Chemistry of 1-alkoxy-1-glycosyl radicals: The manno- and rhamnopyranosyl series. Inversion of α- to β-pyranosides and the fragmentation of anomeric radicals

Article abstract of DOI:10.1021/jo951194h

The formation and stereoselective quenching of 1-mannopyranosyl radicals by a tributyltin hydride-mediated intramolecular 1,5-hydrogen abstraction sequence is described. A competing process is 1,4-hydrogen atom abstraction leading principally to glucopyran-2-ulosides. Fragmentation of the anomeric radical resulting in the formation of ring opened products is a problem in certain series. The chemistry is dictated to a considerable extent by the nature of the protecting groups employed with the 4,6-benzylidene series and, for rhamnose, the Ley 3,4-dispiroketal, being particularly susceptible to the 1,4-hydrogen atom abstraction but less to the fragmentation. Photochemical conditions are described, in which these side reactions are practically eliminated, and applied to the inversion of an α- to a β-mannoside in a disaccharide.

Full text of DOI:10.1021/jo951194h

J . Org. Chem. 1996, 61, 605-615
605
Ch em istr y of 1-Alk oxy-1-glycosyl Ra d ica ls: Th e Ma n n o- a n d
Rh a m n op yr a n osyl Ser ies. In ver sion of r- to â-P yr a n osid es a n d th e
F r a gm en ta tion of An om er ic Ra d ica ls
David Crich,* Sanxing Sun, and J armila Brunckova
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
Received J uly 3, 1995X
The formation and stereoselective quenching of 1-mannopyranosyl radicals by a tributyltin hydride-
mediated intramolecular 1,5-hydrogen abstraction sequence is described. A competing process is
1,4-hydrogen atom abstraction leading principally to glucopyran-2-ulosides. Fragmentation of the
anomeric radical resulting in the formation of ring opened products is a problem in certain series.
The chemistry is dictated to a considerable extent by the nature of the protecting groups employed
with the 4,6-benzylidene series and, for rhamnose, the Ley 3,4-dispiroketal, being particularly
susceptible to the 1,4-hydrogen atom abstraction but less to the fragmentation. Photochemical
conditions are described, in which these side reactions are practically eliminated, and applied to
the inversion of an R- to a â-mannoside in a disaccharide.
In tr od u ction
N-linked glycoproteins,7 in various mannans and gly-
cosphingolipids,8 and in lipopolysaccharides,9 and present
a very considerable challenge to the synthetic chemist.
Several protocols for the highly stereoselective and even
stereospecific generation of 1,2-cis-equatorial glycosides
have been developed in recent years,10 enabling the
synthesis of â-mannopyranoside containing oligosaccha-
rides,11 but none are completely general and there is still
much leeway for improved methods. We, and Curran and
co-workers,12 reasoned that preparation of the much more
readily available R-mannopyranosides,13 followed by in-
tramolecular hydrogen atom abstraction to give the
The preparation and reactions of 1-alkoxy-1-glycopy-
ranosyl radicals has long been a subject of interest in this
laboratory. The fascination stems from the high propen-
sity of these pyramidal, σ-type radicals1 for quenching
by thiols and stannanes along the axial direction2 which
permits the highly stereoselective formation of equatorial
glycosides,3,4 most notably the 2-deoxy-â-glycopyranosides
of interest to many groups because of their presence in
numerous biologically active natural products and due
to the problems inherent in their synthesis.5,6 The 1,2-
cis-equatorial type glycosides (â-mannopyranosides and
â-rhamnopyranosides) occur widely in nature as, for
example, in the common core pentasaccharide of the
(7) (a) Lis, H.; Sharon, N. J . Biol. Chem. 1978, 253, 3468. (b) Li, E.;
Kornfeld, S. J . Biol. Chem. 1979, 254, 1600. (c) Dorland, L.; Van
Halbeek, H.; Vliegenhart, J . H. F.; Lis, H.; Sharon, N. J . Biol. Chem.
1981, 256, 7708. (d) Larkin, M.; Childs, R. A.; Matthews, T. J .; Thiel,
S.; Mizuochi, T.; Lawson, A. M.; Savill, J . S.; Haslett, C.; Diaz, R. Feizi,
T. AIDS 1989, 3, 793. (e) Leonard, H. C.; Spellman, M. W.; Riddle, L.;
Harris, R. J .; Thomas, J . N.; Gregory, T. J . J . Biol. Chem. 1990, 265,
10373.
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X Abstract published in Advance ACS Abstracts, December 15, 1995.
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U. J . Org. Chem. 1979, 44, 1872. (b) Malatesta, V. Ingold, K. U. J .
Am. Chem. Soc. 1981, 103, 609. (c) Gregory, A. R.; Malatesta, V. J .
Org. Chem. 1980, 45, 122.
(2) Axial quenching of 1-alkoxy-1-glycosyl radicals was initially
predictable in so far as it is effectively the microscopic reverse of
hydrogen atom abstraction from alkoxytetrahydropyrans by electro-
philic radicals wherein the axial hydrogen is abstracted up to 8 times
as rapidly as the equatorial one: (a) Hayday, K.; McKelvey, R. D. J .
Org. Chem. 1976, 41, 2222. (b) Beckwith, A. L. J .; Easton, C. J . J . Am.
Chem. Soc. 1981, 103, 615. (c) Beckwith, A. L. J .; Brumby, S. J . Chem.
Soc., Perkin Trans. 2 1987, 1801.
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Paulson, H.; Kutschker, W. Lockhoff, O. Chem. Ber. 1981, 114, 3233.
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P. J .; Ossowski, P. Acta Chem. Scand. 1983, 37, 249. (e) Srivastava,
V. K.; Schuerch, C. Carbohydr. Res. 1980, 79, C13. (f) Srivastava, V.
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1994, 59, 6728.
(3) (a) Crich, D.; Ritchie, T. J . Tetrahedron 1988, 44, 2319. (b) Crich,
D.; Ritchie, T. J . J . Chem. Soc., Chem. Commun. 1988, 986. (c) Crich,
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T. J . J . Chem. Soc., Perkin Trans. 1 1990, 945. (f) Crich, D.; Lim, L. B.
L. Tetrahedron Lett. 1990, 31, 1897. (g) Crich, D.; Lim, L. B. L.
Tetrahedron Lett. 1991, 32, 2565. (h) Crich, D.; Lim, L. B. L. J . Chem.
Soc., Perkin Trans. 1 1991, 2205. (i) Crich, D.; Lim, L. B. L. J . Chem.
Soc., Perkin Trans. 1 1991, 2209. (j) Crich, D.; Hermann, F. Tetrahe-
dron Lett. 1993, 34, 3385.
(4) Also see: (a) Kahne, D.; Yang, D.; Lim, J . J .; Miller, R.; Paguaga,
E. J . Am. Chem. Soc. 1988, 110, 8716. (b) Sugai, T.; Shen, G.-J .;
Ichikawa, Y.; Wong, C.-H. J . Am. Chem. Soc. 1993, 115, 413.
(5) For a review on the chemistry of 2-deoxyglycosides see: Thiem,
J .; Klaffke, W. Topics Curr. Chem. 1990, 154, 267.
(6) For recent reports on the synthesis of 2-deoxy-â-glycosides see:
(a) Toshima, K.; Nozaki, Y.; Mukaiyama, T.; Tamai, M.; Tatsuta, K.;
Kinoshita, M. J . Am. Chem. Soc. 1995, 117, 3717. (b) Roush, W. R.;
Lin, X.-F. J . Am. Chem. Soc. 1995, 117, 2236. (c) Sebesta, D. P.; Roush,
W. R. J . Org. Chem. 1992, 57, 4799. (d) Roush, W. R.; Lin, X.-F. J .
Org. Chem. 1991, 56, 5740. (e) Binkley, R. W. J . Carbohydr. Chem.
1991, 10, 399. (f) Ramesh, S. Kaila, N.; Grewal, G.; Franck, R. W. J .
Org. Chem. 1990, 55, 5. (g) Grewal, G.; Kaila, N.; Franck, R. W. J .
Org. Chem. 1992, 57, 2084. (h) Franck, R. W.; Kaila, N. Carbohydr.
Res. 1993, 239, 71.
0022-3263/96/1961-0605$12.00/0 © 1996 American Chemical Society

606 J . Org. Chem., Vol. 61, No. 2, 1996
Crich et al.
Sch em e 1
clear whether these failures were due to the instability
of the radical precursor, or alternative modes of decom-
position of any radicals generated. Attention was there-
fore turned to more stable tethers and, following their
highly successful application in δ-hydrogen atom abstrac-
tions by the Curran22 and other groups,23 the use of vinyl
radicals.24 Of the various possibilities, the most readily
prepared was C but here, too, no abstraction of the
anomeric hydrogen was observed on treatment with
tributyltin hydride and AIBN despite the use of syringe
pump techniques. A similar result was noted by Cur-
ran.12 Given the success of Curran at δ-hydrogen atom
abstraction with bromovinyl silyl ethers in less confor-
mationally rigid systems,22 this latter failure was as-
cribed to the relative rigidity of the system and the
inability of the intermediate vinyl radical to access the
required transition state. We therefore sought to con-
struct a tether with the least possible conformational
constraints. This essentially meant that the abstracting
radical would have to be a simple, nucleophilic, alkyl
radical. Intramolecular hydrogen atom abstraction in
carbohydrates by alkyl radicals, other than from the
anomeric position, had previously been reported by De
Mesmaeker and co-workers.25,26
1-alkoxy-1-mannopyranosyl radical, and finally axial
quenching by a stannane (Scheme 1) would represent an
attractive entry into â-mannopyranosides. We set out
below the successful implementation of this reaction
scheme and describe a number of interesting side reac-
tions encountered in the course of this work.14
Resu lts a n d Discu ssion
Intramolecular δ-hydrogen atom abstraction through
six-membered cyclic transition states by aminium radical
cations and alkoxy radicals has a long and venerable
history15-17 and is supported by calculations.18 It was
therefore natural that our early attempts at implementa-
tion of the above scheme focused on the generation of
typical, oxygen centered, electrophilic radicals suitably
disposed so as to abstract the anomeric hydrogen atom
through six-membered cyclic transition states. In such
a system the radical precursor must necessarily be bound
to the carbohydrate moiety via the hydroxy group at C-2
which limits the choice somewhat. Attempts at the in
situ generation of systems such as A19,20 and B,21 followed
by photolysis and/or thermolysis, provided no evidence
for anomeric hydrogen atom abstraction, but it was never
To this end, treatment of the alcohol 1 with 1,2-
dibromo-2-methoxypropane, prepared in situ from 2-meth-
oxypropene and bromine, and N,N-dimethylaniline in
CH2Cl2 gave the mixed acetal 2 in 62% isolated yield.
This acetal was isolated as an approximately equimolar
mixture of two diastereomers, which we have thus far
been unable to separate. Tributyltin hydride and AIBN
were added dropwise to a solution of this acetal in
benzene at reflux under Ar resulting in the formation of
a relatively complex reaction mixture which was then
stirred with moist silica gel to achieve hydrolysis of the
O-2 acetal functionality. Subsequent silica gel chroma-
tography enabled the isolation of three major products
(Table 1, entry 1) and a number of minor byproducts. The
major products were the desired â-mannoside 3, the
(11) (a) Lichtenthaler, F. W.; Schneider-Adams, T.; Immel, S. J . Org.
Chem. 1994, 59, 6735. (b) Warren, C. D; Auge, C.; Laver, M. L.; Suzuki,
S.; Power, D.; J eanloz, R. Carbohydr. Res. 1980, 82, 71. (c) Auge, C.;
Warren, C. D.; J eanloz, R. Kiso, M.; Anderson, L. Carbohydr. Res. 1980,
82, 85. (d) Gunter, W.; Kunz, H. Angew. Chem., Int. Ed. Engl. 1990,
29, 1050. (e) Gunther, W.; Kunz, H. Carbohydr. Res. 1992, 228, 217.
(f) Barresi, F. Hindsgaul, H. Can. J . Chem. 1994, 72, 1447. (g) Paulsen,
H.; Lebuhn, R.; Lockhoff, O. Carbohydr. Res. 1982, 103, C7. (h) Ogawa,
T.; Kitajima, T.; Nukada, T. Carbohydr. Res. 1983, 123, C5. (i)
Unverzagt, C. Angew. Chem., Int. Ed. Engl. 1994, 33, 1102. (j) Ito, Y.;
Ogawa, T. Angew. Chem., Int. Ed. Engl. 1994, 33, 1765.
(12) Yamazaki, N.; Eichenberger, E. Curran, D. P. Tetrahedron Lett.
1994, 35, 6623.
(13) For recent advances in the synthesis of R-mannans see: (a)
Douglas, S. P.; Whitfield, D. M.; Krepinsky, J . J . J . Am. Chem. Soc.
1995, 117, 2116. (b) Merritt, J . R.; Naisang, E.; Fraser-Reid, B. J . Org.
Chem. 1994, 59, 4443.
(14) Part of this work has appeared as a preliminary communica-
tion: Brunckova, J .; Crich, D.; Yao, Q. Tetrahedron Lett. 1994, 35,
6619.
(15) For reviews on the Hoffmann-Loeffler-Freitag reaction see: (a)
Wolff, M. E. Chem. Rev. 1963, 63, 55. (b) Neale, R. S. Synthesis 1971,
1. (c) Mackiewicz, P.; Furstoss, R. Tetrahedron 1978, 34, 3241.
(16) For reviews on the Barton reaction and modifications thereof
see: (a) Nussbaum, A. L.; Robinson, C. H. Tetrahedron 1962, 17, 35.
(b) Akhtar, M. Adv. Photochemistry 1964, 2, 263. (c) Barton, D. H. R.
Pure Appl. Chem. 1968, 16, 1. (d) Hesse, R. H. Adv. Free Radical Chem.
1964, 3, 83. (e) Mihailovic, M. L.; Gojkovic, S.; Konstantinovic, S.
Tetrahedron 1973, 29, 3675.
(17) For applications in carbohydrate chemistry see: Lopez, J . C.;
Alonso, R.; Fraser-Reid, B. J . Am. Chem. Soc. 1989, 111, 6471.
