Highly enantio- and diastereoselective reductive aldol reactions catalyzed by chiral spiro bisphosphine oxides

Article abstract of DOI:10.1016/S1872-2067(14)60241-2

A spiro bisphosphine oxide (SpinPO) was found to be an efficient chiral Lewis base catalyst in asymmetric reductive aldol reaction of enones and aldehydes in the presence of trichlorosilane as the reductant, affording a variety of β-hydroxyketones in good yields with moderate to high levels of diastereo- and enantioselectivities.

Full text of DOI:10.1016/S1872-2067(14)60241-2

Chinese Journal of Catalysis 36 (2015) 100–105
a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / c h n j c
Article (Special Issue on Catalysis in Organic Synthesis)
Highly enantio‐ and diastereoselective reductive aldol reactions
catalyzed by chiral spiro bisphosphine oxides
Panke Zhang, Jiawang Liu, Zheng Wang, Kuiling Ding*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A spiro bisphosphine oxide (SpinPO) was found to be an efficient chiral Lewis base catalyst in
asymmetric reductive aldol reaction of enones and aldehydes in the presence of trichlorosilane as
the reductant, affording a variety of β‐hydroxyketones in good yields with moderate to high levels of
diastereo‐ and enantioselectivities.
Received 4 September 2014
Accepted 26 September 2014
Published 20 January 2015
© 2015, Dalian Institute of Chemical Physics, Chinese Academy of Sciences.
Published by Elsevier B.V. All rights reserved.
Keywords:
Aldehyde
Asymmetric catalysis
Enone
Lewis base
Reductive aldol reaction
Spiro bisphosphine oxide
1. Introduction
drogen [12], sometimes diethylzinc [13], or trialkylborane [7]
were used as the stoichiometric reductants. The first example
The reductive aldol reaction between an α,β‐unsaturated
carbonyl compound and an aldehyde or ketone is a powerful
method for stereocontrolled C–C bond formation [1]. These
tandem reactions generally proceed via conjugate reduction of
an enone or enoate followed by aldol reaction of the in‐situ
generated enolate with an aldehyde or ketone electrophile. By
this way, the β‐hydroxy carbonyl products with several con‐
tiguous stereocenters can be directly constructed in a one‐pot
fashion, thus providing an attractive alternative approach for
stereocontrolled synthesis of aldols. Following the seminal
studies by Revis and Hilty in 1987 [2], a variety of catalysts
based on Rh [3], Co [4], Cu [5,6], Ni [7], In [8,9], Sn [10], etc.
[11], have been developed for inter‐ or intramolecular reduc‐
tive aldol reactions, wherein mostly silanes or molecular hy‐
of the asymmetric reductive aldol reaction was reported by
Morken et al. in 2000 [14], and since then a number of chiral
metal–ligand complexes based on Ir [15], Rh [16–21], or Cu
[22–29] have also been used as the catalysts to control the ste‐
reochemistry of the reactions, delivering various chiral aldol
products with synthetically useful diastereo‐ and enantioselec‐
tivities. A notable progress in this area was made recently by
Nakajima and coworkers [30–33], who have developed highly
enantio‐ and diastereoselective asymmetric reductive aldol
reactions using chiral bisphosphine oxides as Lewis base cata‐
lysts. It is also noteworthy that over the decades, Lewis base
catalysis has been established as an attractive and highly com‐
petitive alternative to the methods employing metal complexes,
providing elegant solutions to numerous challenging organic
*Corresponding author. Tel: +86‐21‐54925146; Fax: +86‐21‐64166128; E‐mail: kding@mail.sioc.ac.cn
This work was supported by the National Basic Research Program of China (2010CB833300), the National Natural Science Foundation of China
(21121062, 21232009), the Chinese Academy of Sciences, and the Science and Technology Commission of Shanghai Municipality.
The supporting information of this article is available from the corresponding author.
DOI: 10.1016/S1872‐2067(14)60241‐2 | http://www.sciencedirect.com/science/journal/18722067 | Chin. J. Catal., Vol. 36, No. 1, January 2015

