Process development of halaven: Synthesis of the C1-C13 fragment from d -(-)-gulono-1,4-lactone

Article abstract of DOI:10.1055/s-0032-1317919

A 12-step kilogram-scale synthesis of the C1-C13 fragment, common to halichondrin B and the totally synthetic analogue Halaven (E7389, INN eribulin mesylate), is described. The synthesis features four crystalline intermediates which facilitates throughput, and enhances quality control of all stereogenic centers in the title compound. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0032-1317919

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▌323
cluster
®
Process Development of Halaven : Synthesis of the C1–C13 Fragment from
D-(–)-Gulono-1,4-lactone
Process Development of Halaven : Synthesis of the C1–C13 Fragment
®
Charles E. Chase, Francis G. Fang, Bryan M. Lewis,* Gordon D. Wilkie, Matthew J. Schnaderbeck, Xiaojie Zhu
Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Inc., 4 Corporate Drive, Andover, MA 01810-2441, USA
Fax +1(978)7944910; E-mail: Bryan_Lewis@eisai.com
Received: 13.11.2012; Accepted: 22.11.2012
structural elements of the original halichondrin macrolide.
Abstract: A 12-step kilogram-scale synthesis of the C1–C13 frag-
Specifically, the C29 and C30 sites of the macrolide were
ment, common to halichondrin B and the totally synthetic analogue
®
found to be productive areas for exploration to optimize
Halaven (E7389, INN eribulin mesylate), is described. The synthe-
sis features four crystalline intermediates which facilitates through- biological activity. The macrocyclic ketone analogue 1,
put, and enhances quality control of all stereogenic centers in the bearing a suitably substituted tetrahydrofuran replace-
title compound.
ment for the halichondrin ‘left half’, emerged as the can-
Key words: carbohydrates, chiral pool, drugs, glycosylation, didate compound for clinical evaluation.
stereoselective synthesis
®
Halaven (1) is synthesized in a ten-step process from the
C1–C13 fragment 2 and the C14–C35 fragment (not
shown; see accompanying article). The C1–C13 frag-
ment, common to both 1 and the halichondrins, has previ-
ously been synthesized by Kishi and co-workers from
®
Halaven (1; E7389, INN eribulin mesylate) is a fully
synthetic analogue of the structurally complex marine nat-
ural product halichondrin B. Eribulin has been recently
approved by the FDA for the treatment of certain patients
with metastatic breast cancer. Although the structure of 1
1
4
5
D-galactose, D-(–)-mannonolactone, and D-(–)-ribono-
6
lactone. The initial synthesis of C1–C13 that was used to
2
produce this fragment for clinical evaluation utilized
is substantially simplified relative to the natural product
5b
D-mannonolactone (3) as the starting sugar. However,
®
(
Halaven contains 19 vs. 32 stereogenic centers and a 36
availability and cost of 3 became an obstacle to procuring
larger quantities of 2 needed for full clinical evaluation.
Although D-mannonolactone contains the correct stereo-
chemistry for four of the stereogenic centers in 2 (C8, C9,
C10, and C11), one of these centers, C11, is destroyed
during the synthesis and subsequently re-established.
Thus, D-gulonolactone (4), a sugar epimeric to D-mannon-
olactone at one stereogenic center (that corresponding to
vs. 54 carbon backbone as compared to halichondrin B),
the discovery and development of 1 by total synthesis still
represents a significant challenge. The foundation for
starting these research and development efforts was pro-
vided by the first total synthesis of halichondrin B by
3
Kishi and co-workers at Harvard University. The use of
total synthesis allowed flexible modification of embedded
MeO
1CO2Me
0
3
0
1
H
O
H
O
O
H
HO
O
29
O
O
H
3
5
H
H
OTBS
H2N
MsOH
O
TBSO
O O
O
TBSO
Me
H
13
1
4
13
O
I
2
Halaven® (1)
OH
H
O
11CHO
O
H
O
OH
O
1
1
MeO2C
O
H
O
HO
OH
3
4
: D-(–)-mannonolactone (β-OH at C11)
: D-(–)-gulonolactone (α-OH at C11)
5
®
Scheme 1 Synthetic strategy for Halaven C1–C13 fragment 2
SYNLETT 2013, 24, 0323–0326
Advanced online publication: 10.01.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317919; Art ID: ST-2012-Y0971-C
Georg Thieme Verlag Stuttgart · New York
©

