Copper-catalyzed asymmetric reductions of aryl/heteroaryl ketones under mild aqueous micellar conditions

Article abstract of DOI:10.1021/acs.orglett.1c00746

Enantioselective syntheses of nonracemic secondary alcohols have been achieved in an aqueous micellar medium via copper-catalyzed (Cu(OAc)2·H2O/(R)-3,4,5-MeO-MeO-BIPHEP) reduction of aryl/heteroaryl ketones. This methodology serves as a green protocol to access enantio-enriched alcohols under mild conditions (0-22 °C) using a base metal catalyst, together with an inexpensive, innocuous, and convenient stoichiometric hydride source (PMHS). The secondary alcohol products are formed in good to excellent yields with ee values greater than 90%.

Full text of DOI:10.1021/acs.orglett.1c00746

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Letter
Copper-Catalyzed Asymmetric Reductions of Aryl/Heteroaryl
Ketones under Mild Aqueous Micellar Conditions
David M. Fialho, Elham Etemadi-Davan, Olivia C. Langner, Balaram S. Takale, Amol Gadakh,
Ganesh Sambasivam, and Bruce H. Lipshutz*
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ABSTRACT: Enantioselective syntheses of nonracemic secondary
alcohols have been achieved in an aqueous micellar medium via
copper-catalyzed (Cu(OAc)2·H2O/(R)-3,4,5-MeO-MeO-BI-
PHEP) reduction of aryl/heteroaryl ketones. This methodology
serves as a green protocol to access enantio-enriched alcohols
under mild conditions (0−22 °C) using a base metal catalyst,
together with an inexpensive, innocuous, and convenient
stoichiometric hydride source (PMHS). The secondary alcohol
products are formed in good to excellent yields with ee values
greater than 90%.
There have, likewise, been investigations into the viability of
nantio-enriched alcohols are important building blocks for
1
Ethe preparation of pharmaceuticals and agrochemicals, the base metal copper as a catalyst in ligated form to facilitate
enantioselective transformations.28−34 However, these proce-
including compounds such as anticancer agents (e.g.,
crizotinib),2 antihistamines (e.g., orphenadrine),3 antidepres-
dures require such 1,2-additions be run in toluene at low
temperatures for maximum ee’s.35 Clearly, new technology is
needed that considers sustainability and environmental impact
by (1) avoiding the energy input associated with low
temperature reactions, (2) reducing costs associated with
precious and/or endangered transition metal catalysts, and (3)
minimizing waste creation from reactions run in non-recycled
organic solvents.
sants (e.g., duloxetine),4 and several others.5−9 Asymmetric
hydrogenation (AH) of prochiral ketones is among the most
common methods and is routinely achieved using transition-
metal-based reagents (Figure 1).10 Organocatalysis is yet
another important option.11 Biocatalysis, especially enzymatic
reactions,12 e.g., using a ketoreductase, now possible in tandem
with chemo-catalysis in water,12 represents a rapidly growing
area of considerable potential in synthesis. Industrial processes
tend to utilize hydrogen in the presence of expensive transition
metal catalysts such as rhodium, iridium, and ruthenium.13,14
Pioneering work by Noyori in 1987 showed the potential for
RuCl2[(R)-BINAP] to catalyze enantioselective reductions of
ketones. These reactions are typically performed under 100
atm of H2 and at 0.05 mol % catalyst loading in methanol.14
Later, a variety of related Ru-based catalysts were developed
for asymmetric transfer hydrogenation (ATH), utilizing
hydride donors other than H2.15−19 Catalysts based on Ir
have also been introduced for A(T)H of ketones, as have those
based on Rh and Fe. However, these methodologies still
typically require high pressures of H2 and/or use of organic
solvents as the reaction medium.20−25 While methods exist for
aqueous ATH with26 or without27 surfactant, these still require
the precious metal ruthenium.
We now disclose a new and general process that involves a
copper hydride-catalyzed reduction in a recyclable aqueous
medium. Reactions are run between 0 °C and room
temperature and rely on a commercially available chiral ligand,
leading to nonracemic alcohols, typically in useful isolated
yields and with high ee’s.
Initially, asymmetric reduction of 6′-methoxy-2′-acetonaph-
thone (1a) was selected for evaluation as a model system
(Table 1). CuH was generated in situ starting with Cu(OAc)2·
H2O (3 mol %) in the presence of one of a variety of
nonracemic bis-phosphine ligands in an aqueous solution of
designer surfactant TPGS-750-M (2 wt %), using polyme-
thylhydrosiloxane (PMHS), a convenient and inexpensive
stoichiometric hydride source. Recognizing that the optimal
Received: March 3, 2021
Published: April 27, 2021
Several organocatalytic approaches, such as oxazaborolidine-
based methods developed by Itsuno11a and Corey,11b,c lead to
asymmetric ketone reductions without use of transition metals.
