Practical, highly stereoselective allyl- and crotylsilylation of aldehydes catalyzed by readily available Cinchona alkaloid amide

Article abstract of DOI:10.1039/c3sc50973g

We have demonstrated that bidentate Lewis base catalysts can be constructed based on the Cinchona alkaloid structure that promote highly stereoselective reactions of allyl- and crotyltrichlorosilane with aromatic as well as aliphatic aldehydes (90-99% ee, >98% diastereoselectivity). The catalysts are available in a one-pot procedure in >70% yield from cheap starting materials and promote the allylation reactions at ambient temperature. Gram scale reactions with catalyst recovery and reuse showcased the practicality of the catalytic system.

Full text of DOI:10.1039/c3sc50973g

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Practical, highly stereoselective allyl- and crotylsilylation
of aldehydes catalyzed by readily available Cinchona
alkaloid amide†
Cite this: Chem. Sci., 2013, 4, 3275
*
Yuan Huang, Licheng Yang, Panlin Shao and Yu Zhao
We have demonstrated that bidentate Lewis base catalysts can be constructed based on the Cinchona
alkaloid structure that promote highly stereoselective reactions of allyl- and crotyltrichlorosilane with
aromatic as well as aliphatic aldehydes (90–99% ee, >98% diastereoselectivity). The catalysts are
available in a one-pot procedure in >70% yield from cheap starting materials and promote the allylation
reactions at ambient temperature. Gram scale reactions with catalyst recovery and reuse showcased the
practicality of the catalytic system.
Received 11th April 2013
Accepted 4th June 2013
DOI: 10.1039/c3sc50973g
www.rsc.org/chemicalscience
structures such as I, II and III (Scheme 1a) have proven powerful
bifunctional catalysts for various organic transformations.
Introduction
Cinchona alkaloids and their derivatives have played a signi-
cant role as a privileged scaffold in asymmetric catalysis.1 The
strongly basic quinuclidine nitrogen can effectively serve as a
ligand for metal catalysis2 or as a Brønsted/Lewis base in orga-
nocatalytic reactions.3 By incorporating into the catalyst struc-
ture another H-bond donor4 or a metal-based Lewis acid,5
Surprisingly, the construction of a simple bidentate ligand or
catalyst, employing the quinuclidine nitrogen and another
Lewis basic donor moiety (as shown in Scheme 1b), has
remained elusive in asymmetric catalysis.
Towards the development of such a catalyst scaffold that will
certainly benet from the readily available, inexpensive
Cinchona alkaloids, we chose the addition of allyl- and crotyl-
trichlorosilane to aldehydes as our model reaction, not only
because it is a mechanically well-established reaction that can
be catalyzed by a bidentate Lewis base,6 but more importantly, it
represented the rst catalytic approach to realize predictable,
diastereospecic crotylation (Type I allylation,6a where the use
of E- or Z-crotylsilane provides anti- or syn-products with >98%
delity through the closed chair transition state), which is a key
requirement in the formation of propionate units that are
ubiquitous in polyketide natural products.7 Many catalytic
systems have been developed for this reaction, which are
dominantly chiral phosphoramides and N-oxides reported from
the groups of Denmark and Fu,6d Nakajima et al.,6e,f Malkov and
Kocovsky et al.,6g,h Hayashi et al.,6i and Snapper and Hoveyda.6j
While the great potential of these methods in chemical
synthesis has been demonstrated,8 one common limitation is
the lack of reactivity for aliphatic aldehydes, with the only
exception being the highly stereoselective allyl- and crotylation
of aliphatic aldehydes from the Iseki group that required an
impractically long reaction time (2–4 weeks).6k In a related area
of research, recent work from the Krische group has revolu-
tionized the eld of aldehyde allylation that bypasses the use of
allylmetal reagents and can be conducted from either the
aldehyde or alcohol oxidation level for both aromatic and
aliphatic aldehydes;9 by the clever choice of substituted
allyl acetates or butadiene, crotylation products with high
ˇ
´
Scheme 1 Catalyst design and application. (a) Known catalyst design based on
Cinchona alkaloids. (b) Proposed new bidentate Lewis base catalyst.
