Extension of Pd-Mediated One-Pot Ketone Synthesis to Macrocyclization: Application to a New Convergent Synthesis of Eribulin

Article abstract of DOI:10.1021/jacs.6b11663

Recently reported Pd-mediated one-pot ketone synthesis from an unactivated alkyl bromide and a thioester has been extended to a macrocyclic ketone synthesis. In situ generation of alkylzinc halide via single electron transfer (SET), using NbCpCl₄ and CrCl₃, was the key for the success of macrocyclization. A new convergent synthesis of eribulin has been achieved, using (1) catalytic asymmetric Ni/Cr-mediated coupling to form the C19-C20 bond, (2) base-induced cyclization to form the methylenetetrahydrofuran ring, and (3) Pd-mediated one-pot ketone synthesis to form the macrocyclic ketone.

Full text of DOI:10.1021/jacs.6b11663

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Communication
Extension of Pd-Mediated One-Pot Ketone Synthesis to Macro-
cyclization: Application to a New Convergent Synthesis of Eribulin
Jung Hwa Lee, Zhanjie Li, Ayumi Osawa, and Yoshito Kishi
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b11663 • Publication Date (Web): 08 Dec 2016
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Extension of Pd-Mediated One-Pot Ketone Synthesis to Macro-
cyclization: Application to a New Convergent Synthesis of Eribulin
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Jung Hwa Lee, Zhanjie Li,† Ayumi Osawa, and Yoshito Kishi*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138
Supporting Information Placeholder
unexploited synthetic transformation.8 In this communication,
ABSTRACT: Recently reported Pd-mediated one-pot ketone
we report a macroketocyclization between a non-activated
alkylbromide with a thioester and its application to a synthesis
of eribulin.
synthesis from an unactivated alkyl bromide and a thioester
has been extended to a macrocyclic ketone synthesis. In-situ
generation of alkylzinc halide via single electron transfer
(SET), using NbCpCl4 and CrCl3, was the key for the success
of macrocyclization. A new convergent synthesis of eribulin
has been achieved, using: (1) catalytic asymmetric Ni/Cr-
mediated coupling to form the C19-C20 bond, (2) base-
induced cyclization to form the methylenetetrahydrofuran
ring, and (3) Pd-mediated one-pot ketone synthesis to form
the macrocyclic ketone.
Scheme 1. Structure of Halichondrins A-C and Eribulin
Mesylate
Halichondrins are polyether macrolides, originally isolated
from the marine sponge Halichondria okadai by Uemura,
Hirata, and co-workers.1 This class of natural products dis-
plays interesting structure diversities on the oxidation state at
C12 and C13, cf., halichondrin A-C in Scheme 1. We chose
halichondrin B as a synthetic target and began the experi-
mental work, which led us to the first total synthesis of hali-
chondrin B in 1992. On completion of the synthesis,2 we
asked (the late) Dr. Suffness at the National Cancer Institute
(NCI) and Dr. Littlefield at Eisai Research Institute (ERI) to
test antitumor activities of the totally synthetic halichondrins,
along with several synthetic intermediates. The results were
sensational: their experiments clearly demonstrated that the
antitumor activities of halichondrin B resided in the right por-
tion of the molecule, which served as the foundation for suc-
cessful development of the antitumor drug Halaven (eribulin)
Related to this work, we recently developed a Pd-mediated
one-pot ketone synthesis from non-activated alkyl bromides
and thioesters, with an intention of extending it to a macro-
ketocyclization.9 In this connection, we should note that the
efficiency of this method is excellent, even with use of a ~1:1
molar ratio of two coupling partners. However, in order to
translate the one-pot ketone synthesis to a macroketocycliza-
tion, we need to address one additional question, that is how
to eliminate, or suppress, an intermolecular coupling. For the
case of macrolactonization, a high-dilution technique is com-
monly employed to achieve this goal.
