First total synthesis of (-)-pericosine A from (-)-shikimic acid: Structure revision and determination of the absolute configuration of antitumor natural product pericosine A

Article abstract of DOI:10.1055/s-2006-944197

The first total synthesis of (-)-pericosine A, methyl (3R,4R,5R,6R)-6- chloro-3,4,5-trihydroxy-1-cyclohex-1-enecarboxylate, from (-)-shikimic acid was accomplished, which led to the revision of the relative configuration and the determination of the absol

Full text of DOI:10.1055/s-2006-944197

1
598
LETTER
First Total Synthesis of (–)-Pericosine A from (–)-Shikimic Acid: Structure
Revision and Determination of the Absolute Configuration of Antitumor
Natural Product Pericosine A
F
Y
irst Total
S
ynthes
o
is of (–)-Per
s
icosine
A
h
from (–)-Shi
i
kimic
A
h
cid ide Usami,* Yusuke Horibe, Isao Takaoka, Hayato Ichikawa, Masao Arimoto
Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan
Fax +81(726)901005; E-mail: usami@gly.oups.ac.jp
Received 11 March 2006
This paper is dedicated to the retirement of Professor Tadashi Kataoka of Gifu Pharmaceutical University.
The total synthesis of 3 is summarized in Scheme 1. The
Abstract: The first total synthesis of (–)-pericosine A, methyl
3R,4R,5R,6R)-6-chloro-3,4,5-trihydroxy-1-cyclohex-1-enecar-
boxylate, from (–)-shikimic acid was accomplished, which led to
the revision of the relative configuration and the determination of
the absolute configuration of the natural product as 3S,4S,5S,6S.
basic protocol of the transformations is the same as that of
our previous reports.4 The key reaction is the intro-
duction of a chloro atom at C-6 with retention of the ste-
reochemistry of alcohol 14.
(
,5
Key words: total synthesis, antitumor, natural product, pericosine
A, revised structure, absolute configuration
COOH
COOMe
a, b
c–e
OR
Pericosine A is a metabolite of the fungus Periconia
byssoides OUPS-N133 that was originally separated from
the sea hare Aplysia kurodai, which possesses potent
cytotoxic activity against P388 leukemia cells in vitro and
OH
O
HO
O
OH
shikimic acid (4)
5
6
: R = H
: R = TBDMS
1
significant antitumor activity in vivo. The originally re-
ported structure (1) proposed by Numata and co-workers
is shown in Figure 1. In spite of its remarkable activity
and undetermined absolute structure, there have been no
other reports about pericosine A. In our continuous study
of the syntheses of bioactive natural products and related
HO COOMe
HO COOMe
1
AcO
R O
g
f
OR2
O
O
O
O
O
2
–5
compounds focusing on small molecules, we have been
interested in pericosines because of their unique multi-
functionalized cyclohexenoid structure of carbasugars
10
7
8
: R = H, R2 = TBDMS
1
1
2
: R = Ac, R = TBDMS
1
2
9: R = Ac, R = H
6
that presents the possibility of various activities. We
COOMe
COOMe
attempted the total synthesis of 1 and found that 1 was the
1
AcO
R O
h–j
k
7
incorrect structure of pericosine A. At the same time, the
OR2
diastereomer (2) was also synthesized. Therefore, the
determination of the correct structure of pericosine A
became our next task. Inspired by the original data of the
O
O
O
O
O
1
12: R1 = Ac, R2 = H
natural product in the literature and our previous syn-
11
5
,7
13: R1 = Ac, R2 = TBDMS
thetic compounds, we set the next target molecule (3).
Described herein are the first total synthesis and the struc-
ture revision of the antitumor natural product pericosine A
with the determination of its absolute configuration.
1
4: R1 = H, R2 = TBDMS
COOMe
Cl
l
(–)-3
OR2
O
COOMe
COOMe
COOMe
O
Cl
Cl
Cl
1
5
OH
OH
OH
OH
OH
OH
HO
HO
HO
Scheme 1 Reagents and conditions: a) ref. 9; b) TBDMSCl, imida-
zole, CH Cl (69%); c) cat. OsO , Me NO, t-BuOH–pyridine–
H O = 20:5:1, 90 °C (98%); d) Ac O, pyridine (91%); e) n-Bu NF,
1
2
(+)-3
2
2
4
3
2
2
4
Figure 1
THF (77%); f) Dess–Martin periodinane, CH Cl (quant.); g)
2
2
(
CF CO) O, pyridine, (76%); h) NaBH , THF (95%); i) TBDMSCl,
3
2
4
imidazole, CH Cl (53%); j) K CO , MeOH (74%); k) SOCl , CH Cl
2
2
2
3
2
2
2
SYNLETT 2006, No. 10, pp 1598–1600
2
1
.0
6
.2
0
0
6
(12%); l) CF COOH, MeOH (50%).
3
Advanced online publication: 12.06.2006
DOI: 10.1055/s-2006-944197; Art ID: U02506ST
Georg Thieme Verlag Stuttgart · New York
©

