The 3,4-O-Carbonate Protecting Group as a β-Directing Group in Rhamnopyranosylation in Both Homogeneous and Heterogeneous Glycosylations As Compared to the Chameleon-like 2,3-O-Carbonates

Article abstract of DOI:10.1021/jo035003j

It is demonstrated that the β-selectivity observed in the insoluble silver salt mediated couplings of 2,3-O-carbonate-protected rhamnosyl bromides is uniquely due to the heterogeneous nature of the reaction. In homogeneous solution these same donors are α-selective, a fact that is attributed to the half-chair conformation of these substances which reduces the energy barrier to oxacarbenium ion formation. It is suggested that the 2,3-O-carbonate group be dubbed torsionally arming in the manno- and rhamnopyranose series. When the carbonate group is removed to the 3,4-O-position a β-selective system is formed, in both homogeneous and heterogeneous conditions, and it is demonstrated that this selectivity arises from the combination of the electron-withdrawing nature of the carbonate and its inability to take part in neighboring participation.

Full text of DOI:10.1021/jo035003j

Th e 3,4-O-Ca r bon a te P r otectin g Gr ou p a s a â-Dir ectin g Gr ou p in
Rh a m n op yr a n osyla tion in Both Hom ogen eou s a n d Heter ogen eou s
Glycosyla tion s As Com p a r ed to th e Ch a m eleon -lik e
2,3-O-Ca r bon a tes
David Crich,* A. U. Vinod, and J ohn Picione
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
dcrich@uic.edu
Received J uly 11, 2003
It is demonstrated that the â-selectivity observed in the insoluble silver salt mediated couplings of
2,3-O-carbonate-protected rhamnosyl bromides is uniquely due to the heterogeneous nature of the
reaction. In homogeneous solution these same donors are R-selective, a fact that is attributed to
the half-chair conformation of these substances which reduces the energy barrier to oxacarbenium
ion formation. It is suggested that the 2,3-O-carbonate group be dubbed torsionally arming in the
manno- and rhamnopyranose series. When the carbonate group is removed to the 3,4-O-position a
â-selective system is formed, in both homogeneous and heterogeneous conditions, and it is
demonstrated that this selectivity arises from the combination of the electron-withdrawing nature
of the carbonate and its inability to take part in neighboring participation.
In tr od u ction
limiting the R-face selective SN1 process. Second, it is
supposed that the absorption of the bromide on the
promoter surface occurs in such a way as to shield the
R-face.3ab,4 The first argument is supported by the dem-
onstrated and widely applied principle that the disarming
effect5 of an electron-withdrawing protecting group is
stronger the closer it is to the reactive center,6 i.e, a 2,3-
O-carbonate should be highly effective at oxacarbenium
ion destabilization. The second reason, the preferential
shielding of the R-face by the insoluble promoter, though
widely accepted and quoted, does not appear to be
supported by any published evidence. The first indication
that one or the other of these reasons was flawed arose
from the glycosylation of 3 with the mannosyl donor 4
promoted by benzenesulfenyl triflate, which contrary to
our expectations afforded only the R-anomer 5 (Scheme
1).7
In the realm of carbohydrate chemistry, the cyclic
carbonate protecting group for vicinal diols has earned
a reputation as being one of the few groups capable of
enforcing â-glycosylations in the manno- and rhamnopy-
ranose series. Thus, as reported originally by Gorin and
Perlin,1 a 2,3-O-carbonate-protected mannosyl bromide
1 affords â-mannosides with high diastereoselectivity
when presented with an acceptor alcohol in the presence
of an insoluble silver salt as promoter. The corresponding
effect was reported by Kochetkov and co-workers for the
rhamnosyl bromide 2,2 and numerous subsequent ex-
amples have been collated in reviews.3
This result was in contrast to our expectation, based
on our earlier work with â-selective 4,6-O-benzylidene-
protected mannosyl donors,8 that the two protecting
groups would reinforce each other providing for a highly
â-selective system. In a subsequent synthesis we noted
The effect is usually explained by a combination of two
factors. First, the strongly electron-withdrawing carbon-
ate destabilizes any potential oxacarbenium ions derived
by expulsion of the anomeric leaving group, thereby
(4) van Boeckel, C. A. A.; Beetz, T.; van Aelst, S. F. Tetrahedron
1984, 4097-4107.
