Synthesis of aryl group-modified DIOP dioxides (Ar-DIOPOs) and their application as modular Lewis base catalysts

Article abstract of DOI:10.1039/c2ob25338k

Treatment of an optically pure tartaric acid-derived diiodide and various secondary phosphine oxides with LHMDS provides the corresponding aryl group-modified DIOP dioxides (Ar-DIOPOs). The activities of Ar-DIOPOs as Lewis base catalysts were investigated

Full text of DOI:10.1039/c2ob25338k

View Online / Journal Homepage / Table of Contents for this issue
This article is part of the
Organocatalysis
web themed issue
Guest editors: Professors Keiji Maruoka, Hisashi
Yamamoto, Liu-Zhu Gong and Benjamin List
All articles in this issue will be gathered together online at
www.rsc.org/organocatalysis

Dynamic Article Links
Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 4562
www.rsc.org/obc
PAPER
Synthesis of aryl group-modified DIOP dioxides (Ar-DIOPOs) and their
application as modular Lewis base catalysts†
Yusuke Ohmaru,a Norimasa Sato,a Makoto Mizutani,a Shunsuke Kotani,b Masaharu Sugiura*a and
Makoto Nakajima*a
Received 16th February 2012, Accepted 16th April 2012
DOI: 10.1039/c2ob25338k
Treatment of an optically pure tartaric acid-derived diiodide and various secondary phosphine oxides with
LHMDS provides the corresponding aryl group-modified DIOP dioxides (Ar-DIOPOs). The activities of
Ar-DIOPOs as Lewis base catalysts were investigated for several asymmetric transformations using
chlorosilane reagents. The p-tolyl-substituted DIOPO (p-tolyl-DIOPO) was most effective for the
reductive aldol reaction of chalcone and aldehydes with trichlorosilane, whereas the 2,8-
dimethylphenoxaphosphine-derived DIOPO (DMPP-DIOPO) afforded the best enantioselectivity for the
phosphonylation of conjugated aldehydes and the chlorinative aldol reaction of an ynone and
benzaldehyde.
Introduction
Asymmetric catalysts consist of a catalytically active site, a
chiral backbone, and a pendant moiety (Fig. 1). The constitution
of the chiral backbone is of primary importance for the structure
of the asymmetric catalyst. Kagan et al. first developed C2-sym-
metrical diphosphine DIOP for metal-catalyzed asymmetric
hydrogenation and demonstrated the importance of the backbone
chirality.1,2 The pendant moiety also plays an important role in
further improving the catalytic activity and selectivity. For
example, refining substituents on the phenyl groups of BINAP
Fig. 1 Schematic diagram showing the structural components of an
asymmetric catalyst.
effectively enhances the enantioselectivity of ketone hydrogen-
ation.3 The modifiability of the pendant group on a catalyst is
important for catalyst design.
C2-Symmetrical chiral bisphosphine oxides have found many
applications as asymmetric Lewis base catalysts for the acti-
vation of chlorosilane reagents.4,5 We demonstrated previously
that BINAP dioxide (BINAPO)6a–k and DIOP dioxide
(DIOPO)6l (Fig. 2), prepared by the oxidation of BINAP and
DIOP, respectively, exhibited good catalytic activities in the ally-
lation of aldehydes,6a,d ring-opening of epoxides,6b aldol-type
Fig. 2 The structures of BINAPO, DIOPO, and dinitrones.
reactions,6c,d,h–k phosphonylation of aldehydes,6e reductive aldol
reaction of enones and aldehydes,6f,l and reductive cyclization of
N-acylated β-amino enones;6g however, low accessibility to their
derivatives (synthesis of each diphosphine followed by oxi-
dation) can hinder further optimization.
In this context, we recently demonstrated that chiral dinitrones
aGraduate School of Pharmaceutical Sciences, Kumamoto University,
5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan. E-mail:
msugiura@kumamoto-u.ac.jp, nakajima@gpo.kumamoto-u.ac.jp
bPriority Organization for Innovation and Excellence, Kumamoto
University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
†This article is part of the joint ChemComm-Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue
(Fig. 2), derivatives of which may be prepared in one step from a
C2-symmetrical dihydroxylamine and various aromatic alde-
hydes, served as effective modular Lewis base catalysts for the
allylation of aldehydes using allyltrichlorosilane.7 The aryl
group may be readily modified as a pendant moiety by selecting
the aromatic aldehyde used in the preparation.
4562 | Org. Biomol. Chem., 2012, 10, 4562–4570
This journal is © The Royal Society of Chemistry 2012

Table 1 Optimization of the reaction conditions for the synthesis of
p-tolyl-DIOPO (1a)a
Fig. 3 Retrosynthesis of Ar-DIOPO (1).
Herein, we report the synthesis and application of aryl group-
modified DIOP dioxides (Ar-DIOPOs) (1) as phosphine oxide-
type modular Lewis base catalysts (Fig. 3). 1 can be prepared in
one step from tartaric acid-derived optically pure diiodide (R,R)-
2 (the chiral backbone) and the corresponding secondary diaryl-
phosphine oxides 3 (the modifiable pendant moiety) in the pres-
ence of a base.8 The activities of the Ar-DIOPOs (1) as Lewis
base catalysts are demonstrated using the reductive aldol reaction
with trichlorosilane6f,l,9 and the phosphonylation of aldehydes
with tetrachlorosilane,6e both of which were developed pre-
viously, and in the chlorinative aldol reaction of an ynone with
benzaldehyde, which we report here for the first time.
Entry Base
Temperature 1ab (%) 4ab (%) Rec. 3ab (%)
1
2
3
LHMDS
−20 °C
57
60
5
2
0
5
6
2
37
1
NaHMDS −20 °C
KHMDS
LHMDS
LHMDS
LHMDS
−20 °C
0 °C
0 °C
45
0
4
78 (82)c
77 (80)c
33
11
17c
10
5d
6e
0 °C
a Unless otherwise noted, a solution of diiodide 2 (0.5 mmol) and bis(p-
tolyl)phosphine oxide 3a (1.2 mmol) in THF (4 mL) was treated with a
base (1.2 mmol) at −20 or 0 °C for 18 h. b Yields were determined by
1H-NMR analysis using dibenzyl ether as an internal standard. c Isolated
yields are given in parentheses. d With 3a (1.1 mmol) and LHMDS
(1.0 mmol). e With 3a (0.55 mmol) and LHMDS (0.5 mmol).
Results and discussion
Optimization of the reaction conditions for the synthesis of
p-tolyl-DIOPO
Our investigation began with the reaction of diiodide (R,R)-210
and bis(p-tolyl)phosphine oxide 3a11 for the preparation of p-
tolyl-DIOPO 1a (Table 1). Phosphine oxide 3a was chosen as a
probe substrate because it is highly crystalline, relatively stable,
and, hence, easily handled. Haynes et al. reported the synthesis
of a DIOPO-type bisphosphine oxide from a similar diiodide
and P-chiral tert-butyl(phenyl)phosphine oxide with LDA at
−78 °C.12 However, the synthesis of DIOPO derivatives bearing
any of a variety of diaryl groups has not been investigated.
To a solution of (R,R)-2 (1.0 equiv) and 3a (2.4 equiv) in
THF was added LHMDS (2.4 equiv) at −20 °C, and the mixture
was stirred at that temperature for 18 h. After aqueous workup,
the desired p-tolyl-DIOPO (1a) was obtained in a moderate yield
along with 5% monophosphine oxide 4a (entry 1). The effect of
the amide base counter cation was investigated by examining
NaHMDS and KHMDS (entries 2 and 3). NaHMDS afforded a
yield comparable to LHMDS, but KHMDS decreased the yield.
In these cases, phosphine oxide 3a could not be recovered.13 In
the case of LHMDS, 37% of 3a remained. This indicated that
the phosphinylide intermediate was relatively stable if the
counter cation was lithium. Thus, the reaction temperature was
increased to 0 °C in the presence of LHMDS to further promote
the nucleophilic substitution, and the yield of 1a increased to ca.
