Gold I-catalyzed highly diastereo- and enantioselective alkyne oxidation/cyclopropanation of 1,6-enynes

Article abstract of DOI:10.1002/anie.201407717

A highly enantioselective oxidative cyclo-propanation of 1,6-enynes catalyzed by cationic Au^I/ chiral phophoramidite complexes is presented. The new method provides convenient access to densely functionalized bicyclo[3.1.0]hexanes bearing three contiguous quaternary and tertiary stereogenic centers with high enantioselectivity (up to e.r. 98:2). Control experiments suggest that the quinoline moiety of the b-gold vinyloxyquinolinium intermediate in the reaction plays an important role in promoting good enantiose-lectivity through a transitional auxiliary effect in the transition state.

Full text of DOI:10.1002/anie.201407717

Angewandte
Chemie
DOI: 10.1002/anie.201407717
Asymmetric Catalysis
Gold(I)-Catalyzed Highly Diastereo- and Enantioselective Alkyne
Oxidation/Cyclopropanation of 1,6-Enynes**
Deyun Qian, Haoxiang Hu, Feng Liu, Bin Tang, Weimin Ye, Yidong Wang, and Junliang Zhang*
Abstract: A highly enantioselective oxidative cyclo-
propanation of 1,6-enynes catalyzed by cationic AuI/
chiral phophoramidite complexes is presented. The
new method provides convenient access to densely
functionalized bicyclo[3.1.0]hexanes bearing three
contiguous quaternary and tertiary stereogenic centers
with high enantioselectivity (up to e.r. 98:2). Control
experiments suggest that the quinoline moiety of the b-
gold vinyloxyquinolinium intermediate in the reaction
plays an important role in promoting good enantiose-
lectivity through a transitional auxiliary effect in the
transition state.
A
symmetric cyclopropanation (ACP) of olefins with
metallocarbenes serves as a bedrock for synthetic
chemistry.[1] In this context, the intramolecular ACP
reaction of linear unsaturated diazo precursors for the
stereoselective construction of [n.1.0]bicyclic ring
systems has recently attracted renewed attention
owing to its fundamental scientific interest and
daunting challenge.[1–6] Over the years, remarkable
Scheme 1. Intramolecular cyclopropanation of enynes by gold(I)-catalyzed alkyne
oxidation for the asymmetric synthesis of bicyclo[3.1.0]hexanes, and examples of
compounds containing a bicyclo[3.1.0]hexane ring system. EWG=electron-with-
drawing group.
progress has been described in the formation of optically
active 3-oxa- and 3-azabicyclo[3.1.0]hexane derivatives.[1,2]
More recently, P. Zhang and co-workers successfully devel-
oped an intramolecular ACP reaction leading to 3-
oxabicyclo[3.1.0]hexanes with diverse substituents by the
application of chiral cobalt(II)–porphyrin complexes as
metalloradical catalysts.[3] In contrast, highly catalytic ACP
reactions with metal carbenoids for the synthesis of bicyclo-
[3.1.0]hexanes, in particular those containing a challenging
all-carbon quaternary stereocenter,[4] remain comparatively
rare,[5] although such enantiomerically enriched skeletons are
tremendously important because of their wide occurrence in
bioactive natural products, pharmaceuticals, and conforma-
tionally restricted biological probes as well as their versatility
in organic synthesis as chiral building blocks (Scheme 1,
bottom).[5e,6] Thus, a new and complementary approach that
enables fast access to such architectures with multifunction-
alized stereocenters is still in great demand.
Gold carbenoids, that is, gold carbenes and/or gold-
stabilized carbocations, are promising candidates for the
ACP reaction and provide complementarity and orthogon-
ality to other traditional-metal carbenoids (e.g., Rh) in that
they display increased electrophilicity and are less sterically
demanding than their counterparts.[7–9] In 2005, Toste and co-
workers reported the first example of an intermolecular ACP
reaction exploiting propargyl esters as gold(I)–carbene pre-
cursors.[8a] Recently, Briones and Davies[9a] and Zhou and co-
workers[9b] presented highly enantioselective cyclopropena-
tion and cyclopropanation, respectively, with donor/acceptor-
substituted diazo reagents.
The functionalization of alkynes via a-oxo metal carbe-
noids generated by alkyne oxidation with pyridine/quinoline
N-oxides, as pioneered by L. Zhang and co-workers,[10] is
considered to be a notable breakthrough in gold catalysis.
Moreover, the research groups of Liu,[11a] Li,[11b] and L.
