Regio- and stereoselective synthesis of 4'-thiaspiroacetals from carbohydrates

Full text of DOI:10.1021/jo990416z

6490
J . Org. Chem. 1999, 64, 6490-6494
Sch em e 1
Regio- a n d Ster eoselective Syn th esis of
4′-Th ia sp ir oa ceta ls fr om Ca r boh yd r a tes
Alessandra Bartolozzi, Giuseppe Capozzi,*
Chiara Falciani, Stefano Menichetti,
Cristina Nativi,* and Alessia Paolacci Bacialli
Centro CNR “Chimica dei Composti Eterociclici”,
Dipartimento di Chimica Organica, Universita’ di Firenze,
Via Gino Capponi, 9. I-50121 Firenze, Italy
Received March 8, 1999
In tr od u ction
Many biologically active natural products are charac-
terized by a spiroacetal ring system in their structures.1
Among them there are the structurally simple phero-
mones2 or the more complex polyether antibiotics,3 such
as lenoremycin4 and dianemycin,5 which contain two
spiroacetals substructures. Recently a family of novel
spiro-containing macrocyclic lactones, including the al-
trohyrtins, the spongistatins, and cinachyrolide A, which
exhibit an extremely potent cancer cell growth inhibition,
have also been isolated.6
The relevant role of these compounds has triggered
great interest in their total synthesis and particularly
in the development of a stereoselective method for the
formation of spiro units. The configuration of spiroacetals
is generally due to additive steric and anomeric effects,
which provide the isomer with the most stable configu-
ration at the spiro carbon. Although the acid-catalyzed
cyclization of dihydroxy ketones is still the most used
ring-forming process, elegant alternative methods to
synthesize stereoselectively spiroacetal skeletons involv-
ing radical processes,7 olefinic cyclizations,8 or apparent
conjugate additions9 have been reported. Moreover pho-
tochemical10 and alkoxy radical promoted11 cyclizations
were recently applied to obtain spiroacetals from carbo-
hydrates. As a matter of fact, enantiomerically pure O-10
and C-glycosides11 were successfully used as starting
materials to achieve anomeric spiro derivatives whose
stereochemistry depends on the configuration of the
anomeric carbon of the corresponding glycosides.10-12
We wish to report here on a versatile synthesis to
prepare optically pure thiospiroacetals from easily achiev-
able glycoexoenitols, through an inverse electron demand
Diels-Alder reaction with suitable heterodienes. In pre-
vious papers, we outlined the versatility of R,R′-dioxo-
thiones13 and ortho-thioquinones14 as electron-poor dienes
that could be trapped by glycals as electron-rich dieno-
philes to give 1,4-oxathiins. In this paper, different
glycoexoenitols were used to cycloadd to R,R′-dioxothiones
and ortho-thioquinones to form enantiomerically pure
spiroacetals. To our knowledge, the method we propose
is the first example of sulfur-substituted spiro glycoside
synthesis.
Resu lts a n d Discu ssion
2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-deoxy-D-gluco-
hept-1-enitol (1), prepared following a known procedure,15
was reacted with 3-thiophthalimide-2,4-pentandione (2)13
in the presence of pyridine to afford the spiroderivative
3 as a 2.5:1 mixture of stereoisomers. The phthalimido
derivative 2 in the presence of a weak base like pyridine
underwent proton abstraction to form, after elimination
of phthalimide, the reactive heterodiene 4, which was
trapped by the electron-rich dienophile 1. The diaster-
omers 3a and 3b, formed in 91% overall yield, were
completely separated by flash chromatography on silica
gel. (Scheme 1).
* Tel: +39.055.2757630. Fax: +39.055.2476964. Email: capozzi@
chimorg.unifi.it.
(1) Perron, F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617. (b) Boivin,
T. L. B. Tetrahedron 1987, 43, 3336.
(2) Francke, W.; Hindorf, G.; Reith, W. Angew. Chem., Int. Ed. Engl.
1978, 17, 862. (b) Kitching, W.; Lewis, J . A.; Fletcher, M. T.; Drew, R.
A. I.; Moore, C. J .; Francke, W. J . Chem. Soc., Chem. Commun. 1986,
853.
(3) Davies, H. G.; Green, R. H. Nat. Prod. Rep. 1986, 3, 87.
(4) Kubota, T.; Hinoh, H.; Mayama, M.; Motokawa, K.; Yasuad, Y.
J . Antibiot. 1975, 28, 931.
(5) Czerwinski, E. W.; Steinrauf, L. K. Biochem. Biophys. Res.
Commun. 1971, 45, 1284.
(6) Claffey, M. M.; Heathcock, C. H. J . Org. Chem. 1996, 61, 7646.
(b) Evans, D. A.; Coleman, P. J .; Dias, L. C. Angew. Chem., Int. Ed.
Engl. 1997, 36, 2738.
(7) Kalvoda, J .; Heusler, K. Synthesis 1971, 501.
(8) Mehta, G.; Rao, H. S. P.; Reddy, K. R. J . Chem. Soc., Chem.
Commun. 1987, 78. (b) Ley, S. V.; Lygo, B. Tetrahedron Lett. 1982,
23, 4625. (c) Kraus, G. A.; Thurston, J . Tetrahedron Lett. 1987, 28,
4011.
