Stereoselective glycosylations of a family of 6-deoxy-1,2-glycals generated by catalytic alkynol cycloisomerization

Article abstract of DOI:10.1021/ja994229u

Photolysis of 0.25 equiv of W(CO)₆ in the presence of tertiary amines (triethylamine or DABCO) and highly functionalized terminal alkynyl alcohols catalyzes single-step, high-yield cycloisomerization to endocyclic enol ethers. This transformati

Full text of DOI:10.1021/ja994229u

4304
J. Am. Chem. Soc. 2000, 122, 4304-4309
Stereoselective Glycosylations of a Family of 6-Deoxy-1,2-glycals
Generated by Catalytic Alkynol Cycloisomerization
Frank E. McDonald,* K. Subba Reddy, and Yolanda D´ıaz‡
Contribution from the Department of Chemistry, Emory UniVersity, 1515 Pierce DriVe,
Atlanta, Georgia 30322
ReceiVed December 3, 1999
Abstract: Photolysis of 0.25 equiv of W(CO)6 in the presence of tertiary amines (triethylamine or DABCO)
and highly functionalized terminal alkynyl alcohols catalyzes single-step, high-yield cycloisomerization to
endocyclic enol ethers. This transformation is general for each diastereomeric 3,4-bissilyl ether of 5-hydroxy-
1-hexyne, leading to enantio- and diastereoselective syntheses of each isomer of 6-deoxy-1,2-glycals.
Stereoselective glycosylations have also been demonstrated for each glycal diastereomer, and have been applied
in the preparation of D-digitoxose-â-4-D-digitoxose glycal.
Introduction
2,6-Dideoxyglycoside substructures are found in a variety of
carbohydrate-containing natural products, including many com-
pounds exhibiting anticancer, antibiotic, and cardiotonic effects.1
For instance, digoxin and other cardiac glycosides contain
D-ribo-2,6-dideoxyhexoses,2 and the family of aureolic acid
anticancer natural products (olivomycin, chromomycin, mith-
ramycin) include both D-arabino and D-lyxo diastereomers
(Figure 1).3 The D-xylo configuration is relatively rare but is
present in the cyclopentenyl glycoside passicapsin as well as
the cardenolide glycoside corchorusoside.4 L-Antipodes are also
known, such as the lyxo-2,6-dideoxyhexoses of elaiophylin and
viriplanin.5 These 2,6-dideoxyhexoses are not commercially
available, and must be prepared either by functional group
interconversion of more highly oxygenated sugars or by
stereocontrolled synthetic methods from non-carbohydrate
precursors.
Figure 1. 2,6-Dideoxyhexose diastereomers.
We have previously disclosed transition metal-promoted
endo-selective alkynol cycloisomerization protocols for the
generation of simple pyranose glycals.6 Our invention of this
novel chemical transformation enabled a unique strategy for the
chemical synthesis of oligosaccharides, which we first demon-
strated in the preparation of di- and trisaccharides containing
2,3,6-trideoxyhexose components.7 This work also showed that
Figure 2. Alkynyl alcohol strategy for oligosaccharide construction.
acyclic alkynyl alcohols could also serve as glycosyl acceptors
in glycosylation reactions of glycals, and after glycosylation
could be converted into higher-order oligosaccharide glycals
in a small number of steps (Figure 2). Herein we describe
significant improvements in the alkynol cycloisomerization
transformation, including the discovery of a high-yielding,
single-step, metal-catalyzed general reaction protocol, which is
applied to each diastereomeric configuration of 6-deoxy-1,2-
glycals, coupled with stereoselective glycosylations of each
glycal diastereomer with an alkyne-containing glycosyl acceptor.
‡ Permanent address: Departament de Quimica, Universidad Rovira i
Virgili, 43005 Tarragona, Spain.
(1) Kirschning, A.; Bechthold, A. F.-W.; Rohr, J. Top. Curr. Chem. 1997,
188, 1.
(2) Cardiac Glycosides, Part 1: Experimental Pharmacology. In Hand-
book Exp. Pharmacol. 1981, vol. 56.
(3) (a) Wohlert, S. E.; Ku¨nzel, E.; Machinek, R.; Mende´z, C.; Salas, J.
A.; Rohr, J. J. Nat. Prod. 1999, 62, 119. (b) Thiem, J.; Meyer, B.
Tetrahedron 1981, 37, 551. (c) Thiem, J.; Meyer, B. J. Chem. Soc., Perkin
Trans. 2 1979, 1331. (d) Berlin, Y. A.; Esipov, S. E.; Kolosov, M. N.;
Shemyakin, M. M. Tetrahedron Lett. 1966, 7, 1431; 1643.
(4) (a) Olafsdottir, E. S.; Cornett, C.; Jaroszewski, J. W. Acta Chem.
Scand. 1989, 43, 51. (b) Yoshikawa, M.; Murakami, T.; Shimada, H.;
Fukude, N.; Matsuda, H.; Sashida, Y.; Yamahara, J. Heterocycles 1998,
48, 869.
