Threonine-surfactant organocatalysts for the highly diastereo- and enantioselective direct anti-Mannich reactions of hydroxyacetone

Article abstract of DOI:10.1016/j.tetlet.2010.08.085

In this work, several new l-threonine derivatives as organocatalysts were synthesized in one step for the first time by the reaction of threonine with acyl chlorides at room temperature in trifluoroacetic acid on a large-scale without protecting groups involved or chromatographic techniques, and those threonine-surfactant organocatalysts mediated the direct asymmetric anti-Mannich reactions of hydroxyacetone and anilines with aldehydes to synthesize anti-1,2-amino alcohols in good yields (75-93%) and highly enantioselectivities (up to 99% ee).

Full text of DOI:10.1016/j.tetlet.2010.08.085

Tetrahedron Letters 51 (2010) 5775–5777
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Threonine-surfactant organocatalysts for the highly diastereo- and
enantioselective direct anti-Mannich reactions of hydroxyacetone
⇑
Chuanlong Wu, Xiangkai Fu , Xuebing Ma, Shi Li, Chao Li
College of Chemistry and Chemical Engineering Southwest University, Research Institute of Applied Chemistry Southwest University, Chongqing 400715, China
The Key Laboratory of Applied Chemistry of Chongqing Municipality, Chongqing 400715, China
The Key Laboratory of Eco-environments in Three Gorges Reservoir Region Ministry of Education, Chongqing 400715, China
a r t i c l e i n f o
a b s t r a c t
Article history:
In this work, several new L-threonine derivatives as organocatalysts were synthesized in one step for the
Received 12 June 2010
Revised 24 August 2010
Accepted 27 August 2010
Available online 16 September 2010
first time by the reaction of threonine with acyl chlorides at room temperature in trifluoroacetic acid on a
large-scale without protecting groups involved or chromatographic techniques, and those threonine-sur-
factant organocatalysts mediated the direct asymmetric anti-Mannich reactions of hydroxyacetone and
anilines with aldehydes to synthesize anti-1,2-amino alcohols in good yields (75–93%) and highly enanti-
oselectivities (up to 99% ee).
Ó 2010 Elsevier Ltd. All rights reserved.
The catalytic asymmetric Mannich reaction is an effective car-
bon–carbon bond-forming process for the construction of nitro-
gen-containing chiral molecules, which are common structural
motifs and chiral building blocks for a vast array of biologically ac-
tive and importantly pharmaceutical compounds.1 Due to the
atom-economy, the direct one-pot three-component asymmetric
Mannich reactions are one of the most elegant and synthetically
attractive.2 Shibasaki and co-workers firstly reported the direct
enantioselective Mannich-type reactions catalyzed by heterodime-
tallic complexes.3 The first example of a direct organocatalytic
three-component Mannich reaction was reported by List,4 and fol-
lowed by the excellent work of several groups.5–12 Besides (S)-pro-
line,4–9 proline-derived tetrazole,10 acylic amino acids and their
derivatives,11 and chiral phosphoric acids12 were developed as
enantioselective organocatalysts for the direct one-pot three-
component Mannich reactions. Although 1,2-amino alcohol can be
constructed via Mannich reaction of hydroxyketone to imines,
hydroxyacetone was seldom used as a donor in the asymmetric-cat-
alyzed direct Mannich reactions.4,10,11,13 Threonine derivatives were
developed as organocatalysts for the direct one-pot three-compo-
nent asymmetric Mannich reactions of hydroxyketone to imines
was reported by Barbas and Lu.11b,c However, it should be noted that
among all of the reported asymmetric organocatalysts, most of them
were prepared with strenuous procedure, tiresome purification of
chromatography and/or need some expensive reagents, which cre-
ated the added hurdles for industrial production, so these organo-
catalysts were often used in research laboratories. Therefore, the
development of a new type of effective asymmetric organocatalysts
with natural crude chiral pool, simple preparation procedure, and
inexpensive reagents is urgently needed and is also the true
challenge.
Here we described a novel, simple and efficient surfactant type
of acyl threonine derivatives as the organocatalysts for the asym-
metric Mannich reaction of
a-hydroxyketones. Threonine seems
to be good chiral structural scaffold, as its hydroxy group allows
for the easy attachment of various hydrophobic groups such as
alkyl, acyl and so on.14 Trifluoroacetic acid has been used as the
best medium for selective acylation of hydroxyproline.15 In this
work, we reported that a series of novel
readily available on a large-scale were derived from the one-step
O-acylation of -threonine with acyl chlorides at room temperature
L-threonine derivatives
L
in trifluoroacetic acid (Fig. 1), in the synthetic process of the
acylthreonines, no protecting method of amino groups and chro-
matographic technique were involved. The obtained threonine-
surfactant organocatalysts were able to smoothly mediate the
direct one-step three-component asymmetric anti-Mannich
reaction of hydroxyacetone with 4-methoxyaniline and 4-nitro-
benzaldehyde to give enantiomerical anti-1,2-amino alcohols 2a
(Table 1).
1.acyl chlorides
O
(1.5 equiv),
HO
CO2H
NH2
O
1a n=2
1b n=4
1c n=6
1d n=8
1e n=10
CF3CO2H
CO2H
NH3Cl
n
H3C
2. crystallization
from Et2O
H3C
L-Threonine
1
⇑
Corresponding author. Tel.: +86 23 68253704; fax: +86 23 68254000.
E-mail address: fxk@swu.edu.cn (X. Fu).
Figure 1. Synthetic figure for acyloxythreonines 1: (1) acyl chlorides, CF3CO2H, 0 °C
to room temperature; (2) crystallization from Et2O.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.085

