A new route to furanoeremophilane sesquiterpenoids. Synthesis of
(±)-6b-hydroxyeuryopsin
M. Sundaram Shanmugham and James D. White*
Department of Chemistry, Oregon State University, Corvallis, Oregon 97331-4003, USA.
E-mail: james.white@orst.edu; Fax: 541-737-2660; Tel: 541-737-2173
Received (in Cambridge, UK) 17th September 2003, Accepted 10th November 2003
First published as an Advance Article on the web 21st November 2003
The naturally occurring furanoeremophilane 6b-hydroxyeuryo-
psin was synthesized by a novel route which involved Stille
coupling of a 2-furylstannane with a cyclohexylmethyl bromide,
followed by intramolecular formylation of the furan to complete
the tricyclic nucleus of the sesquiterpenoid.
The eremophilane family is a large, structurally diverse group of
sesquiterpenoids characterized by a decalin skeleton in which a
methyl migration has taken place to produce a non-isoprenoid
substituent pattern.1 A subset of this group, the furanoer-
emophilanes, bears a furan fused to the decalin core which, in
certain cases, appears in oxidized form as a butenolide.
Beginning in 1971 with Piers’ pioneering synthesis of (±)-ere-
mophilenolide,2 a substantial synthetic effort has been devoted to
this class of natural products with the result that several distinct
pathways have been established.3 However, none of these builds
the furanoeremophilane framework through consecutive alkyla-
tions at C2 and then C3 of a preformed furan. We now describe a
synthesis of 6b-hydroxyeuryopsin (1), a furanoeremophilane
isolated from Senecio tolucannus,4 which exemplifies just such a
strategy, and which, in principle, allows access to a broad array of
related sesquiterpenoids such as petasalbine (2) and ligularone
(3).5
Scheme 1 Reagents and conditions: i, Ref. 6; ii, 2-ethyl-2-methyl-
1,3-dioxolane, (CH2OH)2, p-TsOH (0.2 equiv.), rt, 72 h, 75%; iii, p-TsOH
(0.05 equiv.), benzene, 50 °C, 12 h, 57%; iv, K2OsO4 (0.05 equiv.),
K2Fe(CN)4, K2CO3, quinolidine, MeSO2NH2, t-BuOH–H2O, rt, 48 h, 90%;
v, NaIO4, THF, H2O, rt, 12 h, 100%; vi, NaBH4, THF–H2O, rt, 12 h; vii,
TIPSOTf, 2,6-lutidine, CH2Cl2, 278 °C to 0 °C, 4 h, 93%; viii, PPTS (0.3
equiv.), 10% aq. acetone, 60 °C, 4 h, 85%; ix, 2,4,6-triisopropylbenzene-
The synthesis of 1 commenced from the known 2,3-dimethyl-
sulfonylhydrazine, THF, rt, 12 h, 100%; x, tert-BuLi, 10% TMEDA–
2-methallylcyclohexanone (4),6 prepared as a 4 : 1 mixture of cis
hexanes, 278 °C, 30 min, then 0 °C, 1 min, then 278 °C, DMF, 278 °C to
and trans isomers from 2,3-dimethylcyclohexanone (Scheme 1).
Ketalization of the major isomer 4 was selective and was followed
by acid-catalyzed isomerization of the terminal alkene to yield the
trisubstituted olefin 5. This was subjected to oxidative cleavage to
give aldehyde 6.7 The latter was reduced, and the resulting primary
alcohol 7 was protected as its triisopropylsilyl (TIPS) ether 8. Mild
acidic hydrolysis of ketal 8 under conditions that left the TIPS ether
intact produced a ketone which was condensed with 2,4,6-triisopro-
pylbenzenesulfonylhydrazine. Shapiro reaction8 of hydrazide 9
with tert-butyllithium, followed by treatment of the intermediate
lithio alkene with dimethylformamide, afforded a,b-unsaturated
aldehyde 10 which was reduced to primary alcohol 11. This
compound was converted via its mesylate 12 to allylic bromide
13.
0 °C, 4 h; xi, DIBALH, CH2Cl2, 278 °C to 0 °C, 4 h, 75% from 9; xii,
Ms2O, Et3N, CH2Cl2, 278 °C to 0 °C, 2 h, then LiBr, THF, rt, 12 h,
95%.
The furanoid partner required for coupling with 13 was obtained
from furan-3-carboxylic acid (14) (Scheme 2). After reduction of
this acid with borane and conversion of the resulting primary
alcohol to tert-butyldimethylsilyl (TBS) ether 15, the furan was
reacted with n-butyllithium in HMPA to yield 16. This transforma-
tion is presumed to occur via an intramolecular retro-Brook
rearrangement9 of the corresponding 2-lithiofuran and conven-
iently blocks C-2 of the furan against further substitution at this
position. After reductive cleavage of the mesylate of 16 with
lithium triethylborohydride, lithiation of the furan with n-butylli-
Scheme 2 Reagents and conditions: i, BH3·Me2S, THF, rt, 12 h, 85%; ii,
TBSCl, imidazole, CH2Cl2, rt, 2 h, 100%; iii, n-BuLi, HMPA–THF, 278 °C
to rt, 6 h, 89%; iv, Ms2O, Et3N, CH2Cl2, 278 °C to 0 °C, 2 h, then LiEt3BH,
THF, 0 °C, 100%; v, n-BuLi, THF, 278 °C to 0 °C, 6 h, then n-Bu3SnCl,
278 °C to rt, 12 h, 85%.
44
C h e m . C o m m u n . , 2 0 0 4 , 4 4 – 4 5
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4