Enantioselective metal-free reduction of ketones by a user-friendly silane with a reusable chiral additive

Article abstract of DOI:10.1016/j.tetlet.2018.06.032

1-Hydrosilatrane, a safe and easy-to-handle reducing reagent that can be inexpensively accessed, has been shown to reduce prochiral ketones asymmetrically in the presence of chiral 1,2-aminoalcohols with ees ranging from 8% to 86%. The best result was achieved using ephedrine as the source of chirality, which is readily commercially available. The additive can be recovered through extraction and reused without any erosion of enantioselectivity.

Full text of DOI:10.1016/j.tetlet.2018.06.032

Accepted Manuscript
Enantioselective metal-free reduction of ketones by a user-friendly silane with
a reusable chiral additive
Sami E. Varjosaari, Vladislav Skrypai, Sharon M. Herlugson, Thomas M.
Gilbert, Marc J. Adler
PII:
S0040-4039(18)30774-3
https://doi.org/10.1016/j.tetlet.2018.06.032
TETL 50070
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
10 April 2018
5 June 2018
11 June 2018
Please cite this article as: Varjosaari, S.E., Skrypai, V., Herlugson, S.M., Gilbert, T.M., Adler, M.J., Enantioselective
metal-free reduction of ketones by a user-friendly silane with a reusable chiral additive, Tetrahedron Letters (2018),
doi: https://doi.org/10.1016/j.tetlet.2018.06.032
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Enantioselective metal-free reduction of
ketones by a user-friendly silane with a
reusable chiral additive
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Sami E. Varjosaari, Vladislav Skrypai, Sharon M. Herlugson, Thomas M. Gilbert, and Marc J. Adler
Department of Chemistry & Biochemistry, Northern Illinois University, 1425 W. Lincoln Hwy, Dekalb, IL,
6
0115, USA.
Department of Chemistry & Biology, Ryerson University, 350 Victoria Street, Toronto, ON, M5B 2K3, Canada

1
Tetrahedron
Enantioselective metal-free reduction of ketones by a user-friendly silane with a
reusable chiral additive
a
a
a
a
b,
Sami E. Varjosaari , Vladislav Skrypai , Sharon M. Herlugson , Thomas M. Gilbert , and Marc J. Adler 
a
Department of Chemistry & Biochemistry, Northern Illinois University, 1425 W. Lincoln Hwy, Dekalb, IL, 60115, USA.
Department of Chemistry & Biology, Ryerson University, 350 Victoria Street, Toronto, ON, M5B 2K3, Canada
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
1-Hydrosilatrane, a safe and easy-to-handle reducing reagent that can be inexpensively accessed,
has been shown to reduce prochiral ketones asymmetrically in the presence of chiral 1,2-
aminoalcohols with ees ranging from 0 to 86%. The best result was achieved using ephedrine as
the source of chirality, which is readily commercially available. The additive can be recovered
through extraction and reused without any erosion of enantioselectivity.
Available online
2
018 Elsevier Ltd. All rights reserved.
Keywords:
Hydrosilylation
Asymmetric Ketone Reduction
Synthesis of Chiral Alcohols
—
——

Corresponding author. Tel.: +1-416-379-5000 x543461; e-mail: marcjadler@ryerson.ca

