Syn- and enantioselective henry reactions of aliphatic aldehydes and application to the synthesis of safingol

Article abstract of DOI:10.1002/chem.201303650

An amino alcohol copper(II) catalyst was developed for syn- and enantioselective Henry reaction of aliphatic aldehydes. Nitroethane or 2-nitroethanol and aliphatic aldehyde were sequentially added to a solution of Cu(OAc)₂ H₂O and li

Full text of DOI:10.1002/chem.201303650

COMMUNICATION
DOI: 10.1002/chem.201303650
syn- and Enantioselective Henry Reactions of Aliphatic Aldehydes and
Application to the Synthesis of Safingol
Dan-Dan Qin,[a] Wen Yu,[a] Jie-Dan Zhou,[a] Yan-Cheng Zhang,[b] Yuan-Ping Ruan,[a]
Zhao-Hui Zhou,[a] and Hong-Bin Chen*[a]
Dedicated to Prof. Khi-Rui Tsai on the occasion of his 100th birthday
Vicinal (b-) amino alcohol motifs are important and ubiq-
uitous structural features in a diverse range of natural prod-
ucts and pharmaceutical agents as well as chiral ligands and
auxiliaries used in (catalytic) asymmetric synthesis. In most
cases, the biological activities and asymmetric induction ca-
pabilities of vicinal amino alcohols strongly depend upon
their relative (absolute) configurations. Generally, ꢀchiral
poolꢁ approaches were used to prepare such stereospecific
vicinal amino alcohols.[1] However, some side effects, such as
multistep reaction sequences, expensive reagents, and some-
times harsh reaction conditions, greatly constrained their
practical applications. Consequently, the development of
mild, efficient, and economic methods is still of significant
importance.
whereas their applications in diastereo- and enantioselective
Henry reactions are less explored.[6] Previously, we reported
that an easily available b-amino alcohol copper catalyst 1a
efficiently promoted Henry reactions between nitromethane
and aromatic aldehydes.[7] Herein, we report the results of
recent studies into the application of b-amino alcohol li-
gands 1 and 2 (Scheme 1) in syn- and enantioselective
The catalytic asymmetric Henry (nitroaldol) reaction is
a highly atom-economic and powerful tool in organic syn-
thesis because the resulting b-nitro alcohols can easily be
transformed into vicinal amino alcohols and other important
intermediates.[2] Over the past two decades, an extensive col-
lection of efficient catalysts have been developed to pro-
mote Henry reactions between carbonyls and nitromethane
with high enantioselectivity.[3] In contrast, diastereo- and
enantioselective Henry reactions still remain a great chal-
lenge because it is very difficult to rigorously control the ste-
reochemistry of the two carbon stereocenters formed simul-
taneously and, hitherto, only a few successful examples in
syn-selective[4] and anti-selective[5] Henry reactions have
been reported.
Scheme 1. Chiral amino alcohol ligands.
Henry reactions and application to the synthesis of safingol.
In the preliminary studies, ligands 1 and 2 were evaluated
by using hexanal and 4-chlorobenzaldehyde as model sub-
strates and nitroethane as a standard nucleophile. When the
reaction was performed in the presence of 10 mol% of cata-
lyst, in situ generated from the coordination reaction of
amino alcohol and CuACHTUNRGTNEUNG(OAc)2·H2O, both substrates gave the
corresponding Henry adducts with different syn/anti ratios.
For hexanal, ligands 1a–e were superior to 2a–e in terms of
Table 1. Effect of the ligand structure upon the Henry reaction.[a]
Chiral b-amino alcohols are one type of the most impor-
tant ligands that are widely used in asymmetric catalysis,
Entry
Ligand
Yield [%][b]
d.r.[c] (syn/anti)
ee [%][c] (syn/anti)
[a] D.-D. Qin, W. Yu, J.-D. Zhou, Prof. Y.-P. Ruan, Prof. Dr. Z.-H. Zhou,
Prof. Dr. H.-B. Chen
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
72
66
61
38
70
23
48
24
25
46
2.9:1
7.6:1
3.3:1
3.0:1
4.8:1
1.8:1
1.3:1
1.5:1
1.2:1
1.9:1
95:81
97:72
88:73
79:30
88:75
3.5:5.9
33:21
37:34
44:31
38:14
Department of Chemistry and State Key Laboratory of
Physical Chemistry for Solid Surfaces
College of Chemistry and Chemical Engineering
Xiamen University, Xiamen, Fujian 361005 (P. R. China)
Fax : (+86)592-2185192
E-mail: hbchan@xmu.edu.cn
[b] Y.-C. Zhang
Nantong Huafeng Chemical Co. Ltd., Nantong
Jiangsu, 226531 (P. R. China)
10
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201303650.
[a] All reactions were performed on a 1.0 mmol scale. [b] Isolated yield.
[c] Determined by chiral HPLC analysis.
Chem. Eur. J. 2013, 19, 16541 – 16544
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
16541

