Determination of the absolute configuration of the cytotoxic natural product pericosine D

Article abstract of DOI:10.1016/j.tetasy.2008.06.008

The synthesis of two diastereomers of pericosine A from (-)-quinic acid was achieved, thus enabling the confirmation of the relative configuration and elucidation of the absolute stereochemistry of cytotoxic natural product pericosine D assigned as methyl (3R,4R,5S,6R)-6-chloro-3,4,5-trihydroxy-1-cyclohexene-1-carboxylate.

Full text of DOI:10.1016/j.tetasy.2008.06.008

Tetrahedron: Asymmetry 19 (2008) 1461–1464
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Determination of the absolute configuration of the cytotoxic natural product
pericosine D
*
Yoshihide Usami , Koji Mizuki, Hayato Ichikawa, Masao Arimoto
Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of two diastereomers of pericosine A from (ꢀ)-quinic acid was achieved, thus enabling the
confirmation of the relative configuration and elucidation of the absolute stereochemistry of cytotoxic
natural product pericosine D assigned as methyl (3R,4R,5S,6R)-6-chloro-3,4,5-trihydroxy-1-cyclohex-
ene-1-carboxylate.
Received 30 April 2008
Accepted 4 June 2008
Available online 28 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
This paper is dedicated to Professor Takushi
Kurihara on the occasion of his retirement
from Osaka University of Pharmaceutical
Sciences
1. Introduction
COOMe
COOMe
COOMe
MeO
HO
Cl
MeO
HO
In recent research of marine natural products, a new area has
emerged, which involves studies of the metabolites of microorgan-
isms from marine sources.1,2 Over the course of such studies, Nu-
mata et al. isolated a series of unique and highly functionalized
C-7 cyclohexenoid-type natural products designated pericosines
A-D 1–4, which are cytotoxic metabolites of the fungus Periconia
byssoides OUPS-N133 originally separated from the sea hare Aplysia
kurodai.3–7 These compounds are expected to exhibit various bio-
logical activities, including antiviral, antifungal, and antitumor
activities, because of the multi-functionalized carbasugar cyclo-
hexenoid structure.
OH
HO
OH
OH
OH
OH
OH
pericosine A 1
epimer of pericosine B 3
pericosine B 2
(antipode of pericosine C)
COOMe
Cl
COOMe
COOMe
Cl
Cl
Synthetic studies of carbasugars have been actively pursued
worldwide because of their importance in synthetic organic chem-
istry and natural products chemistry.8,9 Over the course of our syn-
thetic studies on bioactive natural products and their analogues,
focusing on small molecules, we have been interested in the peric-
osines because of the reason described above.10–15 The absolute
stereostructures of pericosines A and B were determined by total
syntheses.14–16 However, the relative stereochemistry of 3 and 4
remained ambiguous when we had started this project.4,5 The syn-
thesis of pericosine D, a diastereoisomer of pericosine A 1, was at-
tempted in order to elucidate its relative and absolute
stereostructures. The only certain information about the stereo-
chemistry of pericosine D we were able to determine was the cis-
configuration between H-3 and H-4.5 There are four possible dia-
stereoisomers with such relative chemistries, including 1 and 6,
both of which were synthesized in our previous studies and were
HO
OH
OH
OH
HO
HO
OH
OH
pericosine D 4
OH
diastereomer of
diastereomer of
pericosine A 6
pericosine A 5
Figure 1. Structures of pericosines and related compounds.
different from pericosine D12–15 (Fig. 1). Therefore, the relative con-
figuration of pericosine D must be either 4 or 5. Herein, we report
the short total synthesis of 4 and 5, which enabled confirmation of
the relative stereochemistry and determination of the absolute
configuration of pericosine D 4 as methyl (3R,4R,5S,6R)-6-chloro-
3,4,5-trihydroxy-1-cyclohexene-1-carboxylate.
2. Results and discussion
The synthesis of 4 and 5 was carried out as shown in Scheme 1.
Diene 7,17 prepared from (ꢀ)-quinic acid, was oxidized with
* Corresponding author. Tel.: +81 726901083; fax: +81 726901005.
