Water-more than just a green solvent: a stereoselective one-pot access to all-chiral tetrahydronaphthalenes in aqueous media

Article abstract of DOI:10.1002/chem.200902932

A facile and highly stereose-lective construction of heavily function-alized chiral tetrahydronaphthalene skeletons fused with an oxazolidine moiety has been developed. The pro-cess involves an organocatalytic tandem Michael/nitrone formation/in-tramolecular [3+2] nitrone-olefin cy-cloaddition in aqueous media. Using rationally designed substrates, the reaction conditions have been optimized and the one-pot process has been ap-plied to a series of nitroolefin acrylates and aldehydes. The N-hydroxyphenyla-mine component used in the second step has also been varied. The stereo-chemistry of one product has been verified by an X-ray crystal structure determination. The water used in the strategy not only constitutes an envi-ronmentally benign solvent, but also helps to improve the reactivity and ste-reoselectivity.

Full text of DOI:10.1002/chem.200902932

DOI: 10.1002/chem.200902932
Water—More Than Just a Green Solvent: A Stereoselective One-Pot Access
to All-Chiral Tetrahydronaphthalenes in Aqueous Media
Bin Tan, Di Zhu, Lihong Zhang, Pei Juan Chua, Xiaofei Zeng, and Guofu Zhong*[a]
Dedicated to Professor Koichi Narasaka on the occasion of his 65th birthday
Abstract: A facile and highly stereose-
lective construction of heavily function-
alized chiral tetrahydronaphthalene
skeletons fused with an oxazolidine
moiety has been developed. The pro-
cess involves an organocatalytic
tandem Michael/nitrone formation/in-
tramolecular [3+2] nitrone–olefin cy-
cloaddition in aqueous media. Using
rationally designed substrates, the reac-
tion conditions have been optimized
and the one-pot process has been ap-
plied to a series of nitroolefin acrylates
and aldehydes. The N-hydroxyphenyla-
mine component used in the second
step has also been varied. The stereo-
chemistry of one product has been
verified by an X-ray crystal structure
determination. The water used in the
strategy not only constitutes an envi-
ronmentally benign solvent, but also
helps to improve the reactivity and ste-
reoselectivity.
Keywords: cycloaddition
·
green
chemistry · Michael addition · tetra-
hydronaphthalenes · water
Introduction
Continuously growing interest in tetrahydronaphthalene de-
rivatives in the context of natural product chemistry,[1] as
well as in relation to other molecules of general importance
such as pharmaceuticals[2] and chiral building blocks, has re-
sulted in the development of a great number of synthetic ap-
proaches providing access to these compounds (Scheme 1).
Organocatalytic[3] domino reactions,[4] in which more than
one bond is formed in a multistep one-pot reaction se-
quence, provide access to molecules of complex architecture
without the isolation and purification of intermediates, and
are of great importance in current organic chemistry. The in-
tramolecular 1,3-dipolar cycloaddition of nitrones to al-
kenes[5] is a powerful method that offers high levels of regio-
and stereocontrol in providing access to bicyclic isoxazoli-
dines, which are important precursors of alkaloids, amino
acids, b-lactams, and amino sugars. Therefore, optically pure
Scheme 1. Some natural products and pharmaceuticals containing multi-
substituted tetrahydronaphthalene moieties.
dipoles or dipolarophiles can potentially direct the stereo-
chemistry of the cycloaddition products.
The asymmetric organocatalytic Michael addition of alde-
hydes to nitrostyrenes[6] and related domino reactions[7] have
proved to offer a very efficient approach for obtaining enan-
tiopure molecules bearing functional groups. Despite numer-
ous publications dealing with organocatalytic Michael reac-
tions, there have been very few examples concerned with
strategies based on tandem reactions involving intramolecu-
lar nitrone [3+2] cycloaddition.[8] In the work described
[a] B. Tan, D. Zhu, L. Zhang, P. J. Chua, X. Zeng, Prof. Dr. G. Zhong
Division of Chemistry & Biological Chemistry
School of Physical & Mathematical Sciences
Nanyang Technological University
21 Nanyang Link, Singapore 637371 (Singapore)
Fax : (+65)63168761
E-mail: guofu@ntu.edu.sg
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902932.
3842
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Chem. Eur. J. 2010, 16, 3842 – 3848

FULL PAPER
herein, based on a tandem Michael/intramolecular [3+2] ni-
trone–olefin cycloaddition reaction, we have developed an
asymmetric organocatalytic one-pot synthesis of multisubsti-
tuted tetrahydronaphthalene isoxazolidines. These products
may be further transformed into specific a-hydroxy-g-amino
acids.
used (Scheme 2, II, III, and IV) did not yield any improve-
ment in the results (Table 1, entries 3–6).
Inspired by the recent reports by the groups of Barbas[10]
Scheme 2. Organocatalysts tested in the tandem reaction. Ar=3,5-
(CF3)2C6H3.
Results and Discussion
Rationally designed substrate 1a was synthesized by a series
of simple transformations (for details, see the Supporting In-
formation) in readiness for the Michael reaction directed
[3+2] cycloaddition. Initially, we conducted the Michael ad-
dition using Jørgensen catalyst I[9] under the reported condi-
tions.[7d] Upon completion of the Michael reaction, the
adduct was first isolated by flash chromatography prior to
carrying out the [3+2] nitrone–olefin cycloaddition. The de-
sired product 3a was obtained with good diastereoselectivity
and enantioselectivity (Table 1, entry 1). However, the pu-
rification of intermediate 4 prompted us to explore the reac-
tion conditions required to carry out the reaction in one pot.
