ortho-Thioquinones, new acceptors for the stereoselective synthesis of aryl 2-deoxy-O-glycosides

Article abstract of DOI:10.1002/(SICI)1521-3765(19990604)5:6<1748::AID-CHEM1748>3.0.CO;2-R

α-Hydroxynaphthylthiophthalimide (1) is a suitable precursor of the reactive ortho-thioquinone 2, which can be generated in situ and trapped by glycals. The reaction is an inverse electron-demand [4+2] cycloaddition that occurs in a totally regioselective

Full text of DOI:10.1002/(SICI)1521-3765(19990604)5:6<1748::AID-CHEM1748>3.0.CO;2-R

FULL PAPER
ortho-Thioquinones, New Acceptors for the Stereoselective Synthesis of
Aryl 2-Deoxy-O-Glycosides
Giuseppe Capozzi,* Chiara Falciani, Stefano Menichetti,
Cristina Nativi,* and Barbara Raffaelli[a]
Abstract:
a-Hydroxynaphthylthio-
and electron-poor dienes, respectively,
with chloroform, dimethylformamide,
and dimethyl sulfoxide as solvents. The
stereochemistry of substituents on the
dienophile strongly influences the selec-
tivity of the cycloaddition, which be-
comes totally stereoselective when
galactals 8 ± 10 or arabinals 21 and 22
are employed as dienophiles. Among the
heterodienes tested, the a-naphthol de-
rivative 25 and the tyrosine derivative 26
were successfully used to prepare the
naphthyl-a-O-rhamnoside 32a and the
tyrosine-a-O-glucoside 34, respectively.
Cycloadducts 4a, 17, 24, and 33a were
successfully desulfurized, affording the
corresponding aryl 2-deoxy-a-O-glyco-
sides 39 and 40 ± 42.
phthalimide (1) is a suitable precursor
of the reactive ortho-thioquinone 2,
which can be generated in situ and
trapped by glycals. The reaction is an
inverse electron-demand [4‡2] cycload-
dition that occurs in a totally regiose-
lective and highly stereoselective way. A
series of differently substituted glycals
(3, 5 ± 12, 21, 22, 38) as well as various
ortho-thioquinones (25 ± 27) are success-
fully used as electron-rich dienophiles
Keywords:
desulfurizations
cycloadditions
glycosides
´
´
´
ortho-thioquinones
a new class of electron-poor heterodienes which can be
trapped in situ with suitable electron-rich dienophiles to
synthesize various benzo- and naphtho-condensed thio-sub-
stituted heterocycles[5] and in particular an isovanillin-con-
taining derivative known to be a powerful nonclassical
sweetener.[5] In this paper we report a new protocol for the
stereoselective synthesis of differently substituted 2-thio-O-
benzo- and O-naphthoglycosides and their successful trans-
formation into the corresponding aryl 2-deoxyglycosides.
Introduction
Aryl O-glycoside antibiotics represent an important class of
bioactive molecules which are an attractive target for many
organic chemists.[1] Several types of a- and b-2-deoxyglyco-
sides frequently appear as glycon moieties in naturally
occurring molecules such as the aureolic acid antibiotic
family.[2] The activity of these chemotherapeutic agents,
resulting from the selective inhibition of the DNA-dependent
RNA polymerization,[3] is strongly influenced by their carbo-
hydrate components. For these reasons, the stereoselective
formation of aryl ± glycoside bonds has been the topic of wide-
ranging studies and is still a challenge for the synthetic
carbohydrate chemist. However, the efficient and stereo-
controlled O-glycosidation of 2-deoxy sugars is a difficult
problem to solve, because of the lack of anchimeric assistance
from the substituent at C-2 and the instability of 2-deoxy-
glycosyl donors in acidic media.[4]
Results and Discussion
The easily prepared thiophthalimide derivative 1[5] is the
precursor of the ortho-thionaphthoquinone 2, an electron-
poor heterodiene which can be trapped by the tri-O-benzyl-
glucal 3 to give, with high stereoselectivity and complete
regioselectivity, the aryl O-glucosides 4a and 4b in an 80:20
ratio and in 85% overall yield[6] (Scheme 1). The [4‡2]
cycloaddition is performed in chloroform and in the presence
of 0.8 equivalents of pyridine[7] at 608C for three days. As
shown in Scheme 1, the single regioisomer formed affords the
oxygen of the ortho-thioquinone linked to the anomeric
carbon, while the sulfur is linked to the C-2 of the carbohy-
We reported recently an efficient method for the generation
of ortho-thiobenzoquinones and ortho-thionaphthoquinones,
[a] G. Capozzi, C. Nativi, C. Falciani, S. Menichetti, B. Raffaelli
Centro C.N.R. Chimica dei Composti Eterociclici
Á
Universita di Firenze
via G. Capponi 9, I-50121 Firenze (Italy)
Fax : (‡ 39)055-2476964
1
drate moiety. The analysis of H NMR chemical shifts and
coupling constants allowed the determination of the regio-
chemistry and stereochemistry of the major isomer 4a (d
E-mail: capozzi@chimorg.unifi.it
nativi@chimorg.unifi.it
1748
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Chem. Eur. J. 1999, 5, No. 6

1748±1754
Table 1. Reaction of ortho-thioquinone 2 with glycals 3, 5 ± 12.
Entry Glycal Product Solvent
a/b ratio Reaction Yield [%]
time[a]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
3
3
3
5
5
6
6
6
7
8
8
9
9
4
4
4
CHCl3
80/20
60/40
3 d
4 d
5 d
2 d
6 d
12 d
6 d
27 h
5 d
3 d
4 h
5 d
9 d
4 d
6 d
4 d
30 min
4 d
12 d
9 d
85
79
73
92
39
69
57
56
80
51
64
68
49
56
33
41
55
53
70
52
DMF[b]
DMSO[b] 55/45
13
13
14
14
14
15
16
16
17
17
17
18
18
18
19
20
20
DMF[b]
43/57
DMSO[b] 74/26
CHCl3
95/5
52/48
DMF[b]
DMSO[b] 73/27
CHCl3
90/10
a
DMF[b]
DMSO[b]
CHCl3
Scheme 1. Route from thiophthalimide derivative 1 to aryl O-glucosides
4a and 4b.
a
a
DMF[b]
DMSO[b]
CHCl3
a
9
a
H-1 ˆ 5.82, H-2 ˆ 3.46; J1,2 ˆ 3.0 Hz, J2,3 ˆ 10.2 Hz) and of the
minor isomer 4b (d H-1 ˆ 5.43, H-2 ˆ 3.75; J1,2 ˆ 1.1 Hz, J2,3
not detectable) (see Experimental Section). Quantum me-
chanics calculations indicated that the reaction was controlled
by the LUMO of the diene and the HOMO-1 of the
dienophile,[6, 8] and the orbital coefficients showed a favored
interaction between the sulfur of the ortho-thioquinone 2 and
the C-2 of the glucal 3. The stereochemistry of the result
obtained (see Scheme 1) clearly demonstrates a preferred
attack of the heterodiene from the a site of glucal 3, as it is
known for a glucal with three equatorial substituents.[9, 10]
To evaluate the suitability of this method for the general
synthesis of aryl 2-deoxy-2-thio-O-glycosides and to under-
stand the factors which could influence the stereoselectivity of
the reaction, we prepared a series of unsubstituted and
differently substituted glycals[11] to undergo cycloaddition
with the electron-poor diene 2. Moreover, the cycloadditions
were performed in chloroform, dimethylformamide, and
dimethyl sulfoxide to appraise possible solvent effects. The
dienophiles used (3, 5 ± 12) and the corresponding cyclo-
adducts (4, 13 ± 20), obtained as single regioisomers, are
reported in Table 1 and Scheme 2.
10
10
10
11
12
12
a
DMF[b]
DMSO[b]
DMF[b]
CHCl3
a
a
32/68
63/37
58/42
DMF[b]
[a] The reaction was monitored by tlc until the glycal was completely
consumed. [b] Diene/dienophile ratio ˆ 2/1.
Scheme 2. [4‡2] Cycloadditions between the electron-poor diene 2 and
electron-rich glycals 3, 5 ± 12.
R3
R4
R5
R3'
R4'
R5'
3, 4
OBn
OH
OH
OBn
OH
OBn
OH
H
OBn
OH
OH
OBn
OH
OBn
OH
H
CH2OBn
CH2OBn
CH2OtBDMS
CH2OtBDMS
CH2OH
CH2OBn
CH2OtBDMS
H
H
H
H
H
H
H
H
OH
OBn
H
H
H
H
H
H
H
OH
OBn
H
H
H
H
H
H
H
H
Me
5, 13
6, 14
7, 15
8, 16
9, 17
10, 18
11, 19
12, 20
Unlike the regiochemistry, the stereochemical outcome of
the cycloadditions cannot be explained by a single variable. In
chloroform the all-equatorial glycal series satisfies the general
H
H
H
Abstract in Italian: Lꢀorto-tiochinone 2, generato in situ a
Á
partire dallꢀ a-idrossinaftiltioftalimmide 1, puo essere intrap-
polato da glicali attraverso reazioni regiospecifiche e stereose-
lettive, di cicloaddizione [4‡2] a domanda elettronica inversa.
