Chiral Bifunctional Phosphine Ligand Enabling Gold-Catalyzed Asymmetric Isomerization of Alkyne to Allene and Asymmetric Synthesis of 2,5-Dihydrofuran

Article abstract of DOI:10.1021/jacs.8b12833

The asymmetric isomerization of alkyne to allene is the most efficient and the completely atom-economic approach to this class of versatile axial chiral structure. However, the state-of-the-art is limited to tert-butyl alk-3-ynoate substrates that possess

Full text of DOI:10.1021/jacs.8b12833

Communication
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Chiral Bifunctional Phosphine Ligand Enabling Gold-Catalyzed
Asymmetric Isomerization of Alkyne to Allene and Asymmetric
Synthesis of 2,5-Dihydrofuran
Xinpeng Cheng, Zhixun Wang, Carlos D. Quintanilla, and Liming Zhang*
Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States
S
* Supporting Information
Scheme 1. Soft Propargylic Deprotonation and Chiral 2,5-
Dihydrofuran Synthesis
ABSTRACT: The asymmetric isomerization of alkyne to
allene is the most efficient and the completely atom-
economic approach to this class of versatile axial chiral
structure. However, the state-of-the-art is limited to tert-
butyl alk-3-ynoate substrates that possess requisite acidic
propargylic C−H bonds. Reported here is a strategy based
on gold catalysis that is enabled by a designed chiral
bifunctional biphenyl-2-ylphosphine ligand. It permits
isomerization of alkynes with nonacidic α-C−H bonds
and hence offers a much-needed general solution. With
chiral propargylic alcohols as substrates, 2,5-disubstituted
2,5-dihydrofurans are formed in one step in typically good
yields and with good to excellent diastereoselectivities.
With achiral substrates, 2,5-dihydrofurans are formed with
good to excellent enantiomeric excesses. A novel center-
chirality approach is developed to achieve a stereocontrol
effect similar to an axial chirality in the designed chiral
ligand. The mechanistic studies established that the
precatalyst axial epimers are all converted into the
catalytically active cationic gold catalyst owing to the
fluxional axis of the latter.
xially chiral allenes are versatile and highly valuable
A
intermediates in asymmetric synthesis.1 Various prepara-
tive methods have been documented.2 Notwithstanding, the
direct isomerization of alkyne to chiral allene, the arguably
simplest and the most atom-economic approach, has only been
reported with alkynes featuring rather acidic propargylic
hydrogens,3 such as 1,3-diphenylpropyne3c,f and t-butyl alk-3-
ynoates3d,e, and moreover, high e.e. values are only realized
with the latter substrates. To date, there is no asymmetric
isomerization of a vast range of other alkynes and especially
those devoid of acidic propargylic hydrogens.
the first time be of general utility due to the demonstrated
accommodation of alkyne substrates with nonacidic α-C−H
bonds.4,5
To overcome the inherent equilibrium between alkyne and
allene in the isomerization process, we envisioned that the
chiral allene generated in situ could be trapped in a
stereospecific cyclization of allenylmethanol6 (Scheme 1B).
As such, a readily available chiral propargylic alcohol7 could be
directly converted to a chiral 2,5-dihydrofuran possessing a
new stereogenic center. Chiral 2,5-disubstituted 2,5-dihydro-
furan and the related tetrahydrofuran are structural motifs
presented in various bioactive natural products (for examples,
see Scheme 1C).8 The typical approaches9 to the construction
of the former, however, do not feature increase of stereo-
chemical complexity as the two requisite chiral centers are
either preinstalled (i.e., Scheme 1D, approaches ii9a and iv9b)
We previously reported the isomerization of arylalkynes into
1-aryl-1,3-dienes via the intermediacy of an allene (Scheme
1A).4 This reaction is enabled by a bifunctional biphenyl-2-
ylphosphine (i.e., L1) that features a remote aniline moiety and
was specifically designed to permit the basic aniline group to
deprotonate an Au(I)-activated alkyne. Later on, we reported
that ligands featuring a more basic remote tertiary amino group
such as L2 are likewise effective in promoting the alkyne-to-
allene isomerization.5
It is envisioned that with a chiral version of L1 or L2 as
ligand the isomerization of alkyne into chiral allene could be
realized. Of high significance is that this approach would for
Received: November 29, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.8b12833
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
or derived from existing chiral elements via stereoselective/
stereospecific processes (i.e., approaches i9c and iii9d). An
asymmetric approach starting from only one chiral element, as
in the case of a chiral propargylic alcohol in Scheme 1B, leads
to enhanced stereochemical complexity and is inherently
advantageous but has yet to be realized. Herein, we report an
implementation of Scheme 1B enabled by a designed chiral
version of L2.
