of the natural enantiomer (+)-1, reported in 2002 by Gracza,
started from D-mannitol and required 11 steps, one of which
was nonstereoselective (it generated a 50:50 mixture of
stereoisomers).7a This approach, based on a palladium(II)-
catalyzed oxycarbonylation methodology for the construction
of the tetrahydrofuran ring, was completed with a 0.5%
overall yield. More recently, the same author has reported
an optimized synthesis of (+)-1 that proceeded in 10 steps
and 1% overall yield.7b The second preparation of gonio-
thalesdiol, published by Yoda, provided (-)-1, the unnatural
enantiomer, through a lengthy 16-step reaction sequence that
was based on a Lewis acid induced deoxygenation of a highly
functionalized lactone derived from D-glucurolactone.8 An-
other approach to (+)-1 was reported by Carda´ and Marco
in 2004 and was based on stereoselective anti aldol reactions
of L-erythrulose derivatives.9 This formal synthesis of
goniothalesdiol allowed the preparation, in 11 steps, of a
lactone intermediate (7.6% overall yield), which could be
converted into (+)-1 by means of three additional transfor-
mations (2% overall yield). Very recently,10 Yadav has
described the last synthesis of (+)-goniothalesdiol employing
Sharpless catalytic asymmetric epoxidation and Sharpless
asymmetric dihydroxylation reactions, in 11 steps, starting
from cinnamyl alcohol.
TMSOTf-promoted reductive cyclization/deoxygenation to
generate, respectively, the stereogenic centers at C-5 and C-2
of the tetrahydrofuran ring.
Our asymmetric synthesis of (+)-goniothalesdiol (1) started
with the protection of commercially available (-)-(2S,3S)-
dimethyl D-tartrate (3) with benzyl trichloroacetimidate in
the presence of triflic acid13 to afford, in 69% yield, the
dibenzyl ether derivative (2S,3S)-4 (Scheme 1).14
Scheme 1. Synthesis of Sulfinyl Lactone (3S,4S,5R,SR)-7 from
Commercially Available (-)-(2S,3S)-dimethyl D-tartrate (3)
In connection with a program devoted to asymmetric
synthesis mediated by sulfoxides,11 we have recently de-
scribed a highly stereoselective approach to different sized
cis-disubstituted cyclic ethers based on the Et3SiH/TMSOTf-
promoted reductive cyclization of enantiopure hydroxy
sulfinyl ketones which are, in turn, accessible through the
well established diastereoselective reduction of an adequately
functionalized â-ketosulfoxide.12
In this paper, we extend the scope of this methodology to
the efficient construction of a natural product bearing a
tetrasubstituted tetrahydrofuran structure and four stereogenic
centers.
The stereoselective total synthesis of natural (+)-gonio-
thalesdiol (1) that we are reporting proceeds in a nine-step
reaction sequence and exploits the diastereoselective reduc-
tion of a â-ketosulfoxide and a cis-stereoselective Et3SiH/
The addition of 2 equiv of the anion generated from
enantiomerically pure (-)-(SR)-methyl-p-tolyl sulfoxide15
and LDA to the diester 4 gave rise to the corresponding
â-ketosulfoxide (2S,3S,SR)-5, together with several byprod-
ucts (Scheme 1). The reaction was shown to be very sensitive
to factors such as temperature, scale-up of the reaction and
partial degradation during chromatographic purification.
Under the best conditions (-78 °C, 1.2 mmol of compound
4 and use of demetalated silica gel for column chromatog-
raphy), the maximum yield achieved for derivative 5 was
57%. For this reason, we decided to reduce the carbonyl
group using the isolated, but nonpurified, crude reaction
mixture of compound 5.
Thus, the reduction of the crude â-keto sulfoxide 5 with
diisobutylaluminum hydride (DIBALH) in the presence of
ZnBr2 afforded, in a completely diastereoselective way,
alcohol (2S,3R,4R,SR)-6, bearing the R absolute configuration
at the newly created C-4 stereogenic center. This result
evidenced that the well-established protocol to reduce
â-ketosulfoxides, first reported in 1985 by Solladie´,16 is
(5) Cao, S.-G.; Wu, X.-H.; Sim, K.-Y.; Tan, B. K. H.; Pereira, J. T.;
Gog, S.-H. Tetrahedron 1998, 54, 2143-2148.
(6) Yoda, H.; Shimojo, T.; Takabe, K. Synlett 1999, 1969-1971.
(7) (a) Babjak, M.; Kapita´n, P.; Gracza, T. Tetrahedron Lett. 2002, 43,
6983-6985. (b) Babjak, M.; Kapita´n, P.; Gracza, T. Tetrahedron 2005,
61, 2471-2479.
(8) Yoda, H.; Nakaseko, Y.; Takabe, K. Synlett 2002, 1532-1534.
(9) Murga, J.; Ruiz, P.; Falomir, E.; Carda´, M.; Peris, G.; Marco, J.-A.
J. Org. Chem. 2004, 69, 1987-1992.
(10) Yadav, J. S.; Raju, A. K.; Rao, P. P.; Rajaiah, G. Tetrahedron:
Asymmetry 2005, 16, 3283-3290.
(11) Overviews: (a) Carren˜o, M. C. Chem. ReV. 1995, 95, 1717-1760.
(b) Hanquet, G.; Colobert, F.; Lanners, S.; Solladie´, G. ARKIVOC 2003, 7,
328-401. (c) Carren˜o, M. C.; Urbano, A. Synlett 2005, 1-25. Recent
work: (d) Colobert, F.; Castanet, A.-S.; Abillard, O. Eur. J. Org. Chem.
2005, 3334-3341. (e) Broutin, P.-E.; Colobert, F. Org. Lett. 2005, 7, 3737-
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A. Org. Lett. 2005, 7, 1419-1422. (g) Broutin, P.-E.; Colobert, F. Eur. J.
Org. Chem. 2005, 1113-1128. (h) Carren˜o, M. C.; Gonza´lez-Lo´pez, M.;
Urbano, A. Chem. Commun. 2005, 611-613.
(12) (a) Carren˜o, M. C.; Des Mazery, R.; Urbano, A.; Colobert, F.;
Solladie, G. Org. Lett. 2005, 7, 2039-2042. (b) Carren˜o, M. C.; Des Mazery,
R.; Urbano, A.; Colobert, F.; Solladie´, G. Org. Lett. 2004, 6, 297-299. (c)
Carren˜o, M. C.; Des Mazery, R.; Urbano, A.; Colobert, F.; Solladie´, G. J.
Org. Chem. 2003, 68, 7779-7787.
(13) Miyabe, H.; Ueda, M.; Fujii, K.; Nishimura, A.; Naito, T. J. Org.
Chem. 2003, 68, 5618-5626.
(14) In this reaction, the monobenzylated derivative of 4 could be isolated
in 20% yield, after flash chromatography.
(15) Solladie´, G.; Hutt, J.; Girardin, A. Synthesis 1987, 173-175.
(16) Solladie´, G.; Demailly, G.; Greck, C. Tetrahedron Lett. 1985, 26,
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