First total synthesis of antitumor natural product (+)- and (-)-pericosine A: Determination of absolute stereo structure

Article abstract of DOI:10.1021/jo070715l

(Chemical Equation Presented) The first total synthesis of (+)- and (-)-pericosine A has been achieved, enabling the revision and determination of the absolute configuration of this antitumor natural product as methyl (3S,4S,5S,6S)-6-chloro-3,4,5-trihydro

Full text of DOI:10.1021/jo070715l

First Total Synthesis of Antitumor Natural Product (+)- and
(-)-Pericosine A: Determination of Absolute Stereo Structure†
Yoshihide Usami,* Isao Takaoka, Hayato Ichikawa, Yusuke Horibe, Syunsuke Tomiyama,
Misako Ohtsuka, Yumi Imanishi, and Masao Arimoto
Osaka UniVersity of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan
usami@gly.oups.ac.jp
ReceiVed April 19, 2007
The first total synthesis of (+)- and (-)-pericosine A has been achieved, enabling the revision and
determination of the absolute configuration of this antitumor natural product as methyl (3S,4S,5S,6S)-
6-chloro-3,4,5-trihydroxy-1-cyclohexene-1-carboxylate. Every step of this total synthesis proceeded well
with excellent stereoselectivity. Structures of the intermediates in crucial steps were confirmed by detailed
2D NMR analysis.
Introduction
separated from the sea hare, Aplysia kurodai, was reported in
1997, and their structures (1 and 2) are shown in Figure 1.6
Aside from the significant in vitro cytotoxicity against P388
lymphocytic leukemia cells, pericosine A was reported to have
significant in vivo antitumor activity against murine P388 cells.
Because of the multifunctionalized cyclohexene structure, these
compounds are expected to exhibit various biological activities
in addition to antitumor activity. In the course of our synthetic
studies of bioactive natural products and their analogues,
focusing on small molecules,7-10 we have been interested in
pericosines because of their carbasugar structure.9,10
The synthesis of carbasugars has been actively pursued
worldwide because of their antiviral, antifungal, and antitumor
activities.1 One recent topic of interest was the total synthesis
of the oral anti-influenza drug Tamiflu by two independent
groups of Corey and Shibasaki.2,3 Both groups saw a need to
develop a drug to counter the recent emergence of avian flu.
Such studies are extremely important in current synthetic organic
chemistry and natural product chemistry.4,5
The isolation of antitumor natural products pericosines A and
B as metabolites of Periconia byssoides OUPS-N133 originally
In 1998, Donohoe and co-workers achieved the total synthesis
of 2 to elucidate its absolute configuration.11 However, the
absolute configuration of pericosine A had not been elucidated
† This article is dedicated to Professor Yoshimitsu Nagao on the occasion of
his retirement from Tokushima University.
(1) For reviews, see: (a) Suami, T. Pure Appl. Chem. 1987, 59, 1509.
(b) Suami, T.; Ogawa, S. AdV. Carbohydr. Chem. Biochem. 1990, 48, 21.
(c) Suami, T. Top. Curr. Chem. 1990, 154, 257. (d) Berecibar, A.;
Grandjean, C.; Sinwardena, A. Chem. ReV. 1999, 99, 779.
(2) Yeung, Y.-Y.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128,
6310.
(3) (a) Fukuta, Y.; Mita, T.; Fukuda, N.; Kanai, M.; Shibasaki, M. J.
Am. Chem. Soc. 2006, 128, 6312. (b) Mita, T.; Fukuda, N.; Roca, F. X.;
Kanai, M.; Shibasaki, M. Org. Lett. 2007, 9, 259.
(6) Numata, A.; Iritani, M.; Yamada, T.; Minoura, K.; Matsumura, E.;
Yamori, T.; Tsuruo, T. Tetrahedron Lett. 1997, 38, 8215.
(7) Usami, Y.; Numata, A. Synlett 1999, 723.
(8) Usami, Y.; Ikura, T.; Amagata, T.; Numata, A. Tetrahedron:
Asymmetry 2000, 11, 3711.
(9) Usami, Y.; Numata, A. Chem. Pharm. Bull. 2004, 52, 1125.
(10) Usami, Y.; Hatsuno, C.; Yamamoto, H.; Tanabe, M.; Numata, A.
Chem. Pharm. Bull. 2004, 52, 1130 (erratum: Chem. Pharm. Bull. 2005,
53, 721).
(4) Alibes, R.; Bayon, P.; March, P.; Figueredo, M.; Font, J.; Marjanet,
G. Org. Lett. 2006, 8, 1617.
(5) Sanchez-Abella, L.; Fernandez, S.; Armesto, N.; Ferrero, M.; Gotor,
V. J. Org. Chem. 2006, 71, 5396.
(11) Donohoe, T. J.; Blades, K.; Helliwell, M.; Warning, M. J.;
Newcombe, N. J. Tetrahedron Lett. 1998, 39, 8755.
10.1021/jo070715l CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/12/2007
J. Org. Chem. 2007, 72, 6127-6134
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Usami et al.
FIGURE 1. Structures of pericosines and related compounds.
then treated with TBAF to remove the TBS group to give a
mixture of undesired 13 in 29% yield and desired 14 in 28%
yield with recovery of starting material 12 in 14% yield.
The formation of 13 may proceed via a six-membered boat
intermediate, as illustrated in Scheme 3. Or it could be 1,2 then
1,3 migration, all from chair conformation, but 1-O-acetylated
intermediate in the 1,2 migration process could not be detected.
Diol 14 was oxidized with Dess-Martin periodinane to give
â-hydroxyketone (15) in 64% yield.
FIGURE 2. Coupling constants in the epimer of perocosine B (5)
and natural pericosine A.
Because the synthesis of 15 described above was not efficient
from (-)-quinic acid, alternative route B via 8 and 10 in Scheme
1 was examined.
despite its significant antitumor activity. Our successful asym-
metric total synthesis of 1 led us to conclude that the structure
of 1 was incorrect.12 In that synthetic study, we prepared another
diastereoisomer (3) that was different from pericosine A. Then,
elucidation of the true structure of pericosine A became our
next task. In a comprehensive review of data related to
The synthesis is summarized in Scheme 4. Known methyl
shikimate derivative (16) prepared from (-)-shikimic acid16 was
oxidized with Dess-Martin periodinane followed by NaBH4
reduction to afford known alcohol (17)17 in an 81% two-step
yield. Alcohol 17 was then protected with TBSCl to give silyl
ether (10) in 69% yield. Dihydroxylation of 10 was carried out
with a catalytic amount of OsO4 and 1.0 equiv of trimethylamine
N-oxide to give diol (8) as a single product in almost quantitative
yield. The stereochemistry that assumes a chair conformation
was confirmed by analyzing the NOESY spectra of 8, in which
cross-peaks H-2/H-6â and H-3/H-5 were observed. This ste-
reoselectivity was suggested on the basis of Kishi et al.’s rule.18
Adding 1.0 equiv of acetic anhydride with pyridine to 8 led to
the formation of acetate (18) in 91% yield. Then, the product
was treated with TBAF to give diol (19) in 77% yield.
Subsequent Dess-Martin oxidation of 19 gave 15 quantitatively.
â-Hydroxyketone 15 was dehydrated with TFAA and pyridine
to give R,â-unsaturated ketone (20) in 76% yield.
