Mutually complementary metal- and organocatalysis with collective synthesis: Asymmetric conjugate addition of 1,3-carbonyl compounds to nitroenynes and further reactions of the products

Article abstract of DOI:10.1002/adsc.201200226

The first metal-catalyzed 1,4-selective asymmetric addition of malonates to nitroenynes promoted by a simple chiral nickel(II)-diamine catalyst, was developed, facilitating a mild synthesis of a novel type of multifunctional chiral b-alkynyl acids bearing a nitro group. Based on this protocol, we have developed a practical and collective synthesis of a series of diverse functional molecules and building blocks including new types of chiral balkynyl- γ-amino acids, b-functionalized chiral dketo- γ-lactones, chiral g-alkylidenelactones, alkynylsubstituted pyrrole-3-carboxylic acid derivatives, tetrasubstituted furans and chiral b-alkynyl-γ-lactams. Notably, we discovered two unusual tandem reactions leading to functionalized chiral 1,5-dicarbonyl compounds. In addition, by employing simple bifunctional organocatalysts, we have developed the first regio-, diastereo- and enantioselective conjugate addition of a-substituted b-keto esters to nitroenynes, which is poorly diastereoselective with chiral nickel(II)-diamine catalysts, providing a new entry to adjacent quaternary and tertiary stereocenters in one step. Based on this protocol, we have developed a concise asymmetric synthesis of conformationally constrained bicyclic γ²-amino acids featuring an alkynyl side chain with an adjacent quaternary carbon stereocenter. The study described here demonstrates that the mutually complementary strategy of transition metal catalysis and organocatalysis is a powerful and promising tool in catalytic asymmetric synthesis.

Full text of DOI:10.1002/adsc.201200226

UPDATES
DOI: 10.1002/adsc.201200226
Mutually Complementary Metal- and Organocatalysis with
Collective Synthesis: Asymmetric Conjugate Addition of
1,3-Carbonyl Compounds to Nitroenynes and Further Reactions
of the Products
Xiang Li,a,d Xiaojiao Li,a,c,d Fangzhi Peng,a,* and Zhihui Shaoa,b,*
a
Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Chemical Science and
Technology, Yunnan University, Kunming 650091, Peopleꢀs Republic of China
Fax : (+86)-871-503-5538; phone: (+86)-871-503-1119; e-mail: pengfangzhi@ynu.edu.cn or zhihui_shao@hotmail.com
Key Laboratory of Ethnic Medicine Resource Chemistry, (Yunnan University of Nationalities), State Ethnic Affairs
b
Commission & Ministry of Education, Yunnan University of Nationalities, Kunming 650031, Peopleꢀs Republi of China
School of Resources and Environmental Science, Baoshan College, Baoshan 678000, Peopleꢀs Republic of China
X. Li and X.-J. Li contributed equally to this work
c
d
Received: March 21, 2012; Revised: June 15, 2012; Published online: September 28, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200226.
Abstract: The first metal-catalyzed 1,4-selective
asymmetric addition of malonates to nitroenynes
promoted by a simple chiral nickel(II)-diamine cat-
alyst, was developed, facilitating a mild synthesis of
a novel type of multifunctional chiral b-alkynyl
acids bearing a nitro group. Based on this protocol,
we have developed a practical and collective syn-
thesis of a series of diverse functional molecules
and building blocks including new types of chiral b-
alkynyl-g-amino acids, b-functionalized chiral d-
keto-g-lactones, chiral g-alkylidenelactones, alkynyl-
substituted pyrrole-3-carboxylic acid derivatives,
tetrasubstituted furans and chiral b-alkynyl-g-lac-
tams. Notably, we discovered two unusual tandem
reactions leading to functionalized chiral 1,5-dicar-
bonyl compounds. In addition, by employing simple
bifunctional organocatalysts, we have developed the
first regio-, diastereo- and enantioselective conju-
gate addition of a-substituted b-keto esters to nitro-
enynes, which is poorly diastereoselective with
chiral nickel(II)-diamine catalysts, providing a new
entry to adjacent quaternary and tertiary stereocen-
ters in one step. Based on this protocol, we have de-
veloped a concise asymmetric synthesis of confor-
mationally constrained bicyclic g2-amino acids fea-
turing an alkynyl side chain with an adjacent qua-
ternary carbon stereocenter. The study described
here demonstrates that the mutually complementa-
ry strategy of transition metal catalysis and organo-
catalysis is a powerful and promising tool in catalyt-
ic asymmetric synthesis.
Keywords: asymmetric catalysis; collective synthe-
sis; conjugate addition; metal- and organocatalysis;
nitroenynes
Introduction
The development of new catalytic chemical bond for-
mation strategies with simple catalysts for the practi-
cal asymmetric synthesis of novel chiral multifunc-
tional molecules with both biological and pharmaco-
logical potential as well as versatile synthetic utilities
is one of the most important undertakings in modern
chemical research.
Chiral b-alkynyl acids constitute an important class
of pharmaceutical compounds with diverse biological
activities that include PDE IV inhibitors, TNF inhibi-
tors, GPR40 receptor agonists, and GRP receptor an-
tagonists.[1] However, their asymmetric synthesis re-
mains a significant challenge. The asymmetric meth-
ods that have been described to date for access to this
target class involve the transition metal-mediated
asymmetric conjugate addition of terminal alkynes to
Meldrumꢀs acid alkylidenes[2–4] and a,b-unsaturated
thioamides,[5] respectively. While these reports stand
out as pioneering efforts, they have limitations such
as the requirement of the use of aromatic alkynes,[2]
sterically shielded TMS (trimethylsilyl)acetylene,[3]
a stoichiometric chiral mediator[4] or a complex cata-
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lyst system and a relative high temperature (508C)[5]. with broad substrate scope and low catalyst loading
Thus, the development of a new catalytic asymmetric without bis-Michael addition in good yields and high
strategy to construct chiral b-alkynyl acids,[6] especial- enantioselectivity.
ly a novel type of multifunctional chiral b-alkynyl
On the other hand, the adjacent quaternary and ter-
acids with both biological and pharmacological poten- tiary stereocenters are common structural motifs in
tial as well as versatile synthetic utilities is highly de- complex natural products and biologically important
sirable.
molecules. Significant progress has been made to-
As part of our interest in developing new catalytic wards the asymmetric construction of adjacent quater-
reactions involving alkynes,[7] and in asymmetric nary and tertiary stereocenters.[14] While the regio-,
metal catalysis[7b,c] and organocatalysis,[8] herein we diastereo- and enantioselective conjugate addition of
report the first metal-catalyzed 1,4-selective asymmet- a-substituted b-keto esters to nitroenynes would pro-
ric addition of malonates to nitroenynes promoted by vide a direct approach leading to multifunctional
a simple chiral nickel(II)-diamine catalyst, facilitating chiral molecules containing adjacent quaternary and
a mild synthesis of a novel type of multifunctional tertiary stereocenters in an atom-economical manner,
chiral b-alkynyl acids bearing a nitro group[9] and an such a process has not been reported so far.
alkynyl moiety.[10] Based on this protocol, we have de-
veloped a practical collective synthesis of a series of
diverse functional molecules and building blocks. No- Results and Discussion
tably, we discovered two unusual tandem reactions.
