Total synthesis of halichondrin A, the missing member in the halichondrin class of natural products

Article abstract of DOI:10.1021/ja5013307

A total synthesis of halichondrin A, the phantom member in the halichondrin class of natural products, is reported. The highlights of synthesis include: (1) synthesis of C1-C19 building block 6b via a catalytic asymmetric Cr-mediated coupling of 12 and 13b; (2) synthesis of the right-half of 19 via an asymmetric Ni/Cr-mediated coupling, followed by base-induced furan formation, and Shiina macrolactonization; (3) synthesis of enone 20 via Ni/Cr-mediated coupling of 5 with 19, followed by oxidation; (4) synthesis of halichondrin A from 20, with use of a newly discovered, highly selective TMSOTf-mediated equilibration of C38-epi-halichondrin A to halichondrin A. Two pieces of evidence are presented unambiguously to establish the structure of halichondrin A thus synthesized: one is the synthesis of norhalichondrin A (24) from 19 and 23, and the other is the study of the proton chemical shift difference between synthetic halichondrin A and known members of this class of natural products.

Full text of DOI:10.1021/ja5013307

Article
pubs.acs.org/JACS
Total Synthesis of Halichondrin A, the Missing Member in the
Halichondrin Class of Natural Products
Atsushi Ueda, Akihiko Yamamoto, Daisuke Kato, and Yoshito Kishi*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States
S
* Supporting Information
ABSTRACT: A total synthesis of halichondrin A, the
phantom member in the halichondrin class of natural products,
is reported. The highlights of synthesis include: (1) synthesis
of C1−C19 building block 6b via a catalytic asymmetric Cr-
mediated coupling of 12 and 13b; (2) synthesis of the right-
half of 19 via an asymmetric Ni/Cr-mediated coupling,
followed by base-induced furan formation, and Shiina
macrolactonization; (3) synthesis of enone 20 via Ni/Cr-
mediated coupling of 5 with 19, followed by oxidation; (4)
synthesis of halichondrin A from 20, with use of a newly
discovered, highly selective TMSOTf-mediated equilibration of C38-epi-halichondrin A to halichondrin A. Two pieces of
evidence are presented unambiguously to establish the structure of halichondrin A thus synthesized: one is the synthesis of
norhalichondrin A (24) from 19 and 23, and the other is the study of the proton chemical shift difference between synthetic
halichondrin A and known members of this class of natural products.
INTRODUCTION
■
Halichondrins are polyether macrolides, originally isolated from
the marine sponge Halichondria okadai by Uemura, Hirata, and
co-workers.1 Several additional members, including halistatin,
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, this class of natural products is
subgrouped into halichondrins A−C series or the norhalichon-
drin/halichondrin/homohalichondrin series. Except halichon-
drin A, all the subgroup members have been isolated from the
natural sources (Figure 1).3 Due to their intriguing structural
architecture and extraordinary in vitro and in vivo antitumor
activity, halichondrins have received much attention from the
synthetic community.4,5 In this paper, we report a total
synthesis of halichondrin A, the phantom member in this class
of natural products.
SYNTHETIC ANALYSIS
Figure 1. Structure of the halichondrin class of natural products.
■
We expected that unknown halichondrin A could be
synthesized with the overall synthetic strategy used in the
case of halichondrins B and C, i.e., halichondrins B and C were
constructed from the right-half 4a,b and the left-half 5. Namely,
we proposed a synthesis of “halichondrin A” from 4c and 5. We
then disconnected the right-half 4c into the C1−C19 and
C20−C38 building blocks 6 and 7. We were interested in the
proposed synthetic plan primarily for four reasons. First, we
recognized the possibility that the proposed synthesis of 4c
from 6 and 7 could be achieved by recently developed
asymmetric Ni/Cr-mediated coupling, followed by base-
induced cyclization.6,7 Second, we should be able to utilize
two blocks 5 and 7 used in the previous syntheses.8 Third, we
noticed a higher degree of convergency in this disconnection
than in the previous routes.9 Fourth, we envisioned the
possibility that this approach can be extended to the synthesis
of halichondrins B and C (Scheme 1).
Received: February 12, 2014
Published: March 7, 2014
© 2014 American Chemical Society
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demonstrating the high stereoselectivity of DMDO oxidation.
