Highly enantioselective control of dynamic cascade transformations by dual catalysis: Asymmetric synthesis of polysubstituted spirocyclic oxindoles

Article abstract of DOI:10.1021/cs501975u

The highly enantioselective (up to >99.5:0.5 er) synthesis of polysubstituted spirocyclic oxindoles with four new contiguous stereocenters, including the spiro all-carbon quaternary center, is disclosed. It is accomplished by the highly stereoselective control of a dynamic conjugate/intramolecular allylic alkylation relay sequence based on the synergistic cooperation of metal and chiral amine catalysts in which the careful selection of organic ligand, metal complex, and chiral amine is essential. The intramolecular C-C bond-forming step occurred only when both the metal and chiral amine catalysts were present. (Chemical Equation Presented).

Full text of DOI:10.1021/cs501975u

Letter
pubs.acs.org/acscatalysis
Highly Enantioselective Control of Dynamic Cascade
Transformations by Dual Catalysis: Asymmetric Synthesis of
Polysubstituted Spirocyclic Oxindoles
Samson Afewerki,†,‡ Guangning Ma,† Ismail Ibrahem,† Leifeng Liu,‡,§ Junliang Sun,‡,§
and Armando Cordova*,†,§
́
†Department of Natural Sciences, Mid Sweden University, SE-851 70 Sundsvall, Sweden
§
‡The Berzelii Center EXSELENT, Department of Materials and Environmental Chemistry, Stockholm University, SE-106 91
Stockholm, Sweden
S
* Supporting Information
ABSTRACT: The highly enantioselective (up to >99.5:0.5
er) synthesis of polysubstituted spirocyclic oxindoles with four
new contiguous stereocenters, including the spiro all-carbon
quaternary center, is disclosed. It is accomplished by the highly
stereoselective control of a dynamic conjugate/intramolecular
allylic alkylation relay sequence based on the synergistic
cooperation of metal and chiral amine catalysts in which the
careful selection of organic ligand, metal complex, and chiral amine is essential. The intramolecular C−C bond-forming step
occurred only when both the metal and chiral amine catalysts were present.
KEYWORDS: asymmetric cocatalysis, α,β-unsaturated aldehydes, dynamic transformations, polysubstituted, spirocyclic oxindoles,
all-carbon quaternary stereocenter
he biological activity and structural complex architectures
challenges such as incompatibility between the transition
Tfound in nature have inspired chemists to design strategies metal/organocatalyst and catalyst inhibition.12−14 Thus, there
are very few reports on the synthesis of spirocyclic oxindoles
using “organo/metal cooperative catalysis” and all of them
include the formation of spirocyclic cyclopentene oxindoles as
the key transformation.16
for assembling challenging three-dimensional structures dis-
covered in natural products.1 Despite the tremendous advances
in asymmetric synthesis technology, the creation of strained
polycyclic structures and the generation of all-carbon
quaternary stereocenters2 are very difficult and need further
development. Particularly intriguing is the spirocyclic oxindole
structural motif,3 which is present in a large number of natural
and unnatural compounds with important biological activities,
including potential treatment of malaria3c (Figure 1). This has
led to the elegant development of structure-based design and
diversity-oriented synthesis (DOS) for the preparation of
spirocyclic oxindole derivatives.4 However, because of their
structural complexity described vide supra, it is a great challenge
to do this in an asymmetric fashion. A few methods have
recently been disclosed, which include cycloaddition processes
and the intramolecular Heck reaction.5
Domino and cascade reactions are powerful methodologies
for rapidly achieving molecular complexity and include “green
chemistry” parameters.6−9 In this context, sophisticated metal-
free catalytic technologies have recently been developed for the
asymmetric synthesis of spirocyclic oxindoles.10
The concept of using a transition metal catalyst together with
an organocatalyst in one flask has begun to emerge as a new
tool in organic synthesis.11−15 In 2006, we discovered that
transition metal catalysis can be merged with aminocatalysis.12a
Although recently, several important advances have been
made,12−14 this research area is only in its infancy and faces
Inspired by the vide-supra-described challenges and our
retrocatalytic analysis,12 we envisioned a cocatalytic dynamic
asymmetric Michael/α-allylic alkylation cascade relay sequence
between oxindoles 1 and enals 2 using a simple combination of
Pd and chiral amine 5 catalysts for the construction of
polysubstituted spirocyclic oxindoles 4 with the all-carbon
stereocenter (Scheme 1). However, there are chemoselectivity
issues, such as the Pd-catalyzed intermolecular Tsuji−Trost
reaction of 1 and polymerization or N-alkylation of the amine
catalyst 5 instead of the preferred pathway.17 Furthermore, our
previous research has shown that the Pd/amine-cocatalyzed
cascade transformations are reversible and can deliver a mixture
of four stereoisomers of Michael adducts 3.12h Thus, to get a
predominant stereoisomer out of the possible 16, the dual
catalyst system has to first react via enamine intermediate II at a
higher rate as compared with all the other pathways via IIa−IIc,
followed by oxidative addition of the Pd catalyst to generate π-
allyl intermediate III. Next, a highly stereoselective intra-
molecular nucleophilic attack by its enamine moiety, followed
Received: December 9, 2014
Revised: January 19, 2015
Published: January 21, 2015
© 2015 American Chemical Society
1266
DOI: 10.1021/cs501975u
ACS Catal. 2015, 5, 1266−1272

ACS Catalysis
Letter
Figure 1. Examples of natural products containing the spirocyclopentane oxindole scaffold.
