Gold(I)-catalyzed 5-endo hydroxy- and alkoxycyclization of 1,5-enynes: Efficient access to functionalized cyclopentenes

Article abstract of DOI:10.1002/anie.200604140

(Chemical Equation Presented) The rapid and stereoselective construction of highly functionalized cyclopentenes is possible through gold(I)-catalyzed 5-endo hydroxy- and methoxycyclizations of 1,5-enynes. More complex 5,7-and 5,8-fused bicyclic structures

Full text of DOI:10.1002/anie.200604140

Angewandte
Chemie
DOI: 10.1002/anie.200604140
Homogeneous Catalysis
Gold(I)-Catalyzed 5-endo Hydroxy- and Alkoxycyclization of 1,5-
Enynes: Efficient Access to Functionalized Cyclopentenes**
Andrea K. Buzas, Florin M. Istrate, and Fabien Gagosz*
Dedicated to Dr. Gilles Ouvry
The cyclopentyl unit is found frequently in a wide variety of
natural products that exhibit biological activity.[1] As a
consequence, the development of practical synthetic routes
to form five-membered rings remains of interest. Gold(I)
complexes have emerged as efficient and mild catalysts for
the activation of alkynes towards addition by a variety of
nucleophiles,[2] and their potential has been highlighted by
numerous studies related to the conversion of enynes into
cycloisomerized products.[3] For example, Echavarren and co-
workers reported that 1,6-enynes of type 1 could be trans-
formed into cyclopentadienes of type 3 [Eq. (1a)].[4] The same
substrates also underwent a 5-exo alkoxycyclization to furnish
the exo-methylenecyclopentane derivatives of type 4 when an
alcohol was used as the solvent [Eq. (1b)].[5]
formation of cyclopentene derivatives 7. Furthermore,
whereas the 5-exo alkoxycyclization of 1,6-enynes [Eq. (1b)]
is generally limited to terminal alkynes,[8] we believed that our
proposed 5-endo transformation would be favored with
internal alkynes.[6a] This approach would be very useful
synthetically, as the cyclopentenes thus produced could
serve as valuable precursors for the elaboration of more
complex structures.[9]
In a first attempt, the model substrate 10 was treated with
[10]
Ph3PAuNTf2 (1 mol%) in methanol at room temperature.
We observed the stereoselective formation of the desired
cyclopentene 11, which was isolated in 58% yield along with
by-products derived from the direct methoxylation of the
alkyne (Table 1, entry 1).[11] The use of the bulkier and more
By analogy, we surmised that 1,5-enynes, such as 5, might
be valuable precursors of functionalized cyclopentenes (for
example, 7) if a gold-catalyzed 5-endo alkoxycyclization was
feasible [Eq. (2)].[6]
Table 1: Optimization of the catalytic system.[a]
Entry Catalyst
Solvent
t
Yield [%][b]
1
2
Ph3PAuNTf2
Ad2nBuPAuNTf2
MeOH
MeOH
24 h
24 h
58
64
In contrast to the results of Zhang and Kozmin,[3f] who
found that the intramolecular 6-endo alkoxycyclization of
enyne 8 led to the exclusive formation of cyclohexene 9
[Eq. (3)],[7] we anticipated that the substitution pattern of the
alkene in 5 would favor a 5-endo process and that the
presence of the R group might lead to the stereoselective
3
4
MeOH
40 min 98
CH2Cl2/MeOH (10:1) 20 min 99
[a] Reactions were carried out at room temperature with a substrate
concentration of 0.5m. [b] Yield of the isolated product. Ad=adamantyl,
Tf =trifluoromethanesulfonyl, Cy=cyclohexyl.
[*] A. K. Buzas, F. M. Istrate, Dr. F. Gagosz
Laboratoire de Synth›se Organique
UMR 7652 CNRS/Ecole Polytechnique
91128 Palaiseau (France)
[10]
electron rich catalyst Ad2nBuPAuNTf2 did not lead to a
significant improvement in the yield (Table 1, entry 2).
Remarkably, the treatment of 10 with the biphenylphos-
phine-based catalyst 12[12] furnished 11 cleanly and rapidly in
98% yield (Table 1, entry 3). Moreover, the use of a 10:1
mixture of CH2Cl2 and MeOH as the solvent led to an even
faster reaction to form the desired product in very high yield
(Table 1, entry 4). In the light of these preliminary results, the
Fax: (+33)1-6933-3851
E-mail: gagosz@dcso.polytechnique.fr
[**] The authors thank Prof. S. Z. Zard and Dr. I. Hanna for helpful
discussions and Rhodia Chimie Fine for a gift of HNTf2.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 2: Scope of the AuI-catalyzed alkoxycyclization of enyne 10.