80% (entry 4). Reducing the amounts of both 3a and LHMDS
(2.2 and 2.0 equiv, respectively) at 0 °C did not decrease the
yield of 1a (entry 5).14
Fig. 4 Presumable directing effects of the phosphonoyl group.
the lithium phosphinylide intermediate may accelerate the
second nucleophilic attack (Fig. 4).15
Synthesis of various Ar-DIOPOs
The optimized reaction conditions for the preparation of p-tolyl-
DIOPO (1a) (Table 1, entry 5) were applied to the reaction of
diiodide 2 with other diarylphosphine oxides 3b–j11,16,17
(Table 2). An electron-rich p-methoxyphenyl-substituted phos-
phine oxide 3b and an electron-poor p-chlorophenyl-substituted
one 3c afforded the desired DIOPO derivatives 1b and 1c in
good and high yields, respectively (entries 2 and 3). The elec-
tron-donating methoxy group may lower the stability of the
anionic phosphinylide intermediate, diminishing the yield of 1.18
A similar trend was observed for the reaction of a series of meta-
substituted phosphine oxides 3d–f, giving the corresponding
DIOPO derivatives in moderate to good yields (entries 4–6).
Despite their bulkiness, the o-tolyl- or m-xylyl-substituted phos-
phine oxides 3g and 3h reacted smoothly to afford the DIOPO
Interestingly, even when the amounts of both 3a and LHMDS
were reduced by half (1.1 and 1.0 equiv, respectively), the for-
mation of bisphosphine oxide 1a still dominated the formation
of monophosphine oxide 4a (entry 6). This observation
suggested that coordination of the first introduced PvO group to
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4562–4570 | 4563

Table 2 Synthesis of various Ar-DIOPOs (1)a
Table 3 Ar-DIOPOs-catalyzed reductive aldol reaction of chalcone
and cinnamaldehydea
Entry
Lewis baseb
Yield (%)
syn/antic
Eed (%)
1
2
3
4
5
6
7
8
BINAPO
DIOPO
91
71
78
86
80
81
88
75
54
97
67
0
95/5
95/5
99/1
96/4
97/3
94/6
99/1
96/4
48/52
96/4
94/6
—
51
85
91
89
78
89
88
76
73
87
76
—
p-Tolyl-DIOPO (1a)
p-MeO-DIOPO (1b)
p-Cl-DIOPO (1c)
m-Tolyl-DIOPO (1d)
m-MeO-DIOPO (1e)
m-Cl-DIOPO (1f)
o-Tolyl-DIOPO (1g)
m-Xylyl-DIOPO (1h)
Thienyl-DIOPO (1i)
DMPP-DIOPO (1j)
Entry
Ar (3)
Product (1)b
Yield of 1c (%)
9
10
11
12
1
2
3
4
5
6
7
8
p-Tolyl (3a)
p-MeOC6H4 (3b)
p-ClC6H4 (3c)
m-Tolyl (3d)
m-MeOC6H4 (3e)
m-ClC6H4 (3f)
o-Tolyl (3g)
3,5-Me2C6H3 (3h)
2-Thienyl (3i)
3j
p-Tolyl-DIOPO (1a)
p-MeO-DIOPO (1b)
p-Cl-DIOPO (1c)
m-Tolyl-DIOPO (1d)
m-MeO-DIOPO (1e)
m-Cl-DIOPO (1f)
o-Tolyl-DIOPO (1g)
m-Xylyl-DIOPO (1h)
Thienyl-DIOPO (1i)
DMPP-DIOPO (1j)
DMPP-DIOPO (1j)
80
68
81
71
60
66
70
80
58
57
77
a All reactions were performed using chalcone (0.25 mmol),
cinnamaldehyde (0.3 mmol), and a DIOPO derivative 1 (10 mol%) in
propionitrile (1 mL) at −78 °C for 4.5 h. b (S)-BINAPO or (R,R)-DIOPO
derivatives were used in this study. c Determined by 1H-NMR analysis
of the crude product. d The ee of the syn-isomer. Determined by HPLC
analysis. The (2R,3S)-isomer was the major enantiomer in all cases.
9
10
11d
3j
a Unless otherwise noted, a solution of diiodide 2 (0.5 mmol) and
diarylphosphine oxide (3) (1.1 mmol) in THF (4 mL) was treated with
LHMDS (1.0 mmol) at 0 °C for 18 h. b (R,R)-Isomers in all cases.
c Isolated yields. d 3j (1.5 mmol) and LHMDS (1.2 mmol) were used.
further improvements, although the enantioselectivity exceeded
that resulting from BINAPO (entries 1 and 2).6l The experiments
were performed under the conditions as previously optimized.
To our delight, p-tolyl-DIOPO (1a) provided higher diastereo-
and enantioselectivities than DIOPO (entry 3). The effect of the
para-substituents on the phenyl groups was next investigated
(entries 4 and 5). A more electron-donating p-MeO-DIOPO (1b)
gave a higher yield and resulted in a comparable enantioselectiv-
ity (entry 4). A less electron-donating p-Cl-DIOPO 1c decreased
both the diastereo- and enantioselectivities (entry 5). We postu-
late that a catalyst with an appropriately high Lewis basicity
could coordinate strongly to the trichlorosilyl enol ether inter-
mediate and stabilize the transition structure of the aldol reaction,
leading to a high selectivity. A similar trend was observed for
the meta-substituted series (1d–f, entries 6–8). m-Tolyl- and
m-MeO-DIOPOs gave higher enantioselectivities than DIOPO,
whereas m-Cl-DIOPO showed a lower selectivity. Sterically con-
gested o-tolyl-DIOPO (1g) gave an inferior result (entry 9). In
this case, nearly racemic anti-aldol product was prevalent, imply-
ing that the catalyst did not effectively promote the reaction due
to its bulkiness. Dimethyl-substituted m-xylyl-DIOPO (1h)
afforded the highest yield, but the selectivity was less than 90%
(entry 10). Although thienyl-DIOPO (1i) moderately promoted
the reaction (entry 11), DMPP-DIOPO (1j) did not give the aldol
product at all (entry 12). 1j did not catalyze the conjugate
reduction of chalcone with trichlorosilane even in the absence of
the aldehyde. 1j might strongly coordinate the silicon atom due
to its high basicity and disturb the catalyst turnover.
derivatives (entries 7 and 8). Di(2-thienyl)phosphine oxide (3i)16
and 2,8-dimethylphenoxaphosphine oxide (3j, DMPP)17 pro-
vided the desired products in moderate yields (entries 9 and
10).19 As with the methoxy-substituted phosphine oxides, the
low stabilities of the electron-rich heterocyclic phosphinylide
anions may have accounted for the moderate yields. Indeed, the
phosphine oxides 3i and 3j could not be recovered after workup.
Therefore, an excess amount (three equiv) of 3j was used for the
synthesis of DMPP-DIOPO, and the yield increased to 77%
(entry 11).
Application of Ar-DIOPOs to reductive aldol reaction
The conjugate reduction of α,β-unsaturated carbonyl com-
pounds, followed by the aldol reaction of the resulting enolates
with aldehydes (the reductive aldol reaction) is a powerful syn-
thetic tool in organic synthesis.20 We recently reported the first
organocatalytic variant of this transformation, in which BINAPO
and DIOPO as chiral Lewis base catalysts provided high dia-
stereo- and enantioselectivies.6l
With the new DIOPO derivatives 1a–j in hand, we investi-
gated the reductive aldol reaction of chalcone and cinnamalde-
hyde with trichlorosilane (Table 3). We chose these substrates
because the enantioselectivity obtained with DIOPO required
p-Tolyl-DIOPO was then applied to the reaction of chalcone
with p-anisaldehyde and that with 2-furfural (Scheme 1) and
4564 | Org. Biomol. Chem., 2012, 10, 4562–4570
This journal is © The Royal Society of Chemistry 2012

Table 5 Ar-DIOPO-catalyzed phosphonylation of various aldehydes
DMPP-DIOPOa
BINAPOb
Entry
R
Yieldc (%) Eed (%) Yieldc (%) Eed (%)
Scheme 1 p-Tolyl-DIOPO-catalyzed reactions of chalcone with other
aldehydes.
