Asymmetrie iminium ion catalysis with a novel bifunctional primary amine thiourea: Controlling adjacent quaternary and tertiary stereocenters

Article abstract of DOI:10.1002/chem.200802466

The development of a new bifunctional chiral primary amine thiourea catalyst and its application in the first asymmetric conjugate addition of oxindoles to enales was described. The reaction between 3-methyl oxindole and cinnamaldehyde, a combination of simple and readily available starting materials that targets in organic synthesis, was selected. The poor catalytic performance and the very low selectivity observed suggest a critical role of the thiourea moiety during the steroselective C-C bond-forming step. It is also found that by using 50% of benzoic acid, the catalyst loading is reduced to 10%, while still maintaining high diastero and enantiocontrol, and significant reactivity. The best diasterocontrol is observed for enals that have a naphthyl β substituted and by using oxindole that has a benzyl substitute.

Full text of DOI:10.1002/chem.200802466

DOI: 10.1002/chem.200802466
Asymmetric Iminium Ion Catalysis with a Novel Bifunctional Primary Amine
Thiourea: Controlling Adjacent Quaternary and Tertiary Stereocenters
Patrizia Galzerano, Giorgio Bencivenni, Fabio Pesciaioli, Andrea Mazzanti,
Berardino Giannichi, Letizia Sambri, Giuseppe Bartoli, and Paolo Melchiorre*[a]
Dedicated to the Centenary of the Italian Chemical Society
The development of novel and highly enantioselective
transformations is one of the most exciting goals for organic
chemists involved in the competitive and stimulating field of
asymmetric organocatalysis.[1] In this area, the remarkable
advances in the application of chiral secondary amine cata-
lysts (asymmetric aminocatalysis)[2a,b] are linked with the ac-
cessibility of divergent carbonyl activation modes, through
either nucleophilic enamine[2c] or dienamine[2e] intermedi-
ates, electrophilic iminium ions[2d] or even radical[2f] inter-
mediates. In particular, the incredibly high efficiency and
generality demonstrated by some “privileged” organocata-
lysts such as proline[3a] (I) or the synthetic MacMillan imid-
aminocatalysis as a reliable and powerful synthetic tool for
the chemo- and enantioselective functionalization of carbon-
yl compounds.[2] These general and readily available cata-
lysts represent an important starting point for the investiga-
tions of new asymmetric processes because they often avoid
the need for multiple screening processes of catalysts to de-
termine the optimal reaction conditions. However, because
aminocatalysis may face problems of increasing complexity
and diversity, the privileged catalysts might not always be
the best candidates to solve some specific and challenging
tasks (Scheme 1). In this context, the stereocontrolled conju-
gate addition of prochiral trisubstituted carbon nucleophiles
to a,b-unsaturated aldehydes through iminium activation
still represents a daunting synthetic challenge[4] because the
privileged catalysts generally allow the formation of prod-
ucts with high enantioselectivity but with poor diastereocon-
trol.[5]
ACHTUNGTRENNUNGazACHTUNGTRENNUNG
olidinones[2d] (II) and the silyl-protected diarylprolinols
catalysts[3b] (III) (Scheme 1) have consolidated asymmetric
Herein, we describe the development of a new bifunction-
al chiral primary amine thiourea catalyst and its application
in the first asymmetric conjugate addition of oxindoles to
enals. A bifunctional catalyst was chosen because it was
thought that only concomitant and synergistic activation of
both the reacting partners may enforce high diastereocon-
À
trol during C C bond formation. The high levels of both
enantio- and diastereoselectivity achieved demonstrate the
ability of the catalyst to provide a solution to the challeng-
ing problem of generating valuable chiral scaffolds with con-
tiguous quaternary and tertiary stereocenters.[6] Moreover,
we demonstrated for the first time that chiral primary amine
thiourea catalysts, which during the last two years have been
successfully applied in many enamine-based asymmetric
transformations expanding the synthetic potential of amino-
catalysis,[7] can also be effective for iminium ion activation
of a,b-unsaturated aldehydes.
Scheme 1. The privileged catalysts I, II, and III. Illustration of the chal-
lenging task of creating adjacent stereocenters by iminium ion catalysis.
[a] P. Galzerano, Dr. G. Bencivenni, F. Pesciaioli, Dr. A. Mazzanti,
B. Giannichi, Dr. L. Sambri, Prof. G. Bartoli, Dr. P. Melchiorre
Dipartimento di Chimica Organica “A. Mangini”
Alma Mater Studiorum, Universitꢀ di Bologna
Viale Risorgimento 4, 40136 Bologna (Italy)
Fax : (+39)051-209-3654
For exploratory studies, we selected the reaction between
3-methyl oxindole (1a) and cinnamaldehyde (2a), a combi-
nation of simple and readily available starting materials that
E-mail: p.melchiorre@unibo.it
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802466.
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Chem. Eur. J. 2009, 15, 7846 – 7849