E-mail address: usami@gly.oups.ac.jp (Y. Usami).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.06.008

1462
Y. Usami et al. / Tetrahedron: Asymmetry 19 (2008) 1461–1464
COOMe
COOMe
O
COOMe
O
mCPBA,
CH2Cl2, 40 o
C
HCl
+
O
O
O
8
9
)
70% (
+
O
O
O
7
8
9
COOMe
COOMe
(6.2)
COOMe
COOMe
Cl
HO
(2.1)
(6.2)
Cl
(1.8)
Cl
(5.3)
+
+
+
(2.5)
Cl
OH
(6.6) (1.8)
O
O
RO
OH
OH
RO
O
O
OR
OR
10: R = cyclohexylidene (26%)
11: R = cyclohexylidene (2%)
13
(2%)
12 (3%)
TFA
5
4
: R = H (37%)
: R = H (76%)
12
13
.
Numbers in parenthesis represent coupling constants in
and
Scheme 1. Synthesis of 4 and 5.
mCPBA at 40 °C to give an inseparable mixture of epoxides 8 and 9
in 70% combined yield in a ratio of ca. 3:2.18,19 However, their ste-
reochemical assignment was still ambiguous at this stage, even
when detailed NMR analysis of the mixture of 8 and 9 was con-
ducted. Our stereochemical deduction of 9 did not agree with ace-
tonide 14 illustrated in Figure 2, which was reported to be formed
via a similar synthesis.18,19 The stereochemistry at C-6 in 9 will be
determined later.
Treatment of a mixture of 8 and 9 with HCl in Et2O afforded four
chlorohydrins 10–13 in 26%, 2%, 3%, and 2% yields, respectively,20
with the recovery of unreacted 9 (20%). The structures of these
chlorohydrins were confirmed by 2D NMR analysis. The relative
chemistry of major chlorohydrin 10 was assigned on the basis of
NOESY cross peaks 5-OH/H-4, H-6. From this, the stereochemistry
of the starting epoxide 8 was suggested, as shown in Scheme 1.
COSY, HSQC, and HMBC analyses proved that the minor chlorohy-
drin 11 has the same planar structure as 10, and thus 11 must have
the desired relative configuration leading to 4 because it was
thought to be derived from the same precursor 8. The formation
of chlorohydrin 12, together with the migration of the double bond
in 8, was confirmed from HMBC cross peaks, C-2/H-3, H-4, H-6 and
C-1/H-3, H-5, H-6, and quaternary carbon (d 109.5 ppm)/H-4.
The stereochemistry at C-6 in 12 was determined by comparing
with the closely related compound 15 synthesized previously by us
(Fig. 2).12,13 The planar structure of chlorohydrin 13 was deter-
mined on the basis of COSY, HSQC, and HMBC spectra. This was
confirmed by an independent experiment in which a reaction of
the recovered pure epoxide 9 with HCl afforded 13 in 3% yield with
COOMe
COOMe
COOMe
COOMe
O
O
Cl
HO
(2.6)
(5.3)
(3.2) OH
(4.8)
(2.1)
OH
O
(7.0)
(5.7)
O(8.7)
O
O
O
O
O
O
O
16
17
14
15
COOMe
Cl
(3.9)
OH
COOMe
Cl
(3.7)
OH
COOMe
COOMe
OH
(3.6)
OH
COOMe
OH
(3.5)
OH
Cl
(3.7)
OH
(4.6)
(3.6)
(3.4)
(7.1)
(3.5)
O(7.1)
(5)
HO
(4)
(8.8)
(6.0) (6.0)
(4.6) (9.8)
(10)
OH
O
(8.5)
O
HO
O
O
O
OH
186
11
1923
4
2023
Numbers in parenthesis represent coupling constants in 4,11 and 15 - 20.
Figure 2. Structure and coupling constants of 4, 11 and related compounds.

Y. Usami et al. / Tetrahedron: Asymmetry 19 (2008) 1461–1464
1463
recovery of 9 in 78%. In the stereochemical inspection of 12 and 13,
the similarity of 1H NMR coupling constants to those of known diol
16, which was derived from peroxide 17,21 supported the relative
chemistry of 12 and 13 shown in Scheme 1, as well as the stereo-
chemistry of 8 and 9.
