Axially chiral dicarboxylic acid-catalyzed asymmetric imino aza-enamine reaction/oxidation as a Strecker reaction surrogate

Article abstract of DOI:10.1016/j.tetasy.2010.04.067

Axially chiral dicarboxylic acid-catalyzed highly enantioselective imino aza-enamine reaction was elaborated into a surrogate of the asymmetric Strecker reaction building on the fact that the N,N-dialkylhydrazone moiety can be easily converted to the cyanide moiety by treatment with peracid.

Full text of DOI:10.1016/j.tetasy.2010.04.067

Tetrahedron: Asymmetry 21 (2010) 1187–1188
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Axially chiral dicarboxylic acid-catalyzed asymmetric imino aza-enamine
reaction/oxidation as a Strecker reaction surrogate
*
Takuya Hashimoto, Hidenori Kimura, Keiji Maruoka
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Axially chiral dicarboxylic acid-catalyzed highly enantioselective imino aza-enamine reaction was elab-
orated into a surrogate of the asymmetric Strecker reaction building on the fact that the N,N-dialkylhyd-
razone moiety can be easily converted to the cyanide moiety by treatment with peracid.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 10 March 2010
Accepted 19 April 2010
Available online 22 June 2010
Dedicated to Professor Henri Kagan
on the occasion of his 80th birthday
1. Introduction
preparation of the Strecker-type products without resorting to
the use of highly toxic cyanide sources.
The asymmetric Strecker reaction of aldimines has become one
of the most ideal tools to provide synthetically important natural
R2
R2
Strecker reaction
HN
R1
and unnatural chiral
a-amino acids, owing to the sophistication
N
+
of metal- and organocatalysts.1 However, Strecker reactions funda-
mentally rely on the use of toxic cyanide sources, such as TMSCN,
HCN, and KCN, all of which are hazardous and must be handled
with care.
CN
R1
CN
one-pot
oxidation
R2
The chiral Brønsted acid-catalyzed asymmetric imino aza-
enamine reaction using formaldehyde N,N-dialkylhydrazone as a
nucleophile was recently introduced as an attractive means to pro-
vide Strecker-type products. In the pioneering report, Dixon and
Tillman revealed that the use of BINOL derivative as a chiral
Brønsted acid catalyst facilitates the imino aza-enamine reaction
imino aza-enamine
R
reaction
R2
N
HN
R1
N
N
R
+
N
R
N
R
R1
to give chiral
a-amino N,N-dialkylhydrazones with moderate
enantioselectivities.2 As the oxidative transformation of the N,N-
dialkylhydrazone moiety is known to generate a cyanide moiety,
they also demonstrated the conversion of the isolated adduct to
2. Results and discussion
the corresponding
magnesium monoperoxyphthalate (MMPP) as an oxidant. How-
ever, due to the modest level of enantioselectivities attained in
their catalytic system, the enantiomeric purity of thus a-amino ni-
a-amino nitrile (Strecker-type product) using
According to our previous study, the reaction of benzaldehyde
N-Boc imine and formaldehyde N,N-dialkylhydrazone 2 was con-
ducted by using axially chiral dicarboxylic acid (R)-1 in CHCl3 at
ꢀ20 °C (Table 1, entry 1). Molecular sieves were added to scavenge
adventitious water which deteriorates the yields by hydrolysis
of the N-Boc imines. After completion of the initial imino aza-
enamine reaction, the reaction solution was treated directly with
m-chloroperbenzoic acid (mCPBA) and stirred for an additional
30 min. mCPBA was selected as a suitable oxidant because of its
high solubility in CHCl3. As such, the desired Strecker-type product
3a could be obtained in 81% yield with 96% ee (entry 1). The scope
of this one-pot procedure was then examined by using other aryl-
aldehyde N-Boc imines. Use of N-Boc imines bearing electron-
withdrawing and electron-donating groups was tolerated giving
the Strecker-type products with excellent enantioselectivities
trile obtained remained at an unpractical level (52% ee).
Recently, we succeeded in developing a highly enantioselective
imino aza-enamine reaction of formaldehyde and arylaldehyde
N,N-dialkylhydrazones with N-Boc imines3 by the use of axially
chiral dicarboxylic acid ((R)-1 in Table 1) originally designed in this
group.4 With this efficient catalytic system in hand, we set out to
examine the one-pot sequential asymmetric imino aza-enamine
reaction/oxidation which would provide a practical tool for the
* Corresponding author. Tel./fax: +81 75 753 4041.
E-mail address: maruoka@kuchem.kyoto-u.ac.jp (K. Maruoka).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.067

