thioester 4 in 96% yield. Reduction of 4 with DIBAL afforded
the corresponding aldehyde which was used immediately to form
the terminal alkyne 12 by addition of lithiated trimethylsilyldia-
zomethane involving a Colvin rearrangement.10 Vinyl iodide 13
was subsequently prepared by Zr-catalyzed methylalumination,11
followed by Negishi cross coupling12 with ZnMe2 to afford alkene
14, which after deprotection with TBAF provided alcohol 15
in 87% yield. Ley oxidation13 of 15 afforded the corresponding
aldehyde which was treated with 2-furyl lithium to give the corre-
sponding furyl alcohol in 88% yield (syn : anti = 2 : 1). Subsequent
Ley oxidation of this mixture gave ketone 16 in 98% yield which
was in turn treated with (S)-CBS reagent and borane14 to afford
furyl alcohol 17 in an excellent 94% yield and a syn : anti ratio
>98 : 2. Stereospecific Achmatowicz rearrangement15 of 17 with
vanadyl acetylacetonate and tert-butylhydroperoxide afforded the
hemi-acetal in 69% yield which was subsequently oxidized by
Jones’ reagent16 to the corresponding ketolactone. Finally, Luche
reduction17 gave the upper half 2 as the only diastereomer.
The stereogenic center in the lower half of (-)-rasfonin was in-
troduced by Michael addition of lithium bis(phenylthio)methane8
to butenolide 5 to provide trans-20 as the single diastereomer in
86% yield (Scheme 3). Full reduction of 20 by LiAlH4 afforded
diol 21 in 90% yield which after protection provided 22 in
96% yield. Unmasking of dithiane 22 by HgCl2 and HgO in a
mixture of acetonitrile and water18 went smoothly and afforded
the free aldehyde in 85% yield which upon treatment with lithiated
trimethylsilyldiazomethane provided the terminal alkyne 23 in
67% yield. Terminal alkylation of the alkyne moiety to give 24
was performed by lithiation followed by quenching with methyl
iodide. The subsequent Pd-catalyzed hydrostannation of alkyne 24
with catalytic Pd(PPh3)Cl2 initially gave low yield and incomplete
conversion. We encountered this problem before,19 and again the
method proposed by Semmelhack and Hooley20 strongly improved
the outcome. Switching to catalytic Pd(OAc)2 and tricyclohexyl
phosphine, with hexane as the solvent, led to complete conversion
and 80% yield in 20 min! Vinyl iodide 25 was subsequently
obtained in 75% yield by treating this stannylated compound with
iodine. Stille coupling of acid 2621 and 25 provided lower half 3 in
87% yield.
Scheme 4 Coupling of the upper half and lower half to give (-)-rasfonin
1.
camphorsulfonic acid gave only 40% yield.6 Fortunately, switching
to aq. HF in acetonitrile23 gave in a close to quantitative yield
(-)-rasfonin whose optical rotation and spectroscopic data agreed
with the reported values (except for the presence of approx. 5% of
a diastereomer that could not be separated).
In conclusion, a very efficient total synthesis of the apoptosis
inducer (-)-rasfonin has been developed. CuBr/JosiPhos cat-
alyzed iterative asymmetric conjugate addition of MeMgBr has
been employed to install the stereogenic centers in the upper half
side chain with excellent yield and stereoselectivity. The hydroxy-
lactone core could be prepared by a subsequent stereospecific
hydroxy-directed Achmatowicz rearrangement followed by an
oxidation–reduction sequence. The synthesis of the lower half
3 makes use of the perfect transfer of chirality in the conjugate
addition to butenolide 5 followed by selective construction of
the E,E-diene-ester part. The availability of an effective route to
rasfonin now allows us to study its role in inhibiting the Ras
signalling pathway, provides access to functional analogs and
might lead to the identification of its target protein.
Acknowledgements
T. D. Tiemersma-Wegman (Stratingh Institute for Chemistry) is
acknowledged for chromatography support. Financial support
from NRSC catalysis grant 200910018B is gratefully acknowl-
edged.
Notes and references
1 (a) V. Shekhar, D. K. Reddy, V. Suresh, D. C. Babu and Y.
Venkateswarlu, Tetrahedron Lett., 2010, 51, 946; (b) A. Favre, F.
Carreaux, M. Deligny and B. Carboni, Eur. J. Org. Chem., 2008, 4900;
(c) L. Dong, V. A. Gordon, R. L. Grange, J. Johns, P. G. Parsons, A.
Porzelle, P. Reddell, H. Schill and C. M. Williams, J. Am. Chem. Soc.,
2008, 130, 15262.
2 K. Akiyama, S. Kawamoto, H. Fujimoto and M. Ishibashi, Tetrahedron
Lett., 2003, 44, 8427.
3 T. Tomikawa, K. Shin-Ya, K. Furihato, T. Kinoshita, A. Miyajima, H.
Seto and Y. Hayakawa, J. Antibiot., 2000, 53, 848.
4 (a) H. Fujimoto, E. Sone, E. Okuyama, M. Ishibashi, 120th Annual
Meeting of the Pharmaceutical Society of Japan, Abstracts of Papers
2, 2000; p 68; (b) O. Rocks, A. Peyker, M. Kahms, P. J. Verveer, C.
Koerner, M. Lumbierres, J. Kuhlmann, H. Waldmann, A. Wittinghofer
and P. I. H. Bastiaens, Science, 2005, 307, 1746; (c) L. Brunsveld,
J. Kuhlmann, K. Alexandrov, A. Wittinghofer, R. S. Goody and H.
Waldmann, Angew. Chem., Int. Ed., 2006, 45, 6622; (d) F. J. Dekker,
O. Rocks, N. Vartak, S. Menninger, C. Hedberg, R. Balamurugan,
S. Wetzel, S. Renner, M. Gerauer, B. Scholermann, M. Rusch, J. W.
Scheme 3 Synthesis of the lower half of (-)-rasfonin 1.
The coupling of the upper half 2 and lower half 3 of (-)-rasfonin
was achieved by Yamaguchi esterification22 in 80% yield (Scheme
4). Desilylation initially was not satisfactory as treatment with
30 | Org. Biomol. Chem., 2012, 10, 29–31
This journal is
The Royal Society of Chemistry 2012
©
Huang, Yange
