Enantioselective reduction of α-substituted ketones mediated by the boronate ester TarB-NO2

Article abstract of DOI:10.1016/j.tetlet.2010.09.146

A facile and mild reduction procedure is reported for the preparation of chiral secondary alcohols prepared from α-substituted ketones using sodium borohydride and the chiral boronate ester (l)-TarB-NO₂. Direct reduction of substituted ketones bearing Lewis basic heteroatoms generally provided secondary alcohols of only modest enantiomeric excess likely due to either competition between the target carbonyl and the functionalized sidechains at the Lewis acidic boron atom in TarB-NO₂ or the added steric bulk of the α-sidechain. As an alternative method, these substrates were synthesized using TarB-NO₂ via a two-step procedure involving the reduction of an α-halo ketone to a chiral terminal epoxide, followed by regioselective/regiospecific epoxide opening by various nucleophiles. This procedure provides access to a variety of functionalized secondary alcohols including β-hydroxy ethers, thioethers, nitriles, and amines with enantiomeric excesses of 94% and yields up to 98%.

Full text of DOI:10.1016/j.tetlet.2010.09.146

Tetrahedron Letters 51 (2010) 6418–6421
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantioselective reduction of
a-substituted ketones mediated
by the boronate ester TarB-NO2
Scott Eagon, Nicholas Ball-Jones, Dustin Haddenham, Jaime Saavedra, Cassandra DeLieto,
⇑
Matthew Buckman, Bakthan Singaram
Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA 94086, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and mild reduction procedure is reported for the preparation of chiral secondary alcohols
Received 26 August 2010
Revised 21 September 2010
Accepted 27 September 2010
Available online 7 October 2010
prepared from
a-substituted ketones using sodium borohydride and the chiral boronate ester (L)-TarB-
NO2. Direct reduction of substituted ketones bearing Lewis basic heteroatoms generally provided
secondary alcohols of only modest enantiomeric excess likely due to either competition between the
target carbonyl and the functionalized sidechains at the Lewis acidic boron atom in TarB-NO2 or the
added steric bulk of the
TarB-NO2 via a two-step procedure involving the reduction of an
a
-sidechain. As an alternative method, these substrates were synthesized using
-halo ketone to a chiral terminal
a
epoxide, followed by regioselective/regiospecific epoxide opening by various nucleophiles. This
procedure provides access to a variety of functionalized secondary alcohols including b-hydroxy ethers,
thioethers, nitriles, and amines with enantiomeric excesses of 94% and yields up to 98%.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
of a prochiral a-substituted ketone. Given the versatility of these
compounds, it is of no surprise that a number of reagents have been
b-Functionalized optically active secondary alcohols are ubiqui-
tous in both naturally occurring bioactive compounds and modern
synthetic intermediates. Optically active b-hydroxyamines have
been reported as intermediates in many synthetic methodologies1
and can also be found in a variety of compounds which affect the
central nervous system (CNS) and the respiratory system. These
compounds include the b-adrenoceptor agonist Arfomoterol2
(Brovana) used for the treatment of chronic obstructive pulmonary
disease (COPD), and the recently isolated CNS depressant (+)-11-
hydroxyethratidine.3 Optically active b-hydroxyethers have been
used in a variety of applications as well, such as biological probes,4
molecular switches,5 and synthetic intermediates.6 Enantioen-
riched b-hydroxythioethers have been utilized as intermediates
in a variety of synthetic schemes, including the total synthesis of
abyssomicin C7 and several insect pheromones.8 Optically active
b-hydroxysulfones possess a range of biological activity, including
recent reports of anti-tumor9 and metalloproteinase inhibition
activity.10 They are also a useful functional handle in synthetic
methodology, especially in the Julia Olefination,11 and have been
utilized as intermediates in the synthesis of a diverse array of
compounds.12
developed for this application. Optically active b-hydroxyamines
have been prepared from the enantioselective reduction of a-ami-
noketones by a variety of reagents including ruthenium catalysts,13
rhodium catalysts,14 copper hydrides,15 enzymes,16 oxazaboroli-
dines,17 and the DIP-Cl reagent.18 The enantioselective reduction
of
a-alkoxyketones to b-hydroxyethers has been reported using
ruthenium catalysts,19 a rhodium catalyst,20 enzymes,21 and a spi-
roborate.22 Enantioenriched b-hydroxythioethers have been pre-
pared from the enantioselective reduction of
a-thioketones using
the CBS catalyst,23 an iridium catalyst,24 and several enzymes.25
Optically active b-hydroxysulfones have also been prepared from
a
-sulfonylketones using the CBS catalyst26 and enzymes,27 as well
as a ruthenium hydrogenation catalyst.28
Though many reagents have been developed for the enantiose-
lective reduction of
a-substituted ketones, many obstacles still
prevent their widespread use. Heavy transition metals are difficult
to remove and their associated toxicity precludes their use in the
synthesis of many pharmaceutical reagents. Enzymes are non-toxic
but they are extremely substrate dependant and not suitable for
the reduction of many ketones. Boron based reagents, however,
eschew many of these complications. DIP-Cl and the CBS catalyst,
in particular, have shown exceeding promise in the reduction of
a wide variety of substituted ketones.29 However, both reagents
often require low temperatures (À78 °C) and/or superstoichiomet-
ric quantities to achieve maximal induction. In contrast, the
TarB-NO2 reagent has demonstrated the ability to reduce a variety
of aliphatic and aromatic ketones to highly enantioenriched
One of the most direct methods of preparing b-functionalized
optically active secondary alcohols is via the asymmetric reduction
⇑
Corresponding author.
E-mail address: Singaram@chemistry.ucsc.edu (B. Singaram).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.146

