Unusual gold(I)-catalyzed isomerization of 3-hydroxylated 1,5-enynes: Highly substrate-dependent reaction manifolds

Article abstract of DOI:10.1021/ol051397k

(Chemical Equation Presented) The gold(I) isomerization of diversely substituted 3-hydroxylated enynes has led to the discovery of three new unreported skeletal rearrangements furnishing structures such as alkylidene-cyclopentenes, cyclohexadienes or α,β-

Full text of DOI:10.1021/ol051397k

ORGANIC
LETTERS
2005
Vol. 7, No. 19
4129-4132
Unusual Gold(I)-Catalyzed Isomerization
of 3-Hydroxylated 1,5-Enynes: Highly
Substrate-Dependent Reaction Manifolds
Fabien Gagosz*
Laboratoire de Synthe`se Organique, Ecole Polytechnique, 91128 Palaiseau, France
gagosz@dcso.polytechnique.fr
Received June 16, 2005
ABSTRACT
The gold(I) isomerization of diversely substituted 3-hydroxylated enynes has led to the discovery of three new unreported skeletal rearrangements
furnishing structures such as alkylidene-cyclopentenes, cyclohexadienes or
r,
â
-unsaturated aldehydes under very mild conditions.
Gold(I) complexes have recently emerged as efficient and
mild catalysts for the transformation of substrates possessing
an alkyne functionality into a range of useful structural
motifs.1 The potential of such catalysts has been mostly
highlighted by various studies related to the conversion of
enynes into cycloisomerized products.2 In this respect, we
were particularly intrigued by the possibility that ring A of
the bioactive guanacastepene A3 could be synthesized using
Scheme 1. Retrosynthesis of Guanacastepene A
(1) For a review on homogeneous catalysis by gold, see: Hashmi, A. S.
K. Gold Bull. 2004, 37, 51-65.
(2) (a) Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. J. Am. Chem. Soc.
2000, 122, 11553-11554. (b) Nieto-Oberhuber, C.; Lopez, S.; Echavarren,
A. M. J. Am. Chem. Soc. 2005, 127, 6178-6179. (c) Mun˜oz, M.; Adrio,
J.; Carretero, J. C.; Echavarren, A. M. Organomettalics 2005, 24, 1293-
1300. (d) Nevado, C.; Echavarren, A. M. Chem. Eur. J. 2005, 11, 3155-
3164. (e) Nieto-Oberhuber, C.; Mun˜oz, M.; Bun˜uel, E.; Nevado, C.;
Ca´rdenas, D. J.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43, 2402-
2406. (f) Shi, X.; Gorin, D. J.; Toste, F. D. J. Am. Chem. Soc. 2005, 127,
5802-5803. (g) Luzung, M. R.; Markham, J. P.; Toste, F. D. J. Am. Chem.
Soc. 2004, 126, 10858-10859. (h) Sherry, B. D.; Toste, F. D. J. Am. Chem.
Soc. 2004, 126, 15978-15979. (i) Staben, S. T.; Kennedy-Smith, J. J.; Toste,
F. D. Angew. Chem., Int. Ed. 2004, 43, 5350-5352. (j) Kennedy-Smith, J.
J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 4526-4527.
(k) Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc. 2004, 126, 11806-11807.
(l) Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc. 2005, 127, 6962-6963.
(3) Brady, S. F.; Singh, M. P.; Janso, J.; E.; Clardy, J. J. Am. Chem.
Soc. 2000, 122, 2116-2117.
a gold(I)-catalyzed cycloisomerization of a well defined
enyne (Scheme 1). Actually, this approach would allow the
early introduction of most of the functionalities present on
ring A, while the presence of the cyclopropyl ring could serve
as a springboard for the construction of ring B. We herein
report results concerning these studies that led to the
discovery of three new unusual gold(I)-catalyzed isomer-
izations of 3-hydroxylated 1,5-enynes.4
10.1021/ol051397k CCC: $30.25
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Compound 1 was first chosen as a model substrate to
validate the above-described approach (Scheme 2). To this
structure and stereochemistry were confirmed by full NMR
analyses, is produced by an unreported skeletal rearrangement
and formally corresponds to an endo-metathesis-type com-
pound. The yield of this new rearranged product was
improved to 80% when the reaction was performed starting
from benzyl ether 1b as the substrate. Even in the case of
enyne 1c, a type of compound known to undergo a rapid
1,2-shift of the acetate moiety, the reaction furnished the
corresponding alkylidene-cyclopentene 3c in 74% yield (90%
starting from >97% pure syn 1c) (Scheme 3).
Scheme 2. Cycloisomerization of Enynes 1a and 1b
To determine more precisely the influence of the substitu-
tion pattern of the starting enynes on the course of the new
Scheme 4. Mechanistic Proposal for Alkylidene-cyclopentene
Formation
end, treatment of a mixture of syn- and anti-enynes 1a with
2 mol % (PPh3)AuBF4 at room temperature was attempted.
However, a rapid decomposition of the substrate was
observed under these conditions, and only traces of desired
2a were detected.5 Interestingly, lowering the temperature
to -20 °C addressed the problems of degradation and led
to a fast conversion of the substrate. However, conversion
Scheme 3. Cycloisomerization of Enyne 1c
skeletal reorganization, various enynes 1d-j were synthe-
sized and subjected to gold(I)-catalyzed isomerization. The
results are summarized in Table 1. We first turned our
attention to enynes 1d-g, lacking the methyl group at the
vinylic position. It is interesting to note that the isomerization
required in these cases a longer reaction time and a higher
temperature to reach completion. This may be attributed to
the reduced nucleophilicity of the alkene compared to
a Yields obtained when >97% pure syn isomer 1c was used.
of 1a into 2a was not improved, and we were surprised to
observe instead the formation of alkylidene-cyclopentene 3a,
which was isolated in 55% yield. This compound, whose
(4) For related studies, see: (a) Mamane, V.; Gress, T.; Krause, H.;
Fu¨rstner, A. J. Am. Chem. Soc. 2004, 126, 8654-8655. (b) Harrak, Y.;
Blaszykowski, C.; Bernard, M.; Cariou, K.; Mouries, V.; Dhimane, A.-L.;
Fensterbank, L.; Malacria, M. J. Am. Chem. Soc. 2004, 126, 8656-8657.
(5) A fast coloration of the solution and the formation of very apolar
products were observed. Under the same reaction conditions, product 3a
led to the formation of the same byproducts.
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Org. Lett., Vol. 7, No. 19, 2005

