Iridium-Catalyzed Enantioselective Allylic Substitution of Enol Silanes from Vinylogous Esters and Amides

Article abstract of DOI:10.1021/jacs.5b09980

The enol silanes of vinylogous esters and amides are classic dienes for Diels-Alder reactions. Here, we report their reactivity as nucleophiles in Ir-catalyzed, enantioselective allylic substitution reactions. A variety of allylic carbonates react with these nucleophiles to give allylated products in good yields with high enantioselectivities and excellent branched-to-linear ratios. These reactions occur with KF or alkoxide as the additive, but mechanistic studies suggest that these additives do not activate the enol silanes. Instead, they serve as bases to promote the cyclometalation to generate the active Ir catalyst. The carbonate anion, which was generated from the oxidative addition of the allylic carbonate, likely activates the enol silanes to trigger their activity as nucleophiles for reactions with the allyliridium electrophile. The synthetic utility of this method was illustrated by the synthesis of the anti-muscarinic drug, fesoterodine.

Full text of DOI:10.1021/jacs.5b09980

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Article
Iridium-Catalyzed Enantioselective Allylic Substitution
of Enol Silanes from Vinylogous Esters and Amides
Ming Chen, and John F. Hartwig
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b09980 • Publication Date (Web): 06 Oct 2015
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Iridium-Catalyzed Enantioselective Allylic Substitution of
Enol Silanes from Vinylogous Esters and Amides
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Ming Chen and John F. Hartwig*
Department of Chemistry, University of California, Berkeley, California 94720, United States
Supporting Information Placeholder
ABSTRACT: The enol silanes of vinylogous esters and amides are classic dienes for Diels-Alder reactions. Here, we report their
reactivity as nucleophiles in Ir-catalyzed, enantioselective allylic substitution reactions. A variety of allylic carbonates react with
these nucleophiles to give allylated products in good yields with high enantioselectivities and excellent branched-to-linear ratios.
These reactions occur with KF or alkoxide as the additive, but mechanistic studies suggest that these additives do not activate the
enol silanes. Instead, they serve as bases to promote the cyclometallation to generate the active Ir catalyst. The carbonate anion,
which was generated from the oxidative addition of the allylic carbonate, likely activates the enol silanes to trigger their activity as
nucleophile for reactions with the allyliridium electrophile. The synthetic utility of this method was illustrated by the synthesis of
the anti-muscarinic drug, fesoterodine.
Introduction
diene and Rawal’s diene, Figure 1). In the presence of
[Ir(cod)Cl]2, the phosphoramidite (Ra,Rc,Rc)-L in Figure 1, KF
and 18-crown-6, these reactions proceeded smoothly to give
allylated products in good yields with high enantioselectivities
and excellent branched-to-linear selectivities. Mechanistic
studies revealed that KF does not activate the enol silanes to-
ward the allylic substitution. Instead, it serves as a base to
promote the cyclometallation to generate the active Ir catalyst.
The carbonate anion, which was generated from the oxidative
addition of the allylic carbonate, appears to activate the enol
silane to trigger the subsequent allylic substitution. The syn-
thetic utility of this method was illustrated by the synthesis of
the anti-muscarinic drug, fesoterodine.
Danishefsky’s diene1 and Rawal’s diene2 are widely used
reagents for Diels-Alder and hetero-Diels-Alder reactions to
synthesize carbocycles as well as oxygen- and nitrogen-
containing heterocycles.3 Although both dienes contain an enol
silane unit that could undergo nucleophilic substitution reac-
tions, they have rarely been used as nucleophiles for reactions
besides [4+2] cycloadditions4 and have not been used as nu-
cleophiles for asymmetric allylic substitutions. Ir-catalyzed
asymmetric allylations of these nucleophiles (Figure 1) would
be valuable because the reaction creates a stereocenter β to the
carbonyl group, and the vinylogous ester or amide moiety in
the resulting products can undergo a variety of subsequent
,
transformations.5 6
Iridium-catalyzed allylic substitution7-10 of such enol silanes
would be unusual because the vast majority of prior iridium-
catalyzed allylations of enolates have been conducted with
stabilized enolates containing two electron-withdrawing
groups on the nucleophilic carbon.11-12 The reactions of unsta-
bilized enolates are much less developed and have been lim-
ited in the scope of electrophile.13 In particular, reactions of
aliphatic, unstabilized enolates with aliphatic allylic esters
occurred in modest yield and enantioselectivity.13b Moreover,
the enolates of esters and amides have not undergone iridium-
catalyzed allylic substitution; therefore, it was unclear if reac-
tions of the enol silanes of vinylogous esters and amides
would react like the enol silanes of α, β-unsaturated ketones
that undergo iridium-catalyzed allylation or like the enol
silanes of esters and amides that have, so far, given low yield
of substitution products. In addition, such transformations with
these nucleophiles are challenging because the product gener-
ated from the allylic substitution with these dienes contains a
vinylogous ester or amide unit that could further react with the
enol silanes via an addition-elimination reaction sequence to
give oligomeric or polymeric products.