(18) Calculations on transition state for 1,5-hydrogen atom abstrac-
tion by alkoxy radicals: Dorigo, A. E.; Houk, K. N. J . Org. Chem. 1988,
53, 1650.
(21) tert-Butylperoxydimethylsilyl chloride: Brandes, D.; Blaschette,
A. Monatsh. Chem. 1975, 106, 1299.
(22) ) (a) Curran, D. P.; Kim, D.; Liu, H. T.; Shen, W. J . Am. Chem.
Soc. 1988, 110, 5900. (b) Curran, D. P.; Somayajula, K. V.; Yu, H.
Tetrahedron Lett. 1992, 33, 2295. (c) Curran, D. P.; Shen, W. J . Am.
Chem. Soc. 1993, 115, 6051.
(23) (a) Parsons, P. J .; Pinto, I. J . Chem. Soc., Chem. Commun. 1988,
81. (b) Denenmark, D.; Winkler, T.; Waldner, A.; De Mesmaeker, A.
Tetrahedron Lett. 1992, 33, 3613. (c) Brown, C. D. S.; Simpkins, N. S.;
Clinch, K. Tetrahedron Lett. 1993, 34, 127.
(24) For an interesting study of the effect of substituents on vinyl
radicals and their electrophilicity see: Mawson, S. D.; Routledge, A.;
Weavers, R. T. Tetrahedron 1995, 51, 4665.
(19) Alkoxycarbonyloxy radicals generated in the same manner have
been shown to undergo relatively efficient cyclization onto alkenes in
the 5-exo-trig mode. (a) Newcomb, M.; Kumar, M. U.; Boivin, J .;
Crepon, E.; Zard, S. Z. Tetrahedron Lett. 1991, 32, 49. (b) Beckwith,
A. L. J .; Davison, I. G. E. Tetrahedron Lett. 1991, 32, 49.
(20) Kinetics of decomposition of alkoxycarbonyloxy radicals: Cha-
teauneuf, J .; Lusztyk, J .; Maillard, B.; Ingold, K. U. J . Am. Chem. Soc.
1988, 110, 6727.
(25) De Mesmaeker, A.; Waldner, A.; Hoffmann, P.; Winkler, T.
Synlett. 1994, 330 and references therein.
(26) For other recent reports of intramolecular hydrogen atom
abstraction by alkyl radicals see: (a) Curran, D. P.; Xu, J .; Lazzarini,
E. J . Am. Chem. Soc. 1995, 117, 6603. (b) Winkler, J . D.; Hong, B.-C.
Tetrahedron Lett. 1995, 36, 683. (c) Sugimura, T.; Akira, T.; Koguro,
K. Tetrahedron 1994, 50, 11658. (d) Boivin, J .; da Silva, E.; Ourisson,
G.; Zard, S. Z. Tetrahedron Lett. 1990, 31, 2501 and references therein.

Chemistry of 1-Alkoxy-1-glycosyl Radicals
J . Org. Chem., Vol. 61, No. 2, 1996 607
Sch em e 2
R-mannoside 1, and the ketone 4. Repetition of the
reaction with tributyltin deuteride gave the same three
major products (Table 1, entry 2). Deuterium was
incorporated into 3 at the anomeric site, but not into
either 1 or 4. Evidently, 3 arises from the desired
δ-hydrogen atom abstraction process, inversion of the
anomeric radical, and axial quenching by the stannane.
The R-mannoside 1 is the result of failure of the δ-hy-
drogen atom abstraction process, rather than of equato-
rial quenching of any anomeric radical as shown by the
lack of incorporation of deuterium. The formation of the
ketone 4 was somewhat unexpected as 1,4-hydrogen atom
abstraction reactions, through five-membered cyclic tran-
sition states, are much less common than their 1,5-
counterparts.27 Its structure was established by synthe-
sis of an authentic sample by TPAP/NMNO28 oxidation
of 1, and the anomeric configuration was rigorously
established by the double irradiation of H-3 leading to
the nuclear Overhauser enhancement of H-5 and of the
anomeric methoxy group.
trapping of D. The ratio of I to J will evidently depend
on the ratio of the rate constants kI and kJ as well as on
the concentration of stannane, with less J at higher
concentrations.29 Only minor amounts of the gluco-
isomer 5, from hydrolysis of J , are seen at low concentra-
tion of stannane.
To improve the ratio of 3:1 it is necessary to slow down
the quenching of the initial radical D by the stannane.
This effectively means reducing the concentration of the
stannane or employing a poorer hydrogen atom donor.
Attempts at dropwise addition of the stannane over
significantly longer periods than the 5 h of the initial
reaction were unproductive, presumably owing to the
failure of one or more of the intermolecular steps in the
chain sequence under such dilute conditions. Thus
attention was turned to other methods. A common
approach to maintaining a minimum stannane concen-
tration is the use of a catalytic quantity of a stannyl
chloride in the presence of a borohydride reducing
agent.30,31 Heating 2 in tert-butyl alcohol at reflux with
a catalytic quantity of trimethyltin chloride and sodium
cyanoborohydride under AIBN initiation provided a
cleaner reaction mixture, devoid of the ketone 4, but with
no improvement in the 3:1 ratio (Table 1, entry 3). When
tris(trimethylsilyl)silane,32 with its lower reactivity to-
ward the quenching of simple nucleophilic alkyl radi-
cals,33 was employed in place of the stannane, as much
as 45% of the substrate 2 was recovered indicating a
breakdown of the chain reaction (Table 1, entry 4). More
surprising, however, was the absence of 3 but not of 4
from the reaction mixture. Use of an excess of tris-
(trimethylsilyl)silane resulted in consumption of the
substrate and the isolation of 1 and 4, but again not of 3
(Table 1, entry 5). With hindsight (vide infra) the
The results are best discussed in terms of Scheme 2.
The initial radical D abstracts hydrogen from C-1 to give
E or from C-2 to give F with the ratio of E to F being
k
1,5/k1,4. Radical E inverts to G which is quenched by the
stannane at rate [Bu3SnH]kH to give H which, after
deprotection, provides 3. Radical F , on the other hand,
either suffers fragmentation to the ketone 4 with rate
constant k4 or is quenched by the stannane to give I and
J with rates [Bu3SnH]kI and [Bu3SnH]kJ , respectively.
Product I, the precursor to 1, is also formed by direct
quenching of radical D by the stannane with rate [Bu3-
(29) The quenching stereoselectivity of such radicals must be a
function of the trap employed, of the radical conformation, and of any
C-2 substituent. The methyl 2-deoxy-R-glucopyranos-2-yl radical adds
to activated alkenes with good selectivity from the equatorial site, but
related C-2 substituted radicals are trapped with moderate selectivity
along the axial direction by both oxygen and tributyltin deuteride. (a)
Giese, B.; Groninger, K. Tetrahedron Lett. 1984, 25, 2743. (b) Moutel,
S.; Prandi, J . Tetrahedron Lett. 1994, 35, 8163. (c) Horton, D.; Priebe,
W.; Sznaidman, M. L. J . Org. Chem. 1993, 58, 1821.
(30) (a) Giese, B.; Gonzalez-Gomez, J . A.; Witzel, T. Angew. Chem.,
Int. Ed. Engl. 1984, 23, 69. (b) Stork, G.; Sher, P. M.; Chen, H. L. J .
Am. Chem. Soc. 1986, 108, 6384.
(31) The effectiveness of this protocol in 1,5-hydrogen atom abstrac-
tions with vinyl and aryl radicals has been demonstrated by Curran.22
(32) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188.
SnH]kred
. An increase in the stannane concentration
should (i) increase the yield of I (f 1) by increasing the
rate of quenching of D and of F ; (ii) decrease the yield of
4, by trapping of F ; (iii) decrease the yield of H (f 3), by
(27) 1,4-Hydrogen atom abstraction reactions: (a) Brunton, G.;
Griller, D.; Barclay, L. R. C.; Ingold, K. U. J . Am. Chem. Soc. 1976,
98, 6803. (b) Wallace, T. J .; Gritter, R. J . J . Org. Chem. 1961, 26, 5256.
(c) J ournet, M.; Malacria, M. J . Org. Chem. 1992, 57, 3085.
(28) Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
(33) The rate constants for the trapping of primary alkyl radicals
by Bu3SnH and TMS3SiH respectively at 25 °C are 2.4 × 106 and 1.4
× 105 s-1. (a) Chatgilialoglu, C.; Ingold, K. U.; Scaiano, J . C. J . Am.
Chem. Soc. 1981, 103, 7739. (b) Chatgilialoglu, C.; Dickhaut, J .; Giese,
B. J . Org. Chem. 1991, 56, 6399.

608 J . Org. Chem., Vol. 61, No. 2, 1996
Ta ble 1. In tr a m olecu la r Hyd r ogen Atom Abstr a ction Rea ction s w ith 2
Crich et al.
substrate
concn
additional
reagent
(mol equiv)
reagent
addition reaction
temp R-mannoside â-mannoside
ketone
4: % yield
entry
(mM)a
concn (mM)b time (h) time (h)
(°C)
1: % yield
3: % yield
1
2
18.5
18.5
50
46.5
23
Bu3SnH (1.3)
Bu3SnD (1.3)
Me3SnCl (0.1) + NaBH3CN (2.0)
TMS3SiH (1.0)
TMS3SiH (2.3)
Bu3SnH (1.4)
Bu3SnH (1.0)
97
97
5
9
125
65
5
5
0
1
1
4
1
1
1
1.5
78
78
34
35
52
35
60
57
59
30
22
22
0
10
22
0
31 {[1-2H]-3}
3
∼80
31
0
0
34
30
4c
5
0.25
0.25
5 min
0
78
78
78
rt + hυ
6
7
31
18.5
18.5
0
a
b
Represents the initial concentration of the substrate, before addition of Bu3SnH. Represents the concentration of the Bu3SnH solution
added to the substrate. c 45% of unreacted 2 was also recovered from this reaction.
absence of 3 is readily understood in terms of the
fragmentation of the anomeric radical E/G before quench-
ing by the slow hydrogen atom donor TMS3SiH. Two
further experiments (Table 1, entries 6 and 7) involved
the rapid addition over 5 min of tributyltin hydride to 2
in benzene at reflux, and the photolysis at room temper-
ature of 2 and tributyltin hydride, respectively. Both of
these experiments were clean, and devoid of the ketone
4, with the only products being 1 and 3. Thus, changing
the concentration of tin hydride (or silane) changes the
ratio of 1 and 3 as expected. It also changes the ratio of
3 and 4.
The formation of 2 as a 1:1 diastereomeric mixture
prompts the interesting question of whether one epimer
is responsible for the 1,5-hydrogen atom abstraction
leading to E and so 3, and the other the 1,4-abstraction
resulting in the formation of F and so 4. Thus, it is
readily seen that the S-isomer of radical D may adopt a
chairlike transition state for the hydrogen atom abstrac-
tion in which the requirements of the anomeric effect are
fully satisfied. On the other hand, the R-isomer has the
pendant methoxy group equatorial to the chairlike tran-
sition state, which is consequently higher in energy
perhaps promoting a switch to the more flexible five-
membered transition state of the 1,4-abstraction. Un-
fortunately, our inability at present to separate the two
diastereomers has prevented any experimental investiga-
tion of this hypothesis.34
attainment of the transition state for 1,5-hydrogen atom
abstraction rather than, for 7, any stabilization afforded
to the abstracting radical by the silicon atom.36
In the rhamnopyranosyl series, the mixed acetal 11,
readily prepared from 8 in the normal manner, was
treated with tributyltin hydride and AIBN in benzene
to give a mixture of products, which after hydrolysis with
Dowex, yielded 8, 14, 15, and 18 (Table 2, entry 1). The
first of these (8) results from quenching of the initial
radical. The second (14), somewhat unexpectedly, was
shown by NMR spectroscopy and mass spectrometry to
be methyl 3-O-benzoyl-4-deoxy-R-L-rhamnopyranoside.
This product must arise from a highly unusual, but not
unprecedented,37,38 attack of the stannyl radical on the
carbonyl oxygen of the benzoyl ester followed by frag-
mentation. The anticipated â-glycoside 15 was isolated
in a meager 3% yield. The major product, assigned
structure 18, results from the fragmentation of the
anomeric radical before quenching by the stannane. In
order to provide a cleaner reaction mixture, devoid of the
deoxygenation type product, the 3,4-di-O-benzylrham-
nopyranoside 9 was prepared and converted to the mixed
acetal 12. Treatment of this substance with tributyltin
hydride and AIBN, either by rapid addition, as to 11, or
dropwise over 4 h (Table 2, entries 2 and 3) resulted in
isolation of the reduction product 9, the fragmentation
product 19, and for the rapid addition only the â-rham-
noside 16. The absence of any ketone, formed by 1,4-
hydrogen atom abstraction and fragmentation of the
2-pyranosyl radical, was again noteworthy. The very
significant yields of ring opened products 18 and 19 from
these experiments suggested that the 1-alkoxy-1-glycosyl
radical in the rhamnopyranose series undergoes frag-
mentation much more readily than that in the mannopy-
Looking to broaden the scope of this chemistry the
methyl R-glucopyranosyl system 6 was prepared by the
standard method from 5 and subjected, in benzene at
reflux, to dropwise addition of tributyltin hydride and
AIBN. After hydrolysis, no evidence for the formation
of a â-glucoside was found and the only product isolated,
aside from recovered 5, was the ketone 4 in 70% yield.
Evidently, in this example 1,4-hydrogen atom abstraction
occurs exclusively. The fickleness of the system was
further demonstrated when reduction of the (bromometh-
yl)silane 7 with tributyltin hydride (and Bu3SnD) and
AIBN failed to provide any evidence for intramolecular
hydrogen atom abstraction, be it of the 1,4- or 1,5-type.
These failures are probably best interpreted in terms of
relatively minor structural modifications35 preventing
(35) The SiOC bond angle in simple silyl ethers is typically ∼120°
and the Si-O bond length 1.64 Å: Sheldrick, W. S. In The Chemistry
of Organosilicon Compounds; Patai, S., Rappoport, Z., Eds.; Wiley:
New York, 1989; Vol. 1, p 227 and references therein.
(36) For a recent discourse on the stabilization of carbon radicals
by R- and â-silicon see: Hwu, J . R.; Chen, B.-L.; Shiao, S.-S. J . Org.