by Eisai.3, ,
4 5
Recently, we reported a unified, convergent synthesis of
this class of marine natural products, using: (1) Ni/Cr-
mediated coupling to form the C19-C20 bond, (2) THF SN2
cyclization between C17-Cl and C20-OH, and (3) macrolac-
tonization (Scheme 2).2b, 6 We were interested in extending
this synthetic strategy to the synthesis of eribulin, in which
the first two key synthetic transformations could be achieved
by use of the chemistry developed for the unified synthesis of
halichondrins. The third key synthetic transformation is the
cyclization to form the macrolactone in the halichondrin se-
ries, whereas it is the cyclization to form the macrocyclic
ketone in the eribulin series. Macrolactonization is a well-
precedented synthetic transformation. On the contrary, except
for a few limited cases,7 cyclization to form a macrocyclic
ketone, referred to as macroketocyclization in this paper, is an
Pd-Mediated ketone synthesis is generally considered to in-
volve three distinct steps: (1) oxidative addition of a Pd(0)-
catalyst to a thioester to form RCO-Pd(II)X, (2) transmetalla-
tion from an alkylzinc halide to the resultant Pd(II) species,
and (3) reductive elimination, leading to a ketone and re-
generating the Pd(0)-catalyst. Among these steps, we specu-
lated the second step (transmetallation) to be most critical to
effectively achieve the macroketocyclization under a high-
dilution condition. Upon dilution, an intra-molecular
transmetallation would be favored over the inter-molecular
transmetallation, but would be disfavored over undesired side-
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reactions due to a higher probability of wasting radical and/or
ther (entries 9 – 11). Under these conditions, the desired
organometallic species.10
product was formed, accompanied with only a trace amount
of debrominated product.12
Table 1. Macroketocyclization: Optimizationa
1
2
3
4
5
6
7
Experimentally, it was found that catalytic inter-molecular
ketone synthesis proceeded well even at 25 mM. Among three
conditions, Condition C [(Pd2dba3 (10 mol%), PCy3 (20
mol%), CrCl2 (0.5 equiv), NbCpCl4 (10 mol%), LiI (1 equiv),
TESCl (1.5 equiv), Zn (xs) in DMI)] gave the best conver-
,
sion.11 12
8
9
Scheme 2. Three Key Transformations employed in the
Unified Convergent Synthesis of Halichondrins
10
11
12
13
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17
18
19
20
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Halichondrin-B Series
Me
1
Me
HO
H
H
H
H
OH
1
RO
O
O
c
H
O
O
H
O
O
38
H
O
O
O
H
O
O
RO
O
a
+
O
O
O
O
O
O
Me
I
Me
20
b
Cl
O
CHO
17
3 Key Synthetic Operations:
a. Ni/Cr-mediated coupling
to form the C19-C20 bond
b. THF cyclization between
C17-Cl and C20-OH
19
Right Half of
Halichondrin B
(R = H)
c. Macrolactonization
aConditions: To Pd2dba3 (0.04 mmol) and PCy3 (0.08 mmol) in
DMI (2 mL) were added Zn (0) (xs), CrCl3 (0.2 mmol), and
NbCpCl4 (0.04 mmol) at rt in a glove box. Then, if needed, LiI
(0.4 mmol) and TESCl (0.06 mmol) were added to the reaction
Eribulin Series
Br
1
EtS
MeO
RO
1
MeO
H
O
c
30
O
O
H
O
b
RO
O
H
O
O
H
O
mixture followed by S.M. in THF (2 mL). Roughly estimated
O
35
+
O
O
yield based on a ratio of 5a to side products (debrominated RH
O
O
and dimer) in a crude 1H NMR.12 cPd2dba3 (0.1 equiv), PCy3 (0.2
O
O
O
d
e
Me
Me
Cl
equiv) used. RH was a major product. Reduction of Zn (20-40
equiv) provided slightly lower yield. fTrace amount of RH.
b
O
20
20
17
CHO
a
gLower yield mainly due to dimer. Lower yield mainly due to
h
19
I
3 Key Synthetic Operations:
a. Ni/Cr-mediated coupling
to form the C19-C20 bond
b. THF cyclization between
C17-Cl and C20-OH
1
3 (R = TBS)
debromination, yet dimer-formation was not noticeably reduced.
Abbreviation: DMI = 1,3-dimethyl-2-imidazolidinone; NbCpCl4
2
=
tetrachloro(cyclopeantadienyl)niobium;
Pd2dba3
=
c. Macroketocyclization
tris(dibenzyli-deneacetone)dipalladium(0); PCy3 = tricyclohex-
ylphosphine.
Being encouraged with this observation, we chose substrate
4a to study the feasibility of macroketocyclization (Table 1).
