Enantioselective decarboxylative alkylation reactions: Catalyst development, substrate scope, and mechanistic studies

Article abstract of DOI:10.1002/chem.201003383

α-Quaternary ketones are accessed through novel enantioselective alkylations of allyl and propargyl electrophiles by unstabilized prochiral enolate nucleophiles in the presence of palladium complexes with various phosphinooxazoline (PHOX) ligands. Excellent yields and high enantiomeric excesses are obtained from three classes of enolate precursor: enol carbonates, enol silanes, and racemic β-ketoesters. Each of these substrate classes functions with nearly identical efficiency in terms of yield and enantioselectivity. Catalyst discovery and development, the optimization of reaction conditions, the exploration of reaction scope, and applications in target-directed synthesis are reported. Experimental observations suggest that these alkylation reactions occur through an unusual inner-sphere mechanism involving binding of the prochiral enolate nucleophile directly to the palladium center. Sly as a PHOX: The development of an enantioselective decarboxylative palladium-catalyzed allylic alkylation reaction, utilizing phosphinooxazoline ligands, is described. The catalyst is applied to a range of allyl enol carbonate, silyl enol ether, and allyl β-ketoester substrates to provide alkylated ketone products in excellent yield and good ee (see scheme). The utility of these products is demonstrated by their use in several asymmetric syntheses. Mechanistic studies are reported suggesting an unusual inner-sphere mechanism. Copyright