1
2
Ph
90
80
71
63
83
44
49
41
40
22
17
91
90
87
98
83
89
41
40
22
33
9
p-MeOC6H4
p-BrC6H4
2-Naphthyl
1-Naphthyl
3
4e
5
Table 4 Ar-DIOPO-catalyzed phosphonylation of benzaldehyde with
triethyl phosphitea
6
(E)-PhCHvCH 72
49
a The reactions were conducted using an aldehyde (0.25 mmol), triethyl
phosphite (0.375 mmol), tetrachlorosilane (0.375 mmol),
diisopropylethylamine (1.25 mmol), and (R,R)-DMPP-DIOPO (1j)
(10 mol%) in CH2Cl2 (1 mL) at −78 °C. b The results obtained in the
previous study (ref. 6e) with an aldehyde (0.5 mmol), triethyl phosphite
(0.75 mmol), tetrachlorosilane (0.75 mmol), diisopropylethylamine
(0.75 mmol), and (S)-BINAPO (10 mol%) in CH2Cl2 (2 mL). c Isolated
yields. d Determined by HPLC analysis. e After addition of
tetrachlorosilane, the mixture was stirred for 1 h before workup.
Entry
Lewis baseb
Yieldc (%)
Eed (%)
1
2
3
4
5
6
7
BINAPO
DIOPO
p-Tolyl-DIOPO (1a)
m-Tolyl-DIOPO (1d)
o-Tolyl-DIOPO (1g)
m-Xylyl-DIOPO (1h)
DMPP-DIOPO (1j)
86
57
94
84
76
88
90
41
10
12
14
20
21
44
conditions investigated previously: tetrachlorosilane was added
over 2 h by a syringe pump to a mixture of benzaldehyde,
triethyl phosphite, diisopropylethylamine,22 and catalyst 1 in a
CH2Cl2 at −78 °C.
p-Tolyl-DIOPO (1a), the most effective promoter of the reduc-
tive aldol reaction described in the previous section, and m-tolyl-
DIOPO (1d) gave selectivities as low as that of DIOPO (entries
3 and 4). o-Tolyl-DIOPO (1g) and m-xylyl-DIOPO (1h) gave
a All reactions were performed using benzaldehyde (0.25 mmol), triethyl
phosphite (0.375 mmol), tetrachlorosilane (0.375 mmol),
diisopropylethylamine (1.25 mmol), and a DIOPO derivative 1 (10 mol
%) in CH2Cl2 (1 mL) at −78 °C. b (S)-BINAPO or (R,R)-DIOPO
derivatives were used in this study. c Isolated yields. d Determined by
HPLC analysis. The (R)-isomer was the major enantiomer in all cases.
slightly better enantioselectivities (entries
5
and 6).
DMPP-DIOPO (1j), having a phenoxaphosphine ring, achieved
a selectivity higher than that of BINAPO (entry 7).
To compare DMPP-DIOPO with BINAPO, the phosphonyla-
tion of other aldehydes was next investigated (Table 5). Previous
studies of the BINAPO catalyst are summarized on the right
hand side of Table 5. Interestingly, DMPP-DIOPO showed a low
dependence on the electronics of the aldehyde (entries 1–4),
giving similar enantioselectivities, whereas the steric factor of
the aldehyde significantly affected the selectivity (entries 5 and
6). In most cases, the substrate scope appeared to complement
that of BINAPO (entries 3–6).
gave comparable stereoselectivities as BINAPO6l [72%, syn/anti
= 95/5, 85% ee (syn) for the reaction with p-anisaldehyde; 84%,
syn/anti = 99/1, 90% ee (syn) for that with 2-furfural]. Consider-
ing the availability of both the enantiomers of tartaric acid, Ar-
DIOPOs can be simple and inexpensive Lewis base catalysts.
Application of Ar-DIOPOs to phosphonylation of aldehydes
Phosphonylation of aldehydes with dialkyl or trialkyl phosphites
provides synthetically useful and biologically active α-hydroxy-
phosphonates, and several successful asymmetric metal catalysts
have been developed.21 We reported the first organocatalytic
Abramov-type phosphonylation of aldehydes with trialkyl phos-
phite and tetrachlorosilane;6e however, the selectivity has
remained modest yet.
Ar-DIOPOs (1a–j) were applied toward the phosphonylation
of benzaldehyde with triethyl phosphite (Table 4). In the pre-
vious study, BINAPO provided the best results among the Lewis
bases tested, whereas DIOPO resulted in a low selectivity
(entries 1 and 2).6e Experiments were performed under the
Development of chlorinative aldol reaction of ynone with
aldehyde and application of Ar-DIOPOs
The conjugate addition of a halide anion to α,β-unsaturated car-
bonyl compounds, followed by the aldol reaction with alde-
hydes, namely the halogenative aldol reaction, can provide
synthetically useful α-(1-haloalkyl or 1-haloalkylidene)-
β-hydroxy carbonyl compounds.23 Several effective non-enantio-
selective methods have been developed for achieving this trans-
formation, although enantioselective methods are limited.24
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4562–4570 | 4565

Table 6 Ar-DIOPO-catalyzed chlorinative aldol reaction of ynone 5
and benzaldehydea
Entry Lewis baseb
Yield (%) E/Zc
Eed (%) Eee (%)
1
2
3
4
5
6
7
8
BINAPO
—
DIOPO
p-Tolyl-DIOPO (1a)
p-MeO-DIOPO (1b)
p-Cl-DIOPO (1c)
m-Tolyl-DIOPO (1d) 54
o-Tolyl-DIOPO (1g) 50
m-Xylyl-DIOPO (1h) 73
DMPP-DIOPO (1j)
DMPP-DIOPO (1j)
DMPP-DIOPO (1j)
DMPP-DIOPO (1j)
23
0
60
67
71
52
44/56 18 19
—
47/53
48/52
—
0
8
—
0
8
10
6
6
Scheme 2 Geometrical isomerization of enone 6.
46/50 10
47/53
45/55
44/56
6
6
6
interconversion between these isomers occurred during the reac-
tion. To confirm this possibility, (E)- and (Z)-6, isolated by
column chromatography on silica gel, were subjected to the reac-
tion conditions (Scheme 2). Rapid geometrical isomerization but
no racemization was observed in both cases. Isomerization aver-
aged the enantiomeric excesses of (E)- and (Z)-6, which would
have differed prior to isomerization. The conjugate addition of a
chloride anion to the enone product 6, followed by C–C bond
rotation and elimination of one of the two chloride anions, likely
explains the isomerization mechanism.26
6
9
46/54 20
48/52 37
48/52 37
46/54 28
49/51 29
19
37
37
28
29
10
11f
12g
13h
35
46
89
80
a All reactions were performed by the addition of tetrachlorosilane
(0.375 mmol) to a mixture of ynone 5 (0.25 mmol) and benzaldehyde
(0.375 mmol), a Lewis base catalyst (10 mol%) in CH2Cl2 (1 mL) at
0 °C with stirring for 6 h. b (S)-BINAPO or (R,R)-DIOPO derivatives
1
were used in this study. c Determined by H-NMR analysis of the crude
product. d The ee of (E)-6. e The ee of (Z)-6. f For 19 h. g With 2,6-
lutidine (0.25 mmol) for 12 h. h With 2,6-lutidine (0.25 mmol) at
−20 °C for 19 h.
Extensive studies of the catalyst structure and reaction mech-
anism27 would be necessary to further improve the yield and
selectivity.
In the course of our study of the Lewis base-catalyzed reduc-
tive aldol reactions of α,β-enones and aldehydes with trichloro-
silane,6f,l we tested α,β-ynone as a substrate in place of the
enone. Surprisingly, rather than conjugate reduction, we
observed a chlorinative aldol reaction.
Conclusions
We demonstrated a divergent synthetic approach to aryl group-
modified DIOP dioxides (Ar-DIOPOs) and their utility as Lewis
base catalysts for reductive aldol reaction, phosphonylation, and
chlorinative aldol reaction with chlorosilane reagents. Refining
the aryl group (the pendant moiety) effectively enhanced the
reactivity and selectivity. Further systematic studies in which the
chiral backbone is tuned along with the pendant moiety and
application to other reactions are currently in progress.
Thus, tetrachlorosilane instead of trichlorosilane was subjected
to a mixture of ynone 5, benzaldehyde (1.5 equiv), and BINAPO
(10 mol%) in CH2Cl2 at 0 °C (Table 6, entry 2). Although the
yield and enantioselectivity were low, the chlorinative aldol
product 6 was obtained enantioselectively as a mixture of the
E/Z-isomers. Lewis base catalyst is indispensable for the reac-
tion, because no desired product was obtained in its absence
(entry 2). The use of DIOPO as a catalyst improved the yield to
a large extent, but no enantioselectivity was observed (entry 3).
