Synthesis of septanosides through an oxyglycal route

Article abstract of DOI:10.1021/jo070444e

(Chemical Equation Presented) A new route to synthesize septanoside derivatives from protected 2-hydroxyglycals is reported. Ring expansion of a pyranoside to a septanoside was achieved through key reactions of a cyclopropanation, ring opening, oxidation,

Full text of DOI:10.1021/jo070444e

Synthesis of Septanosides through an Oxyglycal Route
N. Vijaya Ganesh and N. Jayaraman*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
jayaraman@orgchem.iisc.ernet.in
ReceiVed March 4, 2007
A new route to synthesize septanoside derivatives from protected 2-hydroxyglycals is reported. Ring
expansion of a pyranoside to a septanoside was achieved through key reactions of a cyclopropanation,
ring opening, oxidation, and reduction. Methyl septanoside derivatives, namely, methyl R-D-glycero-D-
talo-septanoside and methyl R-D-glycero-L-altro-septanoside, were synthesized in an overall yield of
35% and 46%, respectively, from the corresponding protected 2-hydroxy glycals.
Introduction
Villiger oxidation of inositol derivatives.10 We desired that
2-hydroxyglycals would form as suitable substrates for ring
expansion, leading to the formation of septanoside derivatives,
retained with hydroxyl groups in each carbon of the septanoside.
With this intention, we have explored a ring expansion reaction,
wherein a cyclic six-membered sugar derivative is converted
directly to a cyclic seven-membered sugar derivative, through
a methylene insertion, oxidation, and reduction reactions on
oxyglycal precursors. Syntheses of septanosides, starting from
oxyglycal derivatives of gluco-and galactopyranosides, are
presented herein.
The seven-membered cyclic sugar derivatives, namely, sep-
tanoses and septanosides, are less commonly known sugar
homologues.1 Studies of the acid-catalyzed formation of ac-
etonides from unsubstituted free sugars, by Stevens and co-
workers, have demonstrated the first instance of a preparative
method to isolate the septanoside derivatives.2 Synthesis of
cyclic seven-membered sugars, namely, septanoses, arise inter-
est, partly due to the desire to identify the configurational and
conformational features of septanoses, and the attendant pos-
sibilities to explore their chemical and biological properties.3
A few methods of septanoside formation are the following: (i)
hemiacetal or acetal formation from a linear precursor containing
aldehyde and appropriately positioned hydroxyl group;2,4,5 (ii)
pyridinium chloride mediated ring-opening of a protected
glucopyranoside;6 (iii) condensation of dialdehydes with active
methylene compounds;7 (iv) ring-closing metathesis reactions
of appropriately installed diene derivatives;8 (v) expansion of a
glycal via cyclopropanation and ring opening;9 and (vi) Baeyer-
Results and Discussion
(a) Synthesis of Methyl R-D-glycero-D-talo-Septanoside.
The synthesis was initiated from methyl 2,3,4,6-tetra-O-benzyl-
R-D-glucopyranoside (1). The O-benzyl-protected oxyglycal 4
was synthesized analogous to a procedure reported for the
corresponding O-acetyl- and O-benzoyl-protected oxyglycals.11
Acetolysis of the benzyl derivative 1, followed by treatment
with HBr/AcOH, led to the formation of bromide 2 (Scheme
(1) Collins, P. M.; Ferrier, R. J. Monosaccharides: Their Chemistry and
Their Roles in Natural Products; John Wiley & Sons: Chichester, UK,
1998; pp 40-42.
(8) (a) Ovaa, H.; Leeuwenburgh, M. A.; Overkleeft, H. S.; van der Marel,
G. A.; van Boom, J. H. Tetrahedron Lett. 1998, 39, 3025-3028. (b) Peczuh,
M. W.; Snyder, N. L. Tetrahedron Lett. 2003, 44, 4057-4061. (c) DeMatteo,
M. P.; Snyder, N. L.; Morton, M.; Hadad, C. M.; Peczuh, M. W. J. Org.
Chem. 2005, 70, 24-38. (d) Castro, S.; Fyvie, S.; Hatcher, S. A.; Peczuh,
M. W. Org. Lett. 2005, 21, 4709-4712. (e) DeMatteo, M. P.; Mei, S.;
Fenton, R.; Morton, M.; Hadad, C. M.; Peczuh, M. W. Carbohydr. Res.
2006, 341, 2927-2945.
(9) (a) Ramana, C. V.; Murali, R.; Nagarajan, M. J. Org. Chem. 1997,
62, 7694-7703. (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.
(10) (a) Chida, N.; Tobe, T.; Ogawa, S. Tetrahedron Lett. 1994, 35,
7249-7252. (b) Fukami, H.; Koh, H.-S.; Sakata, T.; Nakajima, M.