R
O
OTMS
Me
OMe
Ph
Ph
OMe
O
O
[Ir]
P
N
or
R
O
Me
OTBS
R
X
NMe2
(Ra, Rc, Rc)-L
NMe2
Figure 1. Proposed Ir-catalyzed Enantioselective Allylic Sub-
stitution with Danishefsky’s Diene and Rawal’s Diene
Results and discussion
Reaction Development. We began our studies by investi-
gating suitable reaction conditions for the asymmetric allylic
substitution of methyl cinnamyl carbonate (1a) with Danishef-
sky’s diene (2). Fluoride additives can promote the α-arylation
of silyl ketene acetals and α-silyl nitriles, as well as the
asymmetric allylation of enol silanes derived from keto-
nes.13a, Therefore, we evaluated several fluoride salts as the
14
additive for the reaction of 1a with 2. As shown in entry 1,
Table 1, treatment of cinnamyl carbonate 1a (1 equiv) and
silane 2 (2 equiv) with 2 mol % [Ir(cod)Cl]2 and 4 mol % of
We report conditions by which Ir-catalyzed enantioselective
allylic substitution reactions occur with unstabilized enolates
derived from vinylogous esters and amides (Danishefsky’s
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Page 2 of 9
the phosphoramidite (Ra,Rc,Rc)-L shown in Figure 1 in the linear selectivity (Table 3). Even the reaction of crotyl car-
1
2
3
4
5
6
7
8
presence of CsF (1 equiv) gave product 4a in 20% yield. The
reaction did not provide any product 4a with other fluoride
salts, such as KF or ZnF2 (entries 2-3, Table 1). When the re-
action was conducted in the presence of soluble fluoride salts,
such as TASF [tris(dimethylamino)sulfonium difluorotrime-
thylsilicate] or TBAT (tetrabutylammonium triphenyldifluoro-
silicate), only decomposition of the starting materials was
observed (entries 4-5, Table 1). The reaction with the combi-
nation of CsF (1 equiv) and 18-crown-6 (1 equiv) as the addi-
tives also led to the decomposition of the starting materials
(entry 6, Table 1). However, the reaction with KF (1 equiv)
and 18-crown-6 (1 equiv) as additives provided product 4a in
81% yield and 94% ee (entry 7, Table 1). Reactions with cata-
lytic amounts of KF and with alternative basic additives will
be discussed later in this paper.
bonate gave the allylation product in good yield with high
branched-to-linear ratio and high enantioselectivity.
Table 2. Scope of the Ir-catalyzed Enantioselective Allylic
Substitution of Allylic Carbonates 1 with Enol Silane 2.a-d
2 mol % [Ir(cod)Cl]2
R
O
OTMS
4 mol % (R)-L
+
R
OCO2Me
OMe
OMe
KF, 18-crown-6
THF, 50 °C, 12 h
1
2
4
9
10
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12
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F3C
OMe
O
O
O
OMe
OMe
OMe
4a, b:l > 50:1
4b, b:l > 20:1
4c, b:l > 50:1
81%, 94% ee
64%, 92% ee
69%, 95% ee
Me
Cl
Br
Table 1. Evaluation of the Reaction Conditions for the Ir-
catalyzed Enantioselective Allylic Substitution of Cinnamyl
Carbonate 1a with Enol Silane 2.a
O
O
O
Ph
O
2 mol % [Ir(cod)Cl]2
4 mol % (R)-L, THF
OTMS
OMe
OMe
OMe
4d, b:l > 50:1
77%, 95% ee
4e, b:l > 50:1
79%, 95% ee
4f, b:l > 50:1
71%, 96% ee
OMe
+
OCO2Me
Ph
OMe
additives
50 °C, 12 h
1a
entry
2
4a
F
Cl
F
Cl
O
yieldb
% eec
additives
O
O
1
2
3
4
5
6
7
20%
N.R.
N.R.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
94%
1.0 equiv CsF
1.0 equiv KF
OMe
OMe
OMe
0.5 equiv ZnF2
1.0 equiv TASF
1.0 equiv TBAT
4g, b:l > 50:1
83%, 96% ee
4h, b:l > 20:1
69%, 96% ee
4i, b:l > 20:1
72%, 94% ee
decomp.
decomp.
decomp.
81%
Boc
N
1.0 equiv CsF, 1.0 equiv 18-crown-6
1.0 equiv KF, 1.0 equiv 18-crown-6
N
O
O
O
O
OMe
OMe
OMe
(a) Reaction conditions: cinnamyl carbonate 1a (0.1 mmol, 1.0 equiv),
enol silane 2 (0.2 mmol, 2.0 equiv), [Ir(cod)Cl]2 (2 mol %), (Ra,Rc,Rc)-L
(4 mol %), THF (0.2 mL), 50 °C, 12 h. (b) Isolated yields of 4a are listed.
(c) Ee % of 4a was determined by chiral HPLC analysis. TASF:
[(Me2N)3S]+[SiMe3F2]-; TBAT: [Bu4N]+[SiPh3F2 ]- ; N.R.: no reaction;
N.D.: not determined.
4j, b:l > 50:1
67%, 95% ee
4k, b:l > 20:1
73%, 95% ee
4l, b:l > 50:1
78%, 93% ee
Me
O
Me
O
OMe
OMe
4m, b:l > 20:1
79%, 92% ee
4n, b:l > 20:1
75%, 90% ee
4f
Table 2 summarizes the scope of allylic carbonates 1 that
undergo the asymmetric allylation with enol silane 2 under the
developed conditions. Allylic substitution of silane 2 with a
variety of substituted cinnamyl carbonates gave the allylation
products 4a-i in good yields with high enantioselectivities.