COMMUNICATION
would readily give access to structurally complex oxindole
3a with a quaternary stereogenic center at C3 (Table 1).[8,9]
Chiral 3,3-disubstituted oxindole frameworks are attractive
in a variety of enamine-based transformations has been re-
cently established.[7] This fact, together with the potential
application of this catalyst architecture in iminium activa-
tion,[10] even of simple a,b-unsaturated aldehydes,[11] led us
to perform an extensive screen of chiral primary amines in-
corporating a thiourea framework, which led to the identifi-
cation of VIa as a promising iminium catalyst. The newly
synthesized catalyst VIa, readily accessible through a one-
step synthesis from commercially available compounds,[12]
induced a high level of stereocontrol with good catalytic ac-
tivity (Table 1, entry 6). The poor catalytic performance and
the very low selectivity observed with VIb and VIc suggest-
ed a critical role of the thiourea moiety during the stereose-
Table 1. Optimization studies.[a]
À
lective C C bond-forming step (Table 1, entries 7 and 8).
Further optimization experiments (see the Supporting Infor-
mation for details) revealed that the nature and the amount
of the acidic additive were crucial parameters to obtain high
levels of stereoselectivity and reaction efficiency. By using
50 mol% of benzoic acid,[13] the catalyst loading was re-
duced to 10 mol%, while still maintaining high diastereo-
and enantiocontrol, and significant reactivity (Table 1,
entry 10).
Entry Catalyst Additive [mol%]
Conv[b]
[%]
dr[c]
[%]
ee[d]
[%]
1
I
none
<5
53
>95
–
–
5
92
2
II
III
DCA (20)
pNO2-C6H4CO2H
(20)
1.1:1
1.1:1
3[e]
As summarized in Table 2, under the optimized condi-
tions, the conjugate addition of oxindoles to enals catalyzed
by 10 mol% of VIa displays a broad scope.
4
5
6
7
8
IV
pNO2-C6H4CO2H
(20)
pNO2-C6H4CO2H
(20)
pNO2-C6H4CO2H
(20)
pNO2-C6H4CO2H
(40)
>95
84
1:1
7
2
V
1:1
Table 2. Diastereo- and enantioselective conjugate addition of oxindoles
VIa
VIb
VIc
55
4.5:1
–
84
–
to enals catalyzed by VIa.[a]
<5
20
pNO2-C6H4CO2H
(20)
1.2:1
40
9
VIa
VIa
PhCO2H (20)
PhCO2H (50)
51
35
6:1
7:1
90
90
10[f]
Entry R1, R2
Ar
3
Yield[b] [%] dr[c] [%] ee[d] [%]
[a] For studies on additional additives and reaction conditions, see the
Supporting Information. DCA: dichloroacetic acid. [b] Conversion, deter-
1
2
Me, H
Bn, H
Bu, H
Ph
Ph
Ph
a
b
c
d
e
f
g
h
i
71
7:1
7:1
5:1
90
92 (>99)
73
1
73[e] (59)
65
mined by H NMR spectroscopy analysis of the crude mixture. [c] Diaste-
reomeric ratio (dr), determined by 1H NMR spectroscopy analysis of the
crude mixture. [d] Enantiomeric excess (ee), determined by chiral HPLC
analysis. [e] Reaction carried out at À108C in AcOEt as the solvent for
66 h. [f] 10 mol% of VIa was used.
3[f]
4
Bn, Me Ph
55
5:1
81
5
Me, H
Bn, H
Bn, H
Bn, H
Me, H
Bn, H
p-NO2-C6H4
70 (56)
7.5:1
11.5:1
5.7:1
12:1
13.2:1
>19:1
88 (>99)
93
85 (97)
83
80
89 (>99)
6[f]
7
p-NO2-C6H4
p-Cl-C6H4
p-CN-C6H4
naphthyl
47[e]
85[e] (77)
56
8[f]
9[f]
10[f]
71
55[e] (49)
targets in organic synthesis because of their promising bio-
logical activities,[9a,b] as well as their wide-ranging utility as
synthetic intermediates for alkaloids, drug candidates, and
clinical pharmaceuticals.[9b,c] The use of the privileged secon-
