Process development of halaven: Synthesis of the C14-C35 fragment via iterative nozaki-hiyama-kishi reaction-williamson ether cyclization

Article abstract of DOI:10.1055/s-0032-1317920

Multikilogram manufacturing process of the Halaven C14-C35 fragment is described. The synthesis features convergent assembly of subunits by iterative asymmetric Ni/Cr-mediated coupling executed in fixed equipment. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0032-1317920

CLUSTER
▌327
®
cluster
Process Development of Halaven : Synthesis of the C14–C35 Fragment via
Iterative Nozaki–Hiyama–Kishi Reaction–Williamson Ether Cyclization
Process Development of Halaven®: Synthesis of the C14–C35 Fragment
Brian C. Austad,a Farid Benayoud,a Trevor L. Calkins,a Silvio Campagna,a Charles E. Chase,*a Hyeong-wook Choi,a
William Christ,a Robert Costanzo,a James Cutter,a Atsushi Endo,a Francis G. Fang,a Yongbo Hu,a Bryan M. Lewis,a
Michael D. Lewis,a Shawn McKenna,a Thomas A. Noland,a John D. Orr,a Marc Pesant,a Matthew J. Schnaderbeck,a
Gordon D. Wilkie,a Taichi Abe,b Naoki Asai,b Yumi Asai,b Akio Kayano,b Yuichi Kimoto,b Yuki Komatsu,b
Manabu Kubota,b Hirofumi Kuroda,b Masanori Mizuno,b Taiju Nakamura,b Takao Omae,b Naoki Ozeki,b
Taeko Suzuki,b Teiji Takigawa,b Tomohiro Watanabe,b Kazuhiro Yoshizawab
a
Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Inc., 4 Corporate Drive, Andover, MA 01810-2441, USA
Fax +1(978)7944910; E-mail: Charles_Chase@eri.eisai.com
b
Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Co., Ltd., 22 Sunayama, Kamisu-Shi, Ibaraki 314-0255, Japan
Received: 13.11.2012; Accepted: 22.11.2012
tem. Thus, establishment of a firm foundation for the
Abstract: Multikilogram manufacturing process of the Halaven®
overall synthesis of eribulin which used not only a C26–
C14–C35 fragment is described. The synthesis features convergent
C27 Ni/Cr-mediated coupling, but also a later-stage C13–
assembly of subunits by iterative asymmetric Ni/Cr-mediated cou-
C14 Ni/Cr-mediated macrocyclization could be accom-
plished by carefully studying and then demonstrating the
viability of C19–C20 Ni/Cr ‘model system’ on kilogram
scale in our pilot plant.
pling executed in fixed equipment.
Key words: antitumor agents, chromium, cyclization, nickel, stere-
oselective synthesis
MeO
Halaven® (1; E7389, INN eribulin mesylate) is a fully
synthetic analogue of the structurally complex marine nat-
ural product halichondrin B.1 Eribulin has been recently
approved by the FDA for the treatment of certain patients
with metastatic breast cancer.2,3 The Halaven® C14–C35
fragment 2 constitutes a major structural element of 1, in
which 10 of the 19 stereogenic centers contained in Hala-
ven® are incorporated.4 The overall approach toward 2
mirrors that used by Kishi and co-workers to construct the
halichondrin C14–C38 fragment:3a Namely, Ni(II)/Cr(II)-
mediated coupling (Nozaki–Hiyama–Kishi reaction) of
the C27–C35 aldehyde 3 and the sulfonate-containing nu-
cleophile 4 followed by Williamson cyclic etherification
was anticipated to form the pyran-containing C14–C35
subunit (Scheme 1).5 The conciseness of this approach
and the functional-group tolerance of the Ni/Cr process
were attractive features for future manufacturing. Never-
theless, there were concerns about scaling up the overall
process due to the somewhat labile nature of the C23 sul-
fonate substrate 4 and the fact that a Ni/Cr coupling had
not previously been demonstrated on kilogram scale in
fixed equipment. At the same time, we considered that in
principle a similar strategy could be employed to con-
struct the tetrahydrofuran-containing C14–C26 subunit. A
strategic advantage of utilizing a Ni/Cr C19–C20 cou-
pling–cyclic etherification sequence for the preparation of
4 would be the opportunity to demonstrate the feasibility
of the Nozaki–Hiyama–Kishi reaction in fixed equipment
on a much less costly and presumably more stabile sys-
30
1
H
O
O
O
H
O
HO
29
H
35
O
H2N
MsOH
O O
O
Me
H
14
13
O
Ni/Cr-mediated
macrocyclization
Halaven® (1)
MeO
SO2Ph
O
TBSO
Ni/Cr-mediated
coupling
27
O
TBSO
cyclic
26
Me
23
etherification
O
OH
2
(C14–C35)
OTf
MsO
26
MeO
SO2Ph
Me
TBSO
14
O
20
TBSO
OPv
17
O
35
cyclic
etherification
27CHO
19
3
4
(C27–C35)
Ni/Cr-mediated
coupling
(C14–C26)
Scheme 1 Synthetic strategy for Halaven® (1)
SYNLETT 2013, 24, 0327–0332
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-0032-1317920; Art ID: ST-2012-Y0973-C
© Georg Thieme Verlag Stuttgart · New York

