Catalytic enantioselective desymmetrization of meso-N-acylaziridines with TMSCN

Article abstract of DOI:10.1021/ja053486y

A catalytic enantioselective desymmetrization of meso-N-p-nitrobenzoylaziridines with TMSCN was developed using a chiral gadolinium catalyst generated from Gd(OⁱPr)₃ and d-glucose-derived ligand 1. In this reaction, the addition of a

Full text of DOI:10.1021/ja053486y

Published on Web 07/23/2005
Catalytic Enantioselective Desymmetrization of meso-N-Acylaziridines with
TMSCN
Tsuyoshi Mita, Ikuo Fujimori, Reiko Wada, Jianfeng Wen, Motomu Kanai,* and
Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Tokyo 113-0033, Japan
Received May 28, 2005; E-mail: mshibasa@mol.f.u-tokyo.ac.jp
Table 1. Optimization of Reaction Conditions
Chiral â-amino acids are important building blocks for natural
products and pharmaceuticals.1 Among them, chiral cyclic â-amino
acids are currently of great interest due to the recent finding that
peptides composed of these amino acids can act as foldamers with
a well-defined secondary structure.2 Despite the emerging impor-
tance, there are few enantioselective synthetic methods that produce
chiral cyclic â-amino acids.3 Specifically, there is no method
available using an artificial enantioselective catalyst to access these
compounds.4 Here, we describe the first such method based on the
catalytic enantioselective desymmetrization of meso-aziridines by
cyanide.
Catalytic enantioselective ring-opening of meso-aziridines with
carbon nucleophiles is a formidable challenge due to both the low
reactivity of aziridines and the general difficulty in differentiation
of enantiotopic centers.5 The only example that begins to address
these difficulties is a dimeric copper-catalyzed aziridine opening
with MeMgBr.6 Although enantioselectivity was excellent (91%
ee) using 30 mol % of catalyst (i.e., 60 mol % of Cu), this reaction
was applied to only one substrate, and the catalyst turned over less
than twice (52% yield). A more sophisticated example in catalytic
desymmetrization of aziridines was reported by Jacobsen using
TMSN3 as a nucleophile.7,8 Regarding the nucleophile, TMSCN is
currently the only carbon nucleophile that can be used for catalytic
enantioselective desymmetrization reactions (epoxide opening).9
Importantly, those reactions appear to be promoted via dual
activation of an electrophile and a nucleophile by bifunctional
asymmetric catalysts.10
entry
R
additives
time (h)
yield (%)a
ee (%)b
1c
2
3
Ts
48
48
48
5
3
2
26
3
20
43
58
63
18
24
16
31d
72
80
83
83
83
87
86
p-Ns
Boc
4
p-NO2-Bz
p-NO2-Bz
p-NO2-Bz
p-NO2-Bz
p-NO2-Bz
p-NO2-Bz
p-NO2-Bz
90
5e
DMPf
>99
>99
67
96
94
6e
DMPf + TFAg
DMPf + TFAh
TFAg
7e
8e
9e,i
10e,i
DMPf + TFAg
TFAg
92
a Isolated yield. b Determined by chiral HPLC. c Toluene was used as
solvent. d Determined by chiral GC. e TMSCN (3 equiv) was used. f DMP
(1 equiv) was used. g TFA (5 mol %) was used. h TFA (10 mol %) was
used. i Temperature ) 0 °C.
in low to moderate yield with low enantioselectivity (entries 1-3).
