A Concise and Flexible Synthesis of the Potent Anti‐Influenza Agents Tamiflu and Tamiphosphor

Abstract

Tamiflu and the highly potent neuraminidase inhibitor tamiphosphor have been synthesized in 11 steps and greater than 20 % overall yields from an haloarene (1S,2S)‐cis‐diol. The key transformations include a regio‐ and stereoselective bromoamidation, and a palladium‐catalyzed carbonylation or phosphonylation reaction (see scheme; tamiflu: A=CO2Et, B=NH3+H2PO4−, tamiphosphor: A=PO(ONH4)2, B=NH2).

Development of Oseltamivir Phosphonate Congeners as Anti-influenza Agents

“…12,13 In brief, d -xylose was modified to intermediate B bearing a diphosphonatomethyl substituent at the C-5 position for the subsequent intramolecular Horner–Wadsworth–Emmons reaction to construct the scaffold of cyclohexenephosphonate ( C ). In another approach, microbial oxidation of bromobenzene provided the enantiopure bromoarene cis -1,2-dihydrodiol ( D ), which was elaborated by a series of functional group transformations to give an intermediate F .…”

“…12,13 The synthetic procedures for tamiphosphor monoethyl ester ( 3c , TP1Et) and guanidino-tamiphosphor monoethyl ester ( 4c , TPG1Et) are described as follows. Purity of these compounds was assessed to be ≥95% by HPLC analyses (Agilent 1100 series) on an HC-C18 column (5 µm porosity, 4.6 × 250 mm) using MeOH/H 2 O (1:1) as the eluent and UV detector at λ = 214 nm.…”

“…3c and 4c : R 1 = H, R 2 = Et. Reagents and conditions : 12,13 (i) Me 2 CO, H 2 SO 4 , CuSO 4 , 25 °C, 24 h; (ii) 0.05 M HCl, 50 °C, 1 h; 95% (2 steps). (iii) Me 3 CCOCl, pyridine, 0 °C, 8 h; 89%.…”

Short Chemoenzymatic Azide‐Free Synthesis of Oseltamivir (Tamiflu): Approaching the Potential for Process Efficiency

“…This commercially available homochiral cis ‐dihydrodiol was also used as a starting material in two other syntheses, those of Fang4p and Banwell,4o respectively. In our first‐ and second‐generation efforts, as well as in the above two preparations, additional transformations were required in order to convert the vinyl bromide functionality in 2 into the acrylate moiety of oseltamivir.…”

Recent Advances in the Construction of Phosphorus‐Substituted Heterocycles, 2009–2019

“…Six‐ or seven‐membered phosphorylated nitrogen heterocycles bearing a C( sp 3 )−P bond such as 8 – 10 are potential anticancer, antimicrobial agents and good clostripain inhibitors . Those variants bearing C( sp 2 )−P bond also exhibit intriguing biological activities such as antagonistic activity against AMPA receptors, inhibitory activity against the neuraminidases of influenza viruses . In addition, the C‐3 phosphoindole framework ( 12 ) represents a group of novel second‐generation NNRTIs (non‐nucleoside reverse transcriptase inhibitors) that display excellent potency against HIV‐1 in vitro (IDX899) .…”