Tetrahedron Lett. 1968, 1701-1704.
(2) Stevens, J. D. Carbohydr. Res. 1972, 21, 490-492.
(3) For review on seven-membered-ring sugars, see: (a) Pakulski, Z.
Pol. J. Chem. 1996, 70, 667-707. (b) Pakulski, Z. Pol. J. Chem. 2006, 80,
1293-1326.
(4) Micheel, F.; Suckfu¨ll, F. Ann. Chem. 1933, 502, 85.
(5) Johnson, C. R.; Golebiowski, A.; Steensma, D. H. J. Am. Chem. Soc.
1992, 114, 9414-9418.
(6) Contour, M. O.; Fayet, C.; Gelas, J. Carbohydr. Res. 1990, 201, 150-
152.
(7) (a) Baschang, G. Ann. Chem. 1963, 663, 167. (b) Wolfrom, M. L.;
Nayak, U. G.; Radford, T. Proc. Natl. Acad. Sci. U.S.A. 1967, 58, 1848.
(c) Butcher, M. E.; Ireson, J. C.; Lee, J. B.; Tyler, M. J. Tetrahedron 1977,
33, 1501-1507.
10.1021/jo070444e CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/22/2007
5500
J. Org. Chem. 2007, 72, 5500-5504

Synthesis of Septanosides
their IR spectral frequencies at 1737 and 3417 cm-1, respec-
tively. Reduction of the keto functionality in 8 with use of
NaBH4 led to isolation of 9. The reduction occurred with high
stereoselectivity. Deprotection of the benzyl groups by hydro-
genolysis afforded D-glycero-D-talo-septanoside 10, in a good
yield (Scheme 3).
SCHEME 1
1
The anomeric proton in 10 resonated as a doublet in the H
NMR spectrum (4.52 ppm, J ) 6.5 Hz). On the other hand, the
H-3 proton resonated as a narrow doublet (3.97 ppm, J ) 1.5
Hz). The structural and stereochemical assignments were
performed further with the aid of HMQC and NOESY spectrum.
The C-1 nucleus in 10 resonated at 102.6 ppm. The R-config-
uration was confirmed on the basis of the observed anomeric
geminal C-H coupling constant (1JC1-H1) of 167.9 Hz, mea-
1
sured from the 13C coupled HMQC experiment. This JC1-H1
value agrees with that reported by Peczuh and co-workers,8c
for other septanoside derivatives. The through-space proximities
were identified by the presence of cross-peaks between the pair
H2-H4 and H2-H6 in the NOESY spectrum and these cross-
peaks indicated the distance between these protons to be ∼4
Å. From the J value of ∼1.5 Hz between H-2-H-3 and H-3-
H-4 protons, cis-relationships of the hydroxyl groups were
identified.
(b) Synthesis of Methyl R-D-glycero-L-altro-Septanoside
(16). Establishing the protocol for the D-glycero-D-talo-sep-
tanoside 10 warranted that the strategy be extended to the
corresponding galacto-derivative. However, as detailed below,
modification of the reaction protocol was required to suit
galactose. The vinyl ether synthon 11 was prepared according
to a known synthesis.11 Cyclopropanation of 11 was effective
only with dichlorocarbene and the dichloroadduct 12 was
obtained as a single isomer in a good yield. Reaction of 11
with dibromocarbene, as exercised in the case of the oxyglycal
4, was unsuccessful even after several attempts. Decomposition
of 11 was observed in the reaction. It is probable that the C-4
axial orientation of the substituent in 11 provides a facile
approach to less bulky dichlorocarbene than that to dibromocar-
bene. Solvolytic ring opening of 12 was carried out under a
reflux condition, using NaOMe in 1,4-dioxane, and the ring-
opened chloro-oxepine derivative 13 was obtained in an
excellent yield (Scheme 4).
The anomeric carbon in 13 exhibited a resonance at 101.9
ppm, whereas the olefinic carbons were ascertained from the
resonances 120.2 and 152.2 ppm in the 13C NMR spectrum.
Mass spectral analysis further confirmed the constitution of 13.
Introduction of oxygen functionalities at C-2 and C-3 in 13 was
attempted through dehalogenation and the epoxidation strategy,
as applied with the oxepine 7 in the gluco-derivative as described
above. However, the reactions were unsuccessful. After several
attempts to introduce the oxygen functionalities across the olefin
in 13, the RuO4-mediated oxidation17 was conducted and the
diketo derivative 14 was obtained in a moderate yield. The
appearance of a signal at 203 ppm in the 13C NMR spectrum
and the presence of a peak at 1740 cm-1 in the IR spectrum
confirmed the presence of keto groups in 14. The corresponding
absence of olefinic carbon signals was also confirmed for the
derivative 14. The mass spectrum of 14 indicated that one keto
group was retained in the hydrated form. Reduction of the ketone
(NaBH4/MeOH) led to the formation of diol 15 (Scheme 5).
1). Dehydrohalogenation of 2 was performed by using 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU)11 in DCE to obtain
2-hydroxyglucal 3, in an overall yield of 60%. The hydroxyg-
lycal ethers and esters are known in a number of reactions,12
including the cyclopropanation reaction.13 The acetate group in
3 was replaced with a benzyl protecting group, providing 2,3,4,6-
tetra-O-benzyl 1,5-anhydro-D-arabino-hex-1-enitol (4) (Scheme
1). Compounds 3 and 4 are obtained previously through different
synthetic procedures.13-15 Methylene insertion in 4 was con-
ducted by using dibromocarbene, prepared in situ by treatment
of CHBr3 with aq NaOH (50%) under phase transfer conditions,
and the dibromocyclo adduct 5 was obtained as a single
diastereomer. By following the rationale that bulky dibromocar-
bene would approach the olefin from a face less-hindered to
the C-3 benzyloxy group,9a the cyclopropyl group was assigned
to occupy an R-configuration at the anomeric center.
The cyclopropyl derivative 5 was subjected to methanolysis
(NaOMe/PhMe) and the fully functionalized oxepine 6 was
obtained in an excellent yield and only one anomer formed
exclusively. An R-configuration at the anomeric center of 6 was
assigned tentatively. It was desired to have a vinyl ether
derivative devoid of the halide moiety, so as to instal the
hydroxy groups at C-2 and C-3. Treatment of bromide 6 with
n-BuLi/THF and quenching with MeOH afforded oxepine 7,
in a good yield (Scheme 2).
With the observation that oxepine 7 was unstable for longer
periods, it was subjected immediately upon its preparation to
an oxidation with use of dimethyldioxirane.16 The epoxidation
reaction was efficient and, under the aqueous alkaline reaction
conditions, epoxide converted to the R-hydroxy ketone 8 in a
good yield. The presence of the newly formed functionalities,
namely, the keto and the hydroxyl groups, was identified from
(11) (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) Jones, G. S.; Scott, W. J. J. Am. Chem. Soc. 1992,
114, 1491-1492.
(12) For example: (a) Lichtenthaler, F. W.; Schwidetzky, S.; Nakamura,
K. Tetrahedron Lett. 1990, 31, 71-74. (b) Boettcher, A.; Lichtenthaler, F.
W. Tetrahedron: Asymmetry 2004, 15, 2693-2701.
(13) Storkey, C. M.; Win, A. L.; Hoberg, J. O. Carbohydr. Res. 2004,
339, 897-899.
(14) Lam, S. N.; Hague, J. G. Carbohydr. Res. 2002, 337, 1953-1965.
(15) (a) Jones, G. S.; Scott, W. J. J. Am. Chem. Soc. 1992, 114, 1491-
1492. (b) Chambers, D. J.; Evans, G. R.; Fairbanks, A. J. Tetrahedron 2004,
60, 8411-8419. (c) Chambers, D. J.; Evans, G. R.; Fairbanks, A. J.
Tetrahedron Lett. 2003, 44, 5221-5223.
(17) (a) Khan, F. A.; Dash, J.; Sudheer, Ch.; Sahu, N.; Parasuraman, K.
J. Org. Chem. 2005, 70, 7565-7577. (b) de Oliveira, L. F.; Costa, V. E.
U. Tetrahedron Lett. 2006, 47, 3565-3567.
(16) Murray, R.; Jeyaraman, R. J. Org. Chem. 1985, 50, 2847-2853.
J. Org. Chem, Vol. 72, No. 15, 2007 5501

Ganesh and Jayaraman
SCHEME 2
SCHEME 3
SCHEME 4
oxyglycal substrate, ring opening of cyclopropyl moiety, oxida-
tion, and reduction reactions are utilized to expand the six-
membered pyranoses to seven-membered septanosides. The
methodology is applied to obtain two configurationally different
septanosides, namely, the methyl R-D-glycero-D-talo-septanoside
and methyl R-D-glycero-L-altro-septanoside. The features of this
method are that the intermediates such as the seven-membered
vinyl halides, vinyl ethers, the diketones, and the diols are
potential sites for many other functionalizations, in principle.
These features will be explored further in functionalizing the
newly formed septanosides.
Experimental Section
6-O-Acetyl-2,3,4-tri-O-benzyl-R-D-glucopyranosyl bromide
(2). To a solution of 1 (4 g, 7.2 mmol) in AcOH:Ac2O medium
(1:1, 40 mL) was added concentrated H2SO4 (0.8 mL) dropwise at
0 °C then the solution was stirred at room temperature for 30 min,
diluted with water (100 mL), and extracted with CHCl3 (2 × 50
mL). The organic layer was washed with aq.NaHCO3 solution (3
× 150 mL) and water (2 × 100 mL), dried (Na2SO4), filtered, and
concentrated in vacuo. The residue was purified (hexane:EtOAc
) 8:2) to afford 1,6-di-O-acetyl-2,3,4-tri-O-benzyl-D-glucopyranose
(9:1, R:â mixture) (3.3 g, 86%) as a pale yellow oil. Rf 0.51 (7:3
hexane/EtOAc); HRMS m/z C31H34O8Na calcd 557.2151, found
557.2161. To a solution of 1,6-di-O-acetyl-2,3,4-tri-O-benzyl-D-
glucopyranose (2 g, 3.7 mmol) in DCE (25 mL) was added HBr/
AcOH (33%, 4.2 mL, 16.8 mmol) dropwise slowly at 0 °C, then
the solution was stirred for 10 min while warming to room
temperature, poured over ice, diluted, and extracted with CHCl3 (2
× 50 mL). The organic layer was washed with aq NaHCO3 solution
(2 × 50 mL) and water (2 × 50 mL), dried (Na2SO4), filtered, and
concentrated in vacuo. The bromo compound 2 was used as such
for the next step without further purification.
1,5-Anhydro-6-O-acetyl-2,3,4-tri-O-benzyl-D-arabino-hex-1-
enitol (3). To a solution of 6-O-acetyl-2,3,4-tri-O-benzyl-R-D-
glucopyranosyl bromide (2) (2.1 g, 3.7 mmol) in DCE (25 mL)
was added DBU (0.73 mL, 4.8 mmol) dropwise at -20 °C, then
the solution was stirred in the dark for 30 min and allowed to warm
to room temperature. The reaction mixture was diluted with CHCl3
(100 mL), washed with aq HCl (5%) (3 × 30 mL), water (2 × 50
mL), and aq NaHCO3 solution (2 × 50 mL), and dried (Na2SO4)
and the solvents were removed in vacuo. The crude product was
purified (hexane:EtOAc ) 8:2) to afford 3 (1.26 g, 71%) as a
colorless oil. Rf 0.57 (4:1 hexane/EtOAc); [R]D +12 (c 1.00, CHCl3);
1H NMR (300 MHz, CDCl3) δ 7.35-7.21 (m, 15H), 6.26 (s, 1H),
4.81-4.57 (m, 6H), 4.39-4.30 (m, 2H), 4.25 (d, J ) 4.8 Hz, 1H),
4.12-4.07 (m, 1H), 3.81 (dd, J ) 6.6, 4.8 Hz, 1H), 2.03 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 170.7, 139.2, 138.1, 137.5, 137.0,
128.4, 128.3, 127.9, 126.8, 75.1, 74.6, 73.9, 72.6, 72.5, 70.9, 62.5,
The reaction occurred with high selectivity and a single
diastereomer was obtained in a good yield. The O-benzyl groups
were deprotected in the final stage to secure the free hydroxyl
groups containing D-glycero-L-altro-septanoside derivative 16,
in an excellent yield.
The constitution and configuration of 16 were confirmed by
NMR spectroscopy and mass spectrometry. The structural
assignments were performed through heteronuclear multiple
quantum correlation (HMQC) and J-coupled correlation spec-
troscopy (COSY).
1
In the H NMR spectrum of 16, protons other than methyl
and H-1 protons appeared as three sets of multiplets, namely,
H-2 and H-3 (4.01-3.96 ppm), H-4, H-5 and H-6 (3.90-3.86
ppm), and H-7a and H-7b (3.59-3.50 ppm). A sharp doublet
at 4.73 ppm with a JH1-H2 value of 3 Hz indicated a cis-
relationship between H-1 and H-2. In the 13C NMR spectrum
of 16, anomeric carbon appeared at 100.1 ppm. Here again the
1JC1-H1 coupling value (1JC1-H1 ) 167.8 Hz) was measured by
utilizing 13C-coupled HMQC experiment, which proved further
the R-anomeric configuration. Since the resonances correspond-
1
ing to H-2 and H-3 protons in the H NMR spectrum of 16
were complex, the homonuclear decoupling experiments were
conducted further on the partially protected derivative 15.
