3. There are a few reports of oxy-Cope reactions involving 1-ethynyl-
2-vinylcycloalkanols in the literature. For examples, see ref. 2a.
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155; (f) C. M. Angelov, D. M. Mondeshka and T. N. Tansheva,
J. Chem. Soc., Chem. Commun., 1985, 647; (g) M. Santelli, D. El
Abed and A. Jellal, J. Org. Chem., 1986, 51, 1199; (h) H. J. Reich,
E. K. Eisenhart, W. L. Whipple and M. J. Kelly, J. Am. Chem.
Soc., 1988, 110, 6432; (i) S. Spino, C. Thibault and S. Gingras,
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A. Galindo and J. A. Palenzuala, Tetrahedron Lett., 2000, 41,
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5. D. E. Ward and M. S. Abaee, Org. Lett., 2000, 2, 3937.
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2003, 68, 2317; (b) L. Barriault, P. A. J. Ang and R. M.
A. Lavigne, Org. Lett., 2004, 6, 1317. For a review on tethers in
cycloadditions, see: (c) K. J. Shea, K. S. Zandi and
D. R. Gauthier, Tetrahedron, 1998, 54, 2289 and references there-
in; (d) M. S. Souweha, A. Arab, M. ApSimon and A. G. Fallis,
Org. Lett., 2007, 9, 615; (e) K. C. Nicolaou and S. T. Harrison,
Angew. Chem., Int. Ed., 2006, 45, 3256(f) A. L. Zografos,
A. Yiotakis and D. Georgiadis, Org. Lett., 2005, 7,
4515(g) D. E. Ward and M. S. Souweha, Org. Lett., 2005, 7,
3533; (h) J.-P. Rath, S. Kinast and M. E. Maier, Org. Lett., 2005,
7, 3089; (i) R. Olsson, F. Bertozzi and T. Fredj, Org. Lett., 2000, 2,
1283; (j) R. A. Batey, A. N. Thadani and A. J. Lough, J. Am.
Chem. Soc., 1999, 121, 450.
7. I. Fleming, Frontier Orbitals and Organic Chemical Reactions,
John Wiley & Sons, Chichester, 1976.
8. The propargyl ethers 7, 14 and 17 were easily prepared in four
steps from commercially available cycloalkene oxide and 20 was
obtained in two steps from the corresponding 2-(cyclohexenyl)-
cyclohexanone. See the ESIw for procedures.
9. Several organomagnesium reagents were tried and we found
freshly made solutions of vinylmagnesium bromide in THF gave
the best results.
10. We found that prolonged exposure to high temperatures
(165–220 1C) is detrimental to the reaction.
11. For the formation of magnesium alkoxide using MgBr2ꢁOEt2 and
triethylamine, see: E. Vedejs and O. Daugulis, J. Org. Chem.,
1996, 61, 5702.
12. Prolonged exposure to the reaction conditions (48 h) led to
complete epimerization at C1 (dr 1 : 2.4).
Scheme 3 Transition states for the HDDA.
with methacrolein and MVK afforded tetracycles 21 and 22 in
44 and 40% yield (entries 9–10). Finally, tandem oxy-
Cope–Claisen–ene–HDDA reaction of 20 with dimethyl fu-
marate furnished 23 in 36% yield.14 Notably, this core pos-
sesses six stereogenic carbon centers where four are
contiguous. Other activated dienophiles such as benzoqui-
none, DIAD and maleic anhydride were tried without any
success. In all cases, only vinylallene 8 was recovered along
with some degradation products.15
In summary, we have developed a novel stereoselective
method for the construction of fused carbocyclic frameworks.
The oxy-Cope–Claisen–ene–HDDA reaction sequence has
proven to be a powerful synthetic process to elaborate mole-
cular complexity. The reaction can be performed in one pot in
toluene using a vinylmagnesium bromide. However, it was
found that a two-pot operation employing a MgBr2ꢁOEt2–2,6-
lutidine combination in CH2Cl2 gave better overall yields.