Chem. 1995, 60, 2448 and references therein cited.
(37) For the cleavage tertiary benzoate esters with Bu3SnH see:
Redlich, H.; Neumann, H.-J .; Paulsen, H. Chem. Ber. 1977, 110, 2911.
(38) It is possible that the cleavage of this particular benzoate ester
by Bu3SnH is accelerated by the â-oxygen effect: (a) Barton, D. H. R.;
Hartwig, W.; Motherwell, W. B. J . Chem. Soc., Chem. Commun. 1982,
447. (b) Crich, D.; Beckwith, A. L. J .; Chen, C.; Yao, Q.; Davison, I. G.
E.; Longmore, R. W.; Anaya de Parrodi, C.; Quintero-Cortes, L.;
Sandoval-Ramirez, J . J . Am. Chem. Soc. 1995, 117, 8757. (c) Roberts,
B. P.; Steel, A. J . J . Chem. Soc., Perkin Trans. 2 1994, 2411.
(34) For a discussion of a similar anomeric effect in radical cycliza-
tions see: Lopez, J . C.; Gomez, A. M.; Fraser-Reid, B. J . Chem. Soc.,
Chem. Commun. 1994, 1533.

Chemistry of 1-Alkoxy-1-glycosyl Radicals
J . Org. Chem., Vol. 61, No. 2, 1996 609
Ta ble 2. F r a gm en ta tion a n d In ver sion Rea ction s
substrate
concn
Bu3SnH
additional
reaction
time (h)
equiv/concn addition
temp R-mannosides â-mannosides fragmentation 1,4-H abstr.
entry substrate
(mM)a
(mM)b
time (h)
(°C)
(% yield)
(% yield)
(% yield)
(% yield)
1
2
3
4
5
6
7
8
9
11
12
12
13
13
28
29
30
31
2
25
25
25
25
25
25
25
25
25
25
13
13
1.5/340
1.5/100
1.5/160
1.5/190
1.5/130
1.5/120
1.5/120
1.5/120
1.5/120
1.5/120
1.2/120
1.2/120
0
0
4
0
6
5
5
5
5
5
0
2
10
10
4
7
3
3
3
3
3
78
78
78
78
78
78
78
78
78
78
rt, hυ
rt, hυ
8 (29), 14 (13)
9 (51)
9 (64)
10 (68)
10 (37)
24 (57)
25 (68)
26 (63)
27 (74)
1 (19)
15 (3)
16 (8)
16 (0)
17 (4)
17 (6)
32 (0)
33 (3)
34 (0)
35 (0)
3 (21)
15 (11)
15 (25)
18 (43)
19 (17)
19 (18)
20 (9)
20 (42)
39 (31)
36 (15)
37 (14)
38 (13)
42 (9)
-
-
-
-
21 (15)
-
-
-
-
10
11
12
3
3
3
4 (6)
-
11
11
8 (89)
8 (75)
18 (0)
18 (0)
-
a
b
Represents the initial concentration of the substrate, before addition of Bu3SnH. Represents the concentration of the Bu3SnH solution
added to the substrate.
ranose series initially studied. We reasoned that this
might be the consequence, in the absence of the severely
constraining 4,6-O-benzylidene group, of a more confor-
mationally mobile pyranose ring being able to adopt the
geometry required for fragmentation or, alternatively,
that of the absence of a polar substituent at C-6.
treated with tributyltin hydride and AIBN dropwise over
5 h. The results were approximately the same in each
case with the isolation of the simple reduction product
and of the fragmentation product. The similar yields of
the fragmentation products 36, 37, and 38 (Table 2,
entries 7-9), and indeed that of 19 obtained under very
similar conditions (Table 2, entry 3), suggests that the
nature of the substituent at C-6 has no significant effect
on the fragmentation reaction. The 4,6-benzylidene
derivative 2 was also subjected to these reaction condi-
tions. As before, the reaction mixture was complex, but
careful chromatography enabled isolation of the reduction
product 1, the â-mannoside 3, the ketone 4, and an
inseparable mixture of two isomeric benzoates 40 and 41,
benzoylation of which gave the dibenzoate 42 (Table 2,
entry 10). It is noteworthy that only with the ben-
zylidene acetal 2, the dispiroacetal 13 (Table 2, entries
5 and 10) and, in the gluco-series, the benzylidene acetal
6 is any evidence for hydrogen atom abstraction at C-2
observed. We therefore conclude that imposing a rela-
tively rigid chairlike conformation on the pyranose ring
promotes somewhat the 1,4-abstraction reaction. Finally,
in this series of reactions, we subjected 11 to the
photolytic conditions found to be optimum for 2. As
indicated in Table 2 (entries 11 and 12) these reactions
were much cleaner, and slow addition of the tributyltin
hydride over 2 h resulted in a 1:3 mixture of â- and
R-rhamnopyranosides without complicating fragmenta-
tion or deoxygenation reactions.
To probe the conformation question we turned to the
1,2-dispiroketal (dispoke) blocking group introduced by
Ley for the protection of trans-diols. Treatment of methyl
R-L-rhamnopyranoside with 2,2′-bis(dihydropyran) as
described by Ley, followed by workup with ethylene
glycol, led to a complex mixture of products from which
10 was isolated in low but sufficient yield.39 Reaction
with dibromomethoxypropane in the usual manner then
gave 13. Rapid addition of tributyltin hydride to 13 at
reflux in benzene gave 4% of the â-rhamnoside 17 and
9% of the fragmentation product 20 together with a
substantial proportion of the reduction product 10.
Dropwise addition of the stannane over 6 h resulted in
the isolation of 42% of the fragmentation product, 6% of
the â-rhamnoside, and 15% of the 6-deoxygluco-, or
R-quinovopyranoside (21), evidence for 1,4-hydrogen atom
abstraction (Table 2, entries 4 and 5).
In order to probe the role of electronegative substitu-
ents at C-6 on the fragmentation reaction the mannose
derivatives 24-27 were synthesized by standard means
from 22 or 23 and converted to the mixed acetals 28-
31. These derivatives, in benzene at reflux, were then
The fragmentation of the 1-alkoxy-1-glycosyl radicals,
and the effect of the protecting groups on it, is of some
interest. Such radicals may cleave in the exocyclic mode
to give the aglycone radical and a lactone, or in the
endocyclic mode to give esters, as observed here. 2-Meth-
(39) (a) Ley, S. V.; Boons, G.-J .; Leslie, R.; Woods, M.; Hollinshead,
D. M. Synthesis 1993, 689. (b) Edwards, P. J .; Entwhistle, D. A.;
Genicot, C.; Ley, S. V.; Visentin, G. Tetrahedron Asym. 1994, 5, 2609.

610 J . Org. Chem., Vol. 61, No. 2, 1996
Crich et al.
Sch em e 3
°C with triflic anhydride followed by warming to 0 °C
over 1 h enabled the isolation of the R-mannoside 48 and
its â-isomer 50 in 58 and 6% yield, respectively. Desi-
lylation with TBAF in THF then gave the hygroscopic
disaccharide 49 in 86% yield. Reaction of 49 with
dibromomethoxypropane according to the standard pro-
tocol provided the radical precursor 52. Photolysis of 52
at room temperature with dropwise addition of tributyltin
hydride and AIBN over 2 h, followed by stirring with
Dowex resulted in the isolation of a mixture of the R-
and â-mannosides 49 and 51 in the ratio 3:1. The
reaction mixture was devoid of any byproducts arising
from hydrogen atom abstraction from C2 and fragmenta-
tion of the anomeric radical. The â-mannoside 51 was
identical with an authentic sample obtained by desily-
lation of 50.
oxy-2-tetrahydropyranyl radicals were initially thought
to undergo preferential fragmentation in the exocyclic
mode to give δ-valerolactone:40 a preference which was
explained in terms of stereoelectronic effects with the
required coplanarity between the singly occupied orbital
and the σ*-orbital of the scissile bond being more readily
accessible in the exocyclic mode.41 However, subsequent
work showed endocyclic cleavage to be a competing, and
even the major, pathway (Scheme 3).2a,42 Increased
substitution at C-6 of the 2-tetrahydropyranyl system
(corresponding to C-5 in the carbohydrate numbering
scheme) favors endocyclic fragmentation (Scheme 3).43
If we assume the anomeric radical to be fully pyrami-
dalized then, in order for the singly occupied orbital to
be coplanar with the scissile bond, fragmentation must
occur from the higher energy configuration with the
aglycone axial and the radical equatorial. The inversion
of configuration of such radicals is estimated1a to have a
barrier of <6 kcal mol-1 and so such a situation is
certainly possible. Alternatively, a boat or twist-boat
conformation must be invoked. Presumably, the slower
fragmentation in the 4,6-benzylidene series reflects a
subtle conformational effect, possibly compounded by
some residual π-character in the anomeric radical,
whereby the configuration and conformation required for
fragmentation is of higher energy than in the other series
studied.
Finally, having defined optimum conditions for man-
noside inversion, we turned to the synthesis of a disac-
charide. Ethyl R-thiomannoside44 was converted to its
4,6-benzylidene derivative 43, with benzaldehyde dim-
ethylacetal, which was subsequently benzylated selec-
tively at O-3, via its 2,3-(dibutylstannyl)acetal,45 to give
44 in 80% yield. Silylation with tert-butyldimethylsilyl
triflate then gave 45 in 95% yield. In view of the
somewhat sterically hindered nature of the glycosyl donor
we chose to adopt the Kahne sulfoxide glycosylation
procotol46 for coupling to the aglycone. Treatment of 45
with magnesium monoperoxphthalate47 in aqueous THF
gave the sulfoxide 46 in 90% yield as an unassigned
diastereomer. Treatment of a mixture of 46, the aglycone
47, and 2,6-di-tert-butyl-4-methylpyridine in ether at -78
In conclusion, conditions have been established for the
inversion of R- to â-mannosides without interference by
detrimental side reactions. The â:R ratio is governed by
the intramolecular hydrogen atom abtraction step which
at present is relatively inefficient. In order for prepara-
tively useful â:R-ratios to be obtained it will be necessary
to improve the rate of this step.
Exp er im en ta l Section
Gen er a l. Melting points were recorded on a Thomas
hotstage microscope and are uncorrected. 1H- and 13C-NMR
spectra were run in CDCl3 at 300 and 75 MHz, respectively.
Chemical shifts are downfield from tetramethylsilane as
internal standard. All solvents were dried and distilled by
standard procedures. All reactions were run under a dry
nitrogen or argon atmosphere. THF was distilled, under N2,
immediately prior to use from sodium benzophenone ketyl.
Ether refers to diethyl ether. Microanalyses were conducted
by Midwest Microanalytical, Indianapolis, IN.
Meth yl 3-O-Ben zoyl-4,6-ben zylid en e-r-D-m a n n op yr a -
n osid e (1). Alcohol 1 was prepared essentially according to
the literature protocol.48 Mp 130-132 °C, lit.48 mp 131-132
(40) Yamagashi, T.; Yoshimoto, T.; Minami, K. Tetrahedron Lett.
1971, 2795.
(41) (a) Perkins, M. J .; Roberts, B. P. J . Chem. Soc., Perkin Trans.
2 1975, 77. (b) Rynard, C. M.; Thankachan, C.; Tidwell, T. T. J . Am.
Chem. Soc. 1979, 101, 1196.
(42) McKelvey, R. D. Carbohydr. Res. 1975, 42, 187.
(43) Bernasconi, C.; Cottier, L.; Descotes, G. Bull. Soc. Chim. Fr.
1977, 101.
(44) Pedretti, V.; Veyrieres, A.; Sinay, P. Tetrahedron 1990, 46, 77.
(45) David, S.; Hanessain, S. Tetrahedron 1985, 41, 643.
(46) (a) Kahne, D.; Walker, S.; Cheng, Y.; Engen, D. V. J . Am. Chem.
Soc. 1989, 111, 6881. (b) Kim, S.-H.; Augeri, D.; Yang, D.; Kahne, D.
J . Am. Chem. Soc. 1994, 116, 1766. (c) Raghavan, S.; Kahne, D. J .
Am. Chem. Soc. 1993, 115, 1580. (d) Sliedregt, L. A. J . M.; van der
Marel, G. A.; van Boom, J . H. Tetrahedron Lett. 1994, 35, 4015.
(47) Heaney, H. Aldrichim. Acta 1993, 26, 35.
1
°C; [R]D ) -24° (c ) 1.3, CH2Cl2); H-NMR, δ: 3.39 (s, 3H),
3.85-4.00 (m, 2H), 4.20-4.40 (m, 3H), 4.79 (d, 1H, J ) 1.5
Hz), 5.56 (dd, 1H, J ) 3.25, 10.23 Hz), 5.60 (s, 1H), 7.25-7.70
(m, 8H), 8.05-8.15 (m, 2H); 13C-NMR, δ: 55.0, 63.7, 68.7, 69.5,
71.4, 76.0, 101.5, 101.7, 126.1, 128.1, 128.3, 128.9, 129.7, 133.1,
137.1, 165.6.
P r ep a r a tion of Ca r boh yd r a te 1-Br om o-2-m eth oxy-2-
p r op yl Eth er s. Meth od A. The substrate (1 mmol) was
dissolved in CH2Cl2 (2 mL) under Ar and cooled to 0-5 °C in
an ice-water bath. 2-Methoxypropene (104 µL, 1.1 mmol) and
N-bromosuccinimide (0.196 g, 1.1 mmol) were then added, and
(48) Seymour, F. R. Carbohydr. Res. 1974, 34, 65.

Chemistry of 1-Alkoxy-1-glycosyl Radicals
J . Org. Chem., Vol. 61, No. 2, 1996 611
the mixture was stirred at ice bath temperature for 1 h and
then warmed to room temperature and stirred for an ad-
ditional 24 h. The reaction mixture was then diluted with CH2-
Cl2 (10 mL) and quenched with saturated aqueous NaHCO3
(4 mL). The organic layer was washed with brine (2 × 3 mL),
dried (MgSO4), and concentrated under vacuum. The crude
reaction mixture typically consisting of the product (20-25%)
and unreacted substrate (75-80%) was then purified by
chromatography on silica gel, eluting with 5-8/1 hexane/ethyl
acetate, to give the desired ethers as approximately 1:1
mixtures of diastereomers.
