Enantioselective Construction of Aryl-Substituted All-Carbon Quaternary Stereocenters by Using Tertiary Amine–Thiourea-Catalyzed Michael Additions

Article abstract of DOI:10.1002/ejoc.201501420

A catalytic enantioselective synthetic strategy for the aryl-substituted all-carbon quaternary stereocenters of bioactive hydrodibenzofuran alkaloids was achieved by the Michael addition reaction of α-cyano ketones and acrylates using a chiral tertiary am

Full text of DOI:10.1002/ejoc.201501420

DOI: 10.1002/ejoc.201501420
Full Paper
All-Carbon Quaternary Stereocenters
Enantioselective Construction of Aryl-Substituted All-Carbon
Quaternary Stereocenters by Using Tertiary Amine–Thiourea-
Catalyzed Michael Additions
Peng Chen,[a] Xu Bao,[b] Le-Fen Zhang,[b] Guo-Jie Liu,[a] and Yi-Jun Jiang*[a]
Abstract: A catalytic enantioselective synthetic strategy for the moderate to good enantioselectivities. The enantiopurity of the
aryl-substituted all-carbon quaternary stereocenters of bio- products could also be enriched up to 99 % ee after one re-
active hydrodibenzofuran alkaloids was achieved by the crystallization. This enantioselective Michael addition features a
Michael addition reaction of α-cyano ketones and acrylates us- low cost, metal-free, and easily operable procedure that can
ing a chiral tertiary amine–thiourea catalyst. This method can provide multifunctionalized enantiopure Michael adducts on a
tolerate steric bulkiness and multiple functional groups, and 32 four-gram scale and supply sufficient amounts of potential pre-
Michael adducts were prepared in good to excellent yields with cursors for a number of hydrodibenzofuran natural products.
Introduction
selective desymmetrized oxa-Michael addition induced by the
chiral precursors that were obtained from a phenolic oxidative
coupling reaction,[4] (2) diastereoselective [3,3] sigmatropic re-
arrangements from chiral precursors,[5] (3) diastereoselective
Heck reactions of chiral precursors,[6] and (4) enantioselective
catalytic Michael addition reactions from racemic substrates.[7]
It should be mentioned that enantioenriched precursors were
used in methods (1)–(3), which require extra steps because of
the employment of the chiral auxiliaries or the careful opera-
tions needed to avoid the racemization of the chiral non-qua-
ternary carbons in the late-stage steps. Therefore, directly intro-
ducing the chirality during the formation of the all-carbon qua-
ternary center by using a catalytic enantioselective method is
more attractive, as no chiral auxiliaries are needed, and it is
difficult to racemize the all-carbon quaternary center once it
has been fabricated. An elegant enantioselective synthesis of
(–)-lycoramine and (–)-galanthamine was reported by Jia and
co-workers using method (4), in which the all-carbon quater-
nary centers were constructed by a catalytic enantioselective
In modern organic synthesis, the catalytic enantioselective con-
struction of quaternary centers is one of the most important
areas of research. In particular, the catalytic enantioselective
construction of all-carbon quaternary centers is one of the more
challenging processes because of the substantial intrinsic steric
bulkiness that arises from four carbon substituents bonded to
a central carbon atom.[1] In recent years, a number of catalytic
reactions that focus on the construction of chiral all-carbon
quaternary centers have been reported. However, few of these
can tolerate multiple functional groups, which limits their appli-
cation for the enantioselective total synthesis of natural pro-
ducts.
Hydrodibenzofuran-type natural products belong to a series
of structurally diverse alkaloids with a wide range of biological
activities (Figure 1).[2] Their highly strained cis-hydrodibenzo-
furan core contains an aryl-substituted all-carbon quaternary
chiral stereocenter, which poses a formidable challenge for syn-
thetic chemists. Among these alkaloids, (–)-lycoramine and (–)-
galanthamine have received much attention from medicinal
and organic chemists because of their remarkable biological
activity and pharmacological potential. The known strategies
for the construction of the chiral aryl-substituted all-carbon
quaternary centers in (–)-lycoramine and (–)-galanthamine can
be divided into four categories (Scheme 1):[3] (1) a diastereo-
[a] State Key Laboratory of Inorganic Synthesis and Preparative Chemistry,
College of Chemistry, Jilin University,
Changchun 130012, P. R. China
E-mail: jiangyijun@jlu.edu.cn
http://supramol.jlu.edu.cn/people/sunjunqi/
[b] College of Chemistry and Chemical Engineering, Lanzhou University,
Lanzhou 730000, P. R. China
Supporting information and ORCID(s) from the author(s) for this article
are available on the WWW under http://dx.doi.org/10.1002/
ejoc.201501420.
Figure 1. Representative members of hydrodibenzofuran alkaloids.
704 © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Michael addition reaction.[7a] However, metal catalysts and li- strategy was flexible, and by changing the substituents on the
gands as well as careful operations were needed for both the phenyl ring of the starting Michael donor D1, we could synthe-
synthesis of the precursors and the key step, in which the chiral- size diversely substituted nuclei N for the total synthesis
ity was introduced. Therefore, catalytic enantioselective strate- of hydrodibenzofuran-type natural products. Therefore, by
gies for the synthesis of (–)-lycoramine and (–)-galanthamine using this new and divergent chiral amine–thiourea-catalyzed
that feature lower costs, easier operations, and lower toxicity Michael addition between α-cyano ketones and acrylates, we
are still highly desirable.
accomplished not only the highly efficient catalytic enantio-
selective synthesis of the galanthamine-type alkaloids (–)-
lycoramine and (–)-galanthamine but also the first enantio-
selective total synthesis of (+)-lunarine, the ring system of
which is different from the galanthamine-type alkaloids.[7b]
During the last two decades, numerous efforts have been
devoted to catalytic enantioselective Michael additions. How-
ever, catalytic enantioselective Michael additions that are capa-
ble of constructing all-carbon quaternary stereocenters have
not been fully explored,[1,8–12] especially for processes that can
tolerate multiple functional groups and be further applied to
the asymmetric total synthesis of complex natural products. Al-
though the abovementioned chiral amine–thiourea-catalyzed
Michael addition reaction between α-cyano ketones and acryl-
ates reported in our previous work[7b] were highly tolerant of
multiple functional groups and showed great potential in the
total synthesis of the hydrodibenzofuran alkaloids, the details
and scope of its application have not been fully addressed.
Herein, we detail the full account of this Michael addition ap-
proach. In addition, we have expanded this method to employ
various substrates and provide a general way to synthesize
highly functionalized building blocks that contain chiral aryl-
substituted all-carbon quaternary stereocenters, which can later
be used as crucial precursors for the total synthesis of related
natural products.
Results and Discussion
By considering the features of the Michael addition reaction of
D1 and Michael acceptor A1 (Figure 2), we envisaged that the
enantioselective reaction could be realized by a mode of cataly-
sis that involves the dual activation of donors and acceptors by
using a chiral bifunctional catalyst that consists of a Brønsted
acid and base (e.g., chiral amine-thiourea catalyst 4,[13] Fig-
ure 2). On the basis of this dual mode of catalysis, α-aryl α-
cyano ketone 1a and 4-bromophenyl acrylate (2a) were se-
lected as the model donor and acceptor and, along with Take-
moto's catalyst 4a,[13] were used to screen the reaction condi-
tions of the Michael addition (Figure 3). Among the various
Scheme 1. The known strategies to construct the chiral all-carbon quaternary
centers in (–)-lycoramine and (–)-galanthamine.
Recently, we reported the enantioselective total synthesis of
(–)-lycoramine and (–)-galanthamine, in which we also used an
enantioselective Michael addition reaction to construct the key
all-carbon quarternary stereocenters from entirely different sub-
strates than those used by Jia and co-workers.[7b] By using the
multifunctionalized Michael adducts that resulted from this key
step, we could construct the nucleus N with a cis-hydrodibenzo-
furan core (Scheme 1). In our strategy, we used an inexpensive
chiral amine–thiourea as the organocatalyst and easily per-
formed the key step on a gram scale. Most importantly, our
Figure 2. Dual activation of donors and acceptors by chiral bifunctional cata-
lyst.
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Figure 3. The model Michael addition catalyzed by chiral bifunctional amine-thiourea catalysts with (R,R)- and (S,S)-1,2-diamine scaffolds (MOM = methoxy-
methyl, THF = tetrahydrofuran, DMSO = dimethyl sulfoxide). [“+” or “–” before the ee values means that the major product has (S) absolute configuration or
(R) absolute configuration, respectively.[15]
]
screened solvents,[14] p-xylene gave the best results in terms of and those that have the (S,S)-diamine moiety led to the re-
enantioselectivity and reactivity. Thus, in p-xylene as the sol- versed enantioselectivity and afforded the (R) absolute configu-
vent, a series of amine-thiourea catalysts 4b–4p, structural vari- ration of 3aa.[15] As a result of the abovementioned experi-
ants of catalyst 4a with the (R,R)-1,2-diamine skeleton, were ments, the optimized reaction conditions for the designed en-
then investigated (Figure 3).[14]
antioselective Michael addition of α-aryl α-cyano ketone 1a and
4-bromophenyl acrylate (2a) were realized in p-xylene as the
solvent at room temperature under the catalysis of tertiary
amine-thiourea 4a [3aa: 90 % yield, 79 % ee, (S) absolute con-
figuration].[15] Importantly, the stereochemistry of 3aa with the
crucial quaternary stereogenic carbon center could be fine-
tuned by using cinchonidine-derived bifunctional catalyst 4o or
4m [3aa: 97 % yield, 81 % ee, (R) absolute configuration],[15]
which provided the possibility of access to the cis-hydrodi-
benzofuran nucleus N (Scheme 1) with the opposite absolute
configuration.
In terms of the catalytic efficiency as well as the availability
of chiral diamines used for the preparations of amine-thiourea
catalysts, 4a and 4o were eventually employed as the catalysts
for the asymmetric control of both product enantiomers. Al-
though the expected product 3aa was only obtained with ee
values of approximately 80 %, the present method proceeds
under mild organocatalysis and constitutes the first example
of this combination of substrates, that is, α-cyano ketones as
Michael donors and acrylates as Michael acceptors. Strategi-
cally, this provides a new way for the direct catalytic enantio-
selective synthesis of chiral aryl-substituted all-carbon quater-
nary centers of multifunctionalized building blocks that contain
cyano, ester, and ketone moieties.
