Facile and efficient synthesis of naturally occurring carbasugars (+)-pericosines A and C

Article abstract of DOI:10.1021/ol9008188

An efficient synthesis of antitumor marine natural product (+)-pericosine A was achieved from (-)-quinic acid in 11.7% overall yield, which is 20 times better than our previously reported synthesis. The crucial steps of this synthesis include the regio- a

Full text of DOI:10.1021/ol9008188

ORGANIC
LETTERS
2009
Vol. 11, No. 12
2699-2701
Facile and Efficient Synthesis of
Naturally Occurring Carbasugars
(+)-Pericosines A and C†
Yoshihide Usami,* Marie Ohsugi, Koji Mizuki, Hayato Ichikawa, and
Masao Arimoto
Osaka UniVersity of Pharmaceutical Sciences, 4-20-1 Nasahara,
Takatsuki, Osaka 569-1094, Japan
usami@gly.oups.ac.jp
Received April 15, 2009
ABSTRACT
An efficient synthesis of antitumor marine natural product (+)-pericosine A was achieved from (-)-quinic acid in 11.7% overall yield, which
is 20 times better than our previously reported synthesis. The crucial steps of this synthesis include the regio- and stereoselective
bromohydrination of an unstable diene and the ring opening of an epoxide. This synthetic route was applicable to a synthesis of (+)-
pericosine C and also to a synthesis of (-)-pericosine C.
The isolation of pericosines A-E, 1-5, respectively, as
cytotoxic metabolites of Periconia byssoides OUPS-N133
originally separated from the sea hare, Aplysia kurodai, was
reported in 1997 and 2007.1,2 Because this series of
compounds have a multifunctionalized cyclohexene core that
is typical of carbasugars,3,4 we have been interested in their
syntheses and the synthesis of their related compounds.5-9
Among them, pericosine A (1) is the most important one
because it was reported to possess significant inhibitory
activity against protein kinase EGFR (epidermal growth
factor receptor) and human topoisomerase II in addition to
antitumor activity against P388 in vivo.2 The absolute
configurations of 1-4 were determined by their total
syntheses.6-8,10 However, the overall yields in the first total
synthesis of (-)- and (+)-1 were not satisfactory, although
the absolute configuration of natural 1 was elucidated.7
† This paper is dedicated to Professor Kaoru Fuji on the occasion of his
retirement from Hiroshima International University.
(1) Numata, A.; Iritani, M.; Yamada, T.; Minoura, K.; Matsumura, E.;
Therefore, we desired to devise a more efficient synthetic
route for (+)-1 in the hope that it could be amenable to the
construction of analogues. Naturally occurring pericosine C
(3) was reported to be an enantiomeric mixture,2 and we
have reported the synthesis of (+)-3,6 which exists as a minor
component in nature. We are also interested in the synthesis
of (-)-3.
Yamori, T.; Tsuruo, T. Tetrahedron Lett. 1997, 38, 8215–8218
(2) Yamada, T.; Iritani, M.; Ohishi, H.; Tanaka, K.; Doi, M.; Minoura,
K.; Numata, A. Org. Biomol. Chem. 2007, 5, 3979–3986
(3) Arjona, O.; Gomez, A. M.; Lopez, J. C.; Plumet, J. Chem. ReV. 2007,
107, 1919–2036
(4) Sanchez-Abella, L.; Fernandez, S.; Armesto, N.; Ferrero, M.; Gotor,
V. J. Org. Chem. 2006, 71, 5396–5399
.
.
.
.
(5) Usami, Y.; Ichikawa, H.; Arimoto, M. Int. J. Mol. Sci. 2008, 9, 401–
421
.
(6) Usami, Y.; Hatsuno, C.; Yamamoto, H.; Tanabe, M.; Numata, A.
Chem. Pharm. Bull 2004, 52, 1130–1133; Erratum Chem. Pharm. Bull. 2005,
(8) Usami, Y.; Mizuki, K.; Ichikawa, H.; Arimoto, M. Tetrahedron:
Asymmetry 2008, 19, 1460–1463
(9) Usami, Y.; Suzuki, K.; Mizuki, K.; Ichikawa, H.; Arimoto, M. Org.
Biomol. Chem. 2009, 7, 315–318
(10) Donohoe, T. J.; Blades, K.; Helliwell, M.; Warning, M. J.;
Newcombe, N. J. Tetrahedron Lett. 1998, 39, 8755–8758
.
53, 271
.
(7) Usami, Y.; Takaoka, I.; Ichikawa, H.; Horibe, Y.; Tomiyama, Y.;
.
Otsuka, M.; Imanishi, Y.; Arimoto, M. J. Org. Chem. 2007, 72, 6127–
6134
.
.
10.1021/ol9008188 CCC: $40.75
Published on Web 05/27/2009
 2009 American Chemical Society

