Toward the synthesis of didemnaketal B: A convergent synthesis of the C9-C28 subunit

Article abstract of DOI:10.1021/ol801395q

(Chemical Equation Presented) Synthesis of the C9-C28 subunit of didemnaketal B has been developed. This subunit was convergently prepared from four chiral synthons and at the longest linear sequence required 16 steps.

Full text of DOI:10.1021/ol801395q

ORGANIC
LETTERS
2008
Vol. 10, No. 17
3873-3876
Toward the Synthesis of Didemnaketal
B: A Convergent Synthesis of the
C9-C28 Subunit
Hisanaka Ito,* Takaya Inoue, and Kazuo Iguchi
School of Life Sciences, Tokyo UniVersity of Pharmacy and Life Sciences, 1432-1
Horinouchi, Hachioji, Tokyo 192-0392, Japan
itohisa@ls.toyaku.ac.jp
Received June 20, 2008
ABSTRACT
Synthesis of the C9-C28 subunit of didemnaketal B has been developed. This subunit was convergently prepared from four chiral synthons
and at the longest linear sequence required 16 steps.
Didemnaketal B (1), which has been recognized as a potent
inhibitor of the HIV-protease, was isolated from ascidian of
the genus Didemnum by Faulkner and co-workers.1 The
planer structure of didemnaketal B was first disclosed in
1991,1 and the stereochemical properties, including an
absolute configuration, were derived from a combination of
spectroscopic and degradative studies.2 Aside from biological
activity, didemnaketal B contains a number of intriguing
structural features such as a spiroketal moiety and two side
chains with eight chiral centers. These structural and biologi-
cal properties have brought interest to synthetic organic
chemists. Although many of the efforts for the synthesis of
didemnaketal B and related compounds have been re-
ported,3,4 a total synthesis has not yet been reported.
Recently, we reported on a model study for the construction
of a spiroketal moiety through an enantioselective direct aldol
reaction using a chiral dinuclear zinc catalyst.5 In this
communication, we report our studies that have led to a
synthesis of the C9-C28 subunit 2 containing the spiroketal
moiety through a highly convergent strategy.
A highly convergent synthetic plan for 2 is shown in
Scheme 1. Subunit 2 would be accomplished by the addition
(3) Fan, X.; Flentke, G. R.; Rich, D. H. J. Am. Chem. Soc. 1998, 120,
8893.
(4) (a) Zhao, X.-Z.; Tu, Y.-Q.; Peng, L.; Li, X.-Q.; Jia, Y.-X. Tetrahe-
dron Lett. 2004, 45, 3713. (b) Zhao, X.-Z.; Peng, L.; Tang, M.; Tu, Y.-Q.;
Gao, S.-H. Tetrahedron Lett. 2005, 46, 6941. (c) Wang, P.-Z.; Tu, Y.-Q.;
Yang, L.; Dong, C.-Z.; Kitching, W. Tetrahedron: Asymmetry 1998, 9, 3789.
(d) Jia, Y.-X.; Wu, B.; Li, X.; Ren, S.-K.; Tu, Y.-Q.; Chan, A. S.-C.;
Kitching, W. Org. Lett. 2001, 3, 847. (e) Jia, Y.-X.; Li, X.; Wu, B.; Zhao,
X.-Z.; Tu, Y.-Q. Tetrahedron 2002, 58, 1697. (f) Jia, Y.-X.; Li, X.; Wang,
P.-Z.; Wu, B.; Zhao, X.; Tu, Y.-Q. J. Chem. Soc., Perkin Trans. 1 2002,
565.
(1) Potts, B. C. M.; Faulkner, D. J.; Chan, J. A.; Simolike, G. C.; Offen,
P.; Hemling, M. E.; Francis, T. A. J. Am. Chem. Soc. 1991, 113, 6321.
(2) Salomon, C. E.; Williams, D. H.; Lobkovsky, E.; Clardy, J. C.;
Faulkner, D. J. Org. Lett. 2002, 4, 1699.
(5) Ito, H.; Kawabe, C.; Iguchi, K. Heterocycles 2006, 67, 695.
10.1021/ol801395q CCC: $40.75
Published on Web 07/24/2008
2008 American Chemical Society

