Novel chiral hydrogen bond donor catalysts based on a 4,5-diaminoxanthene scaffold: Application to enantioselective conjugate addition of 1,3-dicarbonyl compounds to nitroalkenes

Article abstract of DOI:10.1016/j.tetlet.2010.12.067

Novel chiral hydrogen bond donor catalysts based on a 4,5-diamino-9, 9′-dimethylxanthene skeleton were designed and synthesized. Among the phenylurea-amide hybrid molecules prepared from various natural/unnatural chiral amino acids, the phenylalanine-deri

Full text of DOI:10.1016/j.tetlet.2010.12.067

Tetrahedron Letters 52 (2011) 987–991
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel chiral hydrogen bond donor catalysts based on a
4,5-diaminoxanthene scaffold: application to enantioselective conjugate
addition of 1,3-dicarbonyl compounds to nitroalkenes
⇑
Tetsuhiro Nemoto, Kazumichi Obuchi, Shinji Tamura, Takashi Fukuyama, Yasumasa Hamada
Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Novel chiral hydrogen bond donor catalysts based on a 4,5-diamino-9,90-dimethylxanthene skeleton
were designed and synthesized. Among the phenylurea-amide hybrid molecules prepared from various
natural/unnatural chiral amino acids, the phenylalanine-derived catalyst, and the proline-derived cata-
lyst were successfully applied to enantioselective conjugate addition of 1,3-dicarbonyl compounds to
nitroalkenes. Using 2-acetylcyclopentanone and 2-methoxycarbonylcyclopentanone as prochiral nucleo-
philes, asymmetric conjugate addition to b-aryl nitroalkenes proceeded with good diastereoselectivity to
provide the corresponding products bearing an all-carbon quaternary stereocenter in excellent yield with
up to 95% ee.
Article history:
Received 15 November 2010
Revised 10 December 2010
Accepted 16 December 2010
Available online 31 December 2010
Keywords:
Asymmetric synthesis
Bifunctional catalyst
Conjugate addition
Hydrogen bond donor catalyst
Organocatalyst
Ó 2011 Elsevier Ltd. All rights reserved.
Xanthene scaffold
Stereoselectivity of enzyme-mediated biocatalytic reactions is
rigorously controlled by multiple interactions between the sub-
strate and the active site of the enzyme, wherein hydrogen bonds
play a key role in the molecular recognition/activation process.
Such biocatalytic processes have served as the inspiration for many
asymmetric catalysts promoted by hydrogen-bonding interactions.
Various chiral hydrogen bond donor catalysts have been developed
and applied to asymmetric synthesis.1
A 4,5-diaminoxanthene skeleton is a useful scaffold for design-
ing multiple hydrogen bond donors in the field of molecular recog-
nition.2 Bis-urea or bis-thiourea derivatives of 2,7-di-tert-butyl 4,5-
diamino-9,90-dimethylxanthene interact with carboxylate anions
and phosphate anions through 4-point hydrogen-bonding interac-
tions, resulting in a complex with a large association constant. In
addition, the symmetric structure of the diamine scaffold is suit-
able for stepwise introduction of two different functions to the
proximal position. These promising hydrogen bond donor proper-
ties, as well as their synthetic advantages, led us to design novel
bifunctional hydrogen bond donor catalysts based on a 4,5-diami-
no-9,90-dimethylxanthene skeleton.3,4 Herein, we report the design
and synthesis of novel chiral hydrogen bond donor catalysts, that
can be applied to enantioselective conjugate addition of 1,3-dicar-
bonyl compounds to nitroalkenes for constructing an all-carbon
quaternary stereocenter.
Our catalyst design is outlined in Figure 1. The known mode of
carboxylate recognition by bis-urea derivatives indicates that com-
pounds with a nitro group could be recognized through similar
multiple hydrogen-bonding interactions. We hypothesized that,
at this point, the nitro group recognition and activation could be
achieved through 3-point hydrogen-bonding interactions with
the urea-amide hybrid molecules. In such molecules, chirality
can be introduced by changing one urea unit into an optically ac-
tive amide. Commercial availability of various natural and unnatu-
t-Bu
t-Bu
New
Design
O
O
O
N
H
N
H
O
O
R
N
H
N
H
O
R
H
O
H
O
H
O
H
O
N
N
N
Ar
R1
N
N
R'
R'
Known mode of carboxylate
recognition through the 4-point
hydrogen-bonding interaction
Nitro group
recognition
& activation
Introduction
of chirality
⇑
Corresponding author. Tel./fax: +81 43 290 2987.