10 reacted with a variety of nucleophiles in the presence of the
catalyst 12 (1 mol%) to furnish cyclopentenes 13a–f in
generally high yields (Table 2).
Primary alcohols, secondary alcohols, and phenols were
tolerated in the AuI-catalyzed alkoxycyclization of enyne 10
(Table 2, entries 1–4). Water was also successfully employed
as a nucleophile in this transformation: The use of an 8:2:1
CH2Cl2/acetone/H2O ternary mixture gave the best results,
with the quantitative formation of the tertiary alcohol 13e
(Table 2, entry 5). Interestingly, acetic acid was also compat-
ible with the catalytic system and underwent reaction with 10
to give the acetoxycyclopentene 13 f (Table 2, entry 6).
The transformation is not limited to aryl-substituted
alkynes or trisubstituted alkenes. Vinyl and allyl substituents
on the alkyne were also tolerated: The methoxycyclization of
enynes 14 and 17 led to the formation of the synthetically
valuable 1,3-dienes 25 and 28 in 77 and 78% yield, respec-
tively (Table 3, entries 1 and 4), whereas the reactions of 15
and 18 furnished cyclopentenes 26 and 29 in good yield
(Table 3, entries 2 and 5).
Entry
1
ROH
t
Product
13a
Yield [%][a]
2 h
93
95
2[b]
10 min
13b
3
4
iPrOH
cyclohexanol
H2O
45 min
24 h
4.5 h
13c
13d
13e
13 f
98
54
100
68
5[c]
6
AcOH
75 min
[a] Yield of the isolated product. [b] The reaction was carried out with
2 equivalents of p-MeOC6H4OH. [c] The reaction was carried out in a
CH2Cl2/acetone/H2O mixture (8:2:1).
experimental conditions described in entry 4 of Table 1 were
chosen for the study of this transformation.
We first focused our attention on the variation of the
nucleophile. The reaction proved to be quite general. Enyne
The reaction was also efficient when the alkynes were
substituted with functionalized aryl groups (Table 3,
Table 3: Scope of the AuI-catalyzed hydroxy- and methoxycyclization.[a]
Entry
Substrate
Nucleophile
t
Product
Yield [%][b]
1
2
3
14: R=vinyl
15: R=methallyl
16: R=p-(MeO)C6H4
MeOH
MeOH
MeOH
80 min
24 h
20 min
25
26
27
77 (54)[d]
87 (75)[d]
93 (95)[d]
4
5
6
17: R=vinyl (1:1.5)[c]
18: R=allyl (1:2)[c]
19: R=Ph (1:1.5)[c]
MeOH
MeOH
MeOH
6 h
6 h
1 h
28
29
30
78 (1:1.5)[e]
64 (1:2)[e]
90 (1:1.5)[e]
7
8
19: R=Ph
MeOH
H2O
1 h
1 h
30
31
98 (R’=Me)
94 (R’=H)
9
20: R=p-BrC6H4 (1:2)[c]
MeOH
1 h
32
65 (1:2)[e]
10
11
21
MeOH
H2O
1 h
1 h
33
34
87 (R’=Me)
82 (R’=H)
12[f]
13
22: R=Ph
23: R=p-(MeO)C6H4
MeOH
MeOH
2 h
15 min
35
36
77 (1:1)[e]
87 (2:1)[e]
14
24
MeOH
1 h
37
92
[a] Reaction conditions: 1,5-enyne (0.5m), 12 (1 mol%), CH2Cl2/MeOH (10:1) (or CH2Cl2/acetone/H2O (8:2:1)), room temperature. [b] Yield of the
isolated product. [c] Z/E ratio. [d] Yield when methanol was used as the solvent. [e] Diastereoisomeric ratio. [f] The reaction mixture was heated at
reflux.
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entries 3 and 9). It proved to be highly stereoselective: The
methoxycyclization of a 1:1.5 E/Z diastereoisomeric mixture
of enyne 19 led to the formation of cyclopentene 30 in the
same diastereoisomeric ratio (Table 3, entry 6). The diaste-
reomeric ratio also remained unchanged in the product when
enynes 17, 18, and 20 were used as substrates. The stereospec-
ificity of the reaction was proved through the hydroxy- and
methoxycyclizations of the pure E isomer of 19, which
furnished the cyclopentenes 30 and 31 as single isomers
(Table 3, entries 7 and 8).
carbene 40 in combination with the rapid attack of the
nucleophile on this activated species.
To further highlight the synthetic potential of the cyclo-
pentenes obtained in this study, we took advantage of the
pendant alkene functionalities present in compounds 28 and
29 to perform a subsequent ring-closing metathesis reaction.
