Spiro[4,4]-1,6-Nonadiene-based diphosphine oxides in lewis base catalyzed asymmetric double-aldol reactions

Article abstract of DOI:10.1002/anie.201305846

Symmetry swap: A C₂-chiral spiro diphosphine oxide (SpinPO) has been found to be highly efficient and enantioselective in the catalysis of double-aldol reactions of ketones and aldehydes to give the corresponding optically active double-aldol products, which can be readily transformed into optically active C₃- and pseudo-C₃-symmetric molecules. Copyright

Full text of DOI:10.1002/anie.201305846

Angewandte
Chemie
DOI: 10.1002/anie.201305846
Organocatalysis
Spiro[4,4]-1,6-Nonadiene-Based Diphosphine Oxides in Lewis Base
Catalyzed Asymmetric Double-Aldol Reactions**
Panke Zhang, Zhaobin Han, Zheng Wang, and Kuiling Ding*
Dedicated to Professor Teruaki Mukaiyama
The aldol reaction is one of the most fundamental processes in
chemical and biological transformations, and plays an essen-
tial role for carbon–carbon bond formation in synthetic
organic chemistry.[1] Although the direct asymmetric aldol
reaction has been well developed using various chiral
organometallic catalysts[2–4] or organocatalysts,[5–11] very few
examples are known for the synthesis of double-aldol
products to date.[12] In fact, the realization of the first
asymmetric double-aldol reaction of an acyclic ketone with
two aldehyde molecules to afford the corresponding optically
active 1,3-diol derivatives was only recently reported by
Nakajima et al.[13a], in which a chiral diphosphine oxide
be highly efficient for the catalytic hydrogenation of a variety
of imines and a,b-unsaturated carbonyl substrates.[16a–e] As
part of our ongoing efforts to explore new catalyst systems
based on the spiro[4,4]-1,6-nonadiene skeleton, we herein
report the development of a new type of Lewis base catalysts,
SpinPO 1, and their excellent performance in the catalysis of
the direct asymmetric double-aldol reaction of ketones with
aldehydes, as well as the potential applications of the resultant
optically active double-aldol products.
The synthesis of the enantiopure SpinPO diphosphine
oxides 1a–e is shown in Scheme 2 (for detailed procedures
catalyst,
2,2’-bis(diphenylphosphinoxy)-1,10-binaphthyl
(BINAPO), turned out to be the catalyst of choice among
various commonly used Lewis bases, and catalyzed the
reaction with moderate to good activity and stereoselectivity,
albeit with a limited substrate scope.[13a] A spiro backbone has
been recognized as one of the privileged scaffolds for the
construction of chiral ligands and catalysts for various
asymmetric transformations,[14] since it was introduced by
the pioneering work of Chan and co-workers on the develop-
ment of SpirOP (Scheme 1),[15] a diphosphine ligand with
a spiro[4,4]nonane backbone. We have reported the develop-
ment of spiro[4,4]-1,6-nonadiene-based chiral phosphine-
oxazoline ligands (SpinPHOX),[16a–e] for which the complexity
associated with the stereochemistry and the separation of
diastereomers in spiro[4,4]nonane-based scaffolds, can be
avoided.[16a] The IrI complexes of these species were found to
Scheme 2. Preparation of enantiopure phosphine oxides 1a–1e, and
the structures of 1 f–g.
and for the preparation of enantiopure diol (R)-2, starting
from either racemic[16a,g–h] or enantiopure spiro[4,4]nonane-
1,6-dione,[16f] see the Supporting Information). The reaction
of enantiopure diol (R)- or (S)-2 with carbon tetrachloride
and triphenylphosphine afforded the corresponding dichlor-
ide 3 in 89% yield.[17] Treatment of the enantiopure dichloride
3 with Ar2PLi[18] furnished the corresponding bisphosphines,
which were oxidized in situ with hydrogen peroxide to give
the (R)- or (S)-diphosphine oxides 1a–e in high yields (77–
97%). The absolute configuration of (+)-1a was determined
to be S by single-crystal X-ray diffraction analysis (Supporting
Information, Figure S1),[19] whereas those of the remaining
phosphine oxides 1b–e were deduced by comparison of their
CD spectra with that of (S)-(+)-1a (Figure S2). To investigate
the impact of structural rigidity of the backbone on the
catalytic performance, diphosphine oxides 1 f and 1g, which
are close structural analogues of 1a, but which contain only
one or no flexible methylene linker between the spiro[4,4]-
1,6-nonadiene scaffold and the diphenylphosphine oxide unit,
were also synthesized (for details, see the Supporting
Information).
