Organocatalytic asymmetric branching sequence of MBH carbonates: Access to chiral benzofuran-2(3H)-one derivatives with three stereocenters

Article abstract of DOI:10.1002/cjoc.201200809

An organocatalytic asymmetric branching sequence was realized in the presence of 10 mol% of (DHQD)₂AQN, affording the sequential products with three stereocentres, including two quaternary carbon centres, in 47%-79% yields with 85%-99% ee.

Full text of DOI:10.1002/cjoc.201200809

FULL PAPER
DOI: 10.1002/cjoc.201200809
Organocatalytic Asymmetric Branching Sequence of MBH
Carbonates: Access to Chiral Benzofuran-2(3H)-one
Derivatives with Three Stereocenters
Zhu, Chuanle(竺传乐)
Yang, Lijun(杨丽军)
Nie, Jing(聂晶)
Zheng, Yan(郑艳)
Ma, Junan*(马军安)
Department of Chemistry, Tianjin University, Tianjin 300072, China
An organocatalytic asymmetric branching sequence was realized in the presence of 10 mol% of (DHQD)2AQN,
affording the sequential products with three stereocentres, including two quaternary carbon centres, in 47%—79%
yields with 85%—99% ee.
Keywords organocatalysis, Morita-Baylis-Hillman (MBH) carbonates, chloroaldoximes, branching sequences,
enantioselectivity
Introduction
Morita-Baylis-Hillman (MBH) carbonates have
emerged as a highly versatile and readily accessible
class of substrates.[6] These compounds contain multiple
reactive locations including an electrophilic site, a vi-
nylogous moiety, and an ester group. As such, develop-
ing convenient asymmetric methods for their synthetic
transformation is of considerable interest.[7] A goal in
our laboratory is the development of catalytic asymmet-
ric sequential transformations for the construction of
highly functionalized molecules.[8] We recently found
that chiral cinchona alkaloid can catalyze the asymmet-
ric allylic alkylation of 3-substituted benzofuran-2(3H)-
ones with MBH carbonates, to afford enantioenriched
benzofuranone derivatives, which could be further
transformed into highly functionalized products through
one-pot branching sequence (Figure 1). Herein, we dis-
close the successful implementation of this strategy to
generate benzofuranone derivatives with high enantio-
purity and significant opportunities for structural diver-
sification.
In diversity-oriented synthesis (DOS),[1] the
“branching pathway” is a simple and important ap-
proach to access the small-molecule collections. A
common substrate is transformed into diverse and dis-
tinct molecular scaffolds under the influence of different
reagents. The broad potential of this approach has been
embodied in the synthesis of numerous functionalized
compounds.[2] Over the past decade, the need for envi-
ronmentally friendly and metal-free reactions has led to
great progress in the small organic molecule-triggered
asymmetric reactions.[3] Accordingly, development of
the organocatalytic asymmetric branching sequence to
append different sets of building blocks to a common
molecular skeleton is highly desirable but very chal-
lenging. On the other hand, the combination of two or
more distinct reactions into a single pot is a very ap-
pealing strategy as it involves a multistep transforma-
tion that enables a rapid increase in molecular complex-
ity from readily available starting compounds.[4,5] The
significant advantage of these transformations is the
formation of several bonds and the creation of two or
more contiguous stereogenic centers in a single reaction
vessel, without the need for isolation of the intermedi-
ates. Furthermore, the increase in efficiency favors the
economic and ecological feasibility of this type of proc-
ess. Therefore, we envisage that the combination of
several very different transformations in organocatalytic
asymmetric branching sequences would provide an effi-
cient synthetic strategy for the rapid construction of
structurally diverse and complex chiral molecules.
Results and Discussion
Benzofuran-2(3H)-ones are important building blocks
that are found in a large variety of natural products, po-
tential medicines, and other highly functionalized com-
pounds.[9] Many of them feature a chiral quaternary
stereocenter at the C-3 position of the heterocyclic ring.
Catalytic enantioselective introduction of substituents at
the C-3 position represents the most direct approach to
chiral benzofuranones.[10] Recently, our group[11] pre-
sented a catalytic enantioselective amination of benzo-
*
E-mail: njtjuchem@gmail.com, majun_an68@tju.edu.cn; Tel.: 0086-022-27402903; Fax: 0086-022-27403475
Received August 9, 2012; accepted October 18, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200809 or from the author.
Chin. J. Chem. 2012, 30, 2693—2702
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Zhu et al.
FULL PAPER
R1
R2
OBoc O
R1
R2
Organocatalytic asymmetric
branching sequences
O
Ar
OMe
HO
O
N
O
Ar1
O
O
CO2Me
Ar1
Cl
Ar
H
N
Figure 1 Organocatalytic asymmetric branching sequence.
furanones by employing chiral P-spiro quaternary
phosphonium salts as organocatalysts, while Li, Cheng
and coworkers[12] described a cinchona alkaloid-cata-
lytic asymmetric allylic alkylation reaction of 3-substi-
tuted benzofuran-2(3H)-ones with MBH carbonates.
Encouraged by these important precedents, we surmised
that the combination of allylic alkylation of benzofuran-
2(3H)-ones with MBH carbonates and [3＋2] cycload-
dition with chlorinated aldoximes in one-pot asymmet-
ric branching sequences might be realized by using
suitable organocatalysts under mild reaction conditions.
We initiated our studies by evaluating the model reac-
tion between methyl MBH carbonate (1a) and 3-phenyl-
benzofuran-2(3H)-one (2a) using (DHQD)2AQN as or-
ganocatalyst in dichloroethane at 40 ℃.[13] After the
reaction is complete (48 h, detected by TLC), the mix-
ture was cooled at room temperature. Then, α-chloro-
benzaldoxime was added and stirred at the same tem-
perature for 24 h. We observed that allylic alkylation
intermediate constitutes the major product, whereas the
desired sequential product 3a is produced in low yield
(22%). In addition, a significant amount of α-chloro-
benzaldoxime was recovered in this case. These results
suggest that an extra base additive is necessary for rea-
sonable reaction rates of the subsequent [3＋2] cyclo-
addition step. Next, we decided to employ the triethyl-
amine as the additive. We were delighted to find that
one-pot sequential allylic alkylation/cycloaddition trans-
formation could be achieved to afford the major product
in 74% isolated yield with 93% ee and the minor prod-
uct 3a' in 16% yield with 80% ee, respectively (Scheme
1).
Based on the studies described above, we explored
the scope of this one-pot sequence using various MBH
carbonates 1, benzofuran-2(3H)-ones 2, and chloro-
aldoximes. Thus, in a single one-pot experiment, we
could prepare and isolate the focused products 3 with
three contiguous stereogenic centers (in all cases the
major products 3 were made without the isolation of
intermediates), and the results are summarized in Figure
2. The benzofuranone scope appeared to be exceedingly
broad. Electron-neutral, electron-withdrawing, and elec-
tron-donating groups as well as substrates substituted at
different positions on the aromatic rings were good sub-
strates. The desired products 3a—3m were obtained in
50%—78% yields with 85%—99% ee. Further explora-
tion of the substrate scope focused on the MBH carbon-
ates. It is also found that a series of aryl substitution
patterns on the MBH carbonate moiety can be tolerated,
and high stereocontrol (92%—99% ee) was observed
Scheme 1 Organocatalytic asymmetric branching sequence in one-pot
OBoc O
(1) (DHQD)2AQN (10 mol%)
ClCH2CH2Cl, 40 oC, 48 h
+
OMe
OH
Cl
O
(2)
N
(3 equiv.)
O
2a
4-BrC6H4
1a
Et3N ( 3 equiv.), 25 oC, 24 h
Br
Br
Br
Br
N
O
N
N
O
N
O
O
CO2Me
H
CO2Me
H
CO2Me
H
CO2Me
H
O
O
O
O
O
O
O
O
ent-3a
ent-3a'
3a
3a'
16% yield, 80% ee
74% yield, 93% ee
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Chin. J. Chem. 2012, 30, 2693—2702

Organocatalytic Asymmetric Branching Sequence of MBH Carbonates
OH
Ar1
Cl
Ar1
R2
R1
N
R1
N
OBoc O
O
(3 equiv.)