When the reaction was conducted in a one-pot fashion, it
proceeded smoothly albeit with poor diastereoselectivity
(Table 1, entry 2). The low diastereoselectivity in obtaining
the final product was most probably due to the hydroxyla-
mine and other components facilitating the retro-Michael
reaction. Changing of the organic solvents and catalysts
and Ma[6e] that brine and water are good media for the orga-
nocatalytic Michael reactions of aldehydes and nitroolefins,
we hypothesized that water might interact with the dipole of
the reactant and direct the configuration of the [3+2] cyclo-
addition reaction.[11] If the in situ formation of a 1,3-dipole
(nitrone) followed by an intramolecular cycloaddition could
be carried out in water, it would represent a potent and
greener approach to organic synthesis[12] as most of the reac-
tions used to form nitrones are dehydrations of substituted
hydroxylamine and carbonyl compounds that require anhy-
drous conditions, dehydrating agents, or surfactant cata-
lysts.[13] We were pleased to find that the reaction of inter-
mediate 4 and N-hydroxyphenylamine worked well in water
to afford compound 3a in good yield and with excellent ste-
reoselectivity (Table 1, entry 7). When the tandem reaction
was examined in a one-pot protocol, the diastereoselectivity
was similar to that seen for the isolated intermediate 4
(Table 1, entries 8–12). Finally, the optimized conditions
were established by varying the catalyst loading and additive
used (Table 1, entry 12).
Table 1. Screening of reaction conditions for the synthesis of chiral tetra-
hydronaphthalenes by the organocatalytic tandem reaction.[a]
Catalyst I-promoted tandem Michael/nitrone formation/
intramolecular [3+2] nitrone–olefin cycloaddition reactions
between a variety of aldehydes 2 and nitroolefin acrylates 1
under the optimized conditions were then investigated. As
revealed in Table 2, this new methodology provided a facile
and general approach to a range of multisubstituted, highly
functionalized tetrahydronaphthalene oxazolidines in mod-
erate to good yields, with the generation of five new stereo-
genic centers with excellent enantiomeric excesses (>99%
ee) and high diastereoselectivities (94:6 to 99:1 d.r.). It is
noteworthy that steric hindrance played an important role
in influencing the yield of the tandem process (Table 2,
entry 4). Significant variation of the hydroxyphenylamines
in terms of the electronic character of their phenyl units (4-
Me, Cl, Br) could be tolerated in the tandem process
(Scheme 3). Moreover, the process could also be applied to
a less reactive aliphatic hydroxylamine (BnNHOH) with
high efficiency (Scheme 3).
To determine the absolute configuration of the products,
substrate 1c was subjected to the tandem reaction
(Scheme 3). Based on X-ray structural analysis (Figure 1),[14]
the stereochemistry of product 3o could be assigned, which
was in accordance with our prediction. Furthermore, isoxa-
zolidine 3a was transformed into the a-hydroxy-g-amino
acid derivative 5 in almost quantitative yield and with no
loss of enantioselectivity (Scheme 4). The product 5 may
Entry
Cat.
Solvent
Additive
Yield
[%][b]
d.r.[c]
ee [%][d]
1[e]
2
3
4
5
I
I
I
II
III
IV
I
I
III
I
CH2Cl2
CH2Cl2
hexane
CH2Cl2
CH2Cl2
CH2Cl2
H2O
H2O
H2O
H2O
H2O
AcOH
AcOH
none
77
71
35
<5
56
<5
67
56
45
67
72
73
95:5
68:32
72:28
n.d.
81:19
n.d.
92:8
92:8
94:6
92:8
95:5
98:2
>99
>99
>99
n.d.
97
n.d.
>99
>99
97
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
PhCO2H
PhCO2H
PhCO2H
6
7[e]
8
9
10
11[f]
12[g]
>99
>99
>99
I
I
H2O
[a] Reaction conditions: Unless specified otherwise, valeraldehyde (2a,
0.6 mmol, 3.0 equiv) was added to a suspension of catalyst (10 mol%),
additive (20 mol%), and nitroolefin acrylate (1a, 0.2 mmol, 1.0 equiv) in
solvent (1.0 mL). After the nitroolefin 1a had been consumed, N-hy-
droxyphenylamine (0.8 mmol, 4.0 equiv) was added. [b] Yield of iso-
lated product. [c] Determined by 1H NMR spectroscopy and chiral
HPLC. [d] Determined by HPLC analysis. [e] Isolated intermediate 4.
[f] 5 mol% catalyst was used. [g] 2 mol% catalyst was used.
Chem. Eur. J. 2010, 16, 3842 – 3848
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3843

G. Zhong et al.
Table 2. Scope of the organocatalytic tandem Michael/nitrone formation/
Although the mechanism of each step is well established
(Scheme 5), there are still some very noteworthy and inter-
esting aspects of this highly efficient and environmentally
friendly reaction. Based on the above mentioned results, we
propose that added benzoic acid may induce accelerated for-
mation of the enamine species and promote hydrolysis of
the iminium ion in the presence of water. Furthermore, the
catalyst and additive interacted with the reactants through
hydrophobic interactions, and in the process water mole-
cules were excluded from the organic phase. The reaction
occurred efficiently in this concentrated organic phase to
give rise to the product with excellent results.[15] 1H NMR
spectra (Figure 2) demonstrated that the TMS protecting
group on catalyst I was stable in the acidic aqueous medium
for at least a couple of hours. A control experiment was per-
formed in water using catalyst II (Scheme 6), and the nega-
tive results obtained further proved that the catalyst I re-
tained its integrity during the course of the Michael addition
step.
intramolecular [3+2] cycloaddition.[a]
Entry
OR1, R
t [h][b]
Yield
[%][c]
d.r. [d]
ee [%][e]
1
2
3
4
5
6
7
8
9
OEt, nPr
OEt, Me
OEt, Et
OEt, iPr
OEt, CH
OEt, Bn
OEt, BnO
OBn, nPr
OBn, Bn
5 (3)
3 (3)
4 (3)
10 (12)
6 (5)
5 (3)
6 (10)
6 (4)
6 (4)
10 (10)
73
77
83
48
71
72
51
63
73
52
98:2
95:5
98:2
99:1
99:1
98:2
97:3
97:3
98:2
96:4
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
(CH2)5
(CH2)2
G
10
OBn, BnO
(CH2)2
[a] Reaction conditions: See the Supporting Information. [b] Time in pa-
rentheses indicates the reaction time of the cycloaddition step. [c] Yield
of isolated product. [d] Determined by 1H NMR spectroscopy and chiral
HPLC. [e] Determined by HPLC analysis.
