Novel and Efficient Chromium(II)-Mediated Desulfonylation of α-Sulfonyl Ketone

Article abstract of DOI:10.1021/acs.orglett.5b01497

A novel and efficient method for the Cr(II)-mediated desulfonylation of α-sulfonyl ketone by a Cr-ligand-Mn system has been developed during the course of process research on Halaven (eribulin mesylate). This reaction is dramatically accelerated in the presence of an appropriate bipyridyl-type ligand. This system is applicable to reduction of α-sulfur-substituted ketones. In addition, a Cr-Cp₂ZrCl₂-Mn catalytic system is also applicable to desulfonylation of α-sulfonyl ketone.

Full text of DOI:10.1021/acs.orglett.5b01497

Letter
pubs.acs.org/OrgLett
Novel and Efficient Chromium(II)-Mediated Desulfonylation of
α‑Sulfonyl Ketone
Kazato Inanaga,† Takashi Fukuyama,*,‡,§ Manabu Kubota,† Yuki Komatsu,† Hiroyuki Chiba,†
Akio Kayano,† and Katsuya Tagami*,†,§
†API Research, Eisai Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Co. Ltd., 22-Sunayama,
Kamisu-shi, Ibaraki 314-0255, Japan
‡API Research, Eisai Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Co. Ltd., 5-1-3 Tokodai,
Tsukuba-shi, Ibaraki 300-2635, Japan
S
* Supporting Information
ABSTRACT: A novel and efficient method for the Cr(II)-
mediated desulfonylation of α-sulfonyl ketone by a Cr−
ligand−Mn system has been developed during the course of
process research on Halaven (eribulin mesylate). This reaction
is dramatically accelerated in the presence of an appropriate
bipyridyl-type ligand. This system is applicable to reduction of
α-sulfur-substituted ketones. In addition, a Cr−Cp2ZrCl2−Mn catalytic system is also applicable to desulfonylation of α-sulfonyl
ketone.
alaven (1; E7389, eribulin mesylate) is a fully synthetic
course of this research, we discovered a novel and efficient
desulfonylation reaction promoted by Cr(II) species. We have
already investigated a catalytic process for 3 → 4 and found that
the reaction proceeds efficiently by using Ni−neocuproine
complex 6, CrCl3, and 4,4′-di-tert-butyl-2,2′-bipyridyl 7. In this
reaction, addition of LiCl is not necessary.10,11 The same
conditions were applied to the reaction of 2, and macrocyclized
product 5 was obtained in even better yield (95%). Subsequent
desulfonylation of 5 by SmI2 could be employed without
cryogenic conditions (0 °C) to give 4 in excellent yield (92%)
with no side reaction.12 However, we found that a slight
amount of 4 was generated during the NHK reaction of 2. This
H
analogue of the structurally complex marine natural
product halichondrin B (HB).1 Halaven has been approved for
use in more than 50 countries for the treatment of certain
patients with metastatic breast cancer.2
Although the structure of eribulin mesylate is considerably
simpler than that of HB (eribulin mesylate has one-third as
many stereogenic centers on the carbon backbone as does HB),
the total synthesis of eribulin mesylate was a significant
challenge.3 Our efforts to establish a manufacturing process for
eribulin mesylate have led to a stable supply of the drug with
consistent quality through a validated method.4−6 However, we
are continuously seeking ways to make the manufacturing
process more efficient, green, and simple.
13
result implied that there were species other than SmI2 that
could remove the sulfone of 5 under the conditions of the
NHK reaction and encouraged us to find a novel and efficient
desulfonylation system potentially residing in the NHK
reaction.