On the other hand, we have developed the first regio- Metal-Catalyzed Asymmetric 1,4-Addition of
, diastereo- and enantioselective organocatalytic con- Malonates to Nitroenynes: A Collective Synthesis of
jugate addition of a-substituted b-keto esters to nitro- Functional Molecules
enynes, which is poorly diastereoselective with chiral
nickel(II)-diamine catalysts, providing a new entry to Metal-Catalyzed Asymmetric 1,4-Addition of
adjacent quaternary and tertiary stereocenters in one Malonates to Nitroenynes
step. Based on this protocol, we have developed a con-
cise asymmetric synthesis of conformationally con- Considering the biological and pharmacological im-
strained bicyclic g2-amino acids featuring an alkynyl portance of chiral b-alkynyl acids as well as the poten-
side chain with an adjacent quaternary carbon stereo- tial synthetic versatility of asymmetric 1,4-addition
center.
adducts of malonates to nitroenynes, we turned our
Recently, the nitroenynes have emerged as a prom- attention to a metal catalysis strategy and envisioned
ising class of extended Michael acceptors. Neverthe- that metal catalysis could work as a complementary
less, despite their potential utilities, catalytic asym- catalysis strategy to solve the significant problems of
metric reactions involving nitroenynes are quite limit- our previous organocatalytic version.[13] Despite the
ed.[11] This might be due to the following two main potentials of chiral nickel(II)-diamine complexes in
reasons. The first reason is the competition between asymmetric catalysis, the application of this class of
1,4- and 1,6-addition of extended Michael acceptors[12] catalysts in regioselective conjugate addition of nitro-
associated with the difficulties in controlling the re- enynes has not been reported.
gioselectivity. Indeed, in a recent Cu-catalyzed conju-
To our delight, in the presence of only 2 mol%
gate addition of nitroenynes, Alexakis and co-workers chiral Ni(II) catalyst 1c,[15] the desired 1,4-addition
demonstrateded that the regioselectivity of the conju- product 4a was obtained in excellent yield (96%) with
gate addition reaction was largely dependent on the high enantioselectivity (91% ee) (Table 1, entry 3).
types of nucleophilic reagents.[11f] The second possible Notably, no bis-Michael addition by-product was
reason is that, different from nitroolefins, nitroenynes found. The regioselectivity was perfect. A survey of
have the problem of competitive bis-Michael addition solvents showed that m-xylene offered the best enan-
probably due to the linear structure of the triple tioselectivity (93% ee) (entry 4), whereas, interesting-
bond. Recently, we reported the first catalytic asym- ly, DMF led to complete racemization (entry 9).
metric addition of malonates to nitroenynes promoted
Under the optimized reaction conditions, the scope
by chiral organocatalysts.[13] However, this protocol of the Ni-catalyzed conjugate addition reaction was
suffers from the following significant drawbacks or investigated. Pleasingly, di-tert-butyl malonate, an un-
limitations: (i) the reaction yield generally is not good reactive substrate under our previous organocatalytic
due to the competitive bis-Michael addition; (ii) the conditions,[11] reacted smoothly in the presence of
substrate scope is limited, for example, di-tert-butyl 2 mol% chiral Ni(II) catalyst 1c, giving the desired
malonate is not reactive; (iii) the catalyst loading is 1,4-addition product 4b in good yield (81%) with high
high (10 mol%). In view of its potential importance, it enantioselectivity (92% ee) (Table 2, entry 1). After
is highly desirable to develop a new catalytic strategy a single recrystallization, the ee of the product 4b
to achieve this type of asymmetric transformation could reach 99%. Additionally, dimethyl malonate af-
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Mutually Complementary Metal- and Organocatalysis with Collective Synthesis
Table 1. Catalyst and solvent survey for the Ni-catalyzed
Table 2. Regio- and enantioselective 1,4-addition of nitroe-
1,4-addition of diethyl malonate to phenylnitroeneyne.[a]
nynes with malonates catalyzed by nickel(II)-diamine com-
plex 1c.[a]
Entry R1
R2
Time
[h]
Yield
[%][b]
ee
[%][c]
Entry R
Solvent Time Yield
ee
[h]
[%][b]
[%][c]
1
2
Ph (2a)
t-Bu
(3b)
Me
(3c)
Et (3a)
Et (3a)
10
6
81
98
92
(99)[d]
94
1
2
Bn (1a)
PhCH3
PhCH3
5
5
90
90
91
90
Ph (2a)
CH2(4-MeO-
C6H4) (1b)
CH2(4-Br-C6H4)
(1c)
CH2(4-Br-C6H4)
(1c)
CH2(4-Br-C6H4)
(1c)
CH2(4-Br-C6H4)
3
4
Ph (2a)
4-Me-C6H4
(2b)
4-MeO-C6H4
(2c)
4-F-C6H4 (2d) Et (3a)
3-F-C6H4 (2e) Et (3a) 12
5
5
96
96
93
90
3
4
5
6
7
8
9
PhCH3
5
5
9
8
8
8
8
96
96
93
82
78
45
22
91
93
92[d]
90
90
89
0
m-
xylene
m-
xylene
Et2O
5
Et (3a)
8
5
95
91
6
7
8
95
88
92
92
89
>99
CH
U
Et (3a) 10
Et (3a) 10
(1c)
(2f)
CH2(4-Br-C6H4)
(1c)
CH2(4-Br-C6H4)
THF
9
CH
3A
90
89
>99
(2g)
PhCH2CH2
(2h)
DCM
DMF
10
Et (3a)
8
95
(1c)
CH2(4-Br-C6H4)
(1c)
[a]
The reaction was performed with nitroenynes
2
[a]
(0.3 mmol) with malonates 3 (2 equiv.) in the presence of
2 mol% catalyst 1c in m-xylene (0.7 mL) at room temper-
ature.
