Reaction of O-benzyl- and 4,6-O-benzylidene-D-gluco- and D- galactopyranose derivatives with amide-stabilized sulfur ylides: Stereoselectivity and reactivity

Article abstract of DOI:10.1021/jo971824a

The reaction of N,N-diethyl-2-(dimethylsulfuranylidene)acetamide (1) with protected monosaccharides has been extended to several O-benzyl- and 4,6-O-Benzylidene-D-gluco- and -D-galactopyranose derivatives. When the monosaccharide is 2,3,4,6-tetra-O-benzyl-D-glucose (6) or D-galactose (9), elimination of the 3-benzyloxy substituent occurs, to give the unsaturated epoxyamides 7 and 10, respectively, in reasonable yields and poor stereoselectivity. On the other hand, the reaction of 1 with the 4,6-O- benzylidene-D-glucopyranose derivatives 11, 14, and 17 yielded the corresponding epoxyamides 12, 15a:15b, and 18a:18b in good yields and variable stereoselectivity. In accordance with previous studies concerning the configurational assignments for the epoxide derivatives 3, 5a, and 21, obtained from 2, 4, and 20, respectively, the present article confirms the role of the hydroxyl group at C-2 on the stereoselectivity of the reaction. Thus, when the C-2 OH is unprotected (4, 11, 20), the major epoxide formed has the configuration 2S, 3R (epoxyamides 5a, 12, and 21). Conversely, derivatives with the hydroxyl group protected at C-2, or 2-deoxy sugars (2, 14, and 17), yield as the major epoxides the corresponding 2R, 3S isomers (3, 15b, and 18b).

Full text of DOI:10.1021/jo971824a

9630
J . Org. Chem. 1998, 63, 9630-9634
Articles
Rea ction of O-Ben zyl- a n d 4,6-O-Ben zylid en e-D-Glu co- a n d
D-Ga la ctop yr a n ose Der iva tives w ith Am id e-Sta bilized Su lfu r
Ylid es: Ster eoselectivity a n d Rea ctivity
A. M. Heras-Lo´pez, M. S. Pino-Gonza´lez, F. Sarabia-Garc´ıa, and F. J . Lo´pez-Herrera*
Departamento de Bioquı´mica, Biologı´a Molecular, y Qu´ımica Orga´nica, Facultad de Ciencias,
Universidad de Ma´laga, 29071 Ma´laga, Spain
Received October 2, 1997
The reaction of N,N-diethyl-2-(dimethylsulfuranylidene)acetamide (1) with protected monosaccha-
rides has been extended to several O-benzyl- and 4,6-O-Benzylidene-D-gluco- and -D-galactopyranose
derivatives. When the monosaccharide is 2,3,4,6-tetra-O-benzyl-D-glucose (6) or D-galactose (9),
elimination of the 3-benzyloxy substituent occurs, to give the unsaturated epoxyamides 7 and 10,
respectively, in reasonable yields and poor stereoselectivity. On the other hand, the reaction of 1
with the 4,6-O-benzylidene-D-glucopyranose derivatives 11, 14, and 17 yielded the corresponding
epoxyamides 12, 15a :15b, and 18a :18b in good yields and variable stereoselectivity. In accordance
with previous studies concerning the configurational assignments for the epoxide derivatives 3,
5a , and 21,6 obtained from 2, 4, and 20, respectively, the present article confirms the role of the
hydroxyl group at C-2 on the stereselectivity of the reaction. Thus, when the C-2 OH is unprotected
(4, 11, 20), the major epoxide formed has the configuration 2S, 3R (epoxyamides 5a , 12, and 21).
Conversely, derivatives with the hydroxyl group protected at C-2, or 2-deoxy sugars (2, 14, and
17), yield as the major epoxides the corresponding 2R, 3S isomers (3, 15b, and 18b).
In tr od u ction
epoxyamides in good yields and high stereoselectivity.
These results encouraged further studies using other
pyranose derivatives. It is worthy to note that these
preliminary studies revealed the influence of the protect-
ing group at the C-2 hydroxyl of the starting sugars on
the yield and stereoselectivity for the resulting epoxy-
amide. These results also aimed to correlate the absolute
configuration of the major resulting trans-epoxyamides
with the presence or absence of a protecting group of the
C-2 hydroxyl. It was shown that the reaction of ylide 1
with compound 2 by the two-phase method8 produced
only the stereoisomer 3 in a quantitative yield and with
a configuration (2R,3S) opposite to that of the major
product 5a (2S,3R) obtained in a lower yield from 4.
To demonstrate the correlation between stereoselec-
tivity and OH protection at C-2, in this article we report
new reactions of 1 with different monosaccharide deriva-
tives. In this investigation, we have selected O-benzyl
ethers and 4,6-O-benzylidene pyranose derivatives of
D-glucose and D-galactose.