R2
(DHQD)2AQN (10 mol%)
ClCH2CH2Cl, 40 oC, 72 h
+
Et3N (3 equiv.), 25 oC
CO2Me
O
Ar
OMe
H
Ar
O
O
1
2
O
3
Br
Br
Br
Br
Br
N
O
N
O
N
N
O
N
O
O
CO2Me
H
CO2Me
H
CO2Me
H
CO2Me
H
CO2Me
H
Cl
Br
MeO
Me
O
O
O
O
O
O
O
O
O
O
3c
3a
3b
3d
3e
57%, 99% ee (dr 75/25)
74%, 93% ee (dr 80/20)
53%, 86% ee (dr 72/28)
71%, 86% ee (dr 78/22)
59%, 85% ee (dr 77/23)
Br
Br
Br
Br
Br
Br
N
N
N
N
O
N
O
O
O
O
CO2Me
H
CO2Me
H
CO2Me
H
CO2Me
H
CO2Me
H
O
O
O
O
O
O
O
O
O
O
Br
Cl
Me
MeO
3g
3h
3i
3j
3f
54%, 99% ee (dr 68/32)
78%, 85% ee (dr 85/15)
76%, 92% ee (dr 83/17) 65%, 92% ee (dr 70/30)
71%, 98% ee (dr 82/18)
Br
Br
Br
Br
Br
F
Cl
Me
N
N
O
N
O
N
O
N
O
O
CO2Me
H
CO2Me
H
CO2Me
H
CO2Me
H
CO2Me
H
O
O
O
O
O
O
O
O
O
O
OMe
Me
3k
3o
3m
3n
3l
57%, 91% ee (dr 67/23)
54%, 99% ee (dr 68/22)
50%, 99% ee (dr 65/35) 58%, 99% ee (dr 72/28)
76%, 88% ee (dr 83/17)
Br
Br
Br
Br
Br
N
O
N
N
N
N
O
O
O
CO2Me
H
O
CO2Me
H
CO2Me
H
CO2Me
H
CO2Me
H
OMe
O
O
O
O
O
O
O
O
Cl
O
NO2
O
Br
Cl
3s
3t
3p
3q
3r
55%, 99% ee (dr 70/30)
56%, 98% ee (dr 65/35)
71%, 92% ee (dr 79/21)
67%, 93% ee (dr 73/27) 47%, 85% ee (dr 55/45)
OMe
Cl
Me
N
O
N
N
N
O
N
O
O
O
CO2Me
H
CO2Me
H
CO2Me
H
CO2Me
H
CO2Me
H
Br
O
O
O
O
O
O
O
O
O
O
3x
73%, 94% ee (dr 82/18)
3u
3w
79%, 94% ee (dr 85/15)
3y
3v
76%, 93% ee (dr 82/18)
78%, 94% ee (dr 85/15)
66%, 99% ee (dr 75/25)
Figure 2 Scope of the organocatalyzed asymmetric branching sequence of MBH carbonates. Yield is the isolated yields of the major
products, dr values were determined by NMR analysis of the crude product, and the ee values were determined by chiral-phase HPLC
analysis.
Chin. J. Chem. 2012, 30, 2693—2702
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Zhu et al.
FULL PAPER
for the products (3n—3q, 3s, and 3t). It is noteworthy
that the MBH carbonate bearing 4-nitrophenyl group
could also be used as reaction partner to give the se-
quenced product 3r with 85% ee, albeit in lower iso-
lated yield due to decreased reactivity of the electrophile.
Finally, other 1,3-dipole precursors were evaluated for
the [3＋2] cycloaddition reaction. To our delight, the
desired products 3u—3x were obtained in good yield
with high enantioselectivity. The compound 3y proved
to be crystalline, allowing the determination of the ab-
solute configuration of three adjacent stereogenic cen-
ters to be (R,S,S) by means of X-ray crystallographic
analysis (Figure 3: top). In addition, it was found that
the collected crystals of the minor diastereomer 3y'
were racemates (Figure 3: bottom).[14]
synthesis. Further studies on the bioactivities of these
compounds are in progress.
Experimental
Materials
All purchased reagents were used without further
purification. Analytical thin layer chromatography was
performed on 0.20 mm Qingdao Haiyang silica gel
plates. Silica gel (200—300 mesh) (from Qingdao Hai-
yang Chem. Company, Ltd.) was used for flash chro-
matography. Cinchona alkaloids were purchased from
the Sigma-Aldrich.
1H and 13C NMR were recorded on a Bruker AV 400
MHz spectrometer at 400 MHz (1H) and 100 MHz (13C).
Chemical shifts were reported using the solvent reso-
nance as the internal standard (CDCl3: δH＝7.26, δC＝
77.16). High resolution mass spectrometry (HRMS)
spectra were obtained on a MICROTOF-QII Instrument.
Optical rotations were determined using an Autopol IV
automatic polarimeter. IR spectra were recorded on an
AVATAR 360 FT-IR spectrometer. HPLC analyses
were carried out on a Hewlett Packard Model HP 1200
instrument. Melting points were measured on a
WRS-1A digital melting point apparatus and uncor-
rected. X-ray structural analysis was conducted on the
XtaLAB mini (600 W, SHINE, CCD, 75 mm, 0.1 elec-
torns/pixel/sec).
Gerenal procedure for organocatalytic asymmetric
allylic alkylation/[3＋2] cycloaddition sequence
Benzofuran-2(3H)-one 1 (0.1 mmol), Morita-Baylis-
Hillman carbonate
2 (0.12 mmol) and catalyst
(DHQD)2AQN (8.6 mg, 10 mol%) were stirred in DCE
(1 mL) at 40 ℃ for 72 h. The reaction mixture was
cooled to the room temperature, a solution of α-chloro-
benzaldoxime (0.3 mmol) in anhydrous DCE (1 mL)
and triethylamine (30.4 mg, 0.3 mmol) were added or-
derly. The mixture was stirred at the same temperature
for 24 h. Then the reaction was quenched with water (10
mL) and the organic layer was separated. The aqueous
layer was extracted with DCM (5 mL×3). The com-
bined organic layers were dried with anhydrous Na2SO4
and concentrated. The residue was purified by the flash
chromatography on silica gel to afford sequential prod-
uct 3 as a white solid.
Figure 3 X-ray structures of 3y, 3y' and ent-3y'.
(R)-Methyl 3-(4-bromophenyl)-5-((S)-((S)-2-oxo-3-
phenyl-2,3-dihydrobenzofuran-3-yl)(phenyl)methyl)-
4,5-dihydroisoxazole-5-carboxylate (3a): White solid,
74% yield; m.p. 171—73 ℃; [α]2D0 －76.0 (c 1.0,
CH2Cl2); 93% ee, determined by HPLC analysis [Daicel
chiralcel AD-H, V(n-hexane)∶V(i-PrOH)＝70∶30, 0.8
mL/min, 254 nm UV detector, tmajor＝18.2 min, tminor＝
Conclusions
In summary, a method for the organocatalytic
asymmetric branching sequence has been successfully
developed. Key to the success included the integration
of two distinct transformations into a single reaction
vessel. In the presence of chiral biscinchona alkaloid,
this promising process can be carried out under mild
conditions to afford the sequential products in respect-
able yields with high enantioselectivities (up to 99% ee)
from simple starting materials. This strategy will be
useful in medicinal chemistry and diversity-oriented
1
14.1 min]; H NMR (400 MHz, CDCl3) δ: 8.46 (d, J＝
7.2 Hz, 1H), 7.93 (d, J＝7.2 Hz, 2H), 7.46 (d, J＝8.0 Hz,
2H), 7.33—7.41 (m, 2H), 7.10—7.23 (m, 10H), 6.89 (d,
J＝7.6 Hz, 1H), 4.78 (s, 1H), 3.29 (d, J＝18.0 Hz, 1H),
3.20 (s, 3H), 2.97 (d, J＝18.0 Hz, 1H); 13C NMR (100
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Chin. J. Chem. 2012, 30, 2693—2702

Organocatalytic Asymmetric Branching Sequence of MBH Carbonates
MHz, CDCl3) δ: 176.4, 172.1, 156.4, 153.2, 135.1,
134.9, 131.8, 130.8, 129.7, 128.8, 128.5, 128.1, 128.0,
127.7, 127.2, 126.2, 124.8, 123.9, 110.8, 91.8, 60.3,
58.1, 52.5, 43.9; IR (KBr) ν: 3062, 2948, 1795, 1730,
1592, 1490, 1458, 1399, 1361, 1290, 1242, 1189, 1136,
1072, 1008, 906, 825, 756 cm ; HRMS (APCI) calcd
for C32H24BrNO5 ＋H [M ＋H] ＋ 582.0838, found
582.0398.