2
Tetrahedron
1
. Introduction
cost, as chiral sources can be expensive and difficult to recapture
and recycle. Yet the technical difficulty in controlling such
reactions – coupled with the impracticality of using highly
reactive silanes – has prevented significant advancement in the
field of metal-free asymmetric reduction using hydrosilanes.
The asymmetric reduction of ketones represents one of the
most efficient methods to synthesize chiral alcohols, which are of
significant importance in the pharmaceutical, agrochemical, and
1
flavor industries. Many efficient methods have been developed
for this transformation with transition metal and main group
2
reagents, both catalytically and stoichiometrically. Transition
metal catalysts have been used in asymmetric hydrogenation and
hydride transfer reactions with great success, but tend to be
expensive, unstable under ambient conditions, and/or can
contaminate products by metal-leaching, frequently making these
3
,4a
methods difficult to apply on preparative scales. Furthermore,
the chiral ligands required for such reactions are often expensive
and difficult to access. Organocatalysts have emerged as
alternatives to transition metal catalysts without these key
4
drawbacks. Some of the most notable organocatalytic systems
1
c,5
include the CBS method using chiral boranes and chiral Lewis
6
acids with Hantzsch esters.
In comparison, hydrosilanes have been relatively
underdeveloped for the chiral reduction of ketones. Hydrosilanes
are popular reducing agents as they can be inexpensive,
Figure 1. Enantioselective reduction of ketones using hydrosilanes with
a chiral Lewis base (CLB) catalyst and the competing pathway
7
chemically stable, and easy-to-handle hydride sources. The most
successful applications of hydrosilanes to the asymmetric
reduction of prochiral ketones, however, involve the use of
highly reactive silanes such as trialkoxy- or trichlorosilanes,
which are difficult to work with due to their rapid degradative
reaction with atmospheric water. Generally, hydrosilanes require
an exogenous activator or catalyst to effect reduction, and it is
through this additive that stereochemical information is usually
1-Hydrosilatrane 1 (Fig. 2), a caged alkoxysilane, has been
shown to be an effective reducing agent for ketones in the
1
6
presence of a Lewis base additive. As a white crystalline solid,
1-hydrosilatrane 1 is safe and much easier to handle than the
reactive silicon hydride sources, yet it is also a more active atom-
transfer reagent than typical robust hydrosilanes such as
8
communicated. Chiral hydrosilanes can be used for moderate
1
7
enantioselectivity, but can be difficult to synthesize and are
trialkylsilanes. In the course of our study regarding the
reduction of ketones with achiral additives we observed evidence
of diastereoselectivity, which made us believe that using a chiral
Lewis base could result in an enantioselective version of this
reaction. We also saw tentative signs of the silatrane moiety
9
required in stoichiometric amounts.
The first organocatalyzed asymmetric reduction of ketones
was achieved by Hosomi and co-workers, using chiral lithium
diolates and aminoalcoholates to activate trimethoxysilanes,
1
8
preferring to remain attached to the alkoxide product,
forming
secondary alcohols
in
good
yields
and
1
0
potentially indicating the feasibility of running this reaction with
catalytic amounts of the chiral Lewis base.
enantioselectivity. Since then, several other groups have used
chiral anionic Lewis bases to activate alkoxysilanes with varying
degrees of success; the highest enantioselectivities were
1
1
1
1b
achieved with an axially chiral binaphthol derivative. Even
greater enantioselectivity has been achieved using the more
reactive t2richlorosilane with neutral chiral Lewis base
1
activators.
Figure 2. 1-Hydrosilatrane
Polymethylhydrosiloxane (PMHS) is a popular silane due to
1
3
its stability, low cost, and ease of handling. Although PMHS
has shown potential in processes for the asymmetric
hydrosilylation of ketones, the most effective methods require
2. Results and Discussion
1
4
metal catalysts. Furthermore, the active silane species in the
presence of Lewis bases has been suggested to be the more
pyrophoric methylsilane, complicating the use of Lewis bases as
2
.1. Activator screening
This study commenced with a screening of stoichiometric
1
5
organocatalysts in large scale hydrosilylations.
amounts of several chiral Lewis base activators (Table 1). All
activators were deprotonated in situ with sodium hydride and
then cooled prior to the addition of acetophenone and
1-hydrosilatrane. Enantioselectivity was determined by chiral
GCMS, and the stereochemistry of the major product was
determined by comparison to previously reported data in the
literature. Mono-anionic activators (2-4) gave much lower
enantioselectivity (Table 1, entries 1-3) than the ones with two
deprotonated heteroatoms (6, 7, 8) (Table 1, entries 5-7). (1S,2R)-
1,2-Diphenylethanolamine 7 gave the highest enantioselectivity,
followed by (1R,2S)-(-)-ephedrine 8 and cinchonine 6. We were
particularly pleased with the viability of 8 as a source of chirality
as it is a readily available and low-cost reagent; additionally,
In order to observe high enantioselectivity in any asymmetric
catalytic reaction one must have effective catalyst turnover. The
particular issue with the asymmetric reduction of ketones with
hydrosilanes using chiral Lewis base catalysts is that the product
alkoxide can compete with the chiral activator and as a result
erode enantioselectivity; this is further compounded with
alkoxysilanes, where the alkoxide ligands of the silane could also
be released during the r1ebaction and offer competing,
1
enantioambivalent pathways. High enantioselectivity can be
achieved when the silane remains bound to the product alkoxide
and the chiral Lewis base catalyst can turn over efficiently (Fig.
1
). Catalytic systems are useful for minimizing both waste and