Vari glicali diversamente sostituiti (3, 5 ± 12, 21, 22, 38) e orto-
tiochinoni (25 ± 27) sono stati provati rispettivamente come
dienofili elettron-ricchi e dieni elettron-poveri, utilizzando
come solventi cloroformio, dimetilformammide e dimetilsol-
fossido. La stereochimica dei sostituenti presenti sul dienofilo
influenza sensibilmente la selettività della cicloaddizione che
risulta totale nel caso di dienofili quali i galattali 8 ± 10 o gli
arabinali 21 e 22. Tra gli eterodieni studiati il derivato dellꢀ a-
naftolo, 25 e il derivato della tirosina 26 sono stati utilizzati per
la sintesi del naftil-a-O-ramnoside 32a e del tirosin-a-O-
glucoside 34. La desolforazione dei cicloaddotti 4a, 17, 24 e
33a ha portato alla formazione dei corrispondenti 2-deossi-a-
O-glicosidi 39, 40 ± 42.
rule[10, 11] of a preferred a-site attack; the a-site selectivity
becomes strongly favored when a bulky group is present at
C-6 (bottom face; Table 1, entry 1 < entries 6 and 9). The
presence of an axial substituent determines an anti attack
(with respect to the axial group) on glycals, affording
completely stereoselective cycloadditions. In the galactal
series (axial group at C-4) (entries 10 ± 17), the a-cycloadducts
were obtained as single stereoisomers. Moreover, in the
arabinal series (S4, axial group at C-4) the b-cycloadducts
were stereospecifically formed (Scheme 3). The assignment of
the exact structure of 23 and 24 was accomplished by 1H NMR
analysis. Compound 23 showed a diagnostic doublet (J1,2
2.2 Hz) at d ˆ 5.8 for H-1 and a doublet of doublets (J2,3
ˆ
ˆ
12.0 Hz) at d ˆ 4.2 for H-2, while cycloadduct 24 presented a
doublet (J1,2 ˆ 2.8 Hz) at d ˆ 5.8 for H-1 and a doublet of
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G. Capozzi, C. Nativi et al.
FULL PAPER
Scheme 3. Stereochemistry of the cycloaddition in the arabinal series.
doublets (J2,3 ˆ 11.0 Hz) at d ˆ 3.6 for H-2. The stereochem-
istry depicted in Scheme 3 for both the cycloadducts is in
perfect agreement with the NMR data.
The use of the polar solvents dimethyl sulfoxide and
dimethylformamide generally reduces the face selectivity of
the cycloaddition. It is interesting that selectivity is still
observed in entries 5 and 8 of Table 1, where hydrogen
bonding between the solvent and the hydroxyl groups on the
dienophiles is possible. However, selectivity is diminished
when this H-bonding interaction is not possible (Table 1,
entry 3). The effect of solvent on cycloaddition rate is a
complex phenomenon since the heterodiene 2 in dimethyl-
formamide or dimethyl sulfoxide undergoes side reactions
which effectively reduce the concentration of the diene in the
reaction mixture.[12] In fact, when the cycloadditions are
performed in the above solvents, an excess of 2 is necessary to
complete the reaction. An interesting acceleration of the
cycloaddition is evident when glycals 6, 8, and 10 are reacted
in dimethyl sulfoxide (Table 1, entries 8, 11 and 17). Surpris-
ingly it does not occur with other glycals (entries 3, 5, 14).
Although the coordinative character of the solvent plays a
role (in dimethyl sulfoxide, cycloadditions take place even in
the absence of added pyridine), it does not in itself completely
explain the experimental data, which are too limited to
suggest any rationalization.
Figure 1. Molecular structure of cycloadducts reported in Table 2.
The extension of the cycloaddition to heterodienes 25 ± 27,
formed in situ from the parent phthalimidesulfenyl deriva-
tives 28 ± 30, gave the aryl 2-thio-O-glycosides 31 ± 37 as
single regioisomers (see Table 2). The heterodiene 25 came
from the phthalimide derivative 28, a precursor of the
aglycon of the antitumor antibiotic BE-12604B[13] (Figure 1),
while 26 was obtained from the phthalimide derivative 29,
which in turn was prepared by treatment of the N(Cbz)
(phenylmethoxycarbonyl)-protected[14]
tyrosine
methyl
ester with phthalimidesolfenyl chloride[5] (Scheme 4). The
cycloaddition results for dienes 25 ± 27 are summarized in
Table 2.
Scheme 4. Preparation of heterodienes 25 ± 27.
The general trend highlighted for data reported in Table 1 is
reproduced in Table 2. Worthy of mention are the cyclo-
adducts 32a and 34 (entries 2 and 4) obtained by reaction of
glycals 11 and 3 with 25 and 26, respectively. The a-naphthyl-
2,6-dideoxy-2-thio-l-glucoside 32a, completely separable
from 32b by flash chromatography on silica gel, is a precursor
of the 2-thio analogue of the antibiotic BE-12406B[13, 15]
(Figure 1), while the a-glycoside 34, formed in chloroform
with complete regio and stereoselectivity, is an example of a
glycoamino acid, the synthesis of which demonstrates the
potential of this new approach. Cycloadduct 33 was procured
by treating, in dimethylformamide, diene 25 with glycal 38,
prepared from commercially available quinovose following a
literature procedure[11] (Figure 1).
Table 2. Reaction of heterodienes 25 ± 27 with glycals 3, 5, 10, 11, 21, and
38.
Entry Diene Glycal Product Solvent a/b ratio Reaction Yield [%]
time
1
2
3
4
5
6
7
8
25
25
25
26
27
27
27
27
5
11
38
3
3
3
31
32
33
34
35
35
36
37
DMF[a] 4/1[b]
DMF[a] 2/1
DMF[a] 2/1
1.5 d[b] 52[b]
4 d
3 d
9 d
8 d
7 d
14 d
5 d
43
58
40
61
47
18
13
CHCl3
CHCl3
a
10/1
DMF[a] 3/1
10
21
CHCl3
DMSO[a]
a
b
[a] Diene/dienophile ratio ˆ 2/1. [b] After acetylation of the crude product.
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Glycoside Synthesis
1748±1754
residual CHCl3 at d ˆ 7.26 (for 1H) and a central peak of CDCl3 at d ˆ 77.0
(for 13C) served as reference lines. Mass spectra and GC-MS analyses were
obtained with a Carlo Erba gas chromatograph equipped with an OV101
30 m capillary column, interfaced on a mass spectrometer. Melting points
(uncorrected) were determined on a Büchi 510 apparatus. Rotations are
measured on a Jasco DIP-370 polarimeter at 258C. IR spectra were
recorded on a Perkin ± Elmer 881 spectrophotometer. Elemental analyses
were carried out with a Perkin ± Elmer 245 Elementary Analyser. CHCl3,
CH2Cl2 and THF were dried following standard procedures, and all
commercial reagents were used without further purification as obtained
from freshly opened containers. Phthalimidesulfenyl chloride was prepared
as reported elsewhere.[21]
Synthesis of aryl 2-deoxy-O-glycosides: The cycloaddition
protocol reported above allows the stereoselective formation
of an anomeric bond and the introduction of a thio group at
C-2 in a single step. The 2-thioglycosides obtained (Tables 1
and 2) were excellent intermediates, after removal of the
sulfur atom, for the synthesis of the corresponding aryl
2-deoxy-O-glycosides.[16] In fact, treatment of cycloadducts
4a, 17, and 24 with Raney nickel[17] in wet THF at room
temperature afforded the corresponding 2-deoxy-a- or 2-de-
oxy-b-O-glycosides 39, 40, 41 in good yield and without any
undesired rearrangement, which usually occurs when acidic
conditions are used[18, 19] (Scheme 5).
3,4-Di-O-benzyl-6-O-tert-butyldimethylsilyl-d-glucal (7): Compound 7 was
prepared by the monosilylation[22] and benzylation[23] of glucal 5 (216 mg,
1.5 mmol) following literature procedures, followed by flash column
chromatography (dichloromethane); 75% yield; glassy solid; 1H NMR:
d ˆ 0.10 (s, 6H), 0.94 (s, 9H), 3.91 ± 4.04 (m, 4H), 4.22 ± 4.25 (m, 1H), 4.64
(AB system, JAB ˆ 11.7 Hz, 2H), 4.75 ± 4.93 (m, 3H), 6.42 (dd, J ˆ 6.3,
1.1 Hz, 1H, H-1), 7.31 ± 7.38 (m, 10H); 13C NMR: d ˆ 5.4, 5.2, 18.3, 25.9,
61.7, 70.6, 73.9, 74.2, 75.8, 78.0; 99.8 (C-2), 127.6, 127.7, 127.8, 127.9, 128.4,
138.4, 144.7 (C-1); elemental analysis: calcd for C26H36O4Si (440.6): C 70.87,
H 8.23; found: C 70.72, H 8.13.