Allylic carbonates containing heterocycles were tolerated un-
der the reaction conditions. For example, reactions of the al-
lylic carbonates substituted with a furyl, pyridyl or indolyl
group gave products 4j-l in 67-78% yield. Alkenyl- and alkyl-
substituted allylic carbonates also reacted to provide allylated
products 4m-n in 75-79% yield. In all cases, the allylated
products were obtained with ≥90% ee and >20:1 branched-to-
linear selectivity. The absolute configuration of the allylation
product 4f was determined by single crystal X-ray diffraction.
(a) Reaction conditions: allylic carbonate 1 (0.2 mmol, 1.0 equiv), enol
silane 2 (0.4 mmol, 2.0 equiv), [Ir(cod)Cl]2 (2 mol %), (Ra,Rc,Rc)-L (4 mol
%), KF (1.0 equiv), 18-crown-6 (1.0 equiv), THF (0.4 mL), 50 °C, 12 h.
1
(b) Branched-to-linear ratios (b:l) were determined by H NMR analysis
of the crude reaction mixtures. (c) Yields of isolated products are listed
(the average of at least two runs). (d) Enantioselectivities were determined
by chiral HPLC analysis.
Sequential Pd-Catalyzed Isomerization and Ir-Catalyzed
Asymmetric Allylic Substitutions. Ir-catalyzed asymmetric
allylic substitution of racemic, branched allylic esters (e.g. 6)
is a valuable transformation because these branched substrates
are readily accessible from commercially available materials.
However, Ir-catalyzed reactions of racemic, branched allylic
esters often occur with low enantioselectivities because the
Allylic substitutions with enol silane 3 (Rawal’s diene) de-
rived from the vinylogous amide were also explored, and the
results are summarized in Table 3. In general, the reactions
occurred with a wide range of allylic carbonates, including
cinnamyl carbonates containing diverse electronic properties
on the aryl ring, heteroaryl-substituted allylic carbonates,
alkenyl-substituted allylic carbonates, and alkyl-substituted
allylic carbonates. These reactions gave allylated products 5a-
o in 63-83% yield with 91-98% ee and >20:1 branched-to-
,
process occurs with retention of configuration.11i 15 To over-
come this limitation, a sequential catalytic isomerization and
asymmetric allylic substitution process was previously devel-
oped to convert racemic, branched allylic carbonates to al-
lylated products with high enantiomeric excess.16 To evaluate
whether this reaction sequence could be applicable to the
asymmetric allylation with nucleophiles 2 and 3, a series of
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Journal of the American Chemical Society
reactions with racemic, branched carbonates 6 were per- Table 4. Sequential Pd-Catalyzed Isomerization of Branched
1
formed. The results are summarized in Table 4.
Allylic Carbonates 6 and Ir-Catalyzed Asymmetric Allylic
2
Substitutions.
3
4
5
6
7
8
9
Ar
O
OCO2Me
Table 3. Scope of the Ir-catalyzed Enantioselective Allylic
Substitution of Allylic Carbonates 1 with Enol Silane 3.a-d
1 mol % Pd(dba)2
2 or 3
Ar
OCO2Me
R'
Ar
[Ir], THF
2 mol % PPh3, THF
1
4 or 5
6
2 mol % [Ir(cod)Cl]2
4 mol % (R)-L
R
O
OTBS
Me
Cl
+
OCO2Me
R
NMe2
NMe2
KF, 18-crown-6
THF, 50 °C, 12 h
1
3
5
O
O
O
10
11
12
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F
OMe
OMe
OMe
4a, b:l > 20:1
79%, 92% ee
4d, b:l > 20:1
69%, 91% ee
4e, b:l > 20:1
65%, 93% ee
O
F
O
O
NMe2
5a, b:l > 50:1
79%, 92% ee
NMe2
NMe2
NMe2
NMe2
5c, b:l > 20:1
65%, 97% ee
Me
Cl
5b, b:l > 20:1
69%, 91% ee
F
Cl
Br
O
O
O
NMe2
NMe2
NMe2
5a, b:l > 20:1
73%, 92% ee
5h, b:l > 20:1
72%, 93% ee
5e, b:l > 20:1
72%, 91% ee
O
O
O
NMe2
NMe2
Reaction conditions: Step 1: allylic carbonate 6 (0.4 mmol), Pd(dba)2 (1
mol %), PPh3 (2 mol %), THF, rt. Step 2: enol silane 2 or 3 (0.8 mmol, 2.0
equiv), [Ir(cod)Cl]2 (2 mol %), (Ra,Rc,Rc)-L (4 mol %), KF (1 equiv ), 18-
crown-6 (1 equiv), THF (0.8 mL), 50 °C, 12 h.
5d, b:l > 20:1
73%, 95% ee
5e, b:l > 50:1
72%, 93% ee
5f, b:l > 50:1
72%, 91% ee
F3C
Me
OMe
O
O
O
Mechanistic Studies: Investigation of the Role of the Ad-
ditives. To probe the effect of KF and 18-crown-6 on the Ir-
catalyzed enantioselective allylation reaction, a series of ex-
periments with methyl cinnamyl carbonate 1a and enol silane
2 were conducted. As shown in Table 5, the reaction requires
the presence of the catalyst and both of the additives. When
the catalyst or either additive was absent, the reaction did not
provide any of product 4a (entries 1-5, Table 5). However,
reactions conducted with just 0.1 equiv of KF occurred with
yields and selectivities that are similar to those of reactions
with 1 equiv of KF (entry 6, Table 5). The reaction with cata-
lytic amounts of both KF (0.1 equiv) and 18-crown-6 (0.1
equiv) also afforded the allylated product 4a, albeit in a slight-
ly lower yield (entry 7, Table 5). Because a stoichiometric
amount of KF is not required, it is unlikely that a potassium
enolate (derived from KF and enol silane 2) is the nucleophile
in these reactions. This assertion is supported by NMR spec-
troscopy. The 1H NMR signals of enol silane 2 did not change
when silane 2 was treated with 1.0 equivalent of KF and 1.0
equivalent of 18-crown-6 in d8-THF at 50 °C for 12 h.
