Gold/br?nsted acid relay catalysis for enantioselective construction of spirocyclic diketones

Article abstract of DOI:10.1002/chem.201301208

Golden opportunities: A redox-, atom-, and step-economical asymmetric cascade reaction for the synthesis of chiral spirocyclic architectures with two contiguous stereocenters in high yields and excellent enantioselectivities by using a gold/chiral Br?nsted acid relay catalysis system is described (see scheme). The results suggest that the chiral Br?nsted acid rather than the chiral gold phosphate complex serves as the real catalyst of the enantiodetermining step. Copyright

Full text of DOI:10.1002/chem.201301208

DOI: 10.1002/chem.201301208
Gold/Brønsted Acid Relay Catalysis for Enantioselective Construction of
Spirocyclic Diketones
Deyun Qian and Junliang Zhang*[a]
Enantiopure spirocycles[1] represent a structural motif
present in natural products and biologically active com-
pounds such as fusarisetin A, a potent cancer migration in-
hibitor,[2] and acutumine, an alkaloid with antiamnesic and
selective T-cell cytotoxicity.[3] Furthermore, their rigid struc-
tures make them a privileged platform for the development
of chiral ligands.[4] The ability to enantioselectively construct
such important spirocyclic molecules in a rapid and efficient
manner still represents a major challenge in modern organic
synthesis.[5] Moreover, catalytic enantioselective synthesis of
adjacent quaternary and tertiary chiral centers still remains
scarce by existing methodologies.[1,6]
Gold catalysis has witnessed tremendous activity in recent
years, which allows readily available substrates to be con-
verted into diverse carbocyclic or heterocyclic scaffolds with
a significant increase in molecular complexity.[7] Although
inherently apt for asymmetric synthesis, current methods are
mostly based on the principle of a chiral phosphine or car-
bene ligand on the metal center.[8] In this context, the suc-
cessful variant of asymmetric gold catalysis applied to the
cascade or domino reaction has been largely unexplored,
which may result from the fact that enantioselectivity con-
trol in three or more mechanistically distinct reactions in a
consecutive process by one simple gold complex is an ex-
tremely difficult task.[9] Very recently, gold/Brønsted acid
relay catalysis is emerging as an alternative approach for the
creation of new enantioselective transformations (Sche-
me 1a).[10–11] Despite being straightforward, the reported re-
actions have encountered several restrictions: 1) the reaction
type disclosed so far is relatively onefold, in which the gold
catalyst is commonly responsible for the alkyne hydrofunc-
tionalization (hydroamination, hydroxylation, and hydrosi-
loxylation), 2) in most cases, stoichiometric Hantzsch esters
for the asymmetric transfer hydrogenation are required, and
3) the intramolecular cascade version has not been achieved.
Thus the attempted application of this gold/Brønsted acid
relay catalysis strategy to other more various transforma-
Scheme 1. Gold/chiral Brønsted acid catalyzed consecutive transforma-
tions.
tions, especially to those cascade reactions, is highly encour-
aged.
Based on the importance of the spirocyclic scaffold, we
focused our attention on the efficient redox-pinacol-Man-
nich cascade reaction developed by Shin and co-workers
(Scheme 1b).[12] Undoubtedly, ability to control the reaction
enantioselectivity is extremely attractive.[13] If successful,
this would permit facile access to spirocyclic diketones with
contiguous chiral centers, which is still an urgent need for
enantioselective construction of quaternary stereocenters by
using gold catalysts.[8,14] Specifically, it would provide a
redox-, atom-, and step-economic approach to enantiopure
spirocycles by starting from readily available nitrone com-
pounds.
Our exploratory studies began with the first strategy, that
is, using chiral-ligand-derived gold complexes to attempt the
enenatioselective synthesis (Figure 1). Unfortunately, ex-
tremely poor levels of enantioinduction (up to 4% ee; ee=
enantiomeric excess) and low to moderate diastereoselectiv-
ity were obtained when using those privileged chiral ligands
in asymmetric gold catalysis, such as 1,1’-binaphthalene-2,2’-
[a] D. Qian, Prof. J. Zhang
Shanghai Key Laboratory of Green Chemistry
and Chemical Processes, Department of Chemistry
East China Normal University, Shanghai 200062 (P. R. China)
E-mail: jlzhang@chem.ecnu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301208.
