Total synthesis and absolute configuration of koshikalide

Article abstract of DOI:10.1016/j.tetlet.2016.06.002

The first total synthesis of koshikalide, a 14-membered macrolide that contains three olefins, was achieved. The skipped diene in the cyclic system was efficiently constructed by very mild Stille coupling at low temperature. The absolute stereochemistry was established by comparison of the specific optical rotations of natural and synthesized koshikalide.

Full text of DOI:10.1016/j.tetlet.2016.06.002

Accepted Manuscript
Total Synthesis and Absolute Configuration of Koshikalide
Kazuki Kunifuda, Arihiro Iwasaki, Masashi Nagamoto, Kiyotake Suenaga
PII:
S0040-4039(16)30652-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.06.002
TETL 47729
Reference:
Tetrahedron Letters
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Accepted Date:
6 May 2016
26 May 2016
1 June 2016
Please cite this article as: Kunifuda, K., Iwasaki, A., Nagamoto, M., Suenaga, K., Total Synthesis and Absolute
Configuration of Koshikalide, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.06.002
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Total Synthesis and Absolute Configuration
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Kazuki Kunifuda, Arihiro Iwasaki, Masashi Nagamoto, Kiyotake Suenaga

1
Tetrahedron Letters
Total Synthesis and Absolute Configuration of Koshikalide
Kazuki Kunifuda, Arihiro Iwasaki, Masashi Nagamoto and Kiyotake Suenaga*
Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi 3-14-1, Kohoku-ku, Yokohama 223-8522, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The first total synthesis of koshikalide, a 14-membered macrolide that contains three olefins,
was achieved. The skipped diene in the cyclic system was efficiently constructed by very mild
Stille coupling at low temperature. The absolute stereochemistry was established by comparison
of the specific optical rotations of natural and synthesized koshikalide.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Koshikalide
Total synthesis
Marine cyanobacteria
Macrolide
Marine Natural Products
First, the labile skipped diene should be introduced at a point
close to the final step in the scheme, and all subsequent reaction
In 2010, koshikalide (1), a 14-membered macrolide that
exhibits moderate cytotoxicity, was isolated from a marine
cyanobacterium Lyngbya sp., and its relative stereochemistry was
established on the basis of spectroscopic analyses.1 However, its
absolute stereochemistry could not be elucidated due to the
scarcity (0.3 mg) of the sample. To clarify the complete
stereochemistry of 1, we carried out the first total synthesis of
koshikalide (1).
conditions should be as mild as possible. Therefore, a Shiina
macrolactonization was used to construct the lactone skeleton of
1 from 2. For introduction of the conjugated carbonyl group at C-
1, mild oxidation of allyl alcohol 3 could be achieved by TEMPO
oxidation. The skipped diene of 3 could be prepared by a very
mild Stille coupling reaction between stannane 4 and carbonate 5
at 0 °C. Carbonate 5 could be prepared from vinyl iodide 6 and
aldehyde 7 by NHK coupling.3
The structure of 1 includes a 14-membered macrolide
containing two (Z)-trisubstituted olefins and one (E)-disubstituted
olefin. In addition, the two trisubstituted olefins are sequenced as
a skipped-form. Thus, koshikalide (1) is highly functionalized
despite the size of the macrolactone ring. So far, there has been
only one published synthetic study of 1.2 In that report, the
authors encountered isomerization of the skipped diene
throughout the synthesis, and finally achieved the construction of
the 14-membered core structure by a nonbasic lactonization
method using a Mitsunobu reaction. Based on this previous
knowledge, we envisioned the retrosynthesis of koshikalide (1)
as follows (Scheme 1).
Scheme 1. Retrosynthesis of koshikalide(1)
 Corresponding author. Tel.: +81-45-566-1819; fax: +81-45-566-1819; e-mail: suenaga@chem.keio.ac.jp (K. Suenaga)

