with 91% yield. The highly stereoselective reduction of the
ketone functionality of 7 using DIBALH in the presence of
ZnBr2 afforded a 93:7 mixture (86% de) of the (R)- and (S)-
epimeric carbinols at the newly created stereogenic center.13
After flash chromatography, major stereoisomer 8, bearing
the (R)- absolute configuration at C-7, was obtained with
88% yield in optically pure form (>97% ee).
At this point, we decided to transform the hydroxy sulfinyl
ester 8 into the corresponding hydroxy ketone 10, bearing the
sulfinyl group, and submit it to the reductive cyclization con-
ditions we have previously reported for smaller cyclic ethers.
Thus, the treatment of 8 with N,O-dimethylhydroxylamine
hydrochloride in the presence of trimethylaluminum14 afford-
ed, in 70% yield, the Weinreb amide 9, which, after reaction
with n-hexylmagnesium bromide, gave rise to ketone 10 in
90% yield. Nevertheless, when the hydroxy sulfinyl ketone
10 was treated with Et3SiH in the presence of TMSOTf,
formation of the oxocane cyclic ether 11 was not observed.
follow the same synthetic pathway but using the derivatives
lacking the sulfoxide.
Thus, the treatment of the sulfinyl-substituted hydroxy
ester 8 with Raney nickel in ethanol at room temperature
for 1 h afforded the hydroxy ester 12 bearing the (S)- absolute
configuration at the unique stereogenic center, as demon-
strated after transformation into the corresponding Mosher
esters,13 in enantiomerically pure form (>97% ee). The
Weinreb amide (S)-13 was obtained from ester (S)-12 as
above in 85% yield. After addition of n-hexylmagnesium
bromide, (S)-13 was transformed into the corresponding
ketone (S)-14 in quantitative yield. In this case, when
hydroxy ketone (S)-14 was submitted to the reductive
cyclization conditions (TMSOTf, Et3SiH, CH2Cl2, 0 °C, 2
h), we observed formation of the desired eight-membered
cyclic ether 3 together with a byproduct resulting from the
reduction of the carbonyl of 14 to a methylene group. After
SiO2 flash chromatography, we isolated, as the only cyclic
diastereoisomer, the oxocane (-)-cis-lauthisan (3) {[R]20
D
We reasoned that, in this case, the difficulty of formation
of the eight-membered ring from the acyclic precursor could
be enhanced due to the presence of the bulky sulfinyl group
in the starting hydroxy ketone 10. Therefore, we decided to
) -4.0 (c 0.15, CHCl3)},15 in 40% yield. This reductive
cyclization was completely cis stereoselective, and the
corresponding diastereoisomer, trans-lauthisan, was not
detected in the crude reaction mixture. The relative cis
stereochemistry of derivative 3 was determined after a
NOESY experiment, which demonstrated the close spatial
proximity between the two protons H2 and H8 situated on
the carbons adjacent to the oxygen atom (Scheme 1).
The asymmetric synthesis of (+)-cis-lauthisan (3), shown
in Scheme 2, started with the common intermediate keto
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(8) (+)-cis-Lauthisan: (a) Rhee, H. J.; Beom, H. Y.; Kim, H.-D.
Tetrahedron Lett. 2004, 45, 8019-8022. (b) Kim, H.; Ziani-Cherif, Ch.;
Oh, J.; Cha, J. K.; J. Org. Chem. 1995, 60, 792-793. (c) Paquette, L. A.;
Sweeney, T. J. Tetrahedron 1990, 46, 4487-4502. (d) Tsushima, K.; Murai,
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Chem. 1990, 55, 1703-1704. (f) Kotsuki, H.; Ushio, Y.; Kadota, I.; Ochi,
M. J. Org. Chem. 1989, 54, 5153-5161. (g) Carling, R. W.; Holmes, A.
B. J. Chem. Soc., Chem. Commun. 1986, 565-567. (-)-cis-Lauthisan: (h)
Suh, Y.-G.; Koo, B.-A.; Kim, E.-N.; Choi, N.-S. Tetrahedron Lett. 1995,
36, 2089-2092.
Scheme 2. Asymmetric Synthesis of (+)-cis-Lauthisan (3)
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(13) Both the diastereoisomeric excess and the absolute configuration
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sulfinyl ester 7 and followed a synthetic pathway similar to
(15) Reported values for the optical rotation of (+)-cis-lauthisan (see
ref 8) ranged from 5.0 to 13.9, and its enantiomeric excess has never been
determined. We have tried different methods to check the optical purity of
3 (chiral HPLC, chiral lanthanide shift reagents), but we never observed
separation between diastereomers using racemic cis-lauthisan.
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