Stereoselective synthesis of differentially protected anti-α,β-diamino acid derivatives using arylthionitrooxiranes

Article abstract of DOI:10.1055/s-2001-16047

Epoxidation of 1-tolylthio-1-nitroalkenes containing an allylic Z- or Fmoc-protected amino group yields the corresponding syn-epoxides which, although they cannot be isolated, can be trapped with aqueous ammonia to give stereoisomerically pure anti-α,β-diamino acid derivatives.

Full text of DOI:10.1055/s-2001-16047

1214
LETTER
Stereoselective Synthesis of Differentially Protected anti- , -Diamino Acid
Derivatives using Arylthionitrooxiranes
Estelle Dumez,a,b Andrea Szeki,a Richard F.W. Jacksona,b*
a Department of Chemistry, Bedson Building, The University of Newcastle upon Tyne, Newcastle upon Tyne, NE1 7RU, UK
b Department of Chemistry, Dainton Building, The University of Sheffield, Sheffield, S3 7HF, UK
Received 8 May 2001
O
Abstract: Epoxidation of 1-tolylthio-1-nitroalkenes containing an
allylic Z- or Fmoc-protected amino group yields the corresponding
syn-epoxides which, although they cannot be isolated, can be
trapped with aqueous ammonia to give stereoisomerically pure anti-
, -diamino acid derivatives.
H
BocHN
R
STol
NO2
N
O
R
COSTol
4
3
Key words: amino acids, amino aldehydes, epoxides, epoxidation,
stereoselective synthesis
BocHN
STol
O
via
R
NO2
, -Diamino acids 1 and 2 are of interest as components
of natural products,1,2 pharmaceutical leads3 and as metal-
complexing agents. Routes for the synthesis of 2,3-diami-
nobutanoic acid derivatives have used threonine or allo-
threonine.4,5 More general methods that rely on the use of
the chiral pool,6-11 chiral reagents12,13 or asymmetric
catalysts14-16 have extended the range of targets that are
accessible. A useful summary of other routes has been as-
sembled.11 One route that does not appear to have been
widely applied is the Strecker reaction in which an amino
aldehyde is converted into the corresponding homologous
, -diamino acid. Two examples that proceed with mod-
est stereoselectivity have been described.3,17 We now re-
port such a route which allows the synthesis of a variety
of stereoisomerically pure anti- , -diamino acid deriva-
tives.
5
Results and Discussion
We judged that the instability of the syn-epoxides 5 was
principally due to the ease of cyclisation of the tert-butyl
carbamate, either as a result of steric factors, or the intrin-
sically greater nucleophilicity of this group due to the sta-
bility of the electrofugal tert-butyl cation. It seemed
appropriate to choose Z-protection for the amino group,
and we therefore prepared the alkene 6 from (p-tolylth-
io)nitromethane and the corresponding protected alaninal
derivative 7 (Scheme 1). Treatment of the alkene 6 in tol-
uene with lithium tert-butylperoxide,20 followed by work-
up and treatment with aqueous ammonia,19 gave the
monoprotected diamino thioester as a single diastereoiso-
mer 8, which could be converted into the corresponding
diprotected derivative 9. The by-product isolated in the re-
action with ammonia was the oxazoline 10. There was no
evidence for the formation of the other diastereoisomer in
this process, but the moderate yield means that we cannot
exclude its formation to a minor extent.
