α,β-Unsaturated Gold(I) Carbenes by Tandem Cyclization and 1,5-Alkoxy Migration of 1,6-Enynes: Mechanisms and Applications

Article abstract of DOI:10.1002/chem.201602347

1,6-Enynes bearing OR groups at the propargyl position generate α,β-unsaturated gold(I)-carbenes/ gold(I) stabilized allyl cations that can be trapped by alkenes to form cyclopropanes or 1,3-diketones to give products of α-alkylation. The best migrating group is p-nitrophenyl ether, which leads to the corresponding products without racemization. Thus, an improved formal synthesis of (+)-schisanwilsonene A has been accomplished. The different competitive reaction pathways have been delineated computationally.

Full text of DOI:10.1002/chem.201602347

DOI: 10.1002/chem.201602347
Full Paper
&
Au-Catalyzed Reactions
a,b-Unsaturated Gold(I) Carbenes by Tandem Cyclization and 1,5-
Alkoxy Migration of 1,6-Enynes: Mechanisms and Applications
Pilar Calleja,[a] ꢀscar Pablo,[a] Beatrice Ranieri,[a] Morgane Gaydou,[a] Anthony Pitaval,[a]
Marꢁa Moreno,[a] Mihai Raducan,[a] and Antonio M. Echavarren*[a, b]
Abstract: 1,6-Enynes bearing OR groups at the propargyl
position generate a,b-unsaturated gold(I)-carbenes/ gold(I)
stabilized allyl cations that can be trapped by alkenes to
form cyclopropanes or 1,3-diketones to give products of a-
alkylation. The best migrating group is p-nitrophenyl ether,
which leads to the corresponding products without racemi-
zation. Thus, an improved formal synthesis of (+)-schisanwil-
sonene A has been accomplished. The different competitive
reaction pathways have been delineated computationally.
Introduction
The study of gold(I)-catalyzed reactions of 1,n-enynes has led
to the discovery of a wealth of cyclization modes, including
mechanistically intriguing skeletal rearrangements and nucleo-
philic addition reactions to cycloaddition processes.[1] In this
context, we recently found that 1,6-enynes such as 1 bearing
propargyl alcohols, ethers, or silyl ethers react with gold(I) cat-
alysts through the usual type of highly delocalized cyclopropyl
gold(I) intermediates 2,[2] which then undergo a new type of
1,5-migration of the OR groups to generate species 3[3] that we
postulated as intermediate between a,b-unsaturated gold(I)
carbenes and gold(I)-stabilized allyl cations.[2,4] In the presence
of carbon nucleophiles such as indole or furans, products 4[3]
or trienes such as 5[5] were obtained by Friedel–Crafts-type re-
actions (Scheme 1). Intermediates 3 can also react with elec-
tron-rich alkenes to form the corresponding cyclopropanes,[3]
a reaction which is also characteristic of gold(I) carbenes 2.[6–8]
We demonstrated the potential of this tandem cyclization/1,5-
OR migration/cyclopropanation to form products 6 that were
key intermediates in the first total synthesis of the natural ses-
quiterpene (+)-schisanwilsonene A (7).[9]
Scheme 1. Intermolecular trapping of the intermediates of the gold-cata-
lyzed cyclization/1,5-OR migration of enynes 1.
This type of gold(I)-catalyzed 1,5-migration has been found
to compete[10] with 1,2- and 1,3-migrations of propargylic car-
boxylate groups.[10] Related processes have been found in the
gold(I)-catalyzed reactions of dienynes 8, which undergo cycli-
zation/1,5-OR
migration/intramolecular
cyclopropanation
through intermediates 9 to form stereoselectively hexahydroa-
zulenes 10,[3] which were the key intermediates in our total
synthesis of the sesquiterpernes (À)-epiglobulol (11) and (À)-
4b,7a-aromadendranediol (12) (Scheme 2).[11] Alternatively,
when the gold(I)-catalyzed reaction was performed in the pres-
ence of allyl alcohol, this external nucleophile reacted to give
9’, which underwent intramolecular cyclopropanation to give
rise to the sesquiterpene (À)-4a,7a-aromadendranediol (13).[11]
The proposed mechanism for these inter- and intramolecular
reactions was based on the isolation of diverse products but
not on a rigorous study of this intriguing process and its sever-
al possible competitive cycloisomerization pathways. Further-
[a] P. Calleja, Dr. ꢀ. Pablo, Dr. B. Ranieri, M. Gaydou, A. Pitaval, Dr. M. Moreno,
M. Raducan, Prof. A. M. Echavarren
Institute of Chemical Research of Catalonia (ICIQ)
Barcelona Institut of Science and Technology (BIST)
Av. Pa¨ısos Catalans 16, 43007 Tarragona (Spain)
E-mail: aechavarren@iciq.es
[b] Prof. A. M. Echavarren
Departament de Quꢁmica Analꢁtica i Quꢁmica Orgꢂnica
Universitat Rovira i Virgili, C/ Marcel·li Domingo s/n
43007 Tarragona (Spain)
Supporting information for this article and ORCID for one of the authors
can be found under:
http://dx.doi.org/10.1002/chem.201602347.
