4,6-O-[1-cyano-2-(2-iodophenyl)ethylidene] acetals. Improved second-generation acetals for the stereoselective formation of β-D-mannopyranosides and regioselective reductive radical fragmentation to β-D-rhamnopyranosides. Scope and limitations

Article abstract of DOI:10.1021/jo0526688

The [1-cyano-2-(2-iodophenyl)]ethylidene group is introduced as an acetal-protecting group for carbohydrate thioglycoside donors. The group is easily introduced under mild conditions, over short reaction times, and in the presence of a wide variety of oth

Full text of DOI:10.1021/jo0526688

4,6-O-[1-Cyano-2-(2-iodophenyl)ethylidene] Acetals. Improved
Second-Generation Acetals for the Stereoselective Formation of
â-D-Mannopyranosides and Regioselective Reductive Radical
Fragmentation to â-D-Rhamnopyranosides. Scope and Limitations
David Crich* and Albert A. Bowers
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
dcrich@uic.edu
ReceiVed December 29, 2005
The [1-cyano-2-(2-iodophenyl)]ethylidene group is introduced as an acetal-protecting group for
carbohydrate thioglycoside donors. The group is easily introduced under mild conditions, over short
reaction times, and in the presence of a wide variety of other protecting groups by the reaction of the
4,6-diol with triethyl (2-iodophenyl)orthoacetate and camphorsulfonic acid, followed by trimethylsilyl
cyanide and boron trifluoride etherate. The new protecting group conveys strong â-selectivity with
thiomannoside donors and undergoes a tin-mediated radical fragmentation to provide high yields of the
synthetically challenging â-rhamnopyranosides. The method is also applicable to the glucopyranosides
when high R-selectivity is observed in the coupling reaction and R-quinovosides are formed selectively
in the radical fragmentation step. In the galactopyranoside series, â-glycosides are formed selectively on
coupling to donors protected by the new system, but the radical fragmentation is unselective and gives
mixtures of the 4- and 6-deoxy products. Variable-temperature NMR studies for the glycosylation step,
which helped define an optimal protocol, are described.
Introduction
D-rhamnopyranosyl donors beginning from D-mannose and
including an iodination/reduction sequence at the C6 hydroxyl
or a Hanessian-type NBS-mediated cleavage of the 4,6-O-
benzylidene-protected mannosides.2,3 We reason, however, given
Rhamnopyranosides are significant components of bacterial
capsular polysaccharides, which are involved in the propagation
of disease states. Their synthesis presents a means of under-
standing these biointeractions and routes to possible vaccines
against them. While L-rhamnose and its glycosides are wide-
spread, the D-series is being found with greater frequency and
the preparation of oligosaccharides bearing this novel subunit
has become the object of increasing interest from standpoints
of characterization and biophysical investigation.1 The scarcity
of D-rhamnose itself distinguishes the problem of D-rhamnoside
synthesis from that of the L-series, for which the obvious starting
point is the readily available L-rhamnose. The issue of glycosidic
bond formation in the two enantiomeric series may be reconciled
to a single problem by the chemical synthesis of D-rhamnose
or of a suitably protected derivative. Indeed, this has been the
method of choice in other laboratories, with approaches to
(1) (a) Beynon, L. M.; Bundle, D. R.; Perry, M. B. Can. J. Chem. 1990,
68, 1456-1466. (b) Perry, M. B.; Richards, J. C. Carbohydr. Res. 1990,
205, 371-376. (c) Vinogradov, E. V.; Shashkov, A. S.; Knirel, Y. A.
Carbohydr. Res. 1991, 212, 307-311. (d) Vinogradov, E. V.; Campos-
Portuguez, S.; Yokota, A.; Mayer, H. Carbohydr. Res. 1994, 261, 103-
109. (e) Winn, A. M.; Wilkinson, S. G. Carbohydr. Res. 1996, 294, 109-
115. (f) Cerantola, S.; Montrozier, H. Eur. J. Biochem. 1997, 246, 360-
366. (g) Senchenkova, S. y. N.; Shashkov, A. S.; Kecskes, M. L.;
Ahohuendo, B. C.; Knirel, Y. A.; Rudolph, K. Carbohydr. Res. 2000, 329,
831-838. (h) Spitali, M.; Smith, A. R. W. J. Phytopathol. 2000, 148, 563-
568. (i) Knirel, Y. A.; Shashkov, A. S.; Senchenkova, S. Y. N.; Ajiki, Y.;
Fukuoka, S. Carbohydr. Res. 2002, 337, 1589-1591. (j) Molinaro, A.;
Silipo, A.; Lanzetta, R.; Newman, M.-A.; Dow, J. M.; Parilli, M. Carbohydr.
Res. 2003, 338, 277-281. (k) Hirooka, M.; Yoshimura, A.; Saito, I.; Ikawa,
F.; Uemoto, Y.; Koto, S.; Takabatake, A.; Taniguchi, A.; Shinoda, Y.;
Morinaga, A. Bull. Chem. Soc. Jpn. 2003, 76, 1409-1421.
10.1021/jo0526688 CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/25/2006
3452
J. Org. Chem. 2006, 71, 3452-3463