Conclusions
have potential applications in synthetic organic chemistry
and the pharmaceutical industry.
In summary, we have developed an organocatalytic tandem
Michael/nitrone formation/intramolecular [3+2] nitrone–
olefin cycloaddition reaction
strategy for the facile construc-
tion of biologically significant,
heavily functionalized, chiral
tetrahydronaphthalene skele-
tons with multiple stereogenic
centers. This highly stereose-
lective synthetic protocol for
the construction of complex ar-
chitectures seemingly has huge
potential in medicinal chemis-
try and diversity-oriented syn-
thesis. Moreover, the use of
water in this strategy is not
only environmentally benign,
but also helps to improve the
reactivity and stereoselectivity.
Further application of this pro-
cess in organic synthesis will
be reported in due course.
Experimental Section
General: 1H NMR spectra were re-
corded on a Bruker AMX 400 spec-
trophotometer (CDCl3 as solvent);
chemical shifts reported relative to
the signal of CDCl3 (d=7.26 ppm).
13C NMR spectra reported relative to
the signal CDCl3 (d=77.0 ppm, trip-
let). Enantioselectivities were deter-
mined by HPLC analysis employing a
Daicel Chiralpak AD-H or Chiralcel
Scheme 3. Tandem reactions with different hydroxylamines.
3844
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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 3842 – 3848

Asymmetric Synthesis of Tetrahydronaphthalenes in Water
FULL PAPER
MAT 95 ꢁ P spectrometer. Racemates were synthesized by using the
racemic Jørgensen catalyst (Rac-I).
Typical procedure for the synthesis of multisubstituted chiral tetrahydro-
naphthalenes by the organocatalytic one-pot tandem reaction (Table 2,
entry 1): Valeraldehyde (2a, 0.6 mmol, 3.0 equiv) was added to a suspen-
sion of catalyst I (2 mol%), benzoic acid (20 mol%), and nitroolefin ac-
rylate 1a (0.2 mmol, 1.0 equiv) in water (1.0 mL) at room temperature
(238C). When the 1a had been consumed, N-hydroxyphenylamine
(0.8 mmol, 4.0 equiv) was added, and the mixture was stirred for a further
3 h. When the reaction was seen to be complete (monitoring by TLC and
NMR analysis of aliquots taken directly from the solution), the mixture
was extracted with CH2Cl2 (2ꢁ5 mL). The combined organic layers were
washed with brine and dried over Na2SO4, and the solvent was removed
under reduced pressure. The residue was subjected to flash chromatogra-
phy on silica gel (gradient elution, EtOAc/hexane, 1:20 to 1:10) to afford
the product (1R,3aS,4R,5S,9bR)-ethyl 5-(nitromethyl)-3-phenyl-4-propyl-
1,3,3a,4,5,9b-hexahydronaphthoACTHNUTRGNE[NUG 2,1-c]isoxazole-1-carboxylate (3a) in
73% yield. [a]2D4 =88 (c=0.6, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=
7.34–7.25 (m, 5H), 7.19 (d, J=7.6 Hz, 2H), 7.09–7.06 (m, 2H), 4.76 (dd,
J=5.6, 12.0 Hz, 1H), 4.65–4.63 (m, 1H), 4.43 (d, J=7.2 Hz, 1H), 4.27 (q,
J=6.8 Hz, 2H), 4.31–4.23 (m, 1H), 4.10–4.08 (m, 1H), 3.96 (t, J=8.4 Hz,
1H), 2.06–2.02 (m, 1H), 1.53–1.49 (m, 2H), 1.35 (t, J=7.2 Hz, 3H), 1.36–
1.27 (m, 2H), 0.96 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=170.4, 150.3, 134.9, 133.8, 129.7, 128.9, 128.1, 127.7, 127.2, 123.3, 116.4,
84.2, 77.5, 67.3, 61.9, 46.9, 38.7, 37.9, 30.6, 20.2, 14.2, 14.1 ppm; HPLC:
Chiralpak AD-H (hexane/iPrOH=80:20, flow rate 1.0 mLminÀ1
, l=
210 nm), tR (major)=8.1 min, tR (minor)=24.7 min; >99% ee; HRMS
(ESI): m/z calcd for C24H29N2O5: 425.2076 [M+H]; found 425.2075 (see
the Supporting Information for full experimental details).
(1R,3aS,4R,5S,9bR)-Ethyl
4-methyl-5-(nitromethyl)-3-phenyl-
1,3,3a,4,5,9b-hexahydronaphthoACHTUNGTERNN[GUN 2,1-c]isoxazole-1-carboxylate (3b): The
title compound was prepared in 77% yield according to the typical pro-
cedure described above (the first step in 3 h, the second step in 3 h).
