Enantioselective intramolecular crossed rauhut-currier reactions through cooperative nucleophilic activation and hydrogen-bonding catalysis: Scope and mechanistic insight

Article abstract of DOI:10.1002/chem.201100479

A highly efficient and enantioselective intramolecular crossed Rauhut-Currier (RC) reaction of nitroolefins with tethered enonates has been developed through cooperative nucleophilic activation and a hydrogen-bonding catalytic strategy (≤98% ee and 98% yield). The reaction features simple experimental procedures and is completely chemoselective and atom-economic in character. The potential synthetic applications have been demonstrated by the conversion of the RC reaction products into biologically and pharmaceutically valuable compounds with highly diastereoselectivity. In addition, computational investigations were employed to support the proposed mechanism and to obtain a good understanding of the origin of the stereoselectivity in RC reactions. Copyright

Full text of DOI:10.1002/chem.201100479

DOI: 10.1002/chem.201100479
Enantioselective Intramolecular Crossed Rauhut–Currier Reactions through
Cooperative Nucleophilic Activation and Hydrogen-Bonding Catalysis:
Scope and Mechanistic Insight
Xu-Fan Wang,[a] Liang Peng,[b] Jing An,[a] Chao Li,[a] Qing-Qing Yang,[a] Liang-Qiu Lu,[a]
Feng-Long Gu,*[b] and Wen-Jing Xiao*[a]
Abstract: A highly efficient and enan-
tioselective intramolecular crossed
Rauhut–Currier (RC) reaction of nitro-
olefins with tethered enonates has
been developed through cooperative
nucleophilic activation and a hydrogen-
bonding catalytic strategy (ꢀ98% ee
and 98% yield). The reaction features
simple experimental procedures and is
completely chemoselective and atom-
economic in character. The potential
synthetic applications have been dem-
onstrated by the conversion of the RC
reaction products into biologically and
pharmaceutically valuable compounds
with highly diastereoselectivity. In ad-
dition, computational investigations
were employed to support the pro-
posed mechanism and to obtain a good
understanding of the origin of the ste-
reoselectivity in RC reactions.
Keywords: asymmetric catalysis
·
cascade reactions · hydrogen bonds ·
Michael addition · Rauhut–Currier
reaction
Introduction
phosphine-based catalysts and were typically limited to the
use of bis-enones or enone-tethered a,b-unsaturated esters.
In particular, the enantioselective variants of the RC reac-
tions are extremely rare due to the lack of efficient catalytic
systems.[5] In 2007, Aroyan and Miller demonstrated that a
protected cysteine moeity acted as an efficient nucleophilic
promoter to mediate an enantioselective intramolecular RC
reaction [Eq. (1)].[5b] Shortly after, Seidel and Gladysz de-
veloped a chiral rhenium/phosphine complex catalyst for the
intramolecular RC reaction of bis-enones, thus giving a cy-
cloisomerization product with moderate enantiomeric excess
[Eq. (2)].[5c] Wang and co-workers reported in 2008 a one-
pot enantioselective Michael/Michael cascade reaction to
provide highly functionalized thiochromenes in excellent
yields and stereoselectivities.
Since 1963, Rauhut–Currier (RC) and Morita-Baylis-Hill-
man (MBH) reactions have emerged as unique and valuable
carbon-carbon bond-forming protocols.[1] Whereas remark-
able progress has been achieved in regard to the MBH reac-
tion, the RC transformation remains largely undeveloped.
The key challenge has been the difficulty in controlling the
selectivity of the cross-coupling reactions, which involve two
different activated alkenes.[2] In addition, some activated al-
kenes only react sluggishly or provide undesired byproducts
under normal conditions. In 2002, Krische and Roush inde-
pendently disclosed a R3P-catalyzed intramolecular version
of the RC reaction that employed bis-enone substrates.[3b,c]
These pioneering studies cleverly addressed the issue of se-
lectivity in RC reactions. As a consequence, extensive ef-
forts have been devoted toward increasing the power of the
RC process over the past several years.[4] Surprisingly,
almost all of these catalytic protocols primarily utilized
[a] X.-F. Wang, J. An, C. Li, Q.-Q. Yang, L.-Q. Lu, Prof. Dr. W.-J. Xiao
Key laboratory of Pesticide and Chemical Biology
Ministry of Education, College of Chemistry
Central China Normal University
152 Luoyu Road, Wuhan, Hubei 430079 (P.R. China)
Fax : (+86)27-6786-2041
E-mail: wxiao@mail.ccnu.edu.cn
[b] L. Peng, Prof. Dr. F.-L. Gu
Center for Computational Quantum Chemistry
South China Normal University, West 55 Zhongshan Road
Guangzhou, Guangdong 510009 (P.R. China)
Fax : (+86)20-3931-0544
E-mail: gu@scnu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100479.
6484
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 6484 – 6491

FULL PAPER
As described by the authors, the reaction may involve a
dynamic kinetic resolution-mediated RC reaction proce-
dure.[6] Recently, Christmann et al. generated chiral cycloal-
kenes through a dienamine-activated crossed intramolecular
RC-type reaction in an excellent study.[7] Despite the superi-
or Michael acceptor ability of the nitroalkene and the well-
documented synthetic utility of the nitro group, the intramo-
lecular RC-type reaction of conjugated nitroalkenes has not
received much attention to date.[8] Thus, further extension of
the scope of such viable substrates and the development of
asymmetric versions of RC reactions with synthetically
useful enantioselectivities are still highly desirable.
