First enantioselective total synthesis of (-)-Centrolobine.

Article abstract of DOI:10.1021/ol025778z

[structure: see text] The first enantioselective total synthesis of (-)-Centrolobine is described. The key reaction is the synthesis of the cis-disubstituted tetrahydropyran framework by intramolecular cyclization of the enantiopure hydroxyketone 3 with E

Full text of DOI:10.1021/ol025778z

ORGANIC
LETTERS
2002
Vol. 4, No. 10
1723-1725
First Enantioselective Total Synthesis of
(−)-Centrolobine
,†
,†
Franc¸oise Colobert,* Renaud Des Mazery,† Guy Solladie´,* and
,‡
M. Carmen Carren˜o*
Laboratoire de Ste´re´ochimie associe´ au CNRS, UniVersite´ Louis Pasteur, E.C.P.M.,
25 rue Becquerel 67087 Strasbourg Cedex 2, France, and Departamento de Qu´ımica
Orga´nica, UniVersidad Auto´noma, Cantoblanco, E-28049 Madrid, Spain
fcolober@chimie.u-strasbg.fr
Received February 26, 2002
ABSTRACT
The first enantioselective total synthesis of (−)-Centrolobine is described. The key reaction is the synthesis of the cis-disubstituted tetrahydropyran
framework by intramolecular cyclization of the enantiopure hydroxyketone 3 with Et3SiH and TMSOTf. The stereoselective reduction of the
â-ketosulfoxide 4 is the source of chirality. Revision of the absolute configuration of (−)-Centrolobine is proposed.
(-)-Centrolobine, 6[â(p-hydroxyphenyl)ethyl]-2-(p-meth-
oxyphenyl)tetrahydropyran, is a crystalline substance isolated
from the heartwood of Centrolobium robustum1 and from
the stem of Brosinum potabile2 in the amazon forest.
Although the basic structure was elucidated in 1964 by total
synthesis of the racemic methyl ether,1a,b its absolute con-
figuration has not been unequivocally established.
â-Ketosulfoxide (+)-(R)-5 was prepared by condensation
of glutaric anhydride and the carbanion of (+)-(R)-methyl
p-tolyl sulfoxide (Scheme 2).3 Esterification in the presence
of dimethyl sulfate and potassium carbonate gave the ester
4 in 82% yield for the two steps. Although this sequence
had already been reported,4 we have improved the overall
yield by working at -78 °C and modifying the esterifi-
We report in this paper the first enantioselective synthesis
of (-)-Centrolobine and propose a revision of its absolute
configuration.
Scheme 1
As shown in the retrosynthetic Scheme 1, our approach is
based on the synthesis of aldehyde 2, which could proceed
from the intramolecular cyclization of the diastereomerically
pure hydroxyketone 3, readily available by stereoselective
reduction of enantiopure â-keto sulfoxide 4.
† Universite´ Louis Pasteur.
‡ Universidad Auto´noma, Cantoblanco.
(1) (a) De Albuquerque, I. L.; Galeffi, C.; Casinovi, C. G.; Marini-Bettolo,
G.B. Gazz. Chim. Ital. 1964, 287. (b) Galeffi, C.; Casinovi, C. G.; Marini-
Betto`lo, G. B. Gazz. Chim. Ital. 1965, 95. (c) Aragao Craveiro, A.; da Costa
Prado, A.; Gottlieb, O. R.; Welerson de Albuquerque, P. C. Phytochemistry
1970, 9, 1869.
(2) Alcantara, A. F. de C.; Souza, M. R.; Pilo´-Veloso, D. Fitoterapia
2000, 71, 613.
10.1021/ol025778z CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/17/2002

