Organocatalytic asymmetric α-selenenylation of aldehydes

Article abstract of DOI:10.1002/anie.200702318

(Figure Presented) Getting round the (periodic) table: The enamine activation concept has been extended to the asymmetric addition of selenium-based compounds to aldehydes in an organocatalytic transformation that provides high reaction efficiency and ste

Full text of DOI:10.1002/anie.200702318

Communications
DOI: 10.1002/anie.200702318
Asymmetric Organocatalysis
Organocatalytic Asymmetric a-Selenenylation of Aldehydes**
Marcello Tiecco, Armando Carlone, Silvia Sternativo, Francesca Marini,* Giuseppe Bartoli, and
Paolo Melchiorre*
Asymmetric organocatalysis has become a field of central
importance for the stereoselective preparation of chiral,
enantioenriched molecules.[1] In particular, chiral secondary
amine catalysis has proven to be a powerful procedure for the
enantioselective transformation of carbonyl compounds.
Aminocatalysis has enabled the asymmetric a-, b-, and g-
functionalization of aldehydes and ketones with a wide range
of electrophiles and nucleophiles by exploiting catalytic
enamine,[2] SOMO (singly occupied molecular orbital),[3]
iminium ion,[4] and dienamine[5] activation modes
(Scheme 1). Within the realm of the non-inert elements
classified as “non-metals” in the periodic table, only sele-
nium-based compounds have yet to be stereoselectively
incorporated into carbonyl compounds by organocatalysis.[6]
Herein we report the exploitation of the enamine
activation strategy in the first highly enantioselective a-
selenenylation of aldehydes catalyzed by a readily available
chiral secondary amine.[7] This process provides access to
highly attractive a-seleno aldehydes in high yield and with
excellent enantiomeric excess (95–99%) from commercially
available starting materials under mild and simple reaction
conditions. The synthetic utility of such intermediates[8] is
demonstrated by their easy and rapid conversion into
valuable chiral building blocks.
The only access to chiral a-seleno aldehydes reported to
date relies on a “chiral-pool” approach that involves multi-
step procedures.[9] To the best of our knowledge, no catalytic
enantioselective processes are available for the preparation of
these optically active building blocks. In light of this, and
considering our recent efforts to expand the scope of
asymmetric aminocatalysis,[10] we wondered whether the
enamine activation concept might be extended to the highly
enantioselective addition of selenium-based compounds to
aldehydes.
To assess the feasibility of such an asymmetric organo-
catalytic a-selenenylation strategy, we focused on air-stable,
commercially available N-(phenylseleno)phthalimide (2) as
the electrophilic selenium source.[11] Thus, treatment of
propanal (1a) with 2 in the presence of 10 mol% of l-proline
in CH2Cl2 (0.5m) resulted in a clean but poorly selective
selenenylation of the aldehyde (Table 1, entry 1). We then
turned our attention to the use of imidazolidinone A[12] and
the diarylprolinol silyl ethers B and C (TMS = trimethyl-
silyl),[13] which have recently emerged as potentially general
enamine organocatalysts for a broad range of highly selective
a-functionalizations of aldehydes.
Scheme 1. Activation modes for the asymmetric aminocatalysis.
[*]Prof. M. Tiecco, Dr. S. Sternativo, Prof. F. Marini
Dipartimento di Chimica e Tecnologia del Farmaco
Sezione di Chimica Organica
Università di Perugia
06123 Perugia (Italy)
Fax: (+39)075-585-5116
E-mail: marini@unipg.it
A. Carlone, Prof. G. Bartoli, Dr. P. Melchiorre
Dipartimento di Chimica Organica “A. Mangini”
Alma Mater Studiorum—Università di Bologna
Viale Risorgimento, 4, 40136 Bologna (Italy)
Fax: (+39)051-209-3654
As can be seen from Table 1, preliminary studies indicated
that both catalyst B and the TFA salt of catalyst A were able
to promote the reaction with good enantioselectivity (Table 1,
entries 2–5). Extensive evaluation of a variety of catalyst salts
(Table 1, entries 7–12) revealed that imidazolidinone A·DCA
and B·p-NO2C6H4COOH exhibited superior selectivity and
much higher catalytic activity (Table 1, entries 9 and 12,
respectively). These findings allowed us to reduce the loading
of the organocatalysts to 0.5 mol% without compromising the
chemical or optical yields (Table 1, entries 13 and 14).[14]
E-mail: pm@ms.fci.unibo.it
[**]This work was carried out in the framework of the National Project
“Stereoselezione in Sintesi Organica” supported by MIUR, Rome.
Financial support from the Consorzio CINMPIS, Bari, is also
gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Selected screening results for the a-selenenylation of aldehydes.[a]
substituted groups, the desired
products 4 being isolated in excel-
lent enantiomeric excess (95–99%)
and high yields. Similarly, the steri-
cally encumbered aldehyde 1h was
transformed smoothly into the cor-
responding chiral alcohol 4h with
excellent chemical and optical
yields (Table 2, entry 9).[17] It is
notable that no side products result-
ing from aldol dimerization or the
formation of a,a-diseleno alde-
hydes were observed under these
reaction conditions.
