Catalytic enantioselective construction of quaternary stereocenters by direct vinylogous Michael addition of deconjugated butenolides to nitroolefins

Article abstract of DOI:10.1039/c2cc31700a

A direct vinylogous Michael reaction of γ-substituted deconjugated butenolides with nitroolefins has been developed with the help of a newly identified quinine-derived bifunctional catalyst, allowing the synthesis of densely functionalized products with contiguous quaternary and tertiary stereocenters in excellent yield with perfect diastereoselectivity (>20:1 dr) and high enantioselectivity (up to 99:1 er).

Full text of DOI:10.1039/c2cc31700a

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COMMUNICATION
Catalytic enantioselective construction of quaternary stereocenters by
direct vinylogous Michael addition of deconjugated butenolides to
nitroolefinsw
Madhu Sudan Manna, Vikas Kumar and Santanu Mukherjee*
Received 7th March 2012, Accepted 28th March 2012
DOI: 10.1039/c2cc31700a
A direct vinylogous Michael reaction of c-substituted deconjugated
butenolides with nitroolefins has been developed with the help of
a newly identified quinine-derived bifunctional catalyst, allowing
the synthesis of densely functionalized products with contiguous
quaternary and tertiary stereocenters in excellent yield with perfect
diastereoselectivity (420 : 1 dr) and high enantioselectivity
(up to 99 : 1 er).
The enantioselective construction of quaternary stereogenic
centers has long been considered an important yet challenging
task owing to the involved inherent steric repulsion.1 Among
Fig. 1 Selected natural products containing the g-butenolide moiety.
different approaches towards this goal, the combination of
The purpose of this communication is to disclose our
philes has particularly emerged as a very popular strategy.1b
findings on the highly diastereo-and enantioselective Michael
trisubstituted carbon nucleophiles with an ensemble of electro-
addition of several g-substituted deconjugated butenolides to
nitroolefins.
Inspired by the challenges associated with this task, we selected
the direct coupling of a trisubstituted carbon nucleophile with an
acceptor-activated olefin. Accordingly, g-substituted deconju-
gated butenolides were selected as the nucleophilic component
considering the wide abundance of the g-butenolide moiety in
bioactive natural products (Fig. 1). The silyl enol ether deri-
vatives of g-butenolide (silyloxy furans) have been heavily
utilized in asymmetric vinylogous Mukaiyama-type aldol,
Mannich and Michael reactions.2 However, the application
of butenolide itself in asymmetric synthesis remains relatively
underexplored.3 In the same context, the deconjugated 5-methyl
butenolide (a-angelica lactone) started gaining attention only
very recently due to its potential for the construction of a
g-quaternary stereocenter.4,5 Asymmetric allylic alkylation6
and vinylogous Mannich reaction7 have been achieved under
either metal or organocatalytic conditions. Direct Michael
addition of angelica lactone to enals has been reported by
Alexakis and co-workers during the course of our investigation.8
However, despite the vast popularity of nitroolefins as a
Michael acceptor, an asymmetric addition of angelica lactone
to nitroolefin is yet to be achieved.
Our investigation was initiated with the goal of finding the
best catalyst and optimal reaction conditions for the direct
vinylogous Michael reaction between model substrates (angelica
lactone) 1a and o-nitrostyrene 2a (Table 1). The absence of
any background reaction at rt (entry 1) allowed rapid screening of
a selection of catalysts (Fig. 2) including several well-established
bifunctional catalysts I–VII.9 In most of these cases, complete
conversion to the desired vinylogous Michael adduct 3aa was
observed with good to excellent diastereoselectivity within
30 min at rt. We were glad to find that the normal Michael
adduct and the double Michael adduct were not observed in
any of the above cases (see ESIw for details). While the widely
popular Takemoto catalyst I10 failed to induce any enantio-
selectivity to 3aa (entry 2), low enantioselectivities were observed
for reactions with the Cinchona alkaloids II–V (entries 3–6).
Equally low level of enantioselectivity was also obtained with
quinine and cinchonine-derived thiourea catalysts VI and VII
(entries 7 and 8).11 Following the work of Jacobsen and
others,12 we realized that introduction of a second element of
chirality has the potential of improving the enantioselectivity.
