Gold(I)-Catalyzed and Nucleophile-Guided Ligand-Directed Divergent Synthesis

Article abstract of DOI:10.1002/ejoc.201801080

Transition metal catalysts can mediate a plethora of skeleton rearrangements of a range of substrates to construct complex small molecules. Yet, their potential to transform common substrates into distinct molecular scaffolds has not been fully explored to deliver biologically relevant small molecules. Gold(I)-catalyzed transformations of enynes are amongst the most intriguing rearrangements and provide opportunities to access a range of diverse scaffolds efficiently. In ligand-directed divergent synthesis (LDS), variation of ligands in metal complexes determines the fate of substrates during their transformation into distinct scaffolds. For instance, variation of ligands for the gold(I) catalysts helps to transform oxindole derived 1,6-enynes into several distinct molecular frameworks. In this report, we present how ligand variation in gold(I) catalysts, nucleophile-additives and alkyl and alkynyl substitutions on the 1,6-enynes as well as replacement of the oxindole ring with a different privileged ring-system (PRS) influence the LDS approach to access a wider chemical space. Based on the experimental results, we propose several mechanistic pathways in gold(I)-catalyzed cycloisomerizations and cascade reactions of 1,6-enyne substrates leading to structurally distinct chemotypes.

Full text of DOI:10.1002/ejoc.201801080

A Journal of
Accepted Article
Title: Gold(I)-catalyzed and Nucleophile-guided Ligand-directed
Divergent Synthesis
Authors: Yen-Chun Lee, Lena Knauer, Kathrin Louven, Christopher
Golz, Carsten Strohmann, Herbert Waldmann, and Kamal
Kumar
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801080
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10.1002/ejoc.201801080
European Journal of Organic Chemistry
FULL PAPER
Gold(I)-catalyzed and Nucleophile-guided Ligand-directed
Divergent Synthesis
Yen-Chun Lee[a,b], Lena Knauer[b], Kathrin Louven[b], Christopher Golz[b], Carsten Strohmann[b], Herbert
Waldmann*[a,b] and Kamal Kumar*[a]
Dedicated to Prof. Manfred T. Reetz on the occasion of his 75th birthday
Abstract: Transition metal catalysts can mediate a plethora of
skeleton rearrangements of a range of substrates to construct
complex small molecules. Yet, their potential to transform common
substrates into distinct molecular scaffolds has not been fully
explored to deliver biologically relevant small molecules. Gold(I)-
catalyzed transformations of enynes are amongst the most intriguing
rearrangements and provide opportunities to access a range of
diverse scaffolds efficiently. In ligand-directed divergent synthesis
(LDS), variation of ligands in metal complexes determines the fate of
substrates during their transformation into distinct scaffolds. For
instance, variation of ligands in gold(I) catalysts helps oxindole
derived 1,6-enynes transform into a number of distinct molecular
frameworks. In this report, we present how variation in ligands in
gold(I) catalysts, nucleophile-additives and alkyl and alkynyl
substitutions on the 1,6-enynes as well as replacement of the
oxindole ring with a different privileged ring-system (PRS) influence
the LDS approach to access wider chemical space. Based on the
results, we propose several mechanistic pathways in gold(I)-
catalyzed cycloisomerizations and cascade reactions of 1,6-enyne
substrates leading to structurally distinct chemotypes.
simply produce alkyne hydration products (4).[6] In case,
sulfoxides[7] or N-oxides[8] are used, the reaction may lead to
reactive α-oxo gold carbene intermediates (5, Scheme 1a) which
offer new opportunities for developing new synthetic methods.[9]
Introduction
Scheme 1. a) Nucleophilic addition to gold(I) activated acetylene leading
to different transformations. b) Gold(I)-catalyzed divergent scaffold
synthesis. c) Relative electrophilicity of gold(I) catalysts. Mes = 2.4.6-
trimethylphenyl, tBu = tert-butyl, iPr = iso-propyl.