(5) (a) Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-Reid, B.
J . Am. Chem. Soc. 1988, 110, 5583-5584. (b) Andrews, C. W.;
Rodebaugh, R.; Fraser-Reid, B. J . Org. Chem. 1996, 61, 5280-5289.
(6) (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) Green, L. G.; Ley, S. V. In Carbohydrates in
Chemistry and Biology; Ernst, B., Hart, G. W., Sinay¨, P., Eds.; Wiley-
VCH: Weinheim, Germany, 2000; Vol. 1, pp 427-448.
(1) Gorin, P. A. J .; Perlin, A. S. Can. J . Chem. 1961, 39, 2474-2485.
(2) Backinowsky, L. V.; Balan, N. F.; Shashkov, A. S.; Kochetkov,
N. K. Carbohydr. Res. 1980, 84, 225-235.
(3) (a) Barresi, F.; Hindsgaul, O. In Modern Methods in Carbohy-
drate Synthesis; Khan, S. H., O’Neill, R. A., Eds.; Harwood Academic
Publishers: Amsterdam, The Netherlands, 1996; pp 251-276. (b)
Pozsgay, V. In Carbohydrates in Chemistry and Biology; Ernst, B.,
Hart, G. W., Sinay¨, P., Eds.; Wiley-VCH: Weinheim, Germany, 2000;
Vol. 1, pp 319-343. (c) Gridley, J . J .; Osborn, H. M. I. J . Chem. Soc.,
Perkin Trans. 1 2000, 1471-1491.
(7) Crich, D.; Cai, W.; Dai, Z. J . Org. Chem. 2000, 65, 1291-1297.
(8) (a) Crich, D.; Sun, S. Tetrahedron 1998, 54, 8321-8348. (b) Crich,
D.; Sun, S. J . Am. Chem. Soc. 1997, 119, 11217-11223.
10.1021/jo035003j CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/03/2003
J . Org. Chem. 2003, 68, 8453-8458
8453

Crich et al.
SCHEME 1. r-Selective Ma n n osyla tion Dir ected by
a 2,3-O-Ca r bon a te
SCHEME 2. P r ep a r a tion of
2,3-O-Ca r bon a te-P r otected Rh a m n osyl Don or s
in support of the critical insoluble nature of the promoter
in glycosylations with 2 was provided by a series of
couplings with donors 10-15, prepared by reaction of the
corresponding known diols 7-914 with phosgene and then
bromine as set out in Scheme 2, to cholestanol activated
with either silver oxide (insoluble), silver triflate (soluble),
or BSP/Tf2O (soluble) for the thioglycosides (Table 1). The
stereochemistry of the coupled products was assigned on
the basis of the 3J H1,H2 coupling constant in the rhamnose
system, which was typically 3.0 Hz for the â-glycosides
and 0 in the R-series. This assignment follows from our
earlier work in the mannose series,7 that of Kunz in the
mannose series,13 and from our own synthetic work with
6 in the rhamnose series.9a It is important to note (Table
that a 2,3-O-carbonate-protected rhamnosyl thioglycoside
6 was similarly an R-selective donor9 in our powerful
1-benzenesulfinyl piperidine (BSP)/TTBP/triflic anhy-
dride mediated system.10-12
We report here on our attempts to resolve this appar-
ent paradox which have led to the discovery of the 3,4-
O-carbonate as a superior â-directing protecting group
in homogeneous glycosylations in the rhamnose field, a
contravention of the common wisdom that the more
remote electron-withdrawing groups have less effect on
the outcome of glycosylation reactions.6
1
1) that the common J C1,H1 coupling constant method15
of assigning anomeric stereochemistry in the manno- and
rhamnopyranoside series breaks down here and should
not be used. This, again, is a consequence of the half-
chair conformation adopted in the 2,3-O-carbonates.