3,4,6-Tri-O-benzyl-d-galactal (9):[17, 23] Flash column chromatography (eth-
yl acetate:petroleum etherˆ 1:6); 80% yield; oil; 1H NMR: d ˆ 3.66 (A
part of an ABX system, JAB ˆ 10.1 Hz, 1H), 3.80 (B part of an ABX system,
JAB ˆ 10.1 Hz, 1H), 3.94 ± 3.98 (m, 1H), 4.18 ± 4.24 (m, 2H), 4.40 ± 4.71 (m,
5H), 4.82 ± 4.92 (m, 2H), 6.38 (dd, J ˆ 6.3 Hz, 1.5 Hz, 1H), 7.29 ± 7.37 (m,
15H); 13C NMR: d ˆ 68.4, 70.7, 70.8, 71.3, 73.3, 73.4, 75.6, 99.9 (C-2), 127.4,
127.5, 127.6, 127.8, 128.1, 128.3, 128.3, 138.0, 138.3, 138.5, 144.1 (C-1).
6-O-tert-Butyldimethylsilyl-d-galactal (10):[22] Flash column chromatogra-
phy (ethyl acetate:petroleum etherˆ 1:2); 50% yield; oil; 1H NMR: d ˆ
0.11 (s, 6H), 0.91 (s, 9H), 2.28 (brs, 2H), 3.88 ± 4.00 (m, 3H), 4.09 ± 4.12 (m,
1H), 4.30 ± 4.33 (m, 1H), 4.72 (dt, J ˆ 6.2, 2.0 Hz, 1H), 6.38 (dd, J ˆ 6.2,
1.4 Hz, 1H, H-1); 13C NMR: d ˆ 18.2, 25.7, 62.9, 64.1, 65.6 (C-3, C-4, C-5),
76.0 (C-6), 102.9 (C-2), 144.3 (C-1); elemental analysis: calcd for
C12H24O4Si (260.4): C 55.35, H 9.29; found: C 55.02, H 9.20.
Scheme 5. Desulfurization of 2-thioglycoside 4a with Raney nickel to give
39, and the structures of 2-deoxy-O-glycosides 40 ± 42.
Desulfurization of 33a with Raney nickel proved unsat-
isfactory (10% yield) because of its instability in the reaction
medium. Better results were obtained by treating the cyclo-
adduct with NiCl2 ± NaBH4 in a methanol/tetrahydrofuran
solvent mixture[20] at 108C for 10 min. The 2-deoxy glyco-
side 42 was prepared in 45% yield under these milder
conditions.
6-Deoxy-l-glucal (11):[11] Flash column chromatography (dichloro-
methane:methanol ˆ 5:1); 92% yield; oil; 1H NMR ([D4]CH3OH): d ˆ
1.36 (d, J ˆ 7.0 Hz, 3H, CH3), 3.25 ± 3.53 (m, 1H), 3.71 ± 3.85 (m, 1H), 4.09 ±
4.13 (m, 1H), 4.70 (dd, J ˆ 5.8, 2.1 Hz, 1H), 4.98 (s, 2H), 6.33 (d, J ˆ 5.8 Hz,
1H, H-1); 13C NMR ([D4]CH3OH): d ˆ 18.1 (C-6), 71.0 (C-5), 76.4 (C-3),
76.5 (C-4), 105.1 (C-2), 145.5 (C-1); elemental analysis: calcd for C6H10O3
(130.1): C 55.37, H 7.74; found: C 55.50, H 7.76.
d-arabinal
(21):[11]
Flash
column
chromatography
(dichloro-
methane:methanol ˆ 10:1); 98% yield; oil; 1H NMR ([D4]CH3OH): d ˆ
3.88 ± 4.00 (m, 3H, CH2-5, H-4), 4.18 ± 4.23 (m, 1H, H-3), 4.92 ± 4.99 (m,
3H), 6.52 (dd, J ˆ 6.0, 0.8 Hz, 1H); 13C NMR ([D4]CH3OH): d ˆ 65.7, 68.4,
70.1 (C-3, C-4, C-5), 104.9 (C-2), 149.6 (C-1); elemental analysis: calcd for
C5H8O3 (130.1): C 51.72, H 6.94; found: C 51.50, H 6.91.
Conclusion
We have shown that ortho-thioquinones, easily formed in situ
from their phthalimido derivatives, represent an interesting
class of electron-poor heterodienes. The heterodienes can
cycloadd to a variety of glycals, with their hydroxyls blocked
or completely unprotected, to form regio- and stereoselec-
tively the corresponding aryl 2-deoxy-2-thio-a- or b-O-glyco-
sides. Reductive desulfurization of four different 2-thioglyco-
sides gave the expected 2-deoxy-O-glycosides in good yield.
Thus, in a few simple steps, aryl 2-deoxyglycosides were
prepared without recourse to conventional glycoside chem-
istry. Further aspects of the reactivity of this 1,4-oxathiin
system are currently under investigation in our laboratories.
3,4-Di-O-benzyl-d-arabinal (22):[23] Flash column chromatography (ethyl
acetate:petroleum etherˆ 1:5) gave a glassy solid; 73% yield; 1H NMR:
d ˆ 3.75 (dt, J ˆ 9.8, 3.8 Hz, 1H), 3.97 ± 4.12 (m, 3H), 4.50 ± 4.72 (m, 4H),
4.87 (t, J ˆ 5.8 Hz, 1H), 6.40 (d, J ˆ 5.8 Hz, 1H, H-1), 7.28 ± 7.41 (m, 10H).
13C NMR: d ˆ 63.2 (C-5), 66.7, 73.2 (C-3, C-4), 70.87, 71.0, 98.8 (C-2), 127.5,
127.7, 127.8, 127.8, 128.4, 138.05, 138.8, 146.5 (C-1); elemental analysis: calcd
for C19H20O3 (296.4): C 77.00, H 6.80; found: C 76.70, H 6.84.
General procedure for cycloaddition reactions: All the cycloadditions were
performed at 608C by adding 0.8 equiv of freshly distilled pyridine to a
mixture of the sulfenamide and glycal in a 0.8:1 ratio; 0.4 equiv of
sulfenamide was subsequently added in two portions (1.2 equiv in four
portions for reactions performed in DMF or DMSO). The reactions were
monitored by NMR (0.1 mmol scale/CDCl3 or [D6]DMSO) or by TLC
(DMF). The crude reaction mixtures were diluted with CH2Cl2 (30 mL),
washed with saturated NH4Cl (2 Â 15 mL) and water (2 Â 20 mL) and dried
over anhydrous Na2SO4. Flash chromatography on silica gel (ethyl acetate/
petroleum ether) was used to purify the crude products (solids were
recrystallized when necessary). Physical and spectroscopic data of com-
pounds 4, 13 ± 20, 23, 24, 31 ± 37 obtained by this general procedure are as
follows.
Experimental Section
General: H and 13C NMR spectra were recorded on a Varian Gemini in
CDCl3 (unless otherwise specified) at 200 and 50 MHz, respectively;
1
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G. Capozzi, C. Nativi et al.
FULL PAPER
3,4,6-Tri-O-benzyl-2-deoxy-d-glucopyranose[1,2-b]naphtho[1,2-e]-1,4-oxa-
thiin (4a): A white solid was obtained; m.p. 134 ± 1358C (ethyl acetate/
[a]2D0 ˆ ‡8.0 (c ˆ 4.5 in CHCl3); 1H NMR: d ˆ 2.02, 2.10, 2.20 (3s, 9H), 3.80
(dd, J ˆ 2.6, 11.8 Hz, 1H, H-2), 4.21 ± 4.24 (m, 2H), 4.62 ± 4.68 (m, 1H), 5.16
(dd, J ˆ 11.8, 3.1 Hz, 1H), 5.47 ± 5.48 (m, 1H), 5.86 (d, J ˆ 2.6 Hz, 1H, H-1),
7.10 (d, J ˆ 8.8 Hz, 1H), 7.36 ± 7.60 (m, 3H), 7.74 ± 7.83 (m, 2H); 13C NMR:
d ˆ 20.5, 20.6, 20.7 (3CH3), 36.7 (C-2), 61.6 (C-6), 67.3, 67.4, 68.6 (C-3, C-4,
C-5), 94.49 (C-1), 106.9, 119.1, 122.8, 124.6, 126.6, 126.8, 128.4, 129.8, 130.6,
148.5, 169.7, 169.9, 170.4; elemental analysis: calcd for C22H22O8S (446.5): C
59.18, H 4.97; found: C 59.00, H 4.99.
1
petroleum ether); [a]2D0 ˆ ‡4.0 (c ˆ 2.4 in CHCl3); H NMR: d ˆ 3.46 (dd,
J ˆ 3.0, 10.2 Hz, 1H, H-2), 3.72 ± 3.92 (m, 4H), 4.22 (dt, J ˆ 9.4 Hz, 1H),
4.53 ± 4.87 (m, 6H), 5.82 (d, J ˆ 3.0 Hz, 1H, H-1), 7.07 ± 7.61 (m, 19H), 7.79
(d, J ˆ 7.4 Hz, 1H), 7.95 (d, J ˆ 7.8 Hz, 1H); 13C NMR: d ˆ 42.5 (C-2), 68.2
(C-6), 72.9, 73.6, 75.2, 76.4, 78.4, 78.8 (C-3, C-4, C-5, 3CH2), 95.1 (C-1),
107.2, 123.0, 124.4, 126.8, 126.8, 127.9, 128.0, 128.1, 128.4, 128.4, 129.7, 131.2,
137.9, 138.0, 149.7; elemental analysis: calcd for C37H34O5S (590.7): C 75.23,
H 5.80; found: C 75.07, H 5.60.
