Highly stereoselective synthesis of indanes with four stereogenic centers via sequential Michael reaction and [3+2] cycloaddition

Article abstract of DOI:10.1039/c0cc01577f

A highly efficient organocatalytic sequential reaction involving Michael addition of bis(phenylsulfonyl)ethylene, in situ condensation and intramolecular nitrone [3+2] cycloaddition with a variety of aldehydes and hydroxyamines to afford a single diastereomer of indanes with four stereogenic centers in excellent yields and stereoselectivities was developed.

Full text of DOI:10.1039/c0cc01577f

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Highly stereoselective synthesis of indanes with four stereogenic centers
via sequential Michael reaction and [3+2] cycloadditionw
Pei Juan Chua, Bin Tan, Limin Yang, Xiaofei Zeng, Di Zhu and Guofu Zhong*
Received 25th May 2010, Accepted 25th August 2010
DOI: 10.1039/c0cc01577f
A highly efficient organocatalytic sequential reaction involving
Michael addition of bis(phenylsulfonyl)ethylene, in situ
condensation and intramolecular nitrone [3+2] cycloaddition
with a variety of aldehydes and hydroxyamines to afford a single
diastereomer of indanes with four stereogenic centers in
excellent yields and stereoselectivities was developed.
sulfones, we can provide a different dipolarophile to direct the
stereochemistry of the cycloaddition products so as to obtain
the indane skeleton with a very high level of stereocontrol.
Herein, we present a highly stereocontrolled synthesis of
indanes with four stereogenic centers via a sequential reaction
involving Michael addition of bis(phenylsulfonyl)ethylene,
in situ condensation and intramolecular nitrone [3+2]
cycloaddition. This protocol may be useful in the synthesis
of biologically interesting compounds due to the versatility of
the multi-substituents on the tricyclic heterocycles, simple
operating procedures and excellent stereocontrol.
Indane ring structures are widely presented in a number of
naturally occurring products such as Gnetuhainin E1 and
Mirabiloside C,2 and indane derivatives have attracted much
attention due to the broad scope of their biological activities.3
Although several approaches for the synthesis of this skeleton
have been explored, they usually require multi-steps and
expensive reagents. Thus we were interested in developing a
sequential approach that allows the rapid establishment of
these polycyclic indanes in a single operation.
To assess the viability of this sequential approach, we first
synthesized our rationally designed substrate 1a through a
series of simple transformations (for details, see the ESIw). We
started our investigation by conducting the Michael reaction
with aldehyde 1a, 1,1-bis(phenylsulfonyl)-ethylene 2 and
catalyst I in dichloromethane at À20 1C. Upon completion
of reaction, hydroxyamine 3a was then added to the reaction
mixture and stirred at 22 1C for 3 h. To our delight, the desired
product 4a was isolated as a single diastereomer in 92% yield
and 94% enantiomeric excess (ee) (Table 1, entry 1). Changing
the catalyst did not give any significant improvements to the
results (Table 1, entries 2–4). Though catalyst IV11 gave
slightly higher ee, its yield was significantly lower than that
with catalyst I. Thus, catalyst I was chosen for further
optimization of the reaction conditions. Out of curiosity, we
explored the effects of increasing the equivalents of aldehyde
1a to 3 equivalents (Table 1, entry 5). As expected, there were
slight improvements in both the yield and enantioselectivity,
but it seems unjustifiable to use large excess of substrate for
such minor improvements. A brief solvent screening revealed
that toluene is the best solvent as it gave the highest yield and
enantioselectivity (Table 1, entries 6–9). Next, we investigated
the effects of catalyst loading (Table 1, entries 10 and 11).
Decreasing the catalyst loading to 5 mol% of catalyst I
appeared to be the most suitable as a further decrease in the
catalyst loading led to a loss of enantioselectivity. We also
looked into the influence of temperature on the reaction
(Table 1, entry 12). Lower yield and enantioselectivity were
observed for the reaction that was conducted at 4 1C for the
first step. In view of the above optimizations, the most suitable
reaction conditions for the sequential reaction was determined
to be aldehyde 1a (1.5 equiv.), catalyst I (5 mol%) and
1,1-bis(phenylsulfonyl)-ethylene 2 (0.05 mmol) in toluene
(0.3 mL) at À20 1C, followed by addition of hydroxyamine
3a (1.5 equiv.) at 22 1C for 3 h upon completion of the
first step.