Scheme 1. Structures of SpirOP, SpinPHOX, and SpinPO (1).
[*] P. Zhang, Dr. Z. Han, Dr. Z. Wang, Prof. Dr. K. Ding
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry
345 Lingling Road, Shanghai 200032 (P. R. China)
E-mail: kding@mail.sioc.ac.cn
[**] We thank the NSFC (21172237, 21032007, and 21121062), the
Major Basic Research Development Program of China
(2010CB833300), and the Chinese Academy of Sciences for their
support of this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201305846.
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With catalysts SpinPO 1a–g in hand, we then investigated
their catalytic performance in the direct double-aldol reac-
tion, choosing acetophenone (4a) and benzaldehyde (5a) as
the standard substrates. After screening a variety of reaction
parameters, including base, solvent, temperature, catalyst
loading, and substrate concentration (Tables S1–S5), it was
found that the reaction proceeded smoothly in CH2Cl2 (0.1m)
at À308C in the presence of catalyst (R)-1a (10 mol%) and
dicyclohexylmethylamine (cHex2NMe; 5 equiv) as the base,
to give the corresponding 1,3-diol (À)-6aa in 84% yield with
a diastereomeric ratio (d.r.) of 91:9 (chiro/meso) and 94% ee
for chiro-6aa (Table 1, entry 1). Under the optimized reaction
(entries 2 and 3 vs. 1). The introduction of electron-donating
MeO groups on the aryl rings attached to the P atoms led to
a slight decrease in the enantioselectivity of the reaction
(88% ee ; entry 4). Catalyst (S)-1e with 4-tolyl groups on the
P atoms performed comparably to the prototypical catalyst
(R)-1a in terms of reactivity, diastereoselectivity, and enan-
tioselectivity, affording the corresponding 1,3-diol product
(+)-6aa in 84% yield with a diastereoselectivity of 91:9 and
94% ee (entry 5). The examination of diphosphine oxides 1 f
and 1g indicated that the presence of the methylene bridges
between the spiro[4,4]-1,6-nonadiene skeleton and the diphe-
nylphosphine oxide units of the catalyst is critically important
for the stereoselectivity of the reaction (entries 6 and 7 vs.
entry 1). The use of diphosphine oxides with privileged
skeletons, such as (R)-BINAPO[13] (entries 8 and 9) or (R)-
SDPO[14d] (entry 10), as well as our aromatic spiroketal-based
diphosphine oxide (S,S,S)-SKPO[16b] (entry 11), gave only
inferior results (< 78:22 d.r. and < 70% ee) to those obtained
with SpinPO (entry 1). These results emphasize the advanta-
geous features of the spiro[4,4]-1,6-nonadiene-1,6-bis-
(methyl) skeleton of the bisphosphine oxides for this catalytic
system. The reaction in the presence of a monoxide catalyst
(SKPOꢀ; entry 12), did give the expected product, but only in
low yield (12%), poor d.r. (38:62) and modest ee (46%), in
comparison with the results obtained with SKPO (entry 11).
Although we are unable to clarify the underlying reason for
the outstanding catalytic performance of (R)-1a, it is clear
that fine-tuning of the steric and electronic environment of
the phosphine oxide catalyst is critically important in achiev-
ing maximum asymmetric induction.