1
pericosines,6,9,10,12 we noted a close similarity between the H
NMR coupling constants of natural pericosine A6 and those of
the epimer of pericosine B (5), which we had reported
previously10 (Figure 2). This led us to deduce that diastereoi-
somer (4) should be natural pericosine A. Described herein is
the first total synthesis of (+)- and (-)-pericosine A and the
structure revision and determination of the absolute configura-
tion of the antitumor natural product pericosine A in full detail.
Part of this work had been reported in a preliminary form.13
Results and Discussion
The basic synthetic strategy was almost the same as our
previous work on the synthesis of the epimer of pericosine B
(5), as illustrated in Scheme 1, because our target molecule (4)
has the same relative configuration. The key reaction attempted
at an early stage was the SNi-type conversion of the hydroxyl
group at C-6 in intermediate (6) into Cl atom with retention of
configuration. Enol (6) could be synthesized from diol (7 or
8), which was derived from methyl shikimate derivatives (9 or
10), respectively. Both 9 and 10 could be prepared from
commercially available (-)-shikimic acid14 or (-)-quinic acid.15
Synthetic route A was a path via 7 and 9, and route B was a
path via 8 and 10 in Scheme 1.
As shown in Scheme 2, (-)-quinic acid was converted into
diol (7) via 9, as in our previous report.10 When 7 was treated
with excess acetic anhydride, bis-O-acetylated product (11) was
produced in 51% yield together with desired mono-O-acetylated
product (12) in 31% yield. The addition of 2.0 equiv of acetic
anhydride to 7 afforded only 12 in 85% yield. Acetate 12 was
Subsequent reduction of 20 with excess NaBH4 in MeOH at
-10 °C gave desired product (21) in 10% yield with recovery
of 10 in 80% yield. The excess hydride species was thought to
attack C-2 with leaving of the acetyl group at C-6 and migration
of the double bond. When DIBAL was applied as a reducing
agent, the desired reaction did not proceed. The best reducing
condition was the addition of stoichiometric NaBH4 at -78 °C
in dry THF. This condition improved the chemical yield of 21
to 95%.
Then, the stereochemistry of the new stereogenic center at
C-3 in 21 was determined as follows. Treatment of 21 with
TFA in MeOH at room temperature gave triol (24), which was
the same as the compound we had previously synthesized as a
racemate.9 Similarly to our previous report, 24 was treated with
dimethoxypropane and catalytic TsOH to afford a mixture of
acetonides (25 as the major component and 26 as the minor
one), as shown in Scheme 5, and its NOESY spectrum had the
following cross-peaks: H-3/H-5, H-3, H-4/one of the acetonide
(12) Usami, Y.; Ueda, Y. Chem. Lett. 2005, 34, 1062.
(13) Usami, Y.; Horibe, Y.; Takaoka, I.; Ichikawa, H.; Arimoto, M.
Synlett 2006, 1598.
(14) Jiang, S.; Shing, G. Tetrahedron 1998, 54, 4697.
(15) Barco, A.; Benetti, S.; Risi, C. D.; Marchetti, P.; Pollini, G. P.;
Zanirato, V. Tetrahedron: Asymmetry 1997, 8, 3515.
(16) Song, S.; Jiang, S.; Singh, G. Tetrahedron: Asymmetry 2003, 14,
2833. Of course, 16 could be prepared from inexpensive (-)-quinic acid.
(17) Ulibarri, G.; Nadler, W.; Skrydstrup, T.; Audrain, H.; Chianori, A.;
Riche, C.; Grierson, A. A. J. Org. Chem. 1995, 60, 2753.
(18) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron 1984, 40, 2247.
6128 J. Org. Chem., Vol. 72, No. 16, 2007

First Total Synthesis of (+)- and (-)-Pericosine A
SCHEME 1. Synthetic Strategy of 4
SCHEME 2. Synthetis of 15 from (-)-Quinic Acid via Route A
SCHEME 3. Interconversion between 13 and 14 via Intermediates with Boat Conformation
methyl groups in 25, and H-4′,H-5′/one of the acetonide methyl
groups in 26.
obtained by the stoichiomeric addition of SOCl2.13 Other
reagents such as AcCl, TsCl, MsCl, or POCl3 did not give 23.
The structure of key intermediate 23 was confirmed by detailed
1D and 2D NMR studies. The assignment of signals of all
Subsequent protection of 21 was carried out with careful
addition of TBSCl and a stoichiometric amount of imidazole
to give desired product 22 in 53% yield. The direct conversion
of 18 into 22 was not successful with SOCl2, SO2Cl2, POCl3,
Martin’s sulfurane dehydrating agent,19 or Burgess reagent.20
Then, the acetyl group of 22 was removed with K2CO3 to give
enol (6) in 74% yield. At this point, the structure of 6 was
confirmed again with detailed 2D NMR experiments. The
NOESY cross-peak H-3/H-5 in 6 supported the configuration
at C-3 generated by the NaBH4 reduction of 20 to 21 as
described above.
1
protons on the cyclohexene ring was based on the H NMR,
COSY, and NOESY spectra of 23. In the NOESY spectra, cross-
peaks H-5/t-Bu, H-6/t-Bu, H-5/SiMe, H-6/SiMe, and H-3,H-4/
one of cyclohexyl methylenes were observed. The HMBC cross-
peak H-3,H-4/singlet carbon observed at 110.8 ppm of 23
confirmed that the Cl atom was not introduced via an SNi
mechanism as we had aimed early on, but via an SN′ mechanism
with syn selectivity.21,22 Another plausible mechanism is the
[3,3]-sigmatropic rearrangement of chlorosulfonate derived from
6. However, the SN′ mechanism seemed most likely from the
formation of 10 on reduction of 20 with excess NaBH4, as
described above. Unfortunately, the stereochemistry at C-6 in
23 could not be determined by NMR analysis at this step but
was elucidated later as â-configuration.
The key reaction in this total synthesis of Cl atom introduction
was achieved by the addition of excess SOCl2 to 6 in dry CH2-
Cl2 to afford chlorinated product (23) in 42% yield. This yield
is high compared with the previously reported yield of 10%
(19) Alhart, R. J.; Martin, J. C. J. Am. Chem. Soc. 1972, 94, 5003.
(20) Bird, G. S.; Burgess, G. M.; Putney, J. W., Jr. J. Biol. Chem. 1993,
268, 17917.
(21) Fukui, K.; Fujimoto, H. Bull. Chem. Soc. Jpn. 1967, 40, 2018.
(22) Magrid, R. M. Tetrahedron 1980, 36, 1901.
J. Org. Chem, Vol. 72, No. 16, 2007 6129

Usami et al.
SCHEME 4. Total Synthesis of (-)-4′ from (-)-Shikimic Acid via Route B
SCHEME 5. Confirmation of the Stereochemistry at C-3 in 21
SCHEME 6. Total Synthesis of (+)-4 from Quinic Acid
To complete the total synthesis, 23 was deprotected with TFA
to give final product (4′) in 66% yield, which was not the all-
cis diastereoisomer (3) we synthesized previously12 but peri-
cosine A. This result proved the stereochemistry at C-6 in 23.
