Toward the Total Synthesis of Amphidinolide N: Synthesis of the C8-C29 Fragment

Article abstract of DOI:10.1021/acs.orglett.6b00871

A synthesis of the C8-C29 fragment of amphidinolide N, a potent cytotoxic macrolide isolated from the marine dinoflagellate Amphidinium sp., has been achieved. The key features of the synthesis involve a convergent union of the C9-C15 and C16-C29 fragment

Full text of DOI:10.1021/acs.orglett.6b00871

Letter
pubs.acs.org/OrgLett
Toward the Total Synthesis of Amphidinolide N: Synthesis of the
C8−C29 Fragment
†
†
Yuki Kawashima, Atsushi Toyoshima, Haruhiko Fuwa,* and Makoto Sasaki*
Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan
*
S Supporting Information
ABSTRACT: A synthesis of the C8−C29 fragment of
amphidinolide N, a potent cytotoxic macrolide isolated from
the marine dinoflagellate Amphidinium sp., has been achieved.
The key features of the synthesis involve a convergent union of
the C9−C15 and C16−C29 fragments by Steglich ester-
ification and the construction of a pyran unit through a Tebbe
methylenation/ring-closing metathesis sequence.
mphidinolides are a series of cytotoxic marine macrolides
isolated from cultured Amphidinium sp. associated with
configurational assignment was revised to be represented as 3,
with the same gross structure as caribenolide I.
The extremely potent cytotoxicity and complex molecular
4
A
the Okinawan flatworm, Amphiscolops sp., by Kobayashi and co-
1
workers. Amphidinolide N (1) (Figure 1), isolated from
architecture of amphidinolide N and calibenolide I have
5
−7
attracted considerable attention in the synthetic community.
Very recently, Hayashi and co-workers reported the total
8
synthesis of 7,10-epi-amphidinolide N. We previously reported
9
a synthesis route to the C13−C29 segment of 3. However, we
were unable to advance the synthesis because of the difficulties
associated with protecting group manipulations. To address this
problem, we decided to reconsider the overall synthesis plan,
and herein we report a synthesis of the C8−C29 fragment of
amphidinolide N.
Our retrosynthetic analysis for the C8−C29 fragment 4 is
depicted in Scheme 1. For the construction of the challenging
six-membered acetal unit with α,α′-dihydroxy substituents at
5
8
C14−C16, Nicolaou and Hayashi utilized the hydrazone
10
alkylation chemistry developed by Enders and co-workers. By
contrast, we envisioned that an epoxidation and in situ
methanolysis of dihydropyran 5 would enable access to six-
11
12,13
membered acetal 4. In turn, on the basis of previous work
Figure 1. Structures of amphidinolide N and caribenolide I.
we considered that dihydropyran 5 could be traced back to
ester 6 via a methylenation and a ring-closing metathesis
(
RCM). Ester 6 would in turn be accessed from two
Amphidinium sp. (Y-5 strain) in 1994, is the most potent
cytotoxic member of the amphidinolides, with IC50 values of
components of comparable complexity, carboxylic acid 7 and
alcohol 8.
0
.05 and 0.06 ng/mL against murine lymphoma L1210 and
2
The synthesis of carboxylic acid 7 started with the known
human epidermoid carcinoma KB cells, respectively. The gross
structure of 1, including a partial configurational assignment,
was proposed on the basis of extensive 2D NMR analysis and
consists of a 26-membered macrolide backbone containing an
α-methylene epoxide, a six-membered hemiacetal, and 13
stereogenic centers. Almost simultaneously, Shimizu and co-
workers independently reported a closely related macrolide,
caribenolide I (2), isolated from the cultured free-swimming
14
internal alkyne 9 (Scheme 2). Silylcupration of 9 using
Fleming’s reagent (PhMe Si) Cu(CN)Li (THF, −78 to 0
°
Subsequent iododesilylation with NIS (MeCN, 0 °C to room
temperature) proceeded with complete retention of config-
uration to afford vinyl iodide 11 in 83% yield for the two steps
15
2
2
2
C) provided vinylsilane 10 as a single regio- and stereoisomer.
16
(
E/Z >20:1). Halogen−lithium exchange of 11 using t-BuLi
3
(THF, −78 °C) followed by addition of PMB-protected
Caribbean dinoflagellate, Amphidinium sp. S1-36-5. Most
importantly, caribenolide I showed in vivo antitumor activity
against murine tumor P388 (T/C: 150 at a dose of 0.03 mg/
kg). Recently, the structure of amphidinolide N with a full
Received: March 25, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00871
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Retrosynthesis of the C8−C29 Fragment 4
Scheme 2. Synthesis of Carboxylic Acid 7
Scheme 3. Synthesis of Alcohol 8
1
7
glycidol 12 and BF ·OEt (−90 to −78 °C) provided alcohol
3
2
18
1
3 in 65% yield. Oxidative acetalization of PMB ether 13
using DDQ under anhydrous conditions
19
gave a p-
methoxybenzylidene acetal (65%), which was regioselectively
cleaved with DIBALH to provide primary alcohol 14 in 84%
2
0
21,22
yield. A two-stage oxidation
of alcohol 14 delivered