6984
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Chem. Eur. J. 2013, 19, 6984 – 6988

COMMUNICATION
Table 1. Screening of reaction conditions.[a]
Figure 1. Chiral ligands for gold(I)-catalyzed reactions.
diylbis
G
((S)-xylylBI-
NAP), (R)-DTBM-MeO-BIPHEP, and (S)-MonoPHOS-
PE.[8,15] The failure is probably due to the linear coordina-
tion geometry of gold(I), which results in the long distance
between the chiral ligand (L*) and the reaction site generat-
ing the stereocenters (Figure 1, IB*).
À
Entry
1
[Au][b]
B* H
T [8C]
t [h]
ee [%][c]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1c
AuCl3
AuCl3
AuCl3
AuCl3
AuCl3
3a
3b
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
3d
3d
3d
3e
3 f
3d
0
À30
0
4
6
2
35
55
67
77
72
59
35
52
n.d.
n.d.
n.d.
83
83
91
91
92
80
60
Careful analysis of the possible mechanism reveals that an
imine intermediate IB might be generated in situ (Sche-
me 1b). With the knowledge that chiral 1,1’-bi-2,2’-naphthol
(BINOL) phosphoric acids (PPAs) have become recognized
as excellent chiral Brønsted acid catalysts to activate imine
substrates for enantioselective addition,[16] we then turned
our attention to the gold/chiral Brønsted acid relay catalysis
strategy,[10–11] that is, chiral PPAs activate the imine inter-
mediates (shown as IC) which accelerate direct Mannich re-
actions in an enantioselective fashion. The key point to war-
rant in our above hypothesis is the difference between the
reaction rates for Mannich addition of IC (k2) promoted by
chiral PPAs and the background reaction of IB (k1) cata-
lyzed by an achiral gold complex leading to the racemic
form (Scheme 1).
À30
À60
À20
À20
À20
À30
À20
À20
À30
À30
À30
À30
À28
À28
À28
À28
2
30
12
24
60
72
96
96
40
40
2
2
4
20
20
24
A
2A
(IPr)]OTf
(PPh3)]OTf
[Au
[Au
9[e]
10[e]
11[e]
12
13
14
[Au(L1)(Me)]
[Au(L1)]OTf
[Au(L1)]BF4
[Au(L1)]SbF6
[Au(L1)]NTf2
[Au(L1)]SbF6
[Au(L1)]SbF6
[Au(L1)]SbF6
[Au(L1)]SbF6
[Au(L1)]SbF6
[Au(L1)]SbF6
15[f]
16[f,g]
17[f,g]
18[f,g]
19[f,g]
78
[a] Reactions were run on a 0.1 mmol scale in 2.0 mL of toluene, 5 ꢁ mo-
lecular sieves (50 mg) were added. Unless specified otherwise, conver-
sions were >99%. [b] AuI catalysts were generated in situ from the
[AuCl(L)] and AgX salts. [c] Determined by chiral HPLC analysis.
[d] Pic=2-picolinate. [e] The conversion was <10%. [f] 4 ꢁ molecular
sieves (50 mg) were used. [g] PhCF3 as the solvent.