The final assembly process for eribulin mesylate is shown in
Scheme 1 (2 → 3 → 4), where SmI2-mediated desulfonylation7
of α-sulfonyl ketone 2 gives ketone 3, and subsequent
intramolecular Nozaki−Hiyama−Kishi (NHK) reaction affords
macrocyclized ketone 4. Macrocyclization proceeds efficiently
by adopting a stoichiometric asymmetric version of the NHK
reaction in the presence of (S)-sulfonamide ligand.6,8,9 Points of
improvement in these transformations over previous methods
include (1) use of cryogenic desulfonylation conditions, (2) use
of air-sensitive SmI2, and (3) increased yield in the macro-
cyclization step. Because 2 has an aldehyde group, cryogenic
conditions are essential to suppress the side reaction associated
with the aldehyde group. Therefore, if 2 is subjected to NHK
reaction first (2 → 5), it is expected that other options for
desulfonylation can be applied. Regarding the NHK reaction,
Namba and Kishi have already reported the application of a
catalytic NHK reaction to macrocyclization of 3.10 Our research
plan was to develop an optimized catalytic NHK reaction for 2
and practical desulfonylation conditions for 5. During the
Initially, we investigated which species promoted desulfony-
lation of 5 (Table 1). We found that only the combination of
CrCl3, 7, and Mn promoted reaction,14 indicating that Cr(II)
was the essential species for desulfonylation. To the best of our
knowledge, there are no published reports of Cr(II)-mediated
desulfonylation (for a review of other Cr(II)-mediated
reactions, see ref 15). Therefore, to develop an alternative
method for the Cr(II)-mediated desulfonylation of 5, we
focused on the Cr(III)−Mn system as a source of Cr(II)
because it is easy to handle and relatively inexpensive compared
with Cr(II) itself.
Received: May 22, 2015
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.5b01497
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Scheme 1. Alternative Route Finding of 2 to 4
Table 2. Desulfonylation of 5: Ligand Screening
HPLC area ratio
entry
ligand
5
4
1
none
8a
8b
8c
8d
8e
8f
100
100
0
0
0
2
3
100
0
4
100
100
63
5
0
6
37
21
90
90
100
7
79
8
8g
8h
7
10
9
10
10
0
Table 3. Desulfonylation of 5: Solvent Screening
Table 1. Desulfonylation of 5: Investigation of the Essential
Sources
HPLC area
ratio
entry
solvent
Cr(III)−ligand (equiv) Mn (equiv)
5
4
1
2
3
4
5
6
7
THF
6
20
20
20
20
20
5
0
100
100
10
MeOH
toluene
MeCN
DMF
THF
6
0
HPLC area
ratio
6
90
19
2
6
81
entry 6 (equiv) CrCl3 and 7 (equiv) Mn (equiv)
5
4
6
98
1
2
3
4
5
6
0
6
0
6
6
0
6
0
0
6
0
6
0
100
100
100
100
100
0
0
0
0
0
0
0.75
1.5
1.5
13
0
87
0
THF
4
100
100
ab
,
20
0
8
THF
4
b
0
a
CrCl3·6H2O was used instead of CrCl3·3THF. 94% yield (540 mg
scale).
20
20
100
Cr(III) source (entry 8).17 From these results, we decided that
CrCl3·6H2O was the best Cr(III) source because of its ready
availability and low cost.18
Ligand screening showed that desulfonylation of 5 was
dramatically accelerated in the presence of appropriate
bipyridyl-type ligands (Table 2). When ligands having lipophilic
substituents at the 4,4′-positions were employed, reactivity was
high (entries 3, 8−10). In contrast, reactivity was insufficient
when unsubstituted or methoxy-substituted ligands were used
(entries 2, 4−7). We determined that 7 was the best ligand
owing to its availability and cost.
