Urea- and thiourea-substituted cinchona alkaloid derivatives as highly efficient bifunctional organocatalysts for the asymmetric addition of malonate to nitroalkenes: Inversion of configuration at C9 dramatically improves catalyst performance

Article abstract of DOI:10.1002/anie.200501721

(Chemical Equation Presented) Natural not always best: Novel N-aryl urea and thiourea derivatives of dihydrocinchona alkaloids serve as efficient catalysts for the asymmetric addition of dimethyl malonate to a range of nitroalkenes. Catalytic activity and

Full text of DOI:10.1002/anie.200501721

Angewandte
Chemie
Organocatalysis
The ability of chiral urea[11] and thiourea derivatives to
serve as powerful hydrogen-bond-donating organocatalysts
was recently recognized by Jacobsen and co-workers, who
developed a suite of thiourea catalysts that promote a diverse
range of reactions with excellent enantioselectivity.[12] The
compatibility of (thio)ureas with Lewis basic functionality
was also demonstrated recently: Takemoto and co-workers
have introduced the bifunctional catalyst 2, which promotes
Michael-type[13a,b] and aza-Henry[13c] reactions with high
enantioselectivity.[14] Furthermore, we have found that
bisaryl(thio)urea derivatives are significantly more efficient
“mole-per-mole” promoters of the DABCO-catalyzed
Baylis–Hillman reaction than either methanol or water.[15]
We were therefore intrigued by the possibility of modify-
ing the “privileged”[16] cinchona alkaloid structural backbone
by substituting the hydroxy group at C9 with an aryl(thio)urea
moiety with the aim of augmenting the rigidity, tunability, and
hydrogen-bond-donating proclivity of these materials. An
additional advantage associated with this strategy is the
opportunity to examine the (little studied) effect of inversion
of configuration at C9 on catalyst performance. We therefore
prepared 9-(3,5-bistrifluoromethylphenyl)urea derivatives of
dihydroquinine (DHQ) and dihydroquinidine (DHQD)
(DHQU and DHQDU, respectively) together with their C9-
inverted analogues (Scheme 1).[17]
DOI: 10.1002/anie.200501721
Urea- and Thiourea-Substituted Cinchona
Alkaloid Derivatives as Highly Efficient
Bifunctional Organocatalysts for the Asymmetric
Addition of Malonate to Nitroalkenes: Inversion
of Configuration at C9 Dramatically Improves
Catalyst Performance.**
SØamus H. McCooey and Stephen J. Connon*
Inspired by the efficiency, elegance, and selectivity of
enzymatic catalysis, the design of organic molecules capable
of the efficient and enantioselective promotion of carbon–
carbon bond-forming processes is a formidable challenge
which is currently receiving considerable attention.[1] In this
context, one of the fundamental enzymatic catalyst compe-
tencies that is most difficult to engineer in synthetic systems is
bifunctionality;that is, the ability of a catalyst to employ
Lewis/Brønsted acidic and Lewis/Brønsted basic functionality
synergistically to bring about the activation of both the
nucleophilic and electrophilic components of a reaction
simultaneously.[2]
The asymmetric Michael addition of relatively acidic carbon
pronucleophiles (such as malonates) to nitroolefins is an
Over 20 years ago, Wynberg and Hiemstra[3] reported that
cinchona alkaloids were efficient (albeit only moderately
selective) bifunctional organocatalysts for the 1,4-addition of
thiophenol derivatives to cyclohexenones, and proposed
catalyst participation in the deprotonation of the thiol
(through the basic quinuclidine alkaloid nitrogen atom) and
in the stabilization of the enolate resulting from the 1,4-
addition step (through hydrogen bonding with the hydroxy
moiety of the catalyst).[4–6]
À
important C C bond forming reaction that provides access to
synthetically useful enantioenriched nitroalkanes.[18,19] Current
bifunctional organocatalytic systems such as 2[13] and 6’-deme-
thylated quinidine[9] are capable of promoting the reaction with
high enantioselectivity at typical catalyst loadings of 10 mol%,
and efficient metal-based systems (chiral Mg–bisoxazoline[20a,b]
and Ru–amido[20c] complexes at 2–5 mol% loadings) have been
reported which require more stringent control of the reaction
conditions. This reaction therefore seemed to be an ideal test for
the potential activity and selectivity of the novel urea-substi-
tuted cinchona alkaloid structures.
