Targeted glycosyl donor delivery for site-selective glycosylation.

Article abstract of DOI:10.1021/ol0001214

[reaction: see text]n-Pentenyl ortho esters (NPOEs) and n-pentenyl glycosides (NPGs) are interconvertible glycosyl donors which are activated by reaction with halonium ions. In a series of cyclic syn-1,3-diols, NPOEs have been found to specifically glycos

Full text of DOI:10.1021/ol0001214

ORGANIC
LETTERS
2000
Vol. 2, No. 17
2587-2589
Targeted Glycosyl Donor Delivery for
Site-Selective Glycosylation†,1
G. Anilkumar, Latha G. Nair, and Bert Fraser-Reid*
Natural Products and Glycotechnology Research Institute, Inc.,‡
4118 Swarthmore Road, Durham, North Carolina 27707
npgresearch@hotmail.com
Received May 4, 2000
ABSTRACT
n-Pentenyl ortho esters (NPOEs) and n-pentenyl glycosides (NPGs) are interconvertible glycosyl donors which are activated by reaction with
halonium ions. In a series of cyclic syn-1,3-diols, NPOEs have been found to specifically glycosylate the equatorial-OH while the NPG glycosylates
predominantly, but not exclusively, the axial-OH. When the cyclic diol acceptor is presented with equivalent amounts of an NPOE and an NPG
in a three-component-reaction, a single, double-glycosylation product is obtained, which conforms to the foregoing preferences, presenting
evidence for site-selective glycosylation.
The concept of armed/disarmed strategies for controlling
oligosaccharide assembly, initially formulated in the context
of n-pentenyl glycosides,2 was rapidly extended to other
glycosyl donors3 and has become part of the fabric of
synthetic carbohydrate chemistry.4,5 The principle relies on
the logistical deployment of “protecting groups” on the
donor, and the effect can be engendered by electronic6 or
torsional7 factors, the latter being elegantly demonstrated in
recent reports from Crich and co-workers.8 Glycosyl accep-
tors are the other partners in coupling reactions, and it is
well-known that poly-hydroxyl substrates frequently display
selectivity based on orientation,9 hydrogen bonding,10 etc.
Both sets of selectivities are kinetically based. Thus, armed
and disarmed donors can each react with a given acceptor,
but the rates are sufficiently different that in a competitive
setting one product is formed overwhelmingly. In this Letter,
we describe a very different glycosidation phenomenon based
on exquisite paring of donor and acceptor, which can be so
selective that it constitutes evidence for “site-selective
glycosidation”.
n-Pentenyl donors11 are unique among glycosylating agents
currently in use3,12 in that they may function in both 1,2-
ortho ester (NPOE, 1) and glycosidic (NPG, 2a) modali-
† Dedicated to Professor R. U. Lemiuex in honor of his 80th birthday.
‡ A nonprofit organization at Centennial Campus (North Carolina State
University), Raleigh, NC.
(1) Financial support from the Research in Tropical Diseases (TDR)
program of the World Health Organization and the NIH (GM40171) is
gratefully acknowledged.
(2) Mootoo, D. R.; Konradson, P.; Udodong, U.; Fraser-Reid, B. J. Am.
Chem. Soc. 1988, 110, 5583-5584.
(3) Boons, G. J. Tetrahedron 1996, 52, 1095-1121.
(4) Collins, P. M., Ferrier, R. J. Monosaccharides--Their Chemistry and
Their Roles in Natural Products; Wiley & Sons: New York, 1995.
(5) Boons, G.-J. Carbohydrate Chemistry; Blackie Academic and Profes-
sional, Chapman and Hall: London, 1999.
(6) Fraser-Reid, B.; Wu, Z.; Udodong, U. E.; Ottosson, H. J. Org. Chem.
1990, 55, 6068-6070.
(7) Fraser-Reid, B.; Wu, Z.; Andrews, C. W.; Skowronski, E.; Bowen,
J. P. J. Am. Chem. Soc. 1991, 113, 1434-1435. Andrews, C. W.;
Rodebaugh, R.; Fraser-Reid, B. J. Org. Chem. 1996, 61, 5280-5289.
(8) Crich, D.; Cai, W.; Dai, Z.; J. Org. Chem. 2000, 65, 1291-1297.
Crich, D.; Sun, S.; J. Am. Chem. Soc. 1998, 120, 435-436.
(9) Jacquinet, J. C.; Duchet, D.; Milat, M. L.; Sinay, P. J. Chem. Soc.,
Perkin Trans. 1 1981, 326-330. Jacquinet, J. C.; Paulsen, H. Tetrahedron
Lett. 1981, 22, 1387-1390.
(10) Vasella, A. In Bioorganic Chemistry Carbohydrates; Hecht, S. M.,
Ed.; Oxford University Press: New York, 1999; pp 56-88.
(11) Fraser-Reid, B.; Udodong, U. E.; Wu, Z.; Ottosson, H.; Merritt, J.
R.; Rao, C. S.; Roberts, C.; Madsen, R. Synlett 1992, 927-942.
(12) Bioorganic Chemistry: Carbohydrates; Hecht, S. M., Ed.; Oxford
University Press: 1999. PreparatiVe Carbohydrate Chemistry; Hanessian,
S., Ed.; Marcel Dekker, 1997. Modern Methods in Carbohydrate Synthesis;
Khan, S. H., O’Neill, R. A., Eds.; Harwood Academic Publishers: 1996.
10.1021/ol0001214 CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/03/2000

