Asymmetric reduction of ketones by phosphoric acid derived catalysts

Article abstract of DOI:10.1002/anie.201103883

A new path to chiral alcohols: Asymmetric reduction of ketones was achieved utilizing a chiral Bronsted acid as precatalyst for the first time. Using catecholborane as the reducing agent, a highly enantioselective formation of chiral secondary alcohols was found with a broad substrate scope. Mechanistic studies indicate that phosphoryl catechol borate derived from the reaction of the Bronsted acid with catecholborane produced the active catalyst (see scheme).

Full text of DOI:10.1002/anie.201103883

DOI: 10.1002/anie.201103883
Asymmetric Catalysis
Asymmetric Reduction of Ketones by Phosphoric Acid Derived
Catalysts**
Zuhui Zhang, Pankaj Jain, and Jon C. Antilla*
Enantioenriched secondary alcohols represent an important
class of molecules found in numerous intermediates, chiral
building blocks, and biologically active compounds.[1] Asym-
metric reduction of prochiral ketones constitutes the most
straightforward way to form these important moieties. Tradi-
tionally, stoichiometric amounts of chiral ligands were used
together with an aluminium or a boron hydride to achieve
high levels of enantioselectivity.[2] Various catalytic processes
have been developed in the past three decades in an effort to
eliminate the use of stoichiometric amounts of chiral
regents.[2] The Corey–Bakshi–Shibata (CBS) catalyst[2b] and
Noyoriꢀs ruthenium catalyst[2a] represent two of the most well-
known methods for this purpose. Both catalytic systems have
been further developed by altering the ligand or by employing
different metals in efforts to enhance the selectivity or
improve practicality.[3–5] Despite extensive research, the
utilization of simple chiral Brønsted acids as precatalysts for
this asymmetric process is still unknown.
The formation of a new phosphoryl catechol boronate is
proposed based on preliminary spectroscopic evidence. The
phosphoryl borate formed in situ is believed to act as a novel
chiral bifunctional catalytic system.
The reduction of acetophenone (1a) with catecholborane
was chosen as the starting point for optimization of the
reaction conditions. A series of binol-derived phosphoric
acids were screened in toluene at room temperature in the
presence of 5 ꢁ molecular sieves (Table 1, entries 1–6).
Catalyst P3, with a 9-anthryl group in the 3,3’-position of
binol, provided the product with the highest enantioselectiv-
ity (Table 1, entry 3). Chiral N-triflyl phosphoramide P7,
which is a stronger Brønsted acid than its phosphoric acid
counterpart, provided the product with reverse absolute
configuration and low ee (Table 1, entry 7).[15] Further solvent
Table 1: Optimization of reaction conditions.[a]
Chiral phosphoric acids have emerged as highly efficient
and selective catalysts for a variety of transformations since
their first reports, through independent studies by Akiyama
and Terada.[6,7] Early publications using these catalysts relied
on the activation of imine electrophiles. Recently, additional
discoveries have shown an ability for these catalysts to
activate vinyl ether,[8] aziridines,[9] nitroso compounds,[10]
enones,[11] and glyoxylates.[12] However, general carbonyl
compounds, like ketones, have not been used as substrates
in the presence of chiral phosphoric acid. Recently, our group
reported the first highly enantioselective allylboration of
aldehydes catalyzed by a chiral phosphoric acid.[13] Protona-
tion of the boronate oxygen by the catalyst was proposed to
rationalize both the activation and the enantioselectivity.[14]
The broadening of the limited scope of this type of activation
is highly desired. Herein, we describe, to the best of our
knowledge, the first example of highly enantioselective
reduction of ketones catalyzed by a chiral phosphoric acid
derivative. However, this chemistry is believed to differ
mechanistically in comparison to our previous allyboration.
Entry
Solvent
Catalyst[b]
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
toluene
toluene
toluene
toluene
toluene
toluene
toluene
benzene
CH2Cl2
EtOAc
P1
P2
P3
P4
P5
P6
P7
P3
P3
P3
P3
P3
P3
96
94
95
93
97
92
94
95
94