In this study, 4a was subjected to a specified condition, and a
We then carried out the macroketocyclization of 4a under
the condition of entry 10 in a preparative scale (0.2 mmol)
(Scheme 3). In order to achieve the macroketocyclization
effectively, it has become evident that two conditions must be
met: (1) to maintain Pd-, Nb- and Cr-reagents in a stoichio-
metric amount and (2) to maintain the substrate-concentration
above 5 mmol. From a practical point of view, it would be
more attractive if an amount of Pd-, Nb- and Cr-reagents
could be reduced.14 To address this issue, we tested the possi-
bility of recycling the reagents mixture in one-pot. Specifical-
ly, one-half of substrate 4a was added into one-half amount of
the reagent mixture used for the stoichiometric conditions
and, after 7 hours, the remaining half of 4a was added to the
same reaction mixture. Under this setting, the cyclization
completed to give 5a in 58% isolated yield after chromato-
graphic purification. Thus, the macroketocyclization was ef-
fective with use of one-half of the reagents mixture in the
price of time, i.e., 7 vs. 14 hours. Similarly, the macroketocy-
clization was tested by adding 1/4- and 1/8-amounts of 4a into
a 1/4- and 1/8-amount of the reagents mixture, respectively,
every 7 hours, to give 5a in 55%. Overall, under these condi-
tions, the cyclization was achieved with use of ~30% and
~15% of the reagents mixture, in the price of time, i.e., 7
hours vs. 28 and 56 hours.15 This procedure was also found
effective for 16-membered ketone 5b to give 57% yield from
1
yield of 5a was estimated from a H-NMR analysis of crude
product.12 At 50 mM concentration, which was effective for
inter-molecular ketone synthesis (vide ante), 4a gave the
debrominated product and dimer as major products (entry 1).
Considering that the activity of reagents might diminish by
dilution, we then tested the macroketocyclization in the pres-
ence of a stoichiometric amount of metals, thereby demon-
strating that the desired ketone 5a was indeed formed as a
major product at 10 mM concentration with only a small
amount of debrominated product, although the dimer was still
detected in more than 10% (entry 2). Under the stoichiometric
conditions, CrCl2 and NbCpCl4 were essential (entries 4 & 5),
but LiI and TESCl were not (entry 3). Also, reducing the
amount of NbCpCl4 resulted in a lower yield (entry 6). These
observations implicate that SET activation and the early tran-
sition metals (TM) are critical for macroketocyclization. In-
terestingly, this coupling condition corresponds to Condition
C for inter-molecular one-pot ketone synthesis. At present, we
do not have experimental supports to suggest a specific role(s)
of early transition metals. However, we would speculate that
both metals play the same role(s) in both intra- and inter-
molecular couplings.13 Lastly, it was found that Cr(III)Cl3 was
more effective than Cr(II)Cl2 to lower the concentration fur-
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4b. In both cases, dimers and debrominated products were
detected, but only in insignificant amounts (<10%).
A
Br
SO2PhF-
m
HO
1
2
3
4
MeO
TBSO
MeO
RO
MeO
30
30
30
TBSO
RO
O
O
O
35
Scheme 3. Preparative Macroketocyclization
O
O
b
O
c
5
6
Me
Me
Me
OMMTr
20
OP
CHO
7
8
6
: R = Bz, P = H
a
8
1: C20-C35 BB
7: R = TBS, P = MMTr
9
1
MeO
EtS
10
11
12
13
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H
O
H
O
O
O
H
O
O
O
H
O
d
aConditions: To Pd2dba3 (0.1 mmol) and PCy3 (0.2 mmol) in
DMI/THF (10 mL/5 mL) were added CrCl3 (0.5 mmol), Zn (xs),
and NbCpCl4 (0.5 mmol) at rt in a glove box. SM (0.2 mmol) was
added to the reagent mixture in two portions. First, one half (0.1
mmol) of SM in THF (2.5 mL) was added to the reagent mixture
and stirred at rt. After 7 h, the remaining half (0.1 mmol) of SM
O
O
O
O
19
I
I
Cl
Cl
: C1-C19 BB
2
B
b
EtS
O
in THF (2.5 mL) was added and stirred overnight. See Support-
ing Information for details.
1
: C20-C35 BB
2
: C1-C19 BB
Br
(1.2 eq.)