S. Eagon et al. / Tetrahedron Letters 51 (2010) 6418–6421
6419
secondary alcohols at room temperature in 1 h utilizing only
Following the results of the reduction of
TarB-NO2, a variety of other a-substituted ketones were reduced
to further quantify the role of the heteroatom in these reactions.
The results are summarized in Table 1.
a
-aminoketones with
NaBH4.30 A TarB-NO2 analog has also achieved excellent induction
with various ketones without requiring a dry or inert atmo-
sphere.31 Given these promising results, we sought to expand the
scope of the TarB-NO2 reagent by investigating the asymmetric
The optical purity of the isolated secondary alcohol varied
widely depending on the nature of the substrate. Reduction of a
prochiral carbamate and amine salt gave minimal induction (Table
1, entries 1 and 2), but a moderate induction was observed for 2-
cyano- and 2-azidoacetophenone (entries 3 and 5). Reduction of
an n-alkyl cyano derivate gave very poor induction, presumably
due to the lack of any steric difference between the sidechains
flanking the carbonyl (entry 4). Reduction of a thioether resulted
in a racemic product, while reduction of a sulfone gave slight
enantioenhancement (entries 6 and 7). Reduction of 2-methoxy-
acetophenone gave the corresponding (S) alcohol with a good
reduction of various prochiral a-substituted ketones.
2. Results and discussion
Previous reduction studies of aromatic and aliphatic substrates
with the TarB-NO2 reagent indicated that the enantioselectivity of
the reaction was strongly correlated to the sterics about the car-
bonyl center. Carbonyl groups bearing a sterically demanding
group on one side and a significantly smaller group on the other
consistently gave the best results.31 On the basis of this trend, it
was decided to first investigate the asymmetric reduction of aro-
enantiomeric excess of 80% (entry 8), but reductions of
a-phen-
oxyketones were less successful (entries 9 and 10). The higher
enantioselectivity observed in the reduction of 2-methoxyaceto-
phenone and the inversion of configuration observed for 1-phen-
oxy-2-propanone suggests that the steric bulk of the phenyl
ether greatly influences the interaction between the ketone sub-
strate and TarB-NO2. The lack of enantioselectivity observed with
2-phenoxyacetophenone also suggests that the phenoxyether moi-
ety serves as a sterically demanding group, since the TarB-NO2 re-
agent has demonstrated the best enantioselectivity in the
reduction of ketones bearing one small and one sterically demand-
matic a-aminoketones, since the reduction of simple aromatic ke-
tones by TarB-NO2 gives superb results and the molecule bears a
convenient fluorophore. Several of these substrates were synthe-
sized and reduced with 1 equiv of TarB-NO2 and 2 equiv of NaBH4
at room temperature for 1 h. NMR studies showed that the initial
reduction product isolated from the reaction mixture was the b-
hydroxyamine borane. The undesired borane product was removed
in acidic refluxing methanol to yield the desired product as con-
firmed by 1H and 13C NMR spectra. Subsequent analysis of the
product b-hydroxyamines by HPLC and/or the corresponding
Alexakis esters32 revealed only poor enantioselectivity. Reductions
performed at lower temperatures (0 °C, À78 °C) and/or with an ex-
cess of TarB-NO2 also produced alcohols of poor optical purity
(Scheme 1).
ing group attached to the carbonyl. The reduction of a-haloketones
such as 2-bromoacetophenone, however, proceeds smoothly to
give chiral epoxides of high optical purity with TarB-NO2 as re-
ported previously (entry 11).34
The results obtained from the reduction of a-aminoketones sug-
Table 1
gested that these substrates behaved very differently than simple
aromatic and aliphatic ketones. 11B NMR studies were performed
on the initial reaction mixtures prior to the addition of NaBH4 to
determine if a new binding paradigm was present. As a 0.5 M solu-
tion in THF, TarB-NO2 exhibits two signals in the 11B spectrum. One
signal, typically at about 31 ppm, corresponds to the free TarB-NO2
molecule in solution. Another less intense signal is also observed
around 9 ppm. This signal corresponds to a tetrahedral boronate
of the form ArB(OR)3, and is assumed to be either a THF coordina-
tion complex or a dimer of TarB-NO2. A 1:1 molar mixture of TarB-
NO2 and acetophenone in THF yields the same spectrum as TarB-
NO2 alone. Since an acetophenone/TarB-NO2 complex would come
at the same chemical shift as a TarB-NO2 dimer or a THF complex,
this result suggests that acetophenone binds only very weakly to
TarB-NO2 despite the fact that it is reduced with NaBH4 to the
product alcohol with a 99% ee. A 1:1 molar mixture of TarB-NO2
and 2-(piperadinyl)-1-phenyethanone also yields a similar spectra,
but the 9 ppm signal corresponding to a TarB-NO2 complex is
much stronger than the free TarB-NO2 molecule or a 1:1 mixture
of TarB-NO2 and acetophenone.33 This suggests that a new com-
plex has formed between the substrate and TarB-NO2. Since the
Reduction of
a-substituted ketones with (L)-TarB-NO2
Entry
Ketone
% eea
Yield (%)
42
Config.b
—
1
2
6
4
88
—
3
4
5
74
6
85
62
94
(R)
—
61
(S)
6
7
0
35
80
0
53
86
92
87
85
98
—
—
a
-aminoketone bears a tertiary nitrogen atom, it is hypothesized
that the Lewis basic lone pair of the amine is responsible for the
formation of an amine–TarB-NO2 borane complex. Since -ami-
8
(S)
—
a
noketones give very poor enantioselective induction, it is surmised
that formation of this amine–TarB-NO2 complex provides an alter-
native achiral reduction pathway that is responsible for the poor
induction observed with these substrates.
9
10
31
94
(R)
(S)
11
a
Determined via HPLC, GC or analysis of the corresponding Alexakis ester. See
Supplementary data.
b
Determined via optical rotation values in comparison to literature values. See
Supplementary data.
Scheme 1.
a-Aminoketone reduction with (L)-TarB-NO2.

