Influence of the 4,6-O-benzylidene, 4,6-O-phenylboronate, and 4,6-O-polystyrylboronate protecting groups on the stereochemical outcome of thioglycoside-based glycosylations mediated by 1-benzenesulfinyl piperidine/triflic anhydride and N-iodosuccinimide/t

Article abstract of DOI:10.1021/jo0349882

The effect of 4,6-O-benzylidene acetals, 4,6-O-phenylboronate esters, and 4,6-O-polystyrylboronate esters on the stereoselectivity of couplings to galacto-, gluco-, and mannopyranosyl thioglycosides, otherwise protected with benzyl ethers, has been invest

Full text of DOI:10.1021/jo0349882

In flu en ce of th e 4,6-O-Ben zylid en e, 4,6-O-P h en ylbor on a te, a n d
4,6-O-P olystyr ylbor on a te P r otectin g Gr ou p s on th e Ster eoch em ica l
Ou tcom e of Th ioglycosid e-Ba sed Glycosyla tion s Med ia ted by
1-Ben zen esu lfin yl P ip er id in e/Tr iflic An h yd r id e a n d
N-Iod osu ccin im id e/Tr im eth ylsilyl Tr ifla te
David Crich,* Marco de la Mora, and A. U. Vinod
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
dcrich@uic.edu
Received J uly 9, 2003
The effect of 4,6-O-benzylidene acetals, 4,6-O-phenylboronate esters, and 4,6-O-polystyrylboronate
esters on the stereoselectivity of couplings to galacto-, gluco-, and mannopyranosyl thioglycosides,
otherwise protected with benzyl ethers, has been investigated by the benzenesulfinyl piperidine/
trifluoromethanesulfonic anhydride (BSP), diphenyl sulfoxide/trifluoromethanesulfonic anhydride
(Ph2SO), and N-iodosuccinimide/trimethylsilyl trifluoromethanesulfonate (NIS/TMSOTf) methods.
The BSP and Ph2SO methods give comparable results in all three systems whereas the NIS method
affords significantly different stereoselectivities in both the gluco and manno, but not the galacto
series. The benzylidene acetal and boronate esters influence the stereochemistry in a similar manner
in the â-selective manno series and the R-selective galacto series but show significant differences
with the glucose donors. The differences between the glucose, galactose, and mannose series reflect
the established differences in reactivity and, especially for mannose, those in the anomeric effect
and are best interpreted in terms of changes in the relative energetics between the R- and â-covalent
triflate intermediates and the various contact ion pairs with which they are necessarily in
equilibrium.
In tr od u ction
the resting state following activation has been demon-
strated by NMR spectroscopy to be the R-mannosyl
triflate,5 and it is possible that the formation of the
â-glycoside occurs by a direct SN2 reaction or by its
functional equivalent, an SN1 substitution involving a
contact ion pair as the minor component of an equilib-
rium with the R-triflate.7 In the glucose series the
R-triflate is also the only observable intermediate: it is
possible that the R-selectivity arises because of the lower
anomeric effect in glucose (versus mannose), which
permits a small but sufficient population of the more
reactive â-glucosyl triflate to influence the stereochem-
istry of the reaction either by a direct SN2 reaction or a
contact ion pair in which the triflate is closely associated
with the â-face of the transient oxacarbenium ion.6a,8
Recent computational work by Nukada and co-workers
points to the involvement of ion pairs, but the definitive
We have previously remarked that the 4,6-O-ben-
zylidene protecting group has a profound influence on the
stereoselectivity of mannosylation reactions conducted by
the sulfoxide/triflic anhydride method1 or its functional
equivalent the 1-benzenesulfinyl piperidine (BSP)/triflic
anhydride/tri-tert-butylpyrimidine (TTBP) activated
thioglycoside coupling protocol.2 We have also shown that
the 4,6-O-polystyrylboronate protecting group functions
analogously, thereby enabling polymer-supported â-man-
noside synthesis.3 The stereodirecting influence of these
protecting groups arises from their torsionally disarming
effect on glycosyl cations4 (oxacarbenium ions), which
effectively shifts all equilibria toward the covalent R-gly-
cosyl triflates,5 thereby promoting SN2-like displacements
by the incoming acceptor alcohol. In the glucose series,
the 4,6-O-benzylidene group has been demonstrated, on
the other hand, to be R-directing.2,6 In the mannose series,
(6) (a) Crich, D.; Cai, W. J . Org. Chem. 1999, 64, 4926-4930. (b)
Bousquet, E.; Khitri, M.; Lay, L.; Nicotra, F.; Panza, L.; Russo, G.