(1S,2S)-3,4,6-Tri-O-benzyl-2-deoxy-a-d-galactopyranose[1,2-b]naphtho-
[1,2-e]-1,4-oxathiin (17): Compound 17 was obtained as a glassy solid;
1H NMR: d ˆ 3.65 ± 3.71 (m, 3H), 3.97 ± 4.04 (m, 2H), 4.32 (t, J ˆ 6.7 Hz,
1H), 4.45 ± 4.65 (2 AB system and B part of an AB system, 5H), 4.98 (A
part of an AB system, JAB ˆ 11.2 Hz, 1H), 5.86 (d, J ˆ 2.8 Hz, 1H, H-1),
7.02 ± 7.60 (m, 19H), 7.78 (d, J ˆ 8.2 Hz, 1H), 7.99 (d, J ˆ 8.4 Hz, 1H);
13C NMR: d ˆ 38.8 (C-2), 68.5 (C-6), 71.7, 73.5, 74.9 (C-3, C-4, C-5), 72.7,
73.6, 74.8, 95.56 (C-1), 107.6, 123.0, 128.3, 136.5, 126.6, 127.6, 127.6, 127.7,
127.8, 127.9, 128.2, 128.2, 128.3, 128.4, 129.6, 131.1, 137.4, 137.7, 138.2, 149.4;
elemental analysis: calcd for C37H34O5S (590.8): C 75.23, H 5.80; found: C
75.34, H 5.87.
1
Compound 4b: A glassy solid was obtained; H NMR: d ˆ 3.69 ± 3.78 (m,
3H), 4.08 ± 4.25 (m, 3H), 4.48 (AB system, JAB 12.1 Hz, 2H), 4.62 (t, J
11.0 Hz, 2H), 4.90 (AB system, JAB 11.1 Hz, 2H), 5.43 (d, J ˆ 1.1 Hz, 1H,
H-1), 7.12 ± 7.58 (m, 19H), 7.77 (d, J 7.8 Hz, 1H), 8.03 (d, J 7.8 Hz, 1H,);
13C NMR: d ˆ 41.2 (C-2), 68.6, 71.0, 73.4, 75.3 (C-6, 3CH2), 73.7, 77.0, 80.5,
(C-3, C-4, C-5), 91.8 (C-1), 110.2, 119.4, 122.5, 124.4, 126.0, 126.4, 127.4,
127.8, 127.8, 128.0, 128.2, 128.3, 128.4, 128.6, 129.7, 130.9, 137.3, 138.1, 138.2,
145.7; MS (70 eV, EI): m/z (%) ˆ 591 (1) [M‡1], 91 (100).
2-Deoxy-d-glucopyranose[1,2-b]naphtho[1,2-e]-1,4-oxathiin (13a): Com-
pound 13a was obtained as a waxy solid after acetylation under standard
conditions; [a]2D0 ˆ ‡104.6 (c ˆ 0.2 in CHCl3); 1H NMR: d ˆ 1.98, 2.05, 2.13
(3s, 9H), 3.54 (dd, J ˆ 10.6, 2.8 Hz, 1H, H-2), 4.16 ± 4.48 (m, 3H), 5.17 ± 5.33
(m, J ˆ 9.8 Hz, 2H), 5.79 (d, J ˆ 2.8 Hz, 1H, H-1), 7.08 (d, J ˆ 8.8 Hz, 1H),
7.28 ± 7.94 (m, 5H); 13C NMR: d ˆ 20.5, 20.7, 20.9 (3CH3), 40.5 (C-2), 60.2
(C-6), 68.8, 69.6, 69.7 (C-3, C-4, C-5), 93.8 (C-1), 106.8; 118.9, 122.8, 124.6,
126.6, 126.9, 128.3, 130.6, 135.3, 148.6; 169.6, 169.6, 170.6 (3CO); elemental
analysis: calcd for C22H22O8S (446.5): C 59.18, H 4.97; found: C 59.29, H
5.03.
(1S,2S)-6-O-tert-Butyldimethylsilyl-2-deoxy-a-d-galactopyranose[1,2-b]-
naphtho[1,2-e]-1,4-oxathiin (18): Compound 18 was obtained as a white
solid after acetylation under standard conditions; m.p. 62 ± 638C (ethyl
1
acetate/petroleum ether); [a]2D0 ˆ ‡4.1 (c ˆ 16.7 in CHCl3); H NMR: d ˆ
0.05, 0.07 (2s, 6H), 0.87 (s, 9H), 2.02, 2.18 (2s, 6H), 3.63 ± 3.85 (m, 3H),
4.44 ± 4.52 (m, 1H), 5.18 (dd, J ˆ 11.5, 3.1 Hz, 1H), 5.65 ± 5.58 (m, 1H), 5.84
(d, J ˆ 2.6 Hz, 1H, H-1), 7.09 (d, J ˆ 8.8 Hz, 1H), 7.36 ± 7.83 (m, 5H);
13C NMR: d ˆ 5.7, 18.2, 20.6, 20.7, 25.7, 37.1 (C-2), 60.6 (C-6), 67.3, 67.8,
71.0 (C-3, C-4, C-5), 94.7 (C-1), 107.0, 119.2, 122.8, 124.5, 126.6, 126.7, 128.4,
129.8, 130.7, 148.69, 169.74; elemental analysis: calcd for C26H34O7SSi
(518.7): C 60.21, H 6.61; found: C 60.20, H 6.64.
Compound 13b: Compound 13b was obtained as an oil after acetylation
under standard conditions; [a]D20
ˆ
73.8 (c ˆ 0.1 in CHCl3); 1H NMR: d ˆ
1.99, 2.08, 2.12 (3s, 9H), 3.83 ± 3.93 (m, J ˆ 9.4, 4.0 Hz, 1H), 4.06 (brdd, J ˆ
4.4, 1.6 Hz, 1H, H-2), 4.21 (brd, 2H), 5.41 (dd, J ˆ 9.2, 4.4 Hz, 1H), 5.56 (d,
J ˆ 1.6 Hz, 1H, H-1), 5.63 (brt, J ˆ 9.4 Hz, 1H), 7.10 (d, J ˆ 8.8 Hz, 1H,
1H), 7.28 ± 7.94 (m, 5H); 13C NMR: d ˆ 20.5 (3CH3), 40.8 (C-2), 62.2 (C-6),
65.2, 71.9, 73.4 (C-3, C-4, C-5), 91.1 (C-1), 108.8, 119.0, 122.1, 124.4, 126.2,
126.4, 128.2, 130.4, 135.2, 145.1, 169.4, 169.7, 170.5 (3CO); MS (70 eV, EI):
2,6-Dideoxy-l-glucopyranose[1,2-b]naphtho[1,2-e]-1,4-oxathiin
(19a):
Compound 19a was obtained as a white solid after acetylation under
standard conditions; m.p. 148 ± 1508C (ethyl acetate/petroleum ether);
[a]2D0
ˆ
16.7 (c ˆ 3.1 in CHCl3); 1H NMR: d ˆ 1.30 (d, J ˆ 6.2 Hz, 3H),
2.00 (s, 3H), 2.06 (s, 3H), 3.51 (dd, J ˆ 2.8, 11.0 Hz, 1H, H-2), 4.26 ± 4.40 (m,
1H), 4.90 (t, J ˆ 9.7 Hz, 1H), 5.24 (dd, J ˆ 9.4, 10.8 Hz, 1H), 5.74 (d, J ˆ
2.6 Hz, 1H, H-1), 7.09 (d, J ˆ 8.8 Hz, 1H), 7.35 ± 7.60 (m, 3H), 7.73 ± 7.80 (m,
2H); 13C NMR: d ˆ 17.4, 20.6, 41.0 (C-2), 67.7, 69.8, 74.5 (C-3, C-4, C-5),
93.9 (C-1), 107.0, 119.1, 123.0, 124.6, 126.7, 127.0, 128.4, 129.8, 130.8, 149.0,
167.8, 169.8; elemental analysis: calcd for C20H20O6S (388.4): C 61.84, H
5.19; found: C 61.55, H 5.20.
.
‡
m/z (%) ˆ 446 (21.0) [M ], 146 (100).
6-O-tert-Butyldimethylsilyl-2-deoxy-d-glucopyranose[1,2-b]naphtho[1,2-e]-
1,4-oxathiin (14a): Compound 14a was obtained as a white solid; m.p.
134 ± 1368C (ethyl acetate/petroleum ether); [a]D20
ˆ
1.3 (c ˆ 10.55 in
CHCl3); 1H NMR: d ˆ 0.14 (s, 6H), 0.93 (s, 9H), 2.87 (brs, 1H), 3.27 ± 3.34
(m, J ˆ 2.9 Hz, 2H), 3.76 ± 4.078 (m, 5H), 5.75 (d, J ˆ 2.9 Hz, 1H, H-1), 7.07
(d, J ˆ 8.8 Hz, 1H), 7.28 ± 7.94 (m, 5H); 13C NMR: d ˆ 5.4 (2CH3), 18.3,
25.9 (3CH3), 42.8 (C-2), 63.9 (C-6), 70.4, 72.4, 72.9 (C-3, C-4, C-5), 94.4 (C-
1), 119.2, 122.9, 123.6, 124.5, 126.8, 126.9, 128.4, 129.6, 134.3, 149.41;
elemental analysis: calcd for C22H30O5SSi (434.6): C 60.80, H 6.96; found: C
60.53, H 6.85.