328
B. C. Austad et al.
CLUSTER
Herein is described: (i) the enantioselective preparation of tion of the liberated C23 hydroxy group provides 16. The
the two chiral fragments C14–C19 and C20–C26, (ii) the terminal olefin is transformed to an aldehyde by sequen-
asymmetric Ni/Cr coupling–cyclic etherification of the tial osmylation and periodate cleavage. Subsequent chro-
two chiral fragments to provide the tetrahydrofuran-con- matographic purification provides the C20–C26 aldehyde
taining C14–C26 fragment 4 on kilogram scale in fixed 17, in which the C25 diastereomeric ratio is preserved.
equipment, (iii) the chromatography-free process for the
C27–C35 aldehyde 3, (iv) the asymmetric Ni/Cr cou-
h
O
O
23
pling–cyclic etherification of 4 with 3 to synthesize the
pyran-containing C14–C35 backbone on kilogram scale
in fixed equipment, and (v) the completion and crystalli-
zation of the entire C14–C35 fragment 2.
11
12
>99% ee
O
i
j
O
CO2Et
13
Synthesis of the C14–C19 subunit commences with acid-
catalyzed hydration of 2,3-dihydrofuran (5), followed by
tin-mediated 2-bromoallylation to yield crystalline diol 6
as a racemic mixture (Scheme 2). Chemoselective protec-
tion of the primary hydroxyl group provides TBDPS ether
7. Chiral-simulated moving bed (SMB) chromatography,6
employing Chiralpak OD (20 μm) as stationary phase, re-
sulted in the separation of the both enantiomers, 8 and 9,
in >98% ee. The undesired enantiomer 8 is converted into
9 by a Mitsunobu inversion–hydrolysis sequence.7 Final-
ly, tosylation of the C17 hydroxyl group completes the
C14–C19 subunit 10 in >99% ee after chromatography
and crystallization.
23
O
14 (R2 = H)
15 (R2 = Me)
O
25
k
R2
l, m
O
6:1
16 (R3 = CH2)
17 (R3 = O)
26
n, o
OMe
R3
20
N
25
TBSO
Me
Me
Scheme 3 Synthesis of C20–C26 subunit 17. Reagents and condi-
tions: h) (R,R)-Jacobsen’s salen(Co) catalyst, H2O, 20 °C, 40%; i) di-
ethyl malonate, NaOEt, EtOH, 65 °C; j) MgCl2(H2O)6, DMF, 135 °C,
54% from 12; k) LHMDS, MeI, THF, –75 °C, 82%; l) Me3Al, (N,O)-
dimethylhydroxylamine hydrochloride, CH2Cl2–toluene, 0 °C; m)
TBSCl, DMF, 20 °C, 53% from 15; n) OsO4, NMO, CH2Cl2–H2O,
20 °C; o) NaIO4, phosphate buffer (pH 7), 20 °C, 85%.
