2,3-Anhydrosugars in glycoside bond synthesis. Application to 2,6-dideoxypyranosides

Article abstract of DOI:10.1021/jo900131a

We describe here the first use of 2,3-anhydrosugars as glycosylating agents for the preparation of 2-deoxypyranosides. In particular, the methodology was used to assemble 2,6-dideoxysugar glycosides. Glycosylation of a panel of alcohols with one of two 6-

Full text of DOI:10.1021/jo900131a

2,3-Anhydrosugars in Glycoside Bond Synthesis. Application to
2,6-Dideoxypyranosides
Dianjie Hou and Todd L. Lowary*
Alberta Ingenuity Centre for Carbohydrate Science and Department of Chemistry, The UniVersity of
Alberta, Gunning-Lemieux Chemistry Centre, Edmonton, Alberta T6G 2G2, Canada
tlowary@ualberta.ca
ReceiVed January 20, 2009
We describe here the first use of 2,3-anhydrosugars as glycosylating agents for the preparation of
2-deoxypyranosides. In particular, the methodology was used to assemble 2,6-dideoxysugar glycosides.
Glycosylation of a panel of alcohols with one of two 6-deoxy-2,3-anhydrosugar thioglycosides (8 and 9)
in the presence of a Lewis acid afforded 2,6-dideoxy-2-thiotolyl glycoside products in generally excellent
yields with an exclusively syn relationship between the aglycon and the C-3 hydroxyl group. Removal
of the 2-thiotolyl group can be achieved upon reaction with tri-n-butyltin hydride and AIBN to give the
corresponding 2,6-dideoxy pyranosides. Once developed, the method was applied to the synthesis of
oligosaccharide moieties in the natural products apoptolidin and olivomycin A.
Introduction
In all of our previous studies,1-8 the donors employed were
in the furanose ring form, and we were curious as the potential
of their pyranoside counterparts (e.g., 8 and 9) in these reactions,
particularly in the preparation of 2,6-dideoxysugar glycosides.
2,6-Dideoxypyranosides are an important class of carbohydrates,
which are present as essential components of steroidal glyco-
sides, antibiotics, and antitumor compounds.19-21 Specific
examples include the apoptotic agent apoptolidin,22 the anti-
cancer drug daunomycin,23,24 and olivomycin A,25 a member
of the aureolic acid family of antitumor antibiotics. As such,
2,6-dideoxypyranosides and other 2-deoxysugar glycosides
In previous papers, we have described the use of 2,3-
anhydrosugar thioglycosides (e.g., 1-3, Chart 1) for the
preparation of glycosidic bonds.1-8 Depending upon the activa-
tion conditions, these species can be used to produce two
different classes of products. For example, glycosylation of
alcohols with 1 upon treatment with N-iodosuccinimide and
silver triflate leads to the highly stereoselective formation of
2,3-anhydrosugar glycosides (4) in which the newly formed
glycosidic bond is cis to the epoxide moiety.1-7 Alternatively,
glycosylation of alcohols with 1 in the presence of a Lewis acid
leads to the formation of 2-deoxy-2-thiotolylglycosides 5, which
are precursors to 2-deoxy glycosides 6.8 The latter glycosylation
also proceeds with a high degree of stereocontrol, which by
analogy to other similar migration-glycosylation processes,9-18
we attributed to the formation of episulfonium ion intermediate
(e.g., 7).
(11) Stick, R. V.; Tilbrook, D. M. G.; Williams, S. J. Aust. J. Chem. 1999,
52, 885–894.
(12) Bravo, F.; Viso, A.; Alcazar, E.; Molas, P.; Bo, C.; Castillon, S. J. Org.
Chem. 2003, 68, 686–691.
(13) Poopeiko, N.; Fernandez, R.; Barrena, M. I.; Castillon, S.; Fornies-
Camer, J.; Cardin, C. J. J. Org. Chem. 1999, 64, 1375–1379.
(14) Yang, Z.; Yu, B. Carbohydr. Res. 2001, 333, 105–114.
(15) Yu, B.; Yang, Z. Org. Lett. 2001, 3, 377–379.
(1) Callam, C. S.; Gadikota, R. R.; Krein, D. M.; Lowary, T. L. J. Am. Chem.
Soc. 2003, 125, 13112–13119.
(2) Callam, C. S.; Gadikota, R. R.; Lowary, T. L. Synlett 2003, 1271–1274.
(3) Gadikota, R. R.; Callam, C. S.; Lowary, T. L. Org. Lett. 2001, 3, 607–
610.
(4) Gadikota, R. R.; Callam, C. S.; Wagner, T.; Del Fraino, B.; Lowary,
T. L. J. Am. Chem. Soc. 2003, 125, 4155–4165.
(5) Cociorva, O. M.; Lowary, T. L. Tetrahedron 2004, 60, 1481–1489.
(6) Bai, Y.; Lowary, T. L. J. Org. Chem. 2006, 71, 9658–9671.
(7) Bai, Y.; Lowary, T. L. J. Org. Chem. 2006, 71, 9672–9680.
(8) Hou, D.; Lowary, T. L. Org. Lett. 2007, 9, 4487–4490.
(9) Auzanneau, F.-I.; Bundle, D. R. Carbohydr. Res. 1991, 212, 13–24.
(10) Zuurmond, H. M.; van der Klein, P. A. M.; van der Marel, G. A.; van
Boom, J. H. Tetrahedron 1993, 49, 6501–6514.
(16) La´za´r, L.; Bajza, I.; Jakab, Z.; Lipta´k, A. Synlett 2005, 2242–2244.
(17) Sajtos, F.; La´za´r, L.; Borba´s, A.; Bajza, I.; Lipta´k, A. Tetrahedron Lett.
2005, 46, 5191–5194.
(18) Johnston, B. D.; Pinto, B. M. J. Org. Chem. 2000, 65, 4607–4617.
(19) Lindhorst, T. K. In Glycoscience: Chemistry and Chemical Biology;
Fraser-Reid, B., Tatsuta, K., Thiem, J., Eds.; Springer-Verlag: Berlin, 2001; pp
2393-2439.
(20) He, X. M.; Liu, H. W. Curr. Opin. Chem. Biol. 2002, 6, 590–597.
(21) Kirschning, A.; Bechthold, A. F. W.; Rohr, J. Top. Curr. Chem. 1997,
188, 1-84.
(22) Hayakawa, Y.; Kim, J. W.; Adachi, H.; Shin-ya, K.; Fujita, K.-I.; Seto,
H. J. Am. Chem. Soc. 1998, 120, 3524–3525.
(23) Arcamone, F.; Barbieri, W.; Franceschi, G.; Mondelli, R.; Orezzi, P.;
Cassinelli, G. J. Am. Chem. Soc. 1964, 86, 5334–5335.
2278 J. Org. Chem. 2009, 74, 2278–2289
10.1021/jo900131a CCC: $40.75 2009 American Chemical Society
Published on Web 02/27/2009

2,3-Anhydrosugars in Glycoside Bond Synthesis
continue to receive attention as synthetic targets.22,26-35 How-
ever, syntheses of these glycosides are typically challenging,
as the absence of a stereocontrolling group at C-2 often leads
to R/ꢀ mixtures of products.36 Although a number of recent
advances in this area have appeared,37-41 there is still a need
for new methods to prepare 2-deoxy- (and 2,6-dideoxy-)
glycosides. We report here the use of 6-deoxy-2,3-anhydropy-
ranosyl thioglycosides 8 and 9 for the synthesis of 2,6-
dideoxysugar glycosides.
CHART 1
Results and Discussion
Developing the method required first the preparation of
glycosyl donors 8 and 9. Although in the synthesis of 1 and 3
the epoxide rings were installed via a Mitsunobu reaction of a
vicinal diol,4,6 this approach is generally less successful on more
rigid pyranose rings.42 We therefore chose to introduce the
epoxide moieties by way of intramolecular SN2 reactions, as
described previously for the preparation of 2.4,43
SCHEME 1
Synthesis of Donor 8. The preparation of 8 started with the
known benzylidene acetal protected 6-deoxy-D-mannopyrano-
side 1044 (Scheme 1). Application of the Hanessian-Huller
reaction45-47 to 10 led to the formation of 11 in 75% yield.
The location of the benzoate ester on C-2 was readily apparent
from the chemical shift of H-2 (δH ) 5.50 ppm) and C-2 (δC )
73.0 ppm). Further support for the structure came from the
chemical shift of C-3, which appeared at δC ) 52.3 ppm, as
would be expected for a carbon atom attached to a bromine.
The axial orientation of the C-Br bond was ascertained from
the 3JH2,H3 (3.7 Hz) and 3JH3,H4 (3.7 Hz) values of the resonance
assigned to H-3 at δH ) 4.51 ppm. This result provides further
evidence that the stereochemistry of the dioxolane benzylidene
acetal does not affect the regioselectivity of the Hanessian-Huller
reaction, which has been noted previously.48
Methyl glycoside 11 was then cleaved upon reaction with a
catalytic amount of sulfuric acid in acetic anhydride to afford
the corresponding glycosyl acetate in 69% yield. The R-thiogly-
coside 12 was readily and stereoselectively accessed from this
acetate derivative in 93% yield upon treatment with boron
trifluoride etherate and p-thiocresol in dichloromethane at 0 °C.
Subsequently, 12 was reacted with sodium methoxide in
methanol and dichloromethane to provide exclusively the 2,3-
anhydrosugar 13 in 86% yield. The location of the oxirane was
clearly established by the chemical shift of C-2 (δC ) 56.0 ppm)
(24) Arcamone, F.; Mondelli, R.; Orezzi, P.; Franceschi, G.; Cassinelli, G.
J. Am. Chem. Soc. 1964, 86, 5335–5336.
(25) Berlin, Y. A.; Esipov, S. E.; Kolosov, M. N.; Shemyakin, M. M.
Tetrahedron Lett. 1966, 7, 1643–1647.
(26) Crimmins, M. T.; Long, A. Org. Lett. 2005, 7, 4157–4160.
(27) Handa, M.; Smith, W. J.; Roush, W. R. J. Org. Chem. 2008, 73, 1036–
1039.
(28) Nicolaou, K. C.; Li, Y.; Sugita, K.; Monenschein, H.; Guntupalli, P.;
Mitchell, H. J.; Fylaktakidou, K. C.; Vourloumis, D.; Giannakakou, P.; O’Brate,
A. J. Am. Chem. Soc. 2003, 125, 15443–15454.
(29) Wehlan, H.; Dauber, M.; Fernaud, M. T. M.; Schuppan, J.; Keiper, S.;
Mahrwald, R.; Garcia, M.-E. J.; Koert, U. Chem.sEur. J. 2006, 12, 7378–7397.
(30) Sebesta, D. P.; Roush, W. R. J. Org. Chem. 1992, 57, 4799–4802.
(31) Toshima, K.; Nozaki, Y.; Mukaiyama, S.; Tamai, T.; Nakata, M.; Tatsuta,
K.; Kinoshita, M. J. Am. Chem. Soc. 1995, 117, 3717–3727.
(32) Thiem, J.; Gerken, M. J. Org. Chem. 1985, 50, 954–958.
(33) Toshima, K.; Nozaki, Y.; Nakata, M.; Tatsuta, K.; Kinoshita, M.
Tetrahedron Lett. 1993, 34, 5761–5764.
(34) Roush, W. R.; Hartz, R. A.; Gustin, D. J. J. Am. Chem. Soc. 1999, 121,
1990–1991.
(35) Fan, E.; Shi, W.; Lowary, T. L. J. Org. Chem. 2007, 72, 2917–2928.
(36) Marzabadi, C. H.; Franck, R. W. Tetrahedron 2000, 56, 8385–8417.
(37) Kim, K. S.; Park, J.; Lee, Y. J.; Seo, Y. S. Angew. Chem., Int. Ed.
2003, 42, 459–462.
(38) Zhou, M.; O’Doherty, G. A. J. Org. Chem. 2007, 72, 2485–2493.
(39) Tanaka, H.; Yoshizawa, A.; Takahashi, T. Angew. Chem., Int. Ed. 2007,
46, 2505–2507.
(40) Sherry, B. D.; Loy, R. N.; Toste, F. D. J. Am. Chem. Soc. 2004, 126,
4510–4511.
(41) Park, J.; Boltje, T. J.; Boons, G.-J. Org. Lett. 2008, 10, 4367–4370.
(42) Mitsunobu, O. Synthesis 1981, 1–28.
(43) Tilekar, J. N.; Lowary, T. L. Carbohydr. Res. 2004, 339, 2895–2899.
(44) Binkley, R. W. J. Carbohydr. Chem. 1985, 4, 227–242.
(45) Hanessian, S.; Plessas, N. R. J. Org. Chem. 1969, 34, 1035–1044.
(46) Hanessian, S.; Plessas, N. R. J. Org. Chem. 1969, 34, 1045–1053.
(47) Hullar, T. L.; Siskin, S. B. J. Org. Chem. 1970, 35, 225–228.
(48) Bundle, D. R.; Josephson, S. Can. J. Chem. 1978, 56, 2686–2690.
3
and C-3 (δC ) 51.5 ppm) as well as the J of 3.6 Hz in the
doublets assigned to H-3 (δH ) 3.41 ppm) and H-2 (δH ) 3.34
ppm). It should be noted that 13 has a hydroxyl group trans to
the epoxide, which under the basic reaction conditions could,
in principle, lead to the formation of an isomeric epoxide
spanning C-3 and C-4. However, none of this epoxide rear-
rangement product was observed, although in another system
(see below) such a byproduct was formed. The final step in the
synthesis of 8 was the addition of a benzoyl group, which was
achieved under standard conditions, giving a nearly quantitative
yield of the product.
Synthesis of Donor 9. The preparation of 9 proved more
challenging than 8. The first approach started from fucopyranose
tetraacetate 1449 (Scheme 2), which was converted in two steps
and 73% overall yield into thioglycoside 15. Reaction of 15
with di-n-butyltin oxide in toluene yielded the stannylidene
acetal intermediate, which was then treated with methanesulfo-
(49) Mukhopadhyay, B.; Kartha, K. P. R.; Russell, D. A.; Field, R. A. J.
Org. Chem. 2004, 69, 7758–7760.
J. Org. Chem. Vol. 74, No. 6, 2009 2279