Upon comparing the enantioselectivity and catalytic reactiv-
ity of 4a (90 % yield, 79 % ee) with the results obtained by 4b–
4p in the detailed screenings, several interesting features of the
catalyst were revealed. First, one tertiary amine moiety as the
Brønsted basic site was necessary for the efficiency of the
Michael addition, and the catalysts with a secondary, primary,
or deactiviated tertiary amino group (i.e., 4b–4d, Figure 3) were
either less effective or ineffective. Notably, the bulky R7 and R8
substituents (Figure 2) on the tertiary amine group of 4g, 4h,
and 4j–4l reduced the reactivity but had little influence on the
enantioselectivity in most cases, as the (R)-1,1′-binaphthyl-2,2′-
bis(methylene) and (S,S)-diamine scaffolds, or vice versa, consti-
tute a matched case in enantioselectivity. Second, the requisite
catalytic activity of the Brønsted acidic site of the catalyst was
influenced, to some extent, by the variation of N-substituted
group or thiocarbonyl. Catalyst 4f with a sulfonylurea moiety
promoted this reaction very slowly, whereas 4e was completely
ineffective. Third, in addition to the catalysts 4a–4f and 4j–4l,
which were derived from a chiral cyclic diamine (the R5 and R6
groups in 4 are linked, Figure 2), catalysts 4g–4i and 4m–4p,
which stem from chiral acyclic diamines such as 1,2-diphenyl-
ethylenediamine and cinchona alkaloid derivatives[10b] (R5 and
R6 groups in 4 are not linked, Figure 2) were also investigated.
Interestingly, catalysts that contain the (R,R)-diamine moiety en-
To examine the generality of this asymmetric method for
antioselectively gave 3aa with the (S) absolute configuration, the catalytic enantioselective synthesis of aryl-substituted all-
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carbon quaternary stereocenters, various Michael acceptors and of the iodine atom. After one recrystallization procedure, crys-
donors were submitted to the reaction with 4o as the catalyst. tals of (R)-3ag were isolated from the mother liquor with
In Table 1, Entries 1–4, it can be seen that having an ortho or >98 % ee (76 % isolated yield), and the absolute configuration
meta substituent on the phenyl ring of the aryl acrylates did
not improve the yields or ee values. A series of aryl acrylates
Table 2. Various Michael donors for the synthesis of aryl-substituted all-car-
bon quaternary stereocenters under the catalysis of 4o.[a]
with electron-donating and electron-withdrawing para substit-
uents were then examined (Table 1, Entries 5–10). Interestingly,
the results obtained in Table 1, Entries 1–10 clearly demonstrate
that electron-deficient aryl acrylates (i.e., 2a–2g, 2i, and 2j)
were better Michael acceptors. As a comparison, the Michael
addition with phenyl acrylate 2k as the acceptor proceeded
very slowly (Table 1, Entry 11). As a structural comparison with
2k, it is noteworthy that the halogen-substituted aryl acrylates
(i.e., 2a–2c and 2e–2g) had an obvious accelerating effect on
the reactivity, which may be a result of the electronic effect of
the halogen atom. Although the reaction with 1-naphthyl acryl-
ate (2l) as the acceptor proceeded readily, there was no ob-
served improvement in the stereocontrol (Table 1, Entry 12).
Surprisingly, alkyl acrylate 2m was found to be totally ineffect-
ive in the current catalyzed reaction (Table 1, Entry 13). In addi-
tion, acrylic acid derivative 2n as the Michael acceptor would be
potentially useful in the synthesis of the cis-hydrodibenzofuran
nucleus N (Scheme 1), but it would not provide any enantio-
selective improvement (Table 1, Entry 14).
Among the products formed, Michael adduct 3ag (Table 1,
Entry 7) was easily crystallized, mainly because of the presence
Entry Donor
Product Yield [%][b]
ee [%][c]
Yield [%][d]
ee [%]
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
3ag
3bg
3cg
3dg
3eg
3fg
96
93
86
92
95
96
95
95
63
90
88
88
82
85
80
84
94
89
52
69
92
81 (R)
77 (R)[g]
80 (R)
76 (R)
73 (R)
72 (R)
64 (R)
71 (R)
59 (R)
58 (R)
64 (R)
65 (R)
71 (R)
68 (R)
55 (R)
71 (R)
60 (R)
76[i]
76
–
–
99[e,f]
–
–
Table 1. Various Michael acceptors for the synthesis of aryl-substituted all-
carbon quaternary stereocenters under the catalysis of 4o.[a]
–
–
42
64
60
73
41
–
63
54
–
57
47
54
–
90[e]
91[h]
90[h]
87[h]
95[h]
–
7
8
9
1g
1h
1i
3gg
3hg
3ig
Entry Acceptor (X–R4)
Product t [d]
Yield [%][b]
ee [%][c]
10
11
12
13
14
15
16
17
18
19
20
21
1j
1k
1l
1m
1n
1o
1p
1q
1r
3jg
3kg
3lg
86[h]
87[h]
–
1
2
3
4
5
6
7
8
2a (O–4-C6H4Br)
2b (O–3-C6H4Br)
2c (O–2-C6H4Br)
2d (O–2-C6H4NO2)
2e (O–4-C6H4F)
2f (O–4-C6H4Cl)
2g (O–4-C6H4I)
3aa
3ab
3ac
3ad
3ae
3af
2
1.5
4.5
2
4.5
3
97
92
92
89
96
81 (R)[d]
80
66
78
3mg
3ng
3og
3pg
3qg
3rg
88[h]
91[h]
93[h]
–
80
80
90
3ag
3ah
2
7
96 (76)[e]
10
81 [98 (R)][f]
–
28
–
–
2h (O–4-C6H4OMe)
–
1s
1t
1u
3sg
3tg
3ug
54[i]
90[h]
–
9
2i (O–4-C6H4CO2Me) 3ai
2
1
7
3.5
7
94
99
82
99
–
92
81
81
80
67
–
74[i]
10
11
12
13
14
2j (O–4-C6H4NO2)
2k (O–Ph)
2l (O–1-naphthyl)
2m (O–Me)
3aj
3ak
3al
72 (R)
70
98[e]
[a] To an oven-dried Schlenk tube were sequentially added catalyst 4o
(0.04 mmol), α-cyano ketone 1a–1u (0.2 mmol), p-xylene (1.0 mL), and
Michael acceptor 2g (0.4 mmol) at 25 °C. The reaction mixture was stirred at
this temperature until the donor had disappeared upon inspection by thin
layer chromatography. [b] Yield of isolated product. [c] All enantiomeric ex-
cess values were determined by chiral HPLC analysis. The (R) absolute config-
urations of 3ag[7b] and 3ug (see Figure 4) were established by X-ray crystal-
lography, and accordingly the absolute stereochemistry for the major enanti-
omers of 3bg–3tg were assigned provisionally as indicated in the parenthe-
ses. [d] Isolated yield of the enantioenriched product after one recrystalliza-
tion. [e] The ee value of the isolated crystals after one recrystallization. [f] The
reaction was carried out on a 2.5 g (10 mmol) scale of 1a, and 4.0 g of almost
enantiopure (R)-3ag could be obtained from one reaction. [g] In an earlier
report, we further confirmed the (R) absolute configuration by a late-stage
recrystallization of compound 7b.[7b] [h] The ee value of the material collected
from mother liquor after the crystallization of the racemate. [i] Unknown
absolute configuration.
3am
3an
1.5
77
[a] To an oven-dried Schlenk tube were sequentially added catalyst 4o
(0.02 mmol), α-cyano ketone 1a (0.1 mmol), p-xylene (0.5 mL), and Michael
acceptor 2 (0.2 mmol) at 25 °C. The reaction mixture was stirred at this tem-
perature until the donor had disappeared upon inspection by thin layer chro-
matography. [b] Yield of isolated product. [c] Determined by chiral HPLC anal-
ysis. [d] The absolute configuration was assigned by comparison to that re-
ported in Table 1, Entry 7. [e] Yield of isolated crystallized product 3ag after
one recrystallization. [f] The ee value of enantioenriched product 3ag after
one recrystallization. The (R) absolute configuration was confirmed by X-ray
crystallography[7b] (see Supporting Information).
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was further determined by X-ray crystallography.[7b,16] Consider- Table 2, Entries 7, 8, 10, and 11). Despite the asymmetric control
ing that only good to moderate levels of enantioselectivity were of only 60 % ee, one experiment that used an α-alkyl-substi-
observed in screening the potential Michael acceptors (66– tuted Michael donor, that is, α-cyano ketone 1q (Table 2, En-
81 % ee, Table 1), we believe that recrystallization may provide try 17) was also conducted to investigate the construction of
an alternative to increase the ee values of the Michael adducts, an alkyl-substituted all-carbon quaternary stereocenter. Further-
which could be significant, particularly in asymmetric total syn- more, the influence of the group (R′) bonded to the carbonyl
thesis. Consequently, 4-iodophenyl acrylate 2g was selected as carbon was examined by using Michael donors 1r–1t (Table 2,
the ideal acceptor to study this method.
Entries 18–20), and in these cases, the observed enantioselectiv-
ity was lower than that observed with 1a. In addition to the
acyclic cyano ketones, cyclic substrate 1u (Table 2, Entry 21)
was investigated and afforded Michael adduct 3ug in 92 %
yield with 72 % ee (98 % ee after one recrystallization). Notably
with the establishment of (R) absolute configuration of 3ug by
X-ray crystal structure analysis (Figure 4),[16] this example with
a cyclic substrate is mechanistically interesting. During the terti-
ary amine–thiourea-catalyzed reaction, the configurationally
Various Michael donors were then subjected to the current
enantioselective Michael addition catalyzed by 4o (Table 2).
From the results obtained, it can be seen that most of the func-
tionalized products (i.e., 3ag–3ug) were afforded with good to
moderate enantioselectivities in good to excellent yields, which
indicates that challenges still remain in this current catalytic
enantioselective Michael addition of α-cyano ketones and acryl-
ates to install an aryl-substituted all-carbon quaternary center.
Compared with the 65 % ee obtained by using α-phenyl α-
cyano ketones 1l (Table 2, Entry 12), most of the α-cyano
ketones that have an ortho-substituted aryl ring at α-position
(i.e., 1a–1f, 1m, and 1n) gave an improved enantioselectivity
that ranged from 68 to 81 % ee. Notably, to the best of our
knowledge, there are few reports of the catalytic asymmetric
construction of an ortho-substituted arylic all-carbon quater-
nary center through a Michael addition reaction[9a,9c,17] such as
those products found in Table 2, Entries 1–6, 9, and 13–15.
There are slight influences on the stereocontrol (58–71 % ee) of
the reaction by employing Michael donors that have a meta- or
para-substituted aryl ring at α-position (i.e., 1g, 1h, 1j, and 1k,
Figure 4. X-ray crystal structure of (R)-3ug.
Figure 5. Proposed mechanistic rationale for tunable enantioselectivity under the catalysis of 4a and 4o.
