Catalytic Enantioselective Carbon-Oxygen Bond Formation: Phosphine-Catalyzed Synthesis of Benzylic Ethers via the Oxidation of Benzylic C-H Bonds

Article abstract of DOI:10.1021/jacs.6b08486

Benzylic alcohols and ethers are common subunits in bioactive molecules, as well as useful intermediates in organic chemistry. In this Communication, we describe a new approach to the enantioselective synthesis of benzylic ethers through the chiral phosphine-catalyzed coupling of two readily available partners, γ-aryl-substituted alkynoates and alcohols, under mild conditions. In this process, the alkynoate partner undergoes an internal redox reaction. Specifically, the benzylic position is oxidized with good enantioselectivity, and the alkyne is reduced to the alkene.

Full text of DOI:10.1021/jacs.6b08486

Communication
pubs.acs.org/JACS
Catalytic Enantioselective Carbon−Oxygen Bond Formation:
Phosphine-Catalyzed Synthesis of Benzylic Ethers via the Oxidation
of Benzylic C−H Bonds
Daniel T. Ziegler and Gregory C. Fu*
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States
S
* Supporting Information
ABSTRACT: Benzylic alcohols and ethers are common
subunits in bioactive molecules, as well as useful inter-
mediates in organic chemistry. In this Communication, we
describe a new approach to the enantioselective synthesis
of benzylic ethers through the chiral phosphine-
catalyzed coupling of two readily available partners, γ-aryl-
substituted alkynoates and alcohols, under mild conditions.
In this process, the alkynoate partner undergoes an internal
redox reaction. Specifically, the benzylic position is oxidized
with good enantioselectivity, and the alkyne is reduced to
the alkene.
generate benzylic ethers in good enantiomeric excess under
notably simple and mild conditions (eq 1). If desired, the
resulting ethers can be transformed into other useful com-
pounds through functionalization of the olefin or conversion
to a benzylic alcohol.
We recently reported that chiral phosphines can catalyze
the enantioselective intermolecular coupling of an array of
carbon, nitrogen, and sulfur nucleophiles with the γ position of
allenoates and related compounds (Figure 2);6−8 furthermore,
nantioenriched benzylic ethers are valuable targets in
1
Echemistry, both as endpoints and as intermediates in the
synthesis of other useful families of molecules through simple
deprotection,2 coupling reactions,3 and the like. A variety of
strategies for the generation of chiral benzylic ethers have
been described, including catalytic enantioselective processes.
In the latter cases, the benzylic ether is typically produced
from an enantioenriched benzylic alcohol, which is most often
synthesized from a carbonyl compound via asymmetric hydro-
genation or nucleophilic addition (Figure 1).4 The enantio-
selective oxidation of C−H bonds provides an alternative
approach to chiral benzylic alcohols.5
In this Communication, we describe a distinct, direct method
for the catalytic asymmetric synthesis of benzylic ethers.
Specifically, we demonstrate that, with the aid of a chiral phos-
phine catalyst, γ-aryl alkynoates can be coupled with alcohols to
Figure 2. Reports to date of phosphine-catalyzed enantioselective γ
additions (R ≠ H).
corresponding intramolecular reactions of nitrogen and oxygen
nucleophiles can furnish enantioenriched heterocycles.6e,9
More recently, through the use of a bifunctional phosphine
catalyst, Jacobsen also achieved asymmetric intermolecular
couplings of nitrogen nucleophiles.10 With respect to even a
racemic variant of the coupling illustrated in Figure 2, to the best
of our knowledge, there are no reports of phosphine-catalyzed
γ additions of any nucleophiles to alkynoates/allenoates that
bear an aryl group in the γ position,11 and there is only a single
Figure 1. Enantioenriched benzylic ethers: common catalytic
asymmetric methods for their synthesis via benzylic alcohols and
examples of their significance.
