A palladium-catalysed enolate alkylation cascade for the formation of adjacent quaternary and tertiary stereocentres

Article abstract of DOI:10.1038/nchem.518

The catalytic enantioselective synthesis of densely functionalized organic molecules that contain all-carbon quaternary stereocentres is a challenge to modern chemical methodology. The catalytically controlled, asymmetric α-alkylation of ketones represents another difficult task and is of major interest to our and other research groups. We report here a palladium-catalysed enantioselective process that addresses both problems simultaneously and allows the installation of vicinal all-carbon quaternary and tertiary stereocentres at the α-carbon of a ketone in a single step. This multiple bond-forming process is carried out on readily available β-ketoester starting materials and proceeds by conjugate addition of a palladium enolate, generated in situ, to activated Michael acceptors. As a result, the CO₂ moiety of the substrate is displaced by a Cg-C fragment in an asymmetric cut-and-paste reaction with high yield, diastereomeric ratio and enantiomeric excess.

Full text of DOI:10.1038/nchem.518

ARTICLES
PUBLISHED ONLINE: 31 JANUARY 2010 | DOI: 10.1038/NCHEM.518
A palladium-catalysed enolate alkylation cascade
for the formation of adjacent quaternary and
tertiary stereocentres
Jan Streuff1, David E. White1, Scott C. Virgil2 and Brian M. Stoltz1
*
The catalytic enantioselective synthesis of densely functionalized organic molecules that contain all-carbon quaternary
stereocentres is a challenge to modern chemical methodology. The catalytically controlled, asymmetric a-alkylation of ketones
represents another difficult task and is of major interest to our and other research groups. We report here a palladium-
catalysed enantioselective process that addresses both problems simultaneously and allows the installation of vicinal all-
carbon quaternary and tertiary stereocentres at the a-carbon of a ketone in a single step. This multiple bond-forming process
is carried out on readily available b-ketoester starting materials and proceeds by conjugate addition of a palladium enolate,
generated in situ, to activated Michael acceptors. As a result, the CO2 moiety of the substrate is displaced by a C–C fragment
in an asymmetric cut-and-paste reaction with high yield, diastereomeric ratio and enantiomeric excess.
he enantioselective generation of carbon stereocentres with was reported by Jacobsen and co-workers who used chromium–salen
four other carbon substituents (also called quaternary or all- complexes as catalyststo yield quaternarystereocentres19,20. The require-
T
carbon quaternary stereocentres) is a task synthetic chemists ment for tin enolates, which have to be synthesized in advance and are
are confronted with regularly1. Several methods have been devel- presumably toxic, as starting materials is a strong limitation in this case.
oped to address this problem, but catalytic approaches remain chal- Over the past few years, our group has been interested in novel
lenging2,3. Furthermore, when additional carbon stereocentres methodologies for the generation of all-carbon quaternary stereo-
adjacent to the quaternary carbon are required, the available choices centres, which led to the development of an enantioselective, palla-
to install both in one reaction are extremely limited. Although the dium-catalysed allylic a-alkylation of ketones. This process allows
combination of quaternary and secondary stereocentres can be the construction of such stereocentres from silyl enol ethers, enol
introduced by aldol, cycloaddition, Michael or even cross-coupling carbonates21 or readily available racemic b-ketoesters 1 (path I,
reactions, only a few catalytic methods exist that forge adjacent qua- Fig. 1)22. We also demonstrated that the intermediate of this reac-
ternary and tertiary carbon stereocentres. This motif was introduced tion, presumably a palladium enolate (A)23, can be intercepted by
successfully into organic molecules by a-functionalization of carbo- a strong electrophile-like Hþ to generate enantioenriched a-proto-
nyl groups, as demonstrated in recent reports4–9. However, these nated products (path II, Fig. 1)24,25
approaches mostly rely on organic catalysts based on quinine or
.
