A facile stereospecific synthesis of α-hydrazino esters

Article abstract of DOI:10.1016/S0040-4039(02)00352-0

A convenient route to make α-hydrazino esters from their corresponding α-amino esters is reported. A key step is selective nitrosamine reduction using activated Zn, conc. HCl, and methanol at low temperatures giving nearly quantitative yields of the pure α-hydrazino esters.

Full text of DOI:10.1016/S0040-4039(02)00352-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2873–2875
A facile stereospecific synthesis of a-hydrazino esters
Umut Oguz, Garett G. Guilbeau and Mark L. McLaughlin*
Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803, USA
Received 7 January 2002; revised 5 February 2002; accepted 6 February 2002
Abstract—A convenient route to make a-hydrazino esters from their corresponding a-amino esters is reported. A key step is
selective nitrosamine reduction using activated Zn, conc. HCl, and methanol at low temperatures giving nearly quantitative yields
of the pure a-hydrazino esters © 2002 Elsevier Science Ltd. All rights reserved.
dure.10–13 The benzyl protected amino acids 3 are then
There has been significant interest in the design and
nitrosated with tert-butylnitrite in quantitative yields14
and reduced using zinc/HCl at –78°C to generate the
pure a-hydrazino esters 5.17
synthesis of a-hydrazino carboxylic acids for incorpora-
tion into peptides due to the structural effects and
biological activity of the derived peptidomimetics. The
a-hydrazino carboxylic acids can be used as inhibitors
for various amino acid metabolizing enzymes.1 In addi-
tion, the a-hydrazino carboxylic acids are known to
possess antibiotic activities.2 Also, the a-hydrazino car-
boxylic acid containing peptidomimetics are metaboli-
cally stabilized compared to the natural peptides of
similar structure.3
The yield of the imines 2 increases when excess benz-
aldehyde is used and removal of excess benzaldehyde is
not necessary since it does not affect the yield in the
reduction step using excess sodium borohydride; the
overall yield is 90–95%. The imines have a distinctive
benzylidene proton signal, a singlet around 8 ppm in
1
the H NMR, which disappears after the reduction and
Several methods have been reported for the preparation
of a-hydrazino carboxylic acids, most of which involve
expensive reagents, laborious methods, or harsh reac-
tion conditions. Previously reported methods for the
syntheses of these compounds are; electrophilic amina-
tions with oxaziridines,4 rearrangement of hydantoic
acids,1c,5 nucleophilic substitution reactions of a-halo
carboxylic acids6 or 2-nosyloxy esters with hydrazine
derivatives,7 or electrophilic C-amination of chiral eno-
lates by dialkyl azodicarboxylates.8
gives a diastereotopic set of doublets around 3.6 and
3.8 ppm. The b-branched amino acids, Val- and Ile-,
strongly favor the trans imine. Leu- and Phe- also favor
trans imine, but Met- gives almost equal amounts of cis
and trans isomers. Met- has a complex 1H and 13C
NMR due to the overlap of chemical shifts of the two
isomers of the imine, giving sets of multiplets. The
methyl protons of -SꢀCH3 stereoisomers appear at 2.08
and 2.02 ppm.
The nitrosated amino esters 4 form stereoisomers that
Our interest in the synthesis of constrained amino
1
give complex H and 13C NMR spectra. The isomers
acids,9 has led to the need
- a-hydrazino esters with a
L
show similar multiplicity patterns with different chemi-
free Nb- and a benzyl-protected Na-nitrogen. Herein, we
report a very convenient, high yielding method to syn-
thesize a-hydrazino esters from a-amino esters using
inexpensive reagents.
Scheme 1 shows the sequence of steps for the prepara-
tion of a-hydrazino esters. Starting with the readily
available HCl salt of the corresponding L-amino acid
esters 1, the a-amino group is protected by benzyl
substitution via a two-step reductive amination proce-
* Corresponding author. E-mail: mmclaug@lsu.edu
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00352-0

2874
U. Oguz et al. / Tetrahedron Letters 43 (2002) 2873–2875
1
cal shifts and intensities. For Met-, the H NMR sig-
nals of -OCH3 and -SCH3 protons are 3.64, 3.50 and
1.95, 1.80 ppm, respectively, for the two isomers of 4d.