biphenyl-2-ylphosphine L4, which features a chiral center at
C1 in the pendant 1,2,3,4-tetrahydroisoquinoline ring. A R
group in (aR,R)-L4 would largely not affect the catalytic
activity of the Au+ complex as it points away from the catalytic
site. On the other hand, axial rotation of L4 by 180° would
afford (aS,R)-L4, which has the R group pointing to the
catalytic site. A bulky R group would provide sufficient steric
shielding of the nitrogen lone pair electrons to block its
participation in the key deprotonation step. As such, similar to
the stable axial chirality in L3, this center chirality could also
make the remote tertiary amino group only available for
deprotonation when it is behind the biphenyl framework.
While the gold complexes (aR,R)-L4Au+ and (aS,R)-L4Au+
might not be interconvertible and hence (aS,R)-L4Au+,
catalytically inactive, could be wasted; the ease of constructing
center chirality and the anticipated high efficiency in installing
the PAd2 group ortho to a sterically unencumbered axis
propelled us to explore this novel design.
The traditional and obvious approach to developing a chiral
version of the biphenyl-2-ylphosphine L2 is to employ a biaryl
framework with a stable chiral axis (e.g., Scheme 2A). Our
Scheme 2. Our Design of Chiral Bifunctional Biphenyl-2-
ylphosphine Ligands Relying on Center Chirality
On the basis of the design, the chiral ligands L4-1−L4-4
were prepared,12 and their structures are shown underneath
the Table 1 equation. We then set out to study the designed
cycloisomerization by using (R)-dodec-3-yn-2-ol (5a, 99% ee)
as the substrate (Table 1). The pre-existing stereocenter of 5a
permits expedient analysis of the stereoselectivity at the newly
previous work on a related system,10 however, revealed that the
installation of the bulky PAd2 group via a Pd-catalyzed cross
coupling11 can be low yielding (∼14%) due to the requisite
steric congestion around a stable chiral axis. As such, we
envisioned a new design, which is depicted in Scheme 2B.
Instead of relying on axial chirality to orient the remote basic
nitrogen, e.g., behind the top benzene ring as depicted in
L3Au+ in Scheme 2A, we designed an axially fluxional
1
generated chiral center by H NMR. Instead of the desired
cycloisomerization, JohnPhos led expectedly only to the well-
precedented Meyer−Schuster rearrangement (entry 1). With
the achiral L2 as ligand, the desired 2,5-dihydrofuran 7a was
indeed formed in 79% yield but with little diastereoselectivity
(entry 2). This result confirmed again the essential role of the
remote amino group in enabling this reaction and revealed that
a b
,
Table 1. Reaction Optimization
entry
ligand
solvent
temp/time
conv.
yield
trans/cis
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
JohnPhos
L2
DCE (0.1 M)
DCE (0.1 M)
DCE (0.1 M)
DCE (0.1 M)
DCE (0.1 M)
DCE (0.1 M)
DCE (0.1 M)
DCE (0.1 M)
DCE (0.25 M)
DCE (0.05 M)
DCE (0.05 M)
DCE (0.05 M)
toluene (0.05 M)
PhCF3 (0.05 M)
PhF (0.05 M)
60 °C/7 h
60 °C/4 h
60 °C/7 h
60 °C/7 h
60 °C/7 h
60 °C/7 h
40 °C/18 h
80 °C/2 h
80 °C/2 h
80 °C/2 h
80 °C/2 h
80 °C/2 h
80 °C/2 h
80 °C/2 h
80 °C/2 h
>99%
>99%
>99%
48%
<1%
79%
70%
16%
3%
76%
48%
83%
75%
85%
79%
69%
13%
68%
51%
54:46
92:8
89:11
(R)-L4-1
(R)-L4-2
(R)-L4-3
(R)-L4-4
(R)-L4-4
(R)-L4-4
(R)-L4-4
(R)-L4-4
(R)-L4-4
(R)-L4-4
(R)-L4-4
(R)-L4-4
(R)-L4-4
58%
>99%
>99%
>99%
>99%
>99%
>99%
93%
>99%
>99%
>99%
93:7
94:6
93:7
93:7
93:7
92:8
92:8
91:9
93:7
93:7
c
d
a
b
0.05 mmol reaction scale. Conversion and yield determined by using 1,3,5-trimethoxybenzene as NMR internal standard. Except entries 1 and
c
d
13, <5% of the Meyer−Schuster rearrangement product formed. 10 mol % NaBArF4 used. 5 mg of 3 Å MS used.