a
Scheme 1. Pd/Chiral Amine Co-Catalytic Dynamic Cascade Transformation between 1 and 2
a
LG = Leaving group. Only 4 of the possible 16 stereoisomers of 4 are shown.
by reductive elimination and hydrolysis, will deliver the
spirocyclic oxindole 4 as well as regenerate the amine and Pd
catalysts, respectively. Notably, the equilibration between the
stereoisomers ent-3, ent-3′, 3′, and 3 (eperimization,
racemization) must occur because otherwise, the maximum
theoretical yield of 4 and 4′ would be 25%, respectively (kinetic
resolution).18
Here, we disclose that highly enantioselective control of
dynamic cascade relay sequences can be employed for the
synthesis of polysubstituted spirocyclic oxindoles 4 in high
yields and enantiomeric ratios (98.5:1.5 to >99:0.5) employing
a simple dual catalyst system.
We first began to investigate the dynamic cascade trans-
formation between oxindoles (Z)-119 and cinnamic aldehyde 2a
using different conditions in the presence of chiral amines 5
and different in-situ-generated Pd cocatalysts. Representative
results are shown in Table 1.
To our delight, the extensive screening revealed that the
corresponding spirocyclic oxindole 4a was formed in good
conversion with good dr and high er (98.5:1.5) when chiral
amine 5a20 (20 mol %) was used in combination with
Pd2(dba)3 and triarylphosphine 6b or 6d as the ligands,
respectively, in acetonitrile (entries 9 and 11).21 In comparison,
when Pd2(dba)3 was used in combination with ligand 6a, both
the conversion and the enantioselectivity of the transformation
increased (4a: 75% conversion, 99:1 er; entry 5); however, the
dr decreased. Gratifyingly, when increasing the size of the N-
protective group of the oxindole from methyl ((Z)-1a) to
benzyl ((Z)-1b) using 5a as the amine catalyst in combination
with Pd2(dba)3 and ligand 6d, both the conversion and the
enantioselectivity of the transformation increased while keeping
a good dr (4b: 80% conversion, >99.5:0.5 er, 64:36 dr; entry
16). It is noteworthy that when performing this condition at 40
°C, both the efficiency and diastereoselectivity of the
transformation was further improved (4b: >95% conversion,
99.5:0.5 er, 77:23 dr; entry 18). The reaction performed with
only the chiral amine 5a as the catalyst gave the corresponding
Michael adducts 3a and 3a′ in 57:43 ratio (entry 1). The
reaction with only the Pd catalyst led to no product formation
and only some intramolecular Tsuji−Trost reaction of 1 (entry
2). We also probed other chiral amines 5 under this reaction
condition (entries 21−23); however, the highest stereo-
1267
DOI: 10.1021/cs501975u
ACS Catal. 2015, 5, 1266−1272

ACS Catalysis
Letter
a
Table 1. Key results from the reaction development.
b
b
c
d
entry
amine
cat. Pd
ligand
solv.
prod.
t (h)
T (°C)
conv. (%)
dr
er
er
e
1
2
5a
CH3CN
CH3CN
toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
4b
4b
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
12
48
60
65
38
104
20
75
38
72
36
24
80
48
36
24
4
40
22
22
22
22
−22
60
22
22
22
22
40
22
22
22
22
60
40
40
40
40
40
60
40
40
40
40
40
0
Pd2(dba)3
Pd(PPh3)4
Pd(PPh3)4
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
6a
0
>95
20
3
5a
5a
5a
5a
5a
58:42
57:43
58:42
58:42
57:43
n.d.