This organocatalytic enantiose-
lective a-selenenylation reaction of
aldehydes provides highly versatile
chiral building blocks for different
synthetic transformations that lead
to valuable optically active com-
pounds. Scheme 2 shows two exam-
ples. The b-phenylseleno alcohol
4b, for example, which was gener-
ated by direct reduction of the
aldehyde 3b, was converted into
the corresponding carbamate and
then oxidized in situ to generate a
selenonyl group. The stereospecific
intramolecular nucleophilic substi-
tution of this excellent leaving
group by the nitrogen atom of the
carbamate gave rise to a ring closing
Entry
1
Catalyst
Amount
[mol%]
Solvent
T
[C8]
Conversion
[%][b]
ee [%][c]
1[d]
2
3
4
5
6
7
8
9
10
11
12
13[e]
14[f]
15[f]
16[f]
17[f]
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
b
b
l-proline
A·TFA
B
A·TFA
B
10
10
10
10
10
10
10
10
10
10
10
10
0.5
0.5
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
CH2Cl2
toluene
RT
RT
RT
82
>95
>95
44
15
83
53
64
>95
47
54
18
85
84
90
86
78
87
93
94
88
91
91
92
90
95
82
99
À20
À20
À20
À20
À20
À20
À20
À20
À20
0
C
A·p-NO2PhCO2H
A·TCA
A·DCA
B·PhCO2H
B·o-NO2PhCO2H
B·p-NO2PhCO2H
A·DCA
B·p-NO2PhCO2H
B·p-NO2PhCO2H
A·DCA
65
>95 (96)
>95 (95)
>95 (99)
91
0
0
5
5
À20
B·p-NO2PhCO2H
0
95 (89)
[a]Reactions carried out on a 0.2-mmol scale with 1.5 equiv of aldehyde 1; TFA: trifluoroacetic acid;
TCA: trichloroacetic acid; DCA: dichloroacetic acid; RT: room temperature; the absolute configuration
of 3a obtained with catalysts A–C was determined to be (S) by comparison of its specific optical rotation
with the value reported in the literature.[9] [b]Conversion determined by 1H NMR spectroscopy; yield of
isolated product is given in parentheses. [c] ee values were determined by chiral HPLC analysis of the
crude mixture and confirmed after reduction of 3a,b to the corresponding alcohols. [d]The opposite ( R)
enantiomer of 3a was obtained. [e]Reaction time: 16 h; 0.4-mmol scale. [f]Reaction time: 40 h; 0.4-
mmol scale.
Both the employed organocatalysts afforded the a-seleno
aldehyde 3a with an (S) absolute configuration, as deter-
Table 2: Asymmetric a-selenenylation: substrate scope.[a]
mined by comparison of its specific optical rotation with the
value reported in the literature.[9] The sense of asymmetric
induction is consistent with previously reported selectivity
models in which the Re-face of the (E)-configured enamine
intermediate is effectively shielded by the chiral fragment-
s.[6e,12b,13b]
Entry
R (aldehyde)
Yield [%][b] (alcohol)
ee [%][c]
Further optimization of the standard reaction parame-
ters[15] revealed that carrying out the reaction in toluene
(0.5m) in the presence of B·p-NO2C6H4COOH (5 mol%)
allowed greater stereocontrol (95% ee; Table 1, entry 15),
albeit at the expense of reactivity. On this basis, and
considering the results obtained in the organocatalytic a-
selenenylation of isovaleraldehyde (1b; Table 1, entries 16
and 17), these catalytic conditions were identified as the most
consistent and general and were thus selected for further
explorations.
We next examined the applicability of this enantioselec-
tive a-selenenylation strategy to various aldehydes. The
reaction products were isolated as their alcohols 4 after
reduction of the aldehyde moiety with NaBH4 in situ to
facilitate work-up.[16] Reduction of the a-seleno aldehyde 3a
to 4a demonstrated that this process occurs without loss of
optical purity (Table 2, entry 1).
1
2
3
4
5
6
7
8
9
Me (1a)
iPr (1b)
iPr (1b)
Et (1c)
99 (4a)
89 (4b)
94 (ent-4b)
84 (4c)
99 (4d)
81 (4e)
91 (4 f)
94 (4g)
99 (4h)
95
99
99[d]
97
98
97
98
98
99
Bu (1d)
PhCH2 (1e)
allyl (1 f)
CH2SCH3 (1g)
tBu (1h)
[a]Reactions performed on a 0.4-mmol scale with 1.5 equiv of aldehyde
1. [b]Yield of isolated product. [c]Determined by HPLC analysis. [d]( R)-
B was used as the catalyst to afford the (R) enantiomer of 4b.
reaction that afforded the highly enantioenriched 4-substi-
tuted 1,3-oxazolidinone 5.[18] The (R) absolute configuration
of 5, as determined by comparison of its specific optical
rotation with the value reported in the literature,[19] indicates
that the substitution occurs with inversion of configuration. a-
Selenenylated aldehydes can also undergo in situ reductive
The method proved successful for a wide range of
aldehyde substituents, including alkyl, alkenyl, and hetero-
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Brown, M. P. Brochu, C. J. Sinz, D. W. C. MacMillan, J. Am.
