A general and efficient stereoselective synthesis of γ-azido-tetrahydrofuran carboxylic acids from glycals

Article abstract of DOI:10.1016/j.tet.2007.12.032

An efficient, direct and general synthesis of enantiopure γ-azido-tetrahydrofuran carboxylic acid monomers (5-8) from commercially available glycals, suitable to design peptidomimetic oligomers with predisposed conformation, is described. The single cryst

Full text of DOI:10.1016/j.tet.2007.12.032

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2153e2159
www.elsevier.com/locate/tet
A general and efficient stereoselective synthesis of g-azido-
tetrahydrofuran carboxylic acids from glycals*
P. Venkat Reddy a, L. Vijaya Raghava Reddy a, Brijesh Kumar b, Rishi Kumar c,
Prakas R. Maulik c, Arun K. Shaw a,
*
a Division of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226 001, India
b Division of Sophisticated Analytical Instrumentation Facility, Central Drug Research Institute, Lucknow 226 001, India
c Division of Molecular and Structural Biology, Central Drug Research Institute, Lucknow 226 001, India
Received 4 August 2007; received in revised form 22 November 2007; accepted 13 December 2007
Available online 4 January 2008
Dedicated to Professor Subhendu N. Ganguly on his 70th birthday
Abstract
An efficient, direct and general synthesis of enantiopure g-azido-tetrahydrofuran carboxylic acid monomers (5e8) from commercially avail-
able glycals, suitable to design peptidomimetic oligomers with predisposed conformation, is described. The single crystal X-ray study of
8 showed that the compound crystallized in orthorhombic space group. The crystal-packing showed the presence of weak intermolecular
CeH/O and aliphatic CeH/p interactions.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: g-Sugar amino acids; Peptidomimetics; Glycal; Perlin hydrolysis
1. Introduction
at different backbone positions.5 So, over recent years, there
has been increasing interest in the development of new syn-
thetic routes for cyclic g-amino acids.6 Though several reports
appeared in literature for the synthesis of conformationally re-
stricted g-amino acids,5,7e10,4e very few of them dealt with the
synthesis of furanoid g-sugar amino acids (SAAs),11e15 start-
ing from cheaply available sugars. This class of molecules is
of particular interest due to their propensity of the ring hy-
droxyls in the participation of intramolecular hydrogen bond-
ing with the main chain amides.16
Fleet et al. have disclosed the syntheses of conformation-
ally restricted g-SAAs from sugar lactones.13e15 The furanose
g-SAAs 1 and 2 (Fig. 1) synthesized from L-gulunolactone
have been utilized to prepare 99-member library. Initial
screening of the library indicated the biological potential
of the furanose SAA scaffolds.17 Recent studies carried out
by Edwards et al. on the secondary structures of the homoo-
ligomers prepared from g-SAAs 3 and 4, obtained from
D-ribose and L-arabinose, to ascertain the conformational pref-
erence inherent in the monomer units indicated the presence of
g-Amino acids, both achiral and chiral, are receiving im-
mense attention from chemical community due to their poten-
tial use in the design and synthesis of a,g- and b,g-hybrid
peptides that fold into definite secondary structures.1 These
peptides being a new class of foldamers are creating interest
among the synthetic chemists.2 Granja et al. have showed
that cyclic g-amino acids can be a considerable promise to de-
sign new type of peptide nanotubes with hydrophobic cavi-
ties.3 Moreover, appropriate functionalization of this kind of
cyclic amino acid leads to self-assembling peptide nanotubes
(SPNs) with structural and functional properties of interest
for application in biology and material science.4
Among the various g-peptide foldamers studied, most of
the systems are based on linear amino acids with substituents
*
CDRI Communication No. 7291.
* Corresponding author. Tel.: þ91 9415403775.
E-mail address: akshaw55@yahoo.com (A.K. Shaw).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.12.032

2154
P.V. Reddy et al. / Tetrahedron 64 (2008) 2153e2159
N3
BnO
O
OR
N3
N3
N3
TBDPSO
HO
O
OBn
O
H
HO
two
steps
iPrO
O
ref. 20
BnO
R
MeO
MeO
BnO
BnO
OH
OR
OR
N3
O
O
O
4
O
3
O
1
O
OBn
H
O
O
2
12
13
14 R = H
15 R = Ms
i
N3
N3
N3
BnO
BnO
O
BnO
BnO
HO
ii
HO
HO
HO
O
5
O
6
O
7
O
O
O
8
O
N3
N3
N3
BnO
BnO
HO
BnO
iv
Figure 1.
iii
H
O
O
O
17
O
O
O
O
16
5
hydrogen-bonded confirmations in L-ribo series.18 Prompted
by these literature reports we wish to describe a practically ef-
ficient and general strategy to synthesize g-SAAs (5e8) with
three orthogonal points of diversification suitable for rational
combinatorial synthesis and spatial screening starting from
commercially available glycals. The work presented herein
also demonstrates the versatility of our recently synthesized
enantiopure 2,3,4-trisubstituted THF domains19 of general
structure 10 (Scheme 1) towards the synthesis of compounds
of biological importance.