Full text of DOI:10.1002/chem.201003383

FULL PAPER
DOI: 10.1002/chem.201003383
Enantioselective Decarboxylative Alkylation Reactions: Catalyst
Development, Substrate Scope, and Mechanistic Studies
Douglas C. Behenna, Justin T. Mohr, Nathaniel H. Sherden, Smaranda C. Marinescu,
Andrew M. Harned, Kousuke Tani, Masaki Seto, Sandy Ma, Zoltꢀn Novꢀk,
Michael R. Krout, Ryan M. McFadden, Jennifer L. Roizen, John A. Enquist, Jr.,
David E. White, Samantha R. Levine, Krastina V. Petrova, Akihiko Iwashita,
Scott C. Virgil, and Brian M. Stoltz*[a]
Abstract: a-Quaternary ketones are ac-
cessed through novel enantioselective
alkylations of allyl and propargyl elec-
trophiles by unstabilized prochiral eno-
late nucleophiles in the presence of
palladium complexes with various
phosphinooxazoline (PHOX) ligands.
Excellent yields and high enantiomeric
excesses are obtained from three
classes of enolate precursor: enol car-
bonates, enol silanes, and racemic b-ke-
toesters. Each of these substrate classes
functions with nearly identical efficien-
cy in terms of yield and enantioselec-
tivity. Catalyst discovery and develop-
ment, the optimization of reaction con-
ditions, the exploration of reaction
scope, and applications in target-direct-
ed synthesis are reported. Experimen-
tal observations suggest that these al-
kylation reactions occur through an un-
usual inner-sphere mechanism involv-
ing binding of the prochiral enolate nu-
cleophile directly to the palladium
center.
Keywords: alkylation · allylic com-
pounds · asymmetric catalysis · eno-
lates · reaction mechanisms · syn-
thetic methods
Introduction
studied by the groups of Trost, Helmchen, Pfaltz, and others
form tertiary stereocenters by the attack of stabilized anions
(e.g., malonate) on prochiral 1,3-disubstituted allyl frag-
ments.[9] Helmchen and co-workers have shown that reac-
tions with palladium phosphinooxazoline (PHOX) com-
plexes typically occur through outer-sphere malonate attack
at the allyl terminus.[10] Although allylic alkylation mediated
by other metals, especially copper,[11] has successfully gener-
ated quaternary centers on prochiral allyl groups, to our
knowledge, this mode of reactivity has not been realized
with palladium.[12]
An alternative, less common strategy in allylic alkylation
is the use of prochiral nucleophiles. A quaternary stereocen-
ter may be formed on a prochiral nucleophile if it possesses
three distinct substituents. These reactions require a remote
chiral ligand to discriminate between the prochiral faces of
an incoming nucleophile, and thus may seem a more chal-
lenging strategy. However, the groups of Hayashi,[13] Ito,[14]
and Trost[15] have reported the asymmetric allylation of pro-
chiral enolates derived from 1,3-dicarbonyl compounds.
Trost and co-workers have demonstrated that diamine-de-
rived ligands 6 and 7, which were designed to project bulk
in front of the allyl fragment due to their large bite angles,
are able to favor one face of the in situ generated ketone
enolate (Scheme 1).[5,16,17,18] These reactions represented a
significant advance in asymmetric allylation technology by
forming quaternary stereocenters in excellent yield and
good ee. However, the substrate scope of these reactions
was restricted to ketone substrates containing either a single
The catalytic asymmetric synthesis of all-carbon quaternary
stereocenters remains a significant challenge in synthetic
chemistry.[1] Despite the demanding steric requirements of
quaternary stereocenter formation, a number of useful cata-
lytic transformations, including Diels–Alder,[2] Heck,[3] cyclo-
propanation,[4] alkylation,[5] acylation,[6] desymmetrization,[7]
and pericyclic[8] reactions, among others, have been success-
ful in generating these moieties. Although palladium-cata-
lyzed enantioselective allylic alkylation chemistry has been
an important tool in organic synthesis, only relatively recent-
ly has palladium(II) p-allyl chemistry been used for the for-
mation of quaternary stereocenters.[9] The vast majority of
ꢀ
palladium-catalyzed C C bond-forming allylic alkylations
[a] Dr. D. C. Behenna,+ Dr. J. T. Mohr,+ Dr. N. H. Sherden,
S. C. Marinescu, Prof. A. M. Harned, Dr. K. Tani, Dr. M. Seto,
Dr. S. Ma, Dr. Z. Novꢀk, Dr. M. R. Krout, Dr. R. M. McFadden,
Dr. J. L. Roizen, Dr. J. A. Enquist, Jr., Dr. D. E. White, S. R. Levine,
K. V. Petrova, Dr. A. Iwashita, Dr. S. C. Virgil, Prof. B. M. Stoltz
The Warren and Katharine Schlinger Laboratory for
Chemistry and Chemical Engineering
Division of Chemistry and Chemical Engineering
California Institute of Technology
1200 E. California Blvd., MC 101-20, Pasadena, CA 91125 (USA)
Fax : (+1)626-564-9297
E-mail: stoltz@caltech.edu
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003383.
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Scheme 2. Tsujiꢂs
benzylideneacetone), Ph3P, dioxane, 08C; ii) [Pd
iii) [Pd2A(dba)3], 1,2-bis(diphenylphosphino)ethane (DPPE), MeOSnBu3,
dioxane, reflux; iv) [Pd2A(dba)3], DPPE, THF (TMS=trimethylsilyl).
allylation
methods.
i) [Pd
G
(dba=di-
A
CHTUNGTRENNUNG
CTHUNGTRENNUNG
CTHUNGTRENNUNG
ligands.[25] Of additional interest was the regiochemical fidel-
ity observed in the alkylation reactions (Scheme 3). Tsuji
and co-workers demonstrated that both tetrasubstituted
allyl enol carbonate isomer 8 and trisubstituted allyl enol
carbonate isomer 11 undergo the reaction to give allylated
ketones 9 and 12 in ratios essentially unchanged from those
of the substrates.[21a] These reactions were believed to pro-
ceed through oxidative addition of palladium to the allyl
Scheme 1. Trostꢂs allylic alkylation with prochiral nucleophiles. i) (S,S)-6,
[{(h3-C3H5)PdCl}2], lithium diisopropylamide (LDA), Me3SnCl,
C3H5OAc, dimethoxyethane (DME); ii) (R,R)-6, [{(h3-C3H5)PdCl}2], tet-
ramethylguanidine (TMG), C3H5OAc, toluene; iii) (S,S)-7, [{(h3-
C3H5)PdCl}2], sodium hexamethyldisilazide (NaHMDS), C3H5OAc,
DME.
acidic site (e.g., ketone 1 and tetralone 2) or two a-sites that
have a large difference in acidity (e.g., b-ketoester 4 and a-
phenyl ketone 5).[1d] These limitations have prevented direct
access to fundamental a-quaternary ketones, such as 2-allyl-
2-methylcyclohexanone (9), a cyclohexanone derivative not
known as a single enantiomer prior to our work.[19]
We were confronted by these limitations during studies
towards the synthesis of several natural products.[20]
A
survey of the literature revealed that the non-enantioselec-
tive alkylation reactions developed by Tsuji and co-work-
ers[21] in the early 1980s had the proper reactivity and selec-
tivity to form quaternary stereocenters in the presence of
less substituted ketone a-sites of similar acidity. For exam-
ple, allyl enol carbonate and allyl b-ketoester substrates con-
tain both a latent enolate and an allyl fragment (Scheme 2a
and b).[21] Alternatively, enol acetates and silyl enol ethers
may serve as enolate precursors in intermolecular reactions
with allyl carbonates (Scheme 2c and d).[22] These alkyla-
tions have the advantage that the reaction occurs under
nearly neutral conditions and often at mild temperatures.
Despite their advantages, these alkylation reactions were
rarely utilized during the twenty years between 1983 and the
time we began research in 2003.[23,24]
Our analysis of Tsujiꢂs alkylation reaction showed it to be
an ideal candidate for asymmetric catalysis. These high-
yielding alkylation methods are a clear case of ligand-accel-
erated catalysis, occurring only in the presence of phosphine
Scheme 3. Regiochemical fidelity in Tsujiꢂs palladium-catalyzed al-
ACHUTNGRENUlNG ylation. i) [Pd2AHCTUNGTREN(NUNG dba)3], Ph3P, dioxane.
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Enantioselective Decarboxylative Alkylation Reactions
fragment followed by loss of CO2 to give {PdII-
FULL PAPER
Table 1. Initial ligand screening.[27a]
ACHTUNGTRENNUNG(allyl)} complex 13 and enolate 14. However, the
details involving the recombination of the ion pair
to give cyclohexanone 9 and a palladium(0) species
were unclear at the time of original reports by Tsuji
and co-workers.[26] Coupled with the ability to
purify the stable enolate precursors, we believed
that the regiochemical fidelity afforded by the pal-
ladium-catalyzed reaction would provide direct
access to enantioenriched a-quaternary ketones if a
suitable chiral ligand could be found.[27]
Ligand
1,4-Dioxane
Yield ee
[h] [%][a] [%][b]
Tetrahydrofuran
Yield ee[b]
[h] [%][a] [%]
t
t
1
(R)-BINAP
5
92
5[c]
5
76
2[c]
Results and Discussion
Initial screening of chiral ligands: Our initial goal
was to show that a chiral ligand could transmit
useful levels of asymmetric induction in the reac-
tion while maintaining the important property of
enolate regiochemical fidelity found in the non-
enantioselective system. We chose allyl enol car-
bonate 8 as a test substrate to evaluate the effect of
various ligands (Table 1). Although allyl enol carbo-
nates are less common than the other enolate pre-
cursors explored by Tsuji and co-workers, they al-
lowed us to add a single, achiral reagent to our cat-
alyst system without extraneous initiators or coun-
terions that might affect enantioselectivity, whereas
silyl enol ether, enol acetate, and b-ketoester sub-
strates did not. In accord with the reports by Tsuji
and co-workers, we performed our initial trials in
dioxane. Due to the prevalence of bis(phosphine)
ligands in asymmetric catalysis, we began with sev-
eral privileged bis(phosphine) ligands, but found
that only the Trost ligand (6) gave a significant ee.
However, commercially available (R)-QUINAP
(15), a chelating N/P-type ligand,[28] gave less varia-
tion in ee across other ethereal solvents (compare
Table 1, entries 5 and 6 in dioxane and THF). En-
couraged by this result, we quickly found that the
phosphinooxazoline (PHOX) class of N/P-type li-
gands also provided excellent reactivity and promis-
ing levels of enantioselectivity. The numerous readi-
ly available amino acid derived PHOX ligands[29] al-
lowed us to rapidly discover that bulkier aliphatic
groups on the oxazoline provided higher levels of
enantioinduction, with (S)-tBu-PHOX (19) provid-
AHCTUNGTRENNUNG
2
3
5
2
61
91
0
5
2
66
59
0
A
2[c]
2[c]
4
5
6
(R)-MOP
3
2
2
93
97
98
18
3
5
2
47
92
97
13
AHCTUNGTRENNG(UN R,R)-Trost
ligand (6)
46[c]
64[c]
(R)-QUINAP
(15)
61
61
(R)-Ph-PHOX
AHCTUNGTRENN(GUN 16; R=Ph)
7
8
2
3
95
96
62[c]
82[c]
2
2
95
95
65[c]
83[c]
(S)-iPr-PHOX
(17; R=iPr)
(R)-Bn-PHOX
AHCTUNGTRENN(GUN 18; R=Bn)
9
3
2
96
95
65
86
5
2
94
96
63
88
10
(S)-tBu-PHOX
(19; R=tBu)
[a] GC yield of 9 relative to an internal standard (tridecane). [b] Enantiomeric excess
by chiral GC. [c] (R)-9 produced as the major product.
ing a-quaternary ketone (S)-9 in 86% ee with dioxane as
the solvent. Additionally, we observed slightly higher ee
values in reactions with (R)-iPr-PHOX (17) and (S)-tBu-
PHOX (19) if THF was used as the solvent (83 and 88% ee,
respectively).[30] Having attained satisfying levels of enantio-
and regioselectivity in forming ketone 9, we began a more
thorough investigation of the reaction conditions.
several opportunities to optimize the reaction. One impor-
tant experimental parameter was found to be the complexa-
tion time for (S)-tBu-PHOX (19) and tris(dibenzylideneace-
tone)dipalladium(0) ([Pd2ACHTNUTRGENNUG(dba)3]) prior to addition of the
substrate.[31] Mixing the metal and ligand for 30 min before
substrate addition resulted in a balance between short com-
plexation times (e.g., 5 min) in which lower yields but com-
plete consumption of the substrate were observed, and
longer complexation times (e.g., 1–3 h) in which poor con-
version was observed. Storing the ligand–metal complex for
Optimization of reaction parameters: The straightforward
experimental procedure for asymmetric alkylation provided
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B. M. Stoltz et al.
Table 3. Effect of solvent on asymmetric allylation.
an extended time seemed to be complicated by the introduc-
tion of adventitious amounts of O2 that readily oxidized the
ligated PHOX molecule at phosphorus, thereby preventing
significant consumption of the starting material.[32]
We also investigated the effect of concentration on the re-
action (Table 2). At higher concentrations, significantly
lower yields were observed, as well as slightly decreased ee.
No further increase in enantioselectivity was observed
below 0.03m.
Solvent
9[a,b]
t
3[a,b]
Yield
[%][c]
ee
t
ee
[h]
[%][d]
[h]
[%][e]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1,4-dioxane
2
2
2
2
2
3
2
2
2
2
3
2
3
3
6
95
96
98
98
95
82
72
99
99
97
26
72
58
42
0
86
88
89
89
89
81
56
88
88
86
60
89
51
13
–
1
1
1
1
–
–
–
1
1
–
–
–
–
–
–
87
88
80
78
–
–
–
89
87
–
tetrahydrofuran
diethyl ether
tert-butyl methyl ether
diisopropyl ether
anisole
1,2-dimethoxyethane
benzene
toluene
ethyl acetate
acetone
triethylamine
fluorobenzene
dichloromethane
chloroform
Table 2. Effect of concentration on asymmetric allylation.[a]
Concentration [m]
t [h]
Yield [%][b]
ee [%][c]
–
–
–
–
1
2
3
0.500
0.250
0.125
0.063
0.031
3
2
2
2
2
81
90
94
99
95
82
84
84
85
86
4[d]
5
–
[a] Data reported are the average of three experiments. [b] All reactions
proceeded to complete conversion except entries 13–15. [c] GC yield rel-
ative to an internal standard (tridecane). [d] Enantiomeric excess mea-
sured by chiral GC. [e] Enantiomeric excess measured by chiral HPLC.
[a] Unless otherwise noted, data reported are the average of three experi-
ments. [b] GC yield relative to an internal standard (tridecane). [c] Enan-
tiomeric excess measured by chiral GC. [d] Data reported are the aver-
age of two experiments.
Encouraged by our initial discovery that reactions in THF
gave better levels of enantioinduction than those in dioxane,
we undertook a more thorough study of solvent effects on
the reaction (Table 3). Many of the ethereal solvents investi-
gated gave good results. Diethyl ether, tert-butyl methyl
ether (TBME), and diisopropyl ether all provided good
yields and slightly higher ee values than reactions in THF
with allyl enol carbonate 8 (Table 3, entries 3–5). However,
methyl tetralone derived allyl enol carbonate 20 yielded
products with substantially lower ee values in diethyl ether
and TBME. The poor solubility of the catalyst in these less
coordinating ethereal solvents occasionally led to incom-
plete conversion, a disadvantage that outweighed the slight
increase in ee. Interestingly, several non-ethereal solvents
also performed well in the transformation. Reactions in ben-
zene and toluene gave similar yield and enantioinduction to
those in THF (Table 3, entries 8 and 9). The reaction also
tolerated carbonyl-containing solvents; ethyl acetate
(Table 3, entry 10) provided good yields and enantioselectiv-
ity in the asymmetric allylation, although acetone (Table 3,
entry 11) afforded an inferior yield and ee. Interestingly,
triethylamine produced a level of enantioselectivity equal to
that observed with the best ethereal solvents, albeit in lower
yield (Table 3, entry 12). Halogenated solvents fared poorly
in the reaction, suffering from low conversion and yield
(Table 3, entries 13–15). Overall, we were intrigued by the
variety of solvents with vastly different properties that per-
formed equally well.
the reaction by modifying the structure of the PHOX ligand
(Table 4).[33] Hoping to continue the trend of increasing
enantioselectivity initially noted in moving from iPr- to tBu-
PHOX (Table 4, entries 2 and 4), we carried out the synthe-
sis of numerous PHOX ligands with varied steric environ-
ments and evaluated these ligands in the reaction of allyl
enol carbonates 8 and 20. In general, ligands containing sat-
AHCTUNGTREGuNNNU rated substituents on the oxazoline fragment performed
better than those with aryl groups in terms of ee. Moving
the steric bulk away from the oxazoline framework by in-
serting a methylene group (i.e., ligand 23, Table 4, entry 6)
substantially lowered the enantioselectivity. Of particular
note are l-serine-derived ligands 27 and 28 (Table 4, en-
tries 10 and 11),[34] which allowed access to the enantiomeric
(R) product series with nearly the same level of enantiose-
lectivity as that observed with (S)-tBu-PHOX (19), but with-
out the need for the more costly (R)-tert-leucine (21).[35] The
known cis-1-aminoindan-2-ol-derived ligand 29 and borneol-
derived ligand 30, both with uniquely shaped substituents,
gave slightly lower enantioselectivity relative to tBu-PHOX
(19).[36] It is noteworthy that regardless of the shape or type
of substituent on the PHOX ligand, the ketone products
contained quaternary stereocenters with a consistent sense
of configuration (e.g., (S)-PHOX ligands provide (S)-9).[37]
With tBu-PHOX (19) established as the optimal steric
framework, we next considered the electronics of the
ligand.[38]
A number of tBu-PHOX derivatives were synthesized to
probe the importance of phosphine electronics (Table 5).
We investigated ligands ranging from electron-rich to elec-
tron-poor phosphines with allyl enol carbonates 20 and 8
Fine tuning of the phosphinooxazoline ligands: Substantial
effort was invested in improving the enantioselectivity of
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Enantioselective Decarboxylative Alkylation Reactions
FULL PAPER
Table 4. Effect of phosphinooxazoline sterics on enantioselective alkyla-
tion (Cy=cyclohexyl; Bn=benzyl; TBS=tert-butyldimethylsilyl).
table from phosphorus, the arsenic analogue of tBu-PHOX
had excellent activity as a catalyst, but gave tetralone 3 in
only moderate ee (Table 6, entry 2). A nitrogen analogue
showed little catalytic activity, and the small amount of
product generated was nearly racemic (Table 6, entry 3). As
a final derivative that maintains the six-membered ring che-
lation pattern, but changes the hybridization of the back-
bone atoms involved, a known phosphinite ligand, Simple-
PHOX, was found to give only a moderate ee value
(Table 6, entry 4).[41]
Ligand
Product[a] ee [%][b]
1
2
16; R=Ph
17; R=iPr
9
9
65 (R)
83 (R)
Although some electron-deficient derivatives of tBu-
PHOX did provide slightly better product ee values with
certain substrates, ultimately this slight improvement did not
typically offset the added difficulty in synthesizing the sub-
stituted PHOX ligands.[33] Our studies clearly showed that
N/P chelates were particularly effective at inducing high
levels of asymmetry in the allylation reaction. As a result,
we retained the use of (S)-tBu-PHOX (19) in our optimized
conditions for exploring the scope of the reaction.
3
4
18; R=Bn
19; R=tBu
22; R=1-adamantyl
23; R=CH2tBu
24; R=CH2(1-naphthyl)
25; R=Cy
26; R=CHPh2
27; R=C(Me)2OBn
28; R=C(Me)2OTBS
9
9
3
3
9
9
9
3
3
63 (S)
88 (S)
78 (S)
59 (S)
41 (S)
83 (R)
69 (R)
85 (R)
85 (R)
5[c]
6
7
8
9
10
11
Asymmetric allylation of allyl enol carbonates: We have
successfully employed a variety of allyl enol carbonates in
our asymmetric Tsuji allylation (Table 7).[42] The allyl group
may be substituted at the internal position, which results in
slightly higher levels of asymmetric induction (Table 7,
entry 4). The cyclic portion of the substrate may be unsatu-
rated (Table 7, entry 5), substituted (Table 7, entries 6–11),
appended to another ring (Table 7, entries 12 and 13), or en-
larged (Table 7, entries 14 and 15). Among these variations,
several are particularly noteworthy: the presence of a conju-
gated acceptor enone (Table 7, entry 5) does not lead to Mi-
chael addition products, highlighting the essentially neutral
reaction conditions; quaternary stereocenters may be syn-
thesized vicinal to pre-existing, fully substituted carbon
atoms (Table 7, entry 8); the temperature may be lowered in
order to improve enantioselectivity if highly reactive sub-
strates are employed (Table 7, entries 12 and 13), although
the reaction time increases significantly.[43] Overall, we were
pleased to find that a wide range of functionalized, enan-
tioenriched cycloalkanones were accessible by this method.
Our use of allyl enol carbonates enabled direct access to
a-quaternary ketones with multiple acidic sites. However,
allyl enol carbonates are rarely encountered in the litera-
ture, and the synthesis of isomerically pure enol carbo-
nates[44] often required the synthesis of silyl enol ethers as
intermediates. Because Tsuji and co-workers used silyl enol
ethers in their non-enantioselective allylation, we contem-
plated adapting our reaction conditions so that silyl enol
ethers could be employed directly.
12
29
30
3
3
79 (S)
81 (S)
13
[a] All reactions proceeded to complete conversion. [b] Enantiomeric
excess measured by chiral HPLC or GC. [c] Reaction run at 0.2m in diox-
ane.
(Table 5, entries 1–7 and 8–14, respectively). The electronic
perturbation had no significant effect on reaction yield, but
ligands bearing electron-withdrawing groups (especially CF3
groups) gave a significant increase in the rate of the reaction
with allyl enol carbonate substrates.[33a] Furthermore, elec-
tron releasing para substituents on the phenyl rings tended
to lower the ee values of the product relative to that ob-
served with (S)-tBu-PHOX (Table 5, entries 1 and 8). If tet-
ralone-derived allyl enol carbonate 20 was used as the sub-
strate, a slight increase in enantioselectivity was observed
with electron-withdrawing substituents at the para-phenyl
positions (Table 5, entries 3–5). However, the enantioselec-
tivity decreased significantly with extremely electron-poor
PHOX ligands (Table 5, entries 6 and 7). This trend was not
apparent in the enantioselectivity with cyclohexyl-derived
allyl enol carbonate 8 (Table 5, entries 8–14). These results
suggest a subtle interplay between ligand and substrate elec-
tronics.
Asymmetric allylation of silyl enol ethers: Silyl enol ethers
are commonly encountered enolate equivalents. Unlike allyl
enol carbonates, silyl enol ethers render the alkylation reac-
tion intermolecular, with the enolate precursor and allyl
fragment introduced separately. We discovered in our initial
studies that silyl enol ethers were not sufficiently nucleophil-
As a final perturbation of the PHOX ligand structure, we
prepared a number of non-N/P mixed chelates based on the
phenyl oxazoline skeleton of the PHOX ligands (Table 6).[39]
The phosphine oxide of tBu-PHOX is inactive as a catalyst
in this reaction.[32] A sulfur analogue also failed to catalyze
the reaction (Table 6, entry 1).[40] Moving down the periodic
ic to react with the {PdII
ACTHNUTRGNEU(GN allyl)} fragment under our reaction
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B. M. Stoltz et al.
Table 5. Effect of phosphine electronics on enantioselective alkylation.[a]
Table 6. Effect of varied heteroatom chelates on enantioselective alkyla-
tion.
Product Ligand
Solvent
ee
[%][b]
Ligand
Conversion [%]
0[b]
ee [%][a]
31; R1 =Me;
R2 =H
1
2
3
3
1,4-dioxane 81
1,4-dioxane 87
19; R1 =H;
R2 =H
1
2
–
3
4
3
3
32; R1 =F;
R2 =H
1,4-dioxane 88
33; R1 =CF3; 1,4-dioxane 89
R2 =H
99[b]
52
34; R1 =H;
1,4-dioxane 90
R2 =NO2
5
3
3
4
<5[b]
7
38; Ar=m-
6
7
3
3
1,4-dioxane 83
(CF3)2C6H3
39; Ar=C6F5 1,4-dioxane 81
87[c]
56
Pro- Ligand
duct
Solvent Yield ee
[a] Enantiomeric excess measured by chiral HPLC. [b] Conversion esti-
mated by TLC analysis. [c] Experiment performed with allyl enol carbon-
ate 8. Conversion measured by GC relative to an internal standard (tri-
[%][c] [%][d]
AHCTUNGTREGdNNUN ecane). Enantiomeric excess measured by chiral GC.
35;
8
9
9
9
9
R1 =H;
THF
THF
THF
99
86
R2 =OMe
pair, which could collapse directly into the product
(Scheme 3). For the intermolecular reaction, we primarily
used diallyl carbonates as the allyl precursors, although
mixed carbonates were also effective. Oxidative addition of
9
19
96
88
36;
allyl carbonates occurs readily at 258C to give {PdII
ACHTUNGTRENNUNG(allyl)}
10
11
R1 =H;
R2 =CF3
99
89
species 13, CO2, and an alkoxide. The addition of TBAT im-
mediately generates the enolate, which can react with palla-
dium complex 13 by the same enantioselective mechanism
observed for allyl enol carbonates. A substoichiometric
amount of TBAT was sufficient, because the alkoxide
formed in the reaction is also capable of providing the eno-
late in situ. In principle, it should be possible for the small
amount of allyl alkoxide generated from oxidative addition
to initiate the reaction.[45] In practice, we found that
35 mol% TBAT was usually sufficient to ensure complete
conversion of the silyl enol ether (40). Having developed an
effective means of silyl enol ether activation, we attempted
the asymmetric alkylation with a range of tetrasubstituted
silyl enol ethers.
32
33
34
THF
THF
THF
95
97
89
88
87
88
12[e]
13[e]
9
9
37; Ar=
p-
(CF3)C6H4
14
9
THF
99
87
[a] All reactions proceeded to complete conversion. [b] Enantiomeric
excess measured by chiral HPLC. [c] GC yield relative to an internal
standard (tridecane). [d] Enantiomeric excess measured by chiral GC.
[e] Data reported are the average of two experiments.
Gratifyingly, alkylation of the silyl enol ether substrates
occurred with levels of enantioinduction similar to those ob-
served for the allyl enol carbonate substrates and over a
similar range of substrates (Table 8). Specifically, methyl-
and ethyl-substituted quaternary ketones were produced
with the same ee observed in the allyl enol carbonate reac-
tions (Table 8, entries 1 and 2). A tertiary ether stereocenter
was accessible from an a-oxygenated silyl enol ether, albeit
with moderate ee (Table 8, entry 3). In addition to diallyl
conditions at 258C. However, we found that the reaction
could be initiated in the presence of tetra-n-butylammonium
difluorotriphenylsilicate (TBAT), a commercially available
dry fluoride source.
The use of TBAT as an initiator complicated the proposed
catalytic cycle (Scheme 4). In the case of allyl enol carbo-
nates, the oxidative addition of allyl carbonate 8 and rapid
decarboxylation led directly to the enolate/ACTHNUTRGENNGU ACHTUTGNREN(NUGN allyl)} ion
{PdII
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Enantioselective Decarboxylative Alkylation Reactions
FULL PAPER
Table 7. Substrate scope for the asymmetric allylation of allyl enol carbo-
nates.[27a]
Product[a]
Yield
[%][b]
ee
[%][c]
1
85
85
90
87
2[d]
3[f]
86 (96)[e]
89
4[g]
89
91
91
89
5
6
87
86
Scheme 4. General catalytic cycle for silyl enol ether alkylation.
7
R1 =CH2CH3
R1 =tBu
96
92
82
85
88
and NH4PF6 in ethanol,[46] [PdII +A[PF6]ꢀ salt 41
ACTHNUTRGENN(UG allyl)PHOX] CHUTNGTRENNGUN
8[g]
9
55[h]
96
R1 =CH2Ph
R1 =(CH2)3OBn
readily precipitated, and this solid could be recrystallized
and characterized crystallographically as a partial EtOH
adduct.[47] Complex 41 serves as a precatalyst in the enol
silane variant of our enantioselective alkylation reaction,
giving a good yield and a nearly identical product ee com-
pared to that observed with the in situ generated catalyst.
10
87
11
94
92
12[i]
13[i]
R=H
R=OCH3
87
94
91
91
The {PdII}
ACHTNUTRGENNG[U PF6] salt 41 has several practical advantages. It is
an air stable, non-hygroscopic solid that may be stored in-
definitely. Moreover, the use of the preformed [Pd-
AHCTUNGTREG(NNUN allyl)PHOX] catalyst obviated the introduction of dibenz-
14
15
n=1
n=2
81
90
87
79
AHCTUNGTREGyNNUN lideneacetone (dba), which often complicated the purifica-
tion of the a-quaternary ketone products.[48]
[a] Reactions were performed by using the substrate (1.0 mmol) in THF
(0.033m in substrate) at 258C with [Pd2A(dba)3] (2.5 mol%) and (S)-tBu-
CTHUNGTRENNUNG
Enantioselective alkylation of dioxanone substrates for the
synthesis of tertiary ethers and alcohols: Given our success
in preparing a-quaternary cycloalkanones, we wished to ex-
plore the direct synthesis of enantioenriched a-oxygenated
ketones, which are a particularly challenging structure and
appear in a number of biologically active compounds.[49] Our
preliminary attempts to form these systems included a
Baeyer–Villiger oxidation of an a-quaternary ketone (see
below) and a single example of an oxygenated enol silane
that provided a tertiary ether in only moderate ee (Table 8,
entry 3). The latter result indicated that an exocyclic hetero-
PHOX (19; 6.25 mol%), unless otherwise noted. Each reaction was com-
plete in 1–10 h. [b] Isolated yields. [c] Measured by chiral GC or HPLC.
[d] Performed on a 5.1 mmol scale. [e] % ee after one recrystallization of
the corresponding semicarbazone is given in parentheses. [f] Reaction
performed at 128C (GC yield). [g] Performed with 5 mol% [Pd2ACTHNUTRGNEN(UG dba)3]
and 12.5 mol% (S)-19. [h] Isolated yield after conversion to the corre-
sponding diketone through Wacker oxidation. [i] Performed at 108C.
carbonate, dimethalACHTUNGTRENNUNGlyl carbonate served as a suitable allyl
fragment precursor (Table 8, entries 4 and 5). Interestingly,
2-allyl-2-methallylcyclohexanone, containing only a remote
methyl group to engender chirality, formed in 91% ee. As
with the reactions of allyl enol carbonates, substitution on
the ring and larger ring sizes were tolerated as well (Table 8,
entries 6–8).
AHCTUNGTREGaNNUN tom directly attached to the putative enolate intermediate
caused significant disruption of the stereocontrolling ele-
ments of the catalyst. Therefore, we chose to explore a class
of substrates with the heteroatom contained within the ring,
a position from which it would be less likely to interact with
the metal center.[27c] Dioxanone substrates have been em-
ployed in chiral-auxiliary-controlled enolate alkylations, and
we hypothesized that our catalytic enolate-alkylation proce-
dure might provide a more efficient route to these oxygenat-
ed products.[50,51]
In addition to the flexibility afforded by the intermolecu-
lar reaction of silyl enol ethers with diallyl carbonates, the
use of silyl enol ethers as a means to generate enolates inde-
pendent of the allyl fragment allowed the catalytic cycle to
commence at the stage of {PdII
(Scheme 5). Upon mixing (S)-tBu-PHOX, [{PdACHTUNGTRENNUNG
ACHTUNGTRENNUNG
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14205

