Enantioselective one-pot organocatalytic michael addition/goldcatalyzed tandem acetalization/cyclization

Article abstract of DOI:10.1002/anie.200903905

Au-rganocatalytic reaction: A one-pot process consisting of a Michael addition to a nitroenyne and a subsequent acetalization/ cyclization is reported (see scheme; TMS=trimethylsilyl), which results in the formation of nitro-substituted tetrahydrofuranyl ethers with high diastereo- and enantioselectivities. Organocatalysis and gold catalysis are compatible and complementary in a one-pot process

Full text of DOI:10.1002/anie.200903905

Angewandte
Chemie
DOI: 10.1002/anie.200903905
Tandem Reactions
Enantioselective One-Pot Organocatalytic Michael Addition/Gold-
Catalyzed Tandem Acetalization/Cyclization**
Sꢀbastien Belot, Kim A. Vogt, Cꢀline Besnard, Norbert Krause,* and Alexandre Alexakis*
The development of sustainable processes is one of the main
priorities for preparative chemistry in the 21st century.[1] For
several decades, a large effort has been devoted to the
development of new, efficient catalytic transformations to
achieve high molecular complexity from simple starting
materials. Consequently, the combination of very efficient
Scheme 1. Proposal: One-pot organocatalysis/gold-catalysis sequence.
catalytic methods (e.g., organocatalysis[2] and gold catalysis[3])
in a tandem or one-pot process[4] should provide a powerful
tool for saving both energy and resources. These two powerful
methodologies have already been used in total synthesis,
although at different steps of the synthesis.[5]
First, we optimized the organocatalyzed conjugate addi-
tion of isovaleraldehyde (1a) to the phenyl-substituted nitro-
enyne 2a in the presence of diphenylprolinol silyl ether 5. The
best conditions appeared to be 10 equivalents of aldehyde in
the presence of 10 mol% of organocatalyst 5 at À108C
[Eq. (1) in Scheme 2 and see the Supporting Information].
The asymmetric conjugate addition of aldehydes to
nitroolefins catalyzed by a pyrrolidine derivative is an
efficient method for the synthesis of g-nitrocarbonyl building
blocks.[6] Among various nitroolefins, b-nitrostyrenes are the
most widely used because of their possible conversion into
substituted pyrrolidines,[7] butyrolactones,[8] or cyclopen-
tanes.[9] Other functionalized nitroolefins[10] have also been
used, and some of them applied in target-oriented syn-
thesis.[11] However, in all cases, the synthesis of the nitro-
carbonyl compounds and their subsequent conversions were
carried out in a sequential way. Knowing the compatibility of
amines and gold catalysts,[12] and our recent results on 1,4-
additions of aldehydes to nitrodienes,[13] as well as gold-
catalyzed transformations of functionalized alkynes,[14] we
envisaged a one-pot process consisting of an enantioselective
organocatalytic Michael addition of aldehydes 1 to nitro-
enyne 2, and a subsequent gold-catalyzed tandem acetaliza-
tion/cyclization of the corresponding adduct 3 by electrophilic
activation[3] of the triple bond. Herein we disclose our results
on this one-pot reaction which leads to nitro-substituted
tetrahydrofuranyl ethers 4 with high diastereo- and enantio-
selectivities (Scheme 1).
Scheme 2. Optimization of the sequential reaction. TMS=trimethyl-
silyl, p-Ts=para-toluene sulfonyl.
Then we investigated the gold-catalyzed tandem acetaliza-
tion/cyclization of the aldehyde 3a into the expected tetrahy-
drofuranyl ether 4a in the presence of various gold sources
and additives. After optimization, we carried out the reaction
in presence of [PPh3Au]Cl and AgBF4 with 10 mol% of
p-TsOH and only 1.2 equivalents of ethanol in chloroform at
08C, and observed the best diastereoselectivity. [Eq. (2) in
Scheme 2 and see the Supporting Information].
[*] S. Belot, Prof. Dr. A. Alexakis
Dꢀpartement de chimie organique, Universitꢀ de Genꢁve
30 quai Ernest Ansermet, 1211 Genꢁve 4 (Switzerland)
Fax: (+41)223-793-215
E-mail: alexandre.alexakis@unige.ch
C. Besnard
Laboratoire de Cristallographie, Universitꢀ de Genꢁve
24 quai Ernest Ansermet, 1211 Genꢁve 4 (Switzerland)
Having optimized both catalysts and the reaction con-
ditions, we next examined the tandem acetalization/cycliza-
tion on the model substrate 3a in the presence of various
alcohols (Scheme 3). Pleasingly, the reaction tolerates a wide
range of primary and secondary alcohols and afforded the
expected tetrahydrofuran 4a–i in good yields and diastereo-
selectivities. Both simple primary alcohols, such as methyl or
n-propyl alcohol, and more complex primary alcohols, such as
K. A. Vogt, Prof. Dr. N. Krause
Organische Chemie II, Technische Universitꢂt Dortmund
Otto-Hahn-Strasse 6, 44227 Dortmund (Germany)
E-mail: norbert.krause@tu-dortmund.de
[**] We thank the European Community (Marie Curie Early Stage
Researcher Training, MEST-CT-2005-019780).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903905.
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8923

