Design of structurally rigid trans -diamine-based Tf-amide organocatalysts with a dihydroanthracene framework for asymmetric conjugate additions of heterosubstituted aldehydes to vinyl sulfones

Article abstract of DOI:10.1021/ja107897t

Asymmetric conjugate addition of α-heterosubstituted aldehydes such as α-amido and α-alkoxy aldehydes to vinyl sulfone was effected under the influence of structurally rigid trans-diamine-based Tf-amido organocatalyst (S,S)-2 with a dihydroanthracene fram

Full text of DOI:10.1021/ja107897t

Published on Web 11/15/2010
Design of Structurally Rigid trans-Diamine-Based Tf-Amide Organocatalysts
with a Dihydroanthracene Framework for Asymmetric Conjugate Additions of
Heterosubstituted Aldehydes to Vinyl Sulfones
Shin A. Moteki, Senmiao Xu, Satoru Arimitsu, and Keiji Maruoka*
Laboratory of Synthetic Organic Chemistry and Special Laboratory of Organocatalytic Chemistry, Department of
Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo, Kyoto 606-8502, Japan
Received September 2, 2010; E-mail: maruoka@kuchem.kyoto-u.ac.jp
Scheme 1. Synthesis of Catalyst (S,S)-2a
Abstract: Asymmetric conjugate addition of R-heterosubstituted
aldehydes such as R-amido and R-alkoxy aldehydes to vinyl sulfone
was effected under the influence of structurally rigid trans-diamine-
based Tf-amido organocatalyst (S,S)-2 with a dihydroanthracene
framework to furnish R,R-dialkyl(amido)aldehydes and R,R-dialkyl-
(alkoxy)aldehydes with high enantioselectivity. The chiral efficiency
of the structurally unique catalyst (S,S)-2 is apparent in comparison
with (S,S)-1 and (S,S)-4 with similar functionality.
a Reagents and conditions: (a) fumaryl chloride, toluene reflux; (b) (i)
aq. NaN3/toluene, 0 °C; (ii) toluene reflux, then conc. HCl; (iii) aq. NaOH
(56% overall yield); (c) (i) (-)-mandelic acid, MeOH; (ii) aq. NaOH (36%
yield, >99% ee); (d) (i) conc. HCl, (ii) Cbz-Cl, aq. NaOH, MeOH, 0 °C
(83% yield); (e) Tf2O, Et3N, CH2Cl2, -78 °C; Pd/C, H2, MeOH, room temp
(93% yield).
Asymmetric aminocatalysis has been recognized as one of the most
fundamental, yet important reactions in the field of asymmetric
organocatalysis.1 In such asymmetric aminocatalysis, the use of chiral
secondary amine catalysts including proline-derived ones has proven
to be an extremely powerful approach.1b In recent years, primary amine
catalysis using primary amino acids and chiral trans-1,2-cyclohex-
anediamine-derived organocatalysts (e.g., 1) has emerged as a comple-
mentary tool for activating sterically demanding carbonyl substrates,
because of its advantage over chiral secondary amine catalysis.2,3 In
this context, we are interested in designing a structurally rigid, chiral
trans-1,2-cyclohexanediamine-derived organocatalyst of type 2 with
a 9,10-dihydroanthracene subunit in order to shield one side of the
catalyst more efficiently than catalysts 1 and 4 which have similar
functionality. The chiral, bifunctional organocatalyst 2 would be highly
effective for remotely controlled transformations like asymmetric
conjugate additions. Here we wish to report the asymmetric conjugate
addition of R-heterosubstituted aldehydes such as R-amido and
R-alkoxy aldehydes under the influence of structurally unique orga-
nocatalyst 2 to create asymmetric quaternary carbon centers. This
asymmetric transformation has broad substrate generality and provides
general access to the asymmetric synthesis of structurally diverse R,R-
dialkylamino aldehydes, since starting R-amido aldehydes are readily
available from a wide variety of both natural and unnatural R-amino
acids in addition to R-amino nitriles.4
Attempted asymmetric conjugate addition of N-Boc R-aminophe-
nylacetaldehyde 5a6 to 1,1-bis(benzenesulfonyl)-ethylene7 in tolu-
ene in the presence of catalyst (S,S)-2 gave rise to conjugate adduct
6a in 90% yield with 86% ee (entry 1 in Table 1). Use of HCl as
Table 1. Screening of Reaction Conditions for Asymmetric
Conjugate Addition of Heterosubstituted Aldehydesa
time
(h)
%
yieldb
%
eec
entry
catalyst
additive
1
2
3
4
5
6
7
8
(S,S)-2
(S,S)-2
(S,S)-3
(S,S)-3
(S,S)-4
(S,S)-1
(S,S)-2
(S,S)-2
(S,S)-2
(S,S)-2
(S,S)-2
(S,S)-2
(S,S)-2
(S,S)-2
(S,S)-2
(S,S)-2
(S,S)-2
none
HCl
HCl
HCld
HCl
HCl
CF3CO2H
TfOH
PhCO2H
4-(NO2)C6H4CO2H
3-(NO2)C6H4CO2H
2-(NO2)C6H4CO2H
2,6-(NO2)2C6H3CO2H
2-(OH)C6H4CO2H
2,6-(OH)2C6H3CO2H
2,6-(OH)2C6H3CO2H
2,6-(CH3)2C6H3CO2H
24
3
24
24
2
24
3
12
24
36
12
10
0.5
20
0.5
12
60
90
96
98
84
72
58
99
90
94
86
99
96
98
96
99
98
82
86
91
71
60
1
0
89
92
79
76
75
79
93
75
93
95
71
9
10
11
12
13
14
15
16e
17
a Unless otherwise specified, asymmetric conjugate addition of
heterosubstituted aldehydes and 1,1-bis(benzenesulfonyl)ethylene in the
presence of 10 mol % of catalyst (S,S)-1-4 and 10 mol % of additive in
toluene at room temperature under the given conditions. b Isolated yield.
c Enantiopurity of conjugate adducts was determined by HPLC analysis
using a chiral column with hexane-isopropyl alcohol as solvent (see
Supporting Information). d 20 mol % of additive. e At -20 °C.
The requisite catalyst (S,S)-2 can be easily prepared by a
Diels-Alder reaction of fumaryl chloride with anthracene and
subsequent transformations as shown in Scheme 1.5
9
17074 J. AM. CHEM. SOC. 2010, 132, 17074–17076
10.1021/ja107897t  2010 American Chemical Society