*
proline4–7 and only two enantioselective transition-metal catalysed
O
R
O
N
P
[Pd2(dba)3]
O
O
examples have been published so far8,9. Interestingly, in both cases
strongly coordinating substrates, such as 1,3-diketones, b-ketoesters
or a-cyanoesters, were required to achieve good selectivity. Other
examples, for instance the elegant work of Overman and co-workes,
demonstrated the feasibility of palladium catalysis to construct
adjacent quaternary, tertiary or even vicinal quaternary stereocen-
tres in a single double-Heck reaction10,11. These diastereoselective
reactions employ an achiral catalyst and rely on substrate-directed
stereocontrol. Palladium-catalysed tandem reactions of this type
have applications in intramolecular, diastereoselective coupling
No additive
R
Pd
L1 or L2
O
Path I
O
R
– CO2
H+
R
R
1
H
E
R'
P
Path II
A
O
N
O
R'
E+
Path III
Ligand:
L1, R' = H
L2, R' = CF3
R'
reactions12. Intermolecular examples, especially those that involve Figure 1 | Concept for the enantioselective functionalization of palladium
p-allyl palladium species, are less common, but some examples with enolates. Three pathways for the palladium-catalysed generation of
high diastereoselectivities have been reported recently13–15
.
a-functionalized ketones are shown. A palladium catalyst generated from
[Pd2(dba)3] and ligand L undergoes oxidative addition to b-ketoester 1 with
the loss of CO2 to form an enolate intermediate A. This palladium enolate
can either react to yield enantioenriched a-alkylated products (path I) or, in
Therefore, an approach to the formation of vicinal quaternary and
tertiary stereocentres that proceeds via a palladium-catalysed
multiple bond-forming process is appealing.
The enantioselective a-functionalization of ketones has been the presence of a proton source, to give a-protonated products (path II).
achieved by means of palladium catalysis, and over the past decade sig- The envisioned path III would form miscellaneous enantioenriched,
nificant progress has been made in a-allylation16, vinylation17 and ary-
a-substituted ketones depending on other electrophilic additives (Eþ)
lation18 reactions. A transition-metal catalysed a-alkylation of ketones that intercept enolate A.
1The Arnold and Mabel Beckman Laboratories of Chemical Synthesis, Division of Chemistry and Chemical Engineering, California Institute of Technology,
1200 E. California Blvd, Pasadena, California 91125, USA, 2Caltech Center for Catalysis and Chemical Synthesis, California Institute of Technology, 1200
E. California Blvd, Pasadena, California 91125, USA. e-mail: stoltz@caltech.edu
*
192
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.518
ARTICLES
Table 1 | Enantioselective decarboxylative enolate alkylation cascade.
[Pd (dba) ] (5 mol%)
Ph
Ph
O
O
O
X
2
3
R
R
R
CN
CN
(S)-L2 (12.5 mol%)
X = –CH –, –N(Bn)–
CO allyl
2
2
+
+
Ph
1,4-dioxane (0.1 M)
40 °C
NC CN
3a–h
NC CN
4a–h
X
X
(1.0 equiv.)
1a–h
2a
Entry
Substrate
Product
Time (hours)
Yield (%)*
d.r. 3:4†
e.e. 3 (%)
e.e. 4 (%)
O
O
O
O
O
O
O
Ph
O
O
O
NC CN
3a, 4a
1
24
99
1:6.1
77
87
1a
O
Ph
Et
Et
2
48
72
40
65
91
1:3.5
1:3.4
1:1.9
1:1.9
95
88
85
93
99
97
88
94
NC CN
3b, 4b
3‡
4
88
49
65
1b
O
Ph
Bn
Bn
NC CN
3c, 4c
5§
1c
CO Et
2
O
CO Et
2
O
O
O
O
O
NC CN
6
24
56
1:3.3
82
89
O
Ph
1d
3d, 4d
O
O
O
OTBS
O
OTBS
NC CN
7k
24
72
56
57
1:1.3
69
75
70
81
O
Ph
1e
3e, 4e
O
Ph
O
8}
1:2.4
NC CN
3f, 4f
1f
O
Ph
O
NC CN
3g, 4g
9
20
48
97
99
1: .20
1: .20
–
89
97
N
N
Bn
Bn
1g
O
O
O
Ph
Et
Et
O
NC CN
3h, 4h
10
71
N
Bn
N
Bn
1h
General reaction conditions: 1 (0.3 2 0.5 mmol), 2 (1.0 equiv.), [Pd2(dba)3] (5 mol%), L2 (12.5 mol%), 1,4-dioxane (0.1 M), 40 8C. *Combined isolated yield. †Determined by 1H NMR spectroscopy. ‡Reaction
carried out on a 1 mmol scale with 2.5 mol% [Pd2(dba)3] and 6.25 mol% L2. §Reaction carried out at 23 8C. kPd(pmdba)2 (10 mol%) was used as a precatalyst (pmdba ¼ bis(4-methoxybenzylidene)acetone).