With this hypothesis in mind, the asymmetric redox-pina-
col-Mannich cascade reaction of compound 1 in the pres-
ence of various gold complexes and chiral BINOL phos-
phoric acids was investigated as depicted in Table 1. Consis-
tent with our expectations, this combination of gold complex
with BINOL-derived Brønsted acids indeed furnished prom-
ising results. Moreover, the addition of 5 or 4 ꢁ molecular
sieves (MS) resulted in an improvement of ee (see the Sup-
porting Information). Although the reason is yet to be clear,
it is likely that a trace amount of water may compete with
PPA in binding with the imine moiety. Gratifyingly, under
the simple metal salt of AuCl3, the reaction of 1a proceeded
cleanly with excellent diastereoselectivity (diastereomeric
ratio (d.r.)>20:1). It was found that PPA 3b with the elec-
tron-withdrawing aryl groups and the sterically hindered
aryl-substituted catalyst 3c gave moderate enantioselectivity
(55–67% ee; Table 1, entries 2,3). Reaction-temperature
screening showed that À308C was a promising temperature
and lowering the reaction to À608C would not bring further
benefit (entries 3–5). Further investigations of the solvent
effect suggested that the nonpolar toluene was the best sol-
vent for this transformation (see the Supporting Informa-
tion). As for the achiral gold complexes, the role of the
ligand and the counteranion was also examined (entries 6–
13). To our delight, the electron-rich and bulky JohnPhos
ty (83% ee), albeit the reactions required 40 h to be com-
plete (entries 4, 12–13). The lower catalytic activity observed
for [Au(L1)(Me)] (reacting with PPA to give a PPA-derived
gold complex),[11a] [Au(L1)]OTf, and [Au(L1)]BF4 can be ra-
tionalized in terms of the stronger coordinating counteran-
ions (entries 9–11). An excellent ee was obtained in the case
with 1b as the substrate and 3d as the relay catalyst
(91% ee, entry 14). Finally,
a further enhanced result
(92% ee) could be achieved by using trifluorotoluene as the
solvent with longer reaction time (entries 15 vs. 16). Similar-
ly, with phosphoric acids 3e–f as the relay catalysts, no
higher enantiomeric excesses were observed (entries 17–18).
Interestingly, replacing the N-3-CF3-phenyl (1b) with N-3-
Me-phenyl (1c) led to a decrease in the enantioselectivity
(entries 19 vs. 16). All these results suggest that the elec-
tron-withdrawing, sterically demanding CF3 substituent is
beneficial to both the reactivity and enantioselectivity of the
reaction. It is notable that trifluoromethylated arenes are es-
sential structural motifs in a great number of pharmaceuti-
cals, agrochemicals, and organic materials; the introduction
of trifluoromethyl (CF3) into pharmaceuticals can substan-
À
derived cationic gold(I) complexes with either SbF6 or
Tf2NÀ as the counteranion provided higher enantioselectivi-
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6985

J. Zhang and D. Qian
Table 2. Scope of substrates for relay-catalyzed cascade transformation.[a]
nacol rearrangement step. To our delight, this enantioselec-
tive cascade process can be applicable to acyclic gem-dialkyl
substrates, leading to compounds 2q–t with high enantiose-
lectivity. Generally, both electron-withdrawing and -donat-
ing substituents at the C4-position of the aromatic core (1h–
k, 1t) were suitable for this asymmetric relay catalytic reac-
tion (2h–k, 2t). Furthermore, the enantiopurity of 2k and
2s increased to >99% ee after a single recrystallization.
During the investigation of the asymmetric cascade of N-
benzyl-type substrate 1, we found that the corresponding
products 2 underwent racemization at room temperature.
For instance, the enantiomerically enriched 2u (94% ee) in
isopropanol was periodically analyzed by HPLC analysis by
using a chiral stationary phase. Continued analysis of the
solution showed that the ee of 2u was decreasing as shown
in Figure 2. This phenomenon implies that the Mannich ad-
[a] All reactions were preformed with [AuClACTHUNGRTNEUNG(JohnPhos)]/AgSbF6
(5 mol%) and 3d (10 mol%) in PhCF3 at À288C for 2–72 h. Yields are
of materials isolated by silica gel chromatography. G=3-CF3Ph (Boc=
Figure 2. Racemization of 2u.
tert-butoxycarbonyl). [b] ee following
a single recrystallization. [c] A
minor amount of isomers relative to 2r, 2s, and 2t are given in the Sup-
porting Information.
dition is a reversible process in this redox-pinacol-Mannich
cascade reaction. Thus, a suitable N-substituent is also criti-
cal to the successful development of this asymmetric cas-
cade.