As Wynberg predicted,[3] the derivitization of cinchona
alkaloids[7] with the goal of augmenting hydrogen-bond-
donating ability has resulted in an expansion of catalyst
scope: Hatakeyama and co-workers reported that the rigid
phenolic quinidine derivative 1 promotes highly enantiose-
lective (aza)-Baylis–Hillman reactions,[8] and Deng and co-
workers demonstrated that the readily available 6’-demethyl-
ated quinine and quinidine alkaloids are considerably more
active and selective catalysts for the addition of 1,3-dicarbon-
yl compounds to b-nitrostyrenes than their natural 6’-methyl-
ated analogues.[9,10]
The results of initial investigations into the addition of
dimethyl malonate to (E)-b-nitrostyrene (3) catalyzed by
cinchona alkaloid derivatives are presented in Table 1. Initial
screening studies identified toluene as the optimal solvent for
the reaction. The urea-substituted analogues (DHQU and
DHQDU) with the stereochemistry of the “natural” cinchona
alkaloid were more-selective albeit significantly less-active
catalysts than their respective dihydroalkaloid precursors
DHQ and DHQD (Table 1, entries 1, 3 and 4, 5) at room
temperature. Gratifyingly, the C9 diastereoisomers of these
materials (9-epi-DHQU and 9-epi-DHQDU, Figure 1)[21]
exhibited decidedly superior activity and enantioselectivity
(Table 1, entries 6–8);and gave complete conversion of 3 into
nitroalkane 4 with high enantioselectivity at room temper-
ature in the presence of only 2 mol% of catalyst. Further
improvement was observed upon the synthesis and evaluation
of their thiourea analogues (9-epi-DHQTand 9-epi-DHQDT,
Figure 1). Below ambient temperature, 4 could be generated
with quantitative conversion and excellent enantioselectivity
(Table 1, entries 9–11) at low catalyst loadings. It is note-
worthy that inversion of the absolute configuration at C9 in
[*] S. H. McCooey, Dr. S. J. Connon
Centre for Synthesis and Chemical Biology
Department of Chemistry
Trinity College, University of Dublin
Dublin 2 (Ireland)
Fax: (+353)1-671-2826
E-mail: connons@tcd.ie
[**] Financial support from the Irish Research Council for Science
Engineering and Technology isgratefully acknowledged. We would
like to thank TopChem Laboratories Ltd. and the Gunnlaugsson
group (TCD) for the use of their equipment.
Supporting information for thisarticle isavailable on the WWW
under http://www.angewandte.org or from the author.
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these (thio)urea-substituted systems dra-
matically improves catalyst activity and
selectivity without altering the sense of
stereoinduction observed, that is, 9-epi-
DHQU and 9-epi-DHQT promote the
formation of the same antipode of 4 as
DHQU (and DHQ), whereas 9-epi-
DHQDU furnishes the same product
enantiomer as DHQDU (and DHQD).
This is in marked contrast to the
relative performance of the hydroxy-sub-
stituted DHQ and 9-epi-DHQ: epimeri-
zation of C9 of the parent dihydroalkaloid
led to a marginal increase in enantiose-
lectivity (with inversion of the sense of
stereoinduction) and a significant reduc-
tion of catalyst activity (Table 1, entries 1
and 2). It is therefore clear that although
neither inversion of the C9 stereocenter
nor (thio)urea substitution alone endow
the parent alkaloids DHQ and DHQD
with significantly improved catalytic
properties (in the context of the addition
reaction studied), a combination of both
modifications results in a remarkable
enhancement of catalyst efficacy and
enantioselectivity.
We then turned our attention to the
question of catalyst scope. The use of
either 9-epi-DHQT or 9-epi-DHQDT
allowed the conversion of both activated
(6–8) and deactivated (9–11) b-nitrostyr-
enes (Table 2, entries 1–10) into their
corresponding Michael adducts 14–19 in
Scheme 1. Modified cinchona alkaloid derivatives.
excellent yields (91–95%) and enantiose-
lectivities (87–99% ee) at convenient reaction temperatures
between ambient temperature and À208C. Although we did
not observe a strong correlation between the electronic
properties of the substrate and the enantiopurity of the
product, in general, relatively deactivated olefins gave rise to
products of marginally higher enantiopurity than more-
electrophilic analogues. Alkyl-substituted nitroolefins were
also found to be compatible with 9-epi-DHQT;the unhin-
dered 12 proved unproblematic and even the traditionally
challenging substrate 13 (which is inert towards a binary
bifunctional catalyst system, Table 2, entry 13)[22] underwent
conversion into 21 with attenuated enantioselectivity
(75% ee).
9-epi-DHQT and 9-epi-DHQDT are characterized by
excellent catalytic activity at 2–5 mol% loadings and con-
venient reaction temperatures, and are also comparable in
terms of efficacy, scope, and enantioselectivity to benchmark
metal-based systems.[20] At higher concentrations catalytic
asymmetric addition can be conveniently carried out at
unprecedented catalyst loadings without compromising
either efficiency or enantioselectivity, as exemplified by the
synthesis of 16 from 8 in excellent yield and enantioselectivity
promoted by 9-epi-DHQT (0.5 mol%) at 08C (Scheme 2,
compare with Table 2, entry 4).