Hou and Lowary
SCHEME 2
SCHEME 3
CHART 2
nyl chloride, resulting in the formation of 16 in 95% yield. The
location of the methanesulfonyl group was identified by the
downfield chemical shift of both H-3 (δH ) 4.56 ppm) and C-3
(δC ) 84.4 ppm) in the 1H and 13C NMR spectra, respectively.
Having developed a route for the preparation of 16, we next
hoped to convert it into epoxide 17. However, when the reaction
was attempted by stirring 16 with sodium methoxide in
dichloromethane and methanol, the conversion rate was very
slow, and after 16 h, less than 5% of the product was generated.
Attempts to improve the product yield by allowing the reaction
to proceed for a longer period of time (48 h) did not result in
a larger amount of the desired epoxide but instead led to the
formation of byproducts 18 and 19, presumably from 17.
Deprotonation of the hydroxyl group in 17 and epoxide
rearrangement would generate 18. Compound 19 can be formed
by migration of the thioaryl group in 17 to C-2 with concomitant
glycosylation with methoxide or methanol.
Putting a suitable protecting group on the C-4 hydroxyl group
before introducing the oxirane functionality as illustrated in
Scheme 3 solved this problem. First, 15 was treated with 2,2-
dimethoxypropane and catalytic p-TsOH in acetone to form a
3,4-O-isopropylidene acetal intermediate, which upon allylation
(allyl bromide, sodium hydride in DMF) and then acid hydroly-
sis (p-TsOH, methanol) gave the desired diol 20 in 80% overall
yield. Subsequent heating of 20 with di-n-butyltin oxide in
toluene and treatment with methanesulfonyl chloride led to
selective sulfonylation of the C-3 hydroxyl group, yielding 21
in 91% yield.
Because the epoxide-forming reaction proceeds under strongly
basic conditions, a base-stable protecting group was needed for
O-4. Thus, reaction of 21 with p-methoxybenzyl chloride and
sodium hydride gave the corresponding intermediate 22 in 95%
yield. The allyl group in 22 was removed in 88% yield with
Pd(Ph3P)4 in acetic acid to provide 23. Finally, treatment of 23
with sodium hydride led to the formation of 9 in 79% yield
over two steps. The position of the epoxide was apparent from
the chemical shift of C-2 (δC ) 55.1 ppm) and C-3 (δC ) 52.0
ppm) in the 13C NMR spectrum. Further support came from
1
the H NMR spectrum, in which both H-2 (δH ) 3.43 ppm)
and H-3 (δH ) 3.24 ppm) appeared as doublets with a 3J ) 3.1
Hz.
Glycosylation Reactions. With the 6-deoxy-2,3-anhydrosugar
donors in hand, their use in glycosylation reactions for the
formation of 2,6-dideoxy-2-thiotolylpyranosides was investi-
gated. On the basis of previous work in the furanoside series,8
donor 8 was reacted with benzyl alcohol (24, Chart 2), n-octanol
(25), cyclohexanol (26), or tert-butyl alcohol (27) in the presence
of 10 equiv of 4 Å molecular sieves in dichloromethane at reflux.
As detailed in Table 1, these reactions gave the corresponding
2280 J. Org. Chem. Vol. 74, No. 6, 2009

2,3-Anhydrosugars in Glycoside Bond Synthesis
TABLE 1. Glycosylation of 2,3-Anhydro-D-rhamnopyranoside
Donor 8
entry donor alcohol activationa productb yieldc (%) ꢀ/R ratiod
1
2
3
4
5
6
8
8
8
8
8
8
24
25
26
27
28
29
A
A
A
A
B
B
30
31
32
33
34
35
91
90
90
70
84
74
ꢀ only
ꢀ only
ꢀ only
ꢀ only
ꢀ only
ꢀ only
3
FIGURE 1. Key NOE interactions and J1,2 present in 37.
a Method A: 4 Å MS (10 equiv), CH2Cl2, reflux. Method B: Cu(OTf)2
(1 equiv), 4 Å MS (1 equiv, by weight), CH2Cl2, rt. b See Chart 2 for
structures of products. c Isolated yield after chromatography. d Ratio
4
FIGURE 2. 4C1 and C1 conformer of 37.
1
determined by H NMR spectroscopy after chromatography.
lower yield in contrast to the reactions with the simple alcohols
(Table 2, entries 1-4) is ascribed to donor hydrolysis under
the reaction conditions. Similar byproducts were observed in
the reactions with 8.
TABLE 2. Glycosylation of 2,3-Anhydro-6-deoxy-L-gulopyranoside
Donor 9
The products arising from 9 have the R-idopyranose stere-
ochemistry, and these rings often adopt conformations different
from the canonical chair forms, given that both chair conformers
have an unfavorable orientation of substituents.50,51 Thus, the
analysis of the product structures was less straightforward than
in those resulting from 8, which given the ꢀ-glucopyranose
stereochemistry, adopts a single (4C1) chair form. NMR studies
on the products resulting from 9 gave clear evidence that the
R-L-idopyranoside products adopt the 4C1 conformation (Figure
entry donor alcohol activationa productb yieldc (%) ꢀ/Rd ratiod
1
2
3
4
5
6
9
9
9
9
9
9
24
25
26
27
29
29
A
A
A
A
B
B
36
37
38
39
40
41
90
88
90
79
74
73
R only
R only
R only
R only
R only
R only
3
1). In particular, the observed J between H-1 and H-2 was
smaller than 3 Hz in all cases (except 41, where JH1,H2 ) 4.7
a Method A: 4 Å MS (10 equiv), CH2Cl2, reflux. Method B: Cu(OTf)2
(1 equiv), 4 Å MS (1 equiv, by weight), CH2Cl2, rt. b See Chart 2 for
structures of products. c Isolated yield after chromatography. d Ratio
3
Hz). In addition, the other J on the ring were small (∼4 Hz)
as would be expected for this conformer. Moreover, an NOE
study on 37 showed a significant correlation between H-5 and
the octyl group hydrogens immediately adjacent to the glycosidic
oxygen (Figure 1).
1
determined by H NMR spectroscopy after chromatography.
ꢀ-glycosides (30-33, Chart 2) in high yield. The stereochem-
istry of the ꢀ-glycosides was determined from the 3JH1,H2, which
was approximately 10 Hz, as would be expected for a glycoside
with the ꢀ-glucopyranosyl (1,2-trans) stereochemistry. Also
shown in Table 1 is that when the less reactive carbohydrate
alcohols (28 and 29) were used as the acceptor, 1 equiv of
copper(II) triflate was needed to promote the glycosylation.
These results are consistent with what was observed with the
furanoside donors.8 Under these conditions, the primary car-
bohydrate alcohol 28 produced the expected disaccharide 34 in
84% yield. The secondary carbohydrate alcohol acceptor 29 gave
similar results, and the 2,6-dideoxy-2-thiotolyldisaccharide 35
was obtained in 74% yield. The ꢀ-glycoside was the only
glycoside product detected in both cases.
Encouraged by the success in using 8 for the synthesis of
2,6-dideoxy-2-thiotolylglucopyranosides with excellent selectiv-
ity, we next explored the potential of the 2,3-anhydro-6-deoxy-
L-gulopyranoside donor 9 in these reactions. As outlined in Table
2, applying the conditions used for 8 to 9 led to clean reactions.
The products of the glycosylations (36-41) were obtained in
73-90% yield, and in all cases, the stereochemistry at the
anomeric center was R.
All of these data support the proposal that the conformation
of 37, and the other products formed in these reactions, is
predominantly the 4C1 conformer, which has four axial substit-
uents. Despite the axial orientation of the groups at C-1, C-2,
C-3, and C-4, this conformer is presumably stabilized by the
anomeric effect and by the minimization of a steric clash
between the bulky aryl group at C-2 and the aglycon in the 4C1
conformer (Figure 2). In the case of 41, in which JH1,H2 ) 4.7
Hz, it appears that the idopyranose ring adopts a conformation
between the two idealized chair conformations or a mixture of
a number of rapidly interconverting structures.
Desulfurization Reactions. After the glycosylation reactions,
we explored the reductive desulfurization of the 2-thiotolyl
glycosides to generate the 2-deoxy glycosides. In our earlier
studies,8 we had used hydrogenation over Raney nickel to
achieve this transformation, but the yields were somewhat
modest. Therefore, we explored the possibility of a radical
reduction, and monosaccharide 31 and disaccharide 34 were
chosen as representatives to evaluate this desulfurization method.
In both cases, the reactions with tri-n-butyltin hydride and AIBN
in toluene proceeded smoothly and gave the corresponding
products in modest to good yield (Scheme 4). The structure of
The products had the 2,6-dideoxy-2-thioaryl-R-L-idopyranosyl
stereochemistry. As was observed with thioglycoside 8, in the
reaction between 9 and the less reactive carbohydrate alcohols
28 and 29, copper(II) triflate was used as the promotor. The
(50) Snyder, J. R.; Serianni, A. S. J. Org. Chem. 1986, 51, 2694–2702.
(51) Kurihara, Y.; Ueda, K. Carbohydr. Res. 2006, 341, 2565–2574.
J. Org. Chem. Vol. 74, No. 6, 2009 2281