Scheme 1. Proposed pathway for the Rauhut–Currier cyclization reaction.
Boc=tert-butoxycarbonyl, Cbz=carbobenzyloxy.
The continuous exploration of novel and more efficient
methods for the synthesis of heavily functionalized and bio-
logically valuable chiral scaffolds has been of long-standing
interest to the chemical community.[9] In this context, the
chiral chromene plays an important role in various medici-
nal compounds that have a broad and interesting range of
biological activities[10] and becomes a valuable architectural
platform for developing new synthetic methodologies.
Therefore, a number of spectacular advances have been
made for the construction of this “privileged” structural
motif, such as the Pt-catalyzed cyclization of chiral precur-
sors,[11] ring-closing metathesis,[12] and organocatalytic
domino oxo-Michael-aldol-dehydration reactions.[13] Despite
this great progress, the search for more efficient and highly
enantioselective approaches to construct the chromene skel-
eton is still extremely attractive.
efficient catalytic system, we decided to use benzyl tert-bu-
toxycarbonyloxycarbamate (3)[19] as the nucleophilic pro-
moter because of the intrinsic ability of this compound to in-
itiate a reversible Michael addition reaction. Table 1 summa-
rizes our efforts to identify a viable hydrogen-bonding cata-
lyst (HBC) for the process.[20] The combination of achiral 3
Table 1. Evaluation of intramolecular crossed Rauhut–Currier reaction
conditions.[a]
Recently, the concept of combining two distinct catalytic
entities, which work in concert, has been considered to be
state of the art in asymmetric synthesis.[14] The synergistic
activation by such a two-component catalyst system usually
enables efficient stereocontrol in a wide range of reactions
that were previously unsuccessful.[15] In 2008, we disclosed
an unprecedented reaction of sulfur ylides with nitroolefins
sequentially catalyzed by thiourea and 4-dimethylaminopyri-
dine (DMAP) to afford diverse and structurally complex ox-
azolidin-2-ones.[16] Encouraged by the potential of this coop-
erative catalysis, we became interested in the possibility of
using a similar strategy to carry out an enantioselective RC
reaction. Herein, we report the successful execution of this
idea and describe highly enantioselective RC reactions of ni-
troolefins with tethered a,b-unsaturated esters [Eq. (3)].
This methodology provides an efficient access to highly
functionalized 2H-chromenes, 2H-thiochromenes, and 1,2-di-
hydronaphthalenes, all in an atom-economical and chemose-
lective fashion (Scheme 1).[17] Furthermore, to understand
this new RC reaction, a series of experimental and computa-
tional studies on the mechanism and the determining step of
the stereoselectivity will be presented.
Entry
Catalyst
Solvent
T [h]
24
Yield [%][b]
ee [%][c]
1
2
3
4
5
HBC-1
HBC-2
HBC-3
HBC-4
HBC-5
HBC-6
HBC-6
HBC-6
HBC-6
HBC-6
HBC-6
HBC-6
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
Et2O
74
89
67
60
92
98
85
94
83
83
94
92
À50
À72
70
62
82
80
86
86
80
24
24
24
24
24
40
16
120
30
72
6
7[d]
8[d]
9[d]
10[d]
11[d]
12[e]
CH3CN
CH3OH
CHCl3
80
64
92
Results and Discussion
6 days
[a] Conditions: 1a=0.4 mmol, 3=0.48 mmol, HBC=0.08 mmol, and sol-
vent=2 mL. [b] Yield of the isolated product. [c] Determined by chiral
HPLC. [d] The reaction was carried out at 08C. [e] The reaction was car-
ried out at À408C for one day and À208C for five days. Mes=mesityl.
Evaluation of intramolecular crossed Rauhut–Currier reac-
tion conditions: Our investigation began with the intramo-
lecular reaction of nitroolefin enoate 1a.[18] In search of an
Chem. Eur. J. 2011, 17, 6484 – 6491
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6485

W.-J. Xiao, F.-L. Gu et al.
Table 2. Enantioselective intramolecular crossed Rauhut–Currier reactions of nitro-
olefin enoates.[a]
and various chiral HBCs efficiently facilitated the
enantioselective intramolecular RC reaction of 1a. To
our delight, catalyst HBC-6, which is obtained from
optically pure 1,2-diaminocyclohexane and 1,2-diphe-
nylethylenediamine,[21] was identified as the optimal co-
catalyst after extensive screening (Table 1, entry 6). No
background reaction was observed with either 3 or
HBC-6 independently. Notably, the reaction exhibits
complete chemoselectivity with this catalyst combina-
tion because the formation 4a as another possible
product was not observed. On this basis, a brief survey
of the reaction media was performed. The RC reaction
of 1a worked very well in chloroform at À408C and af-
forded 2a 92% yield of the isolated product with
92% ee (Table 1, entry 12).
Entry Nitroolefin
1
Product
Yield [%][b] ee [%][c]
92
93
91
97
86
95
98
87
83
85
74
52
92
92
90
93
91
93
91
98
91
90
73
73
2
3
Scope of the crossed Rauhut–Currier reaction: Experi-
ments that probe the scope of substrates bearing two
tethered activated alkenes are highlighted in Table 2.
