Ring Expansions Within the Gold-Catalyzed Cycloisomerization of O-Tethered 1,6-Enynes. Application to the Synthesis of Natural-Product-like Macrocycles

Full text of DOI:10.1002/cctc.201200484

DOI: 10.1002/cctc.201200484
Ring Expansions Within the Gold-Catalyzed Cycloisomerization of O-
Tethered 1,6-Enynes. Application to the Synthesis of Natural-Product-like
Macrocycles
Antoine Simonneau, Youssef Harrak, Louis Jeanne-Julien, Gilles Lemiꢀre, Virginie Mouriꢀs-Mansuy, Jean-
Philippe Goddard, Max Malacria, and Louis Fensterbank*[a]
Cycloisomerization reactions of enynes by using electrophilic
late-transition-metal salts have attracted intensive research
effort since the pioneering works of Trost et al. almost 30 years
ago.[1,2] In this field, a lot of metal complexes have been identi-
fied to efficiently catalyze cycloisomerizations of enynes, fea-
turing also skeletal rearrangements, the most commonly used
of which are undoubtedly platinum and gold salts.[3] Indeed,
since the discovery in the early 2000s that stable cationic com-
plexes of gold(I) could efficiently promote these latter process-
es at room temperature,[4] many research groups have added
their own contributions to this topic.[5] Thus, new reaction
Scheme 1. Mechanisms for the ring expansion.
pathways, as well as new synthetic applications, have bloomed
in the literature,[6] at the same time illustrating both the versa-
tility of this process and its high “substrate dependence”.
Herein, as a continuation of our previous work on enynes,[7] we
report some results that we have gathered during our explora-
tion of the reactivity of oxygen-tethered 1,6-enynes under gold
catalysis, accompanied by a practical two-steps synthetic pro-
cedure that allows the transformation of the cyclization com-
pounds into macrolactones.
We wondered if the introduction of a strained ring at the
unsubstituted 3 position could give rise to ring expansion by
classic Wagner–Meerwein transposition onto the transition-
metal-stabilized carbocation that originates from the cycliza-
tion pathway (Scheme 1, bottom). Gold has been shown to
effect ring expansions in various reactions.[12] Several examples
have been reported in the context of enyne cycloisomeriza-
tions,[9b,13] some of which have led to useful synthetic applica-
tions.[14] Thus, we synthesized model compound 1a and as-
sessed the activity of various catalysts to test our hypothesis
(Table 1).
It is commonly accepted that the cycloisomerization of
enynes by using carbophilic Lewis acids is initiated by the acti-
vation of the alkyne partner.[8] Depletion of the electronic den-
sity of the triple bond triggers a nucleophilic attack from the
neighboring alkene, which can follow an endo or exo mode of
cyclization. Whereas 1,5-enynes react exclusively through the
endo route,[7b–c,9] 1,6-enynes offer various cycloisomerization
patterns. The cyclization mode is essentially dictated by stereo-
electronic factors that bias the reactivity of an enyne substrate
toward one pathway or the other. For example, heteroatom-
tethered 1,6-enynes will prefer an endo cyclization pathway,
thereby leading to bicylo[4.1.0]heptene skeletons, through key
transition-metal-stabilized cation I[10] (which can also be seen
as a carbene[11]). This latter structure then undergoes a 1,2-hy-
dride shift from the 3 position, thereby allowing the release of
the cyclized compound (Scheme 1, top).
Platinum(II)–chloride and platinum(IV)–chloride salts were
completely inactive, even after prolonged heating (Table 1, en-
Table 1. Catalyst optimization.
Entry Catalyst
Loading
[mol%] [8C]
T
Solvent
t
[h]
Product Yield
[%]
1
2
3
4[a]
5
6
7
8
9
PtCl2
PtCl4
AuCl
AuCl3
[Ph3PAuCl]/AgSbF6
[Ph3PAuCl]/AgNTf2
[(tBu)3PAuCl]/AgSbF6
[L1Au(MeCN)]SbF6
[L2AuCl]/AgSbF6
5
5
2
2
2
2
2
2
2
5
reflux toluene 15
1a
1a
1a
3a
2a
2a
2a
2a
2a
1a
80
RT
RT
RT
RT
RT
RT
RT
toluene
5
CH2Cl2 27
CH2Cl2 27
CH2Cl2 0.5
CH2Cl2 0.5
CH2Cl2 1.5
CH2Cl2 1.5
CH2Cl2 1.5
33
50
49
75
84
85
[a] Dr. A. Simonneau, Dr. Y. Harrak, L. Jeanne-Julien, Dr. G. Lemiꢀre,
Dr. V. Mouriꢀs-Mansuy, Dr. J.-P. Goddard, Prof. Dr. M. Malacria,
Prof. Dr. L. Fensterbank
[b]
[b]
Institut Parisien de Chimie Molꢁculaire (UMR CNRS 7201)
UPMC Univ Paris 06, Sorbonne Universitꢁ
4 place Jussieu, C. 229, 75005 Paris (France)
Fax: (+33)144273078
10
[(IrCp*Cl2)2]
reflux DCE
[a] Compound 3a was obtained with the starting material.