Results and Discussion
(5) (a) Neupert-Laves, K.; Dobler M. HelV. Chim. Acta 1981, 65, 262.
(b) Kawai, H.; Hayakawa, Y.; Nakagawa, M.; Furihata, K.; Seto, H.; Otake,
N. Tetrahedron Lett. 1984, 25, 1937; 1941.
(6) McDonald, F. E.; Zhu, H. Y. H. Tetrahedron 1997, 53, 11061.
(7) McDonald, F. E.; Zhu, H. Y. H. J. Am. Chem. Soc. 1998, 120, 4246.
Substrate Synthesis. The alkynyl alcohol substrates 6-9
were each synthesized from the common intermediate epoxy-
alkynol (2), arising from 1-(trimethylsilyl)-hex-4-en-1-yn-3-one
10.1021/ja994229u CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/20/2000

StereoselectiVe Glycosylations of 6-Deoxy-1,2-glycals
Scheme 1. Preparation of Alkynol Substrates 6-9a
J. Am. Chem. Soc., Vol. 122, No. 18, 2000 4305
Scheme 2. Catalytic, endo-Selective Alkynol
Cycloisomerizations
a Conditions: (a) BH3-SMe2, (R)-2-methyl-CBS-oxazaborolidine,
THF; 91% yield, 97% ee. (b) cat. Ti(O-i-Pr)4, L-(+)-DIPT, PhCMe2OOH,
CH2Cl2, -20 °C; 76% yield, >99% de. (c) Ph3P, DEAD, PhCO2H,
Et2O; 94% yield. (d) 0.5 equiv of KCN, MeOH; 92% yield. (e) Ti(O-
i-Pr)4, PhCO2H, benzene, 70 °C; 100% yield (from 2), 80% yield (from
3). (f) Bu4NF, THF; 99% yield. (g) TBDMSCl (2.5 equiv), imidazole
(5 equiv), DMF; 99% yield. (h) DIBAL, CH2Cl2, -70 °C; 95-98%
yield. (i) Ph3P, DEAD, p-nitrobenzoic acid, Et2O; 93% yield (from 6),
90% yield (from 8a), 55% yield (from 8b, +39% recovered 8b). (j)
TBDPSCl (2.5 equiv), imidazole (5 equiv), DMF; 92-99%.
pyranylidene compounds (six-membered cyclic oxacarbenes),
which upon reaction with triethylamine were converted into
dihydropyran products isomeric to the starting alkynyl alcohols.
This two-step methodology was compatible with a variety of
other functional groups, but gave regrettably low yields of glycal
products in addition to requiring one or more equivalents of
tungsten carbonyl reagent.6,7 For instance, these conditions were
suitable for cyclization of alkynol substrate 7, but overall
conversion to the cycloisomeric glycal 11 proceeded in only
45-50% isolated yield. We surmised that this transformation
might be facilitated by heating the reactants, and found that a
single-step cycloisomerization is achieved with catalytic amounts
of W(CO)6 [generally 25 mol %] when photolyzed at 350 nm
at or near the reflux point of THF in the presence of the alkynol
substrate and triethylamine. The success and endo-selectivity
is highly dependent on maintaining anaerobic conditions, as the
product mixture is contaminated with varying amounts of
exocyclization products when careful technique is not used. This
cycloisomerization transformation has been accomplished with
alkynol substrates 6-9, providing each of the corresponding
glycal diastereomers 10-13 in excellent yields, as shown in
Scheme 2.14,15 This procedure is a significant improvement over
previously reported protocols with regard to isolated yields and
catalyst loading.16 The cycloisomerization transformation likely
proceeds via formation of a tungsten vinylidene intermediate
(1)8 via sequential enantioselective reduction9 and epoxidation10
transformations (Scheme 1). Enantioselective reduction pro-
moted by (R)-oxazaborolidine and epoxidation with the (R,R)-
tartrate-titanium catalyst were matched doubly diastereoselec-
tive processes, whereas the mismatched reactants afforded a 1:1
separable mixture of epoxyalkynol 2 and its epoxide diastere-
omer. We subsequently discovered that Mitsunobu inversion11
of epoxyalkynol 2 proceeded rapidly and efficiently, affording
compound 3 after cyanide-catalyzed removal12 of both acyl and
alkynylsilyl groups. Regioselective titanium-promoted anti-
addition of benzoic acid13 to each epoxyalcohol 2 or 3 gave the
respective diols 4 and 5, which after silylation of each diol and
removal of the benzoyl protective group afforded alkynol
substrates 6 and 8. The remaining diastereomeric substrates were
obtained by Mitsunobu inversion of 6 and 8 (with best results
obtained with p-nitrobenzoic acid)11b,c followed by reductive
deacylation to provide substrates 7 and 9. This asymmetric
synthesis route also permits preparation of the enantiomers of
6-9 from ent-2.
Catalytic Alkynol Cycloisomerization. We have previously
shown that tungsten carbonyl compounds promoted endo-
selective cyclization of terminal alkynyl alcohols to tungsten
(12) (a) Herzig, J.; Nudelman, A.; Gottlieb, H. E.; Fischer, B. J. Org.