Scheme 2. Reagents and conditions: (i) MsCl, Et3N, CH2Cl2, 0 ꢀC/rt,
30 min; (ii) NaN3, Bu4NCl (cat), DMF, 120 ꢀC, 3 h, 90% (for two steps);
(iii) H5IO6 (1.3 equiv), EtOAc, rt, 30 min; (vi) Jones reagent, acetone, 0 ꢀC,
10 min, 60% (for two steps).
presence of catalytic amount of ruthenium chloride trihy-
drate15 ended with a mixture of products which could not be
separated even after repeated column chromatography. How-
ever, the desired g-azido-tetrahydrofuran carboxylic acid 5
(g-SAA) was obtained from 16 via the intermediate aldehyde
17. Here, it is worth noting that the attempted oxidation of 17
by using potassium permanganate and 50% acetic acid23 was
unsatisfactory. Moreover, oxidation of this crude aldehyde
OR
BnO
O
BnO
HO
N3
O
O
1
(>95% pure from H NMR) by the classical Jones reagent24
O
11
O
10
provided the desired compound 5 in 60% isolated yield and
16% overall yield starting from 3,4,6-tri-O-benzyl-D-glucal 12.
After devising the straightforward synthesis of g-SAA 5,
we next focused on the syntheses of remaining three g-
SAAs (6e8) following the same method as described above.
The enantiopure 2,3,4-trisubstituted THF domains 20 and 21
were synthesized from their corresponding enantiopure allylic
alcohols 18 and 19. Subsequently these THF domains were de-
rivatized to their mesyl esters 22 and 23.
OH
BnO
CH2OH
Glycal
OBn
9
Scheme 1. General strategy followed for the synthesis of furanoid SAAs.
2. Results and discussion
The mesyl esters 22 and 23 were smoothly converted into
their azides 24 and 25 accompanied with a little amount of
elimination product in less than 5% yield. Sequential hydroly-
siseoxidation of the acetonide afforded the aldehydes 26 and
27 in almost quantitative yield, which on oxidation with Jones
reagent afforded the SAAs 612 and 7 (Scheme 3) in 10 and
16% overall yields starting from their respective glycals.
The Jones oxidation of the aldehyde 29, an intermediate
utilized by us for the synthesis of jaspine B,20 afforded the
g-SAA 8 in 64% yield (Scheme 4). Diffraction quality crystals
of compound 8 were obtained from ethyl acetate/hexane solu-
tion (1:3) by slow evaporation at room temperature. The com-
pound crystallizes in orthorhombic unit cell with P212121
space group. The single crystal X-ray structure of 8 showed
(Fig. 2) that the furanose ring exists in an envelope conforma-
tion with C2 atom forming the flap (C2 atom is deviated by
The basic strategy followed for the present work is summa-
rized in Scheme 1. The tetrahydrofuran framework of g-SAA
was obtained by the intramolecular asymmetric ring opening
reaction of the acyclic precursor 9, the concept exploited by
us recently to synthesize the naturally occurring cytotoxic an-
hydrosphingosine, pachastrissamine (jaspine B).20 The same
approach was now extended here to synthesize the g-SAAs
of type 11 via 10.
Scheme 2 shows the details of the route followed for the
synthesis of g-SAA 5. The required allylic alcohol 13 was pre-
pared from 3,4,6-tri-O-benzyl-D-glucal 12 in two steps by its
Perlin hydrolysis21 followed by Luche’s reduction22 in 57%
yield. After that, the THF domain 14 was synthesized from
13 in a single step (51% yield) by our reported consecutive ap-
proach19 under Sharpless asymmetric epoxidation conditions.
The azidolysis of the crude mesylate 15 provided the azido de-
rivative 16 with inversion of configuration in 90% yield (for
two steps, from 14). Having this in hand, the next step was
to obtain g-SAA 5.
˚
0.586(7) A from the least-squares plane formed by other
four atoms C1, O1, C4 and C3).
Furthermore, the crystal-packing study of 8 revealed
(Fig. 3) that it has four molecules in the unit cell. The mole-
cule exhibits weak intermolecular CeH/O25 and aliphatic
CeH/p interactions.26 The weak intermolecular CeH/O
The deprotection of acetonide group in 16 followed by the
oxidation of the resulting diol with sodium periodate in the

P.V. Reddy et al. / Tetrahedron 64 (2008) 2153e2159
R2 R1
2155
R1
O
R2
OH
OMs
OH
R1
BnO
CH2OH
i
ref 20
O
O
R2
O
O
O
20. R1=OBn, R2=H
18. R1=OBn, R2=H
22. R1=OBn, R2=H
19. R1=H, R2=OBn
23. R1=H, R2=OBn
21. R1=H, R2=OBn
R1
O
R1
R2
R2
R2
N3
N3
1 N3
R
iii
iv
ii
O
HO
H
O
O
O
O
O
6. R1=OBn, R2=H
26. R1=OBn, R2=H
24. R1=OBn, R2=H
25. R1=H, R2=OBn
7. R1=H, R2=OBn
27. R1=H, R2=OBn
Scheme 3. Reagents and conditions: (i) MsCl, Et3N, CH2Cl2, 0 ꢀC/rt, 30 min; (ii) NaN3, Bu4NCl (cat), DMF, 120 ꢀC, 10 h for 24 (62% from 20), and 3 h for 25
(90% from 21); (iii) H5IO6 (1.3 equiv), EtOAc, 30 min; (iv) Jones reagent, acetone, 0 ꢀC, 10 min, 64% for 6 from 24, 60% for 7 from 25.