Zhang,[11c] as well as our own,[11d] have independently
demonstrated oxidative intramolecular cyclopropanations of
various 1,n-enynes with high efficiency.[12] Such transforma-
tions provide a safe alternative to the use of diazo compounds
as carbene precursors. Despite significant achievements in the
functionalization of alkynes by this novel strategy,[13] there
was no catalytic enantioselective version of the reaction[14]
until Liu and co-workers[15] disclosed a single example of the
asymmetric intramolecular cyclopropanation of a 1,5-enyne,
although unfortunately to afford the cyclopropane as a by-
[*] D. Qian, H. Hu, F. Liu, B. Tang, W. Ye, Y. Wang, 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
[**] We are grateful to the 973 Programs (2011CB808600), the National
Natural Science Foundation of China (21372084), the STCSM
(12XD1402300), and the ECNU “Scholarship Award for Excellent
Doctoral Students” (xrzz2013022) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201407717.
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product with only 17% ee (Scheme 1a). Herein, we describe
a highly diastereo- and enantioselective intramolecular cyclo-
propanation of 1,6-enynes through gold(I)-catalyzed alkyne
oxidation with a chiral phophoramidite ligand.[16] The reac-
tion leads to optically active bicyclo[3.1.0]hexane-2-ones
containing three contiguous quaternary and tertiary stereo-
genic centers (Scheme 1b).[4] Control experiments revealed
that the b-gold vinyloxyquinolinium intermediate rather than
the generally proposed gold carbene is involved in the
enantiodetermining step. Furthermore, the new method
features a practical one-pot protocol without the slow
addition of substrates;[2] that is, ynones can be visualized as
safe and reliable surrogates for acceptor/acceptor diazo
compounds.
Our initial study began with 1,6-enyne 1a as a model
substrate and 8-methylquinoline N-oxide (2a) as the external
oxidant.[11d] Gold(I) complexes derived from chiral phosphor-
amidite ligands were tested, and satisfactory control of the
enantioselectivity was observed. Selected representative
reaction conditions are summarized in Scheme 2. Interest-
ingly, the privileged chiral bisphosphine ligands (R)-2,2’-
bis(diphenylphosphanyl)-1,1’-binaphthyl ((R)-binap) and L1–
3 used in previous gold(I)-catalyzed asymmetric cyclopropa-
nation reactions[8,9] did not induce high enantioselectivity. The
introduction of substituents at the 3- and 3’-positions of the
binaphthol moiety increased the enantiomeric ratio of the
product: Ligand (R,R,R)-L9 with two electron-deficient aryl
substituents afforded (+)-3a with up to e.r. 85:15. The use of
H8-binol analogues L12–L15 did not improve the result. We
explored other chiral-ligand backbones and found that the
spirobiindane phosphoramidite ligand (R)-siphos-PE pro-
duced (+)-3a in 92% yield, but with a low enantiomeric ratio
(e.r. 56:44). Further optimization of the reaction conditions
(see the Supporting Information) revealed that the N-oxide
species 2 had an influence on conversion and enantioselec-
tivity (Table 1, entries 1–3), thus indicating that the oxidant
Table 1: Optimization of the reaction conditions.[a]
Entry
R1, 1
R
T [8C]
t [h] Yield [%][b]
e.r.[c]
1
2
3
4
Ph, 1a
Ph, 1a
Ph, 1a
Ph, 1a
H
Me
iPr
Me
Me
Me
Me
Me
25
25
25
70
10
18
23
96
96
96
10
30
91
90
91
85
55
86
92
90:10
88:12
84:16
89:11
93:7
91:9
94:6
97:3
0
5[d]
6[d]
7[d]
8[d]
Ph, 1a
À15
À15
À15
À15
4-FC6H4, 1b
4-MeC6H4, 1c
4-MeOC6H4, 1d
[a] Reaction conditions: [(S,S,S)-L9AuCl] (5 mol%), AgSbF6 (5 mol%),
1 (0.20 mmol), 2 (0.30 mmol), dichloromethane (4.0 mL). [b] Yield of the
isolated product. [c] The enantiomeric ratio was determined by HPLC
analysis. [d] The reaction was carried out with 2a (0.36 mmol) in the
presence of 4 ꢀ molecular sieves.
may play a key role in the enantiodetermining step. When the
reaction was conducted at À158C with 1.8 equivalents of 2a,
the enantiomeric ratio was improved further (Table 1,
entry 5). Finally, the enantioselectivity increased with the
electron-donating character of the substituent R1; thus, (À)-
3d was isolated with e.r. 97:3 in 92% yield (Table 1, entry 8).
We examined the scope and generality of this asymmetric
oxidative cyclopropanation with various 1,6-enynes
(Scheme 3). The transformation generally afforded bicyclo-
[3.1.0]hexanes with good to excellent enantioselectivity (up to
e.r. 98:2). With respect to the substituent at the alkyne
terminus (R1), not only substituted phenyl but also thienyl
and vinyl-substituted enynes (substrates 1e–i, 1j–m) were
converted into the desired cyclopropanation products with
high yields and e.r. values, although a higher reaction
temperature (258C) was required for vinyl derivative 1m
for the reaction to reach completion. Notably, the reaction of
allyl-substituted substrate 1n gave 3n with high diastereose-
lectivity and enantioselectivity by the strategy of desymmet-
rization. More importantly, alkyl-substituted alkenes (R2 =
alkyl) that are often unreactive in rhodium-catalyzed cyclo-
Scheme 2. Investigation of chiral ligands. Reaction conditions: chiral
gold complex (5 mol%), AgNTf2 (5 mol%), 1a (0.20 mmol), 2a
(0.30 mmol), (CH2Cl)2 (4.0 mL), room temperature. [a] The yield was
determined by H NMR spectroscopy. [b] The enantiomeric ratio was
determined by HPLC on a chiral stationary phase. Tf=trifluorometha-
1
nesulfonyl.