The reaction was performed with phenylnitroeneyne 2a
(0.3 mmol) with diethyl malonate 3a (2 equiv.) in the
presence of 2 mol% catalyst 1 in solvent (0.7 mL) at
room temperature.
[b]
[c]
Isolated yield.
[b]
[c]
Enantiomeric excess (ee) was determined by chiral
HPLC analysis.
After a single recrystallization.
Isolated yield.
Enantiomeric excess (ee) was determined by chiral
HPLC analysis.
At 08C.
[d]
[d]
forded the desired 1,4-addition product 4c in 98%
The asymmetric conjugate addition of other types
yield with 94% ee (entry 2) whereas this substrate of 1,3-dicarbonyl compounds to nitroeneyne 2a using
gave 56% yield and 87% ee under our previous orga- 1c as the catalyst was also investigated [Eq. (1)]. For
nocatalytic conditions.[13] For comparative purposes, 1,3-diketone 3d, and b-keto ester 3e, the correspond-
diethyl malonate was employed as the nucleophile to ing adducts were obtained in good yields (88–90%)
react further with various nitroenynes. As shown in and enantioselectivities (90–92% ee) at the b-position
Table 1, a significant improvement in yield was ob- to the nitro group.
served. Moreover, generally, an improvement in ee
The mild reaction conditions, the easily accessible
was also obtained (entries 3–9). The conjugate addi- catalyst, the low catalyst loading and the synthetic po-
tion worked well not only with electron-neutral tential of the 1,4-addition products offered a practical
(entry 3), electron-rich (entries 4 and 5), and electron- use for the present approach, thus, the reaction on
deficient aryl alkynyl substrates (entries 6 and 7), but a gram-scale was carried out in the presence of
also with alkyl-substituted alkynyl substrates (en- 2 mol% catalyst 1c with the substrates 2a and 3b, af-
tries 8–10). The absolute configurations of 4a and 4c–f fording the desired product 4b in 81% yield with 91%
and 4h–j were determined by comparing the retention ee (Scheme 1).
time of HPLC of products with those in literature
data.[13]
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Scheme 1. Gram-scale version of regio- and enantioselective
Michael addition between 2a and 3b.
Scheme 3. Asymmetric construction of d-keto-g-lactones
and g-alkylidenelactones.
Asymmetric Synthesis of Chiral b-Alkynyl Acids
As illustrated in Scheme 2, the 1,4-addition adduct 4b core of the biologically active natural product phena-
underwent a decarboxylation reaction in the presence tic acid B[16a] (Scheme 3). Notably, this intramolecular
of TsOH under reflux to afford the chiral b-alkynyl electrophilic cyclization is highly diastereoselective
acid 5 (Scheme 2). The ee value of b-alkynyl acid 5 (10:1 dr). The relative configuration of the chiral lac-
was determined by transformation into the corre- tone 6 was confirmed by NOESY. Despite the poten-
sponding methyl ester.
tial utility of PIFA-promoted intramolecular electro-
philic cyclization of alkynyl carboxylic acids,[20b] the
significant diastereoselectivity and enantioselectivity
issues remain unknown, thus limiting its application
in asymmetric synthesis.
Asymmetric Synthesis of Chiral d-Keto-g-lactones
and g-Alkylidenelactones
Under the catalysis of gold(I) species,[21] the chiral
d-Functionalized g-lactones[16] and g-alkylidenelac- b-alkynyl acid 5 underwent the cyclization to provide
tones[17] represent two important types of scaffold chiral g-alkylidenelactone 7 bearing the nitro group
which are frequently encountered as structural subu- which can be further manipulated (Scheme 3).
nits in numerous biologically active products. More-
over, they are also important building blocks in natu-
ral product synthesis[18] and drug synthesis.[19]
Asymmetric Synthesis of Chiral b-Alkynyl-g-amino
The chiral b-alkynyl acid 5 bearing a nitro group Acids and b-Alkynylpyrrolidinones with Discovery of
provides an ideal platform from which to construct Unprecedented Transformations
these chiral heterocycles. Under the catalysis of the
hypervalent iodine reagent PIFA [phenyliodineACTHUNRTGNEUNG(III) Over the last few years, there has been increasing in-
bis(trifluoroacetate)],[20] the chiral b-alkynyl acid 5 terest in the asymmetric design and synthesis of novel
was transformed effectively into optically active b- chiral g-amino acids, in particular those bearing sub-
functionalized d-keto-g-lactone 6, which is also the stituents at the b-position, which can be considered as
potent drugs for the treatment of neurodegenerative
disorders.[22,23] On the other hand, due to their poten-
tial biological activity as specific irreversible enzyme
inhibitors,[24] the design and synthesis of amino acids
with alkyne substituents (acetylenic amino acids)
have received much attention.[25] Thus, chiral b-alkyn-
yl-g-amino acids might be attractive candidates of me-
Scheme 2. Synthesis of a new type of chiral b-alkynyl acids. dicinal interest as this class of molecules merges per-
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Mutually Complementary Metal- and Organocatalysis with Collective Synthesis
Scheme 4. Asymmetric synthesis of chiral b-alkynyl-g-amino acids and b-alkynylpyrrolidinones.
Scheme 5. Unusual esterification and amidation of chiral b-alkynyl acid 5 to chiral 1,5-dicarbonyl compounds. Reaction con-
ditions: (i) BnOH, HOBt, EDC·HCl, Et3N, DCM, 08C to room temperature, 65% of compound 12a (R=Bn); 61% of com-
pound 12b (R=CH3); (ii) BnNH2, HOBt, EDC·HCl, Et3N, DCM, 08C to room temperature, compound 13, 78%; compound
15’, 82%; (iii) Zn, AcOH, 658C, 57%.
fectly g-amino acids and b-side chains containing an acid 5’, was reported to afford the corresponding
alkyne functionality.
amide 15’ in 82% yield.[20b] While the accurate reac-
Starting from the the chiral b-alkynyl acid 5, the tion mechanism is not clear at this stage, these results
chiral b-alkynyl-g-amino acid 10 was synthesized seem to indicate that the nitro group of chiral b-al-
(Scheme 4). Also, from the chiral b-alkynyl acid 5 as kynyl acid 5 might participate in the reaction, giving
the common intermediate, the b-alkynylpyrrolidinone the unexpected functionalized chiral 1,5-dicarbonyl
11 was obtained via a three-step transformation compounds. Notably, these functionalized chiral 1,5-
(Scheme 4).
dicarbonyl compounds bearing a nitro group are po-
While the above route (Scheme 4) seems to be rou- tential precursors to pharmaceutically active mole-
tine, the esterification reaction of the chiral b-alkynyl cules such as conformationally restricted homo-b-pro-
acid 5 to the corresponding chiral b-alkynyl ester 8 is line analogues, which are inhibitors of GABAA as
unusual.
