Enantioselective construction of 2,5-dihydropyrrole skeleton with quaternary stereogenic center via catalytic asymmetric 1,3-dipolar cycloaddition involving α-arylglycine esters

Article abstract of DOI:10.1039/c2ob26566d

A catalytic asymmetric construction of synthetically and biologically important 2,5-dihydropyrrole scaffolds with concomitant creation of multiple chiral carbon centers including one quaternary stereogenic center in high yields (up to 99%) and excellent e

Full text of DOI:10.1039/c2ob26566d

Organic &
Biomolecular Chemistry
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Enantioselective construction of 2,5-dihydropyrrole
skeleton with quaternary stereogenic center via
catalytic asymmetric 1,3-dipolar cycloaddition
involving α-arylglycine esters†
Cite this: Org. Biomol. Chem., 2013, 11,
1482
Feng Shi,* Gui-Juan Xing, Wei Tan, Ren-Yi Zhu and Shujiang Tu*
A catalytic asymmetric construction of synthetically and biologically important 2,5-dihydropyrrole
scaffolds with concomitant creation of multiple chiral carbon centers including one quaternary stereo-
genic center in high yields (up to 99%) and excellent enantioselectivities (up to 99% ee) has been esta-
blished via an organocatalytic 1,3-dipolar cycloaddition using α-arylglycine esters as azomethine
Received 8th August 2012,
Accepted 2nd January 2013
precursors. Moreover,
a detailed investigation has been performed on the catalytic asymmetric
DOI: 10.1039/c2ob26566d
1,3-dipolar cycloadditions of α-arylglycine ester-generated azomethine ylides with alkynes, providing an
efficient way to simultaneously access both 2,5-dihydropyrrole diastereomers in good enantioselectivities.
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Introduction
The 2,5-dihydropyrrole core represents a privileged hetero-
cyclic skeleton which not only exists in a number of natural
alkaloids (Fig. 1),1 but also is able to serve as an important
building block in organic synthesis by means of the rich chem-
istry in the functionalization of its carbon–carbon double
bond.2 Besides, this structural motif is featured in a large
family of medicinally relevant compounds exhibiting important
Fig. 1 Natural alkaloids and bioactive compounds containing a 2,5-dihydro-
pyrrole core.
bioactivities such as antioxidant,3 antimicrobial,4 anti-tumor,5
and anti-inflammatory6 properties (Fig. 1). The importance of
such a structural architecture has led to a great demand for
efficient synthetic methods, especially those producing 2,5-
dihydropyrroles in high optical purity.
The catalytic asymmetric 1,3-dipolar cycloadditions of azo-
methine ylides to electron-deficient olefins by either chiral
metal-based catalysts7 or organocatalysts8 have achieved great
success in the past decades. The azomethine ylides that par-
ticipate in these reactions are mostly generated from glycine
ester in metal-catalyzed transformations or highly reactive
2-aminomalonate in organocatalyzed versions (eqn (1)). In
sharp contrast, α-arylglycine esters have been applied to far
School of Chemistry and Chemical Engineering, Jiangsu Normal University, Xuzhou,
221116, China. E-mail: fshi@jsnu.edu.cn, laotu@jsnu.edu.cn;
Fax: +86 (516) 83500065; Tel: +86 (516) 83500065
†Electronic supplementary information (ESI) available: Experimental details,
characterization, original NMR and HPLC spectra of products 5 and 5′. See DOI:
10.1039/c2ob26566d
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fewer 1,3-dipolar cycloadditions as azomethine ylide precur-
sors, presumably due to the low reactivity inherent in both the
α-arylglycine ester and the resultant azomethine ylide. So far,
the catalytic asymmetric 1,3-dipolar cycloadditions involving
α-arylglycine ester-based azomethine ylides have sporadically
been found in a rather limited number of transformations
with olefins (eqn (2)).9 However, none of these protocols
employed alkynes rather than olefins as dipolarophiles to react
with α-arylglycine ester-derived azomethine ylides (eqn (3)).
Nonetheless, the catalytic asymmetric 1,3-dipolar cycloaddi-
tions of α-arylglycine ester-derived azomethine ylides with
alkynes would allow for the enantioselective access to syntheti-
cally and biologically important 2,5-dihydropyrroles with con-
comitant creation of quaternary chiral centers. In this regard,
the protocol holds great synthetic importance, but remains a
formidable challenge due to the low reactivity of α-arylglycine
esters and the corresponding azomethine ylides.
Scheme 1 The impact of the ratio of reagents on the reaction.
Table 1 Screening of catalysts and optimization of conditionsa
Herein, we report a catalytic asymmetric construction of
synthetically and biologically important 2,5-dihydropyrrole
scaffolds with multiple chiral centers including one quaternary
stereogenic center in high yields (up to 99%) and excellent
enantioselectivities (up to 99% ee) via an organocatalytic 1,3-
dipolar cycloaddition using α-arylglycine esters as azomethine
precursors.
Yieldb
(%)
drc
eed (%)
(5aaa/5aaa′)
Entry
4
Solvent
(5aaa : 5aaa′)
1
2
3
4
4a
4b
4c
Toluene
Toluene
Toluene
Toluene
CH2Cl2
CHCl3
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
60
52
69
78
56
72
74
87
20
55
60
91
84
95
6 : 1
5 : 1
3 : 1
1 : 1
5 : 1
6 : 1
1 : 1
1 : 1
3 : 1
3 : 1
1.5 : 1
1 : 1.5
1 : 1.3
1 : 1
7/26
<5/23
9/62
Results and discussion
4d
4d
4d
4d
4d
4d
4d
4d
4d
4d
4d
63/91
<5/54
<5/45
70/94
87/98
18/66
10/50
87/96
84/97
90/99
72/94
We have established the first catalytic enantioselective 1,3-
dipolar cycloadditions between electron-deficient alkynes and
azomethine ylides generated from 2-aminomalonate in the
presence of chiral phosphoric acid.10 However, the highly
active diethyl 2-aminomalonate was selected as azomethine
precursor in most cases and only one α-aryl amino-ester was
tentatively employed in the reaction but with obviously inferior
reactivity. Thereafter, further investigation on the reactions
involving other α-arylglycine esters under the similar reaction
conditions led to disappointing results with respect to yields
(see ESI†). For example, the reaction temperature had to be
lifted from rt to 50 °C, and the yields were only 32%–59% even
with the considerably long reaction time of 6 days. These pro-
blems prompted us to carefully investigate the 1,3-dipolar
cycloadditions of α-arylglycine ester-generated azomethine
ylides with alkynes.
