Synthesis of aryl, glycosyl, and azido septanosides through ring expansion of 1,2-cyclopropanated sugars

Article abstract of DOI:10.1021/jo801967s

A ring-expansion methodology for the preparation of aryl septanosides, arabinofuranosyl and glucopy- ranosyl septanoside disaccharides, and azido septanosides is reported. A cyclopropanated adduct of the oxyglycal upon reaction with phenols, sugars, and a

Full text of DOI:10.1021/jo801967s

Synthesis of Aryl, Glycosyl, and Azido Septanosides through Ring
Expansion of 1,2-Cyclopropanated Sugars
N. Vijaya Ganesh and N. Jayaraman*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
jayaraman@orgchem.iisc.ernet.in
ReceiVed September 5, 2008
A ring-expansion methodology for the preparation of aryl septanosides, arabinofuranosyl and glucopy-
ranosyl septanoside disaccharides, and azido septanosides is reported. A cyclopropanated adduct of the
oxyglycal upon reaction with phenols, sugars, and azide led to the formation of ring-expanded septano-
side derivatives. The ring expansion was found to be stereoselective with sugars, whereas phenols and
the azide afforded an anomeric mixture of the ring expanded product. It was observed further that the
conversion of the intermediate diketones to the diols, using NaBH4, occurred with high diastereoselectivities
for the R-anomers of the septanosides. This report consolidates further the generality of the oxyglycal
ring-expansion method to prepare septanosides, possessing different substituents at their reducing ends.
Introduction
provide evidence for the ability of the septanoside derivatives
to bind proteins.
Septanoses, the higher homologues of commonly occurring
furanoses and pyranoses, are unnatural sugars.1 These ring-
expanded sugars adopt flexible conformations. Few synthetic
methods have been known previously to prepare septanoses and
septanosides2-6 and are studied further for their conformations.7-9
Recent biological studies10-12 such as protein binding studies
We have reported recently that the ring expansion of
cyclopropanated pyranosides is a useful method to prepare
septanosides from pyranosides.13 The method involves primarily
a ring-opening reaction of a gem-dihalocyclopropane adduct of
oxyglycals in the presence of a methoxide, so as to lead to the
formation of seven-membered oxepines. The ring-opening
reaction was found to be stereoselective, and an exclusive
formation of the R-anomer of oxepines was observed with
methoxide. The R-anomer of the oxepine intermediates, having
keto-functionalities, readily underwent NaBH4-mediated conver-
sion to alcohols, marked with higher diastereoselectivities at
the newly generated C-2 and C-3 centers of the septanoside.
(1) Pakulski, Z. Pol. J. Chem. 2006, 80, 1293–1326.
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Res. 1996, 284, 241–248. (d) Driver, G. E.; Stevens, J. D. Carbohydr. Res. 2001,
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28, 75–85. (b) Molina, J. M.; Olea, D. P.; Baer, H. H. Carbohydr. Res. 1995,
273, 1–10. (c) Ng, C. J.; Craig, D. C.; Stevens, J. D. Carbohydr. Res. 1996,
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Stevens, J. D. Carbohydr. Res. 1996, 284, 265–275.
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10.1021/jo801967s CCC: $40.75
Published on Web 12/04/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 739–746 739

Ganesh and Jayaraman
SCHEME 1
Continuing our efforts to extend the method, as well as to
demonstrate the preparation of a variety of septanosides, the
ring-expansion reaction of the cyclopropanated adduct with
phenoxides, sugars, and azide was undertaken. In the event, it
was found that whereas the ring opening with sugars was highly
stereoselective, leading to an exclusive formation of the R-ano-
mer of sugar oxepines, the phenoxides and azide led to a mixture
of anomers of the corresponding oxepines in a ∼1:1 ratio.
Further, the R-anomer of the oxepine derived intermediates,
having keto-functionalities, underwent NaBH4-mediated conver-
sion to alcohols with higher diastereoselectivities at the newly
generated stereocenters, whereas the ꢀ-anomers did not retain
the diastereoselectivities, in the case of aryl septanosides. The
details of the synthesis of aryl septanosides, septanoside
disaccharides presenting a furanoside and pyranoside units, and
azido septanoside derivatives are described herein.
found to be effective, and the 1,2-C-(dichloromethylene)-R-D-
glycero-hexitol 2 was obtained as a single diastereomer in good
yields (Scheme 1). In the present study, the dichloroadduct 2
served as the starting material for the ring-expansion reactions.
Reaction of phenols with 2 in PhMe, in the presence of K2CO3
1
and 18-C-6, for 48-72 h afforded chloro-oxepine 3. The H
NMR spectrum of 3 (R1, R2 ) H) showed resonances at 5.68
and 5.99 ppm, corresponding to the H-1 nucleus of the R- and
ꢀ-anomers, in a ratio of 1:1, respectively. Similarly, 13C NMR
spectrum showed peaks at 98.7 and 101.5 ppm, corresponding
to the anomeric carbon of the R- and ꢀ-anomers, respectively.
The signals at ∼121 and ∼153 ppm confirmed the presence of
chlorovinyl ether moiety in the product. HR-MS analysis further
confirmed the composition of 3 (R1, R2 ) H).
The chloro-oxepines were not stable, and thus the subsequent
oxidation was conducted immediately after their preparation.
Oxidation of 3 was performed using in situ generated RuO4,21
which led to the formation of the diketone derivative in 70-76%
yield (2 steps). As a result of difficulty in separating the anomers
of the diketones, their subsequent reduction to the diols was
performed, using NaBH4 in MeOH. The diols were obtained in
good yields, as mixtures of anomers and epimers (Table 1). The
isomeric diols 4-8 were separated through column chroma-
tography and the R- and ꢀ-anomers were isolated in an
approximately 1:1 ratio. It is pertinent to note that the ꢀ-anomers
are epimeric, whereas the R-anomers are diastereomerically pure.
It was found that the R-anomers of the aryl-substituted
diketones underwent NaBH4 reduction in a highly diastereose-
lective manner. On the other hand, the ꢀ-anomers yielded a
mixture of isomers. The anomeric proton of the R-anomers in
4r-8r resonated in the range of 5.4-5.7 ppm, as a doublet,
with JH1-H2 of ∼4 Hz. The corresponding C-1 nucleus was
observed at ∼97 ppm, with the exception of o-methoxy
derivative 8r, which resonated at 101.2 ppm. The R-configu-
ration was confirmed further with the observed 1JC1-H1 of 170.2
Hz for 4r. The resonances of the newly generated H-2 and H-3
Results and Discussion
Synthesis of Aryl Septanosides. The ring expansion of a
pyranoside to a septanoside is initiated with the cyclopropanation
of an oxyglycal. Oxyglycals,14-16 containing an oxygen func-
tionality at C-2, are prepared through a dehydrohalogenation
of an appropriately protected pyranosyl bromide. Cyclopropa-
nation and its ring-expansion reactions in the case of glycals,
without an oxygen functionality at C-2, have been studied
previously.17-20 Cyclopropanation of the oxyglucal 113 was
performed using dichlorocarbene. The carbene addition was
(14) (a) Rao, D. R.; Lerner, L. M. Carbohydr. Res. 1972, 22, 345–350. (b)
Varela, O.; de Fina, G. M.; de Lederkremer, R. M. Carbohydr. Res. 1987, 167,
187–196. (c) Ratcliffe, A.; Fraser-Reid, B. J. Chem. Soc., Perkin. Trans. 1 1990,
747–750. (d) Jones, G. S.; Scott, W. J. J. Am. Chem. Soc. 1992, 114, 1491–
1492.
(15) (a) Boettcher, A.; Lichtenthaler, F. W. Tetrahedron: Asymmetry 2004,
15, 2693–2701. (b) Lichtenthaler, F. W.; Weimer, T.; Immel, S. Tetrahedron:
Asymmetry 2004, 15, 2703–2709.
(16) (a) Storkey, C. M.; Win, A. L.; Hoberg, J. O. Carbohydr. Res. 2004,
339, 897–899. (b) Chambers, D. J.; Evans, G. R.; Fairbanks, A. J. Tetrahedron
2004, 60, 8411–8419. (c) Moreno, B.; Quehen, C.; Rose-He´le`ne, M.; Leclerc,
E.; Quirion, J. C. Org. Lett. 2007, 9, 2477–2480.
(17) Duchaussoy, P.; Cesare, P. D.; Gross, B. Synthesis 1979, 198–200.
(18) (a) Hoberg, J. O.; Bozell, J. J. Tetrahedron Lett. 1995, 36, 6831–6834.
