A palladium/chiral amine co-catalyzed enantioselective dynamic cascade reaction: Synthesis of polysubstituted carbocycles with a quaternary carbon stereocenter

Article abstract of DOI:10.1002/anie.201300559

Polysubstituted 5- and 6-membered carbocycles were synthesized by the title reaction. The one-pot dynamic relay process generates four new stereocenters, including a quaternary carbon center, in a highly enantioselective fashion (99.5:0.5→99:0.5 e.r.) by using a simple combination of palladium and chiral amine co-catalysts. Copyright

Full text of DOI:10.1002/anie.201300559

Angewandte
Chemie
DOI: 10.1002/anie.201300559
Asymmetric Catalysis
A Palladium/Chiral Amine Co-catalyzed Enantioselective Dynamic
Cascade Reaction: Synthesis of Polysubstituted Carbocycles with
a Quaternary Carbon Stereocenter
Guangning Ma, Samson Afewerki, Luca Deiana, Carlos Palo-Nieto, Leifeng Liu, Junliang Sun,
Ismail Ibrahem,* and Armando Cꢀrdova*
Domino and cascade reactions that give access to multiple Cꢀ ter, are desirable but difficult to achieve. Based on our
[
6]
C bonds and multiple contiguous stereocenters with high
chemo- and stereoselectivity are important for chemical
synthesis and are performed in nature by multi-enzymatic
previous research on organo/metal cooperative catalysis, we
envisioned a novel dynamic catalytic asymmetric Michael/a-
allylic alkylation cascade reaction between compounds 1 and
enals 2 mediated by a combination of Pd and chiral amine 5
catalysts (Scheme 1). Thus, initial reversible conjugate addi-
tion via an iminium intermediate I would give the corre-
sponding enamine intermediate II, which upon hydrolysis
would provide Michael adduct 3. This process is reversible,
however, oxidative addition of the Pd catalyst to intermediate
II would generate p-allyl intermediate III, ready for intra-
molecular nucleophilic stereoselective attack by its enamine
moiety. Subsequent CꢀC bond formation, hydrolysis, and
[
1]
pathways. Cascade reactions enable the synthesis of com-
plex molecules in a minimal number of synthetic steps and
[2]
with lower amounts of waste and solvents (green chemistry).
Catalytic asymmetric cascade transformations are most
[3]
commonly catalyzed by single metal complexes. However,
recently the use of organic catalysts has resulted in important
[
4]
advances in this research field.
The concept of using a transition metal catalyst together
with a metal-free catalyst in one flask (“organo/metal
[
5–9]
cooperative catalysis”) is gaining increasing interest.
The
protonation would deliver polysubstituted carbocycles 4 as
well as regenerate the amine and Pd catalysts. However, there
are a few main challenges to address. For example, chemo-
selectivity issues, as substrates 1 could undergo a Pd-catalyzed
intermolecular Tsuji–Trost reaction, polymerization, or N-
reactivity and advantages of both metal and organic catalyst
systems are combined and thereby can result in unique
reactivity. However, this research field is still in its infancy
with challenges such as incompatibility between the transition
metal and organocatalyst (e.g. catalyst inhibition and differ-
ent optimal reaction conditions). In 2006, we disclosed the
merging of transition metal and aminocatalysis for the a-
[
11]
alkylation with amine 5 instead of the desired pathway. We
also know from our previous research that the Pd/amine co-
catalyzed conjugate additions can deliver racemic Michael
[6a]
[6g–i]
allylic alkylation of aldehydes.
Since disclosure of this
products.
Thus, the reaction via enamine intermediate II
synergistic catalysis strategy there has been increasing
number of reports on the development of the concept of
organo/metal cooperative catalysis.
has to occur at a higher rate compared to the that via IIa.
Moreover, the equilibration between ent-3 and 3 (racemiza-
tion) must be faster than the carbocyclization for this reaction
to become a dynamic kinetic transformation (DYKAT). If
no racemization occurred, the overall process would have
[5–8]
[
12]
The construction of quaternary carbon stereocenters with
high enantioselectivity is important and challenging goal in
[
10]
organic synthesis.
