Chiral amine-catalyzed enantioselective cascade aza-ene-type cyclization reactions

Article abstract of DOI:10.1002/chem.200800829

A study was conducted to analyze the organocatalytic highly enantioselective cascade anaene-type cyclization reaction. The study is based on a hypothesis that a chiral secondary amine activated enal enabled a nucleophilic attack by enamide to produce intermediate enamine/iminium. The study found that the reaction of trans-4-nitrocinnamaldehyde with enamide and an organic catalyst, depend on the organocatalysts and additives. The study also found that a base additive can activate the enamide through deprotation and catalysis reaction by readily (S)-diphenylprolinol-TMS ether can establish multistep iminium/enamine transformation in one-pot operation. The study also observed that electronic and steric nature of the aryl rings of enals has limited impact on the stereochemical outcome.

Full text of DOI:10.1002/chem.200800829

COMMUNICATION
DOI: 10.1002/chem.200800829
Chiral Amine-Catalyzed Enantioselective Cascade Aza–Ene-Type
Cyclization Reactions
Liansuo Zu,[a] Hexin Xie,[a] Hao Li,[a] Jian Wang,[a] Xinhong Yu,*[b] and Wei Wang*[a, b]
Despite the fact that enamides are versatile synthetic
building blocks, only a handful of examples have been iden-
tified using them as nucleophiles in organic synthesis pre-
sumably due to their much lower reactivity compared with
enamines and enols.[1] Kobayashi and co-workers have de-
veloped nice chiral Lewis acid catalyzed enantioselective nu-
cleophilic addition of enamides and enecarbamates to highly
reactive imines, aldehydes and alkylidenemalonates.[2] Re-
cently, Terada et al. described elegant chiral Brønsted acid
promoted aza–ene-type reactions between imines and enam-
ides.[3] We envisioned that, by taking advantage of the ca-
pacity of a chiral secondary amine promoted activation of
a,b-unsaturated aldehydes, relatively unreactive nucleophilic
enamides could participate in a conjugate addition (aza–
ene-type) process.[4] In this communication, we wish to
report the results of the investigation, which has resulted in
a novel organocatalytic highly enantioselective cascade aza–
ene-type cyclization reaction.[5–8] To our knowledge this
study represents the first example of an enantioselective cas-
cade aza–ene-type cyclization process catalyzed by a chiral
amine. The one-pot process affords enantioenriched synthet-
ically useful six-membered ring hemiaminals. Moreover, sig-
nificantly, we first observe that the cascade process involves
an unprecedented multistep imminium/enamine transforma-
tion.
vated enal 1 (e.g., iminium 5) enabled a nucleophilic attack
by enamide 2 (an aza–ene-type reaction) to give intermedi-
ate enamine/iminium 6, which underwent a reversible enam-
ine/iminium transformation to generate intermediate
7
(Scheme 1). Hydrolysis of 7 releasing catalyst was followed
by spontaneous intramolecular cyclization to afford cyclic
hemiaminal 3.
Scheme 1. Proposed a chiral amine promoted cascade aza–ene-type cycli-
zation reaction.
In the proposed cascade aza–ene-type cyclization se-
quence, we hypothesized that a chiral secondary amine acti-
However, there are two challenging issues we might face
in the designed cascade process. First, intermediate 6 could
undergo an intramolecular Mannich-type reaction. Second,
it would be more problematic if intermediate 7 participates
in the second Mannich reaction because the process would
poison the catalyst. We believed that these problems could
be minimized. It is difficult for these two Mannich reactions
to take place due to the significant steric hindrance in 6 and
7, induced by the bulky organocatalyst and the highly substi-
tuted iminium/enamine moieties. Furthermore, the forma-
tion of strained four-membered cyclobutane is heavily ener-
getically unfavorable. On the other hand, the steric effect
imposed in 7 is a driving force to release catalyst and give
less crowded enamide aldehyde 8, which undergoes an intra-
[a] Dr. L. Zu, H. Xie, H. Li, Dr. J. Wang, Prof. Dr. W. Wang
Department of Chemistry & Chemical Biology
University of New Mexico, MSC03 2060
Albuquerque, NM 87131-0001 (USA)
Fax : (+1)505-277-2609
E-mail: wwang@unm.edu
[b] Prof. Dr. X. Yu, Prof. Dr. W. Wang
School of Pharmacy
East China University of Science & Technology
Shanghai 200237 (P. R. China)
E-mail: xhyu@ecust.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200800829.
