Angewandte
Chemie
DOI: 10.1002/anie.201409411
Abramov Reaction
The Catalytic Asymmetric Abramov Reaction**
Joyram Guin, Qinggang Wang, Manuel van Gemmeren, and Benjamin List*
Abstract: The first catalytic enantioselective Abramov reaction
is described. The process is based on the utilization of a chiral
disulfonimide catalyst, which efficiently avoids the difficulties
encountered with metal-based catalysts. Several functionalized
a-hydroxy phosphonates were synthesized in good yields and
with excellent enantiomeric ratios of up to > 99:1. The process
was shown to be scalable and up to 1 g of starting material
could be employed under mild reaction conditions.
enol species and not the normally dominant carbonyl
tautomer acts as the nucleophile. Here, the preformation of
the enol equivalent has proven useful, for example, in the
Mukaiyama aldol reaction of enolsilanes. Aldol and
Mukaiyama aldol reactions are often complementary and
enantioselective variants of both reaction types have been
thoroughly studied (Figure 1, left). Interestingly, silyl esters of
dialkyl phosphites, which were originally introduced by
[7]
Abramov, display excellent reactivity in hydrophosphony-
[
8]
T
he hydrophosphonylation of aldehydes with dialkyl phos-
lation reactions of aldehydes. However, in contrast to the
analogous Mukaiyama aldol reactions, enantioselective Abra-
mov reactions of aldehydes are entirely unknown (Figure 1,
phites (“Pudovik reaction”) is an atom-economic approach
[
1]
toward a-hydroxy phosphonates (Figure 1, top right). In
[9]
bottom right). Importantly, after hydrolysis of the silyl ether,
the Abramov reaction delivers the same products as the
Pudovik reaction. In extending the aldol analogy further, it
appeared logical and desirable to develop an asymmetric
Abramov reaction, as this would add an additional dimension
of possible reaction conditions to the application of hydro-
phosphonylations in synthesis. Moreover, the initial products
of the Abramov reactions are stable a-silyloxy phosphonates,
in principle allowing for the direct isolation of protected a-
[
10]
hydroxy phosphonates.
We have recently introduced chiral disulfonimides as
effective catalysts for the activation of aldehydes in asym-
[
11]
metric Mukaiyama aldolizations. These catalysts achieve
enantioinduction based on the concept of asymmetric coun-
Figure 1. Analogy between the aldol/Mukaiyama aldol reactions and
the Pudovik/Abramov reactions, respectively.
[
12]
teranion-directed catalysis (ACDC).
This strategy was
shown to offer a general solution to the problem of silylium
[13]
ion background catalysis, which has likely hampered the
light of the potential of enantiopure a-hydroxy phosphonates
development of asymmetric Abramov reactions utilizing
[
2]
[14]
with regard to biological activity and synthetic utility,
significant efforts have been devoted toward developing
chiral metal-based Lewis acids.
Encouraged by these
considerations, we became interested in applying chiral
disulfonimide catalysis to the enantioselective Abramov
reaction and report here the successful realization of this
concept.
[
3]
asymmetric variants of this reaction. As a result, a number
of highly efficient catalytic systems using chiral organic
[
4]
[5]
bases or metal-based chiral Lewis acids have been
developed. Dialkyl phosphites are in equilibrium with their
predominating though unreactive dialkyl phosphonate form,
which can in some cases result in sluggish reactivity and the
After optimizing the reaction conditions with 2-naphthal-
dehyde and commercially available diethyl trimethylsilyl
phosphite (2a) as model system (see the Supporting Infor-
mation, SI), we could indeed obtain the hydrophosphonyla-
tion product 3 in excellent yield and enantioselectivity using
[6]
requirement to use base activation to facilitate the reaction.
This situation is analogous to the aldol reaction, in which an
[
15]
catalyst 1a (Table 1, entry 1).
We also explored several
other substituted silylphosphites in this reaction. These
reagents were either commercially available or readily
synthesized in one step by the silylation of the corresponding
phosphonates with TMSCl (trimethylsilyl chloride) in the
[
*] Dr. J. Guin, Dr. Q. Wang, M. van Gemmeren, Prof. Dr. B. List
Max-Planck-Institut fꢀr Kohlenforschung
Kaiser Wilhelm-Platz 1, 45470 Mꢀlheim an der Ruhr (Germany)
E-mail: list@mpi-muelheim.mpg.de
presence of Et N or with TBSCl (tert-butyldimethylsilyl
3
[
**] We gratefully acknowledge generous financial support from the
Max-Planck-Society, the European Research Council (Advanced
grant “High Performance Lewis Acid Organocatalysis, HIPOCAT” to
BL), and the Alexander von Humboldt Foundation (fellowships for
J.G.).
[10,12a,b,16]
chloride) and LDA (lithium diisopropylamide).
Sub-
stituents on the phosphite nucleophiles had a significant
influence on the reactivity and enantioselectivity. Sterically
less demanding dimethyl-substituted silyl phosphite delivered
the corresponding product 4 with high enantioselectivity
(entry 2). Efficient product formation was also observed by
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!
Guin, Joyram
