Unified synthesis of C1-C19 building blocks of halichondrins via selective activation/coupling of polyhalogenated nucleophiles in (Ni)/Cr-Mediated reactions

Article abstract of DOI:10.1021/jacs.5b03499

A unified synthesis of the C1-C19 building blocks 8-10 of halichondrins A-C was developed from the common synthetic intermediates 26a,b. Acetylenic ketones 26a,b were in turn synthesized via selective activation/coupling of polyhalogenated nucleophiles 23

Full text of DOI:10.1021/jacs.5b03499

Article
pubs.acs.org/JACS
Unified Synthesis of C1−C19 Building Blocks of Halichondrins via
Selective Activation/Coupling of Polyhalogenated Nucleophiles in
(Ni)/Cr-Mediated Reactions
Jingwei Li, Wuming Yan, and Yoshito Kishi*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States
S
* Supporting Information
ABSTRACT: A unified synthesis of the C1−C19 building blocks 8−10
of halichondrins A−C was developed from the common synthetic
intermediates 26a,b. Acetylenic ketones 26a,b were in turn synthesized
via selective activation/coupling of polyhalogenated nucleophiles 23a,b
with aldehyde 11 in a (Ni)/Cr-mediated coupling reaction. Compared
with Ni/Cr-mediated couplings of vinyl iodides and aldehydes, this
(Ni)/Cr-mediated coupling exhibited two unique features. First, the
coupling was found to proceed with a trace amount or no added Ni-
catalyst. Second, TES-Cl, a dissociating agent to regenerate the Cr-
catalyst, was found to give a better yield than Zr(Cp)2Cl2. An
adjustment of the oxidation state was required to transform acetylenic
ketones 26a,b into C1−C19 building blocks 8 and 9 of halichondrins A
and B, respectively. In the halichondrin B series, a hydroxyl-directed
(Me)4NBH(OAc)3 reduction of E- and Z-β-alkoxy-enones 30 was found
cleanly to achieve the required transformation, whereas a DMDO oxidation of E-vinylogous ester 27 allowed to introduce the
C13 hydroxyl group with a high stereoselectivity in the halichondrin A series. In the halichondrin C series, Hf(OTf)4 was used to
convert the double oxy-Michael product 28 into C1−C19 building block 10.
been engaged with the synthetic studies in this field since the
late 1980s, aiming at total syntheses, coupled with development
of a new synthetic strategy and discovery of new synthetic
methods, with particular focus on the Cr-mediated coupling
reactions.5−8
INTRODUCTION
■
Halichondrins are polyether macrolides, originally isolated from
the marine sponge Halichondria okadai by Uemura, Hirata, and
co-workers (Scheme 1).1 Several additional members, including
Scheme 1. Structure of Halichondrins A−C
We recently reported a total synthesis of halichondrin A (1),
a phantom member in this class of natural products.5c Scheme 2
schematically illustrates the high convergence incorporated in
the synthesis. There are two appealing aspects recognized in the
synthesis. First, because of its high degree of convergence, one
can expect a high overall efficiency in synthesis. Interestingly,
the key two couplings have been achieved efficiently with Ni/
Cr-mediated coupling reactions. Second, with a replacement of
8 with 9 and 10, this convergent strategy can be extended to a
synthesis of halichondrins B and C, respectively. Thus, we are
interested in establishing a unified synthesis of C1−C19
building blocks 8, 9, and 10. In this paper, we report a solution
to achieve this goal, with the use of a selective activation/
coupling of polyhalogenated nucleophile 23a,b in the (Ni)/Cr-
mediated coupling reaction as the key C−C bond-forming step.