OMs
N3
BnO
O
BnO
N3
BnO
HO
iii
i,ii
H
O
O
28
O
29
O
8
O
O
Scheme 4. Reagents and conditions: (i) NaN3, Bu4NCl (cat), DMF, 120 ꢀC,
10 h; (ii) H5IO6 (1.3 equiv), EtOAc, 30 min; (iii) Jones reagent, acetone,
0 ꢀC, 10 min, 64% yield.
˚
interaction between C1eH1 and O2eC5 (d¼2.4184 A;
ꢀ
˚
D¼3.2215 A; :CeHeO¼139 ; symm.: 1þx, y, z) is depicted
in Figure 3. In addition, the weak intermolecular CeH/p in-
teractions between the C6eH6B and the centroid (X) of the
aromatic ring formed by atoms C7, C8,ꢀ C9, C10, C11 and
˚
C12 [d(H/p)¼2.91 A; :CeHep¼160 , symm.: 1þx, y, z]
is also shown in Figure 3. These weaker interactions would be
responsible for the conformation of 8. The confirmation of the
Figure 3. The partial crystal-packing of the SAA 8 showing the weak intermo-
lecular CeH/O and CeH/p interactions. Few H-atoms have been omitted
for clarity.
remaining three SAAs (5e7) can be established based on the
X-ray structure of 8.
3. Conclusions
In this paper we disclosed a general, easy to scale up and
straightforward synthetic route to obtain enantiopure g-SAA
monomers (5e8) in seven steps and 10e16% overall yields
Figure 2. ORTEP plot of the SAA 8 (at 30% probability) showing the mole-
cular conformation.

2156
P.V. Reddy et al. / Tetrahedron 64 (2008) 2153e2159
starting from easily available glycal derived enantiopure 2,3,4-
trisubstituted THF domains. The X-ray crystal of one of the g-
SAAs (8) exhibits weak intermolecular CeH/O and aliphatic
CeH/p interactions. Such information is of great significance
for the design of compounds with predisposed conformation,
e.g., peptidomimetics and nanomaterials.18 These chirally
diverse g-SAAs can enable secondary structural study such as
helices, b-turns, etc. Additionally, these g-SAAs can also act
as convenient stereodiverse library scaffolds.
4.3.1. Compound 15 (2S,3S,4R,5R)-1,2-isopropylidine-
3,6-anhydro-4-O-benzyl-5-O-methanesulfonyl-D-glucitol
Purification of a small amount of crude product by column
chromatography for data generation afforded pure mesylate 15
as a syrup. [a]2D8 ꢁ74.0 (c 0.27, CHCl3), column chromatogra-
phy (9/41 ethyl acetate/hexane v/v); Rf¼0.43 (1/1 ethyl ace-
tate/hexane); 1H NMR (300 MHz, CDCl3): d 1.38 (s, 3H,
C(CH3)2), 1.45 (s, 3H, C(CH3)2), 3.03 (s, 3H, SO2CH3),
3.86 (dd, J¼6.1, 8.5 Hz, 1H, H-1a), 3.96e4.13 (m, 4H, H-3,
H-1b, H-6), 4.15e4.26 (m, 2H, H-2, H-4), 4.63 (d,
J¼11.1 Hz, 1H, CH2Ph), 4.76 (d, J¼11.1 Hz, 1H, CH2Ph),
5.33 (dd, J¼3.8, 4.4 Hz, 1H, H-5), 7.33e7.42 (m, 5H, ArH);
13C NMR (75 MHz, CDCl3): d 25.4 (C(CH3)2), 26.9
(C(CH3)2), 39.4 (SO2CH3), 66.2 (C-1), 71.0 (C-6), 73.5
(CH2Ph), 75.9 (C-2), 78.0 (C-5), 78.6 (C-4), 81.2 (C-3),
110.3 (C(CH3)2), 128.7 (ArC), 128.9 (ArC), 129.1 (ArC),
137.5 (ArqC); IR (neat, cmꢁ1): 3032 (]CeH str), 2936
(CeH str), 1597, 1458, 1358 (C]C str), 1259, 1175, 1077
(CeO str). Mass (ESI-MS): m/z 373 (Mþþ1); EI-HRMS:
calcd for C17H24O7S1 (Mþ) 372.1243, measured 372.1246.