In this context, new methods for the
a maximum theoretical yield of 50% (kinetic resolution).
1
catalytic construction of polysubstituted carbocycles with
contiguous stereocenters, including an all-carbon stereocen-
With respect to the construction of carbocycles 4 (E ¼
6
E ), the
cascade transformation is also complex and difficult to control
as Michael adducts (3 having 2 stereocenters) are formed as
four stereoisomers. Herein, we disclose a novel highly
enantioselective dynamic Michael/a-allylic alkylation cascade
transformation that gives polysubstituted cyclopentanes and
cyclohexanes, which have a quaternary carbon stereocenter,
in high yields with excellent enantiomeric ratios (99.5:0.5!
[
*] Dr. G. Ma, S. Afewerki, Prof. Dr. I. Ibrahem, Prof. Dr. A. Cꢀrdova
Department of Natural Sciences, Engineering and Mathematics
Mid Sweden University
85170 Sundsvall (Sweden)
E-mail: ismail.ibrahem@miun.se
armando.cordova@miun.se
acordova@organ.su.se
9
9:0.5 e.r.).
Initially we investigated the dynamic cascade transforma-
L. Deiana, C. Palo-Nieto, Prof. Dr. A. Cꢀrdova
Department of Organic Chemistry, The Arrhenius Laboratory
Stockholm University (Sweden)
tion between (Z)-1a and cinnamic aldehyde 2a under differ-
ent reaction conditions in the presence of chiral amines 5 and
different Pd co-catalysts. Representative results are shown in
Table 1. To our delight, the corresponding cyclopentane 4a
was formed in good conversion with high d.r. (91:9) and e.r.
L. Deiana, C. Palo-Nieto, L. Liu, J. Sun, Prof. Dr. A. Cꢀrdova
The Berzelii Center EXSELENT, Stockholm University (Sweden)
L. Liu, J. Sun
[
13]
(
up to 98:2) when chiral amine 5a (20 mol%) was used in
Department of Materials and Environmental Chemistry, Stockholm
University (Sweden)
combination with [Pd(PPh ) ] (5 mol%) in toluene and
3
4
acetonitrile (entries 3 and 4). The Michael intermediate 3a
was formed as a racemate (3a/ent-3a 50:50 e.r.). Thus, the
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300559.
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Communications
Scheme 1. Pd/chiral amine co-catalytic dynamic cascade reaction between 1 and 2. Only two of the possible four stereoisomers of 3 are shown.
LG=Leaving group.
[
a]
Table 1: Key results from the reaction development.
[
b]
[c]
[b]
[c]
Entry
5
Pd cat.
–
Solv.
4
T
Conv. d.r.
e.r.
Entry
5
Pd cat.
Solv.
4
T
Conv. d.r.
e.r.
[
b]
[b]
[h] [%]
[h] [%]
[
d]
[e]
1
2
3
4
5
6
7
8
9
1
5a
–
CH
3
CN 4a 48 57
n.d. n.d.
11
12
5e [Pd
5 f [Pd (dba) ] CH CN 4a
5a [Pd (dba) ] CH CN 4a
5a [Pd (dba) ] CH CN 4b
2 3 3
5a [Pd(PPh ) ] CH CN 4c
5a [Pd (dba) ] CH CN 4c
5b [Pd (dba) ] CH CN 4c
5a [Pd (dba) ] CH CN 4c
2
(dba)
3
]
CH
3
CN 4a
5
5
5
5
93
22
70
70
96:4 25:75
n.d. n.d.