halistatin 1, were isolated from various marine sponges.2 This
class of natural products displays interesting structure
diversities at two sites, one being the oxidation state at C10,
C12, and C13 of the C8−C14 polycycle and the other being
the length of the carbon backbone. Thus, the halichondrin class
of natural products is subgrouped into halichondrins A−C
series or the norhalichondrin/halichondrin/homohalichondrin
series. Due to their intriguing structural architecture and
extraordinary in vitro and in vivo antitumor activity, the
halichondrin class of marine natural products has received
much attention from the scientific communities.3,4 We have
Received: April 3, 2015
© XXXX American Chemical Society
A
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Scheme 2. Summary of the Synthesis of the Right Half of
Halichondrin A and Requisite C1−C19 Building Blocks
(BBs) of Halichondrins A−C
Scheme 3. Proposed One-Step Synthesis of Acetylenic
Ketones 15a,b via Selective Activation/Coupling of Halo-
Acetylenic Ketones 16a,b
Scheme 4. Substrates, Sulfonamide, and Ni-Catalyst Used for
a
the Model Study
a
The coupling was tested with the molar ratio of 18/19:20 = 1.7:1;
RESULTS AND DISCUSSION
the coupling product was isolated by silica gel chromatography and
yields are based on aldehyde 20.
■
Synthetic Plan. We noticed the possibility that all of C1−
C19 building blocks 8−10 could be synthesized from acetylenic
ketone 15a,b, by adjusting its oxidation state (Scheme 3).
Indeed, C1−C19 building block 8 of halichondrin A was
synthesized with this strategy.5c
Model Study on Coupling Efficiency. In order to assess
the coupling efficiency, we chose six halo-acetylenes 18a−c and
19a−c and aldehyde 20 (Scheme 4). In this study, we first
compared the coupling efficiency of halo-acetylenic ketones
18a−c over halo-acetylenic ketone ketals 19a−c,12 under the
coupling conditions: 10 mol % Cr-catalyst, prepared from (S)-
sulfonamide 21, Ni-catalyst 22 (0.05 mol %), or no added Ni-
catalyst, Zr(Cp)2Cl2 (1.5 equiv), Mn (2 equiv), and LiCl (2
equiv) in MeCN ([C] 0.4M) at room temperature.13,14 This
experiment demonstrated: (1) halo-acetylenic ketones 18a−c
gave the desired product in only modest yields, with the order
of coupling efficiency being 18b (49%) > 18c (20%) > 18a
(11%); (2) halo-acetylenic ketone ketals 19a,b gave the desired
product in good yields, with the order of coupling efficiency
being 19b (93%) > 19a (82%) ≫ 19c (8%); (3) no significant
difference was detected between 0.05 mol % and no added Ni-
catalyst. In addition, a brief study on solvents and concentration
revealed: (1) the solvent choice being EtCN > MeCN > DME
In the halichondrin A synthesis, we synthesized acetylenic
ketone 15a via two (Ni)/Cr-mediated couplings. In light of the
successful selective activation/coupling of polyhalogenated
nucleophile 17 in a Ni/Cr-mediated coupling, we recognized
a possibility of synthesizing 15a,b in one step, cf., 11 + 16a,b →
15a,b. In the halichondrin B series, a selective activation/
coupling of the trans-β-bromoenone was realized with use of a
trace amount of a polyether-type Ni-catalyst.9 For the present
case, because activation of halo-acetylenes is known to require
only a trace amount of Ni-catalyst or even no added Ni-catalyst,
a selective activation of the halo-acetylene over the vinyl iodide
or bromide and saturated chloride present in 16a,b should not
present an issue.10,11 Thus, the remaining question was the
coupling efficiency of the nucleophile generated from 16a,b
with an aldehyde, and we first addressed this issue with model
compounds listed in Scheme 4.
B
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> THF, but not DMF, and (2) the optimum concentration
being a range of 0.4−0.8 M.
alcohol complex and regenerate a Cr-catalyst. TMS-Cl or TES-
Cl and Zr(Cp)2Cl2 are known to be effective dissociating
agents.19 Generally, the overall coupling rate with Zr(Cp)2Cl2 is
significantly faster than that with TMS-Cl or TES-Cl, at least
for the Ni/Cr-mediated coupling of vinyl iodides with
aldehydes. In addition, it is noteworthy that, when the TMS-
Cl procedure is applied for a readily enolizable aldehyde, a
significant amount of aldehyde is recovered, due to a silyl enol
ether formation in situ.
Coupling in the Real Series. With the results gained in
the model study, we began the study on the proposed coupling.