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followed by heating as the developing agent. The products were
purified by flash column chromatography on silica gel (200–
300 mesh) from the Qingdao Marine Chemical Factory in China. The
1H and 13C NMR spectroscopic data were recorded in a CDCl3 or
[D6]DMSO solution with a Bruker AM 400 MHz instrument. Chemical
shifts (δ) were reported in ppm and calibrated by using the residual
undeuterated solvent (for CHCl3, δ = 7.27 ppm; for [D5]DMSO, δ =
2.50 ppm) or tetramethylsilane (δ = 0.00 ppm) as the internal refer-
ence for 1H NMR and the deuterated solvent (for CDCl3, δ =
77.00 ppm; for [D6]DMSO, δ = 39.51 ppm) or tetramethylsilane (δ =
0.00 ppm) as the internal standard for 13C NMR spectroscopy. The
coupling constants are reported in Hz. The following abbreviations
were used to describe the multiplicities: s (singlet), d (doublet), t
(triplet), q (quartet), br. (broad), td (triplet of doublets), dt (doublet
of triplets), and m (multiplet). The MS data were obtained by using
EI (70 eV) or ESI, and the relative intensity (%) is reported in brack-
ets. High resolution mass spectrometry (HRMS) data were measured
with a Bruker Apex II mass spectrometer by employing the ESI tech-
nique. IR spectra were recorded on a Nicolet Nexus 670 FTIR spec-
trometer. Optical rotations were measured by using a 1 mL cell with
defined (Z)-enolate will be unambiguously formed in situ by
deprotonation of 1u, which will help to gain more of an under-
standing about the stereoselectivity in the present enantio-
selective Michael addition.
To improve the optical purity of the Michael adducts contain-
ing the chiral quaternary carbon centers, a mixed solvent re-
crystallization was used. The enantiopurity for most of cases in
Table 2 was enriched from 86 to 99 % ee after one recrystalliza-
tion. Interestingly, a conglomerate crystallization with homochi-
ral recognition (fR,R, fS,S > fR,S) was observed for 3ag, 3eg, and
3ug (Table 2, Entries 1, 5, and 21), which led to the isolation of
crystals with high enantiomeric enrichment (up to 99 % ee). In
most of the recrystallized samples (Table 2, Entries 6–9, 11, 12,
14–16, and 19), the racemate crystallized with preferential hete-
rochiral interaction (fR,S > fR,R, fS,S), which led to the successful
enantiomeric enrichment of the mother liquors.
A mechanistic rationale was proposed for the enantioselect-
ivity observed in the reactions to give 3ag, 3bg, and 3ug (Fig-
ure 5), in which the synergistic noncovalent hydrogen-bonding a 1 cm path length on a Perkin–Elmer 341 polarimeter or by using
a 0.1 mL cell with a 1 cm path length on a Rudolph Autopol IV
automatic polarimeter. The concentrations (c) were reported in
g 100 mL–1. The X-ray single-crystal structure analysis was per-
formed with a Bruker APEX II X-ray single crystal diffractometer.
Analytical HPLC was recorded on an HPLC instrument equipped
with a Waters 1525 Binary HPLC Pump and Waters 2998 Photodiode
Array Detector or an HPLC instrument equipped with an Agilent
1100 series quaternary pump and a UV diode array detector. The
chiral stationary phase was a Daicel Chiracel OD (Ø = 0.46 cm,
length = 25.0 cm), AD (Ø = 0.46 cm, length = 25.0 cm), IC (Ø =
activation of both the Michael donor and acceptor might be
one of the crucial elements for the current stereocontrol. In
contrast to the in situ generation of the configurationally de-
fined (Z)-enolate in the Michael addition of cyclic cyano ketone
1u [Figure 5, Equation (3); Table 2, Entry 21], the (E)-enolates of
the acyclic cyano ketones would be preferentially formed [Fig-
ure 5, Equations (1) and (2)]. The present enantioselectivity ob-
served in the products[16] may be supported by models TS1,
TS2, and TS3, as an energetically unfavorable steric interaction
exists between the donors and acceptors in models TS1′, TS2′, 0.46 cm, length = 25.0 cm), IA-3 (Ø = 0.46 cm, length = 25.0 cm),
IC-3 (Ø = 0.46 cm, length = 25.0 cm), AD-H (Ø = 0.46 cm, length =
25.0 cm), or AY-H (Ø = 0.46 cm, length = 25.0 cm) column. For
complete experimental procedures, copies of the NMR and HPLC
spectra along with X-ray crystal structure analyses for (R)-3ag and
(R)-3ug, see the Supporting Information.
and TS3′, which is consistent with the fact that the planar aryl
moiety of a Michael donor is usually bulkier than the linear
cyano group.
General Experimental Procedure for Solvent and Catalyst
Screenings: To an oven-dried 10 mL Schlenk tube were sequen-
tially added the catalyst (0.02 mmol, 0.2 equiv.), α-cyano ketone 1a
(24.9 mg, 0.1 mmol), the solvent (0.5 mL), and 4-bromophenyl acryl-
ate (2a, 45.4 mg, 0.2 mmol, 2.0 equiv.) at 25 °C. The resulting mix-
ture was stirred at this temperature for the indicated time. Then,
without further evaporation of the solvent, the reaction mixture
was directly subjected to purification by flash column chromatogra-
phy on silica gel to yield the desired Michael adduct 3aa.
Conclusions
We have described the details of the enantioselective Michael
addition of α-cyano ketones and acrylates by using bifunctional
tertiary amine-thiourea catalysts. By using this method, we syn-
thesized 32 chiral all-carbon quaternary stereocentered Michael
adducts with moderate to excellent enantioselectivities and
yields. These multifunctionalized Michael adducts are potential
precursors to a number of hydrodibenzofuran natural products.
In addition, this metal-free, facile method can be increased to
a four-gram scale, which can supply sufficient amounts of pre-
cursors for further transformations toward enantiopure hydrodi-
benzofuran-type natural products and their related derivatives
for biological and medicinal purposes.
General Experimental Procedure Using Acceptors 2a–2n in the
Catalytic Enantioselective Michael Addition Reaction: To an
oven-dried 10 mL Schlenk tube were sequentially added catalyst
4o (11.3 mg, 0.02 mmol, 0.2 equiv.), α-cyano ketone 1a (24.9 mg,
0.1 mmol), p-xylene (0.5 mL), and Michael acceptor 2a–2n
(0.2 mmol, 2.0 equiv.) at 25 °C. The resulting mixture was stirred
at this temperature for the indicated time. Then, without further
evaporation of the solvent, the reaction mixture was directly sub-
jected to purification by flash column chromatography on silica gel
to yield the desired Michael adduct 3aa–3an.
Experimental Section
General Methods: All reactions were carried out in oven- or heat-
dried flasks. When necessary, the solvents used were purified by
Analytical Data for Michael Adducts 3aa–3an
standard drying techniques. Reagents were purchased from com- Compound 3aa: (Table 1, Entry 1). The general experimental proce-
mercial vendors and used without further purification. All reactions
were monitored by thin layer chromatography on silica gel F254
plates by using UV light as the visualizing agent (if applicable) and
a solution of ammonium molybdate tetrahydrate (50 g L–1) in EtOH
dure was followed to afford product 3aa (46.0 mg, 0.097 mmol,
97 % yield); [α]D17 = –35.0 (c = 1.0, CHCl3). The enantiomeric excess
value of 81 % was determined by HPLC (Chiralcel AD; n-hexane/
2-propanol, 90:10; flow rate: 1.0 mL min–1): tR = 32.5 min (major
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enantiomer) and tR = 23.5 min (minor enantiomer). 1H NMR 96 % yield); [α]D18 = –39.0 (c = 1.0, CHCl3). The enantiomeric excess
(400 MHz, CDCl3): δ = 7.49 (d, J = 8.8 Hz, 2 H), 7.23 (d, J = 7.6 Hz,
value of 80 % was determined by HPLC (Chiralcel AD; n-hexane/
1 H), 7.16 (t, J = 7.6 Hz, 1 H), 7.01 (d, J = 7.6 Hz, 1 H), 6.93 (d, J = 2-propanol, 90:10; flow rate: 1.0 mL min–1): tR = 26.6 min (major
8.8 Hz, 2 H), 5.21, 5.19 (ABq, J = 5.2 Hz, 2 H), 3.86 (s, 3 H), 3.54 (s, 3
enantiomer) and tR = 19.8 min (minor enantiomer). 1H NMR
(400 MHz, CDCl3): δ = 7.23 (dd, J = 8.0, 1.0 Hz, 1 H), 7.17 (t, J =
H), 2.85–2.75 (m, 2 H), 2.72–2.64 (m, 1 H), 2.59–2.51 (m, 1 H), 2.25
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 197.5, 170.2, 151.9, 8.0 Hz, 1 H), 7.08–6.98 (m, 5 H), 5.22, 5.19 (ABq, J = 5.2 Hz, 2 H),
149.5, 143.2, 132.4, 132.4, 127.3, 124.2, 123.2, 123.2, 120.5, 118.9, 3.86 (s, 3 H), 3.54 (s, 3 H), 2.84–2.75 (m, 2 H), 2.72–2.64 (m, 1 H),
118.5, 113.8, 99.1, 58.2, 56.5, 55.9, 30.3, 29.1, 26.0 ppm. MS (EI): m/z
(%) = 435 (<1) [M(81Br) – Ac + H]+, 433 (<1) [M(79Br) – Ac + H]+, 403
(<1), 401 (<1), 304 (<1), 272 (1), 262 (<1), 261 (<1), 259 (<1), 245
(<1), 230 (11), 188 (3), 176 (3), 55 (8), 45 (100), 43 (28). HRMS (ESI):
calcd. for C22H2379BrNO6 [M + H]+ 476.0703; found 476.0701.
2.62–2.50 (m, 1 H), 2.25 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 197.5, 170.6, 161.4, 158.9, 151.9, 146.3, 146.2, 143.2, 127.4, 124.2,
122.84, 122.76, 120.4, 118.5, 116.1, 115.8, 113.8, 99.0, 58.1, 56.5, 55.9,
30.2, 29.1, 26.0 ppm. MS (EI): m/z (%) = 373 (<1) [M – Ac + H]+, 341
(<1), 304 (<1), 272 (<1), 259 (<1), 245 (<1), 230 (7), 202 (2), 188 (3),
176 (3), 55 (8), 45 (100), 43 (31). HRMS (ESI): calcd. for C22H23FNO6
[M + H]+ 416.1504; found 416.1497.