98:2
90.5:9.5
n.d.
4
n.d.
99:1
n.d.
96:4
n.d.
5
6a
6a
6a
6a
6b
6c
6d
6d
6e
6f
75
95:5
n.d.
6
75
7
81
63:37
n.d.
f
8
5a
<1
9
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
68
67:33
57:43
74:26
64:36
50:50
50:50
n.d.
98.5:1.5
>89.5:0.5
98.5:1.5
97.5:2.5
99:1
98:2
94:6
94:6
96:4
>99.5:0.5
n.d.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
22
59
54
63
<10
<5
n.d.
6d
6d
6d
6d
6d
6d
6d
6d
6d
6d
6d
6d
6d
6d
n.d.
n.d.
80
64:36
73:27
77:23
58:42
70:30
75:25
76:24
n.d.
>89.5:0.5
98.5:1.5
99.5:0.5
99:1
99:1
94:6
98:2
98:2
98:2
98:2
98:2
n.d.
>95
>95
42
12
72
20
12
12
12
12
12
12
12
12
g
5a
h
5a
83
99.5:0.5
99.5:0.5
99.5:0.5
n.d.
5b
5c
5d
5a
5a
5a
5a
85
83
<10
67
74:26
71:29
56:44
73:27
77:23
96:4
93:7
88:12
93:7
90.5:9.5
98:2
THF
>85
61
96.5:3.5
96:4
CH2CI2
DMSO
CH3CN
>95
>95
98:2
i
5a
99.5:0.5
a
b
The reaction was performed with (Z)-1a (0.2 mmol) or (Z)-1b (0.2 mmol) and 2a (0.1 mmol) in solvent (0.5 mL). Conversion to and Dr of 4 as
c
d
1
determined by H NMR analysis of the crude reaction mixture. er of 4 as determined by chiral-phase HPLC analysis. er of 4′ as determined by
e
f
g
chiral-phase HPLC analysis. 66% conversion to the corresponding Michael adducts 3a and 3a′ in 57:43 ratio. Addition of 7a (20 mol %). Addition
h
i
of benzoic acid (20 mol %). Addition of TEA (25 mol %). Reaction performed at the double scale. TMS = trimethylsilyl, TES = triethylsilyl,
TBDMS = tert-butyldimethylsilyl, dppe =1,2-bis(diphenylphoshino)ethane, dba = dibenzylideneacetone, n.d. = not determined, TEA =
triethylamine, Bn = Benzyl.
selectivity was obtained when 5a was used as the cocatalysts.
With these results in hand, we began to investigate the
cocatalytic dynamic asymmetric cascade reaction between
oxindoles 1b−1d and enals 2 using 5a as the amine catalyst
in combination with Pd2(dba)3 and 6d in CH3CN at 40 °C
(Scheme 2).
The cocatalytic dynamic asymmetric cascade reaction
exhibited a broad scope and both β-aryl- and β-alkyl-substituted
enals 2 could be used as substrates. It is noteworthy that the
reactions were highly stereoselective and the corresponding
polysubstituted spirocyclic oxindoles 4b-4n with their all-
carbon quaternary stereocenter were formed in high yields and
er’s (98.5:1.5 - >99.5:0.5). The dr was good to high in most
1268
DOI: 10.1021/cs501975u
ACS Catal. 2015, 5, 1266−1272

ACS Catalysis
Letter
a
Scheme 2
a
[a] Reactions performed using (Z)-1 (0.3 mmol) and 2 (0.15 mmol) in CH3CN (1.0 mL) for 6 h. See the Supporting Information for details. [b]
1
Same as [a] but reaction time 12 h. [c] Determined by H NMR analysis of the crude reaction mixture. [d] determined by chiral-phase HPLC
analysis. [e] Determined by H NMR analysis of the isolated pure compound.