carboxylic acid 7 in 94% yield for the two steps.
The synthesis of alcohol 8 commenced with the known
9
tetrahydrofuran 15. The terminal olefin of 15 was oxidatively
cleaved by a two-step sequence (OsO /NMO then Pb(OAc) )
group of 19 under acidic conditions gave rise to alcohol 8 in
97% yield.
4
4
2
3
to give aldehyde 16 (Scheme 3). Brown asymmetric allylation
of 16 delivered homoallylic alcohol 17 in 78% yield as a single
diastereomer (dr > 20:1). The absolute configuration of the
With the requisite two fragments in hand, we next focused on
their coupling and crucial formation of a pyran unit, as depicted
in Scheme 4. Condensation of carboxylic acid 7 and alcohol 8
2
4
C19 stereogenic center was established by a modified Mosher
2
5,26
28
analysis.
After protection of the secondary alcohol of 17 as
was performed using DCC/DMAP to yield ester 6 in 91%
its TES ether (TESOTf, 2,6-lutidine, 94%), the terminal olefin
yield. We initially attempted direct olefinic ester cyclization of a
model compound closely related to ester 6 using the Takai−
was hydroborated using dicyclohexylborane to provide alcohol
27
29
18 in 95% yield. Oxidation of 18 with TEMPO/NaClO
Uchimoto reduced titanium reagent according to the Rainier
30
followed by Wittig reaction of the resultant aldehyde using
protocol, but this process resulted only in recovery of the
starting material (90−98%), and no desired dihydropyran was
obtained. Therefore, we decided to construct the dihydropyran
+
−
Ph P CH CH Br /KHMDS delivered (Z)-olefin 19 in 85%
3
2
3
yield for the two steps (Z/E > 20:1). Removal of the TES
B
DOI: 10.1021/acs.orglett.6b00871
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Synthesis of the C8−C29 Fragment 4
ring of 5 by employing a stepwise Tebbe methylenation and
ASSOCIATED CONTENT
Supporting Information
■
1
2
31
RCM. Thus, treatment of ester 6 with Tebbe reagent
Cp Ti(Cl)CH AlMe , THF, 0 °C) afforded enol ether 20,
*
S
(
2
2
2
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00871.
which was subjected to RCM using the second-generation
32
Grubbs catalyst (G-II) to furnish dihydropyran 5 in 72% yield
12,33
for the two steps.
Experimental procedures, characterization data for all
The remaining challenge was to install the C15 and C16
oxygen functionalities in a stereoselective fashion, but this
proved to be more problematic than expected. Epoxidation of 5
with m-CPBA (NaHCO , CH Cl /MeOH, 0 °C) followed by
new compounds, modified Mosher analysis of compound
1
13
1
7, and H and C NMR spectra for all new compounds
(PDF)
3
2
2
in situ epoxide ring opening with MeOH afforded the desired
hydroxy methyl acetal as a mixture of the C16-epimeric
alcohols, along with the unexpected C15-OH and its m-
chlorobenzoate derivatives. Treatment of this mixture with
PPTS (MeOH, 45 °C) effected the conversion of these
unwanted products to the corresponding methyl acetal.
AUTHOR INFORMATION
■
*
*
Corresponding Authors
E-mail: masasaki@m.tohoku.ac.jp.
E-mail: hfuwa@m.tohoku.ac.jp.
34
Author Contributions
†Y.K. and A.T. contributed equally to this work.
Subsequent oxidation with Dess−Martin periodinane deliv-
ered ketone 21 in 42% yield for the three steps. Reduction of
2
1 using L-Selectride (THF, −40 °C) proceeded in a highly
stereoselective manner to furnish alcohol 22 (91% yield, dr
20:1). The relative configuration of the C15 and C16
stereogenic centers was unambiguously established by con-
Notes
The authors declare no competing financial interest.
>
ACKNOWLEDGMENTS
3
■
version to the acetate derivative 23 and its J
NOE data as shown. Protection of the secondary alcohol of 22
with TBSOTf/2,6-lutidine followed by selective removal of the
primary TBDPS group with TBAF/AcOH delivered primary
alcohol 24. Finally, alcohol 24 was converted to the desired
C8−C29 fragment 4 using a three-step sequence involving
Dess−Martin oxidation, methylation using MeLi/CeCl ,
and a second oxidation (73% yield for the three steps).
In conclusion, we have achieved a convergent synthesis of
the C8−C29 fragment of amphidinolide N. The key feature of
the synthesis route includes coupling of two fragments 7 and 8
by a Steglich esterification and a Tebbe methylenation/RCM
sequence to construct a dihydropyran ring. Further studies
aimed at the total synthesis of amphidinolide N are underway
and will be reported in due course.
values and
H,H
We thank Kaneka Corporation for donating (S)-Roche ester.
This work was financially supported in part by a Grants-in-Aid
for Scientific Research (B) (25282228) and Scientific Research
on Innovative Areas “Chemical Biology of Natural Products”
35
37
(
23102016) from the Japan Society for the Promotion of
34
36
Science (JSPS).
3
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DOI: 10.1021/acs.orglett.6b00871
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DOI: 10.1021/acs.orglett.6b00871
Org. Lett. XXXX, XXX, XXX−XXX