4. Experimental
4.1. General
CH2Cl2 was dried over anhydrous calcium chloride over-
night and distilled over phosphorous pentoxide. Ethyl acetate
was distilled and dried over molecular sieves overnight,
Ti(Oei-Pr)4, (þ)-diethyltartrate, (ꢁ)-diethyltartrate, 6.0 M so-
lution of t-BuOOH in nonane were purchased from Aldrich
1
chemical co. All the products were characterized by H, 13C,
IR, ESI-MS, EI-HRMS and DART-HRMS. TLC was performed
using 2.5ꢂ5 cm plates coated with a 0.25 mm thickness of silica
gel (60F-254), and visualization was accomplished with CeSO4.
4.4. Representative procedure for azidation
1
The H and 13C NMR were recorded with Bruker DRX 300
To a magnetically stirred solution of crude mesylate 15
(190 mg, 0.51 mmol) in DMF (15 mL) were added excess
NaN3 (100 mg, 1.50 mmol) and Bu4NCl (catalytic, ꢃ0.01 g),
and the reaction mixture was stirred at 120 ꢀC for 3 h. DMF
was removed under reduced pressure. The residue was washed
with H2O and the aqueous phase was extracted with EtOAc
(3ꢂ15 mL). The combined organic phase was dried (anhydrous
Na2SO4), and evaporated to yield 16 (143 mg) as a syrup.
spectrometers for solution in CDCl3. Chemical shifts were given
in parts per million downfield from internal standard Me4Si.
Carbon atom types (CH, CH2, CH3) were determined by
DEPT pulse sequence. Yields refer to pure compounds after
chromatography unless and otherwise mentioned. IR spectra
were recorded on PerkineElmer 881 and FTIR-8210 PC Shi-
madzu spectrophotometers. Mass spectra were recorded on
a JEOL JMS-600H high-resolution spectrometer using EI
mode at 70 eV, and Accutof DART JMS-T100LC. Optical rota-
tions were determined on an Autopol III polarimeter using
a 1 dm cell, CHCl3 as the solvent; concentrations mentioned
are in g/100 mL.
4.4.1. Compound 16 (2S,3S,4R,5S)-1,2-O-isopropylidine-
3,6-anhydro-4-O-benzyl-5-azido-5-deoxy-D-glucitol
Yield 90% for two steps from 14. [a]2D8 þ38.3 (c 0.23,
CHCl3), column chromatography (1/49 ethyl acetate/hexane
v/v); Rf¼0.66 (3/7 ethyl acetate/hexane); 1H NMR
(300 MHz, CDCl3): d 1.39 (s, 3H, C(CH3)2), 1.47 (s, 3H,
C(CH3)2), 3.85 (dd, J¼2.5, 6.8 Hz, 1H, H-3), 3.90e4.05 (m,
4H, H-1, H-6a, H-5), 4.09e4.19 (m, 3H, H-4, H-2, H-6b),
4.61 (d, J¼11.7 Hz, 1H, CH2Ph), 4.66 (d, J¼11.7 Hz, 1H,
CH2Ph), 7.33e7.39 (m, 5H, ArH); 13C NMR (75 MHz,
CDCl3): d 25.7 (C(CH3)2), 27.2 (C(CH3)2), 66.5 (C-5), 67.6
(C-6), 71.5 (C-1), 72.6 (CH2Ph), 75.8 (C-2), 85.4 (C-4), 85.9
(C-3), 110.2 (C(CH3)2), 128.5 (ArC), 128.6 (ArC), 129.1
(ArC), 137.8 (ArqC); IR (neat, cmꢁ1): 3033 (]CeH str),
2934 (CeH str), 2102 (eN3 str), 1637, 1456, 1373 (C]C
str), 1250, 1153, 1071 (CeO str). Mass (ESI-MS): m/z 292
(Mþþ1ꢁN2); DART-HRMS: calcd for C16H22N3O4 (Mþþ1)
320.16103, measured 320.16265, mass difference 1.62 mmu.
4.2. Preparation of Jones reagent
CrO3 (25 g) was dissolved in 25 mL H2SO4 (concd). The
solution prepared was added slowly to 75 mL H2O, precooled
at 0 ꢀC. The resulting solution was stirred for 5 min.
4.3. Representative procedure for mesylation
To a magnetically stirred solution of alcohol 14 (147 mg,
0.50 mmol) in dry CH2Cl2 cooled to 0 ꢀC (10 mL), Et3N
(0.14 mL, 1.0 mmol) was added. After 5 min of stirring, a so-
lution of methanesulphonylchloride (0.04 mL, 0.60 mmol) in
dry CH2Cl2 (3 mL) was added dropwise and the reaction mix-
ture was allowed to warm up to room temperature. After
30 min of stirring, the reaction was quenched by saturated so-
lution of NaHCO3. The organic phase was washed with water
and brine, extracted with CH2Cl2 (3ꢂ10 mL), dried over anhy-
drous Na2SO4 and evaporated under reduced pressure. The
crude mesylate 15 (190 mg) obtained was directly used in
the next step without further purification.