Organocatalytic sequential reactions have gained importance
in recent years as they provide attractive approaches to
synthesize molecules with complex architecture without
the need to isolate or purify intermediates. Direct Michael
addition of carbonyl donors via enamine activation features an
appealing route to obtain versatile functionalized adducts in
an atom-economical manner. Much investigations have been
done on nitroalkenes as Michael acceptors, but the use of vinyl
sulfones in Michael reactions was left largely unexplored until
Alexakis reported the first organocatalyzed asymmetric
Michael addition of aldehydes to vinyl sulfones in 2005.4 Since
then, there has been some reports on the use of vinyl sulfones
as Michael acceptors for reactions with various aldehydes,5
ketones6 and nitroalkanes.7 However, to the best of our
knowledge, there have been no reports on the application of
vinyl sulfones in sequential reactions.
Besides the Michael reaction, the intramolecular nitrone/
alkene cycloaddition is also another useful methodology that
has attracted much attention in the synthesis of interesting
frameworks found in numerous biologically active compounds.8
Such reactions often provide products with high levels of
regio- and stereocontrol. Our group has recently demonstrated
the combination of these two useful reactions to furnish optically
pure bicyclic isoxazolidines9 and tetrahydronaphthalenes.10
We reasoned that if we change the Michael acceptor to vinyl
Division of Chemistry & Biological Chemistry, School of Physical &
Mathematical Sciences, Nanyang Technological University,
21 Nanyang Link, Singapore, 637371, Singapore.
E-mail: guofu@ntu.edu.sg; Fax: +65 6791 1961;
Tel: +65 6316 8761
w Electronic supplementary information (ESI) available: Experimental
procedures, 1H and 13C spectra, and chiral separations for compounds
1a–e, 4a–k and 5. CCDC 778385. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c0cc01577f
With the optimized reaction conditions in hand, we explored
the generality of the sequential Michael/[3+2] cycloaddition
reaction. For all the substrates investigated, we only observed
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 7611–7613 7611

View Article Online
Table 1 Optimization of reaction conditionsa
hydroxyamines do not significantly affect the yield and
enantioselectivity of the sequential reaction (Table 2, entries
2–6), we noticed that ortho- and meta-substituted hydroxy-
amines require harsher reaction conditions for the cyclo-
addition reaction (Table 2, entries 3 and 5). Not only were
aryl hydroxyamines 3a–3f able to give good results for the
reaction, alkyl hydroxyamine 3g was also able to afford
comparable results (Table 2, entry 7). The yields and enantio-
selectivities were not significantly affected by changing the
ester group (Table 2, entry 8) or the substituents of aldehyde 1
(Table 2, entries 9 and 10).
With the success of employing the above reaction protocol
for ortho-substituted phenylacetaldehydes, we decided to try
linear aldehydes. The reaction proceeded smoothly in the
presence of (E)-methyl 7-oxohept-2-enoate (1e) to afford the
bicyclic compound 4k in 94% yield and 94% ee (Scheme 1).
This demonstrated that the reaction protocol is not only
restricted to ortho-substituted phenylacetaldehyde and is
applicable to linear aldehydes of suitable chain length.
To determine whether the enantioselectivity of this tandem
reaction is dependent on the initial Michael reaction, we
isolated the Michael product A with 97% ee (Scheme 2). This
demonstrated that this stereocenter controls the formation of
the other stereogenic centers.
Entry
Solvent
Catalyst
Yield (%)b
ee (%)c
1
2
3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
THF
I
92
59
75
76
96
81
65
65
89
98
91
82
94
39
60
98
95
97
81
85
97
98
95
76
II
III
IV
I
I
I
I
I
I
I
4
5d
6
7
8
EA
9e
Toluene
Toluene
Toluene
Toluene
10e,f
11e,g
12e,f,h
I
a
Conditions: aldehyde 1a (1.5 equiv.) was added to catalyst
(10 mol%), 1,1-bis(phenylsulfonyl)-ethylene 2 (0.05 mmol) and solvent
(0.1 mL) at À20 1C and upon completion of reaction, hydroxyamine
3a (1.5 equiv.) was then added to the reaction mixture and stirred at
Based on X-ray structural analysis of product 4d, the stereo-
chemistry of 4d was assigned (CCDC 778385w) and this was in
accordance with our prediction. In addition, we subjected indane
4a to the cleavage of the N–O bond to afford a-hydroxy-g-amino
acid derivative 5 in almost quantitative yield and with no
significant loss of enantioselectivity (Scheme 3).