Table 4. Henry reaction of aliphatic aldehydes with nitroethane.[a]
diastereoselectivity and enantioselectivity (Table 1), among
which 1b distinguished itself as the best ligand, which result-
ed in a 7.6:1 syn/anti ratio and 97% ee for syn (Table 1,
entry 3), whereas for 4-chlorobenzaldehyde, 1b was still the
best ligand but could only give a 2.9:1 syn/anti ratio even
under optimal reaction conditions (not listed herein). Con-
sidering that aliphatic b-nitro alcohols are also highly impor-
tant in organic synthesis,[8] we only devoted our efforts to
optimize the reaction conditions for aliphatic aldehydes.
In the subsequent experiments, the effects of various sol-
vents were examined. The results are summarized in Table 2
and clearly show that the reaction was highly sensitive to
the nature of solvent employed, and THF was the best reac-
Entry R1
Yield [%][b] d.r.[c] (syn/anti) ee [%][c] syn/anti
1
2
3
4
6
7
8
9
CH
N
75
70
66
80
83
64
72
69
66
73
74
4.5:1
7.0:1
7.6:1
6.5:1
6.9:1
7.1:1
6.3:1
7.0:1
5.2:1
15.3:1
9.5:1
90:55
97:73
97:72
97:76
95.68
94:72
99:69
98:88
98:82
99:70
96:78
CH
CH
CH
CH
CH
C6H5CH2CH2
(CH3)2CH2
ACHTNUGRTNE(NUGN CH3)2CHCH2
ACHTUNGTRENNUNG
10
11
12
c-hexyl
c-pentyl
Table 2. Effects of solvents upon the Henry reaction.[a]
[a] All reactions were performed on a 1.0 mmol scale. [b] Isolated yield.
[c] Determined by chiral HPLC analysis.
moderate to good yields with modest to excellent syn selec-
tivities and excellent enantioselectivities. Further analysis re-
vealed that the d.r. (syn/anti) was almost not affected by the
chain length of linear aliphatic aldehydes (Table 4, en-
tries 2–8) except that for butanal (entry 1); in addition, a-
branched isobutanal gave a higher d.r. (syn/anti) than that of
b-branched isopentanal (entries 9 and 10), whereas in the
case of aliphatic cyclic aldehydes, the corresponding Henry
adducts were obtained with higher syn selectivity (entries 11
and 12), and cyclohexanecarboxaldehyde even gave up to
15.3:1 syn/anti ratio and 99% ee for syn.
Entry
Solvent
Yield [%][b]
d.r.[c] (anti/syn)
ee [%][c] (syn/anti)
1
2
3
4
5
6
7
8
9
MeOH
EtOH
iPrOH
CH2Cl2
THF
60
75
79
47
66
51
64
41
64
1.7:1
2.6:1
5.0:1
4.4:1
7.6:1
6.5:1
5.6:1
5.8:1
5.5:1
61:27
79:43
94:70
88:50
97:72
95:63
93:66
93:54
94:70
Et2O
Dioxane
CH3CN
EtOAc
[a] All reactions were performed on a 1.0 mmol scale. [b] Isolated yield.
[c] Determined by chiral HPLC analysis.
In addition, 2-nitroethanol was also examined as the nu-
cleophile towards different aliphatic aldehydes. The results
were summarized in Table 5. It was apparent that the isolat-
ed yields and d.r. (syn/anti) of the produced 2-nitro-1,3-diols
were higher than those obtained when using nitroethane, for
example, the reaction of n-octanal with 2-nitroethanol gave
the syn-adduct in 86% isolated yield with 18.6:1 syn/anti
ratio and 99% ee for syn (entry 4). A likely reason for this
was that the hydroxyl group of 2-nitroethanol formed addi-
tional intermolecular hydrogen bonds and hence greatly sta-
bilized the reaction transition states.[7] Single-crystal X-ray
diffraction analysis confirmed that our catalyst exclusively
preferred the formation of the syn diastereomer and all the
major syn isomers possessed (R,R)-configurations (see the
Supporting Information).
tion medium in terms of diastereomeric ratio (d.r.; syn/anti)
and ee values for the syn adduct (Table 2, entry 5).
Catalyst loadings also had a significant effect on the reac-
tion (Table 3). When the amount of catalyst increased from
1 to 10 mol%, the isolated yield, d.r. (syn/anti), and ee value
increased concomitantly (Table 3, entries 1–4). However, at-
tempts to access higher d.r. (syn/anti) by raising the catalyst
loading failed, 15 and 20 mol% of catalysts gave lower dia-
stereoselectivity (entries 5 and 6).
With the optimized reaction conditions in hand, a variety
of aliphatic aldehydes were tested as substrates to demon-
strate the reaction versatility (Table 4). In general, all the
substrates proceeded well to afford the Henry adducts in
Finally, the practical utility of this syn-selective Henry re-
action was demonstrated by the short asymmetric synthesis
Table 3. Effect of catalyst loading upon the Henry reaction.[a]
Table 5. Henry reaction of aliphatic aldehydes with nitroethanol.[a]
Entry
Cat. [%]
Yield [%][b]
d.r.[c] (anti/syn)
ee [%][c] (syn/anti)
Entry R1
Yield [%][b] d.r.[c] (syn/anti) ee [%][c] syn/anti
1
2
3
4
5
6
1
2.5
5
10
15
20
20
23
51
66
61
69
1.3:1
4.0:1
5.6:1
7.6:1
3.8:1
5.1:1
13:3
84:36
95:48
97:72
92:63
94:70
1
2
3
4
5
A
82
93
84
86
92
4.3:1
14.9:1
7.9:1
18.6:1
14.2:1
96:71
99:3.6
94:59
99:43
97:62
CH
CH
CH
N
CHTUNGTRENNUNG
C
c-hexyl
[a] All reactions were performed on a 1.0 mmol scale. [b] Isolated yield.
[c] Determined by chiral HPLC analysis.
[a] All reactions were performed on a 1.0 mmol scale. [b] Isolated yield.
[c] Determined by chiral HPLC analysis.
16542
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ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 16541 – 16544

