Asymmetrie conjugate addition of acetylacetone to nitroolefins with chiral organocatalysts derived from both -amino acids and carbohydrates

Article abstract of DOI:10.1002/ejoc.200900547

Bifunctional chiral tertiary amine thioureas derived from both (α-amino acids and. carbohydrates were developed, These organocatalysts promoted the enantioselective conjugate addition of acetylacetone to various aromatic and aliphatic nitroolefins at room

Full text of DOI:10.1002/ejoc.200900547

FULL PAPER
DOI: 10.1002/ejoc.200900547
Asymmetric Conjugate Addition of Acetylacetone to Nitroolefins with Chiral
Organocatalysts Derived from Both α-Amino Acids and Carbohydrates
Xuewei Pu,[a] Penghui Li,[a] Fangzhi Peng,[a] Xiaojiao Li,[a] Hongbin Zhang,[a] and
Zhihui Shao*[a,b]
Keywords: Amino acids / Asymmetric catalysis / Carbohydrates / Organocatalysis
Bifunctional chiral tertiary amine thioureas derived from
both α-amino acids and carbohydrates were developed.
These organocatalysts promoted the enantioselective conju-
gate addition of acetylacetone to various aromatic and ali-
phatic nitroolefins at room temperature in good yields (up to
93%) and with good enantioselectivity (up to 90%ee).
Furthermore, an interesting matched–mismatched effect of
two different chiral units in a chiral organocatalyst was dis-
closed. Both enantiomers of a product can be achieved in
almost the same enantiomeric excess with the “matched”
and “mismatched” chiral organocatalysts simply by chang-
ing the solvent from THF to toluene.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
readily available. In addition, they possess multiple chiral
centers and functional groups for catalyst performance op-
timization. Given these facts, the rational combination of
stereocontrolling elements of both α-amino acids and
carbohydrates in a single molecule would lead to a new
series of cost-effective, finetunable, chiral organocatalysts.
Quite surprisingly, chiral organocatalysts with this com-
bined strategy are few. Recently, Kunz and co-workers pion-
eered the use of carbohydrates in the development of chiral
organocatalyst by designing a novel and elegant class of
bifunctional Schiff base organocatalysts that catalyzed
enantioselective Strecker and Mannich reactions.[6a] In-
spired by this pioneering work, we designed and synthesized
a new class of chiral bifunctional tertiary amine–thiourea
organocatalysts[7] (Figure 1). To the best of our knowledge,
no chiral amine–thiourea organocatalyst designed by com-
bining both α-amino acids and carbohydrates has been re-
ported so far. The catalytic activities of these catalysts were
evaluated in the asymmetric conjugate addition of acetyl-
acetone to nitroolefins.[8,9] Newly designed organocatalyst
1a derived from -valine and -glucopyranose was shown
to be quite effective in the enantioselective conjugate ad-
dition of acetylacetone to various aromatic and aliphatic
nitroolefins in THF at room temperature in good yields
(80–88%) and with good enantioselectivity (80–89%ee).
Furthermore, we have described an interesting matched–
mismatched effect of two different chiral units in a chiral
organocatalyst. Both enantiomers of each product can be
achieved in almost the same enantiomeric excess with the
“matched” and “mismatched” chiral organocatalysts simply
by changing the solvent from THF to toluene. In this paper,
we wish to report these research results.
Introduction
Design of chiral organocatalysts for efficient asymmetric
transformations has become a focal point of attention in
current asymmetric organocatalysis.[1] Impressive progress
has been made in the development of new, readily available,
and finetunable chiral organocatalysts. In this regard, we
recently developed two new classes of bifunctional chiral
organocatalysts bearing two different types of stereogenic
structures in a single molecule for promoting asymmetric
conjugate addition reactions[2a] and aldol reactions.[2b] Our
continuous interest[3,4] in developing easy-to-prepare,
cheap, and finetunable chiral organocatalysts prompted us
to explore new catalyst design strategies.