Carbohydr. Res. 1998, 311, 171-181. (c) Kim, K. S.; Kim, J . H.; Lee,
Y. J .; Park, J . J . Am. Chem. Soc. 2001, 123, 8477-8481.
(7) (a) Crich, D. In Glycochemistry: Principles, Synthesis, and
Applications; Wang, P. G., Bertozzi, C. R., Eds.; Dekker: New York,
2001, pp 53-75. (b) Crich, D. J . Carbohydr. Chem. 2002, 21, 663-
686.
(1) (a) Crich, D.; Sun, S. J . Org. Chem. 1997, 62, 1198-1199. (b)
Crich, D.; Sun, S. Tetrahedron 1998, 54, 8321-8348.
(2) (a) BSP: Crich, D.; Smith, M. J . Am. Chem. Soc. 2001, 123,
9015-9020. (b) TTBP: Crich, D.; Smith, M.; Yao, Q.; Picione, J .
Synthesis 2001, 323-326. (c) BSP and TTBP are commercially avail-
able from www.lakeviewsynthesis.com.
(3) Crich, D.; Smith, M. J . Am. Chem. Soc. 2002, 124, 8867-8869.
(4) Andrews, C. W.; Rodebaugh, R.; Fraser-Reid, B. J . Org. Chem.
1996, 61, 5280-5289.
(8) All of these possible modes of reaction were invoked by Lemieux
in his seminal paper on glycosylations, albeit with a different coun-
terion: Lemieux, R. U.; Hendriks, K. B.; Stick, R. V.; J ames, K. J .
Am. Chem. Soc. 1975, 97, 4056-4062.
(5) Crich, D.; Sun, S. J . Am. Chem. Soc. 1997, 119, 11217-11223.
10.1021/jo0349882 CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/26/2003
8142
J . Org. Chem. 2003, 68, 8142-8148

Influence of Protecting Groups on Glycosylations
experiments differentiating the two mechanisms have yet
to be conducted.9,10 Whatever the precise details of the
reaction, direct SN2 reaction or SN1 on a transient contact
ion pair, it is clear that the counterion has a critical role
to play in glycosylation.11
We describe here a multifaceted study on the effect of
the 4,6-O-benzylidene and 4,6-O-phenylboronate esters
in the gluco- and galactopyranose series. Additionally,
with a view to underlining the influence of the counter-
ion, we offer a comparison between two different modes
of activation, namely the 1-benzenesulfinyl piperidine/
triflic anhydride system favored in this laboratory2 and
the popular N-iodosuccinimide system for the activation
of thioglycsides.12
F IGURE 1. Pertinent relative reactivity values15b of glucose,
galactose, and mannose donors for activation with NIS/TfOH
at -40 °C to room temperature in dichloromethane. The
apparent inconsistency in Figure 1 with the stated reactivity
trend of galactose > mannose > glucose arises from the use of
the R-thiomannoside as the comparison standard (RRV ) 1.0)
in the RRV series, which is otherwise comprised of â-thiogly-
cosides. It is very well established that R-glycosides are less
reactive than the corresponding â-anomers.