324
C. E. Chase et al.
CLUSTER
C11 in halichondrin.), could serve as a functionally equiv- phine oxide. Direct application of these conditions in the
alent starting carbohydrate. In other words, the stereo- gulono series led to varying degrees of epimerization at
chemistry at C11 is inconsequential in the raw material as C8. Furthermore the subsequent osmylation step was
both sugars degenerate to the common aldehyde inter- found to be sensitive to contamination by phosphines.
mediate 5 (Scheme 1). In order to establish the route from These concerns were addressed by the following proce-
D-gulonolactone, the chemistry reported by the Kishi dural modifications: (i) inverse addition of substrate to a
5
b
group on D-mannonolactone would need to be extended preformed ylid at 0 °C, (ii) use of a maleic anhydride
7
to the epimeric sugar, D-gulonolactone.
workup allowed for the removal of triphenylphosphine,
and (iii) precipitation of triphenylphosphine oxide from
MTBE–heptane afforded crude product with acceptable
stereochemical and impurity profile for use in the next
step without chromatographic purification. Stereoselec-
tive osmylation of 8, proceeded as previously described in
the mannonolactone series to provide ca. 3:1 mixture of
crystalline α-hydroxylactols 9.
This article describes the realization of the chemical se-
quence from D-gulonolactone to C1–C13 fragment 2.
During the course of this investigation, several reactivity
differences in the behavior of the two carbohydrate epi-
mers were noted and incorporated into the overall route
design and purification strategy. The overall synthesis has
been developed and executed on multikilogram scale in
fixed equipment.
Difficulties were encountered in the C-glycosidation of
the diacetate corresponding to 9 due to the unexpected la-
bility of the ancillary cyclohexylidene under the glycosi-
dation conditions. Rather than trying to suppress this
reactivity, we decided to combine cyclohexylidene
The synthetic scheme for transformation of D-gulonolac-
tone (4) to 2 is depicted in Scheme 2. The known biscy-
clohexylidene lactone 6 was reduced with DIBAL-H to
afford lactol 7. The previously reported one-carbon ho-
mologation via Wittig methoxymethylenation in the man-
nono series was conducted in refluxing THF and did not
specify removal of triphenylphosphine and triphenylphos-
8
monodeprotection with acetate formation. A survey of
catalysts for the combined process revealed that treatment
with scandium(III) triflate or zinc(II) chloride in the pres-
O
MeO
OH
HO
H
O
X
O
OH
O
H
O
a
c
d
4
O
O
O
O
O
O
O
O
O
6
7
: X = O
8
9
b
: X = H, OH
OAc
CO2Me
AcO
O
O
SiMe3
H
O
H
+
O
H
e
OAc
OAc
MeO2C
f, g
H
1
1
OH
OH
O
O
11
1
0
O
1
2
CO2Me
CO2Me
CO2Me
H
H
H
O
H
O
H
O
H
O
O
O
h
i
j
l
H
H
OH
OR
2
CHO
RO
O
O
11
O
O
OR
SiMe3
SiMe3
5
13
14: R = H
5: R = TBS
k
1
Scheme 2 Synthesis of 2 (C1–C13) from D-(–)-gulonolactone (4). Reagents and conditions: a) cyclohexanone, PTSA, toluene, 110 °C, crys-
+
–
tallization, 60%; b) DIBAL-H, toluene–THF, –5 °C, quant.; c) KOt-Bu, MeOCH PPh Cl , –5 °C to 30 °C, 81%; d) K OsO ·2H O, NMO, ac-
2
3
2
4
2
etone–H O, 30 °C, 55%; e) ZnCl , AcOH, Ac O, 30 °C, crystallization, 69%; f) 11, BF ·OEt , MeCN, 15 °C, 95%; g) NaOMe, MeOH, MTBE,
2
2
2
3
2
1
5 °C, crystallization, 62%; h) NaIO , EtOAc, 15 °C, quant.; i) CrCl , NiCl , 1-bromo-2-trimethylsilylethene, DMSO, MeCN, 30 °C, 45%; j)
4
2
2
AcOH, H O, 95 °C, crystallization, 70%; k) TBSOTf, 2,6-lutidine, MTBE, 30 °C, crystallization, 75%; l) NIS, MeCN, toluene, TBSCl, 35 °C,
2
8
9%.