The unique alkynophilicity of cationic gold(I) catalysts has been
exploited as a powerful tool to construct structurally complex
molecular frameworks, which otherwise represent difficult
synthetic challenges.[1] In many cases, gold(I) catalysis has
successfully offered synthetic access to natural product-based[2]
or -inspired small molecules[3]. Mechanistically, the electrophilic
character of alkyne substrates (1) is enhanced when the cationic
gold(I) catalyst first coordinates the acetylene moiety (2)
followed by nucleophilic addition to the ensuing gold(I)-acetylene
complexes (2). Often, this addition further triggers a range of
different transformations via cascade type reactions.[4] For
example, interaction of gold(I) activated acetylenes (2) with
olefins may lead to cyclopropyl gold carbene intermediates (3).[5]
In the presence of H2O, the gold(I) activated acetylenes (2) may
One of the most attractive features of cationic gold(I)
catalysis is that introducing subtle changes to the reaction
conditions, for instance, varying solvents,[10] ligands,[11] counter
ions[12] or additives,[13] can lead to structurally distinct products
(Scheme 1b).[14] Recently, we reported
a ligand-directed
divergent synthesis (LDS) approach wherein varying ligands
around a metal center guides the catalytic reactions into different
pathways to form distinct chemotypes.[15] Both the electronic and
the steric features of ligands in gold(I) complexes can influence
the reaction pathways of enyne substrates (Scheme 1c).[16] For
instance, catalyst (I) with electron-rich ligands, like N-
heterocyclic carbenes (NHC),[17] may prefer to form carbene
type intermediates in the transformation of enynes while a gold
complex (III) with electron-deficient ligands, like phosphites may
favor formation of carbocation type intermediates.[18] Similarly,
the steric bulk of the ligand in gold complexes may guide a
reaction intermediate to either follow or avoid a certain reaction
pathway and thereby leading to selective formation of a
particular molecular scaffold.[19] By fine tuning the parameters in
ligands, oxindole based crotylated 1,6-enyne (6a) was
transformed into
[a]
[b]
M. Sc. Y.-C. Lee, Prof. Dr. H. Waldmann, Dr. K. Kumar
Max-Planck Institut für molekulare Physiologie, Abteilung
Chemische Biologie, Otto-Hahn Str. 11, 44227-Dortmund, Germany.
E-mail: kamal.kumar@mpi-dortmund.mpg.de;
herbert.waldmann@mpi-dortmund.mpg.de.
Web: http://www.mpi-dortmund.mpg.de
M. Sc. Y.-C. Lee, M. Sc. L. Knauer, M. Sc. K. Louven, Dr. C. Golz,
Prof. Dr. C. Strohmann and Prof. Dr. H. Waldmann
Fakultät Chemie und Chemische Biologie, Technische Universität
Dortmund, Otto-Hahn Str. 6, 44227-Dortmund, Germany.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201801080
European Journal of Organic Chemistry
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recovery of 10% recovery of (Z)-6a (entry 3) suggests that the
reactivity of (Z)-6a might differ from (E)-6a under these reaction
conditions.
The scope of the ligand directed enyne cycloisomerization
was further investigated by employing (E)-enyne (6b) and (Z)-
enyne (6c) with ethyl substituent (entry 4-9). All reactions were
carried out at 0.1 molar concentration of enyne substrate in
dichloromethane (DCM) and using 5 mol% of gold (I) catalyst
(Table 1). When treated with catalyst I, the (E)-isomer of 6b
provided spirooxindole (9b) in 79% yield that further improved to
88% with a phosphite gold(I) catalyst (III) (entries 4-5). The bulky
phosphine gold(I) catalyst (IIb) altered the reaction pathway and
afforded the quinolone (10b) as the major product in 40% yield
(entry 6). However, in contrast to divergent transformations of
(E)-enyne 6b into spirooxindole (9b) and quinolone (10b), the
(Z)-enyne 6c afforded only quinolone 10c as the major product
with all three catalytic gold(I) complexes (entries 7-9). These
results clearly suggest the key role of the (E)- and (Z)-
stereochemistry of the olefinic part of enynes in directing the
reaction intermediates into distinct chemotypes (9 and 10, vide
infra).
Furthermore, oxindole based 1,6-enynes with variations on
the alkene part (6d-f) were subjected to cycloisomerizations
catalysed by gold complexes I, IIb and III. Replacing the ethyl
group by a bulkier phenyl as R2, 1,6-enyne 6d favoured
quinolone formation under NHC-gold(I) complex (I)-catalysed
reaction condition, and 10d was formed in 40% yield (entry 10).
However, treating 6d with gold(I) catalyst IIb and III led to the
formation of a complex mixture (entry 11-12). Interestingly, allylic
1,6-enyne (6e) appeared to be inert to the gold(I) catalyst I and,
with catalyst III delivered a complex-product mixture. The
phosphine-gold(I) catalyst (IIb) induced enyne cycloisomeriza-
tion of 6e to give quinolone 10e in 56% yield (entry 13-15).
Substitution at the R1 position of the olefin in enynes 6 is
very critical and can introduce steric problems for some
intermediates. This was evident from the gold(I)-catalyzed
cycloisomerization reactions of enyne 6f (R1 = Me). While the
NHC-gold(I) catalyst (I) did not give any product in the reaction
with 6f and led to recovery of the starting material, gold(I)
complexes with a phosphine or phosphite (II and III respectively)
afforded only the spirooxindole (9f) albeit in low yields (entry 17-
18). The yield of the spirooxindole 9f was slightly improved to
46% by using phosphine-gold(I) catalyst (IIb) and diethyl ether
as solvent (entry 19). The relative stereochemistry in 9f was
corroborated by single crystal X-ray structure analysis
(Supporting information).
