Total synthesis of amphidinolide Q

Article abstract of DOI:10.1021/ol902026f

Asymmetric synthesis of amphidinolide Q, a cytotoxic macrolide from the cultured dinoflagellate Amphidinium sp., has been accomplished with Julia coupling, Myers alkylation, and Yamaguchi lactonization. The absolute configuration of amphidinolide Q was co

Full text of DOI:10.1021/ol902026f

ORGANIC
LETTERS
2009
Vol. 11, No. 21
5046-5049
Total Synthesis of Amphidinolide Q
Masahiro Hangyou, Haruaki Ishiyama, Yohei Takahashi, and Jun’ichi Kobayashi*
Graduate School of Pharmaceutical Sciences, Hokkaido UniVersity, Sapporo 060-0812, Japan
jkobay@pharm.hokudai.ac.jp
Received August 31, 2009
ABSTRACT
Asymmetric synthesis of amphidinolide Q, a cytotoxic macrolide from the cultured dinoflagellate Amphidinium sp., has been accomplished
with Julia coupling, Myers alkylation, and Yamaguchi lactonization. The absolute configuration of amphidinolide Q was confirmed to be 1 from
comparison of the NMR data and [r]D values of synthetic and natural amphidinolide Q.
Amphidinolide Q (1) is a cytotoxic 12-membered mac-
rolide having C1 branches at vicinal carbons (C-13 and
C-14) and an R,ꢀ-unsaturated ester moiety, isolated from
the cultured dinoflagellate Amphidinium sp. (Y-5 strain).1
Recently, we have proposed the stereoconfiguration of
amphidinolide Q as 1 on the basis of extensive NMR
experiments, molecular modeling, and chemical deriva-
tization.2 In this paper, we describe the first total synthesis
of amphidinolide Q (1) and establish our proposed absolute
stereochemistry.
As outlined retrosynthetically in Scheme 1, amphidinolide
Q (1) could be obtained by Yamaguchi lactonization3 of seco-
acid 2, which could be provided by aldol reaction of the
C-1-C-5 segment (3) and the C-6-C-16 segment (4). Key
aldehyde 4, containing four stereogenic centers, could be
derived from iodide 5 via Myers alkylation,4 which is
conceived to be obtained through Julia coupling5 between
sulfone 6 and aldehyde 7.
which was oxidized with m-chloroperoxybenzoic acid to
sulfone 6. Alcohol 98 was oxidized with Dess-Martin
periodinane9 to the corresponding aldehyde 7, which was
then subjected to Julia coupling5 with 6 to afford hydroxy
sulfone. Ketone 10 was obtained following oxidation and
reductive removal of the sulfone group.10 Reduction of
ketone 10 with NaBH4 gave diols 11 and 12 (37% and 32%,
respectively). Selective protection of the primary hydroxy
group in 11 provided pivaloate ester 13, the secondary
hydroxy group of which was treated with MOMCl and
i-Pr2NEt to afford MOM ether 14. After removal of the
pivaloyl group in 14, the corresponding alcohol was oxidized
to an aldehyde, then treated with EtMgBr and oxidized to
yield ketone 15. Wittig olefination was followed by depro-
tection and iodination to afford iodide 5.
The absolute configuration at C-11 in 13 was elucidated
by a modified Mosher’s method.11 Treatment of 13 with (R)-
(-)- and (S)-(+)-2-methoxy-2-trifluoro-2-phenylacetyl chlo-
ride (MTPACl) provided the (S)- and (R)-MTPA esters (13a
The synthesis of iodide 5 is described in Scheme 2.
Alcohol 86 was transformed with (PhS)2-Bu3P7 into sulfide,
(6) (a) Ohtawa, M.; Ogihara, S.; Sugiyama, K.; Shiomi, K.; Harigaya,
j
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10.1021/ol902026f CCC: $40.75
Published on Web 10/05/2009
 2009 American Chemical Society

