An improved approach for the synthesis of α,α-dialkyl glycine derivatives by the Ugi-Passerini reaction

Article abstract of DOI:10.1039/b212473b

A general and simple strategy for routine peptide synthesis with α,α-dialkyl glycines taking advantage of the four-component Ugi-Passerini reaction is presented. The isonitrile required for the reaction can be relatively simple and its selection based on cost, as the group it generates is easily removed under acidic conditions; in addition, this removal is not visibly affected by the bulkiness of the α-alkyl groups. Being a good leaving group from the N-terminal amino group of the amino acid, 4-methoxybenzyl was the choice for the amine component of the reaction. The method is illustrated with the synthesis of a series of acyl derivatives of several α,α-dialkyl glycines. The preparation of the latter compounds is also reported.

Full text of DOI:10.1039/b212473b

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An improved approach for the synthesis of ꢀ,ꢀ-dialkyl glycine
derivatives by the Ugi–Passerini reaction†
Susana P. G. Costa, Hernâni L. S. Maia* and Sílvia M. M. A. Pereira-Lima
Department of Chemistry, University of Minho, Gualtar, P-4710-057 Braga, Portugal.
E-mail: hmaia@quimica.uminho.pt
Received 16th December 2002, Accepted 12th March 2003
First published as an Advance Article on the web 28th March 2003
A general and simple strategy for routine peptide synthesis with α,α-dialkyl glycines taking advantage of the four-
component Ugi–Passerini reaction is presented. The isonitrile required for the reaction can be relatively simple
and its selection based on cost, as the group it generates is easily removed under acidic conditions; in addition,
this removal is not visibly affected by the bulkiness of the α-alkyl groups. Being a good leaving group from the
N-terminal amino group of the amino acid, 4-methoxybenzyl was the choice for the amine component of the
reaction. The method is illustrated with the synthesis of a series of acyl derivatives of several α,α-dialkyl glycines.
The preparation of the latter compounds is also reported.
come the above difficulties related to α,α-dialkyl glycines, we
Introduction
were able to take advantage of the crowding typical of these
compounds to develop an improved approach to the synthesis
of α,α-dibenzyl9 and other symmetric sterically hindered
α,α-dialkyl glycines.10 Although Ugi has given little attention to
this class of compounds (Scheme 1; R3, R4 ≠ H), we speculated
that if the above drawbacks could be easily overcome, the Ugi
four-component reaction might also turn into a useful and
possibly the most efficient approach to synthesise peptides
containing residues of α,α-dialkyl glycines.
As the Ugi reactions involving formation of α,α-dialkyl
glycines are already too slow at room temperature, it is not
practical to perform them at temperatures below Ϫ20 ЊC to
avoid isonitrile racemisation. Armstrong and co-workers11 have
devised the concept of “convertible” isonitrile, a reagent that
would allow mild cleavage of the C-terminal amide of the
amino acid residue generated in the Ugi–Passerini reaction.
They found that cyclohexenyl isonitrile fulfils this requirement
and were able to convert this amide into an acid, an ester or
a thioester. However, this isonitrile is difficult to prepare and
to handle and also fairly unstable and, thus, Linderman and
co-workers12 developed a new “convertible” isonitrile, a silyl
derivative of phenyl isonitrile, that although being stable
involves a three-step preparation.
The synthesis of peptides containing residues of α,α-dialkyl
glycines was pioneered during the 1960s by various authors
such as Faust and Lange,1 Diehl and Young,2 and McGahren
and Goodman;3 however, the most representative work was
carried out by Kenner and his co-workers,4 who concentrated
mainly on developing methodologies to deal with these
“sterically hindered” amino acids. In the following decades
peptides containing residues of such amino acids were investi-
gated from the point of view of their conformation and,
especially, with regard to the ability they have to induce special
conformational features in peptides.5 Lately, various important
applications of these amino acids have been devised in connec-
tion with modification of natural peptides in order to enhance
their properties or to prevent their recognition by enzymes.6
Nevertheless, most of the reports found in the literature refer
to the simplest representative of this class of compounds, i.e.
