Synthetic study toward antitumour natural product pericosine A

Article abstract of DOI:10.1246/cl.2005.1062

The stereoselective total synthesis of methyl (3R,4S,5S,6R)-6-chloro-3,4,5- trihydroxy-1-cyclohex-1-enecarboxylate (1), which had been reported as the antitumour marine natural product pericosine A, from (-)-quinic acid was achieved. From the total synthesis, it was confirmed that the reported stereostructure of pericosine A was incorrect because the spectroscopic data of the synthetic product were not identical with those of the natural compound. Copyright

Full text of DOI:10.1246/cl.2005.1062

1062
Chemistry Letters Vol.34, No.7 (2005)
Synthetic Study toward Antitumour Natural Product Pericosine A
Yoshihide Usamiꢀ and Yasuko Ueda
Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094
(Received May 10, 2005; CL-050617)
The stereoselective total synthesis of methyl (3R,4S,5S,6R)-
6-chloro-3,4,5-trihydroxy-1-cyclohex-1-enecarboxylate (1),
and co-workers,5 and its absolute configuration was elucidated.
However, there has been no report of the absolute stereostructure
of 1 so far. Because 1 exhibited significant antitumour activity
in vivo, its total synthesis was attempted. Described herein is
the stereoselective synthesis of 1 from commercially available
(ꢁ)-quinic acid (3).6,7
which had been reported as the antitumour marine natural prod-
uct pericosine A, from (ꢁ)-quinic acid was achieved. From the
total synthesis, it was confirmed that the reported stereostructure
of pericosine A was incorrect because the spectroscopic data of
the synthetic product were not identical with those of the natural
compound.
The synthesis of 1 is summarized in Scheme 1. According to
the literature,8 3 was converted into lactone (4). The trimethylsil-
yl enol ether derived from 4 was chlorinated with N-chlorosuc-
cinimide in DMF in 45% yield. The reaction proceeded with
excellent selectivity to give the desired stereoisomer (5). The
bromination or fluorination of 4 had been reported in literature,8
whereas this is the first report of the chlorination. The stereo-
chemistry at C-6 was deduced from the low-field shift (3.3
In 1997, the isolation and structure determination of perico-
sines A and B, which showed significant cytotoxic activity
against P388 lymphocytic leukemia cells and are the metabolites
of the fungus Periconia byssoides OUPS-N133 that was origi-
nally separated from the sea hare Aplysia kurodai,1 had been
reported by Numata and co-workers as shown in Figure 1
(1 and 2).
1
ppm) of the H-2-ꢀ proton8 in the H NMR spectrum of 5. The
reagent was surmised to approach the silyl enol ether from the
opposite side of the sterically hindered lactone bridge in the
molecule. The improvement of the chemical yield of this step
remains to be accomplished. Chloroketone 5 was reduced with
NaBH4 to give diol (6)9 in 68% yield, which was treated with
tetrabutylammonium fluoride to afford triol (7) in 67% yield.
The lactone ring of acetonide (8) derived from 7 was opened
with NaOMe to afford diol (9) in 90% yield and the generated
secondary hydroxyl group was oxidized with Dess–Martin
periodinane10 to give hydroxyketone (10)11 in 78% yield, which
was never dehydrated by any reagents. Then, the deprotection of
the hydroxyl groups followed by the protection as trimethylsilyl
ether gave ꢁ-hydroxyketone (12), which was dehydrated with
Martin’s sulfrane dehydrating reagent12 (bis[ꢀ,ꢀ-bis(trifluoro-
methyl)benzyloxy]dipheny sulfur) to afford ꢀ,ꢁ-unsaturated
ketone (13)13 in 65% yield. Enone 13 was treated with trifluo-
roacetic acid and MeOH to give dihydroxy-ꢀ,ꢁ-unsaturated
COOMe
COOMe
1
2
MeO
HO
Cl
6
3
4
5
OH
HO
OH
OH
OH
2
1
Figure 1.
They are thought to be a class of carbasugars. As carbasu-
gars have been reported to have antifungal, antiviral, or antitu-
mour activities,2 their stereoselective syntheses are an attractive
challenge for the synthetic chemist and they have been studied
extensively.3 We have been interested in the synthesis of perico-
sines and related compounds.4
In 1998, the total synthesis of 2 was reported by Donohoe
O
O
COOMe
OH
HO
COOH
HO
HO
HO
Cl
a, b, c
g
Cl
X
d, e, f
O
O
3
3
OH
O
R1O
HO
O
O
OH
(−)-quinic acid (3)
OR2
OTBDMS
4 : X = H,
5 : X = Cl
9
6 : R1 = H, R2 = TBDMS
7 : R1 = R2 = H
8 : R1 = R2 = isopropylidene
COOMe
COOMe
COOMe
HO
Cl
Cl
Cl
k, l
h, i, j
m
n
1
O
OH
O
O
R1O
R1O
O
OR2
OR2
15
10 : R1 = R2 = isopropylidene
11 : R1 = R2 = H
12 : R1 = R2 = TMS
13 : R1 = R2 = TMS
14 : R1 = R2 = H
Scheme 1. Reagents and conditions: a) Ref. 8; b) Et3N, TMSOTf, toluene, reflux; c) NCS, DMF, rt (45% in two steps); d) NaBH4 (68%);
e) n-Bu4NF (67%); f) 2,2-dimethoxypropane, CH2Cl2, catalytic TsOH (30%); g) NaOMe, MeOH (90%); h) Dess–Martin periodinane,
CH2Cl2 (78%); i) trifluoroacetic acid (TFA), MeOH (70%); j) TMSCl, Et3N (71%); k) Martin’s sulfrane dehydrating reagent, CH2Cl2
(65%); l) TFA, MeOH (quant.); m) Me4NBH(OAc)3, MeCN/AcOH (64%); n) 2,2-dimethoxypropane, acetone, catalytic TsOH (72%).
