Cooperative Cation-Binding Catalysis as an Efficient Approach for Enantioselective Friedel–Crafts Reaction of Indoles and Pyrrole

Article abstract of DOI:10.1002/adsc.201601198

In this study, we demonstrated the cooperative cation-binding catalysis as an efficient approach for enantioselective Friedel–Crafts reaction of indoles and pyrroles. By using highly accessible chiral oligoethylene glycol (oligoEG) as the cation-binding catalyst and KF as the base, a highly enantioselective Friedel–Crafts reaction of indoles, 4,7-dihydroindoles, and pyrrole with bench-stable α-amidosulfones as in-situ equivalents of sensitive imines was achieved. The scope of this new catalytic protocol was not limited to aromatic imines. Heteroaromatic and aliphatic substrates as well as α-iminoethyl glyoxylate also afforded the desired products with excellent yields and ees. The enforced proximity of the catalyst and substrates in a chiral cage in situ formed by incorporation of the potassium salt enhanced the reactivity and efficiently transferred the stereochemical information, mimicking the action of enzymes. (Figure presented.).

Full text of DOI:10.1002/adsc.201601198

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DOI: 10.1002/adsc.201601198
Cooperative Cation-Binding Catalysis as an Efficient Approach
for Enantioselective Friedel–Crafts Reaction of Indoles and
Pyrrole
Mun Jong Kim,+a Lu Xue,+b Yidong Liu,b Sushovan Paladhi,a Si Joon Park,a
Hailong Yan,b,* and Choong Eui Songa,*
a
Department of Chemistry, Sungkyunkwan University, Suwon 440-746, Korea
E-mail: s1673@skku.edu
b
Innovative Drug Research Centre (IDRC), School of Pharmaceutical Sciences, Chongqing University, 55 Daxuecheng
South Rd., Chongqing 401331, People’s Repuublic of China
E-mail: yhl198151@cqu.edu.cn
+
These authors contributed equally to this work.
Received: October 28, 2016; Revised: December 3, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201601198.
Abstract: In this study, we demonstrated the cooper- aliphatic substrates as well as a-iminoethyl glyoxy-
ative cation-binding catalysis as an efficient approach late also afforded the desired products with excellent
for enantioselective Friedel–Crafts reaction of in- yields and ees. The enforced proximity of the catalyst
doles and pyrroles. By using highly accessible chiral and substrates in a chiral cage in situ formed by in-
oligoethylene glycol (oligoEG) as the cation-binding corporation of the potassium salt enhanced the reac-
catalyst and KF as the base, a highly enantioselective tivity and efficiently transferred the stereochemical
Friedel–Crafts reaction of indoles, 4,7-dihydroin- information, mimicking the action of enzymes.
doles, and pyrrole with bench-stable a-amidosulfones
as in-situ equivalents of sensitive imines was ach- Keywords: a-amidosulfones; cation-binding catalysis;
ieved. The scope of this new catalytic protocol was Friedel–Crafts reaction; indolyl glycines; indolyl-
not limited to aromatic imines. Heteroaromatic and methanamines
Introduction
Furthermore, in the reported processes, unpractical
N-sulfonyl group-protected (e.g., N-Ts and N-Bs)
The Friedel–Crafts addition of indole derivatives to imines are usually required to obtain the desired
imines provides an easy access to enantiopure 3-in- products with high enatioselectivities.[6] However, the
ACHTUNGTRENNUNG
dolylmethanamine derivatives,[1] which are widely removal of such protecting groups is not trivial. The
found as the structural core of many biologically in- reaction of N-Boc-group-protected imine with indole
teresting natural products and pharmaceutically rele- leads to either racemic product[4a] or the formation of
vant compounds.[2] Although a number of useful cata- a bisindole addition by-product.[1d,4b]
lytic asymmetric protocols are available,[3,4] some
Recently, we[7] developed a new type of easily ac-
issues still need to be addressed. Most protocols used cessible 1,1’-bi-2-naphthol (BINOL)-based organoca-
air- and acid-sensitive imines as the electrophilic part- talyst 1 bearing phenols and polyether units for asym-
ners and acidic catalysts which are needed to activate metric cooperative cation-binding catalysis.[8] This
the weakly electrophilic imines. Thus, the scope of the type of catalyst has already been proved to generate
reaction was limited to aromatic imines, because imines in situ from bench-stable a-amidosulfones[9]
alkylACHTUNGTRENNUNGimines readily tautomerize to the corresponding with a fluoride base. Moreover, the acidity of the phe-
enamines under acidic conditions (Scheme 1a).[5] nolic protons can be easily tuned to suppress the for-
Moreover, the acid-sensitive Friedel–Crafts products, mation of bis-indolylmethanes.
3-indolylmethanamines, can react with indoles to
In this study, most of the above-mentioned draw-
form bisin
ACHTUNGTRENNUNG
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bearing iodine atoms at the 3 and 3’ positions of the
binaphthyl scaffold showed the best results in terms
of catalytic activity (70% yield) and enantioselectivity
(98% ee) (entry 2, Table 1). In further experiments
performed with (R)-1b as the optimal catalyst, differ-
ent solvents were examined (entries 6–10). In general,
excellent enantioselectivity was obtained in all the
solvents tested in this study. Among them, m-xylene
proved to be the best in terms of yield (76%) and
asymmetric induction (99% ee) (entry 10). The fur-
ther improvement of the yield was achieved by in-
creasing the equivalents of indole (83% yield and
99% ee, entry 11).
Wide ranges of substituted indoles and a-amidosul-
fones were then tested under the optimized reaction
conditions (1.2 equiv. of indole, 2 equiv. of KF, and
10 mol% of catalyst in m-xylene at room temperature
for 12 h) to explore the generality of the reaction, and
the results are summarized in Scheme 2 and
Scheme 3. These catalytic conditions were found to
be general with a-amidosulfones 3 bearing different
substituents (Scheme 2). Regardless of the electronic
and steric nature of the substituents on the aromatic
ring, the a-amidosulfones 3a–3k as the aromatic
imine precursors tested in this study were smoothly
converted to the corresponding Friedel–Crafts prod-
ucts 4a–4k with moderate to high yields and excellent
Scheme 1. (a) Chiral Brønsted acid-catalyzed enantioselec-
tive addition of indoles to aromatic imines. (b) Songꢁs chiral
oligoEGs 1-catalyzed enantioselective Friedel–Crafts reac-
tion of indoles to in situ generated N-Boc-imines.
adopting the concept of cooperative cation-binding ees after 12 h. Notably, the sterically demanding 1-
catalysis. With highly accessible chiral oligoethylene naphthyl-substituted a-amidosulfone 3b was also
glycol (oligoEG) as the cation-binding catalyst and smoothly converted to the corresponding Friedel–
KF as the base, a general, efficient, and practical Crafts product 4b in 98% yield with 99% ee. Hetero-
asymmetric Friedel–Crafts reaction of indoles, 4,7-di- aromatic substrates such as 2-furanyl (3l) and 3-thien-
hydroindoles, and pyrrole with bench-stable a-amido- yl (3m) also afforded almost quantitative yields and
sulfones as in situ equivalents of sensitive imines was perfect ees. In addition, aliphatic substrates 3n–3q
achieved. The scope of this new catalytic protocol was were also explored for this reaction. To our delight,
not limited to aromatic imines. Heteroaromatic and the reaction turned out to be tolerant to the ene-car-
aliphatic substrates as well as a-iminoethyl glyoxylate bamate formation.[10] Thus, highly challenging primary
also afforded the desired products with excellent alkyl-substituted substrates 3o–3q also afforded the
yields and ees (Scheme 1b). Thus, our method enables desired products in moderate chemical yields with ex-
the synthesis of enantiomerically pure Friedel–Crafts cellent enantioselectivity (96–98% ee).
indole/pyrrole adducts, which are difficult to access by
traditional approaches.
Furthermore, as shown in Scheme 3, this reaction
was also found to be general with indoles 2. The
enantioselectivity was found to be insensitive to the
electronic and steric nature of the indole ring
(Scheme 3). In all the cases, almost perfect ees (95–
99% ee) were achieved under the optimized catalytic
Results and Discussion
Our initial investigation of the asymmetric Friedel– conditions. The absolute configuration of 4j was de-
Crafts reaction of indole 2a with phenyl a-amidosul- termined to be (S) by a single crystal X-ray structure
fone 3a is summarized in Table 1. The effect of cata- analysis.[11] The absolute configurations of other Frie-
lyst structure on the reaction outcome was firstly in- del–Crafts products 4 were assigned by analogy.
vestigated with 10 mol% catalyst loading in toluene
We were further interested to elaborate our catalyt-
(Table 1, entries 1–5). As we expected, based on our ic conditions to the Friedel–Crafts reaction of indoles
knowledge of the catalytic performance of chiral oli- with a-amidosulfone 5 as a precursor of N-Boc-a-imi-
goEG 1,[7] both the ether chain length (entries 1–3) noethyl glyoxylate. The use of imino derivatives of
and a suitable acidity of the phenolic protons (entry 2 glyoxylates as electrophiles in aza-Friedel–Crafts reac-
vs. entries 4 and 5) are critical for the catalytic per- tion afforded the corresponding 3-indolyl glycine de-
formance in this reaction. Consistently, catalyst 1b rivatives, an important class of non-proteinogenic
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Table 1. Optimization of the BINOL-based polyether-catalyzed asymmetric Friedel–Crafts reactions of indole.[a]
Entry
Catalyst
Indole 2a (equiv.)
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
(R)-1a
(R)-1b
(R)-1c
(R)-1d
(R)-1e
(R)-1b
(R)-1b
(R)-1b
(R)-1b
(R)-1b
(R)-1b
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.2
toluene
toluene
toluene
toluene
toluene
CH2Cl2
1,4-dioxane
THF
mesitylene
m-xylene
m-xylene
68
70
59
24
59
70
52
61
75
76
83
61
98
80
1
70
95
91
95
98
99
99
9
10
11
[a]
Reaction conditions: 3a (0.2 mmol), 2a (0.2 mmol), KF (0.4 mmol), catalyst (0.02 mmol) in solvent (1 mL) at room tem-
perature for 12 h, unless otherwise specified.