tially alter their properties, such as metabolic stability, lipo-
philicity, and ability to penetrate the blood/brain barrier.[17]
The scope of substrates for this relay-catalyzed cascade
transformation was then studied under the optimized condi-
tions (Table 2). In most cases, the reactions proceeded
smoothly to give the desired products 2 in good to high
yields (up to 95%) with up to >99% ee. The chiral spirocy-
clic diketones including five- to nine-membered ring struc-
tures (2b–g) could be well constructed. It is noteworthy that
substrates 1m–o containing heteroatoms within their cyclic
skeletons are also compatible, providing excellent stereo-
chemical outcomes (94–95% ee) and moderate to high
yields. However, the result was frustrated by using 1l as the
substrate, giving a complicated mixture, which indicated that
the chiral PPA may not be involved in the stereoselective pi-
Finally, given the possibility of an exchange of the metal
counteranion with chiral PPA, which could lead to the for-
mation of a gold(I) complex cation-chiral counteranion ion
pair to catalyze this reaction.[18] We conducted control ex-
periments exploiting pure chiral gold phosphorate, derived
from [AuCl(L1)] and chiral silver phosphorate Ag-3d as the
catalyst (Table 3). The reaction with chiral gold phosphorate
was incomplete, with a lower enantioselectivity in compari-
son with the optimized conditions. These outcomes indicate
that 1) the anion of chiral phosphate has a higher coordinat-
À
ing character than [SbF6 ], resulting in a much decreased
catalytic performance of the relative gold complex, 2) the
chiral gold phosphorate, even if it was formed, has little in-
6986
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Chem. Eur. J. 2013, 19, 6984 – 6988

Enantioselective Construction of Spirocyclic Diketones
Table 3. Control experiments.
COMMUNICATION
Acknowledgements
We are grateful to the 973 Program (2011CB808600), Fok Ying Tung Ed-
ucation Foundation (121014), and the Program of Eastern Scholar at
Shanghai Institutions of Higher Learning for financial support.
[Au]
[AuCl(L1)]/AgSbF6
[AuCl(L1)]/AgSbF6
[AuCl(L1)]/Ag-3d[a]
[a]
y [mol%]
t [h]
conv. [%]
ee [%]
U
–
10
–
21
4
52
99
99
30
0
92
68
ACHTUNGTRENNUNG
E
Keywords: asymmetric catalysis · gold · quaternary center ·
relay catalysis · spirocycles
[1] For recent reviews on quaternary carbon centers, see: a) C. J. Doug-
las, L. E. Overman, Proc. Natl. Acad. Sci. USA 2004, 101, 3363; b) J.
Christoffers, A. Baro, Adv. Synth. Catal. 2005, 347, 1473; c) B. M.
Trost, C. Jiang, Synthesis 2006, 369; d) B. Wang, Y. Q. Tu, Acc.
Chem. Res. 2011, 44, 1207.
[2] J.-H. Jang, Y. Asami, J.-P. Jang, S.-O. Kim, D. O. Moon, K.-S. Shin,
D. Hashizume, M. Muroi, T. Saito, H. Oh, B. Y. Kim, H. Osada, J. S.
Ahn, J. Am. Chem. Soc. 2011, 133, 6865.
[3] For a recent enantioselective total synthesis of (À)-acutumine, see:
F. Li, S. S. Tartakoff, S. L. Castle, J. Am. Chem. Soc. 2009, 131, 6674.
[4] a) J.-H. Xie, Q.-L. Zhou, Acc. Chem. Res. 2008, 41, 581; b) K. Ding,
Z. Han, Z. Wang, Chem. Asian J. 2009, 4, 32.
fluence on the enantioselective Mannich addition, and
3) the PPA serves as the real catalyst for the enantiodeter-
mining step (Scheme 1, k2 >k1).
In summary, we have successfully developed a gold/chiral
Brønsted acid as a relay catalysis system for the efficient
highly enantioselective redox-pinacol-Mannich cascade.
Chiral b-amino spirocyclic and quaternary diketone deriva-
tives were obtained in moderate to excellent yields with up
to >99% ee. Critical to the successful development of this
asymmetric transformation is the reaction for Mannich addi-
tion promoted by chiral Brønsted acid superior to the back-
ground reaction catalyzed by gold complexes. The reversible
Mannich step in some substrates makes it very difficult to
obtain high enantioselectivity and the rapid isolation opera-
tion is crucial to address this issue. The CF3 groups on the
structure of the solvent and substrate also bring benefit to
improve enantioselectivity and slow down the racemization
process. Further studies of the detailed mechanism and syn-
thetic applications are under investigation.
[5] For reviews of the synthesis of spirocyclic compounds, see: a) M.
Sannigrahi, Tetrahedron 1999, 55, 9007; b) R. Pradhan, M. Patra,
A. K. Behera, B. K. Mishra, R. K. Behera, Tetrahedron 2006, 62,
779; c) S. Kotha, A. C. Deb, K. Lahiri, E. Manivannan, Synthesis
2009, 165; d) R. Rios, Chem. Soc. Rev. 2012, 41, 1060.