Chem. 1986, 51, 727. (b) Alzeev, A.; Vasella, A. HelV. Chim. Acta 1995,
78, 177. (c) AgNO3 is not required for the removal of alkynylsilanes from
our substrates.
(13) Caron, M.; Sharpless, K. B. J. Org. Chem. 1985, 50, 1557.
(14) Our synthetic D-arabino-glycal 12a ([R]D ) -51.6) exhibited 1H
and 13C NMR spectra identical with those of bis-TBDMS ether ent-12a
([R]D ) +53.9) obtained in two steps from 3,4-di-O-acetyl-L-rhamnal: (a)
NaOMe, MeOH; (b) TBDMSCl, imidazole, DMF. This also establishes the
absolute configuration of all glycals 10-13 and confirms absolute and
relative stereoinduction in the preparation of epoxyalkynol 2.
(8) Merault, G.; Bourgeois, P.; Dunogues, J.; Duffaut, N. J. Organomet.
Chem. 1974, 76, 17.
(9) (a) Parker, K. A.; Ledeboer, M. W. J. Org. Chem. 1996, 61, 3214.
(b) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. Engl. 1998, 37, 1986.
(c) Garcia, J.; Lopez, M.; Romeu, J. Synlett 1999, 429.
(10) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(11) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Martin, S. F.; Dodge, J.
A. Tetrahedron Lett. 1991, 32, 3017. (c) Hughes, D. L.; Reamer, R. A. J.
Org. Chem. 1996, 61, 2967.

4306 J. Am. Chem. Soc., Vol. 122, No. 18, 2000
McDonald et al.
Scheme 3. Acid-Catalyzed Glycosylations of Glycals 10-13
Figure 3. Formation of (Et3N)W(CO)5.
14, thus affording regioselective nucleophilic addition to the
terminal carbon atom to give anionic vinyltungsten intermediate
15. Glycal products 10-13 are then formed by in situ proto-
nation of the tungsten-carbon bond with regeneration of the
(Et3N)W(CO)5 catalyst.
In some cases we observe recovery of variable amounts of
W(CO)6, which must be arising from disproportionation of the
ligand-W(CO)5 catalyst species. Thus continuous irradiation
of the reaction mixture may be regenerating ligand-W(CO)5
catalyst from W(CO)6, as shown in Figure 3.
Stereoselective Glycosylations: Acid Catalysis. Stereose-
lective glycosylations were explored for each glycal 10-13 with
1 equiv of alkynyl alcohol 1617 as the common glycosyl
acceptor. Camphorsulfonic acid (CSA)-catalyzed glycosylation
of the ribo-glycal 10 affords â-glycoside 17 with very high
anomeric selectivity (83% isolated yield, Scheme 3), and the
lyxo-glycal 11 gives completely stereoselective formation of the
R-glycoside 18 (91% yield) under similar reaction conditions.18
In both cases, the stereochemistry of the major glycoside product
is consistent with alcohol addition anti to the C3-substituent,
as previously predicted by Franck.19a,b However, acid-catalyzed
glycosylations of arabino- and xylo-glycals 12a and 13a
proceeded with much slower rates, and with relatively poor
anomeric selectivity. For these glycals Ph3P-HBr was a more
effective glycosylation promoter than CSA.
Interestingly, the stereoselectivity of glycosylation in the ribo
series is dependent on acid strength, as the stronger acid
p-toluenesulfonic acid gives only a 70:30 ratio of â: R anomers.
We have also noticed that anomeric stereoselectivity is degraded
if the glycosylations of the ribo- and lyxo-glycals 10-11 are
carried out over a longer period of time, suggesting thermody-
namic equilibration at the anomeric center. Although the detailed
mechanistic and/or conformational factors responsible for these
selectivities is not entirely clear at this time, we note that both
ribo- and lyxo-glycals exhibit a cis-relationship of the two
silyloxy substituents at C3 and C4, and in both cases the major
glycoside products are formed trans to the silyloxy substituents.
The methyl substituent at C5 has only a minor effect on the
glycosylation stereoselectivity, only slightly nonreinforcing the
ribo-glycoside 17 under optimized conditions and reinforcing
the observed R-selectivity in the lyxo case leading to 18. In
contrast, the arabino- and xylo-glycals undergo relatively
inefficient acid-catalyzed glycosylations with lower stereose-
lectivity, and possess a trans relationship of the C3 and C4
silyloxy substituents. In both of these cases the major glycoside
product is formed trans to the C5-methyl substituent.
