Total synthesis of (+)-cheimonophyllon E, a bisabolane sesquiterpenoid

Article abstract of DOI:10.1016/S0040-4039(01)00817-6

Total synthesis of (±)-cheimonophyllon E was accomplished starting from 3-methyl-2-cyclohexen-1-one. Also, synthesis of (+)-cheimonophyllon E, the natural enantiomer, was achieved through optical resolution of a key intermediate in the racemic synthesis.

Full text of DOI:10.1016/S0040-4039(01)00817-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4665–4668
Total synthesis of (+)-cheimonophyllon E, a bisabolane
sesquiterpenoid
Ken-ichi Takao, Manabu Hara, Tomohiro Tsujita, Ken-ichi Yoshida and Kin-ichi Tadano*
Department of Applied Chemistry, Keio University, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
Received 12 April 2001; revised 8 May 2001; accepted 11 May 2001
Abstract—Total synthesis of ( )-cheimonophyllon E was accomplished starting from 3-methyl-2-cyclohexen-1-one. Also, synthesis
of (+)-cheimonophyllon E, the natural enantiomer, was achieved through optical resolution of a key intermediate in the racemic
synthesis. © 2001 Elsevier Science Ltd. All rights reserved.
Six new bisabolane-type sesquiterpenoids, cheimono-
phyllons A (1)–E (2) (Scheme 1) and cheimono-
phyllal, were isolated from the culture fluid of the
basidiomycete Cheimonophyllum candidissimum.1 These
natural products exhibit nematicidal, antifungal,
antibacterial, and cytotoxic activities.1 Their structures
have been determined by spectroscopic analysis; how-
ever, the absolute stereochemistry remained unknown.2
Among them, cheimonophyllon E (2) possesses five
stereogenic carbons in a highly oxygenated 7-oxabi-
cyclo[4.3.0]nonane core skeleton. Our interest in their
intriguing structures and biological activities led us to
study the synthesis of the cheimonophyllons. We
describe here the first total synthesis of cheimonophyl-
lon E, thereby establishing its previously unknown
absolute stereochemistry.
Our retrosynthetic analysis of 2 is shown in Scheme 1.
A 7-oxabicyclo[4.3.0]non-4-ene derivative 3 was consid-
ered to be an advanced synthetic intermediate for 2.
For the construction of the bicyclic core in 3, we
anticipated that a cyclization of g,d-epoxy allylic alco-
hol 4 would proceed regioselectively for the construc-
tion of
a tetrahydrofuran ring in 3. The key
intermediate 4 would be obtained from a 2-cyclohexen-
1-ol derivative 5. Then, we expected the allylic alcohol
5 to be prepared by the aldol reaction of commercially
OH
O
HO
H
HO
H
O
O
O
O
OH
H
H
O
H
3
cheimonophyllon A (1)
cheimonophyllon E (2)
OH
OP
O
H
+
O
O
H
H
OH
6
7
5
4
Scheme 1.
Keywords: biologically active compounds; cyclization; resolution; terpenes and terpenoids.
* Corresponding author. Fax: +81-45-566-1571; e-mail: tadano@applc.keio.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00817-6