Table 1. Isomerizations of Various 3-Hydroxylated 1,5-Enynesa
1
a Reaction conditions: 0.1 M enyne in DCM with 2% (PPh3)AuBF4. b Ratio determined by H NMR. c Isolated as the deprotected enol form.
analogues 1a-c.6 We were further surprised to observe that
such a simple structural modification had a very significant
influence on the course of the reaction. For example, the
rearrangement leading to the alkylidene-cyclopentene skel-
eton was only observed in the case of the syn isomer 1e,
but the corresponding alkylidene-cyclopentene 3e was iso-
lated in only 27% yield. Moreover, a reversal in selectivity
was observed when the reaction was performed using either
syn-enyne 1d or isomeric anti-enyne 1f.7 These results
suggest that the hydroxyl group can indeed act as a
stereodirecting element in this transformation.
and 57% yields, respectively. The presence of an alkyl group
at the allylic position of the substrate is apparently not of
crucial importance for the obtention of alkylidene-cyclopen-
tene-type products but facilitates their formation probably
through steric compression. We were, however, surprised
by the formation of compounds 3h and 3i since the reaction
was performed starting from a substrate possessing an olefin
with a trans configuration. We next examined the influence
of the lateral chain of the alkyne moiety on the course of
the reaction. An experiment was performed on substrate 1j
possessing a bulkier phenyl group at the terminal position
of the alkyne. In that case, alkylidene-cyclopentene 4j was
obtained in 54% yield along with 25% of cyclohexadiene
3j generated by a new unreported isomerization pathway.
Enynes 1h and 1i smoothly reacted at -20 °C, affording
the corresponding alkylidene-cyclopentenes 4h and 4i in 29
(6) For a review on π-nucleophilicity in C-C bond formation, see: Mayr,
H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66-77.
(7) The reason for such a selectivity is still unclear, and studies to
rationalize this result are underway.
On the basis of these observations and previously described
rearrangements of 1,5-enynes,2 we propose the sequence
Org. Lett., Vol. 7, No. 19, 2005
4131