Compound 19b: Compound 19b was obtained as a pale yellow solid after
acetylation under standard conditions; m.p. 188 ± 1908C (ethyl acetate/
1
petroleum ether); [a]2D0 ˆ ‡13.5 (c ˆ 2.4 in CHCl3); H NMR: d ˆ 1.29 (d,
J ˆ 5.8 Hz, 3H), 2.09 (s, 3H), 2.16 (s, 3H), 3.70 ± 3.84 (m, 1H), 4.11 (dd, J ˆ
1.2, 4.0 Hz, 1H, H-2), 5.32 ± 5.46 (m, 2H), 5.53 (d, J ˆ 1.2 Hz, 1H, H-1), 7.12
(d, J ˆ 8.8 Hz, 1H), 7.30 ± 7.58 (m, 3H), 7.75 (d, J ˆ 7.8 Hz, 1H), 7.96 (d, J ˆ
8.4 Hz, 1H); 13C NMR: d ˆ 17.6, 20.7, 41.4 (C-2), 70.2, 72.0, 72.3 (C-3, C-4,
C-5), 91.2 (C-1), 109.1, 119.2, 122.3, 124.6, 126.3, 126.5, 128.3, 129.8, 130.72,
145.3, 169.7, 170.1.
Compound (14b): Compound 14b was obtained as a yellowish solid; m.p.
55 ± 608C (ethyl acetate/petroleum ether); [a]D20
ˆ
4.4 (c ˆ 6.70 in
CHCl3); 1H NMR: d ˆ 0.01 (s, 3H), 0.03 (s, 3H), 0.84 (s, 9H), 3.16 (s,
1H), 3.56 ± 3.63 (m, 1H), 3.76 ± 3.85 (m, 2H), 3.97 ± 4.26 (m, 4H), 5.47 (d,
J ˆ 1.6 Hz, 1H, H-1), 7.09 (d, J ˆ 8.8 Hz, 1H), 7.38 ± 7.55 (m, 3H), 7.74 (d,
J ˆ 7.6 Hz, 1H); 7.99 (d, J ˆ 7.6 Hz, 1H); 13C NMR: d ˆ 5.8, 5.7; 18.0
(Cq); 25.7 (3CH3), 42.6 (C-2), 65.3 (C-6), 71.2, 73.4, 74.8 (C-3, C-4, C-5), 91.7
(C-1), 110.2, 119.2, 122.5, 124.5, 125.9, 126.4, 128.2 129.74, 130.78, 145.35;
3,4-Di-O-benzyl-2,6-dideoxy-l-glucopyranose[2,1-b]naphtho[1,2-e]-1,4-
oxathiin (20a): Compound 20a was obtained as a white solid; m.p. 94± 978C
(ethyl acetate/petroleum ether); [a]D20
ˆ
7.0 (c ˆ 3.1 in CHCl3); 1H NMR:
d ˆ 1.41 (d, J ˆ 6.4 Hz, 3H, CH3), 3.33 (t, J ˆ 9.1 Hz, 1H), 3.43 (dd, J ˆ 3.0,
10.6 Hz, 1H, H-2), 3.73 (dd, J ˆ8.8, 10.6 Hz, 1H), 4.12 ± 4.27 (m, 1H),
4.58 ± 4.93 (m, 4H), 5.74 (d, J ˆ 3.0 Hz, 1H, H-1), 7.12 (d, J ˆ 8.8 Hz, 1H),
7.27 ± 7.62 (m, 13H), 7.79 (d, J ˆ 8.4 Hz, 1H), 7.96 (d, J ˆ 8.0 Hz, 1H);
13C NMR: d ˆ 17.9 (C-6), 42.9 (C-2), 69.6 (C-5), 75.5, 76.4, 78.6, 84.6 (C-3,
C-4), 94.9 (C-1), 107.2, 119.2, 123.0, 124.4, 126.8, 126.9, 127.7, 127.8, 127.9,
128.2, 128.4, 128.5, 129.7, 131.2, 137.9, 138.0, 149.8; elemental analysis: calcd
for C30H28O4S (484.6): C 74.35, H 5.82; found: C 74.15, H 5.90.
.
‡
MS (70 eV, EI): m/z (%) ˆ 434 (6) [M ], 117 (100).
6-O-tert-Butyldimethylsilyl-3,4-di-O-benzyl-2-deoxy-d-glucopyranose[1,2-b]-
naphtho[1,2-e]-1,4-oxathiin (15a): Compound 15a was obtained as a pale
yellow oil; [a]2D0 ˆ ‡48.5 (c ˆ 0.2 in CHCl3); 1H NMR: d ˆ 0.12 (s, 3H), 0.13
(s, 3H), 0.94 (s, 9H), 3.40 (dd, J ˆ 2.8, 10.2 Hz, 1H, H-2), 3.71 ± 4.08 (m,
5H), 4.57 ± 4.90 (m, 4H), 5.79 (d, J ˆ 2.6 Hz, 1H, H-1), 7.09 ± 7.60 (m, 14H),
7.78 (d, J ˆ 8.4 Hz, 1H), 7.95 (d, J ˆ 8.4 Hz, 1H); 13C NMR: d ˆ 5.3, 5.0,
18.3, 25.9, 42.7 (C-2), 61.6 (C-6), 72.1, 75.2, 74.1, 78.2, 78.6 (C-3, C-4, C-5),
95.2 (C-1), 107.3, 119.1, 123.0, 124.4, 126.2, 126.4, 126.7, 127.6, 127.8, 127.9,
128.3, 128.4, 128.5, 128.9, 129.1, 129.7, 131.2, 138.0, 138.2,149.8; elemental
analysis: calcd for C37H42O5SSi (614.9): C 70.32, H 6.88; found: C 70.36, H
6.91.
Compound 20b: Compound 20b was obtained as a white solid; m.p. 80 ±
828C (ethyl acetate/petroleum ether); 1H NMR: d ˆ 1.38 (d, J ˆ 6.2 Hz,
3H, CH3), 3.55 ± 3.70 (m, 1H), 3.77 ± 3.88 (m, 1H), 4.03 ± 4.10 (m, 2H), 4.66
(AB system, JAB ˆ 11.0 Hz, 2H), 4.94 (AB system, JAB ˆ 11.3 Hz, 2H), 5.40
(d, J ˆ 1.2 Hz, 1H, H-1), 7.13 (d, J ˆ 8.8 Hz, 1H), 7.29 ± 7.58 (m, 13H), 7.76
(d, J ˆ 7.0 Hz, 1H), 8.03 (d, J ˆ 8.4 Hz, 1H); 13C NMR: 18.0 (C-6), 41.3 (C-
2), 70.9, 73.2, 75.6, 79.2, 80.4 (C-3, C-4, C-5), 91.8 (C-1), 109.9, 119.3, 122.5,
124.4, 126.1, 126.4, 127.8, 128.1, 128.3, 128.4, 128.6, 129.7, 131.0, 137.3, 138.2,
145.6.
(1S,2S)-2-Deoxy-a-d-galactopyranose[1,2-b]naphtho[1,2-e]-1,4-oxathiin
(16): Compound 16 was obtained as a white solid after acetylation under
standard conditions; m.p. 169 ± 1728C (ethyl acetate/petroleum ether);
1752
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0506-1752 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 6

Glycoside Synthesis
1748±1754
(1R,2R)-2-Deoxy-b-d-arabinopyranose[1,2-b]naphtho[1,2-e]-1,4-oxathiin
(23): Compound 23 was obtained as a waxy solid; m.p. 192 ± 1958C
4.14 (m, 1H), 4.50 ± 4.86 (m, 7H), 5.10 (s, 2H), 5.23 (brd, 1H), 5.68 (d, J ˆ
2.6 Hz, 1H, H-1), 6.76 ± 6.81 (m, 3H), 7.11 ± 7.33 (m, 20H); 13C NMR: d ˆ
37.5, 43.1, 52.3, 54.7 (C-2), 67.0, 68.1 (C-6), 72.9 (C-4), 73.6 (C-3), 75.2, 78.5,
79.0, 95.2 (C-5), 101.7 (C-1), 118.0, 118.2, 123.6, 127.4, 127.8, 127.9, 128.0,
128.1, 128.2, 128.4, 128.5, 128.6, 129.6, 132.6, 137.8, 137.9, 138.0, 151.1, 155.8,
171.8; elemental analysis: calcd for C45H45O9NS (775.9): C 69.66, H 5.85;
found: C 69.50, H 5.91.
