Prins cyclizations in Au-catalyzed reactions of enynes

Article abstract of DOI:10.1002/anie.200601575

Going for gold: Au^I-catalyzed cyclizations of functionalized enynes lead to the ready assembly of tricyclic carbon skeletons that are present in a number of naturally occurring compounds. An alkenyl gold intermediate is formed in the cyclizatio

Full text of DOI:10.1002/anie.200601575

Communications
Cyclization
DOI: 10.1002/anie.200601575
Prins Cyclizations in Au-Catalyzed Reactions of
Enynes**
Eloísa JimØnez-Nfflæez, Christelle K. Claverie,
Cristina Nieto-Oberhuber, and Antonio M. Echavarren*
The hydroxy- or alkoxycyclization of enynes I catalyzed by
electrophilic transition-metal complexes usually takes place
through cyclopropyl metal carbenes II, which react with
nucleophiles R’OH to give intermediates III (Scheme 1). The
reaction is then terminated by proto-demetalation of the
alkenyl metal intermediate III to give IV.[1,2]
Scheme 2. Representative sesquiterpenes with skeletons accessible by
Au-catalyzed cyclizations.
Table 1: AuI-catalyzed reaction of enynes 1a–d.[a]
Entry Enyne [Au]
2/2’
Yield [%] 2/2’
3
Yield [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
1d
A
B
C
2a
2a
2a
35
36
29
58
>50:1 3a 50
>50:1 3a 34
>50:1 3a 50
>50:1 3a 18
AuCl 2a
A
B
C
2b/2b’ 65
2b
2b
2.3:1 3b
9
47
47
79
>50:1 3b 44
>50:1 3b 52
>50:1 3b 10
3.4:1 3c 22
>50:1 3c 45
26:1 3c 39
>50:1 3c 12
3d 77
Scheme 1. Different evolution of intermediate III by proto-demetalation
of the Prinsreaction with oxonium cationsvia V or VI.
AuCl 2b
A
B
C
2c/2c’ 64
2c 49
2c/2c’ 44
We have now found that in the AuI-catalyzed cyclization
of enynes[3,4] the alkenyl metal intermediate can be trapped
with appropriate substituents, as shown in Vand VI in a Prins
cyclization. These new cyclizations allow the one-step syn-
thesis of tricyclic skeletons, such as those of b-kessyl ketone[5a]
and orientalol E (Scheme 2),[5b] from enynes with carbonyl
groups and octahydrocyclobuta[a]pentalenes, such as fasci-
cularone B,[6] kelsoene,[7] and sulcatine G,[8] starting from
cyclopropyl enynes.
AuCl 2c
C
84
–
–
[a] Reactionsat 23 8C with 3 mol% catalyst for 5–30 min (100%
conversion). A: [Au(PPh3)Cl]/AgSbF6, B: [Au(PPh3)(MeCN)]SbF6,
Enynes 1a–c, bearing a carbonyl group at the alkenyl side
chain, are cyclized to give oxatricyclic derivatives 2a–c and
rearranged ketones 3a–c by using AuI catalysts (Table 1). The
reactions were completed at room temperature in 5–30 min.
Aldehyde 1a gave a mixture of tricycle 2a (35%) and ketone
3a (50%) with [AuCl(PPh3)]/AgSbF6 (catalyst A; Table 1,
entry 1). Similar results were obtained with [Au(PPh3)-
(MeCN)]SbF6 (catalyst B) and cationic complex C[3]
(Table 1, entries 2 and 3). A yield of 58% for 2a was achieved
by using AuCl itself (Table 1, entry 4). In the cyclization of
ketones 1b and 1c, 2’b,c were obtained as minor isomers,
although their formation could be minimized by using AuI
catalysts B or C (Table 1, entries 6/7 and 10/11). Results with
catalysts A and B were not identical (compare entries 5/6 and
9/10), which suggest that AgI may not be innocent in some of
these cyclizations.[9] The best yields of 2b–c were achieved
with AuCl (Table 1, entries 8 and 12). Substrate 1d led only to
ketone 3d (77%; Table 1, entry 13).
[*] E. JimØnez-Nfflæez, Dr. C. K. Claverie, C. Nieto-Oberhuber,
Prof. Dr. A. M. Echavarren
Institut Catalµ d’Investigació Química (ICIQ)
Av. Països Catalans 16
43007 Tarragona (Spain)
Fax: (+34)977-920-218
E-mail: aechavarren@iciq.es
[**] We thank the MEC (project CTQ2004-02869 and predoctoral
fellowships to E.J.-N. and C.N.-O.), the AGAUR (postdoctoral
fellowship to C.K.C.), and the ICIQ Foundation for financial support.
We also thank J. Benet-Buchholz (ICIQ) for the X-ray structures of 2c
and 5.
Supporting information for thisarticle isavailable on the WWW
under http://www.angewandte.org or from the author.
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The structures of 2a–d were assigned by NMR spectro-
scopic analysis and by the X-ray diffraction determination of
2c.[10] The cis configuration of ketones 3a–d was based on the
coupling constant 3J = 11.6 Hz, as observed for 3a and in
NOESY experiments.
The carbonyl group acts as an internal nucleophile in the
cyclizations of Table 1, as shown in VII (Scheme 3), thus
Scheme 4. Gold-catalyzed reactionsof epoxides 4a,b. Ts=p-toluene-
methanesulfonate.
Scheme 3. Proposed mechanism for the cyclization of enynes 1a–c.
forming oxonium cation VIII, which undergoes a Prins
reaction[11] to give IX. Intermediate IX is a substituted 4-
tetrahydropyranyl cation, which has been shown to be
aromatic.[12] Elimination of the metal fragment forms tricycles
2a–c. Alternatively, an elimination with fragmentation of the
seven-membered ring via X leads to carbonyl compounds 3a–
d. Minor epimers 2’b,c can arise by a competitive 2-oxonia–
Cope rearrangement[13] via X and XI.
