Parallel and modular synthesis of P-chirogenic P,O-ligands

Article abstract of DOI:10.1021/co2002119

A modular synthesis of P-chirogenic α-alkoxyphosphine ligands has been developed, allowing for the variation of two of the three groups on phosphorus. Oxidation and concomitant desymmetrization of a prochiral alkyl- or aryldimethylphosphine borane afforded α-hydroxyphosphines, which were subsequently deprotonated and alkylated in a parallel fashion. The choice of base and temperature for the alkylation step was found to be crucial for the outcome of the reaction. Selected ligands were subsequently screened in palladium catalyzed allylic substitution, affording product in good to excellent yield but moderate enantioselectivity, indicating that further optimization of the ligand structures is desirable to increase the stereoselectivity.

Full text of DOI:10.1021/co2002119

Research Article
pubs.acs.org/acscombsci
Parallel and Modular Synthesis of P-Chirogenic P,O-Ligands
Magnus J. Johansson,†,§ Susanne Berglund,† Yinjun Hu,‡ Kristian H. O. Andersson, and Nina Kann*,§
Organic Chemistry, Department of Chemical and Biological Engineering, Chalmers University of Technology, 41296 Goteborg,
̈
Sweden
S
* Supporting Information
ABSTRACT: A modular synthesis of P-chirogenic α-alkoxyphos-
phine ligands has been developed, allowing for the variation of two
of the three groups on phosphorus. Oxidation and concomitant
desymmetrization of a prochiral alkyl- or aryldimethylphosphine
borane afforded α-hydroxyphosphines, which were subsequently
deprotonated and alkylated in a parallel fashion. The choice of
base and temperature for the alkylation step was found to be
crucial for the outcome of the reaction. Selected ligands were
subsequently screened in palladium catalyzed allylic substitution,
affording product in good to excellent yield but moderate
enantioselectivity, indicating that further optimization of the ligand structures is desirable to increase the stereoselectivity.
KEYWORDS: chiral phosphine, parallel synthesis, O-alkylation, P-chiral, palladium catalyzed allylic substitution
devoted to the development of new methodology for the
preparation of P-chiral phosphines,13 and have also reported
several examples of chiral phosphine ligand libraries incorporat-
ing pendant carboxy-,14 triazolyl-15 and amino-functionalities16
(1a−c, Figure 1). We here report the synthesis of a different
INTRODUCTION
■
The development of new methods for asymmetric synthesis
and in particular asymmetric catalysis is of great importance
because two enantiomers of a bioactive compound in many
cases exhibit different biological properties.1 The development
of an asymmetric transition metal-catalyzed reaction often
requires screening of a large number of chiral ligands, and
methods for preparing such ligands either in parallel or in a
library format are thus of interest.2 Several research groups have
focused specifically on the synthesis of phosphine- or
phosphorus-containing ligand libraries,3 both chiral4 and
nonchiral.5 An elegant example in this context was described
by Minnaard, de Vries, and Feringa, who prepared a library of
20 chiral phosphoramidite ligands in a parallel format and
subsequently screened these in the rhodium-catalyzed asym-
metric hydrogenation of a variety of alkene substrates,
identifying two ligands that afforded exceptionally high
enantioselectivity.6 Gilbertson and co-workers have reported
several examples of combinatorial libraries of chiral phosphines
and their applications in asymmetric catalysis,7 and Meldal has
developed a solid phase synthesis of peptide-based phosphine
ligands in a combinatorial format.8 Combinatorial mixed-ligand
and hybrid-ligand approaches have also been employed by
several research groups.9 However, examples of phosphine
ligands with P-chirality prepared in a parallel format are far less
common. In a P-chiral phosphine,10 the chirality is placed
closer to the reaction center in comparison to ligands with C-
chirality, and P-chiral phosphines have given excellent results in
the catalytic asymmetric hydrogenation of alkenes.11 Because
such ligands are more complex to prepare,12 they have been less
investigated in asymmetric synthesis in general however, and
the efficient preparation of such ligands in a parallel format for
screening purposes is thus highly important to increase their
scope of application. We have during a number of years been
Figure 1. Libraries of P-chiral phosphine ligands (phosphines shown
in their borane protected form).14−16
.
type of phosphine in a combinatorial format, that is, phosphines
incorporating a pendant alkoxy-group. The application of these
P,O-type ligands in palladium-catalyzed asymmetric allylic
substitution is also described.