P r ep a r a tion of Ca r boh yd r a te 1-Br om o-2-m eth oxy-2-
p r op yl Eth er s. Meth od B. To a stirred solution of 2-meth-
oxypropene (0.7-0.75 M, 1.5 equiv with respect to substrate)
in CH2Cl2 under Ar at -78 °C was added bromine (1.5 equiv
with respect to substrate) dropwise via a syringe. The solution
was stirred for 30 min at -78 °C before an ice cold solution of
the substrate (0.8 M) and N,N-dimethylaniline (1.5 equiv with
respect to substrate) in CH2Cl2 was added dropwise over 10
min. The reaction mixture was stirred for 2 h at -78 °C then
for 12-24 h at room temperature before dilution with CH2-
Cl2, washing with saturated aqueous NaHCO3 and brine, and
drying (MgSO4). After evaporation of the volatiles chroma-
tography on silica gel (eluent: typically hexane/ethyl acetate
50/1 f 10/1 f 3/1) provided the desired ethers as ap-
proximately 1:1 mixtures of diastereomers typically in 60-
70% yield. Residual substrate could be recovered as a more
polar fraction.
Hz, 2H), 3.44 (s, 3H), 3.89-4.05 (m, 2H), 4.23-4.37 (m, 2H),
4.43 (dd, J ) 1.7, 3.2 Hz, 1H), 4.73 (d, J ) 1.7 Hz, 1H), 5.51
(dd, J ) 3.2, 10.3 Hz, 1H), 5.65 (s, 1H), 7.25-7.65 (m, 8H),
8.02-8.15 (m, 2H); 13C-NMR, δ: 16.0, 55.1, 64.2, 68.8, 71.0,
71.4, 75.9, 101.7, 102.3, 126.1, 128.2, 128.4, 128.9, 129.8, 130.0,
133.2, 137.3, 165.9; υmax: 1722, 1276, 1132 cm-1. Anal. Calcd
for C24H29BrO7Si: C, 53.63; H, 5.44. Found: C, 53.83; H, 5.50.
Gen er a l P r otocol for Ra d ica l Rea ction s. The radical
precursor was dissolved in benzene at the concentration given
in Tables 1 and 2 and either heated to reflux or photolyzed at
room temperature in a Rayonet photoreactor (254 nm through
Pyrex) while a solution of tributyltin hydride and AIBN (5 mol
%) in benzene (concentrations and equivalents given in Tables
1 and 2) was added dropwise with a motor driven syringe
pump. When the addition was complete, reflux, or photolysis,
was continued for the time indicated in the tables before the
solvent was removed under vacuum and the residue taken up
in chloroform and stirred overnight with moist silica gel or,
better, Dowex 50 (H+). The products were isolated by filtra-
tion, evaporation, and chromatography on silica gel. For
entries 4 and 5 of Table 1, the same protocol was followed
except that the stannane was replaced by tris(trimethylsilyl)-
silane.
Meth yl 3-O-Ben zoyl-4,6-ben zylid en e-â-D-m a n n op yr a -
n osid e (3).50 An oil. 1H-NMR, δ: 3.50-3.60 (m, 1H), 3.61
(s, 3H), 3.93 (t, 1H, J ) 10.3 Hz), 4.31 (t, 1H, J ) 10.0 Hz),
4.39 (m, 1H), 4.40 (dd, 1H, J ) 4.9, 10.4 Hz), 4.64 (d, 1H, J )
1.0 Hz), 5.30 (dd, 1H, J ) 3.2, 10.2 Hz), 5.61 (s, 1H), 7.25-
7.70 (m, 8H), 8.05-8.15 (m, 2H); 13C-NMR, δ: 57.3, 67.1, 68.6,
69.6, 72.6, 75.5, 101.7, 102.0, 126.1, 128.2, 128.4, 129.7, 129.9,
130.1, 133.2, 133.6, 166.0.
Meth yl 4,6-O-Ben zylid en e-3-O-ben zoyl-2-O-(1-br om o-
2-m eth oxy-2-p r op yl)-r-D-m a n n op yr a n osid e (2). A 1:1 di-
astereomeric mixture prepared by protocol B from 1 in 62%
yield as a white foam. [R]D ) -40° (c ) 2.86); 1H-NMR, δ:
1.51 + 1.37 (2 × s, 3H), 3.28 + 3.19 (2 × s, 3H), 3.43 + 3.40 (2
× s, 3H), 3.29-3.58 (m, 2H), 3.85-4.00 (m, 2H), 4.19-4.35
(m, 2H), 4.43-4.48 (m, 1H), 4.80 + 4.77 (2 × d, J ) 1.7 Hz,
1H), 5.54 + 5.53 (2 × dd, J ) 3.1, 10.5 Hz, 1H), 5.64 + 5.63 (2
× s, 1H), 7.26-7.35 (m, 3H), 7.35-7.50 (m, 4H), 7.50-7.62
(m, 1H), 8.00-8.15 (m, 2H); 13C-NMR, δ: 21.4, 22.0, 35.2, 49.5,
50.1, 55.1, 55.9, 63.8, 64.0, 68.9, 68.92, 70.2, 70.3, 70.4, 70.6,
76.1, 76.8, 100.6, 101.0, 101.3, 101.6, 101.69, 101.7, 126.1,
128.2, 128.3, 128.4, 128.9, 129.7, 129.9, 130.1, 133.0, 133.1,
137.3, 165.8, 166.0; υmax: 1721, 1382, 1096 cm-1. Anal. Calcd
for C25H29BrO8: C, 55.87; H, 5.44. Found: C, 55.49; H, 5.54.
Meth yl 4,6-O-Ben zylid en e-3-O-ben zoyl-2-O-(1-br om o-
2-m eth oxy-2-p r op yl)-r-D-glu cop yr a n osid e (6). A 1:1 di-
astereomeric mixture prepared by protocol A from 549 in 22%
Meth yl 3-O-Ben zoyl-4,6-ben zylid en e-1-r-D-a r a bin oh ex-
op yr a n osid -2-u lose (4). P r ep a r a t ion of a n Au t h en t ic
Sa m p le. A mixture of alcohol 1 (1 g, 2.6 mmol), N-methyl-
morpholine N-oxide (450 mg, 3.8 mmol), and powdered 4 Å
molecular sieves in CH2Cl2 (10 mL) was stirred at room
temperature and treated with tetrapropylammonium perru-
thenate28 (45 mg, 0.13 mmol). The reaction mixture was
stirred for 3 h at room temperature and then filtered through
a plug of silica gel eluting with ether and ethyl acetate. After
removal of the volatiles the residue was purified by chroma-
tography on silica gel (eluent: pentane/ethyl acetate 3/1) to
yield the title ketone as an oil (0.9 g, 90%) whose spectral data
were in accord with those recorded in the literature.51 1H-
NMR, δ: 3.53 (s, 3H), 3.89 (t, J ) 9.1 Hz, 1H), 4.01 (dd, J )
9.2, 10.7 Hz, 1H), 4.33-4.52 (m, 2H), 4.85 (s, 1H), 5.59 (s, 1H),
6.01 (d, J ) 10.8 Hz), 7.30-7.65 (m, 8H), 8.05-8.15 (m, 2H).
Rea ction of 2 w ith Tr im eth yltin Ch lor id e a n d Sod iu m
Cya n obor oh yd r id e. The substrate 2 (54 mg), trimethyltin
chloride (2 mg), AIBN (3.3 mg), and sodium cyanoborohydride
(12.6 mg) were heated to reflux under Ar in tert-butyl alcohol/
benzene (2 mL) for 4 h. The solvents were removed under
vacuum, and the residue was diluted with ether and filtered
on a plug of silica gel eluting with ethyl acetate. The filtrate
was concentrated under vacuum and taken up in dichlo-
romethane (10 mL) and stirred with moist silica gel for 5 h.
The silica gel was then removed by filtration and washed
copiously with dichloromethane and ether. Concentration and
purification by preparative TLC on silica gel (eluent: pentane/
ethyl acetate 2/1) gave the â-mannoside 3 (12 mg, 31%) and
the R-mannoside 1 (20 mg, 52%).
1
yield as a white foam. [R]D ) +26.3° (c ) 0.3); H-NMR, δ:
1.48 + 1.46 (2 × s, 3H), 3.12-3.60 (m, 2H), 3.29 + 3.24 (2 ×
s, 3H), 3.47 (s, 3H), 3.70-3.83 (m, 2H), 3.91-4.04 (m, 1H),
4.04-4.18 (m, 1H), 4.30-4.36 (m, 1H), 4.93 + 4.89 (2 × d, J )
3.5 Hz, 1H), 5.53 + 5.52 (2 × s, 1H), 6.78 + 6.75 (2 × dd, J )
9.3, 9.5 Hz, 1H), 7.20-7.35 (m, 3H), 7.34-7.50 (m, 4H), 7.50-
7.62 (m, 1H), 8.00-8.15 (m, 2H); 13C-NMR, δ: 21.7, 22.4, 34.8,
35.3, 49.0, 50.0, 55.0, 55.2, 62.2, 62.3, 69.0, 70.3, 70.4, 71.3,
72.1, 79.7, 79.8, 99.8, 99.9, 101.3, 101.37, 101.4, 101.6, 126.0,
126.1, 128.1, 128.4, 128.85, 128.9, 129.6, 129.7, 129.9, 130.0,
133.0, 136.9, 165.2, 165.1; υmax: 1726, 1376, 1108 cm-1. Anal.
Calcd for C25H29BrO8: C, 55.87; H, 5.44. Found: C, 55.59; H,
5.77.
Met h yl 4,6-O-Ben zylid en e-3-O-b en zoyl-2-O-[(b r om o-
m et h yl)d im et h ylsilyl]-r-D-m a n n op yr a n osid e (7). Bro-
momethyl dimethylsilyl chloride (0.34 mL, 2.44 mmol) was
added to a solution of 1 (630 mg, 1.63 mmol) and DMAP (298
mg, 2.44 mmol) in CH2Cl2 (4 mL) stirred at 15-18 °C under
Ar. After stirring overnight at room temperature the precipi-
tate was removed by filtration and the filtrate diluted with
CH2Cl2 (15 mL), washed with saturated aqueous NaHCO3 (2
× 5 mL) and brine (2 × 5 mL). The organic layer was dried
(Na2SO4) and the solvent evaporated to give a residue which
after chromatography on silica gel (eluent: pentane/ethyl
acetate 5/1) gave the title compound as a colorless oil which
crystallized from hexane (624 mg, 77%) as white needles. Mp
134 °C; 1H-NMR, δ: 0.19 (s, 3H), 0.25 (s, 3H), 2.44 (d, J ) 0.7
Meth yl 3,4-Di-O-ben zyl-r-L-r h am n opyr an oside (9). This
compound was prepared essentially as described for the
methoxyethoxy dibenzylrhamnopyranoside.52 A mixture of
L-rhamnose monohydrate (3.00 g, 16.5 mmol) and acetyl
bromide (13.6 mL, 184 mmol) was stirred for 1 h at room
temperature and then concentrated to dryness by distillation
with toluene at 40 °C. The residue was dissolved in ni-
(50) Ishido, Y.; Sakairi, N.; Sekiya, M.; Nakazaki, N. Carbohydr.
Res. 1981, 97, 51.
(51) (a) Klemer, A.; Klaffke, W. Liebigs Ann. Chem. 1987, 759. (b)
Yoshimara, J .; Mikami, K.; Sato, K.; Bull. Chem. Soc. J pn. 1976, 49,
1686.
(52) Koto, S.; Morishima, N.; Takenata, K.; Kanemitsu, K.; Shi-
moura, N.; Kase, M.; Kojiro, S.; Nakamura, T.; Kawase, T.; Zen, S.
Bull. Chem. Soc. J pn. 1989, 62, 3549.
(49) Collins, P. M.; Gardiner, D.; Kumar, M. R. S.; Overend, W. G.
J . Chem. Soc., Perkin Trans. 1 1972, 2596.

612 J . Org. Chem., Vol. 61, No. 2, 1996
Crich et al.
tromethane (14 mL), cooled to 0 °C, and treated with 2,6-
lutidine (11.3 mL) and methanol (9.0 mL). After stirring at
room temperature overnight the reaction mixture was diluted
with toluene and thoroughly washed with 5% aqueous NaH-
CO3. The organic layer was concentrated then stirred with
benzyl chloride (86.0 mL) and powdered KOH (43.0 g) at 120
°C for 3 h. After cooling and dilution with toluene the reaction
mixture was washed with water, concentrated, and chromato-
graphed on silica gel which had been pretreated with 5% Et3N
in hexane (eluent: hexane f hexane/ethyl acetate 3/1) to give
the crude, oily orthoester. This preparation was then treated
with BF3‚Et2O (54 µL) in CH2Cl2 (63 mL) for 5 min at room
temperature, the solution washed with brine and dried (Na2-
SO4). Removal of the solvent and chromatography on silica
gel (eluent: hexane/ethyl acetate 3/1) gave the acetate of the
title product, which was dissolved in methanol (50 mL) and
treated with sodium (60 mg) for 2 h at room temperature.
Dowex (50W-X8, H+ form) was then added slowly until the
solution was neutral. After filtration, concentration afforded
the title compound as an oil (2.70 g, 51%). [R]D ) -48.5° (c )
1.51, CHCl3); 1H-NMR, δ: 1.30 (d, J ) 6.2 Hz, 3H), 2.52 (d, J
) 1.7 Hz, 1H), 3.33 (s, 3H), 3.44 (t, J ) 9.2 Hz, 1H), 3.64-
3.72 (m, 1H), 3.81 (dd, J ) 3.4, 9.2 Hz, 1H), 4.01 (t, J ) 1.7
Hz, 1H), 4.60-4.70 (m, 4H), 4.88 (d, J ) 10.9 Hz, 1H), 7.23-
7.36 (m, 10H); 13C-NMR, δ: 17.8, 54.7, 67.1, 68.4, 71.9, 79.8,
80.0, 100.0, 127.7, 127.8, 127.9, 128.3, 128.5, 137.9, 138.3;
100.3, 101.0, 101.3, 127.5, 127.6, 127.8, 127.9, 128.3, 138.3,
138.4, 138.6; υmax: 2934, 1626, 1604, 1494 cm-1. Anal. Calcd
for C25H33BrO6: C, 58.94; H, 6.53. Found: C, 58.90; H, 6.39.