On treatment with p-anisaldehyde dimethyl acetal in the
presence of camphorsulfonic acid (CSA), β-10 gave single p-
methoxybenzylidene acetal 11.10
Scheme 1. Retrosynthetic Analysis of Halichondrin A
RESULTS AND DISCUSSION
Guided by the model study outlined, we began a synthesis of
the C1−C19 building block 6a (Scheme 3). The coupling of
■
a
Scheme 3. Synthesis of C1−C19 Building Block
The central question for the synthesis of building block 6 was
how to construct the C8−C14 polycycle of halichondrin A.
Through the model studies conducted in connection with the
synthesis of halichondrin C, we gained valuable information to
address this question.4b Scheme 2 summarizes a transformation
Scheme 2. Model Studies for Construction of the C8−C14
a
Polycycle of Halichondrin A
a
Reagents and conditions: (a) (1) Ni/Cr-mediated coupling with Cr-
catalyst (20 mol %) derived from (R)-sulfonamide-I and NiCl2·DEP
(0.03 mol %) (12 + 13b) → 14b; 91%. (2) Dess−Martin oxidation,
CH2Cl2, rt; 96%. (b) HF·py, py, MeCN, rt; 59% of 15 and 6% of its Z-
isomer. (c) (1) DMDO, acetone, rt. (2) CSA, CH2Cl2 (wet), rt. (3)
HF·py, MeCN, rt; 92% yield over three-steps. (4) p-TsOH (cat), p-
MeOC6H4CH(OMe)2, CH2Cl2, rt; 76% of 6b and 12% of rsm.
aldehyde 13a with iodoacetylene 12 was effectively achieved
with catalytic asymmetric Ni/Cr-mediated coupling. This
coupling deserves a few comments. First, the study by this
and other laboratories showed that iodoacetylenes are far more
reactive than iodoolefins in the Cr-mediated coupling.11 This
suggested the possibility that the (12 + 13a) coupling can be
achieved without interference from the C19-iodoolefin present
in 6a. Indeed, it was found that the coupling was effectively
achieved with a trace amount of Ni-catalyst or without added
Ni-catalyst. At present, however, it is not clear whether a trace
amount of Ni-catalyst is required for this coupling.11b As the
resultant allylic alcohol is oxidized to the ketone, the C14
stereochemistry outcome is not an issue for this coupling.
However, we noticed that the Cr-catalyst derived from a
sulfonamide ligand such as sulfonamide-I (Figure 2) signifi-
cantly accelerates the coupling. Interestingly, (R)-ligand was
found to be more effective than (S)-ligand. Third, the coupling
was conducted routinely with 15−20 mol % Cr-catalyst.
However, the catalyst loading was improved up to 5 mol %
a
Reagents and conditions: (a) HF·py, py, MeCN, rt; E-9: 69% and Z-
9: 7%. (b) (1) DMDO, acetone, 0 °C; (2) CSA, CH2Cl2 (wet), rt; (3)
HF·py, MeCN, rt; 74% for E-9 → β-10 and 50% for Z-9 → α-10. (c)
CSA (cat), p-MeOC6H4CH(OMe)2, DMF, 100 °C; 67%.
of 8 into 11 possessing the C8−C14 polycycle of halichondrin
A. This transformation involves: (1) selective TBS-deprotection
of both C9-OTBS (equatorial) and C11-OTBS (acyclic) over
C8-OTBS (axial); (2) oxy-Michael addition of the resultant
C9-alcohol to ynone 8, to form preferentially E-isomer with
assistance of hydrogen-bonding stabilization; (3) stereo-
selective DMDO epoxidation from convex face; and (4) acid-
promoted ketalization to form β-10. Interestingly, DMDO
epoxidation of the corresponding Z-isomer Z-9, followed by
acid-treatment, gave α-10 noncontaminated from β-10, thereby
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Scheme 4. Synthesis of the Right-Half of Halichondrin A
Figure 2. Sulfonamide ligands and NiCl2 complex used for Ni/Cr-
mediated coupling reactions.
with the iodoacetylene with TES, i.e., R = TES in 12, without a
loss of the coupling efficiency.
