Asymmetric synthesis of α-alkyl α-selenocarbonyl compounds catalyzed by bifunctional organocatalysts

Article abstract of DOI:10.1021/ol200923p

A new organocatalytic approach for the synthesis of a variety of α-alkyl, α-phenylselenyl ketones as well as their corresponding esters and amides, by the addition of α-selenocarbonyl derivatives to nitroalkenes catalyzed by thiourea or squaramide cinchon

Full text of DOI:10.1021/ol200923p

ORGANIC
LETTERS
2011
Vol. 13, No. 12
3052–3055
Asymmetric Synthesis of r-Alkyl
r-Selenocarbonyl Compounds Catalyzed
by Bifunctional Organocatalysts
†
,†
†
,‡
ꢀ
Vanesa Marcos, Jose Aleman,* Jose L. Garcia Ruano, Francesca Marini,* and
Marcello Tiecco‡
´
ꢀ
ꢀ
Departamento de Quımica Organica (C-I), Universidad Autonoma de Madrid,
Cantoblanco, 28049 Madrid, Spain, and Dipartimento di Chimica e Tecnologia del
Farmaco Sezione di Chimica Organica, Universita di Perugia, 06123 Perugia, Italy
jose.aleman@uam.es; marini@unipg.it
Received April 8, 2011
ABSTRACT
A new organocatalytic approach for the synthesis of a variety of R-alkyl, R-phenylselenyl ketones as well as their corresponding esters and
amides, by the addition of R-selenocarbonyl derivatives to nitroalkenes catalyzed by thiourea or squaramide cinchona catalysts, is presented.
This catalytic system allows the preparation in high yields of enantiomerically enriched selenocarbonyl derivatives bearing two chiral centers with
excellent ee’s and dr’s by using catalytic loadings of 3 mol %.
Organoselenium compounds have become attractive
synthetic targets because of their unique chemo-, regio-,
and stereoselectivities in organic synthesis and their useful
biological and medical properties (antioxidant, antitumor-
al and antimicrobial).1 In particular, R-(phenylselenyl)
carbonyl compounds are of great importance in synthetic
chemistry2 because of their use as starting materials for
preparing R,β-unsaturated ketones2a and other syntheti-
cally useful compounds,2bÀd,3as well as intermediates in the
synthesis of polycyclic compounds via free-radical cycli-
zation processes.4 Additionally, Cotgreave et al.5 reported
gluthathione peroxidase-like biological properties for some
specific series of R-phenylseleno ketones, which can be
employed as antiviral, anticancer, and anti-inflammatory
agents. Moreover, it is well-known that R-(phenylselenyl)-
carbonyl moieties are present in selenoproteins, which are
essential for the human immune system.6 Despite this
(4) (a) Toru, T.; Okumura, T.; Ueno, Y. J. Org. Chem. 1990, 55, 1277.
(b) Kusuda, S.; Watanabe, Y.; Ueno, Y.; Toru, T. J. Org. Chem. 1992,
57, 3145. (c) Hart, D. J.; Krishnamurthy, R. J. Org. Chem. 1992, 57,
4457. (d) Porter, N. A.; Posenstein, I. J. C. Tetrahedron Lett. 1993, 34,
7865. (e) Newcomb, M.; Filipkowski, A.; Johnson, C. C. Tetrahedron
Lett. 1995, 36, 3643. (f) Ryu, I.; Muraoka, H.; Kambe, N.; Komatsu, M.;
Sonoda, N. J. Org. Chem. 1996, 61, 6396.
(5) Cotgreave, I. A.; Moldeus, P.; Brattsand, R.; Hallberg, A.;
Anderson, C. M.; Engman, L. Biochem. Pharmacol. 1992, 43, 793.
(6) In humans, 25 selenoproteins have been identified, many of which
have unknown functions and remain to be explored. For leading
references, see: (a) Kryukov, G. V.; Castellano, S.; Novoselov, S. V.;
Lobanov, A. V.; Zehtab, O.; Guingo, R.; Gladyshev, V. N. Science 2003,
300, 1439. (b) May, S. W. Exp. Opin. Invest. Drugs 1999, 8, 1017. (c)
Medina, D.; Thompson, H.; Ganther, H.; Ip, C. Nutr. Cancer. 2001, 40,
12. For recent examples, see: (d) Wang, J.; Li, H.; Mei, Y.; lou, B.; Xu,
D.; Xie, D.; Guo, H.; Wang, W. J. Org. Chem. 2005, 70, 5678 and
references cited therein.
†
ꢀ
Universidad Autonoma de Madrid.
‡ Universit di Perugia.
