Cu-catalyzed asymmetric conjugate reduction of β-substituted α,β-unsaturated phosphonates: an efficient synthesis of optically active β-stereogenic alkylphosphonates

Article abstract of DOI:10.1016/j.tetlet.2009.09.094

A series of chiral alkylphosphonates bearing β-stereogenic center were synthesized in good enantioselectivities (up to 95% ee) via the CuH-catalyzed asymmetric conjugate reduction of β-substituted α,β-unsaturated phosphonates under optimal conditions usin

Full text of DOI:10.1016/j.tetlet.2009.09.094

Tetrahedron Letters 50 (2009) 6720–6722
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cu-catalyzed asymmetric conjugate reduction of b-substituted
a,b-unsaturated
phosphonates: an efficient synthesis of optically active b-stereogenic
alkylphosphonates
Zheng-Chao Duan a,b, Xiang-Ping Hu a, , Dao-Yong Wang a,b, Sai-Bo Yu a,b, Zhuo Zheng a,
*
*
a Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China
b Graduate School of Chinese Academy of Sciences, Beijing 100039, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 July 2009
Revised 17 September 2009
Accepted 18 September 2009
Available online 24 September 2009
A series of chiral alkylphosphonates bearing b-stereogenic center were synthesized in good enantioselec-
tivities (up to 95% ee) via the CuH-catalyzed asymmetric conjugate reduction of b-substituted ,b-unsat-
a
urated phosphonates under optimal conditions using Cu(OAc)2ÁH2O as the copper source, (R)-SEGPHOS as
the ligand, PMHS as the siloxane, and t-BuOH as the additive.
Ó 2009 Elsevier Ltd. All rights reserved.
Optically active alkylphosphonic acid derivatives have gained
much attention in recent decades because of their interesting bio-
logical properties as phosphorus analogues of carboxylic acids, as
well as their synthetic utility as chiral building blocks.1 However,
the enantioselective synthesis of chiral alkylphosphonates,2 in par-
ticular those bearing b-stereogenic center, remains rarely explored.
The first catalytic enantioselective synthesis of chiral b-stereogenic
alkylphosphonates, based on the Rh-catalyzed asymmetric 1,4-
addition to 1-alkenylphosphonates using arylboroxines as arylating
reagents, was reported by Hayashi et al. in 1999,3 in which a variety
of chiral b-arylalkylphosphonates were achieved in good enantiose-
lectivities. Very recently, we have also reported a highly enantiose-
lective synthesis of chiral b-stereogenic alkylphosphonates via the
first Rh-catalyzed asymmetric hydrogenation of the corresponding
however, an enantioselective asymmetric conjugate reduction
method of ,b-unsaturated phosphonates catalyzed by a copper
hydride has not been reported yet. Herein, we report our studies
on this new strategy for constructing chiral b-stereogenic
alkylphosphonates derivatives.
We started to investigate the asymmetric reductions of diethyl
(E)-1-(2-phenylpropenyl)phosphonate (1a) using 5 mol % of
Cu(OAc)2ÁH2O as the catalytic precursor in the presence of excess
polymethylhydrosiloxane (PMHS) and t-BuOH. Initially, we
screened several chiral C2-symmetrical bisphosphine ligands
(Fig. 1). The results in Table 1 disclosed that the catalyst system
prepared in situ from Cu(OAc)2ÁH2O and (S)-BINAP, (R)-MeO-BIP-
HEP, or (S)-SYNPHOS was not effective for the reduction of (E)-
1a, as only low conversions were observed in these cases (entries
a
b-substituted
a
,b-unsaturated phosphonates.4 However, these
methods have the disadvantages of demanding reaction conditions,
the use of the expensive Rh catalyst, and high catalyst loadings.
These shortcomings prompted us to seek an alternative approach
to synthesize chiral b-substituted alkylphosphonates.