Gratifyingly, the reaction displays excellent generality,
and significant structural variation in nitroolefin
enoates 1a–l can be realized. Typically, methyl and me-
thoxy substituents can be incorporated on the benzene
ring at the meta and/or para positions to the oxygen
atom without loss of reaction efficiency or stereocon-
trol (Table 2, entries 2–4, 9, and 10: 83–97% yield, 90–
93% ee). Moreover, substrates substituted with elec-
tron-deficient para-F, -Cl, or -Br atoms have been suc-
cessfully utilized in this reaction with little influence on
the reaction selectivity (Table 2, entries 5–7: 86–98%
yield, 91–93% ee). It is of note that such halogenated
products would be valuable synthons for the further
construction of molecular complexity through transi-
tion-metal-catalyzed coupling technologies. As expect-
ed the sulfur-tethered substrate 1k produces 2k in
74% yield with good enantiocontrol (Table 2,
entry 11), employment of which would afford function-
alized thiochromenes efficiently. Aliphatic substrates
are also tolerated. For example, nitroolefin enoate 1l
underwent cyclization to give 2l in moderate yield with
good enantioselectivity (Table 2, entry 12). Note that
the absolute configuration of the stereocenter in the
2H-chromene 2g was unambiguously determined to be
the R isomer by X-ray crystallographic studies,[22] and
the stereochemistry of other products could be tenta-
tively assigned by assuming an analogous enantioinduc-
tion (Figure 1).
4
5
6
7[d]
8
9
10
11[e]
12[e]
[a] Conditions: 1a=0.4 mmol, 3=0.48 mmol, HBC=0.08 mmol, and CHCl3 =2 mL at
À408C for one day and À208C for five days. [b] Yield of the isolated product. [c] De-
termined by chiral HPLC. [d] The absolute configuration of 2g was determined by X-
ray studies.[22] [e] The reaction was carried out at 08C for one day and room tempera-
ture for five days.
Moreover, further extension of the scope of substrates in
the present transformation has been successfully achieved.
For example, the reaction of nitroolefin enoate 1a with 1H-
benzo[d]ACHTUNGRTEN[NUNG 1,2,3]triazole (3a) worked very well in the pres-
ence of catalyst HBC-6, thus affording the corresponding
Figure 1. X-ray crystal structure of 2g.
6486
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 6484 – 6491

Cooperative Catalysis of Enantioselective Rauhut–Currier Reactions
FULL PAPER
RC product 2a in 82% yield with 81% ee [Eq. (4)]. Notably,
when para-thiocresol (3b) acted as the nucleophilic promot-
er, the a-methyl-substituted nitroolefin enoate 1m can also
participate in this cascade reaction efficiently to provide the
corresponding product 2 m in good yield (85%) with excel-
lent stereoselectivity [84% ee, >95:5 d.r.; Eq. (5)].[18a]
Table 1) were chosen as the hydrogen-bonding catalysts.
Frequency calculations were performed at the same level of
theory to obtain the values of the zero-point energy (ZPE),
enthalpy, entropy, and Gibbs Free energy and to confirm the
nature of the stationary points. Unless indicated otherwise,
all the energy data discussed herein are for the Gibbs Free
energy at room temperature (298.15 K) in the gas phase.
The solvent effects were computed by using the polarizable
continuum method (PCM; i.e., defaulted integral equation
formalism (IEF) PCM (IEFPCM) method[26]) at the same
level by using the gas-phase optimized structures, except for
the initial reaction between the HBC and nucleophilic pro-
moter (NuP), which was fully optimized (all the PCM calcu-
lations were performed in CH2Cl2 (e=8.93)).
A five-step reaction pathway was suggested for this reac-
tion (Scheme 2 and Figure 2). Initially, the NuP is activated
by the HBC through proton transfer from NuP to the terti-
ary amine of the HBC, thus affording the NuP(ÀH)À/
HBC(H)+ complex.[27,28] DFT calculations show that the
barrier energy of this step is so low (only 3.9 kcalmolÀ1 in
the gas phase and 2.4 kcalmolÀ1 when the solvent effects are
included) that this process should proceed very quickly. Fol-
lowing the proton transfer, a strong hydrogen bond is
formed between the nitro group of the substrate and the
quaternary ammonium group of HBC(H+), therefore acti-
vating the LUMO of the unsaturated substrate. The nitro-
gen atom (N1) of the NuP is oriented by the thiourea group
to attack the carbon atom (C1) of the substrate to provide
INT1. The calculations predicted the same energy barrier
(14.4 kcalmolÀ1) of this step for both the R and S enantio-
mers and suggest that these two reactions compete with
each other. The relative energies of INT1 with regard to the
R and S enantiomers were 2.0 and 3.7 kcalmolÀ1, respective-
ly, which indicate that the R enantiomer is more thermody-
namically favorable. The subsequent intramolecular Michael
addition reaction constructed a six-membered ring inter-
mediate (INT2). The values for the relative Gibbs Free
energy for the R and S enantiomers were DG=16.1 and
21.7 kcalmolÀ1, and the energy barriers of this step were
14.1 and 18.0 kcalmolÀ1, respectively. Whereas, the hydrogen
atom (H1) transfers from the nitrogen atom (N3) of
HBC(H+) to the carbon atom (C4) of the enolate to form
Mechanistic investigation into the crossed Rauhut–Currier
reaction: To investigate the proposed pathway of this RC re-
action, the reaction was quenched after 3 days at À408C,
and the desired RC product 2a and aza-Michael addition re-
action product 2a’ were obtained [Eq. (6)]. When 2a’ was
treated under the standard conditions, it afforded RC prod-
uct 2a without erosion of the enantioselectivity [Eq. (7)].
