Synthesis and characterization of chiral di(N-protected-α-amino) diazo-β-diketones from α-diazoketones and imidazolides derived from amino acids

Article abstract of DOI:10.1016/j.tetlet.2012.01.093

Di(N-protected-α-amino)diazo-β-diketones were prepared by the reaction of activated N-protected-α-amino acids (imidazolides) with α-diazoketones, derived from natural amino acids, in the presence of lithium diisopropylamide in tetrahydrofuran as the solvent at -78 °C.

Full text of DOI:10.1016/j.tetlet.2012.01.093

Tetrahedron Letters 53 (2012) 2023–2025
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Tetrahedron Letters
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Synthesis and characterization of chiral
di(N-protected- -amino)diazo-b-diketones from a-diazoketones
a
and imidazolides derived from amino acids
Ibrahim A.M. Saraireh
Department of Chemistry, Al-Hussein Bin Talal University, Ma’an, Jordan
a r t i c l e i n f o
a b s t r a c t
Article history:
Di(N-protected-
amino acids (imidazolides) with
lithium diisopropylamide in tetrahydrofuran as the solvent at ꢀ78 °C.
a
-amino)diazo-b-diketones were prepared by the reaction of activated N-protected-
a-
Received 10 August 2011
Revised 21 December 2011
Accepted 20 January 2012
Available online 10 February 2012
a
-diazoketones, derived from natural amino acids, in the presence of
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Amino acid
Diazomethane
b-Diketones
Carbonyldiimidazole
The pollution of the environment by metal ions and their ability
to contaminate living species is a significant problem. Removal of
these metal ions from human systems by ligands which can easily
bind these metal ions through the formation of stable complexes is
important. Also, the deficiency of some metal ions in humans can
a
-diazocarbonyls with activated N-protected amino acids. Carbon-
yldiimidazole (CDI) is a suitable activating reagent for N-protected
amino acids and leads to the formation of imidazolides.8–11 These
imidazolides can be treated directly with diazolithioketones to give
high yields of the corresponding diazo-b-diketones.
cause several diseases. Since
L
-amino acids are naturally occurring
N-protected amino acids were converted into a-diazoketones
amino acids, -amino acid diazo-b-diketone ligands may be effec-
tive in binding metal ions for the removal of hazardous metal ions
or for the introduction of important metal ions.
L
via the acid chloride or mixed anhydride by treatment with ethe-
real diazomethane (Scheme 1) in good yields following purification
by chromatography. In addition, N-protected amino acids were
converted into imidazolides by treatment with 1,10-carbonyldiim-
idazole in tetrahydrofuran (Scheme 2).
The N-protected amino acid derived diazoketones 4–6 could be
easily metallated by addition to a solution of LDA in THF at ꢀ78 °C.
The resulting solution was treated with the imidazolides 7–9 to
form the diazo-b-diketones 10–15 (Scheme 3). After aqueous
work-up, purification of the residue by chromatography gave good
yields of pure products.
Numerous papers have been published on the synthesis of N-
protected
amino acids.1 N-protected
pared from -amino acids and dipeptides and used as precursors
for the synthesis of N-protected
-amino b-diketones.2 The synthe-
sis of -amino protected acyldiazomethanes involves the activa-
tion of the carboxyl group of N-protected -amino acids followed
a-amino acids and
a
-diazoketones derived from natural
a-aminodiazoketones have been pre-
L
a
a
a
by acylation with diazomethane. The acid chloride,3 active ester,4
and mixed anhydride methods5 have also been employed for this
type of activation. The acid chloride method is not applicable for
some protecting groups because of their lability toward acid or
oxazolone formation.
In conclusion, N-protected amino acids were converted into
a-diazoketones via the acid chloride or mixed anhydride intermedi-
ates by treatment with ethereal diazomethane. Subsequent reaction
with an imidazolide, prepared by the treatment of an N-protected
amino acid with CDI, gave the title products in good yields.
a-Diazocarbonyl compounds (RCOCHN2) have an acidic hydro-
gen on the methine group, which can readily be removed by a
strong base to furnish a nucleophilic anion capable of condensa-
tion6 with activated N-protected amino acids7 to furnish high
yields of diazo-b-diketones. Lithium diisopropylamide (LDA) is
the base of choice leading to high yields for the condensation of
a
-Diazoketones via mixed anhydrides: General procedure
The N-protected amino acid (27.0 mmol) in dry Et2O (60 ml)
and THF (60 ml) was stirred at ꢀ20 °C under a nitrogen atmo-
sphere. To this solution, Et3N (3.8 ml, 1 equiv) followed by isobutyl
chloroformate (3.7 ml, 1 equiv) were added. The solution was
E-mail address: ibrahim9997@yahoo.com
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.093