(1) (a) Nogueira, C, W; Zeni, G.; Rocha, J. B. T. Chem. Rev. 2004,
104, 6255. (b) Mugesh, G.; du Mont, W. W.; Sies, H. Chem. Rev. 2001,
101, 2125. (c) Parnham, M. J.; Graf, E. Prog. Drug Res. 1991, 36, 9. (d)
Quinhones, E. B.; Jung, E. A. C.; Zeni, G.; Rocha, J. B. T. Inflamm. Res.
2003, 52, 56.
(2) (a) Larock, R. C. Comprehensive Organic Transformations, 2nd
ed.; Willey-VCH: New York, 1999. (b) Paulmier, C. Selenium Reagents and
Intermediates in Organic Synthesis; Pergamon: Oxford, 1986. (c)
Back, T. G. Organoselenium Chemistry: A Practical Approach; Oxford
University Press: New York, 1999. (d) For a recent review in selenium
chemistry, see: Santi, C.; Santoro, S.; Battistelli, B. Curr. Org. Chem. 2010,
14, 2442–2462.
(3) (a) Wirth, T.; Arrica, M. Eur. J. Org. Chem. 2005, 395. (b) Boivin,
S.; Outurquin, F.; Paulmier, C. Tetrahedron 1997, 53, 16767. (c) Boivin,
S.; Outurquin, F.; Paulmier, C. Tetrahedron Lett. 2000, 41, 663.
r
10.1021/ol200923p
Published on Web 05/17/2011
2011 American Chemical Society

large synthetic and biological importance, presumably
more relevant for compounds with the selenium joined to
the tertiary carbons (with higher conformational restric-
tions and precursors of more stable radicals), few meth-
ods affording enantiomerically pure R-(phenylselenyl)-
carbonyl derivatives have been reported (path b, Scheme 1).
The most used procedures for preparing racemic com-
pounds are based on reactions of R-haloketones with
phenylselenide (path a, Scheme 1)7 and those of ketoenols
or ketoenolates with a Se electrophilic source (path c,
Scheme 1).8
R-phenylselenoketone (also ester and amide) derivatives
containing selenylated tertiary stereocenters by reaction of
the selenocarbonyl derivatives with nitroalkenes (path d,
Scheme 1) in the presence of bifunctional thioureas10and
squaramides.11
Our initial trials involved R-selenation of β-ketoesters
with N-(phenylseleno)phthalimide and phenylselenyl
chloride (path c, Scheme 1) catalyzed by different cinchona
bases. Reactions were chemically successful, yielding the
R-seleno-β-ketoesters in moderate conversions (eq 1), but
racemic compounds were isolated in all the studied cases
(see Supporting Information (SI)).
Scheme 1. Different Approaches for the Synthesis of Seleno-
carbonyl Derivatives
One possible reason for the failure of these reactions
could derive from the incompatibility of the electrophilic
selenium species with the catalytic systems used in these
reactions.12 For these reasons, we hypothesized that the
incorporation of the selenium to the nucleophile (β-
selenocarbonyl derivatives) and the reaction with an
electrophile would make possible the synthesis of the
desired R-quaternary-seleno-carbonyl centers (path d,
Scheme 1). Thus, the model reaction for optimization
was carried out with the R-phenylselenylindanone (3a)
and nitrostyrene (4a) catalyzed by cinchona alkaloids
5aÀe and 6bÀe (Figure 1). The obtained results are
collected in Table 1.
Steric reasons determine that the first method was only
successful for secondary halides, thus converting the sec-
ond one in the only available path for preparing carbonyl
compounds with the selenium joined to tertiary carbons.
None of them has been applied to the synthesis of enan-
tiomerically enriched compounds. However, organocata-
lytic methods for preparing secondary centers attached to
Se have appeared in recent years.9 Thus, the first highly
enantioselective approach for synthesizing R-selenyl alde-
hydes was reported in 2007 (path b, Scheme 1).9b,c It is
based on the reaction of electrophilic Se sources with
aldehydes activated with the JørgensenÀHayashi catalyst
which is only valid for aldehydes. However, compounds
containing enantioenriched tertiary selenocenters, as
far as we know, have never been prepared in highly
enantioenriched form. Here, we present the first organo-
catalytic enantio- and diastereoselective synthesis of
Figure 1. Cinchona alkaloid derivatives (5), bifunctional
thioureas (6), and squaramides (7) used in this study.
(7) (a) Sharpless, K. B.; Young, M. W.; Lauer, R. F. Tetrahedron
Lett. 1979, 1973. (b) Sharpless, K. B.; Lauer, R. F. J. Am. Chem. Soc.