Selective irradiation of H-1 in 15 eliminated the doublet of
doublet pattern of H-2 and the JH2-H3 value was identified to
be 6.7 Hz (Figure 1). Irradiations on appropriate protons led to
identifying the coupling constants JH1-H2 ) 3.9 Hz and JH3-H4
≈ 1 Hz. From these J values, the configurations were assigned
for C-1, C-2, and C-3, as presented in Scheme 5.
In conclusion, a new methodology is developed to prepare
unnatural septanoside derivatives. The carbene insertions of an
5502 J. Org. Chem., Vol. 72, No. 15, 2007

Synthesis of Septanosides
SCHEME 5
20.8; HRMS m/z C29H30O6Na calcd 497.1940, found 497.1960.
Compound 3 was converted to 413 by (i) de-O-acetylation under
Zemple´n condition and (ii) O-benzylation with use of BnBr in DMF,
in the presence of NaH.
2H), 4.52-4.41 (m, 2H), 4.33-4.13 (m, 4H), 3.72 (dd, J ) 8.4,
2.1 Hz, 1H), 3.62-3.56 (m, 1H), 3.52-3.51 (m, 1H), 3.49 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 154.2, 138.2, 137.7, 137.2, 136.6,
128.4, 128.3, 128.0, 127.8, 127.7, 127.5, 114.3, 101.1, 80.3, 77.3,
73.0, 72.1, 72.0, 71.3, 71.2, 70.7, 56.3; HRMS m/z C36H37BrO6Na
calcd 667.1671, found 667.1672.
1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1,2-C-(dibromomethylene)-
R-D-glycero-D-galacto-hexitol (5). To a solution of 4 (0.192 g, 0.367
mmol) and benzyltriethylammonium chloride (cat.) in CHBr3 (1
mL) was added aq NaOH (50%, 1 mL) then the solution was stirred
for 15 min, diluted with brine solution (20 mL), and extracted with
CH2Cl2 (3 × 20 mL). The combined organic extracts were dried
(Na2SO4) and concentrated in vacuo. The resulting residue was
purified (hexane:EtOAc ) 9:1) to afford 5 (0.21 g, 81%) as a pale
yellow oil. Rf 0.57 (9:1 hexane/EtOAc); [R]D +47 (c 1.00, CHCl3);
1H NMR (300 MHz, CDCl3) δ 7.43-7.19 (m, 20H), 4.95-4.88
(m, 3H), 4.68-4.59 (m, 3H), 4.44 (d, J ) 11.7 Hz, 1H), 4.31 (d,
J ) 11.7 Hz, 1H), 4.19-4.05 (m, 2H), 4.02 (s, 1H), 3.92-3.89
(m, 1H), 3.61 (dd, J ) 10.5, 3.1 Hz, 1H), 3.47 (dd, J ) 10.5, 3.1
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 138.1, 138.0, 137.6, 137.4,
128.4, 128.3, 128.1, 128.0, 127.8, 127.7, 127.6, 126.9, 80.7, 79.0,
74.5, 73.9, 73.5, 72.7, 71.0, 70.6, 64.3, 64.0, 42.6; HRMS m/z
C35H34Br2O5Na calcd 715.0671, found 715.0692.
Methyl 2-deoxy-3,4,5,7-tetra-O-benzyl-R-D-arabino-hept-2-
enoseptanoside (7). n-BuLi (1.6 M, 0.1 mL, 1.1 mmol) was added
dropwise to a solution of 6 (0.060 g, 0.093 mmol) in THF (5 mL)
at -78 °C. After 4 h, the reaction mixture was quenched by
dropwise addition of MeOH (2 mL), solvents were removed in
vacuo, and the resulting residue was diluted with EtOAc (20 mL),
washed with water (2 × 20 mL), dried (Na2SO4), filtered, and
concentrated in vacuo. The residue was purified (hexane:EtOAc
) 9:1) to afford 7 (0.045 g, 85%) as a colorless oil. Rf 0.40 (9:1
1
hexane/EtOAc); [R]D +21 (c 1.00, CHCl3); H NMR (300 MHz,
CDCl3) δ 7.37-7.11 (m, 20H), 5.38 (s, 1H), 4.78-4.58 (m, 5H),
4.51-4.39 (m, 3H), 4.21 (d, J ) 11.1 Hz, 1H), 4.13-4.08 (m,
2H), 3.68 (dd, J ) 9, 1.5 Hz, 1H), 3.65-3.59 (m, 1H), 3.56-3.51
(m, 1H), 3.42 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 156.2, 138.5,
138.1, 137.6, 136.5, 128.4, 128.3, 128.1, 128.0, 127.9, 127.7, 127.6,
127.5, 127.4, 100.2, 100.1, 80.4, 79.2, 77.3, 72.8, 71.6, 71.1, 70.9,
69.5, 55.0; HRMS m/z C36H38O6Na calcd 589.2566, found 589.2584.