Table 2: AuI-catalyzed reaction of enynes 6a–d.[a]
The higher selectivity for the formation of tricycles 2a–c
using AuCl as the catalyst (Table 1, entries 4, 8, and 12),
relative to the cationic complexes A–C could be explained by
the faster elimination of the more electron-rich metal center
in IX, whereas for complexes A–C the metal center does not
bear a negative charge in intermediates VIII–XI.
Interestingly, 2c was also obtained from epoxide 4a by
using catalyst B (Scheme 4).[14] On the other hand, the
reaction of 4a with catalyst A gave a mixture of 2c/2’c and
oxonorbornane 5, whose structure was confirmed by X-ray
crystallography.[10] Epoxide 4b reacted with catalyst C to give
ketone 3d, a result similar to that from 1d (Table 1, entry 13).
The formation of 2c and 3c,d could proceed through
Entry
Enyne
[Au]
t
Product (ratio)
Yield [%]
1[a]
6a
6a
6a
6a
6b
6b
6c
6c
6d
C
C
C
AuCl
C
C
C
AuCl
B
5 min
5 min
5 min
24 h
5 min
5 min
5 min
2 h
7a/7’a (1:1)
7a/7’a (1:8)
7a/7’a (1:1)
7a/7’a (30:1)[e]
7’b
7b/7’b (2.5:1)
7c/7’c (3.2:1)
7c/7’c (12:1)
7d/7’d (2:1)
88
81
93
80[e]
44
39
60
91
60
2[b]
3[b,c]
4[b,d]
5[a,f]
6[b,f]
7[b,g]
8[b,h,d]
9[b,g]
5 min
[a] Reaction carried out in CH2Cl2 (H2Oꢁ2 ppm) with 3 mol% catalyst at
238C. [b] Reaction with 3–5 mol% water. [c] Reaction with NH4Cl
(2 equiv). [d] Reaction at 08C. [e] Average of five runsand determined
1
by H NMR spectroscopic analysis. [f] E/Z=1:1. [g] Catalyst=2 mol%.
ꢀ
intermediates XII, which suffer C O bond cleavage followed
[h] Catalyst=12 mol%.
by a 1,2-hydrogen shift to form VIII (R = iPr). Model
epoxides do not isomerize to the corresponding carbonyl
compounds under these reaction conditions.[15] We did not
observed the direct addition of the ketone or the epoxide to
the alkyne in any of these cyclizations.[16]
water, whereas the use of AuCl led to the formation of 7a,
although the reaction was relatively slow (Table 2, entries 2
and 4). Low conversions (ca. 20%) were obtained when this
reaction was carried out in the presence of 4-Š molecular
sieves. Cycloprolylenynes 6b–d reacted to give tricycles 7b–d
(Table 2, entries 5–9). Cyclobutanones were also formed as
minor side products in these reactions.[20,21]
A related Prins cyclization, which leads to tricycles with
an octahydrocyclobuta[a]pentalene skeleton (see Scheme 2),
was uncovered in the cyclization of cyclopropylenynes 6a–
d
[17–19] (Table 2). Thus, the reaction of ethyl ether 6a with AuI
gave tricycles 7a/7’a (Table 2, entries 1–3). Interestingly, syn-
7’a was favored with catalyst C in the presence of traces of
A rationale for the results of Table 2 is provided in
Scheme 5. Accordingly, XIII forms cyclopropyl metal carbene
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Communications
single step. The transformation of 1a–d into ketones 3a–d
represents a new type of skeletal rearrangement of enynes.
Received: April 21, 2006
Published online: July 19, 2006
Keywords: cyclization · enynes· gold · Prinsreaction ·
.
rearrangements
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Scheme 5. Proposed mechanism for the gold-catalyzed reaction of
enynes 6a–d.
XIV, which undergoes ring expansion to form XV. The
alkenyl gold complex of XV could react with the oxonium
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7a–d by a Prins reaction.[11] The concerted pathway (XIV!
XV) is favored with AuCl as the catalyst, whereas cationic AuI
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non-stereospecific ring expansion to give mixtures of 7a–d/
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to form XV’.
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with the Furukawa reagent[24] (ꢀ65!238C; Scheme 6). This
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ꢀ
dig Prins reactions to form an additional C C bond. These
AuI-catalyzed cyclizations of functionalized enynes led to the
ready assemblage of tricyclic carbon skeletons that are
present in a number of naturally occurring compounds.
Thus, for example, tricycle 2c, which possesses the same
skeleton and relative configuration of b-kessyl ketone and
orientalol E (Scheme 2), can be obtained in high yield in a
[9] For an example in which AgI catalyzes an additional process, see:
C. Nevado, A. M. Echavarren, Chem. Eur. J. 2005, 11, 3155 –
3164.
[10] See the Supporting Information for details.
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ring expansion of the cyclopropyl ring; details will be published
in a full account of these results.
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[23] Preliminary DFT calculations show a carbocationic structure for
intermediates in which [Au(L)] = [Au(PH3)], whereas for
[Au(L)] = [AuCl]ꢀ the intermediates resemble cyclopropyl
gold(I) carbenes, such as XIV: D. J. Cµrdenas, unpublished
results.
[24] J. Furukawa, N. Kawabata, J. Nishimura, Tetrahedron 1968, 24,
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