Except for the sign of the specific rotation, all the spectral data
and the HPLC retention time agreed with those of natural
pericosine A. Hence, the total synthesis of the antipode of natural
pericosine A was completed, and the absolute configuration of
natural pericosine A was assigned as methyl (3S,4S,5S,6S)-6-
chloro-3,4,5-trihydroxy-1-cyclohexene-1-carboxylate.
Next, the total synthesis of natural pericosine A (4) was
examined. Since antipode 17′ could be prepared from (-)-quinic
6130 J. Org. Chem., Vol. 72, No. 16, 2007

First Total Synthesis of (+)- and (-)-Pericosine A
acid,17 4 should be synthesized with a similar strategy, as
illustrated in Scheme 1.
75.0 (d), 76.4 (s), 78.3 (d), 110.6 (s), 169.9 (s), 172.3 (s); HRMS
m/z calcd for C22H38O8Si (M)+, 458.2334; found, 458.2336.
Methyl (1S,2R,3S,4R,5R)-5-O-Acetyl-3,4-O-cyclohexylidene-
1,2,3,4,5-pentahydroxycyclohexanecarboxylate 13. Methyl (1S,-
2R,3S,4R,5R)-2-O-Acetyl-3,4-O-cyclohexylidene-1,2,3,4,5-penta-
hydroxycyclohexanecarboxylate 14. To a THF solution (15 mL)
of 12 (103.0 mg) was added 1.0 M TBAF in THF (0.2 mL, 1.0
equiv) at room temperature, and the mixture was stirred overnight.
Then, the reaction mixture was treated with aq NH4Cl and extracted
with EtOAc. The organic layer was dried over MgSO4 and filtered,
and the solvent was removed under reduced pressure to give a crude
residue that was purified by silica gel column chromatography
(eluent: 2% MeOH-CH2Cl2) to afford 13 (22.1 mg, 29%) and 14
(21.5 mg, 28%) with recovery of starting material 12 (14.7 mg,
The synthesis of 4 is shown in Scheme 6. Commercially
available (-)-quinic acid was converted into alcohol (17′)
according to the literature with some modifications. Lactone
(27) derived from (-)-quinic acid was treated with NaOMe
followed by neutralization with DOWEX 50W-X8 to give crude
diol (28), which was oxidized to â-hydroxyketone (29), and 29
was dehydrated with TFAA to enone (30) without purification.
Then 30 was reduced with NaBH4 to afford enol (31) in 54%
overall yield from 27. Εnol (31) was converted into 17′ as
described in the literature.17 Then, the following transformations
of 17′ into 4 were accomplished as above. Since all the spectral
data of synthesized (+)-4 including the specific rotation and
the HPLC retention time agreed with the data of natural
pericosine A, the first synthesis of natural pericosine A was
completed.
14%). 13: Oil; [R]22 +8.6 (c 0.12, CH3Cl); IR (liquid film) νmax
D
3446 (OH), 1734 (CdO) cm-1; H NMR (CDCl3) δ 1.20-1.76
1
(10 H, m), 1.86 (1H, dd, J ) 14.8, 7.0 Hz, H-6A), 2.09 (3H, s,
CH3CO), 2.49 (1H, dd, J ) 14.8, 6.0 Hz, H-6B), 3.84 (3H, s,
COOMe), 3.97 (1H, d, J ) 8.0 Hz, H-2), 4.27 (1H, dd, J ) 8.0,
6.7 Hz, H-3), 4.34 (1H, t, J ) 6.7 Hz, H-4), 5.18 (1H, ddd, J )
7.0, 6.7, 6.0 Hz, H-5); 13C NMR (CDCl3) δ 21.2 (q), 23.6 (t), 24.0
(t), 25.0 (t), 34.8 (t), 35.3 (t), 37.6 (t), 53.4 (q), 69.4 (d), 73.7 (d),
76.0 (d), 76.2 (s), 77.2 (d), 110.5 (s), 170.2 (s), 174.5 (s); HRMS
m/z calcd for C16H24O8 (M)+, 344.1470; found, 344.1473. 14: Oil;
[R]22D +80.9 (c 3.8, CH3Cl); IR (liquid film) νmax 3480 (OH), 1747
(CdO) cm-1; 1H NMR (CDCl3) δ 1.20-1.80 (10H, m), 2.08 (3H,
s, CH3CO), 2.11 (1H, m, H-6A), 2.43 (1H, dd, J ) 14.8, 4.3 Hz,
H-6B), 3.77 (3H, s, COOMe), 4.28 (1H, m, H-5), 4.36 (1H, dd J )
7.8, 5.3 Hz, H-3), 4.38 (1H, m, H-4), 5.19 (1H, d, J ) 7.8 Hz,
H-2); 13C NMR (CDCl3) δ 21.3 (q), 23.7 (t), 24.1 (t), 25.1 (t), 34.8
(t), 35.3 (t), 37.1 (t), 53.5 (q), 69.4 (d), 73.7 (d), 76.0 (d), 76.2 (s),
77.2 (d), 110.4 (s), 170.1 (s), 174.3 (s); HRMS m/z calcd for
C16H24O8 (M)+, 344.1470; found, 344.1461.
Conclusion
We have accomplished the first total synthesis of (+)- and
(-)-pericosine A (4, 4′). Every important step in this synthesis
proceeded with excellent stereoselectivity. From this total
synthesis, the structure of antitumor natural product pericosine
A was revised with elucidation of the absolute configuration as
methyl (3S,4S,5S,6S)-6-chloro-3,4,5-trihydroxy-1-cyclohexene-
1-carboxylate.
Experimental Section
Methyl (1S,2R,3S,4R,5R)-1,2-Bis-O-acetyl-5-O-tert-butyldi-
methylsilyl-3,4-O-cyclohexylidene-1,2,3,4,5-pentahydroxycyclo-
hexanecarboxylate 11. Methyl (1S,2R,3S,4R,5R)-2-O-Acetyl-5-
O-tert-butyldimethylsilyl-3,4-O-cyclohexylidene-1,2,3,4,5-
pentahydroxycyclohexanecarboxylate 12. A. A mixture of 7
(214.6 mg), acetic anhydride (1 mL, excess), and pyridine (1 mL)
was stirred at room temperature for 26 h. Then, the reaction
mixture was treated with aq NaHCO3 and extracted with CH2Cl2.
The organic layer was dried over MgSO4 and filtered, and the
solvent was removed under reduced pressure to give a crude resi-
due that was purified by silica gel column chromatography
(eluent: 1% MeOH-CH2Cl2) to afford 11 (85.4 mg, 51%) and 12
(121.2 mg, 33%).