2024
I. A. M. Saraireh / Tetrahedron Letters 53 (2012) 2023–2025
O
H
1. COCl)2 /DMF, (0 oC
O
H
N
or ClCOOCH2CH(CH3)2 /THF, -20 o
2. CH2N2, Et2O, 0 oC
C
N
O
CHN2
O
OH
R
O
R
O
α−diazoketone
N-benzyloxycarbonyl amino acid
4
R = -CH3
(84%)
1 R = -CH
5 R = -CHCH3)2 (75%)
3
2 R = -CH(CH )
6 R = -CH2Ph
(88%)
3 2
3 R = -CH Ph
2
Scheme 1. This reaction shows converted N-protected amino acids into
0 °C.
a-diazoketones via the acid chloride or mixed anhydride by treatment with ethereal diazomethane at
H
N
O
O
O
H
N
THF 25 oC /2 h
O
+
N
N
O
N
N
N
N
OH
O
R
R
O
N-benzyloxycarbonyl-L-amino acid
CDI
imidalzolide
N-benzyloxycarbonyl-L-amino acid
1 R = -CH3
7 R = -CH3
8 R = -CH(CH3)2
9 R = -CH2Ph
2 R = -CH(CH3)2
3
R = -CH2Ph
Scheme 2. This reaction shows converted of N-protected amino acids into imidazolides by treatment with 1,1’-carbonyldiimidazole (CDI) in tetrahydrofuran.
Benzyl [(2R)-4-diazo-3-oxobutan-2-yl]carbamate (4)
H
N
O
H
N
O
+
O
Following the general procedure N-benzyloxycarbonyl-L-ala-
O
N
N
CHN2
nine 1 (27 mmol, 6 g) was converted into title compound 4. Purifi-
cation using EtOAc–hexane as eluent furnished the diazoketone 4
R
O
R
O
(5.7 g, 84%) as a pale-yellow solid. Mp 90–91 °C, ½a D20
ꢁ
ꢀ59.08 (c 1,
LDA, THF
-78 o
C
7
R = -CH3
8 R = -CH(CH3)2
9 R = -CH2Ph
MeOH). Found: C, 58.2; H, 5.22; N, 16.98. C12H13N3O3 requires C,
4 R = -CH
3
5 R = -CH(CH )
3 2
58.3; H, 5.3; N, 17.0.
mmax(KBr) 3315 (NH), 2105 (CHN2), 1722
6 R = -CH Ph
2
(NHCO2Bn), 1645 cmꢀ1 (COCHN2). 1H NMR (300 MHz, CDCl3):
d = 1.21 (3H, d, J = 7.1 Hz, CH3CH), 4.30 (1H, m, CH(N)CO), 5.20
(2H, s, OCH2Ph), 5.54 (1H, br s, CHN2), 5.76 (1H, br s, NH), 7.26–
7.35 (5H, m, ArH). 13C NMR (75 MHz, CDCl3): d = 18.5, 53.7, 54.5,
67.1, 128.2, 128.3, 128.6, 136.4, 155.9, 194.1.
H
N
H
N
O
O
O
O
N2
O
R
R
O
Synthesis of N-Protected-a-amino acid imidazolides
10
R = -CH3
(77%)
(72%)
(80%)
(74%)
(71%)
(76%)
Benzyl [(2R)-1-(1H-imidazol-1-yl)-1-oxopropan-2-yl]carbamate
(7)
11
12
13
R = -CH(CH3)2
R = -CH2Ph
R = -CH3, -CH2Ph
14 R = -CH2Ph, -CH(CH3)2
15 R = -CH(CH3)2, -CH3
To a stirred solution of 1 (3.80 g, 17.2 mmol) in dry THF (50 ml),
carbonyldiimidazole (CDI) (3.07 g, 18.9 mmol) was added under
nitrogen at 25 °C. After stirring for 2 h at 25 °C the in situ prepared
alaninylimidazolide was used directly in the next step without
isolation.
Scheme 3. This reaction shows formation of diazo-peta-diketones from reaction of
metallated of -diazoketone by (LDA) with imidazolide.
a
stirred for 30 min and then allowed to warm to ꢀ10 °C. At this
temperature ethereal CH2N2 (2 equiv), was added via a pressure
equalizing dropping funnel over 30 min. The solution was stirred
for a further 3 h while warming to room temperature. The mixture
was evaporated to a third of its original volume using a rotary
evaporator with an AcOH trap to destroy residual CH2N2. The solu-
tion was diluted with Et2O (50 ml) and washed with H2O (50 ml),
saturated aqueous NaHCO3 (50 ml), and brine (50 ml). The organic
Synthesis of 2-diazo-1,3-diketones 10–15
Dibenzyl [(2R, 6R)-4-diazo-3,5-dioxoheptane-2,6-diyl]carba-
mate (10)
A cold (ꢀ78 °C) solution of LDA (10.8 ml of a 1.6 M solution in
cyclohexane, 17.2 mmol) was added over 15 min under nitrogen
fraction was dried and evaporated to give the crude
a-diazoketone
via a syringe to a stirred solution of carbamate 4, (2.13 g,
which was purified by silica gel chromatography (EtOAc–hexane
2:8–3:7). CAUTION! Diazomethane is toxic and explosive. Extreme
care should be taken in handling and using this compound. See also
the Supplementary data.
8.60 mmol) in dry THF (30 ml) at ꢀ78 °C. A solution of imidazolide
7 (prepared as described above) was added dropwise over 15 min
under nitrogen via a cannula at such a rate so as to keep the
temperature below ꢀ78 °C, and stirring was continued for an

I. A. M. Saraireh / Tetrahedron Letters 53 (2012) 2023–2025
2025
additional 2 h. AcOH (12 lL, 17.2 mmol) in dry THF (5 ml) was
References and notes
added. The mixture was allowed to warm to room temperature
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(3 ꢂ 50 ml) and the combined organic extracts washed with satu-
rated aqueous NaHCO3 (50 ml) and brine (50 ml), dried over anhy-
drous Na2SO4, and concentrated under reduced pressure to give a
brown oil. Purification by column chromatography using EtOAc/n-
hexane (3:7) as eluent furnished the title compound 10 (2.996 g,
77%) as a yellow oil. Anal. Calcd C23H24N4O6 C 61.06, H 5.35, N
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2099 (CN2); 1705 (CO2CH2); 1631 (COCN2); 1520 cmꢀ1 (Ph). 1H
NMR (300 MHz, CDCl3): d = 1.21 (6H, d, J = 7 Hz, CH3CH), 4.48 (2H,
m, 2 N–CH–CO), 5.11 (4H, s, 2 OCH2Ph), 5.41 (2H, br s, 2NH), 7.2–
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Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.01.093.