Enantioselective oxidative gold catalysis enabled by a designed chiral P,N-bidentate ligand

Article abstract of DOI:10.1002/anie.201409300

A newly developed P,N-bidentate ligand enables enantioselective intramolecular cyclopropanation by a reactive α-oxo gold carbene intermediate generated in situ. The ligand design is based on our previously proposed structure (with a well-organized triscoordinated gold center) of the carbene intermediate in the presence of a P,N-bidentate ligand. A C₂-symmetric piperidine ring was incorporated in the ligand as the nitrogen-containing moiety. A range of racemic transformations of α-oxo gold carbene intermediates have been developed recently, and this new class of chiral ligands could enable their modification for asymmetric synthesis, as demonstrated in this study.

Full text of DOI:10.1002/anie.201409300

Angewandte
Chemie
DOI: 10.1002/anie.201409300
Asymmetric Catalysis
Enantioselective Oxidative Gold Catalysis Enabled by a Designed
Chiral P,N-Bidentate Ligand**
Kegong Ji, Zhitong Zheng, Zhixun Wang, and Liming Zhang*
Abstract: A newly developed P,N-bidentate ligand enables
enantioselective intramolecular cyclopropanation by a reactive
a-oxo gold carbene intermediate generated in situ. The ligand
design is based on our previously proposed structure (with
a well-organized triscoordinated gold center) of the carbene
intermediate in the presence of a P,N-bidentate ligand. A C2-
symmetric piperidine ring was incorporated in the ligand as the
nitrogen-containing moiety. A range of racemic transforma-
tions of a-oxo gold carbene intermediates have been developed
recently, and this new class of chiral ligands could enable their
modification for asymmetric synthesis, as demonstrated in this
study.
T
he gold-catalyzed intermolecular oxidation of alkynes[1] has
become an increasingly popular approach to the formation of
highly electrophilic a-oxo gold carbene intermediates since
our first report in 2010[2] (Scheme 1a). This strategy permits
the ready exploration of these reactive intermediates without
the use of hazardous and potentially explosive diazoketone
precursors.[3,4] Although various methods[2,5,6] have been
developed on the basis of this general strategy, a glaring
deficiency[7] in this rapidly evolving area is that the only
known enantioselective example afforded the product with
just 18% ee[8] despite success in a range of other enantio-
selective gold-catalyzed reactions.[4h,9] Herein we report
a successful case of enantioselective intramolecular cyclo-
propanation enabled by a newly designed chiral P,N-bidentate
ligand.
Scheme 1. a) Oxidative gold catalysis: facile access to a-oxo gold
carbenes without the use of diazo compounds. b) A P,N-bidentate
ligand tempers the reactivity of the carbene and enables intermolecular
trapping and intramolecular cyclopropanation reactions. Ad=adaman-
tanyl, Ms=methanesulfonyl.
[14]
À
ered C C double bonds (Scheme 1b). Notably, in the last
three cases, a modified P,N-bidentate ligand[5a,14] or a P,S-
bidentate ligand[13] was used as the optimal metal ligand. The
structure of a-oxo gold carbene intermediates of type A with
a triscoordinated metal center is supported by DFT calcu-
lations[5c] and offers a well-organized reaction site for the
design of chiral ligands for their asymmetric trapping and
consequently enantioselective oxidative gold catalysis.
We reasoned that by installing a C2-symmetric chiral
N heterocycle as the N-containing component of the biden-
tate ligand, a largely C2-symmetric chiral pocket could be
created around the gold carbene center (Scheme 2a). In this
way, its enantioselective transformation might be possible. To
reduce this idea to practice while securing flexible access to
a range of ligands, we chose (3S,4S)-3,4-dihydroxypyrroli-
dine[15] and (3R,5R)-3,5-dihydroxypiperidine[16] as the chiral
N-heterocyclic platforms, both of which are readily available.
The corresponding P,N-bidentate ligands with variably
capped hydroxy groups were readily synthesized (see the
Supporting Information), and selected examples are shown in
Scheme 2b.
