L-Threonine-derived novel bifunctional phosphine-sulfonamide catalyst-promoted enantioselective aza-morita-Baylis-Hillman reaction

Article abstract of DOI:10.1021/ol103145g

A series of novel bifunctional phosphine-sulfonamide organic catalysts were designed and readily prepared from natural amino acids, and they were utilized to promote enantioselective aza-Morita-Baylis-Hillman (MBH) reactions. l-Threonine-derived phosphine

Full text of DOI:10.1021/ol103145g

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1310–1313
L-Threonine-Derived Novel
Bifunctional Phosphine-Sulfonamide
Catalyst-Promoted Enantioselective
Aza-Morita-Baylis-Hillman Reaction
Fangrui Zhong,† Youqing Wang,‡ Xiaoyu Han,† Kuo-Wei Huang,*,§ and Yixin Lu*,†
Department of Chemistry & Medicinal Chemistry Program, Life Sciences Institute,
National University of Singapore, 3 Science Drive 3, Singapore 117543,
Provincial Key Laboratory of Natural Medicine and Immuno-Engineering,
Henan University, Jinming Campus, Kaifeng, Henan, 475004, P. R. China, and
KAUST Catalysis Center & Division of Chemical and Life Science and Engineering,
King Abdullah University of Science and Technology, Kingdom of Saudi Arabia
chmlyx@nus.edu.sg; hkw@kaust.edu.sa
Received December 28, 2010
ABSTRACT
A series of novel bifunctional phosphine-sulfonamide organic catalysts were designed and readily prepared from natural amino acids, and they
were utilized to promote enantioselective aza-Morita-Baylis-Hillman (MBH) reactions. L-Threonine-derived phosphine-sulfonamide 9b was
found to be the most efficient catalyst, affording the desired aza-MBH adducts in high yields and with excellent enantioselectivities.
Nucleophilicorganiccatalysts employingtrivalent phos-
phines as Lewis bases are widely used in synthetic organic
chemistry.1 Compared with similarly substituted amines,
phosphines are generally less basic and more nucleophilic;
thus chiral phosphines often show unique catalytic activ-
ities in asymmetric synthesis.2 Despite tremendous appli-
cations of phosphine-catalyzed reactions in organic
synthesis, development of chiral phosphine catalysts is still
at its early stage, and design of highly efficient and readily
available chiral phosphines remains a huge challenge. Our
group has been investigating primary amino acid based
asymmetric organocatalytic synthetic methods in the past
few years,2p,3 and asymmetric amino catalysis via chiral
primary amines has been established as a powerful and
versatile tool in asymmetric synthesis.4
(2) For selected examples, see: (a) Zhu, G.; Chen, Z.; Jiang, Q.; Xiao,
D.; Cao, P.; Zhang, X. J. Am. Chem. Soc. 1997, 119, 3836. (b) Vedejs, E.;
Daugulis, O. J. Am. Chem. Soc. 1999, 121, 5813. (c) Zhu, X.-F.; Lan, J.;
Kwon, O. J. Am. Chem. Soc. 2003, 125, 4716. (d) Wurz, R. P.; Fu, G. C.
J. Am. Chem. Soc. 2005, 127, 12234. (e) Wilson, J. E.; Fu, G. C. Angew.
Chem., Int. Ed. 2006, 45, 1426. (f) Cowen, B. J.; Miller, S. J. J. Am. Chem.
Soc. 2007, 129, 10988. (g) Fang, Y. Q.; Jacobsen, E. N. J. Am. Chem. Soc.
2008, 130, 5660. (h) Jiang, Y.-Q.; Shi, Y.-L.; Shi, M. J. Am. Chem. Soc.
ꢀ
2008, 130, 7202. (i) Voituriez, A.; Panossian, A.; Fleury-Bregeot, N.;
† National University of Singapore.
Retailleau, P.; Marinetti, A. J. Am. Chem. Soc. 2008, 130, 14030. (j)
Smith, S. W.; Fu, G. C. J. Am. Chem. Soc. 2009, 131, 14231. (k) Smith,
S. W.; Fu, G. C. J. Am. Chem. Soc. 2009, 131, 14231. (l) Chung, Y. K.;
Fu, G. C. Angew. Chem., Int. Ed. 2009, 48, 2225. (m) Sun, J.; C. Fu, G. C.
J. Am. Chem. Soc. 2010, 132, 4568. (n) Sinisi, R.; Sun, J.; Fu, G. C Proc.
Natl. Acad. Sci. U.S.A. 2010, 107, 20652. (o) Xiao, H.; Chai, Z.; Zheng,
C.-W.; Yang, Y.-Q.; Liu, W.; Zhang, J.-K.; Zhao, G. Angew. Chem., Int.
Ed. 2010, 49, 4467. (p) Han, X.; Wang, Y.; Zhong, F.; Lu, Y. J. Am.
Chem. Soc. 2011, 133, 1726.
‡ Henan University.
§ King Abdullah University of Science and Technology.
(1) For reviews, see: (a) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res.
2001, 34, 535. (b) Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004,
346, 1035. (c) Ye, L.-W.; Zhou, J.; Tang, Y. Chem. Soc. Rev. 2008, 37,
1140. (d) Kwong, C. K.-W.; Fu, M. Y.; Lam, C. S.-L.; Toy, P. H.
Synthesis 2008, 2307. (e) Cowen, B. J.; Miller, S. J. Chem. Soc. Rev. 2009,
38, 3102. (f) Marinetti, A.; Voituriez, A. Synlett 2010, 174.
r
10.1021/ol103145g
Published on Web 02/18/2011
2011 American Chemical Society

To further expand amino acid based asymmetric cata-
lysis, we were interested in establishing novel chiral phos-
phines based on simple amino acid scaffolds. Bifunctional
catalytic systems have been widely used in organic chem-
istry, and the synergistic interactions of two functionalities
have been proven to be extremely powerful in asymmetric
catalysis. We envisioned that novel bifunctional phosphine
catalysts can be easily derived from natural amino acids,
and the designing principles are summarized in Figure 1.
based on chiral amine catalysts. Hatakeyama et al.
reported highly enantioselective MBH and aza-MBH re-
actions with hexafluoroisopropyl acrylate (HFIPA) cata-
lyzed by a tertiary amine catalyst β-isocupreidine
(β-ICD).6 Shi and co-workers employed the same catalyst
in the aza-MBH reactions with diverse activated olefins.7
Later, the group of Sasai applied BINOL-derived amine to
promote the aza-MBH reaction.8 Raheem and Jacobsen
also reported a thiourea-mediated aza-MBH reaction.9
More recently, Zhu et al. disclosed that a modified
β-ICD bearing amide functionality (β-ICD amide) could
be applied in the aza-MBH reaction in the presence of
β-naphthnol and excellent enantioselectivity was achieved
with both aromatic and aliphatic sulfinyl imines.10 On the
other hand, chiral phosphine-mediated enantioselective
aza-MBH reactions are rather limited. In this context,
elegant utilization of BINOL-derived phosphines by the
groups of Shi, Sasai, and Ito clearly demonstrated the
enormous potential of chiral phosphines in asymmetric
MBH reactions.11 Our research group recently showed
that dipeptide-derived novel phosphines were powerful
catalysts for the enantioselective allene-acrylate [3 þ 2]
cycloadditions;2p herein, we demonstrate that amino acid
based bifunctional phosphines could effectively catalyze
aza-MBH of acrylates12 with excellent enantiomeric control.
We began our investigation by preparing a number of
L-valine-derived bifunctional chiral phosphines with dif-
ferent hydrogen bond donors (catalysts 4 to 7 in Figure 2).
In particular, thioureas13 and sulfonamides14 are known to
be remarkably useful in hydrogen-bonding (H-bond) in-
teractions. The aza-MBH reaction between imines and
acrylates was chosen as a model reaction, and the results
Figure 1. Novel bifunctional phosphine catalysts based on
natural primary amino acids.
Simple functional group transformations convert the acid
group into a phosphine, and the Brønsted acid site neces-
sary for the bifunctional catalysts can be easily derived
from the amine moiety. Proper selection of side chains then
provides either steric or electronic tuning to the structures
of the catalysts. Moreover, by connecting the phosphorus
atom to a primary carbon, we anticipate higher nucleo-
philicity of the resulting chiral phosphines.
The Morita-Baylis-Hillman (MBH) reaction and its
aza counterpart (Aza-MBH reaction) are among the most
valuable reactions for the construction of densely functio-
nalized products from simple precursors in a highly atom
economic fashion.5 Considerable efforts have been de-
voted to the development of enantioselective versions of
these reactions, and most successful examples are usually
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J. Am. Chem. Soc. 1999, 121, 10219. (b) Kawahara, S.; Nakano, A.;
Esumi, T.; Iwabuchi, Y.; Hatakeyama, S. Org. Lett. 2003, 5, 3103.
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Shi, M.; Xu, Y.-M.; Shi, Y.-L. Chem.;Eur. J. 2005, 11, 1794. (c) Shi, M.;
Qi, M.-J.; Liu, X.-G. Chem. Commun. 2008, 6025.
(8) (a) Matsui, K.; Takizawa, S.; Sasai, H. J. Am. Chem. Soc. 2005,
127, 3680. (b) Matsui, K.; Tanaka, K.; Horii, A.; Takizawa, S.; Sasai, H.
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Chen, L.-H.; Teng, W.-D. Adv. Synth. Catal. 2005, 347, 1781. (c) Shi, M.;
Chen, L.-H.; Li, C.-Q. J. Am. Chem. Soc. 2005, 127, 3790. (d) Liu, Y.-H.;
Chen, L.-H.; Shi, M. Adv. Synth. Catal. 2006, 348, 973. (e) Matsui, K.;
Takizawa, S.; Sasai, H. Synlett 2006, 761. (f) Ito, K.; Nishida, K.;
Gotanda, T. Tetrahedron Lett. 2007, 48, 6147.
(12) For a recent excellent example of aza-MBH reactions with metal
catalysis, see: Yukawa, T.; Seelig, B.; Xu, Y.; Morimoto, H.; Matsunaga,
S.; Berkessel, A.; Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 11988.
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Synth. Catal. 2004, 346, 1141. (h) Dahlin, N.; Bøgevig, A.; Adolfsson, H.
Adv. Synth. Catal. 2004, 346, 1101.
(3) For our work in this research field, see: (a) Jiang, Z.; Liang, Z.;
Wu, X.; Lu, Y. Chem. Commun. 2006, 2801. (b) Cheng, L.; Han, X.;
Huang, H.; Wong, M. W.; Lu, Y. Chem. Commun. 2007, 4143. (c) Cheng,
L.; Wu, X.; Lu, Y. Org. Biomol. Chem. 2007, 5, 1018. (d) Wu, X.; Jiang,
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Lu, Y. Chem. Commun. 2008, 6315. (f) Han, X.; Kwiatkowski, J.; Xue,
F.; Huang, K.-W.; Lu, Y. Angew. Chem., Int. Ed. 2009, 48, 7604. (g) Zhu,
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Jiang, Z.; Lu, Y. Tetrahedron Lett. 2010, 51, 1884. (j) Zhu, Q.; Lu, Y.
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Xu, L.-W.; Kwiatkowski, J.; Huang, K.-W.; Lu, Y. Angew. Chem., Int.
Ed. 2011, 50, 1861.
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asymmetric catalysis, see: (a) Xu, L.-W.; Luo, J.; Lu, Y. Chem. Commun.
2009, 1807. (b) Xu, L.-W.; Lu, Y. Org. Biomol. Chem. 2008, 6, 2047. (c)
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2008, 1919. (e) Bartoli, G.; Melchiorre, P. Synlett 2008, 1759. For
reviews on asymmetric catalysis mediated by synthetic peptides, see:
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107, 5759. (g) Revell, J. D.; Wennemers, H. Curr. Opin. Chem. Biol. 2007,
11, 269.
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Reddy, B. S.; Badsara, S. S. Chem. Rev. 2010, 110, 5447. (b) Langer, P.
Angew. Chem., Int. Ed. 2000, 39, 3049. (c) Basavaiah, D.; Rao, A. J.;
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Basavaiah, D.; Rao, K. V.; Reddy, R. J. Chem. Soc. Rev. 2007, 36,
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Org. Lett., Vol. 13, No. 6, 2011
1311

2-naphthyl acrylate, phosphine-sulfonamide 7 led to the
formation of an aza-MBH adduct in excellent yield and
with moderate enantioselectivity (entry 7). We reasoned
that the isopropyl side chain from valine may not provide
enough steric control in the asymmetric induction, and
withoursuccess inthreonine-basedcatalytic systems,3b-d,g
we decided to synthesize serine-derived catalyst 8 and a
number of threonine-based phosphine-sulfonamides 9a
to 9i, in which various siloxy groups15 were introduced.
The threonine core proved to be superior to that of serine
(entry 9 versus entry 8). Similar enantioselectivities were
observed with bulky siloxy groups, and the thexyldi-
methylsilyl (TDS) group was chosen as it gave marginally
better results (entries 9-13). Exploration of different
sulfonamides in the catalyst structures failed to improve
the results (entries 14-17). The enantiomeric excess could
be further improved by lowering the reaction temperature
(entry 18). When the reaction was performed at -30 °C for
2 days, the desired aza-MBH adduct was obtained in 89%
yield and with 91% ee (entry 19).
Figure 2. Stuctures of bifunctional phosphine catalysts.
are summarized in Table 1. Phosphine-thiourea 4 gave
poor results (entry 1). While catalyst 5 with a Boc group
was completely ineffective, phosphine-amide 6 was able to
catalyze the reaction, although in very low ee (entries 2 and
3). Phosphine-sulfonamide catalyst 7 was found to display
certain reactivity and selectivity (entry 4). We next varied
sulfonamide protection on the imine nitrogen and also
employed different acrylates (entries 5 to7). To ourdelight,
by combining N-(p-methoxybenzenesulfonyl)imine and
Table 2. Enantioselective Aza-MBH Reactions of Various Imi-
nes 1 and Acrylate 2c Catalyzed by 9b
Table 1. Catalyst Screening and Optimization of Reaction
Conditions
entrya
product (R)
3a (Ph)
yield (%)b
ee (%)c
1
89
91
90
96
95
84
93
84
76
85
95
95
93
95
93
95
76
91
90
91
92
92
93
90
92
91
90
97
90
90
91
95
96
88
2
3b (4-Me-Ph)
3c (4-Et-Ph)
3d (4-F-Ph)
3
4
5
3e (4-Br-Ph)
3f (4-Cl-Ph)
entrya
R1/R2
Me/Me
cat.
yield (%)b
ee (%)c
6
7
3g (4-CF3-Ph)
3h (4-NO2-Ph)
3i (3-Me-Ph)
3j (3-Cl-Ph)
1
4
28
-
-13
-
8
2
Me/Me
5
9
3
Me/Me
6
49
42
40
63
90
90
88
90
93
94
91
87
90
43
88
95
89
23
40
55
57
57
64
71
74
73
73
64
74
72
67
60
89
91
10
11
12
13
14
15
16
17
4
Me/Me
7
3k (2-CF3-Ph)
3l (2-Cl-Ph)
5
Me/Ph
7
6
Me/2-naphthyl
OMe/2-naphthyl
OMe/2-naphthyl
OMe/2-naphthyl
OMe/2-naphthyl
OMe/2-naphthyl
OMe/2-naphthyl
OMe/2-naphthyl
OMe/2-naphthyl
OMe/2-naphthyl
OMe/2-naphthyl
OMe/2-naphthyl
OMe/2-naphthyl
OMe/2-naphthyl
7
3m (2-Br-Ph)
3n (2-F-Ph)
7
7
8
8
3o (2-furyl)
9
9a
9b
9c
9d
9e
9f
9g
9h
9i
9b
9b
3p (2-thiophenyl)
3q (2-naphthy)
10
11
12
13
14
15
16
17
18d
19e
a Reactions were performed with imine 1 (0.05 mmol), 2-naphthyl
acrylate 2c (0.06 mmol) and catalyst 9b (0.01 mmol) in dry THF
(0.25 mL) under N2. b Isolated yield. c Determined by HPLC analysis
on a chiral stationary phase.
With the optimized reaction conditions in hand, the scope
of the aza-MBH reaction was evaluated (Table 2). The
reaction is applicable to a wide range of aromatic imines;
excellent chemical yields and very high enantioselectivities
were attainable within 2 days. Notably, the ortho-substituted
aromatic imines, which are well-known to be difficult sub-
strates for the aza-MBH reaction, were found to be suitable,
a Reactions were carried out with 1 (0.05 mmol), 2 (0.1 mmol for 2a
and 0.06 mmol for 2b, 2c), and catalyst (0.005 mmol) in dry THF (0.1 mL
at rt or 0.2 mL at -20 °C or 0.25 mL at -30 °C) under N2. b Isolated
yield. c Determined by HPLC analysis on a chiral stationary phase.
d Reaction was performed with 20 mol % catalyst at -20 °C for 48 h.
e Reaction was performed with 20 mol % catalyst at -30 °C for 48 h.
(15) Xu, L.-W.; Li, L.; Shi, Z.-H. Adv. Synth. Catal. 2010, 352, 243.
Org. Lett., Vol. 13, No. 6, 2011
1312

and the products were obtained in nearly quantitative yields
and with up to 97% ee (entries 11-14). These results
represent by far the best enantioselectivities attainable for
the ortho-substituted substrates in the aza-MBH reaction. In
addition, imines with heterocyclic rings were also applicable;
95% and 96% ee were observed (entries 15-16). A less
satisfactory result was obtained for a cyclohexyl imine.16
The Brønsted acidic sulfonamide and nucleophilic phos-
phine in our bifunctional catalysts are indispensable and
work cooperatively in promoting enantioselective aza-
MBH reactions. When N-methylated sulfonamide 10 was
employed as the catalyst, the reaction became slower and
enantioselectivity was dramatically decreased [eq 1]. This
result suggested that the H-bond donor moiety in the
catalyst contributes significantly to the reaction and is
crucial for the asymmetric induction. Surprisingly, phos-
phine 11 containing N-trifluoromethanesulfonamide was
found to be a very poor catalyst, giving the product in low
yield and with virtually no enantioselectivity, which may
be attributed to the overstabilization of the enolate inter-
mediate by highly acidic N-H in the sulfonamide or for-
mation of a protonated form of the enolate intermediate.
Figure 3. Proposed reaction mechanism.
believe such a H-bond, together with the bulky OTDS
group, favors the formation of a structurally well-
defined phosphonium enolate intermediate A, provid-
ing a confined spatial arrangement for the incoming
imine. Had the OTDS be replaced by a less hindered
OTMS group, the less rigid intermediate A is antici-
pated to provide less stereocontrol. This is consistent
with experimental observations; the MBH adduct was
obtained in 64% ee when OTMS-derived catalyst 9e
was employed, in contrast to a 74% ee attainable with
OTDS-derived 9b under otherwise identical reaction
conditions (entry 13 versus 10, Table 1). A subsequent
Mannich reaction of A with imine yields zwitterionic
intermediate B. The proton transfer from the R-carbon
atom then takes place to yield enolate C, which undergoes
β-elimination to afford the MBH adduct and regenerate 9b
at the same time.
In conclusion, we have introduced a novel class of
bifunctional phosphine catalysts. In particular, we have
derived a series of phosphine-sulfonamide bifunctional
catalysts from natural amino acids. The effectiveness of
our catalysts has been demonstrated in highly enantiose-
lective aza-MBH reactions. DFT calculations are ongoing
toward to a deeper understanding of the reaction mechan-
ism and will be reported in due course.
Despite their enormous applications, the mechanism of
the MBH reactions is not entirely clear. Based on recent
elegant mechanistic studies17 and our experimental obser-
vations, we propose the mechanism of the 9b-promoted
aza-MBH reaction as depicted in Figure 3. The reversible
conjugate addition of phosphine to acrylate generates
intermediate A. Since enolate A is more basic than the
imine substrate, and thus is a better H-bond acceptor, it
forms a H-bond with the Brønsted acid moiety of 9b.18 We
(16) The reaction was run with cyclohexyl tosylimine at -10 °C for
72 h, and the MBH product was obtained in 74% yield and with 72% ee.
(17) (a) Aggarwal, V. K.; Fulford, S. Y.; Lloyd-Jones, G. C. Angew.
Chem., Int. Ed. 2005, 44, 1706. (b) Price, K. E.; Broadwater, S. J.; Jung,
H. M.; McQuade, D. T. Org. Lett. 2005, 7, 147. (c) Price, K. E.;
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70, 3980. (d) Buskens, P.; Klankermayer, J.; Leitner, W. J. Am. Chem.
Soc. 2005, 127, 16762. (e) Kraft, M. E.; Haxell, T. F. N.; Seibert, K. A.;
Abboud, K. A. J. Am. Chem. Soc. 2006, 128, 4174. (f) Amarante, G. W.;
Milagre, H. M. S.; Vaz, B. G.; Vilacha Ferreira, B. R.; Eberlin, M. N.;
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M.; Milagre, H. M. S.; Braga, A. A. C.; Maseras, F.; Eberlin, M. N.;
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Acknowledgment. We are grateful for the generous
financial support from the National University of Singa-
pore and the Ministry of Education (MOE) of Singapore
(R-143-000-362-112) to Y.L. and from King Abdullah
University of Science and Technology to K.-W.H.
Supporting Information Available. Representative ex-
perimental procedures, HPLC chromatogram, and NMR
spectra of compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(18) Such H-bonding interaction was supported by 1H NMR analy-
sis. The chemical shift corresponding to sulfonamide NH disappeared
upon mixing 9b with acrylate 2c, and such resonance remained un-
changed when 9b and 1b were mixed.
Org. Lett., Vol. 13, No. 6, 2011
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