4.5. Representative procedure for the synthesis of aldehyde
A solution of azide acetonide 16 (143 mg, 0.45 mmol) and
periodic acid (122 mg, 0.53 mmol) in 15 mL of dry ethyl ace-
tate was allowed to stir at room temperature for 30 min. The
reaction was quenched with saturated solution of NaHCO3

P.V. Reddy et al. / Tetrahedron 64 (2008) 2153e2159
2157
and extracted with ethyl acetate (3ꢂ15 mL). The combined or-
ganic layer was dried over anhydrous Na2SO4 and evaporated
under reduced pressure to afford 115 mg of crude aldehyde 17
(>95% pure from H NMR) as a colourless syrup which was
immediately used for next step.
1H, H-2), 4.75 (s, 2H, CH2Ph), 5.18 (dd, J¼5.8, 10.7 Hz,
1H, H-5), 7.31e7.42 (m, 5H, ArH); 13C NMR (75 MHz,
CDCl3): d 25.9 (C(CH3)2), 27.3 (C(CH3)2), 38.9 (SO2CH3),
67.1 (C-1), 69.6 (C-6), 74.1 (C-2), 74.6 (CH2Ph), 78.0 (C-5),
78.3 (C-4), 80.9 (C-3), 109.6 (C(CH3)2), 128.5 (ArC), 128.6
(ArC), 129.0 (ArC), 138.2 (ArqC); IR (neat, cmꢁ1): 3433
(OeH str), 2817 (CeH str), 1593, 1460, 1352 (C]C str),
1259, 1177, 1047 (CeO str). Mass (ESI-MS): m/z 373
(Mþþ1); EI-HRMS: calcd for C17H24O7S1 (Mþ) 372.1243,
measured 372.1242.
1
4.5.1. Compound 17
1
Rf¼0.32 (3/7 ethyl acetate/hexane); H NMR (300 MHz,
CDCl3): d 3.96e4.09 (m, 3H, H-4, H-5), 4.15e4.19 (m, 1H,
H-3), 4.35 (br s, 1H, H-2), 4.57 (d, J¼11.6 Hz, 1H, CH2Ph),
4.67 (d, J¼11.6 Hz, 1H, CH2Ph), 7.32e7.40 (m, 5H, ArH),
9.63 (s, 1H, CHO); 13C NMR (75 MHz, CDCl3): d 64.9 (C-
4), 72.1 (C-5), 72.8 (CH2Ph), 85.8 (C-3), 88.1 (C-2), 128.5
(ArC), 128.8 (ArC), 129.2 (ArC), 137.2 (ArqC), 201.7
(CHO); IR (neat, cmꢁ1): 3444 (OeH str), 2926 (]CeH
str), 2104 (eN3 str), 1735 (C]O str), 1635, 1545, 1457
(C]C str), 1316, 1258, 1084 (CeO str). Mass (ESI-MS):
m/z 248 (Mþþ1); EI-HRMS: calcd for C12H12NO3
(Mþꢁ1ꢁN2) 218.0817, measured 218.0799.
4.6.3. Compound 24 (2R,3R,4R,5S)-1,2-O-isopropylidine-
3,6-anhydro-4-O-benzyl-5-azido-5-deoxy-D-glucitol
Yield 62% for two steps from 20. [a]2D8 þ26.2 (c 0.08,
CHCl3), column chromatography (3/97, ethyl acetate/hexane
v/v); Rf¼0.68 (2/3 ethyl acetate/hexane); 1H NMR
(300 MHz, CDCl3): d 1.39 (s, 3H, C(CH3)2), 1.47 (s, 3H,
C(CH3)2), 3.80 (dd, J¼2.0, 9.9 Hz, 1H, H-3), 3.97e4.06 (m,
4H, H-1, H-5, H-6a), 4.09e4.17 (m, 2H, H-4, H-2), 4.37 (q,
J¼6.3 Hz, 1H, H-6b), 4.68 (s, 2H, CH2Ph), 7.33e7.39 (m,
5H, ArH); 13C NMR (75 MHz, CDCl3): d 25.9 (C(CH3)2),
27.2 (C(CH3)2), 65.6 (C-5), 67.6 (C-6), 71.2 (C-1), 73.3
(CH2Ph), 73.7 (C-2), 82.1 (C-4), 83.0 (C-3), 109.5
(C(CH3)2), 128.3 (ArC), 128.6 (ArC), 129.1 (ArC), 137.9
(ArqC); IR (neat, cmꢁ1): 3033 (]CeH str), 2987, 2936
(CeH str), 2103 (eN3 str), 1606, 1457, 1374 (C]C str),
1255, 1156, 1069 (CeO str). Mass (ESI-MS): m/z 292
(Mþþ1ꢁN2); DART-HRMS: calcd for C16H22N3O4 (Mþþ1)
320.16103, measured 320.16210, mass difference 1.07 mmu.
4.6. Representative procedure for oxidation by Jones reagent
To a solution of aldehyde 17 (115 mg, 0.47 mmol) in ace-
tone (5 mL) at 0 ꢀC freshly prepared Jones reagent
(0.50 mL, 0.61 mmol) was added dropwise. After the reaction
was stirred for 10 min methanol was added to destroy the ex-
cess Jones reagent. The solvent was removed under reduced
pressure. The residue was diluted with water and extracted
with ethyl acetate (3ꢂ5 mL), and the combined organic ex-
tract was dried over anhydrous Na2SO4 and evaporated under
reduced pressure. Purification of the residue obtained by
a short column of silica gel furnished the pure SAA 5
(70 mg) as a syrup.