B. M. Stoltz et al.
Table 8. Substrate scope for asymmetric allylation of silyl enol ethers.[27a]
Consequently, we prepared enol silane 42 (Table 9) as a
representative substrate of the dioxanone class.[52] We found
that solvent had a larger effect on the yield and ee of the
Table 9. Effect of solvent on dioxanone alkylation (TES=triethylsilyl).
Product[a]
Yield [%][b]
ee [%][c]
1
2
3
R1 =CH3
95
96
83
87
92
59
R1 =CH2CH3
R1 =OBn
4[d]
5[d]
R1 =CH3
R1 =allyl
79
82
91
91
Solvent
Yield [%][a]
ee [%][b]
1
tetrahydrofuran
diethyl ether
1,4-dioxane
benzene
40
59
65
67
74
81
89
67
84
88
2[c]
3
6
99
81
4
5
toluene
[a] Isolated yield from the reaction of the substrate (0.1 mmol) in a sol-
vent (0.033m in substrate) at 258C with [Pd(dmdba)2] (5 mol%), (S)-tBu-
PHOX (19; 5.5 mol%), diallyl carbonate (1.05 equiv), and TBAT
(1 equiv), unless otherwise noted. Each reaction was complete in 5–7 h.
[b] Measured by chiral HPLC of a derivative.[53] [c] Reaction performed
at 308C.
7
8
n=1
n=2
94
96
86
79
AHCTUNGTRENNUNG
[a] Reactions were performed by using the substrate (1.0 mmol) in THF
(0.033m in substrate) at 258C with [Pd2A(dba)3] (2.5 mol%), (S)-tBu-
CTHUNGTRENNUNG
PHOX (19; 6.25 mol%), diallyl carbonate (1.05 equiv), and TBAT
(35 mol%), unless otherwise noted. Each reaction was complete in 2–5 h.
[b] Isolated yields. [c] Measured by chiral GC or HPLC. [d] Reaction per-
formed with dimethallyl carbonate (1.05 equiv).
product with this class of substrate (Table 9) and that a full
equivalent of TBAT was required for efficient conversion of
the triethylsilyl (TES) enol ethers to the products. In the op-
timal case, exposure of enol ether 42 to the complex derived
from
[Pd
G
(dmdba=3,5,3’,5’-dimethyoxydi-
AHCTUNGTREGbNNNU enzylideneacetone) and (S)-19 in the presence of diallyl
carbonate and TBAT (1 equiv) in toluene at 258C led to di-
oxanone product 43 in 74% yield and 88% ee. We explored
the scope of this transformation and found that substitutions
at the 2-position and on the allyl group were possible while
maintaining high yields and ee values (Table 10). These oxy-
genated products were amenable to a number of subsequent
transformations that enabled the enantioselective synthesis
of several challenging structural motifs (see below).
Our work with silyl enol ethers demonstrated that our
enantioselective process is robust enough to permit the in-
troduction of the enolate and allyl fragments separately and
to tolerate the presence of other ions in solution. Silyl enol
ethers are a more familiar substrate class and greatly in-
crease the practicality of the reaction. However, we rely on
thermodynamically driven silyl enol ether syntheses, which
typically produce a 10:1 ratio of isomers that requires some-
what tedious purification to obtain isomerically pure sub-
strates.[44] A direct method for the synthesis of isomerically
pure substrates would further increase the practicality of
this catalyst system.[26] Nonetheless, the enantioselective al-
kylation reactions employing either allyl enol carbonate or
enol silane substrates provide access to a broad range of
enantioenriched a-quaternary cycloalkanones.
Asymmetric decarboxylative allylation of b-ketoesters: En-
couraged by our previous results, we sought to exploit this
technology for the preparation of a variety of interesting
synthetic targets. In one such effort, we encountered difficul-
ty in the preparation of the requisite enol carbonate or silyl
Scheme 5. Allylation with {PdII}
ACHTUNTRGENNU[G PF6] salt 41. i) [{PdACHTUNGTREN(NGUN allyl)Cl}2], NH4PF6,
EtOH, 228C; ii) 41 (10 mol%), diallyl carbonate, TBAT (37 mol%),
THF, 258C, 1 h.
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Enantioselective Decarboxylative Alkylation Reactions
FULL PAPER
Table 10. Enantioselective alkylation by using dioxanone-derived enol si-
lanes.[27c]
obtained. To address this problem, we sought a different
class of substrates for our catalytic reaction that would rely
on an alternative method of enolate generation that
was: 1) specific for the production of the desired tetrasubsti-
tuted enolate, 2) did not rely on a thermodynamic equilibra-
tion under basic conditions, and 3) maintained high enantio-
selectivity in the overall transformation.
Product[a]
Yield [%][b]
ee [%][c]
1
R1 =H
86
59
59
73
87
89
92
94
2[d,e]
3[f]
4[g]
R1 =CH3
R1 =Cl
R1 =Ph
Enantioselective alkylation with racemic allyl b-ketoesters:
b-Ketoesters represent a classical solution to the problem of
regioselective ketone alkylation (e.g., the acetoacetic ester
synthesis).[54] In 1980, the groups of Tsuji and Saegusa re-
ported allyl b-ketoesters as substrates in non-enantioselec-
tive Pd-catalyzed enolate alkylations.[21] We reasoned that
an allyl b-ketoester might solve the problem of selective
enolate formation in the course of an enantioselective allyla-
tion reaction. However, as stereogenic racemic substrates
for a catalytic asymmetric reaction, allyl b-ketoesters pre-
sented some unique challenges: the catalyst must deallylate
the substrate nonselectively to avoid kinetic resolution of
5
6
R=CH3
R=Ph
79
85
93
86
7
88
93
85
88
8[e]
9
83
92
ꢀ
the substrate, the C C bond must break at a reasonable
temperature in the decarboxylation step to prevent loss of
selectivity in the subsequent bond-forming step, and the ste-
reogenic intermediates must not experience diastereomeric
transition states that are detrimental to the selectivity of the
process.[55] Nonetheless, we prepared the appropriate sub-
strate (44, Scheme 7) using standard methods[53] and exposed
[a] Reactions were performed by using the substrate (0.5 mmol) in PhMe
(0.033m in substrate) at 258C with [Pd(dmdba)2] (5 mol%), (S)-tBu-
AHCTUNGTRENNUNG
PHOX (19; 5.5 mol%), diallyl carbonate (1.05 equiv), and TBAT
(1 equiv), unless otherwise noted. Each reaction was complete in 5–10 h.
[b] Isolated yields. [c] Measured by chiral GC or HPLC, in some cases as
a derivative.[53] [d] Reaction performed with the trimethyl silyl enol ether
with TBAT (35 mol%) in Et2O (0.0167m in substrate). [e] Reaction per-
formed with dimethallyl carbonate (1.05 equiv). The major product is the
enantiomer of the structure shown. [f] Reaction performed with dichloro-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
enol ether starting materials (Scheme 6). A variety of condi-
tions for enolate formation and trapping led to inseparable
mixtures of enol isomers. As a consequence of the high
degree of regiochemical fidelity in the allylation reac-
tion,[21,22] corresponding mixtures of allylated products were
Scheme 7. Enantioselective decarboxylative alkylation with an allyl
b-ketoester.[27b] i) (S)-19 (6.25 mol%), [Pd
308C, 9 h.
2ACHTUNGTREN(NUNG dba)3] (2.5 mol%), Et2O,
racemic (ꢁ)-44 to our standard reaction conditions ([Pd2-
(dba)3], (S)-tBu-PHOX, THF, 258C). Unfortunately, no con-
AHCTUNGTRENNUNG
version was observed (by TLC) under these conditions after
24 h. However, we were delighted to find that elevating the
temperature to 308C and carrying out the reaction in Et2O
restored reactivity, providing enone (ꢀ)-45 in 73% yield
(>99% conversion) and 86% ee after 9 h. This experiment
provided a key proof-of-concept for an enantioconvergent
reaction by using a racemic allyl b-ketoester reagent.
While further exploring this pivotal reaction, we noted
that no significant kinetic resolution of the allyl b-ketoesters
was observed.[56] In fact, this facet of the reaction was criti-
cal to obtain a high yield in a reasonable reaction time. The
similar levels of enantioselectivity observed with the allyl b-
ketoester substrates and the other substrate classes (com-
pare Tables 7 and 8 with Tables 12 and 13) suggest that the
enantiodetermining transition state of the reaction remains
unchanged. Although the extent to which decarboxylation
Scheme 6. Non-selective enolization leading to product mixtures.
Chem. Eur. J. 2011, 17, 14199 – 14223
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14207