96:4 >99.5:0.5
85:15 >99.5:0.5
84:16 98.5:2.5
91:9
90:10 99.5:0.5
93:7 >99.5:0.5
92:8 >99.5:0.5
95:5 >99.5:0.5
[
e]
[Pd (dba) ] CH CN 4a 48
0
–
–
2
3
3
2
3
3
[
[
d]
d]
[f]
[g]
[g]
5a [Pd(PPh ) ] toluene 4a 17 55
5a [Pd(PPh ) ] CH CN 4a
5a [Pd(OAc)2] toluene 4a 22 72
5a [Pd (dba) ] toluene 4a
5a [Pd (dba) ] CH CN 4a
5b [Pd (dba) ] CH CN 4a
5c [Pd (dba) ] CH CN 4a
5d [Pd (dba) ] CH CN 4a
91:9 98:2
91:9 97:3
n.d. n.d.
91:9 >99.5:0.5
96:4 >99.5:0.5
97:3 99:1
91:9 98:2
91:9 92:8
13
3
4
2
3
3
[f]
[g]
8
62
14
3
4
3
[
e]
[d,i]
15
16
17
24 95
19 85
24 69
19 95
24 58
24 91
3
4
3
[
[
[
i]
8
5
5
5
5
95
90
50
27
14
>99.5:0.5
2
3
2
3
3
i]
2
3
3
2
3
3
j]
18
2
3
3
2
3
3
[
j,k]
19
5b [Pd (dba) ] CH CN 4c
2 3 3
5a [Pd (dba) ] CH CN 4c
2 3 3
2
3
3
[
l]
0
20
2
3
3
1
[
a] The reaction was performed with (Z)-1a (0.15 mmol) and 2a (0.1 mmol) in solvent (0.2 mL). [b] Determined by H NMR analysis of the reaction
mixture. [c] Determined by HPLC analysis using a chiral stationary phase. [d] Without dppe. [e] Conversion into the corresponding Michael adducts 3a
with 50:50 e.r. [f] The reaction was performed using (Z)-1a (0.3 mmol) and 2a (0.2 mmol) in CH CN (1.0 mL). [g] Yield of the isolated product. [h] The
3
reaction was performed with p-bromocinnamic aldehyde 2b. [i] The reaction was performed with (Z)-1b (0.15 mmol) and 2a (0.1 mmol) in CH CN
3
(
0.2 mL). [j] The reaction was performed with (Z)-1b (0.15 mmol) and 2a (0.1 mmol) in CH CN (0.5 mL). [k] 10 mol% of 5a. [l] Reaction with (E)-1b
3
(
0.3 mmol) and 2a (0.2 mmol) in CH CN (1.0 mL). dba=dibenzylideneacetone, dppe=1, 2-bis(diphenylphoshino)ethane, n.d.=not determined,
3
TBDMS=tert-butyldimethylsilyl, TES=triethylsilyl, TMS=trimethylsilyl.
[
12]
cascade reactions proceed through a DYKAT process. The
reactions performed with only chiral amine 5a as the catalyst
gave the corresponding Michael adducts 3a as a racemate
conversion and the enantioselectivity of the transformation
increased (4a: > 90% conv., > 99.5:0.5 e.r.; entries 6 and 7).
The highest diastereoselectivity was obtained with CH CN as
3
(
entry 1). In the presence of only the Pd catalyst no desired
solvent (96:4 d.r.; entry 7). We next tested several chiral
amines 5 under these reaction conditions (entries 7–12). The
highest stereoselectivity was obtained when 5a and 5b were
used as the co-catalysts. Moreover, cyclopentanes 4a and 4b
were isolated in high yield with excellent e.r. when the
product was obtained, only some product from the intra-
molecular Tsuji–Trost reaction of 1 was obtained (entry 2).
Notably, when [Pd (dba) ] was used in combination with 1,2-
2
3
bis(diphenylphosphino)ethane (dppe), as the ligand, both the
2
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reaction scale was doubled (entries 13 and 14). Next, the
cascade transformation between (Z)-1b and 2a was inves-
tigated (entries 15–20). It is noteworthy that the reactions
were highly stereoselective and the corresponding cyclo-
pentane 4c having a quaternary carbon stereocenter was
formed with high e.r.. In addition, the highest efficiency was
achieved when the concentration of the enal 2a component
was 0.2m (4c: 95% conv., 93:7 d.r. and > 99.5:0.5 e.r.;
entry 18). When (E)-1b was used the diastereoselectivity
(
95:5 d.r.) of the co-catalytic cascade reaction improved while
the excellent enantioselectivity (> 99.5:0.5 e.r.; entry 20) was
maintained. The stereoselectivity was not affected when the
catalyst loading of the chiral amine 5a was lowered, however,
the reaction rate slightly decreased (entry 18 vs. 19). The
Michael intermediates 3c and 3cꢀ, were formed in 65:35 ratio
during the reaction and were racemic. Thus, the reaction is
[
12]
a DYKAT of type IV.