In general, these organocatalytic approaches also rely on the
use of organic solvents.
https://doi.org/10.1021/acs.orglett.1c00746
© 2021 American Chemical Society
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a
Table 1. Optimization of Asymmetric Ketone Reductions
entry
ligand
T (°C)
(co)solvent
THF
yield (%)
ee (%)
b
1
L1
L1
L6
L7
L8
L9
L7
L7
L1
L7
L7
22
22
22
22
22
22
22
22
18
<10
78
65
0
25
83
80
28
92
95
ND
ND
87
93
ND
18
95
95
90
97
b c
,
2
3
4
5
6
7
8
9
b
b
b
THF
THF
THF
THF
toluene
toluene
toluene
toluene
toluene
Figure 1. Various approaches to asymmetric ketone reduction:
yellow-colored regions represent hydrophobic media, such as organic
solvents, enzyme cores, or micellar cores; blue regions represent bulk
water.
d
0−22
0−22
0−22
10
11
e
96
a
Roche (BIPHEP) and Takasago (SEGPHOS) ligands for
asymmetric hydrosilylation in toluene at −78 to 0 °C35 would
not necessarily behave similarly in aqueous emulsions at room
temperature, screening of ligands was required. It was,
therefore, not surprising that chelated CuH derived from the
previously successful ligand (R)-DTBM-SEGPHOS (L1),33
while leading to an ee for product alcohol 1b of 90% (Table 1;
entry 9), was, indeed, not the best observed result (vide infra).
Yields were also found to be compromised using several other
bis-phosphine ligands that had previously been employed
successfully in organic solvents, including those in the BIPHEP
(L2−L6, Table 1; entry 3) and JosiPhos (L8 and L9, Table 1;
entries 5 and 6) series (see results in the Supporting
Information).33b Synthetically useful results in terms of both
ee’s and isolated yields were eventually realized using 3 mol %
CuH complexed by commercially available (R)-3,4,5-MeO-
MeO-BIPHEP (L7), thus leading to its selection as the
preferred ligand on copper for further optimization (entry 7).
Conducting the reaction under the same conditions “on water”
(i.e., in the absence of surfactant) gave poor results,
emphasizing the key role being played by the micellar medium
(entries 1 and 2).
Employing (S)-L7 on the reduction of 1a gave the opposite
enantiomer of 1b as expected (see the Supporting
Information). Further screening explored the effect of the
order of addition of reactants, the rate and temperature of
PMHS addition, the impact of varying the cosolvent and
additive, and the concentration of both the catalyst and starting
materials (see the Supporting Information).
Addition of PMHS to the aqueous reaction mixture at ice
bath temperatures was found to be beneficial in terms of both
resulting alcohol yields and ee’s. This may be due to the
avoidance of heat associated with an initial “on water”
Unless otherwise noted, all reactions were carried out using 0.1
mmol of 1a, 3 mol % catalyst (5 mol % for trials 1 and 2), 3.3 mol %
ligand, 0.5 mL of solvent, 35 μL of cosolvent, 0.6 mmol of PMHS
(added 0.1 mmol every 25 min), and TPGS-750-M at 2 wt %. All
reactions were carried out under an inert atmosphere. Yields refer to
isolated material and were determined by weight; ee’s were
determined by chiral HPLC. The remaining mass was starting
b
c
material. PMHS added in one portion. Performed in pure water
d
with no surfactant or cosolvent. Performed with 8 mol % catalyst.
e
Performed in pure toluene.
formation of ligated CuH, given the insolubilities of both the
silane and ligated copper(II) salt in an aqueous medium
(Table 1; entries 7 and 10). Attempting the reaction at higher
substrate concentrations proved difficult due to clumping
which inhibited stirring, notwithstanding the presence of
toluene as a cosolvent. Higher catalyst loadings proved not to
be beneficial (entry 7 vs 8). Similar yields and ee’s were
obtained when the reaction was performed in pure toluene,
indicating that the transition to an aqueous medium at the
same temperature leads to results that are as good or better as
those seen in organic solvents (entry 10 vs 11). Scaling the 1a
to 1b reduction employing 20 mg (0.1 mmol) up to 1 g (5
mmol) at 0−5 °C afforded the product in 70% isolated yield
without significant loss of ee (96%).
Following identification of the optimized ligand and
conditions for asymmetric 1,2-addition to model educt 6′-
methoxy-2′-acetonaphthone, other aryl and heteroaryl ketones
were then assessed in 2 wt % aqueous TPGS-750-M (Scheme
1). Various acetophenone derivatives were efficiently reduced
with excellent enantioselectivities. Isolated yields were in the
range 52−99%, while ee’s were between 91 and 100%. Ketones
were chemoselectively converted to their corresponding
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reaction medium could be reused, including not only the
surfactant solution but also the catalyst/ligand (Table 2).