To demonstrate the potential of this chemistry, we
investigated the catalytic desulfonylation of 5. First, to achieve
catalytic desulfonylation, a stoichiometric Cr−ligand complex
capable of dissociating the strong Cr−O bond of the in situ-
generated Cr−enolate derived from the carbonyl group at the
α-position is needed.19 In seminal work in 1996, Furstner and
̈
Next, solvent screening was carried out (Table 3). Full
conversion was achieved with THF or MeOH (entries 1, 2),
whereas 5 remained in the cases of toluene, MeCN, and DMF
(entries 3−5). Stoichiometric amounts of Cr(III), 7, and Mn16
were required to complete the desulfonylation reaction (entry
6). After optimization, 1.5 equiv of Cr(III)−ligand and 4 equiv
of Mn were sufficient for complete reaction (entry 7); a 94%
yield was obtained at the 540 mg scale with CrCl3·6H2O as the
Shi used TMSCl as a dissociating agent of Cr−alkoxides, in a
catalytic process for the NHK reaction.20 In 2004, Namba and
Kishi reported that Cp2ZrCl2 also works as a dissociating agent
of Cr−alkoxides.21 Based on these findings, exploratory studies
aimed at developing a catalytic reduction system showed that
desulfonylation of 5 proceeded smoothly at room temperature
when CrCl3·6H2O (20 mol %), 7 (20 mol %), Mn (4 equiv),
and Cp2ZrCl2 (1.1 equiv) were used (95% yield, Scheme 2). In
B
DOI: 10.1021/acs.orglett.5b01497
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
contrast, low conversion was achieved when TMSCl was used
instead of Cp2ZrCl2 (20% conversion).
ACKNOWLEDGMENTS
■
We are grateful to Yumi Asai, Satoko Sasaki, Eri Ena, Nao
Shibuguchi, and Naoki Asai (Eisai Co. Ltd.) for analytical
support.
a
Scheme 2. Cr−Ligand Catalyzed Desulfonylation of 5
REFERENCES
■
(1) For the original isolation and structural elucidation of
halichondrins, see: (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. Total synthesis of halichondrin B, see: (c) 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.
a
The yield was determined by HPLC.
To evaluate the generality of the Cr−ligand−Mn-mediated
reduction system, we investigated various α-sulfur-substituted
ketones.22 Reductive cleavage of α-(phenylthio), α-(phenyl-
sulfinyl), and α-(phenylsulfonyl) groups (9a−c) proceeded
smoothly in the Cr−ligand−Mn system to give corresponding
cyclohexanone 10 in good yield (Table 4). In addition, 9c
underwent catalytic desulfonylation in >99% yield.
(2) Lin, N. U.; Burstein, H. J. Lancet 2011, 377, 878 and references
therein.
(3) (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) Wang, Y.; Habgood,
G. J.; Christ, W. J.; Kishi, Y.; Littlefield, B. A.; Yu, M. J. Bioorg. Med.
Chem. Lett. 2000, 10, 1029. (c) Seletsky, B. M.; Wang, Y.; Hawkins, L.
D.; Palme, M. H.; Habgood, G. J.; DiPietro, L. V.; 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, 5547. (d) 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.
(4) Austad, B. C.; 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,
24, 327.
Table 4. Cr−Ligand−Mn-Mediated Desulfonylation of
Various α-Sulfur-Substituted Ketones 9a−c
a
entry
X
method
yield of 10 (%)
1
2
3
4
SPh (9a)
A
A
A
B
85
SOPh (9b)
SO2Ph (9c)
SO2Ph (9c)
85
>99
>99
a
Yield of 10 was determined using crude reaction solution by GC in
external standard method.
(5) Chase, C. E.; Fang, F. G.; Lewis, B. M.; Wilkie, G. D.;
Schnaderbeck, M. J.; Zhu, X. Synlett 2013, 24, 323.
In summary, during the course of process research on
eribulin mesylate (Halaven), a novel and practical Cr−ligand−
Mn-mediated reduction system has been developed. This novel
approach is applicable to reductive cleavage of sulfur groups in
α-sulfur-substituted ketones. We expect that this system will be
useful for the total synthesis of natural products and
pharmaceuticals with complicated structures such as that of
eribulin mesylate.
