Angewandte
Chemie
DOI: 10.1002/anie.200905158
Asymmetric Catalysis
Highly Enantioselective Hydrophosphonylation of Aldehydes:
Base-Enhanced Aluminum–salalen Catalysis**
Keitaro Suyama, Yoshifumi Sakai, Kazuhiro Matsumoto, Bunnai Saito, and Tsutomu Katsuki*
a-Hydroxy phosphonates and a-hydroxy phosphonic acids
are an important class of molecules that are widely used in
biological applications.[1] The asymmetric hydrophosphony-
lation of aldehydes with phosphonates is a powerful and
direct method for synthesizing enantioenriched a-hydroxy
phosphonates.[2–4] Thus, intense research has been devoted to
developing highly enantioselective catalysts for this reaction,
and it is now becoming an emerging area in organic chemistry.
A variety of chiral Lewis acid and heterobimetallic catalysts
have been reported and high enantioselectivities have been
achieved. However, most of these methods require relatively
high catalyst loading and a longer reaction time to obtain the
products in acceptable yields.
presuming that the trapping of the phosphite anion by the
catalyst and release of the hydrophosphonylation product
could proceed rapidly enough for the catalytic process to
exclusively occur before the non-catalytic process
(Scheme 1). Herein, we report that inorganic bases signifi-
cantly enhance the rate of reaction of the Al(salalen)-
catalyzed asymmetric hydrophosphonylation of aldehydes,
in which high enantioselectivities ranging from 93 to 98% ee
were achieved for the reactions of both conjugated and non-
conjugated aldehydes.
Dialkyl phosphonates exist in equilibrium between their
phosphite and phosphonate forms. The phosphite form is
thought to be the active species; however, under neutral
conditions the equilibrium lies predominantly toward the
phosphonate form, which leads to sluggish reactivity.[5]
Consequently, the facilitation of phosphite–phosphonate
tautomerization is essential for achieving hydrophosphonyla-
tion with low catalyst loading. For example, Abell and
Yamamoto utilized the reactive reagent (CF3CH2)2PO(OH)
to achieve a highly enantioselective hydrophosphonylation
with only 1 mol% of catalyst.[6] Ooi and co-workers applied
chiral triaminoiminophosphoranes as organic base catalysts
and achieved high yield and enantioselectivity with low
catalyst loading at À988C.[7,8] These results further high-
lighted the importance of rapid phosphite-phosphonate
tautomerization.
Scheme 1. Predicted asymmetric hydrophosphonylation in the pres-
ence of a base.
A simple technique for accelerating the phosphite–
phosphonate tautomerization is the deprotonation of phos-
phonates using a base. However, the hydrophosphonylation
of aldehydes is a well-known base-mediated process,[9] and the
participation of the base-mediated pathway is a critical
problem for the enantioselective reaction. Nevertheless, we
believed that a judicial choice of base and catalyst would
facilitate the Lewis acid catalyzed asymmetric hydrophos-
phonylation reaction without eroding the enantioselectivity,
We have previously reported that Al(salalen) complex 1
effectively promotes the asymmetric hydrophosphonylation
of aldehydes with dimethyl phosphonate to give the a-
hydroxy phosphonates in good to high enantioselectivities
(Scheme 2).[10] However, the reaction proceeded quite slowly,
and a high catalyst loading of 10 mol% and longer reaction
time were required to obtain acceptable yields of the a-
hydroxy phosphonates.
We expected that inorganic bases, such as alkaline metal
carbonates, which have a relatively weak basicity and low
solubility in tetrahydrofuran, would generate an active
phosphite anion at an appropriate rate and enhance the
hydrophosphonylation without reducing the enantioselectiv-
ity. Indeed, the addition of 1.0 equivalent of lithium carbonate
significantly accelerated the asymmetric hydrophosphonyla-
tion of benzaldehyde using catalyst 1 with no erosion of the
enantioselectivity (Table 1, entries 1 and 2).[11] Sodium car-
bonate and potassium carbonate each increased the reaction
rate, but the addition of cesium carbonate resulted in
significantly diminished enantioselectivity (11% ee; Table 1,
[*] K. Suyama, Y. Sakai, Dr. K. Matsumoto, Dr. B. Saito, Prof. T. Katsuki
Department of Chemistry, Faculty of Science, Graduate School,
Kyushu University
Hakozaki, Higashi-ku, Fukuoka 812-8581 (Japan)
Fax: (+81)92-642-2607
E-mail: katsuscc@chem.kyushu-univ.jp
[**] This work was supported by a Grant-in-Aid for Scientific Research
(Specially Promoted Research 18002011) and the Global COE
program “Science for Future Molecular Systems” from MEXT
(Japan).
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2010, 49, 797 –799
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
797