(DHQ)2AQN-catalyzed asymmetric substitution of isatin-derived hydrazones with O-boc-protected morita-baylis-hillman adducts: A strategy for synthesizing enantioenriched azo compounds incorporating an oxindole scaffold

Article abstract of DOI:10.1021/jo5003246

The first example for the preparation of enantioenriched azo compounds from hydrazones and Morita-Baylis-Hillman adducts has been developed, affording azo compounds incorporating an oxindole scaffold in up to 91% yield along with a 93% ee value under the catalysis of (DHQ)₂AQN.

Full text of DOI:10.1021/jo5003246

Article
pubs.acs.org/joc
(DHQ)2AQN-Catalyzed Asymmetric Substitution of Isatin-Derived
Hydrazones with O‑Boc-Protected Morita−Baylis−Hillman Adducts:
A Strategy for Synthesizing Enantioenriched Azo Compounds
Incorporating an Oxindole Scaffold
Hai-Bin Yang, Yun-Zhou Zhao, Rui Sang, and Min Shi*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: The first example for the preparation of enan-
tioenriched azo compounds from hydrazones and Morita−
Baylis−Hillman adducts has been developed, affording azo
compounds incorporating an oxindole scaffold in up to 91%
yield along with a 93% ee value under the catalysis of
(DHQ)2AQN.
compounds.9 To the best of our knowledge, hydrazone has not
INTRODUCTION
■
yet been employed as a nucleophile in the asymmetric SN2′/SN2′
The oxindole framework bearing a tetrasubstituted carbon
substitution of MBH adducts. Inspired by these results, and also
stereocenter at the 3-position is a privileged heterocyclic motif
in conjunction with our efforts on catalytic asymmetric synthesis
that constructs the core of a large family of bioactive natural
of oxindoles bearing a tetrasubstituted stereocenter at the C-3
products and a series of pharmaceutically active compounds.1
position, we decided to apply the asymmetric SN2′/SN2′ sub-
Inspired by these important scaffolds, a variety of synthetic
stitution of MBH adducts to synthesize enantioenriched azo
methods for producing oxindoles bearing a tetrasubstituted
compounds incorporating an oxindole scaffold (Scheme 2).10
carbon stereocenter at the 3-position and for applications to
According to our assumption, t-butoxide ion generated in situ
natural product synthesis have been investigated over the past
from the nucleophilic addition of Lewis base to MBH adduct
decade.1b,c,2
could abstract a proton of hydrazone to give a nucleophile that
Azo compounds constitute an important family of compounds
could undergo an SN2′ substitution to give azo compounds
with traditional uses in organic chemistry. For example, the appli-
(Scheme 3).9,11 Thus, we employed isatin-derived hydrazones as
cation of azodicarboxylates in organic synthesis as nitrogen-
the target molecules to realize this hypothesis.
atom-containing electrophiles/dienophiles and the use of
aromatic azo compounds in the industrial field as pigments and
RESULTS AND DISCUSSION
dyes are well-established.3 The importance of NN bonds in
biologically active molecules and the need for the development
of new antibiotics have stimulated the synthesis of new azo
prodrugs of the general structure Ar−NN−R (R = aryl or
alkyl) that release therapeutically active amine drugs upon site-
specific reduction by bacterial extracellular azoreductase en-
zymes in the human colon (Scheme 1).4 However, the synthesis
of aliphatic azo compounds is less developed and still remains
challenging, presumably due to their inherent instability.5 Thus
far, only a few examples of the enantioselective synthesis of azo
compounds are known. These include the radical carboamina-
tion/biocatalytic resolution procedure,6 the enantioselective
conjugate addition of hydrazones to electron-deficient alkenes
with aminocatalysis or H-bonding catalysis,7 and the formally
heterocarbonyl−ene reaction of hydrazones to ketones with H-
bonding catalysis (Scheme 2).8 Recently, chiral Lewis bases were
used to catalyze asymmetric allylic alkylation using Morita−
Baylis−Hillman (MBH) adducts as electrophiles, through a
SN2′/SN2′ cascade, and this synthetic method has emerged as
a powerful strategy for the construction of multifunctional
■
We first used hydrazone 1a (1.0 equiv) and MBH adduct 2a
(3.0 equiv) as the substrates to determine the reaction outcome
and subsequently optimized the reaction conditions in the pre-
sence of 1,4-diazabicyclo[2,2,2]octane (DABCO) (20 mol %) or
various chiral Lewis bases (20 mol %) derived from cinchona
alkaloids. The results are summarized in Table 1. The treatment
of hydrazone 1a with MBH adduct 2a in the presence of DABCO
gave the desired product 3a in 51% isolated yield (Table 1,
entry 1). Its asymmetric version could be achieved under the
catalysis of Q (quinine) and QD (quinidine) in THF at room
temperature, affording 3a in 74% yield along with a 40% ee value
and in 74% yield along with −39% ee, respectively (Table 1,
entries 2 and 3). A brief survey of the other cinchona alkaloids
derived chiral Lewis bases indicated that (DHQ)2AQN
[(DHQ)2AQN is hydroquinine (anthraquinone-1,4-diyl)-
diether] was the best catalyst for this reaction, giving 3a in
Received: February 11, 2014
Published: March 26, 2014
© 2014 American Chemical Society
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Scheme 1. Design of Prodrug Based on Azoreductase
80% yield and 75% ee value (Table 1, entries 4−9). The
examination of solvent effects using 1a (1.0 equiv) and 2a (3.0
equiv) revealed that EtOAc (ethyl acetate) was the solvent of
choice, giving the desired product 3a in 80% yield along with a
76% ee value (Table 1, entries 10−14). Carrying out the reaction
at 0 °C gave the desired product 3a in 82% yield along with 80%
ee value (Table 1, entry 15). Increasing the concentration of
substrate 1a to 0.1 M and reducing the catalyst loading to 10 mol
% had no influence on the reaction outcome (Table 1, entry 16).
However, when we reduced the catalyst loading to 5 mol %, the
yield of 3a decreased to 75% (Table 1, entry 17). Thus, we
established the optimal reaction conditions for this reaction:
hydrazone 1a (0.1 mmol), MBH adduct 2a (0.3 mmol), and
(DHQ)2AQN (0.01 mmol) were stirred in 1 mL of EtOAc at
0 °C.
but with 31% yield along with incomplete conversion of hy-
drazone 1b, perhaps due to the steric effect (Table 2, entry 4).
As for MBH adduct 2c, whether PG (where PG indicates
protecting group) was a p-bromobenzyl, allyl, or naphthyl group,
the corresponding products 3f−3h could be also obtained in
good yields along with good ee values, and this investigation
disclosed that the enantioselectivity of 3 could be enhanced if the
PG is bearing an aryl moiety (Table 2, entries 5−7). The
presence of an electron-donating group (Me or MeO) at C5, C6,
or C7 position of isatin-derived hydrazones afforded the desired
products 3 in better ee values, demonstrating that the electronic
effect had great influence on the control of enantioselectivity,
presumably due to the π−π stacking interaction between the
oxindole ring of hydrazone and the quinoline motif of
(DHQ)2AQN (Table 2, entries 8−15). When the aryl group
(Ar) of hydrazone was changed to a 3,4-dimethoxyphenyl or
3,4,5-trimethoxyphenyl group, the reaction also proceeded
smoothly to afford the corresponding products 3q and 3r
with good ee values, albeit with lower yields (Table 2, entries 16
and 17). It should be also noted that, when the aryl group (Ar) of
hydrazone was changed to a 3,5-dimethylphenyl group, no
reaction occurred under the standard conditions, suggesting that
it is essential for this asymmetric allylic alkylation of hydrazones
using a strongly electron-donating group as the nitrogen sub-
stituent to enhance the stability of the key intermediate shown in
Scheme 3 (Table 2, entry18).
Because of the important biological meaning of CF3, ethyl
trifluoropyruvate-derived hydrazone was investigated in this
asymmetric allylic alkylation of hydrazone, and the result of this
experiment is shown in Scheme 4.12 When ethyl trifluoropyr-
uvate-derived hydrazone was subjected to the standard con-
ditions, the reaction proceeded smoothly, furnishing the desired
product 3s in 82% yield along with a 68% ee value (Scheme 4).
Furthermore, the chiral product 3i could be smoothly trans-
formed into compound 4a incorporating a biologically inter-
esting isoxazole scaffold in 60% yield along with 2:1 dia-
stereoselectivity via a 1,3-dipolar cycloaddition (The dr value was
1
With these optimal conditions in hand, we next examined a
variety of isatin-derived hydrazones 1 in this reaction, and the
results of these experiments are shown in Table 2. For MBH
adducts 2a−2c (R4 = H), whether R5 was an ethyl, benzyl, or
neopentyl group, the corresponding products 3b−3d could be
obtained in good yields along with good ee values (Table 2,
entries 1−3, where PMP indicates a p-methoxyphenyl group).
However, for MBH adduct 2d (R4 = p-nitrophenyl group and
R5 = ethyl group), the reaction was sluggish to afford the
corresponding product 3e in a 93% ee value and a 11:1 dr value
determined by H NMR spectroscopic data of the crude pro-
duct) (Scheme 5).
In summary, we have established a moderately efficient
process for the asymmetric allylic alkylation of hydrazones under
the catalysis of (DHQ)2AQN. Azo compounds incorporating an
oxindole scaffold could be synthesized in good yields with good
enantioselectivities under mild conditions. As for future studies,
we plan to expand the scope of the substrate and to investigate
the biological activity of these obtained azo compounds incor-
porating an oxindole scaffold.
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Scheme 2. Previous Investigations on the Enantioselective Preparation of Azo Compounds and Our Work
Scheme 3. Our Strategies for the Asymmetric Synthesis of Azo Compounds
procedure.13 A mixture of isatin (1 equiv), arylhydrazine hydrochloride
(1.1 equiv), and sodium acetate (2 equiv) in absolute ethanol was heated
under reflux for 16 h. The reaction mixture was allowed to cool, and the
resulting precipitates were filtered from the solution. The solvent was
removed under reduced pressure, and the residue was purified by silica
gel column chromatography using an ethyl acetate/petroleum ether
gradient mixture to give the corresponding products 1. The (Z)-
configuration of hydrazone substrates 1 has been determined by X-ray
crystal data of compound 1i (see below).