With these results in hand, we
investigated the co-catalytic dynamic asymmetric cascade
reaction between 1b and enals 2 with 5a, as the amine
catalyst, in combination with [Pd (dba) ] and dppe in CH CN
2
3
3
(
Scheme 2).
Both b-aryl and b-alkyl substituted enals 2 could be used
as substrates to give the corresponding cyclopentanes 4c–4n
in high yield, d.r., and e.r. (99.5:0.5 e.r.– > 99.5:0.5). We next
investigated the transformation between (E)-1c and enal 2a
using the same co-catalyst system at 608C; this reaction had
an increased rate (Scheme 3). Gratifying the transformation
gave cyclohexane 4o in 65% yield as a nearly enantiopure
isomer (> 97:3 d.r. and 99.5:0.5 e.r.). Thus, the co-catalytic
reaction is both an entry to highly functionalized 5- and 6-
membered carbocycles 4 with a quaternary carbon stereo-
center.
The absolute and relative configuration of the chiral
carbocycles 4 was determined by single-crystal X-ray analysis
[14]
of 4k (Figure 1). The relative stereochemistry of the minor
diastereoisomer was determined by NOE experiments of 6d’
Scheme 2. [a] Reactions performed using (E)-1b (0.3 mmol) and 2a
0.2 mmol) in CH CN (1.0 mL) for 24 h. See the Supporting Informa-
tion for details. [b] Using (Z)-1b (0.3 mmol) and 2a (0.2 mmol) in
(
obtained by reduction of 4d’, see the Supporting Informa-
tion).
To further investigate the reaction mechanism, HRMS
(
3
CH CN (1.0 mL) for 24 h. [c] Using (Z)-1b (0.3 mmol) and 2a
3
[15]
analysis was performed on the reaction mixtures. HRMS
determined the presence of iminium intermediates I, II, III,
and IV (Scheme 4). We also confirmed that the Michael
intermediates 3 derived from 1b were formed as racemates
(0.2 mmol) in CH CN (1.0 mL) for 23 h. [d] Using (Z)-1b (0.3 mmol)
3
and 2a (0.2 mmol) in CH CN (1.0 mL) for 28 h. [e] Using (Z)-1b
3
(
(
0.3 mmol) and 2a (0.2 mmol) in CH CN (1.0 mL) for 30 h. [f] Using
3
Z)-1b (0.3 mmol) and 2a (0.2 mmol) in CH CN (1.0 mL) for 60 h at
3
4
8C. The e.r. was determined by GC analysis using a chiral stationary
(
50:50 e.r.) with low d.r. under the investigated reaction
phase.
conditions. Thus, the overall cascade reaction can be classified
[12]
as a DYKATof type IV. We also investigated the sequential
catalyst addition approach by first synthesizing the Michael
adduct 3c with 5a as the catalyst in acetonitrile. The Michael
adduct was formed as a racemic compound with 60:40 d.r. (3c/
3
c’). The subsequent addition of [Pd (dba) ] and dppe
2 3
resulted in the formation of 4c in 45% yield after 40 h with
1:9 d.r. and 98:2 e.r. together with the remaining starting
9
cinnamic aldehyde 2a. In comparison, 4c was isolated in 74%
yield with 93:7 d.r. and 99:0.5 e.r. with only trace amounts of
cinnamic aldehyde 2a, when our optimized one-pot proce-
dure was used (Scheme 2). Thus, a significant synergistic
effect is achieved when performing the one-pot operation
with the two co-catalysts present from the beginning. Based
on the absolute configurations and our experimental results,
Scheme 3. Pd/chiral amine co-catalyzed asymmetric synthesis of cyclo-
hexane 4o.