ties.13,14 The latter are readily obtainable from the former
by means of an efficient stereocontrolled, acid-catalyzed
rearrangement.15 The reverse process, 2a f 1, has not been
formally reduced to practice, although it can be readily
conceptualized.16,17
Scheme 2a
Our investigations were triggered by the recent observa-
tions that the partially protected myo-inositol 3 undergoes
selective alkylation at C2-OH18 but selective acylation at C6-
OH (Scheme 1).19 The possibility of comparable site-selective
Scheme 1
a Reaction conditions: (i) 3, NIS (1.3 equiv), TBDMSOTf (cat.),
CH2Cl2, rt, 10 min; (ii) 3, NIS (1.3 equiv), TBDMSOTf (cat.),
CH2Cl2, 0 °C, 20 min.
of improving the yield of 6, we examined n-pentenyl ortho
esters (NPOEs), since these donors have recently served us
well.17,25 Much to our surprise, NPOE glycosidation22 with
5a or 5b displayed the completely alternative preference,
giving 7b or 7c,24 respectively, as the only coupling product
in spot-to-spot conversion.
To determine whether R-face ortho esters would also
exhibit similar preferences, the gluco and galacto NPOEs
8a and 8b were tested with diol 3 (Scheme 3). The products
glycosidation was of interest, since C2 and/or C6 mono- and
diglycosylated inositols occur in inositides of glycosylphos-
phatidylinositols (GPIs)20 and lipoarabinomannans (LAMs),21
the biological “warheads” of malaria and tuberculosis cell-
surface oligosaccharides, respectively.
The major products from the reaction22 of NPG 4a with
the diol acceptor 3 were the R-mannosides 6 and 7a23,24 in
3:1 ratio and ∼65% combined yield (Scheme 2). In the hope
Scheme 3a
(13) Thioortho esters undergo comparable rearrangement, e.g., 1 to 2,14a
but the former are not efficient glycosyl donors.14b
(14) (a) Krog-Jensen, C.; Oscarson, S. Carbohydr. Res. 1998, 308 287-
296. (b) Bernlind, C.; Oscarson, S. Carbohydr. Res. 1997, 297, 251-260.
(15) For a convenient summary, see: Bochkov, A. F.; Zaikov, G. E.
Chemistry of the O-Glycosidic Bond; Pergamon Press: Oxford, U.K., 1979;
Chapter 2.
(16) By two steps involving conversion to the glycosyl bromide,11
followed by treatment with lutidine17 in the usual way.
(17) Roberts, C.; May, C. L.; Fraser-Reid, B. Carbohydr. Lett. 1994, 1,
89-93.
a Reaction conditions: (i) 3, NIS (1.3 equiv), TBDMSOTf (cat.),
CH2Cl2, 0 °C, 20 min.
(18) Jia, Z. J.; Olsson, L.; Fraser-Reid, B. J. Chem. Soc., Perkin Trans.
1 1998, 631-632.
(19) Anilkumar, G.; Jia, Z, J.; Kraehmer, R.; Fraser-Reid, B. J. Chem.
Soc., Perkin Trans. 1 1999, 3591-3596.
(20) Ferguson, M. A. J.; Brimacombe, J. S.; Brown, J. R.; Crossman,
A.; Diz, A.; Field, R. A.; Guther, M. L. S.; Milne, K. G.; Sharma, D. K.;
Smith, T. K. Biochim. Biophys. Acta 1999, 1455, 327-340. Gerold, P.;
Eckert, V.; Schwarz, R. T. Trends Glycosci. Glycotechnol. 1996, 8, 265-
277.
(21) Chatterjee, D.; Khoo, K.-H. Glycobiology 1998, 8, 113-120. Besra,
G. S.; Morehouse, C. B.; Rittner, C. M.; Waechter, C. J.; Brennan, P. J. J.
Biol. Chem. 1997, 272, 18460-18466. Nigou, J.; Gilleron, M.; Puzo.; G.
Biochem. J. 1999, 337, 453-460.
(22) The diol (∼0.092 mmol) and glycosyl donor (∼0.119 mmol) were
dissolved in a small quantity of toluene, azeotroped to dryness, and then
dissolved in CH2Cl2 (2 mL) at 0 °C under an argon atmosphere.
N-Iodosuccinimide (0.119 mmol) was added to the solution, and after stirring
for 3 min, TDBMSOTf (0.027 mmol) was added. The reaction was quenched
after 20 minutes with 10% aqueous sodium thiosulphate and saturated
aqueous sodium bicarbonate, extracted with CH2Cl2, and worked up in the
usual way.
of C6-glycosidation, 9a and 9b, were the only pseudo-
disaccharides obtained in 76 and 72% yields, respectively.
To demonstrate that these observations were not confined
to inositols, we established that the mannoside diol 10
displayed comparable selectivities with both donors (Scheme
4). Thus, reaction with NPG 4b gave 11 as the major product
(69%) along with minor isomeric products, while with NPOE
5b the only isolable disaccharide was 12. Similar equatorial
selectivities were also found for reaction of 10 with the gluco
and galacto ortho esters 8a and 8b.
Rationalization of the results in Schemes 2, 3, and 4 must
await further investigation, but the coincidence of the paired
selectivities RCOX/NPOE versus ArCH2X/NPG is an obvi-
(23) â-Anomers were detected in 5-10% yield with 2-O-benzylated
NPGs.
2588
Org. Lett., Vol. 2, No. 17, 2000

