Stereospecific synthetic approach towards Tamiflu using the Ramberg-Backlund reaction from cysteine hydrochloride

Article abstract of DOI:10.1039/c4ra10391b

The stereospecific formal synthesis of Tamiflu from L-cysteine hydrochloride as the chiral source is described. The notable feature of the present strategy is the Ramberg-Backlund reaction and Sharpless-Reich protocol as the key chemical transformations t

Full text of DOI:10.1039/c4ra10391b

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Stereospecific synthetic approach towards Tamiflu
using the Ramberg–Backlund reaction from
Cite this: RSC Adv., 2014, 4, 62281
cysteine hydrochloride†
Subhash P. Chavan, Prakash N. Chavana and Rajesh G. Gonnadeb
a
*
Received 13th September 2014
Accepted 5th November 2014
The stereospecific formal synthesis of Tamiflu from L-cysteine hydrochloride as the chiral source is
described. The notable feature of the present strategy is the Ramberg–Backlund reaction and Sharpless–
Reich protocol as the key chemical transformations to access the cyclohexene skeleton of Tamiflu.
DOI: 10.1039/c4ra10391b
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consequence there is a huge pressure on the availability of
drugs and raw material supply to meet worldwide demand of
Introduction
Tamiu.
Currently manufacturing process for Tamiu uses (À)-shi-
The H5N1 and H1N1 strains of virus cause viral u and have
been shown to contribute to pandemic disease and pose a
worldwide threat which has caused the deaths of thousands of
people till date.1 These viruses actually cut the surface protein of
the infected host cell and allow their spreading to other cells.
Oseltamivir phosphate (1, Tamiu, Ro 64-0796, GS4104) and
Zanamivir (2, Relenza, GG 167) are currently used as neur-
aminidase inhibitor drugs (Fig. 1).2
Oseltamivir phosphate is recommended as the best choice
due to its bioavailability in an orally active form.3,4 The anti-
inuenza drug 1 was initially discovered by Gilead Sciences5
and subsequently licensed to Roche for production from
(À)-shikimic acid.6 The demand of Tamiu has inevitably
increased due to the threat of avian u and inuenzas. As a
kimic acid as the raw material. The insufficient quantities of
(À)-shikimic acid either by extraction from its natural sources,
fermentation or chemical synthesis, is a drawback in meeting
with the global demands. Thus far the unabated efforts of
chemical community have led to many alternative syntheses of
Tamiu. This synthetic target appears to be deceptively simple
but is synthetically challenging. Some groups have used readily
available and inexpensive starting materials and reported the
key intermediates for Tamiu.7 Despite the existence of several
methods for Tamiu 1 synthesis, there is still a pressing need to
develop synthetic strategy for it, where the use of azide and
aziridine intermediate should be avoided to minimize the
hazard and complexity associated with the processes.
Synthesis of chiral compounds is a vital task and as a result
many chemists have been engaged in the development of
asymmetric methodologies. The chiral diamines are major class
of ligands which provide enantiopure compounds by asym-
metric catalysis. Their preparation is always a challenge and
only a few processes have been reported.8
However, 1,2-diamines are not only used as ligands but are
also important structural motifs of several bioactive
compounds.9
In view of the signicance of chiral diamines and our own
interest in synthesis of biologically active molecules, it was
decided to pursue the synthesis of Tamiu 1. Recently, we have
reported a concise synthesis of Tamiu 1 starting from
D-mannitol employing aziridine chemistry.7y Earlier we have
developed a highly stereospecic protocol for amidoalkylation
of imidazothiazolone and efficiently demonstrated its applica-
tion for the synthesis of (+)-biotin.10 This protocol potentially
and readily provides trans diamine by urea hydrolysis. In
continuation of our interest in trans diamines, we planned to
utilize this novel protocol for the synthesis of Tamiu, which
also has trans diamine motif.
Fig. 1 Structures of neuraminidase inhibitors 1 and 2.
aOrganic Chemistry Division, Dr Homi Bhabha Road, Pune-411008, Maharashtra,
India. E-mail: sp.chavan@ncl.res.in; Fax: +91-20-25892629; Tel: +91-20-25902286
bCenter for Material Characterization CSIR – National Chemical Laboratory, Dr Homi
Bhabha Road, Pune-411008, Maharashtra, India
† Electronic supplementary information (ESI) available: Experimental procedure,
characterization data and copies of 1H and 13C-NMR spectra for the compounds.
CCDC 949233. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c4ra10391b