The substrate was recovered in 32% yield from this experi-
ment.
Meth yl 2-O-(1-Br om o-2-m eth oxy-2-p r op yl)-3,4-O-(oc-
ta h yd r o-2,2′-bip yr a n -2,2′-yl)-r-L-r h a m n op yr a n osid e (13).
Prepared as a diastereomeric mixture in 62% yield from (10)
by protocol B. 1H-NMR, δ: 1.27 (d, J ) 6.0 Hz, 3H), 1.40-
1.80 (m, 15H), 3.30-3.42 (m, 7H), 3.51-3.73 (m, 7H), 3.92-
3.98 (m, 1H), 4.01-4.06 (m, 1H), 4.57+4.59 (2 × d, J ) 1.5
Hz, 1H); 13C-NMR, δ: 16.9, 18.2, 18.3, 21.9, 22.1, 24.8, 24.9,
25.0, 28.4, 28.43, 28.7, 35.6, 36.6, 49.4, 49.7, 54.5, 54.6, 60.5,
60.54, 60.7, 66.1, 66.2, 66.7, 66.71, 67.5, 67.51, 69.4, 70.0, 96.6,
96.9, 97.0, 100.9, 101.0, 101.3, 101.4. The substrate was
recovered in 27% yield.
Met h yl 3-O-Ben zoyl-4-d eoxy-r-L-r h a m n op yr a n osid e
(14). An oil. [R]D ) -1.9° (c ) 1.37, CHCl3); 1H-NMR, δ: 1.19
(d, J ) 6.3 Hz, 3H), 1.78 (q, J ) 11.5 Hz, 1H), 2.00 (d, J )
12.0 Hz, 1H), 2.37 (td, J ) 4.8, 11.5 Hz, 1H), 3.47 (s, 3H), 3.72-
3.92 (m, 2H), 4.65 (d, J ) 3.7 Hz, 1H), 4.69-4.78 (m, 1H), 7.42
(t, J ) 8.0 Hz, 2H), 7.55 (tt, J ) 1.4, 8.0 Hz, 1H), 8.00 (dd, J
) 1.4, 8.0 Hz, 2H); 13C-NMR, δ: 17.4, 33.7, 55.2, 65.9, 67.2,
72.1, 98.5, 128.4, 129.6, 130.0, 133.2, 165.5; υmax: 3572, 2936,
1716, 1447 cm-1; MS, m/z: 266 (M+•).
Meth yl 3,4-Di-O-ben zoyl-â-L-r h a m n op yr a n osid e (15).
Mp 148-151 °C; [R]D ) +63.7° (c ) 0.35, CHCl3); 1H-NMR, δ:
1.35 (d, J ) 6.2 Hz, 3H), 2.35 (bs, 1H), 3.59 (s, 3H), 3.68-3.74
(m, 1H), 4.33 (d, J ) 3.0 Hz, 1H), 4.60 (s, 1H), 5.27 (dd, J )
3.0, 9.8 Hz, 1H), 5.60 (t, J ) 9.8 Hz, 1H), 7.30-7.38 (m, 4H),
7.45-7.50 (m, 2H); 13C-NMR, δ: 17.6, 57.0, 69.3, 70.6, 71.1,
73.8, 100.3, 128.3, 129.6, 129.9, 133.2, 133.24, 165.6, 166.0;
υ
max: 3569, 2908, 1494, 1450, 1388, 1357, 1212, 1128, 1102,
1058, 979.2 cm-1. Anal. Calcd for C21H26O5: C, 70.37; H, 7.31.
Found: C, 70.25; H, 7.24.
Meth yl 3,4-O-(Octah ydr o-2,2′-bipyr an -2,2′-yl)-r-L-r h am -
n op yr a n osid e (10). A mixture of methyl R-L-rhamnopyra-
noside53 (1.92 g, 10.75 mmol), 2,2′-bis(3,4-dihydro-2H-pyran)54
(2.52 g, 14.5 mmol) and camphor-10-sulfonic acid (50 mg) in
CHCl3 (40 mL) was heated to reflux for 2 h. Ethylene glycol
(2 mL) was then added and reflux maintained for a further 1
h. The resulting brown solution was diluted with CH2Cl2,
washed with saturated, aqueous NaHCO3 and then brine, and
dried (Na2SO4). After concentration, purification by chroma-
tography on silica gel (eluent: hexane/ethyl acetate 5/1) gave
the title compound as an oil (0.987 g, 26.7%). [R]D ) -117.0
υ
max: 2930, 1724, 1322 cm-1. Anal. Calcd for C21H22O7: C,
65.28; H, 5.74. Found: C, 65.12; H, 5.73.
Meth yl 3,4-Di-O-ben zoyl-5,6-d id eoxy-L-lyxo-h exon a te
(18). [R]D ) -72.5° (c ) 6.0, CHCl3); 1H-NMR, δ: 0.98 (t, J )
7.4 Hz, 3H), 1.75-1.88 (m, 2H), 3.40 (d, J ) 6.7 Hz, 1H), 3.65
(s, 3H), 4.37 (t, J ) 6.7 Hz, 1H), 5.49 (dd, J ) 4.0, 6.7 Hz, 1H),
5.57-5.63 (m, 1H), 7.39-7.45 (m, 4H), 7.52-7.58 (m, 2H),
8.01-8.07 (m, 4H); 13C-NMR, δ: 9.6, 24.0, 52.9, 69.5, 73.3, 74.2,
128.4, 128.4, 129.2, 129.7, 129.73, 133.2, 133.4, 165.8, 166.2,
172.4; υmax: 3523, 2936, 1724, 1457, 1266 cm-1. Anal. Calcd
for C21H22O7: C, 65.28; H, 5.74. Found: C, 65.34; H, 5.82.
Met h yl 3,4-Di-O-b en zyl-â-L-r h a m n op yr a n osid e (16).
[R]D ) +15.4° (c ) 0.68, CHCl3); 1H-NMR, δ: 1.36 (d, J ) 6.1
Hz, 3H), 2.38 (s, 1H), 3.25-3.40 (m, 1H), 3.51-3.53 (m, 5H),
4.09 (s, 1H), 4.29 (d, J ) 1.1 Hz, 1H), 4.62-4.79 (m, 3H), 4.94
(d, J ) 10.8 Hz, 1H), 7.26-7.40 (m, 10H); 13C-NMR, δ: 17.9,
56.9, 68.4, 71.4(2), 75.5, 79.7, 81.4, 100.6, 127.8, 127.9, 128.1,
128.4, 128.5, 137.8, 138.3; υmax: 3574, 2936, 1450 cm-1. Anal.
Calcd for C21H26O5: C, 70.37; H, 7.31. Found: C, 70.41; H,
7.30.
1
(c ) 0.5, CH3Cl), lit.39 [R]D ) -87.9 (c ) 1, CHCl3); H-NMR,
δ: 1.29 (d, J ) 5.8 Hz, 3H), 1.45-1.85 (m, 12H), 2.42 (bs, 1H),
3.34 (s, 3H), 3.60-3.80 (m, 6H), 3.92 (bs, 1H), 3.97 (dd, J )
3.2, 9.5 Hz, 1H), 4.67 (bs, 1H); 13C-NMR, δ: 16.7, 18.0, 18.1,
24.8, 24.9, 28.4, 28.6, 54.7, 60.6, 60.8, 66.4, 67.4, 69.8, 97.1,
97.4, 100.9; υmax: 3581, 2945, 1466, 1453 cm-1. Anal. Calcd
for C17H28O7: C, 59.29; H, 8.19. Found: C, 59.43; H, 8.16.
Met h yl 3,4-Di-O-b en zoyl-2-O-(1-b r om o-2-m et h oxy-2-
p r op yl)-r-L-r h a m n op yr a n osid e (11). Prepared as a dia-
stereomeric mixture in 65% yield from methyl 3,4-di-O-
benzoyl-R-L-rhamnopyranoside (8)55 by protocol B. Mp 34-
36 °C; 1H-NMR, δ: 1.29-1.49 (m, 6H), 3.16 + 3.27 (2 × s, 3H),
3.30-3.37 (m, 1H), 3.44 (s, 3H), 3.43-3.55 (m, 1H), 4.02 (m,
1H), 4.44-4.46 (m, 1H), 4.74 + 4.78 (2 × d, J ) 1.7 Hz, 1H),
5.52-5.59 (m, 2H), 7.28-7.36 (m, 4H), 7.42-7.50 (m, 2H),
7.88-7.94 (m, 4H); 13C-NMR, δ: 17.7, 21.7, 22.1, 35.16, 35.2,
49.6, 49.9, 55.18, 55.20, 66.5, 66.6, 69.9, 70.2, 71.4, 71.5, 71.58,
71.6, 99.8, 100.2, 101.3, 101.6, 128.3, 128.36, 128.4, 129.6,
129.7, 133.1, 133.2, 165.77, 165.8, 165.9, 166.0; υmax: 2982,
2937, 1721, 1600, 1447 cm-1. Anal. Calcd for C25H29BrO8: C,
55.88; H, 5.44. Found: C, 55.81; H, 5.50. The substrate was
recovered in 27% yield from this experiment.
Meth yl 3,4-Di-O-ben zyl-5,6-dideoxy-L-lyxo-h exon ate (19).
1
[R]D ) +3.18° (c ) 4.25, CHCl3); H-NMR, δ: 0.89 (t, J ) 7.5
Hz, 3H), 1.55-1.70 (m, 1H), 1.70-1.85 (m, 1H), 3.55 (q, J )
5.0 Hz, 1H), 3.63 (d, J ) 7.1 Hz, 1H), 3.75 (s, 3H), 3.80 (t, J )
5.0 Hz, 1H), 4.50 (dd, J ) 5.0, 7.1 Hz, 1H), 4.57 (s, 2H), 4.63
(d, J ) 11.7 Hz, 1H), 4.73 (d, J ) 11.7 Hz, 1H), 7.26-7.42 (m,
10H); 13C-NMR, δ: 9.9, 23.0, 52.3, 71.6, 72.9, 73.3, 80.1, 81.6,
127.8, 127.9, 128.2, 128.4, 137.9, 173.2; υmax: 3506, 2961, 1736,
1455 cm-1
. Anal. Calcd for C21H26O5: C, 70.37; H, 7.31.
Found: C, 70.14; H, 7.22.
Meth yl 3,4-O-(Octah ydr o-2,2′-bipyr an -2,2′-yl)-â-L-r h am -
n op yr a n osid e (17). [R]D ) -76.4° (c ) 0.61, CHCl3); 1H-
NMR, δ: 1.34 (d, J ) 6.1 Hz, 3H), 1.40-1.92 (m, 12H), 2.34
(bs, 1H), 3.44-3.54 (m, 1H), 3.54 (s, 3H), 3.58-3.80 (m, 6H),
4.01 (bs, 1H), 4.40 (bs, 1H); 13C-NMR, δ: 16.8; 17.9, 18.1, 24.9,
28.3, 28.6, 56.9, 60.5, 60.8, 67.0, 69.5, 69.6, 70.7, 97.0, 97.4,
Meth yl 3,4-Di-O-ben zyl-2-O-(1-br om o-2-m eth oxy-2-p r o-
p yl)-r-L-r h a m n op yr a n osid e (12). Prepared as a diastere-
omeric mixture in 60% yield from 9 by protocol B. 1H-NMR,
δ: 1.31 (d, J ) 6.2 Hz, 3H), 1.50 + 1.52 (2 × s, 3H), 3.30-3.31
(4 × s, 6H), 3.32-3.68 (m, 4H), 3.80-3.86 (m, 1H), 4.14-4.19
(m, 1H), 4.57-4.95 (m, 5H), 7.24-7.35 (m, 10H); 13C-NMR, δ:
18.0, 18.1, 21.7, 22.3, 35.5, 36.0, 49.4, 49.6, 54.7, 67.6, 68.0,
69.3, 70.0, 72.5, 72.6, 75.1, 75.2, 79.0, 79.2, 80.2, 80.3, 99.8,
101.1; υmax: 3579, 2937, 1444 cm-1. Anal. Calcd for C17H28
-
O7: C, 59.29; H, 8.19. Found: C, 59.49; H, 8.27.
Meth yl 3,4-O-(Octah ydr o-2,2′-bipyr an -2,2′-yl)-r-L-qu in o-
vop yr a n osid e (21). [R]D ) -145.9° (c ) 0.73, CHCl3); 1H-
NMR, δ: 1.25 (d, J ) 6.2 Hz, 3H), 1.40-1.89 (m, 12H), 2.06
(d, J ) 8.3 Hz, 1H), 3.30 (t, J ) 9.7 Hz, 1H), 3.39 (s, 3H), 3.55-
3.94 (m, 7H), 4.73 (d, J ) 3.9 Hz, 1H); 13C-NMR, δ: 16.8, 18.1,
24.87, 24.9, 28.5 (2), 55.1, 60.6, 60.7, 65.7, 69.5, 70.3, 70.5, 96.8,
(53) Bebault, G. M.; Dutton, G. G. S. Can. J . Chem. 1972, 50, 3373.
(54) Leslie, R.; Ley, S. V.; Tiffin, P. D.; Woods, M. Tetrahedron Lett.
1992, 33, 4767.
(55) Kochetkov, N. K.; Byramova, N. E.; Tsvetkov, Yu. E.; Backi-
nows, L. V. Tetrahedron 1985, 41, 3363.