Selected Ar-DIOPOs were next examined in an attempt to
enhance the enantioselectivity further (entries 4–10). Among
those tested, DMPP-DIOPO (1j) provided the highest enantio-
selectivity (37% ee), although the yield decreased to 35% (entry
10). p-MeO-DIOPO (1b) and m-xylyl-DIOPO (1h) bearing elec-
tron-donating groups tended to give high yields, but the ee of the
product was still less than 20% (entries 5 and 9). Prolonging the
reaction time using DMPP-DIOPO did not improve the yield sig-
nificantly (entry 11). The addition of 2,6-lutidine (1.0 equiv) was
found to increase the yield dramatically, although the enantio-
selectivity was reduced to 28% ee (entry 12).25 Lowering the
reaction temperature to −20 °C did not improve the selectivity,
even with 2,6-lutidine (entry 13).
Experimental section
General
Melting points were uncorrected. 1H, 13C{1H}, and 31P{1H}
NMR spectra were measured in CDCl3 with
a JEOL
JNM-ECX400 spectrometer unless otherwise noted. Tetra-
methylsilane (TMS) (δ = 0 ppm), CDCl3 (δ = 77.0 ppm), and
aq. phosphoric acid sealed in a glass capillary (δ = 0 ppm) were
used for internal standards for H, 13C, and 31P NMR analyses,
1
respectively. Infrared spectra were recorded on JIR-6500W. Mass
spectra were measured with JEOL JMS-DX303HF mass spec-
trometer. Optical rotations were recorded on a JASCO P-1010
polarimeter. High pressure liquid chromatography (HPLC)
was performed with a JASCO P-980 and UV-1575. Thin-layer
chromatography (TLC) analysis was carried out using
Merk silica gel plates. Visualization was accomplished with UV
light and/or phosphomolybdic acid. Column chromatography
Interestingly, the enantiomeric excesses of the (E)- and (Z)-
products
6 were nearly identical. This suggested that
4566 | Org. Biomol. Chem., 2012, 10, 4562–4570
This journal is © The Royal Society of Chemistry 2012

was performed using Kanto Chemical Silica Gel 60N (spherical,
neutral. 63–210 μm). All reactions were performed under
argon atmosphere using oven- and heating gun-dried
glassware equipped with a rubber septum and a magnetic
stirring bar.
THF and CH2Cl2 (dehydrated) were purchased from Kanto
Chemical. All other solvents were purified based on standard
procedures. Trichlorosilane and tetrachlorosilane were purchased
from Tokyo Kasei Kogyo (TCI) and used without further purifi-
cation. LHMDS (1.0 M THF solution) was purchased from
Aldrich. Triethyl phosphite was distilled from sodium. Diisopro-
pylethylamine and 2,6-lutidine were distilled from calcium
hydride. All other chemicals were purified based on standard
procedures.
(brd, J = 10.5 Hz), 109.1, 113.9 (d, J = 12.4 Hz), 114.1 (d, J =
13.4 Hz), 124.1 (d, J = 105.8 Hz), 124.7 (d, J = 106.8 Hz),
132.7 (d, J = 11.5 Hz), 132.9 (d, J = 70.6 Hz), 162.2; 31P{1H}
NMR (162 MHz, CDCl3) δ 29.5; LR-FABMS (CHCl3 + NBA)
m/z 651 (M + H+, 43), 593 (M + H+ − Me2CO, 7), 331 (M + H+
− Me2CO − Ar2POH, 14), 261 (Ar2PO+, 100); HR-FABMS
(CHCl3 + NBA) m/z calcd for C35H41O8P2 (M + H+) 651.2277,
found 651.2305.
(R,R)-p-Cl-DIOPO (1c)
TLC: Rf 0.71 (AcOEt–EtOH = 10 : 1, stained blue with phospho-
molybdic acid–EtOH); mp 253–255 °C; [α]2D4 +17.5 (c 1.00,
CHCl3); IR (KBr, cm−1) 1583, 1483, 1390, 1188, 1088, 1014,
1
754; H-NMR (400 MHz, CDCl3) δ 1.18 (s, 6H), 2.61 (ddd, J =
15.1, 9.2, 6.0 Hz, 2H), 2.79 (ddd, J = 15.1, 13.8, 3.7 Hz, 2H),
4.10–4.20 (m, 2H), 7.45 (brd, J = 6.9 Hz, 8H), 7.68 (ddd, J =
11.0, 8.7, 2.8 Hz, 8H); 13C NMR (100 MHz, CDCl3) δ 26.7,
32.8 (d, J = 71.5 Hz), 76.1 (d, J = 9.5 Hz), 109.5, 129.1 (d, J =
12.4 Hz), 129.2 (d, J = 12.4 Hz), 130.8 (d, J = 101.1 Hz), 131.5
(d, J = 103.0 Hz), 132.2 (d, J = 10.5 Hz), 132.5 (d, J = 10.5
Hz), 138.8 (d, J = 2.9 Hz), 138.8 (d, J = 2.9 Hz); 31P{1H} NMR
(162 MHz, CDCl3) δ 28.5; LR-FABMS (CHCl3 + NBA) m/z
667 (M + H+, 45), 609 (M + H+ − Me2CO, 14), 339 (M + H+ −
Me2CO − Ar2POH, 29), 269 (Ar2PO+,100); HR-FABMS
(CHCl3 + NBA) m/z calcd for C31H29Cl4O4P2 (M + H+)
667.0295, found 667.0267.
General procedure for preparation of Ar-DIOPOs
To a solution of a diarylphosphine oxide (1.1 mmol, 2.2 equiv)
and
(4R,5R)-4,5-bis(iodomethyl)-2,2-dimethyl-1,3-dioxolane
(191.0 mg, 0.5 mmol) in THF (4.0 mL) was added dropwise
LHMDS (1.0 M THF solution, 1.0 mL) at 0 °C. The mixture
was stirred for 18 h at 0 °C, quenched with sat. aq. NH4Cl, and
extracted with AcOEt (3 × 10 mL). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4, filtered,
and evaporated under reduced pressure. The residue was purified
with silica gel column chromatography with AcOEt only and
then CH2Cl2–EtOH (10 : 1–6 : 1) to give the corresponding
Ar-DIOPO.
(R,R)-m-Tolyl-DIOPO (1d)
(R,R)-p-Tolyl-DIOPO (1a)
TLC: Rf 0.66 (AcOEt–EtOH = 10 : 1, stained blue with phospho-
molybdic acid–EtOH); mp 65–68 °C; [α]2D7 +14.9 (c 0.90,
CHCl3); IR (KBr, cm−1) 1596, 1225, 1161, 769, 695, 565, 485;
1H-NMR (400 MHz, CDCl3) 1.20 (s, 6H), 2.36 (s, 12H), 2.58
(ddd, J = 15.1, 9.2, 6.9 Hz, 2H), 2.73 (ddd, J = 15.1, 13.8, 4.1
Hz, 2H), 4.08–4.18 (m, 2H), 7.27–7.36 (m, 8H), 7.52 (dd, J =
11.5, 6.9 Hz, 4H), 7.63 (dd, J = 12.1, 5.3 Hz, 4H); 13C NMR
(100 MHz, CDCl3) δ 21.4, 26.8, 33.1 (d, J = 70.6 Hz), 76.5 (d,
J = 11.4 Hz), 109.2, 127.7 (d, J = 9.5 Hz), 128.0 (d, J = 9.5 Hz),
128.2 (d, J = 12.4 Hz), 129.4 (d, J = 12.4 Hz), 131.3 (d, J = 8.6
Hz), 131.6 (d, J = 9.5 Hz), 132.4, 132.5, 132.6 (d, J = 101.1
Hz), 133.1 (d, J = 101.1 Hz), 138.2 (d, J = 11.4 Hz), 138.4 (d, J
= 12.4 Hz); 31P{1H} NMR (162 MHz, CDCl3) δ 29.7;
LR-FABMS (CHCl3 + NBA) m/z 587 (M + H+, 43), 529 (M +
H+ − Me2CO, 11), 299 (M + H+ − Me2CO − Ar2POH, 15), 229
(Ar2PO+, 100); HR-FABMS (CHCl3 + NBA) m/z calcd for
C35H41O4P2 (M + H+) 587.2480, found 587.2480.