Acyclic α-amino acids have been proven to be useful chi-
ral scaffolds and have been extensively applied in the prepa-
ration of chiral organocatalysts as a result of the availability
of both enantiomers.[5] In contrast, carbohydrates have re-
ceived less attention[6] in the design of chiral organocata-
lysts, although they are potential chiral scaffolds for the
synthesis of chiral organocatalysts. Carbohydrates (i.e.,
monosaccharides) are conformationally stable, cheap, and
[a] Key Laboratory of Medicinal Chemistry for Natural Resource
(Yunnan University), Ministry of Education, School of Chemi-
cal Science and Technology, Yunnan University,
Kunming 650091, P. R. China
[b] School of Chemistry and Biotechnology, Yunnan Nationalities
University,
Kunming 650031, P. R. China
Fax: +86-871-5035538
E-mail: zhihui_shao@hotmail.com
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900547.
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4622–4626

Asymmetric Conjugate Addition of Acetylacetone to Nitroolefins
Figure 1. Key design elements of a new class of chiral tertiary amine–thiourea organocatalysts.
tive, both enantiomers of a chiral compound may often be
Results and Discussion
required in organic synthesis and in the pharmaceutical in-
dustry. Therefore, discovery of a novel approach for the
catalytic asymmetric synthesis of both enantiomers would
be highly desirable. This interesting finding might provide
a novel approach to obtain both enantiomers of a chiral
compound. At the same time, it might have useful implica-
tions, especially in screening organocatalysts for asymmetric
reactions. Then, the effect of the variation of α-amino acids
was briefly studied by using 1c and 1d as the catalysts in
THF and toluene as solvents, respectively. The reactions
were investigated with organocatalyst 1c derived from -
leucine and -glucopyranose as well as organocatalyst 1d
derived from -leucine and -glucopyranose in THF and
toluene, respectively; product 6a was afforded in lower en-
antiomeric excess (Table 1, Entries 8–11).
Organocatalysts 1 were easily synthesized by coupling
primary–tertiary diamine 2[10] derived from α-amino acids
and isothiocyanate 3[11] derived from -glucopyranose
(Scheme 1).
Scheme 1. Synthesis of chiral amine–thiourea organocatalysts 1a–
d.
The catalytic activity of these chiral amine–thioureas was
initially evaluated in the conjugate addition reaction of
acetylacetone (4) to trans-β-nitrostyrene 5a in the presence
of 10 mol-% of catalyst at room temperature, and the results
are summarized in Table 1. Five different solvents with or-
ganocatalyst 1a derived from -valine and -glucopyranose
were examined to find optimum reaction media, and the
conjugate addition reaction with organocatalyst 1a in THF
afforded the best enantioselectivity (85%ee; Table 1, En-
try 5). Next, the conjugate reaction with organocatalyst 1b
derived from -valine and -glucopyranose in THF was
carried out to investigate the “matched–mismatched” effect
of two different chiral units in catalyst 1b. The use of organo-
catalyst 1b in THF provided product 6a with lower
enantioselectivity (76%ee; Table 1, Entry 6), as well as a re-
versal of the absolute configuration of product 6a. These
results indicate that the chiral unit derived from α-amino
acids predominates over the absolute configuration of prod-
uct 6a. In addition, it seems to indicate that the  configura-
tion of valine matched the -glucopyranose, enhancing the
stereochemical control, whereas the  configuration of val-
ine mismatched the -glucopyranose. However, such a con-
clusion is not always right. We were pleased to find that the
conjugate reaction with so-called “mismatched” organocat-
alyst 1b in toluene gave desired product 6a in almost the
Table 1. Enantioselective addition of acetylacetone (4) to trans-β-
nitrostyrene (5a) catalyzed by 1a–d.[a]
Entry Catalyst
Solvent
t [h]
Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1b
1b
1c
1c
1d
1d
DMF
Et2O
DCM
toluene
THF
THF
toluene
THF
75
72
84
90
88
87
90
89
90
86
89
27 (S)
73 (S)
82 (S)
82 (S)
85 (S)
76 (R)
86 (R)
80 (S)
78 (S)
74 (R)
79 (R)
toluene
THF
toluene
10
11
[a] The reaction was performed with 4 (2 equiv.) and 5a (1 equiv.)
in the presence of catalyst (10 mol-%) at room temperature.
[b] Yields of isolated products. [c] Enantiomeric excess values were
determined by chiral HPLC analysis (Chiralpak AS-H).