(9) Danishefsky, S.; Person, W. H. J . Org. Chem. 1983, 48, 3865.
(b) Negri, D. P.; Kishi, Y. Tetrahedron Lett. 1987, 10, 1063.
(10) Kozluk, T.; Cottier, L.; Descotes, G. Tetrahedron 1981, 37, 1875.
(11) Mart´ın, A.; Salazar, J . A.; Sua´rez, E. Tetrahedron Lett. 1995,
36, 4489. (b) Mart´ın, A.; Salazar, J . A.; Sua´rez, E. J . Org. Chem. 1996,
61, 3999. (c) Dorta, R. L.; Mart´ın, A.; Salazar, J . A.; Sua´rez, E. J . Org.
Chem. 1998, 63, 2251.
The cycloaddition was completely regioselective,13,16
1
and the H NMR analysis of the crude mixture of 3a and
3b allowed the assignment of the regiochemistry depicted
in Scheme 1 for both isomers [δ CH2-S 2.65 (3a ), 3.06
(12) Hough, L.; Richardson, A. C. In Carbohydrates. Synthetic
Methods and Applications in Medicinal Chemistry; Ogura, H., Hase-
gawa, A., Suami, T. Eds., VCH: New York, 1992; Chapter 7. (b) Remy,
G.; Cottier, L.; Descotes, G. Can. J . Chem. 1980, 58, 2660.
(13) Capozzi, G.; Franck, R. W.; Mattioli, M.; Menichetti, S.; Nativi,
C.; Valle, G. J . Org. Chem. 1995, 60, 6416.
(14) Capozzi, G.; Falciani, C.; Menichetti, S.; Nativi, C. J . Org. Chem.
1997, 62, 2611.
(15) RajanBabu, T. V.; Reddy, G. S. J . Org. Chem. 1986, 51, 5458.
10.1021/jo990416z CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/03/1999

Notes
J . Org. Chem., Vol. 64, No. 17, 1999 6491
Sch em e 2
Sch em e 4
Sch em e 3
Sch em e 5
(3b)] (see the Experimental Section). Because the struc-
ture of 3a differs from 3b only in the stereochemistry of
C-1, we reasoned that the preferred configuration of the
spirocenter might be determined by the anomeric effects
and tentatively assigned the structure 3a (i.e., the
structure with two anomeric effects17) to the major
isomer. This hypothesis was supported by spectroscopic
evidences. NOESY experiments of the minor compound
(recorded at 500 MHz, see Supporting Information)
showed a diagnostic interaction between the C-5′ protons
and H-5, proving for this isomer the structure 3b; this
interaction was lacking in the case of the major product
(structure 3a ) (Scheme 1). Moreover, we oxidized 3a and
3b (mCPBA,13,18 2 equiv) to the corresponding sulfones
tion conditions the same as reported for 3, spiroacetal 8
in 82% yield as a single isomer (Scheme 4).
The complete stereoselectivity of the cycloaddition can
be rationalized considering the steric hindrance offered
by the substituent at C-3 on exoenitol 7. As it was shown
by molecular mechanics studies using the AM1 force
field,21 the benzyl group on C-2 overlaps the exocyclic
double bond and hinders the attack of the heterodiene
from the â site of the dienophile.22 Therefore, in the case
of the reaction of 7 with 4 the matching of steric and
anomeric effects afforded the thermodynamically more
stable R isomer 8 as a single product and in high yield.
The NOE between H-2 and the methylene on C-5′, as well
as between H-3 and one of the two protons on C-5′,
confirmed the stereochemistry that we assigned to 8
(Scheme 4).
A successful extension of this procedure regarded the
synthesis of dioxaspiro[5.5]undecane thio derivatives, a
new class of spiroacetals with the spirocenter located at
C-5. As a matter of fact, glycoexoenitol 923 cycloadded to
4, giving 10 as a single isomer (Scheme 5). As reported
for 1 and 7, the regiochemistry of the cycloaddition
between 9 and 4 was completely selective.13 Moreover, it
was completely stereoselective, suggesting a disfavored
approach of the diene toward one of the two faces of the
double bond of the dienophile. On the basis of the NMR
spectra, we proposed for 10 the stereochemistry indicated
in Scheme 5, supposing a favored attack of the diene from
1
5a (60%) and 5b (57%) (Scheme 2). The H NMR spectra
of the sulfone derived from the minor product showed a
clear deshielding for the signal of the H-3 (δ 4.10) with
respect to the same signal of the parent sulfide (δ 3.85).
This deshielding was not observed in the case of the
sulfone derived from the major product, suggesting that
the SO2 group is located far from the H-3 and confirming
for the minor product the structure 3b. The major isomer
3a was also the thermodynamically more stable prod-
uct,16 as indicated by the isomerization in acidic media
of 3b into 6 (Scheme 3). The isomerization accomplished
in the presence of acetic anhydride and trimethylsilyl-
trifluoromethane sulfonate was complete in 2 h at -30
°C and gave 6 in 75% yield. As expected,19 under these
conditions the selective transformation of the benzyl
group at C-6 also occurred.