[b]
E-mail: louis.fensterbank@upmc.fr
Supporting information (full experimental details and spectra) for this
article is available on the WWW under http://dx.doi.org/10.1002/
cctc.201200484.
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tries 1 and 2). Gold(I)–chloride
and gold(III)–chloride salts also
did not furnish any cyclized
compounds (Table 1, entries 3
and 4); AuCl3 gave consequent
amounts of elimination product
3a. When we switched to cat-
ionic gold(I) catalysts, we were
pleased to obtain the desired
compound (2a). The PPh3 ligand
led to moderate yields, inde-
pendent of the counteranion
(Table 1, entries 5 and 6). How-
ever, the use of the bulky donor
ligand P(tBu)3 improved the
yield to 75% (Table 1, entry 7).
Thus, we decided to try cationic
gold(I) catalysts with hindered,
strongly donating ligands and
we found that phosphine L1
(Table 1, entry 8) or NHC L2
(Table 1, entry 9) were ideal li-
gands for this cycloisomerization
reaction: the desired compound
was isolated in 84% and 85%
yield, respectively. We also in-
vestigated the activity of an IrIII
dimer complex that has been re-
cently shown to be active in
some enyne-cycloisomerization
processes,[15] but, even after pro-
longed heating in 1,2-dichloro-
ethane (DCE), the starting mate-
Table 2. Gold-catalyzed reactions of O-tethered 1,6-enynes 1b–1p.
Entry
Substrate
Catalyst[a]
t
[h]
Product(s)
Yield
[%]
1
2
2
4
5
6
1b
1c
1d
1e
1 f
R1 =R2 =H
A
B
B
B
B
B
1
14
1.25
14
1.5
1
2b, 4b
2c
2d
2e
2 f
65, 18
R1 =Ph, R2 =H
R1 =Ph, R2 =Me
R1 =iPr, R2 =H
R1 =a,[e] R2 =H
R1 =CO2Et, R2 =H
76
>98
55
62
97 (8:2)[b]
1g
4g, 5g
7
8
9
10
1h
1i
1j
R2 =R3 =R4 =H
B
B
B
B
2
2
18
2
2h
2i
2j
82
81
37
12[c]
R2 =R4 =H, R3 =Ph
R2 =Me, R3 =R4 =H
R2 =H, R3 =R4 =Me
1k
2k
11
12
13
14
1l
1m
1n
1o
R1 =b,[e] R2 =H
R1 =nBu, R2 =H
R1 =nBu, R2 =Me
R1 =Ph, R2 =H
A
A
A
A
4
17
6
2l
2m
2n
2o
81
70
85
15
17
[d]
15
1p
48
2p
52
[a] A=[L1Au(MeCN)]SbF6, B=[L2AuCl]/AgSbF6. [b] Inseparable mixture. [c] Formation of the corresponding
allene was observed. [d] [(2,4-tBuPhO)3PAuCl/AgSbF6] was used as the catalyst. [e]
rial was fully recovered (Table 1, entry 10).
With these optimized conditions in hand (Table 1, entries 8
and 9), we examined the scope and limitations of the ring-ex-
pansion reaction (Table 2). First, we started our study with five-
membered-ring precursors. The treatment of enyne 1b with
catalyst A afforded a mixture of the expected ring-expansion
product (2b) in 65% yield, as well as compound 4b, which ori-
ginated from a 5-exo-dig process, in 18% yield.[5] The selectivity
and yield of the reaction were improved by the introduction of
a phenyl group onto the terminal alkyne by using catalyst B.
Only ring-expansion product 2c was obtained in 76% yield
(Table 2, entry 2). When the double bond was substituted by
a methyl group, compound 2d was obtained in quantitative
yield (Table 2, entry 3). Substitution of the alkyne by isopropyl
or vinyl groups in the presence of catalyst B led to the ring-ex-
pansion compounds in similarly moderate yields (Table 2, en-
tries 4 and 5). When ester-substituted compound 1g was sub-
mitted to the same catalytic system, an inseparable mixture of
products 4g and 5g was obtained in a good yield (97%, 80:20
ratio). Acetylenic–cyclopropyl-substituted substrates 1h–1j af-
forded very good yields of the expected ring-expansion prod-
ucts (Table 2, entries 7 and 8). The expected stereochemistry of
compound 2i was confirmed by X-ray diffraction (Figure 1). In
contrast, when the double bond was substituted by a Me
group at the R2 position, a low yield of product 2j (37%) was
obtained (Table 2, entry 9). Moreover, when a prenyl group
was present (Table 2, entries 10), a very low yield of the ring-
1
expansion product was obtained. Indeed, in the H NMR spec-
trum of the crude product, we noticed the presence of an al-
dehyde signal, as well as large amounts of a volatile allenic
compound, which was confirmed by 13C NMR spectroscopy
with a signal at d=200 ppm. In this case, a competitive 1,5-hy-
dride shift onto the activated triple bond occurred, as reported
by Gagosz and co-workers[16] and ourselves.[7e]
Figure 1. X-ray crystal structure of compound 2i (CCDC-887772).