RESULTS AND DISCUSSION
■
To prepare a library of diverse P-chiral P,O-type phosphine
ligands, the P-chirality was first installed via desymmetrization
of a prochiral phosphine substrate, and an adjacent hydroxyl-
group was subsequently introduced as a handle for
diversification. Prochiral phosphine boranes 2a−c (Scheme 1)
were subjected to enantioselective deprotonation using a chiral
sec-butyl lithium/(−)-sparteine complex, followed by oxidation
with molecular oxygen in the presence of triethylphosphite,
employing a protocol described by Imamoto.17 α-Hydrox-
Received: December 19, 2011
Revised: February 29, 2012
Published: April 9, 2012
© 2012 American Chemical Society
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ACS Combinatorial Science
Research Article
found. A second major fraction could be isolated in many cases,
which turned out to be phosphines of the type 8 (Scheme 3),
where alkylation had taken place directly on the phosphorus
atom. Presumably, this occurs via a deformation reaction,
forming a secondary phosphine borane which is then directly
alkylated by the electrophile. Such deformylation has been
reported when using KOH as the base,17 and can be put to
practical use if the secondary phosphine thus formed retains its
stereochemical integrity. This was not found to be the case
under these reaction conditions, however; analysis of the
products 8 showed that these were racemic. Thus an improved
synthetic protocol for the aryl-substituted phosphines had to be
found.
Scheme 1. Preparation of Chiral α-Hydroxyphosphine
Boranes Used As Precursors
yphosphine boranes 3a−c were formed in moderate to good
yields and with enantioselectivities similar to reported values
using this methodology.
Alkylation of the hydroxy-group of 3a−c was then carried
out (Scheme 2). For hydroxyphosphines 3a and 3b, the
Switching to a milder base such as cesium carbonate, and
performing the initial deprotonation step at −20 °C, before
allowing the reaction to warm up to room temperature, turned
out to solve the problem of concomitant deformylation. Six
reactions using precursor 3a and seven reactions starting from
precursor 3b were then repeated using this new protocol.
Markedly improved yields were obtained in nearly all cases
(Table 1 and Table 2), the exception being compound 6{10}
which was not formed even under these conditions. The
alkylating agent for compound 6{10}, 2-bromomethyl-pyridine
is commercially available in the form of its hydrochloride salt,
necessitating a liberation step involving polymer supported base
(MP-carbonate) prior to reaction. It may be this extra
procedure that somehow interferes with the reaction in this
case, although the analogous 5{10} was formed without any
problem, albeit in a rather moderate yield. The highest yields
(86−94%) were obtained for ligands 5{6}, 5{7}, and 6{7},
indicating that the electron-deficient ortho-nitrobenzyl bromide
is a particularly favorable alkylating agent in this reaction.
To expand the scope of ligands prepared, we also included
anisyl-substituted hydroxyphosphine 3c as a precursor scaffold,
employing the new reaction conditions (Method B) for the
alkylation. Eight electrophiles from chemset 4 were selected,
and the desired alkoxyphosphine products were formed in good
to excellent yield in all cases (Figure 3 and Table 3).
Particularly the alkyl bromides as well as 2-(bromomethyl)-
naphthalene afforded product in over 90% yield. The higher
yields when using substrate 3c may reflect the more electron
rich properties of the phosphine, increasing the nucleophilicity
of the formed alkoxide.
a
Scheme 2. Alkylation of 3a−c with Chemset 4
a
Method A: NaH, KI, R2Br, DMF, r.t., 5 h, then polymer-bound
scavenger, 16 h; Method B: Cs2CO3, R2Br, DMF, −20 °C to r.t., 16 h.
reactions were performed at room temperature in parallel in a
Quest 210 Manual Synthesizer, using sodium hydride in
dimethylformamide (DMF) with catalytic amounts of sodium
iodide (Method A). The alkylating agents used were a set of
alkyl and benzyl bromides with different electronic properties
(Figure 2), including also a heteroaromatic structure (4{10}).
Although the focus in this investigation was to develop
methodology for the modular synthesis of chiral α-alkoxyphos-
phines, a limited investigation into the capability of the
phosphines to act as ligands for asymmetric synthesis was also
carried out. We have earlier studied the use of P-chiral α-
carboxyphosphine ligands in the asymmetric allylic substitution
of 1,3-diphenylpropenyl acetate with dimethyl malonate with
up to 91% enantiomeric excess (ee).14 Imamoto and co-
workers have also employed P-chiral phosphine/sulfide hybrid
ligands of similar structure in the same allylic substitution, with
up to 90% ee,18 and this therefore seemed a suitable reaction in
which to test our P,O-type ligands. This reaction also has the
advantage that phosphine boranes can be used directly as pre-
ligands in the reaction, deprotection of the phosphine taking
place in situ under the reaction conditions, with concomitant
Figure 2. Diversity reagents 4{1−10} used for the alkylation of 3a−c.
Excess electrophile was subsequently scavenged with PS-
thiophenol, and the crude products were isolated and purified
by flash chromatography, affording chiral α-alkoxyphosphine
ligand chemsets 5 and 6. In the case of the tert-butyl substituted
phosphines 5, the desired products were formed in all cases
except one, albeit in rather moderate yields using these
conditions (Figure 3 and Table 1). For the phenyl-substituted
phosphines 6, the outcome was somewhat less successful
(Table 2, ligand structures shown in Figure 3). Approximately
half of the alkylated phosphine ligands were formed, but in
significantly lower yields that for the alkyl-substituted ligands 5.