Scheme 2. a) Gold(I)-based ligand-directed divergent synthesis on oxindole
derived 1,6-enyne system. b) Variation of allyl substitutions and privileged-ring
system in gold(I)-catalyzed divergent scaffold synthesis. Me = methyl, Ph =
phenyl, Nu = nucleophile.
three structurally distinct scaffolds, spiro-oxindole (9a),
quinolone (10a), and dihydrofuranyl oxindole (df-oxindoles, 11a).
The key transformations of the common intermediates (8) i.e.
single cleavage rearrangement (cyclopropane migration),[20]
pinacol type rearrangement (acyl group migration),[21] and O-
migration (cyclopropane opening),[22] respectively led to the
selective formation of distinct scaffolds of 9, 10 and 11 (Scheme
2a).[15] In this gold(I)-catalyzed enyne cycloisomerizations, allyl
substitutions also play an important role in guiding the gold-
carbene intermediates (8) to from diverse products. For instance,
by changing the crotyl- to a prenyl group in the oxindole based
1,6-enyne (7), the gold(I)-catalyzed reaction became selective
towards df-oxindoles (12) supporting an iso-propenyl group. We
now report the further investigation of the potential
diversifications of 1,6-enynes into interesting new scaffolds by
inducing variations in enyne substitutions, addition of external
nucleophiles, and by replacing oxindole with another privileged
ring-systems (PRS)[23] to gain access to a wider chemical space
(Scheme 2b).[24]
Results and Discussion
Oxindole derived 1,6-enynes with various allyl substitutions
We had observed that treating crotyl ether enyne substrate
6a (E:Z = 3:1) with 5 mol% of a cationic gold(I) catalyst with
different ligands could selectively provide spirooxindole 9a and
quinolone 10a in good yields (Table1, entries 1-3).[15] The
cycloisomerization cascade catalysed by NHC-gold(I) catalyst (I)
delivered a spirooxindole 9a as the major product in 43% yield
along with quinolone 10a in 7% yield. (Z)-6a was recovered as
well in 27% (entry 1). The selectivity of the reaction could be
tuned toward quinolone 10a formation by using bulky phosphine
gold(I) catalyst (IIb). In this case, quinolone 10a was formed in
67% yield and a minor epimeric product (epi-10a, R2 = H, R3 =
Me) was obtained in 20% yield (entry 2). The gold(I) catalyst
with electron-deficient phosphite ligand (III) also provided
spirooxindole 9a as the major product in 60% yield. The
Analyzing the ligand-directed gold-catalyzed cycloisomeriza-
tion reaction of 1,6-enynes bearing different allyl substitutions,
we observed that formation of spirooxindole and quinolone was
affected both by olefin substitutions as well as the ligands in
catalytic complexes (Scheme 3). Transformations leading to
spirooxindoles (9) and quinolones (10) share common
intermediates (8) formed after the gold(I)-catalyzed 6-endo-dig
cyclization of 1,6-enynes (6). In spirooxindole formation,
intermediates (8) undergo cyclopropane migration to give
cationic intermediates (13), a process that is favored by NHC-
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10.1002/ejoc.201801080
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and phosphite gold complexes to transform (E)-6 enyne into
methallyl substrate (6f, R1 = Me), the cationic intermediate is
stabilized as 3° carbocation (13f), and therefore gold(I)-
catalyzed cycloisomerization selectively give spirooxindole (9f)
as product (Table 1, entry 17-19).
spirooxindoles (entries 1 and 3, Table 1).[20]
Table 1. Ligand variations in gold(I)-catalyzed divergent scaffold synthesis with
different allyl substitutions.
In order to steer the intermediate into
a ring-expanded
quinolone, steric hindrance between substrate and catalyst
plays a decisive role. Therefore, gold(I)-complex (IIb) supporting
bulky ligand drives the pinacol type ring expansion of the 8
leading to oxocarbenium intermediates (14). The deauration of
the latter provides the quinolones (10, Scheme 3, green arrow,
and Table 1, entry 2, 6 and 14).[25]
Notably, for (Z)-1,6-enynes, for instance 6c, the steric
repulsion of alkyl substitution (Et) at the R3 position and spiro-
ring system may generate
a disfavorable strain in the
intermediate (8ca and 8cb, Scheme 3), and thus inducing the
ring-expansion of the oxindole (8c) leading to the selective
formation of quinolones as observed for all three gold catalysts
(I-III, entries 7-9, Table 1 and Scheme 3). Substrates with
phenyl at R2 could undergo this ring expansion reaction as well,
though only NHC-gold catalyst I provided the desired product (I,
Table 1, entry 10).
