Efficient synthesis of methylene exo-glycals: Another use of glycosylthiomethyl chlorides

Article abstract of DOI:10.1021/jo0623843

A new approach to the synthesis of methylene exo-glycals is described. Oxidation of glycosylthiolmethyl chloride (GTM-Cl) with mCPBA afforded the corresponding glycosylchloromethyl sulfone in almost quantitative yield, which underwent KO^tBu-ind

Full text of DOI:10.1021/jo0623843

SCHEME 1. Known Procedures for the Synthesis of
Methylene exo-Glycals
Efficient Synthesis of Methylene exo-Glycals:
Another Use of Glycosylthiomethyl Chlorides
Xiangming Zhu,* Ying Jin, and John Wickham
Centre for Synthesis and Chemical Biology, UCD School of
Chemistry and Chemical Biology, UniVersity College Dublin,
Belfield, Dublin 4, Ireland
xiangming.zhu@ucd.ie
ReceiVed NoVember 20, 2006
C-glycosidic structures of biological interest.4 For instance, they
have been used to construct different types of glycosyltransferase
inhibitors with C-glycosidic linkages.4d Recently, 1,3-dipolar
cycloaddition of methylene exo-glycals with a nitrone has also
been carried out to prepare a type of novel amino-ketosyl
C-disaccharides.4a On the other hand, direct dimerization of
methylene exo-glycals could also lead to C-linked disaccharides.4k
Also, a Ramberg-Ba¨cklund approach has been developed by
Taylor et al. for the construction of C-linked trehalose, in which
a methylene exo-glucal was used as the key building block.4e
In addition to their wide application in C-glycoside synthesis,
methylene exo-glycals are also very useful in the synthesis of
natural products and their analogues.5 For example, methylene
exo-mannals have been employed to synthesize a 1-C-methyl-
substituted analogue of PI-88,5a a phosphomannopentaose sulfate
with potent heparanase inhibitory activity and antiangiogenesis
properties. Phlorizin, an aryl â-glucoside, can effectively lower
the blood glucose level in diabetic animal models. Its analogues
were also successfully prepared by using a methylene exo-glucal
as the key building block.5b In short, methylene exo-glycals are
important synthetic intermediates in both carbohydrate synthesis
and natural product synthesis as a reseult of the potential for
further elaboration of the enol ether functionality.6 Moreover,
very recent reports7 that methylene exo-glycals could be readily
A new approach to the synthesis of methylene exo-glycals
is described. Oxidation of glycosylthiolmethyl chloride
(GTM-Cl) with mCPBA afforded the corresponding glyco-
sylchloromethyl sulfone in almost quantitative yield, which
underwent KOtBu-induced Ramberg-Ba¨cklund rearrange-
ment to furnish the desired methylene exo-glycal in excellent
yield.
The importance of carbohydrates and glycoconjugates in
diverse biochemical processes has stimulated the development
of glycomimetics as fundamental tools for biological research
and as potential agents for therapeutic intervention. In this
context, C-glycosides have received considerable attention
because of their resistance to chemical and enzymatic hydrolysis
and their similar or even better biological activities compared
to those of the corresponding O-glycosides.1 Therefore, numer-
ous reliable methods2 have been developed in the past two
decades for the synthesis of C-glycosides, C-linked disaccha-
rides, etc., among which exo-glycals are often important
synthetic intermediates.3
(4) There are a large number of reports on C-glycoside synthesis using
methylene exo-glycals. For some examples, see: (a) Li, X.; Takahashi, H.;
Ohtake, H.; Ikegami, S. Tetrahedron Lett. 2004, 45, 4123-4126. (b)
Paterson, D. E.; Griffin, F. K.; Alcaraz, M. L.; Taylor, R. J. K. Eur. J.
Org. Chem. 2002, 1323-1336. (c) Liu, H.; Smoliakova, I. P.; Koikov, L.