Upon analysis of other fractions isolated from the flash
chromatography, an explanation for the low yields could be
́
reduction of Pd(II) to Pd(0) as reported by Juge and co-
workers.19 Six tert-butyl-substituted as well as seven aryl-
substituted phosphines were selected to study the effect of the
substitution pattern (Table 4). In performing the reaction, all
selected phosphines afforded the desired substitution product 9
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ACS Combinatorial Science
Research Article
Figure 3. α-Alkoxyphosphines prepared from 3a−c.
Table 1. Synthesis of α-Alkoxyphosphines 5 from tert-Butyl-
Substituted Phosphine 3a
Table 2. Synthesis of α-Alkoxyphosphines 6 from Phenyl-
Substituted Phosphine 3b
a
b
a
b
entry
ligand
method
yield (%)
entry
ligand
method
yield (%)
1
5{1}
5{2}
A
A
B
A
A
B
A
B
A
B
A
B
A
B
A
25%
28%
50%
41%
28%
52%
24%
65%
29%
94%
41%
93%
n.r.
1
6{1}
6{2}
A
A
B
A
A
B
A
A
B
A
B
A
B
A
B
A
n.r.
2
2
19%
62%
25%
6%
3
3
4
5{3}
5{4}
4
6{3}
6{4}
5
5
6
6
52%
29%
n.r.
7
5{5}
5{6}
5{7}
5{8}
5{9}
7
6{5}
6{6}
8
8
9
9
65%
10%
86%
n.r.
10
11
12
13
14
15
16
10
11
12
13
14
15
16
17
6{7}
6{8}
6{9}
50%
27%
51%
n.r.
52%
45%
45%
5{10}
A
b
6{10}
a
B
b
n.r.
Ligand structures shown in Figure 3. See Scheme 2 for method
details.
a
Ligand structures shown in Figure 3. See Scheme 2 for method
details.
when employed as chiral ligands in the reaction, generally in
good to excellent yields, with the more electron-rich tert-butyl
substituted phosphines giving somewhat better results. In terms
of the enantioselectivity, the bulk of the tert-butyl substituent
seems to be important, as here ligands of the type 5 (entries 1−
6) clearly performed better than the phenyl- or anisyl-
substituted ligands 6 and 7, the latter affording nearly racemic
product (entries 7−12). This is also in line with our earlier
Scheme 3. Deformylation with Concomitant Racemization
As a Side Reaction Using Method A
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ACS Combinatorial Science
Research Article
scavenger. The choice of base and temperature was found to be
crucial for the alkylation reaction to avoid an undesired side
reaction in the form of a deformylation. Using a mild base and
low temperature for the initial deprotonation step, tert-butyl,
phenyl- and anisyl-substituted α-alkoxyphosphine boranes
could be formed in good to excellent yields.
Table 3. Synthesis of α-Alkoxyphosphines 7 from Anisyl-
Substituted Phosphine 3c
a
b
entry
ligand
method
yield (%)
1
2
3
4
5
6
7
8
7{1}
7{3}
7{4}
7{5}
7{6}
7{8}
7{9}
B
B
B
B
B
B
B
95%
91%
76%
65%
93%
66%
51%
49%
ASSOCIATED CONTENT
* Supporting Information
■
S
Details of experimental procedures and spectroscopic data for
synthesized compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
7{10}
B
a
b
Ligand structures shown in Figure 3. See Scheme 2 for method
details.
AUTHOR INFORMATION
Corresponding Author
■
Table 4. Asymmetric Allylic Substitution with Selected α-
*E-mail: kann@chalmers.se. Phone +46-31-7723070. Fax: +46-
31-7723858.
Alkoxyphosphine Ligands
Present Addresses
†AstraZeneca R&D Molndal, SE-43183 Molndal, Sweden.
̈
̈
‡College of Pharmaceutical Sciences, Ritsumeikan University,
1-1-1 Nojihigashi, Kusatsu, Shiga, 525−8577, Japan.
a
entry
compound
ee (%)
yield (%)
Author Contributions
1
5{2}
5{6}
5{7}
5{8}
5{9}
5{10}
6{4}
6{6}
6{7}
6{8}
7{5}
7{10}
17
38
40
33
33
26
1
93
97
77
96
63
99
47
77
99
60
99
99
§Equally contributing authors.
2
3
Funding
4
Financial support from the Swedish Foundation for Strategic
Research, the Swedish Research Council, AstraZeneca R&D
5
6
Molndal, the Magnus Bergvall Foundation, the Carl Tryggers
̈
7
Foundation, and the Lars Hierta memorial foundation is
gratefully acknowledged.
8
2
9
4 (S)
9
Notes
10
11
12
The authors declare no competing financial interest.
17
3
REFERENCES
■
a
Determined by chiral HPLC, see Supporting Information for details.
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̈
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■
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