Solvent-controlled asymmetric strecker reaction: Stereoselective synthesis of α-trifluoromethylated α-amino acids

Article abstract of DOI:10.1021/ol0601186

Stereoselective approaches to α-trifluoromethylated α-amino acids (α-Tim AAs) have been developed. The stereoconfigurations of the resulting α-Tfm AA precursors were well controlled by using different solvents. The optically active (S)-2-amino-2-phenyl-1,

Full text of DOI:10.1021/ol0601186

ORGANIC
LETTERS
2006
Vol. 8, No. 7
1379-1381
Solvent-Controlled Asymmetric Strecker
Reaction: Stereoselective Synthesis of
r
-Trifluoromethylated r-Amino Acids
Hua Wang, Xiaoming Zhao, Youhua Li, and Long Lu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, PRC
lulong@mail.sioc.ac.cn
Received January 15, 2006
ABSTRACT
Stereoselective approaches to
r-trifluoromethylated
r-amino acids (r-Tfm AAs) have been developed. The stereoconfigurations of the resulting
r
-Tfm AA precursors were well controlled by using different solvents. The optically active (S)-2-amino-2-phenyl-1,1,1-trifluoropropanoic acid
was synthesized by this method.
R-Trifluoromethylated (CF3) R-amino acids (R-Tfm AAs)
have been attracting much attention in the field of biochem-
istry and pharmacology because of their unique properties.1
Several synthetic approaches of R-Tfm AAs have been
developed; however they have suffered from some drawbacks
such as, for instance, poor stereocontrol in the formation of
the stereogenic quaternary center.2 Consequently, stereose-
lective construction of the stereogenic quaternary center
under mild conditions is a desirable method.
of the products, is an efficient auxiliary group.3 The use of
N-tert-butylsulfinylimines as chiral templates is thoroughly
described in the diastereoselective synthesis of trifluoro-
methylated derivatives.4 However, there is no example
concerning the nature of the sulfoxide group as a Lewis base
that activates the Lewis acid.5 Herein, we wish to report an
example of the asymmetric Strecker reaction based on the
principles of trimethylsilyl cyanide (TMSCN), a readily
available reagent activated by the sulfoxide group in the
absence of a catalyst.
Chiral sulfinyl amide, which could coordinate with a Lewis
acid as an electronic donor and direct the stereoselectivity
Our research work began with the synthesis of the chiral
CF3-substituted (R)-N-tert-butylsulfinylketoimines (Tfm-NB-
SKIs, 1) (derived from (R)-tert-butylsulfin amide).6 The
(1) (a) Banks, R. E.; Tatlow, J. C.; Smart, B. E. Organofluorine
Chemistry: Principles and Commercial Applications; Plenum Press: New
York, 1994. (b) Sewald, N.; Burger, K. Fluorine-containing Amino Acids:
Synthesis and Properties; Wiley: Chichester, 1995.
(3) For review, see: (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc.
Chem. Res. 2002, 35, 984-995. (b) Davis, F. A.; Zhou, P.; Chen, B.-C.
Chem. Soc. ReV. 1998, 27, 13-18. (c) Ferna´ndez, I.; Khiar, N. Chem. ReV.
2003, 103, 3651-3706.
(4) (a) Prakash, J. K. S.; Mandal, M.; Olah, G. A. Angew. Chem., Int.
Ed. 2001, 40, 589-590. (b) Prakash, J. K. S.; Mandal, M. J. Am. Chem.
Soc. 2002, 124, 6538-6539. (c) Xu, W.; Dolbier, W. R., Jr. J. Org. Chem.
2005, 70, 4741-4745.
(5) (a) Gutmann, V. The Donor-Acceptor Approach to Molecular
Interactions; Plenum: New York, 1978. (b) Jensen, W. B. The Lewis Acid-
Base Concepts; Wiley: New York, 1980; pp 136-137. (c) Denmark, S.
E.; Fu, J. Chem. Commun. 2003, 2, 168-170. (d) Denmark, S. E.; Fu, J.
Chem. ReV. 2003, 103, 2763-2793.
(6) (a) Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997,
119, 9913-9914. (b) Evans, J. W.; Ellman, J. A. J. Org. Chem. 2003, 68,
9948-9957.
(2) (a) Asensio, A.; Bravo, P.; Crucianelli, M.; Farina, A.; Fustero, S.;
Soler, G. J.; Meille, V. S.; Panzeri, W.; Viani, F.; Volonterio, A.; Zanda,
M. Eur. J. Org. Chem. 2001, 1449-1458. (b) Fustereo, S.; Navorro, A.;
Pina, B.; Soler, G. J.; Bartolome, A.; Asensio, A.; Simon, A.; Bravo, P.;
Fronza, G.; Volonterio, A.; Zanda, M. Org. Lett. 2001, 3, 2621-2624. (c)
Crucianelli, M.; Bravo, P.; Arnone, A.; Corradi, E.; Meille, V. S.; Zanda,
M. J. Org. Chem. 2000, 65, 2965-2971. (d) Amii, H.; Kishikawa, Y.;
Kageyama, K.; Uneyama, K. J. Org. Chem. 2000, 65, 3404-3408. (e) Abe,
H.; Amii, H.; Uneyama, K. Org. Lett. 2001, 3, 313-315. (f) Qiu, X.; Meng,
W.; Qing, F. Tetrahedron 2004, 60, 6711-6745. (g) Ogu, K.; Matsumoto,
S.; Akazome, M.; ogura, K. Org. Lett. 2005, 7, 589-592. (h) Bravo, P.;
Viani, F.; Zanda, M.; Soloshonok, V. Gazz. Chim. Ital. 1995, 125,
149-150. (i) Bravo, P.; Capelli, S.; Meille, S. V.; Viani, F.; Zanda, M.;
Kukhar, V. P.; Soloshonok, V. A. Tetrahedron: Asymmetry 1994, 5, 2009-
2018.
10.1021/ol0601186 CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/04/2006