N. Org. Lett. 2002, 4, 3895-3898. (d) Waldscheck, B.; Streiff, M.; Notz,
W.; Kinzy, W.; Schmidt, R. R. Angew. Chem., Int. Ed. 2001, 40, 4007-
4011. (e) Griffin, F. K.; Paterson, D. E.; Taylor, R. J. K. Angew. Chem.,
Int. Ed. 1999, 38, 2939-2942. (f) Campbell, A. D.; Paterson, D. E.;
Raynham, T. M.; Taylor, R. J. K. Chem. Commun. 1999, 1599-1600. (g)
Alcaraz, M. L.; Griffin, F. K.; Paterson, D. E.; Taylor, R. J. K. Tetrahedron
Lett. 1998, 39, 8183-8186. (h) Witczak, Z. J.; Chhabra, R.; Chojnacki, J.
Tetrahedron Lett. 1997, 38, 2215-2218. (i) Gervay, J.; Flaherty, T. M.;
Holmes, D. Tetrahedron 1997, 53, 16355-16364. (j) Haudrechy, A.; Sinay¨,
P. J. Org. Chem. 1992, 57, 4142-4151. (k) Lay, L.; Nicotra, F.; Panza, L.;
Russo, G.; Caneva, E. J. Org. Chem. 1992, 57, 1304-1306.
exo-Glycals are unsaturated sugars that have an exocyclic Cd
C bond attached to the anomeric center. Methylene exo-glycals,
often referred as exo-methylene sugars, are the simplest version
of exo-glycals and have been employed widely to synthesize
(1) For some recent examples of the synthesis of C-glycosides of
biological relevance, see: (a) Yang, G.; Schmieg, J.; Tsuji, M.; Franck, R.
W. Angew. Chem., Int. Ed. 2004, 43, 3818-3822. (b) Kulkarni, S. S.;
Gervay-Hague, J. Org. Lett. 2006, 8, 5765-5768. (c) Postema, M. H. D.;
Piper, J. L.; Betts, R. L. J. Org. Chem. 2005, 70, 829-836. (d) Dondoni,
A.; Catozzi, N.; Marra, A. J. Org. Chem. 2004, 69, 5023-5036. (e)
Abdallah, Z.; Doisneau, G.; Beau, J. M. Angew. Chem., Int. Ed. 2003, 42,
5209-5212.
(2) For some recent reviews on C-glycoside synthesis, see: (a) Taylor,
R. J. K.; McAllister, G. D.; Franck, R. W. Carbohydr. Res. 2006, 341,
1298-1311. (b) Yuan, X.; Linhardt, R. J. Curr. Top. Med. Chem. 2005, 5,
1393-1430. (c) Smoliakova, I. P. Curr. Org. Chem. 2000, 4, 589-608.
(3) Reviewed in: (a) Lin, C. H.; Lin, H. C.; Yang, W. B. Curr. Top.
Med. Chem. 2005, 5, 1431-1457. (b) Taillefumier, C.; Chapleur, Y. Chem.
ReV. 2004, 104, 263-292.
(5) (a) Namme, R.; Mitsugi, T.; Takahashi, H.; Ikegami, S. Tetrahedron
Lett. 2005, 46, 3033-3036. (b) Link, J. T.; Sorensen, B. K. Tetrahedron
Lett. 2000, 41, 9213-9217. (c) Sasaki, M.; Fuwa, H.; Inoue, M.; Tachibana,
K. Tetrahedron Lett. 1998, 39, 9027-9030. (d) Sasaki, M.; Ishikawa, M.;
Fuwa, H.; Tachibana, K. Tetrahedron 2002, 58, 1889-1911.
(6) Hsu, S. J.; Lin, H. C.; Lin, C. H. Carbohydr. Res. 2006, 341, 1428-
1437.
10.1021/jo0623843 CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/28/2007
2670
J. Org. Chem. 2007, 72, 2670-2673

TABLE 1. Synthesis of Glycosylthiomethyl Chloridesa
SCHEME 2. Proposed Procedure for the Synthesis of
Methylene exo-Glycals
transformed into substituted exo-glycals undoubtedly further
enhance their value in synthetic chemistry.