4,6-O-[1-Cyano-2-(2-iodophenyl)ethylidene] Acetals
SCHEME 1. 4,6-O-[r-(2-(2-Iodophenyl)ethylthiocarbonyl)-
the present state of the art in the synthesis of the â-L-
rhamnopyranosides,4 that this is a less than ideal approach to
the â-D-rhamnopyranosides. This is amply documented by a
recent synthesis of a â-D-rhamnopyranoside at the core of a
trisaccharide by means of a 2-O-sulfonyl-protected rhamnosyl
donor, when the anomeric selectivity was limited to 1.1:1 in
favor of the â-anomer.5 Rather, we have preferred an approach
in which the â-D-rhamnopyranosidic linkage is introduced in
the form of a â-D-mannopyranoside which, taking advantage
of the â-directing effect of the 4,6-O-benzylidene acetal
protecting group, is currently one of the easier types of
glycosidic bond to prepare with reproducibly high stereo-
selectivity.6 Once the glycosidic bond has been formed, the 4,6-
O-benzylidene acetal is then cleaved reductively to afford the
â-D-rhamnopyranoside. The most obvious approach to the
reductive cleavage of the 4,6-O-benzylidene acetal is the
Hanessian-Hullar N-bromosuccinimide-mediated cleavage to
the 6-bromo-6-deoxymannoside followed by hydrogenolytic
cleavage of the bromine atom, or the more recent Roberts’
radical cleavage with a catalytic thiol, which leads directly to
the 6-deoxy system.7 However, neither system is really compat-
ible with the presence of benzyl ethers and the like, owing to
benzylidene] Radical Fragmentation
essential hydrogen atom abstraction step from the acetal.8 One
rare exception to this rule is the high-yield cleavage of a
benzylidene acetal of a 1,2-diol in the presence of benzyl ethers
with NBS on a significant scale and in excellent yield reported
in the course of a synthesis of a cyclosporine component.9 It
should be noted, however, that the rate of hydrogen atom
abstraction from the acetal position of 1,3-dioxolanes is ap-
proximately 1 order of magnitude faster than that from the
comparable position in 1,3-dioxanes,10 which accounts for the
selectivity over benzylic hydrogen atom abstraction in this
example.
The central role of benzyl ether type protecting groups in
modern oligosaccharide synthesis and their incompatibility with
the Hanessian-Hullar and Roberts’ 4,6-O-benzylidene acetal
fragmentations spurred the search in our laboratory for an
alternative means of generation of 2-substituted 1,3-dioxan-2-
yl-type radicals, not dependent on hydrogen atom abstraction,
suitable for use in stereoselective glycosylation reactions. This
search led to our development of a first-generation solution in
the form of the 4,6-O-[R-(2-(2-iodophenyl)ethylthiocarbonyl)-
benzylidene] group as a surrogate for the 4,6-O-benzylidene
acetal (Scheme 1) and its subsequent employment in the total
synthesis of the lipopolysaccharide from E. hermanii ATCC
33650/33652 (Scheme 2).11 In this synthesis, both R- and
â-rhamnosyl linkages were formed from donors equipped with
the novel acetal protecting group, and a single radical reaction
step was used to uncover the two latent rhamnopyranosides
simultaneously. This protecting group provided excellent â-
selectivities in coupling reactions, and the high yields in the
fragmentations are decreased only to a minor extent by
formation of a byproduct from reduction of the intermediate
benzylidene radical to the benzylidene radical itself. Notwith-
standing this success, the method suffers from two limitations:
the lengthy sequence required to prepare the thiol and the
transesterification required to introduce the thiol ester, which
limits functional group compatibility.
(2) (a) Haskins, W. T.; Hann, R. M.; Hudson, C. S. J. Am. Chem. Soc.
1946, 68, 628-632. (b) Zorbach, W. W.; Tio, C. O. J. Org. Chem. 1961,
26, 3543-3545. (c) Bundle, D. R.; Eichler, E.; Kihlberg, J. Carbohydr.
Res. 1991, 211, 59-75. (d) Ramm, M.; Lobe, M.; Hamburger, M.
Carbohydr. Res. 2003, 338, 109-112.
(3) (a) Hanessian, S.; Plessas, N. R. J. Org. Chem. 1969, 34, 1035-
1044. (b) Hanessian, S.; Plessas, N. R. J. Org. Chem. 1969, 34, 1045-
1053. (c) Hanessian, S.; Plessas, N. R. J. Org. Chem. 1969, 34, 1053-
1058. (d) Chana, J. S.; Collins, P. M.; Farnia, F.; Peacock, D. J. J. Chem.
Soc., Chem. Commun. 1988, 2, 94-96. (e) Binkley, R. W.; Goewey, G. S.;
Johnston, J. C. J. Org. Chem. 1984, 49, 992-996. (f) Hanessian, S. Org.
Synth. 1987, 65, 243-247. (g) Hullar, T. L.; Siskin, S. B. J. Org. Chem.
1970, 35, 225-227. (e) Hanessian, S. AdV. Chem. Ser. 1968, 74, 159-
201. (h) Szarek, W. A. AdV. Carbohydr. Chem. Biochem. 1973, 28, 225-
306. (i) Paulsen, H. AdV. Carbohydr. Chem. Biochem. 1971, 26, 127-195.
(j) Gelas, J. AdV. Carbohydr. Chem. Biochem. 1981, 39, 71-156.
(4) (a) Crich, D.; Picione, J. Org. Lett. 2003, 5, 781-784. (b) Crich, D.;
Vinod, A. U.; Picione, J. J. Org. Chem. 2003, 68, 8453-8458. (c) Crich,
D.; Hutton, T.; Banerjee, A.; Jayalath, P.; Picione, J. Tetrahedron:
Asymmetry 2005, 16, 105-119.
(5) (a) Bedini, E.; Carabellese, A.; Barone, G.; Parilli, M. J. Org. Chem.
2005, 70, 8064-8070. (b) Bedini, E.; De Castro, C.; Erbs, G.; Manogoni,
L.; Dow, J. M.; Newman, M.-A.; Parilli, M.; Unverzagt, C. J. Am. Chem.
Soc. 2005, 127, 2414-2416.
(6) (a) Crich, D.; Li, H.; Yao, Q.; Wink, D. J.; Sommer, R. D.; Rheingold,
A. L. J. Am. Chem. Soc. 2001, 121, 5826-5828. (b) Crich, D.; Li, H. J.
Org. Chem. 2002, 67, 4640-4646. (c) Crich, D.; Dai, Z. Tetrahedron 1999,
55, 1569-1580. (d) Crich, D.; Barba, G. R. Tetrahedron Lett. 1998, 39,
9339-9342. (e) Crich, D.; de la Mora, M. A.; Cruz, R. Tetrahedron 2002,
58, 35-44. (f) Crich, D.; Banerjee, A.; Yao, Q. J. Am. Chem. Soc. 2004,
126, 14930-14934. (g) Crich, D.; Banerjee, A. Org. Lett. 2005, 7, 1935-
1938. (h) Crich, D.; Dudkin, V. J. Am. Chem. Soc. 2002, 124, 2263-2266.
(i) Dudkin, V. Y.; Crich, D. Tetrahedron Lett. 2003, 44, 1787-1789. (j)
Dudkin, V. K.; Miller, J. S.; Danishefsky, S. J. J. Am. Chem. Soc. 2004,
126, 736-738. (k) Miller, J. S.; Dudkin, V. Y.; Lyon, G. J.; Muir, T. W.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 431-434. (l) Nicolaou,
K. C.; Mitchell, H. J.; Rodriguez, R. M.; Fylaktakidou, K. C.; Suzuki, H.;
Conley, S. R. Chem. Eur. J. 2000, 6, 3149-3165. (m) Kim, K. S.; Kang,
S. S.; Seo, Y. S.; Kim, H. J.; Jeong, K.-S. Synlett 2003, 1311-1314. (n)
Wu, X.; Schmidt, R. R. J. Org. Chem. 2004, 69, 1853-1857. (o) Kwon,
Y. T.; Lee, Y. J.; Lee, K.; Kim, K. S. Org. Lett. 2004, 6, 3901-3904. (p)
Tanaka, S.-i.; Takashina, M.; Tokimoto, H.; Fujimoto, Y.; Tanaka, K.;
Fukase, K. Synlett 2005, 2325-2328.
(7) (a) Roberts, B. P.; Smits, T. M. Tetrahedron Lett. 2001, 42, 3663-
3666. (b) Roberts, B. P.; Smits, T. M. Tetrahedron Lett. 2001, 42, 137-
140. (c) Dang, H.-S.; Roberts, B. P.; Sekhon, J.; Smits, T. M. Org. Biomol.
Chem. 2003, 1, 1330-1341. (d) Fielding, A. J.; Franchi, P.; Roberts, B. P.;
Smits, T. M. J. Chem. Soc., Perkin Trans. 2 2002, 155-163. (e) Cai, Y.;
Dang, H. S.; Roberts, B. P. J. Chem. Soc., Perkin Trans. 1 2002, 2449-
2458. (f) Jeppesen, L. M.; Lundt, I.; Pedersen, C. Acta Chem. Scand. 1973,
27, 3579-3585.
(8) For a rare exception see: Liotta, L. J.; Dombi, K. L.; Kelley, S. A.;
Targontsidis, S.; Morin, A. M. Tetrahedron. Lett. 1997, 38, 7833-7834.
(9) Wenger, R. M. HelV. Chim. Acta 1983, 66, 2308-2321.
(10) (a) Ingold, K. U.; Malatesta, V. J. Am. Chem. Soc. 1981, 103, 609-
614. (b) Beckwith, A. L. J.; Easton, C. J. J. Am. Chem. Soc. 1981, 103,
615-619.
(11) (a) Crich, D.; Yao, Q. Org. Lett. 2003, 5, 2189-2191. (b) Crich,
D.; Yao, Q. J. Am. Chem. Soc. 2004, 126, 8232-8236.
J. Org. Chem, Vol. 71, No. 9, 2006 3453