In comparison to their rhodium counterparts,[3] a-oxo gold
carbenes tend to be more electrophilic.[10] In 2012, we
reported that P,N-bidentate ligands, such as Mor-DalPhos,[11]
could temper the electrophilicity of the carbene center
through the formation of a triscoordinated gold complex
(i.e. A in the case of Mor-DalPhos, Scheme 1b) by the
coordination of both the P and the N atom of the bidentate
ligand.[5c] As a result, the intermolecular trapping of a-oxo
gold carbenes is possible with carboxamides,[5c] MsOH,[12]
carboxylic acids,[5a] allyl sulfides,[13] and rather flexibly teth-
[*] Dr. K. Ji,[+] Z. Zheng, Z. Wang, Prof. Dr. L. Zhang
Department of Chemistry and Biochemistry, University of California
Santa Barbara, CA (USA)
E-mail: zhang@chem.ucsb.edu
Homepage: http://www.chem.ucsb.edu/~zhang/index.html
[+] Current address: College of Science, Northwest A&F University
3 Taicheng Road, Yangling 712100, Shaanxi (China)
We chose the cyclopropanation reaction previously devel-
oped by Liu and co-workers[6e] to develop the intended
enantioselective oxidative gold catalysis. Specifically, ethyl
(E)-3-(2-ethynylphenyl)acrylate (1a), readily accessible from
[**] This research is supported financially by the NIH (R01 GM084254).
L.Z. thanks Prof. Kuiling Ding for providing the chiral ligand L10.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201409300.
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Table 1: Optimization of the reaction conditions for the enantioselective
gold-catalyzed oxidative cyclopropanation.[a]
Entry
L
Conditions
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
L2
L2
DCE, RT, 2 h
DCE, RT, 2 h
DCE, RT, 2 h
DCE, RT, 2 h
DCE, RT, 2 h
DCE, RT, 2 h
DCE, RT, 2 h
DCE, RT, 2 h
DCE, RT, 2 h
DCE, RT, 2 h
DCE, RT, 2 h
DCE, 08C, 12 h
DCE, À208C, 50 h
78
78
74
73
78
62
78
56
78
NR
63
86
85
52
50
23
86
73
3
–
–
90
94
Scheme 2. P,N-bidentate ligands: a) design; b) selected ligands.
Bz=benzoyl, TBS=tert-butyldimethylsilyl, TES=triethylsilyl,
TIPS=triisopropylsilyl.
[c]
–
2-bromobenzaldehyde,[6e] was used as the substrate. In the
original study[6e] the desired product 3a was obtained in 67%
yield using [IPrAuNTf2] (5 mol%, generated in situ from
70
68 (61)[d]
[a] The yield was determined by 1H NMR spectroscopy using diethyl
phthalate as the internal reference. [b] The ee value was determined by
HPLC on a chiral stationary phase. [c] No desired product was observed
in the crude 1H NMR spectrum. [d] The yield of the isolated product is
given in parentheses.
[IPrAuCl]/AgNTf2;
IPr= N,N’-bis(2,6-
diisopropylphenyl)imidazol-2-ylidene) as the catalyst, 8-
methylquinoline N-oxide (2, 3 equiv) as the oxidant, and
1,2-dichloroethene (DCE) as the solvent and carrying out the
reaction at 808C for 3 h. When the ligand L1 with a bis-TBS-
protected (3S,4S)-3,4-dihydroxypyrrolidine moiety was used,
3a was formed in 78% yield and with an encouraging 63% ee
(Table 1, entry 1). The shown absolute configuration of the
major enantiomer of the product was assigned on the basis of
X-ray diffraction studies of analogues (see below). Notably,
the reaction conditions—the use of 1.5 equivalents of 2 at
ambient temperature—are much milder than those required
for the use of IPr as the ligand, which is consistent with the
previously observed benefits of using P,N-bidentate ligands in
a-oxo gold carbene chemistry.[5a,c,12–14]
After attempts to improve enantioselectivity by replacing
the TBS groups of L1 with other protecting groups were
unsuccessful, we reasoned that (3R,5R)-3,5-dihydroxypiper-
idine, which is based on a conformationally more controllable
six-membered ring, might offer a better platform for ligand
optimization. Thus, the corresponding bis-TBS-substituted
ligand L2 was tested in the reaction. Indeed, the ee value of 3a
improved to 86% (Table 1, entry 2). When the TBS groups of
L2 were replaced with TES groups in L3, little change in
enantioselectivity was detected (Table 1, entry 3). However,
the presence of both bigger TIPS groups and much smaller
Me groups led to significantly decreased enantioselectivity
(Table 1, entries 4 and 5). An even lower ee value of 3a was
observed when the HO groups of the ligand piperidine ring
were converted into benzoate groups in L6 (Table 1, entry 6).