Accordingly, a number of methods have been reported so
far to prepare methylene exo-glycals (Scheme 1): methylenation
of sugar lactones with Tebbe or Petasis reagent,8 Julia olefination
of sugar lactones,9 nucleophilic addition of sugar lactones with
MeLi or MeMgX followed by dehydration,10 reductive elimina-
tion of pyranoketosyl bromides in Fischer-Zanch conditions,11
elimination of glycosylmethyl iodides,5d,12 oxidation of glyco-
sylmethyl phenyl selenide followed by elimination,13 tandem
halogenation-Ramberg-Ba¨cklund rearrangement of glycosyl-
methyl sulfones,14 and rearrangement of glycosylmethylene
carbenes generated by Bamford-Stevens reaction of anhydroal-
dose tosylhydrazones.15
However, most of these procedures suffer from either low
yields of the glycosylidenes or extremely harsh conditions
required for the transformations. Additionally, the low avail-
ability of some starting materials, such as anhydroaldose
tosylhydrazones and glycosylmethyl iodides, has also restricted
the further application of the corresponding procedures. In view
of the great utility and potential of methylene exo-glycals in
synthetic chemistry, we present here an efficient procedure based
on Ramberg-Ba¨cklund rearrangement16 for the synthesis of this
type of compound using glycosylthiomethyl chloride (GTM-
Cl), as shown in Scheme 2. Recently, a new sugar species,
GTM-Cl,17 has been developed and successfully applied to the
synthesis of a series of S-linked neoglycoconjugates, such as
novel sugar-triazole conjugates,17 sugar-nucleotide conjugates,18
a All reactions conducted at 0 °C to room temperature; see Experimental
Section for details. b Yield of pure, isolated product with correct analytical
and spectral data.
and neoglycopeptides.19 The chemical stability and good
mimicry of the S-neoglycoconjugates derived from GTM-Cl
render the new species excellent building blocks to potentially
allow access to a greater variety of S-glycosidic structures.
Moreover, GTM-Cl itself could be readily prepared from the
corresponding glycosyl thiol20 by reaction with dichloromethane
under the action of DBU. It should be noted here that Taylor
and co-workers have developed a route for the synthesis of exo-
glycals using the Ramberg-Ba¨cklund rearrangement, as de-
picted in Scheme 1, in which alkyl or aryl thioglycosides were
used as starting materials.14
To generate methylene exo-glycals from GTM-Cl, galactosyl
thiol 121 was chosen as the model compound. It was first treated
with dichloromethane in the presence of DBU as previously
described,17 and expectedly, GTM-Cl 8 was produced in very
good yield, as shown in Table 1. Under the same conditions,
glycosyl thiols 2-722 were all efficiently converted into the
corresponding GTM-Cl 9-14 in very good to high yields (70-
86%). These glycosylthiomethyl chlorides are needed to test
the feasibility of the proposed new route in Scheme 2 for the
synthesis of methylene exo-glycals. In additioin, they could find
(7) (a) Go´mez, A. M.; Barrio, A.; Amurrio, I.; Valverde, S.; Jarosz, S.;
Lo´pez, J. C. Tetrahedron Lett. 2006, 47, 6243-6246. (b) Go´mez, A. M.;
Pedregosa, A.; Valverde, S.; Lo´pez, J. C. Tetrahedron Lett. 2003, 44, 6111-
6116.
(8) (a) RajanBabu, T. V.; Reddy, G. S. J. Org. Chem. 1986, 51, 5458-
5461. (b) Csuk, R.; Gla¨nzer, B. I. Tetrahedron 1991, 47, 1655-1664.
(9) Gueyrard, D.; Haddoub, R.; Salem, A.; Bacar, N. S.; Goekjian, P.
G. Synlett 2005, 520-522.
(10) Yang, W. B.; Yang, Y. Y.; Gu, Y. F.; Wang, S. H.; Chang, C. C.;
Lin, C. H. J. Org. Chem. 2002, 67, 3773-3782.
(11) Lichtenthaler, F. W.; Hahn, S.; Flath, F. J. Liebigs Ann. 1995, 2081.
(12) Martin, O. R.; Xie, F. Carbohydr. Res. 1994, 264, 141-146.
(13) Lancelin, J. M.; Pougny, J. R.; Sinay¨, P. Carbohydr. Res. 1985,
136, 369-374.
(14) (a) Griffin, F. K.; Murphy, P. V.; Paterson, D. E.; Taylor, R. J. K.
Tetrahedron Lett. 1998, 39, 8179-8182. (b) Griffin, F. K.; Paterson, D.