Resu lts a n d Discu ssion
The present series of investigations was intended to
address three principal questions. First, does the 4,6-O-
benzylidene group enforce selectivity (R- or â-) in galac-
topyranosylation with otherwise armed thioglycoside
donors? Second, do 4,6-O-phenyl- and polystyrylboronates
behave analogously to 4,6-O-benzylidene acetals? Third,
are the stereochemical results observed with the BSP/
Tf2O/thioglycoside and Tf2O/glycosyl sulfoxide methods
also seen in other systems, namely, the NIS/TMSOTf and
the very recent diphenyl sulfoxide/Tf2O13 activating
systems for thioglycosides?
With respect to the first question, it is very well-known
that galactosides are more reactive than mannosides,
which in turn are more reactive than glucosides, as
exemplified in the relative rates of hydrolysis of methyl
R-D-gluco-, R-D-manno-, and R-D-galactopyranosides of 1,
2.4, and 5.2, respectively.14 This trend is mirrored in
recent compilations of relative reactivity values for
thioglycoside donors (Figure 1).15
F IGURE 2. Equilibrium anomeric effects in peracetylated
pyranoses17 in 1:1 HOAc/Ac2O (kcal, mol-1).
4C1 donor flattens to the sofa conformation of the oxa-
carbenium ion.14a,15c It has also been suggested that the
enhanced reactivity of galactose is due to a minimization
of unfavorable interactions between the axial 4-C-O
bond and a ring oxygen lone pair in the course of the
same distortion.16 Conversely, the anomeric effect in
activated derivatives of galactose is comparable to that
in glucose and significantly lower than that in mannose
(Figure 2).17 Thus, on grounds of simple reactivity,
galactosyl donors might be expected to be more R-selec-
tive than glucose and mannose, as they have a higher
tendency toward oxacarbenium formation. Similarly, due
to the reduced anomeric effect vis-a`-vis mannose, both
glucosyl and galactosyl donors should be more R-selective
than comparable mannosyl donors if the glycosylation
mechanism involves SN2-like displacement on a more
reactive intermediate â-triflate at equilibrium with the
predominant R-form.
This is usually attributed to the axial alcohol being
subject to a less severe increase in torsional strain as the
(9) Nukada, T.; Be´rces, A.; Whitfield, D. M. Carbohydr. Res. 2002,
337, 765-774.
(10) J encks and co-workers have estimated the pseudo-first-order
rate constant for trapping of glycosyl cations in water to be 1012 s-1
,
consistent with
a lifetime too short to allow complete diffusional
equilibration with dilute solutes or even with solvent molecules, which
further points to the need to include counterions, whether covalently
bound or in contact ion pairs, when considering glycosylation mech-
anisms: Amyes, T. L.; J encks, W. L. J . Am. Chem. Soc. 1989, 111,
7888-7900. Also see: (a) Richard, J . P.; Amyes, T. L.; Toteva, M. M.
Acc. Chem. Res. 2001, 123, 981-988. (b) Zhu, J .; Bennet, A. J . J . Am.
Chem. Soc. 1998, 120, 3887-3893.
(11) Against this background, it is remarkable that papers continue
to be published that purport to describe glycosylation reactions in
nonpolar solvents in terms of naked oxacarbenium ions, that is, in
absentia the counterion: Abdel-Rahman, A. A.-H.; J onke, S.; El Ashry,
E. S. H.; Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 2002, 41, 2972-
2974.
(12) (a) Konradsson, P.; Udodong, U. E.; Fraser-Reid, B. Tetrahedron
Lett. 1990, 31, 4313-4316. (b) Garegg, P. J . Adv. Carbohydr. Chem.
Biochem. 1997, 52, 179-266.
(13) 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.
(14) Green, L. G.; Ley, S. V. In Carbohydrates in Chemistry and
Biology; Ernst, B., Hart, G. W., Sinay¨, P., Eds.; Wiley-VCH: Weinheim,
2000; Vol. 1, pp 427-448.