The introduction of a MeO group para to the phosphorus
atom in L2 resulted in the ligand L7, the use of which,
however, led to essentially the same outcome (Table 1,
entry 7). Interestingly, ligand L8 with one TBS group
removed still enabled fairly good enantioselectivity (Table 1,
entry 8): notably better than that observed with the dime-
thoxy ligand L5. Finally, the sterically much smaller diphe-
nylphosphine ligand L9, although still leading to an efficient
intramolecular cyclopropanation, was very poor in promoting
alkene facial selectivity during the reaction (Table 1, entry 9),
thus indicating the importance of the bulky adamantyl groups
in enforcing a tight reaction site for the asymmetric cyclo-
propanation. In contrast to the chiral P,N-ligands, the
spiroketal bisphosphine ligand L10 (Table 1, entry 10),
which was used successfully in gold-catalyzed, highly enan-
tioselective cyclopropanation reactions with diazooxindole
substrates,[4h] and (R)-DTBM-segphos (entry 11), a popular
ligand for asymmetric gold catalysis,[9a,b] did not facilitate the
desired oxidative gold catalysis under the identical reaction
conditions used. The ee value of the product was further
improved by lowering the reaction temperature to 08C
(Table 1, entry 12) and further to À208C (entry 13), albeit at
the expense of the yield and reaction time. Notably, the
reaction temperature of À208C in the last entry is much lower
than the originally used 808C.[6e]
Having optimized the reaction conditions for the highest
possible enantioselectivity (Table 1, entry 13), we subse-
quently examined the reaction scope (Scheme 3). We found
that substituents on the benzene ring were tolerated (products
3b–e). Specifically, a 5-Me group did not affect the reaction
outcome significantly (product 3b). The presence of electron-
withdrawing groups, such as 5-F, 5-CF3, and 4-Cl (products
3c–e), resulted in decreased but serviceable yields, whereas
the ee value of the products remained good to excellent. The
presence of a 4-MeO group, however, resulted in mostly
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or benzoyl group led to a comparable outcome in the former
case (product 3g) and a higher yield in the latter case (product
3h), despite the expectation that the cyclopropanation
reaction should prefer more electron rich double bonds (see
below). These results are indicative of the highly electrophilic
nature of the even tempered gold carbene intermediates.[5c]
Besides the use of an arene ring to closely position the
ethynyl group and an electron-deficient alkene, cyclic alkenes
were also suited for this purpose. Reactions of the corre-
sponding substrates were slower, as reflected by higher
catalyst loadings (7.5%), a higher temperature, and a longer
reaction times, but significantly cleaner, with yields above
80%, and the enantioselectivity remained good (Scheme 3,
products 3i–k). An acyclic yne–dienoate substrate with a fully
substituted tethering alkene reacted equally well, and 3l was
isolated in 81% yield with 88% ee. However, reactions of
similar substrates with less substituted tethering alkenes led
to poor results (data not shown). In comparison to reactions
of substrates possessing electron-poor alkenes, reactions of
those containing normal alkenes resulted in much higher
yields but notably lower yet still mostly good ee values
(products 3m–o). This phenomenon is expected, as more
reactive alkenes are capable of trapping the reactive gold
carbene more efficiently, and an earlier and hence less
compact cyclopropanation transition state could account for
observed decreased asymmetric induction by the chiral
ligand.
When a methyl substituent was present at the b position to
the ester group of 1a, the reaction proceeded well, but the
ee value of the product 3p was very poor (Scheme 3). In
contrast, the regioisomeric substrate 1q, which has a a-Me
group and was prepared as an inseparable mixture of
geometric isomers (E/Z 5:1), was converted into the separa-
ble cyclopropane diastereomers 3q and 3q’ in an almost
identical ratio and in 91% combined yield, thus indicating
that the cyclopropanation is concerted and stereospecific.