Compound 3ab: (Table 1, Entry 2). The general experimental proce-
dure was followed to afford product 3ab (44.0 mg, 0.092 mmol,
92 % yield); [α]D17 = –36.0 (c = 1.0, CHCl3)]. The enantiomeric excess Compound 3af: (Table 1, Entry 6). The general experimental proce-
value of 80 % was determined by HPLC (Chiralcel AD; n-hexane/
dure was followed to afford product 3af (39.0 mg, 0.090 mmol,
2-propanol, 90:10; flow rate: 1.0 mL min–1): tR = 18.8 min (major
90 % yield); [α]D18 = –31.0 (c = 1.0, CHCl3). The enantiomeric excess
enantiomer) and tR = 15.2 min (minor enantiomer). 1H NMR value of 80 % was determined by HPLC (Chiralcel AD; n-hexane/
(400 MHz, CDCl3): δ = 7.36–7.34 (m, 1 H), 7.25–7.22 (m, 2 H), 7.20–
7.15 (m, 2 H), 7.04–6.97 (m, 2 H), 5.22, 5.19 (ABq, J = 4.8 Hz, 2 H),
3.86 (s, 3 H), 3.54 (s, 3 H), 2.85–2.66 (m, 3 H), 2.60–2.52 (m, 1 H),
2.25 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 197.4, 170.2, 151.9,
2-propanol, 90:10; flow rate: 1.0 mL min–1): tR = 29.8 min (major
enantiomer) and tR = 21.8 min (minor enantiomer). 1H NMR
(400 MHz, CDCl3): δ = 7.33–7.30 (m, 2 H), 7.24–7.21 (m, 1 H), 7.18–
7.14 (m, 1 H), 7.03–6.97 (m, 3 H), 5.22, 5.19 (ABq, J = 5.0 Hz, 2 H),
150.9, 143.3, 130.4, 129.0, 127.2, 125.0, 124.2, 122.2, 120.6, 120.3, 3.86 (s, 3 H), 3.54 (s, 3 H), 2.85–2.75 (m, 2 H), 2.72–2.64 (m, 1 H),
118.5, 113.8, 99.1, 58.2, 56.6, 55.9, 30.3, 29.0, 26.0 ppm. MS (EI): m/z
2.59–2.50 (m, 1 H), 2.25 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 197.5, 170.3, 151.9, 148.9, 143.2, 131.2, 129.4, 129.4, 127.4, 124.2,
(%) = 435 (<1) [M(81Br) – Ac + H]+, 433 (<1) [M(79Br) – Ac + H]+, 403
(<1), 401 (<1), 304 (<1), 272 (1), 259 (2), 245 (<1), 230 (11), 217 (6), 122.8, 122.8, 120.5, 118.5, 113.8, 99.1, 58.2, 56.5, 55.9, 30.3, 29.1,
202 (4), 188 (4), 175 (8), 55 (15), 45 (100), 43 (52). HRMS (ESI): calcd.
26.0 ppm. MS (EI): m/z (%) = 391 (<1) [M(37Cl) – Ac + H]+, 389 (<1)
[M(35Cl) – Ac + H]+, 359 (<1), 357 (<1), 304 (<1), 274 (<1), 272 (<1),
261 (<1), 245 (<1), 230 (10), 202 (2), 188 (2), 176 (3), 55 (9), 45 (100),
43 (32). HRMS (ESI): calcd. for C22H2335ClNO6 [M + H]+ 432.1208;
found 432.1209.
for C22H2379BrNO6 [M + H]+ 476.0703; found 476.0699.
Compound 3ac: (Table 1, Entry 3). The general experimental proce-
dure was followed to afford product 3ac (44.0 mg, 0.092 mmol,
92 % yield); [α]D18 = –19.0 (c = 1.0, CHCl3). The enantiomeric excess
value of 66 % was determined by HPLC (Chiralcel AD; n-hexane/
2-propanol, 90:10; flow rate: 1.0 mL min–1): tR = 22.4 min (major
Compound 3ag: (Table 1, Entry 7). The general experimental proce-
dure was followed to afford product 3ag (50.0 mg, 0.096 mmol,
enantiomer) and tR = 17.3 min (minor enantiomer). 1H NMR 96 % yield). For the analytic data, recrystallization procedure, and
(400 MHz, CDCl3): δ = 7.60–7.57 (m, 1 H), 7.34–7.29 (m, 1 H), 7.25–
7.23 (m, 1 H), 7.20–7.08 (m, 3 H), 7.04–7.01 (m, 1 H), 5.22, 5.20 (ABq,
J = 4.8 Hz, 2 H), 3.87 (s, 3 H), 3.54 (s, 3 H), 2.92–2.80 (m, 2 H), 2.76–
2.58 (m, 2 H), 2.26 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
197.5, 169.7, 151.9, 148.0, 143.1, 133.3, 128.4, 127.44, 127.38, 124.3,
123.6, 120.4, 118.6, 116.0, 113.8, 99.0, 58.2, 56.4, 55.9, 30.2, 29.2,
26.0 ppm. MS (EI): m/z (%) = 435 (<1) [M(81Br) – Ac + H]+, 433 (<1)
[M(79Br) – Ac + H]+, 403 (<1), 401 (<1), 304 (<1), 272 (1), 259 (<1),
245 (<1), 230 (11), 188 (4), 176 (4), 55 (9), 45 (100), 43 (29). HRMS
(ESI): calcd. for C22H2379BrNO6 [M + H]+ 476.0703; found 476.0690.
X-ray crystal structure analysis of 3ag, see below (Table 2, Entry 1).
Compound 3ai: (Table 1, Entry 9). The general experimental proce-
dure was followed to afford product 3ai (43.0 mg, 0.094 mmol, 94 %
yield); [α]D19 = –40.0 (c = 1.0, CHCl3). The enantiomeric excess value
of 81 % was determined by HPLC (Chiralcel AD; n-hexane/2-prop-
anol, 65:35; flow rate: 1.0 mL min–1): tR = 13.1 min (major enantio-
mer) and tR = 11.4 min (minor enantiomer). 1H NMR (400 MHz,
CDCl3): δ = 8.05–8.03 (m, 2 H), 7.24–7.22 (m, 1 H), 7.18–7.10 (m, 3
H), 7.02–7.00 (m, 1 H), 5.21, 5.19 (ABq, J = 5.2 Hz, 2 H), 3.90 (s, 3 H),
3.85 (s, 3 H), 3.53 (s, 3 H), 2.87–2.65 (m, 3 H), 2.61–2.52 (m, 1 H),
2.24 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 197.4, 170.0, 166.2,
154.1, 151.9, 143.2, 131.0, 131.0, 127.7, 127.3, 124.2, 121.4, 121.4,
Compound 3ad: (Table 1, Entry 4). The general experimental proce-
dure was followed to afford product 3ad (39.2 mg, 0.089 mmol,
89 % yield); [α]D18 = –30.0 (c = 1.0, CHCl3). The enantiomeric excess 120.5, 118.5, 113.8, 99.1, 58.1, 56.5, 55.9, 52.1, 30.4, 29.1, 26.0 ppm.
value of 78 % was determine by HPLC (Chiralcel AD; n-hexane/2-
MS (EI): m/z (%) = 413 (<1) [M – Ac + H]+, 381 (1), 304 (<1), 281
propanol, 65:35; flow rate: 1.0 mL min–1): tR = 13.8 min (major (<1), 272 (1), 259 (<1), 245 (<1), 230 (9), 217 (3), 202 (4), 188 (3),
enantiomer) and tR = 10.6 min (minor enantiomer). 1H NMR 176 (4), 121(7), 55 (7), 45 (100), 43 (33). HRMS (ESI): calcd. for
(400 MHz, CDCl3): δ = 8.10–8.07 (m, 1 H), 7.68–7.63 (m, 1 H), 7.42–
7.38 (m, 1 H), 7.24–7.15 (m, 3 H), 7.04–7.01 (m, 1 H), 5.23, 5.18 (ABq,
J = 5.2 Hz, 2 H), 3.87 (s, 3 H), 3.54 (s, 3 H), 2.94–2.78 (m, 2 H), 2.76–
2.61 (m, 2 H), 2.25 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
197.5, 169.9, 152.0, 143.9, 143.1, 141.5, 134.8, 127.4, 126.7, 125.8,
125.2, 124.3, 120.4, 118.5, 113.9, 99.0, 58.2, 56.4, 55.9, 30.2, 29.0,
26.0 ppm. MS (EI): m/z (%) = 400 (<1) [M – Ac + H]+, 368 (2), 304
(<1), 272 (3), 245 (1), 230 (2), 217 (2), 202 (3), 188 (5), 175 (3), 156 (1),
128 (2), 55 (8), 45 (100), 43 (25). HRMS (ESI): calcd. for C22H23N2O8
[M + H]+ 443.1449; found 443.1445.
C24H26NO8 [M + H]+ 456.1653; found 456.1654.
Compound 3aj: (Table 1, Entry 10). The general experimental pro-
cedure was followed to afford product 3aj (43.8 mg, 0.099 mmol,
99 % yield); [α]D18 = –43.0 (c = 1.0, CHCl3). The enantiomeric excess
value of 81 % was determined by HPLC (Chiralcel AD; n-hexane/
2-propanol, 65:35; flow rate: 1.0 mL min–1): tR = 25.3 min (major
enantiomer) and tR = 15.9 min (minor enantiomer). 1H NMR
(400 MHz, CDCl3): δ = 8.25–8.22 (m, 2 H), 7.25–7.21 (m, 3 H), 7.19–
7.14 (m, 1 H), 7.03–7.01 (m, 1 H), 5.21, 5.19 (ABq, J = 5.2 Hz, 2 H),
3.86 (s, 3 H), 3.53 (s, 3 H), 2.89–2.77 (m, 2 H), 2.73–2.56 (m, 2 H),
2.24 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 197.4, 169.7, 155.1,
151.9, 145.2, 143.2, 127.1, 125.1, 125.1, 124.2, 122.3, 122.3, 120.4,
Compound 3ae: (Table 1, Entry 5). The general experimental proce-
dure was followed to afford product 3ae (40.0 mg, 0.096 mmol,
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118.4, 113.8, 99.1, 58.1, 56.5, 55.9, 30.4, 29.0, 26.0 ppm. MS (EI): m/z
(%) = 400 (<1) [M – Ac + H]+, 368 (2), 304 (<1), 272 (2), 259 (<1),
Michael adduct 3ag (5.2 g, 9.9 mmol, 99 % yield). The enantiomeric
excess value of 81 % was determined by HPLC (Chiralcel AD; n-
245 (<1), 230 (4), 217 (1), 202 (3), 188 (3), 176 (4), 55 (8), 45 (100), hexane/2-propanol, 80:20; flow rate: 1.0 mL min–1): tR = 20.5 min
43 (28). HRMS (ESI): calcd. for C22H23N2O8 [M + H]+ 443.1449; found
443.1432.