NMe2
NMe2
5g, b:l > 20:1
63%, 92% ee
5h, b:l > 50:1
80%, 94% ee
5i, b:l > 20:1
69%, 94% ee
Cl
Boc
N
OMe
O
Cl
O
O
NMe2
NMe2
NMe2
5j, b:l > 50:1
72%, 96% ee
5k, b:l > 20:1
75%, 92% ee
5l, b:l > 50:1
83%, 94% ee
Me
O
O
Me
O
O
NMe2
5m, b:l > 50:1
68%, 98% ee
NMe2
5n, b:l > 20:1
69%, 98% ee
NMe2
5o, b:l > 20:1
68%, 93% ee
(a) Reaction conditions: allylic carbonate 1 (0.2 mmol, 1.0 equiv), enol
silane 3 (0.4 mmol, 2.0 equiv), [Ir(cod)Cl]2 (2 mol %), (Ra,Rc,Rc)-L (4 mol
%), KF (1.0 equiv), 18-crown-6 (1.0 equiv), THF (0.4 mL), 50 °C, 12 h.
1
(b) Branched-to-linear product ratios (b:l) were determined by H NMR
analysis of the crude reaction mixtures. (c) Yields of isolated products are
listed (the average of at least two runs). (d) Enantioselectivities were de-
termined by chiral HPLC analysis.
We considered that KF could be facilitating the generation
of the metallcyclic catalyst by serving as a base. If so, other
bases should be able to replace KF, the base would not be
needed in stoichiometric amounts, and a preformed metallacy-
clic Ir catalyst should be able to catalyze the reaction without
any additive. Studies with several different bases in varying
amounts are shown in Table 5. These studies showed that the
allylic substitution with 0.1 equiv of KOMe and either 1.0
equiv or 0.1 equiv of 18-crown-6 provided allylated product
4a in 43-49% yield (entries 8-9, Table 5). A significant
amount of cinnamyl alcohol was also isolated from these reac-
tions. When 4 mol% of KOMe and 0.1 equiv of 18-crown-6
were used, the amount of cinnamyl alcohol byproduct de-
creased to 11% (entry 10, Table 5). The formation of cinnamyl
alcohol was completely suppressed by utilizing the t-butyl
cinnamyl carbonate as the electrophile, affording product 4a in
83% yield (entry 11, Table 5).17
The isomerization reactions of branched cinnamyl car-
bonates 6 were conducted in the presence of 1 mol% of
Pd(dba)2 and 2 mol% PPh3. Typically, the process was com-
1
plete within 1-4 h, based on H NMR analysis of the crude
reaction mixture. After isomerization, the reaction mixture
was filtered through silica, and the resulting crude linear car-
bonate in THF was subjected to the Ir-catalyzed allylic substi-
tution with silanes 2 or 3 under the standard reaction condi-
tions. This reaction sequence provided the allylated products 4
and 5 in 65-79% yield and 91-93% ee. Using this reaction
sequence, racemic, branched cinnamyl carbonates 6 were ef-
fectively converted to enantioenriched products 4 and 5.
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Table 5. Evaluation of the Effect of Additives on the Ir-
catalyzed Enantioselective Allylic Substitution of Carbonate
1a with Enol Silane 2.a,b
the presence of 1 equiv of Bu4NOAc as the additive were per-
1
formed.18 This system led to complete decay of the H NMR
1
2
3
4
5
6
7
8
signals corresponding to allyl complex 8 after 30 minutes at
ambient temperature and formed a 1:0.3:1 mixture of the silyl
ether of allylated product 9, allylated product 4a, and cinnam-
yl acetate 10 (entry 3, Table 6). The same reaction conducted
for 18 hours formed a 1:0.4 mixture of 9 and 4a (entry 4, Ta-
ble 6). The reaction conducted in the presence of 1.0 equiv of
KF, 18-crown-6 and Bu4NOAc gave a 1:0.5:1 mixture of 9, 4a
and 10 (entry 5, Table 6). After 12 h at ambient temperature,
4a became the major component of the reaction mixture (entry
6, Table 6). Product 4a was isolated in 78% yield, with >20:1
branched-to-linear selectivity and 92% ee, which is consistent
with the results of the catalytic reaction shown in Table 2.
These results are consistent with our hypothesis that the car-
bonate anion activates enol silane 2 for the subsequent addi-
tion to the allyliridium intermediate.
OTMS
2 mol % [Ir(cod)Cl]2
4 mol % (R)-L, THF
Ph
O
+
OCO2Me
Ph
OMe
OMe
additives
50 °C, 12 h
1a
2
4a
entry
yield
additives
1
2
81%
N.R.
N.R.
N.R.
N.R.