To prepare spiroacetals from furanose exoenitols, diene
4 was reacted with 2,5-anhydro-3,4,6-tri-O-benzyl-1-
deoxy-D-arabino-hex-1-enitol (7)15,20 to give, under reac-
(16) Totally regioselective [4 + 2] cycloadditions of 4 with electron
rich dienophiles have been already reported; for examples, see: (a)
ref 13 (b) Capozzi, G.; Dios, A.; Franck, R. W.; Geer, A.; Marzabadi,
C.; Menichetti, S.; Nativi, C.; Tamarez, M. Angew. Chem., Int. Ed. Engl.
1996, 35, 777.
(17) Deslongchamps, P.; Rowan, D. D.; Pothier, N.; Sauve´, T.;
Saunders, J . K. Can. J . Chem. 1981, 59, 1105.
(18) Capozzi, G.; Fratini, P.; Menichetti, S.; Nativi, C. Tetrahedron
1996, 52, 12233.
(19) Kobertz, W. R.; Bertozzi, C. R.; Bednarski, M. D. J . Org. Chem.
1996, 61, 1894. (b) Hung, S.-C.; Lin, C.-C.; Wong, C.-H. Tetrahedron
Lett. 1997, 5419.
(20) Cipolla, L.; Liguori, L.; Nicotra, F.; Giangiacomo, T.; Vismara,
E. Chem. Commun. 1996, 1253.
(21) AM1 semiempirical calculations as implemented in PC Spartan
Plus program.
(22) Capozzi, G.; Falciani, C.; Menichetti, S.; Nativi, C.; Raffaelli,
B. Chem. Eur. J . 1999, 5, 1748.
(23) Das, S. K.; Mallet, J .-M.; Sinay¨, P. Angew. Chem., Int. Ed. Engl.
1997, 36, 493. (b) Sakairi, N.; Kuzuhara, H. Tetrahedron Lett. 1982,
23, 5327.

6492 J . Org. Chem., Vol. 64, No. 17, 1999
Ta ble 1. Rea ction of Glycoexoen itols 1, 7, a n d 9 w ith Th ion es 13 a n d 14
Notes
Sch em e 6
with 13 and 14 showed the same regio- and stereoselec-
tivity observed for heterodiene 4. A single isomer was
obtained with 7 and 9 (entry 2-5), and two isomers were
produced with 1 (entry 1). Cycloadduct 17a (entry 1),
formed in a 2.5:1 ratio with respect to 17b, presents the
maximum number of anomeric effects. The spirocenter
of compounds 18, 19 and 20, 21 have the same stereo-
chemistry as depicted for 8 and 10, respectively. The
higher energy of the LUMO of 14 (-2.05 eV) compared
to that of 13 (-2.15 eV), determining a higher HOMO-
LUMO gap between the dienophiles and the diene
involved in the cycloadditions, probably influences the
experimental conditions (temperature and reaction time),
which are more severe in the case of the ortho-thio-
quinone 14 (entries 3 and 5) with respect to the R,R′-
dioxothione 13 (entries 2 and 4).
the opposite side of the axial methoxyl group. To support
this hypothesis, we prepared the â-methyl glycoexoenitol
11,23 removing the hindrance offered by the anomeric
axial group (Scheme 5). Dienophile 11 was afterward
reacted with 4, affording an inseparable mixture of two
stereoisomers, 12a and 12b, in a 1:1.2 ratio.24
To evaluate the applicability of this new protocol to the
synthesis of aromatic spiro carbohydrate-containing de-
rivatives, we performed the cycloadditions of dienophiles
1, 7, and 9 with the aromatic R,R′-dioxothione 13 and
ortho-thioquinone 14, which were generated in situ as
described for 4 from the corresponding phthalimido
derivatives 1513 and 1625 (Scheme 6). Spiroacetals ob-
tained, reaction conditions, and the energy values of the
HOMO and LUMO orbitals involved in the reactions26
are reported in Table 1. The cycloadditions performed
In conclusion, in this paper several examples of opti-
cally pure spiro glycosides were reported. Alkyl and aryl
4′-thiaspiroacetals, with the spirocenter at C-1 or C-5,
were prepared in one step from substituted exoenitols
and in situ generated heterodienes, with total regio- and
remarkable or total stereoselectivity.
Exp er im en ta l Section
Gen er a l Meth od . 1H and 13C NMR spectra were recorded
(where not specified) in CDCl3 at 200 and 50 MHz, respectively,
1
using the residual CHCl3 peak at 7.26 ppm for H and the central
peak of CDCl3 at 77.0 ppm for 13C as reference lines. Only
noteworthy IR (cm-1) absorptions are listed. CHCl3, CH2Cl2, and
THF were dried following standard procedures. All commercial
reagents were used without further purifications as obtained
from freshly opened containers. Thiophthalimides 2, 15, and 16
were prepared as reported elsewhere.13 Physical and spectro-
scopic data are as follows.
(24) Calculated by 1H NMR analysis of the crude mixture.
(25) Capozzi, G.; Falciani, C.; Menichetti, S.; Nativi, C. Gazz. Chim.
Ital. 1996, 126, 227.
(26) Oxothiones 13 and 14 and dienophiles 1, 7, and
minimized with geometry optimization AM1 calculations.