b
c
22 1C for 3 h, unless otherwise stated. Isolated yields. Determined
by chiral phase HPLC. 3 equiv. of 1a used. 0.3 mL of toluene.
d
e
f
g
5 mol% catalyst loading. 2 mol% catalyst loading. Reaction
h
conducted at 4 1C for the first step.
Furthermore, we also treated indane 4j with magnesium for
desulfonylation. To our surprise, in addition to successful
desulfonylation, the cleavage of the N–O bond afforded
a-hydroxy-g-lactam derivative 6 in moderate yield with
94% ee (Scheme 4). Both derivatives 5 and 6 may have
potential applications in synthetic organic chemistry and the
pharmaceutical industry.
a single diastereomer for the sequential reactions and the
products were obtained in excellent yields and ee with a variety
of aldehydes 1 and hydroxyamines 3 (Table 2). First of all, we
investigated the effects of using different hydroxyamines
(Table 2, entries 1–7). Although the position and electronic
properties of the substituents on the aromatic rings of
Table 2 Generality of the sequential Michael reaction–[3+2] cycloadditiona
Entry
R1
R2
R3
Product
Yield (%)b
ee (%)c
1
2
H
H
H
H
H
H
H
H
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Me
CO2Et
CO2Et
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
98
92
97
92
97
96
91
90
98
97
98
96
98
98
95
98
98
98
92
99
4-BrC6H4
3-ClC6H4
4-ClC6H4
2-CH3C6H4
4-CH3C6H4
CH2Ph
Ph
3d
4e
5d
6
7
8
9e,f
10
3-OMe
3,4-OCH2O
Ph
Ph
4j
a
Conditions: corresponding aldehyde 1 (1.5 equiv.) was added to catalyst I (5 mol%), 1,1-bis(phenylsulfonyl)ethylene 2 (0.1 mmol) and toluene
(0.6 mL) at À20 1C and upon completion of reaction, respective hydroxyamine 3 (1.5 equiv.) was then added to the reaction mixture and stirred at
b
c
d
22 1C for 3 h, unless otherwise stated. Isolated yields. Determined by chiral phase HPLC. Reaction conducted at 50 1C for the second
step. Reaction was conducted for 4 h for the second step. Reaction was conducted for 48 h for the first step.
e
f
c
7612 Chem. Commun., 2010, 46, 7611–7613
This journal is The Royal Society of Chemistry 2010

View Article Online
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 from Nanyang
Technological University for performing the X-ray crystallo-
graphic analysis.
Notes and references
Scheme 1 Synthesis of bicyclic compound 4k.
1 K.-S. Huang, Y.-H. Wang, R.-L. Li and M. Lin, J. Nat. Prod.,
2000, 63, 86.
2 H. Murata, I. IIiya, T. Tanaka, M. Furasawa, T. Ito, K.-i. Nakaya,
M. Oyama and M. Iinuma, Chem. Biodiversity, 2005, 2, 773.
3 (a) T. J. Caulfield, J. Clemens, R. S. Francis, B. S. Freed, S. John,
T.-B. Le, B. Pedgrift, A. D. Ramos, G. Rosse, M. Smrcina,
D. S. Thorpe, W. Wire and J. Zhao, PCT Int. Appl., WO
2008151211, 2008; (b) R. A. Fairhurst, D. A. Sandham,
D. Beattie, I. Bruce, B. Cuenoud, R. Madden, N. J. Press,
R. J. Taylor, K. L. Turner and S. J. Watson, PCT Int. Appl.,
WO 2004087142, 2004; (c) J. E. Wood, J. L. Baryza,
C. R. Brennan, S. Choi, J. H. Cook, B. R. Dixon, P. Erlich,
D. E. Gunn, P. Liu, D. B. Lowe, I. McAlexander, A. M. Redman,
W. J. Scott and Y. Wang, PCT Int. Appl., WO 2002026706, 2002.
4 (a) S. Mosse and A. Alexakis, Org. Lett., 2005, 7, 4361;
(b) S. Sulzer-Mosse and A. Alexakis, Chem. Commun., 2007, 3123.