Communications
ethers 4a–i prepared in this work have the same configu-
ration.
To shed light on the reaction mechanism, we performed a
deuterium labeling experiment on the tandem acetalization/
cyclization of the aldehyde 3a in the presence of [PPh3Au]Cl,
AgBF4, and p-TsOH with 1.2 equivalents of deuterated
methanol in chloroform. According to NMR spectra, the
deuterium was located on the exocyclic double bond. There-
fore, we propose the mechanistic model shown in Scheme 4.
Knowing that the reaction also occurs in the absence of a
Brønsted acid, we assume that the reaction is initiated by the
formation of the cationic gold catalyst, [PPh3Au]BF4, which
acts as an oxophilic Lewis acid to catalyze the acetalization
reaction of the aldehyde A. This step enables the generation
of the corresponding hemiacetal salt B. Then, as gold catalysts
are well-known for activating alkynes by forming p-com-
plexes,[3] the triple bond is activated towards the attack by the
oxygen atom, leading to the tetrahydrofuran C which then
undergoes protodemetalation, because of the presence of
HBF4, to afford the corresponding tetrahydrofuranyl ether.
We decided then to turn our attention towards the
optimization of the one-pot reaction. To accelerate the
study, we optimized the conditions by starting directly from
the intermediate 3a and adding all the components of the
organocatalyzed step (i.e., the diphenylprolinol silyl ether 5
and 1a) and the gold-catalyzed step (e.g., [PPh3Au]Cl, AgBF4,
p-TsOH, and ethanol). Therefore, the influence of the
temperature and the ratio of organocatalyst to p-TsOH
upon the reaction could be tested (Table 1).
Scheme 3. Scope of the sequential reaction. The d.r. values are
reported for cis/trans relationship between the stereogenic centers
labeled (a) and (c).
Table 1: Optimization of the one-pot reaction.
(R)-2-phenylpropan-1-ol, and benzylic alcohols work well.
Moreover the expected tetrahydrofuran could also be
obtained from secondary alcohols (isopropyl alcohol and
cyclohexanol). In contrast to this, no reaction took place in
the presence of water or tert-butyl alcohol. The relative and
absolute configuration of 4i was determined by X-ray
crystallography to be cis (Figure 1 and see the Supporting
Information).[15] We assume that the other tetrahydrofuranyl
Entry
5
p-TsOH
T [8C] t [h] d.r.[a]
(cis/trans)
Yield [%][b]
(mol%) (mol%)
1
2
3
4
5
6
7
8
20
10
10
10
10
10
10
10
10
10
0
10
25
50
100
25
23
23
23
0
0
0
0
À10
24
1
24
1
1
1
–
0
84
0
87
79
84
81
89
90:10
–
91:9
92:8
93:7
95:5[c]
93:7
1
2
[a] The d.r. values are given for the stereogenic centers labeled (a) and
1
(c). Determined by H NMR analysis or super critical fluid chromatog-
raphy (SFC) of the crude product using a chiral stationary phase. [b] Yield
of isolated product after a flash column chromatography on SiO2.
[c] Epimerization of syn-3a into the anti-3a occurs.
Interestingly, these investigations clearly show a tremen-
dous effect of the p-TsOH upon the reaction. Indeed, no
reaction occurred when the amount of organocatalyst 5
exceeded that of p-TsOH (entries 1 and 3, Table 1). However,
when equimolar amounts are used, the expected tetrahydro-
furan 4a is formed with nearly the same diastereoselectivity
Figure 1. Single-crystal X-ray structure analysis of 4i. Thermal ellip-
soids shown at 70% probability.[15]
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Angewandte
Chemie
presence of ethanol, methanol, or isopropanol.
Pleasingly, in all cases, the tetrahydrofuranyl ethers
4a–c and 6–10 were obtained in better yields in the
one-pot reaction, when compared to the sequential
reaction, and with excellent diastereoselectivities
(Table 2).
Independent of the substitution pattern and the
electronic character of the functional group attached
to the aromatic ring of the nitroenynes, the tetrahy-
drofuranyl ethers 4a–c and 6–9 were obtained in
excellent yields and diatereoselectivities either with
ethanol, methanol, or isopropanol (entries 1–3,
Table 2). Moreover it should be noted that the
procedure is applicable to heteroaromatic substitu-
ents such as 3-thienyl groups (entry 8, Table 2).
In conclusion, although some asymmetric gold-
catalyzed cyclizations are known using either chiral
ligands or chiral anions,[16] we developed a third
alternative strategy: a one-pot process consisting of
an enantioselective organocatalytic Michael addition
Scheme 4. Proposed mechanism for the gold-catalyzed tandem acetalization/
cyclization.
Table 2: Scope of the one-pot reaction.