}Reaction carried out at 60 8C.
To expand this enolate-trapping approach towards the broader
In our first experiments carbon electrophiles, such as acyclic or
goal of establishing vicinal stereocentres and to provide a general cyclic enones, were probed for their capability to intercept the inter-
approach for the a-functionalization of ketones, we examined the mediate enolate, but in these cases only the regular allylic alkylation
use of other prochiral electrophiles (path III, Fig. 1). An electrophilic product was observed. As a consequence, we were drawn to earlier
additive had to be identified that met the following crucial reports by Yamamoto and co-workers of intercepted enolate alkyl-
requirements:
ation by highly electrophilic conjugate acceptors, such as benzylide-
nemalononitrile 2a (Table 1)26,27
Herein, we describe the
† There should be no interference with the oxidative addition of development of an enantioselective, palladium-catalysed decarbox-
the palladium(0) catalyst into the allyl ester functionality.
ylative alkylation of ketones that forges all-carbon quaternary
.
† The reaction of the palladium enolate with the electrophilic addi- stereocentres with an adjacent tertiary stereocentre in good yield
tive must be preferred to intramolecular allylic a-allylation.
† A scavenger for the allyl fragment must be provided.
and stereoselectivity. This reaction represents a rare example of an
asymmetric palladium-catalysed tandem process.
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.518
ARTICLES
Table 2 | Asymmetric enolate alkylation of substrates 1a or 1b with different electrophiles.
Entry
Electrophile
Product
Time (hours)
Yield (%)*
d.r. 3:4†
e.e. 3 (%)
e.e. 4 (%)
OMe
CN
OMe
O
1
68
78
1:8.2
71
86
CN
2b
2c
NC CN
3i, 4i
OMe
MeO
CN
CN
O
2
3
36
87
76
1:7.8
1:6.2
73
75
88
87
NC CN
3j, 4j
CN
CN
O
2d
16
NC CN
3k, 4k
Me N
2
NMe
2
CN
CN
4
18
18
22
54
1:8.9
78
99
99
O
2e
5‡
1: .20
n.d.
NC CN
3l, 4l
CN
CN
O
O
O
6
7
36
36
87
92
1:3.5
1:2.3
65
89
81
2f
2f
NC CN
3m, 4m
CN
CN
O
O
O
Et
96
NC CN
3n, 4n
O
O
O
O
O
CN
CN
8
24
24
99
83
1:14.0
58
64
95
82
2g
2h
NC CN
3o, 4o
CN
CN
9§
1:9.4
O
NC CN
3p, 4p
For general reaction conditions, see Table 1. *Combined isolated yield. †Determined by 1H NMR spectroscopy. ‡Pd(dmdba)2 (10 mol%) was used as a catalyst precursor and the reaction carried out on 0.1 mmol
scale (n.d. ¼ not determined). §Only the 1,4-addition product was observed as determined by gradient heteronuclear multiple-bond correlation NMR spectroscopy.
Results
the combination of an electronically modified phosphinooxazoline
In our initial experiments, we found that the exposure of the ligand (L2, 12.5 mol%)30 and [Pd2(dba)3] (5 mol%) in 1,4-dioxane
b-ketoester (+)-1a (Table 1)28 to catalytic amounts of tris(dibenzyli- at 40 8C produced diastereomers in high enantioselectivity. With
deneacetone)dipalladium [Pd2(dba)3] and (S)-t-butylphosphinooxa- only one equivalent of electrophile 2a, the diastereomeric products
zoline (L1)29 in the presence of electrophile 2a followed the desired 3a and 4a were isolated in 99% yield, 1:6.1 d.r., and 77% e.e. and
reaction pathway, and efficiently produced diastereomers 3a and 4a 87% e.e., respectively (Table 1, entry 1).
(82% conversion), albeit with moderate diastereomeric ratio (d.r.)