Methyl (1S,2R,3S,4R)-2-O-Acetyl-3,4-O-cyclohexylidene-5-
oxo-1,2,3,4-tetrahydroxylcyclohexanecarboxylate 15. To a sus-
pension of Dess-Martin periodinane (93.3 mg, 2.0 equiv) in CH2Cl2
(2 mL) was added 14 (38.3 mg) in CH2Cl2 (1 mL) at room
temperature, and stirring was commenced for 1.5 h. After being
diluted with MTBE, the reaction mixture was treated with aq
Na2S2O3 and aq NaHCO3. The organic layer was washed with brine,
dried over MgSO4, and filtered, and the solvent was removed under
reduced pressure to give a crude residue that was purified by silica
gel column chromatography (eluent: 1% MeOH-CH2Cl2) to afford
15 (24.4 mg, 64%). 15: Oil; [R]22D +38.8 (c 1.8, CH3Cl); IR (liquid
1
film) νmax 3464 (OH), 1742 (CdO) cm-1; H NMR (CDCl3) δ
1.30-1.80 (10H, m), 2.12 (3H, s, CH3CO), 2.66 (1H, dd, J ) 16.9,
1.4 Hz, H-6A), 3.16 (1H, d, J ) 16.9 Hz, H-6B), 3.79 (3H, s,
COOMe), 4.56 (1H, dd, J ) 6.8, 1.4 Hz, H-4), 4.58 (1H, dd, J )
6.8, 6.2 Hz, H-3), 5.45 (1H, d, J ) 6.2 Hz, H-2); 13C NMR (CDCl3)
δ 20.7 (q), 23.6 (t), 23.8 (t), 24.8 (t), 35.2 (t), 37.0 (t), 45.1 (t),
53.7 (q), 74.9 (d), 76.1 (s), 77.4 (d), 77.4 (t), 112.5 (s), 169.4 (s),
171.8 (s), 201.7 (s); HRMS m/z calcd for C16H22O8 (M)+, 342.1313;
found, 342.1314.
Methyl (3R,4R,5S)-3,4-O-Cyclohexylidene-3,4,5-trihydroxy-
1-cyclohexene-1-carboxylate 17. To a suspension of Dess-Martin
periodinane (7.34 g, 1.1 equiv) in CH2Cl2 (8 mL) was added 16
(4.25 g, 15.9 mmol) in CH2Cl2 (2 mL) at room temperature, and
stirring was commenced for 2 h. After being diluted with MTBE,
the reaction mixture was treated with aq Na2S2O3 and aq NaHCO3.
The organic layer was washed with brine, dried over MgSO4, and
filtered, and the solvent was removed under reduced pressure to
give a crude ketone (4.15 g). To a suspension of NaBH4 (0.60 g,
4.0 equiv based on 16) in MeOH (10 mL) was added a solution of
crude ketone in MeOH (10 mL) at 0 °C. After being stirred for 1.5
h, the reaction mixture was quenched with aq NH4Cl and extracted
with EtOAc. The organic layer was dried over MgSO4, filtered,
and evaporated to give crude residue, which was purified by silica
gel column chromatography (eluent: 3% MeOH-CH2Cl2) to give
pure 17 (3.40 g, 81% in two steps).
B. A mixture of 7 (160.0 mg), acetic anhydride (72.7 µL, 2
equiv), and pyridine (1 mL) was stirred at room temperature for 3
h. A treatment similar to that described above led to the isolation
of 12 (149.8 mg, 85%).
11: Oil; [R]22 +74.7 (c 4.7, CH3Cl); IR (KBr) νmax 1753 (Cd
D
O) cm-1; H NMR (CDCl3) δ 0.09 (3H, s, SiMe), 0.10 (3H, s,
1
SiMe), 0.89 (9H, s, tBu), 1.25-1.72 (10H, m), 2.07 (3H, s, CH3-
CO), 2.10 (3H, s, CH3CO), 2.54 (1H, dd, J ) 15.6, 4.8 Hz, H-6A),
2.62 (1H, ddd, J ) 15.6, 4.6, 1.1 Hz, H-6B), 3.67 (3H, s, COOMe),
4.16 (1H, ddd, J ) 5.5, 3.0, 1.1 Hz, H-4), 4.30 (1H, ddd, J ) 4.8,
4.6, 3.0 Hz, H-5), 4.46 (1H, dd, J ) 8.7, 5.5 Hz, H-3), 5.06 (1H,
d, J ) 8.7 Hz, H-2); 13C NMR (CDCl3) δ -5.2 (q), -5.0 (q), 18.4
(s), 20.8 (q), 21.4 (q), 23.7 (t), 23.9 (t), 24.9 (t), 25.8 (q), 33.3 (t),
35.1 (t), 37.5 (t), 52.8 (q), 67.7 (d), 73.1 (d), 73.8 (t), 79.1 (d),
79.7 (s), 109.9 (s), 168.9 (s), 169.8 (s), 170.3 (s); HRMS m/z calcd
for C24H40O9Si (M)+, 500.2439; found, 500.2429.
12: Oil; [R]22D +49.9 (c 2.3, CH3Cl); IR (liquid film) νmax 3452
(OH), 1746 (CdO) cm-1; 1H NMR (CDCl3) δ 0.14 (3H, s, SiMe),
0.15 (3H, s, SiMe), 0.91 (9H, s, tBu), 1.20-1.80 (10H, m), 1.99
(1H, ddd, J ) 14.8, 5.0, 1.1 Hz, H-6A), 2.11 (3H, s, CH3CO), 2.41
(1H, dd, J ) 14.8, 3.9 Hz, H-6B), 3.73 (3H, s, COOMe), 4.19 (1H,
m), 4.39 (2H, m), 5.23 (1H, d, J ) 8.4 Hz, H-2); 13C NMR (CDCl3)
δ -5.0 (q), -4.9 (q), 18.0 (s), 21.0 (q), 23.8 (t), 24.0 (t), 25.0 (t),
25.7 (q), 35.4 (t), 36.0 (t), 37.6 (t), 52.9 (q), 68.8 (d), 74.6 (d),
J. Org. Chem, Vol. 72, No. 16, 2007 6131

Usami et al.
Methyl (3R,4R,5S)-5-O-tert-Butyldimethylsilyl-3,4-O-cyclo-
hexylidene-3,4,5-trihydroxy-1-cyclohexene-1-carboxylate 10. To
a CH2Cl2 solution (5 mL) of 17 (775.5 mg) were added TBSCl
(547.9 mg, 1.2 equiv), imidazole (393.5 mg, 2.0 equiv), and a
catalytic amount of DMAP at room temperature. After being stirred
overnight, the reaction mixture was treated with aq NaHCO3 and
extracted with CH2Cl2. The organic layer was dried over MgSO4
and filtered, and the solvent was removed under reduced pressure
to give a crude residue that was purified by silica gel column
chromatography (eluent: 1% MeOH-CH2Cl2) to afford 10 (802.7
TBAF in THF (0.31 mL, 1.0 equiv) at room temperature, and the
mixture was stirred overnight. The reaction mixture was treated
with aq NH4Cl and extracted with EtOAc. The organic layer was
dried over MgSO4 and filtered, and the solvent was removed under
reduced pressure to give a crude residue that was purified by silica
gel column chromatography (eluent: 2% MeOH-CH2Cl2) to afford
19 (82.4 mg, 77%). 19: Oil; [R]22D -12.3 (c 2.4, MeOH); IR (liquid
1
film) νmax 3478 (OH), 1747 (CdO) cm-1; H NMR (CDCl3) δ
1.30-1.85 (10H, m), 2.06 (1H, ddd, J ) 13.5, 5.2, 0.9 Hz, H-6A),
2.07 (3H, s, CH3CO), 2.28 (1H, dd, J ) 13.5, 11.2 Hz, H-6B), 3.75
(3H, s, COOMe), 4.26 (1H, dd, J ) 7.8, 4.8 Hz, H-3), 4.30 (1H,
br ddd, J ) 11.2, 5.2, 4.1 Hz, H-5), 4.45 (1H, br dd, J ) 4.8, 4.1
Hz, H-4), 5.24 (1H, d, J ) 7.6 Hz, H-2); 13C NMR (CDCl3) δ 20.8
(q), 23.7 (t), 23.9 (t), 24.9 (t), 35.4 (q), 36.0 (t), 37.5 (t), 53.4 (q),
65.0 (d), 75.1 (d), 75.7 (d), 76.4 (d), 110.8 (s), 169.7 (s), 173.4 (s);
HRMS m/z calcd for C16H24O8 (M)+, 344.1469; found, 344.1475.