Hou and Lowary
SCHEME 4
CHART 3
FIGURE 3. Retrosynthetic analysis of 44.
methane and methanol failed to remove the acetyl group; only
the starting material was recovered. This problem was overcome
by cleavage of the acetate group in 50 with DIBALH at -78
°C to give the corresponding alcohol 46 in 77% yield.
Presumably, the bulky silyl group hinders the attack of meth-
oxide on the acetyl carbonyl group, and the use of the smaller
hydride ion circumvents this problem. The difficulty in convert-
ing 50 into 46 foreshadowed a problem in using this compound
as a glycosyl acceptor. Attempts to glycosylate 46 with 8 using
copper(II) triflate as the catalyst yielded the expected disaccha-
ride only in trace amount (as confirmed by mass spectrometry).
This failure is presumably because the presence of the bulky
silyl protecting group next to the C-4 hydroxyl group in 46
decreases the nucleophilicity of the alcohol.
After realizing that the silyl group appeared to be suppressing
the glycosylation, diol 51, which has no TBS group, was
prepared from glycal 47 in 86% yield by reaction with NIS
and benzyl alcohol (Scheme 6). It was hoped that it would be
possible to glycosylate the less hindered secondary alcohol in
51 in preference to the tertiary alcohol. Indeed, the glycosylation
of 51 with 8 proceeded efficiently, affording two ꢀ-linked
disaccharides 52 and 53 in an overall yield of 64%. Although
the glycosylation had proceeded without difficulty, the reaction
was not as regioselective as we had hoped and, frustratingly,
the two regioisomers were inseparable. Nevertheless, using 1H
NMR spectroscopy, it was possible to establish that they were
both ꢀ-glycosides, and that they were formed in a 3:1 ratio with
52 predominating.
This mixture of glycosides was then carried forward in the
hope that it could be separated at a later step. Next, the
introduction of a methyl ether on the free hydroxyl group was
explored. To do this, methylation was attempted with trimethy-
loxonium tetrafluoroborate and a proton sponge in dichloro-
methane. These conditions were used to prevent removal or
migration of the benzoyl protecting group, which we anticipated
would occur under more usual methylation conditions involving
the use of a base. Unfortunately, when the mixture of 52 and
53 was reacted under these conditions, no product was detected
after stirring at room temperature overnight.
Faced with these failures, we re-evaluated the approach to
the target. In the new route, we changed the structure of the
glycosyl donor to include a sufficiently stable protecting group
for O-4, one that could survive a methylation process under
basic conditions. As a consequence, the benzoate ester in 8 was
replaced with a benzyl ether. As shown in Scheme 7, this
compound, 54, could be prepared in a straightforward manner
from 13 in 96% yield. In this new approach, we also changed
the structure of the acceptor from the benzyl glycoside 51 to
2-deoxy glycosides was clearly confirmed by the chemical shift
of C-2 in compounds 42 (δC ) 39.5 ppm) and 43 (δC ) 39.3
ppm).
Application of the Methodology to Target Molecules. Once
the methodology was developed, we applied it to the preparation
of two naturally occurring 2,6-dideoxysugar-containing oligo-
saccharides. As targets we chose components of two natural
products: the disaccharide moiety of apoptolidin22 (44, Chart
3) and the trisaccharide unit in olivomycin A25 (45). The
deoxysugar residues in these and other antibiotics have cus-
tomarily been considered as molecular components that affect
only the pharmacokinetic properties of the drug. However,
studies on olivomycin A52 and apoptolidin53 indicate that the
presence of the carbohydrate moieties is key to the bioactivity
of these natural products.
The disaccharide unit in apoptolidin (44) contains a ꢀ-gly-
coside linkage between two 2,6-dideoxysugar units. Several
groups have reported studies toward the synthesis of this
disaccharide, either alone or in the context of the synthesis of
the natural product,22,26-29 and our methodology is also well
suited for its preparation. We envisioned that it could be
produced from the 2,3-anhydro-D-rhamnopyranosyl donor 8 and
the L-olivomycose acceptor 46 (Figure 3).
The preparation of 46 began from glycal 4754 (Scheme 5).
Regioselective protection of the diol was accomplished by
reaction with 1.1 equiv of acetic anhydride with DMAP at room
temperature in pyridine giving an 84% yield of 48. Subsequent
reaction of the alcohol in 48 with tert-butyldimethylsilyl triflate
and 2,6-lutidine provided 49 in 75% yield. NIS-promoted
glycosylation between 48 and benzyl alcohol provided the
R-glycoside 50 as a single anomer in 59% yield. The stereo-
chemistry of anomeric center was established by the measure-
1
ment of the JC1,H1 (173.4 Hz), which clearly confirmed the
stereochemistry of the glycosidic linkage as R.55
The deprotection of 50 proved to be more difficult than
anticipated. Treatment with sodium methoxide in dichloro-
(52) Daniel, P. T.; Koert, U.; Schuppan, J. Angew. Chem., Int. Ed. 2006, 45,
872–893.
(53) Sastry, M.; Patel, D. J. Biochemistry 1993, 32, 6588–6604.
(54) Jung, G.; Klemer, A. Chem. Ber. 1981, 114, 740–745.
(55) Bock, K.; Pedersen, C. J. Chem. Soc., Perkin Trans. 2 1974, 293–297.
2282 J. Org. Chem. Vol. 74, No. 6, 2009

2,3-Anhydrosugars in Glycoside Bond Synthesis
SCHEME 5
SCHEME 6
SCHEME 7
SCHEME 8
the methyl glycoside 55, which was derived from 47 in 90%
yield (Scheme 7). The reason for this change was due to fact
that the benzyl glycoside moiety in 51 would not survive in the
last deprotection step en route to the target molecule,
hydrogenolysis.
Having synthesized both donor 54 and diol 55, they were
reacted to give two ꢀ-linked disaccharides 56 and 57 in a ratio
of 4:1 in 80% total yield (Scheme 7). As was observed with
the products arising from glycosylation of 51, disaccharides 56
and 57 could not be separated and were then carried forward to
the next step as a mixture. Treatment with tri-n-butyltin hydride
and AIBN led to the simultaneous reduction of the C-I and
C-S bonds in 67% yield (Scheme 8), and at this stage, the two
disaccharides, 58 and 59, could be separated and their structures
determined. In the HMBC spectrum of the major isomer, a
correlation between H-4 and C-1′ as well as C-4 and H-1′
indicated that the major disaccharide is the desired product 58.
The remaining steps were straightforward. First, a methyl group
was introduced in 80% yield to the secondary hydroxyl group
in 58 using standard conditions. That the methylation had
occurred on O-3′ was apparent from the chemical shift of C-3
(80.8 ppm), which was further downfield from where this
resonance occurred in the spectrum of 58. The final step
involved hydrogenolysis of the benzyl ether using palladium
hydroxide on carbon as the catalyst to afford 61 in quantitative
yield.
J. Org. Chem. Vol. 74, No. 6, 2009 2283

Hou and Lowary
FIGURE 4. Retrosynthetic analysis of 45.
SCHEME 9
SCHEME 10
Having completed the synthesis of the disaccharide moiety
in apoptolidin we turned our attention to the trisaccharide motif
in olivomycin A. Other groups have previously synthesized this
oligosaccharide, and we viewed our methodology as very well
suited for its preparation.30-34 The retrosynthetic analysis for
the assembly of this trisaccharide, as its benzyl glycoside (45),
is shown in Figure 4. We envisioned that glycosyl acetate 62
could be the precursor to the terminal R-L-olivomycose residue,
whereas the two other ꢀ-linked residues could both be introduced
using thioglycoside 8 by way of disaccharide 63. Monosaccharide
62 could, in turn, be produced from epoxide 9.
H-5 and methyl group at C-3. Having installed the branching
methyl group, ceric ammonium nitrate was then used to cleave
off the p-methoxybenzyl ether, which afforded under the reaction
conditions diol 69 in 37% yield, together with the 3,4-O-p-
methoxybenzylidene acetal byproduct 70 in 41% yield.
Different approaches were examined to convert the axial
hydroxyl group at C-4 in 69 to equatorial stereochemistry.
Standard Mitsunobu reaction conditions were applied to com-
pound 69, but none of the product, 71, could be detected, even
though the reaction mixture was heated to 50 °C for 16 h.
Attempted inversion by way of an oxidation-reduction sequence
also failed, as oxidation of the secondary alcohol with
Dess-Martin periodinane was also unsuccessful and only
unreacted starting alcohol was obtained.
After these failed attempts, a different glycosyl donor was
synthesized and evaluated for the preparation of the target
(Scheme 10). The secondary hydroxyl group in 47 was reacted
with isobutyryl chloride and pyridine in dichloromethane at -20
°C to afford compound 72 selectively in 94% yield. Next, a
tert-butyldimethylsilyl protecting group was installed at the
tertiary hydroxyl group to afford 73 in 90% yield.
The synthesis of 62 began with benzyl 2-thiotolyl-R-L-
idopyranoside 36, which was obtained from 9 in 90% yield upon
reaction with 4 Å molecular sieves and benzyl alcohol (Table
2 and Scheme 9). Oxidation of the hydroxyl group in compound
36 was achieved with Dess-Martin periodinane in dichlo-
romethane. The resulting ketone 64 could be detected by TLC
and by mass spectrometry of the crude reaction mixture.
However, after chromatography, the elimination product 65 was
isolated as the major product in 81% yield.
To overcome the elimination side reaction, the thiotolyl group
was removed before the oxidation step. Thus, reaction of 36
with tri-n-butyltin hydride and AIBN yielded 66 in 70% yield.
Oxidation of the hydroxyl group in 66 was accomplished with
Dess-Martin periodinane in 94% yield without any elimination
product being detected. Addition of a methyl group to ketone
67, via methyl magnesium bromide, occurred at -78 °C to
afford the desired product in 78% yield. The stereoselectivity
of the methyl group addition to the top face of the ring was
presumably due to steric hindrance from the p-methoxybenzyl
ether at C-4. The C-3 stereochemistry of 68 was established by
a TROESY experiment, by a strong NOE correlation between
With a practical route to glycosyl donor 73 in place, we turned
our attention to the synthesis of the olivomycin A trisaccharide
(Scheme 11). First, alcohol 42 (see Chart 2) was reacted with
2284 J. Org. Chem. Vol. 74, No. 6, 2009

2,3-Anhydrosugars in Glycoside Bond Synthesis
SCHEME 11
8 in the presence of copper (II) triflate. The product, 74, was
obtained in 76% yield. Next, using tri-n-butyltin hydride and
AIBN, 74 was reduced to disaccharide 63 in 65% yield.56 The
construction of trisaccharide 75 proceeded smoothly through
coupling of 63 with 73 in the presence of NIS. A 75% yield of
the product was obtained in an R/ꢀ ratio of 10:1. The
R-glycosidic linkage in 75 was established by the measurement
position, we attempted to install this group in 77. Thus, this
trisaccharide was heated with di-n-butyltin oxide in toluene for
five hours, which we hoped would form a stannylidene acetal.
However, upon subsequent addition of isobutyryl chloride no
desired product (45) was observed, and efforts to install this
ester were therefore abandoned.
In conclusion, we have described the first use of 2,3-
anhydrosugars as glycosylating agents for the preparation of
2-deoxypyranosides. In the particular application described here,
the methodology was used to assemble 2,6-dideoxysugar
glycosides. Glycosylation of a panel of alcohols with 8 and 9
afforded 2-deoxy-2-thiotolyl glycoside products in generally
excellent yields with exclusive stereoselectivity. The relationship
between the anomeric group and that at C-3 is syn. The
2-thiotolyl group can be readily removed upon reaction with
tri-n-butyltin hydride and AIBN to give the corresponding
2-deoxypyranosides. This method was successfully applied to
the synthesis of the disaccharide unit in apoptolidin (61). The
key step of this synthesis involved a highly stereoselective
ꢀ-glycosylation of the secondary alcohol in 55 using 54 as the
glycosyl donor. We also accomplished a convergent and
stereoselective synthesis of the trisaccharide moiety of olivo-
mycin A (77). A key feature of this synthesis was the
construction of two ꢀ-glycosidic linkages using 2,3-anhydro-
D-rhamnopyranosyl donor 8, which afforded the products in high
yield and stereoselectivity.
3
1
of the coupling constant JH1,H2 (3.6 Hz) as well as the JC1,H1
(173.4 Hz), which clearly confirmed the R-stereochemistry.55
Once the trisaccharide was assembled, reaction of 75 with
tri-n-butyltin hydride and AIBN resulted in cleavage of the
carbon-iodine bond in 95% yield, giving 76. However, selective
removal of the TBS ether in 76 by TBAF or hydrogen
fluoride-pyridine proved unsuccessful. Although we anticipated
that it would be possible to remove the silyl ether in the presence
of the hindered isobutyl ester, both were cleaved by reaction
with TBAF at 70 °C for 16 h. The use of heat was required
because at room temperature the reaction did not proceed at an
appreciable rate. While cleavage of the isobutyl ester was
efficient, removal of the benzoyl groups with sodium methoxide
proved sluggish. The successful completion of the reaction
required that the solution be heated at reflux in methanol and
THF using lithium methoxide and lithium fluoride for 16 h.
The fully deprotected product 77 was obtained in 70% yield
over the two steps. With regard to the difficulty in removing
the benzoate esters, it should mentioned that in the only total
synthesis of olivomycin A reported to date,34 much more labile
chloroacetyl protecting groups were used at these positions. This
choice was made on the basis of earlier work57 on model
systems demonstrating that acetate groups could not be removed
in the presence of the isobutyl ester moiety. Thus, it appears
that esters at these positions are resistant to nucleophilic attack.
In an attempt to synthesize the natural trisaccharide motif of
olivomycin A, which contains the isobutyl ester at the C-4′′
Experimental Section
p-Tolyl 2,3-Anhydro-4-O-benzoyl-1-thio-r-D-rhamnopyrano-
side (8). Alcohol 13 (1.81 g, 7.18 mmol) was dissolved in CH2Cl2
(30 mL) and cooled to 0 °C, and then pyridine (2.9 mL, 35.91
mmol) and benzoyl chloride (1.25 mL, 10.77 mmol) were added.
The reaction mixture was stirred for 4 h at rt and then concentrated.
The resulting crude product was purified by chromatography (6:1
hexane-EtOAc) to give 8 (2.48 g, 97%) as a colorless oil: Rf 0.90
(2:1 hexane-EtOAc); [R]D +368.8 (c 0.5, CH2Cl2); 1H NMR (500
MHz, CDCl3, δH) 8.14-8.11 (m, 2H, Ar), 7.66-7.59 (m, 1H, Ar),
7.53-7.40 (m, 4H, Ar), 7.19-7.14 (m, 2H, Ar), 5.65 (s, 1H, H-1),
4.98 (d, 1H, J4,5 ) 9.6 Hz, H-4), 4.36-4.26 (m, 1H, H-5), 3.43 (d,
1H, J2,3 ) 3.5 Hz, H-3), 3.41 (d, 1H, J2,3 ) 3.5 Hz, H-2), 2.36 (s,
3H, tolyl CH3), 1.27 (d, 3H, J5,6 ) 6.2 Hz, 3 × H-6); 13C NMR
(56) We also explored the possibility of producing a disaccharide containing
two 2-thiotolyl groups by reaction of 30 with 8 (Table 1), thus providing a
compound in which both C-S bonds could be reduced in a single step. Although
the glycosylation reaction was successful, it was difficult to purify the product,
and therefore, we adopted the approach outlined in Scheme 11, in which the
thioaryl groups were removed in separate steps.
(57) Roush, W. R.; Briner, K.; Kesler, B. S.; Murphy, M.; Gustin, D. J. J.
Org. Chem. 1996, 61, 6098–6099.
J. Org. Chem. Vol. 74, No. 6, 2009 2285

