Asymmetric Michael reaction catalyzed by proline lithium salt: Efficient synthesis of L-proline and isoindoloisoquinolinone derivatives

Article abstract of DOI:10.1002/chem.201202409

Lithium makes it possible: The enantioselective Michael addition of aldehydes to nitroalkenes was catalyzed by the readily available proline lithium salt. Remarkably, the asymmetric Michael reaction was scaled up to 50 mmol with 23:1 d.r. and 90 % ee. Cop

Full text of DOI:10.1002/chem.201202409

COMMUNICATION
DOI: 10.1002/chem.201202409
Asymmetric Michael Reaction Catalyzed by Proline Lithium Salt:
Efficient Synthesis of l-Proline and Isoindoloisoquinolinone Derivatives
Kun Xu, Sheng Zhang, Yanbin Hu, Zhenggen Zha, and Zhiyong Wang*[a]
Enamine catalysis has emerged as a powerful method for
the potential application of carbonyl activation in asymmet-
ric catalysis.[1] Since List, Lerner, and Barbas first reported
the proline-catalyzed direct aldol reaction,[2] many pyrroli-
dine-type[3] and imidazolidinone-type[4] chiral amine cata-
lysts have been developed with highly effective stereoinduc-
tion. In most cases, these catalysts were designed by increas-
ing the steric bulk on the pyrrolidine moiety,[1j,5] such as in
the Jørgensen–Hayashi catalyst.[6] By contrast, when amino
acid metal salts were employed as enamine catalysts, the
stereoselectivity was hardly controlled through shielding one
face of the enamine intermediate. The seminal work of the
reported methods can afford good-to-excellent diastereo-
and enantioselectivities, the need for a large excess of Mi-
chael donors, as well as the use of expensive and not readily
available catalysts, seriously limit the application of this re-
action on a large scale, especially on an industrial scale. To
overcome these limitations, the immobilization of organoca-
talysts has been pursued to facilitate product separation and
catalyst reuse. However, this approach has always led to a
decrease in the reaction activity and enantioselectivity.[23]
Very recently, the Wennemers group successfully lowed the
catalyst loading to as little as 0.1 mol% following kinetic
studies.[24] Moreover, the groups of Ni[25] and Wang[26] descri-
bed highly efficient reusable catalysts for the excellent dia-
stereo- and enantioselective Michael reaction. Although sig-
nificant progress has been made, the development of low-
molecular-weight, inexpensive, and readily available cata-
lysts for the highly stereoselective Michael reaction with var-
ious linear, a-branched, and unsaturated aldehydes[27] as
donors is still of significance. Herein, we report a highly
stereoselective Michael addition of aldehydes to nitroal-
kenes catalyzed by proline lithium salt. Remarkably, the
asymmetric Michael reaction could be scaled up to 50 mmol
with 23:1 d.r. and 90% ee. Furthermore, the useful building
blocks were successfully transformed into biologically im-
portant l-proline and isoindoloisoquinolinone derivatives on
the gram scale.
The asymmetric Michael addition of n-butylaldehyde (1a)
to nitrostyrene (2a) was selected as a model reaction for
our initial optimization studies (Table 1). Preliminary ex-
periments identified l-proline lithium salt as a suitable cata-
lyst (see the Supporting Information, Table S1, entry 1),
whereas other secondary amino acid metal salts gave inferi-
or results with respect to the yields and stereoselectivities
(Table 1, entries 2–5). The primary acid lithium salts showed
minimal catalytic activity under the same reaction condi-
tions (Table 1, entries 6 and 7), which may be attributed to
the unfavorable equilibrium between the imine and the sec-
ondary enamine. When l-proline was employed as the cata-
lyst, no Michael adduct was obtained (Table 1, entry 8).
Then, the effect of water on the reaction was studied
(Table 1, entries 9–12). The results indicated that a small
amount of water was essential to obtaining a high yield
(Table 1, entry 1 versus entry 11); however, the diastereo-
and enantioselectivities decreased with an increased amount
of water (Table 1, entry 1 versus entries 9 and 10). The pres-
ence of molecular sieves during the catalytic reaction de-
À
Yamaguchi group, who employed a proline rubidium cata-
lyst,[7] as well as the groups of Feng,[8] Reiser,[9] and
others,[10] have demonstrated that amino acid metal salts are
attractive alternatives to organocatalysts and other metal-
based catalysts. Lithium, the closest congener of hydrogen,
can form lithium-bonding interactions that are analogous to
hydrogen-bonding interactions but with stronger bonding
ability.[11] We believe that the suitable combination of pro-
line and lithium would facilitate reactions that proline alone
cannot.
The asymmetric Michael addition of unmodified alde-
hydes to nitroalkenes has attracted much attention because
the installation of the formyl and nitro groups in a single
step allows subsequent versatile transformations.[12] More-
over, the Michael reaction has also been widely used as one
of the steps in cascade reactions that allows for the construc-
tion of molecular complexity in a single procedure.[13] Since
Barbas and co-workers reported the first example of the
asymmetric addition of an unmodified aldehyde to a nitroal-
kene,[14] the groups of Alexakis,[15] Wang,[16] Hayashi,[5a]
Palomo,[17] Jacobsen,[18] Chen,[19] and Loh,[20] among many
others,[21,22] have developed a series of efficient secondary
and thioACHTUNGTRENNUNG(urea)-primary amines to improve the stereoselec-
tivity and substrate scope of this reaction. Although these
[a] K. Xu, S. Zhang, Y. Hu, Z. Zha, Prof. Z. Wang
Hefei National Laboratory for Physical Sciences at
Microscale, CAS Key Laboratory of Soft Matter Chemistry
and Department of Chemistry
University of Science and Technology of China
Hefei, Anhui, 230026 (P. R. China)
Fax :ACHTUNGTRENNUNG(+86)551-3631760
E-mail: zwang3@ustc.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202409.
Chem. Eur. J. 2013, 19, 3573 – 3578
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Table 1. Optimization
of
the
reaction
conditions.[a]
Table 2. Scope of the asymmetric addition of n-butylaldehyde to nitro-
AHCTUNGTRENNUNG
alkenes.[a]
Entry
Catalyst
Solvent
Yield
d.r.
(syn/anti)[c]
ee
[%][b]
N
[%][d]
Entry
R
Product
Yield
[%][b]
d.r.
(syn/anti)[c]
ee
N
[%][d]
1
2
3
4
5
6
7
8
ProLi
ProNa
ProK
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
Et2O
89
89
90
91
93
<10
<10
n.r.
90
90
64
<10
85
87
63
76
30:1
27:1
27:1
24:1
30:1
—
93
80
79
75
83
—
—
–
89
86
95
–
88
80
rac
81
78
1
C6H5
4-FC6H4
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3am
3an
89
92
93
93
86
87
80
89
84
85
85
83
71
74
30:1
33:1
29:1
24:1
30:1
42:1
40:1
45:1
22:1
48:1
30:1
26:1
13:1
16:1
93
95
96
95
97
95
91
97
96
97
92
94
92
95
2[e]
3[e]
4[e]
5[e]
6
ProRb
ProCs
PhgOLi
PheOLi
Proline
ProLi
ProLi
ProLi
ProLi
ProLi
ProLi
ProLi
ProLi
ProLi
4-ClC6H4
4-BrC6H4
4-CF3C6H4
4-MeC6H4
4-OMeC6H4
3-ClC6H4
2-ClC6H4
2-CF3C6H4
1-naphthyl
2-furyl
—
–
7
9[e]
10[f]
11[g]
12[h]
13
14
15
16
17
30:1
23:1
33:1
–
25:1
29:1
14:1
37:1
22:1
8[e]
9
10
11[f]
12
13[g]
14[g]
THF
Cy
MeOH
toluene
CH2Cl2
C6H5CH2CH2
[a] Conditions: Compound 1a (0.6 mmol), compound 2 (0.2 mmol), ProLi
(0.02 mmol), water (0.04 mmol), MTBE (0.5 mL), À208C, 48 h. [b] Yield
of isolated product based on compound 2. [c] Determined by 1H NMR
spectroscopy. [d] Determined by HPLC analysis on chiral columns.