[a]2D4 =87.3 (c=1.1, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=7.34–7.23
(m, 5H), 7.21 (d, J=7.6 Hz, 2H), 7.08–7.04 (m, 2H), 4.78–4.68 (m, 2H),
4.42 (d, J=7.2 Hz, 1H), 4.25 (q, J=7.2 Hz, 2H), 4.20 (t, J=7.2 Hz, 1H),
4.10 (dd, J=7.2, 11.6 Hz, 1H), 3.80 (t, J=7.2 Hz, 1H), 2.38–2.33 (m,
1H), 1.31 (t, J=7.2 Hz, 3H), 1.05 ppm (d, J=6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=170.3, 150.0, 134.3, 133.9, 129.7, 128.9, 128.0,
127.8, 126.6, 123.7, 117.0, 83.7, 77.5, 68.9, 61.9, 47.3, 39.5, 33.0, 14.1,
13.9 ppm; HPLC: Chiralpak AD-H (hexane/iPrOH=80:20, flow rate
1.0 mLminÀ1, l=220 nm), tR (major)=14.5 min, tR (minor)=35.5 min;
>99% ee; HRMS (ESI): m/z calcd for C22H25N2O5: 397.1763 [M+H];
found 397.1760.
Figure 1. X-ray crystallographic determination of 3o.
Scheme 4. Synthesis of a-hydroxy-g-amino acid derivative 5.
OD-H column. Optical rotations were measured in CH2Cl2 on a Schmidt +
Haensdch polarimeter (Polartronic MH8) with a 1.0 mL cell (c given in g
per 100 mL). Absolute configuration of the products was determined by
X-ray. High-resolution mass spectrometry was recorded on a Finnigan
(1R,3aS,4R,5S,9bR)-Ethyl 4-ethyl-5-(nitromethyl)-3-phenyl-1,3,3a,4,5,9b-
hexahydronaphthoACHTNUTGRNEUNG[2,1-c]isoxazole-1-carboxylate (3c): The title com-
pound was prepared in 83% yield according to the typical procedure de-
scribed above (the first step in 4 h, the second step in 3 h). [a]2D4 =89.5
(c=0.9,
CH2Cl2);
1H NMR
(400 MHz, CDCl3): d=7.32–7.21 (m,
5H), 7.16 (d, J=8.4 Hz, 2H), 7.08–
7.01 (m, 2H), 4.72 (dd, J=5.6,
12.0 Hz, 1H), 4.61–4.56 (m, 1H), 4.41
(d, J=7.2 Hz, 1H), 4.25 (q, J=
6.8 Hz, 2H), 4.28–4.21 (m, 1H), 4.10–
4.08 (m, 1H), 3.96 (t, J=8.4 Hz, 1H),
2.17–2.10 (m, 1H), 1.32 (t, J=7.2 Hz,
3H), 1.34–1.27 (m, 1H), 1.08 ppm (t,
J=7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=170.4, 150.4, 134.9, 133.8,
129.6, 128.9, 128.1, 127.7, 127.3, 123.2,
116.2, 84.2, 77.5, 67.1, 61.9, 46.9, 39.8,
38.4, 21.4, 14.1, 11.5 ppm; HPLC:
Chiralpak AD-H (hexane/iPrOH=
80:20, flow rate 1.0 mLminÀ1
210 nm), tR (major)=18.1 min, tR
(minor)=30.5 min; >99% ee;
HRMS (ESI): m/z calcd for
, l=
Scheme 5. Catalytic cycle and reaction pathway of the final product formation.
Chem. Eur. J. 2010, 16, 3842 – 3848
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3845

G. Zhong et al.
7.19 (d, J=8.4 Hz, 2H), 7.10–7.04 (m,
2H), 4.76 (dd, J=5.6, 12.0 Hz, 1H),
4.65–4.63 (m, 1H), 4.43 (d, J=6.8 Hz,
1H), 4.31–4.25 (m, 3H), 4.10 (m,
1H), 3.96 (t, J=8.4 Hz, 1H), 2.24–
2.20 (m, 1H), 1.53–1.49 (m, 2H),
1.46–1.30 (m, 13H), 0.90 ppm (t, J=
7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=170.4, 150.4, 134.9, 133.8,
129.6, 128.9, 128.1, 127.7, 127.1, 123.3,
116.3, 84.2, 77.5, 67.3, 61.9, 46.9, 38.7,
38.0, 31.7, 29.4, 28.4, 26.9, 22.6, 14.1,
14.0 ppm; HPLC: Chiralpak AD-H
(hexane/iPrOH=80:20, flow rate
1.0 mLminÀ1
(major)=7.1 min,
,
l=210 nm),
tR
tR (minor)=
18.7 min; >99% ee; HRMS (ESI):
m/z calcd for C27H35N2O5: 467.2546
[M+H]; found 467.2543.
(1R,3aS,4R,5S,9bR)-Ethyl 4-benzyl-5-
(nitromethyl)-3-phenyl-1,3,3a,4,5,9b-
hexahydronaphthoACTHNUTRGNE[UNG 2,1-c]isoxazole-1-
carboxylate (3 f): The title compound
was prepared in 72% yield according
to the typical procedure described
above (the first step in 5 h, the
second step in 3 h). [a]2D4 =132.4 (c=
1.4, CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=7.34–7.14 (m, 10H), 7.01–
6.92 (m, 4H), 4.79–4.77 (m, 2H), 4.44
(d, J=6.8 Hz, 1H), 4.30 (t, J=7.2 Hz,
1H), 4.22 (q, J=7.2 Hz, 1H), 4.03–
3.97 (m, 2H), 2.58–2.51 (m, 2H),
Figure 2. 1H NMR spectra of catalysts I and II in D2O + AcOH.
1.28 ppm
(t,
J=7.2 Hz,
3H);
13C NMR (100 MHz, CDCl3): d=170.0, 149.8, 138.4, 134.6, 134.0, 129.7,
129.1, 128.9, 128.8, 128.0, 127.8, 126.8, 126.1, 123.2, 116.5, 83.9, 77.2, 65.7,
61.9, 47.4, 41.3, 37.7, 34.0, 14.1 ppm; HPLC: Chiralcel OD-H (hexane/i-
PrOH=80:20, flow rate 1.0 mLminÀ1, l=210 nm), tR (major)=12.8 min,
tR (minor)=43.8 min; >99% ee; HRMS (ESI): m/z calcd for
C28H29N2O5: 473.2076 [M+H]; found 473.2080.
