A new approach to the bicyclo[4.3.0] ring system of natural products from the liverwort: Total synthesis of (±)-chiloscyphone and (±)-isochiloscyphone

Article abstract of DOI:10.1016/j.tetlet.2004.10.033

Tricyclic intermediate 5 was synthesized by using the intramolecular Diels-Alder reaction as the key step. Total synthesis of (±)- chiloscyphone and (±)-isochiloscyphone was accomplished. Construction of the tricyclic derivative 5, a common intermediate f

Full text of DOI:10.1016/j.tetlet.2004.10.033

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9033–9036
A new approach to the bicyclo[4.3.0] ring system of natural
products from the liverwort: total synthesis of ( )-chiloscyphone
and ( )-isochiloscyphone
Junichi Shiina and Shigeru Nishiyama*
Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi 3-14-1, Kohoku-ku,
Yokohama 223-8522, Japan
Received 6 September 2004; revised 2 October 2004; accepted 7 October 2004
Abstract—Construction ofthe tricyclic derivative 5, a common intermediate for the synthesis of sesquiterpenoids 1–4, was
accomplished by using the intramolecular Diels–Alder reaction. Availability of 5 was demonstrated by effective total synthesis of
chiloscyphone 1 and isochiloscyphone 2.
Ó 2004 Elsevier Ltd. All rights reserved.
The genus liverwort produces a variety ofsesquiterpe-
noids, such as chiloscyphone 1,1 isochiloscyphone 2,2
O
O
acutifolone A 33 and pinguisenol 4,4 which possess fish
killing, anticancer and antimicrobial activities, along
with inhibition ofornithine decarboxylase and cathepsin
B.5 Among them, chiloscyphone 1 was isolated from
Chiloscyphus polyanthos in 1969. After revision of its
structure as depicted in Scheme 1,2 total synthesis of 1
has been reported by several groups.6 Their approach
generally included intramolecular cycloaddition of
appropriate cyclopentane rings. Construction ofthe
skeleton by using intramolecular, 1,4-addition,6a aldol
O
O
O
2
1
OH
5
O
2
CO Me
3
6e
reaction,6b–d and cyclization ofhaloalkane derivatives
4
IMDA
was reported. However, in their synthesis, the undesired
diastereomers ofthe cycloadduct, which could not be
converted into useful forms, were co-produced. Against
such background, we envisaged a more efficient synthe-
sis ofthe liverwort-type sesquiterpenoids than the con-
ventional methodology. We initiated a synthesis ofa
common precursor 5 ofthe sesquiterpenoid by using
intramolecular Diels–Alder reaction for simultaneous
construction ofthe cis-oriented continuous substitutions
in the bicyclo[4.3.0] structure ofthis sesquiterpenoid
family. In a previous paper,7 asymmetric synthesis of
the Diels–Alder product (type-5) was accomplished.
OH
O
H
OTBS
O
O
7
6
Scheme 1.
We describe herein an improved synthetic protocol of
the racemic 5 and its application to total synthesis of
( )-1 and ( )-2.
Retrosynthetic analysis ofchiloscyphone 1 and isochi-
loscyphone 2 is illustrated in Scheme 1. The key interme-
diate 5 of 1 and 2 would be obtained by the
intramolecular Diels–Alder reaction ofthe precursor 6.
Keywords: Chiloscyphone; Total synthesis; Intramolecular Diels–Alder
reaction; Sesquiterpenoid; Desulfurization.
*
Corresponding author. Tel./fax: +81 45 566 1717; e-mail: nisiyama@
chem.keio.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.033