∼40 Hz (38 Hz in 6) and around 80 Hz in the [5(S),S(R)]
epimers.7 This correlation will be determinant in the final
comparison with natural (-)-Centrolobine.
Scheme 2
Without protection of the hydroxyl group, the methyl ester
6 was transformed into the N-methyl-N-methoxyamide
(Weinreb amide)8 7 in 93% yield. The hydroxyketone 3 was
then obtained in 71% yield by addition of p-methoxy-
phenylmagnesium bromide reagent to the Weinreb amide 7.
With the hydroxyketone 3 in hand, we tried the cyclization
under catalytic acid conditions (p-toluenesulfonic acid9 or
camphorsulfonic acid10) and obtained 50% of the starting
hydroxyketone 3 and 50% of the dihydropyran 8 (Scheme
3). In these acidic conditions, it was impossible to isolate
Scheme 3
the intermediate hemiketal 9, which was dehydrated quickly
to the very stable and highly conjugate dihydropyran 8. It
was not possible to improve the yield.
Following the work of Olah11 and Nicolaou12 who
described the trimethylsilyl triflate catalyzed preparation of
unsymmetrical ethers by reductive condensation of carbonyl
compounds with alkoxysilanes, we treated the hydroxyketone
3 with an excess of Et3SiH and TMSOTf in CH2Cl2 at 0 °C.
After 15 min, we obtained in good yield (81%) the
tetrahydropyran 10 with complete syn stereoselectivity
(Scheme 4). The syn stereochemistry of 10 was assigned by
cation procedure. According to our previous results,5 the
reduction of the â-ketosulfoxide 4 with DIBAL/ZnBr2
yielded [5(R),S(R)]-â-hydroxysulfoxide 6 in 80% yield and
98% de. The (R) configuration of the hydroxylic carbon was
expected from the reaction mechanism already proposed5d
and also from our 1H NMR characterization of the product.
From the numerous examples of reduction of â-ketosulfox-
ides already reported,5b,c,f,6 we noticed that the nonequiva-
lence of the methylene hydrogens R to the sulfoxide group
is quite different in the two diastereomers: in the [5(R),S(R)]
configuration, the ∆ν value between these two hydrogens is
Scheme 4
(3) Solladie´, G.; Hutt, J.; Girardin, A. Synthesis 1987, 173.
(4) Solladie´, G.; Maestro, M. C.; Rubio, A.; Pedregal, C.; Carren˜o M.
C.; Garcia-Ruano, J. L. J. Org. Chem. 1991, 56, 2317.
(5) (a) Solladie´, G.; Demailly, G.; Greck, C. Tetrahedron Lett. 1985,
26, 435. (b) Solladie´, G.; Demailly, Greck, C. J. Org. Chem. 1985, 50,
1552. (c) Solladie´, G.; Frechou, C.; Demailly, G.; Greck, C. J. Org. Chem.
1986, 51, 1912. (d) Solladie´-Cavallo, A.; Suffert, J.; Adib, A.; Solladie´, G.
Tetrahedron Lett. 1990, 31, 6649. (e) Solladie´, G.; Rubio, A.; Carren˜o M.
C.; Garcia-Ruano, J. L. Tetrahedron: Asymmetry. 1990, 1, 187. (f) Carren˜o,
M. C.; Garcia Ruano, J. L.; Martin, A.; Pedregal, C.; Rodriguez, J. H.;
Rubio, A.; Sanchez, J.; Solladie´, G. J. Org. Chem. 1990, 55, 2120
(6) (a) Solladie´, G.; Huser, N . Recl. TraV. Chim. Pays-Bas 1995, 114,
153. (b) Solladie´, G.; Carren˜o, M. C. In Organosulfur Chemistry: Synthetic
Aspects; Page, P. C. B., Ed.; Academic Press: New York, 1995; p 1. (c)
Carren˜o, M. C. Chem. ReV. 1995, 95, 1717.
1H NMR spectroscopy on the basis of NOESY experiments.
The configuration at the new stereogenic center must be
(7) Solladie´, G.; Huser, N.; Garc´ıa Ruano, J. L.; Adrio, J.; Carren˜o, M.
C.; Tito, A. Tetrahedron Lett. 1994, 35, 5297.
(8) Boukouvalas, J.; Fortier, G.; Radu, I. I. J. Org. Chem. 1998, 63, 916.
1724
Org. Lett., Vol. 4, No. 10, 2002