Figure 1. The ∆δ values for H2-8, H-9, H2-10, and H3-19
Scheme 1. Retrosynthetic Analysis of Amphidinolide Q (1)
Figure 1. ∆δ values [∆δ (in ppm) ) δS - δR] obtained for (S)-
and (R)-MTPA esters at C-11 (13a and 13b, respectively) of alcohol
13.
were positive, while negative ∆δ values are observed for
H2-12, H-13, H2-14, and H3-20. These results indicated that
the absolute configuration at C-11 was S.
As shown in Scheme 3, alcohol 12 was also converted
into 16. Selective hydroxy group protections furnished 17.
After removal of TIPS ether in 17, alcohol 18 was oxidized
to the corresponding aldehyde and then treatment with
EtMgBr afforded alcohol, which was oxidized with Dess-
Martin periodinane to ketone 19. Wittig reaction to install
an exomethylene followed by treatment of DDQ yielded
alcohol 16, which was transformed into iodide 5 as described
in Scheme 2.
Alcohol 2012 was protected as pivaloate ester to afford
the C-1-C-5 segment (3) (Scheme 4). Myers alkylation4 was
used to install the C-7 stereocenter essentially as a single
diastereomer. Reductive cleavage of the auxiliary by using
LDA-BH3·NH3 complex provided alcohol 22. Oxidation of
22 with Dess-Matin periodinane and then aldol reaction of
and 13b, respectively) of 13. ∆δ values (∆δ ) δS - δR)
obtained from H NMR data of 13a and 13b are shown in
1
Scheme 2. Synthesis of the C-8-C-16 Segment (5) from 8
Org. Lett., Vol. 11, No. 21, 2009
5047

Scheme 3. Synthesis of the C-8-C-16 Segment (16) from 12
Scheme 4. Synthesis of the C-1-C-16 Segment (24) from 5
Scheme 5. Synthesis of Amphidinolide Q (1) from 24
5048
Org. Lett., Vol. 11, No. 21, 2009

the corresponding aldehyde and 3 with KHMDS afforded
ꢀ-hydroxy ketone 23. Reduction of 23 with NaBH4 and
CeCl3·7H2O followed by selective protection of the allylic
hydroxy group yielded TIPS ether 24 as a diasteromeric
mixture.
Removal of the pivaloyl group in 24 with DIBAL followed
by oxidation with Dess-Martin periodinane provided alde-
hyde 25 as a single diastereomer after silica gel column
separation (Scheme 5). After aldehyde 25 was oxidized under
Pinnick oxidation conditions13 to carboxylic acid, the MOM
group was removed with PPTS to afford seco-acid 2. The
seco-acid (2) was then subjected to macrolactonization by
using the Yamaguchi procedure3 to provide macrolactone
26. Finally, removal of the TIPS group in 26 with TBAF
and AcOH furnished amphidinolide Q (1). The absolute
configuration at C-4 in 1 was confirmed by a modified
Mosher’s method as in the previous report.2 Synthetic
amphidinolide Q (1) was identical with natural amphidinolide
Q (1H and 13C NMR, IR, UV, MS, and optical rotation),1,2
thus allowing confident assignment of the absolute configu-
rations and validating our earlier proposal.2
Acknowledgment. We thank S. Oka and A. Tokumitsu,
Equipment Management Center, Hokkaido University, for
ESIMS measurements. This work was partly supported by
a grant from the Uehara Memorial Foundation and Grant-
in-Aid for Scientific Research from the Ministry of Educa-
tion, Culture, Sports, Science and Technology of Japan.
(11) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
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900. (b) Klimko, P. G.; Singleton, D. A. Synthesis 1994, 979–982. (c)
Greatrex, B. W.; Kimber, M. C.; Taylor, D. K.; Tiekink, E. R. T. J. Org.
Chem. 2003, 68, 4239–4246.
Supporting Information Available: Experimental details
and spectroscopic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(13) (a) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron
1981, 37, 2091–2096. (b) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand.
1973, 27, 888–890.
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