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as the ligand (Table 1, entries 8 and 9). The best results were
obtained using the less electrophilic catalysts D–G with more
donating NHC ligands (Table 1, entries 10–13), which have
been proposed to enhance the carbene-like character of the
intermediates in gold(I)-catalyzed reactions.[1g,h]
Table 1. Gold(I)-catalyzed reaction of enynes 1a–g with 1,3-diphenyl-1,3-
propandione.
Scheme 2. Intramolecular trapping of the intermediates of the gold-cata-
lyzed cyclization/1,5-OR migration of dienynes 8.
more, although the chirality transfer in the intramolecular pro-
cesses was satisfactory, partial racemization was observed in
the formation of intermediates 2 when RO=AcO, which led to
(+)-schisanwilsonene A (7) with 9:1 e.r. Here we report that
1,3-dicarbonyl compounds can also be used as the C-nucleo-
philes to trap the putative a,b-unsaturated gold(I) carbenes 3
leading to products of formal alkylation. This and additional
studies on the intermolecular trapping of intermediates 3 with
alkenes have allowed selecting p-nitrophenyl ether as the pro-
tecting group of choice in these reactions. This led us to devel-
op an improved formal synthesis of (+)-schisanwilsonene A (7)
in which the key step proceeds with total retention of configu-
ration. We have also found cases in which a skeletal rearrange-
ment takes place preferentially to form six-membered ring
compounds. A detailed computational study has been per-
formed to understand the mechanisms of these complex trans-
formations.
Entry
[AuLL’]X
1a–g
14a–g
(yield) [%]
1
2
3
4
5
6
7
8[a]
9[a]
10
11
12
13
A
A
A
A
A
A
A
B
C
D
E
1a
1b
1c
1d
1e
1 f
1g
1a
1a
1a
1a
1a
1a
14a (58)
14b (14)
14c (18)
14d (14)
14e (44)
14 f (À)
14g (À)
14a (8)
14a (8)
14a (67)
14a (67)
14a (62)
14a (71)
F
G
[a]=70–75 min
Results and Discussion
Selection of the best OR migration group
1,3-Dicarbonyl compounds react as C-nucleophiles with 1,6-
enynes in the presence of gold(I) catalysts by formal attack at
the alkene via opening of the cyclopropane of intermediates
of type 2.[1h] We therefore decided to examine whether enynes
1 would react with this type of nucleophiles at the alkene,
through intermediates 2, or at the terminal alkyne carbon
through intermediates 3. In the event, reaction of enynes
1 with 1,3-diphenyl-1,3-propandione in the presence of gold(I)
complexes gave products of a-alkylation of the dicarbonyl
compounds 14 by trapping of intermediates 3 at C-1 (Table 1).
Using catalyst [(JohnPhos)Au(NCMe)]SbF6 (A), the best migrat-
ing group proved to be p-nitrophenyl (PNP) ether in substrate
1a, which led to adduct 14a in 58% yield after 30 min at 248C
(Table 1, entry 1). p-Anisyl ether derivative 1e gave 14e in
a moderate 44% yield (Table 1, entry 5), whereas lower yields
(14–18%) were obtained with the free alcohol 1b, methyl
ether 1c, and acetate 1d, and benzyl ethers 1 f,g failed to give
any of the expected products 14 f,g (Table 1, entries 2–7). Poor
results were obtained with catalysts B and C bearing tBuXphos
1,6-Enyne 1a reacted smoothly with other 1,3-dicarbonyl
compounds and b-ketoesters as the C-nucleophiles using the
optimal IPr gold(I) complex G to form adducts 14h–n in 59–
82% yield in 30 min at 248C (Table 2).