After oxidation of the propargyl alcohol, 14a was subjected to
the selective TBS-deprotection condition, to give enone 15 (E-
isomer: 62%; Z-isomer: 6%). DMDO oxidation, followed by
acid treatment and then p-anisaldehyde dimethyl acetal,
furnished the desired C1−C19 building block 6a in 45%
overall yield. However, we noticed that the product thus
obtained was a 2:1 mixture of desired 6a and acetylene 16. An
NMR analysis showed that this byproduct formation took place
in the DMDO step.
A literature search revealed no example known for DMDO-
mediated transformation of iodoolefins to acetylenes.12 We
speculate that formation of 16 involved DMDO oxidation of
the iodine to iodoso intermediate A, followed by syn-
elimination reported by Reich.13 In spite of some efforts, we
were unable to find the oxidation condition to avoid the iodine
oxidation. For this reason, we carried out the synthesis with
bromoolefin aldehyde 13b. The synthesis of this series
proceeded in the parallel way with the 13a series, except for:
(1) as anticipated, there was no acetylene byproduct 16 formed
and (2) the efficiency of Ni/Cr-mediated (12 + 13b)-coupling
was slightly higher in this series (70% overall yield from 15).
As planned, coupling of the C1−C19 building block 6b with
the C20−C38 building block 714 was realized by Ni/Cr-
mediated reaction in the presence of the Cr-catalyst derived
from (R)-sulfonamide II (Scheme 4).7 However, to overcome
the poorer reactivity of the bromoolefin of 6b, this coupling was
carried out with 40 mol % Cr reagent. The induced cyclization
of the resultant allylic alcohol with AgOTf-Ag2O gave desired
product 17 in 70% overall yield from 7, with 20:1 stereo-
selectivity.15
On treatment with aq. LiOH, both acetate and methyl ester
of 17 were hydrolyzed to yield the expected seco-acid,
macrolactonization of which was effected with Shiina’s reagent
to furnish 18 in 77% overall yield.16 Selective deprotection of
the 1°-TBS at C38 over the 2°-TBS at C35 was effected with
HF·py and imidazole in MeCN at 4 °C, to furnish the
halichondrin-A right-half 19 in 85% yield.17
After Dess−Martin oxidation, 19 was subjected to Ni/Cr-
mediated coupling with the halichondrin left-half 5, followed by
oxidation, to furnish the trans-enone 20 in 85% yield (Scheme
6). Once again, (S)-sulfonamide-I was used to accelerate the
coupling rate.
Reagents and conditions: (a) (1) Ni/Cr-mediated coupling with Cr-
catalyst (40 mol %) derived from (R)-sulfonamide-II and NiCl2·DEP
(10 mol %); 91% yield (dr = 20:1). (2) AgOTf, Ag2O, THF, rt; 78%
yield. (b) (1) LiOH, aq. MeOH, rt. (2) 2-methyl-6-nitrobenzoic
anhydride, i-Pr2NEt, DMAP, toluene, 70 °C; 77% over two-steps. (c)
HF·py, imidazole, MeCN, 4 °C; 85% yield.
group at C12/C13. In the total synthesis of halichondrins B
and C, we have demonstrated that this overall transformation,
except for the last anisylidene deprotection, can be achieved
with the three-step protocol, i.e., TBAF, DDQ, and CSA or
PPTS treatments, in a stereocontrolled manner.4
We expected that the anisylidene group could be removed by
PPTS in protic solvent, and therefore the transformation of 20
into halichondrin A could be achieved with use of the three-
step protocol with a small modification. With this analysis, we
subjected 20 to TBAF, DDQ, and then PPTS treatments.
Specifically, the previously established protocol was used for the
first two steps, but PPTS treatment was done in i-propanol,
instead of methylene chloride. In the TBAF and DDQ steps, we
found that 20 exhibited the behavior perfectly parallel with that
observed in the halichondrins B and C cases. In the third step
(PPTS in i-propanol at RT), the anisylidene group was indeed
removed, but two major products (ca. 3:2 ratio) were formed.
MS and 1H NMR analysis suggested that the major and minor
products were likely to correspond to C38-epi-halichondrin A
and halichondrin A, respectively. This result was surprising for
us, as the corresponding acid-treatment step in the halichon-
drins B and C series furnished the desired stereoisomer as the
major product.18 Naturally, we were curious about the
reason(s) why the product distribution in the halichondrin A
series was noticeably different from that observed in the
halichondrins B and C.