NH2
NH2
CO2H
CO2H
R
R
NH2
NH2
1
2
We have reported that it is possible to prepare anti- -hy-
droxy- -amino acid derivatives as the cis-oxazolidinones
3 by nucleophilic epoxidation of the Boc-protected -ami-
no (tolylthio)nitroalkenes 4,18 via the inferred intermedia-
cy of the corresponding syn-epoxides 5. Attempts to
isolate and characterise the syn-epoxides 5 were unsuc-
cessful. Although this process provided convenient access
to anti- -hydroxy- -amino acid derivatives, the instabili-
ty of the epoxides 5 appeared to prohibit their use in a
ring-opening reaction with aqueous ammonia, a process
that we had previously developed for the synthesis of
-amino- -hydroxy acid derivatives.19
The relative stereochemistry of the diamino thioester 8
was established by conversion into the corresponding cy-
clic urea 11 using bis(trichloromethyl)carbonate. The
magnitude (9.0 Hz) of the coupling constant between the
two ring protons allowed us to establish that the cyclic
urea was cis-fused, and therefore that the precursor pro-
tected , -diamino acid derivative 8 was anti. The enanti-
omeric purity of the diamino acid derivative 9 was
established by hydrolysis of the thioester to the carboxylic
acid 12, which exhibited a melting point and specific ro-
tation that compared well with literature values.21
Synlett 2001, No. 8, 1214–1216 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Stereoselective Synthesis of Differentially Protected anti- , -Diamino Acid
1215
1. O2NCH2STol
tBuOK in tBuOH/THF
1. O2NCH2STol
tBuOK in tBuOH/THF
ZHN
STol
NO2
FmocHN
R
STol
NO2
ZNH
FmocNH
R
CHO
CHO
2. MeSO2Cl
2. MeSO2Cl
iPr2NEt/CH2Cl2
85% overall
iPr2NEt/CH2Cl2
6
7
13a, R = Me
14a, R = Me
13b, R = PhCH2
13c, R = iPrCH2
14b, R = PhCH2
14c, R = iPrCH2
1. LiOOtBu,
Toluene
2. NH3
1. LiOOtBu,
Toluene
2. NH3
ZHN
ZHN
(Boc)2O, THF, 99%
COSTol
NHBoc
COSTol
(Boc)2O, THF
FmocHN
R
FmocHN
NH2
8, 42%
+
COSTol
NH2
COSTol
NHBoc
R
9
OBn
H2O2, NaOH, 83%
17a, R = Me
15a, R = Me
17b, R = PhCH2
17c, R = iPrCH2
15b, R = PhCH2
15c, R = iPrCH2
N
O
ZHN
COSTol
H2O2, NaOH
CO2H
10, 15%
OCH2(9-Fl)
NHBoc
FmocHN
R
12
N
O
CO2H
NHBoc
18a, R = Me
(Cl3CO)2CO
O
R
COSTol
iPr2NEt, THF
ZN
NH
COSTol
16a, R = Me
16b, R = PhCH2
16c, R = iPrCH2
11
18b, R = PhCH2
18c, R = iPrCH2
49%
11
Scheme 1
O
iPr2NEt, THF
(Cl3CO)2CO
Fmoc
NH
COSTol
The encouraging results obtained for the Z-protected ami-
no aldehyde, encouraged us to apply the same process to
the Fmoc-protected analogue, 13a. This compound was
converted into the corresponding alkene 14a, and epoxi-
dation followed by treatment with ammonia gave the cor-
responding monoprotected diamino thioester anti 15a
(along with the corresponding oxazoline 16a). Protection
15a
52%
19
Scheme 2
then gave the doubly protected derivative 17a, which ment. This encouraged us to explore the further applica-
could be converted into the corresponding acid 18a tion of this process, and we have therefore carried out an
(Scheme 2).22 Treatment of 15a with bis(trichlorometh- analogous series of reactions on the Fmoc-protected alde-
yl)carbonate gave the cis-cyclic urea 19, whose stere- hydes 13b and 13c derived from phenylalanine and leu-
ochemistry was again inferred from the large coupling cine, respectively, to give the protected diamino acids 18b
constant (9.0 Hz) between the two ring protons (Scheme and 18c.22,23 The results were broadly comparable, al-
2). We were pleased to find that the overall yields were though the yield for the formation of the amino thioester
higher, and the reaction less sensitive to the speed with 15b derived from phenylalanine was lower than for the
which the crude epoxide was subjected to ammonia treat- other two examples (Table).
Table
* Not isolated
Synlett 2001, No. 8, 1214–1216 ISSN 0936-5214 © Thieme Stuttgart · New York

1216
E. Dumez et al.
LETTER
hexanes, 160 L, 0.4 mmol, 1.2 equiv.) was added dropwise,
at -78 °C under nitrogen, to a solution of tert-butylhydro-
peroxide (3.82M solution in toluene, 130 L, 0.5 mmol, 1.5
equiv.) in toluene (10 mL), and left to stir for 15 min. The
alkene 6 or 14 (0.33 mmol) in toluene (5 ml) was added
dropwise at -78 °C and the reaction stirred for 2 h at this
temperature before quenching with saturated aqueous NH4Cl
solution (10 mL) and allowing to warm to room temperature.