Procedure for the Synthesis of Hydrazone 1o. Compound 1o
was prepared by a previously reported procedure.14 3,4,5-Trimethox-
yaniline (410 mg, 2.26 mmol) was dissolved in the mixture of water
(2.40 mL), THF (0.57 mL), and conc. hydrochloric acid (0.76 mL), and
EXPERIMENTAL SECTION
■
General Remarks. 1H and 13C NMR spectra were recorded at 400
(or 300) MHz, respectively. HRMS spectra were recorded by
electrospray ionization (ESI-TOF). The employed solvents were
dried by standard methods when necessary. Commercially obtained
reagents were used without further purification. All reactions were
monitored by TLC with silica-gel-coated plates. Flash column
chromatography was carried out using 300−400 mesh silica gel at
increased pressure. The (Z)-configuration of hydrazone substrates 1 has
been determined by X-ray crystal data of compound 1i (see the
Supporting Information).
Procedure for the Synthesis of Hydrazones 1a−1n and 1p.
Compounds 1a−1n and 1p were prepared by a previously reported
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(d, J = 9.2 Hz, 2H), 7.63 (d, J = 7.2 Hz, 1H), 12.81 (brs, 1H); 13C NMR
(100 MHz, CDCl3, TMS) δ 25.3, 55.5, 108.2, 114.7, 115.4, 118.4, 121.3,
122.3, 125.7, 127.4, 136.4, 140.5, 155.9, 162.1; HRMS (ESI) Calcd for
C16H15N3O2 requires (M+ + H): 282.1237, Found: 282.1240.
Table 1. Optimization of the Asymmetric Allylic Alkylation of
Hydrazones
Compound 1b. Yield: 280 mg, 78%. A yellow solid. m.p.: 141−
142 °C. IR (neat) ν 3026, 2960, 2931, 2835, 1661, 1609, 1594, 1557,
1
1518, 1495, 1464, 1362, 1237, 1160, 1101, 1035, 821, 741 cm−1; H
NMR (400 MHz, CDCl3, TMS) δ 3.81 (s, 3H), 4.99 (s, 2H), 6.78 (d, J =
7.6 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 7.07 (td, J = 7.6 Hz, 0.8 Hz, 1H),
7.15 (td, J = 7.6 Hz, 1.2, Hz, 1H), 7.26−7.34 (m, 7H), 7.64 (d, J = 7.2 Hz,
1H), 12.85 (brs, 1H); 13C NMR (100 MHz, CDCl3, TMS) δ 43.1, 55.6,
109.2, 114.8, 115.6, 118.5, 121.5, 122.5, 125.5, 127.2, 127.4, 127.6, 128.8,
135.9, 136.3, 139.7, 156.1, 162.2; HRMS (ESI) Calcd for C22H19N3O2
requires (M+ + H): 358.1550, Found: 358.1554.
Compound 1c. Yield: 240 mg, 46%. A yellow solid. m.p.: 178−
180 °C. IR (neat) ν 3231, 3042, 2964, 2920, 2838, 1654, 1608, 1592,
1560, 1516, 1357, 1231, 1160, 1098, 1037, 1009, 825, 791, 781 cm−1; 1H
NMR (400 MHz, CDCl3, TMS) δ 3.81 (s, 3H), 4.93 (s, 2H), 6.74 (d, J =
7.6 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 7.09 (t, J = 7.6 Hz, 1H), 7.14−7.19
(m, 3H), 7.32 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.64 (d, 1H),
12.82 (brs, 1H); 13C NMR (100 MHz, CDCl3, TMS) δ 42.5, 55.6, 109.0,
114.8, 115.6, 118.6, 121.5, 121.6, 122.6, 125.3, 127.4, 128.9, 131.9, 134.9,
136.2, 139.3, 156.2, 162.1; HRMS (ESI) Calcd for C22H18BrN3O2
requires (M+ + H): 436.0655, Found: 436.0660.
a
b
c
entry
cat.
DABCO
solvent
T (°C) yield (%)
ee (%)
1
2
toluene
THF
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
51
74
74
79
53
74
76
80
76
81
85
66
80
80
82
84
75
Q
40
−39
−34
48
3
QD
THF
4
β-lCD
THF
5
(DHQ)2PHAL
(DHQ)2PYDZ
(DHQ)2PYR
(DHQ)2AQN
(DHQD)2AQN
(DHQ)2AQN
(DHQ)2AQN
(DHQ)2AQN
(DHQ)2AQN
(DHQ)2AQN
(DHQ)2AQN
(DHQ)2AQN
(DHQ)2AQN
THF
6
THF
40
7
THF
17
8
THF
75
9
THF
−30
57
10
11
12
13
14
15
CH2Cl2
acetone
PhCF3
Et2O
60
Compound 1d. Yield: 244 mg, 79%. A yellow solid. m.p.: 122−
57
123 °C. IR (neat) ν 3197, 3049, 2834, 1655, 1609, 1557, 1516, 1464,
1
1356, 1229, 1171, 1047, 940, 821, 782 cm−1; H NMR (400 MHz,
69
EtOAc
EtOAc
EtOAc
EtOAc
76
CDCl3, TMS) δ 3.81 (s, 3H), 4.43 (d, J = 5.2 Hz, 2H), 5.21−5.25 (m,
2H), 5.84−5.94 (m, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.92 (d, J = 9.2 Hz,
2H), 7.10 (t, J = 7.2 Hz, 1H), 7.22 (t, J = 7.2 Hz, 1H), 7.31 (d, J = 9.2 Hz,
2H), 7.64 (d, J = 7.6 Hz, 1H), 12.81 (brs, 1H); 13C NMR (100 MHz,
CDCl3, TMS) δ 41.6, 55.6, 109.1, 114.7, 115.5, 117.5, 118.5, 121.4,
122.4, 125.5, 127.3, 131.4, 136.3, 139.7, 156.0, 161.9; HRMS (ESI)
Calcd for C18H17N3O2 requires (M+ + H): 308.1394, Found: 308.1394.
Compound 1e. Yield: 319 mg, 78%. A yellow solid. m.p.: 186−
188 °C. IR (neat) ν 3000, 2926, 2834, 1652, 1607, 1549, 1362, 1231,
80
d
16
0
80
e
17
0
80
a
Hydrazone 1 (0.1 mmol), MBH adduct 2a (0.3 mmol), and catalyst
(0.02 mmol) were stirred in 2 mL of solvents for 2 days. Yield of iso-
lated product. Determined by HPLC analysis on a chiral stationary
phase. [1a]0 = 0.1 M and 10 mol % of the catalyst loading. [1a]0 =
b
c
d
e
0.1 M and 5 mol % of the catalyst loading, and the reaction time is 1 week.
1
1165, 1039, 1011, 826, 812,781 cm−1; H NMR (400 MHz, CDCl3,
TMS) δ 3.82 (s, 3H), 5.16 (s, 2H), 6.82 (d, J = 8.0 Hz, 1H), 6.93 (d, J =
8.8 Hz, 2H), 7.07 (t, J = 7.2 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 7.34 (t, J =
9.2 Hz, 2H), 7.41−7.48 (m, 3H), 7.65 (d, J = 7.2 Hz, 1H), 7.74−7.81 (m,
4H), 12.88 (brs, 1H); 13C NMR (100 MHz, CDCl3, TMS) δ 43.4, 55.6,
109.3, 114.8, 115.6, 118.5, 121.6, 122.5, 125.1, 125.6, 125.97, 126.02,
126.3, 127.4, 127.7, 127.8, 128.8, 132.8, 133.28, 133.34, 136.4, 139.7,
156.1, 162.3; HRMS (ESI) Calcd for C26H21N3O2 requires (M+ + H):
408.1707, Found: 408.1706.
the solution was cooled to 0 °C. Then, a solution of sodium nitrite
(156 mg, 2.26 mmol) in water (0.67 mL) was slowly added with stirring
so that the temperature was maintained between 0 and 5 °C. The
solution of aryldiazonium salt was stirred at 0 °C for a further 2 h.
The solution of aryldiazonium salt was added dropwise to an
ethanolic (10 mL) suspension of 1-benzylindolin-2-one (536 mg,
2.26 mmol) and sodium hydroxide (678 mg in 2.7 mL of water) at 0 °C.
Then, the reaction mixture was allowed to stand at 0 °C until the
reaction was complete. The mixture was diluted with CH2Cl2 and
washed with water. The solvent was removed under reduced pressure,
and the residue was purified by column chromatography (silica gel, ethyl
acetate:petroleum ether = 1:2) to give the corresponding product 1o
(273 mg, 30%).
Procedure for the Synthesis of Hydrazone 1q. Compound 1q
was prepared by a previously reported procedure with slight
modification.15 To a stirred solution of pyridine (119 mg, 1.5 mmol)
in 2 mL of CH2Cl2 was added arylhydrazine hydrochloride (262 mg,
1.5 mmol). After the mixture was stirred for a further 30 min, ethyl-3,3,3-
trifluoropyruvate (255 mg, 1.5 mmol) was added. The reaction was
stirred for 18 h at room temperature before POCl3 (299 mg, 1.95 mmol)
and pyridine (154 mL, 1.95 mmol) were added dropwise sequentially.
The solution was stirred at room temperature for 18 h, before being
diluted with brine, the organic layer was separated, and the aqueous layer
was extracted with CH2Cl2. The solvent was removed under reduced
pressure, and the residue was purified by column chromatography
(silica gel, CH2Cl2:petroleum ether = 2:1) to give the corresponding
product 1q (216 mg, 50%).