1973, 95, 2697. (c) Sharpless, K. B.; Lauer, R. F.; Teranishi, A. Y. J. Am.
Chem. Soc. 1973, 95, 6137.
(8) (a) Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973, 95,
6137. (b) Lebarillier, L.; Outurquin, F.; Paulmier, C. Tetrahedron 2000, 56,
7483 and references cited therein. (c) Brockson, T. G.; Petragnani, N.;
Rodriguez, R. J. Org. Chem. 1974, 39, 2114. (d) Reich, H. J.; Reich, I. L.;
Renga, J. M. J. Am. Chem. Soc. 1973, 95, 5813. (e)Reich, H. J.; Reich, I. L. J.
Am. Chem. Soc. 1975, 97, 5434. (f) Denis, J. M.; Dumont, W.; Krief, A.
Tetrahedron Lett. 1976, 453. (g) Houllemarer, D.; Ponthieux, S.; Outurquin,
F.; Paulmier, C. Synthesis 1996, 101.
(10) For a recent review about a bifunctional cinchona alkaloid based
on thiourea catalysis, see: (a) Connon, S. J. Chem. Commun. 2008, 2499.
For an account of multifunctional thioureas, see: (b) Miyabe, H;
Takemoto, Y. Bull. Chem. Soc. Jpn. 2008, 81, 785. For selected recent
examples of thiourea bifunctional catalysis, see: (a) Wang, J.; Xie, H.;
ꢀ
Wang, W. Angew. Chem., Int. Ed. 2008, 47, 4177. (b) Aleman, J.; Milelli,
(9) Despite their interest, only a very few methods concerning the
organocatalytic synthesis of enantiomerically pure secondary seleno
compounds have been reported. For example, see: (a) Winberg, H.;
Pluim, H. Tetrahedron Lett. 1979, 1251. (b) Tiecco, M.; Carlone, A.;
Sternativo, S.; Marini, F.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int.
A.; Cabrera, S.; Reyes, E.; Jørgensen, K. A. Chem.;Eur. J. 2008, 14,
~
€
10958. (c) Garcıa Mancheno, O.; Tangen, P.; Rohlmann, R.; Frohlich,
ꢀ
R.; Aleman, J. Chem.;Eur. J. 2011, 17, 984. (d) Gao, Y. J.; Ren, Q.; Wu,
H.; Li, M. G.; Wang, J. Chem. Commun. 2010, 46, 9232. (e) Ren, Q.; Gao,
Y. J.; Wang, J. Chem.;Eur. J. 2010, 16, 13594. (f) Gao, Y. J.; Ren, Q.;
Siau, W.-Y.; Wang, J. Chem. Commun. 2011, DOI: 10.1039/
C1CC11124H.
ꢀ
ꢀ
Ed. 2007, 46, 6882. (c) Sunden, H.; Rios, R.; Cordova, A. Tetrahedron
Lett. 2007, 48, 7865.
Org. Lett., Vol. 13, No. 12, 2011
3053

was observed when EDG at the aromatic group was used
(p-OMe, 4d) (entry 5, Table 2). The substitution of the
phenyl group by the 2-furyl aromatic ring (4e, entry 6,
Table 2) had a similar influence. Haloarylnitrostyrenes
4fÀh also evolved with a very high enantiomeric ratio and
90:10 dr (entries 7À9, Table 2). Unfortunately, no reaction
was observed starting from the alkyl nitroalkene 4i
(Table 2, entry 10) under the same reaction conditions.
We also studied the addition of indanones 3bÀd to nitros-
tyrene 4a (Table 2, entries 11À13). In these cases, the
influence of the substituents on the aromatic rings seems
to be opposite to that observed in the previous cases; EWG
(3b, entry 11) decreased the dr whereas EDG (3c and 3d,
entries 12 and 13) increased the dr.
Table 1. Selected Screening Results for the Michael Addition of
3a to Nitrostyrene 4aa
entry
cat. (mol %)
convb
drb
erc
1
5a (20)
5b (20)
5c (20)
5d (20)
5e (20)
6a (3)
70
70
86:14
85:15
65:35
76:24
77:23
80:20
95:5
80:20
81:19
60:40
66:33
60:40
87:13
97:3
2
3
>98
>98
>98
>98
>98
85
4
5
6
7
8
6b (3)
6c (3)
68:32
80:20
83:17
87:13
95:5
Table 2. Results Obtained with Nitroalkenes 4aÀi and Inda-
nones 3aÀda
9
6d (3)
6e (3)
92
10
96
70:30
a Performed at rt in CH2Cl2 (0.2 mL) by using 0.1 mmol of 3a and
0.13 mmol of 4a. b Determined by 1H NMR. c Determined by chiral-
stationary phase HPLC (major isomer).