Crich and Bowers
SCHEME 3. Preparation and Fragmentation of a
SCHEME 2. Synthesis of a Lipopolysaccharide from
E. hermanii ATCC 33650/33652
Pyruvate-Based Mannosyl Donor
It was hoped that broader versatility could be achieved by
another radical methodology, perhaps also capable of decreasing
the reduction byproduct observed with the first-generation
system. On the basis of seminal work by Beckwith on the radical
migration of cyano groups, and subsequent applications to
synthesis by Rychnovsky and co-workers,12 we hypothesized
that a 2-cyano-1,3-dioxane would serve as a suitable precursor
to the 1,3-dioxan-2-yl radical by intramolecular transfer of the
cyano group to an appropriately placed radical. The successful
implementation of this second-generation method is described
herein.
Benzenesulfinylpiperidine (BSP)-mediated coupling17 of do-
nor 8 in the presence of the hindered base, tri-tert-butyl
pyrimidine (TTBP),18 proceeded to give disaccharide 10 in 76%
yield with 5% recovered starting material, whereas coupling
with the stronger thiophile generated from the Ph2SO/Tf2O
combination19 saw complete activation with an 80% yield. In
both instances, only the â-isomer could be isolated by silica
gel chromatography, in keeping with observations made with
the first- generation system itself. Dropwise addition of AIBN
and tributyltin hydride to substrate 10 in refluxing toluene,
according to the procedure used with the first-generation system,
provided the â-D-rhamnoside 11 in 74% yield with 15% of the
ethylidene acetal byproduct 12 isolated after deacylation and
column chromatography (Scheme 3). This result parallels very
closely those obtained earlier with the first-generation series
and indicates that the 1,3-dioxan-2-yl radical need not carry a
2-phenyl substituent for a highly regioselective cleavage favor-
ing fragmentation of the primary C-O bond. The analogous
observation was also made by the Roberts’ group with their
thiyl radical-based hydrogen atom abstraction/fragmentation
system. The fact that results with the methyl group prove similar
to those with a phenyl group suggests that the transition state
for fragmentation is late and the contribution from destabilization
of the radical is equally countered by loss of the delocalization
obtained in the conjugated benzoate ester, again in accord with
theoretical calculations performed by Roberts.7
Results and Discussion
Acetal Design and Development. Before embarking on the
development of the second generation system it was necessary
to ascertain the effect of the 2-substituent on the fragmentation,
more especially the regioselectivity, of substituted 1,3-dioxan-
2-yl radicals. Additionally, it was reasoned that substitution of
a methyl group for the phenyl group of the traditional benzyl-
idene fragmentation could destabilize the incipient radical at
the acetal carbon leading to a faster rate of fragmentation and
diminishing amounts of reduced product.
To this end, we prepared a modified first-generation system
beginning with the diol 5. Collins et al. observed that acetal
exchange with the methyl pyruvate dimethyl acetal provides
high yields of an undesired isomerization product; in our hands,
similar results were observed and the byproduct proved all but
intractable in most solvent systems.13 Of the literature methods
surveyed, Ziegler’s proved the most workable, yielding 31%
of a 2:1 (equatorial methyl/axial methyl) mixture of isomers,14,15
with the remainder of the starting material undergoing decom-
position during the course of reaction, a result observed by other
groups in use of the method.16 The separated isomer with an
equatorial methyl group was then smoothly transesterified at
room temperature to give the new donor 8 in 76% yield.
(12) (a) Beckwith, A. L. J.; O’Shea, D. M.; Westwood, S. W. J. Am.
Chem. Soc. 1988, 110, 2565-2575. (b) Rychnovsky, S. D.; Swenson, S. S.
Tetrahedron 1997, 53, 16489-16502.
Turning to the use of nitriles as radical precursors, we first
investigated briefly the intermolecular abstraction of this group
by a stannyl radical, based on the demonstration of Curran and
co-workers of radical monodecyanation of gem-dicyano acetals
using AIBN/Bu3SnH.20 Accordingly, donor 14 was synthesized
(13) (a) Hind, C. R. K.; Collins, P. M.; Renn, D.; Cook, R. B.; Caspi,
D.; Baltz, M. L.; Pepys, M. B. J. Exp. Med. 1984, 159, 1058-1069. (b)
Liptak, A.; Szabo, L. Carbohydr. Res. 1984, 184, C5-C8. (c) Hashimoto,
H.; Hiruma, K.; Tamura, J.-I. Carbohydr. Res. 1988, 177, C9-C12. (d)
Collins, P. M.; McKinnon, A. C.; Manro, A. Tetrahedron Lett. 1989, 30,
1399-1400.
(14) For a review of methods, see: Ziegler, T. Top. Curr. Chem. 1997,
186, 203-229.
(17) Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015-9020.
(18) Crich, D.; Smith, M.; Yao, Q.; Picione, J. Synthesis 2001, 323-
326.
(19) (a) Code´e, J. D. C.; Litjens, R. E. J. N.; den Heeten, R.; Overkleeft,
H. S.; van Boom, J. H.; van der Marel, G. A. Org. Lett. 2003, 5, 1519-
1522. (b) Code´e, J. D. C.; van den Bos, L. J.; Litjens, R. E. J. N.; Overkleeft,
H. S.; van Boeckel, C. A. A.; van Boom, J. H.; van der Marel, G. A.
Tetrahedron 2004, 60, 1057-1064.
(15) For the BF3(OEt)2-promoted method, see: (a) Ziegler, T.; Herold,
G. Liebigs. Ann. Chem. 1994, 859-866. (b) Ziegler, T. Tetrahedron Lett.
1994, 35, 6857-6860.
(16) (a) Wardrop, D. J.; Velter, A. I.; Forslund, R. E. Org. Lett. 2001, 3,
2261-2264. (b) Wardrop, D. J.; Forslund, R. E.; Landrie, C. L.; Velter, A.
I.; Wink, D.; Surve, B. Tetrahedron: Asymmetry 2003, 14, 929-940.
3454 J. Org. Chem., Vol. 71, No. 9, 2006

4,6-O-[1-Cyano-2-(2-iodophenyl)ethylidene] Acetals
SCHEME 4. Radical Decyanation-Based Ethylidene
Fragmentation
via Utimoto’s Lewis acid assisted TMSCN protocol.21 From a
mixture of diastereomers of the preformed ortho ester, the latter
reaction provided a single isomer cleanly and in good yield.
The diphenyl sulfoxide/Tf2O coupling protocol yielded 67% of
the pure â-anomer 16 with 20% of the unactivated donor
recovered. The incomplete activation was unexpected given use
of the strong thiophile; the cause was not investigated at this
stage, however, due to uncertainty of how the product would
behave under conditions of radical fragmentation. Unfortunately,
repeated attempts at heating in toluene with AIBN/Bu3SnH
induced no fragmentation, and the disaccharide was recovered
quantitatively each time (Scheme 4). Evidently, the generation
of a somewhat stabilized 2-methyl-1,3-dioxan-2-yl radical is
insufficient to promote the desired intermolecular nitrile abstrac-
tion reaction.
We turned, therefore, to intramolecular nitrile abstraction
following the precedent of the Beckwith and Rychnovsky
groups.12 Thus, the requisite ortho ester 19 was prepared
according to standard Pinner synthesis via the imidate salt 18
of 2-iodophenylacetonitrile in 57% over two steps with the
known carboxylate ester as the major byproduct.22 Acid-
catalyzed ortho ester exchange in the presence of the acid ester,
followed directly by BF3.OEt2-promoted cyanation, without prior
purification provided the desired donor in 80% yield after silica
gel chromatography. The presumed stereochemical outcome of
cyanation of 20, based on stereoelectronic effects,23 was
rigorously proven by X-ray crystallographic analysis (Figure
1) of the â-mannoside 21 after coupling to methyl 2,3-O-
isopropylidene-R-L-rhamnopyranoside by the Ph2SO/Tf2O pro-
tocol (Scheme 5). Dropwise addition of tributyltin hydride and
AIBN to a solution of mannoside 21 in toluene at reflux finally
gave the â-rhamnopyranoside 22 in 76% yield, with no
indication of the formation of the regioisomeric 4-deoxy product
(Scheme 5).
FIGURE 1. X-ray structure of disaccharide 21.
helped definite an optimal protocol for preparative-scale cou-
plings in which the mixture of thioglycoside and diphenyl
sulfoxide was warmed to -20 °C after addition of triflic
anhydride then cooled back to -78 °C before the acceptor was
introduced. In this manner, a number of couplings were
conducted in high yield, with excellent â-selectivity as reported
in Table 1.
With the couplings in hand, other measures were then
considered to favor the desired fragmentation pathway. To this
end, tris(trimethylsilyl)silane was employed as a weaker hy-
drogen donor and addition times and temperatures were adjusted
until optimized parameters were found,24 as summarized in
Table 2. Of note, the silane proved an inefficient propagator,
and an amount of starting material was recovered in all such
trials. Also, it was found that the pathway leading to the 6-deoxy
sugars was favored at higher temperature, though no conditions
were obtained which eliminated formation of the reduced acetal
1
altogether. No 4-deoxy sugars were observed in the H NMR
spectra of the crude reaction mixtures indicating complete
regioselectivity of radical fragmentation in the mannose series.
Overall, therefore, the 4,6-O-[1-cyano-2-(2-iodophenyl)]eth-
ylidene group provides the â-D-rhamnopyranosides rapidly and
in high yields from thiomannosides.
Subsequently, the optimized fragmentation conditions were
applied to the complete series of â-D-mannosides, resulting in
each case in high isolated yields of the corresponding â-D-
rhamnopyranosides, as set out in Table 3, entries 1-5.
To probe the scope and limitations of this second-generation
system, the glucopyranose and galactopyranose systems were
also investigated. In the glucose series four donors were
prepared, equipped with 2-naphthylmethyl, p-methoxybenzyl,
and standard benzyl protecting groups as outlined in Scheme
6. Contrary to our expectations, couplings to glucosyl donors
29, 30, and 32 resulted in relatively complex reaction mixtures
and, ultimately, low yields of the coupled products (Table 1,
entries 7 and 8). Neither the use of higher equivalents of
activator nor variation of temperature was able to increase these
coupling yields. Only the 2,3-di-O-benzyl-protected donor 31
Glycosylation and Radical Fragmentation. With proof of
principle for the complete second-generation sequence in hand,
a series of VT-NMR experiments, described in detail below,
(20) Curran, D. P.; Seong, C. M. Synlett 1991, 107-108.
(21) Utimoto, K.; Wakabayashi, Y.; Horiie, T.; Inoue, M.; Shishiyama,
Y.; Obayashi, M.; Nozaki, H. Tetrahedron 1983, 39, 967-973.
(22) For a review of ortho ester formation: DeWolfe, R. H. Synthesis
1974, 153-172.
(23) (a) Eliel, E.; Nader, F. W. J. Am. Chem. Soc. 1970, 92, 584-589.
(b) Eliel, E.; Nader, F. W. J. Am. Chem. Soc. 1970, 92, 3050-3055. (c)
Rychnovsky, S. D.; Kim, J. Tetrahedron Lett. 1991, 32, 7223-7224. (d)
Cf. ref 16 and references therein.
(24) (a) Chatgilialoglu, C.; Griller, D.; Lesage, M. J. Org. Chem. 1988,
53, 3641-3642. (b) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188-
194. (c) Chatgilialoglu, C.; Griller, D.; Lesage, M. J. Org. Chem. 1989,
54, 2492-2494. (d) Giese, B.; Kopping, B. Tetrahedron Lett. 1989, 30,
681-684.
J. Org. Chem, Vol. 71, No. 9, 2006 3455

