Remote Cooperative Group Strategy Enables Ligands for Accelerative Asymmetric Gold Catalysis

Article abstract of DOI:10.1021/jacs.7b09136

An accelerative asymmetric gold catalysis is achieved for the first time via chiral ligand metal cooperation. An asymmetrically positioned remote amide group in the designed chiral binaphthyl-based ligand plays the essential role of a general base catalyst and selectively accelerates the cyclizations of 4-allen-1-ols into one prochiral allene face. The reactions are mostly highly enantioselective with achiral substrates, and due to the accelerated nature of the catalysis catalyst loadings as low as 100 ppm are allowed. With a pre-existing chiral center at any of the backbone sp³-carbons, the reaction remained highly efficient and most importantly maintained excellent allene facial selectivities regardless of the substrate stereochemistry. By using different combinations of ligand and substrate enantiomers, it is now possible to access all four stereoisomers of versatile 2-vinyltetrahydrofurans with exceedingly high selectivity. The underpinning design of this chemistry reveals a novel and conceptually distinctive strategy to tackle challenging asymmetric gold catalysis, which to date has relied on decelerative asymmetric steric hindrance approaches.

Full text of DOI:10.1021/jacs.7b09136

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Communication
Remote Cooperative Group Strategy Enables
Ligands for Accelera-tive Asymmetric Gold Catalysis
Zhixun Wang, Corrado Nicolini, Cedric Hervieu, Yuk-Fai Wong, Giuseppe Zanoni, and Liming Zhang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b09136 • Publication Date (Web): 23 Oct 2017
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Remote Cooperative Group Strategy Enables Ligands for Accelerative
Asymmetric Gold Catalysis
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Zhixun Wang,† Corrado Nicolini,‡ Cedric Hervieu,† Yuk-Fai Wong,† Giuseppe Zanoni,‡* and
Liming Zhang†*
† Department of Chemistry & Biochemistry, University of California, Santa Barbara, CA 93106
‡ Department of Chemistry, University of Pavia, Viale Taramelli, 10, 27100 Pavia - Italy
Supporting Information Placeholder
progress.5 However, highly enantioselective ones hardly de-
ABSTRACT: An accelerative asymmetric gold catalysis is
achieved for the first time via chiral ligand metal cooperation.
ploy ligand accelerated catalysis3e and mostly rely on deceler-
ative and hence efficiency-lowering steric hindrance (i.e., Fig-
ure 1B) imposed by chiral ligands,6 counter anions,7 or their
combination.8 As such, these reactions typically requires rela-
tively high catalyst loadings due to decreased reaction rates.
An asymmetrically positioned remote amide group in the de-
signed chiral binaphthyl-based ligand plays the essential role
of a general base catalyst and selectively accelerates the cycli-
zations of 4-allen-1-ols into one prochiral allene face. The re-
actions are mostly highly enantioselective with achiral sub-
strates, and due to the accelerated nature of the catalysis cat-
alyst loadings as low as 100 ppm are allowed. With a preexist-
ing chiral center at any of the backbone sp3-carbons, the reac-
tion remained highly efficient and most importantly main-
tained excellent allene facial selectivities regardless of the sub-
strate stereochemistry. By using different combinations of lig-
and and substrate enantiomers, it is now possible to access all
four stereoisomers of versatile 2-vinyltetrahydrofurans with
exceedingly high selectivity. The underpinning design of this
chemistry reveals a novel and conceptually distinctive strategy
to tackle challenging asymmetric gold catalysis, which to date
has relied on decelerative asymmetric steric hindrance ap-
proaches.
Herein we reported a first asymmetric ligand-accelerated
gold catalysis, where the formation of one enantiomer is se-
lectively accelerated via asymmetric ligand substrate interac-
tion. This interaction enables ligand metal cooperation4 and
is realized in the secondary ligand sphere by a remote and
asymmetrically positioned Lewis basic group in new chiral
binaphthyl-2-ylphosphine ligands. The utility of this accelera-
tive strategy is demonstrated by the very low catalyst loadings
(as low as 100 ppm) and the generally excellent stereoselectiv-
ities in the cyclization of 4-allen-1-ols. Importantly, it demon-
strates a new and highly efficient strategy to achieve challeng-
ing asymmetric gold catalysis, which to date has mostly been
limited to the scenario depicted in Figure 1B.