α,α-dimethylglycine (Aib, for α-aminoisobutyric acid), which
is certainly due to the discouraging difficulties usually
encountered during syntheses.4 In fact, apart from a few
exceptions, α,α-dialkyl glycines are not readily available
compounds, their synthesis being most commonly carried out
by hydrolysis of specially prepared hydantoins or Schiff bases.7
Owing to steric crowding, reactions involving these compounds
and their derivatives are slow and lead almost always to low
yields.
Meanwhile, Goodman and co-workers13 reported that the
amide bond at the C-terminus of N,α,α-trimethylglycine,
Aib(Me), is labile to acid; recently they proposed14 that this
is due to intramolecular attack by the carbonyl oxygen atom
of the N-terminus of this residue, leading to an oxazolinium
intermediate; we had also found a similar behaviour15 with
various N,α,α-trialkyl glycines. This result suggests that no
special isonitrile is required to ensure selective cleavage at the
C-terminus of the generated amino acid. Thus, we decided to
test this hypothesis, by using different isonitriles in the synthesis
of N-acyl-α,α-dialkyl glycines, together with the use of the
4-methoxybenzyl group, which is known to cleave from amides
with trifluoroacetic acid (TFA).16 Now we report a general and
simple strategy for routine peptide synthesis with these amino
acids taking advantage of the four-component Ugi–Passerini
reaction.
As early as 1971, Ugi proposed8 the use of a four-component
reaction as a complement or even an alternative to classical
peptide synthesis with common amino acids (Scheme 1; R4 =
H), but one can hardly find any such application in the
literature. This may be due to the fact that the synthetic
simplifications offered by this reaction are overcome by two
inherent drawbacks: (i) the high tendency to racemise above
Ϫ20 ЊC shown by amino acid and peptide isonitriles required
for the reaction and (ii) the need for cleavage of the N-alkyl
group formed during the reaction. Having it in mind to over-
Scheme 1
Results and discussion
Schiff bases 1 were prepared by azeotropic reflux of 4-methoxy-
benzylamine and diethyl, dipropyl, diisobutyl or dibenzyl
ketone in toluene and the product distilled in all cases but the
† Electronic supplementary information (ESI) available: spectroscopic
data for compounds 1-5. See http://www.rsc.org/suppdata/ob/b2/
b212473b/
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 4 7 5 – 1 4 7 9
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Table 1 Synthesis of CH3CON(4-CH3OC6H4CH2)CR2CONHRЈ (3)
Compound no.
R
RЈ
Yield (%)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3(CH2)2
CH3(CH2)2
CH3(CH2)2
CH3(CH2)2
(CH3)2CHCH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
CH3CH2OCOCH2
4-CH3OC6H4
2,4-(CH3O)2C6H3
4-CH3OC6H4CH2
CH3CH2OCOCH2
4-CH3OC6H4
2,4-(CH3O)2C6H3
4-CH3OC6H4CH2
CH3CH2OCOCH2
CH3CH2OCOCH2
4-CH3OC6H4
2,4-(CH3O)2C6H3
4-CH3OC6H4CH2
2,4-(CH3O)2C6H3CH2
60
80
80
87
51
88
85
84
49
41
61
68
69
59
Table 2 Synthesis of CH3CONHCR2CO2H (4) by cleavage of CH3CON(4-CH3OC6H4CH2)CR2CONHRЈ (3)
Product
Starting material
R
RЈ
Yield (%)
4a
4a
4a
4a
4b
4b
4b
4b
4c
4d
4d
4d
4d
4d
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3(CH2)2
CH3(CH2)2
CH3(CH2)2
CH3(CH2)2
(CH3)2CHCH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
CH3CH2OCOCH2
4-CH3OC6H4
2,4-(CH3O)2C6H3
4-CH3OC6H4CH2
CH3CH2OCOCH2
4-CH3OC6H4
2,4-(CH3O)2C6H3
4-CH3OC6H4CH2
CH3CH2OCOCH2
CH3CH2OCOCH2
4-CH3OC6H4
2,4-(CH3O)2C6H3
4-CH3OC6H4CH2
2,4-(CH3O)2C6H3CH2
87
94
74
77
91
81
78
98
78
81
89
78
99
63
last one in the series owing to its high boiling point. The
required isonitriles 2 were prepared from the corresponding
formamides by treating them with triphosgene in the presence
of triethylamine, as usual, and the reaction products purified by
flash chromatography. Then, with a few exceptions, each of the
Schiff bases was combined with each of the isonitriles and
acetic acid in dry methanol and allowed to react at room
temperature for one to two weeks to give the expected Ugi–
Passerini adducts 3, usually in high yields independently of the
bulkiness of the reagents or that of the reaction products
(Scheme 2, Table 1). The lower yields obtained in the case of
the dibenzyl derivatives may have resulted from the use of the
Schiff base as a crude material. The low stability of the glycine
ester isonitrile is reflected in the lower yields found in the case
of these dipeptide derivatives.
