 1^a

^a Reagents and conditions: (a) TIPSOTf, 2,6-lutidine, CH₂Cl₂, 0→23 °C, 96%; (b) H₂, Pd–C, MeOH, 23 °C, 98%; (c) n-Bu₂SnO, PhMe, reflux; CsF; PMBCl, DMF, 23 °C, 56%; (d) TBSCl, imidazole, DMAP, CH₂Cl₂, 23 °C, 97%; (e) Ac₂O, Et₃N, DMAP, CH₂Cl₂, 23 °C, >99%; (f) DDQ, MeOH, H₂O, 0→23 °C, 86%.

Scheme 2^a

^a Reagents and conditions: (a) Ph₂SO, Tf₂O, TBP, CH₂Cl₂, −78→23 °C, 84%; (b) TBAF, THF, 0→23 °C, 95%; (c) Et₂Zn, Pd(PPh₃)₄, Et₂O, 23 °C; 68%; (d) TIPSCl, imidazole, DMAP, DMF, 23 °C, 75%; (e) Ph₂SO, Tf₂O, TBP, CH₂Cl₂, −78→23 °C, 75%; (f) 4, TBSOTf, CH₂Cl₂, 0 °C, 86%; (g) K₂CO₃, H₂O, MeOH, 23 °C; (h) PhCH(OMe)₂, p-TsOH, 23 °C, 94% (two steps); (i) p-TsOH, H₂O, MeOH, 23 °C, 71%; (j) BnBr, Bu₄NBr, NaOH, H₂O, CH₂Cl₂, 23 °C, 84%; (k) 3, TMSOTf, Et₂O, −45 °C, 86%; (l) DIBAL-H, CH₂Cl₂, −78 °C, 92%; (m) TESOTf, 2,6-lutidine, CH₂Cl₂, 0→23 °C, 99%; (n) TBAF, THF, 0 °C, >99%; (o) CCl₃CN, DBU, CH₂Cl₂, 0 °C, 92%; (p) TMSOTf, 4Å ms, CH₂Cl₂, −15 °C, 62%; (q) TBAF, THF, 0 °C; (r) CCl₃CN, DBU, CH₂Cl₂, 0→23 °C, 84% (two steps).

Scheme 3^a

^a Reagents and conditions: (a) 16, BF₃·OEt₂, 4Å ms, CH₂Cl₂, −78→23 °C, 71%; (b) TFA, H₂O, CH₂Cl₂, 0 °C; H₂, Pd–C, EtOH, THF, 23 °C, 71%; (c) KOH, EtOH, H₂O, 80 °C; (d) TESOTf, Py, 40 °C; (e) CbzCl, Py, TBP, CH₂Cl₂, 23 °C, 68%; (f) 16, BF₃·OEt₂, 4Å ms, CH₂Cl₂, −78→23 °C, 80%; (g) H₂, Pd–C, EtOH, THF, 23 °C; TFA, H₂O, 0 °C, 77%.