(1R,3aS,4R,5S,9bR)-Ethyl
phenyl-1,3,3a,4,5,9b-hexahydronaphthoACHTUNGTRENNUNG
4-[2-(benzyloxy)ethyl]-5-(nitromethyl)-3-
[2,1-c]isoxazole-1-carboxylate
(3g): The title compound was prepared in 61% yield according to the
typical procedure described above (the first step in 6 h, the second step
in 10 h). [a]2D4 =65.1 (c=0.4, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=
7.38–7.27 (m, 10H), 7.19 (d, J=8.0 Hz, 2H), 7.09–7.00 (m, 2H), 4.80 (dd,
J=5.2, 8.4 Hz, 1H), 4.73–4.70 (m, 1H), 4.55–4.53 (m, 2H), 4.44 (d, J=
6.8 Hz, 1H), 4.27 (q, J=7.2 Hz, 2H), 4.28–4.23 (m, 1H), 4.17 (m, 1H),
4.07 (t, J=8.0 Hz, 1H), 3.66–3.65 (m, 2H), 2.47–2.44 (m, 1H), 1.66–1.63
(m, 2H), 1.32 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
170.3, 150.2, 138.1, 134.9, 133.9, 129.6, 128.9, 128.5, 128.0, 127.8, 127.7,
127.0, 123.2, 116.3, 84.1, 77.6, 73.3, 68.2, 61.9, 47.1, 38.9, 36.5, 28.8,
14.1 ppm; HPLC: Chiralcel OD-H (hexane/iPrOH=80:20, flow rate
1.0 mLminÀ1, l=210 nm), tR (major)=13.6 min, tR (minor)=42.8 min;
>99% ee; HRMS (ESI): m/z calcd for C30H33N2O6: 517.2339 [M+H];
found 517.2337.
Scheme 6. Control experiment for mechanistic investigation.
C23H27N2O5: 411.1920 [M+H]; found 411.1916.
(1R,3aS,4R,5S,9bR)-Ethyl
4-isopropyl-5-(nitromethyl)-3-phenyl-
1,3,3a,4,5,9b-hexahydronaphthoACHTUNGTERNN[GUN 2,1-c]isoxazole-1-carboxylate (3d): The
title compound was prepared in 48% yield according to the typical pro-
cedure described above (the first step in 10 h, the second step in 12 h).
[a]2D4 =93.3 (c=1.5, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=7.35–7.23
(m, 7H), 7.11–7.06 (m, 2H), 4.72 (dd, J=5.6, 12.0 Hz, 1H), 4.84–4.82 (m,
2H), 4.42 (d, J=7.2 Hz, 1H), 4.27–4.22 (m, 4H), 4.13 (t, J=7.2 Hz, 1H),
2.13–2.10 (m, 1H), 1.88–1.86 (m, 1H), 1.33 (t, J=7.2 Hz, 3H), 1.01 (d,
J=6.8 Hz, 3H), 0.92 ppm (d, J=5.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=170.2, 149.5, 135.3, 134.4, 129.4, 129.0, 127.9, 127.6, 125.9,
123.8, 117.2, 84.0, 78.1, 65.5, 61.9, 47.9, 44.1, 39.2, 28.2, 22.4, 20.9,
14.1 ppm; HPLC: Chiralcel OD-H (hexane/iPrOH=80:20, flow rate
(1R,3aS,4R,5S,9bR)-Benzyl
5-(nitromethyl)-3-phenyl-4-propyl-
1,3,3a,4,5,9b-hexahydronaphthoACHTUNGTERNN[GUN 2,1-c]isoxazole-1-carboxylate (3h): The
title compound was prepared in 63% yield according to the typical pro-
cedure described above (the first step in 6 h, the second step in 4 h).
[a]2D4 =38.5 (c=1.5, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=7.42 (m,
5H), 7.40–7.19 (m, 4H), 7.17–7.12 (m, 3H), 7.08–7.02 (m, 2H), 5.25 (s,
2H), 4.74 (dd, J=5.6, 12.0 Hz, 1H), 4.60 (m, 1H), 4.47 (d, J=7.2 Hz,
1H), 4.22 (t, J=7.2 Hz, 1H), 4.08 (m, 1H), 3.94 (t, J=8.0 Hz, 1H), 2.25–
2.23 (m, 1H), 1.53–1.46 (m, 2H), 1.32–1.27 (m, 2H), 0.95 ppm (t, J=
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=170.2, 150.3, 135.0, 134.8,
133.5, 129.7, 128.9, 128.74, 128.71, 128.66, 128.1, 127.7, 127.2, 123.3, 116.3,
84.1, 77.5, 67.6, 67.5, 46.9, 38.7, 37.8, 30.6, 20.2, 14.2 ppm; HPLC: Chiral-
1.0 mLminÀ1
, l=210 nm), tR (major)=7.7 min, tR (minor)=13.2 min;
>99% ee; HRMS (ESI): m/z calcd for C24H29N2O5: 425.2076 [M+H];
found 425.2079.
(1R,3aS,4R,5S,9bR)-Ethyl 4-hexyl-5-(nitromethyl)-3-phenyl-1,3,3a,4,5,9b-
hexahydronaphthoACHTUNGTRENNUNG[2,1-c]isoxazole-1-carboxylate (3e): The title com-
pound was prepared in 71% yield according to the typical procedure de-
scribed above (the first step in 6 h, the second step in 5 h). [a]2D4 =73.7
(c=0.9, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=7.34–7.23 (m, 5H),
3846
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 3842 – 3848

Asymmetric Synthesis of Tetrahydronaphthalenes in Water
FULL PAPER
pak AD-H (hexane/iPrOH=80:20, flow rate 1.0 mLminÀ1, l=210 nm),
tR (major)=13.3 min, tR (minor)=37.4 min; >99% ee; HRMS (ESI): m/
z calcd for C29H31N2O5: 487.2233 [M+H]; found 487.2232.