(15) (a) Douglas, N. L.; Ley, S. V.; Lucking, U.; Warriner, S. L. J .
Chem. Soc., Perkin Trans. 1 1998, 51-65. (b) Zhang, Z.; Ollmann, I.
R.; Ye, X.-S.; Wischnat, R.; Baasov, T.; Wong, C.-H. J . Am. Chem. Soc.
1999, 121, 734-753. (c) Namchuk, M. N.; McCarter, J . D.; Becalski,
A.; Andrews, T.; Withers, S. G. J . Am. Chem. Soc. 2000, 122, 1270-
1277.
Turning to the question of cyclic boronate esters,18 we
were intrigued by the possibility that the slightly longer
B-O bond lengths, compared to the C-O bond lengths
in benzylidene acetals, and the sp2 hybridization of the
boron and oxygen atoms, as opposed to the sp3 acetal
carbon and oxygens in benzylidene acetals, may make
the boronate esters sufficiently different from the ben-
zylidene acetals as to confer a different reactivity pattern.
Added to the obvious conformational difference of the
(16) Miljkovic, M.; Yeagley, D.; Deslongchamps, P.; Dory, Y. L. J .
Org. Chem. 1997, 62, 7597-7604.
(17) Lemieux, R. U. In Molecular Rearrangements, Part 2; De Mayo,
P., Ed.; Wiley: New York, 1964; pp 709-769.
(18) Reviewed in (a) Duggan, P. J .; Tyndall, E. M. J . Chem. Soc.,
Perkin Trans. 1 2002, 1325-1339. (b) Ferrier, R. J . Adv. Carbohydr.
Chem. Biochem. 1978, 35, 31-80.
J . Org. Chem, Vol. 68, No. 21, 2003 8143

Crich et al.
F IGURE 3. Pertinent structural features from X-ray crystal structures.19
SCHEME 1. Assem bly of Glu cosyl Don or s
emerge. First, the BSP and diphenyl sulfoxide methods
give comparable selectivities, favoring the R-anomer with
both 2 and 4 but to a greater extent with the benzylidene
protected system 2. The R-selectivity in couplings to 2
by these methods is consistent with our expectations from
the earlier studies.2,6 With NIS/TMSOTf the selectivity
is considerably lower with 2 but higher with 4. Self-
evidently, the NIS/TMSOTf reaction proceeds through a
different mechanism to the BSP and diphenyl sulfoxide
reactions, and this mechanism is affected in a different
manner by the switch from 4,6-O-benzylidene to 4,6-O-
phenylboronate. When the coupling of 4 to the less
hindered alcohol 3â-cholestanol (16) was studied, no
selectivity was observed by the BSP method, whereas the
standard NIS/TMSOTf conditions resulted only in the
formation of the R-anomer, thereby accentuating the
differences between the BSP and NIS methods. Interest-
ingly, when 4 was preactivated with NIS/TMSOTf prior
to the addition of the acceptor, bringing the conditions
closer to those used in the BSP method, a dramatic
change in selectivity was observed with the two anomers
formed in a 1:1 mixture.20 With 1-adamantanol as nu-
cleophile, coupling to 4 by the BSP method afforded a
2.8:1 R:â mixture of anomers. This is to be contrasted
with the previous coupling of 1-adamantanol to the
R-phenylthio analogue of the benzylidene-protected donor
2 with activation by benzenesulfenyl triflate, an anteced-
ent of the more convenient BSP method, when only the
R-anomer was formed.6a The standard NIS/TMSOTf pro-
tocol for the coupling of 4 and adamantanol again pro-
vided the clean R-anomer. Overall, in the glucose series
it is clear that results observed with 4,6-O-benzylidene
protected donors cannot be directly transposed to the
corresponding 4,6-O-phenylboronate donors owing to a
general erosion of the R-selectivity. Similarly, in the
glucose series the use of the NIS/TMSOTf method results
in considerably different stereoselectivities to those
obtained by the BSP and diphenyl sulfoxide methods.