Hou and Lowary
(125 MHz, CDCl3, δC) 165.3 (CdO), 138.0 (Ar), 133.5 (2 × Ar),
132.4 (2 × Ar), 129.8 (2 × Ar), 129.7 (2 × Ar), 129.3 (Ar), 128.5
(2 × Ar), 83.8 (C-1), 69.2 (C-4), 64.0 (C-5), 53.9 (C-2), 50.8 (C-
3), 21.0 (tolyl CH3), 18.3 (C-6); HRMS (ESI) calcd (M + Na)+
C20H20O4S 379.0975, found 379.0973.
purified by chromatography (4:1 hexane-EtOAc) to yield 12 (4.06
g, 93%) as a colorless oil: Rf 0.85 (2:1 hexane-EtOAc); [R]D +64.5
1
(c 0.3, CH2Cl2); H NMR (500 MHz, CDCl3, δH) 8.08-8.03 (m,
2H, Ar), 7.62-7.57 (m, 1H, Ar), 7.49-7.38 (m, 4H, Ar), 7.14-7.09
(m, 2H, Ar), 5.71 (dd, 1H, J2,3 ) 4.7 Hz, J1,2 ) 2.9 Hz, H-2), 5.35
(d, 1H, J1,2 ) 2.9 Hz, H-1), 4.98 (dd, 1H, J4,5 ) 7.7 Hz, J3,4 ) 3.8
Hz, H-4), 4.70-4.62 (m, 2H, H-3, H-5), 2.33 (s, 3H, tolyl CH3),
2.16 (s, 3H, CH3CdO), 1.36 (d, 3H, J6,5 ) 6.5 Hz, 3 × H-6); 13C
NMR (125 MHz, CDCl3, δC) 169.9 (CdO), 164.8 (CdO), 138.0
(Ar), 133.6 (Ar), 132.3 (2 × Ar), 131.8 (Ar), 129.9 (2 × Ar), 129.8
(2 × Ar), 129.1 (Ar), 128.5 (2 × Ar), 85.9 (C-1), 74.3 (C-2), 71.7
(C-4), 65.9 (C-5), 47.1 (C-3), 21.1 (tolyl CH3), 20.9 (CH3CdO),
16.7 (C-6); HRMS (ESI) calcd (M + Na)+ C22H23O5SBr 501.0342,
found 501.0340.
p-Tolyl 2,3-Anhydro-6-deoxy-4-O-p-methoxybenzyl-1-thio-ꢀ-
L-gulopyranoside (9). To a solution of 23 (4.44 g, 9.49 mmol) in
DMF (100 mL) at 0 °C was added sodium hydride (60% in mineral
oil, 0.57 g, 14.25 mmol). The reaction mixture was stirred at rt for
5 h before it was quenched by the addition of water (10 mL). After
concentration of the solution, it was diluted with CH2Cl2 (100 mL)
and washed with water (2 × 100 mL). The organic layer was dried
(Na2SO4), filtered, and concentrated, and the crude product was
purified by chromatography (5:1 hexane-EtOAc) to give 9 (3.19
g, 90%) as a colorless oil: Rf 0.88 (2:1 hexane-EtOAc); [R]D +14.7
p-Tolyl 2,3-Anhydro-1-thio-r-D-rhamnopyranoside (13). To
a solution of 12 (4.0 g, 8.33 mmol) in 1:1 CH2Cl2-CH3OH (160
mL) was added 1 M NaOCH3 in CH3OH (16 mL). After being
stirred for 2 h at rt, the reaction mixture was neutralized with
Amberlite IR-120 H+ resin, filtered, and concentrated. The resulting
oil was purified by chromatography (4:1 hexane-EtOAc) to afford
13 (1.81 g, 86%) as a white solid: Rf 0.29 (4:1 hexane-EtOAc);
1
(c 0.1, CH2Cl2); H NMR (500 MHz, CDCl3, δH) 7.54-7.48 (m,
2H, Ar), 7.32-7.27 (m, 2H, Ar), 7.07-7.01 (m, 2H, Ar), 6.94-6.88
(m, 2H, Ar), 5.08 (s, 1H, H-1), 4.60 (s, 2H, ArCH2), 3.83 (s, 3H,
ArOCH3), 3.65 (dq, 1H, J5,6 ) 6.6 Hz, J4,5 ) 2.0 Hz, H-5), 3.54
(dd, 1H, J3,4 ) 2.2 Hz, J4,5 ) 2.0 Hz, H-4), 3.43 (d, 1H, J2,3 ) 3.1
Hz, H-2), 3.24 (dd, 1H, J2,3 ) 3.1 Hz, J3,4 ) 2.2 Hz, H-3), 2.31 (s,
3H, tolyl CH3), 1.25 (d, 3H, J5,6 ) 6.6 Hz, 3 × H-6); 13C NMR
(125 MHz, CDCl3, δC) 159.4 (Ar), 137.6 (Ar), 132.4 (2 × Ar),
130.2 (Ar), 129.6 (2 × Ar), 129.5 (2 × Ar), 129.2 (Ar), 113.8 (2
× Ar), 80.6 (C-1), 72.8 (ArCH2), 72.1 (C-4), 69.6 (C-5), 55.3
(ArOCH3), 55.1 (C-2), 52.0 (C-3), 21.1 (tolyl CH3), 16.4 (C-6);
HRMS (ESI) calcd (M + Na)+ C21H24O4S 395.1288, found
395.1289.
1
[R]D +332.1 (c 0.4, CH2Cl2); H NMR (500 MHz, CDCl3, δH)
7.43-7.37 (m, 2H, Ar), 7.16-7.11 (m, 2H, Ar), 5.57 (s, 1H, H-1),
3.95-3.86 (m, 1H, H-5), 3.62 (d, 1H, J4,5 ) 8.9 Hz, H-4), 3.41 (d,
1H, J2,3 ) 3.6 Hz, H-3), 3.34 (d, 1H, J2,3 ) 3.6 Hz, H-2), 2.34 (s,
3H, tolyl CH3), 2.27 (br s, 1H, 4-OH), 1.28 (d, 3H, J5,6 ) 6.2 Hz,
3 × H-6); 13C NMR (125 MHz, CDCl3, δC) 137.9 (Ar), 132.4 (2
× Ar), 130.0 (Ar), 129.9 (2 × Ar), 83.8 (C-1), 68.2 (C-4), 66.8
(C-5), 56.0 (C-2), 51.5 (C-3), 21.1 (tolyl CH3), 18.4 (C-6); HRMS
(ESI) calcd (M + Na)+ C13H16O3S 275.0712, found 275.0715.
p-Tolyl 1-Thio-ꢀ-L-fucopyranoside (15). To a solution of 1449
(10 g, 30.1 mmol) and p-thiocresol (4.48 g, 36.1 mmol) in CH2Cl2
(200 mL) at 0 °C was added BF3 ·OEt2 (4.57 mL, 36.1 mmol)
dropwise over 10 min. The reaction mixture was stirred for 5 h at
0 °C, diluted with CH2Cl2 (100 mL), and washed with satd aq
NaHCO3 solution (100 mL) and brine (100 mL). The organic layer
was dried with Na2SO4, filtered, and concentrated. The resulting
residue was dissolved in 1:1 CH2Cl2-CH3OH (200 mL), and 1 M
NaOCH3 in CH3OH (30 mL) was added. After being stirred for
15 h at rt, the reaction mixture was neutralized with Amberlite IR-
120 H+ resin, filtered, and concentrated. The resulting oil was
purified by chromatography (10:1 CH2Cl2-CH3OH) to afford
compound 15 (5.94 g, 73%) as a white amorphous solid: Rf 0.39
(10:1 CH2Cl2-CH3OH); [R]D +41.3 (c, 0.2 CH3OH); 1H NMR (500
MHz, CD3OD, δH) 7.43-7.38 (m, 2H, Ar), 7.13-7.08 (m, 2H,
Ar), 4.46 (d, 1H, J1,2 ) 9.4 Hz, H-1), 3.65-3.58 (m, 2H, H-4,
H-5), 3.52 (dd, 1H, J1,2 ) 9.4 Hz, J2,3 ) 9.3 Hz, H-2), 3.46 (dd,
1H, J2,3 ) 9.3 Hz, J3,4 ) 3.3 Hz, H-3), 2.30 (s, 3H, tolyl CH3),
1.25 (d, 3H, J5,6 ) 6.5 Hz, 3 × H-6); 13C NMR (125 MHz, CD3OD,
δC) 138.5 (Ar), 133.0 (2 × Ar), 132.1 (Ar), 130.5 (2 × Ar), 90.4
(C-1), 76.5 (C-3), 76.0 (C-4), 73.2 (C-5), 70.9 (C-2), 21.1 (tolyl
CH3), 17.0 (C-6); HRMS (ESI) calcd (M + Na)+ C13H18O4S
293.0818, found 293.0818.
Methyl 2-O-Benzoyl-3-bromo-3,6-dideoxy-r-D-altropyrano-
side (11). To a solution of 1044 (4.77 g, 17.93 mmol) and BaCO3
(7.08 g, 35.87 mmol) suspended in CCl4 (200 mL) was added
N-bromosuccinimide (4.47 g, 25.11 mmol). The mixture was heated
at reflux for 2 h and then cooled to rt and filtered; the reaction
flask was washed with CH2Cl2 (100 mL), and the solution was
filtered. The combined filtrate was concentrated, and the resulting
residue was purified by chromatography (4:1 hexane-EtOAc) to
yield11(4.50g,73%)asacolorlessoil:Rf 0.61(2:1hexane-EtOAc);
[R]D -13.9 (c 0.7, CH2Cl2); 1H NMR (400 MHz, CDCl3, δH)
8.05-8.00 (m, 2H, Ar), 7.60-7.54 (m, 1H, Ar), 7.46-7.40 (m,
2H, Ar), 5.50 (dd, 1H, J2,3 ) 3.7 Hz, J1,2 ) 1.4 Hz, H-2), 4.71 (br
s, 1H, H-1), 4.51 (dd, 1H, J2,3 ) 3.7 Hz, J3,4 ) 3.7 Hz, H-3),
4.09-4.00 (m, 1H, H-5), 3.59 (dd, 1H, J4,5 ) 8.5 Hz, J3,4 ) 3.7
Hz, H-4), 3.41 (s, 3H, OCH3), 2.38 (br s, 1H, 4-OH), 1.37 (d, 3H,
J5,6 ) 6.4 Hz, 3 × H-6); 13C NMR (100 MHz, CDCl3, δC) 164.9
(CdO), 133.6 (Ar), 129.9 (2 × Ar), 129.0 (Ar), 128.5 (2 × Ar),
99.0 (C-1), 73.0 (C-2), 69.6 (C-4), 65.7 (C-5), 55.4 (OCH3), 52.3
(C-3), 17.2 (C-6); HRMS (ESI) calcd (M + Na)+ C14H17O5Br
367.0152, found 367.0154.
p-Tolyl 4-O-Acetyl-2-O-benzoyl-3-bromo-3,6-dideoxy-1-thio-
r-D-altropyranoside (12). To a solution of 11 (3.81 g, 11.08 mmol)
in acetic anhydride (100 mL) was added concd H2SO4 (1 mL) at 0
°C. The reaction mixture was stirred for 2 h at 0 °C and then
quenched by the addition of anhydrous NaHCO3. The reaction
mixture was filtered and the filtrate concentrated. The resulting oil
was dissolved in CH2Cl2 (100 mL) and washed successively with
water (50 mL) and satd aq NaHCO3 (50 mL). The organic phase
was dried (Na2SO4), filtered, and concentrated, and the crude
product was purified by chromatography (4:1 hexane-EtOAc) to
give 1,4-di-O-acetyl-2-O-benzoyl-3-bromo-3,6-dideoxy-D-altropy-
ranose (3.0 g, 65%) as a colorless oil: Rf 0.65 (2:1 hexane-EtOAc).
The material was used immediately in the next step without further
characterization. To a solution of p-thiocresol (1.36 g, 10.97 mmol)
and 1,4-di-O-acetyl-2-O-benzoyl-3-bromo-3,6-dideoxy-D-altropy-
ranose (3.78 g, 9.13 mmol) in CH2Cl2 (100 mL) at 0 °C was added
BF3 ·OEt2 (3.47 mL, 27.39 mmol) dropwise over 10 min. The
reaction mixture was stirred for 5 h at 0 °C and was then diluted
with CH2Cl2 (50 mL) and washed with satd aq NaHCO3 solution
(100 mL) and brine (100 mL). The organic layer was dried
(Na2SO4), filtered, and concentrated, and the crude product was
p-Tolyl 3-O-Methanesulfonyl-1-thio-ꢀ-L-fucopyranoside (16).
Compound 15 (3.5 g, 13.0 mmol) was dissolved in toluene (100
mL), and n-Bu2SnO (3.55 g, 14.3 mmol) was added. The reaction
mixture was heated to 105 °C, stirred for 4 h, and then cooled to
room temperature before MsCl (5.03 mL, 65.0 mol) was added.
The reaction mixture was stirred at rt for 16 h and concentrated,
and the crude product was purified by chromatography (2:1
hexane-EtOAc) to give 16 (4.30 g, 95%) as a white solid: Rf 0.21
1
(1:1 hexane-EtOAc); [R]D +18.6 (c, 0.2 CH2Cl2); H NMR (500
MHz, CDCl3, δH) 7.48-7.44 (m, 2H, Ar), 7.17-7.13 (m, 2H, Ar),
4.56 (dd, 1H, J2,3 ) 9.5 Hz, J3,4 ) 3.2 Hz, H-3), 4.44 (d, 1H, J1,2
) 9.5 Hz, H-1), 3.97 (br s, 1H, H-4), 3.81 (dd, 1H, J1,2 ) J2,3
)
9.5 Hz, H-2), 3.70 (q, 1H, J5,6 ) 6.4 Hz, H-5), 3.16 (s, 3H,
OSO2CH3), 2.65 (br s, 1H, OH), 2.35 (s, 3H, tolyl CH3), 2.23 (br
s, 1H, OH), 1.36 (d, 3H, J5,6 ) 6.4 Hz, 3 × H-6); 13C NMR (125
MHz, CD3Cl, δC) 138.9 (Ar), 133.5 (2 × Ar), 129.9 (2 × Ar),
2286 J. Org. Chem. Vol. 74, No. 6, 2009