Panke Zhang et al. / Chinese Journal of Catalysis 36 (2015) 100–105
101
transformations in general [34], and including the Mukaiyama
aldol reactions in particular [35]. In this context, we recently
reported the successful development of a class of spiro[4,4]‐
1,6‐nonadiene‐based phosphino‐oxazoline ligands/catalysts
[36–47] and bisphosphine oxides (SpinPO) [48], and the use of
SpinPO as chiral Lewis base catalysts in the direct asymmetric
double‐aldol reaction of ketones with aldehydes. As an ongoing
effort to develop efficient Lewis base catalyzed asymmetric
synthesis, herein we report a highly enantio‐ and diastereose‐
lective reductive aldol reaction of enones and aldehydes with
SpinPO as the catalyst and trichlorosilane as the reductant.
2 (0.25 mmol), chiral phosphine oxide (S)‐1c (15.1 mg, 0.025
mmol), and the aldehyde 3 (0.30 mmol) in anhydrous THF (1.0
mL) was added dropwise trichlorosilane (0.17 mL, 0.5 mmol)
at 78 °C. The resultant yellowish emulsion was stirred at 78
°C for 24 h, and the reaction was quenched by saturated
aqueous sodium bicarbonate solution (5.0 mL). The mixture
was stirred for 0.5 h at this temperature, warmed to r.t., and
stirred for further 0.5 h, and the solids were removed by
filtration through a pad of celite. The filtrate was extracted with
ethyl acetate (20 mL × 3), and the combined organic phases
were washed sequentially with saturated aqueous sodium
bicarbonate solution and brine, dried over anhydrous sodium
sulfate, and filtered. After removal of the volatiles under
reduced pressure, the residue was purified by column
chromatography on silica gel with petroleum ether/EtOAc
(15/1–10/1) as the eluents, to give the aldol product 4 as a
diastereomeric mixture. The diastereomeric ratio (dr, syn/anti)
and the enantiomeric excess (ee) values of the optically
2. Experimental
2.1. General methods
Unless otherwise noted, all reactions and manipulations
involving air‐ or moisture‐sensitive compounds were
performed using standard Schlenk techniques or in a glovebox.
All solvents were purified and dried using standard
procedures. Melting points were measured on an RY‐I
1
enriched 4a–q were determined by chiral HPLC, while the H,
13C, and 19F NMR spectral data were recorded on the
diastereomeric samples of 4a–q obtained from the
corresponding reductive aldol reactions catalyzed by racemic
BINAP dioxide (BINAPO) or achiral triphenylphosphine oxide.
1
apparatus and uncorrected. H, 13C, 31P, and 19F NMR spectra
were recorded on Varian Mercury 300 MHz or 400 MHz
spectrometers. Chemical shifts (δ values) were reported in ppm
downfield from internal TMS (1H NMR), internal CDCl3 (13C
NMR), external 85% H3PO4 (31P NMR), and external CF3CO2H
(19F NMR), respectively. Optical rotations were determined
using a Perkin Elmer 341 MC polarimeter. The IR spectra were
measured on a Bruker Tensor 27 FT‐IR spectrometer. ESI‐MS
and HRMS (ESI) spectra were taken on a Shimadzu LCMS‐
2010EV and an Agilent Technologies 6224 TOF LC/MS
spectrometer, respectively. HPLC analyses were performed on
a JASCO 2089 liquid chromatograph. Trichlorosilane, the α,β‐
unsaturated ketones, and aldehydes were purchased from
commercial sources and used without further purification.
3. Results and discussion
3.1. SpinPO catalyzed asymmetric reductive aldol reaction of
chalcone with benzaldehyde
3.1.1. Optimization of the reaction conditions
Nakajima et al. [30] have shown that trichlorosilane can be
activated by an appropriate Lewis base to undergo conjugate
reduction with an enone, and the in situ generated
trichlorosilyl enolate may react with a coexisting aldehyde to
give the reductive aldol product. Denmark et al. [4952] have
extensively investigated the aldol additions of trichlorosilyl
enolates derived from various carbonyl compounds and
demonstrated that the reactions proceeded via the catalysis of
some hypervalent silicon species stabilized by a suitable Lewis
base. Inspired by these pioneering studies, we initiated the
study by examining the viability of SpinPO catalysts of
asymmetric reductive aldol reaction, using substoichiometric
(S)‐1a in the reaction of chalcone (2a) and benzaldehyde (3a)
with two equivalents of trichlorosilane as the reductant. As
shown in Table 1, a large variation in reactivity and
stereoselectivity was observed, depending on the temperature,
solvent, and/or catalyst loading used in the reactions. For the
2.2. Synthesis of the chiral spiro[4,4]‐1,6‐nonadiene‐based
bisphosphine oxides (SpinPO)
The chiral SpinPO (S)‐1a‐c, (R)‐1d‐e, ()‐1f, and (S)‐1g (Fig.
1) were synthesized by following our previously reported
procedures [48].
2.3. General procedure for the spiro phosphine oxides catalyzed
asymmetric reductive aldol reactions
To a Schlenk tube containing a stirred solution of the enone
Fig. 1. Chiral spiro[4,4]‐1,6‐nonadiene‐based bisphosphine oxides (S)‐1a‐c, (R)‐1d‐e, ()‐1f, and (S)‐1g.