Department of Chemistry, National University of Singapore, 3 Science Drive 3, 117543,
Republic of Singapore. E-mail: zhaoyu@nus.edu.sg
† Electronic supplementary information (ESI) available: Experimental details,
characterization data, and NMR spectral charts. See DOI: 10.1039/c3sc50973g
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diastereo- and enantioselectivities can also be accessed.10 synthetically useful but was not previously available using Lewis
However, considering the diastereospecic nature of Type I base catalysis (Table 1). Quinine 3 and quinine ester 4 that were
allylation, where pure anti- or syn-isomers can be accessed previously widely used as nucleophilic catalysts3 proved ineffi-
simply based on the choice of crotylating reagent, chiral Type I cient for our purpose, presumably due to limited Lewis base
reagents (mainly allylborations such as Brown allylation,11 activation from the monodentate quinuclidine nitrogen (entries
Roush allylation12 and the recent addition of allylsilylation from 1–2). The well-established bifunctional catalysts4 (Brønsted base
the Leighton group13) are still commonly used in asymmetric coupled with H-bond donor) urea 5 and thiourea 6 were also
synthesis; a catalytic Type I allylation that can address the poor catalysts (entries 3 and 4). Sulfonamide 7 (ref. 15) and
limitations of previous systems is therefore still desired.14 Here phosphoric amide 8 may serve as bidentate Lewis bases, and
we present a Cinchona alkaloid amide as a highly efficient and interestingly we did obtain product enriched in the opposite
stereoselective catalyst for the allylation and crotylation of a enantiomer (40% ee with 7 or 8 vs. À41% ee by using 5),
wide range of aldehydes, and in particular, aliphatic aldehydes however the level of efficiency and selectivity were far from
(95–99% ee). This system also provides signicant practical satisfactory (entries 5 and 6). To our delight, a simple quinine
advantages that enable large scale production: the catalyst can amide such as 9, that has rarely proved successful in asym-
be prepared in a one-pot procedure from inexpensive starting metric catalysis,16,17 provided the desired product with high
materials, can be easily recovered and reused, and promotes the efficiency and excellent enantioselectivity (entry 7). Evaluation
allylation reactions at ambient temperature (instead of low of the electronics of the aryl group (entries 7–9) clearly showed
ꢀ
temperatures of À40 to À78 C for most previous systems).
that the amide moiety serves as a Lewis base (instead of a
H-bond donor in which case the catalyst would be more effec-
tive with an electron-withdrawing substituent installed such as
10), with catalyst 11 possessing a strongly electron-donating
Results and discussion
We initiated our studies by examining the catalytic activity of a dimethylamino group being the optimal catalyst (88% conv.,
variety of quinine-derived compounds for the addition of allyl- 96% ee). Cinchonidine-derived 12 (only lacking the methoxy
trichlorosilane to 1a, the product of which is highly substituent on quinoline) provided essentially the same result
Table 1 Optimization of allylation of aliphatic aldehydesa
Entry
Catalyst
Conv.b (%)
eec (%)
Entry
Catalyst
Conv.b (%)
eec (%)
1d
2d
3
4
5
3
4
5
6
7
8
15
10
30
40
36
45
À8
À5
7
8
9
10
11
12
9
83
35
88
83
35
88
95
81
96
96
9
10
11
12
13
14
À41
À20
40
6
40
À96
a
b
c
Unless otherwise stated, reactions were run for 24 h. See ESI for details. Conv. determined by 1H NMR of the crude reaction mixture. ee
determined by HPLC analysis. d Reactions were run for 48 h.
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Table 2 Substrate scope for allylation of aldehydesa
as 11, suggesting that the quinoline moiety in the catalyst
structure is not directly involved in activation of the silylating
reagent (entry 10). Compound 13, possessing the analogous
chiral amide moiety but lacking quinuclidine, was much less
efficient and selective, which further supported our hypothesis
of bidentate Lewis base activation of allyltrichlorosilane (entry
11). Finally, as Cinchona alkaloids exist as pseudo-enantiomers,
quinidine-derived 14 was also tested, and provided the enan-
tiomeric product ent-2a with the same excellent enantiose-
lectivity (entry 12).
With 11
With 14
Entry Product 2
Yield (%); ee (%) Yield (%); ee (%)
1
2
83; 96
89; 99
86; À97
82; À98
The evaluation of reaction parameters showed that DIPEA
was necessary for the reaction to take place. THF was the
optimal solvent in terms of reactivity as well as enantiose-
lectivity. The optimal reaction conditions can be employed to
produce a wide range of homoallylic alcohols in excellent
enantioselectivity (Table 2). The reactions were carried out with
11 or 14 that yielded both antipodes of the products in
comparable excellent enantioselectivity. The enantioselectiv-
ities for allylations of aliphatic aldehydes are uniformly high
(95–99%). It is noteworthy that various functional groups such
as ethers and silyl ethers (entries 1–3), esters (entry 4) as well as
N-heterocycles (entry 5) are all well-tolerated, in addition to
simple alkyl and alkenyl aldehydes (entries 6–10). This
unprecedented scope bodes well for application in complex
natural product synthesis. The allylation of b-chiral aldehyde 1o
was also examined (Scheme 2). While allylation of 1o (96% ee)
catalyzed by 11 provided 2o with 98 : 2 diastereomeric ratio,
suggesting >98% selectivity for the installation of the new
stereogenic center, the other diastereomer epi-2o could be
obtained with a high diastereomeric ratio of 97.5 : 2.5 from the
reaction catalyzed by 14. Aromatic aldehydes also work under
the same conditions to yield products with enantioselectivities
ranging between 90 and 94% ee (entries 11–14, Table 2).