1
cases, demonstrating a faster intramolecular α-allylic alkylation
of isomer 3 over 3′ by the dual catalyst system. Only the
cascade reaction with the β-furfuryl-substituted enal 2e
provided the corresponding spirocyclic oxindoles 4f and 4f′
in a 54:46 ratio with high er’s (98.5:1.5 and 97:3, respectively).
The absolute and relative configuration of the chiral carbocycles
4 was determined by X-ray analysis of (1S,2R,3R,4S)-4i (Figure
2).22 The relative stereochemistry of the minor diastereoisomer
was determined by NOE experiments of 4d′ (see the SI).
To further establish the reaction mechanism, HRMS analysis
was performed on the crude reaction mixtures for the
cocatalyzed transformation between oxindole (Z)-1c and
2g.23 The HRMS determined the presence of iminium and
enamine intermediates I, II, and IV, respectively (Scheme 3).
We also found that the isolated intermediates 3 can undergo
retro-Michael reactions to enals 1 in the presence of the dual
catalyst system. They were also formed in a significantly lower
er as compared with the spirocycles 4. For example, after 4h, 3b
was formed with 73.5:26.5 er (47% ee) as compared with the
>99.5:0.5 er (>99% ee) of 4a. Moreover, the Michael
intermediates 3 did not undergo carbocyclization to 4 without
the presence of the chiral amine catalyst 5a. We also performed
a crossover experiment and found that starting with a mixture
of Michael adducts 3b, 3b′, and 4-Br-cinnamic aldehyde 2d in
the presence of the Pd/chiral amine 5a system led to the
exclusive conversion to spirocyclic oxindole 4e (67%
1269
DOI: 10.1021/cs501975u
ACS Catal. 2015, 5, 1266−1272

ACS Catalysis
Letter
The above results demonstrate that the reaction is a dynamic
cascade relay process in which the Pd and chiral amine catalyst
operate in synergy during the carbocyclization step. However,
as compared with our previous carbocyclization using less bulky
donors,12h which proceeds via a DYKAT of type IV18
mechanism, the Michael intermediates 3 were not racemic.
On the basis of the absolute configurations and our
experimental results, we propose the following mechanism to
account for the stereochemical and product outcome of the
spirocyclic oxindoles 4 with an all-carbon stereocenter (Scheme
3). Thus, initial reversible stereoselective conjugate addition of
1, preferably to the less sterically hindered Si face (R = Aryl) of
the in-situ-generated iminium intermediate I, results in
predominant formation of the major stereoisomers 3 and 3′
over the minor stereoisomers ent-3 and ent-3′, which are in a
slow equilibration via the corresponding enamine intermediates
(II-IIc). Next, oxidative addition of the Pd catalyst occurs
predominantly to enamine intermediate II and delivers the
corresponding electrophilic π-allyl palladium complex III.
Subsequent irreversible stereoselective intermolecular nucleo-
philic Si-facial attack by the chiral enamine via a 5-membered
transition state followed by protonation and reductive
elimination generates iminium intermediate IV and releases
the Pd catalyst. Next, hydrolysis of IV delivers spirocyclic
oxindole 4 and regenerates the chiral amine catalyst 5. Our
proposal for the reaction pathway to be much faster via
enamine II as compared with the pathway via IIb is that less-
steric repulsion between the axial aryl group and the R-group in
transition state III favors it, whereas for the latter one, the
bulkier N-alkyl amido group is less favored and in closer
proximity to the R-group when the right ligand 6 for the
catalytically active Pd complex is employed.
Figure 2. Ortep picture of crystal 4i and structures 4i and 4d′.
conversion, 59:41 dr, 98:2 er) and cinnamic aldehyde 2a
(Scheme 4). It is noteworthy that product 4b was not formed.
Thus, the retro-Michael reaction of 3b was faster than the
intramolecular C−C bond-forming step of 3b, and subsequent
Michael/carbocyclization cascade of 1b with enal 2d was
favored over 2a.
