An aldol approach to the enantioselective synthesis of (-)-oseltamivir phosphate

Article abstract of DOI:10.1039/c1ob06248d

A formal asymmetric synthesis of the antiviral agent (-)-oseltamivir phosphate is achieved using two aldol reactions as key steps.

Full text of DOI:10.1039/c1ob06248d

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An aldol approach to the enantioselective synthesis of (-)-oseltamivir
phosphate†
Milos Trajkovic, Zorana Ferjancic* and Radomir N. Saicic*
Received 25th July 2011, Accepted 16th August 2011
DOI: 10.1039/c1ob06248d
A formal asymmetric synthesis of the antiviral agent (-)-
oseltamivir phosphate is achieved using two aldol reactions
as key steps.
The arsenal of antiviral therapeutic agents is relatively modest,
as compared to antibacterials, or antifungals.1 The most recent
illustration of this fact has been provided by the actual spread of
the avian influenza, where the therapy is practically limited to only
two compounds, namely oseltamivir phosphate (TamifluTM) and
zanamivir (RelenzaTM). The former is much more popular, due to
the oral administration, and a high public demand for the com-
pound apparently can not be satisfied by the industrial production,
which relies on the impressive semisynthesis from (-)-quinic, or
(-)-shikimic acid, developed by Gilead and Roche chemists.2,3
This stimulated extensive efforts of the synthetic community, with
the aim of developing an efficient total synthesis applicable on a
large scale.4 The challenge resulted in quite a number of ingenious
Scheme 1 Retrosynthetic analysis of oseltamivir.
synthetic approaches to this small, but densely functionalized
molecule, where a range of mechanistically different reactions were
used as key steps in syntheses.5 Interestingly, an approach relaying
on the aldol reaction has not been reported so far although, in
our opinion, this reaction is well suited for the construction of the
array of three contiguous stereocenters in the target structure. We
decided to pursue this synthetic possibility.
converted into the corresponding Evans oxazolidinone 4 via a
mixed anhydride method (Scheme 2).
The aldehyde partner for the coupling (3) was obtained from
the known, (S)-glutamic acid derived, Boc-protected monoester
6,6 via a two step procedure involving its conversion to the
corresponding thioester 7, followed by the ionic hydrogenation.7
Initial attempts to perform the aldol coupling using the lithium
enolate of 4 were unsuccessful, as the aldol product was ob-
tained as a 1 : 1 mixture of diastereoisomers (44% yield). We
suspected that the lack of stereoselectivity might be caused by
the racemization of configurationally unstable aldehyde 3 in the
presence of strongly basic lithium enolate. Attempts to use less
basic titanium enolates were unsuccessful, as the corresponding
oxazolidinone, oxazolidinethione and thiazolidinethione rapidly
decomposed under the enolization conditions.8 However, the use
of a boron enolate proved fruitful:9 although steric hindrance and
lower reactivity of boron enolates (with respect to alkali metal
enolates) slowed down the reaction, after 4 h at -20 ◦C the desired
product 8 was obtained as a single isomer. Attempts to cleave
the oxazolidinone core in 8 with nucleophiles, such as methoxide,
ethoxide or ethanetiolate, led to the oxazolidinone ring opening,
or decomposition of starting material. Therefore, 8 was protected
as aminal 9, whose treatment with sodium borohydride in aqueous
THF furnished alcohol 10. Oxidation of 10 with DMP provided
the precursor 11 for the aldol condensation. Unfortunately, this
Compound 1 was recognized as a suitable advanced intermedi-
ate: its conversion to oseltamivir has been described earlier, and
it contains necessary structural prerequisites for the consecutive
application of two aldol transforms, as delineated in Scheme
1. The aldol condensation transform dissects the cyclohexene
ring of 1 into ester-aldehyde 2, in its turn amenable to further
retrosynthetic simplification by an enantioselective aldolization
transform. While the retrosynthetic cleavage of stereocenters at
C-3 and C-4 in 1 relies on the reagent controlled reaction, the
absolute configuration of C-5 (the nitrogen-bound carbon atom) is
inherited (imported) from the glutamate derived chiral synthon 3.
The aldol addition was envisaged to proceed via a chiral
enolate. To this end, 2-(pentan-3-yloxy)acetic acid 5 was prepared
by a modification of the literature procedure and subsequently
Faculty of Chemistry, University of Belgrade, Studentski trg 16, 11158
Belgrade 118, P. O. B. 51, PAC: 105305, Serbia. E-mail: rsaicic@
chem.bg.ac.rs, zferjan@chem.bg.ac.rs; Fax: +381 11 32 82 537.
† Electronic supplementary information (ESI) available: Experimental
details, spectroscopic data and copies of NMR spectra for new compounds.
See DOI: 10.1039/c1ob06248d
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Scheme 2 Synthesis of oseltamivir.
transformation was unfeasible, as we isolated only the starting
compound 11 under a variety of conditions.
activated esters are known in the literature, to the best of our
knowledge this is the first example of the reduction of an ester
not containing alkoxy, amino, or any other activating group in
neither a nor b position. Upon exposure to excess DMP, diol 12
was converted into dialdehyde 13, which was not isolated, but
treated with dibenzylamine to cyclize into enal 14 (52% over 2
steps). Treatment of 14 with oxone effected both oxidation12 of the
aldehyde and the deprotection of the cyclic aminal functionality
in 14; subsequent esterification under basic conditions5o gave
optically pure intermediate 1. Epimerization of 1, which was
Therefore, we resorted to the dialdehyde cyclization protocol,
introduced by Woodward,10 improved by Corey,11 and success-
fully applied by Mandai5o in a recent synthesis of oseltamivir.
Interestingly, upon exposure to sodium borohydride in aqueous
THF, ester-oxazolidinone 9 was slowly reduced to diol 12. As the
reaction required several days at room temperature, it proved more
practical to perform it at 65 ◦C, where it was complete within
4 h. Although examples of sodium borohydride reductions of
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15, thus completing the formal synthesis of oseltamivir.5i,w
Conclusions
Formation of all carbon–carbon bonds and stereocenters, in a
formal enantioselective synthesis of (-)-oseltamivir phosphate,
was achieved using two aldol reactions: three stereocenters in the
acyclic intermediate were installed in the reaction of the Evans
oxazolidinone derived boron enolate with glutaraldehyde, while
the cyclization was achieved via enamine catalyzed intramolecular
condensation. Research oriented towards the development of
an anti-selective aldol reaction, thus obviating the need for the
epimerization in the later step of the synthesis (1→15), is underway
in our laboratories.
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The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 6927–6929 | 6929
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