24.8, 35.2, 37.4, 46.1, 49.3, 52.3, 70.0, 70.8, 111.6, 127.1, 140.2,
165.5. Compound 9: 1H NMR (CDCl3) d 1.35–1.70 (10H, m), 3.81
(3H, s, COOMe), 3.92 (1H, d, J = 1.8 Hz, H-6), 4.49 (1H, ddd,
J = 7.1, 2.5, 1.8 Hz, H-4), 4.78 (1H, dd, J = 7.1, 1.8 Hz, H-5), 5.88
(1H, ddd, J = 10.2, 2.5, 0.7 Hz, H-3), 6.39 (1H, dd, J = 10.2, 1.8 Hz,
H-2); 13C NMR (CDCl3) d 23.7, 23.9, 24.9, 35.3, 37.3, 51.8, 52.9,
55.0, 69.8, 70.3, 111.5, 121.0, 132.1, 168.9.
Deprotection of 10 with TFA gave target compound 5,22 which
was different from pericosine D, in 76% yield. From this result,
the relative chemistry of pericosine D was confirmed as 4.6 Finally,
11was deprotected in the same way to afford 4 in 37% yield with
recovery of 11 in 23%. Since the spectral data of synthesized 4
agreed with those of natural 4, including the specific rotation,7
the absolute configuration of natural pericosine D was assigned
as methyl (3R,4R,5S,6R)-6-chloro-3,4,5-trihydroxy-1-cyclohexene-
1-carboxylate. Similarity of coupling constants in 1H NMR spectra
of 4 and 11 to those of closely related compounds 18–206,23shown
in Figure 2 also supported our conclusion for correction of the data
of natural 4.
4.3. Methyl (3R,4R,5S,6S)-6-chloro-3,4-O-cyclohexylidene-3,4,5-
trihydroxy-1-cyclohexene-1-carboxylate 10, methyl
(3R,4R,5S,6R)-6-chloro-3,4-O-cyclohexylidene-3,4,5-trihydroxy-
1-cyclohexene-1-carboxylate 11, methyl (3R,4S,5R,6S)-6-chloro-
3,4-O-cyclohexylidene-3,4,5-trihydroxy-1-cyclohexene-1-
carboxylate 12 and methyl (3R,4S,5R,6S)-3-chloro-3,4-O-
cyclohexylidene-4,5,6-trihydroxy-1-cyclo hexene-1-carboxylate
13
To a mixture of 8 and 9 (125.7 mg, combined amount) in Et2O
(40 mL) was added 1.0 M HCl in Et2O (600 lL). After stirring over-
3. Conclusion
night at rt, the reaction mixture was condensed under a reduced
pressure to afford a crude residue which was purified by prepara-
tive TLC (eluent: 2% MeOH in CH2Cl2) to give 10 (37.0 mg, 26%), 11
(3.2 mg, 2%), 12 (3.7 mg, 3%), and 13 (2.6 mg, 2%) with recovery of 9
(24.6 mg, 20%).
We have synthesized two diastereomers of pericosine A thus
confirming the relative chemistry of pericosine D. Our conclusion
is in agreement with a recent report on natural pericosines.6 Fur-
thermore the undefined absolute stereochemistry of natural peric-
osine D 4 was elucidated to be methyl (3R,4R,5S,6R)-6-chloro-
3,4,5-trihydroxy-1-cyclohexene-1-carboxylate.