Compound 1f. Yield: 250 mg, 67%. A yellow solid. m.p.: 164−
165 °C. IR (neat) ν 3007, 2914, 2838, 1663, 1616, 1594, 1561, 1520,
1483, 1435, 1349, 1230, 1183, 1125, 1110, 1039, 875, 826, 797 cm−1; 1H
NMR (400 MHz, CDCl3, TMS) δ 2.35 (s, 3H), 3.81 (s, 3H), 4.97 (s,
2H), 6.67 (d, J = 8.0 Hz, 1H), 6.91−6.97 (m, 3H), 7.25−7.33 (m, 7H),
7.47 (s, 1H), 12.83 (brs, 1H); 13C NMR (100 MHz, CDCl3, TMS) δ
21.1, 43.1, 55.6, 109.0, 114.8, 115.5, 119.1, 121.5, 125.7, 127.2, 127.6,
128.0, 128.8, 132.0, 136.0, 136.4, 137.6, 156.0, 162.3; HRMS (ESI)
Calcd for C23H21N3O2 requires (M+ + H): 372.1707, Found: 372.1704.
Compound 1g. Yield: 105 mg, 27%. A yellow solid. m.p.: 180−
182 °C. IR (neat) ν 3170, 3065, 2919, 2840, 1652, 1557, 1518, 1348,
1233, 1162, 1035, 829, 778 cm−1; 1H NMR (400 MHz, CDCl3, TMS) δ
3.81 (s, 3H), 4.96 (s, 2H), 6.66 (d, J = 8.8 Hz, 1H), 6.92 (d, J = 6.8 Hz,
2H), 7.07 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.25−7.34 (m, 7H), 7.58 (d, J =
1.6 Hz, 1H), 12.87 (brs, 1H); 13C NMR (100 MHz, CDCl3, TMS) δ
43.2, 55.5, 110.1, 114.8, 115.8, 118.5, 122.9, 124.3, 126.8, 127.2, 127.8,
128.0, 128.9, 135.5, 135.9, 137.8, 156.5, 162.0; HRMS (ESI) Calcd for
C22H18ClN3O2 requires (M+ + H): 392.1160, Found: 392.1156.
Compound 1h. Yield: 263 mg, 68%. A yellow solid. m.p.: 169−
172 °C. IR (neat) ν 3001, 2944, 2827, 1654, 1560, 1480, 1232, 1160,
1034, 859, 827 cm−1; 1H NMR (400 MHz, CDCl3, TMS) δ 3.80 (s, 3H),
3.81 (s, 3H), 4.95 (s, 2H), 6.65 (d, J = 8.8 Hz, 1H), 6.70 (dd, J = 8.8 Hz,
2.4 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 2.4 Hz, 1H), 7.24−7.33
(m, 7H), 12.88 (brs, 1H); 13C NMR (100 MHz, CDCl3, TMS) δ 43.1,
55.5, 55.8, 104.0, 109.8, 113.6, 114.7, 115.6, 122.4, 125.8, 127.2, 127.6,
Compound 1a. Yield: 370 mg, 74%. A yellow solid. m.p.: 120−
122 °C. IR (neat) ν 3061, 2996, 2831, 1668, 1611, 1565, 1515, 1468,
1
1375, 1215, 1176, 1093, 1034, 824, 780 cm−1; H NMR (400 MHz,
CDCl3, TMS) δ 3.31 (s, 3H), 3.82 (s, 3H), 6.88 (d, J = 8.0 Hz, 1H), 6.92
(d, J = 9.2 Hz, 2H), 7.11 (t, J = 7.6 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 7.31
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Table 2. Substrate Scope of the Asymmetric Allylic Alkylation of Hydrazones
a
b
c
entry
R1/R2/R3, PG, Ar
1b, H/H/H, Bn, PMP
R4/R5
2a, H/Et
yield (%)
ee (%)
1
2
3
3b, 83
3c, 70
3d, 82
3e, 31
3f, 85
3g, 82
3h, 75
3i, 80
3j, 84
3k, 91
3l, 82
3m, 64
3n, 71
3o, 75
3p, 81
3q, 50
3r, 50
85
87
89
93
90
86
91
90
77
90
92
80
90
68
72
86
87
1b, H/H/H, Bn, PMP
2b, H/Bn
1b, H/H/H, Bn, PMP
2c, H/neopentyl
2d, p-nitrophenyl/Et
2c, H/neopentyl
2c, H/neopentyl
2c, H/neopentyl
2c, H/neopentyl
2c, H/neopentyl
2c, H/neopentyl
2c, H/neopentyl
2c, H/neopentyl
2c, H/neopentyl
2c, H/neopentyl
2c, H/neopentyl
2c, H/neopentyl
2c, H/neopentyl
2a, H/Et
d
4
1b, H/H/H, Bn, PMP
5
6
1c, H/H/H, p-bromobenzyl, PMP
1d, H/H/H, allyl, PMP
7
1e, H/H/H, naphthyl, PMP
1f, Me/H/H, Bn, PMP
8
9
1g, Cl/H/H, Bn, PMP
10
11
12
13
14
15
16
17
18
1h, MeO/H/H, Bn, PMP
1i, H/Me/H, Bn, PMP
1j, H/Br/H, Bn, PMP
1k, H/Br/H, Bn, PMP
1l, Me/H/Me, Bn, PMP
1m, H/H/F, Bn, PMP
1n, H/H/H, Bn, 3,4-dimethoxyphenyl
1o, H/H/H, Bn, trimethoxyphenyl
1p, H/H/H, Me, dimethoxyphenyl
a
b
Hydrazone 1 (0.1 mmol), MBH adduct 2a (0.3 mmol), and catalyst (0.01 mmol) were stirred in 1 mL of EtOAc at 0 °C for 2 days. Yield of
c
d
isolated product. Determined by HPLC analysis on a chiral stationary phase. The dr value was determined by 1H NMR spectroscopic data of the
crude product.
Scheme 4. Asymmetric Allylic Alkylation of Ethyl Trifluoropyruvate-Derived Hydrazone
Scheme 5. Transformation of Chiral Azo Compounds Incorporating an Oxindole Scaffold
128.8, 133.6, 135.9, 136.3, 155.9, 156.1, 162.3; HRMS (ESI) Calcd for
C23H21N3O3 requires (M+ + H): 388.1656, Found: 388.1649.
Compound 1i. Yield: 222 mg, 60%. A yellow solid. m.p.: 168−
171 °C. IR (neat) ν 3004, 2931, 2836, 1667, 1615, 1564, 1517, 1439,
1383, 1236, 1143, 1080, 1024, 828, 809, 765 cm−1; 1H NMR (400 MHz,
CDCl3, TMS) δ 2.33 (s, 3H), 3.81 (s, 3H), 4.98 (s, 2H), 6.61 (s, 1H),
6.88−6.93 (m, 3H), 7.25−7.35 (m, 7H), 7.52 (d, J = 7.6 Hz, 1H), 12.76
(brs, 1H); 13C NMR (100 MHz, CDCl3, TMS) δ 22.1, 43.0, 55.6, 109.9,
114.7, 115.4, 118.4, 118.9, 123.3, 125.8, 127.1, 127.6, 128.8, 136.0, 136.5,
137.9, 140.0, 155.9, 162.5; HRMS (ESI) Calcd for C23H21N3O2 requires
(M+ + H): 372.1707, Found: 372.1704.
1.6 Hz, 1H), 7.26−7.36 (m, 7H), 7.48 (d, J = 8.0 Hz, 1H), 12.85 (brs,
1H); 13C NMR (100 MHz, CDCl3, TMS) δ 43.2, 55.6, 112.4, 114.8,
115.8, 119.6, 120.5, 120.6, 124.5, 125.4, 127.2, 127.9, 128.9, 135.4, 136.1,
140.5, 156.4, 162.1; HRMS (ESI) Calcd for C22H18BrN3O2 requires
(M+ + H): 436.0655, Found: 436.0651.
Compound 1k. Yield: 317 mg, 82%. A yellow solid. m.p.: 183−
184 °C. IR (neat) ν 3030, 2936, 2833, 1665, 1559, 1519, 1489, 1439,
1351, 1230, 1149, 1115, 1103, 1033, 1015, 824 cm−1; 1H NMR
(400 MHz, CDCl3, TMS) δ 2.23 (s, 3H), 2.31 (s, 3H), 3.79 (s, 3H), 5.22
(s, 2H), 6.72 (s, 1H), 6.90 (d, J = 8.8 Hz, 2H), 7.13−7.15 (m, 2H),
7.20−7.24 (m, 1H), 7.27−7.31 (m, 4H), 7.37 (s, 1H), 12.85 (brs, 1H);
13C NMR (100 MHz, CDCl3, TMS) δ 18.5, 20.8, 44.3, 55.5, 114.7,
115.5, 117.0, 119.8, 122.3, 125.60, 125.65, 127.2, 128.8, 132.0, 132.1,
135.6, 136.4, 137.7, 156.0, 162.9; HRMS (ESI) Calcd for C24H23N3O2
requires (M+ + H): 386.1863, Found: 386.1857.
Compound 1j. Yield: 316 mg, 72%. A yellow solid. m.p.: 196−
198 °C. IR (neat) ν 3004, 1673, 1599, 1581, 1557, 1515, 1225, 1150,
1105, 1022, 824, 813, 701 cm−1; 1H NMR (400 MHz, CDCl3, TMS) δ
3.82 (s, 3H), 4.96 (s, 2H), 6.91−6.93 (m, 3H), 7.20 (dd, J = 8.0 Hz,
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Compound 1l. Yield: 221 mg, 51%. A yellow solid. m.p.: 177−
178 °C. IR (neat) ν 3007, 2935, 2830, 1720, 1660, 1591, 1552, 1519,
1495, 1462, 1454, 1442, 1231, 1149, 1090, 1028, 1000 cm−1; 1H NMR
(400 MHz, CDCl3, TMS) δ 3.82 (s, 3H), 5.51 (s, 2H), 6.92 (d, J =
8.8 Hz, 2H), 6.96 (t, J = 7.6 Hz, 1H), 7.22−7.26 (m, 3H), 7.29−7.33 (m,
5H), 7.63 (d, J = 7.6 Hz, 1H), 12.93 (brs, 1H); 13C NMR (100 MHz,
CDCl3, TMS) δ 43.8, 55.6, 102.9, 114.8, 115.9, 117.4, 123.6, 124.1,
124.8, 126.3, 127.2, 128.6, 132.8, 135.9, 136.5, 137.5, 156.5, 162.7;
HRMS (ESI) Calcd for C22H18BrN3O2 requires (M+ + H): 436.0655,
Found: 436.0651.
products 5. To compound 5 (1.0 equiv) in CH2Cl2 was added dropwise
di-tert-butyl dicarbonate (1.0 equiv) and 4-dimethylaminopyridine
(0.05 equiv) in CH2Cl2 at 0 °C. The reaction naturally returned to rt and
was stirred overnight. The mixture was washed with saturated aqueous
NaHCO3 and brine and dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure, and the residue was purified by
column chromatography (silica gel, ethyl acetate:petroleum ether =
1:20) to give the corresponding products 2.