Synthesis of Hydroxyketone 15 from Diol 19. To a suspension
of Dess-Martin periodinane (262.2 mg, 2.0 equiv) in 5 mL of CH2-
Cl2 was added 19 (105.4 mg) in CH2Cl2 (1 mL) at room
temperature, and stirring was commenced for 1 h. After being
diluted with MTBE, the reaction mixture was treated with aq
Na2S2O3 and aq NaHCO3. The organic layer was washed with brine,
dried over MgSO4, and filtered, and the solvent was removed under
reduced pressure to give a crude residue that was purified by silica
gel column chromatography (eluent: 1% MeOH-CH2Cl2) to afford
15 (104.6 mg, 100%).
mg, 69%). 10: Oil; [R]22 -11.5 (c 2.1, MeOH); IR (KBr) νmax
D
1723 (CdO), 1652, 1436 (CdC) cm-1; 1H NMR (CDCl3) δ 0.115
(3H, s, SiMe), 0.118 (3H, s, SiMe), 0.87 (9H, s, tBu), 1.20-1.70
(10H, m), 2.50 (2H, m, H-6A, 6B), 3.77 (3H, s, COOMe), 3.92 (1H,
ddd, J ) 9.8, 5.8, 2.1 Hz, H-3), 4.31 (1H, br d, J ) 5.8 Hz, H-4),
4.67 (1H, m, H-5), 6.66 (1H, m, H-2); 13C NMR (CDCl3) δ -4.6
(q), -4.4 (q), 18.3 (s), 23.8 (t), 24.0 (t), 25.0 (t), 25.9 (q), 27.8 (t),
36.0 (t), 37.4 (t), 52.0 (q), 68.8 (d), 73.4 (d), 76.0 (d), 110.6 (s),
129.2 (s), 135.4 (d), 167.0 (s); HRMS m/z calcd for C20H34O5Si
(M)+, 382.2173; found, 382.2176.
Methyl (1S,2R,3S,4R,5S)-5-O-tert-Butyldimethylsilyl-3,4-O-
cyclohexylidene-1,2,3,4,5-pentahydroxycyclohexanecarbox-
ylate 8. Olefin (10) (1.30 g, 3.4 mmol) was dissolved in 10 mL of
solvent (t-BuOH/py/H2O ) 20:5:1). OsO4 (100 mg, cat. amount)
and trimethylamine oxide (380 mg, 1.0 equiv) were added to the
solution at room temperature, and the reaction mixture was refluxed
for 3 h. After cooling, EtOAc (50 mL) and a small amount of
saturated aq Na2S2O3 were added to the reaction mixture, and this
was extracted with EtOAc. The organic layer was dried over MgSO4
and filtered, and the solvent was removed under reduced pressure
to give a crude residue that was purified by silica gel column
chromatography (eluent: 2% MeOH-CH2Cl2) to afford 8 (1.40 g,
Methyl (4R,5R,6S)-6-O-Acetyl-4,5-O-cyclohexylidene-4,5,6-
trihydroxy-3-oxo-1-cyclohexene-1-carboxylate 20. To a CH2Cl2
solution (10 mL) of 15 (3.06 g) were added TFAA (2.5 mL, 2.0
equiv) and pyridine (4 mL) at 0 °C. After being stirred for 1 h at
room temperature, the reaction mixture was treated with aq NaHCO3
and extracted with CH2Cl2. The organic layer was dried over MgSO4
and filtered, and the solvent was removed under reduced pressure
to give a crude residue that was purified by silica gel column
chromatography (eluent: 1% MeOH-CH2Cl2) to afford 20 (2.21
98%). 8: Colorless crystals (CH2Cl2); mp 158-161 °C; [R]22
D
-16.3 (c 3.0, MeOH); IR (KBr) νmax 3474 (OH), 1729 (CdO)
cm-1; 1H NMR (CDCl3) δ 0.09 (3H, s, SiMe), 0.11 (3H, s, SiMe),
0.91 (9H, s, tBu), 1.36-1.81 (10H, m), 1.83 (1H, dd, J ) 13.5,
4.6 Hz, H-6A), 2.27 (1H, dd, J ) 13.5, 10.8 Hz, H-6B), 3.82 (3H,
s, COOMe), 3.98 (1H, d, J ) 7.6 Hz, H-2), 4.01 (1H, dd, J ) 7.6,
4.8 Hz, H-3), 4.26 (1H, dd, J ) 4.8, 4.3 Hz, H-4), 4.34 (1H, ddd,
J ) 10.5 4.6, 4.3 Hz, H-5); 13C NMR (CDCl3) δ -4.7 (q), -4.6
(q), 18.2 (s), 23.6 (t), 24.0 (t), 25.7 (t), 25.8 (q), 35.2 (t), 37.0 (t),
38.0 (t), 53.3 (q), 65.9 (d), 74.3 (d), 76.3 (d), 76.9 (s), 79.1 (d),
110.4 (s), 174.6 (s); HRMS m/z calcd for C20H36O7Si (M)+,
416.2228; found, 416.2227.
g, 76%). 20: Pale yellow oil; [R]22 +40.2 (c 0.99, CH3Cl); IR
D
(liquid film) νmax 1750 (CdO), 1734 (CdO), 1698 (CdO), 1654
(CdC) cm-1; 1H NMR (CDCl3) δ 1.35-1.80 (10H, m), 2.09 (3H,
s, CH3CO), 3.88 (3H, s, COOMe), 4.43 (1H, d, J ) 5.3 Hz, H-4),
4.55 (1H, dd, J ) 5.3, 2.1 Hz, H-5), 6.15 (1H, d, J ) 2.1 Hz, H-6),
6.96 (1H, s, H-2); 13C NMR (CDCl3) δ 20.7 (q), 23.6 (t), 23.7 (t),
24. 8 (t), 35.0 (t), 37.0 (t), 53.1 (q), 64.1 (d), 73.5 (d), 75.0 (d),
111.5 (s), 134.4 (d), 141.0 (s), 164.9 (s), 169.3 (s), 196.0 (s); HRMS
m/z calcd for C16H20O7 (M)+, 324.1207; found, 324.1206.