(b) Hoberg, J. O. J. Org. Chem. 1997, 62, 6615–6618. (c) Cousins, G. S.; Hoberg,
J. O. Chem. Soc. ReV. 2000, 29, 165–174. (d) Batchelor, R.; Hoberg, J. O.
Tetrahedron Lett. 2003, 44, 9043–9045.
(19) Ramana, C. V.; Murali, R.; Nagarajan, M. J. Org. Chem. 1997, 62,
7694–7703.
(20) Kirsch, V.; Wolff, C.; Na¨ther, C.; Tochtermann, W. Eur. J. Org. Chem.
2000, 1741–1744.
(21) (a) Khan, F. A.; Prabhudas, B.; Dash, J.; Sahu, N. J. Am. Chem. Soc.
2000, 122, 9558–9559. (b) Chou, T. C.; Liao, K. C.; Lin, J. J. Org. Lett. 2005,
7, 4843–4846. (c) de Oliveira, L. F.; Costa, V. E. U. Tetrahedron Lett. 2006,
47, 3565–3567. (d) Frunzke, J.; Loschen, C.; Frenking, G. J. Am. Chem. Soc.
2004, 126, 3642–3652.
740 J. Org. Chem. Vol. 74, No. 2, 2009

Synthesis of Aryl, Glycosyl, and Azido- Septanosides
TABLE 1. Synthesis of Various Aryl Septanosides 4-8
pyranoside 17 were synthesized by (i) tritylation; (ii) benzyla-
tion, and (iii) detritylation reactions.22 The ring-opening reaction
of 2 was conducted with 14 and 17 (2 molar equiv), under reflux
conditions, in the presence of K2CO3 (10 molar equiv), in PhMe.
The resulting chlorooxepine disaccharide derivatives 15 and 18
were obtained in moderate yields. Unlike the phenols, the ring
opening with 14 and 17 occurred in a highly stereoselective
manner, and only the R-anomers were obtained (Scheme 2).
1H NMR spectra of 15 and 18 showed resonances at ∼5.5
ppm for the anomeric proton; the corresponding 13C NMR
spectra showed a signal at ∼99.6 ppm for the anomeric carbon.
HR-MS analysis further confirmed the composition of 15 and
18. The RuO4-mediated oxidation of the double bond, followed
by NaBH4 reduction of diketones, afforded the corresponding
disaccharides 16 and 19, containing two free hydroxyl groups.
The reactions were observed to occur with high diastereose-
lectivities and led to the formation of a single diastereomer, in
good yields.
1
In the H NMR spectra, H-1 of the septanoside moiety in
disaccharides 16 and 19 appeared as a doublet at ∼5.02 ppm
(J ) ∼4.3 Hz). The signal corresponding to H-2 of 16 appeared
as a broadband at 4.0 ppm. A selective irradiation of H-1 in 16
resulted in a clear doublet for H-2, and JH2-H3 was found to be
9.3 Hz. Thus, the configurations of the newly formed stereo-
centers were assigned as shown in Scheme 2. The anomeric
carbon corresponding to the septanoside unit in 16 and 19
appeared at 99.8 and 98.7 ppm, respectively.
The O-benzyl groups in the disaccharides 16 and 19 were
deprotected (Pd/C, H2) to afford the free hydroxyl groups
containing D-glycero-D-galacto-septanoside disaccharides 20 and
21, quantitatively (Figure 2). The composition of the disaccha-
rides 20 and 21 were confirmed by NMR spectroscopic and
HR-MS techniques.
It is emphasized that the present method providing the
disaccharides is different from the existing methods. Hindsgaul
and co-workers23 reported disaccharide-containing septanoses
that were formed through glycosylation of preformed saccha-
rides. Recently Peczuh and co-workers4,24 reported the synthesis
of disaccharides containing septanosides, including septanose
disaccharides linked through a 1,7-linkage. The disaccharides
were prepared through epoxide ring opening of preformed
septanose glycal epoxides, as well as by glycosylation of a
thiophenyl septanoside donor. In the method presented herein,
the ring-opening reaction with sugars occurs in conjunction with
the formation of the septanoside.
a R/ꢀ anomeric ratio is ∼1:1. b In the case of the ꢀ-anomers the ratio
1
was determined by H NMR spectroscopy.
of the R-anomers 4r-8r merged with the benzylic protons,
thereby precluding their assignments in the presence of the
protecting groups.
Characterization of the ꢀ-anomers 4ꢀ-8ꢀ showed that the
anomeric proton resonated at ∼5.5 ppm (app.s) and at ∼5.35
ppm (app.s). The resonances of H-1 had varied ratios for each
septanoside because of the epimeric mixture, and the ratios are
given in Table 1. The 13C NMR spectra of 4ꢀ-8ꢀ also exhibited
a set of resonance for C-1, in the range of 98.6-99.9 ppm. The
1JC1-H1 values for 4ꢀ at 160.0 and 157.4 Hz confirmed that the
ꢀ-anomer was an epimeric mixture. This epimeric mixture was
inferred to arise at the C-3 configuration, on the basis that the
observed JH1-H2 values of ∼1 Hz corresponding to a cis-
orientation of the C-1 and C-2 substituents.
Subsequent hydrogenolysis was performed on 4-8, in both
the anomeric forms, to secure the free-hydroxyl group containing
D-glycero-D-galacto-septanosides 9r-13r and D-glycero-D-ido/
talo-septanosides 9ꢀ-13ꢀ (Figure 1). In the 1H NMR spectrum,
the anomeric proton in 9r-13R resonated as a doublet at
5.5-5.6 ppm (JH1-H2 ) ∼3.3 Hz). The H-2 and H-3 appeared
as a set of double doublets at 4.17-4.25 ppm (JH1-H2 ) ∼3.3
Hz, JH2-H3 ) ∼7.6 Hz) and 4.13-4.22 ppm (JH2-H3 ) ∼7.6
Hz, JH3-H4 ) ∼2.0 Hz), respectively. From these observed J
values, the configurations at C-1, C-2, and C-3 were assigned,
as given in Figure 1. In the 13C NMR spectrum, the C-1 of the
R-anomers 9r-13r was observed in the range of 96-99 ppm.
The anomeric proton of 9ꢀ-13ꢀ appeared as an apparent
singlet at ∼5.3 ppm and was seen with consistent upfield shift,
when compared to the R-anomers 9r-13r. The absence of
coupling of H-1 with H-2 indicated a cis-orientation of these
protons. On the other hand, the ꢀ-anomers 9ꢀ-12ꢀ showed
resonances at ∼101.5 and 102.5 ppm for the C-1 nucleus in
the 13C NMR spectrum, thereby confirming the epimeric nature
of the ꢀ-anomers. The o-methoxy derivative 13ꢀ showed the
C-1 resonance at 103.1 ppm.
Disaccharides Containing Septanosides. An appropriately
protected sugar was chosen as the acceptor component in the
ring-opening reaction, so as to afford disaccharides containing
the septanose unit. The partially protected furanoside 14 and
Synthesis of Azido Septanosides. The use of an azide25 in
the ring opening of a cyclopropanated pyranoside was antici-
pated to afford azido septanosides. Although a ring-opening
reaction with NaN326 in PhMe and under reflux conditions did
not proceed well, it was possible to secure the ring-expanded
1-azido chloro oxepine product 22 in a quantitative yield when
DMF was used as the solvent (Scheme 3).
(22) (a) Bernotas, R. C.; Pezzone, M. A.; Ganem, B. Carbohydr. Res. 1987,
167, 305–311. (b) Tennant-Eyles, R. J.; Davis, B. G.; Fairbanks, A. J.
Tetrahedron: Asymmetry 2000, 11, 231–243.
(23) Mc Auliffe, J. C.; Hindsgaul, O. Synlett 1998, 307–309.
(24) (a) Peczuh, M. W.; Snyder, N. L.; Fyvie, W. S. Carbohydr. Res. 2004,
339, 1163–1171. (b) Fyvie, W. S.; Morton, M.; Peczuh, M. W. Carbohydr. Res.
2004, 339, 2363–2370.
(25) The ring-opening reaction of 2 with amines such as benzyl amine, n-octyl
amine, and morpholine was attempted initially. However, the reactions were
not successful even after modifying the temperature, reaction duration, and
concentrations. In most cases, decomposition of the starting material was
observed.
(26) The use of TMSN3 as an azide source resulted no product formation.
J. Org. Chem. Vol. 74, No. 2, 2009 741

Ganesh and Jayaraman
FIGURE 1. Molecular structures of the aryl septanosides 9-13.
