Gold-catalyzed heterocycle synthesis using homopropargylic ethers as latent electrophiles

Article abstract of DOI:10.1021/ol060574u

Homopropargylic ethers with pendent nucleophiles, when subjected to Au catalysts in aqueous solvent, provide heterocyclic ketones. The reactions are efficient, tolerant of functionality and ambient atmosphere, and operationally simple. Diastereoselectivity can be predicted on the basis of product thermodynamics. This process demonstrates the viability of homopropargylic ethers to serve as latent electrophiles that can be unraveled under highly selective conditions to promote heterocycle formation through nucleophilic additions to α,β-unsaturated ketones.

Full text of DOI:10.1021/ol060574u

ORGANIC
LETTERS
2006
Vol. 8, No. 9
1949-1951
Gold-Catalyzed Heterocycle Synthesis
Using Homopropargylic Ethers as Latent
Electrophiles
Hyung Hoon Jung and Paul E. Floreancig*
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
florean@pitt.edu
Received March 8, 2006
ABSTRACT
Homopropargylic ethers with pendent nucleophiles, when subjected to Au catalysts in aqueous solvent, provide heterocyclic ketones. The
reactions are efficient, tolerant of functionality and ambient atmosphere, and operationally simple. Diastereoselectivity can be predicted on the
basis of product thermodynamics. This process demonstrates the viability of homopropargylic ethers to serve as latent electrophiles that can
be unraveled under highly selective conditions to promote heterocycle formation through nucleophilic additions to
r,â-unsaturated ketones.
Selectively activating a single functional group in the
presence of other, similar functional groups represents a
significant impediment to efficient complex molecule syn-
thesis. This issue can be addressed by utilizing functional
group surrogates that react under unique conditions and
subsequently unravel to yield the desired moiety. Transition
metal catalysts are proving to be remarkably useful agents
for implementing this strategy, particularly with respect to
generating electrophiles through their association π-bonds.1
Recently gold catalysts2 have emerged as superior reagents
for selectively activating alkenes3 and alkynes4 toward
reactions with an impressive range of nucleophiles. We have
initiated a program to exploit the unique chemoselectivity
of gold catalysis in the synthesis of polyfunctional molecules.
In this manuscript we detail a new, efficient, and mild
approach to the preparation of heterocyclic ketones in which
homopropargylic ethers serve as latent electrophiles. Mecha-
nistic studies that elucidate the reaction sequence and explain
the stereochemical outcomes of the process are also de-
scribed.
We viewed homopropargylic ethers as intriguing substrates
for this study because of their ease of preparation, generally
inert behavior toward nucleophiles, and wealth of potential
reaction pathways upon treatment with gold catalysts. In
(4) Recent examples: (a) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2005,
44, 6990. (b) Gorin, D. J.; Davis, N. R.; Toste, F. D. J. Am. Chem. Soc.
2005, 127, 11260. (c) Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2004,
126, 15978. (d) Staben, S. T.; Kennedy-Smith, J. J.; Toste, F. D. Angew.
Chem., Int. Ed. 2004, 43, 5350. (e) Luzung, M. R.; Markham, J. P.; Toste,
F. D. J. Am. Chem. Soc. 2004, 126, 10858. (f) Kennedy-Smith, J. J.; Staben,
S. T.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 4526. (g) Zhang, L.;
Kozmin, S. A. J. Am. Chem. Soc. 2005, 127, 6962. (h) Zhang, L.; Kozmin,
S. A. J. Am. Chem. Soc. 2004, 126, 11806. (i) Nieto-Oberhuber, C.; Lo´pez,
S.; Mun˜oz, M. P.; Ca´rdenas, D. J.; Bun˜uel, E.; Nevado, C.; Echavarren, A.
M. Angew. Chem., Int. Ed. 2005, 44, 6146. (j) Nieto-Oberhuber, C.; Lo´pez,
S.; Echavarren, A. M. J. Am. Chem. Soc. 2005, 127, 6178. (k) Nieto-
Oberhuber, C.; Mun˜oz, M. P.; Bun˜uel, E.; Nevado, C.; Ca´rdenas, D. J.;
Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43, 2402. (l) Antoniotti,
S.; Genin, E.; Michelet, V.; Geneˆt, J.-P. J. Am. Chem. Soc. 2005, 127, 9976.
(m) Zhu, J.; Germain, A. R.; Porco, J. A., Jr. Angew. Chem., Int. Ed. 2004,
43, 1239.
(1) (a) Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc.
2005, 127, 17778. (b) Yip, K.-T.; Li, J.-H.; Lee, O.-Y.; Yang, D. Org.
Lett. 2005, 7, 5717. (c) Kerber, W. D.; Gagne´, M. R. Org. Lett. 2005, 7,
3379. (d) Koh, J. H.; Gagne´, M. R. Angew. Chem., Int. Ed. 2004, 43, 3459.
(e) Pei, T.; Wang, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2003, 125,
648. (f) Hahn, C.; Cucciolito, M. E.; Vitagliano, A. J. Am. Chem. Soc.
2002, 124, 9038.
(2) Recent reviews: (a) Hoffmann-Ro¨der, A.; Krause, N. Org. Biomol.
Chem. 2005, 3, 387. (b) Hashmi, A. S. K. Gold Bull. 2004, 37, 51.
(3) (a) Yang, C.-G.; He, C. J. Am. Chem. Soc. 2005, 127, 6966. (b) Yao,
X.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 6884.
10.1021/ol060574u CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/04/2006