Ring-closing metathesis was conducted with the Grubbs II
catalyst (10 mol%) in dichloromethane at reflux [Eq. (4)].
Enyne 21 was also converted into derivatives 33 and 34 in
good yield without concomitant isomerization of the second
alkene functionality (Table 3, entries 10 and 11). Finally, the
methoxycyclization was applied to alcohols 22 and 23, which
were converted into cyclopentenes 35 and 36, respectively, as
mixtures of diastereoisomers (Table 3, entries 12 and 13). No
competitive formation of the bicyclo[3.1.0]hexanone was
observed, thus confirming the rapid nucleophilic attack of
methanol.[13] The introduction of an additional methoxy unit
in 35 and 36 might result from a nonselective gold-catalyzed
substitution of the intermediate acid-sensitive allylic alcohol
by methanol.[14]
To account for all these observations, a mechanism for the
formation of the cyclopentenes is proposed in Scheme 1.
Gold(I) activation of the triple bond in enyne 38 promotes the
We were pleased to observe the rapid consumption of the
substrates and the quantitative formation of the correspond-
ing 5,7- and 5,8-fused bicyclic products 43, 44, and 45. Such
bicyclic motifs are found in many terpenes, two examples of
which are 46 and 47.[9]
In summary, we have developed an efficient stereoselec-
tive gold(I)-catalyzed 5-endo hydroxy- and alkoxycyclization
of 1,5-enynes which provides concise access to functionalized
cyclopentenes. The combination of this cyclization with the
powerful ring-closing metathesis reaction furnishes structures
that are even more complex. Further studies on this new
gold(I)-catalyzed process and its application to the synthesis
of natural products are underway.
Scheme 1. Proposed mechanism.
Experimental Section
General procedure: The catalyst 12 (2.4 mg, 1 mol%) was added to a
solution of the 1,5-enyne (0.25 mmol, 1 equiv) in CH2Cl2/MeOH
(10:1; 0.5m). The resulting mixture was stirred at room temperature
and monitored periodically by TLC. Upon completion of the reaction,
the mixture was evaporated to dryness and eluted through a column
of silica gel to give the methoxycyclization product.
nucleophilic addition of the pendant alkene and leads to the
formation of the stabilized gold carbene intermediate 40. A
subsequent stereoselective attack of the oxygenated nucleo-
phile on this intermediate furnishes the vinyl gold species 41,
which is finally protodemetalated to give cyclopentene 42.[15]
The exclusive formation of cyclopentenes could be attributed
to the substitution pattern of the alkene moiety in 38, which
ultimately results in the regioselective cleavage of the weakest
bond of the cyclopropyl ring in intermediate 40 upon attack
by the oxygenated nucleophile.
The stereoselectivity observed may be explained by
considering the half-chair transition state corresponding to
39, in which the acetoxy group occupies a pseudoequatorial
position. The complete transfer of the stereoinformation from
the cis- or trans-substituted alkene to the final cyclopentene
42 may arise from the configurational stability of the gold
Received: October 9, 2006
Revised: November 2, 2006
Published online: December 13, 2006
À
Keywords: C C coupling · cyclization · cyclopentenes · gold ·
metathesis
.
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Communications
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[7] A single example was reported in which
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a cyclopentene
[8] A single example of the methoxycyclization of a 1,6-enyne in
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[11] For the hydration or alkoxylation of alkynes, see: a) J. H. Teles,
S. Brode, M. Chabanas, Angew. Chem. 1998, 110, 1475 – 1478;
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4747; Angew. Chem. Int. Ed. 2002, 41, 4563 – 4565.
[12] Biphenylphosphine-based catalysts were reported to be superior
for the methoxycyclization of 1,6-enynes; see: S. Lopez, C.
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127, 6178 – 6179.
[13] a) V. Mamane, T. Gress, H. Krause, A. Fꢀrstner, J. Am. Chem.
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[14] An alternative gold-catalyzed propargylic substitution could be
envisaged; see: M. Georgy, V. Boucard, J.-M. Campagne, J. Am.
Chem. Soc. 2005, 127, 14180 – 14181.
[4] See Ref. [2c] and [3i]; see also: C. Nieto-Oberhuber, S. Lopez, M.
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[6] Two 5-endo gold(I)-catalyzed processes have been reported
previously: a) S. T. Staben, J. J. Kennedy-Smith, F. D. Toste,
Angew. Chem. 2004, 116, 5464 – 5466; Angew. Chem. Int. Ed.
[15] This mechanism is supported by deuterium-labeling experiments
(see Supporting Information).
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