In 1990, two Japanese groups jointly reported the isolation
of the first chlorine-containing shikimate-related metabolite
(6) from two fungi.11 In 1993, an Italian group isolated
cyathiformines C (7) and A (8)12 from the Basidiomycetous
fungus, and 7 was synthesized from 6 in a previous study.11
Two papers on the synthesis of 7 via 8 based on the
biosynthetic hypothesis were published independently.13,14
Structurely, these chlorine-containing natural products are
closely related to pericosines. Inspired by these series of
studies, we have devised a simpler and more effective
synthetic route for (+)-1. The key reactions of our new
avenue involve the regio- and stereoselective bromohydri-
nation of an unstable diene and the regio- and stereoselective
ring opening of an epoxide. Described herein are the simple,
facile, and efficient synthesis of (+)-1 from (-)-quinic acid
in 12 steps and its application to the synthesis of both
enantiomers of pericosine C. The synthesis of (+)-1 is
summarized in Scheme 1. Commercially available (-)-quinic
Figure 1. Structures of naturally occurring pericosines and related
compounds.
Scheme 1. Synthesis of (+)-Pericosine A
at room temperature to give bromohydrins 12 and 13 in 48%
and 20% yields, respectively. The constitution of 12 and 13
were determined on the basis of 2D-NMR analysis, including
COSY, HSQC, and HMBC. The relative stereochemistry of
12 was determined on the basis of NOESY analysis where
cross peaks H-4/H-6 and 6-OH/H-5 were observed. The
relative stereochemistry of 13 was determined by comparing
the coupling constants in the 1H NMR spectra with those of
related compounds that were synthesized previously.8
A
plausible explanation for production of 12 is formation of
the cyclic bromonium cation on the less hindered R-face by
NBS followed by SN2-type ring opening. A probably minor
part of the cyclic bromonium cation was opened with the
double bond rearrangement into an incipient carbocation,
which was attacked from the less hindered R-face by water,
affording 13. The same reaction at 0 °C lowered the product
yield.
Bromohydrin 12 was treated with LHMDS to afford
epoxide 14 in 85% yield. The relative configuration of 14
was confirmed by comparing with the trans-epoxide that
appeared in our previous paper.7 This assignment supported
the relative stereochemistry of 12 and 13. Epoxide 14 was
treated with HCl in dry diethyl ether to give chlorohydrin
15 in 85% yield as the sole product, whereas a similar
reaction involving the corresponding trans-epoxide afforded
several isomers in our previous study.8 The ring-opening
reaction of 14 excluded the SN′-type side reaction. A plausible
explanation for this excellent selectivity is illustrated in
Figure 2. The original π*C1-C2 orbital for the SN′-type
reaction is distorted to become highly reactive, which means
that the energy level is lowered, and more extended in the
acid was converted into methyl ent-3-epiquinate derivative
9 according to a literature method.7 Alcohol 9 was esterified
into triflate 10, which was eliminated with CsOAc to afford
an unstable diene 1115,16 in 39% isolated yield. Diene 11
was reacted with NBS in a H2O/1,4-dioxane solvent system
(11) Kitamura, E.; Hirora, A.; Nakagawa, M.; Nakamura, M.; Nozaki,
H.; Tada, T.; Nukina, M.; Hirota, H. Tetrahedron Lett. 1990, 30, 4605–
4608.
(12) Arnone, A.; Cardillo, R.; Nasini, G.; Vajna de Pava, O. Tetrahedron
1993, 49, 7251–7258.
(15) Huntley, C. F. M.; Wood, H. B.; Ganem, B. Tetrahedron Lett. 2000,
41, 2031–2034.
(13) Meier, R.-M.; Ganem, B. Tetrahedron 1994, 50, 2715–2720
.
(16) Griesbeck, A. G.; Maria, C.; Neudoerfl, J. ARKIVOC 2007, 216–
(14) Tu, C.; Berchtold, G. A. J. Org. Chem. 1993, 58, 6915–6916
.
223.
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Org. Lett., Vol. 11, No. 12, 2009