we propose the following mechanism. Thus, initial reversible
conjugate addition of 1b or 1c to the in situ generated
iminium intermediate I results in an initial rapid equilibration
between the four stereoisomers 3, ent-3, 3’, and ent-3’ via the
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chiral amine co-catalytic dynamic kinetic asymmetric cascade
process for the concise synthesis of polysubstituted cyclo-
pentane and cyclohexane products from structurally simple
starting materials. Mechanistically, the co-catalytic reaction is
a dynamic kinetic asymmetric transformation that proceeds
through a Michael/a-allylic alkylation reaction sequence and
generates four stereocenters in a one-pot operation with
excellent enantioselectivity (99.5:0.5– > 99.5:0.5 e.r.). Nota-
bly, the co-catalytic dynamic cascade reaction can be applied
for the synthesis of carbocycles with an all-carbon stereocen-
ter with up to > 99.5:0.5 e.r. We believe that this co-catalysis
cascade concept will be additionally explored and utilized for
the synthesis of highly functionalized molecules. Research
towards these goals will be undertaken in due course.
Figure 1. Ortep diagram of crystal 4k (with thermal ellipsoids set at
0% probability) and structure of 6d’.
9
corresponding enamine intermediates (II–IIc). Next, oxida-
tive addition of the Pd catalyst occurs predominantly to
enamine intermediate II and results in the corresponding
electrophilic p-allyl palladium complex III. Subsequent
irreversible stereoselective intermolecular nucleophilic Si-
facial attack by the chiral enamine (via a Zimmerman–
[16]
Traxler-type transition state IIIa when n = 2), followed by
protonation and reductive elimination generates iminium
intermediate IVand releases the Pd catalyst. Next, hydrolysis
of IV gives carbocycle 4 and regenerates the chiral amine
catalyst 5. We believe that the reaction pathway via enamine
II is much faster compared to those via IIa–IIc, because
transition state III is favored owing to less steric repulsion
between the equatorial CN and the axial R group, whereas for
in the transition states for the pathways via IIa–IIc the bulkier
ester group would be in closer proximity to the R group.
In summary, we have designed, developed, and used
a conceptually novel highly chemo- and enantioselective Pd/
Experimental Section
Representative procedure: An oven-dried vial (8 mL) equipped with
a magnetic stir bar was charged with [Pd (dba) ]·CHCl (10.4 mg,
2
3
3
0
.01 mmol, 5 mol%), and 1,2-bis(diphenylphoshino)ethane (dppe)
(8.0 mg, 0.02 mmol, 10 mol%), fitted with a septum, sealed and
flushed with N for 10 min. Next, anhydrous CH CN (300 mL) was
added and the resulting mixture was stirred at room temperature for
2
3
7
min. In parallel, an oven-dried vial (8 mL) was charged with catalyst
5
a (13.0 mg, 0.04 mmol, 20 mol%) and sealed. After flushing with N2,
allyl acetate 1 (0.3 mmol, 1.5 equiv in CH CN (300 mL)) was added
followed by enal 2 (0.2 mmol, in CH CN (300 mL)) under N2
atmosphere. After stirring at room temperature for 7 min, the
resulting mixture was transferred to the vial containing the mixture
3
3
Scheme 4. Proposed catalytic cycle.
4
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of palladium catalyst and ligand by a syringe. More anhydrous
Deiana, S. Afewerki, C. Palo-Nieto, O. Verho, E. V. Johnston, A.
CH CN was added to transfer all the solution and reach a final
volume of 1.0 mL ([2] = 0.2m). Next, the mixture was stirred at room
Cꢀrdova, Sci. Rep. 2012, 49, 851; j) S. Santoro, L. Deiana, G-L.
Zhao, S. Lin, F. Himo, A. Cꢀrdova, Manuscript.