Compound 2b. Yield: 710 mg, 69%. A colorless liquid. IR (neat) ν
2981, 2945, 1743, 1456, 1395, 1369, 1302, 1278, 1256, 1154, 1099, 950,
859 cm−1; 1H NMR (400 MHz, CDCl3, TMS) δ 1.48 (s, 9H), 4.82 (s,
2H), 5.22 (s, 2H), 5.91 (s, 1H), 6.42 (s, 1H), 7.26−7.37 (s, 5H); 13C
NMR (100 MHz, CDCl3, TMS) δ 27.5, 64.5, 66.5, 82.2, 127.7, 127.9,
128.1, 128.4, 134.9, 135.4, 152.9, 164.6; HRMS (ESI) Calcd for
C16H20O5 requires (M+ + NH4): 310.1649, Found: 310.1643.
Compound 5c. Yield: 1.80 g, 86%. A colorless liquid. IR (neat) ν
3433, 2959, 2871, 1712, 1634, 1466, 1390, 1367, 1304, 1263, 1155,
1052, 944, 817 cm−1; 1H NMR (400 MHz, CDCl3, TMS) δ 0.98 (s, 9H),
2.33 (brs, 1H), 3.88 (s, 2H), 4.36 (d, J = 6.4 Hz, 2H), 5.85 (s, 1H), 6.28
(s, 1H); 13C NMR (100 MHz, CDCl3, TMS) δ 26.4, 31.4, 62.5, 74.1,
125.4, 139.5, 166.3; HRMS (ESI) Calcd for C9H16O3 requires
(M+ + Na): 195.0992, Found:195.0999.
Compound 1m. Yield: 231 mg, 62%. A yellow solid. m.p.: 160−
163 °C. IR (neat) ν 3032, 3001, 2935, 1659, 1552, 1519, 1494, 1463,
1
1454, 1231, 1168, 1149, 1090, 1000, 826, 789, 723 cm−1; H NMR
(400 MHz, CDCl3, TMS) δ 3.82 (s, 3H), 5.14 (s, 2H), 6.89−6.93 (m,
3H), 6.97−7.02 (m, 1H), 7.24−7.38 (m, 7H), 7.42 (d, J = 7.6 Hz, 1H),
12.93 (brs, 1H); 13C NMR (100 MHz, CDCl3, TMS) δ 44.9 (d, J =
4.4 Hz), 55.6, 114.3 (d, J = 3.0 Hz), 114.8, 115.0 (d, J = 19.4 Hz), 115.8,
123.0 (d, J = 6.8 Hz), 124.6 (d, J = 4.4 Hz), 124.9 (d, J = 4.3 Hz), 125.9
(d, J = 9.7 Hz), 127.5, 127.6, 128.6, 136.0, 137.0, 147.8 (d, J = 241.9 Hz),
156.4, 162.0; 19F NMR (376 MHz, CDCl3, CFCl3) δ −134.6 (dd,
J = 11.6 Hz, 4.5 Hz); HRMS (ESI) Calcd for C22H18FN3O2 requires
(M+ + H): 376.1456, Found: 376.1453.
Compound 1n. Yield: 357 mg, 92%. A yellow solid. m.p.: 156−
157 °C. IR (neat) ν 3231, 3059, 3000, 2903, 2833, 1664, 1602, 1553,
1465, 1231, 1197, 1165, 1041, 1028, 843, 780 cm−1; 1H NMR
(400 MHz, CDCl3, TMS) δ 3.89 (s, 3H), 3.96 (s, 3H), 5.01 (s, 2H),
6.80−6.88 (m, 3H), 7.07−7.11 (m, 2H), 7.17 (dt, J = 7.6 Hz, 0.8 Hz,
1H), 7.26−7.33 (m, 5H), 7.67 (d, J = 7.2 Hz, 1H), 12.88 (brs, 1H); 13C
NMR (100 MHz, CDCl3, TMS) δ 43.1, 55.9, 56.2, 98.6, 106.2, 109.2,
111.9, 118.6, 121.4, 122.5, 125.7, 127.2, 127.5, 127.7, 128.8, 135.9, 136.7,
139.7, 145.5, 150.0, 162.2; HRMS (ESI) Calcd for C23H21N3O3 requires
(M+ + H): 388.1656, Found: 388.1655.
Compound 1o. Yield: 273 mg, 30%. A yellow solid. m.p.: 177−
179 °C. IR (neat) ν 3000, 2935, 1768, 1595, 1571, 1514, 1498, 1466,
1415, 1164, 1129, 996 cm−1; 1H NMR (400 MHz, CDCl3, TMS) δ 3.84
(s, 3H), 3.91 (s, 6H), 5.01 (s, 2H), 6.62 (s, 2H), 6.82 (d, J = 7.6 Hz, 1H),
7.09 (t, J = 7.2 Hz, 1H), 7.19 (dt, J = 7.6 Hz, 1.2 Hz, 1H), 7.26−7.36 (m,
5H), 7.68 (d, J = 7.2 Hz, 1H), 12.85 (brs, 1H); 13C NMR (100 MHz,
CDCl3, TMS) δ 43.2, 56.1, 61.1, 91.7, 109.3, 118.9, 121.3, 122.6, 126.4,
127.3, 127.8, 127.9, 128.9, 134.1, 135.7, 138.8, 140.0, 154.1, 162.3;
HRMS (ESI) Calcd for C24H23N3O4 requires (M+ + H): 418.1761,
Found: 418.1765.
Compound 2c. Yield: 1.58 g, 56%. A colorless liquid. IR (neat) ν
1
2960, 1744, 1277, 1255, 1155, 1099, 949, 857, 792 cm−1; H NMR
(400 MHz, CDCl3, TMS) δ 0.97 (s, 9H), 1.50 (s, 9H), 3.87 (s, 2H), 4.82
(s, 2H), 5.88 (s, 1H), 6.40 (s, 1H); 13C NMR (100 MHz, CDCl3, TMS)
δ 26.5, 27.7, 31.4, 64.8, 74.2, 82.5, 127.4, 135.3, 153.0, 165.1; HRMS
(ESI) Calcd for C14H24O5 requires (M+ + NH4): 290.1962, Found:
290.1968.
General Procedure for the Asymmetric Allylic Alkylation of
Hydrazones. Hydrazone 1 (0.1 mmol), MBH adduct 2a (0.3 mmol),
and (DHQ)2AQN (0.01 mmol) were stirred in 1 mL of EtOAc at 0 °C
for 2 days until TLC showed that hydrazone 1 disappeared completely.
The solvent was removed under reduced pressure, and the residue
was purified by silica gel column chromatography using a CH2Cl2/
petroleum ether gradient mixture to give the corresponding products 3.
Compound 3a. Yield: 35 mg, 84%. A deep yellow oil. IR (neat) ν
2978, 2936, 2838, 1714, 1602, 1508, 1492, 1469, 1250, 1145, 1024, 839,
751 cm−1; 1H NMR (400 MHz, CDCl3, TMS) δ 1.12 (t, J = 7.2 Hz, 3H),
3.248 (s, 3H), 3.252 (d, J = 13.6 Hz, 1H), 3.69 (d, J = 13.6 Hz, 1H), 3.83
(s, 3H), 3.88−4.01 (m, 2H), 5.58 (s, 1H), 6.07 (s, 1H), 6.82 (d, J =
8.0 Hz, 1H), 6.90 (d, J = 9.2 Hz, 2H), 7.00 (t, J = 7.6 Hz, 1H), 7.28 (t, J =
7.2 Hz, 2H), 7.71 (d, J = 9.2 Hz, 2H); 13C NMR (100 MHz, CDCl3,
TMS) δ 14.0, 26.3, 35.0, 55.5, 60.7, 81.1, 108.1, 113.8, 122.2, 124.6,
126.3, 126.8, 128.4, 129.3, 135.4, 143.9, 145.8, 162.1, 166.9, 174.5;
HRMS (ESI) Calcd for C24H21N3O4 requires (M+ + H): 416.1605,
Found: 416.1587. Enantiomeric excess was determined by HPLC with a
Chiralcel AD-H column [λ = 230 nm; eluent: hexane/isopropanol =
70/30; flow rate: 0.50 mL/min; tminor = 12.26 min, tmajor = 16.47 min;
ee% = 80%; [α]2D0 = 63.0 (c 0.50, CH2Cl2)].
Compound 1p. Yield: 640 mg, 76%. A yellow solid. m.p.: 215−
218 °C. IR (neat) ν 2962, 2916, 2858, 1674, 1610, 1597, 1557, 1470,
1
1374, 1275, 1222, 1098, 1051, 799, 783, 764, 748 cm−1; H NMR
(400 MHz, CDCl3, TMS) δ 2.34 (s, 6H), 3.30 (s, 3H), 6.70 (s, 1H), 6.87
(d, J = 7.6 Hz, 1H), 7.00 (s, 2H), 7.11 (t, J = 7.6 Hz, 1H), 7.27 (t, J =
7.6 Hz, 1H), 7.66 (d, J = 7.2 Hz, 1H), 12.71 (brs, 1H); 13C NMR
(100 MHz, CDCl3, TMS) δ 21.4, 25.4, 108.3, 112.1, 118.7, 121.3, 122.4,
125.1, 126.5, 127.7, 139.2, 140.8, 142.5, 162.2; HRMS (ESI) Calcd for
C17H17N3O requires (M+ + H): 280.1444, Found: 280.1447.