5
6
7e
8f
9g
10h
11i
12j
13k
14l
a Unless indicated otherwise, the reaction was carried out on 0.1 mmol
scale in solvent (1 mL) with 3 Å MS (100 mg) for 60 h, and the molar
ratio of 1a : 2a : 3a was 2 : 1 : 2.4. b Isolated yield. c The dr was
determined by 1H NMR. d The ee was determined by HPLC. e 4 Å MS
(100 mg) was used. f 5 Å MS (100 mg) was used. g In the absence of MS.
h Catalyzed by 5 mol% 4d. i At 0 °C. j At 40 °C. k The molar ratio of
1a : 2a : 3a was 1.5 : 1 : 1.8. l The molar ratio of 1a : 2a : 3a was 2.5 : 1 : 3.
The preliminary experiments revealed that the ratio of the bearing bulky 9-anthracenyl substituents at the 3- and 3′-posi-
reagents was crucial to this reaction in terms of delivering tions of the BINOL backbone was still much superior to other
high yield. As indicated in Scheme 1, when the ratio of sub- phosphoric acids, delivering 2,5-dihydropyrrole compounds
strates 1f : 2a : 3a was changed from 1 : 2.5 : 1.2 to 2 : 1 : 2.4, the 5aaa and 5aaa′ in a high yield of 78% and with acceptable
yield was remarkably improved from 32% to 99% but with an enantiomeric excess (entry 4 vs. 1–3). A survey of solvents
obvious erosion of the enantioselectivity. Therefore, additional found that toluene was a more suitable reaction media than
studies on the optimization of conditions were initially per- dichloromethane and chloroform (entry 4 vs. 5–6). Screening
formed for the three-component reaction of methyl 2-amino- of molecular sieves (MS) disclosed that the addition of 5 Å MS
2-phenylacetate 1a, 1-phenylprop-2-yn-1-one 2a and 4-nitro- rendered a much more efficient and enantioselective reaction,
benzaldehyde 3a with the molar ratio of 2 : 1 : 2.4 in toluene at providing 87% yield and 87%/98% ees (entry 8). On the con-
25 °C in the presence of 10 mol% of various chiral phosphoric trary, both the yield and enantioselectivity decreased dramati-
acids 411,12 (Table 1). The results revealed that the catalyst 4d cally in the absence of MS (entry 9), which indicated that MS
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Table 2 Scope of α-arylglycine estersa
Table 3 Scope of ethynyl aronesa
Yieldb drc
eed (%)
Yieldb
(%)
drc
(5 : 5′)
eed (%)
(5/5′)
Entry 5 (5′)
Ar
R1 (%)
(5 : 5′) (5/5′)
Entry
5 (5′)
Ar
1
2
3
4
5
6
7
8
5aaa (5aaa′) Ph (1a)
5baa (5baa′) 4-OMeC6H4 (1b) Me 66
5caa (5caa′) 4-FC6H4 (1c)
5daa (5daa′) 3-FC6H4 (1d)
5eaa (5eaa′) 4-ClC6H4 (1e)
Me 84
1 : 1.3 90/99
1.8 : 1 92/92
1 : 1.4 89/97
1 : 2.8 86/99
1 : 1.6 90/98
1 : 2.4 87/96
1
2
3
4
5
6
7
8
9
5aaa (5aaa′)
5aba (5aba′)
5aca (5aca′)
5ada (5ada′)
5aea (5aea′)
5afa (5afa′)
5aga (5aga′)
5aha (5aha′)
5aia (5aia′)
5aja (5aja′)
Ph (2a)
84
80
84
79
66
86
77
77
88
75
1 : 1.3
1.7 : 1
1 : 1.1
1 : 1.6
1 : 1.4
1 : 1
1 : 1.2
1 : 1.5
1 : 1.2
1 : 1.6
90/99
87/97
85/96
85/97
79/95
78/94
72/92
83/93
86/96
79/96
2-Naphthyl (2b)
3-MeC6H4 (2c)
4-MeC6H4 (2d)
4-MeOC6H4 (2e)
4-CF3C6H4 (2f)
4-FC6H4 (2g)
2-FC6H4 (2h)
3,4-F2C6H3 (2i)
2-Thiophenyl (2j)
Me 79
Me 95
Me 90
Me 83
Me 99
5faa (5faa′)
5ga (5ga′)
3-ClC6H4 (1f)
2-ClC6H4 (1g)
1 : 3
67/99
5haa (5haa′) PhC6H4 (1h)
Et
Et
Et
Et
81
89
77
99
1 : 1.3 93/93
1 : 1.1 92/98
1 : 2.4 89/97
9
10
11
5iaa (5iaa′)
5jaa (5jaa′)
4-ClC6H4 (1i)
3-ClC6H4 (1j)
10
5kaa (5kaa′) 2-ClC6H4 (1k)
1 : 2
77/99
a Unless indicated otherwise, the reaction was carried out on 0.1 mmol
a Unless indicated otherwise, the reaction was carried out on 0.1 mmol scale in toluene (1 mL) with 5 Å MS (100 mg) for 60 h, and the molar
scale in toluene (1 mL) with 5 Å MS (100 mg) for 60 h, and the molar ratio of 1a : 2 : 3a was 1.5 : 1 : 1.8. b Isolated yield. c The dr was
ratio of 1 : 2a : 3a was 1.5 : 1 : 1.8. b Isolated yield. c The dr was determined by 1H NMR. d The ee was determined by HPLC.
determined by 1H NMR. d The ee was determined by HPLC.
5). Moreover, the use of ethyl 2-amino-2-arylacetates (1h–1k) as
played an important role both in reactivity and in enantioselec-
tivity control. Lowering the catalyst loading to 5 mol% led to
an inferior yield and enantioselectivity albeit with an improved
diastereoselectivity (entry 10), which demonstrated that 10 mol%
of 4d was necessary to this reaction. Variation of the reaction
temperature could not give better results with regard to enan-
tioselectivity (entries 11–12). Finally, fine-tuning the molar
ratio of 1a : 2a : 3a to 1.5 : 1 : 1.8 gave a high yield of 84% and
excellent enantioselectivities of 90%/99% ees (entry 13).
azomethine precursors also enabled the reactions to proceed
smoothly in high yields (77–99%) and good to excellent
enantioselectivities (77–93% ees for trans-5 and 93–99% ees
for cis-5′, entries 8–11).
