Highly asymmetric Michael addition to α,β-unsaturated ketones catalyzed by 9-amino-9-deoxyepiquinine

Article abstract of DOI:10.1002/anie.200603612

(Chemical Equation Presented) Michael-Michael-retro-Michael cascade reactions are promoted by the highly efficient organocatalyst 9-amino-9-deoxyepiquinine (1). The asymmetric direct vinylogous Michael addition of α,α-dicyanoalkenes to α,β-unsaturated ket

Full text of DOI:10.1002/anie.200603612

Angewandte
Chemie
DOI: 10.1002/anie.200603612
Asymmetric Synthesis
Highly Asymmetric Michael Addition to a,b-Unsaturated Ketones
Catalyzed by 9-Amino-9-deoxyepiquinine**
Jian-Wu Xie, Wei Chen, Rui Li, Mi Zeng, Wei Du, Lei Yue, Ying-Chun Chen,* Yong Wu, Jin Zhu,
and Jin-Gen Deng*
Dedicated to Prof. Yao-Zhong Jiang on the occasion of his 70th birthday
The in situ generation of an iminium ion from a chiral
aminocatalyst and a carbonyl compound is thought to lower
the LUMO energy of the system and is a powerful strategy for
a range of asymmetric transformations.[1] The commonly
applied catalysts are ammonium salts of secondary amines
derived from chiral a-amino acids or 1,2-diphenylethylenedi-
amine. Highly efficient asymmetric reactions,including con-
jugate addition and pericyclic reactions,have been described
for a,b-unsaturated aldehydes,even at very low temper-
atures.[2] However,the reactions of a,b-unsaturated ketones
catalyzed by secondary amine salts usually suffer from a
sluggish reaction rate at room temperature,[3] and some
reactions could not be promoted at all,probably because of
poor generation of the corresponding iminium cations.
Therefore,an alternative catalyst with stronger activating
ability,broader applicability,and improved enantioselectivity
would be highly desirable.
intriguing to consider that a,a-dicyanoalkenes might be
applied successively as Michael donors and Michael acceptors
in some domino sequences. Inspired by the recent reports on
tandem iminium–enamine activation of a,b-unsaturated
aldehydes by chiral secondary aminocatalysts,[6] we envisaged
that sequential Michael–Michael addition reactions would be
possible between a,a-dicyanoalkenes and a,b-unsaturated
ketones,as outlined in Scheme 1,to provide a straightforward
protocol for the synthesis of chiral cyclic products with
multiple substituents.
Recently,we reported that the electron-deficient a,a-
dicyanoalkenes could act as versatile direct vinylogous donors
in asymmetric Michael addition reactions of nitroalkenes and
a,b-unsaturated aldehydes with excellent chemo- and stereo-
selectivity.[4] These activated alkenes also behave as good
hydride acceptors in conjugate reduction reactions.[4a–b,5] It is
Scheme 1. Proposed domino Michael–Michael addition reactions
based on iminium–enamine activation.
[*] W. Chen, R. Li, M. Zeng, W. Du, L. Yue, Prof. Dr. Y.-C. Chen,
Prof. Dr. Y. Wu
Unfortunately,we found that the secondary-amine cata-
lysts,such as l-proline and its analogues,that have been used
successfully in the asymmetric Michael reactions of Jørgensen
and co-workers,[3d–f] were completely inert for the vinylogous
Michael reactions of a,a-dicyanoalkenes and a,b-unsaturated
ketones. As the relative bulkiness of secondary amines might
be unfavorable for the formation of iminium ions with a,b-
unsaturated ketones [Eq. (a)],we envisaged that the gener-
ation of a ketimine cation from a primary amine salt and a
ketone would be more feasible and lead to the activation of
the a,b-unsaturated system [Eq. (b)]. Moreover,the applica-
tion of primary amines as iminium catalysts for a,b-unsatu-
rated ketones has rarely been explored.[7]
Key laboratory of Drug-Targeting of the Education Ministry
Department of Medicinal Chemistry
West China School of Pharmacy, Sichuan University
Chengdu, 610041 (P.R. China)
Fax: (+86)28-85502609
E-mail: ycchenhuaxi@yahoo.com.cn
J.-W. Xie, Prof. J. Zhu, Prof. Dr. J.-G. Deng
Key Laboratory of Asymmetric Synthesis &
Chirotechnology of Sichuan Province
Union Laboratory of Asymmetric Synthesis
Chengdu Institute of Organic Chemistry
Chinese Academy of Sciences
Chengdu, 610041 (P.R. China)
Fax: (+86)28-852-239-78
E-mail: jgdeng@cioc.ac.cn
The vinylogous Michael addition of a,a-dicyanoalkene 2a
to benzylideneacetone (3a) was indeed promoted by the
J.-W. Xie
Graduate School of the Chinese Academy of Sciences
Beijing (P.R. China)
[**] We are grateful for the financial support of the National Natural
Science Foundation of China (20502018), the Ministry of Education
(NCET-05-0781), and Sichuan University.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2007, 46, 389 –392
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
389

Communications
trifluoroacetic acid (TFA) salt of the primary aminoalcohol
The ee value was dramatically decreased when TFA and 1d
were used in a 1:1 ratio (Table 1,entry 5). A variety of other
acid additives and solvents were screened; however,inferior
results to that with 1d were observed (Table 1,entries 6–12).