Entry[a]
6
R1
R2
R3
[Au]
product
Yield
(%)
1[b]
2[b]
3[b]
4
6a
6a
6a
6b
6b
6b
6c
6c
6c
6d
6d
6d
6e
6e
6e
6f
H
Me
Me
Me
Et
Et
Et
H
H
H
H
H
H
H
Et
Et
Et
H
H
H
H
H
H
H
H
H
H
I
9a[c]
10a[d]
9a[e]
9b
43
67
60
79
88
40
58
37
63
40
-
H
IIb
III
I
H
H
5
H
III
IIb
I
9b
6
H
10b
10c
10c
10c
10d
7
H
8
H
H
IIb
III
I
9
H
H
10
11
12
13
14
15
16
17
18
19[h]
H
Ph
Ph
Ph
H
[f]
H
IIb
III
I
-
[f]
H
-
-
[g]
H
-
-
H
H
IIb
III
I
10e
56
-
[f]
H
H
-
Scheme 3. Proposed reaction mechanisms of spirooxindole 9 and quinolone
10 formation.
[g]
Me
Me
Me
Me
H
-
-
6f
H
IIb
III
IIb
9f
9f
9f
37
17
46
As compared to enynes 6a-f, prenylated substrates 7
exhibited a different pattern of transformations under the
influence of gold catalysts (Table 2). Surprisingly, when in situ
generated Ph3PAuOTf was used as catalyst (10 mol%),
substrate 7 provided six different products, i.e. df-oxindoles (12
in 8% yield, 15 in 26% yield, and 16 in 5% yield), spirooxindoles
(17 in 16% yield and 18 in 12% yield), and Meyer-Schuster
rearrangement (MS) product (19 in 7% yield, entry 1)[6a]. Except
for the MS product, the relative configuration of the other
products, 12, 15, 16, 17, and 18 were determined by single
crystal X-ray structure analysis (Supporting information).
Moreover, under standard reaction conditions, no reaction was
6f
H
6f
H
[a] Reaction condition: [Au] 5 mol%, DCM (0.1 M), rt, overnight; [b] E:Z = 3:1.
[c] 10a was obtained in 7% yield and (Z)-6a was in 27% recovery; [d] epi-10a
(R2 = H, R3 = Me) was obtained in 20% yield; [e] (Z)-6a was in 10% recovery;
[f] Complex mixture formation; [g] Starting material recovery; [h] Solvent is
diethyl ether.
Plausibly, the cationic intermediates subsequently eliminate the
gold(I) catalyst to open up the cyclopropane ring, giving
spirooxindoles 9a/9b as products (Scheme 3, blue arrow). With
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10.1002/ejoc.201801080
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recorded with NHC-gold(I) catalyst (I, entry 2). However, at
higher concentration (0.2 M), a complex mixture was observed
(entry 3). Fortunately, treating 7 with a gold(I) catalyst with bulky
phosphine ligand (IIa) led to a full conversion of starting material
and trans-df-oxindole (12) was formed in 50% yield (entry 4).
Changing the solvent from DCM to THF further improved the
yield of trans-df-oxindole (12) to 91% (entry 5). When gold(I)
complex with sterically bulky phosphine ligand (IIb) was used, a
slightly lower yield of df-oxindole was obtained (entry 6). In the
presence of phosphite-gold(I) catalyst (III), 40% of the substrate
enyne was recovered, along with formation of trans-df-oxindole
(12) and spirooxindoles (17, 18) in 17%, 30% and 13% yield,
respectively (entry 7). Thus, treating 7 with catalyst IIa in THF
provided an ideal condition to selectively transform enyne 7 into
df-oxindole 12.
proton elimination to provide a common intermediate (21) for the
formation of diverse products. Direct protodeauration of the vinyl
gold intermediate (21) gives diastereomeric spirooxindoles (17
and 18, blue arrow). In an alternative reaction pathway, non-
stereoselective
protonation
generates
gold
carbene
intermediates (22). Subsequently, insertion of an ether oxygen
to the gold carbene leads to highly strained oxonium
intermediates
(23)
that
concomitantly
rearrange
to
diastereomeric df-oxindoles (12 and 15) as products (green
arrow).[22] The selectivity of product formation can be
significantly improved by employing a bulky phosphine ligand in
gold complex (IIb). With the catalyst IIb, the direct
protodeauration of the vinyl gold intermediate was completely
prohibited as the biphenyl group in phosphine ligand blocks the
sterically less hindered face and directs a stereoselective
protonation (24). In this scenario, the trans-df-oxindole (12) was
obtained exclusively in good yield (magenta arrow).
Table 2. Ligand variations in gold(I)-catalyzed divergent scaffold synthesis
with oxindole-based prenylated 1,6-enyne.