TLC: Rf 0.63 (AcOEt–EtOH = 10 : 1, stained blue with phospho-
molybdic acid–EtOH); mp 223–225 °C; [α]2D7 +14.8 (c 1.16,
CHCl3); IR (KBr, cm−1) 1603, 1178, 1119, 1099, 806, 651, 539;
1H-NMR (400 MHz, CDCl3) δ 1.20 (s, 6H), 2.37 (s, 12H), 2.55
(ddd, J = 15.1, 9.8, 6.6 Hz, 2H), 2.76 (ddd, J = 15.1, 13.2, 3.9
Hz, 2H), 4.03–4.16 (m, 2H), 7.23 (brd, J = 7.2 Hz, 8H), 7.65
(dd, J = 11.5, 7.8 Hz, 8H); 13C NMR (100 MHz, CDCl3) δ 21.5,
26.8, 33.2 (d, J = 70.6 Hz), 76.5 (brd, J = 10.5 Hz), 109.1,
129.1 (d, J = 12.4 Hz), 129.2 (d, J = 13.3 Hz), 129.6 (d, J =
103.0 Hz), 130.1 (d, J = 103.0 Hz), 130.7 (d, J = 9.5 Hz), 131.0
(d, J = 9.5 Hz), 141.9, 142.0; 31P{1H} NMR (162 MHz, CDCl3)
δ 29.7; LR-FABMS (CHCl3 + NBA) m/z 587 (M + H+, 78), 529
(M + H+ − Me2CO, 13), 299 (M + H+ − Me2CO − Ar2POH,
18), 229 (Ar2PO+, 100); HR-FABMS (CHCl3 + NBA + NaI)
m/z calcd for C35H40O4P2Na (M + Na+) 609.2300, found
609.2317.
(R,R)-p-MeO-DIOPO (1b)
(R,R)-m-MeO-DIOPO (1e)
TLC: Rf 0.23 (AcOEt–EtOH = 10 : 1, stained blue with phospho-
molybdic acid/EtOH); mp 170–172 °C; [α]2D7 +17.0 (c 0.995,
CHCl3); IR (KBr, cm−1) 1599, 1504, 1294, 1255, 1173, 1122,
TLC: Rf 0.54 (AcOEt–EtOH = 10 : 1, stained blue with phospho-
molybdic acid–EtOH); mp 96–99 °C; [α]1D8 +22.1 (c 0.995,
CHCl3); IR (KBr, cm−1) 1592, 1575, 1484, 1422, 1252, 1180,
1
1
1026, 802, 550; H-NMR (400 MHz, CDCl3) δ 1.21 (s, 6H),
1041, 783, 695, 500; H-NMR (400 MHz, CDCl3) δ 1.22 (s,
2.52 (ddd, J = 15.1, 9.6, 6.4 Hz, 2H), 2.75 (ddd, J = 15.1, 13.3,
3.7 Hz, 2H), 3.83 (s, 12H), 4.02–4.12 (m, 2H), 6.94 (brd, J =
7.3 Hz, 8H), 7.68 (dd, J = 11.0, 8.7 Hz, 8H); 13C NMR
(100 MHz, CDCl3) δ 26.8, 33.5 (d, J = 70.6 Hz), 55.3, 76.6
6H), 2.60 (ddd, J = 15.1, 9.6, 6.0 Hz, 2H), 2.79 (ddd, J = 15.1,
13.8, 3.7 Hz, 2H), 3.80 (s, 6H), 3.82 (s, 6H), 4.10–4.17 (m, 2H),
7.02 (dd, J = 8.2, 1.8 Hz, 4H), 7.25–7.40 (m, 12H); 13C NMR
(100 MHz, CDCl3) δ 26.8, 33.2 (d, J = 70.6 Hz), 55.38, 55.43,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4562–4570 | 4567

76.5 (brd, J = 10.5 Hz), 109.3, 115.5 (d, J = 10.5 Hz), 115.8 (d,
J = 10.5 Hz), 118.1, 122.8 (d, J = 9.5 Hz), 123.1 (d, J = 9.5 Hz),
129.6 (d, J = 14.3 Hz), 129.8 (d, J = 14.3 Hz), 134.0 (d, J =
99.2 Hz), 134.5 (d, J = 99.2 Hz), 159.5 (d, J = 10.5 Hz), 159.6
(d, J = 10.5 Hz); 31P{1H} NMR (162 MHz, CDCl3) δ 29.7;
LR-FABMS (CHCl3 + NBA) m/z 651 (M + H+, 61), 593 (M +
H+ − Me2CO, 17), 331 (M + H+ − Me2CO − Ar2POH, 31), 261
(Ar2PO+, 100); HR-FABMS (CHCl3 + NBA) m/z calcd for
C35H41O8P2 (M + H+) 651.2277, found 651.2294.
7.09 (d, J = 3.7 Hz, 4H), 7.37 (dd, J = 11.7, 2.5 Hz, 8H); 13C
NMR (100 MHz, CDCl3) δ 21.3, 26.9, 33.2 (d, J = 70.6 Hz),
76.6 (d, J = 10.5 Hz), 109.2, 128.3 (d, J = 9.5 Hz), 128.7 (d, J =
9.5 Hz), 132.7 (d, J = 99.2 Hz), 133.20 (d, J = 99.2 Hz), 133.25
(d, J = 1.9 Hz), 133.4 (d, J = 1.9 Hz), 137.9 (d, J = 12.4 Hz),
138.2 (d, J = 12.4 Hz); 31P{1H} NMR (162 MHz, CDCl3) δ
29.8; LR-FABMS (CHCl3 + NBA) m/z 643 (M + H+, 74), 585
(M + H+ − Me2CO, 13), 327 (M + H+ − Me2CO − Ar2POH,
18), 257 (Ar2PO+, 100); HR-FABMS (CHCl3 + NBA) m/z calcd
for C39H49O4P2 (M + H+) 643.3106, found 643.3124.
(R,R)-m-Cl-DIOPO (1f)
(R,R)-Thienyl-DIOPO (1i)
TLC: Rf 0.71 (AcOEt–EtOH = 10 : 1, stained blue with phospho-
molybdic acid–EtOH); mp 72–74 °C; [α]1D7 +14.8 (c 1.03,
CHCl3); IR (KBr, cm−1) 1566, 1469, 1403, 1186, 1134, 685;
1H-NMR (400 MHz, CDCl3) δ 1.20 (s, 6H), 2.64 (ddd, J = 15.1,
9.2, 6.9 Hz, 2H), 2.76 (ddd, J = 15.1, 14.7, 4.1 Hz, 2H),
4.10–4.22 (m, 2H), 7.43 (dddd, J = 8.2, 7.8, 3.4, 2.3 Hz, 4H),
7.51 (brd, J = 8.2 Hz, 4H), 7.63 (dd, J = 11.0, 7.8 Hz, 4H), 7.78
(brd, J = 11.9 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ 26.7,
32.8 (d, J = 71.5 Hz), 76.1 (d, J = 10.5 Hz), 109.7, 128.6 (d, J =
9.5 Hz), 129.0 (d, J = 9.5 Hz), 130.1 (d, J = 12.4 Hz), 130.3 (d,
J = 13.4 Hz), 130.6 (d, J = 10.5 Hz), 131.1 (d, J = 10.5 Hz),
132.2 (d, J = 2.9 Hz), 132.3 (d, J = 1.9 Hz), 134.4 (d, J = 98.2
Hz), 135.0 (d, J = 99.2 Hz), 135.1 (d, J = 15.3 Hz), 135.3 (d, J
= 16.2 Hz); 31P{1H} NMR (162 MHz, CDCl3) δ 27.8;
LR-FABMS (CHCl3 + NBA) m/z 667 (M + H+, 34), 609 (M +
H+ − Me2CO, 23), 339 (M + H+ − Me2CO − Ar2POH, 54), 269
(Ar2PO+, 100); HR-FABMS (CHCl3 + NBA) m/z calcd for
C31H29Cl4O4P2 (M + H+) 667.0295, found 667.0325.