3H), 2.94 (d, J＝18.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ: 175.9, 172.0, 156.4, 151.5, 134.8, 134.2,
132.0, 131.8, 130.9, 129.8, 129.3, 128.9, 128.7, 128.4,
128.1, 127.9, 127.8, 127.1, 124.9, 111.9, 91.7, 60.9,
58.2, 52.5, 44.3; IR (KBr) ν: 3065, 2952, 1799, 1733,
1595, 1493, 1467, 1358, 1296, 1261, 1242, 1193, 1137,
1074, 1039, 1008, 874, 822, 705 cm ; HRMS (APCI)
calcd for C32H22BrClNO5 ＋H [M＋H]＋ 618.0428,
found 618.0484.
－
1
－
1
Methyl 3-(4-bromophenyl)-5-(2-oxo-3-phenyl-2,3-
dihydrobenzofuran-3-yl)(phenyl)methyl)-4,5-dihydro-
isoxazole-5-carboxylate (3a'): White solid, 16% yield;
m.p. 193—195 ℃; [α]2D0 9.3 (c 1.0, CH2Cl2); 80% ee,
determined by HPLC analysis [Daicel chiralcel AD-H,
V(n-hexane)∶V(i-PrOH)＝70∶30, 0.8 mL/min, 254
(R)-Methyl 3-(4-bromophenyl)-5-((S)-((S)-5-methyl-
2-oxo-3-phenyl-2,3-dihydrobenzofuran-3-yl)(phenyl)-
methyl)-4,5-dihydroisoxazole-5-carboxylate
(3d):
White solid, 71% yield; m.p. 213—215 ℃; [α]D20
－42.0 (c 1.0, CH2Cl2); 86% ee, determined by HPLC
analysis [Daicel chiralcel IA-H, V(n-hexane) ∶
V(i-PrOH)＝80∶20, 1.0 mL/min, 254 nm UV detector,
tmajor＝10.9 min, tminor＝11.9 min]; 1H NMR (400 MHz,
CDCl3) δ: 8.21 (s, 1H), 7.91 (d, J＝7.2 Hz, 2H), 7.47 (d,
J＝8.4 Hz, 2H), 7.13—7.25 (m, 11H), 6.79 (d, J＝8.4
Hz, 1H), 4.77 (s, 1H), 3.31 (d, J＝18.0 Hz, 1H), 3.20 (s,
3H), 3.02 (d, J＝18.0 Hz, 1H), 2.57 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ: 176.6, 172.2, 156.4, 151.1, 135.4,
135.0, 133.3, 131.8, 130.8, 130.1, 128.7, 128.5, 128.4,
128.1, 127.9, 127.6, 127.3, 126.1, 124.7, 110.4, 91.8,
60.4, 57.9, 52.5, 43.7, 21.7; IR (KBr) ν: 3065, 2948,
1790, 1729, 1595, 1487, 1440, 1358, 1300, 1259, 1236,
1
nm UV detector, tmajor＝37.5 min, tminor＝27.8 min]; H
NMR (400 MHz, CDCl3) δ: 7.46—7.52 (m, 5H), 7.37—
7.41 (m, 2H), 7.18—7.26 (m, 6H), 7.10—7.14 (m, 4H),
7.02 (d, J＝8.0 Hz, 1H), 4.85 (s, 1H), 3.92 (d, J＝18.0
Hz, 1H), 3.67 (d, J＝18.0 Hz, 1H), 3.35 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ: 177.5, 171.3, 155.4, 152.9,
136.8, 135.1, 131.9, 131.1, 130.9, 129.4, 128.4, 128.2,
128.2, 128.1, 128.0, 127.7, 124.7, 123.6, 111.0, 91.2,
58.6, 57.5, 52.8, 43.0; IR (KBr) ν: 3066, 2951, 1794,
1731, 1590, 1488, 1460, 1401, 1360, 1289, 1241, 1193,
－
1
1140, 1067, 1006, 893, 824, 756 cm ; HRMS (APCI)
calcd for C32H24BrNO5＋H [M＋H]＋ 582.0838, found
582.0398.
－
1
1193, 1150, 1073, 1040, 1009, 874, 820, 705 cm ;
HRMS (APCI) calcd for C33H25BrNO5＋H [M＋H]＋
598.0974, found 598.1051.
(R)-Methyl 5-((S)-((S)-5-bromo-2-oxo-3-phenyl-2,3-
dihydrobenzofuran-3-yl)(phenyl)methyl)-3-(4-bromo-
phenyl)-4,5-dihydroisoxazole-5-carboxylate (3b): White
solid, 53% yield; m.p. 231—233 ℃; [α]2D0 －116.0 (c
1.0, CH2Cl2); 86% ee, determined by HPLC analysis
[Daicel chiralcel IA-H, V(n-hexane)∶V(i-PrOH)＝90∶
10, 1.0 mL/min, 254 nm UV detector, tmajor＝19.5 min,
(R)-Methyl 3-(4-bromophenyl)-5-((S)-((S)-5-meth-
oxy-2-oxo-3-phenyl-2,3-dihydrobenzofuran-3-yl)(phe-
nyl)methyl)-4,5-dihydroisoxazole-5-carboxylate (3e):
White solid, 49% yield; m.p. 215—217 ℃; [α]D20
－70.9 (c 1.0, CH2Cl2); 85% ee, determined by HPLC
analysis [Daicel chiralcel IA-H, V(n-hexane) ∶
V(i-PrOH)＝80∶20, 1.0 mL/min, 254 nm UV detector,
tmajor＝13.8 min, tminor＝15.2 min]; 1H NMR (400 MHz,
CDCl3) δ: 8.01 (s, 1H), 7.92 (d, J＝6.4 Hz, 2H), 7.46 (d,
J＝8.0 Hz, 2H), 7.15—7.24 (m, 10H), 6.91 (d, J＝8.4
Hz, 1H), 6.82 (d, J＝8.8 Hz, 1H), 4.78 (s, 1H), 3.99 (s,
3H), 3.31 (d, J＝18.0 Hz, 1H), 3.22 (s, 3H), 3.02 (d,
J＝18.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 176.7,
172.1, 156.4, 156.2, 147.2, 135,3, 135.0, 131.8, 128.8,
128.4, 128.0, 127.7, 127.7, 127.3, 126.8, 124.8, 116.4,
115.3, 111.1, 91.9, 60.8, 57.9, 56.2, 52.5, 43.6; IR (KBr)
ν: 3067, 2929, 1791, 1730, 1597, 1486, 1433, 1357,
1293, 1271, 1231, 1197, 1139, 1073, 1038, 1009, 875,
1
tminor＝20.9 min]; H NMR (400 MHz, CDCl3) δ: 8.64
(s, 1H), 7.88 (d, J＝7.2 Hz, 2H), 7.47 (d, J＝8.4 Hz,
3H), 7.15—7.25 (m, 10H), 6.77 (d, J＝8.4 Hz, 1H),
4.76 (s, 1H), 3.30 (d, J＝18.0 Hz, 1H), 3.22 (s, 3H),
2.96 (d, J＝18.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ: 175.7, 172.0, 156.4, 152.0, 134.8, 134.2, 133.5, 132.8,
132.0, 131.8, 128.9, 128.7, 128.4, 128.1, 128.1, 127.8,
127.1, 124.7, 116.7, 112.3, 91.7, 60.8, 58.2, 52.5, 44.2;
IR (KBr) ν: 3063, 2949, 1797, 1730, 1600, 1492, 1461,
1441, 1358, 1297, 1264, 1191, 1142, 1072, 1037, 1006,
873, 822, 705 cm － 1; HRMS (APCI) calcd for
＋
C32H23Br2NO5 ＋ H [M ＋ H]
661.9923, found
662.0060.
