Synthesis of novel glycopeptidomimetics via Nβ-protected- amino alkyl isonitrile based Ugi 4C reaction

Article abstract of DOI:10.1016/j.tetlet.2013.06.013

The Ugi-4C reaction employing N^β-protected-amino alkyl isonitrile, amino acid ester, aldehyde, and glycosyl acid has resulted in novel glycosylated peptidomimetics. The extension of MCR products for the synthesis of N,N′-orthogonally protected

Full text of DOI:10.1016/j.tetlet.2013.06.013

Tetrahedron Letters 54 (2013) 4409–4413
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of novel glycopeptidomimetics via Nb-protected-amino
alkyl isonitrile based Ugi 4C reaction
⇑
Basavalingappa Vasantha, Girish Prabhu, Hosmani Basavaprabhu, Vommina V. Sureshbabu
Peptide Research Laboratory, Department of Studies in Chemistry, Bangalore University, Room No. 109, Central College Campus, Dr. B.R. Ambedkar Veedhi, Bangalore 560 001, India
a r t i c l e i n f o
a b s t r a c t
The Ugi-4C reaction employing Nb-protected-amino alkyl isonitrile, amino acid ester, aldehyde, and gly-
cosyl acid has resulted in novel glycosylated peptidomimetics. The extension of MCR products for the
synthesis of N,N0-orthogonally protected glycosylated peptidomimetics has also been demonstrated.
Ó 2013 Elsevier Ltd. All rights reserved.
Article history:
Received 7 April 2013
Revised 1 June 2013
Accepted 5 June 2013
Available online 11 June 2013
Keywords:
Ugi-MCR
N-protected-b-amino alkyl isonitrile
Sugar acid
Glycopeptidomimetic
Isonitriles have unique reactive features due to their ability to
form reactive -adducts on reaction with both nucleophiles and
Glycopeptides play a significant role in cell growth regulation,
cancer cell metastasis, protein folding, cell adhesion, viral, bacte-
rial, and parasitical infections.10,11 Also there is a pressing need
for methods that provide access to glycopeptides to explore vari-
ous biological functions such as in cellular differentiation, cell–cell
communication, immune response, and also for the development
of glycopeptide-based drugs with improved pharmacokinetic
properties.12 Due to this wide spread application several groups
have reported the synthesis of glycopeptide derivatives via Ugi
four-component condensation (4CC) reaction.13–15 Recently,
Volonterio and co-workers reported the synthesis of diverse pep-
tide sugar conjugates through a regiospecific four-component
reaction.16 Thus in view of their biological significance there is
an untiring interest over the protocols that generate diverse glyco-
peptides and glycopeptidomimetics.17 An interesting application of
N-protected-b-amino alkyl isonitriles in the Ugi MCR for generat-
ing a new variety of glycosylated peptidomimetics has been dem-
onstrated in the present work.
a
electrophiles at the same atom under mild conditions. Isonitrile
based multicomponent reactions1,2 (IMCRs) such as Ugi four-com-
ponent reaction3 (U4CR) and Passerini three-component reaction4
(P3CR) have shown tremendous synthetic potential for the conver-
gent synthesis of plethora of diverse molecular scaffolds over the
last decade. The U4CR involves mainly, condensation of an amine,
aldehyde, isonitrile, and a carboxylic acid bearing substrates to
generate a plethora of peptide-like molecules.5–7 Robustness of this
reaction makes it possible to access molecular complexity and
diversity which is useful for organic synthesis and drug discovery
program, simply by suitable design of the starting materials in an
atom- and step-economical way. Thus far, the majority of the re-
ports on Ugi-MCR have employed isocyano esters/carboxamides
that are prepared by the dehydration of formyl-amino esters/
amides as the isonitrile components.4b Nb-protected amino alkyl
isonitriles prepared through carboxy modification of correspond-
ing b-amino acids were first reported by our group as an alternate
class of isonitriles derived from amino acids.8 Switching the isoni-
trile position from N- to C-terminus of the amino acid skeleton
leads to an entirely new repertoire of Ugi products that were hith-
erto not accessible by classical isonitrile esters. Presently, we are
engaged in demonstrating its synthetic utility in isonitrile based
MCRs leading to novel peptidomimetics as well as
glycopeptidomimetics.9
To execute the designed protocol, the essential starting materi-
als are N-protected-b-amino alkyl isonitriles, sugars equipped with
a carboxylic group,
a-amino alkyl esters, and commercially avail-
able aldehydes. Nb-protected amino alkyl isonitriles were prepared
as reported by us previously.8 A further task at this stage was to
equip sugar components with a carboxy group, that is, to install
a carboxy group on the sugar or to attach a carboxy functionalized
molecule to a suitably protected sugar. Thus, three different kinds
of sugar acids were prepared following established protocols18–23
and employed in this study (Fig. 1).
⇑
Corresponding author. Tel.: +91 80 2296 1339, mobile: +91 9986312937.
E-mail addresses: hariccb@hotmail.com, sureshbabuvommina@rediffmail.com,
For the synthesis of galactose-6-acid 1, initially,
a-D-galactose
was protected as (1,2),(3,4)-diacetylgalactopyranose by treating
hariccb@gmail.com (V.V. Sureshbabu).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.013

4410
B. Vasantha et al. / Tetrahedron Letters 54 (2013) 4409–4413
D-Galactose
D-Glucose
D-Glucose
1. CuSO4, H+,
acetone
2. TEMPO
BzO
O
AcO
BzO
O
AcO
N3
BzO
AcO
BzO
Br
OAc
1. H-Gly-OMe
2. -OH
COOH
"click"
O
OH
O
BzO
AcO
N
O
O
N
N
H
O
O
O
BzO
BzO
N
COOH AcO
AcO
OH
OBz
O
O
OAc
1
2
3
Figure 1. Sugar acids employed in Ugi-MCR.
biologically significant triazole moiety.20,22,23 Commercially avail-
able benzaldehyde, isovaleraldehyde, and furfuraldehyde were
used as the aldehyde components, while methyl esters of several
amino acids as amine components in the present work.
In an initial experiment, equimolar quantities of benzaldehyde
and H-Phe-OMe were stirred in MeOH to generate an imine. After
the complete formation of the imine (by TLC analysis), Fmoc-Ala-
R3 CO2CH3
O
N
OCH3
H
H
N
H
H
R3
H
H
attack from top face
attack from top face
(R3 bulkier than CO2CH3)
w
[CH2NC] 4a and (1,2),(3,4)-diacetylgalactopyranosyl-6-acid 1 in
MeOH were added. The reaction mixture was stirred at rt for
48 h. A simple aqueous work-up followed by chromatographic
purification afforded the glycoconjugate 5a in 85% yield.24 How-
ever, the possible diastereomers generated due to the new chiral
center at aldehydic carbon, could not be separated through column
chromatography. The chiral HPLC analysis of 5a showed the diaste-
reomers in 97.5:2.5 ratio.25 The high diastereoselectivity observed
for the Ugi 4CR product can be attributed to the use of amino acid
ester as the amine component, which is in agreement with the ear-
lier reports.3,9,26 According to the well known Ugi-4CC mechanism,
diastereoselectivity can be explained by the preferential attack of
carbenoid carbon of isocyanide on protonated imine from top face,
as described in Figure 2. In a similar way, two other glycosylated
Figure 2. Conformations of protonated iminium ion of amino acid ester for high
diastereoselectivity via Ugi-MCR.
with CuSO4/cat. H2SO4 in acetone and later subjected to oxidation
using (2,2,6,6-tetramethylpiperidin-1-yl)oxyl [TEMPO] to convert
C6–CH2OH into COOH.18 The glycosyl acid 2 was obtained by a
reaction of 2,3,4,6-tetra-O-benzoyl-a-D-glucopyranosyl-1-bro-
mide19 with Gly-OMe in the presence of K2CO3 followed by the es-
ter hydrolysis. The sugar acid 3 was prepared by Cu-mediated
‘click’ reaction of sugar-1-azide with propiolic acid.20,21 The latter
molecule would be interesting by itself owing to the presence of
R1
R3
R2 CHO
NC
+
+
H2N COOMe
PgHN
4
S
1
u
d
g
a
ci
r
a
a
r
c
i
d
ga
u
3
S
Sugar acid 2
R1
R2 R3
N
R1
R2 R3
N
R1
R2 R3
N
H
N
H
N
H
N
PgHN
COOMe PgHN
O
COOMe PgHN
AcO
COOMe
O
O
O
O
O
O
BzO
O
AcO
O
O
NH
O
BzO
BzO
N
N
O
O
N
AcO
OBz
OAc
7a-7c
5a-5c
6a
Scheme 1. Synthesis of N-glycosylated peptidomimetics via Ugi-MCR.

B. Vasantha et al. / Tetrahedron Letters 54 (2013) 4409–4413
4411
Table 1
List of Ugi products prepared
Entry Ugi construct
Yield
(%)
HRMS [M+Na]+
obsd (calcd)
Entry Ugi construct
Yield
(%)
HRMS [M+Na]+
obsd (calcd)
Ph
Ph
O
O
S
2
H
Ph
N
H
N
FmocHN
N
COOMe
O
BocHN
N
COOBn
O
O
870.3571
(870.3578)
5a
85
7a
76
1029.40a (1029.35)
O
O
AcO
O
O
O
O
N
N
AcO
N
AcO
OAc
Ph
Ph
H
N
H
N
FmocHN
FmocHN
N
COOMe
O
ZHN
AcO
N
COOMe
892.4361
(892.4360)
931.3701
(931.3701)
O
5b
83
7b
82
O
O
N
O
O
AcO
O
O
N
O
O
N
AcO
OAc
BnOOC
Ph
O
O
NHBoc
H
N
4
H
N
FmocHN
N
COOMe
O
N
COOMe
O
O
5c
80
969.45 (969.45)a
7c
78
1125.40 (1125.41)a
AcO
O
O
O
N
N
AcO
O
N
AcO
O
O
OAc
Ph
H
N
ZHN
N
COOMe
O
1127.4269
(1127.4266)
6a
81
O
BzO
O
NH
BzO
BzO
OBz
a
ESI-MS.
peptides 5b and 5c were obtained based on sugar acid 1. In the
next set of experiments sugar acid components 2 and 3 were also
used successfully in the Ugi MCR to afford corresponding adducts
6a and 7a–c (Scheme 1, Table 1) 27. Chiral HPLC analysis of the
products 6a and 7a revealed two peaks corresponding to the two
diastereomeric products in the ratios 97:3 and 95:5, respectively.
Thus obtained Ugi-adducts were stable and available to be in-
serted into a peptide chain upon deprotection of either terminus
as per the design. We demonstrated terminal extensions on a
few selected Ugi-adducts either by N-deprotection and coupling
with another N-protected amino acid or by hydrolysis of the ester
followed by carboxy activation and coupling to an amine head
(Scheme 2).
tained in 88% and 85% yields, respectively, using a combination of
Fmoc/Z and Z/Boc groups, respectively. The reaction was facile and
the products were characterized by NMR and mass spectral analy-
ses. The orthogonality of the protecting groups on compounds 12
allowed the selective chain extension on either terminus which
was demonstrated by preparing 13a and 13b from their parent
Ugi-adducts 12a and 12b, respectively (Scheme 4).
In summary, N-protected amino alkyl isonitriles have been em-
ployed in the Ugi multi-component reaction for constructing a new
class of neoglycopeptidomimetics. Three different types of glycosyl
acids were employed to obtain novel Ugi scaffolds. All the Ugi-ad-
ducts are isolated as stable compounds, characterized, and some of
them were engaged in chain extension on either terminus to dem-
onstrate their further synthetic utility. With the ever expanding
importance of glycoconjugates in various drug discovery programs,
the molecular scaffolds that are presented in this work expand the
repertoire of arsenal at the disposal of chemists working in this
exciting area.
In the second part of the study, another variety of glycopepti-
domimetics viz., N,N0-orthogonally protected glycosylated peptides
were prepared simply by exchanging the amine and carboxy con-
tributors in the above described reaction. In effect, the reaction in-
a
volved 2,3,4,6-tetra-O-acetyl-glucopyranosyl-1-amine and an N -
protected amino acid along with Nb-protected amino alkyl isoni-
trile and aldehyde. Orthogonality for the N-protecting groups of
the participating reactants viz., isonitrile and acid was maintained
so as to enable selective deprotection/chain extension after the
assembly of MCR adducts (Scheme 3). Thus 12a and 12b were ob-
Acknowledgment
We thank the Board of Research in Nuclear Sciences (BRNS),
Mumbai (No. 2011/37C/35/BRNS) for the financial assistance.

4412
B. Vasantha et al. / Tetrahedron Letters 54 (2013) 4409–4413
R1
R2 R3
N
O
R1
R2 R3
N
DEA:DCM (1:1) for 5a-c
TFA:DCM for 7a
H
N
H
N
PgHN
PgHN
COOX
N
H
COOX
EDC/HOBt
R4
O
O
R
O
Pg-CH(R4)-OH
O
R
R = sugar acid (5a-c)
R = triazole acid (7a)
8a: Pg = Z; X = CH3; R1 = CH3; R2 = C6H5; R3 = CH2C6H5; R4 = CH2C6H5 (82%)
8b: Pg = Boc; X = CH3; R1 = CH2CH(CH3)2; R2 = CH2CH(CH3)2; R3 = CH2C6H5; R4 = CH3 (83%)
8c: Pg = Z; X = CH3; R1 = CH(CH3)2; R2 = C4H4O; R3 = (CH2)4NHBoc; R4 = H (85%)
10a: Pg = Fmoc; X = CH2C6H5; R1 = (CH2)2SCH3; R2 = C4H4O; R3 = C6H5; R4 = CH(CH3)2 (83%)
1N LiOH for 8a-c
Pd-C/H2 for 10a
O
R1
R2 R3
N
H
N
H
N
PgHN
COOMe
N
H
EDC/HOBt
R4
O
O
R5
H-CH(R5)-OMe
O
R
9a: Pg = Z; R1 = CH3; R2 = C6H5; R3 = CH2C6H5; R4 = CH2C6H5; R5 = CH3 (85%)
9b: Pg = Boc; R1 = CH2CH(CH3)2; R2 = CH2CH(CH3)2; R3 = CH2C6H5; R4 = CH3; R5 = H (81%)
9c: Pg = Z; R1 = CH(CH3)2; R2 = C4H4O; R3 = (CH2)4NHBoc; R4 = H; R5 = C6H5 (82%)
11a: Pg = Fmoc; R1 = (CH2)2SCH3; R2 = C4H4O; R3 = C6H5; R4 = CH(CH3)2; R5 = CH3 (79%)
Scheme 2. Chain extension on N-glycosylated peptidomimetics 5 and 7.
R3
R1
R2
O
R1
AcO
Pg2HN COOH
H
N
NHPg2
R2 CHO
O
+
Pg1HN
NC
AcO
NH2
+
Pg1HN
N
AcO
R3
OAc
O
O
OAc
12a, b
OAc
OAc
OAc
Pg1
12a Fmoc
12b
R2
Pg2
Z
Boc CH3
R1
CH2C6H5
R3
Yield (%)
CH3
88
CH(CH3)2 85
Ph
iBu
Z
Scheme 3. Synthesis of orthogonally protected N-glycosylated peptidomimetics.
PVC-Pd0/H2 for 12a
R4
R1
R2
O
R1
R2
O
H
N
H
N
TFA:DCM (1:1) for 12b
H
N
NHPg2
Pg1HN
NHPg2
N
Pg1HN
N
EDC/HOBt
O
R3
OAc
OAc
O
O
R3
Pg-CH(R4)-OH
O
O
OAc
12a, b
13a, b
OAc
OAc
OAc
OAc
OAc
Pg1
Pg2
Yield (%)
85
R2
R4
CH(CH3)2
CH(CH3)2 CH2C6H5 80
R1
R3
CH3
13a Fmoc Boc CH2C6H5
Ph
iBu
13b
Z
Fmoc CH3
Scheme 4. Chain extension on orthogonally protected Ugi products 12a and 12b.
Supplementary data
References and notes
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.06.
013.
3. Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168.

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13. Drabik, J. M.; Achatz, T.; Ugi, I. Proc. Estonian Acad. Sci. Chem. 2002, 51, 156.
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60.9, 67.5, 70.3, 70.5, 70.9, 96.8, 109.1, 110.1, 126.1, 126.4, 127.0, 127.6, 127.7,
127.9, 128.3, 128.8, 129.1, 129.3, 129.9, 130.7, 141.2, 143.9, 155.9, 168.2, 170.3,
170.9; HR-MS calcd for C48H53N3O11 m/z 870.3578 [M+Na]+, found 870.3571.
Compound 6a: 1H NMR (DMSO-d6, 400 MHz) d 0.98 (d, J = 6.4 Hz, 6H), 1.71 (m,
2H), 1.81 (m, 2H), 3.12 (d, J = 6.2 Hz, 2H), 3.45 (m, 3H), 3.65 (s, 3H), 4.11 (s, 2H),
4.43 (t, J = 4.8 Hz, 1H), 4.50 (m, 2H), 4.61 (d, J = 6.4 Hz, 2H), 4.75 (m, 1H), 4.81
(m, 1H), 5.15 (m, 1H), 5.25 (s, 2H), 5.34 (m, 1H), 6.11 (br s, 1H), 6.99 (m, 2H),
7.25–7.50 (m, 30H); 13C NMR (DMSO-d6, 100 MHz) d 20.2, 21.5, 37.8, 41.3, 44.1,
44.3, 44.8, 50.1, 51.8, 52.5, 64.8, 65.1, 70.5, 71.2, 72.2, 73.1, 76.5, 125.9, 127.1,
127.8, 128.2, 128.6, 128.9, 129.3, 129.8, 130.5, 137.8, 140.9, 155.8, 165.1, 166.5,
168.9, 171.2; HR-MS calcd for C62H64N4O15 m/z 1127.4266 [M+Na]+, found
1127.4269.
Compound 7a: 1H NMR (DMSO-d6, 400 MHz) d 1.27 (s, 9H), 1.81 (m, 2H), 1.99
(s, 12H), 2.11 (s, 3H), 2.38 (t, J = 4.8 Hz, 2H), 3.35 (m, 2H), 4.12 (m, 1H), 4.25 (d,
J = 5.2 Hz, 2H), 4.51 (m, 1H), 4.68 (m, 1H), 4.71 (m, 1H), 5.12 (m, 1H), 5.25 (s,
2H), 5.68 (s, 1H), 6.01 (m, 1H), 6.12 (s, 1H), 6.20 (m, 1H), 6.25 (d, J = 5.8 Hz, 1H),
7.05–7.25 (m, 11H), 6.98 (br s, 2H), 8.11 (s, 1H); 13C NMR (DMSO-d6, 100 MHz)
d 16.8, 20.5, 27.9, 28.3, 30.5, 43.1, 49.8, 52.5, 55.3, 58.1, 65.1, 67.7, 70.8, 71.3,
75.2, 78.9, 89.3, 105.6, 109.8, 126.7, 128.9, 129.8, 131.5, 134.5, 141.8, 143.7,
152.3, 155.5, 162.1, 168.5, 170.1, 171.5; ESI-MS calcd for C48H58N6O16S m/z
1029.35 [M+Na]+, found 1029.40.
Compound 8a: 1H NMR (DMSO-d6, 400 MHz) d 1.18 (s, 3H), 1.45 (s, 12H), 3.01
(d, J = 5.2 Hz, 2H), 3.25 (d, J = 5.2 Hz, 2H), 3.51 (m, 2H), 3.65 (s, 3H), 4.12 (m,
1H), 4.21 (m, 1H), 4.35 (m, 1H), 4.48 (d, J = 5.6 Hz, 1H), 4.85–4.93 (m, 3H), 5.12
(d, J = 5.2 Hz, 1H), 5.35 (s, 2H), 5.51 (s, 1H), 6.91–6.99 (m, 3H), 7.12–7.20 (m,
20H); 13C NMR (DMSO-d6, 100 MHz) d 19.1, 25.1, 33.8, 36.9, 45.3, 51.2, 52.5,
54.4, 58.6, 63.3, 65.1, 66.2, 67.2, 71.1, 71.9, 98.9, 106.9, 109.8, 125.7, 127.1,
127.7, 128.6, 129.1, 129.7, 135.7, 139.4, 141.1, 155.5, 168.1, 169. 3, 171.5; HR-
MS calcd for C50H58N4O12 m/z 929.3949 [M+Na]+, found 929.3944.
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Compound 9b: 1H NMR (DMSO-d6, 400 MHz) d 0.95 (d, J = 6.0 Hz, 12H), 1.37 (s,
9H), 1.43 (s, 12H), 1.45–1.51 (m, 5H), 1.62 (m, 2H), 1.81 (m, 2H), 2.99 (d,
J = 5.4 Hz, 2H), 3.25 (m, 2H), 3.65 (s, 3H), 4.11 (d, J = 4.8 Hz, 2H), 4.25 (m, 2H),
4.40 (m, 1H), 4.55 (m, 2H), 4.81–4.88 (m, 3H), 5.15 (d, J = 5.0 Hz, 1H), 6.85–6.91
(m, 4H), 7.05–7.21 (m, 5H); 13C NMR (DMSO-d6, 100 MHz) d 18.1, 21.2, 21.5,
22.7, 22.8, 26.4, 28.1, 34.8, 37.9, 39.5, 41.3, 44.8, 45.9, 49.3, 50.4, 51.0, 52.3,
66.2, 66.8, 71.5, 72.1, 78.9, 98.7, 125.7, 127.1, 128.5, 155.5, 168.5, 169.6, 171.5,
172.0; HR-MS calcd for C44H69N5O13 m/z 898.4790 [M+Na]+, found 898.4795.
Compound 11a: 1H NMR (DMSO-d6, 400 MHz) d 0.99 (d, J = 5.6 Hz, 6H), 1.29 (d,
J = 5.2 Hz, 3H), 1.81 (m, 2H), 2.05 (s, 15H), 2.31 (t, J = 4.8 Hz, 2H), 2.61 (m, 1H),
3.12 (m, 2H), 3.66 (s, 3H), 4.12 (d, J = 4.6 Hz, 2H), 4.25 (m, 1H), 4.35 (t,
J = 4.2 Hz, 1H), 4.50 (m, 1H), 4.58 (d, J = 5.0 Hz, 1H), 4.63 (m, 1H), 4.68 (m, 1H),
4.73 (m, 1H), 4.80 (d, J = 5.0 Hz, 2H), 5.13 (m, 1H), 5.35 (s, 1H), 5.98 (s, 1H), 6.04
(d, J = 5.4 Hz, 1H), 6.12 (m, 1H), 6.29 (d, J = 5.6 Hz, 1H), 6.98–7.04 (m, 4H), 7.17–
7.68 (m, 14H), 8.12 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) d 17.5, 17.7, 18.0,
20.9, 30.1, 30.8, 31.5, 42.5, 46.6, 47.1, 48.5, 52.5, 54.8, 57.5, 59.5, 65.6, 67.4,
68.1, 71.0, 72.1, 75.2, 91.3, 105.3, 110.4, 125.1, 126.7, 127.1, 128.0, 128.5, 129.0,
129.5, 131.0, 135.6, 141.1, 141.9, 143.5, 143.9, 151.6, 155.6, 161.8, 168.5, 168.9,
170.1, 170.9, 171.5; HR-MS calcd for C60H70N8O18S m/z 1245.4426 [M+Na]+,
found 1245. 4430.
18. Zhao, M.; Li, J.; Mano, E.; Song, Z.; Tschaen, D. M.; Grabowski, E. J. J.; Reider, P. J.
J. Org. Chem. 1999, 64, 2564.
19. Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R. Vogel’s Textbook of
Practical Organic Chemistry, 5th ed.; Addison Wesley Longman Limited, 1989.
20. (a) Deng, S.; Gangadharmath, U.; Chang, C. T. J. Org. Chem. 2006, 71, 5179; (b)
Tornoe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057.
21. Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004.
22. (a) Miller, N.; Williams, G. M.; Brimble, M. A. Int. J. Pept. Res. Ther. 2010, 16, 125;
(b) Miller, N.; Williams, G. M.; Brimble, M. A. Org. Lett. 2009, 11, 2409. and
references cited there in.
23. Kuijpers, B. H. M.; Groothuys, S.; Soede, A. C.; Keereweer, A. R.; Quaedflieg, P. J.
L. M.; Blaauw, R. H.; van Delft, F. L.; Rutjes, F. P. J. T. Bioconjugate Chem. 2007,
18, 1847.
24. General procedure for the synthesis of compounds 5a–7c: The amine (1 mmol)
and aldehyde (1 mmol), dissolved in 2 mL MeOH were stirred at rt until
complete formation of imine (TLC analysis, 30 min). Then the isocyanide
(1 mmol) and acid component (1 mmol) dissolved in MeOH (1 mL) were added
to the reaction mixture and stirred for 2 days. After completion of the reaction
as monitored by TLC the solvent was evaporated and compound was extracted
into EtOAc (15 mL) washed with Na2CO3 (5%, 5 mL), citric acid (10%, 5 mL),
water (5 mL), and brine, and dried over anhydrous Na2SO4. Evaporation of
solvent in vacuo followed by column chromatography (EtOAc/hexane; 4:6)
affords Ugi products 5a–7c.
Compound 12a: 1H NMR (DMSO-d6, 400 MHz) d 1.21 (d, J = 6.8 Hz, 3H), 1.99 (s,
12H), 2.56 (d, J = 6.2 Hz, 2H), 3.35 (m, 2H), 4.12 (t, J = 4.8 Hz, 1H), 4.25 (m, 2H),
4.45 (d, J = 5.8 Hz, 2H), 4.61 (m, 1H), 4.75 (m, 1H), 4.77 (m, 1H), 4.81 (m, 1H),
5.08 (m, 1H), 5.24 (s, 2H), 5.29 (m, 1H), 5.45 (m, 1H), 6.11 (m, 1H), 7.18–7.72
(m, 23H), 7.79–7.82 (m, 3H); 13C NMR (DMSO-d6, 100 MHz) d 19.1, 21.3, 21.5,
39.8, 43.5, 47.5, 49.5, 51.5, 52.8, 62.9, 65.1, 67.6, 68.0, 68.5, 68.9, 71.9, 79.5,
125.0, 125.5, 126.0, 126.2, 126.4, 126.5, 126.9, 127.1, 127.3, 127.5, 127.7, 127.9,
128.1, 128.4, 128.7, 128.8, 129.0, 135.1, 138.5, 139.8, 141.5, 143.6, 155.8, 156.5,
168.5, 170.5, 171.0; HR-MS calcd for C57H60N4O15 m/z 1063.3953 [M+Na]+,
found 1063. 3960.
25. Chiral-HPLC analysis was carried out (Agilent 1100 series having G1311A VWD
at k = 254 nm, flow 1.0 mL/min, column: phenominex made Lux, pore size-5 l,
Cellusole-1, diameter ꢀ length = 250 ꢀ 4.6 mm; method: 85:15 n-hexane/
isopropanol in isocratic mode, 40 min run). Chiral-HPLC profile of 5a showed
two peaks one at Rt = 21.65 min and another peak at Rt = 27.23 min in the ratio
97.5:2.5, respectively. Similarly, chiral-HPLC profile of 6a had two peaks at
Rt = 18.63 min and Rt = 24.21 min in the ratio 97:3. Also, chiral-HPLC analysis
carried out on 7a showed two peaks in the ratio 95:5 at Rt = 14.56 min and
Rt = 19.64 min. 7b had two peaks in the ratio 94:6 at Rt = 16.54 min and
Rt = 20.55 min and 7c showed two peaks at Rt = 17.21 min and Rt = 22.35 min
in the ratio 95:5.
Compound 13a: 1H NMR (DMSO-d6, 400 MHz) d 1.00 (d, J = 6.2 Hz, 6H), 1.21 (d,
J = 5.8 Hz, 3H), 1.32 (s, 9H), 2.01 (s, 12H), 2.59 (m, 1H), 2.71 (d, J = 6.4 Hz, 2H),
3.32 (m, 2H), 4.21 (d, J = 6.2 Hz, 2H), 4.35 (t, J = 4.8 Hz, 1H), 4.51 (m, 1H), 4.59
(m, 1H), 4.64 (m, 1H), 4.69 (d, J = 6.0 Hz, 2H), 4.73 (m, 2H), 5.21–5.28 (m, 2H),
5.31 (m, 1H), 6.12 (d, J = 6.6 Hz, 1H), 6.91–6.99 (br s, 4H), 7.25–7.77 (m, 18H);
13C NMR (DMSO-d6, 100 MHz) d 17.0, 18.1, 20.9, 27.5, 30.0, 41.2, 43.4, 47.1,
51.3, 53.8, 57.7, 64.5, 67.1, 68.5, 69.8, 71.3, 72.5, 78.4, 125.1, 126.7, 127.1,
128.2, 128.4, 128.8, 129.3, 129.7, 135.1, 137.8, 141.3, 143.5, 155.6, 156.1, 168.5,
170.1, 171.3; HR-MS calcd for C59H71N5O16 m/z 1128.4794 [M+Na]+, found
1128.4798.
26. Faggi, C.; Marcaccini, S.; Pepino, R.; Pozo, M. C. Synthesis 2002, 2756.
27. Spectroscopic data for few representative compounds
Compound 5a: 1H NMR (DMSO-d6, 400 MHz) d 1.21–1.35 (m, 12H), 1.44 (d,
J = 6.2 Hz, 3H), 3.33–3.43 (m, 4H), 3.62 (s, 3H), 4.01–4.36 (m, 6H), 4.64–4.76
(m, 3H), 5.33 (m, 1H), 5.68 (s, 1H), 7.25–7.45 (m, 18H), 7.69–7.76 (m, 2H); 13C
NMR (DMSO-d6, 100 MHz) d 18.6, 26.1, 35.9, 45.2, 47.3, 47.7, 51.4, 52.6, 60.8,