Br
OH
6 (R1 = H)
c
a, b
OR1
17
7 (R1 = TBDPS)
O
5
Union of the two subunits, 10 (C14–C19) and 17 (C20–
C26), is achieved by employing the asymmetric Ni/Cr
coupling using the chiral ligand 18 (Scheme 4).9 Repro-
ducibility of C19–C20 Ni/Cr coupling was achieved by in
situ reaction monitoring with ReactIR™ thus establishing
a firm understanding of critical process parameters. Spe-
cific findings include: (i) effective temperature for li-
gand–Cr complexation is >30 °C, and (ii) tight control of
oxygen is essential throughout the process, (iii) catalytic
activity of Ni is better preserved by minimizing time-lag
between addition of NiCl2 and substrate mixture and
maintaining a low temperature (0–5 °C) during each addi-
tion. Additionally, it was noted that low levels of a p-tol-
uenesulfinate impurity in 10 dramatically decreased the
conversion of Ni/Cr coupling.10 The coupled adduct 20 is
treated with silica gel in 2-propanol to induce cyclization
to the tetrahydrofuran ring.11 It should be noted that at-
tempted base-induced cyclization resulted in significant
β-elimination of the homoallylic C17 tosylate to generate
the 1,3-diene byproduct. Subsequent chromatography re-
moves raw materials and process-related impurities re-
sulting in 21 as a mixture of C20 and C25 stereoisomers
(C20 dr = 8:1; C25 dr = 6:1). Grignard addition to the
Weinreb amide 21 provides the corresponding methyl ke-
tone that is purified by chromatography. The ketone 21 is
subjected to kinetic deprotonation with KHMDS followed
by trapping the resultant enolate with phenyl triflimide to
yield the corresponding enol triflate. Acidic desilylation
followed by chromatography provides the diol 22 as a
mixture of C20 and C25 diastereomers. Enhancement of
diastereomeric purity is achieved by preparative HPLC
Br
Br
OH
OH
d
OTBDPS
raffinate >98% ee
8
e, f
OTBDPS
9
extract >98% ee
Br
OTs
g
14
OTBDPS
>99% ee
10
19
Scheme 2 Synthesis of C14–C19 subunit 10. Reagents and condi-
tions: a) Amberlyst 15, H2O, 5 °C; b) 2,3-dibromo-1-propene, Sn,
HBr, H2O, 35 °C, 50% from 5; c) TBDPSCl, imidazole, DMF, 0–15
°C, 88%; d) SMB chromatography, Chiralpak-OD (20 μm), 8 43%
and 9 44%; e) p-nitrobenzoic acid, DEAD, Ph3P, toluene, 0 °C; f)
LiOH, THF–H2O, 20 °C, 83% from 8; g) TsCl, Et3N, DMAP, CH2Cl2,
20 °C, 78%.
Synthesis of the C20–C26 starts with (±)-1,2-epoxyhex-5-
ene (11), which is subjected to Jacobsen Hydrolytic Ki-
netic Resolution8 to provide the desired enantiomer 12 in
>99% ee (Scheme 3). Epoxide opening with diethyl mal-
onate and spontaneous cyclization provides the α-ethoxyl-
carbonyl lactone 13. MgCl2-mediated hydrolysis of the
ethyl ester followed by decarboxylation leads to 14. Lac-
tone enolate alkylation installs the C25 methyl group in
favor of the desired diastereomer 15, in which the C25
configuration is properly regulated relative to the pre-es-
tablished C23 stereogenic center (C25 dr = 6:1). Lactone
opening as the Weinreb amide followed by TBS protec-
Synlett 2013, 24, 327–332
© Georg Thieme Verlag Stuttgart · New York

CLUSTER
Process Development of Halaven®: Synthesis of the C14–C35 Fragment
329
purification. Selective C14 pivaloylation followed by C23 the deoxyacetonide 26 as a crystalline solid. DIBAL-H re-
mesylation completes the C14–C26 subunit 4.
duction and addition of trimethylsilylmethylmagnesium
chloride to lactol 27 provides β-hydroxysilane adduct 28.
Direct treatment with KHMDS induces reductive elimina-
tion of trimethylsilanol to yield the olefin 29. Ether forma-
tion as previously described affords benzyl ether 30. A
Sharpless asymmetric dihydroxylation installs the C34
stereogenic center in a diastereomeric ratio of 3:1 (C34) as
previously reported. Treatment of 31 with benzoyl chlo-
ride and pyridine gives the dibenzoate 32 as oil. C-Glyco-
sidation of 32 with allyltrimethylsilane, as previously
OMe
O
N
TBSO
Me
10
p
q
Me
+
20
OH
OTs
17
OTBDPS
17
20
OMe
N
6:1
O
OTf
Me
TBSO
Me
HO
H
H
Me
Me
OH
O
O
O
25
O
O
r–u
x
30
23
34
Me
O
14
O
OH
29
O
20
R4
O
O
HO
D-glucurono-3,6-lactone (23)
OTBDPS
OH
H
H
24, R4 = α-OH
25, R4 = β-Cl
y
8:1
21
22
H
Me
Me
Me
Me
HO
O
O
O
R5
bb
z
HO
Me
*
TfO
O
Me3Si
O
Me
26
O
O
MsO
H
26, R5 = O
27, R5 = H, OH
28
aa
dd
v, w
O
N
Me
14
O
R6O
NHMs
Me
3:1
Me
Me
Me
O
BnO
OPv
O
cc
ee
R7O
Me
R7O
O
O
O
29, R6 = H
30, R6 = Bn
29
4
34
O
18 (R), 19 (S)
31, R7 = H
32, R7 = Bz
ff
Scheme 4 Synthesis of C14–C26 subunit 4. Reagents and condi-
tions: p) NiCl2, CrCl2, Et3N, 18, THF, 25 °C; q) SiO2, 2-PrOH, 25 °C,
60% based on 10; r) MeMgCl, THF, 0 °C; s) KHMDS, PhN(Tf)2,
THF–toluene, –70 °C; t) 6 M HCl in 2-PrOH, MeOH, 15 °C, 56%
from 21; u) preparative HPLC, 54%; v) pivaloyl chloride, 2,4,6-colli-
dine, DMAP, CH2Cl2, 0 °C, 94%; w) MsCl, Et3N, THF, 0 °C, 99%.