Synthesis of Safingol
COMMUNICATION
Keywords: aliphatic aldehydes
·
amino alcohols
·
asymmetric synthesis · Henry reactions · safingol
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Scheme 2. Synthesis of safingol.
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steps with satisfactory overall yield. The reaction of hexade-
canal with 2-nitroethanol in the presence of 10 mol% of cat-
alyst ent-1b furnished syn-nitro alcohol 19 in 79% isolated
yield with a d.r. (syn/anti) of up to 16.5:1 and an ee of up to
98% for syn. Further experiments showed that when the re-
action was performed on a 10.0 mmol scale, pure (2S,3S)-19
could be obtained by recrystallization with a yield of 68%;
in addition, ligand ent-1b could be easily recovered by
a simple operation (see the Supporting Information). Subse-
quently, 19 was catalytically hydrogenated to give safingol
20 in 72% yield. Notably, in comparison with the La-Li-
BINOL (LLB) catalyst,[5g] our catalytic system seemed more
simpler, milder, and efficient.
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Henry reaction of aliphatic aldehydes. By using this catalyst,
safingol was prepared in two steps with a 57% overall yield.
Further applications of this catalyst towards some bioactive
molecules are currently in progress.
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Experimental Section
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General method: Nitroethane (0.72 mL, 10.0 mmol) or 2-nitroethanol
(0.273 g, 3.0 mmol) and aliphatic aldehyde (1.0 mmol) were sequentially
added to a solution of CuACHTUNRGTNEUNG(OAc)2·H2O (20 mg, 0.10 mmol) and ligand 1b
(26.7 mg, 0.10 mmol) in THF (3 mL). The reaction mixture was stirred at
208C for 48–72 h, and then concentrated under reduced pressure. The
residue was purified by flash column chromatography on silica gel eluting
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This work was financially supported by the Fundamental Research Funds
for the Central Universities (No. 2010121014) and the Natural Science
Foundation of Fujian Province (No. 2013J10011).
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Received: September 16, 2013
Published online: November 4, 2013
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Chem. Eur. J. 2013, 19, 16541 – 16544