9 were

Notes
2,3,4,6-Tetr a -O-ben zyl-1-d eoxy-D-glu cop yr a n ose-1-sp ir o-
J . Org. Chem., Vol. 64, No. 17, 1999 6493
29.4 (t); 29.6 (q); 62.5 (t); 70.9, 75.2, 75.7 (3t + 1s, 4C); 77.9,
81.8, 82.9 (d, 3C); 95.3 (s); 107.3 (s); 127.4, 127.8, 128.1, 128.2,
128.3, 128.5 (d, 15C); 137.2, 137.3, 138.1 (s, 3C); 156.1 (s); 170.6
(s); 195.6 (s). Anal. Calcd for C35H38O8S: C, 67.94; H, 6.19.
Found: C, 67.70; H,6.31.
6′-[1′-(5′H-2′-m eth yl-1′,4′-oxa th iin -3′-yl)eta n on e] (3). Gen -
er a l P r oced u r e. To a solution of 1 (150 mg, 0.28 mmol) in 4
mL of CHCl3 were added 77.6 mg (0.28 mmol) of 2 and 18 µL
(0.22 mmol) of pyridine. The reaction was stirred at room
temperature for 4 days diluted with CH2Cl2 (10 mL), and washed
with NH4Cl. Drying and concentrating afforded the crude
mixture (250 mg) of two stereoisomers in 91% yield (3a :3b )
2.5:1, based on 1H NMR). Flash chromatography (petroleum
2,5-An h yd r o-3,4,6-tr i-O-ben zyl-D-a r a bin ofu r a n ose-h ex-
1-en itol (7). A solution of 2,3,5-tri-O-benzyl-arabino-1,4-lactone
(1.23 g, 2.94 mmol) in 4 mL of dry THF was cooled to -25°C,
and then 4 mL (2.65 mmol) of Tebbe’s reagent (0.5 M in toluene)
was slowly added. The reaction mixture was stirred at -25°C
for 30 min, and then it was allowed to reach room temperature.
In 2 h the reaction was complete (monitored by TLC) and was
then cooled to 0 °C and quenched by the dropwise addition of 2
mL of NaOH (15% aqueous solution). The organic layer was
diluted with 10 mL of CH2Cl2 and washed twice with NaOH
(15% aqueous solution). Drying, concentrating, and flash chro-
matography on silica gel (petroleum ether:ethyl acetate ) 3:1)
afforded 1.04 g (85%) of 7 (Rf ) 0.76). 1H NMR δ 3.61-3.62 (B
part of an ABX system, J ) 6.0, 2.2 Hz, 1H); 3.64-3.65 (A part
of an ABX system, J ) 6.0, 2.2 Hz, 1H); 4.06 (at, 1H); 4.19 (d, J
) 1.0 Hz, 1H); 4.39-4.71 (m, 9H); 7.28-7.33 (m, 15H). 13C NMR
δ 69.7 (t); 70.7, 71.7, 73.3 (t, 3C); 81.5, 82.0 (d, 2C); 83.5 (d);
85.7 (t); 127.6, 127.7, 127.8, 128.3, 128.4 (d, 15C); 137.4, 137.6,
137.8 (s, 3C); 159.8 (s).
ether:ethyl acetate ) 4:1) gave 121 mg of 3a (Rf ) 0.58) and 48
1
mg of 3b (Rf ) 0.6). (3a ): [R]25 +38 (c 0.12, CH2Cl2). H NMR
D
δ 2.29 (s, 3H); 2.33 (s, 3H); 2.65 (AB system J ) 12.8 Hz, 2H);
3.53 (d, 1H, J ) 9.6 Hz, 1H); 3.67-3.82 (m, 4H); 4.18-4.27 (m,
1H); 4.80-4.97 (m, 8H); 7.16-7.37 (m, 20H). 13C NMR δ 22.3
(q); 25.5 (q); 29.5 (t); 68.4 (t); 72.8, 73.3, 74.9, 75.0 (t, 4C); 75.4,
77.5, 82.9, 83.2 (d, 4C); 97.1 (s); 106.7 (s); 127.61, 127.71, 127.77,
127.87, 127.95, 128.13, 128.33, 128.39, 128.46, 128.52 (d, 20C);
137.7, 137.9, 138.0, 138.2 (s, 4C); 157.24 (s); 195.46 (s). IR (neat)
3030; 2919; 1673; 1536 cm-1. Anal. Calcd for C40H42O7S: C,
72.05; H, 6.35. Found: C, 72.19; H, 6.48 (3b): [R]25D +23 (c 0.16,
CH2Cl2). 1H NMR δ 2.29 (s, 6H); 3.06 (s, 2H); 3.72-3.87 (m, 6H);
4.53-4.83 (m, 8H); 7.16-7.32 (m, 20H). 13C NMR δ 21.8 (q); 29.5
(q); 29.8 (t); 68.0 (t); 73.1, 73.4, 75.2, 75.6 (t, 4C); 75.7, 78.0, 81.7,
83.0 (d, 4C); 95.7 (s); 107.2 (s); 127.6, 127.7, 127.8, 127.9, 128.1,
128.3, 128.4, 128.5 (d, 20C); 137.3, 137.8, 138.0, 138.3 (s, 4C);
156.43 (s); 195.7 (s).