E.; Murphy, P. V.; Taylor, R. J. K. Eur. J. Org. Chem. 2002, 1305-1322.
(c) Murphy, P. V.; McDonnell, C.; Ha¨mig, L.; Paterson, D. E.; Taylor, R.
J. K. Tetrahedron: Asymmetry 2003, 14, 79-85.
(15) To´th, M.; Somsa´k, L. J. Chem. Soc., Perkin Trans. 1 2001, 942-
943.
(19) Zhu, X.; Pachamuthu, K.; Schmidt, R. R. Org. Lett. 2004, 6, 1083-
1085.
(16) For reviews on the Ramberg-Ba¨cklund reaction, see: (a) Taylor,
R. J. K.; Casy, G. Org. React. 2003, 62, 357-475. (b) Paquette, L. A. Org.
React. 1977, 25, 1-71.
(17) Zhu, X.; Schmidt, R. R. J. Org. Chem. 2004, 69, 1081-1085.
(18) Zhu, X.; Stolz, F.; Schmidt, R. R. J. Org. Chem. 2004, 69, 7367-
7370.
(20) It is important to note that glycosyl thiol could be readily prepared
in a large scale by the following procedure: Cˇ erny´, M.; Vrkocˇ, J.; Staneˇk,
J. Collect. Czech. Chem. Commun. 1959, 24, 64-69.
(21) Zhu, X. Tetrahedron Lett. 2006, 47, 7935-7938.
(22) All glycosyl thiols were prepared by our previous procedure; see
ref 21.
J. Org. Chem, Vol. 72, No. 7, 2007 2671

TABLE 2. Synthesis of Glycosylchloromethyl Sulfonesa
TABLE 3. Synthesis of Methylene exo-Glycalsa
a All reactions conducted at room temperature; see Experimental Section
for details. b Yield of pure, isolated product with correct analytical and
spectral data.
a All compounds have been fully characterized by standard spectral
methods. b Isolated yields based on starting chlorides after chromatographic
separation.
the synthesis of methylene exo-glycals but, to some extent,
verified this assumption.
valuable and versatile use in thioglycoside chemistry as
mentioned above. Considering the fact that basic conditions may
be required to effect the final Ramberg-Ba¨cklund rearrange-
ment, non-base-labile protecting groups were used to protect
these sugars. Synthesis of these methyl-, benzyl-, isopropy-
lidene-, or benzylidene-protected glycosylthiomethyl chlorides
also diversified the protecting group patterns of GTM-Cl,
because GTM-Cl was only prepared previously with acyl-type
protecting groups, such as acetyl and benzoyl.
With these glycosylchloromethyl sulfones in hand, Ramberg-
Ba¨cklund rearrangement induced by potassium tert-butoxide was
investigated.23 As expected, treatment of sulfone 15 with
excessive KOtBu in dimethyl sulfoxide gave rise to the desired
exo-methylenic sugar 22 in very high yield (Table 3, entry 1).
Gratifyingly, this reaction proceeded very cleanly as indicated
by TLC, without any byproduct formation observed. Although
â-elimination of the 2-alkoxy group to form endo-glycal could
be a side reaction, the possible anomeric carbanion generated
in the reaction must be intercepted completely by the γ-elimina-
tion process to form the episulfone intermediate because of the
much better leaving property of the chloro group. The ready
formation of compound 22 offered a preliminary suggestion that
the present procedure may provide a general and convenient
means to methylene exo-glycals. Indeed, the yields with other
investigated sulfones (16-21) were invariably high, as show
in Table 3, and the simplicity of the reaction conditions makes
this approach an attractive way of preparing methylene exo-
glycals, the versatile intermediates in the synthesis of carbo-
hydrate and glycoconjugate mimetics. Also, it is noteworthy
that recently Gueyrard et al. used the Julia olefination to prepare
exo-glucal 24 in only modest yield (53%),9 while Lin et al.