Synlett 2013, 24, 323–326
© Georg Thieme Verlag Stuttgart · New York

®
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Process Development of Halaven : Synthesis of the C1–C13 Fragment
325
ence of acetic acid and acetic anhydride cleanly effected Acknowledgment
monocyclohexylidene removal and peracetylation to af-
We thank Eisai Chemical Development for the execution of the
pilot plant batches.
ford the crystalline tetraacetate 10. C-Glycosidation of 10
with commercially available methyl 3-trimethylsilyl-4-
pentenoate (11) proceeded as previously reported in the D-
mannonolactone series, the product of which, upon direct
treatment of with sodium methoxide, underwent global
deacetylation, olefin conjugation, and oxy-Michael addi-
tion to form the crystalline diol-pyran 12. The crystallinity
of 12 stood in sharp contrast to the noncrystallinity of the
C11 epimer corresponding to the D-mannonolactone se-
ries. Sodium periodate mediated cleavage of diol-pyran
References
(
1) (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.
®
(2) For discovery and development of Halaven (1), see:
(
a) Towle, M. J.; Salvato, K. A.; Budrow, J.; Wels, B. F.;
Kuznetsov, G.; Aalfs, K. K.; Welsh, S.; Zheng, W.; Seletsky,
B. M.; Palme, M. H.; Habgood, G. J.; Singer, L. A.; DiPietro,
L. V.; Wang, Y.; Chen, J. J.; Quincy, D. A.; Davis, A.;
Yoshimatsu, K.; Kishi, Y.; Yu, M. J.; Littlefield, B. A.
Cancer Res. 2001, 61, 1013. (b) Zheng, W.; Seletsky, B. M.;
Palme, M. H.; Lydon, 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.
12 generated aldehyde 5, the intermediate common to
both D-mannonolactone and D-gulonolactone synthetic
sequences. The overall route from gulonolactone is one
step shorter owing to the combined cyclohexylidene
removal and tetraacetate formation.
Ni(II)/Cr(II)-mediated coupling, as previously reported,
stereoselectively re-established the C11 alcohol of 13
with a 10:1 diastereomeric ratio at C11. The remaining cy-
clohexylidene ring was now cleaved under mild acidic
conditions using AcOH–water to afford a crystalline triol
(
d) Littlefield, B. A.; Palme, M. H.; Seletsky, B. M.; Towle,
M. J.; Yu, M. J.; Zheng, W. US 6365759, 2002.
e) Littlefield, B. A.; Palme, M. H.; Seletsky, B. M.; Towle,
14. Silylation with tert-butyldimethylsilyl triflate provid-
(
ed the crystalline trisilylether 15. Interestingly, it was
found that use of MTBE as solvent (in place of dichloro-
methane) for the reaction allowed complete suppression
of silylation on the C11 epimer. Simple crystallization of
the product provided the C1–C13 fragment with complete
stereochemical homogeneity.
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, 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,
Completion of 2 is achieved by electrophilic substitution
of the vinylsilane to form the vinyl iodide. The reaction
was previously demonstrated using the known sensitizer
chloroacetonitrile as reaction co-solvent. As these condi-
tions pose an unnecessary risk to manufacturing person-
nel, an alternate process was required. In the Kishi group,
conditions using stoichiometric TBSCl in acetonitrile
were reported as a suitable reaction matrix for the vinyl si-
2
7, 2954. (i) Chiba, H.; Tagami, K. J. Synth. Org. Chem.