Isolated yield.
Enantiomeric excess (ee) was determined by chiral HPLC.
[b]
[c]
amino acids useful for synthetic intermediates and (Scheme 4). Thus, at 708C, the reaction was complete
building blocks for natural products such as dragmaci- within 10 h, affording the product with a yield of 79%
dins.[12] Although some organocatalytic methods are and 98% ee. Thus, the substrate scope was then inves-
available, enantioselectivities obtained to date are still tigated at 708C. Substituted indoles 2, containing
unsatisfactory (up to 88% ee even at low tempera- either electron-donating groups or electron-withdraw-
tures).[13,14] Furthermore, catalysts were found to be ing groups at the ortho-, meta- and para-positions of
less effective for 2-substituted indole derivatives.[13b] the phenyl ring, were tested in the reaction with a-
Because of the moderate to low enantioselectivities, amidosulfone 5 (Scheme 4). In all the cases, excellent
low reaction temperature, and limited substrate scope ees were achieved for the desired 3-indolyl-N-Boc-a-
of the reported methods, a new and more efficient amino esters (91–98% ee, Scheme 4). Even the 2-
catalytic protocol is highly desirable. Delightfully, the methylindole derivatives, known to be poor substrates
reaction of indole 2a with a-amidosulfone 5 in the in the literature,[13b] also gave high enantioselectivity
presence of catalyst (R)-1b (10 mol%) and KF (98% ee for 6n). This method was also applicable to
(3 equiv.) in toluene at room temperature for 48 h af- the pyrrole substrate affording pyrrolyl-3-glycine de-
forded the desired product, 3-indolyl-N-Boc-a-amino rivative 6o with 74% yield and 91% ee. The absolute
ester, 6a in 79% yield with perfect enantioselectivity configuration of 3-indolyl-N-Boc-a-amino ester 6a
(99% ee), along with bisindole addition by-product. was determined to be (R), by conversion to the corre-
Interestingly, the reaction rate increased with temper- sponding N-tosylated analogue (see the Supporting
ature rise without diminishing the enantioselectivi- Information for details). The absolute configurations
ty.[15] Notably, the Friedel–Crafts reaction of indoles of other indolyl glycine derivatives 6 were assigned by
at low temperatures generally suppresses bisindolyl- analogy.
methane formation. However, surprisingly, bisindolyl-
Furthermore, 2-indolyl-N-Boc-a-amino ester 8 was
methane formation did not increase even at 708C also successfully synthesized by the reaction between
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Scheme 2. Substrate scope for the Friedel–Crafts reactions of indole 2a with different a-amidosulfones 3. Reactions of 2a
(0.24 mmol), 3 (0.2 mmol), KF (0.4 mmol) and (R)-1b (0.02 mmol) were performed in m-xylene (1.0 mL) at room tempera-
ture for 12 h. The yields were determined after chromatographic purification and % ee were determined by HPLC analysis
using a chiral stationary phase.
4,7-dihydro-1H-indole 7 and a-amidosulfone 5 under hance the reactivity and efficiently transfer the stereo-
identical reaction conditions as mentioned in chemical information, mimicking the action of en-
Scheme 4, followed by oxidation with p-benzoquinone zymes. To our delight and surprise, all the proposed
(Scheme 5).[16] To the best of our knowledge, this is intermediates I, II, III, and IV were identified by
the first catalytic example of the asymmetric synthesis electrospray ionization high-resolution mass spectros-
of 2-indolyl glycine derivatives.
copy (ESI-HR-MS) (positive ion mode), strongly sup-
Based on our experimental results and our previous porting our proposed mechanism. The peaks at m/z=
reports regarding cation-binding catalysis,[7] the plau- 1228.8160, 1571.9253, 1429.9176, and 1546.9745 are
À
sible reaction mechanism is illustrated in Figure 1. At consistent with [IÀFÀ], [IIÀFÀ], [IIIÀPhSO2 ], and
À
the first step, complex I is formed by the complexa- [IVÀPhSO2 ], respectively.
tion of KF with catalyst, which then forms complex II
by the reaction with a-amidosulfone. Subsequently,
elimination of the sulfinate group from the amidosul- Conclusions
fone affords an imine, complex III being activated
through hydrogen bonding. Subsequent addition of In summary, we have developed a highly enantiose-
the activated indole to the imine (complex IV) deliv- lective Friedel–Crafts reaction of indoles, 4,7-dihy-
ers the alkylation product. The enforced proximity of droindole and pyrrole with a-amidosulfones as sensi-
the catalyst and substrates in a chiral cage in situ tive imine surrogates by using a highly accessible
formed by the incorporation of potassium salt can en- chiral oligoethylene glycol (oligoEG) as the coopera-
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Scheme 3. Substrate scope for the Friedel–Crafts reactions of indoles 2 with a-amidosulfone 3k. Reactions of 2 (0.24 mmol),
3k (0.2 mmol), KF (0.4 mmol) and (R)-1b (0.02 mmol) were performed in m-xylene (1.0 mL) at room temperature for 12 h.
Scheme 4. Reactions of 2 (0.36 mmol), 5 (0.3 mmol), KF (0.9 mmol) and (R)-1b (0.03 mmol) were performed in toluene
(3.0 mL) at 708C.
tive cation-binding catalyst and KF as the base. With protocol provides a highly useful catalytic approach
excellent ees (>99% ee) and unprecedently broad towards biologically relevant 3-indolylmethanamine
scope for both indoles/pyrrole and imine partners, this as well as 2- and 3-indolyl glycine derivatives. The
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Experimental Section
Gerneral Information
The organocatalysts 1a–1e were obtained starting from
BINOL according to the literature procedure.[7d,e] a-Amido-
sulfones were synthesized according to the reported proce-
dure.[17] Thin-layer chromatography (TLC) was performed
using silica gel plates (Merck, Kieselgel 60 F254 0.25 mm).
1H and 13C NMR spectra were recorded on Bruker Avance
III 500, Agilent 400MR DD2 (400 MHz) and 600MR DD2
(600 MHz) spectrometers. Chemical shifts are reported in
parts per million (ppm), and tetramethylsilane or the residu-
1
Scheme 5. Synthesis of 2-indolyl-N-Boc-a-amino ester 8.
al solvent peak was used as an internal reference: H (tetra-
methylsilane d=0.00, CDCl3: d=7.26), 13C (chloroform d=
77.00). Data are reported as follows: chemical shift, multi-
plicity (s=singlet, d=doublet, t=triplet, q=quartet, m=
multiplet, br=broad), coupling constants (Hz) and integra-
tion. Enantiomeric excesses (ee) were determined by HPLC
analysis on Agilent 1260 Infinity instruments, Varian Pro
Star Series instrument and YL9100 HPLC System instru-
ment using chiral column as mentioned in the analytical
analysis section. High resolution mass spectra (HR-MS)
were performed on Bruker solarix 7.0 T and Bruker com-
pact spectrometers. The IR spectra were obtained using
a Bruker Vertex 70 spectrometer with the MIRacle Micro
ATR accessory. The melting points (mp) were determined
with a Buchi M-560 melting point apparatus. Optical rota-
cation-binding catalysis in a densely confined chiral
space in situ formed by the incorporation of potassi-
um salt is the key to this successful catalysis. Like en-
zymes, in a confined space, catalytic sites simultane-
ously activate both imine and indole and keep them
in close proximity, thus enhancing the reactivity and
efficiently transferring the stereochemical informa-
tion. This proposed mechanism was clearly supported
by the ESI-MS analysis.
Figure 1. Proposed reaction mechanism and observation of the intermediates.
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tion was measured using a Perkin–Elmer Polarimeter 343
plus. X-ray crystallographic analysis of single crystals was
performed on a Agilent SuperNova-CCD X-Ray diffractom-
eter. Unless otherwise stated, all reagents were purchased
from commercial suppliers and used without further purifi-
cation.
345.1567; HPLC analysis: (Chiralcel AD-H, hexane/i-
PrOH=85:15, flow rate=1.0 mLminÀ1, wave length=
254 nm): tR =8.8 min (minor), tR =17.7 min (major); 99% ee.
Compound 4b: Isolated yield: 73.0 mg (98%); white solid;
1H NMR (400 MHz, CDCl3): d=8.05 (s, 1H), 7.95 (d, J=
8.5 Hz, 1H), 7.82 (d, J=7.9 Hz, 1H), 7.77 (d, J=8.0 Hz,
1H), 7.63 (d, J=7.7 Hz, 1H), 7.54 (d, J=6.9 Hz, 1H), 7.46–
7.36 (m, 2H), 7.34–7.25 (m, 2H), 7.18 (t, J=7.5 Hz, 1H),
7.11 (t, J=7.4 Hz, 1H), 6.94 (d, J=7.6 Hz, 1H), 6.40 (s,
1H), 5.27 (d, J=8.6 Hz, 1H), 1.46 (s, 9H); 13C NMR
(100 MHz, CDCl3): d=155.13, 137.47, 136.57, 133.81, 130.98,
128.50, 127.92, 126.00, 125.50, 125.23, 123.95, 123.76, 123.42,
122.34, 119.75, 119.27, 117.45, 111.30, 79.63, 48.41, 28.40;
HR-MS (ESI): m/z=395.1730, calcd. for [C24H24N2NaO2,
M+Na]+: 395.1712; HPLC analysis: (Chiralcel AD-H,
hexane/i-PrOH=80:20, flow rate=1.0 mLminÀ1, wave
length=254 nm), tR =7.6 min (minor), tR =12.1 min (major);
99% ee.
General Experimental Procedure for the Synthesis of
Products 4
In a 10-mL flame-dried Schlenk tube with a stirring bar, a-
amidosulfone (0.2 mmol), indole (0.24 mmol), potassium
fluoride (23.2 mg, 0.4 mmol) and the catalyst (R)-1b
(23.8 mg, 0.02 mmol) were added. m-Xylene (1 mL) was in-
jected into the tube. After stirring for 12 h at room tempera-
ture, the mixture was purified by neutral aluminum oxide
column chromatography (PE/EA=3:1) to afford the prod-
ucts.