Initially, we used HOBt and EDC·HCl as activating
well as GABAB receptor binding.[26]
The normal chiral b-alkynyl amide 15 bearing the
reagents to perform the esterification reaction of nitro group can be achieved by using the following
chiral b-alkynyl acid 5. Surprisingly, the desired method [(Eq. (2)].
esterification product 8 was not obtained, instead, the
chiral 1,5-dicarbonyl compound 12 (CCDC 863799)
bearing a nitro group was unexpectedly obtained
(Scheme 5). This transformation can be also extended
to the synthesis of the functionalized chiral 1,5-dicar-
bonyl compound 13 (Scheme 5). Interestingly, under
the identical conditions, the unsubstituted b-alkynyl
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Scheme 6. Synthesis of alkynyl-substituted pyrrole-3-carboxylic acid derivative 17.
Synthesis of Alkynyl-Substituted Pyrrole-3-carboxylic
Acid Derivatives
of an AuCl3-catalyzed cycloisomerization of b-alkyn-
yl-b-keto ester to generate a tetrasubstituted furan.
The pyrrole framework is a ubiquitous structural
motif found in a wide range of biologically active nat- Organocatalytic Asymmetric 1,4-Addition of a-
ural products and pharmaceutically active agents.[27]
Substituted b-Keto Esters to Nitroenynes: A Concise
To derive the substituted pyrroles, the 1,4-conjuagte Syntheis of Bicyclic g2-Amino Acids Featuring an
addition product 4l of phenylnitroeneyne with ethyl Alkynyl Side Chain
acetoacetate was subjected to the conditions (FeCl3,
toluene, reflux) recently reported by Bi and Zhang.[28] Organocatalytic Asymmetric 1,4-Addition of
Interestingly, the normal pyrrole product 16 was not a-Substituted b-Keto Esters to Nitroenynes
obtained, instead, the alkynyl-substituted pyrrole-3-
carboxylic acid ethyl ester 17 was achieved, which is Under identical reaction conditions as for the Ni-cata-
of medicinal interest as it combines a pyrrole-3-car- lyzed conjugate addition of malonates to nitroenynes,
boxylic acid moiety[27d] and the alkyne functionality[24] we explored the conjugate addition reaction of 2-oxo-
(Scheme 6). To account for the current results, we cyclopentanecarboxylate 19a to phenylnitroeneyne 2a.
proposed a possible mechanism depicted in Scheme 6 Unfortunately, although the enantioselectivity of this
(path b).
reaction was good, the diastereoselectivity was quite
poor (53:47 dr) [Eq. (3)]. It is interesting to note that
Synthesis of Multisubstituted Furans
Multisubstituted furans are of importance because nu-
merous compounds bearing such a heterocyclic ring
exhibit a wide range of biological activities and are
also building blocks for organic synthesis.[29,30] The de-
velopment of new and efficient syntheses of multisub-
stituted furans having specific substitution patterns is
an important objective.[31]
Under the catalysis of AuCl3, the 1,4-conjugate ad- with NaH as the only base or catalyst, the racemic re-
dition product 4l underwent cycloisomerization[32] to action can be achieved in 80:20 dr. We turned our at-
provide the new tetrasubstituted furan 18 (Scheme 7). tention to organocatalysis again, hoping that organo-
While the yield is moderate, this is the first example catalysis could also serve as a complementary strategy
to impart both high diastereoselectivity and enantio-
selectivity.
To our delight, in the presence of bifunctional orga-
nocatalyst 21a (Figure 1), the desired addition product
20a was obtained in good yield (91%) with good
enantioselectivity (90% ee) and diastereoselectivity
(95:5 dr) (Table 3, entry 1). Decreasing the tempera-
Scheme 7. Synthesis of tetrasubstituted furans.
ture to À308C led to 97% ee and 93:7 dr but 77%
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Mutually Complementary Metal- and Organocatalysis with Collective Synthesis
Figure 1. Bifunctional organocatalysts tested in this study.
yield (entry 2). To examine the effect of catalyst struc- high to excellent diastereoselectivity and enantiose-
ture on the diastereo- and enantioselectivity as well lectivity (entries 1–6).
as to further improve these two parameters, a series
In addition to five-membered cyclic b-keto esters,
of other types of organocatalysts was subsequently in- the six-membered cyclic b-keto ester 19b was also
vestigated (Figure 1). The Cinchona alkaloid-derived a good nucleophile, leading to the addition product in
catalysts[33] 21b–d proved to be promising, affording 97:3 dr and 84% ee (entry 7). The 2-acetylbutyrolac-
82–91% ee and 95:5–98:2 dr (entries 3–5). The widely tone 19c also reacted with nitroenyne providing the
used 1,2-cyclohexanediamine-derived catalyst 21g, desired product in 98: 2 dr and 78% ee (entry 8). In
Takemotoꢀs catalyst,[34] resulted in À69% ee and 91:8 view of the importance of fluorinated compounds in
dr (entry 8). The catalyst 21e bearing central and medicinal chemistry[35a] and material chemistry,[35b] the
axial chiral elements[8d] afforded À71% ee and 94:6 dr acyclic a-fluorinated b-keto ester 19d was examined,
(entry 6), whereas its diastereomer 21f offered 87% affording high enantioselectivity (96% ee) but moder-
ee and 87:13 dr (entry 7). The differences observed in ate diastereoselectivity (63:37 dr) (entry 9). The rela-
dr and ee suggested that the structure of the base had tive and absolute configurations of the products of
an effect on these two parameters. The further tuna- Michael reactions of nitroenynes with a-substituted b-
blility of the structure of the base led to the catalyst keto esters were assigned on the basis of an X-ray
21h, giving À93% ee and 97:3 dr (entry 9). The 1,2-di- crystal structural analysis of the product of 20a [Flack
phenylethanediamine-derived organocatalyst 21i af- parameter 0.03(15), Figure 2].[36]
forded moderate ee (57%) but excellent dr (99:1)
High diastereoselectivity and enantioselectivity
(entry 10). These results indicated that the diamine could be explained via the transition state models
scaffolds of the catalysts have a significant impact on shown in Figure 3.