Jpn. 2011, 69, 600.
(
3) 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. Total synthesis of
norhalichondrin B by Phillips: (b) Jackson, K. L.;
Henderson, J. A.; Motoyoshi, H.; Phillips, A. J. Angew.
Chem. Int. Ed. 2009, 48, 2346. Total synthesis of
halichondrin C: (c) Yamamoto, A.; Ueda, A.; Brémond, P.;
Tiseni, P. S.; Kishi, Y. J. Am. Chem. Soc. 2012, 134, 893.
Review of synthetic work on halichondrins: (d) Jackson, K.
L.; Henderson, J. A.; Phillips, A. J. Chem. Rev. 2009, 109,
9
lane–vinyl iodide transformation. With this lead refer-
ence, we further investigated the reaction parameters and
found that catalytic TBSCl in acetonitrile and toluene is
sufficient for accomplishing N-iodosuccinimide (NIS)
1
0
mediated conversion of 15 to target compound 2.
In summary, the synthesis of the halichondrin B and erib-
ulin mesylate C1–C13 fragment 2 from readily available
D-(–)-gulono-1,4-lactone 4 has been accomplished. The
overall process is a direct extension of the D-(–)–mannon-
olactone route reported by the Kishi group. During the
demonstration of this new route, several findings were
noted which had practical consequences: (i) the lability of
the ancillary cyclohexylidene group in the gulono series
allowed combination of the deprotection and acetate for-
mation steps, (ii) the C1–C12 diol 12 proved to be highly
crystalline thus facilitating purification, and (iii) the pen-
ultimate intermediate 15 was found to be crystalline en-
abling a late-stage overall control of stereochemical
quality.
3
044; and references therein.
(
(
4) Aicher, T. A.; Kishi, Y. Tetrahedron Lett. 1987, 28, 3463.
5) (a) Duan, J. J.-W.; Kishi, Y. Tetrahedron Lett. 1993, 34,
7
3
541. (b) Stamos, D. P.; Kishi, Y. Tetrahedron Lett. 1996,
7, 8643.
(6) Choi, H.-W.; Demeke, D.; Kang, F.-A.; Kishi, Y.; Nakajima,
K.; Nowak, P.; Wan, Z.-K.; Xie, C. Pure Appl. Chem. 2003,
7
7) Austad, B.; Chase, C. E.; Fang, F. G. WO2005118565, 2005.
8) Scandium(III)triflate-catalyzed acetalization: (a) Ishihara,
K.; Karumi, Y.; Kubota, M.; Yamamoto, H. Synlett 1996,
5, 1.
(
(
839. Scandium(III)triflate-catalyzed acylation: (b) Ishihara,
K.; Kubota, M.; Kurihara, H.; Yamamoto, H. J. Org. Chem.
1996, 61, 4560.
(
9) Stamos, D. P. PhD Dissertation; Harvard University: USA,
1
996.
©
Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 323–326

326
C. E. Chase et al.
CLUSTER
(
10) (a) Experimental procedure for conversion of vinyl silane 15
Hz, 1 H), 4.03 (dd, J = 6.8, 2.8 Hz, 1 H), 4.15 (dd, J = 2.2,
2.2 Hz, 1H), 5.00 (ddd, J = 7.8, 3.8, 0.8 Hz, 1 H), 6.37 (dd,
into vinyl iodide 2: Into the reactor were placed 15 (3.23 kg,
4
0
.50 mol), NIS (4.04 kg, 30.2 mol), and TBSCl (0.032 kg,
.21 mol) in a mixture of toluene (8.5 kg), acetonitrile (15.2
J = 14.8, 0.8 Hz, 1H), 6.88 (dd, J = 14.4, 8.0 Hz, 1H). 13
C
NMR (100 MHz, acetone-d ): δ = –4.45, –4.15, –4.18,
6
kg). The mixture was stirred at 25–30 °C for 22 hours. An
aqueous mixture of Na S O /KHCO (Na S O : 1.5 kg,
–3.41, –3.35, –3.12, 18.79, 19.44, 19.70, 26.55, 26.91,
27.16, 29.65, 31.30, 41.14, 51.66, 65.11, 71.56, 73.83,
74.80, 75.10, 77.94, 79.45, 81.72, 147.85, 171.70. ESI-
2
2
3
3
2
2
3
KHCO : 2.9 kg, water: 29 kg) was added to the reaction
3
+
mixture at 0–30 °C and stirring was continued for 30 min.