The requisite nucleophiles 23a,b were readily prepared from
the previously reported, optically pure aldehydes 14a,b
(Scheme 5).15,16 With respect to the electrophile, several
possible C8,C9-protecting groups were screened, thereby
showing bis-TBS aldehyde 11 as the best option.17
For the present case, it was found that the coupling rate with
TES-Cl was slower than that with Zr(Cp)2Cl2, yet the coupling
yield with TES-Cl was noticeably better than that with
Zr(Cp)2Cl2, i.e., 85% with TES-Cl vs 70% with Zr(Cp)2Cl2.20
Although its mechanistic reason was not clear, the TES-Cl
condition made it possible to achieve the proposed coupling
with the synthetically useful efficiency.
Scheme 5. Synthesis of Nucleophiles 23a,b
As noted before, Cr-mediated coupling of a halo-acetylene
with an aldehyde is known to proceed with only a trace amount
of Ni-catalyst or even no added Ni-catalyst.11 For this reason,
we studied the coupling of 11 + 23a → 26a “with” and
“without” added Ni-catalyst, thereby showing the coupling
efficiency to be comparable (Scheme 6). There is no definite
For the simplicity of presentation, we will discuss first the
coupling experiments in the nucleophile 23a series, although
the studies were carried out on both 23a,b simultaneously.
In the proposed coupling, one chiral center is introduced at
the C11 position. Based on the previous work, we were aware
that a nucleophilic addition to an aldehyde such as 11
predominantly, often exclusively, gives the desired C11β
alcohol.7e,11a With this background, we subjected 11 and 23a
to the coupling reaction under the condition used in the model
study, to furnish the desired product 26a in 55% yield, with a
10:1 stereoselectivity. The structure of 26a was established via
correlation with the authentic sample obtained in the previous
route.5c As anticipated, we did not detect a product derived
through activation of the vinyl bromide or saturated chloride
present in 23a.
a
Scheme 6. (Ni)/Cr-Mediated Couplings
In order to improve the observed stereoselectivity, we
adopted the toolbox approach and screened a representative set
of sulfonamides (Table 1).7e,18 This screening showed that (1)
Table 1. Sufonamides Tested for a Ligand Search with a
Toolbox Approach
a
Coupling conditions: Cr-catalyst prepared from (R)-21: 20 mol %;
Ni-catalyst (0.05 mol %) or no added Ni-catalyst; TES-Cl (2.5 equiv);
LiCl (4 equiv); Mn (4 equiv); EtCN ([C] 0.4 M); RT. The coupling
was done with the molar ratio of 18/19:20 = 1.7:1; the coupling
product was isolated by silica gel chromatography and yields are based
on aldehyde 11.
experimental evidence to conclude whether this coupling
involves activation of bromoacetylene with Ni-catalyst, followed
by Cr-mediated coupling, or activation/coupling with only a
Cr-catalyst. In this connection, it is worthwhile mentioning that
the homodimer of bromoacetylene was isolated in ca. 0.3%
yield (based on 23a) in the coupling without added Ni-catalyst.
Formation of the dimer with no added Ni-catalyst may support
that Ni-catalyst, or some unknown metal, activated halo-
acetylene 23a prior to the C−C bond formation.21 However,
reflecting this ambiguity, we refer to the coupling as (Ni)/Cr-
mediated reaction in this paper.
as previously observed, the stereochemistry outcome was
dictated by the substrate structure rather than the chirality
present in the Cr-catalyst and (2) for this coupling,
sulfonamides in the (R)-series gave a better stereoselectivity
than the corresponding sulfonamides in the (S)-series. Among
the tested ligands, we chose sulfonamide (R)-21 and Ni-catalyst
22 for the following study.
Naturally, we were anxious to improve the coupling
efficiency. Particularly, we wondered how we could enhance
the efficiency of Cr-catalytic cycle. In a catalytic Cr-mediated
carbonyl addition, it is required to dissociate a Cr/product
As mentioned, we carried out the coupling studies with both
23a,b simultaneously and obtained the virtually identical results
in the both series, although a small reduction in yield was
noticed in the 23b series.