p-Nitrophenyl ether 1a was also the substrate of choice for
the cyclization/1,5-OR migration/intermolecular cyclopropana-
tion with cyclohexene and norbornene to form cyclopropanes
15a,b in satisfactory yields as mixtures of exo and endo diaste-
reomers by using catalyst A under very mild conditions
(Scheme 3). Dihydropyrane reacted similarly to give 14c, al-
though in this case catalyst D gave better results. Indene, ben-
zofuran, 5-bromobenzofuran, and benzothiophene gave the
corresponding adducts 15d–g more stereoselectively. The con-
figuration of the mayor product 15g in the reaction with ben-
zothiophene was assigned by X-ray diffraction.[12] This product
was formed in lower yield most likely as a consequence of the
inhibition of the catalytic reaction by coordination of gold(I) to
the thioether 15g. Interestingly, in the last three cases, the
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Table 2. Products of the reaction of 1,6-enyne 1a with 1,3-dicarbonyl
compounds and b-ketoesters in the presence of catalyst
G (248C,
30 min).
Scheme 4. First-generation synthesis of (+)-schisanwilsonene A (7) via cycli-
zation/1,5-OR migration/cyclopropanation.[9]
This partial racemization was explained as a result of a 1,2-acy-
loxy rearrangement competing as a minor pathway.[9]
Although the formation of enantioenriched 6b allowed us
to complete the first total synthesis of (+)-schisanwilsonene A
(7) via hexahydroazulene diol 16a (90:10 e.r.) (Scheme 4),
a better solution has now been found by using enantioen-
riched 1a as the substrate for the cyclization/1,5-OR migration/
cyclopropanation cascade. Thus, alcohol 1b was protected as
the PNP ether by nucleophilic aromatic substitution of its po-
tassium salt with p-fluoronitrobenzene and 18-crown-6 to give
1a with full retention of the configuration (94.5:5.5 e.r.)
(Scheme 5). The key gold(I)-catalyzed reaction of 1a with the
bis-TBS ether of 2-methylenepropane-1,3-diol, followed by de-
silylation with TBAF, provided diol 6c in 68% yield without de-
tectable racemization, within experimental error (94:6 e.r.). The
configuration of 6c was determined by X-ray diffraction.[12] This
result demonstrates that the enyne cyclization/1,5-OR migra-
tion/cyclopropanation cascade takes place without any racemi-
zation, which excludes the involvement of a propargyl carbo-
cation as an intermediate in the process. In the racemic series,
6c has been converted into hexahydroazulene diol 16a ac-
cording to the original sequence followed by a two-setp de-
protection of the PNP group (76% yield).[13]
Scheme 3. Gold(I)-catalyzed cyclization/1,5-OR migration/intermolecular cy-
clopropanation of 1a.
electron-rich heterocycles undergo cyclopropanation, which is
in contrast to what we observed previously for indole, which
gave product 4 after formal alkylation at C-3 (Scheme 1).[3]
Exceptions to the rule: no migration of the propargyl group
We also tried the reaction of 1,6-enynes 17a,b with a propar-
gylic amine (Scheme 6). In the case of 17a, the electron-rich p-
methoxyphenyl amine undergoes a gold(I)-catalyzed intramo-
lecular hydroarylation with the terminal alkyne[14] to give dihy-
droquinoline 18, whereas PNP derivative 17b afforded 7-meth-
ylene-2-azabicyclo[2.2.1]heptane 19 as the major product,
whose structure was determined by X-ray diffraction.[12]
A second-generation formal synthesis of (+)-schisanwilso-
nene A
The gold(I)-catalyzed reaction of racemic 1a with the bis-TBS
ether of 2-methylenepropane-1,3-diol gave 6a in good yield as
a single diasteromer (Scheme 4).[9] Enantioenriched acetate 1d
(96:4 e.r.) reacted in slightly lower yield to afford 6b in 91:9 e.r.
We had reported that 1,6-enyne 20a reacts with methanol
in the presence of catalyst A to give stereoselectively adduct
21 in which the migration of the benzyloxy group has not
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Scheme 5. Enantio-retentive synthesis of key intermediate 6c in the synthe-
sis of (+)-schisanwilsonene A (7).