The Ugi–Passerini adducts were reacted with neat trifluoro-
acetic acid (TFA) under reflux; as shown by TLC, the reactions
were complete after a few minutes. The residue obtained
by evaporating the acid was treated with aqueous sodium
hydroxide, followed by washing and precipitation at low pH to
allow separation of the required N-acetylamino acids 4
(Scheme 3, Table 2). As shown in the Table, neither the bulki-
ness of the dialkyl glycine side chains nor the nature of the
isonitrile moiety seems to affect the lability of the amide bond
at their C-terminus, thus allowing good cleavage selectivity and
yields in all cases. Thus, the choice of the isonitrile should be
based only on the availability and price of the starting material.
In addition, the use of 4-methoxybenzylamine seems to be a
good choice to allow the easy removal of the N-alkyl group
present in the Ugi–Passerini adduct (3).
Scheme 3
Table 3 shows the excellent yields obtained in the hydrolysis
of the N-acetylamino acids to the corresponding free deriv-
atives or their hydrochlorides (5). Our results suggest that this is
the best route to the synthesis of bulky α,α-dialkyl glycines, as it
Scheme 2
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Table
3
Synthesis of NH2CR2CO2H (5) by cleavage of CH3-
evaporation of the reaction solvent, once it decomposed before
distilling. Anal. Found: C, 84.0; H, 7.0; N, 3.9. Calc. for
C23H23NO: C, 83.9; H, 7.0; N, 4.2%.
CONHCR2CO2H (4)
Product
Starting material
R
Yield (%)
General procedure for the synthesis of isonitriles 2
5a
5b
5c
5d
4a
4b
4c
4d
CH3CH2
97
92
90
96
CH3(CH2)2
(CH3)2CHCH2
C6H5CH2
The required formamide (0.05 mol) was dissolved in dichloro-
methane (125 ml) and 16.0 ml (0.12 mol) of triethylamine
added. The mixture was cooled in an ice bath and a solution of
5.44 g (0.06 mol) of triphosgene in dichloromethane (50 ml)
added dropwise under vigorous stirring. When the addition was
finished, the reaction mixture was set aside at room temperature
under stirring and samples collected for TLC; when the form-
amide had been consumed (usually an hour was enough), dis-
tilled water (75 ml) was added and the organic layer separated
and dried over anhydrous MgSO4. The residue from evapor-
ation of the solvent was chromatographed through a silica gel
column using dichloromethane as the eluent. The fractions con-
taining the isonitrile were collected and the solvent evaporated
under reduced pressure without heating, the residue being used
without delay.
involves simple procedures in clean reactions leading to high
overall yields, usually above 60%.
Experimental
All ketones except dibenzyl ketone were freshly distilled. Meth-
anol and toluene were dried by standard procedures. All other
solvents and reagents were used as obtained from commercial
sources. The formamides required for the synthesis of iso-
nitriles were prepared from the corresponding amines by the
usual methods. TLC analyses were carried out on 0.25 mm
thick precoated silica plates (Merck Fertigplatten Kieselgel
60F254) and spots were visualised under UV light or by exposure
to vaporised iodine. Preparative chromatography was carried
out on Merck Kieselgel 60 (230–400 mesh). All melting points
were measured on a Gallenkamp melting point apparatus and
Ethyl isocyanoacetate 2a
The reaction was carried out on a 0.1-molar scale to yield iso-
nitrile 2a (8.08 g, 72%) (lit.,8 77%) as a light yellow oil.
1
are uncorrected. H NMR spectra were recorded at 25 ЊC in
4-Methoxyphenyl isonitrile 2b
∼5% CDCl3 solution on a Varian 300 Unity Plus spectrometer;
all shifts are given in δ ppm using δH Me4Si = 0 and J-values
are given in Hz. Assignments were made by comparison of
chemical shifts, peak multiplicity and J-values. 13C NMR spec-
tra were recorded with the same instrument at 75.4 MHz and
using the solvent peak as internal reference; assignments were
carried out by the DEPT 135, HMQC and HMBC techniques.
IR spectra were run on an FTIR Perkin-Elmer 1600 spectro-
photometer. Elemental analyses were carried out on a Leco
CHNS 932 instrument.
The reaction was carried out on a 0.05-molar scale to
yield isonitrile 2b (6.35 g, 95%) (lit.,8 63%) as a light yellow
solid.
2,4-Dimethoxyphenyl isonitrile 2c
The reaction was carried out on a 0.05-molar scale and the
crude product recrystallised from dichloromethane–petroleum
ether (40–60 ЊC) to yield isonitrile 2c (7.07 g, 87%) (lit.,8 41%) as
a pink solid, mp 70–71 ЊC. Anal. Found: C, 66.2; H, 5.7; N, 8.6.
Calc. for C9H9NO2: C, 66.2; H, 5.6; N, 8.6%.
General procedure for the synthesis of Schiff bases 1
The required ketone (0.36 mol) was dissolved in dry toluene (60
ml) and 45.27 g (0.33 mol) of 4-methoxybenzylamine added.
This solution was refluxed overnight under nitrogen and the
condensate collected in a Dean–Stark device to separate the
water. Except for compound 1d, after evaporation of the
solvent, the residue was distilled under reduced pressure and
kept in the cold under nitrogen.
4-Methoxybenzyl isonitrile 2d
The reaction was carried out on a 0.05-molar scale to
yield isonitrile 2d (6.97 g, 95%) (lit.,8 25%) as a light yellow
oil.
2,4-Dimethoxybenzyl isonitrile 2e
The reaction was carried out on a 0.015-molar scale and the
crude product recrystallised from dichloromethane–petroleum
ether (40–60 ЊC) to yield isonitrile 2e (2.30 g, 87%) as a light
yellow solid, mp 66–67 ЊC. Anal. Found: C, 67.6; H, 6.4; N, 8.2.
Calc. for C10H11NO2: C, 67.8; H, 6.3; N, 7.9%.
N-(4-Methoxybenzyl)-3-pentanimine 1a
The crude product was distilled under reduced pressure to yield
imine 1a (53.90 g, 80%) as a colourless oil, bp 126–130 ЊC
(2 mmHg). Anal. Found: C, 75.8; H, 9.4; N, 6.7. Calc. for
C13H19NO: C, 76.1; H, 9.3; N, 6.8%.
General procedure for the Ugi–Passerini reaction
(preparation of 3)
N-(4-Methoxybenzyl)-4-heptanimine 1b
Acetic acid (0.6 g, 0.01 mol) was added to dry methanol (5 ml)
containing the Schiff base (1, 0.01 mol). The mixture was
stirred for 15 minutes and then 0.01 mol of isonitrile (2) was
added and the mixture left at room temperature under nitrogen
in the dark. The reaction was followed by IR spectroscopy,
by monitoring the isonitrile peak fading within the range
2100–2200 cmϪ1. If a precipitate formed either in the course of
the reaction or by concentration at the end, it was filtered off
and recrystallised; otherwise, the residue from evaporation was
chromatographed through a silica gel column that was eluted
with dichloromethane–hexane (1 : 1), followed by neat dichloro-
methane and then by dichloromethane–methanol (50 : 1). The
fractions containing the product (3) were collected and the
solvent evaporated under reduced pressure. The solid residue
was recrystallised.
The crude product was distilled under reduced pressure to yield
imine 1b (61.84 g, 80%) as a colourless oil, bp 140–142 ЊC
(2 mmHg). Anal. Found: C, 77.3; H, 10.2; N, 6.0. Calc. for
C15H23NO: C, 77.2; H, 9.9; N, 6.0%.
N-(4-Methoxybenzyl)-2,6-dimethyl-4-heptanimine 1c
The crude product was distilled under reduced pressure to yield
imine 1c (65.39 g, 76%) as a colourless oil, bp 162–166 ЊC
(2 mmHg). Anal. Found: C, 77.9; H, 10.4; N, 5.4. Calc. for
C17H27NO: C, 78.1; H, 10.4; N, 5.4%.
N-(4-Methoxybenzyl)-1,3-diphenyl-2-propanimine 1d
A slight excess of ketone was used to prepare imine 1d (95.62 g,
88%), which was utilised without purification immediately after
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N-Acetyl-N-(4-methoxybenzyl)-ꢀ,ꢀ-diethylglycylglycine ethyl
ester 3a
N-Acetyl-N-(4-methoxybenzyl)-ꢀ,ꢀ-diisobutylglycylglycine ethyl
ester 3i
The reaction was carried out on a 0.025-molar scale and the
crude product recrystallised from diethyl ether to yield adduct
3a (5.57 g, 60%) as a white solid, mp 95–96 ЊC. Anal. Found: C,
63.2; H, 8.0; N, 7.5. Calc. for C20H30N2O5: C, 63.5; H, 8.0; N,
7.4%.
The reaction was carried out on a 0.015-molar scale to yield
adduct 3i (3.08 g, 49%) as a light yellow oil.
N-Acetyl-N-(4-methoxybenzyl)-ꢀ,ꢀ-dibenzylglycylglycine ethyl
ester 3j
The reaction was carried out on a 0.015-molar scale and the
crude product recrystallised from dichloromethane–diethyl
ether to yield adduct 3j (3.08 g, 41%) as a white solid, mp
156–158 ЊC. Anal. Found: C, 71.4; H, 6.7; N, 5.7. Calc. for
C30H34N2O5: C, 71.7; H, 6.8; N, 5.6%.
N-Acetyl-N-(4-methoxybenzyl)-ꢀ,ꢀ-diethylglycine 4-methoxy-
phenyl amide 3b
The reaction was carried out on a 0.02-molar scale and the
crude product recrystallised from ethyl acetate to yield adduct
3b (6.38 g, 80%) as a white solid, mp 139–140 ЊC. Anal. Found:
C, 69.1; H, 7.5; N, 7.1. Calc.for C23H30N2O4: C, 69.3; H, 7.6; N,
7.0%.
N-Acetyl-N-(4-methoxybenzyl)-ꢀ,ꢀ-dibenzylglycine 4-methoxy-
phenyl amide 3k
The reaction was carried out on a 0.0165-molar scale and the
crude product recrystallised from ethyl acetate–diethyl ether
to yield adduct 3k (4.79 g, 61%) as a light yellow solid, mp
192–194 ЊC. Anal. Found: C, 75.9; H, 6.5; N, 5.4. Calc. for
C33H34N2O4: C, 75.8; H, 6.6; N, 5.4%.
N-Acetyl-N-(4-methoxybenzyl)-ꢀ,ꢀ-diethylglycine 2,4-dimeth-
oxyphenyl amide 3c
The reaction was carried out on a 0.015-molar scale and the
crude product recrystallised from diethyl ether to yield adduct
3c (5.11 g, 80%) as a white solid, mp 131–132 ЊC. Anal. Found:
C, 67.1; H, 7.6; N, 6.7. Calc. for C24H32N2O5: C, 67.3; H, 7.5; N,
6.5%.
N-Acetyl-N-(4-methoxybenzyl)-ꢀ,ꢀ-dibenzylglycine 2,4-dimeth-
oxyphenyl amide 3l
The reaction was carried out on a 0.02-molar scale and the
crude product recrystallised from dichloromethane–diethyl
ether to yield adduct 3l (7.51 g, 68%) as a white solid, mp 200–
201 ЊC. Anal. Found: C, 73.7; H, 6.6; N, 5.1. Calc. for
C34H36N2O5: C, 73.9; H, 6.6; N, 5.1%.
N-Acetyl-N-(4-methoxybenzyl)-ꢀ,ꢀ-diethylglycine 4-methoxy-
benzyl amide 3d
The reaction was carried out on a 0.015-molar scale and the
crude product recrystallised from diethyl ether to yield adduct
3d (5.40 g, 87%) as a white solid, mp 96–97 ЊC. Anal. Found: C,
69.8; H, 7.8; N, 7.0. Calc. for C24H32N2O4: C, 69.9; H, 7.8; N,
6.8%.
N-Acetyl-N-(4-methoxybenzyl)-ꢀ,ꢀ-dibenzylglycine 4-methoxy-
benzyl amide 3m
The reaction was carried out on a 0.01-molar scale and the
crude product recrystallised from ethyl acetate–diethyl ether to
yield adduct 3m (3.71 g, 69%) as a white solid, mp 163–165 ЊC.
Anal. Found: C, 75.9; H, 6.8; N, 5.5. Calc. for C34H36N2O4: C,
76.1; H, 6.8; N, 5.2%.
N-Acetyl-N-(4-methoxybenzyl)-ꢀ,ꢀ-dipropylglycylglycine ethyl
ester 3e
The reaction was carried out on a 0.015-molar scale and the
crude product recrystallised from diethyl ether–petroleum ether
(40–60 ЊC) to yield adduct 3e (3.10 g, 51%) as a white solid, mp
121–122 ЊC. Anal. Found: C, 64.9; H, 8.3; N, 7.0. Calc. for
C22H34N2O5: C, 65.0; H, 8.4; N, 6.9%.
N-Acetyl-N-(4-methoxybenzyl)-ꢀ,ꢀ-dibenzylglycine 2,4-dimeth-
oxybenzyl amide 3n
The reaction was carried out on a 0.013-molar scale and the
crude product recrystallised from ethyl acetate–diethyl ether to
yield adduct 3n (3.25 g, 59%) as a white solid, mp 170–171 ЊC.
Anal. Found: C, 74.0; H, 6.8; N, 4.9. Calc. for C35H38N2O5: C,
74.2; H, 6.8; N, 4.9%.
N-Acetyl-N-(4-methoxybenzyl)-ꢀ,ꢀ-dipropylglycine 4-methoxy-
phenyl amide 3f
The reaction was carried out on a 0.01-molar scale and the
crude product recrystallised from ethyl acetate–petroleum ether
(40–60 ЊC) to yield adduct 3f (3.73 g, 88%) as a white solid, mp
134–135 ЊC. Anal. Found: C, 70.1; H, 7.9; N, 6.7. Calc. for
C25H34N2O4: C, 70.4; H, 8.0; N, 6.6%.
General procedure for the synthesis of the N-acetyl-ꢀ,ꢀ-dialkyl
glycines 4
The Ugi–Passerini adduct (3, 1 g) was dissolved in 5 ml of TFA
and refluxed for 5–10 minutes, during which the solution
became purple. The residue from evaporation of the solvent
was taken up in a 2 M aqueous solution of sodium hydroxide
and the pH adjusted to 12. After leaving for 2 hours under
stirring, the solid residue formed was removed by filtration and
the solution acidified to pH 1 with 6 M aqueous HCl solution.
The precipitate (4) was filtered off, washed with petroleum ether
(40–60 ЊC) and dried in a vacuum oven.
N-Acetyl-N-(4-methoxybenzyl)-ꢀ,ꢀ-dipropylglycine 2,4-dimeth-
oxyphenyl amide 3g
The reaction was carried out on a 0.015-molar scale and the
crude product recrystallised from methanol–diethyl ether to
yield adduct 3g (5.81 g, 85%) as a white solid, mp 154–155 ЊC.