2,3-Anhydrosugars in Glycoside Bond Synthesis
127.3 (Ar), 88.8 (C-1), 84.4 (C-3), 74.6 (C-5), 71.4 (C-4), 66.9
(C-2), 38.6 (OSO2CH3), 21.2 (tolyl CH3), 16.5 (C-6); HRMS (ESI)
calcd (M + Na)+ C14H20O6S2 371.0594, found 371.0596.
2H, Ar), 5.99-5.86 (m, 1H, CH2dCHCH2O), 5.28-5.15 (m, 2H,
CH2)CHCH2O), 4.89 (d, 1H, J ) 11.1 Hz, ArCH2), 4.63 (d, 1H,
J ) 11.1 Hz, ArCH2), 4.50 (dd, 1H, J3,4 ) 9.5 Hz, J2,3 ) 3.0 Hz,
H-3), 4.47 (d, 1H, J1,2 ) 9.7 Hz, H-1), 4.46-4.39 (m, 1H,
CH2dCHCH2O), 4.15-4.08 (m, 1H, CH2dCHCH2O), 3.83-3.74
(m, 5H, 3 × PhOCH3, H-2, H-4), 3.54 (dd, 1H, J4,5 ) 6.4 Hz, J5,6
) 6.4 Hz, H-5), 3.07 (s, 3H, OSO2CH3), 2.32 (s, 3H, tolyl CH3),
1.18 (d, 3H, J5,6 ) 6.4 Hz, 3 × H-6); 13C NMR (125 MHz, CDCl3,
δC) 159.3 (Ar), 137.6 (Ar), 134.2 (CH2)CHCH2O), 132.2 (2 ×
Ar), 130.1 (2 × Ar), 130.0 (Ar), 129.9 (Ar), 129.6 (2 × Ar), 117.5
(CH2dCHCH2O), 113.6 (2 × Ar), 88.0 (C-1), 85.2 (C-3), 77.5 (C-
2), 74.9 (ArCH2), 74.6 (C-4), 74.3 (C-5), 74.1 (CH2dCHCH2O),
55.3 (ArOCH3), 38.0 (OSO2CH3), 21.1 (tolyl CH3), 16.8 (C-6);
HRMS (ESI) calcd (M + Na)+ C25H32O7S2 531.1482, found
531.1478.
p-Tolyl 2-O-Allyl-1-thio-ꢀ-L-fucopyranoside (20). To a solution
of 15 (4.57 g, 16.90 mmol) in acetone (150 mL) were added 2,2-
dimethoxypropane (4.16 mL, 33.80 mmol) and p-TSA (0.30 g, 1.69
mmol). After being stirred for 16 h at rt, the reaction mixture was
neutralized with Et3N (5 mL) and concentrated. The resulting oil
was dissolved in DMF (20 mL), and allyl bromide (2.83 mL, 32.70
mmol) was added. To this solution was added sodium hydride (60%
in mineral oil, 1.31 g, 32.70 mmol) at 0 °C. The reaction mixture
was stirred at rt for 5 h before it was quenched by the addition of
water (10 mL). The mixture was concentrated and then diluted with
CH2Cl2 (100 mL) before being washed with water (2 × 100 mL).
The organic layer was dried (Na2SO4), filtered, and concentrated.
The resulting oil was dissolved in CH3OH (150 mL), and p-TsOH
(0.30 g, 1.69 mmol) was added. After being stirred for 16 h at rt,
the reaction mixture was neutralized with Et3N (5 mL) and
concentrated. The crude product was purified by chromatography
(2:1 hexane-EtOAc) to give 20 (4.20 g, 80%) as a white solid: Rf
p-Tolyl 3-O-Methanesulfonyl-4-O-p-methoxybenzyl-1-thio-ꢀ-
L-fucopyranoside (23). To a solution of 22 (5.49 g, 10.81 mmol)
in AcOH (100 mL) at rt was added Pd(PPh3)4 (1.25 g, 1.08 mmol).
The reaction mixture was stirred at rt for 48 h and then diluted
with CH2Cl2 (100 mL). The resulting solution was then washed
with water (2 × 100 mL) and satd aq NaHCO3 (2 × 100 mL). The
organic layer was dried (Na2SO4), filtered, and concentrated, and
the resulting crude product was purified by chromatography (3:1
hexane-EtOAc) to give 23 (4.44 g, 88%) as a colorless oil: Rf
1
0.19 (2:1 hexane-EtOAc); [R]D +4.8 (c 0.1, CH2Cl2); H NMR
(500 MHz, CDCl3, δH) 7.48-7.43 (m, 2H, Ar), 7.15-7.09 (m, 2H,
Ar), 6.04-5.94 (m, 1H, CH2dCHCH2O), 5.33-5.19 (m, 2H, 2 ×
CH2)CHCH2O), 4.48 (d, 1H, J1,2 ) 9.6 Hz, H-1), 4.47-4.41 (m,
1H, CH2dCHCH2O), 4.24-4.18 (m, 1H, CH2dCHCH2O), 3.76
1
0.40 (2:1 hexane-EtOAc); [R]D +6.8 (c 0.9, CH2Cl2); H NMR
(br s, 1H, H-4), 3.65-3.58 (m, 2H, H-3, H-5), 3.40 (dd, 1H, J1,2
)
(500 MHz, CDCl3, δH) 7.46-7.42 (m, 2H, Ar), 7.30-7.26 (m, 2H,
Ar), 7.09-7.06 (m, 2H, Ar), 6.90-6.84 (m, 2H, Ar), 4.85 (d, 1H,
J ) 11.2 Hz, ArCH2), 4.60 (d, 1H, J ) 11.2 Hz, ArCH2), 4.59 (dd,
1H, J2,3 ) 9.5 Hz, J3,4 ) 3.0 Hz, H-3), 4.42 (d, 1H, J1,2 ) 9.5 Hz,
H-1), 3.94 (dd, 1H, J1,2 ) 9.5 Hz, J2,3 ) 9.5 Hz, H-2), 3.82 (s, 3H,
ArOCH3), 3.76 (d, 1H, J4,5 ) 3.0 Hz, H-4), 3.63-3.57 (m, 1H,
H-5), 3.13 (s, 3H, OSO2CH3), 2.56 (br s, 1H, 2-OH), 2.33 (s, 3H,
tolyl CH3), 1.22 (d, 3H, J5,6 ) 6.4 Hz, 3 × H-6); 13C NMR (125
MHz, CDCl3, δC) 159.3 (Ar), 138.3 (Ar), 132.9 (2 × Ar), 130.0
(Ar), 129.9 (2 × Ar), 129.8 (2 × Ar), 127.9 (Ar), 113.6 (2 × Ar),
89.1 (C-1), 84.7 (C-3), 77.5 (C-4), 74.9 (ArCH2), 74.8 (C-5), 67.3
(C-2), 55.3 (ArOCH3), 38.3 (-OSO2CH3), 21.2 (tolyl CH3), 16.8
(C-6); HRMS (ESI) calcd (M + Na)+ C22H28O7S2 491.1169, found
491.1167.
9.6 Hz, J2,3 ) 9.1 Hz, H-2), 2.61 (br s, 1H, OH), 2.34 (3H, tolyl
CH3), 2.09 (br s, 1H, OH), 1.35 (d, 3H, J5,6 ) 6.5 Hz, 3 × H-6);
13C NMR (125 MHz, CD3Cl, δC) 137.7 (Ar), 134.7
(CH2)CHCH2O), 132.5 (2 × Ar), 130.0 (Ar), 129.6 (2 × Ar), 117.8
(CH2dCHCH2O), 87.7 (C-1), 78.0 (C-2), 75.3 (C-5), 74.4 (C-3),
74.2 (CH2dCHCH2O), 71.8 (C-4), 21.1 (tolyl CH3), 16.6 (C-6);
HRMS (ESI) calcd (M + Na)+ C16H22O4S 333.1131, found
333.1129.
p-Tolyl 2-O-Allyl-3-O-methanesulfonyl-1-thio-ꢀ-L-fucopyrano-
side (21). Diol 20 (4.11 g, 13.24 mmol) was dissolved in toluene
(100 mL), and n-Bu2SnO (3.96 g, 15.91 mmol) was added. The
reaction mixture was heated to 105 °C, stirred for 4 h, and then
cooled to rt before MsCl (5.13 mL, 66.2 mmol) was added. The
reaction mixture was stirred at rt for 16 h and then concentrated.
Thecrudeproductwaspurifiedbychromatography(3:1hexane-EtOAc)
to give 21 (4.68 g, 91%) as a colorless oil: Rf 0.49 (2:1
hexane-EtOAc); [R]D +0.4 (c 0.2, CH2Cl2); 1H NMR (500 MHz,
CDCl3, δH) 7.48-7.44 (m, 2H, Ar), 7.15-7.11 (m, 2H, Ar),
5.98-5.89 (m, 1H, CH2dCHCH2O), 5.30-5.16 (m, 2H,
CH2)CHCH2O), 4.53-4.48 (m, 2H, H-1, H-3), 4.47-4.41 (m, 1H,
allyl CH2dCHCH2O), 4.17-4.11 (m, 1H, CH2dCHCH2O), 4.00
(br s, 1H, H-4), 3.67-3.61 (m, 2H, H-2, H-5), 3.09 (s, 3H,
OSO2CH3), 2.34 (s, 3H, tolyl CH3), 2.00 (br s, 1H, 4-OH), 1.34 (d,
3H, J5,6 ) 6.5 Hz, 3 × H-6); 13C NMR (125 MHz, CDCl3, δC)
138.1 (Ar), 134.1 (CH2)CHCH2O), 132.7 (2 × Ar), 129.8 (2 ×
Ar), 129.4 (Ar), 117.7 (CH2dCHCH2O), 88.1 (C-1), 84.8 (C-3),
74.4 (C-2), 74.3 (CH2dCHCH2O), 74.1 (C-5), 71.3 (C-4), 38.5
(OSO2CH3), 21.1 (tolyl CH3), 16.5 (C-6); HRMS (ESI) calcd (M
+ Na)+ C17H24O6S2 411.0907, found 411.0907.
p-Tolyl 2-O-Allyl-3-O-methanesulfonyl-4-O-p-methoxybenzyl-
1-thio-ꢀ-L-fucopyranoside (22). Alcohol 21 (9.43 g, 24.30 mmol)
was dissolved in DMF (100 mL), and p-methoxybenzyl chloride
(3.95 mL, 29.16 mmol) was added. This solution was cooled to 0
°C, and sodium hydride (60% in mineral oil, 1.17 g, 29.16 mmol)
was added. The reaction mixture was stirred at rt for 5 h before it
was quenched by the addition of water (10 mL). The solution was
concentrated, diluted with CH2Cl2 (100 mL), and washed with water
(2 × 100 mL). The organic layer was dried (Na2SO4), filtered, and
concentrated, and the resulting crude product was purified by
chromatography (5:1 hexane-EtOAc) to give 22 (12.35 g, 95%)
as a colorless oil: Rf 0.70 (2:1 hexane-EtOAc); [R]D -4.4 (c 0.4,
CH2Cl2); 1H NMR (500 MHz, CDCl3, δH) 7.47-7.42 (m, 2H, Ar),
7.36-7.31 (m, 2H, Ar), 7.07-7.02 (m, 2H, Ar), 6.93-6.86 (m,
Methyl 4-O-Benzyl-2,6-dideoxy-2-p-tolylthio-ꢀ-D-glucopyrano-
syl-(1f4)-2,6-dideoxy-2-iodo-3-C-methyl-r-L-mannopyrano-
side (56) and Methyl 2,6-Dideoxy-4-O-benzyl-2-p-tolylthio-ꢀ-D-
glucopyranosyl-(1f3)-2,6-dideoxy-2-iodo-3-C-methyl-r-L-
mannopyranoside (57). To a solution of 54 (253 mg, 0.74 mmol)
and 55 (186 mg, 0.62 mmol) in CH2Cl2 (25 mL) was added crushed
4 Å molecular sieves (500 mg). After the mixture was stirred at rt
for 30 min, Cu(OTf)2 (223 mg, 0.62 mmol) was added, and the
reaction mixture was stirred for an additional 2 h. After neutraliza-
tion with Et3N, the reaction mixture was concentrated to give a
cruderesiduethatwaspurifiedbychromatography(4:1hexane-EtOAc)
to afford an inseparable 4:1 ratio of 56 and 57 (317 mg, 80%) as
a colorless oil: Rf 0.70 (2:1 hexane-EtOAc). This material was
not further characterized but was carried on to the next step.
Methyl 4-O-Benzyl-2,6-dideoxy-ꢀ-D-arabino-hexopyranosyl-
(1f4)-2,6-dideoxy-3-C-methyl-r-L-arabino-hexopyranoside (58)
and Methyl 2,6-Dideoxy-4-O-benzyl-ꢀ-D-arabino-hexopyranosyl-
(1f3)-2,6-dideoxy-3-C-methyl-r-L-arabino-hexopyranoside (59).
The mixture of 56 and 57 (340 mg, 0.53 mmol) was dissolved in
toluene (30 mL), and n-Bu3SnH (2.84 mL, 10.55 mmol) was added.
The solution was heated at 105 °C, and then AIBN (866 mg, 5.27
mmol) dissolved in toluene (10 mL) was added in portions over
1 h. The solution was stirred for an additional 1 h at 105 °C and
then cooled to rt. The solvent was removed, and the residue was
purified by chromatography (2:1 hexane-EtOAc) to afford 58 (112
mg, 54%) and 59 (28 mg, 13%) both as colorless oils. Data for 58:
1
Rf 0.25 (1:1 hexane-EtOAc); [R]D -106.3 (c 1.1, CH2Cl2); H
NMR (500 MHz, CDCl3, δH) 7.39-7.29 (m, 5H, Ar), 4.82 (dd,
1H, J1′,2ax′ ) 9.9 Hz, J1′,2eq′ ) 2.0 Hz, H-1′), 4.77 (d, 1H, J ) 11.4
Hz, ArCH2), 4.72-4.67 (m, 2H, 1 × ArCH2, H-1), 3.74-3.66 (m,
J. Org. Chem. Vol. 74, No. 6, 2009 2287