Crich and Bowers
SCHEME 5. Nitrile Transfer-Based Fragmentation
produced satisfactory yields and only upon employing protocol
B, as developed with the mannose donor 20. In line with the
precedent for coupling to 2,3-di-O-benzyl-4,6-O-benzylidene-
protected glucosyl donors, the reactions were R-selective.25 As
discussed below, VT-NMR experiments were again conducted
in an attempt to understand the problematic couplings.
Only two examples of the radical fragmentation were studied
in the glucose series; nevertheless, excellent selectivities for
fragmentation of the primary bond leading to the 6-deoxy-D-
glucoside, or D-quinovoside, were obtained (Table 3, entries 7
and 8). This selectivity parallels exactly that seen with the first-
generation system in the glucose series, as well as that seen by
Roberts and Hanessian in their fragmentation of standard 4,6-
O-benzylidene acetals in the glucopyranose series. In other
words, the radical fragmentation in the glucose series is no
different from that in the mannose case with very high selectivity
for formation of the 6-deoxy isomer.
was converted to the second-generation acetal by a three-step
protocol including removal of the benzylidene group with
neopentyl glycol and catalytic camphorsulfonic acid, introduc-
tion of the ortho ester, and finally, the nitrile (Scheme 7). As
expected for the more reactive galactopyranoside series, activa-
tion of this donor was efficient. However, the addition of
1-adamantanol, usually an excellent glycosyl acceptor, resulted
not in the isolation of the anticipated â-galactoside 36 but in
the formation of a relatively complex mixture. To elucidate this
problem, we returned to the more plentiful benzylidene acetal
33, which on activation and attempted coupling delivered a 74%
yield of an unexpected disaccharide 34.27 We were able to
circumvent this problem, with its obvious roots in acetoxy
migration and neighboring group participation, simply by
switching to the corresponding benzoate ester 37 when the
adamantanyl â-galactopyranoside 38 was formed in 89% yield.
SCHEME 7. Preparation and Coupling of Galactoside
Donors
SCHEME 6. Preparation of Glucosyl Donors
Working in the galactopyranose series, we began with the
known benzylidene acetal proctected thioglycoside 33,26 which
(25) Crich, D.; Cai, W. J. Org. Chem. 1999, 64, 4926-4930.
(26) Deng, S.; Yu, B.; Guo, Z.; Hui, Y. J. Carbohydr. Chem. 1998, 17,
439-452.
3456 J. Org. Chem., Vol. 71, No. 9, 2006

4,6-O-[1-Cyano-2-(2-iodophenyl)ethylidene] Acetals
TABLE 1. Glycosylation Reactions with [1-Cyano-2-(2-iodophenyl)]ethylidene-Protected Donors
a Isolated yields of analytically pure material. Procedure A: Tf2O added at -78 °C and reaction maintained at -78 °C until ∼1.5 h after addition of
acceptor. Procedure B: Tf2O added at -78 °C and reaction mixture warmed to -20 °C for ∼20 min. Mixture then cooled to -78 °C, acceptor added, and
resulting mixture stirred at -78 °C for ∼1.5 h.
J. Org. Chem, Vol. 71, No. 9, 2006 3457

Crich and Bowers
TABLE 2. Optimization of the Radical Fragmentation with Disaccharide 21
6-deoxy 22
acetal 23
entry
solvent
initiator
propagator
addition (h)
yield (%)
yield (%)
recovered 21 (%)
1
2
3
4
5
6
toluene
toluene
xylenes
xylenes
xylenes
xylenes
AIBN
AIBN
AIBN
AIBN
Bz2O2
AIBN
Bu3SnH
((CH3)Si)3SiH
Bu3SnH
Bu3SnH
Bu3SnH
3
3
3
2
2
2
76
68
56
81
61
70
15
6
2
5
10
5
0
15
30
0
0
20
((CH3)Si)3SiH
TABLE 3. Radical Fragmentations of Coupled â-D-Mannopyranosides and r-D-Glucopyranosides
a All yields refer to isolated yields from 2 h addition of 1.5 equiv of Bu3SnH and 0.2 equiv of AIBN in refluxing xylenes. b 17% unreacted starting
material recovered.
A series of further couplings were then conducted with this
donor as reported in Table 1 (entries 12-15), all of which
proceeded in high yield and with excellent â-selectivity. The
synthesis of donor 37 (Scheme 7) serves to highlight two
advantages of the second-generation radical precursor over and
above the first-generation system (Scheme 1), both of which
revolve around compatibility with ester protecting groups. First,
the second-generation system may be introduced in the presence
of esters, whereas the transesterification step required for the
(27) Precedent for the formation of similar substances combining two
molecules of a glycosyl donor, with migration of a single ester to the
anomeric position, can be found in the work of Whitfield and co-workers:
Nukada, T.; Berces, A.; Whitfield, D. M. J. Org. Chem. 1999, 64, 9030-
9045.
3458 J. Org. Chem., Vol. 71, No. 9, 2006

4,6-O-[1-Cyano-2-(2-iodophenyl)ethylidene] Acetals
TABLE 4. Radical Fragmentations of â-D-Galactopyranosides
a All yields refer to isolated yields from 2 h addition of 1.5 equiv of Bu3SnH and 0.2 equiv of AIBN in refluxing xylenes. b Yields after radical reaction
and selective saponification of the ester on the primary hydroxyl with 1 equiv of guanidine in CH2Cl2/EtOH (1:9).
first generation system precluded their use. Second, saponifica-
tion may be readily carried out in the presence of the second-
generation system under standard conditions, which was obvi-
ously not possible for the first-generation, thiol ester-based
radical precursor.28
product 68.11a Scrutiny of the spectral data for 65-69 revealed
these structures to have been misassigned in the original
publication, and we now revise these structures, along with their
precursors described in the original Supporting Information, to
the galactofuranoside substrates 70 and 71 and the 5- and
6-deoxygalactofuranoside products 72, 73, and 74. The error
in assignment of these structures arose because of a methyl
galactopyranoside to methyl galactofuranoside rearrange-
ment31,32 that had gone undetected during the Lewis acid
(TMSOTf) mediated acetalization of 75, which it is now clear
gave the furanosides 76 and not the pyranosides 77. The
sequence employed originally in the intended synthesis of 65
and 66 was predicated on the need to introduce the acetal and
complete the subsequent transesterification step to the thiol ester
before introduction of any ester protecting groups. It serves to
highlight, therefore, one of the significant advantages of the
second-generation series presented here, namely the full com-
patibility with esters as apparent in Scheme 7 and as discussed
above.
Radical fragmentation of the galactosides prepared in this
manner led to mixtures of the 6-deoxy (fucopyranosides)
products and the 4-isomers, typically with a slight excess of
the 4-deoxy regioisomer (Table 4). To facilitate separation of
the mixture of regioisomers, chemoselective saponification of
the primary ester in the 4-deoxy product was achieved with
guanidine in ethanol.29 The lack of regioselectivity in these
galactoside fragmentations matches well that found by Roberts
in his thiyl radical-mediated cleavage of galactose-based ben-
zylidene acetals.30 The observed regioselectivity and the high
degree of agreement with the Roberts work prompted a
reinspection of our earlier work on the application of the first-
generation radical trigger to the galactose series. Thus, we
reported previously that acetals 65 afforded an 89/9 mixture of
67 and 69 and that acetal 66 gave exclusively the 4-deoxy
VT NMR Studies on Glycosylation Intermediates. The
unexpectedly incomplete activation of the glycosyl donor 20 at
-78 °C, with 20% unchanged thioglycoside recovered from the
example reported in Scheme 5, prompted an investigation by
(28) However, it did prove possible to selectively cleave a chloroacetate
ester in the presence of the first-generation radical precursor with ethyl-
enediamine, cf. ref 11b.
(29) Kunesch, N.; Miet, C.; Poisson, J. Tetrahedron Lett. 1987, 28, 3569-
3572.
(31) Precedent exists in the literature for this type of Lewis acid mediated
methyl galactopyranoside to methyl galactofuranoside rearrangement.
Ziegler, T.; Eckhardt, E.; Herold, G. Liebigs Ann. Chem. 1992, 441-451.
(32) This galactopyranoside to furanoside rearrangement is readily
apparent from the downfield shifts of the anomeric hydrogen and carbon
in the 1H and 13C NMR spectra, respectively, as well as from the collapse
of the anomeric proton signal to a broad singlet in the furanose, as discussed
by Ziegler.31
(30) Comparison with the Hanessian-Hullar NBS mediated cleavage
reveals significant differences between the two reactions in the galacto-
pyranose series, but this is due to the operation of different mechanisms.
The work described here, like that of Roberts, is a pure radical fragmentation,
whereas the Hanessian-Hullar reaction is a nucleophilic ring opening by
the bromide ion: McNulty, J.; Wilson, J.; Rochon, A. C. J. Org. Chem.
2004, 69, 563-565.
J. Org. Chem, Vol. 71, No. 9, 2006 3459