The product 4aa was formed with slightly lower enantiose-
lectivity but in excellent yield when an excess of the a,a-
dicyanoalkene 2a was used (Table 1,entry 13).
1a (20 mol%; Scheme 2) derived from l-valine. The addition
product 4aa was formed with complete anti selectivity and
isolated in 40% yield with 69% ee after 96 h at room
Having established the optimal reaction conditions,we
then examined a range of a,a-dicyanoalkenes (Scheme 3) and
Scheme 2. Structures of the chiral primary amine catalysts used.
Bn=benzyl.
[8]
temperature (Table 1,entry 1).
However,the expected
Scheme 3. Structures of the a,a-dicyanoalkenes used.
intramolecular Michael reaction through enamine activation
did not occur,probably because of steric reasons. A slightly
a,b-unsaturated ketones to explore the generality of this
novel catalytic system (Table 2). The reaction scope proved to
be quite broad with respect to both the a,a-dicyanoalkene
and the substitution pattern of the electrophile. Excellent
diastereoselectivity was observed for all the reactions tested.
High ee values were observed in the vinylogous Michael
reactions of a,a-dicyanoalkene 2a and the variously substi-
tuted enones 3a–3h (Table 2,entries 1–8),and the product
was formed with over 99% ee in the case of the cyclic enone
substrate 3h (Table 2,entry 8). Although low reactivity was
observed for the other nucleophiles 2b–2g,the Michael
Table 1: Screening of primary amine catalysts in the Michael reaction of
a,a-dicyanoalkene 2a with benzylideneacetone (3a).[a]
Entry
Catalyst
Solvent
Additive
Yield [%][b]
ee [%][c]
1[d,e]
2[d,e]
3
1a
1b
1c
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
THF
THF
THF
THF
THF
THF
THF
THF
CH2Cl2
toluene
ethanol
ether
THF
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3SO3H
HClO4
40
36
75
88
83
13
83
80
90
50
50
53
99
À69
À76
À70
93
78
65
87
92
85
88
4
Table 2: Asymmetric vinylogous Michael addition of a,a-dicyanoalkenes
2 to a,b-unsaturated ketones 3.[a]
5[e]
6
7
8
9
10
11
12
13[f]
HCl
CF3COOH
CF3COOH
CF3SO3H
CF3COOH
CF3COOH
69
84
91
Entry
2
R1
R2
3
4
Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
2a Ph
2a p-ClC6H4
2a p-(MeO)ClC6H4 Me 3c 4ac 83
Me 3a 4aa 88
Me 3b 4ab 85
93
[a] Reaction conditions, unless otherwise noted: 2a (0.1 mmol), 3a
(0.2 mmol), catalyst (20 mol%), THF (1 mL), 08C, 96 h. [b] Yield of the
isolated product. [c] Determined by HPLC analysis on a chiral phase.
[d] Reaction was carried out at room temperature. [e] TFA: 20 mol%.
[f] 2a/3a=1.5:1.
90
91[d]
97
2a 2-furanyl
2a Ph
2a Ph
2a nPr
À
Me 3d 4ad 82
Et 3e 4ae 78
nPr 3 f 4af 81
Me 3g 4ag 76
3h 4ah 80
Me 3a 4ba 69
Me 3a 4ca 60
Me 3a 4ga 51
Me 3g 4ag 78
3h 4ah 98
95
98[d]
98
À
2a
(CH2)3
>99
89
91
9[e]
10[e]
11[e]
2b Ph
2c Ph
2g Ph
higher ee value was attained in the presence of 1b–TFA
(Table 1,entry 2). Subsequently,we found that a combination
of TFA (40 mol%) and 9-amino-9-deoxyepicinchonine (1c;
20 mol%),which is readily accessible from natural cincho-
nine,[9] exhibited much higher catalytic activity,and 4aa was
obtained in 75% yield with 70% ee after 96 h at 08C (Table 1,
entry 3). Gratifyingly,the addition product was formed with
excellent enantioselectivity (93% ee) and in 88% yield when
the TFA salt of 9-amino-9-deoxyepiquinine 1d was used. This
catalyst afforded the desired product with the opposite
configuration to that obtained with 1c (Table 1,entry 4).