For this reason, we initiated a study on the behavior of the
[5,5]-spiroketal at C38, in particular acid-catalyzed equilibra-
tion. In this connection, it is worth noting that the C11−C14
portion of halichondrins is known to be prone to furan
formation under acidic conditions.19 Related to the proposed
equilibration, Blunt and Munro studied C38-epi-homohalichon-
drin B and its acid-catalyzed reactivity, showing that the C38
stereocenter epimerizes to yield a 1:1 mixture in TFA-
CH2Cl2.20 Compared with [6,6]-spiroketals,21 the stereo-
chemical behaviors of [5,5]-spiroketals are complex,22 and it
In order to convert 20 to halichondrin A, we need to achieve
the following chemical transformations: (1) deprotection of the
five TBS groups; (2) hemiketal formation at C44; (3) oxy-
Michael addition of the resultant hemiketal hydroxyl group to
the αβ-unsaturated ketone to form the [6,6]-spiroketal at C44;
(4) deprotection of the C41-MPM group; (5) formation of
[5,5]-spiroketal at C38; and (6) deprotection of the anisylidene
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is not straightforward to suggest a chemical means to favor
halichondrin A over C38-epi-halichondrin A or vice versa. With
this background, we studied the equilibration of C38-epi-
halichonrin A (Table 1). After numerous attempts, we
from 20, along with C38-epi-halichondrin A (22; ca. 3%). It is
worth noting that 21 was the major product observed in this
four-step transformation, although the isolated yield was
modest.25
Table 1. [5,5]-Spiroketal Equilibration
Scheme 6. Completion of the Total Synthesis
CH2Cl2
Et2O
MeCN
MeOH
PPTS at RT
CSA at RT
3:2
2:1
1:1
1:1
2:1
1:1
1:2
1:2
NA
a
TMSOTf at −78 °C
>10:1
1:>5
3:1
a
Done at −40 °C.
eventually found a simple but remarkably effective method to
make the equilibration in favor to either halichondrin A (21) or
C38-epi-halichondrin A (22); 21 and 22 were formed as the
major stereoisomer on treatment with TMSOTf in CH2Cl2 or
Et2O, respectively.23 It is worthwhile noting that no furan
formation was observed under the conditions employed and
that both halichondrins B and C exhibited the identical
reactivity.
Realizing that solvents play the key role,24 we would
speculate a possible mechanistic explanation; the C35−C44
moiety of halichondrins provides a polyether-type cavity for
cations such as Me3Si+ in nonoxygen-containing solvents, which
shifts the equilibration in favor to halichondrin A (Scheme 5).
Reagents and conditions: (a) (1) Dess−Martin oxidation of 19,
CH2Cl2, rt; 96% yield. (2) Ni/Cr-mediated coupling with Cr-catalyst
(5 equiv) derived from (S)-sulfonamide-I and NiCl2·DEP (2 mol %).
(3) Dess−Martin oxidation; 85% yield over two-steps. (b) (1) TBAF,
imidazole·HCl, DMF, rt. (2) DDQ, t-BuOH, CH2Cl2, phosphate
buffer (pH = 7.0), rt. (3) PPTS, i-PrOH, rt. (4) TMSOTf, CH2Cl2,
−78 °C; 39% isolated yield of 21 and ∼3% of 22 over four-steps.
Scheme 5. Possible Mechanism for the Observed Solvent-
Dependent [5,5]-Spiroketal Equilibration
As mentioned in the Introduction, halichondrin A is the
missing member in this class of natural products. Thus, the
structure proof of synthetic halichondrin A (21) presented a
challenge. To establish the structure of synthetic halichondrin A
unambiguously, we conducted two experiments.
First, norhalichondrin A (24) was synthesized with coupling
19 and 23 (Scheme 7).26,27 It should be noted that 23 was the
left-half used for the synthesis of norhalichondrin B.4a Synthetic
norhalichondrin A (24) thus obtained was confirmed to be
identical with natural norhalichondrin A (1H- and 13C NMR,
HR-MS, TLC), thereby establishing the structure of the
halichondrin right-half 19. Noteworthily, norhalichondrin A
(24) played the central role in structure elucidation of this class
of natural products, i.e., the X-ray structure analysis of its p-
bromophenacyl ester.1 Also, it should be noted that the left-half
(5) was successfully transformed into halichondrins B and C.4
Combined together, there was no ambiguity left on the
structure of the two building blocks 5 and 19 used for the
current halichondrin A synthesis.