Chemistry of 1-Alkoxy-1-glycosyl Radicals
J . Org. Chem., Vol. 61, No. 2, 1996 613
99.5; υmax: 3563, 2952, 1441 cm-1. Anal. Calcd for C17H28O7:
C, 59.29; H, 8.19. Found: C, 59.44; H, 8.25.
tosylate, and the mixture was stirred at room temperature for
3 days. The volatiles were then removed under vacuum, and
the residue was extracted with chloroform. Concentration of
the chloroform extracts under vacuum gave the title compound
as an oil (0.849 g, 86%). [R]D ) +58.4° (c ) 0.86, CHCl3); 1H-
NMR, δ: 1.25 (t, J ) 7.4 Hz, 3H), 2.51 (bs, 1H), 2.55-2.72 (m,
3H), 2.95 (dd, J ) 2.1, 13.6 Hz, 1H), 3.40 (s, 3H), 3.67 (t, J )
9.0 Hz, 1H), 3.72-3.82 (m, 1H), 3.86 (dd, J ) 3.3, 9.0 Hz, 1H),
4.03 (bs, 1H), 4.62-4.75 (m, 4H), 4.92 (d, J ) 11.1 Hz, 1H),
7.25-7.37 (m, 10H); 13C-NMR, δ: 14.6, 27.0, 33.3, 54.7, 68.2,
71.7, 71.9, 75.2, 77.0, 80.2, 99.7, 127.7, 127.8, 127.84, 128.4,
128.5, 137.7, 138.2; υmax: 3580, 2918, 1599 cm-1. Anal. Calcd
for C33H30O5S: C, 66.00; H, 7.22. Found: C, 66.02; H, 7.30.
Meth yl 3,4-Di-O-ben zyl-6-O-p iva loyl-r-D-m a n n op yr a -
n osid e (25). To a solution of methyl 3,4-di-O-benzyl-R-D-
mannopyranoside (23) (0.853 g, 2.28 mmol) in pyridine (8 mL)
at 0 °C was added a solution of pivaloyl chloride (0.42 mL,
3.42 mmol) in CH2Cl2 (4 mL) by syringe pump over 6 h. The
reaction mixture was poured in water (100 mL) and extracted
with CH2Cl2 (3 × 30 mL). The extracts were washed with 1
M HCl, saturated aqueous NaHCO3, and brine, dried (Na2-
SO4), concentrated, and purified by column chromatography
on silica gel (eluent: hexane/ethyl acetate 5/1) to give the title
compound as an oil (1.003 g, 96%). [R]D ) +50.5° (c ) 2.14,
CHCl3); 1H-NMR, δ: 1.20 (s, 9H), 3.34 (s, 3H), 3.71 (t, J ) 8.8
Hz, 1H), 3.75-3.83 (m, 1H), 3.87 (dd, J ) 3.3, 8.8 Hz, 1H),
4.01 (bs, 1H), 4.20 (dd, J ) 5.6, 11.7 Hz, 1H), 4.41 (dd, J )
1.8, 11.7 Hz, 1H), 4.56 (d, J ) 10.7 Hz, 1H), 4.67 (s, 2H), 4.73
(d, J ) 1.5 Hz, 1H), 4.87 (d, J ) 10.7 Hz, 1H), 7.24-7.35 (m,
10H); 13C-NMR, δ: 27.2, 38.8, 54.7, 63.3, 68.1, 69.4, 72.0, 74.3,
75.2, 80.1, 100.0, 127.9, 127.95, 128.0, 128.03, 128.5, 128.6,
137.7, 137.9, 178.2; υmax: 3572, 2972, 1722 cm-1. Anal. Calcd
for C26H34O7: C, 68.10; H, 7.47. Found: C, 67.82; H, 74.7.
Meth yl 3,4-Di-O-ben zyl-6-ch lor o-6-deoxy-r-D-m an n opy-
r a n osid e (26). To a solution of methyl 3,4-di-O-benzyl-R-D-
mannopyranoside (23) (29.6 mg, 0.08 mmol) in pyridine (1 mL)
at 0 °C was added triphenylphosphine (41.4 mg, 0.16 mmol)
and tetrachloromethane (10.5 µL, 0.11 mmol), followed by
stirring overnight at room temperature. After dilution with
water, the reaction mixture was extracted with CH2Cl2, and
the extracts were washed with 1 M HCl, saturated aqueous
NaHCO3, and brine, dried (Na2SO4), concentrated, and chro-
matographed on silica gel (eluent: hexane/ethyl acetate 3/1)
Meth yl 3,4-O-(Octa h yd r o-2,2′-bip yr a n -2,2′-yl)-5,6-d id e-
oxy-L-lyxo-h exon a te (20). [R]D ) -118.0° (c ) 0.86, CHCl3);
1H-NMR, δ: 1.02 (t, J ) 7.2 Hz, 3H), 1.22-1.89 (m, 14H), 2.97
(d, J ) 6.8 Hz, 1H), 3.55-3.67 (m, 4H), 3.68-3.82 (m, 4H),
3.86 (dd, J ) 3.0, 9.6 Hz, 1H), 4.25 (dd, J ) 3.0, 6.8 Hz, 1H);
13C-NMR, δ: 9.8, 18.1, 18.2, 23.3, 24.9, 25.1, 28.2, 28.6, 52.4,
60.5, 60.8, 68.5, 71.4, 73.5, 95.7, 96.2, 172.8; υmax: 3553, 2945,
1732, 1466 cm-1. Anal. Calcd for C17H28O7: C, 59.29; H, 8.19.
Found: C, 58.88; H, 8.18.
Meth yl 2-O-Acetyl-3,4-d i-O-ben zyl-r-D-m a n n op yr a n o-
sid e (22). To a stirred solution of 3,4,6-tri-O-acetyl-1,2-(1-
methoxyethylidene)-â-D-mannospyranose56 (8.27 g, 22.8 mmol)
in methanol (400 mL) was added sodium (20 mg). After
stirring overnight the solution was neutralized by addition of
Dowex (50W-X8, H+), filtered, and concentrated to give a syrup
which was directly dissolved in 2,6-lutidine (70 mL) and
treated with trityl chloride (7.00 g, 24.9 mmol) and stirred at
40 °C for 16 h. The solution was then filtered, treated with
benzyl chloride (25.0 mL, 217 mmol) and sodium hydride (60%
in oil, 5.3 g, 132.5 mmol), and heated to 120 °C for 3 h. After
cooling to room temperature the reaction mixture was diluted
with saturated aqueous NaHCO3 and extracted with chloro-
form. The extracts were washed with brine, dried (Na2SO4),
concentrated, and chromatographed on silica gel that had been
washed with 5% triethylamine in hexane (eluent: hexane/ethyl
acetate 5/1) to give 3,4-di-O-benzyl-1,2-(1-methoxyethylidene)-
6-O-trityl-â-D-mannospyranose. This was then dissolved in
CH2Cl2 (300 mL) and treated with BF3‚OEt2 (0.2 mL) for 5
min, followed by addition of trifluoroacetic acid (20 mL), then
water (20 mL). After stirring overnight at room temperature
the reaction mixture was washed with water, saturated
aqueous NaHCO3, and brine, dried (Na2SO4), concentrated,
and purified by chromatography on silica gel (eluent: hexane/
ethyl acetate 5/1 f 2/1) to give the title compound as an oil
(5.27 g, 56%). [R]D ) +18.7° (c ) 1.5, CHCl3); 1H-NMR, δ: 1.90
(bs, 1H), 2.13 (s, 3H), 3.33 (s, 3H), 3.65 (dt, J ) 9.7, 3.6 Hz,
1H), 3.70-3.85 (m, 3H), 3.96 (dd, J ) 3.3, 9.3 Hz, 1H), 4.51
(d, J ) 11.3 Hz, 1H), 4.58 (d, J ) 10.9 Hz, 1H), 4.66 (s, 1H),
4.68 (d, J ) 11.3 Hz, 1H), 4.90 (d, J ) 10.9 Hz, 1H), 5.35 (dd,
J ) 1.8, 3.3 Hz, 1H), 7.24-7.35 (m, 10H); 13C-NMR, δ: 21.0,
54.9, 62.2, 68.6, 71.6, 71.7, 74.1, 75.2, 78.0, 98.9, 127.7, 127.8,
127.9, 128.0, 128.37, 128.4, 137.9, 138.3, 170.3; υmax: 3693,
3606, 2929, 1743, 1600 cm-1. Anal. Calcd for C23H28O7: C,
66.33; H, 6.78. Found: C, 66.22; H, 6.79.
to give the title compound as an oil (25.0 mg, 81%). [R]D
)
+47.1° (c ) 1.6, CHCl3); 1H-NMR, δ: 2.55 (bs, 1H), 3.39 (s,
3H), 3.71-3.92 (m, 5H), 4.05 (bs, 1H), 4.66 (d, J ) 11.8 Hz,
1H), 4.68 (d, J ) 11.0 Hz, 1H); 4.73 (d, J ) 11.0 Hz, 1H), 4.82
(d, J ) 1.5 Hz, 1H), 4.96 (d, J ) 11.8 Hz, 1H), 7.24-7.40 (m,
10H); 13C-NMR, δ: 44.7, 55.0, 68.2, 70.7, 72.0, 75.0, 75.3, 80.1,
100.3, 127.65, 127.7, 127.9, 128.0, 128.5, 128.6, 137.7, 138.1;
Meth yl 3,4-Di-O-ben zyl-r-D-m a n n op yr a n osid e (23).57
Sodium (20 mg) was added to a solution of 22 (0.949 g, 2.28
mmol) in methanol (30 mL), and the resulting mixture was
stirred overnight, before treatment with Dowex (50W-X8, H+)
until neutral. Filtration and concentration under vacuum gave
23 as an oil (0.853 g, 100%). [R]D ) +72.7° (c ) 0.11, CHCl3);
1H-NMR, δ: 2.15 (bs, 1H), 2.66 (bs, 1H), 3.32 (s, 3H), 3.59-
3.67 (m, 1H), 3.72-3.86 (m, 4H), 4.01 (bs, 1H), 4.64 (d, J )
11.0 Hz, 1H), 4.68 (s, 2H), 4.75 (d, J ) 1.5 Hz, 1H), 4.87 (d, J
) 11.0 Hz, 1H), 7.24-7.35 (m, 10H); 13C-NMR, δ: 54.7, 62.1,
68.3, 71.3, 72.1, 74.0, 75.2, 80.0, 100.2, 127.8, 127.9, 128.4,
υ
max: 3569, 2917, 1498 cm-1. Anal. Calcd for C21H25ClO5: C,
64.20; H, 6.41. Found: C, 63.98; H, 6.35.
Meth yl 3,4-Di-O-ben zyl-2-(1-br om o-2-m eth oxy-2-p r o-
pyl)-6-deoxy-6-(eth ylth io)-r-D-m an n opyr an oside (28). Pre-
pared by protocol B and isolated in 66% yield together with
21% of substrate. 1H-NMR, δ: 1.23 (t, J ) 7.4 Hz, 3H), 1.48
+ 1.50 (2 × s, 3H), 2.60 (q, J ) 7.4 Hz, 2H), 2.65-2.73 (m,
1H), 2.94 (dd, J ) 2.0, 13.5 Hz, 1H), 3.2-3.45 (m, 7H), 3.51-
3.56 (m, 1H), 3.68-3.79 (m, 2H), 3.85-3.89 (m, 1H), 4.14-
4.19 (m, 1H), 4.59-4.66 (m, 3H), 4.69-4.75 (m, 1H), 4.91 +
4.95 (2 × d, J ) 11.4 Hz, 1H), 7.24-7.35 (m, 10H); 13C-NMR,
δ: 14.8, 21.6, 22.3, 26.6, 26.7, 33.5, 35.4, 35.8, 49.3, 49.8, 54.7,
69.0, 69.7, 71.9, 72.3, 72.4, 75.0 (2), 77.2, 77.3, 79.1, 79.3, 99.6,
100.1, 100.7, 101.2, 127.6, 127.7, 127.8, 128.3, 138.1, 138.2,
128.6, 137.8, 138.3; υmax: 3584, 2926, 1497 cm-1
.
Meth yl 3,4-Di-O-ben zyl-6-d eoxy-6-(eth ylth io)-r-D-m a n -
n op yr a n osid e (24). A mixture of 22 (0.982 g, 2.36 mmol)
and tosyl chloride (0.899 g, 4.72 mmol) was stirred overnight
at room temperature in pyridine (5 mL) and then diluted with
water (100 mL) and extracted with CH2Cl2 (3 × 30 mL). The
extracts were washed with 1 M HCl, saturated aqueous
NaHCO3, and brine, dried (Na2SO4), concentrated, and purified
by chromatography on silica gel (eluent: hexane/ethyl acetate
5/1) to yield the 6-O-tosyl derivative. Butyllithium (1.6 M in
hexane, 3.5 mL) was added at -78 °C to ethanethiol (30 mL)
followed, after warming to room temperature, by the above
138.4; υmax: 2927, 1453, 1360 cm-1. Anal. Calcd for C27H37
BrO6S: C, 56.94; H, 6.55. Found: C, 57.04; H, 6.60.
-
Meth yl 3,4-Di-O-ben zyl-2-(1-br om o-2-m eth oxy-2-p r o-
p yl)-6-O-p iva loyl-r-D-m a n n op yr a n osid e (29). Prepared by
protocol B and isolated in 62% yield together with 25% of
substrate. 1H-NMR, δ: 1.20 (s, 9H), 1.49 + 1.50 (2 × s, 3H),
3.29 + 3.30 + 3.31 + 3.32 (4 × s, 6H), 3.34-3.40 (m, 1H), 3.47-
3.52 (m, 1H), 3.67-3.76 (m, 1H), 3.78-3.92 (m, 2H), 4.14-
4.19 (m, 1H), 4.25-4.41 (m, 2H), 4.49-4.55 (m, 1H), 4.59-
4.68 (m, 2H), 4.69-4.77 (m, 1H), 4.85 + 4.94 (2 × d, J ) 10.8
Hz, 1H), 7.24-7.35 (m, 10H); 13C-NMR, δ: 21.7, 22.3, 27.2,
35.2, 35.7, 38.9, 49.3, 49.9, 54.8, 63.0, 66.9, 69.7, 70.1, 70.2,
(56) Koto, S.; Takenaka, K.; Morishima, N.; Sugimoto, A.; Zen, S.
Bull. Chem. Soc. J pn. 1984, 57, 3603.
(57) For alternative syntheses of this compound see: (a) Koto, S.;
Morishima, N.; Yoshida, T. Bull. Chem. Soc. J pn. 1983, 56, 1171. (b)
Brockhausen, I.; Hull, E.; Hindsgaul, O.; Schachter, H.; Shah, R. N.;
Michnick, S. W.; Carver, J . P. J . Biol. Chem. 1989, 264, 11211.

614 J . Org. Chem., Vol. 61, No. 2, 1996
Crich et al.
72.5, 72.6, 74.3, 75.2, 79.0, 79.1, 99.7, 100.1, 101.0, 101.3, 127.7,
1.96-2.10 (m, 1H), 3.44-3.52 (m, 2H), 3.54 (d, J ) 6.9 Hz,
1H), 3.69 (s, 3H), 3.80 (t, J ) 4.8 Hz, 1H), 3.84-3.92 (m, 1H),
4.38 (d, J ) 11.8 Hz, 1H), 4.43 (d, J ) 11.8 Hz, 1H), 4.44-
4.49 (m, 2H), 4.55 (d, J ) 11.0 Hz, 1H), 4.58 (d, J ) 11.6 Hz,
1H), 4.67 (d, J ) 11.6 Hz, 1H), 7.24-7.32 (m, 10H); 13C-NMR,
δ: 30.5, 52.3, 66.3; 71.6, 72.9, 73.1, 73.3, 77.3, 80.3, 127.6,
127.7, 127.8, 128.0, 128.2, 128.3, 128.4, 137.8, 128.3, 173.1;
127.8, 127.83, 127.9, 128.4, 138.1, 178.2; υmax: 2953, 1722, 1281
cm-1
.
Anal. Calcd for C30H41BrO8: C, 59.11; H, 6.78.
Found: C, 58.75; H, 6.78.
Meth yl 3,4-Di-O-ben zyl-2-(1-br om o-2-m eth oxy-2-p r o-
p yl)-6-ch lor o-6-d eoxy-r-D-m a n n op yr a n osid e (30). Pre-
pared by protocol B and isolated in 66% yield together with
15% of substrate. 1H-NMR, δ: 1.48 + 1.52 (2 × s, 3H), 3.31 +
3.34 (2 × s, 6H), 3.34-3.40 (m, 1H), 3.49-3.57 (m, 1H), 3.70-
3.91 (m, 5H), 4.15-4.19 (m, 1H), 4.58-4.80 (m, 4H), 4.91 +
4.95 (2 × d, J ) 10.9 Hz, 1H), 7.24-7.30 (m, 10H); 13C-NMR,
δ: 21.6, 22.3, 35.4, 35.7, 45.0, 49.4, 49.7, 55.0, 68.9, 69.6, 71.3,
71.5, 72.3, 72.5, 75.2, 75.3, 78.9, 79.1, 99.6, 100.4, 101.0, 101.3,
127.7, 127.8, 127.9, 128.4, 138.1, 138.16; υmax: 2939, 1455, 1363
υ
max: 3532, 3067, 2954, 1743 cm-1. Anal. Calcd for C28H32
O6: C, 72.39; H, 6.94. Found: C, 72.30; H, 6.82.
-
Meth yl 2,3-Di-O-ben zoyl-4,6-ben zylid en e-5-d eoxy-lyxo-
h exon a te (42). Radical fragmentation of 2 led to the isolation
of an inseparable mixture of the 2- and 3- benzoates 40 and
41 in 9% isolated yield. To facilitate identification this mixture
was benzoylated under standard conditions to give the title
dibenzoate. [R]D ) +73.3° (c ) 0.3, CHCl3); 1H-NMR, δ: 1.68
(broad d, J ) 12.6 Hz, 1H), 2.13 (dq, J ) 4.7, 12.6 Hz, 1H),
3.64 (s, 3H), 4.02 (dt, J ) 2.8, 12.6 Hz, 1H), 4.32 (broad dd, J
) 4.7, 12.6 Hz, 1H), 4.38-4.45 (m, 1H), 5.49 (s, 1H), 5.70 (d,
J ) 6.3 Hz, 1H), 5.81 (dd, J ) 4.7, 6.3 Hz, 1H), 7.28-7.33 (m,
3H), 7.40-7.47 (m, 6H), 7.54-7.62 (m, 2H), 8.03-8.08 (m, 4H);
13C-NMR, δ: 26.7, 52.6, 66.4, 70.4, 72.7, 75.0, 101.2, 126.0,
128.2, 128.5 (2), 128.8, 130.0, 133.5, 133.7, 138.0, 165.3, 165.5,
cm-1
. Anal. Calcd for C25H32BrClO6: C, 55.21; H, 5.93.
Found: C, 55.44; H, 5.93.
Meth yl 3,4,6-Tr i-O-ben zyl-2-(1-br om o-2-m eth oxy-2-pr o-
p yl)-r-D-m a n n op yr a n osid e (31). Prepared from methyl
3,4,6-tri-O-benzyl-R-D-mannopyranoside (27)58 in 60% yield by
method B. [R]D ) +21.2° (c ) 1.87); 1H-NMR, δ: 1.55 + 1.54
(2 × s, 3H), 3.33 + 3.32 (2 × s, 3H), 3.38 + 3.37 (2 × s, 3H),
3.35-3.60 (m, 2H), 3.70-3.85 (m, 3H), 3.85-3.98 (m, 2H), 4.21
(m, 1H), 4.45-4.95 (m, 7H), 7.10-7.50 (m, 15H); 13C-NMR, δ:
21.7, 22.8, 35.4, 35.8, 49.4, 49.8, 54.7, 69.0, 69.2, 69.3, 69.8,
71.7, 71.8, 72.4, 72.5, 73.2, 73.21, 74.6, 74.9, 79.1, 79.2, 99.8,
100.3, 100.9, 101.2, 127.4, 127.5, 127.6, 127.61, 127.7, 127.8,
128.2, 128.3, 128.34, 138.2, 138.3, 138.4, 138.5; υmax: 2916,
1457, 1104, 1071 cm-1. Anal. Calcd for C32H39BrO7: C, 62.44;
H, 6.39. Found: C, 62.31; H, 6.47.
Meth yl 3,4-Di-O-ben zyl-5,6-d id eoxy-L-lyxo-h exen on a te
(39). [R]D ) -28.7° (c ) 0.72, CHCl3); 1H-NMR, δ: 3.32 (d, J
) 7.0 Hz, 1H), 3.69 (s, 3H), 3.79 (dd, J ) 3.8, 6.5 Hz, 1H), 4.10
(t, J ) 6.5 Hz, 1H), 4.37 (d, J ) 11.5 Hz, 1H), 4.41 (dd, J )
3.8, 7.0 Hz, 1H), 4.60 (d, J ) 11.5 Hz, 1H), 4.69 (d, J ) 11.7
Hz, 1H), 4.75 (d, J ) 11.7 Hz, 1H), 5.36 (d, J ) 6.3 Hz, 1H),
5.37 (d, J ) 17.1 Hz, 1H), 5.84-5.97 (m, 1H), 7.24-7.32 (m,
10H); 13C-NMR, δ: 52.3, 70.9, 71.6, 74.0, 81.4, 82.3, 119.8,
168.1; υmax: 2957, 2930, 1727, 1452 cm-1
. HRMS, calcd for
C28H26O8 (M + H): 491.1706. Found: 491.1709.
Eth yl 3-O-Ben zyl-4,6-O-ben zylid en e-1-d eoxy-1-th io-r-
D-m a n n op yr a n osid e (44). A mixture of ethyl 4,6-O-ben-
zylidene-1-deoxy-1-thio-R-D-mannopyranoside (43)59 (4.22 g,
13.51 mmol) and dibutyltin oxide (4.05 g, 16.2 mmol) was
heated to reflux in methanol (130 mL) for 1 h, before
concentration under vacuum, dilution with DMF (100 mL), and
treatment, at room temperature, with benzyl bromide (3.5 mL,
29.7 mmol). The reaction mixture was then heated to 110 °C
for 30 min, cooled to room temperature, and poured into a two-
phase mixture of ethyl acetate and saturated aqueous NaH-
CO3. After separation, the organic layer was washed with
brine, dried (Na2SO4), concentrated, and purified by column
chromatography (eluent: hexane/ethyl acetate 10/1 f 3/1) to
give the title compound as an oil (4.35 g, 80%). [R]D ) +145.2°
(c ) 1.45, CHCl3); 1H-NMR, δ: 1.27 (t, J ) 7.4 Hz, 3H), 2.55-
2.64 (m, 2H), 2.81 (s, 1H), 3.86-3.91 (m, 2H), 4.09-4.16 (m,
2H), 4.19-4.24 (m, 2H), 4.68 (d, J ) 11.7 Hz), 4.84 (d, J )
11.7 Hz, 1H), 5.35 (s, 1H), 5.60 (s, 1H), 7.29-7.38 (m, 8H),
7.46-7.50 (m, 2H); 13C-NMR, δ: 14.8, 24.9, 63.7, 68.6, 71.4,
73.1, 75.8, 79.1, 84.0, 101.6, 126.0, 127.8, 128.0, 128.2, 128.5,
128.9, 137.4, 137.7; υmax: 3688, 3606, 2930, 1602 cm-1. Anal.
Calcd for C22H26O5S: C, 65.65; H, 6.51. Found: C, 65.46; H,
6.51.
Eth yl 3-O-Ben zyl-4,6-O-ben zylid en e-2-O-(ter t-bu tyld i-
m eth ylsilyl)-1-d eoxy-1-th io-r-D-m a n n op yr a n osid e (45). A
solution of alcohol 44 (4.00 g, 9.94 mmol) and tert-butyldi-
methylsilyl triflate (3.4 mL, 14.9 mmol) and 2,6-lutidine (2.9
mL, 25 mmol) in CH2Cl2 (10 mL) was stirred at room
temperature for 30 min and then washed with 1 M HCl,
saturated aqueous NaHCO3, and brine, and dried (Na2SO4).
Concentration and chromatography on silica gel (eluent:
hexane/ethyl acetate 25/1) gave the title compound as an oil
(4.88 g, 95%). [R]D ) +78.3° (c ) 4.1, CHCl3); 1H-NMR, δ: 0.10
(s, 3H), 0.12 (s, 3H), 0.95 (s, 9H), 1.30 (t, J ) 7.4 Hz, 3H),
2.55-2.71 (m, 2H), 3.81-3.90 (m, 2H), 4.16-4.26 (m, 4H), 4.70
(d, J ) 12.0 Hz, 1H), 4.82 (d, J ) 12.0 Hz, 1H), 5.15 (s, 1H),
5.65 (s, 1H), 7.25-7.41 (m, 8H), 7.50-7.54 (m, 2H); 13C-NMR,
δ: 15.0, 18.2, 25.2, 25.8, 64.7, 68.7, 72.8, 76.1, 79.4, 86.7, 101.4,
127.7, 127.8, 128.0, 128.3, 134.5, 137.8, 138.0, 172.8; υmax
:
-
3534, 3033, 2955, 1740, 1497 cm-1. Anal. Calcd for C21H24
O5: C, 70.77; H, 6.79. Found: C, 70.51; H, 6.92.
Meth yl 3,4-Di-O-ben zyl-6-O-p iva loyl-â-D-m a n n op yr a -
n osid e (33). [R]D ) -8.1° (c ) 0.58, CHCl3); 1H-NMR, δ: 1.20
(s, 9H), 3.44-3.51 (m, 1H), 3.52 (s, 3H), 3.58 (dd, J ) 3.1, 9.0
Hz, 1H), 3.81 (t, J ) 9.3 Hz, 1H), 4.09 (d, J ) 2.6 Hz, 1H),
4.21 (dd, J ) 6.1, 11.7 Hz, 1H), 4.33 (d, J ) 1.1 Hz, 1H), 4.45
(dd, J ) 2.3, 11.7 Hz, 1H), 4.59 (d, J ) 10.7 Hz, 1H), 4.68 (d,
J ) 11.9 Hz, 1H), 4.77 (d, J ) 11.9 Hz, 1H), 4.94 (d, J ) 10.7
Hz, 1H), 7.26-7.40 (m, 10H); 13C-NMR, δ: 27.2, 38.8, 56.7,
63.2, 66.0, 71.5, 73.3, 74.3, 75.3, 81.3, 100.6, 128.0, 128.1, 128.5,
137.6, 137.9, 178.2; υmax: 3570, 2968, 1725 cm-1. Anal. Calcd
for C26H34O7: C, 68.10; H, 7.47. Found: C, 67.91; H, 7.57.
Meth yl 3,4-Di-O-ben zyl-5-d eoxy-6-O-p iva loyl-lyxo-h ex-
on a te (36). [R]D ) +32.1° (c ) 1.77, CHCl3); 1H-NMR, δ: 1.15
(s, 9H), 1.62 (bs, 1H), 1.88-1.94 (m, 1H), 2.01-2.06 (m, 1H),
3.38 (d, J ) 6.3 Hz, 1H), 3.72 (s, 3H), 3.74-3.84 (m, 2H), 4.06-
4.12 (m, 2H), 4.45-4.49 (m, 2H), 4.59 (d, J ) 11.0 Hz, 1H),
4.61 (d, J ) 11.6 Hz, 1H), 4.70 (d, J ) 11.6 Hz, 1H), 7.24-
7.34 (m, 10H); 13C-NMR, δ: 27.2, 29.8, 38.7, 52.5, 60.8, 71.7,
73.3, 73.5, 76.5, 80.4, 127.9, 128.2, 128.5, 137.5, 137.6, 172.9,
178. 3; υmax: 3531, 2958, 1723, 1480 cm-1. HRMS, calcd for
C26H35O7 (M + H): 459.2383. Found: 459.2370.
Meth yl 3,4-Di-O-ben zyl-6-ch lor o-5,6-d id eoxy-lyxo-h ex-
on a te (37). [R]D ) +35.5° (c ) 0.44, CHCl3); 1H-NMR, δ:
2.05-2.14 (m, 2H), 3.27 (d, J ) 5.9 Hz, 1H), 3.55 (dd, J ) 5.6,
7.2 Hz, 2H), 3.72 (s, 3H), 3.84 (t, J ) 4.5 Hz, 1H), 3.89-3.94
(m, 1H), 4.44 (dd, J ) 4.5, 5.9 Hz, 1H), 4.50 (d, J ) 11.1 Hz,
1H), 4.61 (d, J ) 11.7 Hz, 1H), 4.64 (d, J ) 11.1 Hz, 1H), 4.69
(d, J ) 11.7 Hz, 1H), 7.24-7.32 (m, 10H); 13C-NMR, δ: 33.5,
41.5, 52.5, 71.4, 73.5, 73.7, 80.2, 128.0, 128.2, 128.5, 137.7,
172.8; υmax: 3526, 3033, 2955, 1738, 1497 cm-1. Anal. Calcd
for C21H25ClO5: C, 64.20; H, 6.41. Found: C, 64.30; H, 6.55.