Methyl 4,5,7-tri-O-benzyl-R-D-manno-sept-3-uloside (8). To
a stirred solution of oxepine 7 (0.040 g, 0.071 mmol) in acetone (4
mL) was added aq NaHCO3 (0.031 g in 1 mL water) at 0 °C. After
10 min, Oxone (0.114 g, 0.185 mmol) was added in portion, and
the reaction mixture was stirred for 10 h at room temperature,
diluted with EtOAc (15 mL), washed with water (2 × 20 mL),
dried (Na2SO4), concentrated in vacuo, and purified (hexane:EtOAc
Methyl 2-bromo-2-deoxy-3,4,5,7-tetra-O-benzyl-R-D-arabino-
hept-2-enoseptanoside (6). A solution of 5 (0.07 g, 0.1 mmol) in
PhMe (5 mL) was admixed with NaOMe/CH3OH (0.5 M, 2 mL),
refluxed for 8 h, diluted with EtOAc (20 mL), washed with water
(2 × 20 mL), dried (Na2SO4), and concentrated in vacuo. The
resulting residue was purified (hexane:EtOAc ) 9:1) to afford 6
(0.061 g, 94%) as a pale yellow oil. Rf 0.50 (9:1 hexane/EtOAc);
1
[R]D -38 (c 1.00, CHCl3); H NMR (300 MHz, CDCl3) δ 7.32-
7.07 (m, 20H), 5.24 (s, 1H), 4.73-4.69 (m, 2H), 4.61-4.55 (m,
FIGURE 1. (a) Partial 1H NMR spectrum of 15; (b) partial 1H NMR spectrum of 15 upon H-1 irradiation; (c) partial 1H NMR spectrum of 15 upon
1
1
H-2 irradiation; (d) partial H NMR spectrum of 15 upon H-3 irradiation; (e) partial H NMR spectrum of 15 upon H-4 irradiation.
J. Org. Chem, Vol. 72, No. 15, 2007 5503

Ganesh and Jayaraman
) 8:2) to afford 8 (0.027 g, 79%) as a colorless oil. Rf 0.30 (5:1
MHz, CDCl3) δ 152.2, 138.2, 137.9, 137.7, 136.9, 128.4, 128.3,
128.1, 128.0, 127.6, 127.5, 120.2, 102.0, 79.3, 76.7, 73.4, 73.3,
71.1, 70.1, 57.1; HRMS m/z C36H37ClO6Na calcd 623.2176, found
623.2153.
1
hexane/EtOAc); [R]D +19 (c 1.00, CHCl3); H NMR (400 MHz,
CDCl3) δ 7.45-7.14 (m, 15H), 4.86 (d, J ) 10.4 Hz, 1H), 4.78 (d,
J ) 13.6, 2H), 4.59-4.51 (m, 3H), 4.45-4.32 (m, 3H), 3.80-
3.62 (m, 3H), 3.45 (s, 3H), 3.36 (d, J ) 7.6 Hz, 1H), 2.6 (br s,
1H); 13C NMR (100 MHz, CDCl3) δ 204.3, 137.8, 137.1, 137.0,
128.6, 128.5, 128.4, 128.3, 128.0, 127.9, 127.8, 127.7, 104.1, 88.7,
78.3, 76.3, 75.2, 73.4, 73.2, 70.2, 70.1, 56.4; HRMS m/z calcd
C29H32O7Na 515.2046, found 515.2025.
Methyl 4,5,7-tri-O-benzyl-R-D-lyxo-sept-2,3-diuloside (14). To
a stirred solution of chloro-oxepine 13 (0.090 g, 0.150 mmol) in
MeCN:CCl4 (5 mL, 1:1) at 0 °C was added a solution of RuCl3
(cat.) and NaIO4 (0.080 g, 0.375 mmol) in water (2 mL) dropwise.
After 8 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. The resulting residue was purified
(hexane:EtOAc ) 7:3) to afford 14 (0.055 g, 75%), in the hydrated
form, as a colorless oil. Rf 0.48 (1:1 hexane/EtOAc); [R]D +20 (c
1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.42-7.21 (m, 15H),
5.16 (s, 1H), 4.95-4.89 (m, 2H), 4.73-4.67 (m, 2H), 4.54 (d, J )
11.3 Hz, 1H), 4.47 (d, J ) 11.3 Hz, 1H), 4.40 (d, J ) 7.1 Hz, 1H),
4.36 (m, 1H), 4.15-4.10 (m, 1H), 3.56-3.49 (m, 2H), 3.48 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 203.0, 137.6, 137.4, 137.0,
128.7, 128.6, 128.5, 128.4, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6,
100.6, 93.2, 85.0, 77.8, 74.4, 73.5, 71.2, 68.7, 56.8; HRMS m/z
C29H30O7Na‚H2O calcd 531.1995, found 531.2003.