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.7 (2005)
1063
G. Casiraghi, Org. Lett., 1, 1213 (1999). b) M. L. Paoli, S. Piccini,
M. Rodriquez, and A. Sega, J. Org. Chem., 69, 2881 (2004).
c) S.-H. Yu and S. Chung, Tetrahedron: Asymmetry, 15, 581
(2004). d) C. Gravier-Pelletier, W. Maton, T. Dintinger, C.
Tellier, and Y. Le Merrer, Tetrahedron, 59, 8705 (2003).
a) Y. Usami and A. Numata, Chem. Pharm. Bull., 52, 1125
(2004). b) Y. Usami, C. Hatsuno, H. Yamamoto, M. Tanabe,
and A. Numata, Chem. Pharm. Bull., 52, 1130 (2004).
T. J. Donohoe, K. Blades, M. Helliwell, M. J. Waring, and
N. J. Newcombe, Tetrahedron Lett., 39, 8755 (1998).
A. Barco, S. Benetti, C. D. Risi, P. Marchetti, G. P. Pollini, and
V. Zanirato, Tetrahedron: Asymmetry, 8, 3515 (1997).
M. G. Banwell, N. L. Hungerford, and K. A. Jolliffe, Org. Lett., 6,
2737 (2004).
COOMe
Cl
COOMe
Cl
a, b
c
13
R1O
OH
HO
O
OR2
O
4
16 : R1 = R2 = TMS
17 : R1 = R2 = H
18
5
6
7
8
9
Scheme 2. Reagents and conditions: a) NaBH4, MeOH, ꢁ10 ꢃC;
b) TFA, MeOH (quant. in 2 steps); c) 2,2-dimethoxypropane,
catalytic TsOH, acetone (55%).
ketone (14) quantitatively, and 14 was reduced with tetramethyl-
ammonium triacetoxyborohydride14 in a stereoselective manner
to give the desired 115 in 64% yield. The stereochemistry of C-3
in 1 was proved by the following experiments.
M. K. Manthey, C. Gonzalez-Bello, and C. Abell, J. Chem. Soc.,
Perkin Trans. 1, 1997, 625.
Diol (6) was converted to tetraol (19) by treatment with trifluoro-
acetic acid in methanol under reflux. The stereochemistry of 19
was confirmed by analysis of 1H NMR spectroscopic data. 19:
(CD3OD) ꢂ 1.81 (1H, dd, J ¼ 13:5, 11.7 Hz, H-2ꢁ), 2.19 (1H,
dd, J ¼ 13:5, 5.0 Hz, H-2ꢀ), 3.45 (1H, dd, J ¼ 9:6, 3.0 Hz, H-
4), 3.78 (3H, s, COOMe), 3.98 (1H, ddd, J ¼ 11:7, 9.6, 5.0 Hz,
H-3), 4.10 (1H, dd, J ¼ 3:0, 2.8 Hz, H-5), 4.49 (1H, d, J ¼ 2:8
Hz, H-6). Observation of the NOESY cross peaks H-6/H-4,
H-6/H-2ꢁ, and H-4/H-2ꢁ in 19 supported the conformation
shown below. These results elucidated the stereochemistry of
C-6 in 5 or C-5 in 6.
As shown in Scheme 2, common intermediate 13 was re-
duced with NaBH4 to give 16. The subsequent deprotection of
16 gave 17,16 which is different from both 1 and natural perico-
sine A. 3,4-O-acetonide formation of 18 from diastereoisomer
17 implied that 3-OH and 4-OH in 17 had the cis-configuration.
Observation of the NOESY cross peaks between one of methyl
groups of acetonide and H-3, H-4 in 18 led the same assignment.
Therefore, the hydroxyl group at C-3 in synthesized 1 must have
the ꢁ-configuration. However, the spectroscopic data of 1 and
those of acetonide (15) were not identical with those of natural
pericosine A and those of its acetonide reported in the literature.1
Furthermore, an isopropylidene bridge in 15 was present not be-
tween O-3 and O-4 as described in the literature,1 but between
O-4 and O-5. The structure of 15 was suggested by observing
the cross peaks between the proton signal of one of two methyl
groups of the isopropylidene moiety and H-4 or H-5 in its
NOESY spectra. From this synthetic study, it became apparent
that 1 is the incorrect stereostructure of pericosine A.