－
1
(R)-Methyl 3-(4-bromophenyl)-5-((S)-((S)-5-chloro-
2-oxo-3-phenyl-2,3-dihydrobenzofuran-3-yl)(phenyl)-
methyl)-4,5-dihydroisoxazole-5-carboxylate (3c): White
solid, 57% yield; m.p. 243—245 ℃; [α]2D0 －49.1 (c
1.0, CH2Cl2); 99% ee, determined by HPLC analysis
[Daicel chiralcel AD-H, V(n-hexane)∶V(i-PrOH) ＝
70∶30, 0.8 mL/min, 254 nm UV detector, tmajor＝14.9
823, 706 cm ; HRMS (APCI) calcd for C33H25BrNO6＋
H [M＋H]＋ 614.0923, found 614.0906.
(R)-Methyl 5-((S)-((S)-6-bromo-2-oxo-3-phenyl-2,3-
dihydrobenzofuran-3-yl)(phenyl)methyl)-3-(4-bromo-
phenyl)-4,5-dihydroisoxazole-5-carboxylate (3f): White
solid, 71% yield; m.p. 210—212 ℃; [α]2D0 －79.4 (c
1.0, CH2Cl2); 98% ee, determined by HPLC analysis
[Daicel chiralcel IA-H, V(n-hexane)∶V(i-PrOH)＝80∶
20, 1.0 mL/min, 254 nm UV detector, tmajor＝33.8 min,
1
min]; H NMR (400 MHz, CDCl3) δ: 8.53 (s, 1H), 7.91
(d, J＝6.8 Hz, 2H), 7.48 (d, J＝8.4 Hz, 2H), 7.32 (d,
J＝8.4 Hz, 1H), 7.16—7.25 (m, 10H), 6.82 (d, J＝8.4
Hz, 1H), 4.77 (s, 1H), 3.30 (d, J＝18.0 Hz, 1H), 3.22 (s,
1
tminor＝17.6 min]; H NMR (400 MHz, CDCl3) δ: 8.39
(d, J＝8.4 Hz, 1H), 7.88 (d, J＝6.8 Hz, 2H), 7.52 (d,
Chin. J. Chem. 2012, 30, 2693—2702
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
2697

Zhu et al.
FULL PAPER
J＝8.0 Hz, 1H), 7.47 (d, J＝8.0 Hz, 2H), 7.06—7.23 (m,
11H), 4.76 (s, 1H), 3.28 (d, J＝18.0 Hz, 1H), 3.21 (s,
3H), 2.93 (d, J＝18.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ: 175.8, 171.9, 156.5, 153.5, 134.8, 134.3,
132.2, 131.8, 128.9, 128.7, 128.4, 128.2, 128.1, 127.8,
127.1, 127.0, 125.3, 124.9, 122.9, 114.4, 91.7, 60.4,
58.2, 52.5, 44.3; IR (KBr) ν: 3061, 2951, 1804, 1761,
1733, 1608, 1494, 1475, 1447, 1401, 1258, 1192, 1093,
CDCl3) δ: 8.33 (d, J＝8.8 Hz, 1H), 7.91 (d, J＝6.8 Hz,
2H), 7.46 (d, J＝8.4 Hz, 2H), 6.91—7.23 (m, 11H),
6.45 (d, J＝3.2 Hz, 1H), 4.74 (s, 1H), 3.82 (s, 1H), 3.30
(d, J＝18.0 Hz, 1H), 3.19 (s, 3H), 2.96 (d, J＝18.4 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ: 176.7, 172.1,
160.8, 156.4, 154.2, 135.6, 135.2, 131.7, 131.4, 128.7,
128.5, 128.4, 128.1, 127.9, 127.7, 127.3, 124.7, 117.5,
110.0, 96.9, 91.9, 60.0, 58.2, 55.6, 52.5, 43.8; IR (KBr)
ν: 3060, 2951, 1793, 1761, 1734, 1629, 1592, 1499,
1447, 1359, 1288, 1260, 1158, 1092, 1073, 1010, 967,
－
1
1059, 1010, 912, 824, 702 cm ; HRMS (APCI) calcd
for C32H23Br2NO5 ＋H [M ＋H] ＋ 661.9923, found
661.9980.
－
1
825, 705 cm ; HRMS (APCI) calcd for C33H25BrNO6＋
(R)-Methyl 3-(4-bromophenyl)-5-((S)-((S)-6-chloro-
2-oxo-3-phenyl-2,3-dihydrobenzofuran-3-yl)(phenyl)-
methyl)-4,5-dihydroisoxazole-5-carboxylate (3g): White
solid, 54% yield; m.p. 228—230 ℃; [α]2D0 －140.1 (c
1.0, CH2Cl2); 94% ee, determined by HPLC analysis
[Daicel chiralcel IA-H, V(n-hexane)∶V(i-PrOH)＝80∶
20, 1.0 mL/min, 254 nm UV detector, tmajor＝25.3 min];
1H NMR (400 MHz, CDCl3) δ: 8.45 (d, J＝8.4 Hz, 1H),
7.89 (d, J＝6.8 Hz, 2H), 7.47 (d, J＝8.4 Hz, 2H), 7.37
(d, J＝8.0 Hz, 1H), 7.15—7.23 (m, 10H), 6.91 (s, 1H),
4.76 (s, 1H), 3.28 (d, J＝18.4 Hz, 1H), 3.21 (s, 3H),
2.93 (d, J＝18.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ: 175.9, 171.9, 156.5, 153.5, 135.2, 134.8, 134.4, 131.9,
131.8, 128.9, 128.7, 128.2, 128.1, 127.8, 127.1, 124.9,
124.7, 124.1, 111.6, 91.7, 60.4, 58.3, 52.5, 44.3; IR
(KBr) ν: 3063, 2954, 1798, 1761, 1733, 1604, 1484,
1444, 1409, 1287, 1257, 1182, 1095, 1068, 1009, 917,
825, 703 cm－1; HRMS (APCI) calcd for C32H23Br-
ClNO5＋H [M＋H]＋ 618.0428, found 618.0487.
(R)-Methyl 3-(4-bromophenyl)-5-((S)-((S)-6-methyl-
2-oxo-3-phenyl-2,3-dihydrobenzofuran-3-yl)(phenyl)-
H [M＋H]＋ 614.0923, found 614.0973.
(R)-Methyl 3-(4-bromophenyl)-5-((S)-((S)-3-(4-bro-
mophenyl)-2-oxo-2,3-dihydrobenzofuran-3-yl)(phenyl)-
ethyl)-4,5-dihydroisoxazole-5-carboxylate (3j): White
solid, 65% yield; m.p. 232—233 ℃;[α]2D0 53.8 (c 1.0,
CH2Cl2); 92% ee, determined by HPLC analysis [Daicel
chiralcel AD-H, V(n-hexane)∶V(i-PrOH)＝70∶30, 0.8
mL/min, 254 nm UV detector, tmajor＝25.7 min, tminor＝
1
19.7 min]; H NMR (400 MHz, CDCl3) δ: 8.45 (d, J＝
7.2 Hz, 1H), 7.80 (d, J＝7.6 Hz, 2H), 7.52 (d, J＝8.4 Hz,
2H), 7.31—7.41 (m, 3H), 6.88—7.20 (m, 9H), 4.70 (s,
1H), 3.37 (d, J＝18.0 Hz, 1H), 3.22 (s, 3H), 3.08 (d, J＝
18.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 176.2,
171.8, 156.2, 153.1, 134.7, 134.0, 132.0, 131.8, 130.7,
130.4, 129.9, 128.1, 128.0, 127.7, 127.0, 125.8, 125.0,
124.0, 123.0, 110.9, 91.6, 60.0, 58.9, 52.5, 44.6; IR
(KBr) ν: 3060, 2950, 1791, 1735, 1593, 1487, 1457, 1358,
1288, 1237, 1185, 1143, 1078, 1042, 1010, 908, 828, 706
－
1
cm ; HRMS (APCI) calcd for C32H23Br2NO5＋H [M＋
H]＋ 661.9923, found 662.0136.