BnO
R8
R9O
SO2Ph
gg
ii
BzO
BzO
BzO
hh
BzO
Me
O
O
33, R8 = β-OH, α-H
34, R8 = O
35, R9 = Bn
36, R9 = H
jj
Me
HO
SO2Ph
R11
O
SO2Ph
The C27–C35 aldehyde 3 represents a new synthetic inter-
mediate required to synthesize Halaven® (1) (Scheme 5).
The synthesis of C34–C35 acetonide analogue of 3 has
been reported by Kishi and co-workers.12 The use of read-
ily available building block D-glucurono-3,6 lactone (23)
along with a series of stereoselective transformations ef-
fectively resolved all stereochemical issues in this frag-
ment. However, a number of process-development
challenges were identified as areas for improvement to-
ward industrial-scale manufacture, which include: (i) re-
placement of the tin hydride in the C33 deoxygenation,
(ii) replacement of the Wittig olefination to avoid triphe-
R10
O
kk
mm
O
O
R10
O
O
O
39, R11 = H
37, R10 = Bz
38, R10 = H
nn
MeO
ll
MeO
40, R11 = Me
SO2Ph
SO2Ph
qq
oo
R12
R12
O
TBSO
O
TBSO
O
O
35
41, R12 = H
42, R12 = TBS
3
27
CHO
pp
Scheme 5 Synthesis of C27–C35 subunit 3. Reagents and conditions:
nylphosphine oxide generation, (iii) replacement of a x) H2SO4, acetone–MeCN, 65 °C; y) SO2Cl2, pyridine, MeCN, 0 °C,
79% from 23; z) Pd/C, H2, pyridine, THF, 25 °C, 79%; aa) DIBAL-
H, toluene, –20 °C, 95%; bb) Mg, TMSCH2Cl, THF, 60 °C, 92%; cc)
15 wt% KHMDS in toluene, THF, 25 °C, quant.; dd) BnBr, KOt-Bu,
THF, –10 °C, quant.; ee) (DHQ)2AQN, OsO4, K3Fe(CN)6, K2CO3, t-
Swern oxidation at C30, (iv) control of a heterogeneous
debenzylation step preceding the reduction of conjugate
sulfone,13 (v) replacement of silver-mediated C31 methyl
ether formation,13 and (vi) removal of chromatography
BuOH, H2O, 0 °C, 98%; ff) BzCl, DMAP, NMM, toluene, 75 °C,
from the latter half of the synthesis. D-Glucurono-3,6-lac-
tone acetonide (24) is prepared by slight modifications of
the literature procedure (Scheme 5). Deoxygenation of the
α-hydroxylactone can be accomplished by a number of
methods, among which the following process was devel-
oped for production. Treatment of 24 with pyridine and
sulfuryl chloride generates the corresponding chloride 25,
which is subjected to catalytic hydrogenation in the pres-
ence of pyridine to undergo smooth reduction to provide
99%; gg) allyltrimethylsilane, TiCl4, Ti(Oi-Pr)4, toluene, 25 °C,
quant.; hh) DMSO, trichloroacetic anhydride, Et3N, toluene, –10
°C, quant.; ii) (EtO)2P(O)CH2SO2Ph, LHMDS, THF–toluene, 0–20
°C, 98%; jj) TMSI, toluene–MeCN, 60 °C, 88%; kk) NaBH(OAc)3,
(n-Bu)4NCl, DME–toluene, 80 °C, quant.; ll) K2CO3, MeOH, 50 °C,
79%; mm) 2-methoxypropene, H2SO4, DME, 40 °C, 96%; nn) NaOt-
Bu, MeI, DME–NMP, 10 °C, 98%; oo) 2 M HCl, MeOH, 25 °C, 99%;
pp) TBSCl, imidazole, DMF, 25 °C, 89%; qq) O3, 2-PrOH, <50 °C;
BHT in 2-PrOH, Lindlar’s catalyst, H2, 15 °C, 89%.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 327–332

