Palladium-catalyzed asymmetric benzylation of azlactones

Article abstract of DOI:10.1002/chem.201302390

Asymmetric benzylation of prochiral azlactone nucleophiles enables the catalytic introduction of a benzyl group towards the synthesis of α,α-disubstituted amino acids. Herein, we report an enantioselective palladium-catalyzed process using chiral bis(diphenylphosphinobenzoyl)diamine (dppba) ligands. Naphthalene- and heterocycle-based methyl carbonates react with a number of azlactones derived from both natural and unnatural amino acids. Monocyclic benzylic electrophiles, for which the barrier to ionization is higher, must employ a phosphate leaving group in order to react. Reaction conditions for electron-rich and -neutral benzylic electrophiles have been developed, and the scope of the reaction has been explored with respect to both reaction partners. The high levels of asymmetric induction, as well as the reactivity pattern of the electrophiles, suggest an η³-benzyl intermediate that arises through two distinct pathways. Attack on benzyl: Palladium-catalyzed asymmetric benzylation methodology is demonstrated on prochiral azlactone nucleophiles. The use of naphthyl, heterocyclic, and monocyclic benzylic electrophiles demonstrates the wide reaction scope (see scheme; Cp=cyclopentadienyl). The benzylation products are readily converted into enantioenriched α,α-disubstituted amino acids.

Full text of DOI:10.1002/chem.201302390

FULL PAPER
DOI: 10.1002/chem.201302390
Palladium-Catalyzed Asymmetric Benzylation of Azlactones
Barry M. Trost* and Lara C. Czabaniuk[a]
Abstract: Asymmetric benzylation of
from both natural and unnatural amino
acids. Monocyclic benzylic electro-
philes, for which the barrier to ioniza-
tion is higher, must employ a phos-
phate leaving group in order to react.
Reaction conditions for electron-rich
and -neutral benzylic electrophiles
prochiral azlactone nucleophiles ena-
bles the catalytic introduction of a
benzyl group towards the synthesis of
a,a-disubstituted amino acids. Herein,
we report an enantioselective palladi-
um-catalyzed process using chiral bis-
have been developed, and the scope of
the reaction has been explored with re-
spect to both reaction partners. The
high levels of asymmetric induction, as
well as the reactivity pattern of the
electrophiles, suggest an h3-benzyl in-
termediate that arises through two dis-
tinct pathways.
ACHTUNGTRENNUNG(diphenylphosphinobenzoyl)diamine
Keywords: amino acids · asymmet-
ric catalysis · azlactones · benzyla-
tion · palladium
(dppba) ligands. Naphthalene- and het-
erocycle-based methyl carbonates react
with a number of azlactones derived
Introduction
Palladium-catalyzed benzylation processes have been devel-
oped to effect the reaction of benzylic electrophiles with
both carbon and heteroatom nucleophiles.[1] In the absence
of detailed mechanistic data, the proposed mechanism for
this process is analogous to that for allylic alkylation. De-
spite the similarities between the two net processes, the
structural differences between a benzyl and an allyl group
may suggest a different mechanistic pathway. On the one
hand, allylic alkylation is initiated by p coordination to pal-
ladium, facilitating ionization to a cationic h3 intermediate
(Scheme 1, path A).[2] On the other hand, studies by Stille
and co-workers on the oxidative addition of palladium(0) to
benzyl halides suggest an SN2 displacement reaction by pal-
ladium to form the h1 species (Scheme 1, path B).[3] This in-
termediate could then isomerize to form the p complex and
complete the catalytic cycle.
Scheme 1. Potential mechanistic pathways for the palladium-catalyzed
benzylation reaction.
The structure of the cationic intermediate also remains
unclear. Formation of the p-benzyl palladium complex re-
quires the dearomatization of the aryl system, perhaps disfa-
voring this intermediate. A number of h3-palladium–benzyl
complexes have been synthesized and characterized, demon-
strating that isomerization to the p complex is feasible.[4]
One way to probe the proposal for the h3 structure of the
catalytic benzylation intermediate would be to examine the
ability of the chiral ligands that induce good enantioselectiv-
ity in allylation reactions to effect asymmetric induction in
the benzylation processes.
Chiral bis(diphenylphosphinobenzoyl)diamine (dppba) li-
gands (Figure 1) have been shown to induce high levels of
enantioselectivity in a broad range of asymmetric allylic al-
kylation (AAA) reactions.[5] We recently reported the suc-
cess of these ligands in a method for asymmetric benzylic al-
kylation of a prochiral oxindole nucleophile.[6] Given our
successes in this area, we sought to develop a process for
highly enantioselective catalytic benzylation of azlactones.
Azlactones are synthesized from amino acids through acy-
lation and dehydrative cyclization and are highly reactive at
the acidic 4-position.[7] Asymmetric functionalization of
azlactones can be achieved through phase-transfer alkyla-
tion,[8] Mannich addition,[9] and Michael reactions.[10] Trost
and co-workers have developed methodology for asymmet-
ric allylation of azlactones by using a number of electro-
[a] Prof. B. M. Trost, Dr. L. C. Czabaniuk
Department of Chemistry, Stanford University
337 Campus Drive Stanford, CA 94305 (USA)
E-mail: bmtrost@stanford.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302390.
