Novel and efficient transformation of α-amino nitrile to α-imino and α-amide nitriles in asymmetric Strecker synthesis

Article abstract of DOI:10.1016/S0040-4039(01)00551-2

Oxidation of α-amino nitrile 4 with ozone gave rise to a mixture of α-imino nitrile 5 and a novel fragmentation product of 6 in one-step. The mixture was converted to a variety of α-substituted α-amino acids 7 in high yields, which enabled the asymmetric transferring Strecker synthesis to be a widely useful method.

Full text of DOI:10.1016/S0040-4039(01)00551-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3733–3736
Novel and efficient transformation of a-amino nitrile to a-imino
and a-amide nitriles in asymmetric Strecker synthesis
Kosuke Namba, Masanori Kawasaki, Ichinori Takada, Seiji Iwama, Masashi Izumida,
Tetsuro Shinada* and Yasufumi Ohfune*
Graduate School of Science, Osaka City University, Sugimoto, Osaka 558-8585, Japan
Received 23 February 2001; revised 26 March 2001; accepted 30 March 2001
Abstract—Oxidation of a-amino nitrile 4 with ozone gave rise to a mixture of a-imino nitrile 5 and a novel fragmentation product
of 6 in one-step. The mixture was converted to a variety of a-substituted a-amino acids 7 in high yields, which enabled the
asymmetric transferring Strecker synthesis to be a widely useful method. © 2001 Elsevier Science Ltd. All rights reserved.
The Strecker synthesis is a pivotal methodology to
access proteinogenic and non-proteinogenic amino
acids. Recently, we have reported an asymmetric ver-
sion of the Strecker synthesis (asymmetric transferring
Strecker synthesis: ATS) which was successfully applied
to the synthesis of various classes of b-hydroxy-a-sub-
stituted a-amino acids in an optically active form.1 The
synthesis consists of the following sequence of transfor-
mations: (i) formation of a cyclic ketimine intermediate
active a-substituted a-amino acids with excellent stereo-
control in satisfactory overall yields. However, we
recently observed that the oxidation of sterically con-
gested a-amino nitriles such as 1, 4b, and 4e resulted in
a serious decrease in yields or did not give any a-imino
nitrile at all (c to d). These results led us to investigate
an alternative method to improve the process (iii). In
this report, we describe that ozone oxidation is an
efficient protocol for this conversion which accompa-
nied an imine and an unusual fragmentation product,
a-amide nitrile, both of which are transformed to the
corresponding amino acid in high yields.
b from a-acyloxyketone a having L- or D-amino acid as
the acyloxy group; (ii) stereoselective addition of a
cyanide ion to b to give an amino nitrile c; (iii) oxida-
tive conversion of c to an a-imino nitrile d and (iv)
removal of the chirality transferring amino acid and
hydrolysis of the nitrile group under acidic conditions
to give an amino acid e (Scheme 1). In most cases, these
transformations proceeded smoothly to give optically
The oxidation of a-amino nitrile to a-imino nitrile is
often performed by initial N-chlorination with t-BuOCl
and subsequent dehydrochlorination with Et3N
(Scheme 1). However, the latter step is very slow or
Scheme 1.
* Corresponding authors.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00551-2

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K. Namba et al. / Tetrahedron Letters 42 (2001) 3733–3736
does not proceed at all when the substrates 1, 4b and 4e
are employed. Since an external base (A) such as Et3N
could not abstract the hydrogen at C2 due mainly to
steric reasons, we postulated that a bidentate oxidant
would act as the internal base after oxidation of the
amino group (B). However, treatment of the a-amino
nitrile 1 with PhIO, PhSeCl, Me2SCl, CuBr2, etc.2
resulted in a complete recovery of 1 where the initial
oxidation step in (iii) did not proceed with these
reagents. Finally, we examined ozone known as a
strong and less bulky oxidant. The oxidation of 1 in
methanol at −78°C gave the desired a-imino nitrile 2,
which led to our successful total synthesis of man-
zacidin A (Scheme 2).3
Encouraged by this finding, structurally simple a-amino
nitrile 4a was subjected to the ozone oxidation to
optimize the reaction conditions (Table 1, entries 1–7).
Contrary to 1, the reaction afforded a mixture of
desired a-imino nitrile1a,5 and an unexpected a-amide
nitrile 6a.4 Hydrolysis of 5a and 6a with concd hydro-
chloric acid gave a-methylserine (7a) in >99% yield,
respectively. Thus, the best yield of the mixture was
obtained when ethyl acetate was used as the solvent,
and the overall yield from 4a to 7a (two-steps) was 97%
(entry 3) which was much superior to that attained in
the previous three-step conversion (87%).1a The prod-
ucts ratio was slightly affected by the solvent and
temperature: the use of CH2Cl2 afforded 5a while its
Scheme 2.
Table 1. Conversion of 4 into amino acid 7 by ozone oxidation and subsequent hydrolysis
Entry
Substrates
Conditions
Time (min)
Yield (%)
Ratio of 5:6
Yield (%) of 7 from 4
(two-steps)
1
2
3
4
5
6
4a
4a
4a
4a
4a
4a
MeOH, −78°C
MeOH, −40°C
AcOEt, −78°C
AcOEt, −40°C
AcOEt, 0°C
30
40
30
15
15
60
80
32
1:1
5:2
3:2
3:2
3:7
5:3
98 (86)a
99
97 (85)c
99
93
AcOEt, AcOH (10 equiv.),
−78°C
7
8
9
10
11
12
13
4a
4b
4c
4d
4e
4f
Dist. CH2Cl2, −78°C
AcOEt, −78°C
AcOEt, −78°C
AcOEt, −78°C
AcOEt, −78°C
AcOEt, −78°C
AcOEt, −78°C
120
120
40
30
25
80
\20:1
1:1
83 (61)a
98 (80)a
94 (55)a
93 (0)a
64 (16)a,b
73 (43)a
66 (19)c
98 (61)c
94 (52)c
90
3:2
2:1
2:1
1:1
95
25
50–60 (6)c
–
4g
1:0
a Yield (%) of imine 5 using t-BuOCl/Et3N.
b Recovery of 4f (23%).
c Yield (%) of 7 via an oxidation using t-BuOCl/Et3N.
Scheme 3.

