Chiral Cationic CpxRu(II) Complexes for Enantioselective Yne-Enone Cyclizations

Article abstract of DOI:10.1021/jacs.5b08232

The cyclopentadienyl (Cp) group is a ligand of great importance for many transition-metal complexes used in catalysis. Cationic CpRu^II complexes with three free coordination sites are highly versatile catalysts for many atom-economic transformations. We report the synthesis of a family of Cp^xRu^II complexes with chiral Cp ligands keeping the maximum number of available coordination sites. The cationic members are efficient and selective catalysts for yne-enone cyclizations via formal hetero-Diels-Alder reactions. The transformation proceeds in <1 h at -20 °C and provides pyrans in up to 99:1 er. Unsaturated ester or Weinreb-amide substrates directly yield the iridoid skeleton.

Full text of DOI:10.1021/jacs.5b08232

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Chiral Cationic CpRu(II) Complexes for
Enantioselective Yne-Enones Cyclizations
David Kossler, and Nicolai Cramer
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b08232 • Publication Date (Web): 15 Sep 2015
Downloaded from http://pubs.acs.org on September 19, 2015
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Journal of the American Chemical Society
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Chiral Cationic CpxRu(II) Complexes for Enantioselective Yne-Enones
Cyclizations
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David Kossler and Nicolai Cramer*
Laboratory of Asymmetric Catalysis and Synthesis, Institute of Chemical Sciences and Engineering, Ecole Polytechnique
Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
Supporting Information Placeholder
for the more complex chiral Cpx ligands. Despite many attempts,
ABSTRACT: The cyclopentadienyl (Cp) group is a ligand of
Mann’s protocol using CpTl,10 which was used as well for the
great importance for many transitionꢀmetal complexes used in
synthesis other chiral Cp ruthenium(II) complexes,3n proved to be
the best method (Scheme 1). The use of [(C6H6)RuCl2] instead of
the more common [(cymene)RuCl2]2 reduced the formation of
undesired ruthenocene byproducts and provided in moderate to
good yields of complexes 2aCl-2lCl. At this stage, the chloride
ion could be exchanged by salt metathesis for any desired anion,
catalysis. Cationic CpRuII complexes with three free coordination
sites are highly versatile catalysts for many atomꢀeconomic transꢀ
formations. We report the synthesis of a family of CpxRuII comꢀ
plexes with chiral Cp ligands keeping the maximum number of
available coordination sites. The cationic members are efficient
and selective catalysts for enoneꢀyne cyclizations via formal
heteroꢀDielsꢀAlder reactions. The illustrated transformation proꢀ
ceeds in less than one hour at ꢀ20°C and provides pyrans in enanꢀ
tioselectivities of up to 99:1 er. Unsaturated ester or Weinrebꢀ
amide substrates directly yield the iridoid skeleton.
ꢀ
mainly for very weakly coordinating anions such as PF6ꢀ or SbF6 .
Crystallized arene complex 2b-PF6 showed the expected geomeꢀ
try with a good shielding from the chiral CpX ligand (Figure 1).11
Subsequently, the cationic complexes were dissolved in acetoniꢀ
trile and photolyzed under ambient conditions, inducing a decomꢀ
plexation of the benzene ligand in exchange for three acetonitrile
molecules. Complexes 3 are in their solid state stable orange
powders.
Scheme 1. Synthesis of the chiral CpxRuII complexes 3.
The cyclopentadienyl (Cp) ligand is of fundamental importance
for organometallic chemistry and as such found in countless
transitionꢀmetal catalysts.1 For instance, CpRuII and Cp*RuII
fragments are established powerful catalysts enabling many synꢀ
thetically versatile and atomꢀeconomic transformations.2 In conꢀ
trast to other ligand classes, chiral Cpx ligands enabling enantioseꢀ
lective transformations lag behind.3 When the transformation does
not require all three coordination sites of the Ru(II)ꢀbased cataꢀ
lyst, enantioselective reactions are achieved by employing a tethꢀ
ering strategy4 or an exogenous source of chirality.5 This enꢀ
hanced transmission of stereochemistry comes at the expense of a
reduced number of available coordination sites on the ruthenium
center. However, a significant number of cationic CpRuII cataꢀ
lyzed reactions need all three coordination sites for functionality.2
Hence, a tethering approach fails to produce a reactive catalyst,
thus requiring the design of chiral Cpx ligand backbones. We
recently developed two chiral Cpx ligand systems6 showing good
performance for RhIIIꢀcatalyzed enantioselective CꢀH functionaliꢀ
zations of aryl hydroxamates.7ꢀ8 Further exploration of these
ligands as steering element on Ru complexes would be a major
step to close the gap in asymmetric Ruꢀcatalysis. Herein, we
report the preparation of chiral CpxRuII complexes and demonꢀ
strate their potential in enantioselective cyclizations giving chiral
pyrans.
Figure 1. Xꢀray crystal structure of CpxRu(C6H6)PF6 (2b-PF6).