TLC: Rf 0.57 (AcOEt–EtOH = 10 : 1, stained blue with phospho-
molybdic acid–EtOH); mp 171–173 °C; [α]2D8 +3.2 (c 1.01,
CHCl3); IR (KBr, cm−1) 1502, 1406, 1188, 1176, 1095, 1016,
714, 536; 1H-NMR (400 MHz, CDCl3) δ 1.26 (s, 6H), 2.66
(ddd, J = 15.1, 10.1, 6.9 Hz, 2H), 2.86 (ddd, J = 15.1, 14.7, 4.6
Hz, 2H), 4.17–4.27 (m, 2H), 7.17–7.20 (m, 4H), 7.63–7.68 (m,
4H), 7.70–7.74 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 26.8,
37.0 (d, J = 79.1 Hz), 76.2 (d, J = 11.4 Hz), 109.6, 128.2 (d, J =
11.4 Hz), 128.4 (d, J = 10.5 Hz), 133.50 (d, J = 4.8 Hz), 133.58
(d, J = 4.6 Hz), 133.64 (d, J = 114.4 Hz), 134.2 (d, J = 114.4
Hz), 135.6 (d, J = 9.5 Hz), 135.9 (d, J = 10.5 Hz); 31P{1H}
NMR (162 MHz, CDCl3) δ 18.8; LR-FABMS (CHCl3 + NBA)
m/z 555 (M + H+, 99), 497 (M + H+ − Me2CO, 18), 283 (M +
H+ − Me2CO − Ar2POH, 24), 213 (Ar2PO+, 100); HR-FABMS
(CHCl3 + NBA) m/z calcd for C23H25O4P2S4 (M + H+)
555.0111, found 555.0107.
(R,R)-DMPP-DIOPO (1j)
(R,R)-o-Tolyl-DIOPO (1g)
TLC: Rf 0.23 (AcOEt–EtOH = 10 : 1, stained blue with phospho-
molybdic acid–EtOH); mp 120–124 °C; [α]2D0 −21.0 (c 1.00,
CHCl3); IR (KBr, cm−1) 2981, 1612, 1587, 1473, 1396, 1281,
TLC: Rf 0.71 (AcOEt–EtOH = 10 : 1, stained blue with phospho-
molybdic acid–EtOH); mp 61–63 °C; [α]2D8 −4.0 (c 0.98,
CHCl3); IR (KBr, cm−1) 1593, 1453, 1178, 750; 1H-NMR
(400 MHz, CDCl3) δ 1.15 (s, 6H), 2.30 (s, 12H), 2.67–2.77 (m,
4H), 4.20–4.30 (m, 2H), 7.12–7.20 (m, 4H), 7.20–7.30 (m, 4H),
7.33–7.42 (m, 4H), 7.71 (dd, J = 12.8, 7.8 Hz, 2H), 7.84 (dd, J
= 13.3, 7.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 21.3, 26.7,
31.9 (d, J = 71.5 Hz), 76.2 (dd, J = 11.9, 3.3 Hz), 109.0, 125.3
(d, J = 12.4 Hz), 125.6 (d, J = 11.5 Hz), 131.2 (d, J = 97.3 Hz),
131.5 (d, J = 10.5 Hz), 131.63, 131.66 (d, J = 10.5 Hz), 131.7,
131.8 (d, J = 10.5 Hz), 132.0 (d, J = 97.3 Hz), 132.4 (d, J =
10.5 Hz), 141.3 (d, J = 8.6 Hz), 141.7 (d, J = 9.5 Hz); 31P{1H}
NMR (162 MHz, CDCl3) δ 31.8; LR-FABMS (CHCl3 + NBA)
m/z 587 (M + H+, 100), 529 (M + H+ − Me2CO, 13), 299 (M +
H+ − Me2CO − Ar2POH, 24), 229 (Ar2PO+, 90); HR-FABMS
(CHCl3 + NBA) m/z calcd for C35H41O4P2 (M + H+) 587.2480,
found 587.2465.
1
1230, 1163, 822, 762; H-NMR (400 MHz, CDCl3) δ 1.03 (s,
6H), 2.07–2.12 (ddd, J = 15.1, 9.6, 9.6 Hz, 2H), 2.31 (ddd, J =
16.1, 15.1, 2.8 Hz, 2H), 2.37 (s, 6H), 2.39 (s, 6H), 3.70–3.80
(m, 2H), 7.12 (ddd, J = 8.2, 6.4, 2.3 Hz, 4H), 7.35 (ddd, J = 8.4,
4.1, 2.1 Hz, 4H), 7.72 (brd, J = 13.3 Hz, 2H), 7.77 (dd, J = 13.3
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 20.6, 26.6, 37.2 (d, J =
79.1 Hz), 76.3 (dd, J = 14.3, 4.8 Hz), 109.1, 113.6 (d, J = 99.2
Hz), 114.4 (d, J = 99.2 Hz), 117.73 (d, J = 5.7 Hz), 117.79 (d, J
= 5.7 Hz), 130.0 (d, J = 3.8 Hz), 131.1 (d, J = 3.8 Hz), 133.1 (d,
J = 10.5 Hz), 133.4 (d, J = 10.5 Hz), 134.7, 153.22 (d, J = 3.8
Hz), 153.31 (d, J = 3.8 Hz); 31P{1H} NMR (162 MHz, CDCl3)
δ 5.2; LR-FABMS (CHCl3 + NBA) m/z 615 (M + H+, 75), 557
(M + H+ − Me2CO, 9), 313 (M + H+ − Me2CO − Ar2POH, 12),
243 (Ar2PO+, 100); HR-FABMS (CHCl3 + NBA) m/z calcd for
C35H37O6P2 (M + H+) 615.2065, found 615.2067.
(R,R)-m-Xylyl-DIOPO (1h)
General procedure for reductive aldol reaction of chalcone and
aldehydes catalyzed by Ar-DIOPO
TLC: Rf 0.71 (AcOEt–EtOH = 10 : 1, stained blue with phospho-
molybdic acid–EtOH); mp 156–158 °C; [α]2D7 +24.8 (c 1.00,
CHCl3); IR (KBr, cm−1) 1601, 1454, 1419, 1377, 1273, 1182,
To a solution of Ar-DIOPO (10 mol%), chalcone (0.25 mmol)
and an aldehyde (0.3 mmol, 1.2 equiv) in dry propionitrile
(2 mL) was added dropwise trichlorosilane (ca. 3 M CH2Cl2 sol-
ution, 0.5 mmol) at −78 °C. The mixture was stirred for the
1
1128, 1043, 852, 694, 571; H-NMR (400 MHz, CDCl3) δ 1.22
(s, 6H), 2.31 (s, 24H), 2.50–2.67 (m, 4H), 4.08–4.16 (m, 2H),
4568 | Org. Biomol. Chem., 2012, 10, 4562–4570
This journal is © The Royal Society of Chemistry 2012

indicated time at that temperature and quenched with sat. aq.
NaHCO3 (1.5 mL). After addition of AcOEt (5 mL), the mixture
was stirred for 1 h, filtered through a Celite pad, and extracted
with AcOEt (3×). The combined organic layers were washed
with brine (1×), dried over anhydrous MgSO4, filtered, and evap-
orated. The residue was purified by silica gel column chromato-
graphy with hexane–AcOEt (15 : 1–3 : 1) to give a reductive
aldol product. After separation of the product, the Lewis base
could be recovered by eluting with CH2Cl2–EtOH (10 : 1)
without loss of the optical purity. For physical data and HPLC
analysis of the products, see ref. 6l.
295 (M + Na+, 64), 105 (PhCO+, 100); HR-FABMS (CHCl3 +
NBA + NaI) m/z calcd for C16H13ClO2Na (M + Na+) 295.0502,
found 295.0507; HPLC (CHIRALPAK AS-H, hexane/2-propa-
nol = 39 : 1, flow rate 1.0 mL min−1, UV detection at 254 nm):
tR = 23.6 min (major), 36.8 min (minor).