C
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Synthesis of C1−C19 Building Blocks of Halichondrins
A−C from the Common Synthetic Intermediate 26.
Synthesis of C1−C19 Building Block of Halichondrin A. In the
halichondrin A synthesis, we already established the trans-
formation of 26a into C1−C19 building block 8 (Scheme 7).
Scheme 8. Synthesis of C1−C19 Building Blocks (BBs) in
the Halichondrin B Series
Scheme 7. Synthesis of C1−C19 Building Blocks (BBs) in
the Halichondrin A and C Series
the furan.9 Thus, although it was a minor product, Z-enone was
wasted. Second, this reduction gave the desired E-enone 30 as
the major product, but the isolated yield varied from 55% up to
80%. Apparently, the problem was over-reduction. Despite
extensive efforts, we were unable to identify a condition to
achieve the reduction with a high reproducibility and high yield.
Under this circumstance, we decided to focus on reduction of
E-enone E-30. Once again, we attempted several known
methods, including various CuH reagents, H2/Crabtree
catalyst, and Na2S2O4, but with only limited success.24
Ultimately, we found that (Me)4NBH(OAc)3 reduced the
vinylogous ester cleanly to give 31 in 80% yield as a 5:1 mixture
of 12α:12β diastereomers.
(Me)4NBH(OAc)3 is well recognized as an excellent hydride
donor in a so-called hydroxyl-directing setting.25 However, a
literature search revealed that no example was reported for
reduction of a vinylogous ester with (Me)4NBH(OAc)3.
Nonetheless, we would assume that, like the case of β-hydroxyl
ketones,26 the reduction was facilitated via a ligand exchange of
(Me)4NBH(OAc)3 with the C11-hydroxyl group, followed by
an intramolecular hydride delivery in a conjugated fashion, to
yield the 12α-alcohol as the major product. Consistent with this
suggestion, we found that the substrate with the C11-OH
masked with a TBS was inert to the reduction.
The key reactions in this transformation included: (1) a
selective TBS-deprotection to form E-enone 27 and (2) a
highly stereoselective DMDO-oxidation to introduce the C13
hydroxyl group. It should be noted that C1−C19 building block
8 bears the C19 vinyl bromide, because the corresponding vinyl
iodide was not compatible with the DMDO oxidation.5c,22
Synthesis of C1−C19 Building Block of Halichondrin C. In
the halichondrin C synthesis, we reported a synthetic route to
construct the polycyclic ring system from an acetylenic
ketone.5b Although the transformation was carried out on the
macrolactone framework, we felt confident in extending this
synthetic method to the present acyclic system; indeed, we had
no unexpected difficulty in the transformation of 26b to 10 in
60% overall yield (Scheme 7). The key reactions in this
transformation included: (1) double oxy-Michael addition of
C8,C9-hydroxyl groups to the acetylenic ketone to form ketal
28 and (2) Hf(OTf)4-induced conversion of the double oxy-
Michael product 28 to polycycle 10 in allyl alcohol. The
structure 10 was fully supported by the spectroscopic data
1
(HR-MS, H and 13C NMR).
Synthesis of C1−C19 Building Block of Halichondrin B. In
order to synthesize C1−C19 building block 9 in the
halichondrin B series from the common synthetic intermediate,
we obviously needed an acetylene-to-olefin reduction and
tested first the reactivity of 26b and its C11-OTBS derivative
against CuH, HNNH, and CrCl2 (Scheme 8), thereby
indicating that the C11-OTBS substrate exhibited a very poor
reactivity. Based on this observation, we used 26b for a search
of a satisfactory reducing reagent/condition. Among reagents
tested, (BDP)CuH, a Stryker CuH modified by Lipshutz, gave a
most promising result (Scheme 8).23 Yet, we had two issues to
address. First, this reduction gave a mixture of E- and Z-enones.
As discussed in the preceding companion paper (DOI:
10.1021/jacs.5b03498),9 Z-enone was found to form readily
We anticipated that the intramolecular hydride delivery
should yield predominantly 12α-stereoisomer, which is the
undesired stereoisomer. However, we were aware that it should
not be an issue, because the C12-configuration is prone to
isomerization via a retro oxy-Michael/oxy-Michael process;
indeed, the ratio of 12α:12β stereoisomers varied from one
experiment to other, likely due to a different degree of
isomerization during workup.