9034
J. Shiina, S. Nishiyama / Tetrahedron Letters 45 (2004) 9033–9036
Triene 6 would be prepared from aldehyde 7, readily
available from 1,5-pentanediol.
obtained under heating (180°C) in a sealed tube. The
low yield of 12 might be owing to steric hindrance of
the protecting group.10 On the other hand, after depro-
tection ofthe siloxy group, heating of 6 in the presence
ofBHT in a sealed tube (0.1M in PhMe), produced
cycloadduct 13 in 65% yield, as a diastereomeric mixture
(1:1.1:0.6). The tricyclic compound 13 in hand was oxi-
dized, followed by isomerization with DBU to furnish
the desired intermediate ( )-5 in excellent yield.
Along this line, synthesis ofthe tricyclic compound
was commenced from 7, which was produced by the
5
8
known manipulation of1,5-pentanediol (Scheme 2).
Thus, reaction of 7 with butadienyl lithium9 gave the
corresponding alcohol, which was protected as a
TBDPS ether to furnish 8. Selective removal ofthe
TBS group, followed by oxidation, gave the correspond-
ing aldehyde, which was further oxidized with PDC,
leading to the methyl ester 9. Compound 9 was submit-
ted to the aldol reaction with THPOCH2CHO, followed
by removal ofthe THP group and cyclization under ba-
sic conditions to afford 10. The lactone 10 was acetyl-
ated, followed by elimination under DBU conditions
to give the triene 11, which was submitted to the Lewis
acid or thermal-mediated intramolecular Diels–Alder
reactions. Attempts using Et2AlCl in refluxing CH2Cl2
or LiClO4 in refluxing PhMe, provided no expected cyc-
lization product. Reaction of 11 with a stronger Lewis
acid, EtAlCl2, at ambient temperature was unsuccessful,
owing to deprotection ofthe TBDPS group and rear-
rangement ofthe diene moiety to give the product A.
Among reactions of 11 carrying a TBDPS group under
thermal conditions, an inseparable mixture ofcycload-
duct 12 and unreacted 11 (12/11 = 1:5, 94% yield) was
Synthesis of 19 and 20 from 5 is outlined in Scheme 3.
The tricyclic compound 5 was converted with TMSOTf
into a TMS enol ether, followed by oxidation with
11
Pd(OAc)2, and the Michael addition to give ketone
14 as a single isomer, owing to steric hindrance ofthe
lactone moiety. Successive process involving reduction,
mesylation and elimination, selectively afforded a trisub-
stituted olefin, according to the Saytzeff rule. Reduction
ofthe lactone moiety gave the diol 15, which was pro-
tected as a TBDPS ether to furnish 16. Selective epoxi-
dation ofthe electron-rich trisubstituted olefin of 16,12
and the epoxide opening by LiEt3BH afforded the terti-
ary alcohol 17.13 Oxidation ofthe terminal olefin by
OsO4 and oxidative cleavage gave an aldehyde, which
was reduced with NaBH4 and etherified as an MPM
ether to afford 18. Dehydroxylation ofthe tertiary alco-
hol was attempted to obtain the tri-substituted olefins 19
O
OTBDPS
OTBDPS
O
O
OH
OH
d - g
a - c
5
a, b
c - f
7
O
OMe
15
TBSO
14
9
8
OTBDPS
OTBDPS
OTBDPS
OTBDPS
OTBDPS OH
i , j
h
j, k
g - i
O
O
OH
17
10
16
O
OTBDPS
O
OR
OTBDPS
m
MPMO
k - m
n
O
O
RO
OH
18
OTBDPS
OTBDPS
: R = TBDPS
: R = H
11
6
12 : R = TBDPS
l
: R = H
13
OTBDPS
OTBDPS
MPMO
MPMO
+
HO
n, o
5
O
O
A
19
20
Scheme 2. Reagents and conditions: (a) (E)-nBu3SnCH@
CHCH@CH2, nBuLi, THF, À78°C, 93%; (b) TBDPSCl, Imid,
DMF, rt, 92%; (c) PPTS, EtOH, rt, 95%; (d) SO3Æpy, DMSO, Et3N,
CH2Cl2, 0°C; (e) PDC, DMF, rt, 92% in two steps; (f) K2CO3, MeI,
DMF, 0°C, 91%; (g) LDA, THPOCH2CHO, THF, À78°C; (h) PPTS,
MeOH, rt; (i) Et3N, MeOH, rt, 69% in three steps; (j) Ac2O, py,
CH2Cl2, rt; (k) DBU, PhMe, 0°C, 93% in two steps; (l) TBAF, AcOH,
THF, rt, 83%; (m) BHT, PhMe, in a sealed tube, 180°C, 65%; (n)
TFAA, DMSO, Et3N, CH2Cl2, À60°C; (o) DBU, PhMe, 0°C, 64% in
two steps.
Scheme 3. Reagents and conditions: (a) TMSOTf, Et3N, CH2Cl2, 0°C;
(b) Pd(OAc)2, CH3CN, rt, 98% in two steps; (c) CH2@CHMgBr, CuI,
THF, À70°C, 75%; (d) NaBH4, MeOH, 0°C; (e) MsCl, py, rt; (f)
AcOK, DMF, H2O, 80°C; (g) DIBAL, CH2Cl2, 0°C; (h) TBDPSCl,
Imid, DMF, rt, 73% in five steps; (i) mCPBA, NaH2PO4, CH2Cl2, 0°C;
(j) LiEt3BH, THF, rt, 53% in two steps; (k) OsO4, Me3NO, acetone,
H2O, rt, then NaIO4, 0°C; (l) NaBH4, MeOH, 0°C, 57% in two steps;
(m) MPMCl, NaH, nBu4NI, DMF, 0°C, 70%; (n) POCl3, py, 50°C,
94%.