Moreover, the ee value of 3q, which was formed from the
E isomer, was 93%, and higher than that of 3q’, formed from
the Z isomer. In comparison to the reaction of 1a, the
excellent yield in this case could be attributed to the increased
À
electron density of the C C double bond and the conforma-
tion control offered by the Me group (e.g., forcing the
diconjugation of the benzene ring and the enoate moiety in
order to avoid A1,3 strain). The beneficial impact of an a-Me
group as revealed by this case prompted us to examine
a related phenone substrate. The oxidative cyclopropanation
proceeded well to give product 3r in 82% yield with excellent
enantioselectivity (93% ee).
The absolute configurations of the cyclopropanation
products were established on the basis of single-crystal X-
ray diffraction studies[17] of 3e and 3g. Both products were
found to have the 1R,1aS,6aR configuration (Figure 1a). The
stereochemical outcome of the reaction could be rationalized,
although in depth DFT calculations might provide detailed
understanding of the cyclopropanation mechanism and the
factors controlling facial selectivity. As outlined in Figure 1b,
the chiral ligand coordinates to the metal center of the a-oxo
gold carbene as a bidentate ligand, and the axial TBSO group
on the ligand piperidine ring shields the Re face of the
Scheme 3. Reaction scope. Reactions were carried out in vials. Yields
given are for the isolated product. [a] The reaction was carried out with
[L2AuCl] (7.5 mol%) and NaBARF (15 mol%). [b] The reaction was
carried out at 08C. Toluene was used as the solvent. NaBARF=sodium
tetrakis(3,5-bis(trifluoromethyl)phenyl)borate.
double oxidation. A better 70% yield was observed with
a naphthalene-based substrate, and the isolated product 3 f
had 90% ee. Somewhat to our surprise, the replacement of
the ester group in 1a with a more electron withdrawing acetyl
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carbene intermediates have recently been developed, this
new class of chiral ligands could usher in a new and
synthetically highly valuable phase of exploiting these versa-
tile intermediates in asymmetric synthesis.
Received: September 19, 2014
Published online: && &&, &&&&
Keywords: asymmetric catalysis · carbenes · cyclopropanation ·
.
gold · oxidation
[1] L. Zhang, Acc. Chem. Res. 2014, 47, 877 – 888.
[2] L. Ye, L. Cui, G. Zhang, L. Zhang, J. Am. Chem. Soc. 2010, 132,
3258 – 3259.
[3] M. P. Doyle, M. A. McKervey, T. Ye, Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds: From Cyclo-
propanes to Ylides, Wiley, New York, 1998.
[4] For examples of gold catalysis involving the use of diazo
compounds, see: a) M. R. Fructos, T. R. Belderrain, P. de Frꢀ-
mont, N. M. Scott, S. P. Nolan, M. M. Dꢁaz-Requejo, P. J. Pꢀrez,
Angew. Chem. Int. Ed. 2005, 44, 5284 – 5288; Angew. Chem.
2005, 117, 5418 – 5422; b) A. Prieto, M. R. Fructos, M. M. Dꢁaz-
Requejo, P. J. Pꢀrez, P. Pꢀrez-Galꢂn, N. Delpont, A. M. Echa-
varren, Tetrahedron 2009, 65, 1790 – 1793; c) S. K. Pawar, C.-D.
Wang, S. Bhunia, A. M. Jadhav, R.-S. Liu, Angew. Chem. Int. Ed.
2013, 52, 7559 – 7563; Angew. Chem. 2013, 125, 7707 – 7711;
d) V. V. Pagar, A. M. Jadhav, R.-S. Liu, J. Org. Chem. 2013, 78,
5711 – 5716; e) A. M. Jadhav, V. V. Pagar, R.-S. Liu, Angew.
Chem. Int. Ed. 2012, 51, 11809 – 11813; Angew. Chem. 2012, 124,
11979 – 11983; f) Z. Yu, B. Ma, M. Chen, H.-H. Wu, L. Liu, J.