E-mail address: hamada@p.chiba-u.ac.jp (Y. Hamada).
Figure 1. Design of amino acid-derived chiral hydrogen bond donor catalysts based
on 3-points substrate–catalyst interaction.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.067

988
T. Nemoto et al. / Tetrahedron Letters 52 (2011) 987–991
b
c, d
O
O
O
NH2
HN
X
N
H
HN
X
N
H
N
H
O
P
H
Boc
H
H
R1
N
R1
N
1 (P = H)
2 (P = Boc)
3a (X = S, R1 = CF3)
3b (X = S, R1 = H)
3c (X = O, R1 = CF3)
3d (X = O, R1 = H)
a
R2
4a–4d [R2 = NHBoc]
5a–5d [R2 = N(CH3)2]
e, f
R1
R1
Scheme 1. Synthesis of (S)-phenylalanine-derived catalysts 5a–d. Reagent and conditions: (a) (Boc)2O (1.05 equiv), AcOH (12.5 mol %), CH2Cl2, rt; (b) Ar–NCO or Ar–NCS
(1.5 equiv), CH2Cl2, rt; (c) TFA, rt; (d) N-Boc-(S)-phenylalanine (2 equiv), HOAt (1.2 equiv), HATU (2 equiv), Et3N (2 equiv), DMF, 0 °C to rt; (e) TFA, rt; (f) aq HCHO, Pd–C, H2,
EtOH, rt.
ral chiral amino acids enables divergent derivatization for screen-
ing the optimal catalyst. In addition, the tert-amine unit in the ami-
no acid moiety would function as a base to activate nucleophiles.
Synthesis of the designed catalysts started with 4,5-diamino-
9,9-dimethyl-xanthene 1, which was prepared from commercially
available 9,9-dimethylxanthene using the known method (Scheme
1).5 First, 1 was reacted with (Boc)2O in the presence of a catalytic
amount of acetic acid to give mono-protected adduct 2,6 which
was transformed into N-aryl thioureas 3a and 3b, as well as N-aryl
ureas 3c and 3d, by treating with the corresponding aryl isothiocy-
anates and aryl isocyanates, respectively (99% yield for 3d). After
cleavage of the Boc group, amide bond formation with N-Boc-(S)-
phenylalanine was performed using O-(7-azabenzotriazol-1-yl)-
N,N,N0N0-tetramethyluronium hexafluorophosphate (HATU) as a
coupling reagent (69% yield over two steps for 4d). Subsequent
deprotection of the Boc group in 4a–d, followed by dimethylation
under reductive alkylation conditions, afforded (S)-phenylalanine-
derived chiral catalysts 5a–d (43% yield over two steps for 5d).7
To evaluate the ability to function as chiral hydrogen bond do-
nor catalysts, we then examined asymmetric conjugate addition of
acetylacetone to nitrostyrene 6a using 5a–d (Table 1).8 3,5-Bis(tri-
fluoromethyl)-phenylthiourea has been used as an effective hydro-
gen bond donor motif in various precedent catalysts. Therefore, we
first performed the reaction using 10 mol % of 5a in toluene at 4 °C.
The reaction proceeded very sluggishly to give (R)-7a in 88% yield
with 27% ee after 4 days (entry 1). Catalyst screening revealed that
both the reactivity and enantioselectivity increased when phenylu-
rea derivative 5d was used as the hydrogen bond donor catalyst
(24 h, >99% yield, 73% ee) (entry 4). The enantiomeric excess of
(R)-7a further increased to 90% ee when the reaction was per-
formed at ꢀ40 °C (entry 6). On the other hand, both reactivity
and enantioselectivity decreased when dimethyl malonate was
used as a nucleophile (entry 7).
