Concise asymmetric synthesis of a model compound, (4S,5S,6S)-6-(2,2-dimethoxy)ethyl-4,5-epoxy-6-hydroxy-2-cyclohexenone, for the cyclohexenone core of scyphostatin

Article abstract of DOI:10.1016/S0040-4039(02)00916-4

The optically pure cyclohexenone core of scyphostatin (1) has been synthesized from cyclohexadiene acetal 5. The crucial aspects of our synthesis include the intramolecular bromoetherification of 5, the SeO₂ oxidation of 7, and the enone formation of 13 to 4 in the final step.

Full text of DOI:10.1016/S0040-4039(02)00916-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4825–4828
Concise asymmetric synthesis of a model compound,
(4S,5S,6S)-6-(2,2-dimethoxy)ethyl-4,5-epoxy-
6-hydroxy-2-cyclohexenone, for the cyclohexenone core
of scyphostatin
Hiromichi Fujioka,* Naoyuki Kotoku, Yoshinari Sawama, Yasushi Nagatomi and Yasuyuki Kita*
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan
Received 22 March 2002; revised 7 May 2002; accepted 10 May 2002
Abstract—The optically pure cyclohexenone core of scyphostatin (1) has been synthesized from cyclohexadiene acetal 5. The
crucial aspects of our synthesis include the intramolecular bromoetherification of 5, the SeO2 oxidation of 7, and the enone
formation of 13 to 4 in the final step. © 2002 Elsevier Science Ltd. All rights reserved.
Scyphostatin (1), isolated from Dasyscyphus mollissimus
SANK-13892 in 1997, possesses potent inhibitory activ-
ity against a neutral sphingomyelinase (N-SMase).1 Its
promising biological profile, still now the most powerful
among the few known inhibitors of the enzyme, makes
it a lead compound for the treatment of inflammation
and autoimmune diseases, because N-SMase promotes
the transformation of sphingomyelin to ceramide which
plays an important role in these disease pathways.2 Its
structure consists of the highly functionalized (oxy-
genated) cyclohexenone unit and a side chain. Although
its attractive structure in addition to its biological profile
makes it a very attractive synthetic target, only five
reports concerning the synthetic studies of scyphostatin
analogues have been published so far.3 Gurjar and
Hotha synthesized the dihydroxylated cyclohexenone
2,3a and Katoh and Izuhara prepared the benzyl ana-
logue 3a and more recently, the potential precursor
3b.3b–d They were prepared in the optically active form
from natural products, 2 from glucose and 3a,b from
quinic acid. Their methodologies still require many
reaction steps. Although quite recently, Runcie and
Taylor reported other analogues 3c–f prepared in a
concise way, they were prepared in racemic forms.3e
Therefore, a concise method for obtaining the cyclo-
hexenone unit of 1 in an enantioselective manner is
strongly desired.
We present here our concise asymmetric synthesis of
(4S,5S,6S) - 6 - (2,2 - dimethoxy)ethyl - 4,5 - epoxy - 6-
hydroxy-2-cyclohexenone 4, a model compound for the
cyclohexenone core of 1 (Fig. 1).
Figure 1.
Keywords: asymmetric synthesis; model compound of cyclohexenone core of scyphostatin; cyclohexadiene acetal; chiral hydrobenzoin.
* Corresponding authors. Tel.: +81-6-6879-8225; fax: +81-6-6879-8229; e-mail: kita@phs.osaka-u.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00916-4