Having established (R)-1a as the most effective catalyst,
we subsequently investigated the double-aldol reaction of
various ketones with benzaldehyde (5a) under the optimized
conditions. As shown in Table 2, the reaction of 5a with
aromatic (4b–k), heteroaromatic (4l and 4m), olefinic (4n) or
aliphatic (4o and 4p) ketones proceeded smoothly, giving the
corresponding double-aldol adducts in high yields with good
to excellent diastero- and enantioselectivities. The reaction
tolerates both electron-withdrawing and electron-donating
substituents on the aromatic ring of the ketones; however,
a slightly negative effect was observed in the case of
a sterically demanding 2-methyl (entry 3) or a strongly
electron-withdrawing 4-NO2 group (entry 7). In the reaction
of 4-bromoacetophenone with benzaldehyde, the chiro prod-
uct (À)-6ga was obtained with an ee value of > 99%. With
ketones 4l and 4m, which contain heteroaromatic rings,
remarkable reactivities (87% and 91% yield, respectively)
and enantioselectivities (96% ee) were observed for the
reaction with 5a (entries 11 and 12). Similarly, the reactions of
olefinic and aliphatic ketones afforded the corresponding
adducts in high yields and stereoselectivities (entries 13 and
14). In the double-aldol reaction of butanone 4p, a sterically
less-hindered ketone with two enolizable a-carbon positions,
the two aldol reactions occurred at the two different
a-carbons of the carbonyl group. Thus adduct 6pa was
obtained in good yield with excellent diastereo- and enantio-
selectivity (Scheme 3a), results comparable to those achieved
by Nakajima and co-workers using BINAPO as the cata-
lyst.[13b]
Table 1: Catalyst optimization for the asymmetric double-aldol reaction
of acetophenone (4a) with benzaldehyde (5a).[a]
Entry
Catalyst
Yield[b] [%]
d.r.[c]
ee[d] [%]
1
2
3
4
5
6
7
8
(R)-1a
(R)-1b
(R)-1c
(S)-1d
84
76
60
82
84
45
83
62
86
50
38
12
91:9
94 (S,S)
84 (S,S)
74 (S,S)
88 (R,R)
94 (R,R)
66 (R,R)
57 (R,R)
54 (R,R)
70 (R,R)
34 (R,R)
58 (S,S)
46 (S,S)
86:14
72:28
92:8
91:9
50:50
92:8
75:25
78:22
58:42
52:48
38:62
(S)-1e
(À)-1 f
(S)-1g
(S)-BINAPO
(S)-BINAPO
(R)-SDPO
(S,S,S)-SKPO
(S,S,S)-SKPO’[f]
9[e]
10
11
12
[a] Unless otherwise noted, the reactions were carried out by addition of
silicon tetrachloride (0.8 mmol) to a solution of 4a (0.2 mmol), 5a
(0.44 mmol), cHex2NMe (1.0 mmol), and the catalyst (10 mmol%) in
CH2Cl2 (2 mL) at À308C. [b] Yields of the isolated chiro-diastereomers.
[c] Determined by 1H NMR analysis of the crude reaction mixtures (chiro/
meso). [d] Determined by HPLC analysis on a chiral stationary phase
(AD-H column). The absolute configurations were assigned by com-
paring the optical rotation obtained with values reported in the
literature.[13a] [e] The data is cited from Ref. [13a]. [f] (S,S,S)-SKPO’ is the
monooxide counterpart of (S,S,S)-SKPO.