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K. Takao et al. / Tetrahedron Letters 42 (2001) 4665–4668
available 3-methyl-2-cyclohexen-1-one (6) and (E)-5-
methyl-2-hexenal (7).3
afford the desired allylic alcohol 10 with a high level of
diastereoselectivity (d.r.=20:1). By a protection–depro-
tection sequence, 10 was converted into 12 (correspond-
ing to 5: P=triethylsilyl=TES). A vanadium-catalyzed
oxidation7 of the allylic alcohol 12 predominantly pro-
vided anti-a,b-epoxy alcohol 13 (anti/syn=5.6:1).
Introduction of the exo-methylene group in the tetra-
hydrofuran ring in 2 was carried out by a Peterson
olefination strategy.8 Thus, 13 was oxidized with Dess–
Martin periodinane,9 and the resulting ketone 14 was
reacted with TMSCH2MgCl to provide 15 as a single
diastereomer, which was then subjected to b-elimina-
tion with KHMDS to give exo-methylene-epoxide 16.
Desilylation of the TES group in 16 with n-Bu4NF gave
4. Exposure of 4 to a catalytic amount of CSA under-
went intramolecular cyclization as a result of the
stereoselective epoxy ring opening. As expected, the
5-exo cyclization product ( )-3 was obtained exclusively
in an almost quantitative yield. Oxidation of 3 gave
ketone 17, which was finally subjected to OsO4–NMO
oxidation. Stereoselective dihydroxylation occurred
First, we explored a racemic synthesis of cheimonophyl-
lon E (2). The aldol reaction of enone 6 and aldehyde 7
using LDA as a base at −78°C afforded an inseparable
mixture of 8-syn and 8-anti in a combined yield of 63%
(Scheme 2).† The relative configurations (syn or anti ) in
1
the aldols were determined by H NMR analysis.4 The
ratio of the desired 8-syn to the isomer 8-anti was
determined to be 1:4.5. It has been reported that
diastereoselectivity in the aldol reaction of cyclohex-
anone lithium enolate with benzaldehyde depends
strongly on the reaction temperature.5 In fact, when the
reaction mixture of 6 and 7 was allowed to warm to
−18°C, the syn/anti stereoselectivity was improved to
1.2:1, and the yield of the diastereomeric mixture was
66%. Benzoylation of the aldol mixture provided 9-syn
and 9-anti, which were cleanly separated by chromato-
graphy on silica gel. The 1,2-reduction of the enone in
9-syn was conducted using the Luche’s conditions6 to
O
OR
O
OR
a, b
+
6 + 7
8-syn: R = H
9-syn: R = Bz
8-anti: R = H
9-anti: R = Bz
OR1
OTES
O
f
c, d, e
O
H
H
H
OR2
OH
13
OBz
9-syn
10: R1 = H, R2 = Bz
11: R1 = TES, R2 = Bz
12: R1 = TES, R2 = H
OTES
O
OTES
OR
i, j
g
h
O
O
H
H
H
OH
O
TMS
16: R = TES
4: R = H
14
15
H
O
H
H
O
m
k
l
(±)-3
(±)-2
+
O
O
OH
H
OH
(±)-17
(±)-18
Scheme 2. Reagents and conditions: (a) LDA, THF, −18°C, 66% (1.2:1 mixture); (b) BzCl, pyridine, 50% for 9-syn and 43% for
9-anti; (c) NaBH4, CeCl3·7H2O, MeOH, 0°C, quant. (d.r.=20:1); (d) imidazole, TESCl, DMF, 0°C, 91% (d.r.=20:1); (e) Dibal-H,
CH2Cl2, −78°C, 90% for 12 and 4% for its diastereomer; (f) VO(acac)2, t-BuOOH, CH2Cl2, 0°C, 78% for 13 and 14% for
syn-epoxide; (g) Dess–Martin periodinane, CH2Cl2; (h) TMSCH2MgCl, THF, 0°C, 87% for two steps; (i) KHMDS, THF, 0°C,
93%; (j) n-Bu4NF, THF, 0°C, 98%; (k) CSA, CH2Cl2, −18°C, 98%; (l) Dess–Martin periodinane, CH2Cl2, 0°C, 98%; (m) OsO4,
NMO, acetone–t-BuOH–H2O, 0°C, 48% for 2 and 19% for 18.
† All new compounds were fully characterized by spectroscopic means [1H (270 or 300 MHz in CDCl3) and 13C (75 MHz in CDCl3) NMR, IR]
and gave satisfactory HRMS. Yields refer to homo-geneous samples purified by chromatography on silica gel.