As expected from the above consideration, we observed that
(Me)4NBH(OAc)3 reduction of the corresponding Z-enone Z-
30 gave 31 as a mixture of 12α:12β stereoisomers. Thus, for the
D
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N. A.; Rutzler, K. C. J. Med. Chem. 1991, 34, 3339. (b) Pettit, G. R.;
̈
preparative purpose, it was not necessary to separate E- and Z-
enones 30.
Tan, R.; Gao, F.; Williams, M. D.; Doubek, D. L.; Boyd, M. R.;
Schmidt, J. M.; Chapuis, J.-C.; Hamel, E.; Bai, R.; Hooper, J. N. A.;
Tackett, L. P. J. Org. Chem. 1993, 58, 2538. (c) Litaudon, M.; Hart, J.
B.; Blunt, J. W.; Lake, R. J.; Munro, M. H. G. Tetrahedron Lett. 1994,
35, 9435. (d) Litaudon, M.; Hickford, S. J. H.; Lill, R. E.; Lake, R. J.;
Blunt, J. W.; Munro, M. H. G. J. Org. Chem. 1997, 62, 1868.
(e) Hickford, S. J. H.; Blunt, J. W.; Munro, M. H. G. Bioorg. Med.
Chem. 2009, 17, 2199.
(3) For example, see: (a) Hart, J. B.; Lill, R. E.; Hickford, S. J. H.;
Blunt, J. W.; Munro, M. H. G. Drugs from the Sea; Fusetani, N., Ed.;
Karger: Basel, Switzerland, 2000, p 134. (b) Jackson, K. L.; Henderson,
J. A.; Phillips, A. J. Chem. Rev. 2009, 109, 3044.
(4) For the development of anticancer drug Eribulin based on the
right-half structure of halichondrin B, see: (a) 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. (b) Yu, M. J.; Zheng, W.; Seletsky, B. M.; Littlefield, B.
A.; Kishi, Y. Annu. Rep. Med. Chem. 2011, 46, 227.
(5) For the synthetic work on the halichondrins from this group, see:
(a) Halichondrin B: 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. (b) Halichondrin C:
On TBAF treatment, 31 furnished 32 as a ∼1:1 mixture of
12α:12β diastereomers. With an ion-exchange resin-based
device,27 this mixture was transformed cleanly to C1−C19
building block 9 of halichondrin B without isolation/
separation/equilibration of intermediates. On comparison of
spectroscopic data (1H and 13C NMR, MS, TLC), 9 thus
obtained was found to be superimposable on the authentic
sample.9
CONCLUSION
■
A unified synthesis of the C1−C19 building blocks 8−10 of
halichondrins A−C was developed from the common synthetic
intermediates 26a,b. Acetylenic ketones 26a,b were in turn
synthesized via selective activation/coupling of polyhalogenated
nucleophiles 23a,b with aldehyde 11 in a (Ni)/Cr-mediated
coupling reaction. Compared with Ni/Cr-mediated couplings
of vinyl iodides and aldehydes, this (Ni)/Cr-mediated coupling
exhibited two unique features. First, the coupling was found to
proceed with a trace amount or no added Ni-catalyst. Second,
TES-Cl, a dissociating agent to regenerate the Cr-catalyst, was
found to give a better yield than Zr(Cp)2Cl2.
́
Yamamoto, A.; Ueda, A.; Bremond, P.; Tiseni, P. S.; Kishi, Y. J. Am.
Chem. Soc. 2012, 134, 893. (c) Halichondrin A: Ueda, A.; Yamamoto,
A.; Kato, D.; Kishi, Y. J. Am. Chem. Soc. 2014, 136, 5171 and references
cited therein.