Zhang, J. Am. Chem. Soc. 2014, 136, 6904 – 6907; g) J. F. Briones,
H. M. L. Davies, J. Am. Chem. Soc. 2012, 134, 11916 – 11919;
h) Z.-Y. Cao, X. Wang, C. Tan, X.-L. Zhao, J. Zhou, K. Ding, J.
Am. Chem. Soc. 2013, 135, 8197 – 8200.
[5] For selected examples reported by our research group, see: a) K.
Ji, Y. Zhao, L. Zhang, Angew. Chem. Int. Ed. 2013, 52, 6508 –
6512; Angew. Chem. 2013, 125, 6636 – 6640; b) Y. Wang, K. Ji, S.
Lan, L. Zhang, Angew. Chem. Int. Ed. 2012, 51, 1915 – 1918;
Angew. Chem. 2012, 124, 1951 – 1954; c) Y. Luo, K. Ji, Y. Li, L.
Zhang, J. Am. Chem. Soc. 2012, 134, 17412 – 17415; d) L. Ye, W.
He, L. Zhang, Angew. Chem. Int. Ed. 2011, 50, 3236 – 3239;
Angew. Chem. 2011, 123, 3294 – 3297; e) W. He, C. Li, L. Zhang,
J. Am. Chem. Soc. 2011, 133, 8482 – 8485; f) L. Ye, W. He, L.
Zhang, J. Am. Chem. Soc. 2010, 132, 8550 – 8551; g) B. Lu, C. Li,
L. Zhang, J. Am. Chem. Soc. 2010, 132, 14070 – 14072.
[6] For examples reported by others, see: a) C.-W. Li, G.-Y. Lin, R.-
S. Liu, Chem. Eur. J. 2010, 16, 5803 – 5811; b) C.-W. Li, K. Pati,
G.-Y. Lin, S. M. A. Sohel, H.-H. Hung, R.-S. Liu, Angew. Chem.
Int. Ed. 2010, 49, 9891 – 9894; Angew. Chem. 2010, 122, 10087 –
10090; c) R. B. Dateer, K. Pati, R.-S. Liu, Chem. Commun. 2012,
48, 7200 – 7202; d) S. Ghorpade, M.-D. Su, R.-S. Liu, Angew.
Chem. Int. Ed. 2013, 52, 4229 – 4234; Angew. Chem. 2013, 125,
4323 – 4328; e) D. Vasu, H.-H. Hung, S. Bhunia, S. A. Gawade,
A. Das, R.-S. Liu, Angew. Chem. Int. Ed. 2011, 50, 6911 – 6914;
Angew. Chem. 2011, 123, 7043 – 7046; f) S. Bhunia, S. Ghorpade,
D. B. Huple, R.-S. Liu, Angew. Chem. Int. Ed. 2012, 51, 2939 –
2942; Angew. Chem. 2012, 124, 2993 – 2996; g) D. Qian, J. Zhang,
Chem. Commun. 2012, 48, 7082 – 7084; h) D. Qian, J. Zhang,
Chem. Eur. J. 2013, 19, 6984 – 6988; i) D. Qian, J. Zhang, Chem.
Commun. 2011, 47, 11152 – 11154; j) P. W. Davies, S. J. C.
Albrecht, Angew. Chem. Int. Ed. 2009, 48, 8372 – 8375; Angew.
Chem. 2009, 121, 8522 – 8525; k) P. W. Davies, Pure Appl. Chem.
2010, 82, 1537 – 1544; l) P. W. Davies, A. Cremonesi, N. Martin,
Chem. Commun. 2011, 47, 379 – 381; m) G. Henrion, T. E. J.
Chavas, X. Le Goff, F. Gagosz, Angew. Chem. Int. Ed. 2013, 52,
Figure 1. a) Structures of 3e and 3g with the absolute configuration
established by single-crystal diffraction studies. b) Rationale for the
observed enantioselectivity. c) Structures of l-glutamic acid and
LY354740 (which can be synthesized from 4).
carbene center from alkene attack (as in B); consequently, its
Si face is open for the ensuing alkene cyclopropanation (as
shown in A), thereby leading to the predominant enantiomer.
This enantioselective gold-catalyzed oxidative cyclopro-
panation could facilitate access to novel constrained ana-
logues of l-glutamic acid, the principal excitatory amino acid
neurotransmitter in the human central nervous system (CNS).