The satisfactory results in the conventional reaction system led
us to turn our attention to construct an all-carbon quaternary ste-
reocenter through an asymmetric conjugate addition. Catalytic
asymmetric construction of a quaternary carbon center is a formi-
dable challenge in organic synthesis.9 Asymmetric conjugate addi-
tion of prochiral nucleophiles to nitroalkenes is one of the most
straightforward approaches toward this end. Various reaction sys-
tems using chiral organocatalysts, as well as chiral metal-based
catalysts, have been reported to date.10,11 First, asymmetric conju-
gate addition of 2-acetylcyclopentanone to nitrostyrene 6a was
examined using (S)-phenylalanine-derived chiral catalysts 5a–d
(Table 2). Among the catalysts, 5d gave the best reactivity and
enantioselectivity. The reaction proceeded in the presence of
10 mol % of 5d at 4 °C, providing the corresponding products 8a
and 8a0, bearing contiguous quaternary–tertiary chiral centers, in
good yield with 83% ee, despite only moderate diastereoselectivity
(8a:8a0 = 3.4:1) (entry 4). Encouraged by this result, we next at-
tempted to improve the stereoselectivity by tuning the structure
of the amino acid part. Optimizations were performed using chiral
phenylurea-type catalysts 5e–n (Fig. 2), which could be easily pre-
pared from commercially available natural and unnatural amino
acid derivatives by the general procedure shown in Scheme 1.
Among the examined catalysts, (S)-proline-derived chiral catalyst
5m gave the best results. The corresponding product was obtained
in quantitative yield with a 6.5:1 diastereomeric ratio and the
enantiomeric excess of the major diastereomer 8a was 88% ee
(ee of 8a0: 89% ee) (entry 13).
Table 1
Asymmetric conjugate addition of acetylacetone or dimethyl malonate to nitrosty-
rene using 5a–d
O
(S)-Catalyst (10 mol%)
O
R
R
acetylacetone or
NO2
dimethyl malonate(2 eq)
toluene (1 M)
6a
NO2
H
Having developed efficient conditions, we next examined the
scope and limitations of different substrates using 10 mol % of
5m (Table 3). Asymmetric conjugate addition of 2-acetylcyclo-
pentanone to nitrostyrene 6a could be performed at ꢀ20 °C,
affording the product in quantitative yield with a 7.9:1 diaste-
reomeric ratio (entry 2). The enantiomeric excess of the major
isomer 8a was 91% ee. Compounds 5b–g, bearing electron-donat-
ing and electron-withdrawing functionalities on the aromatic
ring, were tolerant to this reaction, giving the products in good
diastereomeric ratios with 83–88% ee (entries 3–8). Substrates
with a heteroaromatic substituent or a 2-naphthyl substituent
were also applicable to this reaction, affording the corresponding
products with 86% ee and 95% ee, respectively (entries 9 and
10). Asymmetric conjugate addition to compound 6j, with an al-
kyl substituent at the b-position, was also examined under the
same reaction conditions. The reaction proceeded very sluggishly,
7a (R = CH3), 7b (R = OCH3)
Entry Catalyst Temp (°C) Time (h) Product Yielda (%) Ee (% ee)b
1
2
3
4
5
6
7
5a
5b
5c
5d
5d
5d
5d
4
4
4
96
72
96
24
46
7a
7a
7a
7a
7a
7a
7b
88 27
>99 48
17 16
4
>99 (95)c 73
ꢀ10
ꢀ40
4
>99
80
115
96
98 90
56 57
Determined by 1H NMR analysis of the crude reaction mixture.
Determined by chiral HPLC analysis.
Isolated yield.
a
b
c

T. Nemoto et al. / Tetrahedron Letters 52 (2011) 987–991
989
Table 2
Optimization of the catalyst structure
O
O
(S)-Catalyst (10 mol%)
2
2
NO2
CH3
NO2
CH3
NO2
2-acetylcyclopentanone (2 eq)
3
3
+
O
O
toluene (1 M)
6a
H
H
8a (2S,3S)
8a' (2R,3S)
Entry
Catalyst (Chiral source)
Time (h)
Yielda (%)
dra
Ee (% ee)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
5a [(S)-Phenylalanine]
5b [(S)-Phenylalanine]
5c [(S)-Phenylalanine]
5d [(S)-Phenylalanine]
5e [(S)-Alanine]
5f [(S)-Valine]
5g [(S)-Leucine]
5h [(S)-Serine]
5i [(S)-Phenylglycine]
5j [(S)-Homophenylalanine]
5k [(S)-Tyrosine]
5l [(S)-Cyclohexylalanine]
5m [(S)-Proline]
96
45
96
17
26
12
26
96
96
19
6
>99
>99
68
>99
85
<5
99
76
95
>99
>99
>99
>99
88
4.3:1
67 (72)
54 (62)
8 (13)
83 (86)
38 (23)
—
4.0:1
10.4:1
3.4:1
5.5:1
—
3.4:1
6.1:1
5.6:1
4.5:1
4.4:1
3.9:1
6.5:1
6.2:1
46 (49)
6 (8)
23 (7)
67 (70)
80 (82)
66 (66)
88 (89)
38 (24)
96
24
96
5n [(S)-Homoproline]
a
Determined by 1H NMR analysis of the crude sample.