MeO
TBSO
e
H
O
TBSO
O
H
O
Having demonstrated the feasibility of one-pot macroketo-
cyclization, we shifted our focus onto its application to a syn-
thesis of eribulin (Scheme 2). The synthesis of aldehyde 1
was started from the known sulfone 6.16 Protecting group
manipulation, hydroxylation of sulfone 7 to alcohol 8,16 fol-
lowed by tosylation and bromide substitution proceeded une-
ventfully (Scheme 4). However, deprotection of 4-
methoxytrityl (MMTr) ether required an optimization, be-
cause of a concomitant deprotection of the primary TBS
group; 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), which was
known effective for selective deprotection of 4,4-
dimethoxytrityl (DMTr),17 resulted in only partial deprotec-
tion of MMTr at 40 °C. Assuming that a MMTr-cation accep-
tor might enhance the deprotection, we eventually found that
an addition of water (HFIP/H2O = 40/1) allowed us selective-
ly to complete the required deprotection at rt. Then, the result-
ing alcohol was oxidized to aldehyde 1. On the other hand,
thioester 2 was straightforwardly prepared from the known
methyl ester 9 in two-steps:6 hydrolysis by Me3SnOH18 and
coupling with EtSH by DCC.
O
10
O
OH Cl
O
f
O
20
17
Me
O
10
11
g
O
OMe
N
NH
MeO
TBSO
1
O
S
O
30
H
O
Me
Me
Me
TBSO
O
O
H
O
O
35
Cr-Ligand I
O
R2
O
O
R2
R1
Me
O
R2
R2
N
N
Ni
Cl
3
R1
Cl
h
Ni-complex I: R1 = Et; R2 = H
Ni-complex II: R1 = R2 = Me
Eribulin
aReagents and Conditions: a. 1. MMTrCl, i-Pr2NEt, CH2Cl2,
93%. 2. K2CO3, MeOH. 3. TBSCl, imidazole, 88% for 2 steps. b.
n-BuLi, THF, -78 °C; HBSia2, -10 °C to rt, >12 h; H2O2, 3M
NaOH, 0 °C, 81%. c. 1. TsCl, DMAP (cat.), Et3N, CH2Cl2, 88%.
2. NaBr, Bu4NBr (cat.), acetone, reflux, 90%. 3.
(CF3)2CHOH/H2O = 40/1, 3 h, 90%. 4. Dess-Martin Ox., 90%.
d. 1. Me3SnOH, 80 ~ 85 °C, DCE; 0.1 N HCl. 2. EtSH, DCC,
DMAP, 94%. e. CrCl2 (20 mol%), Cr-Ligand I (24 mol%), pro-
ton sponge (24 mol%), Ni-complex II (5 mol%), LiCl, Mn,
ZrCp2Cl2, CH3CN/EtOAc= 3/1 (0.15 M), 86%. f. SrCO3 (xs), t-
BuOH/H2O = 20/1 (4 mM), 95°C, open to air, 87%. g. Pd2dba3 (1
equiv), PCyp3 (2 equiv),20 CrCl3 (5 equiv), NbCpCl4 (1 equiv),
Zn (0) (xs), DMI/THF (1/1, 27 mM), 64%. h. see reference 24.
Abbreviation: DCC = dicyclohexylcarbodiimide; PCyp3 = tricy-
clopentylphosphine.
With both aldehyde 1 and vinyl iodide 2 in hand, we stud-
ied the C19-20 Ni/Cr-mediated coupling. Initially, the condi-
tion optimized for the synthesis of halichondrin A was applied
for coupling of 1 and 2 with Ni-complex I,2b but gave the
desired product 10 only in a modest yield (~40%). We specu-
lated that the low yield might be attributed to a poor selectivi-
ty in activation of the C19-vinyl iodide – note the presence of
an alkyl bromide as well as a thioester, which might potential-
ly be activated with low-valent Ni. With this speculation, we
searched for a Ni-catalyst, which would allow us selectively
to activate the C19-vinyl iodide and consequently improve the
efficiency of Ni/Cr-mediated coupling of 2 with 1. Through
this search, it was found that a combination of Ni-complex II,
prepared from electron-rich 2,3,4,7,8,9-hexamethyl-1,10-
phenanthroline, and Cr-catalyst, prepared from unnat-i-
Pr/Me/OMe sulfonamide I, gave a satisfactorily high coupling
yield (86% yield; dr = ~10:1 (1H-NMR)).19
The next task was to cyclize 10 to 11, which had been done
with AgOTf/Ag2O in the synthesis of halichondrin A. Appar-
enly, this condition was not suitable to the substrate 10, be-
cause of the presence of thioester- and bromide-groups. Thus,
we tested the cyclization conditions reported by Britton (100
°C in water),21 which gave the desired product 11, although
Scheme 4. A New Convergent Synthesis of Eribulin
accompanied with
a
large amount of unidentified
decomposition products. We speculated that the liberated HCl
might have caused the decomposition, and began an extensive
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search for a suitable base, leading us to a satisfactory
condition: SrCO3(s) at 95
C.22 Under the optimized condi-
tions, 11 was isolated in 87% yield and fully characterized.