[6] a) X. Tian, K. Jiang, J. Peng, W. Du, Y.-Q. Chen, Org. Lett. 2008, 10,
3583; b) H. Qiu, M. Li, L.-Q. Jiang, F.-P. Lv, L. Zan, C.-W. Zhai,
M. P. Doyle, W.-H. Hu, Nat. Chem. 2012, 4, 733.
[7] For selected reviews on gold catalysis, see: a) A. S. K. Hashmi, G. J.
Hutchings, Angew. Chem. 2006, 118, 8064; Angew. Chem. Int. Ed.
2006, 45, 7896; b) Z. Li, C. Brouwer, C. He, Chem. Rev. 2008, 108,
3239; c) A. Arcadi, Chem. Rev. 2008, 108, 3266; d) A. Fꢂrstner,
Chem. Soc. Rev. 2009, 38, 3208; e) B.-L. Lu, L.-Z. Dai, M. Shi,
Chem. Soc. Rev. 2012, 41, 3318.
[8] For recent reviews on enantioselective gold catalysis, see: a) R. A.
Widenhoefer, Chem. Eur. J. 2008, 14, 5382; b) D. J. Gorin, B. D.
Sherry, F. D. Toste, Chem. Rev. 2008, 108, 3351; c) N. Bongers, N.
Krause, Angew. Chem. 2008, 120, 2208; Angew. Chem. Int. Ed. 2008,
47, 2178; d) S. Sengupta, X. Shi, ChemCatChem 2010, 2, 609;
e) A. S. K. Hashmi, C. Hubbert, Angew. Chem. 2010, 122, 1026;
Angew. Chem. Int. Ed. 2010, 49, 1010; f) A. Pradal, P. Y. Toullec, V.
Michelet, Synthesis 2011, 1501; g) H. G. Raubenheimer, Angew.
Chem. 2012, 124, 5128; Angew. Chem. Int. Ed. 2012, 51, 5042.
[9] For representative examples of gold-catalyzed enantioselective cas-
cade reactions, see: a) S. G. Sethofer, T. Mayer, F. D. Toste, J. Am.
Chem. Soc. 2010, 132, 8276; b) G. Cera, M. Chiarucci, A. Mazzanti,
M. Mancinelli, M. Bandini, Org. Lett. 2012, 14, 1350.
[10] For recent reviews on a combination of metals and chiral phosphoric
acids, see: a) Z. Shao, H. Zhang, Chem. Soc. Rev. 2009, 38, 2745;
b) M. Rueping, R. Koenigs, I. Atodiresei, Chem. Eur. J. 2010, 16,
9350; c) J. Zhou, Chem. Asian J. 2010, 5, 422; d) C. Zhong, X. Shi,
Eur. J. Org. Chem. 2010, 2999; e) N. T. Patil, V. S. Shinde, B. Gajula,
Org. Biomol. Chem. 2012, 10, 211; f) C. C. J. Loh, D. Enders, Chem.
Eur. J. 2012, 18, 10212.
[11] For asymmetric reactions catalyzed by gold/Brønsted acid relay cat-
alysis systems, see: a) Z. Y. Han, H. Xiao, X. H. Chen, L. Z. Gong,
J. Am. Chem. Soc. 2009, 131, 9182; b) X. Y. Liu, C. M. Che, Org.
Lett. 2009, 11, 4204; c) C. Wang, Z. Y. Han, H. W. Luo, L. Z. Gong,
Org. Lett. 2010, 12, 2266; d) Z.-Y. Han, R. Guo, P.-S. Wang, D.-F.
Chen, H. Xiao, L. Z. Gong, Tetrahedron Lett. 2011, 52, 5963; e) Z.-
Y. Han, D.-F. Chen, Y.-Y. Wang, R. Guo, P.-S. Wang, C. Wang, L. Z.
Gong, J. Am. Chem. Soc. 2012, 134, 6532; f) N. T. Patil, A. K. Mu-
tyala, A. Konala, R. B. Tella, Chem. Commun. 2012, 48, 3094; g) H.
Wu, Y.-P. He, L. Z. Gong, Org. Lett. 2013, 15, 460.