The first hurdle of using chiral Cp ligand scaffolds in Ruꢀ
catalysis consisted in the securing access to the corresponding
complexes by a reliable preparative method. The majority of
synthetic methods for the targeted pianoꢀstool CpRu complexes
require a large excess of the corresponding cyclopentadiene preꢀ
cursor.9 While this is tolerable for CpH and Cp*H, it is prohibitive
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Next, we gauged the potential of these CpxRuII complexes in a
challenging benchmark transformation. We selected Trost’s cyꢀ
clization reaction of yneꢀenone 4a providing 4Hꢀpyran 5a or
diketone 6a, depending upon the reaction conditions (Eq. 1,
Z=C(CO2Me)2).12 The transformation requires all three coordinaꢀ
tion sites of the ruthenium center and the addition of one equivaꢀ
lent of triphenylphosphine immediately inactivated the catalyst.
anion were less reactive and selective (Entry 4 and 5). Surprisingꢀ
1
2
3
4
5
6
7
8
ly, the complex with a covalently bound chloride gave the oppoꢀ
site enantiomer of 5a in 28:72 er, although with significantly
reduced reactivity (Entry 6), requiring four hours for the reaction
to go to completion (Entry 7). At present, the underlying effect of
this reversed selectivity is not clear and subject to more detailed
investigations. The observed trend in selectivity translated to the
ꢀ
more selective phenylꢀbearing complex 3e. With the SbF6 anion,
a slightly higher enantioselectivity of 91:9 was obtained (Entry 8).
Conducting the cyclization at ꢀ20°C for 1 h increased the selectivꢀ
ity further and provided 5a in 90% yield and 93.5:6.5 er (Entry 9).
Table 2. Counterion effect on the selectivitya
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We initially evaluated several CpxRuII complexes with substrate
4a (Table 1). The reaction went to completion within 10 minutes
at ambient temperature in THF. From the tested PF6ꢀbearing
complexes 3aꢀ3l, 3,3’ꢀmethoxy derivative 3b gave good reactivity
and an enantioselectivity of 86:14 (Entry 2), only surpassed by the
3,3’ꢀphenyl congener 3e with 89.5:10.5 er (Entry 5). Consequentꢀ
ly, ligands with different substituted 3,3’ꢀarenes were tested and a
tremendous impact on the catalyst performance was found. An
orthoꢀsubstituted arene shut down the reactivity (Entry 6), while
metaꢀsubstitution just slightly diminished the enantioselectivity
(Entry 7). The large influence of the substitution at the paraꢀ
position of the arene substituent is noteworthy. A pꢀbiphenyl or pꢀ
methoxyphenyl ligand led to almost complete loss of selectivity
(Entries 10 and 11). The pꢀcyanophenyl substitution totally inactiꢀ
vated the catalyst (Entry 12). We speculate that the cyano group
of 3l coordinates to the ruthenium center, abolishing its catalytic
performance. Although 2ꢀnaphthyl or pentafluorophenyl groups
resulted in selectivities comparable to 3e, they render the comꢀ
plexes somewhat less reactive (Entries 8 and 9).
entry
R
X
conv. (%)b 5a (%)b
erc
1
2
3
4
5
6
OMe
OMe
OMe
OMe
PF6
100
100
29
98
98
22
42
32
13
80
95
90f
86.5:13.5
86:14
SbF6
BF4
NTf2
30.5:69.5
72:28
42
OMe BARF24
35
58.5:41.5
28:72
OMe
Cl
Cl
13
7d OMe
100
100
100
30.5:69.5
91:9
Table 1. Screening of different CpxRu complexes 3a
8
9e
Ph
Ph
SbF6
SbF6
93.5:6.5
a Conditions: 25 ꢁmol 4a, 1.25 ꢁmol 3, 0.13 M in THF, 23 °C,
10 min. b Determined by HꢀNMR with an internal standard.
1
c
e
d
Determined by HPLC with a chiral stationary phase. for 4 h.
0.1 mmol scale at ꢀ20°C for 1 h. f isolated yield.
The scope for the enantioselective rutheniumꢀcatalyzed pyran
formation was subsequently established with the aforementioned
optimized conditions (Table 3). A variety of arene groups R1 are
tolerated and provide the cyclized product 5 in good yields and
selectivities (Entries 1ꢀ6). Besides arenes, the reaction retains
most selectivity with R1 being an alkyl group (Entry 7). The subꢀ
stituent R2 can be changed for longer or functionalized alkyl
chains keeping the good reaction characteristics (Entries 8ꢀ10). A
phenyl group in this position slightly reduces the selectivity and
requires a reaction temperature of 0°C (Entry 11). Moreover, the
malonate tether could be replaced without loss of selectivity by a
NTs group (Entry 12) or by a simple methylene bridge (Entry 13).