76%
69%
43%
49%
69%
83%
23%
1.0 equiv KF, 1.0 equiv 18-crown-6
no additives (no KF and 18-crown-6)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
no catalyst, 1.0 equiv KF, 1.0 equiv 18-crown-6
1.0 equiv KF, no 18-crown-6
4
5
no KF, 1.0 equiv 18-crown-6
6
0.1 equiv KF, 1.0 equiv 18-crown-6
0.1 equiv KF, 0.1 equiv 18-crown-6
0.1 equiv KOMe, 1.0 equiv 18-crown-6
0.1 equiv KOMe, 0.1 equiv 18-crown-6
4 mol % KOMe, 0.1 equiv 18-crown-6
4 mol % KOMe, 0.1 equiv 18-crown-6
0.1 equiv KOt-Bu, 0.1 equiv 18-crown-6
7
8
9
10
11c
12
Table 6. Stoichiometric Reactions of Ir-allyl Complex 8 with
Enol Silane 2.
(a) Reaction conditions: cinnamyl carbonate 1a (0.1 mmol, 1.0 equiv),
enol silane 2 (0.2 mmol, 2.0 equiv), [Ir(cod)Cl]2 (2 mol %), (Ra,Rc,Rc)-L
(4 mol %), THF (0.2 mL), 50 °C, 12 h. (b) Isolated yields were listed. (c)
t-Butyl cinnamyl carbonate was utilized.
O
O
Ph
OTMS
Finally, the reaction catalyzed by the preformed metallacy-
clic Ir catalyst 7 was performed. The reaction of 1a and 3 cata-
lyzed by 4 mol% of the Ir-ethylene complex 7 in the absence
of other additives formed the allylation product 5a in 62%
yield and 93% ee (Scheme 1). On the basis of these data, we
conclude that KF, KOMe, and KOt-Bu serve as bases to pro-
mote the formation of the metallacyclic Ir catalyst, not as
Lewis base to bind and activate the enol silanes.
d8-THF
Ir
P
N
+
BF4
conditions
OMe
Me
2
Ph Ph
8
OTMS
O
+
+
Ph
OAc
OMe
OMe
4a
10
9
entry
conditions
ratio (9:4a:10)
Scheme 1. Allylic Substitution of 1a with Enol Silane 3 in the
Presence of the Ir-ethylene Complex 7 as the Catalyst.
1
2
3
4
5
6
no KF, 1.0 equiv 18-crown-6, 50 °C, 12 h
1.0 equiv KF, 1.0 equiv 18-crown-6, 50 °C, 12 h
N.R.
N.R.
Ph
O
OTBS
no KF, no 18-crown-6, 1 equiv Bu4NOAc, rt, 0.5 h
no KF, no 18-crown-6, 1 equiv Bu4NOAc, rt, 18 h
1:0.3:1
1:0.4:0
1:0.5:1
0:10:1
4 mol% 7, THF
50 °C, 12 h
NMe2
5a, 62%, 93% ee
Ph
OCO2Me
+
NMe2
1.0 eq KF, 1.0 eq 18-crown-6, 1 eq Bu4NOAc, rt, 0.5 h
1.0 eq KF, 1.0 eq 18-crown-6, 1 eq Bu4NOAc, rt, 12 h
1a
3
O
Resting State of the Catalyst in the Catalytic Reaction
with the Catalyst Generted in situ. To identify the resting
state of the catalyst in the reaction, we monitored by 31P NMR
spectroscopy the reaction catalyzed by the system generted in
situ from [Ir(cod)Cl]2, (Ra,Rc,Rc)-L, KF and 18-crown-6. The
31P spectra were recorded after 10 min, 1 hour, 2 hours and 12
hours at 50 °C. The 31P spectra of this reaction indicated that
the major iridium complex in solution is complex A (δ 115.6
ppm) , which is catalytically inactive (Scheme 2). In the pres-
ence of a base, cyclometalated Ir-complex B, which is the
active catalyst for the allylic substitution, is generated. How-
ever, complex B was not present in amounts detectable by 31P
spectroscopy. These data suggested that the equilibrium
between the acyclic complex A and cyclometallated complex
B lies to the side of complex A. Only a small amount of the
active catalyst, complex B, is generated.
O
Ir
P
N
Me
7
Ph
Ph
Stoichiometric Reactions of Ir-allyl Complexes. To gain
further insight into the mechanism of the reaction, Ir-allyl
complex 8 was synthesized,8e-f and stoichiometric reactions of
complex 8 with enol silane 2 were performed (Table 6). As
expected, the stoichiometric reaction did not occur in the ab-
sence of the added KF (entry 1, Table 6). However, the reac-
tion also did not form the allylation product 4a when the sto-
ichiometric reaction was conducted in the presence of 1 equiv
of KF and 1 equiv of 18-crown-6 for 12 h at 50 °C (entry 2,
Table 6). This result is consistent with the conclusion that KF
does not serve to activate enol silane 2 in the allylation reac-
tion.