conditions, a variety of spiro[4,4]-1,6-nonadiene-based chiral
phosphine oxides, including (R)- or (S)-1b–e with different
aryl substituents at the P atoms, were then tested as catalysts
for the double-aldol reaction between 4a and 5a. As shown in
Table 1, the steric hindrance of the aryl groups on the P atoms
has
a significant impact on the asymmetric induction
(entries 1 and 2). With catalysts (R)-1b and (R)-1c bearing
3,5-xylyl and 2-tolyl moieties, respectively, on the P atoms, the
diastereo- and enantioselectivities decreased in comparison
with the results obtained with their structural analogue 1a
2
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Table 2: Asymmetric double-aldol reaction of various ketones (4b–4o)
with benzaldehyde (5a).[a]
Table 3: SpinPO-catalyzed asymmetric double-aldol reaction of aceto-
phenone (4a) with various aldehydes (5b–n).[a]
Entry
Ketone
R
Yield[b] [%]
d.r.[c]
ee[d] [%]
Entry
Aldehyde
R
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4b
4c
4d
4e
4 f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-MeOC6H4
2-MeOC6H4
4-BrC6H4
4-NO2C6H4
4-FC6H4
82
83
80
76
93
78
86
79
76
81
87
91
76
87
90:10
88:12
86:14
93:7
85:15
84:16
74:26
88:12
78:22
87:13
91:9
94 (À)
94 (À)
81 (À)
91 (À)
92 (+)
>99 (À)
90 (À)
95 (À)
90 (À)
94 (À)
96 (À)
96 (+)
95 (À)
90 (À)
1
2
3
4
5b
5c
5d
5e
5 f
5g
5h
5i
5j
5k
5l
5m
5n
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-MeOC6H4
2-MeOC6H4
4-BrC6H4
4-FC6H4
4-CF3C6H4
2-naphthyl
2-thienyl
81
82
92
71
90
80
80
82
78
88
87
91
90
83:17
91:9
97:3
77:23
91:9
83:17
83:17
85:15
86:14
87:13
94:6
95 (À)
97 (À)
91 (À)
94 (À)
93 (À)
94 (À)
93 (À)
95 (À)
95 (+)
96 (+)
96 (+)
88 (+)
90 (+)
4[e]
5[f]
6
5[e]
6
7[f]
8
7
8
9
9
4-CF3C6H4
2-naphthyl
2-thienyl
10
11
12[f]
13
14
10[e]
11[e]
12[e]
13[e]
2-furyl
2-furyl
88:12
80:20
93:7
=
C6H5CH CH
55:45
74:26
=
C6H5CH CH
cyclopropyl
cyclopropyl
[a] Unless otherwise noted, the reactions were carried out by addition of
silicon tetrachloride (0.8 mmol) to a solution of 4a (0.2 mmol), 5
(0.44 mmol), cHex2NMe (1.0 mmol), and the catalyst (10 mmol%) in
CH2Cl2 (2 mL) at À308C. [b] The yield of isolated chiro-diastereomer.
[a] Unless otherwise noted, the reactions were carried out by addition of
silicon tetrachloride (0.8 mmol) to a solution of 4 (0.2 mmol), 5a
(0.44 mmol), cHex2NMe (1.0 mmol), and the catalyst (10 mmol%) in
CH2Cl2 (2 mL) at À308C. [b] The yield of the isolated chiro-diastereomer.
[c] Determined by 1H NMR analysis of the crude reaction mixtures (chiro/
meso). [d] Determined by HPLC analysis on a chiral stationary phase
(AD-H or AS-H column). [e] Reaction temperature: À608C. [f] The yield
of chiro- and meso- diastereomers.
1
[c] Determined by H NMR analysis of crude reaction mixtures (chiro/
meso). [d] Determined by HPLC analysis on a chiral stationary phase
(AD-H or AS-H column). [e] The yield of chiro- and meso-diastereomers.
the double-aldol reaction was observed, to give (À)-6on in
79% yield with 83:17 d.r. and 95% ee (Scheme 3b).
To demonstrate potential applications of this method, the
optically active double-aldol adduct (S,S)-(À)-6aa (94% ee)
was then reduced with NaBH4 in methanol, to afford the
corresponding optically active triols, (S,S,S)-(+)-8aa and
(S,S,R)-(À)-8aa, in 1:2 d.r. with excellent ee values (94%)
for both diastereomers (Scheme 4). Both (S,S,S)-(+)-8aa and
(S,S,R)-(+)-8aa can be readily isolated by flash column
chromatography, thus providing a facile approach to C3- and
pseudo-C3-symmetric triols.[20] As shown in Figure 1, the
molecular structure of (S,S,S)-(+)-8aa is C3 symmetric, with
a suprafacial orientation for all three hydroxy groups in the
molecule. The reaction of (S,S,S)-(+)-8aa with P(NMe2)3
(HMPT) afforded an optically pure cage-like phosphite
Scheme 3. Aldol reactions of aliphatic ketones 4p and 4o with the
aromatic aldehyde 5a and the aliphatic aldehyde 5n, respectively,
catalyzed by (R)-1a.