K. Namba et al. / Tetrahedron Letters 42 (2001) 3733–3736
3735
yield decreased to 80%, and 6a was obtained as the
major product at the elevated temperature. In addition
to these experiments, the isolated imino nitrile 5a was
subjected to the ozone oxidation in ethyl acetate. The
reaction resulted in a complete recovery of starting
material 5a even at 0°C, indicating that 6a was not
produced from 5a under the conditions (Scheme 3).
From these results, we propose the following reaction
pathway to produce a mixture of 5a and 6a: (i) abstrac-
tion of the C2 hydrogen from a trioxo species f to give
an enol g; (ii) formation of the imino nitrile 5a from g
via an elimination of O2 and H2O (path A); (iii) further
oxidation of the enol g with ozone to give an epoxide h,
and (iv) carbonꢀcarbon bond cleavage to form a car-
bonate i whose work-up gave 6a (path B). The less
polar solvent would destabilize the enol g to prefer the
formation of 5a. On the other hand, oxidation of the
enol g at 0°C would proceed faster than that performed
at lower temperature.
The present method was proven to be extremely effec-
tive for the conversion of the other a-amino nitriles
4b–g (Table 2). Not only mono-cyclic amino nitrile
(entry 8) but also bi- and tri-cyclic substrates having
sterically bulky substituents (entries 9–12) gave a mix-
ture of the corresponding 5b–f and 6b–f in good to
excellent yields. The substrate 4g gave a-imino nitrile
5g, exclusively. It is noteworthy that the yields of the
mixtures including their conversion to the correspond-
ing amino acids 7b–f were dramatically improved while
previous conversions using the t-BuOCl/base system
were 0% to moderate yields.
Table 2. Structures of a-amino, a-imino, and a-amide nitriles and the corresponding amino acids

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K. Namba et al. / Tetrahedron Letters 42 (2001) 3733–3736
In summary, the problematic oxidation of a-amino
nitrile in ATS was much improved by the use of ozone.
This method is advantageous in view of its simple
operation and high yield. Furthermore, its utility was
exemplified by the conversion of the mixture into vari-
ous types of optically active b-hydroxy-a-amino acids
as well as the total synthesis of natural products pos-
sessing an amino group attached to a quaternary car-
bon center.2,6
Yamaguchi, J.; Takeda, T. Chem. Lett. 1992, 1933–1936.
PhIꢁO: (a) Larsen, J.; Jorgensen, K. A. J. Chem. Soc.,
Perkin Trans. 2 1992, 8, 1213; (b) Muller, P.; Gilabelt, D.
M. Tetrahedron 1988, 44, 7171–7175.
4. Typical experimental procedure: To a solution of a-amino
nitrile 4a (52 mg, 0.29 mmol) in AcOEt (15 mL) was
bubbled O3 (flow rate of O2:150 NL/h, which corre-
sponded to 3 g/h of O3) in a cooling bath (−78°C) for 30
min. The mixture was concentrated in vacuo. The residue
was purified by flash column chromatography on silica gel
(hexane/AcOEt=4:1) to give 5a (27 mg, 55%) and 6a (20
mg, 43%), respectively. Compound 5a: colorless crystals;
Acknowledgements
1
mp 45–46°C (Et2O–hexane); H NMR (300 MHz, CDCl3):
l 4.58 (d, J=11.7 Hz, 1H), 4.30 (d, J=11.7 Hz, 1H), 3.24
(sep, J=6.8 Hz, 1H), 1.71 (s, 3H), 1.17 (d, J=6.8 Hz, 3H),
1.15 (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): l
168.6, 153.2, 117.7, 70.4, 52.7, 32.2, 22.4, 19.3, 19.1. Anal.
calcd for C9H12N2O2: C, 59.99; H, 6.71; N, 15.55. Found:
C, 60.05; H, 6.76; N, 15.53. IR (CHCl3): 3032, 2988, 2948,
2884, 1756, 1634, 1518, 1466, 1448, 1428, 1400, 1380, 1336,
1284, 1210, 1170, 1114 cm−1; [h]D23 +69.6 (c 1.00, CHCl3).
This study was supported by a grant from the Research
for the Future Program from the Japan Society for the
Promotion of Science (JSPS). K.N. is grateful to the
JSPS for a Research Fellowship for Young Scientists.
References
1
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