5 Q. Zhu and Y. Lu, Chem. Commun., 2010, 46, 2235.
Scheme 2 Isolated Michael product A.
6 (a) A. Quintard, S. Belot, E. Marchal and A. Alexakis, Eur. J. Org.
Chem., 2010, 927; (b) A. Landa, M. Maestro, C. Masdeu,
A. Puente, S. Vera, M. Oiarbide and C. Palomo, Chem.–Eur. J.,
2009, 15, 1562; (c) S. Sulzer-Mosse, A. Alexakis, J. Mareda,
G. Bollot, G. Bernardinelli and Y. Filinchuk, Chem.–Eur. J.,
2009, 15, 3204; (d) A. Quintard, C. Bournaud and A. Alexakis,
Chem.–Eur. J., 2008, 14, 7504.
Scheme 3 Synthesis of a-hydroxy-g-amino acid 5.
7 Q. Zhu and Y. Lu, Org. Lett., 2009, 11, 1721.
8 (a) T. Kano, T. Hashimoto and K. Maruoka, J. Am. Chem. Soc.,
2005, 127, 11926; (b) J. N. Martin and R. C. F Jones, in Synthetic
Applications of 1,3-Dipolar Cycloaddition Chemistry Toward
Heterocycles and Natural Products, ed. A. Padwa and
W. H. Pearson, Wiley, Hoboken, NJ, 2003, ch. 1, p. 1;
(c) K. V. Gothelf, in Cycloaddition Reactions in Organic Synthesis,
ed. S. Kobayashi and K. A. Jørgensen, Wiley-VCH, Weinheim,
2002, ch. 6, p. 211; (d) S. Kanemasa, in Cycloaddition Reactions in
Organic Synthesis, ed. S. Kobayashi and K. A. Jørgensen,
Wiley-VCH, Weinheim, 2002, ch. 7, p. 249; (e) O. Tamura,
N. Mita, T. Okabe, T. Yamaguchi, C. Fukushima,
M. Yamashita, Y. Morita, N. Morita, H. Ishibashi and
M. Sakamoto, J. Org. Chem., 2001, 66, 2602; (f) K. V. Gothelf
and K. A. Jørgensen, Chem. Rev., 1998, 98, 863.
Scheme 4 Synthesis of a-hydroxy-g-lactam 6.
9 D. Zhu, M. Lu, L. Dai and G. Zhong, Angew. Chem., Int. Ed.,
2009, 48, 6089.
10 B. Tan, D. Zhu, L. Zhang, P. J. Chua, X. Zeng and G. Zhong,
Chem.–Eur. J., 2010, 16, 3842.
11 (a) P. J. Chua, B. Tan and G. Zhong, Green Chem., 2009, 11, 543;
(b) D. Zhu, M. Lu, P. J. Chua, B. Tan, F. Wang, X. Yang and
G. Zhong, Org. Lett., 2008, 10, 4585; (c) M. Lu, D. Zhu, Y. Lu,
Y. Hou, B. Tan and G. Zhong, Angew. Chem., Int. Ed., 2008, 47,
10187; (d) K. Sakthivel, W. Notz, T. Bui and C. F. Barbas III,
J. Am. Chem. Soc., 2001, 123, 5260; (e) X. Zhu, F. Tanaka, Y. Hu,
A. Heine, R. Fuller, G. Zhong, A. J. Olson, R. A. Lerner, C. F. III.
Barbas and I. A. Wilson, J. Mol. Biol., 2004, 343, 1269.
In conclusion, we have developed an organocatalytic
sequential approach involving Michael addition of bis(phenyl-
sulfonyl)ethylene, in situ condensation and intramolecular
nitrone [3+2] cycloaddition with a variety of aldehydes and
hydroxyamines to afford a single diastereomer of indanes with
four stereogenic centers with excellent yields and stereo-
selectivities. The advantages of this reaction protocol lie in the
versatility of the multi-substituents on the indane core structure,
simple operating procedures and excellent stereocontrol.
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 7611–7613 7613