(m, 1H), 3.91 (t, J=8.0 Hz, 1H), 2.23–2.21 (m, 1H), 1.51–1.45 (m, 2H),
1.34 (t, J=7.2 Hz, 3H), 1.34–1.29 (m, 2H), 0.95 ppm (t, J=7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=170.3, 148.9, 134.7, 133.6, 129.6, 128.9,
128.4, 128.1, 127.8, 127.1, 117.7, 84.2, 77.2, 67.4, 62.0, 47.1, 38.4, 37.8, 30.4,
20.2, 14.2, 14.1 ppm; HPLC: Chiralpak AD-H (hexane/iPrOH=80:20,
flow rate 1.0 mLminÀ1, l=210 nm), tR (major)=9.3 min, tR (minor)=
38.1 min; >99% ee; HRMS (ESI): m/z calcd for C24H28N2O5Cl: 459.1687
[M+H]; found 459.1686.
(1R,3aS,4R,5S,9bR)-Benzyl
4-benzyl-5-(nitromethyl)-3-phenyl-
1,3,3a,4,5,9b-hexahydronaphthoACHTUNGTERNN[GUN 2,1-c]isoxazole-1-carboxylate (3i): The
title compound was prepared in 73% yield according to the typical pro-
cedure described above (the first step in 6 h, the second step in 4 h).
[a]2D4 =96.1 (c=1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=7.38–7.13
(m, 15H), 7.00–6.96 (m, 2H), 6.91–6.89 (m, 2H), 5.22–5.16 (m, 2H), 4.78
(m, 2H), 4.49 (d, J=6.8 Hz, 1H), 4.28 (t, J=7.2 Hz, 1H), 3.98–3.95 (m,
2H), 2.57–2.53 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d=169.8,
149.6, 138.3, 135.0, 134.6, 133.8, 129.7, 129.1, 128.9, 128.7, 128.65, 128.0,
127.8, 126.8, 123.2, 116.5, 83.7, 77.2, 67.6, 65.9, 47.5, 41.2, 37.7, 34.0 ppm;
(1R,3aS,4R,5S,9bR)-Ethyl 3-(4-bromophenyl)-5-(nitromethyl)-4-propyl-
1,3,3a,4,5,9b-hexahydronaphthoACHTUNTRGNEU[GN 2,1-c]isoxazole-1-carboxylate (3m): The
title compound was prepared in 67% yield according to the general pro-
cedure described above (the second step in 3 h). [a]2D4 =87.5 (c=0.9,
CH2Cl2); 1H NMR (400 MHz, CDCl3): d=7.42 (d, J=8.8 Hz, 2H), 7.3–
7.25 (m, 3H), 7.08–7.05 (m, 1H), 7.06 (d, J=8.8 Hz, 1H), 4.74 (dd, J=
6.0, 12.0 Hz, 1H), 4.67–4.64 (m, 1H), 4.43 (d, J=6.8 Hz, 1H), 4.28 (q, J=
7.2 Hz, 2H), 4.22 (t, J=7.2 Hz, 1H), 4.10–4.08 (m, 1H), 3.91 (t, J=
8.0 Hz, 1H), 2.23–2.18 (m, 1H), 1.65 (m, 1H), 1.52–1.46 (m, 2H), 1.34 (t,
J=7.2 Hz, 3H), 1.29–1.26 (m, 1H), 0.95 ppm (t, J=7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=170.3, 149.5, 134.7, 133.6, 131.8, 129.6,
128.2, 127.8, 127.0, 117.9, 115.8, 84.2, 77.2, 67.3, 62.0, 47.1, 38.5, 37.9, 30.5,
20.2, 14.2, 14.1 ppm; HPLC: Chiralpak AD-H (hexane/iPrOH=80:20,
flow rate 1.0 mLminÀ1, l=210 nm), tR (major)=8.7 min, tR (minor)=
34.0 min; >99% ee; HRMS (ESI): m/z calcd for C24H28N2O5Br: 504.3846
[M+H]; found 504.3848.
HPLC: Chiralcel OD-H (hexane/iPrOH=80:20, flow rate 1.0 mLminÀ1
,
l=210 nm), tR (major)=20.9 min, tR (minor)=28.3 min; >99% ee;
HRMS (ESI): m/z calcd for C33H31N2O5: 435.2233 [M+H]; found
535.2237.
