Our initial investigations, using a racemic propargylic
alcohol (()-4a17 and phenol 5,18 established the enyne RCM
reaction as a highly chemoselective means to create the
vinylcyclohexene 7 (Scheme 2). However, it transpired that
Scheme 1. Proposed Synthetic Route to (-)-Galanthamine
Scheme 2. Synthesis of a Racemic ABD Ring System
heterocyclic C and D rings (Scheme 1). Formation of the D
ring, and corresponding quaternary stereogenic center, would
be achieved by application of the Heck strategy introduced
by Fels and Parsons.11,12 The proposal centered on the use
of an enyne ring-closing metathesis (RCM) reaction to create
the vinyl-substituted cyclohexene ring within a structure
containing all of the carbon atoms required in the final
target.14 Joining the two fragments would be effected through
Mitsunobu coupling of a phenol 3 with an enantiomerically
enriched propargylic alcohol 4a,15 readily available through
asymmetric ketone reduction. Ultimately, we imagined that
such an approach could be adapted to incorporate the
galanthamine allylic hydroxyl group within the fragment
4b.16
(9) Lycoramine (racemic): (a) Hazama, N.; Irie, H.; Mizutani, T.; Shingu,
T.; Takada, M.; Uyeo, S.; Yoshitake, A. J. Chem. Soc. (C) 1968, 2947-
2953. (b) Misaka, Y.; Mizutani, T.; Sekido, M.; Uyeo, S. J. Chem. Soc.
(C) 1968, 2954-2959. (c) Schultz, A. G.; Yee, Y. K.; Berger, M. H. J.
Am. Chem. Soc. 1977, 99, 8065-8067. (d) Martin, S. F.; Garrison, P. J. J.
Org. Chem. 1981, 46, 3567-3568. (e) Martin, S. F.; Garrison, P. J. J. Org.
Chem. 1982, 47, 1513-1518. (f) Sa´nchez, I. H.; Soria, J. J.; Lo´pez, F. J.;
Larraza, M. I.; Flores, H. J. J. Org. Chem. 1984, 49, 157-163. (g) Ackland,
D. J.; Pinhey, J. T. J. Chem. Soc., Perkin Trans. I 1987, 2695-2700. (h)
Parker, K. A.; Kim, H. J. J. Org. Chem. 1992, 57, 752-755. (i) Ishizaki,
M.; Ozaki, K.; Kanematsu, A.; Isoda, T.; Hoshino, O. J. Org. Chem. 1993,
58, 3877-3885. (j) Essamkaoui, M.; Benharref, A.; Moskowitz, H.;
Mayrargue, J.; Thal, C. Heterocycl. Commun. 1996, 2, 319-323. (k) Gras,
E.; Guillou, C.; Thal, C. Tetrahedron Lett. 1999, 40, 9243-9244. (l) Fan,
C. A.; Tu, Y. Q.; Song, Z. L.; Zhang, E.; Shi, L.; Wang, M.; Wang, B. M.;
Zhang, S. Y. Org. Lett. 2004, 6, 4691-4694. (m) Liang, P. H.; Liu, J. P.;
Hsin, L. W.; Cheng, C. Y. Tetrahedron 2004, 60, 11655-11660.
(10) Racemic syntheses (narwedine): (a) Holton, R. A.; Sibi, M. P.;
Murphy, W. S. J. Am. Chem. Soc. 1988, 110, 314-316. (Galanthamine):
(b) Guillou, C.; Beunard, J. L.; Gras, E.; Thal, C. Angew. Chem., Int. Ed.
2001, 40, 4745-4746. (c) Hu, X.-D.; Tu, Y.-Q.; Zhang, E.; Gao, S.; Wang,
S.; Wang, A.; Fan, C.-A.; Wang, M. Org. Lett. 2006, 8, 1823-1825.
(11) Synthetic approaches/formal syntheses: (a) Parsons, P. J.; Charles,
M. D.; Harvey, D. M.; Sumoreeah, L. R.; Shell, A.; Spoors, G.; Gill, A.
L.; Smith, S. Tetrahedron Lett. 2001, 42, 2209-2211. (b) Pilger, C.;
Westermann, B.; Florke, U.; Fels, G. Synlett 2000, 1163-1165.
(12) Trost, B. M.; Tang, W. P.; Toste, F. D. J. Am. Chem. Soc. 2005,
127, 14785-14803.
Pd-catalyzed arylation of the diene 7 did not provide the
desired product and instead favored C-C bond formation
at the less sterically encumbered end of the 1,3-diene system,
affording diene 8.19 Presumably, the intermediacy of a π-allyl
palladium species also favors the observed regioselectivity.
The required C-C bond formation was realized by selective
hydration of the less-substituted olefin prior to the Heck
reaction, securing the tricyclic ABD system 11 in high overall
yield.11,12,20,21
Although the ultimately successful route to the tricycle
11 came at the expense of additional functional group
interconversions and protecting group manipulations, it was
easy to envisage its adaptation to provide a streamlined
asymmetric synthesis of galanthamine. Accordingly, the
(16) For the synthesis of protected 4b, see: Smith, A. B.; Ott, G. R. J.
Am. Chem. Soc. 1998, 120, 3935-3948.
(13) For some examples of galanthamine analogues, see: (a) Bores, G.
M.; Kosley, R. W. J. Drugs Future 1996, 21, 621-635. (b) Poschalko, A.;
Welzig, S.; Treu, M.; Nerdinger, S.; Mereiter, K.; Jordis, U. Tetrahedron
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Kirchhausen, T.; Shair, M. D. J. Am. Chem. Soc. 2001, 123, 6740-6741.
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Heterocycles 2001, 55, 1727-1735.
(17) Padwa, A.; Lipka, H.; Watterson, S. H.; Murphree, S. S. J. Org.
Chem. 2003, 68, 6238-6250.
(18) Markovich, K. M.; Tantishaiyakul, V.; Hamada, A.; Miller, D. D.;
Romstedt, K. J.; Shams, G.; Shin, Y.; Fraundorfer, P. F.; Doyle, K.; Feller,
D. R. J. Med. Chem. 1992, 35, 466-479.
(19) For a discussion of intermolecular palladium-catalyzed diene
arylation, see: Heck, R. F. Palladium Reagents in Organic Syntheses;
Academic Press: New York, 1985; pp 223-227.
(14) Enyne metathesis: (a) Diver, S. T.; Giessert, A. J. Chem. ReV. 2004,
104, 1317-1382. (b) Poulsen, C. S.; Madsen, R. Synthesis 2003, 1-18.
(15) Kiankarimi, M.; Lowe, R.; McCarthy, J. R.; Whitten, J. P.
Tetrahedron Lett. 1999, 40, 4497-4500.
(20) (a) Gibson, S. E.; Middleton, R. J. Contemp. Org. Synth. 1996, 3,
447-471. (b) Overman, L. E. Pure Appl. Chem. 1994, 66, 1423-1430.
(21) For a related application of the Heck reaction, see: Uchida, K.;
Yokoshima, S.; Kan, T.; Fukuyama, T. Org. Lett. 2006, 8, 5311-5313.
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