Crich and Bowers
variable-temperature NMR spectroscopy, our method of choice
for probing such questions.33 Accordingly, a CD2Cl2 solution
of donor 20 and diphenyl sulfoxide was treated at -78 °C and
the spectrum recorded. The anomeric peak of donor 20 at δ
5.26 (Figure 2a) was immediately consumed after addition of
Tf2O, giving rise to two new peaks, the first at δ 6.09 and the
second at δ 5.90 (Figure 2b). Upon warming in 10° intervals to
-30 °C, it was observed that the first peak decreased and then
disappeared altogether as the second peak increased relative to
the methylene chloride peak present at δ 5.32 (Figure 2c).
Further warming witnessed the disappearance of the peak at δ
5.90 and emergence of a new peak at δ 6.28 at 0 °C. In a
subsequent experiment, it was observed that, after enriching the
peak at δ 5.90 by warming to -20 °C, the reaction mixture
could be recooled to -78 °C with no detriment and then
quenched with methanol to give the anomeric mixture of methyl
glycosides. The last result suggests that the peak at δ 5.90 is
the active species, the glycosyl triflate, in such couplings, which
decomposes at 0 °C to be replaced by a signal at δ 6.28. We
tentatively assign this signal to glycal 90 (H1) on the basis of
the previous isolation of such 2-alkoxyglycals from this type
of experiment.25
FIGURE 2. Low-temperature NMR spectra for (a) thiomannoside 20
at -78 °C, before activation, (b) glycosyl triflate (δ 5.90) and byproduct
(δ 6.09) at -78 °C, and( c) the glycosyl triflate alone at -20 °C, after
conversion of the other intermediate.
ature the onset of decomposition was observed. If the reaction
mixture was warmed to -20 °C and then recooled to -78 °C
(Table 1, protocol B) a good yield of the coupled product could
be obtained. Addition of triflic anhydride to donor 32 likewise
led to the formation of two new peaks at δ 5.95 (d, J ) 2.7
Hz) and δ 5.70 (d, J ) 9.0 Hz), indicative of an R- and a
â-derivative, respectively (see the Supporting Information for
VT-spectra). Quenching of the mixture at -78 °C with methanol
resulted in the loss of the signal at δ 5.95 in favor of an anomeric
mixture of methyl glucosides, which suggests this resonance to
be that of the R-glucosyl triflate. However, in contrast to the
di-O-benzyl system 31, and to the mannosyl donor 20, on
warming of the mixture from the activation of 32 to -50 °C
the upfield peak (δ 5.70) was observed to have decreased,
relative to the methylene chloride peak at δ 5.32, in favor of a
new, poorly resolved peak at δ 5.61. By -30 °C, the δ 5.70
peak had disappeared completely and the anomeric triflate peak
at δ 5.95 was diminished in size, while the resonance at δ 5.61
had both increased in intensity and was better resolved into a
doublet with coupling constant of 4.0 Hz, consistent with an
R-glucosyl derivative. Finally, at -20 °C, the downfield peak
had disappeared completely, leaving only the δ 5.61 resonance.
Exactly analogous results were observed with the 2,3-di-O-
benzyl-protected glucosyl donor 31 (see the Supporting Infor-
mation for VT-spectra). Thus, on addition of Tf2O to a CD2Cl2
mixture of 31 and Ph2SO at -78 °C, the substrate was consumed
and two new anomeric signals were formed at δ 6.02 (d, J )
3.3 Hz) and δ 5.63 (d, J ) 9.6 Hz), representing an R- and a
â-derivative, respectively. On warming, the signal at δ 5.63 was
converted to that at δ 6.02 by -20 °C, which we assign to the
R-triflate. This triflate was stable to -10 °C at which temper-
(33) Crich, D.; Sun, S. J. Am. Chem. Soc. 1997, 119, 11217-11223.
3460 J. Org. Chem., Vol. 71, No. 9, 2006