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lectivity was maintained in
CH2Cl2, and the yield in-
creased to 95% (Table 1,
entry 9). Incomplete conver-
sion of the starting materials
and lower yields were observed
in dichloroethane (DCE) and
MeCN, but the observed ee re-
mained high (Table 1, en-
tries 10 and 11). As was previ-
ously seen,[9] the presence of
tBuOH was beneficial both to
the reactivity and the enantio-
selectivity of the benzylation; a
Figure 1. Bisphosphine ligands used in asymmetric allylation and benzylation.
Table 1. Selected optimization experiments for the benzylation reaction
with a naphthalene electrophile.[a]
philes in the presence of chiral bidentate ligands, under both
palladium and molybdenum catalysis.[11]
Catalytic asymmetric benzylation of prochiral azlactones
would provide access to a,a-disubstituted amino acids con-
taining a benzylic substituent. Currently, levels of enantioin-
duction in the phase-transfer benzylation of an azlactone
are moderate, and substrates aside from benzyl bromide
have not been investigated.[8a] The interesting biological and
pharmaceutical properties of a,a-disubstituted amino acids
have driven the development of synthetic methods towards
these products.[12] Traditionally, enantioenriched amino acids
have been obtained through chiral resolution and the use of
chiral auxiliaries; more recently, a number of methods for
the asymmetric synthesis of chiral a,a-disubstituted amino
acids have been developed.[13]
A preliminary report of the asymmetric benzylation of
azlactones has demonstrated the ability to access a,a-disub-
stituted amino acids without the need for chiral auxiliaries
or resolution processes.[14] Herein, we report the develop-
ment of the method, its broad scope, and the implications of
this work for the mechanism of palladium-catalyzed benzy-
lation reactions.
Entry
L*
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12[d]
13[e]
L1
L2
L3
L4
L3
L3
L3
L3
L3
L3
L3
L3
L3
dioxane
dioxane
dioxane
dioxane
DME
22
0
76
–
67
76
52
48
71
89
95
49
45
43
92
86
30
85
90
93
93
93
91
90
86
93
THF
toluene
benzene
CH2Cl2
DCE
MeCN
CH2Cl2
CH2Cl2
[a] Reactions performed on a 0.2 mmol scale at 0.4m by using 1 (1 equiv),
2a (1 equiv), [(h3-C3H5)PdCp] (5.0 mol%), L* (6.0 mol%), and tBuOH
(5 equiv) for 20 h. [b] Yield of the isolated product. [c] Determined by
chiral HPLC. [d] Reaction performed without tBuOH. [e] Reaction run
for 3 h.
Results and Discussion
Asymmetric benzylation with naphthalene- and heterocycle-
based electrophiles: Initial studies into the benzylation of
azlactone nucleophiles investigated the reaction between
carbonate 1 and alanine-derived azlactone 2a. By using con-
ditions previously developed for asymmetric benzylation, a
screen of Trost-style chiral bisphosphine ligands (Figure 1)
was performed. Superior reactivity was observed in the pres-
ence of L3 and L4 (Table 1, entries 3 and 4), and benzylated
product 3a was obtained in 86% ee when L3 was employed
(Table 1, entry 3). Reaction in ethereal solvents (dime-
thyoxyethane (DME) and THF) provided 3 in moderate
yield and comparable enantioselectivites to dioxane
(Table 1, entries 5 and 6). The yield of the isolated product
and enantioselectivity increased in aromatic solvents (tol-
uene and benzene; Table 1, entries 7 and 8). High enantiose-
drop in yield (43%) and ee (86%) was observed in the ab-
sence of the additive (Table 1, entry 12). Studies into the re-
action time showed that the reaction was complete in three
hours, furnishing 3 in 92% yield and 93% ee (Table 1,
entry 13)
With conditions for the benzylation of an azlactone in
high yield and enantioselectivity in hand, we turned our at-
tention towards the investigation of the reaction scope. A
series of azlactones with varying steric demands were sub-
jected to the optimized conditions in the reaction with 1.
Azlactones derived from leucine and phenylalanine (2b and
2c, respectively), were benzylated in high yield and enantio-
selectivity (Table 2, entries 1 and 2). Use of azlactone 2d
demonstrated that a thioether was a compatible functionali-
ty under the reaction conditions (Table 2, entry 3). Valine-
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Asymmetric Benzylation of Azlactones
FULL PAPER
Table 2. Scope of the asymmetric benzylation towards the nucleophile
with a naphthalene electrophile.[a]
pressive 89% ee (Table 2, entry 5). An aryl-substituted
azlactone (2g) was also highly reactive. At ambient temper-
ature, 3g was formed in 81% ee; higher enantioselectivity
was obtained at 48C (Table 2, entry 6).