Next, the substrate scope with respect to ethynyl arones 2
was explored by the reactions of 2-amino-2-phenylacetate 1a,
4-nitrobenzaldehyde 3a with a variety of ethynyl arones 2
under the optimized reaction conditions (Table 3). In general,
this protocol was not only applicable to various ethynyl arones
2 with electronically different substituents on their aromatic
rings (entries 1–9), but also amenable to ethynyl hetero-
aromatic ketones such as 2j (entry 10) in high yields (66–88%)
and good to excellent enantioselectivities (72–90% ees for
trans-5 and 92–99% ees for cis-5′). It seemed that ethynyl arone
2e with strong electron-donating group exhibited lower reactiv-
ity than others (entry 5), while ethynyl arones with electron-
neutral or weakly electron-donating groups delivered higher
yields and retained good enantioselectivities (entries 1–4).
Among ethynyl arones bearing electron-withdrawing substitu-
ents, disubstituted ethynyl arone 2i appeared to be a superior
substrate, offering a high yield of 88% and good enantio-
selectivities of 86%/96% ees (entry 9 vs. 6–8).
We also investigated the generality of the reaction for
different aromatic aldehydes. When aldehyde 3b was employed
as a substrate to react with amino-ester 1a and ethynyl arone
2a under the optimized reaction conditions, the desired pro-
ducts 5aab and 5aab′ were afforded in acceptable yield and
diastereoselectivity but with unsatisfactory enantioselectivities
(Table 4, entry 1). Thus, the reaction parameters such as
solvent and ratio of reagents were further optimized to
improve the enantioselectivity. When increasing the stoichio-
metry of the azomethine ylide generated in situ from 1a and
3b, the yield and diastereoselectivity were significantly
With the optimal conditions in hand, the generality of the
reaction for α-arylglycine esters 1 was explored in the reaction
with 1-phenylprop-2-yn-1-one 2a and 4-nitrobenzaldehyde 3a.
As shown in Table 2, this protocol was amenable to a wide
scope of α-arylglycine esters bearing either an electronically
poor, neutral, or rich substituent on their aromatic ring,
offering 2,5-dihydropyrroles 5 and 5′ in high yields (up to 99%)
and with good to excellent enantioselectivities (up to 93% ee
for trans-5 and up to 99% ee for cis-5′). α-Arylglycine esters sub-
stituted with electron-withdrawing groups were seemingly
more reactive than their counterparts substituted with elec-
tron-donating groups in terms of yield (entries 3–7 vs. 2), but
the latter (1b) was capable of affording two diastereomers,
both with high enantioselectivity of 92% ee (entry 2). In most
cases, the cis-diastereomers 5′ were obtained with higher
enantioselectivities (92–99% ees) than their trans-counterparts
5 (67–93% ees). The position of the substituents of benzene
ring appeared to exert some impact on the diastereoselectivity
of the reaction as well as the enantioselectivity of the trans-
product 5 (entries 5–7). Among chlorine-substituted α-aryl-
glycine esters 1e–1g, the ortho-substituted α-arylglycine ester 1g
provided the highest diastereoselectivity of 1 : 3 (entry 7), while
the para-substituted α-arylglycine ester 1e delivered the trans-
product 5eaa with the best enantioselectivity of 90% ee (entry
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Table 4 Further optimization of reaction conditionsa
Table 5 Scope of aromatic aldehydesa
Yieldb
(%)
drc
(5 : 5′)
eed (%)
(5/5′)
Molar ratio
Entry of 1a : 2a : 3b Solvent
Yieldb drc
eed (%)
Entry 5 (5′)
Ar
(%)
(5aab : 5aab′) (5aab/5aab′)
1
5aab (5aab′) 4-CO2MeC6H4 (3b) 44 (99e) 1.2 : 1
79/91
1
2
3
4
5
6
7
8
2 : 1 : 2.4
3 : 1 : 3.6
4 : 1 : 4.8
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
PhF
PhCl
PhBr
1,2-Cl2C6H4 42
1,3-Cl2C6H4 33
61
64
99
58
56
27
42
44
40
42
35
2.7 : 1
3.3 : 1
11 : 1
2.2 : 1
2.5 : 1
2.6 : 1
2.5 : 1
1.2 : 1
1.5 : 1
2.5 : 1
2 : 1
33/69
25/59
13/50
53/80
55/77
69/82
74/81
79/91
36/60
73/80
82/88
67/70
72/73
(11 : 1e) (13/50e)
2
3
4f
5
6
7
5aac (5aac′) 4-CNC6H4 (3c)
5aad (5aad′) 4-CF3C6H4 (3d)
5aaa (5aaa′) 4-NO2C6H4 (3a)
5aae (5aae′) 3-NO2C6H4 (3e)
52
33
84
37
40
36
1 : 1.3
2.5 : 1
1 : 1.3
1.8 : 1
>20 : 1
5 : 1
77/89
68/72
90/99
77/74
66g
1 : 1.2 : 1.2
1 : 2.4 : 1.2
1 : 3.6 : 1.2
1 : 4.8 : 1.2
1 : 2.4 : 2.4
1 : 2.4 : 2.4
1 : 2.4 : 2.4
1 : 2.4 : 2.4
1 : 2.4 : 2.4
1 : 2.4 : 2.4
5aaf
5aag
2-NO2C6H4 (3f)
4-CH3C6H4 (3g)
24g
9
a Unless indicated otherwise, the reaction was carried out on 0.1 mmol
scale in toluene (1 mL) with 3 Å MS (100 mg) for 60 h, and the molar
ratio of 1a : 2a : 3 was 1 : 2.4 : 2.4. b Isolated yield. c The dr was
determined by 1H NMR. d The ee was determined by HPLC. e The
molar ratio of 1a : 2a : 3b was 4 : 1 : 4.8. f The molar ratio of 1a : 2a : 3a
was 1.5 : 1 : 1.8, and 5 Å MS was used instead of 3 Å MS. g The ee value
of major trans-diastereomer 5.
10
11
12
13
4 : 1
4 : 1
a Unless indicated otherwise, the reaction was carried out on 0.1 mmol
scale in solvent (1 mL) with 3 Å MS (100 mg) for 60 h. b Isolated yield.
c The dr was determined by 1H NMR. d The ee was determined by
HPLC.
to deliver high yield and enantioselectivity (entry 4), and meta-
nitrobenzaldehyde was better than ortho-nitrobenzaldehyde in
terms of enantioselectivity (entry 5), while ortho-nitrobenz-
aldehyde offered the highest diastereoselectivity (>20 : 1 dr,
entry 6). Moreover, electronically rich benzaldehydes such as
para-methyl benzaldehyde 3g could also be applied to this
reaction with high diastereoselectivity but in low yield and
with inferior enantioselectivity (entry 8). These results could
largely be ascribed to the low reactivity associated with azo-
methine ylides generated from amino-esters, especially from
α-arylglycine esters with electronically rich benzaldehydes.9c,10
In spite of the fact that the electronic features of the alde-
hydes had some delicate effect on the reaction, this protocol
could be applied to a wide range of α-arylglycine esters and
ethynyl arones, affording synthetically and biologically impor-
tant 2,5-dihydropyrroles with quaternary stereogenic centers in
high yields and with good to excellent enantioselectivities.
