Synthesis and application in asymmetric C-C bond formation of solution phase ligand libraries of monodentate phosphoramidites

Article abstract of DOI:10.1039/b404996a

The synthesis of solution phase libraries of chiral monodentate phosphoramidite by using the automated parallel protocol was analyzed. It was observed that the method leads to the analysis of effective enantioselective catalysts for tranformations and association with the monodentate ligand combination approach. The automated parallel protocol provided a powerful tool for the combinatorial asymmetric catalysis. The chromatography was performed at the end of the phosphoramidite synthesis by a filtration process, due to more simple automated procedure.

Full text of DOI:10.1039/b404996a

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Synthesis and application in asymmetric C–C bond formation of
solution phase ligand libraries of monodentate phosphoramidites†
a
b
b
b
Ate Duursma, Laurent Lefort, Jeroen A. F. Boogers, André H. M. de Vries,
a,b
a
a
Johannes G. de Vries,* Adriaan J. Minnaard* and Ben L. Feringa*
a
Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute,
University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands.
E-mail: b.l.feringa@chem.rug.nl; Fax: (ϩ31) 50-3634296; Tel: (ϩ31) 50-3634278
DSM Pharma Chemicals-Advanced Synthesis, Catalysis and Development, P.O. Box 18,
b
6
160 MD Geleen, The Netherlands
Received 2nd April 2004, Accepted 12th May 2004
First published as an Advance Article on the web 25th May 2004
A library of 96 unique monodentate phosphoramidite
ligands has been synthesized in solution and used in the
asymmetric conjugate addition of potassium vinyltrifluoro-
borate to enones resulting in up to 88% ee.
Combining enantioselective homogeneous catalysis and
combinatorial chemistry in an efficient way is a highly desirable
goal since it leads to the rapid discovery of new catalysts
1
for important asymmetric transformations. However, combin-
2
atorial approaches are often based on mixtures of compounds,
whereas asymmetric catalysis requires the ability to individually
detect the activity and selectivity of each catalyst in a library.
3
Parallel reactions (one catalyst per vial), followed by high-
4
throughput screening, has emerged as the method of choice
combining these two fields. Impressive results have been
5
obtained using solid-phase bound ligand libraries. However,
the translation of solution phase chemistry to the solid-phase
and vice versa can be quite problematic, as illustrated by recent
examples employing solid-phase bound phosphoramidite lig-
Fig. 1 Library synthesis.
6
ands. We focused on an automated solution phase parallel
synthesis of phosphoramidite libraries, since it allowed the
preparation of libraries (up to 96 members) in sufficient
quantities using existing methodology. Phosphoramidites can
be easily obtained by the reaction of a phosphorochloridite
with a primary or secondary amine in the presence of triethyl-
amine as a base. The modular structure makes them highly
7
Scheme 2 Phosphorochloridites used.
suitable for synthesis in a combinatorial way (Scheme 1).
containing phosphorochloridites A–C, giving 96 different crude
phosphoramidites based on three diols and 32 amines.
After two hours of agitation at room temperature on an
orbital shaker, the precipitated triethylamine hydrochloric acid
salts were removed via parallel filtration. By placing the oleo-
phobic filterplate on top of a 96-well microplate and applying
vacuum, a library of 96 clear stock solutions of phos-
Scheme 1 Phosphoramidite ligand synthesis.
The automation of the synthesis is achieved by using all
reagents as stock solutions, which are transferred by a liquid
31
8
phoramidites in toluene was obtained. P-NMR demonstrated
that the ligands were formed with >90% purity. The ligand
library was subsequently screened in the asymmetric conjugate
addition of potassium vinyltrifluoroborate (2) to cyclo-
handling robot placed in a glove box. The chromatography
normally performed at the end of the phosphoramidite syn-
thesis, is replaced by a simple filtration, not only because it
allows for a much more simple automated procedure, but also
because phosphoramidites based on primary and/or aromatic
amines tend to decompose during chromatography. For the
parallel synthesis of the 96 ligand library according to Fig. 1,
toluene stock solutions of the three BINOL-based phos-
phorochloridites (Scheme 2) were added to a 96-well oleophobic
filterplate in three areas of 32 wells respectively (Fig. 1).
9
hexenone (1) (Scheme 3). The introduction of a vinyl-group