3
various stereoisomers are also commercially available for further
investigation. Somewhat surprisingly, (R)-(+)-diphenylprolinol 5
gave no enantioselectivity and very poor conversion (Table 1,
entry 4), possibly because the oxygen is too sterically hindered
for effective activation of the silatrane.
enantioselectivity (Table 2, entry 3). Hexane, diethyl ether and
m-xylene gave poor conversion and enantioselectivity (Table 2,
entries 5, 6, 9, respectively), most likely due to the poor
dissolution of 1-hydrosilatrane.
Table 2. Solvent optimization
a
Table 1. Screening of activators
b
c
Entry
1
Activator
Conversion (%)
50
ee (%)
0
Entry
Solvent
T
°C)
Conversion
ee
(%)
70
62
60
56
54
52
50
42
24
10
a
(
(%)
>99
98
98
99
1
2
3
4
5
6
7
8
9
THF
2-MeTHF
/2-MeTHF (2:1)
-30
0
-10
d
2
28
0
C
6
H
6
b
C
6
H
6
5 to 25
b
b
hexane
Et
-96 to 25
-30
-95 to 25
-8
20
14
>99
90
21
2
O
toluene
DMF
m-xylene
MeCN
3
4
86
10
0
0
-30
-10
1
0
35
a
ee determined by GCMS; the (R) enantiomer was the major product in all
cases.
b
o
2
Reaction mixture frozen with N (l) (-196 C) prior to the addition of 1-
hydrosilatrane, and allowed to warm to 25 °C.
2
.3. Temperature optimization
d
5
>99
44
70
The temperature dependence of enantioselectivity was tested
(
Fig. 3) and a correlation between the decreased temperature and
increased enantioselectivity was observed down to -30 °C; below
this temperature no benefit was seen with respect to the
enantioselectivity and the rate of reaction was impractically slow.
6
7
99
85
e
64
Figure 3. Effect of temperature on the enantioselectivity
a
Reaction conditions: acetophenone (0.1 mmol), deprotonated activator (0.11
2
.4. Activator loading
mmol), 1-hydrosilatrane (0.2-0.3 mmol), dry THF (3 mL), -30 °C, 6 h.
b
Deprotonated in situ with NaH (2 equiv.) with respect to the activator.
We next examined the impact of additive loading on
c
ee determined by GCMS; the (R) enantiomer was the major product except
enantioselectivity. Gratifyingly, asymmetric induction was
observed using catalytic amounts of 7, however the ees in these
cases were modest and the conversions were unacceptably low
1
9
where noted.
d
Reaction ran at -10 °C.
e
The (S) enantiomer was the major product.
(
Table 3, entries 1-2). The conversions and enantiomeric ratio
were significantly lower compared to a stoichiometric amount of
the activator (Table 3, entry 3). Increasing the loading of
activator 7 from 1 equivalent to 2 equivalents increased the
enantioselectivity (Table 3, entry 3 vs. 4), however the 6%
increase in ee was much less prominent than expected.
Coincidentally the same increase (6%) was observed when
doubling the amount (1 equivalent to 2 equivalents) of activator 8
We decided to push forward with optimization using
compound 7, which was identified as the best activator in this
initial screening.
2
.2. Solvent screening
Solvent screening (Table 2) demonstrated THF as the best
solvent for this reaction, giving high conversion and good
enantioselectivity (Table 2, entry 1). 2-MeTHF was a suitable
alternative, but due to its relatively high freezing point, the
temperature could not be lowered below 0 °C (Table 2, entry 2).
Mixing 2-Me-THF with benzene allowed for a slightly lower
reaction temperature but did not significantly improve the
(
Table 3, entry 5 vs 6). Increasing the activator loading of 8 to 8
equivalents gave the highest ee of 86% (Table 3, entry 7). This
large excess of 8 is not ideal as a general method, though with
activator recycling could be useful. As activator 7 gave better
conversion and higher enantioselectivity at lower equivalents, the

