Enantioselective organocatalytic conjugate addition of aldehydes to nitrodienes

Article abstract of DOI:10.1021/ol801772p

(Chemical Equation Presented) The asymmetric organocatalyzed Michael addition of aldehydes to α,β-γ,δ-unsaturated nitro compounds has been accomplished using only 5 mol % of (S)-diphenylprolinol silyl ether and 2 equiv of aldehyde in a mixture of ethanol and water (5% v/v). The Michael adducts were obtained in good yields, diastereoselectivities up to 94/6, and ee's up to 99%. This process provides synthetically useful compounds which can easily lead to more complex molecules, as exemplified with substituted tetrahydropyran or cyclohexene.

Full text of DOI:10.1021/ol801772p

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4557-4560
Enantioselective Organocatalytic
Conjugate Addition of Aldehydes to
Nitrodienes
Se´bastien Belot,† Assunta Massaro,† Alice Tenti,‡ Alessandro Mordini,‡ and
Alexandre Alexakis*,†
Department of Organic Chemistry, UniVersity of GeneVa, 30, quai Ernest Ansermet,
CH-1211 GeneVa 4, Switzerland, and Istituto di Chimica dei Composti
OrganoMetallici, Area di Ricerca CNR di Firenze, Via Madonna del Piano 10,
50019 Sesto Fiorentino (Firenze), Italy
alexandre.alexakis@chiorg.unige.ch
Received July 31, 2008
ABSTRACT
The asymmetric organocatalyzed Michael addition of aldehydes to r,ꢀ-γ,δ-unsaturated nitro compounds has been accomplished using only
5 mol % of (S)-diphenylprolinol silyl ether and 2 equiv of aldehyde in a mixture of ethanol and water (5% v/v). The Michael adducts were
obtained in good yields, diastereoselectivities up to 94/6, and ee’s up to 99%. This process provides synthetically useful compounds which
can easily lead to more complex molecules, as exemplified with substituted tetrahydropyran or cyclohexene.
More than 30 years after the first organocatalyzed intramo-
lecularasymmetricaldolreaction,knownastheHajos-Parish-
Wiechert reaction,1 proline was rediscovered as an efficient
enantioselective catalyst for intermolecular aldolisation.2 This
enabled intensive growth especially in asymmetric enamine
catalysis, and many research teams developed over the recent
years their own pyrrolidine-based organocatalyst for a large
scope of reactions.3 Among them, asymmetric conjugate
addition of aldehydes to ꢀ-nitrostyrene catalyzed by a
pyrrolidine derivative appeared to be a useful synthetic
method for the synthesis of γ-nitrocarbonyl compounds.4,5
Nevertheless, the main drawback in enamine catalysis
remains to be the high catalytic loading of amine (generally
around 15 mol %) and the quantity of aldehyde (up to 10
equiv). Palomo and co-workers were the first to use only 5
mol % of a new designed organocatalyst and a slight excess
(4) For general reviews on organocatalytic asymmetric conjugate
addition, see: (a) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701. (b) Almasi,
D.; Alonso, D. A.; Na´jera, C. Tetrahedron: Asymmetry 2007, 18, 299. (c)
Sulzer-Mosse´, S.; Alexakis, A. Chem. Commun. 2007, 3123
.
(5) For selected references, see:(a) List, B.; Pojarliev, P.; Martin, H. J.
Org. Lett. 2001, 3, 2423. (b) Betancort, J. M.; Sakthivel, K.; Thayumanavan,
R.; Barbas, C. F., III Tetrahedron Lett. 2001, 42, 4441. (c) Betancort, J. M.;
Barbas, C. F., III Org. Lett. 2001, 3, 3737. (d) Alexakis, A.; Andrey, O.
Org. Lett. 2002, 4, 3611. (e) Enders, D.; Seki, A. Synlett 2002, 26. (f)
Andrey, O.; Alexakis, A.; Tomassini, A.; Bernardinelli, G. AdV. Synth. Catal.
