Organocatalytic Enantioselective Synthesis of P-Stereogenic Chiral Oxazaphospholidines

Article abstract of DOI:10.1002/ejoc.201600100

The enantioselective synthesis of P-stereogenic chiral organophosphines under organocatalysis is a challenging research field, and reports that use this approach are rare. Herein, we have developed the enantioselective synthesis of P-stereogenic chiral oxazaphospholidines by using a bicyclic thiazole as the organocatalyst in the P-N and P-O bond-forming reaction. The P-chiral products were prepared in high yields with moderate enantioselectivities. The base that was used in this process had a significant influence on the enantioselectivity of the reaction and in some cases led to the opposite configuration of the P-chiral center.

Full text of DOI:10.1002/ejoc.201600100

DOI: 10.1002/ejoc.201600100
Full Paper
P-Stereogenic Chirality
Organocatalytic Enantioselective Synthesis of P-Stereogenic
Chiral Oxazaphospholidines
Lanlan Wang, [[ Zhijun Du, Qiang Wu,
a,b]
[a]
[a,b]
Rizhe Jin, Zheng Bian, Chuanqing Kang,*
[a]
[a]
[a]
a]
[a]
[a]
Haiquan Guo, Xiaoye Ma, and Lianxun Gao*
Abstract: The enantioselective synthesis of P-stereogenic chiral The P-chiral products were prepared in high yields with moder-
organophosphines under organocatalysis is a challenging re- ate enantioselectivities. The base that was used in this process
search field, and reports that use this approach are rare. Herein, had a significant influence on the enantioselectivity of the reac-
we have developed the enantioselective synthesis of P-stereo- tion and in some cases led to the opposite configuration of the
genic chiral oxazaphospholidines by using a bicyclic thiazole as P-chiral center.
the organocatalyst in the P–N and P–O bond-forming reaction.
Introduction
successful strategy for their preparation. In 2009, Gouverneur
Chiral phosphorus compounds that have a P-stereogenic center
and Hoveyda reported the enantioselective synthesis of phos-
[
1]
[2]
[3]
are often used as ligands, organocatalysts, and prodrugs
phorus compounds through a desymmetrizing Mo-catalyzed
because of their unique stereochemical and biochemical prop-
erties. P-Chiral phosphoramidates and oxazaphospholidines
contain P–N, P–O or P=O, and P–C bonds around an organo-
phosphorus(V) center, which results in the P-chirality, and these
P-chiral phosphorus heterocycles can be used as organocata-
lysts and precursors in the synthesis of P-chiral phosphines as
well as in the development of pesticides and pharmaceuticals.
Enantiomerically pure P-chiral phosphorus compounds are
often prepared by the chiral resolution of a mixture or by using
a stoichiometric amount of a chiral auxiliary. Asymmetric ca-
talysis remains a challenge in the area, and examples that em-
ploy this approach are rare. Early attempts of metal-catalyzed
asymmetric additions of P–H bonds to alkenes and alkynes re-
sulted in low to moderate enantioselectivity. However, G.
Helmchen performed the highly enantioselective synthesis of
chiral triarylphosphines by using a Pd-catalyzed P–C cross-cou-
pling reaction. In addition, Glueck along with Bergman and
Toste conducted extensive studies on the Pd-, Pt-, and Ru-cata-
lyzed asymmetric arylation and alkylation of phosphine, which
resulted in good enantioselectivity. In 2014, Leung and Haya-
shi achieved the Pd-catalyzed asymmetric addition of diaryl-
phosphines to benzoquinones with excellent enantioselectiv-
[
11]
ring-closing metathesis of symmetric acyclic phosphines.
In
2
015, Han, Duan, and Liu independently developed Pd-cata-
lyzed desymmetrizing C–H arylations for the synthesis of
P-stereogenic chiral phosphoramides with excellent enantiose-
[
12]
lectivity.
[
4]
[
5]
Compared with metallocatalytic reactions for the synthesis of
P-chiral phosphorus compounds, organocatalytic methods have
been investigated much less, with two reports to date. Initial
attempts in this field by Zhang employed a kinetic resolution
for the preparation of P-chiral phosphoramidates and used a
chiral imidazole as the organocatalyst. However, this approach
[
6]
[
13]
resulted in low to moderate enantioselectivity.