Moreover, detailed computational studies were performed
to understand the mechanism and enantioinduction of the
reaction.
Computational studies were performed by using the
Gaussian 03[23] program to in-
vestigate the proposed mecha-
nism of the RC reaction
(Scheme 2). Density functional
theory (DFT) with the Becke
three-parameter hybrid ex-
change functional and Lee-
Yang-Parr correlation function-
al (B3LYP)[24] with the 6-31G-
ACHTUNGTRENNUNG
(d,p) basis set[25] were employed
in the calculations. Modified
HBC-3–6 (with the inclusion of
a
thiourea and dimethyl-ring
alkyl group and replacement of
Figure 2. Profile of the Gibbs Free energy values for the RC reaction. COM=Complex, DG = relative Gibbs
other groups by methyl groups; free energy, PRO = product.
Chem. Eur. J. 2011, 17, 6484 – 6491
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6487

W.-J. Xiao, F.-L. Gu et al.
enantiomer are all smaller than
that of the corresponding
S
enantiomer (Figure 2). The
largest energy difference of
5.6 kcalmolÀ1 between the
R
and
S
enantiomers occurs
during the intramolecular Mi-
chael reaction (TS2). We calcu-
lated the energies of both the R
and
S
configurations for
HBC(H+) and the remaining
portion (Sub+NuPÀ(ÀH)) sep-
arately for TS2 to account for
the enantioselectivity of this re-
action (Figure 3). It was found
that HBC(H+) contributed to
nearly half of the energy be-
tween the two enantiomers,
thus indicating that the energy
difference comes from the in-
termolecular steric effect of the
HBC. The remaining energy or-
iginated from the difference in
the strength of the hydrogen
bond. The distances of 1.614
and 1.758 ꢁ between the hydro-
gen of the quaternary ammoni-
um group and the oxygen of
Scheme 2. Proposed pathway for the Rauhut–Currier cyclization reaction. INT=intermediate, TS=transition
state.
INT3. The energy barrier of this step was only 1.6 and
1.2 kcalmolÀ1 for the R and S configurations without the
zero-point energy (ZPE) correlation. Note that the energy
of TS3 was lower than INT2 when the ZPE is included, as
shown in the Gibbs Free energy profile (Figure 2). Vibra-
tional frequency calculations confirmed that TS3 was a
saddle point and the negative eigenvalues of R and S enan-
tiomers are À754.7 and À406.1 i, respectively. The vibration-
al mode with the imaginary frequency corresponds to the
movement of H1 between N3 and C3. The calculated ener-
gies indicate that the proton transfer proceeds very easily.[29]
The elimination of the NuP is a two-step reaction: the H4
transfers from C2 to the tertiary amine N3 of the HBC fol-
lowed by a retro-aza-Michael reaction. The values of the rel-
ative Gibbs Free energy of the transition states are DG=
17.3 and À1.2 kcalmolÀ1 for the R enantiomer and DG=
21.8 and 3.2 kcalmolÀ1 for the S enantiomer. The reaction
barriers are 28.6 and 8.5 kcalmolÀ1 for the R enantiomer
and 28.1 and 8.2 kcalmolÀ1 for the S enantiomer. The size of
the energy barrier of the proton-transfer step suggests that
it was the rate-determining step of this reaction, and it could
also explain why the reaction was slow. Further investigation
of the TS4 of the R enantiomer showed that if a water mole-
cule was included in the proton-transfer reaction, the reac-
tion barrier would decrease to 17.1 kcalmolÀ1.[27,30]
Figure 3. Structure of TS2 and the energy gap of the separated part of
TS2 (distance in ꢁ and energy in kcalmolÀ1).
the nitro group for the R and S enantiomers suggested that
the former had a stronger hydrogen-bonding effect than the
latter. These results indicate that the HBC was more suita-
ble to catalyze the formation of the R enantiomer.