Received: August 13, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.6b08486
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Journal of the American Chemical Society
Communication
example of an intermolecular coupling of an oxygen nucleophile
with any γ-substituted alkynoate/allenoate.12
Table 2. Phosphine-Catalyzed Asymmetric Synthesis of
Benzylic Ethers: Scope with Respect to the Aryl Group
a
We were therefore pleasantly surprised to determine that,
under the simple conditions presented in Table 1, commercially
Table 1. Phosphine-Catalyzed Asymmetric Synthesis of
a
Benzylic Ethers: Effect of Reaction Parameters
a
b
All data are the average of two experiments. The yield was
1
determined via H NMR spectroscopy, using diphenylmethane as an
internal standard. Yield of purified product.
c
a
b
All data are the average of two experiments. Yield of purified,
c
d
isolated product. Catalyst loading: 10% (S)-1. Amount of
available spirophosphine 16e,9,13 catalyzes the coupling of an
alcohol with an alkynoate that is substituted with a phenyl group
in the γ position, furnishing the desired benzylic ether with
very good enantioselectivity and in high yield (97% ee, 94%
yield; entry 1). This internal redox process oxidizes the benzylic
carbon while reducing the alkyne. Use of the corresponding
allenoate leads to essentially the same ee, although the yield
is slightly lower (88%; entry 2). Phosphepine 2, which has
served as an effective catalyst for other couplings,6b,f provides
the desired benzylic ether with diminished efficiency (62% ee,
74% yield; entry 3). Use of a lower catalyst loading or less of
the alcohol has no impact on enantioselectivity, but results in a
minor erosion in yield (80−89%; entries 4−6). Similarly, the ee
of the coupling is unaffected by the presence of a small amount
of water, although the yield is modestly lower (84%; entry 7).
We next examined the scope of this new transformation with
regard to the aryl substituent of the alkynoate; these substrates
are readily accessible via the coupling of benzylic chlorides with
tert-butyl propiolate.14 We have established that this phosphine-
catalyzed asymmetric synthesis of benzylic ethers proceeds
with good enantioselectivity with a wide array of aryl groups,
furnishing the desired products under straightforward and mild
conditions (Table 2). For example, the aromatic substituent can
be electron-rich or electron-poor (entries 2 and 3), and it can
be ortho-substituted, although in such cases a higher catalyst
loading is required in order to obtain good yields (10% catalyst;
entries 4 and 5). Furthermore, the aryl group can be an
extended π-system (entries 6 and 7), and it can be a sulfur or a
nitrogen heterocycle (entries 8−10). On a gram scale (1.40 g of
product), the coupling depicted in entry 2 proceeds in 94% ee
and 91% yield.15
nucleophile: 2.0 equiv.
in Table 2. For example, substrates that bear an amide rather
than an ester group (eq 2), as well as a methyl rather than an
aryl substituent (eq 3), can be employed.16 In both cases, the
desired coupling product is generated with high enantiose-
lectivity and in very good yield.
A variety of primary alcohols can be employed as the
nucleophilic coupling partner (Table 3). For example, benzyl
alcohol as well as an electron-poor benzylic alcohol are suitable
substrates, furnishing ee’s and yields that are similar to those
observed for p-methoxybenzyl alcohol (entries 1−3). Other
functionalized, as well as unfunctionalized, alcohols also afford
the desired benzylic ether with very good enantioselectivity
(entries 4−10). The efficiency of C−O bond formation is
sensitive to the steric demand of the nucleophile: although
coupling proceeds in fairly good yield with a β-branched
primary alcohol (entry 10), cyclohexanol is not a useful partner
under our standard conditions (<20% yield). An initial attempt
to employ water as the nucleophile was not successful.