2,3,5-Tr i-O-ben zyl-1-d eoxy-D-a r a bin ofu r a n ose-1-sp ir o-6′-
[1′-(5′H -2′-m et h yl-1′,4′-oxa t h iin -3′-yl)et a n on e] (8). Com-
pound 7: 100 mg, 0.24 mmol. After 48 h at room temperature
the reaction was complete. Flash chromatography on silica gel
(petroleum ether:ethyl acetate ) 4:1) afforded 108 mg (82%) of
8 (Rf ) 0.53). [R]25D +32 (c 0.06, CHCl3). 1H NMR δ 2.29 (s, 3H);
2.33 (s, 3H); 3.00 (AB system, J ) 13.2 Hz, 2H); 3.61-3.62 (B
part of an ABX system, J ) 5.0, 3.2 Hz, 1H); 3.63-3.64 (A part
of an ABX system, J ) 5.0, 3.2 Hz, 1H); 4.03 (dd, J ) 2.2, 4.8
Hz, 1H); 4.04 (d, J ) 2.2 Hz, 1H); 4.42-4.57 (m, 7H); 7.26-7.35
(m, 15H). 13C NMR δ 22.0 (q); 27.4 (q); 29.4 (t); 69.4 (t); 71.8,
72.6, 73.3 (t, 3C); 82.6, 83.0 (d, 2C); 86.5 (d); 105.6 (s); 123.3 (s);
127.46, 127.55, 127.62, 127.70, 127.92, 128.24, 128.30, 128.35
(d, 15C); 137.0, 137.5, 137.8 (s, 3C); 157.5 (s); 195.4 (s). IR (neat)
3030; 2922; 1672; 1554; 1451; 1413; 1244 cm-1. Anal. Calcd for
C32H34O6S: C, 70.31; H, 6.27. Found: C, 70.21; H, 6.38.
1-Meth yl-2,3,4-tr i-O-ben zyl-5-d eoxy-r-D-glu cop yr a n ose-
5-spir o-6′-[1′-(5′H-2′-m eth yl-1′,4′-oxath iin -3′-yl)etan on e] (10).
Compound 9: 20 mg, 0.04 mmol. After 24 h at 60 °C, the reaction
was complete. Flash chromatography on silica gel (petroleum
ether:ethyl acetate ) 3:1) afforded 24 mg (93%) of 10 (Rf ) 0.53).
1H NMR δ 2.25 (s, 3H); 2.34 (s, 3H); 3.18 (s, 2H); 3.61 (s, 3H);
3.68 (dd, J ) 3.6, 9.2 Hz, 1H, H-2); 3.80 (d, J ) 9.4 Hz, 1H,
H-4); 3.95 (at, J ) 9.4 Hz, 1H, H-3); 4.61-4.92 (m, 7H); 7.25-
7.36 (m, 15H). 13C NMR δ 22.0 (q); 29.5 (q); 29.9 (t); 58.8 (q);
73.8, 75.5, 75.7 (t, 3C); 77.7 (d); 78.8 (d); 84.1 (d); 98.8 (s); 100.2
(d, C-1); 106.6 (s); 127.72, 127.89, 127.95, 128.12, 128.20, 128.37,
128.55 (d, 15C); 137.7, 137.8 (s, 3C); 138.3 (s); 156.7 (s). IR (neat)
3030; 2922; 1676; 1562; 1451; 1415; 1246 cm-1. Anal. Calcd for
C33H36O7S: C, 68.73; H, 6.29. Found: C, 68.85; H, 6.47.
1-Meth yl-2,3,4-tr i-O-ben zyl-5-d eoxy-â-D-glu cop yr a n ose-
5-spir o-6′-[1′-(5′H-2′-m eth yl-1′,4′-oxath iin -3′-yl)etan on e] (12).
Compound 11: 26 mg, 0.06 mmol. After 20 h at 60 °C, the
reaction was complete (12a /12b ) 1.2/1 based on 1H NMR of
the crude). Flash chromatography on silica gel (petroleum ether:
ethyl acetate ) 3:1) afforded 22 mg (66% yield) of 12a + 12b
2,3,4,6-Tetr a -O-ben zyl-1-d eoxy-D-glu cop yr a n ose-1-sp ir o-
6′-[1′-(5′H -2′-m e t h y l-S ,S -d io x o -1′,4′-o x a t h iin -3′-y l)e t -
a n on e] (5a ). To a solution of 3a (25 mg, 0.038 mmol) in 1.5 mL
of CH2Cl2, cooled to 0 °C, was added dropwise 26 mg (0.084
mmol) of m-chloroperbenzoic acid (55%) dissolved in 1.5 mL of
CH2Cl2. After 0.5 h at 0 °C, the mixture was allowed to reach
room temperature. In 24 h the reaction was complete, and the
mixture was diluted with 10 mL of CH2Cl2 and washed with
10% aqueous Na2S2O3, a saturated solution of Na2CO3, and
water. The organic layer was dried (Na2SO4) and concentrated;
the crude mixture was purified by flash chromatography on silica
gel (petroleum ether:ethyl acetate ) 4:1) to give 17 mg of 5a
1
(57%) (Rf ) 0.35) as yellowish oil. H NMR δ 2.37 (s, 3H); 2.57
(s, 3H); 2.91-2.98 (B part of an AB system, J ) 13.8 Hz, 1H);
3.37 (d, J ) 9.4 Hz, 1H); 3.57-3.64 (A part of an AB system, J
) 13.8 Hz, 1H); 3.72-3.89 (m, 4H); 4.12 (at, 1H); 4.59-4.95 (m,
8H); 7.18-7.39 (m, 20H). 13C NMR δ 21.9 (q); 31.8 (q); 53.9 (t);
67.7 (t); 73.7, 75.4, 75.7, 75.9 (t, 4C); 74.8, 77.2, 80.3, 82.1 (d,
4C); 102.2 (s); 120.7 (s); 127.6, 127.7, 127.9, 128.0, 128.1, 128.3,
128.5, 128.8, 128.9 (d, 20C); 136.5, 137.5, 137.9, 138.1 (s, 4C);
166.6 (s); 191.3 (s). IR (neat) 3032; 2931; 1686; 1552; 1309; 1126
cm-1. Anal. Calcd for C40H42O9S: C, 68.75; H, 6.06. Found: C,
68.59; H, 6.33.