An adjustment of the oxidation state was required to
transform acetylenic ketones 26a,b into C1−C19 building
blocks 8 and 9 of halichondrins A and B, respectively. In the
halichondrin B series, a hydroxyl-directed (Me)4NBH(OAc)3
reduction of E- and Z-β-alkoxy-enones 30 was found cleanly to
achieve the required transformation, whereas a DMDO
oxidation of E-vinylogous ester 27 allowed to introduce the
C13 hydroxyl group with a high stereoselectivity in the
halichondrin A series. In the halichondrin C series, Hf(OTf)4
was used to convert double oxy-Michael product 28 into C1−
C19 building block 10.
(6) For synthetic efforts on halichondrin Bs by Salomon, Burke,
Yonemitsu, Phillips, and Yadav see: (a) Henderson, J. A.; Jackson, K.
L.; Phillips, A. J. Org. Lett. 2007, 9, 5299. Jackson, K. L.; Henderson, J.
A.; Motoyoshi, H.; Phillips, A. J. Angew. Chem., Int. Ed. 2009, 48, 2346
and the references cited therein. (b) Burke, S. D.; Buchanan, J. L.;
Rovin, J. D. Tetrahedron Lett. 1991, 32, 3961. Lambert, W. T.; Hanson,
G. H.; Benayoud, F.; Burke, S. D. J. Org. Chem. 2005, 70, 9382 and the
references cited therein. (c) Kim, S.; Salomon, R. G. Tetrahedron Lett.
1989, 30, 6279. Cooper, A. J.; Pan, W.; Salomon, R. G. Tetrahedron
Lett. 1993, 34, 8193 and the references cited therein. (d) Horita, K.;
Hachiya, S.; Nagasawa, M.; Hikota, M.; Yonemitsu, O. Synlett 1994,
38. Horita, K.; Nishibe, S.; Yonemitsu, O. Phytochem. Phytopharm.
2000, 386 and the references cited therein. (e) Yadav, J. S.; Reddy, C.
N.; Sabitha, G. Tetrahedron Lett. 2012, 53, 2504.
Lastly, we note that an application of the synthetic method
developed in the halichondrin A synthesis5c should allow us to
transform C1−C19 building blocks 8−10 into halichondrins
A−C, respectively.
(7) For the work on the Cr-mediated coupling reactions from this
group, see: (a) Jin, H.; Uenishi, J.-I.; Christ, W. J.; Kishi, Y. J. Am.
Chem. Soc. 1986, 108, 5644. (b) Wan, Z.-K.; Choi, H.-w.; Kang, F.-A.;
Nakajima, K.; Demeke, D.; Kishi, Y. Org. Lett. 2002, 4, 4431. (c) Choi,
H.-w.; Nakajima, K.; Demeke, D.; Kang, F.-A.; Jun, H.-S.; Wan, Z.-K.;
Kishi, Y. Org. Lett. 2002, 4, 4435. (d) Namba, K.; Kishi, Y. Org. Lett.
2004, 6, 5031. (e) Guo, H.; Dong, 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. (f) Liu, X.; Henderson, J. A.; Sasaki, T.; Kishi, Y. J. Am. Chem.
Soc. 2009, 131, 16678. (g) Liu, X.; Li, X.; Chen, Y.; Hu, Y.; Kishi, Y. J.
Am. Chem. Soc. 2012, 134, 6136 and references cited therein.
(8) For reviews on Cr-mediated carbon-carbon bond-forming
reactions, see: (a) Saccomano, N. A. in Comprehensive Organic
Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, characterization data, and copies of
spectra data. The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
jacs.5b03499.
■
S
AUTHOR INFORMATION
Corresponding Author
*kishi@chemistry.harvard.edu
Notes
■
The authors declare no competing financial interest.
1, p 173. (b) Furstner, A. Chem. Rev. 1999, 99, 991. (c) Wessjohann, L.
̈
A.; Scheid, G. Synthesis 1999, 1. (d) Takai, K.; Nozaki, H. Proc. Japan
Acad. Ser. B 2000, 76, 123. (e) Takai, K. Organic Reactions 2004, 64,
253. (f) Hargaden, G. C.; Guiry, P. J. Adv. Synth. Catal. 2007, 349,
2407.
ACKNOWLEDGMENTS
Financial support from the Eisai USA Foundation is gratefully
acknowledged.