B
DOI: 10.1021/jacs.8b12833
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Journal of the American Chemical Society
Communication
a b
,
the pre-existing stereocenter has little directing effect on the
configuration of the newly generated stereocenter and likely
the proceeding allene chirality. To our delight, with (R)-L4-1
featuring a sterically demanding cyclohexyl group at its chiral
center, the gold catalysis afforded 7a in 70% yield and with a
trans/cis ratio of 92/8 (entry 3). This amounts to >11:1
preference for the (R)-configuration at the new chiral center.
Changing the ligand N-substituent from methyl in (R)-L4-1 to
bulkier ethyl in (R)-L4-2 or benzyl in (R)-L4-3 resulted in a
significant decrease in conversion and, moreover, reaction
yields (entries 4 and 5). The installation of an inductively
electron-withdrawing CF3 group on the C4 of (R)-L4-1
delivered the ligand (R)-L4-4, which led to a better yield
(76%) and a slightly improved diastereoselectivity (trans/cis =
93:7, entry 5). Further studies (entries 6−10) with (R)-L4-4 as
ligand revealed that a better yield (85%) could be achieved by
running the gold catalysis at 80 °C and in a lower substrate
initial concentration of 0.05 M (entry 10). A lower loading of
NaBArF4 or the addition of 3 Å MS led to a slightly lower yield
(entries 11 and 12). It was also found that the solvent DCE
was important for the optimal yield as PhCF3, toluene, and
PhF led to lower yields (entries 13−15). Of note, except
entries 1 and 13, little Meyer−Schuster product (<5%) was
detected in all the other entries.
Table 2. Reaction Scope
With the optimized reaction conditions in hand, we set out
to investigate the reaction scope (Table 2). Initially, a series of
chiral secondary propargylic alcohols (5, R1 = Me, R2 = H)
were examined. Various functional groups such as C−C double
bond (7b), phenyl (7c), benzyloxy (7d), phthalimide (7e),
and chloro (7f) were all readily tolerated at the R3 group, and
moderate to high yields and good diastereoselectivities were
realized. Changing R3 from linear chains to more steric
hindered cyclopentyl (7g), cyclohexyl (7h), and 1-adamantyl
(7i) groups led to excellent diastereoselectivities without
compromising the reaction yields. Switching the R1 group from
methyl to n-pentyl (7j), isopropyl (7k), or phenyl (7m) also
resulted in excellent yield and diastereoselectivity. A tert-butyl
group, however, appeared detrimental and led to a much lower
yield of 7l, albeit the trans/cis selectivity remained excellent.
Importantly, the cis-counterpart of (2S,5R)-7d, i.e., (2S,5S)-
7d, was readily accessed from the corresponding substrate
enantiomer in a higher 80% yield and with a slightly improved
cis/trans selectivity. Notably, (2S,5S)-7d is a key intermediate
employed in the total synthesis of (−)-varitriol.13 A similar
phenomenon was observed in the cases of (2R,5S)-7h and
(2R,5R)-7h. Moreover, by employing the ligand enantiomer,
i.e., (S)-L4-4, (2S,5R)-7h was isolated in 88% yield and with
an identical 97/3 diastereomeric ratio. These results
established that by using different combinations of L4-4 and
substrate enantiomers, all four stereoisomers of 2,5-disub-
stituted 2,5-dihydrofuran can be accessed with high to
excellent levels of stereoselectivity.
a
b
[(S)-L4-4]AuCl used. <5% Meyer−Schuster rearrangement prod-
c
uct. 10 mol % [(R)-L4-4]AuCl used.
high enantiomeric ratios. The tolerance of steric hindrance in
these cases is notable. Outstanding asymmetric inductions by
our chiral ligand were observed in the cases of 8h, 8i, and 8j
due largely to increased steric bulk around the C−C triple
bond. In the last case where the substrate was derived from
estrone, the reaction was slow, likely due to steric hindrance,
and required a higher catalyst loading and a longer reaction
time. However, the cycloisomerization is exceptionally
diastereoselective (>50:1).
