An efficient synthetic approach towards trans-β2,3-amino acids and demonstration of their utility in the design of therapeutically important β2,3-peptides and α,β2,3-peptide aldehydes

Article abstract of DOI:10.1016/j.tet.2009.09.072

An efficient synthetic approach towards trans-β^2,3-amino acids involving anti-selective aldol, azidation and controlled hydrolysis as key steps is discussed. Apart from structural elaboration of these building blocks to homo- and hetero-dipepti

Full text of DOI:10.1016/j.tet.2009.09.072

Tetrahedron 65 (2009) 10074–10082
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An efficient synthetic approach towards trans-
b
2,3-amino acids and
demonstration of their utility in the design of therapeutically
important
b
2,3-peptides and
a,
b
2,3-peptide aldehydes
*
Dhayalan Balamurugan, Kannoth M. Muraleedharan
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600 036, India
a r t i c l e i n f o
a b s t r a c t
An efficient synthetic approach towards trans-b
2,3-amino acids involving anti-selective aldol, azidation
Article history:
Received 12 June 2009
Received in revised form
11 September 2009
Accepted 17 September 2009
Available online 23 September 2009
and controlled hydrolysis as key steps is discussed. Apart from structural elaboration of these building
blocks to homo- and hetero-dipeptides, possibility of selective endocyclic cleavage of the chiral auxiliary
was advantageously used in the preparation of a,b-hybrid peptide alcohols and corresponding aldehydes,
which are promising candidates for biological evaluation against proteases of therapeutic interest.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
trans-b
2,3-Amino acids
Betapeptides
Peptide aldehydes
1. Introduction
‘medicines’ to ‘material science’ as shown by recent reports on
liquid crystalline
b
-peptides.7
Similarity in the folding behaviour of
b-peptides with that of
Anti-periplanar arrangement of side chains in trans-b
2,3-amino
their natural counterpart coupled with their superior stability in
biological milieu has generated a great deal of interest in the design
of structurally and functionally important molecular frameworks
acids and tendency of their peptides to form extended structures
suggest that such systems are ideal for creating new molecular
topologies with tunable polarity characteristics.1a,8 Among the
from
b
-amino acids.1 Pioneering efforts, especially from the labo-
notable approaches to prepare trans-b
2,3-amino acids,9 the one
ratories of Seebach, Gellman and De-Grado have laid a strong
foundation to this area and have resulted in molecules with pre-
dictable conformational characteristics,2 with potential application
in drug design.3 Important observations from studies on folding
developed by Ellman et al. makes use of Ti(O-i-Pr)3 ester enolate
addition to tert-butanesulfinyl imines, and has been shown to be
applicable to a variety of substrates. New methods towards such
building blocks using readily accessible chiral auxiliaries would be
highly useful in structure design, and results from our investigation
in this direction are discussed below.
preferences of such oligomers include (i) 314-helices from
tides and - and
2,3-peptides with like configurations at
tions,4 (ii) extended structures when the monomeric 2,3-amino
acids have unlike configurations (S,R or R,S) at - and
-centres,1a,2d
b
3-pep-
b-posi-
b
a
b
a
b
2. Results and discussion
and (iii) 10-membered turn if the amide bond is in between two
substituted carbon atoms (i.e., b2b3-dipeptide).5 Related studies
A sequence involving directed anti-aldol reaction of N-acylox-
azolidinones with suitable aldehydes, followed by inversion at the
have also shown that the presence of
b-amino acids at specific
locations in -peptide hairpins or helices are tolerated without
a
b-carbon using amine equivalents was envisaged to give com-
significant perturbation in the structure, highlighting the compat-
ibility of such monomeric units with natural peptides in creating
new hybrid molecules.6 Further, unique aggregation characteristics
of such molecules have extended their use beyond the realm of
pounds of desired stereochemistry (Scheme 1). Possibility of
modulating hydrolytic conditions to effect either exocyclic or
endocyclic cleavage of the chiral auxiliary to prepare
b
2,3-amino
acids or
a,b
-hybrid systems was also explored.10
In a typical experiment, the acid chloride derived from valeric
acid was reacted with in situ-generated anion of (4S)-4-benzylox-
azolidin-2-one (1) to give 2a quantitatively, which, when subjected
to Evans MgCl2 catalyzed anti-aldol reaction11 with benzaldehyde
* Corresponding author. Tel.: þ91 44 2257 4233; fax: þ91 44 2257 4202.
E-mail address: mkm@iitm.ac.in (K.M. Muraleedharan).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.072

D. Balamurugan, K.M. Muraleedharan / Tetrahedron 65 (2009) 10074–10082
10075
n = 2
n = 1
1. MgCl2 (20 mol%)
n-BuLi,
Et3N, RCHO
TMSCl, EtOAc,
rt, 24 h
O
O
OH
O
O
3a (83%) 3b (82%)
3c (80%) 3d (73%)
Cl
O
R = Ph
n
4-OMeC6H4
furan-2-yla
R
N
NH
Bn
O
O
O
N
O
3e (81%)
3f (76%)
-
THF, -78 °C,
1 h
2. MeOH, TFA
n
n
Bn
a
Bn
3a-g
4-NO2C6H4
3g (71%)
1
n = 2 (2a, 95%)
n = 1 (2b, 86%)
CH2Cl2,
Et3N,
MsCl
0 °C to rt, 2 h
NaN3
O
O
O
R
N3
O
H
H
OMs
R
O
O
DMF
24 h
N3
R
O
O
N
N
H
n
H
N
+
O
n
6c-g
50 °C
n
Bn
Bn
5a-g
4a-g
Bn
Boc2o,
EtOAc, rt, 8 h
R
10% Pd/C,
H2
5f-g
b,c
O
O
R = Ph
4-OMeC6H4 furan-2-yl 4-NO2C6H4 4-NH2C6H4
n = 2
NHBoc
7a (91%) 7c (94%) 7e (93%) 7f (41%)
7h (84%)
7i (80%)
N
O
n
n = 1
7b (92%) 7d (95%)
-
7g (47%)
Bn
7a-e,h,i
Scheme 1. Synthesis of b-
2,3-amino acid precursors. (a) 0.3 equiv of NaSbF6 used as additive, (b) PPh3, THF–H2O, (c) Boc2o, EtOAc (2 steps).
afforded the alcohol 3a in 83% yield (dr¼91:9,12 Scheme 1). Our
spectrum, the Cb-H signal in compounds 5a–5g appeared as a clear
doublet with J values in the range of 8.4–10.0 Hz. The corre-
sponding value in 6c–g was 10.8 Hz consistent with the anti-peri-
initial attempts to invert the
b
-carbon configuration using amine
equivalents under Mitsunobu-conditions proved ineffective, most
likely due to steric reasons. A nucleophilic displacement route
through mesylate 4a using sodium azide was later considered,
which afforded the desired isomer 5a in 71% yield. Through a one-
pot reduction–Boc-protection sequence,13 this azide was converted
planar positioning of C
Interestingly, the use of
this strategy led to
2,3-amino acids having opposite relative ste-
a- and Cb-hydrogens in these compounds.
L-phenylalanine derived chiral auxiliary in
b
reochemistry compared to those prepared using tert-butanesulfinyl
to the N-protected
b
-amino acid precursor 7a in 91% yield. Results
directing group, reported earlier.9b The decrease in stereoselectivity
from similar reaction sequences involving anisaldehyde, 2-fur-
aldehyde, 4-nitrobenzaldehyde and other N-acyloxazolidinones are
also presented in Scheme 1 and Table 1. Unlike mesylates 4a–e,
azidation of nitroderivatives 4f and 4g gave better conversion on
using DMSO in place of DMF. Reactions in these cases however had
to be stopped before the complete consumption of starting mate-
rials to avoid formation of side products such as 4-nitrobenzonitrile
and N-acyloxazolidinones 2a/2b. Selective reduction of the azide
units in 5f and 5g was achieved under Staudinger reaction condi-
tion and the corresponding amines were converted to the Boc-
derivatives 7f (41%) and 7g (47%) using Boc2o. At the same time,
simultaneous reduction of both nitro- and azide-units in these
compounds under Pd–C/H2 condition and subsequent selective
Boc-protection of Cb-NH2 using 1 equiv of Boc2o afforded the
amino derivatives 7h and 7i as the major products.
Table 1
Azidation of mesylates 4a–g
S. no.
n
R
Azide
dr (5:6)a
Yield (%)
1
2
3
4
5
6
7
2
1
2
1
2
2
1
Ph
Ph
a
b
c
d
e
f
d
71b
71b
79
d
4-OMeC6H4
4-OMeC6H4
Furan-2-yl
4-NO2C6H4
4-NO2C6H4
61:39
63:37
67:33
95:5
97:3
75
82
75c,d
84c,d
g
Diastereomeric ratio was determined from 1H NMR spectrum of the crude
reaction mixture.
a
b
Only the stereoisomer 5 was isolated.
Based on the amount of recovered starting material.
DMSO was used as the solvent.
c
d
The absolute stereochemistry of the alcohol 3c and the corre-
sponding azide 5c, determined by X-ray crystallographic analysis
(Fig. 1),14 is in agreement with our expectations. In their 1H NMR
Fig. 1. ORTEP diagrams of compounds 3c and 5c.

10076
D. Balamurugan, K.M. Muraleedharan / Tetrahedron 65 (2009) 10074–10082
during azidation of 4c, 4d and 4e can be attributed to the prefer-
ence towards a contact ion-pair mechanism during substitution.
As mentioned, an interesting aspect of this method is the pos-
sibility of adjusting reaction conditions to effect regioselective
hydrolysis of the chiral auxiliary. Thus, exocyclic cleavage of 7c
using in situ-generated lithium hydroperoxide afforded the N-Boc
amino acid (8) in 93% yields.10 Hydrolysis of 7b and 7c using LiOH at
the same time gave alcohols 9a and 9b, respectively, in high yields
through endocyclic cleavage (Scheme 2). Peptide aldehydes such as
10a and 10b, which can be readily prepared from 9a and 9b, are
potential candidates for targeting proteases of therapeutic
interest.15
OMe
O
H
H3C
i
NHBoc
MeO2C
N
H
( )2
11
OMe
OMe
ii
O
O
NHBoc
HO
NH3+Cl -
O
( )2
R
R
( )2
8
12
iii
i
O
O
O
OMe
OMe
N
NHBoc
NHBoc
HO
O
N
( )n
( )n
Bn
7b (n = 1, R = H)
7c (n = 2, R = OMe)
O
8 (n = 2, R = OMe)
O
O
R
NHBoc
( )2
( )2
H
13
Scheme 3. Synthesis of hybrid peptide 11 and trans-b2,3 dipeptide 13: (i) H2NAlaO-
Me$HCl, i-Pr2NEt, EDCI, HOBt, CH2Cl2, 0 ꢀC to rt, 27 h, 80%; (ii) SOCl2, MeOH, 0 ꢀC to rt,
24 h, 88%; (iii) i-Pr2NEt, EDCI, HOBt, CH2Cl2, 0 ꢀC to rt, 27 h, 71%.
ii
O
Bn
NHBoc
R'
N
H
( )n
3. Experimental
R = H
n = 1
R = OMe
3.1. General procedures
n = 2
R' = CH2OH
R' = CHO
9a (81%)
9b (87%)
All reactions were carried out under nitrogen atmosphere using
dry solvents under anhydrous conditions, unless otherwise men-
tioned. Triethylamine and chlorotrimethylsilane were dried over
calcium hydride and distilled under nitrogen atmosphere. HPLC-
grade ethyl acetate from Finar chemicals Ltd., was used as received.