Compound 4c: Isolated yield: 45.1 mg (67%); white solid;
1H NMR (400 MHz, CDCl3): d=8.23–8.14 (m, 1H), 7.50 (d,
J=7.7 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.25 (d, J=7.6 Hz,
2H), 7.17 (t, J=7.6 Hz, 1H), 7.12 (d, J=7.4 Hz, 2H), 7.07
(t, J=7.4 Hz, 1H), 6.70 (s, 1H), 6.15 (s, 1H), 5.21 (s, 1H),
2.33 (s, 3H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3): d=
155.24, 139.00, 136.67, 136.58, 129.02, 126.70, 125.87, 123.18,
122.27, 119.66, 119.39, 117.89, 111.29, 79.49, 51.45, 28.39,
General Experimental Procedure for the Synthesis of
Products 6
In a well-equipped 10-mL flame-dried Schlenk tube, a-ami-
dosulfone 5 (0.3 mmol), indole 2 (0.36 mmol), potassium
fluoride (0.9 mmol) and the catalyst (R)-1b (0.03 mmol)
were added. Subsequently, toluene (3 mL) was added into
the tube and the reaction was stirred for 10–36 h at 708C.
Next, the reaction mixture was poured into the water. The
organic layer was washed with brine, separated, and dried
over anhydrous Na2SO4. The solvents were removed under
reduced pressure. The residue was then purified by silica gel
chromatography(hexanes/ethyl acetate=7/1) to afford the
products.
21.07;
HR-MS
(ESI):
m/z=359.1730,
calcd.
for
[C21H24N2NaO2, M+Na]+: 359.1713; HPLC analysis: (Chir-
alcel
AD-H,
hexane/i-PrOH=80:20,
flow
rate=
1.0 mLminÀ1, wave length=254 nm): tR =6.3 min (minor),
tR =11.3 min (major); 97% ee.
Compound 4d: Isolated yield: 34.3 mg (51%); white solid;
1H NMR (400 MHz, CDCl3): d=8.27 (s, 1H), 7.59 (d, J=
7.5 Hz, 1H), 7.37 (d, J=7.2 Hz, 1H), 7.30 (d, J=8.0 Hz,
1H), 7.24–7.13 (m, 3H), 7.10 (t, J=6.8 Hz, 2H), 6.41 (s,
1H), 6.32 (d, J=7.3 Hz, 1H), 5.20 (d, J=6.9 Hz, 1H), 2.21
(s, 3H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3): d=
155.14, 140.08, 136.65, 135.66, 130.45, 126.95, 126.10, 125.89,
125.40, 123.50, 122.28, 119.65, 119.16, 116.81, 111.33, 79.50,
48.48, 28.39, 19.02; HR-MS (ESI): m/z=359.1730, calcd. for
[C21H24N2NaO2, M+Na]+: 359.1713; HPLC analysis: (Chir-
General Experimental Procedure for the Synthesis of
Products 8
In a well-equipped 10-mL flame-dried Schlenk tube, a-ami-
dosulfone 5 (0.3 mmol), dihydroindole 7 (0.36 mmol), potas-
sium fluoride (0.9 mmol) and the catalyst (R)-1b
(0.03 mmol) were added. Subsequently, toluene (3 mL) was
added into the tube and the reaction was stirred for 12 h at
room temperature. Next, the reaction mixture was extracted
with ethyl acetate (5 mL). The organic layer was washed by
brine, separated, and dried over anhydrous Na2SO4. The sol-
vents were removed under reduced pressure. The residue
was dissolved in 10 mL DCM, and 3 equiv of p-benzoqui-
none was added to the crude mixture and the reaction was
stirred for overnight. After the reaction was completed, the
reaction mixture was diluted with 5 mL of DCM and the or-
ganic layer was washed with water, and dried over anhy-
drous Na2SO4. The organic layer was concentrated under
vacuum. The residue was purified by silica gel column chro-
matography to afford the title compound 8; yield: 80%.
Compound 4a: Isolated yield: 53.5 mg (83%); white solid;
1H NMR (400 MHz, CDCl3): d=8.27 (s, 1H), 7.49 (d, J=
7.6 Hz, 1H), 7.36 (d, J=7.2 Hz, 2H), 7.31 (t, J=7.2 Hz,
3H), 7.28–7.22 (m, 1H), 7.17 (t, J=7.5 Hz, 1H), 7.07 (t, J=
7.5 Hz, 1H), 6.63 (s, 1H), 6.27–6.10 (m, 1H), 5.25 (s, 1H),
1.45 (s, 9H); 13C NMR (100 MHz, CDCl3): d=155.27,
142.00, 136.64, 128.31, 127.04, 126.77, 125.83, 123.30, 122.30,
119.68, 119.29, 117.63, 111.34, 79.56, 51.67, 28.38; HR-MS
(ESI): m/z=345.1573, calcd, for [C20H22N2NaO2, M+Na]+:
alcel
AD-H,
hexane/i-PrOH=90:10,
flow
rate=
1.0 mLminÀ1, wave length=254 nm): tR =11.3 min (minor),
tR =30.9 min (major); 90% ee.
Compound 4e: Isolated yield: 52.4 mg (72%); white solid;
1H NMR (400 MHz, CDCl3): d=8.19 (s, 1H), 7.52 (d, J=
7.8 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.29 (d, J=8.0 Hz,
2H), 7.18 (d, J=8.0 Hz, 3H), 7.08 (t, J=7.5 Hz, 1H), 6.75
(s, 1H), 6.18 (d, J=7.0 Hz, 1H), 5.27–5.13 (m, 1H), 2.89 (dt,
J=13.8, 6.9 Hz, 1H), 1.45 (s, 9H), 1.24 (d, J=6.9 Hz, 6H);
13C NMR (100 MHz, CDCl3): d=155.23, 147.59, 139.26,
136.66, 126.74, 126.39, 125.93, 123.17, 122.30, 119.67, 119.48,
118.07, 111.28, 79.45, 51.41, 33.72, 28.40, 24.00; HR-MS
(ESI): m/z=387.2043, calcd. for [C23H28N2NaO2, M+Na]+:
387.2030; HPLC analysis: (Chiralcel AD-H, hexane/i-
PrOH=80:20, flow rate=1.0 mLminÀ1, wave length=
254 nm): tR =5.5 min (minor), tR =10.1 min (major); 99% ee.
Compound 4f: Isolated yield: 62.8 mg (83%); white solid;
1H NMR (400 MHz, CDCl3): d=8.38–8.26 (m, 1H), 7.51 (d,
J=6.3 Hz, 1H), 7.38–7.21 (m, 5H), 7.15 (t, J=7.4 Hz, 1H),
7.07 (d, J=7.0 Hz, 1H), 6.66 (s, 1H), 6.18 (s, 1H), 5.25 (s,
1H), 1.45 (s, 9H), 1.29 (s, 9H); 13C NMR (100 MHz,
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CDCl3): d=155.32, 149.77, 138.85, 136.65, 126.45, 125.87,
125.19, 123.22, 122.15, 119.53, 119.32, 117.65, 111.36, 79.47,
51.35, 34.39, 31.35, 28.39; HR.MS (ESI): m/z=401.2199,
calcd. for [C24H30N2NaO2, M+Na]+: 401.2179; HPLC analy-
sis: (Chiralcel AD-H, hexane/i-PrOH=85:15, flow rate=
1.0 mLminÀ1, wave length=254 nm): tR =6.6 min (minor),
tR =15.2 min (major); 97% ee.
123.29, 122.50, 120.83, 119.85, 119.13, 116.96, 111.42, 79.83,
51.23, 28.35; HR-MS (ESI): m/z=423.0678, calcd. for
[C20H21BrN2NaO2, M+Na]+: 423.0672; HPLC analysis:
(Chiralcel AD-H, hexane/i-PrOH=80:20, flow rate=
1.0 mLminÀ1, wave length=254 nm): tR =6.8 min (minor),
tR =12.9 min (major); 99% ee.
Compound 4l: Isolated yield: 61.8 mg (99%); white solid;
1H NMR (400 MHz, CDCl3): d=8.19 (s, 1H), 7.55 (d, J=
7.7 Hz, 1H), 7.36 (d, J=12.0 Hz, 2H), 7.20 (t, J=7.5 Hz,
1H), 7.11 (t, J=7.4 Hz, 1H), 7.01 (s, 1H), 6.30 (d, J=
30.1 Hz, 3H), 5.33–5.17 (m, 1H), 1.46 (s, 9H); 13C NMR
(100 MHz, CDCl3): d=155.03, 154.46, 141.85, 136.43, 125.62,
122.75, 122.37, 119.83, 119.29, 115.28, 111.31, 110.20, 106.48,
79.75, 46.04, 28.36; HR-MS (ESI): m/z=335.1366, calcd. for
[C18H20N2NaO3, M+Na]+: 335.1351; HPLC analysis: (Chir-
Compound 4g: Isolated yield: 52.1 mg (74%); white solid;
1H NMR (400 MHz, CDCl3): d=8.34 (s, 1H), 7.47 (d, J=
7.4 Hz, 1H), 7.38–7.20 (m, 3H), 7.16 (t, J=7.4 Hz, 1H), 7.06
(t, J=7.3 Hz, 1H), 6.83 (d, J=7.9 Hz, 2H), 6.66 (s, 1H),
6.21–6.06 (m, 1H), 5.31–5.15 (m, 1H), 3.76 (s, 3H), 1.45 (s,
9H); 13C NMR (100 MHz, CDCl3): d=158.50, 155.27,
136.68, 134.18, 127.89, 125.77, 123.18, 122.19, 119.56, 119.32,
117.75, 113.66, 111.33, 79.49, 55.18, 51.18, 28.38; HR-MS
(ESI): m/z=375.1679, calcd. for [C21H24N2NaO3, M+Na]+:
375.1661; HPLC analysis: (Chiralcel AD-H, hexane/i-
PrOH=80:20, flow rate=1.0 mLminÀ1, wave length=
254 nm): tR =9.0 min (minor), tR =17.8 min (major); 95% ee.