(R)-Methyl 3-(4-bromophenyl)-5-((S)-((S)-3-(4-chlo-
rophenyl)-2-oxo-2,3-dihydrobenzofuran-3-yl)(phenyl)-
methyl)-4,5-dihydroisoxazole-5-carboxylate
(3h):
White solid, 78% yield; m.p. 219—221 ℃; [α]D20
－68.1 (c 1.0, CH2Cl2); 85% ee, determined by HPLC
analysis [Daicel chiralcel IA-H, V(n-hexane) ∶
V(i-PrOH)＝80∶20, 1.0 mL/min, 254 nm UV detector,
tmajor＝38.5 min, tminor＝15.9 min]; 1H NMR (400 MHz,
CDCl3) δ: 8.30 (d, J＝8.0 Hz, 1H), 7.91 (d, J＝6.8 Hz,
2H), 7.46 (d, J＝8.4 Hz, 2H), 6.72—7.23 (m, 11H),
6.72 (s, 1H), 4.76 (s, 1H), 3.30 (d, J＝18.0 Hz, 1H),
3.19 (s, 3H), 2.98 (d, J＝18.4 Hz, 1H), 2.39 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ: 176.7, 172.1, 156.4, 153.2,
140.2, 135.5, 135.1, 131.7, 130.3, 128.7, 128.5, 128.4,
128.1, 127.9, 127.7, 127.3, 124.7, 124.6, 123.0, 111.4,
91.8, 60.1, 58.1, 52.5, 43.8, 21.6; IR (KBr) ν: 3061,
2951, 1798, 1761, 1734, 1628, 1494, 1445, 1358, 1284,
methyl)-4,5-dihydroisoxazole-5-carboxylate
(3k):
White solid, 57% yield; m.p. 225—227 ℃; [α]D20
－82.8 (c 1.0, CH2Cl2); 91% ee, determined by HPLC
analysis [Daicel chiralcel AD-H, V(n-hexane) ∶
V(i-PrOH)＝70∶30, 0.8 mL/min, 254 nm UV detector,
tmajor＝24.8 min, tminor＝18.7 min]; 1H NMR (400 MHz,
CDCl3) δ: 8.44 (d, J＝7.2 Hz, 1H), 7.87 (d, J＝8.0 Hz,
2H), 7.51 (d, J＝8.4 Hz, 2H), 7.34—7.41 (m, 3H),
6.89—7.22 (m, 10H), 4.70 (s, 1H), 3.37 (d, J＝18.0 Hz,
1H), 3.22 (s, 3H), 3.08 (d, J＝18.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ: 176.2, 171.8, 156.2, 153.1, 134.8,
134.7, 133.7, 131.9, 130.6, 130.1, 129.9, 128.8, 128.1,
127.9, 127.7, 127.0, 125.9, 125.0, 124.0, 110.9, 91.7,
59.8, 58.9, 52.5, 44.5; IR (KBr) ν: 2923, 2853, 1789,
1735, 1593, 1489, 1458, 1400, 1358, 1289, 1234, 1143,
－
1
1259, 1154, 1095, 1071, 1008, 902, 825, 703 cm ;
HRMS (APCI) calcd for C33H26BrNO5＋H [M＋H]＋
598.0974, found 598.1063.
(R)-Methyl 3-(4-bromophenyl)-5-((S)-((S)-6-meth-
oxy-2-oxo-3-phenyl-2,3-dihydrobenzofuran-3-yl)(phen-
－
1
1079, 1042, 1014, 907, 826, 763, 705 cm ; HRMS
(APCI) calcd for C32H24BrClNO5 ＋H [M ＋H] ＋
616.0448, found 616.0470.
(R)-Methyl 3-(4-bromophenyl)-5-((S)-((S)-2-oxo-
3-p-tolyl-2,3-dihydrobenzofuran-3-yl)(phenyl)methyl)-
4,5-dihydroisoxazole-5-carboxylate (3l): White solid,
76% yield; m.p. 185—187 ℃; [α]2D0 －57.9 (c 1.0,
CH2Cl2); 88% ee, determined by HPLC analysis [Daicel
chiralcel AD-H, V(n-hexane)∶V(i-PrOH)＝70∶30, 0.8
mL/min, 254 nm UV detector, tmajor＝24.7 min, tminor＝
yl)methyl)-4,5-dihydroisoxazole-5-carboxylate
(3i):
White solid, 76% yield; m.p. 185—187 ℃; [α]D20
－83.2 (c 1.0, CH2Cl2); 92% ee, determined by HPLC
analysis [Daicel chiralcel IA-H, V(n-hexane) ∶
V(i-PrOH)＝80∶20, 1.0 mL/min, 254 nm UV detector,
tmajor＝40.2 min, tminor＝24.3 min]; 1H NMR (400 MHz,
2698
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 2693—2702

Organocatalytic Asymmetric Branching Sequence of MBH Carbonates
1
1
15.3 min]; H NMR (400 MHz, CDCl3) δ: 8.48 (d, J＝
tmajor＝19.5 min]; H NMR (400 MHz, CDCl3) δ: 8.43
7.2 Hz, 1H), 7.80 (d, J＝7.6 Hz, 2H), 7.48 (d, J＝8.4 Hz,
2H), 7.31—7.39 (m, 2H), 6.86—7.19 (m, 10H), 4.74 (s,
1H), 3.28 (d, J＝18.0 Hz, 1H), 3.21 (s, 3H), 3.05 (d, J＝
18.0 Hz, 1H), 2.12 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ: 176.6, 172.1, 156.3, 153.1, 138.4, 135.1, 131.8, 131.7,
130.9, 129.5, 129.4, 128.5, 128.1, 127.9, 127.6, 127.4,
126.4, 124.7, 123.8, 110.7, 91.8, 60.2, 58.6, 52.4, 44.3,
20.7; IR (KBr) ν: 3035, 2952, 1798, 1732, 1592, 1488,
1459, 1401, 1360, 1288, 1241, 1175, 1136, 1077, 1013,
908, 880, 822, 760, 706 cm ; HRMS (APCI) calcd for
C33H26BrNO5＋H [M＋H]＋ 598.0974, found 598.0994.
(R)-Methyl 3-(4-bromophenyl)-5-((S)-((S)-3-(4-
fluorophenyl)-2-oxo-2,3-dihydrobenzofuran-3-yl)(phen-
(d, J＝6.4 Hz, 1H), 7.91 (d, J＝6.4 Hz, 2H), 7.46 (d,
J＝8.4 Hz, 2H), 7.33—7.40 (m, 2H), 6.90—7.23 (m,
10H), 4.73 (s, 1H), 3.70 (s, 3H), 3.24—3.30 (m, 4H),
2.93 (d, J＝18.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ: 176.5, 172.1, 159.1, 156.5, 153.2, 135.2, 131.8, 130.8,
129.6, 128.8, 128.4, 128.1, 127.3, 126.8, 126.2, 124.8,
123.8, 113.0, 110.8, 92.0, 60.5, 57.3, 55.0, 52.6, 43.7;
IR (KBr) ν: 3063, 2952, 1800, 1738, 1612, 1512, 1461,
1399, 1356, 1250, 1183, 1135, 1070, 1040, 1011, 911,
－
－
1
1
826, 758 cm ; HRMS (APCI) calcd for C33H25BrNO6＋
H [M＋H]＋ 612.0944, found 612.0587.