These data also suggest that the rate of the reaction with a
cyclometalated Ir-complex, such as 7 in Scheme 1, should be
significantly faster than the rate of the reaction with the cata-
lyst generted in situ. Indeed, when the reaction was conducted
with 4 mol % Ir-ethylene complex 7 as the catalyst, product 5a
We hypothesized that the carbonate anion (generated from
the oxidative addition of the allylic carbonate in the catalytic
reaction) activates enol silane 2. To probe this hypothesis,
stoichiometric reactions of Ir-complex 8 and enol silane 2 in
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Journal of the American Chemical Society
was obtained in 75% yield with 93% ee at ambient tempera- To evaluate the generality of reactions with the cyclometala-
1
2
3
4
5
6
7
8
ture after 24 h. In contrast, the reaction with the catalyst gener-
ted in situ provided the product in less than 5% yield at ambi-
ent temperature after 24 h (Scheme 2). These data are consis-
tent with the obsevation that complex A is the resting state of
the iridium in the reaction when the catalyst is generated in
situ and that a small amount of the active catalyst, complex B,
is generated from cyclometalation of A promoted by KF.
ted Ir-ethylene complex 7 as the catalyst, reactions of several
allylic carbonates were conducted, and the results are summa-
rized in Table 7. Reactions with electron-rich or electron-
neutral cinnamyl carbonates were complete in 24 h at ambient
temperature (entries 1-3, Table 7). The rates of the reactions
with less reactive substrates, such as electron-poor or alkyl-
substituted allylic carbonates, were slower at ambient tempera-
ture (entries 4-6, Table 7), but occurred to completion in 12 h
at 40 °C. In general, the yield and enantioselectivity of the
products obtained from the reactions catalyzed by the cyclo-
metalated Ir-ethylene complex 7 were comparable to those
with the catalyst generated in situ. It has been shown that ally-
lic substitution of 2-methoxy cinnamyl carbonate gave prod-
ucts with moderate enantioselectivity.13b Under the reaction
conditions described in Table 3, the allylation of 2-methoxy
cinnamyl carbonate with silane 3 provided product 5p in 76%
yield with 80% ee. In contrast, when the reaction was con-
ducted at ambient temperature with the cyclometalated Ir-
ethylene complex 7 as the catalyst, product 5p was obtained in
87% yield with 87% ee. The high reactivity of complex 7 al-
lowed the reaction to be run at 0 °C, and at this temperature,
the enantiomeric excess of product 5p improved to 89% ee
(entry 7, Table 7).
9
Scheme 2. Analysis of the Identity and Reactivity of the Rest-
ing State of the Catalytic System.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
I
Cl
O
O
Ir
KF, THF
Ir
+ KCl + HF
O
P
N
O
P
N
18-crown-6
Me
Me
Me
Ph
Ph
Ph
Ph
A, resting state, 31P: 115.6 ppm
B
II
Ph
O
OTBS
4 mol% 7
NMe2
5a, 75%, 93% ee
+
+
Ph
Ph
OCO2Me
NMe2
THF, rt, 24 h
1a
3
2 mol % [Ir(cod)Cl]2
4 mol % (R)-L
Ph
O
OTBS
OCO2Me
NMe2
NMe2
KF, 18-crown-6
THF, rt, 24 h
1a
3
5a, < 5%
Table 8. Ir-catalyzed Enantioselective Allylic Substitution
with KOMe and 18-Crown-6 as the Additives.a-e
I. Resting state of the reaction with the catalyst generted in situ.
II. Comparison of the reaction at room temperature catalyzed by
the cyclometallated, ethylene complex 7 and by the catalyst gene-
rated in situ.
2 mol % [Ir(cod)Cl]2
R
O
O[Si]
4 mol % (R)-L
+
OCO2t-Bu
R'
R
R'
4 mol% KOMe
10 mol% 18-crown-6
THF, 50 °C, 12 h
11
2 or 3
4 or 5
Table 7. Enantioselective Allylic Substitution with Ethylene
Complex 7 as the Catalyst.a-d
Me
OMe
R
O
OTBS
O
O
O
4 mol % 7, THF
+
OCO2Me
R
NMe2
NMe2
OMe
OMe
OMe
RT, 24 h
or 40 °C, 12 h
1
3
5
4a, b:l > 50:1
4d, b:l > 50:1
4c, b:l > 20:1
83%, 93% ee
74%, 95% ee
73%, 93% ee
Me
OMe
Me
OMe
O
O
O
O
O
O
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
5a, b:l > 50:1
75%, 93% ee
5h, b:l > 50:1
88%, 94% ee
5i, b:l > 50:1
86%, 95% ee
5a, b:l > 50:1
74%, 93% ee
5h, b:l > 50:1
78%, 93% ee
5i, b:l > 20:1
77%, 94% ee
F3C
Me
Me
Me
O
O
O
Me
O
O
OMe
OMe
4n, b:l > 20:1
68%, 89% ee
4m, b:l > 20:1
72%, 91% ee
NMe2
NMe2
NMe2
5g, b:l > 50:1
73%, 92% ee
5n, b:l > 20:1
71%, 96% ee
5o, b:l > 20:1
75%, 94% ee
(a) Reaction conditions: allylic carbonate 16 (0.2 mmol, 1.0 equiv), enol
silane 2 or 3 (0.4 mmol, 2.0 equiv), [Ir(cod)Cl]2 (2 mol %), (Ra,Rc,Rc)-L (4
mol %), KOMe (4 mol %), 18-crown-6 (10 mol %), THF (0.4 mL), 50 °C,
conditions in Table 3
b:l > 50:1
76%, 80% ee
1
12 h. (b) Branched-to-linear product ratios (b:l) were determined by H
NMR analysis of the crude reaction mixtures. (c) Yields of isolated prod-
ucts are listed. (d) Enantioselectivities were determined by chiral HPLC
analysis. (e) t-Butyl allyl carbonates 11 were utilized to suppress the for-
MeO
O
with catalyst 7, rt, 24 h
b:l > 50:1
87%, 87% ee
with catalyst 7, 0 °C, 48 h
b:l > 50:1
70%, 89% ee
NMe2
5p
mation of allylic alcohol side products.