Derivatizations of the Rauhut–Currier reaction adduct: Per-
haps more importantly, the enantio-enriched RC adducts
can be readily transformed into biologically and pharma-
ceutically valuable compounds (Scheme 3). For example, the
RC reaction product 2h reacted with 1-methyl-1H-indole
under the conditions developed by Xu and co-workers,[31]
thus producing the highly functionalized indole-containing
chroman derivative 5. Furthermore, a formal [4+2] cycload-
dition of 2h to 2-propenylindole took place smoothly to
generate the tetrahydrocarbazole derivative 6 in 87% yield
of the isolated product with greater than 95:5 diastereoselec-
Understanding of origin of the enantioselectivity: The
values of the Gibbs Free energy for the formation of the R
6488
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 6484 – 6491

Cooperative Catalysis of Enantioselective Rauhut–Currier Reactions
FULL PAPER
the pure product 2a as a yellow oil
(92%, 92% ee). [a]1D6 =72.40 (c=0.94
in CHCl3); HPLC (Chiralpak AD-H
column,
hexane/2-propanol=95:5,
; l=254 nm, 258C, t1 =
0.7 mLminÀ1
18.92 min, t2 =21.10 min); 1H NMR
(400 MHz, CDCl3): d=7.86 (s, 1H),
7.43–7.34 (m, 1H), 7.30 (dd, J=7.6,
1.5 Hz, 1H), 7.04 (t, J=7.5 Hz, 1H),
6.95 (d, J=8.2 Hz, 1H), 6.04 (dd, J=
9.4, 3.5 Hz, 1H), 4.18 (m, 4.3 Hz, 2H),
2.86 (dd, J=15.1, 9.4 Hz, 1H), 2.71
(dd, J=15.1, 3.5 Hz, 1H), 1.27 ppm (t,
J=7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=168.81, 152.63, 140.59,
134.35, 130.39, 129.30, 122.86, 117.68,
117.46, 69.65, 61.07, 37.70, 14.02 ppm;
MS: m/z: 261.8 [M+H]+; elemental
analysis (%) calcd for C13H13NO5: C
59.31, H 4.98, N 5.32; found: C 59.30,
H 4.95, N 5.30.
Scheme 3. Derivatizations of the Rauhut–Currier reaction adduct 2h. Tf=trifluoromethyl.
tivity by using our recently developed strategy.[32] This archi-
tecture widely exists in various naturally occurring alkaloids
and synthetic analogues of medicinal importance,[33] some of
which can be potentially used as tumor-growth inhibitors
Acknowledgements
and protein kinase C inhibitors.[34] Notably, trebenzomine
analogue 7 can be easily synthesized in 54% overall yield
through an operationally simple three-step procedure from
2h,[35] thus indicating that potentially medicinal candidates
can be readily accessed from simple starting materials.
We are grateful to the National Science Foundation of China (No.
20872043, 21072069, and 21002036), the National Basic Research Pro-
gram of China (2011CB808600), and the Program for Changjiang Schol-
ars and Innovative Research Team in University (IRT0953) for support
of this research.
Conclusion
[1] For a review, see: a) C. E. Aroyan, A. Dermenci, S. J. Miller, Tetra-
hedron 2009, 65, 4069–4084; for pioneering studies, see: b) A. B.
Baylis, M. E. D. Hillman, Celanese Corp. , Ger. Offen. DE 2155113,
1972; Chem. Abstr. 1972, 77, 434174; c) K. Morita, Z. Suzuki, H.
Hirose, Bull. Chem. Soc. Jpn. 1968, 41, 2815; d) M. M. Rauhut, H.
Currier, American Cyanamid Co. , U.S. Patent 307499919630122,
1963; Chem. Abstr. 1963, 58, 11224a.
We have developed a highly enantioselective crossed RC re-
action of nitroolefins with tethered a,b-unsaturated esters
by merging nucleophilic activation and hydrogen-bonding
catalysis. The reaction itself features simple experimental
procedures and is completely atom economical under
benign conditions. The synthetic utility of the RC reaction
products are documented by the production of biologically
and pharmaceutically valuable compounds in highly diaste-
reoselectivity. In addition, computational investigations led
to a good understanding of the proposed mechanism, which
indicates that the stereoselectivity of the RC reaction is de-
termined by an intramolecular-Michael addition step and
the rate-determining step is a retro-aza-Michael addition re-
action. The configuration of the RC reaction product pre-
dicted by computational calculations is in good agreement
with the experimental observations.
[2] For a Lewis acid-catalyzed reaction, see: T. E. Reynolds, M. S. Bink-
ley, K. A. Scheidt, Org. Lett. 2008, 10, 2449–2452.
[3] a) R. K. Thalji, W. R. Roush, J. Am. Chem. Soc. 2005, 127, 16778–
16779; b) S. A. Frank, D. J. Mergott, W. R. Roush, J. Am. Chem.
Soc. 2002, 124, 2404–2405; c) L.-C. Wang, A. L. Luis, K. Agapiou,
H.-Y. Jang, M. J. Krische, J. Am. Chem. Soc. 2002, 124, 2402–2403;
for a pioneering example of an intramolecular RC process, see:
d) J. K. Ergꢂden, H. W. Moore, Org. Lett. 1999, 1, 375–377.
[4] For representative examples, see: a) W.-J. Yao, Y.-H. Wu, G. Wang,
Y.-P. Zhang, C. Ma, Angew. Chem. 2009, 121, 9893–9896; Angew.
Chem. Int. Ed. 2009, 48, 9713–9716; b) C. Zhong, Y.-F. Chen, J. L.
Petersen, N. G. Akhmedov, X.-D. Shi, Angew. Chem. 2009, 121,
1305–1308; Angew. Chem. Int. Ed. 2009, 48, 1279–1282; c) N. T.
McDougal, S. E. Schaus, Angew. Chem. 2006, 118, 3189–3191;
Angew. Chem. Int. Ed. 2006, 45, 3117–3119; d) D. J. Mergott, S. A.