4.6.4. Compound 26
1
Rf¼0.55 (4/6 ethyl acetate/hexane); H NMR (300 MHz,
CDCl3): d 3.99e4.09 (m, 2H, H-4, H-5a), 4.29e4.35 (m,
2H, H-3, H-5b), 4.41 (dd, J¼1.7, 5.0 Hz, 1H, H-2), 4.53e
4.62 (m, 2H, CH2Ph), 7.32e7.37 (m, 5H, ArH), 9.64 (d,
J¼2.3 Hz, 1H, CHO); 13C NMR (75 MHz, CDCl3): d 65.1
(C-4), 72.2 (C-5), 73.6 (CH2Ph), 85.0 (C-3), 85.1 (C-2),
128.5 (ArC), 128.9 (ArC), 129.3 (ArC), 136.9 (ArqC), 200.5
(CHO); IR (neat, cmꢁ1): 3445, 2926 (CeH str), 2106 (eN3
str), 1737 (C]O str), 1636, 1544, 1459 (C]C str), 1260,
1084 (CeO str). Mass (ESI-MS): m/z 248 (Mþþ1).
4.6.1. Compound 5
Yield 60% for two steps from 16. [a]2D8 þ34.3 (c 0.07,
CHCl3), column chromatography (9/1 chloroform/hexane
v/v); Rf¼0.37 (9/1 chloroform/methanol, two drops acetic
1
acid); H NMR (300 MHz, CDCl3): d 4.03e4.10 (m, 3H, H-
4, H-5a, eOH), 4.29 (br s, 1H, H-3), 4.49 (br s, 1H, H-5b),
4.58e4.75 (m, 3H, H-2, CH2Ph), 7.34 (br s, 5H, ArH); 13C
NMR (75 MHz, CDCl3): d 65.6 (C-4), 72.1 (C-5), 72.8
(CH2Ph), 83.0 (C-3), 86.8 (C-2), 128.5 (ArC), 128.7 (ArC),
129.1 (ArC), 137.5 (ArqC), 174.4 (COOH); IR (neat, cmꢁ1):
3448 (OeH str), 2927 (]CeH str), 2114 (eN3 str), 1720
(C]O str), 1681, 1459, 1356 (C]C str), 1271, 1206, 1082
(CeO str). Mass (ESI-MS): m/z 236 (Mþþ1ꢁN2); EI-
HRMS: calcd for C12H12O4N1 (Mþꢁ1ꢁN2) 234.0766, mea-
sured 234.0765.
4.6.5. Compound 6
Yield 64% for two steps from 24. [a]2D8 þ35.0 (c 0.3,
CHCl3), column chromatography (9/1 chloroform/hexane
v/v); Rf¼0.59 (9/1 chloroform/methanol, two drops acetic
1
acid); H NMR (300 MHz, CDCl3): d 3.94e4.02 (m, 2H, H-
4, H-5a), 4.26e4.33 (m, 2H, H-5b, H-3), 4.57e4.69 (m, 3H,
H-2, CH2Ph), 7.31e7.38 (m, 5H, ArH); 13C NMR (75 MHz,
CDCl3): d 65.1 (C-4), 72.2 (C-5), 74.0 (CH2Ph), 80.5 (C-3),
83.5 (C-2), 128.6 (ArC), 128.9 (ArC), 129.2 (ArC), 137.0
(ArqC), 173.1 (COOH); IR (neat, cmꢁ1): 3449 (OeH str),
2934 (]CeH str), 2105 (eN3 str), 1720 (C]O str), 1629,
1421, 1345 (C]C str), 1311, 1261, 1063 (CeO str). Mass
(ESI-MS): m/z 286 (Mþþ23); EI-HRMS: calcd for
C12H12N1O4 (Mþꢁ1ꢁN2) 234.0766, measured 234.0766.