Chem. Eur. J. 2008, 14, 6333 – 6335
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6333

molecular cyclization giving rise to kinetically favorable six-
against highly strained four-membered ring structure.
actions. As revealed in Table 2, the cascade process serves
as a general approach to the preparation of highly function-
alized chiral cyclic hemiaminals. Notably, the new stereogen-
ic center is created in high enantioselective control (90–
97% ee) in all cases. Significant structural variation of both
a,b-unsaturated aldehydes 1 and enamides 2 can be tolerat-
ed. The electronic and steric nature of the aryl rings of enals
1 has apparently limited influence on the stereochemical
outcome. The similar trend is also observed for the enam-
ides 2. It is noted that in some cases (Table 2, entries 3–8
and 10), 2,4-dinitrobenzoic acid (DNBA) instead of
PhCO2H as additive is used since PhCO2H gives much
lower yields.
Guided by the above consideration and our previous suc-
cessful use of chiral diarylprolinol silyl ethers as an effective
promoter for activation of a,b-unsaturated aldehydes,[8,9] we
initially investigated a reaction of trans-4-nitrocinnamalde-
hyde (1a) with enamide (2a) in the presence of an organic
catalyst in CH2Cl2 (Table 1). It was found that the reaction
highly depended on the organocatalysts and additives used.
No reaction occurred with (S)-diphenylprolinol–TMS ether
I without an additive (entry 1). We surmised that a base ad-
ditive (NaOAc) could activate the enamide 2a via facilitat-
ing deprotation. Disappointingly, the same outcome was ob-
tained (Table 1, entry 2). However, to our delight, switching
to an acid additive (PhCO2H) led to a smooth transforma-
tion to afford desired cyclic hemiaminal (3a) in 80% yield
and high enantioselectivity (90%) (Table 1, entry 3). The ee
of the formed product was determined through conversion
to acyclic ketoaldehyde 4a. Notably, as designed, we did not
observe the formation of cyclobutane products. Encouraged
by the promising results, we probed more bulky prolinol
ether II for the reaction under the same reaction conditions
(Table 1, entry 8). The process proceeded much slower
(48 h) with lower yield. Reactions did not take place for III
and MacMillanꢁs catalyst IV (Table 1, entries 9 and 10).
With the best promoter I in hand, we turned attention on
optimizing reaction conditions. Probing acid additives result-
ed in the use of PhCO2H (Table 1, entries 3–5). Finally,
Table 2. Catalyst I promoted cascade aza–ene-type cyclization reactions
of a,b-unsaturated aldehydes (1) with enamides (2).[a,10]
Entry R1
R2
t [h] Yield
[%] 3[b]
Yield
ee
[%] 4[c] [%][d]
1
2
4-NO2C6H4
3-FC6H4
2-NO2C6H4
4-MeOC6H4 Ph
3-MeOC6H4 Ph
1-naphthyl
4-MeOC6H4 4-MeOC6H4 15
4-MeOC6H4 4-FC6H4
4-NO2C6H4 3-MeC6H4
4-MeOC6H4 3-MeC6H4
4-NO2C6H4 3-BrC6H4
Ph
Ph
Ph
24
24
12
10
10
10
85[c], 88[b] 56
87 51
79,[c] 82[b] 55
90
93
93
95
94
97
90
92
94
94[f]
90
3[e]
4[e]
5[e]
6[e]
7[e]
8[e]
9
77
80
82
82
80
53
54
53
54
53
Ph
15
14
14
40
80,[c] 80[b] 51
73,[c] 78[b] 50
45,[c] 50[b] 30
screening of a variety of solvents revealed that Cl(CH2)2Cl
G
10[e]
11
was the choice for the process (Table 1, entries 3, 6, and 7).