Iodoacetate Formation and Glycosylation. As we could not
achieve satisfactory yields or stereoselectivities in acid-catalyzed
glycosylations of arabino- and xylo-glycals 12a-13a, we
subsequently explored formation of 2-iodo-1-acetate derivatives
from these glycals, as other iodoacetates have been shown to
be effective glycosyl donors for stereospecific glycosylations.20
The stereochemistry of iodoacetate formation from arabino-
glycals has been reported to give varying ratios of iodoacetate
diastereomers depending on the choice of electrophilic reagent,
although we have also noticed that some differences may also
be associated with the type of O-protective groups utilized. Most
of the work in this area to date has resulted in optimization
toward the 2-deoxy-2-iodo-manno-R-acetate diastereomer over
the gluco-â-acetate isomer, with some selectivity observed with
[Ph3P(NR2)]+[I(OAc)2]- reagents,21 and even higher selectivity
demonstrated with (NH4)2Ce(NO3)6/NaI/HOAc.22 Other prece-
dents from the Roush laboratories indicated that N-iodosuccin-
imide (NIS)-promoted additions of acetic acid to glycal 12a
(15) Cycloisomerizations of substrates 6 and 7 (leading to glycals ribo-
10 and lyxo-11) are facile and proceed in nearly quantitative yields, whereas
the cyclization of 8a/b to arabino-glycals 12a/b is slightly slower. Substrates
9a/b leading to xylo-glycals 13a/b proceed in satisfactory yield but in all
cases approximately 10% of exo-cyclization product is formed along with
the major endo-cyclization products 13a/b.
(16) (a) McDonald, F. E.; Bowman, J. L. J. Org. Chem. 1998, 63, 3680.
(b) McDonald, F. E.; Zhu, H. Y. H. Tetrahedron 1997, 53, 11061.
(17) Prepared from 4 in 83% yield: TBDMSCl (1.0 equiv), imidazole
(2.0 equiv), DMF.
(18) Toshima, K.; Tatsuta, K.; Kinoshita, M. Bull. Chem. Soc. Jpn. 1988,
61, 2369.
(20) (a) Roush, W. R.; Briner, K.; Sebesta, D. P. Synlett 1993, 264. (b)
Roush, W. R.; Bennett, C. E. J. Am. Chem. Soc. 1999, 121, 3541. (c) Roush,
W. R.; Narayan, S. Org. Lett. 1999, 1, 899. For representative direct
iodoglycosylations, see: (d) Thiem, J.; Karl, H.; Schwentner, J. Synthesis
1978, 696. (e) Friesen, R. W.; Danishefsky, S. J. J. Am. Chem. Soc. 1989,
111, 6656.
(19) (a) Kaila, N.; Blumenstein, M.; Bielawska, H.; Franck, R. W. J.
Org. Chem. 1992, 57, 4576. (b) Franck, R. W.; Kaila, N.; Blumenstein,
M.; Geer, A.; Huang, X. L.; Dannenberg, J. J. J. Org. Chem. 1993, 58,
5335. (c) Bolitt, V.; Mioskowski, C.; Lee, S.-G.; Falck, J. R. J. Org. Chem.
1990, 55, 5812.
(21) (a) Kirschning, A.; Plumeier, C.; Rose, L. Chem. Commun. 1998,
33. (b) Kirschning, A.; Jesberger, M.; Monenschein, H. Tetrahedron Lett.
1999, 40, 8999.
(22) Roush, W. R.; Narayan, S.; Bennett, C. E.; Briner, K. Org. Lett.
1999, 1, 895.

StereoselectiVe Glycosylations of 6-Deoxy-1,2-glycals
J. Am. Chem. Soc., Vol. 122, No. 18, 2000 4307
Scheme 4. Iodoacetate Formation from arabino- and
xylo-Glycals 12-13
gave a 1:1 mixture of â-gluco- and R-manno-iodoacetates,20a
whereas Kirschning observed that â-gluco anomer was the major
product arising when Bu4NI(OAc)2 was utilized in glycosylation
of TBDPS-glycal ent-12b.23
Figure 4. Conformations of glycals 12-13.
We observe that the ratios of iodoacetates produced from
glycals 12a and 12b are essentially identical regardless of the
reagent employed (NIS/HOAc, Bu4NI(OAc)2, or I(coll)2ClO4/
HOAc). Although tert-butyldimethylsilyl (TBDMS) glycal 12a
exhibits virtually no selectivity (1.1:1) with all three reagents,
the sterically bulkier tert-butyldiphenylsilyl (TBDPS) glycal 12b
provides â-gluco anomer as the major component of a 9:1
mixture with all three reagents (Scheme 4). Iodoacetate forma-
tion from both xylo-glycals 13a and 13b proceeds with poor
stereoselectivity, although the major diastereomer obtained from
13a is â-gulo 23a whereas the R-ido isomer 22b is the
predominant product from TBDPS glycal 13b. Minor amounts
of one of the cis-iodoacetate diastereomers are also observed
from both 13a and 13b.