We then applied these conditions to a series of substrates with
and enantiomeric excess (e.e.) (1:3.1 d.r., 42% and 63% e.e.; see different substitutions at the a-carbon, the allyl functionality or
Supplementary Information for details). After careful optimization, the backbone of the cyclic ketone. The enantiomeric excess
194
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.518
ARTICLES
a Absolute configuration of products
O
O
O
Ph
O
Ph
Et
Et
Et
Et
H
R
S
R
R
S
R
NC CN
NC CN
3b (X-ray)
4b (X-ray)
5
6
d Proposed catalytic cycle
O
O
O
R'
b Michael-acceptors other than malononitriles
R
R
O
O
Ph
*
[Pd2(dba)3] (5 mol%)
O
CN
N
L
P
L
NC CN
(S)-L2 (12.5 mol%)
Ph
4.1:1:0:0 d.r.
64% e.e. (major)
1a
+
+
Pd
CO2Me
(
)-1
3,4
NC CO2Me
1,4-dioxane (0.1 M)
40 °C, 36 h
Reductive
alkylation
2i
Oxidative addition
decarboxylation
3q, 4q (15%)
C
Ph
O
O
Ph
*
[Pd2(dba)3] (5 mol%)
O
*
O
R'
O
O
O
N
P
(S)-L2 (12.5 mol%)
R
1:1.2 d.r.
43% e.e. (major)
N
P
Pd
CN
1a
CO2
Pd
O
O
1,4-dioxane (0.1 M)
40 °C
O
CN
B
R
2j
3r, 4r (66%)
A
c Michael-acceptors with alkylidene groups
Conjugate
addition
CN
2
[Pd2(dba)3] (5 mol%)
R'
dppe (12.5 mol%)
NC
CN
NC CN
1a
+
1,4-dioxane (0.1 M)
60 °C
CN
2k
7 (76%)
Figure 2 | Absolute stereochemistry and limitations of the palladium-catalysed enolate alkylation. a, The absolute configuration at the a-carbon of the
major diastereomer 4b matched the product from the previously reported palladium-catalysed decarboxylative protonation (6) and is opposite to the
configuration of the regular decarboxylative allylic alkylation (5). b, For Michael acceptors (other than malononitriles), electrophiles 2i and 2j also led to the
required products, but with diminished yields and stereoselectivities. Products 3q and 4q, however, have three continuous quaternary and tertiary
stereocentres. c, An alkyl-substituted electrophile (alkylidene Michael acceptor) did not yield any desired product. Instead, olefin isomerization and allylic
alkylation of 2k were observed. d, A catalytic cycle is proposed, which starts with an oxidative addition to the substrate that involves decarboxylation to give
intermediate A, followed by conjugate addition (intermediate B) and reductive alkylation to give intermediate C.
improved significantly when the a-substituent was changed to an configuration at the a-quaternary centre is inverted compared
ethyl group, and the desired product was isolated with 99% e.e. with the products from our standard, asymmetric allylic alkylation
(Table 1, entry 2). Other a-substituents, such as benzyl groups, (compare 3b and 4b with 5), but matches the cyclohexanone
esters or protected alcohols, were also tolerated (Table 1, entries products obtained from our protonation procedure (for example,
4–7), but in some cases allylic alkylation of the enolate was 6) (Fig. 2).
observed as a side reaction, which led to decreased yields
Strong electron-withdrawing groups on the Michael acceptor are
(Table 1, entries 4, 6 and 7). This side reaction was suppressed necessary to achieve the desired conjugate addition. It was possible
by lowering the reaction temperature to 23 8C (Table 1, entry 5). to use reagents other than malononitriles, such as a-cyanoacetate
Moreover, the reaction also tolerated substitution on the allyl frag- and Meldrum’s acid derivatives, but the yields and stereoselectivities
ment (Table 1, entry 8). In addition to cyclohexanones, 1,4-piper- were reduced significantly (Fig. 2b). Although products 3q and 4q
idinone-derived substrates furnished the corresponding products were isolated in only 15% yield, in this case a series of two quatern-
in high yield and good enantioselectivity, with remarkably high ary and one tertiary neighbouring stereocentres was formed by a
diastereomeric ratio (Table 1, entries 9 and 10).
single palladium-catalysed transformation, albeit with 64% e.e.