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Scheme 2. Synthetic transformations of a-seleno aldehydes.
amination upon treatment with benzylamine and NaCNBH3
without loss of enantiomeric purity.[20] Interestingly, the
phenylseleno amine 6, which can be generated in good yield
and high enantioselectivity, is a useful intermediate for the
preparation of several compounds.[8]
In summary, we have reported an organocatalytic asym-
metric a-selenenylation of aldehydes that employs unmodi-
fied and commercially available starting materials and
catalysts under mild reaction conditions. Besides expanding
the scope of asymmetric aminocatalysis, this transformation
provides the first catalytic access to highly enantioenriched
(ee values ranging from 95 to 99%) a-seleno aldehydes, which
are versatile chiral intermediates that lead to valuable,
optically active compounds. A full account of the scope of
this methodology will be reported in due course.
[7] For a direct preparation of racemic a-seleno carbonyl com-
pounds promoted by secondary amines by enamine catalysis,
see: a) W. Wang, J. Wang, H. Lao, Org. Lett. 2004, 6, 2817; b) J.
Wang, H. Li, Y. Mei, B. Lou, D. Xu, D. Xie, H. Guo, W. Wang, J.
Org. Chem. 2005, 70, 5678. Initial attempts to perform an
asymmetric catalytic version using the (S)-pyrrolidine tosyl
sulfonamide and the MacMillan second generation imidazolidi-
none afforded poor selectivity (60% and 40% ee, respectively);
see also: c) F. Giacalone, M. Gruttadauria, A. Mossuto Marcu-
lescu, R. Noto, Tetrahedron Lett. 2007, 48, 255.
Received: May 25, 2007
Published online: August 6, 2007
[8] a) Top. Curr. Chem. (Ed.: T. Wirth), Springer, 2000; b) Organo-
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[11] The use of a different electrophilic selenium source such as
PhSeCl for the selenenylation of 1a in the presence of catalysts
A or B resulted in a sluggish reaction with low conversion and
poor enantioselectivity (lower than 10% ee).
[12] For selected examples, see: a) M. P. Brochu, S. P. Brown,
D. W. C. MacMillan, J. Am. Chem. Soc. 2004, 126, 4108;
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Soc. 2005, 127, 11598.
Keywords: aldehydes · asymmetric synthesis · organocatalysis ·
selenium · synthetic methods
.
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[2] For recent reviews, see: a) B. List, Chem. Commun. 2006, 819;
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[3] a) T. D. Beeson, A. Mastracchio, J.-B. Hong, K. Ashton, D. W. C.
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[4] For an excellent review on iminium-ion activation, see: a) G.
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[5] S. Bertelsen, M. Marigo, S. Brandes, P. DinØr, K. A. Jørgensen, J.
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[14] This is in response to the current trend of reducing the catalyst
loading, which until recently has been a long-standing limitation
and source of criticism of asymmetric organocatalysts (S.
Borman, Chem. Eng. News 2006, 84, 13). For recent examples
of asymmetric organocatalytic transformations with catalyst
loadings lower than 1 mol%, see: a) M. He, G. J. Uc, J. W. Bode,
J. Am. Chem. Soc. 2006, 128, 15088; b) F. Wu, R. Hong, J. Khan,
X. Liu, L. Deng, Angew. Chem. 2006, 118, 4407; Angew. Chem.
Int. Ed. 2006, 45, 4301.
[15] Solvent screening for a-selenenylation of 3a (10 mol% catalyst,
À208C, 1 h reaction time): catalyst A·DCA: CH2Cl2: > 95%
conversion, 94% ee; toluene: 47% conversion, 90% ee; THF:
50% conversion, 70% ee; acetone: 85% conversion, 87% ee.
Catalyst B·p-NO2C6H4COOH: CH2Cl2: 65% conversion,
91% ee; toluene: 20% conversion, 95% ee; EtOAc: 15%
conversion, 90% ee; Et2O: 23% conversion, 94% ee; acetone:
29% conversion, 80% ee; EtOH: no reaction; CHCl3: 17%
conversion, 90% ee.
[16] The optically active a-seleno aldehyde 3a slowly racemizes
during column chromatography on silica gel; see the Supporting
Information for details.
[17] a,a-Disubstituted aldehydes such as 2-phenylpropanal react
smoothly under our a-selenenylation conditions to form quater-
nary stereocenters, albeit with low enantioselectivity (À208C,
10 mol% catalyst B·p-NO2C6H4COOH, 24 h, > 95% conver-
sion, 34% ee).
[18] M. Tiecco, L. Testaferri, A. Temperini, L. Bagnoli, F. Marini, C.
Santi, Chem. Eur. J. 2004, 10, 1752.
[19] M. Feroci, A. Inesi, L. Palombi, L. Rossi, G. Sotgiu, J. Org.
Chem. 2001, 66, 6185.
[20] The a-selenenylation step was carried out in CH2Cl2 at À108C in
the presence of B·p-NO2C6H4COOH (10 mol%) as the catalyst
to afford the aldehyde intermediate 3b with 98% ee.
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