ORGANIC
LETTERS
2009
Vol. 11, No. 19
4370-4373
An Unexpected Oxidation in the
Generation of Cyclopenta[c]piperidines
by Ring-Closing Metathesis
Mercedes Amat,* Elisa Brunaccini, Begon˜a Checa, Maria Pe´rez, Nu´ria Llor, and
Joan Bosch*
Laboratory of Organic Chemistry, Faculty of Pharmacy, and Institute of Biomedicine
(IBUB), UniVersity of Barcelona, 08028 Barcelona, Spain
joanbosch@ub.edu; amat@ub.edu
Received July 28, 2009
ABSTRACT
Ring-closing metathesis reaction of dienes A (n ) 1, R) CO2R′) leads to fused cyclopentenones C instead of the expected cyclopentene
derivatives B. RCM reaction of the other dienes A takes place satisfactorily, affording the expected fused cycloalkene derivatives B. Cyclohexene
B (n ) 2, R ) CO2R′) also undergoes oxidation to the corresponding cyclohexenone C.
Chiral nonracemic amino alcohol-derived oxazolopiperidone
lactams have proven to be versatile scaffolds for the
enantioselective synthesis of piperidine-containing alkaloids
and bioactive compounds.1 These conceptually simple enan-
tiopure molecules bear tactically versatile functionality that
enables them to be elaborated into a great diversity of targets.
stituted piperidine libraries, we devised a general route to
highly substituted piperidines bearing a five-, six-, or seven-
membered carbocyclic ring cis fused on the c side of the
heterocycle. The key steps would be a stereoselective
conjugate addition of a vinyl residue to an activated
unsaturated lactam already bearing an alkyl substituent at
the ꢀ-position of the piperidine ring, a stereoselective
alkylation of the resulting ꢀ-oxo ester with unsaturated chains
of different length, a ring-closing olefin metathesis (RCM)
from the resulting dienes, and finally the reductive removal
of the chiral inductor. We report here an unexpected
oxidation after ring-closing metathesis in the cyclopenta- and
cyclohexa[c]piperidine series.
To further expand the scope of our enantiomeric scaffold-
ing strategy2 for the construction of enantiopure polysub-
(1) For reviews, see: (a) Romo, D.; Meyers, A. I. Tetrahedron 1991,
47, 9503–9569. (b) Meyers, A. I.; Brengel, G. P. Chem. Commun. 1997,
1–8. (c) Groaning, M. D.; Meyers, A. I. Tetrahedron 2000, 56, 9843–9873.
(d) Escolano, C.; Amat, M.; Bosch, J. Chem.sEur. J. 2006, 12, 8198–
8207. For more recent work, see: (e) Amat, M.; Pe´rez, M.; Minaglia, A. T.;
Peretto, B.; Bosch, J. Tetrahedron 2007, 63, 5839–5848. (f) Amat, M.;
Lozano, O.; Escolano, C.; Molins, E.; Bosch, J. J. Org. Chem. 2007, 72,
4431–4439. (g) Amat, M.; Santos, M. M. M.; Bassas, O.; Llor, N.; Escolano,
C.; Go´mez-Esque´, A.; Molins, E.; Allin, S. M.; McKee, V.; Bosch, J. J.
Org. Chem. 2007, 72, 5193–5201. (h) Amat, M.; Pe´rez, M.; Minaglia, A. T.;
Bosch, J. J. Org. Chem. 2008, 73, 6920–6923. (i) Amat, M.; Griera, R.;
Fabregat, R.; Molins, E.; Bosch, J. Angew. Chem., Int. Ed. 2008, 47, 3348–
3351. (j) Amat, M.; Fabregat, R.; Griera, R.; Bosch, J. J. Org. Chem. 2009,
74, 1794–1797. (k) Amat, M.; Go´mez-Esque´, A.; Escolano, C.; Santos,
M. M. M.; Molins, E.; Bosch, J. J. Org. Chem. 2009, 74, 1205–1211. (l)
Amat, M.; Checa, B.; Llor, N.; Molins, E.; Bosch, J. Chem. Commun. 2009,
2935–2937.
Scheme 1 outlines the preparation of the starting dienes 3
from the known3 lactam 1. The conjugate addition of the
vinyl group was accomplished in excellent chemical yield
and complete exo-facial selectivity, cis with respect to the
(2) Coombs, T. C.; Lee, M. D.; Wong, H.; Armstrong, M.; Cheng, B.;
Chen, W.; Moretto, A. F.; Liebeskind, L. S. J. Org. Chem. 2008, 73, 882–
888.
(3) Amat, M.; Pe´rez, M.; Llor, N.; Bosch, J.; Lago, E.; Molins, E. Org.
Lett. 2001, 3, 611–614.
10.1021/ol901704f CCC: $40.75
Published on Web 09/09/2009
2009 American Chemical Society