Scheme 1. CuH-Catalyzed Asymmetric Reductions of Aryl/
Heteroaryl Ketones
a
Table 2. Recycling Study
reaction cycle
yield (%)
ee (%)
initial reaction
first recycling
second recycling
75
79
54
96
96
96
Recycling was performed by filtering the reaction under argon
after completion to remove the solid product, oxidized PMHS,
and remaining starting material. The filtrate was then reused
for the subsequent reaction. Good to moderate yields could be
obtained for three cycles of the same reaction medium without
any loss of ee. By recycling the reaction medium, the loading of
Cu/reaction drops to 1 mol % while the amount of organic
waste created is minimized, as quantified by the associated low
E factor (7.6; see the Supporting Information for calcu-
lations).38
Sequential reactions run in a one-pot operation are easily
accommodated given the commonality of water as a reaction
medium, thereby dramatically reducing both the time invested
per reaction and waste being generated (associated with
individual workups). As illustrated in Scheme 2, following an
Scheme 2. One-Pot L*CuH-Catalyzed Reduction Followed
by a Suzuki−Miyaura Coupling in Water at rt
a
Reactions were either (A) performed in sealed vials or (B) set up
from a stock solution of the catalyst complex and run under argon.
initial CuH-catalyzed asymmetric reduction, a Suzuki−Miyaura
coupling on the derived bromopyridine led to the anticipated
biaryl product in good isolated yield, generated in 93% ee.
The mechanism of these copper-catalyzed ketone reductions
in water most likely follows that of analogous copper-catalyzed
1,2-additions in organic solvents (Scheme 3).33b Nonracemi-
cally ligated copper(I) hydride (L-CuH; i) is first generated in
situ. Hydride transfer then occurs in a 4-centered transition
state ii, with oxygen binding to copper to afford the copper
alkoxide, complex iii. Through another 4-membered transition
state iv involving PMHS, the initially formed product silyl
ether (v) is generated in concert with regeneration of the
ligated copper hydride catalyst (i). By either hydrolysis or
quenching with fluoride, the silyl ether v is cleaved to give the
sec-alcohol (vi).
In summary, a new protocol has been developed that
transforms prochiral aryl and heteroaryl ketones to enantio-
enriched secondary alcohols, making use of mild, environ-
mentally responsible conditions, as well as a readily available
copper pre-catalyst and inexpensive PMHS. A previously
underutilized ligand as part of a copper hydride catalyst has
alcohols in the presence of other reducible functional groups,
such as alkenes (12b), alkynes (8b−10b), and esters (10b,
23b). Heteroaryl ketones, including 2-acetylpyridines and 2-
acetylthiophenes are also amenable, leading to products 16b−
19b and 20b−21b, respectively. However, while the former
could be reduced efficiently, 2-acetylthiophenes gave only
moderate yields of secondary alcohols. This may be due to
electronic effects: 2-acetylpyridines are electron-deficient,
whereas 2-acetylthiophenes are comparatively electron-rich.
In cases leading to low isolated yields, most of the remaining
mass was recovered as starting material, perhaps indicative of a
far slower reduction.
To demonstrate utility of this methodology, syntheses of
several intermediates associated with pharmaceuticals were
undertaken. Compounds 22b, 23b, and 24b, precursors to
fluoxetine/atomoxetine,36 ezetimibe,37 and aprepitant,5 respec-
tively, could all be formed in good yields and excellent ee’s
from their respective aryl ketones.
Once the initial reduction was complete, recycling studies
were performed to determine the extent to which the entire
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Notes
Scheme 3. Proposed Mechanism of L*CuH-Catalyzed
Asymmetric Ketone Reduction
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support provided by Anthem Biosciences, PHT
International, and the NSF (CHE 18-56406) is warmly
acknowledged with thanks.
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AUTHOR INFORMATION
Corresponding Author
■
Bruce H. Lipshutz − Department of Chemistry &
Biochemistry, University of California, Santa Barbara,
California 93106, United States; orcid.org/0000-0001-
9116-7049; Email: lipshutz@chem.ucsb.edu
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David M. Fialho − Department of Chemistry & Biochemistry,
University of California, Santa Barbara, California 93106,
United States
Elham Etemadi-Davan − Department of Chemistry &
Biochemistry, University of California, Santa Barbara,
California 93106, United States
Olivia C. Langner − Department of Chemistry &
Biochemistry, University of California, Santa Barbara,
California 93106, United States
Balaram S. Takale − Department of Chemistry &
Biochemistry, University of California, Santa Barbara,
California 93106, United States; orcid.org/0000-0001-
8279-944X
Amol Gadakh − Anthem Biosciences Private Limited,
Bommasandra, Bangalore 560 099, India
Ganesh Sambasivam − Anthem Biosciences Private Limited,
Bommasandra, Bangalore 560 099, India
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