Scheme 3. Proposed Catalytic Cycle
1270
DOI: 10.1021/cs501975u
ACS Catal. 2015, 5, 1266−1272

ACS Catalysis
Letter
Scheme 4. Crossover Experiment
In summary, we have designed, optimized, controlled, and
executed a dynamic Michael/α-allylic alkylation cascade relay
sequence for the synthesis of polysubstituted spirocyclic
oxindoles with four new contiguous stereocenters, including
the spiro all-carbon quaternary center, from simple starting
materials employing a dual Pd/chiral amine catalyst system. It is
noteworthy that this valuable class of functionalized molecules
is constructed in one pot with high chemo- and enantiose-
lectivity from a mixture of stereoisomeric intermediates, which
is possible by the synergistic catalysis generated from the “right”
combination of ligand, metal complex, and chiral amine. The
simplicity, high enantioselectivity, and modularity of the
disclosed cocatalysis concept make it suitable for the synthesis
of highly functionalized molecules and DOS. Thus, further
expansion of it along these research themes as well as
mechanistic studies are ongoing and will be disclosed in due
course.
ASSOCIATED CONTENT
* Supporting Information
The following file is available free of charge on the ACS
■
S
Publications website at DOI: 10.1021/cs501975u
Experimental procedures, preparation of starting materi-
als, and spectra (PDF)
.
AUTHOR INFORMATION
Corresponding Author
*Fax: +(46) 8-154908. E-mails: armando.cordova@miun.se,
acordova@organ.su.se.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the European
Union, Mid Sweden University, and Swedish National Research
Council.
EXPERIMENTAL SECTION
■
Representative procedure: An oven-dried vial (8 mL) equipped
with a magnetic stir bar was charged with Pd2(dba)3 CHCl3
(10.4 mg, 0.01 mmol, 5 mol %) and ligand 6d (7.0 mg, 0.02
mmol, 10 mol %), fitted with a septum, sealed, and flushed with
a stream of N2 for 10 min. Next, anhydrous CH3CN (200 μL)
was added, and the resulting mixture was stirred at room
temperature for 7 min. In parallel, an oven-dried vial (8 mL)
was charged with catalyst 5a (13.0 mg, 0.04 mmol, 20 mol %)
and sealed. After flushing with a stream of N2, oxindole 1 (0.4
mmol, 2.0 equiv in CH3CN (800 μL)) was added followed by
enal 2 (0.2 mmol) under N2 atmosphere. After stirring at room
temperature for 7 min, the resulting mixture was transferred to
the vial containing the mixture of palladium catalyst and ligand
via a syringe (final volume of 1.0 mL ([2] = 0.2 M)). Next, the
mixture was stirred at room temperature for the time shown in
Scheme 2. The conversion and diastereomeric ratio were
REFERENCES
■
(1) (a) Fischer, E. Ber. Deutsch Chem. Ges. 1890, 23, 799−805.
(b) Corey, E. J. Angew. Chem., Int. Ed. 1991, 30, 455−465. (c) Noyori,
R. Chem. Commun. 2005, 1807−1811. (d) Nicolaou, K. C.;
Vourloumis, D.; Winssinger, N.; Baran, P. S. Angew. Chem., Int. Ed.
2000, 39, 44−122. (e) Nicolaou, K. C.; Snyder, S. A. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 11929−11936. (f) Li, J. W. H.; Vederas, J. C.
Science 2009, 325, 161−165.
(2) (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998,
37, 388−401. (b) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J.
Org. Chem. 2007, 2007, 5969−5994. (c) Christoffers, J.; Mann, A.
Angew. Chem., Int. Ed. 2001, 40, 4591−4597. (d) Trost, B. M.; Jiang,
C. Synthesis 2006, 369−396. (e) Rios, R. Chem. Soc. Rev. 2012, 41,
1060−1074.
(3) (a) Bond, R. F.; Boeyens, J. C. A.; Holzapfel, C. W.; Steyn, P. S. J.
Chem. Soc. Perkin Trans. 1 1979, 1751−1761. (b) Galliford, C. V.;
Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748−8758.
(c) Mugishima, T.; Tsuda, M.; Kasai, Y.; Ishiyama, H.; Fukushi, E.;
Kawabata, J.; Watanabe, M.; Akao, K.; Kobayshi, J. J. Org. Chem. 2005,
70, 9430−9435. (d) Rottmann, M.; McNamara, C.; Yeung, B. K. S.;
Lee, M. C. S.; Zou, B.; Russell, B.; Seitz, P.; Plouffe, D. M.; Dharia, N.
1
monitored by H NMR analysis of the crude reaction mixture.
Upon completion, the mixture was directly loaded onto a silica-
gel column, and immediate flash chromatography (petroleum
ether/EtOAc mixtures) gave the pure products 4 as yellowish
oils.
