Synthesis of the C7-26 fragment of amphidinolides G and H

Article abstract of DOI:10.1021/ol201547q

A new approach to the synthesis of the C7-26 fragment of amphidinolides G and H was developed. In the sequence, the C7-18 portion of this fragment was synthesized using an acetylide coupling protocol, while an Evans alkylation and Sharpless asymmetric dihydroxylation were employed as key steps in construction of the C19-26 subfragment. Finally, both of these units were joined by utilizing an aldol coupling reaction to produce the target C7-26 fragment in good yield.

Full text of DOI:10.1021/ol201547q

ORGANIC
LETTERS
2011
Vol. 13, No. 15
4036–4039
Synthesis of the C7-26 Fragment of
Amphidinolides G and H
Akihiro Hara, Ryo Morimoto, Yuichi Ishikawa, and Shigeru Nishiyama*
Department of Chemistry, Faculty of Science and Technology, Keio University,
Hiyoshi 3-14-1, Kohoku-ku, Yokohama 223-8522, Japan
nisiyama@chem.keio.ac.jp
Received June 9, 2011
ABSTRACT
A new approach to the synthesis of the C7-26 fragment of amphidinolides G and H was developed. In the sequence, the C7-18 portion of this
fragment was synthesized using an acetylide coupling protocol, while an Evans alkylation and Sharpless asymmetric dihydroxylation were
employed as key steps in construction of the C19-26 subfragment. Finally, both of these units were joined by utilizing an aldol coupling reaction to
produce the target C7-26 fragment in good yield.
Amphidinolides G (1) and H (2), isolated by Kobayashi
and co-workers from the Okinawan flatworm Amphisco-
lops sp.,1 possess remarkably strong cytotoxicity against
L1210 murinelymphoma (IC50 = 5.4 ng/mL for1 and 0.48
ng/mL for 2) and KB human epidermoid2 (IC50 = 5.9 ng/
mL for 1 and 0.52 ng/mL for 2), and 2 has the potential to
activate actin polymerization by covalently linking to the
actin cytoskeleton3 (Figure 1). Both of these natural
products contain allyl epoxide, s-cis-diene units, five hy-
droxyl groups, and nine stereocenters in respective 26- and
27-membered macrocyclic lactone moieties. Interestingly,
amphidinolides G (1) and H (2) exist in equilibrium with
each other under acidic or basic conditions.4,6 The interesting
biological activities and unique structural features of these
natural products have attracted the organic synthesis
community.5 Despite this activity, only one total synthesis
of these substances has been reported since the time of their
isolation.6 In a recent effort, we have developed a new route
for the preparation of the C7-26 fragment of these targets.
Observations made in this study are described below.
(1) Kobayashi, J.; Shigemori, H.; Ishibashi, M.; Yamasu, T.; Hirota,
H.; Sasaki, T. J. Org. Chem. 1991, 56, 5221–5224.
(2) Kobayashi, J.; Shimbo, K.; Sato, M.; Tsuda, M. J. Org. Chem.
2002, 67, 6585–6592.
(3) Usui, T.; Kazami, S.; Dohmae, N.; Mashimo, Y.; Kondo, H.;
Tsuda, M.; Terasaki, A. G.; Ohashi, K.; Kobayashi, J.; Osada, H. Chem.
Biol. 2004, 11, 1269–1277.
Figure 1. Structure of amphidinolides G (1) and H (2).
(4) Kobayashi, J.; Shimbo, K.; Sato, M.; Shiro, M.; Tsuda, M. Org.
Lett. 2000, 2, 2805–2807.
On the basis of a strategy represented in the retrosyn-
thetic analysis displayed in Scheme 1, amphidinolide G (1)
would be generated from the alcohol 3 through a sequence
that utilizes esterification with an appropriate unsaturated
(5) For synthetic studies aimed at amphidinolides G and H, see: (a)
Petri, A. F.; Schneekloth, J. S.; Mandal, A. K.; Crews, C. M. Org. Lett.
2007, 9, 3001–3004. (b) Deng, L.; Ma, Z.; Zhang, Y.; Zhao, G. Synlett
2007, 87–90. (c) Deng, L.; Ma, Z.; Zhao, G. Synlett 2008, 728–732. (d)
Formentin, P.; Murga, J.; Carda, M.; Marco, J. A. Tetrahedron:
Asymmetry 2006, 17, 2938–2942. (e) Liesener, F. P.; Kalesse, M. Synlett
2005, 2236–2238. (f) Liesener, F. P.; Jannsen, U.; Kalesse, M. Synthesis
2006, 2590–2602. (g) Chakraborty, T. K.; Suresh, V. R. Tetrahedron
Lett. 1998, 39, 7775–7778. (h) Chakraborty, T. K.; Suresh, V. R.
Tetrahedron Lett. 1998, 39, 9109–9112.
€
ꢀ
(6) Furstner, A.; Bouchez, L. C.; Funel, J.; Liepins, V.; Poree, F.;
Gilmour, R.; Beaufils, F.; Tamiya, M. Angew. Chem., Int. Ed. 2007, 46,
9265–9270.
r
10.1021/ol201547q
Published on Web 07/11/2011
2011 American Chemical Society