Next, the scope of the electrophile was explored. The reaction Notably, the conversion increased significantly with the achiral,
performed well with arylidenemalononitriles derived from but more electron-rich, bis(diphenylphosphino)ethane (dppe)
m- and p-anisaldehyde, which allowed the introduction of substi- ligand (96%) and the same two predominant diastereomers were
tuted aryl groups at the stereocentre b to the ketone (Table 2, observed as with ligand L2. However, initial attempts to use alkyl-
entries 1 and 2). Methyl or dimethylamino substituents were also substituted acceptors were not successful and, instead, transfer of
introduced at the 4-position (Table 2, entries 3 and 4). the allyl group to the alkylidenemalononitrile proceeded to yield
Although the diastereo- and enantioselectivity were impressive in adduct 7 (Fig. 2c).
the latter case, the yield was again low because of significant
allylic enolate alkylation. Here, a change of the palladium Discussion
precursor to Pd(dmdba)2 (dmdba ¼ bis(3,5-dimethoxybenzyli- In general, the diastereoselectivity is good for most products and
dene)acetone) slightly increased the reaction outcome towards some examples show remarkable results with only trace amounts
the conjugate addition product (Table 2, entry 5). Importantly, the of a second diastereomer formed. The amount of direct allylic alkyl-
versatile 2-furanyl substituent was installed with both high yield ation, as observed in some cases, was lowered either by a tempera-
and high enantioselectivity (Table 2, entries 6 and 7). Finally, a ben- ture change or by using a different palladium precursor, which
zodioxole and a styrene group were introduced successfully at the suggests a possible dependence on the coordination behaviour of
tertiary centre in good yield and selectivity (Table 2, entries 8 and the acceptor and the catalyst. Indeed, preliminary experimental
9), with exclusive regioselectivity in the latter case.
results suggest a resting state different to that of the h1-allylpalla-
As an initial probe to study the mechanism, the absolute stereo- dium carboxylate observed for the enantioselective allylic alkylation
chemistry of diastereomeric products 3b and 4b was determined as of ketones and may involve coordination of the electrophile31.
(R,R) and (R,S) by single-crystal X-ray analysis (Fig. 2a, see Further studies are currently underway and any comment on the
Supplementary Information for details). Interestingly, the absolute specific details of the process is speculative at this stage. Although
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.518
ARTICLES
12. Poli, G., Giambastiani, G. & Heumann, A. Palladium in organic synthesis:
fundamental transformations and domino processes. Tetrahedron 56,
5959–5989 (2000).
13. Balme, G., Bossharth, E. & Monteiro, N. Pd-assisted multicomponent synthesis
of heterocycles. Eur. J. Org. Chem. 4101–4111 (2003).
14. Shu, W., Jia, G. & Ma S. Palladium-catalyzed three-component cascade
cyclization reaction of bisallenes with propargylic carbonates and organoboronic
acids: efficient construction of cis-fused bicyclo[4.3.0]nonenes. Angew. Chem.
Int. Ed. 48, 2788–2791 (2009).
15. Patil, N. T., Huo, Z. & Yamamoto, Y. Palladium-catalyzed decarboxylative
aza-Michael addition–allylation reactions between allyl carbamates and
activated olefins. Generation of quaternary carbon adjacent to secondary amine
carbon center. J. Org. Chem. 71, 6991–6995 (2006).
it is not possible to provide a detailed picture at this time, a plausible
simplified catalytic cycle is outlined in Fig. 2d. First, palladium(0)
catalyst C reacts with substrate 1, with the loss of CO2, to form
the h1-allylpalladium enolate A. Next, conjugate addition to 2
occurs and results in stabilized intermediate B, which consists of a
p-allyl palladium cation and a deprotonated malononitrile.
Reductive alkylation then yields the diastereomeric products 3 and
4 and regenerates catalyst C.
In conclusion, a highly enantio- and diastereoselective, palla-
dium-catalysed a-alkylation process has been developed that pro-
ceeds via the trapping of an intermediary palladium-enolate
species by conjugate addition to a prochiral activated Michael accep-
tor. From simple racemic b-ketoester starting materials, the reaction
allows the asymmetric construction of densely functionalized mol-
ecules that possess an all-carbon quaternary centre next to a tertiary
centre. Currently, expansion of this methodology to include other
substrates and applications in multistep synthesis is in progress.
Finally, mechanistic studies are also underway and will be reported
in due course.
16. Mohr, J. T. & Stoltz, B. M. Enantioselective Tsuji allylations. Chem. Asian J. 2,
1476–1491 (2007).