both diastereo- and enantioselectivity. Subsequently,
a series of solvents was examined. Et2O provided the
best results (95% ee, 98:2 dr and 92% yield) Asymmetric Synthesis of Constrained Bicyclic
(entry 13).
g2-Amino Acid Featuring an Alkynyl Side Chain
With the optimized reaction conditions in hand, we
investigated the scope of the reaction (Table 4). Vari- g2-Amino acids represent potential building blocks for
ous aromatic and aliphatic nitroenynes reacted g-peptide[37] and heterogeneous backbone foldam-
smoothly with five-membered cyclic b-keto esters to ers.[38] On the other hand, bicyclic unnatural amino
give the desired adducts containing diverse alkynyl, acids have been developed as reverse turn mimetics
nitro, ketone and ester groups, featuring adjacent qua- and dipeptide isosteres, and the constraint imposed by
ternary and tertiary stereocenters, in good yields with their structures has been reported as a tool for con-
trolling the conformational preferences of modified
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Xiang Li et al.
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Table 3. Catalyst and solvent survey for the regio-, diaster-
eo- and enantioselective 1,4-addition of 2a with 19a cata-
lyzed by organic catalysts.[a]
Conclusions
We developed the first metal-catalyzed 1,4-selective
asymmetric addition of malonates to nitroenynes pro-
moted by a simple chiral nickel(II)-diamine catalyst,
facilitating a mild synthesis of novel types of multi-
functional chiral b-alkynyl acids bearing the nitro
group. Based on this protocol, we developed a practi-
cal collective synthesis of a series of diverse functional
molecules and building blocks including new types of
chiral b-alkynyl-g-amino amino acids, b-functionalized
chiral d-keto-g-lactones, chiral g-alkylidenelactones,
alkynyl-substituted pyrrole-3-carboxylic acid deriva-
tives, tetrasubstituted furans and chiral b-alkynyl-g-
lactams. Notably, we discovered two unusual tandem
reactions leading to functionalized chiral 1,5-dicar-
bonyl compounds. In addition, by employing simple
bifunctional organocatalysts, we have developed the
first regio-, diastereo- and enantioselective conjugate
addition of a-substituted b-keto esters to nitroenynes,
which is poorly diastereoselective with chiral nickel-
Entry Catalyst Solvent
Yield [%][b] ee [%][c] dr[d]
1
2
3
4
5
6
7
8
21a
21a
21b
21c
21d
21e
21f
21g
21h
21i
21h
21h
21h
21h
21h
21h
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
m-xylene 85
THF
Et2O
DCM
CHCl3
DCE
91
77
82
86
87
85
89
88
90
75
90
97
91
95:5
93:7[e]
95:5
96:4
98:2
94:6
87:13
91:8
97:3
99:1
98:2
97:3
98:2
97:3
96:4
98:2
À87
À82
À71
87
À69
À93
57
À88
À92
À95
À81
À84
À90
9
AHCTUNGTREG(NNUN II)-diamine catalysts, providing a new entry to adja-
10
11
12
13
14
15
16
cent quaternary and tertiary stereocenters in one step.
Based on this protocol, we developed a concise asym-
metric synthesis of conformationally constrained bicy-
clic g2-amino acids featuring an alkynyl side chain
with an adjacent quaternary carbon stereocenter. The
study described here demonstrates that the mutually
complementary strategy of transition metal catalysis
and organocatalysis is a powerful and promising tool
in catalytic asymmetric synthesis.
87
92
88
90
85
[a]
The reaction was performed with 2a (0.3 mmol) and 19a
(0.15 mmol) in the presence of 10 mol% catalyst 21 in
solvent (0.5 mL) at À108C.
[b]
[c]
Isolated yield.
Enantiomeric excess (ee) was determined by chiral
HPLC analysis.
Determined by H NMR analysis or HPLC.
At À308C.
Experimental Section
[d]
[e]
1
General Methods
1H NMR and 13C NMR spectra were recorded on
a 300 MHz spectrophotometer. Chemical shifts (d) are ex-
pressed in ppm, and J values are given in Hz. The enantio-
meric excess was determined by HPLC using Chiralpak
AD-H, Chiralcel OD-H and Chiralcel OJ-H column with n-
hexane and 2-propanol as eluents. High resolution mass
spectrometry (HR-MS) was recorded on a VG Auto Spec-
3000 spectrometer. Optical rotations were measured on
a JASCO DIP-370 polarimeter. All chemicals and solvents
were used as received without further purification unless
otherwise stated. Flash column chromatography was per-
formed on silica gel (230–400 mesh).
peptides.[39] In addition, due to their potential biologi-
cal activity as specific irreversible enzyme inhibi-
tors[24], the amino acids with alkyne substituents (ace-
tylenic amino acids) have aroused much interest.[24,25]
In view of these factors, as a novel type of conforma-
tionally constrained bicyclic g2-amino acid derivatives,
the chiral bicyclic g2-amino acid derivatives bearing
an alkynyl side chain such as 23 might have potential
in peptide foldamer research and pharmaceutical syn-
thesis.
Starting from the organocatalytic 1,4-addition prod-
uct 20a, a concise synthesis of the conformationally
constrained bicyclic g2-amino acid derivative 23 fea-
turing a chiral alkynyl side chain with an adjacent
quaternary carbon stereocenter was developed
(Scheme 8).
General Procedure for Ni-Catalyzed Regio- and
Enantioselective Conjugate Addition of Malonates to
Nitroenynes
To a solution of catalyst 1c (2 mol%) in m-xylene (0.7 mL)
was added malonate 3 (0.6 mmol, 2 equiv.) and nitroenyne 2
(0.3 mmol). The resulting solution was stirred at room tem-
perature until the reaction was complete (monitored by
TLC). The volatile components were removed under re-
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Adv. Synth. Catal. 2012, 354, 2873 – 2885

Mutually Complementary Metal- and Organocatalysis with Collective Synthesis
Table 4. Regio-, diastereo- and enantioselective 1,4-addition of nitroenynes with a-substituted b-keto esters catalyzed by bi-
functional organocatalyst 21h.[a]
Entry
19
2
Product
Yield [%][b]
ee [%][c]
dr[d]
1
2
3
4
5
6
7
8
9
19a
19a
19a
19a
19a
19a
19b
19c
19d
2a
2b
2c
2d
2e
2f
2a
2a
2a
20a
20b
20c
20d
20e
20f
20g
20h
20i
92
84
93
80
87
85
80
66
73
95
96
92
94
95
95
84
78
96
98:2
94:6
95:5
95:5
99:1
99:1
97:3
98:2
63:37
[a]
The reaction was performed with nitroenynes 2 (0.3 mmol) with a-substituted b-keto esters 19 (0.15 mmol) in the pres-
ence of 10 mol% catalyst 21h in Et2O (0.5 mL) at À108C.