Scheme 5. Stereoselective Formatin of Iodoglycosides
24-25
TBDMSOTf-catalyzed glycosylation20,24 of iodoacetate prod-
uct 21 (9:1 inseparable mixture) with alkynyl alcohol 16
selectively furnishes the 2-iodo-â-glycoside 24 isomer in good
yield with some recovery of the minor R-manno-2-iodo-1-
acetate, thus providing pure â-glycoside in the arabino series25
(Scheme 5). In the case of the xylo-derived mixture of
iodoacetates 22a/23a, inadvertent exposure to methanol was
observed to selectively convert minor isomer 22a to the
corresponding methyl glycoside, whereas the major isomer 23a
remained unchanged. Encouraged by this serendipitous observa-
tion, we then treated the mixture of 22a/23a with alkynol 16
and TBDMSOTf, and obtained only one glycoside R-25a,
accompanied by the unreacted major iodoacetate 23a. The
TBDPS-iodoacetates 22b/23b also reacted with alkynol 16 and
TBDMSOTf at low temperature to afford only one glycoside
R-25b, accompanied by quantitative recovery of the minor
â-gulo-iodoacetate 23b.
conformations of these glycals, in line with the similar lack of
selectivity in iodoacetate formation. However, it is worth noting
that the more reactive R-ido-iodoacetates 22a and 22b exhibit
trans-diaxial relationships between the 2-iodo and 1-acetate
substituents, suggesting that such conformations are much more
conducive for glycosylation transformations.
Analysis of coupling constants in the arabino glycal series
suggests that 12a with TBDMS substituents exists in a mixture
of 4H5 and 5H4 conformations, whereas the larger TBDPS
4
substituents of 12b disfavor the trans-diequatorial H5 confor-
mation so that 5H4 is the predominant ground state conformer,
with C3 and C4-OTBDPS groups trans-diaxial (Figure 4).26 In
the xylo series 13a,b, we observe little difference in the
Conclusions
In summary, we have discovered an effective tungsten-
catalyzed procedure for the endo-selective cycloisomerization
of 1-alkyn-5-ols bearing silyloxy substituents at the C3 and C4
positions. Each member of the resulting family of 6-deoxyglycal
diastereomers can be converted into a single O-glycoside anomer
(23) Kirschning, A. Eur. J. Org. Chem. 1998, 63, 2267.
(24) The use of TMSOTf gave slightly lower yields of glycosylation
products along with byproduct arising from loss of the TBDMS protective
group.
(25) Similar behavior has been observed with 2-phenylseleno-1-O-acetate
mixtures derived from arabino-glycal 12a: Dra¨ger, G.; Garming, A.; Maul,
C.; Noltemeyer, M.; Thiericke, R.; Zerlin, M.; Kirschning, A. Chem. Eur.
J. 1998, 4, 1324.
(26) Similar behavior has been observed in C-glycosylations of 2,6-
dideoxyglucosyl fluorides: Hosoya, T.; Ohashi, Y.; Matsumoto, T.; Suzuki,
K. Tetrahedron Lett. 1996, 37, 663.

4308 J. Am. Chem. Soc., Vol. 122, No. 18, 2000
McDonald et al.
25.9, 25.8, 18.5, 18.3, 18.2, 18.1, 15.9, -3.3, -4.1, -4.5, -4.6, -4.8,
-4.9; HRMS (FAB+) Calcd for C37H66O7Si3Li [(M + Li)+] 713.4276,
found 713.4271. Anal. Calcd for C37H66O7Si3: C, 62.84; H, 9.41.
Found: C, 62.73; H, 9.41.
Scheme 6. Iterative Synthesis of
D-ribo-â-D-ribo-Disaccharide Glycal 27
(2R,3R,4S)-3-O-Hex-5-yn-2-benzoyloxy-(3,4-bis-(tert-butyldi-
methylsilyl)-2-6-dideoxy)-r-L-galactopyranoside (18). A mixture of
glycal 10 (50 mg, 0.139 mmol), alkynol acceptor 16 (53 mg, 0.15
mmol), and 4 Å activated powdered molecular sieves (32 mg) was
suspended in dry CH2Cl2 (1 mL). Dry camphorsulfonic acid (3 mg, 10
mol %) was added and the reaction mixture was stirred for 6 h at room
temperature. Triethylamine was added dropwise to neutralize CSA,
followed by water and extraction with ethyl acetate. The organic extracts
were washed with brine, dried over Na2SO4, and concentrated, and
purification by silica gel chromatography (pentane:Et3N, 300:1) gave
â-isomer 18 (89 mg, 91%) as a colorless oil. The anomeric selectivity
for 18 was determined by 1H NMR analysis of the crude reaction
with high stereoselectivity, although each diastereomeric glycal
exhibits unique stereoselectivity and reactivity. One iterative
application of this methodology is demonstrated from alkynol
26, generated by DIBAL removal of the benzoate protective
group from ribo-â-glycoside 17, and the disaccharide glycal
27 is obtained in 70% isolated yield when DABCO is used rather
than Et3N for the W(CO)6-catalyzed cycloisomerization (Scheme
6). Additional studies on iterative applications of this methodol-
ogy to the synthesis of natural and nonnaturally occurring
oligosaccharides are in progress.