Highly functionalized acyclic monosaccharide deriva-
tives are products of interest in organic synthesis with
utility as building blocks1 for the synthesis of bioactive
compounds.2 The elongation of the monosaccharide chain
with the incorporation of an epoxide group is especially
interesting, taking into account the diverse synthetic
possibilities that this functional group offers.3 In addition,
the stereochemistry of the epoxide ring is an important
factor for the synthesis of bioactive products. Recently,
we reported the reaction of N,N-diethyl 2-(dimethylsul-
furanylidene)acetamide (1) with acyclic aldehydosugars,4
furanose,5 and pyranose6,7 derivatives to give acyclic
(1) Lichtenthaler, F. W. Pure Appl. Chem. 1978, 50, 1342. (b)
Vasella, A. Chiral Building Blocks in Enantiomer Synthesis-ex Sugars.
In Modern Synthetic Methods; Scheffold, R., Ed.; 1980, p 174. (c) Inch,
T. D. Tetrahedron 1984, 40, 3161. (d) Hudlicky, T. Chem. Rev. 1996,
96, 3-30.
(2) (a) Hanessian, S. Total Synthesis of Natural Products: The
Chiron Approach, Pergamon: New York, 1983. (b) Fraser-Reid, B.;
Anderson, R. C. Carbohydrate Derivatives in the Asymmetric Synthesis
of Natural Products, Fortschr. Chem. Org. Naturst. Springer-Verlag:
Wien, 1980, p 1. (c) Casiraghi, G.; Zanardi, F.; Rassu, G.; Spanu, P.
Chem. Rev. 1995, 95, 1677-1716.
(3) (a) Seebach, D.; Weidmann, B.; Wilder, L. Modern Synthetic
Methods 1983, Scheffold, R., Ed.; Otto Salle Verlag: Frankfurt, 1983,
p 323. (b) Besse, P.; Veschambre, H. Tetrahedron 1994, 50, 8885-8927.
(4) Valpuesta-Ferna´ndez, M.; Durante Lanes, P.; Lo´pez-Herrera, F.
J . Tetrahedron 1990, 46, 7911-7922.
(5) Valpuesta-Ferna´ndez, M.; Durante Lanes, P.; Lo´pez-Herrera, F.
J . Tetrahedron 1993, 49, 9547-9560.
Resu lts a n d Discu ssion
Initially, we considered the reactions of the perbenzyl
derivatives, taking into account that benzyl ethers are
valuable protecting groups widely used in carbohydrate
chemistry. However, it is known that benzyl monosac-
charides are sometimes unstable under basic conditions,
(6) Lo´pez-Herrera, F. J .; Heras-Lo´pez, A.; Pino-Gonza´lez, M. S.;
Sarabia-Garc´ıa, F. J . Org. Chem. 1996, 61, 8839-8848.
(7) Lo´pez-Herrera, F. J .; Sarabia-Garc´ıa, F.; Heras-Lo´pez, A.; Pino-
Gonza´lez, M. S. J . Org. Chem. 1997, 62, 6056-6059.
(8) Lo´pez-Herrera, F. J .; Pino-Gonza´lez, M. S.; Sarabia-Garc´ıa, F.;
Heras-Lo´pez, A.; Ortega-Alca´ntara, J . J .; Pedraza-Cebria´n, M. G.
Tetrahedron: Asymmetry 1996, 7, 2065-2071 and refs cited therein.
10.1021/jo971824a CCC: $15.00 © 1998 American Chemical Society
Published on Web 12/04/1998

Reactions of Several D-Gluco- and D-Galactopyranose Derivatives
J . Org. Chem., Vol. 63, No. 26, 1998 9631
Ta ble 1. Rea ction of Ylid e 1 w ith Der iva tives 6, 9, 11,
14, a n d 17
Sch em e 1
starting
sugar
reaction yield
equiv of 1 time (h) (%)
product
(ratio)
solvent
6
MeCN/THFa
(7:1)
1.0
72
76
7 (1:1.4)c
6
9
11
14
CH2Cl2/H2Ob
CH2Cl2/H2Ob
THFa
2.0
1.0
4.0
8.0
23
7
12
21
67
54
54
93
7 (1:1.3)c
10 (1:1)
12 (100:0)
15a :15b
(1:2)
THFa
17
THFa
2.0
12
30
18a :18b
(1:1.6)
a
Reaction with ylide 1. b Two-phase method. c Z, E assignments
were not made.
Thus, the reaction of 11 with 1, with the presence of a
free hydroxyl group at C-2, should (i) lead to the
preferential formation of the epoxyamide 12, and (ii)
protect the proton at C-2 against abstraction due to the
higher acidity of the OH group. In accord with these
assumptions, and as it is shown in Table 1, epoxyamide
12 was obtained as the only product. The configurational
assignment at C-2 and C-3 was confirmed by benzylation
of 12 to the corresponding tri-O-benzyl derivative 13, the
same product obtained by benzylation of 21, and stereo-
chemistry has previously been established.6
Sch em e 2
For 2-O-benzyl derivative 14, its reaction with 1 should
furnish the trans-epoxyamide with the opposite config-
uration at C-2 and C-3 with regard to 12. In fact, this
reaction provided epoxyamide 15b as the major product
but in rather lower stereoselectivity (see Table 1).
Similarly, the stereochemistry for the major isomer 15b
was established by benzylation of a pure sample of the
minor isomer 15a , obtaining 13.
The disappointing yields obtained in the reactions in
which the OH at C-2 of the starting sugar is free can be
ascribed to a Payne rearrangement13 of the resulting
epoxyamide to produce a 3,4-epoxyamide. Subsequent
intramolecular cyclizations of 3,4-epoxyamides should
give C-furanosides as we have previously reported for 20.6
For the case in which the OH is protected at C-2, such
as the glucopyranose derivative 14, epoxyamides were
obtained in very high yield (95%), although with low
stereoselectivity. This poor stereoselectivity may be the
result of two competitive electrostatic and dipolar repul-
sions between the carbonyl group in the open-chain form
of 14, and the partial oxyanions generated at C-3 or C-5,
of which the latter appears to be dominant.
Finally, the reaction was extended to other C-2 modi-
fied 4,6-O-benzylidene-D-glucopyranoses. Thus, 2-deoxy-
D-glucopyranose derivative 1714 was reacted with 1 to
obtain a mixture of the corresponding trans-epoxyamides
18a and 18b in low yield (30%) and stereoselectivity (1:
1.6). We attribute this low stereoselectivity to the absence
of a C-2 hydroxyl and the accompanying higher confor-
mational flexibility around the C1-C2 and C2-C3 bonds
in the open form of the sugar. This flexibility allows an
increased separation of the carbonyl group and the
oxyanions generated at C-3 or C-5.
affording elimination products. Thus, reactions of 2,3,4,6-
tetra-O-benzyl-D-glucopyranose (6) and 2,3,4,6-tetra-O-
benzyl-D-galactopyranose (9) with the ylide 1 yielded the
corresponding γ,δ-unsaturated-R,â-trans-epoxyamides 7
and 10, respectively, as a result of the elimination of
benzyl alcohol at C-3 of 6 and 9 and subsequent conden-
sation with 1. Attempts to avoid this elimination were
in all cases unsuccessful. A possible explanation for this
observation is that the basic medium generated by the
presence of the ylide caused abstraction of the proton at
the R position adjacent to the carbonyl group of the
starting sugar, giving the corresponding R,â-unsaturated
aldehyde, which reacted with 1. Similar benzylic elimina-
tions have been previously reported for the Wittig reac-
tion of several tetra-O-benzyl-D-glucopyranoses with
ethoxycarbonylmethylene triphenylphosphorane.9 This
elimination was likewise observed in reactions of 6 with
methylene dimethylsulfurane and oxosulfurane.10
In light of these discouraging results, we decided to
study the reaction of 1 with the 3-O-benzyl- and 2-O-
benzyl-4,6-O-benzylidene-D-glucopyranose (11)11 and (14),12
respectively. These sugars were chosen to avoid the
elimination at C-3 and also to introduce some conforma-
tional restriction to the open oxo-form of these derivatives
by the presence of the 4,6-O-benzylidene ring, to influence
the stereoselectivity of the ylide addition process.
Con clu sion
(9) Nicotra, F.; Ronchetti, F.; Russo, G.; Toma, L. Tetrahedron Lett.
1984, 49, 5697-5700.
The present study confirms the crucial role of the
protecting group at the hydroxyl on C-2 of the starting
(10) Fre´chou, C.; Dheilly, L.; Beaupe`re, D.; Uzan, R.; Demailly, G.
Tetrahedron Lett. 1992, 33, 5067-5070.
(11) Prentice, N.; Cuendet, L. S.; Smith, F. J . Am. Chem. Soc. 1956,
78, 4439-4440.
(12) Lubineau, A.; Queuneau, Y. Tetrahedron 1989, 45, 6697-6712.
(13) Payne, G. B. J . Org. Chem. 1962, 3819-3822.
(14) Overend, W. G.; Stacey, M.; Stanek, J . J . Chem. Soc. 1949,
2841-2845.

9632 J . Org. Chem., Vol. 63, No. 26, 1998
Heras-Lo´pez et al.
Sch em e 3
δ 165.4, 165.3, 153.3, 152.5, 138.0, 137.8, 137.7, 136.6, 128.2,
128.1, 128.0, 127.9, 127.8, 127.6, 127.5, 127.4, 127.3, 127.1,
113.6, 113.1, 74.4, 73.5, 73.1, 72.6, 72.1, 71.8, 70.7, 70.6, 70.2,
70.0, 56.1, 53.1, 52.8, 41.3, 40.6, 14.6, 12.7; FAB HRMS (NBA/
CsI) m/e 678.1848, M + Cs+ calcd for C33H39O6N 678.1832.
N,N-Dieth yl-7-O-a cetyl-2,3-a n h yd r o-5-d eoxy-4,6,8-tr i-
O-ben zyl-D-a ltr o a n d D-glu co-oct-4-en on a m id es (8). Ep-
oxyamide 7 (95 mg, 0.17 mmol) was dissolved in pyridine (2
mL) and treated with acetic anhydride (0.06 mL, 0.57 mmol)
at 0 °C. After 12 h at room temperature, the crude mixture
was diluted with CH2Cl2 (5 mL), washed with 10% aqueous
HCl (5 mL), and the organic layer was separated. The aqueous
phase was extracted with CH2Cl2 (3 × 5 mL) and the combined
organic solution was dried (Na2SO4), filtered, and concentrated.