Compound 3b. Yield: 39 mg, 83%. A deep yellow oil. IR (neat) ν
3061, 2932, 2839, 1716, 1602, 1585, 1507, 1487, 1466, 1360, 1251,
Compound 1q. Yield: 216 mg, 50%. A yellow solid. m.p.: 46−48 °C.
IR (neat) ν 3190, 2953, 2913, 2832, 1677, 1541, 1509, 1298, 1209, 1185,
1105, 1037, 1012, 834, 788 cm−1; 1H NMR (400 MHz, CDCl3, TMS) δ
1.37 (t, J = 7.2 Hz, 3H), 3.80 (s, 3H), 4.35 (q, J = 7.2 Hz, 2H), 6.90 (d, J =
9.2 Hz, 2H), 7.23 (d, J = 9.2 Hz, 2H), 12.64 (brs, 1H); 13C NMR
(100 MHz, CDCl3, TMS) δ 13.9, 55.3, 61.3, 114.6, 114.9 (q, J =
35.8 Hz), 116.4, 121.6 (q, J = 269.1 Hz), 135.2, 156.9, 161.8; 19F NMR
(376 MHz, CDCl3, CFCl3) δ −64.5; HRMS (ESI) Calcd for
C12H13F3N2O3 requires (M+ + H): 291.0951, Found: 291.0952.
Procedure for the Synthesis of MBH Adducts. Compounds 2a,
2d, and 5b are known compounds.16 Compounds 2b and 2c were
prepared by a previously reported procedure.16a Acrylate (3 equiv), 30%
of aqueous formaldehyde (1 equiv), and 1,4-diazabicyclo[2.2.2]octane
(1 equiv) were stirred in water and 1,4-dioxane at room temperature for
about 1 week. The mixture was extracted with ethyl ether. The organic
phase was washed with saturated aqueous NaHCO3 and brine, and dried
over anhydrous Na2SO4. The solvent was removed under reduced
pressure, and the residue was purified by column chromatography (silica
gel, ethyl acetate:petroleum ether = 1:2) to give the corresponding
1
1177, 1145, 1027, 838, 751, 696 cm−1; H NMR (400 MHz, CDCl3,
TMS) δ 1.09 (t, J = 7.2 Hz, 3H), 3.35 (d, J = 13.2 Hz, 1H), 3.80 (d, J =
13.2 Hz, 1H), 3.84 (s, 3H), 3.88−4.01 (m, 2H), 4.95 (d, J = 16.0 Hz,
1H), 4.99 (d, J = 16.0 Hz, 1H), 5.63 (s, 1H), 6.08 (s, 1H), 6.64 (d, J =
7.6 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.96 (t, J = 7.6 Hz, 1H), 7.13 (td,
J = 7.6 Hz, 0.8 Hz, 1H), 7.25−7.34 (m, 6H), 7.72 (d, J = 8.8 Hz, 2H); 13C
NMR (100 MHz, CDCl3, TMS) δ 14.0, 34.9, 43.7, 55.5, 60.7, 81.2,
109.2, 113.9, 122.2, 124.6, 126.3, 127.1, 127.2, 127.4, 128.6, 128.8, 129.2,
135.3, 135.4, 143.1, 145.7, 162.1, 167.0, 174.7; HRMS (ESI) Calcd for
C28H27N3O4 requires (M+ + Na): 492.1894, Found: 492.1903.
Enantiomeric excess was determined by HPLC with a Chiralcel AD-H
column [λ = 230 nm; eluent: hexane/isopropanol = 90/10; flow rate:
0.50 mL/min; tminor = 57.89 min, tmajor = 79.73 min; ee% = 85%; [α]D20
62.6 (c 0.50, CH2Cl2)].
=
Compound 3c. Yield: 37 mg, 70%. A deep yellow oil. IR (neat) ν
3063, 2961, 2918, 1716, 1602, 1585, 1507, 1466, 1360, 1257, 1174,
1145, 1028, 750, 696 cm−1; 1H NMR (400 MHz, CDCl3, TMS) δ 3.38
(d, J = 13.6 Hz, 1H), 3.83 (s, 3H), 3.84 (d, J = 13.6 Hz, 1H), 4.89−4.97
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(m, 4H), 5.67 (s, 1H), 6.13 (s, 1H), 6.63 (d, J = 8.0 Hz, 1H), 6.89−6.93
(m, 3H), 7.12 (td, J = 7.6 Hz, 0.8 Hz, 1H), 7.16−7.31 (m, 11H), 7.71 (d,
J = 9.2 Hz, 2H); 13C NMR (100 MHz, CDCl3, TMS) δ 34.9, 43.8, 55.5,
66.4, 81.2, 109.2, 113.9, 122.2, 124.6, 126.3, 127.0, 127.1, 127.4, 127.96,
128.01, 128.4, 128.6, 129.2, 129.4, 135.0, 135.4, 135.7, 143.1, 145.7,
162.2, 166.8, 174.7; HRMS (ESI) Calcd for C33H29N3O4 requires
(M+ + H): 532.2231, Found: 532.2236. Enantiomeric excess was
determined by HPLC with a Chiralcel AD-H column [λ = 230 nm;
(100 MHz, CDCl3, TMS) δ 26.4, 31.2, 34.9, 42.3, 55.5, 74.0, 81.1, 109.0,
113.8, 117.3, 122.2, 124.6, 126.4, 126.9, 128.3, 129.2, 131.1, 135.4, 143.2,
145.8, 162.1, 167.0, 174.3; HRMS (ESI) Calcd for C27H31N3O4 requires
(M+ + H): 462.2387, Found: 462.2396. Enantiomeric excess was
determined by HPLC with a Chiralcel AD-H column [λ = 230 nm;
eluent: hexane/isopropanol = 70/30; flow rate: 0.50 mL/min; tminor
=
10.26 min, tmajor = 11.77 min; ee% = 86%; [α]2D0 = 50.0 (c 0.50, CH2Cl2)].
Compound 3h. Yield: 42 mg, 75%. A deep yellow oil. IR (neat) ν
2957, 2869, 1717, 1602, 1508, 1487, 1466, 1029, 994, 838, 812,
750 cm−1; 1H NMR (400 MHz, CDCl3, TMS) δ 0.78 (s, 9H), 3.37 (d,
J = 13.6 Hz, 1H), 3.55 (d, J = 10.4 Hz, 1H), 3.59 (d, J = 10.4 Hz, 1H),
3.83 (s, 3H), 3.87 (d, J = 13.6 Hz, 1H), 5.07 (d, J = 15.6 Hz, 1H), 5.19 (d,
J = 15.6 Hz, 1H), 5.70 (s, 1H), 6.13 (s, 1H), 6.68 (d, J = 7.6 Hz, 1H),
6.91−6.96 (m, 3H), 7.09 (t, J = 7.6 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H),
7.43−7.47 (m, 3H), 7.73−7.81 (m, 6H); 13C NMR (100 MHz, CDCl3,
TMS) δ 26.3, 31.1, 34.8, 44.0, 55.5, 74.0, 81.3, 109.2, 113.9, 122.2, 124.6,
125.3, 125.9, 126.0, 126.2, 126.3, 127.0, 127.6, 127.7, 128.50, 128.53,
129.3, 132.7, 132.9, 133.2, 135.5, 143.1, 145.8, 162.2, 167.1, 174.8;
HRMS (ESI) Calcd for C35H35N3O4 requires (M+ + H): 562.2700,
Found: 562.2710. Enantiomeric excess was determined by HPLC with
a Chiralcel AD-H column [λ = 230 nm; eluent: hexane/isopropanol =
70/30; flow rate: 0.50 mL/min; tminor = 15.64 min, tmajor = 20.42 min;
ee% = 91%; [α]2D0 = 28.8 (c 0.50, CH2Cl2)].
eluent: hexane/isopropanol = 70/30; flow rate: 0.50 mL/min; tminor
=
43.86 min, tmajor = 53.45 min; ee% = 87%; [α]2D0 = 57.4 (c 0.50, CH2Cl2)].
Compound 3d. Yield: 42 mg, 82%. A deep yellow oil. IR (neat) ν
2957, 2869, 1716, 1602, 1585, 1508, 1487, 1466, 1364, 1251, 1176,
1145, 838, 750, 730, 696 cm−1; 1H NMR (400 MHz, CDCl3, TMS) δ
0.80 (s, 9H), 3.33 (d, J = 13.6 Hz, 1H), 3.55 (d, J = 10.4 Hz, 1H), 3.59 (d,
J = 10.4 Hz, 1H), 3.83 (s, 3H), 3.84 (d, J = 13.6 Hz, 1H), 4.93 (d, J =
16.0 Hz, 1H), 5.01 (d, J = 16.0 Hz, 1H), 5.65 (s, 1H), 6.09 (s, 1H), 6.65
(d, J = 8.0 Hz, 1H), 6.91 (d, J = 9.2 Hz, 2H), 6.95 (t, J = 7.2 Hz, 1H), 7.13
(t, J = 7.6 Hz, 1H), 7.23−7.34 (m, 6H), 7.72 (d, J = 9.2 Hz, 2H); 13C
NMR (100 MHz, CDCl3, TMS) δ 26.3, 31.1, 34.8, 43.8, 55.5, 74.0, 81.2,
109.1, 113.9, 122.2, 124.6, 126.3, 127.0, 127.2, 127.4, 128.4, 128.6, 129.2,
135.4, 135.5, 143.1, 145.7, 162.1, 167.1, 174.8; HRMS (ESI) Calcd
for C31H33N3O4 requires (M+ + H): 512.2544, Found: 512.2548.