product
R1
H-3a
R2
(%b)
drc
erd
The use of 5aÀe as catalysts gave good conversions but
only moderate diastereo- and enantiomeric ratios (entries
1À5). Interestingly, the use of bifunctional thiourea-cinch-
ona catalysts 6aÀe (entries 6À10) gave the most promising
results, demonstrating that the thiourea and the tertiary
amine functionalities cooperate in increasing the diasteo-
and enantiocontrol of this reaction providing nearly full
conversions, remarkably with only 3 mol % of catalytic
loading required. The best results were obtained with 6b
(dr = 95:5 and 94% ee, entry 7).13
With these optimized conditions, we studied the scope of
the reaction by using different nitroalkenes 4aÀi (entries
1À10, Table 2) and selenoindanones 3aÀd (entries, 11À13,
Table 2). We first checked that the results obtained in the
reaction of 4a with selenoindanone 3a in the presence of 6b
(entry 7, Table 1 and entry 1, Table 2) are not substantially
modified when the reaction was scaled up to 1.0 mmol
(Table 2, entry 2). The incorporation of EWG to the
aromatic ring of the nitrostyrene (4b and 4c, entries 3À4,
Table 2) slightly improved the diastereomeric ratio, but
loweryieldswereobtained. Bycontrast, adecreaseinthedr
entry
1
Ph-4a
Ph-4a
8a (80)
8a (74)
95:5
97:3
96:4
97:3
97:3
97:3
97:3
97:3
2e
3
H-3a
H-3a
p-NO2-C6H4-4b 8b (53)
p-CN-C6H4-4c 8c (65)
p-MeO-C6H4-4d 8d (72)
4
H-3a
5
H-3a
87:13 97:3
8e (56)g 85:15 91:9
6
H-3a
2-Furyl-4e
p-F-C6H4-4f
o-F-C6H4-4g
7
H-3a
8f (80)
8g (86)
90:10 97:3
90:10 95:5
8
H-3a
9
H-3a
3,4-Dichloro-4h 8h (70) 90:10 94:6
10
11
12
13
H-3a
n-Et-4i
Ph-4a
Ph-4a
Nrf
À
À
6-CF3-3b
5-Me-3c
8i (86)
8j (70)
8k (60)
88:12 95:5
97:3 98:2
>98:2 >99:1
3,4-MeO-3d Ph-4a
a Performed at rt in CH2Cl2 (0.2 mL) using 0.1 mmol of 3, 0.13 mmol
of 4, and catalyst 6b (3 mol %). b Isolated yield of the major diastereoi-
somer. c Determined by 1H NMR. d Determined by chiral-stationary
phase HPLC (major isomer). e Reaction carried out at 1.0 mmol scale.
f No reaction. g Separation of the diastereisomers was not possible.
Encouraged by these results, we widened the scope,
extending the reaction to other R-selenocarbonyl deriva-
tives 9À11 (Table 3). R-Selenocyclopentanone 914 did not
react with catalyst 6b (Table 3, entry 1) or other thioureas
catalysts 6a, 6c, and 6d. With the R-selenocumarone 10and
the R-selenooxoindol 11 (Table 3, entries 4,7), we observed
the formation of 13 and 14 respectively. However both
enantiomeric and diastereomeric excesses of these com-
pounds were quite low. These negative results forced us to
investigate other bifunctional catalysts. In the past two
years, squaramides11 (such as 7a and 7b, Figure 1) have
emerged as promising catalysts, strongly increasing in
(11) For pioneering work in this field, see: (a) Malerich, J. P.;
Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc. 2008, 130, 14416. (b)
For a recent review, see: Storer, R. Ian; Aciro, Caroline; Jones, Lyn H.
ꢀ
Chem. Soc. Rev. 2011, 40, 2330. (c) Aleman, J.; Parra, A.; Jiang, H.;
Jørgensen, K. A. Chem.;Eur. J. 2011, DOI: 10.1002/chem.201003694.
(12) We have studied the changes produced in the NMR spectra of
the quinine 5c and thiourea 6b catalysts by mixing 1 equiv of the
corresponding catalyst with 1 equiv of Cl-Se-Ph in CD2Cl2 (see SI).
The OH group at the quinine is presumably converted into O-Se-Ph (for
an example in the reaction of PhSeCl with alcohols, see: Osajda, M.;
Mzochowski, J. Tetrahedron 2002, 58, 7531), whereas the thiourea
evolves into a very complex mixture of species. It would explain the
absence of catalytic activity and the formation of the racemic mixtures.