330
B. C. Austad et al.
CLUSTER
reported, gives alcohol 33, which is recrystallized to allow
for efficient removal of the C34 epimer. Oxidation of the
C30 secondary hydroxy group had previously been ac-
complished by Swern oxidation. A modified Moffat oxi-
dation (DMSO–trichloroacetic anhydride) proved to be an
effective alternative for Swern oxidation. Horner–Wad-
sworth–Emmons reaction of the ketone 34 gives the un-
saturated sulfone 35. Iodotrimethylsilane was found to be
an effective homogeneous replacement for the previously
employed heterogeneous process (iron chloride molecular
sieves) to smoothly cleave the C31 benzyl ether and pro-
vides the hydroxysulfone 36. Hydroxy-directed conjugate
reduction, as previously reported, stereoselectively af-
fords the β-C30 phenylsulfonylmethyl product 37.
MeO
SO2Ph
O
TBSO
TBSO
27
3
+
4
HO
26
MsO
rr
23
Me
O
OPv
20
43
MeO
SO2Ph
O
TBSO
TBSO
With all five stereogenic centers in place, one of the re-
maining objectives was to identify a crystalline intermedi-
ate to allow for nonchromatographic purification of the
C27–C35 fragment throughout the synthesis. To that end,
the dibenzoate 37 is subjected to base treatment to provide
the crystalline triol 38, which serves as a convenient puri-
fication anchor for the second half of the synthesis. The
vicinal diol is tied up as the acetonide 39 to provide a sta-
ble platform to explore the silver-free C31 etherification.
The use of NaOt-Bu as base turned out to be optimal to
minimize sulfone α-methylation.14 With a view toward
matching protecting groups in the C1–C13 fragment, the
C34–C35 acetonide needed to be replaced with two TBS
ethers. The installation of two TBS ethers had the added
benefit of yielding multiple crystalline intermediates.
Thus, acidic deprotection of 40 followed by silylation pro-
vides 42. Ozonolysis of the terminal olefin followed by re-
ductive workup yields the crystalline aldehyde 3, thus
completing an entirely chromatography-free 20-step pro-
cess to C27–C35 fragment of Halaven®.
ss
O
Me
O
OR13
44 (R13 = Pv)
2 (R13 = H)
tt
Scheme 6 Completion of C14–C35 fragment 2. Reagents and condi-
tions: rr) NiCl2, CrCl2, Et3N, 19, THF, 25 °C; ss) KHMDS, THF–tol-
uene, –20 °C, 65% from 4; tt) DIBAL-H, toluene, –70 °C, 79% from
44.
With the desired two subunits 4 (C14–C26) and 3 (C27–
C35) in hand, the stage is set to apply the key transforma-
tions to more advanced substrates (Scheme 6). Knowl-
edge gained in the study of reaction parameters for the
C19–C20 bond formation could now directly be applied to
the more advanced C26–C27 coupling. In combination
with the S-ligand 19,12 asymmetric Ni/Cr coupling of the
triflate 4 with the aldehyde 3 results in a diastereomeric
ratio of 20:1 at the newly created C27 stereogenic cen-
ter.15
Subsequent cyclic etherification is achieved by careful ti-
tration with KHMDS at low temperature to furnish the
C23–C27 pyran ring.16,17 Although the C23 stereogenic
center is established in configurationally stable form ear-
lier in the sequence, appreciable level of the epi-C23 iso-
mer was formed at this stage. The instability of the C23
mesylate intermediate is presumably associated with
neighboring-group participation from the C20 ether oxy-
gen.18 Finally, reductive cleavage of the C14 pivaloate fol-
lowed by chromatography and crystallization from n-
heptane provides the C14–C35 fragment 2 as a white crys-
talline solid19. The crystal structure of 2 displays an H-
bond between the C14–OH and C20 ether oxygen and
Figure 1 X-ray crystal structure of 2
proximity of the sulfone α-protons to this H-bond ensem-
ble (Figure 1).