The crude mixture was purified by preparative TLC (silica gel,
AcOEt) to afford an irresoluble mixture of two isomers of 8
(79 mg, 77%) as a colorless oil: 1H NMR (200 MHz, CDCl3) δ
7.31-7.18 (m, 15 H), 5.30-5.05 (m, 2 H), 4.90-4.70 (2 × 2d,
2 H), 4.69-4.50 (m, 1 H), 4.48-4.19 (m, 4 H), 3.72-3.50 (m, 4
H), 3.50-3.25 (m, 4 H), 2.02 (s, 3 H), 1.15 (q, J ) 7.3 Hz, 6 H);
13C NMR (50.3 MHz, CDCl3) δ 170.2, 170.0, 165.4, 165.3, 153.6,
152.8, 137.9, 137.8, 136.7, 136.6, 128.3, 128.2, 128.1, 128.0,
127.8, 127.6, 127.4, 113.5, 112.0, 74.8, 73.3, 73.1, 72.9, 71.7,
70.9, 70.4, 70.3, 68.3, 68.2, 56.0, 55.5, 53.3, 52.8, 41.4, 40.7,
21.0, 14.7, 12.7.
N,N-Dieth yl-2,3-a n h yd r o-5-d eoxy-4,6,8-tr i-O-ben zyl-D-
th r eo-L-id o a n d L-ga la cto-oct-4-en on a m id es (10). To a
stirred solution of 915 (50 mg, 0.09 mmol) in CH2Cl2 (2 mL)
was added N,N-diethylcarbamoylmethyl dimethylsulfonium
chloride (22 mg, 0.10 mmol) and aqueous NaOH (0.5 mL, 50%
w/v) at 0 °C. After 1 h at 0 °C, the reaction mixture was allowed
to stir at room temperature for 7 h. Water (4 mL) was added,
the organic phase was separated, and the aqueous phase
extracted with tert-butyl methyl ether (2 × 4 mL). The
combined organic solution was dried (Na2SO4) and concen-
trated under reduced pressure. The crude oil thus obtained
was subjected to preparative TLC (silica gel, 10:1:2 HCCl3/
MeOH/hexanes) to obtain an irresoluble mixture of the ep-
oxyamides 10a and 10b (25 mg, 54%) as a colorless oil: 1H
NMR (200 MHz, CDCl3) δ 7.35-7.20 (m, 15 H), 5.19 and 5.15
(2d, J and J ′ ) 9.7 Hz, 1 H), 4.93-4.69 (m, 2 H), 4.57-4.18
(m, 6 H), 3.70 (m, 1 H), 3.69 and 3.55 (2d, J ) 2.1 Hz and J ′
) 2.0 Hz, 1 H), 3.55-3.33 (m, 6 H), 2.68 and 2.66 (2 d, J and
J ′ ) 4.2 Hz, 1 H), 1.30-1.17 (m, 6 H); 13C NMR (50.3 MHz,
CDCl3) δ 166.1, 165.9, 153.1, 138.1, 137.0, 128.5-126.9, 113.4,
112.9, 74.5, 72.9, 72.6, 68.4, 56.1, 55.8, 53.6, 53.2, 41.5, 40.8,
14.9, 14.8, 12.9; FAB HRMS (NBA/CsI) m/e 678.1847, M + Cs+
calcd for C33H39O6N 678.1832.
4,6-O-benzylidene-D-glucopyranose. Furthermore, the size
of the substituent at C-2 and the presence of a 4,6-O-
benzylidene group were shown to be important factors
in determining the yield and stereoselectivity for these
reactions.
Exp er im en ta l Section
Gen er a l Tech n iqu es. All reactions were carried out under
a dry argon atmosphere using freshly distilled solvents unless
otherwise noted. Reactions were monitored by TLC on E.
Merck silica gel plates (0.25 mm) and visualized using UV light
(254 nm) or heating with p-anisaldehyde solution (340 mL of
ethanol, 9.2 mL of p-anisaldehyde, 12.5 mL of sulfuric acid,
and 3.75 mL of acetic acid). Flash chromatography was
performed on E. Merck silica gel (60, particle size 0.040-0.063
mm). Melting points are given uncorrected. NMR spectra were
recorded at 200 MHz on a Bruker WP200SY spectrometer at
ambient temperature. Chemical shifts are reported relative
to the residual solvent peak. Multiplicities are designated as
singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m),
and broad singlet (bs). Coupling constants are expressed as J
values in Hertz units. Mass spectra were recorded on a
Hewlett-Packard 5988A instrument. Microanalyses were per-
formed by the “Servicio de Microana´lisis” of the University of
Ma´laga. Exact masses were recorded on a Kratos MS 80 RFA
instrument of the University of Seville. Specific rotations were
measured with a Perkin-Elmer 241 polarimeter.
N,N-Dieth yl-2,3-a n h yd r o-5-d eoxy-4,6,8-tr i-O-ben zyl-D-
a ltr o- a n d D-glu co-oct-4-en on a m id es (7). Meth od A (on e
p h a se): To a solution of 615 (0.5 g, 0.92 mmol) in 20 mL of
CH3CN/THF (7:1 v/v) was added portionwise 1 (0.2 g, 1.03
mmol). After 3 days, TLC (CH2Cl2:MeOH:hexanes, 10:1:2)
showed the depletion of 6 and the solvents were removed under
reduced pressure. Flash column chromatography (silica gel,
25% AcOEt in hexanes) followed by purification on preparative
TLC furnished an inseparable mixture of epoxyamides 7 (1:
1.4) (383 mg, 76%) as a colorless oil. Met h od
B (t w o
p h a ses): To a cooled solution of 6 (0.5 g, 0.92 mmol) in
CH2Cl2 (20 mL) was sequentially added N,N-diethylcarbam-
oylmethyl dimethylsulfonium chloride (0.5 g, 2.31 mmol) and
sodium hydroxide (2.5 mL, 50% w/v) with vigorous stirring.