SCHEME 2
The presence of the newly introduced azide functionality was
identified from IR spectra (ν 2109 cm-1). The 1H NMR spectrum
of 22 showed signals at 5.09 and 5.90 ppm, in a ratio of 2:1,
corresponding to an R- and ꢀ-mixture. Similarly, 13C NMR
spectrum showed peaks at 91.7 and 91.2 ppm, corresponding
to the anomeric carbon of the anomers. The signals at ∼119
and ∼153 ppm confirmed the presence of chlorovinyl ether
moiety in the product. HR-MS analysis further confirmed the
composition of 22.
The azido chlorooxepine 22 was subjected to RuO4 oxidation,
followed by NaBH4 reduction, so as to afford the azido
septanose derivatives 23, in a good yield. The reduction led to
the formation of azido diols 23 in a 2:1 ratio of R/ꢀ mixture
(Scheme 3). The diols 23r and 23ꢀ were separated through
column chromatography.
In the 1H NMR spectrum of 23r, the anomeric proton
resonated as a doublet, at 5.57 ppm with J ) ∼3 Hz. The
anomeric carbon of 23r resonated at 87.7 ppm. On the other
hand, the resonances corresponding to H-2 and H-3 were found
to be complex. Irradiation of H-1 led the signal for H-2 to appear
as a doublet with J ) 6.6 Hz. This observation indicated a cis
and trans relationship between H-1-H-2 and H-2-H-3, re-
spectively. Similarly, the anomeric proton of ꢀ-azide diol (23ꢀ)
appeared as an apparent singlet, at 5.03 ppm, and the signal for
H-2 was observed as a broad peak at 3.96 ppm. The configu-
ration at C-2 and C-3 in 23ꢀ was resolved through irradiation
FIGURE 2. Molecular structures of the disaccharides containing
septanosides 20 and 21.
742 J. Org. Chem. Vol. 74, No. 2, 2009

Synthesis of Aryl, Glycosyl, and Azido- Septanosides
SCHEME 3
experiments. The H-2 signal appeared as a sharp doublet (J )
3.1 Hz) upon irradiation of H-1, which confirmed that H-1, H-2,
and H-3 were oriented cis to each other.
Experimental Section
1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1,2-C-(dichloromethylene)-
r-D-glycero-D-galacto-hexitol (2). To a solution of 1 (1.3 g, 2.5
mmol) and benzyltriethylammonium chloride (TEBAC) (cat.) in
CHCl3 (8 mL), aqueous NaOH (50%, 7 mL) was added. The
mixture was stirred for 2 h, then diluted with brine solution (50
mL), and extracted with CH2Cl2 (3 × 50 mL). The combined
organic extracts were dried (Na2SO4) and concentrated in vacuo.
The resulting residue was purified (hexane/EtOAc ) 9:1) to afford
Having the azide diol 23r, a one-step azide reduction and
benzyl group deprotection was performed by hydrogenolysis
(Pd/C, H2). However, the reaction was not successful, leading
to the formation of a complex mixture. The selective reduction
of the anomeric azide to amine was thus attempted using PPh3/
THF.27 Treatment of 23r (1 molar equiv) with PPh3 (4 molar
equiv), in THF/H2O (4:1), for 36 h, afforded amino septanose
2 (1.32 g, 88%), as a colorless oil. Rf 0.70 (hexane/EtOAc ) 9:1);
[R]24 +34.7 (c 1.00, CH2Cl2); H NMR (400 MHz, CDCl3) δ
1
1
D
24 in a moderate yield. In the H NMR spectrum of anomeric
7.40-7.20 (m, 20H), 4.95-4.85 (m, 3H), 4.68-4.59 (m, 3H), 4.45
(d, J ) 12.0 Hz, 1H), 4.32 (d, J ) 12.0 Hz, 1H), 4.14 (d, J ) 10.0
Hz, 1H), 4.05 (dd, J ) 10.2 Hz, 10.0 Hz,1H), 3.97 (s, 1H),
3.89-3.86 (m, 1H), 3.60 (dd, J ) 10.4, 2.9 Hz, 1H), 3.47 (dd, J )
10.4, 3.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 138.1, 137.8,
137.6, 137.4, 128.4, 128.3, 128.1, 128.0, 127.8, 127.7, 127.6, 127.5,
80.7, 77.2, 74.5, 73.9, 73.5, 72.8, 71.3, 70.5, 66.9, 65.4, 63.7; HRMS
m/z C35H34Cl2O5Na calcd 627.1681, found 627.1680.
amine 24, resonances of the septanose ring protons appeared
as sets of multiplets at 4.84-4.35, 4.13-3.81, and 3.69-3.54
ppm. The 13C NMR spectrum showed peaks at 78.4, 74.4, 70.1,
and 69.9 ppm, corresponding to the ring carbons of the amino
septanose 24. HR-MS analysis confirmed the presence of the
anticipated anomeric amine 24, in addition to a peak that could
be attributed to a disaccharide, formed through condensation
of two septanosides, with the loss of an ammonia molecule.
In conclusion, the ring-opening reaction of cyclopropanated
pyranosides, in the presence of phenols, sugars, and azides was
examined. Important observations are the following: (i) The ring-
opening reactions with phenols, sugars, and azides are found
to be effective and provided the chlorooxepines in good yields.
(ii) The stereoselectivity of the product formed during the ring-
opening reaction was affected with phenolates and azide,
whereas the presence of sugars did not have an effect and highly
stereoselective products formed. This observation leads us to
presume that the π-orbitals in the phenolate and azide may have
a role in the product formation, wherein the addition of
these nucleophiles occur via a SN1-type mechanism, involving
the oxocarbenium ion of the septanose. On the other hand, the
sugars might experience a kinetic anomeric effect upon addition
to the oxocarbenium ion of the septanose, thereby resulting in
the R-anomeric product, similar to the previously studied
NaOMe as the nucleophile. (iii) The NaBH4-mediated reduction
of diketone intermediates of the R-anomers was diastereose-
lective, whereas the ꢀ-anomers led to an epimeric mixture of
diols in case of aryl septanosides. The diketone intermediate of
the ꢀ-anomer of azido septanoside afforded a diastereoselective
product upon reduction. The previously established ring-
expansion reaction of the pyranosides to septanosides proved
to be a reiterative method to synthesize aryl septanosides,
disaccharides, and azido septanosides.
General Procedure for the Synthesis of Chloro-oxepine (3).
To a stirred solution of 2 (1 mmol), K2CO3 (20 mmol), and 18-
C-6 (cat.) in PhMe (20 mL) was added phenol (5 mmol), and the
mixture was refluxed for 48-72 h. The reaction mixture was filtered
through basic alumina using hexane/EtOAc (1:1), and solvents were
removed in vacuo to afford an anomeric mixture of the chloro-
oxepine derivatives 3. The crude chloro-oxepine was subjected
immediately to the next reaction without further purification.
Phenyl 2-Chloro-2-deoxy-3,4,5,7-tetra-O-benzyl-r/ꢀ-D-ara-
bino-hept-2-enoseptanoside 3. (R1, R2 ) H) Isolated as a mixture
of isomers. Colorless oil; Rf 0.47 (hexane/EtOAc ) 9:1); 1H NMR
(300 MHz, CDCl3) δ 7.36-7.12 (m, 50H), 5.99 (s, 1H), 5.68 (s,
1H), 4.82-4.61 (m, 6H), 4.55-4.45 (m, 5H), 4.42-4.23 (m, 9H),
3.91 (dd, J ) 8.1, 2.4 Hz, 1H), 3.82-3.73 (m, 1H), 3.65 (dd, J )
8.1, 2.1 Hz, 1H), 3.60-3.51 (m, 2H), 3.42 (dd, J ) 10.5, 3.3 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 157.7, 157.4, 153.6, 153.2,
138.1, 138.0, 137.7, 137.3, 136.9, 136.8, 129.7, 129.4, 129.3, 128.9,
128.4, 127.9, 127.3, 122.5, 121.3, 121.1, 120.6, 117.0, 115.3, 101.5,
98.7, 80.0, 79.9, 78.2, 73.4, 73.1, 72.5, 72.3, 72.2, 71.4, 71.2, 71.1,
70.8, 70.2; HRMS m/z C41H39ClO6Na calcd 685.2333, found
685.2330.