Compound 4h: Isolated yield: 51.4 mg (73%); white solid;
1H NMR (400 MHz, CDCl3): d=8.25 (s, 1H), 7.53 (d, J=
7.7 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.25–7.14 (m, 2H),
7.08 (t, J=7.4 Hz, 1H), 7.01–6.90 (m, 2H), 6.80 (d, J=
7.8 Hz, 1H), 6.67 (s, 1H), 6.17 (d, J=7.2 Hz, 1H), 5.31–5.21
(m, 1H), 3.75 (s, 3H), 1.46 (s, 9H); 13C NMR (100 MHz,
CDCl3): d=159.52, 155.27, 143.67, 136.58, 129.32, 125.76,
123.32, 122.23, 119.63, 119.13, 117.32, 112.49, 112.33, 111.35,
79.57, 55.09, 51.59, 29.64, 28.36; HR-MS (ESI): m/z=
375.1679, calcd. for [C21H24N2NaO3, M+Na]+: 375.1677;
HPLC analysis: (Chiralcel AD-H, hexane/i-PrOH=80:20,
flow rate=1.0 mLminÀ1, wave length=254 nm): tR =7.9 min
(minor), tR =13.2 min (major); 95% ee.
Compound 4i: Isolated yield: 56.5 mg (83%); white solid;
1H NMR (400 MHz, CDCl3): d=8.27 (s, 1H), 7.47 (d, J=
7.6 Hz, 1H), 7.37–7.25 (m, 3H), 7.19 (t, J=7.6 Hz, 1H), 7.09
(t, J=7.5 Hz, 1H), 7.00 (t, J=8.6 Hz, 2H), 6.67 (s, 1H),
6.24–6.06 (m, 1H), 5.31–5.13 (m, 1H), 1.45 (s, 9H);
13C NMR (100 MHz, CDCl3): d=160.65, 155.23, 136.66,
128.36, 128.28, 125.67, 123.20, 122.47, 119.81, 119.25, 115.23,
115.02, 111.38, 79.74, 51.14, 28.37; HR-MS (ESI): m/z=
363.1479, calcd. for [C20H21FN2NaO2, M+Na]+: 363.1477;
HPLC analysis: (Chiralcel AD-H. hexane/i-PrOH=90:10,
flow rate=1.0 mLminÀ1, wave length=254 nm): tR =
13.2 min (minor), tR =31.2 min (major); 98% ee.
alcel
AD-H,
hexane/i-PrOH=80:20,
flow
rate=
1.0 mLminÀ1, wave length=254 nm): tR =7.0 min (minor),
tR =10.2 min (major); 98% ee.
Compound 4m: Isolated yield: 63.7 mg (97%); white
1
solid; H NMR (400 MHz, CDCl3): d=8.45 (s, 1H), 7.48 (d,
J=7.2 Hz, 1H), 7.31 (d, J=7.9 Hz, 1H), 7.25–7.05 (m, 4H),
6.98 (d, J=4.2 Hz, 1H), 6.76 (s, 1H), 6.34–6.18 (m, 1H),
5.25 (s, 1H), 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3): d=
155.27, 143.38, 136.56, 126.98, 125.75, 125.63, 122.94, 122.21,
121.13, 119.60, 119.24, 116.89, 111.40, 79.64, 47.98, 28.36;
HR-MS (ESI): m/z=351.1137, calcd. for [C18H20N2NaO2S,
M+Na]+: 351.1122; HPLC analysis (Chiralcel AD-H,
hexane/i-PrOH=80:20, flow rate=1.0 mLminÀ1, wave
length=254 nm): tR =6.5 min (minor), tR =12.2 min (major);
98% ee.
Compound 4n: Isolated yield: 36.7 mg (56%); pale yellow
solid; 1H NMR (500 MHz, CDCl3): d=8.15 (bs, 1H), 7.64
(d, J=7.9 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.19 (t, J=
7.5 Hz, 1H), 7.11 (t, J=7.5 Hz, 1H), 7.01 (s, 1H), 4.94–4.81
(m, 1H), 4.75 (t, J=7.6 Hz, 1H), 1.93 (d, J=12.3 Hz, 1H),
1.87 (d, J=7.8 Hz, 1H), 1.77 (d, J=12.5 Hz, 1H), 1.63 (dd,
J=21.9, 11.4 Hz, 3H), 1.42 (s, 9H), 1.27–0.97 (m, 5H);
13C NMR (125 MHz, CDCl3): d=155.76, 136.52, 126.13,
122.09, 121.85, 119.49, 116.91, 111.33, 79.04, 53.30, 42.77,
30.54, 28.46, 26.40, 26.20; HR-MS (ESI): m/z=351.2044,
calcd. for [C20H28N2NaO2, M+Na]+: 351.2043; HPLC analy-
sis: (Chiralpak IA, hexane/i-PrOH=95:5, flow rate=
1.0 mLminÀ1, wave length=220 nm): tR =11.7 min (minor),
tR =19.1 min (major); 76% ee.
Compound 4j: Isolated yield: 64.9 mg (91%); pink solid;
1H NMR (400 MHz, CDCl3): d=8.35 (s, 1H), 7.47 (d, J=
7.9 Hz, 1H), 7.37–7.24 (m, 5H), 7.19 (t, J=7.5 Hz, 1H), 7.08
(t, J=7.4 Hz, 1H), 6.63 (s, 1H), 6.14 (d, J=6.4 Hz, 1H),
5.33–5.14 (m, 1H), 1.45 (s, 9H); 13C NMR (100 MHz,
CDCl3): d=155.23, 140.55, 136.61, 132.67, 128.44, 128.10,
125.59, 123.28, 122.47, 119.82, 119.13, 117.03, 111.42, 79.81,
51.17, 28.35; HR-MS (ESI): m/z=379.1183, calcd. for
[C20H21ClN2NaO2, M+Na]+: 379.1181; HPLC analysis:
(Chiralcel AD-H, hexane/i-PrOH=85:15, flow rate=
1.0 mLminÀ1, wave length=254 nm): tR =7.8 min (minor),
tR =16.9 min (major); 99% ee.
Compound 4k: Isolated yield: 79.4 mg (99%); white solid;
1H NMR (400 MHz, CDCl3): d=8.34 (s, 1H), 7.45 (dd, J=
18.2, 7.8 Hz, 3H), 7.31 (d, J=8.1 Hz, 1H), 7.27–7.16 (m,
3H), 7.09 (t, J=7.5 Hz, 1H), 6.64 (s, 1H), 6.13 (d, J=
6.3 Hz, 1H), 5.23 (s, 1H), 1.45 (s, 9H); 13C NMR (100 MHz,
CDCl3): d=155.21, 141.09, 136.61, 131.39, 128.48, 125.59,
Compound 4o: Isolated yield: 40.5 mg (64%); white solid;
1H NMR (500 MHz, CDCl3): d=8.18 (bs, 1H), 7.69 (d, J=
7.6 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.18 (t, J=7.5 Hz,
1H), 7.11 (t, J=7.4 Hz, 1H), 7.00 (s, 1H), 5.14 (d, J=
3.6 Hz, 1H), 4.75 (d, J=6.1 Hz, 1H), 1.97 (dd, J=14.1,
4.6 Hz, 1H), 1.80 (dd, J=13.3, 7.9 Hz, 1H), 1.43 (s, 9H),
0.98 (s, 9H); 13C NMR (125 MHz, CDCl3): d=155.05,
136.65, 125.75, 122.14, 121.02, 119.90, 119.48, 111.33, 79.05,
49.43, 45.17, 30.71, 29.94, 28.50; HR-MS (ESI): m/z=
339.2045, calcd. for [C19H28N2NaO2, M+Na]+: 339.2043;
HPLC analysis: (Chiralpak IA, hexane/i-PrOH=90:10, flow
rate=1.0 mLminÀ1, wave length=220 nm): tR =6.3 min
(minor), tR =18.0 min (major); 98% ee.
Compound 4p: Isolated yield: 39.6 mg (52%); brown
1
liquid; H NMR (500 MHz, CDCl3): d=8.09 (bs, 1H), 7.67
(d, J=7.9 Hz, 1H), 7.37 (d, J=8.1 Hz, 1H), 7.21 (t, J=
7.6 Hz, 1H), 7.13 (t, J=7.5 Hz, 1H), 7.09 (d, J=1.3 Hz,
1H), 4.97 (d, J=6.3 Hz, 1H), 4.78 (d, J=4.5 Hz, 1H), 3.38
Adv. Synth. Catal. 0000, 000, 0 – 0
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(t, J=6.7 Hz, 2H), 2.04–1.95 (m, 2H), 1.95–1.87 (m, 2H),
1.57–1.48 (m, 2H), 1.45 (s, 9H); 13C NMR (125 MHz,
CDCl3): d=155.49, 136.58, 125.92, 122.43, 121.32, 119.76,
119.39, 117.43, 111.34, 79.23, 77.02, 47.68, 34.59, 33.71, 32.47,
28.45, 25.08; HR-MS (ESI): m/z=403.0994, calcd. for
[C18H25BrN2NaO2, M+Na]+: 403.0992; HPLC analysis:
(Chiralcel AD-H, hexane/i-PrOH=90:10, flow rate=
1.0 mLminÀ1, wave length=220 nm), tR =13.5 min (minor),
tR =22.8 min (major); 96% ee.
8.6 Hz, 1H), 6.70 (s, 1H), 6.13–5.99 (m, 1H), 5.17 (s, 1H),
1.46 (s, 9H); 13C NMR (100 MHz, CDCl3): d=155.16,
140.62, 134.98, 131.55, 128.47, 126.72, 125.66, 124.53, 122.94,
121.10, 118.72, 116.95, 112.41, 80.11, 51.11, 28.36; HR-MS
(ESI): m/z=457.0288, calcd. for [C20H20BrClN2NaO2, M+
Na]+: 457.0284; HPLC analysis: (Chiralcel AD-H, hexane/i-
PrOH=85:15, flow rate=1.0 mLminÀ1, wave length=
254 nm): tR =6.5 min (minor), tR =15.2 min (major); 99% ee.