With the optimal reaction conditions in hand, we further
same enantiomeric excess with opposite absolute configura- studied the generality of the asymmetric conjugate addition
tion (86% ee; Table 1, Entry 7). From a synthetic perspec- reactions of 4 to nitroolefins 5a–h in the presence of cata-
Eur. J. Org. Chem. 2009, 4622–4626
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4623

X. Pu, P. Li, F. Peng, X. Li, H. Zhang, Z. Shao
FULL PAPER
lysts 1a and 1b, and the results are shown in Table 2. Both amine–thiourea organocatalysts derived from trans cyclo-
catalysts exhibited good enantioselectivity in the asymmet- hexane-1,2-diamine and -glucopyranose in the asymmetric
ric conjugate addition reactions. Generally, both enantio- conjugate addition of acetylacetone to aromatic nitroole-
mers of a product could be achieved in almost the same fins.[9k] However, these organocatalysts could not catalyze
enantiomeric excess with catalyst 1a in THF and with cata- the asymmetric addition of acetylacetone to aliphatic ni-
lyst 1b in toluene, respectively (Table 2, Entries 1–8). The troolefins. These results might indicate the advantage of in-
use of organocatalyst 1a always gave conjugate adducts 6a– corporating α-amino acids into chiral tertiary amine–thio-
h with (S) configuration,[12] whereas the use of organocata- urea organocatalysts.
lyst 1b afforded ent-6a–h with the (R) configuration.[12] It
appears that the position and the electronic property of the
substituents for aromatic rings of nitroolefins 5a–g are well
tolerated by the conjugate addition reactions. Whether elec-
tron-withdrawing (Table 2, Entries 2–4), -donating (Table 2,
Entries 5–7), or -neutral (Table 2, Entry 1) groups on the
aromatic rings were used, the reactions proceeded smoothly
to give the desired adducts in good yields (80–93%) and
with good enantioselectivity (83–89%ee). Notably, the con-
jugate reactions of aliphatic nitroolefin 5h with 4 not only
worked well in the presence of organocatalysts 1a and 1b
but also afforded desired product 6h and ent-6h with almost
the same enantiomeric excess (80%ee in THF, 81%ee in
toluene; Table 2, Entry 8). Few examples of the asymmetric
addition of acetylacetone to aliphatic nitroolefins have been
described so far as a result of the lower reactivity of ali-
phatic nitroolefins than aromatic nitroolefins.[2a,9i] The
highest enantioselectivity in the asymmetric addition of
acetylacetone to aliphatic nitroolefins so far was reported
to be 85%ee.[9i] During the course of our study, the group
of Zhou reported the application of similar chiral tertiary
Conclusions
In summary, we have developed a class of novel and fine-
tunable chiral tertiary amine–thiourea organocatalysts de-
rived from commercially available, inexpensive α-amino ac-
ids and carbohydrates. These organocatalysts promoted the
asymmetric conjugate addition of acetylacetone to various
nitroolefins at room temperature in good yields (up to 93%)
and with good enantioselectivity (up to 90%ee). Further-
more, we described an interesting matched–mismatched ef-
fect of two different chiral units in a chiral organocatalyst.
Both enantiomers of a product can be achieved in almost
the same enantiomeric excess with the “matched” and “mis-
matched” chiral organocatalysts simply by changing the
solvent from THF to toluene. This finding provides a novel
approach to obtain both enantiomers of a chiral com-
pound. At the same time, it might have useful implications,
especially in screening the organocatalysts for asymmetric
reactions. Further investigation of the efficacy of these or-
ganocatalysts in other catalytic asymmetric reactions and
development of the chiral primary amine–thiourea organo-
catalysts derived from both α-amino acids and carbo-
hydrates are under way in our laboratory.
Table 2. Organocatalytic enantioselective conjugate addition of
acetylacetone (4) to various nitroolefins 5a–h promoted by amine–
thioureas 1a and 1b.[a]
Experimental Section
General: 1H NMR and 13C NMR spectra were recorded with a
Bruker Avance 300 spectrometer. Chemical shifts (δ) are expressed
in ppm, and J values are given in Hz. The enantiomeric excess was
determined by HPLC (Agilent 1100 series) by using Chiralpak AS-
H or AD-H and Chiralcel OD-H column with n-hexane and 2-
propanol as eluents. High-resolution mass spectra were taken with
an AB QSTAR Pulsar mass spectrometer. Optical rotations were
obtained with a UV-210A spectrometer. All chemicals and solvents
were used as received without further purification unless otherwise
stated. Flash column chromatography was performed on silica gel
(230–400 mesh).