Moreover, we have checked that this reaction occured in the absence of
catalyst.
(14) R-Selenocyclohexanone and the opened derivatives (1,2-diphe-
nyl-2-(phenylselanyl)ethanone and 1-1-phenyl-2-(phenylselanyl)propan-
1-one) did not react under any of the catalytic conditions of
Tables 2 and 3.
(13) Several and different conditions of varying solvent, tempera-
tures, and equivalence were tried. For more details, see SI.
3054
Org. Lett., Vol. 13, No. 12, 2011

crystals of 8a (right, Figure 2; see SI for more details).15
The configuration ofent-8awas establishedby comparison
of its specific rotation and HPLC data. The same criteria
were used to assign the absolute configuration of 12À14
and their enantiomers.
Table 3. Scope of Different Selenocarbonyl Derivatives 3a,
9À11 with Nitrostyrene 4ab
Based on previous mechanistic proposals,10,11 the direct
approach ofthe deprotonatedβ-selenoketone from the Re-
face to the nitroalkene would justify the observed stereo-
chemistry (left, Figure 2) for the formation of products 8.
The H-bond association of the Se could aid this
approach.16
Figure 2. X-ray ORTEP structure of 8a and stereochemical
proporsal.
a Starting material. b Performed in CH2Cl2 (0.2 mL) at 0.1 mmol
scale. c Isolated yields after flash chromatography except cases in
parentheses which are conversions determined by 1H NMR. d Diaster-
eomeric ratio determined by 1H NMR. e Enantiomeric ratio determined
by chiral-stationary phase HPLC. f No reaction. g Not determined.
In conclusion, we have found a new approach for the
synthesis of a variety of R-seleno ketones, esters, and
amides with quaternary carbons joined to selenium. It
consists of the addition of β-selenocarbonyl derivatives
to nitroalkenes catalyzed by thiourea or squaramide cinch-
ona catalysts. This catalytic system allows the synthesis of
optically enriched selenocarbonyl derivatives with two
chiral centers with excellent ee’s, dr’s and good yields. Very
low catalytic loadings (3 mol %) are required with bifunc-
tional thiourea catalysts.
many cases the reactivity of many substrates. Thus we
studied reactions of 9 with nitroalkene 4a catalyzed by 7b
(entry 2, Table 3). To our delight, 12 was obtained in 68%
conversion, in very good diastereomeric and enantiomeric
ratios. Better conversions and good results were obtained in
reactions of the amide 10 and the lactone 11 with 4a and
catalyst 7b, affording 13 and 14, respectively (entries 5 and 8).
The major enantiomer obtained in these reactions was the
same as that obtained by using 6b as the catalyst, which is
not unexpected taking into account that 6b and 7b have the
same relative configuration (see Figure 1). At this point we
also studied the reactions of 9À11 with 4a under 7a
catalysis (it is the pseudo-enantiomer of 7b). As it was
expected, the major compounds obtained in these reac-
tions are the enantiomers of those resulting under 7b
catalysis. It is remarkable that enantiomeric and diaster-
eomeric excesses obtained under 7a catalysis are slightly
better than those resulting with 7b. Finally reaction of 3a
with 4a catalyzed by 7a affords ent-8a (entry 11), the
enantiomer of 8a which had been obtained under 6b
catalysis (entry 10, Table 3).
Acknowledgment. Financial support by the Ministerio
ꢀ
de Educacion y Ciencia (CTQ-2009-12168) and Comuni-
dad de Madrid (“programa AVANCAT CS2009/PPQ-
1634”) is gratefully acknowledged. V.M. is thankful for a
predoctoral fellowship, and J.A. thanks the “Spanish
ꢀ
ꢀ
Ministerio de Ciencia e Innovacion” for a “Ramon y Cajal
contract”. MIUR, National Projects PRIN 2007, Italy,
University of Perugia and Consorzio CINMPIS, Bari are
also gratefully acknowledged.
Supporting Information Available. Experimental pro-
cedures and NMR spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The absolute configuration of products 8 was unequi-
vocally determined by X-ray analysis of appropriated
(15) CCDC 809359 (8a) contains the supplementary crystallographic
data. These data can be obtained free of charge at www.ccdc.cam.ac.uk/
conts/retrieving.html [E-mail: deposit@ccdc.cam.ac.uk].
(16) For a computational study of the H-bond with Se compounds,
see: Madzhidov, T. I.; Chmutova, G. A. J. Mol. Struct. 2010, 959, 1.
Org. Lett., Vol. 13, No. 12, 2011
3055