Compound 4ke: Isolated yield: 73.2 mg (84%); white
1
Compound 4q: Isolated yield: 31.5 mg (45%); yellow
solid; H NMR (400 MHz, CDCl3): d=8.43 (s, 1H), 7.43 (d,
1
liquid; H NMR (500 MHz, CDCl3): d=8.13 (bs, 1H), 7.67
J=7.2 Hz, 2H), 7.36–7.26 (m, 2H), 7.21 (d, J=7.9 Hz, 2H),
7.04 (d, J=8.2 Hz, 1H), 6.65 (s, 1H), 6.18–5.95 (m, 1H),
5.27–5.12 (m, 1H), 1.46 (s, 9H); 13C NMR (100 MHz,
CDCl3): d=155.19, 140.63, 136.96, 131.49, 128.45, 128.39,
124.17, 123.82, 121.06, 120.57, 120.00, 117.14, 111.30, 80.05,
51.11, 28.34; HR-MS (ESI): m/z=457.0288, calcd. for
[C20H20BrClN2NaO2, M+Na]+: 457.0273; HPLC analysis:
(Chiralcel AD-H, hexane/i-PrOH=85:15, flow rate=
1.0 mLminÀ1, wave length=254 nm): tR =7.7 min (minor),
tR =20.2 min (major); 99% ee.
(d, J=7.9 Hz, 1H), 7.37 (d, J=8.1 Hz, 1H), 7.23–7.18 (m,
1H), 7.15–7.10 (m, 1H), 7.06 (d, J=1.9 Hz, 1H), 4.96 (d, J=
6.7 Hz, 1H), 4.77 (d, J=5.1 Hz, 1H), 3.49 (t, J=6.7 Hz,
2H), 2.04–1.90 (m, 2H), 1.79–1.71 (m, 2H), 1.50–1.47 (m,
2H), 1.45 (s, 9H), 1.42–1.30 (m, 2H); 13C NMR (125 MHz,
CDCl3): d=155.53, 136.59, 125.95, 122.35, 121.30, 119.69,
119.41, 117.67, 111.33, 79.17, 77.03, 47.82, 45.03, 35.44, 32.57,
28.45, 26.71, 25.78; HR-MS (ESI): m/z=373.1656, calcd. for
[C19H27ClN2NaO2, M+Na]+: 373.1653; HPLC analysis (Chir-
alpak IA (Hexane/iPrOH=90:10, flow rate=1.0 mLminÀ1,
wave length=210 nm): tR =10.9 min (minor), tR =19.3 min
(major); 96% ee.
Compound 4kf: Isolated yield: 95.0 mg (99%); white
1
solid; H NMR (400 MHz, CDCl3): d=8.99 (s, 1H), 7.36 (d,
J=7.5 Hz, 2H), 7.26 (d, J=7.6 Hz, 1H), 7.19 (t, J=7.1 Hz,
3H), 6.97 (t, J=7.8 Hz, 1H), 6.56–6.43 (m, 2H), 5.34–5.16
(m, 1H), 1.43 (s, 9H); 13C NMR (100 MHz, CDCl3): d=
155.06, 141.46, 137.97, 131.24, 128.60, 126.06, 124.32, 124.20,
123.15, 120.69, 116.90, 113.58, 110.92, 79.79, 50.84, 28.41;
HR-MS (ESI): m/z=500.9783, calcd. for [C20H20Br2N2NaO2,
M+Na]+: 500.9777; HPLC analysis (Chiralcel AD-H,
hexane/i-PrOH=85:15, flow rate=1.0 mLminÀ1, wave
length=254 nm): tR =7.5 min (minor), tR =19.1 min (major);
99% ee.
Compound 4ka: Isolated yield: 65.4 mg (78%); white
solid; 1H NMR (400 MHz, CDCl3): d=8.78–8.59 (m, 1H),
7.38 (d, J=7.6 Hz, 2H), 7.18 (d, J=7.6 Hz, 2H), 7.12–7.01
(m, 2H), 6.84–6.67 (m, 2H), 6.19 (d, J=7.4 Hz, 1H), 5.50–
5.38 (m, 1H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3):
d=157.44, 155.38, 141.48, 139.57, 139.45, 131.26, 128.43,
123.47, 123.04, 122.96, 120.77, 114.95, 114.40, 114.20, 107.67,
107.65, 105.09, 104.89, 79.85, 51.27, 28.38; HR-MS (ESI):
m/z=441.0584, calcd. for [C20H20BrFN2NaO2, M+Na]+:
441.0573; HPLC analysis (Chiralcel AD-H, hexane/i-
PrOH=85:15, flow rate=1.0 mLminÀ1, wave length=
254 nm): tR =5.2 min (minor), tR =12.8 min (major); 99% ee.
Compound 4kb: Isolated yield: 51.9 mg (62%); white
Compound 4kg: Isolated yield: 78.7 mg (82%); white
1
solid; H NMR (400 MHz, CDCl3): d=8.41 (s, 1H), 7.43 (d,
J=8.1 Hz, 2H), 7.38 (d, J=7.7 Hz, 1H), 7.34 (d, J=7.6 Hz,
1H), 7.22 (d, J=8.2 Hz, 2H), 6.95 (t, J=7.8 Hz, 1H), 6.79
(s, 1H), 6.12 (s, 1H), 5.19 (s, 1H), 1.45 (s, 9H); 13C NMR
(100 MHz, CDCl3): d=155.09, 140.67, 135.30, 131.39, 128.52,
126.82, 124.88, 123.67, 121.09, 118.52, 118.40, 104.85, 79.97,
51.25, 28.35; HR-MS (ESI): m/z=500.9783, calcd. for
[C20H20Br2N2NaO2, M+Na]+: 500.9760; HPLC analysis
(Chiralcel OD-H, hexane/i-PrOH=95:5, flow rate=
1.0 mLminÀ1, wave length=254 nm): tR =14.4 min (minor),
tR =26.1 min (major); 99% ee.
1
solid; H NMR (400 MHz, CDCl3): d=8.44 (s, 1H), 7.44 (d,
J=7.1 Hz, 2H), 7.22 (d, J=7.9 Hz, 3H), 7.09 (d, J=8.0 Hz,
1H), 6.93 (t, J=8.5 Hz, 1H), 6.69 (s, 1H), 6.13–5.97 (m,
1H), 5.27–5.10 (m, 1H), 1.46 (s, 9H); 13C NMR (100 MHz,
CDCl3): d=158.84, 156.50, 155.20, 140.68, 133.10, 131.49,
128.44, 125.98, 125.88, 124.93, 121.01, 117.07, 112.16, 111.07,
110.80, 104.24, 104.00, 80.03, 51.19, 28.34; HR-MS (ESI):
m/z=441.0584, calcd. for [C20H20BrFN2NaO2, M+Na]+:
441.0572; HPLC analysis (Chiralcel AD-H, hexane/i-
PrOH=85:15, flow rate=1.0 mLminÀ1, wave length=
254 nm): tR =7.6 min (minor), tR =14.2 min (major); 97% ee.
Compound 4kc: Isolated yield: 69.6 mg (83%); white
solid; 1H NMR (400 MHz, CDCl3): d=8.35 (s, 1H), 7.53–
7.30 (m, 3H), 7.23 (d, J=8.0 Hz, 2H), 7.00 (d, J=9.0 Hz,
1H), 6.85 (t, J=8.8 Hz, 1H), 6.65 (s, 1H), 6.17–6.02 (m,
1H), 5.29–5.08 (m, 1H), 1.45 (s, 9H); 13C NMR (100 MHz,
CDCl3): d=161.22, 158.85, 155.17, 140.80, 136.66, 136.54,
131.47, 128.47, 123.53, 122.23, 121.01, 120.01, 119.91, 117.18,
108.81, 108.57, 97.80, 97.54, 79.98, 51.28, 28.35; HR-MS
(ESI): m/z=441.0584, calcd. for [C20H20BrFN2NaO2, M+
Na]+: 441.0572; HPLC analysis (Chiralcel AD-H, hexane/i-
PrOH=85:15, flow rate=1.0 mLminÀ1, wave length=
254 nm): tR =7.8 min (minor), tR =15.1 min (major); 95% ee.
Compound 4kd: Isolated yield: 86.2 mg (99%); white
solid; 1H NMR (400 MHz, CDCl3): d=8.37–8.27 (m, 1H),
7.45 (d, J=7.6 Hz, 3H), 7.27–7.21 (m, 3H), 7.14 (d, J=
Compound 4kh: Isolated yield: 84.4 mg (99%); white
1
solid; H NMR (400 MHz, CDCl3): d=9.63 (s, 1H), 7.53 (d,
J=8.2 Hz, 1H), 7.48–7.29 (m, 3H), 7.15 (t, J=7.4 Hz, 3H),
6.79 (s, 1H), 6.36 (d, J=6.7 Hz, 1H), 5.46–5.31 (m, 1H),
1.44 (s, 9H); 13C NMR (100 MHz, CDCl3): d=155.02,
140.74, 137.01, 131.44, 128.66, 127.21, 126.60, 125.02, 121.78,
121.11, 119.20, 116.80, 101.73, 80.08, 50.80, 30.93, 28.40; HR-
MS (ESI): m/z=448.0631, calcd. for [C21H20BrN3NaO2, M+
Na]+: 448.0622; HPLC analysis (Chiralcel AD-H, hexane/i-
PrOH=90:10, flow rate=1.0 mLminÀ1, wave length=
254 nm): tR =11.5 min (minor), tR =27.3 min (major); 99%
ee.