Scheme 1. Synthetic Plan of the C9-C28 Subunit
of bromide 3 to aldehyde 4 and following spiroketalization.
Fragment 3 would be synthesized from commercially avail-
able chiral synthons 5 and 6 through asymmetric dihydroxy-
lation. Fragment 4 would be prepared through the addition
of fragment 8 to fragment 7. Fragments 7 and 8 are
synthesized through diastereoselective methylation from an
L-glutamic acid (9) and an enantioselective alcoholysis of
10 using lipase, respectively.
a hydroxyl group, was examined. The SN2 reaction of the
anion, derived from 14, with a bromide 15 did not proceed
due to steric reasons around the carbon atom bearing a
Scheme 3. Synthesis of Fragment 7
Synthesis of the fragment 3 containing four chiral centers
began with a commercially available chiral synthon 5
(Scheme 2). Protection of the hydroxyl group of 5 and half-
reduction gave known aldehyde 11.6 Subsequent formation
of a carbon-carbon triple bond by the treatment of 11 with
the Ohira-Bestmann reagent 127 gave alkyne 13 in 61%
yield over the three steps. Subsequent treatment of 13 with
a Schwalts reagent (Cp2ZrHCl) and iodine provided (E)-
iodoalkene 14 in 89% yield. The coupling reaction of two
fragments 14 and 15, prepared from 6 by the protection of
Scheme 2. Synthesis of Fragment 3
bromine atom on 15. The coupling reaction of 14 with 15
was achieved by employing the Suzuki-Miyaura coupling
reaction8 after converting 15 to an organoboron reagent, and
16 was obtained in excellent yield (96%). The Sharpless
asymmetric dihydroxylation of 16 for the creation of two
Scheme 4. Synthesis of Fragment 8
3874
Org. Lett., Vol. 10, No. 17, 2008

Scheme 5. Synthesis of Subunit 2 through Coupling Reactions of Three Fragments, 7, 8, and 3
chiral centers and following protection of the resulting diol
moiety gave 17 in 57% yield for the two steps as a single
isomer. After deprotection of the TBDPS group of 17 and
bromination of the resulting hydroxy group, fragment 3 was
obtained (93% yield for the two steps).
Fragment 7 possessing two chiral centers was prepared
from L-glutamic acid (9) as shown in Scheme 3. Known
compound 18 was prepared from 9 through a three-step
sequence according to the literature procedure.9 Stereose-
lective methylation of 18 with LDA and iodomethane gave
19 in 95% yield (dr ) 10:1).10 The reduction of 19 to afford
the known diol 2011 and both hydroxyl groups of 20 were
converted to allyl ethers to obtain compound 21 (98% yield
for the two steps). Deprotection of the trityl group of 21,
followed by oxidation of the hydroxyl group, gave fragment
7 (73% yield for the two steps).
with a borane-dimethylsulfide complex, protection of the
hydroxyl group, and reduction of the isopropyl ester with
DIBAL-H gave 23 (64% for the three steps). The hydroxyl
group of 23 was tosylated, and the following introduction
of the acetylene unit by the addition of the lithium
acetylide-ethylenediamine complex gave 24 in 72% yield
over the two steps. Introduction of the methyl group to
terminal alkyne (92%) and site- and stereoselective iodination
of 25 using a Schwartz reagent and iodine produced fragment
8 in 80% yield.
Fragment 4 was synthesized through the coupling reaction
of fragments 7 with 8 (Scheme 5). The addition reaction of
a vinyllithium derivative, which was prepared from 8 by
treatment with an s-BuLi, with aldehyde 7 proceeded to give
26 in 77% yield as a diastereomeric mixture (1:1). Although
the addition reaction of the analogues of fragment 7 having
other protecting groups (MPM or MOM) was examined, the
diastereoselectivity of the reaction did not improve. At this
stage, separation of the diastereomer was not successful.
Therefore, 26 was converted to 28 as a diastereomeric
mixture. Deprotection of allyl groups of 26 using a reaction
The synthesis of fragment 8 is shown in Scheme 4.
Compound 22 was prepared from 3-methylglutaric anhydride
(10) by enantioselective alcoholysis using lipase PS with
n-PrOH according to the literature procedure (98% yield,
92% ee).12 Reduction of the carboxylic acid moiety of 22
(6) Nicolaou, K. C.; Patron, A. P.; Ajito, K.; Richter, P. K.; Khatuya,
H.; Bertinato, P.; Miller, R. A.; Tomaszewski, M. J. Chem.-Eur. J. 1996,
2, 847.
(7) (a) Ohira, S. Synth. Commun. 1989, 19, 561. (b) Mu¨ller, S.; Liepold,
B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521.
(8) (a) Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun. 1979,
866. (b) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 20,
3437. (c) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11,
513.
(9) (a) Takano, S.; Yonaga, M.; Chiba, K.; Ogasawara, K. Tetrahedron
Lett. 1980, 21, 3697. (b) Takano, S.; Yonaga, M.; Ogasawara, K. Synthesis
1981, 265.
(10) Tomioka, K.; Cho, Y.-S.; Sato, F.; Koga, K. Chem. Lett. 1981,
1621.
(11) Kigoshi, H.; Suenaga, K.; Mutou, T.; Ishigaki, T.; Atsumi, T.;
Ishiwata, H.; Sakakura, A.; Ogawa, T.; Ojika, M.; Yamada, K. J. Org. Chem.
1996, 61, 5326.
Figure 1. NOE correlations of the spiroketal moiety of 2.
Org. Lett., Vol. 10, No. 17, 2008
3875

of a zirconocene equivalent13 and selective protection of a
1,2-diol moiety using 2,2-dimethoxypropane gave 28 in 86%
yield for two steps. After separation of diastereomers, the
desired diastereomer of 2814 was converted to a bromide 29
in 79% yield. One carbon elongation was examined by the
formylation of 29 using a t-BuLi with DMF, and fragment
4 was obtained in 53% yield. The coupling reaction of
fragments 3 and 4 was achieved as follows (Scheme 5).
Lithiation of 3 by the reaction of 3 with t-BuLi and an
addition of the resultant anion to aldehyde 4 gave compound
30 in excellent yield (94%). The hydroxyl group of 30 was
oxidized by Swern oxidation to give 31 in 76% yield. The
formation of a spiroketal moiety was achieved during the
deprotection of two acetonide groups by treating 31 with
TsOH in methanol, and subunit 2 was obtained in 86% yield
as a single isomer. The relative stereochemistry of the
spiroketal moiety of subunit 2 was determined by NOESY
spectra: NOE correlations of 2 are shown in Figure 1.
In conclusion, we have described a convergent synthesis
of the C9-C28 subunit of didemnaketal B. The present
strategy required only 16 steps even in the longest linear
sequence.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from the Ministry of Educa-
tion, Culture, Sports, Science, and Technology, Japan.
Supporting Information Available: Detailed experimen-
tal procedure and characterization data for new compounds
and 1H and 13C NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
(12) (a) Yamamoto, Y.; Yamamoto, K.; Nishioka, T.; Oda, J. Agric.
Biol. Chem. 1988, 52, 3087. (b) Yamamoto, Y.; Yamamoto, K.; Nishioka,
T.; Oda, J. Tetrahedron Lett. 1988, 29, 1717.
(13) Ito, H.; Taguchi, T.; Hanzawa, Y. J. Org. Chem. 1993, 58, 774.
(14) Relative stereochemistry of both diastereomers was determined by
NOESY spectra.
OL801395Q
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