A recyclable organocascade reaction system: Stereoselective precipitation of optically active cis-δ-lactols with quaternary stereocenters during the Michael-hemiacetalization reaction

Article abstract of DOI:10.1002/adsc.201000553

A cascade Michael-hemiacetalization reaction between β-substituted β-nitroethanols and α,β-unsaturated aldehydes is described, which provides a convenient and efficient synthesis for cis-δ-lactols with quaternary stereocenters in moderate yields with excellent enantioselectivity. Based on the selective precipitation of cis-δ-lactols, which were isolated by filtration, the catalytic system in the filtrate can be reused directly and recycled for eight times without any obvious deterioration in enantioselectivity. Copyright

Full text of DOI:10.1002/adsc.201000553

COMMUNICATIONS
DOI: 10.1002/adsc.201000553
A Recyclable Organocascade Reaction System: Stereoselective
Precipitation of Optically Active cis-d-Lactols with Quaternary
Stereocenters during the Michael–Hemiacetalization Reaction
Fanglin Zhang,a Mohui Wei,a Junfang Dong,a Yirong Zhou,a Dengfu Lu,a
Yuefa Gong,a,* and Xiangliang Yangb
a
Department of Chemistry, Huazhong University of Science and Technology, Wuhan 430074, Peopleꢀs Republic of China
Fax : (+86)-27-8754-3632; phone: (+86)-27-8754-3232; e-mail: gongyf@mail.hust.edu.cn
College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Peopleꢀs
b
Republic of China
Received: July 13, 2010; Revised: September 12, 2010; Published online: November 17, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201000553.
Abstract: A cascade Michael–hemiacetalization re-
action between b-substituted b-nitroethanols and
a,b-unsaturated aldehydes is described, which pro-
vides a convenient and efficient synthesis for cis-d-
lactols with quaternary stereocenters in moderate
yields with excellent enantioselectivity. Based on
the selective precipitation of cis-d-lactols, which
were isolated by filtration, the catalytic system in
the filtrate can be reused directly and recycled for
eight times without any obvious deterioration in
enantioselectivity.
try.[6] Consequently, the development of efficient
strategies to access these compounds is still a hot re-
search topic, and to date, several organocatalytic
methods have been established.[7,8] To the best of our
knowledge, however, there is no report describing the
asymmetric Michael addition of non-equivalent a,a-
dialkyl-substituted nitromethanes to a,b-unsaturated
aldehydes, although this transformation is an attrac-
tive approach for the stereoselective formation of N-
substituted quaternary stereogenic centers. Obviously,
the paucity of the transformations is mainly due to
their relatively poor reactivity.
Keywords: cascade reaction; green chemistry; hy-
drogen bonding; organocatalysis; quaternary stereo-
centers
We presumed that non-equivalent a,a-dialkyl-sub-
stituted nitromethanes 1 would be activated by intro-
ducing a hydroxy group into the corresponding b-po-
sition in view of the significant role of hydrogen
bonding in substrate activation (Scheme 1).[9] More-
over, these transformations can furnish d-lactols with
N-substituted quaternary carbons adjacent to the hy-
Since the pioneering works by List, MacMillan and droxy group, which are precursors in the synthesis of
their co-workers in 2000,[1] asymmetric organocataly- natural products[10] and biologically active pharma-
sis has been widely studied over the past decade[2] ceuticals,[11] for example, manzacidins,[10b] dichomito-
and has become a powerful tool for the synthesis of ne,[10c] shahamin K,[10d] inhibitors of purine nucleoside
natural products and optically active compounds.[3] As phosphorylase[11b] and peptidomimetics.[11c] In addi-
response to the increasing economic and ecological tion, this kind of d-lactol core, as a versatile synthetic
pressure, the development of recyclable organocata- platform, can be easily converted to useful products[12]
lysts has undoubtedly attracted researchersꢀ attention such as d-lactones, tetrahydropyrans, b-amino alco-
and a number of successful strategies have been re- hols, a- and g-amino acids. In this communication, we
ported.[4] Meanwhile, the simplicity of product purifi- describe one efficient secondary amine-catalyzed cas-
cation and direct circulation of excess reagents are cade reaction involving an initial Michael addition of
also very important to improve the sustainability of b-alkyl-b-nitroethanols 1 to a,b-unsaturated aldehydes
reaction processes in large-scale industrial produc- 2 and a subsequent hemiacetalization.[13] In this pro-
tion.[5]
cess, functional group-rich d-lactol derivatives 3 were
Chiral building blocks possessing an N-substituted formed with excellent enantioselectivity. More inter-
quaternary stereocenter have important applications estingly, a highly stereoselective precipitation of the
in biological, medicinal and synthetic organic chemis- cis-3 was observed during the reaction, and cis-3, as a
Adv. Synth. Catal. 2010, 352, 2875 – 2880
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2875

Fanglin Zhang et al.
COMMUNICATIONS
Scheme 1. Synthesis of d-lactols by a Michael–hemiacetalization cascade process.
Table 1. Representative screening results of the cascade re-
single enantiomer, can be easily isolated by filtration
from the reaction mixture. Furthermore, the catalyst
and excess reagents can be directly reused in the next
cycle, which demonstrates the recyclability of the ho-
mogeneous organocatalytic system.
action.[a]
The cascade reaction of 3-(furan-2-yl)-2-nitro-1-
propanol (1a) and cinnamaldehyde (2a) was first in-
vestigated in chloroform at room temperature, in the
presence of different amine catalysts[14] together with
co-catalyst benzoic acid (Table 1, entries 1–5). To our
delight, the reaction proceeded smoothly and was
completed within 24 h. Among these pyrrolidine-
based organocatalysts, only diphenylprolinol silyl
ether (I) gave good enantioselectivity for 3a (90% ee;
Table 1, entry 1). The interesting thing is that just cis-
3a selectively precipitated as a single diastereomer
during the reaction although the diastereoselectivity
of 3a is moderate in all cases. In fact, cis-3a can be
isolated by filtration with moderate yields, thus avoid-
ing time-consuming chromatographic purification.
Subsequently, using I as the catalyst and lowering the
reaction temperature to 48C, our evaluation turned to
the solvent and we found that chloroform was the
best solvent for the reaction in terms of chemical
yields and enantioselectivities (Table 1, entries 6–11).
In neat chloroform, 3a was generated with a 3:1 dia-
steromeric ratio in an enantiopure form (Table 1,
entry 6). Addition of methanol into chloroform led to
an obvious decrease both in the diastereomeric ratio
and in enantioselectivity (1:1 dr; 92% ee; Table 1,
entry 10), and in methanol, only small amount of 3a
was formed (Table 1, entry 11). To probe the function
of the hydroxy group of 1a, the two similar structures
VI and VII were tested under the same conditions,
but no Michael adduct was detected (Scheme 2). In
Entry Catalyst Solvent T [8C]/t
Yield
[%][b]
dr[c] ee
[%][d]
[days]
1
I
CHCl3 r.t./1
CHCl3 r.t./1
CHCl3 r.t./1
CHCl3 r.t./1
CHCl3 r.t./1
CHCl3 4/4
PhCH3 4/4
CH2Cl2 4/4
CH3CN 4/4
CHCl3 4/4
CH3OH 4/4
51/82[e] 2:1 90
2
II
III
IV
V
I
I
I
I
I
I
47
53
50
49
62
58
55
54
32
<5
3:2 –
3[f]
4
2:1 30
2:1 52
2:1 43
3:1 >99
3:1 >99
2:1 99
2:1 99
1:1 93
5
6[g]
7
8
9
10[h]
11
–
–
[a]
Reactions performed with 1a (0.30 mmol), 2a
(0.90 mmol), catalyst (0.06 mmol) and benzoic acid
(0.06 mmol) in different solvents (0.6 mL).
[b]
[c]
[d]
Isolated yield of cis-3a by filtration.
1
Determined by H NMR spectroscopy.
The ee value of cis-3a, which was determined by HPLC
analysis after conversion to the corresponding d-lactone.
Isolated yield of 3a by flash chromatography over silica
gel.
[e]
[f]
No benzoic acid.
[g]
In fact, when cis-3a was isolated by flash chromatogra-
phy, its ee value was determined to be 98%.
CH3OH (3 mmol) added.
[h]
addition, we have analyzed the interaction between system[13q] but also plays a role in enhancing the reac-
the chiral catalyst I and 1a by means of NMR spec- tivity of disubstituted nitromethane through intramo-
troscopy, and confirmed the formation of a tight com- lecular hydrogen bonding.
plex 1a·I (see the Supporting Information, F). All
With the optimized reaction conditions in hand, the
these results may suggest that the hydroxy group of scope of the organocascade reaction was explored. A
1a not only acts as an active site to form the d-lactol wide range of b-substituted b-nitroethanols 1 and a,b-
and to promote the Michael addition in the cascade unsaturated aldehydes 2 were tested. As summarized
2876
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 2875 – 2880

A Recyclable Organocascade Reaction System: Stereoselective Precipitation of Optically Active cis-d-Lactols
Scheme 2. Reaction of VI or VII with 2a.
in Table 2, both electron-donating and electron-with- the precipitation of cis-3a during the reaction, this
drawing groups, as well as the substitution patterns on catalytic system can be reused directly in next cycle
the aryl substituent of 1 and 2 were tolerated. In each only by adding 1a and 2a after filtration of cis-3a. The
case, cis-3 was easily isolated by filtration in good results shown in Table 3 demonstrate that this catalyt-
yield (53–79%) and excellent enantioselectivity as de-
temined by the corresponding d-lactones (see the
Supporting Information). In the case of an aliphatic
substituent (e.g., R1 =methyl), no precipitation ap-
peared and a moderate yield of cis-3p was isolated by
flash chromatography over silica gel. Unfortunately,
when an aliphatic unsaturated aldehyde like crotonal-
dehyde was tested, the cascade reaction only gave low
yield of the d-lactol without any precipitation during
the reaction.
Table 3. Recycling in the organocascade reaction of 1a and
2a.[a]
Cycle Time
Yield
ee
[%]
Cycle Time
Yield
ee
[%]
[days] [%][b]
[days] [%][b]
1
2
3
4
5
5
5
5
64
76
79
81
99
99
99
99
5
6
7
8
6
7
8
9
78
76
77
75
99
99
98
98
Encouraged by the results of the reaction scope,
the recyclability of the catalytic system was examined
on a large scale reaction between 1a and 2a. Due to
[a]
The cascade reaction was carried out using 1a (10 mmol)
and 2a (30 mmol) with 20 mol% of I and 20 mol% ben-
zoic acid in cycle 1, and in cycles 2–8 only 1a (10 mmol)
and 2a (10 mmol) were added.
Table 2. Reaction of b-substituted b-nitroethanols 1 with 2.[a]
[b]
Isolated yield of cis-3a by filtration.
ic system was readily recyclable for eight cycles with-
out obvious deterioration in both enantioselectivity
and yield. In the end, trans-3a was separated from the
filtrate with excellent enantioselectivity (98% ee) by
flash chromatography over silica gel (see the Support-
ing Information).
R1, R2
Yield [%][b] dr ee[c] [%]
2-furanyl, C6H5
C6H5, C6H5
4-FC6H4, C6H5
4-NO2C6H4, C6H5
4-ClC6H4, C6H5
4-CH3OC6H4, C6H5
3,4-(OCH2O)C6H3, C6H5
3-NO2C6H4, C6H5
2-ClC6H4, C6H5
4-NO2C6H4, 4-CH3C6H4
4-NO2C6H4, 4-ClC6H4
4-NO2C6H4, 4-CH3OC6H4
4-NO2C6H4, 2-FC6H4
3a, 63
3b, 54
3c, 57
3d, 79
3e, 71
3f, 53
3g, 56
3h, 73
3i, 69
3j, 63
3k, 71
3l, 53
3m, 61
3:1 >99
2:1 >99[d]
3:1 >99[d]
5:1 99
Next, the synthetic versatility of the functional
group-rich cis-d-lactols 3 has also been explored
(Scheme 3). Quaternary d-lactone cis-4a and tetrahy-
dropyran 5 could be readily synthesized directly from
cis-3a in 82% and 92% yields, respectively. In addi-
tion, reduction of cis-3a with Zn in AcOH, followed
by protection with benzyl chloroformate, provided the
quaternary prolinol 6 in 68% total yield via two steps.
The absolute configuration of the cis-d-lactol was
determined to be 2S,4R,5S by single-crystal X-ray
analysis of the compound 5 and NOE analysis of cis-
3a (Figure 1). Unexpectedly, the absolute configura-
tion of the stereocenter bearing the Ph group was op-
posed to that of the results obtained in other Michael
additions of a,b-unsaturated aldehydes to nitroal-
kanes catalyzed by (S)-a,a-diphenylprolinol trime-
thylsilyl ether I.[13m,15]
5:1 >99
3:1 >99[d]
3:1 >99[d]
5:1 >99
4:1 >99
3:1 >99
5:1 >99
2:1 >99[d]
3:1 >99[d]
3:1 >99[d]
3:1 96[d]
4-NO2C6H4, 3,4-(OCH2O)C6H3 3n, 63
4-NO2C6H4, 3,4-(CH3O)C6H3
CH3, C6H5
4-ClC6H4, CH3
3o, 59
3p, 56[e]
<10
2:1 95
–
–
[a]
Reactions performed using 1 (0.50 mmol), 2 (1.50 mmol),
I (0.10 mmol) and benzoic acid (0.10 mmol) in chloro-
form (1.0 mL) for 4 days at 48C.
Furthermore, we have studied the relationship be-
tween the enantiomeric excess of d-lactone cis-4a,
which was derived from the cascade reaction product
3a by in situ oxidation, and the optical purity of the
catalyst I. The observed results, graphically depicted
[b]
[c]
Isolated yield of cis-3 by filtration.
The ee value of cis-3, which was determined by HPLC
analysis after conversion to the corresponding d-lactone.
For 9 days at À208C.
[d]
[e]
Isolated yield by column chromatography.
Adv. Synth. Catal. 2010, 352, 2875 – 2880
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2877

Fanglin Zhang et al.
COMMUNICATIONS
Scheme 3. Synthetic transformations of cis-3a.
Figure 1. X-ray crystal structure of 5[16] and results of the NOE measurements of cis-3a.
in Figure 2, clearly demonstrate a modest, but real, that precipitates stereoselectively during the reaction
negative non-linear effect.[17] This suggested the possi- can be isolated in good yield just by filtration. Fur-
bility that the cascade reaction could proceed through thermore, the catalyst and excess reagents in the fil-
a pathway involving two catalyst molecules in the trate can be reused directly and recycled on a large
transition state of the enantioselective step.[18]
scale for eight times without deterioration in both
In summary, we have developed a reliable and con- enantioselectivity and yield. Chiral d-lactones, tetra-
venient method to access d-lactols containing quater- hydropyrans and prolinols with a quaternary stereo-
nary stereocenters via an organocascade reaction be- center, which can be easily derived from cis-d-lactols,
tween a,b-unsaturated aldehydes and b-substituted b- are of great potential value in the total synthesis of
nitroethanols activated by intramolecular hydrogen natural products and medicinal chemistry. Therefore,
bonding. The resulting functionalized enantiomeri- the method presented here has distinct advantages in
cally pure cis-d-lactol with unusual stereochemistry terms of operational simplicity, the recyclability of
catalytic system, and suitability for large-scale indus-
trial production. To elucidate the mechanistic details
about the present cascade system, further investiga-
tions are ongoing.
Experimental Section
Representative Procedures for the Synthesis of cis-3
(Table 2, entry 1)
Figure 2. d-Lactone 4a ee values versus catalyst I ee for the
cascade reaction of 1a with 2a carried out in CHCl3 at 48C.
The dashed line represents the expected linear relationship.
A vial equipped with a stirring bar was charged with 3-
(furan-2-yl)-2-nitro-1-propanol 1a (0.5 mmol, 85 mg,
2878
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 2875 – 2880

A Recyclable Organocascade Reaction System: Stereoselective Precipitation of Optically Active cis-d-Lactols
1 equiv.), benzoic acid (0.1 mmol, 12 mg, 0.2 equiv.), and
neat chloroform (1.0 mL). After addition of cinnamaldehyde
2a (1.5 mmol, 198 mg, 3 equiv.) and a,a-diphenylprolinol tri-
methylsilyl ether (0.1 mmol, 33 mg, 0.2 equiv), the reaction
mixture was stirred for 4 days at 48C. The cis-3a was isolat-
ed and purified by direct filtration/washing with chloroform
304–308; d) A. Dondoni, A. Massi, Angew. Chem.
2008, 120, 4716–4739; Angew. Chem. Int. Ed. 2008, 47,
4638–4660; e) P. Melchiorre, M. Marigo, A. Carlone,
G. Bartoli, Angew. Chem. 2008, 120, 6232–6265;
Angew. Chem. Int. Ed. 2008, 47, 6138–6171; f) S. Ber-
telsen, K. A. Jørgensen, Chem. Soc. Rev. 2009, 38,
2178–2189; g) M. Nielsen, C. B. Jacobsen, N. Holub,
M. W. Paix¼o, K. A. Jørgensen, Angew. Chem. 2010,
122, 2726-2738; Angew. Chem. Int. Ed. 2010, 49, 2668–
2679.
1
(0.3 mL); yield: 95 mg (63%). H NMR (400 MHz, DMSO):
d=1.65 (d, J=13.2 Hz, 1H), 2.28 (t, J=13.2 Hz, 1H), 3.24
(d, J=15.6 Hz, 1H), 3.46 (d, J=15.6 Hz, 1H), 3.82 (d, J=
13.2 Hz, 1H), 3.80–3.87 (m, 1H), 4.22 (d, J=13.2 Hz, 1H),
5.32 (s, 1H), 6.11 (d, J=2.8 Hz, 1H), 6.36 (s, 1H), 6.60 (d,
J=2.8 Hz, 1H), 7.28–7.35 (m, 5H), 7.56 (s, 1H); 13C NMR
(100 MHz, DMSO): d=32.9, 33.9, 41.6, 62.6, 90.0, 90.1,
109.8, 111.1, 128.0, 128.5, 129.8, 138.7, 143.4, 148.8; HR-MS
(ESI): m/z=326.09946, calculated for C16H17NNaO5 [M+
Na]+: 326.09989.
[3] For reviews, see: a) R. M. D. Figueiredo, M. Christ-
mann, Eur. J. Org. Chem. 2007, 2575–2600; b) M. Ban-
dini, A. Eichholzer, Angew. Chem. 2009, 121, 9786–
9824; Angew. Chem. Int. Ed. 2009, 48, 9608–9644; c) Ł.
Albrecht, A. Albrecht, H. Krawczyk, K. A. Jørgensen,
Chem. Eur. J. 2010, 16, 28–48; d) C. Grondal, M.
Jeanty, D. Enders, Nature Chem. 2010, 2, 167–178;
e) M. G. NfflÇez, P. García, R. F. Moro, D. Díez, Tetra-
hedron 2010, 66, 2089–2109.
Representative Procedures for the Synthesis of cis-4
A vial equipped with a stirring bar was charged with cis-3a
(0.2 mmol, 61 mg, 1 equiv.), pyridinium chlorochromate
(PCC, 0.3 mmol, 65 mg, 1.5 equiv.), anhydrous sodium ace-
tate (0.6 mmol, 49 mg, 3 equiv.), and 3 mL CH2Cl2. The mix-
ture was vigorously stirred at 308C for 12 h until the com-
pletion of the reaction. Ethyl acetate (5 mL) was then
added, the precipitate was filtered off, and the filtrate was
concentrated under reduced pressure. The crude lactone
product was purified by column chromatography (eluent
CH2Cl2) to afford cis-4a; yield: 50 mg (83%); [a]1D1: +25.6 (c
1.0 in CHCl3); HPLC (Chiralpak AD-H, i-PrOH/hexane=
[4] For reviews, see: a) M. Benaglia, A. Puglisi, F. Cozzi,
Chem. Rev. 2003, 103, 3401–3429; b) F. Cozzi, Adv.
Synth. Catal. 2006, 348, 1367–1390; c) M. Gruttadauria,
F. Giacalone, R. Noto, Chem. Soc. Rev. 2008, 37, 1666–
1688; d) A. F. Trindade, P. M. P. Gois, C. A. M. Afonso,
Chem. Rev. 2009, 109, 418–514; for examples, see:
e) S. Z. Luo, X. L. Mi, L. Zhang, S. Liu, H. Xu, J. P.
Cheng, Angew. Chem. 2006, 118, 3165–3169; Angew.
Chem. Int. Ed. 2006, 45, 3093–3097; f) C. O Dµlaigh,
S. A. Corr, Y. Gun’ko, S. J. Connon, Angew. Chem.
2007, 119, 4407–4410; Angew. Chem. Int. Ed. 2007, 46,
4329–4332; g) E. Alza, C. Rodríguez-Escrich, S. Saya-
lero, A. Bastero, M. A. Pericàs, Chem. Eur. J. 2009, 15,
10167–10172; h) Z. Dalicsek, F. Pollreisz, T. Soós,
Chem. Commun. 2009, 4587–4589; i) Z.-L. Zheng,
B. L. Perkins, B. Ni, J. Am. Chem. Soc. 2010, 132, 50–
51; j) D. Vuluga, J. Legros, B. Crousse, D. Bonnet-
Delpon, Chem. Eur. J. 2010, 16, 1776–1779.
[5] For reviews, see: a) J.-I. Yoshida, K. Itami, Chem. Rev.
2002, 102, 3693–3716; b) C. C. Tzschucke, C. Markert,
W. Bannwarth, S. Roller, A. Hebel, R. Haag, Angew.
Chem. 2002, 114, 4136–4173; Angew. Chem. Int. Ed.
2002, 41, 3964–4000; for examples, see: c) N. Halland,
P. S. Aburel, K. A. Jørgensen, Angew. Chem. 2004, 116,
1292–1297; Angew. Chem. Int. Ed. 2004, 43, 1272–
1272; d) J. W. Yang, M. Stadler, B. List, Angew. Chem.
2007, 119, 615–617; Angew. Chem. Int. Ed. 2007, 46,
609–611; e) B. Tan, X. Zhang, P. J. Chua, G. F. Zhong,
Chem. Commun. 2009, 779–781.
[6] a) G. A. Cordell, in: The Alkaloids: Chemistry and
Biology, Vol. 60, Elsevier, San Diego, 2003; b) Y.
Ohfune, T. Shinada, Eur. J. Org. Chem. 2005, 5127–
5143; c) C. Cativiela, M. Mario OrdóÇez, Tetrahedron:
Asymmetry 2009, 20, 1–63.
[7] For reviews, see: a) M. Bella, T. Gasperi, Synthesis
2009, 1583–1614; for some selected examples, see: b)
A. Singh, J. N. Johnston, J. Am. Chem. Soc. 2008, 130,
5866–5867; c) S. Cabrera, E. Reyes, J. Alemµn, A.
Milelli, S. Kobbelgaard, K. A. Jørgensen, J. Am. Chem.
Soc. 2008, 130, 12031–12037; d) F. R. Bou-Hamdan,
J. L. Leighton, Angew. Chem. Int. Ed. 2009, 48,
24032406; e) M. Terada, H. Tanaka, K. Sorimachi, J.
Am. Chem. Soc. 2009, 131, 34303431; f) S. Nakamura,
50/50, flow rate=0.5 mLminÀ1, l=254 nm): tminor
=
13.48 min, tmajor =16.93 min, ee 99%; 1H NMR (400 MHz,
CDCl3): d=2.66 (d, J=16 Hz, 1H), 2.85 (dd, J1 =18 Hz, J2 =
6.8 Hz, 1H), 2.94 (dd, J1 =18.2 Hz, J2 =4 Hz, 1H), 3.32 (d,
J=15.6 Hz, 1H), 4.07 (t, J=4.8 Hz, 1H), 4.49 (d, J=14 Hz,
1H), 4.95 (dd, J1 =14 Hz, J2 =1.6 Hz, 1H), 6.04 (d, J=
3.2 Hz, 1H), 6.26 (dd, J1 =3.2 Hz, J2 =2 Hz, 1H), 7.31 (dd,
J1 =6 Hz, J2 =1.6 Hz, 3H), 7.40–7.50 (m, 3H); 13C NMR
(100 MHz, CDCl3): d=32.9, 34.0, 45.0, 68.5, 90.1, 110.0,
110.8, 128.6, 129.1, 129.5, 136.3, 143.1, 146.3, 168.0; HR-MS
(ESI): m/z=324.08388, calculated for C16H15NNaO5 [M+
Na]+: 324.08424.
Acknowledgements
This work was supported by National Natural Science Foun-
dation of China (20872041; 20902030). The Center of Analy-
sis and Testing of Huazhong University of Science and Tech-
nology is thanked for characterization of new compounds.
References
[1] a) B. List, R. A. Lerner, C. F. Barbas III, J. Am. Chem.
Soc. 2000, 122, 2395–2396; b) K. A. Ahrendt, C. J.
Borths, D. W. C. MacMillan, J. Am. Chem. Soc. 2000,
122, 4243–4244.
[2] For reviews, see: a) Enantioselective Organocatalysis,
(Ed.: P. I. Dalko), Wiley-VCH, Weinheim, 2007; b) B.
List, (guest editor), Chem. Rev. 2007, 107, No. 12 (spe-
cial issue); c) D. W. C. MacMillan, Nature 2008, 455,
Adv. Synth. Catal. 2010, 352, 2875 – 2880
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2879

Fanglin Zhang et al.
COMMUNICATIONS
M. Hayashi, Y. Hiramatsu, N. Shibata, Y. Funahashi, T.
Toru, J. Am. Chem. Soc. 2009, 131, 1824018241; g) P.
Galzerano, F. Pesciaioli, A. Mazzanti, G. Bartoli, P.
Melchiorre, Angew. Chem. 2009, 121, 8032–8034;
Angew. Chem. Int. Ed. 2009, 48, 7892–7894.
K. A. Jørgensen, Chem. Eur. J. 2007, 13, 9068–9075;
i) D. Enders, M. R. M. Hüttl, J. Runsink, G. Raabe, B.
Wendt, Angew. Chem. 2007, 119, 471–473; Angew.
Chem. Int. Ed. 2007, 46, 467–469; j) A. Carlone, S.
Cabrera, M. Marigo, K. A. Jørgensen, Angew. Chem.
2007, 119, 1119–1122; Angew. Chem. Int. Ed. 2007, 46,
1101–1104; k) O. Penon, A. Carlone, A. Mazzanti, M.
Locatelli, L. Sambri, G. Bartoli, P. Melchiorre, Chem.
Eur. J. 2008, 14, 4788–4791; l) M. Rueping, E. Sugiono,
E. Merino, Angew. Chem. 2008, 120, 3089–3092;
Angew. Chem. Int. Ed. 2008, 47, 3046–3049; m) H.
Gotoh, D. Okamura, H. Ishikawa, Y. Hayashi, Org.
Lett. 2009, 11, 4056–4059; n) P. G. McGarraugh, S. E.
Brenner, Org. Lett. 2009, 11, 5654–5657; o) F.-L.
Zhang, A.-W. Xu, Y.-F. Gong, M.-H. Wei, X.-L. Yang,
Chem. Eur. J. 2009, 15, 6815–6818; p) M. Rueping, A.
Kuenkel, F. Tato, J. W. Bats; Angew. Chem. 2009, 121,
3754–3757; Angew. Chem. Int. Ed. 2009, 48, 3699–
3702; q) E. Reyes, G. Talavera, J. L. Vicario, D. Badía,
L. Carrillo, Angew. Chem. 2009, 121, 5811–5814;
Angew. Chem. Int. Ed. 2009, 48, 5701–5704; r) Y.
Wang, R.-G. Han, Y.-L. Zhao, S. Yang, P.-F. Xu, D. J.
Dixon, Angew. Chem. 2009, 121, 10018–10022; Angew.
Chem. Int. Ed. 2009, 48, 9834–9838; s) S. B. Jones, B.
Simmons, D. W. C. MacMillan, J. Am. Chem. Soc. 2009,
131, 13606–13607; t) S. P. Lathrop, T. Rovis, J. Am.
Chem. Soc. 2009, 131, 13628–13630; u) B.-C. Hong, P.
Kotame, C.-W. Tsai, J.-H. Liao, Org. Lett. 2010, 12,
776–779; v) K. L. Jensen, P. T. Franke, C. Arróniz, S.
Kobbelgaard, K. A. Jørgensen, Chem. Eur. J. 2010, 16,
1750–1753; w) G.-L. Zhao, F. Ullah, L. Deiana, S.-Z
Lin, Q Zhang, J.-L. Sun, I. Ibrahem, P. Dziedzic, A.
Córdova, Chem. Eur. J. 2010, 16, 1585–1591; x) X.-S.
Zhang, S.-L. Zhang, W. Wang, Angew. Chem. Int. Ed.
2010, 49, 1481–1484; y) D. Enders, C. Wang, M. Muka-
nova A. Greb, Chem. Commun. 2010, 46, 2447–2449.
[14] D. F. Lu, Y. F. Gong, W. Z. Wang, Adv. Synth. Catal.
2010, 352, 644–650.
[8] a) H.-M. Li, Y. Wang, L. Tang, F. H. Wu, X. F. Liu,
C. Y. Guo, B. M. Foxman, L. Deng, Angew. Chem.
2005, 117, 107–110; Angew. Chem. Int. Ed. 2005, 44,
105–108; b) H. H. Lu, X. F. Wang, C. J. Yao, J. M.
Zhang, H. Wu, W. J. Xiao, Chem. Commun. 2009,
42514253; c) B. R. Linton, M. H. Reutershan, C. M.
Aderman, E. A. Richardson, K. R. Brownell, C. W.
Ashley, C. A. Evans, S. J. Miller, Tetrahedron Lett.
2007, 48, 1993–1997.
[9] For reviews, see: a) A. G. Doyle, E. N. Jacobsen, Chem.
Rev. 2007, 107, 5713–5743; for examples, see: b) M.
Shi, L. H. Chen, C. Q. Li, J. Am. Chem. Soc. 2005, 127,
3790–3800; c) T. Inokuma, Y. Hoashi, Y. Takemoto, J.
Am. Chem. Soc. 2006, 128, 9413–9414; d) C. K. Jung,
M. J. Krische, J. Am. Chem. Soc. 2006, 128, 17051–
17056.
[10] For reviews, see: a) S. H. Kang, S. Y. Kang, H.-S. Lee,
A. J. Buglass, Chem. Rev. 2005, 105, 4537–4558; for ex-
amples, see: b) J. Kobayashi, F. Kanda, M. Ishibashi, H.
Shigemori, J. Org. Chem. 1991, 56, 4574–4576; c) Z.-L.
Huang, Y. Dan, Y.-C. Huang, L.-D. Lin, T.-H. Li, W.-H.
Ye, X.-Y. Wei, J. Nat. Prod. 2004, 67, 2121–2123;
d) E. D. Silva, S. A. Morris, S.-C. Miao, E. Dumdei,
R. J. Andersen, J. Nat. Prod. 1991, 54, 993–997.
[11] For reviews, see: a) O. N. Burchak, S. Py, Tetrahedron
2009, 65, 7333–7356; for examples, see: b) D. Damour,
F. Herman, R. Labaudini›re, G. Pantel, M. Vulihorgne,
S. Mignani, Tetrahedron 1999, 55, 10135–10154; c) T.
Yokomatsu, Y. Hayakawa, T. Kihara, S. Koyanagi, S.
Soeda, H. Shimenob, S. Shibuya, Bioorg. Med. Chem.
2000, 8, 2571–2579.
[12] R. Ballini, G. Bosica, D. Fiorini, A. Palmieri, M. Petri-
ni, Chem. Rev. 2005, 105, 933–971.
[13] For reviews on organocatalytic domino reactions, see:
a) D. Enders, C. Grondal, M. R. M. Hüttl, Angew.
Chem. 2007, 119, 1590–1601; Angew. Chem. Int. Ed.
2007, 46, 1570–1581; b) X. Yu, W. Wang, Org. Biomol.
Chem. 2008, 6, 2037–2046; for selected examples of
secondary-amine-catalyzed cascade reactions, see:
c) D. B. Ramachary, N. S. Chowdari, C. F. Barbas III,
Angew. Chem. 2003, 115, 4365–4369; Angew. Chem.
Int. Ed. 2003, 42, 4233–4237; d) Y. Huang, A. M. Walji,
C. H. Larsen, D. W. C. MacMillan, J. Am. Chem. Soc.
2005, 127, 15051–15053; e) M. Marigo, T. Schulte, J.
Franzen, K. A. Jørgensen, J. Am. Chem. Soc. 2005, 127,
15710–15711; f) H. SundØn, I. Ibrahem, L. Eriksen, A.
Córdova, Angew. Chem. 2005, 117, 4955–4958; Angew.
Chem. Int. Ed. 2005, 44, 4877–4880; g) D. Enders,
M. R. M. Hüttl, C. Grondal, G. Raabe, Nature 2006,
441, 861–863; h) H. Jiang, J. B. Nielsen, M. Nielsen,
[15] a) H. Gotoh, H. Ishikawa, Y. Hayashi, Org. Lett. 2007,
9, 5307–5309; b) Y. C. Wang, P. F. Li, X. M. Liang,
T. Y. Zhang, J. X. Ye, Chem. Commun. 2008, 1232–
1234.
[16] CCDC 771632 (5) contains the supplementary crystal-
lographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
[17] For recent reviews on non-linear effects, see: a) D. G.
Blackmond, Acc. Chem. Res. 2000, 33, 402–411; b) K.
Mikami, M. Yamanaka, Chem. Rev. 2003, 103, 3369–
3400; c) T. Satyanarayana, S. Abraham, H. B. Kagan,
Angew. Chem. 2009, 121, 464–503; Angew. Chem. Int.
Ed. 2009, 48, 456–494.
[18] For a similar explanation, see: I. Fleischer, A. Pfaltz,
Chem. Eur. J. 2010, 16, 95–99.
2880
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 2875 – 2880