(major enantiomer) and tR = 15.1 min (minor enantiomer). H NMR
(400 MHz, CDCl3): δ = 7.66 (d, J = 8.0 Hz, 2 H), 7.23 (d, J = 8.0 Hz,
1 H), 7.16 (t, J = 8.0 Hz, 1 H), 7.01 (d, J = 8.0 Hz, 1 H), 6.81 (d, J =
8.0 Hz, 2 H), 5.21, 5.19 (ABq, J = 5.2 Hz, 2 H), 3.86 (s, 3 H), 3.54 (s, 3
H), 2.84–2.64 (m, 3 H), 2.59–2.51 (m, 1 H), 2.25 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 197.5, 170.2, 151.9, 150.3, 143.2, 138.4,
138.4, 127.4, 124.2, 123.6, 123.6, 120.5, 118.5, 113.8, 99.1, 89.9, 58.2,
56.5, 55.9, 30.3, 29.1, 26.1 ppm. MS (EI): m/z (%) = 481 (<1) [M – Ac
+ H]+, 449 (<1), 304 (1), 272 (<1), 264 (1), 245 (<1), 230 (28), 202 (5),
1
Compound 3ak: (Table 1, Entry 11). The general experimental pro-
cedure was followed to afford product 3ak (32.6 mg, 0.082 mmol,
82 % yield); [α]D18 = –35.0 (c = 1.0, CHCl3). The enantiomeric excess
value of 80 % was determined by HPLC (Chiralcel AD; n-hexane/
2-propanol, 90:10; flow rate: 1.0 mL min–1): tR = 19.9 min (major
enantiomer) and tR = 16.5 min (minor enantiomer). 1H NMR
(400 MHz, CDCl3): δ = 7.36 (t, J = 8.0 Hz, 2 H), 7.25–7.15 (m, 3 H),
7.05–7.01 (m, 3 H), 5.22, 5.20 (ABq, J = 5.0 Hz, 2 H), 3.86 (s, 3 H),
3.55 (s, 3 H), 2.86–2.66 (m, 3 H), 2.61–2.53 (m, 1 H), 2.26 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 197.6, 170.6, 152.0, 150.5, 143.2,
129.3, 129.3, 127.5, 125.8, 124.2, 121.4, 121.4, 120.5, 118.6, 113.8,
99.0, 58.2, 56.5, 55.9, 30.4, 29.2, 26.1 ppm. MS (EI): m/z (%) = 396
(<1) [M – H]+, 355 (<1) [M – Ac + H]+, 323 (<1), 272 (<1), 259 (2),
245 (<1), 230 (9), 217 (4), 202 (3), 188 (4), 175 (6), 94 (11), 77 (5), 55
(18), 45 (100), 43 (43). HRMS (ESI): calcd. for C22H24NO6 [M + H]+
398.1598; found 398.1589.
188 (5), 176 (6), 55 (9), 45 (100), 43 (32). IR: ν = 2240, 1479, 1199,
˜
1165, 1140, 1097, 1077, 923 cm–1. HRMS (ESI): calcd. for C22H26IN2O6
[M + NH4]+ 541.0830; found 541.0837. The obtained product 3ag
(5.2 g, 9.9 mmol, 81 % ee) was dissolved in CHCl3 (15 mL) followed
by the sequential addition of 2-propanol (40 mL) and n-hexane
(400 mL). The mixed solution was allowed to stand at room temper-
ature for 7 d. The mixture was filtered, and the crystals were washed
with n-hexane (4 × 5 mL) to give the enantioenriched crystal 3ag
(4.0 g, 7.6 mmol, 76 % yield, 99 % ee); m.p. 112–114 °C. [α]D26 = –39.0
(c = 1.0, CHCl3). A second recrystallization of crystal 3ag (100 mg,
99 % ee) from a mixed solution of CHCl3 (0.3 mL), 2-propanol
(0.8 mL), and n-hexane (10 mL) gave the single crystal (99.5 % ee)
that was used to determine the absolute configuration by X-ray
crystal structure analysis.
Compound 3al: (Table 1, Entry 12). The general experimental pro-
cedure was followed to afford product 3al (44.4 mg, 0.099 mmol,
99 % yield); [α]D18 = –31.0 (c = 1.0, CHCl3). The enantiomeric excess
value of 67 % was determined by HPLC (Chiralcel AD; n-hexane/
2-propanol, 90:10; flow rate: 1.0 mL min–1): tR = 26.8 min (major
enantiomer) and tR = 20.7 min (minor enantiomer). 1H NMR
(400 MHz, CDCl3): δ = 7.88–7.83 (m, 2 H), 7.75–7.73 (m, 1 H), 7.54–
7.49 (m, 2 H), 7.47–7.43 (m, 1 H), 7.30–7.27 (m, 1 H), 7.22–7.17 (m,
2 H), 7.04–7.02 (m, 1 H), 5.25, 5.23 (ABq, J = 5.2 Hz, 2 H), 3.87 (s, 3
H), 3.57 (s, 3 H), 3.07–2.99 (m, 1 H), 2.95–2.87 (m, 1 H), 2.84–2.72
(m, 2 H), 2.29 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 197.5,
170.6, 152.0, 146.4, 143.2, 134.6, 127.9, 127.5, 126.6, 126.41, 126.40,
126.0, 125.3, 124.3, 121.1, 120.5, 118.6, 117.9, 113.8, 99.1, 58.2, 56.6,
55.9, 30.3, 29.3, 26.1 ppm. MS (EI): m/z (%) = 386 (<1) [M – MOMO]+,
372 (<1), 324 (<1), 304 (1), 272 (<1), 262 (<1), 245 (<1), 230 (10),
202 (3), 188 (5), 144 (6), 115 (9), 55 (7), 45 (100), 43 (28). HRMS (ESI):
calcd. for C26H26NO6 [M + H]+ 448.1755; found 448.1738.
General Experimental Procedure Using Donors 1b–1u in the
Catalytic Enantioselective Michael Addition Reaction: To an
oven-dried 10 mL Schlenk tube were sequentially added catalyst
4o (22.6 mg, 0.04 mmol, 0.2 equiv.), α-cyano ketone 1b–1u
(0.2 mmol), p-xylene (1.0 mL), and 4-iodophenyl acrylate (2g,
109.6 mg, 0.4 mmol, 2.0 equiv.) at 25 °C. The resulitng mixture was
stirred at this temperature until the donor had disappeared upon
inspection by thin layer chromatography. Then, without further
evaporation of solvent, the reaction mixture was directly subjected
to purification by flash column chromatography on silica gel to
yield the desired Michael adduct 3bg–3ug.
Analytic Data for Michael Adducts 3bg–3ug
Compound 3an: (Table 1, Entry 14). The general experimental pro-
cedure was followed to afford product 3an (35.8 mg, 0.092 mmol,
Compound 3bg: (Table 2, Entry 2). The general experimental proce-
dure was followed to afford product 3bg (106.8 mg, 0.187 mmol,
92 % yield); [α]D18 = –42.0 (c = 1.0, CHCl3). The enantiomeric excess 93 % yield); [α]D24 = +6.0 (c = 1.0, CHCl3). The enantiomeric excess
value of 77 % was measured by HPLC (Chiralcel AD; n-hexane/2-
value of 77 % was determined by HPLC (Chiralcel OD; n-hexane/
propanol, 65:35; flow rate: 1.0 mL min–1): tR = 16.4 min (major
2-propanol, 85:15; flow rate: 1.0 mL min–1): tR = 15.6 min (major
enantiomer) and tR = 18.1 min (minor enantiomer). 1H NMR enantiomer) and tR = 12.2 min (minor enantiomer). 1H NMR
(400 MHz, CDCl3): δ = 7.20 (dd, J = 8.0, 1.2 Hz, 1 H), 7.13 (t, J =
8.0 Hz, 1 H), 6.99 (dd, J = 8.0, 1.2 Hz, 1 H), 5.19, 5.15 (ABq, J = 5.2 Hz,
2 H), 4.42–4.33 (m, 2 H), 4.03–3.87 (m, 2 H), 3.85 (s, 3 H), 3.53 (s, 3
H), 3.13–3.05 (m, 1 H), 2.98–2.89 (m, 1 H), 2.73–2.58 (m, 2 H), 2.25
(400 MHz, CDCl3): δ = 7.72 (d, J = 2.4 Hz, 1 H), 7.68–7.65 (m, 2 H),
7.50 (dd, J = 8.8, 2.4 Hz, 1 H), 7.08 (d, J = 8.8 Hz, 1 H), 6.83–6.79 (m,
2 H), 5.16, 5.14 (ABq, J = 6.8 Hz, 2 H), 3.44 (s, 3 H), 2.85–2.57 (m, 4
H), 2.22 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 197.2, 170.0,
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 197.8, 171.6, 153.2, 153.1, 150.2, 138.4, 138.4, 133.8, 131.3, 125.0, 123.5, 123.5, 117.6,
151.8, 143.1, 127.7, 124.1, 120.6, 118.7, 113.7, 99.0, 62.1, 58.1, 56.3,
55.9, 42.4, 31.2, 28.8, 26.2 ppm. MS (EI): m/z (%) = 348 (<1) [M – Ac
+ H]+, 316 (4), 304 (<1), 272 (<1), 259 (1), 229 (10), 217 (5), 201 (5),
188 (9), 175 (6), 88 (7), 55 (17), 45 (100), 43 (70). HRMS (ESI): calcd.
for C19H23N2O7 [M + H]+ 391.1500; found 391.1492.
116.2, 114.7, 94.5, 90.0, 56.8, 55.9, 30.1, 28.0, 25.9 ppm. IR: ν = 2240,
˜
1759, 1734, 1482, 1200, 1164, 1137, 976 cm–1. HRMS (ESI): calcd. for
C21H2379BrIN2O5 [M + NH4]+ 588.9830; found 588.9819.
Compound 3cg: (Table 2, Entry 3). The general experimental proce-
dure was followed to afford product 3cg (94.5 mg, 0.172 mmol,
86 % yield); [α]D24 = –34.0 (c = 1.0, CHCl3). The enantiomeric excess
value of 80 % was determined by HPLC (Chiralcel AD; n-hexane/
2-propanol, 80:20; flow rate: 1.0 mL min–1): tR = 15.5 min (major
enantiomer) and tR = 13.5 min (minor enantiomer). 1H NMR
Gram-Scale Reaction for Preparation of 3ag: (Table 2, Entry 1).
To an oven-dried round-bottom flask were sequentially added cata-
lyst 4o (1.13 g, 2.0 mmol, 0.2 equiv.), α-cyano ketone 1a (2.48 g,
10.0 mmol), p-xylene (50 mL), and 4-iodophenyl acrylate (2g, 5.48 g,
20.0 mmol, 2.0 equiv.) at 25 °C. The resulting mixture was stirred at (400 MHz, CDCl3): δ = 7.65 (d, J = 8.4 Hz, 2 H), 7.22 (d, J = 8.0 Hz,
this temperature for 2.5 d. Then, without further evaporation of the
solvent, the reaction mixture was directly subjected to purification
by flash column chromatography on silica gel to yield the desired
1 H), 7.16 (t, J = 8.0 Hz, 1 H), 7.01 (d, J = 8.0 Hz, 1 H), 6.81 (d, J =
8.4 Hz, 2 H), 5.98–5.88 (m, 1 H), 5.37–5.20 (m, 4 H), 4.27, 4.19 (dABq,
J = 5.6, 12.8 Hz, 2 H), 3.85 (s, 3 H), 2.83–2.50 (m, 4 H), 2.25 (s, 3
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H) ppm. 13C NMR (100 MHz, CDCl3): δ = 197.4, 170.1, 151.9, 150.3,
95 % yield). The enantiomeric excess of 64 % value was determined
143.2, 138.3, 138.3, 133.7, 127.4, 124.2, 123.6, 123.6, 120.5, 118.5, by HPLC (Chiralcel AD; n-hexane/2-propanol, 80:20; flow rate:
117.5, 113.8, 96.8, 89.8, 71.0, 56.5, 55.9, 30.3, 29.2, 26.1 ppm. IR: ν =
1.0 mL min–1): tR = 15.5 min (major enantiomer) and tR = 11.1 min
˜
1
2237, 1761, 1479, 1270, 1201, 1167, 1144, 930 cm–1. HRMS (ESI): (minor enantiomer). H NMR (400 MHz, CDCl3): δ = 7.69–7.65 (m, 2
calcd. for C24H28IN2O6 [M + NH4]+ 567.0987; found 567.0990.