93
95
94
95
1
12
46
10
28
À31
À17
33
39
38
9
10
11
12[c]
13[d]
[*] Dr. Z. Zhang, P. Jain, Prof. Dr. J. C. Antilla
Department of Chemistry, University of South Florida
4202 E. Fowler Avenue, CHE 205A, Tampa, FL 33620 (USA)
E-mail: jantilla@usf.edu
Et2O
toluene
toluene
7
78
67
Homepage: http://chemistry.usf.edu/faculty/antilla/
[a] Reaction conditions: 1a (0.10 mmol), catecholborane (0.16 mmol,
1.6 equiv), catalyst (5 mol%), 5 ꢀ MS (50 mg), solvent (1 mL, 0.1m)
under argon. Yields refer to isolated product. Enantiomeric excess was
determined by chiral HPLC analysis using a chiral column. [b] The
catalysts in entries 1–12 were washed with HCl after purification by silica
gel chromatography. [c] T=À208C. [d] P3 was purified on silica gel
without re-acidification with HCl, T=À208C.
[**] We thank the National Institutes of Health (NIH GM-082935) and
the National Science Foundation CAREER program (NSF-0847108)
for financial support. We also thank the referees very valuable
suggustions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103883.
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Communications
screening using benzene, dichloromethane, ethyl acetate, or
dine (chiral). In each case lower ee values were observed
(Table 2, entries 9–12).
diethyl ether gave inferior selectivities when compared to the
use of toluene as solvent (Table 1, entries 8–11). To our
delight, an increase to 78% ee was obtained by lowering the
reaction temperature to À208C (Table 1, entry 12). Interest-
ingly, the catalyst purified by silica gel chromatography, which
is known to be contaminated by metal impurities, as shown by
Ishihara,[16] List,[17] and our group,[18] can also catalyze the
reaction, albeit with slightly lower levels of enantioselectivity
(Table 1, entry 13). This result prompted us to investigate
different phosphate salts, in an attempt to further improve the
enantioselectivity. P3 metal phosphates of calcium, magne-
sium and lithium afforded similar selectivities as the catalyst
obtained from reacidification by HCl (Table 2, entries 1–3).
With the optimized conditions in hand, the scope of the
reaction was studied. As shown in Table 3, the substrates
bearing either electron-donating or electron-withdrawing
groups on the phenyl ring furnished the resulting chiral
alcohols with good selectivity (Table 3, 2b–2l). Labile func-
tional groups, such as nitrile, nitro, ester, iodide and bromide,
Table 3: Substrate scope.[a]
Table 2: Additives screening.[a]
Entry
Additive (mol%)
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
Ca(OMe)2 (2.5)
Mg(tBu)2 (2.5)
nBuLi (5)
96
94
94
95
96
92
93
93
97
95
94
95
80
79
83
83
58
67
83
92
48
63
25
7
pyridine (5)
2,2’-bipyridine (2.5)
4,4’-bipyridine (2.5)
quinoline (5)
DMAP (5)
pyrrolidine (5)
Et3N (5)
(+)-cinchonine (5)
(À)-cinchonine (5)
9
10
11
12
[a] Reaction conditions: 1a (0.20 mmol), catecholborane (0.32 mmol,
1.6 equiv), P3 (5 mol%), additive (x mol%), 5 ꢀ MS (100 mg), toluene
(2 mL, 0.1m) under argon.
When pyridine was used as an additive, a higher selectivity
(83% ee) was obtained, presumably due to the formation of
the pyridium phosphate salt (Table 2, entry 4).[19] Pyridine
deviratives, such as 2,2’-bipyridine, 4,4’-bipyridine and quin-
oline, did not further improve the ee (Table 2, entries 5–7).
However, excellent enantioselectivity was obtained using 4-
(dimethylamino)pyridine (DMAP) as an additive (Table 2,
entry 8). It was proposed that P8, a very weak acid, is formed
(Figure 1).[20] Other amine additives evaluated included
pyrrolidine (secondary), triethylamine (tertiary), and cincho-
[a] Reaction conditions: 1a–1o (0.20 mmol), catecholborane
(0.32 mmol, 1.6 equiv), P3 (5 mol%), DMAP (5 mol%), 5 ꢀ MS
(100 mg), toluene (2 mL, 0.1m) at À208C under argon. Yields refer to
isolated product. Enantiomeric excess was determined by chiral HPLC
analysis using a chiral column. [b] The reactions were run at À788C
without DMAP. [c] The reaction was run using LiOiPr (5 mol%) instead
of DMAP as additive. [d] The reactions were run at À558C without
DMAP.
Figure 1. Phosphoric acid–DMAP complex.
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Angew. Chem. Int. Ed. 2011, 50, 10961 –10964