J. Shiina, S. Nishiyama / Tetrahedron Letters 45 (2004) 9033–9036
9035
Table 1. Deoxygenation of cis-oriented diol 21 using its derivatives 22–
25
and 20. The regiochemistry ofthe olefin was confirmed
by transformation of 20 into the precursor 16 (1.
DDQ; 2. IBX; 3. Ph3PMeBr, NaHMDS). Reaction with
POCl3 at 50°C gave 19 and 20 in the ratio of1:10. Upon
using SOCl2 in pyridine, lower reaction temperature de-
creased the ratio of 20 (19/20 in the ratio of1:7 at 23 °C,
1:5 at 0°C and 1:3.5 at À30°C). Reaction ofa mixture of
19 and 20 in the presence ofWilkinson catalysts effected
no olefin isomerization. Although, at this stage, specific
production ofeach product could not be achieved, both
compounds could be used for synthesis of 1 and 2, as
follows.
Entry Substrate Conditions
Result
1
2
3
4
5
22
22
23
24
25
LiAlH4, THF, reflux
LiEt3BH, THF, reflux
Ba
Ba
nBu3SnH, AIBN, PhMe, reflux No reaction
nBu3SnH, AIBN, PhMe, reflux Unknown
Raney Ni W-4, THF, reflux
26 (60%)
a Compound B was not purified, due to its instability.
molecular radical coupling to obtain a complicated
mixture (entry 4). When the alcohols were activated step-
wise, the intramolecular cycloadducts were obtained.
Finally, reaction of 22 with Na2SÆ9H2O furnished the
cyclic sulfide 25, which was submitted to desulfurization
with Raney Ni W-415 to give the desired 26 in 60% yield
(entry 5). Oxidative removal ofthe MPM group
afforded the primary alcohol 27. Compound 27 was
oxidized with IBX, followed by alkylation with
CH2@C(Me)MgBr and oxidation with PCC6e to give
( )-2. By employing essentially the same procedure,
total synthesis of 1 was accomplished from 19 (Scheme
4). Synthetic ( )-1 and ( )-2 were superimposable to
the reported data.1,2
In the case of 20, removal ofthe TBDPS group provided
the diol 21 (Scheme 4). Deoxygenation of 21 to the syn-
dimethyl derivative 26 was examined (Table 1). When
the mesylate 22 produced from 21 was reacted with
LiAlH4 or LiEt3BH, the desired product 26 was not ob-
tained (entries 1 and 2). In contrast to general deoxygen-
ation, which cleaves the C–O bond, cleavage ofthe S–O
bond14 gave an alcohol and successive cyclization af-
forded the product B. After conversion of the diol 21
into the corresponding dichloride, radical reduction pro-
vided no desired 26 (entry 3). Radical reduction ofthe
xanthate 24 was also unsuccessful, owing to an intra-
In conclusion, tricyclic compound 5 was synthesized by
using the intramolecular Diels–Alder reaction as the key
step in far better yield than that of a previous report.7
Efficiency of 5 for synthesis of the sesquiterpenoids car-
rying the bicyclo[4.3.0] system was demonstrated by the
total synthesis of( )-chiloscyphone 1 and ( )-isochi-
loscyphone 2. Synthesis ofsesquiterpenoids 3 and 4 car-
rying the related structures is now in progress.
R
a
R
Table 1
MPMO
20
21
22
S
: R = OH
e
MPMO
b
c
d
: R = OMs
23
24
: R = Cl
Acknowledgements
: R = OC(S)SMe
25
This work was supported by Grant-in-Aid for the 21st
Century COEprogram ꢀKeio Life Conjugated Chemis-
tryꢁ from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
MPMO
HO
f
27
26
2
References and notes
O
MPMO
g - i
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B
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MPMO
j - m
n - q
19
1
28
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Scheme 4. Reagents and conditions: (a) TBAF, THF, 50°C, 94%; (b)
MsCl, py, rt; (c) SOCl2, py, rt; (d) NaH, CS2, MeI, THF, 0°C; (e)
Na2SÆ9H2O, DMF, 50°C; (f) DDQ, CH2Cl2, H2O, 0°C, 85%; (g) IBX,
DMSO, THF, rt; (h) CH2@C(Me)MgBr, THF, 0°C; (i) PCC, CH2Cl2,
rt, 60% in three steps; (j) TBAF, THF, 50°C, 90%; (k) MsCl, py, rt; (l)
Na2Æ9H2O, DMF, 50°C; (m) Raney Ni W-4, THF, reflux, 66% in three
steps; (n) DDQ, CH2Cl2, H2O, 0°C, 92%; (o) IBX, DMSO, THF, rt;
(p) CH2@C(Me)MgBr, THF, 0°C; (q) PCC, CH2Cl2, rt, 62% in three
steps.

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J. Shiina, S. Nishiyama / Tetrahedron Letters 45 (2004) 9033–9036
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