Experimental Section
General: In a sealed dry glass tube, [AuClACTHNUTRGNE(NUG JohnPhos)] (0.005 mmol,
5 mmol%) and AgSbF6 (0.005 mmol, 5 mmol%) under an argon atmos-
phere were taken up in trifluorotoluene (0.01m based on substrate) and
stirred at RT for 13 min. In another sealed dry glass tube, a solution of
chiral PPA 3d (0.01 mmol), nitrone-tethered tertiary propargyl alcohol 1
(0.1 mmol), and 4 ꢁ molecular sieves (50 mg) in trifluorotoluene
(1.5 mL) under an argon atmosphere was cooled to À288C for 15 min.
The gold catalyst solution (0.5 mL) was quickly transferred to the sub-
strate solution and the reaction was kept with stirring at À288C for 2–
72 h. The resulting mixture was quenched with three drops of Et3N (ca.
150 mL), diluted with AcOEt, and filtered through a pad of Celite. The
filtrate was concentrated in vacuo to give a residue, which was purified
by column chromatography on Et3N deactivated silica (hexanes/AcOEt
20:1 to hexanes/AcOEt 4:1) to yield the corresponding product 2.
Chem. Eur. J. 2013, 19, 6984 – 6988
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J. Zhang and D. Qian
[12] a) H.-S. Yeom, Y. Lee, J. Jeong, E. So, S. Hwang, J.-E. Lee, S. S. Lee,
S. Shin, Angew. Chem. 2010, 122, 1655; Angew. Chem. Int. Ed. 2010,
49, 1611.
[15] See the Supporting Information for full details on the screening of
conditions, such as different chiral ligands, gold complexes, solvents,
and additives.
[13] For our work on enantioselective gold catalysis, see: a) F. Liu, D.
Qian, L. Li, X. Zhao, J. Zhang, Angew. Chem. 2010, 122, 6819;
Angew. Chem. Int. Ed. 2010, 49, 6669; b) G. Zhou, F. Liu, J. Zhang,
Chem. Eur. J. 2011, 17, 3101; c) Y. Zhang, J. Zhang, Chem.
Commun. 2012, 48, 4710.
[14] For selected examples on the construction of quaternary carbon cen-
ters using chiral gold complexes, see: a) I. D. G. Uemura, M.
Watson, M. Katsukawa, F. D. Toste, J. Am. Chem. Soc. 2009, 131,
3464; b) F. Kleinbeck, F. D. Toste, J. Am. Chem. Soc. 2009, 131,
9178; c) A. D. Melhado, G. W. Amarante, Z. J. Wang, M. Luparia,
F. D. Toste, J. Am. Chem. Soc. 2011, 133, 3517; d) H. Teller, M.
Corbet, L. Mantilli, G. Gopakumar, R. Goddard, W. Thiel, A. Fꢂrst-
ner, J. Am. Chem. Soc. 2012, 134, 15331; e) A. K. Mourad, J. Leut-
zow, C. Czekelius, Angew. Chem. 2012, 124, 11311; Angew. Chem.
Int. Ed. 2012, 51, 11149.
[16] For seminal studies of chiral phosphoric acid catalysts, see: a) T.
Akiyama, J. Itoh, K. Yokota, K. Fuchibe, Angew. Chem. 2004, 116,
1592; Angew. Chem. Int. Ed. 2004, 43, 1566; b) D. Uraguchi, M.
Terada, J. Am. Chem. Soc. 2004, 126, 5356.
[17] a) K. Mꢂller, C. Faeh, F. Diederich, Science 2007, 317, 1881; b) W. K.
Hagmann, J. Med. Chem. 2008, 51, 4359; c) T. Furuya, A. S. Kamlet,
T. Ritter, Nature 2011, 473, 470.
[18] a) G. L. Hamilton, E. J. Kang, M. Mba, F. D. Toste, Science 2007,
317, 496; For recent reviews, see: b) R. J. Phipps, G. L. Hamilton,
F. D. Toste, Nat. Chem. 2012, 4, 603; c) M. Mahlau, B. List, Angew.
Chem. 2013, 125, 540; Angew. Chem. Int. Ed. 2013, 52, 518.
Received: March 30, 2013
Published online: April 22, 2013
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