Copper-catalysed domino silylative aldol reaction leading to stereocontrolled chiral quaternary carbons

Article abstract of DOI:10.1002/chem.201000907

(Chemical Equation Presented) Asymmetric aldol reaction: A domino silylation-aldol reaction between enoyloxazolidinones and various aldehydes has been developed (see scheme). The process catalysed by a copper complex in the presence of a borosilane led to high diastereoselectivities. Yields between 59 and 90 % and d.r. values between 78:22 to 95:5 were obtained. When methacryloyloxazolidinones were used, a controlled chiral quaternary carbon was generated. BPin=4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl.

Full text of DOI:10.1002/chem.201000907

DOI: 10.1002/chem.201000907
Copper-Catalysed Domino Silylative Aldol Reaction Leading to
Stereocontrolled Chiral Quaternary Carbons
Alexandre Welle,[a] Julien Petrignet,[a] Bernard Tinant,[b] Johan Wouters,[c] and
Olivier Riant*[a]
Domino reactions are processes in which several bonds
are formed in one step without isolating intermediates,
changing the conditions of the reaction or adding reagents.[1]
These reactions are ecologically and economically favour-
ACHTUNGTRENNUNGable because work, time and materials are spared. Amongst
domino reactions, the reductive aldol reaction has been de-
veloped as an efficient alternative one-pot procedures for
the production of aldol derivatives without the need to gen-
erate a metal enolate prior to the condensation with an al-
dehyde or a ketone. Versions based on various transition-
metal catalysts[2] have been reported, in particular with
copper.[3] Since the pioneering work of Maruoka[4] and
Chiu,[5] intramolecular racemic[6] and enantioselective,[7] as
well as intermolecular racemic[8] and enantioselective[9]
methods, have been developed based on this metal. These
reactions are proposed to proceed by the in situ formation
of a metal enolate through the conjugated reduction of a
metal hydride species onto the Michael acceptor as de-
scribed in [Eq. (1)]. Then, the generated nucleophile is
trapped by the electrophile to form the aldol-type adduct
after final reaction with the hydride source.
Copper(I) catalysts have been show to catalyse the conjugat-
ed addition of disilane[11] and silylmetal nucleophiles[12] on
electrophilic double bonds. Although the use of disilanes re-
quires harsh conditions to proceed, the use of silyl–metal
species is not suitable for silylative aldol because of poten-
tial direct addition of the silyl group to the aldehyde. This
problem of chemoselectivity is well known in copper hy-
dride chemistry.[7d,9e] Recently, an asymmetric conjugated
addition of borosilanes on electrophilic double bonds with
high enantioselectivities was reported by Hoveyda by using
chiral copper–diaminocarbene complexes with an example
of a tandem aldol reaction.[13]
In our initial experiments (Scheme 1) we tested the three-
component domino reaction between benzaldehyde 1,
methyl acrylate 2 and a stoichiometric quantity of borosi-
lane[15] 5 in toluene at room temperature in the presence of
We were interested in applying this methodology with
borosilanes as pronucleophiles. The addition of this family
of reagents catalysed by Pd, Rh or Pt is well documented.[10]
(PPh3)3]·2MeOH[14] 3, and (rac)-
a catalytic amount ofACTHNGUTERNNU[G CuFACTHUNGTRENNUNG
[a] A. Welle, Dr. J. Petrignet, Prof. O. Riant
Unitꢀ de chimie organique et mꢀdicinale
Universitꢀ Catholique de Louvain, Place Louis Pasteur 1
1348 Louvain-la-Neuve (Belgium)
Fax : (+)1047-4168
E-mail: Olivier.riant@uclouvain.be
[b] Prof. B. Tinant
Unitꢀ de chimie structurale et des mꢀcanismes rꢀactionnels
Universitꢀ Catholique de Louvain, Place Louis Pasteur 1
1348 Louvain-la-Neuve (Belgium)
[c] Prof. J. Wouters
Unitꢀ de Chimie Physique Thꢀorique et Structurale
Facultꢀs Universitaires Notre-Dame de la Paix
Rue de Bruxelles 61, 5000 Namur (Belgium)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000907.
Scheme 1. Initial experiments for copper-catalysed silylative aldol reac-
tions.
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Chem. Eur. J. 2010, 16, 10980 – 10983

