T. Akindele et al. / Tetrahedron Letters 46 (2005) 7235–7238
7237
OH
O
CH2Bn
O
CH2Bn
CH2Bn
CH2Bn
O
HO
b,c
d,e
a
O
O
O
CH2Bn
CH2Bn
CH2Bn
HO
10
CH2Bn
7
9
f
O
CH2Bn
O
CH2Bn
O
Me3SiO
Me3SiO
CH2Bn
CH2Bn
O
i
h
g
O
CH2Bn
CH2Bn
CH2Bn
CH2Bn
H
H
8
12
13
11
6.9% nOe
Scheme 2. Reagents and conditions: (a) MePPh3Br, n-BuLi, THF, 0 ꢁC to rt (76%); (b) PCC, CH2Cl2, rt (81%); (c) CH2@CHMgBr, THF, 0 ꢁC to rt
(83%); (d) 5% (Pcy3)2Cl2Ru@CHPh, CH2Cl2, rt (86%); (e) PCC, CH2Cl2, rt (99%); (f) iPrMgCl, LiCl, CuI, TMSCl, Et3N, THF, ꢀ78 ꢁC to rt (71%);
(g) Et2Zn, CH2I2, toluene, rt (20%); (h) Fe(NO3)3, 1,4-cyclohexadiene, DMF, rt; (i) MePPh3Br, n-BuLi, THF, 0 ꢁC to rt (20%, two steps).
isopropyl group, and subsequently to perform a ring
expansion to furnish the desired ketone 8.
(University of Leeds) for carrying out the X-ray crystal-
lographic determination.
Methylenation of lactol 7 with methylenetriphenylphos-
phorane was followed by oxidation of the primary alco-
hol and addition of vinylmagnesium bromide to give
diene 9 (Scheme 2). Ring-closing olefin metathesis, fol-
lowed by oxidation of the allylic alcohol, gave the target
enone 10. Copper-catalysed addition of isopropylmag-
nesium chloride to 10 in the presence of chlorotrimeth-
ylsilane gave direct access to enol ether 11 as a single
diastereoisomer. The addition reaction is presumed to
take place by addition to the convex face of the oxabicy-
clo[3.3.0]octene ring system, an assignment supported
by a strong (6.9%) NOE enhancement between the
allylic CH adjacent to the isopropyl group and the pro-
ton at position 2 of the tetrahydrofuran. To effect ring
expansion, we employed the radical fragmentation of sil-
oxycyclopropanes popularised by Booker-Milburn and
Thompson.24 Simmons–Smith cyclopropanation of silyl
enol ether 11 gave a single diastereoisomer of the target
cyclopropane 12, which was treated with iron(III)
nitrate and 1,4-cyclohexadiene to give ketone 8. Finally,
methylenation of 8 gave the core exo-methylene octa-
hydroisobenzofuran 13 contained within eunicellins
such as sclerophytin.25
References and notes
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In summary, a stereocontrolled synthesis of the bicyclic
core of the eunicellins has been achieved in 16 steps from
crotonyl oxazolidinone 4. The extension of this work to
encompass a total synthesis of the eunicellins can readily
be envisaged by the use of appropriately substituted
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forming condensation sequence. Further studies in this
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Acknowledgements
We thank the EPSRC and AstraZeneca for an Industrial
CASE award (T.A.). We also thank Mr. Colin Kilner
17. Miles, S. M.; Marsden, S. P.; Leatherbarrow, R. J.;
Coates, W. J. J. Org. Chem. 2004, 69, 6874–6882.