The scope with respect to the electrophile is not limited to
aryl- and ester-substituted compounds of the type depicted
Although saturated secondary alcohols such as cyclohexanol
are not effective coupling partners under our standard conditions,
B
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Journal of the American Chemical Society
Communication
alcohol or that of the phosphine catalyst. Because different
diastereomers of the benzylic ether are favored in these two
couplings (both reactions proceed with >20:1 dr), we conclude
that the stereochemical course is catalyst-controlled.17
Table 3. Phosphine-Catalyzed Asymmetric Synthesis of
Benzylic Ethers: Scope with Respect to the Alcohol
a
The enantioenriched benzylic ethers that are produced in
these phosphine-catalyzed asymmetric couplings bear an olefin
that can be further functionalized. For example, conjugate
addition and dihydroxylation proceed with good diastereose-
lectivity and in good yield (eqs 7 and 8); the diol generated via
dihydroxylation is related to an intermediate employed in the
total synthesis of (+)-crassalactone A.18 If the enantioenriched
benzylic alcohol, rather than the ether, is the target, then
deprotection can be achieved in good yield (eq 9).
a
b
All data are the average of two experiments. Yield of purified,
c
d
isolated product. Amount of nucleophile: 2.0 equiv. The methyl
rather than the tert-butyl ester of the alkynoate was used. Catalyst
e
loading: 20% (S)-1.
during our study of the use of primary alcohols as nucleophiles
(Table 3), we observed that unsaturated alcohols such as benzyl
alcohol and allyl alcohol are significantly more reactive than
saturated alcohols (eq 4). This enhanced reactivity enables
A possible mechanism for this method for the catalytic
asymmetric synthesis of benzylic ethers is outlined in Figure 3.7
Nucleophilic addition of the phosphine to the β position of the
alkynoate generates a zwitterion (A) that tautomerizes to form
the application of our phosphine-catalyzed asymmetric coupling
to a benzylic secondary alcohol, 1-phenylethanol (eqs 5 and 6).
By examining the stereochemical outcome for the reaction
of each enantiomer of this chiral alcohol, catalyzed by (S)-1, we
can determine whether the stereochemistry of the new benzylic
stereocenter is primarily controlled by the stereochemistry of the
Figure 3. Outline of a possible pathway for the phosphine-catalyzed
asymmetric synthesis of benzylic ethers. For the sake of simplicity, all
steps are drawn as irreversible, and all alkenes are illustrated as single
isomers.
C
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Journal of the American Chemical Society
Communication
Scale; Blaser, H.-U., Federsel, H.-J., Eds.; Wiley-VCH: Weinheim,
2010. (b) For a discussion of the catalytic enantioselective alkylation
of aldehydes, see: Santanilla, A. B.; Leighton, J. L. In Science of
Synthesis, Stereoselective Synthesis; De Vries, J. G., Molander, G. A.,
Evans, P. A., Eds.; Georg Thieme Verlag: Stuttgart, 2011; Vol. 2, pp
401−447.
(5) For a discussion and leading references, see: Andrus, M. B. In
Science of Synthesis, Stereoselective Synthesis; De Vries, J. G., Molander,
G. A., Evans, P. A., Eds.; Georg Thieme Verlag: Stuttgart, 2011; Vol. 3,
pp 469−482.
new zwitterion B. Intermediate B deprotonates the alcohol
(ROH) to afford an ion pair (C). The alkoxide then adds to
the electrophilic γ carbon, producing ylide D. Tautomerization
furnishes zwitterion E, which eliminates the phosphine to
regenerate the catalyst and yield the product.
For the enantioselective coupling illustrated in entry 2 of
Table 2, we have determined through 31P NMR spectroscopy
that the free phosphine (1) is the resting state of the catalyst
1
during the reaction. In addition, through H NMR spectros-
copy, we have discovered that the alkynoate isomerizes to the
allenoate to a significant extent during the coupling, presumably
via elimination of the phosphine from intermediate A (Figure 3).
In summary, commercially available chiral phosphine 1
serves as an effective catalyst for the enantioselective coupling
of alcohols with γ-aryl alkynoates, thereby directly generating
benzylic ethers in good ee from readily available starting materials
under simple and mild conditions. Although related asymmetric
phosphine-catalyzed intermolecular couplings have been reported,
no success has been described with an electrophile that bears an
aryl substituent in the γ position or with an oxygen nucleophile.
A wide range of aromatic groups (including heterocycles) and
a broad array of primary alcohols are compatible with this
new process. The resulting enantioenriched benzylic ethers can
be useful both as endpoints and as intermediates in organic
chemistry. Further investigations of the use of phosphines as
chiral nucleophilic catalysts are underway.