Frank, W. R. Roush, Proc. Natl. Acad. Sci. USA 2004, 101, 11955–
11959; e) C. A. Evans, S. J. Miller, J. Am. Chem. Soc. 2003, 125,
12394–12395; f) D. G. Jellerichs, J.-R. Kong, M. J. Krische, J. Am.
Chem. Soc. 2003, 125, 7758–7759.
Experimental Section
[5] Although the RC reaction was first reported in 1963, there are few
reports on the enantioselective variants to date; see: a) C. E.
Aroyan, A. Dermenci, S. J. Miller, J. Org. Chem. 2010, 75, 5784–
5796; b) C. E. Aroyan, S. J. Miller, J. Am. Chem. Soc. 2007, 129,
256–257; c) F. Seidel, J. A. Gladysz, Synlett 2007, 0986–0988; during
the preparation of this report, Wu and co-workers developed the
first example of a bifunctional phosphinothiourea-catalyzed enantio-
selective intramolecular Rauhut–Currier reaction of bis-enones, see:
Representative procedure: Nitroolefin enoate 1a (0.4 mmol, 105 mg) was
added to a vial containing HBC-6 (0.08 mmol, 46 mg) and benzyl (tert-
butoxycarbonyl)oxycarbamate (3; 0.48 mmol, 128 mg) in CHCl3 (2 mL)
at À408C. The resulting reaction mixture was stirred at À408C for 1 day
and warmed to À208C. After the reaction was determined to be com-
plete by TLC analysis, the crude product was purified by flash chroma-
tography on silica gel (petroleum ether/ethyl acetate 20:1~15:1) to give
Chem. Eur. J. 2011, 17, 6484 – 6491
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6489

W.-J. Xiao, F.-L. Gu et al.
d) J.-J. Gong, T.-Z. Li, K. Pan, X.-Y. Wu, Chem. Commun. 2011, 47,
1491–1493.
[6] J. Wang, H.-X. Xie, L.-S. Zu, W. Wang, Angew. Chem. 2008, 120,
4245–4247; Angew. Chem. Int. Ed. 2008, 47, 4177–4179.
[18] a) X.-F. Wang, Q.-L. Hua, Y. Cheng, X.-L. An, Q.-Q. Yang, J.-R.
Chen, W.-J. Xiao, Angew. Chem. 2010, 122, 8557–8561; Angew.
Chem. Int. Ed. 2010, 49, 8379–8383; b) L.-Q. Lu, F. Li, J. An, J.-J.
Zhang, X.-L. An, Q.-L. Hua, W.-J. Xiao, Angew. Chem. 2009, 121,
9706–9709; Angew. Chem. Int. Ed. 2009, 48, 9542–9545.
[19] a) F. Pesciaioli, F. D. Vincentiis, P. Galzerano, G. Bencivenni, G. Bar-
toli, A. Mazzanti, P. Melchiorre, Angew. Chem. 2008, 120, 8831–
8834; Angew. Chem. Int. Ed. 2008, 47, 8703–8706; b) J. Vesely, I.
Ibrahem, G.-L. Zhao, R. Rios, A. Cꢄrdova, Angew. Chem. 2007,
119, 792–795; Angew. Chem. Int. Ed. 2007, 46, 778–781.
[7] E. Marquꢃs-Lꢄpez, R. P. Herrera, T. Marks, W. C. Jacobs, D. Kçn-
ning, R. M. de Figueiredo, M. Christmann, Org. Lett. 2009, 11,
4116–4119.
[8] Despite the superior Michael acceptor ability of the nitroalkene and
the well-documented synthetic utility of the nitro group; for selected
reviews, see: a) O. M. Berner, L. Tedeschi, D. Enders, Eur. J. Org.
Chem. 2002, 1877–1894; b) N. Ono, The Nitro Group in Organic
Synthesis,Wiley-VCH, New York, 2001; to our knowledge, only one
single example has been reported about the intramolecular RC-type
reaction of nitroalkenes, see reference [7]).
[9] a) E. M. Carreira, L. Kvaerno, Classics in Stereoselective Synthesis,
Wiley-VCH, Weinheim, 2008; b) Asymmetric Synthesis: The Essen-
tials (Eds.: M. Christmann, S. Brꢅse), Wiley-VCH, Weinheim, 2007.
[10] a) H. C. Shen, Tetrahedron 2009, 65, 3931–3952; b) G. Zeni, R. C.
Larock, Chem. Rev. 2004, 104, 2285–2310; c) B. A. Keay in Compre-
hensive Heterocyclic Chemistry II, Vol. 2 (Eds. A. R. Katritzky, C. W.
Rees, E. F. V. Scriven), Pergamon, Oxford, 1996, p. 395.
[11] S. J. Pastine, S. W. Youn, D. Sames, Org. Lett. 2003, 5, 1055–1058.
[12] a) C. Hardouin, L. Burgaud, A. Valleix, E. Doris, Tetrahedron Lett.
2003, 44, 435–437; b) P. Wipf, W. S. Weiner, J. Org. Chem. 1999, 64,
5321–5324; c) J. P. A. Harrity, D. S. La, D. R. Cefalo, M. S. Visser,
A. H. Hoveyda, J. Am. Chem. Soc. 1998, 120, 2343–2351; d) J. P. A.
Harrity, J. S. Wisser, J. D. Gleason, A. H. Hoveyda, J. Am. Chem.
Soc. 1997, 119, 1488–1489.
[13] a) B. C. Das, S. Mohapatra, P. D. Campbell, S. Nayak, S. M. Mahalin-
gam, T. Evans, Tetrahedron Lett. 2010, 51, 2567–2570; b) S.-P. Luo,
Z.-B. Li, L.-P. Wang, Y. Guo, A.-B. Xia, D.-Q. Xu, Org. Biomol.
Chem. 2009, 7, 4539–4546; c) P. Kotame, B.-C. Hong, J.-H. Liao, Tet-
rahedron Lett. 2009, 50, 704–707; d) K.-G. Liu, A. Chougnet, W.-D.
Woggon, Angew. Chem. 2008, 120, 5911–5913; Angew. Chem. Int.
Ed. 2008, 47, 5827–5829; e) H. Sundꢃn, I. Ibrahem, G.-L. Zhao, L.
Eriksson, A. Cꢄrdova, Chem. Eur. J. 2007, 13, 574–581; f) H. Li, J.
Wang, T. E-Nunu, L.-S. Zu, W. Jiang, S.-H. Wei, W. Wang, Chem.
Commun. 2007, 507–509.
[14] For recent reviews, see: a) C. Zhong, X.-D. Shi, Eur. J. Org. Chem.
2010, 2999–3052; b) Z. Shao, H. Zhang, Chem. Soc. Rev. 2009, 38,
2745–2755; c) S. J. Connon, Chem. Commun. 2008, 2499–2510;
d) A. G. Doyle, E. N. Jacobsen, Chem. Rev. 2007, 107, 5713–5743;
e) J.-A. Ma, D. Cahard, Angew. Chem. 2004, 116, 4666–4683;
Angew. Chem. Int. Ed. 2004, 43, 4566–4583.
[15] For selected examples, see: a) H. Xu, S. J. Zuend, M. G. Woll, Y.
Tao, E. N. Jacobsen, Science 2010, 327, 986–990; b) B. Cardinal-
David, D. E. A. Raup, K. A. Scheidt, J. Am. Chem. Soc. 2010, 132,
5345–5347; c) S. P. Lathrop, T. Rovis, J. Am. Chem. Soc. 2009, 131,
13628–13630; d) T. Yang, A. Ferrali, F. Sladojevich, L. Campbell,
D. J. Dixon, J. Am. Chem. Soc. 2009, 131, 9140–9141; e) C. Li, B.
Villa-Marcos, J. Xiao, J. Am. Chem. Soc. 2009, 131, 6967–6969;
f) W.-H. Hu, X.-F. Xu, J. Zhou, W.-J. Liu, H.-X. Huang, J. Hu, L.-P.
Yang, L.-Z. Gong, J. Am. Chem. Soc. 2008, 130, 7782–7783; g) A.
Duschek, S. F. Kirsch, Angew. Chem. 2008, 120, 5787–5789; Angew.
Chem. Int. Ed. 2008, 47, 5703–5705; h) B.-Q. Zeng, X. Zhou, X.-H.
Liu, X.-M. Feng, Tetrahedron 2007, 63, 5129–5136; i) I. Ibrahem, A.
Cꢄrdova, Angew. Chem. 2006, 118, 1986–1990; Angew. Chem. Int.
Ed. 2006, 45, 1952–1956; j) N. Yamagiwa, H. Qin, S. Matsunaga, M.
Shibasaki, J. Am. Chem. Soc. 2005, 127, 13419–13427; k) G. M.
Sammis, H. Danjo, E. N. Jacobsen, J. Am. Chem. Soc. 2004, 126,
9928–9929; l) J. E. Imbriglio, M. M. Vasbinder, S. J. Miller, Org.
Lett. 2003, 5, 3741–3743.
[20] See the Supporting Information for more details on optimization of
the conditions and synthetic transformations.
[21] a) X.-Q. Dong, H.-L. Teng and C.-J. Wang, Org. Lett. 2009, 11,
1265–1268; b) C.-J. Wang, Z.-H. Zhang, X.-Q. Dong, X.-J. Wu,
Chem. Commun. 2008, 1431–1433; c) C.-J. Wang, X.-Q. Dong, Z.-H.
Zhang, Z.-Y. Xue, H.-L. Teng, J. Am. Chem. Soc. 2008, 130, 8606–
8607.
[22] The configuration of 2g was determined by X-ray crystallographic
analysis. CCDC-763160 (2g) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[23] Gaussian 03, Revision C.02, M. J. Frisch, G. W. Trucks, H. B. Schle-
gel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, J. A. Montgom-
AHCTUNGTREGeNNUN ry, Jr., T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S.
Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani,
N. Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,
O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratchian,
J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E.
Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W.
Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P. Salvador, J. J.
Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C.
Strain, O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari,
J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cio-
slowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaro-
mi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng,
A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W.
Chen, M. W. Wong, C. Gonzalez, J. A. Pople, Gaussian, Inc., Wall-
ingford CT, 2004..
[24] a) A. D. Becke, J. Chem. Phys. 1993, 98, 5648–5652; b) C. Lee, W.
Yang, R. G. Parr, Phys. Rev. B 1988, 37, 785–789.
[25] a) Y. Takano, K. N. Houk, J. Chem. Theory Comput. 2005, 1, 70–77;
b) W. J. Hehre, L. Radom, P. v. R. Schleyer, J. A. Pople, Ab Initio
Molecular Orbital Theory, Wiley, New York, 1986 and references
cited therein.
[26] a) M. T. Cancꢆs, B. Mennucci, J. Tomasi, J. Chem. Phys. 1997, 107,
3032–3037; b) B. Mennucci, J. Tomasi, J. Chem. Phys. 1997, 106,
5151–5158; c) B. Mennucci, E. Cancꢆs, J. Tomasi, J. Phys. Chem. B
1997, 101, 10506–10517; d) J. Tomasi, B. Mennucci, E. Cancꢆs, J.
Mol. Struct. (Theochem) 1999, 464, 211–226.
[27] See the Supporting Information for more details on the proton-
transfer reaction between the NuP and HBC, the solvent effect
(using the PCM model) to the RC reaction, and the influence of a
water molecule on the TS4.
[28] A. Hamza, G. Schubert, T. Soꢄs, I. Pꢇpai, J. Am. Chem. Soc. 2006,
128, 13151–13160.
[29] L. Ding, W.-H. Fang, J. Org. Chem. 2010, 75, 1630–1636.
[30] For selected examples of how water accelerated the rate of reaction,
see: a) J. J. Devery III, J. C. Conrad, D. W. C. MacMillan, R. A.
Flowers II, Angew. Chem. 2010, 122, 6242–6246; Angew. Chem. Int.
Ed. 2010, 49, 6106–6110; b) Y. Liang, H.-L. Zhou, Z.-X. Yu, J. Am.
Chem. Soc. 2009, 131, 17783–17785; c) T. D. Beeson, A. Mastrac-
chio, J.-B. Hong, K. Ashton, D. W. C. MacMillan, Science 2007, 316,
582–585; d) Y.-Z. Xia, Y. Liang, Y.-Y. Chen, M. Wang, L. Jiao, F.
Huang, S. Liu, Y.-H. Li, Z.-X. Yu, J. Am. Chem. Soc. 2007, 129,
3470–3471.
[16] L.-Q. Lu, Y.-J. Cao, X.-P. Liu, J. An, C.-J. Yao, Z.-H. Ming, W.-J.
Xiao, J. Am. Chem. Soc. 2008, 130, 6946–6948.
[17] For selected references, see: a) K. C. Nicolaou, J. A. Pfefferkorn,
A. J. Roecker, G.-Q. Cao, S. Barluenga, H. J. Mitchell, J. Am. Chem.
Soc. 2000, 122, 9939–9953; b) E. E. Schweizer, O. Meeder-Nycz in
Chromenes, Chromanones, and Chromones (Ed.: G. P. Ellis), Wiley-
Interscience, New York, 1977.
[31] S.-F. Lu, D.-M. Du, J.-X. Xu, Org. Lett. 2006, 8, 2115–2118.
6490
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 6484 – 6491

Cooperative Catalysis of Enantioselective Rauhut–Currier Reactions
FULL PAPER
[32] X.-F. Wang, J.-R. Chen, Y.-J. Cao, H.-G. Cheng, W.-J. Xiao, Org.
Lett. 2010, 12, 1140–1143.
2008, 12, 76–80; b) A. L. Sabb, R. L. Vogel, G. P. Stack, D. A.
Evrard, A. A. Failli, L. Krishnan, A. W. Chan, J. Ren, C. Guinosso,
R. B. Baudy, J. Y.-C. Sze, Y. Li, C. J. Stanton III, A. Nikitenko,
Wyeth Corp. , New Jersey, PCT Int. Appl. WO 2006/089053; Chem.
Abstr. 2006, 145, 271641; c) B. Gopalan, H. V. Joshi, D. M. Shah,
S. R. Ghorpade, Glenmark Pharm. Ltd., Mumbai, PCT Int. Appl.
WO 2005/033099.
[33] For selected examples, see: a) H.-J. Knçlker, R. R. Kethiri, Chem.
Rev. 2002, 102, 4303–4428; b) C. J. Moody, Synlett 1994, 681–688;
c) N. Misra, R. Luthra, K. L. Singh, S. Kumar in Comprehensive Nat-
ural Products Chemistry, Vol. 4 (Eds.: J. W. Kelly, D. Barton, K. Na-
kanishi, O. Meth-Cohn), Elsevier, Amsterdam, 1999, p. 54; d) D. P.
Chakraborty in Progress in the Chemistry of Organic Natural Prod-
ucts, Vol. 34 (Eds.: W. Herz, H. Grisebach, G. W. Kirby), Springer-
Verlag, Wien, 1977, pp. 299–371.
[35] M. Stanley, J. Rotrosen, N. Sculerati, S. Gershon, C. Kuhn, B. M.
Cohen, Psychopharmacology 1979, 66, 23–27.
[34] a) A. Nikitenko, D. Evrard, A. L. Sabb, R. L. Vogel, G. Stack, M.
Young, M. Lin, B. L. Harrison, J. R. Potoski, Org. Process Res. Dev.
Received: February 12, 2011
Published online: April 27, 2011
Chem. Eur. J. 2011, 17, 6484 – 6491
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6491