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Scheme 4. Possible mechanistic pathway and control experiment.
Qn=8-methylquinoline.
intermediate.[10,11,13] On the other hand, it is possible that
species B is sufficiently long-lived to undergo enantioselective
cyclopropanation through a stepwise or concerted process.[17]
To distinguish between these two plausible mechanisms, we
examined the gold-catalyzed reactions of the authentic diazo
carbonyl species 4 and 1,5-enyne 5. These reactions led to
products 3a and 3d with lower enantiomeric ratios (see
Table S3 and Schemes S4 and S5 for details). Furthermore,
the coordination of the N-oxide or quinoline to the gold
complex was revealed by a series of NMR spectroscopic
experiments (see Scheme S6 and Figures S2 and S3).[13f,h]
Consequently, the reaction of diazo compound 4 would be
seriously suppressed by 2a/Qn, thus indicating that the alkyne
might be a better ligand for gold than the weakly nucleophilic
acceptor/acceptor-substituted diazo compound.[18] These con-
trol experiments imply that the pure a-oxo gold carbene C
may not be the true reactive intermediate in the enantiode-
termining step (EDS) and that the quinoline moiety of species
B is required for this process. The quinoline moiety (Qn) most
likely acts as a transient ancillary group in B to facilitate both
conversion and enantioselectivity through a intramolecular
cyclopropanation process. Additionally, the large dihedral
angle of L9 (61.58) may provide sufficient steric protection to
the gold center (see Figure S1), thereby placing the Au center
more effectively in a chiral environment.[7,16] Alternatively to
what has been generally proposed,[10,11,13] and to take into
account the effect of the substituent, the ligand, and the gold
fragment in the limiting form C and gold-stabilized carbocat-
ion,[19] we propose that the reactive intermediate is better
pictured as a b-gold vinyloxyquinolinium intermediate B. In
fact, the mechanistic aspects that determine the outcome of
Scheme 3. Generality of the reaction. [a] The reaction was carried out
with 1d (2.71 mmol) and [(S,S,S)-L9AuCl]/AgSbF6 (4 mol%). [b] The
diastereomeric ratio was determined by 1H NMR spectroscopic and
HPLC analysis. [c] The minor diastereomer was obtained with e.r.
85.5 :14.5. PMP=4-methoxyphenyl. Bn=benzyl, TBS=tert-butyldime-
thylsilyl.
propanation reactions of acceptor/acceptor diazo reagents
were successfully transformed into the corresponding cyclo-
propanes in moderate yields with good to excellent selectivity
(substrates 1p–w).[2c] Furthermore, the N-methylamide-
linked 1,6-enyne 1x also underwent asymmetric cyclopropa-
nation to form 3-azabicyclo[3.1.0]hexan-2-one 3x in high
yield with high stereoselectivity. All of the above catalytic
reactions generated the bicyclo[3.1.0]hexan-2-one products as
a single diastereomers. To test the practicality of the method-
ology, we carried out a large-scale synthesis of chiral bicyclic
3d. The treatment of 1d on a 2.7 mmol scale gave the desired
product (À)-3d in 81% yield with e.r. 96:4.
Two plausible pathways that account for this asymmetric
oxidative cyclopropanantion are depicted in Scheme 4 (top).
In one mechanism, a chiral gold(I)-derived carbene C
generated from B by back donation from the gold to the C1
center with loss of the quinoline moiety (Qn) is a key
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gold-catalyzed alkyne oxidation are still under debate (gold
carbene versus b-gold vinyloxyquinolinium intermedi-
ate).[10,11,13] Herein, we offer strong evidence in support of
the b-gold vinyloxyquinolinium species rather than the simple
gold carbene in the cyclopropanation step.[20]
To further demonstrate synthetic applications of our
method, we carried out several transformations of the
bicyclo[3.1.0]hexan-2-one derivatives. The reactions pro-
ceeded smoothly with no decrease in the enantiomeric ratio
(Scheme 5). Furthermore, the relative and absolute config-
uration of 8 was unambiguously determined to be 1S,5S,6S by
X-ray crystal-structure analysis (see Figure S4). The PMP
group on the ketone directs the regioselectivity of a subse-
Keywords: alkyne oxidation · carbenoids · cyclopropanation ·
enantioselectivity · gold
.
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Received: July 29, 2014
Published online: September 24, 2014
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