as obtained in the sequential reaction (entries 2 and 4,
Table 1). It seems that the excess of p-TsOH prevents
deactivation of the gold catalyst by coordination to the
nitrogen atom of the diphenylprolinol silyl ether 5.
When we performed the same reaction with an excess of
p-TsOH at 08C, we observed an improvement of the
diastereoselectivity (entries 4–7, Table 1). However, in the
presence of 100 mol% of acid, we observed an increase of the
tetrahydrofuran coming from the anti adduct (entry 7,
Table 1). This is a result of the conversion of the syn-adduct
3a into the anti adduct through epimerization. Indeed experi-
ments clearly showed that the syn-3a could racemize in the
presence of p-TsOH to afford the anti adduct. Fortunately,
the reaction is slow. We also observed a moderate effect of the
temperature on the reaction in terms of the diastereoselec-
tivity (entry 8, Table 1). Therefore, after this study, it appears
that the best compromise seems to be a slight excess of
p-TsOH (25 mol%) relative to the diphenylprolinol silyl
ether 5 (10 mol%), a temperature of À108C, and the same
concentration of the starting material (0.11 molLÀ1) used in
the organocatalyzed step.
Entry R1
R2
Yield
[%][a]
d.r. of 3[b] d.r.[c]
(syn/anti) (cis/trans) (syn)
ee [%][d]
1
2
3
4
5
6
7
8
Et
Ph
4a: 80 96:4
4b: 81 96:4
4c: 78 96:4
92:8
93:7
88:12
92:8
91:9
93:7
91:9
89:11
99
99
99
>99
>99
>96[e]
>99
99
Me Ph
iPr
Et
Et
Et
Et
Et
Ph
p-BrC6H4
p-MeOC6H4 7: 77
p-CF3C6H4
m-MeC6H4
3-thienyl
6: 86
97:3
95:5
96:4
96:4
8: 84
9: 86
10: 75 97:3
With the optimized conditions for the one-pot reaction in
hand, we investigated the scope of the reaction with the
various aldehydes 1 and nitroenynes 2 in the presence of
10 mol% of diphenylprolinol silyl ether 5 in chloroform at
À108C for the first step. After completion of the organo-
catalyzed conjugate addition, 5 mol% of [PPh3Au]Cl/AgBF4,
25 mol% of p-TsOH, and 1.2 equivalents of the correspond-
ing alcohol were directly added to the reaction mixture
containing the adduct, at À108C (Table 2). Pleasingly, the
gold-catalyzed tandem acetalization/cyclization afforded
almost the same diastereoselectivity as observed for the
optimization (entry 1, Table 2). As isovaleraldehyde (1a)
gave the best results for the organocatalyzed step, it was
chosen as representative aldehyde for the one-pot reaction.
Therefore the scope of the one-pot reaction was studied using
isovaleraldehyde with the nitroenynes 2a–f, and then in
[a] Overall yield of isolated product. [b] Determined by 1H NMR analysis
or SFC on the crude product using a chiral stationary phase. [c] The
d.r. values are given for the steroegenic centers, labeled (a) and (c), of
compounds 4a–c and 6–10. Determined by 1H NMR analysis of the
crude reaction mixture. [d] Determined by SFC using a chiral stationary
phase for the syn-adducts 3a–f. [e] Accuracy problem resulting from the
partial separation of the enantiomers.
to a nitroenyne and a subsequent gold-catalyzed acetaliza-
tion/cyclization. This sequence leads to nitro-substituted
tetrahydrofuranyl ethers with high diastereo- and enantiose-
lectivities. Moreover, we have demonstrated that organo-
catalysis and gold catalysis are compatible and complemen-
tary in a one-pot process, thereby enabling isolation of the
products in higher yields relative to those for the sequential
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Communications
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Experimental Section
Typical procedure: (S)-(À)-(Diphenyltrimethylsiloxymethyl)-pyrroli-
dine (8 mg, 0.02 mmol) was added to a solution of the nitroenyne
(0.23 mmol) and aldehyde (2.30 mmol) in amylene-stabilized chloro-
form (2 mL) maintained at À108C. The reaction mixture was stirred
at À108C and the conversion was monitored by TLC analysis. Then
the alcohol (0.28 mmol), p-TsOH (10 mg, 0.06 mmol), Ph3PAuCl
(6 mg, 0.01 mmol), and AgBF4 (2 mg, 0.01 mmol) were successively
added while maintaining the reaction mixture at À108C. The resulting
heterogeneous reaction mixture was stirred for 3–5 h at À108C. At
this point, water (1 mL) was added, and the mixture was extracted
with CH2Cl2. The combined organic layers were dried over Na2SO4,
filtered, and concentrated under reduced pressure. The crude product
was purified by flash column chromatography on silica gel.
Received: July 16, 2009
Revised: September 21, 2009
Published online: October 21, 2009
Keywords: cyclization · gold · heterocycles · Michael addition ·
.
organocatalysis
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