(Z)-3-Chloro-2-(hydroxy(phenyl)methyl)-1-phenylprop-2-en-1-
one ((Z)-6)
TLC: Rf 0.28 (hexane–AcOEt = 5 : 1, stained green with phos-
phomolybdic acid in EtOH); [α]2D2 +12.3 (c 1.17, CHCl3, for
28% ee); IR (neat, cm−1) 3446, 3064, 1662, 1653, 1595, 1450,
1
1323, 1228, 700; H NMR (400 MHz, CDCl3) δ 2.88 (dd, J =
General procedure for phosphonylation of aldehydes catalyzed
by Ar-DIOPO
1.4, 3.2 Hz, 1H), 5.65 (d, J = 3.2 Hz, 1H), 6.45 (d, J = 1.4 Hz,
1H), 7.26–7.80 (m, 10H); 13C NMR (100 MHz, CDCl3) δ 75.1,
120.5, 126.5, 128.4, 128.6, 128.7, 129.5, 133.8, 135.8, 139.7,
143.8, 196.0; LR-FABMS (CHCl3 + NBA + NaI) m/z 295 (M +
Na+, 100), 105 (PhCO+, 52); HR-FABMS (CHCl3 + NBA +
NaI) m/z calcd for C16H13ClO2Na (M + Na+) 295.0502, found
295.0504; HPLC (CHIRALPAK AS-H, hexane–2-propanol =
Triethyl phosphite (0.375 mmol) was added to a solution of an
i
aldehyde (0.25 mmol), Pr2NEt (0.375 mmol) and Ar-DIOPO
(10 mol%) in CH2Cl2 (1 mL) at −78 °C and then tetrachloro-
silane (0.75 M CH2Cl2 solution, 0.5 mL) was introduced over
2 h using a syringe pump. After checking completion of the reac-
tion by TLC analysis, deionized water (1 mL), sat. aq. NaHCO3
(2.5 mL), and AcOEt (2.5 mL) were added in turn to the reaction
mixture. After being stirred for 1 h, the mixture was filtered via a
Celite pad and extracted with AcOEt (3 × 5 mL). The combined
organic layers were washed with brine, dried over anhydrous
MgSO4, filtered, and evaporated under reduced pressure. The
residue was purified with silica gel column chromatography with
hexane–acetone (2 : 1–1 : 1) to give the corresponding α-hydro-
xyphosphonate. After separation of the product, the Lewis base
could be recovered by eluting with CH2Cl2–EtOH (10 : 1)
without loss of the optical purity. For physical data and HPLC
analysis of the products, see ref. 6e.
39 : 1, flow rate 1.0 mL min−1, UV detection at 254 nm): tR
=
42.8 min (major), 46.4 min (minor).
Notes and references
1 For the seminal reports of 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis
(diphenylphosphino)butane (DIOP), see: (a) T. P. Dang and H.
B. Kagan, J. Chem. Soc. D, 1971, 481; (b) H. B. Kagan and T.-P. Dang,
J. Am. Chem. Soc., 1972, 94, 6429–6433.
2 For reviews on the development of chiral ligands, see: (a) Asymmetric
Catalysis in Organic Synthesis, ed. R. Noyori, Wiley, New York, 1994;
(b) Comprehensive Asymmetric Catalysis, ed. E. N. Jacobsen, A. Pfaltz
and H. Yamamoto, Springer, Germany, 1999, vol. 1–3; (c) Catalytic
Asymmetric Synthesis, ed. I. Ojima, Wiley-VCH, New York, 2000;
(d) W. Tang and X. Zhang, Chem. Rev., 2003, 103, 3029–3069;
(e) A. Pfaltz and W. J. Drury III, Proc. Natl. Acad. Sci. U. S. A., 2004,
101, 5723–5726; (f) X. Zhang, Y. Chi and X. Zhang, Acc. Chem. Res.,
2007, 40, 1278–1290.
General procedure for chlorinative aldol reaction of a ynone and
benzaldehyde catalyzed by Ar-DIOPOs
3 For reviews of 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP)
and its derivatives, see: (a) R. Noyori and T. Ohkuma, Angew. Chem.,
Int. Ed., 2001, 40, 40–73; (b) H. Shimizu, I. Nagasaki and T. Saito, Tetra-
hedron, 2005, 61, 5405–5432.
4 For reviews of Lewis base catalysts, see: (a) Y. Orito and M. Nakajima,
Synthesis, 2006, 1391–1401; (b) S. E. Denmark and G. L. Beutner,
Angew. Chem., Int. Ed., 2008, 47, 1560–1638; (c) M. Benaglia,
S. Guizzetti and L. Pignataro, Coord. Chem. Rev., 2008, 252, 492–512;
(d) M. Benaglia and S. Rossi, Org. Biomol. Chem., 2010, 8, 3824–3830.
5 For recent reports on phosphine oxide-type, chiral Lewis base catalysts,
To a solution of ynone 5 (32.5 mg, 0.25 mmol), benzaldehyde
(38 μL, 0.375 mmol) and Ar-DIOPO (10 mol%) in CH2Cl2
(1.0 mL) was added tetrachlorosilane (43 μL, 0.375 mmol) at
0 °C. After being stirred for 6 h, the mixture was quenched with
sat. aq. NaHCO3. The mixture was stirred for 30 min, filtered
through a Celite pad, and extracted with AcOEt (3×). The com-
bined organic layers were dried over anhydrous MgSO4, filtered,
and evaporated. The residue was purified by silica gel column
chromatography with hexane–AcOEt (15 : 1–5 : 1) to give (E)-6
(less polar isomer) and (Z)-6 (polar isomer).
see:
(a) S. Rossi, M. Benaglia, A. Genoni, T. Benincori and
G. Celentano, Tetrahedron, 2011, 67, 158–166; (b) S. Rossi,
M. Benaglia, F. Cozzi, A. Genoni and T. Benincori, Adv. Synth. Catal.,
2011, 9, 848–854. See also ref. 4d.
6 (a) M. Nakajima, S. Kotani, T. Ishizuka and S. Hashimoto, Tetrahedron
Lett., 2005, 46, 157–159; (b) E. Tokuoka, S. Kotani, H. Matsunaga,
T. Ishizuka, S. Hashimoto and M. Nakajima, Tetrahedron: Asymmetry,
2005, 16, 2391–2392; (c) S. Kotani, S. Hashimoto and M. Nakajima,
Synlett, 2006, 1116–1118; (d) S. Kotani, S. Hashimoto and M. Nakajima,
Tetrahedron, 2007, 63, 3122–3132; (e) K. Nakanishi, S. Kotani,
M. Sugiura and M. Nakajima, Tetrahedron, 2008, 64, 6415–6419;
(f) M. Sugiura, N. Sato, S. Kotani and M. Nakajima, Chem. Commun.,
2008, 4309–4311; (g) M. Sugiura, M. Kumahara and M. Nakajima,
Chem. Commun., 2009, 3585–3587; (h) Y. Shimoda, T. Tando, S. Kotani,
M. Sugiura and M. Nakajima, Tetrahedron: Asymmetry, 2009, 20, 1369–
1370; (i) S. Kotani, Y. Shimoda, M. Sugiura and M. Nakajima, Tetrahe-
dron Lett., 2009, 50, 4602–4605; ( j) S. Kotani, S. Aoki, M. Sugiura and
M. Nakajima, Tetrahedron Lett., 2011, 52, 2834–2836; (k) Y. Shimoda,
S. Kotani, M. Sugiura and M. Nakajima, Chem.–Eur. J., 2011, 17, 7992–
(E)-3-Chloro-2-(hydroxy(phenyl)methyl)-1-phenylprop-2-en-1-
one ((E)-6)
TLC: Rf 0.39 (hexane–AcOEt = 5 : 1, stained green with phos-
phomolybdic acid in EtOH); mp 89–91 °C; [α]2D1 −42.6 (c
1.325, CHCl3, for 28% ee); IR (KBr, cm−1) 3477, 3061, 1633,
1
1593, 1446, 1336, 1039, 841, 731, 698; H NMR (400 MHz,
CDCl3) δ 4.65 (d, J = 10.8 Hz, 1H), 6.12 (d, J = 10.8 Hz, 1H),
7.00 (s, 1H) 7.25–7.62 (m, 10H); 13C NMR (100 MHz, CDCl3)
δ 71.5, 125.3, 127.6, 128.5, 128.6, 129.6, 133.3, 135.2, 137.2,
141.3, 141.9, 196.7; LR-FABMS (CHCl3 + NBA + NaI) m/z
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4562–4570 | 4569

7995; (l) M. Sugiura, N. Sato, Y. Sonoda, S. Kotani and M. Nakajima,
Chem.–Asian J., 2010, 5, 478–481.
required for the reaction with Ar-DIOPOs, whereas 1.5 equiv were suffi-
cient for BINAPO catalysis (see ref. 6e).