Meth yl 3,4,6-Tr i-O-ben zyl-5-d eoxy-lyxo-h exon a te (38).
[R]D ) -6.1° (c ) 0.57, CHCl3); 1H-NMR, δ: 1.85-1.95 (m, 1H),
126.1, 127.4, 127.8, 128.1, 128.14, 128.8, 137.7, 138.4; υmax
:
2954, 1602, 1471 cm-1. Anal. Calcd for C28H40O5SSi: C, 65.08;
H, 7.80. Found: C, 65.04; H, 7.74.
Eth yl 3-O-Ben zyl-4,6-O-ben zylid en e-2-O-(ter t-bu tyld i-
m eth ylsilyl)-1-d eoxy-1-th io-r-D-m a n n op yr a n osid e S-Ox-
id e (46). To a solution of 45 (2.09 g, 4.0 mmol) in THF (25
mL) and water H2O (2 mL) at 0 °C was added portionwise
magnesium monperoxyphthalate (0.9 g) until all the substrate
was consumed. The reaction mixture was then concentrated
and extracted with ether. The extracts were washed with
saturated aqueous NaHCO3 and brine, dried (Na2SO4), con-
(58) Franks, N. E.; Montgomery, R. Carbohydr. Res. 1968, 6, 286.
(59) Garegg, P. J .; Haelgreen, C. J . Carbohydr. Chem. 1992, 11, 425.

Chemistry of 1-Alkoxy-1-glycosyl Radicals
J . Org. Chem., Vol. 61, No. 2, 1996 615
centrated, and purified by chromatography on silica gel
(eluent: hexane/ethyl acetate 5/1) to give the title sulfoxide
as an oil (1.94 g, 90%). [R]D ) -0.12° (c ) 0.85, CHCl3); H-
sid e (49). To a solution of 48 (140 mg, 0.18 mmol) was added
tetrabutylammonium fluoride (1.0 M in THF, 1.0 mL, 1.0
mmol) in THF (1 mL), followed by stirring for 1 h at room
temperature. The reaction mixture was then diluted with
ether, washed with 1 M HCl, saturated aqueous NaHCO3, and
brine, dried (Na2CO3), concentrated, and purified by chroma-
tography on silica gel (eluent: hexane/ethyl acetate 2/1) to give
the disaccharide 49 as an oil (102.6 mg, 86%). [R]D ) +110.4°
1
NMR, δ: 0.09 (2 s, 6H), 0.88 (s, 9H), 1.38 (t, J ) 7.5 Hz, 3H),
2.63-2.71 (m, 1H), 2.92-2.99 (m, 1H), 3.61-3.70 (m, 1H), 3.76
(t, J ) 10.0 Hz, 1H), 3.99 (dd, J ) 3.1, 10.0 Hz, 1H), 4.17 (dd,
J ) 4.4, 10.0 Hz, 1H), 4.23 (t, J ) 10.0 Hz, 1H), 4.41 (d, J )
1.3 Hz, 1H), 4.69-4.75 (m, 2H), 4.81 (d, J ) 11.8 Hz, 1H), 5.61
(s, 1H), 7.24-7.35 (m, 8H), 7.42-7.45 (m, 2H); 13C-NMR, δ:
5.8, 25.8, 43.9, 67.4, 68.3, 70.2, 73.2, 75.7, 78.0, 95.3, 101.6,
126.0, 127.6, 127.9, 128.2, 129.0, 137.2, 138.1; υmax: 3005, 2930,
1603 cm-1. Anal. Calcd for C28H40O6SSi: C, 63.12; H, 7.57.
Found: C, 62.98; H, 7.68.
1
(c ) 1.4, CHCl3); H-NMR, δ: 2.00 (s, 3H), 2.01 (s, 3H), 2.06
(s, 3H), 2.64 (s, 1H), 3.34 (s, 3H), 3.53 (dd, J ) 2.1, 11.4 Hz,
1H), 3.71-3.95 (m, 5H), 4.03-4.09 (m, 2H), 4.20 (dd, J ) 4.0,
9.4 Hz, 1H), 4.70 (d, J ) 11.7 Hz, 1H), 4.83-4.92 (m, 4H), 5.06
(t, J ) 9.8 Hz, 1H), 5.45 (t, J ) 9.8 Hz, 1H), 5.58 (s, 1H), 7.24-
7.38 (m, 8H), 7.45-7.49 (m, 2H); 13C-NMR, δ: 20.6, 55.3, 63.4,
65.3, 67.8, 68.7, 69.8, 70.3, 70.7, 73.1, 75.3, 78.6, 96.6, 99.9,
101.6, 126.0, 127.8, 127.9, 128.1, 128.4, 128.8, 137.5, 137.9,
169.4, 170.1; υmax: 3688, 2937, 1752, 1601 cm-1. HRMS, calcd
for C33H41O14 (M + H): 661.2496. Found: 661.2493.
Met h yl 2,3,4-Tr i-O-a cet yl-6-O-(3-O-b en zyl-4,6-O-b en -
zylid en e-â-D-m a n n op yr a n osyl)-(1f6)-r-D-glu cop yr a n o-
sid e (51). The conditions used for desilylation of 48 above
were applied to 50 resulting in the recovery of 65% of 50 and
the isolation of 51 as an oil (31%). [R]D ) +49.9° (c ) 2.0,
CHCl3); 1H-NMR, δ: 1.99 (s, 3H), 2.00 (s, 3H), 2.05 (s, 3H),
2.53 (s, 1H), 3.27-3.35 (m, 1H), 3.36 (s, 3H), 3.52-3.65 (m,
2H), 3.85 (t, J ) 10.3 Hz, 1H), 3.92-4.00 (m, 2H), 4.08-4.15
(m, 2H), 4.30 (dd, J ) 4.9, 10.4 Hz, 1H), 4.49 (d, J ) 0.9 Hz,
1H), 4.73-4.91 (m, 4H), 4.96 (t, J ) 10.1 Hz, 1H), 5.46 (t, J )
10.1 Hz, 1H), 5.58 (s, 1H), 7.24-7.37 (m, 8H), 7.45-7.49 (m,
2H); 13C-NMR, δ: 20.7, 55.3, 66.9, 68.2, 68.4, 68.5, 69.0, 69.6,
70.0, 70.8, 72.5, 78.3, 96.4, 100.9, 101.5, 126.0, 127.8, 127.84,
Met h yl 2,3,4-Tr i-O-a cet yl-6-O-[3-O-b en zyl-4,6-O-b en -
zylid en e-2-O-(ter t-b u t yld im et h ylsilyl)-r-D-m a n n op yr a -
n osyl]-(1f6)-r-D-glu cop yr a n osid e (48) a n d Meth yl 2,3,4-
Tr i-O-a cetyl-6-O-[3-O-ben zyl-4,6-O-ben zylid en e-2-O-(ter t-
b u t yld im e t h ylsilyl)-â-D -m a n n op yr a n osyl]-(1f6)-r-D -
glu cop yr a n osid e (50). To a stirred solution of 46 (0.106 g,
0.199 mmol), 47 (0.190 g, 0.60 mmol),60 and 2,6-di-tert-butyl-
4-methylpyridine (44.9 mg, 0.22 mmol) in ether (10 mL) at
-78 °C was added, dropwise, triflic anhydride (36.6 µL). The
cloudy reaction mixture was stirred at -78 °C for 1 h and then
allowed to warm to 0 °C over 1 h and maintained at that
temperature for a further 1 h, before it was quenched with
saturated aqueous NaHCO3, washed with brine, dried (Na2-
SO4), concentrated, and purified by silica gel chromatography
(eluent: hexane/ethyl acetate 5/1) to give the R-linked disac-
charide 48 as an oil (90.2 mg, 59%) and the â-linked disac-
charide 50, also an oil (9.1 mg, 6%). The R-linked disaccharide
1
48: [R]D ) +69.7° (c ) 1.4, CHCl3); H-NMR, δ: 0.07 (s, 3H),
128.2, 128.4, 128.9, 137.4, 137.9, 169.9, 170.0, 170.1; υmax
:
0.09 (s, 3H), 0.90 (s, 9H), 2.02 (s, 6H), 2.08 (s, 3H), 3.33 (s,
3H), 3.52 (dd, J ) 2.2, 11.4 Hz, 1H), 3.66-3.86 (m, 4H), 3.86-
3.96 (m, 1H), 4.04 (dd, J ) 1.5, 2.9 Hz, 1H), 4.10 (t, J ) 9.4
Hz, 1H), 4.19 (dd, J ) 4.4, 9.8 Hz, 1H), 4.69 (d, J ) 1.5 Hz,
1H), 4.70 (d, J ) 12.0 Hz, 1H), 4.81 (d, J ) 12.0 Hz, 1H), 4.85-
4.92 (m, 2H), 5.06 (t, J ) 9.8 Hz, 1H), 5.46 (t, J ) 9.8 Hz, 1H),
5.60 (s, 1H), 7.24-7.39 (m, 8H), 7.47-7.51 (m 2H); 13C-NMR,
δ: -5.2, -4.5, 18.1, 20.6, 25.7, 55.2, 64.4, 65.0, 67.9, 68.8, 70.3,
70.7, 71.1, 72.9, 75.2, 79.0, 96.5, 101.5, 126.1, 127.3, 127.9,
128.0, 128.7, 137.7, 138.6, 169.4, 170.1; υmax: 2955, 1751, 1465
3683, 2938, 1750, 1601 cm-1. HRMS, calcd for C33H41O14 (M
+ H): 661.2496. Found: 661.2500.
Met h yl 2,3,4-Tr i-O-a cet yl-6-O-[3-O-b en zyl-4,6-O-b en -
zyliden e-2-O-(1-br om o-2-m eth oxy-2-pr opyl)-r-D-m an n opy-
r a n osyl]-(1f6)-r-D-glu cop yr a n osid e (52). This mixed ac-
etal was prepared from 51 as a mixture of two diastereomers
by protocol B (34% recovered substrate). It was isolated in
62% yield as an oil. 1H-NMR, δ: 1.42 + 1.53 (2 × s, 3H), 1.95-
2.10 (m, 9H), 3.10-3.42 (m, 7H), 3.42-3.61 (m, 2H), 3.70-
3.93 (m, 5H), 4.09-4.21 (m, 3H), 4.67-4.92 (m, 5H), 4.99-
5.08 (m, 1H), 5.45 + 5.48 (2 × d, J ) 9.5 Hz, 1H), 5.60 + 5.61
(2 × s, 1H), 7.24-7.37 (m, 8H), 7.47-7.51 (m, 2H); 13C-NMR,
δ: 20.7, 21.6, 22.4, 25.0 25.3, 35.2, 35.9, 49.5, 49.6, 50.0, 55.2,
55.3, 64.2, 65.4, 67.9, 68.8, 68.9, 69.0, 69.6, 70.3, 70.8, 70.9,
72.9, 73.2, 73.3, 74.4, 74.6, 78.6, 78.7, 96.5, 96.53, 99.7, 100.2,
101.4, 101.5, 101.6, 101.7, 126.1, 127.4, 127.55, 127.6, 127.8,
128.1, 128.2, 128.7, 128.8, 137.6, 137.7, 138.1, 138.3, 138.5,
cm-1
.
Anal. Calcd for C39H54O14Si: C, 60.45; H, 7.02.
Found: C, 60.18; H, 6.97. The â-linked disaccharide 50: [R]D
1
) +40.0° (c ) 0.6, CHCl3); H-NMR, δ: 0.13 (s, 3H), 0.16 (s,
3H), 1.25 (s, 9H), 2.01 (s, 3H), 2.04 (s, 3H), 2.07 (s, 3H), 3.25-
3.34 (m, 1H), 3.40 (s, 3H), 3.43-3.55 (m, 2H), 3.84-4.10 (m,
3H), 4.09 (t, J ) 9.4 Hz, 1H), 4.17 (d, J ) 2.6 Hz, 1H), 4.26-
4.32 (m, 2H), 4.72 (d, J ) 12.4 Hz, 1H), 4.78 (d, J ) 12.4 Hz,
1H), 4.85 (dd, J ) 3.6, 9.8 Hz, 1H), 4.93 (d, J ) 3.6 Hz, 1H),
5.05 (t, J ) 9.8 Hz, 1H), 5.50 (t, J ) 9.8 Hz, 1H), 5.60 (s, 1H),
7.24-7.41 (m, 8H), 7.48-7.52 (m, 2H); 13C-NMR, δ: -4.9,
-4.2, 18.5, 20.7, 25.9, 55.5. 67.6, 68.3, 68.6, 68.7, 68.8, 70.0,
70.8, 71.1, 72.14, 77.7, 78.7, 96.5, 101.4, 102.5, 126.0, 127.4,
169.5, 170.1; υmax: 2936, 1751, 1602 cm-1
.
Ack n ow led gm en t. We are grateful to NSF (CHE
9222697) for support of this work. D.C. is a Fellow of
the A. P. Sloan Foundation.
127.7, 128.1, 128.13, 128.8, 137.5, 138.3, 169.7, 170.1; υmax
:
2932, 1749, 1602 cm-1. Anal. Calcd for C39H54O14Si: C, 60.45;
H, 7.02. Found: C, 60.12; H, 7.02.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H- and
13C-NMR spectra of 13, 14, 36, 42, 49, 51, and 52 (14 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
Met h yl 2,3,4-Tr i-O-a cet yl-6-O-(3-O-b en zyl-4,6-O-b en -
zylid en e-r-D-m a n n op yr a n osyl)-(1f6)-r-D-glu cop yr a n o-
(60) Whistler, R. L.; Doner, L. W.; Kosik, M. Methods in Carbohy-
drate Chemistry; Whistler, R. L., BeMiller, J . N., Eds.; Academic
Press: New York, 1972; Vol. 6, p 411.
J O951194H