Scheme 7. Cyclizations of enynes 20a,b and 22 with gold(I) catalyst A with-
out OR migration and the proposed mechanism for the formation of 23.
entries 1–5 and 8; Figure 1), whereas enynes 26 f,g with
a more electron-rich anisyl group gave complex reaction mix-
tures (Table 3, entries 6 and 7). Somewhat surprisingly, the re-
Table 3. Gold(I)-catalyzed reaction of 1,6-enynes 26a–h to give endo-
type single-cleavage rearrangement products 27a–h.
Entry
Enyne
R1
R2
Product
(yield) [%]
1
2
3
4
5
6
7
8
26a
26b
26c
26d
26e
26 f
26g
26h
H
TMS
H
TMS
H
H
H
H
27a (52)
27b (95)
27c (88)
27d (72)
27e (98)
27 f (À)
27g (À)
27h (84)
p-NO2
p-NO2
o-NO2
p-OMe
p-OMe
o-Br
Scheme 6. Reaction of propargyl amines 17a,b with gold(I) catalyst A.
TMS
H
taken place[15] (Scheme 7). Interestingly, alcohol 20b also react-
ed in the presence of catalyst A without migration of the OH
group to give 22, the product of an endo-type single cleavage
rearrangement.[16] This reaction was better performed in the
presence of 4 ꢃ molecular sieves. Surprisingly, in the absence
of molecular sieves, diene 23 was obtained as the major prod-
uct of the reaction, whose structure was determined by X-ray
diffraction. A speculative mechanism for the formation of this
unexpected product could involve a reaction of 22 with allyl
cation 24 to form a new allyl cation 25, followed by aromatiza-
tion by proton loss and dehydration (Scheme 7).
1,6-Enynes 26a–h with tertiary propargyl hydroxyl or trime-
thylsilyloxy groups and different aryl groups at the alkene also
react with catalyst A to give endo-type single cleavage rear-
rangement products 27 under mild conditions (Table 3). The
reaction proceeds satisfactorily with substrates bearing phenyl
or aryl groups with electron-withdrawing substituents (Table 3,
Figure 1. X-ray diffraction structure of product 27h (Table 3, entry 8).
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action of the corresponding methyl ethers led only to decom-
position.
Mechanistic discussion
We examined computationally the evolution of enynes Ia–c co-
ordinated with AuL+ (L=PMe3). In all cases, in agreement with
calculations, Ia–c reacted by 5-exo-dig pathways to form pref-
erentially IIa–c (Schemes 8 and 9), which correspond to inter-
mediates of type 2 in Scheme 1.[17] The alternative 6-endo-dig
pathway leading to IIIa–c was less favorable in all cases.
Whereas in the case of PNP-protected intermediate IIa, the mi-
gration to form VIa proceeds in a direct manner through TS3a
(Scheme 8), the migration of the OR group in complexes IIb
and IIc proceeds via bicyclic intermediates IVb and IVc, which
then lead to products of 1,5-migration VIb and VIc through
very low barrier transition states TS5b and TS5c, respectively
(Scheme 9). The alternative evolution of IIa–c to products of
single-cleavage rearrangement Va–c was found to be thermo-
dynamically the most favorable pathway,[18] although kinetically
the 1,5-migration is more favorable as TS4a–c have higher ener-
gies than TS3a–c (Schemes 8 and 9).
Scheme 9. Alternative reaction pathways for the evolution of gold(I) com-
plexes Ib and Ic into the products of 1,5-OR migration VIb and VIc. DFT cal-
culations (B3LYP, 6-31G(d,p) (C, H, P, O) and SDD (Au), CH2Cl2). Values for free
energies in kcalmolÀ1
.
Figure 2. Computed structure for minimum VIb (Scheme 9). Bond lengths
are in ꢃ.
Scheme 8. Alternative reaction pathways for the evolution of gold(I) com-
plexes Ia into the product of 1,5-OR migration VIa (L=PMe3). DFT calcula-
tions (B3LYP, 6-31G(d,p) (C, H, P, O, N) and SDD (Au), CH2Cl2). Values for free
Table 4. Evaluation on the ligand effect for the computed trends of
gold(I) complex Ib.[a]
energies in kcalmolÀ1
.