After 22-23 h at room temperature, the reaction mixture was
diluted with water (20 mL). The organic phase was separated
and the aqueous phase was extracted with tert-butyl methyl
ether (4 × 20 mL). The combined organic solution was dried
(Na2SO4), filtered, and the solvents removed under vacuum.
Flash column chromatography (silica gel, 25% AcOEt in
hexanes) furnished an inseparable mixture of epoxyamides 7a
a n d 7b (1:1.4) (331 mg, 67%): 1H NMR (200 MHz, CDCl3) δ
7.30-7.10 (m, 15 H), 5.25 and 5.20 (2 d, two isomers, J ) 9.6
Hz and J ′ ) 9.3 Hz, 1 H), 4.94-4.74 (2 d, 2 H), 4.56-4.28 (m,
5 H), 3.91-3.80 (m, 1 H), 3.67 (2d, J ) 1.9 Hz and J ′ ) 2.0
Hz, 1 H), 3.65 and 3.55 (2d, J ) 1.9 Hz and J ′ ) 2.0 Hz, 1 H),
3.54-3.33 (m, 6 H), 2.37 and 2.30 (2d, J ) 4.7 Hz, and J ′ )
4.9 Hz, 1 H), 1.25-1.05 (m, 6 H); 13C NMR (50.3 MHz, CDCl3)
3-O-Ben zyl-4,6-O-b en zylid en e-D-glu cop yr a n ose (11).
Powdered zinc chloride (2.3 g) was added portionwise to a
mixture of benzaldehyde (25 mL) and 3-O-benzyl-D-glucose11
(4.6 g, 17.0 mmol). The reaction mixture was stirred magneti-
cally at 25 °C for 5 h and the resulting suspension was poured
into an Erlenmeyer flask containing ice-water (50 mL) and
hexanes (50 mL) to separate a yellow oil. After cooling for
several hours, the precipitate was filtered and washed with
cold water and hexanes. The residue was dissolved in methanol/
water and neutralized with sodium bicarbonate. The crude
product obtained after evaporation was poured into water (50
(15) Compounds 6 and 9 were purchased from Sigma Aldrich.

Reactions of Several D-Gluco- and D-Galactopyranose Derivatives
J . Org. Chem., Vol. 63, No. 26, 1998 9633
mL) and extracted with CHCl3 (3 × 25 mL). The combined
organic layer was washed with cold water (1 × 25 mL), dried
over Na2SO4, and concentrated under reduced pressure. The
residue was crystallized from ethyl acetate/diethyl ether as a
5 mL), and the combined organic layer was dried (MgSO4),
filtered, and concentrated under reduced pressure. Purification
by flash column chromatography (silica gel, 25% EtOAc in
hexanes) provided pure tri-O-benzyl epoxyamide 13 (120 mg,
87%). Similarly, compound 13 (145 mg, 85%) was prepared
from epoxyamide 21 (100 mg, 0.26 mmol) according to the
white solid (3.2 g, 53% yield): [R]25 +19.0° (c 2.3, CHCl3); 1H
D
NMR (200 MHz, CDCl3) δ 7.50-7.20 (m, 10 H), 5.57 (s, 1 H),
5.29 (d, J ) 3.1 Hz, 1 H), 5.02-4.72 (m, 3 H), 4.40-4.25 (m, 1
H), 4.08 (dd, J ) 4.3, 9.8 Hz, 1 H), 3.92-3.41 (m, 3 H), 2.50 (d,
J ) 5.4 Hz, 1 H); 13C NMR (50.3 MHz, CDCl3) δ 138.3, 138.1,
137.3, 137.1, 129.0-126.0, 101.3, 101.2, 97.1, 92.9, 82.0, 81.4,
80.3, 78.3, 75.2, 74.9, 74.4, 72.2, 69.0, 68.6, 66.5, 62.7; Anal.
Calcd for C20H22O6: C, 67.03; H, 6.19; found: C, 67.52; H, 6.48.