were well tolerated (Table 3, 2d–2h). When employing the
above conditions, moderate selectivity was obtained for an
alkyl methyl ketone (47% ee), which could be improved to
85% ee using P3 at À788C (Table 3, 2n).[21] The lithium salt of
P3 proved to be a better catalyst for the reduction of phenyl
pentyl ketone (74% ee) compared to P8 which only give 45%
ee (Table 3, 2o).[21] Likewise, the selectivity for the cyclic
ketone 1-tetralone can be improved from 52% ee under the
standard conditions to 78% ee using P3 at À558C (Table 3,
2p).[21] However, a low ee was obtained in the case of alkynyl
ketone (Table 3, 2q).
DMAP–catecholborane complex as shown in Scheme 3 (d =
9.59 ppm, doublet, J = 150 Hz), the major boron signal was
tentatively assigned to P10. With the proposed catalyst
In order to examine the mechanism of this new catalytic
system, 11B NMR experiments were carried out. As shown in
Scheme 1, a [D8]toluene solution of P3 was placed in a NMR
Scheme 3. 11B NMR study of the reaction of DMAP with catecholbor-
ane.
structure, we envision a transition state shown in Figure 2.
The boron center is believed to act as a Lewis acid to activate
=
the carbonyl, while the P O moiety can act as a Lewis base to
increase the nucleophilicity of catecholborane.[22] Simultane-
ously, the hydride from unreacted catecholborane is added to
the activated carbonyl in a chiral environment to form the
enantioenriched hydroboration product and regenerate the
catalyst. However, since many additives were explored and
each can induce a myriad of different possible mechanisms, an
in-depth investigation is required to completely understand
the mechanistic pathway.
Scheme 1. 11B NMR study of the reaction of P3 with catecholborane.
tube under Ar, and was treated with an equal amount of
catecholborane. Interestingly, evolution of gas was observed
after the addition of catecholborane. 20 min later, the
11B NMR spectrum (1H-coupled) clearly showed that the
resonance for catecholborane (d = 28.73 ppm, doublet, J =
194 Hz) shifted upfield to 22.13 ppm as a singlet. Based on
these results, it was proposed that the phosphoric acid
interacted with the catecholborane to form hydrogen gas
and a new boron species, P9. In the case of P8, the same
experiment was studied (Scheme 2). The gas evolution was
also observed with a major peak at 6.06 ppm in the 11B NMR
spectrum (1H-coupled). Compared with the chemical shift of
Figure 2. Proposed transition state.
In conclusion, we have developed a catalyst system for the
asymmetric reduction of ketones using a phosphoric acid
derivative (P8) as the precatalyst. Using catecholborane as a
reducing agent, chiral secondary alcohols were produced with
high levels of enantioselectivities over a reasonably broad
substrate scope. Preliminary 11B NMR studies suggest the
reaction of the Brønsted acid with catecholborane forms the
phosphoryl catechol borate as the active catalyst, which is a
potentially powerful bifunctional catalyst that could find
application to further reactions. Mechanistic investigations
and applications of the catalyst are currently underway in our
laboratory and will be reported in due course.
Scheme 2. 11B NMR study of the reaction of P8 with catecholborane.
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Communications
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General procedure: To a flame-dried test tube was added P3 (7.0 mg,
0.010 mmol, 5 mol%), 4-(dimethylamino)pyridine (DMAP, 1.2 mg,
0.010 mmol, 5 mol%) and activated 5 ꢁ MS (100 mg). The vessel was
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mixture was allowed to warm to room temperature gradually and
stirring was continued for another 1 h before the mixture was
extracted with EtOAc (10 mL ꢂ 3), dried over Na2SO4 and concen-
trated in vacuo. The residue was purified by silica gel column
chromatography (eluent: hexanes/ethyl acetate = 6/1) to afford pure
product 2.
ˇ
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Received: June 7, 2011
Revised: August 8, 2011
Published online: September 22, 2011
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Keywords: asymmetric catalysis · chiral alcohol · ketone ·
phosphoric acids · reduction
.
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Angew. Chem. Int. Ed. 2011, 50, 10961 –10964