Asymmetric Strecker synthesis by addition of trimethylsilyl cyanide to aldehyde SAMP-hydrazones

Article abstract of DOI:10.1016/j.tetlet.2003.09.098

The asymmetric 1,2-addition of trimethylsilyl cyanide to aldehyde SAMP-hydrazones in the presence of titanium tetrachloride and diethylether in dichloromethane at -100°C up to room temperature, removal of the chiral auxiliary and acid hydrolysis affords α-amino acids in high enantiomeric excesses (ee=94-97%).

Full text of DOI:10.1016/j.tetlet.2003.09.098

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8479–8481
Asymmetric Strecker synthesis by addition of trimethylsilyl
cyanide to aldehyde SAMP-hydrazones
Dieter Enders* and Michael Moser
Institut fu¨r Organische Chemie, Rheinisch-Westfa¨lische Technische Hochschule, Professor Pirlet-Str. 1, 52074 Aachen, Germany
Received 24 June 2003; revised 12 September 2003; accepted 12 September 2003
Abstract—The asymmetric 1,2-addition of trimethylsilyl cyanide to aldehyde SAMP-hydrazones in the presence of titanium
tetrachloride and diethylether in dichloromethane at −100°C up to room temperature, removal of the chiral auxiliary and acid
hydrolysis affords a-amino acids in high enantiomeric excesses (ee=94–97%).
© 2003 Elsevier Ltd. All rights reserved.
Efficient asymmetric syntheses of naturally occurring
and nonproteinogenic a-amino acids are of consider-
able interest because of their importance in biological
systems and their usefulness as chiral building blocks in
organic synthesis.1 Since Strecker published his report2
on the three component reaction in 1850 to synthesize
a-amino nitriles there have been strong efforts recently
to perform this reaction in an enantioselective way.
Among the stoichiometric approaches the addition of
cyanide to imines or hydrazones using chiral auxiliaries
such as phenylethylamine,3 (4S,5S)-5-amino-2,2-
dimethyl-4-phenyl-1,3-dioxane,4 a-phenylglycinol,5 1-
method and the resulting a-amino nitriles were then
converted into a-amino acids by acidic hydrolysis.
As is depicted in Scheme 1, the SAMP-hydrazones 1
were synthesized from the corresponding aldehydes and
SAMP by condensation.10 Their reaction with TMSCN
in the presence of titanium tetrachloride as Lewis acid
to activate the CꢁN bond proceeded at −100°C up to
room temperature for 12 h in dichloromethane. The
strong influence of the solvent used in cyano additions
to the CꢁN double bond has already been described by
Kunz et al.6 Also under our conditions it was found
that the diastereofacial selectivity in the Strecker syn-
amino-tetra-O-pivaloyl-b-
D
-galacto-pyranose,6
sulfi-
nates7
and
(S)-1-amino-2-methoxymethyl-indoline
(SAMI)8 has already been investigated. However, in the
case of using enantiopure hydrazones as starting mate-
rial in the Strecker synthesis the cleavage of the NꢀN
bond of the created a-hydrazino nitriles to obtain a-
amino nitriles9 was unsuccessful so far.
In this paper we report the diastereoselective addition
of trimethylsilyl cyanide (TMSCN) to (S)-1-amino-2-
methoxymethyl-pyrrolidine (SAMP) aldehyde hydra-
zones in the presence of titanium tetrachloride and
diethylether to obtain a-hydrazino nitriles in high yields
and diastereo-selectivities. The NꢀN bond of the a-
hydrazino nitriles was cleaved with an oxidative
Scheme 1. Reagents and conditions: (a) TiCl4 (2 equiv.),
TMSCN (3 equiv.), diethylether (4.2 equiv.), CH2Cl2, −100°C
to rt, 12 h; (b) MocCl (10 equiv.), K2CO3 (20 equiv.), CH2Cl2,
reflux, 7 h; (c) MMPP (9 equiv.), methanol, rt, 1 week; (d) 6
M HCl, H2O, reflux, 7 h.
Keywords: asymmetric synthesis; a-amino acids; a-amino nitriles;
hydrazones; 1,2-addition.
* Corresponding author. Tel.: +49-241-8094676; fax: +49-241-
8092127; e-mail: enders@rwth-aachen.de
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.098

