address the synthesis of the products in an enantioselective
fashion. Although several interesting asymmetric approaches
to seven-membered carbocycles have been reported,9 in the
case of eight- or nine-membered rings the progress has been
much slower. Enantioselective access to rings of this size
has primarily relied on the elaboration of naturally occurring
chiral precursors, mainly carbohydrates,10 albeit a few
examples based on diastereoselective transformation of
nonnatural, optically active precursors have also been
reported.11,12
Scheme 1
We have recently developed an atom-economical protocol
for assembling oxygen-bridged medium-sized carbocycles
from readily accessible precursors.13 The route involves a
ruthenium-catalyzed alkyne-alkene C-C bond-forming
reaction between 1-trimethylsilyl-1-alkyn-3-ols and allyl
ethers to yield a mixed acetal of type 2, followed by a Lewis
acid-promoted Prins-type cyclization (Scheme 1).
tions and hence for the unmasking of the embedded medium-
sized carbocycle (4).14
Since the approach relies on the use of chiral alkynols as
starting materials, it was reasoned that it might be feasible
to develop an asymmetric alternative if such alcohols could
be reliably prepared in an optically active form. Herein we
show that this can be accomplished using a Ru-catalyzed
asymmetric reduction of readily available ketones and
demonstrate that the resulting alkynols can be rapidly
homologated into a variety of enantiorich carbocyclic systems
containing either eight- or nine-membered rings.
Our first efforts to obtain the chiral propargylic alcohols
1 focused on the use of the catalytic enantioselective
alkynylation of aldehydes recently developed by Carreira and
co-workers.15,16 Unfortunately, addition of the required
aldehydes to a toluene solution of trimethylsilylacetylene and
Et3N, in the presence of catalytic proportions of Zn(OTf)2
and (+)-N-methylephedrine,15a did not produce the desired
alkynols 1. In these experiments, we could only isolate small
proportions of aldol self-condensation products. This out-
come is probably due to the absence of R-branching in the
aldehydes, which favors the self-condensation reaction over
the desired coupling.17 At room temperature, in the presence
of stoichiometric amounts of the reagents,15b we could get
the desired products 1, albeit in a low 20% yield, with the
aldol byproducts again being predominant.18
Remarkably, the presence of the exocyclic double bond
in the resulting oxabridged adducts, a functionality created
in the Ru-catalyzed coupling reaction, allows for reductive
opening of the oxygen bridge under electron-transfer condi-
(6) (a) Randall, M. L.; Lo, P. C.-K.; Bonitatebus, P. J.; Snapper, M. L.
J. Am. Chem. Soc. 1999, 121, 4534-4535. (b) Imai, A. E.; Sato, Y.;
Nishhida, M.; Mori, M. J. Am. Chem. Soc. 1999, 121, 1217-1225. (c)
Kinney, W. A.; Coghlan, M. J.; Paquette, L. A. J. Am. Chem. Soc. 1985,
107, 7352-7360 and references therein.
(7) (a) Salem, B.; Suffert, J. Angew. Chem., Int. Ed. 2004, 43, 2826-
2830. (b) White, B. H.; Snapper, M. L. J. Am. Chem. Soc. 2003, 125,
14901-14904 and references therein. (c) Paquette, L. A.; Nakatani, S.;
Zydowsky, T. M.; Edmondson, S. D.; Sun, L.-Q.; Skerlj, R. J. Am. Chem.
Soc. 1999, 64, 3244-3254.
(8) (a) Wender, P. A.; Ihle, N. C. J. Am. Chem. Soc. 1986, 108, 4678-
4679. (b) Wender, P. A.; Correa, A. G.; Sato, Y.; Sun, R. J. Am. Chem.
Soc. 2000, 122, 7815-7816. (c) Wender, P. A.; Gamber, G. G.; Hubbard,
R. D.; Zhang, L. J. Am. Chem. Soc. 2002, 124, 2876-2877. (d) Evans, P.
A.; Robinson, J. E.; Baum, E. W.; Fazal, A. N. J. Am. Chem. Soc. 2002,
124, 8782-8783. (e) Gilbertson, S. R.; DeBoef, B. J. Am. Chem. Soc. 2002,
124, 8784-8785. (f) Varela, J. A.; Castedo, L.; Saa´, C. Org. Lett. 2003, 5,
2841-2844.
(9) For cycloaddition-based strategies, see: (a) Barluenga, J.; Aznar, F.;
Mart´ın, A.; Vazquez, J. T. J. Am. Chem. Soc. 1995, 117, 9419-9426. (b)
Davies, H. M. L.; Stafford, D.; Houser, J. H.; Doan, B. D. J. Am. Chem.