Further studies to extend the scope of this reaction and its
application to the total synthesis of complex diterpenes are
underway and will be reported in due course.
We thank the Natural Science and Engineering Research
Council of Canada (NSERC), Merck Research Laboratories,
Merck Frosst Canada, Boehringer Ingelheim, AstraZeneca,
PREA, Canada Foundation for Innovation, Ontario Innova-
tion Trust and the University of Ottawa for generous funding.
RC and CG thank the NSERC for post-graduate scholarships
(PGS-A and CGS-D).
13. The relative stereochemistry of 13 was unambiguously established
by NOESY correlation on the corresponding triol.
Notes and references
1. (a) L. F. Tietze, G. Brasche and K. Gericke, Domino Reactions in
Organic Synthesis, Wiley-VCH, Weinheim, 2006; (b) T.-L. Ho,
Tandem Organic Reactions, Wiley, New York, 1992; (c) F. Ziegler,
in Comprehensive Organic Synthesis Combining C–C a Bonds, ed.
L. A. Paquette, Permagon Press, Oxford, 1991, vol. 5, ch. 7.3;
(d) L. F. Tietze and U. Beifuss, Angew. Chem., Int. Ed. Engl., 1993,
32, 131. For recent reviews, see: (e) K. C. Nicolaou,
D. J. Edmonds and P. G. Bulger, Angew. Chem., Int. Ed., 2006,
45, 7134; (f) F. Tietze, Chem. Rev., 1996, 96, 115(g) S. E. Denmark
and A. Thorarensen, Chem. Rev., 1996, 96, 137; (h) J. D. Winkler,
Chem. Rev., 1996, 96, 167; (i) I. Ryu, N. Sonoda and D. P. Curran,
Chem. Rev., 1996, 96, 177; (j) P. J. Parsons, C. S. Penkett and
A. J. Shell, Chem. Rev., 1996, 96, 195; (k) K. K. Wang, Chem.
Rev., 1996, 96, 207; (l) A. Padwa and M. D. Weingarten, Chem.
Rev., 1996, 96, 223; (m) M. Malacria, Chem. Rev., 1996, 96, 289;
(n) G. A. Molander and C. R. Harris, Chem. Rev., 1996, 96, 307.
2. (a) S. Arns and L. Barriault, Chem. Commun., 2007, 2211 and
references therein; (b) E. L. O. Sauer and L. Barriault, J. Am.
Chem. Soc., 2004, 126, 8569; (c) E. L. O. Sauer, J. Hooper, T. Woo
and L. Barriault, J. Am. Chem. Soc., 2007, 129, 2112.
14. To our surprise, side products 24 and 25 were obtained in 27 and
4% yields, respectively (entries 1–4) A. mechanism to account for
these side products is depicted in the ESI.w By contrast, we were
unable to characterize or isolate any similar side products from the
crude reaction mixtures for entries 5–11.
.
15. It was found that vinylallene 8 is unstable on silica gel even doped
with 5% NEt3. IR (neat, cmꢀ1) 3441(br), 2932(s), 2855(m),
1954(w), 1713(w), 1687(w), 1447(m); 1H NMR (CDCl3)
d
5.80–5.75 (m, 2H), 4.93 (s, 1H), 4.90 (s, 1H), 4.88 (s, 1H), 4.74
(d, J 1.2 Hz, 1H), 2.94 (d, JAB 19.2 Hz), 2.77 (dd, JAB 19.2, JAX 5.0
Hz), 2.23–2.19 (m, 2H), 1.82–1.22 (m, 8H); 13C NMR d 209.8,
146.2 (C), 137.9 (Ct), 126.7 (CH), 108.8 (CH2), 90.3 (CH), 77.0
(CH2), 72.3 (C), 49.1 (CH), 36.6, 35.0, 26.0, 23.6, 21.5 (CH2);
HRMS (EI) m/z calc. for C14H18
202.1359
O ) 202.1358, found
(M+
ꢂc
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3006 | Chem. Commun., 2008, 3004–3006