C O M M U N I C A T I O N S
Scheme 2. Tandem, One-Pot Process
Table 2. Palladium-Catalyzed [4 + 3] Cycloaddition
We thus investigated whether this reaction can be combined with
the cycloaddition so that both processes can be carried out in a
one-pot process (Scheme 2). Indeed, treatment of sodium carbanion
7 with such a tosylate in presence of Pd2dba3, L4, and dppe gave
the bicyclic adduct 5d (56% yield).
In summary, we have unveiled a new type of metal-catalyzed
cycloaddition that allows the synthesis of appealing, stereochemi-
cally rich 5,7-fused bicyclic systems from readily accessible
dienylidenecyclopropanes.13 To the best of our knowledge, this work
represents the first report on a metal-catalyzed [4 + 3] intramo-
lecular cycloaddition reaction and provides the first examples of
an enantioselective variant. Further studies to broaden the scope
and chemoselectivity of the method and to develop efficient
asymmetric versions are underway.
Acknowledgment. This work was supported by the Spanish
MEC (SAF2004-01044) and Consolider Ingenio 2010 (CSD2007-
00006), and the Xunta de Galicia (GRC2006/132). M.G. and J.D.
thank the Xunta de Galicia and MEC for predoctoral fellowships.
F.L. thanks the Spanish MEC for a Ramo´n y Cajal contract. We
also thank Johnson-Matthey for the gift of Pd2dba3.
Note Added after ASAP Publication. After this paper was
published ASAP on August 21, 2007, an error was corrected in
the last sentence of the fifth paragraph (the correct substrate is 4f).
The corrected version was published ASAP on August 22, 2007.
Supporting Information Available: Experimental details and
characterization data for new compounds. This material is available
References
a Ratio of 5,7- and 5,5-cycloadducts determined by NMR and/or GC of
crude reaction mixtures. The 5,5-cycloadducts are obtained as single
diastereoisomers. b Conditions A: dioxane, 101 °C (50 mM), for 2-3 h,
using 6% of Pd2dba3 and 24% of phosphoramidite L3. c Conditions B: L4
used as the ligand. d Isolated yields. e The yield refers to the 5/6 mixture
of cycloadducts, as 6 could not be removed by chromatography.
(1) Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49-92.
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(4) An intermolecular Pd-catalyzed [4 + 3] cycloaddition of methylenecy-
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substrate 4f also underwent the cycloaddition providing the adduct
5f in 40% isolated yield.
Nonactivated, methyl-substituted substrates 4g and 4i failed to
undergo the cycloaddition reaction, providing a relatively complex
mixture of products. However, their [4 + 3] cycloaddition reactivity
can be recovered upon activation with an ester substituent (sub-
strates 4h and 4j). Using conditions B, 5h was obtained in 64% ee
and 59% yield.11 Interestingly, substrate 4g underwent a clean and
stereoselective [3 + 2] cycloaddition when the reaction was carried
out in presence of phosphite L2 (eq 1). This result is remarkable
as the homologous enylidenecyclopropane 4k provides mixtures
of products when heated under the same conditions.12 Isomer 4i
also experienced an efficient and diastereoselective [3 + 2] process
(see the Supporting Information).
(5) (a) Trost, B. M.; MacPherson, D. T. J. Am. Chem. Soc. 1987, 109, 3483-
3484. (b) Trost, B. M. Pure Appl. Chem. 1988, 60, 1615-1626.
(6) For the synthesis of the precursors, see the Supporting Information.
(7) The reaction can be carried out with 4% of the Pd source and 13% of
ligand with similar efficiencies, but use of lower loadings leads to a slower
reaction and poorer conversions.
(8) The enantiomeric excess was determined by HPLC, on the R,â-unsaturated
ester isomer (see the Supporting Information).
(9) The assignment of the structure and stereochemistry of the cycloadducts
is discussed in the Supporting Information.
(10) An alternative stepwise process involving zwitterionic intermediates similar
to those proposed for the reactions from the Pd-TMM complexes (see ref
4) is less consistent with the observed stereospecificity.
(11) This type of methylated bicyclic frames is an important structural motif
in a large variety of natural products: (a) Rigby, J. H. In Studies in Natural
Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier Science Publishers
B. V.: Amsterdam, 1988; Vol. 12, p 233. (b) Wender, P. A.; Zhang, L.
Org. Lett. 2000, 2, 2323-2326.
(12) A related beneficial effect of the conjugated double bond has been observed
on a Rh-catalyzed Pauson-Khand processes: Wender, P. A.; Deschamps,
N. M.; Gamber, G. G. Angew. Chem., Int. Ed. 2003, 42, 1853-1857.
(13) For the synthesis of related compounds by cycloaddition methods, see:
(a) Wender, P. A.; Glorius, F.; Husfed, C. O.; Langkopf, E.; Love, J. A.
J. Am. Chem. Soc. 1999, 121, 5348-5349. (b) Giguere, R. J.; TAssely,
S. M.; Rose, M. I. Tetrahedron Lett. 1990, 31, 4577-4580.
Cycloaddition precursors such as 4d can be readily assembled
through a Pd-catalyzed coupling between 1-vinylcyclopropyltosylate
and the sodium salt of diethyl 2-[(E)-penta-2,4-dienyl]malonate.
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