General Procedure for Synthesis of Aryl 4,5,7-Tri-O-benzyl-
r/ꢀ-D-glycero-D-galacto/ido/talo-septanoside (4-8). To a stirred
solution of chloro-oxepine (3) (1 mmol) in MeCN/EtOAc (25 mL,
1:1) a solution of RuCl3 ·3H2O (0.07 mmol) and NaIO4 (1.3 mmol)
in water (5 mL) dropwise at 0 °C. After stirring (1-4 h) at room
temperature, the reaction mixture was diluted with EtOAc (20 mL)
and CH2Cl2 (20 mL), filtered through a pad of silica gel, washed
with EtOAc (2 × 30 mL), and the solvents were removed in vacuo.
The resulting residue was purified (hexane/EtOAc ) 3:2) to afford
2,3-diketo derivative as an anomeric mixture. Overall yield:
70-76% (2 steps).
(27) (a) Staudinger, H.; Meyer, J. HelV. Chim. Acta 1919, 2, 635–646. (b)
Vaultier, M.; Knouzi, N.; Carrie´, R. Tetrahedron Lett. 1983, 24, 763–764.
J. Org. Chem. Vol. 74, No. 2, 2009 743

Ganesh and Jayaraman
To a solution of the 2,3-diketo derivative (1 mmol) in MeOH (6
mL) was added NaBH4 (5 mmol) was added at 0 °C, stirred for
2 h. Solvents were removed in vacuo, the resulting residue was
dissolved in EtOAc (30 mL), washed with brine (20 mL), dried
(Na2SO4), and concentrated in vacuo, and the crude product was
purified (hexane/EtOAc ) 3:2) to afford the diols 4-8.
Phenyl 4,5,7-Tri-O-benzyl-r-D-glycero-D-galacto-septanoside
(4r). Isolated as a single isomer. Colorless oil; Rf 0.44 (hexane/
EtOAc ) 7:3); [R]24D +56.6 (c 0.7, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.41-7.01 (m, 20H), 5.73 (d, J ) 4.3 Hz, 1H), 4.83-4.75
(m, 2H), 4.46-4.39 (m, 2H), 4.38-4.36 (m, 1H), 4.30-4.19 (m,
3H), 4.12-4.08 (m, 2H), 3.78 (dd, J ) 9.5, 9.4 Hz, 1H), 3.49 (dd,
J ) 10.5, 4.1 Hz, 1H), 3.32 (dd, J ) 10.5, 2.3 Hz, 1H), 2.81 (br s,
1H), 2.47 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 156.3, 138.4,
138.1, 137.7, 129.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.8, 127.7,
127.4, 122.7, 116.5, 96.6, 80.5, 77.7, 73.5, 73.0, 72.8, 71.1, 70.5,
70.2, 70.1; HRMS m/z C34H36O7Na calcd 579.2359, found 579.2370.
Phenyl 4,5,7-Tri-O-benzyl-ꢀ-D-glycero-D-ido/talo-septanoside
(4ꢀ). Isolated as a mixture of isomers. Amorphous solid; Rf 0.35
(hexane/EtOAc ) 7:3); 1H NMR (400 MHz, CDCl3) (C-3 epimeric
ratio, 1.3:1.0) δ 7.36-7.19 (m, 41.4H), 7.05-6.98 (m, 4.6H), 5.53
(app.s, 1.3H), 5.39 (s, 1H), 4.64-4.36 (m, 13.5H), 4.20-4.07 (m,
8.5H), 3.96-3.92 (m, 2.5H), 3.85 (dd, J ) 5.6, 2.4 Hz, 1.3H), 3.68
(d, J ) 4.8 Hz, 1H), 3.64-3.54 (m, 4.6H), 3.46 (dd, J ) 7.8, 7.2
Hz, 1.3H), 3.29 (d, J ) 8.7 Hz, 1H), 3.17 (d, J ) 10.7 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 156.8, 156.7, 137.9, 137.8, 137.3,
137.1, 136.8, 129.5, 128.6, 128.5, 128.4, 128.2, 128.1, 128.0, 127.9,
127.8, 127.7, 122.6, 122.4, 117.1, 116.9, 98.9, 98.6, 84.6, 81.2,
80.7, 80.3, 79.2, 76.8, 76.0, 75.4, 74.8, 74.2, 73.6, 73.4, 73.3, 72.1,
71.2, 70.9, 70.7, 67.5; HRMS m/z C34H36O7Na calcd 579.2359,
found 579.2360.
p-Tolyl 4,5,7-Tri-O-benzyl-r-D-glycero-D-galacto-septanoside
(5r). Isolated as a single isomer. Colorless oil; Rf 0.47 (hexane/
EtOAc ) 7:3); [R]24D -3.9 (c 1.00, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 7.43-6.96 (m, 19H), 5.68 (d, J ) 4.5 Hz, 1H), 4.83-4.74
(m, 2H), 4.47-4.40 (m, 2H), 4.37-4.32 (m, 1H), 4.31-4.16 (m,
3H), 4.12-4.08 (m, 2H), 3.77 (dd, J ) 9.6, 9.5 Hz, 1H), 3.49 (dd,
J ) 10.5, 4.2 Hz, 1H), 3.33 (dd, J ) 10.6, 2.1 Hz, 1H), 2.80 (br s,
1H), 2.48 (br s, 1H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
154.3, 138.4, 138.2, 137.9, 132.1, 130.0, 128.4, 128.2, 127.8, 127.5,
117.0, 116.4, 96.9, 80.6, 77.8, 73.6, 73.1, 72.9, 71.2, 70.5, 70.2,
20.6; HRMS m/z C35H38O7Na calcd 593.2515, found 593.2515.
p-tert-Butyl Phenyl 4,5,7-Tri-O-benzyl-ꢀ-D-glycero-D-ido/talo-
septanoside (6ꢀ). Isolated as a mixture of isomers. Amorphous
solid; Rf 0.53 (hexane/EtOAc ) 7:3); 1H NMR (400 MHz, CDCl3)
(C-3 epimeric ratio, 1.7:1.0) δ 7.33-7.20 (m, 46H), 6.99-6.92 (m,
5.4H), 5.48 (s, 1.7H), 5.35 (s, 1H), 4.62-4.37 (m, 17.3H),
4.19-4.07 (m, 9.2H), 3.94 (br s, 2H), 3.85-3.82 (m, 1.6H),
3.67-3.44 (m, 7.5H), 3.31-3.19 (m, 3H), 1.28 (s, 24.3H); 13C NMR
(100 MHz, CDCl3) δ 154.7, 145.2, 137.9, 137.2, 137.0, 129.8,
128.6, 128.4, 128.1, 127.9, 126.3, 125.2, 116.6, 116.4, 99.2, 99.0,
84.6, 81.1, 80.4, 79.1, 75.9, 75.6, 74.8, 74.3, 73.7, 73.5, 72.1, 71.4,
71.2, 70.9, 67.7, 65.6, 34.2, 31.5; HRMS m/z C38H44O7Na calcd
635.2985, found 635.3000.
o-Tolyl 4,5,7-Tri-O-benzyl-r-D-glycero-D-galacto-septanoside
(7r). Isolated as a single isomer. Colorless oil; Rf 0.43 (hexane/
EtOAc ) 7:3); [R]24D +36.0 (c 1.00, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 7.43-6.89 (m, 19H), 5.72 (d, J ) 3.9 Hz, 1H), 4.84-4.74
(m, 2H), 4.49-4.25 (m, 6H), 4.09-4.04 (m, 2H), 3.82 (dd, J )
9.6, 9.3 Hz, 1H), 3.49 (dd, J ) 10.5, 3.9 Hz, 1H), 3.32 (dd, J )
10.5, 2.4 Hz, 1H), 2.23 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
154.4, 138.4, 138.1, 137.9, 130.8, 128.3, 128.2, 128.1, 127.9, 127.7,
127.1, 126.8, 122.3, 114.4, 96.5, 80.8, 73.5, 73.1, 73.0, 71.3, 70.8,
70.3, 16.3; HRMS m/z C35H38O7Na calcd 593.2515, found 593.2527.