dary amines I and II as iminium catalysts of this challenging
reaction afforded poor results, whereas the silyl-protected
diarylprolinol III provided very high enantioselectivity, al-
though an almost 1:1 mixture of the two diastereomers was
formed (Table 1, entries 1–3). This evidence supports the
lack of substrate-controlled stereoselectivity in the process.
We speculated that a key factor to improve the stereocon-
trol of the process might be to use a bifunctional catalyst ca-
pable of synergistically arranging and activating both of the
reagents. The ability of primary amine thiourea catalysts to
induce high stereocontrol through a cooperative mechanism
naphthyl
j
[a] Unless noted, the reactions were carried out on a 0.2 mmol scale with
1.5 equiv of 2 and [1]0 =0.5m in toluene for 5 days in the presence of
10 mol% of VIa and 50 mol% of PhCO2H. [b] Isolated yield (sum of dia-
stereomers). The yield of the single major diastereomer obtained after a
single crystallization is given in brackets. [c] Determined by 1H NMR
spectroscopy of the crude mixture. [d] Determined by chiral HPLC anal-
ysis. The values in parenthesis are the ee values obtained after a single
crystallization. [e] Yield refers to the single major diastereoisomer ob-
tained after chromatography. [f] The ee value determined on the corre-
sponding alcohols after reduction with NaBH4.
High enantioselectivity and useful levels of diastereoselec-
tivity were obtained with different combinations of substi-
tuted oxindoles and a variety of aldehydes.[14] These results
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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
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Stereoselective Addition
COMMUNICATION
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[12] Both enantiomers of VIa are easily accessible from a single-step
synthesis, see the Supporting Information.
[13] It is likely that the acid serves to facilitate catalyst turnover by pro-
moting iminium formation/imine hydrolysis; for similar effects with
primary amine thiourea catalysts in enamine catalysis, see referen-
ces [7b,c].
[14] Enals with alkyl b substituents afforded poor results; for example,
crotonaldehyde (2.3:1 dr; 24% ee); the presence of a chlorine on
the oxindole scaffold (R2 =Cl) led to a decreased stereoselectivity in
the reaction with 2a (1.5:1 dr; 11% ee).
[15] CCDC-710802 (4) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif
[16] Replacement of the primary amine moiety with a tertiary one
(NMe2) in the catalyst scaffold led to a complete loss of catalytic ac-
tivity and this evidence ruled out possible activation of the nucleo-
phile through chiral Brønsted base catalysis.
[17] The employment of the N-Boc protected oxindole under the best re-
action conditions afforded low stereocontrol, albeit with improved
reactivity (18 h; >95% conversion; 2:1 dr; 67% ee).
[18] The presence of the primary amine is crucial for the catalytic activi-
ty, see reference [16]; at this stage of the investigations a plausible
Brønsted acid activation of unsaturated aldehydes cannot be ruled
out.
Received: November 25, 2008
Published online: January 29, 2009
Chem. Eur. J. 2009, 15, 7846 – 7849
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7849