Methyl 4,5,7-tri-O-benzyl-R-D-glycero-L-altro-septanoside (15).
To a solution of 14 (0.050 g, 0.102 mmol) in MeOH (4 mL) at
0 °C was added NaBH4 (0.019 g, 0.510 mmol), then the mixture
was stirred for 2 h, solvents were removed in vacuo, the resulting
residue was dissolved with EtOAc (3 × 15 mL), washed with brine
(10 mL), dried (Na2SO4), and concentrated in vacuo, and the crude
product was purified (hexane:EtOAc ) 6:4) to afford 15 (0.042 g,
83%) as a colorless oil. Rf 0.39 (1:1 hexane/EtOAc); [R]D +29 (c
1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.49-7.26 (m, 15H),
5.02 (d, J ) 11.5 Hz, 1H), 4.85 (d, J ) 3.9 Hz, 1H), 4.78 (d, J )
11.7 Hz, 1H), 4.63-4.57 (m, 2H), 4.50-4.48 (m, 1H), 4.44-4.34
(m, 2H), 4.27-4.24 (dd, J ) 6.7, 3.9 Hz, 1H), 4.15-4.07 (m, 2H),
3.99-3.98 (m, 2H), 3.51-3.47 (m, 1H), 3.45 (s, 3H), 3.42-3.38
(m, 1H), 2.78 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 138.4,
138.0, 129.9, 128.7, 128.5, 127.9, 127.7, 99.1, 79.3, 77.8, 75.7,
73.4, 73.1, 71.8, 71.7, 69.8, 69.6, 55.7; HRMS m/z C29H34O7Na
calcd 517.2202, found 517.2211.
Methyl 4,5,7-tri-O-benzyl-R-D-glycero-D-talo-septanoside (9).
To a solution of 8 (0.027 g, 0.055 mmol) in MeOH (2 mL) was
added NaBH4 (0.010 g, 0.274 mmol) at 0 °C then the solution was
stirred for 2 h, solvents were removed in vacuo, and the resulting
residue was dissolved in EtOAc (3 × 10 mL) and washed with
brine (10 mL). The combined organic extracts were dried (Na2-
SO4) and concentrated in vacuo and purified (hexane:EtOAc ) 1:1)
to afford 9 (0.021 g, 77%) as a colorless oil. Rf 0.26 (1:1 hexane/
1
EtOAc); [R]D +32 (c 1.00, CHCl3); H NMR (400 MHz, CDCl3)
δ 7.35-7.16 (m, 15H), 4.76 (d, J ) 11.3 Hz, 1H), 4.73 (d, J ) 5.6
Hz, 1H), 4.69 (s, 2H), 4.59 (d, J ) 11.5 Hz, 1H), 4.52-4.48 (m,
2H), 4.2 (br s, 1H), 3.86 (d, J ) 3.6 Hz, 2H), 3.72-3.68 (m, 3H),
3.63-3.61 (m, 1H), 3.43 (s, 3H), 2.84 (br s, 1H), 2.56 (br s, 1H);
13C NMR (100 MHz, CDCl3) δ 138.1, 138.0, 137.6, 128.5, 128.4,
128.3, 128.0, 127.7, 127.6, 102.7, 85.3, 77.2, 74.6, 74.5, 73.3, 73.1,
71.6, 71.1, 70.6, 56.0; HRMS m/z C29H34O7Na calcd 517.2202,
found 517.2214.
Methyl R-D-glycero-D-talo-Septanoside (10). To a solution of
9 (0.020 g, 0.040 mmol) in MeOH (15 mL) was added Pd/C (10%,
0.030 g), then the solution was stirred at room temperature under
a pressure of hydrogen gas for 10 h. The reaction mixture was
filtered over a celite pad and washed with MeOH (3 × 15 mL),
and solvents were removed in vacuo to afford 10 (0.008 g, 89%)
as a colorless oil. Rf 0.58 (1:1 CH3OH/ CHCl3); [R]D +51 (c 1.00,
1
CH3OH); H NMR (500 MHz, D2O) δ 4.52 (d, J ) 6.5 Hz, 1H),
3.97 (d, J ) 1.5 Hz, 1H), 3.78-3.76 (m, 2H), 3.64 (dd, J ) 13.5,
3.5 Hz, 1H), 3.58-3.49 (m, 3H), 3.41(s, 3H); 13C NMR (125 MHz,
D2O) δ 102.6, 76.3, 76.0, 72.1, 71.5, 70.3, 62.0, 55.6; HRMS m/z
C8H16O7Na calcd 247.0794, found 247.0794.