3
temperature for the time shown in Scheme 2. The conversion and
diastereomeric ratio were monitored by H NMR spectroscopy of the
reaction mixture. Upon completion, the mixture was directly loaded
on a silica-gel column purified by flash chromatography (petroleum
ether/EtOAc mixtures) to give the pure products 4 as colorless or
yellowish oils.
[7] a) B. Vulovic, F. Bihelovic, R. Matovic, R. N. Saicic, Tetrahedron
2009, 65, 10485; b) S. Mukherjee, B. List, J. Am. Chem. Soc. 2007,
129, 11336; c) J. T. Binder, B. Crone, T. T. Haug, H. Menz, S. F.
Kirsch, Org. Lett. 2008, 10, 1025; d) D. Liu, F. Xie, W. Zhang,
Tetrahedron Lett. 2007, 48, 7591; e) X. Zhao, D. Liu, F. Xie, W.
Zhang, Tetrahedron 2009, 65, 512; f) X. Zhao, D. Liu, F. Xie, Y.
Liu, W. Zhang, Org. Biomol. Chem. 2011, 9, 1871; g) A. E. Allen,
D. W. C. MacMillan, J. Am. Chem. Soc. 2010, 132, 4986; radical
activation: h) T. D. Beeson, A. Mastracchio, J. Hong, K. Ashton,
D. W. C. MacMillan, Science 2007, 316, 582; i) J. J. Devery III,
J. C. Conrad, D. W. C. MacMillan, R. A. Flowers II, Angew.
Chem. 2010, 122, 6242; Angew. Chem. Int. Ed. 2010, 49, 6106;
j) A. Mastracchio, A. A. Warkentin, A. M. Walji, D. W. C.
MacMillan, Proc. Natl. Acad. Sci. USA 2010, 107, 20648; k) D.
Nicewicz, D. W. C. MacMillan, Science 2008, 322, 77; l) A. Allen,
D. W. C. MacMillan, J. Am. Chem. Soc. 2011, 133, 4260;
m) D. W. C. MacMillan, J. Am. Chem. Soc. 2011, 133, 4260;
n) G. Jiang, B. List, Angew. Chem. 2011, 123, 9643; Angew.
Chem. Int. Ed. 2011, 50, 9471.
1
Received: January 22, 2013
Published online: && &&, &&&&
Keywords: aldehydes · asymmetric catalysis · carbocycles ·
.
co-catalysis · quaternary carbon stereocenters
[
1] a) L. F. Tietze, Chem. Rev. 1996, 96, 115; b) K. C. Nicolaou, D. J.
Edmonds, P. G. Bulger, Angew. Chem. 2006, 118, 7292; Angew.
Chem. Int. Ed. 2006, 45, 7134; c) D. J. Ramꢀn, M. Yus, Angew.
Chem. 2005, 117, 1628; Angew. Chem. Int. Ed. 2005, 44, 1602;
d) H. Guo, J. Ma, Angew. Chem. 2006, 118, 362; Angew. Chem.
Int. Ed. 2006, 45, 354; e) Y. Huang, A. M. Walji, C. H. Larsen,
D. W. C. MacMillan, J. Am. Chem. Soc. 2005, 127, 1505.
2] a) P. T. Anastas, J. C. Warner, Green Chemistry: Theory and
Practice, Oxford University Press, Oxford, 2000; b) P. A. Clarke,
S. Santos, W. H. Martin, Green Chem. 2007, 9, 438; c) Green
Chemistry Metrics. Measuring and Monitoring Sustainable Pro-
cesses (Eds.: A. Lapkin, D. Constable), Wiley-Blackwell, Hobo-
ken, 2008.