The substrate scope of aldehydes was also found to be
quite general. As shown in Table 3, the reaction of acetophe-
none (4a) proceeded well with a number of aldehydes. Those
with aromatic (5b–j), heteroaromatic (5k and 5l), olefinic
(5m) or aliphatic (5n) substituents afforded the correspond-
ing products in 71–92% yield with 88–97% ee. Neither the
electronic properties nor the steric hindrance of the aromatic
aldehydes had a major influence on the enantioselectivity
(entries 1–11), but some drops in diastereoselectivity were
observed in the reactions of olefinic and aliphatic aldehydes
(entries 12 and 13). For the reaction of two aliphatic
substrates, sterically hindered 1-cyclopropylethanone (4o)
and cyclopropanecarbaldehyde (5n), the general pattern of
Scheme 4. Synthetic application of double-aldol adduct (S,S)-(À)-6aa
for the preparation of optically active triol compounds and phosphite
derivative (S,S,S)-(+)-9aa.
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Figure 1. X-ray crystal structures of (S,S,S)-(+)-8aa (a) and its phos-
phite derivative (S,S,S)-(+)-9aa (b). Thermal ellipsoids set at 30%
probability.[22]
[4] For leading examples using Zn catalysts, see: a) B. M. Trost, H.
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Fried, J. Am. Chem. Soc. 2009, 131, 1674.
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ligand (S,S,S)-(+)-9aa with perfect C3 symmetry (Figure 1b)
in 79% yield. Its application in the Rh-catalyzed asymmetric
hydrogenation of N-(1-phenylvinyl)acetamide led to excel-
lent enantiocontrol (92% ee; for details, see the Supporting
Information). These results clearly indicate that this method
can provide ready access to molecules that might be of
interest for asymmetric catalysis or chiral recognition.[21]
In summary, a new class of chiral spiro phosphine oxides
based on the spiro[4,4]-1,6-nonadiene backbone (SpinPO)
has been developed and successfully applied as Lewis base
catalysts in the direct double-aldol reactions of a ketone with
two molecules of an aldehyde, affording the corresponding
double-aldol adducts in high yields (71–93%) and excellent
stereoselectivities (up to 97:3 d.r. and 99% ee). The resulting
optically active aldol adduct can be readily reduced by NaBH4
to provide optically active C3-chiral and pseudo-C3-chiral triol
molecules. These results might stimulate future work on the
use of SpinPO catalysts and C3-chiral triols in the areas of
asymmetric catalysis or molecular recognition.
Received: July 5, 2013
Published online: && &&, &&&&
Keywords: aldol reactions · asymmetric catalysis ·
.
organocatalysis · phosphine oxide · spiro compounds
[1] For the discovery of the Mukaiyama reaction, see: a) T.
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These are not the final page numbers!

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[22] CCDC 929111 [(S,S,S)-(+)-8aa] and 940390 [(S,S,S)-(+)-9aa]
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Organocatalysis
P. Zhang, Z. Han, Z. Wang,
K. Ding*
&&&& — &&&&
Spiro[4,4]-1,6-Nonadiene-Based
Diphosphine Oxides in Lewis Base
Catalyzed Asymmetric Double-Aldol
Reactions
Symmetry swap: A C2-chiral spiro
give the corresponding optically active
double-aldol products, which can be
readily transformed into optically active
C3- and pseudo-C3-symmetric molecules.
diphosphine oxide (SpinPO) has been
found to be highly efficient and enantio-
selective in the catalysis of double-aldol
reactions of ketones and aldehydes to
6
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!