in an enantioselective fashion using a monodentate phos-
phoramidite ligand is highly desirable since versatile synthons
are produced, which up to now have only been obtained using
10
Rh-BINAP catalysts.
The addition of a stoichiometric amount of triethylamine to
each of the 96 wells was followed by the addition of a stoichio-
metric amount of 32 different amines (Table 1) to each area
†
Electronic supplementary information (ESI) available: experimental
details. See http://www.rsc.org/suppdata/ob/b4/b404996a
Scheme 3 Asymmetric conjugate addition of vinyltrifluoroborate.
1
682
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 6 8 2 – 1 6 8 4
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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1
2
Table 1 Amines used
50% ee). The BINOL (A) based phosphoramidites perform
13
much better, and the 8H-BINOL (B) based ligands even
improve these results. Ligands based on primary aromatic
amines lead to low conversions (5–39%) and ee values
(
11–37%). The most successful ligands are based on 8H-
BINOL and secondary aliphatic amines like ethylmethylamine
Fig. 2, 8e, 80% conv., 82% ee) and diethylamine (Fig. 2, 1f, 81%
(
conv., 87% ee). To validate the results these two ligands were
synthesized individually on a larger scale, including purification
by column chromatograghy. The results correspond neatly with
the ones from the solution phase library (96% conv., 86% ee for
8
e and 99% conv., 88% ee for 1f ) demonstrating the potential
of this concept. Next to a cyclic enone, the acyclic enone benzyl-
idene acetone (4) was also used a substrate in the screening of
the library (Scheme 4).
Scheme 4 Conjugate addition to benzylidene acetone.
The reaction was run overnight and conversion and ee
determined by chiral GC. The results are shown in Fig. 3.
As in the case of cyclohexenone, the BINOL (A) and 8H-
BINOL (B) based phosphoramidites perform much better than
the 3,3Ј-dimethyl-BINOL (C) based ligands; the latter giving
conversions up to only 22% and ee values up to 29% (Fig. 3, 4l).
The most effective ligands, showing high conversion although
moderate ee so far, are based on cyclic amines containing ester
substituents (3d, 3h, and 4b with ee values of 42%, 40%, and
Using the liquid handling robot, a part of the entire solution
phase library was transferred to 96 corresponding reaction
vials, followed by a stock solution of the rhodium source and
substrate 1 in ethanol. After the addition of trifluoroborate 2
4
1%, respectively).
11
the vials were sealed, placed in a Premex 96-Multi Reactor,
and heated at reflux for two hours. In order to allow a struc-
ture–activity and structure–selectivity analysis a short reaction
time (2 h) was used whereby the reactions did not run to com-
pletion and a broad range of conversions and ee values is
obtained. Analysis by chiral GC gave the results shown in Fig. 2.
All the ligands based on the 3,3Ј-dimethyl-BINOL backbone
(
C) give low conversions and ee values, with the phos-
phoramidite based on aniline as the best ligand (21% conv.,
Fig. 3 Results of the library screening for the 1,4-addition of 2 to 4.
In summary we have shown that solution phase libraries of
chiral monodentate phosphoramidite are rapidly synthesized
and screened in asymmetric C–C bond forming reactions using
an automated parallel protocol. This method leads to the quick
discovery of (leads for) effective enantioselective catalysts for
various transformations and, in association with the mono-
14
dentate ligand combination approach recently introduced,
provides
catalysis.
a
powerful tool for combinatorial asymmetric
Fig. 2 Results of the library screening for the 1,4-addition of 2 to 1
(
ee upper row, conversion lower row).
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 6 8 2 – 1 6 8 4
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L. Lefort, J. A. F. Boogers, A. H. M. de Vries and J. G. de Vries,
Org. Lett., 2004, 6, 1733.
Acknowledgements
We thank the European Commission (IHP Network grant
9 For the 1,4-addition of arylboronic acids using phosphoramidite
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“
CombiCat” HPRN-CT-2000-00014) for financial support.
(
c) A. Duursma, R. Hoen, J. Schuppan, R. Hulst, A. J. Minnaard
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see:
www.premex-reactorag.ch/e/specialloesungen/produkteneuheiten.
12 The poorer results with sterically hindered phosphorochloridite C
are not the result of incomplete ligand formation as was evident
from NMR analysis.
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O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 6 8 2 – 1 6 8 4