The optimal reaction conditions were exploited to probe
the limitation of the organocatalyst I promoted cascade re-
[a] Reaction conditions: unless specified, see Experimental Section.
[b] Determined by 1H NMR spectroscopy using BnOH as internal stan-
dard due to the difficulty of separation of product 3 from starting materi-
al 2. [c] Isolated yields. [d] Determined by chiral HPLC analysis (Chiral-
pak AS-H or OJ-H) by converting 3 to 4. [e] DNBA used as additive.
[f] Determined by converting to corresponding enone with Ph3P=
CHCOPh.
Table 1. Exploration of organocatalytic enantioselective cascade aza–
ene-type cyclization reaction of trans-4-nitrocinnamaldehyde (1a) with
enamide (2a).[a]
Hemiaminals 3 as versatile building blocks can be ex-
plored for further synthetic elaborations. We have demon-
strated they can be conveniently transformed to pyridines
[Eq. (1)], enamides [Eq. (2)], aminals [Eq. 3)] in addition to
1,5-dicarbonyls (Table 1). Notably, the method affords an al-
terative approach to 1,5-dicarbonyls, which is complementa-
ry to that of our early strategy relying on the Mukaiyama–
Entry Cat. Additive Solvent
t [h] Yield [%] 3a[b] ee [%] 4a[c]
1
2
3
4
I
I
I
I
none
CH2Cl2
24
24
24
6
<5
<5
80
nd[d]
nd[d]
90
NaOAc CH2Cl2
PhCO2H CH2Cl2
DNBA[e] CH2Cl2
83
80
5
I
TMSCl
CH2Cl2
24
89
70
6
I
PhCO2H Cl
A
85
90
7
8
9
10
I
PhCO2H EtOH
PhCO2H CH2Cl2
PhCO2H CH2Cl2
p-TsOH CH2Cl2
24
48
24
24
65
75
<5
<5
88
II
III
IV
90
nd[e]
nd[e]
[a] Reaction conditions: unless specified, see Experimental Section.
[b] Isolated yields. [c] Determined by chiral HPLC analysis (Chiralpak
AS-H). [d] Not determined. [e] 2,4-Dinitrobenzoic acid.
6334
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Chem. Eur. J. 2008, 14, 6333 – 6335

Cascade Reactions
COMMUNICATION
[3] a) M. Terada, K. Machioka, K. Sorimachi, Angew. Chem. 2006, 118,
2312; Angew. Chem. Int. Ed. 2006, 45, 2254; b) M. Terada, K. Ma-
chioka, K. Sorimachi, J. Am. Chem. Soc. 2007, 129, 10336.
[4] Recently, Hayashi reported an organocatalytic ene-reaction: H.
Gotoh, R. Masui, H. Ogino, M. Shoji, Y. Hayashi, Angew. Chem.
2006, 118, 7007; Angew. Chem. Int. Ed. 2006, 45, 6853.
[5] Recent reviews of organocatalysis, see: a) A. Berkessel, H. Groger,
Asymmetric Organocatalysis—From Biomimetic Concepts to Appli-
cations in Asymmetric Synthesis; Wiley-VCH, Weinheim (Germany),
2005; b) Special Issues on Asymmetric Organocatalysis: Acc. Chem.
Res. 2004, 37, 487 and Chem. Rev. 2007, 107, 5413.
Michael reaction of silyl enol ethers with a,b-unsaturated al-
dehydes.[10]
[6] Reviews of organocatalytic cascade reactions, see: a) D. Enders, C.
Grondal, M. R. M. Hꢂttl, Angew. Chem. 2007, 119, 1590; Angew.
Chem. Int. Ed. 2007, 46, 1570; b) A. M. Walji, D. W. C. MacMillan,
Synlett 2007, 1477.
