Carbohydrate-derived conformationally restricted bicyclic dipeptides as potential hetero foldamer building blocks

Article abstract of DOI:10.1016/j.tetasy.2012.08.007

Starting from carbohydrate precursors, hetero foldamer building blocks featuring diverse amino acid side chains and stereochemistry have been accessed via a multi-step synthetic protocol. These conformationally restricted bicyclic dipeptide building blocks are characterized by a constrained β-lactam ring fused with a pyrrolidine ring carrying a hydroxyethylamine isostere (HEA) on the backbone. These building blocks offer the possibility of developing foldamers with interesting structural architectures, conspicuously different from those classically observed. Furthermore, such hetero-building blocks have the potential to augment the conformational space available for foldamer design with diverse backbone conformations and structural architectures.

Full text of DOI:10.1016/j.tetasy.2012.08.007

Tetrahedron: Asymmetry 23 (2012) 1400–1404
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Carbohydrate-derived conformationally restricted bicyclic dipeptides as
potential hetero foldamer building blocks
Veera V. E. Ramesh a, Vedavati G. Puranik b, Gangadhar J. Sanjayan a,
⇑
a Division of Organic Chemistry, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
b Center for Materials Characterization, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Starting from carbohydrate precursors, hetero foldamer building blocks featuring diverse amino acid side
chains and stereochemistry have been accessed via a multi-step synthetic protocol. These conformation-
ally restricted bicyclic dipeptide building blocks are characterized by a constrained b-lactam ring fused
with a pyrrolidine ring carrying a hydroxyethylamine isostere (HEA) on the backbone. These building
blocks offer the possibility of developing foldamers with interesting structural architectures, conspicu-
ously different from those classically observed. Furthermore, such hetero-building blocks have the poten-
tial to augment the conformational space available for foldamer design with diverse backbone
conformations and structural architectures.
Received 7 August 2012
Accepted 14 August 2012
Available online 10 September 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Synthetic oligomers featuring well-defined conformational fea-
tures, also known as foldamers, have attracted considerable atten-
tion from chemists primarily due to the fact that they have
considerable potential in the development of oligomers with di-
verse structural architectures, shapes, and function, quite often
closely mimicking the conformational and functional features of
native peptides.1 In order to attain shape diversity of the oligomer
backbone, building blocks with diverse structural architectures are
being developed. For instance, Fleet et al.2 and others3 have re-
ported a huge repertoire of carbohydrate-based foldamer building
blocks. Extensive investigations of many of their oligomers have
provided a wealth of information regarding conformational pro-
pensities4 and biomedical potential.5
Herein we report a set of conformationally constrained sugar-
derived dipeptide building blocks carrying different amino acid res-
idues at the C-terminus (Fig. 1). These hetero building blocks fea-
ture a biomedically important b-lactam core8–10 armed with a
hydroxyethylamine isostere (HEA) on the backbone. It is notewor-
thy that HEA isosteres are one of the most important peptide tran-
sition-state mimics developed so far, and many drug candidates are
known to feature this proteolytically stable peptide bond mimic.11
The synthesis of the conformationally restricted dipeptide
building blocks 1a–d was straightforward, mainly involving two
key steps (Scheme 1).
The use of the mannitol-derived D
-glyceraldehyde 312 in the
construction of b-lactam 5a–d via a Staudinger ketene-imine
cycloaddition13 remained an important step in this synthetic pro-
tocol. The Staudinger synthesis not only helped us to access the
b-lactam as a single diastereomer, but also furnished a vicinal
glycol, which was amenable to further functional manipulations
Among the numerous foldamers reported to date, hetero folda-
mers containing amino acid residues of different conformational
preferences have gained special status mainly because of two rea-
sons. Firstly, hetero foldamers have been proven to be capable of
displaying a unique structural architecture, distinctly different
from their homo oligomer counterparts.6 Secondly, by varying
the constitutional ratios of the individual amino acid residues, it
would be possible to augment the conformational diversity of the
OH
BocHN
O
BocN
O
R
oligomers.7 For instance, hetero foldamers containing different
a,
NH
N
R
R
b, and
c residues on the backbone have been shown to adopt heli-
cal structures with very different H-bonding patterns.7a–c
CO2Me
CO2Me
flexible
constrained
dipeptide
dipeptide
Figure 1. Design strategy of
foldamer building block with an embedded HEA isostere and a b-lactam core (the
dipeptide backbones are highlighted in blue and the HEA moiety in pink).
a
constrained bicyclic dipeptide heterogeneous
⇑
Corresponding author. Tel.: +91 020 2590 2082; fax: +91 020 2590 2629.
E-mail address: gj.sanjayan@ncl.res.in (G.J. Sanjayan).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.08.007

V. V. E. Ramesh et al. / Tetrahedron: Asymmetry 23 (2012) 1400–1404
1401
O
O
H
OH
O
C
-5
H
O
O
C
-4
O
C
-3
H
ii
i
O
N
H
R
OH
O
O
H3COOC
3
2
4a-d
4a: R = (S)-CH3
4b: R = (S)-CH(CH3)2
4c: R = (S)-CH2CH(CH3)2
4d: R = (R)-CH2C6H5
HO
OH
O
O
H
H
N3
H
N3
H
H
H
iii
iv
N
N
R
R
O
O
H3COOC
H3COOC
6a-d
5a-d
5a
5b
5c
: R = (S)-CH3 (46%)
6a
: R = (S)-CH3 (89%)
: R = (S)-CH(CH3)2 (48%)
6b
6c
6d
: R = (S)-CH(CH3)2 (88%)
: R = (S)-CH2CH(CH3)2 (91%)
: R = (R)-CH2C6H5 (89%)
Figure 2. Views of the crystal structure of 1a with and without hydrogens (top) and
self-assembly aided by the C-5 hydroxyl group as the H-bonding donor, and tBoc
carbonyl as H-bonding acceptor (bottom). Note: tBoc methyls have been deleted in
the self-assembled structure for the sake of clarity.
: R = (S)-CH2CH(CH3)2 (49%)
5d: R = (R)-CH2C6H5 (51%)
HO
H
OTs
structural architecture of the pyrrolidine ring displaying the hydro-
xyl group at C-5 is reminiscent of a constrained HEA isostere, as
noted earlier.11 The crystal structure16 of 1a also clearly establishes
the cis-geometry of the C-3 and C-4 positions of the b-lactam ring.