synthesized the same compound in even lower yield (45%) via
the nucleophilic addition-dehydration procedure.10 Notably, by
Taylor’s Ramberg-Ba¨cklund approach,14b a satisfactory yield
Our attention turned then toward the formation of glycosyl-
chloromethyl sulfones from these GTM-Cl. m-Chloroperoxy-
benzoic acid (mCPBA) was chosen as the oxidant to bring about
the transformations. Fortunately, as outlined in Table 2, all
reactions proceeded smoothly and led to the desired products
15-21 in excellent yields. Interestingly, although isopropylidene
and benzylidene protecting groups are acid-labile, they are very
stable under the present conditions as indicated by the quantita-
tive yields of sulfones 20 and 21. In addition, it should be noted
here that a similar glycosyl R′-bromosulfone14b was reported
as the reaction intermediate in Taylor’s Ramberg-Ba¨cklund
approach to exo-glycals and afterward could be converted
smoothly into the expected exo-glycals. Nevertheless, neither
glycosylbromomethyl sulfone nor glycosylchloromethyl sulfone
has been reported in the literature, although they were assumed
to be the intermediates in the tandem chlorination-Ramberg-
Ba¨cklund reaction and tandem bromination-Ramberg-Ba¨cklund
reaction of glycosylmethyl sulfones, respectively. Hence, the
research presented here not only offered a new procedure for
(23) Schmittberger, T.; Uguen, D. Tetrahedron Lett. 1996, 37, 29-32.
2672 J. Org. Chem., Vol. 72, No. 7, 2007

column chromatography (cyclohexane/EtOAc, 1:1) to afford title
compound 15 (115 mg, 99%) as a white amorphous solid: TLC Rf
) 0.19 (cyclohexane/EtOAc, 1:1); [R]20D -62.3 (c 1.0 CHCl3); 1H
NMR (CDCl3, 400 MHz) δ 4.76, 4.39 (AB peak, J ) 12.2 Hz,
2H, H-1′), 4.53 (d, J ) 9.2 Hz, 1H, H-1), 3.99 (t, J ) 9.4 Hz, 1H,
H-2), 3.71 (dd, J ) 2.8, 0.8 Hz, 1H, H-4), 3.68-3.54 (overlapped
m, 3H, H-5, H-6), 3.64, 3.57, 3.56, 3.39 (4s, 12H, Me), 3.35 (dd,
J ) 9.2, 2.8 Hz, H-3); 13C NMR (CDCl3, 100 MHz) δ 87.9 (C-1),
85.7 (C-3), 78.5 (C-5), 75.2 (C-2), 74.7 (C-4), 70.4 (C-6), 61.6,
61.2, 59.4, 58.6 (4 Me), 54.2 (C-1′); ESI-MS m/z 355.2 [M + Na]+,
371.2 [M + K]+; ESI-HRMS calcd for C11H21ClNaO7S [M + Na]+
355.0594, found 355.0587.
2,3,4,6-Tetra-O-methyl-1-deoxy-1-methylidene-D-galactopy-
ranose (22). KOtBu (1.0 M) in THF (1.32 mL, 1.32 mmol) was
added dropwise to a solution of chloride 15 (110 mg, 0.33 mmol)
in DMSO (5 mL) at room temperature, and the solution was stirred
for 4 h and then diluted with Et2O (30 mL) and water (5 mL). The
aqueous phase was separated and extracted with Et2O. The
combined organic layer was washed brine, dried over MgSO4, and
evaporated to a residue, which was purified by flash column
chromatography (cyclohexane/EtOAc, 2:1 + 1% Et3N) to afford
the desired product 22 (65 mg, 85%) as a colorless syrup: TLC Rf
) 0.30 (cyclohexane/EtOAc, 2:1); [R]20D +54.2 (c 0.8 CHCl3); 1H
NMR (CDCl3, 400 MHz) δ 4.69 (dd, J ) 1.6, 0.8 Hz, 1H, H-1′a),
4.58 (dd, J ) 1.6, 0.8 Hz, 1H, H-1′b), 3.89 (dt, J ) 8.8, 1.6 Hz,
1H, H-2), 3.76-3.72 (m, 2H, H-4, H-5), 3.62-3.54 (m, 2H, H-6),
3.53, 3.49, 3.48, 3.37 (4s, 12H, Me), 3.28 (dd, J ) 8.8, 3.2 Hz,
1H, H-3); 13C NMR (CDCl3, 100 MHz) δ 156.9 (C-1), 95.5 (C-
1′), 83.5 (C-3), 78.6 (C-2), 78.2 (C-5), 75.8 (C-4), 70.9 (C-6), 60.9,
59.40, 59.37, 58.6 (4 Me); ESI-MS m/z 255.3 [M + Na]+; ESI-
HRMS calcd for C11H20NaO5 [M + Na]+ 255.1208, found
255.1212.
