Early introduction of the amino group to the C27-C35 building block of Eribulin

Article abstract of DOI:10.1016/j.tetlet.2013.10.077

A new synthetic strategy towards the C27-C35 subunit of Eribulin (1) has been devised to include a protected 1,2-amino alcohol at C34-C35. Early introduction of the C35 amino group in the synthesis of 1 increases the efficiency of the route. This new approach can be accomplished on a multi-gram scale and allows for the successful synthesis of Eribulin.

Full text of DOI:10.1016/j.tetlet.2013.10.077

Tetrahedron Letters 54 (2013) 7059–7061
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Tetrahedron Letters
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Early introduction of the amino group to the C27–C35 building
block of Eribulin
⇑
Alena Rudolph, Dino Alberico, Robert Jordan, Ming Pan, Fabio E. S. Souza, Boris Gorin
Alphora Research, 2395 Speakman Drive, Mississauga, Ontario L5K 1B3, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
A new synthetic strategy towards the C27–C35 subunit of Eribulin (1) has been devised to include a
protected 1,2-amino alcohol at C34–C35. Early introduction of the C35 amino group in the synthesis of
1 increases the efficiency of the route. This new approach can be accomplished on a multi-gram scale
and allows for the successful synthesis of Eribulin.
Received 21 August 2013
Revised 11 October 2013
Accepted 16 October 2013
Available online 22 October 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Eribulin
Halichondrin B
Ammonolysis
1,2-Amino alcohols
Introduction
ate 9 reacts further with ammonia to provide 1. Utilizing this
strategy at the end of the synthesis can be particularly problematic,
Eribulin (1), is a fully synthetic analog of the marine natural
product Halichondrin B (2), a congener of the Halichondrin polycy-
clic macrolides first isolated from the marine sponge Halichondria
okadai by Uemura, Hirata and co-workers (Fig. 1).1–3 This class of
molecules initially received much attention due to their structural
complexity, in addition to their in vitro and in vivo anti-tumour
activity.3 Following the first total synthesis of 2 by Kishi and
co-workers,2a extensive drug discovery efforts were undertaken
resulting in the discovery of Eribulin that has been recently
approved by the FDA as a mesylate salt for the treatment of certain
patients with metastatic breast cancer.4
The synthesis of 1 represents a formidable challenge, particu-
larly when considering a scale-up development for industrial man-
ufacture of this substance as an active pharmaceutical ingredient.
The most common synthetic strategy relies on the convergent
assembly of subunits 3–5, followed by macrocyclization, formation
of the polycyclic ketal moiety and completed by the introduction of
the primary amine at C35 (Scheme 1).5
as the primary amine that is formed in 1 is more reactive than
ammonia and may react with 9 instead, thereby generating di-
meric byproduct 10.6 Early introduction of the C35 amino group
would avoid this byproduct formation and loss of precious material
at the end of the multistep synthetic sequence. In general, fewer
synthetic steps would be necessary at the later stages of produc-
tion, which would involve more costly and potentially cytotoxic
intermediates, including difficult handling in isolation suites.
Furthermore, we hoped that early introduction of an amine would
provide an opportunity for crystalline intermediates via ammo-
nium salts, to assist in their purification. Thus, we looked towards
the construction of the C27–C35 subunit as a convenient point to
introduce the C35 amino group, with our results presented herein
(See Scheme 3).
Results and discussion
Beginning from advanced intermediate 11,7 the secondary alco-
hol is oxidized to ketone 12 via Swern oxidation and subsequently
From a standpoint of synthetic scale-up development, we envi-
sioned that establishment of the amino functionality at C35 much
earlier in the synthesis of 1 would greatly improve the efficiency of
the route. In particular, the conversion of 7 into 1 (Scheme 2)
requires tosylation of the primary alcohol, which upon treatment
with alcoholic ammonium hydroxide, forms epoxide 9. Intermedi-
undergoes
a Horner–Wadsworth–Emmons reaction to afford
unsaturated aryl sulfones 14a and 14b, as a mixture of Z:E geomet-
rical isomers. We found the Z:E selectivity of the Horner–Wads-
worth–Emmons reaction to be highly dependent on the nature of
the O-alkyl group of the phosphonate coupling partner (13,
Table 1).8 The ratio of Z:E increases significantly as the steric bulk
of R increases from Me to i-Pr (entries 1–3). High ratios of the Z
geometrical isomer proved to be integral in later stages of the
synthetic route (vide infra).
⇑
Corresponding author.
E-mail address: boris.gorin@alphoraresearch.com (B. Gorin).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.077

