Modular Assembling of Eribulin as a Highly Potent Anti-Cancer Agent
Xianshu Zhang, Fudou Ding, Mingyuan Tang, Shufang Liu, Min Sun, Fang Liu, Linlin Chen, Jack Gengcheng Yang*, James Zhinong Gao,
Qiang Gao, Baofu Zheng
Shanghai Haoyuan Chemexpress Co., Ltd., Shanghai, PR China; MedChemExpress LLC, New Jersey, USA
Background
HO
About Eribulin: On June 17, 2021, Eisai Co., Ltd. and Bristol-Myers Squibb Company
announced to enter into an exclusive global strategic collaboration agreement for the
co-development and co-commercialization of MORAb-202, an antibody drug conjugate
(ADC) made of anti-folate receptor alpha (FRα) antibody and anti-cancer agent Eribulin,
using an enzyme cleavable linker.
Eribulin was developed by Eisai as an anticancer agent, acting as an inhibitor of
microtubule dynamics by binding to a small number of high affinity sites at the plusends of existing microtubules predominantly. It terminates cancer cells by both
cytotoxic and non-cytotoxic mechanisms of action. Its cytotoxic effects are related to the
antimitotic activities, by which apoptosis of cancer cells is induced following prolonged
and irreversible mitotic blockade. Some preclinical studies in human breast cancer
models have shown that Eribulin exerted complex effects on the biology of active
cancer cells and residual tumors that appear unrelated to its antimitotic effects. A couple
of different oncological disorders have shown responses to Eribulin treatment. Due to
the high efficacy against broad types of cancer, as well as the promising clinical results
of the new ADC drug MORAb-202, more investigators are using Eribulin as the
warhead in the design of ADC drugs recently.
Eribulin is a fully synthetic macrocyclic ketone analogue of the marine natural product
halichondrin B (HC-B), the parent molecule, which is a naturally occurring, potent
mitotic inhibitor with a unique mechanism of action (Figure 1). The organic synthesis of
Eribulin was first published in 2001; a new synthetic route to the drug was published in
2009. The most popular salt form of Eribulin is its salt with one equivalent of mesylate.
OH
H2N
O
O
O
O O
O
O
H
O
H
O
Halichondrin B
Cytotoxic IC50 0.30 nM
Found in marine sponge Halichondria okadai
O
H
O
O O
O
O
MeO
+
H
+
O
O
O
H
HO
O O
S
I
OHC
O
OPiv
O
OTBS
O
I
Synthetic Challenges and Strategies
Module 1
As shown in Scheme 1, using D-glucuronic acid-3,6-lactone as the starting material,
the key intermediate module 1 was obtained through 19 steps of reaction. During the
preparation process of the key intermediate, the isomer impurities were effectively
controlled through stereospecific organic synthesis and chiral purification, so that the
purity of the module 1 meets the need for the subsequent coupling. The production of
module 1 can reach multiple hundred grams to a kilogram in one batch with high quality.
HO
O
OTBS
OTBS
O
O
OPiv
Module 3
C41H63NO14S
Mol. Wt.: 826
Module 1
Eribulin
Module 2
Module 3
Scheme 3. Synthesis of Module 3 through 18 Steps of Reaction
Figure 2. Modular assembling strategy of the synthesis of Eribulin
Assembling to Make Eribulin
OMe
HO
O
O
H
O
19 steps
OH
TBSO
OTBS
O
O
S
O
H
R
O
OH
(3S,3aR,6R,6aR)-3,5,6-trihydroxytetrahydrofuro[3,2-b]furan-2(5H)-one
Module 1
Scheme 1. Synthesis of Module 1 through 19 steps of reaction
Module 2
HO
HO
Eribulin is one of the most complex compounds for organic synthesis. So far, the total
synthesis still requires more than 60 steps. Because there are 19 chiral centers, the
stereochemistry purity has to be strictly controlled. Qualitative and quantitative analysis
of enantiomers and diastereomers are challenging along the long route of synthesis. In
order to have an accurate control of the structure, a three-modular assembling strategy
was developed. With such a modular approach, the key intermediates could be
prepared separately under close control. The three modules were assembled together
to make Eribulin. Figure 2 shows the strategic design of the assembling plan.
