Gold(I)-catalyzed stereoselective formation of functionalized 2,5-dihydrofurans

Article abstract of DOI:10.1021/ol0606839

A study concerning the gold(I)-catalyzed rearrangement of butynediol monobenzoates into functionalized 2,5-dihydrofurans is described. The mild reaction conditions employed allow the efficient and rapid stereoselective synthesis of a variety of 2,5-dihydrofurans via a sequence of two gold(I)-catalyzed isomerization steps.

Full text of DOI:10.1021/ol0606839

ORGANIC
LETTERS
2006
Vol. 8, No. 9
1957-1959
Gold(I)-Catalyzed Stereoselective
Formation of Functionalized
2,5-Dihydrofurans
Andrea Buzas, Florin Istrate, and Fabien Gagosz*
Laboratoire de Synthe`se Organique, UMR 7652 CNRS/Ecole Polytechnique,
Ecole Polytechnique, 91128 Palaiseau, France
gagosz@dcso.polytechnique.fr
Received March 20, 2006
ABSTRACT
A study concerning the gold(I)-catalyzed rearrangement of butynediol monobenzoates into functionalized 2,5-dihydrofurans is described. The
mild reaction conditions employed allow the efficient and rapid stereoselective synthesis of a variety of 2,5-dihydrofurans via a sequence of
two gold(I)-catalyzed isomerization steps.
2,5-Dihydrofurans and their derivatives are structural motifs
that are frequent in a wide variety of natural products
Scheme 1. Synthetic Approach to Functionalized
exhibiting interesting biological activity.1 As a consequence,
2,5-Dihydrofurans
the development of practical synthetic routes to access such
structures is of major interest.
In this respect, Krause and co-workers have recently
reported that gold(III) chloride efficiently catalyzed the
cyclization of allenols to polysubstituted 2,5-dihydrofurans.2
Since it has been recently shown that gold(I) complexes
catalyzed the rearrangement of propargylic esters into
allenes,3 we surmised that a suitable propargylic ester 1 might
be a valuable precursor for the synthesis of 2,5-dihydrofuran
2 through a gold-catalyzed sequence of allene formation and
cycloisomerization (Scheme 1, eq 1).4,5 This approach would
be especially advantageous because the corresponding chiral
substrates are easily accessible, allowing perhaps an enan-
tioselective synthesis of 2,5-dihydrofurans.
(1) For selected reviews, see the following. Polyether antibiotics: Faul,
M. M.; Huff, B. E. Chem. ReV. 2000, 100, 2407-2474. Marine polyethers:
Compounds of type 3 were first chosen as model substrates
to validate this approach (Scheme 1, eq 2). Among the esters
tested, the benzoate derivative was the best precursor. It was
rearranged in the presence of 1% of (Ph3P)AuNTf2 in
dichloromethane to afford the desired 2,5-dihydrofuran 4 in
83% yield.6 In contrast, the acetate and pivalate gave very
poor results.
Fernandez, J. J.; Souto, M. L.; Norte, M. Nat. Prod. Rep. 2000, 23, 26-
78. Marine natural products: Blunt, J. W.; Copp, B. R.; Munro, M. H. G.;
Northcote, P. T.; Prinsep, M. R. Nat. Prod. Rep. 2006, 17, 235-246.
(2) Hoffmann-Ro¨der, A.; Krause, N. Org. Lett. 2001, 3, 2537-2538.
See also: Morita, N.; Krause, N. Org. Lett. 2004, 6, 4121-4123.
(3) (a) Zhang, L.; Wang, S. J. Am. Chem. Soc. 2006, 128, 1442-1443.
(b) Zhang, L. J. Am. Chem. Soc. 2005, 127, 16804-16805. (c) Ag
catalysis: Sromek, A. W.; Kel’in, A. V.; Gevorgyan, V. Angew. Chem.,
Int. Ed. 2004, 43, 2280-2282.
10.1021/ol0606839 CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/30/2006