1
2
3
°
Finally, 11 was subjected to macroketocyclization under the
stoichiometric conditions. It is worthwhile noting that,
contrary to model compounds 4a,b, the major side-reaction in
this series was the reductive quentching of -CH2Br to CH3
rather than the dimerization, thereby suggesting the possibility
of using a higher concentration. We assume that the
difference in behavior might be attributed to the difference in
conformational property of 11, compared to 4; namely, 11
might have adopted a favorable conformation required for the
macroketocyclization. Consistent with this assumption, the
macroketocyclization was achieved, without noticeable di-
merization, even at 27 mM concentration, to furnish ketone 3
in 64% yield (52 mg scale).23 Spectroscopic comparisons (1H-
and 13C-NMR, HR-MS) firmly established that 3 thus ob-
tained was identical with the authentic sample.3,5 Lastly, mac-
rocyclic ketone 3 was converted into eribulin in three steps.24
2 (a) Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.;
4
5
6
7
8
9
Jung, S. H.; Kishi, Y.; Matelich, M. C.; Scola, P. M.; Spero, D. M.;
Yoon, S. K. J. Am. Chem. Soc. 1992, 114, 3162. (b) Ueda, A.;
Yamamoto, A.; Kato, D.; Kishi, Y. J. Am. Chem. Soc. 2014, 136,
5171 and references cited therein.
3 For discovery of eribulin, see: Zheng, W.; Seletsky, B. M.; Pal-
me, 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.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4 For reviews on discovery of eribulin, see: (a) Yu, M. J.; M.; Ki-
shi, Y.; Littlefield, B. A. Anticancer Agents from Natural Products;
CRC Press: 2005, p 241. (b) Yu, M. J.; Zheng, W.; Seletsky, B. M.;
Littlefield, B. A.; Kishi, Y. Annu. Rep. Med. Chem.; John, E. M., Ed.;
Academic Press: 2011, Vol. 46, p 227.
5 For process development of eribulin, see: 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.; Ishi-
zuka, H.; Kajima, T.; Kayano, A.; Komatsu, Y.; Kubota, M.; Kuroda,
H.; Miyazawa, M.; Tagami, K.; Watanabe, T. Synlett 2013, 24, 333
and preceding two papers.
In summary, a method has been developed for macroketo-
cyclization between an alkyl bromide and a thioester under
mild conditions. NbCpCl4 and CrCl3 are key components not
only for in-situ activation of alkyl bromide to alkylzinc halide
via a SET process but also for acceleration of Pd-mediated
coupling. Notably, this unique macroketocyclization does not
require any special template or functional group to be re-
moved after cyclization. Overall, the newly-developed
macroketocyclization has allowed us to synthesize eribulin
with the same synthetic strategy as the one used in the hali-
chondrins.
6 (a) ref. 2b. (b) Li, J.; Yan, W.; Kishi, Y. J. Am. Chem. Soc. 2015,
137, 6226 and the preceding paper.
7 For selected examples for macroketocyclization, see: (a) Nishi-
kawa, K.; Yoshimi, Y.; Maeda, K.; Morita, T.; Takahashi, I.; Itou, T.;
Inagaki, S.; Hatanaka, M. J. Org. Chem. 2013, 78, 582. (b) Tsuna,
K.; Noguchi, N.; Nakada, M. Tetrahedron Lett. 2011, 52, 7202. (c)
Porter, N. A.; Chang, V. H. T.; Magnin, D. R.; Wright, B. T. J. Am.
Chem. Soc. 1988, 110, 3554. (d) Kong, K.; Romo, D.; Lee, C. An-
gew. Chem., Int. Ed. 2009, 48, 7402. (e) Boger, D. L.; Mathvink, R.