Although the diastereoselectivity was not satisfactory, this pro-
tocol could provide an easy access to both of the diastereomers
in good enantioselectivities simultaneously.
enhanced to 99% and 11 : 1 dr, but the enantioselectivity
sharply decreased (entries 1–3). On the contrary, increasing
the stoichiometry of ethynyl arone 2a led to the improvement
of enantioselectivity but with inferior yield (entries 4–7). Ulti-
mately, the highest enantioselectivities of 79% ee for 5aab and
91% ee for 5aab′ were achieved with an acceptable yield by
tuning the ratio of 1a : 2a : 3b to 1 : 2.4 : 2.4 (entry 8). During
the course of fine-tuning the ratio of reagents, the two factors
of yield and enantioselectivity were obviously restricted by
each other, thereby excellent enantioselectivity accompanied
by high yield could rarely be simultaneously obtained in this
case and a compromise between them should be made. So, the
molar ratio of 1 : 2.4 : 2.4 was utilized as the optimal ratio of
reagents to further screen other benzene-related solvents. The
results revealed that no other tested solvents were better than
toluene with regard to yield and enantioselectivity (entries
9–13 vs. 8).
Under the newly optimized reaction conditions, a number
of aromatic aldehydes were examined (Table 5). The electronic
nature of the aromatic aldehydes had an evident effect on the
reaction. Generally, this protocol is amenable to aromatic alde-
hydes substituted with electron-withdrawing groups, delivering
good or acceptable enantioselectivities albeit with unsatisfac-
tory yields in some cases (entries 1–6). However, quantitative
yield could be obtained at the mole ratio of 4 : 1 : 4.8 but with
low enantioselectivities as exemplified by 3b (entry 1, in par-
entheses). Besides, the substituent position of aromatic
aldehydes seemed to impose some impact on the reactivity
and stereoselectivity as illustrated by the examples of nitro-
substituted benzaldehydes 3a, 3e and 3f (entries 4–6). Among
the three aldehydes, para-nitrobenzaldehyde was the best one
The structures of the synthesized 2,5-dihydropyrroles 5 and
5′ were unambiguously characterized by IR, 1H NMR, 13C NMR
and HRMS (ESI). The relative configuration of compound 5caa
1
was assigned to be trans by comparison of its H NMR proton
shift with the same known compound, whose configuration
was confirmed by the single crystal of its derivative.10 Conse-
quently, the relative configuration of compound 5caa′ was
assigned to be cis accordingly. In simple terms, the chemical
shift of the proton linked to the CvC bond in trans-2,5-di-
hydropyrrole ring is higher (6.90 in 5caa) than its cis-counter-
part (6.77 in 5caa′), while the chemical shift of the tertiary CH
proton in trans-5 (5.69 in 5caa) is lower than cis-5 (5.87 in
5caa). The absolute configurations of compounds 5caa and
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Scheme 3 The formation of byproduct.
products 5faa and 5faa′ were greatly improved at this ratio of
reagents.
Scheme 2 Possible reaction pathway and transition states.
Conclusions
5caa′ were respectively determined to be (2R, 5S) and (2S, 5S)
by comparing their optical rotations with those of the same
known compounds.10 The relative and absolute configurations
of other new 2,5-dihydropyrroles 5 and 5′ were assigned by
analogy.
In summary, we have established a catalytic enantioselective
construction of synthetically and biologically important 2,5-
dihydropyrrole scaffolds with multiple chiral centers including
one quaternary stereogenic center in high yields (up to 99%)
and with excellent enantioselectivities (up to 99% ee) in most
cases. More importantly, this work has realized the first in-
depth study on catalytic asymmetric 1,3-dipolar cycloadditions
of α-arylglycine ester-generated azomethine ylides with
alkynes, providing an efficient way to access both of the 2,5-
dihydropyrrole diastereomers in good enantioselectivities sim-
ultaneously. This protocol also combines the merits of organo-
catalysis and multicomponent reactions, furnishing structurally
diverse 2,5-dihydropyrroles with quaternary chiral center.
On the basis of our experimental results and previous
studies on the reaction mechanism,9f,10 we proposed the poss-
ible pathway and transition states of the reaction to explain the
stereochemistry experimentally observed (Scheme 2). The 1,3-
dipolar cycloaddition might also proceed via a sequential
Michael addition and Mannich-type cyclization rather than a
concerted pathway.10 The chiral phosphoric acid 4d served as
a Brønsted acid/Lewis base bifunctional catalyst to simul-
taneously activate both the α-arylglycine ester-derived azo-
methine ylide and ethynyl arone by H-bonding interactions.
The enantioselective [3+2] reaction occurred because of the
chiral environment created by the (R)-BINOL backbone and
the congested 3,3′-substituents of the catalyst 4d, thereby
leading to the formation of the experimentally observed (2R,
5S)- and (2S, 5S)-configured products 5 and 5′. The two stable
configurations of α-arylglycine ester-generated azomethine
ylide had little difference in steric hindrance and could iso-
merize to each other easily, thereby resulting in the low
diastereoselectivities.
As mentioned above, the ratio of the reagents was crucial to
the yield of the 1,3-dipolar cycloadditions. We also investigated
the possible reasons. As illustrated in Scheme 3, when the
molar ratio of 1f : 2a : 3a was 1 : 2.5 : 1.2, the excess amount of
2a would undergo self-trimerization under the amine catalysis
to give 1,3,5-tribenzoylbenzene 6.13 Due to the low reactivity
and small amount of azomethine ylide generated from α-aryl-
glycine ester 1f and aldehyde 3a, ethynyl arone 2a might
undergo self-trimerization more easily than 1,3-dipolar cyclo-
addition. Therefore, the low yields of products 5faa and 5faa′
were mainly ascribed to the formation of byproduct 6, which
consumed a large amount of reagent 2a. However, when
the molar ratio of 1f : 2a : 3a was 2 : 1 : 2.4, the amount of
azomethine ylide was much greater than that of dipolarophile
2a, thus facilitating the 1,3-dipolar cycloaddition and avoiding
Experimental
General information
NMR spectra were measured at 400 and 100 MHz on a
Brucker-400 MHz spectrometer. The solvent used for NMR
spectroscopy was CDCl3, using tetramethylsilane as the
internal reference. HRMS (Bio TOF Q) spectra were recorded
with an ESI resource on P-SIMS-Gly of Bruker Daltonics Inc.