More importantly, we demonstrated that our catalytic system
can be applied to the crotylation of aliphatic aldehydes with
high enantioselectivity as well as reliable diastereospecicity,
characteristic of Type I allylation. As shown in Table 3, with the
use of either E- or Z-crotyltrichlorosilane 15 (each prepared in
one step from commercially available starting materials),18 the
alcohol products 16 of the two ether-containing substrates were
obtained with excellent ee as well as high dr (>99% transfer of
the geometry of crotylsilane to the product diastereomeric
ratio). In contrast, the classical chiral Lewis acid-catalyzed
addition of allylic organometallic reagents (Si, Sn, B) to alde-
hydes (Type II allylation; open transition state) provides a
mixture of diastereomers, predominantly syn-isomer, indepen-
dent of starting allylic geometry, while the addition of allylic
organometallic reagents (Cr, Zn, In) generated in situ from the
corresponding allylic halides catalyzed by chelating ligands
(Type III allylation) yields predominantly the anti-isomer
regardless of starting allylic geometry.6a
3
4
70; 95
90; 98
73; À96
88; À98
5
75; 95
80; À96
6
80; 96
76; 96
76; 97
78; 97
74; À96
71; À95
70; À98
85; À96
7
8b
9
10
83; 96
77; 90
80; À96
75; À91
11c
12c
13c
83; 92
77; 94
90; À92
80; À93
14c
86; 93
89; À92
a
All reactions were carried out at ambient temperature for 24 h. The
yields are isolated yields based on the average of two runs. See ESI for
b
c
details. 20 mol% catalyst was used. Toluene was used as the
solvent that provided higher conversion for aromatic aldehydes.
Practical, scalable allylation and crotylation
received from popular vendors without further purication. As
It is noteworthy that the current catalytic system is simple to stated earlier, the catalyst can be easily prepared from inex-
apply at ambient temperature using a readily available catalyst, pensive starting materials via a one-pot procedure that includes
and commercial reagents (allyltrichlorosilane, DIPEA, etc.) as the previously reported Mitsunobu reaction of quinine with
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Scheme 2 Allylation of chiral aldehyde.
diphenylphosphoryl azide followed by Staudinger reaction to
yield 9-amino-9-deoxy-quinine,19 and nally acylation using
commercially available 4-(dimethylamino)benzoyl chloride to
yield the amide catalyst (Scheme 3a). The yield for the one-pot
procedure, aer a single purication by silica gel chromatog-
raphy, was over 70%. To further showcase the utility of the
system, gram-scale allylation of 1a was carried out that yielded
2a with comparable chemical yield and enantioselectivity to the
small scale reactions (Scheme 3b vs. Table 2). The selectivity of
this system is not sensitive towards concentration or heat
transfer (as it is carried out at ambient temperature) so scaling
up was straightforward. Although a relatively high catalyst
loading of 10 mol% is required for the reaction, the catalyst
could be easily recovered nearly quantitatively. When the
recovered catalyst was used for another gram-scale crotylation
of 1a, alcohol 16b was obtained in high diastereo- and enan-
tioselectivity (Scheme 3c).
Scheme 3 One-pot catalyst synthesis and gram-scale reactions with catalyst
recovery and reuse.
aliphatic aldehydes, however, this chloride adds to the aldehyde
to form the corresponding a-chloro silyl ether 18 that is
presumably responsible for the lack of allylation reactivity for
such substrates. In our case, it was also observed that catalyst 11
binds to SiCl4 to liberate a chloride that quickly adds to
aliphatic aldehydes to generate the a-chloro silyl ethers (>60%
conv. in 10 min). On the other hand, the related product was not
clearly observed when we mixed 11 with allyltrichlorosilane and
aliphatic aldehyde (Scheme 4). This is in large contrast to the
control experiment using HMPA, which promotes this unde-
sired reaction with both SiCl4 and allyltrichlorosilane. This may
be due to the relatively lower Lewis basicity of our catalyst
compared to HMPA, which is a fortunate character for the
success of aliphatic aldehyde allylation.