102
Panke Zhang et al. / Chinese Journal of Catalysis 36 (2015) 100–105
Table 1
(S)‐1a catalyzed asymmetric reductive aldol reaction of chalcone (2a) with benzaldehyde (3a).
Entry
1
2
3
4
X (mol%)
10
T (°C)
–78
–60
–40
–78
–78
–78
–78
–78
–78
–78
–78
–78
–78
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
DCE
CHCl3
CH3CN
Toluene
THF
Et2O
TBME
DME
THF
THF
Yield a (%)
drb,c
ee (syn)c (%)
ee (anti)c (%)
48
82
89
45
20
52
38
72
6
45:55
36:64
50:50
9:91
10:90
22:78
44:56
93:7
90
80
76
64
37
76
72
93
89
86
89
81
75
0
4
4
0
6
10
10
10
10
5
6
7
8
9
10
11
12
13
10
10
10
10
10
54
7
15
15
6
82:18
92:8
10
5
10
5
1
63
29
14
92:8
89:11
87:13
4
5
Reaction conditions: 2a (0.25 mmol), 3a (0.30 mmol), HSiCl3 (0.50 mmol), 24 h.
a Yield of the isolated product 4a. b dr = syn:anti. c Determined by chiral HPLC analyses.
reactions performed in dichloromethane in the presence of 10
mol% of (S)‐1a, varying the temperatures from 78 to 40 °C
raised the yield of the aldol adduct 4a, but the
diastereoselectivities (dr) were only modest (entries 1–3).
Replacing dichloromethane with other types of aprotic polar or
nonpolar solvents (entries 4–11) has been found to improve
the dr values in most cases, but sometimes at a cost of poor
conversion (entries 5, 9, and 10) or moderate ee values (entries
4 and 6). The coordinating ether THF and DME turned out to be
the most favorable solvents for the reaction, affording
preferentially syn‐4a in good yields and high levels of
diastereo‐ and enantioselectivities (entries 8 and 11). Further
attempts to optimize the reaction by reducing the catalyst
loadings of (S)‐1a from 10 to 5 or 1 mol% were unsuccessful,
resulting in poor yields and decreased dr and ee values (entries
12 and 13 vs 8). Thus, the optimized conditions as in entry 8
were used in subsequent catalyst survey studies.
3.1.2. Catalyst optimization
To further optimize the reaction results, the family of
SpinPO catalysts 1a–g was screened against reductive aldol
reaction of chalcone (2a) and benzaldehyde (3a) using
trichlorosilane as the reductant. The reactions were allowed to
proceed in THF for 24 h at 78 °C in the presence of 10 mol% of
1a–g, and the relevant results are summarized in Table 2.
Generally moderate to high yields (41%86%) were obtained
for the β‐hydroxyketone 4a, whereas the sense and level of
stereoselection fluctuated to some degree depending upon the
SpinPO structure (entries 1–7). Both the steric effects and the
skeleton flexibility in SpinPO structure appeared to be
important for the diastereo‐ and enantioselectivity. While high
diastereoselectivities (syn/anti ca 96/4) and excellent
Table 2
Screening of the SpinPO 1a‐g for the catalytic asymmetric reductive aldol reaction.
Entry
Catalyst
(S)‐1a
(S)‐1b
(S)‐1c
(R)‐1d
(R)‐1e
()‐1f
(S)‐1g
Yielda (%)
drb,c
93:7
96:4
96:4
82:18
20:80
97:3
94:6
ee (syn)c (%)
93 (R, R)
92 (R, R)
94 (R, R)
81 (S, S)
0 (S, S)
ee (anti)c (%)
1
2
3
4
5
6
7
72
78
86
59
41
82
78
7
14
13
4
14
6
68 (S, S)
15 (R, R)
1
Reaction conditions: 2a (0.25 mmol), 3a (0.30 mmol), HSiCl3 (0.50 mmol), 1 (0.025 mmol), THF (1.0 mL), 78 °C, 24 h.
a Yield of the isolated product 4a. b dr = syn:anti. c Determined by chiral HPLC analyses. The absolute configurations of the syn‐4a were assigned by
comparison of the specific rotations with that reported in Ref. [31].