Johnson de-
[
7]
veloped a highly diastereoselective and enantioselective phos-
phorus version of an iodolactonization reaction, which, under
chiral Brønsted acid catalysis, produced a C- and P-chiral oxaza-
phospholidine from an alkenyl-containing phosphoramidic
[
8]
[
14]
acid.
The activation of a phosphorus substrate, the interac-
tion of phosphorus substrate with a catalyst, and the mecha-
nisms of stereoinduction in the formation of P-chiral centers are
not well-known. Organocatalysis seems more challenging, but
it also more promising because of its metal-free character.
[
9]
[
10]
ity. Besides direct P-functionalizations that afford chiral phos-
phines, the desymmetrization of achiral phosphines is another
An alternate strategy for the synthesis of P-chiral oxazaphos-
pholidines uses ephedrine and other amino alcohols as chiral
auxiliaries to induce the P-chirality in reactions with phosphinic
[
a] State Key Laboratory of Polymer Physics and Chemistry, Changchun
[6h,15]
dichlorides.
This inspired us to consider whether P-chiral
Institute of Applied Chemistry, Chinese Academy of Sciences,
oxazaphospholidines 3 can be prepared from phosphonic di-
chloride 1 and simple achiral amino alcohols 2 through P–N
and P–O bond formation under catalytic conditions (Scheme 1).
There have been no reports of this strategy to the best of our
knowledge. This method would avoid the use of stoichiometric
amounts of expensive chiral auxiliaries, particularly ephedrine,
5
625 Renmin Street, Changchun 130022, P. R. China
E-mail: kangcq@ciac.ac.cn
lxgao@ciac.ac.cn
http://www.ciac.ac.cn
[
b] University of Chinese Academy of Sciences,
1
9A Yuquan Road, Beijing 100049, P. R. China
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600100.
[
14]
and the preparation of phosphoramidic acids for cyclization.
Eur. J. Org. Chem. 2016, 2024–2028
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Instead, it would be a more economically viable and generally
applicable process.
Table 1. Optimization of organocatalytic conditions.[a]
Entry Catalyst
Base
% Yield[b]
% ee[c]
1
2
3
4
5
6
7
8
9
1
1
A
B
C
D
E
F
G
H
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
DIPEA
94.2
75.8
72.1
53.7
78.6
65.7
68.9
88.6
78.9
69.0
66.8
63.0
80.9
91.8
88.5
95.3
89.2
77.5
72.2
72.1
55.8
80.4
90.2
50.4
68.5
76.1
86.9
89.5
83.2
60.7
36
12
11
0
0
–15
0
Scheme 1. Reaction design (Nu* = chiral organocatalyst).
We are interested in the use of a nucleophilic chiral organo-
catalyst and 1 for the reversible formation of an intermediate
that is highly reactive towards achiral amino alcohols. The cata-
lytic stereoselectivity would control the formation of the P–N
and P–O bonds. In this reaction, there would be a preference
by the chiral organocatalyst for the substitution of one of the
chloro groups of the prochiral phosphine, which would deter-
mine the P-chirality of the intermediate (Scheme 1). The spatial
conformation and direction then taken by the amino alcohol,
upon attack of the phosphorus center, would influence the en-
antioselectivity of the product. By following this approach, we
have conducted the enantioselective synthesis of P-chiral
oxazaphospholidines by using chiral tertiary amines as organo-
catalysts and, herein, present the results.