1271
DOI: 10.1021/cs501975u
ACS Catal. 2015, 5, 1266−1272

ACS Catalysis
Letter
V.; Tan, J.; Cohen, S. B.; Spencer, K. R.; Gonzal
́
ez-Pae
́
z, G. E.;
252. (d) Ibrahem, I.; Breistein, P.; Cor
́
dova, A. Angew. Chem., Int. Ed.
Lakshminarayana, S. B.; Goh, A.; Suwanarusk, R.; Jegla, T.; Schmitt, E.
K.; Beck, H.-P.; Brun, R.; Nosten, F.; Renia, L.; Dartois, V.; Keller, T.
H.; Fidock, D. A.; Winzeler, E. A.; Diagana, T. T. Science 2010, 329,
1175−1180. (e) Greshock, T. J.; Grubbs, A. W.; Jiao, P.; Wicklow, D.
T.; Gloer, J. B.; Williams, R. M. Angew. Chem., Int. Ed. 2008, 48, 3573−
3577.
(4) (a) Lo, M. M.-C.; Neumann, C. S.; Nagayama, S.; Perlstein, E.
O.; Schreiber, S. L. J. Am. Chem. Soc. 2004, 126, 16077−16086.
(b) Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Qiu, S.; Ding, Y.; Gao,
W.; Stuckey, J.; Krzysztof, K.; Roller, P. P.; Tomita, Y.; Parrish, D. A.;
Deschamps, J. R.; Wang, S. J. Am. Chem. Soc. 2005, 127, 10130−
10131.
(5) (a) Chen, X.-H.; Wei, Q.; Luo, S.-W.; Xiao, H.; Gong, L.-Z. J. Am.
Chem. Soc. 2009, 131, 13819−13825. (b) Trost, B. M.; Cramer, N.;
Silverman, S. M. J. Am. Chem. Soc. 2007, 129, 12396−12397.
(c) Antonchick, A. P.; Gerding-Reimers, C.; Catarinella, M.;
Schurmann, M.; Preut, H.; Ziegler, S.; Rauh, D.; Waldmann, H. Nat.
Chem. 2010, 2, 735−740. (d) Dounay, A. B.; Overman, L. E. Chem.
Rev. 2003, 103, 2945−2964.
(6) (a) Tietze, L. F. Chem. Rev. 1996, 96, 115−136. (b) Nicolaou, K.
C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45,
7134−7186. (c) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44,
1602−1634. (d) Guo, H.-C.; Ma, J.-A. Angew. Chem., Int. Ed. 2006, 45,
354−366. (e) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2005, 127, 15051−15053.
2011, 50, 12036−12041. (e) Ibrahem, I.; Ma, G.; Afewerki, S.;
Cordova, A. Angew. Chem., Int. Ed. 2013, 52, 878−882. (f) Zhao, G.-L.;
Ullah, F.; Deiana, L.; Lin, S.; Zhang, Q.; Sun, J.; Ibrahem, I.; Dziedzic,
P.; Cor
dova, A. Chem.Eur. J. 2010, 16, 1585−1591. (g) Lin, S.;
Zhao, G.-L.; Deiana, L.; Sun, J.; Zhang, Q.; Leijonmarck, H.; Cordova,
A. Chem.Eur. J. 2010, 16, 13930−13934. (h) Ma, G.; Afewerki, S.;
Deiana, L.; Palo-Nieto, C.; Liu, L.; Sun, J.; Ibrahem, I.; Cordova, A.
Angew. Chem., Int. Ed. 2013, 52, 6050−6054.
́
́
́
́
(13) (a) Vulovic, B.; Bihelovic, F.; Matovic, R.; Saicic, R. N.
Tetrahedron 2009, 65, 10485−10495. (b) Mukherjee, S.; List, B. J. Am.
Chem. Soc. 2007, 129, 11336−11337. (c) Binder, J. T.; Crone, B.;
Haug, T. T.; Menz, H.; Kirsch, S. F. Org. Lett. 2008, 10, 1025−1028.
(d) Liu, D.; Xie, F.; Zhang, W. Tetrahedron Lett. 2007, 48, 7591−7594.
(e) Cherevatskaya, M.; Neumann, M.; Fuldner, S.; Harlander, C.;
̈
Kummel, S.; Dankesreiter, S.; Pfitzner, A.; Zeitler, K.; Konig, B. Angew.