Structural mimicry of bioactive conformations of this amino
acid can lead to high potency and target selectivity. For
example, LY354740 is an exceptionally potent agonist for
group 2 metabotropic glutamate receptors[18] and has been
implicated as a potential agent for the treatment of various
CNS diseases (Figure 1c);[19] however, its asymmetric syn-
thesis has been limited to inefficient resolution,[20] a rather
lengthy chiral-pool approach,[21] and approaches showing
poor diastereoselectivity[22] (in one case, separation from four
diastereomers).[22b] Since LY354740 can be readily accessed
from the bicyclic cyclopentenone 4, which is embedded in the
structures prepared in this study, this gold catalysis would
offer asymmetric access to substituted analogues[23] of
LY354740.
In summary, we have described an enantioselective
oxidative gold catalysis, in which a novel P,N-bidentate
ligand enables reactive a-oxo gold carbene intermediates
generated in situ to undergo asymmetric intramolecular
cyclopropanation. The design of the ligand relies on our
previously proposed structure (with a well-organized tris-
coordinated gold center) of the carbene intermediate in the
presence of a P,N-bidentate ligand. The ligand was con-
structed by incorporating a C2-symmetric 3,5-bissiloxylated
piperidine ring as the nitrogen-containing moiety. The gold-
catalyzed reaction provides facile access to bicyclic cyclo-
propane products with mostly good to excellent ee values.
Since a large array of racemic transformations of a-oxo gold
4
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Angewandte
Chemie
6277 – 6282; Angew. Chem. 2013, 125, 6397 – 6402; n) M. Xu, T.-
T. Ren, C.-Y. Li, Org. Lett. 2012, 14, 4902 – 4905; o) T. Wang, S.
Shi, M. M. Hansmann, E. Rettenmeier, M. Rudolph, A. S. K.
Hashmi, Angew. Chem. Int. Ed. 2014, 53, 3715 – 3719; Angew.
Chem. 2014, 126, 3934 – 3939; p) A. S. K. Hashmi, T. Wang, S.
Shi, M. Rudolph, J. Org. Chem. 2012, 77, 7761 – 7767; q) S. Shi, T.
Wang, W. Yang, M. Rudolph, A. S. K. Hashmi, Chem. Eur. J.
2013, 19, 6576 – 6580.
D. Vourloumis, V. E. Gregor, G. Winters, T. Hermann, B. Ayida,
Z. Sun, D. Murphy, K. B. Simonsen, WO2005028467A1, 2005.
[17] 3e: CCDC 1030194; 3g: 1030188.
[18] D. D. Schoepp, B. G. Johnson, R. A. Wright, C. R. Salhoff, N. G.
Mayne, S. Wu, S. L. Cockerham, J. P. Burnett, R. Belegaje, D.
Bleakman, J. A. Monn, Neuropharmacology 1997, 36, 1 – 11.
[19] a) J. C. Gewirtz, A. C. Chen, R. Terwilliger, R. C. Duman, G. J.
Marek, Pharmacol. Biochem. Behav. 2002, 73, 317 – 326; b) R. X.
Moldrich, M. Jeffrey, A. Talebi, P. M. Beart, A. G. Chapman,
B. S. Meldrum, Neuropharmacology 2001, 41, 8 – 18; c) A.
[7] While this mansucript was under review, a related study was
published: D. Qian, H. Hu, F. Liu, B. Tang, W. Ye, Y. Wang, J.
Zhang, Angew. Chem. Int. Ed. 2014, DOI: 10.1002/
anie.201407717; Angew. Chem. 2014, DOI: 10.1002/
ange.201407717.
´
Kłodzinska, M. Bijak, E. Chojnacka-Wꢃjcik, B. Kroczka, M.
´
Swia˛der, S. J. Czuczwar, A. Pilc, Naunyn-Schmiedeberg’s Arch.
Pharmacol. 2000, 361, 283 – 288; d) S. R. Bradley, M. J. Marino,
M. Wittmann, S. T. Rouse, H. Awad, A. I. Levey, P. J. Conn, J.
Neurosci. 2000, 20, 3085 – 3094; e) J. Konieczny, K. Ossowska, S.