(6) (a) Chiba, H.; Tagami, K. J. Synth. Org. Chem. Jpn. 2011, 69, 600.
(b) Austad, B. C.; Calkins, T. L.; Chase, C. E.; Fang, F. G.;
Horstmann, 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, 24, 333.
(7) Molander, G. A.; Hahn, G. J. Org. Chem. 1986, 51, 1135.
(8) Wan, Z.-K.; Choi, H.-W.; Kang, F.-A.; Nakajima, K.; Demeke, D.;
Kishi, Y. Org. Lett. 2002, 4, 4431.
(9) Austad, B.; Chase, C. E.; Fang, F. G. WO 2005118565, 2005.
(10) Namba, K.; Kishi, Y. J. Am. Chem. Soc. 2005, 127, 15382.
(11) Chi, H.-W.; Nakajima, K.; Demeke, D.; Kang, F.-A.; Jun, H.-S.;
Wan, Z.-K.; Kishi, Y. Org. Lett. 2002, 4, 4435.
(12) We have already reported a part of these studies, see: Inanaga
K.; Kubota, M.; Kayano, A.; Tagami, K. PCT Int. Appl.
WO2009064029, 2009.
(13) We investigated desulfonylation of 5 with some metals or
amalgams such as Zn, Zn-Cu, Mg-MeOH, and lithium naphthalenide.
Only lithium naphthalenide gave product 4 in good yield (88%). The
others were very low conversion or decomposition. Lithium
naphthalenide was needed for cryogenic conditions, and lithium
naphthalenide itself had problems handling SmI2.
(14) Both the combination of CrCl2 and Mn, and 7 and Mn resulted
in no reaction.
(15) Review of Cr(II) mediated reactions, see: (a) Furstner, A. Chem.
Rev. 1999, 99, 991. (b) Wessjohann, L. A.; Scheid, G. Synthesis 1999, 1.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details and analytical data. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/acs.orglett.5b01497.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: t2-fukuyama@hhc.eisai.co.jp.
*E-mail: k-tagami@hhc.eisai.co.jp.
Author Contributions
§T.F. and K.T. contributed equally to this work.
̈
Notes
The authors declare no competing financial interest.
(c) Hargaden, G. C.; Guiry, P. J. Adv. Synth. Catal. 2007, 349, 2407.
C
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(16) Various metals (Zn, Mg, Al, Fe) were investigated. Zn was
effective as reducing reagent, but the reactivity was slightly lower
compared with Mn. See Supporting Information.
(17) We investigated one step conversion of 2 to 4. Reaction
conditions (not optimized): 6 (0.1 equiv), CrCl3 (2.1 equiv), 7 (2.1
equiv), Mn (10 equiv), Cp2ZrCl2 (1.5 equiv), THF, rt, 81% yield.
(18) CrCl3, CrCl3·6H2O, CrCl3·3THF, and CrBr3·6H2O showed
same reactivity in this reaction system, and CrCl3·6H2O was selected
in terms of its commercial availability and cost. However, Cr(OAc)3
and Cr(acac)3 showed low reactivity. See Supporting Information.
(19) After the reaction, Cr-enolate (detected in LCMS analysis) and
some metal-sulfonium salt were generated.
(20) (a) Furstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 2533.
̈
(b) Furstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349.
̈
(21) Namba, K.; Kishi, Y. Org. Lett. 2004, 6, 5031.
(22) Review of cleavage of heteroatom-carbon bonds at an α-
carbonyl groups, see: (a) Fry, A. J. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 8,
Chapter 4.8, pp 983−997. (b) Manthorpe, J. M.; Kong, H. I.; Palko, J.
W.; Gill, M. A. In Comprehensive Organic Synthesis II; Knochel, P.,
Molander, G. A., Clayden, J., Eds.; Elsevier: Amsterdam, 2014; Vol. 8,
Chapter 8.28, pp 1031−1085.
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