(R)-Methyl 3-(4-bromophenyl)-5-((S)-(4-chloro-
phenyl)((S)-2-oxo-3-phenyl-2,3-dihydrobenzofuran-3-
yl)methyl)-4,5-dihydroisoxazole-5-carboxylate
(3m):
yl)methyl)-4,5-dihydroisoxazole-5-carboxylate
(3p):
White solid, 50% yield; m.p. 216—217 ℃; [α]D20
－68.7 (c 1.0, CH2Cl2); 99% ee, determined by HPLC
analysis [Daicel chiralcel AD-H, V(n-hexane) ∶
V(i-PrOH)＝70∶30, 0.8 mL/min, 254 nm UV detector,
White solid, 71% yield; m.p. 175—177 ℃; [α]D20
－47.2 (c 1.0, CH2Cl2); 92% ee, determined by HPLC
analysis [Daicel chiralcel AD-H, V(n-hexane) ∶
V(i-PrOH)＝70∶30, 0.8 mL/min, 254 nm UV detector,
tmajor＝17.8 min, tminor＝16.1 min]; 1H NMR (400 MHz,
CDCl3) δ: 8.42 (d, J＝6.8 Hz, 1H), 7.90 (d, J＝6.4 Hz,
2H), 7.46 (d, J＝8.4 Hz, 2H), 7.34—7.40 (m, 2H),
6.91—7.23 (m, 10H), 4.76 (s, 1H), 3.26—3.30 (m, 4H),
2.95 (d, J＝18.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ: 176.3, 171.9, 156.5, 153.1, 134.8, 134.2, 133.6, 131.8,
130.7, 129.7, 128.9, 128.6, 128.4, 128.1, 127.9, 127.1,
125.8, 124.9, 124.0, 111.0, 91.6, 60.2, 57.4, 52.7, 43.9;
IR (KBr) ν: 3062, 2951, 1801, 1742, 1593, 1491, 1464,
1402, 1354, 1275, 1244, 1176, 1135, 1069, 1011, 893,
826, 757 cm－1; HRMS (APCI) calcd for C32H24Br-
ClNO5＋H [M＋H]＋ 616.0448, found 616.0063.
1
tmajor＝22.8 min]; H NMR (400 MHz, CDCl3) δ: 8.43
(d, J＝6.8 Hz, 1H), 7.89—7.92 (m, 2H), 7.50 (d, J＝8.4
Hz, 2H), 7.34—7.41 (m, 2H), 6.88—7.22 (m, 10H),
4.72 (s, 1H), 3.39 (d, J＝18.0 Hz, 1H), 3.22 (s, 3H),
3.06 (d, J＝18.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ: 176.4, 171.9, 156.2, 153.2, 134.8, 131.9, 130.9, 130.5,
130.4, 129.8, 128.0, 127.9, 127.7, 127.1, 126.1, 125.0,
124.0, 115.7, 115.5, 111.0, 91.7, 59.7, 58.5, 52.5, 44.1;
IR (KBr) ν: 3065, 2952, 1797, 1734, 1597, 1505, 1460,
1401, 1357, 1285, 1239, 1168, 1137, 1078, 1012, 908,
822, 759, 705 cm － 1; HRMS (APCI) calcd for
＋
C33H27BrFN2O5 ＋ H [M ＋ H]
602.0723, found
602.0807.
(R)-Methyl 3-(4-bromophenyl)-5-((S)-(4-bromo-
phenyl)((S)-2-oxo-3-phenyl-2,3-dihydrobenzofuran-3-
(R)-Methyl 3-(4-bromophenyl)-5-((S)-((S)-2-oxo-3-
phenyl-2,3-dihydrobenzofuran-3-yl)(p-tolyl)methyl)-4,5-
dihydroisoxazole-5-carboxylate (3n): White solid, 58%
yield; m.p. 219—220 ℃; [α]2D0 －61.4 (c 1.0, CH2Cl2);
99% ee, determined by HPLC analysis [Daicel chiralcel
AD-H, V(n-hexane)∶V(i-PrOH)＝70∶30, 0.8 mL/min,
yl)methyl)-4,5-dihydroisoxazole-5-carboxylate
(3q):
White solid, 67% yield; m.p. 188—190 ℃; [α]D20
－79.4 (c 1.0, CH2Cl2); 93% ee, determined by HPLC
analysis [Daicel chiralcel AD-H, V(n-hexane) ∶
V(i-PrOH)＝70∶30, 0.8 mL/min, 254 nm UV detector,
tmajor＝19.2 min, tminor＝17.5 min]; 1H NMR (400 MHz,
CDCl3) δ: 8.41 (d, J＝8.0 Hz, 1H), 7.89 (d, J＝6.8 Hz,
2H), 7.47 (d, J＝8.4 Hz, 2H), 7.34—7.40 (m, 2H),
6.92—7.23 (m, 10H), 4.75 (s, 1H), 3.26—3.30 (m, 4H),
2.95 (d, J＝18.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ: 176.3, 171.9, 156.5, 153.1, 134.8, 134.1, 131.8, 130.9,
130.7, 129.9, 128.9, 128.6, 128.4, 128.1, 127.1, 125.8,
124.9, 124.0, 122.5, 111.0, 91.5, 60.2, 57.4, 52.7, 43.9;
IR (KBr) ν: 3061, 2950, 1801, 1742, 1592, 1488, 1464,
1402, 1353, 1274, 1243, 1177, 1135, 1071, 1046, 1011,
1
254 nm UV detector, tmajor＝16.6 min]; H NMR (400
MHz, CDCl3) δ: 8.44 (d, J＝6.8 Hz, 1H), 7.92 (d, J＝
6.8 Hz, 2H), 7.46 (d, J＝7.6 Hz, 2H), 7.33—7.40 (m,
2H), 6.89—7.23 (m, 10H), 4.74 (s, 1H), 3.29 (d, J＝
18.0 Hz, 1H), 3.20 (s, 3H), 2.97 (d, J＝18.0 Hz, 1H),
2.20 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 176.4,
172.1, 156.4, 153.2, 137.6, 135.2, 131.8, 131.7, 130.8,
129.6, 128.7, 128.5, 128.4, 128.1, 127.3, 126.2, 124.7,
123.8, 110.8, 91.9, 60.3, 57.7, 52.5, 43.7, 21.0; IR (KBr)
ν: 3058, 3030, 2949, 1803, 1741, 1592, 1488, 1463,
1436, 1399, 1353, 1278, 1246, 1177, 1145, 1045, 1008,
895, 825, 756 cm － 1; HRMS (APCI) calcd for
C33H26BrNO5＋H [M＋H]＋ 596.0994, found 596.0603.
(R)-Methyl 3-(4-bromophenyl)-5-((S)-(4-methoxy-
phenyl)((S)-2-oxo-3-phenyl-2,3-dihydrobenzofuran-3-
894, 826, 757 cm － 1; HRMS (APCI) calcd for
＋
C32H22Br2NO5 ＋ H [M ＋ H]
661.9922, found
661.9991.
(R)-Methyl 3-(4-bromophenyl)-5-((S)-(4-nitro-
phenyl)((S)-2-oxo-3-phenyl-2,3-dihydrobenzofuran-3-
yl)methyl)-4,5-dihydroisoxazole-5-carboxylate
(3o):
yl)methyl)-4,5-dihydroisoxazole-5-carboxylate
(3r):
White solid, 54% yield; m.p. 227—229 ℃; [α]D20
－55.2 (c 1.0, CH2Cl2); 99% ee, determined by HPLC
analysis [Daicel chiralcel IB-H, V(n-hexane) ∶
V(i-PrOH)＝90∶10, 1.0 mL/min, 254 nm UV detector,
White solid, 47% yield; m.p. 204—206 ℃; [α]D20
－22.3 (c 1.0, CH2Cl2); 85% ee, determined by HPLC
analysis [Daicel chiralcel IA-H, V(n-hexane) ∶
V(i-PrOH)＝80∶20, 1.0 mL/min, 254 nm UV detector,
Chin. J. Chem. 2012, 30, 2693—2702
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
2699

Zhu et al.