Entry[a]
[Au] (mol%)
Yield (%)
Scheme 4. Proposed reaction mechanisms of gold(I) catalysed
cycloisomerization of oxindole derived prenylated 1,6-enyne (7).
12
15
26
-
16
17
16
-
18
12
-
19
7
-
1
Ph3PAuOTf (10)
I (5)
8
5
-
-
-
-
-
-
[b]
2
-
Enyne-cycloisomerizations in the presence of external
nucleophiles
[d]
3[c]
4
I (5)
-
-
-
-
-
The alkynophilic gold(I) catalyst enhances the electrophilic
nature of acetylene moiety in enyne substrates and thus may
invite an intramolecular nucleophilic attack by a proximal
electron-rich olefin, and subsequently follows various skeleton
rearrangements.[22] Moreover, if external nucleophiles are
present, they can also add to the gold-activated intermediates
and deliver structurally distinct products. With a series of 1,6-
enynes (6a-f, and 7) in hand, we utilized alcohol (MeOH),
sulfoxide (25), and N-oxide (26) as representative external
nucleophiles and phosphine-gold(I) complex (IIa) as the catalyst
to achieve a nucleophile-guided divergent scaffold synthesis
(Table 3).
IIa (5)
50
91
49
17
-
-
-
-
5[e]
6
IIa (5)
-
-
-
-
IIb (5)
-
-
-
-
7[f]
III (5)
-
30
13
-
[a] Reaction condition: [Au] 5 mol%, DCM (0.1 M), r t, overnight; [b] starting
material recovery; [c] DCM (0.2 M); [d] Complex mixture formation; [e] THF
was used as solvent; [f] enyne 7 recovered (40%).
Mechanistically, gem-dimethyl groups in prenylated enyne
substrate 7 may help generate a stabilized 3°-carbocation
intermediate (20) after gold(I)-catalyzed 6-endo-dig cyclization
(Scheme 4). This relatively stable carbocation (20) undergoes a
In the presence of methanol as nucleophile, the crotylated
1,6-enynes 6a-b (E:Z = 3:1) afforded the df-oxindoles (11a-b) in
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10.1002/ejoc.201801080
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73 and 67% yields respectively along with minor MS product (19,
entries 1-2, Table 3). When (Z)-6c was employed in the same
reaction, the MS product (17) was formed as the major product
(67%) and the df-oxindole 11c was obtained in only 20% yield
(entry 3). Thus, enyne substrates with (E)-olefin favored the
formation of df-oxindoles. Even when steric bulk was enhanced
by introducing phenyl group as R2 (6d), the reaction smoothly
delivered the df-oxindole 11d in 56% yield (entry 4). However,
allyl substituted enyne 6e did not follow the desired
cycloisomerization and the MS product (17) was the only
product formed in this reaction (entry 5). -Methallyl 1,6- enyne
substrate (6f) yielded an inseparable complex mixture of
products (entry 6). Prenylated substrate (7) nicely and
expectedly provided the corresponding df-oxindole (11g) in 66%
yield, though isopropenyl-df-oxindole (12) was also isolated in
23% yield (entry 7).
In order to further unravel distinctive transformations
guided by nucleophiles, sulfoxide (25) and quinoline-N-oxide
(26) endowed with nucleophilic and oxidant nature were
employed in the gold(I)-catalyzed transformations (entry 8-10).
Notably, these reagents are frequently utilized for oxidizing the
gold carbene intermediate to form a carbonyl functionality or
react with gold(I) activated acetylene to give -oxo gold carbene,
a reactive intermediate, which may undergo oxidative cyclization
or skeleton rearrangements (Scheme 1a).[26] In our screening,
the oxygen addition product was not formed when (E)-enyne 6b
was treated with 2 equivalents of diphenyl sulfoxide 25, albeit
quinolone 10b was isolated in 60% yield (entry 8). Resorting to
N-oxide 26 as oxidative nucleophile, 6b successfully gave an
oxygen addition product 27 in 83% yield (entry 9). In a
competition experiment the 1,6-enyne 6b was exposed to
methanol, and N-oxide 26, under gold(I) catalysis. The reaction
afforded 10b as single product in 70% yield (entry 10)
demonstrating that N-oxide 26 is the most favorable nucleophile
to react with the activated acetylene under the presented gold(I)-
catalyzed reaction condition.
Table 3. Variations of allyl substitutions and nucleophiles in gold(I)-
catalyzed divergent scaffold synthesis.