pericosine C reported in the literature.2 Deprotection of 16
with TFA in MeOH afforded desired (+)-3 in 77% yield.
Another application of this new synthetic route toward (+)-
pericosine B (2) was also attempted. Chlorohydrin 15 was
treated with NaOMe in MeOH aiming for the SN2 process.
To our surprise, the product of this reaction was not the
precursor of 2 but alcohol (-)-176 in 55% yield, which is
the precursor of naturally preferred enantiomer (-)-3 as
shown in Scheme 2. The SN2 process around C-6 was
completely inhibited by steric hindrance by the neighboring
3,4-O-cyclohexylidene moiety. One possible explanation for
formation of (-)-17 is the R-face-selective SN′ reaction17,18
on 15 as seen in the first synthesis of 17 and the other is the
SN′-type reaction on 14, which should be regenerated from
15 under the basic condition. Then 14 was treated with
NaOMe in order to elucidate the mechanism. Production of
(-)-17 in 90% yield suggested the latter explanation is
reasonable.
Figure 2. Inhibition of SN′ reaction attacking distorted π* in 14.
ꢀ-face by orbital mixing with σ*C6-O in phase.17,18 However,
the ꢀ-face is markedly sterically hindered by the 3,4-O-
cyclohexylidene moiety in 15 such that a side reaction could
not occur. Assigned relative configuration of 15 was sup-
ported by agreement of the spectral data with those of the
reported acetonide of natural pericosine A.1,2
The enantiospecific synthesis was completed by adding TFA
in MeOH to give desired (+)-1 in 89% yield. When the
conversion of 9 into 12 was performed without purification of
intermediates, the isolated yield of 12 was improved to 35%
for the three steps. Thus, the overall yield of this 12-step
synthesis from (-)-quinic acid was 11.7%, which is 20 times
better than that of our initially reported synthesis.7
The synthesis of (-)-3 was completed by treating (-)-17
with TFA in MeOH in 97% yield. Noteworthy is the fact
that both enantiomers were prepared from single intermediate
14. This finding might give us a hint to understand the
biosynthetic pathway of naturally occurring 3 as an enan-
tiomeric mixture, as mentioned above. At the same time,
this result implies that there is a more rapid way to access
(+)- and (-)-3, because the antipode of 11 can be prepared
in four steps from (-)-quinic acid, whereas eight steps are
required from (-)-quinic acid to 11.
Not only is this synthetic route efficient, it is also
applicable to the synthesis of pericosine analogues. Therefore,
we demonstrated the synthesis of (+)-pericosine C (3), as
illustrated in Scheme 2. Treatment of epoxide 14 with
In summary, we have developed a facile and efficient total
synthesis of (+)-pericosine A (1). The overall yield of this
total synthesis from (-)-quinic acid improved to reach 11.7%
compared to 0.57% for the first synthesis. Using this new
synthetic route, both enantiomers (+)- and (-)-pericosine
C were prepared. Development of a more rapid preparation
of pericosine analogues via the antipode of 11 as mentioned
above and biological evaluation of synthesized pericosines
are ongoing.
Scheme 2. Synthesis of (+)- and (-)-Pericosine C
Acknowledgment. We are grateful to Dr. K. Minoura and
Ms. M. Fujitake of this University for NMR and MS
measurements, respectively. We especially express our thanks
to Professor Tony K. M. Shing of The Chinese University
of Hong Kong for useful discussion and many advices. This
work was supported in part by a Grant-in-Aid from “Dou-
soukai” of Osaka University of Pharmaceutical Sciences to
Y.U.
catalytic HCl in MeOH as solvent at room temperature
afforded 5-R-methoxyalcohol 16 in 91% yield. Relative
configuration of 16 was also assigned by comparison of the
NMR spectral data to those of an acetonide of natural
Supporting Information Available: Experimental pro-
1
cedures and copies of H and 13C NMR spectra of all new
compounds and synthesized (+)-1, (+)-3, (-)-3. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) Fukui, K.; Fujimoto, H. Bull. Chem. Soc. Jpn. 1967, 40, 2018–
2025
.
(18) Magid, R. M. Tetrahedron 1980, 36, 1901–1930
.
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