Compound 10: colorless oil; ½a D25
ꢁ
¼ þ4:1 (c 1.65, CHCl3); IR (li-
quid film) mmax 3447 (OH), 1726 (C@O), 1653 (C@C) cmꢀ1
;
1H
NMR (CDCl3) d 1.37–1.76 (10H, m), 2.48 (1H, d, J = 4.1 Hz, 5-OH),
3.83 (3H, s, COOMe), 4.31 (1H, br dd, J = 5.7, 5.0 Hz, H-4), 4.43
(1H, br ddd, J = 5.0, 4.8, 4.1 Hz, H-5), 4.74 (1H, ddd, J = 4.8, 1.8,
0.9 Hz, H-6), 4.76 (1H, ddd, J = 5.7, 3.9, 1.1 Hz, H-3), 6.89 (1H,
ddd, J = 3.9, 0.9, 0.7 Hz, H-2); 13C NMR (CDCl3) d 23.7, 23.8, 24.9,
35.4, 37.5, 52.4, 52.7, 70.3, 72.1, 74.4, 111.7, 130.1, 135.8, 165.4;
4. Experimental
4.1. General information
HRMS m/z calcd for C14H19O35Cl (M)+ 302.0921, found 302.0920,
IR spectra were obtained with a JEOL FT/IR-680 Plus spectro-
meter. EIMS was determined with a JEOL JMS-700 (2) mass spec-
trometer. NMR spectra were recorded at 27 °C on Varian UNITY
INOVA-500 and Mercury-300 spectrometers in CDCl3 with tetra-
methylsilane (TMS) as internal reference. Specific rotations were
measured using a JASCO model DIP181 spectrometer. Liquid
column chromatography was conducted over silica gel (SILICYCLE,
Silia Flash F60, mesh 230–400). Analytical TLC was performed on
precoated Merck aluminum sheets (DC-Alufolien Kieselgel 60
F254), and compounds were detected by spraying an ethanol
solution of phosphomolybdic acid followed by heating. Dry THF
was distilled over sodium benzophenone ketyl under an argon
atmosphere.
5
m/z calcd for C14H19O37Cl (M)+ 304.0892, found 304.0891.
5
Compound 11: oil; ½a D25
ꢁ
¼ ꢀ121:3 (c 0.2, CHCl3); IR (liquid film)
m
max 3445 (OH), 1735 (C@O), 1644 (C@C) cmꢀ1 1H NMR (CDCl3) d
;
1.25–1.80 (10H, m), 2.39 (1H, d, J = 7.1 Hz, 5-OH), 3.83 (3H, s,
COOMe), 3.83 (1H, m, H-5), 4.39 (1H, dd, J = 8.8, 7.1 Hz, H-4),
4.88 (1H, dd, J = 7.1, 3.5 Hz, H-3), 5.03 (1H, d, J = 3.7 Hz, H-6),
7.11 (1H, d, J = 3.5 Hz, H-2); 13C NMR (CDCl3) d 23.6, 24.4, 25.0,
34.4, 37.3, 52.6, 55.0, 71.4, 72.0, 75.3, 111.0, 132.4, 137.2, 164.2;
HRMS m/z calcd for C14H19O35Cl (M)+ 302.0921, found 302.0920,
5
m/z calcd for C14H19O37Cl (M)+ 304.0892, found 304.0897.
5
Compound 12: oil; ½a D25
ꢁ
¼ þ18:1 (c 0.14, CHCl3); IR (liquid film)
m
max 3447 (OH), 1725 (C@O), 1653 (C@C) cmꢀ1 1H NMR (CDCl3) d
;
1.25–1.61 (10H, m), 2.19 (1H, d, J = 10.5 Hz, 3-OH), 3.85 (3H, s,
COOMe), 4.41 (1H, ddd, J = 10.5, 6.2, 1.8 Hz, H-3), 4.65 (1H, ddd,
J = 6.6, 1.8, 1.1 Hz, H-4), 4.84 (1H, dd, J = 6.6, 1.8 Hz, H-5), 5.07
(1H, dd, J = 1.8, 0.4 Hz, H-6), 7.33 (1H, br d, J = 6.2 Hz, H-2); 13C
NMR (CDCl3) d 23.5, 23.8, 25.0, 33.8, 36.1, 49.1, 52.5, 66.1, 76.5,
4.2. Methyl (3R,4R,5S,6R)-3,4-O-cyclohexylidene-5,6-epoxy-3,4-