particular, we wanted to study the behavior of homoprop-
argylic ethers that bear a distal nucleophilic group toward
the objective of catalyzing cyclization reactions. Subjecting
facilitate the process.9 While we propose that enone activation
arises from alkene coordination, carbonyl activation is also
possible. A supporting role for trace amounts of HCl, formed
through the reaction of the gold catalyst with H2O, cannot
be rigorously excluded, but treating 1 with dilute HCl in CH2-
Cl2 led to no reaction.
This mechanistic hypothesis, coupled with literature
precedents, provided the foundation for our efforts at reaction
optimization. To ensure smooth alkyne hydration, water-
saturated CH2Cl2 was used as the solvent. Based on the
ability of simpler gold species to effect some of the
elementary steps in this sequence, NaAuCl4 was employed
as the catalyst for many transformations. Reactions proceeded
most smoothly and reproducibly when heated to 35 °C.
The scope and efficiency of this process are summarized
in Table 1. Several aspects of this study are noteworthy. The
5
homopropargylic ether 1 to Ph3PAuCl and AgSbF6 in
unpurified CH2Cl2 under standard atmospheric conditions
indeed resulted in the formation of tetrahydropyranyl ketone
2 in 48% yield (Scheme 1). Similar treatment of ether 3,
Scheme 1. Gold-Mediated Tetrahydropyran Synthesis
Table 1. Reaction Scope
prepared as a mixture of diastereomers, yielded 4 as a single
diastereomer in 60% yield.
These results, coupled with experimental observations and
literature precedents, led us to propose the sequence in
Scheme 2 as a mechanism for the process. Ag(I) serves to
Scheme 2. Proposed Mechanism
abstract the chloride from the Ph3PAuCl, forming a more
electrophilic catalyst. Control reactions demonstrated that
both metals are essential for this process. Gold-mediated
hydration of the alkyne with adventitious water6 provides
ketone 5. Methanol elimination yields enone 6,7 which
undergoes metal-promoted conjugate addition to produce the
cyclized product. In support of this mechanism, we have
isolated small amounts of 5 in reactions that were stopped
at partial conversion, resubjected it to the reaction conditions,
and observed cyclization. The formation of a single diaste-
reomer of 4 from a diastereomeric mixture of 3 suggests a
planar intermediate along the reaction coordinate. Although
1,4-additions of heteroatom nucleophiles into R,â-unsaturated
carbonyl compounds normally require significantly harsher
conditions,8 transition metal catalysis has been shown to
a Procedure A: substrate in water-saturated CH2Cl2 (∼60 mM), NaAuCl4
(5 mol %), 35 °C. Procedure B: substrate in water-saturated CH2Cl2 (∼60
mM), Ph3PAuCl (5 mol %), AgSbF6 (5 mol %), 35 °C. b Yields are reported
for isolated, purified products unless otherwise noted. c Yield determined
by GC. d Yield based on 81% starting material consumption.
(5) Teles, J. H.; Brode, S.; Chabanas, M. Angew. Chem., Int. Ed. 1998,
37, 1415.
(6) (a) Fukuda, Y.; Utimoto, K. J. Org. Chem. 1991, 56, 3729. (b)
Mizushima, E.; Sato. K.; Hayashi, T.; Tanaka, M. Angew. Chem., Int. Ed.
2002, 41, 4563.
(7) Fukada, Y.; Utimoto, K. Bull. Chem. Soc. Jpn. 1991, 64, 2013.
(8) (a) Bhattacharjee, A.; Soltani, O.; De Brabander, J. K. Org. Lett.
2002, 4, 481. (b) Evans, D. A.; Ripin, D. H. B.; Halstead, D. P.; Campos,
K. R. J. Am. Chem. Soc. 1999, 121, 6816.
overall transformations are, in general, quite efficient, with
several reactions proceeding in nearly quantitative yield.
Although NaAuCl4 is a suitable catalyst for many reactions,
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Org. Lett., Vol. 8, No. 9, 2006