Anal. Found: C, 68.3; H, 8.1; N, 6.1. Calc. for C26H36N2O5: C,
68.4; H, 8.0; N, 6.1%.
N-Acetyl-ꢀ,ꢀ-diethylglycine 4a
The reaction was carried out on a 0.006-molar scale from 3b to
yield the N-acetylamino acid 4a (0.98 g, 94%) as a white solid,
mp 209–211 ЊC. Anal. Found: C, 55.2; H, 8.5; N, 8.1. Calc. for
C8H15NO3: C, 55.5; H, 8.7; N, 8.0%.
N-Acetyl-N-(4-methoxybenzyl)-ꢀ,ꢀ-dipropylglycine 4-methoxy-
benzyl amide 3h
The reaction was carried out on a 0.03-molar scale and the
crude product recrystallised from ethyl acetate–diethyl ether to
yield adduct 3h (11.12 g, 84%) as a white solid, mp 114–115 ЊC.
Anal. Found: C, 71.1; H, 8.4; N, 6.6. Calc. for C26H36N2O4: C,
70.9; H, 8.2; N, 6.4%.
N-Acetyl-ꢀ,ꢀ-dipropylglycine 4b
The reaction was carried out on a 0.005-molar scale from 3h to
yield the N-acetylamino acid 4b (1.02 g, 98%) as a white solid,
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mp 196–197 ЊC. Anal. Found: C, 58.7; H, 9.5; N, 7.0. Calc. for
filtered off and dried to give amino acid 5d (2.45 g, 96%) as a
C10H19NO3: C, 58.7; H, 9.5; N, 7.0%.
white solid, mp 290–297 ЊC. Anal. Found: C, 74.9; H, 6.7; N,
5.5. Calc. for C16H17NO2: C, 75.3; H, 6.7; N, 5.5%.
N-Acetyl-ꢀ,ꢀ-diisobutylglycine 4c
The reaction was carried out on a 0.002-molar scale from 3i to
yield the N-acetylamino acid 4c (1.79 g, 78%) as a white solid,
mp 216–218 ЊC. Anal. Found: C, 62.5; H, 9.8; N, 6.2. Calc. for
C12H23NO3: C, 62.8; H, 10.1; N, 6.1%.
Acknowledgements
We thank the Foundation for Science and Technology
(Portugal) for providing financial support to the Institute of
Biotechnology and Fine Chemistry (University of Minho).
N-Acetyl-ꢀ,ꢀ-dibenzylglycine 4d
The reaction was carried out on a 0.006-molar scale from 3m to
yield the N-acetylamino acid 4d (1.47 g, 99%) as a white solid,
mp 233–235 ЊC. Anal. Found: C, 72.4; H, 6.5; N, 4.7. Calc. for
C18H19NO3: C, 72.7; H, 6.4; N, 4.7%.
References
1 G. Faust and H. Lange, J. Prakt. Chem., 1960, 11, 153.
2 J. F. Diehl and E. A. Young, J. Med. Chem., 1964, 7, 820.
3 W. J. McGahren and M. Goodman, Tetrahedron, 1967, 23,
2017.
General procedure for the synthesis of ꢀ,ꢀ-dialkyl glycine hydro-
chlorides 5
4 D. S. Jones, G. W. Kenner, J. Preston and R. C. Sheppard, J. Chem.
Soc., 1965, 6227.
5 C. Toniolo, Janssen Chim. Acta, 1993, 11, 10 (review article);
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M. Crisma and C. Toniolo, Eur. J. Org. Chem., 2001, 1821.
6 V. De Filippis, F. De Antoni, M. Frigo, P. P. Laureto and
A. Fontana, Biochemistry, 1998, 37, 1686; H. Medzihradszky-
Schweiger, K. Medzihradszky, H. Nádasi and H. Suli-Vargha, in
Peptides 1998, Proceedings of the 25th European Peptide Symposium,
eds. S. Bajusz and F. Hudecz, Akadémiai Kiadó, Budapest, 1999,
p. 606.
The required N-acetyl-α,α-dialkyl glycine (4, 0.01 mol) was
refluxed for 2 hours in a 6 M aqueous HCl solution (50 ml). The
solvent was then evaporated to dryness and the residue (5) dried
in a vacuum oven. In the case of the dibenzyl derivative aque-
ous HBr (48%) was used, as the compound resisted dissolution
in HCl.
7 L. Goodson, I. L. Honigberg, J. J. Lehman and W. H. Burton, J. Org.
Chem., 1960, 25, 1920; B. Lygo, J. Crosby and J. A. Peterson,
Tetrahedron Lett., 1999, 40, 8671.
8 G. Gokel, P. Hoffmann, H. Kleimann, H. Klusacek, G. Ludke,
D. Marquaerding and I. Ugi, in Isonitrile Chemistry, ed. I. Ugi,
Academic Press, New York and London, 1971, p. 201.
9 H. L. Maia, B. Ridge and H. N. Rydon, J. Chem. Soc., 1973, 98.
10 A. M. Freitas and H. L. S. Maia, in Peptides 1988, Proceedings of the
20th European Peptide Symposium, eds. G. Jung and E. Bayer, Walter
de Gruyter, Berlin and New York, 1989, p. 13.
11 R. W. Armstrong, A. P. Combs, P. A. Tempest, S. D. Brown and
T. A. Keating, Acc. Chem. Res., 1996, 29, 123 and refs. therein;
see also C. Hulme, J. Peng, S.-Y. Tang, C. J. Burns, I. Morize and
R. Labaudiniere, J. Org. Chem., 1998, 63, 8021.
ꢀ,ꢀ-Diethylglycine hydrochloride 5a
The reaction was carried out on a 0.0058-molar scale to yield
amino acid 5a (0.94 g, 97%) as a white solid, mp > 288 ЊC (dec.).
Anal. Found: C, 42.8; H, 8.3; N, 8.3. Calc. for C6ClH14NO2: C,
43.0; H, 8.4; N, 8.4%.
ꢀ,ꢀ-Dipropylglycine hydrochloride 5b
The reaction was carried out on a 0.01-molar scale to yield
amino acid 5b (1.80 g, 92%) as a white solid, mp > 290 ЊC (dec.).
Anal. Found: C, 49.1; H, 9.1; N, 7.4. Calc. for C8ClH18NO2: C,
49.1; H, 9.3; N, 7.2%.
12 R. J. Linderman, S. Binet and S. R. Petrich, J. Org. Chem., 1999, 64,
336.
13 J. R. Spencer, N. G. J. Delaet, A. Toy-Palmer, V. V. Antonenko and
M. Goodman, J. Org. Chem., 1993, 58, 1635.
14 C. J. Creighton, T. T. Romoff, J. H. Bu and M. Goodman, J. Am.
Chem. Soc., 1999, 121, 6786.
15 S. P. G. Costa, H. L. S. Maia and S. M. M. A. Pereira-Lima,
communication no. P022 to the 16th American Peptide Symposium,
Minneapolis, 1999; S. P. G. Costa, H. L. S. Maia and S. M. M. A.
Pereira-Lima, in Peptides 2000, Proceedings of the 26th European
Peptide Symposium, eds. J. Martinez and J.-A. Fehrentz, EDK, Paris,
2001, p. 367.
ꢀ,ꢀ-Diisobutylglycine hydrochloride 5c
The reaction was carried out on a 0.01-molar scale to yield
amino acid 5c (2.01 g, 90%) as a white solid, mp 271–273 ЊC.
Anal. Found: C, 53.8; H, 9.6; N, 6.4. Calc. for C10ClH22NO2: C,
53.7; H, 9.9; N, 6.3%.
ꢀ,ꢀ-Dibenzylglycine 5d
The reaction was carried out on a 0.01-molar scale. After
evaporation of the solvent, the residue was dissolved with a 1 M
solution of NaOH, precipitated at pH 5; the precipitate was
16 T. Johnson, M. Quibell, D. Owen and R. C. Sheppard, J. Chem. Soc.,
Chem. Commun., 1992, 1573.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 4 7 5 – 1 4 7 9
1479