1188
T. Hashimoto et al. / Tetrahedron: Asymmetry 21 (2010) 1187–1188
Table 1
formation of the Strecker-type product 3a in 83% yield without
any detrimental effect on the enantioselectivity.
One-pot axially chiral dicarboxylic acid-catalyzed asymmetric imino aza-enamine
reaction/oxidationa
3. Conclusion
Boc
CN
Boc
N
(R)-1 (5 mol%) mCPBA (2 equiv)
N
HN
R1
N
+
In conclusion, we have succeeded in demonstrating the poten-
tial of the asymmetric imino aza-enamine reaction as an alterna-
tive of asymmetric Strecker reaction. The synthetic method
provided herein offered an access to the highly enantioselective
Strecker-type products having a N-Boc-protecting group. More-
over, the catalyst loading could be reduced to 0.1 mol % without
affecting the enantioselectivity.
R1
CHCl3, MS4Å –20 ºC, 30 min
–20 ºC, 4 h
2
3a~f
Ar
Me
tBu
CO2H
CO2H
Ar =
(R)-1
Me
Acknowledgment
Ar
This work was partially supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan.
Entry
R1
% Yieldb
% eec
1
2
3
4
5
6
Ph 3a
4-ClC6H4 3b
4-MeOC6H4 3c
2-Np 3d
3-MeC6H4 3e
2-Furyl 3f
81
61
70
85
78
88
96
97
94
96
96
92
References and notes
1. For reviews, see: (a) Gröger, H. Chem. Rev. 2003, 103, 2795; (b) Merino, P.;
Marqués-López, E.; Tejero, T.; Herrera, R. P. Tetrahedron 2009, 65, 1219.
2. (a) Dixon, D. J.; Tillman, A. L. Synlett 2005, 2635; (b) Rueping, M.; Sugiono, E.;
Theissmann, T.; Kuenkel, A.; Kockritz, A.; Pews-Davtyan, A.; Nemati, N.; Beller,
M. Org. Lett. 2007, 9, 1065.
3. Hashimoto, T.; Hirose, M.; Maruoka, K. J. Am. Chem. Soc. 2008, 130, 7556.
4. (a) Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2007, 129, 10054; (b)
Hashimoto, T.; Maruoka, K. Synthesis 2008, 3703; (c) Hashimoto, T.; Uchiyama,
N.; Maruoka, K. J. Am. Chem. Soc. 2008, 130, 14380.
a
Reactions were performed with arylaldehyde N-Boc imine (0.10 mmol) and
formaldehyde N,N-dialkylhydrazone 2 (0.12 mmol) in the presence of 5 mol % (R)-1
(0.005 mmol) for 4 h. mCPBA (0.20 mmol) was then added.
b
Isolated yield.
Determined by chiral HPLC analysis.
c
5. General procedure for the one-pot asymmetric imino aza-enamine reaction/
oxidation sequence. The reaction flask containing powdered molecular sieves
4 Å (50 mg) was flame dried under vacuum. To the flask were added (R)-1
(0.005 mmol), N-Boc imine (0.10 mmol), and chloroform (1.0 mL) and the
solution was cooled to ꢀ20 °C. To the mixture was then added formaldehyde
N,N-dialkylhydrazone 2 (0.12 mmol) and the reaction mixture was stirred for
4 h at ꢀ20 °C. To the mixture was then added m-chloroperbenzoic acid
(0.2 mmol) and the reaction mixture was stirred for additional 30 min at
ꢀ20 °C. The mixture was treated with saturated NaHCO3 and extracted with
CH2Cl2. The combined organic layer was dried over Na2SO4 and concentrated.
The residue was then purified by column chromatography on silica gel (eluting
with hexane/ethyl acetate = 6:1) to give the Strecker-type product.
i) (R)-1 (0.1 mol%)
CHCl3, MS4Å
Boc
Boc
CN
N
N
HN
Ph
N
–20 ºC, 5 days
+
Ph
(2.0 mmol)
ii) mCPBA (2 equiv)
2 (1.05 eq)
3a 83% yield
–20 ºC, 1 h
96% ee
Scheme 1. One-pot asymmetric imino aza-enamine reaction/oxidation at low
catalyst loading.
6. Data for compound 3d is as follows: white solid; 1H NMR (400 MHz, CDCl3) d
7.99 (1H, br), 7.82–7.92 (3H, m), 7.51–7.57 (2H, m), 7.49 (1H, dd, J = 8.6, 1.7 Hz),
5.95 (1H, br s), 5.21 (1H, br s), 1.50 (9H, s); 13C NMR (100 MHz, CDCl3) d 154.2,
133.4, 133.0, 130.6, 129.5, 128.2, 127.7, 127.2, 127.0, 126.3, 123.9, 117.7, 81.7,
(entries 2 and 3). The reaction system could also be applied to N-
Boc imines having a fused aromatic ring, a different substituent
pattern, and a hetero-aromatic ring as well (entries 4–6).5–7
The successful implementation of the one-pot procedure
prompted us to further improve the synthetic practicality by
decreasing the catalyst loading to 0.1 mol % (Scheme 1). Although
the prolonged reaction time was required, the reaction led to the
46.3, 28.2; IR (neat) 3333, 1686, 1514, 1369, 1313, 1247, 1159, 1051 cmꢀ1
;
HRMS (ESI) exact mass calcd for C17H18N2O2: m/z 305.1260 ([M+Na]+), found: m/
z 305.1247 ([M+Na]+); ½a D18
¼ ꢀ13:5 (c 1.0, CHCl3).
ꢁ
7. Determination of the absolute configuration: 3a was treated with 6 N HCl at
reflux for 20 h. Removal of water afforded the crude material of (R)-
phenylglycine hydrochloride as a white solid {½a D18
¼ ꢀ94:2 (c 1.0, 1 M HCl)}.
ꢁ
The specific rotation was compared with the commercial sample of (R)-
phenylglycine {½a D18
¼ ꢀ149:3 (c 1.0, 1 M HCl)}.
ꢁ