4,6-O-[1-Cyano-2-(2-iodophenyl)ethylidene] Acetals
The product corresponding to this last anomeric signal was
isolated and characterized as decomposition product 91, arising
from electrophilic aromatic substitution by the anomeric oxa-
carbenium ion on the naphthylmethyl protecting group. The
difference between the performance of the 2,3-di-O-benzyl
donor 31 and the 2,3-di-O-naphthylmethyl donors 30 and 32,
apparent from the preparative scale coupling reactions (Table
1) is therefore seen to be the result of the more facile aromatic
substitution onto the naphthalene ring, which competes with
the conversion of the unknown intermediate at δ 5.70 to the
anomeric triflate on warming. Although no VT-NMR experi-
ments were conducted, a parallel problem presumably underlies
the poor yield obtained with the 2,3-di-O-(4-methoxybenzyl)
donor 29 (Table 1, entry 6).
the pathway to the glycosyl triflate. By a similar token, once
formed the glycosyl triflates should be more stable than those
observed with simple benzylidene acetal protecting groups as
is reflected in the decomposition temperature of 0 °C. This in
turn leads to tighter transient oxacarbenium triflate ion pairs
and enhanced â-selectivity38 over that seen with the simple
benzylidene acetals.
Conclusion
The [1-cyano-2-(2-iodophenyl)]ethylidene group, an acetal
protecting group for carbohydrate thioglycoside donors, has been
developed. The group is easily introduced under mild conditions,
over short reaction times, and in the presence of a wide variety
of other protecting groups. It conveys strong â-selectivity with
thiomannoside donors and undergoes a tin-mediated radical
fragmentation to provide high yields of the synthetically
challenging â-rhamnopyranosides.
The one remaining unknown is the identity of the substances
characterized by anomeric resonances at δ 6.09 in the mannose
series and δ 5.63 (J ) 9.6 Hz, 2,3-di-O-benzyl system) and δ
5.70 (J ) 9.7 Hz, 2,3-di-O-naphthylmethyl system) in the
glucose series and which is slowly converted to the correspond-
ing R-anomeric triflates on warming. We considered O-glycosyl
sulfoxonium ions, as observed by Gin,34 but excluded this
possibility with the aid of an experiment in which the diphenyl
sulfoxide was preactivated at -78 °C with triflic anhydride,
thereby removing all nucleophilic sulfoxide from the reaction
mixture, before addition of the thioglycoside, when the same
resonances were displayed as in the normal mode of activation.
We also considered the possibility of glycosyl thiosulfonium
salts, such as might arise from reaction of a glycosyl triflate or
an oxacarbenium ion with disulfide formed in situ from reaction
between the thioglycoside and the activating mixture.35 How-
ever, the addition of diethyl disulfide to the initial reaction
mixture arising from activation of 32 resulted in loss of both
the anomeric triflate signal at δ 5.95 and the signal in question
at δ 5.70, giving a spectrum devoid of resonances in the region
δ 5.4-7.0. That this occurrence was not simply due to
decomposition, but to the formation of a third, likely thio-
sulfonium intermediate, was confirmed by subsequently increas-
ing the probe temperature to -20 °C, where the familiar
decomposition product due to electrophilic aromatic substitution
was observed to appear. The identities of the products, with
anomeric peaks at δ 6.09 in mannose and δ 5.70 in glucose,
therefore remain unknown at present, but it appears likely that
they are initial intermediates formed on reaction between the
thioglycoside and the activated diphenyl sulfoxide and persist
due to the somewhat disarmed nature of the donors. These
results call to mind the work of Lowary and co-workers who
observed a number of intermediates by VT-NMR spectroscopy
during the activation of a series of 2,3-anhydrothiofuranoside
sulfoxides with Tf2O, which only coalesced to the apparent
glycosyl triflate on warming to -40 °C.36 If, as Bols has
demonstrated in recent work, the effect of 4,6-O-acetals in
disarming sugar donors is partially torsional and partially
electronic, it must be assumed that an apical nitrile or other,
more severely electron-withdrawing group could be capable of
enhancing the electron-withdrawing, disarming effect,37 leading
to enhanced stability of any intermediate sulfonium salts along
Experimental Section
Ethyl (2-Iodophenyl)iminoacetate Hydrochloride (18). To 5.00
g of dry 2-iodophenylacetonitrile was added 1.400 mL (1.2 equiv)
of absolute ethanol under inert atmosphere. The solution was cooled
to 0 °C, saturated with anhydrous HCl gas, and then allowed to
stand at 0 °C overnight. The resultant white solid was triturated
with ethyl ether, filtered, and dried under vacuum, providing the
product in 92% yield. White solid. Mp: 125-128 °C (sublimes).
1H NMR (DMSO-d6): δ 7.86 (d J ) 8.0 Hz, 1H), 7.43 (d J ) 6.5
Hz, 1H), 7.38 (t J ) 7.0 Hz, 1H), 7.06 (dt J ) 1.0, 7.5 Hz, 1H),
4.44 (q J ) 7.0 Hz, 2H), 4.20 (s, 2H), 1.20 (t J ) 7.0 Hz, 3H). 13
C
NMR (DMSO-d6): δ 176.7, 139.8, 135.9, 131.7, 130.4, 129.2,
101.9, 70.2, 43.7, 13.8. Anal. Calcd for C10H13ClINO: C, 36.89;
H, 4.02. Found: C, 36.79; H, 3.91.
Triethyl (2-Iodophenyl)orthoacetate (19). A 6.00 g portion of
imidate 18 was dissolved in 40 mL of absolute ethanol and stirred
under inert atmosphere for 2 days at room temperature. A volume
of ethyl ether equal to that of ethanol used (40 mL) was added to
the reaction mixture. The reaction was then filtered through Celite
to remove the precipitated ammonium chloride, and solvents were
evaporated to yield the crude ortho ester together with the byproduct
carboxylate ester in 62% yield by NMR. The ortho ester was best
used as the crude mixture itself.
General Procedure for Preparation of 4,6-O-[1-Cyano-2-(2-
iodophenyl)ethylidene]-Protected Donors. One equivalent of
relevant diol and 0.05 equiv of CSA were dissolved in dry CH2Cl2
(to ∼0.1 M) and stirred under inert atmosphere at 0 °C. Crude ortho
ester 19 (1.2 equiv based on NMR) in a sparing amount of CH2Cl2
was then added dropwise to the reaction mixture over ∼10 min.
The reaction was allowed to warm to room temperature and left to
stir for ∼3 h, after which time TLC showed that no starting material
remained. The mixture was diluted with CH2Cl2, washed with
aqueous NaHCO3 and brine, and dried over Na2SO4. Evaporation
of solvents and azeotropic removal of water with benzene provided
the crude ortho ester as a mixture of isomers, which was reacted
without further purification. The crude ortho ester was taken up in
CH2Cl2 (to ∼0.1 M), and 4 equiv of TMSCN was added in one
portion. The mixture was stirred at 0 °C while 0.4 equiv of
BF3(OEt2) in a sparing amount of CH2Cl2 was added dropwise.
The reaction mixture was stirred at room temperature ∼1.5 h further,
after which time TLC showed that all starting material had been
converted to a slightly more polar compound. Solid K2CO3 was
added and the mixture stirred ∼10 min before being diluted with
(34) Gin, D. Y.; Garcia, B. A. J. Am. Chem. Soc. 2000, 122, 4269-
4279.
(35) Such intermediates are well-known in DMTST activations. For a
recent example, see: Davis, B. G.; Grayson, E. J.; Ward, S. J.; Hall, A. L.;
Rendle, P. M.; Gamblin, D. P.; Batsanov, A. S. J. Org. Chem. 2005, 70,
9740-9754.
(36) Callam, C. S.; Gadikota, R. R.; Krein, D. M.; Lowary, T. L. J. Am.
Chem. Soc. 2003, 125, 13112-13119.
(37) Jensen, H. H.; Nordstrom, L. U.; Bols, M. J. Am. Chem. Soc. 2004,
126, 9205-9213.
(38) Crich, D.; Chandrasekera, S. Angew. Chem., Int. Ed. 2004, 43, 5386-
5389.
J. Org. Chem, Vol. 71, No. 9, 2006 3461