Soc. 1998, 120, 3326-3331. (c) Wender, P. A.; Husfeld, C. O.; Langkopf,
E.; Love, J. A.; Pleuss, N. Tetrahedron 1998, 54, 7203-7220. (d) Lo´pez,
F.; Castedo, L.; Mascaren˜as, J. L. Chem Eur. J. 2002, 8, 884-899. For
desymmetrization approaches, see: (e) Lautens, M.; Hiebert, S.; Renaud,
J.-L. Org. Lett. 2000, 2, 1971-1973. (f) Hodgson, D. M.; Maxwell, C. R.;
Miles, T. J.; Paruch, E.; Stent, M. A. H.; Matthews, I. R.; Wilson, F. X.;
Witherington, J. Angew. Chem., Int. Ed. 2002, 41, 4313-4316. (g)
Weatherhead, G. S.; Cortez, G. A.; Schrock, R. R.; Hoveyda, A. H. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5805-5809.
(14) For references on the utility of oxabicyclic systems in organic
synthesis, see: (a) Vogel, P. Bull. Soc. Chim. Belg. 1990, 99, 395-439.
(b) Molander, G. A.; Swallow, S. J. Org. Chem. 1994, 59, 7148-7151. (c)
Lampe, T. F. J.; Hoffmann, H. M. R. J. Chem. Soc., Chem. Commun. 1996,
1931-1932. (d) Davies, H. M. L.; Ahmed, G.; Churchill, M. R. J. Am.
Chem. Soc. 1996, 118, 10774-10782 and references therein. (e) Chiu, P.;
Lautens, M. In Topics in Current Chemistry; Metz, P., Ed.; Springer-
Verlag: Berlin, 1997; Vol. 190, pp 1-85.
(15) (a) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123,
9687-9688. (b) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem.
Soc. 2000, 122, 1806-1807. (c) Boyall, D.; Lo´pez, F.; Sasaki, H.; Frantz,
D. E.; Carreira, E. M. Org. Lett. 2000, 2, 4233-4236.
(16) (a) For a recent review on this topic, see: Pu, L. Tetrahedron 2003,
59, 9873-9886. See also: (b) Xu, Z.; Chen, C.; Xu, J.; Miao, M.;
Yan, W.; Wang, R. Org. Lett. 2004, 1193-1195. (c) Li, M.; Zhu, X.-Z.;
Yuan, K.; Cao, B.-X.; Hou, X.-L. Tetrahedron: Asymmetry 2004, 15, 219-
222. (d) Chen, Z.; Xiong, W.; Jiang, B. Chem. Commun. 2002, 2098-
2099. (e) Jiang, B.; Chen, Z.; Xiong, W. Chem. Commun. 2002, 1524-
1525. (f) Lu, G.; Li, X.; Chan, W. L.; Chan, A. S. C. Chem. Commun.
2002, 172-173.
(17) This side reaction has been reported previously (see ref 15b).
(18) R-Unsubstituted, easily enolizable aldehydes continue to be chal-
lenging substrates for enantioselective alkynylations. For instance, see:
Trost, B. M.; Ameriks, M. K. Org. Lett. 2004, 6, 1745-1748.
(10) (a) Wang, W.; Zhang, Y.; Sollogoub, M.; Sinay¨, P. Angew. Chem.,
Int. Ed. 2000, 39, 2466-2467. (b) Van Hooft, P. A. V.; Litjens, R. E. J. N;
van der Marel, G. A.; van Boeckel, C. A. A.; van Boom, J. H. Org. Lett.
2001, 3, 731-733. (c) Sasmal, P. K.; Maier, M. E. J. Org. Chem. 2003,
68, 824-831.
(11) (a) Fillion, E.; Beingessner, R. L. J. Org. Chem. 2003, 68, 9485-
9486. (b) Deiters, A.; Fro¨hlich, R.; Hoppe, D. Angew. Chem., Int. Ed. 2000,
39, 2105-2107. (c) Limanto, J.; Snapper, M. J. Am. Chem. Soc. 2000, 122,
8071-8072. (d) Harmata, M.; Rashatasakhon, P. Org. Lett. 2000, 2, 2913-
2915. (e) Paley, R. S.; Estroff, L. A.; Gauguet, J.-M.; Hunt, D. K.; Newlin,
R. C. Org. Lett. 2000, 2, 365-368.
(12) For asymmetric approaches to oxygen-bridged eight- and nine-
membered carbocycles, see: (a) Go´mez Arraya´s, R.; Liebeskind, L. S. J.
Am. Chem. Soc. 2003, 125, 9026-9027. (b) Yu, C.-M.; Lee, J.-Y.; So, B.;
Hong, J. Angew. Chem., Int. Ed. 2002, 41, 161-163. (c) Barluenga, J.;
Die´guez, A.; Rodr´ıguez, F.; Flo´rez, J.; Fan˜anas, F. J. J. Am. Chem. Soc.
2002, 124, 9056-9057. (d) de Armas, P.; Garc´ıa-Tellado, F.; Marrero-
Tellado, J. J. Eur. J. Org. Chem. 2001, 4423-4427.
(13) Lo´pez, F.; Castedo, L.; Mascaren˜as, J. L. J. Am. Chem. Soc. 2002,
124, 4218-4219.
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