H), 7.40–7.36 (m, 1 H), 7.04–6.93 (m, 3 H), 6.85–6.81 (m, 2 H), 3.84
(s, 3 H), 2.78–2.63 (m, 2 H), 2.55–2.45 (m, 2 H), 2.30 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 197.5, 169.9, 160.5, 150.2, 138.4,
138.4, 134.2, 130.9, 123.6, 123.6, 118.5, 118.3, 114.5, 112.2, 89.9, 58.8,
Compound 3dg: (Table 2, Entry 4). The general experimental proce-
dure was followed to afford product 3dg (104.7 mg, 0.184 mmol,
92 % yield); [α]D24 = –21.0 (c = 1.0, CHCl3). The enantiomeric excess
value of 76 % was determined by HPLC (Chiralcel IC; n-hexane/2-
propanol, 80:20; flow rate: 1.0 mL min–1): tR = 11.3 min (major
enantiomer) and tR = 13.8 min (minor enantiomer). 1H NMR
(400 MHz, CDCl3): δ = 7.68 (d, J = 8.6 Hz, 2 H), 7.49–7.33 (m, 5 H),
7.22–7.16 (m, 2 H), 7.09–7.04 (m, 1 H), 6.84 (d, J = 8.6 Hz, 2 H), 5.21,
5.15 (ABq, J = 10.8 Hz, 2 H), 3.91 (s, 3 H), 2.87–2.52 (m, 4 H), 2.20 (s,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 197.6, 170.1, 152.8, 150.2,
144.8, 138.3, 138.3, 136.6, 128.30, 128.30, 128.28, 128.28, 128.2,
128.0, 124.3, 123.6, 123.6, 119.8, 118.9, 113.8, 89.8, 74.1, 55.9, 55.8,
55.4, 31.0, 30.3, 26.6 ppm. IR: ν = 2236, 1481, 1291, 1256, 1207,
˜
1171, 1134, 1047 cm–1. HRMS (ESI): calcd. for C20H22IN2O4 [M +
NH4]+ 481.0619; found 481.0624. The obtained product 3gg
(88.0 mg, 0.190 mmol, 64 % ee) was dissolved in CHCl3 (0.3 mL)
followed by the sequential addition of 2-propanol (0.5 mL) and n-
hexane (10 mL). The mixed solution was allowed to stand at 4 °C
for 6 h. The crystals with the lower ee value were separated from
the solution by filtration, and the mother liquor was collected to
afford the enantioenriched product 3gg (55.5 mg, 0.120 mmol,
60 % yield, 90 % ee); [α]D24 = –38.0 (c = 1.0, CHCl3).
30.2, 29.4, 26.3 ppm. IR: ν = 2238, 1760, 1730, 1478, 1273, 1202,
˜
1169, 1143 cm–1. HRMS (ESI): calcd. for C27H28IN2O5 [M + NH4]+
587.1037; found 587.1043.
Compound 3hg: (Table 2, Entry 8). The general experimental proce-
dure was followed to afford product 3hg (87.8 mg, 0.190 mmol,
95 % yield). The enantiomeric excess value of 71 % was determined
by HPLC (Chiralcel AD; n-hexane/2-propanol, 80:20; flow rate:
1.0 mL min–1): tR = 20.4 min (major enantiomer) and tR = 16.4 min
(minor enantiomer). 1H NMR (400 MHz, CDCl3): δ = 7.67 (d, J =
8.8 Hz, 2 H), 7.37 (d, J = 8.8 Hz, 2 H), 6.97 (d, J = 8.8 Hz, 2 H), 6.83
(d, J = 8.8 Hz, 2 H), 3.84 (s, 3 H), 2.77–2.61 (m, 2 H), 2.54–2.45 (m, 2
H), 2.29 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 197.9, 170.0,
160.3, 150.3, 138.4, 138.4, 127.6, 127.6, 124.4, 123.6, 123.6, 118.8,
Compound 3eg: (Table 2, Entry 5). The general experimental proce-
dure was followed to afford product 3eg (93.5 mg, 0.190 mmol,
95 % yield). The enantiomeric excess value of 73 % was determined
by HPLC (Chiralcel AD; n-hexane/2-propanol, 80:20; flow rate:
1.0 mL min–1): tR = 15.7 min (major enantiomer) and tR = 14.0 min
(minor enantiomer). 1H NMR (400 MHz, CDCl3): δ = 7.66 (d, J =
8.8 Hz, 2 H), 7.17–7.12 (m, 2 H), 7.03–6.99 (m, 1 H), 6.82 (d, J =
8.8 Hz, 2 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 2.84–2.50 (m, 4 H), 2.25 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 197.6, 170.1, 152.8, 150.3,
145.9, 138.4, 138.4, 127.9, 124.2, 123.6, 123.6, 119.6, 118.7, 113.9,
115.1, 115.1, 90.0, 58.1, 55.4, 31.0, 30.3, 26.5 ppm. IR: ν = 2240,
˜
1760, 1727, 1511, 1257, 1199, 1169, 1141 cm–1. HRMS (ESI): calcd.
for C20H22IN2O4 [M + NH4]+ 481.0619; found 481.0626. The obtained
product 3hg (87.8 mg, 0.190 mmol, 71 % ee) was dissolved in Et2O
(1.5 mL) followed by addition of n-hexane (10 mL). The mixed solu-
tion was allowed to stand at room temperature for 5 d. The crystals
with the lower ee value were separated from the solution by filtra-
tion, and the mother liquor was collected to afford the enantioen-
riched product 3hg (67.8 mg, 0.146 mmol, 73 % yield, 87 % ee);
[α]D24 = –52.0 (c = 1.0, CHCl3).
89.9, 60.3, 55.9, 55.8, 30.3, 29.3, 26.1 ppm. IR: ν = 2238, 1759, 1479,
˜
1275, 1198, 1168, 1142, 1004 cm–1
.
HRMS (ESI): calcd. for
C21H24IN2O5 [M + NH4]+ 511.0724; found 511.0715. The obtained
product 3eg (93.5 mg, 0.190 mmol, 73 % ee) was dissolved in CHCl3
(0.5 mL) followed by the sequential addition of 2-propanol (1.5 mL)
and n-hexane (10 mL). The mixed solution was allowed to stand at
room temperature for 15 h. The mixture was filtered, and the crys-
tals were washed with n-hexane (4 × 1 mL) to give the enantioen-
riched crystal 3eg (41 mg, 0.0831 mmol, 42 % yield, 90 % ee); m.p.
110–115 °C. [α]D29 = –2.0 (c = 1.0, CHCl3).
Compound 3ig: (Table 2, Entry 9). The general experimental proce-
dure was followed to afford product 3ig (64 mg, 0.125 mmol, 63 %
yield). The enantiomeric excess value of 59 % was determined by
HPLC (Chiralcel AD; n-hexane/2-propanol, 80:20; flow rate:
1.0 mL min–1): tR = 20.5 min (major enantiomer) and tR = 14.1 min
Compound 3fg: (Table 2, Entry 6). The general experimental proce-
dure was followed to afford product 3fg (89.0 mg, 0.192 mmol,
96 % yield). The enantiomeric excess value of 72 % was determined
by HPLC (Chiralcel IC; n-hexane/2-propanol, 80:20; flow rate:
1.0 mL min–1): tR = 14.1 min (major enantiomer) and tR = 12.6 min
1
(minor enantiomer). H NMR (400 MHz, CDCl3): δ = 7.80–7.78 (m, 1
H), 7.69–7.66 (m, 3 H), 7.53–7.49 (m, 1 H), 7.36–7.32 (m, 1 H), 6.85–
6.81 (m, 2 H), 2.93–2.78 (m, 3 H), 2.59–2.49 (m, 1 H), 2.29 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 197.2, 169.9, 150.3, 138.5,
138.5, 135.6, 132.9, 131.0, 130.5, 128.6, 123.6, 123.6, 121.9, 117.4,
1
(minor enantiomer). H NMR (400 MHz, CDCl3): δ = 7.67–7.61 (m, 3
H), 7.45–7.40 (m, 1 H), 7.13–7.08 (m, 1 H), 6.96–6.93 (m, 1 H), 6.82–
6.78 (m, 2 H), 3.80 (s, 3 H), 2.82–2.70 (m, 2 H), 2.65–2.47 (m, 2 H),
2.17 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 198.0, 170.2, 155.9,
150.3, 138.4, 138.4, 130.9, 128.8, 123.6, 123.6, 122.6, 121.5, 118.2,
90.0, 60.0, 30.3, 28.4, 26.8 ppm. IR: ν = 2239, 1760, 1728, 1479, 1200,
˜
1167, 1145, 1009 cm–1. HRMS (ESI): calcd. for C19H1979BrIN2O3 [M +
NH4]+ 528.9618; found 528.9627. The obtained product 3ig (64 mg,
0.125 mmol, 59 % ee) was dissolved in CHCl3 (0.4 mL) followed by
the sequential addition of 2-propanol (1.0 mL) and n-hexane
(10 mL). The mixed solution was allowed to stand at 4 °C for 29 h.
The crystals with the lower ee value were separated from the solu-
tion by filtration, and the mother liquor was collected to afford
the enantioenriched product 3ig (42 mg, 0.0820 mmol, 41 % yield,
95 % ee); [α]D24 = +2.0 (c = 1.0, CHCl3).
111.7, 89.8, 56.4, 55.3, 30.3, 28.0, 25.7 ppm. IR: ν = 2238, 1760, 1732,
˜
1485, 1253, 1200, 1168, 1141 cm–1
.
HRMS (ESI): calcd. for
C20H22IN2O4 [M + NH4]+ 481.0619; found 481.0626. The obtained
product 3fg (89.0 mg, 0.192 mmol, 72 % ee) was dissolved in CHCl3
(0.5 mL) followed by the sequential addition of 2-propanol (1.2 mL)
and n-hexane (10 mL). The mixed solution was allowed to stand at
4 °C for 5 d. The crystals with the lower ee value were separated
from the solution by filtration, and the mother liquor was collected
to afford the enantioenriched product 3fg (59.0 mg, 0.127 mmol,
64 % yield, 91 % ee); [α]D24 = –21.0 (c = 1.0, CHCl3).