o-Tolyl 4,5,7-Tri-O-benzyl-ꢀ-D-glycero-D-ido/talo-septanoside
(7ꢀ). Isolated as a mixture of isomers. Colorless oil; Rf 0.30 (hexane/
1
EtOAc ) 7:3); H NMR (300 MHz, CDCl3) (C-3 epimeric ratio,
3.3:1.0) δ 7.31-6.92 (m, 82H), 5.45 (s, 3.3H), 5.31 (s, 1H),
4.62-4.36 (m, 30H), 4.16-4.03 (m, 11.1H), 3.97-3.84 (m, 8.5H),
3.69-3.54 (m, 7.5H), 3.49-3.44 (m, 1H), 3.32 (br s, 2.5H), 3.18
(d, J ) 10.2 Hz, 3.5H), 2.27 (s, 13H); 13C NMR (75 MHz, CDCl3)
δ 155.2, 137.9, 137.8, 137.3, 137.2, 136.9, 130.9, 130.7, 128.6,
128.5, 128.4, 127.9, 127.8, 127.6, 127.2, 126.9, 126.8, 122.7, 122.6,
115.9, 115.8, 99.9, 99.6, 81.1, 80.3, 79.1, 76.0, 74.4, 74.3, 73.7,
73.6, 73.5, 73.4, 73.3, 71.5, 71.3, 70.7, 70.6, 16.4; HRMS m/z
C35H38O7Na calcd 593.2515, found 593.2513.
o-Methoxy Phenyl 4,5,7-Tri-O-benzyl-r-D-glycero-D-galacto-
septanoside (8r). Isolated as a single isomer. White foam; Rf 0.50
1
(hexane/EtOAc ) 3:2); [R]24 +23.4 (c 1.00, CHCl3); H NMR
D
(400 MHz, CDCl3) δ 7.44-6.69 (m, 19H), 5.42 (d, J ) 4 Hz, 1H),
4.88-4.75 (m, 2H), 4.52-4.39 (m, 3H), 4.37-4.32 (m, 1H),
4.29-4.21 (m, 2H), 4.18-4.09 (m, 2H), 3.83 (s, 3H), 3.63-3.49
(m, 4H), 3.07 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 150.3,
146.8, 138.5, 138.1, 137.7, 128.6, 128.3, 128.2, 128.1, 127.9, 127.8,
127.6, 127.5, 124.2, 121.3, 120.1, 111.5, 101.2, 79.7, 78.3, 73.6,
73.1, 72.3, 71.1, 70.4, 70.0, 55.6; HRMS m/z C35H38O8Na calcd
609.2464, found 609.2455.
p-Tolyl 4,5,7-Tri-O-benzyl-ꢀ-D-glycero-D-ido/talo-septanoside
(5ꢀ). Isolated as a mixture of isomers. White foam; Rf 0.35 (hexane/
1
EtOAc ) 7:3); H NMR (400 MHz, CDCl3) (C-3 epimeric ratio,
o-Methoxy Phenyl 4,5,7-Tri-O-benzyl-ꢀ-D-glycero-D-talo-sep-
tanoside (8ꢀ). Isolated as a single isomer. White solid; mp 101
°C; Rf 0.26 (hexane/EtOAc ) 3:2); [R]24D -41.3 (c 1.00, CHCl3);
1H NMR (300 MHz, CDCl3) δ 7.34-6.78 (m, 19H), 5.38 (s, 1H),
4.56-4.25 (m, 7H), 4.13 (br s, 1H), 4.05-4.00 (m, 2H), 3.89-3.74
(m, 4H), 3.61-3.52 (m, 2H), 3.42 (dd, J ) 7.5, 7.2 Hz, 1H), 3.19
(br s, 1H); 13C NMR (75 MHz, CDCl3) δ 150.9, 145.7, 137.9, 137.5,
137.3, 128.6, 128.5, 128.4, 128.1, 127.9, 127.8, 120.8, 112.4, 99.9,
84.6, 81.2, 75.7, 74.8, 73.2, 72.0, 70.9, 67.9, 55.9; HRMS m/z
C35H38O8Na calcd 609.2464, found 609.2460.
General Procedure for the Synthesis of Aryl r/ꢀ-D-glycero-
D-galacto/ido/talo-septanosides (9-13). To a solution of the diols
4-8 (0.17 mmol) in EtOAc/MeOH (1:1, 25 mL) Pd/C (10%, 0.030
g) was added, and the mixture was stirred under a positive pressure
of hydrogen gas for 15 h. The reaction mixture was filtered over a
celite pad and washed with MeOH (3 × 20 mL), and solvents were
removed in vacuo to afford aryl septanosides 9-13. Yield:
93-98%.
1.5:1.0) δ 7.32-7.07 (m, 38H), 7.04-6.89 (m, 10H), 5.47 (s, 1.5H),
5.38 (s, 1H), 4.59-4.35 (m, 13.5H), 4.19-4.06 (m, 9H), 3.96-3.93
(m, 3H), 3.83 (dd, J ) 5.4, 2.4 Hz, 1H), 3.70 (d, J ) 3.6 Hz, 1.5H),
3.65-3.53 (m, 5H), 3.45 (dd, J ) 7.5, 7.2 Hz, 1.5H), 3.29 (d, J )
7.5 Hz, 1H), 3.19-3.17 (m, 1H), 2.28 (s, 8H); 13C NMR (100 MHz,
CDCl3) δ 154.7, 154.6, 137.9, 137.8, 137.3, 137.1, 136.8, 131.9,
131.8, 129.9, 128.6, 128.5, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8,
127.7, 127.6, 117.1, 116.9, 99.3, 98.9, 84.5, 81.1, 80.7, 80.3, 79.2,
76.8, 75.9, 75.5, 74.8, 74.2, 73.6, 73.4, 73.3, 72.0, 71.3, 71.0, 70.7,
67.5, 20.6, 20.5; HRMS m/z C35H38O7Na calcd 593.2515, found
593.2515.
p-tert-Butyl Phenyl 4,5,7-Tri-O-benzyl-r-D-glycero-D-galacto-
septanoside (6r). Isolated as a single isomer. Colorless oil; Rf 0.61
1
(hexane/EtOAc ) 7:3); [R]24 +46.1 (c 1.00, CHCl3); H NMR
D
(300 MHz, CDCl3) δ 7.45-7.01 (m, 19H), 5.68 (d, J ) 3.9 Hz,
1H), 4.84-4.74 (m, 2H), 4.45-4.32 (m, 3H), 4.28-4.18 (m, 3H),
4.13-4.07 (m, 2H), 3.77 (dd, J ) 9.6, 9.3 Hz, 1H), 3.50 (dd, J )
10.2, 3.9 Hz, 1H), 3.35 (dd, J ) 10.5, 2.1 Hz, 1H), 2.83 (br s, 1H),
2.46 (br s, 1H), 1.27 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 154.2,
145.5, 138.4, 138.2, 137.8, 128.4, 128.3, 128.2, 128.0, 127.9, 127.7,
127.4, 126.3, 116.0, 96.9, 80.4, 77.7, 73.5, 73.0, 72.8, 71.1, 70.4,
70.3, 70.1, 34.2, 31.4; HRMS m/z C38H44O7Na calcd 635.2985,
found 635.2972.
Phenyl r-D-Glycero-D-galacto-septanoside (9r). Colorless oil;
Rf 0.67 (CH3OH/CHCl3 ) 1:1); [R]24D +35.3 (c 1.00, MeOH); 1H
NMR (400 MHz, D2O) δ 7.32-7.25 (m, 2H), 7.04-6.96 (m, 3H),
5.55 (d, J ) 3.6 Hz, 1H), 4.17 (dd, J ) 7.6, 3.6 Hz, 1H), 4.13 (dd,
J ) 7.6, 2 Hz, 1H), 3.89-3.85 (m, 2H), 3.56 (dd, J ) 7.4, 7.3 Hz,
1H), 3.44-3.43 (m, 2H); 13C NMR (100 MHz, D2O) δ 156.0, 129.8,
744 J. Org. Chem. Vol. 74, No. 2, 2009

Synthesis of Aryl, Glycosyl, and Azido- Septanosides
122.9, 117.0, 95.9, 74.1, 73.1, 71.1, 70.5, 70.4, 62.1; HRMS m/z
C13H18O7Na calcd 309.0950, found 309.0948.
(c 1.00, MeOH); 1H NMR (400 MHz, D2O) δ 7.15 (d, J ) 8.8 Hz,
1H), 7.04-7.00 (m, 2H), 6.92-6.89 (m, 1H), 5.50 (d, J ) 3.2 Hz,
1H), 4.23 (dd, J ) 7.2, 3.2 Hz, 1H), 4.17 (dd, J ) 7.2, 2.4 Hz,
1H), 3.96-3.90 (m, 2H), 3.76 (s, 3H), 3.59 (dd, J ) 8.0, 7.6 Hz,
1H), 3.48-3.47 (m, 2H); 13C NMR (100 MHz, D2O) δ 151.1, 146.2,
126.7, 124.0, 121.1, 115.7, 99.4, 76.3, 75.9, 73.9, 73.3, 72.5, 64.5,
58.3; HRMS m/z C14H20O8Na calcd 339.1056, found 339.1051.
o-Methoxy Phenyl ꢀ-D-Glycero-D-talo-septanoside (13ꢀ). White
foam; Rf 0.40 (CH3OH/CHCl3 ) 1:4); [R]24D +8.4 (c 1.00, MeOH);
1H NMR (400 MHz, D2O) δ 7.07-6.93 (m, 4H), 5.29 (app.s, 1H),
4.28 (br s, 1H), 4.09 (br s, 1H), 3.96-3.86 (m, 1H), 3.79-3.50
(band, 6H), 3.39 (br s, 1H); 13C NMR (100 MHz, D2O) δ 150.8,
146.3, 125.6, 122.7, 119.7, 114.5, 103.1, 83.6, 79.0, 75.2, 72.1,
70.4, 64.2, 57.2; HRMS m/z C14H20O8Na calcd 339.1056, found
339.1051.