When N-p-nitrobenzoyl aziridine was used, the reaction was
completed within 5 h with a significantly improved enantioselec-
tivity of 72% ee (entry 4). Similar to the finding in the catalytic
enantioselective Strecker reaction,11c enantioselectivity was further
improved in the presence of 2,6-dimethylphenol (DMP, entry 5).13
Other benzoyl derivatives gave comparable or less satisfactory
results.14
To further improve the enantioselectivity, we next investigated
the effects of additional strong acids aimed at the enhancement of
the Lewis acidity of the Gd through conjugation to an acid (see
complex 5). Among the acids screened, the addition of 5 mol %
(half the amount of Gd) of TFA (trifluoroacetic acid) improved
enantioselectivity to 83% ee (Table 1, entry 6).14 Although the
improvement was not large, higher enantiomeric excess was
generally and reproducibly obtained in the presence of TFA.15
Catalyst activity decreased dramatically when more TFA was used
(entry 7). Interestingly, high enantioselectivity was produced even
in the absence of DMP if 5 mol % of TFA was present (entry 4 vs
8). In this case, however, the reaction rate was retarded (entry 6 vs
8, 9 vs 10). Finally, the optimum enantioselectivity (87% ee) was
produced when the reaction was conducted at 0 °C in the presence
of 5 mol % of TFA and 1 equiv of DMP (entry 9).
The optimized reaction conditions were applied to substrates with
different ring size and acyclic aziridines (Table 2). Although the
reaction temperature was dependent on the substrates, high enan-
tioselectivity was generally obtained from a wide range of aziridines.
The products were crystalline, and enantiomerically pure materials
were obtained through recrystallization (entries 1, 4, and 5). Thus,
this is the first example of catalytic enantioselective desymmetri-
We developed several catalytic enantioselective cyanation reac-
tions using Gd complexes derived from ligand 1.11 The active
catalyst structure was proposed as a 2:3 complex of Gd and 1 (2;
catalyst for Strecker reaction of ketoimines11c and conjugate addition
of cyanide11d). These catalysts are thought to promote the reactions
through a dual activation mechanism: one Gd atom acts as a Lewis
acid to activate an electrophile, while the other Gd generates a
reactive nucleophile via transmetalation. This mechanism and high
cyanation activity of the catalyst prompted us to investigate an
enantioselective meso-aziridine opening with TMSCN.
We initially screened substituents on the nitrogen atom using
cyclohexene-derived aziridines as substrates, TMSCN as the
nucleophile, and the Gd complex (10 mol %) as the catalyst (Table
1).12 When N-benzyl and N-phosphinoyl aziridines were used, the
ring-opening reaction did not proceed. On the other hand, N-sulfonyl
aziridines and N-Boc aziridine produced the corresponding adducts
9
11252
J. AM. CHEM. SOC. 2005, 127, 11252-11253
10.1021/ja053486y CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Catalytic Enantioselective Desymmetrization of
meso-p-Nitrobenzoylaziridines with TMSCN
Figure 1. Proposed catalyst structure in the presence of TFA.
TFA-incorporated chiral Gd complex derived from 1. The products
can be efficiently transformed into chiral â-amino acids. This
contribution provides a new strategy for the construction of this
important group of chiral amino acids.
Acknowledgment. Financial support was provided by a Grant-
in-Aid for Specially Promoted Research of MEXT. We thank Mr.
Ryo Takita for assistance with ESI-MS studies.
Supporting Information Available: Experimental procedures and
characterization of the products. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
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Seebach, D. Eur. J. Org. Chem. 2000, 1. (c) Fu¨lo¨p, F, Chem ReV. 2001,
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(3) Diastereoselective reactions using chiral amine derivatives are the main
method. For selected examples, see: (a) Enders, D.; Wiedemann, J.;
Bettray, W. Synlett 1995, 369. (b) LePlae, P. R.; Umezawa, N.; Lee, H.-
S.; Gellman, S. H. J. Org. Chem. 2001, 66, 5629.
(4) For enzymatic synthesis, see: Kanerva, L. T.; Csomo´s, P.; Sundholm,
O.; Berna´th, G.; Fu¨lo¨p, F. Tetrahedron: Asymmetry 1996, 7, 1705.
(5) Jacobsen, E. N.; Wu, M. H. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag:
Heidelberg, 1999; Vol. III, Chapter 35.
a Isolated yield. b Determined by chiral HPLC. c After recrystallization.