B. M. Stoltz et al.
slowed at ambient temperature varied from substrate to sub-
strate, b-ketoesters were uniformly more sluggish in decar-
boxylation than allyl enol carbonates.[57] However, the rate
of reaction increased greatly at slightly higher temperatures,
and thus reasonable reaction times (ꢂ2 h) could be
achieved by increasing the reaction temperature by about
58C, which had a negligible effect on the ee (Table 11).
readily prepared by the aforementioned methods and suc-
cessfully underwent enantioconvergent decarboxylative al-
AHCTUNGTREGlNNUN ylation (Table 12). The system accomodated an array of
functionality and substitution, and allowed the formation of
Table 12. Enantioconvergent decarboxylative allylation of a-substituted
2-carboxyallylcyclohexanones.[27b]
Table 11. The effect of the temperature on the decarboxylative allylation
of allyl b-ketoesters.
R
t [h]
Yield [%][a]
ee [%][b]
1
CH3
CH3
prenyl
CH2CH2CN
CH2CH2CO2Et
CH2C6H5
CH2(4-CH3OC6H4)
CH2(4-CF3C6H4)
CH2OTBDPS
F
7.5
4.75
6
6.5
6
0.5
10
0.5
5
3.5
85
89
97
97
96
99
80
99
86
80
88
88
91
88
90
85
86
82
81
91
2[c]
3[c,d]
4[c]
5[c,e]
6
T [8C]
t [h]
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
18
25
30
35
40
60
48
7.5
2.25
1.25
0.67
0.15
0
85
82
85
86
82
–
88
87
86
85
83
7
8
9[e]
10[c,d]
[a] Isolated yield from the reaction of the substrate (1.0 mmol) at 0.033m.
[b] Determined by chiral GC.
[a] Isolated yield from reaction of the substrate (1.0 mmol) with [Pd2-
(dba)3] (2.5 mol%) and (S)-tBu-PHOX (19; 6.25 mol%) at 0.033m in
AHCTUNGTRENNUNG
THF at 258C, unless otherwise noted. [b] Enantiomeric excess deter-
mined by chiral GC or HPLC. [c] Performed in Et2O. [d] Performed at
308C. [e] [Pd2ACTHNUTRGNEUNG(dba)3] (4 mol%), (S)-19 (10 mol%) at 0.021m.
This enantioconvergent reaction is unusual due to the use
of quaternary b-ketoesters (Scheme 8). Typical stereomuta-
tive enantioconvergent processes (e.g., dynamic kinetic reso-
lution) involve a pre-equilibrium epimerization of the start-
products in excellent yield and high ee. Remarkably, the pre-
sumed enolate intermediate tolerated both enolizable
(Table 12, entries 4 and 5) and b-heteroatom (Table 12,
entry 9) substituents without the formation of side products
corresponding to enolate scrambling or b-elimination.[62]
Our conditions also allowed for incorporation of a fluorine
atom for the high-yielding synthesis of a stereodefined terti-
ary fluoride (Table 12, entry 10). Following our initial dis-
AHCTUNGTREGcNNNU losure, others have utilized this chemistry to prepare a
range of tertiary fluoride-containing compounds that could
be of interest as non-epimerizable pharmaceutical ana-
logues.[42c,e,h,j,63]
In addition to modifications at the a-position of the sub-
strate, the decarboxylative asymmetric allylation of b-
ketoesters was also amenable to a wide variety of modifica-
tions to the carbocycle and allyl fragment (Table 13). In par-
ticular, the reaction was exceptionally tolerant of the steric
demands of substitution at the 3-, 4-, 5-, and 6-positions of
the cyclohexane ring; each position can be fully substituted
without significantly affecting yield or enantioselectivity
(Table 13, entries 1–4). Importantly for multi-step synthetic
efforts, we found the protocol to be scalable with no detri-
mental effect on the results (Table 13, entry 2).[64] Unsaturat-
ed substrates (Table 13, entries 5 and 6), as well as sub-
strates that contain seven-membered rings (Table 13, en-
tries 7 and 8), performed well in the reaction. As with the
previous substrate classes (i.e., allyl enol carbonates and
silyl enol ethers), substitution at the central position of the
allyl fragment had a beneficial effect on the enantioselectivi-
ty of the reaction (Table 13, entries 9–11).[65] The incorpora-
Scheme 8. Stereoablative enantioconvergent catalysis.
ing material, A, followed by enantioselective conversion to
form product B (Pathway I).[58] However, quaternary stereo-
centers are not typically epimerizable, and we believe that
both enantiomers of the starting material, A, convert irre-
versibly into a prochiral intermediate, C,[59] which preferen-
tially forms one enantiomer of the product, B, under the in-
fluence of the chiral catalyst (Pathway II). We have termed
such transformations stereoablative enantioconvergent pro-
cesses due to a lack of an existing term to adequately de-
scribe this interesting reaction pathway.[60,61]
As a result of the facile synthesis of racemic quaternary
b-ketoester substrates, we have been able to expand the sub-
strate scope of the asymmetric alkylation greatly.[53]
A
number of a-substituted 2-carboxyallylcyclohexanones were
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Enantioselective Decarboxylative Alkylation Reactions
FULL PAPER
Table 13. Enantioconvergent decarboxylative allylation of b-ketoesters
tion of a chlorine atom on the allyl fragment (Table 13,
entry 10) provides both another functional group handle for
further manipulation and a higher oxidation state. Inclusion
of a phenyl group on the allyl fragment (Table 13, entry 11)
produced the highest ee product we have observed to date
(94% ee). Heterocyclic compounds were also accessible by
this method (Table 13, entry 12). Vinylogous esters were
competent in the reaction, but elevated temperatures (up to
808C) were required in some cases to achieve high conver-
sion and the ee was somewhat decreased (Table 13,
entry 13). However, employing a vinylogous thioester low-
ered the required temperature and permitted the isolation
of a highly enantioenriched product (Table 13, entry 14).[66]
This particular vinylogous thioester was employed in the
enantioselective syntheses of (+)-carissone[24e] and (+)-cas-
siol[24f] (see below). We have demonstrated that dioxanones
are viable substrates as well (Table 13, entries 15 and 16).
The tetrasubstituted a-alkoxycarbonyl products were fur-
nished in good yields and enantiomeric excesses, and the
products could be readily derivatized to give a number of
enantioenriched a-hydroxycarbonyl compounds.[27c]
with substituted carbocycles and allyl fragments.[24e,f,27a]
Product
Yield [%][a]
ee [%][b]
1
94
94
85
86
2[c]
3
4
89
90
90
85
5[d,e]
77
97
90
92
6[d]
7
83
98
87
90
Challenging Substrate Classes
Synthesis of tertiary stereocenters from acyclic enolate precur-
sors: Although we have principally employed our asymmet-
ric allylation for the synthesis of fully substituted stereocen-
ters, the mild and nearly neutral conditions of the reaction
are well suited for the synthesis of tertiary stereocenters a
to carbonyls (Table 14).[67] This type of stereocenter is prone
to epimerization and over-alkylation under the strongly
basic conditions traditionally used for enolate generation.[68]
We found that the allyl enol carbonate underwent allylation
to form phenyl ketone (R)-46 in 67% ee (Table 14, entry 1).
In analogy to the results of Hou and co-workers,[18e] we
found that the addition of AgBr gave a significant increase
in the ee of the product (Table 14, entry 2). Both trimethyl-
silyl (TMS)[69] and tert-butyldimethylsilyl (TBS)[70] enol
8[f]
9[d,e]
R=CH3
R=Cl
87
87
92
91
10[d,e]
11[g]
96
91
94
92
12
13[h]
14[i]
R=iBuO
R=PhS
86
85
75
92
Table 14. Enantioselective allylation of allyl enol carbonates and silyl
enol ethers not contained in a ring.
15[d,j]
16[d,j]
R=H
R=Cl
68
97
83
91
[a] Isolated yield from reaction of the substrate (1.0 mmol), [Pd2ACTHNUTRGNEN(UG dba)3]
(2.5 mol%) and (S)-tBu-PHOX (19; 6.25 mol%) at 0.033m in THF at
25–358C, unless otherwise noted. Each reaction was complete in 1.5–
12 h. [b] Determined by chiral GC or HPLC. [c] Substrate (25 mmol),
R
Additive
Yield [%][a]
ee [%][b]
1
2
CO2allyl
CO2allyl
TMS
TBS
TMS
none
79
75
60
82
79
20
38
67
79
62
73
77
79
82
AgBr[c]
TBAT[e]
TBAT[e]
CsF[f]
[Pd
[d] Performed in Et2O. [e] [Pd
0.021m. [f] Substrate (3.17 mmol), [Pd
(3.8 mol%) at 0.060m. [g] [Pd(dmdba)2] (2.5 mol%) and (S)-19
(2.5 mol%). [h] [Pd2A(pmdba)3] (2.5 mol%) and (S)-19 (6.25 mol%) in
PhMe at 808C. [i] [Pd2A(pmdba)3] (2.5 mol%) and (R)-19 (6.25 mol%) in
PhMe at 508C; major product was the enantiomer of the shown struc-
ture. [j] [Pd(dmdba)2] (5 mol%) and (S)-19 (6.25 mol%).
(dba)3] (1.5 mol%), and (S)-19 (3.75 mol%), 24 h reaction time.
2A(dba)3] (4 mol%) and (S)-19 (10 mol%) at
(dmdba)2] (3 mol%), and (S)-19
3[d]
4[d]
5[d]
6[d]
7[d,g]
CTHUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
TMS
TMS
CsF[f]; AgBr[c]
CsF[f]
CHTUNGTRENNUNG
CHTUNGTRENNUNG
[a] Isolated yield from reactions with the substrate (0.092 mmol) in THF
(0.092m) with [Pd2A(dba)3] (2.5 mol%) and (S)-tBu-PHOX (19;
ACHTUNGTRENNUNG
CTHUNGTRENNUNG
6.25 mol%), unless otherwise noted. [b] Measured by chiral HPLC.
[c] 40 mol% additive. [d] Reaction performed with diallyl carbonate
(1.05 equiv). [e] 35 mol% additive. [f] 48 mol% additive. [g] Performed
in Et2O.
Chem. Eur. J. 2011, 17, 14199 – 14223
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14209

B. M. Stoltz et al.
ethers were successful as enolate precursors if TBAT was
used as an initiator (Table 14, entries 3 and 4). Unlike the
tetrasubstituted silyl enol ethers, CsF proved to be the opti-
pKa (i.e., stabilized enolates) as a group gave by far the
lowest levels of enantioselectivity we have observed with
the Pd–PHOX catalyst system (Table 16). Despite the low
mal fluoACHTUNGTRENNUNGride source for the less substituted silyl enol ethers,
resulting in noticeably higher ee values (Table 14, entry 5).
Unfortunately, the use of AgBr in the presence of CsF
greatly reduced reactivity and only slightly increased the
product ee (Table 14, entry 6). Similarly, the use of diethyl
ether as a solvent increased the enantioselectivity at the ex-
pense of yield (Table 14, entry 7). Although our allylation
methods have provided tertiary stereocenters in only moder-
ate ee, we have recently disclosed a complementary decar-
boxylative protonation of quaternary allyl b-ketoesters
based on a similar catalyst system that provides access to
tertiary stereocenters a to ketones in excellent ee.[71]
Table 16. Asymmetric alkylation via stabilized allyl enol carbonates.
Substrate
Product
Yield [%][a]
ee [%][b]
1
2
3
89
24[c]
87
99
2
11[c]
Application of the palladium–PHOX catalyst system to prop-
argylation: In addition to allylation, we also explored prop-
argylation of enol carbonates with the Pd–PHOX catalyst
system (Table 15).[72] Our preliminary studies show that
4
5
93
89
0
2
Table 15. Enantioselective propargylation.
[a] Isolated yield from reaction of the substrate (1.0 mmol) in THF
(0.033m) at 258C with [Pd2A(dba)3] (2.5 mol%) and (S)-tBu-PHOX (19;
CTHUNGTRENNUNG
6.25 mol%). Each reaction was complete in 2 h. [b] Measured by chiral
GC or HPLC. [c] Absolute stereochemistry of products assigned by anal-
ogy.
Ligand
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
19, R=tBu
23, R=CH2tBu
18, R=CH2Ph
24, R=CH2(1-naphthyl)
49, R=CH2(2-naphthyl)
84
83
54
57
71
94
80
12
32
26
37
26
25
44
enantioselectivity, these substrates consistently gave excel-
lent yields of the allylated products. It is noteworthy that
the b-ketoester (Table 16, entries 1 and 2) and a-aryl ketone
(Table 16, entries 3 and 4) derived enolates, which gave ex-
cellent enantioselectivity in the asymmetric allylation reac-
tions previously published by Trost and co-workers,[15,16b]
failed to give useful levels of enantioinduction under our
conditions.[74] An oxazole substrate, designed with the inten-
tion of performing an enantioselective synthesis of a,a-di-
50, R=CH
51, R=CH2(9-anthracenyl)
2ACHTUNGTRENNUNG(3,5-CAHTUNGTERNN(UGN tBu)2Ph)
[a] GC yield relative to an internal standard (tridecane). [b] Enantiomer-
ic excess measured by chiral GC. In all cases, (S)-48 was the major enan-
tiomer.
propargylation of enol carbonate 47 required significantly
higher temperatures than are required for allylation.[73] Ad-
ditionally, the optimal structure of the PHOX ligand is sig-
nificantly different for propargylation than for allylation.
Moving the bulk of the tBu group away from the oxazoline
by insertion of a methylene group gave (S)-48 in higher ee
(Table 15, entries 1 and 2). Unlike allylation (compare with
Table 4), PHOX ligands prepared from phenylalanine deriv-
atives gave higher ee products than those prepared from sa-
ACHTUNGTRENsNUNG ubstituted amino acids, also underwent allylation with little
enantioselectivity, presumably due to the stability of the in-
termediate aromatic enolate (Table 16, entry 5). The ortho-
gonality of the substrate scope, in terms of asymmetric in-
duction, between our method and the early reports by Trost
and co-workers may be indicative of fundamentally different
mechanisms underlying the two allylation reactions and is
an important piece of evidence in our mechanistic hypothe-
sis.[26,75]
ACHTUNGTRENNUNGturated amino acids, with 9-anthracenylalanine derivative 51
giving the highest level of enantioselectivity (Table 15,
entry 7). Although still preliminary, these studies suggest
that the Pd–PHOX catalyst system may find uses with elec-
trophiles other than allyl groups.[27e,71]
Substrates containing five-membered rings: Although enolate
precursors contained in six-membered rings composed the
bulk of our substrates, we have demonstrated that seven-
and eight-membered rings are tolerated with only a slight
decrease in ee (see Tables 7, 8, and 13). Allyl b-ketoesters
constructed on five-membered rings provided modest to
useful levels of enantioselectivity (Table 17). These sub-
Substrates proceeding via weakly basic enolates: The alkyla-
tion of substrates derived from ketones of unusually low
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Chem. Eur. J. 2011, 17, 14199 – 14223