95
12[e,f] 2a nPr
13[e,f] 2a
À87
À
À
(CH2)3
À99
[a] Reaction conditions, unless otherwise noted:
2
(0.1 mmol), 3
(0.2 mmol), 1d (20 mol%), TFA (40 mol%), THF (1 mL), 08C, 96 h.
[b] Yield of the isolated product. [c] Determined by HPLC analysis on a
chiral phase. [d] The absolute configuration was determined to be C8: S,
C13: R by X-ray crystallographic analysis.[10] [e] DIPEA (15 mol%) was
added, and the reaction was conducted at À208C. [f] Amine 1c was used
as the organocatalyst.
390
www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 389 –392

Angewandte
Chemie
reactions could be greatly accelerated by adding DIPEA
(diisopropylethylamine; 15 mol%),even at À208C. The
products were obtained with high ee values and in good
yields when the cyclic substrates 2b and 2c were used
(Table 2,entries 9 and 10). Excellent enantioselectivity was
also observed for the simple a,a-dicyanoalkene 2g,although
the yield of the isolated product was only moderate after this
period of time (Table 2,entry 11). Furthermore,the desired
adducts with the opposite configuration could be obtained
with high enantioselectivity upon catalysis by 1c at À208C
(Table 2,entries 12 and 13).
highly reactive precursors of ketones in such reactions.
Finally,the reaction of the aliphatic cyclic substrate 2 f gave
the annulated product 6 with three contiguous chiral centers,
including a quaternary center surrounded by four carbon
atoms,[14] with excellent enantioselectivity; in this case the
elimination of malononitrile did not take place under these
[15]
conditions [Scheme 4,Eq. (3)].
Although the straightforward intramolecular Michael
addition of the products in Table 2 was not successful in the
presence of bulky chiral primary amines,such reactions could
be promoted in a separate step. As illustrated in Scheme 5,
Interestingly,under the same conditions as above,the
reaction of the acyclic b-phenyl-a,a-dicyanoalkenes 2d and
2e with 3a gave not only the vinylogous Michael products 4da
and 4ea,but also the 2-cyclohexen-1-one derivatives 5da and
5ea,[11] respectively,with higher optical purity (Scheme 4,
Scheme 5. Domino Michael–retro-Michael reactions promoted by an
achiral primary aminocatalyst.
the vinylogous product 4ba could be converted cleanly into
the annulated compound 5ba by catalysis with achiral
benzylamine without affecting the ee value. Slightly forcing
conditions were needed for the conversion of 4ae,in which
the carbonyl group has an ethyl substituent. Thus,this
methodology provides a versatile protocol for the construc-
tion of a variety of chiral 2-cyclohexen-1-ones with multiple
substituents.
In conclusion,we have presented the first asymmetric
direct vinylogous Michael addition of a,a-dicyanoalkenes and
a,b-unsaturated ketones. The reaction scope is quite sub-
stantial and excellent stereoselectivity was generally observed
with a chiral primary aminocatalyst derived from quinine.
Moreover,enantiomerically pure polysubstituted 2-cyclo-
hexen-1-one derivatives,which have not been readily acces-
sible to date,could be prepared smoothly through the novel
organocatalytic Michael–Michael–retro-Michael reaction
cascade. This domino reaction sequence is highly efficient,
and two reagents act alternately and selectively as the
Michael donor and acceptor under readily controllable
conditions. To the best of our knowledge,this is the first
example of asymmetric domino reactions catalyzed by chiral
primary amines. We also believe that the strategy applied in
this study may lead to the design and application of primary
aminocatalysts in other asymmetric transformations of a,b-
unsaturated ketones. The investigation of potential trans-
formations of this type is well underway in our laboratory,and
the results will be reported in due course.
Scheme 4. Domino Michael–Michael reactions based on iminium–
enamine activation.
Eq. (1) and (2)). Apparently the expected domino Michael–
Michael reactions occurred and were followed by a further
retro-Michael reaction to generate the observed enone
products. Moreover,a kinetic resolution was associated with
the intramolecular Michael reaction of the enamine inter-
mediate,as verified through a cyclization experiment with the
isolated adduct 4da (Scheme 4,Eq. (4)). As direct organo-
catalytic asymmetric Michael reactions of unmodified
ketones,especially aryl ketones,with a,b-unsaturated ketones
have not been feasible to date,[12,13] readily available and
easily handled a,a-dicyanoalkenes could act as versatile and
Received: September 4,2006
Keywords: amines · asymmetric synthesis · domino reactions ·
.
