by Kozmin,8j McDonald,19 and Fu¨rstner,8b the methyl group
positioning on an epoxide influences the ring-opening
regiochemistry by distorting the epoxonium intermediate to
localize charge at the most substituted center.20,21
Unexpectedly, 5-Me diester 11 did not yield the expected
[5.4.0] bicyclic ether, but instead provided the 9-endo product
12 as a single stereoisomer. Traces of this cyclization mode
were detected for compound 9 (∼10%), but its production
could not be improved. Fused medium-ring ethers are, of
course, ubiquitous in marine-derived natural products. Chang-
ing the epoxide stereochemistry in 13 led to stereoisomeric
14a,b (c.f. 2a,b), indicative of a cyclization that was
stereospecific and invertive at the epoxide.
proceeded by epoxide opening and allene hydroalkoxyla-
tion.22 This alternative pathway was investigated by precy-
clizing 1 with 1% TfOH to 15, and then carrying out a hydro-
alkoxylation to 2a,b (eq 2). Unlike the direct cyclization of
1, 2a,b was obtained in a 1:1 ratio, suggesting an allene first
mechanism for 1.
To investigate the feasibility of a tricyclization cascade,
the isomerically pure diepoxide 16 was prepared using the
asymmetric epoxidation protocols of Sharpless23 and Shi24
(eq 3). Upon exposure to the standard reaction conditions,
isomerization ensued to form tricyclic ether 17. Notably, 17
was formed in analogy to product 4 (Table 1) without
significant loss in yield or diastereoselectivity, lending further
support to the feasibility of the current methodology for
multicyclization events in complex molecule synthesis.
One mechanistic quandary revolved around whether the
reaction initiated at the allene as envisioned in Figure 1, or
(9) For a related Hg(II)-catalyzed variant, see: (a) Imagawa, H.; Iyenaga,
T.; Nishizawa, M. Org. Lett. 2005, 7, 451–453. For Pt(II), see: (b) Nelsen,
D. L.; Gagne´, M. R. Organometallics 2009, 28, 950–952.
(10) (a) Dai, L.-Z.; Shi, M. Chem.sEur. J. 2008, 14, 7011–7018. (b)
Dai, L.-Z.; Shi, M. Tetrahedron Lett. 2008, 49, 6437–6439. (c) Lin, G.-Y.;
Li, C.-W.; Hung, S.-H.; Liu, R.-S. Org. Lett. 2008, 21, 5059–5062. (d)
Cordonnier, M. C.; Blanc, A.; Pale, P. Org. Lett. 2008, 10, 1569–1572. (e)
Dai, L.-Z.; Qi, M.-J.; Shi, Y.-L.; Liu, X.-G.; Shi, M. Org. Lett. 2007, 9,
3191–3194.
(11) Previous (unpublished) efforts in our laboratories with “carbophilic”
Lewis acids always resulted in epoxide activation over alkene, which has
also been observed by Yang and He under gold(III)/silver activation
catalysis. See for example: (a) Liu, Y.; Li, X.; Lin, G.; Xiang, Z.; Xiang,
J.; Zhao, M.; Chen, J.; Yang, Z. J. Org. Chem. 2008, 73, 4625–4629. (b)
Shi, Z.; He, C. J. Am. Chem. Soc. 2004, 126, 5964–5965.
(12) For an example of exclusive Au(I)-catalyzed epoxide O-activation,
see: Li, Y.; Tang, P. P; Chen, Y. X; Yu, B. J. Org. Chem. 2008, 73, 4323–
4325.
(13) (a) Tarselli, M. A.; Chianese, A. R.; Lee, S. J.; Gagne´, M. R. Angew.
Chem., Int. Ed. 2007, 46, 6670–6673. (b) Tarselli, M. A.; Gagne´, M. R. J.
Org. Chem. 2008, 73, 2439–2441. (c) Tarselli, M. A.; Liu, A.; Gagne´, M. R.
Tetrahedron 2009, 65, 1785–1789.
In conclusion, a method to generate polyether skeletons
from allene-epoxide cascades has been developed. The
method provides access to several ring structures commonly
encountered in natural products and promises to yield catalyst
control over cyclization regiochemistry. Studies are underway
to utilize other heteroatomic traps and to elucidate the
cyclization mechanism.
(14) Gold-allene activations were early to appear Hashmi, A. S. K.;
Schwarz, L.; Choi, J.-H.; Frost, T. M. Angew. Chem., Int. Ed. 2000, 39,
2285–2288.
(15) Other silver additives (AgSbF6, AgBF4, AgNTf2, AgClO4, AgOTs)
or phosphine ligands (EtPh2P, Cy3P, (4-Cl-Ph)3P, (4-MeO-Ph)3P) led to
lower yields of bicyclic product. Other solvents (PhMe, THF) led to complex
mixtures.
(16) Exposure to AgOTf in the absence of Au(I) did not produce any
discernable allene activation. In preliminary (unpublished) reactivity studies
for related transition metal-catalyzed cyclization of allenyl esters, Yb(III)
and Pd(II) showed negligible levels of desired reactivity.
(17) A pseudo-axial preference has been noted in previous electrophilic
cyclizations, see for example: (a) Johnson, W. S.; Telfer, S. J.; Cheng, S.;
Schubert, U. J. Am. Chem. Soc. 1987, 109, 2517–2518. (b) Koh, J. H.;
Gagne´, M. R. Angew. Chem., Int. Ed. 2004, 43, 3459–3461. (c) Wan, S.;
Gunayadin, H.; Houk, K. N.; Floreancig, P. E. J. Am. Chem. Soc. 2007,
129, 7915–7923.
Acknowledgment. We thank Prof. Michael Crimmins and
Prof. Jeff Johnson (UNC) for helpful discussions. We
acknowledge NIH Institutes of General Medicine (GM-
60578) for financial support. J.L.Z. thanks the National
Research Council for a Postdoctoral Fellowship, and S.J.L.
thanks the ARO for Staff Research Funding.
(18) The role of the A-ring substituents on cyclization dr is not yet
understood.
(19) McDonald, F. E.; Wang, X.; Do, B.; Hardcastle, K. I. Org. Lett.
2000, 2, 2917–2919.
Supporting Information Available: Experimental pro-
cedures, spectra of new compounds, and CIF data for 2a.
This material is available free of charge via the Internet at
(20) (a) Stork, G.; Burgstahler, A. W. J. Am. Chem. Soc. 1955, 77, 5068–
5077. (b) Gamboni, G.; Schniz, H.; Eschenmoser, A. HelV. Chim. Acta 1954,
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(21) Jamison recently showed that water can overturn this propensity,
see ref 6a for details
.
OL901391S
(22) (a) Paton, R. S.; Maseras, F. Org. Lett. 2009, 11, 2237–2240. (b)
Zhang, Z.; Widenhoefer, R. A. Org. Lett. 2008, 10, 2079–2081. (c) Nishina,
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