In summary, kilogram-scale manufacturing of the
Halaven® C14–C35 fragment 2 using iterative Nozaki–
Hiyama–Kishi reaction–Williamson ether cyclization was
established. The overall strategy benefits from the high
functional-group tolerance of Ni/Cr-mediated coupling,
which allows for convergent assembly of the structurally
complex fragment. A key feature of the overall strategy
was to manage risk for the later stage Nozaki–Hiyama–
Synlett 2013, 24, 327–332
© Georg Thieme Verlag Stuttgart · New York

CLUSTER
Process Development of Halaven®: Synthesis of the C14–C35 Fragment
331
(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,
3044; and references therein.
Kishi–cyclization sequence by carefully studying and
demonstrating the kilogram-scale process on the tetra-
hydrofuran ring system. Thus, the first examples of kilo-
gram-scale Ni/Cr couplings applied to multiple key bond
formations in a single molecule have been achieved.
While the power of the Nozaki–Hiyama–Kishi reaction is
clearly demonstrated in the construction of this complex
fragment, the need for extensive chromatography to con-
trol quality of the C14–C26 fragment synthesis points to
an opportunity for future improvements. By contrast, an
entirely chromatography-free process has been estab-
lished for manufacture of C27–C35 fragment 3. More-
over, the discovery that the entire C14–C35 sulfone
alcohol 2 was crystalline had important implications from
the standpoint of quality control, logistics, and under-
standing of subsequent processing towards Halaven® (1).
Efforts along these lines will be reported in due course.
(4) New syntheses of Halaven® C14–C35 and halichondrin
C14–C38 building blocks: (a) Kim, D.-S.; Dong, C.-G.;
Kim, J. T.; Guo, H.; Huang, J.; Tiseni, P. S.; Kishi, Y. J. Am.
Chem. Soc. 2009, 131. 15636. (b) Dong, C.-G.; Henderson,
J. A.; Kaburagi, Y.; Sasaki, T.; Kim, D.-S.; Kim, J. T.;
Urabe, D.; Guo, H.; Kishi, Y. J. Am. Chem. Soc. 2009, 131,
15642. (c) Shan, M.; Kishi, Y. Org. Lett. 2012, 14, 660.
(d) Liu, L.; Henderson, J. A.; Yamamoto, A.; Brémond, P.;
Kishi, Y. Org. Lett. 2012, 14, 2262.
(5) Austad, B.; Chase, C. E.; Fang, F. G. WO 2005118565,
2005.
(6) Broughton, D. B.; Gerhold, C. G. US 2985589, 1961.
(7) Mitsunobu, O. Synthesis 1981, 1.
Acknowledgment
We thank Dr. Richard J. Staples (Crystallographic Resources, Inc.)
for X-ray structural analyses of 2 and 10.
(8) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N.
Science 1997, 277, 936.
Primary Data for this article are available online at
http://www.thieme-connect.com/ejournals/toc/synlett (X-ray cry-
stallographic files in CIF format for compounds 2 and 10) and can
(9) (a) Wan, Z.-K.; Choi, H.-W.; Kang, F.-A.; Nakajima, K.;
Demeke, D.; Kishi, Y. Org. Lett. 2002, 4, 4431. (b) Choi, H.-
W.; Nakajima, K.; Demeke, D.; Kang, F.-A.; Jun, H.-S.;
Wan, Z.-K.; Kishi, Y. Org. Lett. 2002, 4, 4435. (c) Kurosu,
M.; Lin, M.-H.; Kishi, Y. J. Am. Chem. Soc. 2004, 126,
12248; and references cited therein.
be cited using the following DOI:mPiDrayrmaPitrDayra
1
t
0.4125/pd0039th.mPirayrDaZtahenl1
0
1Chemyrst
(10) (a) N-Tosyltriethylammonium chloride presumably
undergoes reductive elimination to generate the
References and Notes
corresponding sulfinic acid. Formation of the mixed
anhydride by reaction of the sulfinic acid with the sulfonyl
chloride, followed by sulfinylation of 9 results in the
sulfinate. For a plausible mechanism of a similar reaction,
see ref. 10b. The use of alternate base, such as DMAP or 1-
methylimidazole, serves to suppress formation of the C17
sulfinate. (b) Schreiber, S. L. Tetrahedron Lett. 1980, 21,
1027.
(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.
(d) Littlefield, B. A.; Palme, M. H.; Seletsky, B. M.; Towle,
M. J.; Yu, M. J.; Zheng, W. US 6365759, 2002.
(11) Acid-induced cyclization to form the halichondrin C17–C20
tetrahydrofuran ring was first noted by Yu and co-workers at
Eisai. Acidic acetonide cleavage of erythrose derivative A
resulted in clean in situ cyclization to furnish the C14–C21
subunit (Scheme 7). See: Yu, M. J.; Tremblay, L.; Davis, H.
