A catalytic enantioselective total synthesis of (-)-Wodeshiol

Article abstract of DOI:10.1021/ol991151d

(formula presented) (-)-Wodeshiol of >99% ee has been synthesized from the α,β-enone shown using a number of noteworthy steps including a novel C-C coupling reaction.

Full text of DOI:10.1021/ol991151d

ORGANIC
LETTERS
1999
Vol. 1, No. 11
1871-1872
A Catalytic Enantioselective Total
Synthesis of (−)-Wodeshiol
Xiaojun Han and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
corey@chemistry.harVard.edu
Received October 15, 1999
ABSTRACT
(−)-Wodeshiol of >99% ee has been synthesized from the r,â-enone shown using a number of noteworthy steps including a novel C−C
coupling reaction.
The lignan class of natural products consists of a large
structurally diverse group of molecules which are all bio-
synthesized in chiral form from the achiral precursor
coniferyl alcohol, (E)-3′-methoxy-4′-hydroxycinnamyl alco-
hol, by remarkable sequences of oxidation dimerization and
cyclization events. Most of the reported chemical syntheses
of lignans either lead to racemic compounds or utilize chiral
starting materials, e.g., sugars.1 Described herein is a short,
stereocontrolled and enantioselective synthesis of (-)-
wodeshiol (1),2 (also known as kigeliol2c) a member of the
2,6-diaryl-3,7-dioxabicyclo[3.3.0]octane subclass of lignans,
using a chiral oxazaborolidine for catalytic control of absolute
configuration. This synthesis also demonstrates the utility
of a novel C-C bond-forming homocoupling reaction
employing bimetallic catalysis.
The starting point in the synthesis of 1 was 3,4-methyl-
enedioxybenzaldehyde (piperonal) which was converted to
vinyl ketone 2 by sequential reaction with vinyllithium (THF,
-78 °C, 30 min, 97%) and activated MnO2 (CH2Cl2, 0 °C,
30 min, 75%). Ketone 2 was transformed in one flask into
the R-bromo derivative 3 by R,â-addition of Br2 followed
by Et3N-promoted elimination of HBr under the conditions
indicated in Scheme 1. Enantioselective reduction of 3 by
catecholborane with the (R)-proline derived B-methyl CBS
catalyst3 provided the allylic bromo alcohol 44 (88% ee, 84%
yield) which was subjected to Br-Li exchange and stannyl-
ation to give the corresponding tributyltin compound 5
(84%).
The next step in the synthesis of 1 utilized a newly
developed coupling reaction of 1-substituted vinyltri-n-
butylstannanes to form 2,3-disubstituted 1,3-butadienes.5-7
When 5 was heated with 10 mol % of Pd(PPh3)4, 5 equiv of
CuCl, and 2 equiv of CuCl2 in DMSO at 60 °C for 2 h, the
desired coupled 1,3-diene 6 was obtained in 99.2% ee and
82% yield after silica gel chromatography.8 Hydroxyl-assisted
(3) For a recent review on this catalytic enantioselective method, see:
Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. Engl. 1998, 37, 1986.
(4) The (R)-enantiomer 4 can be predicted to predominate in this product
on the basis of extensive earlier results and the mechanistic model.3
(5) Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121,
7600.
(6) For a related Cu(I)-promoted dimerization of â-Me3Sn-substituted
R,â-unsaturated carbonyl compounds, see: (a) Piers, E.; McEachern, E. J.;
Romero, M. A. Tetrahedron Lett. 1996, 37, 1173. (b) Piers, E.; McEachern,
E. J.; Romero, M. A.; Gladstone, P. L. Can. J. Chem. 1997, 75, 694. (c)
Piers, E.; Gladstone, P. L.; Yee, J. G. K.; McEachern, E. J. Tetrahedron
1998, 54, 10609.
(1) For recent reviews see: (a) Ward, R. S. Nat. Prod. Rep. 1999, 16,
75. (b) Ward, R. S. Tetrahedron 1990, 46, 5029.
(2) (a) Anjaneyulu, A. S. R.; Ramaiah, P. A.; Row, L. R.; Venkateswarlu,
R.; Pelter, A.; Ward, R. S. Tetrahedron 1981, 37, 3641. (b) Pelter, A.; Ward,
R. S.; Venkateswarlu, R.; Kamakshi, C. Tetrahedron 1992, 48, 7209. (c)
Inoue, K.; Inouye, H.; Chen, C.-C. Phytochemistry 1981, 20, 2271.
(7) Pd(II)-promoted homocoupling reactions of vinylstannanes have also
been reported; see: (a) Alcaraz, L.; Taylor, R. J. K. Synlett 1997, 791. (b)
Kang, S.-K.; Namkoong, E.-Y.; Yamaguchi, T. Synth. Commun. 1997, 27,
641. (c) Borzilleri, R. M.; Weinreb, S. M.; Parvez, M. J. Am. Chem. Soc.
1995, 117, 10905.
(8) A minor amount (∼10%) of the meso isomer of 6 was also present.
10.1021/ol991151d CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/02/1999