Compound 3jg: (Table 2, Entry 10). The general experimental pro-
cedure was followed to afford product 3jg (91.7 mg, 0.179 mmol,
90 % yield); [α]D24 = –19.0 (c = 1.0, CHCl3). The enantiomeric excess
value of 58 % was determined by HPLC (Chiralcel AD; n-hexane/
Compound 3gg: (Table 2, Entry 7). The general experimental proce-
dure was followed to afford product 3gg (88.0 mg, 0.190 mmol,
Eur. J. Org. Chem. 2016, 704–715
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2-propanol, 80:20; flow rate: 1.0 mL min–1): tR = 14.4 min (major
Compound 3ng: (Table 2, Entry 14). The general experimental pro-
enantiomer) and tR = 10.7 min (minor enantiomer). 1H NMR cedure was followed to afford product 3ng (76.5 mg, 0.170 mmol,
(400 MHz, CDCl3): δ = 7.68 (d, J = 8.4 Hz, 2 H), 7.63–7.56 (m, 2 H),
85 % yield). The enantiomeric excess value of 68 % was determined
7.43–7.33 (m, 2 H), 6.84 (d, J = 8.4 Hz, 2 H), 2.79–2.67 (m, 2 H), 2.55–
by HPLC (Chiralcel AD; n-hexane/2-propanol, 80:20; flow rate:
2.43 (m, 2 H), 2.33 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 1.0 mL min–1): tR = 12.3 min (major enantiomer) and tR = 10.6 min
1
197.1, 169.7, 150.2, 138.5, 138.5, 135.0, 132.7, 131.3, 129.3, 124.9, (minor enantiomer). H NMR (400 MHz, CDCl3): δ = 7.70–7.65 (m, 3
124.0, 123.6, 123.6, 118.0, 90.0, 58.4, 31.1, 30.3, 26.8 ppm. IR: ν =
H), 7.50–7.44 (m, 1 H), 7.35–7.30 (m, 1 H), 7.19–7.13 (m, 1 H), 6.84–
˜
2241, 1762, 1730, 1477, 1200, 1166, 1139, 1009 cm–1. HRMS (ESI): 6.80 (m, 2 H), 2.84–2.74 (m, 2 H), 2.61–2.50 (m, 2 H), 2.30 (s, 3
calcd. for C19H1979BrIN2O3 [M + NH4]+ 528.9618; found 528.9612.
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 196.2, 169.8, 160.8, 158.4,
150.2, 138.4, 138.4, 131.72, 131.64, 129.39, 129.36, 125.47, 125.44,
123.6, 123.6, 121.44, 121.32, 117.28, 117.15, 116.93, 90.0, 56.0, 30.3,
Compound 3kg: (Table 2, Entry 11). The general experimental pro-
cedure was followed to afford product 3kg (89.8 mg, 0.175 mmol,
88 % yield). The enantiomeric excess value of 64 % was determined
by HPLC (Chiralcel AD; n-hexane/2-propanol, 80:20; flow rate:
1.0 mL min–1): tR = 15.9 min (major enantiomer) and tR = 14.4 min
(minor enantiomer). 1H NMR (400 MHz, CDCl3): δ = 7.68 (d, J =
8.6 Hz, 2 H), 7.61 (d, J = 8.6 Hz, 2 H), 7.35 (d, J = 8.6 Hz, 2 H), 6.82
(d, J = 8.6 Hz, 2 H), 2.78–2.65 (m, 2 H), 2.54–2.44 (m, 2 H), 2.32 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 197.3, 169.8, 150.2, 138.5,
138.5, 133.0, 133.0, 131.8, 128.0, 128.0, 123.9, 123.6, 123.6, 118.2,
28.95, 28.93, 26.1 ppm. IR: ν = 2241, 1759, 1734, 1484, 1226, 1200,
˜
1167, 1142 cm–1. HRMS (ESI): calcd. for C19H19FIN2O3 [M + NH4]+
469.0419; found 469.0421. The obtained product 3ng (76.5 mg,
0.170 mmol, 68 % ee) was dissolved in CHCl3 (0.3 mL) followed by
the sequential addition of 2-propanol (0.5 mL) and n-hexane
(10 mL). The mixed solution was allowed to stand at 4 °C for 2 d. The
crystals with the lower ee value were separated from the solution
by filtration, and the mother liquor was collected to afford the en-
antioenriched product 3ng (51.5 mg, 0.114 mmol, 57 % yield,
88 % ee); [α]D24 = –14.0 (c = 1.0, CHCl3).
90.0, 58.4, 31.1, 30.2, 26.8 ppm. IR: ν = 2241, 1760, 1730, 1482, 1199,
˜
1167, 1141, 1008 cm–1. HRMS (ESI): calcd. for C19H1979BrIN2O3 [M +
NH4]+ 528.9618; found 528.9622. The obtained product 3kg
(89.8 mg, 0.175 mmol, 64 % ee) was dissolved in Et2O (1.5 mL) fol-
lowed by the addition of n-hexane (10 mL). The mixed solution was
allowed to stand at room temperature for 5 d. The crystals with the
lower ee value were separated from the solution by filtration, and
the mother liquor was collected to afford the enantioenriched prod-
uct 3kg (64.8 mg, 0.127 mmol, 63 % yield, 86 % ee); [α]D24 = –32.0
(c = 1.0, CHCl3).
Compound 3og: (Table 2, Entry 15). The general experimental pro-
cedure was followed to afford product 3og (74.8 mg, 0.160 mmol,
80 % yield). The enantiomeric excess value of 55 % was determined
by HPLC (Chiralcel AD; n-hexane/2-propanol, 80:20; flow rate:
1.0 mL min–1): tR = 18.1 min (major enantiomer) and tR = 12.9 min
1
(minor enantiomer). H NMR (400 MHz, CDCl3): δ = 7.80–7.77 (m, 1
H), 7.67 (d, J = 8.8 Hz, 2 H), 7.49–7.40 (m, 3 H), 6.82 (d, J = 8.8 Hz,
2 H), 2.90–2.72 (m, 3 H), 2.57–2.49 (m, 1 H), 2.27 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 197.0, 169.8, 150.2, 138.4, 138.4, 132.5,
131.9, 131.4, 130.9, 130.1, 128.1, 123.6, 123.6, 117.4, 90.0, 58.7, 30.3,
Compound 3lg: (Table 2, Entry 12). The general experimental pro-
cedure was followed to afford product 3lg (75.8 mg, 0.175 mmol,
88 % yield). The enantiomeric excess value of 65 % was determined
by HPLC (Chiralcel AD; n-hexane/2-propanol, 80:20; flow rate:
1.0 mL min–1): tR = 14.6 min (major enantiomer) and tR = 11.5 min
(minor enantiomer). 1H NMR (400 MHz, CDCl3): δ = 7.67 (d, J =
8.8 Hz, 2 H), 7.50–7.42 (m, 5 H), 6.83 (d, J = 8.8 Hz, 2 H), 2.79–2.67
(m, 2 H), 2.56–2.45 (m, 2 H), 2.30 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 197.7, 169.9, 150.2, 138.4, 138.4, 132.8, 129.8, 129.8,
129.4, 126.2, 126.2, 123.6, 123.6, 118.5, 90.0, 58.8, 31.1, 30.3,
28.1, 26.4 ppm. IR: ν = 2239, 1759, 1730, 1479, 1200, 1166, 1143,
˜
1008 cm–1. HRMS (ESI): calcd. for C19H1935ClIN2O3 [M + NH4]+
485.0123; found 485.0122. The obtained product 3og (74.8 mg,
0.160 mmol, 55 % ee) was dissolved in Et2O (1.5 mL) followed by
the addition of n-hexane (10 mL). The mixed solution was allowed
to stand at room temperature for 3 d and then at 4 °C for 24 h. The
crystals with the lower ee value were separated from the solution
by filtration, and the mother liquor was collected to afford the en-
antioenriched product 3og (43.8 mg, 0.0937 mmol, 47 % yield,
91 % ee); [α]D24 = –1.0 (c = 1.0, CHCl3).
26.7 ppm. IR: ν = 2240, 1760, 1728, 1481, 1199, 1166, 1140,
˜
1008 cm–1. HRMS (ESI): calcd. for C19H20IN2O3 [M + NH4]+ 451.0513;
found 451.0518. The obtained product 3lg (75.8 mg, 0.175 mmol,
65 % ee) was dissolved in CHCl3 (0.2 mL) followed by sequential
addition of 2-propanol (0.5 mL) and n-hexane (10 mL). The mixed
solution was allowed to stand at 4 °C for 30 h. The crystals with the
lower ee value were separated from the solution by filtration, and
the mother liquor was collected to afford the enantioenriched prod-
uct 3lg (46.8 mg, 0.108 mmol, 54 % yield, 87 % ee); [α]D24 = –29.0
(c = 1.0, CHCl3).
Compound 3pg: (Table 2, Entry 16). The general experimental pro-
cedure was followed to afford product 3pg (81.3 mg, 0.168 mmol,
84 % yield). The enantiomeric excess value of 71 % was determined
by HPLC (Chiralcel AD; n-hexane/2-propanol, 95:5; flow rate:
1.0 mL min–1): tR = 35.3 min (major enantiomer) and tR = 32.9 min
1
(minor enantiomer). H NMR (400 MHz, CDCl3): δ = 7.99–7.95 (m, 3
H), 7.85–7.82 (m, 1 H), 7.65 (d, J = 8.8 Hz, 2 H), 7.62–7.54 (m, 3 H),
Compound 3mg: (Table 2, Entry 13). The general experimental pro- 6.77 (d, J = 8.8 Hz, 2 H), 3.06–2.82 (m, 3 H), 2.60–2.51 (m, 1 H), 2.12
cedure was followed to afford product 3mg (73.2 mg, 0.164 mmol,
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 200.3, 170.0, 150.2,
82 % yield); [α]D24 = +12.0 (c = 1.0, CHCl3). The enantiomeric excess 138.4, 138.4, 134.6, 130.9, 129.8, 129.6, 128.6, 127.8, 127.0, 126.6,
value of 71 % was determined by HPLC (Chiralcel AD; n-hexane/
125.4, 123.5, 123.5, 122.5, 118.3, 89.9, 59.8, 30.4, 29.0, 26.1 ppm. IR:
˜
2-propanol, 80:20; flow rate: 1.0 mL min–1): tR = 13.7 min (major
ν = 2238, 1759, 1722, 1480, 1200, 1168, 1143, 776 cm–1. HRMS (ESI):
enantiomer) and tR = 11.7 min (minor enantiomer). 1H NMR calcd. for C23H22IN2O3 [M + NH4]+ 501.0670; found 501.0669. The
(400 MHz, CDCl3): δ = 7.67 (d, J = 8.8 Hz, 2 H), 7.61–7.57 (m, 1 H),
obtained product 3pg (81.3 mg, 0.168 mmol, 71 % ee) was dis-
7.38–7.33 (m, 2 H), 7.28–7.24 (m, 1 H), 6.82 (d, J = 8.8 Hz, 2 H), 2.86– solved in CHCl3 (0.4 mL) followed by sequential addition of 2-prop-
2.72 (m, 2 H), 2.70–2.61 (m, 2 H), 2.33 (s, 3 H), 2.18 (s, 3 H) ppm. 13
NMR (100 MHz, CDCl3): δ = 199.2, 170.1, 150.2, 138.4, 138.4, 136.2,
133.3, 131.2, 129.4, 127.8, 127.3, 123.6, 123.6, 118.3, 90.0, 59.1, 30.2,
C
anol (1.0 mL) and n-hexane (10 mL). The mixed solution was al-
lowed to stand at room temperature for 38 h. The crystals with the
lower ee value were separated from the solution by filtration, and
the mother liquor was collected to afford the enantioenriched prod-
28.7, 26.1, 20.2 ppm. IR: ν = 2239, 1760, 1725, 1482, 1201, 1167,
˜
1143, 1008 cm–1. HRMS (ESI): calcd. for C20H22IN2O3 [M + NH4]+ uct 3pg (52.4 mg, 0.108 mmol, 54 % yield, 93 % ee); [α]D24 = –16.0
465.0670; found 465.0675.