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H. Fujioka et al. / Tetrahedron Letters 43 (2002) 4825–4828
Our synthetic strategy is shown in Scheme 1. Since the
selective intramolecular bromoetherification of ene
acetals have been achieved by us,4 the same reaction
of cyclohexadiene acetal 5 would selectively proceed to
give the cyclohexene acetal 6. The conformation of the
cyclohexene ring of 6 is fixed by the eight-membered
acetal. If the SeO2 oxidation would stereoselectively
proceed to give 8 with an a-tert-alcohol after reduc-
tion of the bromo atom of 6, the epoxidation of the
double bond of 8 would then stereoselectively occur to
give the a-epoxide, and the further transformations
would afford 4, the cyclohexenone core of 1.
yield. The stereochemistry of 6 was determined by an
NOE experiment and the X-ray analysis of 7 obtained
by the radical reduction of 6. The trans-relationship
between the bromo atom and ether oxygen atom in 6
was determined by a 1H NMR spectrum showing a
large coupling constant (9.0 Hz) between Ha and Hb
and the mechanistic consideration7 (Fig. 2). The SeO2
oxidation of 7 gave the hydroxylated compound 8 as a
single isomer in 42% yield (20% of 7 was recovered.
The yield based on the consumed 7 is 52.4%.). The
stereochemistry of 8 was determined as follows. Epoxi-
dation of 8 with vanadium(IV) oxide acetylacetonate
(VO(acac)2) and tert-butylhydroperoxide (TBHP)8
gave the cis-epoxy alcohol 9 as a single isomer
(Scheme 2). The stereochemistry of 9 was determined
by an NOE experiment. Namely, the relation between
the epoxide and the tert-alcohol must be cis from the
many examples of the stereoselective Sharpless epoxi-
dation.8 The observation of the presence of NOE
According to the synthetic plan in Scheme 1, the
intramolecular bromoetherification of the cyclohexadi-
ene acetal 5, prepared from cyclohexa-2,5-
dienylethanal diethylacetal5 and (R,R)-hydrobenzoin,6
in the presence of MeOH was accomplished to
stereoselectively give the bromo ene acetal 6 in 63%
Ph
O
MeO
HO
MeO
O
Ph
Ph
Ph
Ph
Ph
O
O
O
O
4
Br
8
6
5
Scheme 1.
Ph
MeO
MeOH
Ph
Ph
O
O
Ph
NBS
Bu3SnH/AIBN
O
O
Ph
Ph
benzene, reflux
O
O
MeOH
CH3CN
+
Br
-40 °C~0 °C
Br
5
(63%)
6
MeO
O
MeO
MeO
HO
Ph
Ph
Ph
Ph
Ph
Ph
O
O
cat. VO(acac)2
TBHP (3 eq.)
SeO2, pyridine
dioxane, 70 °C
HO
O
O
O
O
benzene
r.t.
(75%)
9
(42%)
8
7
(89%)
Scheme 2.
Figure 2.

H. Fujioka et al. / Tetrahedron Letters 43 (2002) 4825–4828
4827
MeO
OMe
VO(acac)2, TBHP
MeOH, PPTS, r.t.
8
OH
benzene, r.t.
HO
O
Ph
Ph
10
(91%)
MeO
HO
MeO
MeO
OMe
O
OMe
O
OMe
OH
nOe
H
TPAP, NMO
Ca
OH
HO
HO
O
H
liq. NH3,
-78 °C
CH2Cl2, MS-4A
0 °C
Ph
O
O
Ph
(82%)
(80%)
13
(70%)
12
11
1H NMR: (CDCl3) δ 1.91 (1H, dd, J = 6.3, 13.9 Hz), 2.09
(1H, dd, J = 4.2, 13.9 Hz), 3.24 (3H, s), 3.36 (3H, s), 3.57
(1H, dt, J = 1.2, 3.9 Hz), 3.75 (1H, d, J = 3.9 Hz), 3.98 (1H,
s), 4.50 (1H, dd, J = 4.2, 6.3 Hz), 6.20 (1H, dd, J = 1.2, 9.8
Hz), 7.06 (1H, dd, J = 3.9, 9.8 Hz); 13C NMR: (CDCl3) δ
29.6, 41.0, 47.8, 53.2, 54.2, 56.1, 100.8, 130.7, 143.1, 200.9.
IR: 3465 (br), 1697, 1118, 1103, 1060 cm-1.
MeO
OMe
O
LDA, THF
HO
Ph
Cl
+
NtBu
O
S
-78 °C
4
(55%)
[α]D26 -97.8 (c 0.12, CHCl3), Colorless oil.
Scheme 3.
Acknowledgements
between the hydrogen atom on the acetal carbon and
the hydrogen atom on the oxirane ring proved the
stereochemistry of the epoxy ring to be a (Fig. 2), and
the results revealed the stereochemistry of 8. As we
expected from the conformation of 7, the stereochem-
istry of the tert-alcohol of 8 was a.
Financial support from Monbusho (Grant-in-Aid for
Scientific Research on Priority Areas, No. 706:
Dynamic Control of Stereochemistry) and Promotion
of Science (No. 12672054) is gratefully acknowledged.
Although opening of the acetal ring of 9 by cat. PPTS
in MeOH gave a complex mixture and the Birch reduc-
tion of 9 showed fruitless results, compound 8 afforded
the dimethyl acetal 10 under the same acidic methanoly-
sis. The epoxidation of 10 with VO(acac)2 and TBHP
gave the epoxy alcohol 11 as a single isomer, whose
stereochemistry was determined by the presence of an
NOE between the hydrogen atom on the epoxide and
the hydrogen atom of the side chain. The Birch reduc-
tion of 11 with Ca metal in liq. NH3 afforded the
dihydroxy epoxy acetal 12. The oxidation of the sec-
ondary alcohol of 12 with tetrapropylammonium per-
ruthenate (TPAP) and 4-methylmorpholine N-oxide
(NMO) afforded the epoxy ketone 13.9 The LDA treat-
ment of 13 and the reaction with N-tert-butylphenyl-
sulfinimidoyl chloride gave the enone 4 in 55% yield10
(Scheme 3).
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acetal works not only as a chiral auxiliary for the
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4828
H. Fujioka et al. / Tetrahedron Letters 43 (2002) 4825–4828
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