For Phe-, the chemical shifts of -OCH3 protons of the
two isomers of 4e are 3.63 and 3.51 ppm. The purity of
the nitrosamines was verified by elemental analysis.14,15
To summarize, we report a convenient, high-yielding
synthesis of a-hydrazino esters from the corresponding
a-amino esters. The key step is chemoselective reduc-
tion of the N=O bond of the nitrosamine intermediates
without any NꢀN bond cleavage using Zn/conc. HCl/
MeOH/−78°C. The a-hydrazino esters are susceptible
to self-condensation, so they must be prepared and
used that same day or they maybe stored as dilute
solutions at –10°C for 24 h. The Na-benzyl-protecting
group can be removed by hydrogenolysis without
reducing the NꢀN bond of the hydrazine.
The key to the overall synthesis is the reduction of the
nitrosamines to the corresponding hydrazines. Previ-
ously reported literature procedures for related reac-
tions gave very little to no yield of the desired
hydrazine. In most cases, NMR and mass spectrometry
results showed the formation of the parent amine, as a
result of the cleavage of the NꢀN bond. We initially
studied the reduction under the following conditions:
Zn/AcOH/65°C, Zn/AcOH/rt, Zn/aq. HCl/rt, TiCl3/rt,
TiCl3/NH4OAc/rt,16 Sn/aq. HCl, Zn/conc. HCl/MeOH/
rt. The reduction with TiCl3, and Sn did not give any
hydrazine product. The reduction with Zn in aqueous
HCl at rt gave useful yields of hydrazine product 5
along with the parent amino ester 1. Attempted separa-
tion of these mixtures on flash column, enriched the
sample in the amount of parent amino ester 1. The b-N
of 4 is apparently much more nucleophilic than the a-N
of 1 causing much faster oligomer formation due to
intermolecular attack on its ester carbon. Therefore, we
carefully optimized the conditions to enable facile and
rapid isolation of the pure hydrazines 5.
Acknowledgements
We thank the National Institutes of Health (AI 17981
and 17983) for support of this work and Rene´e Sims
for timely mass spectrometric data.
References
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The best results were obtained with Zn/conc. HCl/
MeOH/−78°C.17 There was a significant increase in the
hydrazine 5/amine 1 ratio with Zn/conc. HCl/MeOH in
the order rt, 0°C, −78°C, giving 60/40, 82/18 and 100/0,
respectively. For all the nitrosated amino esters tried,
we obtained the respective hydrazines in high yield
using Zn/conc. HCl/MeOH/−78°C. Reduction using
more dilute HCl is not useful due to solidification of the
reaction mixture. Reduction at low temperatures appar-
ently increases the selectivity for reduction of the NꢁO
bond over the NꢀN bond. It is important to perform
2. Morley, J. S.; Payne, J. W.; Hennessey, T. D. Gen.
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3. Chen, S.; Chrusciel, R. A.; Nakanishi, H.; Raktabutr, A.;
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FAB-MS, H and 13C NMR on the hydrazine immedi-
1
ately after the work-up due to the high reactivity of the
hydrazine to undergo self-condensation. The hydrazines
should be derivatized by acylation on the b-N or they
can be stored as dilute solutions in H2CCl2 at –10°C for
5. (a) Shestakov, P. Z. Angew. Chem. 1903, 16, 1061; (b)
Karady, S.; Ly, M. G.; Pines, S. H.; Sletzinger, M. J.
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24 h. The complex H and 13C NMR spectra of the
1
nitrosamine stereoisomeric mixtures are greatly sim-
plified in the analogous hydrazines.17 We observed a
broad singlet for the b-N protons around 3.2 ppm.
6. Sawayama, T.; Kinugasa, H.; Nishimura, H. Chem.
Pharm. Bull. 1976, 24, 326–329.