Table 1: Catalyst evaluation in the addition of dimethyl malonate to 3.
Entry
Catalyst
mol%
t
[h]
Conv.
[%][a]
ee
Product
config.[c]
[%][b]
1
2
3
4
5
6
7
8
9
DHQ
9-epi-DHQ
DHQD
DHQU
DHQDU
9-epi-DHQU
9-epi-DHQU
9-epi-DHQDU
9-epi-DHQT
9-epi-DHQDT
9-epi-DHQT
5
5
5
5
5
5
2
2
2
2
2
24
>98
46
>98
26
12
18
1
(S)
(R)
(R)
(S)
(R)
(S)
(S)
(R)
(S)
(R)
(S)
144
24
24
144
5
24
30
24
30
30
25
17
74
88
79
90
85
99[e]
25
>98
>98
>98
>98
>98
>98[d]
10
11
[a] Determined by 1H NMR spectroscopy. [b] Determined by chiral
stationary phase (CSP)-HPLC (see Supporting Information). [c] Absolute
configuration asdetermined by comparison with literature CSP-HPLC
retention timesand optical rotation data (references[9] and [13a]).
[d] 93% yield of isolated product. [e] Reaction at À208C.
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Table 2: Catalyst scope for the the conversion of both activated and deactivated b-nitrostyrenes.
contact with the large catalyst sub-
stituents, thus allowing the proxi-
mal Brønsted basic aliphatic het-
erocycle to bring about enolate
generation at the Si face of the
electrophile, leading to the forma-
tion of (S)-4 (Figure 1, B and
Table 1, entry 7).
Entry
Substr.
R
Catalyst
mol%
T
[8C]
t
[h]
Prod.
Yield
[%][a]
ee
[%][b]
A similar MM2 examination of
DHQU identifies C as the mini-
mum-energy conformer, which
would clearly be ill suited to
efficient bifunctional catalysis
and would be expected to furnish
the opposite enantiomer to that
observed experimentally (Figure 1,
C and Table 1, entry 4,). We there-
fore propose that bifunctional cat-
alysis involving DHQU may pro-
1
2
3
4
5
6
7
8
9
10
11
12
13
6
6
6
7
8
4-BrC6H4
4-BrC6H4
4-BrC6H4
2-NO2C6H4
2-thienyl
2-MeC6H4
2-MeC6H4
1-naphthyl
4-MeOC6H4
4-MeC6H4
n-hexyl
9-epi-DHQT
9-epi-DHQT
9-epi-DHQDT
9-epi-DHQT
9-epi-DHQT
9-epi-DHQT
9-epi-DHQT
9-epi-DHQT
9-epi-DHQT
9-epi-DHQDT
9-epi-DHQT
9-epi-DHQT
quinuclidine[c]
2
2
2
2
2
5
5
2
5
5
5
5
20
20
17
14
14
14
15
16
17
17
18
19
19
20
21
21
92
94
80
91
94
93
95
94
92
90
88
63
0
87
93
93
90
95
93
94
93
99
91
86
75
–
À20
À20
À20
À20
20
40
55
69
23
25
30
31
30
38
69
147
72
9
9
0
0
0
0
10
11
11
12
13
13
À20
cyclohexyl
cyclohexyl
20
ceed predominantly through
a
20
minor conformer represented by
D, in which the bifunctional cata-
lyst components are more suitably
[a] Refersto the yield of the isolated product after column chromatography. [b] Determined by CSP-
HPLC (see Supporting Information).
oriented to cooperate catalytically and to generate the
product enantiomer observed. The catalyst components,
however, are still poorly situated relative to the catalytically
active components of 9-epi-DHQU in terms of both prox-
imity of the quinuclidine ring to the aryl urea and the ability
of the catalyst to bind the nitroalkene selectively.[26]
In summary we have developed a new class of highly
active and selective (thio)urea-substituted cinchona alkaloid
based catalysts for the addition of dimethyl malonate to
nitroalkenes. A systematic investigation into the effects of the
relative stereochemistry at C8 and C9 of these materials on
catalyst performance has implicated bifunctional catalysis and
revealed that C9 epimeric catalysts are remarkably more
efficacious in terms of rate and selectivity than analogues of
Scheme 2. Catalysis by 9-epi-DHQT at low catalyst loading.