1.3 equiv of each type of donor. The results in Scheme 6
show that a single trisaccharide, 17 or 18, was obtained as
Scheme 4a
Scheme 6a
a Reaction conditions: (i) 4b (1.3 equiv), NIS (1.3 equiv),
TBDMSOTf (cat.), CH2Cl2, rt, 20 min, 66%; (ii) 5b (1.3 equiv),
NIS (1.3 equiv), TBDMSOTf (cat.), CH2Cl2, 0 °C, 20 min, 69%.
a Reaction conditions: (i) NIS (2.6 equiv), TBDMSOTf (cat.),
CH2Cl2, 0 °C to rt, 1 h, 79% (1:1), (ii) 4a (1.3 equiv), NIS (1.3
equiv), TBDMSOTf (cat.), CH2Cl2, rt, 1 h, 14%; (iii) NIS (2.6
equiv), TBDMSOTf (cat.), CH2Cl2, 0 °C to rt, 1 h, 93% (∼1.5:1);
(ii) 4b (1.3 equiv), NIS (1.3 equiv), TBDMSOTf (cat.), CH2Cl2,
rt, 1 h, 36%.
ous starting point. The corresponding key reacting entities
are the tetrahedral intermediate 13/trioxolenium ion 14 versus
benzylic carbocation 15/oxocarbenium ion 16. In terms of
charge delocalization, 13 and 14 may be considered diffuse
and 15 and 16 compact.26,27
In this regard, 2a is an NPG-but the C2-O-acyl group
permits formation of the trioxolenium ion 14, and it should
show the same selectivity as the NPOE. Indeed, reaction of
the C2-O-benzoyl NPG obtained from 5a, led to the
equatorial glycoside 7b as the only product in somewhat
lower yield (58%).
the major product in each case. Notably, the minor product
was disaccharide 7c or 12, which arises from glycosylation
with the NPOE rather than the NPG.
Thus, although rationalization for these mutual selectivi-
ties, and the implications of the diffuse versus compact
concept, must await further experimentation, the advantage
is apparent from the one-pot, site-selective, double-glycosi-
dation leading to 17, the core of the lipoarabinomannan
antigen of Mycobacterium tuberculosis.20
For challenging evaluations of the summary in Scheme
5, the diol acceptors, 3 or 10, were separately presented with
Scheme 5
Supporting Information Available: Experimental details.
This information is available free of charge via the Internet
at http://pubs.acs.org.
OL0001214
(24) In a typical proof of regioselectivity, the product was acylated and
the downshifted proton analyzed for two large (e.g., 6) or two small (e.g.,
7) couplings.
(25) Allen, J. G.; Fraser-Reid, B. J. Am. Chem. Soc. 1999, 121, 468-
469.
(26) SN2- and SN1-like27 are alternatives for diffuse and compact, but
the former terms have other mechanistic connotations that may be
inappropriate in the present context. HARD and SOFT are also possibilities,
but which is which?
(27) Angyal, S. J.; Tate, M. E. J. Chem. Soc. 1965, 6964-6951.
Org. Lett., Vol. 2, No. 17, 2000
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