7. Hoffman, R. V.; Kim, H.-O. Tetrahedron Lett. 1990, 31,
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8. (a) Evans, D. A.; Britton, T. C.; Dorow, R. L.; Dellaria,
J. F., Jr. Tetrahedron 1988, 44, 5525–5540; (b) Gennari,
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108, 6394–6395; (c) Trimble, L. A.; Vederas, J. C. J. Am.
Chem. Soc. 1986, 108, 6397–6399.
The scheme described here is analogous to the route
first used by Enders and co-workers in their synthesis of
RAMP and SAMP.18 The difference being that they
used LAH reduction of their nitrosamine intermediate,
which is not useful in our synthesis since it would
reduce the ester function as well.
9. Oguz, U.; Gauthier, T. J.; McLaughlin, M. L. ‘Proceed-
ings of the 17th American Peptide Symposium’, in press.
10. Basile, T.; Bocoum, A.; Savoia, D.; Umani-Ronchi, A. J.
Org. Chem. 1994, 59, 7766–7773.
11. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.;
Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61,
3849–3862.
In model studies, we have derivatized the b-N of 5a and
5b and the benzyl group was cleanly removed by
hydrogenolysis in 95:5 EtOH–AcOH using 10% Pd/C
and 50 psi H2 in a Paar Hydrogenator. The NꢀN bond
is completely inert to these conditions. This selectivity
has precedent.19

U. Oguz et al. / Tetrahedron Letters 43 (2002) 2873–2875
2875
12. Typical experimental procedure for Schiff base formation
(2). The HCl salt of the amino acid 1 (25.5 mmol) is
dissolved in dry THF (25 mL) and brought to 0°C. Then
MgSO4 (5.1 g), benzaldehyde (51 mmol, 2 equiv.), TEA
(25.5 mmol, 1 equiv.) are added and stirred at rt under
argon for 5 h. The reaction mixture is filtered and solvent
is evaporated under reduced pressure, giving imine 2 as
yellow oil, along with excess benzaldehyde.
13. Typical experimental procedure for reduction (3). The
Schiff base 2 (25.5 mmol)/benzaldehyde from the previ-
ous step is dissolved in dry MeOH (75 mL) and NaBH4
(51 mmol, 2 equiv.) is slowly added. The reaction mixture
is stirred under argon for 30 min, quenched with 1N
NaOH (20 mL), and extracted three times with ether.
Combined ether layers are extracted with saturated NaCl
solution, dried with Na2SO4, and evaporated under
reduced pressure. The benzyl alcohol was removed under
high vacuum at rt, giving amine 3 as colorless oil, yield
90–95%.
characterized quickly or stored at low temperature as
dilute solutions.
Methyl N-amino-N-benzyl-(S)-valinate (5a). 1H NMR
(250 MHz, CDCl3) l 7.33–7.26 (m, 5H), 3.78 (s, 2H), 3.74
(s, 3H), 3.16 (broad, 2H), 3.03 (d, J=10.2 Hz, 1H),
2.30–2.15 (m, 1H), 1.09 (d, J=6.6 Hz, 3H), 0.92 (d,
J=6.7 Hz, 3H); 13C NMR (250 MHz, CDCl3) l 173.66,
138.87, 129.11, 128.83, 127.67, 74.41, 63.16, 51.26, 28.57,
20.16, 20.00; FAB-MS 237.2 (M+H)+.
Methyl N-amino-N-benzyl-(S)-leucinate (5b). 1H NMR
(250 MHz, CDCl3) l 7.35–7.28 (m, 5H), 3.97 (d, J=13.3
Hz, 1H), 3.87 (d, J=13.3 Hz, 1H), 3.73 (s, 3H), 3.56 (dd,
J=5.7, 9.1 Hz, 1H), 3.22 (broad, 2H), 1.90–1.83 (m, 2H),
1.62–1.48 (m, 1H), 0.97 (d, J=6.4 Hz, 3H), 0.91 (d,
J=6.4 Hz, 3H); 13C NMR (250 MHz, CDCl3) l 174.50,
138.95, 129.21, 128.88, 127.70, 65.68, 62.93, 51.56, 39.39,
25.07, 23.61, 22.01; FAB-MS 251.4 (M+H)+.
