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
[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
Angew. Chem. Int. Ed. 2011, 50, 10961 –10964
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
10961