Infrared spectra were recorded on a Nicolet MX-1E FT-IR
spectrometer. HPLC analysis was performed on Waters-Breeze
(2487 Dual Absorbance Detector and 1525 Binary HPLC Pump)
or Agilent 1200. Chiralpak IC, IA, and AD columns were pur-
chased from Daicel Chemical Industries, Ltd. Optical rota-
tion values were measured with instruments operating at
λ = 589 nm, corresponding to the sodium D line at the temp-
eratures indicated.
Analytical grade solvents for column chromatography and
commercially available reagents were used as received.
Toluene was dried over Na and distilled prior to use. All com-
mercially available starting materials were used directly. Cata-
lysts 4a–4d were prepared according to previously described
procedures11a,b,14 and 4d was acidified with 4 N HCl before
use. α-Arylglycine esters 1a–1k were prepared using previously
reported methods.9f Substrates 2a–2j were obtained according
to the literature methods.10,15
the self-trimerization of 2a. As
a result, the yields of
1486 | Org. Biomol. Chem., 2013, 11, 1482–1489
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General procedure for asymmetric 1,3-dipolar cycloadditions
of alkynes with azomethine ylides generated from
α-arylglycine esters and 4-nitrobenzaldehyde 3a
135.0, 133.3, 130.2, 129.0, 128.7, 128.5, 128.4, 126.1, 124.1,
123.9, 78.6, 68.3, 53.5; IR (KBr): 3381, 3074, 2924, 2853, 1734,
1648, 1596, 1520, 1450, 1344, 1236, 1185, 1106, 1079, 1024,
851, 782, 722, 695; ESI FTMS exact mass calcd for
The solution of α-arylglycine esters 1 (0.15 mmol), 4-nitrobenz-
aldehyde 3a (0.18 mmol), the catalyst 4d (0.01 mmol), and
5 Å molecular sieves (100 mg) in toluene (0.5 mL) was stirred
at 25 °C for 20 min. Then to this resultant mixture was added
the solution of ethynyl arones 2 (0.1 mmol) in toluene
(0.5 mL). The reaction mixture was stirred at 25 °C for 60 h.
Then the reaction mixture was filtered to remove mole-
cular sieves, and the solid powder was washed with ethyl
acetate. The resultant solution was evaporated under reduced
pressure, and the residue was purified through flash
column chromatography on silica gel to yield pure products 5
and 5′.
(C25H19ClN2O5
+
H)+ requires m/z 463.1061, found m/z
463.1061; enantiomeric excess: 87%, determined by HPLC
(Daicel Chirapak IA, hexane–isopropanol = 70 : 30, flow rate
1.0 mL min−1, T = 30 °C, 254 nm): tR = 10.91 min (major),
tR = 16.37 min (minor).
5faa′: yellow oil; [α]2D0 = +89.6 (c 0.2, CHCl3); 1H-NMR
(CDCl3, 400 MHz) δ (ppm): 8.11 (dt, J = 2.3 Hz, 4.2 Hz, 2H),
7.69–7.67 (m, 3H), 7.58–7.54 (m, 4H), 7.45–7.39 (m, 4H), 6.76
(d, J = 2.1 Hz, 1H), 5.88 (d, J = 1.9 Hz, 1H), 3.95 (s, 1H), 3.77
(s, 3H); 13C-NMR (CDCl3, 100 MHz) δ (ppm): 191.0, 172.8,
149.4, 147.4, 144.5, 143.2, 139.3, 137.1, 135.0, 133.4, 130.2,
129.0, 128.7, 128.5, 126.5, 124.3, 123.6, 78.2, 67.7, 53.8; IR
(KBr): 3356, 3072, 2924, 2855, 1733, 1651, 1596, 1520, 1450,
1342, 1237, 1077, 1016, 853, 791, 712; ESI FTMS exact mass
Selected examples of characterization of new compounds 5
Methyl
dihydro-1H-pyrrole-2-carboxylate (5daa and 5daa′). Reaction m/z 463.1062; enantiomeric excess: 96%, determined by HPLC
4-benzoyl-2-(3-fluorophenyl)-5-(4-nitrophenyl)-2,5- calcd for (C25H19ClN2O5 + H)+ requires m/z 463.1061, found
time = 60 h; dr (5daa : 5daa′) = 1 : 2.8; total yield: 95%.
(Daicel Chirapak IC, hexane–isopropanol = 70 : 30, flow rate
5daa: yellow oil; [α]2D0 = +43.6 (c 0.2, CHCl3); 1H-NMR 1.0 mL min−1, T = 30 °C, 254 nm): tR = 9.31 min (minor),
(CDCl3, 400 MHz) δ (ppm): 8.18 (d, J = 8.4 Hz, 2H), 7.77–7.72 tR = 11.17 min (major).
(m, 2H), 7.61–7.54 (m, 3H), 7.46 (t, J = 7.6 Hz, 2H), 7.38–7.26
Ethyl
4-benzoyl-2-(4-chlorophenyl)-5-(4-nitrophenyl)-2,5-
(m, 3H), 7.06–6.98 (m, 1H), 6.89 (d, J = 2.0 Hz, 1H), 5.70 (d, J = dihydro-1H-pyrrole-2-carboxylate (5ia and 5ia′). Reaction time
1.6 Hz, 1H), 3.88 (s, 3H), 3.19 (s, 1H); 13C-NMR (CDCl3, = 60 h; dr (5iaa : 5iaa′) = 1 : 1.1; total yield: 89%.
100 MHz) δ (ppm): 190.8, 172.8, 163.1 (J = 245.9 Hz), 148.7,
5iaa: yellow oil; [α]D20 = +74.0 (c 0.2, CHCl3); 1H-NMR (CDCl3,
147.7, 143.6, 141.2, 137.2, 133.3, 130.5, 128.9, 128.7, 128.4, 400 MHz) δ (ppm): 8.18 (dt, J = 2.4 Hz, 4.3 Hz, 2H), 7.75–7.72
124.1, 121.3, 115.3 (J = 20.0 Hz), 113.2, 113.0, 78.6, 68.3, 53.5; (m, 2H), 7.59–7.56 (m, 3H), 7.50–7.44 (m, 4H), 7.36–7.33
IR (KBr): 3380, 3075, 2954, 2925, 2859, 1735, 1651, 1597, 1447, (m, 2H), 6.89 (d, J = 2.0 Hz, 1H), 5.69 (d, J = 2.0 Hz, 1H),
1345, 1232, 854, 693; enantiomeric excess: 86%, determined 4.39–4.28 (m, 2H), 3.19 (s, 1H), 1.31 (t, J = 7.1 Hz, 3H);
by HPLC (Daicel Chirapak IA, hexane–isopropanol = 70 : 30, 13C-NMR (CDCl3, 100 MHz) δ (ppm): 191.0, 172.7, 148.9, 147.9,
flow rate 1.0 mL min−1, T = 30 °C, 254 nm): tR = 11.90 min 143.7, 141.9, 139.9, 137.7, 134.6, 133.6, 129.4, 129.3, 129.0,
(major), tR = 16.91 min (minor).
128.4, 127.2, 124.1, 78.5, 68.3, 62.6, 14.2; IR (KBr): 3381, 3077,
5daa′: yellow oil; [α]2D0 = +103.1 (c 0.5, CHCl3); 1H-NMR 2924, 2853, 1730, 1649, 1598, 1520, 1488, 1448, 1344, 1232,
(CDCl3, 400 MHz) δ (ppm): 8.10 (d, J = 8.8 Hz, 2H), 7.71–7.66 1092, 1014, 956, 850, 720, 696; ESI FTMS exact mass calcd for
(m, 2H), 7.60–7.54 (m, 3H), 7.46–7.39 (m, 5H), 7.13–7.07 (C26H21ClN2O5
+
H)+ requires m/z 477.1217, found m/z
(m, 1H), 6.75 (d, J = 2.0 Hz, 1H), 5.88 (s, 1H), 3.94 (s, 1H), 3.77 477.1216; enantiomeric excess: 92%, determined by HPLC
(s, 3H); 13C-NMR (CDCl3, 100 MHz) δ (ppm): 190.0, 171.8, (Daicel Chirapak IA, hexane–isopropanol = 70 : 30, flow rate
162.1 (J = 242.0 Hz), 148.5, 146.4, 142.8, 142.7, 138.5, 136.1, 1.0 mL min−1, T = 30 °C, 254 nm): tR = 13.84 min (major),
132.4, 129.6, 129.5, 128.0, 127.7, 122.6, 120.7, 114.3 (J = 21.0 tR = 20.81 min (minor).
Hz), 112.6, 112.4, 76.9, 66.3, 52.5; IR (KBr): 3357, 3076, 2953,
5iaa′: yellow oil; [α]2D0 = +104.9 (c 0.3, CHCl3); 1H-NMR
2925, 2855, 1733, 1651, 1519, 1344, 1232, 850, 721; (CDCl3, 400 MHz) δ (ppm): 8.10 (dt, J = 2.3 Hz, 4.0 Hz, 2H),
enantiomeric excess: 99%, determined by HPLC (Daicel Chira- 7.69–7.67 (m, 2H), 7.65–7.62 (m, 2H), 7.58–7.54 (m, 3H),
pak IA, hexane–isopropanol = 70 : 30, flow rate 1.0 mL min−1
,
7.46–7.40 (m, 4H), 6.75 (d, J = 2.1 Hz, 1H), 5.88 (d, J = 1.8 Hz,
T = 30 °C, 254 nm): tR = 9.47 min (minor), tR = 13.22 min 1H), 4.28–4.15 (m, 2H), 3.96 (s, 1H), 1.23 (t, J = 7.2 Hz, 3H);
(major).
13C-NMR (CDCl3, 100 MHz) δ (ppm): 191.3, 172.6, 149.9, 147.6,
Methyl-4-benzoyl-2-(3-chlorophenyl)-5-(4-nitrophenyl)-2,5- 144.5, 140.2, 139.9, 137.4, 134.5, 133.6, 129.3, 129.0, 128.9,
dihydro-1H-pyrrole-2-carboxylate (5faa and 5faa′). Reaction 127.8, 123.8, 78.1, 67.6, 63.0, 14.3; IR (KBr): 3356, 3075, 2924,
time = 60 h; dr (5faa : 5faa′) = 1 : 2.4; total yield: 83%.
5faa: yellow oil; [α]2D0 = +47.0 (c 0.1, CHCl3); 1H-NMR (CDCl3, 1095, 1019, 838, 718, 698; ESI FTMS exact mass calcd for
400 MHz) δ (ppm): 8.19 (dt, J = 2.4 Hz, 4.3 Hz, 2H), 7.76–7.73 (C26H21ClN2O5
H)+ requires m/z 477.1217, found m/z
2855, 1729, 1651, 1599, 1520, 1485, 1450, 1401, 1341, 1230,
+
(m, 2H), 7.59–7.54 (m, 4H), 7.48–7.44 (m, 2H), 7.42–7.38 (m, 477.1216; enantiomeric excess: 98%, determined by HPLC
1H), 7.32–7.30 (m, 2H), 6.89 (d, J = 2.0 Hz, 1H), 5.70 (d, J = 2.0 (Daicel Chirapak IA, hexane–isopropanol = 70 : 30, flow rate
Hz, 1H), 3.88 (s, 3H), 3.19 (s, 1H); 13C-NMR (CDCl3, 100 MHz) 1.0 mL min−1, T = 30 °C, 254 nm): tR = 12.95 min (major),
δ (ppm): 190.8, 172.7, 148.6, 147.7, 143.7, 143.0, 141.1, 137.2, tR = 14.97 min (minor).
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Ethyl
Organic & Biomolecular Chemistry
4-benzoyl-2-(3-chlorophenyl)-5-(4-nitrophenyl)-2,5- 7.44–7.40 (m, 1H), 6.84 (d, J = 2.1 Hz, 1H), 5.87 (d, J = 1.9 Hz,
dihydro-1H-pyrrole-2-carboxylate (5jaa and 5jaa′). Reaction 1H), 3.93 (s, 1H), 3.76 (s, 3H); 13C-NMR (CDCl3, 100 MHz)
time = 60 h; dr (5jaa : 5jaa′) = 1 : 2.4; total yield: 77%.