(decomp) (ethyl acetate/petroleum ether); [a]D20
ˆ
9.0 (c ˆ 3.05 in
MeOH); 1H NMR ([D4]CH3OH): d ˆ 3.71 (A part of an ABX system,
JAB ˆ 10.6 Hz, 1H), 3.78 (B part of an ABX system, JAB ˆ 10.6 Hz, 1H),
3.86 ± 3.95 (m, 2H), 4.22 ± 4.28 (d, J ˆ 12.0 Hz, 1H), 5.53 (s, 2H), 5.80 (d,
J ˆ 2.2 Hz, 1H, H-1), 7.10 (d, J ˆ 8.8 Hz, 1H), 7.38 ± 7.65 (m, 3H), 7.81 (d,
J ˆ 8.0 Hz, 1H), 7.95 (d, J ˆ 8.4 Hz, 1H); 13C NMR ([D4]CH3OH): d ˆ 41.2
(C-2), 66.4, 67.7, 70.2 (C-3, C-4, C-5), 96.8 (C-1), 108.8, 120.11, 124.0, 125.4,
127.5, 129.4, 131.1, 132.5, 135.4, 150.7; elemental analysis: calcd for
C15H14O4S (290.3): C 62.05, H 4.86; found: C 61.87, H 4.81.
3,4,6-Tri-O-benzyl-2-deoxy-d-glucopyranose[2,1-b](5-methoxy)benzo-
[2,1-e]-1,4-oxathiin (35a): Compound 35a was obtained as a white solid;
m.p. 85 ± 878C (ethyl acetate/petroleum ether); 1H NMR: d ˆ 3.22 ± 3.29
(dd, J ˆ 2.8, 10.2 Hz, 1H, H-2), 3.65 ± 3.86 (m, 7H); 4.09 ± 4.14 (m, 1H);
4.50 ± 4.90 (m, 6H), 4.74, (d, J ˆ 2.8 Hz, 1H, H-1), 6.47 ± 6.54 (m, 2H), 6.99
(d, J ˆ 8.2 Hz, 1H), 7.14 ± 7.36 (m, 15H); 13C NMR: d ˆ 42.9 (OCH3), 55.4
(C-2), 68.1 (C-6), 72.8 (C-4), 73.6, 75.2; 76.3 (C-3), 95.6 (C-5), 103.2 (C-1),
104.8, 109.6, 127.7, 127.8, 127.9, 128.0, 128.1, 128.4, 128.6, 129.4, 137.8, 138.0,
(1R,2R)-3,4-Di-O-benzyl-2-deoxy-b-d-arabinopyranose[1,2-b]naphtho-
[1,2-e]-1,4-oxathiin (24): Compound 24 was obtained as a glassy solid;
[a]2D0
ˆ
15.0 (c ˆ 1.1 in CHCl3); 1H NMR: d ˆ 3.65 (dd, J ˆ 2.8 Hz,
11.0 Hz, 1H), 3.78 ± 3.80 (m, 1H), 3.99 ± 4.06 (m, 3H), 4.52 (s, 2H), 4.79
(AB system, JAB ˆ 12.4 Hz, 2H), 5.87 (d, J ˆ 2.6 Hz, 1H, H-1), 7.03 ± 7.58
(m, 14H), 7.78 (d, J ˆ 8.8 Hz, 1H), 8.01 (d, J ˆ 8.6 Hz, 1H); 13C NMR
(75 MHz): d ˆ 38.2 (C-2), 62.6 (C-5), 71.8, 72.2, 72.5, 73.2 (C-3, C-4), 95.6
(C-1), 107.8, 118.9, 122.8, 123.1, 124.3, 126.4, 126.6, 126.8, 127.5, 127.6, 127.8,
127.9, 128.1, 128.3, 129.6, 131.1, 137.4, 138.0, 149.2; elemental analysis: calcd
for C29H26O4S (470.6): C 74.02, H 5.57; found: C 73.60, H 5.80.
.
‡
153.0, 158.9; MS (70 eV, EI): m/z (%) ˆ 570 (10.7) [M ], 462 (33), 208 (26),
91 (100); elemental analysis: calcd for C34H34O6S (570.7): C 71.56, H 6.00;
found: C 71.38, H 6.25.
Compound 35b: Compound 35b was obtained as an oil; 1H NMR: d ˆ
3.68 ± 4.11 (m, 9H), 4.51 ± 4.89 (m, 6H), 5.31 (d, J ˆ 1.8 Hz, 1H, H-1), 6.52 ±
6.57 (m, 2H), 6.99 (d, J ˆ 9.7 Hz, 1H), 7.18 ± 7.37 (m, 15H); 13C NMR: d ˆ
41.3 (OCH3), 55.4 (C-2), 68.6 (C-6), 70.8 (C-3), 73.4, 73.5, 75.2 (C-4), 80.4
(C-5), 92.2 (C-1), 103.8, 107.4, 109.6, 127.5, 127.8, 127.9, 128.0, 128.2, 128.4,
128.5, 137.3, 138.1, 158.3.
2-Deoxy-d-glucopyranose[1,2-b](4-acetoxy-8-benzyloxy)naphtho[2,1-e]-
1,4-oxathiin (31a): Compound 31a was obtained as a glassy solid after
acetylation under standard conditions; 1H NMR: d ˆ 1.96, 2.02, 2.05 (3s,
9H), 2.41 (s, 3H), 3.23 (A part of an ABX system, JAB ˆ 12.8 Hz, 1H), 3.41
(dd, J ˆ 10.6, 2.8 Hz, 1H), 3.94 (B part of an ABX system, JAB ˆ 12.8 Hz,
1H), 4.05 ± 4.11 (m, 1H), 5.06 ± 5.36 (m, 4H), 5.86 (d, J ˆ 2.6 Hz, 1H, H-1),
6.91 (s, 1H), 7.01 (t, J ˆ 4.4 Hz, 1H), 7.36 ± 7.57 (m, 7H); 13C NMR: d ˆ 20.5,
20.6, 20.9, 41.0 (C-2), 60.9 (C-6), 68.5, 69.5, 69.9 (C-3, C-4, C-5), 71.7, 94.8
(C-1), 107.8, 109.7, 114.1, 119.7, 123.5, 126.6, 127.1, 128.0, 128.1, 128.6, 134.2,
136.6, 140.6, 145.4, 155.4, 169.3, 169.5, 169.8, 170.5; elemental analysis:
calcd for C31H30O11S (610.6): C 60.98, H 4.95; found: C 60.65; H 5.00.
(1S,2S)-6-tert-Butyldimethylsilyl-2-deoxy-a-d-galactopyranose[1,2-b]-
(5-methoxy)benzo[2,1-e]-1,4-oxathiin (36): Compound 36 was obtained as
an oil; 1H NMR: d ˆ 0.01, 0.12 (2s, 6H), 0.90 (s, 9H), 2.69 (d, 1H); 3.50 (dd,
J ˆ 3.2, 10.8 Hz, 1H, H-2), 3.65 ± 4.22 (m, 9H), 5.75 (d, J ˆ 3.0 Hz, 1H,
H-1), 6.40 ± 6.53 (m, 2H), 6.99 (d, J ˆ 8.4 Hz, 1H); 13C NMR: d ˆ 5.6,
18.2, 25.8, 39.9 (C-2), 55.4 (OCH3), 63.7, 67.0, 69.2, 71.1 (C-3, C-4, C-5, C-6),
95.5 (C-1), 107.8, 103.2, 109.3, 123.6, 152.8, 158.9; elemental analysis: calcd
for C19H30O6SiS (414.6): C 55.04, H 7.29; found: C 55.18, H 7.13.
2,6-Dideoxy-a-l-glucopyranose[1,2-b](4-acetoxy-8-benzyloxy)naphtho-
[2,1-e]-1,4-oxathiin (32a): Compound 32a was obtained as a pale yellow
(1R,2R)-2-Deoxy-b-d-arabinopyranose[1,2-b](5-methoxy)benzo[2,1-e]-
1,4-oxathiin (37): Flash column chromatography (dichloromethane/meth-
anol) gave compound 37 as an oil; 1H NMR ([D4]CH3OH): d ˆ 3.60 (dd,
J ˆ 2.8, 10.8 Hz, 1H, H-2), 3.77 ± 4.06 (m, 6H), 4.25 ± 4.32 (m, 1H), 5.05
(brs, 2H), 5.83 (d, J ˆ 3.0 Hz, 1H, H-1), 6.61 ± 6.71 (m, 2H), 7.15 (d, J ˆ
8.4 Hz, 1H); 13C NMR ([D4]CH3OH): d ˆ 41.3 (OCH3), 55.8 (C-2), 66.3,
67.3, 70.0 (C-3, C-4, C-5), 97.4 (C-1), 106.3, 104.1, 110.1, 129.0, 154.2, 160.3;
elemental analysis: calcd for C12H14O5S (270.3): C 53.32, H 5.22; found: C
53.12, H 5.23.
solid; m.p. 175 ± 1798C (ethyl acetate/petroleum ether); [a]D20
ˆ
326.3
1
(c ˆ 0.1 in CHCl3); H NMR: d ˆ 0.95 (d, J ˆ 6.4 Hz, 3H, CH3-6), 2.41 (s,
3H), 2.49 (brs, 1H), 2.92 (brs, 1H), 3.16 (dd, J ˆ 2.8, 10.8 Hz, 1H, H-2),
3.26 (t, J ˆ 9.4 Hz, 1H), 3.71 (t, J ˆ 9.7 Hz, 1H), 3.86 ± 3.94 (m, 1H), 5.14
(AB system, JAB ˆ 11.7 Hz, 2H), 5.74 (d, J ˆ 2.6 Hz, 1H, H-1), 6.93 ± 6.70
(m, 2H), 7.32 ± 7.57 (m, 7H); 13C NMR: d ˆ 17.3 (C-6), 20.9, 43.5 (C-2), 69.8,
70.7, 71.9 (C-3, C-4, C-5), 76.5, 95.3 (C-1), 107.0, 110.1, 114.0, 117.8, 126.7,
127.7, 127.81, 128.5, 136.9, 140.1, 146.4, 155.6, 169.6; elemental analysis:
calcd for C25H24O7S (468.5): C 64.09, H 5.16, found: C 64.20, H 5.35.