shown in Scheme 4 as the most likely mechanism for the
formation of the new cycloisomerized products. In the case
of syn-enynes, the nucleophilic attack of the olefin onto the
gold(I)-alkyne complex produces the gold-stabilized car-
bocation A, which normally collapses to B by a 1,2-hydride
shift and release of gold(I). The presence of bulky substit-
uents on the cyclopropyl ring (R1, R2, and R3) dramatically
alters the normal reaction pathway leading to B. A double
1,2-alkyl shift process, favored by a decrease of steric
congestion in A, can operate instead and lead to intermediate
C and then D.2k The latter finally fragments to regenerate
the catalyst and furnish alkylidene-cyclopentenes E. Alter-
natively, steric interactions may sufficiently reduce the rate
of the cyclopropyl ring formation and therefore stabilize
carbocationic intermediate F. A competitive diastereoselec-
tive 1,2-hydride shift leading to G may then be involved,
which would explain the formation of a six-membered cycle
in 3j and justify the stereochemistry of the final compound.
Cyclohexadiene H is generated by subsequent 1,2-hydride
shift followed by elimination of the gold(I) catalyst. This
rearrangement seems to be unlikely in the case of the
corresponding anti isomers due to a disfavored interaction
between the OR3 group and the cyclopropane moiety in
intermediate I.
Scheme 6. Cycloisomerization of Enyne 1k
to the corresponding intermediate D. However, we were
pleased to isolate instead aldehyde 2k in 68% yield, whose
formation may be rationalized by the mechanism proposed
in Scheme 6.
A 6-endo-dig attack of the olefin onto the gold(I)-alkyne
complex results in the formation of intermediate M. Sub-
sequent Grob-type fragmentation affords allenol N, which
spontaneously tautomerizes to aldehyde 2k. This unreported
transformation corresponding to an acetylenic oxy-Cope
rearrangement is remarkable since it operates rapidly under
very mild conditions and without isomerization of the dienic
system.8
In summary, we have demonstrated that the gold(I)-
catalyzed isomerization of 3-hydroxylated 1,5-enynes may
follow highly divergent reaction pathways depending on the
substitution pattern and the relative configuration of the
substrate since three unreported types of skeletal rearrange-
ment have been discovered. Further studies related to the
exploitation of these new synthetically useful transformations
are underway and will be reported in due course.
Therefore, the 1,2-hydride shift occurs to afford com-
pounds J. In the case of enynes 1i-j, the formation of
isomers 2i-j and 3i-j may be explained by a fast equilib-
rium between conformers K and L driven by a plausible
decrease of the steric interactions in intermediate K (Scheme
5). In this way, both epimers 2h:3h and 2i:3i can be produced
Scheme 5. Formation of Epimers 2h:3h and 2i:3i
Acknowledgment. The author wishes to thank Prof. S.
Z. Zard, Dr. B. Quiclet-Sire, Dr. I. Hanna, Dr. P. Le Floch
and Dr. N. Me´zailles for helpful discussions.
Supporting Information Available: Experimental pro-
cedures and spectral data for new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
despite the unique geometry of the starting olefins 1h and
1i.
A final experiment was performed on terminal alkyne 1k
(Scheme 6). No alkylidene-cyclopentene was formed in this
case due to the unlikely possibility of a 1,2-alkyl shift leading
OL051397K
(8) For an example of the silver(I)-catalyzed acetylenic oxy-Cope process,
see: Bluthe, N.; Gore, J.; Malacria, M. Tetrahedron 1986, 42, 1333-1344.
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