17. Chieffi, A., Kamikawa, K., Åhman, J., Fox, J. M. & Buchwald, S. L. Catalytic
asymmetric vinylation of ketone enolates. Org. Lett. 3, 1897–1900 (2001).
18. Liao, X., Weng, Z. & Hartwig, J. F. Enantioselective a-arylation of ketones with
aryl triflates catalyzed by difluorphos complexes of palladium and nickel. J. Am.
Chem. Soc. 130, 195–200 (2008).
19. Doyle, A. G. & Jacobsen, E. N. Enantioselective alkylation of acyclic a,a-
disubstituted tributyltin enolates catalyzed by a fCr(salen)g complex. Angew.
Chem. Int. Ed. 46, 3701–3705 (2007).
20. Doyle, A. G. & Jacobsen, E. N. Enantioselective alkylations of tributyltin enolates
catalyzed by Cr(salen)Cl: access to enantiomerically enriched all-carbon
quaternary centers. J. Am. Chem. Soc. 127, 62–63 (2005).
21. Behenna, D. C. & Stoltz, B. M. The enantioselective Tsuji allylation. J. Am. Chem.
Soc. 126, 15044–15045 (2004).
22. Mohr, J. T., Behenna, D. C., Harned, A. M. & Stoltz, B. M. Deracemization of
quaternary stereocenters by Pd-catalyzed enantioconvergent decarboxylative
allylation of racemic b-ketoesters. Angew. Chem. Int. Ed. 44, 6924–6927 (2005).
23. Keith, J. A. et al. The inner-sphere process in the enantioselective Tsuji allylation
reaction with (S)-t-Bu-phosphinooxazoline ligands. J. Am. Chem. Soc. 129,
11876–11877 (2007).
24. Marinescu, S. C., Nishimata, T., Mohr, J. T. & Stoltz, B. M. Homogeneous
Pd-catalyzed enantioselective decarboxylative protonation. Org. Lett. 10,
1039–1042 (2008).
25. Mohr, J. T., Nishimata, T., Behenna, D. C. & Stoltz, B. M. Catalytic enantioselective
decarboxylative protonation. J. Am. Chem. Soc. 128, 11348–11349 (2006).
26. Patil, N. T. & Yamamoto, Y. Palladium-catalyzed cascade reactions of highly
activated olefins. Synlett 1994–2005 (2007).
27. Shim, J.-G., Nakamura, H. & Yamamoto, Y. Palladium catalyzed regioselective
b-acetonation-a-allylation of activated olefins in one shot. J. Org. Chem. 63,
8470–8474 (1998).
Methods
A flame-dried 50 ml Schlenk tube was charged with [Pd2(dba)3] (13.7 mg,
0.015 mmol, 5 mol%) and L2 (22.2 mg, 0.0375 mmol, 12.5 mol%) under argon, and
3 ml of freshly distilled 1,4-dioxane added. After stirring for 30 minutes at 23 8C, 1
(0.3 mmol, 1.0 equiv.) and 2 (0.3 mmol, 1.0 equiv.) were added simultaneously. The
resulting yellow–green solution was stirred at the reported temperature for the
reported amount of time (see Tables 1 and 2). The consumption of starting material
was monitored by thin layer chromatography (KMnO4 stain) or by NMR analysis of
a small sample. The solvent was removed under reduced pressure and the
diastereomeric ratio determined by crude 1H NMR spectroscopy. Isolation and
separation of products 3 and 4 were achieved by flash chromatography in hexane–
ethyl acetate mixtures in the given combined yields (Tables 1 and 2). The
enantiomeric excess was determined by either high-performance liquid
chromatography or supercritical fluid chromatography of the purified product
(see Supplementary Information).
Received 7 September 2009; accepted 4 December 2009;
published online 31 January 2010
28. Mohr, J. T., Krout, M. R. & Stoltz, B. M. Preparation of (S)-2-allyl-2-
methylcyclohexanone. Org. Synth. 86, 194–211 (2009).
29. Helmchen, G. & Pfaltz, A. Phosphinooxazolines – a new class of versatile,
modular P,N-ligands for asymmetric catalysis. Acc. Chem. Res. 33,
336–345 (2000).
30. White, D. E., Stewart, I. C., Grubbs, R. H. & Stoltz, B. M. The catalytic
asymmetric total synthesis of elatol. J. Am. Chem. Soc. 130, 810–811 (2008).