4.6.2. Compound 22 (2R,3R,4R,5R)-1,2-O-isopropylidine-
3,6-anhydro-4-O-benzyl-5-O-methanesulfonyl-D-glucitol
[a]2D8 ꢁ15.3 (c 0.13, CHCl3); Rf¼0.51 (2/3 ethyl acetate/
hexane); 1H NMR (300 MHz, CDCl3): d 1.37 (s, 3H,
C(CH3)2), 1.43 (s, 3H, C(CH3)2), 2.99 (s, 3H, SO2CH3),
3.95e4.05 (m, 4H, H-1, H-3, H-6a), 4.07e4.15 (m, 1H, H-
6b), 4.30 (t, J¼4.8 Hz, 1H, H-4), 4.37 (dd, J¼6.2, 12.9 Hz,

2158
P.V. Reddy et al. / Tetrahedron 64 (2008) 2153e2159
1
4.6.6. Compound 23 (2R,3R,4S,5R)-1,2-O-isopropylidine-
3,6-anhydro-4-O-benzyl-5-O-methanesulfonyl-D-galactitol
[a]2D8 þ7.2 (c 0.11, CHCl3), crystallization in ethyl acetate/
hexane, mp 101e102 ꢀC; Rf¼0.64 (2/3 ethyl acetate/hexane);
1H NMR (300 MHz, CDCl3): d 1.36 (s, 3H, C(CH3)2), 1.44 (s,
3H, C(CH3)2), 3.02 (s, 3H, SO2CH3), 3.85e3.94 (m, 2H, H-1a,
H-3), 4.02e4.17 (m, 4H, H-1b, H-2, H-6), 4.30 (d, J¼3.0 Hz,
1H, H-4), 4.67 (d, J¼12.1 Hz, 1H, CH2Ph), 4.72 (d,
J¼12.1 Hz, 1H, CH2Ph), 5.15 (d, J¼3.5 Hz, 1H, H-5),
7.32e7.39 (m, 5H, ArH); 13C NMR (75 MHz, CDCl3):
d 25.6 (C(CH3)2), 27.2 (C(CH3)2), 39.2 (SO2CH3), 67.4 (C-
1), 72.3 (C-6), 72.7 (CH2Ph), 75.6 (C-2), 83.4 (C-5), 84.6
(C-4), 85.8 (C-3), 110.2 (C(CH3)2), 128.5 (ArC), 128.6
(ArC), 129.0 (ArC), 137.7 (ArqC); IR (KBr, cmꢁ1): 3468
(OeH str), 2992 (]CeH str), 2938 (CeH str), 1633, 1455,
1356 (C]C str), 1245, 1147, 1058 (CeO str). Mass (ESI-
MS): m/z 373 (Mþþ1); EI-HRMS: calcd for C17H24O7S1
(Mþ) 372.1243, measured 372.1245.
acid); H NMR (300 MHz, CDCl3): d 3.91e4.19 (m, 3H, H-
5, H-4), 4.37 (br s, 1H, H-3), 4.58 (d, J¼3.8 Hz, 1H, H-2),
4.75 (d, J¼12.1 Hz, 1H, CH2Ph), 4.81 (d, J¼12.1 Hz, 1H,
CH2Ph), 7.33e7.48 (m, 5H, ArH); 13C NMR (75 MHz,
CDCl3): d 61.2 (C-4), 71.3 (C-5), 73.4 (CH2Ph), 80.9 (C-3),
82.7 (C-2), 128.5 (ArC), 128.7 (ArC), 129.1 (ArC), 137.3
(ArqC), 176.0 (COOH); IR (neat, cmꢁ1): 3433 (OeH str),
3034 (]CeH str), 2927 (CeH str), 2108 (eN3 str), 1741
(C]O str), 1653, 1457, 1352 (C]C str), 1269, 1203, 1095
(CeO str). Mass (ESI-MS): m/z 236 (Mþþ1ꢁN2); EI-
HRMS: calcd for C12H12N1O4 (Mþꢁ1ꢁN2) 234.0766, mea-
sured 234.0769.
4.6.10. Compound 8
Yield 64%, crystallization in ethyl acetate/hexane, mp
121e123 ꢀC. [a]D28 þ61.7 (c 0.06, CHCl3); Rf¼0.44 (9/1 chlo-
roform/methanol, two drops acetic acid); 1H NMR (300 MHz,
CDCl3): d 3.87 (dd, J¼4.7, 6.9 Hz, 1H, H-4), 4.10 (d,
J¼7.1 Hz, 2H, H-5), 4.45 (t, J¼4.9 Hz, 1H, H-3), 4.63 (d,
J¼5.3 Hz, 1H, H-2), 4.75 (s, 2H, CH2Ph), 7.25e7.35 (m,
5H, ArH); 13C NMR (75 MHz, CDCl3): d 61.4 (C-4), 69.9
(C-5), 75.0 (CH2Ph), 80.0 (2C, C-2, C-3), 128.6 (ArC),
128.7 (ArC), 128.9 (ArC), 137.0 (ArqC), 171.5 (COOH); IR
(KBr, cmꢁ1): 3485 (OeH str), 3040 (]CeH str), 2938 (Ce
H str), 2105 (eN3 str), 1734 (C]O str), 1609, 1494, 1456
(C]C str), 1103, 1091 (CeO str). Mass (ESI-MS): m/z 264
(Mþþ1); EI-HRMS: calcd for C12H14N3O4 (Mþþ1)
264.0984, measured 264.0980.