the Ph3PAuCl/AgSbF6 system produces a more active catalyst
that is preferable for slower reactions (entries 5 and 7-9).
Silyl-protected nucleophiles are sufficiently reactive to
engage in this process (entry 3), alleviating the need for their
cleavage prior to cyclization, but reactions that employ
unprotected nucleophiles produce methanol as the only side
product. Homopropargylic alcohols are not suitable sub-
strates, with the reaction stopping after the hydration step
(data not shown). Tetrahydrofurans and oxepanes can also
be accessed through this process (entries 4-6) with enone
14 also being isolated from the cyclization of 12, presumably
as a result of the diminished rate for closing seven-membered
rings relative to lower homologues .10 In further support of
the mechanism in Scheme 2, resubjecting 14 to the reaction
conditions indeed provided 13. The reaction is tolerant of
functional groups, with ester, alkoxy, and hydroxy groups
proving to be compatible with the conditions, though
methanolysis is observed for the ester-containing substrate
(entry 9). Terminal alkynes proved to be essential for this
transformation, with internal alkynes undergoing hydration
to provide the carbonyl group on the distal carbon with
respect to the methoxy group.11 For reactions in which
diastereomers can be formed, selectivity follows expected
trends based on product stability, suggesting that alkyl group
conformational preferences should override alkoxy group
preferences in complex substrates. Of note, all substrates that
contain secondary alcohols were prepared from selective
additions to alkynyl aldehydes, highlighting the utility of
homopropargylic ethers as latent electrophiles.
Scheme 3. Product Equilibration
that were identical to those that were observed in the original
cyclization reactions. These studies provide compelling
evidence that diastereocontrol results from product equilibra-
tion.
We have demonstrated that electrophilic gold catalysts
mediate efficient heterocycle syntheses using homopropar-
gylic ethers as latent electrophiles through a sequence of
alkyne hydration, â-alkoxy group elimination, and 1,4-
addition. The process is operationally simple, tolerant of
substrate functionality and ambient atmosphere, and viable
with protected nucleophiles. Diastereoselectivity in these
transformations can be predicted on the basis of product
stability, in accord with studies that products equilibrate
under the reaction conditions. Au(III) and cationic Au(I)
catalysts effectively promote these reactions, with the cationic
Au(I) catalyst showing superior reactivity and the Au(III)
catalyst being economically preferable. The cyclic ethers that
are formed in these reactions are integral components of
several biologically natural products.12 In addition to the
application described herein, our observations suggest that
gold catalysts should be useful for effecting intramolecular
nucleophilic additions into electrophilic alkenes under ex-
ceptionally mild conditions.
We further examined these transformations to determine
whether kinetic factors or thermodynamic factors are re-
sponsible for the diastereocontrol that results in these
transformations. In principle the reaction products, being
â-alkoxy ketones, could undergo elimination and readdition
until reaching a thermodynamic equilibrium. To test this
hypothesis we subjected single diastereomers of 11 and 16
to the reaction conditions (Scheme 3). As postulated,
equilibration was observed to yield diastereomeric mixtures
Acknowledgment. We thank the National Institutes of
Health (GM-62924) for generous support of this work.
Supporting Information Available: Synthetic schemes
for all cyclization substrates. Experimental procedures and
characterization for all cyclization reactions. This material
is available free of charge via the Internet at http://pubs.acs.org.
(9) (a) Kobayashi, S.; Kakumoto, K.; Sugiura, M. Org. Lett. 2002, 4,
1319. (b) Trost, B. M.; Yang, H.; Wuitschik, G. Org. Lett. 2005, 7, 4761.
(10) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95.
(11) For a recent report of a useful method to control the regiochemistry
of alkyne hydration, see: Zhang, L.; Wang, S. J. Am. Chem. Soc. 2006,
128, 1442.
OL060574U
(12) Faulkner, D. J. Nat. Prod. Rep. 1999, 16, 155.
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