Enantiomeric excess was determined by HPLC with a Chiralcel AD-H
column [λ = 230 nm; eluent: hexane/isopropanol = 70/30; flow rate:
Compound 3i. Yield: 42 mg, 80%. A deep yellow oil. IR (neat) ν
2956, 2925, 2855, 1721, 1603, 1508, 1497, 1254, 1168, 1146, 838, 808
cm−1; 1H NMR (400 MHz, CDCl3, TMS) δ 0.82 (s, 9H), 2.24 (s, 3H),
3.32 (d, J = 13.6 Hz, 1H), 3.54 (d, J = 10.4 Hz, 1H), 3.65 (d, J = 10.4 Hz,
1H), 3.83 (d, J = 13.6 Hz, 1H), 3.84 (s, 3H), 4.93 (d, J = 16.0 Hz, 1H),
4.98 (d, J = 16.0 Hz, 1H), 5.63 (s, 1H), 6.08 (s, 1H), 6.54 (d, J = 8.0 Hz,
1H), 6.92 (d, J = 8.8 Hz, 3H), 7.12 (s, 1H), 7.22−7.33 (m, 5H), 7.72 (d,
J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3, TMS) δ 21.0, 26.4, 31.2,
34.6, 43.8, 55.5, 74.0, 81.3, 108.9, 113.9, 124.6, 126.9, 127.1, 127.2,
127.4, 128.3, 128.5, 129.5, 131.7, 135.5, 135.6, 140.7, 145.8, 162.1, 167.2,
174.7; HRMS (ESI) Calcd for C32H35N3O4 requires (M+ + H):
526.2700, Found: 526.2707. Enantiomeric excess was determined by
HPLC with a Chiralcel AD-H column [λ = 230 nm; eluent: hexane/
0.50 mL/min; tminor = 23.78 min, tmajor = 16.45 min; ee% = 89%; [α]D20
56.2 (c 0.50, CH2Cl2)].
=
Compound 3e. Yield: 18 mg, 31%. A deep yellow oil. IR (neat) ν
3064, 2930, 2840, 1714, 1602, 1519, 1508, 1466, 1345, 1250, 1146,
1026, 839, 728 cm−1; 1H NMR (400 MHz, CDCl3, TMS) δ 1.16 (t, J =
7.2 Hz, 3H), 3.84 (s, 3H), 3.85 (s, 3H) (minor isomer), 4.00−4.14 (m,
2H), 4.80 (d, J = 15.6 Hz, 1H), 4.85 (d, J = 15.6 Hz, 1H), 5.60 (s, 1H)
(minor isomer), 5.65 (s, 1H), 5.68 (s, 1H) (minor isomer), 5.72 (s, 1H),
6.34 (s, 1H) (minor isomer), 6.42 (s, 1H), 6.66 (d, J = 8.4 Hz, 1H)
(minor isomer), 6.71 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 7.01
(t, J = 7.6 Hz, 0.8 Hz, 1H), 7.10−7.12 (m, 2H), 7.18−7.24 (m, 4H),
7.41−7.44 (m, 3H), 7.61 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.8 Hz, 2H)
(minor isomer), 7.95 (d, J = 9.2 Hz, 2H) (minor isomer), 8.00 (d, J =
9.2 Hz, 2H); 13C NMR (100 MHz, CDCl3, TMS) δ 14.0, 43.8, 49.8,
55.6, 61.4, 82.7, 109.5, 114.0, 122.5, 123.2, 124.7, 125.9, 127.3, 127.4,
127.6, 128.5, 129.7, 131.1, 135.2, 139.0, 142.8, 145.3, 145.6, 147.0, 162.4,
167.2, 173.8; HRMS (ESI) Calcd for C34H30N4O6 requires (M+ + H):
591.2238, Found: 591.2246. Enantiomeric excess was determined by
HPLC with a Chiralcel OD-H column [λ = 230 nm; eluent: hexane/
isopropanol = 90/10; flow rate: 0.50 mL/min; tminor = 17.67 min, tmajor
=
16.66 min; ee% = 90%; [α]2D0 = 24.1 (c 0.50, CH2Cl2)].
Compound 3j. Yield: 48 mg, 84%. A deep yellow oil. IR (neat) ν
2957, 2924, 2854, 1724, 1604, 1508, 1464, 1258, 1175, 1147, 1096,
1029, 804 cm−1; 1H NMR (400 MHz, CDCl3, TMS) δ 0.85 (s, 9H), 3.34
(d, J = 14.0 Hz, 1H), 3.56 (d, J = 10.8 Hz, 1H), 3.74 (d, J = 10.8 Hz, 1H),
3.81 (d, J = 14.0 Hz, 1H), 3.85 (s, 3H), 4.93 (d, J = 16.0 Hz, 1H), 4.98 (d,
J = 16.0 Hz, 1H), 5.66 (s, 1H), 6.11 (s, 1H), 6.55 (d, J = 8.4 Hz, 1H), 6.93
(d, J = 8.8 Hz, 2H), 7.09 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.24−7.34 (m,
6H), 7.73 (d, J = 9.2 Hz, 2H); 13C NMR (100 MHz, CDCl3, TMS) δ
26.3, 31.2, 34.9, 43.9, 55.5, 74.1, 81.1, 110.1, 114.0, 124.7, 126.8, 127.1,
127.6, 128.6, 128.7, 128.8, 129.2, 135.0, 135.1, 141.6, 145.6, 162.4, 166.9,
174.4; HRMS (ESI) Calcd for C31H32ClN3O4 requires (M+ + Na):
568.1974, Found: 568.1983. Enantiomeric excess was determined by
HPLC with a Chiralcel AD-H column [λ = 230 nm; eluent: hexane/
isopropanol = 80/20; flow rate: 0.50 mL/min; tminor = 36.42 min, tmajor
=
27.0 min; ee% = 93%; [α]2D0 = −32.0 (c 0.50, CH2Cl2)].
Compound 3f. Yield: 50 mg, 85%. A deep yellow oil. IR (neat) ν
2957, 2869, 1717, 1603, 1508, 1488, 1466, 1363, 1296, 1252, 1175,
1146, 1012, 838, 751 cm−1; 1H NMR (400 MHz, CDCl3, TMS) δ 0.81
(s, 9H), 3.34 (d, J = 13.2 Hz, 1H), 3.55 (d, J = 10.4 Hz, 1H), 3.59 (d, J =
10.4 Hz, 1H), 3.82 (d, J = 13.2 Hz, 1H), 3.84 (s, 3H), 4.88 (d, J = 16.0
Hz, 1H), 4.93 (d, J = 16.0 Hz, 1H), 5.65 (s, 1H), 6.09 (s, 1H), 6.61 (d, J =
7.6 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.97 (t, J = 7.6 Hz, 1H), 7.14 (t, J =
7.6 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 6.8 Hz, 1H), 7.43 (d,
J = 8.0 Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3,
TMS) δ 26.3, 31.1, 34.8, 43.2, 55.5, 74.0, 81.1, 108.9, 113.9, 121.4, 122.4,
124.6, 126.4, 127.0, 128.4, 129.0, 129.2, 131.7, 134.5, 135.4, 142.7, 145.7,
162.2, 167.0, 174.7; HRMS (ESI) Calcd for C31H32BrN3O4 requires
(M+ + H): 590.1649, Found: 590.1673. Enantiomeric excess was
determined by HPLC with a Chiralcel AD-H column [λ = 254 nm;
isopropanol = 90/10; flow rate: 0.50 mL/min; tminor = 26.46 min, tmajor
=
29.92 min; ee% = 77%; [α]2D0 = −6.7 (c 0.50, CH2Cl2)].
Compound 3k. Yield: 49 mg, 91%. A deep yellow oil. IR (neat) ν
2957, 2837, 1713, 1601, 1507, 1494, 1435, 1252, 1179, 1144, 1026, 838,
810, 730 cm−1; 1H NMR (400 MHz, CDCl3, TMS) δ 0.81 (s, 9H), 3.33
(d, J = 13.6 Hz, 1H), 3.57 (d, J = 10.8 Hz, 1H), 3.65 (d, J = 10.8 Hz, 1H),
3.71 (s, 3H), 3.82 (d, J = 13.6 Hz, 1H), 3.84 (s, 3H), 4.92 (d, J = 16.0 Hz,
1H), 4.98 (d, J = 16.0 Hz, 1H), 5.65 (s, 1H), 6.10 (d, J = 0.8 Hz, 1H),
6.54 (d, J = 8.4 Hz, 1H), 6.65 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 6.92 (d, J =
9.2 Hz, 2H), 6.95 (d, J = 2.8 Hz, 1H), 7.24−7.33 (m, 5H), 7.72 (d, J =
8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3, TMS) δ 26.3, 31.2, 34.7,
43.9, 55.5, 55.7, 74.0, 81.5, 109.5, 113.3, 113.9, 114.0, 124.6, 127.2,
127.4, 128.2, 128.4, 128.6, 135.4, 135.5, 136.4, 145.8, 155.5, 162.2,
167.1, 174.5; HRMS (ESI) Calcd for C32H35N3O5 requires (M+ + H):
542.2649, Found: 542.2654. Enantiomeric excess was determined by
HPLC with a Chiralcel AD-H column [λ = 230 nm; eluent: hexane/
eluent: hexane/isopropanol = 70/30; flow rate: 0.70 mL/min; tminor
=
11.63 min, tmajor = 16.49 min; ee% = 90%; [α]2D0 = 49.1 (c 0.50, CH2Cl2)].
Compound 3g. Yield: 38 mg, 82%. A deep yellow oil. IR (neat) ν
2957, 2869, 2839, 1710, 1603, 1585, 1505, 1488, 1466, 1360, 1178,
1029, 989, 838, 751 cm−1; 1H NMR (400 MHz, CDCl3, TMS) δ 0.83 (s,
9H), 3.28 (d, J = 13.6 Hz, 1H), 3.55 (d, J = 10.8 Hz, 1H), 3.58 (d, J = 10.8
Hz, 1H), 3.78 (d, J = 13.6 Hz, 1H), 3.83 (s, 3H), 4.28 (dd, J = 17.2 Hz,
4.8 Hz, 1H), 4.50 (dd, J = 17.2 Hz, 4.8 Hz, 1H), 5.19−5.27 (m,2H),
5.64(s, 1H), 5.78−5.87 (m,1H), 6.09 (s, 1H), 6.78 (d, J = 8.0 Hz, 1H),
6.90 (d, J = 9.2 Hz, 2H), 6.98 (t, J = 7.6 Hz, 1H), 7.22 (dt, J = 7.6 Hz,
0.8 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 9.2 Hz, 2H); 13C NMR
isopropanol = 90/10; flow rate: 0.50 mL/min; tminor = 53.77 min, tmajor
=
50.38 min; ee% = 90%; [α]2D0 = 18.3 (c 0.50, CH2Cl2)].