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Encouraged by our earlier success of generating protected
trans diamine functionality, it was decided to extend this
strategy for construction of trans diamine of Tamiu.
It was surmised that the intermediate 5 can be explored and
exploited, for the synthesis of Tamiu 1. The intermediate 5 can
be easily synthesised from L-cysteine hydrochloride, which is
commercially readily available in enantiomerically pure form as
the renewable resource. We envisioned that the synthesis of
enone 3, which is the known intermediate reported by Shiba-
saki et al.7c can be obtained by urea hydrolysis, Birch reduction,
epoxidation and regiospecic epoxide ringopening followed by
oxidation of cyclohexene compound 4. The compound 4 can be
readily derived from intermediate 5 using stereospecic ami-
doalkylation protocol developed by us, intramolecular thiol
olen cyclisation and Ramberg–Backlund reaction. The inter-
mediate 5 in turn can be readily obtained from L-cysteine
hydrochloride salt 6 (Scheme 1).10
Actual synthesis began with crude thiol 7, which was
obtained from 5 by Zn induced C–S bond cleavage. Compound 5
in turn was obtained from abundantly available L-cysteine by
the reported procedure by us.10 The thiol 7 on treatment with
DBU underwent intramolecular cyclisation to afford cyclic seven
membered sulphide 8 in 54% yield. The yield of sulphide 8 was
improved to 81% by simply stirring the thiol 7 in water as a
medium without any base.11 It is pertinent to mention here that
to the best of our knowledge this is rst report of formation and
utilization of cyclic sulde in water for synthesis of Tamiu.
Having synthesized cyclic sulphide 8, our next plan was to
obtain compound 4. Accordingly, cyclic sulphide 8 was oxidised
by oxone to afford sulfone 9 in 84% yield. Sulfone 9 was sub-
jected for Ramberg–Backlund reaction12 to furnish the cyclo-
hexene urea 4 in 62% yield.
With success in synthesis of key intermediate 4, next task
was to access diboc derivative 10 from cyclic urea 4 (Scheme 2).
Generally cyclic ureas are quite stable to both acidic as well as
basic conditions. This was once again conrmed when
numerous efforts to cleave the cyclic urea moiety under basic as
well as acidic conditions proved to be futile. So, urea 4 was
reduced with LAH to furnish imidazolidine, which without
purication was directly subjected to hydrolysis with 1% HCl, to
Scheme 2 Synthesis of intermediate 11.
afford corresponding vicinal diamine. The crude diamine was
masked as its carbamate derivative by treatment with neat Boc
anhydride to afford diboc derivative 10 in 67% yield.13 Attempts
to epoxidize compound 10 unexpectedly met with failure and
this was attributed to steric hindrances exerted by benzyl and
boc groups. In order to minimise the steric crowding,
compound 10 was subjected to debenzylation under Birch
reduction conditions at À78 ꢀC in THF, herein the debenzylated
compound 11 was obtained in 91% yield.
The compound 11 when subjected to similar epoxidation
condition, smoothly furnished epoxide 12 in 97% yield as a
single diastereomer giving credence to our hypothesis (Scheme
3).14 The relative stereochemistry of epoxide 12 was conrmed
by NOE and NOESY studies. A signicant NOESY correlation
was observed between H3–H2 and H3–H1 conrming syn rela-
tionship between H3, H2 and H1. The molecular structure of
Scheme 1 Retrosynthetic analysis for Tamiflu (1).
62282 | RSC Adv., 2014, 4, 62281–62284
Scheme 3 Synthesis of enone 3.
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and no additional purication is required to upgrade the
enantiopurity as compared to the reported method.7c
Acknowledgements
PNC thanks CSIR, New Delhi for research fellowship. We thank
Dr U. R. Kalkote and Dr H. B. Borate for useful discussions. The
authors thank CSIR, New Delhi for nancial support as of XII
Five Year plan programme under title ORIGIN (CSC-0108) and
ACT (CSC-0301). We also thank Mr Shridhar and Mr Amol
Kotmale for single crystal X-ray analysis and NOSEY studies
respectively.
Fig. 2 NOSEY and X-ray single crystal analysis of epoxide 12 (ORTEP
diagram; ellipsoids are drawn at 30 probability).
Notes and references
epoxide 12 was further unambiguously conrmed by its single
crystal X-ray analysis (Fig. 2).15
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Conclusions
In conclusion, the formal synthesis of Tamiu has been ach-
ieved from inexpensive and abundant L-cysteine hydrochloride
as the natural renewable resource. The notable features of the
synthesis involve utilisation of efficient stereospecic ami-
doalkylation protocol and rst report on exploitation of intra-
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