Mechanistically, in gold(I)-catalyzed reactions of enynes,
external nucleophiles can either add to one of the enyne-
cycloisomerization gold carbene intermediates or simply to the
gold(I) activated acetylene moiety. In the former case, 1,4-
addition of methanol to the cyclopropane gold carbene
intermediate (8) forms the df-oxindole vinyl gold species 28
(Scheme 5). After stereoselective protonation of 28, the resulting
gold carbene intermediate (29) follows the O-migration cascade
to give methoxy adduct of df-oxindole (11, Scheme 5). In the
second case, methanol may add to the gold(I) activated
acetylene and follows a MS rearrangement to give an oxindole
(19, Scheme 5).[6a] These two reactions compete with each other
and in particular are influenced by the nucleophilicity or electron-
rich nature of the olefin moiety in enyne substrates. Therefore,
enyne (7) with nucleophilic trisubstituted olefin quickly followed
the cycloisomerization before methanol could trap the gold(I)
activated acetylene to give the MS product (19), and led to form
methoxyl-df-oxindole (11g, Table 3, entry 7) via intermediate (8).
Most of the disubstituted olefin substrates afforded a mixture of
methoxy-df-oxindoles (11) and the MS product (19, entry 1-4),
except for substrate 6f (entry 6). Likewise, the mono-substituted,
as relatively electron-poor olefin substrate (6e), exclusively
provided the MS product 19 (entry 5).
Entry[a]
6/7
R1
R2
R3
Nu.[b]
Yield (%)
10
11
73
67
20
56
12
19
18
15
67
8
27
1[c]
2
6a
6b
6c
6d
6e
6f
H
H
H
H
H
Me
H
H
H
H
Me
Et
H
H
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
25
H
3
Et
H
4
Ph
H
86
5
H
[d]
6
H
H
-
66[e]
23
The oxidative nucleophile N-oxide 26 also reacted with the
gold(I) activated acetylene and triggered a rearrangement
cascade leading to quinolone 27 (Scheme 5). Mechanistically,
we assume that after the nucleophilic addition of N-oxide 26, the
quinoline segment of N-oxide (Z) is eliminated from the vinyl
gold intermediate (31) and -oxo gold carbene (32) is generated.
Subsequently, pinacol type rearrangement leads to ring
expansion and deauration closes the catalytic cycle to yield
quinolone (27, Scheme 5).[27]
7
7
Me
Et
Et
Et
Me
H
60
8
6b
6b
6b
83
70
9
H
26
10
H
MeOH
+ 26
[a] Reaction condition: catalyst IIa 5 mol%, DCE (0.1 M), 60 °C, overnight; [b]
Amount of nucleophile: MeOH (10 eq), 25 (2 eq), 26 (1.1 eq); [c] E:Z = 3:1; [d]
complex mixture was formed; [e] 11g
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10.1002/ejoc.201801080
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Cycloisomerizations of oxindole derived 1,6-enyne with a
terminal alkyne
After studying the role of substitutions on the olefin moiety
of 1,6-enynes in guiding the gold(I)-catalyzed cycloisomerization
reactions, we investigated the influence of terminal alkyne in
enyne 34 on gold(I)-catalyzed divergent scaffold synthesis. In
order to discover new reaction pathways leading to novel
scaffolds, a reaction screening with different gold(I) catalysts as
well as with different nucleophiles was carried out (Table 4).[29] In
the absence of a nucleophile, and with gold(I) catalysts, I and IIa,
enyne 34 yielded an inseparable mixture of products and trace
amounts of spirooxindoles 35 (entry 1-2). Electrophilic
phosphite-gold(I) catalyst III afforded the diastereomeric
hydroxyl adducts (35) in 57% yield (dr = 1:1, entry 3). We
anticipated that the products were formed by nucleophilic
addition of a trace amount of water to a reaction intermediate.
Indeed, when the same reaction was performed in the presence
of 4 Å molecular sieves (4 Å MS), starting material (34) was fully
recovered (entry 4).
Scheme 5. Proposed reaction mechanisms of nucleophiles-guided gold(I)
catalysed cycloisomerizations of oxindole derived 1,6-enynes.
Chirality transfer
The proposed reaction mechanisms of ligand-directed
gold(I)-catalyzed cycloisomerization of oxindole based 1,6-
enynes depicts 8 as the initial intermediate leading to the
formation of spirooxindole, quinolone as well as df-oxindole
scaffolds (Scheme 3 - 5) and understandably plays a crucial role
in establishing all the stereogenic centers in the final products.