[b]
[c]
[d]
Isolated yield.
Enantiomeric excess (ee) was determined by chiral HPLC analysis.
1
Determined by H NMR analysis or HPLC.
Figure 3. Transition-state models of organocatalytic asym-
metric 1,4-addition of a-substituted b-keto esters.
1
Yellow solid; [a]20: À6.3 (c 1.0 CHCl3). H NMR (300 MHz,
CDCl3): d=7.36 D(m, 2H), 7.28 (m, 3H), 4.78 (m, 2H), 4.05
(m, 1H), 3.60 (m, 1H), 1.49 (brs, 18H); 13C NMR (75 MHz,
CDCl3): d=166.1, 165.8, 131.8, 128.6, 128.3, 122.1, 85.3, 83.8,
83.1, 82.9, 76.5, 55.0, 30.7, 27.9, 27.8. HR-MS: m/z=
389.1824, calcd. for C21H27NO6 [M]+: 389.1838; HPLC (Chir-
Figure 2. X-ray structure of compound 20a.
alpak AD-H, 2–propanol/hexane=10/90, flow rate
1.0 mLminÀ1, l=254 nm): tmajor =7.9 min, tminor =10.4 min.
duced pressure and the crude product was purified by flash
silica gel chromatography (petroleum ether/ethyl acetate as
eluents).
Characterization of a representative compound – (R)-di-
tert-butyl 2-(1-nitro-4-phenylbut-3-yn-2-yl)malonate (4b):
Asymmetric Synthesis of Chiral b-Alkynyl Acid 5
To a solution of compound 4b (30 mg, 0.077 mmol) in PhH
(2.5 mL) was added TsOH (3 mg, 0.2 equiv.). The resulting
solution was stirred for 3 h under reflux. After removal of
Adv. Synth. Catal. 2012, 354, 2873 – 2885
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asc.wiley-vch.de
2881

Xiang Li et al.
UPDATES
Scheme 8. Asymmetric synthesis of constrained bicyclic g2-amino acid derivative 23 bearing the alkynyl side chain.
solvent, the crude product was purified through column
chromatography on silica gel (petroleum ether/ethyl acetate
as eluents) to afford the compound 5; yield: 15 mg (83%);
C12H11NO4 [M]+: 233.0688; HPLC (Chiralcel OD-H, 2-prop-
anol/hexane=20/80, flow rate 0.8 mLminÀ1, l=254 nm):
tminor =8.2, tmajor =17.4 min.
1
[a]2D0: À17.4 (c 0.8 CHCl3). H NMR (300 MHz, CDCl3): d=
9.51 (m, 1H), 7.44 (m, 2H), 7.28 (m, 3H), 4.65 (m, 2H),
3.89 (m, 1H), 2.82 (d, J=6.6 Hz, 2H); 13C NMR (75 MHz,
CDCl3): d=176.1, 131.8, 128.7, 128.3, 128.1, 122.0, 84.8, 84.6,
76.6, 36.4, 27.5; HR-MS: m/z=233.0687, calcd. for
C12H11NO4 [M]+: 233.0688.
Asymmetric Synthesis of Chiral b-Alkynyl-g-amino
Acid 10
To a solution of compound 5 (93 mg, 0.40 mmol) in DCM
(5 mL) was added (COCl)2 (52 mg, 0.40 mmol) followed by
DMF (1 drop) at 08C. The resulting mixture was stirred for
1 h at 08C. Then MeOH (19 mg, 0.6 mmol, 1.5 equiv.) was
added at 08C. The reaction solution was stirred for 2 h at
08C and extracted with EtOAc. The separated organic
phase was washed by saturated aqueous NaHCO3. The com-
bined organic phase was dried over anhydrous Na2SO4.
After removal of solvent, the crude product was purified
through column chromatography on silica gel (petroleum
ether/ethyl acetate as eluents) to afford the compound 8;
yield: 63 mg (64%); [a]20: À4.7 (c 0.8 CHCl3). 1H NMR
(300 MHz, CDCl3): d=7D.39–7.29 (m, 5H), 4.67 (m, 2H),
3.88 (m 1H), 3.75 (s, 3H), 2.77 (d, J=6.6 Hz, 2H);
13C NMR (75 MHz, CDCl3): d=170.5, 131.8, 128.6, 128.3,
122.1, 84.9, 84.6, 76.6, 52.1, 36.4, 27.7; HR-MS: m/z=
270.0739, calcd. for C13H13NO4Na [M+Na]+: 270.0742;
HPLC (Chiralcel OD-H, 2-propanol/hexane=15/85, flow
rate 0.7 mLminÀ1, l=210 nm): tminor =21.8, tmajor =27.2 min.
To a solution of compound 8 (49 mg, 0.20 mmol) in EtOH
(2 mL) was added Zn powder (195 mg, 15 equiv.). The re-
sulting mixture was stirred for 10 min at 358C. 4M HCl
(1.25 mL) was added. The reaction mixture was stirred over-
night. After filtration, the filtrate was evaporated under
vacuum. Then 2M NaOH was added to the residue, and the
resulting solution was stirred for 5 min. The reaction mix-
ture was extracted with DCM and the combined organic
phase was dried over anhydrous Na2SO4. After removal of
solvent, the crude product was used for next step without
further purification.
Asymmetric Synthesis of b-Functionalized d-
Ketolactone 6
To
a solution of compound 5 (56 mg, 0.24 mmol) in
CF3CH2OH (2 mL) was added PIFA (155 mg, 0.36 mmol,
1.5 equiv.) at 08C. The resulting mixture was stirred for 2 h
at 08C. The solution was extracted with CH2Cl2 and the sep-
arated organic phase was washed by saturated aqueous
NaHCO3. The organic phase was dried over anhydrous
Na2SO4. After removal of solvent, the crude product was
purified through column chromatography on silica gel (pe-
troleum ether/ethyl acetate as eluents) to afford the com-
pound 6; yield: 32 mg (54%); [a]2D0: À5.1 (c 0.6 CHCl3).