Enantioselective Decarboxylative Alkylation Reactions
FULL PAPER
Table 17. Enantioconvergent decarboxylative allylation of b-ketoesters
containing five-membered rings.
Product
Yield [%][a]
ee [%][b]
1
2
3
R=CH2CH3
R=CH(CH3)2
R=CH2NPhth
82
77
67
86
84
48
AHCTUNGTRENNUNG
4[c]
5
R=Me
R=Bn
82
93
80
71
6
7
8
R=OMe
R=Me
R=CF3
84
84
83
73
73
60
[a] Isolated yield from reaction of the substrate (1.0 mmol) in THF
(0.033m) with [Pd2A(dba)3] (2.5 mol%) and (S)-tBu-PHOX (19;
CHTUNGTRENNUNG
6.25 mol%), unless otherwise noted. Each reaction was complete in 1–
3 h. [b] Enantiomeric excess measured by chiral GC or HPLC. [c] Per-
formed on
a 0.1 mmol scale with [Pd2ACHTUNGTNRUEGN(dba)3] (5 mol%) and (S)-19
(12.5 mol%).
strates generally produced a-quaternary ketone products in
good yields with enantiomeric excesses about 10% lower
than observed for the cyclohexanone analogue. Ethyl-substi-
tuted cyclopentanone was formed in 86% ee, only 6% lower
than observed with the corresponding cyclohexanone
(Table 17, entry 1). Indanones were produced in good yield
and with useful ee values (Table 17, entries 4 and 5). Benzyl-
substituted cyclopentanone substrates gave consistent yields,
but electron-deficient aromatic rings decreased product ee
more significantly than in the reactions of six-membered
ring b-ketoesters (Table 17, entries 6–8).
Scheme 9. Useful derivatives of enantioenriched cyclic ketones.[27a,c]
i) PdCl2, O2, CuACTHNUTRGEN(UNG OAc)2·H2O, dimethylacetamide (DMA), H2O; ii) KOH,
EtOH, 60–808C; iii) 53, methyl vinyl ketone (MVK), CH2Cl2, 408C;
iv) H2, Pd/C, EtOAc; v) KOH, EtOH, 658C; vi) ethylene glycol, pyridini-
um para-toluenesulfonate (PPTS); vii) BH3·THF, NaBO3·4H2O; viii)
(COCl)2, DMSO, Et3N; ix) MeMgBr, THF; x) (COCl)2, DMSO, Et3N;
xi) TsOH·H2O, acetone, H2O; xii) KOH, EtOH, 608C; xiii) peracetic acid,
Na2CO3, CH2Cl2, 0–258C; xiv) 53 (3 mol%), CH2Cl2, 408C; xv) ethylene
glycol, PhH, Dean–Stark; xvi) O3, CH2Cl2, ꢀ788C then Me2S; xvii) KOH,
EtOH, 758C; xviii) TsOH·H2O, MeOH; xix) H5IO6, THF/H2O; xx) CH3I,
K2CO3, DMF; xxi) O3, MeOH, ꢀ788C then Na2SO3.
Synthetic applications: The a-quaternary cycloalkanones
produced in the asymmetric Tsuji alkylation are very useful
chiral building blocks. Each product contains at least two
functional groups, a ketone and an olefin, for further manip-
ulation. Moreover, the preceding section of this paper has
shown these allylation reactions to be highly functional-
group tolerant. The application of this suite of allylation re-
actions to the catalytic asymmetric synthesis of natural prod-
ucts is an ongoing topic of research in our laboratory.[24,31]
To further demonstrate the utility of these products, we
transformed ketone (S)-9 into several familiar cyclic frame-
works (Scheme 9a). Wacker oxidation of (S)-9 followed by
aldol condensation gave enone 52 in good yield. Another
functionalized [6,5] skeleton was formed in a three-step se-
quence by olefin cross metathesis with methyl vinyl ketone
catalyzed by the Grubbs second-generation Ru complex
(53),[76] olefin hydrogenation, and aldol condensation under
basic conditions to afford exocyclic enone 54. Carbocyclic
[6,6] ring systems were accessible as well; multi-step elabo-
ration of the allyl group afforded an intermediate diketone,
which underwent aldol condensation to form enone 55 in
42% overall yield. Enone 55, which has been classically pro-
duced by Robinson annulation, has been used extensively in
organic synthesis.[77] As a final transformation of (S)-9, we
performed a Baeyer–Villiger oxidation with peracetic acid
to give caprolactone 56. This transformation demonstrates
the conversion of our enantioenriched quaternary stereocen-
ter into a latent tertiary alcohol with defined absolute ste-
reochemistry and entry into acyclic systems.
Carbocyclic spiro compounds represent a particularly
challenging subclass of quaternary stereocenters. To comple-
ment the syntheses of fused cyclic skeletons above, allyl
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14211

B. M. Stoltz et al.
methallyl ketone 57 was used for the synthesis of ring sys-
tems containing spiro quaternary stereocenters. Ketone 57
could be treated with the Grubbs second-generation catalyst
(53)[76] in dichloromethane to give a good yield of spiro-
ACHTUNGTRENNUNG[4.5]ketone 58 (Scheme 9b). SpiroACHUTNGTRENN[NGU 5.5]enone 59 was pro-
duced in modest yield by treatment of ketone 57 with stan-
dard ketal protection conditions, followed by ozonolysis, and
exposure to a base (Scheme 9c).
The dioxanone class of substrates provided routes to
other important derivatives (Scheme 9d). Cleavage of the
acetal with para-toluenesulfonic acid generated dihydroxy
ketones (e.g., 60!61). These dihydroxy ketones underwent
selective oxidative cleavage upon exposure to periodic acid
and after esterification the corresponding hydroxyesters
were isolated (e.g., 62). Overall yields for the transformation
from dioxanone to the hydroxyester (60!62) were 41–81%
for three steps. In the case of chlorinated compound 62, sub-
sequent ozonolysis formed citramalic acid dimethyl ester
(63), which was correlated to literature data to establish the
absolute configuration of dioxanone (ꢀ)-60 to be S.[78]
Similar tactics have enabled the use of the enantioselec-
tive Tsuji alkylation in a number of synthetic efforts.[24,31]
Ketone (S)-64 (Scheme 10a) was readily converted into
enone 65, which could be recrystallized via the semicarba-
zone derivative to 97% ee. Enantioenriched enone 65 was
then elaborated to the antipode of the natural product di-
chroanone (66) in seven additional steps.[24a] A strategy com-
prising enantioselective allylation and ring-closing metathe-
sis was employed to synthesize the spirocyclic natural prod-
uct elatol (69) and the purported structure of laurence-
ACHTUNGTRENNUNG
none B (68) from vinylogous ester 67 (Scheme 10b).[24c,31]
Ongoing attempts to prepare the marine alkaloid zoanthe-
nol (72) feature a-quaternary ketone 70 as a key synthon
for the preparation of the ABC tricyclic substructure (71) of
the target molecule (Scheme 10c).[24b] Dioxanone 73 was
converted into cyclohexane 74 in three steps and 50% yield
(Scheme 10d). Hydroxy acid 74 has previously been em-
ployed in the synthesis of quinic acid (75),[79] a common
chiral pool starting material used in many synthetic
routes,[80] including the total synthesis of dragmacidin F re-
ported by our laboratory.[81] Vinylogous ester 76 is a versa-
tile precursor and can be elaborated into the natural prod-
ucts carissone (77)[24e] and cassiol (78).[24f]
Scheme 10. Enantioenriched cyclic ketones in the synthesis of natural
products.[24,27c]
AHCTUNGTREGlNNUN ylation strategy in the total synthesis of the cyathin diterpe-
noid cyanthiwigin F (84, Scheme 11c).[24d]
In an effort to construct more than one quaternary stereo-
center in a single transformation, we designed substrate 79
(Scheme 11a), which contains a latent allyl b-ketoester
moiety to be revealed by the reaction of the allyl enol car-
bonate portion of the molecule. To our delight, a cascade al-
lylation occurred to afford C2-symmetric ketone 80 as the
predominant product in 92% ee with 4:1 d.r. Similarly,
bis(b-ketoester) substrates may be employed in a stereocon-
vergent process during which each of the three stereoiso-
meric starting materials (i.e., two C2 symmetric enantiomers
and one meso diastereomer) are converted into enantioen-
riched products with excellent stereocontrol (e.g., 81!80,
Scheme 11b and 82!83, Scheme 11c). We have successfully
employed this double enantioselective decarboxylative al-
Mechanistic insights: Although we have not fully elucidated
the fine mechanistic details of the enantiodiscrimination
with the Pd–PHOX catalyst system, an intriguing picture of
the reactionꢂs general mechanism has emerged from our ex-
perimental studies. A number of experimental observations
suggest that the mechanism of our allylation of prochiral nu-
cleophiles differs substantially from that of the Pd–PHOX-
catalyzed malonate alkylation of prochiral allyl fragments,
which has been studied in detail by the groups of Helm-
AHCTUNGTRENNUNG
the asymmetric allylic alkylation of prochiral allyl electro-
philes (R¼H, Scheme 12) with Pd–PHOX catalysts involves
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Enantioselective Decarboxylative Alkylation Reactions
FULL PAPER
Moreover, a gearing effect through the allyl ligand is unlike-
ly given the lack of sterically large groups (R=H).
In addition to these hypothetical arguments, we have
made several experimental observations that do not corre-
late well with an outer-sphere enolate attack mechanism.
The high enantioselectivity under our conditions appears to
correspond with circumstances that would keep ion pairs
tightly associated. The range of effective solvents found
during our optimization studies demonstrated this trend;
ethereal solvents (e.g., THF), aromatic solvents (e.g., ben-
zene), ethyl acetate, and triethylamine share few properties
other than having low dielectric constants in the range 2–8,
but each provided products in high ee (see Table 3). In
media with such low dielectric constants, dissociative solva-
tion of ion pairs is difficult.[85] In conjunction with the lack
of other counterions in the reaction, the low dielectric value
would tend to enforce an inner-sphere mechanism wherein
close contact of the enolate and the chiral environment
would facilitate discrimination between the prochiral eno-
late faces.[86]
Scheme 11. Enantioselective cascade allylations generating two quaterna-
Based on our initial reasoning and empirical observations,
we have developed a working model for the course of the
reaction through an inner-sphere mechanism (Scheme 13).
Oxidative addition of Pd0–PHOX complex 88 to substrate 8
ry centers.[27b,24d] i) (S)-19 (10 mol%), [Pd
CHTUNGTERN(NUNG dba)3] (4 mol%), THF, 408C,
2A
(pmdba)3] (pmdba=di(para-methoxybenzylidene)ace-
tone), THF, 258C; iii) (S)-19, [Pd(dmdba)2], Et2O.
6 h; ii) (S)-19, [Pd2ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
or 10 leads to [PdACTHNUTRGNEUNG(allyl)PHOX] complex 41 and carboxylate
89 or mixed carbonate 90. We believe that an equilibrium
exists between the charge-separated form and the coordina-
tion complex bearing an h1-allyl group (e.g., 91). We have
isolated and characterized b-ketocarboxylate analogue 91 by
X-ray crystallography and found that it can decompose to
deliver enantioenriched ketone 9, and therefore appears to
be an important intermediate along the reaction pathway.[87]
Subsequent loss of CO2, which is most likely Pd-assisted,
leads to enolate 14 and Pd complex 41. Association of these
two fragments leads to five-coordinate intermediate 92, a
compound resembling a transition state for associative sub-
stitution with the enolate bound to the sterically less-encum-
bered apical position of the square-planar metal. By slightly
different means, allyl enol carbonate and silyl enol ether
substrates may intercept the key structure 92. Shifting of the
allyl group from an h3- to an h1-binding mode allows the
enolate fragment to move into the square plane and form
intermediate 93, thus completing the associative ligand sub-
stitution. From this complex, a standard three-centered re-
ductive-elimination pathway would require a shift from an
O- to a C-bound Pd enolate.[88] Although possible, we rea-
soned that this isomerization would be unfavorable due to
the steric demands of the resulting tertiary palladium spe-
cies. As an alternative, we postulated an extended reduc-
tive-elimination pathway proceeding through a cyclic seven-
membered pericyclic transition state (94-boat or 94-chair)
similar to a sigmatropic rearrangement.[89,90] Importantly, sit-
uating the carbocyclic ring of the enolate fragment away
from the bulky tBu group of the oxazoline provides a plausi-
ble predictive model for the observed absolute enantiofacial
selectivity.[37] Liberation of the product ketone (9) from
complex 95 regenerates catalytic Pd0 species 88.
Scheme 12. Helmchenꢂs outer-sphere mechanism for asymmetric allyla-
tion of prochiral allyl electrophiles.
attack at one allyl terminus of a (PHOX)Pd–p-allyl complex
by an outer-sphere malonate anion. The allyl group isomers
85 and 86 are in rapid equilibrium such that the nucleo-
phileꢂs preferred attack (86), from the open quadrant at the
allyl terminus trans to phosphorus, is nearly the exclusive re-
action pathway. The resulting Pd0–olefin complexes (e.g.,
87) have been observed by low temperature NMR spectro-
scopy.[82a,b] Notably, stereoinduction in these alkylation reac-
tions suffered if the steric bulk of the allyl substituents was
reduced (e.g., 96% ee for R=iPr and 71% ee for R=
Me).[83] It was difficult to rationalize the high levels of ste-
reoinduction observed in our allylation by this outer-sphere
mechanism because our substrates typically have unsubsti-
tuted allyl termini. Additionally, the formation of the new
stereocenter on the enolate through an outer-sphere mecha-
nism would require the chiral Pd complex to differentiate
between the prochiral faces of an unassociated enolate, for
which steric and electronic interactions between the nucleo-
phile and the distant chiral backbone would be minimal.[84]
Chem. Eur. J. 2011, 17, 14199 – 14223
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14213

B. M. Stoltz et al.
Scheme 13. Proposed inner-sphere mechanism for asymmetric alkylation of prochiral enolate nucleophiles.
Typically, inner- and outer-sphere processes may be dif-
spect to Pd–PHOX concentration is most consistent with
the experimental observations, tentatively supporting the
notion that a single metal center is involved in the mecha-
nism (Figure 1). Additionally, the lack of an observed non-
linear effect between product and ligand ee is also consistent
with the action of a single metal center in the enantiodeter-
mining step (Figure 2).[93] Interestingly, kinetic studies also
found a zero-order dependence on substrate concentration
in the allyl enol carbonate (Figure 3) and b-ketoester
(Figure 4) cases.[94] Based on these results, we suspect that
the rate-limiting step is either loss of CO2 from a Pd–car-
boxylate intermediate (e.g., 91!41+14, Scheme 13), or
ACHTUNGTRENNUNG
ꢀ
C C bond formation (e.g., 93!95, Scheme 13). The isola-
tion of relatively stable Pd–carboxylate complex 91 is indica-
tive of a slow decarboxylation step. The longer reaction
times observed with b-ketoester substrates compared with
those of the corresponding allyl enol carbonates is also
more consistent with decarboxylation as the rate-determin-
ing step because the rate difference would be attributed to
Because it is conceivable that multiple ion pairs could be
involved in the transition state (e.g., an enolate bound to
one {PdACHTUNGTRENNUNG(allyl)PHOX} fragment could attack the Pd-bound
allyl fragment associated with another enolate), we conduct-
ed simple kinetics experiments that support a pathway in-
volving a single metal center (Figures 1–4).[53] Initial at-
tempts to examine the kinetics of the reaction with respect
to the Pd–PHOX complex did not give clear results. We sus-
pect that the precision of the calculated initial rates may be
complicated by inconsistent aerobic oxidation of the phos-
phine ligand,[32] leading to some uncertainty in the effective
catalyst concentration. A fit to a first-order rate law with re-
ꢀ
the difference in breaking a C C bond (b-ketoester) com-
ꢀ
pared to a C O bond (enol carbonate). However, we cannot
rule out the possibility that different substrate classes may
have different rate-determining steps.
In addition to these studies, we designed other experi-
ments to differentiate our proposed mechanism from that
elucidated by Helmchen and co-workers.[82] Enolates in
which charge is delocalized (e.g., those derived from
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Chem. Eur. J. 2011, 17, 14199 – 14223

Enantioselective Decarboxylative Alkylation Reactions
FULL PAPER
Figure 1. Plot of kobs versus concentration of the [Pd
ACHTUNGTREN(NGNU PHOX)] complex
Figure 3. Plot of allyl enol carbonate 1H NMR integral versus time [s].
for an allyl enol carbonate. i) [Pd2A(dba)3] (X mol%), (S)-tBu-PHOX
CTHUNGTRENNUNG
(2.5X mol%), THF (0.03 m), 258 C, tridecane internal standard (0.15
i) [Pd2ACTHNUGTRNE(UNG dba)3] (5 mol%), (S)-tBu-PHOX (12.5 mol%), [D8]THF (0.1 m),
mmol), 0.3 mmol scale.
08 C, 1,4-dimethoxybenzene internal standard (0.0175 mmol), 0.05 mmol
scale.
Figure 4. Plot of allyl b-ketoester 1H NMR integral versus time [s].
i) [Pd2ACTHNUGTRNE(UNG dba)3] (5 mol%), (S)-tBu-PHOX (12.5 mol%), [D8]THF (0.1 m),
258 C, 0.05 mmol scale.
Figure 2. Plot of iPr-PHOX ee versus product ee.[95] i) [Pd
2ACTHNUTRGNE(UNG dba)3]
(5 mol%), iPr-PHOX (12.5 mol%), THF (0.033 m), 258 C, 0.1 mmol
bond formation typically impedes the rate of reaction.[97]
However, in our case there is little difference in the reaction
time, yield, or enantioselectivity when comparing the forma-
tion of ketone 9 with that of more sterically demanding ke-
tones (Scheme 14). This observation is more consistent with
an intramolecular reaction mechanism.
Another observation at odds with an external attack
mechanism is the unusual tolerance to water (Table 18).
Multiple equivalents of water introduced into the reaction
have only a moderate effect on the yield of the reaction.
This contrasts with typical enolates, which are rapidly
quenched by water even at low temperatures, and suggests
that once decarboxylation occurs the intermediate enolate
scale.
b-ketoesters or a-aryl ketones), which should tend to form
weak ion pairs, give high yields but extremely low levels of
enantioselectivity (see Table 16).[96] This result suggests that,
in such cases, allylation proceeds primarily through the
more conventional, although in this case poorly selective,
outer-sphere attack. The reactivity of sterically demanding
substrates in our reaction is also inconsistent with an outer-
sphere, intermolecular nucleophilic enolate attack. In a nu-
cleophilic bimolecular reaction, such as the Helmchen al-
ACHTUNGTRENNUNGlylation mechanism (Scheme 12), steric bulk near the site of
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B. M. Stoltz et al.
ate would not be readily protonated by water,[101] and this
delocalized anion may facilitate crossover by dissociation
from the metal center. In the case of b-ketoester substrates,
a b-ketocarboxylate intermediate (e.g., 91) may play an
analogous role.[102]
To validate our hypothesis regarding the persistence of an
intermediate carboxylate or mono-alkyl carbonate (89 or 90,
respectively), we collected 31P NMR data during the reac-
tion.[27d,53] Non-ligated tBu-PHOX (19) exhibited a 31P reso-
Scheme 14. Comparison of sterically varied products formed at 258C in
THF.
nance at ꢀ5.9 ppm. If [Pd
2ACHTUNGRTEN(NUNG dba)3] and tBu-PHOX were com-
Table 18. Effect of water on asymmetric alkylation.[a]
plexed, a new resonance was observed at 18.8 ppm along
with excess ligand (Figure 5a). If substrate (ꢁ)-10 was
added, the resonance at 18.8 ppm disappeared immediately
and the only observed intermediate was found at 30.9 ppm,
which persisted until the end of the reaction (Figure 5b). If
the substrate was completely consumed, the initial Pd–
PHOX complex returned at 18.8 ppm (Figure 5c).[103] Inter-
H2O added [equiv][b]
Yield [%][c]
ee [%][d]
1
2
3
4
5
6
0
95
99
88
70
67
63
86
87
84
61
49
40
0.55
1.64
8.25
16.5
33.3
[a] Data reported are the average of three experiments. [b] H2O added
after Pd/PHOX complexation, but before the substrate. [c] GC yield rela-
tive to an internal standard (tridecane). [d] Enantiomeric excess mea-
sured by chiral GC.
formed in the reaction is tightly associated with or covalent-
ly bound to its Pd counterion for most of its lifetime.[98]
In an effort to trace the fate of the allyl and enolate frag-
ments in the course of the reaction, we performed crossover
experiments with a 1:1 mixture of deuterated allyl enol car-
bonates 97 and 98 in THF, dioxane, and benzene
(Scheme 15).[99] Analysis of the products by high-resolution
mass spectrometry revealed the presence of all four possible
product masses in nearly equal amounts.[100] In conjunction
with the water addition experiments, this observation sug-
gests that a palladium enol carbonate species (41+90 or
41·90) may be a long-lived intermediate. Such an intermedi-
Figure 5. 31P NMR spectra collected during the enantioselective allylation
reaction: a) [(PHOX)PdACHTNUTGRNEUNG
(dba)] complex (18.8 ppm)[27d] and excess PHOX
ligand (S)-19 (ꢀ5.9 ppm) prior to addition of substrate; b) after addition
of substrate (ꢁ)-10 during the reaction (carboxylate 91 is observed at
30.9 ppm); and c) after complete consumption of the substrate. i) (S)-19,
Scheme 15. Crossover experiments with deuterated allyl enol carbona-
tes.[27b] i) [Pd
2A
(14 mol%), [Pd2ACTHUNGTERNUN(G dba)3] (5 mol%), THF.
14216
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Chem. Eur. J. 2011, 17, 14199 – 14223

Enantioselective Decarboxylative Alkylation Reactions
FULL PAPER
estingly, similar behavior was observed in reactions with
allyl carbonates, although the chemical shifts of the inter-
mediate species differed slightly.
isomeric fidelity found in Tsujiꢂs non-enantioselective
system. The reactivity and enantioselectivity of the alkyla-
tion reactions have proven to be quite general with respect
to substrate steric bulk, ring size, unsaturation, and diverse
functional groups. We have demonstrated the relevance of
the a-quaternary ketones produced in the reaction by their
conversion into a number of carbocyclic chiral building
blocks, including several spiro motifs, as well as in the asym-
metric syntheses of several natural products. Studies direct-
ed toward further development of the scope of this reaction
and catalyst system are ongoing. Additionally, the continued
application of our asymmetric alkylation as a key enantiode-
termining step in natural product synthesis will be reported
in due course.
The separately prepared [PdII +A[PF6]ꢀ com-
ACHTUNGTREN(NGUN allyl)ACHTUNTRGEG(NNUN PHOX)] CHTNUGTRENNUGN
plex (41, Scheme 5) exhibited two 31P resonances (other
ꢀ
than those due to PF6 ) at 23.5 and 22.5 ppm in a 2:1 ratio
(in THF), due to the mixture of endo- an exo-allyl iso-
mers.[82] The different chemical shifts for this PdII complex
than those observed during the reaction suggest a different
ligation environment about the Pd center. To correlate these
two different species, nBu4NOAc was added to a solution of
[PdII
served at 30.9 ppm, which matches that of the independently
synthesized [PdII (OAc)] complex.[27d] Based
(allyl)(PHOX)
on these experiments, we believe that the observed catalyst
+A[PF6]ꢀ, and a new species was ob-
ACHTUNGTRENNUNG(allyl)ACHTUNGTRENNUNG(PHOX)] CHTNUGTRENNUGN
A
R
ACHTUNGTRENNUNG
resting state in solution is likely the [PdII (PHOX)]+
ACTHNUTRGENNU(G allyl)ACHTUGNTRENNUGN
/[carboxylate]ꢀ ion pair (41+89, Scheme 13) or coordination
complex 91. Efforts to fully characterize additional inter-
mediate structures are ongoing.
Experimental Section
Representative procedure for the enantioselective decarboxylative al-
The solid-state structure of the independently prepared
A
A round-bottom flask (50 mL)
[PdII +A[PF6]ꢀ salt (41) lends credence to the
ACHTUNGTRENNUNG(allyl)PHOX] CHTUNGTRENNUNG
possibility of an apically bound palladium enolate. As
shown in Scheme 5, after recrystallization the complex par-
tially co-crystallizes with a molecule of ethanol in its unoc-
cupied quadrant.[47] We envision that this is the likely site of
enolate coordination (e.g., apically bound enolate complex
92, Scheme 13).
CTHUNGTRENNUNG
0.025 equiv) and (S)-tBu-PHOX (19, 24.2 mg, 0.0625 mmol, 0.0625 equiv)
were added. After the flask was flushed with argon, THF (30 mL) was
added, and the contents were stirred at 258C for 30 min, at which time
allyl enol carbonate 8 (196.2 mg, 1.0 mmol, 1.0 equiv) was added by sy-
ringe in one portion. When the reaction was complete by TLC (2 h), the
reaction mixture was dried under reduced pressure, and the residue puri-
fied by chromatography (2!3% Et2O in pentane on SiO2) to afford (S)-
Given the body of evidence accrued in these experimental
studies and our inability to probe the mechanism through
classical stereochemical labeling experiments,[91] we initiated
a collaboration with the Goddard group at Caltech to inves-
tigate the details of the mechanism through computational
modeling.[75] The computational studies carried out have cor-
roborated our initial hypothesis regarding the inner-sphere
mechanism, the difficult isomerization between the O- and
C-bound Pd enolates, and the unusual cyclic seven-mem-
bered reductive-elimination pathway (Scheme 13). Notably,
these calculations have found that the traditional outer-
sphere mechanism (Scheme 12) is significantly higher in
energy than the inner-sphere pathway. The simulations have
not yet elucidated the fine details of the origin of the enan-
tioselectivity. Experiments and computational studies to
better characterize the reaction mechanism are under way
with the hope of improving the enantioselectivity and scope
of the asymmetric alkylation.
2-allyl-2-methylACHTNUTGRNEUNGcyclohexanone ((S)-9; 129.6 mg, 85.1%, 87% ee) as a col-
orless oil. [a]2D1 =ꢀ49.64 (c=2.38 in hexane, 98% ee); 1H NMR
(300 MHz, CDCl3): d=5.75–5.61 (m, 1H), 5.05 (s, 1H), 5.01–4.99 (m,
1H), 2.40–2.31 (m, 3H), 2.21 (dd, J=13.8, 7.5 Hz, 1H), 1.90–1.65 (m,
5H), 1.63–1.50 (m, 1H), 1.06 ppm (s, 3H); 13C NMR (75 MHz, CDCl3):
d=215.4, 133.7, 117.9, 48.4, 41.9, 38.8, 38.5, 27.4, 22.6, 21.0 ppm; IR (neat
film NaCl): 2934, 2865, 1707, 1451, 912 cmꢀ1; HRMS (EI): m/z calcd for
C10H16O+: 152.1201 [M]+; found: 152.1204.
Representative procedure for the enantioselective decarboxylative al-
AHCTUNGTRENNUNG
CTHUNGTRENNUNG
PHOX (19, 24.2 mg, 0.0625 mmol, 0.0625 equiv), and TBAT (189 mg,
0.35 mmol, 0.35 equiv) were added. After the flask was flushed with
argon, THF (30 mL) was added, and the contents were stirred at 258C
for 30 min, at which time diallyl carbonate (150.6 mL, 1.05 mmol,
1.05 equiv) and silyl enol ether SI23 (see the Supporting Information;
184.35 mg, 1.0 mmol, 1.0 equiv) were added sequentially by syringe in
single portions. When the reaction was complete by TLC (2 h), the reac-
tion mixture was dried under reduced pressure, and the residue purified
by chromatography (2!3% Et2O in pentane on SiO2) to afford ketone
(S)-9 (144.3 mg, 94.8%, 87% ee).
Representative procedure for the enantioselective decarboxylative al-
Conclusion
ACHTUNGTRENNUNG
CTHUNGTRENNUNG
To address a significant deficiency in the asymmetric alkyla-
tion literature, we have developed a strategy to prepare
enantioenriched cycloalkanones in high yield. This work
provides direct routes to valuable enantioenriched a-quater-
nary ketones from readily accessible enolate precursors.
Critical to our success was the use of enolate precursors,
which can be converted into enolates under mild conditions,
and the use of a chiral catalyst that exhibited the enolate
(S)-tBu-PHOX (19, 24.2 mg, 0.0625 mmol, 0.0625 equiv) were added. The
flask containing the solids was evacuated for 15 min and then refilled
with dry nitrogen. Dry THF (30 mL) was then added and the resulting
solution stirred at 258C for 30 min. At this point, allyl 1-methyl-2-oxo-
cyclohexanecarboxylate ((ꢁ)-10) was added through a syringe in one por-
tion. When the reaction was complete by TLC (7.5 h), the reaction mix-
ture was evaporated under reduced pressure, and the residue purified by
column chromatography (SiO2, 1.5!2.5% Et2O in pentane) to afford
ketone (S)-9 (129.6 mg, 85%, 88% ee).
Chem. Eur. J. 2011, 17, 14199 – 14223
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www.chemeurj.org
14217