FULL PAPER
tmajor＝29.0 min, tminor＝35.0 min]; 1H NMR (400 MHz,
CDCl3) δ: 8.41 (d, J＝7.2 Hz, 1H), 7.97 (d, J＝8.0 Hz,
1H), 7.87 (d, J＝7.2 Hz, 2H), 7.36—7.52 (m, 7H),
7.17—7.27 (m, 5H), 6.91—7.04 (m, 1H), 4.92 (s, 1H),
3.27—3.33 (m, 4H), 3.02 (d, J＝18.0 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ: 176.0, 171.6, 156.5, 152.9,
147.4, 134.4, 132.0, 131.9, 130.4, 130.2, 129.0, 128.8,
128.3, 128.2, 128.1, 127.8, 126.8, 125.1, 124.2, 122.7,
111.2, 91.1, 60.0, 57.6, 52.8, 44.0; IR (KBr) ν: 3069,
2948, 1796, 1741, 1598, 1521, 1461, 1399, 1348, 1246,
1194, 1133, 1070, 1046, 1009, 901, 826, 756 cm ;
HRMS (APCI) calcd for C32H23BrClN2O7 [M＋H]＋
628.0668, found 627.9385.
(R)-Methyl 3-(4-bromophenyl)-5-((S)-(3-methoxy-
phenyl)((S)-2-oxo-3-phenyl-2,3-dihydrobenzofuran-3-
CH2Cl2); 94% ee, determined by HPLC analysis [Daicel
chiralcel AD-H, V(n-hexane)∶V(i-PrOH)＝70∶30, 0.8
mL/min, 254 nm UV detector, tmajor＝14.1 min, tminor＝
1
11.3 min]; H NMR (400 MHz, CDCl3) δ: 8.45—8.48
(m, 1H), 7.93 (d, J＝7.2 Hz, 2H), 7.32—7.40 (m, 4H),
6.88—7.26 (m, 11H), 4.78 (s, 1H), 3.84 (s, 3H), 3.29 (d,
J＝17.6 Hz, 1H), 3.20 (s, 3H), 2.97 (d, J＝17.6 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ: 176.4, 172.1, 156.3,
153.2, 136.4, 135.1, 135.0, 130.8, 129.6, 128.8, 128.7,
128.5, 128.4, 127.9, 127.9, 127.6, 126.8, 126.2, 123.8,
110.9, 91.8, 60.3, 58.2, 52.4, 44.0; IR (KBr) ν: 3063,
2952, 1795, 1762, 1731, 1598, 1495, 1460, 1359, 1286,
1257, 1240, 1173, 1136, 1073, 1041, 908, 829, 756, 702
－
1
－
1
cm ; HRMS (APCI) calcd for C32H24ClNO5＋H [M＋
H]＋ 538.1343, found 538.1416.
yl)methyl)-4,5-dihydroisoxazole-5-carboxylate
(3s):
(R)-Methyl 5-((S)-((S)-2-oxo-3-phenyl-2,3-dihydro-
benzofuran-3-yl)(phenyl)methyl)-3-p-tolyl-4,5-dihydro-
isoxazole-5-carboxylate (3v): White solid, 76% yield;
m.p. 179—181 ℃; [α]2D0 －73.7 (c 1.0, CH2Cl2); 93%
ee, determined by HPLC analysis [Daicel chiralcel
AD-H, V(n-hexane)∶V(i-PrOH)＝70∶30, 0.8 mL/min,
254 nm UV detector, tmajor＝12.0 min, tminor＝8.7 min];
1H NMR (400 MHz, CDCl3) δ: 8.48—8.50 (m, 1H),
7.93 (d, J＝7.6 Hz, 2H), 7.53—7.75 (m, 1H), 7.32—
7.40 (m, 2H), 7.10—7.24 (m, 11H), 6.88 (d, J＝7.2 Hz,
1H), 4.79 (s, 1H), 3.30 (d, J＝18.0 Hz, 1H), 3.20 (s, 3H),
2.98 (d, J＝18.0 Hz, 1H), 2.37 (s, 3H); 13C NMR (100
MHz, CDCl3) δ: 176.5, 172.4, 157.2, 153.2, 140.7,
135.2, 135.2, 131.0, 130.9, 129.6, 129.2, 128.8, 128.8,
128.5, 128.4, 127.9, 127.6, 126.6, 126.3, 125.5, 123.8,
110.7, 91.5, 60.4, 57.9, 52.4, 44.2, 21.4; IR (KBr) ν:
White solid, 53% yield; m.p. 229—231 ℃; [α]D20
－64.1 (c 1.0, CH2Cl2); 99% ee, determined by HPLC
analysis [Daicel chiralcel AD-H, V(n-hexane) ∶
V(i-PrOH)＝70∶30, 0.8 mL/min, 254 nm UV detector,
1
tmajor＝20.7 min]; H NMR (400 MHz, CDCl3) δ: 8.46
(d, J＝7.2 Hz, 1H), 7.92 (d, J＝6.8 Hz, 2H), 7.47 (d,
J＝8.0 Hz, 2H), 7.35—7.41 (m, 2H), 6.67—7.24 (m,
10H), 4.77 (s, 1H), 3.40—3.82 (m, 3H), 3.30 (d, J＝
18.0 Hz, 1H), 3.24 (s, 3H), 3.01 (d, J＝18.0 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ: 176.3, 172.0, 158.7,
156.4, 153.3, 136.3, 135.1, 131.8, 130.8, 129.6, 129.4,
128.8, 128.5, 128.1, 127.2, 126.4, 124.8, 123.8, 110.9,
91.8, 60.3, 58.1, 55.1, 52.5, 43.9; IR (KBr) ν: 3059,
2951, 1798, 1760, 1733, 1593, 1491, 1462, 1400, 1256,
－
1
1169, 1136, 1072, 1009, 914, 825, 760 cm ; HRMS
(APCI) calcd for C33H25BrNO6＋H [M＋H]＋ 612.0944,
found 612.0587.
3033, 2957, 1796, 1756, 1730, 1613, 1459, 1358, 1256,
1170, 1132, 1070, 1043, 894, 814, 753, 701 cm－
;
1
(R)-Methyl 3-(4-bromophenyl)-5-((R)-(2-chloro-
phenyl)((S)-2-oxo-3-phenyl-2,3-dihydrobenzofuran-3-
HRMS (APCI) calcd for C33H27NO5 ＋H [M＋H]＋
518.1889, found 518.1932.
yl)methyl)-4,5-dihydroisoxazole-5-carboxylate
(3t):
(R)-Methyl 3-(4-methoxyphenyl)-5-((S)-((S)-2-oxo-
3-phenyl-2,3-dihydrobenzofuran-3-yl)(phenyl)methyl)-
4,5-dihydroisoxazole-5-carboxylate (3w): White solid,
79% yield; m.p. 168—170 ℃; [α]2D0 －70.3 (c 1.0,
CH2Cl2); 94% ee, determined by HPLC analysis [Daicel
chiralcel AD-H, V(n-hexane)∶V(i-PrOH)＝70∶30, 0.8
mL/min, 254 nm UV detector, tmajor＝14.7 min, tminor＝
White solid, 56% yield; m.p. 181—183 ℃; [α]D20
－35.6 (c 1.0, CH2Cl2); 98% ee, determined by HPLC
analysis [Daicel chiralcel AD-H, V(n-hexane) ∶
V(i-PrOH)＝70∶30, 0.8 mL/min, 254 nm UV detector,
tmajor＝31.1 min, tminor＝25.7 min]; 1H NMR (400 MHz,
CDCl3) δ: 8.18—8.20 (m, 1H), 7.78 (d, J＝7.6 Hz, 2H),
7.47 (d, J＝8.0 Hz, 2H), 7.37—7.39 (m, 2H), 7.33 (d,
J＝8.0 Hz, 1H), 7.19—7.26 (m, 6H), 7.10 (t, J＝7.6 Hz,
1H), 6.98—7.00 (m, 1H), 6.92 (t, J＝7.6 Hz, 1H), 5.62
(s, 1H), 3.50 (d, J＝18.0 Hz, 1H), 3.23—3.27 (m, 4H);
13C NMR (100 MHz, CDCl3) δ: 175.1, 171.5, 156.4,
153.4, 136.1, 136.0, 133.0, 131.8, 131.7, 130.0, 129.7,
129.5, 129.4, 128.7, 128.3, 128.1, 127.2, 126.8, 126.1,
124.9, 123.9, 111.1, 91.5, 58.9, 52.6, 51.7, 43.1; IR
(KBr) ν: 3062, 2948, 1794, 1753, 1592, 1463, 1399,
1356, 1247, 1206, 1133, 1062, 1008, 890, 825, 756
cm－1; HRMS (APCI) calcd for C32H23BrClNO5＋H
[M＋H]＋ 616.0448, found 616.0069.