In conclusion, we have developed a new organocatalytic,
highly enantioselective cascade aza–ene-type cyclization re-
action. The process, efficiently catalyzed by readily available
(S)-diphenylprolinol–TMS ether, establishes an unprece-
dented multistep iminium/enamine transformation in one-
pot operation. Furthermore, the simplicity and practical
nature of the asymmetric protocols presented here is under-
scored by the use of simple starting materials and the gener-
ation of synthetically useful, high optically active and heavi-
ly functionalized products. Future studies of the cascade re-
action are aimed at investigating its full scope and applica-
tions in target-directed synthesis.
[7] For selected examples of organocatalytic cascade reactions, see:
a) D. Enders, M. R. M. Hꢂttl, J. Runsink, G. Raabe, B. Wendt,
Angew. Chem. 2007, 119, 471; Angew. Chem. Int. Ed. 2007, 46, 467;
b) Y. Hayashi, T. Okano, S. Aratake, D. Hazelard, Angew. Chem.
2007, 119, 5010; Angew. Chem. Int. Ed. 2007, 46, 4922; c) J. Zhou, B.
List, J. Am. Chem. Soc. 2007, 129, 7498; d) J. L. Vicario, S. Rebore-
do, D. Badꢃa, L. Carrillo, Angew. Chem. 2007, 119, 5260; Angew.
Chem. Int. Ed. 2007, 46, 5168; e) A. Carlone, S. Cabrera, M. Marigo,
K. A. Jørgensen, Angew. Chem. 2007, 119, 1119; Angew. Chem. Int.
Ed. 2007, 46, 1101; f) B. Wang, F. Wu, Y. Wang, X. Liu, L. Deng, J.
Am. Chem. Soc. 2007, 129, 768; g) M. M. Biddle, M. Lin, K. A.
Scheidt, J. Am. Chem. Soc. 2007, 129, 3830; h) A. Chan, K. A.
Scheidt, J. Am. Chem. Soc. 2007, 129, 5334; i) D. Enders, M. R. M.
Hꢂttl, C. Grondal, G. Raabe, Nature 2006, 441, 861; j) M. Rueping,
A. P. Antonchick, T. Theissmann, Angew. Chem. 2006, 118, 3765;
Angew. Chem. Int. Ed. 2006, 45, 3683; k) S. Brandau, E. Maerten,
K. A. Jørgensen, J. Am. Chem. Soc. 2006, 128, 14986; l) R. Rios, H.
Sunden, I. Ibrahem, G.-L. Zhao, L. Eriksson, A. Cꢄrdova, Tetrahe-
dron Lett. 2006, 47, 8547; m) Y. Hoashi, T. Yabuta, P. Yuan, H.
Miyabe, Y. Takemoto, Tetrahedron 2006, 62, 365; n) H. Sunden, I.
Ibrahem, G.-L. Zhao, L. Eriksson, A. Cꢄrdova, Chem. Eur. J. 2007,
13, 574; o) Y. Huang, A. M. Walji, C. H. Larsen, D. W. C. MacMil-
lan, J. Am. Chem. Soc. 2005, 127, 15051; p) J. W. Yang, M. T. H. Fon-
seca, B. List, J. Am. Chem. Soc. 2005, 127, 15036; q) Y. Yamamoto,
N. Momiyama, H. Yamamoto, J. Am. Chem. Soc. 2004, 126, 5962;
r) Y. Hoashi, T. Yabuta, Y. Takemoto, Tetrahedron Lett. 2004, 45,
9185; s) D. B. Ramachary, N. S. Chowdari, C. F. Barbas, III, Angew.
Chem. 2003, 115, 4365; Angew. Chem. Int. Ed. 2003, 42, 4233; t) T.
Dudding, A. M. Hafez, A. E. Taggi, T. R. Wagerle, T. Lectka, Org.
Lett. 2002, 4, 387.
Experimental Section
General procedure (Table 2, entry 1): The reaction was carried out with
1a (0.12 mmol) and 2a (0.1 mmol) in the presence of 20 mol% catalyst I
and 20 mol% PhCO2H in ClCH2CH2Cl (0.2 mL) at room temperature
for 24 h. Then the reaction mixture was treated with FeCl3·6H2O (27 mg,
0.1 mmol) in CH2Cl2 at room temperature for 6 h. The crude product was
purified by column chromatography on silica gel to give product in 85%
yield, 90% ee (HPLC on a Chiralpak AS-H column, hexanes/iPrOH
80:20 at 0.8 mLminÀ1, l=254 nm); tmajor =49.00, tminor =53.13 min; [a]2D3
+34.5 (c=1.0, CHCl3).