It is evident from Table 1 that when a homogeneous,
soluble promoter system is used, i.e., silver triflate with
the bromides or BSP/Tf2O with the thioglycosides, the
2,3-O-carbonate is highly R-directing whereas the in-
soluble silver oxide promoter leads to â-selective cou-
plings. Clearly, the â-selective couplings widely reported
in the literature with 1 and 2 do derive their selectivity
from their heterogeneous nature which, in reality, over-
comes the true R-directing effect of the 2,3-O-carbonate
in homogeneous solution.16 Further inspection of Table
1 reveals that the nature of the protecting group on O-4,
be it ester or ether, has little influence on the outcome
of the couplings, homogeneous or heterogeneous, thereby
eliminating the possibility of neighboring group partici-
pation by esters at that position having a role to play in
the â-selective couplings.4,17,18
Resu lts a n d Discu ssion s
In attempting to rationalize the observations of Scheme
1 we hypothesized that the R-selectivity was a case of
ground-state destabilization. More precisely, we sug-
gested that the glycosyl triflate,8b formed on activation
of 4, adopted the OH5 half-chair conformation and that
this reduced the energy gap between the covalent triflate
and the sofa conformation oxacarbenium ion thereby
facilitating formation of the R-selective cation.7 Moreover,
it was obvious that this effect was not a small one as it
completely overrode the normal â-directing effect of the
4,6-O-benzylidene group. Our argument was supported
by NMR analyses of 2,3-O-carbonate-protected manno-
sides reported by Kunz which indicated the OH5 confor-
mation.13 This being the case, it was evident that the
success of the insoluble silver method with donors 1 and
2 was not due to any strongly disarming effect of the
carbonate but must be related to the promoter. Evidence
(14) (a) 7: Pozsgay, V. Carbohydr. Res. 1992, 235, 295-302. (b) 8:
Pozsgay, V. J . Org. Chem. 1998, 63, 5983-5999. (c) 9: Kim, S.-H.;
Augeri, D.; Yang, D.; Kahne, D. J . Am. Chem. Soc. 1994, 116, 1766-
1775.
(15) Bock, K.; Pedersen, C. J . Chem. Soc., Perkin Trans. 2 1974,
293-297.
(9) (a) Crich, D.; Li, H. J . Org. Chem. 2002, 67, 4640-4646. (b) For
a related observation with other 2,3-O-carbonyl rhamnosyl donors in
homogeneous solution see: 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.
(16) The magnitude of the anomeric effect in mannose (and by
extension rhamnose) is such that any mechanism involving SN2-like
displacement of transient â-rhamnosyl triflates in the formation of
â-rhamnosides from 10-12 and 13 in homogeneous solution in the
presence of triflate anion is highly unlikely. The same situation
pertains with donors 26 and 40. Note that pentaacetyl R-mannopyra-
nose is favored over its â-anomer by 1.69 kcal‚mol-1 whereas in the
glucose series the equilibrium only favors the R-anomer by 1.10 kcal‚
mol-1: Lemieux, R. U.; Morgan, A. R. Can. J . Chem. 1965, 43, 2214.
(17) (a) Demchenko, A. V.; Rousson, E.; Boons, G.-J . Tetrahedron
Lett. 1999, 40, 6523-6536. (b) Kimura, Y.; Suzuki, M.; Matsumoto,
T.; Abe, R.; Terashima, S. Bull. Chem. Soc. J pn. 1986, 59, 423-431.
(c) Yamanoi, T.; Nakamura, K.; Takeyama, H.; Yanagihara, K.; Inazu,
T. Bull. Chem. Soc. J pn. 1994, 67, 1359-1366.
(10) (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.
(11) BSP and TTBP are commercially available from Lakeviewsyn-
thesis.com.
(12) A related reversal of selectivity was reported for the coupling
of the O-benzoyloxime of 1-bromo-1-deoxy-R-D-arabino-hexopyranos-
2-ulose 3,4,6-tribenzoate to a typical glucopyranose 4-OH acceptor. In
a heterogeneous system mediated by silver carbonate the coupling was
â-selective, whereas with silver triflate and tetramethylurea in dichlo-
romethane solution the â-anomer was obtained: Kaji, E.; Matsui, E.;
Kobayashi, M.; Zen, S. Bull. Chem. Soc. J pn. 1995, 68, 1449-1454.
(13) Guenther, W.; Kunz, H. Carbohydr. Res. 1992, 228, 217-241.
(18) For an actual example of neighboring group participation
involving a seven-membered cyclic intermediate see: Wilen, S. H.;
Delguzzo, L.; Saferstein, R. Tetrahedron 1987, 43, 5089-5094.