Scheme 1. Retrosynthetic Analysis of Amphidinolide G (1)
Scheme 3. Synthesis of C14-18 Fragment (7)
The terminal acetylene coupling partner 7 was produced
from the previously described alcohol 128 (Scheme 3).
Sharpless asymmetric epoxidation of 12 proceeded
smoothly to afford the corresponding epoxy alcohol with
96% ee. Treatment of this substance with AlMe3 led to
generation of diol 13, which was cleaved using NaIO4 to
produce the corresponding aldehyde, which was then
converted into acetylene 7 (77% yield, 3 steps) by utilizing
the CoreyꢀFuchs protocol.9
carboxylic acid and ring closing metathesis as key steps. In
addition, owing to its lability under acidic and basic
conditions, the allylic epoxide moiety in the target would
be introduced by employing a late-stage Sharpless epox-
idation. We envisaged that ketone 3, corresponding to the
C7-26 fragment of 1, would serve as the key synthetic
intermediate in this approach and would be prepared by
the aldol reaction of aldehyde 4 with methyl ketone 5, the
former being derived from an acetylide coupling between
aldehyde 6 and acetylene 7.
Scheme 4. Synthesis of C7-18 Fragment (4)
Synthesis of the aldehyde segment 6 was initiated by
employing Evans alkylation of the known acylated oxa-
zolidinone8withallyl iodide 9. This process formed adduct
10 in 81% yield as a single diastereomer (Scheme 2).7
Scheme 2. Synthesis of C7-13 Fragment (6)
The coupling reaction between alkyne 7 and aldehyde 6
was successfully performed using n-BuLi to generate the
key lithium acetylide. TPAP oxidation of the resulting
propargylic alcohol gave the R,β-unsaturated ketone 14
in 84% yield (2 steps) (Scheme 4). Cleavage of the PMB
group from 14 with DDQ produced the corresponding
Reductive removal of the chiral auxiliary in this substance
followed by the tosylation of the resulting alcohol and
cyanide substitution gave nitrile 11, which upon DIBAL
reduction at ꢀ78 °C furnished aldehyde 6.
(8) Oka, T.; Murai, A. Tetrahedron 1998, 54, 1–20.
(9) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769–3772.
(7) Shindo, M.; Sugioka, T.; Umaba, Y.; Shishido, K. Tetrahedron
Lett. 2004, 45, 8863–8866.
Org. Lett., Vol. 13, No. 15, 2011
4037