Ligand accelerated catalysis (LAC)1 offers a versatile plat-
form in metal catalysis for achieving efficient asymmetric ca-
talysis. An often-practiced approach to realizing enantioselec-
tivity in LAC is to introduce asymmetric steric hindrance to
selectively slow down the formation of one of the enantio-
mers, albeit it may still be faster than the non-accelerated sce-
nario (Figure 1C vs. 1A).2 This is a superior strategy to those
based only on steric retardation (Figure 1B) due to faster reac-
tions and lower catalyst loadings. Alternatively but relatively
rare in transition metal catalysis, high enantioselectivity could
be achieved by selectively accelerating the formation of only
one of the enantiomers via asymmetric ligand substrate inter-
actions3 and/or ligand metal cooperation4 (Figure 1D). In com-
parison to the scenario in Figure 1C, this latter approach does
not accelerate the formation of the minor enantiomer and
hence offers enhanced chances of achieving excellent enanti-
oselectivity.
Figure 1. Common scenarios of asymmetric catalysis.
We recently developed a series of novel biphenyl-2-
ylphosphine ligands9 featuring basic functional groups at the
bottom half of the pendant phenyl ring.10 With WangPhos
(Scheme 1A)10a,10c possessing a 3’-amide group as ligand, the
gold-catalyzed nucleophilic attack of carboxylic acid is accel-
erated by an estimated 800 fold, comparing to non-function-
alized JohnPhos, due to the cooperation of the remote amide
Asymmetric gold catalysis, despite the challenge stemming
from the linear structure of Au(I) complexes and the anti at-
tack by incoming nucleophile, has experienced significant
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group in the form of general basic catalysis.10b In the context
thesis,14 and the vinyl group in cyclization product can be
readily manipulated.
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of asymmetric gold catalysis, we envisioned that this coopera-
tive strategy can be applied to the cyclization of 4-allen-1-ols
such as 1a (Scheme 1A), where a new chiral center is created.
To our delight, comparing to JohnPhos, a sterically and elec-
tronically comparable ligand but lacking any remote coopera-
tive group, WangPhos promotes the gold-catalyzed cycliza-
tion of 1a to racemic 2-vinyltetrahydrofuran rac-2a at a rate at
least 88 times faster. This dramatic rate acceleration can be
readily rationalized by invoking ligand metal cooperative ca-
talysis and specifically the general base catalysis by the remote
amide group. As depicted in Scheme 1B, the coordinated al-
lene would lead to two diastereomeric complexes I and II. In
contrast to complex II, complex I places the alcohol adjacent
to the pendent amide group and hence permits a general base
catalysis in the form of H-bonding, which would enhance the
nucleophilicity of alcohol via partial deprotonation in transi-
tion state. As a result, Si-face attack that produces (S)-2a in
complex I would largely (presumably ≥88 times faster) out-
compete Re-face attack in complex II, where the amide group
is too far from the alcohol HO group to allow H-bonding and
hence should undergo cyclization in a similar rate to that with
JohnPhos as ligand. However, due to the low barrier of rotat-
ing C1-C1’ bond in the ligand and likely its gold complex,
WangPhosAu+ would exist in equal amount as the enantiomer
or enantiomeric conformer to that in complex I. The resulting
complex III would equally accelerate the Re-face attack, which
delivers racemic 2a as a net result. It is anticipated that by us-
ing a chiral version of WangPhos with the rotation of C1-C1’
locked the cyclization of 4-allenols could become asymmetric.
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Figure 2. (A) Selected ligands for this study. (B) ORTEP draw-
ings of (R)-L2AuCl with 50% ellipsoid probability.
At the outset, we chose the configurationally much more
stable binaphthyl as the ligand framework, and targeted the
(1,1’-binaphthyl)-2-yldi(adamantan-1-yl)phosphine ligands L1-
L3 (Figure 2A). They can be readily synthesized from commer-
cially available (R)-BINOL in a short sequence of 3-4 steps (see
supporting information for details). Much to our delight, ini-
tial study with 5 mol% (R)-L1AuCl as the catalyst precursor
delivered (R)-2a in 98.4% ee within 5 min. The absolute con-
figuration of 2a was assigned as (R) based on literature prece-
dent,11a and is consistent with the rationale/design shown in
Scheme 1B, where the front-orienting amide in I leads to the
(S)-product. This exceptional initial result validated our lig-
and design concept and, moreover, was achieved with the very
first chiral ligand of this type!
Table 1. Optimization of reaction conditions towards en-
antioselective gold-catalyzed 4-allen-1-ol cyclization.a
Scheme 1. (A) Rate comparison between JohnPhos and
WangPhos in cyclization of 4-allen-1-ol 1a. (B) Rationale
Entr
y
1
2
3
4
Temp.