An investigation into the scope of the reaction with re-
spect to the electrophile was conducted with a number of
methyl carbonates under the optimized reaction conditions.
The isomeric 2-naphthalene electrophile 4a was highly reac-
tive and selective, providing 5a in 70% yield and 95% ee
(Table 3, entry 1). Electron-donating and -withdrawing
groups at the 4-position of naphthalene were well tolerated
with respect to the reactivity and selectivity (Table 3, en-
tries 2 and 3). The compatibility of an aryl bromide in this
Pd0-catalyzed benzylation process is particularly noteworthy.
Sulfur heterocycles are also compatible in the reaction.
Thus, a benzothiophene electrophile provided 5d in 88%
yield and 86% ee (Table 3, entry 4). A somewhat lower
yield was obtained when benzofuran-containing electrophile
4e was utilized, but the enantioselectivity was quite high, at
87% (Table 3, entry 5). An indole-based electrophile pro-
vided the product in lower enantioselectivity (Table 3,
entry 6), likely due to an increase in the amount of the back-
ground reaction with such an electron-rich heterocycle. A
survey of monocyclic heterocyclic electrophiles was also per-
formed for reaction with azlactone 2a. Thiophene-based
electrophile 4g reacted to form 5g in 78% yield and
91% ee (Table 3, entry 7). Similar reactivity, but lower enan-
tioselectivity, was observed with the furan electrophile 4h
(Table 3, entry 8).
Entry Nucleophile
Product
Yield ee
[%][b] [%][c]
1
2b
2c
2d
2e
2 f
3b 95
80
95
94
94
89
2
3c 97
3d 97
3e 96
3 f 36
3
4[d]
To determine the absolute configuration of the benzylated
products, 5a was hydrolyzed in HCl (6m) at reflux
(Scheme 2). The amino acid hydrochloride 8 was isolated in
94% yield with an optical rotation indicative of the S con-
figuration at the newly formed tetrasubstituted stereocen-
ter.[15] The stereochemical configuration of all other benzyla-
tion products was assigned by analogy.
5[e]
6[f]
2g
3g 76
88
Asymmetric benzylation with electron-rich monocyclic ben-
zylic electrophiles: To expand the scope of the asymmetric
benzylation to include monocyclic benzylic electrophiles,
benzyl alcohol derived carbonate 7 was subjected to the op-
timized reaction conditions. Benzylated azlactone 8a was
obtained in 12% yield, but, gratifyingly, in 90% ee
(Scheme 3). The yield increased to 25% with an identical ee
value in toluene at 758C. The lack of a noticeable effect of
temperature on the ee is quite unusual.
[a] Reactions performed on a 0.2 mmol scale at 0.4m by using 1 (1 equiv),
2b–g (1 equiv), [(h3-C3H5)PdCp] (5.0 mol%), (S,S)-L3 (6.0 mol%), and
tBuOH (5 equiv) for 3 h. [b] Yield of the isolated product. [c] Deter-
mined by chiral HPLC. [d] Reaction run at 358C. [e] Reaction run at
758C in toluene. [f] Reaction run at 48C.
derived nucleophile 2e, containing increased steric bulk, was
slower to react (63% yield of 3e). Increasing the reaction
temperature to 358C was suffi-
cient to induce complete con-
version, and 3e was obtained
in 96% yield (Table 2, entry 4).
At ambient temperature, bulky
reagent 2 f was very slow to
react, and 3 f was isolated in
only 15% yield. Performing
the reaction at elevated tem-
perature in toluene, the yield
increased to 36% with an im-
Scheme 2. Complete hydrolysis of azlactone 5a to determine the absolute configuration.
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B. M. Trost and L. C. Czabaniuk
Table 3. Scope of the asymmetric benzylation reaction towards naphtha-
lene and heterocyclic electrophiles.[a]
Subsequent efforts were directed towards facilitating ioni-
zation of the reactive intermediate through use of a more
labile leaving group. To this end, the diethyl phosphate of 4-
methoxylbenzyl alcohol (9a) was studied.[16] In toluene at
758C, the product was isolated in 10% yield, which repre-
sents a decrease in comparison with the reaction of the car-
bonate (Table 4, entry 1). Reasoning that the carbonate
Entry Electrophile
Product
Yield ee
[%][b] [%][c]
Table 4. Selected optimization experiments for the benzylation reaction
with a diethyl phosphate electrophile.[a]
1
4a
4b
4c
5a 70
95
87
97
Entry
Cs2CO3
[equiv]
Solvent
T
[8C]
Yield
[%][b]
ee
G
[%][c]
2
3
5b 87
1
2
3
4
0
toluene
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
75
25
25
25
25
25
10
25
23
63
90
17
78
91
97
97
96
88
0.1
0.1
0.5
0.6
0.6
5[d]
6[d,e]
5c 90
[a] Reactions performed on
a 0.2 mmol scale at 0.4m by using 9a
(1 equiv), 2a (1 equiv), [(h3-C3H5)PdCp] (5.0 mol%), (S,S)-L3
(6.0 mol%), and tBuOH (5 equiv) for 20 h. [b] Yield of the isolated prod-
uct. [c] Determined by chiral HPLC. [d] Reaction performed by using
1.5 equivalents of 2a. [e] Reaction performed without tBuOH.