B. M. Stoltz et al.
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Acknowledgements
This publication is based on work supported by award number KUS-11–
006–02, made by the King Abdullah University of Science and Technolo-
gy (KAUST). We thank the NIH-NIGMS (R01 GM080269–01 and post-
doctoral fellowships to AMH and DEW), The Fannie and John Hertz
Foundation (predoctoral fellowship to DCB), Eli Lilly (predoctoral fel-
lowships to JTM, RMM, and MRK), Ono Pharmaceutical Co., Ltd.
(postdoctoral fellowship to KT), The Hungarian–American Enterprise
Scholarship Fund (postdoctoral fellowship to ZN), Takeda Pharmaceuti-
cal Co., Ltd. (postdoctoral fellowship to MS), The California Tobacco-
Related Disease Research Program of the University of California (pre-
doctoral fellowship to JLR, grant number 14DT-0004), Marcella R. Bon-
sall and the Dalton Fund (undergraduate fellowships to SRL), the Cal-
tech Amgen Scholars Program (undergraduate fellowship to KVP), The
21st Century COE Program for Frontiers in Fundamental Chemistry
from the Ministry of Education, Culture, Sports, Science and Technology,
Japan (financial support to AI), the A. P. Sloan Foundation, Research
Corporation, the Dreyfus Foundation, Bristol–Myers Squibb, Glaxo-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Dr. Mike Day and Larry Henling for assistance with X-ray crystallogra-
phy. Ruthenium olefin metathesis catalysts were generously donated by
Materia.
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Enantioselective Decarboxylative Alkylation Reactions
FULL PAPER
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Stoltz, Angew. Chem. 2007, 119, 4155–4158; Angew. Chem. Int. Ed.
2007, 46, 4077–4080; c) D. E. White, I. C. Stewart, R. H. Grubbs,
B. M. Stoltz, J. Am. Chem. Soc. 2008, 130, 810–811; d) J. A. En-
quist, Jr., B. M. Stoltz, Nature 2008, 453, 1228–1231; e) S. R.
Levine, M. R. Krout, B. M. Stoltz, Org. Lett. 2009, 11, 289–292;
f) K. V. Petrova, J. T. Mohr, B. M. Stoltz, Org. Lett. 2009, 11, 293–
295; g) G. N. Varseev, M. E. Maier, Angew. Chem. 2009, 121, 3739–
3742; Angew. Chem. Int. Ed. 2009, 48, 3685–3688; h) H. Mukher-
jee, N. T. McDougal, B. M. Stoltz, Org. Lett. 2011, 13, 825–827.
[14] a) M. Sawamura, H. Nagata, H. Sakamoto, Y. Ito, J. Am. Chem.
Soc. 1992, 114, 2586–2592; b) M. Sawamura, M. Sudoh, Y. Ito, J.
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[15] B. M. Trost, R. Radinov, E. M. Grenzer, J. Am. Chem. Soc. 1997,
119, 7879–7880.
[16] a) B. M. Trost, G. M. Schroeder, Chem. Eur. J. 2005, 11, 174–184;
b) B. M. Trost, G. M. Schroeder, J. Kristensen, Angew. Chem. 2002,
114, 3642–3645; Angew. Chem. Int. Ed. 2002, 41, 3492–3495;
c) B. M. Trost, G. M. Schroeder, J. Am. Chem. Soc. 1999, 121,
6759–6760; for related work from Trost and co-workers that has
resulted in enantioselective trimethylenemethane (TMM)-cycload-
ditions which are capable of generating quaternary stereocenters,
see: d) B. M. Trost, J. P. Stambuli, S. M. Silverman, U. Schwçrer, J.
Am. Chem. Soc. 2006, 128, 13328–13329; e) B. M. Trost, N.
Cramer, S. M. Silverman, J. Am. Chem. Soc. 2007, 129, 12396–
12397; f) B. M. Trost, P. J. McDougall, O. Hartmann, P. T. Wathen,
J. Am. Chem. Soc. 2008, 130, 14960–14961.
[17] For other reports of the alkylation of ketone enolates to generate
quaternary stereocenters by using different ligand systems, see:
a) S.-L. You, X.-L. Hou, L.-X. Dai, X.-Z. Zhu, Org. Lett. 2001, 3,
149–151; b) Ref. [5]; c) for related studies on an intramolecular
variant of this decarboxylative transformation that have also
proven successful, see: R. Shintani, M. Murakami, T. Hayashi, J.
Am. Chem. Soc. 2007, 129, 12356–12357.
[18] Significant progress has also been made regarding the Pd-catalyzed
alkylation of pregenerated, unstabilized enolates to produce terti-
ary stereocenters; for examples, see: a) M. Braun, P. Meletis, M.
Fidan, Org. Synth. 2009, 86, 47–58; b) X. Zhao, D. Liu, F. Xie, W.
Zhang, Tetrahedron 2009, 65, 512–517; c) M. Braun, T. Meier, F.
Laicher, P. Meletis, M. Fidan, Adv. Synth. Catal. 2008, 350, 303–
314; d) W.-H. Zheng, B.-H. Zheng, Y. Zhang, X.-L. Hou, J. Am.
Chem. Soc. 2007, 129, 7718–7719; e) X.-X. Yan, C.-G. Liang, Y.
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2005, 117, 6702–6704; Angew. Chem. Int. Ed. 2005, 44, 6544–6546;
f) M. Braun, F. Laicher, T. Meier, Angew. Chem. 2000, 112, 3637–
3640; Angew. Chem. Int. Ed. 2000, 39, 3494–3497.
[19] For recent reviews on the allylic alkylation of ketone enolates, see:
a) M. Braun, T. Meier, Angew. Chem. 2006, 118, 7106–7109;
Angew. Chem. Int. Ed. 2006, 45, 6952–6955; b) S.-L. You, L.-X.
Dai, Angew. Chem. 2006, 118, 5372–5374; Angew. Chem. Int. Ed.
2006, 45, 5246–5248; c) M. Braun, T. Meier, Synlett 2006, 0661–
0676; d) U. Kazmaier, Curr. Org. Chem. 2003, 7, 317–328.
[25] Treatment of allyl enol carbonate 8 with [Pd2ACTHUNGTERNU(NG dba)3] in dioxane
with no phosphine ligand gave no reaction after 24 h.
[26] For studies on the stereochemical course of alkylation of Pd p-allyl
complexes, see: a) B. M. Trost, T. R. Verhoeven, J. Org. Chem.
1976, 41, 3215–3216; b) B. M. Trost, T. R. Verhoeven, J. Am.
Chem. Soc. 1980, 102, 4730–4743; c) J.-E. Bꢃckvall, R. E. Nord-
berg, J. Am. Chem. Soc. 1981, 103, 4959–4960; d) J.-E. Bꢃckvall,
R. E. Nordberg, J. Vꢄgberg, Tetrahedron Lett. 1983, 24, 411–412;
e) E. Keinan, Z. Roth, J. Org. Chem. 1983, 48, 1769–1772; f) F. K.
Sheffy, J. K. Stille, J. Am. Chem. Soc. 1983, 105, 7173–7175;
g) F. K. Sheffy, J. P. Godschalx, J. K. Stille, J. Am. Chem. Soc. 1984,
106, 4833–4840; h) Y. Tsuji, M. Funato, M. Ozawa, H. Ogiyama, S.
Kajita, T. Kawamura, J. Org. Chem. 1996, 61, 5779–5787; i) D. K.
Rayabarapu, J. A. Tunge, J. Am. Chem. Soc. 2005, 127, 13510–
13511.
[27] For our initial communications concerning this chemistry, see:
a) D. C. Behenna, B. M. Stoltz, J. Am. Chem. Soc. 2004, 126,
15044–15045; b) J. T. Mohr, D. C. Behenna, A. M. Harned, B. M.
Stoltz, Angew. Chem. 2005, 117, 7084–7087; Angew. Chem. Int. Ed.
2005, 44, 6924–6927; c) M. Seto, J. L. Roizen, B. M. Stoltz, Angew.
Chem. 2008, 120, 6979–6982; Angew. Chem. Int. Ed. 2008, 47,
6873–6876; d) N. H. Sherden, D. C. Behenna, S. C. Virgil, B. M.
Stoltz, Angew. Chem. 2009, 121, 6972–6975; Angew. Chem. Int. Ed.
2009, 48, 6840–6843; e) J. Streuff, D. E. White, S. C. Virgil, B. M.
Stoltz, Nat. Chem. 2010, 2, 192–196; f) A. Y. Hong, M. R. Krout, T.
Jensen, N. B. Bennett, A. M. Harned, B. M. Stoltz, Angew. Chem.
2011, 123, 2808–2812; Angew. Chem. Int. Ed. 2011, 50, 2756–2760;
g) for our recent review of the development of the enantioselective
variants of these reactions to date by our lab and others, see: J. T.
Mohr, B. M. Stoltz, Chem. Asian J. 2007, 2, 1476–1491.
[28] For a review of chiral N/P ligands in asymmetric catalysis, see: P. J.
Guiry, C. P. Saunders, Adv. Synth. Catal. 2004, 346, 497–537.
[29] a) G. Helmchen, A. Pfaltz, Acc. Chem. Res. 2000, 33, 336–345;
b) J. M. J. Williams, Synlett 1996, 705–710, and references therein;
c) M. Peer, J. C. de Jong, M. Kiefer, T. Langer, H. Rieck, H. Schell,
P. Sennhenn, J. Sprinz, H. Steinhagen, B. Wiese, G. Helmchen, Tet-
rahedron 1996, 52, 7547–7583; d) for a recent review of oxazoline-
Chem. Eur. J. 2011, 17, 14199 – 14223
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B. M. Stoltz et al.
containing ligands, see: G. C. Hargaden, P. J. Guiry, Chem. Rev.
2009, 109, 2505–2550.
[30] THF also offers the practical advantage of being easier to obtain as
a pure and dry liquid than dioxane. The lower boiling point of
THF also aided in isolation of volatile ketones like 9.
[36] B. Wiese, G. Helmchen, Tetrahedron Lett. 1998, 39, 5727–5730.
[37] a) To definitively assign the absolute stereochemistry of the newly
formed quaternary stereocenter, we prepared the corresponding
semicarbazones i and ii, each bearing an isopinocampheylamine
portion of known configuration, which were then characterized by
X-ray crystallography. In addition, we converted ketone 9 into cy-
cloalkanones iii and 64, which matched the major enantiomer of
[31] The rate and selectivity of the reaction are typically unchanged
when Pd0 sources other than [Pd
CHTUNGTRENNUNG
2A
dimethoxybenzylidene)acetone]palladium(0) ([Pd
tris[di(4-methoxybenzylidene)acetone]dipalladium(0)
(pmdba)3])). For a case in which the choice of Pd0 source affected
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
conversion, see: D. E. White, I. C. Stewart, B. A. Seashore-Ludlow,
R. H. Grubbs, B. M. Stoltz, Tetrahedron 2010, 66, 4668–4686; for a
discussion of the utility of [PdCAHUTGTNRENNUG(dmdba)2] and [Pd2ACHUTNGTERN(NUGN pmdba)3], see
Ref. [48].
[32] We have studied the 31P NMR spectra of the reaction at length
(see Figure 5 and the Supporting Information), and we believe that
phosphine oxide iv is produced as a catalyst decomposition product
when O2 is present. In the absence of Pd, PHOX ligand 19 does
not oxidize significantly in the solid state or in solution. Phosphine
oxide iv may be observed during the reaction by 31P NMR spec-
troscopy (27 ppm) in typical benchtop experiments. Typically, the
rate of ligand oxidation is slow relative to the time frame of the de-
carboxylative alkylation (<12 h), and reactions may be carried out
routinely on the benchtop under inert atmosphere in dry, degassed
solvents. Substrates that are particularly slow to react are often
more efficiently converted to products in a glovebox to extend the
lifetime of the catalyst (Figure 5 shows virtually no ligand oxidation
occurs if the reaction is rigorously protected from air). We have in-
dependently synthesized (S)-tBu-PHOX oxide (iv) and found that
if used as a ligand for the conversion of tetralone-derived allyl enol
carbonate 19 into ketone 3 no reaction was observed.
products formed in the direct allylation reactions (see the Support-
ing Information for details). The S configuration of tetralone 3 was
confirmed by comparison with literature data (see Ref. [16b]).
Based on the consistent sense of enantiofacial selectivity, the ster-
eochemistries of the remaining allylation products are inferred by
analogy; b) the recrystallization of semicarbazone derivatives as a
means to increase the ee of our products has proven to be of gener-
al use with the a-quaternary ketones and their derivatives; for an
example, see: Ref. [24a]; c) for an optimized procedure for the
preparation and recrystallization of the semicarbazone (a single re-
crystallization from toluene provided material of 98% ee), see: J. T.
Mohr, M. R. Krout, B. M. Stoltz, Org. Synth. 2009, 86, 194–211.
[38] Trudeau and Morken synthe-
sized PHOX-like ligand viii, as
well as some structurally related
ligands. These were tested in a
decarboxylative alkylation with
carbonate substrate 20, provid-
ing ketone 3 in up to 59% ee;
see: S. Trudeau, J. P. Morken,
[33] As a result of our desire to generate a large variety of PHOX li-
Tetrahedron 2006, 62, 11470–
ꢀ
11476.
gands, we adapted a procedure for C P bond formation disclosed
[39] These reactions were carried out before the optimal solvent and
concentration (THF at 0.031m) were determined. We believe that
reexamining these reactions under the optimized reaction condi-
tions would not significantly change the outcome, as only increases
in ee and yield would be anticipated.
by Buchwald and co-workers for the synthesis of PHOX ligands,
see: a) K. Tani, D. C. Behenna, R. M. McFadden, B. M. Stoltz, Org.
Lett. 2007, 9, 2529–2531; b) M. R. Krout, J. T. Mohr, B. M. Stoltz,
Org. Synth. 2009, 86, 181–193; c) D. Gelman, L. Jiang, S. L. Buch-
wald, Org. Lett. 2003, 5, 2315–2318; d) for an alternative cross-cou-
pling with phosphine oxides, see: N. T. McDougal, J. Streuff, H.
Mukherjee, S. C. Virgil, B. M. Stoltz, Tetrahedron Lett. 2010, 51,
5550–5554.
[40] G. J. Dawson, C. G. Frost, C. J. Martin J. M. J. Williams, S. J. Coote,
Tetrahedron Lett. 1993, 34, 7793–7796.
[41] S. P. Smidt, F. Menges, A. Pfaltz, Org. Lett. 2004, 6, 2023–2026.
[42] Subsequent to our initial report on asymmetric allylation, several
related reports have appeared: a) for a review, see Ref. [27g];
b) B. M. Trost, J. Xu, J. Am. Chem. Soc. 2005, 127, 2846–2847;
c) M. Nakamura, A. Hajra, K. Endo, E. Nakamura, Angew. Chem.
2005, 117, 7414–7417; Angew. Chem. Int. Ed. 2005, 44, 7248–7251;
d) B. M. Trost, J. Xu, J. Am. Chem. Soc. 2005, 127, 17180–17181;
e) E. C. Burger, B. R. Barron, J. A. Tunge, Synlett 2006, 2824–
2826; f) B. M. Trost, R. N. Bream, J. Xu, Angew. Chem. 2006, 118,
3181–3184; Angew. Chem. Int. Ed. 2006, 45, 3109–3112; g) B. M.
Trost, J. Xu, M. Reichle, J. Am. Chem. Soc. 2007, 129, 282–283;
h) ꢅ. Bꢆlanger, K. Cantin, O. Messe, M. Tremblay, J.-F. Paquin, J.
Am. Chem. Soc. 2007, 129, 1034–1035; i) S. R. Schulz, S. Blechert,
Angew. Chem. 2007, 119, 4040–4044; Angew. Chem. Int. Ed. 2007,
46, 3966–3970; j) ꢅ. Bꢆlanger, C. Houzꢆ, N. Guimond, K. Cantin,
J.-F. Paquin, Chem. Commun. 2008, 3251–3253; k) B. M. Trost, J.
Xu, T. Schmidt, J. Am. Chem. Soc. 2009, 131, 18343–18357;
l) Refs. [35] and [38].
[34] Synthesized in analogy to PHOX ligands prepared by Helmchen
and co-workers, see Ref. [29c].
[35] Additionally, we have prepared the similar ligands v and vi. In our
prototypical reaction (8!9), the product was formed in 86 and
79% ee , respectively, with complete substrate conversion. A recent
publication from another laboratory has put forth related ligand
vii, which can be synthesized from valine, as an alternative to tBu-
PHOX. The authors report comparable levels of enantioinduction
with fluorinated enol silane substrates; see: ꢅ. Bꢆlanger, M.-F. Pou-
liot, J.-F. Paquin, Org. Lett. 2009, 11, 2201–2204.
14220
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Chem. Eur. J. 2011, 17, 14199 – 14223

