With the appropriate diene (2)-6 in hand, selective epoxidation
of the more electron-rich alkene with m-CPBA resulted in the
desired cis-isomer (+)-7 (95% crude yield) of sufficient purity to be
used directly in the next step. The observed stereoselectivity can be
attributed to the directing effect of the carbamate moiety.21
Reaction of (+)-7 with sodium azide gave the azido alcohol 8 in
95% crude yield followed by mesylation and purification to afford
(+)-9 in 68% yield. Treatment of (+)-9 with triphenylphosphine
followed by Et3N, formed the aziridine which was acetylated in situ
to give 10 with an overall yield of 65% after chromatography.
The final stage of our synthetic design involved opening of the
aziridine ring by nucleophilic attack of 3-pentanol in the presence
of a Lewis acid. A similar approach has been used in the synthetic
routes starting from (2)-quinic and (2)-shikimic acid,3–6 in some
instances to introduce the b-amino functionality and others the
alkoxy moiety, as is required for this synthesis. The first attempt
utilised BF3?OEt2 as the Lewis acid to facilitate not only aziridine
ring opening, but also the b-amino BOC-deprotection, to afford
free base oseltamivir in one step. Unfortunately, while some
product has been observed, appropriate conditions are yet to be
achieved. Alternatively, Cu(OTf)2 has been found to be an
efficient catalyst for such ring openings,10 and was utilised to
afford the oseltamivir precursor (2)-11 in comparable yield and
high purity, with analytical data as reported in the literature. It is
therefore foreseeable that concomitant removal of the BOC
protecting group and precipitation with phosphoric acid would
afford oseltamivir phosphate.10 Thus, this novel route employing
iron carbonyl chemistry allows the synthesis of oseltamivir
phosphate in a total of 12 steps from cyclohexadienoic acid ethyl
ester (1).
Notes and references
{ Compounds 3, 5 and 6 were individually synthesised as both
enantiomers to allow assignment of absolute configuration, however,
only the required enantiomer is shown.
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The highlight of this particular approach to the synthesis of
oseltamivir is the potential for greater access to analogues in the
future. It is anticipated that all four substituents on the
cyclohexene scaffold of oseltamivir can be varied (Fig. 2) via (1)
employing nucleophiles (Nu) other than BOC–NH2 for the
nucleophilic attack on the iron carbonyl cation; (2) using an
activated ester of 3 (e.g., R1 = p-nitrophenyl), which after oxidative
decomplexation can be converted to different esters/amides; (3)
using alternate alcohols (R3) or other nucleophiles in the aziridine
ring-opening; (4) varying the aziridine acylating reagent (R2).
Studies concerning the versatility of the iron carbonyl chemistry to
such a diversity oriented approach have been initiated both
employing polymer-bound reagents16a and on solid phase,22 and
results from further investigations toward oseltamivir analogues
will be reported in due course.
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The authors thank AstraZeneca R&D Mo¨lndal and the Swedish
Foundation for Strategic Research (SSF) for financial support.
This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 3183–3185 | 3185