Hou and Lowary
1H, H-3′), 3.62 (dq, 1H, J4,5 ) 9.5 Hz, J5,6 ) 6.2 Hz, H-5),
3.41-3.33 (m, 2H, H-4, H-5′), 3.30 (s, 3H, OCH3), 2.98 (dd, 1H,
J3′,4′ ) 9.0 Hz, J4′,5′ ) 9.0 Hz, H-4′), 2.44 (s, 1H, OH), 2.22-2.16
(m, 2H, OH, H-2eq′), 1.96 (dd, 1H, J2eq,2ax ) 13.6 Hz, J1,2eq )1.4
Hz, H-2eq), 1.85 (dd, 1H, J2eq,2ax ) 13.6 Hz, J1,2ax ) 4.5 Hz, H-2ax),
1.69 (ddd, 1H, J2eq′,2ax′ ) 12.0 Hz, J2ax′,3′ ) 12.0 Hz, J1′,2′ax ) 9.9
Hz, H-2ax′), 1.38-1.35 (m, 6H, 3 × H-6′, 3 × H-7), 1.28 (d, 3H,
J5,6 ) 6.2 Hz, 3 × H-6); 13C NMR (125 MHz, CDCl3, δC) 138.2
(Ar), 128.7 (2 × Ar), 128.1 (Ar), 127.9 (2 × Ar), 99.7 (C-1′), 98.2
(C-1), 85.8 (C-4′), 84.0 (C-4), 75.1 (ArCH2), 71.8 (C-3), 71.5 (C-
5′), 71.3 (C-3′), 65.9 (C-5), 54.7 (OCH3), 43.2 (C-2), 38.3 (C-2′),
23.4 (C-7), 18.4 (C-6′), 18.2 (C-6); HRMS (ESI) calcd (M + Na)+
C21H32O7 419.2040, found 419.2041. Data for 59: Rf 0.30 (1:1
hexane-EtOAc); [R]D -81.1 (c 3.6, CH2Cl2); 1H NMR (500 MHz,
CDCl3, δH) 7.40-7.30 (m, 5H, Ar), 4.79-4.67 (m, 4H, 2 × PhCH2,
H-1′, H-1), 3.73-3.67 (m, 2H, H-5, H-3′), 3.39-3.34 (m, 2H, H-4,
H-5′), 3.31 (s, 3H, OCH3), 2.99 (dd, 1H, J3′,4′ ) 8.9 Hz, J4′,5′ ) 8.9
Hz, H-4′), 2.96 (d, 1H, JOH,4 ) 2.9 Hz, 4-OH), 2.17 (d, 1H, JOH,3′
) 3.4 Hz, 3′-OH), 2.06-2.01 (m, 1H, H-2eq′), 1.98-1.93 (m, 1H,
H-2eq), 1.92-1.89 (m, 1H, H-2ax), 1.72-1.64 (m, 1H, H-2ax′),
1.42 (s, 3H, 3 × H-7), 1.35 (d, 3H, J5′,6′ ) 6.2 Hz, 3 × H-6′), 1.31
(d, 3H, J5,6 ) 6.1 Hz, 3 × H-6); 13C NMR (125 MHz, CDCl3, δC)
138.1 (Ar), 128.7 (2 × Ar), 128.1 (Ar), 127.9 (2 × Ar), 98.4 (C-
1′), 92.8 (C-1), 85.5 (C-4′), 78.9 (C-3), 76.0 (C-5′), 75.2 (ArCH2),
71.33 (C-3′), 71.27 (C-4), 66.2 (C-5), 54.8 (OCH3), 40.0 (C-2),
39.7 (C-2′), 20.5 (C-7), 18.4 (C-6′), 18.3 (C-6); HRMS (ESI) calcd
(M + Na)+ C21H32O7 419.2040, found 419.2042.
Methyl 4-O-Benzyl-2,6-dideoxy-3-O-methyl-ꢀ-D-arabino-hex-
opyranosyl-(1f4)-2,6-dideoxy-3-C-methyl-r-L-arabino-hexopy-
ranoside (60). Diol 58 (90 mg, 0.23 mmol) was dissolved in DMF
(10 mL), CH3I (15.6 µL, 0.25 mmol) was added, and the mixture
was cooled to 0 °C. To this solution was added sodium hydride
(60% in mineral oil, 14 mg, 0.34 mmol). The reaction mixture was
stirred at rt for 5 h before it was quenched by the addition of CH3OH
(5 mL). After concentration of the reaction mixture, it was diluted
with CH2Cl2 (20 mL) and washed with water (2 × 20 mL). The
organic layer was dried (Na2SO4), filtered, and concentrated, and
the crude product was purified by chromatography (4:1 hexane-
EtOAc) to give 60 (75 mg, 80%) as a colorless oil: Rf 0.29 (2:1
hexane-EtOAc); [R]D -97.4 (c 0.6, CH2Cl2); 1H NMR (500 MHz,
CDCl3, δH) 7.36-7.27 (m, 5H, Ar), 4.89 (d, 1H, J ) 11.1 Hz,
ArCH2), 4.77 (dd, 1H, J1′,2ax′ ) 10.1 Hz, J1′,2eq′ ) 2.0 Hz, H-1′),
4.71 (dd, 1H, J1,2ax ) 4.5 Hz, J1,2eq ) 1.1 Hz, H-1), 4.63 (d, 1H, J
) 11.1 Hz, ArCH2), 3.62 (dq, 1H, J4,5 ) 9.5 Hz, J5,6 ) 6.3 Hz,
H-5), 3.44 (s, 3H, OCH3), 3.41-3.33 (m, 3H, H-4, H-3′, H-5′),
3.30 (s, 3H, OCH3), 3.02 (dd, 1H, J3′,4′ ) 9.0 Hz, J4′,5′ ) 9.0 Hz,
H-4′), 2.37 (s, 1H, 3-OH), 2.32 (ddd, 1H, J2eq′,2ax′ ) 12.1 Hz, J2eq′,3′
) 5.1 Hz, J1′,2eq′ ) 2.0 Hz, H-2eq′), 1.98-1.84 (m, 2H, H-2ax,
H-2eq), 1.56 (ddd, 1H, J2ax′,2eq′ ) 12.1 Hz, J2ax′,3′ ) 11.9 Hz, J1′,2ax′
) 10.1 Hz, H-2ax′), 1.38 (s, 3H, 3 × H-7), 1.30 (d, 3H, J5′,6′ ) 6.3
Hz, 3 × H-6′), 1.29 (d, 3H, J5,6 ) 6.3 Hz, 3 × H-6); 13C NMR
(125 MHz, CDCl3, δC) 138.6 (Ar), 128.4 (2 × Ar), 128.0 (2 ×
Ar), 127.7 (Ar), 99.7 (C-1′), 98.2 (C-1), 84.0 (C-4), 83.4 (C-4′),
81.4 (C-3′), 75.0 (ArCH2), 71.8 (C-3), 71.5 (C-5′), 66.0 (C-5), 57.0
(OCH3), 54.7 (OCH3), 43.3 (C-2), 35.8 (C-2′), 23.4 (C-7), 18.5
(C-6), 18.1 (C-6′); HRMS (ESI) calcd (M + Na)+ C22H34O7
433.2197, found 433.2195.
4H, H-4, OCH3), 3.34-3.28 (m, 4H, H-5′, OCH3), 3.22-3.10 (m,
2H, H-3′, H-4′), 2.51 (d, 1H, JOH,4′ ) 1.9 Hz, 4′-OH), 2.35-2.31
(m, 2H, H-2eq′, 3-OH), 1.97 (dd, 1H, J2eq,2ax ) 13.7 Hz, J1,2eq
)
1.2 Hz, H-2eq), 1.86 (dd, 1H, J2eq,2ax ) 13.7 Hz, J1,2ax ) 4.5 Hz,
H-2ax), 1.51 (ddd, 1H, J2ax′,2eq′ ) 12.1 Hz, J2ax′,3′ ) 11.3 Hz, J1′,2ax′
) 10.0 Hz, H-2ax′), 1.38 (s, 3H, 3 × H-7), 1.33 (d, 3H, J5′,6′ ) 6.1
Hz, 3 × H-6′), 1.29 (d, 3H, J5,6 ) 6.2 Hz, 3 × H-6); 13C NMR
(125 MHz, CDCl3, δC) 99.9 (C-1′), 98.2 (C-1), 84.0 (C-4), 80.8
(C-3′), 75.5 (C-4′), 71.9 (C-3), 71.8 (C-5′), 66.0 (C-5), 56.4 (OCH3),
54.7 (OCH3), 43.4 (C-2), 34.6 (C-2′), 23.4 (C-7), 18.4 (C-6), 17.8
(C-6′); HRMS (ESI) calcd (M + Na)+ C15H28O7 343.1727, found
343.1726.