The organic layer was separated and the aqueous layer
extracted with dichloromethane (3 10 mL). The combined
organic portions were washed with 10% aqueous sodium
sulphite, brine, then dried (MgSO4) and filtered.The filtrate
was cooled to 0 °C and aqueous ammonia (14.7 M, 115 L,
1.67 mmol, 5 equiv.) was added dropwise and the reaction was
left to stir for 15 h at 0 °C. The reaction mixture was filtered
using a phase separator paper and absorbed on silica, and the
solvent was removed under reduced pressure. A quick
purification by flash chromatography (petrol:diethyl ether
1:6) gave the amines 8 and 15.
Di-tert butyl dicarbonate (44 mg, 0.2 mmol, 1.05 equiv.) in
THF (2 mL) was added to a solution of the free -amino
thioester 8 or 15 (1.9 mmol) in THF (10 mL). The mixture was
refluxed for 15 h then cooled to room temperature and the
solvent was removed under reduced pressure. Purification by
flash chromatography (petrol:ethyl acetate 5:1) gave the N,N’-
diprotected , -diamino acid derivatives 9 and 17.
Aqueous hydrogen peroxide (30 w/w, 45 L, 0.4 mmol, 4
equiv.) was added dropwise at 0 °C to a solution of the
thioester 9 or 17 (0.1 mmol) in THF (5 mL) and the resulting
solution was stirred for 15 min. at 0 °C. Aqueous sodium
hydroxide (0.22M, 1.4ml, 0.3 mmol, 3 equiv.) was added
dropwise and the reaction stirred for 1 h at room temperature.
The solvent was removed under reduced pressure and the
residue taken up in water (15 mL) and diethyl ether (15mL).
The organic layer was removed and the aqueous layer
extracted with diethyl ether (2 10 mL). The aqueous layer
was carefully acidified to pH 3 with 1 M HCl and extracted
with ethyl acetate. The combined ethyl acetate extracts were
dried (MgSO4), filtered and the solvent removed under
reduced pressure to give the crude acids 12 and 18.
In conclusion, we have shown that an appropriate choice
of N-protecting group allows -amino aldehydes to be
converted into stereoisomerically pure anti- , -diamino
acid derivatives 12 and 18 in which the two amino groups
are orthogonally protected as a natural conseqeunce of the
reaction sequence.
Acknowledgement
We thank the EPSRC (studentship to A.S.) and the European Com-
mission for a Marie Curie Fellowship number HPMF-CT-1999-
00107 (E.D.). We also thank Mr E.Hart for preparation of (p-to-
lylthio)nitromethane.
References and Notes
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Pharm. Bull. 1985, 33, 3053-3056.
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Ulm, E. H.; Vassil, T. C. J. Med. Chem. 1985, 28, 434-442.
(4) Nakamura, Y.; Hirai, M.; Tamotsu, K.; Yonezawa, Y.; Shin,
C.-g. Bull. Chem. Soc. Jpn. 1995, 68, 1369-1377.
(5) Schmidt, U.; Mundinger, K.; Riedl, B.; Haas, G.; Lau, R.
Synthesis 1992, 1201-1202.
(6) Dunn, P. J.; Haner, R.; Rapoport, H. J. Org. Chem. 1990, 55,
5017-5025.
(7) Palomo, C.; Aizpurua, J. M.; Cabre, F.; Cuevas, C.; Munt, S.;
Odriozola, J. M. Tetrahedron Lett. 1994, 35, 2725-2728.
(8) Palomo, C.; Aizpurua, J. M.; Galarza, R.; Mielgo, A. J. Chem.
Soc., Chem. Commun. 1996, 633-634.
(9) Merino, P.; Lanaspa, A.; Merchan, L.; Tejero, T. Tetrahedron
Lett. 1997, 38, 1813-1816.
(10) Merino, P.; Lanaspa, A.; Merchan, F. L.; Tejero, T.
Tetrahedron: Asymmetry 1998, 9, 629-646.
(11) Luo, Y.; Blaskovich, M. A.; Lajoie, G. A. J. Org. Chem. 1999,
64, 6106-6111.
(12) Burke, A. J.; Davies, S. G.; Hedgecock, C. J. R. Synlett 1996,
621-622.
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1998, 39, 475-478.
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2048.
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2001, 57, 2139-2145.
(17) Herranz, R.; Vinuesa, S.; Castro-Pichel, J.; Pérez, C.; García-
López, M. T. J. Chem. Soc., Perkin Trans. I 1992, 1825-1830.
(18) Ambroise, L.; Jackson, R. F. W. Tetrahedron Lett. 1996, 37,
2311-2314.