/Time
rt/15 min
rt/15 min
rt/1 h
rt/15 min
rt/15 min
rt/15 min
rt/15 min
Yldb eec
(%) (%)
98 95.5
97 96.6
Cat. (mol%)
MX (mol%)
(R)-L1AuCl (1)
(R)-L2AuCl (1)
(R)-L3AuCl (2)
(R)-L2AuCl (1.2)
(R)-L2AuCl (1.2)
(R)-L2AuCl (1.2)
(R)-L2AuCl (1)
(R)-L2AuCl (1)
(R)-L2AuCl (1)
(R)-L2AuCl (1)
(R)-L2AuCl (0.1)
NaBArF4 (5)
NaBArF4 (5)
NaBArF4 (5)
AgNTf2 (1)
AgOTf (1)
11
-8.8
96 93.4
95 78.9
92 94.1
92 97.5
5
6
AgSbF6 (1)
NaBArF4 (5)
7d
8d
9d
10d,e
11d
12d
NaBArF4 (5) -20 °C /30 min 90 95.5
NaBArF4 (5) 40 °C /15 min 89 97.0
NaBArF4 (5) 60 °C /15 min 94 97.1
NaBArF4 (1)
rt/30 min
rt/2.5 h
rt/1 h
94 97.1
92f 96.9
92 95.7
(R)-L2AuCl (0.01) NaBArF4 (0.5)
13d,g (R)-L2AuCl (0.01) NaBArF4 (0.5)
a Reactions were performed in vials. b Yields and conversions
were estimated by NMR using 1,3,5-triisopropylbenzene as in-
ternal reference. All conversions >99% otherwise noted. c ee
values of olefin metathesis products were determined by
HPLC on a chiral stationary phase. d 3 Å molecular sieves were
added. e DCE was used as solvent. f 98% NMR conversion. 93%
isolated yield, 97.1% ee. g 0.25 M in DCM.
for the rate acceleration and for enantioselective catalysis.
It is noteworthy that cyclization of allenols have been stud-
ied extensively in asymmetric gold5 and silver catalysis.11 Most
highly enantioselective cyclizations of 4-allenols 1 employ
non-stereogenic trisubstituted allenes as substrate,7,8b,12 with
one exception,6a the distal symmetric disubstitution of which,
however, require excessive steps for installation13 and of no ap-
parent synthetic utility. On the contrary, mono-substituted al-
lenes such as 1a is easily accessible via the Crabbe allene syn-
The exceptional ee with the substrate 1a left little room for
condition optimization and ligand development. To this end,
reaction optimization was conducted with 4-allenol 1b as the
substrate. Due to lack of desirable UV absorption for chiral
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HPLC analysis of the product 2b, a subsequent olefin metath-
2-tert-butyldiphenylsilanoxyl group, but the allene facial se-
1
2
3
4
5
6
7
8
esis was carried out to install a styryl group as the chromo-
phore. Our control experiment with 2a established that there
is no erosion of stereochemistry in the cross metathesis step.
Gladly, treating 1b with 1 mol% L1AuCl as catalyst and 5%
NaBArF4 as chloride scavenger furnished 2b in 98% yield and
95.5% ee within 15 min (Table 1, Entry 1). Consistent with the
case of 2a, its configuration is assigned as (R). Moreover, using
L2 with a pyrrolidin-1-ylcarbonyl group, which is more basic
than N,N-dimethylcarbamyl group in L1, a better enantiose-
lectivity (96.6% ee) was achieved. Whereas (R)-L3 bearing no
cooperative amide group was used as control experiment, an
expected steep drop of reaction rate and a poor ee (-8.8%)
were observed, which confirmed the cooperative nature of the
lectivities are excellent with both substrate enantiomers (en-
try 13). Finally, the reaction of a 3-benzyloxy group in 1o (entry
14) was also highly stereoselective, despite a moderate yield.
Notably, in all these cases using racemic substrates (entries 7-
14), the reactions exhibited poor cis/trans selectivities, con-
firming that the cyclization stereochemical outcomes can be
little controlled by the substrate preexisting chiral centers.
Table 2. Reaction scopea.