31. Sherden, N. H., Behenna, D. C., Virgil, S. C. & Stoltz, B. M. Unusual
allylpalladium carboxylate complexes: identification of the resting state of
catalytic enantioselective decarboxylative allylic alkylation reactions of ketones.
Angew. Chem. Int. Ed. 48, 6840–6843 (2009).
References
1. Das, J. P., Chechik, H. & Marek, I. A unique approach to aldol products for the
creation of all-carbon quaternary stereocenters. Nature Chem. 1,
128–132 (2009).
2. Christoffers, J. & Baro, A. Quaternary Stereocenters, Challenges and Solutions in
Organic Synthesis (Wiley-VCH, 2005).
3. Trost, B. M. & Jiang, C. Catalytic enantioselective construction of all-carbon
quaternary stereocenters. Synthesis 369–396 (2006).
4. Bencivenni, G. et al. Targeting structural and stereochemical complexity by
organocascade catalysis: construction of spirocyclic oxindoles having multiple
stereocenters. Angew. Chem. Int. Ed. 48, 7200–7203 (2009).
5. Wu, F., Li, H., Hong, R. & Deng, L. Construction of quaternary stereocenters by
efficient and practical conjugate additions to a,b-unsaturated ketones with a
chiral organic catalyst. Angew. Chem. Int. Ed. 45, 947–950 (2006).
6. Li, H. et al. Stereocontrolled creation of adjacent quaternary and tertiary
stereocenters by a catalytic conjugate addition. Angew. Chem. Int. Ed. 44,
105–108 (2005).
7. Mase, N., Thayumanavan, R., Tanaka, F. & Barbas, C. F. III Direct asymmetric
organocatalytic Michael reactions of a,a-disubstituted aldehydes with
b-nitrostyrenes for the synthesis of quaternary carbon-containing products.
Org. Lett. 6, 2527–2530 (2004).
8. Hamashima, Y., Hotta, D. & Sodeoka, M. Direct generation of nucleophilic
chiral palladium enolate from 1,3-dicarbonyl compounds: catalytic
enantioselective Michael reaction with enones. J. Am. Chem. Soc. 124,
11240–11241 (2002).
9. Taylor, M. S. & Jacobsen, E. N. Enantioselective Michael additions to
a,b-unsaturated imides catalyzed by a salen-Al complex. J. Am. Chem. Soc. 125,
11204–11205 (2003).
Acknowledgements
The authors thank the National Institute of Health’s National Institute of General Medical
Sciences (R01 GM 080269-01 and a postdoctoral fellowship to D.E.W.), the German
Academic Exchange Service (DAAD, postdoctoral fellowship to J.S.), Abbott Laboratories,
Amgen, Merck, Bristol-Myers Squibb, Boehringer Ingelheim, the Gordon and Betty Moore
Foundation and Caltech for financial support. We thank S. Reisman for discussions.
L. Henling and M. Day carried out the X-ray crystallographic analysis. The Bruker KAPPA
APEXII X-ray diffractometer was purchased with a National Science Foundation
Chemistry Research Instrumentation and Facilities: Departmental Multi-User
Instrumentation award to the California Institute of Technology (CHE-0639094).
Author contributions
J.S. planned and carried out the experimental work and wrote the manuscript. D.E.W. and
S.C.V. took part in the initial reaction development and screening experiments. B.M.S.
initiated and directed the project. All authors commented on the manuscript.
10. Abelman, M. M. & Overman, L. E. Palladium-catalyzed polyene cyclizations of Additional information
dienyl aryl iodides. J. Am. Chem. Soc. 110, 2328–2329 (1988).
11. Overman, L. E., Paone, D. V. & Stearns, B. A. Direct stereo- and
enantiocontrolled synthesis of vicinal stereogenic quaternary carbon centers.
Total syntheses of meso- and (2)-chimonanthine and (þ)-calycanthine. J. Am.
Chem. Soc. 121, 7702–7703 (1999).
The authors declare no competing financial interests. Supplementary information and
chemical compound information accompany this paper at www.nature.com/
naturechemistry. Reprints and permission information is available online at http://npg.nature.
com/reprintsandpermissions/. Correspondence and requests for materials should be
addressed to B.M.S.
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