Indeed, replacing the aryl substituent of thiourea VII with a
tert-leucine-derived chiral substituent resulted in thiourea VIII,
which was found to be significantly superior and ent-3aa
was obtained with improved enantioselectivity (entry 9).
However, we were surprised to find that with VIII, the sense
of stereoinduction is dictated by the tert-leucine segment of the
catalyst (compare entries 8 and 9). With the corresponding
Department of Organic Chemistry, Indian Institute of Science,
Bangalore 560 012, India. E-mail: sm@orgchem.iisc.ernet.in;
Fax: +91-80-2360-0529; Tel: +91-80-2293-2850
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization data for all relevant compounds
together with HPLC traces for all the products. CCDC 870478. For
ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c2cc31700a
c
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Chem. Commun., 2012, 48, 5193–5195 5193

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Table 1 Catalyst optimization for the direct asymmetric vinylogous
Michael reaction of angelica lactone 1a with nitrostyrene 2aa
Table 2 Catalytic asymmetric direct vinylogous Michael reaction of
butenolide 1b with various nitroolefinsa
Entry Catalyst Solvent
T/1C tb/h
drc
—
erd
Entry R
t/h Product Yieldb (%) drc
erd
e
1
2
3
4
5
6
7
8
—
I
II
III
IV
V
VI
VII
VIII
IX
IX
IX
IX
IX
X
XI
XII
XII
XII
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
25
—
1
Ph (2a)
24 3ba
48 3bb
30 3bc
32 3bd
69 3be
94
94
92
87
90
97
91
90
96
97
92
96
59
420 : 1 95.5 : 4.5
420 : 1 96 : 4
420 : 1 95 : 5
420 : 1 95 : 5
420 : 1 94 : 6
420 : 1 96.5 : 3.5
420 : 1 96 : 4
420 : 1 95 : 5
420 : 1 95.5 : 4.5
420 : 1 93.5 : 6.5
420 : 1 96 : 4
420 : 1 97 : 3
420 : 1 95.5 : 4.5
25
25
25
25
25
25
25
25
25
0
o0.5 12 : 1
o0.5 15 : 1
o0.5 14 : 1
50 : 50
40 : 60
41 : 59
65 : 35
58 : 42
46 : 54
61 : 39
29 : 71
2
3
4
5
4-ClC6H4 (2b)
3-ClC6H4 (2c)
4-FC6H4 (2d)
4-BrC6H4 (2e)
1.5
10 : 1
o0.5 12 : 1
o0.5 14 : 1
o0.5 13 : 1
6
7
8
9
4-OMeC6H4 (2f) 60 3bf
4-MeC6H4 (2g) 60 3bg
1-Naphthyl (2h) 44 3bh
2-Naphthyl (2i) 50 3bi
9
1.5
15 : 1
10
11
12
13
14
15
16
17
18
19
o0.5 420 : 1 82.5 : 17.5
10
11
12
13e
2-Furyl (2j)
2-Thienyl (2k)
2,4-Cl2C6H3 (2l) 60 3bl
i-Bu (2m) 96 3bm
60 3bj
42 3bk
2
420 : 1 86.5 : 13.5
420 : 1 91 : 9
420 : 1 92 : 8
420 : 1 92.5 : 7.5
420 : 1 91.5 : 8.5
420 : 1 90.5 : 9.5
420 : 1 91 : 9
420 : 1 88 : 12
420 : 1 94.5 : 5.5
Toluene À36
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
À36
À50
À36
À36
11
50
9
14
24
9
a
Reactions were carried out using 1.0 equiv. of 1 and 1.5 equiv. of 2
b
under an argon atmosphere. Isolated yield of the products after
column chromatography. Determined by 1H-NMR analysis of the
c
Toluene À36
d
crude reaction mixture. Determined by HPLC analysis using a
CH2Cl2
CHCl3
À36
e
stationary phase chiral column (see ESI). Reaction was conducted
À36
34
at À20 1C.
a
Reactions were carried out using 1.0 equiv. of 1a and 1.5 equiv. of 2a.