̈
̈
Chem., Int. Ed. 2012, 51, 4062−4066. (f) Krutwald, S.; Sarlah, D.;
Schafroth, M. A.; Carreira, E. M. Science 2013, 340, 1065−1068.
(g) Allen, A. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132,
4986−4987. (h) Beeson, T. D.; Mastracchio, A.; Hong, J.; Ashton, K.;
MacMillan, D. W. C. Science 2007, 316, 582−585. (i) Nicewicz, D. A.;
MacMillan, D. W. C. Science 2008, 322, 77−80. (j) Yoshida, M.;
Masaki, E.; Terumine, T.; Hara, S. Synthesis 2014, 46, 1367−1373.
(14) (a) Yang, T.; Ferrali, A.; Campbell, L.; Dixon, D. J. Chem.
Commun. 2008, 2923−2925. (b) Binder, J. T.; Crone, B.; Haug, T. T.;
Menz, H.; Kirsch, S. F. Org. Lett. 2008, 10, 1025−1028. (c) Sun, W.;
Zhu, G.; Wu, C.; Hong, L.; Wang, R. Chem.Eur. J. 2012, 18, 6737−
6741.
(7) (a) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and
Practice; Oxford University Press: Oxford, New York, 2000. (b) Clarke,
P. A.; Santos, S.; Martin, W. H. C. Green Chem. 2007, 9, 438−440.
(c) Lapkin, A.; Constable, D. J. C. Green Chemistry Metrics. Measuring
and Monitoring Sustainable Processes; Wiley-Blackwell: Chichester,
Ames (Iowa), 2008.
(15) (a) Jellerichs, B. G.; Kong, J.-R.; Krische, M. J. J. Am. Chem. Soc.
2003, 125, 7758−7759. (b) Nakoji, M.; Kanayama, T.; Okino, T.;
Takemoto, Y. Org. Lett. 2001, 3, 3329−3331. (c) Chen, G.; Deng, Y.;
Gong, L.; Mi, A.; Cui, X.; Jiang, Y.; Choi, M. C. K.; Chan, A. S. C.
Tetrahedron: Asymmetry 2001, 12, 1567−1571.
(8) (a) Tietze, L. F.; Durfert, A. In Catalytic Asymmetric Conjugate
̈
(16) (a) Sun, W.; Zhu, G.; Wu, C.; Hong, L.; Wang, R. Chem.Eur.
Reactions; Cor
(b) Shindoh, N.; Takemoto, Y.; Takasu, K. Chem.Eur. J. 2009, 15,
12168−12179. (c) Toure, B. B.; Hall, D. G. Chem. Rev. 2009, 109,
́
dova, A., Ed.; Wiley-VCH, Weinheinheim, 2010; p 321.
J. 2012, 18, 13959−13963. (b) Deiana, L.; Ghisu, L.; Afewerki, S.;
́
Verho, O.; Johnston, E. V.; Hedin, N.; Bacsik, Z.; Cordova, A. Adv.
́
Synth. Catal. 2014, 356, 2485−2492. (c) Deiana, L.; Jian, Y.; Palo-
4439−4486.
Nieto, C.; Afewerki, S.; Incerti-Pradillos, C.; Verho, O.; Tai, C.-W.;
(9) For selected reviews on organocatalytic cascade catalysis, see:
Johnston, E. V.; Cor
3451. (d) Santoro, S.; Deiana, L.; Zhao, G.-L.; Lin, S.; Himo, F.;
Cordova, A. ACS Catal. 2014, 4, 4474−4484.
́
dova, A. Angew. Chem., Int. Ed. 2014, 53, 3447−
(a) Yu, X.; Wang, W. Org. Biomol. Chem. 2008, 6, 2037−2046.
(b) Enders, D.; Grondal, C.; Huttl, M. R. M. Angew. Chem., Int. Ed.
̋
́
2007, 46, 1570−1581. (c) Grondal, C.; Jeanty, M.; Enders, D. Nat.
Chem. 2010, 2, 167−178. (d) List, B. Chem. Rev. 2007, 107, 5413−
5415.
(17) (a) Helmchen, G.; Dahnz, A.; Dubon, P.; Schelwies, M.;
Weihofen, R. Chem. Commun. 2007, 675−691. (b) Trost, B. M.;
Crawley, M. L. Chem. Rev. 2003, 103, 2921−2944.