A.; Palme, M. H.; Sexton, K. A.; Zheng, W. Book of
Abstracts, 219th ACS National Meeting, San Francisco, CA,
March 26-30, 2000;American Chemical Society:
Washington DC 2000; Abstract ORGN-739.
(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, FL, 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,
27, 2954. (i) Chiba, H.; Tagami, K. J. Synth. Org. Chem.
Jpn. 2011, 69, 600.
O
O
14
O
HCl
HO
OPiv
20
17
OPiv
21
OMs
Scheme 7
(12) Choi, H.-W.; Demeke, D.; Kang, F. A.; Kishi, Y.; Nakajima,
K.; Nowak, P.; Wan, Z.-K.; Xie, C. Pure Appl. Chem. 2003,
75, 1.
(13) Kishi and co-workers recently reported a synthesis of
Halaven® C27–C35 subunit which avoids C31
benzylation/debenzylation and the use of silver salt for C31
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 327–332

332
B. C. Austad et al.
CLUSTER
methylation. For detail, see: Yang, Y.-R.; Kim, D.-S.; Kishi,
Y. Org. Lett. 2009, 4516.
kg) and MTBE (350 kg) to give 44 (1.2 kg, 1.3 mol, 65%
yield from 3), which was dissolved in n-heptane (4.0 kg) and
used directly in the next stage.
(14) Selection of counterion is critical for chemoselective C31
methylation. The use of KOt-Bu resulted in a several percent
of sulfone α-methylation byproduct.
(15) Experimental procedure for C26–C27 NHK coupling
(3+4→43): (S)-Ligand 19 (2.69 kg, 9.08 mol) was dissolved
in THF (17.6 kg) and the solution was flushed with N2 to
achieve O2 content 200 ppm. CrCl2 (1.11 kg, 9.03 mol) was
added and the mixture was warmed to 28–32 °C. Et3N (0.92
kg, 9.1 mol) was added between 30–35 °C and the
(18) (a) Hori, N.; Nagasawa, K.; Shimizu, T.; Nakata, T.
Tetrahedron Lett. 1999, 40, 2145. (b) Sakamoto, Y.;
Tamegai, K.; Nakata, T. Org Lett. 2002, 4, 675.
(19) (a) Experimental procedure for reductive deprotection
of 44 and crystallization of 2: The solution of 44 in n-
heptane from the previous step was concentrated to dryness
(2.54 kg, 2.72 mol). Toluene (15 kg) was added and the
resulting solution was cooled to –75 to –60 °C. A solution of
DIBAL-H (1 M solution in toluene, 5.24 kg, 6.1 mol) was
added over 30 min keeping the temperature between –75 and
–60 °C. Upon complete conversion, MeOH (0.25 kg, 7.8
mol) was added over 30 min. keeping the temperature
between –75 °C and –60 °C. The reaction mixture was
warmed up to 15–25 °C, and 32% HCl (3.12 kg, 27 mol) in
water (24.2 kg) was added over 1 h between 15 and 25 °C.
MTBE (50.4 kg) was added and the mixture was stirred. The
aqueous layer was extracted with MTBE (30.9 kg). The
combined organic layers were washed sequentially with
water, 9 wt% aqueous NaHCO3 (8.4 kg) and 26% aqueous
NaCl (8.6 kg). The organics were concentrated to dryness
and dissolved in MTBE (1.9 kg) and n-heptane (4.5 kg). The
resulting solution was purified by flash chromatography on
silica gel (Biotage 400 L cartridge × 1) eluting with MTBE
(1225 kg) and n-heptane (250 kg). Fractions containing
product were pooled and concentrated to dryness. The
residue was azeotroped with n-heptane. The residue (2.03
kg, 2.38 mol, 87% yield) was dissolved in n-heptane (13.5
kg) at 20 °C and cooled to –5 to 0 °C. The solution was
seeded with 2 (1 g) and the solution was stirred for 3 h at –5
to 0 °C. The suspension was cooled to –20 to –15 °C and
held for 3 h. The suspension was filtered and the cake was
washed with –20 °C n-heptane (3–5 kg). The solids were
dried to constant weight to provide 2 (1.85 kg, 2.17 mol,
91% crystallization recovery, 79% yield based on 44).