optimized reactions were performed in hexane distilled from
Na/benzophenone in the presence of 1.5 equiv of Ti(OiPr)4,
where Tfm-NBSKIs were obtained in 47-80% yields (Table
1). It must be pointed out that Tfm-NBSKIs have to be
The Strecker reaction in hexane was successful with a
variety of substrates, and the scope of the reaction was
outlined in Table 3. 2a-h were obtained in 69-92% yields
with good dr value. The addition of 0.2 equiv of Ti(OiPr)4
accelerated the reaction; however, this resulted in a decrease
of stereoselectivity, presumably because of the strong Ti-O
interaction that inhibits the activation of TMSCN by sul-
foxide (Table 3). An X-ray diffraction study of both 2e and
2a7 indicated that the absolute configuration of 2 was (S,
Rs). Therefore, we deduced the absolute configuration of 3
was (R, Rs).
Table 1. Preparation of the Tfm-NBSKIs
To study this Strecker reaction in DMF, 1a-h were
subjected to the optimized reaction conditions. All of them
underwent the Strecker reaction in several hours at -35 °C
and gave 2 and 3 in 69-89% yields with up to a 1:19 dr
value (Table 3).
On the basis of the diastereoselectivity observed (Table
1), a possible mechanism was proposed. The Strecker
reaction in hexane proceeds via the six-membered chairlike
models8 (T1 and T2, Scheme 1), and the chiral tert-
entry
R
product
t (h)
yielda (%)
1
2
3
4
5
6
7
8
Me-
Et-
1a
1b
1c
1d
1e
1f
3
3
12
4
4
12
8
47
61
81
56
58
50
65
80
n-C6H13
BnCH2-
Ph-
p-MePh-
p-MeOPh-
p-ClPh-
-
1g
1h
8
a Yields were determined by 19F NMR.
Scheme 1. Proposed Mechanism for Asymmetric Strecker
Reaction
generated and isolated quickly prior to use because they are
readily hydrolyzed upon prolonged standing on silica gel. 1
was not fully characterized because of the same reason.
With these compounds in hand, we investigated the
Strecker reaction of 1e with TMSCN in hexane at room
temperature. A mixture of 2e and 3e was obtained in 91%
yield and 99:1 dr (2e/3e) (Table 2, entry 1). Solvent effects
Table 2. Effect of Solvents on the Asymmetric Strecker
Reaction
butylsulfinyl group directs the configuration of T1 and T2.
As mentioned before, the sulfinyl group in Tfm-NBSKI
activates TMSCN to undergo the Strecker reaction. T1 is
unfavored because of the predominant electrostatic repulsion
between the lone pairs on the sulfur and the electron-rich
CF3 group. The six-membered transition state in hexane gives
2 (S, Rs) as the major product. However, the Strecker reaction
in DMF undertakes Fujisawa’s model9 (T3 and T4 transition
state) because DMF is not only a polar solvent but also a
Lewis base, which activates TMSCN instead of the sulfinyl
entry
solvent
hexane
dra (2e/3e)
total yieldb (%)
1
2
3
4
5
6
99:1
3:1
1:1
91
73
70
Et2O
EtOAc
1,4-dioxane
DMSO
DMF
1:3
1:6
33
86
a Diastereomeric ratios were determined by 19F NMR spectroscopy on
the crude reaction mixture. b Total yields of two analytically pure isomers.
(7) See Supporting Information. Crystallographic data for X-ray structures
have been deposited with the Cambridge Crystallographic Center [2a (CCDC
280989), 2e (CCDC 280988)]. Copies of the data can be obtained free of
charge from the Cambridge Crystallographic Data Center, 12 Union Road,
Cambridge CB2 1EZ, U.K.. E-mail: deposit@ccdc.cam.ac.uk.
(8) Hose, D. R. J.; Mahon, M. F.; Molly, K.; Raynham, C.; Wills, T. M.
J. Chem. Soc., Perkin Trans. 1 1996, 691-703.
were investigated and summarized in Table 2. Polar solvents
usually led to a decrease in the 2e/3e ratio except for 1,4-
dioxane, in which a decomposition of imine was observed.
It is noteworthy that the reaction in DMF afforded 2e and
3e in a 1:6 ratio, which is a diastereoselectivity opposite to
the reaction in hexane (Table 2, entry 6).
(9) Fujisawa, T.; Kooriyama, Y.; Shimizu, M. Tetrahedron Lett. 1996,
37, 3881-3884.
1380
Org. Lett., Vol. 8, No. 7, 2006