Mechanistic considerations
It has been showcased by the Denmark group that a Lewis base
can liberate a chloride ion from SiCl4 or allyltrichlorosilane to
form a silicate intermediate (17 in Scheme 4a).20 In the case of
Table 3 Diastereospecific crotylation of aliphatic aldehydesa
With 11
With 14
Entry
1
15 E : Z
Product 16
Yield (%); ee (%)
Yield (%); ee (%)
78; 97;
94 : 6 dr
75; À98;
(E)-15; 94 : 6
94 : 6 dr
78; 96;
98 : 2 dr
75; À95;
2
3
(Z)-15; 2 : 98
(E)-15; 94 : 6
98 : 2 dr
74; 96;
94 : 6 dr
70; À98;
94 : 6 dr
72; 96;
98 : 2 dr
73; À97;
4
(Z)-15; 2 : 98
98 : 2 dr
a
See Table 2 and ESI.
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Scheme 5 Proposed reaction transition state model.
On the basis of the principles and mechanistic studies pre-
sented by the Denmark group22a and others,22b,c the
aldehyde was placed trans to chloride to increase its electro-
philicity; the allyl group, on the other hand, would coordinate
trans to the strongly Lewis basic quinuclidine nitrogen,
rendering it more nucleophilic. While the quinoline moiety
points away to the back, the quinuclidine moiety effectively
blocks the top of the complex so that the aldehyde is placed
underneath. Allylation/crotylation through the chair like Zim-
merman–Traxler transition state23 then provides the desired
product in excellent enantioselectivity and predictable, perfect
diastereoselectivity.
Scheme 4 Exploration of chloride ion liberation and catalyst modification.
It is noteworthy that the secondary amide moiety in our
catalyst may react with allyltrichlorosilane in the presence of
DIPEA to generate the corresponding O-silyl imidate, in which
process the chloride ion that is liberated from the silane will be
sequestered as part of the DIPEA$HCl salt (and thus avoid the
undesired a-chloro silyl ether formation). As stated earlier,
DIPEA was found to be essential for the allylation reaction to
proceed to high conversion. Preliminary NMR studies by mixing
the catalyst, silane, and DIPEA in a 1 : 1 : 1 ratio were incon-
clusive as a complex mixture was formed; however, the resulting
mixture was shown to be catalytically active. We have further
tested the activity of catalyst 19 with a methylated amide moiety,
which, under otherwise identical conditions, led to only <10%
conv. to the allylation product with <5% ee (Scheme 4b). While
the steric hindrance of this catalyst may certainly contribute to
this low activity and selectivity, it provides support for the O-silyl
imidate formation from catalyst 11 and 14. More extensive
mechanistic studies as well as calculations will be carried out to
further elucidate the nature of the active catalytic species as well
as the turnover of the “anionic” catalyst.
Conclusions
In conclusion, we have demonstrated, for the rst time, the
utility of bidentate Lewis base catalysts constructed from
Cinchona alkaloids in the highly stereoselective allyl- and cro-
tylsilylation of aldehydes. The catalytic procedure provides a
practical, scalable preparation of various homoallylic alcohols
that are useful building blocks in organic synthesis. Current
efforts in these laboratories are focused on detailed mechanistic
studies to further elucidate the origin of the asymmetric
induction, further extending the synthetic utility of the
system to allyl/crotylation of chiral aldehydes and application of
this family of catalysts to other important organic
transformations.
The conformational analysis of related Cinchona alkaloid
amides both in solution and in the solid state has been per-
formed by the Brunner group using NMR, X-ray as well as
molecular orbital calculations during their studies of enantio-
selective decarboxylation reactions using these catalysts as
chiral Brønsted bases.16 These studies showed that these
molecules prefer the open conformation,21 where the quinucli-
dine nitrogen points away from the quinoline unit, and in turn,
towards the 9-amide moiety. In particular, the calculated
minimum energy conformation of the protonated cinchonine
amide 20 (Scheme 5a) possesses a H-bond interaction between
the amide oxygen and the ammonium hydrogen.16b These data
pointed to the possibility of 9-amide and quinuclidine serving
as a bidentate catalyst. We have also carried out kinetic studies
of our catalytic system, which suggested that the allylation
reaction is rst-order dependent on the catalyst (see ESI† for
details), lending further evidence for the bidentate nature of our
catalyst. Based on the above rationale, we propose the transition
state model (with catalyst 11) in Scheme 5b.
Acknowledgements
We are grateful for the generous nancial support from the
Singapore National Research Foundation (NRF Fellowship) and
the National University of Singapore.
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