dihydroxy-1-cyclohexene-1-carboxylate 8 and methyl
(1S,4R,5S,5S)-3,4-O-cyclohexylidene-1,6-epoxy-4,5-dihydroxy-
2-cyclohexene-1-carboxylate 9
77.7, 109.5, 132.7, 141.1, 164.8; HRMS m/z calcd for C14H19O35Cl
5
(M)+ 302.0921, found 302.0918, m/z calcd for C14H19O37Cl (M)+
To a solution of diene 7 (113.1 mg, 0.45 mmol) in CH2Cl2
(10 mL) was added mCPBA (93.7 mg, 1.2 equiv). After stirring at
40 °C for 15 h, the reaction mixture was treated with aq NaHCO3
and extracted with CH2Cl2. The organic layer was washed with
brine, dried over MgSO4 and filtered, after which the solvent was
removed under reduced pressure to give a crude residue that
was purified by column chromatography (eluent: hexane–
EtOAc = 10:1) to afford a mixture of 8 and 9 (85.1 mg, 70% in com-
bined yield). Data for the mixture of 8 and 9: IR (liquid film) mmax
1723 (C@O), 1654 (C@C) cmꢀ1; HRMS m/z calcd for C14H18O5
(M)+ 266.1154, found 266.1158. Compound 8: 1H NMR (CDCl3) d
1.35–1.70 (10H, m), 3.69 (1H, ddd, J = 3.7, 2.1, 0.5 Hz, H-5), 3.84
(3H, s, COOMe), 3.99 (1H, ddd, J = 3.7, 1.6, 0.7 Hz, H-6), 4.58 (1H,
dd, J = 6.9, 2.3 Hz, H-3), 4.81 (1H, ddt, J = 6.9,2.1,0.7 Hz, H-4), 6.83
(1H, ddd, J = 2.3, 1.6, 0.7 Hz, H-2); 13C NMR (CDCl3) d 23.7, 23.9,
5
304.0891, found 304.0892.
Compound 13: oil; ½a D25
ꢁ
¼ þ302:8 (c 0.009, CHCl3); IR (liquid
1H NMR
film) mmax 3458 (OH), 1723 (C@O), 1652 (C@C) cmꢀ1
;
(CDCl3) d 1.32–1.63 (10H, m), 3.00 (1H, d, J = 6.0 Hz, OH), 3.84
(3H, s, COOMe), 4.54-4.60 (3H, overlapped), 4.71 (1H, ddd, J = 5.8,
2.2, 0.9 Hz), 7.06 (1H, dd, J = 4.8, 1.1 Hz, H-2); 13C NMR (CDCl3) d
23.6 (t), 23.9 (t), 25.0 (t), 34.2 (t), 36.8 (t), 52.5 (q), 53.4 (d), 65.7
(d), 77.6 (d), 109.7 (s), 133.2 (s), 137.5 (d), 166.1 (s); 1H NMR (ace-
tone-d6) d 1.35–1.65 (10H, m), 3.79 (3H, s, COOMe), 4.55 (1H, dd,
J = 6.2, 2.1, H-5), 4.62 (1H, ddd, J = 6.2, 2.5, 0.9 Hz, H-4) 4.70 (1H,
dd, J = 5.3, 2.5 Hz, H-3), 4.76 (1H, d, J = 2.1 Hz, H-6), 6.99 (1H, dd,
J = 5.3, 0.9 Hz, H-2); 13C NMR (acetone-d6) d 24.4 (t), 24.7 (t),
25.7 (t), 35.0 (t), 37.6 (t), 52.4 (q), 55.1 (d), 64.4 (d), 78.1 (d), 78.9
(d), 109.8 (s), 134.4 (s), 137.0 (d), 166.6 (s); HRMS m/z calcd for

1464
Y. Usami et al. / Tetrahedron: Asymmetry 19 (2008) 1461–1464
C14H19O35Cl (M)+ 302.0921, found 302.0916, m/z calcd for
acetonide 186,7 of natural pericosine D with useful discussion, and
MS measurement, respectively. This work was supported in part by
a Grant-in-Aid from ‘Dousoukai’ of Osaka University of Pharmaceu-
tical Sciences to Y.U.
5
C
14H19O37Cl (M)+ 304.0892, found 304.0898.