3525
dx.doi.org/10.1021/jo5003246 | J. Org. Chem. 2014, 79, 3519−3528

The Journal of Organic Chemistry
Article
Compound 3l. Yield: 43 mg, 82%. A deep yellow oil. IR (neat) ν
(d, J = 15.0 Hz), 55.5, 74.0, 81.1, 113.9, 117.4 (d, J = 59.4 Hz), 122.30,
122.33, 122.9 (d, J = 18.3 Hz), 124.7, 127.4, 127.5, 128.4, 128.8, 129.9,
134.9, 136.8, 145.6, 147.2 (d, J = 291.5 Hz), 162.3, 167.0, 174.5;
19F NMR (376 MHz, CDCl3, CFCl3) δ −133.8 (t, J = 7.2 Hz); HRMS
(ESI) Calcd for C31H32FN3O4 requires (M+ + Na): 552.2269, Found:
552.2272. Enantiomeric excess was determined by HPLC with a
Chiralcel IC column [λ = 230 nm; eluent: hexane/isopropanol = 80/20;
flow rate: 0.50 mL/min; tminor = 39.15 min, tmajor = 19.21 min; ee% =
72%; [α]2D0 = 58.1 (c 0.50, CH2Cl2)].
Compound 3q. Yield: 27 mg, 50%. A deep yellow oil. IR (neat) ν
2956, 2925, 2854, 1721, 1603, 1508, 1497, 1466, 1364, 1147, 1029 cm−1;
1H NMR (400 MHz, CDCl3, TMS) δ 0.80 (s, 9H), 3.33 (d, J = 13.6 Hz,
1H), 3.55 (d, J = 10.4 Hz, 1H), 3.59 (d, J = 10.4 Hz, 1H), 3.85 (d, J =
13.6 Hz, 1H), 3.91 (s, 3H), 3.93 (s, 3H), 4.93 (d, J = 16.0 Hz, 1H), 5.04
(d, J = 16.0 Hz, 1H), 5.65 (s, 1H), 6.08 (s, 1H), 6.66 (d, J = 8.0 Hz, 1H),
6.92 (d, J = 8.4 Hz, 1H), 6.96 (t, J = 7.2 Hz, 1H), 7.14 (dt, J = 8.0 Hz,
1.2 Hz, 1H), 7.24−7.34 (m, 7H), 7.46 (dd, J = 8.4 Hz, 2.0 Hz, 1H); 13C
NMR (100 MHz, CDCl3, TMS) δ 26.3, 31.2, 34.9, 43.9, 55.95, 56.05,
74.0, 81.2, 102.0, 109.2, 110.0, 120.5, 122.3, 126.4, 127.0, 127.3, 127.5,
128.4, 128.6, 129.3, 135.4, 135.5, 143.1, 145.7, 149.3, 152.0, 167.1,
174.8; HRMS (ESI) Calcd for C32H35N3O5 requires (M+ + H):
542.2649, Found: 542.2659. Enantiomeric excess was determined
by HPLC with a Chiralcel IC column [λ = 230 nm; eluent: hexane/
2957, 2869, 1716, 1620, 1602, 1507, 1374, 1251, 1146, 837, 810, 733,
1
697 cm−1; H NMR (400 MHz, CDCl3, TMS) δ 0.80 (s, 9H), 2.22
(s, 3H), 3.30 (d, J = 13.6 Hz, 1H), 3.54 (d, J = 10.4 Hz, 1H), 3.62 (d, J =
10.4 Hz, 1H), 3.82 (d, J = 13.6 Hz, 1H), 3.83 (s, 3H), 4.91 (d, J =
15.6 Hz, 1H), 4.99 (d, J = 15.6 Hz, 1H), 5.63 (d, J = 0.8 Hz, 1H), 6.07 (d,
J = 0.8 Hz, 1H), 6.48 (s, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.91 (d, J = 9.2 Hz,
2H), 7.19 (d, J = 7.6 Hz, 1H), 7.24−7.34 (m, 5H), 7.71 (d, J = 8.8 Hz,
2H); 13C NMR (100 MHz, CDCl3, TMS) δ 21.8, 26.3, 31.1, 34.7, 43.7,
55.5, 74.0, 81.1, 109.9, 113.8, 122.9, 124.0, 124.6, 126.1, 127.1, 127.4,
128.3, 128.6, 135.5, 135.6, 139.5, 143.2, 145.8, 162.1, 167.2, 175.1;
HRMS (ESI) Calcd for C32H35N3O4 requires (M+ + H): 526.2700,
Found: 526.2704. Enantiomeric excess was determined by HPLC with a
Chiralcel AD-H column [λ = 230 nm; eluent: hexane/isopropanol = 90/
10; flow rate: 0.50 mL/min; tminor = 32.91 min, tmajor = 16.42 min; ee% =
92%; [α]2D0 = 79.8 (c 0.50, CH2Cl2)].
Compound 3m. Yield: 38 mg, 64%. A deep yellow oil. IR (neat) ν
2957, 2869, 1716, 1601, 1507, 1484, 1430, 1370, 1252, 1175, 1145,
1029, 839, 730, 697 cm−1; 1H NMR (400 MHz, CDCl3, TMS) δ 0.81 (s,
9H), 3.31 (d, J = 13.6 Hz, 1H), 3.55 (d, J = 10.8 Hz, 1H), 3.62 (d, J =
10.8 Hz, 1H), 3.81 (d, J = 13.6 Hz, 1H), 3.85 (s, 3H), 4.88 (d, J = 16.0
Hz, 1H), 4.98 (d, J = 16.0 Hz, 1H), 5.66 (s, 1H), 6.08 (s, 1H), 6.79 (d, J =
2.0 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 7.09 (dd, J = 8.0 Hz, 1.6 Hz, 1H),
7.19 (d, J = 8.0 Hz, 1H), 7.26−7.36 (m, 5H), 7.70 (d, J = 9.2 Hz, 2H);
13C NMR (100 MHz, CDCl3, TMS) δ 26.3, 31.2, 34.8, 43.9, 55.5, 74.1,
80.9, 112.4, 114.0, 123.1, 124.7, 125.1, 125.8, 127.2, 127.7, 127.9,
128.7, 128.8, 134.9, 135.1, 144.5, 145.6, 162.3, 167.0, 174.6; HRMS
(ESI) Calcd for C31H32BrN3O4 requires (M+ + H): 590.1649, Found:
590.1672. Enantiomeric excess was determined by HPLC with a
Chiralcel IC column [λ = 230 nm; eluent: hexane/isopropanol = 80/20;
flow rate: 0.50 mL/min; tminor = 43.20 min, tmajor = 20.49 min; ee% =
80%; [α]2D0 = 64.4 (c 0.50, CH2Cl2)].
Compound 3n. Yield: 38 mg, 71%. A deep yellow oil. IR (neat) ν
2957, 2869, 1715, 1601, 1507, 1348, 1252, 1146, 1028, 997, 837,
732 cm−1; 1H NMR (400 MHz, CDCl3, TMS) δ 0.86 (s, 9H), 2.16 (s,
3H), 2.21 (s, 3H), 3.33 (d, J = 14.0 Hz, 1H), 3.57 (d, J = 10.8 Hz, 1H),
3.68 (d, J = 10.8 Hz, 1H), 3.84 (s, 3H), 3.86 (d, J = 14.0 Hz, 1H), 5.17 (d,
J = 16.8 Hz, 1H), 5.27 (d, J = 16.8 Hz, 1H), 5.64 (s, 1H), 6.13 (s, 1H),
6.71 (s, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.98 (s, 1H), 7.22−7.33 (m, 5H),
7.73 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3, TMS) δ 18.5,
20.7, 26.4, 31.2, 34.6, 45.1, 55.5, 74.0, 80.8, 113.8, 119.4, 124.60, 124.63,
125.8, 127.0, 127.9, 128.3, 128.6, 131.7, 133.8, 135.7, 137.5, 138.7, 145.8,
162.1, 167.3, 175.6; HRMS (ESI) Calcd for C33H37N3O4 requires (M+ +
H): 540.2857, Found: 540.2857. Enantiomeric excess was determined
by HPLC with a Chiralcel AD-H column [λ = 230 nm; eluent: hexane/
isopropanol = 80/20; flow rate: 0.50 mL/min; tminor = 85.82 min, tmajor
=
52.86 min; ee% = 86%; [α]2D0 = 67.8 (c 0.50, CH2Cl2)].
Compound 3r. Yield: 30 mg, 50%. A deep yellow oil. IR (neat) ν
2957, 2870, 1717, 1599, 1496, 1465, 1364, 1220, 1176, 1126, 1001, 847,
751, 732, 697 cm−1; 1H NMR (400 MHz, CDCl3, TMS) δ 0.80 (s, 9H),
3.33 (d, J = 13.6 Hz, 1H), 3.55 (d, J = 10.4 Hz, 1H), 3.59 (d, J = 10.4 Hz,
1H), 3.87 (d, J = 13.6 Hz, 1H), 3.88 (s, 3H), 3.91 (s, 6H), 4.92 (d, J =
15.6 Hz, 1H), 5.05 (d, J = 15.6 Hz, 1H), 5.65 (s, 1H), 6.08 (s, 1H), 6.68
(d, J = 8.4 Hz, 1H), 6.98 (t, J = 7.6 Hz, 1H), 7.05 (s, 2H), 7.16 (dd, J =
7.2 Hz, 6.8 Hz, 1H), 7.26−7.34 (m, 6H); 13C NMR (100 MHz, CDCl3,
TMS) δ 26.3, 31.2, 34.7, 43.9, 56.2, 61.0, 74.0, 81.5, 100.3, 109.2, 122.3,
126.4, 126.7, 127.3, 127.5, 128.5, 128.6, 129.4, 135.3, 135.4, 140.7, 143.2,
147.3, 153.3, 167.1, 174.5; HRMS (ESI) Calcd for C33H37N3O6 requires
(M+ + Na): 594.2575, Found: 594.2583. Enantiomeric excess was
determined by HPLC with a Chiralcel PA-2 column [λ = 230 nm;
eluent: hexane/isopropanol = 60/40; flow rate: 0.80 mL/min; tminor
=
35.86 min, tmajor = 24.76 min; ee% = 87%; [α]2D0 = 68.8 (c 0.50, CH2Cl2)].