Benzyl 4-O-Benzoyl-2,6-dideoxy-ꢀ-D-arabino-hexopyranosyl-
(1f3)-4-O-benzoyl-2,6-dideoxy-ꢀ-D-arabino-hexopyranoside (63). Di-
saccharide 74 (177 mg, 0.25 mmol) was dissolved in toluene (20
mL), and n-Bu3SnH (1.36 mL, 5.06 mmol) was added. The solution
was heated to 105 °C, and then AIBN (208 mg, 1.27 mmol)
dissolved in toluene (10 mL) was added in portions over 1 h. The
mixture was stirred for an additional 1 h at 105 °C. After the mixture
was cooled to rt, the solvent was removed and the resulting residue
was purified by chromatography (3:1 hexane-EtOAc) to give 63
(95 mg, 65%) as a white foam: Rf 0.43 (2:1 hexane-EtOAc); [R]D
-58.0 (c 0.4, CH2Cl2); 1H NMR (500 MHz, CDCl3, δH) 8.09-8.04
(m, 2H, Ar), 8.02-7.98 (m, 2H, Ar), 7.60-7.53 (m, 2H, Ar),
7.47-7.30 (m, 9H, Ar), 4.98-4.91 (m, 2H, H-4, 1 × ArCH2),
4.67-4.58 (m, 3H, 1 × ArCH2, H-1, H-1′), 4.53 (dd, 1H, J3′,4′
)
9.2 Hz, J4′,5′ ) 9.2 Hz, H-4′), 4.10-4.04 (m, 1H, H-3), 3.84-3.76
(m, 1H, H-3′), 3.59 (dq, 1H, J4,5 ) 9.6 Hz, J5,6 ) 6.2 Hz, H-5),
3.44 (dq, 1H, J4′,5′ ) 9.2 Hz, J5′,6′ ) 6.2 Hz, H-5′), 2.40-2.31 (m,
2H, 3′-OH, H-2eq), 2.20 (ddd, 1H, J2eq′,2ax′ ) 12.8 Hz, J1′,2eq′ ) 5.2
Hz, J2eq′,3′ ) 2.0 Hz, H-2eq′), 1.86 (ddd, 1H, J2eq,2ax ) 12.3 Hz,
J2ax,3 ) 12.3 Hz, J21,2ax ) 9.8 Hz, H-2ax), 1.62 (ddd, 1H, J2eq′,2ax′
)
12.8 Hz, J2ax′,3′ ) 11.8 Hz, J21′,2ax′ ) 9.6 Hz, H-2ax′), 1.33 (d, 3H,
J5,6 ) 6.2 Hz, 3 × H-6), 1.04 (d, 3H, J5′,6′ ) 6.2 Hz, 3 × H-6′);
13C NMR (125 MHz, CDCl3, δC) 167.0 (CdO), 165.9 (CdO), 137.4
(Ar), 133.4 (Ar), 132.9 (Ar), 130.4 (Ar), 129.85 (Ar), 129.76 (2 ×
Ar), 129.5 (2 × Ar), 128.54 (Ar), 128.50 (2 × Ar), 128.46 (2 ×
Ar), 128.2 (Ar), 128.09 (Ar), 128.06 (Ar), 127.9 (Ar), 98.1 (C-1′),
96.4 (C-1), 79.0 (C-4′), 75.3 (C-4), 74.3 (C-3), 70.44 (ArCH2), 70.37
(C-5′), 70.1 (C-5), 69.9 (C-3′), 39.7 (C-2′), 36.8 (C-2), 17.9 (C-6),
17.6 (C-6′); HRMS (ESI) calcd (M + Na)+ C33H36O9 599.2252,
found 599.2250.
Benzyl4-O-Benzoyl-2,6-dideoxy-2-p-tolylthio-ꢀ-D-glucopyrano-
syl-(1f3)-4-O-benzoyl-2,6-dideoxy-ꢀ-D-arabino-hexopyrano-
side (74). To a solution of 42 (50 mg, 0.15 mmol) and 8 (62 mg,
0.17 mmol) in CH2Cl2 (15 mL) was added crushed 4 Å molecular
sieves (100 mg). After the mixture was stirred at rt for 30 min,
Cu(OTf)2 (53 mg, 0.15 mmol) was added, and the reaction mixture
was stirred for an additional 2 h. After neutralization with Et3N,
the reaction mixture was concentrated to a crude residue that was
purified by chromatography (4:1 hexane-EtOAc) to give 74 (78
mg, 76%) as a white foam: Rf 0.59 (2:1 hexane-EtOAc); [R]D
-70.3 (c 1.7, CH2Cl2); 1H NMR (500 MHz, CDCl3, δH) 8.09-8.04
(m, 2H, Ar), 8.01-7.96 (m, 2H, Ar), 7.58-7.53 (m, 2H, Ar),
7.46-7.30 (m, 11H, Ar), 7.10-7.07 (m, 2H, Ar), 4.97 (dd, 1H,
J4,5 ) J3,4 ) 9.3 Hz, H-4), 4.94 (d, 1H, J ) 12.0 Hz, 1 × ArCH2),
4.89 (dd, 1H, J4′,3′ ) 9.3 Hz, J4′,5′ ) 9.3 Hz, H-4′), 4.65 (d, 1H, J
) 12.0 Hz, 1 × ArCH2), 4.61 (dd, 1H, J1,2ax ) 9.9 Hz, J1,2eq ) 1.9
Hz, H-1), 4.44 (d, 1H, J1′,2′ ) 8.8 Hz, H-1′), 4.11-4.04 (m, 1H,
H-3), 3.61-3.52 (m, 2H, H-3′, H-5), 3.38-3.31 (m, 1H, H-5′),
2.92 (dd, 1H, J2′,3′ ) 11.0 Hz, J1′,2′ ) 8.8 Hz, H-2′), 2.85 (d, 1H,
Methyl 2,6-Dideoxy-3-O-methyl-ꢀ-D-arabino-hexopyranosyl-
(1f4)-2,6-dideoxy-3-C-methyl-r-L-arabino-hexopyranoside (61).
To a solution of 60 (50 mg, 0.12 mmol) in 1:1 CH3OH-EtOAc
(10 mL) was added 20% Pd(OH)2 on carbon (10 mg), and the
reaction mixture was stirred for 24 h under a hydrogen atmosphere.
The reaction mixture was filtered through Celite and then concen-
trated. The crude product was purified by chromatography (2:1
hexane-EtOAc) to give 61 (39 mg, 100%) as a colorless oil: Rf
0.17 (2:1 hexane-EtOAc); [R]D -136.1 (c 1.4, CH2Cl2); 1H NMR
JOH,3′ ) 2.6 Hz, 3′-OH), 2.43 (ddd, 1H, J2ax,2eq ) 12.6 Hz, J2eq,3
)
5.2 Hz, J1,2eq ) 1.9 Hz, H-2eq), 2.33 (s, 3H, tolyl CH3), 1.87 (ddd,
1H, J2ax,2eq ) 12.6 Hz, J2ax,3 )12.3 Hz, J1,2ax ) 9.9 Hz, H-2ax),
1.34 (d, 3H, J5,6 ) 6.2 Hz, 3 × H-6), 0.90 (d, 3H, J5′,6′ ) 6.2 Hz,
3 × H-6′); 13C NMR (125 MHz, CDCl3, δC) 165.9 (CdO), 165.6
(CdO), 137.7 (Ar), 137.4 (Ar), 133.2 (Ar), 133.0 (Ar), 132.5 (2 ×
Ar), 130.4 (Ar), 129.82 (2 × Ar), 129.80 (2 × Ar), 129.76 (2 ×
Ar), 129.7 (Ar), 129.6 (Ar), 128.5 (2 × Ar), 128.4 (2 × Ar), 128.3
(500 MHz, CDCl3, δH) 4.80 (dd, 1H, J1′,2ax′ ) 10.0 Hz, J1′,2eq′
)
2.0 Hz, H-1′), 4.71 (dd, 1H, J1,2ax ) 4.5 Hz, J1,2eq ) 1.2 Hz, H-1),
3.62 (dq, 1H, J4,5 ) 9.6 Hz, J5,6 ) 6.2 Hz, H-5), 3.42-3.39 (m,
2288 J. Org. Chem. Vol. 74, No. 6, 2009