(b) Characterization of 2: mp 58–60 °C. [α]D20 –17.6 (c
1.05, EtOH). IR (neat oil, KBr): 3455, 3073, 2929, 1651,
1363, 1152, 777 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 7.93–7.97 (m, 2 H), 7.66–7.72 (m, 1 H), 7.57–7.64 (m, 2
H), 4.90–4.92 (m, 1 H), 4.85 (s, 1 H), 4.78 (d, J = 3.0 Hz 1
H), 4.65–4.67 (m, 1 H), 4.28 (s, 1 H), 3.92–4.01 (m, 1 H),
3.78–3.89 (m, 3 H), 3.53–3.74 (m, 5 H), 3.44–3.52 (m, 1 H),
3.32–3.44 (m, 5 H), 2.98–3.10 (m, 2H), 2.53–2.67 (m, 2 H),
2.15–2.29 (m, 3 H), 1.98–2.08 (m, 1 H), 1.20–1.92 (m, 11
H), 1.00–1.12 (m, 4 H), 1.02–1.10 (m, 4 H), 0.90 (s, 18 H),
suspension was stirred at 28–32 °C for at least 2.5 h before
cooling to –10 to 5 °C. NiCl2 (0.030 kg, 0.23 mol) was added
followed by a N2-flushed solution of C27–C35 aldehyde 3
(1.169 kg, 1.95 mol) and C14–C26 triflate 4 (1.48 kg, 2.56
mol) in THF. The reaction mixture was warmed up to 23–
25 °C and stirred for 10–16 h. Upon complete conversion,
the reaction mixture was cooled down to –10 to 5 °C and
ethylenediamine (1.54 kg, 26 mol) was added between 0–
5 °C. The reaction mixture was stirred for 1 h and warmed to
20–25 °C. Water (12 kg) was added over 10 min followed by
n-heptane (20 kg) and the mixture was stirred for 30 min.
The aqueous phase was removed and extracted with MTBE
(22 kg). The combined organic layers were washed with a
solution of NaHCO3 (1.5 kg) and NaCl (4 kg) in water (25
kg) and concentrated under reduced pressure at 25 °C. The
solution was azeotroped with THF (10 kg) to achieve water
<500 ppm. The solution was used as is in the next stage.
(16) Cyclization is initiated once residual S-ligand 19 from the
previous step is fully deprotonated. Careful monitoring is
required to avoid decomposition of 44 caused by excess
charge of KHMDS.
(17) Experimental procedure for Williamson ether
cyclization (43→44): The solution of the NHK coupling
product 43 in THF was diluted with THF (140 kg) and
cooled down to –20 to –15 °C. 0.5 M KHMDS in toluene
was added (18.0 kg; 4 equiv) at –15 to –20 °C. The final
charge of KHMDS was determined based on HPLC reaction
conversion (titrated to >99% conversion). Upon complete
conversion, the reaction mixture was transferred to NH4Cl
(8.1 kg) in water (112 kg) at –5 to 0 °C. n-Heptane (71 kg)
was added and the mixture was warmed to 22 °C. The
aqueous layer was removed and extracted with MTBE (77
kg). The organic layers were washed with a solution of NaCl
(24 kg) in water (66 kg), and then concentrated under
reduced pressure at 25–30 °C. n-Heptane (61 kg) was added,
and the resulting slurry of ligand 19 was cooled down to –15
to –10 °C for 1 h. The suspension was filtered and the cake
of 19 was washed with n-heptane (10–20 kg). The filtrate
was concentrated and n-heptane (2 kg) was added to the
residue. Ligand 19 was filtered off and rinsed with n-heptane
(0.5 kg). The combined filtrates were concentrated and the
residue purified by flash chromatography on silica gel
(Biotage 400 L cartridge × 2) eluting with n-heptane (1200
0.09 (s, 3 H), 0.08 (s, 3H), 0.05 (s, 3 H), 0.04 (s, 3 H). 13
C
NMR (100 MHz, CDCl3): δ = 134.0, 129.5, 127.9, 104.9,
85.8, 80.7, 79.5, 78.3, 77.2, 76.9, 75.3, 71.4, 67.8, 62.6, 58.1,
57.5, 43.3, 42.6, 39.0, 37.5, 35.5, 33.1, 32.2, 31.7, 31.3, 29.6,
26.0, 26.0, 17.9, –4.1, –4.7, –5.3. HRMS (ESI): m/z calcd for
C45H79O9SSi2 [M+H]+: 851.4983; found: 851.4983.
Synlett 2013, 24, 327–332
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