controlled by greater stability giving the syn diequatorial
compound. Taking into account the absolute configuration
of the precursor 3, we assigned the [2(S),6(R),S(R)] config-
uration to the resulting sulfinyl tetrahydropyran 10. The final
comparison with the [R]D of natural Centrolobine will indeed
confirm this result.
Scheme 5
To transform the sulfoxide 10 into the aldehyde 2 under
very mild conditions, we used the classical TFAA-2,4,6-
collidine Pummerer conditions.13 Subsequent treatment of
the Pummerer product with saturated aqueous sodium
hydrogen carbonate afforded the aldehyde 2 in 82% yield
(Scheme 5).
Compound 2 was then submitted to a Wittig reaction en
route to (-)-Centrolobine. The necessary 4-benzyloxy-
benzyltriphenylphosphonium salt 13 was prepared from the
commercially available 4-benzyloxybenzyl alcohol 11 in 95%
overall yield.14 The Wittig reaction between the salt 13 (2
equiv) and the aldehyde 2 was carried out in the presence
of 2 equiv of BuLi to give the olefin 14 in excellent yield
(96%).15 Simultaneous reduction of the double bond and
deprotection of the benzyl ether by catalytic hydrogenation
afforded (-)-Centrolobine 1 in 93% yield.
1H and 13C NMR spectra, IR spectroscopic data, melting
point (95 °C), and optical rotation ([R]D -93, (c 1, CHCl3))
of 1 were identical to those described for the natural
product.1,2 De Albuberque and co-workers1c proposed a
[2(R),6(S)] absolute configuration for (-)-Centrolobine 1 on
the basis of Brewster’s empirical rules16 on the correlation
between molecular rotation and absolute configuration. We
would like to revise the absolute configuration of (-)-
Centrolobine 1 to [2(S),6(R)] on the basis of the absolute
configuration of the â-hydroxysulfoxide [5(R),S(R)]-6, in turn
established considering the well-known behavior of â-keto-
sulfoxide [S(R)]-4 in the reductions with DIBAL/ZnX2.
In conclusion, we have reported the first efficient (nine
steps and 26% overall yield from glutaric anhydride)
asymmetric synthesis of (-)-Centrolobine 1, which allowed
the revision of its absolute configuration. Further application
of this method to the asymmetric synthesis of differently
substituted tetrahydropyran natural derivatives is in progress.
(9) (a) Pothier, N.; Goldstein, S.; Deslongchamps, P. HelV. Chim. Acta
1992, 604. (b) Chen, J.; Fletcher, M. T.; Kitching, W. Tetrahedron:
Asymmetry 1995, 6, 967. (c) White, J. D.; Bolton, G. L.; Dantanarayana,
A. P.; Fox, C. M. J.; Hiner, R. N.; Jackson, R. W.; Sakuma, K.; Warrier,
U. S. J. Am. Chem. Soc. 1995, 117, 1908.
(10) Evans, D. A.; Carter, P. H.; Carreira, E. M.; Prunet, J. A.; Charrette,
A. B.; Lautens, M. Angew. Chem., Int. Ed. 1998, 37, 2354.
(11) Sassaman, M. B.; Kotian, K. D.; Prakash, G. K. S.; Olah, G. A. J.
Org. Chem. 1987, 52, 4314
(12) Nicolaou, K. C.; Hwang, C.-K.; Nugiel, D. A. J. Am. Chem. Soc.
1989, 111, 4136.
(13) Sugihara, H.; Tanikaya, R.; Kaji, A. Synthesis 1978, 881.
(14) Whalley, J. L.; Oldfield, M. F.; Botting, N. P. Tetrahedron 2000,
56, 455
Acknowledgment. We thank CNRS (PICS 537) and
Comunidad Auto´noma de Madrid for financial support. R.
Des Mazery thanks the Ministe`re Franc¸ais de l’Enseignement
et de la Recherche for a fellowship.
(15) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 863.
(16) Brewster, J. H. J. Am. Chem. Soc. 1959, 81, 5481.
OL025778Z
Org. Lett., Vol. 4, No. 10, 2002
1725