0
2
I
0
1
A (50 mol-%)
A (30 mol-%)
A (20 mol-%)
A (10 mol-%)
35
32
32
20
33
33
42
–52
–12
–50
–14
–10
–5
13
12
30
4
12
1
1
1
1
17
18
3
4
5
6
[
[
d]
e]
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
2-MeIm
imidazole
2-phenylimidazole
2-ethylimidazole
2-isopropylimidazole
N-methylimidazole
4-methylmorpholine
xylidine
19
20
21
22
23
24
25
26
27
28
DBU[
DABCO
pyridine
2-picoline
2,6-lutidine
4-(dimethylamino)pyridine
f]
Results and Discussion
[f]
–23
–5
3
First, chiral tertiary amines A–I (Scheme 2) were screened as
organocatalysts in the model reaction of 1 and N-methylami-
noethanol (2a, Table 1). Amines A–I were expected to form a
P–N bond with 1 through the substitution of one of its chloro
groups to form a cationic intermediate, which then underwent
a reaction with another substrate (Scheme 1). An initial experi-
ment that employed 40 mol-% of A as the catalyst and triethyl-
amine (TEA) as the base at –20 °C afforded an excellent yield of
29
30
2
[
a] Reagents and conditions: Unless otherwise noted, 2a (0.2 mmol), 1
(0.3 mmol), base (0.6 mmol), and catalyst (40 mol-%) in CH Cl (4 mL) were
stirred at –20 °C for 12 h under N . [b] Isolated yields are provided. [c] Deter-
mined by HPLC analysis by using a chiral Diacel CHIRALPAK AD-H column.
d] Reaction was carried out at room temp. [e] Reaction was carried out at
40 °C. [f] DBU = 1.3-diazobicyclo[5.4.0]undec-7-ene, DABCO = 1,4-diazobicy-
2
2
2
[
–
94.2 % with an enantioselectivity of 36 % ee (Table 1, Entry 1).
clo[2.2,2]octane.
Catalysts B–I also gave good yields but with low or no enantio-
selectivity (Table 1, Entries 2–9). An increase or decrease in the
catalyst loading of A or a change in the reaction temperature
The base that is used in this reaction has a significant influ-
did not improve the results (Table 1, Entries 10–15). Therefore, ence over the enantioselectivity. Compared with TEA, N,N-diiso-
the optimum reaction conditions for the employment of A as propylethylamine (DIPEA) improved the enantioselectivity to
the organocatalyst at –20 °C were selected to further optimize 42 % ee without compromising the yield (Table 1, Entry 16). The
the base.
enantioselectivity increased along with an unexpected inverse
in the chiral preference (–52 % ee) when 2-methylimidazole (2-
MeIm) was used as the base (Table 1, Entry 17). However, when
imidazole was employed, there was a sharp decrease in the
enantioselectivity (Table 1, Entry 18). We then changed the sub-
stituent at the 2-position of imidazole to phenyl, ethyl, and iso-
propyl, but larger substituents had a negative effect (Table 1,
Entries 19–21). The use of N-methylimidazole resulted in a
marked decrease in the enantioselectivity (Table 1, Entry 22).
Other bases such as aliphatic amines and aromatic amines gave
poor enantioselectivity results (Table 1, Entries 23–30). Further-
more, the reaction did not proceed when inorganic bases such
as K CO , Na CO , and NaHCO were used. Alkyl or arylamines
that have an sp -hybridized nitrogen atom or heteroarylamines
Scheme 2. Organocatalysts that were used to optimize the reaction condi-
tions.
2
3
2
3
3
3
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2
that contain an sp -hybridized nitrogen atom and result in a dered 2o gave low yields (Table 2, Entries 14 and 15). The bases
reversal in the preference for the P-chirality can be used for TEA and 2-MeIm did not provide a remarkable difference in the
the synthesis of P-chiral compounds with prevailing divergent yields of 3, with the exception of 3l and 3o (Table 2, Entries 12
configurations. A few examples of stereoselective substitution and 15). In addition, TEA and 2-MeIm afforded products with
at phosphorus and sulfur centers have also demonstrated an opposite configurations in the synthesis of 3a, 3e, 3g, and 3n
inverse in the chiral preference, which was induced by TEA and (Table 2, Entries 1, 5, 7, and 14). The results indicate that this
[
16]
pyridine.