Compound 4ki: Isolated yield: 53.7 mg (63%); white
1
solid; H NMR (400 MHz, CDCl3): d=8.90 (s, 1H), 7.80 (s,
1H), 7.46 (d, J=7.4 Hz, 2H), 7.38 (s, 2H), 7.27–7.19 (m,
2H), 6.85 (s, 1H), 6.12 (s, 1H), 5.22 (s, 1H), 1.46 (s, 9H);
13C NMR (100 MHz, CDCl3): d=155.14, 140.14, 138.39,
131.72, 128.48, 125.49, 125.37, 125.33, 124.90, 121.43, 120.45,
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118.02, 112.39, 102.92, 80.40, 51.07, 28.34; HR-MS (ESI):
m/z=448.0631, calcd. for [C21H20BrN3NaO2, M+Na]+:
448.0620; HPLC analysis (Chiralcel AD-H, hexane/i-
PrOH=85:15, flow rate=1.0 mLminÀ1, wave length=
254 nm): tR =8.7 min (minor), tR =12.3 min (major); 99% ee.
Compound 4kj: Isolated yield: 57.3 mg (69%); white
3H); 13C NMR (125 MHz, CDCl3): d=171.79, 155.26,
136.38, 125.47, 123.29, 122.62, 120.17, 119.23, 111.50, 80.02,
61.60, 51.12, 28.37, 14.09; IR (neat): n=3351, 2980, 1697,
1495, 1368, 1164, 1052, 1027, 911, 884 cmÀ1; HR-MS (ESI):
m/z=341.1471 [M+Na]+, calcd. for C17H22N2O4: 341.1472;
HPLC analysis (Chiralcel AD-H, (hexane/i-PrOH=90:10;
flow rate: 1.0 mLminÀ1; 254 nm): tR =17.8 min (major), tR =
20.9 min (minor); 98% ee.
Compound 6b: Isolated yield: 45.6 mg (62%); pale brown
solid; TLC (EtOAc:n-hexane, 1:2 v/v): Rf =0.35; [a]2D0:
À102.8 (c=0.25 CHCl3, 97% ee); mp 858C; 1H NMR
(500 MHz, CDCl3): d=9.02 (bs, 1H), 7.99 (d, J=8.1 Hz,
1H), 7.92 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.58–
7.49 (m, 2H), 7.44 (t, J=7.2 Hz, 1H), 7.24 (d, J=2.5 Hz,
1H), 5.67 (d, J=7.4 Hz, 1H), 5.51 (d, J=7.1 Hz, 1H), 4.30–
4.12 (m, 2H), 1.46 (s, 9H), 1.20 (t, J=7.1 Hz, 3H);
13C NMR (125 MHz, CDCl3): d=171.81, 155.19, 131.11,
130.53, 128.87, 125.69, 124.33, 121.63, 121.47, 121.12, 121.09,
119.37, 118.87, 113.58, 80.04, 61.65, 51.05, 28.35, 14.08; IR
(neat): n=3355, 2979, 1693, 1494, 1392, 1368, 1161, 1053,
1028, 909, 871 cmÀ1; HR-MS (ESI): m/z=391.1627 [M+
Na]+, calcd. for C21H24N2O4: 391.1628; HPLC analysis (Chir-
1
solid; H NMR (400 MHz, CDCl3): d=8.06 (s, 1H), 7.45 (d,
J=8.2 Hz, 2H), 7.34 (s, 1H), 7.26 (d, J=8.6 Hz, 2H), 7.08–
6.99 (m, 2H), 6.74 (s, 1H), 6.14 (s, 1H), 5.19 (s, 1H), 2.47 (s,
3H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3): d=155.16,
141.19, 136.21, 131.41, 128.53, 125.18, 123.11, 122.88, 120.84,
120.61, 120.21, 117.74, 116.96, 79.76, 51.32, 28.36, 16.55; HR-
MS (ESI): m/z=437.0835, calcd. for [C21H23BrN2NaO2, M+
Na]+: 437.0828; HPLC analysis (Chiralcel AD-H, hexane/i-
PrOH=85:15, flow rate=1.0 mLminÀ1, wave length=
254 nm): tR =7.8 min (minor), tR =20.7 min (major); 98% ee.
Compound 4kk: Isolated yield: 93.3 mg (92%); white
1
solid; H NMR (400 MHz, CDCl3): d=8.39 (s, 1H), 7.35 (s,
3H), 7.18 (d, J=8.1 Hz, 2H), 7.15–7.09 (m, 2H), 7.06 (t, J=
7.9 Hz, 1H), 6.96 (d, J=8.3 Hz, 2H), 6.82 (d, J=7.8 Hz,
2H), 6.51 (d, J=7.7 Hz, 1H), 6.19 (d, J=9.4 Hz, 1H), 6.06
(d, J=9.5 Hz, 1H), 5.04 (d, J=10.7 Hz, 1H), 4.85 (d, J=
10.7 Hz, 1H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCl3):
d=155.57, 151.88, 142.67, 138.81, 135.95, 130.72, 128.50,
128.39, 128.18, 123.12, 122.35, 119.87, 115.70, 115.49, 105.16,
100.55, 79.04, 70.06, 50.78, 28.42; HR-MS (ESI): m/z=
529.1097, calcd. for [C27H27BrN2NaO3, M+Na]+: 529.1080;
HPLC analysis (Chiralcel AD-H, hexane/i-PrOH=85:15,
flow rate=1.0 mLminÀ1, wave length=254 nm): tR =7.1 min
(minor), tR =11.4 min (major); 99% ee.
alcel
AD-H,
hexane/i-PrOH=85:15;
flow
rate:
1.0 mLminÀ1; 254 nm): tR =21.8 min (minor), tR =25.4 min
(major); 97% ee.
Compound 6c: Isolated yield: 60.2 mg (84%); white solid;
TLC (EtOAc:n-hexane, 1:2 v/v): Rf =0.37; [a]2D0: À102 (c=
0.25 CHCl3, 98% ee); mp 718C; 1H NMR (500 MHz,
CDCl3): d=8.06 (bs, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.14 (d,
J=2.5 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 5.57 (d, J=7.5 Hz,
1H), 5.43 (d, J=7.2 Hz, 1H), 4.30–4.09 (m, 2H), 3.03 (dt,
J=12.0, 7.4 Hz, 4H), 2.24–2.16 (m, 2H), 1.44 (s, 9H), 1.21
(t, J=7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=171.79,
155.14, 139.25, 133.55, 125.75, 124.01, 122.46, 117.21, 117.18,
112.26, 79.85, 61.53, 51.15, 33.06, 29.81, 28.35, 25.37, 14.10;
IR (neat): n=3334, 2978, 1697, 1497, 1368, 1331, 1166, 1053,
913, 804, 739, 652, 612 cmÀ1; HR-MS (ESI): m/z=381.1787
[M+Na]+, calcd. for C20H26N2O4: 381.1785; HPLC analysis
Compound 4kl: Isolated yield: 78.9 mg (95%); white
1
solid; H NMR (400 MHz, CDCl3): d=8.10 (s, 1H), 7.38 (d,
J=8.3 Hz, 2H), 7.22 (d, J=6.1 Hz, 3H), 7.09 (dt, J=15.1,
7.8 Hz, 2H), 6.95 (t, J=7.5 Hz, 1H), 6.12 (d, J=6.9 Hz,
1H), 5.33–5.25 (m, 1H), 2.34 (s, 3H), 1.45 (s, 9H); 13C NMR
(100 MHz, CDCl3): d=155.51, 141.32, 135.30, 132.67, 131.26,
128.12, 126.27, 121.32, 120.43, 119.59, 118.35, 111.50, 110.57,
79.74, 50.17, 28.36, 11.98; HR-MS (ESI): m/z=437.0835,
calcd. for [C21H23BrN2NaO2, M+Na]+: 437.0828; HPLC
analysis (Chiralcel OD-H, hexane/i-PrOH=90:10, flow
rate=1.0 mLminÀ1, wave length=254 nm): tR =11.0 min
(minor), tR =18.1 min (major); 98% ee.
(Chiralpak
IA,
hexane/i-PrOH=90:10;
flow
rate:
1.0 mLminÀ1; 220 nm): tR =14.9 min (major), tR =16.4 min
(minor); 98% ee.
Compound 6d: Isolated yield: 35.8 mg (54%); pale brown
solid; TLC (EtOAc:n-hexane, 1:2 v/v): Rf =0.3; [a]2D0: À94.8
(c=0.25 CHCl3, 98% ee); mp 988C; 1H NMR (500 MHz,
CDCl3): d=8.34 (bs, 1H), 7.21 (d, J=8.2 Hz, 1H), 7.13–7.07
(m, 2H), 6.91 (d, J=7.1 Hz, 1H), 5.81 (d, J=7.4 Hz, 1H),
5.18 (d, J=6.9 Hz, 1H), 4.31–4.15 (m, 2H), 2.72 (s, 3H),
1.45 (s, 9H), 1.24 (t, J=7.1 Hz, 3H); 13C NMR (125 MHz,
CDCl3): d=172.55, 154.89, 136.51, 130.69, 124.62, 122.88,
122.80, 122.03, 112.07, 109.33, 80.00, 61.47, 51.29, 28.33,
19.85, 14.06; IR (neat): n=3349, 2979, 1696, 1490, 1368,
1157, 1055, 1027, 909, 733 cmÀ1; HR-MS (ESI): m/z=
355.1625 [M+Na]+, calcd. for C18H24N2O4: 355.1628; HPLC
analysis: (Chiralcel OJ-H, hexane/i-PrOH=95:5; flow rate:
1.0 mLminÀ1; 220 nm): tR =20.2 min (major), tR =26.5 min
(minor); 98% ee.
Compound 4km: Isolated yield: 77.2 mg (90%); white
1
solid; H NMR (400 MHz, CDCl3): d=8.02 (s, 1H), 7.38 (d,
J=8.2 Hz, 2H), 7.21 (d, J=8.0 Hz, 2H), 7.09 (d, J=8.1 Hz,
1H), 6.94 (s, 1H), 6.90 (d, J=8.2 Hz, 1H), 6.10 (d, J=
6.3 Hz, 1H), 5.35–5.23 (m, 1H), 2.33 (s, 3H), 2.28 (s, 3H),
1.46 (s, 9H); 13C NMR (100 MHz, CDCl3): d=155.55,
141.49, 133.61, 132.65, 131.27, 128.95, 128.19, 126.64, 122.93,
120.42, 118.12, 111.20, 110.23, 79.73, 50.18, 28.39, 21.51,
12.11;
HR-MS
(ESI):
m/z=451.0991,
calcd.
for
[C22H25BrN2NaO2, M+Na]+: 451.0984; HPLC analysis
(Chiralcel AD-H (hexane/i-PrOH=90:10, flow rate=
1.0 mLminÀ1, wave length=254 nm): tR =8.4 min (minor),
tR =11.8 min (major); 98% ee.
