1048
M. Honzumi, K. Ogasawara / Tetrahedron Letters 43 (2002) 1047–1049
give the tertiary alcohol 8 as a single diastereomer, [h]D22
+33.4 (c 1.2, CHCl3). In order to carry out regioselec-
tive cleavage of the epoxide functionality, the alcohol 8
was first deprotected to give the diol 9, mp 71–72°C,
[h]2D4 +32.8 (c 1.2, CHCl3), the secondary hydroxyl
functionality of which was oxidized under Dess–Martin
conditions12 to afford the keto-alcohol 10, [h]2D2 −11.7 (c
1.4, CHCl3). After some experimentation, it was found
that the regioselective cleavage was best carried out
using aluminum amalgam13 to give the keto-3,4-diol 11,
mp 71–72°C, [h]2D9 −104 (c 1.1, CHCl3), as a single
product. Unfortunately, complete convex-face selectiv-
ity was no longer exhibited by 11 on reaction with
sodium borohydride. An inseparable mixture (10:3) of
the endo- and exo-hydroxy-lactones 12 formed by in
situ lactonization, was obtained under these reaction
conditions. Since the intramolecular bromo-etherifica-
tion of 11 prior to the reduction failed, giving rise
instead to a complex mixture, we decided to use the
crude alcohol mixture 12. The retro-Diels–Alder reac-
tion of both 12 and its secondary monosilyl ether 13, in
refluxing diphenyl ether however resulted in decomposi-
tion. Moreover, attempted dehydration of the ether 13
into the corresponding butenolide under several condi-
tions also failed. Therefore, 13 was silylated to give the
disilyl ether 14, which was heated in refluxing diphenyl
ether to furnish the cyclohexene 15 as an inseparable
mixture in good yield (Scheme 1).
found to be completely racemic. As a result, menisdau-
rilide 2 obtained from 18 by diastereoselective reduction
was racemic. The resulting racemization may be due to
a facile enolization of the butenolide moiety at the
b-elimination step via the hydroxyfuran 19 or in the
oxidation step via the trienone 20. These concluded us
that the route involving the b-elimination of 15 was
inappropriate for the enantioselective synthesis of
menisdaurilide 2 (Scheme 2).
We next explored a route to the (+)-dihydroaquiledi-
olide 5 utilizing the same intermediate 15. Thus, 15 was
hydrogenated under catalytic conditions to afford the
separable 1,4-syn-ether 21 and the 1,4-anti-ether 23 in
yields of 78 and 21%, respectively. The major com-
pound 21 gave the tertiary alcohol 23 on exposure to
dilute hydrochloric acid, which was dehydrated with
methanesulfonyl chloride and triethylamine to give the
butenolide 25. Under these conditions, epimerization
did not take place with the dihydro-derivative. Desilyla-
tion of 25 with hydrofluoric acid in acetonitrile fur-
nished (+)-dihydroaquilediolide 5, mp 107–108°C, [h]D26
+125 (c 0.9, MeOH){lit.:6 [h]D24 +113 (c 1.0, MeOH)
(90% ee)}, the spectroscopic data of which were identi-
cal with those of the natural product. The overall yield
of 5 from 21 was 55%. On the other hand, the minor
isomer 22, under the same conditions, afforded (+)-
dihydromenisdaurilide ent-4, mp 79–80°C, [h]2D6 +123 (c
0.2, MeOH), the enantiomer of the natural (−)-dihy-
dromenisdaurilide 4, [h]2D6 −112 (c 2.0, MeOH) (90%
ee),6 in 35% overall yield from 22 without epimerization
(Scheme 3).
To obtain (−)-menisdaurilide 2, 15 was treated with
potassium carbonate in methanol to induce b-elimina-
tion. The expected reaction occurred to give the
butenolide 16 as an inseparable mixture. Exposure of
16 to hydrofluoric acid in acetonitrile afforded an
inseparable mixture 17 of menisdaurilide 2 and aquile-
giolide 3. Interestingly, the ratio changed from 10:3 to
Acknowledgements
1
2:3 during the elimination reaction as evidenced by H
NMR. A similar epimerization has previously been
reported3 during the isolation of (−)-aquileginolide 3.
The mixture was oxidized with pyridinium chlorochro-
mate (PCC) to give the single enone5 18, which was
We are grateful to the Ministry of Education, Culture,
Sports, Science and Technology, Japan for support of
this research.
CO2Et
HO
CO2Et
Dess-Martin
(98 %)
HO
O
O
O
30 % H2O2
Triton B
THF
LDA
AcOEt
THF
(93 %)
O
O
TBSO
RO
(93 %)
TBSO
O
7
6
8: R=TBS
9: R=H
TBAF
10
THF
(99 %)
O
OTMS
CO2Et
OH
R2O
HO
O
Ph2O
reflux
NaBH4
EtOH
Al-Hg
O
O
aq. EtOH
(88 %)
R1O
O
OTBS
15
(70 % from 11)
11
12: R1=R2=H
TBS-Cl
imidazole
TMS-Cl
13: R1=TBS, R2=H
14: R1=TBS, R2=TMS
imidazole
Scheme 1.