In the galactose series (Table 2), coupling of the 4,6-
O-benzylidene-protected donor 6 by the BSP/Tf2O method
with the rhamnosyl acceptor 13 gave an 81% yield of the
galactoside 20 as a 4.8:1 mixture favoring the R-anomer.
Coupling of the comparable 4,6-O-phenylboronate-pro-
tected donor 8 with 13 under the same conditions gave a
comparable yield and selectivity. Application of the NIS/
TMSOTf method to the coupling of 8 and 13 resulted in
a 75% isolated yield of the R-galactoside with none of the
â-anomer observed.
SCHEME 2. Assem bly of Ga la ctosyl Don or s
boronate esters, there is also the more electropositive
nature of boron (2.0), as compared to carbon (2.5), which
admits the possibility that the 4,6-O-boronates might also
function in part as a more classical electron-withdrawing,
disarming protecting group (Figure 3).19
With these considerations in mind, a series of donors
was rapidly assembled as set out in Schemes 1 and 2.
For comparison purposes, several couplings were also
conducted with the known mannosyl donors 10-12.1-3
Beginning in the glucose series (Table 1) the rhamnosyl
acceptor 13 was challenged with the donors 2 and 4
differing in only the 4,6-O-protecting group by each of
three different coupling methods, from which two trends
With the less reactive glucosyl 4-OH acceptor 25, 4,6-
O-benzylidene-protected 6 gave moderate yields of the
R-galactoside 26 as the only isolated product by both the
(19) (a) Salazar-Pereda, V.; Martinez-Martinez, L.; Flores-Para, A.;
Rosales-Hoz, M. J .; Ariza-Castolo, A.; Contreras, R. Heteroatom Chem.
1994, 5, 139-143. (b) Gururaja, T. L.; Venugopalan, P.; Levine, M. J .
J . Chem. Crystallogr. 1998, 28, 747-759.
(20) This change in selectivity with NIS/TMSOTf with order of
mixing recalls that observed1 for the mannosyl sulfoxides and warrants
further investigation.
8144 J . Org. Chem., Vol. 68, No. 21, 2003

Influence of Protecting Groups on Glycosylations
TABLE 1. Cou p lin g Rea ction s w ith Glu cosyl Don or s
BSP/Tf2O method and the more recent diphenyl sulfoxide/
Tf2O method introduced by van Boom and co-workers.
The coupling of 25 to the 4,6-O-polystyrylboronate-
protected glycosyl donor 9 was also investigated, result-
ing after cleavage from the resin in the isolation of the
R-galactoside 27 as the only coupled product in excellent
yield by both the BSP and NIS methods. The polystyryl-
boronate-supported donor 9 was also coupled to the
galactosyl 2-OH acceptor 28 by both the BSP and NIS
methods, resulting in both cases in the isolation of the
R-coupled product in high yield and selectivity.21
We next turned to the use of 1-adamantanol as glycosyl
acceptor: with the 4,6-O-benzylidene-protected donor 6,
the reaction was high yielding and moderately â-selec-
tive, whether promoted by BSP/Tf2O or NIS/TMSOTf. On
the other hand, the coupling of adamantanol to the 4,6-
O-phenylboronate 8 and to the corresponding polystyryl-
boronate 9 was R-selective with ratios varying between
2:1 and 4.8:1, dependent on the coupling method em-
ployed. This reversal in anomeric selectivity observed
with 1-adamantanol on going from the benzylidene acetal
to either of the two boronate esters is the only instance
of such a change that we observed and deserves comment.