1H NMR (300 MHz, CDCl3): d=8.01 (d, J=7.2 Hz, 2H),
7.68 (m, 1H), 7.54 (m, 2H), 5.62 (d, J=4.5 Hz, 1H), 4.71
(m, 1H), 4.57 (m, 1H), 3.35 (brs, 1H), 2.96 (m, 1H), 2.47
(dd, J=5.4, 5.4 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=
192.9, 173.1, 134.9, 133.5, 129.3, 129.1, 79.3, 75.8, 35.7, 31.0.
HR-MS: m/z=249.0654, calcd. for C12H11NO5 [M]+:
249.0637; HPLC (Chiralpak AD-H, 2-propanol/hexane=20/
80, flow rate 0.7 mLminÀ1, l=210 nm): tminor =30.9, tmajor
=
37.0 min.
Asymmetric Synthesis of Chiral g-Alkylidenelactone
7
To a solution of compound 5 (23 mg, 0.1 mmol) in acetoni-
trile (0.5 mL) at room temperature was added gold chloride
(10 mol%) and K2CO3 (0.1 equiv.). The reaction mixture
was stirred until disappearance of the starting material 5
(TLC monitoring). The reaction solution was extracted with
DCM and the combined organic layers were dried over
Na2SO4. After removal of solvent, the crude product was
purified by column chromatography on silica gel (petroleum
ether/ethyl acetate as eluents) to afford the compound 7;
yield: 14 mg (61%); [a]2D0: À7.4 (c 0.3 CHCl3). 1H NMR
(300 MHz, CDCl3): d=7.55 (d, J=7.5 Hz, 2H), 7.36 (m,
3H), 5.62 (m, 1H), 4.71 (m, 1H), 4.57 (m, 1H), 4.02 (m,
1H), 3.08 (m, 1H), 2.71 (dd, J=4.8, 4.8 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d=171.6, 145.8, 132.6, 128.7, 128.6, 127.8,
107.2, 77.0, 37.0, 31.6. HR-MS: m/z=233.0683, calcd. for
To a solution of the crude product obtained in THF
(2 mL) was added (Boc)2O (25 mg, 0.18 mmol) followed by
DIPEA (15 mg, 0.18 mmol) at 08C. The resulting solution
was stirred for 30 min. After removal of solvent, the residue
was purified through column chromatography on silica gel
(petroleum ether/ethyl acetate as eluents) to afford the com-
pound 9; yield: 32 mg (48% over two steps); [a]2D0: À1.5 (c
1
0.4 CHCl3). H NMR (300 MHz, CDCl3): d=7.38 (m, 2H),
7.27 (m, 3H), 4.90 (brs, 1H), 4.18 (q, J=7.2 Hz, 2H), 3.32
(m, 3H), 2.58 (d, J=6.6 Hz, 2H), 1.40 (s, 9H), 1.27 (t, J=
7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=171.1, 155.8,
131.7, 128.2, 128.1, 123.0, 88.9, 83.1, 79.6, 60.7, 44.0, 37.4,
30.1, 28.4, 14.2; HR-MS: m/z=354.1680, calcd. for
C19H25NO4Na [M+Na]+: 354.1681; HPLC (Chiralcel OD-H,
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Adv. Synth. Catal. 2012, 354, 2873 – 2885

Mutually Complementary Metal- and Organocatalysis with Collective Synthesis
2-propanol/hexane=10/90, flow rate 0.8 mLminÀ1, l=
254 nm): tmajor =9.5 min, tminor =11.3 min.
Synthesis of Substituted Pyrrole-3-carboxylic Acid 17
To a solution of compound racemic 4l (30 mg, 0.10 mmol)
and BnNH2 (13 mg, 0.12 mmol) in toluene (2 mL) was
added FeCl3 (2 mg, 10 mol%) under an atmosphere of N2.
The resulting mixture was stirred for 3 h under reflux. After
removal of solvent, the crude product was purified through
column chromatography on silica gel (petroleum ether/ethyl
acetate as eluents) to afford the compound 17 as a yellow
To a solution of compound 9 (17 mg, 0.05 mmol) in
MeOH/H2O (2:1) (1.5 mL) was added LiOH (6 mg,
0.25 mmol, 5 equiv.). The resulting mixture was stirred for
2 h at room temperature, acidified with 10% citric acid and
extracted with EtOAc. The combined organic phase was
evaporated under vacuum. The residue was purified through
column chromatography on silica gel (petroleum ether/ethyl
acetate as eluents) to afford the compound 10; yield: 14 mg
(91%); [a]2D0: À4.4 (c 0.2 CHCl3). 1H NMR (300 MHz,
CDCl3): d=7.40 (m, 2H), 7.28 (m, 3H), 4.98 (brs, 1H), 3.28
(m, 3H), 2.65 (brs, 2H), 1.45 (s, 9H); 13C NMR (75 MHz,
CDCl3): d=175.6, 156.2, 131.8, 128.2, 128.1, 122.9, 88.6, 83.2,
78.0, 43.7, 37.1, 29.9, 28.3. HR-MS: m/z=303.1480, calcd.
for C17H21NO4 [M]+: 303.1471.
1
solid; yield: 22 mg (65%). H NMR (300 MHz, CDCl3): d=
7.49 (d, J=6.9 Hz, 2H), 7.30 (m, 6H), 7.03 (d, J=6.6 Hz,
2H), 6.90 (s, 1H), 5.04 (s, 2H), 4.33 (t, J=6.9 Hz, 2H), 2.46
(s, 3H), 1H), 1.39 (t, J=6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=164.9, 136.5, 136.2, 131.3, 129.0, 128.2, 128.0,
127.5, 126.5, 126.1, 124.3, 113.5, 105.0, 89.9, 84.1, 59.7, 50.7,
14.5, 11.3; HR-MS: m/z=343.1567, calcd. for C23H21NO2
[M]+: 343.1572.