Crich and Bowers
CH2Cl2, washed with aqueous NaHCO3 and brine, and dried over
Na2SO4. Column chromatography provided the donors in 74-89%
yield from the diols.
equiv of Bu3SnH and 0.20 equiv of AIBN in degassed xylenes (to
∼0.025 M in Bu3SnH) was added via syringe pump to the refluxing
reaction mixture. Upon completion of the addition, the mixture was
cooled to room temperature and solvent evaporated and taken up
in 5 mL of ethanol. NaBH4 (2.0 equiv) was added and the reaction
stirred for ∼15 min. The ethanol was removed under vacuum, and
the mixture was diluted with CH2Cl2 and washed with water and
brine. Evaporation of solvents followed by column chromatography
provided the deoxygenated sugars.
Ethyl 2,3-Di-O-benzyl-4,6-O-[1-cyano-2-(2-iodophenyl)]eth-
ylidene-R-D-thiomannopyranoside (20). A 0.72 g (1.8 mmol)
portion of dry diol 5 and 0.77 g (2.1 mmol, 1.2 equiv) of crude
ortho ester 19 were combined according to the general procedure
to give 0.93 g of 20 (80% over two steps) after column chroma-
tography (eluent 10:1 hexanes/EtOAc). [R]24D: +90.7 (c 1, CHCl3).
IR (thin film): 2251 (CN) cm-1. 1H NMR (CDCl3): δ 7.90 (dd J
) 1.0, 8.5 Hz, 1H), 7.52 (dd J ) 1.0, 7.5 Hz, 1H), 7.39-7.29 (m,
11H), 6.99 (dd J ) 1.5, 8.0 Hz, 1H), 5.26 (d J ) 1.5 Hz, 1H), 4.77
(d, J ) 12.5 Hz, 1H), 4.69 (d J ) 12.5 Hz, 1H), 4.66 (d J ) 11.5
Hz, 1H), 4.55 (d J ) 11.5 Hz, 1H), 4.52-4.49 (m, 1H), 4.12-
4.09 (m, 3H), 3.89 (dd J ) 1.0, 3.0 Hz, 1H), 3.82 (dd J ) 3.5, 9.5
Hz, 1H), 3.56 (dd J ) 6.5, 14.5 Hz, 2H), 2.63-2.53 (m, 2H), 1.25
(t J ) 7.5 Hz, 3H). 13C NMR (CDCl3): δ 139.9, 138.3, 137.8,
135.8, 131.6, 129.4, 128.5, 128.4, 128.3, 128.2, 127.9, 127.70,
127.65, 114.6, 103.1, 96.9, 83.9 (1JCH ) 166.2 Hz), 78.0, 76.7,
76.3, 73.24, 73.18, 65.8, 63.6, 49.0, 25.5, 14.9. HRMS (ESI): m/z
calcd for C31H32INO5S (M + Na)+ 680.0944, found 680.0936.
General Procedure for Coupling of Thiogalactopyranoside
37 (Protocol A). Dry donor (1 equiv), together with 1.3 equiv of
diphenyl sulfoxide, 1 equiv of TTBP, and freshly activated
molecular sieves, was taken up in dry CH2Cl2 (0.05 M in substrate)
and brought to -70 °C under inert atmosphere. 0.080 mL (0.477
mmol, 1.4 equuiv) Triflic anhydride was then added. After the
mixture was stirred at -70 °C for ∼30 min, 2 equiv of the acceptor
alcohol dissolved in dry CH2Cl2 was added all at once. The mixture
was allowed to stir at -70 °C for 2 h before being filtered, quenched
with NaHCO3, washed with brine, and dried over Na2SO4.
Evaporation of solvent and column chromatography provided the
coupled products.
General Procedure for Coupling of Thiomannopyranoside
20 (Protocol B). Dry donor (1.0 equiv), together with 1.5 equiv of
diphenyl sulfoxide and 3 equiv of TTBP, was dissolved in dry
CH2Cl2 (0.05 M to substrate with the thiomannosides and 0.01 M
to substrate with the thioglucosides) and brought to -70 °C under
inert atmosphere. Triflic anhydride (1.7 equiv) was then added and
the mixture allowed to rise to -20 °C over 30 min. After being
stirred at -20 °C for ∼15 min, the mixture was then brought back
to -70 °C, and 2 equiv of the acceptor alcohol dissolved in 1 mL
of dry CH2Cl2 was added all at once. The mixture was allowed to
stir at -70 °C for 2 h before being quenched with NaHCO3, washed
with brine, and dried over Na2SO4. Evaporation of solvent and
column chromatography provided the coupled products.
Methyl 4-O-(2,3-Di-O-benzyl-4-O-(2-cyanophenyl)acetyl-â-D-
rhamnopyranosyl)-2,3-O-isopropylidene-R-L-rhamnopyrano-
side (22) and Byproduct Methyl 4-O-(2,3-Di-O-benzyl-4,6-O-
[2-(2-cyanophenyl)]ethylidene-â-D-mannopyranosyl)-2,3-O-
isopropylidene-R-L-rhamnopyranoside (23). According to the
general procedure, 0.093 g (0.114 mmol) of 21 yielded 0.062 g
(0.092 mmol, 81%) of 22 and 0.004 g (0.006 mmol, 5%) of 23.
22. Clear oil. [R]24D: -56.2 (c 0.5, CHCl3). IR (thin film): 2229
1
(CN) cm-1. H NMR (CDCl3): δ 7.60 (dd J ) 1.5, 7.5 Hz, 1H),
7.42 (dd J ) 1.0, 7.0 Hz, 1H), 7.38-7.16 (m, 12H), 5.23 (t J )
10.0 Hz, 1H), 4.89 (s, 1H), 4.88 (d J ) 13.0 Hz, 1H), 4.87 (s, 1H),
4.73 (d J ) 12.5 Hz, 1H), 4.37 (d J ) 12.5 Hz, 1H), 4.20 (d J )
12.5 Hz, 1H), 4.14-4.08 (m, 2H), 3.90 (d J ) 2.5 Hz, 1H), 3.81
(q J ) 15.5 Hz, 2H), 3.70-3.64 (m, 2H), 3.44 (dd J ) 3.5, 10.0
Hz, 1H), 3.39 (s, 3H), 3.39-3.35 (m, 1H), 1.51 (s, 3H), 1.34 (d J
) 6.0 Hz, 3H), 1.23 (d J ) 6.5 Hz, 3H). 13C NMR (CDCl3): δ
168.8, 138.7, 138.1, 137.5, 132.9, 132.8, 130.6, 128.3, 128.1, 128.0,
127.8, 127.5, 127.4, 127.1, 117.7, 113.3, 109.4, 99.3 (1JCH ) 157.4
Hz), 97.9 (1JCH ) 171.2 Hz), 79.4, 78.5, 77.5, 77.2, 76.1, 74.1,
74.0, 71.0, 70.6, 64.3, 54.9, 39.7, 27.9, 26.5, 17.7, 17.5. HRMS
(ESI): m/z calcd for C39H45NO10 (M + Na)+ 710.2941, found
1
710.2937. 23. Clear oil. [R]24D: -41.2 (c 0.5, CHCl3). H NMR
(CDCl3): δ 7.60 (dd J ) 1.0, 8.0 Hz, 1H), 7.49 (dt J ) 1.5, 7.5
Hz, 1H), 7.42-7.20 (m, 12H), 4.93 (s, 1H), 4.88-4.84 (m, 3H),
4.76 (d J ) 12.5 Hz, 1H), 4.54 (d J ) 12.5 Hz, 1H), 4.48 (d J )
12.5 Hz, 1H), 4.13-4.06 (m, 3H), 3.90 (t J ) 10.0 Hz, 1H), 3.89
(d J ) 3.0 Hz, 1H), 3.71 (t J ) 5.0 Hz, 1H), 3.61 (m, 2H), 3.53
(dd J ) 3.5, 10.0 Hz, 1H), 3.38 (s, 3H), 3.23-3.19 (m, 3H), 1.50
(s, 3H), 1.33 (s, 3H), 1.30 (d J ) 6.0 Hz, 3H). 13C NMR (CDCl3):
δ 139.9, 138.5, 132.8, 132.5, 131.0, 128.4, 128.3, 128.1, 127.5,
127.4, 127.2, 118.2, 113.7, 109.4, 101.3 (1JCH ) 156.1 Hz), 100.1
(1JCH ) 158.6 Hz), 97.9 (1JCH ) 167.4 Hz), 78.6, 78.4, 78.0, 77.8,
76.3, 76.1, 74.7, 72.4, 68.3, 54.9, 39.4, 27.9, 26.4, 17.7. HRMS
(ESI): m/z calcd for C39H45NO10 (M + Na)+ 710.2941, found
710.2933.
Methyl 2,3,4-Tri-O-benzyl-6-O-[2,3-di-O-benzoyl-4-deoxy-
6-O-(2-cyanophenyl)acetyl-â-D-galactopyranosyl]-R-D-gluco-
pyranoside (81), Methyl 2,3,4-Tri-O-benzyl-6-O-[2,3-di-O-
benzoyl-4-O-(2-cyanophenyl)acetyl-â-D-fucopyranosyl]-R-D-gluco-
pyranoside (82), and Byproduct Methyl 2,3,4-Tri-O-benzyl-6-
O-[2,3-di-O-benzoyl-4,6-O-(2-cyanophenyl)ethylidene-â-D-galac-
topyranosyl]-R-D-glucopyranoside (83). According to the general
procedure, 0.086 g (0.079 mmol) of 51 yielded after column
chromatography 0.045 g (0.047 mmol, 61%) of a 1.5:1 mixture of
6-deoxy and 4-deoxy products as determined by NMR, together
with 0.010 g (0.010 mmol, 13%) of 83. The mixture of deoxy sugars
was dissolved in 2 mL of EtOH/CH2Cl2 (9:1), and 0.003 g (1 equiv)
of guanidine (obtained by neutralization of the HCl salt with NaOEt
and filtration under argon) was added. The mixture was stirred for
15 min, after which time TLC showed complete disappearance of
one of the two isomers and emergence of a more polar compound.
Aqueous workup with extraction into CH2Cl2 and column chro-
matography afforded 0.027 g of 82 (36% from 51) and 0.015 g of
81 (24% from 51). 81. Clear oil. [R]24D: +21.6 (c 0.25, CHCl3).
1H NMR (CDCl3): δ 7.93-7.88 (m, 4H), 7.51-7.48 (m, 1H),
7.40-7.17 (m, 18H), 7.03 (m, 2H), 5.45 (dd J ) 7.5, 10.0 Hz,
1H), 5.37 (dt J ) 5.5, 11.0 Hz, 1H), 4.88 (d J ) 11.0 Hz, 1H),
4.75 (d J ) 12.0 Hz, 1H), 4.69 (d J ) 11.0 Hz, 1H), 4.66 (d J )
7.5 Hz, 1H), 4.60 (d J ) 12.5 Hz, 1H), 4.49 (d J ) 4.0 Hz, 1H),
4.45 (d J ) 11.0 Hz,1H), 4.28 (d J ) 11.0 Hz, 1H), 4.10 (dd J )
Methyl 4-O-(2,3-Di-O-benzyl-4,6-O-[1-cyano-2-(2-iodophenyl)]-
ethylidene-â-D-mannopyranosyl)-2,3-O-isopropylidene-R-L-
rhamnopyranoside (21). Coupling of 0.100 g (0.15 mmol)
of 20 with 0.066 g (0.30 mmol) of 9 according to protocol B
afforded 0.114 g (0.14 mmol, 92%) of 21 as a white solid. [R]24
:
D
-42.4 (c 1, CHCl3). Mp: 112-115 °C. IR (KBr pellet): 2230 (CN)
1
cm-1. H NMR (CDCl3): δ 7.87 (dd J ) 1.0, 8.0 Hz, 1H), 7.49
(dd J ) 1.5, 7.5 Hz, 1H), 7.39-7.22 (m, 11H), 6.97 (dt J ) 2.0,
8.0, 1H), 4.94 (s, 1H), 4.86 (s, 1H), 4.84 (d J ) 12.0 Hz, 1H), 4.79
(d J ) 12.0 Hz, 1H), 4.54 (d J ) 12.5 Hz, 1H), 4.48 (d J ) 12.5
Hz, 1H), 4.38 (t J ) 10.0 Hz, 1H), 4.14 (s, 1H), 4.12 (d J ) 2.5
Hz, 1H), 4.08 (d J ) 1.5 Hz, 1H), 3.91 (d J ) 2.5 Hz, 1H), 3.63-
3.62 (m, 2H), 3.56-3.49 (m, 3H), 3.40 (s, 3H), 3.20 (m, 1H), 1.51
(s, 3H), 1.34 (s, 3H), 1.31 (d J ) 6.0 Hz, 3H). 13C NMR (CDCl3):
δ 139.8, 138.4, 138.3, 135.8, 131.4, 129.4, 128.4, 128.3, 128.2,
128.1, 127.6, 127.53, 127.46, 114.7, 109.3, 103.0, 100.1 (1JCH
)
158.6 Hz), 97.8 (1JCH ) 168.7 Hz), 96.7, 78.3, 78.1, 76.3, 76.2,
76.1, 74.8, 72.5, 66.6, 65.9, 64.1, 55.0, 49.0, 27.9, 26.4, 17.7. Anal.
Calcd for C39H44INO10: C, 57.57; H, 5.45. Found: C, 57.34; H,
5.57.
General Procedure for Radical Fragmentation of Glyco-
pyranosides. Substrate (1 equiv) was dissolved in degassed xylenes
(to ∼0.006 M) and brought to reflux under argon. Over 2 h, 1.5
3462 J. Org. Chem., Vol. 71, No. 9, 2006