(1R,3aS,4R,5S,9bR)-Benzyl
phenyl-1,3,3a,4,5,9b-hexahydronaphthoACHTUNGTRENNUNG
4-[2-(benzyloxy)ethyl]-5-(nitromethyl)-3-
[2,1-c]isoxazole-1-carboxylate
(3j): The title compound was prepared in 62% yield according to the typ-
ical procedure described above (the first step in 10 h, the second step in
10 h). [a]2D4 =50.7 (c=1.3, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=
7.39–7.30 (m, 10H), 7.26–7.13 (m, 7H), 7.08–7.01 (m, 2H), 5.23 (s, 2H),
4.79 (dd, J=5.2, 12.0 Hz, 1H), 4.70–4.68 (m, 1H), 4.56–4.47 (m, 3H),
4.24 (t, J=7.2 Hz, 1H), 4.16–4.14 (m, 1H), 4.04 (t, J=8.0 Hz, 1H), 3.65–
3.63 (m, 2H), 2.46–2.43 (m, 1H), 1.98–1.84 (m, 1H), 1.66–1.64 ppm (m,
1H); 13C NMR (100 MHz, CDCl3): d=170.1, 150.1, 138.1, 135.0, 134.8,
133.6, 129.7, 128.9, 128.7, 128.5, 128.0, 127.8, 127.73, 127.71, 127.0, 123.2,
116.2, 84.0, 77.6, 73.2, 68.2, 67.6, 67.2, 47.2, 38.8, 36.4, 28.8 ppm; HPLC:
(1R,3aS,4R,5S,9bR)-Ethyl
3-benzyl-5-(nitromethyl)-4-propyl-
1,3,3a,4,5,9b-hexahydronaphthoACHTUNGTERNN[GUN 2,1-c]isoxazole-1-carboxylate (3n): The
title compound was prepared in 48% yield according to the general pro-
cedure described above (the second step in 24 h). [a]2D4 =À4.6 (c=0.8,
CH2Cl2); 1H NMR (400 MHz, CDCl3): d=7.42 (d, J=6.8 Hz, 2H), 7.36–
7.21 (m, 6H), 6.98 (d, J=7.6 Hz, 1H), 4.61 (m, 1H), 4.52 (dd, J=6.4,
12.0 Hz, 1H), 4.37–4.12 (m, 5H), 4.02–4.00 (m, 2H), 3.24 (t, J=7.2 Hz,
1H), 1.85 (m, 1H), 1.33 (t, J=7.2 Hz, 3H), 1.36–1.30 (m, 3H), 0.93–0.90
(m, 1H), 0.85 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
171.4, 136.9, 134.7, 134.3, 129.7, 129.2, 128.4, 127.8, 127.6, 127.5, 126.3,
83.8, 77.2, 66.2, 61.8, 61.6, 48.3, 37.9, 29.9, 20.2, 14.2, 14.1 ppm; HPLC:
Chiralpak AD-H (hexane/iPrOH=80:20, flow rate 1.0 mLminÀ1
, l=
210 nm), tR (major)=17.4 min, tR (minor)=29.7 min; >99% ee; HRMS
(ESI): m/z calcd for C35H35N2O6: 579.2495 [M+H]; found 579.2498.
General procedure for the tandem reactions with different hydroxyla-
mines: Valeraldehyde (2a, 0.6 mmol, 3.0 equiv) was added to a suspen-
sion of catalyst I (2 mol%), benzoic acid (20 mol%), and nitroolefin ac-
rylate 1a (0.2 mmol, 1.0 equiv) in water (1.0 mL) at room temperature.
After 5 h, the nitroolefin 1a had been consumed, whereupon the requi-
site hydroxylamine (4-Me-C6H4NHOH, 4-Cl-C6H4NHOH, 4-Br-
C6H4NHOH, or BnNHOH) (0.8 mmol, 4.0 equiv) was added and the re-
sulting mixture was stirred for 3–24 h. When the reaction was complete
(monitoring by TLC and NMR analysis of aliquots taken directly from
the solution), the mixture was extracted with CH2Cl2 (2ꢁ5 mL). The
combined organic layers were washed repeatedly with brine and dried
over Na2SO4. The solvent was removed under reduced pressure and the
residue was subjected to flash chromatography on silica gel (EtOAc/
hexane, 1:20–1:12) to afford the product.
Chiralpak AD-H (hexane/iPrOH=80:20, flow rate 1.0 mLminÀ1
, l=
210 nm), tR (major)=5.7 min, tR (minor)=9.3 min; >99% ee; HRMS
(ESI): m/z calcd for C25H31N2O5: 439.2233 [M+H]; found 439.2233.
General procedure for the synthesis of 3o for X-ray analysis: Propional
(2b, 0.6 mmol, 3.0 equiv) was added to
a suspension of catalyst I
(2 mol%), benzoic acid (20 mol%), and nitroolefin acrylate 1c
(0.2 mmol, 1.0 equiv) in water (1.0 mL) at room temperature. After 5 h,
the nitroolefin 1c had been consumed, whereupon 4-chloro-N-hydroxy-
phenylamine (0.8 mmol, 4.0 equiv) was added and the resulting mixture
was stirred for 4 h. When the reaction was complete (monitoring by TLC
and NMR analysis of aliquots taken directly from the solution), the mix-
ture was extracted with CH2Cl2 (2ꢁ5 mL). The combined organic layers
were washed three times with brine, dried over Na2SO4, and the solvent
was removed under reduced pressure. The residue was subjected to flash
chromatography on silica gel to afford 3o in 61% yield (EtOAc/hexane,
(1R,3aS,4R,5S,9bR)-Ethyl
5-(nitromethyl)-4-propyl-3-p-tolyl-
1,3,3a,4,5,9b-hexahydronaphthoACHTUNGTERNN[GUN 2,1-c]isoxazole-1-carboxylate (3k): The
title compound was prepared in 74% yield according to the general pro-
cedure described above (the second step in 3 h). [a]2D4 =74.0 (c=1.0,
CH2Cl2); 1H NMR (400 MHz, CDCl3): d=7.28–7.24 (m, 3H), 7.15–7.07
(m, 5H), 4.76 (dd, J=5.6, 12.0 Hz, 1H), 4.66–4.63 (m, 1H), 4.41 (d, J=
7.2 Hz, 1H), 4.29 (q, J=7.2 Hz, 2H), 4.23 (t, J=7.2 Hz, 1H), 4.12 (m,
1H), 3.88 (t, J=8.0 Hz, 1H), 2.33 (s, 3H), 2.18–2.16 (m, 1H), 1.51–1.42
(m, 2H), 1.36 (t, J=7.2 Hz, 3H), 1.29–1.22 (m, 2H), 0.96 ppm (t, J=
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=170.5, 147.7, 134.8, 134.0,
133.3, 129.7, 129.5, 128.0, 127.6, 127.0, 117.2, 84.0, 77.5, 67.5, 61.9, 47.0,
38.6, 37.7, 30.4, 20.7, 20.2, 14.2, 14.1 ppm; HPLC: Chiralpak AD-H
(hexane/iPrOH=80:20, flow rate 1.0 mLminÀ1, l=210 nm), tR (major)=
10.7 min, tR (minor)=30.2 min; >99% ee; HRMS (ESI): m/z calcd for
C25H31N2O5: 439.2233 [M+H]; found 439.2234.