The dipeptide building block 1a assumes an extended sheet struc-
ture in the solid-state, aided by intermolecular hydrogen-bonding
interaction between the C-5 hydroxyl group of one molecule and
the tBoc carbonyl of another molecule. The hydrogen-bond geome-
try is characterized by the bond distances d(Oꢀ ꢀ ꢀO) = 2.7 Å and
d(Hꢀ ꢀ ꢀO) = 1.9 Å, and the bond angle (O–Hꢀ ꢀ ꢀO) = 162°.
H
N3
H
BocN
H
OH
H
vi
v
H
N
R
N
R
O
O
H3COOC
H3COOC
1a-d
7a-d
7a
7b
7c
: R = (S)-CH3 (92%)
1a: R = (S)-CH3 (94%)
: R = (S)-CH(CH3)2 (91%)
1b: R = (S)-CH(CH3)2 (96%)
: R = (S)-CH2CH(CH3)2 (88%)
1c
: R = (S)-CH2CH(CH3)2 (95%)
7d: R = (R)-CH2C6H5 (90%)
1d
: R = (R)-CH2C6H5 (93%)
3. Conclusion
Scheme 1. Reagents and conditions: (i) NaIO4, H2O, 0 °C, 30 min.; (ii) R-NH2, H2O-
1,2-dichloroethane, rt, 2 h; (iii) potassium azido acetate, triphosgene, Et3N, DCM,
0 °C, then rt, 15 h; (iv) PTSA, THF:H2O, reflux, 16 h; (v) tosyl chloride, Bu2SnO, Et3N,
DCM, rt, 8 h; (vi) Pd-C, H2, (Boc)2O, 60 psi, 8 h.
In conclusion we have reported on a set of conformationally re-
stricted bicyclic dipeptides derived from readily available carbohy-
drate precursors through efficient multi-step synthetic protocols.
The decoration of the foldamer backbone with biologically relevant
moieties such as a rigid fused b-lactam and a hydroxyl ethylamine
isostere (HEA) is noteworthy. Oligomers carrying these building
blocks are expected to show distinctly different conformational
preferences, very different from their homogenous counterparts.
to effect the second key step of cyclization leading to the formation
of the constrained building blocks 1a–d. The acetonide protected
D-
glyceraldehyde 3, readily available from
D
-mannitol diacetonide12
2 by NaIO4-mediated oxidative cleavage, was converted into the
aminoacid-conjugated Schiff bases 4a–d, which without purifica-
tion, were subjected to the standard Staudinger reaction with azi-
doacetyl chloride, generated in situ by reacting potassium azido
acetate with triphosgene. The cis-stereochemistry of the b-lactam
was readily indicated by the coupling constants (J = 5–6 Hz), which
is characteristic of cis-b-lactams.14 Deprotection of acetonides
5a–d cleanly furnished diols 6a–d, which were then subjected to
selective dibutyltin oxide-mediated tosylation15 to afford the O-to-
syl derivatives 7a–d in excellent yields. Azide reduction within 7a–
d with concomitant Boc protection cleanly afforded the cyclized
target building blocks 1a–d in excellent yield (93–96%), without
the requirement for special conditions for effecting cyclization.
The conformational characteristics of the heterogeneous
dipeptide building blocks 1a–d are clearly evident from the crystal
structure of 1a (Fig. 2).
4. Experimental
4.1. (R)-2,2-Dimethyl-1,3-dioxolane-4-carbaldehyde 3
To a chilled solution of NaIO4 (2 equiv) in H2O, 1,2,5,6-di-isopro-
pylidine-D-mannitol 2 (2 equiv) was added in portions with stirring.
After completion of addition, the reaction mixture was stirred for
30 min. The reaction mixture was filtered through a sintered funnel
to provide an aqueous solution of the crude product 3, which was
used for subsequent reactions without further purification.
4.2. General procedure for the preparation of azido -lactams 5a–
d
This dipeptide foldamer building block 1a, which readily crystal-
lized from chloroform, features a biomedically significant b-lactam
fused with a 5-membered pyrrolidine ring. It is noteworthy that the
To the cooled filtrate of 3, a solution of amino ester (1 equiv) in
1,2-dichloroethane (EDC) was added. The reaction mixture was

1402
V. V. E. Ramesh et al. / Tetrahedron: Asymmetry 23 (2012) 1400–1404
stirred at room temperature for 2 h. The organic layer was sepa-
rated. The aqueous layer was saturated with sodium chloride and
extracted with dichloromethane. The combined organic layer
containing the Schiff bases 4a–d was dried over anhydrous Na2SO4.
The solvent was removed under reduced pressure and re-dissolved
in dry dichloromethane cooled at 0 °C. Potassium azido acetate
(1 equiv) was added to the above mixture, followed by the sequen-
tial addition of Et3N (6 equiv) and a solution of triphosgene
(0.8 equiv) in dry dichloromethane. After stirring for 15 h at room
temperature, the reaction mixture was diluted with dichlorometh-
ane, sequentially washed with water, saturated NaHCO3, brine and
dried over anhydrous Na2SO4. The solvent was removed under re-
duced pressure to furnish crude products 5a–d, which were then
purified by column chromatography.
4.3. General procedure for the preparation of dihydroxy -
lactams 6a–d
A mixture of azido -lactams 5a–d and PTSA (0.33 equiv) in aq
THF was refluxed for 16 h. The reaction mixture was then neutral-
ized with NaHCO3. The residue obtained after removing the sol-
vents under reduced pressure was dissolved in ethyl acetate,
washed with brine solution and dried over anhydrous Na2SO4.
Evaporation of the solvent under reduced pressure afforded 6a–d,
which were purified by column chromatography.
4.3.1. (S)-Methyl 2-((2R,3R)-3-azido-2-((S)-1,2-dihydroxyethyl)-
4-oxoazetidin-1-yl)propanoate 6a
Viscous liquid. Yield: 1.53 g (89%); ½a D25
¼ þ164 (c 0.2, CHCl3);
ꢁ
IR (CHCl3)
m
(cmꢂ1): 3399, 2117, 1753, 1733, 1654, 1637, 1450,
1412, 1021, 770; 1H NMR (200 MHz, CDCl3):
d 4.71 (d,
4.2.1. (S)-Methyl 2-((2R,3R)-3-azido-2-((S)-2,2-dimethyl-1,3-di
J = 5.06 Hz, 1H), 4.38 (q, 1H), 4.01–3.86 (m, 2H), 3.82–3.78 (m,
1H), 3.76 (s, 3H), 3.73–3.70 (m, 1H), 3.62–3.54 (m, 1H), 2.98(br s,
1H), 1.64(d, J = 7.46 Hz, 3H); 13C NMR (50 MHz, CDCl3): d 172.0,
164.5, 70.6, 63.9, 63.7, 59.2, 52.8, 52.7, 16.1; ESI MS: 259.23
(M+H)+, 281.20 (M+Na)+, 297.20 (M+K)+; Anal. Calcd for
C9H14N4O5: C, 41.86; H, 5.46; N, 21.70. Found: C, 42.02; H, 5.29;
N, 21.57.
oxolan-4-yl)-4-oxoazetidin-1-yl)propanoate 5a
Viscous liquid. Yield: 2.1 g (46%); ½a D25
¼ þ160 (c 1, CHCl3); IR
ꢁ
(CHCl3)
m
(cmꢂ1): 3392, 2109, 1769, 1382, 1068, 756; 1H NMR
(200 MHz, CDCl3): d 4.72 (d, J = 5.31 Hz, 1H), 4.41(q, 1H), 4.21–
4.12 (m, 2H), 3.93 (dd, J = 5.31 Hz, 8.85 Hz, 1H), 3.72 (s, 3H), 3.62
(q, 1H), 1.59 (d, J = 7.45 Hz, 3H), 1.36 (s, 3H), 1.29 (s, 3H); 13C
NMR (50 MHz, CDCl3): d 170.5, 163.9, 109.7, 75.8, 66.3, 63.8,
60.0, 52.3, 51.0, 26.5, 24.9, 16.3; ESI MS: 299.40 (M+H)+, 321.39
(M+Na)+; Anal. Calcd for C12H18N4O5: C, 48.32; H, 6.08; N, 18.78.
Found: C, 48.50; H, 5.89; N, 18.62.
4.3.2. (S)-Methyl 2-((2R,3R)-3-azido-2-((S)-1,2-dihydroxyethyl)-
4-oxoazetidin-1-yl)-3-methylbutanoate 6b
Viscous liquid. Yield: 1.54 g (88%); ½a D25
¼ þ100 (c 1, CHCl3); IR
ꢁ
(CHCl3)
m
(cmꢂ1): 3400, 2117, 1743, 1651, 1408, 1020, 758; 1H
4.2.2. (S)-Methyl 2-((2R,3R)-3-azido-2-((S)-2,2-dimethyl-1,3-di
NMR (200 MHz, CDCl3): d 4.72 (d, J = 4.80 Hz, 1H), 3.92–3.80 (m,
4H), 3.74 (s, 3H), 3.74–3.56 (m, 2H), 3.18 (br s, 1H), 2.62–2.44
(m, 1H), 1.02 (d, J = 6.57 Hz, 3H), 0.94 (d, J = 6.82 Hz, 3H); 13C
NMR (50 MHz, CDCl3): d 170.9, 164.4, 70.9, 64.2, 63.5, 63.4, 59.6,
52.4, 29.5, 19.7, 19.4; ESI MS: 287.28 (M+H)+, 309.24 (M+Na)+,
325.25 (M+K)+; Anal. Calcd for C11H18N4O5: C, 46.15; H, 6.34; N,
19.57. Found: C, 46.29; H, 6.15; N, 19.41.
oxolan-4-yl)-4-oxoazetidin-1-yl)-3-methylbutanoate 5b
Viscous liquid. Yield: 2.40 g (48%); ½a D25
¼ þ118 (c 1.5, CHCl3);
ꢁ
IR (CHCl3)
m
(cmꢂ1): 3461, 2110, 1769, 1742, 1675, 1373, 1215,
755; 1H NMR (200 MHz, CDCl3): d 4.69 (d, J = 5.31 Hz, 1H), 4.26–
4.07 (m, 2H), 3.85–3.73 (m, 2H), 3.71 (s, 3H), 3.62–3.53 (m, 1H),
2.63–2.45 (m, 1H), 1.39 (s, 3H), 1.28 (s, 3H), 1.02 (d, J = 6.70 Hz,
3H), 0.96 (d, J = 6.82 Hz, 3H); 13C NMR (50 MHz, CDCl3): d 169.7,
163.8, 109.7, 75.8, 66.3, 63.6, 63.2, 60.8, 51.9, 28.9, 26.5, 24.8,
19.8, 19.7; ESI MS: 349.12 (M+Na)+, 365.12 (M+K)+; Anal. Calcd
for C14H22N4O5: C, 51.52; H, 6.79; N, 17.17. Found: C, 51.43; H,
6.61; N, 17.33.
4.3.3. (S)-Methyl 2-((2R,3R)-3-azido-2-((S)-1,2-dihydroxyethyl)-
4-oxoazetidin-1-yl)-4-methylpentanoate 6c
Viscous liquid. Yield: 1.60 g (91%); ½a D25
¼ þ150 (c 1, CHCl3); IR
ꢁ
(CHCl3)
m
(cmꢂ1): 3444, 2111, 1765, 1755, 1747, 1270, 757; 1H
NMR (200 MHz, CDCl3): d 4.70 (d, J = 4.67 Hz, 1H), 4.28–4.21 (m,
1H), 3.97–3.91 (m, 2H), 3.86–3.76 (m, 2H), 3.76 (s, 3H), 3.66–
3.56 (m, 2H), 2.33–2.14 (m, 1H), 1.73–1.54 (m, 2H), 0.96 (d,
J = 3.03 Hz, 3H), 0.93 (d, J = 2.91 Hz, 3H); 13C NMR (50 MHz, CDCl3):
d 172.1, 164.5, 70.6, 63.8, 63.8, 59.7, 56.0, 52.7, 38.4, 25.1, 22.8,
21.0; ESI MS: 301.30 (M+H)+, 323.26 (M+Na)+, 339.25 (M+K)+; Anal.
Calcd for C12H20N4O5: C, 47.99; H, 6.71; N, 18.66. Found: C, 48.15;
H, 6.90; N, 18.47.
4.2.3. (S)-Methyl 2-((2R,3R)-3-azido-2-((S)-2,2-dimethyl-1,3-di
oxolan-4-yl)-4-oxoazetidin-1-yl)-4-methylpentanoate 5c
Viscous liquid. Yield: 2.56 g (49%); ½a D25
¼ þ146 (c 1, CHCl3); IR
ꢁ
(CHCl3)
m
(cmꢂ1): 3026, 2118, 1772, 1742, 1372, 1216, 756; 1H
NMR (200 MHz, CDCl3): d 4.73 (d, J = 5.31 Hz, 1H), 4.36–4.30 (m,
1H), 4.21–4.12 (m, 2H), 3.94–3.87 (m, 1H), 3.71 (s, 3H), 3.63–
3.55 (m, 1H), 2.21–2.10 (m, 1H), 1.71–1.51 (m, 2H), 1.37 (s, 3H),
1.29 (s, 3H), 0.94 (d, J = 1.14 Hz, 3H), 0.91 (d, J = 1.51 Hz, 3H); 13C
NMR (50 MHz, CDCl3) d 170.8, 164.6, 109.7, 75.8, 66.4, 63.7, 60.4,
54.1, 52.3, 38.2, 26.5, 24.9, 24.8, 22.9, 20.7; ESI MS: 363.30
(M+Na)+, 379.30 (M+K)+; Anal. Calcd for C15H24N4O5: C, 5; H,
7.11; N, 16.46. Found: C, 53.01; H, 6.99; N, 16.65.
4.3.4. (R)-Methyl 2-((2R,3R)-3-azido-2-((S)-1,2-dihydroxyethyl)-
4-oxoazetidin-1-yl)-3-phenylpropanoate 6d
Viscous liquid. Yield: 1.58 g (89%); ½a D25
¼ þ118 (c 1, CHCl3); IR
ꢁ
(CHCl3)
m
(cmꢂ1): 3422, 2116, 1764, 1739, 1399, 1215, 757; 1H
NMR (200 MHz, CDCl3): d 7.35–7.19 (m, 5H), 4.82–4.74 (m, 1H),
4.43 (d, J = 5.31 Hz, 1H), 3.83–3.79 (m, 1H), 3.75 (s, 3H), 3.72–
3.62 (m, 3H), 3.59–3.39 (m, 2H), 3.37–3.22 (m, 2H); 13C NMR
(50 MHz, CDCl3): d 171.7, 165.4, 136.0, 128.6, 128.4, 127.1, 70.8,
63.5, 63.2, 58.3, 56.3, 52.8, 34.5; ESI MS: 335.15 (M+H)+, 357.15
(M+Na)+, 373.14 (M+K)+; Anal. Calcd for C15H18N4O5: C, 53.89; H,
5.43; N, 16.76. Found: C, 54.05; H, 5.30; N, 16.58.
4.2.4. (R)-Methyl 2-((2R,3R)-3-azido-2-((S)-2,2-dimethyl-1,3-di
oxolan-4-yl)-4-oxoazetidin-1-yl)-3-phenylpropanoate 5d
Viscous liquid. Yield: 2.93 g (51%); ½a D25
¼ þ170 (c 0.2, CHCl3);
ꢁ
IR (CHCl3)
m
(cmꢂ1): 3020, 2110, 1771, 1744, 1602, 1422, 1216,
771; 1H NMR (200 MHz, CDCl3): d 7.37–7.19 (m, 5H), 4.65 (dd,
J = 5.93 Hz, 10.61 Hz, 1H), 4.51 (d, J = 5.16 Hz, 1H), 4.10–4.02
(m,1H), 3.81–3.69 (m, 1H) 3.79 (s, 3H), 3.63–3.37 (m, 4H), 1.43
(s, 3H), 1.24 (s, 3H); 13C NMR (50 MHz, CDCl3): d 169.7, 163.9,
136.5, 128.6, 128.5, 126.8, 109.6, 75.7, 66.0, 63.3, 59.4, 56.7, 52.5,
34.2, 26.5, 24.7; ESI MS: 375.22 (M+H)+, 397.19 (M+Na)+, 413.18
(M+K)+; Anal. Calcd for C18H22N4O5: C, 57.75; H, 5.92; N, 14.96.
Found: C, 57.57; H, 6.11; N, 15.08.
4.4. General procedure for the preparation of tosyl -lactams 7a–d
To a solution of dihydroxy -lactams 6a–d (1 equiv) dissolved in
dry dichloromethane, dibutyltin oxide (1 equiv) was added and
the reaction mixture was stirred for 5 min at room temperature.

V. V. E. Ramesh et al. / Tetrahedron: Asymmetry 23 (2012) 1400–1404
1403
After cooling the reaction mixture to 0 °C, Et3N (1.1 equiv) and tosyl
chloride (1.05 equiv) were added. After the addition was completed,
the reaction mixture was allowed to stir at room temperature for
6 h, diluted with dichloromethane, washed sequentially with water
and saturated brine and dried over anhydrous Na2SO4. The solvent
was removed under reduced pressure to give the crude products
7a–d, which were then purified by column chromatography.
mixture was hydrogenated at 60 psi for 4 h. The reaction
mixture was filtered over a Celite pad and washed several times
with ethyl acetate. The combined ethyl acetate washings were
washed sequentially with saturated KHSO4, and brine solutions
and the organic layer was separated and dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure to
give crude 1a–d, which were then purified by column
chromatography.
4.4.1. (S)-Methyl 2-((2R,3R)-3-azido-2-((S)-1-hydroxy-2-(tosyl
oxy)ethyl)-4-oxoazetidin-1-yl)propanoate 7a
4.5.1. (1R,4R,5R)-tert-Butyl 4-hydroxy-6-((S)-1-methoxy-1-
oxopropan-2-yl)-7-oxo-2,6-diazabicyclo[3.2.0]heptane-2-
carboxylate 1a
Viscous liquid. Yield: 1.90 g (92%); ½a D25
¼ þ154 (c 1, CHCl3); IR
ꢁ
(CHCl3)
m
(cmꢂ1): 3400, 2114, 1743, 1652, 1632, 1407, 1176, 757;
1H NMR (200 MHz, CDCl3): d 7.79 (d, J = 8.34 Hz, 2H), 7.38 (d,
J = 7.96 Hz, 2H), 4.60 (d, J = 4.80 Hz, 1H), 4.30 (q, 1H), 4.09–4.08
(m, 2H), 4.01–3.92 (m, 2H), 3.88–3.84 (m, 1H), 3.74 (s, 3H), 2.43
(s, 3H), 1.62 (d, J = 7.45 Hz, 3H); 13C NMR (50 MHz, CDCl3): d
171.8, 163.9, 145.4, 131.7, 129.6, 127.9, 71.2, 68.4, 63.6, 58.4,
52.8, 52.7, 21.5, 16.0; ESI MS: 413.41 (M+H)+, 435.41 (M+Na)+,
451.31 (M+K)+; Anal. Calcd for C16H20N4O7S: C, 46.60; H, 4.89; N,
13.58. Found: C, 46.79; H, 5.12; N, 13.39.
White solid. Yield: 0.99 g (94%); mp: 143–145 °C; ½a D25
¼ þ180
ꢁ
(c 0.7, CHCl3); IR (CHCl3)
m
(cmꢂ1): 3368, 1752, 1733, 1684, 1655,
1420, 1024; 1H NMR (400 MHz, CDCl3): d 5.20 (br s, 1H), 4.45 (q,
1H), 4.30 (d, J = 3.02 Hz, 1H), 4.28 (d, J = 3.51 Hz, 1H), 4.02–3.99
(m, 1H), 3.74 (s, 3H), 3.52 (dd, J = 3.26 Hz, 13.05 Hz, 1H), 3.16 (br
s, 1H), 1.49 (d, J = 7.45 Hz, 3H), 1.46 (s, 9H); 13C NMR (100 MHz,
CDCl3): d 170.9, 165.3, 165.3, 154.1, 81.0, 69.8, 67.5, 63.6, 52.6,
52.4, 49.9, 28.2, 16.6; ESI MS: 315.33 (M+H)+, 337.29 (M+Na)+,
353.28 (M+K)+; Anal. Calcd for C14H22N2O6: C, 53.49; H, 7.05; N,
8.91. Found: C, 53.57; H, 6.99; N, 9.09.
4.4.2. (S)-Methyl 2-((2R,3R)-3-azido-2-((S)-1-hydroxy-2-(tosyl
oxy)ethyl)-4-oxoazetidin-1-yl)-3-methylbutanoate 7b
Viscous liquid. Yield: 1.82 g (91%); ½a D25
ꢁ
¼ þ96 (c 1, CHCl3); IR
4.5.2. (1R,4R,5R)-tert-Butyl 4-hydroxy-6-((S)-1-methoxy-3-
methyl-1-oxobutan-2-yl)-7-oxo-2,6-
(CHCl3)
m
(cmꢂ1): 3455, 2114, 1764, 1661, 1359, 1176, 756; 1H
NMR (200 MHz, CDCl3): d 7.80 (d, J = 8.34 Hz, 2H), 7.37 (d,
J = 7.96 Hz, 2H), 4.62 (d, J = 4.80 Hz, 1H), 4.12–4.06 (m, 2H), 3.95–
3.84 (m, 2H), 3.80–3.73 (m, 2H), 3.71(s, 3H), 2.54–2.32 (m, 1H),
2.42 (s, 3H), 0.98 (d, J = 6.57 Hz, 3H), 0.91 (d, J = 6.69 Hz, 3H); 13C
NMR (50 MHz, CDCl3): d 170.5, 163.9, 145.2, 131.9, 129.8, 127.8,
70.9, 68.8, 63.8, 63.2, 58.6, 52.3, 29.6, 21.4, 19.6, 19.3; ESI MS:
441.43 (M+H)+, 463.44 (M+K)+; Anal. Calcd for C18H24N4O7S: C,
49.08; H, 5.49; N, 12.72. Found: C, 48.92; H, 5.61; N, 12.51.
diazabicyclo[3.2.0]heptane-2-carboxylate 1b
White solid. Yield: 1.03 g (96%); mp: 76–78 °C; ½a D25
¼ þ110 (c
ꢁ
1, CHCl3); IR (CHCl3)
m
(cmꢂ1): 3422, 1740, 1697, 1416, 1165,
756; 1H NMR (200 MHz, CDCl3): d 5.12 (br s, 1H), 4.31 (br s, 1H),
4.23 (d, J = 3.92 Hz, 1H), 4.02–3.92 (m, 2H), 3.71 (s, 3H), 3.61 (br
s, 1H), 3.51 (dd, J = 3.54 Hz,13.01 Hz, 1H), 2.24–2.06 (m, 1H), 1.43
(s, 9H), 0.98 (d, J = 6.69 Hz, 3H), 0.92 (d, J = 6.70 Hz, 3H); 13C NMR
(50 MHz, CDCl3): d 169.7, 166.0, 153.9, 80.8, 69.2, 67.2, 64.8,
61.5, 52.6, 52.0, 30.0, 28.1, 19.5, 19.1; ESI MS: 343.54 (M+H)+,
365.47 (M+Na)+, 381.47 (M+K)+; Anal. Calcd for C16H26N2O6: C,
56.13; H, 7.65; N, 8.18. Found: C, 55.97; H, 7.84; N, 8.28.
