A practical synthesis of C14-C26 fragment of anticancer drug, eribulin mesylate Dedicated to Dr. M. Lakshmi Kantam on her 60th birthday

Article abstract of DOI:10.1016/j.tetlet.2015.05.077

High yielding synthesis of C14-C26 fragment of eribulin is achieved from commercially available R-(+)-citronellol and 1,4-butane diol utilizing the chirality of citronellol 'methyl' centre as C25, organocatalytic epoxidation to install C23 chirality and Sharpless asymmetric dihydroxylation to install chirality at C20 and C17.

Full text of DOI:10.1016/j.tetlet.2015.05.077

Accepted Manuscript
A practical synthesis of C14-C26 fragment of anticancer drug, eribulin mesylate
Nadella Lavanya, Nayani Kiranmai, Prathama S. Mainkar, Srivari
Chandrasekhar
PII:
S0040-4039(15)00910-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.05.077
TETL 46349
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 May 2015
20 May 2015
21 May 2015
Please cite this article as: Lavanya, N., Kiranmai, N., Mainkar, P.S., Chandrasekhar, S., A practical synthesis of
C14-C26 fragment of anticancer drug, eribulin mesylate, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/
j.tetlet.2015.05.077
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A practical synthesis of C14-C26 fragment of
anticancer drug, eribulin mesylate
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Nadella Lavanya, Nayani Kiranmai, Prathama S. Mainkar and Srivari Chandrasekhar*

Tetrahedron Letters
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A practical synthesis of C14-C26 fragment of anticancer drug, eribulin mesylate
Nadella Lavanya, Nayani Kiranmai, Prathama S. Mainkar and Srivari Chandrasekhar *
Division of Natural Products Chemistry, CSIR- Indian Institute of Chemical Technology, Hyderabad – 500 007, India
ARTICLE INFO
ABSTRACT
High yielding synthesis of C14-C26 fragment of Eribulin is achieved from commercially
available R-(+)-citronellol and 1,4-butane diol utilizing the chirality of citronellol ‘methyl’
centre as C25, organocatalytic epoxidation to install C23 chirality and Sharpless asymmetric
dihydroxylation to install chirality at C20 and C17.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords
Chemotherapeutic agent
Neurotoxic effects
Keck allylation
SN2 cyclization
Eribulin mesylate (1) (Halaven®) has attracted global attention as The retrosynthetic delineation is shown in scheme 1. We have
the last line of chemotherapeutic agent in the cure of metastatic planned to construct the tetrahydrofuran ring of 3 from alcohol 4
cancer for patients who have already undergone chemotherapy through Sharpless asymmetric dihydroxylation followed by an
with other drugs and not responded. Also, this drug has become a insitu SN2-cyclization. The alcohol 4 could be synthesized by
reference drug in the text books as pruned version of Halichondrin cross-metathesis reaction between 5 and 6, which inturn could be
B.1 Eribulin (1) induces apoptotic mechanism on cancer cells with obtained from R-(+)-citronellol and 1,4-butane diol, respectively.
minimal neurotoxic effects on patients.2 The seminal contributions
in discovering this drug through total synthesis by Kishi et al.3
inspired several research groups globally to develop new synthetic
strategies.3-6 Sticking to the basic retrosynthetic plan, a good
number of improved strategies have been designed. More recently,
an industrially viable synthesis of eribulin is reported by
researchers from Eisai Company, Japan.7 Despite all these efforts,
treatment regimen costs an average of ~4,000 USD per cycle.8
Thus more efficient, scalable and cost effective approaches are
welcome. Recently, we have reported a synthesis of C14-C26
fragment as our initial effort9 towards the gigantic target (Figure
1).
Figure 1. Structure of eribulin mesylate (1)
Scheme 1: Retrosynthetic analysis for C14-C26 fragment of Eribulin
The primary hydroxyl group of commercially available R-(+)-
citronellol was protected as tert-butyldiphenylsilyl ether,
ozonolysis of the olefinic bond yielded aldehyde11a which was
converted to epoxy silyl ether 7 using organocatalytic reaction
conditions,11b,12,13 in multiples of grams. CuI catalyzed
Our continuous efforts have now resulted in achieving C1-C13
(see the preceeding paper)10a and C28-C35 fragments (see the
following paper)10b very efficiently. Herein, we report a short and
practical synthesis of C14-C26 fragment 2 of eribulin, starting
from commercially available R-(+)-citronellol and 1,4-butane diol.
regioselective opening14 of epoxide
7 was achieved with
allylmagnesium bromide to get alcohol 8 in 94% yield. The
liberated secondary hydroxyl group has been protected as acetate 5
by reacting with Ac2O/Et3N/DMAP in CH2Cl2 at rt for 12 h in
91% yield (Scheme 2).
*Corresponding author. Tel.: +91 40 27193210; fax: +91 40 27160512.
E-mail address: srivaric@iict.res.in (S. Chandrasekhar).
Dedicated to Dr. M. Lakshmi Kantam on her 60th birthday.

insitu SN2 cyclization9,19 to provide hydroxytetrahydrofuran
derivative 3 in 61% yield with 80% de. The free hydroxyl group of
3 was oxidized with Dess-Martin periodinane in CH2Cl2 to keto
derivative 12 in 83% yield, which upon Wittig reaction provided
the target exomethylene tetrahydrofuran 2 in 76% yield.
In conclusion, a practical and high yielding synthesis of C14-
C26 fragment of Eribulin is achieved having all the required
functionalities to elaborate the total synthesis.
Acknowledgments
Scheme 2: Preparation of acetate 5
NL thanks CSIR, New Delhi, for research fellowship and NK
thanks CSIR-Senior Research Associateship (Scientist’s Pool
Scheme) for financial assistance. SC and PSM thanks CSIR,
Ministry of Science and Technology, Govt. of India, for XII
five year plan project NICE-P (CSC-0109) for funding.
The homoallyl alcohol 10 was synthesized on gram scale from
aldehyde 9 (obtained from 1,4-butane diol).15 The asymmetric
Keck allylation16 on 4-benzyloxybutyraldehyde 9 catalysed by (S)-
BINOL gave homoallyl alcohol 10 in 80% yield with 95% ee
(determined by chiral HPLC).17 The secondary alcohol 10 was
silylated to 6 using TBSCl and imidazole in 96% yield (Scheme
3).
References and notes
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Supporting Information
Supplementary data associated with this article, experimental and
characterization data, can be found in the online version.