Compound 3s. Yield: 36 mg, 82%. A deep yellow oil. IR (neat) ν
1
2960, 2843, 1747, 1719, 1603, 1509, 1253, 1144, 1029, 839 cm−1; H
NMR (400 MHz, CDCl3, TMS) δ 0.91 (s, 9H), 1.26 (t, J = 7.2 Hz, 3H),
3.44 (s, 2H), 3.71 (s, 2H), 3.87 (s, 3H), 4.22−4.30 (m, 2H), 5.67 (d, J =
0.8 Hz, 1H), 6.27 (d, J = 1.2 Hz, 1H), 6.96 (d, J = 8.8 Hz, 2H), 7.74 (d,
J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3, TMS) δ 13.9, 26.4, 31.3,
31.6, 55.6, 62.2, 74.3, 81.9 (q, J = 23.5 Hz), 114.1, 123.9 (q, J =
283.7 Hz), 125.1, 129.4, 134.6, 145.4, 163.0, 165.4, 166.9; 19F NMR
(376 MHz, CDCl3, CFCl3) δ −70.4; HRMS (ESI) Calcd for
C21H27F3N2O5 requires (M+ + H): 445.1945, Found: 445.1949.
Enantiomeric excess was determined by HPLC with a Chiralcel PC-2
column [λ = 230 nm; eluent: hexane/isopropanol = 24/1; flow rate:
isopropanol = 90/10; flow rate: 0.30 mL/min; tminor = 69.03 min, tmajor
=
59.54 min; ee% = 90%; [α]2D0 = 99.8 (c 0.50, CH2Cl2)].
Compound 3o. Yield: 44 mg, 75%. A deep yellow oil. IR (neat) ν
2957, 2927, 1717, 1601, 1507, 1462, 1449, 1345, 1252, 1166, 1146,
1027, 994, 838, 731 cm−1; 1H NMR (400 MHz, CDCl3, TMS) δ 0.87
(s, 9H), 3.33 (d, J = 13.6 Hz, 1H), 3.59 (d, J = 10.4 Hz, 1H), 3.63 (d, J =
10.4 Hz, 1H), 3.84 (s, 3H), 3.85 (d, J = 13.6 Hz, 1H), 5.38 (d, J =
16.8 Hz, 1H), 5.51 (d, J = 16.8 Hz, 1H), 5.62 (s, 1H), 6.10 (s, 1H), 6.85
(t, J = 8.0 Hz, 1H), 6.92 (d, J = 9.2 Hz, 2H), 7.24−7.33 (m, 7H), 7.71 (d,
J = 9.2 Hz, 2H); 13C NMR (100 MHz, CDCl3, TMS) δ 26.4, 31.2, 34.8,
44.7, 55.5, 74.1, 80.4, 102.2, 113.9, 123.5, 124.7, 125.6, 126.5, 126.9,
128.3, 129.0, 130.2, 134.9, 135.2, 137.3, 140.8, 145.6, 162.3, 167.0,
175.4; HRMS (ESI) Calcd for C31H32BrN3O4 requires (M+ + H):
590.1649, Found: 590.1676. Enantiomeric excess was determined
by HPLC with a Chiralcel IC column [λ = 230 nm; eluent: hexane/
0.50 mL/min; tminor = 15.05 min, tmajor = 13.44 min; ee% = 68%; [α]D20
−56.1 (c 0.50, CH2Cl2)].
=
Procedure for the Conversion of Product 3i. Compound 3i (115
mg, 0.22 mmol), N-hydroxybenzimidoyl chloride (51 mg, 0.33 mmol),
and Et3N (33 mg, 0.33 mmol) were stirred in 2 mL of CH2Cl2 at rt. The
solvent was removed under reduced pressure, and the residue was
purified by column chromatography (silica gel, ethyl acetate:petroleum
ether = 1:5) to give the major diastereoisomer of compound 4a (56 mg,
40%) and the minor diastereoisomer of compound 4a (28 mg, 20%).
Major Diastereoisomer of Compound 4a. Yield: 56 mg, 40%. A
yellow foam. m.p.: 88−90 °C. IR (neat) ν 2957, 2924, 2853, 1717, 1602,
1507, 1496, 1360, 1253, 1172, 1144, 1028, 838, 807, 759 cm−1; 1H NMR
(400 MHz, CDCl3, TMS) δ 0.89 (s, 9H), 2.21 (s, 3H), 3.40 (d, J =
14.4 Hz, 1H), 3.47 (d, J = 14.4 Hz, 1H), 3.50 (d, J = 17.2 Hz, 1H), 3.54
(d, J = 10.8 Hz, 1H), 3.71 (d, J = 10.8 Hz, 1H), 3.80 (d, J = 17.2 Hz, 1H),
3.83 (s, 3H), 4.76 (d, J = 16.0 Hz, 1H), 5.20 (d, J = 16.0 Hz, 1H), 6.57 (d,
J = 7.6 Hz, 1H), 6.87−6.90 (m, 3H), 7.09 (s, 1H), 7.27−7.37 (m, 6H),
7.43 (d, J = 7.2 Hz, 2H), 7.47−7.49 (m, 2H), 7.65 (d, J = 8.8 Hz, 2H);
isopropanol = 80/20; flow rate: 0.50 mL/min; tminor = 47.31 min, tmajor
=
20.34 min; ee% = 67%; [α]2D0 = 128.8 (c 0.50, CH2Cl2)].
Compound 3p. Yield: 43 mg, 81%. A deep yellow oil. IR (neat) ν
2957, 2869, 1717, 1628, 1601, 1507, 1473, 1344, 1249, 1187, 1146,
1029, 838, 730 cm−1; 1H NMR (400 MHz, CDCl3, TMS) δ 0.82 (s, 9H),
3.32 (d, J = 13.6 Hz, 1H), 3.56 (d, J = 10.4 Hz, 1H), 3.60 (d, J = 10.4 Hz,
1H), 3.82 (d, J = 13.6 Hz, 1H), 3.84 (s, 3H), 5.07 (d, J = 15.2 Hz, 1H),
5.13 (d, J = 15.2 Hz, 1H), 5.60 (s, 1H), 6.04 (s, 1H), 6.90−6.94 (m, 4H),
7.10−7.12 (m, 1H), 7.25−7.33 (m, 3H), 7.37−7.39 (m, 2H), 7.70 (d, J =
9.2 Hz, 2H); 13C NMR (100 MHz, CDCl3, TMS) δ 26.3, 31.2, 34.9, 45.4
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13C NMR (100 MHz, CDCl3, TMS) δ 21.0, 26.3, 31.4, 39.1, 41.9, 44.0,
55.5, 74.8, 78.8, 87.4, 109.3, 113.9, 124.6, 125.9, 126.7, 127.4, 127.5,
128.1, 128.5, 128.6, 128.9, 129.8, 130.1, 131.9, 135.6, 140.9, 145.5, 157.1,
162.3, 170.3, 174.7; HRMS (ESI) Calcd for C39H40N4O5 requires
(M+ + Na): 667.2891, Found: 667.2891. Enantiomeric excess was
determined by HPLC with a Chiralcel AD-H column [λ = 230 nm;
Chem. 2009, 44, 3922−3929. (c) Cassano, R.; Trombino, S.; Cilea, A.;
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35.22 min, tmajor = 30.00 min; ee% = 90%; [α]2D0 = 40.0 (c 1.00, CH2Cl2)].
Minor Diastereoisomer of Compound 4a. Yield: 28 mg, 20%. A
yellow foam. m.p.: 82−85 °C. IR (neat) ν 2958, 2923, 2853, 1724, 1602,
1585, 1507, 1497, 1360, 1254, 1174, 1146, 1028, 908, 806, 759 cm−1; 1H
NMR (400 MHz, CDCl3, TMS) δ 0.86 (s, 9H), 2.27 (s, 3H), 3.26 (d, J =
14.4 Hz, 1H), 3.51 (d, J = 10.0 Hz, 1H), 3.58 (d, J = 14.4 Hz, 1H), 3.66
(d, J = 17.2 Hz, 1H), 3.71 (d, J = 17.2 Hz, 1H), 3.74 (d, J = 10.0 Hz, 1H),
3.84 (s, 3H), 4.73 (d, J = 16.0 Hz, 1H), 5.14 (d, J = 16.0 Hz, 1H), 6.52 (d,
J = 8.0 Hz, 1H), 6.90−6.94 (m, 3H), 7.18 (s, 1H), 7.24−7.43 (m, 8H),
7.58−7.60 (m, 2H), 7.66 (d, J = 9.2 Hz, 2H); 13C NMR (100 MHz,
CDCl3, TMS) δ 21.0, 26.3, 31.3, 40.1, 44.0, 45.6, 55.5, 75.1, 78.9, 87.1,
109.3, 113.9, 124.8, 126.7, 126.8, 127.27, 127.28, 127.7, 128.57, 128.61,
128.9, 129.8, 130.2, 131.6, 135.7, 141.2, 145.6, 155.9, 162.2, 171.6,
175.2; HRMS (ESI) Calcd for C39H40N4O5 requires (M+ + Na):
667.2891, Found: 667.2895. Enantiomeric excess was determined by
HPLC with a Chiralcel OD-H column [λ = 230 nm; eluent: hexane/
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19.72 min; ee% = 90%; [α]2D0 = 31.3 (c 1.00, CH2Cl2)].
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectroscopic and analytic data of the
compounds 1a−1q, 3a−3s, 2b−2c, and 4a as well as X-ray
crystal data of 1i are included. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: mshi@mail.sioc.ac.cn. Fax: 86-21-64166128.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Shanghai Municipal Committee of Science and
Technology (11JC1402600), the National Basic Research
Program of China (973)-2010CB833302, the Fundamental
Research Funds for the Central Universities, and the National
Natural Science Foundation of China for financial support
(21072206, 20472096, 21102166, 21372241, 21302203,
21361140350, 20672127, 21121062, and 20732008).
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