6420
S. Eagon et al. / Tetrahedron Letters 51 (2010) 6418–6421
Scheme 2. Preparation of b-functionalized secondary alcohols utilizing (L)-TarB-NO2.
Though functionalized chiral alcohols of sufficient optical purity
could not be prepared via the direct reduction of -substituted
amino-, thio-, sulfonyl-, cyano-, alkoxy-, or phenoxyketones, they
can be prepared indirectly using TarB-NO2 via optically active
epoxides. Starting from (S)-styrene oxide prepared from the reduc-
tion of 2-bromoacetophenone by (L)-TarB-NO2 and NaBH4, a vari-
ety of b-substituted secondary alcohols were prepared in high
optical yield (Scheme 2).
lows: H > alkyl > Br,Cl > CN,OR > SO2R > CO2R,SR,NR2. Experimental
evidence suggests that competition at the Lewis acidic boron atom
in TarB-NO2 between the target carbonyl and the functionalized
a
sidechains or the added steric bulk of the a-sidechain is responsi-
ble for the poor enantioselectivity of the reaction. Despite these
challenges, several functionalized and highly enantioenriched sec-
ondary alcohols were prepared via regioselective and regiospecific
epoxide opening reactions of (S)-styrene oxide prepared with TarB-
NO2. These reactions offer a simple two-step alternative to the di-
A b-hydroxyamine was prepared using a regiospecific epoxide
opening procedure reported previously by our lab via the reaction
of (S)-styrene oxide with an in situ generated lithium amide in
THF.35 Preparation of a b-hydroxyether was achieved using isopro-
panol and sodium metal, providing the desired secondary alcohol
along with some of the undesired primary alcohol formed via the
attack of the isopropoxide nucleophile at the benzylic carbon in
an 87:13 mixture. Separation of the two isomers via column chro-
matography with a dichloromethane/ethyl acetate 6:1 eluent pro-
vided the desired product in 69% yield. While thiolysis of styrene
epoxides are known to generally favor attack at the b-carbon, the
addition of indium (III) chloride has been shown to give excellent
rect reduction of
a-substituted ketones to prepare bioactive and
synthetically useful b-functionalized secondary alcohols of high
optical purity.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.09.146.
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