Amine-catalyzed cyclizations of tethered α,β-unsaturated carbonyl compounds

Article abstract of DOI:10.1002/anie.200704688

(Chemical Equation Presented) Various linked unsaturated dicarbonyl compounds were cyclized by dienamine catalysis. Depending on the substrates, alternative pathways were observed, leading to mono- and bicyclic products in high enantiomeric excess.

Full text of DOI:10.1002/anie.200704688

Communications
DOI: 10.1002/anie.200704688
Asymmetric Synthesis
Amine-Catalyzed Cyclizations of Tethered a,b-Unsaturated Carbonyl
Compounds**
Renata Marcia de Figueiredo, Roland Fröhlich, and Mathias Christmann*
Dedicated to Professor Thomas R. Hoye
Intramolecular reactions of linked a,b-unsaturated carbonyl
compounds provide an elegant entry to mono- and bicyclic
ring systems. Most cyclizations are initiated by the addition of
electrons,[1] hydride[2] or other nucleophiles[3] to one of the
Michael acceptors and subsequent attack of the activated
species to the other Michael acceptor. If the nucleophile is
eliminated, the overall process is commonly dubbed a
Rauhut–Currier reaction.[4] Moreover, carbene organocata-
lysts[5] have been demonstrated to activate a,b-unsaturated
carbonyl compounds.[6] Scheidt and co-workers have used
carbenes to transform a,b-unsaturated aldehydes into ester
enolate equivalents, which were used in Michael-type cycli-
zations.[7]
catalysts for the activation of saturated and unsaturated
aldehydes.[13]
In their seminal g-amination work, Jørgensen and co-
workers[14] observed the electron-rich dienamine[15] 2 by NMR
spectroscopy. Trapping of this species was possible with
maleimide 3 (Scheme 1) to afford cycloadduct 4, which was
incapable of eliminating the catalyst 1e and therefore
constituted a dead end in a possible catalytic cycle.
Triggered by the enal annulations of Hong and co-
workers,[8] we investigated vinylogous reactivity on tethered
a,b-unsaturated aldehydes by using an organocatalytic[9,10]
approach. Already in the 1970s Yamada et al.[11] used proline
derived vinylogous enamines in stoichiometric asymmetric
Scheme 1. Jørgensen’s [4+2] addition of dieneamine 2 and maleimide
3. T MS=trimethylsilyl.
ꢀ
C C bond-forming reactions. Nowadays, diarylprolinol silyl
ethers (1)[12] have proven to be an excellent class of organo-
At this point it is important to emphasize the mechanistic
complementarity to iminium catalysis. In the latter, small
organic molecules are used to activate the dienophile by
covalent binding, and this concept has been applied success-
fully in intermolecular[16] and intramolecular Diels–Alder
(IMDA) reactions[17] as well as conjugate additions of
preformed dienolates (silylketene acetals) to a,b-unsaturated
aldehydes.[18] Herein, we use an organic catalyst to generate
chiral electron-rich dienes, which in turn direct the facial
approach of the a,b-unsaturated carbonyl moiety.
Our investigations started with dialdehydes 5, which we
previously used in a diversity-oriented synthesis of lepido-
pteran sex pheromones.[19] Assuming that vinylogous enamine
activation is operative (Scheme 2), a rapid IMDA reaction
[*] Dr. R. M. de Figueiredo, Dr. M. Christmann
RWTH Aachen, Institute of Organic Chemistry
Landoltweg 1, 52074 Aachen (Germany)
Fax: (+49)241–8092127
E-mail: christmann@oc.rwth-aachen.de
Homepage: http://134.130.101.5/akenders/christmann/
Christmann.html
Dr. R. Fröhlich[+]
University of Münster
Institute of Organic Chemistry
Corrensstr. 40, 48149 Münster (Germany)
[+] X-ray structure analysis.
[**] We thank the Fonds der Chemischen Industrie (Liebig fellowship to
M.C.), the DFG (SPP1179 Organokatalyse), and Prof. D. Enders for
their support. M. T. Martin is thanked for helpful NMR experiments.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 2. Proposed catalytic cycle for the cyclization of unsaturated
dialdehydes 5.
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Chemie
(6!7) and subsequent elimination of catalyst 1 leads to 8. In a
tentative catalytic cycle, 5 condenses with catalyst 1 to form
the electron-rich diene 6. This intermediate presumably
adopts a conformation that minimizes repulsion with the
bulky aryl substituents and exposes the unshielded face of the
p system to an endo approach of the enal.
mild carboxylic acids as the cocatalyst (Table 2).[21] The data
indicate a strong, but not yet understood correlation between
the pKa value and the reaction rate. Accordingly, the acid
cocatalyst must be involved in an intricate enamine–iminium–
Table 2: Acid screening.
The cycloadduct 7, in contrast to 4, is prone to b-hydride
elimination to regenerate catalyst 1. It is conceivable that a
second catalyst molecule assists this elimination through