Relative and absolute configuration of the product was determined by
b
X-ray diffraction analysis (see ESI). Time required for complete
reaction rate (entries 12 and 13). Lowering the reaction
temperature to À50 1C was not beneficial as the reaction rate
reduced by several fold with little effect on the enantio-
selectivity (entry 14). The optimum catalyst was identified after
steric tuning at the 6-position of quinoline: the tri-iso-butyl
catalyst XII afforded 3aa in 94.5 : 5.5 er when the reaction was
conducted in CHCl3 at À36 1C (entry 19). Catalyst loading
could be reduced to 5 mol% without any deleterious effect on
the product enantioselectivity (see ESIw).
c
conversion of 1a. Determined by 1H-NMR analysis of the crude
d
reaction mixture. Determined by HPLC analysis using a stationary
e
phase chiral column (see ESI). No conversion after 72 h.
With the newly identified bifunctional catalyst XII and
optimized reaction conditions in hand (Table 1, entry 19), we
set out to elucidate the scope and limitations of this asymmetric
vinylogous Michael reaction with respect to nitroolefins as well
as butenolides. We first examined the viability of various nitro-
olefins with different steric and electronic properties using ethyl-
substituted deconjugated butenolide 1b. As can be seen from
Table 2, the Michael adducts are generally obtained in excellent
yield and with impeccable diastereoselectivity. The reaction rate
and enantioselectivity seem to be dependent on the electronic
nature of the nitroolefin. Nevertheless, both electron-rich and
electron-poor aromatic groups on nitroolefin are well tolerated
and adducts were obtained in high enantioselectivity (up to
97 : 3 er) within reasonable time scale. Heteroaromatic nitro-
olefins are also excellent substrates for this reaction (entries 10
and 11). When employing the more challenging and less reactive
aliphatic nitroolefin 2m, the Michael adduct 3bm was acquired
with high level of stereocontrol (95.5 : 4.5 er) but only in moderate
yield after prolonged reaction time at slightly elevated temperature
(entry 13). However, when this reaction was carried out at 0 1C
(for 66 h) the product (3bm) was obtained in very good yield
(87%) with only slightly reduced enantioselectivity (93 : 7 er).
After demonstrating success with various nitroolefins
and ethyl-substituted butenolide 1b, we turned our attention
Fig. 2 A selection of catalysts screened for the vinylogous Michael
reaction.
quinine-derived catalyst IX, the product was obtained essentially
as a single diastereomer and with 82.5 : 17.5 er (entry 10). The
same trend with the sense of stereoinduction was followed here as
well (compare entries 7 and 10). Lowering the reaction temperature
up to À36 1C and changing the reaction solvent to CH2Cl2
resulted in improved enantioselectivity, albeit at the expense of
c
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Table 3 Catalytic asymmetric direct vinylogous Michael reaction of
various butenolides and nitroolefinsa
Efforts towards developing a more efficient catalyst to include
less reactive butenolides and nitroolefins as well as models for
stereoinduction are currently underway in our laboratory.
A generous start-up grant from Indian Institute of Science,
Bangalore, is gratefully acknowledged. We thank DST, New
Delhi, for funding this project (Grant No. SR/FT/CS-90/2010).
M.S.M. thanks CSIR for a doctoral fellowship and V.K. thanks
IISc for a postdoctoral fellowship. We thank Mr Bappaditya
Gole for his help with the X-ray crystallographic analysis.
Yieldb
Entry R1
R2
t/h Product (%)
erc
1
2
3
4
5
6
7
8
Me (1a)
Ph (2a)
3-ClC6H4 (2c)
4-OMeC6H4 (2f) 60 3af
4-MeC6H4 (2g) 65 3ag
4-CF3C6H4 (2n) 30 3an
34 3aa
38 3ac
92
86
94
90
88
92
91
95
90
92
93
96
89
95
97
98
99
94.5 : 5.5d
92 : 8
95.5 : 4.5
95 : 5
90 : 10
97 : 3
97 : 3
96.5 : 3.5
98 : 2
98 : 2
Notes and references
Me (1a)
Me (1a)
Me (1a)
Me (1a)
n-Pr (1c)
1 For reviews see: (a) J. P. Das and I. Marek, Chem. Commun., 2011,
47, 4593; (b) M. Bella and T. Gasperi, Synthesis, 2009, 1583;
(c) B. M. Trost and C. Jiang, Synthesis, 2006, 369;
(d) J. Christoffers and A. Baro, Adv. Synth. Catal., 2005,
347, 1473; (e) C. J. Douglas and L. E. Overman, Proc. Natl. Acad.