Entry Catalyst
R
t
[h]
Yield
[%][b]
Product
(ee [%])[c]
1
2
3
4
5
6
7
8
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
Ph (5a)
17
14
18
15
20
15
18
14
20
20
18
15
36
32
40
48
88
90
80
92
84
93
80
87
86
90
82
89
80
87
81
85
6a (85)
ent-6a (86)
6b (88)
ent-6b (86)
6c (86)
ent-6c (88)
6d (83)
ent-6d (88)
6e (86)
ent-6e (88)
6f (90)
ent-6f (87)
6g (85)
ent-6g (88)
6h (80)[d]
ent-6h (81)[d]
4-ClC6H4 (5b)
4-BrC6H4 (5c)
2-CF3C6H4 (5d)
4-MeC6H4 (5e)
4-MeOC6H4 (5f)
2-BnOC6H4 (5g)
iBu (5h)
General Procedure for the Preparation of Catalysts 1a–d: To a solu-
tion of primary–tertiary diamine 2 derived from α-amino acids
(1 mmol) in dry THF (5 mL) was added dropwise a solution of
isothiocyanate 3 derived from -glucopyranose (1.2 mmol) in dry
THF (10 mL) under a nitrogen atmosphere. The resulting mixture
was stirred at 35 °C, and the reaction was monitored by TLC. After
removal of the solvent, the residue was purified by column
chromatography on silica gel to give the amine–thiourea catalysts.
[a] The reaction was performed with 4 (2 equiv.) and 5a–h (1 equiv.)
in the presence of catalyst 1a or 1b (10 mol-%) at room tempera-
ture. [b] Yields of isolated products. [c] Enantiomeric excess was de-
termined by chiral HPLC analysis (Chiralpak AS-H, AD-H and
Chiralcel OD-H). [d] Absolute configuration was not determined.
(4S,5S,6R)-2-(Acetoxymethyl)-6-{3-[(S)-1-(dimethylamino)-3-meth-
ylbutan-2-yl]thioureido}tetrahydro-2H-pyran-3,4,5-triyl Triacetate
(1a): Yield: 431 mg (83%). [α]2D0 = –9.8 (c = 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 6.15 (br. s, 1 H), 5.74 (t, J = 8.8 Hz, 1 H),
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Asymmetric Conjugate Addition of Acetylacetone to Nitroolefins
5.32 (t, J = 9.5 Hz, 1 H), 5.07 (t, J = 9.7 Hz, 1 H), 4.93 (t, J =
9.3 Hz, 1 H), 4.26 (dd, J = 4.1, 3.9 Hz, 1 H), 4.15 (dd, J = 2.0,
2.3 Hz, 1 H), 3.88 (m, 1 H), 3.28 (br. s, 1 H), 2.50–2.46 (m, 2 H),
2.32 (s, 6 H), 2.04 (s, 6 H), 2.02 (s, 6 H), 1.83 (m, 1 H), 0.96 (d, J
= 6.9 Hz, 3 H), 0.95 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 184.0, 170.5, 170.1, 169.8, 83.9, 73.3, 71.3, 68.5, 63.5,
61.9, 59.7, 44.9, 31.5, 20.8, 20.6, 18.1, 18.0 ppm. HRMS (FAB+):
calcd. for C22H38N3O9S [M + 1]+ 520.232877; found 520.232998.
Acknowledgments
We thank the National Natural Science Foundation of China
(20702044), Yunnan Province Government (2008CD064), and Yun-
nan University (Program for Yunnan University Key Young Teach-
ers) for financial support.