(18) Steinreiber, J.; Faber, K.; Griengl, H. Chem.Eur. J. 2008, 14,
8060−8072.
(10) For reviews, see: (a) Cheng, D.; Ishihara, Y.; Tan, B.; Barbas, C.
F., III ACS Catal. 2014, 4, 743−762. (b) Hong, L.; Wang, R. Adv.
Synth. Catal. 2013, 355, 1023−1052. (c) For selected examples, see:.
(d) Tin, B.; Candeias, N. R.; Barbas, C. F., III Nat. Chem. 2011, 3,
473−477. (e) Sun, W.; Zhu, G.; Wu, C.; Hong, L.; Wang, R. Chem.
Eur. J. 2012, 18, 6737−6741. (f) Tan, B.; Candeias, N. R.; Barbas, C.
F., III J. Am. Chem. 2011, 133, 4672−4675. (g) Tian, X.; Melchiorre, P.
Angew. Chem., Int. Ed. 2013, 52, 5360−5363. (h) Ding, L.-Z.; Zhong,
T.-S.; Wu, H.; Wang, Y.-M. Eur. J. Org. Chem. 2014, 5139−5143.
(i) Bencievenni, G.; Wu, L.-Y.; Mazzanti, A.; Giannichi, B.; Pesciaioli,
F.; Song, M.-P.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009,
48, 7200−7203. (j) Albertshofer, K.; Tan, B.; Barbas, C. F., III Org.
Lett. 2012, 14, 1834−1837. (k) Albertshofer, K.; Anderson, K. E.;
Barbas, C. F., III Org. Lett. 2012, 14, 5968−5971. (l) Zhong, F.; Han,
X.; Wang, Y.; Lu, Y. Angew. Chem., Int. Ed. 2011, 50, 7837−7841.
(m) Voituriez, A.; Pinto, N.; Neel, M.; Retailleau, P.; Marinetti, A.
Chem.Eur. J. 2010, 16, 12541−12544.
́
(19) For methods of preparing compounds 1, see: (a) Liegault, B.;
Petrov, I.; Gorelsky, S. I.; Fagnou, K. J. Org. Chem. 2010, 75, 1047−
1060. (b) Marti, C.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127,
11505−11515. (c) Marti, C.; Carreira, E. M. J. Am. Chem. Soc. 2005,
127, 11505−11515. (d) Xu, Y.-C.; Roughton, A. L.; Plante, R.;
Goldstein, S.; Deslongchamps, P. Can. J. Chem. 1993, 71, 1152−1168.
́ ́
(e) Betancort, J. M.; Martín, V. S.; Padron, J. M.; Palazon, J. M.;
Ramírez, M. A.; Soler, M. A. J. Org. Chem. 1997, 62, 4570−4583.
(f) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590−4591.
(20) For a review on the use of protected prolinols as catalysts, see:
Mielgo, A.; Palomo, C. Chem.Asian J. 2008, 3, 922−948.
(21) The use of N-Boc or N-Cbz-protected (Z)-1 did not give any
products.
(22) CCDC 977648 (4i) contains 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.
(23) Marquez, C. A.; Fabbretti, F.; Metzger, J. O. Angew. Chem., Int.
Ed. 2007, 46, 6915−6917.
(11) (a) Shao, Z.; Zhang, H. Chem. Soc. Rev. 2009, 38, 2745−2755.
(b) Du, Z.; Shao, Z. H. Chem. Soc. Rev. 2013, 42, 1337−1378.
(c) Allen, A. E.; MacMillan, D. W. C. Chem. Sci. 2012, 3, 633−658.
(d) Deng, Y.; Kumar, S.; Wang, H. Chem. Commun. 2014, 50, 4272−
4284.
(12) (a) Ibrahem, I.; Cor
1952−1956. (b) Afewerki, S.; Ibrahem, I.; Rydfjord, J.; Breistein, P.;
Cor
dova, A. Chem.Eur. J. 2012, 18, 2972−2977. (c) Ibrahem, I.;
Santoro, S.; Himo, F.; Cordova, A. Adv. Synth. Catal. 2011, 353, 245−
́
dova, A. Angew. Chem., Int. Ed. 2006, 45,
́
́
1272
DOI: 10.1021/cs501975u
ACS Catal. 2015, 5, 1266−1272