■
(9) Yan, W.; Li, Z.; Kishi, Y. J. Am. Chem. Soc., 2015; DOI: 10.1021/
jacs.5b03498 (preceding paper).
REFERENCES
■
(10) Cr-mediated couplings of halo-acetylenes with aldehydes were
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5585. It should be noted, however, that the work had been done
before a special role of Ni-salt was recognized in the Cr-mediated
coupling reactions.
(1) (a) Uemura, D.; Takahashi, K.; Yamamoto, T.; Katayama, C.;
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E
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(12) Dimethyl ketal, ethylene glycol ketal, and 2,2-dimethyl-1,3-
propylene glycol ketal were also tested as a ketone protecting group of
19a−c.
(13) The standard coupling conditions used in the toolbox approach;
see ref 7e.
(14) Three Ni-complexes were screened for this coupling, thereby
showing that the order of effectiveness was 22 ∼ i > ii. Based on this
observation, 22 was chosen for this study.
(15) Liu, S.; Kim, J. T.; Dong, C.-G.; Kishi, Y. Org. Lett. 2009, 11,
4520.
(16) (Ni)/Cr-mediated coupling of ICCTMS with 14 gave the
desired product. However, considering its cost relative to TMS
acetylene, we chose the synthesis shown in Scheme 5. We also
attempted the coupling of TMS-CC-I with 14, induced by
tetrabutylammonium difluorotriphenylsilicate, but did not give a
promising result.
(17) C8,C9-Protecting groups tested included: cyclohexylidene ketal,
anisylidene acetal, methylene acetal, bis-MOM ether, diacetate,
dibenzoate, carbonate, and others.
(18) We originally used sulfonamide iii for ligand search in the
toolbox approach (see ref 7e). In order to expand the space of ligand
search, we have recently added sulfonamides iv and v to this approach;
see the structure highlighted by a green box. Sulfonamides (S)- and
(R)-24 and 25 were sulfonamides used in that study.
(19) (a) Furstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 2533; J.
̈
Am. Chem. Soc. 1996, 118, 12349. (b) See ref 7d.
(20) The coupling product at this stage was a mixture of C11-OTES
(major) and C11-OH (minor). On the following acid treatment, both
products gave 26.
(21) There is a paper reporting homo-dimerization of halo-acetylenes
without metal; see: Chen, Z.; Jiang, H.; Wang, A.; Yang, S. J. Org.
Chem. 2010, 75, 6700. For transition-metal-free homo-dimerization,
see: Krasovskiy, A.; Tishkov, A.; del Amo, V.; Mayr, H.; Knochel, P.
Angew. Chem., Int. Ed. 2006, 45, 5010.
(22) For the next Ni/Cr-mediated coupling to form the C19−C20
bond, the vinyl iodide at the C19 is a better nucleophile than the
corresponding vinyl bromide.
(23) (a) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am.
Chem. Soc. 1988, 110, 291. Mahoney, W. S.; Stryker, J. M. J. Am. Chem.
̌
̌ ́
Soc. 1989, 111, 8818. (b) Baker, B. A.; Boskovic, Z. V.; Lipshutz, B. H.
Org. Lett. 2008, 10, 289. Deutsch, C.; Krause, N.; Lipshutz, B. H.
Chem. Rev. 2008, 108, 2916.
(24) (a) Crabtree, R. H.; Felkin, H.; Fellebeen-Khan, T.; Morris, G.
E. J. Organomet. Chem. 1979, 168, 183. (b) Stork, G.; Kahne, D. E. J.
Am. Chem. Soc. 1983, 105, 1072.
(25) For a classic review on substrate-directable chemical reactions,
see: Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93,
1307.
(26) (a) Evans, D. A.; Chapman, K. T. Tetrahedron Lett. 1986, 27,
5939. (b) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem.
Soc. 1988, 110, 3560.
(27) (a) Namba, K.; Jun, H.-S.; Kishi, Y. J. Am. Chem. Soc. 2004, 126,
7770. (b) Kaburagi, Y.; Kishi, Y. Org. Lett. 2007, 9, 723 and ref 9.
F
DOI: 10.1021/jacs.5b03499
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX