P. Melchiorre et al.
are in sharp contrast with the very low dr values (from 1:1
to 2:1) obtained in the same process by using III as the imi-
nium catalyst (see the Supporting Information for details).
The best diastereocontrol was observed for enals that have a
naphthyl b substituent (up to 19:1 dr; Table 2, entries 9 and
10) and by using oxindole that has a benzyl substituent.
Importantly, in many cases the main diastereomer can be
isolated by column chromatography (Table 2, entries 2, 5–7,
and 10). This observation, taken together with the possibility
of obtaining a single diastereomer in almost enantiopure
form after a single crystallization (Table 2, entries 2, 5, 7,
and 10), renders this novel catalytic system a useful synthet-
ic route to valuable chiral scaffolds with contiguous quater-
nary and tertiary stereocenters.
um ion activation of a,b-unsaturated aldehydes. In addition
to expanding the applicability of this class of bifunctional or-
ganocatalysts beyond enamine catalysis, the present study
provides a straightforward solution to the challenging prob-
lem of generating valuable chiral scaffolds with contiguous
quaternary and tertiary stereocenters; a daunting challenge
in asymmetric aminocatalysis. The bifunctional activation
mode of the novel organocatalyst VIa allows the develop-
ment of a previously elusive asymmetric conjugate addition
of oxindoles to enals. Studies towards a more detailed mech-
anistic understanding are ongoing, aimed at further expand-
ing the efficiency and scope of the novel chiral primary
amine thiourea in iminium catalysis.
The relative and absolute configuration of compound 3e
was determined to be 3S,3’R by anomalous dispersion X-ray
crystallography of the corresponding tosylated alcohol 4, ob-
tained by simple aldehyde reduction (Figure 1).[15]
Experimental Section
All of the reactions were carried out in undistilled toluene without any
precautions to exclude water. In a test tube equipped with a magnetic
stirring bar, catalyst VIa (0.02 mmol, 11.1 mg, 10 mol%) was dissolved in
toluene (400 mL). After addition of benzoic acid (0.1 mmol, 12.2 mg,
50 mol%), the solution was stirred for 5 min at room temperature. The
a,b-unsaturated aldehyde 2 (0.3 mmol, 1.5 equiv) was added to the mix-
ture and after being stirred for 10 min, the oxindole derivative
1
(0.20 mmol, 1 equiv) was added in one portion, the tube was capped with
a rubber stopper, and stirring was continued at 238C for the indicated
time (generally 5 days). The crude reaction mixture was diluted with di-
chloromethane/AcOEt (1:1; 1 mL) and flushed through a short plug of
silica gel by using the same mixture as the eluent. The solvent was re-
moved in vacuo, and the residue was purified by flash chromatography to
yield the desired compound 3.
Acknowledgements
Figure 1. X-ray structure of toluene-4-sulfonic acid 4.
The MIUR National Project “Stereoselezione in Sintesi Organica” and
Bologna University are gratefully acknowledged for financial support.
P.M. thanks Dr. Mauro Marigo for fruitful discussions.
Generally, the stereoselective one-step construction of
highly congested products, such as 3, is dependent on the ca-
pability of the catalyst to activate and orient the Michael
donor and the acceptor simultaneously by means of a net-
work of hydrogen-bonding interactions. Modifications of the
catalyst scaffold revealed that the presence of the primary
amine[16] and the thiourea group play an active role during
the catalysis (compare entries 6–8 in Table 1). To gain some
insight into the substrate–catalyst interactions, we ran the
reaction by using catalyst VIa in combination with 50 mol%
of PhCO2H, 2a and the N-methyl oxindole as the nucleo-
phile.[17] The very poor reactivity and selectivity observed
(less than 10% conversion after 5 days; 1.4:1 d.r.) strongly
suggest a direct interaction of the amidic nitrogen in the nu-
cleophilic component with the catalyst. On these grounds, a
plausible bifunctional activation mode of the chiral primary
amine thiourea VIa can be envisaged, in which the thiourea
moiety activates the oxindole, stabilizing its enol form, and
the primary amine activates the unsaturated aldehyde
through iminium ion formation.[18]
Keywords: asymmetric catalysis
· chirality · conjugate
addition · primary amine · thioureas
[1] For recent reviews, see: a) Enantioselective Organocatalysis (Ed.:
P. I. Dalko), Wiley-VCH, Weinheim, 2007; b) A. Dondoni, A. Massi,
4638; for a commentary on the advent of asymmetric organocataly-
[2] For recent reviews on aminocatalysis, see: a) B. List, Synlett 2001,
1687; b) P. Melchiorre, M. Marigo, A. Carlone, G. Bartoli, Angew.
review on enamine catalysis, see: c) S. Mukherjee, J. W. Yang, S.
nium catalysis, see: d) G. Lelais, D. W. C. MacMillan, Aldrichimica
Acta 2006, 39, 79; for a seminal paper on dienamine catalysis, see:
e) S. Bertelsen, M. Marigo, S. Brandes, P. Dinꢂr, K. A. Jørgensen, J.
SOMO catalysis, see: f) T. D. Beeson, A. Mastracchio, J.-B. Hong,
In summary, for the first time, a chiral primary amine
thioACHTUNGTRENNUNGurea catalyst has been successfully applied for the imini-
7848
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 7846 – 7849