[
8] For selected examples combined metal and organocatalysis for
the synthesis of cyclopentenes and five-membered heterocycles
see: Ref. [6g–i], [7c], and a) T. Yang, A. Ferrali, L. Campbell,
D. J. Dixon, Chem. Commun. 2008, 2923; b) W. Sun, G. Zhu, L.
Hong, R. Wang, Chem. Eur. J. 2011, 17, 13958; c) W. Sun, G. Zhu,
C. Wu, L. Hong, R. Wang, Chem. Eur. J. 2012, 18, 6737; d) K. L.
Jensen, P. T. Franke, C. Arrꢀniz, S. Kobbelgaard, K. A. Jørgen-
sen, Chem. Eur. J. 2010, 16, 1750; e) C. Yu, Y. Zhang, S. Zhang, J.
He, W. Wang, Tetrahedron Lett. 2010, 51, 1742; see also: f) M. Li,
S. Datta, D. M. Barber, D. J. Dixon, Org. Lett. 2012, 14, 6350.
9] For selected examples of combined metal and organocatalysis,
which do not proceed through enamine activation, for intermo-
lecular allylations, see: a) M. Nakoji, T. Kanayama, T. Okino, Y.
Takemoto, Org. Lett. 2001, 3, 3329; b) G. S. Chen, Y.-J. Deng, L.-
Z. Gong, A.-Q. Mi, X. Cui, Y. Z. Jiang, M. C. K. Choi, A. S. C.
Chan, Tetrahedron: Asymmetry 2001, 12, 1567; c) M. Nakoji, T.
Kanayama, T. Okino, Y. Takemoto, J. Org. Chem. 2002, 67, 7418;
for intramolecular allylations, see: d) B. G. Jellerichs, J.-R. Kong,
M. J. Krische, J. Am. Chem. Soc. 2003, 125, 7758.
[
[
3] See Ref. [1] and a) L. F. Tietze, A. Dꢁrfert in Catalytic Asym-
metric Conjugate Reactions (Ed. A. Cꢀrdova), Wiley-VCH,
Weinheim, 2010, chap. 8, p. 321; b) N. Shindoh, Y. Takemoto, K.
Takasu, Chem. Eur. J. 2009, 15, 12168; c) B. B. Tourꢂ, D. G. Hall,
Chem. Rev. 2009, 109, 4439.
[
[
4] For reviews see: a) X. Yu, W. Wang, Org. Biomol. Chem. 2008, 6,
2037; b) D. Enders, C. Grondal, M. R. M. Hꢁttl, Angew. Chem.
2007, 119, 1590; Angew. Chem. Int. Ed. 2007, 46, 1570; c) C.
Grondal, M. Jeanty, D. Enders, Nat. Chem. 2010, 2, 167; d) B.
List, Organocatalysis, Chem. Rev. 2007, Issue 12; for selected
references for organocatalytic enantioselective cascade reac-
tions for the formation of cyclopentanes see: e) D. Enders, C.
Wang, J. W. Bats, Angew. Chem. 2008, 120, 7649; Angew. Chem.
Int. Ed. 2008, 47, 7539; f) J. Wang, H. Li, L. Zu, X. Shen, W.
Wang, Angew. Chem. 2007, 119, 9208; Angew. Chem. Int. Ed.
[
10] a) E. J. Corey, A. Guzman-Perez, Angew. Chem. 1998, 110, 2092;
Angew. Chem. Int. Ed. 1998, 37, 388; b) P. G. Cozzi, R. Hilgraf,
N. Zimmermann, Eur. J. Org. Chem. 2007, 5969; c) J. Christoff-
ers, A. Mann, Angew. Chem. 2001, 113, 4725; Angew. Chem. Int.
Ed. 2001, 40, 4591; d) B. M. Trost, C. Jiang, Synthesis 2006, 369.
11] a) B. M. Trost, M. L. Crawley, Chem. Rev. 2003, 103, 2921; b) G.
Helmchen, A. Dahnz, P. D. Jbon, M. Schelwies, R. Weihofen,
Chem. Commun. 2007, 675.
2
007, 46, 9050; g) L. Zu, H. Li, H. Xie, J. Wang, W. Jiang, Y. Tang,
W. Wang, Angew. Chem. 2007, 119, 3806; Angew. Chem. Int. Ed.
007, 46, 3732; h) A. Ma, D. Ma, Org. Lett. 2010, 12, 3634; i) I.