divergence in the enantioselectivity depends on the structures
Under the optimized conditions, the scope and limitations of the substrates employed in the asymmetric formation of the
of the reaction were evaluated by using several amino alcohols P-chiral center. For the substrates with N-methyl, N-ethyl, and
(
Table 2). With limited screenings to optimize the reaction for N-arylmethyl groups, that is, 2a, 2b, and 2e–2k, the use of 2-
each amino alcohol, DIPEA was found to be a better base than MeIm induced a higher enantioselectivity than TEA (Table 2,
TEA for the reactions that afforded 3a and 3e (Table 2, Entries 1 Entries 1, 2, and 5–11). For 2n, which contains an N-tosyl group,
and 5). However, TEA was selected as the base that had the TEA afforded a higher enantioselectivity (Table 2, Entry 14). For
largest scope for the reaction. Considering the possibility of a the other amino alcohols, both bases induced comparable en-
base-dependent inversion of the chiral preference in the stereo- antioselectivities. The absolute configuration of the predomi-
[
16]
selective substitution reaction at the phosphorus center,
we nant enantiomer of 3n, which was obtained by using TEA as
also used 2-MeIm as the base to examine whether there was a the base, was determined to have the (R) configuration by con-
divergence in the enantioselectivity of the reaction by using verting 3n into a known P-chiral phosphorus oxide and com-
different amino alcohols. The presence of different N-substitu- paring the optical rotations (see Section S6, Supporting Infor-
[
6h,6i,15e,17]
ents in the amino alcohol substrate showed that most alkyl and mation).
aryl groups were well-tolerated under the reaction conditions Insights into the catalytic enantioselective formation of the
to give excellent yields and moderate enantioselectivities of up P–N and P–O bonds were pursued through control experi-
to –58 % ee. However, N-tosyl-substituted 2n and sterically hin- ments. Although 2 equiv. of A were used, the reaction of 1 and
2a in the absence of a base did not proceed, which suggests
Table 2. Scope of the A-catalyzed synthesis of oxazaphospholidines.[a]
that the base is vital for the activation of the amino alcohol.
The reaction between 1 and 2a in the presence of TEA but
without any catalyst gave racemic 3a in a yield of 79.0 %. Fur-
ther studies of a mixture of 1 and catalysts A–G by 31P NMR
spectroscopic analysis revealed the formation of the presumed
intermediate Im1 in moderate yields with a diastereomeric ex-
cess (de) value of up to 90 % (Table 3 and Figures S1–S6, Sup-
porting Information). Im1 was believed to be the active species
with a P-chiral center that undergoes a reaction with the nu-
[
13,15e,18]
cleophilic substrate.
However, there is a significant de-
crease in the the enantiomeric excess values of 3a that result
from the reactions catalyzed by A–G compared with the dia-
stereomeric excess values of Im1 (Table 3). Products 3b–3o,
which are formed from reactions catalyzed by A, show the same
trend (Table 2).
Table 3. Diasteroselective formation of complex from reaction of 1 and
organocatalyst.[
a]
Entry
Catalyst
Yield of Im1[b]
% de of Im1[c]
% ee of 3a[d]
1
2
3
4
5
6
A
B
C
D
E
45 %
63 %
61 %
60 %
64 %
65 %
72
84
74
90
76
84
36.6
12.0
10.9
0
0
0
[
a] Reaction conditions: Unless otherwise noted, 2 (0.2 mmol), 1 (0.3 mmol),
TEA or 2-MeIm (0.6 mmol), catalyst (40 mol-%) and CH Cl (4 mL) were stirred
at –20 °C for 12 h under N . [b] Isolated yields are provided. [c] Determined
2
2
G
2
by HPLC analysis by using a chiral Diacel CHIRALCEL OD-H or CHIRALPAK AD-
H column. [d] N,N-diisopropylethylamine was used as the base. [e] The reac-
tion was carried out at 0 and –10 °C for TEA and 2-MeIm, respectively, as the
base. [f] The reaction was carried out at –10 °C. [g] The (R) enantiomer was
predominant.
[a] Reagents and conditions: 1 (0.15 mmol) and a catalyst (0.04 mmol) in
3
1
CD
2 2
Cl (1.0 mL) at room temp. for 1 h and then analysis by P NMR spectro-
3
1
scopy. [b] Yield determined by P NMR analysis based on the catalyst. [c] Dia-
3
1
stereomeric excess value determined by P NMR spectroscopic analysis.
[d] See Table 1.