The reaction proved to be quite general and various
substituted butynediol monobenzoates 5a-g reacted using
2% of (Ph3P)AuNTf2 as the catalyst to furnish the corre-
sponding 2,5-dihydrofurans 6a-g in generally high yields
(69-99%) (Table 1).7 The presence of extra protected
reacted with the same efficiency, and no noticeable difference
in reactivity was observed when primary or secondary
alcohols were used. The moderate yield obtained in the case
of substrate 5f was due to the competitive formation of enone
7 arising from a gold(I)-catalyzed Rupe-type reaction.8
Various enantioenriched butynediol monobenzoates 8a-h
were next synthesized according to the procedure9 developed
by Carreira and co-workers and subjected to the gold(I)-
catalyzed rearrangement using the same experimental condi-
tions. As attested by the results compiled in Table 2, these
were also converted into the corresponding 2,5-dihydrofurans
9a-h in high yields (83-99%). Furthermore, enantio-
enriched alcohol 8a furnished compound 9a without loss of
Table 1. Au(I)-Catalyzed Synthesis of 2,5-Dihydrofurans
6a-ga
Table 2. Au(I)-Catalyzed Stereoselective Synthesis of
2,5-Dihydrofurans 9a-ha
a Reaction conditions: 0.5 M substrate in CH2Cl2, 2% of (Ph3P)AuNTf2,
rt. b Isolated yields. c 23% of enone 7 were also isolated.
alcohols was tolerated. The time required to reach completion
was in most cases shorter than 1 h. Mono- (entry 6), di-
(entries 1-5), and trisubstituted (entry 7) propargylic esters
(4) A similar Ag(I)-catalyzed transformation of propargyl esters to
dihydrofurans has been previously reported: (a) Shigemasa, Y.; Yasui, M.;
Ohrai, S.-I.; Sasaki, M.; Sashiwa, H.; Saimoto, H. J. Org. Chem. 1991, 56,
910-912. (b) Saimoto, H.; Yasui, M.; Ohrai, S.-I.; Oikawa, H.; Yohoyama,
K.; Shigemasa, Y. Bull. Chem. Soc. Jpn. 1999, 72, 279-284. However,
this transformation required 10% of AgBF4 in refluxing benzene and
furnished the dihydrofurans in moderate yields (∼60%). Moreover, the
cyclization was limited to the use of tertiary alcohols.
(5) For a recent review on gold catalysis, see: Hashmi, A. S. K. Gold
Bull. 2004, 37, 51-65. Selection of recent developments in gold catalysis:
(a) Antoniotti, S.; Genin, E.; Michelet, V.; Geneˆt, J.-P. J. Am. Chem. Soc.
2005, 127, 9976-9977. (b) Asao, N.; Sato, K.; Yamamoto, Y. J. Org. Chem.
2005, 70, 3682-3685. (c) Hashmi, A. S. K.; Weyrauch, J. P.; Frey, W.;
Bats, J. W. Org. Lett. 2004, 6, 4391-4394. (d) Sherry, B. D.; Toste, F. D.
J. Am. Chem. Soc. 2004, 126, 15978-15979. (e) Gorin, D. J.; Davis, N.
R.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260-11261. (f) Nieto-
Oberhuber, C.; Lopez, S.; Echavarren, A. M. J. Am. Chem. Soc. 2005, 127,
6178-6179. (g) Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc. 2005, 127,
6962-6963. (h) Shi, X.; Gorin, D. J.; Toste, F. D. J. Am. Chem. Soc. 2005,
127, 5802-5803. (i) Ferrer, C.; Echavarren, A. M. Angew. Chem., Int. Ed.
2006, 45, 1105-1109. (j) Johansson, M. J.; Gorin, D. J.; Staben, S. T.;
Toste, F. D. J. Am. Chem. Soc. 2005, 127, 18002-18003. (k) Sromek, A.
W.; Rubina, M. A. V.; Gevorgyan, V. J. Am. Chem. Soc. 2005, 127, 10500-
10501.
a Reaction conditions: 0.5 M substrate in CH2Cl2, 2% of (Ph3P)AuNTf2,
rt. b Isolated yields, dr and ee determined by chiral HPLC.
(6) For the synthesis and use of this stable Au(I) catalyst, see: Mezailles,
N.; Ricard, L.; Gagosz, F. Org. Lett. 2005, 7, 4133-4136.
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Org. Lett., Vol. 8, No. 9, 2006