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amide moiety (Table 1, Entry 3). Replacing BArF - with more
4
coordinative counter anions caused diminished enantioselec-
tivities (Table 1, Entries 4-6). We also observed that the re-
moval water by 3 Å MS improved ee to 97.5% (Table 1, entry
7), possibly because the residual water, being able to act as
both H-bonding donor and acceptor, would disrupt the H-
bonding between the alcohol and amide group. In contrast to
the common temperature profiles in asymmetric catalysis,
lowering the reaction temperature led to a decreased ee while
higher temperatures did not cause much ee erosion (Table 1,
entries 8-10). Owning to the accelerated nature of the cataly-
sis, the catalyst loadings could be dramatically lowered down
to 100 ppm without noticeably affecting ee (Table 1, entries 11-
12). At last, a higher concentration was proven to be detri-
mental to ee despite a faster reaction rate (Table 1, entry 13),
which can be attributed to the disruption of ligand-substrate
H-bonding by unreacted alcohol. To confirm the identity of
the optimal ligand (R)-L2, we ascertained the structure and
stereochemistry of its gold complex by X-ray diffraction stud-
ies (Figure 2B). With the best conditions in hand, we promptly
explored the reaction scope. As shown in Table 2, entries 1-4,
4-allenols with germinal di-substitutions at the sp3-carbons
generally exhibited excellent yield and enantioselectivity (up
to 99.7%, entry 3) with 100-ppm catalyst loadings. This in-
cludes the tertiary alcohol 1e (entry 4), indicating the steric
hindrance around the HO group is inconsequential. On the
other hand, sterics next to the allene moiety, as in entry 5, led
to a moderate ee (Table 2, entry 5). In absence of the Thorpe-
Ingold effect, the cyclization of the parent 4-allenol 1g re-
mained highly enantioselective (94.1% ee, entry 6).
1
2
3
2a, rt, 3 h
99% yield
99.1% ee
2c, rt, 5 h
59 (89)% yieldb
97.0% eec
2d, rt, 6 h
83% yield
99.7% eec
4
7
5
6
9
2e, rt, 8 h
95% yield
95.8% ee
2f, rt, 3 d
92% yieldb
49.8% eec
2g, rt, 9 h
74% yieldb
94.1% eec
8
2hd, 40 °C, 15 h
83% yield
trans/cis = 1.11/1.00
2ie, rt, 33 h
84% yield
trans/cis = 1.04/1.00
2je, rt, 48 h
87% yield
trans/cis = 1.35/1.00
de-R, 94.7%;
de-R, 94.6%;
de-S, 93.3%
de-R, 95.8%;
de-S, 92.1%
de-S, 92.5%c
10
11
12
2k, rt, 24 h
74% yield
trans/cis = 1/1
de-R: 94.4%,
de-S, 93.0%c
2l, 40 °C, 15 h
86% yield
2m, rt, 55 h
90% yield
trans/cis = 1.00/1.31
trans/cis = 1.06/1.00
de-R, 95.9%;
de-R, 98.7%;
de-S, 88.4%
de-S, 95.4%c
13
14
Besides the achiral 4-allen-1-ols, we also expand the scope
to the ones with preexisting stereogenic centers, which are
complicated by diastereoselective outcomes but of high syn-
thetic significance due to their frequent occurrence in com-
plex molecule synthesis. As shown in entries 7-11, 4-allen-1-ols
with various substituents at C1 such as phenylethynyl (entry
7), phenyl (entry 8), alkenyl (entry 9), cyclohexyl (entry 10)
and phenethyl (entry 11) underwent the cyclization smoothly,
affording the cyclized products in good yields (74% - 87%).
Most importantly, these reactions exhibited excellent allene
Re face selectivities regardless the substrate configurations. In
each entry, the de-R and de-S values reflect the diastereomeric
excesses of the products derived from the (R)- and (S)-sub-
strates, respectively, and are calculated based on complete
separation of the four product stereoisomers by chiral HPLC.
The reaction of a 2-phenyl-substituted 4-allen-1-ol, i.e., 1m, ex-
hibited exceptional 98.7% de-R, and a lower yet still good de-
S (entry 12). On the other hand, the reaction of 1n demanded
a higher catalyst loading (0.5 mol %), possibly due to the bulky
2nf, rt, 6 h
94% yield
2og, 40 °C, 36 h
65% yield
trans/cis = 1.33/1.00
trans/cis = 1.00/1.01
de-S, 98.9%;
de-R, 95.3%;
de-R, 97.5%
de-S, 92.4%
a Reactions were performed in vials. Yields given are for the
isolated product. For allenols with a preexisting chiral center,
the de value is given for each enantiomeric substrate and des-
ignated by its configuration. b Volatile product. c The product
was converted into its styryl derivative via olefin cross metath-
d
esis for subsequent chiral HPCL analysis. 500 ppm catalyst
e
f
were used. 200 ppm catalyst were used. 0.5 mol% catalyst
and 1 mol% NaBArF4 were used. g 0.2 mol % catalyst was used.