In general, in our studies, we have found 1-adamantanol
to be an excellent acceptor alcohol: in the case of the 4,6-
O-benzylidene-protected mannosyl donors, it consistently
provides the â-glycoside with excellent selectivity, whether
the reaction is carried out with activation by benzene-
sulfenyl triflate1b or BSP/Tf2O.2 Likewise, it gives excel-
lent â-selectivity with a 4,6-O-polystyrylboronate-pro-
tected mannosyl donor3 and with a 2-O-sulfonyl-protected
rhamnosyl donor.22,23 Indeed, 1-adamantanol is typically
such a good nucleophile in these reactions that, ulti-
mately, it is a poor model with which to probe the
stereoselectivity of a particular system. The most reason-
able explanation for the results observed here is that
most couplings observed in Table 2 proceed via the aegis
of a loose ion pair, that is, with nucleophilic attack on a
glycosyl oxacarbenium ion in an R-selective manner. The
formation of the adamantanyl â-galactoside 23 is best
explained by an SN2-like attack of the more nucleophilic
adamantanol on an intermediate R-galactosyl triflate or
the contact ion pair with which it is in equilibrium. On
going from the 4,6-O-benzylidene-protected system to the
more open 4,6-O-boronate esters, a shift to the right in
the covalent-triflate/contact ion pair equilibrium/solvent
(21) The formation of the R-galactoside in the coupling of 9 and 28
was contrary to our initial expectations, as it had been reported that
with NIS/TMSOTf the â-galactoside was obtained: Belogi, G.; Zhu,
T.; Boons, G.-J . Tetrahedron Lett. 2000, 41, 6965-6968. However, it
was subsequently established that this was a drawing error and that
the original data supported the structure reported here: Belogi, G.
Ph.D. Thesis; The University of Birmingham, 2000. We thank Prof.
Geert-J an Boons for his help in clarifying this matter.
(22) Crich, D.; Picione, J . Org. Lett. 2003, 5, 781-784.
(23) For the synthesis of an adamantanyl â-D-rhamnoside, see:
Crich, D.; Yao, Q. Org. Lett. 2003, 5, 2189-2191.
J . Org. Chem, Vol. 68, No. 21, 2003 8145

Crich et al.
TABLE 2. Cou p lin g Rea ction s w ith Ga la ctosyl Don or s
8146 J . Org. Chem., Vol. 68, No. 21, 2003

Influence of Protecting Groups on Glycosylations
TABLE 2 (Con tin u ed )
TABLE 3. Cou p lin g Rea ction s w ith Ma n n osyl Don or s
a
b
From ref 2. From ref 3.
separated ion pair, resulting from the change in hybrid-
ization and conformation in the second ring, is manifested
by an increased R-selectivity. In other words, in most
instances in the galactose series neither the 4,6-O-
benzylidene acetal, the 4,6-O-phenylboronate, nor the 4,6-
O-polystyrylboronate sufficiently stabilize any interme-
diate R-galactosyl triflate to permit the SN2-like â-selective
process to predominate: this latter process only becomes
possible with the more nucleophilic adamantanol and
then only for the 4,6-O-benzylidene acetal. Looked at in
yet another way, differences between the benzylidene-
and boronate-protected donors only become apparent in
systems that that are on the cusp, i.e., when minor
conformational changes can force the selectivity in either
direction. In the mannose series, with the greater ano-
meric effect and more rigid trans-fused nature of the
benzylidene acetals and boronate esters, the SN2-like
process always predominates.
Several other couplings were conducted between alco-
hols of intermediate reactivity and the benzylidene-
protected galacostyl donor, as recorded in Table 2 with
selectivities clustered either side of the R:â threshold, as
expected on the basis of the above discussion.
One further point of note again concerns the â-selective
coupling between the benzylidene-protected donor 6 and
adamantanol, when conducted by the NIS/TMSOTf
method. The donor in this reaction was a â-phenyl
thioglycoside, which rules out the possibility of a direct
SN2-like attack on the initial activated thioglycoside.
Rather, it seems apparent that even under these condi-
J . Org. Chem, Vol. 68, No. 21, 2003 8147

Crich et al.
tions there is the formation of another transient inter-
mediate, possibly the R-glycosyl triflate or iodide.