N-(4-Acetoxy-8-benzyloxy-1-hydroxynaphthyl-2-thio)phthalimide
(28):
143 mg (0.67 mmol) of phthalimidesulfenyl chloride was added to a
solution of 204 mg (0.42 mmol) of 4-acetoxy-8-benzyloxy-1-hydroxynaph-
thalene[24] in 3 mL dry CHCl3. The reaction mixture was refluxed for 2 h,
diluted with CH2Cl2 (40 mL), washed with saturated NH4Cl and water and
dried over anhydrous Na2SO4. Flash column chromatography (dichloro-
methane) gave 169 mg (83% yield) of 28 as a yellow solid; m.p. 98 ± 1008C
Compound 32b: Compound 32b was obtained as a glassy solid; [a]D20
ˆ
1
‡43.3 (c ˆ 0.14 in CHCl3); H NMR: d ˆ 1.33 (d, J ˆ 6.2 Hz, 3H, CH3-6),
2.39 (s, 3H), 3.04 (brs, 1H), 3.38 ± 3.52 (m, 2H), 3.70 (t, J ˆ 8.2 Hz, 1H),
3.80 ± 3.85 (m, 2H), 5.14 (AB system, JAB ˆ 11.9 Hz, 2H), 5.32 (s, 1H),
6.83 ± 6.97 (m, 2H), 7.23 ± 7.59 (m, 7H); 13C NMR: d ˆ 17.6 (C-6), 20.9, 43.4
(C-2), 72.4, 73.2, 73.7 (C-3, C-4, C-5), 91.4 (C-1), 107.2, 111.7, 114.6, 118.0,
126.1, 127.2, 128.1, 128.3, 137.6, 140.3, 142.0, 155.1, 169.8.
1
(decomp); H NMR: d ˆ 2.38 (s, 3H), 5.27 (s, 2H), 6.93 (dd, J ˆ 7, 1.8 Hz,
1H), 7.28 ± 7.46 (m, 8H), 7.45 ± 7.80 (m, 4H), 10.08 (s, 1H); 13C NMR: d ˆ
20.8, 71.9, 107.0, 113.6, 115.1, 115.2, 122.4, 123.8, 127.8, 127.9, 128.9, 134.4,
138.4, 152.2, 155.5, 167.8, 169.3; elemental analysis: calcd for C27H19O6NS
(485.5): C 66.79, H 3.94; found: C 66.68, H 3.57.
2,6-Dideoxy-a-l-glucopyranose[1,2-b](4-acetoxy-8-benzyloxy)naphtho-
[2,1-e]-1,4-oxathiin (33a): Compound 33a was obtained as a waxy solid;
1H NMR: d ˆ 0.95 (d, J ˆ 5.8 Hz, 3H, CH3-6), 2.41 (s, 3H), 2.64 (brs, 1H),
3.10 (brs, 1H), 3.16 (dd, J ˆ 2.8, 10.4 Hz, 1H, H-2), 3.27 (brt, J ˆ 9.2 Hz,
1H), 3.72 (dd, J ˆ 8.9, 10.4 Hz, 1H), 3.86 ± 3.95 (m, 1H), 5.14 (AB system,
JAB ˆ 10.0 Hz, 2H), 5.74 (d, J ˆ 2.8 Hz, 1H, H-1), 6.93 (s, 1H), 6.98 (t, J ˆ
4.2 Hz, 1H), 7.33 (m, 4H), 7.56 (m, 2H); 13C NMR: d ˆ 17.4, 31.0, 43.4 (C-2),
63.51 (C-5), 69.8, 70.6 (C-3, C-4), 71.8, 95.3 (C-1), 107.1, 110.1, 112.3, 114.0,
117.8, 118.7, 126.6, 127.8, 128.4, 128.50, 136.8, 140.7, 146.3, 156.0, 169.6;
elemental analysis: calcd for C25H24O7S (468.5): C 64.09, H 5.16; found: C
63.89, H 5.31.
N[(S)-2-N-carbobenzyloxyamino-3-(4-hydroxyphenylthio)methylpropio-
nate]phthalimide (29): Compound 29 was obtained as a waxy solid by flash
column chromatography (dichloromethane), as for 28; 55% yield;
1H NMR: d ˆ 3.01 ± 3.08 (m, 2H), 3.78 (s, 3H), 4.59 ± 4.63 (m, 1H), 5.02
(s, 2H), 5.19 (brs, 1H), 6.92 (d, J ˆ 8.4 Hz, 1H), 7.09 ± 7.14 (dd, J ˆ 8.4,
2.2 Hz, 1H), 7.33 (m, 5H), 7.60 (d, J ˆ 2.2 Hz, 1H), 7.74 ± 7.89 (m, 4H), 8.29
(brs, 1H); 13C NMR: d ˆ 36.8, 52.5, 54.7, 66.9, 117.1, 118.2, 124.2, 127.9,
128.1, 128.5, 131.8, 134.8, 135.8, 138.8, 155.5, 158.0, 168.3, 171.6; elemental
analysis: calcd for C26H22 N2O7S (506.5): C 61.65, H 4.38; found: C 61.79, H
4.30.
Compound (33b): Compound 33b was obtained as a waxy solid; 1H NMR:
d ˆ 1.33 (d, J ˆ 6.3 Hz, 3H, CH3-6), 2.39 (s, 3H), 2.81 (brs, 1H), 3.19 (brs,
1H), 3.38 ± 3.52 (m, 1H), 3.66 ± 3.84 (m, 3H), 5.14 (AB system, JAB
ˆ
2-O-(2-Deoxy-3,4,6-tri-O-benzyl-a-d-glucopyranosyl)naphthalene (39): To
a solution of 23 mg (0.04 mmol) of 4a in 1.5 mL of THF was added 150 mg
Raney nickel, activated according to a literature procedure.[25] The mixture
was vigorously stirred for 2 h at room temperature, diluted with 3 mL of
THF, and filtered over Celiteꢁ. After evaporation of the solvent, the crude
product was chromatographed (petroleum ether/ethyl acetate ˆ 2.5 ± 1) to
give 14.8 mg of 39 (68% yield) as colorless oil. [a]2D0 ˆ ‡165.3 (c ˆ 0.16 in
11.8 Hz, 2H), 5.31 (d, J ˆ 1.1 Hz, 1H, H-1), 6.90 (s, 1H), 6.94 ± 6.98 (m,
1H), 7.28 ± 7.59 (m, 7H).
(1S,2S)-3,4,6-Tri-O-benzyl-2-deoxy-a-d-glucopyranose[1,2-b](4-N-carbo-
benzyloxyalaninebenzylester)benzo[2,1]-1,4-oxathiin (34): Compound 34
was obtained as a glassy solid; 1H NMR: d ˆ 3.00 ± 3.02 (m, 2H), 3.24 ± 3.31
(X part of a AMX system, J ˆ 3.0, 10.6 Hz, 1H), 3.67 ± 3.86 (m, 7H), 4.10 ±
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G. Capozzi, C. Nativi et al.
FULL PAPER
CHCl3); 1H NMR: d ˆ 1.92 ± 2.05 (A part of an AMPX system, J ˆ 3.4, 9.8,
13.2 Hz, 1H, H-2ax), 2.54 ± 2.63 (M part of an AMPX system, J ˆ 1.0, 5.2,
13.1 Hz, 1H, H-2eq), 3.58 ± 4.97 (m, 11H), 5.88 (m, 1H), 7.15 ± 7.79 (m,
22H); 13C NMR: d ˆ 35.4 (C-2), 68.6 (C-6), 71.4, 72.0, 73.3, 75.0, 77.4, 77.9,
95.8 (C-1), 110.4, 118.9, 124.1, 126.3, 127.2, 127.6, 127.7, 127.9, 128.3, 128.4,
129.3, 129.4, 134.4, 138.0, 138.4, 138.6, 154.2; elemental analysis: calcd for
C37H36O5 (560.7): C 79.26, H 6.47; found: C 79.41, H 6.52.
[3] a) W. A. Remers, The Chemistry of Antitumor Antibiotics, Wiley-
Interscience, New York, 1979, Ch. 3; b) G. R. Pettit, Biosynthetic
Products for Cancer Chemotherapy, Vol. 1, Plenum, New York, 1977,
p. 143.
[4] For reviews on the synthesis of 2-deoxyglycosides, see a) R. W. Franck,
S. M. Weinreb, Studies in Natural Products Chemistry (Ed.: Atta-Ur-
Rahman), Elsevier, Amsterdam, 1989, p. 173; b) J. Thiem, W. Klaffke,
Top. Curr. Chem. 1990, 154, 285.