LETTER
First Total Synthesis of (–)-Pericosine A from (–)-Shikimic Acid
1599
COOMe
COOMe
COOMe
2
,2-dimethoxypropane
catalytic TsOH
AcO
AcO
HO
AcO
HO
TFA/MeOH
12
+
OH
OH
OH
O
O
O
O
16
17
18
Scheme 2
Shikimic acid (4), which can be synthesized from (–)- be 3 and the absolute stereochemistry of the natural prod-
8
quinic acid, was transformed into known alcohol 5 uct was elucidated to have the 3S,4S,5S,6S-configuration.
9
with a known method. Treatment of 5 with tert-butyl- Again, we note here that the structure of key intermediate
dimethylsilyl chloride and imidazole gave silyl ether 6 in 15 with the b-configuration of the chloro atom at C-6 was
6
9% yield. Then, dihydroxylation with a catalytic amount proved by disagreement of 3 against 2. From the structure
of osmium tetroxide and one equivalent of trimethylamine of 15, we speculated that this key stereospecific reaction
N-oxide with heating at 90 °C gave a single diastereomer of chloro induction proceeded not in a S i manner as we
N
7
in 98% yield. The stereochemistry of the newly generat- aimed, but in a S 2¢ manner. Further efforts to improve
N
ed hydroxyl groups was confirmed by analysis of the the chemical yield of this process are ongoing.
NOESY spectra of 7, revealing cross peaks H-2/H-6b and
In conclusion, we have accomplished the first total syn-
thesis of (–)-pericosine A (3) from (–)-shikimic acid (4),
which is the antipode of the natural product. Each stereo-
selective process in this synthesis proceeded with excel-
lent selectivity. From this total synthesis, the structure of
natural pericosine A was revised with elucidation of the
absolute configuration to methyl (3S,4S,5S,6S)-6-chloro-
H-3/H-5. Treatment of 7 with one equivalent of acetic an-
hydride and pyridine gave monoacetate 8 in 91% yield,
and this was followed by deprotection of the silyl group
with tetrabutylammonium fluoride to afford alcohol 9 in
7
9
7% yield. Subsequent oxidation of the hydroxyl group in
with Dess–Martin periodinane gave the corresponding
b-hydroxyketone 10 quantitatively, and then 10 was treat-
ed with trifluoroacetic anhydride and pyridine to afford
a,b-unsaturated ketone 11 in 76% yield. The following
careful reduction of 11 with a stoichiometric amount of
3
,4,5-trihydroxy-1-cyclohex-1-enecarboxylate.
Acknowledgment
NaBH in dry THF at –10 °C gave a single diastereomer
4
We are grateful to Mr. K. Minoura and Ms. M. Fujitake of this
University for NMR and MS measurements, respectively. And we
1
0
1
2 in 95% yield with recovery of 3% of 11. The addition
of an excess amount of reductant gave a mixture of de- are also appreciative of Dr. T. Yamada for kindly providing the
1
2
sample of natural pericosine A. This work was supported in part
by a Grant-in-Aid for the ‘High-Tech Research Center’ Project for
Private Universities: matching fund subsidy from MEXT (Ministry
of Education, Culture, Sports, Science, and Technology), 2002–
sired 12 and reproduced 6. In the reaction forming 6, the
acetoxy group at C-6 in 11 was cleaved off, together with
double bond migration by the hydride attack at C-2. The
subsequent protection process was also carried out
carefully to give the desired product 13 in 53% yield with
recovery of 12 in 25% yield by adding tert-butyldimethyl-
silyl chloride and a stoichiometric amount of imidazole.4
Then, 13 was converted into enol 14 in 74% yield. The
subsequent key reaction in this synthesis was carried out
with the addition of thionyl chloride at 0 °C in dry dichlo-
romethane to give the chlorinated product 15 in 12%
yield. The structure of 15 except for the stereochemistry
at C-6 was confirmed by the detailed analyses of 1-D and
2
006, Japan.
References and Notes
(
1) Numata, A.; Iritani, M.; Yamada, T.; Minoura, K.;
Matsumura, E.; Yamori, T.; Tsuruo, T. Tetrahedron Lett.
1997, 38, 8215.
2) Usami, Y.; Numata, A. Synlett 1999, 723.
3) Usami, Y.; Ikura, T.; Amagata, T.; Numata, A. Tetrahedron:
Asymmetry 2000, 11, 3711.
4) Usami, Y.; Numata, A. Chem. Pharm. Bull. 2004, 52, 1125.
5) (a) Usami, Y.; Hatsuno, C.; Yamamoto, H.; Tanabe, M.;
Numata, A. Chem. Pharm. Bull. 2004, 52, 1130. (b) Usami,
Y.; Hatsuno, C.; Yamamoto, H.; Tanabe, M.; Numata, A.
Chem. Pharm. Bull. 2005, 53, 271.
(
(
(
(
2
-D NMR spectra, such as COSY, NOESY, HMQC, and
HMBC. In the NOESY spectra of 15, cross peaks H-3/H-
, H-5/t-Bu, H-6/t-Bu, H-5/SiMe, H-6/SiMe and H-3, H4/
5
one of cyclohexyl methylene were observed. Observing
the cross peaks H-3, H-4/singlet carbon at d = 110.75 ppm
in HMBC spectra of 15 also supported the structure. Then,
the deprotection of 15 with trifluoroacetic acid gave the
(
6) For reviews, see: (a) Suami, T. Pure Appl. Chem. 1987, 59,
1
509. (b) Suami, T.; Ogawa, S. Adv. Carbohydr. Chem.
Biochem. 1990, 48, 21. (c) Suami, T. Top. Curr. Chem.
990, 154, 257. (d) Berecibar, A.; Grandjean, C.;
1
1
1
final product 3 in 50% yield, which was not the same as
the diastereomer 2 that had an all-cis stereochemistry of
the functional groups on the cyclohexene ring we synthe-
Sinwardena, A. Chem. Rev. 1999, 99, 779.
(
7) Usami, Y.; Ueda, Y. Chem. Lett. 2005, 34, 1062.
(8) Barco, A.; Benetti, S.; Risi, C. D.; Marchetti, P.; Pollini, G.
P.; Zanirato, V. Tetrahedron: Asymmetry 1997, 8, 3515.
9) Ulibarri, G.; Nadler, W.; Skrydstrup, T.; Audrain, H.;
7
sized previously, but was pericosine A except for the sign
(
of the specific rotation. From these results, the revised
relative stereochemistry of pericosine A was proposed to
Chianori, A.; Riche, C.; Grierson, A. A. J. Org. Chem. 1995,
60, 2753.
Synlett 2006, No. 10, 1598–1600 © Thieme Stuttgart · New York

1
600
Y. Usami et al.
LETTER
(
10) The stereochemistry of the new stereogenic center at C-3 in
(11) HPLC conditions: column: SHIMPACK ODS, 2 × 25 cm,
12 was determined by the following experiments. Treatment
Shimadzu; eluent: MeOH–CH Cl (50:50); flow rate: 4 mL/
2
2
of 12 with TFA in MeOH at r.t. gave triol 16, which was the
same as the compound we synthesized as racemate.
min; t = 32 min.
R
4
20
Spectroscopic data of synthesized (–)-3: oil; [a]D –98 (c
Similarly to our previous report, 12 was treated with
dimethoxypropane and catalytic TsOH to afford a mixture of
acetonides (17 as the major component and 18 as the minor
component) as shown below, and its NOESY spectrum had
cross peaks H-3/H-5, H-3, H-4/one of acetonide methyl
groups in 17 and H-4¢, H-5¢/one of acetonide methyl groups
in 18 (Scheme 2).
0.04, EtOH). IR (liquid film): 3366 (OH), 1725 (C=O), 1653
–
1 1
(C=C) cm . H NMR (acetone-d ): d = 3.80 (3 H, s,
6
COOMe), 4.07 (1 H, dd, J = 4.4, 1.9 Hz, H-4), 4.12 (1 H, dd,
J = 4.6, 1.9 Hz, H-5), 4.38 (1 H, br dd, J = 4.4, 3.9 Hz, H-3),
4.90 (1 H, dd, J = 4.6, 0.8 Hz, H-6), 6.91 (d, J = 3.9 Hz, H-
3
5
+
2). HRMS (EI): m/z calcd for C H O Cl [M + H] :
223.0372; found: 223.0370.
8
12
5
(
12) HPLC conditions: same as above; t = 32 min. Specific
R
rotation of natural (+)-3: [a] +104 (c, 0.04, EtOH).
D
Synlett 2006, No. 10, 1598–1600 © Thieme Stuttgart · New York