Pyran 5n is very labile and was therefore hydrolyzed to diketone
6n for isolation. A larger tether reduced the reaction performance
with the current catalyst (Entry 14).
entry
1
R
conv. (%)b 5a (%)b
erc
3-PF6
3a
3b
3c
Me
100
100
18
94
98
11
62
98
16
25
65
22
27
29
<5
68:32
2
OMe
86:14
3
OMOM
OTIPS
33:67
4
67
79.5:20.5
89.5:10.5
45.5:54.5
81.5:18.5
89.5:10.5
87.5:12.5
55.5:44.5
45:55
3d
3e
5
Ph
100
24
6
2,6ꢀMeꢀC6H3
3,5ꢀMeꢀC6H3
C6F5
3f
7
25
3g
3h
3i
8
74
9
2ꢀnaphthyl
4ꢀPhꢀC6H4
4ꢀMeOꢀC6H4
4ꢀCNꢀC6H4
24
Table 3. Scope for the synthesis of 4H-pyrans 5a
10
11
12
35
3j
30
3k
3l
<5
22.5:77.5
a Conditions: 25 ꢁmol 4a, 1.25 ꢁmol 3, 0.13 M in THF, 23 °C,
1
c
10 min. b Determined by HꢀNMR with an internal standard.
Determined by HPLC with a chiral stationary phase.
entry
yield (%)b
erc
4
5
Next, the role of the counterion was evaluated (Table 2). The
nature of the anion has a considerable effect on both, the reactiviꢀ
ty and the enantioselectivity. The best reactivities were observed
ꢀ
ꢀ
with PF6 and SbF6 (Entry 1 and 2). Triflimide and the BARF24
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Besides enones, α,βꢀunsaturated ester 4p and amide 4q were
viable substrates (Scheme 2). The intermediately formed ketene
acetal 7 could not be isolated, and instead was directly hydrolyzed
lactone 8a. Dihydropyranone 8a consists of the full iridoid skeleꢀ
ton found in a large number of natural products.13 The tertꢀbutyl
ester 4p did not provide any enatioinduction to give 8a as a raceꢀ
mic mixture. In contrast, α,βꢀunsaturated Weinrebꢀamides 4q and
4r are converted to 8a and 8b in a very good selectivity of
94.5:5.5 er, respectively 98:2 er. The absolute configuration of the
cyclization was assigned by Xꢀray crystallography of 8b to be
(S).11
1
2
3
4
5
6
7
8
1e
71
77
97:3
4b 5b
2
96.5:3.5
4c 5c
9
10
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3
4
5
87
86
94
98.5:1.5
91:9
4d 5d
4e 5e
Scheme 2. Dihydropyranones from esters and amides.
Based on the preceding reports,14 the following mechanism for
the pyran cyclization is likely (Scheme 3). Initial coordination of
the alkyne and olefin moiety of substrate 4 to the cationic CpxRuII
complex initiates the catalytic cycle. Enantiodetermining oxidaꢀ
tive cyclization of 9 leads to ruthenacyclopentene 10. Isomerizaꢀ
tion of the Cꢀbound enolate to the corresponding Oꢀbound enoꢀ
late15 forms ruthenaoxacycloheptadiene 11. In turn, reductive
elimination delivers the pyran 5, closing the catalytic cycle.
98.5:1.5
4f
5f
6
95
89:11
4g 5g
4h 5h
Scheme 3. Proposed mechanism and enantiodetermining
step in the formation of pyran 5.
7
8
86
78
91:9
99:1
4i
4j
5i
5j
9
72
98:2
10
53
95
95.5:4.5
82:18
4k 5k
To gain further insights on the formation of the diketone prodꢀ
uct 6,12 several experiments for the cyclization were conducted in
wet THF (Scheme 4). Quenching the reaction directly after full
conversion (5 min), a 1:1.23 mixture of pyran 5 and diketone 6
was observed. In the presence of acid, 5 hydrolyzed slowly to 6
within 24 h. An analysis of the optical purity before the hydrolysis
revealed that 6 is formed in 91:9 er whereas 5 has a significantly
lower value of 77:23 er. The optical purity of 6 after hydrolysis
was 85:15 er, the expected averaged value.
11d
4l
5l
12
95
98:2
4m 5m
Scheme 4. Hydrative cyclization under wet conditions.
90
13
95.5:4.5
71:29
4n 6n
4o 5o
(7.5:1 dr)
14f
36
a Conditions: 0.10 mmol 4 (Z=C(CO2Me)2), 5.0 ꢁmol 3e-SbF6,
0.13 M in THF, ꢀ20 °C, 20ꢀ60 min. b Isolated yields. c Determined
by HPLC with a chiral stationary phase. d at 0 °C. e 10.0 ꢁmol 3e-
SbF6. f 10.0 ꢁmol 3b-SbF6, 23°C, 24 h.
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60
The initially detected amount of diketone 6 is formed directly
without passing by pyran 5, suggesting that two different catalytic
cycles are simultaneously operative under wet conditions. The
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