Sci. U. S. A., 2004, 101, 5363.
2 For reviews see: (a) S. V. Pansare and E. K. Paul, Chem.–Eur. J.,
2011, 17, 8770; (b) G. Casiraghi, L. Battistini, C. Curti, G. Rassu
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F. Zanardi, L. Battistini and G. Rassu, Synlett, 2009, 1525;
(d) G. Casiraghi and G. Rassu, Synthesis, 1995, 607.
3 For selected examples, see: (a) J. Luo, H. Wang, X. Han,
L.-W. Xu, J. Kwiatkowski, K.-W. Huang and Y. Lu, Angew.
Chem., Int. Ed., 2011, 50, 1861; (b) M. Terada and K. Ando,
Org. Lett., 2011, 13, 2026; (c) H. Ube, N. Shimada and M. Terada,
Angew. Chem., Int. Ed., 2010, 49, 1858; (d) J. Wang, C. Qi, Z. Ge,
T. Cheng and R. Li, Chem. Commun., 2010, 46, 2124; (e) Y. Zhang,
C. Yu, Y. Ji and W. Wang, Chem.–Asian J., 2010, 5, 1303;
(f) B. M. Trost and J. Hitce, J. Am. Chem. Soc., 2009, 131, 4572;
(g) A. Yamaguchi, S. Matsunaga and M. Shibasaki, Org. Lett.,
2008, 10, 2319.
4 For a non-asymmetric g-arylation of 5-substituted butenolides,
see: A. M. Hyde and S. L. Buchwald, Org. Lett., 2009, 11, 2663.
5 For catalytic asymmetric routes to enantioenriched butenolides,
see: (a) D. A. Devalankar, P. V. Chouthaiwale and A. Sudalai,
Tetrahedron: Asymmetry, 2012, 23, 240; (b) Y. Wu, R. P. Singh
and L. Deng, J. Am. Chem. Soc., 2011, 133, 12458; (c) B. Mao,
Ph (2a)
36 3ca
46 3da
n-Pent (1d) 4-MeC6H4 (2g) 48 3dg
n-Pent (1d) Ph (2a)
9
i-Pr (1e)
i-Pr (1e)
i-Bu (1f)
i-Bu (1f)
i-Bu (1f)
Bn (1g)
Bn (1g)
Bn (1g)
Bn (1g)
Ph (2a)
4-MeC6H4 (2g) 96 3eg
Ph (2a) 24 3fa
4-MeC6H4 (2g) 24 3fg
i-Bu (2m)
Ph (2a)
4-ClC6H4 (2b)
4-BrC6H4 (2e)
2,4-Cl2C6H3 (2l) 24 3gl
60 3ea
10
11
12
13e
14
15
16
17
97 : 3
97 : 3
94 : 6
72 3fm
36 3ga
24 3gb
22 3ge
97 : 3
98 : 2d
97.5 : 2.5
99 : 1
a
Reactions were carried out using 1.0 equiv. of 1 and 1.5 equiv. of 2
b
under an argon atmosphere. Isolated yield of the products after
column chromatography. In all cases products were obtained with
c
420 : 1 dr. Determined by HPLC analysis using a stationary phase
chiral column (see ESI). Products 3aa and 3gb were obtained with
d
499.5 : 0.5 er after a single recrystallization from EtOAc–PetEther.
e
Reaction was conducted at 0 1C.
K. Geurts, M. Fananas-Mastral, A. W. v. Zijl, S. P. Fletcher,
´
A. J. Minnaard and B. L. Feringa, Org. Lett., 2011, 13, 948.
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2012, 48, 2439; (b) H.-L. Cui, J.-R. Huang, J. Lei, Z.-F. Wang,
S. Chen, L. Wu and Y.-C. Chen, Org. Lett., 2010, 12, 720.
7 L. Zhou, L. Lin, J. Ji, M. Xie, X. Liu and X. Feng, Org. Lett.,
2011, 13, 3056.
8 (a) A. Quintard and A. Alexakis, Chem. Commun., 2011, 47, 7212;
(b) A. Quintard, A. Lefranc and A. Alexakis, Org. Lett., 2011,
13, 1540.
9 For reviews, see: (a) L.-Q. Lu, X.-L. An, J.-R. Chen and
W.-J. Xiao, Synlett, 2012, 490; (b) M. D. D. de Villegas,
´ ´ ´
J. A. Galvez, P. Etayo, R. Badorrey and P. Lopez-Ram-de-Vıu,
Chem. Soc. Rev., 2011, 40, 5564; (c) T. Marcelli and H. Hiemstra,
Synthesis, 2010, 1229; (d) W.-Y. Siau and J. Wang, Catal. Sci.
Technol., 2011, 1, 1298; (e) S. J. Connon, Chem. Commun., 2008,
2499.
Scheme 1 Synthetic utility of Michael adduct 3aa.
to other butenolides, with the results summarized in Table 3.
It is evident that the reaction conditions are tolerant to diverse
substituents on either butenolide or nitroolefin. The products
from angelica lactone 1a were acquired with somewhat lower
enantioselectivities (entries 1–5). However, an enantiopure product
can be achieved after a single recrystallization as exemplified in the
case of 3aa (entry 1). For all other butenolides with either long
alkyl chain substituents (n-Pr 1c, n-Pent 1d; entries 6–8), branched
alkyl groups (i-Pr 1e, i-Bu 1f; entries 9–13) or alkyl chains with an
aromatic moiety (Bn 1g; entries 14–17), products were
obtained with uniformly high enantioselectivity in very good
yield. Once again, in all cases only a single diastereomer of the
10 For selected examples, see: (a) S. Sakamoto, T. Inokuma and
Y. Takemoto, Org. Lett., 2011, 13, 6374; (b) T. Okino, Y. Hoashi
and Y. Takemoto, J. Am. Chem. Soc., 2003, 125, 12672. For a
review, see: (c) Y. Takemoto, Chem. Pharm. Bull., 2010, 58, 593.
11 (a) S. H. McCooey and S. J. Connon, Angew. Chem., Int. Ed., 2005,
44, 6367; (b) J. Ye, D. J. Dixon and P. S. Hynes, Chem. Commun.,
1
products could be detected by H-NMR analysis.
The synthetic utility of our reaction products is illustrated
by reductive aza-Michael cyclization of 3aa, which afforded
the bicyclic adduct 4 in reasonable yield (Scheme 1).
2005, 4481; (c) B. Vakulya, S. Varga, A. Csampai and T. Soos,
´ ´
Org. Lett., 2005, 7, 1967.
12 For selected examples, see: (a) J. A. Birrell, J.-N. Desrosiers and
E. N. Jacobsen, J. Am. Chem. Soc., 2011, 133, 13872; (b) S. C. Pan,
J. Zhou and B. List, Angew. Chem., Int. Ed., 2007, 46, 612;
(c) M. S. Taylor, N. Tokunaga and E. N. Jacobsen, Angew. Chem.,
Int. Ed., 2005, 44, 6700; (d) A. Berkessel, S. Mukherjee,
In summary, we have developed a quinine-derived thiourea-
based bifunctional organocatalyst containing a second element of
chirality for direct asymmetric vinylogous Michael addition of
deconjugated butenolides to nitroolefins. Synthetically versatile
highly functionalized g-butenolides with contiguous quaternary
and tertiary stereocenters were prepared stereoselectively.
F. Cleemann, T. N. Muller and J. Lex, Chem. Commun., 2005,
¨
1898; (e) P. Vachal and E. N. Jacobsen, J. Am. Chem. Soc., 2002,
124, 10012.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 5193–5195 5195