In conclusion, we have accomplished the stereoselective to-
tal synthesis of methyl (3R,4S,5S,6R)-6-chloro-3,4,5-trihydroxy-
1-cyclohex-1-enecarboxylate (1) from (ꢁ)-quinic acid. The dis-
agreement of the spectroscopic data of 1 with those of natural
pericosine A suggested that the reported stereostructure of
pericosine A was incorrect. We will continue our synthetic study
toward the other stereoisomers in order to elucidate the correct
structure of pericosine A.
O
H
H
H
H
O
4
6
H
4
H
6
OH
H
Cl
HO
HO
HO
2
H
COOMe
H
H
Cl
OH
H
H
OH
OTBDMS
6
19
Figure 2.
10 D. B. Dess and J. C. Martin, J. Am. Chem. Soc., 113, 7277 (1991).
11 Observing the NOESY cross peaks H-6/H-4, H-6/H-2ꢁ, and
H-4/H-2ꢁ in 10 as in 19 suggested the configuration at C-4 as
shown in Scheme 1.
12 R. J. Alhart and J. C. Martin, J. Am. Chem. Soc., 94, 5003 (1972).
13 Observation of the NOESY cross peak between H-4 and H-6 in 13
suggested that H-4 and H-6 had the cis-configuration. And as
described in text part, observation of the cross peaks between
the proton signal of one of acetonide-methyl groups and H-4
or H-5 in the NOESY spectra of 15, which was derived from
13 via 1, implied that H-4 and H-5 had cis-configuration in 13.
Therefore the possibility of epimerization at C-4 or C-6 during
transformation from 12 to 13 was denied.
We are grateful to Mr. K. Minoura, Mrs. M. Fujitake, and
Mrs. S. Okabe of this university for NMR, and MS measure-
ments, and elemental analysis, respectively. This work was
supported in part by a Grant-in-Aid for ‘‘High-Tech Research
Center’’ Project for Private Universities: matching fund subsidy
from MEXT (Ministry of Education, Culture, Sports, Science
and Technology), 2002–2006, Japan.
14 D. A. Evans and K. T. Chapman, Tetrahedron Lett., 27, 5939
(1986).
30
15 Spectroscopic data of 1: oil; ½ꢀꢂD ꢁ71:1 (c 0.09, EtOH); IR
(liquid film) ꢃmax 3383 (OH), 1721 (C=O), 1652 (C=C) cmꢁ1
;
1H NMR (acetone-d6) ꢂ 3.72 (1H, dd, J ¼ 5:9, 2.3 Hz, H-4),
3.77 (3H, s, COOMe), 4.16 (1H, dd, J ¼ 4:1, 2.3 Hz, H-5), 4.46
(1H, m, H-3), 5.07 (1H, dt, J ¼ 4:1, 1.4 Hz, H-6), 6.73 (1H, d,
J ¼ 3:0, 1.4 Hz, H-2). 13C NMR (acetone-d6) ꢂ 52.22 (q), 57.99
(d), 69.56 (d), 70.64 (d), 75.28 (d), 130.87 (d), 141.63 (s),
166.44 (s). HRCIMS Calcd for C8H12O5 35Cl ðM þ HÞþ,
223.0372; Found, 223.0360.
This paper is dedicated to the memory of the late Professor
Kiyoshi Tanaka of University of Shizuoka.
30
References and Notes
16 Spectroscopic data of 17: oil; ½ꢀꢂD þ58:3 (c 0.01, EtOH); IR
1
A. Numata, M. Iritani, T. Yamada, K. Minoura, E. Matsumura,
T. Yamori, and T. Tsuruo, Tetrahedron Lett., 38, 8215 (1997).
For a review: a) T. Suami, Pure Appl. Chem., 59, 1509 (1987).
b) T. Suami and S. Ogawa, Adv. Carbohydr. Chem. Biochem.,
48, 21 (1990). c) T. Suami, Top. Curr. Chem., 154, 257 (1990).
d) A. Berecibar, C. Grandjean, and A. Sinwardena, Chem. Rev.,
99, 779 (1999).
(liquid film) ꢃmax 3373 (OH), 1726 (C=O), 1653 (C=C) cmꢁ1
;
1H NMR (acetone-d6) ꢂ 3.76 (3H, s, COOMe), 3.94 (1H, dd,
J ¼ 5:0, 2.1 Hz, H-5), 4.09 (1H, m, H-4), 4.33 (1H, m, H-3),
4.99 (1H, br d, J ¼ 5:0 Hz, H-6), 6.79 (1H, br dd, J ¼ 2:5,
1.3 Hz, H-2). 13C NMR (acetone-d6) ꢂ 52.32 (q), 56.46 (d),
68.83 (d), 68.98 (d), 71.59 (d), 132.03 (d), 142.7þ1 (s), 168.00
(s). HRCIMS Calcd for C8H12O5 35Cl ðM þ HÞ , 223.0372;
Found, 223.0379.
2
3
a) G. Rassu, L. Auzzas, L. Pinna, F. Zanardi, L. Battistini, and
Published on the web (Advance View) June 25, 2005; DOI 10.1246/cl.2005.1062