7 Y. S. Oh, S. Kotani, M. Sugiura and M. Nakajima, Tetrahedron: Asymme-
try, 2010, 21, 1833–1835.
23 For leading references, see: (a) M. Taniguchi, T. Hino and Y. Kishi, Tet-
rahedron Lett., 1986, 27, 4767–4770 [Et2AlI or TiCl4
+
nBu4NI]
8 Aryl group-modified DIOP derivatives were synthesized from a tartaric
acid-derived ditosylate and diarylphosphide anions. For leading refer-
ences, see: (a) C. F. Hobbs and W. S. Knowles, J. Org. Chem., 1981, 46,
4422–4427; (b) T. Morimoto, M. Chiba and K. Achiwa, Tetrahedron
Lett., 1988, 29, 4755–4758; (c) T. Morimoto, M. Chiba and K. Achiwa,
Tetrahedron Lett., 1989, 30, 735–738; (d) T. Morimoto, M. Chiba and
K. Achiwa, Chem. Pharm. Bull., 1989, 37, 3161–3163. See also ref. 1b.
9 For recent reviews on trichlorosilane-mediated reactions, see:
(a) S. Guizzetti and M. Benaglia, Eur. J. Org. Chem., 2010, 5529–5541;
(b) S. Jones and C. J. A. Warner, Org. Biomol. Chem., 2012, 10, 2189–
2200.
10 Diiodide 2 was prepared according to the literature: (a) M. Carmack and
C. J. Kelley, J. Org. Chem., 1968, 33, 2171–2173; (b) E. A. Mash, A.
K. Nelson, S. Van Deusen and B. Hemperly, Org. Synth., 1990, 68, 92–
98; (c) S. P. Khanapure, N. Najafi, S. Manna, J.-J. Yang and J. Rokach,
J. Org. Chem., 1995, 60, 7548–7551.
11 Diarylphospine oxides 3a–h were prepared according to the literature:
(a) H. R. Hays, J. Org. Chem., 1968, 33, 3690–3694; (b) C. A. Busacca,
J. C. Lorenz, N. Grinberg, N. Haddad, M. Hrapchak, B. Latli, H. Lee,
P. Sabila, A. Saha, M. Sarvestani, S. Shen, R. Varsolona, X. Wei and C.
H. Senanayake, Org. Lett., 2005, 7, 4277–4280.
12 R. K. Haynes, T.-L. Au-Yeung, W.-K. Chan, W.-L. Lam, Z.-Y. Li, L.-
L. Yeung, A. S. C. Chan, P. Li, M. Koen, C. R. Mitchell and S.
C. Vonwiller, Eur. J. Org. Chem., 2000, 3205–3216.
(b) T. Kataoka and H. Kinoshita, Eur. J. Org. Chem., 2005, 45–58 [TiCl4
+ chalcogenide] (c) H. X. Wei, J. Hu, D. W. Purkiss and P. W. Paré, Tetra-
hedron Lett., 2003, 44, 949–952 [MgI2] (d) H. X. Wei, R. L. Jasoni,
J. Hu, G. Li and P. W. Paré, Tetrahedron, 2004, 60, 10233–10237
[MgBr2] (e) J. S. Yadav, B. V. S. Reddy, M. K. Gupta and S. K. Pandey,
J. Mol. Catal. A: Chem., 2007, 264, 309–312 [GaI3] (f) M. Shi, J.-
K. Jiang and Y.-S. Feng, Org. Lett., 2000, 2, 2397–2400 [reaction of
methyl vinyl ketone with aldehydes, TiCl4 + nBu4NI].
24 (a) G. Li, H.-X. Wei, B. S. Phelps, D. W. Purkiss and S. H. Kim, Org.
Lett., 2001, 3, 823–826; (b) D. Chen, C. Timmons, J. Liu, A. Headley
and G. Li, Eur. J. Org. Chem., 2004, 3330–3335; (c) B. K. Senapati, G.-
S. Hwang, S. Lee and D. H. Ryu, Angew. Chem., Int. Ed., 2009, 48,
4398–4401. For an enantioselective method using a stoichiometric chiral
Lewis acid, see: (d) D. Chen, L. Guo, S. R. S. S. Kotti and G. Li, Tetra-
hedron: Asymmetry, 2005, 16, 1757–1762.
25 2,6-Lutidine likely promotes catalyst turnover in addition to diisopropyl-
ethylamine (see ref. 22). Use of diisopropylethylamine instead of 2,6-luti-
dine in this case resulted in a low yield due to the formation of benzyl
alcohol and cinnamaldehyde. The former may be generated via reduction
of benzaldehyde by the amine, and the latter via condensation of benzal-
dehyde with the enamine (iPr2NCHvCH2), formed by the above
reduction. For related reactions, see: (a) S. Kotani, K. Osakama,
M. Sugiura and M. Nakajima, Org. Lett., 2011, 13, 3968–3971;
(b) A. Clerici, N. Pastori and O. Porta, Tetrahedron Lett., 2004, 45,
1825–1827.
13 Low recovery of diiode 2 was observed as well. The high basicity of the
base or the phosphinylide anion may induce decomposition of 2.
26 Plausible intermediates for the geometrical isomerization are shown
below.
t
14 Other bases (LDA, BuLi, and BuOK) were also tested, but provided
inferior yields of 1a.
15 It was reported that lithium diphenylphosphinylide exists as the
O-bound lithium species (Ph2P–O–Li) in THF, see: K. Goda, H. Gomi,
M. Yoshifuji and N. Inamoto, Bull. Chem. Soc. Jpn., 1977, 50, 545–546.
16 3i was prepared from 2-thienyllithium: A. B. Koldobskii, N. P. Tsvetkov
and V. N. Kalinin, Dokl. Chem., 2010, 432, 133–135.
17 3j was prepared from di-p-tolyl ether and phosphorus trichloride: I.
I. Ponomarev, Yu. Yu. Rybkin, E. I. Goryunov, P. V. Petrovskii and K.
A. Lyssenko, Russ. Chem. Bull., 2004, 53, 2881–2883.
18 Oxidation of 3 to the corresponding phosphinic acid was observed. A
possible mechanism for the oxidation of lithium phosphinylide by
oxygen was discussed in the literature: R. A. Strecker, J. L. Snead and G.
P. Sollott, J. Am. Chem. Soc., 1973, 95, 210–214.
.
27 The following reaction pathway for the current chlorinative aldol reaction
is proposed. First, the conjugate addition of a chloride anion to the ynone
5 generates a pair of chiral allenylic trichlorosilyl enol ethers 7 and ent-7,
depicted below (the chlorination step). Second, these intermediates react
with benzaldehyde via six-membered cyclic transition states to give the
product 6 (the aldol step). This aldol step is controlled by the chiral
Lewis base catalyst and may generate all four stereoisomers of product 6
from either 7 or ent-7. The geometrical isomerization of product 6 com-
plicates the identification of the stereochemical course.
19 Synthesis of the corresponding diphosphine DMPP-DIOP was reported,
see ref. 8a.
20 For reviews: (a) H. Nishiyama and T. Shiomi, in Topics in Current
Chemistry, ed. M. J. Krische, Springer-Verlag, Germany, 2007, vol. 279,
p. 105; (b) H. Iida, M. J. Krische, in Topics in Current Chemistry, ed.
M. J. Krische, Springer-Verlag, Germany, 2007, vol. 279, p. 77.
21 For a recent review of the synthesis of phosphonic acid derivatives: C.
S. Demmer, N. Krogsgaard-Larsen and L. Bunch, Chem. Rev., 2011, 111,
7981–8006.
22 Diisopropylethylamine was used as an additive to promote catalyst turn-
over, see: M. Nakajima, M. Saito, M. Shiro and M. Hashimoto, J. Am.
Chem. Soc., 1998, 120, 6419–6420. Five equiv of the amine were
.
4570 | Org. Biomol. Chem., 2012, 10, 4562–4570
This journal is © The Royal Society of Chemistry 2012