5
Data of pure 9; ½a D25
ꢁ
¼ þ108:6 (c 0.73, CHCl3); oil; IR (liquid
film) mmax 1729 (C@O), 1652 (C@C) cmꢀ1 1H and 13C NMR same
;
as above; HRMS m/z calcd for C14H18O5 (M)+ 266.1154, found
266.1150.
References
1. Newman, D. J.; Cragg, G. M. Curr. Drug Targets 2006, 7, 279.
2. Fenical, W.; Jensen, P. R. Nat. Chem. Biol. 2006, 2, 666.
3. Numata, A.; Iritani, M.; Yamada, T.; Minoura, K.; Matsumura, E.; Yamori, T.;
Tsuruo, T. Tetrahedron Lett. 1997, 38, 8215.
4.4. Methyl (3R,4R,5S,6S)-6-chloro-3,4,5-trihydroxy-1-
cyclohexene-1-carboxylate 5
4. Yamada, T. Ph.D. dissertation, Osaka University of Pharmaceutical Sciences,
Japan, 2002.
Chlorohydrin 10 (7.1 mg) was dissolved in MeOH (0.5 mL) and
TFA (0.5 mL, excess). After stirring for 2 days at rt, the reaction
mixture was condensed under reduced pressure to afford a crude
residue which was purified by silica gel chromatography (eluent:
5% MeOH in CH2Cl2) to give 5 (3.9 mg, 76%). Compound 5: oil;
5. Yamada, T.; Minoura, K.; Numata, A. Abstract 2, 119th Annual Meeting of
Pharmaceutical Society of Japan, 1999; Tokushima, Japan, p 159.
6. Yamada, T.; Iritani, M.; Ohishi, H.; Tanaka, K.; Doi, M.; Minoura, K.; Numata, A.
Org. Bioorg. Chem. 2007, 5, 3979.
7. The spectral data of which appeared in the literature6 are incorrect as well as
those of another diastereomer of pericosine. The correct data of natural 4 were
presented as follows from our independent deprotection experiment against
½
a 2D5
ꢁ
¼ ꢀ101:0 (c 0.20, EtOH); IR (liquid film) mmax 3410 (OH),
1724 (C@O), 1668 (C@C) cmꢀ1 1H NMR (acetone-d6) d 3.74 (1H,
;
18. Natural 4: oil; ½a D25
ꢁ
¼ ꢀ273:6 (c 0.01, EtOH); IR (liquid film)
mmax 3382 (OH),
br dd, J = 7.8, 4.1 Hz, H-4), 3.78 (3H, s, COOMe), 4.25 (1H, dd,
J = 7.8, 5.0 Hz, H-5), 4.42 (1H, br dd, J = 4.3, 4.1 Hz, H-3), 4.66 (1H,
ddd, J = 5.0, 1.1, 0.9 Hz, H-6), 6.81 (1H, dd, J = 4.3, 0.9 Hz, H-2);
13C NMR (acetone-d6) d 52.2 (q), 57.9 (d), 66.1 (d), 71.2 (d), 74.1
1712 (C@O), 1654 (C@C) cmꢀ1
;
1H NMR (acetone-d6) d 3.78 (3H, s, COOMe),
3.94 (1H, dd, J = 9.8, 4.6, H-4), 4.05 (1H, dd, J = 9.8, 3.9 Hz, H-5), 4.47 (1H, t,
J = 4.6 Hz, H-3), 5.07 ( 1H, d, J = 3.9 Hz, H-6), 6.90 (1H, d, J = 4.6 Hz, H-2); 13C
NMR data could not be obtained due to a shortage of the material; HR-EIMS m/z
calcd for C7H8O345Cl (MꢀOMe)+ 191.0111, found 191.0100.
8. Arjona, Odon; Gomez, Ana M.; Lopez, J. Cristobal; Plumet, Joaquin Chem. Rev.
2007, 107, 1919.
9. Sanchez-Abella, L.; Fernandez, S.; Armesto, N.; Ferrero, M.; Gotor, V. J. Org.
Chem. 2006, 71, 5396.