C O M M U N I C A T I O N S
an additive enhanced both reactivity and selectivity (entry 2).
However, diamine hydrochloride, (S,S)-3•HCl, and (S,S)-3•(HCl)2
lowered the enantioselectivity (entries 3-4). Notably, amino Tf-
amide catalysts of type (S,S)-1 and (S,S)-4 totally lost the enanti-
oselection (entries 5-6). Additional optimizations with regard to
additives led to the reaction conditions using 2,6-dinitro- and 2,6-
dihydroxybenzoic acid as additives (entries 7-17), and by using
these additives, conjugate adduct 6a was obtained with a short
reaction time with 93% ee (entries 13 and 15). Further, 95% ee
was achieved by lowering the reaction temperature (entry 16).
With the optimized conditions in hand, we investigated the scope
of this asymmetric conjugate addition using R-heterosubstituted
aldehydes and vinyl sulfone as shown in Table 2. As for the
R-amino-substituted aldehydes 5a-e possessing the different sub-
stituent pattern of aromatic groups, m- and p-electron-donating
substituents, as well as the fused ring and the electron-withdrawing
group, were all tolerated, providing the corresponding conjugated
adducts 6a-e with uniformly high selectivity (entries 1-5). In the
case of R-amino-substituted aliphatic aldehydes 5f-g having sec-
and tert-alkyl groups, the reaction provided the conjugated adducts
6f-g consistently with 94% ee (entries 6 and 7). Whereas the
reaction with benzyl-substituted aldehyde 5h resulted in moderately
high enantioselectivity (entry 8), use of methyl-substituted analogue
5i furnished the conjugate adduct 6i with 81% ee (entry 9). In
general, the conjugate addition of R-amino-R-alkyl-substituted
aldehydes 5f-i proceeded slowly at -20 °C and required room
temperature (entries 6-9).8 Other substituted aldehydes such as
R-oxy and R-methyl aldehydes 5j-k7b were also employable with
high enantioselectivities (entries 10-12).
The absolute stereochemistry of the conjugate adduct 6a was
unambiguously determined to be S by conversion to the known
(S)-2-amino-2-phenyl-1-butanol as shown in the Supporting
Information.9 Based on the absolute configuration of (S)-6a, a
possible transition state model has been proposed as shown in
Figure 1 to account for the observed absolute configuration of
conjugate adduct 6a. In the generation of Z-enamine derived
from N-Boc R-aminophenylacetaldehyde 5a and the catalyst
(S,S)-2 under the experimental conditions, the Z-enamine 9 would
be stabilized by the hydrogen bonding between the ammonium
hydrogen and N-Boc group. Here, ArCO2- as an additive would
effectively shield the backside of 9. Then, 1,1-bis(benzenesulfo-
nyl)ethylene might approach from the upper side via additional
hydrogen bonding of a sulfonyl group with the Tf-amide
hydrogen, leading to conjugate adduct 6a with the observed S
configuration.
Table 2. Asymmetric Conjugate Addition of Heterosubstituted
Aldehydes Catalyzed by (S,S)-2a
Figure 1. A possible transition state structure.
In summary, we have succeeded in the asymmetric conjugate
addition of heterosubstituted aldehydes such as R-amido and
R-alkoxy aldehydes under the influence of structurally unique
organocatalyst 2. This strategy is, in principle, applicable to other
catalytic systems, and further effort to this end is currently underway
in our laboratory.
time
(h)
%
%
entry
substrate 5 (R,X)
yieldb
eec
1d
2
5a (Ph, NHBoc)
5b (m-MeO-C6H4,
NHBoc)
12
10
98
98
95
95
3
4
5c (p-MeO-C6H4,
NHBoc)
5d (p-Cl-C6H4,
NHBoc)
5e (R-Np, NHBoc)
5f (t-Bu, NHBoc)
5g (i-Pr, NHBoc)
5h (PhCH2, NHBoc)
5i (Me, NHBoc)
5j (Ph, OMe)
5j (Ph, OMe)
5k (Ph, Me)
10
25
98
90
94
94
Acknowledgment. The work was supported by a Grant-in-Aid
for Specially Promoted Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
5e
6
7
24
48
7
5
3
36
16
24
99
94
95
90
99
99
93
96
91
94
94
86
81
92
93
93
Supporting Information Available: Experimental details and
characterization data for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
8
9
10d
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11d f
,
12d
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a Unless otherwise specified, asymmetric conjugate addition of
heterosubstituted aldehydes and 1,1-bis(benzenesulfonyl)ethylene in the
presence of 10 mol
% of catalyst (S,S)-2 and 10 mol % of
2,6-dihydroxybenzoic acid in toluene at room temperature under the
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a chiral column with
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