7060
A. Rudolph et al. / Tetrahedron Letters 54 (2013) 7059–7061
MeO
O
O
OH
H
H2N
H
O
O
H
O
O
O
O
O
O
O
O
O
O
H
O
O
O
H
O
H
O
O
O
H
O
O
H
O
O
HO
1
2
HO
HO
Figure 1. Structures of Eribulin (1) and Halichondrin B (2).
PhO2S
MeO
OTBS
OTBS
TBSO
MeO
O
SO2Ph
I
TBSO
O
C34
O
O
TBSO
CHO OHC
C2 7
O
O
TBSO
C35
O
OTBS
TBSO
OTBS
3
4
O
+
OTBS
OTf
subunit assembly
and macrocyclization
OMs
O
6
OH
O
OPiv
5
MeO
MeO
OH
OH
HO
H2N
C34
O
O
O
O
O
O
O
O
C35
O
O
C27
O
O
O
O
O
O
conversion to
deprotection and
ketalization
C14
1,2-amino alcohol
O
O
7
1
Scheme 1. Synthetic route to Eribulin.
MeO
OH
MeO
O
RO
O
O
O
O
O
O
O
O
O
NH4OH
iPrOH
NH4OH
iPrOH
O
O
O
O
O
O
O
C14
C1 4
7, R = H
8, R = Ts
Ts2O
O
O
9
1
+
OMe
MeO
OH
H
N
OH
O
O
O
O
O
O
O
O
O
O
H
O
O
O
O
O
O
O
O
10
Scheme 2. Late stage amination of C35 to form 1 and potential byproduct 10.
The benzyl group was removed according to known procedures
to give secondary alcohol 15, which subsequently directs the selec-
tive reduction of the vinyl sulfone to afford 16. In our hands, the
minor E geometrical isomer of 14 reacted significantly slower, or
not at all, in the removal of the benzyl group and the selective reduc-
tion of the vinyl sulfone, thus necessitating the high levels of Z selec-
tivity in the synthesis of 14. Diol 18 can be accessed by the selective
methylation of the secondary alcohol with trimethyloxonium
tetrafluoroborate and proton sponge,9 followed by the basic
methanolysis of the benzoyl groups. Alternatively, 18 can be fur-
nished by basic methanolysis of the benzoyl groups to yield a triol,
selective protection of the 1,2-diol as the acetonide, methylation of
the free secondary alcohol with MeI and removal of the acetonide.
The primary alcohol is converted to tosylate 19, which then under-
goes a three-step sequence of ammonolysis,6 Boc- and acetonide10
protection to afford the protected 1,2-amino alcohol 22. The
sequence is completed by dihydroxylation of the terminal olefin,
followed by periodate cleavage to afford aldehyde 23. This sequence