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D. Enders, M. Moser / Tetrahedron Letters 44 (2003) 8479–8481
Table 1. Enantioselective synthesis of a-amino acids 5
2–5
R
Yield 2 (%)a
de 2 (%)b
Yield 3 (%)a
Yield 4 (%)a
Yield 5 (%)a
ee 5 (%)c
a
b
c
d
e
Et
85
90
75
91
93
91
88
90
90
90
93
94
91
90
92
78
74
38
50
59
60
60
85
81
98
97
95
96
94
96
n-Pr
i-Pr
i-Bu
Bn
a Determined after column chromatography.
b Determined by 13C NMR.
c Determined by Mosher amides.
thesis can be reversed by changing the solvent from
dichloromethane to diethylether.
Williams, R. M. Synthesis of Optically Active h-Amino
Acids; Pergamon Press: Exeter, 1989; (c) Duthaler, O. R.
Tetrahedron 1994, 50, 1539.
Interestingly, the diastereoselectivity of the reaction in
dichloromethane increases from 60% up to 91% de in
the presence of a small amount of diethylether. Under
these conditions the (S,S)-diastereomers of the a-hydra-
zino nitriles 2 are formed in excess. The de values could
be improved by column chromatography (Table 1).
2. Strecker, A. Liebigs. Ann. Chem. 1850, 75, 27.
3. (a) Harada, K. Nature (London) 1963, 200, 1201; (b)
Harada, K.; Fox, S. W. Naturwissenschaften 1964, 51,
106; (c) Patel, M. S.; Worsley, M. Can. J. Chem. 1970, 48,
1881; (d) Harada, K.; Okawara, T. J. Org. Chem. 1973,
38, 707; (e) Ojima, I.; Inaba, S. Chem. Lett. 1975, 737; (f)
Weinges, K.; Gries, K.; Stemmle, B.; Schrank, W. Chem.
Ber. 1977, 110, 2098.
4. (a) Weinges, K.; Brune, G.; Droste, H. Liebigs Ann.
Chem. 1980, 212; (b) Weinges, K.; Brachmann, H.; Stah-
necker, P.; Rodewald, H.; Nixdorf, M.; Irngartinger, H.
Liebigs Ann. Chem. 1985, 566.
To remove the chiral auxiliary reductive methods are
useless because of the presence of the cyano group.
Therefore, we decided to use magnesium monoperoxy
phthalate (MMPP) as an oxidative cleavage reagent.11
It is necessary to activate the NꢀN bond by adding
methoxycarbonyl chloride (MocCl) to the hydrazines
(S,S)-2. Thus, the protected a-hydrazino nitriles (S,S)-3
were obtained by treatment of the hydrazines (S,S)-2
with 10.0 equiv. MocCl and 20 equiv. potassium car-
bonate in dichloromethane for 7 h under reflux. The
formation of the protected a-amino nitriles (S)-4 under
oxidative NꢀN bond cleavage was achieved by treat-
ment of the protected a-hydrazino nitriles (S,S)-3 with
9.0 equiv. MMPP for 1 week in methanol. The prod-
ucts (S)-4 were hydrolyzed with concurrent removal of
the Moc protecting group with 6 M HCl under reflux
for 7 h. The enantiomeric excesses of the a-amino acids
(S)-5 were detected via the (R)-(+)-MTPA amides as
described by Mosher (Table 1).12
5. Chakraborty, T. K.; Hussain, K. A.; Reddy, G. V. Tetra-
hedron 1995, 51, 9179.
6. (a) Kunz, H.; Sager, W. Angew. Chem. 1987, 99, 595;
Angew. Chem., Int. Ed. 1987, 26, 557; (b) Kunz, H.;
Sager, W.; Pfrengle, W.; Schanzenbach, D. Tetrahedron
Lett. 1988, 29, 4397; (c) Kunz, H.; Pfrengle, W. J. Am.
Chem. Soc. 1988, 110, 651.
7. (a) Davis, F. A.; Reddy, R. E.; Portonovo, P. S. Tetra-
hedron Lett. 1994, 35, 9351; (b) Davis, F. A.; Portonovo,
P. S.; Reddy, R. E.; Chiu, Y. J. Org. Chem. 1996, 61, 440.
8. Choi, J. Y.; Kim, Y. H. Tetrahedron Lett. 1996, 37, 7795.
9. For a review see: Enders, D.; Shilvock, J. P. Chem. Soc.
Rev. 2000, 29, 359.
10. (a) Enders, D.; Eichenauer, H. Chem. Ber. 1979, 112,
2933; (b) Review: Job, A.; Janeck, C. F.; Bettray, W.;
Peters, R.; Enders, D. Tetrahedron 2002, 58, 2253.
11. (a) Ferna´ndez, R.; Ferrete, A.; Lassaletta, J. M., Llera, J.
M.; Monge, A. Angew. Chem. 2000, 112, 3015; Angew.
Chem., Int. Ed. 2000, 39, 2893; (b) Enders, D.; Braig, V.;
Raabe, G. Can. J. Chem. 2001, 79, 1528.
In summary, the asymmetric Strecker synthesis of a-
amino acids (S)-5 was achieved in overall yields of
22–50% for the four steps and high enantiomeric
excesses (ee=94–97%) employing aldehyde SAMP-
hydrazones as electrophiles. Key to the success was the
first NꢀN bond cleavage of the intermediate a-hydra-
zino nitriles to remove the chiral auxiliary.13–15
12. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem.
1969, 34, 2543.
13. General procedure for the preparation of compounds
(S,S)-2 and (S)-4.
Acknowledgements
Synthesis of a-hydrazino nitriles (S,S)-2: 2.0 equiv. 1.0 M
TiCl4 solution in CH2Cl2 were treated with 1.0 equiv.
hydrazone (S)-1 in abs. CH2Cl2 (5 mL/mmol (S,S)-2) at
−78°C and stirred for 15 min. 4.2 equiv. diethylether were
added and after 15 min the mixture was cooled to −
100°C. 1.5 equiv. TMSCN were added rapidly and the
solution was stirred overnight while it was allowed to
warm up to room temperature. Upon aqueous work up
(aq. NH4F, CH2Cl2, MgSO4) the a-hydrazino nitriles
(S,S)-2 were purified by column chromatography (SiO2,
n-pentane/diethylether).
This work was supported by the Fonds der Chemischen
Industrie. We thank Degussa AG, BASF AG and
Bayer AG for the donation of chemicals.
References
1. (a) Barrett, G. C. Chemistry and Biochemistry of the
Amino Acids; Chapman and Hall: London, 1985; (b)