After phase separation, the upper layer was washed with 9%
aq NaCl (32 kg × 2). The organic layer was concentrated by
distillation. The residue was dissolved with n-heptane (9 kg).
The solution was purified by column chromatography on
silica gel (39.2 kg; preconditioned with 91 kg n-heptane)
with n-heptane–MTBE (100:0 → 93:7; 354 kg) as the eluent.
The main fractions were combined in the reactor and
concentrated by distillation (40–50 °C external
HRMS: m/z calcd for C H IO Si +Na : 793.2824
3
2
63
7
3
+
20
[M+Na] ; found 793.2824. [α]D –39.0 (c 1.25, toluene).
(b) Characterization of 2: FT-IR (thin film): νmax = 2953,
2930, 2857, 1745, 1607, 1472, 1361, 1255, 1080 cm . H
–
1 1
NMR (400 MHz, acetone-d ): δ = 0.07–0.18 (m, 18 H),
6
0.90–0.99 (m, 27 H), 1.25–1.34 (m, 1 H), 1.31–1.41 (m, 1
H), 1.78–1.83 (m, 1 H), 1.85–1.90 (m, 1 H), 2.47–2.49 (m, 2
H), 3.03 (dd, J = 9.6, 2.4 Hz, 1 H), 3.49 (ddd, J = 10.1, 10.1,
4.5 Hz, 1 H), 3.63 (s, 3 H), 3.78–3.85 (m, 1 H), 3.83 (dd,
J = 6.8, 3.6 Hz, 1 H), 4.03 (dd, J = 6.8, 2.8 Hz, 1 H), 4.15
(dd, J = 2.2, 2.2 Hz, 1H), 5.00 (ddd, J = 7.8, 3.8, 0.8 Hz, 1
H), 6.37 (dd, J = 14.8, 0.8 Hz, 1H), 6.88 (dd, J = 14.4, 8.0
temperature). The residue was dissolved with toluene and
concentrated by distillation again (40–50 °C external
temperature) to afford 2 (3.09 kg, 4.01 mol, 89% yield).
Characterization of 2: FT-IR (thin film): νmax = 2953, 2930,
13
Hz, 1H). C NMR (100 MHz, acetone-d ): δ = –4.45, –4.15,
6
–
1 1
2
857, 1745, 1607, 1472, 1361, 1255, 1080 cm . H NMR
–4.18, –3.41, –3.35, –3.12, 18.79, 19.44, 19.70, 26.55,
26.91, 27.16, 29.65, 31.30, 41.14, 51.66, 65.11, 71.56,
73.83, 74.80, 75.10, 77.94, 79.45, 81.72, 147.85, 171.70.
(
(
400 MHz, acetone-d ): δ = 0.07–0.18 (m, 18 H), 0.90–0.99
m, 27 H), 1.25–1.34 (m, 1 H), 1.31–1.41 (m, 1 H), 1.78–
6
+
1
(
1
.83 (m, 1 H), 1.85–1.90 (m, 1 H), 2.47–2.49 (m, 2 H), 3.03
dd, J = 9.6, 2.4 Hz, 1 H), 3.49 (ddd, J = 10.1, 10.1, 4.5 Hz,
H), 3.63 (s, 3 H), 3.78–3.85 (m, 1 H), 3.83 (dd, J = 6.8, 3.6
ESI-HRMS: m/z calcd for C H IO Si +Na : 793.2824
32
63
20
7
3
+
[M+Na] ; found 793.2824. [α]D –39.0 (c 1.25, toluene).
Synlett 2013, 24, 323–326
© Georg Thieme Verlag Stuttgart · New York

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