2-O-Ben zyl-4,6-O-ben zylid en e-D-glu cop yr a n ose (14). To
a solution of 2-O-benzyl-D-glucose12 (4.9 g, 18.1 mmol) in DMF
(25 mL) was added benzaldehyde dimethyl acetal (6.0 mL, 40.0
mmol) and p-toluenesulfonic acid (35 mg, 0.18 mmol) at 50
°C. After 9 h, DMF was removed under reduced pressure and
the residue purified on column chromatography (silica gel, 10:
1:8 CHCl3:MeOH:hexanes). The obtained product was crystal-
lized from ethyl ether to obtain pure 14 (1.5 g, 23% yield, 1:1
mixture of R:â anomers) as a white solid: Rf ) 0.81 (silica gel,
procedure described above. [13]: [R]25 +4.5° (q 2.3, CHCl3);
D
1H NMR (200 MHz, CDCl3) δ 7.53-7.22 (m, 20 H), 5.53 (s, 1
H), 4.92-4.33 (m, 8 H), 4.19 (dd, J ) 1.2, 9.2 Hz, 1 H), 4.07
(dd, J ) 1.8, 6.1 Hz, 1 H), 3.97 (m, 1 H), 3.69 (t, J ) 10.4 Hz,
1 H), 3.62 (t, J ) 4.9 Hz, 1 H), 3.49-3.27 (m, 3 H), 2.98-2.81
(m, 2 H), 0.95 (t, J ) 6.7 Hz, 3 H), 0.78 (t, J ) 6.7 Hz, 3 H);
13C NMR (50.3 MHz, CDCl3) δ 166.7, 137.9, 137.7, 137.3,
128.6-125.9, 101.1, 79.0, 78.7, 76.8, 74.1, 72.4, 71.3, 69.4, 68.0,
54.8, 50.7, 41.1, 40.4, 14.1, 12.9; FAB HRMS (NBA/CsI) m/e
784.7091, M + Cs+ calcd for C40H45O7N 784.7079.
N,N-Dieth yl-2,3-an h ydr o-4-O-ben zyl-6,8-O-ben zyliden e-
D-er yt h r o-L-ga la cto a n d L-id o-oct on a m id es (15a a n d
15b). Epoxyamides 15a and 15b (1.35 g, 93%) were prepared
from 2-O-benzyl-4,6-O-benzylidene-D-glucopyranose (14) (1.1
g, 3.1 mmol) by treatment with N,N-diethylcarbamoylmethyl
dimethyl sulfonium (4.2 g, 23.96 mmol) in THF (50 mL)
according to the procedure described above for 12. Purification
by flash column chromatography (silica gel, 50% AcOEt in
hexanes) provided pure epoxyamide 15b (250 mg) and a 1:1
mixture of 15a :15b (1.1 g, total yield 93%) as colorless oils.
[15b]: [R]25D -3.8° (c 7.1, CHCl3); 1H NMR (200 MHz, CDCl3)
δ 7.54-7.24 (m, 10 H), 5.51 (s, 1 H), 4.90 and 4.63 (2d, 2 H),
4.28 (dd, J ) 4.3, 10.4 Hz, 1 H), 4.11 (m, 1 H), 4.05-3.00 (m,
12 H), 1.12 (q, J ) 6.7 Hz, 6 H); 13C NMR (50.3 MHz, CDCl3)
δ 166.4, 137.6, 137.5, 128.6-125.9, 100.7, 80.8, 80.1, 72.6, 70.8,
69.4, 60.7, 57.5, 50.6, 41.2, 40.6, 14.4, 12.7; FAB HRMS (NBA/
CsI) m/e 494.2147, M + Cs+ calcd for C26H33O7N 494.2155.
15a (fr om a m ixtu r e w ith 15b): 13C NMR (50.3 MHz,
CDCl3) δ 166.7, 137.7, 137.5, 128.7-125.8, 100.8, 81.4, 80.0,
72.2, 60.0, 57.7, 50.3, 41.2, 40.7, 14.4, 12.7.
N,N-Dieth yl-2,3-a n h yd r o-4,5,7-tr i-O-ben zyl-6,8-O-ben -
zylid en e-D-er yth r o-L-ga la cto-octon a m id e (13) fr om 15a .
A solution of 15a (90 mg, 0.19 mmol) in THF (2 mL) was
treated with NaH (27 mg, 0.70 mmol, in 60% mineral oil),
tetrabutylammonium bromide (11 mg, 0.03 mmol), and benzyl
bromide (0.04 mL, 0.27 mmol) at 0 °C according to the
procedure described above for 13 from 12. Purification by TLC
(silica gel, 25% EtOAc in hexanes) provided pure 13 (44 mg,
35%), the spectroscopic and physical properties of which were
identical to 13 obtained above.
1
10:1:2 HCCl3:MeOH:hexanes); H NMR (200 MHz, CDCl3) δ
7.60-7.22 (m, 10 H), 5.49 (s, 1 H), 5.22 (dd, J ) 3.5, 12.0 Hz,
0.5 H), 5.00-4.74 (m, 2.5 H), 4.40-4.18 (m, 1 H), 4.05 (dd, J
) 3.8, 8.8 Hz, 1 H), 3.84-3.22 (m, 4 H); 13C NMR (50.3 MHz,
CDCl3) δ 137.9, 137.3, 136.8, 136.7, 129.6-126.0, 101.8, 101.6,
97.3, 91.5, 82.6, 80.9, 80.2, 79.3, 73.1, 72.9, 70.1, 68.7, 68.4,
65.7, 62.0.