Enantioselective Decarboxylative Alkylation Reactions
FULL PAPER
[43] Reactions below 108C typically do not show conversion to product
and are only reliably performed with highly activated substrates;
for an example, see: N. T. Goodwin, Ph. D. Thesis, California Insti-
tute of Technology (USA), 2006.
[44] Although isomerically pure enol carbonates and silyl enol ethers
were desired for substrate characterization and to maximize the
yield of a-quaternary ketone, it should be noted that this is not re-
quired for the allylation reaction. The less substituted enolate pre-
cursors are cleanly transformed into 2,6-substituted ketones, which
are typically readily removed by chromatography and have no
effect on the ee of the desired product.
b) J.-F. Detalle, A. Riahi, V. Steinmetz, F. Hꢆnin, J. Muzart, J. Org.
Chem. 2004, 69, 6528–6532.
[60] For a highlight of recent approaches to catalytic enantioselective
stereoablative reactions, see: J. T. Mohr, D. C. Ebner, B. M. Stoltz,
Org. Biomol. Chem. 2007, 5, 3571–3576.
[61] For examples of stereoablative enantioconvergent catalysis, see:
a) T. Hamada, A. Chieffi, J. ꢈhman, S. L. Buchwald, J. Am. Chem.
Soc. 2002, 124, 1261–1268; b) N. Mase, F. Tanaka, C. F. Barbas III,
Angew. Chem. 2004, 116, 2474–2477; Angew. Chem. Int. Ed. 2004,
43, 2420–2423; c) C. Fischer, G. C. Fu, J. Am. Chem. Soc. 2005,
127, 4594–4595; d) I. T. Raheem, P. S. Thiara, E. A. Peterson, E. N.
Jacobsen, J. Am. Chem. Soc. 2007, 129, 13404–13405; e) T. Nishi-
mura, T. Katoh, K. Takatsu, R. Shintani, T. Hayashi, J. Am. Chem.
Soc. 2007, 129, 14158–14159; f) D. Enders, A. A. Narine, F. Toul-
goat, T. Bisschops, Angew. Chem. 2008, 120, 5744–5748; Angew.
Chem. Int. Ed. 2008, 47, 5661–5665.
[62] Although only trace amounts of b-elimination were observed with
this substrate, substrates with better leaving groups (e.g., OAc) pre-
dominantly underwent b-elimination to form the a,b-unsaturated
compounds.
[63] Fluorinated compounds are frequently used in medicinal chemistry,
see: a) L. Zoute, C. Audouard, J.-C. Plaquevent, D. Cahard, Org.
Biomol. Chem. 2003, 1, 1833–1834; b) K. Nagai, T. A. Davies,
B. E. Dewasse, M. R. Jacobs, P. C. Appelbaum, J. Antimicrob. Che-
mother. 2001, 48, 365–374.
[64] For an optimized, large-scale procedure, see Ref. [37c].
[65] Increased enantiomeric excess was also observed with a Trost
ligand derived catalyst if the central position of the allyl fragment
was substituted, see: Ref. [15l].
[66] A similar increase in reactivity for vinylogous thioester substrates
was observed with a Trost ligand derived catalyst, see: Ref. [42f].
[67] For similar approaches to the synthesis of tertiary stereocenters a
to carbonyls by Trost and co-workers, see: a) B. M. Trost, K. Lehr,
D. J. Michaelis, J. Xu, A. K. Buckl, J. Am. Chem. Soc. 2010, 132,
8915–8917; b) Ref. [42d]; c) Ref. [42g].
[45] Sodium and potassium methoxide (1 equiv) could be used directly
as silyl enol ether activators. However, lower yields (14 and 36%,
respectively) and slightly lower ee values (81 and 80% ee, respec-
tively) were observed.
[46] For the procedure, see: S. Liu, J. F. K. Mꢇller, M. Neuburger, S.
Schaffner, M. Zehnder, J. Organomet. Chem. 1997, 549, 283–293.
[47] ACHTUNGTRENNUNG
[PF6]ꢀ counterions removed for clarity. Two out of four of the crys-
tallographically unique [PdACTHUNRTGNEUNG(allyl)PHOX] complexes in the unit cell
crystallized with a molecule of ethanol. The endo- and exo-allyl iso-
mers were present in essentially equal electron density and are
modeled as a superposition of the two isomers.
[48] In some cases we have encountered difficulty in separating the cy-
cloalkanone products from the residual dba introduced with the
palladium source. As a practical consideration, it is often useful to
employ
([Pd(dmdba)2]) or tris[di(4-methoxybenzylidene)acetone]dipalladi-
um(0) ([Pd2A(pmdba)3]) as the source of palladium because of the
bis[di(3,5-dimethoxybenzylidene)acetone]palladium(0)
ACHTUNGTRENNUNG
CHTUNGTRENNUNG
difference in polarity of dmdba and pmdba relative to dba.
[49] G. M. Coppola, H. F. Schuster, a-Hydroxy Acids in Enantioselective
Syntheses, Wiley-VCH, Weinheim, 1997.
[50] a) D. Enders, B. Bockstiegel, Synthesis 1989, 493–496; b) D.
Enders, I. Breuer, E. Drosdow, Synthesis 2005, 3239–3244.
[51] For a proline-catalyzed aldol reaction with dioxanones, see: a) D.
Enders, C. Grondal, Angew. Chem. 2005, 117, 1235–1238; Angew.
Chem. Int. Ed. 2005, 44, 1210–1212; b) for a review, see: D.
Enders, M. Voith, A. Lenzen, Angew. Chem. 2005, 117, 1330–1351;
Angew. Chem. Int. Ed. 2005, 44, 1304–1325.
[52] The corresponding trimethylsilyl enol ethers were relatively unsta-
ble and often could not be purified in high yield by silica gel chro-
matography. Comparable yield and ee values could be obtained if
TMS enol ethers were employed in the allylation reaction. See the
Supporting Information for details.
[53] See the Supporting Information for details.
[54] A. Michael, K. Wolgast, Ber. Dtsch. Chem. Ges. 1909, 42, 3176–
3177.
[55] For a discussion of double stereodifferentiation, see: E. L. Eliel,
S. H. Wilen, Stereochemistry of Organic Compounds, Wiley, New
York, 1994, pp. 965–971.
[56] Aliquots taken during the reaction with b-ketoester (ꢁ)-10 at 308C
in THF show that the starting material reaches a maximum of
5% ee at 83% conversion for a krel of 1.1.
[68] Under our conditions we found that negligible racemization of aryl
ketone 46 were observed if it was allowed to remain under the re-
action conditions for an additional 12 h.
[69] O. MuÇoz-MuÇiz, M. Quintanar-Audelo, E. Juaristi, J. Org. Chem.
2003, 68, 1622–1625.
[70] G. Trimitsis, S. Beers, J. Ridella, M. Carlon, D. Cullin, J. High, D.
Brutts, J. Chem. Soc. Chem. Commun. 1984, 1088–1089.
[71] a) J. T. Mohr, T. Nishimata, D. C. Behenna, B. M. Stoltz, J. Am.
Chem. Soc. 2006, 128, 11348–11349; b) S. C. Marinescu, T. Nishi-
mata, J. T. Mohr, B. M. Stoltz, Org. Lett. 2008, 10, 1039–1042;
c) for a recent review of enantioselective protonation reactions as a
means of generating tertiary stereocenters, see: J. T. Mohr, A. Y.
Hong, B. M. Stoltz, Nat. Chem. 2009, 1, 359–369.
[72] For examples of the propargylation of similar enolates, see: a) I.
Matsuda, K.-I. Komori, K. Itoh, J. Am. Chem. Soc. 2002, 124,
9072–9073; b) H. Bienaymꢆ, Tetrahedron Lett. 1994, 35, 7383–
7386; c) H. Bienaymꢆ, Tetrahedron Lett. 1994, 35, 7387–7390.
[73] In addition to a-propargylated
ꢀ
[57] Presumably, this is the result of cleavage of a C C bond during de-
ketone 48, trace amounts of (S)-
allene ix were produced in
56% ee with ligand 23.
ꢀ
carboxylation, rather than the C O bond found in carbonates. The
exact nature of the rate-determining step of the reaction has not
yet been determined.
[74] Careful tuning of the phosphine
[58] For reviews, see: a) R. Noyori, M. Tokunaga, M. Kitamura, Bull.
Chem. Soc. Jpn. 1995, 68, 36–56; b) H. Stecher, K. Faber, Synthesis
1997, 1–16; c) F. F. Huerta, A. B. E. Minidis, J.-E. Bꢃckvall, Chem.
Soc. Rev. 2001, 30, 321–331; d) H. Pellissier, Tetrahedron 2003, 59,
8291–8327; e) for representative stereomutative examples, see: A.
Pfaltz, M. Lautens in Comprehensive Asymmetric Catalysis III,
Vol. 2 (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer,
New York, 1999, pp. 833–884; f) B. M. Trost, R. C. Bunt, R. C. Le-
moine, T. L. Calkins, J. Am. Chem. Soc. 2000, 122, 5968–5976.
[59] This hypothesis has been experimentally supported for non-enan-
tioselective systems, see: a) J. Tsuji, T. Yamada, I. Minami, M.
Yuhara, M. Nisar, I. Shimizu, J. Org. Chem. 1987, 52, 2988–2995;
electronics in the PHOX frame-
work could improve these re-
sults somewhat, see: N. T.
McDougal, S. C. Virgil, B. M.
Stoltz, Synlett 2010, 1712–1716.
[75] For a computational discussion of the mechanism of this reaction,
developed in collaboration with the group of W. A. Goddard at
Caltech, see: J. A. Keith, D. C. Behenna, J. T. Mohr, S. Ma, S. C.
Marinescu, J. Oxgaard, B. M. Stoltz, W. A. Goddard III, J. Am.
Chem. Soc. 2007, 129, 11876–11877.
[76] M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett. 1999, 1,
953–956.
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ꢀ
[89] Similar transition states have been proposed previously for C C
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ꢀ
[90] Similar transition states have been proposed previously for C O
bond formation, see: a) J.-E. Bꢃckvall, R. E. Nordberg, E. E.
Bjçrkman, C. Moberg, J. Chem. Soc. Chem. Commun. 1980, 943–
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[91] For representative examples, see Ref. [26].
[92] A representative experiment with a cyclic carbonate is shown
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5263–5275.
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[94] We believe that the slight curvature in the data plots shown in Fig-
ures 3 and 4 are the result of catalyst decomposition during the re-
action. Attempts to fit the data to higher-order polynomial expres-
sions were not productive.
[95] For these experiments, iPr-PHOX was used because of the availa-
bility of both enantiomers of valine at approximately the same
cost.
[96] Substrates that would lead to highly basic enolate intermediates,
such as lactone xi and lactam xii, have been problematic, presuma-
bly because decarboxylation is slow.
[84] Although such an outer-sphere mechanism intuitively seemed im-
probable to us, decarboxylative allylic alkylation experiments in-
volving stereochemically labeled allyl fragments and catalyzed by a
Pd–Trost ligand complex suggest that an outer-sphere mechanism
operates in that system, see: a) Refs. [42b] and [42l]; b) Ref. [86].
[85] For the related system by Trost and co-workers, a solvent-caged
ion pair was proposed based on a lack of crossover between eno-
late and alkyl fragments (Ref. [42b]). However, we observed very
different results from crossover experiments on our system
(Scheme 15), suggesting that the details of the mechanisms of these
two systems may be substantially different. In later studies
(Ref. [42l]), Trost and co-workers did observe crossover in a similar
experiment, although an explanation for the differing results in
Ref. [42b] was not provided.
[86] Unusual patterns in enantioselectivity in Trost ligand based asym-
metric allylation systems have led Trost and co-workers to consider
allylation mechanisms involving a metal-coordinated enolate as
well, see: a) Refs. [42b] and [42l]; b) B. M. Trost, Y. Zhang, J. Am.
Chem. Soc. 2006, 128, 4590–4591; c) recently, Lloyd-Jones, Norrby,
and co-workers have postulated a mechanism involving hydrogen
bonding of the enolate to the ligand, but not the coordination of
the enolate directly to palladium, see: C. P. Butts, E. Filali, G. C.
Lloyd-Jones, P.-O. Norrby, D. A. Sale, Y. Schramm, J. Am. Chem.
Soc. 2009, 131, 9945–9957.
[87] The crystals are composed of two diastereomeric carboxylate com-
plexes. For clarity, only one of these is shown in Scheme 13; see:
Ref. [27d].
[88] For representative examples of O- and C-bound Pd enolates, see:
a) E. R. Burkhardt, R. G. Bergman, C. H. Heathcock, Organome-
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[97] For example, replacement of the CH2 group of the malonate nu-
ACHUTNGRENcNUG leophile with CHHCATUNGTRENN(UGN NHAc) increased the required reaction time
from 1 h to 3–4 days; see Ref. [83].
[98] Also consistent with the presence of a Pd-bound enolate intermedi-
ate is the fact that stronger acids (e.g., formic acid) may be used to
achieve an enantioselective protonation reaction. In addition, acti-
vated Michael acceptors can be employed to achieve enantioselec-
tive conjugate addition/alkylation cascades. However, empirical ob-
ꢀ
ꢀ
servations indicate that the mechanism of C H and C C bond for-
mation with these alternative electrophiles differs significantly
ꢀ
from that of C C bond formation in the case of allyl electrophiles,
see: a) Ref. [71]; b) Ref. [27e].
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Chem. Eur. J. 2011, 17, 14199 – 14223

Enantioselective Decarboxylative Alkylation Reactions
FULL PAPER
[99] A separate reaction with dideuterio allyl enol carbonate 97 con-
firms that the allyl termini are scrambled during the course of the
reaction, see the Supporting Information for details.
proportions. The slight excess of the 155 m/z ion is likely due to
the natural abundance of 13C present in the dideuterio product.
[101] The pKa of related monomethyl carbonic acid has been estimated
at 2.92 (H2O solvent, 258C), see: J. P. Guthrie, Can. J. Chem. 1978,
56, 2342–2354.
[102] Saegusa and co-workers suggested similar crossover pathways in a
related, non-enantioselective system that uses a [Pd
lyst, see Ref. [21b].
ACHTUNGTRNEN(UNG PPh3)4] cata-
[103] If the reaction mixture is exposed to air, tBu-PHOX is cleanly con-
verted into the corresponding phosphine oxide. Pd catalyzes this
conversion. See the Supporting Information for details.
[100] Although the total ion counts are not rigorously quantitative, they
are consistent with the presence of all four masses in nearly equal
Received: November 24, 2010
Revised: July 29, 2011
Published online: November 14, 2011
Chem. Eur. J. 2011, 17, 14199 – 14223
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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