4
5
6
4d
4e
4 f
5d 88
5e 57
5 f 98
86
86
4
leaving group in substrates 1 and 4 also served as a base, we
tested whether an exogenous base might be necessary to
promote the nucleophilic attack. Thus, a catalytic amount of
Cs2CO3 was added to the reaction mixture. The isolated
yield increased to 25%, and 91% ee was observed (Table 4,
entry 2). Complete consumption of the starting materials
was observed under these reaction conditions. Running the
reaction at ambient temperature in an attempt to prevent
substrate decomposition in CH2Cl2 gave a nearly identical
result (Table 4, entry 3). Observing that the yield of 8a cor-
related well with the normality of the base (0.2 from
0.1 equivalents of Cs2CO3), the amount of Cs2CO3 was in-
creased to 0.5 equivalents. This change led to an increase in
the yield to 63% (Table 4, entry 4). Complete consumption
of 2a was still observed, so the stoichiometry of 2a was in-
creased to 1.5 equivalents relative to the electrophile. The
amount of Cs2CO3 was also increased to 0.6 equivalents, and
the yield increased to 90% (Table 4, entry 5). In the absence
of tBuOH, the yield of 8a was 17% and a decrease in ee to
88% was observed (Table 4, entry 6).
7
8
4g
4h
5g 78
91
73
5h 69
The scope of the benzylation reaction with respect to nu-
cleophile 9a was investigated (Table 5). Leucine-, phenylala-
nine-, and methionine-derived azlactones led to products
8b–d in high yield and enantioselectivity (Table 5, entries 1–
3). The use of phenyl-substituted azlactone 2g furnished 8e
in only 50% ee (Table 5, entry 4). This lower enantioselec-
tivity was due to the competitive background reaction. A
[a] Reactions performed on a 0.2 mmol scale at 0.4m by using 4a–h
(1 equiv), 2a (1 equiv), [(h3-C3H5)PdCp] (5.0 mol%), (S,S)-L3
(6.0 mol%), and tBuOH (5 equiv) for 3–4 h. [b] Yield of the isolated
product. [c] Determined by chiral HPLC.
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Asymmetric Benzylation of Azlactones
FULL PAPER
indicated that L3 was still the
optimal ligand for reactivity
and enantioselectivity (Table 7,
entries 2–4). Interestingly, in
this reaction DCE behaved
quite differently to CH2Cl2, a
solvent with a similar dielectric
constant (Table 7, entry 5). De-
creased reactivity occurred in
toluene
(Table 7,
entry 6).
Scheme 3. Asymmetric benzylation with monocyclic benzylic methyl carbonate.
Ethereal solvents promoted
high enantioselectivity with the
series of diethyl phosphate electrophiles with electron-rich
aryl rings were synthesized and subjected to the optimized
reaction conditions. A methoxymethyl (MOM) ether was
tolerated under the reaction conditions, yielding 8 f in
96% ee (Table 5, entry 5). A biphenyl electrophile reacted
to form 8g in 92% yield and 91% ee (Table 5, entry 6). Dis-
ubstitution of the phenyl ring was also investigated, provid-
ing benzylated products 8h and 8i in high yield and ee
(Table 5, entries 7 and 8). Conducting the reaction between
9d and 2a on a 1 mmol scale provided an identical result.
Electrophiles with lower electron density on the aromatic
ring were significantly less reactive, which is reflected in di-
minished yields; thus, a para-tolyl electrophile led to 8j in
25% yield, whereas an unsubstituted electrophile provided
8k in only 17% yield (Table 5, entries 9 and 10).
highest yield resulting from use of dioxane (Table 7, en-
tries 7–9). The yield increased to 77% when the reaction
was conducted at 508C in dioxane, most notably with almost
no effect on enantioselectivity (Table 7, entry 10). An in-
crease in reaction concentration to 0.67m led to an improve-
ment in yield to 83% while maintaining high enantioselec-
tivity (Table 7, entry 11). The removal of tBuOH from the
reaction mixture was detrimental to reactivity, with isolation
of only a 34% yield of 8k (Table 7, entry 12).
Various azlactones were reacted with 10a to investigate
the scope of the reaction towards nucleophiles (Table 8). As
was previously seen, azlactones 2b and 2d were highly reac-
tive nucleophiles that provided 8l and 8m in high enantiose-
lectivity (Table 8, entries 1 and 2). A competitive back-
ground reaction occurred when 2 f was used as a nucleo-
phile, and only a 44% ee of 8n was obtained (Table 8,
entry 3). A series of relatively electron-neutral diphenyl-
phosphate electrophiles were synthesized and subjected to
the optimized reaction conditions. Ambient temperature
was sufficient for high reactivity by using a fluoro-substitut-
ed phosphate (Table 8, entry 4). A significant improvement
in yield, from 25 to 91%, was obtained by using the para-
tolyl electrophile under the new reaction conditions
(Table 8, entry 5). Dimethyl substitution was well-tolerated,
and 8p was obtained in 87% yield and 93% ee (Table 8,
entry 6). Placing an electron-withdrawing group at the meta-
position in addition to the presence of an electron-donating
group at the para-position was postulated to maintain suffi-
cient electron richness in the aryl ring to promote ionization.
This hypothesis of a push–pull electrophile was realized in
the high yields of 8q and 8r (Table 8, entries 7 and 8). On
Asymmetric benzylation with electron-neutral monocyclic
benzylic electrophiles: To improve azlactone benzylation
with less-electron-rich benzyl electrophiles, reoptimization
of the reaction conditions was performed by using 9g as a
test electrophile. A screen of exogenous bases was per-
formed by using a number of organic and inorganic bases in
the appropriate stoichiometry to have 1.2 equivalents of
basic site. Screening carbonate bases, a counterion effect
was observed for which the smallest, least polarizable
cation, sodium, provided the highest yield (Table 6, entries 1
and 2). Bicarbonate bases were less successful in promoting
the desired reaction (Table 6, entries 3 and 4). The highest
yields were obtained in the presence of organic tertiary
amine bases, with addition of triethylamine (TEA) and dii-
sopropylethylamine (DIPEA) furnishing 8k in 38 and 36%
yield, respectively (Table 6, en-
tries 5 and 6).
The leaving group on the
electrophile was changed to a
diphenyl phosphate with the
hypothesis that an even more
labile leaving group would fa-
cilitate reactivity. The change
in leaving group (10a) led to
an increase in yield from 38 to
55% with no change in enan-
tioselectivity under the same
reaction conditions (Table 7,
entry 1). A screen of ligands
Scheme 4. Methanolysis of azlactone benzylation products.
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B. M. Trost and L. C. Czabaniuk
Table 5. Scope of the asymmetric benzylation reaction towards the diethyl phospha-
te.[a]
the other hand, a decrease in electron density through
removal of the electron-donating group resulted in di-
minished yield of 8s, underscoring the requirement for
electron density for reactivity (Table 8, entry 9).
Methanolysis of 8a and 8k was performed in the
presence of triflic acid (TfOH, Scheme 4). Esters 11a
(resynthesized by using (R,R)-L3) and 11b were ob-
tained in 86 and 92% yield. Comparison of optical ro-
tations to known products indicated that R stereochem-
istry arises from use of (R,R)-L.[17] This stereochemistry
of the nucleophilic attack by azlactone matches that
observed for benzylation with a naphthalene electro-
phile.
To further demonstrate the synthetic utility of asym-
metric benzylation of azlactones, studies to convert 8h
into a-methyldopa (12), an antihypertensive pharma-
ceutical, were performed.[18] The first reported synthesis
of enantiopure 12 was achieved through chiral resolu-
tion,[19] and asymmetric synthesis of methyldopa has
been reported through alkylation of protected amino
acids containing a chiral auxiliary.[20] However, a cata-
lytic asymmetric method for the introduction of the
stereocenter had not yet been reported. Hydrolysis of
8h in the presence of acetic acid and phenol led to the
formation of 12 as its HCl salt in 94% yield
(Scheme 5). The optical rotation of the acid was found
to be +2.9, which means that a-methyl-d-dopa was
synthesized.[18]
Entry Electrophile
Nucleophile Product
Yield ee
[%][b] [%][c]
1
9a 2b
8b 65
88
82
92
2
3
9a 2c
8c 78
9a 2d
8d 86
4
5
9a 2g
8e 80
50
96
Conclusion
The bis(diphenylphosphinobenzoyl)diamine (dppba) li-
gands, previously shown to induce high enantioselectiv-
ity in allylation reactions of prochiral azlactones, also
effect high asymmetric induction in Pd0-catalyzed ben-
zylation reactions. Because nucleophilic attack is enan-
tiodetermining, this observation supports the notion
that the electrophilic partner that undergoes nucleo-
philic attack corresponds to an h3-benzyl-type structure.
With respect to ionization, the different factors affect-
ing the rate of the reaction with different aryl groups
suggest a more complicated catalytic cycle. With a car-
bonate as the leaving group and aryl groups in which
the loss of aromaticity is less energetically unfavorable,
like naphthalenes and five-membered heterocycles, a
mechanism of p-coordination of the aryl ring to Pd0
followed by ionization to directly form the h3-benzyl
structure may operate. On the other hand, when the
aryl ring is a simple substituted phenyl group, it ap-
pears that p coordination to one of the double bonds
of the aromatic ring requires too high an energy cost.
9b 2a
8 f 94
6
7
8
9c 2a
9d 2a
9e 2a
8g 92
8h 83
8i 99
91
90
94
À
Thus, direct oxidative addition of the benzyl X bond
to Pd0, leading to an h1-benzyl structure, occurs first
with inversion, as has been observed by Stille and co-
workers.[3] The effects of the nature of the leaving
group and the nature of the substituents on the ben-
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Asymmetric Benzylation of Azlactones
Table 5. (Continued)
FULL PAPER
nylazlactone gave good ee with the naphthalene elec-
trophile, but not with the phenyl electrophiles because
of a competitive background reaction in the latter
case. The subtlety of this balance is particularly evi-
dent in the dependence of the ee on the nature of the
phosphate leaving group in forming azlactone 8j.
Entry Electrophile
Nucleophile Product
Yield ee
[%][b] [%][c]
9
9 f 2a
8j 25
70
Practically, those benzylpalladium intermediates
that allow the use of a carbonate as a leaving group do
not require any additional base. When the loss of aro-
maticity exacts too high a price, such that a more reac-
tive phosphate leaving group is needed, then a stoi-
chiometric amount of base is needed. The availability
of the two pathways now enables a wide range of elec-
trophiles to react in this asymmetric benzylation reac-
tion. The development of conditions for monocyclic
benzylic electrophiles introduces a new class of such
partners to the reaction with prochiral nucleophiles.
The direct access to a,a-disubstituted acids by this
methodology is highlighted by the development of the
first catalytic asymmetric synthesis of a-methyldopa.
10[d]
9g 2a
8k 17
71
[a] Reactions performed on a 0.2 mmol scale at 0.4m by using 9a–g (1 equiv), 2a–d
and g (1.5 equiv), [(h3-C3H5)PdCp] (5.0 mol%), (R,R)-L3 (6.0 mol%), and tBuOH
(5 equiv) for 20 h. [b] Yield of the isolated product. [c] Determined by chiral HPLC.
[d] Reaction performed by using (S,S)-L3.
Table 6. Screen of bases for the asymmetric benzylation reaction of an
electron-neutral diethyl phosphate.[a]
Experimental Section
General procedure for the asymmetric benzylation of naphthalene and
heterocycle electrophiles: Methyl carbonate (0.2 mmol) and azlactone
(0.2 mmol) were added to a flask. The reaction flask was evacuated,
filled three times with argon, and placed in an argon-filled environment.
In a separate flask, [(h3-C3H5)PdCp] (2.1 mg, 0.01 mmol, 5 mol%) and
(S,S)-L3 (9.5 mg, 0.012 mmol, 6 mol%) were combined. The flask was
evacuated, filled three times with argon, and placed under an argon at-
mosphere. Degassed CH2Cl2 (0.35 and 0.15 mL respectively) was added
to the flasks, and the catalyst solution was stirred for 20 min. tert-Butanol
Entry
Base ([equiv])
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
K2CO3 (0.6)
Na2CO3 (0.6)
CsHCO3 (1.2)
KHCO3ACTHNUTRGNEUG(N 1.2)
TEA (1.2)
24
34
11
6
38
36
95
95
94
94
95
96
DIPEA (1.2)
Table 7. Selected optimization experiments for the benzylation reaction
with a diphenyl phosphate electrophile.[a]
[a] Reactions performed on
a 0.2 mmol scale at 0.4m by using 9g
(1 equiv), 2a (1.5 equiv), [(h3-C3H5)PdCp] (5.0 mol%), (S,S)-L3
(6.0 mol%), and tBuOH (5 equiv) for 20 h. [b] Yield of the isolated prod-
uct. [c] Determined by chiral HPLC.
Entry
L*
Solvent
T
[8C]
Yield
[%][b]
ee
[%][c]
1[d]
2[d]
3
4
5
6
7
8
9
L3
L1
L2
L4
L3
L3
L3
L3
L3
L3
L3
L3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
toluene
DME
THF
dioxane
dioxane
dioxane
dioxane
25
25
25
25
25
25
25
25
25
50
50
50
55
53
47
28
53
40
23
42
57
77
83
34
À94
À54
83
59
73
96
96
95
95
Scheme 5. Hydrolysis to synthesize a-methyl-d-dopa.
10
11[e]
13[e,f]
93
93
93
zene ring support this contention. However, the h1-complex
relaxes to the h3-complex prior to alkylation. Furthermore,
in this final scenario, there is a delicate competition between
oxidative addition to Pd0 at the benzylic center and direct
substitution at that center by the azlactone. Thus, the phe-
[a] Reactions performed on a 0.2 mmol scale at 0.4m by using 10a
(1 equiv), 2a (1.5 equiv), [(h3-C3H5)PdCp] (5.0 mol%), L* (6.0 mol%),
and tBuOH (5 equiv) for 20 h. [b] Yield of the isolated product. [c] De-
termined by chiral HPLC. [d] Reaction performed by using (S,S)-L*.
[e] Reaction run at 0.67m. [f] Reaction run without tBuOH.
Chem. Eur. J. 2013, 00, 0 – 0
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B. M. Trost and L. C. Czabaniuk
Table 8. Scope of the asymmetric benzylation reaction towards diphenyl phosphates.[a]
(95 mL, 1 mmol) was added to the catalyst solution. The
solution containing the electrophile and nucleophile was
added to the catalyst solution through a cannula. The reac-
tion mixture was stirred for 3–4 h at 258C. The crude reac-
tion mixture was directly purified by chromatography.
Entry Electrophile
Nucleophile Product
Yield ee
[%][b] [%][c]
Acknowledgements
We thank the NSF (CHE-1145236) for their generous sup-
port of our programs. L.C. thanks the Evelyn Laing
McBain Fellowship Fund for financial support. We also
thank Johnson–Matthey for their generous gift of palladi-
um salts.
1
10a 2b
8l 88
93
85
2
3
10a 2d
8m 80
[1] R. Kuwano, Synthesis 2009, 1049–1061.
[2] a) B. M. Trost, M. L. Crawley, Chem. Rev. 2003, 103,
2921–2944; b) B. M. Trost, T. Zhang, J. D. Sieber,
Chem. Sci. 2010, 1, 427–440.
[3] a) K. S. Y. Lau, R. W. Fries, J. K. Stille, J. Am. Chem.
Soc. 1974, 96, 4983–4986; b) K. S. Y. Lau, P. K. Wong,
J. K. Stille, J. Am. Chem. Soc. 1976, 98, 5832–5840.
[4] a) A. Sonoda, P. M. Bailey, P. M. Maitlis, J. Chem.
Soc. Dalton Trans. 1979, 346–350; b) K. Onitsuka, M.
Yamamoto, S. Suzuki, S. Takahashi, Organometallics
2002, 21, 581–583; c) R. D. Dewhurst, R. Muller, M.
Kaupp, K. Radacki, K. Gotz, Organometallics 2010,
29, 4431–4433.
[5] B. M. Trost, M. R. Machacek, A. Aponick, Acc.
Chem. Res. 2006, 39, 747–760.
[6] B. M. Trost, L. C. Czabaniuk, J. Am. Chem. Soc. 2010,
132, 15534–15536.
10a 2g
8n 83
44
94
4[d]
10b 2a
10c 2a
10d 2a
8o 74
8j 91
8p 87
[7] J. S. Fisk, R. A. Mosey, J. J. Tepe, J. Chem. Soc. Rev.
2007, 36, 1432–1440.
5
95
93
84
[8] a) D. Uraguchi, Y. Asai, Y. Seto, T. Ooi, Synlett 2009,
658–660; b) S. Tarꢁ, A. Avila, R. Chinchilla, C.
Najera, Tetrahedron: Asymmetry 2012, 23, 176–180.
[9] a) D. Uraguchi, Y. Ueki, T. Ooi, J. Am. Chem. Soc.
2008, 130, 14088–14089; b) X. Liu, L. Deng, X. Jiang,
W. Yan, C. Liu, R. Wang, Org. Lett. 2010, 12, 876–
879.
6
[10] a) S. Cabrera, E. Reyes, J. Aleman, A. Milelli, S. Kob-
belgaard, K. A. Jorgensen, J. Am. Chem. Soc. 2008,
130, 12031–12037; b) Y. Hayashi, K. Obi, Y. Ohta, D.
Okamura, H. Ishikawa, Chem. Asian J. 2009, 4, 246–
249; c) Y. Huang, A. M. Walji, C. H. Larsen, D. W. C.
MacMillan, J. Am. Chem. Soc. 2005, 127, 15051–
15053; d) J. Alemꢂn, A. Milelli, S. Cabrera, E. Reyes,
K. A. Jorgensen, Chem. Eur. J. 2008, 14, 10958–
10966; e) A.-N. R. Alba, X. Companyo, G. Valero, A.
Moyano, R. Rios, Chem. Eur. J. 2010, 16, 9884.
[11] a) B. M. Trost, X. Ariza, Angew. Chem. 1997, 109,
2749–2751; Angew. Chem. Int. Ed. Engl. 1997, 36,
2635–2637; b) B. M. Trost, X. Ariza, J. Am. Chem.
Soc. 1999, 121, 10727–10737; c) B. M. Trost, K.
Dogra, J. Am. Chem. Soc. 2002, 124, 7256–7257;
d) B. M. Trost, C. Lee, J. Am. Chem. Soc. 2001, 123,
12191–12201; e) B. M. Trost, C. Jakel, B. Plietker, J.
Am. Chem. Soc. 2003, 125, 4438–4439.
7
10e 2a
8q 82
8
9
10 f 2a
8r 79
78
83
[12] For a,a-disubstituted amino acids in biology, see:
a) A. Szekeres, B. Leitgeb, L. Kredics, Z. Antal, L.
Hatvani, L. Manczinger, C. Vagvolgi, Acta Microbiol.
Immunol. Hung. 2005, 52, 137–168; b) T. Degenkolb,
A. Berg, W. Gams, B. Schlegel, U. Grafe, J. Pept. Sci.
2003, 9, 666–678; c) S. Polinelli, Q. B. Broxterman,
H. E. Schoemaker, W. H. J. Boesten, W. M. Crisma,
10g 2a
8s 28
[a] Reactions performed on a 0.2 mmol scale at 0.67m by using 9a–g (1 equiv), 2a–d and g
(1.5 equiv), [(h3-C3H5)PdCp] (5.0 mol%), (R,R)-L3 (6.0 mol%), and tBuOH (5 equiv) for 20 h.