4.6.7. Compound 25 (2R,3R,4S,5S)-1,2-O-isopropylidine-
3,6-anhydro-4-O-benzyl-5-azido-5-deoxy-D-galactitol
Yield 90% for two steps from 21. [a]2D8 þ71.5 (c 0.13,
CHCl3), column chromatography (1/24 ethyl acetate/hexane
v/v); Rf¼0.37 (1/4 ethyl acetate/hexane); 1H NMR
(300 MHz, CDCl3): d 1.34 (s, 3H, C(CH3)2), 1.41 (s, 3H,
C(CH3)2), 3.79e3.95 (m, 4H, H-1a, H-3, H-5, H-6a), 3.99e
4.05 (m, 2H, H-1b, H-6b), 4.08e4.18 (m, 2H, H-2, H-4),
4.63 (d, J¼11.6 Hz, 1H, CH2Ph), 4.72 (d, J¼11.6 Hz, 1H,
CH2Ph), 7.32e7.42 (m, 5H, ArH); 13C NMR (75 MHz,
CDCl3): d 25.5 (C(CH3)2), 27.0 (C(CH3)2), 61.4 (C-5), 66.7
(C-1), 70.3 (C-6), 73.3 (CH2Ph), 76.2 (C-2), 80.5 (C-4), 83.2
(C-3), 110.3 (C(CH3)2), 128.6 (ArC), 128.7 (ArC), 129.0
(ArC), 137.8 (ArqC); IR (neat, cmꢁ1): 3449 (OeH str),
3032 (]CeH str), 2929 (CeH str), 2106 (eN3 str), 1602,
1457, 1375 (C]C str), 1262, 1214, 1071 (CeO str). Mass
(ESI-MS): m/z 292 (Mþþ1ꢁN2); DART-HRMS: calcd for
C16H22N3O4 (Mþþ1) 320.16103, measured 320.16033, mass
difference 0.70 mmu.
4.7. Crystal data for 8
C12H13N3O4, M¼263.25, orthorhombic, P212121, a¼5.375
3
˚
˚
(1), b¼9.309 (1), c¼25.382 (3) A, V¼1270.0(3) A , T¼293
(2) K, Z¼4, Dc¼1.377 g cmꢁ3, m¼0.105 mmꢁ1, F(000)¼552,
˚
l (Mo Ka)¼0.71073 A, reddish block, crystal size 0.250ꢂ
0.125ꢂ0.050 mm, 1917 reflections measured (Rint¼0.0201),
1706 unique, R1¼0.0441 for 903, Fo>4s (Fo) and 0.1131
for all 1706 data, S¼0.965 for all data and 174 parameters.
Unit cell determinations and intensity data collection
(2q¼49.43ꢀ) were performed on a Bruker P4 diffractometer
at 293(2) K. Structure solutions by direct methods and refine-
ments by full-matrix-least-squares methods on F2. Programs:
XSCANS [(Siemens Analytical X-ray Instruments Inc.: Madi-
son, Wisconsin, USA 1996) were used for data collection
and data processing], SHELXTL-NT [(Bruker AXS Inc.: Mad-
ison, Wisconsin, USA 1997) was used for structure determina-
tion, refinements and molecular graphics]. Further details of
the crystal structure investigation can be obtained from the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge, CB21EZ, UK (CCDC deposit no. 659847).
4.6.8. Compound 27
1
Rf¼0.20 (2/3 ethyl acetate/hexane); H NMR (300 MHz,
CDCl3): d 3.85e3.89 (m, 1H, H-4), 4.02e4.05 (m, 2H, H-
5), 4.22e4.26 (m, 1H, H-3), 4.37 (dd, J¼1.1, 5.7 Hz, 1H, H-
2), 4.66e4.77 (m, 2H, CH2Ph), 7.33e7.39 (m, 5H, ArH),
9.66 (s, 1H, CHO); 13C NMR (75 MHz, CDCl3): d 61.5 (C-
4), 71.6 (C-5), 73.5 (CH2Ph), 80.5 (C-3), 86.1 (C-2), 128.6
(ArC), 128.9 (ArC), 129.2 (ArC), 137.1 (ArqC), 200.7
(CHO); IR (neat, cmꢁ1): 2931 (CeH str), 2108 (eN3 str),
1635, 1459, 1384 (C]C str), 1273, 1076 (CeO str). Mass
(ESI-AQTOF): m/z 265 (MþNHþ4 ), 247 (Mþ); ESI-HRMS:
calcd for C12H17N4O3 (MþNHþ4 ) 265.13006, measured
265.13203, mass difference 1.96 mmu.
Acknowledgements
4.6.9. Compound 7
Yield 60% for two steps from 25. [a]2D8 þ45.1 (c 0.41,
CHCl3), column chromatography (9/1 chloroform/hexane
v/v); Rf¼0.43 (9/1 chloroform/methanol, two drops acetic
This research project was funded by ICMR (ref: IRIS Cell
No. 200-02220), New Delhi. We are thankful to Sophisticated
Analytical Instrumentation Facility, CDRI for providing

P.V. Reddy et al. / Tetrahedron 64 (2008) 2153e2159
2159
´
9. Carballido, M.; Castedo, L.; Gonzalez-Bello, C. Eur. J. Org. Chem. 2004,
spectral data and Mr. A. K. Pandey for technical assistance.
P.V.R., L.V.R.R. and R.K. thank CSIR for providing
fellowships.
3663e3668.
10. Gnad, F.; Poleschak, M.; Reiser, O. Tetrahedron Lett. 2004, 45, 4277e
4280.
11. For examples of furanoid SAAs, see reviews: (a) Risseeuw, M. D. P.;
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Supplementary data
Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2007.12.032.
12. Edwards, A. A.; Sanjayan, G. J.; Hachisu, S.; Soengas, R.; Stewart, A.;
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