PMe3
PPh3
NHC[b]
The calculated structure for minimum VIb shows very similar
CÀC bond lengths of 1.41 and 1.39 ꢃ (Figure 2). The AuÀC
bond length is 2.04 ꢃ, which might correspond to a single
metal–carbon bond, and is similar to that found in well-charac-
terized heteroatom-stabilized gold(I) carbenes.[3,4] Overall, the
calculated structure fits better with a gold(I)-stabilized allylic
cation.
Ib
TS1b
IIb
0.0
3.6
À1.1
7.4
À3.1
2.1
À6.6
À6.6
À15.7
6.7
0.0
5.8
À1.5
9.3
À2.5
4.4
À4.3
À5.1
À13.9
7.0
0.0
9.5
1.6
11.3
0.1
TS2b
IIIb
TS3b
IVb
TS5b
VIb
TS4b
Vb
7.9
À2.3
À0.7
À13.3
11.0
À33.1
The observed reactivity trends when L=PMe3 are repro-
duced in cases where the ligand on gold(I) is changed to bulki-
er PPh3 phosphine or the model NHC ligand 1,3-dimethylimi-
dazol-2-ylidene (Table 4).
À37.5
À35.4
[a] DG energies are given in kcalmolÀ1. [b] 1,3-Dimethylimidazol-2-yli-
dene.
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MEC (FPU fellowship to M.R. and P.C.), the European Research
Council (Advanced Grant No. 321066), the AGAUR (2014 SGR
818), the Marie Curie program (postdoctoral fellowship
658256-MSCA-IF-EF-ST to B.R.), and the ICIQ Foundation. We
also thank the ICIQ X-ray diffraction and chromatograpy units.
Keywords: cycloisomerization · cyclopropanation · density
functional calculations · gold · rearrangement
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Scheme 10. Alternative reaction pathways for the evolution of gold(I) com-
plex Id into the product of 1,5-OR migration VId. Numbers in red corre-
spond to the formation and evolution of IId“, the diastereomer of IId. DFT
calculations (B3LYP, 6-31G(d,p) (C, H, P, O) and SDD (Au), CH2Cl2). Values for
free energies in kcalmolÀ1
.
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Conclusions
In general, 1,6-enynes bearing OR groups at the propargyl po-
sition react through intermediates that can be formulated in
a simplified manner as a,b-unsaturated gold(I) carbenes, which
react in general with alkenes to form cyclopropanes or 1,3-di-
ketones to form products of a-alkylation. We have found that
among the various migrating OR groups, p-nitrophenyl ether
gives the best results. In addition, we have established that
the gold(I)-catalyzed enyne cyclization/1,5-OR migration/cyclo-
propanation cascade takes place without racemization, which
demonstrates that propargyl carbocations are not formed
under the reaction conditions. This has been applied for the
preparation of key intermediates for the synthesis of (+)-schi-
sanwilsonene A with higher enantiomeric purity. DFT calcula-
tions suggest that after the initial cyclization, the 1,5-OR migra-
tion proceeds stepwise through a cyclic intermediate although
the cleavage occurs through a very low barrier. However, addi-
tional mechanistic work is still required to understand why in
cases in which propargyl group does not migrate an endo-type
single-cleavage rearrangement is the most favorable reaction
pathway.
Acknowledgements
We thank MINECO (Severo Ochoa Excellence Accreditation
2014–2018 (SEV-2013-0319), project CTQ2013-42106-P), the
Received: May 17, 2016
Published online on && &&, 0000
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ꢂ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
FULL PAPER
1,6-Enynes with propargyl OR groups
generate a,b-unsaturated gold(I) car-
benes that react with alkenes or 1,3-di-
ketones to form cyclopropanes or prod-
ucts of a-alkylation. p-Nitrophenyl ether
was found to be the best migrating OR
group.
&
Au-Catalyzed Reactions
P. Calleja, ꢀ. Pablo, B. Ranieri, M. Gaydou,
A. Pitaval, M. Moreno, M. Raducan,
A. M. Echavarren*
&& – &&
a,b-Unsaturated Gold(I) Carbenes by
Tandem Cyclization and 1,5-Alkoxy
Migration of 1,6-Enynes: Mechanisms
and Applications
Chem. Eur. J. 2016, 22, 1 – 7
www.chemeurj.org
7
ꢂ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