=
Acknowledgements
Financial support of this research is supported by the NSF (CHE-
0704015) and the ACS-PRF.
[8] Recently, we have developed organocatalytic cascade processes, see:
a) W. Wang, H. Li, J. Wang, L. Zu, J. Am. Chem. Soc. 2006, 128,
10354; b) H. Li, J. Wang, H. Xie, L. Zu, W. Jiang, E. N. Duesler, W.
Wang, Org. Lett. 2007, 9, 965; c) L. Zu, J. Wang, H. Li, H. Xie, W.
Jiang, W. Wang, J. Am. Chem. Soc. 2007, 129, 1306; d) H. Li, J.
Wang, T. E-Nunu, L. Zu, W. Jiang, S. Wei, W. Wang, Chem.
Commun. 2007, 507; e) H. Li, L. Zu, H. Xie, J. Wang, W. Jiang, W.
Wang, Org. Lett. 2007, 9, 1833; f) L. Zu, H. Li, H. Xie, J. Wang, W.
Jiang, W. Wang, Angew. Chem. 2007, 119, 3806; Angew. Chem. Int.
Ed. 2007, 46, 3732.
[9] For a review of diaryl prolinol ethers catalysis, see: a) C. Palomo, A.
Mielgo, Angew. Chem. 2006, 118, 8042; Angew. Chem. Int. Ed. 2006,
45, 7876 and leading references, see: b) M. Marigo, T. C. Wabnitz,
D. Fielenbach, K. A. Jørgensen, Angew. Chem. 2005, 117, 804;
Angew. Chem. Int. Ed. 2005, 44, 794; c) Y. Hayashi, H. Gotoh, T.
Hayashi, M. Shoji, Angew. Chem. 2005, 117, 4284; Angew. Chem.
Int. Ed. 2005, 44, 4212; d) Y.-G. Chi, S. H. Gellman, J. Am. Chem.
Soc. 2006, 128, 6804.
Keywords: aldehydes
· cascade reactions · enamides ·
organocatalysis
[1] a) P. J. Jessup, C. B. Petty, J. Roos, L. E. Overman, Org. Synth. 1980,
59, 1; b) T. Shono, Y. Matsumura, K. Tsubata, Y. Sugihara, S.
Yamane, T. Kanazawa, T. Aoki, J. Am. Chem. Soc. 1982, 104, 6697;
c) L. Eberson, M. Malmberg, K. Nyberg, Acta. Chem. Scand. 1984,
38, 391; d) O. K. Meth-Cohn, T. Westwood, J. Chem. Soc. Perkin
Trans. 1 1984, 1173; e) M. Chigr, H. Fillion, A. Rougny, Tetrahedron
Lett. 1987, 28, 4529; f) P. Wipf, X. Wang, Tetrahedron Lett. 2000, 41,
8747.
[2] a) R. Matsubara, Y. Nakamura, S. Kobayashi, Angew. Chem. 2004,
116, 1711; Angew. Chem. Int. Ed. 2004, 43, 1679; b) R. Matsubara,
Y. Nakamura, S. Kobayashi, Angew. Chem. 2004, 116, 3320; Angew.
Chem. Int. Ed. 2004, 43, 3258; c) F. Berthiol, R. Matsubara, N.
Kawai, S. Kobayashi, Angew. Chem. 2007, 119, 7949; Angew. Chem.
Int. Ed. 2007, 46, 7803; d) T. J. Harrison, B. O. Patrick, G. R. Dake
Org. Lett. 2007, 9, 367.
[10] Absolute configurations are determined by comparison with known
chiral compounds: W. Wang, H. Li, J. Wang, Org. Lett. 2005, 7, 1637.
Received: May 2, 2008
Published online: June 11, 2008
Chem. Eur. J. 2008, 14, 6333 – 6335
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6335