2,3-Anhydrosugars in Glycoside Bond Synthesis
(2 × Ar), 128.1 (2 × Ar), 127.9 (Ar), 100.9 (C-1′), 98.1 (C-1),
76.4 (C-4′), 76.3 (C-4), 75.8 (C-3), 72.4 (C-3′), 70.5 (C-5′), 70.4
(ArCH2), 69.7 (C-5), 58.1 (C-2′), 36.8 (C-2), 21.1 (tolyl CH3), 17.9
(C-6), 17.1 (C-6′); HRMS (ESI) calcd (M + Na)+ C40H42O9S
721.2442, found 721.2444.
H-5′′), 2.36-2.31 (m, 1H, H-2eq′), 2.30 (hept, 1H, J ) 7.1 Hz,
(CH3)2CH), 2.22-2.17 (m, 1H, H-2eq), 1.87-1.80 (m, 3H, H-2ax′,
H-2eq′′, H-2ax′′), 1.68-1.61 (m, 1H, H-2ax), 1.33 (d, 3H, J5′,6′
)
6.2 Hz, 3 × H-6′), 1.10 (s, 3H, 3 × H-7′′), 0.95 (d, 3H, J5,6 ) 6.2
Hz, 3 × H-6), 0.94 (d, 6H, J ) 7.1 Hz, 2 × (CH3)2CH), 0.76 (d,
3H, J5′′,6′′ ) 6.2 Hz, 3 × H-6′′), 0.73 (s, 9H, (CH3)3CSi(CH3)2),
0.00 (s, 3H, (CH3)3CSi(CH3)2), -0.05 (s, 3H, (CH3)3CSi(CH3)2);
13C NMR (125 MHz, CDCl3, δC) 175.3 (CdO), 165.9 (CdO), 165.5
(CdO), 137.4 (Ar), 133.1 (Ar), 132.9 (Ar), 130.4 (Ar), 129.9 (Ar),
129.8 (2 × Ar), 129.6 (2 × Ar), 128.5 (2 × Ar), 128.3 (2 × Ar),
128.2 (2 × Ar), 128.1 (2 × Ar), 127.9 (Ar), 98.1 (C-1′), 96.3 (C-
1), 92.7 (C-1′′), 78.6 (C-4′′), 75.4 (C-4′), 75.0 (C-4), 73.9 (C-3′),
72.8 (C-3′′), 71.1 (C-3), 70.41 (C-5′), 70.38 (ArCH2), 70.3 (C-5),
65.1 (C-5′′), 44.5 (C-2′′), 36.9 (C-2′), 35.5 (C-2), 34.1 (CH(CH3)2),
25.5 ((CH3)3CSi(CH3)2), 18.9 (C-6′), 18.7 (C-6), 17.9 (C-6′′), 17.5
((CH3)3CSi(CH3)2), 17.3 (2 × CH(CH3)2), 13.6 (C-7′′), -2.1
((CH3)3CSi(CH3)2), -2.2 ((CH3)3CSi(CH3)2); HRMS (ESI) calcd
(M + Na)+ C50H68O13Si 927.4321, found 927.4323.
Benzyl 3-O-tert-Butyldimethylsilyl-4-O-isobutyryl-2,6-dideoxy-
2-iodo-3-C-methyl-r-L-mannopyranosyl-(1f3)-4-O-benzoyl-2,6-
dideoxy-ꢀ-D-arabino-hexopyranosyl-(1f3)-4-O-benzoyl-2,6-
dideoxy-ꢀ-D-arabino-hexopyranoside (75). Glycal 73 (46 mg, 0.14
mmol) and disaccharide 63 (41 mg, 0.07 mmol) were dissolved in
CH2Cl2 (15 mL), and crushed 4 Å molecular sieves (100 mg) were
added. After the mixture was stirred at rt for 30 min, NIS (48 mg,
0.21 mmol) was added, and the solution was then stirred at rt for
16 h before concentration. The resulting residue was purified by
chromatography (8:1 hexane-EtOAc) to give 75 (55 mg, 75%) as
a colorless oil: Rf 0.71 (3:1 hexane-EtOAc); [R]D -68.5 (c 0.6,
CH2Cl2); 1H NMR (500 MHz, CDCl3, δH) 8.09-8.05 (m, 2H, Ar),
8.00-7.96 (m, 2H, Ar), 7.59-7.56 (m, 2H, Ar), 7.47-7.30 (m,
9H, Ar), 5.19 (d, 1H, J1′′,2′′ ) 3.6 Hz, H-1′′), 4.97-4.91 (m, 2H, 1
× ArCH2, H-4), 4.82-4.78 (m, 2H, H-4′′, H-4′), 4.64 (d, 1H, J )
12.1 Hz, 1 × ArCH2), 4.62-4.56 (m, 2H, H-1, H-1′), 4.10-4.03
(m, 1H, H-3), 4.01 (d, 1H, J1′′,2′′ ) 3.6 Hz, H-2′′), 3.91-3.84 (m,
1H, H-3′), 3.58 (dq, 1H, J4,5 ) 9.5 Hz, J5,6 ) 6.2 Hz, H-5), 3.47
(dq, 1H, J4′,5′ ) 9.5 Hz, J5′,6′ ) 6.2 Hz, H-5′), 3.34 (dq, 1H, J5′′,4′′
) 9.1 Hz, J5′′,6′′ ) 6.2 Hz, H-5′′), 2.38-2.21 (m, 3H, H-2eq, H-2eq′,
(CH3)2CH), 1.89-1.80 (m, 1H, H-2ax′), 1.64-1.52 (m, 1H, H-2ax),
1.33 (d, 3H, J5,6 ) 6.2 Hz, 3 × H-6), 1.27 (s, 3H, 3 × H-7′′), 1.01
(d, 3H, J5′,6′ ) 6.2 Hz, 3 × H-6′), 0.98 (d, 3H, J ) 7.0 Hz,
(CH3)2CH), 0.93 (d, 3H, J ) 7.0 Hz, (CH3)2CH), 0.84 (s, 9H,
(CH3)3CSi(CH3)2), 0.75 (d, 3H, J ) 6.2 Hz, 3 × H-6′′), 0.14 (s,
3H, (CH3)3CSi(CH3)2), 0.03 (s, 3H, (CH3)3CSi(CH3)2); 13C NMR
(125 MHz, CDCl3, δC) 175.3 (CdO), 165.9 (CdO), 165.5 (CdO),
137.4 (Ar), 133.1 (Ar), 133.0 (Ar), 130.4 (Ar), 129.8 (2 × Ar),
129.6 (2 × Ar), 128.5 (2 × Ar), 128.3 (2 × Ar), 128.2 (2 × Ar),
128.1 (2 × Ar), 127.9 (2 × Ar), 100.4 (C-1′′), 98.1 (C-1′), 96.2
(C-1), 75.8 (C-4′′), 75.3 (C-4′), 75.2 (C-4), 74.2 (C-3), 74.0 (C-
3′′), 73.1 (C-3′), 70.43 (C-5′), 70.36 (ArCH2), 70.1 (C-5), 66.8 (C-
5′′), 43.2 (C-2′′), 36.8 (C-2′), 36.0 (C-2), 34.0 (CH(CH3)2), 26.1
((CH3)3CSi(CH3)2), 18.9 (C-6′), 18.5 (C-6), 18.4 ((CH3)3CSi(CH3)2),
Benzyl 2,6-Dideoxy-3-C-methyl-r-L-arabino-hexopyranosyl-
(1f3)-2,6-dideoxy-ꢀ-D-arabino-hexopyranosyl-(1f3)- 2,6-dideoxy-
ꢀ-D-arabino-hexopyranoside (77). To a solution of 76 (33 mg,
0.04 mmol) in THF (10 mL) was added 1 M TBAF in THF (0.1
mL, 0.08 mmol). The reaction mixture was heated to 70 °C and
stirred at this temperature for 15 h. After being cooled to rt, the
solution was diluted with EtOAc (20 mL) and washed with brine
(15 mL). The organic layer was dried (Na2SO4), filtered, and
concentrated, and the resulting residue was dissolved in 1:1
THF-CH3OH (20 mL) containing LiOCH3 (10 mg) and LiF (10
mg). The solution was heated to 70 °C and stirred at this temperature
for 15 h. The reaction mixture was then neutralized with Amberlite
IR-120 H+ resin, filtered, and concentrated. The resulting residue
was purified by chromatography (20:1 CH2Cl2-CH3OH) to yield
77 (13 mg, 70%) as a white foam: Rf 0.34 (10:1 CH2Cl2-CH3OH);
1
[R]D -53.9 (c 0.3, CH3OH); H NMR (500 MHz, CDCl3, δH)
7.36-7.27 (m, 5H, Ar), 4.97 (dd, 1H, J1′′,2ax′′ ) 4.4 Hz, J1′′,2eq′′
)
1.2 Hz, H-1′′), 4.90 (d, 1H, J ) 12.0 Hz, 1 × ArCH2), 4.60 (d,
1H, J ) 12.0 Hz, 1 × ArCH2), 4.51 (dd, 1H, J1′,2ax′ ) 9.9 Hz,
J1′,2eq′ ) 2.0 Hz, H-1′), 4.51 (dd, 1H, J1,2ax ) 9.9 Hz, J1,2eq ) 2.0
Hz, H-1), 4.42 (s, 1H, OH), 4.16 (s, 1H, OH), 3.87 (dq, 1H, J4′′,5′′
) 9.3 Hz, J5′′,6′′ ) 6.2 Hz, H-5′′), 3.51-3.41 (m, 2H, H-3′, H-3),
3.33-3.21 (m, 3H, H-4′′, H-5′, H-5), 3.15-3.06 (m, 2H, H-4′, H-4),
2.25-2.10 (m, 2H, H-2eq, H-2eq′), 2.08-1.90 (m, 3H, H-2eq′′,
H-2ax′′, OH), 1.83-1.62 (m, 2H, H-2ax, H-2ax′), 1.42-1.38 (m,
6H, 3 × H-7′′, 3 × H-6′), 1.37 (d, 3H, J5,6 ) 6.1 Hz, 3 × H-6),
1.33 (d, 3H, J5′′,6′′ ) 6.2 Hz, 3 × H-6′′); 13C NMR (125 MHz,
CDCl3, δC) 137.5 (Ar), 128.4 (2 × Ar), 128.0 (2 × Ar), 127.8
(Ar), 99.6 (C-1′), 98.1 (C-1), 97.6 (C-1′′), 82.3 (C-4′′), 80.9 (C-
4′), 79.1 (C-4), 75.3 (C-3′), 75.2 (C-3), 72.1 (C-5′), 72.0 (C-5),
71.1 (C-3′′), 70.3 (ArCH2), 68.1 (C-5′′), 43.4 (C-2′′), 37.5 (C-2′),
37.1 (C-2), 22.1 (C-6′), 18.0 (C-6), 18.0 (C-7′′), 17.8 (C-6′′); HRMS
(ESI) calcd (M + Na)+ C26H40O10 535.2514, found 535.2505.
18.0 (C-7′′), 17.9 (C-6′′), 17.5 (2
×
CH(CH3)2), -1.9
((CH3)3CSi(CH3)2), -2.1 ((CH3)3CSi(CH3)2); HRMS (ESI) calcd
(M + Na)+ C50H67IO13Si 1053.3288, found 1053.3286.
Benzyl 3-O-tert-Butyldimethylsilyl-4-O-isobutyryl-2,6-dideoxy-
3-C-methyl-r-L-arabino-hexopyranosyl-(1f3)-4-O-benzoyl-2,6-
dideoxy-ꢀ-D-arabino-hexopyranosyl-(1f3)-4-O-benzoyl-2,6-
dideoxy-ꢀ-D-arabino-hexopyranoside (76). Trisaccharide 75 (37
mg, 0.04 mmol) was dissolved in toluene (10 mL), and n-Bu3SnH
(0.11 mL, 0.4 mmol) was added. The solution was heated to 100
°C, and following the addition of AIBN (6 mg, 0.04 mmol), it was
stirred for 3 h at this temperature. The reaction mixture was then
cooled to rt and concentrated, and the resulting residue was purified
by chromatography (5:1 hexane-EtOAc) to give 76 (31 mg, 95%)
as a colorless oil: Rf 0.71 (3:1 hexane-EtOAc); [R]D -58.3 (c 0.3,
CH2Cl2); 1H NMR (500 MHz, CDCl3, δH) 8.08-8.05 (m, 2H, Ar),
8.01-7.97 (m, 2H, Ar), 7.57-7.52 (m, 2H, Ar), 7.46-7.31 (m,
9H, Ar), 4.95-4.91 (m, 2H, 1 × ArCH2, H-4′), 4.81 (dd, 1H, J4,5
) 9.4 Hz, J4,5 ) 9.4 Hz, H-4), 4.77 (dd, 1H, J1′′,2eq′′ ) 3.7 Hz,
J1′′,2ax′′ ) 1.7 Hz, H-1′′), 4.64 (d, 1H, J ) 12.0 Hz, 1 × ArCH2),
4.63-4.57 (m, 2H, H-1, H-1′), 4.52 (d, 1H, J4′′,5′′ ) 10.2 Hz, H-4′′),
4.10-4.04 (m, 1H, H-3′), 3.90-3.84 (m, 1H, H-3), 3.58 (dq, 1H,
J4′,5′ ) 9.5 Hz, J5′,6′ ) 6.2 Hz, H-5′), 3.42 (dq, 1H, J4,5 ) 9.5 Hz,
J5,6 ) 6.2 Hz, H-5), 3.33 (dq, 1H, J4′′,5′′ ) 10.2 Hz, J5′′,6′′ ) 6.2 Hz,
Acknowledgment. This work was supported by the Natural
Sciences and Engineering Research Council of Canada, and The
Alberta Ingenuity Centre for Carbohydrate Science.
Supporting Information Available: Details on the synthesis
of and data for additional new compounds not included in text;
1H and 13C NMR spectra for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO900131A
J. Org. Chem. Vol. 74, No. 6, 2009 2289