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(1b): Yield: 420 mg (81%). [α]2D0 = +44.0 (c = 0.5, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 5.76 (m, 1 H), 5.23 (t, J = 9.4 Hz, 1 H),
5.01 (t, J = 9.6 Hz, 1 H), 4.87 (t, J = 9.4 Hz, 1 H), 4.18 (d, J =
12.3 Hz, 1 H), 4.06 (d, J = 12.4 Hz, 1 H), 3.76 (m, 1 H), 2.63–2.37
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1.94 (s, 3 H), 1.19 (m, 1 H), 0.88 (d, J = 4.5 Hz, 3 H), 0.81 (d, J =
2.5 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 185.1, 170.6,
170.3, 169.9, 169.7, 83.6, 76.6, 73.5, 73.4, 71.3, 68.4, 62.0, 45.1,
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(1c): Yield: 426 mg (80%). [α]2D0 = –9.8 (c = 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 6.16 (br. s, 1 H), 5.71 (br. s, 1 H), 5.33 (t,
J = 9.5 Hz, 1 H), 5.08 (t, J = 9.7 Hz, 1 H), 4.94 (t, J = 9.5 Hz, 1
H), 4.28 (dd, J = 3.6, 3.4 Hz, 1 H), 4.15 (d, J = 12.3 Hz, 1 H), 3.88
(m, 1 H), 3.53 (br. s, 1 H), 2.57–2.41 (m, 2 H), 2.33 (s, 6 H), 2.08
(s, 3 H), 2.05 (s, 3 H), 2.03 (s, 3 H), 2.02 (s, 3 H), 1.68 (m, 1 H),
1.36–1.22 (m, 2 H), 0.93 (d, J = 6.5 Hz, 3 H), 0.90 (d, J = 6.2 Hz,
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(4S,5S,6R)-2-(Acetoxymethyl)-6-{3-[(R)-1-(dimethylamino)-4-meth-
ylpentan-2-yl]thioureido}tetrahydro-2H-pyran-3,4,5-triyl Triacetate
(1d): Yield: 426 mg (80%). [α]2D0 = +41.0 (c = 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 5.81 (m, 1 H), 5.33 (t, J = 9.4 Hz, 1 H),
5.08 (t, J = 9.7 Hz, 1 H), 4.96 (t, J = 9.1 Hz, 1 H), 4.28 (dd, J =
4.3, 4.3 Hz, 1 H), 4.12 (d, J = 12.3 Hz, 1 H), 3.86 (m, 1 H), 2.70–
2.18 (m, 8 H), 2.07 (s, 3 H), 2.05 (s, 3 H), 2.04 (s, 3 H), 2.01 (s, 3
H), 1.69 (m, 1 H), 1.26 (m, 2 H), 0.94 (d, J = 6.4 Hz, 3 H), 0.87
(d, J = 6.8 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 185.4,
170.6, 169.9, 169.7, 83.2, 73.4, 71.2, 68.5, 66.1, 62.0, 52.8, 45.2,
42.6, 24.9, 22.7, 20.7, 20.6 ppm. HRMS (FAB+): calcd. for
C23H40N3O9S [M + 1]+ 534.248527; found 534.245654.
General Procedure for the Asymmetric Conjugate Addition Reaction
of Acetylacetone (4) to Nitroolefins 5 Catalyzed by Catalyst 1a or
1b: Catalyst 1a or 1b (10.4 mg, 0.02 mmol, 10 mol-%) was added
to a vial containing 4 (40 mg, 0.4 mmol) and 5 (0.2 mmol) in dry
THF or toluene (0.6 mL) at room temperature. The resulting mix-
ture was stirred at room temperature, and the reaction was moni-
tored by TLC. The reaction mixture was quenched with 1  aque-
ous HCl solution, extracted with EtOAc, and dried with Na2SO4.
The crude product was purified by flash silica gel chromatography
to give desired adducts 6. The ee values were determined by chiral
HPLC analysis.
Supporting Information (see also the footnote on the first page of
this article): NMR spectroscopic data and chiral HPLC data of 6a–
h.
Eur. J. Org. Chem. 2009, 4622–4626
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4625

X. Pu, P. Li, F. Peng, X. Li, H. Zhang, Z. Shao
FULL PAPER
J. Org. Chem. 2008, 4563–4566; l) J. Luo, L. Xu, R. A. S. Hay,
Y. Lu, Org. Lett. 2009, 11, 437–440; m) J. Lubkoll, H. Wenne-
mers, Angew. Chem. Int. Ed. 2007, 46, 6841–4844. See also ref.
2a.
[11] M. J. Camarasa, P. FernandezResa, M. T. Garcia Lopez, F. G.
Delas Heras, P. P. Mendez Castrillon, A. S. Felix, Synthesis
1984, 509–510.
[12] Absolute configurations of compounds 6a–g were determined
by comparing the HPLC retention times of the products with
those given in the literature.
[10] I. Coldham, P. O’Brien, J. J. Patel, S. Raimbault, A. J. San-
derson, D. Stead, D. T. E. Whittaker, Tetrahedron: Asymmetry
2007, 18, 2113–2119.
Received: May 18, 2009
Published Online: July 29, 2009
4626
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4622–4626