Michael addition · organocatalysis
Angew. Chem. Int. Ed. 2007, 46, 389 –392
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
391

Communications
[7] a) S. Tsogoeva,S. B. Jagtap, Synlett 2004,2624; b) just after the
acceptance of this manuscript,the application of valine ester
phosphate salts in the asymmetric transfer hydrogenation of
cyclic enones was reported; see: N. J. A. Martin,B. List, J. Am.
Chem. Soc. 2006, 128,13368.
[8] Complete diastereoselectivity was also observed in other vinyl-
ogous Michael reactions of a,a-dicyanoalkenes as a result of
kinetic control; see ref. [4a–c].
[9] a) H. Brunner,J. Bügler,B. Nuber, Tetrahedron: Asymmetry
1995, 6,1699; b) for a review on cinchona alkaloids as organo-
catalysts,see: S.-K. Tian,Y. Chen,J. Hang,L. Tang,P. McDaid,
L. Deng, Acc. Chem. Res. 2004, 37,621.
[10] CCDC-621781 (4ac) and CCDC-621782 (4af) contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[11] The chiral compound 5ea was prepared in seven steps from
[1] For reviews,see: a) P. I. Dalko,L. Moisan, Angew. Chem. 2004,
116,5248; Angew. Chem. Int. Ed. 2004, 43,5138; b) B. List,
Chem. Commun. 2006,819; c) A. Berkessel,H. Gröger,
Asymmetric Organocatalysis,Wiley-VCH,Weinheim, 2005.
[2] a) K. A. Ahrendt,C. J. Borths,D. W. C. MacMillan,
J. Am.
Chem. Soc. 2000, 122,4243; b) Y. K. Chen,M. Yoshida,D. W. C.
MacMillan, J. Am. Chem. Soc. 2006, 128,9328; c) J. W. Yang,
M. T. Hechavarria Fonseca,B. List, Angew. Chem. 2004, 116,
6829; Angew. Chem. Int. Ed. 2004, 43,6660; d) T. Kano,Y.
Tanaka,K. Maruoka, Org. Lett. 2006, 8,2687; e) S. Brandau,A.
Landa,J. FranzØn,M. Marigo,K. A. Jørgensen, Angew. Chem.
2006, 118,4411; Angew. Chem. Int. Ed. 2006, 45,4305; f) W.
Chen,X.-H. Yuan,R. Li,W. Du,Y. Wu,L.-S. Ding,Y.-C. Chen,
Adv. Synth. Catal. 2006, 348,1818; for examples of primary
aminocatalysts,see: g) K. Ishihara,K. Nakano, J. Am. Chem.
Soc. 2005, 127,10504; h) A. Sakakura,K. Suzuki,K. Nakano,K.
Ishihara, Org. Lett. 2006, 8,2229.
acetophenone: a) F. -Y,ZhangE, . J. Corey,
Org. Lett. 2000, 2,
[3] a) M. Yamaguchi,T. Shiraishi,M. Hirama, J. Org. Chem. 1996,
61,3520; b) S. Hanessian,V. Pham, Org. Lett. 2000, 2,2975,and
references therein; c) A. B. Northrup,D. W. C. MacMillan, J.
Am. Chem. Soc. 2002, 124,2458; d) N. Halland,P. S. Aburel,
K. A. Jørgensen, Angew. Chem. 2003, 115,685; Angew. Chem.
Int. Ed. 2003, 42,661; e) N. Halland,T. Hansen,K. A. Jørgensen,
Angew. Chem. 2003, 115,5105; Angew. Chem. Int. Ed. 2003, 42,
4955; f) N. Halland,P. S. Aburel,K. A. Jørgensen, Angew. Chem.
2004, 116,1292; Angew. Chem. Int. Ed. 2004, 43,1272; g) A.
Prieto,N. Halland,K. A. Jørgensen, Org. Lett. 2005, 7,3897;
h) K. R. Knudsen,C. E. T. Mitchell,S. V. Ley, Chem. Commun.
2006,66.
1097; for the synthesis of racemic substituted 2-cyclohexen-1-
ones by metal catalysis,see: b) T. Okano,Y. Satou,M. Tamura,J.
Kiji, Bull. Chem. Soc. Jpn. 1997, 70,1879.
