ORGANIC
LETTERS
2005
Vol. 7, No. 1
75-77
Highly Stereoselective and Efficient
Total Synthesis of ( )-Laurencin
+
Seungyoup Baek, Hyunil Jo, Hansoo Kim, Hyoungsu Kim, Sanghee Kim, and
Deukjoon Kim*
College of Pharmacy, Seoul National UniVersity, San 56-1, Shillim-Dong, Kwanak-Ku,
Seoul 151-742, Korea
Received October 14, 2004
ABSTRACT
A highly stereoselective and efficient asymmetric total synthesis of (
5 in 15 steps. The route features an efficient internal alkylation to form oxocene 3 from 4 and a novel use of acetonitrile anion as a two-carbon
acetaldehyde equivalent for direct synthesis of ketone 2 from -alkoxy amide 3.
+)-laurencin (1) has been accomplished from the known oxazolidinone
r
(+)-Laurencin (1), a halogenated C15 acetogenin, was first
isolated from the red alga Laurencia glandulifera by Irie and
co-workers in 1965.1 Its structure was elucidated by a
combination of chemical degradation, spectroscopic methods,
and X-ray crystallography.1-3 The absolute stereochemistry
of this oxacyclic marine natural product was assigned by
the application of Prelog atrolactic acid method to its
octahydrodeacetyllaurencin derivative4 and confirmed later
by the first asymmetric total synthesis by Murai and
co-workers.5b The interesting molecular structure of this
oxocene natural product has served as an attractive target
for synthetic organic chemists to test new synthetic strategies
for stereoselective construction of eight-membered ring
ethers.5,6 Since the report of the first total synthesis of (()-
laurencin by the Masamune group in 1977,5a four asymmetric
total syntheses and three formal syntheses of the natural
product have been reported to date.5 Described here is a new,
efficient, and highly stereoselective total synthesis of (+)-
laurencin (1) based upon our olefin geometry-dependent
internal alkylation methodology6a for the construction of
eight-membered ether rings and a novel strategy for the
manipulation of the side chain appendage at C(7) (laurencin
numbering).
(1) Irie, T.; Suzuki, M.; Masamune, T. Tetrahedron Lett. 1965, 1091-
1099.
(2) Irie, T.; Suzuki, M.; Masamune, T. Tetrahedron 1968, 24, 4193-
4205.
(3) Cameron, A. F.; Cheung, K. K.; Ferguson, G.; Robertson, J. M. J.
Chem. Soc., Chem. Commun. 1965, 638.
As shown in Scheme 1, we envisaged that (+)-laurencin
(1) might be secured via a new synthetic sequence from
cyano ketone 2, which in turn could be obtained by addition
(4) Cameron, A. F.; Cheung, K. K.; Ferguson, G.; Robertson, J. M. J.
Chem. Soc. B 1969, 559-564.
(6) (a) Kim, H.; Choi, W. J.; Jung, J.; Kim, S.; Kim, D. J. Am. Chem.
Soc. 2003, 125, 10238-10240 and references cited therein. For recent
examples of C-C bond-forming approaches to oxocene construction, see:
(b) Suh, Y.-G.; Koo, B.-A.; Kim, E.-N.; Choi, N.-S. Tetrahedron Lett. 1995,
36, 2089-2092. (c) Alvarez, E.; Delgado, M.; Diaz, M. T.; Hanxing, L.;
Perez, R.; Martin, J. D.; Tetrahedron Lett. 1996, 37, 2865-2868. (d)
Linderman, R. J.; Siedlecki, J.; O’Neill, S. A.; Sun, H. J. Am. Chem. Soc.
1997, 119, 6919-6920. (e) Edwards, S. D.; Lewis, T.; Taylor, R. J. K.
Tetrahedron Lett. 1999, 40, 4267-4270. (f) Coster, M. J.; De Voss, J. J.
Org. Lett. 2002, 4, 3047-3050. (g) Cossy, J.; Taillier, C.; Bellosta, V.
Tetrahedron Lett. 2002, 43, 7263-7266. (h) Kadota, I.; Uyehara, H.;
Yamamoto, Y. Tetrahedron 2004, 60, 7361-7365. (i) Clark, J. S.; Freeman,
R. P.; Cacho, M.; Thomas, A. W.; Swallow, S.; Wilson, C. Tetrahedron
Lett. 2004, 45, 8639-8642.
(5) For a racemic total synthesis, see: (a) Murai, A.; Murase, H.; Matsue,
H.; Masamune, T. Tetrahedron Lett. 1977, 2507-2510. For asymmetric
total syntheses, see: (b) Tsushima, K.; Murai, A. Tetrahedron Lett. 1992,
33, 4345-4348. (c) Bratz, M.; Bullock, W. H.; Overman, L. E.; Takemoto,
T. J. Am. Chem. Soc. 1995, 117, 5958-5966. (d) Burton, J. W.; Clark, J.
S.; Derrer, S.; Stork, T. C.; Bendall, J. G.; Holmes, A. B. J. Am. Chem.
Soc. 1997, 119, 7483-7498. (e) Crimmins, M. T.; Emmitte, K. A. Org.
Lett. 1999, 1, 2029-2032. For asymmetric formal syntheses, see: (f) Mujica,
M. T.; Afonso, M. M.; Galindo, A.; Palenzuela, J. A. Synlett 1996, 983-
984. (g) Kru¨ger, J.; Hoffmann, R. W. J. Am. Chem. Soc. 1997, 119, 7499-
7504. (h) Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc. 1999, 121,
5653-5660.
10.1021/ol047877d CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/10/2004