4.4.3. (S)-Methyl 2-((2R,3R)-3-azido-2-((S)-1-hydroxy-2-(tosyl
oxy)ethyl)-4-oxoazetidin-1-yl)-4-methylpentanoate 7c
Viscous liquid. Yield: 1.72 g (88%); ½a D25
¼ þ112 (c 1, CHCl3); IR
ꢁ
(CHCl3)
m
(cmꢂ1): 3300, 2116, 1771, 1744, 1599, 1262, 768; 1H
4.5.3. (1R,4R,5R)-tert-Butyl 4-hydroxy-6-((S)-1-methoxy-4-
methyl-1-oxopentan-2-yl)-7-oxo-2,6-
NMR (200 MHz, CDCl3): d 7.81 (d, J = 8.34 Hz, 2H), 7.39 (d,
J = 7.96 Hz, 2H), 4.62 (d, J = 5.05 Hz, 1H), 4.24–4.16 (m, 1H), 4.12–
4.10 (m, 2H), 4.05–3.97 (m, 1H), 3.97 (q, 1H), 3.75 (s, 3H), 3.72–
3.66 (m, 1H), 2.45 (s, 3H), 2.29–2.13 (m, 1H), 1.74–1.51 (m, 2H),
0.95 (d, J = 1.77 Hz, 3H), 0.92 (d, J = 1.39 Hz, 3H); 13C NMR
(50 MHz, CDCl3): d 172.0, 164.1, 145.1, 131.8, 130.0, 127.9, 71.2,
68.5, 63.5, 58.9, 55.9, 52.8, 38.3, 25.0, 22.8, 21.6, 21.0; ESI MS:
477.15 (M+Na)+; Anal. Calcd for C19H26N4O7S: C, 50.21; H, 5.77;
N, 12.33. Found: C, 50.35; H, 5.95; N, 12.04.
diazabicyclo[3.2.0]heptane-2-carboxylate 1c
White solid. Yield: 1.03 g (95%); mp: 66–68 °C; ½a D25
¼ þ125 (c
ꢁ
0.8, CHCl3); IR (CHCl3)
m
(cmꢂ1): 3422, 1763, 1742, 1685, 1420,
1216, 757; 1H NMR (200 MHz, CDCl3): d 5.24 (br s, 1H), 4.41 (d,
J = 7.58 Hz, 1H), 4.33–4.27 (m, 2H), 4.07 (d, J = 12.89 Hz, 1H), 3.75
(s, 3H), 3.57 (dd, J = 3.53 Hz, 13.01 Hz, 1H), 2.49 (br s, 1H), 1.80–
1.53 (m, 3H), 1.48 (s, 9H), 0.98 (d, J = 0.76 Hz, 3H), 0.94 (d,
J = 0.69 Hz, 3H); 13C NMR (50 MHz, CDCl3): d 170.6, 165.8, 153.9,
80.7, 69.1, 67.1, 64.0, 53.0, 52.5, 52.3, 39.0, 28.0, 24.7, 22.5, 21.1;
ESI MS: 379.46 (M+Na)+, 395.46 (M+K)+; Anal. Calcd for
4.4.4. (R)-Methyl 2-((2R,3R)-3-azido-2-((S)-1-hydroxy-2-(tosyl
oxy)ethyl)-4-oxoazetidin-1-yl)-3-phenylpropanoate 7d
C17H28N2O6: C, 57.29; H, 7.92; N, 7.86. Found: C, 57.37; H, 7.88;
Viscous liquid. Yield: 1.70 g (90%); ½a D25
¼ þ124 (c 1, CHCl3); IR
ꢁ
N, 7.74.
(CHCl3)
m
(cmꢂ1): 3420, 2114, 1772, 1764, 1738, 1641, 1216, 769;
1H NMR (200 MHz, CDCl3): d 7.80–7.75 (m, 2H), 7.38–7.20 (m,
7H), 4.80–4.72 (m, 1H), 4.29 (d, J = 4.80 Hz, 1H), 4.04–4.03 (m,
2H), 3.81–3.77 (m, 1H), 3.75 (s, 3H), 3.73–3.70 (m, 2H), 3.43–
3.18 (m, 2H), 2.44 (s, 3H); 13C NMR (50 MHz, CDCl3): d 171.5,
164.9, 145.2, 135.9, 131.8, 129.8, 128.6, 128.4, 127.8, 127.0, 70.4,
68.4, 63.3, 57.3, 56.1, 52.8, 34.4, 21.4; ESI MS: 511.39 (M+Na)+,
527.33 (M+K)+; Anal. Calcd for C22H24N4O7S: C, 54.09; H, 4.95; N,
11.47. Found: C, 53.91; H, 5.08; N, 11.59.
4.5.4. (1R,4R,5R)-tert-Butyl 4-hydroxy-6-((R)-1-methoxy-1-oxo-
3-phenylpropan-2-yl)-7-oxo-2,6-diazabicyclo[3.2.0]heptane-2-
carboxylate 1d
White solid. Yield: 0.94 g (93%); mp: 122–124 °C; ½a D25
¼ þ190
ꢁ
(c 1, CHCl3); IR (CHCl3)
m
(cmꢂ1): 3443, 1764, 1744, 1644, 1216,
772; 1H NMR (200 MHz, CDCl3): d 7.35–7.19 (m, 5H), 5.00 (br
s,1H), 4.50–4.42 (m, 1H), 4.05 (d, J = 3.28 Hz, 1H), 4.00 (d,
J = 3.54 Hz, 1H), 3.79–3.74(m, 1H), 3.74 (s, 3H), 3.37–3.14 (m,
3H), 3.08–3.00 (m, 1H), 1.43 (s, 9H); 13C NMR (50 MHz, CDCl3): d
170.2, 165.8, 153.9, 136.1, 128.7, 128.4, 127.7, 80.7, 68.9, 67.0,
63.4, 56.4, 52.6, 52.4, 35.0, 28.1; ESI MS: 413.31 (M+Na)+, 429.31
(M+K)+; Anal. Calcd for C20H26N2O6: C, 61.53; H, 6.71; N, 7.18.
Found: C, 61.38; H, 6.90; N, 6.99.
4.5. General procedure for the preparation of the b-lactam
foldamer building blocks 1a–d
To a solution of 7a–d (1 equiv) in ethyl acetate, 10% Pd-C, Et3N
(1.2 equiv) and Boc anhydride (1.1 equiv) were added. The reaction

1404
V. V. E. Ramesh et al. / Tetrahedron: Asymmetry 23 (2012) 1400–1404
Tetrahedron 2012, 68, 4399; (m) Priya, G.; Kotmale, A. S.; Gawade, R. L.; Mishra,
Acknowledgments
D.; Pal, S.; Puranik, V. G.; Rajamohanan, P. R.; Sanjayan, G. J. Chem. Commun.
2012. http://dx.doi.org/10.1039/c2cc33235c.
VVER thanks the Council of Scientific and Industrial Research
(CSIR), New Delhi, for a fellowship. G.J.S. thanks NCL-IGIB (CSIR,
New Delhi), for funding.
5. (a) Steer, D. L.; Lew, R. A.; Perlmutter, P.; Smith, A. I.; Aguilar, M. I. Curr. Med.
Chem. 2002, 9, 811; (b) Sadowsky, J. D.; Schmitt, M. A.; Lee, H. S.; Umezawa, N.;
Wang, S.; Tomita, Y.; Gellman, S. H. J. Am. Chem. Soc. 2005, 127, 11966; (c)
Claudon, P.; Violette, A.; Lamour, K.; Decossas, M.; Fournel, S.; Heurtault, B.;
Godet, J.; Mely, Y.; Gregoire, B. J.; Petit, M. C. A.; Briand, J. P.; Duportail, G.;
Monteil, H.; Guichard, G. Angew. Chem., Int. Ed. 2010, 49, 333; (d) Xiao, X.; Yu,
P.; Lim, H. S.; Sikder, D.; Kodadek, T. Angew. Chem., Int. Ed. 2007, 46, 2865; (e)
Tew, G. N.; Scott, R. W.; Klein, M. L.; Degrado, W. F. Acc. Chem. Res. 2010, 43, 30;
(d) Bautista, A. D.; Appelbaum, J. S.; Craig, C. J.; Michel, J.; Schepartz, A. J. Am.
Chem. Soc. 2010, 132, 2904.
6. Roy, A.; Prabhakaran, P.; Baruah, P. K.; Sanjayan, G. J. Chem. Commun. 2011, 47,
11593.
7. (a) Guo, L.; Zhang, W.; Guzei, I. A.; Spencer, L. C.; Gellman, S. H. Tetrahedron
2012, 68, 4413; (b) Choi, S. H.; Guzei, I. A.; Spencer, L. C.; Gellman, S. H. J. Am.
Chem. Soc. 2008, 130, 6544; (c) Guo, L.; Chi, Y.; Almeida, A. M.; Guzei, I. A.;
Parker, B. K.; Gellman, S. H. J. Am. Chem. Soc. 2009, 131, 16018.
References
1. (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173; (b) Hill, D. J.; Mio, M. J.; Prince,
R. B.; Hughes, T. S.; Moore, J. S. Chem. Rev. 2001, 101, 3893; (c) Hecht, S.; Huc, I.
Foldamer: Structure, Properties, and Applications; Wiley-VCH: Weinheim,
Germany, 2007; (d) Goodman, C. M.; Choi, S.; Shandler, S.; DeGrado, W. F.
Nat. Chem. Biol. 2007, 3, 252; (e) Li, X.; Wu, Y. D.; Yang, D. Acc. Chem. Res. 2008,
41, 1428; (f) Seebach, D.; Gardiner, J. Acc. Chem. Res. 2008, 41, 1366; (g) Haldar,
D.; Schmuck, C. Chem. Soc. Rev. 2009, 38, 363; (h) Saraogi, P. I.; Hamilton, A. D.
Chem. Soc. Rev. 2009, 38, 1726; (i) Juwarker, H.; Jeong, K. S. Chem. Soc. Rev. 2010,
39, 3664; (j) Tomasini, C.; Angelici, G.; Castellucci, N. Eur. J. Org. Chem. 2011,
3648; (k) Vasudev, P. G.; Chatterjee, S.; Shamala, N.; Balaram, P. Chem. Rev.
2011, 111, 657; (l) Guichard, G.; Huc, I. Chem. Commun. 2011, 47, 5933; (m)
Martinek, T. A.; Fulop, F. Chem. Soc. Rev. 2012, 41, 687; (n) Horne, W. S. Expert
Opin. Drug Discov. 2011, 6, 1247; (o) Prabhakaran, P.; Priya, G.; Sanjayan, G. J.
Angew. Chem., Int. Ed. 2012, 51, 4006.
2. (a) Claridge, T. D. W.; Goodman, J. M.; Moreno, A.; Angus, D.; Barker, S. F.;
Taillefumier, C.; Watterson, M. P.; Fleet, G. W. J. Tetrahedron Lett. 2001, 42,
4251; (b) Edwards, A. A.; Fleet, G. W. J.; Tranter, G. E. Chirality 2006, 18, 265; (c)
Claridge, T. D. W.; Ortega, B. L.; Jenkinson, S. F.; Fleet, G. W. J. Tetrahedron:
Asymmetry 2008, 19, 984; (d) Johnson, S. W.; Jenkinson, S. F.; Angus, D.;
Victoria, I. P.; Edwards, A. A.; Claridge, T. D. W.; Tranter, G. E.; Fleet, G. W. J.;
Jones, J. H. J. J. Pept. Sci. 2005, 11, 517.
3. (a) Jagadeesh, B.; Prabhakar, A.; Sarma, G. D.; Chandrasekhar, S.;
Chandrashekar, G.; Reddy, M. S.; Jagannadh, B. Chem. Commun. 2007, 371; (b)
Sharma, G. V. M.; Reddy, P. S.; Chatterjee, D.; Kunwar, A. C. J. Org. Chem. 2011,
76, 1562; (c) Sharma, G. V. M.; Jadhav, V. B.; Ramakrishna, K. V. S.; Jayaprakash,
P.; Narsimulu, K.; Subash, V.; Kunwar, A. C. J. Am. Chem. Soc. 2006, 128, 14657;
(d) Chakraborty, T. K.; Koley, D.; Ravi, R.; Krishnakumari, V.; Nagaraj, R.;
Kunwar, A. C. J. Org. Chem. 2008, 73, 8731; (e) Prasad, S.; Mathur, A.; Jaggi, M.;
Sharma, R.; Gupta, N.; Reddy, V. R.; Sudhakar, G.; Kumar, S. U.; Kumar, S. K.;
Kunwar, A. C.; Chakraborty, T. K. J. Pept. Res. 2005, 66, 75.
4. (a) Fremaux, J.; Fischer, L.; Arbogast, T.; Kauffmann, B.; Guichard, G. Angew.
Chem., Int. Ed. 2011, 50, 11382; (b) Rajagopal, A.; Aravinda, S.; Raghothama, S.;
Shamala, N.; Balaram, P. Biopolymers 2011, 96, 744; (c) Sawada, T.; Gellman, S.
H. J. Am. Chem. Soc. 2011, 133, 7336; (d) Delauriere, L.; Dong, Z.; Laxmi-Reddy,
K.; Godde, F.; Toulme, J.-J.; Huc, I. Angew. Chem., Int. Ed. 2012, 51, 473; (e)
Lengyel, G. A.; Frank, R. C.; Horne, W. S. J. Am. Chem. Soc. 2011, 133, 4246; (f)
Pilsl, L. K. A.; Reiser, O. Amino Acids 2011, 41, 709; (g) Kulikov, O. V.; Incarvito,
C.; Hamilton, A. D. Tetrahedron Lett. 2011, 52, 3705; (h) Santis, E. D.;
Hjelmgaard, T.; Caumes, C.; Faure, S.; Alexander, B. D.; Holder, S. J.; Siligardi,
G.; Taillefumier, C.; Edwards, A. A. Org. Biomol. Chem. 2012, 10, 1108; (i) Jones,
C. R.; Baruah, P. K.; Thompson, A. L.; Scheiner, S.; Smith, M. D. J. Am. Chem. Soc.
2012, 134, 12064; (j) Prabhakaran, P.; Kale, S. S.; Puranik, V. G.; Rajamohanan,
P. R.; Chetina, O.; Howard, J. A. K.; Hofmann, H.-J.; Sanjayan, G. J. J. Am. Chem.
Soc. 2008, 130, 17743; (k) Prabhakaran, P.; Puranik, V. G.; Chandran, J. N.;
Rajamohanan, P. R.; Hofmann, H.-J.; Sanjayan, G. J. Chem. Commun. 2009, 3446;
(l) Ramesh, V. V. E.; Priya, G.; Rajamohanan, P. R.; Hofmann, H. J.; Sanjayan, G. J.
8. (a)Chemistry and Biology of b-Lactams; Morin, R. B., Gorman, M., Eds.; Academic
Press Inc: New York, 1982–1983. Vol. 1–3; (b) Alcaide, B.; Almendros, P.;
Aragoncillo, C. Chem. Rev. 2007, 107, 4437.
9. For b-lactam-based synthetic peptides/mimics, see (a) Ojima, I. Acc. Chem. Res.
1995, 28, 383; (b) Ojima, I.; Delaloge, F. Chem. Soc. Rev. 1997, 26, 377; (c)
Palomo, C.; Aizpurua, J. M.; Benito, A.; Miranda, J. I.; Fratila, R. M.; Matute, C.;
Domercq, M.; Gago, F.; Martin-Santamaria, S.; Linden, A. J. Am. Chem. Soc. 2003,
125, 16243; (d) Palomo, C.; Aizpurua, J. M.; Balentova, E.; Azcune, I.; Santos, J. I.;
Jimenez-Barbero, J.; Can ada, J.; Miranda, J. I. Org. Lett. 2008, 10, 2227; (e)
Aizpurua, J. M.; Ganboa, J.; Palomo, C.; Loinaz, I.; Oyarbide, J.; Fernandez, X.;
Balentov, E.; Fratila, R. M.; Jimnez, A.; Miranda, J.; Laso, A.; Avila, S.; Castrillo, J.
L. ChemBioChem 2011, 12, 401.
10. For related bridged monobactams, see (a) Heinze-Krauss, I.; Angehrn, P.;
Charnas, R. L.; Gubernator, K.; Gutknecht, E.-M.; Hubschwerlen, C.; Kania, M.;
Oefner, C.; Page, M. G. P.; Sogabe, S.; Specklin, J.-L.; Winkler, F. J. Med. Chem.
1998, 41, 3961; (b) Christian, H.; Markus, B.; Philippe, P.; Jean-Luc, S. Eur. Pat.
Appl. EP 671401 A1 1995, 119.; (c) Marc, M.; Xiaoping, W.; Lin, X. PCT Int. Appl.
WO2009037229 A1 2009, 4.; (d) Chen, H. Bioorg. Med. Chem. Lett. 2011, 21,
4267.
11. For selected articles, see (a) Marcin, L. R. Bioorg. Med. Chem. Lett. 2011, 21, 537;
(b) Sova, M.; Cadez, G.; Turk, S.; Majce, V.; Polanc, S.; Batson, S.; Lloyd, A. J.;
Roper, C. D. I.; Fishwick, W. G.; Gobec, S. Bioorg. Med. Chem. Lett. 2009, 19, 1376;
(c) Gautier, A.; Pitrat, D.; Hasserodt, J. Bioorg. Med. Chem. 2006, 14, 3835; (d)
Kale, S. S.; Chavan, S. T.; Sabharwal, S. G.; Puranik, V. G.; Sanjayan, G. J. Org.
Biomol. Chem. 2011, 9, 7300.
12. (a) Banik, B. K.; Manhas, M. S.; Kaluxa, Z.; Barakat, K. J.; Bose, A. K. Tetrahedron
Lett. 1992, 33, 3603; (b) Bose, A. K.; Banik, B. K.; Mathur, C.; Wagle, D. R.;
Manhas, M. S. Tetrahedron 2000, 56, 5603; (c) Wagle, D. R.; Garaj, C.; Chaing, J.;
Monteleone, M. G.; Kurys, B. E.; Strohmeyer, T. W.; Hedge, V. R.; Manhas, M. S.;
Bose, A. K. J. Org. Chem. 1988, 53, 4227.
13. Staudinger, H. Liebigs Ann. Chem. 1907, 356, 51.
14. (a) Banik, B. K.; Becker, F. F. Tetrahedron Lett. 2000, 41, 6551; (b) Kugun, H. B.;
Busselier, J. J.; Luche, J. L. Tetrahedron Lett. 1964, 5, 941; (c) Decuzes, P. J.; Luche,
J. L.; Kugan, H. B. Tetrahedron Lett. 1970, 11, 3661.
15. Kong, X.; Grindley, T. B. Can. J. Chem. 1994, 72, 2396.
16. Crystallographic data for 1a have been deposited with the Cambridge
Crystallographic Data Centre (CCDC-878820).