O
O
O
PPh2
PPh2
PPh2 MeO
PPh2 MeO
PPh2
PPh2
In the past decade, copper hydride (Cu-H) with chiral ligands
has emerged as a powerful reagent for effecting asymmetric
a
,b-unsaturated compounds,5 such as enon-
O
reductions of various
es,6 ,b-unsaturated esters,7 nitroalkenes,8
sulfones,9 ,b-unsaturated nitriles,10 and more recently 2-alke-
nylheteroarenes.11 Due to the structural similarity between these
,b-unsaturated compounds and b-substituted ,b-unsaturated
phosphonates of interest, we envision that an asymmetric 1,4-
reduction of b-substituted ,b-unsaturated phosphonates via the
(R)-MeO-BIPHEP
O
(S)-SYNPHOS
(S)-BINAP
a
a,b-unsaturated
t Bu
a
OMe
a
a
O
O
O
P
P
tBu
2
O
O
tBu
PPh2
PPh2
a
copper hydride catalysis is an attractive alternative to prepare chi-
ral b-stereogenic alkylphosphonates. To the best of our knowledge,
O
OMe
O
tBu
2
(R)-SEGPHOS
(S)-DTBM-SEGPHOS
* Corresponding authors. Tel.: +86 411 84379276; fax: +86 411 84684746.
E-mail addresses: xiangping@dicp.ac.cn (X.-P. Hu), zhengz@dicp.ac.cn (Z. Zheng).
Figure 1. Bisphosphine ligands evaluated in asymmetric reduction.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.094

Z.-C. Duan et al. / Tetrahedron Letters 50 (2009) 6720–6722
6721
Table 1
Cu-catalyzed asymmetric conjugate reduction of (E)-(2-phenyl-1-propenyl)phosphonate (1a)a
O
P
O
OEt
OEt
OEt
OEt
Cu(OAc)2 / L* / t-BuOH
silane, solvent, rt, 24 h
*
P
1a
2a
Entry
Ligand
Silane (equiv)
Cu-source
Additive (equiv)
Solvent
Conv.b (%)
eec (%)
d
d
d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
(S)-BINAP
PMHS (4)
PMHS (4)
PMHS (4)
PMHS (4)
PMHS (4)
PMHS (4)
PMHS (4)
PMHS (4)
PMHS (2)
PMHS (8)
Et3SiH (4)
TMDS (4)
PhSiH3 (4)
Ph2SiH2 (4)
PMHS (4)
PMHS (4)
PMHS (4)
PMHS (4)
PMHS (4)
PMHS (4)
PMHS (4)
PMHS (4)
PMHS (4)
PMHS (4)
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
CuCl/NaOt-Bu
CuF(PPh3)3ÁMeOH
CuF2Á2H2O
t-BuOH (4)
t-BuOH (4)
t-BuOH (4)
t-BuOH (4)
t-BuOH (4)
—
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
34
37
36
85
52
36
46
38
25
62
<10
<10
26
99
55
65
<10
72
92
15
85
81
79
91
—
—
—
(R)-MeO-BIPHEP
(S)-SYNPHOS
(R)-SEGPHOS
(S)-DTBM-SEGPHOS
(R)-SEGPHOS
(R)-SEGPHOS
(R)-SEGPHOS
(R)-SEGPHOS
(R)-SEGPHOS
(R)-SEGPHOS
(R)-SEGPHOS
(R)-SEGPHOS
(R)-SEGPHOS
(R)-SEGPHOS
(R)-SEGPHOS
(R)-SEGPHOS
(R)-SEGPHOS
(R)-SEGPHOS
(R)-SEGPHOS
(R)-SEGPHOS
(R)-SEGPHOS
(R)-SEGPHOS
(R)-SEGPHOS
93
90
91
d
t-BuOH (2)
t-BuOH (8)
t-BuOH (4)
t-BuOH (4)
t-BuOH (4)
t-BuOH (4)
t-BuOH (4)
t-BuOH (4)
t-BuOH (4)
t-BuOH (4)
t-BuOH (4)
t-BuOH (4)
t-BuOH (4)
t-BuOH (4)
t-BuOH (4)
t-BuOH (4)
t-BuOH (4)
t-BuOH (4)
—
—
—
—
—
—
—
d
d
d
d
d
d
66
92
92
d
—
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
93
92
Et2O
CH2Cl2
Et2O/toluene
Et2O/THF (1/1)
Et2O/THF (2/1)
Et2O/THF (4/1)
d
—
94
94
93
94
a
All reactions were performed at 5 mol % of catalyst loadings prepared in situ from Cu-precursor and 1.2 equiv of chiral diphosphine ligand with 0.25 mmol of substrate
(1a) at room temperature in 2 mL of solvent for 24 h.
b
Degrees of conversion were determined by GC.