1
11.7 min]; H NMR (400 MHz, CDCl3) δ: 8.49 (d, J＝
7.6 Hz, 2H), 7.94 (d, J＝7.2 Hz, 2H), 7.34—7.40 (m,
2H), 7.32—7.40 (m, 2H), 6.83—7.27 (m, 13H), 4.78 (s,
1H), 3.84 (s, 3H), 3.29 (d, J＝17.6 Hz, 1H), 3.20 (s, 3H),
2.97 (d, J＝17.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ: 176.5, 172.5, 161.3, 156.8, 153.2, 135.2, 135.2, 131.0,
129.5, 128.8, 128.7, 128.5, 128.4, 128.2, 127.9, 127.6,
126.3, 123.8, 120.9, 113.9, 110.7, 91.4, 60.4, 60.0, 55.3,
52.4, 44.3; IR (KBr) ν: 3060, 2954, 1796, 1759, 1730,
1608, 1461, 1360, 1252, 1179, 1134, 1070, 1045, 880,
755 cm－1; HRMS (APCI) calcd for C33H27NO5＋H
[M＋H]＋ 534.1838, found 534.1898.
(R)-Methyl 3-(4-chlorophenyl)-5-((S)-((S)-2-oxo-3-
phenyl-2,3-dihydrobenzofuran-3-yl)(phenyl)methyl)-
4,5-dihydroisoxazole-5-carboxylate (3u): White solid,
78% yield; m.p. 180—182 ℃; [α]2D0 －68.4 (c 1.0,
(R)-Methyl 5-((S)-((S)-2-oxo-3-phenyl-2,3-dihydro-
benzofuran-3-yl)(phenyl)methyl)-3-phenyl-4,5-dihydro-
isoxazole-5-carboxylate (3x): White solid, 73% yield;
m.p. 220—222 ℃; [α]2D5 －83.4 (c 1.0, CH2Cl2); 94%
2700
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 2693—2702

Organocatalytic Asymmetric Branching Sequence of MBH Carbonates
ee, determined by HPLC analysis [Daicel chiralcel
AD-H, V(n-hexane)∶V(i-PrOH)＝70∶30, 0.8 mL/min,
254 nm UV detector, tmajor＝9.3 min, tminor＝8.3 min];
1H NMR (400 MHz, CDCl3) δ: 8.48 (d, J＝7.2 Hz, 1H),
7.94 (d, J＝7.6 Hz, 2H), 7.32—7.41 (m, 8H), 7.11—
7.24 (m, 7H), 6.89 (d, J＝7.6 Hz, 1H), 4.79 (s, 1H),
3.33 (d, J＝18.0 Hz, 1H), 3.20 (s, 3H), 3.02 (d, J＝18.0
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 176.4, 172.3,
157.3, 153.2, 135.2, 135.1, 130.9, 130.4, 129.6, 128.8,
128.5, 128.4, 128.3, 127.9, 127.6, 126.7, 126.3, 123.8,
110.7, 91.6, 60.3, 60.0, 52.4, 44.1; IR (KBr, CH2Cl2) ν:
2955, 1799, 1730, 1600, 1487, 1461, 1257, 1220, 1144,
References
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1
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1059, 756 cm ; HRMS (APCI) calcd for C32H24BrNO5
＋H [M＋H]＋ 504.1733, found 504.1806.
(R)-Methyl 5-((S)-((S)-5-bromo-2-oxo-3-phenyl-2,3-
dihydrobenzofuran-3-yl)(phenyl)methyl)-3-phenyl-4,5-
dihydroisoxazole-5-carboxylate (3y): White solid, 66%
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CH2Cl2); 99% ee, determined by HPLC analysis [Daicel
chiralcel IA-H, V(n-hexane)∶V(i-PrOH)＝80∶20, 1.0
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1
mL/min, 254 nm UV detector, tmajor＝9.1 min]; H
NMR (400 MHz, CDCl3) δ: 8.67 (d, J＝2.0 Hz, 1H),
7.90 (d, J＝7.6 Hz, 2H), 7.46—7.49 (m, 1H), 7.33—
7.40 (m, 6H), 7.13—7.25 (m, 7H), 6.77 (d, J＝8.4 Hz,
1H), 4.78 (s, 1H), 3.32 (d, J＝18.0 Hz, 1H), 3.22 (s, 3H),
2.97 (d, J＝18.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ: 175.8, 172.2, 157.3, 152.0, 134.9, 134.2, 133.7, 132.8,
130.5, 128.9, 128.7, 128.5, 128.3, 128.2, 128.1, 127.8,
126.7, 116.7, 112.3, 91.4, 60.8, 58.0, 52.5, 44.4; IR
(KBr, CH2Cl2) ν: 2951, 1803, 1724, 1595, 1490, 1458,
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－
1
1270, 1234, 1143, 1060, 758, 700 cm ; HRMS (APCI)
calcd for C32H24BrNO5＋H [M＋H]＋ 584.0817, found
584.0889.
Methyl 5-(5-bromo-2-oxo-3-phenyl-2,3-dihydro-
benzofuran-3-yl)(phenyl)methyl)-3-phenyl-4,5-dihydro-
isoxazole-5-carboxylate (3y'): White solid, 14% yield;
m.p. 233—235 ℃; [α]2D5 －10.1 (c 1.0, CH2Cl2); 90%
ee, determined by HPLC analysis [Daicel chiralcel IA-H,
V(n-hexane)∶V(i-PrOH)＝80∶20, 0.8 mL/min, 254
nm UV detector, tmajor＝12.6 min, tminor＝19.8 min ]; 1H
NMR (400 MHz, CDCl3) δ: 8.84 (s, 1H), 7.81 (d, J＝
7.6 Hz, 2H), 7.51—7.53 (m, 1H), 7.30—7.43 (m, 9H),
7.02—7.17 (m, 4H), 6.80 (d, J＝8.4 Hz, 1H), 4.85 (s,
1H), 3.44 (d, J＝17.6 Hz, 1H), 3.22 (d, J＝18.0 Hz, 1H),
3.16 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 175.9,
172.8, 156.4, 152.2, 134.1, 134.1, 133.3, 132.7, 130.5,
129.2, 128.6, 128.5, 128.4, 128.2, 128.1, 126.7, 116.5,
112.1, 90.0, 61.0, 57.2, 52.8, 47.6; IR (KBr, CH2Cl2) ν:
2948, 1801, 1721, 1597, 1490, 1460, 1268, 1237, 1140,
1061, 758, 701 cm － 1; HRMS (APCI) calcd for
C32H24BrNO5＋H [M＋H]＋ 584.0817, found 584.0889.
Acknowledgement
This work was supported financially by the National
Natural Science Foundation of China (Nos. 20972110
and 20902067).
[9] (a) Adediran, S. A.; Vabaret, D.; Drouillat, B.; Pratt, R. F.;
Chin. J. Chem. 2012, 30, 2693—2702
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
2701

Zhu et al.
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[14] The relative and absolute configuration of 3y was confirmed by
X-ray crystal structure analysis, with other sequential products as-
signed by analogy. See Supporting information for further details.
Crystallographic data for 3y and 3y' have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publica-
tion number CCDC 813086 and 905764.
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2702
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Chin. J. Chem. 2012, 30, 2693—2702