[12] For the intermolecular Michael addition of unmodified alde-
hydes to vinyl ketones,see: a) P. Melchiorre,K. A. Jørgensen, J.
Org. Chem. 2003, 68,4151; b) T. J. Peelen,Y. Chi,S. H. Gellman,
J. Am. Chem. Soc. 2005, 127,11598; c) Y. Chi,S. H. Gellman,
Org. Lett. 2005, 7,4253; the Michael addition of aldehydes to b-
substituted enones has only been conducted in an intramolecular
fashion; see: d) M. T. Hechavarria Fonseca,B. List, Angew.
Chem. 2004, 116,4048; Angew. Chem. Int. Ed. 2004, 43,3958;
e) Y. Hayashi,H. Gotoh,T. Tamura,H. Yamaguchi,R. Masui,
M. Shoji, J. Am. Chem. Soc. 2005, 127,16028; f) see ref. [6b].
[13] The unmodified ketones only show reactivity with highly
activated alkenes in the presence of aminocatalysts; for nitro-
alkenes,see: a) D. Enders,S. Chow, Eur. J. Org. Chem. 2006,
4578; b) N. Mase,K. Watanabe,H. Yoda,K. Takabe,F. Tanaka,
C. F. Barbas III, J. Am. Chem. Soc. 2006, 128,4966; c) C.-L. Cao,
[4] a) D. Xue,Y.-C. Chen,L.-F. Cun,Q.-W. Wang,J. Zhu,J.-G.
Deng, Org. Lett. 2005, 7,5293; b) J.-W. Xie,L. Yue,D. Xue,X.-L.
Ma,Y.-C. Chen,Y. Wu,J. Zhu,J.-G. Deng,
Chem. Commun.
2006,1563; for similar studies,see: c) T. B. Poulsen,M. Bell,
K. A. Jørgensen, Org. Biomol. Chem. 2006, 4, 63; d) T. B.
Poulsen,C. Alemparte,K. A. Jørgensen, J. Am. Chem. Soc. 2005,
127,11614.
M.-C. Ye,X.-L. Sun,Y. Tang,
Org. Lett. 2006, 8,2901,and
[5] a) Y.-C. Chen,D. Xue,J.-G. Deng,X. Cui,J. Zhu,Y.-Z. Jiang,
Tetrahedron Lett. 2004, 45,1555; b) D. Xue,Y.-C. Chen,X. Cui,
Q.-W. Wang,J. Zhu,J.-G. Deng, J. Org. Chem. 2005, 70,3584.
[6] a) D. B. Ramachary,C. F. Barbas III, Chem. Eur. J. 2004, 10,
5323; b) J. W. Yang,M. T. Hechavarria Fonseca,B. List, J. Am.
Chem. Soc. 2005, 127,15036; c) Y. Huang,A. Walji,C. H.
Larsen,D. W. C. MacMillan, J. Am. Chem. Soc. 2005, 127,15051;
references therein; d) Y. Xu,A. Cꢀrdova, Chem. Commun. 2006,
460; e) B. List,P. Pojarliev,H. Martin, Org. Lett. 2001, 3,2423;
f) D. Enders,A. Seki, Synlett 2002,26; for alkylidenemalonates,
see: g) J. M. Betancort,K. Sakthivel,R. Thayumanavan,F.
Tanaka,C. F. Barbas III, Synthesis 2004,1509,and references
therein.
[14] For recent reviews on the catalytic enantioselective construction
of quaternary chiral with only carbon-centered substituents,see:
a) J. Christoffers,A. Baro, Adv. Synth. Catal. 2005, 347,1473;
b) E. A. Peterson,L. E. Overman, Proc. Natl. Acad. Sci. USA
2004, 101,11943.
d) M. Marigo,T. Schulte,J. FranzØn,K. A. Jørgensen,
J. Am.
Chem. Soc. 2005, 127,15710; e) D. Enders,M. R. M. Hüttl,C.
Grondal,G. Raabe, Nature 2006, 441,861; f) M. Marigo,S.
Bertelsen,A. Landa,K. A. Jørgensen, J. Am. Chem. Soc. 2006,
128,5475; g) W. Wang,H. Li,J. Wang,L. Zu, J. Am. Chem. Soc.
2006, 128,10354; h) see also ref. 3f; for a review on tandem
reactions,see: i) H.-C. Guo,J.-A. Ma, Angew. Chem. 2006, 118,
362; Angew. Chem. Int. Ed. 2006, 45,354.
[15] The relative configuration of 6 was assigned by extensive NMR
spectroscopic analysis; see Supporting Information.
392
www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 389 –392