Recrystallization yield and its ee are shown in parentheses. d Absolute
configuration was determined to be (1S,2S). e With 20 mol % of Gd(OiPr)3
and 40 mol % of 1. f TFA (2.5 mol %) was used. g CH3CH2CN/CH2Cl2 )
1/2 was used as solvent. h Absolute configuration was determined to be
1
(2S,3S). i Ratio of diastereomers determined by H NMR analysis.
Scheme 1. Typical Conversion to Chiral â-Amino Acids
(6) Muller, P.; Nury, P. Org. Lett. 1999, 1, 439.
(7) Li, Z.; Ferna´ndez, M.; Jacobsen, E. N. Org. Lett. 1999, 1, 1611.
(8) For other catalytic enantioselective desymmetrizations of aziridines, see:
(a) Zhang, Z. D.; Scheffold, R. HelV. Chim. Acta 1993, 76, 2602. (b)
Hayashi, M.; Ono, K.; Hoshimi, H.; Oguni, N. J. Chem. Soc., Chem.
Commun. 1994, 2699.
(9) (a) Cole, B. M.; Shimizu, K. D.; Krueger, C. A.; Harrity, J. P. A.; Snapper,
M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. Engl. 1996, 35, 1668. (b)
Shimizu, K. D.; Cole, B. M.; Krueger, C. A.; Kuntz, K. W.; Snapper, M.
L.; Hoveyda, A. H. Angew. Chem., Int. Ed. Engl. 1997, 36, 1704. (c)
Schaus, S. E.; Jacobsen, E. N. Org. Lett. 2000, 2, 1001.
zation of meso-aziridines with TMSCN that produces synthetically
useful catalyst activity and enantioselectivity. The resulting â-amino
nitriles were easily converted to the corresponding â-amino acids
via acid hydrolysis and purification through ion exchange chro-
matography (Scheme 1).14
(10) (a) Rowlands, G. J. Tetrahedron 2001, 57, 1865. (b) Kanai, M.; Kato,
N.; Ichikawa, E.; Shibasaki, M. Synlett 2005, 1491.
(11) (a) Yabu, K.; Masumoto, S.; Yamasaki, S.; Hamashima, Y.; Kanai, M.;
Du, W.; Curran, D. P.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 9908.
(b) Masumoto, S.; Usuda, H.; Suzuki, M.; Kanai, M.; Shibasaki, M. J.
Am. Chem. Soc. 2003, 125, 5634. (c) Kato, N.; Suzuki, M.; Kanai, M.;
Shibasaki, M. Tetrahedron Lett. 2004, 45, 3147. (d) Mita, T.; Sasaki, K.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 514.
(12) Other lanthanide metals gave less satisfactory results than Gd. In all entries,
the isomeric isonitriles were produced in less than detectable amounts.
(13) Addition of HCN instead of DMP produced less satisfactory results (89%
yield, 74% ee).
To obtain insight into the origin of the beneficial additive TFA
effect, catalyst composition was investigated using ESI-MS (Figure
1).14 It was previously proposed that a 2:3 complex 2 is the active
catalyst in the presence of excess TMSCN and DMP.11c The
addition of 0.5 equiv of TFA to Gd generated a new 2:3 complex
5 possessing TFA (observed MW ) 1949, calcd for [M - CN]+
) 1949).16 This incorporated TFA might bridge the two Gd atoms17
of the catalyst, thus stabilizing the enantioselective 2:3 complex.
In addition, enhancement of the Lewis acidity of Gd as well as
fine-tuning of the relative positions of the two Gd atoms might
also contribute to the improved enantioselectivity. Detailed structural
studies of the catalyst are ongoing.
(14) See Supporting Information for details.
(15) For example, 4d and 4h were obtained with 78 and 82% ee in the absence
of TFA (82 and 85% ee in the presence of TFA; see Table 2).
(16) The same MS peak was observed in the absence of DMP, which was
consistent with the experimental results that DMP did not change the
enantioselectivity.
(17) For example, see: Yang, X.; Jones, R. A. J. Am. Chem. Soc. 2005, 127,
7686.
In conclusion, we developed an enantioselective desymmetriza-
tion reaction of meso-aziridines with TMSCN catalyzed by a new
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