Synthesis of Tetrasubstituted Furan 18
Asymmetric Synthesis of Chiral b-Alkynyl-g-lactam
11
To a solution of compound racemic 4l (30 mg, 0.10 mmol) in
MeOH (2 mL) was added AuCl3 (1.5 mg, 5 mol%). The re-
sulting mixture was stirred for 26 h at 658C. After removal
of solvent, the crude product was purified through column
chromatography on silica gel (petroleum ether/ethyl acetate
as eluents) to afford the compound 18 as a yellow solid;
yield: 12 mg (40%). 1H NMR (300 MHz, CDCl3): d=7.33
(m, 3H), 7.17 (m, 2H), 5.42 (s, 2H), 4.28 (q, J=7.2 Hz, 2H),
3.99 (s, 2H), 2.55 (s, 3H), 1.21 (t, J=7.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=163.5, 159.4, 153.5, 136.3, 128.9, 128.4,
127.1, 110.5, 69.1, 60.5, 32.2, 14.1, 14.0; HR-MS: m/z=
303.1109, calcd. for C16H17NO5 [M]+: 303.1107.
The compound 9 (23, 0.07 mmol) was dissolved in dry PhMe
(1.5 mL). The solution was cooled to À208C. Then a solution
of AlMe3 (0.055 mL, 0.11 mmol, 2.0M in PhMe) was added
dropwise slowly under the atmosphere of N2. The reaction
was stirred at À208C for 2 h and then quenched with satu-
rated aqueous Rochelleꢀs salt (2.0 mL). The mixture was
warmed to room temperature and extracted with EtOAc.
The combined organic phases were dried over Na2SO4, fil-
tered, concentrated under vacuum, and purified by column
chromatography on silica gel (petroleum ether/ethyl acetate
as eluents) to afford the compound 11;[6] yiele: 16 mg
1
(78%). H NMR (300 MHz, CDCl3): d=7.40 (m, 2H), 7.32
General Procedure for Organocatalytic Asymmetric
Conjugate Addition of a-Substituted b-Keto Esters to
Nitroenynes
(m, 3H), 4.09 (t, J=8.1 Hz, 1H), 3.78 (t, J=7.5 Hz, 1H),
3.37 (t, J=8.1 Hz, 1H), 2.87 (m, 1H), 2.73 (m, 1H), 1.56
(brs, 9H).
To a solution of catalyst 21h (10 mol%) in Et2O (0.5 mL)
was added a-substituted b-keto ester 19 (0.15 mmol) and ni-
troenyne 2 (0.3 mmol) at À108C. The resulting solution was
stirred at À108C until the reaction was complete (monitored
by TLC). The volatile components were removed under re-
duced pressure and the crude product was purified by flash
silica gel chromatography (petroleum ether/ethyl acetate as
eluents).
Characterization of a representative compound – (R)-
ethyl 1-[(S)-1-nitro-4-phenylbut-3-yn-2-yl]-2-oxocyclopent-
anecarboxylate (20a): [a]2D0: À7.0 (c 1.0 CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.33 (m, 5H), 4.85 (dd, J=4.2,
4.2 Hz, 1H), 4.53 (t, J=12.3 Hz, 1H), 4.31 (m, 1H), 4.21 (q,
J=7.2 Hz, 2H), 2.53 (m, 2H), 2.26 (m, 2H), 2.17 (m, 2H),
1.28 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=
211.4, 168.5, 131.8, 128.8, 128.3, 121.8, 86.0, 83.7, 76.0, 62.4,
61.1, 38.1, 35.3, 30.4, 20.1, 14.0; HR-MS: m/z=329.1268,
calcd. for C18H19NO5 [M]+: 329.1263; HPLC (Chiralcel OJ-
H, 2-propanol/hexane=10/90, flow rate 0.8 mLminÀ1, l=
254 nm): tminor =39.2 min, tmajor =44.8 min.
General Procedure for Asymmetric Synthesis of
Chiral 1,5-Dicarbonyl Compounds
To a solution of compound 5 (39 mg, 0.17 mmol) in dry
DCM (5 mL) was added EDC·HCl (48 mg, 0.26 mmol,
1.5 equiv.), HOBt (34 mg, 0.26 mmol, 1.5 equiv.) and BnOH
(28 mg, 0.26 mmol, 1.5 equiv.). The resulting solution was
cooled to 08C and Et3N (25 mg, 0.26 mmol, 1.5 equiv.) was
added. The reaction mixture was stirred for 6 h at room
temperature. Then the reaction solution was washed by 1M
HCl and saturated aqueous NaHCO3. After removal of sol-
vent, the residue was purified through column chromatogra-
phy on silica gel (petroleum ether/ethyl acetate as eluents)
to afford the compound 12a; yield: 38 mg (65%).
Characterization of a representative compound – (S)-
benzyl 3-(nitromethyl)-5-oxo-5-phenylpentanoate (12a):
1
[a]2D0: À1.9 (c 0.5 CHCl3); H NMR (300 MHz, CDCl3): d=
7.91 (d, J=8.1 Hz, 2H), 7.59 (m, 1H), 7.47 (m, 2H), 7.28
(m, 5H), 5.14 (s, 2H), 4.67 (d, J=4.8 Hz, 2H), 3.33 (m, 1H),
3.28 (brs, 2H), 2.67 (d, J=6.3 Hz, 2H); 13C NMR (75 MHz,
CDCl3): d=197.3, 171.1, 135.5, 133.6, 128.8, 128.6, 128.3,
128.0, 127.0, 77.4, 66.7, 39.0, 35.4, 28.0; HR-MS: m/z=
341.3054, calcd. for C19H19NO5 [M]+: 341.3056; HPLC (Chir-
alpak AD-H, 2-propanol/hexane=10/90, flow rate
0.8 mLminÀ1, l=254 nm): tmajor =35.7 min, tminor =37.8 min.
Adv. Synth. Catal. 2012, 354, 2873 – 2885
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2883

Xiang Li et al.
UPDATES
Zhang, C. Zhu, J. Nie, J. Ma, J. Org. Chem. 2010, 75,
1402; f) M. Tissot, D. Muller, S. Belot, A. Alexakis,
Org. Lett. 2010, 12, 2770.
Acknowledgements
We gratefully acknowledge financial support from the NSFC
(20962023, 21162034) and the Program for New Century Ex-
cellent Talents in University (NCET-10-0907).
[12] For an elegant review on the regioselectivity of conju-
gate addition reactions of extended Michael acceptors:
N. Krause, S. Thorand, Inorg. Chim. Acta 1999, 296, 1,
and references cited therein.
[13] X. Li, F. Peng, X. Li, W. Wu, Z. Sun, Y. Li, S. Zhang,
Z. Shao, Chem. Asian J. 2011, 6, 220.
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