Highly diastereoselective and enantioselective direct Michael addition of phthalide derivatives to nitroolefins

Article abstract of DOI:10.1039/c3cc42187b

The first asymmetric Michael addition of 3-substituted phthalides to nitroolefins promoted by amino acid-incorporating multifunctional catalysts has been developed. The reported method led to the synthesis of 3,3-disubstituted phthalide derivatives in high yields, and in a highly diastereoselective and enantioselective manner. Facile synthesis of a chiral bicyclic lactam has also been demonstrated.

Full text of DOI:10.1039/c3cc42187b

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Highly diastereoselective and enantioselective direct
Michael addition of phthalide derivatives to
nitroolefins†
Jie Luo,a Haifei Wang,b Fangrui Zhong,a Jacek Kwiatkowski,a Li-Wen Xuc and
Yixin Lu*ac
Cite this: Chem. Commun., 2013,
49, 5775
Received 26th March 2013,
Accepted 7th May 2013
DOI: 10.1039/c3cc42187b
www.rsc.org/chemcomm
The first asymmetric Michael addition of 3-substituted phthalides however, focus on the asymmetric synthesis of 3-monosubstituted
to nitroolefins promoted by amino acid-incorporating multifunc- phthalides. The 3,3-disubstituted phthalides bearing a quater-
tional catalysts has been developed. The reported method led to nary stereogenic center are molecules of biological significance,9
the synthesis of 3,3-disubstituted phthalide derivatives in high and approaches to these challenging synthetic targets are much
yields, and in a highly diastereoselective and enantioselective less common. In 2007, Tanaka et al. described a rhodium-
manner. Facile synthesis of a chiral bicyclic lactam has also been catalyzed one-pot transesterification and [2+2+2] cycloaddition
demonstrated.
for the synthesis of enantioenriched 3,3-disubstituted phtha-
lides.10 As part of our ongoing research efforts towards
Functionalized phthalides are structural motifs widely present the construction of quaternary stereogenic centers,11 we are
in many natural products and therapeutically useful agents.1 interested in effective asymmetric methods for creating 3,3-
Given their biological importance,
a range of catalytic disubstituted chiral phthalide derivatives. Our previous studies
methods have been devised for the facile construction of chiral demonstrated that phthalides containing an activating group at
3-substituted phthalides. The first catalytic asymmetric the 3-position are suitable substrates for the direct Mannich
example was reported by Noyori et al., in which an enantio- reaction,12 as well as for the asymmetric allylic alkylations with
selective transfer hydrogenation reaction was utilized.2 Later, MBH carbonates.13 Herein, we describe a highly diastereo-
Butsugan et al. disclosed an approach utilizing a chiral amine selective and enantioselective Michael addition of 3-substituted
alcohol mediated addition of zinc reagent to aldehydes.3
Ni(II)–(S)-BINAP complex catalyzed tandem addition–cyclization
A
phthalides to nitroolefins.
The organocatalysts containing a tertiary amine and a
reaction was reported by Lin et al., for the synthesis of halogen- Brønsted acid moiety seem to be suitable for promoting the
substituted phthalides.4 Yamamoto et al. then described a projected Michael addition. The bifunctional organic catalysts
Rh(I)-catalyzed one-pot four-component coupling method.5 employed in this study are summarized in Scheme 1. We have
Recently, Trost and Weiss reported a ProPhenol-promoted recently developed a series of novel Cinchona and amino acid
enantioselective alkynylation as the key step in the preparation derived tertiary amine catalysts. Quinidine-derived sulfon-
of enantioenriched phthalides.6 Cheng et al. devised a cobalt- amide (QD-4) was found to be a good catalyst for the Michael
catalyzed cocyclization reaction of 2-iodobenzoates with alde- addition of a-ketoesters to nitroolefins.11j L-Tryptophan-derived
hydes to afford substituted phthalide derivatives in one pot.7
Very recently, Wang et al. developed an organocatalytic approach
for the synthesis of 3-substituted phthalides, involving an enantio-
selective sequential aldol-lactonization reaction.8 The above methods,
a Department of Chemistry and Medicinal Chemistry Program, Life Sciences Institute,
National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore.
E-mail: chmlyx@nus.edu.sg
b Hunan University of Technology, Hunan, P. R. China
c Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of
Education, Hangzhou Normal University, Hangzhou 310012, P. R. China.
E-mail: liwenxu@hznu.edu.cn
† Electronic supplementary information (ESI) available. CCDC 930671. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c3cc42187b
Scheme 1 Bifunctional and multifunctional catalysts screened in the study.
Chem. Commun., 2013, 49, 5775--5777 5775
c
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(Trp-1) and L-threonine-based thioureas were shown to be nitroolefins (Table 2). Consistently high enantioselectivities
effective in promoting the Mannich reaction of fluorinated and excellent diastereoselectivities were observed for a wide
methines,11k cascade reactions14 and vinylogous aldol reaction range of aryl nitroolefins (entries 1–14). Alkyl nitroolefins could
of furanones.15 We also incorporated amino acids into the be tolerated, and the Michael adducts were obtained virtually as
Cinchona alkaloid structural scaffolds to create a series of one diastereomer and with good enantioselectivities (entries 15
novel multifunctional catalysts (QD-5-8, C-1, Q-1), and these and 16). The aryl moiety of the phthalide could also be varied,
catalysts have been applied successfully in conjugate addition and excellent diastereoselectivity and enantioselectivity were
to vinyl sulfone,11f and cyclopropanation of oxindoles.16
maintained (entry 17). The X-ray crystal structure of 3f (Fig. 1) was
For our preliminary investigation, we chose Michael addi- obtained, and its absolute configuration was assigned accordingly.
tion of phthalide derivative 1a to nitroolefins17 2a as a model A proposed transition state is illustrated in Scheme 2.
reaction, and the results are summarized in Table 1. Commer-
The asymmetric Michael reaction described here represents
cially available quinidine and 60-demethylated quinidine only a novel method for the preparation of chiral 3,3-disubstituted
led to poor enantioselectivities (entries 1 and 2). Quinidine- phthalides which are of biological significance. In addition, the
derived thiourea QD-3, a powerful catalyst amply demonstrated Michael products are rich in functionality, and thus serve as
in the literature, also turned out to be disappointing (entry 3). valuable synthetic intermediates. As an illustration, 3a was
Quinidine-derived sulfonamide QD-4 and L-tryptophan-based treated with TFA, followed by methylation to give intermediate
Trp-1 were also found to be ineffective (entries 4 and 5). We 4. The nitro group was then reduced, and the subsequent
next turned our attention to our recently developed amino acid-
incorporating multifunctional catalysts. To our delight, when
different amino acid residues were incorporated into the
Table 2 Substrate scopea
quinidine core, the enantioselectivity of the reaction was sub-
stantially improved (entries 6–9). The subsequent solvent screen-
ing revealed that dichloroethane (DCE) was the solvent of choice
(entries 10–14). Further improvement on the enantioselectivity of
the reaction was achieved by employing multifunctional catalysts
containing a tert-leucine moiety (entries 15–17). Under optimized
reaction conditions, the desired Michael adduct could be
obtained in 91% yield, and with >19 : 1 dr and 94% ee.
With the best reaction conditions in hand, we next studied
the scope of the reaction by employing different phthalides and
Entry
1
R
3
Yieldb (%)
drc
eed (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
4-Me-Ph
2-Naphthyl
1-Naphthyl
3,4-OMe-Ph
4-Br-Ph
3-Br-Ph
2-Br-Ph
4-Cl-Ph
2-Cl-Ph
4-F-Ph
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
89
86
91
85
93
82
83
87
86
93
91
85
87
90
81
65
90
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
93
87
85
88
91
91
86
93
98
92
92
97
92
92
80
81
98
Table 1 Catalyst screening for asymmetric Michael addition of phthalide 1a to
nitroolefin 2a a
9
10
11
12
13
14
15e
16e
17
2-F-Ph
4-CN-Ph
3-CN-Ph
2-Furan
n-Propanyl
i-Butyl
Entry
Solvent
Cat.
Yieldb (%)
drc
eed (%)
Ph
a
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
CHCl3
THF
QD-1
QD-2
QD-3
QD-4
Trp-1
QD-5
QD-6
QD-7
QD-8
QD-5
QD-5
QD-5
QD-5
QD-5
C-1
89
91
90
>19 : 1
>19 : 1
>19 : 1
—
30
25
33
—
Reactions were carried out using 1 (0.05 mmol), 2 (0.06 mmol), Q-1
b
(0.005 mmol) in DEC (2.5 mL) at room temperature. Isolated yield.
c
d
Determined by 1H NMR analysis of the crude products. Determined
e
o50
by chiral HPLC analysis on a chiral stationary phase. The reaction
time was 60 h.
93
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
11
73
70
73
ꢀ72
63
66
39
56
81
84
88
94
92
90
88
85
92
91
82
88
95
92
92
91
9
10
11
12
13
14
15
16
17e
Et2O
DCE
DCE
DCE
Q-1
Q-1
DCE
a
Reactions were carried out using 1a (0.05 mmol), 2a (0.06 mmol), the
catalyst (0.005 mmol) in the solvent specified (0.5 mL) at room tempera-
b
c
ture. Yield of the isolated product. Determined by 1H NMR analysis of
d
the crude products. Determined by chiral HPLC analysis on a chiral
stationary phase. The reaction was performed in 2.5 ml solvent.
e
Fig. 1 ORTEP structure of 3f.
c
5776 Chem. Commun., 2013, 49, 5775--5777
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In conclusion, we have developed the first asymmetric
Michael addition of 3-substituted phthalide derivatives to
nitroolefins, catalyzed by an amino acid-incorporating multi-
functional catalyst. The Michael products were obtained in
high yields, and with very high diastereoselectivities and
enantioselectivities. The synthetic method reported represents
an effective approach to access the biologically important
3,3-disubstituted phthalides. We are currently evaluating the
biological activities of our novel synthetic chiral phthalides.
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c
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Chem. Commun., 2013, 49, 5775--5777 5777