To probe how the ligand works, we first attempted to
separate the two precatalyst atropisomers. To our delight, they
form crystals of different shapes and could be manually
separated. X-ray diffraction studies confirmed their epimeric
structures (Scheme 3A). In the case of [(aS,R)-L4-4]AuCl, the
cyclohexyl group clearly intrudes into the space occupied by Cl
and should block the binding of π-substrates during catalysis.
In the case of [(aR,R)-L4-4]AuCl, the cyclohexyl group points
away from the metal. Though an inversion of the pyramidal
nitrogen in [(aR,R)-L4-4]AuCl is needed in order to point its
lone pair electrons to Au, such a process should have an easily
surmountable barrier. When a 1:1.7 mixture of [(aR,R)-L4-
4]AuCl and [(aS,R)-L4-4]AuCl was heated at 80 °C in DCE
for 1 h, the ratio did not change, revealing that the ligand axial
We turned our attention next to achiral propargylic alcohol
substrates 6. The enantioselective cycloisomerization occurred
smoothly. In the cases of 8a and 8b, despite that chiral
arylallenes are known to undergo rapid epimerization under
gold catalysis,14 the products were still obtained with good
enantiomeric ratios, suggesting the HO 5-endo-trig cyclization
must be rapid. 8c with a 2-benzyl group was formed in a low
yield, which could be due to a competitive isomerization
toward a 1,2-dien-1-ol intermediate, but its homologues
derived from achiral tertiary propargylic alcohols such as
8d−8g were all formed in good to excellent yields and with
C
DOI: 10.1021/jacs.8b12833
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Journal of the American Chemical Society
Communication
outcome, assuming that the subsequent protodeauration is
stereoretentive, which is well documented.16
Scheme 3. Study of the Axial Chirality of Gold Catalysts and
the Stereochemical Model
In conclusion, for the first time a generally applicable
asymmetric isomerization of alkynes to chiral allenes is realized
via a homogeneous gold catalysis enabled by a designed chiral
bifunctional biphenyl-2-ylphosphine ligand. Instead of relying
on a chiral biaryl axis to achieve asymmetry, this catalysis
employs a more readily installed center chirality in the
designed ligand. With chiral or achiral propargylic alcohols as
substrates, chiral 2,5-dihydrofurans are directly formed in
mostly good yields and importantly with good to excellent
levels of stereoselectivity at the newly generated stereocenter.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b12833.
■
S
Experimental details, compound characterization, and
spectra (PDF)
CIF file for [(aS,R)-L4-4]AuCl (CIF)
CIF file for [(aR,R)-L4-4]AuCl (CIF)
AUTHOR INFORMATION
Corresponding Author
*zhang@chem.ucsb.edu
■
ORCID
Zhixun Wang: 0000-0001-5688-5002
Liming Zhang: 0000-0002-5306-1515
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank NSF (Grant CHE 1800525) and NIGMS
(Grant R01GM123342) for generous financial support and
NIH shared instrument Grant S10OD012077 for the
acquisition of a 400 MHz NMR spectrometer. The authors
thank Dr. Guang Wu for X-ray structure determination and Dr.
Hongjun Zhou for NMR assistance.
configuration is stable when ligated to AuCl. Interestingly, as
shown in Scheme 3B, eq 1, a 1:1 mixture of [(aR,R)-L4-
4]AuCl and [(aS,R)-L4-4]AuCl was completely converted into
[(aR,R)-L4-4]AuCl when a solution of it in DCE was first
treated with NaBArF4, a chloride abstractor, and 6-dodecyne,
then heated at 80 °C and at last quenched with
tetrabutylammonium chloride. This experiment suggests that
the ligand biaryl axis, most likely in the sterically minimum
form of cationic (L4-4)Au+, could rotate at 80 °C and,
moreover, its configuration requisite for our asymmetric
catalysis is thermodynamically much favored. This result
suggests that the existence of stable precatalyst axial isomers
is inconsequential. This conclusion is nicely supported by the
experiments shown in Scheme 3B, eq 2, where the conversions
and the yields correlate to the total amounts of (L4-4)AuCl
instead of that of [(aR,R)-L4-4]AuCl alone.
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D
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Journal of the American Chemical Society
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