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A mechanism for the catalytic enantioselective synthesis of high yields. The possibility of a side reaction between base-
P-stereogenic chiral oxazaphospholidines is proposed that is in activated amino alcohol and 1 is the most likely explanation for
agreement with the above results (Scheme 3). First, intermedi- this moderate selectivity. The employed base had a significant
ate Im1 forms from the reaction of 1 and a catalyst, whereupon influence on the enantioselectivity and in some cases led to the
a rapid equilibrium between 1, the catalyst, (S )-Im1, and (R )- opposite configuration at the P-chiral center of the product.
P
P
Im1 is established. The base-activated amino alcohol then at- This study demonstrates the synthesis of P-chiral phosphorus
tacks 1 and both enantiomers of Im1 to form the P–N bonds compounds by employing an organocatalytic approach and has
and produce phosphoramide intermediates (R )-Im2 and (S )- potential applications toward the development of P-chiral cata-
P
P
Im2. The enantioselectivity of this step is determined by the lysts, ligands, and bioactive compounds.
preference of the activated amino alcohol to undergo a reaction
with the major diastereomer of Im1 over the minor enantiomer
and 1. This side reaction between 1 and the activated amino
alcohol, which gives racemic Im2, hinders the possibility of
achieving a highly enantioselective reaction, but it difficult to
Experimental Section
General Methods: The N-substituted aminoethanols 2a–2e, 2m,
and 2n were obtained from commercial sources, and the other N-
substituted aminoethanols 2 were prepared according to a litera-
avoid under the current conditions. Finally, (R )- and (S )-Im2
P
P
are converted into the corresponding P-stereogenic chiral
oxazaphospholidines (S )- and (R )-3, respectively, through an
[
19]
ture procedure.
Catalysts A, F, H, and I were purchased from
P
P
commercial sources, and B–E and G were prepared according to a
intramolecular cyclization and P–O bond formation. Both the
formation of P–N and P–O bonds are assumed to be S 2-type
[20]
literature procedure. The NMR spectroscopic data were recorded
N
with a Bruker Avance III spectrometer. CDCl or CD Cl was used as
3
2
2
[
18]
reactions at the phosphorus center.
the NMR solvent. Either the solvent or TMS was used as the internal
standard for the 1H and C NMR spectroscopic data, and phos-
13
31
phoric acid was used as the external standard for P NMR spectro-
scopy. High resolution mass spectrometry was performed with a
Bruker Autoflex III MALDI-TOF mass spectrometer. HPLC analysis was
performed on a Shimidzu LC-10AD with a Class-VP system and by
using Diacel ChiralPak® AD-H or ChiralCel® OD-H columns.
General Procedure for the Catalytic Synthesis of P-Stereogenic
Oxazaphospholidines 3: The catalyst (0.08 mmol, 0.4 equiv.) and
N-substituted aminoethanol 2 (0.2 mmol, 1.0 equiv.) were dissolved
in DCM (4.0 mL), and the resulting mixture was stirred at the corre-
sponding temperature for 5 min. The base (0.6 mmol, 3.0 equiv.)
and PhP(O)Cl (0.3 mmol, 1.5 equiv.) were successively added. The
2
mixture was stirred for 12 h and then concentrated under reduced
pressure. The residue was purified by flash chromatography on silica
gel (ethyl acetate/petroleum ether) to afford compound 3 (for anal-
ysis and characterization of the products, see Supporting Informa-
tion).
Acknowledgments
The authors appreciate the financial support from the Natural
Science Foundation of Jilin Province, P. R. China (grant number
2
0130101005JC).
Keywords: Synthetic methods · Organocatalysis · Asymmetric
synthesis · Enantioselectivity · Phosphorus heterocycles
Scheme 3. Proposed reaction mechanism.
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thesis of P-stereogenic chiral oxazaphospholidines was devel-
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the P–N and P–O bond-forming reaction. The reaction between
phenylphosphonic dichloride (1) and the organocatalyst af-
forded active intermediate Im1 with good diastereoselectivity.
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stereogenic chiral oxazaphospholidines was moderate with
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Received: January 28, 2016
Published Online: March 29, 2016
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