Intrigued by the â-selectivity in the NIS/TMSOTf-
mediated coupling of adamantanol and 6, we briefly
investigated the same activation system in the mannose
series. As recorded in Table 3, the reaction was, how-
ever, devoid of selectivity and thereby provided our first
sample of an adamantanyl 4,6-O-benzylidene-protected
R-mannoside. Activation of the thioglycoside 6 with the
diphenyl sulfoxide/Tf2O system of van Boom and co-
workers restored the â-selectivity with both adaman-
tanol and the much more demanding glucose 4-OH
system.
In summary, in the glucose series results obtained with
the 4,6-O-benzylidene-protected donor cannot be trans-
posed to the corresponding 4,6-O-phenylboronate, owing
to a general erosion of the R-selectivity. The NIS/TMSOTf
method affords significantly different stereoselectivities
in the glucose series to either the BSP/Tf2O or the
diphenyl sulfoxide/Tf2O methods. On the other hand, in
the galactose series 4,6-O-benzylidene-, 4,6-O-phenylbo-
ronate-, and 4,6-O-polystyrylboronate-protected 2,3-di-
O-benzyl thioglycosides have all been shown to favor the
formation of R-galactosides when activated with either
the BSP/Tf2O, Ph2SO/Tf2O, or NIS/TMSOTf systems. The
exceptions to this rule involve the more reactive alcohols,
especially 1-adamantanol, when moderate â-selectivity
is observed in the 4,6-O-benzylidene series but not with
the boronate esters. As was already known, the 4,6-O-
benzylidene and 4,6-O-polystyrylboronates in the man-
nose series are highly â-selective with the BSP/Tf2O and
diphenyl sulfoxide/Tf2O methods. The NIS/TMSOTf
method has, however, been found to afford much reduced
â-selectivity in the mannose series.
changes in the relative energetics between the R- and
â-covalent triflate intermediates and the various con-
tact ion pairs with which they are necessarily in equi-
librium.
In closing, we find it somewhat ironic that it is in the
mannose series, with its long history of problems neces-
sitating synthesis of the â-glycosides by any of a signifi-
cant number of indirect routes,24 that the chemistry is
most predictable with no significant difference between
the benzylidene- and boronate-protected donors notice-
able as long as an activating method likely to promote
formation of the intermediate R-triflates is selected.
Ack n ow led gm en t. We thank the NIGMHS (GM
62160) for support of this work and Prof. Geert-J an
Boons for a helpful exchange of information.
Note Ad d ed a fter P r in t P u blica tion : Due to a
production error, the structure block on p 8144 was
replaced with a duplicate Figure 2 in the version posted
on the Web September 26, 2003 (ASAP) and published
in the October 17, 2003 issue (Vol. 68, No. 21, pp 8142-
8148); the correct electronic version of the paper was
published on October 28, 2003, and an Addition and
Correction appears in the November 28, 2003 issue (Vol.
68, No. 24).
Su p p or tin g In for m a tion Ava ila ble: Full experimental
details and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O0349882
(24) Reviewed in (a) Pozsgay, V. In Carbohydrates in Chemistry and
Biology; Ernst, B., Hart, G. W., Sinay¨, P., Eds.; Wiley-VCH: Weinheim,
2000; Vol. 1, pp 319-343. (b) Gridley, J . J .; Osborn, H. M. I. J . Chem.
Soc., Perkin Trans. 1 2000, 1471-1491. (c) Barresi, F.; Hindsgaul, O.
In Modern Methods in Carbohydrate Synthesis; Khan, S. H., O’Neill,
R. A., Eds.; Harwood Academic Publishers: Amsterdam, 1996; pp 251-
276.
The differences between the glucose, galactose, and
mannose series reflect the differences in relative re-
activity values and, especially for mannose, those in the
anomeric effect and are best interpreted in terms of
8148 J . Org. Chem., Vol. 68, No. 21, 2003