D. Enders, M. Moser / Tetrahedron Letters 44 (2003) 8479–8481
8481
Synthesis of Moc-protected a-amino nitriles (S)-4: Moc-
protected a-hydrazino nitriles (S,S)-3 were dissolved in
methanol (20 mL/mmol (S,S)-3). 3.0 equiv. MMPP were
added and the mixture was stirred 1 week at room
temperature while it was added every day 1.0 equiv.
MMPP. Upon aqueous work up (aq. NaHCO3, CH2Cl2,
MgSO4) the a-amino nitriles (S)-4 were purified by
column chromatography (SiO2, n-pentane/diethylether).
14. Selected analytical and spectroscopic data of compounds
(S,S)-2c and (S)-4c.
130, 129, 97, 85, 84, 71, 70, 61, 55, 82, 45; IR (film): 3581,
3298, 2965, 2876, 2831, 2391, 2243, 1640, 1466, 1390,
1372, 1355, 1302, 1254, 1193, 1099, 1001, 971, 917, 879,
818, 632, 589, 527 cm−1; HRMS: C11H21N3O: calcd
211.1685; found 211.1684.
(S)-4c: 1H NMR (400 MHz, CDCl3): l=1.08/1.11 (2d,
J=6.9/6.9 Hz, 6H, CH(CH3)2), 2.06 (m, 1H, CH(CH3)2),
3.73 (s, 3H, OCH3), 4.49 (m, 1H, CHCN), 5.74 (d, J=7.4
Hz, 1H, NH); 13C NMR (100 MHz, CDCl3): l=18.0,
18.6, 31.8, 49.1, 52.9, 118.0, 156.3; MS (EI): m/z=156,
115, 114, 99, 82, 74, 61, 59, 55, 54, 45; IR (film): 3324,
2969, 2880, 2245, 1712, 1530, 1467, 1393, 1373, 1336,
1271, 1197, 1150, 1099, 1038, 983, 953, 887, 841, 814, 781,
716, 617, 479 cm−1; HRMS: C11H21N3O: calcd 156.0899;
found 156.0898.
(S,S)-2c: 1H NMR (400 MHz, CDCl3): l=1.07 (d, J=
6.9 Hz, 6H, CH(CH3)2), 1.51 (m, 1H, NCHCHHCH2),
1.72–2.03 (m, 4H, NCHCHHCH2, NCHCH2CH2,
CH(CH3)2), 2.36 (q, J=8.9 Hz, 1H, NCHH), 2.74 (m,
1H, NCHCH2CH2), 3.32–3.62 (m, 5H, CH2O, NCHH,
CHCN, NH), 3.38 (s, 3H, OCH3); 13C NMR (100 MHz,
CDCl3): l=17.8, 19.5, 20.9, 25.7, 29.8, 56.5, 58.8, 58.8,
64.6, 75.6, 119.9; MS (EI): m/z=211, 167, 166, 164, 139,
15. All new compounds showed characteristic spectroscopic
data (NMR, MS, IR) and correct HRMS or elemental
analyses.