(c = 1.0, CHCl3).
713
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Compound 3qg: (Table 2, Entry 17). The general experimental pro-
cedure was followed to afford product 3qg (84 mg, 0.188 mmol,
123.6, 123.6, 120.0, 118.9, 113.5, 98.7, 89.8, 58.0, 55.8, 53.8, 31.3,
30.4 ppm. IR: ν = 2235, 1700, 1479, 1270, 1227, 1200, 1168,
˜
94 % yield); [α]D24 = +3.0 (c = 1.0, CHCl3). The enantiomeric excess 1140 cm–1. HRMS (ESI): calcd. for C27H28IN2O6 [M + NH4]+ 603.0987;
value of 60 % was determined by HPLC (Chiralcel IC; n-hexane/2-
propanol, 80:20; flow rate: 1.0 mL min–1): tR = 8.8 min (major
enantiomer) and tR = 9.7 min (minor enantiomer). 1H NMR
(400 MHz, CDCl3): δ = 7.69 (d, J = 8.4 Hz, 2 H), 7.39–7.26 (m, 5 H),
6.87 (d, J = 8.4 Hz, 2 H), 3.16, 3.02 (ABq, J = 13.4 Hz, 2 H), 2.81–2.73
(m, 1 H), 2.67–2.59 (m, 1 H), 2.53–2.45 (m, 1 H), 2.23–2.14 (m, 1 H),
2.19 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 202.2, 169.7, 150.2,
138.4, 138.4, 133.4, 129.9, 129.9, 128.8, 128.8, 128.0, 123.5, 123.5,
found 603.0983.
Compound 3ug: (Table 2, Entry 21). The general experimental pro-
cedure was followed to afford product 3ug (92.2 mg, 0.182 mmol,
92 % yield). The enantiomeric excess value of 72 % was determined
by HPLC (Chiralcel AD, n-hexane/2-propanol, 80:20; flow rate:
1.0 mL min–1): tR = 29.0 min (major enantiomer) and tR = 35.5 min
1
(minor enantiomer). H NMR (400 MHz, CDCl3): δ = 7.67–7.62 (m, 2
H), 7.26–7.16 (m, 2 H), 7.00–6.96 (m, 1 H), 6.82–6.76 (m, 2 H), 4.55–
4.48 (m, 1 H), 3.89 (s, 3 H), 3.81–3.74 (m, 1 H), 2.89–2.80 (m, 1 H),
2.70–2.40 (m, 6 H), 2.04–1.94 (m, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 200.3, 170.3, 152.2, 150.4, 145.4, 138.4, 138.4, 129.8,
125.6, 123.6, 123.6, 120.4, 118.4, 113.1, 89.8, 74.2, 55.9, 54.1, 35.7,
119.9, 90.0, 54.7, 43.2, 30.8, 30.2, 29.9 ppm. IR: ν = 2238, 1759, 1723,
˜
1481, 1200, 1168, 1143, 1009 cm–1
.
HRMS (ESI): calcd. for
C20H22IN2O3 [M + NH4]+ 465.0670; found 465.0664.
Compound 3rg: (Table 2, Entry 18). The general experimental pro-
cedure was followed to afford product 3rg (98.3 mg, 0.178 mmol,
89 % yield); [α]D24 = –25.0 (c = 1.0, CHCl3). The enantiomeric excess
value of 76 % was determined by HPLC (Chiralcel AD; n-hexane/
2-propanol, 80:20; flow rate: 1.0 mL min–1): tR = 14.8 min (major
enantiomer) and tR = 11.2 min (minor enantiomer). 1H NMR
(400 MHz, CDCl3): δ = 7.67–7.63 (m, 2 H), 7.24–7.21 (m, 1 H), 7.17–
7.13 (m, 1 H), 7.02–6.99 (m, 1 H), 6.83–6.79 (m, 2 H), 5.21, 5.17 (ABq,
J = 5.2 Hz, 2 H), 3.85 (s, 3 H), 3.53 (s, 3 H), 2.83–2.68 (m, 3 H), 2.61–
2.41 (m, 3 H), 1.74–1.58 (m, 2 H), 0.89 (t, J = 7.4 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 199.8, 170.2, 151.9, 150.3, 143.2, 138.3,
138.3, 127.4, 124.1, 123.6, 123.6, 120.6, 118.7, 113.7, 99.0, 89.8, 58.0,
32.3, 29.9, 29.6 ppm. IR: ν = 2235, 1759, 1723, 1480, 1281, 1201,
˜
1168, 1134 cm–1. HRMS (ESI): calcd. for C22H24IN2O5 [M + NH4]+
523.0724; found 523.0715. The obtained product 3ug (92.2 mg,
0.182 mmol, 72 % ee) was dissolved in CHCl3 (0.5 mL) followed by
sequential addition of 2-propanol (1.5 mL) and n-hexane (10 mL).
The mixed solution was allowed to stand at room temperature for
14 h. The mixture was filtered, and the crystals were washed with n-
hexane (3 × 1 mL) to give the enantioenriched crystal 3ug (70.4 mg,
0.139 mmol, 70 % yield, 98 % ee); m.p. 123–125 °C. [α]D19 = +43.0
(c = 1.0, CHCl3). A second recrystallization of crystal 3ug (30.0 mg,
98 % ee) from a mixed solution of CHCl3 (0.2 mL), 2-propanol
(1.0 mL), and n-hexane (8.0 mL) gave the single crystal (99.7 % ee),
which was used to determine the absolute configuration by X-ray
crystal structure analysis.
56.4, 55.9, 40.4, 30.4, 29.2, 17.3, 13.3 ppm. IR: ν = 2236, 1761, 1479,
˜
1271, 1200, 1168, 1142, 930 cm–1. HRMS (ESI): calcd. for C24H30IN2O6
[M + NH4]+ 569.1143; found 569.1136.
Compound 3sg: (Table 2, Entry 19). The general experimental pro-
cedure was followed to afford product 3sg (62.0 mg, 0.103 mmol,
52 % yield). The enantiomeric excess value of 54 % was determined
by HPLC (Chiralcel IC; n-hexane/2-propanol, 80:20; flow rate:
1.0 mL min–1): tR = 15.3 min (major enantiomer) and tR = 24.5 min
Acknowledgments
The authors are grateful for financial support from the National
Natural Science Foundation of China (NSFC) (grant number
21302061), the Jilin Province Science & Technology Develop-
ment Program (grant number 20140520084JH), the China Post-
doctoral Science Foundation (grant numbers 2013T60318,
2012M510130), and the Specialized Research Fund for the
Doctoral Program of Higher Education (grant number
20130061120016).
1
(minor enantiomer). H NMR (400 MHz, CDCl3): δ = 7.67–7.63 (m, 2
H), 7.33–7.25 (m, 4 H), 7.23–7.16 (m, 3 H), 7.07–7.04 (m, 1 H), 6.80–
6.77 (m, 2 H), 5.23, 5.20 (ABq, J = 5.2 Hz, 2 H), 3.93–3.75 (m, 5 H),
3.50 (s, 3 H), 2.87–2.69 (m, 3 H), 2.62–2.53 (m, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 197.4, 170.2, 152.0, 150.3, 143.3, 138.4, 138.4,
133.3, 129.8, 129.8, 128.4, 128.4, 127.1, 124.3, 123.6, 123.6, 120.8,
118.5, 114.0, 99.1, 89.8, 58.2, 56.6, 56.0, 44.9, 30.3, 29.3 ppm. IR: ν =
˜
2236, 1757, 1479, 1271, 1199, 1167, 1143, 929 cm–1. HRMS (ESI):
calcd. for C28H30IN2O6 [M + NH4]+ 617.1143; found 617.1134. The
obtained product 3sg (62.0 mg, 0.103 mmol, 54 % ee) was dissolved
in Et2O (1.0 mL) followed by addition of n-hexane (10 mL). The
mixed solution was allowed to stand at room temperature for 8 d.
The crystals with the lower ee value were separated from the solu-
tion by filtration, and the mother liquor was collected to afford
the enantioenriched product 3sg (34 mg, 0.0567 mmol, 28 % yield,
90 % ee); [α]D24 = –19.0 (c = 1.0, CHCl3).
Keywords: Asymmetric catalysis · Organocatalysis · Michael
addition · Enantioselectivity
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propanol, 80:20; flow rate: 1.0 mL min–1): tR = 15.9 min (major
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(400 MHz, CDCl3): δ = 7.91–7.87 (m, 2 H), 7.66 (d, J = 8.4 Hz, 2 H),
7.48–7.39 (m, 2 H), 7.33–7.28 (m, 2 H), 7.21–7.16 (m, 1 H), 6.95–6.92
(m, 1 H), 6.83 (d, J = 8.4 Hz, 2 H), 5.08, 4.91 (ABq, J = 5.2 Hz, 2 H),
3.75 (s, 3 H), 3.52 (s, 3 H), 3.06–2.76 (m, 3 H), 2.65–2.57 (m, 1 H) ppm.
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138.3, 138.3, 133.6, 133.3, 129.6, 129.6, 128.7, 128.2, 128.2, 124.3,
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[15] The stereochemical assignment of 3aa in Figure 3 was determined by
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the absolute configuration of 3ag (Table 1, Entry 7).
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[10] For acyclic α-cyano ketones as donors in the enantioselective Michael
Received: November 9, 2015
addition reaction with highly active acrolein for the synthesis of aryl-
Published Online: January 5, 2016
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim