Thiourea-phosphonium salts from amino acids: Cooperative phase-transfer catalysts in the enantioselective aza-Henry reaction

Article abstract of DOI:10.1039/c3cc42864h

New chiral bifunctional thiourea-phosphonium salts have been developed based on natural amino acids as highly efficient phase-transfer catalysts in the enantioselective aza-Henry reaction.

Full text of DOI:10.1039/c3cc42864h

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Thiourea-Phosphonium Salts From Amino Acids: Cooperative
Phase-Transfer Catalysis in Enantioselective aza-Henry Reaction
Dongdong Cao,a Zhuo Chai,b Jiaxing Zhang,b Zhengqing Ye,b Hua Xiao,a Hongyu Wang,a Jinhao Chen,b
Xiaoyu Wua and Gang Zhao*a,b
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
First published on the web Xth XXXXXXXXX 200X
DOI: 10.1039/b000000x
expanded the application scope of phase transfer catalysis.
Amino acids are privileged scaffolds for the development
of new chiral organocatalysts due to their facile tunings of the
catalytic efficiency through structural modifications.7 The
recently developed organocatalysts based on amino acids such
as primaryꢀsecondary amines, tertiary amineꢀthioureas,
aminophosphines in our group7f,8 have demonstrated high
efficiency in a variety of asymmetric reactions. The excellent
New chiral bifunctional thiourea-phosphonium salts have been
developed based on natural amino acids as highly efficient
phase-transfer catalysts in the enantioselective aza-Henry
reaction.
Asymmetric phaseꢀtransfer catalysis has evolved into one of
the most versatile and powerful tools for the syntheses of
chiral organic compounds at both academic and industrial
levels.1 As a key factor in fuelling the rapid progress in this
field, the development of new chiral phaseꢀtransfer catalysts
has inarguably been one of the research focuses.2 So far, the
most reported successful phaseꢀtransfer catalysts are based on
the skeletons of cinchona alkaloids,1aꢀb chiral binaphthyls1cꢀe
asymmetric
catalysis
demonstrated
by
these
bifunctional/multifunctional catalysts is usually ascribed to
the cooperative catalysis of the different functionalities
present in these catalysts. Although the concept of cooperative
catalysis has been widely employed in the design of various
new catalysts, its application to phaseꢀtransfer catalysts is still
very limited.9 We now describe novel bifunctional
thioureaꢀaromatic phosphonium catalysts synthesized from
amino acids (Figure 2), which are highly efficient in
catalyzing asymmetric azaꢀHenry reactions through
cooperative phase transfer catalysis. These novel bifunctional
phosphonium phaseꢀtransfer catalysts are easily accessible
(see the †ESI for details), and airꢀ and moistureꢀstable for
routine handling.
and most of these catalysts have
a
quaternary
tetraalkylammonium center surrounded by large steric
hindrance. On the other hand, examples with alternative
onium centers like phosphonium were rather limited,3 which
might be due to the ready elimination of phosphoniums under
the basic conditions that usually required in phase transfer
catalysis.4 Recent impressive progress in this area includes the
binaphthylꢀmodified quaternary phosphonium catalysts
developed by Maruoka,5a,5b Lectka5c and Ma5d groups (Figure
1, I), and the Pꢀspiro tetraaminophosphonium catalysts
developed by Ooi and coworkers (Figure 1, II).6 These new
chiral phosphoniumꢀcentered catalysts have significantly
O
Bn
O
Bn
X
Bn
Ar1
Ar1
N
Ar1
N
H
N
H
N
Br
Br
Br
H
H
PPh3
PPh2Bn
PPh2Bn
1a
1b
1c X = O
1d X = S
Ar1 = 3,5-bis(trifluoromethyl)phenyl
S
Ph
S
tBu
S
Ar1
Ar1
Ar1
Br
Br
Y
N
H
N
H
N
N
N
H
N
H
H
H
PPh2Bn
PPh2Bn
PPh2Bn
1e
1f
1g Y = Br
1h Y = Cl
R
MeO
R =
S
S
Br
Br
N
H
N
H
N
N
H
H
PPh2Bn
PPh2R
Figure 1. Chiral quaternary phosphonium catalysts (Anions are omitted)
1i R = H
1j R = p-OMe
1k R = p-F
Br
1l
1m
a Department of Chemistry, University of Science and Technology of
China, Hefei, Anhui 230026, China.
Figure 2. Chiral thioureaꢀphosphonium salts.
E-mail: zhaog@mail.sioc.ac.cn
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Lu, Shanghai 200032, China.
†Electronic Supplementary Information (ESI) available: Experimental
details, analytical data, HPLC chromatography and NMR spectra of
products. See DOI: 10.1039/b000000x/
Using the NꢀBoc imine in situ generated from
amidosulfone 2a,10 and nitromethane 3a, we first examined
the catalytic efficiency of a series of bifunctional aromatic
phosphonium salts in this azaꢀHenry reaction (Table 1). The
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modular structures of these catalysts include three basic
components: the acidic amine moiety, the amino acid skeleton
and the phosphonium centre, and each would allow facile
modifications for better catalytic efficiency. As for the acidic
amine moiety, the thiourea structure with two
hydrogenꢀbonding donors has obvious advantages over other
structures such as acyl amines and urea in terms of
Next, a series of amidosulfones 2 were tested under the
optimized reaction conditions and a broad substrate scope was
observed (Table 2). Specifically, when R was an aromatic
group, high to excellent yields, and excellent ee values were
generally obtained, irrespective of the electronic nature and
positions of the substituents on the benzene ring (Table 2,
entries 1ꢀ11). Heteroaromatic substrates 2l and 2m also
participated in the reaction well (Table 2, entries 12ꢀ13).
Moreover, the more challenging aliphatic substrates were also
well tolerated in the reaction, albeit with a slight drop in the
enantioselectivity (Table 2, entries 14ꢀ15).
enantioselectivity when
Lꢀphenylalanineꢀderived catalysts
1bꢀ1d were used (entries 2ꢀ4). These results, together with
11]
other results,[8f,
suggest the important role of dual
hydrogenꢀbonding interaction in this type of catalytic system.
Table 2. Scope study with different amidosulfones 2. a
Then catalysts 1eꢀ1h derived from other amino acids were
screened, and the
Lꢀisoleucineꢀderived 1g was selected for
further investigation in view of the total results (entries 5ꢀ7).
Notably, changing the counteranion from bromide to chloride
did not affect the reaction (entry 8). To our delight, the
3,5ꢀbis(trifluoromethyl)phenyl of the thiourea could be
replaced by more common and cheaper aryl groups to give
comparable catalytic efficiency (entries 9ꢀ11). Increasing the
volume of the phosphonium centre by using larger benzylic
groups (1lꢀ1m) brought little influence on the results (entries
12ꢀ13) while the use of triphenylphosphine (1a) was
detrimental to the reaction (entry 1).12 Also of note is the high
catalytic efficiency of these novel catalysts in that the reaction
were usually completed in 5 h, which is a remarkable
improvement over previously used chiral ammonium salt
catalysts.13,9f As a compromise of factors like the cost and
accessibility, catalyst 1j was selected for further optimisation
of other reaction parameters such as solvent, base, catalyst
loading amount and reaction temperature and no better results
was obtained (see the †ESI for details). Thus, the optimum
reaction condition was determined as follows: 5 equiv of KOH
Entry
1
R
Yield (%)b Ee (%)c
2
2a
2b
2c
2d
2e
2f
4
4a
4b
4c
4d
4e
4f
Ph
79
77
80
78
82
81
84
68
92
83
95
98
92
88
88
96
97
97
97
96
97
98
95
96
97
91
93
92
88
88
2
pꢀFC6H4
3
p ꢀClC6H4
p ꢀBrC6H4
p ꢀMeC6H4
p ꢀMeOC6H4
p ꢀCF3C6H4
p ꢀNO2C6H4
αꢀNaphthyl
mꢀClC6H4
oꢀFC6H4
4
5
6
7
2g
2h
2i
4g
4h
4i
8
9
o
10
11
12
13
14d
15d
2j
4j
and 5 mol% of 1j in toluene were used at ꢀ20 C (entry 10).
Table 1. Screen of catalystsa
2k
2l
4k
4l
1 (5 mol%)
o ꢀfuryl
NHBoc
SO2Ph
NHBoc
NO2
KOH (5 equiv)
toluene, -20 C
5 h
CH3NO2
+
o ꢀthienyl
cyclohexyl
phenyl ethyl
2m
2n
2o
4m
4n
4o
Ph
Ph
2a
Entry
3a
4a
Catalyst
Yield (%)b
ee (%)c
ꢀ16
43
a
Reaction conditions: 2 (0.1 mmol), 3a (0.5 mmol) and KOH (0.5 mmol) in the
presence of 1j (5 mol%) in toluene (1.0 mL). b Isolated yields.c Determined by chiral
1
2
75
64
98
71
83
68
75
75
83
79
68
71
75
1a
1b
1c
1d
1e
1f
stationary phase HPLC. The absolute configurations of 4 were determined by
d
comparison of the specific optical rotation values with literature data. 5 mol% of
3
74
catalyst 1g was used at ꢀ30 ℃.
4
89
5
92
To further explore the scope of the reaction, several
substituted nitroalkanes were then evaluated with
amidosulfone 2a (Scheme 1). With the simple nitroalkanes 3b
and 3c used, a mixture of synꢀ and antiꢀproducts was obtained
in quantitative yields, with high enantioselectivities for both
products. The reaction with functionalized nitroalkane 3c also
proceeded smoothly to give the two diastereomers of the
product 4r with nearly the same high enantioselectivity. As an
illustration of the utility of the reaction, the product 4r was
transformed to a chiral aminioꢀsubstituted γꢀlactam 5, which
represents an important structural motif found in many
physiologically active substances.14 The stereochemical
integrity of 4r was basically maintained in the oneꢀstep
hydrogenation using Raney Ni.
6
96
7
1g
1h
1i
95
8
95
9
93
10
11
12
13
96
1j
95
1k
1l
96
96
1m
a Reaction conditions: 2a (0.1 mmol), 3a (0.5 mmol) and base (0.5 mmol) in the
presence of 1 (5 mol%) in various solvents (1.0 mL). b Isolated yields. c Determined
by chiral stationary phase HPLC.
In order to gain insight into the cooperative catalysis of
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3. (a) T. Shioiri, A. Ando, M. Masui, T. Miura, T. Tatematsu, A.
Bohsako, M. Higashiyama, C. Asakura, ACS Symposium Series,
1997, 659, 136; (b) K. Manabe, Tetrahedron, 1998, 54, 14465; (c)
K. Manabe, Tetrahedron Lett., 1998, 39, 5807; (d) T. Werner, Adv.
Synth. Catal. 2009, 351, 1469; (e) D. Enders, T. V. Nguyen, Org.
Biomol. Chem. 2012, 10, 5327; (f) S. Shirakawa, A. Kasai, T.
these bifunctional thioureaꢀphosphonium salts in the catalytic
process, two control experiments were run in the presence of
catalyst 1n with a single hydrogenꢀbond NꢀMethylthiourea
and 1o without the phosphonium center under the conditions
used in table 1 (Figure 1). Compared to the results obtained
with 1d (71% yield and 89% ee in table 1, entry 4), with these
two modified catalysts, both the yield and the
enantioselecitivity of the product were significantly lower.
These results indicated that both the dual hydrogenꢀbond sites
of the thiourea moiety and the phosphonium centre of this
bifunctional phaseꢀtransfer catalysts were crucial to achieve
excellent enantiocontrol in the azaꢀHenry reaction.15
Tokuda, K. Maruoka, Chem. Sci., 2013, 4, 2248
.
4. (a) G. Wittig, G. Geissler, Justus Liebigs Ann. Chem. 1953, 580, 44;
(b) G. Wittig, U. Schöllkopf, Chem. Ber. 1954, 87, 1318.
5. (a) R. He, X. Wang, T. Hashimoto, K. Maruoka, Angew. Chem. Int.
Ed. 2008, 47, 9466; (b) R. He, K. Maruoka, Synthesis 2009, 2289;
(c) R. He, C. Ding, K. Maruoka, Angew. Chem. Int. Ed. 2009, 48,
4559; (d) C. J. Abraham, D. H. Paull, C. DogoꢀIsonagie, T. Lectka,
Synlett 2009, 1651; (e) C.ꢀL. Zhu, F.ꢀG. Zhang, W. Meng, J. Nie, D.
Cahard, J.ꢀA. Ma, Angew. Chem. Int. Ed. 2011, 50, 5869.
NHBoc
1j (5 mol %)
NHBoc
6. For selected recent examples: (a) D. Uraguchi, S. Sakaki, T. Ooi, J.
Am. Chem. Soc. 2007, 129, 12392; (b) D. Uraguchi, Y. Ueki, T. Ooi,
J. Am. Chem. Soc. 2008, 130, 14088; (c) D. Uraguchi, D.
Nakashima, T. Ooi, J. Am. Chem. Soc. 2009, 131, 7242; (d) D.
Uraguchi, Y. Asai, T. Ooi, Angew. Chem. Int. Ed. 2009, 48, 733; (e)
D. Uraguchi, T. Ito, T. Ooi, J. Am. Chem. Soc. 2009, 131, 3836; (f)
D. Uraguchi, Y. Ueki, T. Ooi, Science 2009, 326, 120; (g) D.
Uraguchi, S. Nakamura, T. Ooi, Angew. Chem. Int. Ed. 2010, 49,
7562; (h) D. Uraguchi, T. Ito, S. Nakamura, T. Ooi, Chem. Sci.
2010, 1, 488; (i) D. Uraguchi, N. Kinoshita, T. Ooi, J. Am. Chem.
Soc. 2010, 132, 12240; (j) D. Uraguchi, Y. Ueki, T. Ooi, Angew.
Chem. Int. Ed. 2011, 50, 3681; (k) M. T. Corbett, D. Uraguchi, T.
Ooi, J. S. Johnson, Angew. Chem. Int. Ed. 2012, 51, 4685; (l) D.
Uraguchi, Y. Ueki, T. Ooi, Chem. Sci. 2012, 3, 842; (m) D.
Uraguchi, N. Kinoshita, D. Nakashima, T. Ooi, Chem. Sci. 2012, 3,
3161; (n) D. Uraguchi, K. Yoshioka, Y. Ueki, T. Ooi, J. Am. Chem.
Soc. 2012, 134, 19370.
R
KOH (5 equiv)
+
Ph
SO2Ph
NO2
Ph
R
PhCH3, -20 o
5 h
C
NO2
4p: R = H, 99% yield
dr(syn:anti) = 37:63, ee = 89%/97%
3b: R = H
3c: R = Me
2a
4q: R = Me, 99% yield
dr(syn:anti) = 22:78, ee = 86%/96%
Same conditions as
3b and 3c
3d: R = CH2CO2Et
NHBoc
NHBoc
Ph
Raney Ni
yield = 65%
syn:anti = 43:57
ee = 88%/88%
CO2Et
Ph
H2 (1atm)
EtOAc, RT
48 h
HN
NO2
4r
5
O
syn:anti = 47:53, ee = 89%/86%
Scheme 1. Reactions with nitroalkanes 3 and a useful
transformation of the product 4r.
7. (a) E. A. Colby Davie, S. M. Mennen, Y. Xu, S. J. Miller, Chem.
Rev. 2007, 107, 5759; (b) L.ꢀW. Xu, J. Luo, Y. Lu, Chem. Commun.,
2009, 1807; (c) J. Paradowska, M. Stodulski, J. Mlynarski, Angew.
Chem. Int. Ed. 2009, 48, 4288; (d) L.ꢀW. Xu, Y. Lu, Org. Biomol.
Chem. 2008, 6, 2047; (e) L.ꢀW. Xu, L. Li, Z.ꢀH. Shi, Adv. Synth.
Catal. 2010, 352, 243; (f) Z. Chai, G. Zhao, Catal. Sci. Technol.
2012, 2, 29.
CF3
CF3
S
Bn
S
Bn
Br
F3C
N
N
F3C
N
N
H
H
H
PPh2Bn
PPh2
8. H. Xiao, Z. Chai, D. Cao, H. Wang, J. Chen, G. Zhao, Org. Biomol.
Chem. 2012, 10, 3195.
1n (single H-bond)
4a, 5 h, 83% yield, 5% ee
1o (no phosphonium salt)
4a, 48 h, 20% yield, 13% ee
Results:
9. (a) T. Ooi, D. Ohara, M. Tamura, K. Maruoka, J. Am. Chem. Soc.
2004, 126, 6844; (b) R. He, S. Shirakawa, K. Maruoka, J. Am.
Chem. Soc. 2009, 131, 16620; (c) T. Ooi, D. Ohara, K. Fukumoto,
K. Maruoka, Org. Lett. 2005, 7, 3195; (d) X. Wang, Q. Lan, S.
Shirakawa, K. Maruoka, Chem. Commun. 2010, 46, 321; (e) L.
Wang, S. Shirakawa, K. Maruoka, Angew. Chem. Int. Ed. 2011, 50,
5327; (f) K. M. Johnson, M. S. Rattley, F. Sladojevich, D. M.
Barber, M. G. Nuñez, A. M. Goldys, D. J. Dixon, Org. Lett. 2012,
14, 2492; (g) For an excellent review about bifunctional chiral
quaternary ammonium salt catalysts, see: J. Novacek, M. Waser,
Eur. J. Org. Chem. 2013, 637.
Figure 3. Control experiment results in support of cooperative catalysis
for the bifunctional catalysts .
In summary, we have developed novel chiral bifunctional
quaternary phosphonium salts as highly efficient
phaseꢀtransfer catalysts in the azaꢀHenry reaction from readily
available and inexpensive chiral amino acids. The easy
tunability of catalytic activities enabled by their modular
structures as well as their ready accessibility hold a great
promise for extensive applications in phaseꢀtransfer catalysis.
Efforts towards the application of these new phaseꢀtransfer
catalysts to other reactions as well as a deeper mechanistic
understanding of the catalytic process are underway in our
laboratory.
Research support from National Basic Research Program of
China(973 Program, 2010CB833200) the National Natural
Science Foundation of China (Nos.20172064, 203900502,
20532040, 20290180) and Science and Technology
Commission of Shanghai Municipality (11XD1406400).
10. For a review about the reactions of amidosulfones, see: B. Yin,Y.
Zhang, L.ꢀW. Xu Synthesis, 2010, 3583.
11. For a review, see: S.ꢀX. Wang, X. Han, F. Zhong, Y. Wang, Y. Lu,
Synlett 2011, 2766.
12. To study the stability of these thioureaꢀphosphonium salts under the
strongly basic reaction conditions, we performed 31P NMR analysis
of the catalyst in the reaction mixture and no decomposition signal
was observed. See the ESI for details.
13. (a) C. Palomo, M. Oiarbide, A. Laso, R. López, J. Am. Chem. Soc.
2005, 127, 17622; (b) F. Fini, V. Sgarzani, D. Pettersen, R. Herrera,
L. Bernardi, A. Ricci, Angew. Chem. Int. Ed. 2005, 44, 7975; (c) E.
GomezꢀBengoa, A. Linden, R. Lόpez, I. MúgicaꢀMendiola, M.
Oiarbide, C. Palomo, J. Am. Chem. Soc. 2008, 130, 7955; (d) G.
Kumaraswamy, A. Pitchaiah, Tetrahedron 2011, 67, 2536; (e) Y.
Wei , W. He, Y. Liu,, P. Liu , S. Zhang Org. Lett. 2012, 14 , 704.
14. A. K. Ghosh, S. LeshchenkoꢀYashchuk, D. D. Anderson, A.
Baldridge, M. Noetzel, H. B. Miller, Y. Tie, Y.ꢀF. Wang, Y. Koh, I.
T. Weber, H. Mitsuya, J. Med. Chem. 2009, 52, 3902
Notes and references
1. For selected reviews: (a) M. J. O′Donnell, Acc. Chem. Res. 2004,
37, 506; (b) B. Lygo, B. I. Andrews, Acc. Chem. Res. 2004, 37, 518;
(c) T. Ooi, K. Maruoka, Acc. Chem. Res. 2004, 37, 526; (d) T. Ooi,
K. Maruoka, Angew. Chem. Int. Ed. 2007, 46, 4222; (e) T.
Hashimoto, K. Maruoka, Chem. Rev. 2007, 107, 5656.
15. See the †ESI for a tentative transition state for the expalnation of the
stereochemical results of the reaction.
2. (a) V. Rauniyar, A. D. Lackner, G. L. Hamilton, F. D. Toste,
Science 2011, 334, 1681; (b) W.ꢀQ. Zhang, L.ꢀF. Chen, J. Yu, L.ꢀZ.
Gong, Angew. Chem. Int. Ed. 2012, 51, 4085.
This journal is © The Royal Society of Chemistry [year]Journal Name, [year], [vol], 00–00 |3