The dependence of catalytic efficiency and selectivity on
both the presence of (thio)urea functionality and the relative
stereochemistry at C8/C9 strongly implies that these modified
cinchona alkaloid systems operate through a bifunctional
mechanism, that is, quinuclidine-
moiety-assisted generation of the de-
protonated malonate nucleophile and
its addition to a single face of the
(thio)urea-bound nitroolefin electro-
phile. A preliminary selectivity prin-
ciple based on the results presented in
Table 1 is outlined in Figure 1. An
examination of models and MM2
calculations[23] indicate that A is a
reasonable representation of the least
strained conformation of the active
and selective catalyst 9-epi-DHQU in
which the bulky alkyl groups at the C9
stereogenic centre avoid steric inter-
actions with each other and with the
carbonyl group of the urea function-
ality.[24] In this conformation it would
be expected that the nitroolefin would
Figure 1. Selectivity model. A: Proposed catalytically active conformation of 9-epi-DHQU (MM2). B: Possible
pre-TS assembly for enantioselective addition to 3 promoted by 9-epi-DHQU. C: Proposed lowest energy con-
formation (MM2) of DHQU. D: Proposed catalytically active conformation of DHQU. E: Possible pre-TS
bind (through both oxygen atoms)[25]
as shown in pretransition state (TS)
assembly B (Figure 1) to minimize assembly for addition to 3 promoted by DHQU.
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[13] a) T. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003,
125, 12672;b) T. Okino, Y. Hoashi, T. Furukawa, X. Xu, Y.
Takemoto, J. Am. Chem. Soc. 2005, 127, 119;c) T. Okino, S.
Nakamura, T. Furukawa, Y. Takemoto, Org. Lett. 2004, 6, 625.
[14] For recent applications of 2 (and modified derivatives) in kinetic
resolution, see: a) A. Berkessel, F. Cleemann, S. Mukherjee,
T. N. Müller, J. Lex, Angew. Chem. 2005, 117, 817; Angew. Chem.
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[16] T. P. Yoon, E. N. Jacobsen, Science 2003, 299, 1691.
[17] While this manuscript was being prepared, two reports detailing
a similar strategy have appeared: a) for a report disclosing the
synthesis of two C-1,2-didehydro cinchonidine/chinchonine-
derived variants of 9-epi-DHQT (amongst others) which
promoted the efficient addition to thiophenol to a-b-unsaturated
imides with low selectivity (up to 17% ee), see: B.-J. Li, L. Jiang,
M. Liu, Y.-C. Chen, L.-S. Ding, Y. Wu, Synlett, 2005, 603;b) 9-
epi-DHQT and C-1,2-didehydro analogues have been prepared
for use in the efficient enantioselective addition of nitromethane
to chalcones, and a clear dependence of catalyst activity and
selectivity on the relative stereochemistry at C8/C9 has been
“natural” cinchona alkaloid stereochemistry. Highly active 9-
epi-DHQT and 9-epi-DHQDT (which are readily available
from DHQ and DHQD - see Supporting Information) have
been identified as efficient and enantioselective catalysts with
substrate-scope and selectivity profiles on a par with current
benchmark literature systems and can be conveniently
employed at relatively low catalyst loadings (0.5–5 mol%).
Studies to determine the solution-state structure of these
materials and to explore their potential as promoters of a
variety of reactions susceptible to the influence of bifunc-
tional catalysis are underway.
Received: May 19, 2005
Published online: September 1, 2005
Keywords: asymmetric catalysis · cinchona alkaloids ·
.
Michael addition · organocatalysis · ureas
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[21] The prefix “epi” usually refers only to inversion of configuration
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catalyst at C8/C9.
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[22] To the best of our knowledge only Deng et al. (ref. [9]) have thus
far successfully selectively converted this hindered substrate by
using 20 mol% 6’-demethylated quinine.
[23] MM2 force-field energy-minimization calculations were carried
out with CS Chem3D Std v.4.0 software. Conformers were
minimized to a minimum RMS gradient of 0.02.
[24] The catalysts were obtained as amorphous solids, and several
attempts to recrystallize these materials were unsuccessful.
Conformation A is in very good agreement with structural data
associated with other (thio)urea-based catalysts in the literature
which incorporate a chiral methine group adjacent to the
(thio)urea functionality.[12e, 13b]
.
[25] B. J. Hay, T. K. Firman, B. A. Moyer, J. Am. Chem. Soc. 2005,
127, 1810.
[26] This would account for the observed product stereochemistry,
and the decrease in catalyst efficiency and selectivity associated
with DHQU relative to 9-epi-DHQU. However, it is acknowl-
edged that alternative rationales are possible, for example,
reversal of binding selectivity relative to 9-epi-DHQU, etc. It is
envisaged that ongoing structural studies will provide more
detailed insight into the catalytic behaviour of these C9
diastereomers.
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