Table 3. Asymmetric Strecker Reaction between Tfm-NBSKIs and TMSCN in Hexane and DMF
substrate (R)
t (h)
total yielde (%)
hexane DMF
dra,b (2/3)
hexane
entry
productc
hexanef
DMFg
DMF
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
(Me-)
(Et-)
2a,d 3a
2b, 3b
2c, 3c
2d, 3d
2e,d 3e
2f, 3f
24
24
48
48
24
24
12
12
8
8
8
12
12
12
12
12
69
77
88
92
85
87
89
83
71
76
84
89
72
69
78
71
27:1 (4:1)
7:1 (3:1)
14:1 (2:1)
7:1 (7:1)
99:1 (7:1)
11:1 (1:1)
14:1 (4:1)
8:1 (1:1)
1:19
1:10
1:11
1:15
1:6
1:7
1:9
1:6
(n-C6H1-)
(BnCH2-)
(Ph-)
(p-MePh-)
(p-MeOPh-)
(p-ClPh-)
1g
1h
2g, 3g
2h, 3h
19
a Diastereomeric ratios were determined by F NMR spectroscopy of the crude reaction mixture. b In parentheses are the dr values with 20 mol % of
Ti(OiPr)4 as catalyst. c Configurations were assigned from the transition-state model. d Configurations were determined by X-ray crystallographic data. e Total
yields of two analytically pure isomers. f Hexane as the solvent at room temperature. g DMF as solvent at -35 °C.
group of Tfm-NBSKIs. T3 is more favored than T4 because
of the electrostatic repulsion between CF3 and the lone pairs
of sulfur in T4. Hence, 3 (R, Rs) is obtained as the major
product (Scheme 1).
It must be indicated that the sulfinimines without CF3
cannot proceed in such reactions under similar conditions.
The CF3 group might play an important role: (1) electrostatic
repulsion causes CF3 to be far away from the lone pairs of
the sulfur atoms; (2) the steric effect of CF3 is approximately
equivalent to isopropyl,10 and therefore an e bond is more
stable than an a bond in six-membered chairlike models; (3)
the electron-withdrawing nature of the CF3 group increases
the reactivity of sulfinimines, therefore facilitating the
Strecker reaction.
deprotection and hydrolysis of 2e in HCl (12 N) at refluxing
temperature gave the desired optically active R-CF3 R-amino
acid in one pot. (S)-2-amino-2-methyl-1,1,1-trifluoropro-
panoic acid (4b)2i was synthesized from 2a in the same way.
In summary, an effective method for the formation of
stereogenic quaternary centers via solvent-controlled asym-
metric Strecker reactions was developed. The reaction in
hexane afforded predominantly (S, Rs)-product, whereas in
DMF, the (R, Rs)-isomer was the major product. Further
deprotection and hydrolysis resulted in R-trifluoromethyl
R-amino acid. This method provided a stereoselective
approach to the optically active R-trifluoromethyl R-amino
acids
Acknowledgment. We thank the National Natural Sci-
ence Foundation of China (Grant Numbers 29825104 and
29632003) and the Chinese Academy of Science for financial
support.
To demonstrate further the synthetic utility of these
findings, (S)-2-amino-2-phenyl-1,1,1-trifluoropropanoic acid
(4a) was readily synthesized from 2e (Scheme 2). The
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org
Scheme 2. Hydrolysis and Deprotection of 2e
OL0601186
(10) Riggi, I.; Virgili, A.; Moragas, de M.; Jaime, C. J. Org. Chem. 1995,
60, 27-31.
Org. Lett., Vol. 8, No. 7, 2006
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