primary alcohol which, on treatment with TESCl and
Et3N, afforded ketone 15. Treatment of 15 with the Gil-
man reagent promoted conjugate addition, leading to
formation of the desired (E)-enone 16 in 98% yield with
a moderate E:Z selectivity (2.5:1). The isomers 16 and 160
were easily separated using flash silica gel column chro-
matography. The enone was then converted by Wittig
olefination10 to triene 17, whose s-cis-diene geometry was
assigned by NOE methods. Removal of the TES group
from 17, employing PPTS at 0 °C, followed by IBX
oxidation of the derived alcohol provided aldehyde 4.
cleavage of the diol moiety in 18 followed by Wittig
olefination to introduce the acrylate moiety, hydrogena-
tion, and ester hydrolysis gave the carboxylic acid 19. The
Wittig olefination process was carried out using the crude
aldehyde derived from 18 to avoid undesired epimeriza-
tion. Stereoselective methylation of 21 was accomplished
by using the chiral auxiliary directed Evans protocol.
Reductive removal of the chiral auxiliary from product
21 gave the corresponding alcohol which, on treatment
with PivCl and DMAP, afforded pivaloate ester 22. Re-
moval of the acetonide from 22 followed by protection of
the resulting diol as the bis-TBS ether, DIBAL reduction,
TEMPO oxidation, and Wittig olefination gave the acry-
late ester 23. Sharpless asymmetric dihydroxylation of this
intermediate afforded a single diastereomer of the corre-
sponding diol, which was treated with TBSOTf and 2,6-
lutidine to produce the fully silyl ether protected tetraol 24.
DIBAL reduction of the ester moiety in 24, followed by
ParikhꢀDoering oxidation, MeLi addition, and TPAP
oxidation led to the desired methyl ketone 5, whose
stereochemistry was confirmed by using X-ray crystal-
lographic analysis.
Scheme 5. Synthesis of C19-26 Fragment (5)
Table 1. Aldol Reaction between 4 and 5
entry
additive
temp (°C)a
yield (%)b
selectivity (S/R)c
1
2
3
4
5
6
none
ꢀ78
ꢀ40
ꢀ20
ꢀ10
0
44
54
74
74
50
36
1:4.1
1:3.5
1:1.5
1.3:1
1.2:1
1:2.8
none
none
none
none
TMEDA
ꢀ40
a Compound 4 was added to the enolate derived from 5 in THF at the
temperature. The enolate was obtained by treatment of 5 with a base at
room temperature. b Combined yield of (S)-25 and (R)-25. c The ratio
was determined by 1H NMR spectoscopy.
With the requisite fragments in hand, the key aldol
coupling process between 4 and 5 was explored (Table 1).
Although ketone 5 was readily deprotonated using LHMDS
at room temperature, treatment of the derived lithium
The ketone 5 partner, whose aldol reaction with alde-
hyde 4 serves as the key step in the approach to the C7-26
fragment of amphidinolide G (1), was prepared by a route
starting with the known diol 1811 (Scheme 5). Oxidative
(12) Diastereomers (R)-25 and (S)-25 were separated by using silica
gel column chromatography (WAKO gel C-300).
(13) The O-PMB (ref 6) or O-MOM (refs 5b and 5c) substituents at
C21 are known to induce the formation of S-configuration at C18 of 25
via the strong 1,4-anti chelation effect. However, deprotection of these
groups at the final stage of the synthesis was troublesome owing to the
lability of the s-cis-diene and allyl epoxide units under the standard
deprotective conditions (DDQ, CAN for the O-PMB: acidic conditions
such as BF3OEt2 for the O-MOM).
(10) Ohi, K.; Nishiyama, S. Synlett 1999, 571–572.
(11) Abushanab, E.; Raymond, P. P. J. Org. Chem. 1988, 53, 2598–
2602.
4038
Org. Lett., Vol. 13, No. 15, 2011

in a reduced yield (entry 6). The combined results show
that the desired diastereomer of the target C7-26 fragment
25 of amphidinolide G can be generated in a modest yield
and diastereoselectivity.
In conclusion, a synthesis of the C7-26 fragment of 1 and
2 has been accomplished. The C7-18 fragment (4) was
produced by employing an acetylide coupling as a key step.
Furthermore, we demonstrated that the s-cis-diene moiety
of 1 and 2 could be constructed through a 1,4-addition and
a Wittig reaction. Finally, we succeeded in synthesizing the
desired aldol (S)-25 as a major product by aldol coupling
between 4 and 5. Further efforts toward total synthesis of
amphidinolides G and H are currently continuing in our
laboratory.
Acknowledgment. This work was financially supported
by High-Tech Research Center project for Private Uni-
versities Matching Fund (2006-2011) and by The Science
Research Promotion Fund from The Promotion and
Mutual Aid Corporation for Private Schools of Japan
from MEXT. A.H. was financially indebted to the Sasa-
gawa Foundation. We thank Professor Kakiuchi and
Dr. Kochi (Keio University) for the X-ray crystallographic
analysis of 5.
Figure 2. Data for the assignment of the C18 configuration of 25.
enolate with aldehyde 4 at ꢀ78 °C provided the undesired
diastereomer (S/R = 1:4.1, entry 1) of aldol product 25 in
44% yield.12 The absolute configuration at C18 of 25 was
assigned by employing a modification of the Mosher
method14 (Figure 2). Interestingly, temperature plays an
important role in both the yield and diastereoselectivity of
this process (entries 2ꢀ4). For example, aldol reaction of 4
with5, carried out atꢀ10°C, afforded25in 74% yield with
moderate stereoselectivity13 (S/R = 1.3:1, entry 4). In
contrast, reaction at temperatures above 0 °C led to
formation of the corresponding enone in low yield (entry
5). In addition, the use of TMEDA as an additive resulted
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092–4096.
Org. Lett., Vol. 13, No. 15, 2011
4039