Methyl (1S,2R,3S,4R,5S)-2-O-Acetyl-5-O-tert-butyldimethyl
silyl-3,4-O-cyclohexylidene-1,2,3,4,5-pentahydroxycyclohex-
anecarboxylate 18. To a solution of 8 (203.8 mg) in CH2Cl2 (2
mL) were added acetic anhydride (50 µL, 1.1 equiv), pyridine (1.0
mL), and a catalytic amount of DMAP at room temperature. After
being stirred overnight, the reaction mixture was treated with aq
NaHCO3 and extracted with CH2Cl2. The organic layer was dried
over MgSO4 and filtered, and the solvent was removed under
reduced pressure to give a crude residue that was purified by silica
gel column chromatography (eluent: 1% MeOH-CH2Cl2) to give
Methyl (3S,4S,5R,6S)-6-O-Acetyl-4,5-O-cyclohexylidene-3,4,5,6-
tetrahydroxy-1-cyclohexene-1-carboxylate 21. To a suspension
of NaBH4 (15.1 mg, 1.05 equiv) in dry THF (10 mL) was added
dropwise 20 (470.2 mg) in THF (3 mL) at -78 °C. After being
stirred for 1 h, the reaction mixture was treated with aq NH4Cl
and extracted with EtOAc. The organic layer was dried over MgSO4
and filtered, and the solvent was removed under reduced pressure
to give a crude residue that was purified by silica gel column
chromatography (eluent: 1% MeOH-CH2Cl2) to afford 21 (424.0
mg, 95%) together with 10 (12.6 mg, 3%). 21: Oil; [R]22 +53.4
D
18 (203.6 mg, 91%). 18: Oil; [R]22 -10.4 (c 0.76, MeOH); IR
(c 3.5, MeOH); IR (liquid film) νmax 3477 (OH), 1739 (CdO), 1733
(CdO), 1653 (CdC) cm-1; 1H NMR (CDCl3) δ 1.20-1.80 (10H,
m), 2.01 (3H, s, CH3CO), 3.03 (1H, d, J ) 10.6 Hz, 3-OH), 3.80
(3H, s, COOMe), 4.48 (1H, ddd, J ) 10.6, 4.8, 2.0 Hz, H-3), 4.56
(1H, dd, J ) 7.0, 2.2 Hz, H-5), 4.67 (1H, ddd, J ) 7.0, 4.8, 1.5
Hz, H-4), 5.84 (1H, ddd, J ) 2.2, 1.5 1.1 Hz, H-6), 7.14 (1H, dd
J ) 2.0, 1.1 Hz, H-2); 13C NMR (CDCl3) δ 21.1 (q), 23.8 (t), 24.1
(t), 25.3 (t), 34.1 (t), 35.8 (t), 52.3 (q), 65.4 (d), 66.8 (d), 74.2 (d),
74.8 (d), 109.9 (s), 127.8 (s), 148.2 (d), 164.2 (s), 168.8 (s); HRMS
m/z calcd for C16H22O7 (M)+, 326.1364; found, 326.1366.
Confirmation of the Stereochemistry at C-3 in 21. Enol 21
(6.0 mg) was dissolved in MeOH (1 mL) with TFA (0.1 mL,
excess). After being stirred for 30 min at room temperature, the
solvent was removed under reduced pressure to give a residue that
was purified by preparative TLC (eluent: 5% MeOH-CH2Cl2) to
D
(liquid film) νmax 3484 (OH), 1750 (CdO) cm-1; 1H NMR (CDCl3)
δ 0.10 (3H, s, SiMe), 0.12 (3H, s, SiMe), 0.91 (9H, s, tBu), 1.30-
1.80 (10H, m), 1.86 (1H, ddd, J ) 13.3, 4.8, 1.0 Hz, H-6A), 2.06
(3H, s, CH3CO), 2.43 (1H, dd, J ) 13.3, 11.4 Hz, H-6B), 3.73 (3H,
s, COOMe), 4.18 (1H, dd, J ) 7.8, 4.8 Hz, H-3), 4.30 (1H, ddd, J
) 4.8, 3.9, 1.0 Hz, H-4), 4.36 (1H, ddd, J ) 11.4 4.8, 3.9 Hz,
H-5), 5.24 (1H, d, J ) 7.8 Hz, H-2); 13C NMR (CDCl3) δ -4.7
(q), -4.6 (q), 18.2 (s), 20.8 (q), 23.6 (t), 23.9 (t), 25.0 (t), 25.8 (q),
35.4 (t), 36.0 (t), 37.6 (t), 53.3 (q), 65.2 (d), 75.1 (d), 75.7 (s), 76.4
(d), 76.4 (d), 110.6 (s), 169.7 (s), 173.7 (s); HRMS m/z calcd for
C22H38O8Si (M)+, 458.2333; found, 458.2339.
Methyl (1S,2R,3S,4S,5S)-2-O-Acetyl-3,4-O-cyclohexylidene-
1,2,3,4,5-pentahydroxycyclohexanecarboxylate 19. To a THF
solution (2 mL) of 18 (143.0 mg, 0.31 mmol) was added 1.0 M
6132 J. Org. Chem., Vol. 72, No. 16, 2007

First Total Synthesis of (+)- and (-)-Pericosine A
afford 24 (4.0 mg, 89%). Obtained 24 was treated with 2,2-
dimethoxypropane (0.1 mL, excess) and catalytic TsOH‚H2O in
acetone (0.2 mL) at room temperature for 30 min. The volatile part
was removed under reduced pressure to give a crude residue that
was then purified by preparative TLC (eluent: 1% MeOH-CH2-
Cl2) to afford a mixture of 25 and 26 in almost 2:1 ratio (overall
3.5 mg, 80%). Spectral data of 24, 25, and 26 were identical to
those in ref 9.
69.8 (d), 70.5 (d), 72.8 (d), 110.8 (s), 130.2 (s), 138.3 (d), 165.4
(s); HRMS m/z calcd for C20H33O5ClSi (M)+, 416.1775; found,
416.1774.
(-)-Pericosine A (4′): Methyl (3R,4R,5R,6R)-6-Chloro-3,4,5-
trihydroxy-1-cyclohexene-1-carboxylate. Chloride 23 (15.0 mg)
was dissolved in MeOH (1.0 mL) and TFA (0.1 mL, excess). After
being stirred overnight at 0 °C, the reaction mixture was allowed
to return to room temperature and condensed under reduced pressure
to afford a crude residue that was purified by RP-HPLC (eluent:
60% MeOH in H2O, flow rate: 4 mL/min, retention time: 14′ 50′′)
to give 4′ (5.3 mg, 66%). 4′: [R]22D -98.0 (c 0.04, EtOH); Oil; IR
(liquid film) νmax 3366 (OH), 1725 (CdO), 1653 (CdC) cm-1; 1H
NMR (acetone-d3) δ 3.80 (3H, s, COOMe), 4.07 (1H, dd, J ) 4.4,
1.9 Hz, H-4), 4.12 (1H, dd, J ) 4.6, 1.9 Hz, H-5), 4.38 (1H, br dd,
J ) 4.4, 3.9 Hz, H-3), 4.90 (1H, dd, J ) 4.6, 0.8 Hz, H-6), 6.91
(1H, d, J ) 3.9 Hz, H-2); 13C NMR (acetone-d3) δ 52.4 (q), 57.8
(d), 67.1 (d), 68.6 (d), 75.7 (d), 130.5 (s), 141.9 (d), 166.2 (s);
HRMS m/z calcd for C8H12O535Cl (M + H)+, 223.0372; found,
223.0370.
24: [R]22 +53.2 (c 0.37, MeOH).
D
Methyl (3S,4R,5R,6S)-6-O-Acetyl-3-O-tert-butyldimethylsilyl-
4,5-O-cyclohexylidene-3,4,5,6-tetrahydroxy-1-cyclohexene-1-car-
boxylate 22. To a CH2Cl2 solution (10 mL) of 21 (424.0 mg, 1.3
mmol) were added TBSCl (234.1 mg, 1.2 equiv) and imidazole
(88.5 mg, 1.0 equiv) at room temperature. After being stirred
overnight, the reaction mixture was treated with aq NaHCO3 and
extracted with CH2Cl2. The organic layer was dried over MgSO4
and filtered, and the solvent was removed under reduced pressure
to give a crude residue that was purified by silica gel column
chromatography (eluent: 0.5% MeOH-CH2Cl2) to afford 22 (303.4
Natural Pericosine A: Specific rotation, [R]22 +104 (c 0.04,
mg, 53%) with recovery of 21 (107.1 mg, 25%). 22: Oil; [R]22
D
D
EtOH) (lit.* [R]D +57 (c 3.16, EtOH));6 the retention time in RP-
HPLC: 32 min (eluent, 50% MeOH in H2O; flow rate, 4 mL/min)
or 14′ 50′′ (eluent: 60% MeOH in H2O, flow rate: 4 mL/min).
+47.5 (c 1.1, MeOH); IR (liquid film) νmax 1747 (CdO), 1652
(CdC) cm-1; 1H NMR (CDCl3) δ 0.16 (6H, s, SiMe), 0.95 (9H, s,
tBu), 1.30-1.80 (10H, m), 2.00 (3H, s, CH3CO), 3.78 (3H, s,
COOMe), 4.45 (1H, dd, J ) 6.8, 1.6 Hz, H-5), 4.57 (1H, ddd, J )
6.8, 3.8, 1.6 Hz, H-4), 4.67 (1H, dd, J ) 3.8, 2.0 Hz, H-3), 5.74
(1H, br t, J ) 1.6 Hz, H-6), 7.12 (1H, dt, J ) 2.0, 1.6 Hz, H-2);
13C NMR (CDCl3) δ -3.9 (q × 2), 18.8 (s), 21.4 (q), 24.0 (t), 24.2
(t), 25.6 (t), 26.2 (q), 34.1 (t), 36.0 (t), 52.3 (q), 66.5 (d), 68.4 (d),
75.6 (d), 76.7 (d), 109.9 (s), 127.4 (s), 149.6 (d), 164.4 (s), 168.9
(s); HRMS m/z calcd for C22H36O7Si (M)+, 440.2227; found,
440.2233.
Preparation of 31 from 27. Lactone (27) (2.58 g) derived from
(-)-quinic acid was treated with NaOMe (0.55 g, 1.0 equiv) in
MeOH (30 mL) with stirring at room temperature for 3 h. DOWEX
50W-X8 was added carefully to the dark brown reaction mixture
until the color changed to pale yellow, and pH was measured using
universal pH test paper. When neutralization was completed, the
reaction mixture was filtered into a flask, and the solvent was
evaporated under reduced pressure to afford crude diol (28). To a
CH2Cl2 solution (20 mL) of 28 was added Dess-Martin periodinane
(4.96 g, 1.2 equiv), and the reaction mixture was stirred overnight
at room temperature. Usual treatment of the reaction mixture
afforded a crude residue of 29. To a solution of crude 29 in CH2-
Cl2 (30 mL) was added TFAA (1.4 mL, 1.0 equiv) with pyridine
(0.82 mL, 1.6 equiv) and catalytic DMAP (100 mg) at 0 °C. After
being stirred for 2 h, the reaction mixture was quenched with aq
NaHCO3 then neutralized with aq NH4Cl, then extracted with CH2-
Cl2. The organic layer was dried over MgSO4, filtered, and
evaporated to give crude 30. To a suspension of NaBH4 (189.1
mg, 2.0 equiv based on 27) in MeOH (30 mL) was added a solution
of crude 30 in MeOH (10 mL) at 0 °C. After being stirred for 2 h,
the reaction mixture was quenched with aq NH4Cl and extracted
with EtOAc. The organic layer was dried over MgSO4, filtered,
and evaporated to give crude residue, which was purified by silica
gel column chromatography (eluent: 1% MeOH-CH2Cl2) to give
Methyl (3S,4R,5R,6S)-3-O-tert-Butyldimethylsilyl-4,5-O-cy-
clohexylidene-3,4,5,6-tetrahydroxy-1-cyclohexene-1-carboxy-
late 6. To a MeOH solution (5 mL) of 22 (120.0 mg) was added
K2CO3 (37.7 mg, 1.0 equiv) at 0 °C. After being stirred for 30 min
at room temperature, the reaction mixture was treated with aq NH4-
Cl and extracted with CH2Cl2. The organic layer was dried over
MgSO4 and filtered, and the solvent was removed under reduced
pressure to give a crude residue that was purified by silica gel
column chromatography (eluent: 1% MeOH-CH2Cl2) to afford 6
(80.0 mg, 74%). 6: Colorless crystals (CH2Cl2); mp 84-86 °C;
[R]22D +14.8 (c 1.5, MeOH); IR (KBr) νmax 3436 (OH), 1739 (Cd
O), 1656 (CdC), 1538 (CdC) cm-1; 1H NMR (CDCl3) δ 0.14 (6H,
s, SiMe), 0.94 (9H, s, tBu), 1.30-1.80 (10H, m), 3.78 (3H, s,
COOMe), 4.47 (1H, dd, J ) 6.8, 1.9 Hz, H-5), 4.55 (1H, ddd, J )
6.8, 3.8, 1.7 Hz, H-4), 4.71 (1H, m, H-6), 4.76 (1H, dd, J ) 3.8,
2.2 Hz, H-3), 7.04 (1H, m, H-2); 13C NMR (CDCl3) δ -4.0 (q),
-3.9 (q), 18.7 (s), 24.0 (t), 24.3 (t), 25.4 (t), 26.2 (q), 34.1 (t),
36.1 (t), 52.2 (q), 65.3 (d), 68.1 (d), 76.9 (d), 77.4 (d), 109.4 (s),
130.3 (s), 147. 7 (d), 165.4 (s); HRMS m/z calcd for C20H34O6Si
(M)+, 398.2123; found, 398.2116.
1
pure 31 (1.45 g, 54% in four steps). 31: Oil; H NMR (CDCl3) δ
1.2-1.65 (10H, m), 1.95 (1H, br d, J ) 16.4 Hz, H-6A), 3.04 (1H,
dd, J ) 16.4, 2.0 Hz, H-6B), 3.76 (3H, s, COOMe), 4.07 (1H, m),
4.56 (1H, ddd, J ) 7.3, 4.8, 1.3 Hz), 4.64 (1H, ddd, J ) 7.3, 3.8,
2.4 Hz), 6.93 (1H, m, H-2); 13C NMR (CDCl3) δ 23.9, 24.2, 25.5,
26.8, 34.2, 35.7, 52.0, 68.0, 71.9, 75.5, 109.3, 127.9, 142.0, 165.5.17
Methyl (3R,4R,5R,6R)-6-Chloro-5-O-tert-butyldimethylsilyl-
3,4-O-cyclohexylidene-3,4,5-trihydroxy-1-cyclohexene-1-carbox-
ylate 23. To a dry CH2Cl2 solution (2 mL) of 6 (35.0 mg) was
added SOCl2 (5 mL, excess) at 0 °C. After being stirred for 3 h,
the reaction mixture was poured slowly into ice-cooled aq Na2-
CO3 and extracted three times with CH2Cl2. The organic layer was
dried over MgSO4 and filtered, and the solvent was removed under
reduced pressure to give a crude residue that was purified by
preparative TLC (eluent: 1% MeOH-CH2Cl2) to afford 23 (15.2
mg, 42%). 23: Colorless oil; [R]22D -68.5 (c 1.5, MeOH); IR (KBr)
All 1H NMR, 13C NMR, IR, and HRMS data for the compounds
described below were identical with the data of the antipodes above.