formation of an iminium ion with the remaining aldehyde
functionality, either prior to or after the cycloaddition step. In
a preliminary screen, 10 mol% of 1c proved sufficient to
convert the dialdehydes (5) into the bicyclic products 8. The
aldehydes were reduced and converted into the correspond-
ing nitrobenzoates 9a and (not depicted) 9b (Scheme 3).
Their relative and absolute configurations were confirmed by
X-ray crystallographic analysis, and the results support our
stereochemical rationale.
Entry
Acid[a]
pKa
t [h]
ee [%]
1
2
3
4
5
6
none
CH3CO2H
p-MeOC6H4CO2H
C6H5CO2H (BzOH)
p-ClC6H4CO2H
p-NO2C6H4CO2H
–
144
12
12
3
4
2
80[b]
82
84
90
88
4.76
4.47
4.20
3.99
3.44
86
[a] 1c·acid in toluene (0.1m) at room temperature. [b] 50% conversion.
dienamine equilibrium, but it may also play a role in the
activation of the dienophile/Michael acceptor. The reactions
can be run in a variety of solvents with comparable results
(Table 3). Toluene is the preferred solvent over benzene and
halogenated solvents, although chloroform and methylene
chloride led to slightly faster reaction times.
Table 3: Solvent screening.
Entry
Solvent[a]
t [h]
ee [%]
Scheme 3. Crystallography results support the suggested mechanism.
a) NaBH4, EtOH, RT, 85% (87% from 8b); b) 4-NO2C6H4COCl,
pyridine, RT, 100% (80% for 9b).
1
2
3
4
5
6
C6H5CH3
C6H6
CHCl3
CH2Cl2
THF
3
4
2
1
96
5
90
85
86
29
–
67
[b]
Upon this foundation, we investigated reaction parame-
ters such as solvent, catalyst, and acid additive and explored
the substrate scope. In addition to (S)-proline, the cyclization
reaction can be promoted by a variety of diarylprolinol silyl
ethers (Table 1). We found that increasing bulk in the
diarylsilyloxy moiety (1c < 1b; 1c < 1d[20] < 1e) lowers the
reaction rate. Interestingly, hydrogen bond donors in the
catalyst (1a, proline) led to the opposite enantiomer, albeit
with lower selectivity. These findings suggest that precautions
have to be taken to avoid acidic removal of the catalystꢀs silyl
protecting groups in order to prevent erosion of the enantio-
meric excess during the reaction. We therefore screened for
MeCN
[a] 1c·BzOH in solvent (0.1m) at room temperature. [b] No conversion.
Whereas 10a and 10b (Table 4) were accessible in good
yield and high enantioselectivity, larger bicyclic ring systems
(10c) could not be isolated. Compounds 5d and 5e were
chosen to test the limits of position selectivity. It can be
speculated that the rate of dienamine formation determines
the ratio of two regioisomeric products, which is 2:1 for the
methyl derivative 10d and 4:1 for the gem-dimethyl deriva-
tive 10e favoring the less hindered position. Therefore we
conclude that site-specific enamine and iminium formation
remains a difficult task.[22]
The substrates 5 f and 5g each bearing an a-methylene
group,[23] were synthesized by using the Pihko methylena-
tion.[24] In Baldwinꢀs terminology,[25] the intramolecular
Michael addition of 5 f is a disfavored 5-endo-trig process,
whereas the 5-exo-trig vinylogous aldol condensation path-
way is allowed, leading to alkylidenecyclopentene 10 f
(Scheme 4). Alternatively, the formation of 10 f can be
explained by a vinylogous Mannich condensation,[26] which
might also explain the fast 6-exo ring closure to afford 10g.
When one of the aldehyde functions is replaced by an a,b-
unsaturated ketone as the acceptor (12), no formal [4+2]
cycloaddition was observed; instead, a direct enantioselective
vinylogous Michael addition[27] lead to 13 (Scheme 5).[28]
Ketoaldehyde 13 has orthogonal reactive functionality for
subsequent transformations. Organocatalytic cyclization cas-
Table 1: Catalyst screening.
Entry
Catalyst[a]
t [h]
ee [%]
1
2
3
4
5
6
(S)-proline
22
24
20
3
48
2
ꢀ14
ꢀ60[b]
88
90
94
1a
1b
1c
1d
1e
–
[a] Catalyst·BzOH in toluene (0.1m) at room temperature. [b] 50%
conversion.
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Communications
Table 4: Substrate scope.
Entry
Substrate
Product
1[a]
Scheme 5. Intramolecular vinylogous Michael addition. Bz=benzoyl.
Our results complement previous organocatalytic approaches
by installing the transient chiral directing group at the diene
moiety. As a demonstration, novel mono- and bicyclic
scaffolds were synthesized by g-activation of tethered unsa-
turated dicarbonyl precursors. The products were obtained in
good yield and excellent selectivity, and their conversion into
biologically relevant natural products[30] will be reported in
due course.
2[b]
3[b]
4[b]
Received: October 10, 2007
Published online: January 10, 2008
Keywords: aldehydes · cyclization · Diels–Alder reactions ·
.
Michael addition · organocatalysis
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