2,3,4,6-Tetr a -O-ben zyl-1-d eoxy-D-glu cop yr a n ose-1-sp ir o-
6′-[1′-(5′H -2′-m e t h y l-S ,S -d io x o -1′,4′-o x a t h iin -3′-y l)e t -
a n on e] (5b). As reported for 5a . Flash chromatography on silica
gel (petroleum ether:ethyl acetate ) 4:1) afforded 14 mg (57%)
of 5b (Rf ) 0.38). 1H NMR δ 2.30 (s, 3H); 2.60 (s, 3H); 3.61-
3.86 (m, 7H); 4.01 (at, 1H); 4.43-4.81 (m, 8H); 7.11-7.35 (m,
20H). 13C NMR δ 22.2 (q); 31.8 (q); 49.2 (t); 67.3 (t); 73.4, 74.9,
75.0, 75.3 (d, 4C); 74.4, 76.7, 81.9, 82.5 (d, 4C); 103.0 (s); 119.9
(s); 127.8, 127.9, 128.2, 128.2, 128.4, 128.4, 128.5, 128.6 (d, 20C);
137.0, 137.8 (s, 4C); 167.8 (s); 191.1 (s). IR (neat) 3033; 2918;
1684; 1362; 1067 cm-1. Anal. Calcd for C40H42O9S: C, 68.75; H,
6.06. Found: C, 68.50; H, 6.37.
1
(Rf ) 0.53). H NMR δ 2.27-2.40 [m, 6H (12a ) 2CH3; 7H (12b)
2,3,4-Tr i-O-ben zyl-6-a cetyl-1-d eoxy-D-glu cop yr a n ose-1-
sp ir o-6′-[1′-(5′H-2′-m eth yl-1′,4′-oxa th iin -3′-yl)eta n on e] (6).
To a solution of 3b (20 mg, 0.03 mmol) in 0.5 mL of dry CH2Cl2,
cooled to -30 °C, were added 144 µL (1.4 mmol) of acetic
2CH3+ A part of an AB system]; 2.91 [B part of an AB system
(12b), J ) 12.8 Hz, 1H]; 3.02 [as, 2H, (12a )]; 3.47 [s, 3H (12a ),
3H (12b)]; 3.47-3.75 (m, 4H); 4.02 [d, 1H (12a ), J ) 8.0 Hz,
H-1]; 4.08-4.18 (m, 1H); 4.52 [d, 1H (12b) J ) 8 Hz, H-1]; 4.60-
5.0 (m, 13H); 7.25-7.36 (m, 30H). 13C NMR δ 21.6 (q); 22.2 (q);
27.8 (q); 29.5 (t); 29.5 (q); 30.1 (t); 56.6 (q); 57.2 (q); 73.8, 75.0,
75.5, 76.0 (t, 6C); 80.7, 80.8, 81.1, 82.2, 82.5, 82.6 (d, 6C); 92.0,
96.2 (s, 2C); 101.0, 101.2 (d, 2C); 106.4, 107.3 (s, 2C); 127.7, 127.8,
127.9, 128.0, 128.2, 128.2, 128.4, 128.4, 128.5 (d, 30C); 137.7,
137.9, 138.1, 138.2 (s, 6C); 156.9 (s, 2C); 195.5, 195.8 (s, 2C).
Anal. Calcd for C33H36O7S: C, 68.73; H, 6.29. Found: C, 68.50;
H, 6.36.
anhydride and
6 µL (0.03 mmol) of trimethylsilyltrifluo-
romethane sulfonate. After 2 h at -30 °C, the reaction was
complete and was quenched with 1 mL of a saturated solution
of NaHCO3. The mixture was allowed to reach room tempera-
ture, diluted with CH2Cl2 (10 mL), and washed with water.