5776
C. Wu et al. / Tetrahedron Letters 51 (2010) 5775–5777
Table 1
Screening of organocatalystsa
PMP
NH2
CHO
NO2
O
O
HN
Catalyst 1
+
OH
+
OH
2a
Solvent, 0 ºC
NO2
OMe
Entry
Catalyst
Cat. loading [%]
Solvent
Yieldb [%]
anti:sync
eed [%]
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1c
1c
1c
20
20
20
20
20
20
20
20
20
NMP
NMP
NMP
NMP
NMP
DMSO
DMF
ClCH2CH2Cl
NMP
91
92
92
89
79
91
90
75
51
84:16
89:11
92:8
84:16
66:34
85:15
85:15
50:50
75:25
91
94
98
92
73/30
92
90
27/23
65
L
-Thr
10e
1c
1c
10
5
NMP
NMP
80
70
73:27
53:47
86/15
80/36
11f
a
The reactions were performed with p-nitrobenzaldehyde (1.1 mmol), hydroxyacetone (3 mmol), 4-methoxyaniline (1 mmol), Et3N (0.2 mmol), and catalyst (0.2 mmol) at
0 °C.
b
Isolated yield.
c
d
e
f
The ratios of anti to syn were determined by 1H NMR analysis of the crude product and by HPLC.
The ee values of the anti-isomer were determined by chiral HPLC using a chiralpak AD-H.
The molar ratio of aldehyde/hydroxyacetone/4-methoxyaniline/Et3N/catalyst was 1.2:3:1:01:0.1.
The molar ratio of aldehyde/hydroxyacetone/4-methoxyaniline/Et3N/catalyst ratio was 1.2:3:1:0.05:0.05.
In our initial screening, a three-component asymmetric Man-
terms of the yields and enantioselectivities (Table 1, entries 6–8).
nich reaction of hydroxyacetone with 4-nitrobenzaldehyde and
4-methoxyaniline was carried out with 20 mol % of catalyst 1 in
NMP at 0 °C (Table 1, entries 1–5). The L-threonine provided the
moderate anti-selectivity (anti:syn = 75:25) and enantioselectivity
(65% ee) (Table 1, entry 9). Among the five synthesized threo-
nine-surfactant derivatives by the O-acylation of L-threonine with
acyl chlorides, it was found that the chain length (n) dramatically
affected the yields and the enantioselectivities. Neither very long
(n = 8, 10) nor very short carbon chains (n = 2, 4) were effective,
whereas catalyst 1c containing the n-octanoic group (n = 6) gave
the best yield (92%), diastereoselectivity (anti:syn = 92:8) and
enantioselectivity (98% ee) (Table 1, entry 3). Other polar solvents
such as DMSO, DMF, and ClCH2CH2Cl were less satisfactory in
Unfortunately, the yields (70–80%), diastereoselectivities (anti:-
syn = 73:27; 54:47), and enantioselectivities (80–86% ee) signifi-
cantly decreased when the used amount of catalyst 1c decreased
to 10 mol % and 5 mol % in NMP (Table 1, entries 10 and 11).
Under the optimized reaction conditions, the direct anti-Man-
nich reaction in NMP catalyzed by catalyst 1c was extended to a
series of aldehydes to explore the generality of this catalytic sys-
tem. The catalytic results were summarized in Table 2. The Man-
nich products were obtained in good yields with up to 99% ee
and dr values ranging from 51/49 to 92/8. The stereochemical out-
come depended significantly on the electronic properties of the
substituted groups on benzaldehydes. The electron-withdrawing
groups had a positive effect on the enantioselectivities (entries
1–9).
Table 2
Table 3
The three-component direct asymmetric Mannich reactions of different aldehydesa
The three-component direct asymmetric Mannich reactions of different aniline
componentsa
PMP
CHO
R1
NH2
O
O
HN
20 mol%1c
+
+
R2
CHO
NO2
NH2
R1
OH
O
O
HN
NMP, 0 ºC
OH
2a-2i
20 mol%1c
OMe
R2
+
+
OH
Yieldb [%]
anti:sync
eed [%]
NMP, 0 ºC
OH
Entry
R1
Product
NO2
2a, 2j-2n
1
2
3
4
5
6
7
8
9
4-NO2
3- NO2
2- NO2
4-CN
4-F
4-Cl
2-Cl
4-Br
H
2a
2b
2c
2d
2e
2f
2g
2h
2i
92
93
90
91
92
90
87
90
75
92:8
98
90
91
>99
94
96
97
98
70
80:20
86:14
80:20
54:46
80:20
89:11
90:10
51:49
Entry
R2
Product
Yieldb [%]
anti:sync
eed [%]
1
2
3
4
5
6
4-MeO
3-MeO
4-Me
2,4-Me2
4-Cl
2a
2j
2k
2l
2m
2n
92
91
93
95
95
89
92:8
92:9
93:7
96:4
96:4
90:10
98
99
96
96
95
98
H
a
a
The reactions were performed with aldehydes (1.1 mmol), hydroxyacetone
The reactions were performed with p-nitrobenzaldehyde (1.1 mmol), hydrox-
(3 mmol), 4-methoxyaniline(1 mmol), Et3N (0.2 mmol) and catalyst1c (0.2 mmol)
yacetone (3 mmol), aniline (1 mmol), Et3N (0.2 mmol), and catalyst (0.2 mmol) in
in NMP(3 mL) at 0 °C.
NMP (3 mL) at 0 °C.
b
b
Isolated yield.
Isolated yield.
c
c
The ratio of anti to syn was determined by 1H NMR analysis of the crude
The ratio of anti to syn was determined by 1H NMR analysis of the crude
products and by HPLC.
products and by HPLC.
d
d
The ee value of the anti-isomer was determined by chiral HPLC using a chiralpak
The ee value of the anti-isomer was determined by chiral HPLC using a chiralpak
AD-H.
AD-H.