Therefore, we were curious to determine the influence of the
spirocenter in enantiomerically enriched substrates on the newly
generated stereogenic centers in the gold(I)-catalyzed
cycloisomerizations. To this end, experiments were initiated by
preparation of optically enriched (E)-enyne 6b* (36%
Table 4. Nucleophile-guided gold(I)-catalyzed divergent scaffold synthesis
with terminal alkyne substrate.
enantiomeric excess, ee), employing
a Zn(OTf)2-catalyzed
enantioselective alkylation (see Supporting information).[28] In the
gold(I)-mediated reaction leading to spirooxindole (9b*), the
chirality was maintained as 36% ee. Thus, in this particular
reaction, no epimerization at the spirocarbon occurs during the
cycloisomerization cascade. The enantiomeric excess, however,
slightly decreased from 36% to 30% when 1,6-enyne 6b
followed the quinolone formation (10b*) and further drastically
decreased to 14% during its transformation into the df-oxindole
formation (11b*) (Scheme 6). In other words, although a
complete chirality transfer from substrate to spirooxindole was
observed, the same was not depicted in the formation of
quinolone and df-oxindole scaffolds wherein reduction of the
enantiomeric excess in the products was observed (Scheme 6).
Therefore, further experiments needs to be designed and
executed to unravel the influence of oxindole 1,6-enynes (6) on
the stereogenic control over the diverse scaffolds formed.
Entry[a]
[Au]
(5 mol%)
Nu.(eq)
Yield (%)
35
36
37
1
I
-
trace[b]
trace[b]
57[c]
2
IIa
III
III
I
-
3
-
4[d]
5
-
-
[e]
81
72
90
MeOH (20)
MeOH (20)
MeOH (20)
25 (1.2)
25 (1.2)
25 (1.2)
25 (1.2)
26 (1.2)
26 (1.2)
26 (1.2)
6
IIa
III
I
-
7
Trace
16
8
trace
trace
trace
9
IIa
III
III
I
10
11[d]
12[f]
13[f]
14[f]
21
52
[b]
trace
[e]
-
IIa
III
[e]
-
Scheme 6. Chirality transfer in gold(I)-catalyzed divergent scaffold synthesis.
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10.1002/ejoc.201801080
European Journal of Organic Chemistry
FULL PAPER
Replacing the privileged-ring-system: Cycloisomerization of
camphor-ring based 1,6-enynes
[a] Reaction condition: DCE (0.03 M), rt, overnight; [b] Complex mixture
formation; [c] dr = 1:1; [d] Addition of 4 Å MS; [e] Starting material recovery; [f]
60 °C seal tube.
In the light of successful access to structurally intriguing
scaffolds from oxindole based 1,6-enynes described above,
another naturally occurring ring-system, i.e. the camphor
framework was introduced into enyne system to investigate the
LDS strategy.[32] The camphor based 1,6-enyne was prepared
by means of lithium phenylacetylide addition to the carbonyl
group of camphorquinone and followed by O-allylation of newly
generated propargyl alcohol (see the Supporting information).
By employing the optimal conditions developed for the LDS in
the crotylated 1,6-enyne system, we observed that the ring
expansion products (52 and 54) were selectively generated from
camphor based crotylated 1,6-enynes (51 and 53, Scheme 8).
The bicyclic [3.2.1] products (52) can be prepared in 50% yield
from the substrate 51 by using sterically demanding phosphine
gold(I) catalyst IIb at 60 °C (condition A, Scheme 8a). A better
yield was obtained when phosphite-gold(I) complex III was used
as catalyst at room temperature (56%, condition B, Scheme 8a).
Having MeOH as external nucleophile could not trap the gold
carbene cyclopropane intermediate to follow the O-migration
reaction and only the ring expansion product (52) was obtained
in low yield (condition C, Scheme 8a).
In order to efficiently trap the intermediate, MeOH was
employed
as
nucleophile
in
the
gold(I)-catalyzed
cycloisomerization reaction. The NHC- or phosphine-gold(I)
catalysts, I or IIa, delivered the methoxy adduct (36) in high
yields (entry 5-6). The relative configuration of 36 was
determined by single crystal X-ray structure analysis (Supporting
information). The best yield of 36 (90%) was obtained employing
phosphite-gold(I) catalyst (III, entry 7) in the cycloisomerization
reaction.
We also examined sulfoxide (19) as oxidative nucleophile for
gold(I) catalysed transformation of enyne 34. Using NHC-gold(I)
catalyst (I), only a trace amount of cyclopropyl spirooxindole (37)
was observed (entry 8). Further reaction screening revealed that
phosphite gold(I) complex III enhanced the yield of spirooxindole
37 to 21% (entry 10). Since hydroxylated adducts were always
observed in the crude products, we tried to perform the reaction
in anhydrous condition. Thus, in the presence of molecular
sieves (4 Å), the desired product 37 was formed in 52% yield
(entry 11, for single crystal X-ray structure analysis, see
Supporting information). On the other hand, using N-oxide (26)
as oxidative nucleophile in cycloisomerization reactions, either
non-selective product formation was observed or starting
material was recovered (entry 12-14).