Concentration and column chromatography on silica gel (petro-
leum ether:ethyl acetate ) 5:1) afforded 14 mg (70%) of 6 (Rf )
1
0.3) as colorless oil. [R]25 +26 (c 0.20, CHCl3). H NMR δ 2.00
D
(s, 3H); 2.31 (s, 3H); 2.33 (s, 3H); 2.65 (AB system, J ) 12.8 Hz,
2H); 3.48 (d, J ) 9.4 Hz, 1H); 3.63 (dd, J ) 8.8, 9.8 Hz, 1H);
3.73-3.81 (m, J ) 2.2, 4.8 Hz, 1H); 4.15-4.36 (m, 3H); 4.56-
4.98 (m, 6H); 7.30-7.39 (m, 15H). 13C NMR δ 20.7 (q); 21.7 (q);
2,3,4,6-Tetr a -O-ben zyl-1-d eoxy-D-glu cop yr a n ose-1-sp ir o-
6′-(5′H-1′-oxa -4′-th ia ) p h en a n th r en e (17). Compound 1: 110
mg, 0.20 mmol. After 20 h at 60 °C, the reaction was complete
(17a /17b ) 1.5/1 based on 1H NMR of the crude). Flash

6494 J . Org. Chem., Vol. 64, No. 17, 1999
Notes
chromatography (petroleum ether:ethyl acetate ) 10:1) afforded
82 mg of 17a (Rf ) 0.3) and 53 mg of 17b (Rf ) 0.4) (79% overall
130.81 (d+s, 22C); 137.3, 137.8, 138.0 (s, 4C); 147.2 (s). IR (neat)
3061; 2925; 1618; 1227 cm-1. Anal. Calcd for C37H34O5S: C,
75.23; H, 5.80. Found: C, 75.19; H, 6.00.
yield). 17a : [R]25 +63 (c 0.06, CHCl3). 1H NMR δ 3.40 (AB
D
system, J ) 14.1 Hz, 2H); 3.65-3.91 (m, 5H); 4.04-4.08 (m, 1H);
4.37-4.98 (m, 8H); 7.10-7.96 (m, 26H). 13C NMR δ 29.6 (t); 68.4
(t); 72.9, 73.3, 75.2, 75.8 (t, 4C); 78.4, 83.3 (d, 4C); 96.1 (s); 111.9
(s); 120.2, 122.6, 124.4, 125.9, 126.4, 127.8, 127.9, 128.1, 128.3,
128.5, 128.6, 129.6, 130.7, (d, 26C); 137.9, 138.5 (s, 4C); 147.2
1-Meth yl-2,3,4-tr i-O-ben zyl-5-d eoxy-â-D-glu cop yr a n ose-
5-spir o-6′-[1′-(5′H-2′-ph en yl-1′,4′-oxath iin -3′-yl)ph en on e] (20).
Compound 9: 42 mg, 0.09 mmol. After 30 h at 60 °C, the reaction
was complete. Flash chromatography on silica gel (petroleum
ether:ethyl acetate ) 4:1) afforded 63 mg of 20 (96%) (Rf ) 0.48).
[R]25D -24 (c 0.19, CHCl3). 1H NMR δ 3.46 (AB system, J ) 13.2
Hz, 2H); 3.65 (s, 3H); 3.86 (dd, J ) 3.6, 8.4 Hz, 1H); 3.96-4.10
(m, 2H); 4.60-4.93 (m, 7H); 7.00-7.78 (m, 25 H). 13C NMR δ
30.83 (q); 58.88 (t); 73.67, 75.20, 75.49 (d, 3C); 77.80, 78.45, 83.32
(t, 3C); 98.26 (s); 99.94 (s); 109.53 (s); 127.79, 127.83, 127.97,
128.06, 128.15, 128.32, 128.43, 128.59, 129.01, 129.25, 129.54,
132.18 (d, 25C); 134.35, 135.42, 137.68, 137.73, 138.06, 138.40
(s, 5C); 152.48 (s); 194.70 (s). Anal. Calcd for C43H40O7S: C,-
73.69; H,5.75. Found: C,73.35; H,5.71.
(s). 17b: [R]25 -4 (c 0.14, CHCl3).1H NMR δ 3.02 (AB system J
D
) 12.6 Hz, 2H); 3.53-3.73 (m, 3H); 3.80-3.95 (m, 2H); 4.35-
5.08 (m, 9H); 7.09-7.55 (m, 24H); 7.76-7.96 (m, 2H). 13C NMR
δ 28.9 (t); 68.2 (t); 73.2, 75.0, 75.6, 75.8, (t, 4C); 82.2, 83.8 (d,
4C); 93.9 (s); 111.2 (s); 120.3, 122.7, 125.6, 126.3, 127.4, 127.9,
128.0, 128.2, 128.4, 128.5, 128.6, 128.8, 129.7, 131.0 (d, 26C);
137.6, 138.4 (s, 4C); 146.0 (s). IR (neat) 3032; 2933; 1616; 1258
cm-1. Anal. Calcd for C45H42O6S: C, 76.03; H, 5.96. Found: C,
76.30; H, 6.12.