C. Wu et al. / Tetrahedron Letters 51 (2010) 5775–5777
5777
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Acknowledgment
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Supplementary data
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References and notes
16. General procedure for the catalytic asymmetric Mannich reaction in NMP: A
mixture of 1-methyl-2-pyrrolidinone (NMP, 3 mL), p-anisidine (1 mmol), p-
nitrobenzaldehyde (1.2 mmol), hydroxyacetone (3 mmol), and catalyst 1c
(0.2 mmol) was vigorously stirred at 0 °C and monitored with TLC. The
reaction mixture was diluted with 5 mL of AcOEt, was added 5 mL of
unsaturated ammonium chloride solution and then extracted with AcOEt
(3 Â 5 mL). The combined organic layers were washed with brine (3 Â 3 mL),
dried over anhydrous MgSO4, concentrated in vacuo and were purified by flash
column chromatography (hexanes/ethyl acetate (v/v = 1:1)) to afford the
desired Mannich product 2a. 1H NMR (300 MHz, CDCl3): d 2.23 (s, 3H), 3.55
(br s, 1H), 3.69 (s, 3H), 4.56 (br s, 1H), 4.71 (d, 1H, 3J = 3.5 Hz), 4.88 (d, 1H,
3J = 3.5 Hz), 6.53 (d, 2H, 3J = 9.0 Hz), 6.70 (d, 2H, 3J = 9.0 Hz), 7.46 (d, 2H,
3J = 9.0 Hz), 8.13 (d, 2H, 3J = 9.0 Hz). The diastereoselectivities and
enantioselectivities were determined by HPLC (Daicel Chiralpak AD, hexane/
i-PrOH = 80:20, flow rate 1.00 mL/min, k = 254 nm): tR (anti major enantiomer,
(3R,4R)-4) = 27.28 min, tR (anti minor enantiomer, (3S,4S)-4) = 21.78 min, tR
(syn major enantiomer, (3S,4R)-4) = 33.03 min, tR (syn minor enantiomer,
(3R,4S)-4) = 39.60 min.
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