Compound 6a: Isolated yield: 50.3 mg (79%); pale yellow
solid; TLC (EtOAc:n-hexane, 1:2 v/v): Rf =0.35; [a]2D0:
À111.6 (c=0.25 CHCl3, 98% ee); mp 778C; 1H NMR
(500 MHz, CDCl3): d=8.44 (bs, 1H), 7.72 (d, J=7.9 Hz,
1H), 7.36 (d, J=8.1 Hz, 1H), 7.21 (t, J=7.5 Hz, 1H), 7.17–
7.11 (m, 2H), 5.59 (d, J=7.3 Hz, 1H), 5.45 (d, J=6.8 Hz,
1H), 4.28–4.09 (m, 2H), 1.45 (s, 9H), 1.20 (t, J=7.0 Hz,
Compound 6e: Isolated yield: 56.5 mg (85%); pale brown
solid; TLC (EtOAc:n-hexane, 1:2 v/v): Rf =0.35; [a]2D0: À99.6
(c=0.25 CHCl3, 97% ee); mp 758C; 1H NMR (500 MHz,
CDCl3): d=8.10 (bs, 1H), 7.50 (s, 1H), 7.26 (d, J=8.1 Hz,
1H), 7.16 (d, J=2.5 Hz, 1H), 7.05 (d, J=8.3 Hz, 1H), 5.57
(d, J=7.5 Hz, 1H), 5.39 (d, J=7.2 Hz, 1H), 4.29–4.12 (m,
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2H), 2.46 (s, 3H), 1.45 (s, 9H), 1.22 (t, J=7.1 Hz, 3H);
13C NMR (125 MHz, CDCl3): d=171.91, 155.33, 134.74,
129.46, 125.70, 124.22, 123.49, 118.71, 111.24, 110.74, 80.04,
61.57, 51.17, 28.39, 21.52, 14.08; IR (neat): n=3349, 2982,
1698, 1493, 1368, 1171, 1053, 1030, 914, 881 cmÀ1; HR-MS
(ESI): m/z=355.1628 [M+Na]+, calcd. for C18H24N2O4:
355.1628; HPLC analysis (Chiralcel OD-H, hexane/i-
1.45 (s, 9H), 1.21 (t, J=7.1 Hz, 3H); 13C NMR (125 MHz,
CDCl3): d=171.55, 157.96 (d, 1JC,F =235.4 Hz), 155.31,
132.94, 125.74 (d, 3JC,C,C,F =10.1 Hz), 125.04, 112.27 (d,
3
2JC,C,F =9.7 Hz), 111.47, 111.03 (d, JC,C,C,F =26.4 Hz), 104.19
(d, 2JC,C,F =24.2 Hz), 80.25, 61.75, 51.18, 28.35, 14.05;
19F NMR (470 MHz, CDCl3): d=À123.41 (s, 1F); IR (neat):
n=3333, 2981, 1696, 1489, 1369, 1166, 1053, 1027, 940,
860 cmÀ1; HR-MS (ESI): m/z=359.1378 [M+Na]+, calcd.
for C17H21FN2O4: 359.1378; HPLC analysis (Chiralpak IA,
hexane/i-PrOH=90:10; flow rate: 1.0 mLminÀ1; 220 nm):
tR =12.0 min (major), tR =13.6 min (minor); 96% ee.
PrOH=90:10; flow rate: 1.0 mLminÀ1
;
220 nm): tR =
24.3 min (minor), tR =26.4 min (major); 97% ee.
Compound 6f: Isolated yield: 55.8 mg (84%); pale yellow
solid; TLC (EtOAc:n-hexane, 1:2 v/v): Rf =0.32; [a]2D0: À99.2
1
(c=0.25 CHCl3, 97% ee); mp 1038C; H NMR (500 MHz,
Compound 6j: Isolated yield: 38.6 mg (50%); pale yellow
CDCl3): d=8.12 (bs, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.16 (s,
1H), 7.11 (d, J=2.4 Hz, 1H), 6.99 (dd, J=8.2, 0.8 Hz, 1H),
5.56 (d, J=7.5 Hz, 1H), 5.42 (d, J=7.0 Hz, 1H), 4.28–4.10
(m, 2H), 2.45 (s, 3H), 1.44 (s, 9H), 1.21 (t, J=7.1 Hz, 3H);
13C NMR (125 MHz, CDCl3): d=171.77, 155.16, 136.78,
132.57, 123.27, 122.53, 121.97, 118.90, 111.52, 111.30, 79.90,
61.54, 51.06, 28.34, 21.66, 14.09; IR (neat): n=3370, 2979,
1695, 1506, 1368, 1157, 1054, 1027, 912, 748 cmÀ1; HR-MS
(ESI): m/z=355.1630 [M+Na]+, calcd. for C18H24N2O4:
355.1628; HPLC analysis (Chiralcel OD-H, hexane/i-
PrOH=90:10; flow rate: 1.0 mLminÀ1; 220 nm): tR =8.1 min
(major), tR =9.3 min (minor); 97% ee.
Compound 6g: Isolated yield: 38.5 mg (58%); pale yellow
solid; TLC (EtOAc:n-hexane, 1:2 v/v): Rf =0.42; [a]2D0: À114
(c=0.25 CHCl3, 98% ee);mp 608C; 1H NMR (500 MHz,
CDCl3): d=8.22 (s, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.19 (d,
J=2.5 Hz, 1H), 7.07 (t, J=7.5 Hz, 1H), 7.02 (d, J=7.1 Hz,
1H), 5.58 (d, J=7.4 Hz, 1H), 5.44 (d, J=6.8 Hz, 1H), 4.28–
4.10 (m, 2H), 2.47 (s, 3H), 1.44 (s, 9H), 1.20 (t, J=7.1 Hz,
3H); 13C NMR (125 MHz, CDCl3): d 171.76, 155.17, 135.94,
125.02, 123.14, 122.94, 120.64, 120.42, 116.95, 112.19, 79.91,
61.56, 51.13, 28.35, 16.55, 14.09; IR (neat): n=3368, 2984,
1702, 1498, 1393, 1168, 1056, 912, 735 cmÀ1; HR-MS (ESI):
m/z=355.1631 [M+Na]+, calcd. for C18H24N2O4,: 355.1628;
HPLC analysis (Chiralcel OD-H, hexane/i–PrOH=90:10;
flow rate: 1.0 mLminÀ1; 220 nm): tR =7.5 min (major), tR =
8.6 min (minor); 98% ee.
solid; TLC (EtOAc:n-hexane, 1:2 v/v): Rf =0.29; [a]2D0: À93.2
1
(c=0.25 CHCl3, 97% ee); mp 1128C; H NMR (500 MHz,
CDCl3): d=8.77 (bs, 1H), 8.01 (s, 1H), 7.37 (dd, J=18.8,
8.0 Hz, 2H), 7.21 (s, 1H), 5.60 (dd, J=18.7, 6.9 Hz, 2H),
4.28–4.12 (m, 2H), 1.46 (s, 9H), 1.21 (t, J=6.9 Hz, 3H);
13C NMR (125 MHz, CDCl3): d=171.31, 155.23, 137.74,
1
2
125.16(q, JC,F =235.4 Hz), 124.84, 124.75, 122.55 (q, JC,C,F
=
9.7 Hz), 121.93, 119.33, 117.13, 112.81, 111.76, 80.38, 61.94,
50.99, 28.33, 13.98; 19F NMR (470 MHz, CDCl3): d=À60.35
(s, 3F); IR (neat): n=3319, 2983, 1694, 1499, 1331, 1274,
1159, 1114, 1051, 907, 811 cmÀ1; HR-MS (ESI): m/z=
409.1346 [M+Na]+, calcd. for C18H21F3N2O4: 409.1345;
HPLC analysis (Chiralcel OJ-H, hexane/i-PrOH=95:5; flow
rate: 1.0 mLminÀ1
; 220 nm): tR =16.0 min (minor), tR =
20.3 min (major); 97% ee.
Compound 6k: Isolated yield: 45.2 mg (57%); pale brown
solid; TLC (EtOAc:n-hexane, 1:2 v/v): Rf =0.32; [a]2D0: À86.0
1
(c=0.25 CHCl3, 96% ee); mp 1048C; H NMR (500 MHz,
CDCl3): d=8.39 (bs, 1H), 7.85 (s, 1H), 7.28 (dd, J=8.6,
1.4 Hz, 1H), 7.21 (d, J=8.6 Hz, 1H), 7.16 (d, J=2.6 Hz,
1H), 5.53 (d, J=7.1 Hz, 1H), 5.47 (d, J=6.4 Hz, 1H), 4.29–
4.11 (m, 2H), 1.46 (s, 9H), 1.23 (t, J=7.0 Hz, 3H);
13C NMR (125 MHz, CDCl3): d=171.36, 155.14, 135.01,
127.13, 125.59, 124.38, 121.93, 113.53, 112.87, 111.55, 80.23,
61.79, 50.98, 28.36, 14.09; IR (neat): n=3313, 2982, 1696,
1495, 1368, 1162, 1054, 1027, 909, 887 cmÀ1; HR-MS (ESI):
m/z=419.0576 [M+Na]+, calcd. for C17H21BrN2O4:
419.0577; HPLC analysis (Chiralcel OJ-H, hexane/i-PrOH=
95:5; flow rate: 1.0 mLminÀ1; 220 nm): tR =23.8 min (minor),
tR =29.4 min (major); 96% ee.