4,6-O-[1-Cyano-2-(2-iodophenyl)ethylidene] Acetals
1.5, 10.5 Hz, 1H), 3.88 (t J ) 9.5 Hz, 1H), 3.80-3.66 (m, 2H),
3.46-3.35 (m, 2H), 3.24 (s, 3H), 2.27 (ddd J ) 1.0, 5.0, 12.0 Hz,
1H), 2.06 (t J ) 6.5 Hz, 1H), 1.82 (q J ) 11.5 Hz, 1H). 13C NMR
(CDCl3): δ 166.0, 165.3, 138.8, 138.2, 133.3, 133.0, 129.73,
129.70, 129.4, 129.3, 128.5, 128.4, 128.3, 128.2, 127.9, 127.6, 1275,
101.4 (1JCH ) 155.4 Hz), 98.1 (1JCH ) 170.2 Hz), 81.9, 79.7, 79.1,
77.3, 77.2, 75.6, 74.7, 73.5, 72.6, 72.4, 71.7, 69.5, 68.3, 64.8, 55.1,
32.0, 25.7. HRMS (ESI): m/z calcd for C48H50NO12 (M + Na)+
841.3200, found 841.3206. 82. Clear oil. [R]24D: +10.0 (c 0.15,
CHCl3). 1H NMR (CDCl3): δ 7.88 (dd J ) 1.0, 7.5 Hz, 2H), 7.78
(d J ) 7.5 Hz, 2H), 7.61 (d J ) 7.5 Hz, 1H), 7.47 (q J ) 8.0 Hz,
2H), 7.40 (t J ) 6.5 Hz, 1H), 7.36-7.24 (m, 17H), 7.21 (t J ) 7.5
Hz, 2H), 7.11 (d J ) 6.0 Hz, 2H), 5.69 (dd J ) 8.0, 10.5 Hz, 1H),
5.50 (d J ) 3.0 Hz, 1H), 5.40 (dd J ) 3.0, 10.0 Hz, 1H), 4.89 (d
J ) 11.0 Hz, 1H), 4.73 (d J ) 12.0 Hz, 1H), 4.69 (d J ) 10.5 Hz,
1H), 4.68 (d J ) 8.0 Hz, 1H), 4.58 (d J ) 12.0 Hz, 1H), 4.55 (d
J ) 11.0 Hz, 1H), 4.46 (d J ) 3.0 Hz, 1H), 4.37 (d J ) 11.0 Hz,
1H), 4.15 (d J ) 9.0 Hz, 1H), 4.03 (d J ) 17.0 Hz, 1H), 3.95 (d
J ) 17.0 Hz, 1H), 3.92-3.89 (m, 2H), 3.74-3.69 (m, 2H), 3.41
(dd J ) 3.5, 9.5 Hz, 1H), 3.37 (t J ) 9.5 Hz, 1H), 3.20 (s, 3H),
1.30 (d J ) 6.5 Hz, 3H). 13C NMR (CDCl3): δ 169.4, 165.6, 165.2,
138.8, 138.2, 137.1, 133.3, 133.1, 132.9, 130.5, 129.7, 128.5,
128.41, 128.37, 128.34, 128.1, 127.9, 127.8, 127.7, 127.6, 117.4,
113.5, 101.4 (1JCH ) 157.4 Hz), 97.9 (1JCH ) 173.2 Hz), 82.0,
79.8, 77.6, 75.6, 74.7, 73.4, 72.1, 71.6, 69.6, 69.4, 68.3, 55.0, 39.1,
16.2. HRMS (ESI): m/z calcd for C57H55NO13 (M + Na)+ 984.3571,
found 984.3568. 83. Clear oil. [R]24D: +8.6 (c 0.5, CHCl3). IR
7.18-7.10 (m, 4H), 5.84 (dd J ) 8.0, 10.0 Hz, 1H), 5.23 (dd J )
3.5, 10.0 Hz, 1H), 4.90 (d J ) 11.0 Hz, 1H), 4.79 (dd J ) 4.0, 6.5
Hz, 1H), 4.71 (d J ) 12.0 Hz, 1H), 4.70 (d J ) 10.5 Hz, 1H), 4.68
(d J ) 8.5 Hz, 1H), 4.61 (d J ) 12.0 Hz, 1H), 4.58 (d J ) 12.0
Hz, 1H), 4.43 (d J ) 4.0 Hz, 1H), 4.42 (d J ) 11.0 Hz, 1H), 4.28
(d J ) 4.0 Hz, 1H), 4.22 (dd J ) 1.0, 12.5 Hz, 1H), 4.16 (dd J )
1.5, 11.0 Hz, 1H), 3.90 (t J ) 8.5 Hz, 1H), 3.88 (dd J ) 2.0, 13.0
Hz, 1H), 3.74 (ddd J ) 1.5, 5.0, 10.0 Hz, 1H), 3.67 (dd J ) 5.0,
11.0 Hz, 1H), 3.49 (d J ) 1.5 Hz, 1H), 3.38 (dd J ) 3.5, 9.5 Hz,
1H), 3.34 (dd J ) 8.5, 9.5 Hz, 1H), 3.30-3.20 (m, 2H), 3.19 (s,
3H). 13C NMR (CDCl3): δ 165.8, 165.2, 139.6, 138.8, 138.3, 138.2,
133.4, 133.0, 132.4, 132.2, 132.0, 129.9, 129.7, 128.5, 128.39,
128.37, 128.1, 127.92, 127.90, 127.6, 127.5, 126.9, 118.1, 113.0,
101.4 (1JCH ) 163.7 Hz), 100.1 (1JCH ) 170.0 Hz), 97.8 (1JCH
)
171.2 Hz), 82.0, 79.8, 77.8, 75.6, 74.7, 73.3, 72.9, 72.5, 69.7, 69.0,
68.4, 68.1, 66.5, 55.0, 39.4. HRMS (ESI): m/z calcd for C57H55NO13
(M + Na)+ 984.3571, found 984.3535.
Acknowledgment. We thank the NIH (GM 57335) for
support, Professor Duncan Wardrop for helpful discussions, and
Professor Donald Wink for the X-ray structure.
Supporting Information Available: Complete experimental
details, copies of spectra of all new compounds, copies of
VT-NMR spectra, and crystallographic data for disaccharide 21.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
(thin film): 2224 (CN), 1728 (CO) cm-1. H NMR (CDCl3): δ
7.91 (dd J ) 1.0, 8.5 Hz, 2H), 7.88 (dd J ) 1.0, 8.5 Hz, 2H),
7.54-7.40 (m, 4H), 7.36 (t J ) 7.0 Hz, 2H), 7.33-7.23 (m, 15H),
JO0526688
J. Org. Chem, Vol. 71, No. 9, 2006 3463