Methyl (3S,4S,5R)-5-O-tert-Butyldimethylsilyl-3,4-O-cyclo-
hexylidene-1-cyclohexane-1-carboxylate 10′. Desired product 10′
(6.39 g) was obtained in 87% yield from 17′ (5.14 g) in the same
manner as that for the preparation of 10. 10′: [R]22 +8.6 (c 2.0,
D
MeOH).
Methyl (1R,2S,3R,4S,5R)-5-O-tert-Butyldimethylsilyl-3,4-O-
cyclohexylidene-1,2,3,4,5-pentahydroxycyclohexanecarbox-
ylate 8′. Desired product 8′ (0.66 g) was obtained in 100% yield
from 10′ (0.58 g) in the same manner as that for the preparation of
1
νmax 1726 (CdO), 1654 (CdC) cm-1; H NMR (CDCl3) δ 0.10
(3H, s, SiMe), 0.13 (3H, s, SiMe), 0.86 (9H, s, tBu), 1.20-1.80
(10H, m), 3.81 (3H, s, COOMe), 4.23 (1H, dd, J ) 4.8, 3.4 Hz,
H-5), 4.58 (1H, dd, J ) 7.1, 3.4 Hz, H-4), 4.72 (1H, dd, J ) 7.1,
3.0 Hz, H-3), 4.83 (1H, d, J ) 4.8 Hz, H-6), 7.04 (1H, d, J ) 3.0
Hz, H-2); 13C NMR (CDCl3) δ -5.2 (q), -4.4 (q), 18.1 (s), 23.7
(t), 23.9 (t), 25.1 (t), 25.7 (q), 34.4 (t), 36.1 (t), 52.3 (q), 53.3 (d),
8. 8′: [R]22 +14.5 (c 2.0, MeOH).
D
Methyl (1R,2S,3R,4S,5R)-2-O-Acetyl-5-O-tert-butyldimethyl
silyl-3,4-O-cyclohexylidene-1,2,3,4,5-pentahydroxycyclohexane-
carboxylate 18′. Desired product 18′ (5.77 g) was obtained in
J. Org. Chem, Vol. 72, No. 16, 2007 6133

Usami et al.
96% yield from 8′ (5.49 g) in the same manner as that for the
Methyl (3S,4S,5S,6S)-6-Chloro-5-O-tert-butyldimethylsilyl-
3,4-O-cyclohexylidene-3,4,5-trihydroxy-1-cyclohexene-1-carbox-
ylate 23′. Desired product 23′ (25.7 mg, 28%) was obtained
from 6′ (87.4 mg) with recovery of 6′ (20.0 mg, 23%) in the same
manner as that for the preparation of 23. 23′: [R]22D +73.0 (c 2.1,
MeOH).
preparation of 18. 18′: [R]22 +13.0 (c 0.75, MeOH).
D
Methyl (1R,2S,3R,4R,5R)-2-O-Acetyl-3,4-O-cyclohexylidene-
1,2,3,4,5-pentahydroxycyclohexanecarboxylate 19′. Desired
product 19′ (2.03 g) was obtained in 47% yield from 18′ (5.77 g)
in the same manner as that for the preparation of 19. 19′: [R]22
+15.7 (c 1.0, MeOH).
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(+)-Pericosine A (4): Methyl (3S,4S,5S,6S)-6-Chloro-3,4,5-
trihydroxy-1-cyclohexene-1-carboxylate. Desired product 4 (15.0
mg) was obtained in 63% yield from 23′ (44.5 mg) in the same
manner as that for the preparation of 4′ and separated by RP-
HPLC (eluent: 60% MeOH in H2O, flow rate: 4 mL/min, retention
Methyl (1R,2S,3R,4S)-2-O-Acetyl-3,4-O-cyclohexylidene-5-
oxo-1,2,4-trihydroxy-1-cyclohexenecarboxylate 15′. Desired prod-
uct 15′ (1.69 g) was obtained in 84% yield from 19′ (2.03 g) in the
same manner as that for the preparation of 15. 15′: [R]22 -32.4
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(c 1.8, MeOH).
time: 14′ 50′′). 4: [R]22 +102.0 (c 0.12, EtOH). Natural 4 was
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Methyl (4S,5S,6R)-6-O-Acetyl-4,5-O-cyclohexylidene-4,5,6-
trihydroxy-3-oxo-1-cyclohexene-1-carboxylate 20′. Desired prod-
uct 20′ (38.5 mg) was obtained in 68% yield from 15′ (59.9 mg)
applied to the same RP-HPLC conditions (eluent: 60% MeOH in
H2O, flow rate: 4 mL/min) to show the same retention time
of 14′ 50′′.
in the same manner as that for the preparation of 20. 20′: [R]22
-35.6 (c 0.99, MeOH).
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Methyl (3R,4R,5S,6R)-6-O-Acetyl-4,5-O-cyclohexylidene-3,4,5,6-
tetrahydroxy-1-cyclohexene-1-carboxylate 21′. Desired product
21′ (20.9 mg) was obtained in 68% yield from 20′ (30.5 mg) in
the same manner as that for the preparation of 21. 21′: [R]22D -54.6
(c 2.1, MeOH).
Supporting Information Available: General experimental
methods and copies of 1H- and 13C-NMR spectra of all new
compounds, 31, (-)-4′ and (+)-4. This material is available free
of charge via the Internet at http://pub.acs.org.
Methyl (3R,4S,5S,6R)-6-O-Acetyl-3-O-tert-butyldimethylsilyl-
4,5-O-cyclohexylidene-3,4,5,6-tetrahydroxy-1-cyclohexene-1-car-
boxylate 22′. Desired product 22′ (292.7 mg) was obtained in 53%
yield from 21′ (410.0 mg) with recovery of 21′ (100 mg, 34%) in
the same manner as that for the preparation of 22. 22′: [R]22D -49.0
(c 1.1, MeOH).
Acknowledgment. We are grateful to Dr. K. Minoura and
Ms. M. Fujitake of this university for NMR and MS measure-
ments, respectively. We also thank Dr. T. Yamada of this
university for providing a precious sample of natural pericosine
A. This work was supported in part by a Grant-in-Aid for “High-
Tech Research Center” Project for Private Universities: match-
ing fund subsidy from MEXT (Ministry of Education, Culture,
Sports, Science, and Technology), 2002-2006, Japan.
Methyl (3R,4S,5S,6R)-3-O-tert-Butyldimethylsilyl-4,5-O-cy-
clohexylidene-3,4,5,6-tetrahydroxy-1-cyclohexene-1-carboxy-
late 6′. Desired product 6′ (212.0 mg) was obtained in 80% yield
from 22′ (292.7 mg) in the same manner as that for the preparation
of 6. 6′: [R]22 -16.8 (c 1.5, MeOH).
JO070715L
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6134 J. Org. Chem., Vol. 72, No. 16, 2007