4,6-O-Ben zylid en e-2-d eoxy-D-glu cop yr a n ose (17). Com-
pound 17 was prepared from 2-desoxi-D-arabino-hexose14 (3.0
g, 18.3 mmol) by treatment with benzaldehyde dimethyl acetal
(9.0 mL, 60.0 mmol) and p-toluenesulfonic acid (68 mg, 0.36
mmol) according to the procedure described above for the
preparation of 14, obtaining pure 17 (2.1 g, 46%) as a white
solid: 1H NMR (200 MHz, CDCl3) δ 7.62-7.35 (m, 5 H), 5.56
(s, 0.5 H), 5.54 (s, 0.5 H), 5.34 (s, 0.5 H), 4.86 (m, 0.5 H), 4.35-
4.13 (m, 2 H), 4.09-3.94 (m, 1 H), 3.93-3.28 (m, 4 H), 2.85-
2.60 (m, 1 H), 2.40-2.15 (m, 1 H), 1.82-1.52 (m, 1 H); 13C NMR
(50.3 MHz, CDCl3) δ 137.2, 137.1, 129.1-126.2, 101.9, 101.8,
94.4, 92.4, 84.0, 83.7, 69.0, 68.6, 67.9, 66.3, 65.2, 62.6, 37.7,
36.5.
N,N-Dieth yl-2,3-an h ydr o-5-O-ben zyl-6,8-O-ben zyliden e-
D-er yth r o-L-ga la cto-octon a m id e (12). A solution of 3-O-
benzyl-4,6-O-benzylidene-D-glucopyranose (11) (1.0 g, 2.8 mmol)
in THF (40 mL) was cooled to 0 °C and then N,N-diethylsul-
furanylidene acetamide (1) was added dropwise (2.0 g, 11.4
mmol). The mixture was allowed to stir at room temperature
for 12 h. After this time, the reaction mixture was neutralized
with 0.1 N HCl and the solvents were concentrated. The crude
product was extracted with CHCl3 (3 × 100 mL) and the
combined organic layer was dried (Na2SO4), filtered, and
concentrated under reduced pressure. Purification by flash
column chromatography (silica gel, 10:1:8 HCCl3:MeOH:hex-
anes) provided pure epoxyamide 12 (0.7 g, 54% yield) as a
white solid. Recrystallization was performed from CHCl3/
Et2O: [R]25D +13.7° (c 1.8, CHCl3); 1H NMR (200 MHz, CDCl3)
δ 7.55-7.22 (m, 10 H), 5.48 (s, 1 H), 4.78 (s, 2 H), 4.29 (dd, J
) 4.3, 11.0 Hz, 1 H), 4.25-3.92 (m, 4 H), 3.70 (d, J ) 2.4 Hz,
1 H), 3.59 (dd, J ) 9.8, 10.4 Hz, 1 H), 3.54-3.23 (m, 6 H), 3.15
(d, J ) 5.4 Hz, 1 H), 1.11 (m, 6 H); 13C NMR (50.3 MHz, CDCl3)
δ 166.5, 137.8, 137.6, 128.8-126.1, 100.8, 81.1, 79.9, 74.7, 70.9,
69.3, 62.4, 58.4, 50.7, 41.4, 40.7, 14.4, 12.8; FAB HRMS (NBA/
NaI) m/e 494.2146, M + Na+ calcd for C26H33O7N 494.2155.
N,N-Dieth yl-2,3-a n h yd r o-4,5,7-tr i-O-ben zyl-6,8-O-ben -
zylid en e-D-er yth r o-L-ga la cto-octon a m id e (13). To a cooled
solution (0 °C) of epoxyamide 12 (100 mg, 0.21 mmol) in THF
(2 mL) was added NaH (32 mg, 0.80 mmol, 60% in mineral
oil). The reaction mixture was stirred at 0 °C for 30 min and
then tetrabutylammonium bromide (9 mg, 0.03 mmol) and
benzyl bromide (0.03 mL, 0.27 mmol) were sequentially added.
The resulting mixture was allowed to stir at 25 °C for 2 days.
After this time, MeOH (0.25 mL) was carefully added at 0 °C,
then ether (5 mL) and saturated aqueous NH4Cl solution (5
mL) were sequentially added and the organic layer was
separated. The aqueous phase was extracted with ether (2 ×
N,N-Diet h yl-2,3-a n h yd r o-5,7-d i-O-a cet yl-4-O-b en zyl-
6,8-O-b en zylid en e-D-er yth r o-L-ga la cto a n d L-id o-oct on -
a m id es (16a a n d 16b). Acetylation of a mixture of 15a and
15b (157 mg, 0.33 mmol) was accomplished with acetic
anhydride (0.64 mL, 6.66 mmol) in pyridine (1.3 mL) by the
same procedure described above for 7, to obtain, after purifica-
tion by flash column chromatography (silica gel, 20% EtOAc
in hexanes), pure 16b (21 mg) and a 1:1 mixture of 16a :16b
(104 mg, 75% overall).