(72%) of 24 could only be achieved under the harsh conditions
(KOH, CCl4, aqueous BuOH, 60 °C); otherwise a significant
t
amount of byproduct, exo-glucosylidenyl bromide, would be
produced under other conditions (KOH/Al2O3, CBr2F2, tBuOH,
CH2Cl2, 5 °C), resulting in a relatively low yield of the desired
compound 24 (54%). Structural assignment of the new exo-
glycals was made on the basis of NMR spectroscopy and exact
mass spectral data.
In summary, from the new sugar species GTM-Cl, methylene
exo-glycals were efficiently synthesized via a two-step oxida-
tion-Ramberg-Ba¨cklund rearrangement procedure. The high
yields and the mild conditions of this approach, together with
the ready availability of GTM-Cl, are attractive features
compared with previous methods. Extended studies on the scope
and application of the procedure are currently underway.
Experimental Section
Chloromethyl 2,3,4,6-Tetra-O-methyl-1-thio-â-D-galactopy-
ranoside (8). To a stirred solution of the thiol 1 (120 mg, 0.48
mmol) in CH2Cl2 (20 mL) was added DBU (0.14 mL, 0.93 mmol)
at 0 °C. The reaction mixture was stirred overnight at room
temperature, after which time TLC indicated the disappearance of
the starting material. Dichloromethane was then removed in vacuo,
and the residue was purified by flash column chromatography
(cyclohexane/EtOAc, 2:1) to give the desired product 8 (112 mg,
78%) as a white amorphous solid: TLC Rf ) 0.36 (cyclohexane/
1
EtOAc, 2:1); [R]20 -46.7 (c 1.2 CHCl3); H NMR (CDCl3, 400
D
MHz) δ 4.99, 4.75 (AB peak, J ) 11.8 Hz, 2H, H-1′), 4.55 (d, J
) 9.6 Hz, 1H, H-1), 3.72 (d, J ) 2.8 Hz, 1H, H-4), 3.60-3.54
(overlapped m, 3H, H-5, H-6), 3.58 (s, 3H, Me), 3.57 (s, 3H, Me),
3.55 (s, 3H, Me), 3.45 (t, J ) 9.6 Hz, 1H, H-2), 3.40 (s, 3H, Me),
3.24 (dd, J ) 9.2, 3.2 Hz, 1H, H-3); 13C NMR (CDCl3, 100 MHz)
δ 86.0 (C-3), 82.3 (C-1), 79.6 (C-2), 77.3 (C-5), 75.2 (C-4), 70.7
(C-6), 61.6, 61.3, 59.4, 58.5 (4 Me), 46.1 (C-1′); ESI-MS m/z 323.1
[M + Na]+; ESI-HRMS calcd for C11H21ClNaO5S [M + Na]+
323.0696, found 323.0685.
Acknowledgment. This work was supported by the Program
for Research in Third-Level Institutions (PRTLI) Cycle 3,
administered by the High Education Authority (HEA) of Ireland.
The authors thank Dr. Dilip Rai for high-resolution mass
spectrometry measurements.
2,3,4,6-Tetra-O-methyl-â-D-galactopyranosyl Chloromethyl
Sulfone (15). To a stirred solution of chloride 8 (105 mg, 0.35
mmol) in CH2Cl2 (13 mL) was added in one portion 70% mCPBA
(345 mg, 1.40 mmol) at 0 °C. The resulting mixture was vigorously
stirred for 20 h at ambient temperature; diluted with CH2Cl2; washed
successively with H2O, saturated aqueous NaHCO3, and brine; dried
over MgSO4; and concentrated. The residue was purified by flash
Supporting Information Available: Experimental procedures
and analytical and spectral characterization data for all other
compounds; copies of NMR spectra of compounds 8-28. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO0623843
J. Org. Chem, Vol. 72, No. 7, 2007 2673