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Next, we switched our attention to four-membered-ring de-
rivatives. Substrates 1l–1n led to ring-expansion products 2l–
2n in good yields with catalyst B (Table 2, entries 11–13). In
the case of compound 1o, a very low yield (15%) was ob-
tained (Table 2, entry 14). Indeed, this product seemed to be
more unstable than its homologue (2c; Table 2, entry 2) and
decomposed in a few hours as a solution in CDCl3.
Finally, compound 1p, bearing an acetate group on the cy-
clobutane moiety, was reacted with catalysts A and B but only
the corresponding allene was isolated in quantitative yield in
each case. To avoid this undesired reactivity, we used the
more-electrophilic catalyst [(2,4-tBuPhO)3PAuCl/AgSbF6], which
was reported by Gagosz and co-workers to be inefficient at
promoting 1,5-hydride shifts.[16] Thus, the desired ring-expan-
sion product (2p) was obtained in 52% yield (Table 2,
entry 15), albeit with a non-negligible amount of allene
byproduct.
Scheme 3. Oxidative cleavage of enol ether 2.
Next, we were interested in developing a two-step synthetic
sequence for the synthesis of medium-sized-ringed lactones
from products 2,[7d] first by oxidation of the enol–ether func-
tion and then by opening of the cyclopropane moiety. Such
a synthetic sequence could provide access to macrocyclic skel-
etons that are reminiscent of natural products (Scheme 2).[17]
Scheme 2. Strategy for the synthesis of macrolactones.
First, the oxidative cleavage of enol-ether 2a was performed
in fair yield (about 60%) by using either pyridinium chlorochro-
mate (PCC) or Ru complexes in combination with NaIO4, there-
by giving macrolactone 6a (Scheme 3). By using Ru-complex
conditions, we were able to obtain macrolactones 6c and 6l in
59% and 68% yield, respectively.
Scheme 4. Synthesis of various macrolactones.
onitrile (AIBN)[20] and successfully obtained the desired macro-
cycle 8a in 65% yield, albeit with incomplete conversion of
the starting material (Scheme 4). Then, we extended this syn-
thetic sequence to cyclized compounds 6c and 6l and we ob-
tained their expected corresponding deca- and undeca-5-keto-
lactones (8c and 8l) in moderate yields (50 and 57%, respec-
tively; Scheme 4).
To promote the cyclopropane-opening step, we naturally
considered homolytic methods, given the fact that a ketone
was present at the a position of this strained moiety
(Scheme 4).
Because photochemical conditions[18] were completely ineffi-
cient, we submitted compound 6a to a 2:1 SmI2/hexamethyl-
phosphoramide (HMPA) mixture[19] and obtained carboxylic
acid 7a. Although the cyclopropane was clearly opened, com-
pound 7a was not the expected product and presumably
arose from a reduction of the secondary radical generated
after cyclopropane opening, thereby leading to the elimination
of the carboxylate group. We expected that this undesired
step could be avoided if a hydrogen donor was present in the
reaction mixture. Thus, we switched to Bu3SnH/azobisisobutyr-
In conclusion, we have reported the gold-catalyzed cycloiso-
merization of O-tethered 1,6-enynes, which featured a small-
sized ring expansion. Thus, we obtained fused tricyclic com-
pounds that contained a substituted dihydropyrane moiety. In
this study, we found that bulky donor ligands on the cationic
gold(I) center were necessary to efficiently promote this cycloi-
somerization process. Skeletal reorganization with no ring ex-
pansion can become competitive and can completely prevail
when hydrogen or electron-withdrawing groups are placed at
the acetylenic position. Finally, we have developed a two-step
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synthetic sequence that allows the conversion of these cy-
clized compounds into valuable macrocycles that are reminis-
cent of natural products; we are currently working on the ap-
plication of this sequence to the synthesis of natural products.
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Acknowledgements
The authors thank the UPMC, the CNRS, ANR Blan 0302 “Allenes”
(postdoctoral grant to Y.H.), the MRES (PhD grants to A.S. and
G.L.), the IUF (L.F. and M.M.), and FR2769 for technical support.
Keywords: cycloisomerization
reactions · ring expansion
· enynes · gold · radical
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Received: July 18, 2012
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COMMUNICATIONS
A. Simonneau, Y. Harrak, L. Jeanne-Julien,
G. Lemiꢀre, V. Mouriꢀs-Mansuy,
J.-P. Goddard, M. Malacria,
L. Fensterbank*
&& – &&
Ring Expansions Within the Gold-
Catalyzed Cycloisomerization of O-
Tethered 1,6-Enynes. Application to
the Synthesis of Natural-Product-like
Macrocycles
Goldenyne: O-tethered 1,6-enynes that
contain a strained ring at the 3 position
can cycloisomerize upon cationic gold(I)
catalysis through a ring-expansion pro-
cess. A two-step sequence allows the
transformation of the cyclized com-
pounds into ketomacrolactones, which
are reminiscent of natural products.
ChemCatChem 0000, 00, 1 – 4
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemcatchem.org
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