[
[
2
Ibrahem, G.-L. Zhao, R. Rios, J. Vesely, H. Sunden, P. Dziedzic,
A. Cꢀrdova, Chem. Eur. J. 2008, 14, 7867.
12] J. Steinreiber, K. Faber, H. Griengl, Chem. Eur. J. 2008, 14, 8060.
The reaction between (E)-1ba (E = CO tBu) and 2a was also
2
[
5] a) Z. Shao, H. Zhang, Chem. Soc. Rev. 2009, 38, 2745; b) Z. Shao,
H. Zhang, Chem. Soc. Rev. 2013, 42, 1337; c) A. E. Allen,
D. W. C. MacMillan, Chem. Sci. 2012, 3, 633.
investigated. The reaction was slower as compared to the
transformation with (E)-1b (entry 20) giving the corresponding
carbocycle 4ca in 32% yield with 96:4 d.r. and 99:1 e.r. after 43 h.
Thus, the use of a more bulky ester group slightly increased the
d.r. but reduced the reaction rate.
[
6] a) I. Ibrahem, A. Cꢀrdova, Angew. Chem. 2006, 118, 1986;
Angew. Chem. Int. Ed. 2006, 45, 1952; < lit b > S. Afewerki, I.
Ibrahem, J. Rydfjord, P. Breistein, A. Cꢀrdova, Chem. Eur. J.
[
13] For a review on the use of protected prolinols as catalysts, see: A.
Mielgo, C. Palomo, Chem. Asian J. 2008, 3, 922.
14] CCDC 908881 (4k) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
2
012, 18, 2972; c) S. Afewerki, P. Breistein, K. Pirttila, L. Deiana,
P. Dziedzic, I. Ibrahem, A. Cꢀrdova, Chem. Eur. J. 2011, 17,
784; d) I. Ibrahem, S. Santoro, F. Himo, A. Cꢀrdova, Adv.
[
8
Synth. Catal. 2011, 353, 245; e) I. Ibrahem, P. Breistein, A.
Cꢀrdova, Angew. Chem. 2011, 123, 12242; Angew. Chem. Int. Ed.
2
011, 50, 12036; f) I. Ibrahem, G. Ma, S. Afewerki, A. Cꢀrdova,
Angew. Chem. 2013, 125, 912; Angew. Chem. Int. Ed. 2013, 52,
78; < lit g > G.-L. Zhao, F. Ullah, L. Deiana, S. Lin, Q. Zhang,
J. Sun, I. Ibrahem, P. Dziedzic, A. Cꢀrdova, Chem. Eur. J. 2010,
6, 1585; h) S. Lin, G.-L. Zhao, L. Deiana, J. Sun, Q. Zhang, H.
Leijonmarck, A. Cꢀrdova, Chem. Eur. J. 2010, 16, 13930; i) L.
[
15] C. A. Marquez, F. Fabbretti, J. O. Metzger, Angew. Chem. 2007,
1
19, 7040; Angew. Chem. Int. Ed. 2007, 46, 6915.
16] H. E. Zimmerman, M. D. Traxler, J. Am. Chem. Soc. 1957, 79,
920.
8
[
1
1
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Asymmetric Catalysis
G. Ma, S. Afewerki, L. Deiana,
C. Palo-Nieto, L. Liu, J. Sun, I. Ibrahem,*
A. Cꢁrdova*
&&&& — &&&&
A Palladium/Chiral Amine Co-catalyzed
Enantioselective Dynamic Cascade
Reaction: Synthesis of Polysubstituted
Carbocycles with a Quaternary Carbon
Stereocenter
Polysubstituted 5- and 6-membered car-
bocycles were synthesized by the title
reaction. The one-pot dynamic relay pro-
cess generates four new stereocenters,
including a quaternary carbon center, in
a highly enantioselective fashion
(99.5:0.5!99:0.5 e.r.) by using a simple
combination of palladium and chiral
amine co-catalysts.
6
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!