Scheme 1
bis-epoxidation9,10 of 6 gave after silica gel chromatography
and highly functionalized lignan. It also supports the previ-
ously assumed2 absolute configuration (as shown in structure
1) since the highly enantioselective CBS reduction of 3 would
be expected on the basis of much prior knowledge3 to
produce the absolute configuration shown in 4. This suc-
cessful first synthesis of 1 illustrates the value of the
bimetallic homocoupling reaction which has recently been
developed.5 Finally, it is coincidental but of interest that the
present synthesis and the biosynthetic pathway of wodeshiol
involve as the sole carbon source a starting material having
the carbon skeleton Ar-C-C-C.
the desired diol 7 (along with a minor diastereomer; 14:1
diastereoselection) using t-BuOOH as oxidant and VO(acac)2
as catalyst at 0 °C. Mild acid treatment of 7 (2.2 equiv of
pyridinium tosylate in benzene at 80 °C) produced (-)-
wodeshiol in 61% yield: mp 152-153 °C (lit.2 mp 153-
154 °C); [R]23 -11.7 (c 0.7, CHCl3) (lit.2 [R]D ) -12 in
D
CHCl3); HRMS (FAB) [M + Na]+, m/z 409.0899, calcd
409.0879. The 1H and 13C NMR data obtained for synthetic
1 agreed well with those reported2 for natural wodeshiol.
Finally, a single-crystal X-ray diffraction analysis of synthetic
1 unambiguously confirmed the structure as shown in Figure
1.11
Acknowledgment. This research was assisted financially
by research grants from the National Institute of Health and
the National Science Foundation. We thank Mr. Eduardo J.
Martinez and Dr. Richard Staples for the X-ray crystal-
lographic analysis of 1.
Supporting Information Available: Full experimental
procedures for the synthesis of 1. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL991151D
(9) Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973, 95,
6136.
(10) Bailey, M.; Marko´, I. E.; Ollis, W. D. Tetrahedron Lett. 1991, 32,
2687.
Figure 1. ORTEP structure of wodeshiol as determined by X-ray
diffraction.
(11) (a) X-ray data (0.71073 Å, 213(2) K) for synthetic wodeshiol:
C20H18O8, orthorhombic; P212121; a ) 9.2575(3) Å, b ) 17.7010(5) Å, c
) 20.765(2) Å, R ) â ) γ ) 90°; Z ) 8; R1[I > 2σ(I)] ) 0.0540, wR2
) 0.0703; GOF on F2 ) 0.916. (b) Detailed X-ray diffraction data are
available from the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK.
The synthesis of wodeshiol reported herein fully confirms
the previous assignment of structure 12 to this interesting
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Org. Lett., Vol. 1, No. 11, 1999