1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1,2-C-(dichloromethylene)-
R-D-glycero-L-altro-hexitol (12). To a stirred solution of oxygalactal
1111 (0.198 g, 0.327 mmol) and benzyltriethylammonium chloride
(cat.) in CHCl3 (1 mL) was added aq NaOH (50%, 1.1 mL)
dropwise at room temperature, then the solution was stirred at 40
°C for 2 h, diluted with brine (20 mL), extracted with CH2Cl2 (3
× 20 mL), dried (Na2SO4), and concentrated in vacuo, and the
resulting residue was purified (hexane:EtOAc ) 9:1) to afford 12
(0.195 g, 85%) as a colorless oil. Rf 0.64 (9:1 hexane/EtOAc); [R]D
Methyl R-D-glycero-L-altro-Septanoside (16). To a stirred
solution of 15 (0.040 g, 0.081 mmol) in MeOH (20 mL) was added
Pd/C (10%, 0.023 g) with continued stirring at room temperature
under a pressure of hydrogen gas for 12 h. The reaction mixture
was then filtered through a celite pad and washed with MeOH (3
× 15 mL), and solvents were removed in vacuo to afford 16 (0.016
g, 91%) as a colorless oil. Rf 0.45 (1:1 CH3OH/CHCl3); [R]D +54
(c 1.00, CH3OH); 1H NMR (500 MHz, D2O) δ 4.73 (d, J ) 3 Hz,
1H), 4.0 (dd, J ) 6.5, 3 Hz, 1H), 3.97-3.95 (m, 1H), 3.90-3.86
(m, 3H), 3.58-3.55 (dd, J ) 11.5, 7 Hz, 1H), 3.54-3.50 (dd, J )
11.5, 5.5 Hz, 1H), 3.34 (s, 3H); 13C NMR (125 MHz, D2O) δ 100.1,
74.5, 73.2, 71.9, 71.5, 69.3, 61.7, 55.8; HRMS m/z C8H16O7Na calcd
247.0794, found 247.0793.
1
+9 (c 1.00, CH2Cl2); H NMR (300 MHz, CDCl3) δ 7.36-7.17
(m, 20H), 5.03-4.97 (m, 3H), 4.68-4.56 (m, 3H), 4.48-4.36 (m,
2H), 4.08 (d, J ) 2.1 Hz, 1H), 3.95 (s, 1H), 3.92-3.90 (m, 2H),
3.57-3.47 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 138.3, 138.1,
138.0, 128.8, 128.7, 128.5, 128.4, 128.2, 127.8, 77.8, 75.5, 74.4,
73.9, 73.8, 72.3, 71.2, 69.2, 67.2, 63.2, 62.3; HRMS m/z C35H34-
Cl2O5Na calcd 627.1681, found 627.1679.
Acknowledgment. We thank NMR Research Center, IISc,
Bangalore, for their assistance to record 2-D NMR spectra. We
are grateful to Department of Science and Technology, New
Delhi, for financial support. N.V.G. thanks the Council of
Scientific and Industrial Research, New Delhi, for a research
fellowship.
Methyl 2-chloro-2-deoxy-3,4,5,7-tetra-O-benzyl-R-D-lyxo-hept-
2-enoseptanoside (13). To a stirred solution of 12 (0.102 g, 0.168
mmol) in dioxane (5 mL) was added NaOMe/CH3OH (0.5 M, 2
mL), then the reaction mixture was refluxed for 48 h and solvents
were removed in vacuo. The resulting residue was extracted with
CH2Cl2 (3 × 20 mL), washed with brine (20 mL), dried (Na2SO4),
concentrated in vacuo, and purified (hexane:EtOAc ) 9:1) to afford
13 (0.101 g, 95%) as a colorless oil. Rf 0.47 (9:1 hexane/EtOAc);
[R]D -39 (c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.42-
7.19 (m, 20H), 5.18 (s, 1H), 4.84 (d, J ) 2.4 Hz, 2H), 4.78 (d, J
) 11.7 Hz, 1H), 4.63-4.41 (m, 6H), 4.30-4.26 (m, 1H), 3.90 (d,
J ) 3.0 Hz, 1H), 3.78-3.70 (m, 2H), 3.46 (s, 3H); 13C NMR (100
Supporting Information Available: General experimental
1
procedure and H and 13C NMR spectra of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO070444E
5504 J. Org. Chem., Vol. 72, No. 15, 2007