Determined by chiral HPLC analysis. The ee value in parentheses is the enantiomeric excess of the minor diastereomer. Absolute configuration was determined by
b
comparing the measured optical rotations with the reported data, see the Supplementary data.
however, affording the corresponding product in only 6% yield
(entry 11).12 2-Methoxycarbonylcyclopentanone was also appli-
cable to the present catalyst system (Scheme 2). Asymmetric
conjugate addition to 6a proceeded to completion with good
O
O
O
N
H
N
H
O
O
N
H
N
H
O
R
H
H
H
H
N
N
Ph
Ph
N
N
O
5m–5n
(S)-5m (10mol%)
5e–5l
n
2-methoxycarbonyl-
98% yield
OCH3
cyclopentanone (2 eq)
(dr = 15.4:1)
5m: n = 1
5n: n = 2
5e: R = CH3
5f: R = CH(CH3)2
5g: R = CH2CH(CH3)2 5k: R = CH2(p-OH-C6H4)
5h: R = CH2OH 5l: R = CH2-C6H11
5i: R = C6H5
O
6a
88% ee
(major isomer)
5j: R = CH2CH2C6H5
toluene (1 M)
4 °C, 48 h
NO2
9a
H
Scheme 2.
Figure 2. Structure of catalysts 5e–n.
Table 3
Scope and limitations
O
H
O
(S)-5m (10 mol%)
NO2
6a–6j
CH3
NO2
CH3
2-acetylcyclopentanone (2 eq)
R
+
O
O
R
toluene (1 M)
R
H
NO2
8a–8j (major)
8a'–8j' (minor)
Entry
Substrate
Temp (°C)
Time (h)
Product
Yielda (%)
dra
6.5:1
Ee (% ee)b
1
2
3
4
5
6
7
8
9
6a (R = C6H5)
6a (R = C6H5)
4
ꢀ20
4
4
4
4
4
4
4
24
72
72
24
24
48
48
72
72
24
72
8a
8a
8b
8c
8d
8e
8f
8g
8h
8i
>99
>99
>99
90
88 (89)
91 (92)
84 (88)
85 (83)
85 (80)
83 (83)
87 (86)
88 (84)
86 (87)
95 (84)
— (—)
7.9:1
7.9:1
7.6:1
18.4:1
7.2:1
6.6:1
6.5:1
5.3:1
6.7: 1
11.0:1
6b (R = 4-MeO–C6H4)
6c (R = 3-MeO–C6H4)
6d (R = 2-Me–C6H4)
6e (R = 4-F–C6H4)
6f (R = 3-F–C6H4)
6g (R = 2-F–C6H4)
6h (R = 2-Thienyl)
6i (R = 2-Naphthyl)
6j (R = i-Butyl)
76
>99
>99
96
>99
97
10
11
4
4
8j
6c
a
b
c
Isolated yield.
Determined by chiral HPLC analysis. The ee value in parentheses is the enantiomeric excess of the minor diastereomer.
Determined by 1H NMR analysis of the crude sample.

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T. Nemoto et al. / Tetrahedron Letters 52 (2011) 987–991
(A)
(B)
O
O
O
H
O
H
N
N
H
H
N
N
Ph
N
Ph
N
O
O
O
O
H
H
O
N
O
N
H
H
N
N
CH3
CH3
Nu
Nu
Nu
:
nucleophile
Disfavored
O
O
N
N
O
H
H
2
N
CH3
NO2
O
CH3
Ph
H
O
3
H
N
O
N
O
H
CH3
H
O
(C)
major isomer
8a (2S,3S)
Figure 3. Working model.
diastereoselectivity (dr = 15.4:1), affording 9a10a in 88% ee (61%
ee for the minor isomer).