Second, three chiral centers at C38, C40, and C44 were
introduced at the transformation from the enone 20 to the final
product. The fact that norhalichondrin A (24) was successfully
obtained by using the virtually same procedure strongly
suggests that the newly introduced three chiral centers match
with those present in the halichondrin class natural products.
Nevertheless, close NMR analysis provided us with further
evidence. The panel A in Chart 1 summarizes the proton
In oxygen-containing solvents, the cavity effect is canceled out
with solvents and an unfavorable dipole−dipole interaction
between the C38−O and C40−O bonds in halichondrin A
shifts the equilibrium toward C38-epi-halichondrin A.
Based on the insight on the [5,5]-spiroketal behavior, we
were able to complete a total synthesis of halichondrin A in a
stereoselective manner. Namely, the product mixture obtained
in the PPTS step was subjected to the TMSOTf-promoted
equilibration, followed by chromatographic separation, to
furnish synthetic halichondrin A (21) in 39% overall yield
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structure. Similarly, the panel B in Chart 1 shows the proton
chemical shift differences between synthetic halichondrin A and
halichondrin B (red) and halichondrin C and synthetic
halichondrin A (blue), thereby demonstrating that these three
halichondrins share the same left-half structure. The two NMR
comparisons once again proved that halichondrin A obtained
through the total synthesis indeed corresponds to the missing
member of this class of natural products.
Scheme 7. Total Synthesis of Norhalichondrin A
As mentioned in the Introduction, halichondrin A is not
isolated from marine sponges thus far. With synthetic
halichondrin A in hand, we are in a good position to test
whether halichondrin A is present in natural sources.28 In
addition, it would be interesting to study its biological profile.
CONCLUSION
■
We have reported a total synthesis of halichondrin A, the
phantom member in this class of natural products. The
highlights of total synthesis include: (1) synthesis of C1−C19
building block 6b via a catalytic asymmetric Cr-mediated
coupling of 12 and 13b; (2) synthesis of right-half 19 via an
asymmetric Ni/Cr-mediated coupling, followed by base-
induced furan formation and then Shiina macrolactonization;
(3) synthesis of enone 20 via Ni/Cr-mediated coupling of 5
with 19, followed by Dess−Martin oxidation; (4) synthesis of
halichondrin A (21) from 20, with use of a newly discovered,
highly selective TMSOTf-mediated equilibration of C38-epi-
halichondrin A (22) to halichondrin A (21). We have
presented two pieces of evidence unambiguously to establish
the structure of synthetic halichondrin A; one is the synthesis of
norhalichondrin A (24) from 19 and 23, and the other is the
studies on the proton chemical shift difference between
synthetic halichondrin A and known members of the
halichondrin class of natural products.
Reagents and conditions: (a) same as step (a) in Scheme 6. 83%
overall yield. (b) (1−4) Same as step (b) in Scheme 6. (5) LiOH, aq.
THF, rt; 30% isolated yield of 24 over five steps.
a
Chart 1. Proton Chemical Shift Differences
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization data, and copies of
spectra data. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
kishi@chemistry.harvard.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Eisai USA Foundation is gratefully
acknowledged. We thank Professor Uemura for a sample of
natural norhalichondrin A.
a
The x-axis represents carbon number at which protons in question
are attached. The y-axis shows proton chemical shift differences in
ppm. Panel A, red: Δδ = (norhalichondrin A) − (synthetic
halichondrin A); blue: Δδ = (synthetic halichondrin A) −
homohalichondrin A. Panel B, red: Δδ = (synthetic halichondrin A)
− (halichondrin B); blue: Δδ = (halichondrin C) − (synthetic
halichondrin A). *Methyl group attached at the indicated carbon; and
**exo-methylene group attached at the indicated carbon.
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■
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N.; Sabitha, G. Tetrahedron Lett. 2012, 53, 2504.
(24) Solvent tested included: (a) non-oxygen containing solvents:
toluene and dichloroethane; (b) oxygen-containing solvents; THF and
H2O.