2-O-(2-Deoxy-3,4,6-tri-O-benzyl-a-d-galactopyranosyl)naphthalene (40):
Flash column chromatography (dichloromethane) gave compound 40 as
an oil; 48% yield; 1H NMR: d ˆ 2.24 ± 2.30 (m, 1H, H-2ax), 2.39 ± 2.53 (m,
1H, H-2eq), 3.54 (A part of an ABX system, JAB ˆ 9.3 Hz, 1H), 3.67 (B part
of an ABX system, JAB ˆ 9.3 Hz, 1H), 4.04 ± 4.23 (m, 3H), 4.36 (AB system,
JAB ˆ 11.6 Hz, 2H), 4.66 (A part of an AB system, JAB ˆ 11.6 Hz, 1H), 4.70
(s, 2H), 4.99 (B part of an AB system, JAB ˆ 11.6 Hz, 1H), 5.88 (d, 1H),
7.16 ± 7.47 (m, 19H), 7.67 ± 7.88 (m, 3H); 13C NMR: d ˆ 31.2 (C-2), 69.2,
70.6, 70.7, 72.9, 73.3, 74.4, 74.5, 96.6 (C-1), 110.8, 124.0, 126.3, 127.2, 127.4,
127.6, 127.6, 127.7, 128.2, 128.3, 128.5, 129.3, 129.5, 134.4, 137.9, 138.5, 138.8,
154.6; elemental analysis: calcd for C37H36O5 (560.7): C 79.26, H 6.47;
found: C 79.18, H 6.52.
[5] G. Capozzi, C. Falciani, S. Menichetti, C. Nativi, J. Org. Chem. 1997,
62, 2611.
[6] For preliminary communication, see G. Capozzi, C. Falciani, S.
Menichetti, C. Nativi, R. W. Franck, Tetrahedron Lett. 1995, 36, 6755.
[7] Pyridine and lutidine are suitable bases for generation of the
heterodiene. The optimal base/substrate ratio is 0.5 ± 0. 8. The reaction
becomes very sluggish when less than 0.5 equiv base is used. No
improvement is observed with amounts of base above 0.8 equiv.
[8] AM1 calculations carried out on
2 and 3 were obtained with
geometrical optimization implemented by a Spartan program. Calcu-
lated energies (eV): 2 HOMO ˆ 8.824, LUMO ˆ 2.046; 3 HO-
MO 1 ˆ 9.370, LUMO ˆ 0.327.
2-O-(2-Deoxy-3,4-di-O-benzyl-b-d-arabinopyranosyl)naphthalene
(41):
[9] Examples of below-plane selectivity in glycal cycloaddition: a) Y.
Leblanc, B. J. Fitzsimmons, J. P. Springer, J. Rokach, J. Am. Chem.
Soc. 1989, 111, 2995; b) R. B. Gupta, R. W. Franck, J. Am. Chem. Soc.
1989, 111, 7668.
Flash column chromatography (ethyl acetate:petroleum etherˆ 1:4) gave
compound 41 as a white solid; 57% yield (21% of 3,4-di-O-benzyldihy-
dropyran was also obtained); m.p. 58 ± 608C; 1H NMR: d ˆ 2.15 ± 2.25 (m,
1H, H-2ax), 2.42 ± 2.56 (m, 1H, H-2eq), 3.76 ± 4.08 (m, 3H), 4.12 ± 4.20 (m,
1H), 4.65 (s, 2H), 4.79 (s, 2H), 5.86 (t, J ˆ 2.9 Hz, 1H), 7.17 ± 7.48 (m, 14H),
7.72 ± 7.80 (m, 3H); 13C NMR: d ˆ 31.9 (C 2), 61.8, 70.4, 71.6, 72.3, 72.5, 96.6
(C-1), 110.4, 118.8, 124.0, 126.3, 127.1, 127.6, 127.6, 127.8, 128.4, 128.4, 129.3,
129.4, 134.4, 138.5, 138.5, 154.5; elemental analysis: calcd for C29H28O4
(440.5): C 79.07, H 6.41; found: C 79.26, H 6.50.
[10] R. W. Franck, N. Kaila, M. Blumenstein, R. Geer, X. L. Huang, J. J.
Dannenberg, J. Org. Chem. 1993, 58, 5335.
[11] For the preparation of glycals, see L. Somsak, I. Nemeth, J. Carbohydr.
Chem. 1993, 12, 679.
[12] When glycal 3 was reacted with 2 in MeOH as solvent, 10% of methyl-
2-deoxy-2-thio(2-naphthyl)-d-glucopyranoside was also formed.
[13] T. Hosoya, E. Takashiro, T. Matsumoto, K. Suzuki, Tetrahedron Lett.
1994, 35, 4591.
[14] T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis,
Wiley, New York, 1991.
[15] S. Nakajima, K. Kojiri, H. Suda, M. Okanishi, J. Antibiotics 1991, 44,
1061.
[16] K. Toshima, S. Mukaiyama, T. Ishiyama, K. Tatsuta, Tetrahedron Lett.
1990, 31, 3339.
[17] G. Capozzi, A. Dios, R. W. Franck, A. Geer, C. Marzabadi, S.
Menichetti, C. Nativi, M. Tamarez, Angew. Chem. 1996, 108, 805;
Angew. Chem. Int. Ed. Engl. 1996, 35, 777.
[18] We proved that aryl O-glycoside 39 undergoes O- to C-glycoside
rearrangement when treated with catalytic amounts of BF3OEt2 in
CH2Cl2 at room temperature; see ref. [19].
4-Acetoxy-8-benzyloxy-1-O-(2,6-dideoxy-a-d-glucopyranosyl)naphtha-
lene (42): 141 mg (0.6 mmol) of NiCl2 ´ 6H2O and 67 mg (1.8 mmol) of
NaBH4O were added to a solution of 40 mg (0.08 mmol) of 33a in 2.4 mL
THF/MeOH (3/1) kept at 108C. After 30 min at 108C, the reaction
mixture was diluted with MeOH (10 mL) and filtered over Celiteꢁ. Flash
chromatography (ethyl acetate:petroleum ether:dichloromethane ˆ 2:1:1)
1
gave 17 mg (45% yield) of 42 as a glassy solid; H NMR: d ˆ 1.21 (d, J ˆ
6.2 Hz, 3H), 1.48 ± 1.62 (m, 1H, H-2ax), 1.85 ± 1.95 (m, 1H, H-2eq), 2.44 (s,
3H), 2.98 ± 3.08 (m, 1H), 3.33 ± 3.40 (m, 1H), 3.65 ± 3.74 (m, 1H), 5.10 (s,
2H), 5.52 (dd, J ˆ 0.4, 3.6 Hz, 1H), 6.96 ± 7.20 (m, 1H), 7.13 (s, 2H), 7.41 ±
7.62 (m, 7H); 13C NMR: d ˆ 17.7, 21.0, 37.8 (C-2), 68.5, 69.1, 71.4, 96.9 (C-1),
107.6, 109.7, 113.8, 118.7, 119.9, 128.1, 128.7, 129.4, 130.0, 137.3, 151.2, 152.0,
.
‡
154.1, 156.5, 169.7; HRSM calcd for C25H26O7 [M ] 438.1678; found: m/e ˆ
438.1678.
[19] a) T. Hosoya, E. Takashiro, T. Matsumoto, K. Suzuki, J. Am. Chem.
Soc. 1994, 116, 1004; b) G. Matsuo, S. Matsumura, K. Toshima, Chem.
Commun. 1996, 2173.
[20] T. G. Back, D. L. Baron, K. Yang, J. Org. Chem. 1993, 58, 2407.
[21] M. U. Bombala, S. V. Ley, J. Chem. Soc. Perkin Trans. I 1979, 3013.
[22] B. Lou, G. V. Reddy, H. Wang, S. Hanessian, in Preparative
Carbohydrate Chemistry (Ed.: S. Hanessian), Dekker, New York,
1996, p. 401.
Acknowledgments
This work was funded by MURST Progetto Nazionale Stereoselezione in
Sintesi Organica. Metodologie ed Applicazioni and by CNR, Italy.
[23] M. T. Bilodeau, T. K. Park, S. Hu, J. T. Randolph, S. J. Danishefsky,
P. O. Livingstone, S. Zhang, J. Am. Chem. Soc. 1995, 117, 7840.
[24] H. Laatsch, Liebigs Ann. Chem. 1985, 1847.
[25] A. I. Vogel, in Practical Organic Synthesis, Longman, Birmingham,
AL, 1962, p. 870.
[1] K. Toshima, K. Tatsuta, Chem. Rev. 1993, 93, 1503.
[2] a) W. R. Roush, X.-F. Lin, Tetrahedron Lett. 1993, 43, 6829; b) K.
Toshima, Y. Nozaki, S. Mukaiyama, T. Tamai, M. Nakata, K. Tatsuta,
M. Kinoshita, J. Am. Chem. Soc. 1995, 117, 3717; c) D. P. Sebesta,
W. R. Roush, J. Org. Chem. 1992, 57, 4799.
Received: May 25, 1998 [F1170]
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