Synthesis of highly functionalised dibenzylglycine derivatives via the Suzuki-Miyaura coupling reaction

Article abstract of DOI:10.1016/S0960-894X(01)00686-2

Several α,α-dibenzylglycine (α-benzylphenylalanine) derivatives were prepared by alkylation of the ethyl isocyanoacetate with different benzyl bromide derivatives. Various aryl groups were introduced in the dibenzylglycine moiety via the Suzuki-Miyaura coupling reaction.

Full text of DOI:10.1016/S0960-894X(01)00686-2

Bioorganic & MedicinalChemistry Letters 12 (2002) 105–108
Synthesis of Highly Functionalised Dibenzylglycine Derivatives
Via the Suzuki–Miyaura Coupling Reactiony
Sambasivarao Kotha,* Manoranjan Behera and Ramanatham Vinod Kumar
Department of Chemistry, Indian Institute of Technology-Bombay, Powai, Mumbai 400 076, India
Received 13 September 2001; accepted 13 October 2001
Abstract—Several a,a-dibenzylglycine (a-benzylphenylalanine) derivatives were prepared by alkylation of the ethyl isocyanoacetate
with different benzyl bromide derivatives. Various aryl groups were introduced in the dibenzylglycine moiety via the Suzuki–
Miyaura coupling reaction. # 2001 Elsevier Science Ltd. All rights reserved.
a,a-Disubstituted amino acids (a,aAAs) are important
members of modified amino acids.1 Replacement of the
a-hydrogens of glycine by an alkyl group leads to
a,aAAs. The steric hindrance of the quaternary centre
of the a-aminoisobutyric acid (Aib) combined with helix
forming capacity of this amino acid has attracted the
attention of structural biologists and protein crystal-
lographers.2 The dibenzylglycine (Dbzg) is a special
structuralvariant of Aib. In recent years, there has been
an increasing interest in the synthesis of structuralvar-
iants of Aib with the aim of incorporating them into
peptides instead of Aib. The presence of two benzyl
groups at a position of Dbzg not only provides rigidity
to the peptide backbone in which it is incorporated, but
also acts as a useful vehicle for studying p–p interac-
tions.3,4 In this context, a generalapproach for the
synthesis of Dbzg derivatives is of immense importance.
equivalents of base.9 Although this method is suitable
for commercially available and inexpensive bromides, it
is not suitable for the preparation of highly functiona-
lised substrates. Surprisingly, in some instances even
glycine-based chiral auxiliaries10 have been used to pre-
pare achiralDbzg derivatives, as there are no simpel
glycine equivalents available which can undergo dialky-
lation with benzyl bromides.
Herein, we describe for the first time a generaland use-
fulmethod for the preparation of a variety of Dbzg
derivatives using the ethylisocyanoacetate as a gylcine
equivalent.11 We have also shown that these a,aAA
derivatives can further be modified by the Suzuki–
Miyaura12 coupling reaction as a key step. To test this
idea, severalgylcine equivaenl ts were screened for
dibenzylation and found that the reaction of benzyl
bromides with ethylisocyanoacetate in NaH/DMSO
conditions13 gave a mixture of both the mono- and di-
alkylated products. In this regard, alkylation of various
glycine equivalents under phase-transfer catalysis (PTC)
conditions was investigated.14,15 We found that under
PTC conditions [tetrabutylammonium hydrogensulfate
(TBAHS), K2CO3, CH3CN, reflux] the ethyliso-
cyanoacetate can be dibenzylated in high yield. Having
found the suitable conditions for the dialkylation with
various benzylbromide derivatives (Scheme 1), the
A perusalof ilterature reveaeld that the preparation of
Dbzg is not a trivialexercise. For exampel, preparation
of the Dbzg by the Bucherer–Berg method,5 or the Ugi-
three-component procedure6 or the Schmidt rearrange-
ment method7 is limited to only simple substitution
pattern. The dibenzylhydantoin prepared by the
Bucherer–Berg method have been difficult to hydrolyse
to the free amino acid under drastic reaction conditions
due to steric hindrance.8 A more recent method invol-
ving alkylation of the ketimine derivative with benzyl
bromides require 5 equivalents of alkyl halide and 10
yA portion of the work was presented at the 13th Research Scholars
Meet, UDCT, Mumbai, 2–3 February 2001; Behera, M., Kotha, S.
Development of New Methodologies for the Synthesis of Dibenzyl-
glycine (a-Benzylphenylalanine) Derivatives
*Corresponding author. Tel.: +91-22-576-7160; fax: +91-22-572-
3480 or 91-22-576-7152; e-mail: srk@chem.iitb.ac.in
Scheme 1. (i) Benzylbromide, PTC, K 2CO3; (ii) concd HCl, EtOH;
(iii) Ac2O, DMAP; (iv) concd HCl, diethyl ether; (v) Boc2O, chloro-
form.
0960-894X/02/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00686-2

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S. Kotha et al. / Bioorg. Med. Chem. Lett. 12 (2002) 105–108
Table 1. List of various derivatives prepared under PTC conditions
S no.
Dialkylated product
Yield (%)
88
Hydrolysis product
Yield (%)
72
Mp (ꢀC)
163–165
1
2
3
4
5
70
70
32
33
98
59
71
66
104–106
110–112
158–160
138–140
attention was then directed towards the hydrolysis of
the isonitrile moiety to generate various amino ester
derivatives of Dbzg. In this regard, isonitrile derivative
method. Moreover, preparation of the building block 2
allows the synthesis of highly substituted Dbzg deriva-
tives easily.
was treated with concd HClin ethanolto give an amino
16
ester along with N-formylderivative.
Attempts to
In summary, the methodology developed here increase
the scope of the application of ethyl isocyanoacetate as
a glycine equivalent. Since incorporation of a,aAA into
peptides lead to modified analogues with increased
lipophilicity and increased resistance to enzymatic
hydrolysis, the methodology developed here is likely to
find usefulappiclations in bioorganic and medicinal
chemistry. The strategy adopted here for the generation
of various Dbzg derivatives via the Suzuki–Miyuara
coupling reaction may be useful for the development of
lead modification in peptide drugs by a combinatorial
approach.
separate the amino compound from N-formylderivative
by acid-base work up procedure was ineffective. Conse-
quently, the total hydrolysis mixture was treated with
acetic anhydride in the presence of 4-(dimethylamino)-
pyridine. After standard workup, we were unable to
separate the acetyland formylderivatives by siilca gel
column chromatography. Therefore, the isonitrile deri-
vative was treated with concd HClin ether to deliver the
N-formylderivative as the soel product and thus avoid-
ing the separation of the contaminated acetylderivative.
Various formylderivatives prepared by this procedure
are shown in Table 1. The required benzyl bromides are
either commercially available or prepared by tactical
adoption of the known procedures.17
General Procedure for Alkylation of Ethyl
Isocyanoacetate with Various Benzyl Bromides
Having prepared various dibenzylglycine derivatives,
the attention was then focused on the Suzuki–Miyaura
coupling of the dibromo derivative 1. Attempts to cou-
ple 1 with various boronic acid derivatives under Pd(0)
catalysis conditions proved to be ineffective (Scheme 2).
Although, various ligands are known to catalyse the
unreactive arenes for Suzuki–Miyaura coupling,18 the
diiodo compound 2 was chosen as the starting substrate
to test the Suzuki–Miyaura reaction. In this regard, the
coupling reaction of the diiodo compound 2 with var-
ious boronic acids was attempted and the cross-cou-
pling products were obtained in good yield (Table 2).
Since N-Boc derivatives are usefulin peptide synthesis
we have prepared N-Boc protected derivative 3 and
performed the coupling reaction. The cross-coupling
products reported in Tables 2 and 3 shows that this
approach is more versatile than the direct alkylation
To a solution of the ethyl isocyanoacetate (0.5 mmol) in
acetonitrile (12 mL) was added finely powdered K2CO3
(6 mmol) and TBAHS (0.3 mmol) and the electrophile
(1 mmol). The resulting heterogeneous mixture was
heated at 70–80 ꢀC for 12–20 h (or stirred at rt in case of
Scheme 2. (i) ArB(OH)2, Pd(0), Na2CO3, THF/toluene, H2O.

S. Kotha et al. / Bioorg. Med. Chem. Lett. 12 (2002) 105–108
107
Table 2. List of various N-formyl derivatives of dibenzylglycines
prepared by Suzuki–Miyaura coupling reaction
Table 3. List of various N-Boc derivatives of dibenzylglycines pre-
pared by Suzuki–Miyaura coupling reaction
S no.
Cross-coupling product
Yield (%)
72
Mp (ꢀC)
145–147
S no.
Cross-coupling product
Yield
(%)
Mp
(ꢀC)
1
72
172–73
1
2
3
4
5
81
86
70
93
151–153
176–178
216–218
124–126
2
3
4
5
96
72
53
79
—
62–64
150–52
142–44
6
92
130–132
General Procedure for Suzuki Coupling Reactions
To the solution of 2 (1 equiv) in THF/toluene (1:1), aryl
boronic acid (4 equiv) and Na2CO3 (4 equiv) in H2O
was added. Then, the reaction mixture was degassed for
30 min and Pd(PPh3)4 (10 mol%) was added. The
resultant mixture was heated to (70–80 ꢀC) for several
hours untilalthe starting materialhas been consumed
(TLC monitoring). The reaction mixture was cooled to
rt and extracted with dichloromethane, washed with
water, brine and dried over MgSO4. The solvent was
evaporated and the product was purified by silica gel
column chromatography. Elution of the column with
ethylacetate/pet ether mixture gave the cross-coupilng
product.19
thiophene) untilalthe starting materialhad been con-
sumed (TLC monitoring). Then, the reaction mixture
was cooled and filtered through a cintered glass crucible
to remove the unwanted salts. Then, the solid material
was washed with acetonitrile and the filtrate was eva-
porated. The residue was taken in diethylether and
washed with water, brine and dried over MgSO4. The
solvent was evaporated and the material was purified by
silica gel column chromatography. Elution of the col-
umn with ethylacetate/pet ether mixture gave the iso-
nitrile derivative.
Acknowledgements
General Procedure for the Hydrolysis of the Coupling
Product
We acknowledge the RSIC-Mumbai for recording the
1
spectraldata ( H NMR & Mass). M.B. thanks CSIR-
New Delhi for the award of Research Fellowship.
A solution of the coupling product (1 mmol) in diethyl
ether (5–10 mL) was added a few drops of concentrated
HClat 0 ꢀC and the reaction mixture was stirred at rt.
At the end of the reaction (TLC monitoring), water (4–6
mL) was added and the reaction mixture was extracted
with diethylether and washed with water, brine and
dried over MgSO4. Then the solvent was evaporated at
reduced pressure and the product was purified by silica
gel column chromatography. Elution of the column
with ethylacetate/pet ether mixture gave the required
N-formylderivative.
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