Panke Zhang et al. / Chinese Journal of Catalysis 36 (2015) 100–105
103
enantioselectivities (92%94% ee) for syn‐4a were reached in
the cases of (S)‐1a–c (entries 1–3), considerable losses in
stereoselectivities were observed for the reactions catalyzed by
(R)‐1d–e with bulkier aryl substituents (entries 4 and 5). In
contrast to flexible 1a–c with two methylene moieties between
the spiro scaffold and the Ar2PO units, their structurally more
rigid analogs 1f–g bearing only one or no flexible methylene
group led to a substantial decline in enantioselectivities
(entries 6 and 7 vs 1). Among the SpinPO family, (S)‐1c was
identified as the optimal Lewis base catalyst for the reaction,
affording preferentially syn‐4a in high levels of diastereo‐ and
enantioselectivities (dr 96/4, 94% ee, entry 3).
diastereo‐ and enantioselectivities (dr 8/92–100/0, up to 95%
ee for the syn‐isomers). For the reactions of chalcone (2a) with
the aromatic aldehydes 3a–j, steric properties of the aldehyde
component seem to be less significant, as aldehydes 3a–f and 3j
afforded the corresponding aldol products 4a–f and 4j with
comparable stereoselectivities (dr 90/10–97/3, 78%94% ee
for the major syn‐diastereomers), regardless of the o‐, m‐, or
p‐locations of the electron‐donating substituent on their phenyl
rings (entries 1–6 and 10). On the other hand, the electronic
nature of the aldehydes appears to play a major role in
determining the stereoselectivities. Compared to their electron‐
rich homologues, aldehydes 3g and 3i bearing strongly
electron‐withdrawing p‐nitro or p‐trifluomethyl groups,
respectively, gave the products 4g and 4i in drastically reduced
stereoselectivities (syn/anti 46/54 and 53/47, 15%, and 44%
ee for the syn‐ and racemic for anti‐isomers, respectively)
(entries 7 and 9), probably as a result of less favorable
interaction with the hypervalent silicon species. The reaction of
2a and 3h is an exception, therein a high level of diastereo‐ and
enantioselectivity was attained (dr 95/5, 94% ee for syn‐4h)
despite the presence of electron‐withdrawing F atom on the
aldehyde reactant (entry 8). Aldehydes 3k–m containing
heteroaromatic or naphthyl groups also reacted smoothly with
2a (entries 11–13), to deliver β‐hydroxyketone products 4k–m
3.2. Substrate scope for the asymmetric reductive aldol reaction
The substrate adaptability of the protocol was evaluated
with the reductive aldol reactions of chalcones (2a and 2c) or
(E)‐1‐phenylbut‐2‐en‐1‐one (2b) and various aromatic,
aliphatic, α,β‐unsaturated, and heteroaromatic aldehydes
(3a–p) using trichlorosilane as the hydride source. The
reactions were performed in THF at 78 °C for 24 h using 10
mol% of (S)‐1c as the catalyst, and the representative results
were presented in Table 3. The β‐hydroxyketone products 4a–r
were obtained in 45%88% yields, generally good to excellent
Table 3
(S)‐1c catalyzed asymmetric reductive aldol reaction of enones (2a–b) with aldehydes (3a–o).
2a-c
Entry
1
2
3
4
Enone
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
R
Ph
Ph
Ph
Ph
Aldehyde
3a
R’
Ph
Product
(R,R)‐4a
()‐4b
()‐4c
()‐4d
(R,R)‐4e
(R,R)‐4f
(+)‐4g
()‐4h
()‐4i
()‐4j
()‐4k
(+)‐4l
(R,R)‐4m
()‐4n
(+)‐4o
()‐4p
(+)‐4q
(+)‐4r
Yielda (%)
86
drb,c
96:4
95:5
92:8
97:3
97:3
95:5
46:54
95:5
53:47
90:10
98:2
92:8
99:1
8:92
96:4
100:0
87:13
94:6
ee (syn)c (%) ee (anti)c (%)
94
92
94
94
86
78
15
94
44
93
88
93
84
1
13
1
7
0
4
3b
3c
3d
3e
2‐CH3C6H4
3‐CH3C6H4
4‐CH3C6H4
4‐MeOC6H4
4‐BrC6H4
4‐O2NC6H4
4‐FC6H4
4‐CF3C6H4
2‐MeOC6H4
2‐Thienyl
2‐Naphthyl
2‐Furyl
78
81
75
85
5
Ph
6
7
8
9
10
11
12
13
14
15
16
17
18
Ph
Ph
Ph
Ph
Ph
Ph
3f
3g
3h
3i
3j
78
83
86
87
75
86
3
0
0
0
6
18
5
1
54
0
3k
3l
Ph
Ph
Ph
Ph
Ph
Me
p‐tolyl
73
80
45
88
76
75
3m
3n
3o
3p
3a
(E)‐PhCH=CMe
(E)‐PhCH=CH
Cyclopropyl
Ph
94
23
95
88
—
5
3a
Ph
87
11
Reaction conditions: 2 (0.25 mmol), 3 (0.30 mmol), HSiCl3 (0.50 mmol), (S)‐1c (0.025 mmol), THF (1.0 mL), 78 °C, 24 h.
a Yield of the isolated products 4a–r. b dr = syn:anti. c Determined by chiral HPLC analyses. Where appropriate, the absolute configurations were as‐
signed by comparison of the specific rotations with those reported in Ref. [31].

