Ketone 13 was then converted into the corresponding
pyrrolidine enamine and subsequently alkylated to generate
ethyl ester 14 as a mixture of diastereomers. Ester hydrolysis
proceeded cleanly to afford the corresponding acid 15, which
was then successfully cyclized to produce the desired
butenolide atractylolide 3 in good yield.
Scheme 1. Proposed Biosynthesis of Biatractylolide 1 and
Biepiasterolide 2
Once the butenolide atractylolide 3 was available, we
focused our attention on the dimerization step. As in the case
with the model system,9 we initially explored the possibility
of using DTBP (di-tert-butyl peroxide) as a radical generator.
DTBP has been reported as a model for hydrogen atom
abstraction reactions in biological systems11 as well being
known to effect the dehydrodimerizations of polyhaloalkanes,
alcohols, ethers, amides, and esters.12
Unfortunately, treatment of atractylolide 3 under previ-
ously optimized reaction conditions (0.5 equiv of DTBP,
acetone, 140 °C, 24 h)9 failed to produce any of the desired
dimers 1 or 2. However, treatment of atractylolide 3 under
more forceful conditions only afforded polymeric material
as well as crude traces of what appeared to be the product
of the tBuO• radical having been incorporated. The presence
of these undesired side products increased as the severity of
the reaction conditions increased (Scheme 4).
We have recently reported our work on the model
monomer radical 8, which was efficiently generated and its
dimerization chemistry explored to successfully generate the
model dimer 9 with high RR/SS-RS/SR diastereoselectivity
(Scheme 2).9
Scheme 2. Synthesis of the Dimer Core 9 from Monomer
Unit 8
Scheme 4. Attempted DTBP Dimerization of Atractylolide 3a
We now report the synthesis of the complete monomer
units atractylolide 3 and hydroxyatractylolide 4 and their
potential as synthons for the captodative stabilized radical 7
to enable a biomimetic dimerization to generate both
biatractylolide 1 and biepiasterolide 2.
The synthesis of the complete monomer unit 3 followed
minor modification of the work by Minato and Nagasaki and
began with ketone 10, which was reduced to the correspond-
ing alcohol and then subjected to Birch reduction conditions
to generate enol ether 11. Careful Oppenauer oxidation of
alcohol 11 followed by a 1,4-cuprate addition with simul-
taneous trapping of the resulting enolate, followed by careful
silyl ether hydrolysis, generated the desired ketone 12. Wittig
olefination followed by methyl ether hydrolysis generated
the known key ketone intermediate 13 (Scheme 3).10
a Key: (a) DTBP (0.5 equiv-2.0 equiv), acetone, 120-170 °C,
24 h.
Although disappointing, this lack of dimerization is not
surprising considering the increase in functionality in atrac-
tylolide 3 compared with our model system 8 (i.e., the
exocylic double bond and the C8 methyl group), which may
have detrimental effects on the dimerization.
To shed some light on this process, the exocyclic double
bond was removed before dimerization, by hydrogenation
to afford butenolide 16 as a mixture of diastereomers.
However, treatment of butenolide 16 under the DTBP
dimerization conditions still failed to afford any dimerization
adducts (Scheme 5).
Scheme 3. Synthesis of Atractylolide 3a
This result points to the possibility that we could be
observing a high degree of steric hindrance between the axial
(7) E.g., a pinacol-type dimerization of the keto form of 4, followed by
bis-lactonization.
(8) Hikino, H.; Hikino, Y.; Yosioka, I. Chem. Pharm. Bull. 1962, 10,
641.
(9) Bagal, S. K.; Adlington, R. M.; Marquez, R.; Baldwin, J. E.; Cowley,
A. Tetrahedron Lett. 2003, 44, 4993.
(10) Minato, H.; Nagasaki, T. J. Chem. Soc. C 1966, 1866.
(11) Tanko, J. M.; Friedline, R.; Suleman, N. K.; Castagnoli, N. J. Am.
Chem. Soc. 2001, 123, 5808.
t
a Key: (a) NaBH4, CH3OH, rt, 3 h; (b) Na, NH3, BuOH, -33
°C, 2 h; (c) Al(OiPr)3, toluene, acetone, 87 °C (oil bath), 4.5 h; (d)
CuI, MeMgBr, TMEDA, TMSCl, THF, rt, 16 h; (e) TBAF, THF,
rt, 20 min; (f) PPh3CH2, DMSO, 55 °C, 18 h; (f) 35% aq HCl; (h)
pyrrolidine, PhH, reflux, 6 h; (i) ethyl R-bromopropionate, dioxane,
reflux, 16 h; (j) dioxane, H2O, reflux, 1 h; (k) KOH-CH3OH (5%
w/v), rt, 2 h then HCl, H2O; (l) NaOAc, Ac2O, reflux, 2 h.
(12) Paquette, L. A. Encyclopedia of Reagents for Organic Synthesis;
Wiley: Chichester, 1995; Vol. 3, p 1616.
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Org. Lett., Vol. 5, No. 17, 2003