A bifunctional spiro-type organocatalyst with high enantiocontrol: Application to the aza-Morita-Baylis-Hillman reactions

Article abstract of DOI:10.1039/c1cc12784e

A unique spiro-type Bronsted acid-Lewis base organocatalyst has been developed. The new bifunctional organocatalyst promoted aza-Morita-Baylis- Hillman reactions to yield adducts with up to 98% ee.

Full text of DOI:10.1039/c1cc12784e

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COMMUNICATION
A bifunctional spiro-type organocatalyst with high enantiocontrol:
application to the aza-Morita–Baylis–Hillman reactionsw
Shinobu Takizawa, Kimiko Kiriyama, Kenta Ieki and Hiroaki Sasai*
Received 12th May 2011, Accepted 4th July 2011
DOI: 10.1039/c1cc12784e
A unique spiro-type Brønsted acid–Lewis base organocatalyst
has been developed. The new bifunctional organocatalyst
promoted aza-Morita–Baylis–Hillman reactions to yield adducts
with up to 98% ee.
Enantioselective organocatalysis has been recognized as an
environmentally benign and practical methodology for asym-
metric synthesis.1 With organocatalysts, metal contamination
of products does not occur because these catalysts contain no
Scheme 1 Spiro-type acid–base organocatalyst (S)-1 for the aza-MBH
reaction.
toxic or expensive metals. So far, numerous enantioselective
organocatalysts derived from chiral natural products and
chiral BINOL derivatives have been prepared and applied in
catalysis,8 spiro organocatalysts containing the Brønsted acid
and Lewis base units have not yet been reported.
As shown in Scheme 2, the synthesis of spiro-type organo-
various asymmetric reactions.2 Over a decade, we have studied
catalyst 1 was achieved in 72% overall yield after two simple
steps starting from the known compound (S)-5.8a To confirm
the catalytic activity of organocatalyst 1, we studied the effects
the design and synthesis of chiral spiro compounds that can be
used either as ligands or catalysts.3 As a continuation of our
study, this communication investigates the first spiro-type
of solvent and temperature on the reaction of methyl vinyl
ketone (2a) with p-chlorophenyl N-tosylimine (3a) (Table 1).
organocatalyst with Brønsted acid and Lewis base units (1)
for the enantioselective aza-Morita–Baylis–Hillman (aza-MBH)
We found that the solvent effects were critical to accelerate the
reaction (entries 1–4). The addition of 3 A molecular sieves
reaction (Scheme 1). Spiro organocatalyst 1 exhibited high
asymmetric induction yielding adduct 4 with up to 98% ee.
(MS 3 A) was beneficial to suppress the decomposition
of moisture-sensitive N-tosylimines (3a, entries 5 and 6).
The aza-MBH reaction of an electron-deficient alkene with
an imine promoted by Lewis base catalysts, such as nucleo-
philic amines or phosphines, is recognized as one of the most
Lowering the reaction temperature improved enantioselectivity
and the ee value of 4a reached 91% (entry 8).
useful and atom-economical carbon–carbon bond-forming
Furthermore, using chloroform at ꢀ10 1C with MS 3 A
afforded the best outcome; 4a was obtained in 86% yield with
92% ee (Table 2, entry 1). Under the optimal conditions as
shown in Table 2, organocatalyst 1 promoted the aza-MBH
reaction with high enantioselectivities for various substituted
phenyl N-tosylimines with 2a. 2-Naphthyl tosylimine (3m) was
also found to be a suitable substrate (entry 13). The reaction of
ethyl vinyl ketone (2b) afforded the corresponding adduct 4n
with excellent enantioselectivity (entry 14).
Shi et al. reported that (R)-20-(diphenylphosphino)-1,10-
binaphthyl-2-ol (7)9 functioned as an acid–base organocatalyst
for the aza-MBH reaction. Interestingly, in almost all cases,
spiro-type organocatalyst 1 yielded 4 with enantioselectivities
reactions.4 The aza-MBH adducts are highly functionalized
allylic amines, which are valuable building blocks for medicinal
chemistry.5 We previously developed (S)-3-(N-isopropyl-N-3-
pyridinylaminomethyl)BINOL6a,b,d,e and (S)-3-[2-(diphenyl-
phosphino)phenyl]BINOL6c,d as the Brønsted acid–Lewis base
organocatalysts for the aza-MBH reaction. In these catalyses,
the acid–base moieties act cooperatively to activate substrates
(enones and N-tosylimines), thus facilitating a carbon–carbon
bond-forming reaction that occurs with high enantioselectivity.
Owing to our interest in the development of novel acid–base
organocatalysts, we focused on 1,1-spirobiindane as a potential
platform for these bifunctional organocatalysts.7 Although
the 1,1-spirobiindane backbone is well-established in metal
The Institute of Scientific and Industrial Research (ISIR),
Osaka University, Mihogaoka, Ibaraki-shi, Osaka 567-0047, Japan.
E-mail: sasai@sanken.osaka-u.ac.jp; Fax: +81 6 6879 8465;
Tel: +81 6 6879 8469
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c1cc12784e
Scheme 2 Synthesis of (S)-1.
c
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Chem. Commun., 2011, 47, 9227–9229 9227

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Table 1 Optimization of the reaction conditionsa
with up to 98% ee. Further investigations to expand the reaction
scope and application in organic synthesis are currently
underway.
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science and Technology, Japan. We thank the technical staff
of the ISIR Comprehensive Analysis Center at Osaka University.
Entry Solvent Temp/1C Time/days Additive Yieldb (%) eec (%)
1d
2d
3d
4d
5
6
7
8
THF
Et2O
Toluene Rt
CH2Cl2 Rt
CH2Cl2
CH2Cl2
Rt
Rt
3
3
3
1
4
4
4
4
—
—
—
—
—
2
—
—
—
—
81
89
90
91
Notes and references
Trace
18
27
1 (a) M. J. Gaunt, C. C. C. Johansson, A. McNally and N. T. Vo,
Drug Discovery Today, 2007, 12, 8; (b) D. Enders, C. Grondal and
M. R. M. Huttl, Angew. Chem., Int. Ed., 2007, 46, 1570;
(c) A. M. Walji and D. W. C. MacMillan, Synlett, 2007, 1477;
(d) L.-W. Xu, J. Luo and Y. Lu, Chem. Commun., 2009, 1807;
(e) M. G. Nunez, P. Garcıa, R. F. Moro and D. Dıez, Tetrahedron,
2010, 66, 2089; (f) C. Grondal, M. Jeanty and D. Enders, Nat.
Chem., 2010, 2, 167; (g) H. Ishikawa, M. Honma and Y. Hayashi,
Angew. Chem., Int. Ed., 2011, 50, 2824.
0
0
49
MS 3 A 91
MS 3 A 82
MS 3 A 75
CH2Cl2 ꢀ5
CH2Cl2 ꢀ10
a
b
3 eq. of 2a were used. Isolated yield. Determined by HPLC
c
d
(Daicel Chiralpak AS). Rac-1 was used.
2 (a) P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed., 2001,
40, 3726; (b) K. Kacprzak and J. Gawronski, Synthesis, 2001, 961;
(c) E. R. Jarvo and S. J. Miller, Tetrahedron, 2002, 58, 2481;
(d) M. Benaglia, A. Puglisi and F. Cozzi, Chem. Rev., 2003,
103, 3401; (e) P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed.,
2004, 43, 5138; (f) P. M. Pihko, Angew. Chem., Int. Ed., 2004,
43, 2062; (g) Asymmetric Organocatalysis, ed. A. Berkessel and
H. Groger, Wiley-VCH, Weinheim, 2005; (h) Y. Takemoto, Org.
Biomol. Chem., 2005, 3, 4299; (i) T. Marcelli, J. H. van Maarseveen
and H. Hiemstra, Angew. Chem., Int. Ed., 2006, 45, 7496;
(j) S. J. Connon, Chem.–Eur. J., 2006, 12, 5418; (k) M. Marigo
and K. A. Jørgensen, Chem. Commun., 2006, 2001;
(l) Enantioselective Organocatalysis, ed. P. I. Dalko, Wiley-VCH,
Weinheim, 2007; (m) S. Sulzer-Mosse and A. Alexakis, Chem.
Commun., 2007, 3123; (n) H. Pellissier, Tetrahedron, 2007,
63, 9267; (o) S. Mukherjee, J. W. Yang, S. Hoffmann and B. List,
Chem. Rev., 2007, 107, 5471; (p) A. Dondoni and A. Massi, Angew.
Chem., Int. Ed., 2008, 47, 4638; (q) P. Melchiorre, M. Marigo,
A. Carlone and G. Bartoli, Angew. Chem., Int. Ed., 2008, 47, 6138;
(r) Z. Zhang and P. R. Schreiner, Chem. Soc. Rev., 2009, 38, 1187;
(s) S. J. Connon, Synlett, 2009, 354; (t) Y. Takemoto, Chem. Pharm.
Bull., 2010, 58, 593.
3 For recent reviews on the chiral spiro compounds as ligands and
catalysts, see (a) M. L. Patil and H. Sasai, Chem. Rec., 2008, 8, 98;
(b) G. B. Bajracharya, M. A. Arai, P. S. Koranne, T. Suzuki,
S. Takizawa and H. Sasai, Bull. Chem. Soc. Jpn., 2009, 82, 285;
(c) K. Ding, Z. Han and Z. Wang, Chem.–Asian. J., 2009, 4, 32.
4 For recent reports on aza-MBH reaction, see (a) G. Masson,
C. Housseman and J. Zhu, Angew. Chem., Int. Ed., 2007,
46, 4614; (b) K. Ito, K. Nishida and T. Gotanda, Tetrahedron Lett.,
2007, 48, 6147; (c) J. Vesely, P. Dziedzic and A. Cordova, Tetra-
hedron Lett., 2007, 48, 6900; (d) N. Utsumi, H. Zhang, F. Tanaka
and C. F. Barbas III, Angew. Chem., Int. Ed., 2007, 46, 1878;
(e) Y.-L. Shi and M. Shi, Adv. Synth. Catal., 2007, 349, 2129;
(f) N. Fleury-Bregeot, L. Jean, P. Retailleau and A. Marinetti,
Tetrahedron, 2007, 63, 11920; (g) M. Shi, G.-N. Ma and J. Gao,
J. Org. Chem., 2007, 72, 9779; (h) N. Abermil, G. Masson and
J. Zhu, J. Am. Chem. Soc., 2008, 130, 12596; (i) L. He, Y.-R. Zhang,
X.-L. Huang and S. Ye, Synthesis, 2008, 2825; (j) M.-J. Qi, T. Ai,
M. Shi and G. Li, Tetrahedron, 2008, 64, 1181; (k) Y.-Q. Fang and
E. N. Jacobsen, J. Am. Chem. Soc., 2008, 130, 5660; (l) G.-N. Ma,
J.-J. Jiang, M. Shi and Y. Wei, Chem. Commun., 2009, 5496;
(m) X. Wang, Y.-F. Chen, L.-F. Niu and P.-F. Xu, Org. Lett.,
2009, 11, 3310; (n) J.-M. Garnier, C. Anstiss and F. Liu, Adv. Synth.
Catal., 2009, 351, 331; (o) T. Yukawa, B. Seelig, Y. Xu,
H. Morimoto, S. Matsunaga, A. Berkessel and M. Shibasaki,
J. Am. Chem. Soc., 2010, 132, 11988; (p) S. Takizawa, N. Inoue,
S. Hirata and H. Sasai, Angew. Chem., Int. Ed., 2010, 49, 9725;
(q) J. Shah, Z. Yacob, A. Bunge and J. Liebscher, Synlett, 2010,
2079; (r) C. Anstiss, J.-M. Garnier and F. Liu, Org. Biomol. Chem.,
2010, 8, 4400; (s) K. Yuan, H.-L. Song, Y. Hu, J.-F. Fang and
X.-Y. Wu, Tetrahedron: Asymmetry, 2010, 21, 903; (t) C. Anstiss
and F. Liu, Tetrahedron, 2010, 66, 5486; (u) N. Abermil, G. Masson
and J. Zhu, Adv. Synth. Catal., 2010, 352, 656; (v) S. Takizawa,
Table 2 Substrate scope of the aza-MBH reactiona
Entry 3: R1
4: R2
Time/days Yieldb (%) eec,d (%)
1
2
3
4
5
6
7
8
Me (2a) 4-Cl-C6H4 (3a)
4
9
8
9
6
5
4
4
5
4a, 86
4b, 86
4c, 72
4d, 83
4e, 79
4f, 99
4g, 97
4h, 92
4i, 97
4j, 94
4k, 91
4l, 95e
4m, 94e
4n, 73
92 (94)
93 (88)
95 (61)
94 (83)
87 (81)
90 (—)
93 (—)
97 (—)
96 (94)
94 (90)
93 (84)
88 (83)
85 (—)
98 (88)
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
3-Cl-C6H4 (3b)
2-Cl-C6H4 (3c)
4-Br-C6H4 (3d)
4-F-C6H4 (3e)
4-CN-C6H4 (3f)
3-CN-C6H4 (3g)
2-CN-C6H4 (3h)
4-NO2-C6H4 (3i)
9
10
11
12
13
14
3-NO2-C6H4 (3j) 4.5
2-NO2-C6H4 (3k)
Ph (3l)
2-Naphthyl (3m)
6
8
9
7
Et (2b) 3i
a
b
c
3 eq. of 2 were used. Isolated yield. Determined by HPLC (Daicel
Chiralpak AS for 4a and 4k; Daicel Chiralpak AD-H for 4b–j and
4l–n). Values in parentheses are results obtained using catalyst 7.9
e
d
20 mol% of (R)-1 was used.
higher than those achieved using catalyst 7 (Table 2, ee values
in parentheses). A spiro organocatalyst would provide a
geometrically distinct and more rigid chiral pocket than its
BINOL-derived counterpart. The rigid spiro catalyst backbone
could reduce the conformational flexibility in the transition
state for the catalyzed reactions resulting in the formation of
the aza-MBH adducts with excellent enantioselectivities.3b
In summary, we have developed a new spiro-type organo-
catalyst with the Brønsted acid and Lewis base units for the
enantioselective aza-MBH reaction. Spiro organocatalyst 1
was found to show high asymmetric induction to yield products
c
9228 Chem. Commun., 2011, 47, 9227–9229
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A. Horii and H. Sasai, Tetrahedron: Asymmetry, 2010, 21, 891;
(w) J. Mansilla and J. M. Saa, Molecules, 2010, 15, 709; (x) Y. Wei
and M. Shi, Acc. Chem. Res., 2010, 43, 1005; (y) L. B. Saunders,
B. J. Cowen and S. J. Miller, Org. Lett., 2010, 12, 4800; (z) F. Zhong,
Y. Wang, X. Han, K.-W. Huang and Y. Lu, Org. Lett., 2011,
13, 1310.
5 (a) S. E. Drewes and G. H. P. Roos, Tetrahedron, 1988, 44, 4653;
(b) D. Basavaiah, A. J. Rao and T. Satyanarayana, Chem. Rev.,
2003, 103, 811; (c) T. Kataoka and H. Kinoshita, Eur. J. Org.
Chem., 2005, 45; (d) Y.-L. Shi and M. Shi, Eur. J. Org. Chem., 2007,
2905; (e) V. Singh and S. Batra, Tetrahedron, 2008, 64, 4511;
(f) P. R. Krishna, R. Sachwani and P. S. Reddy, Synlett, 2008,
2897; (g) G.-N. Ma, J.-J. Jiang, M. Shi and Y. Wei, Chem.
Commun., 2009, 5496; (h) V. Declerck, J. Martinez and
F. Lamaty, Chem. Rev., 2009, 109, 1; (i) D. Basavaiah,
B. S. Reddy and S. S. Badsara, Chem. Rev., 2010, 110, 5447.
6 (a) K. Matsui, S. Takizawa and H. Sasai, J. Am. Chem. Soc., 2005,
127, 3680; (b) K. Matsui, K. Tanaka, A. Horii, S. Takizawa and
H. Sasai, Tetrahedron: Asymmetry, 2006, 17, 578; (c) K. Matsui,
S. Takizawa and H. Sasai, Synlett, 2006, 761; (d) S. Takizawa,
K. Matsui and H. Sasai, J. Synth. Org. Chem. Jpn., 2007, 65, 1089;
(e) S. Takizawa, N. Inoue and H. Sasai, Tetrahedron Lett., 2011,
52, 377.
7 V. B. Birman, A. L. Rheingold and K.-C. Lam, Tetrahedron:
Asymmetry, 1999, 10, 125.
8 (a) J.-H. Xie, L.-X. Wang, Y. Fu, S.-F. Zhu, B.-M. Fan, H.-F. Duan
and Q.-L. Zhou, J. Am. Chem. Soc., 2003, 125, 4404; (b) J.-H. Xie
and Q.-L. Zhou, Acc. Chem. Res., 2008, 41, 581; (c) T. Dohi,
A. Maruyama, N. Takenaga, K. Senami, Y. Minamitsuji,
H. Fujioka, S. B. Caemmerer and Y. Kita, Angew. Chem., Int.
Ed., 2008, 47, 3787; (d) Y. K. Chung and G. C. Fu, Angew. Chem.,
Int. Ed., 2009, 48, 2225; (e) I. Coric, S. Muller and B. List, J. Am.
Chem. Soc., 2010, 132, 17370; (f) F. Xu, D. Huang, C. Han,
W. Shen, X. Lin and Y. Wang, J. Org. Chem., 2010, 75, 8677;
(g) S. F. Zhu, Y. Cai, H.-X. Mao, J.-H. Xie and Q.-L. Zhou, Nat.
Chem., 2010, 2, 546; (h) S. Li, S.-F. Zhu, C.-M. Zhang, S. Song
and Q.-L. Zhou, J. Am. Chem. Soc., 2008, 130, 8584, also see
ref. 3b and c.
9 (a) M. Shi and L. H. Chen, Chem. Commun., 2003, 1310; (b) M. Shi,
L.-H. Chen and C.-Q. Li, J. Am. Chem. Soc., 2005, 127, 3790.
c
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Chem. Commun., 2011, 47, 9227–9229 9229