1
Methyl N-amino-N-benzyl-(S)-isoleucinate (5c). H NMR
(250 MHz, CDCl3) l 7.36–7.26 (m, 5H), 3.77 (s, 2H), 3.76
(s, 3H), 3.16 (d, J=10.2 Hz, 1H), 3.09 (broad, 2H),
2.16–1.99 (m, 1H), 1.89–1.73 (m, 1H), 1.46–1.19 (m, 1H),
0.94–0.88 (m, 6H); 13C NMR (250 MHz, CDCl3) l
173.72, 138.82, 129.15, 128.82, 127.67, 72.50, 63.27, 51.24,
34.19, 25.75, 16.08, 10.75; FAB-MS 251.2 (M+H)+.
Methyl N-amino-N-benzyl-(S)-methioninate (5d). 1H
NMR (250 MHz, CDCl3) l 7.34–7.27 (m, 5H), 3.96 (s,
2H), 3.76 (s, 3H), 3.68 (dd, J=4.8, 9.9 Hz, 1H), 3.13
(broad, 2H), 2.78–2.60 (m, 2H), 2.32–2.17 (m, 1H), 2.10–
1.90 (m, 4H); 13C NMR (250 MHz, CDCl3) l 173.81,
138.74, 129.23, 128.94, 127.81, 66.04, 63.75, 51.77, 31.44,
29.73, 15.78; FAB-MS 269.2 (M+H)+.
14. Typical experimental procedure for nitrosoamine formation
(4). The benzyl protected amine 3 (1.14 mmol) is dis-
solved in DCM (10 mL), brought to 0°C, and tert-butyl-
nitrite (1.25 mmol, 1.1 equiv.) in DCM was added from
an addition funnel. The mixture is brought to rt, refluxed
for 3 h, and stirred overnight. The solvent is evaporated
under reduced pressure, giving nitrosoamine 4 as yellow
oil, yield 100%.
15. Most nitrosoamines and hydrazines are potent carcino-
gens and must be handled cautiously.
16. Lunn, G.; Sansone, E. B. J. Org. Chem. 1984, 49, 3470–
3474.
17. Typical experimental procedure for hydrazine formation
(5). The nitrosoamine 4 (1.60 mmol) is dissolved in dry
MeOH (15 mL) under argon and charged with conc. HCl
(12.8 mmol, 8 equiv.). The reaction mixture is cooled to
−78°C, and activated Zn (12.8 mmol, 8 equiv.) is
slowly added to the stirred suspension from a solid
addition funnel, and stirred under argon at −78°C for 3
h. The excess Zn is filtered cold, and the filtrate is treated
with cold 6N KOH until strongly basic, pH 12–13, and
extracted with three equal portions of cold ether. Ether
layers are combined, dried with Na2SO4, and evaporated
under reduced pressure from a rt water bath, yield 88%.
The neat oil will oligomerize, so the hydrazines must be
Methyl N-amino-N-benzyl-(S)-phenylalaninate (5e). 1H
NMR (250 MHz, CDCl3) l 7.32 (m, 10H); 3.97 (d,
J=13.4 Hz, 1H), 3.89 (d, J=13.4 Hz, 1H), 3.77–3.66 (m,
1H), 3.73 (s, 3H), 3.22–3.18 (m, 2H); 13C NMR (250
MHz, CDCl3) l 173.35, 139.19, 138.55, 129.71, 129.16,
128.83, 128.62, 127.71, 126.69, 69.38, 63.69, 51.74, 36.35;
FAB-MS 285.2 (M+H)+.
18. Enders, D.; Eichenauer, H. Chem. Ber. 1979, 112, 2933–
2960.
19. Roussi, F.; Chauveau, A.; Bonin, M.; Micouin, L.; Hus-
son, H.-P. Synthesis 2000, 8, 1170–1179.