The ee values were determined by HPLC on a chiral column.
Not determined.
c
d
1–3). To our delight, we found that with (R)-SEGPHOS the reaction
proceeded smoothly and yielded the desired product in good con-
version (85%) and high enantioselectivity (93% ee) (entry 4).
Although high enantioselectivity was obtained in the absence of
t-BuOH additive, the observable decrease in the reaction rate was
observed (entry 6). This result proved that t-BuOH additive is very
important for this reduction. The amount of t-BuOH and PMHS has
some influence in the conversions. Both the reduction and the in-
crease in the amount of t-BuOH and PMHS led to the decrease in
the conversions (entries 7–10). These results are the same as those
reported by Buchwald and co-workers in which 4 equiv of PMHS is
formed at a catalyst loading of 5 mol % prepared in situ from
Cu(OAc)2ÁH2O and 1.2 equiv of (R)-SEGPHOS in the presence of
4 equiv of PMHS and t-BuOH in Et2O/THF (4/1) at room tempera-
ture for 24 h. The results are summarized in Table 2.
The effect of substituent positioning was investigated using
methyl- and methoxy-substituted substrates (E)-1b–g (entries
2–7). The results revealed that the substituent on the meta- or
para-position of phenyl ring of the substrate had no major influence
on the enantioselectivity. All of the meta- and para-methyl or meth-
oxy-substituted substrates gave moderate yields and good enanti-
oselectivities (entries 3, 4, 6, and 7). However, the substrates
bearing an ortho-substituent were surprisingly not reduced in the
present catalytic conditions (entries 2 and 5). The reason is probably
due to the steric effect that inhibits the copper hydride coordinating
to the C@C bond of substrate and the subsequent hydride transfer
onto the b-carbon. The electronic properties of the para-substituent
on the phenyl ring of the substrate observably impacted the yield of
the reduction. The substrates having an electron-withdrawing
group on the para-position of the phenyl ring were reduced in higher
yields than those with an electron-donating group. However, the
stereoselectivity of this catalytic reduction was highly tolerant of
para-substituents on the phenyl ring, regardless of their electronic
properties. For example, substrate (E)-1g with a para-methoxy
group was reduced in 46% yield and 93% ee (entry 7); while the
para-CF3-substituted substrate 1i gave 96% yield and 94% ee (entry
9). The reduction of thiophene-substituted substrate also gave good
enantioselectivity but relatively low yield (entry 14).
necessary to reduce
a
,b-unsaturated esters.7a Subsequent experi-
ments in an effort to improve the conversion and enantioselectivity
by the variation of the silane reagent proved less fruitful. We found
that the use of Et3SiH, TMDS, and PhSiH3 in the reaction resulted in
dramatically decreased conversions (entries 11–13). However,
using Ph2SiH2 led to higher conversion, but lower enantioselectiv-
ity (entry 14). The copper sources also significantly affected this
reduction. The reaction with CuCl, CuF(PPh3)3ÁMeOH, or CuF2Á2H2O
gave lower conversion than that with Cu(OAc)2ÁH2O (entries 15–
17). Solvent-screening experiments revealed that the nature of
the solvents had a profound effect on the catalytic reaction. Thus,
the reaction performed in Et2O gave an increased conversion and
slightly decreased enantioselectivity (entry 19); while the reaction
performed in CH2Cl2 showed very low reaction rate (entry 20).
Interestingly, a mixed solvent, Et2O/THF (4/1) was found to favor
this reduction. In this case, 91% conversion and 94% ee were
achieved (entry 24).