[16b]: [R]25 -5.2° (c 1.2, CHCl3); 1H NMR (200 MHz,
D
CDCl3) δ 7.45-7.23 (m, 10 H), 5.35 (dd, J ) 1.8 Hz, 1 H), 5.33
(s, 1 H), 4.89-4.54 (m, 3 H), 4.54 (dd, J ) 4.9, 10.4 Hz, 1 H),
4.37 (m, 1 H), 4.16 (dd, J ) 2.5, 9.8 Hz, 1 H), 3.74 (dd, J ) 6.7,
9.2 Hz, 1 H), 3.57 (t, J ) 10.4 Hz, 1 H), 3.55-3.24 (m, 6 H),
2.08 (s, 3 H), 2.03 (s, 3 H), 1.15-1.10 (m, 6 H); 13C NMR (50.3
MHz, CDCl3) δ 169.6, 169.8, 165.3, 136.8, 128.9-125.8, 101.1,
76.5, 75.1, 72.9, 68.2, 67.8, 61.5, 57.9, 50.7, 41.2, 40.5, 20.5,
14.6, 12.6; FAB HRMS (NBA/CsI) m/e 688.1543, M + Cs+ calcd
for C30H37O9N 688.1523. 16a (fr om a m ixtu r e w ith 16b): 1H
NMR (200 MHz, CDCl3) δ 7.51-7.21 (m, 10 H), 5.53 (s, 1 H),
5.21 (dd, J ) 1.8 Hz, 1 H), 4.96-4.36 (m, 4 H), 4.54 (m, 1 H),
4.24-3.20 (m, 8 H), 2.07 (s, 3 H), 2.03 (s, 3 H), 1.24-1.07 (m,
6 H); 13C NMR (50.3 MHz, CDCl3) δ 170.0, 165.6, 163.7, 129.0-
125.9, 101.2, 75.8, 72.3, 71.4, 70.3, 69.2, 61.7, 56.2, 49.3, 41.2,
40.5, 20.5, 14.4, 12.6.
N,N-Dieth yl-2,3-a n h yd r o-4-d eoxy-6,8-O-ben zylid en e-D-
glycer o-D-id o a n d D-ga la cto-octon a m id es (18a a n d 18b).
Epoxyamides 18a and 18b (1.11 g, 69%, 1:1.6 mixture) were
prepared from 17 (1.1 g, 4.3 mmol) by treatment with N,N-

9634 J . Org. Chem., Vol. 63, No. 26, 1998
Heras-Lo´pez et al.
diethylcarbamoylmethyl dimethyl sulfonium (1.5 g, 8.5 mmol)
in THF (40 mL) according to the procedure described above
for 12. Epoxyamides 18a :18b could not be separated by
purification by flash column chromatography (silica gel, 10:
3:4 HCCl3:MeOH:hexanes). Mixture 18a :18b (1:1.6): 1H NMR
(200 MHz, CDCl3) δ 7.50-7.12 (m, 5 H), 5.47 (s, 1 H), 4.45-
3.11 (m, 11 H), 2.34-2.06 (m, 2 H), 1.27-1.05 (m, 6 H); 13C
NMR (50.3 MHz, CDCl3) δ 167.1, 137.6, 137.5, 128.8-126.1,
100.8, 83.6, 83.0, 71.0, 67.1, 66.5, 61.1, 60.8, 56.3, 56.0, 53.8,
53.0, 41.5, 40.8, 35.4, 34.3, 14.5, 12.8; FAB HRMS (NBA/NaI)
m/e 366.1922, M + H+ calcd for C19H28O6N 366.1917.
N,N-Dieth yl-2,3-a n h yd r o-4-d eoxy-5,7-d i-O-a cetyl-6,8-O-
ben zylid en e-D-glycer o-D-id o a n d D-ga la cto-octon a m id es
(19a a n d 19b). Acetylation of a mixture of 18a and 18b (73
mg, 0.33 mmol) was accomplished with acetic anhydride (1.90
mL, 6.66 mmol) in pyridine (3.8 mL) by the same procedure
described above for 7, to obtain, after purification by flash
column chromatography (silica gel, 20% EtOAc in hexanes), a
mixture of 19a and 19b (48 mg, 54%) as a colorless oil: 1H
NMR (500 MHz, CDCl3) δ 7.54-7.20 (m, 5 H), 5.55 and 5.53
(2s, two isomers, 1H), 5.47 (m, 1 H), 4.98 (m, 1 H), 4.38 (dd, J
) 5.3, 10.5 Hz, 1 H), 4.05 (m, 1 H), 3.77-3.56 (m, 2H, H-3,
H-8a), 3.56-3.18 (m, 6 H), 2.09 (s, 3 H), 2.06 (s, 3 H), 1.27-
1.05 (m, 6 H); 13C NMR (50.3 MHz, CDCl3) δ 170.3, 169.6,
166.1, 136.8, 130.7-126.0, 101.3, 78.5, 78.2, 67.7, 67.6, 67.1,
61.9, 61.8, 54.5, 54.4, 53.3, 53.1, 41.3, 40.6, 31.8, 31.6, 20.7,
20.5, 14.6, 14.5, 12.6; FAB HRMS (NBA/NaI) m/e 472.1938,
M + Na+ calcd for C23H31O8N 472.1947.
Ack n ow led gm en t. This work was financially sup-
ported by the Direccio´n General de Investigacio´n y
Cient´ıfica Te´cnica (ref. PB94-1487) and by the Direccio´n
General de Universidades e Investigacio´n, Consejer´ıa
de Educacio´n y Ciencia, J unta de Andaluc´ıa (FQM
0158). We thank Dr. J . I. Trujillo from The Scripps
Research Institute (La J olla, CA) for assistance in the
preparation of this manuscript. We thank Unidad de
Espectroscop´ıa de Masas de la Universidad de Sevilla
for exact mass spectroscopic assistance.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and 13C NMR spectra (10 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O971824A