(25) In addition to 21 and 22, one unknown product was isolated. Its
molecular weight corresponded to (21 + H2O), but it was not the
seco-acid resulted from macrolactone hydrolysis. It is worthwhile
noting that the modest yield was due to the first three steps, rather
than the TMSOTf-mediated equilibration. In the halichondrin C
series, the overall yield of corresponding three steps was 30%. Having
learned the chemical behaviors of C-38 epimer, we re-examined the
crude product obtained after the PPTS treatment, revealing that C-38
epimer was indeed present in 7∼10% overall yield from the enone.
(26) Fang, F. G.; Kishi, Y.; Matelich, M. C.; Scola, P. M. Tetrahedron
Lett. 1992, 33, 1557.
(27) The enone in the homohalichondrin series was also synthesized
from 19 and the vinyl iodide reported as 8 in ref 25. However, the
four-step protocol outlined in Scheme 6 did not give homohalichon-
drin A. One of the problems encountered was the difficulty in
removing all the four TBS groups under the condition of TBAF,
imidazole·HCl, DMF, rt; namely, one of the four TBS groups, likely
one at C48, was not deprotected. With a modification on the TBAF-
mediated TBS deprotection step, i.e., TBAF (50 equiv instead of 10
equiv) and reaction temperature (50 °C instead of rt), homohalichon-
drin A was obtained in 5% overall yield. Synthetic homohalichondrin A
was found to be identical with natural homohalichondrin A (HR-MS,
1H NMR, and TLC). In spite of the poor overall efficiency, this
experiment has established that the C50/C51/C53/C54 stereo-
chemistry of homohalichondrin A corresponds to the one shown in
vinyl iodide 8 in ref 26.
(6) 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.
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. Jpn.
Acad., Ser. B 2000, 76, 123. (e) Hargaden, G. C.; Guiry, P. J. Adv.
Synth. Catal. 2007, 349, 2407.
(7) (a) 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.
(b) 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. (c) 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.
(d) Liu, X.; Henderson, J. A.; Sasaki, T.; Kishi, Y. J. Am. Chem. Soc.
2009, 131, 16678 and references cited therein.
(8) Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S. H.; Kishi, Y.;
Scola, P. M.; Yoon, S. K. Tetrahedron Lett. 1992, 33, 1553.
(9) In the previous synthesis of halichondrins B and C, the C8−C14
polycycle was built after the macrolactonization.
(10) Anisylidene formation of β-10 gave a single stereoisomer, whose
stereochemistry was assigned, based on the NOE experiments done on
6a. For details, see Supporting Information.
(11) For example, see: (a) Aicher, T. D.; Kishi, Y. Tetrahedron Lett.
1987, 28, 3463. (b) Usanov, D. L.; Yamamoto, H. J. Am. Chem. Soc.
2011, 133, 1286.
(28) With the use of synthetic halichondrin A as the authentic
sample, we searched for natural halichondrin A in a crude extract of
the marine sponge Halichondria okadai, stored over 20 years in the
Uemura laboratory, but unsuccessfully.
(12) For possibly relevant examples, see: (a) Mahadevan, A.; Fuchs,
P. L. J. Am. Chem. Soc. 1995, 117, 3272. (b) Knapp, S.; Naughton, A.
B. J.; Murali Dhar, T. G. Tetrahedron Lett. 1992, 33, 1025.
(13) Reich, H. J.; Peake, S. L. J. Am. Chem. Soc. 1978, 100, 4888.
(14) For the details of synthesis, see Supporting Information.
(15) Kang, B.; Mowat, J.; Pinter, T.; Britton, R. Org. Lett. 2009, 11,
1717.
(16) Shiina, I.; Kubota, M.; Ibuka, R. Tetrahedron Lett. 2002, 43,
7535.
(17) In the previous syntheses, we used a four-step protocol, i.e., (1)
TBAF, imidazole·HCl, THF. (2) PNB-Cl, Et3N, DMAP, CH2Cl2, −20
°C. (3) TBSOTf, 2,6-lutidine, CH2Cl2, −78 °C. (4) K2CO3, MeOH-
CH2Cl2, rt, for the transformation corresponding to 18→19. Each step
in that transformation was very selective and high yielding (overall
yield: ∼90%). Although the selectivity of C38-TBS over C35-TBS
deprotection was not perfect, the current method allowed trans-
forming 18 to 19 in a single step in a yield comparable to the previous
four-step procedure.
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