4
Tetrahedron
optimal conditions were set at 2 equivalents of activator 7 in
inverted when using 10 compared to 8, demonstrating that the
oxygen stereocenter dictates the absolute stereochemistry of the
product in this instance.
o
THF, at -30 C for 6 h.
Table 3. Activator loading-to-enantioselectivity relationship
Table 4. Effect of activator stereochemistry on enantioselectivity in reduction
of acetophenone with hydrosilatrane
a
b
Entry
Activator (equiv.)
Conversion (%)
ee (%)
22
40
70
76
1
2
3
4
5
6
7
7
(0.08)
(0.6)
(1.0)
(2.0)
(1.0)
(2.0)
(8.0)
14
34
99
>99
85
>99
>99
7
7
7
8
8
8
a
b
c
Entry
Activator
ee (%)
Stereochemistry of
the major product
64
70
86
c
c
a
Deprotonated in situ with NaH (2 equiv.) with respect to the activator.
b
ee determined by GCMS; the (R) enantiomer was the major product except
1
76
R
S
where noted.
c
The (S) enantiomer was the major product.
As discussed in the introduction, the development of a truly
catalytic metal-free hydrosilane reduction requires significant
molecular engineering, and while this may certainly be an
attainable goal it is worthwhile to consider practical solutions.
Two ways to mitigate the negative impact of using stoichiometric
2
3
78
70
(or superstoichiometric) amounts of the additive are a) to use an
inexpensive, readily available source of chirality and b) have the
ability to easily recover and reuse the additive. Catalyst 8 (and its
2
0
S
stereoisomers) can satisfy a) with a cost of less than $10/g; and
to address b) we demonstrated that catalyst 7 can be recovered
during work up with a simple acid-base wash and reused on the
same scale with no loss in enantioselectivity (Fig. 4a). Note that
this reaction was run in benzene to assist in activator recovery,
however this was shown to be unnecessary. Catalyst 7 was
extracted from the combined waste of multiple reactions run in
THF and reused in a larger scale (1.0 mmol) reaction (Fig. 4b). In
this scaled-up reaction the product was obtained with 67% ee in
an 86% isolated yield, and catalyst 7 was again recovered (98%).
We believe these features indicate the practicality of this method
for generating important chiral building blocks.
4
52
R
a
Deprotonated in situ with NaH (2 equiv.) with respect to the activator.
b
ee determined by GCMS; conversion in all cases was >99%.
2
.6. Reaction Scope
Further studies involved reducing a small range of ketones to
investigate the scope and limitations of the asymmetric reduction
using 1-hydrosilatrane and activator 7 (Fig. 5). Increasing the
electron density of the aromatic ring (12 vs. 13, 14, 16) decreased
the enantioselectivity, whilst substituting phenyl with naphthyl
(12 vs. 15) had no significant effect (though conversion was not
as efficient in the latter). Results of the reduction of α-substituted
acetophenone derivatives were mixed. Cyclic α-substitution
significantly decreased conversion (12 vs. 16). A methyl group at
the α position resulted in only a small decrease in selectivity (12
vs 17), but a second methyl group, dramatically reduced the
enantioselectivity to 22% ee (12 vs 18), whilst substituting it with
a cyclohexyl group (19) further reduced the enantioselectivity to
Figure 4. a) Demonstration of the direct reusability of activator 7, and b)
larger scale reaction with recycled 7.
2
.5. Effect of activator stereochemistry
8
% ee. The reaction conditions were not effective to form
The reduction was then tested to see how different
aliphatic alcohol 20 from the dialkyl prochiral ketone precursor.
stereoisomers of the examined activators affected the
enantioselectivity (Table 4). Exchanging activator 7 for its
enantiomer 9 gave full inversion and no loss in enantioselectivity
3
. Conclusion
(
Table 4, entries 1 vs. 2) as expected. In contrast, exchanging
activator 8 with its epimer 10 (in which the C-O stereocenter is
inverted) resulted in a decrease of the enantioselectivity (Table 4,
entries 3 vs. 4). Interestingly, the sense of enantioselectivity was
In summary, we have developed a method for the asymmetric
reduction of prochiral ketones using chiral Lewis bases as
activators and 1-hydrosilatrane as the hydride source. The

5
pp 941–974; (b) Rossi, S.; Benaglia, M.; Massolo, E.; Raimondi,
L. Catal. Sci. Technol. 2014, 4, 2708.
enantioselectivity is good in several cases, with ees up to 86%.
While stoichiometric (or more) amounts of the chiral activator
are required for useful outcomes, the reused activator remains
just as effective as in its initial use. The studied reaction
demonstrates both utility in its current state and promise for
future studies that are able to expand on the number of chiral
Lewis base activators examined.
5
.
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1
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1
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1
1
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Figure 5. Scope of select prochiral ketones. Reaction conditions: 1-
hydrosilatrane 1 (2 equiv.), activator 7 (1 equiv.), dry THF (3 mL), -30 °C, 6
h. ee and conversion determined by GCMS; the enantiomer shown was the
major product.
3
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2
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The authors thank the Technology Transfer Office at Northern
Illinois University for providing funding for this work.
1
1
1
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catalytic, see the ESI
1
1
1
(
1
2
0. The cost of (1R,2S)-ephedrine on the Sigma Aldrich website
2
.
(USA) was $960 USD/100g as of December 2017.
Supplementary Material
1
014.
The ESI contains general information and procedures,
characterization of products, yields, chiral GCMS data, and NMR
spectra.
3
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1
1
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organocatalysis (Ed.; Dalko, P. I.), Wiley-VCH, Weinheim, 2013,

6
Tetrahedron
Asymmetric reduction of ketones using easy-to-handle
and inexpensive silatrane.
Commercially available 1,2-aminoalcohols served to
induce chirality (ees up to 86%).
Chiral additives are used stoichiometrically, but recyclable
with full activity).
(