J. J. Am. Chem. Soc. 1990, 112, 4008. (f) Kende, A. S.; Liu, K.; Kal-
dor, I.; Dorey, G.; Koch, K. J. Am. Chem. Soc. 1995, 117, 8258. (g)
Wu, J.; Panek, J. S. J. Org. Chem. 2011, 76, 9900. (h) Lowe, J. T.;
Panek, J. S. Org. Lett. 2008, 10, 3813.
ASSOCIATED CONTENT
Supporting Information
Additional data for Table 1, experimental procedures, characteri-
zation data, and copies of spectra. The Supporting Information is
available free of charge on the ACS Publications website.
8
In the previous synthesis, the macrocyclization was achieved by
an intramolecular Ni/Cr-mediated coupling at C13-C14, before con-
struction of the C8-C14 polycycle: see, (a) ref. 3. (b) Namba, K.;
Kishi, Y. J. Am. Chem. Soc. 2005, 127, 15382, (c) ref. 5. (d) Inanaga,
K.; Fukuyama, T.; Kubota, M.; Komatsu, Y.; Chiba, H.; Kayano, A.;
Tagami, K. Org. Lett. 2015, 17, 3158.
AUTHOR INFORMATION
Corresponding Author
9 Lee, J. H.; Kishi, Y. J. Am. Chem. Soc. 2016, 138, 7178.
10 We hoped to suppress undesired side-reactions by either slow
activation of RX and/or acceleration of transmetallation to avoid
accumulation of generated alkylzinc halides.
*kishi@chemistry.harvard.edu
Present Addresses
†The Dow Chemical Company, 2200 W. Salzburg Road,
Midland, MI 48686
11 The conversion was 58%, 71%, and 80% under Conditions A, B,
and C, respectively.
12 See Supporting Information for details.
Notes
13 For the case of intermolecular ketone coupling, we have sug-
gested a possibility that the early transition metals might shift equi-
librium from stable RZnX to higher-order orgnozincates and/or might
break Pd-Zn to restore Pd reactivity, respectively.
No competing financial interests have been declared.
ACKNOWLEDGMENT
14 There was one additional benefit in reducing an amount of the
reagent, i.e., isolation of the product was much easier with a lesser
amount of the reagent.
Financial support from the Eisai USA Foundation is gratefully
acknowledged.
15 These experimental data should allow us to identify a proper set-
ting for use of a syringe-pump.
REFERENCES
16 Liu, L.; Henderson, J. A.; Yamamoto, A.; Brémond, P.; Kishi,
Y. Org. Lett. 2012, 14, 2262.
17 Leonard, N. J.; Neelima Tetrahedron Lett. 1995, 36, 7833.
18 Nicolaou, K. C.; Estrada, A. A.; Zak, M.; Lee, S. H.; Safina, B.
S. Angew. Chem., Int. Ed. 2005, 44, 1378.
19 With the Cr-catalyst derived from unnat-i-Pr/PhCl2/OCy(Me)2
sulfonamide, the dr observed for this Ni/Cr-mediated coupling was
around 20:1 in the halichondrin series: see ref. 2b and Guo, H.; Dong,
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.
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C.-G.; Kim, D.-S.; Urabe, D.; Wang, J.; Kim, J. T.; Liu, X.; Sasaki,
T.; Kishi, Y. J. Am. Chem. Soc. 2009, 131, 15387.
20 PCyp3 is better than PCy3 for this type of substrates, see ref. 9
21 Kang, B.; Chang, S.; Decker, S.; Britton, R. Org. Lett. 2010, 12,
1716.
23 Reductive debromination was observed at 18 mM concentration,
but not at 25 mM concentration. On the other hand, dimerization was
not observed even at 27 mM concentration.
24 See (a) ref. 3. (b) ref. 5. (c) Kaburagi, Y.; Kishi, Y. Tetrahedron
Lett. 2007, 48, 8967.
22
Interestingly, soluble amine bases gave complicated side
reactions such as halide exchange.
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EtS
O
Br
MeO
MeO
TBSO
H
O
H
O
O
H
O
TBSO
O
H
O
O
O
O
10
O
O
O
O
Pd2dba3, PCy3, NbCpCl4,
CrCl2, Zn, DMI/THF (27 mM)
64% isolated yield
O
O
Me
Me
O
O
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