2,3,5-Tr i-O-ben zyl-1-d eoxy-D-a r a bin ofu r a n ose-1-sp ir o-6′-
[1′-(5′H-2′-p h en yl-1′,4′-oxa th iin -3′-yl)p h en on e] (18). Com-
pound 7: 20 mg, 0.05 mmol. After 22 h at room temperature,
the reaction was complete. Flash chromatography on silica gel
(petroleum ether:ethyl acetate ) 3:1) afforded 27 mg (83%) of
18 (Rf ) 0.59).1H NMR δ 3.31 (s, 2H); 3.67-3.75 (B part of an
ABX system, J ) 10.6, 5.8 Hz, 1H); 3.78-3.86 (A part of an ABX
system, J ) 10.6, 5.2 Hz, 1H); 4.16 (ad, J ) 4.0 Hz, 1H); 4.30
(as, 1H); 4.55-4.73 (m, 7H); 6.85-7.11 (m, 5H); 7.18-7.35 (m,
18H); 7.58 (d, J ) 7.0 Hz, 2H). 13C NMR δ 28.7 (t); 70.1 (t); 72.2,
72.7, 73.5 (t, 3C); 83.7, 84.2 (d, 2C); 85.8 (d); 105.8 (s); 109.5 (s);
127.7, 127.8, 127.9, 128.0, 128.1, 128.2, 128.4, 128.5, 128.6, 128.7,
129.0, 129.2, 129.3, 129.5, 129.6, 129.9, 130.5, 131.9, 132.7, 134.3,
134.6 (d, 25C); 132.4, 135.3, 136.9, 137.5, 137.9 (s, 5C); 153.4
(s); 194.7 (s). IR (neat) 3029; 2862; 1635; 1560 cm-1. Anal. Calcd
for C42H38O6S: C, 75.20; H, 5.71. Found: C, 74.95; H, 5.42.
2,3,5-Tr i-O-ben zyl-1-d eoxy-D-a r a bin ofu r a n ose-1-sp ir o-6′-
(5′H-1′-oxa -4′-th ia ) p h en a n th r en e (19). Compound 7: 120 mg,
0.29 mmol. After 6 days at 60 °C, the reaction was complete.
Flash chromatography on silica gel (petroleum ether:ethyl
acetate ) 4:1) afforded 110 mg of 19 (65%) (Rf ) 0.64).1H NMR
δ 3.33 (s, 2H); 3.71 (A part of an ABX system, J ) 8.8, 2.6 Hz,
1H); 3.65 (B part of an ABX system, J ) 8.8, 2.8 Hz, 1H); 4.17
(dd, J ) 2.6, 5.2 Hz, 1H); 4.27 (d, J ) 2.6 Hz, 1H); 4.47-4.65
(m, 7H); 7.12 (d, J ) 8.8 Hz, 1H); 7.26-7.59 (m, 18H); 7.69 (d,
J ) 8.4 Hz, 1H); 7.95 (d, J ) 8.4 Hz, 1H). 13C NMR δ 27.9 (t);
69.5 (t); 71.8, 72.5, 73.4 (t, 3C); 82.5, 83.3 (d, 2C); 87.3 (d); 103.7
(s); 111.1 (s); 120.11, 122.73, 124.20, 125.86, 126.22, 127.55,
127.62, 127.73, 127.92, 128.19, 128.26, 128.35, 129.42, 129.48,
1-Meth yl-2,3,4-tr i-O-ben zyl-5-d eoxy-r-D-glu cop yr a n ose-
5-sp ir o-6′-[1′-(3′H-1′-oxa -4′-th ia )p h en a n th r en e] (21). Com-
pound 9: 30 mg, 0.07 mmol. After 3 days at 60 °C, the reaction
was complete. Flash chromatography on silica gel (petroleum
ether:ethyl acetate ) 4:1) afforded 32 mg of 21 (77%) (Rf ) 0.58).
[R]25 +39 (c 0.29, CH2Cl2). 1H NMR δ 3.52 (AB system, J )
D
13.6 Hz, 2H); 3.67 (s, 3H); 3.77 (dd, J ) 4.0, 7.4 Hz, 1H); 3.94-
4.06 (m, 2H); 4.51-4.98 (m, 7H); 7.04 (d, J ) 8.8 Hz, 1H); 7.25-
7.49 (m, 17H); 7.55 (dd, J ) 8.8 Hz, 1H); 7.77 (d, J ) 7.4 Hz,
1H); 7.95 (d, J ) 8.4 Hz, 1H). 13C NMR δ 29.8 (q); 58.9 (q); 73.7,
75.3, 75.7 (t, 3C); 77.8, 78.9, 84.5 (d, 3C); 97.4 (s); 100.1 (d); 111.3
(s); 119.6, 122.6, 124.4, 125.9, 126.3, 127.68, 127.7, 128.0, 128.1,
128.2, 128.2, 128.3, 128.3, 128.5 (d, 21C) 129.6, 130.0 (s, 2C);
137.8, 137.9, 137.5 (s, 3C); 146.6 (s). Anal. Calcd for C38H36O6S:
C, 73.52; H, 5.85. Found: C, 73.90; H, 6.00.
Ack n ow led gm en t. This work was supported by
MURST “Progetto Nazionale Stereoselezione in Sintesi
Organica. Metodologie ed Applicazioni” and by CNR,
Italy. We thank Dr. Stefano Roelens for helpful discus-
sion on NMR data.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
componds 3a (200 MHz) and 3b (500 MHz) and NOESY
spectra for componds 3a (200 MHz), 3b (500 MHz), and 8 (200
and 500 MHz). This material is available free of charge via
the Internet at http://pubs.acs.org.
J O990416Z