[e] 30 h. [f] Aldehyde (0.4 mmol, 2 equiv). [g] À108C.
71
[a] Conditions: Compound 1a (0.6 mmol), compound 2a (0.2 mmol), cat-
alyst (0.02 mmol), water (0.04 mmol), solvent (0.5 mL), À208C, 48 h.
[b] Yield of isolated product based on compound 2a. [c] Determined by
1H NMR spectroscopy. [d] Determined by HPLC analysis on a DAICEL
CHIRAL OD-H column. [e] Water (0.1 mmol). [f] Water (0.2 mmol).
[g] Without water. [h] With 4 ꢁ M.S. (20 mg). MTBE=methyl tert-butyl
ether, Pro=proline, Phg=phenylglycine, Phe=phenylalanine.
Table 3. Scope of the asymmetric addition of aldehydes to nitrostyrene.[a]
creased the chemical yield remarkably (Table 1, entry 12).
Subsequently, different polar and nonpolar solvents were ex-
amined (Table 1, entries 13–17) and the results revealed the
superiority of methyl tert-butyl ether (MTBE) as a solvent
in terms of yield and ee value compared to other solvents
(Table 1, entry 1 versus entries 13–17).
Entry
R1
R2
Product
Yield
[%][b]
d.r.
ee
G
[%][d]
1
2
CH3
nBu
n-C10H21
iPr
CH3
allyl
H
H
H
H
CH3
H
3ba
3ca
3da
3ea
3 fa
3ga
85
85
79
74
69
86
20:1
86:1
40:1
96:1
–
95
96
91
99
88
88
With the optimized conditions in hand, the scope and lim-
itations of this reaction were determined by evaluating a va-
riety of nitroalkenes. As shown in Table 2, both electron-
withdrawing and electron-donating functionalities on the ar-
omatic ring of b-nitrostyrenes were tolerated (Table 2, en-
tries 1–7). In general, substrates with electron-deficient sub-
strates were more reactive and gave better results with re-
spect to yield and enantioselectivity (Table 2, entries 2–5
versus entries 6 and 7). In addition, all possible monosubsti-
tuted nitroalkenes (o, m, and p) were well-tolerated and
gave their corresponding Michael adducts in 84–89% yield
with excellent diastereo- and enantioselectivities (Table 2,
entries 8–10). In the case of 1-naphthyl derivative 3k, the
corresponding adduct (3ak) was obtained in 85% yield,
with 30:1 d.r. and 92% ee (Table 2, entry 11). A nitroal-
kene-bearing heteroaromatic b-substituent was also found
to be a suitable substrate for this reaction, thus giving Mi-
chael adduct 3al in 83% yield with 26:1 d.r. and 94% ee
(Table 2, entry 12). With less-reactive aliphatic nitroalkenes,
their corresponding Michael adducts were obtained in mod-
erate yields, with good diastereoselectivities and excellent
enantioselctivities (Table 2, entries 13 and 14).
3[e]
4[f]
5[g]
6
45:1
[a] Conditions: Compound 1 (0.6 mmol), compound 2a (0.2 mmol), ProLi
(0.02 mmol), water (0.04 mmol), MTBE (0.5 mL), À208C, 48 h. [b] Yield
of isolated product based on compound 2a. [c] Determined by 1H NMR
spectroscopy. [d] Determined by HPLC analysis (OD-H column). [e] Al-
dehyde (0.4 mmol, 2 equiv). [f] 60 h. [g] Compound 1 f (0.6 mmol), com-
pound 2a (0.2 mmol), ProNa (0.02 mmol), o-chlorophenol (0.1 mmol),
THF (0.5 mL), À108C, 80 h.
After testing the scope of a series of nitroalkenes, the
scope of the reaction was investigated with respect to the al-
dehyde substrate (Table 3). For linear aldehydes, higher dia-
stereoselectivities were achieved by increasing the bulkiness
of the substituents on the aldehyde (Table 3, entries 1–3).
Notably, n-dodecyl aldehyde (1d) was also found to be a
suitable substrate, as exemplified by the preparation of
adduct 3da in 79% yield with 40:1 d.r. and 91% ee (Table 3,
entry 3). To the best of our knowledge, examples of highly
stereoselective Michael addition reactions with such long-
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Asymmetric Michael Reaction Catalyzed by Proline Lithium Salt
COMMUNICATION
chain aldehydes (C12) have rarely been reported. In the
case of the bulky isovaleraldehyde, the corresponding
adduct (3ea) was obtained in 74% yield with 96:1 d.r. and
>99% ee (Table 3, entry 4). When a-branched isobutyralde-
hyde was employed as the substrate, Michael adduct 3 fa
was obtained in only 51% yield and 74% ee with the aid of
o-chlorophenol (0.1 mmol) as an acid additive.[28] However,
switching the catalyst to l-ProNa and the solvent to anhy-
drous THF improved the yield and enantioselectivity
(Table 3, entry 5). Significantly, when unsaturated 4-pentenal
was employed as the Michael donor, the corresponding
adduct (3ga) was obtained in 86% yield with 45:1 d.r. and
88% ee (Table 3, entry 6).
tivation of the nitro-olefin for nucleophilic attack. Experi-
mentally, the interactions between the proline lithium ion
and the nitro group in nitrostyrene (2a) were determined by
extractive electrospray ionization (EESI) mass spectrometry
and by MS (EESI)/MS analysis of the ion peak at m/z 289
(for details, see the Supporting Information).[29] However,
the hydrogen-bond-accepting capability of the nitro group is
lower than that of carbonyl or imine groups,[30] which results
in the inefficient activation of the nitro group by proline.[31]
The Michael adducts (3) are versatile potential building
blocks and one can envision further elaboration of both the
formyl functionality and the nitro moiety. Thus, we used bi-
functional molecule 3aa as a model to illustrate this synthet-
ic potential (Scheme 3 and Scheme 4). The treatment of
compound 3aa with ethylene glycol and then reduction of
the nitro functionality followed by the amine protection af-
The large-scale preparation of Michael adduct 3aa high-
lights the utility and operational simplicity of this procedure
(Scheme 1; for details, see the Supporting Information):
Scheme 1. Asymmetric Michael addition reaction on a gram scale.
Upon scaling up the reaction to 10 mmol, the product (3aa)
was obtained in 94% yield with 35:1 d.r. and 94% ee; when
the reaction was further scaled up to 50 mmol, compound
3aa was obtained in 90% yield with 23:1 d.r. and 90% ee.
After the reaction had been completed, the catalyst could
also be recovered by washing with water. Because this cata-
lyst is inexpensive and readily available, accompanied by
this facile separation process, this method may provide a
possibility for laboratory applications.
Although further studies are required to firmly elucidate
the mechanism of this Michael reaction, we suggest that it
proceeds through an enamine pathway and that the absolute
stereochemistry of the products can be explained by the pro-
posed transition state, as shown in Scheme 2: The approach
Scheme 3. Enantioselective synthesis of 3,4-disubstituted l-proline on a
gram scale. a) Ethylene glycol, p-toluenesulfonic acid, toluene, reflux,
20 h, 87% yield; b) NiCl2·6H2O, NaBH4, MeOH, 08C, 1 h, 84% yield;
c) conditions 1. Et3N, TsCl (or p-NsCl), CH2Cl2, 08C to RT, 12 h, 96%
(or 94%) yield; conditions 2. CbzCl, Na2CO3, CH2Cl2, 08C to RT, 12 h,
83% yield; conditions 3. Et3N, (Boc)2O, CH2Cl2, 08C, 12 h, 89% yield;
d) CSA, MeOH, RT, 91% yield; e) TMSCN, BF3·Et2O, MeCN, 08C, 12 h,
89% yield; f) LiOH·H2O, PhSH, MeCN, 108C, 1 h, 74% yield; g) 8m
HCl, reflux, 8 h, 93% yield. Ts=p-methylphenylsulfonyl, CBz=carboxy-
benzyl, Boc=tert-butoxycarbonyl, TMS=trimethylsilyl.
Scheme 2. Proposed transition state.
of the nitro-olefin from the si face of the enamine lead to
the (2R,3S)-configured, predominantly syn, diastereomer.
Because the control experiments showed that l-proline
couldn’t promote the asymmetric addition under our stand-
ard conditions, the lithium ion may play a crucial role in the
observed high yield and excellent stereoselectivity, that is,
the lithium ion could serve as a Lewis acid to ensure the ac-
Scheme 4. Synthesis of isoindoloisoquinolinone derivative on
a gram
scale. a) NaBH4, MeOH, RT, 1 h, 97% yield; b) NiCl2·6H2O, NaBH4,
MeOH, 08C, 3 h; c) Et3N, phthlandione, toluene, reflux, N2, 20 h, 81%
yield (steps b and c); d) NaBH4, methanesulfonic acid (2m in EtOH),
EtOH, À58C to 108C, overnight; e) TiCl4, CH2Cl2, À308C to RT, over-
night, 49% yield (steps d and e).
Chem. Eur. J. 2013, 19, 3573 – 3578
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3575

Z. Wang et al.
forded amine 6. With the aid of (Æ)-10-camphorsulfonic
acid (CSA), amine 6 could undergo cyclization to afford pyr-
rolidine derivative 7. Then, treatment of compound 7 with
BF3·Et2O and TMSCN provided aminonitrile 8. The stereo-
selectivity of the nucleophilic attack of the cyanide anion
differed greatly when different amine protecting groups
were employed: When a p-nitrobenzenesulfonyl (p-Ns)
group was employed as the protecting group, the desired
aminonitrile (8a) was obtained as a single diastereomer. De-
protection of the p-Ns group and subsequent hydrolysis of
the cyanide group led to the formation of 3,4-disubstituted
l-proline 10. The absolute configuration of compound 8a
(PG=p-Ns) was determined by single-crystal X-ray diffrac-
tion (for details, see the Supporting Information).[34] The
3,4-disubstituted l-proline framework is a basic scaffold that
is found in numerous biologically active natural products,
such as phenylkainic acid and acromelic acid E (Figure 1).[32]
lytic procedure has several merits, including the use of a
readily available catalyst, the simplicity of catalyst separa-
tion, the large-scale production of the Michael adduct, and
high levels of stereocontrol over a wide range of substrates.
Mechanistic studies to elucidate the precise role of the lithi-
um ion are underway.
Experimental Section
General procedure for the asymmetric Michael addition reaction: To a
mixture of proline lithium salt (0.02 mmol) and nitrostyrene (0.2 mmol)
in MTBE (0.5 mL) in a sealed tube (5 mL) was added water (0.04 mmol)
and the mixture was stirred at À308C for 1 h. Then, the aldehyde
(0.6 mmol) was added slowly and the mixture was allowed to warm to
À208C before being kept at the same temperature for 48 h. After the re-
action was complete, water (10 mL) was added to the reaction mixture.
The mixture was extracted with EtOAc (3ꢂ7 mL) and the combined or-
ganic phase was dried with Na2SO4 and evaporated under vacuum. Purifi-
cation of the residue by flash column chromatography on silica gel (pe-
troleum ether/EtOAc, 10:1 to 6:1) afforded the desired Michael adduct.
The ee value of the product was determined by HPLC analysis.
Acknowledgements
We are grateful to the National Natural Science Foundation of China
(20932002, 20972144, 90813008, 21172205, 21272222, J1030412) and the
973 program (2010CB912103).
Keywords: asymmetric catalysis
Michael addition · proline
· enamines · lithium ·
Figure 1. Bioactive compounds that contain 3,4-disubstituted proline and
tetrahydroisoquinoline units.
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15 was performed (Scheme 4). Substituted isoindoloisoqui-
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syn manner. The lithium ion plays a crucial role in improv-
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Asymmetric Michael Reaction Catalyzed by Proline Lithium Salt
COMMUNICATION
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Received: July 6, 2012
Revised: December 31, 2012
Published online: February 10, 2013
3578
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 3573 – 3578