104
Panke Zhang et al. / Chinese Journal of Catalysis 36 (2015) 100–105
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diastereomers (dr 92/8–99/1) and high enantioselectivities
(84%93% ee). High levels of diastereoselectivity were also
observed in the reactions involving α,β‐unsaturated aldehydes
3n and 3o (entries 14 and 15), but only the reaction of
cinnamaldehyde 3o gave the corresponding adduct syn‐4o with
excellent enantioselectivity as well (94% ee, entry 15). The
reaction of 2a with alkyl aldehyde was examined using 3p as a
substrate, to result in the exclusive formation of syn‐4o albeit
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standard conditions, affording the corresponding aldol product
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4. Conclusions
We have developed a highly diastereo‐ and enantioselective
synthesis of optically enriched β‐hydroxyketones. Using the
spiro bisphosphine oxides SpinPO as chiral Lewis base cata‐
lysts, the asymmetric reductive aldol reactions of enones and a
range of aldehydes proceeded smoothly with trichlorosilane
reductant, to afford the corresponding aldol adducts 4a–r in
45%88% yields, generally high syn‐diastereoselectivity, and
good to excellent enantioselectivity (up to 95% ee). Substrates
with diverse stereoelectronic natures were tolerated, generally
affording good yields and high stereoselectivities.
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Graphical Abstract
Chin. J. Catal., 2015, 36: 100–105 doi: 10.1016/S1872‐2067(14)60241‐2
Highly enantio‐ and diastereoselective reductive aldol reactions catalyzed by chiral spiro bisphosphine oxides
Panke Zhang, Jiawang Liu, Zheng Wang, Kuiling Ding*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
O
R
OH
R'
O
R
OH
R'
HSiCl3 (2 equiv)
THF, -78 oC, 24 h
O
R'CHO
Ph
Ph
Ph
R
O
P(p-tol)2
(10 mol%)
syn
anti
P(p-tol)2
O
18 examples, 45%-88% yields
syn/anti 8:92-100:0, up to 95% ee
A spiro bisphosphine oxide (SpinPO) was found to be a highly enantio‐ and diastereoselective Lewis base catalyst in reductive aldol reac‐
tions of enones and aldehydes in the presence of trichlorosilane as the stoichiometric reductant.

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