(6) Carbon nucleophiles: (a) Smith, S.; Fu, G. C. J. Am. Chem. Soc.
2009, 131, 14231−14233. (b) Sinisi, R.; Sun, J.; Fu, G. C. Proc. Natl.
Acad. Sci. U. S. A. 2010, 107, 20652−20654. Sulfur nucleophiles:
(c) Sun, J.; Fu, G. C. J. Am. Chem. Soc. 2010, 132, 4568−4569.
(d) Fujiwara, Y.; Sun, J.; Fu, G. C. Chem. Sci. 2011, 2, 2196−2198.
Nitrogen nucleophile: (e) Lundgren, R. J.; Wilsily, A.; Marion, N.; Ma,
C.; Chung, Y. K.; Fu, G. C. Angew. Chem., Int. Ed. 2013, 52, 2525−
2528. Carbon nucleophile: (f) Kalek, M.; Fu, G. C. J. Am. Chem. Soc.
2015, 137, 9438−9422.
(7) For pioneering studies of non-enantioselective processes (no γ
substituent), see: (a) Trost, B. M.; Li, C.-J. J. Am. Chem. Soc. 1994,
116, 3167−3168. (b) Zhang, C.; Lu, X. Synlett 1995, 1995, 645−646.
(8) For the initial investigation of asymmetric catalysis wherein the
stereochemistry at the δ (not the γ) position of the product is
controlled, see: Chen, Z.; Zhu, G.; Jiang, Q.; Xiao, D.; Cao, P.; Zhang,
X. J. Org. Chem. 1998, 63, 5631−5635.
(9) Chung, Y. K.; Fu, G. C. Angew. Chem., Int. Ed. 2009, 48, 2225−
2227.
(10) Nitrogen nucleophile: Fang, Y.-Q.; Tadross, P. M.; Jacobsen, E.
N. J. Am. Chem. Soc. 2014, 136, 17966−17968.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b08486.
(11) For examples of failed attempts, see the following: (a) Footnote
12 in ref 6f. (b) Entry 5 of Table 3 in Zhou, Q.-F.; Zhang, K.; Kwon,
O. Tetrahedron Lett. 2015, 56, 3273−3276.
■
S
(12) See eq 2 in Trost, B. M.; Li, C.-J. J. Am. Chem. Soc. 1994, 116,
10819−10820.
Procedures and characterization data PDF)
X-ray data for P16308 CIF)
X-ray data for p16227ja (CIF)
X-ray data for jap16228 (CIF)
(13) Xie, J.-H.; Zhou, Q.-L. Acc. Chem. Res. 2008, 41, 581−593.
(14) Davies, K. A.; Abel, R. C.; Wulff, J. E. J. Org. Chem. 2009, 74,
3997−4000.
(15) Phosphine catalyst 1 was recovered in 87% yield as the
corresponding phosphine oxide after deliberate oxidation with t-
BuOOH.
AUTHOR INFORMATION
Corresponding Author
*gcfu@caltech.edu
■
(16) Under our standard conditions, if the alkyl substituent in the γ
position is larger than a methyl group, good ee but modest yield is
observed.
(17) When racemic 1-phenylethanol is employed as the nucleophile, a
very modest kinetic resolution is observed (s = 2.2).
(18) Shekhar, V.; Reddy, D. K.; Suresh, V.; Babu, D. C.;
Venkateswarlu, Y. Tetrahedron Lett. 2010, 51, 946−948.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support has been provided by the National Institutes of
Health (National Institute of General Medical Sciences, R01-
GM57034 and R01-GM062871). We thank William Reichard,
Jun Myun Ahn (X-ray crystallography), and Dr. Michael K.
Takase (X-ray crystallography) for assistance.
REFERENCES
■
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(4) (a) For some leading references on the catalytic asymmetric
hydrogenation of ketones, see: Asymmetric Catalysis on Industrial
D
DOI: 10.1021/jacs.6b08486
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