2004, 346, 1147. (g) Mitchell, C. E. T.; Cobb, A. J. A.; Ley, S. V. Synlett
2005, 611. (h) Hayashi, Y.; Gotoh, H.; Hayashi, H. T.; Shoji, M. Angew.
Chem., Int. Ed. 2005, 44, 4212. (i) Mase, N.; Watanabe, K.; Yoda, H.;
Takabe, K.; Tanaka, F.; Barbas, C. F., III J. Am. Chem. Soc. 2006, 128,
4966. (j) Mosse´, S.; Laars, M.; Kriis, K.; Kanger, T.; Alexakis, A. Org.
† University of Geneva.
‡ Istituto di Chimica dei Composti OrganoMetallici.
(1) (a) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed 1971,
10, 496. (b) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615.
(2) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000,
122, 2395.
(3) (a) Bressy, C.; Dalko, P. I. EnantioselectiVe Organocatalysis; Wiley-
VCH: Weinheim. (b) Mukherjee, S.; Yang, J. W.; Hoffmann, S. Chem.
ReV. 2007, 107, 5471.
Lett. 2006, 8, 2559
.
10.1021/ol801772p CCC: $40.75
Published on Web 09/11/2008
2008 American Chemical Society

of the aldehyde substrate for the addition to ꢀ-nitrostyrene.6
Then, the group of Wennemers described a tripeptide as a
very efficient organocatalyst for this reaction (1 mol %).7
Finally (a more simple molecule) diphenylprolinol silyl ether
(0.5-2 mol %), turned out to be highly effective in water.8
Among all nitroolefins, ꢀ-nitrostyrenes are the most widely
used because of their possible conversion into useful
compounds such as substituted pyrrolidines5a,g or γ-butyro-
lactones.6 Nevertheless, other nitroolefins have also been used
in synthesis, for instance (-)-Botryodiplodin9 and potent H3
agonist Sch50917.10 Moreover, fonctionalized nitroolefins
such as ꢀ-nitroacroleine dimethyl acetal11 and 3-nitroacry-
late8 have also been tested in asymmetric organocatalyzed
conjugate addition. Herein, we report the organocatalyzed
conjugate addition of aldehydes 1 to nitrodienes 2. The
Michael addition of 10 equiv of isovaleraldehyde 1a to
phenylnitrodiene 2a in the presence of 20 mol % of
organocatalyst was selected as the model reaction. Thus, (S)-
diphenylprolinol silyl ether 3 appeared to be the best
organocatalyst in terms of diastereo- and enantioselectivities
(see Supporting Information).
Table 1. Solvent’s Optimization
drb
entry
solvent
CHCl3
time
yielda (syn/ anti)
eec
1
2
3
4
5
6
7
8
24 h
24 h
2 days
14 h
91
95
87
89
97
78
88
87
88/12
92/8
87/13
92/8
92/8
80/20
92/8
>99
>99
99
>99
>99
97
CH2Cl2
neat
beerd
H2O/EtOH 5% v/v 14 h
winee
H2O
20 h
14 h
50 h
98
88
EtOH
65/35
a Yield of isolated product after flash column chromatography on SiO2.
b Determined by 1H NMR or chiral SFC of crude product. c Determined by
chiral SFC on the syn adduct. d Heineken. e White wine of Jura, France.
Surprisingly, no trace of 1,6-addition adduct has ever been
observed during the preliminary optimization study. Only
1,4-addition occurred with perfect control of the regioselec-
tivity for the adduct 4a. Furthermore, the water and ethanol
5% v/v system was proved to be the most suitable solvent
for our mode reaction (Table 1, entry 5). Beer also gave the
same results with a diastereoselectivity of 92/8 in favor of
the syn adduct and a perfect enantioselectivity (Table 1, entry
6). Dichloromethane gave similar results, but the reaction
time was longer (Table 1, entry 2). Choloroform and neat
conditions led also to excellent enantioselectivity but lower
diastereoselectivity (Table 1, entry 1 and 3). A decrease of
both diastereo- and enantioselectivities has also been ob-
served when beer was replaced by wine to increase the
alcohol proof (Table 1, entry 6). Subsequently, moderate
results were obtained when the reaction was performed in
ethanol as the solvent (Table 1, entry 8), whereas water
showed to be as suitable as the water and ethanol 5% v/v
system, though isolated yields are slightly lower (Table 1,
entry 7). Moreover, a slight amount of ethanol appeared to
be useful in some cases to solubilize the starting materials.
Further studies showed also that it was possible to decrease
both the quantity of aldehyde 1a (2 equiv) and the amount
of (S)-diphenylprolinol silyl ether 3 (5 mol %) (see Sup-
porting Information). No changes in term of reaction time
or enantioselectivity were observed, only a slight improve-
ment for the diastereoselectivity, since these conditions
afforded the expected product within the same reaction time,
the same enantioselectivity, and a slight improvement of
diastereoselectivity (Table 2, entry 1). With these new
Table 2. Scope of the Reaction: Aldehydes 1a-f
entry
R1
R2
time
yielda (%) drb (syn/anti) eec (%)
1
2
3
iPr
Me
nPr
allyl
Me
H
H
H
H
14 h
10 h
10 h
36 h
4a: 91
4b: 81
4c: 91
4d: 84
4e: 72
4f: 78
94/6
80/20
93/7
52/48
-
>99
96
99
93
68
4
5d
6
Me 5 days
Ph 4 days
Me
95/5
16
a Yield of isolated product after flash column chromatography on SiO2.
b Determined by 1H NMR or chiral SFC of crude product. c Determined by
chiral SFC on the syn adduct. d 10 mol % of catalyst.
optimized conditions in hand, we investigated the scope and
limitations of this reaction by testing phenylnitrodiene 2a
with a variety of aldehydes 1a-f (Table 2).
Thus, unbranched aldehydes such as propionaldehyde 1b,
pentanal 1c, and penten-4-al 1d underwent the 1,4-addition
in excellent yield and excellent enantioselectivities (Table
2, entries 2-4). On the other hand, R-branched aldehydes,
isobutyraldehyde 1e, and 2-phenylpropanal 1f led to good
isolated yield but moderate enantiocontrol (Table 2, entries
5 and 6). It is also interesting to notice that among
unbranched aldehydes, only penten-4-al 1d gave no diaste-
reoselectivity (Table 2, entry 4). We then continued to
evaluate the scope of the reaction by testing the Michael
addition of isovaleraldehyde 1a to various nitrodienes 2a-e
(6) Palomo, C.; Vera, S.; Mielgo, A.; Gomez-Bengoa, E. Angew. Chem.,
Int. Ed 2006, 45, 5984.
(7) Wiesner, M.; Revell, J. F.; Wennemers, H. Angew. Chem., Int. Ed.
2008, 47, 1871.
(8) Zhu, S.; Yu, S.; Ma, D. Angew. Chem., Int. Ed. 2008, 47, 545.
(9) Andrey, O.; Vidonne, A.; Alexakis, A. Tetrahedron Lett. 2003, 44,
7901.
(10) Aslanian, R.; Lee, G.; Iyer, R. V.; Shih, N.-Y.; Piwinski, J. J.;
Draper, R. W.; McPhail, A. T. Tetrahedron: Asymmetry 2000, 11, 3867.
(11) Reyes, E.; Vicario, J. L.; Bad´ıa, D.; Carillo, L. Org. Lett. 2006, 8,
6135.
4558
Org. Lett., Vol. 10, No. 20, 2008

in the presence of 5 mol % of organocatalyst in a mixture
of water and ethanol 5% v/v (Table 3).
Scheme 1. Determination of the Absolute Configuration of 4a
Table 3. Scope of the Reaction: Nitrodienes 2a-e
c
yielda
(%)
drb
(syn/anti)
ee
[c]
entry
R
time
14 h
(%)
1
Ph (2a)
4a: 91
5b: 94
5b: 94
5c: 93
5d: 81
94/6
>99
89
98
98
85
genation of the CdC double bond of the adduct 4a, whose
absolute configuration has to be determined, in the presence
of palladium on charcoal. This could be achieved in good
yield by letting the reaction run under a hydrogen atmosphere
for only 5 min. Through this way and thanks to SFC analysis,
the absolute configuration of 7 could be compared and was
found to be the same, i.e., (R,R).
2
pMeO-Ph (2b) 2 days
pMeO-Ph (2b) 4 days
66/34
72/28
92/8
90/10
88/12
94/6
3d
4
pCl-Ph (2c)
Et (2d)
36 h
8 h
5
6d
7
Et (2d)
c-Hex (2e)
10 days 5d: 78
2 days 5e: 62
a Yield of isolated product after flash column chromatography on SiO2.
b Determined by 1H NMR or chiral SFC of crude product. c Determined by
chiral SFC on the syn adduct. d The reaction was carried out in chloroform.
82
95
The 1,4-adducts, thus obtained through our method, are
interesting building blocks, which can be easily converted
into other compounds by taking advantage of the CdC
double bond. Therefore, we first envisaged to introduce a
new access to tetrahydropyran 9. Therefore, the 1,4-adduct
4a was first converted into the corresponding alcohol 8 in
the presence of NaBH4 in methanol, with a nearly quantita-
tive yield (Scheme 2). Then, the alcohol 8 was treated with
Nitrodiene substituted with electron-rich arene 2b gave the
1,4-adduct 5b in moderate diastereoselectivity and good enan-
tioselectivity in the mixture of water and ethanol 5% v/v (Table
3, entry 2). Selectivities could be improved by carrying out the
reaction in chloroform instead, with however a longer reaction
time (Table 3, entry 3). By testing the addition to nitrodiene
substituted with electron-poor arene 2c, we could observe
excellent yield and selectivities for the adduct 5c (Table 3, entry
4). Aliphatic nitrodienes gave products in good yield and good
diastereoselectivities. In the case of cyclohexyl 2e, excellent
enantioselectivity could be achieved (Table 3, entry 7). With
an ethyl group 2d, the enantioselectivity was good, and we did
not succeed in improving it by performing the reaction in
chloroform. Moreover, the reaction became five times longer
than the reaction in a water and ethanol 5% v/v mixture (Table
3, entries 5 and 6).
Scheme 2. Access to Tetrahydropyran 9
Furthermore, the absolute configuration of the adduct 4a
could be determined by a simple manner. By carrying out
the synthesis of compound 7 through two differents path-
ways, SFC analyses revealed that both products presented
the same absolute configuration (Scheme 1).
PhSeCl at -78 °C to afford the expected tetrahydropyran 9
as a mixture of two major diastereoisomers (Scheme 2).
Those might be converted to C-aryl glycosides, which
constitute a family of natural products of interest.13
The first was the organocatalyzed conjugate addition of
isovaleraldehyde 1a to (E)-(4-nitrobut-3-enyl)benzene 6
leading to the 1,4-adduct 7 whose absolute configuration is
known. Indeed, it has been well established that the addition
of an aldehyde to a nitroolefin gives preferentially the syn
adduct with the (R,R) configuration, thanks to Seebach’s
model.12 The second way consisted of the selective hydro-
Second, we also considered metathesis to take advantage
of our adducts (Scheme 3). As penten-4-al 1d gave poor
results in terms of diastereoselectivity (Table 1, entry 4), we
decided to do the Michael addition with hexen-5-al 1g. We
performed the reaction of this aldehyde to the nitrodiene 2d
substituted by an ethyl group under the previously developed
conditions. The expected adduct 10 was obtained in high
isolated yield and with an excellent enantioselectivity of 95%.