(a) Reaction conditions: allylic carbonate 1 (0.2 mmol, 1.0 equiv), enol
silane 3 (0.4 mmol, 2.0 equiv), 7 (4 mol %), THF (0.4 mL), rt, 24 h or 40
°C, 12 h. (b) Branched-to-linear product ratios (b:l) were determined by
1H NMR analysis of the crude reaction mixtures. (c) Yields of isolated
products are listed. (d) Enantioselectivities were determined by chiral
HPLC analysis.
Reactions with Substoichiometric Alkoxide Activator. To
assess the generality of the reactions with either KOMe/18-
crown-6 or Bu4NOAc as the additive, a set of reactions of
several allylic carbonates with enol silanes 2 and 3 were con-
ducted, and the results are summarized in Tables 8 and 9. In
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Journal of the American Chemical Society
general, allylic substitution of enol silanes 2 and 3 proceeded
Page 6 of 9
1
2
3
4
5
6
7
8
smoothly with either KOMe/18-crown-6 or Bu4NOAc as the
additive. The allylated products were obtained in comparable
yields, enantioselectivities and branched-to-linear selectivities
as those obtained from the reactions conducted with KF and
18-crown-6 as the additive.
Me
Me
Me
Me
Me
N
OH
Me
Me
N
Me
O
Me HO
Me
Me
O
(R)-tolterodine (Detrol LA)
fesoterodine
(Toviaz)
Cl
Cl
Table 9. Ir-catalyzed Enantioselective Allylic Substitution
with Bu4NOAc as the Additive.a-d
O
O
OMe
9
2 mol % [Ir(cod)Cl]2
4 mol % (R)-L
O[Si]
R
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
OCO2Me
R
R'
R'
OMe
NMe2
OMe
OH
10 mol% Bu4NOAc
THF, 50 °C, 12 h
NH
1
2 or 3
4 or 5
Me
OMe
sertraline (Zoloft)
(R)-4-methoxydalbergione
mimosifoliol
Me
OMe
Figure 2. Representive Enantioenriched Bisarylalkane Contain-
ing Natural Products and Pharmaceuticals.
O
O
O
OMe
OMe
4a, b:l > 20:1
72%, 92% ee
4d, b:l > 20:1
70%, 93% ee
4c, b:l > 20:1
63%, 95% ee
However, these methods do not translate to the synthesis of
fesoterodine because the synthesis of this compound requires a
polysubstituted aryl nucleophile or a polysubstituted electro-
phile that is not commercially available. Therefore, a multi-
step preparation of the requisite polysubstituted aryl halides or
arylboronic acids would be required. In fact, almost all the
routes to prepare enantioenriched fesoterodine rely on kinetic
Me
OMe
O
O
O
NMe2
NMe2
5a, b:l > 20:1
72%, 91% ee
5h, b:l > 20:1
68%, 94% ee
5i, b:l > 20:1
62%, 92% ee
,23
resolution of a racemic intermediate.22
Me
Scheme 3. Enantioselective Synthesis of Fesoterodine.
Me
O
O
OMe
OMe
4n, b:l > 20:1
62%, 90% ee
4m, b:l > 20:1
67%, 95% ee
Me
Me
Me
N
OH
(a) Reaction conditions: carbonate 1 (0.2 mmol, 1.0 equiv), enol silane 2
or 3 (0.4 mmol, 2.0 equiv), [Ir(cod)Cl]2 (2 mol %), (Ra,Rc,Rc)-L (4 mol
%), Bu4NOAc (10 mol%), THF (0.4 mL), 50 °C, 12 h. (b) Branched-to-
linear product ratios (B:L) were determined by H NMR analysis of the
crude reaction mixtures. (c) Yields of isolated products are listed. (d)
Enantioselectivities were determined by chiral HPLC analysis.
CO2Et
NMe2
Me
O
Me
Me
TBSO
1
O
fesoterodine
(Toviaz)
12
1) NaHMDS, −78 to −40 °C;
TBSCl, −78 °C to rt, THF
O
Synthetic Applications of the Allylation of Danishefsky
and Rawal Dienes. Enantioenriched 1,1-diarylalkanes are
present in many biologically active natural products and
pharmaceutical agents,19 such as methoxydalbergione, mimosi-
foliol as well as Toviaz, Detrol LA and Zoloft (Figure 2).20
Because of the importance of enantioenriched 1,1-
diarylalkanes in the synthesis of natural products and pharma-
ceutical candidates, significant effort has been devoted to the
development of enantioselective methods to access these mol-
ecules.21
CO2Et
NMe2
2) toluene, 50 °C
5a
CO2Et
TBSO
13, 77%
DIBAL
TBSCl, Im
OH
OTBS
THF, 0 °C
DMF, rt
TBSO
TBSO
14, 89%
15, 96%
Fesoterodine and tolterodine are antimuscarinic drugs that
contain an enantioenriched 1,1-diarylalkane structural motif
(Figure 2). Many routes have been developed for the synthesis
of tolterodine,20 In contrast, approaches to its closely related
analog, fesoterodine, the active ingredient of Toviaz, are lim-
H
1. NaBH(OAc)3
DIPA, DCE, rt
1. 9-BBN, THF then NaBO3
2. Dess-Martin, CH2Cl2, rt
O
OTBS
2. TBAF, THF, rt
TBSO
16, 77% in two steps
,23
ited.22 The enantioenriched 1,1-diarylalkane structural motif
Me
in tolterodine has been synthesized by several different asym-
metric transformations, including Rh-catalyzed asymmetric
addition of arylboronic acids to coumarins and Pd-catalyzed
asymmetric cross coupling of aryl halides with alkyl boro-
nates. These reactions are conducted with commercially avail-
able arylboronic acids and aryl halides.20
Me
ref 22
Me
Me
N
OH
Me
Me
N
OH
Me
O
Me HO
17, 76% over two steps
Me
Me
O
fesoterodine
(Toviaz)
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Journal of the American Chemical Society
company may benefit financially from the expected results of the
PHS-funded research conducted in his laboratory.