[b] Yield of the isolated product. [c] Determined by chiral HPLC. [d] Reaction was run at
258C.
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Asymmetric Benzylation of Azlactones
FULL PAPER
G. Valle, C. Toniolo, J. Kamphuis, Bioorg. Med. Chem. Lett. 1992, 2,
453–456; d) S. J. OꢃConnor, Z. Liu, Synlett 2003, 2135–2138;
e) H. R. Almond, D. T. Manning, C. Niemann, Biochemistry 1962, 1,
243–249; f) M. C. Khosla, K. Stachowiak, R. R. Smeby, F. M.
Bumpus, F. Piriou, K. Lintner, S. Fermandjian, Proc. Natl. Acad. Sci.
USA 1981, 78, 757–760; g) T. L. Sourkes, Arch. Biochem. Biophys.
1954, 51, 444–456; h) P. Fasella, A. Giartosio, G. G. Hammes, Bio-
chemistry 1966, 5, 197–202; i) J. J. Walsh, D. E. Metzler, D. Powell,
R. A. Jacobson, J. Am. Chem. Soc. 1980, 102, 7136–7138; j) D. Schir-
lin, F. Gerhart, J. M. Hornsperger, M. Hamon, J. Wagner, J. M. Jung,
J. Med. Chem. 1988, 31, 30–36.
Murahashi, Tetrahedron Lett. 1982, 23, 5549–5552; b) Y. Hanzawa,
S. Ishizawa, Y. Kobayashi, Chem. Pharm. Bull. 1988, 36, 4209–4212;
c) S.-I. Murahashi, Y. Taniguchi, Y. Imada, Y. Tanigawa, J. Org.
Chem. 1989, 54, 3292–3303.
[17] a) D. Obrecht, C. Lehmann, R. Ruffieux, P. Schonholzer, K. Muller,
Helv. Chim. Acta 1995, 78, 1567–1587; b) S. Rojas-Lima, O. Tellez-
Zenteno, H. Lopez-Ruiz, L. Loubet-Gonzalez, A. Alvarez-Hernan-
dez, Heterocycles 2005, 65, 59–75.
[18] The Merck Index, 14th ed., Merck, Whitehouse Station, 2007,
p. 6055.
[19] E. W. Tristram, J. ten Broeke, D. F. Reinhold, M. Sletzinger, D. E.
Williams, J. Org. Chem. 1964, 29, 2053–2056.
[13] For reviews on the asymmetric synthesis of a,a-disubstituted amino
acids, see: a) C. Cativiela, M. D. Diaz-de-Villegas, Tetrahedron:
Asymmetry 1998, 9, 3517–3599; b) C. Cativiela, M. D. Diaz-de-Ville-
gas, Tetrahedron: Asymmetry 2007, 18, 569–623; c) H. Vogt, S.
Brase, Org. Biomol. Chem. 2007, 5, 406–430.
[14] B. M. Trost, L. C. Czabaniuk, J. Am. Chem. Soc. 2012, 134, 5778–
5781.
[15] J. E. Green, D. M. Bender, S. Jackson, M. J. OꢃDonnell, J. R. McCar-
thy, Org. Lett. 2009, 11, 807–810.
[20] a) D. F. Reinhold, R. A. Firestone, W. A. Gaines, J. M. Chemerda,
M. Sletzinger, J. Org. Chem. 1968, 33, 1209–1213; b) T. Kawabata,
H. Suzuki, Y. Nagae, K. Fuji, Angew. Chem. 2000, 112, 2239–2241;
Angew. Chem. Int. Ed. 2000, 39, 2155–2157; c) J. L. Leꢄn-Romo, C.
Virues, J. Avina, I. Regla, U. Juaristi, Chirality 2002, 14, 144–150;
d) D. Seebach, J. D. Aebi, R. Naef, T. Webber, Helv. Chim. Acta
1985, 68, 144–154.
[16] For selected examples of allylic phosphates in Pd-catalyzed allylic
substitution, see: a) Y. Tanigawa, K. Nishimura, A. Kawasaki, S.-I.
Received: June 21, 2013
Published online: && &&, 0000
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B. M. Trost and L. C. Czabaniuk
Asymmetric Catalysis
B. M. Trost,*
L. C. Czabaniuk .............. &&&& — &&&&
Palladium-Catalyzed Asymmetric
Benzylation of Azlactones
Attack on benzyl: Palladium-catalyzed
asymmetric benzylation methodology
is demonstrated on prochiral azlactone
nucleophiles. The use of naphthyl, het-
erocyclic, and monocyclic benzylic
electrophiles demonstrates the wide
reaction scope (see scheme). The ben-
zylation products are readily converted
into enantioenriched a,a-disubstituted
amino acids.
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These are not the final page numbers!