Wolfarth, A. Pilc, Naunyn-Schmiedeberg’s Arch. Pharmacol.
1998, 358, 500 – 502.
[8] D. B. Huple, S. Ghorpade, R.-S. Liu, Chem. Eur. J. 2013, 19,
12965 – 12969.
[9] For reviews on enantioselective gold catalysis, see: a) A. Pradal,
P. Y. Toullec, V. Michelet, Synthesis 2011, 1501 – 1514; b) S.
Sengupta, X. Shi, ChemCatChem 2010, 2, 609 – 619; c) Y.-M.
Wang, A. D. Lackner, F. D. Toste, Acc. Chem. Res. 2014, 47, 889 –
901.
[10] W. He, L. Xie, Y. Xu, J. Xiang, L. Zhang, Org. Biomol. Chem.
2012, 10, 3168 – 3171.
[11] R. J. Lundgren, B. D. Peters, P. G. Alsabeh, M. Stradiotto,
Angew. Chem. Int. Ed. 2010, 49, 4071 – 4074; Angew. Chem.
2010, 122, 4165 – 4168.
[20] J. A. Monn, M. J. Valli, S. M. Massey, R. A. Wright, C. R.
Salhoff, B. G. Johnson, T. Howe, C. A. Alt, G. A. Rhodes, R. L.
Robey, K. R. Griffey, J. P. Tizzano, M. J. Kallman, D. R. Helton,
D. D. Schoepp, J. Med. Chem. 1997, 40, 528 – 537.
[21] C. Domꢁnguez, J. Ezquerra, L. Prieto, M. Espada, C. Pedregal,
Tetrahedron: Asymmetry 1997, 8, 511 – 514.
[22] a) V. K. Aggarwal, E. Grange, Chem. Eur. J. 2006, 12, 568 – 575;
´
b) J. Krysiak, W. H. Midura, W. Wieczorek, L. Sieron, M.
[12] G. Wu, R. Zheng, J. Nelson, L. Zhang, Adv. Synth. Catal. 2014,
356, 1229 – 1234.
[13] J. Li, K. Ji, R. Zheng, J. Nelson, L. Zhang, Chem. Commun. 2014,
50, 4130 – 4133.
[14] K. Ji, L. Zhang, Org. Chem. Front. 2014, 1, 34 – 38.
[15] R. Łysek, P. Vogel, Helv. Chim. Acta 2004, 87, 3167 – 3181.
[16] For the preparation of 3,5-diaminopiperidine-substituted (het-
ero)aromatic compounds as antibacterial agents, see: Y. Zhou,
Mikołajczyk, Tetrahedron: Asymmetry 2010, 21, 1486 – 1493.
[23] a) A. Nakazato, K. Sakagami, A. Yasuhara, H. Ohta, R.
Yoshikawa, M. Itoh, M. Nakamura, S. Chaki, J. Med. Chem.
2004, 47, 4570 – 4587; b) C. Pedregal, W. Prowse, Bioorg. Med.
Chem. 2002, 10, 433 – 436; c) T. J. Woltering, G. Adam, P.
Huguenin, J. Wichmann, S. Kolczewski, S. Gatti, A. Bourson,
J. N. C. Kew, G. Richards, J. A. Kemp, V. Mutel, F. Knoflach,
ChemMedChem 2008, 3, 323 – 335.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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These are not the final page numbers!

.
Angewandte
Communications
Communications
Asymmetric Catalysis
K. Ji, Z. Zheng, Z. Wang,
L. Zhang*
&&&& — &&&&
Enantioselective Oxidative Gold Catalysis
Enabled by a Designed Chiral P,N-
Bidentate Ligand
Giving gold a new shine: A chiral P,N-
bidentate ligand containing a C2-sym-
metric piperidine ring enabled enantio-
selective intramolecular cyclopropana-
tion by an a-oxo gold carbene intermedi-
ate generated in situ (see scheme; Ad=
adamantyl). The ligand design is based
on the well-organized triscoordinated
gold center in a previously proposed
structure of the carbene intermediate in
the presence of a P,N-bidentate ligand.
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!