mixture to be >99:1. [R]23 -41.7 (CHCl3, c 1.04); IR (neat) 3310,
D
2117, 1722, 1272, 1256, 1106, 1067, 1032 cm-1; 1H NMR (300 MHz,
CDCl3) δ 8.07-7.38 (m, 5H), 5.59 (dq, J ) 6.6, 2.7 Hz, 1H), 5.20
(app. d, J ) 3.0 Hz, 1H), 4.43 (dd, J ) 5.1, 2.1 Hz, 1H), 4.14 (ddd, J
) 12.0, 4.2, 2.1 Hz, 1H), 4.06 (app. q, J ) 6.6 Hz, 1H), 3.97 (dd, J )
5.1, 2.7 Hz, 1H), 3.58 (app. s, 1H), 2.42 (d, J ) 2.1 Hz, 1H), 2.12
(app. td, J ) 12.0, 3.6 Hz, 1H), 1.73 (app. dd, J ) 12.3, 4.2 Hz, 1H),
1.37 (d, J ) 6.3 Hz, 3H), 1.15 (d, J ) 6.3 Hz, 3H), 0.89 (s, 9H), 0.89
(s, 9H), 0.88 (s, 9H), 0.14 (s, 3H), 0.12 (s, 3H), 0.09 (s, 3H), 0.06 (s,
3H), 0.05 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 165.6, 132.8, 130.5,
129.6, 128.3, 99.0, 83.1, 81.0, 74.0, 73.8, 71.4, 68.4, 68.3, 64.3, 33.2,
26.2, 26.1, 25.7, 18.6, 18.5, 18.1, 17.7, 14.9, -3.7, -4.4, -4.6, -4.7,
-5.3; HRMS (FAB+) Calcd for C37H66O7Si3Li [(M + Li)+] 713.4276,
found 713.4276. Anal. Calcd for C37H66O7Si3: C, 62.84; H, 9.41.
Found: C, 62.76; H, 9.42.
Experimental Section
Representative Procedure for Alkynol Cycloisomerizations: 3,4-
Bis-(tert-butyldimethylsilyl)-1,5-anhydro-2,6-dideoxy-L-lyxo-hex-1-
enitol (11). An oven-dried Schlenk flask fitted with a reflux condenser
and a stir bar, under nitrogen atmosphere, was charged with tungsten
hexacarbonyl (0.176 g, 0.5 mmol, dried under vacuum) and alkynol
substrate (7, 0.716 g, 2 mmol, azeotropically dried from toluene). This
mixture was dissolved in freshly distilled dry THF (5 mL) and
triethylamine (1.25 mL). The solution was irradiated under an inert
atmosphere for 5 h at 350 nm (Rayonet photoreactor) without cooling,
so that the solvent reflux point was reached. Volatile components were
removed under reduced pressure and the product was purified by silica
gel chromatography using an eluent mixture of pentane:triethylamine
(99:1) to afford product glycal 11 (0.659 g, 92% yield) as a colorless
3,4-Bis(tert-butyldiphenylsilyl)-2,6-dideoxy-2-iodo-â-D-glucopy-
ranose, Acetate Ester (21). Glycal 12b (0.606 g, 1 mmol) and HOAc
(0.360 g, 6 mmol) were dissolved in toluene (4 mL). NIS (0.450 g, 2
mmol) was added, and the reaction mixture was placed in a 100 °C oil
bath for 5 min with stirring. The reaction mixture was then allowed to
cool to room temperature. Aqueous 1 M Na2S2O3 was added to the
purple solution until it became colorless, followed by NaHCO3 and
EtOAc. The layers were separated and the aqueous layer was further
extracted with EtOAc. The combined organic layers were washed with
brine and dried before concentrating under reduced pressure to give
crude product, which was purified by silica gel chromatography to
oil. [R]23 +56.0 (CHCl3, c 1.40); IR (neat) 3066, 1644, 1252, 1106
D
1
cm-1; H NMR (400 MHz, CDCl3) δ 6.19 (dd, J ) 6.2, 1.0 Hz, 1H),
4.56 (dd, J ) 6.2, 3.2 Hz, 1H), 4.24-4.34 (br s, 1H), 4.05 (m, 1H, J
) 6.4, 2.4, 1.2, Hz), 3.79 (app. t, J ) 2.8 Hz, 1H), 1.32 (d, J ) 6.4
Hz, 3H), 0.91 (s, 9H), 0.90 (s, 9H), 0.10 (s, 3H), 0.08 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 142.7, 102.5, 73.7, 70.1, 26.1, 26.0, 18.4,
-3.8, -4.5, -4.6, -4.7; HRMS (FAB+) Calcd for C18H38O3Si2Li [(M
+ Li)+] 365.2520, found 365.2520. Anal. Calcd for C18H38O3Si2: C,
60.28; H, 10.68. Found: C, 60.42; H, 10.68.
1
afford an inseparable mixture of iodoacetates [(9:1 â /R, H NMR),
0.768 g, 97% yield] favoring 21. This product was a thick oil which
solidified to a white solid on standing. From the â/R (9:1) mixture:
1
IR (neat) 1768, 1229, 1212, 1112, 1054 cm-1; H NMR (300 MHz,
CDCl3) δ 7.63-7.20 (m, 20H), 6.43 (d, J ) 8.1 Hz, 1H), 4.69 (d, J )
3.3 Hz, 1H), 3.98 (d, J ) 7.8 Hz, 1H), 3.94 (app. q, J ) 6.9 Hz, 1H),
3.62 (d, J ) 3.3 Hz, 1H), 2.13 (s, 3H), 1.08 (s, 9H), 1.02 (s, 9H), 0.85
(d, J ) 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 169.2, 136.0, 135.9,
135.7, 135.7, 135.5, 132.8, 132.7, 132.6, 132.5, 129.8, 129.7, 127.7,
127.60, 127.5, 94.7, 80.0, 78.8, 74.0, 27.1, 27.0, 26.3, 21.1, 19.7, 19.1;
HRMS (FAB+) Calcd for C40H49IO5Si2Li [(M + Li)+] 799.2280, found
799.2323. Anal. Calcd for C40H49IO5Si2: C, 60.59; H, 6.23. Found:
C, 60.39; H, 6.06.
(2R,3R,4S)-3-O-Hex-5-yn-2-benzoyloxy-[3,4-bis-(tert-butyldi-
methylsilyl)-2,6-dideoxy]-â-D-allopyranoside (17). A mixture of
glycal 10 (0.716 g, 2 mmol) and alkynol acceptor 16 (0.696 g, 2 mmol)
was azeotropically dried (twice, from toluene). Dry CSA (2.5 mg, 0.5
mol %) was introduced followed by dry toluene (2 mL) under inert
atmosphere. The resulting mixture was allowed to stir for 12 h at room
temperature. The reaction mixture was diluted with Et2O (100 mL),
washed with water (1 × 20 mL) and brine (1 × 20 mL), dried, and
then concentrated to give crude product in a 96:4 (â:R, 1H NMR)
mixture. The major â isomer 17 was separated from the mixture by
silica gel column chromatography in 83% (1.172 g) yield as a colorless
oil, which solidified to a crystalline white solid upon standing. Mp
78-80 °C; [R]23D +14.9 (CHCl3, c 2.04); IR (KBr) 3303, 2931, 1713,
1276, 1252, 1118, 885, 839 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.05-
8.03 (m, 2H), 7.57-7.51 (m, 1H), 7.44-7.38 (m, 2H), 5.66 (dq, J )
6.5, 2.7 Hz, 1H), 5.11 (dd, J ) 9.5, 2.1 Hz, 1H), 4.78 (dd, J ) 3.3, 2.1
Hz, 1H), 4.02 (app. t, J ) 3.1 Hz, 1H), 3.99 (app. dd, J ) 3.9, 2.1 Hz,
1H), 3.84 (app. dq, J ) 6.3, 2.4 Hz, 1H), 3.23 (dd, J ) 9.0, 2.4 Hz,
1H), 2.45 (d, J ) 2.4 Hz, 1H), 2.04 and 2.00 (ddd, J ) 13.2, 4.2, 2.1
Hz, 1H,), 1.72, 1.68, and 1.64 (ddd, J ) 13.3, 3.9, 2.1 Hz, 1H), 1.42
(d, J ) 6.6 Hz, 3H), 1.13 (d, J ) 6.3 Hz, 3H), 0.91 (s, 9H), 0.90 (s,
9H), 0.83 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H), 0.07 (s, 3H), 0.05 (s, 6H),
0.04 (s, 3H);13C NMR (75 MHz, CDCl3) δ 165.4, 132.6, 130.6, 129.5,
128.1, 98.6, 82.8, 82.0, 75.3, 73.9, 71.4, 69.9, 69.3, 65.3, 39.9, 26.2,
(2R,3R,4S)-3-O-Hex-5-yn-2-benzoyloxy-[3-4-bis-(tert-butyldi-
phenylsilyl)-2-6-dideoxy-2-iodo]-â-D-glucopyranoside (24). Iodo-
acetate 21 (â /R, 9:1 mixture, 50 mg, 0.063 mmol), alkynol acceptor
16, (28.1 mg, 0.082 mmol), and 4 Å MS (32 mg) were mixed with dry
CH2Cl2 (1 mL), and the mixture was stirred for 30 min at room
temperature. The mixture was cooled to -70 °C and then TBDMSOTf
(4.4 µL, 0.019 mmol) was added. After being stirred for 4 h between
-70 and -50 °C, the reaction mixture was quenched with Et3N (0.1
mL) at -70 °C. The cold bath was removed and saturated NaHCO3
was added. Extractive workup (CH2Cl2/H2O) and silica gel chroma-
tography (hexanes:EtOAc, 19:1 to 9:1) afforded glycoside 24 (52.9 mg,
78%) as a white solid. Mp 53-55 °C; [R]23 +12.6 (CHCl3, c 0.84);
D
IR (neat) 2120, 1719, 1112 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.18-
7.19 (m, 25H), 5.72 (dq, J ) 6.4, 2.6 Hz, 1H), 5.29 (d, J ) 7.8 Hz,
1H), 4.81 (app. t, J ) 2.6 Hz, 1H), 4.71 (d, J ) 3.2 Hz, 1H), 3.99 (d,
J ) 7.8 Hz, 1H), 3.85 (app. t, J ) 2.6 Hz, 1H), 3.55 (q, J ) 6.8 Hz,

StereoselectiVe Glycosylations of 6-Deoxy-1,2-glycals
J. Am. Chem. Soc., Vol. 122, No. 18, 2000 4309
1H), 3.41 (d, J ) 3.2 Hz, 1H), 2.48 (d, J ) 2.6 Hz, 1H), 1.53 (d, J )
6.8 Hz, 3H), 0.98 (s, 9H), 0.90 (s, 9H), 0.87 (s, 9H), 0.61 (d, J ) 6.6
Hz, 3H), 0.12 (s, 6H);13C NMR (100 MHz, CDCl3) δ 165.8, 136.1,
135.9, 135.8, 133.1, 132.9, 132.9, 132.6, 132.5, 130.7, 130.0, 129.9,
129.8, 129.7, 129.7, 128.2, 127.8, 127.6, 127.5, 104.8, 83.6, 82.7, 79.7,
79.4, 74.1, 74.0, 71.6, 65.5, 31.6, 29.7, 28.7, 27.0, 26.9, 25.7, 19.6,
19.0, 18.6, 18.2, 16.0, 14.12, -4.8, -5.10; HRMS (FAB+) Calcd for
C57H73IO7Si3Li [(M + Li)+] 1087.3914, found 1087.3869. Anal. Calcd
for C57H73IO7Si3: C, 63.31; H, 6.80. Found: C, 63.25; H, 6.74.
4-O-[3,4-Bis-(tert-butyldimethylsilyl)-2,6-dideoxy-â-D-allopy-
ranosyl]-3-(tert-butyldimethylsilyl)-1-5-anhydro-2,6-dideoxy-D-
ribo--hex-1-enitol (27). The representative procedure described for
glycal 11 was employed except DABCO was used as the tertiary amine
base instead of Et3N. Thus a mixture of alkynol 26 (0.360 g, 0.6 mmol),
W(CO)6 (53 mg, 0.15 mmol), DABCO (175 mg, 1.56 mmol, dried
azeotropically), and THF (5 mL) was irradiated under N2 for 5 h. The
solvent was removed under reduced pressure to give crude reaction
mixture, which was purified by careful column chromatography
(pentane:Et3N, 99:1) to give the desired disaccharide 27 (252 mg, 70%)
as a colorless oil. [R]23D + 141 (CHCl3, c 0.50); IR (neat) 3064, 2931,
1642, 1472, 1254, 1087, 837, 776 cm-1; 1H NMR (300 MHz, CDCl3)
δ 6.28 (app. d, J ) 8.0 Hz, 1H), 4.92 (dd, J ) 9.5, 1.8 Hz, 1H), 4.77
(app. t, J ) 5.7 Hz,1H), 4.21 (dd, J ) 5.7, 3.6 Hz, 1H), 4.09 (dq, J )
10.2, 4.2 Hz, 1H), 3.98 (br dd, J ) 3.9, 1.8 Hz, 1H), 3.83 (dq, J ) 7.6,
6.3 Hz, 1H), 3.42 (dd, J ) 10.4, 3.9 Hz, 1H), 3.17 (dd, J ) 9.2, 2.4
Hz, 1H), 1.99 and 1.94 (ddd, J ) 13.4, 4.2, 1.8 Hz, 1H), 1.68, 1.64,
and 1.61 (ddd, J ) 13.2, 3.8, 2.1 Hz), 1.27 (d, J ) 6.3 Hz, 3H), 1.14
(d, J ) 6.3 Hz, 3H), 0.90 (s, 9H), 0.89 (s, 9H), 0.09 (s, 3H), 0.08 (s,
3H), 0.07 (s, 3H), 0.06 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 144.60,
102.91, 99.52, 80.50, 75.42, 69.97, 69.25, 69.18, 64.19, 39.64, 26.12,
26.09, 25.89, 18.71, 18.46, 18.20, 18.17, 17.42, -3.36, -4.04, -4.20,
-4.47, -4.52, -4.62; HRMS (FAB+) Calcd for C30H62O6Si3Li [(M +
Li)+], 609.4014, found 609.4025. Anal. Calcd for C30H62O6Si3: C,
59.75; H, 10.36. Found: C, 59.97; H, 10.33.
Acknowledgment. This research was supported by the
National Institutes of Health (CA-59703). F.E.M. also thanks
Novartis Pharmaceuticals and the Camille and Henry Dreyfus
Foundation for additional funding.
Supporting Information Available: Experimental proce-
dures and tabulated spectroscopic data for compounds 2-7, 8a,
8b, 9a, 9b, 10, 12a, 12b, 13a, 13b, 16, 23a, 23b, 25a, 25b,
and 26 (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
JA994229U