General Procedure for the Synthesis of Chloro-oxepine 15
and 18. To a stirred solution of 2 (1 mmol), K2CO3 (10 mmol),
and 18-C-6 (cat.) in PhMe (20 mL) was added sugar alcohol 14/17
(2 mmol). Then the reaction mixture was refluxed for 72-74 h,
and solvents were removed in vacuo. The resulting residue was
purified (hexane/EtOAc ) 9:1) to afford chloro oxepine derivatives
15 (58%)/18 (63%).
Methyl-O-(2-chloro-2-deoxy-3,4,5,7-tetra-O-benzyl-r-D-ara-
bino-hept-2-eno septanosyl)-(1f5)-2,3-di-O-benzyl-r-D-arabino-
furanoside (15). Isolated as a single isomer. Colorless oil; Rf 0.38
(hexane/EtOAc ) 8:2); 1H NMR (300 MHz, CDCl3) δ 7.32-7.05
(m, 30H), 5.42 (s, 1H), 4.92 (s, 1H), 4.71 (dd, J ) 12.5, 11.5 Hz,
2H), 4.59-4.41 (m, 9H), 4.31-4.18 (m, 4H), 4.04-3.93 (m, 3H),
3.77-3.70 (m, 2H), 3.59-3.48 (m, 2H), 3.35 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 152.8, 138.2, 138.0, 137.8, 137.6, 137.3, 136.8,
128.3, 128.2, 127.9, 127.8, 127.6, 127.5, 122.2, 107.2, 99.7, 88.3,
83.7, 80.6, 80.4, 72.9, 72.4, 72.3, 72.0, 71.8, 71.4, 71.2, 70.6, 67.8,
54.9; HRMS m/z C55H57ClO10Na calcd 935.3538, found 935.3529.
Methyl-O-(2-chloro-2-deoxy-3,4,5,7-tetra-O-benzyl-r-D-ara-
bino-hept-2-eno septanosyl)-(1f6)-2,3,4-tri-O-benzyl-r-D-gluco-
pyranoside (18). Isolated as a single isomer. Colorless oil; Rf 0.30
(hexane/EtOAc ) 8:2); 1H NMR (300 MHz, CDCl3) δ 7.37-7.04
(m, 35H), 5.52 (s, 1H), 4.95 (d, J ) 10.8 Hz, 1H), 4.86-4.74 (m,
2H), 4.69 (d, J ) 5.1 Hz, 6H), 4.64-4.52 (m, 4H), 4.43 (dd, J )
12.6, 12.0 Hz, 2H), 4.29 (d, J ) 11.7 Hz, 1H), 4.18 (d, J ) 11.6
Hz, 2H), 4.00-3.93 (m, 1H), 3.89-3.86 (m, 1H), 3.74-3.65 (m,
3H), 3.57-3.47 (m, 3H), 3.53 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 152.5, 140.8, 138.9, 138.3, 138.2, 137.8, 137.3, 136.8, 128.5,
128.4, 128.3, 128.2, 128.0, 127.7, 127.6, 127.5, 126.9, 122.6, 99.6,
97.9, 81.9, 80.6, 80.2, 77.9, 77.2, 75.7, 74.9, 73.4, 72.9, 72.3, 72.1,
71.1, 70.9, 70.7, 66.0, 65.4, 55.1; HRMS m/z C63H65ClO11Na calcd
1055.4113, found 1055.4108.
Phenyl ꢀ-D-Glycero-D-ido/talo-septanoside (9ꢀ). Isolated as a
mixture of isomers. White foam; Rf 0.47 (CH3OH/CHCl3 ) 2:3);
1H NMR (400 MHz, D2O) (C-3 epimeric ratio, 1.3:1.0) δ 7.27-7.22
(m, 4.6H), 7.00-6.92 (m, 7H), 5.32 (d, J ) 1.8 Hz, 2.3H), 4.15
(br s, 1.3H), 4.01 (br s, 1H), 3.89-3.78 (m, 3.2H), 3.68-3.62 (m,
3.1H), 3.58-3.45 (m, 6.2H), 3.23-3.28 (m, 1.3H); 13C NMR (100
MHz, D2O) δ 155.9, 131.2, 124.5, 124.4, 118.5, 118.3, 102.0, 101.2,
82.9, 81.9, 79.1, 75.6, 75.1, 74.6, 73.4, 72.2, 70.9, 64.2, 63.5; HRMS
m/z C13H18O7Na calcd 309.0950, found 309.0943.
p-Tolyl r-D-Glycero-D-galacto-septanoside (10r). White foam;
Rf 0.32 (CH3OH/CHCl3 ) 1:4); [R]24D +64.1 (c 1.00, MeOH); 1H
NMR (400 MHz, D2O) δ 7.17 (d, J ) 8 Hz, 2H), 7.03 (d, J ) 8.4
Hz, 2H), 5.61 (d, J ) 2.4 Hz, 1H), 4.25 (dd, J ) 7.6, 3.2 Hz, 1H),
4.22 (dd, J ) 7.6, 2 Hz, 1H), 3.99-3.96 (m, 2H), 3.67 (dd, J )
7.6, 7.2 Hz, 1H), 3.55-3.54 (m, 2H), 2.24 (s, 3H); 13C NMR (100
MHz, D2O) δ 156.4, 135.4, 132.7, 119.6, 98.7, 76.7, 75.7, 73.7,
73.0, 64.7, 22.1; HRMS m/z C14H20O7Na calcd 323.1107, found
323.1107.
p-Tolyl ꢀ-D-Glycero-D-ido/talo-septanoside (10ꢀ). Isolated as
a mixture of isomers. Colorless oil; Rf 0.31 (CH3OH/CHCl3 ) 1:4);
1H NMR (400 MHz, D2O) (C-3 epimeric ratio, 1.5:1.0) δ 7.18-7.16
(d, J ) 8 Hz, 5H), 6.96 (t, J ) 8 Hz, 5H), 5.36 (app.s, 2.5H), 4.25
(s, 1.5H), 4.12 (s, 1H), 3.95-3.90 (m, 3.5H), 3.81-3.73 (m, 3.7H),
3.66-3.59 (m, 5.5H), 3.45-3.40 (m, 2.3H), 2.24 (s, 7.5H); 13C
NMR (100 MHz, D2O) δ 155.6, 134.4, 131.4, 118.5, 118.2, 102.3,
101.5, 82.8, 81.8, 78.9, 75.6, 75.0, 74.3, 73.3, 72.0, 70.7, 64.1, 63.3,
20.8; HRMS m/z C14H20O7Na calcd 323.1107, found 323.1107.
o-Tolyl r-D-Glycero-D-galacto-septanoside (11r). White foam;
Rf 0.43 (CH3OH/CHCl3 ) 1:4); [R]24D +29.8 (c 1.00, MeOH); 1H
NMR (400 MHz, D2O) δ 7.19-7.06 (m, 3H), 6.96-6.89 (m, 1H),
5.56 (d, J ) 2.8 Hz, 1H), 4.21 (dd, J ) 7.2, 3.2 Hz, 1H), 4.17 (dd,
J ) 7.2, 1.6 Hz, 1H), 3.93-3.91 (m, 2H), 3.59 (dd, J ) 8.1, 8.0
Hz, 1H), 3.45-3.41 (m, 2H), 2.15 (s, 3H); 13C NMR (100 MHz,
D2O) δ 155.2, 132.5, 129.9, 128.3, 124.2, 116.9, 96.9, 75.1, 74.9,
72.5, 72.2, 71.4, 63.3, 16.7; HRMS m/z C14H20O7Na calcd 323.1107,
found 323.1103.
o-Tolyl ꢀ-D-Glycero-D-ido/talo-septanoside (11ꢀ). Isolated as
a mixture of isomers. Amorphous solid; Rf 0.40 (CH3OH/CHCl3
1
) 1:4); H NMR (400 MHz, D2O) (C-3 epimeric ratio, 3.3:1.0) δ
7.18-7.12 (m, 8.6H), 7.00-6.94 (m, 8.6H), 5.31 (app.s, 3.3H),
5.26 (s, 1H), 4.22 (br s, 1.5H), 4.03 (br s, 1H), 3.95-3.85 (m, 4.5H),
3.72-3.67 (m, 7.6H), 3.58-3.48 (m, 12H), 3.40-3.37 (m, 3.5H),
2.15(s, 12.9H); 13C NMR (100 MHz, D2O) δ 155.6, 155.4, 132.4,
130.4, 128.3, 124.6, 120.7, 117.7, 102.9, 101.9, 83.2, 82.0, 78.9,
75.8, 75.4, 75.2, 74.5, 73.2, 72.1, 70.7, 64.2, 63.4, 16.7; HRMS
m/z C14H20O7Na calcd 323.1107, found 323.1102.