Supplementary data
Although the complete transition state model for the construc-
tion of a quaternary carbon is not clear, the observed stereoselec-
tion in the asymmetric conjugate addition can be explained by
the working model shown in Figure 3. During the C–C bond forma-
tion, the hydrogen atom on the chiral carbon should locate inside
the hydrogen bond donor pocket to avoid steric repulsion between
the substrate and the pyrrolidine ring moiety. As a consequence,
the tert-amine moiety is placed beneath the amide plane in the
case of (S)-proline-derived catalyst to activate 1,3-dicarbonyl com-
pounds. The observed absolute configuration of the benzylic posi-
tion of 7a,13 as well as 8a, indicates that the C–C bond formation
occurs on the Re-face of b-aryl nitroalkenes. Between the two pos-
sible modes of catalyst–substrate interaction suitable for the Re-
face attack, interaction (A) would be more favored because of the
severe steric repulsion between the aryl moiety and the pyrroli-
dine ring moiety in interaction (B). Based on the absolute configu-
ration of the quaternary carbon of the major isomer 8a, working
model (C) is proposed as a plausible transition state.14 As shown
in Table 3, the observed enantioselectivity of the minor diastereo-
mer is similar to that of the corresponding major isomer. This fact
indicates that the diastereomeric ratio would be mainly dependent
on the enantiofacial selection of the prochiral enolate derived from
2-acetylcyclopentanone.15
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.12.067.
References and notes
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were successfully applied to enantioselective conjugate addition
of 1,3-dicarbonyl compounds to nitroalkenes for constructing an
all-carbon quaternary stereocenter (up to 95% ee). Mechanistic
investigations into the present asymmetric catalysis, as well as
studies to apply the developed catalysts to other enantioselective
reactions, are in progress.
7. Partial racemization occurred when N,N-dimethyl (S)-phenylalanine was
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Acknowledgment
This work was supported in part by a Grant-in Aid for Encour-
agement of Young Scientists (B) from the Ministry of Education,
Culture, Sports, Science, and Technology, Japan.

T. Nemoto et al. / Tetrahedron Letters 52 (2011) 987–991
991
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center, see: (a) Ju, Y.-D.; Xu, L.-W.; Li, L.; Lai, G.-Q.; Qiu, H.-Y.; Jiang, J.-X.; Lu, Y.
Tetrahedron Lett. 2008, 49, 6773; (b) Jakubec, P.; Helliwell, M.; Dixon, D. J. Org.
Lett. 2008, 10, 4267; (c) Luo, J.; Xu, L.-W.; Hay, R. A. S.; Lu, Y. Org. Lett. 2009, 11,
437; (d) Chen, Z.; Furutachi, M.; Kato, Y.; Matsunaga, S.; Shibasaki, M. Angew.
Chem., Int. Ed. 2009, 48, 2218; (e) Yu, Z.; Liu, X.; Zhou, L.; Feng, X. Angew. Chem.,
Int. Ed. 2009, 48, 5195; (f) Tan, B.; Lu, Y.; Zeng, X.; Chua, P. J.; Zhong, G. Org. Lett.
2010, 12, 2682; (g) Murai, K.; Fukushima, S.; Hayashi, S.; Takahara, Y.; Fujioka,
H. Org. Lett. 2010, 12, 964.
12. No reaction occurred when 2-acetylcyclohexanone was used as the
nucleophile.
13. Asymmetric conjugate addition of acetylacetone to 6a using (S)-proline-
derived catalyst 5m gave (R)-7a in 65% yield with 71% ee (4 °C, 96 h),
analogous to the case of (S)-phenylalanine-derived catalyst 5d (Table 1, entry
4).
14. Another possibility that 1,3-dicarbonyl compounds interact with the urea
catalyst based on a 4,5-diaminoxanthene scaffold through multiple hydrogen
bonds would not be excluded at the present stage. For the theoretical studies of
the mode of interaction between bifunctional thiourea derivatives and 1,3-
dicarbonyl compounds in asymmetric conjugate addition to nitroalkenes, see:
Hamza, A.; Schubert, G.; Soóe, T.; Pápai, I. J. Am. Chem. Soc. 2006, 128, 13151.
See also reference 11f.
15. At the present stage, the origin of enantiofacial discrimination of the prochiral
enolate is unknown.