COMMUNICATION
Table 1. Copper-catalysed silylative–aldol reaction between enoylox
AHCTUNGTRENNUNG
idinones and various aldehydes[a]
ACHTUNGTRENNUNGazol-
BINAP ((rac)-BINAP: racemic 2,2’-bis(diphenylphosphino)-
1,1’-binaphthyl) (Scheme 1). The corresponding aldol
4
adduct 6 was isolated in 87% yield, albeit without any dia-
stereoselectivity. Replacing benzaldehyde 1 by acetophe-
none 7 led to the tertiary chiral alcohol 8 in 78% yield.
Switching methyl acrylate 2 to methyl methacrylate 9 gave
compound 10, which has a chiral quaternary carbon in 81%
yield. Although no diastereoselectivities were observed with
these substrates, we observed an excellent reactivity of our
catalytic system because excellent yields of the three compo-
nent adducts were obtained in each case with low catalyst
loading and short reaction time.
Entry
R1
R2
Yield (%)[b]
d.r.[c]
Product
The use of methyl methacrylate 9 as an enolate precursor
and acetophenone 7 as the aldol partner are particularly
striking. It indeed allows the formation of either tertiary al-
cohols (such as in 8) or quaternary chiral centres (such as in
10) in a single catalytic reaction and starting from simple
substrates. The control of the stereochemistry of chiral qua-
ternary centres is one of the major challenge of organic
methodology and there are still few reported examples of
efficient methodologies that use the aldol condensation.[16,17]
Our hypothesis was that the stereochemistry could be
controlled by using chiral auxiliaries such as oxazolidinones
on the Michael acceptors. After optimisation of the catalytic
system and a survey of various achiral diphosphine ligands,
we found that better reproducibility was achieved by replac-
ing (rac)-BINAP 4 by DPPF (DPPF : 1,1’-bis(diphenylphos-
phino)ferrocene) 11 when the reaction was carried out in
THF instead of toluene (Table 1). Moreover, aqueous work-
up may be avoided by adding silica to the reaction medium
followed by a simple filtration on silica gel. Prior to investi-
gating the formation of quaternary carbon centres, we evalu-
ated simple chiral acryloyl-based Michael acceptors and ob-
tained very promising results with acceptor 12. We were
indeed pleased to find that under the optimised catalytic
conditions, the reaction between benzaldehyde 1 and acryl-
oyloxazolidinone 12 (Table 1, entry 1) gave the correspond-
1
2
3
4
5
6
7
8
C6H5
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
80
79
70
59
90
77
69
64
61
59
75
74
>95:5
83:17
86:14
>95:5
>95:5
81:19
88:12
92:8
90:10
87:13
86:14
78:22
13
16
17
18
19
20
21
22
23
24
25
26
3,5-(tBu)2-C6H3
4-MeO-C6H4
4-F-C6H4
C6H5
3,5ACHTGUNETRNNU(G tBu)2-C6H3
4-MeO-C6H4
4-F-C6H4
9
3,5
N
10
11
12
4-CN-C6H4
2-Furyl
2-Thienyl
[a] The reactions were carried out on a 0.5 mmol scale in a 0.2m solution
in THF at room temperature under an oxygen-free argon atmosphere in
the presence of [CuFACHTNUTRGNE(UNG PPh3)3]·2MeOH (2 mol%), DPPF (2 mol%), boro-
silane (1.2 equiv), aldehyde (1 equiv) and enoyloxazolydinone (1 equiv)
for 1 h. [b] Yield of isolated product. [c] Determined by 1H NMR analy-
sis.
1
ing syn-aldol adduct (syn/anti>95:5 by H NMR analysis on
the crude reaction mixture) 13 in 80% yield and with a
complete control of the stereochemistry (d.r.>95:5). We
next investigated the substrate generality with other aromat-
ic aldehydes (Table 1, entries 2–4). Electron-rich aromatic
aldehydes (Table 1, entries 2 and 3) led to good yields but
reduced diastereoselectivities. With a more electron-poor al-
dehyde (Table 1, entry 4) the yield was slightly lower and
the diastereoselectivity was excellent. The absolute configu-
ration of compound 16 was determined by X-ray diffraction
(Figure 1). We have assumed that the absolute configura-
tions are the same through the examples considered.
We next investigated the use of methacryloyloxazolidi-
none 14 (Table 1, entries 5–12). This Michael acceptor react-
ed with the silylboronate and benzaldehyde under the opti-
mised catalytic conditions (Table 1, entry 5) to afford the
corresponding adduct 19 in excellent yield and only one dia-
stereoisomers was detected in the NMR spectrum of the
crude reaction mixture. The structure of the aldol adduct
was first attributed to a simple open structure such as 25
Figure 1. 50% Thermal ellipsoids structure of 16.