8454 J . Org. Chem., Vol. 68, No. 22, 2003

Homogeneous and Heterogeneous Glycosylations
TABLE 1. Glycosyla tion of 3â-Ch olesta n ol w ith 2,3-O-Ca r bon a te-P r otected Rh a m n osyl Don or s
The above results, wherein the electron-withdrawing
nature of the 2,3-O-carbonate is more than compensated
for by a conformational effect, which merits the name
torsionally arming, led us to consider the possibility of
employing a 3,4-O-carbonate group in rhamnosylation.
Thus, we hypothesized that the conformational trap of
the 2,3-O-carbonates, with their half-chair conformation
predisposed to oxacarbenium ion formation, could be
escaped by removing the carbonate from the anomeric
center by one carbon to the 3,4-position where it would
have a trans-fused ring junction to the pyranose ring. To
test this possibility donors 26, 27, and 28 were prepared
from â-phenyl thiorhamnoside 2219,20 as set out in Scheme
3 and coupled to a selection of acceptor alcohols by the
BSP/Tf2O method with the results indicated in Table 2.
The tri-O-benzyl rhamnosyl donor 2921 was also included
in this study for comparison purposes.
It is immediately evident from the couplings of
cholestanol to donors 26, 27, and 29 that the 3,4-O-
carbonate, unlike the 2,3-O-carbonates of Table 1, is
uniquely â-directing in these homogeneous glycosylation
reactions. The contrast between the â-selective nature
(20) The R-phenylthio analogue of 26 was also prepared by a directly
analogous route but the â-anomer illustrated was generally superior
owing to the more crystalline nature of several intermediates which
facilitate isolation and thereby improve the overall yield. Coupling of
the â-phenylthio analogue of 26 to cholestanol by the BSP method in
dichloromethane solution gave a 61% yield of 30 with a â:R ratio of
6:1, indicating the â-directing effect of 26 is not a function of the initial
stereochemistry of the thioglycoside.
(19) Crich, D.; Picione, J . Org. Lett. 2003, 5, 781-784.
(21) Qiu, D.; Schmidt, R. R. Synthesis 1990, 875-877.
J . Org. Chem, Vol. 68, No. 22, 2003 8455

Crich et al.
TABLE 2. Rh a m n osyla tion s w ith Don or s 26-29 by th e BSP /Tf2O Meth od
a
The values in parentheses refer to the coupling constants for the anomeric carbon of the sugar at the reducing end of disaccharides.
of the coupling with the 3,4-O-carbonate 26 and that with
the 3,4-di-O-acetyl donor 27 illustrates the need for the
inclusion of the electron-withdrawing carbonyl group in
a ring rendering it incapable of neighboring group
participation. We have previously observed7 a 3-O-
carboxylate group to be R-directing in the closely related
mannose series even in the presence of a 4,6-O-ben-
zylidene acetal and, so, the R-selective coupling with
diacetate 27 was not unexpected. When donor 26 was
coupled to the glucose 4-OH acceptor (33) the anomeric
selectivity was understandably much reduced in view of
the relatively poor reactivity of this alcohol. However,
when the same alcohol was coupled to the 3,4-O-isopro-
pylidene acetal 28, the reaction was completely R-selec-
tive indicating the â-selectivity of cyclic carbonate 26 was
not due in any major way to a conformational effect
arising from the cyclic nature of the protecting group.22
Overall, it is clear that the â-selectivity of 26 is due both
to its electron-withdrawing nature destabilizing the
anomeric oxacarbenium ion and its cyclic nature, which
prevents neighboring group participation. With the less
hindered, more reactive glucose 6-OH acceptor (36) a
return to significant â-selectivity was observed as an-
ticipated. Finally, in this series of reactions, the coupling
of 26 to 1-adamantanol was conducted resulting in the
formation of the â-anomer as the only coupling product
detected. This high â-selectivity with the tertiary alcohol
acceptor mirrors that seen in the 4,6-O-benzylidene-
protected mannosyl donors8a and, indeed, with the 4-O-
benzoyl-2-O-sulfonylrhamnosyl donor 39.19
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Homogeneous and Heterogeneous Glycosylations
TABLE 3. Selected Dep r otection s in th e 3,4-O-Ca r bon a te a n d Isop r op ylid en e Ser ies
a
The values in parentheses refer to the coupling constants for the anomeric carbon of the sugar at the reducing end of disaccharide.