Compound 6h: Isolated yield: 62.0 mg (89%); pale yellow
solid; TLC (EtOAc:n-hexane, 1:2 v/v): Rf =0.29; [a]2D0:
+93.2 (c=0.25 CHCl3, 95% ee); mp 908C; 1H NMR
(500 MHz, CDCl3): d=8.10 (bs, 1H), 7.26 (d, J=8.8 Hz,
1H), 7.19–7.14 (m, 2H), 6.88 (dd, J=8.8, 2.4 Hz, 1H), 5.58
(d, J=7.6 Hz, 1H), 5.39 (d, J=7.3 Hz, 1H), 4.29–4.14 (m,
2H), 3.86 (s, 3H), 1.45 (s, 9H), 1.23 (t, J=7.1 Hz, 3H);
13C NMR (125 MHz, CDCl3): d=171.76, 155.22, 154.44,
131.33, 125.99, 123.63, 113.15, 112.17, 111.48, 100.66, 79.97,
77.28, 77.03, 76.77, 61.57, 55.84, 50.91, 28.35, 14.12; IR
(neat): n=3358, 2979, 1696, 1488, 1368, 1215, 1170, 1052,
1028, 923, 885 cmÀ1; HR-MS (ESI): m/z=371.1579 [M+
Na]+, calcd. for C18H24N2O5, 371.1577; HPLC analysis (Chir-
Compound 6l: Isolated yield: 40.2 mg (57%); pale brown
solid; TLC (EtOAc:n-hexane, 1:2 v/v): Rf =0.29; [a]2D0: À98.0
1
(c=0.25 CHCl3, 97% ee); mp 1108C; H NMR (500 MHz,
CDCl3): d=8.29 (bs, 1H), 7.70 (s, 1H), 7.27 (d, J=10.4 Hz,
1H), 7.21 (d, J=2.5 Hz, 1H), 7.16 (dd, J=8.6, 1.6 Hz, 1H),
5.54 (d, J=7.3 Hz, 1H), 5.46 (d, J=6.8 Hz, 1H), 4.29–4.14
(m, 2H), 1.46 (s, 9H), 1.23 (t, J=7.1 Hz, 3H); 13C NMR
(125 MHz, CDCl3): d=171.39, 155.16, 134.74, 126.47, 125.99,
124.56, 123.02, 118.83, 112.46, 111.58, 80.21, 61.78, 51.00,
28.36, 14.08; IR (neat): n=3344, 2981, 1696, 1496, 1466,
1368, 1163, 1055, 1027, 897, 869 cmÀ1; HR-MS (ESI): m/z=
375.1081 [M+Na]+, calcd. for C17H21ClN2O4: 375.1082;
HPLC analysis (Chiralpak IA, hexane/i-PrOH=95:5; flow
alcel OD-H,hexane/i-PrOH=90:10; flow rate: 1.0 mLminÀ1
;
220 nm): tR =11.1 min (major), tR =18.1 min (minor); 95%
ee.
Compound 6i: Isolated yield: 49.7 mg (74%); pale yellow
solid; TLC (EtOAc:n-hexane, 1:2 v/v): Rf =0.27; [a]2D0:
À100.4 (c=0.25 CHCl3, 96% ee); mp 1168C; 1H NMR
(500 MHz, CDCl3): d=8.40 (bs, 1H), 7.38 (dd, J=9.6,
1.6 Hz, 1H), 7.26 (dd, J=8.7, 4.3 Hz, 1H), 7.20 (d, J=
2.5 Hz, 1H), 6.95 (td, J=9.0, 2.2 Hz, 1H), 5.53 (d, J=
7.2 Hz, 1H), 5.47 (d, J=6.9 Hz, 1H), 4.28–4.12 (m, 2H),
rate: 1.0 mLminÀ1
; 220 nm): tR =27.1 min (major), tR =
30.5 min (minor); 97% ee.
Compound 6m: Isolated yield: 37.7 mg (55%); pale
brown solid; TLC (EtOAc:n-hexane, 1:2 v/v): Rf =0.16;
1
[a]20: À77.6 (c=0.25 CHCl3, 98% ee); mp 1078C; H NMR
(50D0 MHz, CDCl3): d=8.66 (bs, 1H), 8.11 (s, 1H), 7.41 (dd,
J=21.6, 8.4 Hz, 2H), 7.30 (d, J=2.4 Hz, 1H), 5.58 (s, 2H),
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4.30–4.14 (m, 2H), 1.46 (s, 9H), 1.23 (t, J=7.1 Hz, 3H);
13C NMR (125 MHz, CDCl3): d=171.00, 155.07, 138.00,
125.53, 125.29, 125.25, 125.19, 120.41, 113.16, 112.36, 103.47,
80.44, 62.04, 50.82, 28.33, 14.08; IR (neat): n=3321, 2982,
2223, 1701, 1497, 1369, 1166, 1051, 1027, 910, 810 cmÀ1; HR-
MS (ESI): m/z=366.1426 [M+Na]+ calcd. for C18H21N3O4:
366.1424; HPLC analysis (Chiralpak IA, hexane/i-PrOH=
and Innovation Foundation of Chongqing, China
(CYB16032) and the Ministry of Science, ICT, and Future
Planning in Korea (Grant No: NRF-2014R1A2A1A01005794
and NRF-2016R1A4A1011451).
90:10; flow rate: 1.0 mLminÀ1
; 220 nm): tR =14.9 min
(major), tR =16.4 min (minor); 98% ee.
References
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Compound 6n: Isolated yield: 63.7 mg (88%); pale
yellow; TLC (EtOAc:n-hexane, 1:2 v/v): Rf =0.39; [a]2D0:
À132 (c=0.25 CHCl3, 98% ee); mp 688C; 1H NMR
(500 MHz, CDCl3): d=7.85 (s, 1H), 7.16 (d, J=8.7 Hz, 1H),
7.07 (s, 1H), 6.78 (dd, J=8.7, 2.4 Hz, 1H), 5.52–5.42 (m,
2H), 4.27–4.05 (m, 2H), 3.85 (s, 3H), 2.47 (s, 3H), 1.44 (s,
9H), 1.18 (t, J=7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3):
d=171.70, 155.28, 154.30, 134.50, 130.10, 126.88, 111.17,
106.99, 100.73, 79.81, 61.50, 55.94, 50.43, 28.38, 14.16, 12.03;
IR (neat): n=3357, 2979, 1669, 1591, 1487, 1368, 1252, 1167,
1096, 1055, 913, 860 cmÀ1; HR-MS (ESI): m/z=385.1734
[M+Na]+, calcd. for C19H26N2O5: 385.1739; HPLC analysis
(Chiralpak
IA.
hexane/i-PrOH=95:5;
flow
rate:
1.0 mLminÀ1; 220 nm): tR =22.3 min (minor), tR =25.3 min
(major); 98% ee.
Compound 6o: Isolated yield: 39.7 mg (74%); red liquid;
TLC (acetone:n-hexane, 1:4 v/v): Rf =0.24; [a]2D0: À82.8 (c=
0.25 CHCl3, 91% ee); mp 888C; 1H NMR (500 MHz,
CDCl3): d=8.82 (bs, 1H), 6.76 (td, J=2.6, 1.6 Hz, 1H), 6.13
(dd, J=5.7, 2.8 Hz, 1H), 6.05 (s, 1H), 5.50 (d, J=5.6 Hz,
1H), 5.40 (d, J=7.3 Hz, 1H), 4.27 (dd, J=14.2, 7.1 Hz, 2H),
1.45 (s, 9H), 1.30 (t, J=7.1 Hz, 3H); 13C NMR (125 MHz,
CDCl3): d=170.33, 155.57, 126.88, 118.61, 108.30, 106.40,
80.38, 62.02, 51.72, 28.29, 14.07; IR (neat): n=3379, 2980,
1702, 1500, 1368, 1335, 1164, 1054, 1028, 867, 788, 729 cmÀ1
;
HR-MS (ESI): m/z=291.1315 [M+Na]+, calcd. for
C13H20N2O4: 291.1315; HPLC analysis (Chiralpak IA,
hexane/i-PrOH=90:10; flow rate: 1.0 mLminÀ1; 220 nm):
tR =9.2 min (major), tR =26.4 min (minor); 91% ee.
Compound 8: Isolated yield: 50.7 mg (80%); pale yellow
solid; TLC (acetone:n-hexane, 1:4 v/v): Rf =0.37; [a]2D0:
À68.8 (c=0.25 CHCl3, 84% ee); mp 1138C; 1H NMR
(500 MHz, CDCl3): d=8.77 (bs, 1H), 7.56 (d, J=7.9 Hz,
1H), 7.34 (d, J=8.1 Hz, 1H), 7.18 (t, J=7.6 Hz, 1H), 7.09
(t, J=7.5 Hz, 1H), 6.39 (s, 1H), 5.64 (s, 1H), 5.57 (d, J=
7.2 Hz, 1H), 4.36–4.22 (m, 2H), 1.45 (s, 9H), 1.31 (t, J=
7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=169.87,
155.50, 136.22, 133.73, 127.72, 122.45, 120.68, 120.03, 111.11,
100.66, 80.69, 62.35, 52.18, 28.28, 14.08; IR (neat): n=3373,
2981, 1703, 1501, 1369, 1160, 1056, 1027, 909, 733 cmÀ1; HR-
MS (ESI): m/z=343.1626 [M+Na]+, calcd. for C17H24N2O4:
343.1628; HPLC analysis (Chiralcel OD-H, hexane/i-
PrOH=99:1; flow rate: 1.0 mLminÀ1; 220 nm): tR =39.7 min
(major), tR =48.1 min (minor); 84% ee.
Acknowledgements
This study was supported by the Fundamental Research
Funds for the Central Universities in China (Grant No:
0236015205004), the Scientific Research Foundation of China
(Grant No: 0236011104404), Graduate Scientific Research
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14 Cooperative Cation-Binding Catalysis as an Efficient
Approach for Enantioselective Friedel–Crafts Reaction of
Indoles and Pyrrole
Adv. Synth. Catal. 2017, 359, 1 – 14
Mun Jong Kim, Lu Xue, Yidong Liu, Sushovan Paladhi,
Si Joon Park, Hailong Yan,* Choong Eui Song*
Adv. Synth. Catal. 0000, 000, 0 – 0
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