(Figure 2, X=H) but a rearranged structure was later attrib-
uted when an X-xay crystal-structure analysis of the 2-furyl
carboxaldehyde adduct was carried out to analyse the abso-
lute configuration of the newly formed asymmetric carbon
centres. The rearranged adduct 28 (X=H) is assumed to
arise from an intramolecular ring opening of the oxazoli-
done moiety by the hydroxyl group of the aldol adduct. Al-
though we can assume that a strong Thorpe–Ingold effect
brought by the newly formed quaternary carbon centre
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O. Riant et al.
The true mechanism of this effective and selective
domino process is still unclear and should be carefully inves-
tigated because the true nature of the reactive intermediates
has not yet been identified. The conjugated addition of a
copper-bound silyl nucleophile on the chiral Michael accept-
or such as 12 is expected to yield an intermediate copper
enolate, which should in turn be expected to react with an
aldehyde. The stererochemistry obtained with the acryloy-
loxazolidinone derivative 12 suggests the formation of a Z-
copper enolate and a classical cyclic Evans transition
state.[18] However, care should be taken with such a model
because copper(I) is known to be a weak Lewis acid and a
chelation model might be rendered unlikely by this property.
Furthermore, we cannot exclude the intervention of a boron
enolate, which could arise from a fast reaction of the copper
enolate with the silylboron reagent 5. However, we have not
yet been able to isolate a boron enolate to check its reactivi-
ty and test this hypothesis. In summary, we have developed
a domino silylation–aldol reaction between enoyloxazolidi-
nones and various aldehydes. The process catalysed by a
copper–phosphane complex in the presence of a borosilane
led to high diastereoselectivities. Yields between 59 and
90% and d.r. between 78:22 to 95:5 were obtained. When
methacryloyloxazolidinones were used, a controlled chiral
quaternary carbon was generated. Absolute configurations
were confirmed unambiguously by X-ray diffraction. The
diastereoselectivity was improved by replacing the phenyl
by a tert-butyl group on the chiral auxiliary. Work is now in
progress to study the replacement of the silyl group on the
enantiopure adducts to broaden the scope of application of
those aldol adducts that have quaternary centres.[19] Efforts
will be also be carried out to investigate the true mechanism
of this reaction and the nature of the enolate intermediate
that is responsible for the high stereoselectivity of the aldol
condensation.
Figure 2. 50% Thermal ellipsoids structure of 25 (X=H).
strongly favoured this ring-opening–cyclisation rearrange-
ment process, it is not clear whether this rearrangement
occurs immediately after the aldol condensation (Figure 2,
X=[CuL]) or during the work-up of the reaction (Figure 2,
X=H). The influence of electronic parameters was then
checked with various aromatic and heteroaromatic alde-
hydes. Moderate to excellent isolated yields were obtained
(59–90%) and diastereoselectivities in the range of 78:22
to>95:5 were achieved. This means that the absolute ste-
reochemistry of the all-carbons chiral quaternary centre is
controlled. Electron-rich aromatic aldehydes (Table 1, en-
tries 6 and 7) led to good yields and slightly reduced selec-
tivities. Electron-poor aromatic aldehydes (Table 1, en-
tries 8–10) gave reduced yields but better diastereomeric
ratios. With electron-rich heteroaromatic aldehydes
(Table 1, entries 11 and 12), good yields were obtained but
the selectivities were lower, in particular with thiophene-2-
carbaldehyde 27.
We finally investigated the effect of the structure of the
chiral auxiliary (Scheme 2). The optimisation was carried
out with thiophene-2-carbaldehyde 27 as the electrophile be-
Acknowledgements
This work was supported by the Universitꢀ Catholique de Louvain and
FNRS.
Keywords: aldol reaction · asymmetric synthesis · copper ·
quaternary stereocenters · silylation
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Copper-Catalysed Domino Silylative Aldol Reaction
COMMUNICATION
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Received: April 11, 2010
Published online: August 4, 2010
Chem. Eur. J. 2010, 16, 10980 – 10983
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10983