(23) Data for 18a: mp 102-103 C; [ ]D18-26.1 (c 0.18 in MeOH);
H (500 MHz; (CD3)2SO) 1.02 (3H, d, J 7.0), 1.37 (9H, s),
3.93-3.96 (1H, m), 4.14 (1H, dd, J 8.5, 6.5), 4.16-4.20 (2H,
m), 4.25-4.29 (1H, m), 6.96 (1H, d, J 8.5), 7.28 (1H, m), 7.28-
7.33 (2H, m), 7.39 (2H, t, J 7.5), 7.66-7.88 (2H, m), 7.87 (2H,
d, J 7.3); C (125 MHz; (CD3)2SO) 16.3, 28.2, 46.7, 48.6, 58.5,
65.2, 78.1, 120.1, 125.2, 127.0, 127.6, 140.7, 143.3, 154.8,
155.9, 172.2.
Data for 18b mp 107-108 C; [ ]D18-17.8 (c 0.14 in MeOH);
H (500 MHz; (CD3)2SO) 0.86 (3H, d, J 6.5), 0.92 (3H, d, J
6.5), 1.10-1.15 (1H, m), 1.44 (9H, s), 1.55-1.60 (1H, m), 1.61-
1.64 (1H, m), 3.98-4.03 (1H, m), 4.21 (1H, dd, J 8.5, 6.0),
4.26-4.35 (3H, m), 6.94 (1H, d, J 8.5), 7.30 (1H, d, J 9.0),
7.35-7.40 (2H, m), 7.47 (2H, t, J 7.5), 7.74 (1H, d, J 7.5), 7.77
(1H, d, J 7.5), 7.95 (2H, d, J 7.7); C (125 MHz; (CD3)2SO)
21.1, 23.5, 24.1, 28.2, 38.2, 46.8, 49.7, 57.5, 65.4, 78.2, 120.1,
125.3, 127.0, 127.6, 140.7, 143.7, 155.7, 155.8, 172.2.
Data for 18c: : mp 99-100 C; [ ]D18-13.3 (c 0.16 in MeOH);
H (500 MHz; (CD3)2SO) 1.46 (9H, s), 2.76-2.86 (2H, m),
4.09-4.27 (5H, m), 6.94-6.99 (1H, m), 7.19-7.21 (1H, m),
7.24-7.40 (7H, m), 7.44-7.48 (2H, m), 7.68 (2H, t, J 6.5), 7.93
(2H, d, J 7.5); C (125 MHz; (CD3)2SO) 28.2, 36.8, 46.6, 54.3,
57.3, 65.5, 78.1, 120.0, 125.4, 125.9, 127.6, 127.9, 128.1,
129.2, 137.5, 140.6, 143.7, 155.5, 155.6, 172.6.
(19) Jackson, R. F. W.; Palmer, N. J.; Wythes, M. J.; Clegg, W.;
Elsegood, M. R. J. J. Org. Chem. 1995, 60, 6431-6440.
(20) Meth-Cohn, O.; Moore, C.; Taljaard, H. C. J. Chem. Soc.,
Perkin Trans.1 1988, 2663-2674.
(21) Data for 12: mp 106-107 C, (lit.,4 112-113 C); [ ]D18-20.6
26
(c 0.97 in MeOH), [lit.,4 [ ]D 21.0 (c 0.3 in MeOH); H (500
MHz; (CD3)2SO) 1.09 (3H, d, J 6.5), 1.45 (9H, s,), 3.98-4.01
(1H, m), 4.18-4.21 (1H, m), 5.05 & 5.10 (2H, AB system, J
12.5), 7.00-7.02 (1H, m), 7.30 (1H, br d, J 7.3), 7.36-7.43 (5H,
m); C (125 MHz; (CD3)2SO) 16.3, 28.3, 47.8, 57.0, 65.3,
78.4, 127.6, 127.8, 128.4, 137.3, 155.5, 156.3, 172.2. [lit.,4
C
(125 MHz; (CD3)2SO) 16.2, 28.2, 47.4, 57.2, 65.2, 78.3,
127.5, 127.7, 128.4, 137.2, 155.4, 155.7, 172.2].
(22) General procedure for the synthesis of N,N’-protected , -
diamino acids 12 and 18: n-Butyllithium (2.5M solution in
Article Identifier:
1437-2096,E;2001,0,08,1214,1216,ftx,en;D12101ST.pdf
Synlett 2001, No. 8, 1214–1216 ISSN 0936-5214 © Thieme Stuttgart · New York