10. Usami, Y.; Numata, A. Chem. Pharm. Bull. 2004, 52, 1125.
11. Usami, Y.; Hatsuno, C.; Yamamoto, H.; Tanabe, M.; Numata, A. Chem. Pharm.
Bull. 2004, 52, 1130 (Erratum: Chem. Pharm. Bull. 2005, 53, 271).
12. Usami, Y.; Ueda, Y. Chem. Lett. 2005, 34, 1062.
(d), 132.2 (s), 139.8 (d), 166.2 (s); HRMS m/z calcd for C8H12O35Cl
5
(M+H)+ 223.0373, found 223.0377.
4.5. (ꢀ)-Pericosine D: methyl (3R,4R,5S,6R)-6-chloro-3,4,5-
trihydroxy-1-cyclohexene-1-carboxylate 4
Chlorohydrin 11 (2.6 mg) was dissolved in MeOH (0.5 mL) and
TFA (0.5 mL, excess). After stirring for 3 h at 0 °C, the reaction mix-
ture was allowed to return to room temperature and condensed
under reduced pressure to afford a crude residue that was purified
by silica gel chromatography (eluent: 5% MeOH in CH2Cl2, then
acetone) to give 4 (0.7 mg, 37%) with recovery of 11 (0.6 mg,
13. Usami, Y.; Ueda, Y. Synthesis 2007, 3219.
14. Usami, Y.; Horibe, Y.; Takaoka, I.; Ichikawa, H.; Arimoto, M. Synlett 2006, 1598.
15. Usami, Y.; Takaoka, I.; Ichikawa, H.; Horibe, Y.; Tomiyama, Y.; Otsuka, M.;
Imanishi, Y.; Arimoto, M. J. Org. Chem. 2007, 72, 6127.
16. Donohoe, T. J.; Blades, K.; Helliwell, M.; Warning, M. J.; Newcombe, N. J.
Tetrahedron Lett. 1998, 39, 8755.
17. Huntley, C. F. M.; Wood, H. B.; Ganem, B. Tetrahedron Lett. 2000, 41, 2031–2034.
18. Bowles, S.; Campbell, M. M.; Sainsbury, M. Tetrahedron Lett. 1989, 30, 3711.
19. Bowles, S. A.; Campbell, M. M.; Sainsbury, M.; Davies, G. M. Tetrahedron 1990,
46, 3981.
23%). Compound 4: Oil; ½a D25
¼ ꢀ275:4 (c 0.04, EtOH); IR (liquid
ꢁ
film) m
max 3381 (OH), 1713 (C@O), 1654 (C@C) cmꢀ1; 1H NMR (ace-
20. Sutherland, J. K.; Watkins, W. J.; Bailey, J. P.; Chapman, A. K.; Davies, G. M. J.
Chem. Soc., Chem. Commun. 1989, 1386.
tone-d6) d 3.78 (3H, s, COOMe), 3.95 (1H, dd, J = 9.8, 4.6, H-4), 4.06
(1H, dd, J = 9.8, 3.9 Hz, H-5), 4.48 (1H, t, J = 4.6 Hz, H-3), 5.07 (1H, d,
J = 3.9 Hz, H-6), 6.90 (1H, d, J = 4.6 Hz, H-2); 13C NMR (acetone-d6) d
52.5 (q), 58.9 (d), 66.4 (d), 68.4 (d), 69.2 (d), 132.3 (s), 140.7 (d),
21. Griesbeck, A. G.; Maria, C.; Neudoerfl, J. ARKIVOC 2007, 216.
22. Usami, Y.; Mizuki, K.; Ichikawa, H.; Arimoto, M. Abstract, 57th Annual Meeting
of the Pharmaceutical Society of Japan Kinki-branch, 2007; Osaka, Japan, p 36.
23. Blacker, A. J.; Booth, R. J.; Davies, G. M.; Sutherland, J. K. J. Chem. Soc., Perkin
Trans. 1 1995, 2861.
165.7 (s); HRMS m/z calcd for C7H12O35Cl (MꢀOMe)+ 191.0111,
4
found 191.0102.7
Acknowledgments
We are grateful to Drs. K. Minoura, T. Yamada, and Ms. M. Fuji-
take of this University for measurement of 2D NMR and for a gift of