General Procedure for the Synthesis of 16 and 19. To a stirred
solution of chloro-oxepine 15/18 (1 mmol) in MeCN/EtOAc (25
mL, 1:1) at 0 °C was added a solution of RuCl3 ·3H2O (0.07 mmol)
and NaIO4 (1.3 mmol) in water (5 mL) dropwise. After 10 h of
stirring at room temperature, the reaction mixture was diluted with
EtOAc (20 mL) and CH2Cl2 (20 mL), filtered through a pad of
silica gel, and washed with EtOAc (2 × 30 mL), and the solvents
were removed in vacuo. To the crude 2,3-diketo derivative in MeOH
(6 mL) at 0 °C was added NaBH4 (2 mmol), the mixture was stirred
for 3 h, and solvents were removed in vacuo. The resulting residue
was dissolved in EtOAc (30 mL), washed with brine (20 mL), dried
(Na2SO4), and concentrated in vacuo, and the crude product was
purified (hexane/EtOAc ) 3:2) to afford diol 16 (86%)/19 (77%).
Methyl-O-(4,5,7-tri-O-benzyl-r-D-glycero-D-galacto-septano-
syl)-(1f5)-2,3-di-O-benzyl-r-D-arabino-furanoside (16). Isolated
as a single isomer. Colorless oil; Rf 0.33 (hexane/EtOAc ) 6:4);
p-tert-Butyl Phenyl r-D-Glycero-D-galacto-septanoside (12r).
Colorless oil; Rf 0.65 (CH3OH/CHCl3 ) 3:7); [R]24D +81.7 (c 1.00,
1
MeOH); H NMR (400 MHz, D2O) δ 7.42 (d, J ) 8.7 Hz, 2H),
7.08 (d, J ) 8.7 Hz, 2H), 5.51 (d, J ) 3.3 Hz, 1H), 4.25 (dd, J )
7.6, 3.2 Hz, 1H), 4.21 (dd, J ) 7.6, 1.6 Hz, 1H), 3.99-3.95 (m,
2H), 3.66 (dd, J ) 7.6, 7.2 Hz, 1H), 3.55-3.54 (m, 2H), 1.25 (s,
9H);13C NMR (100 MHz, D2O) δ 156.4, 148.9, 129.2, 119.3, 98.7,
76.7, 75.6, 73.6, 73.0, 64.7, 36.1, 33.2; HRMS m/z C17H26O7Na
calcd 365.1576, found 365.1576.
p-tert-Butyl Phenyl ꢀ-D-Glycero-D-ido/talo-septanoside (12ꢀ).
Isolated as a mixture of isomers. White foam; Rf 0.44 (CH3OH/
CHCl3 ) 3:7); 1H NMR (400 MHz, D2O) (C-3 epimeric ratio, 1.7:
1.0) δ 7.47-7.45 (d, J ) 7.6 Hz, 5.4H), 7.05 (m, 5.4H), 5.43 (app.s,
2.7H), 4.30 (br s, 1H), 4.16 (br s, 1.7H), 3.99-3.94 (m, 2.8H),
3.82-3.65 (band, 11.7H), 3.48-3.43 (m, 1.7H), 1.29 (s, 24.3H);
13C NMR (100 MHz, D2O) δ 156.0, 148.8, 127.9, 118.3, 118.0,
102.2, 101.5, 82.8, 81.8, 79.0, 75.6, 75.0, 74.4, 73.3, 72.0, 70.8,
64.1, 63.3, 35.8, 31.9; HRMS m/z C17H26O7Na calcd 365.1576,
found 365.1570.
[R]24 +58.6 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ
D
7.40-7.10 (m, 25H), 5.01 (d, J ) 4.5 Hz, 1H), 4.95 (s, 1H), 4.80
(d, J ) 12.1 Hz, 1H), 4.69 (d, J ) 12.1 Hz, 1H), 4.54-4.40 (m,
6H), 4.35 (d, J ) 11.0 Hz, 1H), 4.11-4.08 (m, 2H), 4.01-3.92
(m, 6H), 3.84 (d, J ) 9.7 Hz, 1H), 3.67 (dd, J ) 12.4, 2.2 Hz,
1H), 3.49-3.43 (m, 3H), 3.35 (s, 3H), 3.17 (br s, 1H), 2.56 (br s,
o-Methoxy Phenyl r-D-Glycero-D-galacto-septanoside (13r).
Amorphous solid; Rf 0.43 (CH3OH/ CHCl3 ) 1:4); [R]24 +36.5
D
J. Org. Chem. Vol. 74, No. 2, 2009 745

Ganesh and Jayaraman
1H); 13C NMR (75 MHz, CDCl3) δ 138.6, 138.3, 137.7, 137.5,
136.9, 128.5, 128.4, 128.3, 128.2, 128.0, 127.9, 127.6, 127.5, 107.2,
99.8, 87.2, 83.1, 82.2, 79.7, 78.7, 73.5, 73.4, 73.3, 72.2, 72.1, 71.5,
70.9, 70.0, 69.6, 68.2, 54.7; HRMS m/z C48H54O11Na calcd
829.3564, found 829.3597.
was added a solution of RuCl3 ·3H2O (cat.) and NaIO4 (0.064 g,
0.297 mmol) in water (1 mL) dropwise. After 3 h of stirring at
room temperature, the reaction mixture was diluted with EtOAc
(10 mL) and CH2Cl2 (10 mL), filtered through a pad of silica gel,
and washed with EtOAc (2 × 20 mL), and the solvents were
removed in vacuo. To the crude 2,3-diketo derivative in MeOH (3
mL) at 0 °C was added NaBH4 (0.017 g, 0.455 mmol), the mixture
was stirred for 3 h, and solvents were removed in vacuo. The
resulting residue was dissolved in EtOAc (2 × 20 mL), washed
with brine (10 mL), dried (Na2SO4), and concentrated in vacuo,
and the crude product was purified (hexane/EtOAc ) 3:2) to afford
23r (0.064 g, 55%) and 23ꢀ (0.032 g, 28%).
Azido 4,5,7-Tri-O-benzyl-r-D-glycero-D-galacto-septanoside
(23r). Isolated as a single isomer. Colorless oil; Rf 0.44 (hexane/
EtOAc ) 7:3); [R]24D +59.5 (c 1.00, CHCl3); IR (neat) 3443, 3032,
2916, 2115, 1722, 1454, 1260, 1080, 737, 698; 1H NMR (400 MHz,
CDCl3) δ 7.34-7.12 (m, 15H), 5.57 (d, J ) 3 Hz, 1H), 4.78-4.56
(m, 4H), 4.47-4.41 (m, 2H), 4.34 (d, J ) 10.8 Hz, 1H), 4.10 (dd,
J ) 6.6, 1.5 Hz, 1H), 4.05-4.02 (m, 1H), 3.96 (dd, J ) 6.6, 3 Hz,
1H), 3.95-3.86 (m, 1H), 3.65 (d, J ) 3.4 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 138.0, 137.8, 137.7, 128.7, 128.5, 128.4, 128.3,
128.1, 127.9, 127.8, 127.6, 87.7, 80.9, 76.1, 74.2, 74.1, 73.7, 73.3,
71.1, 70.9, 70.6; HRMS m/z C28H31N3O6Na calcd 528.2111, found
528.2120.