To expand the scope of this new procedure, some other
a,b-
Encouraged by the promising result obtained in the reduction of
(E)-1a, the conjugate reduction of a variety of diethyl 1-(2-arylp-
ropenyl)phosphonates was examined. The reactions were per-
unsaturated phosphonates were subjected to the catalytic reduc-
tion. As shown in Figure 2, substrate (E)-1o without an aryl group
at the prochiral carbon was also selectively reduced and it behaved

6722
Z.-C. Duan et al. / Tetrahedron Letters 50 (2009) 6720–6722
Table 2
In conclusion, we have developed a copper-catalyzed asymmet-
ric conjugate reduction of b-substituted ,b-unsaturated phospho-
nates that provides ready access to optically active b-stereogenic
alkylphosphonates. A wide range of b-substituted ,b-unsaturated
phosphonates were reduced with high enantioselectivities (up to
95% ee) under optimal conditions using a Cu(OAc)2ÁH2O/(R)-SEG-
PHOS catalytic system in the presence of PMHS and t-BuOH. The
reduction was sensitive to the substitution pattern and to the elec-
tronic properties of the substituent on the phenyl ring of the sub-
strate. Generally, the substrates having an electron-withdrawing
group at the para-position of the phenyl ring were reduced in high-
er yields than those with an electron-donating group. Further
applications of this methodology are in progress.
Enantioselective conjugate reduction of a
,b-unsaturated phosphonatesa
a
Cu(OAc)2.H2O (5 mol%)
(R)-SEGPHOS (6 mol%)
a
O
P
O
P
OEt
OEt
OEt
OEt
*
Ar
Ar
PMHS (4 equiv.)
t-BuOH (4 equiv.)
Et2O/THF (4/1), rt, 24 h
2a-n
(E)-1a-n
Entry
Substrate (Ar)
Yieldb (%)
86
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
(E)-1a: Ar = Ph
94 (S)
d
d
(E)-1b: Ar = 2-MeC6H4
(E)-1c: Ar = 3-MeC6H4
(E)-1d: Ar = 4-MeC6H4
(E)-1e: Ar = 2-MeOC6H4
(E)-1f: Ar = 3-MeOC6H4
(E)-1g: Ar = 4-MeOC6H4
(E)-1h: Ar = 3-CF3C6H4
(E)-1i: Ar = 4-CF3C6H4
(E)-1j: Ar = 4-FC6H4
(E)-1k: Ar = 4-ClC6H4
(E)-1l: Ar = 4-BrC6H4
(E)-1m: Ar = 2-naphthyl
(E)-1n: Ar = 2-thiophenyll
—
—
71
61
94
94
d
d
—
—
57
46
92
96
80
95
79
77
41
95
93
94
94
94
93
93
92
90
Acknowledgments
We thank the National Natural Science Foundation of China
(20802076, 20873145) and the Knowledge Innovation Program of
the Chinese Academy of Sciences (DICP-S200802) for financial
support.
a
References and notes
All reactions were performed at 5 mol % of catalyst loadings prepared in situ
from Cu(OAc)2ÁH2O and 1.2 equiv of (R)-SEGPHOS with 0.25 mmol of substrate in
the presence of 4 equiv of PHMS and 4 equiv of t-BuOH in 2 mL of Et2O/THF (4/1) at
room temperature for 24 h.
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*
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(-)-2o (89% yield, 86% ee)
(E)-1o
(Z)-1o
O
OEt
*
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OEt
OEt
Cu(OAc)2.H2O (5 mol%)
(R)-SEGPHOS (6 mol%)
(+)-2o (68% yield, 68% ee)
O
O
P
PMHS (4 equiv.)
t-BuOH (4 equiv.)
Et2O/THF (4/1), rt, 24 h
OEt
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*
P
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O
O
OEt
OEt
OEt
*
P
P
OEt
(-)-2q (31% yield, 93% ee)
,b-unsaturated phosphonates evaluated in asymmetric
(E)-1q
Figure 2. Some other
a
reduction.
similarly to its aryl cohorts. However, (Z)-configuration in the sub-
strate seems to be unfavorable to both reactivity and enantioselec-
tivity. Thus, (Z)-1o was reduced in 68% yield and 68% ee,
significantly lower than that obtained with (E)-1o. The reduction
of b-ethyl-b-phenyl-substituted substrate (E)-1p and b-propyl-b-
phenyl-substituted substrate (E)-1q gave similar enantioselectivi-
ties but lower yields in comparison with the result obtained with
their methyl analogue (E)-1a.