合成路线1

Aldol condensation of 6-chloro-5-fluoroisatin (XIX) with acetone (XX) by means of Et2NH and K2CO3 gives the hydroxyl-ketone (XXI),which is protected with ethylene glycol (XXII) in the presence of HC(OEt)3 and p-TsOH in CH2Cl2 to yield the corresponding ketal (XXIII). Reduction of compound (XXIII) with Red-Al in THF, followed by treatment with aqueous HCl leads to 1-(6-chloro-5-fluoroindol-3-yl)acetone (XXIV). Alternatively, reduction of nitropropenyl intermediate (XVI) with H2 over Raney-Ni in MeOH/H2O or sequential reduction to oxime with H2 over Pt/C in EtOAc and then hydrolysis using NaHSO3 in EtOH furnishes ketone (XXIV). Enzymatic transamination of intermediate (XXIV) with isopropylamine hydrochloride (XXV) in the presence of transaminase SEQ ID 134 and pyridoxal-5’-phosphate (PLP) in H2O/PEG200 produces the corresponding (S)-amine, which is isolated as the camphorsulfonate salt (XXVI) by treatment with CSA in i-PrOAc. Condensation of tryptamine derivative (XXVI) with 5-chloroisatin (XII) in the presence of Et3N in refluxing i-PrOH and subsequent Pictet-Spengler cyclization in the presence of CSA provides cipargamin camphorsulfonate (XXVII), which is finally treated with Na2CO3 in EtOH/H2O .