Methyl-O-(4,5,7-tri-O-benzyl-r-D-glycero-D-galacto-septano-
syl)-(1f6)-2,3,4-tri-O-benzyl-r-D-gluco-pyranoside (19). Isolated
as a single isomer. Colorless oil; Rf 0.38 (hexane/EtOAc ) 6:4);
[R]24 +55.3 (c 1.00, CHCl3); 1H NMR (300 MHz, CDCl3) δ
D
7.38-7.05 (m, 30H), 5.04 (d, J ) 4.2 Hz, 1H), 4.96 (d, J ) 11
Hz, 1H), 4.84-4.73 (m, 6H), 4.68 (d, J ) 6.6 Hz, 1H), 4.63-4.52
(m, 2H), 4.47-4.29 (m, 3H), 4.15-3.94 (m, 7H), 3.74-3.67(m,
2H), 3.55-3.41(m, 4H), 3.34 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 138.6, 138.5, 138.2, 138.1, 137.8, 128.5, 128.4, 128.3, 128.2,
128.0, 127.9, 127.7, 127.6, 127.4, 98.7, 97.9, 81.9, 80.1, 80.0, 78.0,
77.2, 75.7, 74.9, 73.5, 73.3, 73.1, 72.6, 71.2, 71.1, 70.3, 70.2, 69.6,
67.5, 55.3; HRMS m/z C56H62O12Na calcd 949.4139, found
949.4130.
General Procedure for the Synthesis of Disaccharides 20
and 21. To a solution of the diols 16/19 (0.062 mmol) in MeOH
(15 mL) was added Pd/C (10%, 0.020 g), and the mixture was
stirred under a positive pressure of hydrogen gas for 20 h. The
reaction mixture was filtered over a celite pad and washed with
MeOH (3 × 20 mL), and solvents were removed in vacuo to afford
disaccharides 20 (96%) and 21 (98%).
Methyl-O-(r-D-glycero-D-galacto-septanosyl)-(1f5)-r-D-ara-
bino-furanoside (20). White foam; Rf 0.50 (MeOH/CHCl3 ) 1:1);
[R]24D +116.1 (c 1.00, MeOH); 1H NMR (400 MHz, D2O) δ 4.75
(d, J ) 3.0 Hz, 1H), 4.73 (s, 1H), 4.00-3.96 (m, 1H), 3.92 (d, J
) 6.9 Hz, 1H), 3.88-3.82 (m, 4H), 3.74-3.67 (m, 2H), 3.64-3.59
(m, 2H), 3.54 (dd, J ) 6.8, 6.4 Hz, 1H), 3.45 (t, J ) 8.4 Hz, 1H),
3.19 (s, 3H); 13C NMR (75 MHz, D2O) δ 109.4, 97.9, 83.7, 81.4,
77.4, 74.5, 74.1, 72.2, 71.7, 70.7, 68.1, 62.9, 55.8; HRMS m/z
C13H24O11Na calcd 379.1216, found 379.1201.
Azido 4,5,7-Tri-O-benzyl-ꢀ-D-glycero-D-talo-septanoside (23ꢀ).
Isolated as a single isomer. Colorless oil; Rf 0.38 (hexane/EtOAc
) 7:3); [R]24D +22.7 (c 1.00, CHCl3); IR (neat) 3447, 3033, 2917,
1
2115, 1722, 1455, 1260, 1079, 737, 698; H NMR (400 MHz,
CDCl3) δ 7.37-7.12 (m, 15H), 5.03 (app.s, 1H), 4.62-4.42 (m,
6H), 4.22-4.18 (m, 1H), 4.16-4.14 (m, 1H), 4.05-3.99 (m, 2H),
3.96 (br s, 1H), 3.69 (dd, J ) 9.6, 6.5 Hz, 1H), 3.52 (dd, J ) 9.5,
6.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 137.8, 136.6, 136.3,
128.6, 128.5, 128.4, 128.2, 128.0, 127.8, 127.7, 87.8, 81.6, 79.9,
79.2, 77.7, 73.6, 73.5, 72.9, 70.9, 70.5; HRMS m/z C28H31N3O6Na
calcd 528.2111, found 528.2123.
Synthesis of Amino 4,5,7-Tri-O-benzyl-r-D-glycero-D-galacto-
septanose (24). To a stirred solution of 23r (0.040 g, 0.079 mmol)
in THF/H2O (4 mL, 4:1) at room temperature was added PPh3
(0.083 g, 0.316 mmol). Then the mixture was stirred for 36 h, and
solvents were removed in vacuo. The resulting residue was purified
(CHCl3/MeOH ) 4:1) to afford 24 (0.024 g, 64%) as a colorless
oil; [R]24D +18.1 (c 1.00, CHCl3); IR (neat) 3361, 3059, 2919, 1725,
1445, 1162, 1119, 722, 696; 1H NMR (300 MHz, CDCl3) δ
7.54-7.26 (m, 15H), 4.84-4.35 (m, 8H), 4.13-3.81 (m, 4H),
3.69-3.54 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 138.4, 138.1,
137.8, 133.6, 133.2, 132.1, 128.7, 128.5, 128.4, 128.2, 128.1, 127.9,
127.8, 127.6, 78.4, 78.1, 74.4, 74.2, 74.1, 73.4, 71.3, 71.2, 70.1,
69.9; HRMS m/z C28H33NO6Na + H calcd 503.2284, found
503.2262; m/z C56H63NO12Na + H calcd 965.4326, found 965.4371.
Methyl-O-(r-D-glycero-D-galacto-septanosyl)-(1f6)-r-D-gluco-
pyranoside (21). White foam; Rf 0.30 (MeOH/CHCl3 ) 1:1); [R]24
D
+117.3 (c 1.00, MeOH); 1H NMR (400 MHz, D2O) δ 4.73 (d, J )
2.8 Hz, 1H), 3.90-3.80 (m, 3H), 3.73 (d, J ) 8.0 Hz, 1H),
3.70-3.61 (m, 4H), 3.58-3.51 (m, 2H), 3.48-3.41 (m, 2H),
3.36-3.30 (m, 2H), 3.19 (s, 3H); 13C NMR (75 MHz, D2O) δ 100.6,
97.8, 75.3, 74.2, 72.6, 72.4, 72.3, 71.3, 70.6, 67.4, 63.2, 56.4; HRMS
m/z C14H26O12Na calcd 409.1322, found 409.1315.
Synthesis of Azido 2-Chloro-2-deoxy-3,4,5,7-tetra-O-benzyl-
r/ꢀ-D-arabino-hept-2-enoseptanoside (22). To a stirred solution
of 2 (0.102 g, 0.168 mmol) in DMF (2 mL) was added NaN3 (0.044
g, 0.674 mmol). Then the reaction mixture was heated to 75 °C
for 36 h, and solvents were removed in vacuo. The resulting residue
was purified (hexane/EtOAc ) 9:1) to afford 22 (0.095 g, 97%) as
a colorless oil. Isolated as a mixture of isomers. Rf 0.50 (hexane/
EtOAc ) 9:1); IR (neat) 3061, 3029, 2864, 2109, 1640, 1452, 1097,
1
1073, 736, 696; H NMR (400 MHz, CDCl3) (R:ꢀ ratio, 2:1) δ
Acknowledgment. We thank Department of Science and
Technology, New Delhi for a financial support. N.V.G. thanks
Council of Scientific and Industrial Research, New Delhi for a
research fellowship.
7.35-7.04 (m, 60H), 5.90 (s, 1H), 5.09 (s, 2H), 4.76-4.41 (m,
20H), 4.30-4.14 (m, 10H), 3.77 (dd, J ) 8.2, 2.1 Hz, 1H),
3.68-3.60 (m, 3H), 3.56-3.40 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ 153.8, 153.5, 138.0, 137.9, 137.5, 137.3, 136.9, 136.7,
136.4, 136.3, 128.5, 128.4, 128.3, 128.2, 128.1, 127.9, 127.8, 127.7,
127.6, 119.8, 119.5, 91.7, 91.2, 79.5, 78.3, 78.1, 76.2, 74.1, 73.4,
73.2, 72.5, 72.3, 72.2, 71.2, 70.8, 70.4, 70.1; HRMS m/z
C35H34ClN3O5Na calcd 634.2085, found 634.2085.
Supporting Information Available: General experimental
procedure, 1H and 13C NMR data and spectra of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Synthesis of Azido 4,5,7-Tri-O-benzyl-r/ꢀ-D-glycero-D-galacto/
talo-septanoside (23). To a stirred solution of azido chloro-oxepine
(22) (0.140 g, 0.229 mmol) in MeCN/EtOAc (4 mL, 1:1) at 0 °C
JO801967S
746 J. Org. Chem. Vol. 74, No. 2, 2009