We envisioned an alternative strategy to construct the enan-
1
2
3
4
5
6
7
8
tioenriched 1,1-diarylalkane motif in fesoterodine that would
be enabled by the iridium-catalyzed allylic substitution devel-
oped in the current study. The substituted aryl group would be
formed by a [4+2] cycloaddition between a dienophile (e.g.
ethyl propiolate) and a diene (e.g. 12), which would be derived
from compound 5, a product of asymmetric allylic substitution
with a Rawal diene as nucleophile (Scheme 3). The enantio-
meric excess of compound 5 would translate to that of the 1,1-
diarylalkane cycloaddition adduct.
REFERENCES
1.
2.
3.
Danishefsky, S. J.; Kitahara, T. J. Am. Chem. Soc. 1974, 96, 7807.
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9
The synthesis of fesoterodine by this strategy is shown in
Scheme 3. The vinylogous amide 5a was prepared according
to the procedure described in Table 3. Compound 5a was then
converted into diene 12 with NaHMDS and TBSCl.2 [4+2]
Cycloaddition of diene 12 and ethyl propiolate at 50 °C in
toluene provided 1,1-diarylalkane 13 in 77% yield from 5a.
DIBAL reduction of the ethyl ester of 13 gave alcohol 14,
which was then protected as the bis-TBS ether 15. Hydrobora-
tion and oxidation of 15, followed by Dess-Martin oxidation24
of the resulting primary alcohol afforded aldehyde 16 in 77%
yield over two steps. Reductive amination25 of aldehyde 16
with diisopropyl amine and NaBH(OAc)3, followed by depro-
tection of the two TBS groups with TBAF provided amine 17
in 76% yield. Amine 17 can be converted to fesoterodine in
one step by a procedure reported by Dirat and co-workers. 22
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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27
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Conclusion
In conclusion, we have developed the Ir-catalyzed enantio-
selective allylic substitution of enol silanes derived from viny-
logous esters and amides. Asymmetric allylation of a wide
variety of allylic carbonates with silanes 2 or 3 gave vinylo-
gous esters 4 or amides 5 in good yields with high enantiose-
lectivities and excellent branched-to-linear selectivities. Sub-
sequent studies revealed that the additive KF does not bind to
the enol silanes and activate them for addition to the allyl in-
termediate. Instead, KF promotes cyclometalation to generate
the active iridacyclic catalyst. The carbonate anion, which was
generated from the oxidative addition of the allylic carbonate
to the iridacycle serves as the activator of the enol silanes to
trigger the subsequent nucleophilic addition.26 This conclusion
allowed the development of reaction conditions for the asym-
metric allylation with enol silanes 2 and 3 in the presence of
acetate or alkoxide bases. The synthetic utility of this reaction
was demonstrated by the enantioselective synthesis of fesoter-
odine through a [4+2] cycloaddition approach for the synthesis
of the enantioenriched 1,1-diarylalkane. Further studies with
these nucleophiles are currently underway in this laboratory.
6.
7.
For recent reviews of Ir-catalyzed asymmetric allylation, see: (a) Helm-
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8.
9.
For seminal contributions, see: (a) Takeuchi, R.; Kashio, M. Angew.
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ASSOCIATED CONTENT
Experimental procedures and spectroscopic data for all new com-
pounds (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
jhartwig@berkeley.edu
Funding Sources
Financial support provided by the National Institutes of Health
(GM-58108) is gratefully acknowledged. We thank Johnson-
Matthey for gifts of [Ir(cod)Cl]2. M.C. thanks Dr. Wenyong Chen
for helpful discussions. J.F.H. is a founder of Catylix; he and the
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4a in 23% yield. Reactions with amine bases such as TBD did not pro-
vide any product 4a.
18. It has been shown that the acetate anion of Bu4NOAc can serve as the
carbonate anion equivalent in allylic substitution reactions, see reference
10a.
26. We have conducted studies to investigate the role of KF with the previ-
ously reported nucleophiles in ref 10e and 10f. The results are consistent
with the conclusion that it serves as a base to promote the formation of
active catalyst in allylic substitution, rather than activating the nucleo-
phile.
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O
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OTMS
OMe
4: 64-83%
90-96% ee
b:l > 20:1
OMe
2 mol % [Ir(cod)Cl]2
4 mol % (R)-L, THF
2
+
OCO2Me
R
1
KF, 18-crown-6
50 °C, 12 h
OTBS
R
O
NMe2
NMe2
3
5: 63-83%
91-98% ee
b:l > 20:1
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