SCHEME 3. P r ep a r a tion of Rh a m n osyl Don or s
SCHEME 4. P r ep a r a tion a n d Cou p lin g of a
26-28
3,4-O-Ca r bon a te-P r otected Rh a m n osyl Br om id e
bonate, i.e., by the insoluble silver salt method (Scheme
4). The product (30) was isolated as 7:1 â:R mixture
thereby demonstrating that the 3,4-O-carbonate system,
unlike the 2,3-O-carbonates of Table 1, functions analo-
gously whether in homogeneous or heterogeneous cou-
pling reactions.
Overall, the â-selectivity observed with donor 26 (and
40) falls short, with the exception of coupling to 1-ada-
mantanol, of that seen with the alternative â-rhamnosyl
donor 39, but this is to be expected given that the
electron-withdrawing group in 26 is further removed
from the site of reactivity. It remains to be seen whether
a combination of 26 and 39, i.e., a 3,4-O-carbonyl-2-O-
sulfonyl donor, will provide enhanced selectivity over the
present donors.
Donor 26 was converted to the somewhat unstable
corresponding R-bromide 40, which was coupled with
cholestanol in dichloromethane by means of silver car-
(22) Both Danishefsky and Roush have previously employed 3,4-O-
carbonyl-protected â-selective galactosyl donors, which they attributed
to greatly enhanced conformational rigidity in the donor. Our results
clearly show the effect not to be conformational but rather due to the
blocking of neighboring group participation coupled to the electron-
withdrawing effect of the carbonate: (a) Randolph, J . T.; Danishefsky,
S. J . J . Am. Chem. Soc. 1995, 117, 5693-5700. (b) Durham, T. B.;
Roush, W. R. Org. Lett. 2003, 5, 1871-1874.
With respect to the assignment of configuration in the
3,4-O-carbonate-protected products, we examined both
3
1
the rhamnose J H1,H2 proton and the J C1H1 coupling
constants collected in Table 2. Unlike the 2,3-O-carbonate
J . Org. Chem, Vol. 68, No. 22, 2003 8457

Crich et al.
3
series, there is no useful pattern in the J H1,H2 proton
mides is uniquely due to the heterogeneous nature of the
reaction. Indeed, in homogeneous solution these same
donors are R-selective, a fact that is attributed to the half-
chair conformation of these substances, which reduces
the energy gap to oxacarbenium ion formation. When the
carbonate group is removed to the 3,4-O-position a
â-selective system is formed, in both homogeneous and
heterogeneous conditions, and it is demonstrated that
this selectivity arises from the combination of the electron-
withdrawing nature of the carbonate and its inability to
take part in neighboring participation. Although it has
not been explicitly demonstrated here, we fully expect
that the results observed and conclusions drawn will
translate uneventfully to the closely analogous mannopy-
ranoside series.
coupling constants, with both anomers typically display-
ing the anomeric proton as a broad singlet, or as a doublet
with a minimal coupling constant. However, the usual
pattern15 in the anomeric J C1H1 coupling constants,
1
whereby the R-anomer, with its equatorial hydrogen, has
the larger numerical value was observed. To recapitulate,
this is distinct from the J C1H1 coupling constants in the
2,3-O-carbonate series (Table 1) which are not reliable
because of the half-chair conformation of the pyranoside
ring in those cases. Final verification of the anomeric
stereochemistry in the 3,4-O-carbonate series was achieved
by removal of the carbonate group in selected examples
by means of saponification. As seen from Table 3, the
resulting 2-O-benzyl rhamnosides display a completely
1
1
normal pattern of J C1H1 coupling constant variation
between the two anomers. The identity of the product
(42R) from the saponification of 34R and from the removal
of the acetonide group in 35R confirms the R-selective
nature of the coupling to the acetonide-protected donor
28.
In summary, it has been demonstrated that the
â-selectivity observed in the insoluble silver salt mediated
couplings of 2,3-O-carbonate-protected rhamnosyl bro-
Ack n ow led gm en t. We thank the NIH (GM 57335,
GM 62160) for financial support.
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 O035003J
8458 J . Org. Chem., Vol. 68, No. 22, 2003