We assume that under gold(I) catalysis, the terminal alkyne
substrate (34) follows a 5-exo-dig cyclization (Scheme 7), which
is very different from the enyne substrates with aryl substituted
alkyne (6 and 7, 6-endo-dig). Thus, gold(I) activated enyne (38)
undergoes a 5-exo-dig cyclization to give spiro-intermediates (39
and 40). Trace amount of water may serve as nucleophile and
add to the relatively stable benzylic cation in 39 forming adducts
41 which undergo protodeauration to form diastereomeric
hydroxyl-df-oxindoles (35). With an excess of MeOH, the alcohol
undergoes 1,4-addition to open up the cyclopropane of bicyclic
gold carbene intermediate (40), giving vinyl gold intermediate
(42). After protodeauration of 42, the methoxy-df-oxindole (36) is
formed.[30] It seems that, instead of 1,4-addition, sulfoxide (19)
proceeds via a 1,2-addition to the bicyclic gold carbene
intermediate (40), which sequentially oxidizes the gold carbene
to the carbonyl moiety and thus forming a cyclopropane-fused
tetracyclic aldehydic spirooxindole (37).[31]
Scheme 8. a) Cationic gold(I) catalyzed bicyclic [3.2.1] system formation via
acyl migration; and b) Natural products containing the bicyclic [3.2.1] system.
The camphor-based-crotylated 1,6-enyne 53 did not
undergo enyne cycloisomerization at room temperature. At
higher reaction temperature, i.e. at 60 °C, the desired ring
expansion product (54) was obtained in 56% yield using gold(I)
catalyst IIb (condition A, Scheme 8a). The phosphite gold(I)
catalyst III gave afforded higher yield for 54 (conditions B,
Scheme 8a). Having MeOH again as external nucleophile with
gold(I)-complex II provided inconsequential and led to form 54 in
moderate yield (conditions A and C, Scheme 8a). The relative
configurations of bicyclic [3.2.1] products (52 and 54) were
unambiguously determined by 2D NMR analysis, i.e. by COSY,
Scheme 7. Proposed reaction mechanisms of nucleophile guided gold(I)
catalysed cycloisomerizations of terminal alkyne substrate.
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10.1002/ejoc.201801080
European Journal of Organic Chemistry
FULL PAPER
was concentrated under reduced pressure, followed by silica gel column
chromatography (EtOAc / Petroleum ether as eluents) to obtain desired
product. In some cases, it is required to add 4 Å MS (10 mg) to reaction
mixture (see Table 4 and Supporting information).
HSQC, HMBC, and NOESY (see supporting information).
Apparently, the pinacol type acyl migration is the major pathway
for releasing the intrinsic ring strain between the camphor
backbone and the gold catalysts to generate enantiomerically
pure bicyclic [3.2.1] products (52 and 54). The bicyclic [3.2.1]
core-structure is frequently found in many natural products, such
as (+)-hopeanol,[33] geisemine,[34] and nominine[35] (Scheme 8b),
and therefore small molecules based on this molecular scaffold
may offer interesting bio-modulating properties.
X-ray crystallography
CCDC 1448387 (9f), CCDC 1577705 (15), CCDC 1577695 (16), CCDC
1577715 (17), CCDC 1577690 (18), CCDC 1577276 (36), and CCDC
1577691 (37) contain crystallographic data for this paper. These data can
be obtained from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
Conclusions
Y.-C.L. would like to thank Ministry of Education (Taiwan) for the
MOE Technologies Incubation Scholarship. This research was
supported by funding from the Max-Planck-Gesellschaft.
In summary, the ligand-directed divergent synthesis strategy
to deliver distinct molecular scaffolds was explored using gold(I)-
catalyzed cycloisomerization reactions of 1,6-enynes. The role
and influence of various substitutions on the olefin moiety of the
enynes as well as that of external nucleophiles in directing and
guiding different reaction pathways from common reactive
intermediates was investigated. Overall, about 10 different
Keywords: gold(I) catalysis • enynes • heterocycles • divergent
synthesis • scaffold diversity
gold(I)-catalysed
transformations
were
identified
that
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General procedure for gold(I)-catalyzed cycloisomerization
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10.1002/ejoc.201801080
European Journal of Organic Chemistry
FULL PAPER
A ligand-directed divergent scaffold synthesis was explored by varying the ligands in the
gold(I) catalysts and the nucleophiles in the cycloisomerization reactions of oxindole based
1,6-enynes. The strategy afforded a number of distinct and structurally complex molecular
scaffolds.
Key topic: Gold(I) Catalysis
FULL PAPER
Y.-C. Lee, L. Knauer, K. Louven, C.
Golz, C. Strohmann, H. Waldmann and
K. Kumar*
Page No. – Page No.
Gold(I)-catalyzed and Nucleophile-
guided Ligand-directed Divergent
Synthesis
Text for Table of Contents
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