K. Takao et al. / Tetrahedron Letters 42 (2001) 4665–4668
4667
preferentially at the endocyclic double bond to provide
( )-cheimonophyllon E (2) along with a small amount
of the regioisomeric diol ( )-18. The spectroscopic data
difference in the chemical shift (ppm) [Dl=l(22)−
1
l(21)] in the H NMR spectra of 22 and 21 indicated
that the absolute configuration of 21 was that depicted
in Scheme 3.12,13 In addition, 19 was subjected to a
Sharpless asymmetric dihydroxylation14 with AD-mix-b
to produce 23 with excellent stereoselectivity in a high
yield of 96%.‡ By contrast, treatment of 20 under the
same conditions led to an inseparable mixture (1.2:1) of
24 and 25 in low yield.‡ This is a mismatched case
resulting from the fact that the substrate and the chiral
reagent have opposite stereofacial preferences. Conse-
quently, on the basis of the Sharpless’ mnemonic
device,14,15 the structures of 19 and 20 were determined
to be those shown. These results are consistent with the
result obtained from the modified Mosher’s method.
Enantiomerically pure (+)-3 was eventually converted
into (+)-cheimonophyllon E (2) using the same reaction
sequence used for the racemic synthesis.§ Synthetic opti-
cally active 2 had an identical specific rotation with that
1
(IR, H and 13C NMR, LR and HRMS) of synthetic
( )-2 were well matched with those reported for natural
2.2
Having established an efficient route to racemic 2, we
next focused our attention on the synthesis of an opti-
cally active 2. When racemic ( )-3 was acylated with
(S)-O-acetylmandelic
acid,10
readily
separable
diastereomers 19 and 20 were isolated (Scheme 3).
Dibal-H reduction of 19 and 20 produced optically
pure (+)- and (−)-3, respectively. Assignment of the
absolute stereochemistries for both enantiomers was
carried out by the following two methods. Condensa-
tion of (+)- or (−)-3 with (R)-a-methoxy-a-(tri-
fluoromethyl)phenylacetic acid (MTPA)11 afforded
MTPA esters 21 or 22, respectively. As shown, the
H
H
O
O
a
(±)-3
+
O
O
O
O
H
H
AcO
Ph
AcO
Ph
19
20
-0.32
H
-0.25
H
+0.04
+0.16
+0.03
OMTPA
+0.08
-0.15
-0.10
H
H
H
O
O
O
b, c
b, c
20
19
H
OR
H
-0.22
OR
-0.03
-0.15
-0.15
H
∆δ values (ppm)
[δ(22) – δ(21)]
(+)-3: R = H
(–)-3: R = H
21: R = (R)-MTPA
22: R = (R)-MTPA
OH
H
OH
H
OH
HO
HO
HO
H
O
O
O
d
d
20
19
+
O
O
O
O
O
O
(mismatched)
(matched)
H
H
H
AcO
Ph
AcO
Ph
AcO
Ph
23
24
25
OH
H
HO
O
f
e
(–)-18
(+)-17
(+)-3
+
O
H
(+)-cheimonophyllon E (2)
Scheme 3. Reagents and conditions: (a) (S)-O-acetylmandelic acid, WSC·HCl, Et3N, 4-DMAP, CH2Cl2, 46% for 19 and 47% for
20; (b) Dibal-H, CH2Cl2, −78°C, quant. for (+)-3, or 96% for (−)-3; (c) (R)-MTPA, DCC, 4-DMAP, CH2Cl2, 16% for 21 and 52%
for recovered (+)-3, or 17% for 22 and 48% for recovered (−)-3; (d) AD-mix-b, MsNH2, t-BuOH–H2O, 0°C, 22 h, 96% for 23,
or 40% for the mixture (1.2:1) of 24 and 25 and 60% for recovered 20; (e), (f) same as (l); (m) in Scheme 2.
‡ Treatment of 19 or 20 with standard achiral reagents (OsO4–NMO) gave exclusively 23 (84%) or 24 (91%), respectively. Under these conditions
as well as the Sharpless asymmetric conditions, no dihydroxylation of the exo-methylene group in 19 or 20 occurred.
§ Analogously, (−)-3 was converted into (−)-cheimonophyllon E {[h]D23 −126 (c 2.47, CHCl3)}, the unnatural enantiomer.

4668
K. Takao et al. / Tetrahedron Letters 42 (2001) 4665–4668
of natural 2 {[h]2D2 +123 (c 2.29, CHCl3) for synthetic,
lit.2 [h]D +125 (c 2.2, CHCl3) for natural}. Thus, the
absolute stereochemistry of natural 2 was established as
depicted.
5. Hirama, M.; Noda, T.; Takeishi, S.; Itoˆ, S. Bull. Chem.
Soc. Jpn. 1988, 61, 2645–2646.
6. Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103,
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7. Rossiter, B. E.; Verhoeven, T. R.; Sharpless, K. B. Tetra-
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8. Ager, D. J. Org. React. 1990, 38, 1–223.
9. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277–7287.
10. (a) Whitesell, J. K.; Reynolds, D. J. Org. Chem. 1983, 48,
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512–519.
In conclusion, we have achieved the total synthesis of
( )-cheimonophyllon E in 13 steps starting with com-
mercially available enone 6. Furthermore, optical reso-
lution of the key intermediate ( )-3 led to the syntheses
of natural (+)- and unnatural (−)-cheimonophyllon E.
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