To confirm the exceptional allene facial selectivities with
chiral substrates, we prepared the enantiomerically enriched
(R)-1n (98.8% ee) from (S)-glycidol and subjected it to the
gold catalysis with (S)- and (R)-L2AuCl as catalyst precursor,
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respectively. As expected, a complete switch of diastereoselec-
Corresponding Author
1
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3
4
5
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7
8
tivity was observed along with excellent yields (Eq. 1); moreo-
ver, the de values are nearly identical to those obtained with
racemic 1n.
zhang@chem.ucsb.edu; gz@unipv.it
Notes
The authors declare no competing financial interests.
We attempted to briefly demonstrate the synthetic poten-
tial of this chemistry toward the synthesis of C-glycosides. As
shown in Eq. 2, the partially protected allene-polyol 1p was
prepared from D-xylose. When it was subject to the gold catal-
ysis with (S)-L2 as ligand, the vinyl C-xyloside α-2p was
formed exclusively in 82% yield. With the ligand antipode, β-
2p was obtained in 76% yield and in a 6.5:1 diastereoselectiv-
ity. As the intrinsic diastereoselectivity with WangPhos favors
α-2p by a ratio of 16:1, this fair yet serviceable selectivity for
the much disfavored β-isomer is noteworthy and can be syn-
thetically useful. Notably, when JohnPhos was used as gold lig-
and, the reaction was messy and little 2p was formed, which
reveals the versatility of our designed ligands for cyclizations
regardless asymmetric induction.
ACKNOWLEDGMENT
We thank Regione Lombardia – Cariplo Foundation Grant
(Sottomisura B/2016), POR FESR 2014-2020/Innovazione e
competitività, progetto VIPCAT and NSF CHE-1301343 for
finanical support and NIH S10OD012077 for the purchase of a
400 MHz NMR spectrometer. ZW thanks the Mellichamp Ac-
ademic Initiative in Sustainability for a fellowship.
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Ed. 2006, 45, 5455-5459.
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In conclusion, we have achieved for the first time an accel-
erative asymmetric gold catalysis via chiral ligand metal coop-
eration. An asymmetrically positioned remote amide group in
the designed chiral binaphthyl-based ligand plays the essen-
tial role of a general base catalyst and selectively accelerates
the cyclizations of 4-allen-1-ols into one prochiral allene face.
The reactions are mostly highly enantioselective with achiral
substrates, and due to the accelerated nature of the catalysis
catalyst loadings as low as 100 ppm are allowed. With a preex-
isting chiral center at any of the backbone sp3-carbons, the re-
action remained highly efficient and most importantly main-
tained excellent allene facial selectivities regardless of the sub-
strate stereochemistry. Of exceptional synthetic significance
is that all four stereoisomers of versatile 2-vinyltetrahydrofu-
rans can be prepared with exceedingly high selectivity by us-
ing different combinations of ligand and substrate enantio-
mers. The underpinning design of this chemistry offers new
yet rational strategies to tackle challenging asymmetric gold
catalysis, which to date has relied on decelerative chiral steric
approaches.
ASSOCIATED CONTENT
Supporting Information
Experimental details, compound characterization and spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(12)Teller, H.; Flügge, S.; Goddard, R.; Fürstner, A. Angew. Chem., Int. Ed.
2010, 49, 1949-1953.
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Commun. 1979, 859-860.
AUTHOR INFORMATION
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L2AuCl (0.5 mol%)
NaBArF4 (1 mol%)
O
O
OTBDPS
OH
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+
3Å MS, DCM, rt
OTBDPS
(2R,4R)-2n
OTBDPS
(2S,4R )-2n
(R)-1n
derived from S-glycidol
dr
L2
(S)
(R)
yield(time)
de
99.2%
88%(1.5 h)
250 : 1
1 : 86
97.7%
91%(3.75 h)
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PAd2
rare asymmetric ligand-accelerated gold catalysis
catalyst loadings as low as 100 ppm
axially
chiral
OMe
7 cases with achiral substrates, e.e. up to 99.7%
10 cases with chiral/racemic substrates, de up to 98.9%
O
N
(R)-L2
permitting the synthesis of all four stereoisomers of 2-
vinyltetrahydrofurans with excellent selectivity
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