Butyryl chloride, valeryl chloride and various aldehydes used in the
reactions were also distilled before use. Thin-layer chromatography
(TLC) was performed on 0.25 mm silica gel plates (60 F254 grade)
from Merck, and were analyzed using a 254 nm UV light. The
chromatographic separation was carried out on 100–200 mesh
silica gel. Melting points were obtained on electro-thermal appa-
ratus and are uncorrected. 1H NMR and 13C NMR spectra were
recorded on Bruker Avance 400 MHz and 500 MHz instruments,
and the chemical shifts are reported in parts per million (ppm)
relative to tetramethylsilane, with J values in hertz. The splitting
patterns in 1H NMR spectra are reported as follows: s¼singlet;
d¼doublet; t¼triplet; q¼quartet; qn¼quintet; dd¼doublet of
doublet; ddd¼doublet of doublet of doublet; dddd¼doublet of
doublet of doublet of doublet; br s¼broad singlet; br d¼broad
doublet; br t¼broad triplet; m¼multiplet. 13C NMR data are
reported with the solvent peak (CDCl3¼77.0, DMSO-d6¼39.5) as the
internal standard. High-resolution mass spectra (HRMS) were
recorded on a Waters Q-Tof microÔ spectrometer with lock spray
source. Infrared spectra were recorded using a Nicolet 6700 FT-IR
spectrophotometer. Optical rotations were measured on an Auto-
polÒ IV automatic polarimeter from Rudolph Research Analytical
with a cell of 50 mm path length and Elemental analysis was done
on ThermoFinnigan FLASH EA 1112 CHNS analyser at IISc Bangalore,
India.
iii
10a (80%)
10b (83%)
Scheme 2. Regioselective hydrolysis of the chiral auxiliary and preparation of a, -
b2,3
hybrid systems 9 and 10: (i) H2O2, LiOH$H2O, THF–H2O (3:1), 0 ꢀC to rt, 6 h, 93%;
(ii) LiOH$H2O, THF–H2O (3:1), 0 ꢀC to rt, 10 h; (iii) 2-iodoxybenzoic acid (IBX), DMSO,
rt, 8 h.
Versatility of these
b
2,3-amino acid building blocks in the
design of homo- and hetero-oligomers is demonstrated through
preparation of compounds 11 and 13 as depicted in Scheme 3. The
a
,
b
-hybrid peptide 11 was prepared in 80% yield by reacting Boc-
protected
b
2,3-amino acid 8 with the free amine from alanine
methylester hydrochloride under EDCI/HOBt-mediated coupling
condition. Our initial attempts to couple the free amine from 7c
with 8 gave only very low yields of the dipeptide, most likely due
to increased steric bulk at the adjacent carbon atoms. To over-
come this, 8 was first subjected to one-pot Boc-deprotection/es-
terification sequence using thionylchloride in methanol to get 12,
which was then coupled with 8 to afford the dipeptide 13 in 71%
yield.
It is important to note that application of peptide alcohols,16
b
-peptides,3e,3h,17 and -hybrid systems3b,3c,18 as drug candidates
a,b
or their intermediates is well documented in literature, and the
present strategy is expected to be useful in generating libraries of
such compounds for biological evaluation.
To summarize, we delineate a useful method towards trans-
b
a
2,3-amino acids, their peptides and 2,3-hybrid systems through
a,b
unique route involving directed anti-aldol, stereo-selective
-carbon and controlled hydrolysis as the key steps.
inversion at the
b
Such molecules can find applications in the fields of drug design,
and in creating well-defined molecular surfaces to understand
phenomena like membrane-protein interaction.
The intensity data collection during X-ray crystallographic
analysis was carried out on a Bruker AXS (kappa apex II) diffrac-
tometer19 equipped with graphite monochromated Mo (Ka)

D. Balamurugan, K.M. Muraleedharan / Tetrahedron 65 (2009) 10074–10082
10077
radiation. The data were collected for
ation. and scans were employed to collect the data. The frame
width for
was set to 0.5ꢀ for data collection. The frames were
q
up to 25ꢀ for Mo K
a
radi-
3.97 (dd,1H, J¼2.8, 9.2 Hz, (PhCH2)CHCHaHbO–), 2.62 (dd,1H, J¼3.2,
13.6 Hz, (PhCHaHb)CH), 2.01–1.83 (m, 3H, (PhCHaHb)CH and
CH2CH3), 0.95 (t, 3H, J¼7.6 Hz, CH2CH3); 13C NMR (100 MHz, CDCl3)
u
4
u
integrated and data were reduced for Lorentz and polarization
correction using SAINT-Plus. The multi-scan absorption correc-
tion20 was applied to data. All structures were solved using SIR-92
and refined using SHELXL-97.21 The molecular and packing dia-
grams were drawn using ORTEP-322 (Oak Ridge Thermal Ellipsoid
Plot) and Mercury 1.4.2. The non-hydrogen atoms were refined
with anisotropic displacement parameter. All hydrogen atoms
could be located in the difference Fourier map. However, the
hydrogen atoms bonded to carbons were fixed at chemically
meaningful positions and were allowed to ride with parent atom
during the refinement.
d 173.3, 152.8, 137.4, 135.1, 129.2 (2C), 128.9 (2C), 128.7 (3C), 128.0
(2C), 127.2, 67.6, 65.6, 54.9, 49.2, 36.9, 23.2, 11.0; HRMS (ESI) exact
mass calcd for C21H22N4O3Na [MþNa]þ 401.1590, found 401.1590.
3.2.3. (S)-3-((R)-2-((R)-Azido(4-methoxyphenyl) methyl) pentanoyl)-
4-benzyloxazolidin-2-one (5c). The alcohol 3c (1 g, 2.52 mmol) in
dry dichloromethane (10 mL) was reacted with mesyl chloride
(0.29 mL, 3.78 mmol) in presence of triethylamine (0.70 mL,
5.04 mmol) according to the procedure discussed above to get the
mesylate 4c as a yellow residue (1.1 g, 92%). The compound 4c (1 g,
2.1 mmol) in DMF (10 mL) was subsequently converted to the azide
using NaN3 (0.274 g, 4.2 mmol) to afford diastereomers 5c and 6c in
61:39 ratio (combined weight¼700 mg, 79% yield). [Found: C,
3.2. Azidation of anti-aldol products23
65.40; H, 6.40; N, 11.94. C23H26N4O4 requires C, 65.39; H, 6.20; N,
30
3.2.1. (S)-3-((R)-2-((R)-Azido(phenyl)methyl)pentanoyl)-4-benzyl ox-
azolidin-2-one (5a). To a stirred solution of 3a (400 mg, 1.09 mmol)
in dry dichloromethane (4 mL) at 0 ꢀC under N2 atmosphere, was
added triethylamine (0.30 mL, 2.18 mmol), followed by mesyl
chloride (0.13 mL, 1.64 mmol). The reaction was monitored by TLC,
and after complete consumption of the starting material (2 h), it was
washed with 5% NaHCO3 solution (25 mL) and brine (25 mL). The
organic layer was dried over anhydrous Na2SO4 and concentrated
under reduced pressure to get the mesylate 4a as a gummy solid
(470 mg, 97%). To a stirred solution of the above mesylate (400 mg,
0.89 mmol) in DMF (4 mL) was added NaN3 (116.9 mg, 1.79 mmol)
and the mixture was heated at 50 ꢀC for 24 h. The reaction mixture
was diluted with EtOAc (25 mL), washed with water (3 ꢁ 25 mL),
followed by brine (25 mL) and then dried over anhydrous Na2SO4. It
was filtered and concentrated under reduced pressure to get a resi-
due, which was purified by chromatography on silica gel using 5%
13.26%.] mp 67–69 ꢀC; Rf (20% EtOAc/Hexane) 0.57; [
a
]
þ136.3 (c
D
1, CHCl3); IR (neat) nmax 2959, 2933, 2872, 2099, 1775, 1692, 1610,
1513, 1384, 1248, 1208, 1100, 1031, 703 cmꢂ1 1H NMR (400 MHz,
CDCl3)
7.36 (d, 2H, J¼8.8 Hz, Ar–H), 7.30–7.22 (m, 3H, Ph–H), 6.95
;
d
(d, 2H, J¼8.0 Hz, Ph–H), 6.89 (d, 2H, J¼8.4 Hz, Ar–H), 4.68 (d, 1H,
J¼10.0 Hz, ArCHN3), 4.60–4.49 (m, 2H, (PhCH2)CH and
CH(CH2CH2CH3)), 4.06 (dd, 1H, J¼8.8, 8.8 Hz, (PhCH2)CH(CHaHbO–
)), 3.97 (dd, 1H, J¼2.4, 8.8 Hz, (PhCH2)CH(CHaHbO–)), 3.77 (s, 3H,
4-OCH3–C6H4), 2.66 (dd, 1H, J¼3.2, 13.2 Hz, (PhCHaHb)CH), 1.98 (dd,
1H, J¼10.0, 13.6 Hz, (PhCHaHb)CH), 1.90–1.78 (m, 2H, CH2CH2CH3),
1.39–1.24 (m, 2H, CH2CH2CH3), 0.93 (t, 3H, J¼7.2 Hz, CH2CH2CH3);
13C NMR (100 MHz, CDCl3)
d 173.7, 159.9, 152.8, 135.1, 129.5, 129.4
(2C), 129.3 (2C), 128.9 (2C), 127.2, 114.1 (2C), 67.7, 65.6, 55.3, 54.9,
48.0, 37.0, 32.5, 20.2, 14.2; HRMS (ESI) exact mass calcd for
C23H26N4O4Na [MþNa]þ 445.1852, found 445.1855.
EtOAc/hexanes system to afford 5a (250 mg, 71%) as a white crys-
3.2.3.1. (S)-3-((R)-2-((S)-Azido(4-methoxyphenyl)methyl)penta-
30
talline solid; mp 57–59 ꢀC; Rf (20% EtOAc/Hexane) 0.60; [
a
]
þ106.3
noyl)-4-benzyloxazolidin-2-one (6c). 91:9 mixture of 6c and 5c as
D
30
(c 1, CHCl3); IR (neat) nmax 2961, 2931, 2100, 1778, 1693, 1385, 1263,
per 1H NMR; Rf (20% EtOAc/Hexane) 0.57; [
a]
ꢂ438.8 (c 1, CHCl3);
D
1209, 1100, 733, 700 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
7.43 (d, 2H,
IR (neat) nmax 2960, 2931, 2873, 2098, 1775, 1693, 1610, 1514, 1385,
1349, 1250, 1208, 1177, 1100, 831, 703 cmꢂ1 1H NMR (400 MHz,
CDCl3)
7.39–7.33 (m, 4H, Ar–H), 7.30 (d, 3H, J¼7.2 Hz, Ar–H), 6.95
J¼7.2 Hz, Ph–H), 7.37 (t, 2H, J¼7.2 Hz, Ph–H), 7.33 (d, 1H, J¼6.8 Hz,
Ph–H), 7.30–7.20 (m, 3H, Ph–H), 6.95 (d, 2H, J¼7.6 Hz, Ph–H), 4.72 (d,
1H, J¼9.6 Hz, PhCHN3), 4.59–4.49 (m, 2H, (PhCH2)CH and
CH(CH2CH2CH3)), 4.05 (dd, 1H, J¼8.9, 8.9 Hz, (PhCH2)CH(CHaHbO–)),
3.96 (dd, 1H, J¼2.6, 9.2 Hz, (PhCH2)CH(CHaHbO–)), 2.61 (dd, 1H,
J¼3.2, 13.6 Hz, (PhCHaHb)CH), 1.94–1.83 (m, 3H, (PhCHaHb)CH and
CH2CH2CH3), 1.38–1.25 (m, 2H, CH2CH2CH3), 0.93 (t, 3H, J¼7.2 Hz,
;
d
(d, 2H, J¼8.4 Hz, Ar–H), 4.80–4.73 (m, 1H, (PhCH2)CH(CH2O)), 4.67
(d, 1H, J¼10.8 Hz, ArCHN3), 4.56–4.50 (m, 1H, CH(CH2CH2CH3)), 4.19
(d, 2H, J¼4.8 Hz, (PhCH2)CH(CH2O–)), 3.84 (s, 3H, 4-OCH3–C6H4),
3.44 (dd, 1H, J¼3.2, 13.6 Hz, (PhCHaHb)CH), 2.80 (dd, 1H, J¼10.0,
13.6 Hz, (PhCHaHb)CH), 1.60–1.49 (m, 1H, CHaHbCH2CH3), 1.20–1.10
(m, 3H, CHaHbCH2CH3 and CH2CH2CH3), 0.75 (t, 3H, J¼6.8 Hz,
CH2CH2CH3); 13C NMR (100 MHz, CDCl3)
d 173.6, 152.8, 137.4, 135.1,
129.2 (2C), 128.9 (2C), 128.8 (3C), 128.1 (2C), 127.2, 68.1, 65.6, 54.9,
48.0, 36.9, 32.4, 20.1, 14.2; HRMS (ESI) exact mass calcd for
C22H24N4O3Na [MþNa]þ 415.1746, found 415.1739.
CH2CH2CH3); 13C NMR (100 MHz, CDCl3)
d 175.0, 160.0, 153.3, 135.5,
129.5 (2C), 129.3 (2C), 128.9 (2C), 128.7, 127.3, 114.3 (2C), 68.7, 65.8,
55.7, 55.3, 47.3, 37.6, 32.2, 19.9, 14.0; HRMS (ESI) exact mass calcd
for C23H26N4O4Na [MþNa]þ 445.1852, found 445.1855.
3.2.2. (S)-3-((R)-2-((R)-Azido(phenyl)methyl)butanoyl)-4-benzylox-
azolidin-2-one (5b). The alcohol 3b (250 mg, 0.708 mmol) in dry
dichloromethane (2.5 mL) was reacted with mesyl chloride
(0.08 mL, 1.062 mmol) in presence of triethylamine (0.2 mL,
1.416 mmol) according to the procedure discussed above to get the
mesylate 4b as a yellow residue (290 mg, 95%). Compound 4b
(250 mg, 0.58 mmol) in DMF (2.5 mL) was subsequently subjected
to azidation using NaN3 (75.4 mg, 1.16 mmol) and the product
mixture was chromatographed on silica gel using 5% EtOAc/hex-
3.2.4. (S)-3-((R)-2-((R)-Azido(4-methoxyphenyl)methyl) butanoyl)-4-
benzyloxazolidin-2-one (5d). The alcohol 3d (500 mg, 1.30 mmol) in
dichloromethane (10 mL) was reacted with mesyl chloride (0.15 mL,
1.96 mmol) in presence of triethylamine (0.37 mL, 2.61 mmol)
according to the procedure discussed above to get the mesylate 4d
as a yellow residue (580 mg, 96%). The compound 4d (580 mg,
1.26 mmol) in DMF (10 mL) was subsequently converted to the azide
using NaN3 (0.163 g, 2.52 mmol) to afford diastereomers 5d and 6d
anes system to afford 5b as a white crystalline solid (155 mg, 71%);
in 63:37 ratio (combined weight¼384 mg, 75% yield); mp 112–
30
30
mp 125–128 ꢀC; Rf (20% EtOAc/Hexane) 0.42; [
a
]
D
þ151.7 (c 1,
114 ꢀC; Rf (20% EtOAc/Hexane) 0.47; [
a]
þ141.7 (c 1, CHCl3); IR
D
CHCl3); IR (neat) nmax 3031, 2968, 2929, 2878, 2099, 1774, 1689,
1455, 1382, 1202, 1104, 1022, 740, 699 cmꢂ1 1H NMR (400 MHz,
CDCl3)
(neat) nmax 2966, 2929, 2099, 2872, 2835, 1774, 1691, 1610, 1513,
1383, 1348, 1248, 1209, 1177, 1105, 1031, 830, 703 cmꢂ1 1H NMR
(400 MHz, CDCl3)
;
;
d
7.43 (d, 2H, J¼7.0 Hz, Ph–H), 7.38 (t, 2H, J¼7.2 Hz, Ph–H),
d
7.35 (d, 2H, J¼8.4 Hz, Ar–H), 7.29–7.20 (m, 3H,
7.34–7.20 (m, 4H, Ph–H), 6.94 (d, 2H, J¼8.0 Hz, Ph–H), 4.75 (d, 1H,
J¼10.0 Hz, PhCHN3), 4.58–4.46 (m, 2H, (PhCH2)CH and
CH(CH2CH3)), 4.06 (dd, 1H, J¼8.0, 8.0 Hz, (PhCH2)CH(CHaHbO–)),
Ph–H), 6.94 (d, 2H, J¼7.6 Hz, Ph–H), 6.90 (d, 2H, J¼8.4 Hz, Ar–H), 4.71
(d, 1H, J¼9.6 Hz, ArCHN3), 4.55 (dddd, 1H, J¼2.8, 2.8, 6.0, 10.8 Hz,
(PhCH2)CH(CH2O–)), 4.48 (ddd, 1H, J¼3.6, 9.6, 9.6 Hz, CH(CH2CH3)),

10078
D. Balamurugan, K.M. Muraleedharan / Tetrahedron 65 (2009) 10074–10082
4.07 (dd, 1H, J¼8.4, 8.4 Hz, (PhCH2)CH(CHaHbO–)), 3.99 (dd, 1H,
J¼2.8, 9.2 Hz, (PhCH2)CH(CHaHbO–)), 3.77 (s, 3H, 4-OCH3–C6H4),
2.67 (dd, 1H, J¼3.2, 13.6 Hz, (PhCHaHb)CH), 2.03 (dd, 1H, J¼9.6,
13.6 Hz, (PhCHaHb)CH), 2.01–1.82 (m, 2H, CH2CH3), 0.95 (t, 3H,
37.6, 32.2, 19.7, 14.1; HRMS (ESI) exact mass calcd for C20H22N4O4Na
[MþNa]þ 405.1539, found 405.1538.
3.2.6. (S)-3-((R)-2-((R)-Azido(4-nitrophenyl)methyl) pentanoyl)-4-
benzyloxazolidin-2-one (5f). The alcohol 3f (1 g, 2.43 mmol) in dry
dichloromethane (10 mL) was reacted with mesyl chloride
(0.28 mL, 3.65 mmol) in presence of triethylamine (0.67 mL,
4.86 mmol) according to the procedure discussed above to get the
mesylate 4f as a yellow solid (1.18 g, 99%). The mesylate (280 mg,
0.571 mmol) in DMSO (5.6 mL) was subjected to azidation using
NaN3 (74.3 mg, 1.143 mmol) for 16 h and the product mixture was
chromatographed on silica gel using 5–10% EtOAc/hexanes system
to afford 5f as a colourless viscous liquid (120 mg, 75% yield based
on 64% consumption of the starting material). Crude 1H NMR
showed the presence of diastereomers 5f and 6f in 95:5 ratio.
J¼7.2 Hz, CH2CH3); 13C NMR (100 MHz, CDCl3)
d 173.5, 159.9, 152.9,
135.1, 129.5, 129.3 (2C), 129.2 (2C), 128.9 (2C), 127.2, 114.1 (2C), 67.2,
65.6, 55.3, 54.9, 49.2, 37.0, 23.3,11.0; HRMS (ESI) exact mass calcd for
C22H24N4O4Na [MþNa]þ 431.1695, found 431.1688.
3.2.4.1. (S)-3-((R)-2-((S)-Azido(4-methoxyphenyl) methyl)butanoyl)-
4-benzyloxazolidin-2-one (6d). mp 123–125 ꢀC; Rf (20% EtOAc/Hex-
30
ane) 0.47; [
a
]
D
ꢂ104.3 (c 1, CHCl3); IR (neat) nmax 2966, 2913, 2099,
2835, 1778, 1694, 1513, 1388, 1250, 1210, 1108, 1031, 831, 703 cmꢂ1
;
1H NMR (400 MHz, CDCl3)
d
7.39–7.27 (m, 7H, Ar–H), 6.94 (d, 2H,
J¼8.6 Hz, Ar–H), 4.82–4.74 (m, 1H, (PhCH2)CH–), 4.71 (d, 1H,
J¼10.8 Hz, ArCHN3), 4.46 (ddd, 1H, J¼4.0, 10.4, 10.4 Hz,
CH(CH2CH3)), 4.20 (d, 2H, J¼4.8 Hz, (PhCH2)CH(CH2O–)), 3.83
(s, 3H, 4-OCH3–C6H4–), 3.43 (dd, 1H, J¼3.2, 13.6 Hz, (PhCHaHb)CH),
2.82 (dd, 1H, J¼10.0, 13.6 Hz, (PhCHaHb)CH), 1.59–1.47 (m, 1H,
CHaHbCH3), 1.34–1.24 (m, 1H, CHaHbCH3), 0.78 (t, 3H, J¼7.6 Hz,
However, 6f could not be isolated in pure form; Rf (20% EtOAc/
34
Hexane) 0.33; [
a
]
D
þ94.5 (c 1, CHCl3); IR (neat) 3028, 2961, 2924,
2864, 2102,1775,1692,1605,1523,1386,1350,1255,1209,1103, 856,
700 cmꢂ1; 1H NMR (400 MHz, CDCl3)
8.25 (d, 2H, J¼8.8 Hz, Ar–H),
d
7.65 (d, 2H, J¼8.8 Hz, Ar–H), 7.30–7.22 (m, 3H, Ph–H), 6.99 (d, 2H,
J¼7.6 Hz, Ph–H), 4.97 (d, 1H, J¼8.4 Hz, CHN3), 4.59 (dddd, 1H, J¼3.2,
3.2, 8.0, 10.8 Hz, (PhCH2)CH(CH2O–)), 4.39 (ddd, 1H, J¼3.6, 8.4,
9.6 Hz, CH(C3H7)), 4.14 (dd, 1H, J¼8.8, 8.8 Hz, (PhCH2)CH(CHaHbO–
)), 4.07 (dd, 1H, J¼2.4, 8.8 Hz, (PhCH2)CH(CHaHbO–)), 2.87 (dd, 1H,
J¼3.2, 13.2 Hz, (PhCHaHb)CH), 2.23 (dd, 1H, J¼10.0, 13.6 Hz,
(PhCHaHb)CH), 1.96–1.86 (m, 1H, CHaHbCH2CH3), 1.75–1.66 (m, 1H,
CHaHbCH2CH3), 1.35–1.20 (m, 2H, CH2CH2CH3), 0.91 (t, 3H, J¼7.2 Hz,
CH2CH3); 13C NMR (100 MHz, CDCl3)
d 174.8, 160.0, 153.3, 135.4,
129.5 (2C), 129.3 (2C), 129.0 (2C), 128.7, 127.3, 114.3 (2C), 68.3, 65.8,
55.6, 55.3, 48.7, 37.7, 23.1, 10.8; HRMS (ESI) exact mass calcd for
C22H24N4O4Na [MþNa]þ 431.1695, found 431.1702.
3.2.5. (S)-3-((R)-2-((S)-Azido(furan-2-yl)methyl)pentanoyl)-4-ben-
zyloxazolidin-2-one (5e). The alcohol 3e (300 mg, 0.84 mmol) in
dry dichloromethane (3 mL) was reacted with mesyl chloride
(0.1 mL, 1.26 mmol) in presence of triethylamine (0.23 mL,
1.68 mmol) according to the procedure discussed above to get the
mesylate 4e as a yellow viscous liquid (360 mg, 98%). This mesylate
(350 mg, 0.805 mmol) in DMF (3.5 mL) was subjected to azidation
using NaN3 (104.6 mg, 1.609 mmol) and the product mixture was
chromatographed on silica gel using 5% EtOAc/hexanes system to
afford 5e as a colourless viscous liquid (combined weight¼252 mg,
CH2CH2CH3); 13C NMR (100 MHz, CDCl3)
d 172.7, 152.9, 147.9, 144.9,
134.6, 129.1 (2C), 129.0 (2C), 128.8 (2C), 127.5, 123.9 (2C), 66.6, 65.9,
55.2, 48.3, 37.3, 31.1, 20.0, 14.1; HRMS (ESI) exact mass calcd for
C22H23N5O5Na [MþNa]þ 460.1597, found 460.1594.
3.2.7. (S)-3-((R)-2-((R)-Azido(4-nitrophenyl)methyl)butanoyl)-4-
benzyloxazolidin-2-one (5g). The alcohol 3g (1 g, 2.51 mmol) in
dry dichloromethane (10 mL) was reacted with mesyl chloride
(0.29 mL, 3.77 mmol) in presence of triethylamine (0.69 mL,
5.02 mmol) according to the procedure discussed above to get the
mesylate 4g as a yellow solid (1.15 g, 96%). The mesylate (250 mg,
0.525 mmol) in DMSO (5 mL) was subjected to azidation using
NaN3 (68 mg, 1.049 mmol) for 12 h and the product mixture was
chromatographed on silica gel using 5–10% EtOAc/hexanes system
to afford 5g as a white crystalline solid (138 mg, 84% yield based on
74% consumption of the starting material). Crude 1H NMR showed
the presence of diastereomers 5g and 6g in 97:3 ratio. However, 6g
82%; crude 1H NMR showed the presence of diastereomers 5e and
34
6e in 67:33 ratio); Rf (20% EtOAc/Hexane) 0.47; [
a
]
þ130.8 (c 0.75,
D
CHCl3); IR (neat) 3015, 2961, 2913, 2871, 2099, 1775, 1692, 1384,
1203, 1102, 1010, 743, 701, 633 cmꢂ1 1H NMR (400 MHz, CDCl3)
7.42 (d, 1H, J¼2.0 Hz, furan-H), 7.33–7.22 (m, 3H, Ph–H), 7.10 (d,
;
d
2H, J¼6.8 Hz, Ph–H), 6.44 (d, 1H, J¼3.2 Hz, furan-H), 6.36 (dd, 1H,
J¼2.0, 3.6 Hz, furan-H), 4.78 (d, 1H, J¼10.0 Hz, CHN3), 4.67–4.56
(m, 2H, (PhCH2)CH(CH2O–) and CH(C3H7)), 4.13 (dd, 1H, J¼8.8,
8.8 Hz, (PhCH2)CH(CHaHbO–)), 4.08 (dd, 1H, J¼3.2, 9.2 Hz,
(PhCH2)CH(CHaHbO–)), 2.92 (dd, 1H, J¼3.2, 13.6 Hz, (PhCHaHb)CH),
2.33 (dd, 1H, J¼10.4, 13.6 Hz, (PhCHaHb)CH), 1.92–1.78 (m, 2H,
CH2CH2CH3), 1.41–1.30 (m, 2H, CH2CH2CH3), 0.94 (t, 3H, J¼7.2 Hz,
could not be isolated in pure form; mp 85–87 ꢀC; Rf (20% EtOAc/
30
Hexane) 0.30; [
a
]
þ132.3 (c 1, CHCl3); IR (neat) 3036, 2971,2925,
D
2868, 2103, 1776, 1692, 1523, 1386, 1347, 1209, 1105, 852, 746,
700 cmꢂ1; 1H NMR (400 MHz, CDCl3)
8.25 (d, 2H, J¼8.8 Hz, Ar–H),
CH2CH2CH3); 13C NMR (100 MHz, CDCl3)
d
173.2, 152.8, 150.8, 143.0,
d
135.1, 129.3 (2C), 128.9 (2C), 127.3, 110.5, 108.9, 65.8, 60.1, 55.3, 45.5,
37.4, 32.2, 19.7, 14.2; HRMS (ESI) exact mass calcd for C20H22N4O4Na
[MþNa]þ 405.1539, found 405.1542.
7.65 (d, 2H, J¼8.8 Hz, Ar–H), 7.32–7.22 (m, 3H, Ph–H), 6.98 (d, 2H,
J¼7.2 Hz, Ph–H), 4.99 (d, 1H, J¼8.4 Hz, CHN3), 4.60 (dddd, 1H, J¼2.8,
2.8, 6.0, 10.8 Hz, (PhCH2)CH(CH2O–)), 4.35 (ddd, 1H, J¼3.6, 9.2,
9.2 Hz, CH(C2H5)), 4.14 (dd, 1H, J¼8.8, 8.8 Hz, (PhCH2)CHCHaHbO–),
4.07 (dd,1H, J¼2.4, 8.8 Hz, (PhCH2)CHCHaHbO–), 2.87 (dd,1H, J¼3.2,
13.2 Hz, (PhCHaHb)CH), 2.26 (dd, 1H, J¼9.6, 13.2 Hz, (PhCHaHb)CH),
2.02–1.89 (m, 1H, CHaHbCH3), 1.88 1.76 (m, 1H, CHaHbCH3), 0.93 (t,
3.2.5.1. (S)-3-((R)-2-((S)-Azido(furan-2-yl)methyl)pentanoyl)-4-
benzyloxazolidin-2-one (6e). 90:10 mixture of 6e and 5e as per 1H
34
NMR; Rf (20% EtOAc/Hexane) 0.47; [
a
]
ꢂ62.7 (c 0.75, CHCl3); IR
D
(neat) 2954, 2927, 2865, 2100, 1779, 1694, 1388, 1207, 1105, 1012,
748 cmꢂ1; 1H NMR (400 MHz, CDCl3)
7.48 (d, 1H, J¼1.2 Hz, furan-
3H, J¼7.6 Hz, CH2CH3); 13C NMR (100 MHz, CDCl3)
d 172.5, 153.0,
d
147.9, 145.0, 134.6, 129.1 (2C), 128.9 (2C), 128.8 (2C), 127.5, 123.9
(2C), 66.2, 65.9, 55.1, 49.6, 37.3, 22.1, 10.9; HRMS (ESI) exact mass
calcd for C21H21N5O5Na [MþNa]þ 446.1440, found 446.1438.
H), 7.40–7.33 (m, 2H, Ph–H), 7.33–7.27 (m, 3H, Ph–H), 6.46 (d, 1H,
J¼3.2 Hz, furan-H), 6.41 (dd, 1H, J¼1.6, 2.8 Hz, furan-H), 4.84 (d, 1H,
J¼10.4 Hz, CHN3), 4.81–4.72 (m, 1H, (PhCH2)CH–), 4.68 (ddd, 1H,
J¼3.6, 9.6, 9.6 Hz, CH(C3H7)), 4.25–4.18 (m, 2H, (PhCH2)CH(CH2O–)),
3.38 (dd, 1H, J¼3.2, 13.6 Hz, (PhCHaHb)CH), 2.81 (dd, 1H, J¼9.6,
13.6 Hz, (PhCHaHb)CH), 1.60–1.49 (m, 1H, CHaHbCH2CH3), 1.35–1.16
(m, 3H, CHaHbCH2CH3 and CH2CH2CH3), 0.81 (t, 3H, J¼7.2 Hz,
3.3. Conversion of azides to Boc-protected
precursors
b-amino acid
3.3.1. tert-Butyl(1R,2R)-2-((S)-4-benzyl-2-oxooxazolidine-3-
carbonyl)-1-phenylpentylcarbamate (7a). To solution of 5a
(40 mg, 0.102 mmol) and Boc2O (33.4 mg, 0.153 mmol) in EtOAc
CH2CH2CH3); 13C NMR (100 MHz, CDCl3)
d
174.2, 153.0, 149.5, 143.5,
a
135.3, 129.5 (2C), 129.0 (2C), 127.3, 110.4, 110.1, 65.8, 61.2, 55.5, 45.5,

D. Balamurugan, K.M. Muraleedharan / Tetrahedron 65 (2009) 10074–10082
10079
(0.5 mL) at room temperature was added 10% Pd/C (4 mg) and the
solution was stirred under an atmosphere of hydrogen for 8 h. After
the completion of the reaction, the catalyst was removed by fil-
tration through Celite, the filtrate evaporated under reduced
pressure and the resulting residue was purified by chromatography
on silica gel column using 15% EtOAc/hexanes solvent system to get
7a (43 mg, 91%) as a white crystalline solid. [Found: C, 69.48; H,
20.7, 14.1; HRMS (ESI) exact mass calcd for C28H36N2O6Na [MþNa]þ
519.2471, found 519.2465.
3.3.4. tert-Butyl(1R,2R)-2-((S)-4-benzyl-2-oxooxazolidine-3-car-
bonyl)-1-(4-methoxyphenyl) butylcarbamate (7d). The reduction–
Boc-protection procedure was repeated with 5d (25 mg,
0.0613 mmol) and Boc2O (20 mg, 0.0919 mmol) in EtOAc (0.5 mL) to
get 7d (28 mg, 95%) as a white crystalline solid. [Found: C, 67.17; H,
7.56; N, 5.92. C27H34N2O5 requires C, 69.50; H, 7.35; N, 6.00%.] mp
30
123–124 ꢀC; Rf (20% EtOAc/Hexane) 0.37; [
a
]
D
þ29.0 (c 1, CHCl3); IR
7.31; N, 5.99. C27H34N2O6 requires C, 67.20; H, 7.10; N, 5.81%.] mp
30
(neat) nmax 3371, 2961, 2930, 2872, 1773, 1693, 1496, 1384, 1350,
137–139 ꢀC; Rf (20% EtOAc/Hexane) 0.23; [
a]
þ35.4 (c 1, CHCl3);
D
1248, 1165, 1099, 1015, 735, 700 cmꢂ1 1H NMR (400 MHz, CDCl3)
;
IR (neat) nmax 3371, 2974, 2932, 2875, 2836, 1776, 1698, 1513, 1388,
d
7.42 (d, 2H, J¼6.8 Hz, Ph–H), 7.37–7.21 (m, 6H, Ph–H), 7.10 (d, 2H,
1367,1246,1169,1105,1034, 832, 763, 703 cmꢂ1; 1H NMR (400 MHz,
J¼6.4 Hz, Ph–H), 5.26 (br t, 1H, PhCHNHBoc), 5.07 (d, 1H, J¼9.2 Hz,
PhCHNHBoc), 4.60 (br t, 1H, (PhCH2)CH(CH2O–)), 4.34 (br t, 1H,
CH(CH2CH2CH3)), 4.14–4.03 (m, 2H, (PhCH2)CH(CH2O–), 2.96 (d,1H,
J¼13.2 Hz, PhCHaHbCH), 2.25 (t, 1H, J¼11.6 Hz, PhCHaHbCH),
1.92–1.81 (m, 1H, CHaHbCH2CH3), 1.39 (s, 9H, NH(C]O)OC(CH3)3),
1.40–1.10 (m, 3H, CHaHbCH2CH3 and CH2CH2CH3), 0.85 (t, 3H,
CDCl3)
d
7.36–7.20 (m, 5H, Ar–H), 7.08 (d, 2H, J¼6.0 Hz, Ar–H),
6.86 (d, 2H, J¼8.4 Hz, Ar–H), 5.19 (br t, 1H, 4-OMeC6H4CHNHBoc),
5.00 (d, 1H, J¼8.4 Hz, 4-OMeC6H4CHNHBoc), 4.61 (br t, 1H,
(PhCH2)CH(CH2O–)), 4.26 (br t, 1H, CH(CH2CH3)), 4.14–4.00 (m, 2H,
(PhCH2)CH(CH2O–)), 3.76 (s, 3H, 4-OCH3–C6H4), 2.97 (d, 1H,
J¼12.8 Hz, PhCHaHbCH), 2.26 (t, 1H, J¼11.2 Hz, PhCHaHbCH), 1.91–
1.80 (m, 1H, CHaHbCH3), 1.54 (br s, 1H, merged with water peak,
CHaHbCH3), 1.39 (s, 9H, NH(C]O)OC(CH3)3), 0.87 (t, 3H, J¼6.8 Hz,
J¼7.2 Hz, CH2CH2CH3); 13C NMR (125 MHz, CDCl3)
d 173.5, 155.1,
153.2, 140.5, 135.6, 129.3 (2C), 128.9 (4C), 128.5, 127.4, 127.2, 126.8,
79.7, 66.0, 55.7, 55.3, 48.9, 37.2, 29.0, 28.3 (3C), 20.8, 14.1; HRMS
(ESI) exact mass calcd for C27H34N2O5Na [MþNa]þ 489.2365, found
489.2359.
CH2CH3); 13C NMR (100 MHz, CDCl3)
d 173.5, 158.9, 155.1, 153.2,
135.5,132.8,129.2 (2C), 128.9 (3C),128.0,127.1, 113.9 (2C), 79.6, 65.9,
55.3, 55.2 (2C), 50.6, 37.2, 28.3 (3C), 20.4, 11.8; HRMS (ESI) exact
mass calcd for C27H34N2O6Na [MþNa]þ 505.2315, found 505.2305.
3.3.2. tert-Butyl(1R,2R)-2-((S)-4-benzyl-2-oxooxazolidine-3-
carbonyl)-1-phenylbutylcarbamate (7b). The above one-pot re-
duction–Boc-protection procedure was repeated with a solution of
5b (100 mg, 0.265 mmol) and Boc2O (0.09 mL, 0.397 mmol) in
EtOAc (1 mL) to get 7b (110 mg, 92%) as a white crystalline solid.
[Found: C, 69.05; H, 7.35; N, 6.43. C26H32N2O5 requires C, 69.00;
3.3.5. tert-Butyl(1R,2R)-2-((S)-4-benzyl-2-oxooxazolidine-3-car-
bonyl)-1-(furan-2-yl) pentylcarbamate (7e). The reduction–Boc-pro-
tection procedure was repeated with 5e (100 mg, 0.262 mmol) and
Boc2O (0.09 mL, 0.392 mmol) in EtOAc (1 mL) to get 7e (110 mg, 93%)
34
as a colourless viscous liquid; Rf (20% EtOAc/Hexane) 0.40; [a]
D
H, 7.13; N, 6.19%.] mp 145–147 ꢀC; Rf (20% EtOAc/Hexane) 0.33;
þ39.1 (c 1, CHCl3); IR (neat) nmax 3363, 3028, 2967, 2929, 2872, 1777,
1701, 1498, 1387, 1210, 1169, 1101, 1013, 742, 702 cmꢂ1 1H NMR
(400 MHz, CDCl3) 7.36 (br s, 1H, furan-H), 7.34–7.28 (m, 2H, Ph–H),
30
[
a
]
þ43.2 (c 1, CHCl3); IR (neat) nmax 3382, 3019, 2971, 2925,
;
D
2856, 1777, 1698, 1499, 1386, 1215, 1169, 1103, 1014, 760. 702 cmꢂ1
;
d
1H NMR (400 MHz, CDCl3)
d
7.40 (d, 2H, J¼7.2 Hz, Ph–H), 7.36–7.20
7.27–7.22 (m, 1H), 7.18 (d, 2H, J¼7.2 Hz, Ph–H), 6.30 (dd, 1H, J¼3.2,
2.0 Hz, furan-H), 6.25 (d, 1H, J¼3.2 Hz, furan-H), 5.38 (dd, 1H, J¼9.6,
7.2 Hz, CHNHBoc), 5.06 (d, 1H, J¼10.0 Hz, CHNHBoc), 4.62 (dddd, 1H,
J¼3.2, 3.2, 6.8,13.6 Hz, (PhCH2)CH(CH2O–)), 4.34 (br s,1H, CH(C3H7)),
4.16–4.07 (m, 2H, (PhCH2)CH(CH2O–)), 3.23 (d, 1H, J¼12.8 Hz,
(PhCHaHb)CH), 2.50 (t, 1H, J¼11.6 Hz, (PhCHaHb)CH), 1.93–1.85 (m,
1H, CH(CHaHbCH2CH3)), 1.42 (s, 9H, NH(C]O)OC(CH3)3), 1.40–1.15
(m, 3H, CH(CHaHbCH2CH3) and CH(CH2CH2CH3)), 0.88 (t, 3H,
(m, 6H, Ph–H), 7.09 (d, 2H, J¼6.0 Hz, Ph–H), 5.25 (br t, 1H, J¼6.8 Hz,
PhCHNHBoc), 5.06 (d, 1H, J¼9.2 Hz, PhCHNHBoc), 4.61 (br t, 1H,
(PhCH2)CH(CH2O–)), 4.29 (br t, 1H, CH(CH2CH3)), 4.13–4.03 (m, 2H,
(PhCH2)CH(CH2O–)), 2.93 (d, 1H, J¼12.8 Hz, PhCHaHbCH), 2.24
(t, 1H, J¼12.0 Hz, PhCHaHbCH), 1.93–1.83 (m, 1H, CHaHbCH3), 1.60–
1.42 (br s, 1H, CHaHbCH3), 1.39 (s, 9H, NH(C]O)OC(CH3)3), 0.87
(t, 3H, J¼6.8 Hz, CH2CH3); 13C NMR (100 MHz, CDCl3)
d 173.3, 155.1,
153.2, 140.5, 135.5, 129.2 (3C), 128.9 (3C), 128.5, 127.4, 127.1, 126.9,
79.7, 65.9, 55.6, 55.2, 50.5, 37.1, 28.3 (3C), 20.3, 11.8; HRMS (ESI)
exact mass calcd for C26H32N2O5Na [MþNa]þ 475.2209, found
475.2201.
J¼7.2 Hz, CH(CH2CH2CH3)); 13C NMR (100 MHz, CDCl3)
d 172.9,155.0,
153.2, 141.9 (2C), 135.8,129.3 (2C), 128.9 (2C), 127.1, 110.3,106.6, 79.8,
66.0, 55.5, 50.1, 47.4, 37.4, 29.3, 28.2 (3C), 20.4,14.1; HRMS (ESI) exact
mass calcd for C25H33N2O6 [MþH]þ 457.2339, found 457.2336.
3.3.3. tert-Butyl(1R,2R)-2-((S)-4-benzyl-2-oxooxazolidine-3-
carbonyl)-1-(4-methoxy phenyl)pentylcarbamate (7c). The re-
duction–Boc-protection procedure was repeated with a solution of
5c (200 mg, 0.47 mmol) and Boc2O (0.16 mL, 0.71 mmol) in EtOAc
(2 mL) to get 7c (220 mg, 94%) as a white crystalline solid. [Found:
3.3.6. tert-Butyl(1R,2R)-2-((S)-4-benzyl-2-oxooxazolidine-3-car-
bonyl)-1-(4-nitrophenyl)pentylcarbamate (7f). To a stirred mixture
of 5f (65 mg, 0.149 mmol) in dry THF was added triphenylphos-
phine (46.8 mg, 0.179 mmol) and water (26.8 mg, 1.49 mmol). The
reaction mixture was stirred at room temperature for 30 min, then
heated to 60 ꢀC and continued stirring at the same temperature for
10 h. The solvent was removed under reduced pressure, EtOAc
(1 mL) and Boc2o (0.05 mL, 0.223 mmol) were added to the residue
and the mixture was stirred for 6 h at room temperature. Excess
solvent was evaporated and the crude product was purified by
column chromatography using 10% EtOAc/Hexanes as mobile phase
C, 68.08; H, 7.45; N, 5.57. C28H36N2O6 requires C, 67.72; H, 7.31; N,
30
5.64%.] mp 68–70 ꢀC; Rf (20% EtOAc/Hexane) 0.27; [
a
]
þ35.6 (c 1,
D
CHCl3); IR (neat) nmax 3375, 2962, 2872, 1774, 1697, 1512, 1386,
1365, 1246, 1210, 1167, 1099, 1031, 833, 762, 703 cmꢂ1 1H NMR
(400 MHz, CDCl3)
7.36–7.21 (m, 5H, Ar–H), 7.09 (d, 2H, J¼6.4 Hz,
;
d
Ar–H), 6.86 (d, 2H, J¼8.4 Hz, Ar–H), 5.19 (br t, 1H, 4-
OMeC6H4CHNHBoc), 5.01 (d, 1H, J¼8.4 Hz, 4-OMeC6H4CHNHBoc),
4.60 (br t, 1H, (PhCH2)CH(CH2O)), 4.31 (br t, 1H, CH(CH2CH2CH3)),
4.13–4.05 (m, 2H, (PhCH2)CH(CH2O–)), 3.76 (s, 3H, 4-OCH3–C6H4–),
2.98 (d, 1H, J¼12.8 Hz, PhCHaHbCH), 2.27 (t, 1H, J¼10.8 Hz,
PhCHaHbCH), 1.90–1.80 (m, 1H, CHaHbCH2CH3), 1.39 (s, 9H, NH
(C]O)OC(CH3)3), 1.50–1.10 (m, 3H, CHaHbCH2CH3 and CH2CH2CH3),
0.86 (t, 3H, J¼7.2 Hz, CH2CH2CH3); 13C NMR (100 MHz, CDCl3)
to give 7f as a white crystalline solid (31 mg, 41%); mp 155–157 ꢀC;
30
Rf (20% EtOAc/Hexane) 0.40; [
a]
þ2.6 (c 1, CHCl3); IR (neat) nmax
D
3365, 3032, 2966, 2930, 2871, 1774, 1697, 1521, 1387, 1348, 1251,
1166, 1104, 1017, 858, 701 cmꢂ1 1H NMR (400 MHz, CDCl3)
;
d
8.21
(d, 2H, J¼8.4 Hz, Ar–H), 7.64 (d, 2H, J¼8.4 Hz, Ar–H), 7.21–7.35 (m,
3H, Ph–H), 7.14 (d, 2H, J¼6.4 Hz, Ph–H), 5.42 (br s, 1H, CHNHBoc),
5.21 (d,1H, J¼8.4 Hz, CHNHBoc), 4.69 (br s,1H, (PhCH2)CH(CH2O–)),
4.31–4.13 (m, 3H, (PhCH2)CH(CH2O–) and CH(C3H7)), 3.15 (d, 1H,
J¼12.4 Hz, (PhCHaHb)CH), 2.55 (t, 1H, J¼10.8 Hz, (PhCHaHb)CH), 1.87
d
173.6, 158.9, 155.1, 153.2, 135.5, 132.7, 129.2 (2C), 128.9 (3C), 127.9,
127.1, 113.8 (2C), 79.6, 65.9, 55.2, 55.1 (2C), 48.8, 37.2, 29.1, 28.3 (3C),

10080
D. Balamurugan, K.M. Muraleedharan / Tetrahedron 65 (2009) 10074–10082
(ddd, 1H, J¼4.4, 12.4, 12.4 Hz, CH(CHaHbCH2CH3)), 1.39 (s, 9H,
NH(C]O)OC(CH3)3), 1.40–1.00 (m, 3H, CH(CHaHbCH2CH3) and
CH(CH2CH2CH3)), 0.82 (t, 3H, J¼6.8 Hz, CH(CH2CH2CH3)); 13C NMR
55.3, 55.2, 50.6, 37.1, 28.3 (3C), 20.6,11.8; HRMS (ESI) exact mass calcd
for C26H34N3O5 [MþH]þ 468.2498, found 468.2496.
(100 MHz, CDCl3)
d
172.6, 155.0, 153.3, 148.0, 147.2, 135.1, 129.2 (2C),
3.4. Regioselective hydrolysis of oxazolidinone ring
129.0 (2C), 127.6 (2C), 127.4, 123.7 (2C), 80.3, 66.3, 55.4, 54.9, 48.4,
37.4, 28.2 (3C), 27.4, 20.8, 13.9; HRMS (ESI) exact mass calcd for
C27H33N3O7Na [MþNa]þ 534.2216, found 534.2212.
3.4.1. (R)-2-((R)-(tert-Butoxycarbonylamino)(4-methoxyphenyl)
methyl)pentanoic acid (8). To a solution of 7c (250 mg, 0.50 mmol)
in 3:1 THF–H2O (10 mL) at 0 ꢀC was added 30% H2O2 (0.16 mL,
5 mmol), followed by 2.0 equiv of LiOH.H2O (42.2 mg, 1.00 mmol).
The mixture was stirred for 1 h, allowed to warm to room tem-
perature and continued stirring at that temperature for 5 h. After
completion of the reaction, the excess peroxide was quenched at
0 ꢀC with 1 mL of 1.5 N aq Na2SO3. The solvents were removed
under reduced pressure, the residue extracted with CH2Cl2 to
remove the oxazolidinone chiral auxiliary and the aqueous layer
was acidified using solid KHSO4 (pH 1–2). This was extracted with
EtOAc (3 ꢁ10 mL), dried (Na2SO4) and the solvent was removed
under reduced pressure to get the carboxylic acid 8 as a white solid
3.3.7. tert-Butyl(1R,2R)-2-((S)-4-benzyl-2-oxooxazolidine-3-car-
bonyl)-1-(4-nitrophenyl)butylcarbamate (7g). The reduction–Boc-
protection procedure for converting 5f to 7f was repeated with 5g
(50 mg, 0.118 mmol) to get 7g as a white crystalline solid (28 mg,
30
47%); mp 139–141 ꢀC; Rf (20% EtOAc/Hexane) 0.25; [
a
]
þ4.6 (c 1,
D
CHCl3); IR (neat) nmax 3363, 3032, 2974, 2930, 2871, 1774, 1697,
1521, 1387, 1348, 1214, 1166, 1109, 1014, 856, 701 cmꢂ1 1H NMR
(400 MHz, CDCl3)
8.21 (d, 2H, J¼8.8 Hz, Ar–H), 7.63 (d, 2H,
;
d
J¼8.4 Hz, Ar–H), 7.34–7.24 (m, 3H, Ph–H), 7.13 (d, 2H, J¼6.0 Hz,
Ph–H), 5.42 (br s, 1H, CHNHBoc), 5.21 (d, 1H, J¼8.8 Hz, CHNHBoc),
4.70 (br s, 1H, (PhCH2)CH(CH2O–)), 4.30–4.10 (m, 3H,
(PhCH2)CH(CH2O–)) and CH(C2H5)), 3.13 (d, 1H, J¼12.8 Hz,
(PhCHaHb)CH), 2.54 (t, 1H, J¼10.4 Hz, (PhCHaHb)CH), 1.91–1.84
(m, 1H, CH(CHaHbCH3), 1.39 (s, 10H, NH(C]O)OC(CH3)3 and
CH(CHaHbCH3)), 0.84 (t, 3H, J¼7.2 Hz, CH(CH2CH3)); 13C NMR
(157 mg, 93%). [Found: C, 64.27; H, 8.10; N, 4.36. C18H27NO5 requires
30
C, 64.07; H, 8.07; N, 4.15%.] Rf (40% EtOAc/Hexane) 0.37; [
a
]
þ41.4
D
(c 1, CHCl3); IR (neat) nmax 2960, 2933, 2873, 1704, 1613, 1513, 1393,
1367, 1247, 1165, 1035, 832, 733 cmꢂ1 1H NMR (400 MHz, CDCl3)
;
d
7.19 (d, 2H, J¼8.4 Hz, Ar–H), 6.75 (d, 2H, J¼8.8 Hz, Ar–H), 5.15 (br s,
(100 MHz, CDCl3)
d
172.4, 155.0, 153.3, 148.1, 147.2, 135.0, 129.2
1H, NHBoc), 4.82 (br s, 1H, Ar–CHNHBoc), 3.71 (s, 3H, 4-OCH3–
C6H4), 2.70 (br s, 1H, CH(CH2CH2CH3)COOH), 1.64–1.54 (m, 1H,
CHaHbCH2CH3), 1.50–1.15 (m, 3H, CHaHbCH2CH3 and CH2CH2CH3),
1.33 (s, 9H, NH(C]O)OC(CH3)3), 0.83 (t, 3H, J¼7.2 Hz, CH2CH2CH3),
carboxylic acid proton was not seen; 13C NMR (125 MHz, CDCl3)
(3C), 129.0 (2C), 127.6, 127.4, 123.7 (2C), 80.3, 66.2, 55.3, 54.8, 50.1,
37.4, 28.2 (3C), 18.9, 11.9; HRMS (ESI) exact mass calcd for
C26H31N3O7Na [MþNa]þ 520.2060, found 520.2056.
3.3.8. tert-Butyl (1R,2R)-1-(4-aminophenyl)-2-((S)-4-benzyl-2-oxo-
oxazolidine-3-carbonyl)pentylcarbamate (7h). The reduction–Boc-
protection procedure was repeated with a solution of 5f (25 mg,
0.057 mmol), 10% Pd/C (5 mg) and Boc2O (12.5 mg, 0.057 mmol) in
d 178.4, 158.9, 155.2, 132.1, 127.9 (2C), 113.8 (2C), 79.8, 55.3, 55.2,
51.2, 30.6, 28.3 (3C), 20.7, 13.9; HRMS (ESI) exact mass calcd for
C18H27NO5Na [MþNa]þ 360.1787, found 360.1787.
EtOAc (1 mL) to get 7H (23 mg, 84%) as a brown viscous liquid; Rf
3.4.2. tert-Butyl(1R,2R)-2-((S)-1-hydroxy-3-phenylpropan-2-ylcar-
bamoyl)-1-phenylbutylcarbamate (9a). To a stirred solution of 7b
(50 mg, 0.11 mmol) in THF (2 mL) at 0 ꢀC was added a solution of
LiOH (9.28 mg, 0.22 mmol) in 0.5 mL of water. After allowing the
mixture to warm to room temperature, the stirring was continued
for another 10 h. The solution was then concentrated, the pre-
cipitated product was filtered, washed with water, followed by
30
(40% EtOAc/Hexane) 0.37; [
a
]
þ31.7 (c 1, CHCl3); IR (neat) nmax
D
3368, 2966, 2929, 2870, 1773, 1697, 1624, 1516, 1386, 1250, 1212,
1168, 1101, 1016, 833, 703 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
7.32–
7.21 (m, 3H, Ar–H), 7.17 (d, 2H, J¼7.6 Hz, Ar–H), 7.09 (d, 2H, J¼6.4 Hz,
Ar–H), 6.62 (d, 2H, J¼8.4 Hz, Ar–H), 5.11 (br s, 1H, ArCHNHBoc), 4.97
(br s, 1H, ArCHNHBoc), 4.62–4.56 (m, 1H, (PhCH2)CH), 4.30 (br s, 1H,
CH(CH2CH2CH3)), 4.15–4.02 (m, 2H, (PhCH2)CH(CH2O–)), 3.62 (br s,
2H, Ar–NH2), 2.99 (d, 1H, J¼12.4 Hz, (PhCHaHb)CH), 2.26 (br s, 1H,
(PhCHaHb)CH), 1.89–1.79 (m, 1H, CH(CHaHbCH2CH3)), 1.50–1.34 (m,
1H, CH(CHaHbCH2CH3)), 1.40 (s, 9H, NH(C]O)OC(CH3)3), 1.33–1.19
(m, 2H, CH2CH2CH3) 0.86 (t, 3H, J¼7.2 Hz, CH2CH2CH3); 13C NMR
hexanes and dried under reduced pressure to get 9a (38 mg, 81%) as
30
a white amorphous solid; Rf (10% MeOH/CHCl3) 0.57; [
a
]
D
ꢂ0.78 (c
1, CH3OH); IR (neat) nmax 3363, 3328, 2962, 2950, 2932, 2864, 1681,
1639, 1520, 1289, 1168, 1070, 1040, 1014, 698, 643 cmꢂ1 1H NMR
(400 MHz, CDCl3) 7.32–7.24 (m, 5H, Ph–H), 7.24–7.17 (m, 3H, Ph–
;
d
(100 MHz, CDCl3)
d
173.8, 155.2, 153.2, 145.7, 135.8, 130.5, 129.3 (2C),
H), 7.07 (d, 2H, J¼6.4 Hz, Ph–H), 5.46 (d, 2H, J¼7.2 Hz,
CH(Bn)NH(C]O) and CHNHBoc), 4.82 (br s, 1H, PhCHNHBoc), 3.98
(br s, 1H, CH(CH2OH)), 3.47 (br s, 2H, CH2OH), 2.59 (br s, 2H, CH2Ph),
2.40 (br s, 1H, CH(CH2CH3)), 2.33 (br s, 1H, CH2OH), 1.63–1.50 (br s,
2H, CH2CH3), 1.41 (s, 9H, NH(C]O)OC(CH3)3), 0.84 (t, 3H, J¼7.2 Hz,
128.9 (2C), 127.9 (2C), 127.1, 115.0 (2C), 79.5, 65.9, 55.4, 55.2, 49.0,
37.2, 29.4, 28.3 (3C), 20.8, 14.1; HRMS (ESI) exact mass calcd for
C27H36N3O5 [MþH]þ 482.2655, found 482.2659.
3.3.9. tert-Butyl(1R,2R)-1-(4-aminophenyl)-2-((S)-4-benzyl-2-oxooxa-
zolidine-3-carbonyl) butylcarbamate (7i). The reduction–Boc-pro-
tection procedure was repeated with a solution of 5g (25 mg,
0.059 mmol), 10% Pd/C (5 mg) and Boc2O (13.6 mg, 0.059 mmol) in
CH2CH3); 13C NMR (100 MHz, CDCl3þCD3OD)
d 172.9, 155.8, 143.0,
137.4, 128.3 (2C), 127.4 (2C), 127.3 (1C), 126.4 (3C), 125.3 (2C), 78.5,
61.2, 56.2, 54.4, 51.6, 35.6, 27.0 (3C), 21.8, 10.4; HRMS (ESI) exact
mass calcd for C25H34N2O4Na [MþNa]þ 449.2416, found 449.2411.
EtOAc (1 mL) to get 7i (22 mg, 80%) as a brown viscous liquid; Rf (40%
34
EtOAc/Hexane) 0.33; [
a
]
þ35.1 (c 1, CHCl3); IR (neat) nmax 3364,
3.4.3. tert-Butyl(1R,2R)-2-((S)-1-hydroxy-3-phenylpropan-2-ylcarba-
moyl)-1-(4-methoxyphenyl) pentylcarbamate (9b). To a stirred so-
lution of 7c (100 mg, 0.20 mmol) in THF (4 mL) at 0 ꢀC was added
a solution of LiOH (16.9 mg, 0.40 mmol) in 1.5 mL of water. After
allowing the mixture to warm to room temperature, the stirring
was continued for another 10 h. The solution was then concen-
trated, the precipitated product was filtered, washed with water,
followed by hexanes and dried under reduced pressure to get 9b
(83 mg, 87%) as a white amorphous solid. [Found: C, 69.09; H, 8.08;
D
2969, 2925, 2857, 1774, 1698, 1622, 1512, 1382, 1212, 1170, 1103, 1014,
830, 753, 704 cmꢂ1 1H NMR (400 MHz, CDCl3)
;
d
7.35–7.20 (m, 3H,
Ar–H), 7.17 (d, 2H, J¼7.6 Hz, Ar–H), 7.10 (d, 2H, J¼6.4 Hz, Ar–H), 6.63
(d, 2H, J¼8.4 Hz, Ar–H), 5.12 (t,1H, J¼6.8 Hz, ArCHNHBoc), 4.98 (d, 1H,
J¼9.2 Hz, ArCHNHBoc), 4.61 (br s, 1H, (PhCH2)CH), 4.24 (br s, 1H,
CH(CH2CH3)), 4.12–4.03 (m, 2H, (PhCH2)CH(CH2O–)), 3.66 (br s,
2H, Ar–NH2), 2.97 (d, 1H, J¼13.2 Hz, (PhCHaHb)CH), 2.26 (t, 1H,
J¼11.2 Hz, (PhCHaHb)CH),1.90–1.80 (m,1H, CH(CHaHbCH3)), 1.61 (br s,
1H, CHaHbCH3), 1.39 (s, 9H, NH(C]O)OC(CH3)3), 0.87 (t, 3H, J¼6.8 Hz,
N, 6.02. C27H38N2O5 requires C, 68.91; H, 8.14; N, 5.95%.] Rf (10%
30
CH2CH3); 13C NMR (100 MHz, CDCl3)
d
173.6, 155.1, 153.2, 145.7, 135.7,
MeOH/CHCl3) 0.52; [
a
]
D
þ12.99 (c 1, CH3OH); IR (neat) nmax 3349,
130.5, 129.3 (2C), 128.9 (2C), 127.9 (2C), 127.1, 115.0 (2C), 79.5, 65.9,
3315, 2956, 2933, 1678, 1637, 1513,1454, 1299, 1244, 1167, 1019, 830,

D. Balamurugan, K.M. Muraleedharan / Tetrahedron 65 (2009) 10074–10082
10081
698, 644 cmꢂ1
;
1H NMR (400 MHz, CDCl3)
d
7.32–7.18 (m, 3H, Ar–
carbodiimide hydrochloride (EDCI, 12.3 mg, 0.064 mmol). The re-
action mixture was stirred at 0 ꢀC for 3 h and then at room tem-
perature for 24 h. It was then diluted with CH2Cl2, washed with 5%
HCl (10 mL) followed by saturated NaHCO3 solution (10 mL) and
water (10 mL). The organic layer was dried over anhydrous Na2SO4,
filtered, solvent evaporated under reduced pressure and the
resulting residue was purified by chromatography on silica gel
H), 7.09 (d, 4H, J¼8.0 Hz, Ar–H), 6.82 (d, 2H, J¼8.4 Hz, Ar–H), 5.48
(br d, 1H, NH(C]O)CH(C2H5)), 5.41 (br s, 1H, CHNHBoc), 4.74 (br s,
1H, ArCHNHBoc), 3.99 (br s, 1H, CH(CH2OH)), 3.77 (s, 3H, 4-OCH3–
C6H4), 3.51 (br s, 2H, CH2OH), 2.78–2.53 (br d, 2H, CH2Ph), 2.48 (br s,
2H, CH(CH2CH3) and CH2OH), 1.41 (br s, 11H, NH(C]O)OC(CH3)3
and CH2CH2CH3), 1.25–1.15 (m, 2H, CH2CH2CH3), 0.83 (t, 3H,
J¼6.8 Hz, CH2CH2CH3); 13C NMR (100 MHz, CDCl3þCD3OD)
d
173.3,
column using 0.5% MeOH-CHCl3 solvent system to get 11 (15 mg,
30
158.6, 155.7, 137.8, 132.7, 128.9 (2C), 128.1 (2C), 127.8 (2C), 126.1,
113.4 (2C), 79.4, 62.5, 56.1, 54.9, 53.3, 52.2, 36.2, 30.9, 28.0 (3C),
20.3, 13.7; HRMS (ESI) exact mass calcd for C27H38N2O5Na [MþNa]þ
493.2678, found 493.2676.
80%) as a white solid; Rf (5% MeOH/CHCl3) 0.58; [
a
]
þ5.4 (c 1,
D
CHCl3); IR (neat) nmax 3350, 2924, 2856, 1748, 1679, 1643, 1523,
1456, 1252, 1171, 1026, 829, 662 cmꢂ1 1H NMR (400 MHz, CDCl3)
;
d
7.16 (d, 2H, J¼8.4 Hz, Ar–H), 6.82 (d, 2H, J¼8.8 Hz, Ar–H), 5.81 (br s,
1H, NHCH(Me)-CO2Me), 5.19 (br s, 1H, CHNHBoc), 4.73 (br s, 1H,
ArCHNHBoc), 4.41 (qn, 1H, J¼6.7 Hz, NHCH(Me)-CO2Me), 3.77 (s,
3H, 4-OCH3C6H4), 3.70 (s, 3H, –COOCH3), 2.47 (br s, 1H, CH(C3H7)),
1.75–1.50 (m, 2H, CH2CH2CH3), 1.40 (s, 9H, NH(C]O)OC(CH3)3),
1.28–1.17 (m, 2H, CH2CH2CH3),1.06 (br s, 3H, CH(CH3)COOCH3), 0.89
3.5. Conversion of alcohols to aldehydes
3.5.1. tert-Butyl(1R,2R)-2-((S)-1-oxo-3-phenylpropan-2-ylcarba-
moyl)-1-phenylbutylcarbamate (10a). To a stirred solution of 9a
(25 mg, 0.0587 mmol)inDMSO(0.6 mL)wasadded2-iodoxybenzoic
acid (IBX, 19.7 mg, 0.070 mmol) at room temperature. After stirring
for 8 h, the reaction mixture was admixed with water (25 mL) and
EtOAc (25 ml). The precipitate formed was filtered off, the organic
layer was dried (Na2SO4), concentrated under reduced pressure,
and the residue purified by chromatography on silica gel using
(t, 3H, J¼7.6 Hz, CH2CH2CH3); 13C NMR (100 MHz, CDCl3)
d 173.3,
172.0,158.9,155.3,133.0,128.0 (2C),113.7 (2C), 79.6, 56.3, 55.3, 53.5,
52.4, 47.6, 31.0, 28.3 (3C), 20.8, 18.1, 14.1; HRMS (ESI) exact mass
calcd for C22H34N2O6Na [MþNa]þ 445.2315, found 445.2312.
3.6.2. (1R,2R)-2-(Methoxycarbonyl)-1-(4-methoxyphenyl)pentan-1-
0.5% CH3OH–CHCl3 solvent system to get 10a as a white solid
aminium chloride (12). To a stirred solution of 8 (100 mg,
30
(20 mg, 80%); Rf (5% MeOH/CHCl3) 0.38; [
a
]
ꢂ1.3 (c 1, CHCl3); IR
0.297 mmol) in dry methanol (2 mL) at 0 ꢀC under nitrogen at-
mosphere was added thionylchloride (0.11 mL, 1.485 mmol). After
1 h, the mixture was allowed to warm to room temperature and
stirring was continued for another 24 h. Removal of solvent under
reduced pressure gave an off-white semi solid, which was washed
with diethyl ether to give 12 as a white spongy solid (75 mg, 88%).
D
(neat) nmax 3357, 2973, 2932, 2809, 1736, 1676, 1644, 1521, 1362,
1294, 1257, 1172, 750, 700 cmꢂ1 1H NMR (400 MHz, CDCl3)
;
d
9.42
(s, 1H, CHO), 7.33–7.17 (m, 8H, Ph–H), 6.92 (br s, 2H, Ph–H), 5.86 (br
s, 1H, NHCH(Bn)CHO), 5.26 (br s, 1H, Ar–CHNHBoc), 4.85 (br s,
1H, ArCHNHBoc), 4.57 (q, 1H, J¼6.5 Hz, (PhCH2)CH(CHO)), 2.96 (dd,
1H, J¼5.8, 13.8 Hz, PhCHaHb), 2.78 (br s, 1H, PhCHaHb), 2.43 (br s,
1H, CH(CH2CH3)), 1.62 (2H, CH2CH3, merged with H2O peak), 1.40
(s, 9H, NH(C]O)OC(CH3)3), 0.87 (t, 3H, J¼7.2 Hz, CH2CH3); 13C
[Found: C, 57.39; H, 7.58; N, 5.05. C14H22NO3Cl requires C, 58.43; H,
30
7.71; N, 4.87%.] [
a
]
ꢂ2.2 (c 1, CH3OH); IR (neat) nmax 2863, 2658,
D
2605, 1728, 1612, 1513, 1431, 1303, 1248, 1174, 1029, 986, 833,
NMR (100 MHz, CDCl3)
d
198.7, 172.5, 155.2, 135.5 (2C), 129.2 (2C),
758 cmꢂ1; 1H NMR (400 MHz, D2O)
d
7.34 (d, 2H, J¼8.8 Hz, Ar–H),
128.8 (2C), 128.5 (2C), 127.6, 127.1, 126.9 (2C), 79.8, 59.4, 56.6, 55.2,
35.2, 28.3 (3C), 22.1, 12.0; HRMS (ESI) exact mass calcd for
C25H33N2O4 [MþH]þ 425.2440, found 425.2440.
7.05 (d, 2H, J¼8.8 Hz, Ar–H), 4.52 (d, 1H, J¼9.2 Hz, ArCH), 3.84 (s,
3H, 4-OCH3C6H4–), 3.55 (s, 3H, COOCH3), 3.19 (ddd, 1H, J¼6.4, 9.2,
9.2 Hz, CH(C3H7)COOCH3), 1.76–1.65 (m, 2H, CH2CH2CH3), 1.42–
1.27 (m, 2H, CH2CH2CH3), 0.93 (t, 3H, J¼7.6 Hz, CH2CH2CH3); 13C
3.5.2. tert-Butyl(1R,2R)-1-(4-methoxyphenyl)-2-((S)-1-oxo-3-phenyl-
propan-2-ylcarbamoyl)pentylcarbamate (10b). Oxidation of alcohol
9b (40 mg, 0.085 mmol) using IBX (28 mg, 0.102 mmol) according to
NMR (100 MHz, D2O) d 174.6, 159.7, 128.7 (2C), 126.7, 114.6 (2C),
55.9, 55.4, 52.5, 50.1, 30.7, 19.7, 12.9; HRMS (ESI) exact mass calcd
for C14H22NO3 [MþH]þ 252.1600 (for free amine), found 252.1597.
the above procedure gave 10b (33 mg, 83%) as a white solid; Rf (10%
30
MeOH/CHCl3) 0.39; [
a
]
þ7.0 (c 1, CH3OH); IR (neat) nmax 3363,
3.6.3. (R)-Methyl-2-((R)-((R)-2-((R)-(tert-butoxycarbonyl
amino)(4-methoxy phenyl)methyl)pentanamido)(4-methoxyphenyl)
methyl)pentanoate (13). To a mixture of 8 (29 mg, 0.087 mmol), 12
(25 mg, 0.087 mmol) and HOBT (14 mg, 0.104 mmol) in dry CH2Cl2
at 0 ꢀC under anhydrous conditions was added i-Pr2NEt (0.037 mL,
0.218 mmol) and EDCI (20 mg, 0.104 mmol). The reaction mixture
was stirred at 0 ꢀC for 3 h and then at room temperature for 24 h. It
was then diluted with CH2Cl2 and washed with 5% HCl (10 mL)
followed by saturated NaHCO3 solution (10 mL) and water (10 mL).
The organic layer was dried over anhydrous Na2SO4, filtered, sol-
vent evaporated under reduced pressure and the resulting residue
was purified by chromatography on silica gel column using 0.5–1%
D
3313, 2958, 2921, 2864, 1673, 1633, 1516, 1415, 1250, 1170, 1014,
753 cmꢂ1; 1H NMR (400 MHz, DMSO-d6)
d
8.93 (s, 1H, CHO), 8.31 (d,
1H, J¼7.2 Hz, NHCH(Bn)CHO), 7.29 (d, 1H, J¼9.6 Hz, Ar–CHNHC]O),
7.22–7.10 (m, 5H, Ar–H), 6.97 (d, 2H, J¼7.2 Hz, Ar–H), 6.78 (d, 2H,
J¼8.8 Hz, Ar–H), 4.75–4.50 (m, 1H, Ar–CHNHBoc), 3.91 (br s, 1H,
(PhCH2)CH(CHO)), 3.69 (s, 3H, 4-OCH3–C6H4–), 2.90 (dd, 1H, J¼4.8,
14.4 Hz, PhCHaHb), 2.65–2.50 (m, 2H, PhCHaHb and CH(C3H7)), 1.60–
1.40 (m, 2H, CH2CH2CH3), 1.35 (s, 9H, NH(C]O)OC(CH3)3), 1.30–1.10
(m, 2H, CH2CH2CH3), 0.81 (t, 3H, J¼7.2 Hz, CH2CH2CH3); 13C NMR
(100 MHz, DMSO-d6)
d 200.1, 173.2, 158.0, 155.1, 137.7, 134.4, 128.8
(2C), 128.5 (2C), 128.0 (2C), 126.0, 113.0 (2C), 77.6, 59.4, 55.5, 54.9,
51.3, 33.2, 31.5, 28.2 (3C), 19.8, 14.1; HRMS (ESI) exact mass calcd for
C27H37N2O5 [MþH]þ 469.2702, found 469.2702.
MeOH–CHCl3 solvent system in a gradient mode to give 13 (35 mg,
30
71%) as a white spongy solid; Rf (5% MeOH/CHCl3) 0.55; [
a
]
þ86.4
D
(c 0.9, CH3OH); IR (neat) nmax 3365, 3329, 2955, 2929, 2870, 2835,
3.6. Preparation of
dipeptide 13
a
,
b
2,3-hybrid peptide 11 and trans-b2,3
-
1734, 1680, 1637, 1517, 1461, 1295, 1249, 1168, 1019, 826, 560 cmꢂ1
;
1H NMR (400 MHz, CDCl3þCD3OD)
d
7.49 (d, 1H, J¼7.2 Hz,
ArCHNH), 7.00 (br s, 2H, Ar–H), 6.75 (br s, 2H, Ar–H), 6.65 (d, 2H,
J¼7.6 Hz, Ar–H), 6.54 (d, 2H, J¼6.8 Hz, Ar–H), 6.15 (br s, 1H, NHBoc),
4.90 (d, 1H, J¼9.2 Hz, ArCHNHC(O)), 4.55 (br s, 1H, ArCHNHBoc),
3.78 (s, 3H, 4-OCH3–C6H4–), 3.67 (s, 3H, 4-OCH3–C6H4), 3.42 (s, 3H,
COOCH3), 2.67 (ddd, 1H, J¼3.6, 10.7, 10.7 Hz, CH(C3H7)CONH),
2.52 (br s, 1H, CH(C3H7)COOCH3), 1.78–1.67 (br s, 1H, propyl CH),
1.67–1.52 (m, 2H, Propyl CH), 1.50–1.14 (m, 5H, Propyl CH), 1.37 (s,
3.6.1. (S)-Methyl-2-((R)-2-((R)-(tert-butoxycarbonylamino)(4-methoxy-
phenyl)methyl)pentanamido)propanoate (11). To mixture of
(15 mg, 0.045 mmol), alanine methylester hydrochloride
(6.8 mg, 0.049 mmol) and 1-hydroxybenzotriazole (HOBT,
8.65 mg, 0.064 mmol) in dry CH2Cl2 at 0 ꢀC was added i-Pr2NEt
(0.02 ml, 0.111 mmol) and 1-ethyl-3-[3-(dimethylamino)propyl]-
a
8

10082
D. Balamurugan, K.M. Muraleedharan / Tetrahedron 65 (2009) 10074–10082
Weisblum, B.; Gellman, S. H. J. Am. Chem. Soc. 2002, 124, 12774–12785 and ref-
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2460–2468.
9H, NH(C]O)OC(CH3)3), 0.94 (t, 3H, J¼6.8 Hz, CH2CH2CH3), 0.86 (t,
3H, J¼7.2 Hz, CH2CH2CH3); 13C NMR (125 MHz, CDCl3þCD3OD)
d
174.1, 172.7, 158.1, 158.0, 132.7, 131.5, 127.5 (2C), 127.4 (2C), 113.0
6. (a) Gopi, H. N.; Roy, R. S.; Raghothama, S. R.; Karle, I. L.; Balaram, P. Helv. Chim.
Acta 2002, 85, 3313–3330; (b) Karle, I. L.; Gopi, H. N.; Balaram, P. Proc. Natl.
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Balaram, P. Proc. Natl. Acad. Sci. USA 2004, 101, 16478–16482.
7. (a) Pizzey, C. L.; Pomerantz, W. C.; Sung, B.-J.; Yuwono, V. M.; Gellman, S. H.;
Hartgerink, J. D.; Yethiraj, A.; Abbott, N. L. J. Chem. Phys. 2008, 129, 095103/1–
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(4C), 79.1, 56.2, 54.5, 54.3, 53.4, 53.2, 51.1, 51.0, 30.9 (2C), 27.7 (3C),
20.3, 20.1, 13.5, 13.3; HRMS (ESI) exact mass calcd for C32H46N2O7Na
[MþNa]þ 593.3203, found 593.3210.
Acknowledgements
Financial support of this work by the Department of Science and
Technology (DST), INDIA (Grants SR/S1/OC-13/2007) is gratefully
acknowledged. We thank Mr. V. Ramkumar, IIT Madras for his help
during X-ray crystallographic analysis. D. Balamurugan thanks DST
for the research fellowship.
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Supplementary data
12. Diastereomeric ratio was determined from 1H NMR spectrum of the crude
reaction mixture.
Supplementary data associated with this article can be found in
online version, at doi:10.1016/j.tet.2009.09.072.
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723172), 5d (CCDC-722248) and 6d (CCDC-722249) are available free of charge
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lowing address: Cambridge Crystallographic Data Centre, 12 Union Road, GB-
Cambridge CB21EZ. Fax: þ44 (0)1223 336033; or deposit@ccdc.cam.ac.uk.
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