A. Rudolph et al. / Tetrahedron Letters 54 (2013) 7059–7061
7061
ArO2S
O
OH
BnO
BzO
BnO
BzO
BnO
BzO
a
b
O
BzO
BzO
O
BzO
O
11
ArO2S
HO
12
14
SO2Ar
SO2Ar
SO2Ar
MeO
HO
BzO
HO
BzO
c
e-f
d
or
O
O
O
HO
BzO
TsO
BzO
H2N
g-j
18
15
16
SO2Ar
SO2Ar
SO2Ar
MeO
HO
MeO
HO
MeO
k
l
m-n
O
O
O
O
BocN
19
20
22
MeO
O
CHO
o-p
O
BocN
23a Ar = Ph
23b
Ar = p-tolyl
Scheme 3. Synthetic route towards C27–C35 building block 23. Reagents and conditions: (a) (COCl)2, DMSO, Et3N, CH2Cl2; (b) (RO)2P(O)CH2SO2Ar (13a–d), LHMDS, toluene,
85–100% over 2 steps; (c) TMSI, CH3CN, 73%; (d) NaBH(OAc)3, Bu4NCl, toluene/DME, 78%; (e) Me3OBF4, proton sponge, CH2Cl2, 83%; (f) K2CO3, MeOH, quant; (g) K2CO3, MeOH;
(h) 2,2-dimethoxypropane, pTSA-H2O, acetone; (i) MeI, KOtBu, THF; (j) 2 N HCl, MeOH 87% over 4 steps; (k) TsCl, Et3N, Bu2SnO, CH2Cl2, 80–85%; (l) 7 N NH3/MeOH; (m) Boc2O,
NaOH, dioxane 80–87% over 2 steps; (n) 2,2-dimethoxypropane, pTSA-H2O, acetone 79–85%; (o) OsO4, NMO, CH2Cl2; (p) NaIO4, EtOAc/H2O, 77–83% over 2 steps.
P. J.; Singer, L. A.; Chase, C. E.; Lemelin, C. A.; Shen, Y.; Davis, H.; Tremblay, L.;
Towle, M. J.; Salvato, K. A.; Wels, B. F.; Aalfs, K. K.; Kishi, Y.; Littlefield, B. A.; Yu,
M. J. Bioorg. Med. Chem. Lett. 2004, 14, 5551; (c) Littlefield, B. A.; Palme, M. H.;
Seletsky, B. M.; Towle, M. J.; Yu, M. J. Zheng, W. US 6214865, 2001.; (d)
Littlefield, B. A.; Palme, M. H.; Sletsky, B. M.; Towle, M. J.; Yu, M. J.; Zheng, W.
US 6365759, 2002.; (e) Littlefield, B. A.; Palme, M. H.; Seletsky, B. M.; Towle, M.
J.; Yu, M. J.; Zheng, W. WO 9965894, 1999.; (f) Yu, M. J.; Kishi, Y.; Littlefield, B.
A. In Anticancer Agents from Natural Products; Cragg, G. M., Kingston, D. G. I.,
Newman, D. J., Eds.; CRC Press: Boca Raton, 2005; pp 241–265; (g) Newman, S.
Curr. Opin. Invest. Drugs 2007, 8, 1057; (h) Vahdat, L. T.; Pruitt, B.; Fabian, C. J.;
Rivera, R. R.; Smith, D. A.; Tan-Chiu, E.; Wright, J.; Tan, A. R.; DaCosta, N. A.;
Chuang, E.; Smith, J.; O’Shaughnessy, J.; Shuster, D. E.; Meneses, N. L.;
Chandrawansa, K.; Fang, F.; Cole, P. E.; Ashworth, S.; Blum, J. L. J. Clin. Oncol.
2009, 27, 2954; (i) Chiba, H.; Tagami, K. J. Synth. Org. Chem. Jpn. 2011, 69, 600.
2. For the first total synthesis of Halichondrin B: (a) Aicher, T. D.; Buszek, K. R.;
Fang, F. G.; Forsyth, C. J.; Jung, S. H.; Kishi, Y.; Matelich, M. C.; Scola, P. M.;
Spero, D. M.; Yoon, S. K. J. Am. Chem. Soc. 1992, 114, 3162; For a review of the
synthetic work on the halichondrin family: (b) Jackson, K. L.; Henderson, J. A.;
Phillips, A. J. Chem. Rev. 2009, 109, 3044.
Table 1
Dependence on the structure of phosphonate 13 ((RO)2P(O)CH2SO2Ar) towards the
Z:E selectivity in the Horner–Wadsworth–Emmons reaction
Entry
Phosphonate
R
Ar
Product
Z:E (14)a
1
2
3
4
13a
13b
13c
13d
Me
Et
i-Pr
Et
Phenyl
Phenyl
Phenyl
p-Tolyl
14a
14a
14a
14b
5:1
8:1
27:1
6:1
a
Z:E ratio determined by 1H NMR.
can be conveniently carried out on >100 g scale to afford multi-gram
quantities of 23. Compound 23 has been applied in the successful
synthesisandisolationof Eribulin, moreoverwith fewer transforma-
tions after the installation of the polycyclic ketal moiety at C14 and
without formation of the undesired dimer 10.
In conclusion, we have demonstrated that the C35 amino group
of Eribulin (1) can be easily introduced during the construction of
the C27–C35 subunit 23 and carried forward as a protected 1,2-
amino alcohol. This sequence is amenable to an industrial scale
and will aid at increasing the overall efficiency of the commercial
synthesis of 1.
3. For the isolation of Halichondrins from marine sponge Halichondria okadai: (a)
Uemura, D.; Takahashi, K.; Yamamoto, T.; Katayama, C.; Tanaka, J.; Okumura,
Y.; Hirata, Y. J. Am. Chem. Soc. 1985, 107, 4796; (b) Hirata, Y.; Uemura, D. Pure
Appl. Chem. 1986, 58, 701.
4. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm233863.htm.
5. For the most recent communication on the commercial development of
Eribulin: (a) Chase, C. E.; Fang, F. G.; Lewis, B. M.; Wilkie, G. D.; Schnaderbeck,
M. J.; Zhu, X. Synlett 2013, 323; (b) Austad, B. A.; Benayoud, F.; Calkins, T. L.;
Campagna, S.; Chase, C. E.; Choi, H.-w.; Christ, W.; Costanzo, R.; Cutter, J.; Endo,
A.; Fang, F. G.; Hu, Y.; Lewis, B. M.; Lewis, M. D.; McKenna, S.; Noland, T. A.; Orr,
J. D.; Pesant, M.; Schnaderbeck, M. J.; Wilkie, G. D.; Abe, T.; Asai, N.; Asai, Y.;
Kayano, A.; Kimoto, Y.; Komatsu, Y.; Kubota, M.; Kuroda, H.; Mizuno, M.;
Nakamura, T.; Omae, T.; Ozeki, N.; Suzuki, T.; Takigawa, T.; Watanabe, T.;
Yoshizawa, K. Synlett 2013, 327; (c) Austad, B. A.; Calkins, T. L.; Chase, C. E.;
Fang, F. G.; Hortstmann, T. E.; Hu, Y.; Lewis, B. M.; Niu, X.; Noland, T. A.; Orr, J.
D.; Schnaderbeck, M. J.; Zhang, H.; Asakawa, N.; Asai, N.; Chiba, H.; Hasebe, T.;
Hoshino, Y.; Ishizuka, H.; Kajima, T.; Kayano, A.; Komatsu, Y.; Kubota, M.;
Kuroda, H.; Miyazawa, M.; Tagami, K.; Watanabe, T. Synlett 2013, 333.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
10.077.
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1. For the development of Eribulin: (a) Towle, M. J.; Salvato, K. A.; Budrow, J.;
Wels, B. F.; Kuznetsov, G.; Aalfs, K. K.; Welsh, S.; Zheng, W.; Seletsky, B. M.;
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