2
Tetrahedron Letters
Scheme 2. Synthesis of carbonate 5
Scheme 3. Total synthesis of koshikalide (1)
Table 1. Optical rotation of koshikalide (1)
First, we synthesized carbonate 5 as follows (Scheme 2). The
Type
Specific rotation
known aldehyde 84 was converted to vinyl iodide 6 by a Takai
reaction,5 and aldehyde 7 was prepared from allyl alcohol 96 in
two steps. These two fragments (6 and 7) were connected by
NHK coupling to afford allyl alcohol 10 in 36% yield along with
its epimer at C-11.7 The stereochemistry of the hydroxyl group in
10 was established by a modified Mosher’s method.8 Methylation
of 10 gave methyl ether 11,9 and methanolysis of the acetyl group
in 11 followed by carbonation using methyl chloroformate
afforded carbonate 5 in good yield (91% in three steps).
Halogen-lithium exchange of the known vinyl iodide 1210
followed by tin-lithium exchange and deprotection of a hydroxyl
group afforded allyl alcohol 4, quantitatively. The very mild
Stille coupling reaction between 4 and 5 at 0 °C proceeded
quantitatively to give skipped diene 3 as a 1:2 mixture of E:Z
isomers without migration of olefins. The TBS group of 3 was
removed with TBAF in good yield (88%), and the resulting allyl
alcohol was oxidized in two steps to afford carboxylic acid 2. To
avoid the undesired isomerization of olefins, macrolactonization
of 2 was carried out under mild conditions using Shiina
macrolactonization.11 Finally, deprotection of the trityl group by
PTSA afforded koshikalide (1) (Scheme 3). We did not obtain
any products derived from the 5E isomer of 3; they might de-
compose during macrolactonization.
Synthetic
Natural
[α]D25 -165 (c 0.02, MeOH)
[α]D22 +156 (c 0.03, MeOH)
In conclusion, the first total synthesis of koshikalide (1) was
achieved in 14 steps (longest linear sequence from nerol, a
precursor of 8.). Based on a comparison of the signs of the
specific rotations, the absolute stereochemistry of natural
koshikalide was determined to be (+)-1. Formation of the skipped
diene moiety was achieved using very mild Stille coupling at 0
°C without the migration of olefins.
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific
Research (B) (No. 24310160) from the Japan Society for the
Promotion of Science and the MEXT-Supported Program for the
Strategic Research Foundation at Private Universities, 2009-2013
from the Ministry of Education, Culture, Sports, Science and
Technology, Japan. We thank Sanyo Fine Co., Ltd. for their gift
of chiral trityl glycidyl ether.
References and notes
The spectral data of synthesized koshikalide (1) matched those
of natural koshikalide, except for the sign of the specific rotation
(Table 1). Therefore, the absolute stereochemistry of natural
koshikalide was established as an enantiomer of the synthesized
compound, (+)-1.
1.
2.
Iwasaki, A.; Teruya, T.; Suenaga, K. Tetrahedron Lett. 2010, 51,
959-960.
Venkanna, A.; Sreedhar, E.; Siva, B.; Babu, K.S.; Prasad, K. R.;
Rao, J. M. Tetrahedron: Asymmetry 2013, 24, 1010-1022.
Kishi, Y. Pure and Applied Chemistry 1998, 70, 339-344.
Fillion, E.; Beingessner R. L. J. Org. Chem. 2003, 68, 9485-9488.
3.
4.

3
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6.
Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408−7410.
Faul, M. M.; Winneroski, L. L.; Krumrich, C. A.; Sullivan, K. A.;
Gillig, J. R.; Neel, D. A.; Rito, C. J.; Jirousek, M. R. J. Org.
Chem. 1998, 63, 1961-1973.
At this stage, an undesired coupling product derived from Z-
isomer of 6 was also obtained (12%). This by-product was
removed by column chromatography.
Supplementary Material
Supplementary material (Experimental procedures and
spectroscopic data of new compounds) associated with this
article can be found, in the online version, at XXX.
7.
8.
9.
Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092–4096.
Frost, J. R.; Pearson, C. M.; Snaddon, T. N.; Booth, R. A.; Ley, S.
V. Angew. Chem. Int. Ed. 2012, 51, 9366-9371.
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10. Wang, Q.; Wei, H.; Schlosser, M. Eur. J. Org. Chem. 1999, 3263-
3268.
11. The yield of the macrolactonization step was poor, probably due
to the polymerization of 2.

Highlights
The first total synthesis of koshikalide was achieved.
The absolute configuration of koshikalide was established.
Formation of a skipped diene moiety was achieved using very mild Stille coupling.