δ (ppm): 190.0, 173.3, 149.4, 147.4, 143.9, 141.6, 141.0, 140.0,
5jaa: yellow oil; [α]D20 = +46.8 (c 0.2, CHCl3); 1H-NMR (CDCl3, 134.9 (J = 32.6 Hz), 129.6, 129.4, 129.1, 128.6, 126.3, 126.1
400 MHz) δ (ppm): 8.19 (dt, J = 2.4 Hz, 4.2 Hz, 2H), 7.75–7.72 (J = 3.7 Hz), 125.7, 123.6, 78.3, 67.2, 53.4; IR (KBr): 3356, 3200,
(m, 2H), 7.60–7.52 (m, 4H), 7.48–7.44 (m, 2H), 7.43–7.40 2924, 2855, 1731, 1655, 1519, 1449, 1402, 1325, 1254, 1169,
(m, 1H), 7.31–7.30 (m, 2H), 6.88 (d, J = 2.0, 1H), 5.71 (d, J = 1125, 1066, 853, 810, 703; ESI FTMS exact mass calcd for
1.9 Hz, 1H), 4.39–4.31 (m, 2H), 3.19 (s, 1H), 1.32 (t, J = 7.1 Hz, (C26H19F3N2O5
+
H)+ requires m/z 497.1324, found m/z
3H); 13C-NMR (CDCl3, 100 MHz) δ (ppm): 190.8, 172.2, 148.7, 497.1327; enantiomeric excess: 94%, determined by HPLC
147.6, 143.8, 143.4, 141.7, 137.6, 135.3, 133.6, 130.5, 129.3, (Daicel Chirapak IA, hexane–isopropanol = 70 : 30, flow rate
129.1, 128.8, 128.6, 126.1, 124.1, 123.9, 78.6, 68.3, 62.7, 14.2; 1.0 mL min−1, T = 30 °C, 254 nm): tR = 9.76 min (minor), tR
=
IR (KBr): 3379, 2924, 2854, 1730, 1650, 1597, 1521, 1452, 1405, 12.69 min (major).
1343, 1234, 1104, 1025, 853, 786, 720, 696; ESI FTMS exact
Methyl
4-(4-fluorobenzoyl)-5-(4-nitrophenyl)-2-phenyl-2,5-
mass calcd for (C26H21ClN2O5 + H)+ requires m/z 477.1217, dihydro-1H-pyrrole-2-carboxylate (5ag and 5ag′). Reaction time
found m/z 477.1218; enantiomeric excess: 89%, determined by = 60 h; dr (5aga : 5aga′) = 1 : 1.2; total yield: 77%.
HPLC (Daicel Chirapak IA, hexane–isopropanol = 70 : 30, flow
rate 1.0 mL min−1, T = 30 °C, 254 nm): tR = 10.13 min (major), (CDCl3, 400 MHz) δ (ppm): 8.18 (dt, J = 1.9 Hz, 4.3 Hz, 2H),
tR = 13.10 min (minor). 7.82–7.77 (m, 2H), 7.60–7.57 (m, 2H), 7.49–7.46 (m, 2H),
5aga: yellow oil; [α]2D0 = +54.2 (c 0.1, CHCl3); 1H-NMR
5jaa′: yellow oil; [α]D20 = +142.0 (c 0.3, CHCl3); 1H-NMR 7.41–7.33 (m, 3H), 7.16–7.10 (m, 2H), 6.89 (d, J = 2.0 Hz, 1H),
(CDCl3, 400 MHz) δ (ppm): 8.11 (dt, J = 2.3 Hz, 2.0 Hz, 2H), 5.73 (d, J = 1.8 Hz, 1H), 3.87 (s, 3H), 3.18 (s, 1H); 13C-NMR
7.70–7.68 (m, 3H), 7.60–7.54 (m, 4H), 7.45–7.38 (m, 4H), 6.75 (CDCl3, 100 MHz) δ (ppm): 189.3, 173.5, 166.2 (J = 254.0 Hz),
(d, J = 2.1 Hz, 1H), 5.88 (d, J = 1.8 Hz, 1H), 4.29–4.16 (m, 2H), 149.2, 147.9, 143.4, 142.0, 141.2, 133.9, 132.0, 131.9, 129.4,
3.96 (s, 1H), 1.25 (t, J = 7.1 Hz, 3H); 13C-NMR (CDCl3, 128.8, 125.9, 124.3, 116.0 (J = 21.9 Hz), 79.0, 68.2, 53.3; IR
100 MHz) δ (ppm): 191.0, 172.2, 149.5, 147.4, 144.3, 143.3, (KBr): 3380, 3073, 2951, 2924, 2854, 1733, 1651, 1598, 1520,
139.4, 137.1, 134.9, 133.3, 130.1, 129.0, 128.7, 128.4, 126.5, 1442, 1410, 1343, 1235, 1154, 1107, 1073, 1022, 965, 852, 752,
124.3, 123.6, 77.9, 67.3, 62.9, 14.0; IR (KBr): 3353, 3069, 2923, 698; ESI FTMS exact mass calcd for (C25H19FN2O5 + H)+
2853, 1729, 1651, 1597, 1520, 1451, 1415, 1342, 1229, 1166, requires m/z 447.1356, found m/z 447.1358; enantiomeric
1102, 1022, 855, 793, 719, 694; ESI FTMS exact mass calcd for excess: 72%, determined by HPLC (Daicel Chirapak IA,
(C26H21ClN2O5
477.1216; enantiomeric excess: 97%, determined by HPLC 30 °C, 254 nm): tR = 15.76 min (major), tR = 36.28 min (minor).
(Daicel Chirapak IC, hexane–isopropanol = 70 : 30, flow rate
5aga′: yellow oil; [α]2D0 = +119.1 (c 0.2, CHCl3); 1H-NMR
1.0 mL min−1, T = 30 °C, 254 nm): tR = 9.19 min (minor), (CDCl3, 400 MHz) δ (ppm): 8.09 (dt, J = 1.9 Hz, 4.2 Hz, 2H),
t = 10.36 min (major). 7.77–7.72 (m, 2H), 7.67–7.64 (m, 2H), 7.60–7.57 (m, 2H),
+
H)+ requires m/z 477.1217, found m/z hexane–isopropanol = 70 : 30, flow rate 1.0 mL min−1, T =
Methyl 5-(4-nitrophenyl)-2-phenyl-4-(4-(trifluoromethyl)- 7.50–7.46 (m, 2H), 7.43–7.39 (m, 1H), 7.12–7.08 (m, 2H), 6.79
benzoyl)-2,5-dihydro-1H-pyrrole-2-carboxylate (5af and (d, J = 2.1 Hz, 1H), 5.87 (s, 1H), 3.91 (s, 1H), 3.76 (s, 3H);
5af′). Reaction time = 60 h; dr (5afa : 5afa′) = 1 : 1; total 13C-NMR (CDCl3, 100 MHz) δ (ppm): 189.6, 173.2, 166.2 (J =
yield: 86%.
254.2 Hz), 149.6, 147.4, 144.1, 141.3, 140.1, 133.8, 131.9, 129.0,
5afa: yellow oil; [α]D20 = +64.4 (c 0.3, CHCl3); 1H-NMR (CDCl3, 128.7, 126.1, 123.6, 115.9 (J = 21.9 Hz), 78.3, 67.3, 53.4; IR
400 MHz) δ (ppm): 8.2 (dt, J = 2.3 Hz, 1.9 Hz, 2H), 7.83 (d, J = (KBr):3357, 3071, 2923, 2853, 1733, 1651, 1597, 1519, 1447,
8.1 Hz, 2H), 7.73 (d, J = 8.2 Hz, 2H), 7.59 (dt, J = 2.3 Hz, 1.8 Hz, 1410, 1343, 1234, 1156, 1105, 1068, 1014, 977, 853, 738, 699;
2H), 7.5–7.47 (m, 2H), 7.41–7.34 (m, 3H), 6.95 (d, J = 2.0 Hz, ESI FTMS exact mass calcd for (C25H19FN2O5 + H)+ requires
1H), 5.73 (d, J = 1.8 Hz, 1H), 3.87 (s, 3H), 3.21 (s, 1H); 13C-NMR m/z 447.1356, found m/z 447.1358; enantiomeric excess: 92%,
(CDCl3, 100 MHz) δ (ppm): 189.9, 172.9, 148.7, 147.7, 143.3, determined by HPLC (Daicel Chirapak IA, hexane–isopropanol
143.2, 141.0, 140.5, 134.8 (J = 32.7 Hz), 129.5, 129.4, 128.8, = 85 : 15, flow rate 1.0 mL min−1, T = 30 °C, 254 nm): tR
128.7, 126.1 (J = 3.7 Hz), 125.5, 124.0, 79.0, 68.0, 53.4; IR (KBr): 18.87 min (minor), tR = 20.91 min (major).
=
3380, 3068, 2924, 2853, 1735, 1656, 1603, 1522, 1442, 1409,
Methyl
4-(3,4-difluorobenzoyl)-5-(4-nitrophenyl)-2-phenyl-
1324, 1237, 1169, 1130, 1068, 1018, 964, 853, 822, 738, 699; ESI 2,5-dihydro-1H-pyrrole-2-carboxylate (5ai and 5ai′). Reaction
FTMS exact mass calcd for (C26H19F3N2O5 + H)+ requires m/z time = 60 h; dr (5aia : 5aia′) = 1 : 1.2; total yield: 88%.
497.1324, found m/z 497.1324; enantiomeric excess: 78%,
5aia: yellow oil; [α]D20 = +56.7 (c 0.1, CHCl3); 1H-NMR (CDCl3,
determined by HPLC (Daicel Chirapak IA, hexane–isopropanol 400 MHz) δ (ppm): 8.19 (dt, J = 2.3 Hz, 1.9 Hz, 2H), 7.62–7.56
= 70 : 30, flow rate 1.0 mL min−1, T = 30 °C, 254 nm): tR
12.92 min (major), tR = 26.84 min (minor).
=
(m, 4H), 7.52–7.46 (m, 2H), 7.42–7.33 (m, 2H), 7.28–7.22
(m, 1H), 6.92 (d, J = 2.0 Hz, 1H), 5.72 (d, J = 1.9 Hz, 1H), 3.88
5afa′: yellow oil; [α]2D0 = +117.7 (c 0.3, CHCl3); 1H-NMR (s, 3H), 3.22 (s, 1H); 13C-NMR (CDCl3, 100 MHz) δ (ppm):
(CDCl3, 400 MHz) δ (ppm): 8.11 (dt, J = 2.4 Hz, 1.9 Hz, 2H), 188.3, 173.3, 148.0 (J = 98.5 Hz), 142.6, 142.4, 140.7, 129.1,
7.79 (d, J = 8.1 Hz, 2H), 7.7 (d, J = 8.1 Hz, 2H), 7.67–7.63 128.5, 128.4, 125.5, 124.0, 118.3 (J = 16.6 Hz), 117.7 (J =
(m, 2H), 7.6 (dt, J = 2.3 Hz, 1.9 Hz, 2H), 7.5–7.46 (m, 2H), 17.6 Hz), 79.0, 68.2, 53.4; IR (KBr): 3436, 3385, 3074, 2922,
1488 | Org. Biomol. Chem., 2013, 11, 1482–1489
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2854, 1733, 1653, 1604, 1517, 1427, 1343, 1279, 1234, 1109,
1063, 1023, 957, 852, 818, 761, 698; ESI FTMS exact mass calcd
for (C25H18F2N2O5 + H)+ requires m/z 465.1262, found m/z
465.1262; enantiomeric excess: 86%, determined by HPLC
(Daicel Chirapak IA, hexane–isopropanol = 70 : 30, flow rate
1.0 mL min−1, T = 30 °C, 254 nm): tR = 15.25 min (major), tR =
33.92 min (minor).
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5aia′: yellow oil; [α]2D0 = +126.7 (c 0.2, CHCl3); 1H-NMR
(CDCl3, 400 MHz) δ (ppm): 8.1 (dt, J = 2.3 Hz, 1.9 Hz, 2H),
7.66–7.63 (m, 2H), 7.6–7.56 (m, 3H), 7.5–7.46 (m, 4H),
7.44–7.40 (m, 1H), 6.81 (d, J = 2.1 Hz, 1H), 5.85 (d, J = 1.9 Hz,
1H), 3.95 (s, 1H), 3.77 (s, 3H); 13C-NMR (CDCl3, 100 MHz)
δ (ppm): 188.3, 173.8, 148.7 (J = 190.3 Hz), 142.7 (J = 260.1 Hz),
140.9, 134.3, 129.4, 129.1, 128.7, 126.3, 123.9, 118.1 (J = 18.3
Hz), 117.6 (J = 17.9 Hz), 78.3, 67.3, 53.4; IR (KBr): 3437, 2922,
2854, 1732, 1668, 1644, 1609, 1554, 1515, 1449, 1342, 1279,
1021, 952, 702; ESI FTMS exact mass calcd for (C25H18F2N2O5 +
H)+ requires m/z 465.1262, found m/z 465.1262; enantiomeric
excess: 96%, determined by HPLC (Daicel Chirapak IC,
hexane–isopropanol = 70 : 30, flow rate 1.0 mL min−1, T =
30 °C, 254 nm): tR = 9.51 min (minor), tR = 10.46 min (major).
Acknowledgements
We are grateful for financial support from National Natural
Science Foundation of China (21002083 and 21232007) and
PAPD of Jiangsu Higher Education Institutions.
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