The diastereoselectivity was good in this case (Scheme 3).
(12) (a) Blarer, S. J.; Seebach, D. Chem. Ber. 1983, 116, 3086. (b) Ha¨ner,
R.; Laube, T.; Seebach, D. Chimia 1984, 38, 255. (c) Seebach, D.; Beck,
A. K.; Golinski, J.; Hay, J. N.; Laube, T. HelV. Chim. Acta 1981, 64, 1413.
(d) Seebach, D.; Beck, A. K.; Golinski, J.; Hay, J. N.; Laube, T. HelV.
Chim. Acta 1985, 68, 162.
(13) Hacksell, U.; Daves, G. D. Prog. Med. Chem. 1985, 38, 1280.
Org. Lett., Vol. 10, No. 20, 2008
4559

Scheme 3
.
Metathesis: Access to Substituted Cyclohexene 11
Table 4. Organocatalyzed Conjugate Addition of
Isovaleraldehyde 1a to Phenylnitroeneyne 12
n
x
yielda
drb
eec
entry
1
conditions
equiv mol % 13 (%) (syn/anti) (%)
Then we treated the adduct 10 with Grubbs second
generation14 catalyst in toluene to obtain the corresponding
substituted cyclohexene 11 in excellent yield and without
any loss of enantioselectivity (Scheme 3).
H2O/EtOH 5% v/v;
23 °C
CHCl3/-25 °C
2
5
60
83
83/17
94/6
98
94
2
10
10
a Yield of isolated product after flash column chromatography on SiO2.
b Determined by 1H NMR or chiral SFC of crude product. c Determined by
chiral SFC on the syn adduct.
Finally, to complete the study, we investigated the
feasibility of our reaction, starting from nitro compounds
bearing a triple bond. Therefore, we decided to start from
phenylnitroeneyne 12 and to do the Michael addition of
isovaleraldehyde 1a. After optimization, we found two
suitable methods. The first one has been successfully
developed for the addition of aldehydes 1a-g to nitrodienes
2a-e: 2 equiv of aldehyde, 5 mol % of (S)-diphenylprolinol
silyl ether 3 in a mixture of water and ethanol 5% v/v. This
enabled us to obtain excellent enantioselectivity but moderate
diastereoselectivity for the syn-adduct 13 (Table 4, entry 1).
The second one is “usual” conditions in organocatalysis: 10
equiv of aldehyde 1a, 10 mol % of catalyst in chloroform at
-25 °C. By this way, excellent diastereoselectivity could
be achieved with very good enantioselectivity (Table 4, entry
1). It should be noticed that as for nitrodienes 1,6-addition
has never been observed.
v/v). The Michael adducts were obtained in good yields,
diastereoselectivities up to 94/6, and up to 99% ee in the
case of nitrodienes. This process provides synthetically useful
compounds which can easily lead to both substituted tet-
rahydropyran and cyclohexene. Moreover, the Michael
addition has also been developed for nitroeneyne where the
triple bond of the corresponding adduct appeared to be
interesting. In all cases, only 1,4-addition occurred without
any trace of the 1,6-adduct.
Acknowledgment. We thank the Marie-Curie EST Pro-
gram Indac-Chem (MEST-CT-2005-019780) for financial
support.
In conclusion, we succeeded in developing the asymmetric
organocatalyzed Michael addition of aldehydes to R,ꢀ-γ,δ-
unsaturated nitro compounds. This has been accomplished
using only 5 mol % of (S)-diphenylprolinol silyl ether and 2
equiv of aldehyde in a mixture of ethanol and water (5%
Supporting Information Available: Experimental pro-
cedures, 1H and 13C spectra, and chiral separations for
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
OL801772P
4560
Org. Lett., Vol. 10, No. 20, 2008