1
1:20–1:10). [a]2D4 =86.5 (c=0.5, CH2Cl2); H NMR (400 MHz, CDCl3): d=
7.26 (d, J=8.8 Hz, 2H), 7.09 (d, J=8.8 Hz, 1H), 6.72 (s, 1H), 6.55 (s,
1H), 5.95 (s, 2H), 4.70–4.61 (m, 2H), 4.36 (d, J=7.2 Hz, 1H), 4.28 (q, J=
7.2 Hz, 2H), 4.03 (t, J=7.2 Hz, 1H), 3.93–3.91 (m, 1H), 3.72 (t, J=
8.0 Hz, 1H), 2.33–2.28 (m, 1H), 1.32 (t, J=7.2 Hz, 3H), 1.10 ppm (d, J=
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=170.2, 148.8, 147.5, 147.4,
128.9, 128.5, 127.5, 126.7, 118.0, 109.2, 106.9, 101.4, 84.0, 77.6, 68.7, 62.1,
47.2, 40.2, 32.8, 14.2, 14.1 ppm; HPLC: Chiralpak AD-H (hexane/
iPrOH=80:20, flow rate 1.0 mLminÀ1, l=210 nm), tR (major)=16.0 min,
tR (minor)=35.5 min; >99% ee; HRMS (ESI): m/z calcd for
C23H23N2O7Cl: 475.1272 [M+H]; found 475.1275.
General procedure for the synthesis of a-hydroxy-g-amino acid deriva-
tives:
(1R,3aS,4R,5S,9bR)-Ethyl 3-(4-chlorophenyl)-5-(nitromethyl)-4-propyl-
1,3,3a,4,5,9b-hexahydronaphthoACHTUNTRGNEU[GN 2,1-c]isoxazole-1-carboxylate (3l): The
title compound was prepared in 64% yield according to the general pro-
cedure described above (the second step in 3 h). [a]2D4 =83.9 (c=1.0,
CH2Cl2); 1H NMR (400 MHz, CDCl3): d=7.29–7.23 (m, 5H), 7.13–7.07
(m, 3H), 4.74 (dd, J=6.0, 12.0 Hz, 1H), 4.67–4.64 (m, 1H), 4.43 (d, J=
7.2 Hz, 1H), 4.28 (q, J=7.2 Hz, 2H), 4.22 (t, J=7.2 Hz, 1H), 4.10–4.08
(R)-Ethyl 2-hydroxy-2-[(1R,2S,3R,4S)-4-(nitromethyl)-2-(phenylamino)-
3-propyl-1,2,3,4-tetrahydronaphthalen-1-yl]acetate (5): 10% Pd/C
(30 mg) was added to a solution of 3a (0.1 mmol) in methanol (5.0 mL)
at room temperature, which was maintained under an atmosphere of hy-
drogen by means of a balloon. After stirring for 2 h, the mixture was fil-
Chem. Eur. J. 2010, 16, 3842 – 3848
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3847

G. Zhong et al.
tered through Celite. Removal of the solvent from the filtrate under re-
duced pressure afforded the product in almost quantitative yield. [a]D24
2009, 48, 758; q) H. Jiang, P. Elsner, K. L. Jensen, A. Falcicchio, V.
Marcos, K. A. Jørgensen, Angew. Chem. 2009, 121, 6976; Angew.
Chem. Int. Ed. 2009, 48, 6844; r) L. Wu, G. Bencivenni, M. Manci-
nelli, A. Mazzanti, G. Bartoli, P. Melchiorre, Angew. Chem. 2009,
121, 7332; Angew. Chem. Int. Ed. 2009, 48, 7196; s) G. Bencivenni,
L. Wu, A. Mazzanti, B. Giannichi, F. Pesciaioli, M. Song, G. Bartoli,
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=
À28.0 (c=1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=7.40–7.21 (m,
3H), 7.16 (t, J=7.2 Hz, 1H), 7.04 (d, J=8.0 Hz, 1H), 6.71 (t, J=7.2 Hz,
1H), 6.55 (d, J=8.0 Hz, 2H), 4.65 (s, 1H), 4.60 (dd, J=4.8, 12.0 Hz, 1H),
4.53–4.50 (m, 1H), 4.01–3.92 (m, 4H), 3.78–3.76 (m, 2H), 3.56–3.51 (m,
1H), 3.29 (s, 1H), 2.70–2.68 (m, 1H), 1.56–1.51 (m, 3H), 1.12–0.98 (m,
1H), 1.01 (t, J=7.2 Hz, 3H), 0.94 ppm (t, J=7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=174.0, 146.7, 136.3, 135.1, 129.4, 129.0, 127.9,
127.5, 127.4, 117.8, 112.4, 78.4, 75.6, 62.0, 52.3, 42.9, 38.9, 30.2, 20.0, 14.4,
13.9 ppm; HPLC: Chiralpak AD-H (hexane/iPrOH=90:10, flow rate
0.8 mLminÀ1, l=210 nm), tR (minor)=15.2 min, tR (major)=17.6 min;
>99% ee; HRMS (ESI): m/z calcd for C24H31N2O5: 427.2233 [M+H];
found 427.2230.
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Acknowledgements
Research support from the Ministry of Education in Singapore (ARC12/
07, no. T206B3225) and Nanyang Technological University (URC RG53/
07) is gratefully acknowledged. We also thank Dr. Yongxin Li for per-
forming the X-ray crystallographic analysis and Miss Wendy Wen Yi
Leong for English polishing.
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Received: October 22, 2009
Revised: December 6, 2009
Published online: February 11, 2010
3848
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