optical purity. The rearrangement of substrate 8b possessing
two asymmetric centers also took place witht a complete
transfer of chirality and furnished trans-2,5-disubstituted
dihydrofuran 9b in 97% yield.10 The parent diastereoisomer
8c reacted equally well to give the cis-isomer 9c in 99%
yield. Under the same reaction conditions, primary alcohols
8d and 8e led, respectively, to enantiomers 9d and 9e, but
with partial loss of optical purity (entries 4 and 5a).
to the 1,3-shift of the benzoate group and the subsequent
stereoselective formation of the intermediate allene 12, after
catalyst regeneration.3,5d A further gold(I) activation of the
allene promotes the nucleophilic attack of the alcohol causing
the stereoselective formation of the vinyl-gold species 13.2,3,5k
This latter is finally protonated to furnish 2,5-dihydrofuran
14. This mechanism may account for the regioselective 1,3-
shift of the benzoate moiety and for the inversion of
configuration at the carbon center initially bearing this
benzoate group. A gold(I) isomerization of the intermediate
allene 12, prior to the attack of the alcohol, may be
responsible for the partial loss of the stereochemical
information.5d This route seems to be effective in the case
of unsubstituted free propargylic alcohols cyclizing onto
sterically hindered carbon centers (Table 2, entries 4-6).
To further highlight the potential of this new process, we
attempted to trap the intermediate vinyl-gold species 13 by
a source of electrophilic iodine prior to protonation. To this
end, alkyne 5c was treated with 1% of (Ph3P)AuNTf2 and a
slight excess of NIS in acetone (Scheme 3, eq 3).12 We were
This effect was much more pronounced when the reaction
was performed on substrate 8f bearing a bulkier cyclohexyl
group (entry 6a). This racemization might be due to a
competition between a possible gold(I)-catalyzed isomer-
ization of the intermediate allene5d and the nucleophilic attack
of the alcohol onto the gold-activated allene. The untoward
erosion of optical purity could be largely eliminated by a
proper choice of experimental conditions and the gold
catalyst (entries 5b-e). Thus, conducting the cycloisomer-
6
ization of 8e at 0 °C with 2% of (Ad2n-BuP)AuNTf2 gave
rise to 9e in nearly quantitative yield and 90% ee.11
Interestingly, tertiary alcohol 8g smoothly rearranged under
the general conditions furnishing 2,5-dihydrofuran 9g in 95%
yield with a complete transfer of chirality. This reactivity
might be due to a Thorpe-Ingold effect approaching the
nucleophilic alcohol closer to the gold(I)-activated allene.
To further explore the potential of this process, the reaction
of functionalized alkyne 8h bearing three asymmetric centers
was examined. The transformation was exceptionally ef-
ficient and gave the corresponding trans-2,5-disubstituted
dihydrofuran 9h in 99% yield and complete transfer of the
stereochemical information.10
Scheme 3
To account for these observations, a mechanistic manifold
for the formation of the 2,5-dihydrofurans is proposed in
Scheme 2. Gold(I) activation of the triple bond in alkyne 10
pleased to observe the formation of vinyliodide 15, which
was isolated in 73% yield.
In addition, the functionalized 2,5-dihydrofurans can lend
themselves to a number of useful transformations. For
example, hydrogenation of compound 9e with 10% of Pd/C
in EtOAc resulted in the diastereoselective formation of
tetrahydrofuran 16 in 91% yield (Scheme 3, eq 4).
In summary, we have shown that phosphine gold(I)
complexes efficiently catalyze the stereoselective formation
of various functionalized 2,5-dihydrofurans from readily
available butynediol monobenzoates. A mechanism involving
two gold(I)-catalyzed isomerization steps accounts for the
observed regio- and stereoselectivities. Further studies related
to this new gold(I)-catalyzed process as well as its application
to the synthesis of natural products are underway.
Scheme 2. Proposed Mechanism for the Formation of
2,5-Dihydrofurans
Acknowledgment. We thank Prof. S. Z. Zard, Dr. B.
Quiclet-Sire, and Dr. I. Hanna for helpful discussions, J-P.
Pulicani for HPLC analyses, and Rhodia Chimie Fine for a
donation of HNTf2.
promotes the nucleophilic attack of the benzoate moiety and
the subsequent formation of the stabilized cationic species
11. Fragmentation of the allylic C-O bond in 11 can lead
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.
(7) Isomerization of 5g into 6g was performed from the acetate derivative
for convenience reasons since the corresponding 3-acetoxy-3-methylbut-
1-yne was commercially available.
(8) Georgy, M.; Boucard, V.; Campagne, J.-M. J. Am. Chem. Soc. 2005,
127, 14180-14181.
OL0606839
(9) See, for instance: (a) Boyall, D.; Frantz, D. E.; Carreira, E. M. Org.
Lett. 2002, 4, 2605-2606. (b) El-Sayed, E.; Anand, N. K.; Carreira, E. M.
Org. Lett. 2001, 3, 3017-3020. (c) Anand, N. K.; Carreira, E. M. J. Am.
Chem. Soc. 2001, 123, 9687-9688.
(11) (Ad2n-BuP)AuNTf2 is a less electrophilic catalyst than (Ph3P)-
AuNTf2. Its use might slow the isomerization of the intermediate allene
without disfavoring the cyclization.
(10) Structure and stereochemistry determined by full NMR analysis.
(12) Buzas, A.; Gagosz, F. Org. Lett. 2006, 8, 515-518.
Org. Lett., Vol. 8, No. 9, 2006
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