O
18 steps
O
OTBS
H
OTBS
Module 2 can be produced at multiple hundred grams to a kilogram in every batch with
≥ 99%ee.
Eribulin (NSC-70738, Halaven)
Cytotoxic IC50 0.27 nM
19 chiral centers, 62 steps
Figure 1. Eribulin is a fully synthetic macrocyclic ketone analogue of the
marine natural product halichondrin B (HC-B)
Shanghai Haoyuan ChemExpress Co. Ltd.
H2 N
O
O
R
H
As shown in Scheme 2, using relatively inexpensive D-ribose as the starting material,
module 2 was synthesized through 18 steps. Along the route of synthesis, stereospecific reactions and chiral purification techniques were used a couple of times to
effectively control the content of chiral isomers in each step in order to meet the need
for subsequent assembling.
H
O
MeO
OH
O
I
H
O
OH
18 steps
OH
(3R,4S,5R)-5-(hydroxymethyl)tetrahydrofuran-2,3,4-triol
OHC
O
H
OTBS
O
I
OTBS
OTBS
Module 2
Scheme 2. Synthesis of Module 2 through 18 steps of reaction
At last, the three modules 1, 2 and 3 were assembled together through another 13
steps of reaction to build Eribulin.
Along the route, the reaction processes for key intermediates have also been
optimized. For each step, reaction parameters were screened for optimal conditions.
The quality specifications of the key intermediates have been established according to
specified criteria. The analytical methods for the characterization of relevant impurities
and impurity profiles have been developed. All impurities of interest have been tracked
for the source and fate. The impurity removal protocols were developed to ensure
consistent product quality from batch to batch. Overall, a robust process has been
developed for the synthesis of Eribulin mesylate in scales of about 100 grams in every
batch.
Quality of Eribulin
Because the identity and purity of the key modules were controlled strictly, Eribulin
produced in such a assembling approach was identified correct from both regiochemistry and stereo-chemistry aspects. For details about this HP API, please refer to
https://www.medchemexpress.com/eribulin.html
 Eribulin mesylate (B1939 mesylate;
E7389 mesylate; ER-086526
mesylate), Catalog # HY-13442A
 Eribulin (Synonyms: B1939; E7389;
ER-086526), Catalog #HY-13442A
 Correct regio and chiral structure by
2D-NMR, 1H and 13C NMR, XRPD,
CD, etc.
 Purity: ≥ 99% by HPLC
Module 3
As shown in Scheme 3, starting from an inexpensive diacetone glucose, module 3 was
synthesized through 16 steps.
Likewise for module 2, stereo-specific synthesis and chiral purification techniques were
used multiple times to effectively control the content of chiral isomers in each step. This
helped meeting the need for the subsequent reactions.
Currently, the capacity to make module 3 can reach kilogram scales for every batch.
References
1. Yu MJ, Kishi Y, Littlefield BA (2005). "Discovery of E7389, a fully synthetic macrocyclic ketone analogue
of halichondrin B". In Newman DJ, Kingston DG, Cragg GM (eds.). Anticancer agents from natural products.
Washington, DC: Taylor & Francis. ISBN 978-0-8493-1863-4
2. Towle MJ, et al, "In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of
halichondrin B". Cancer Research, 2001, 61 (3): 1013–21.
3. Seletsky BM, et al, "Structurally simplified macrolactone analogues of halichondrin B“, Bioorganic &
Medicinal Chemistry Letters, 2004, 14 (22): 5547–50.
4. Kim DS, et al, "New syntheses of E7389 C14-C35 and halichondrin C14-C38 building blocks: doubleinversion approach”, Journal of the American Chemical Society, 2009, 131 (43): 15636–41.
Address: 1 Deer Park Dr, Suite Q, Monmouth Junction, NJ 08852; Tel (609) 375-6525, Contact author & BD: jackg.yang@chemexpress.com; Marketing: info@chemexpress.com
13th World ADC San Diego – Sept. 6th ~ 9th, 2022