Preparation, properties, and applications of n-pentenyl arabinofuranosyl donors

Article abstract of DOI:10.1021/ol0490680

(Chemical Equation Presented) The development of n-pentenyl furanosyl donors has been tested using arabinose as a model. The readily prepared ortho ester (NPOE) is converted into disarmed (NPG_AC) and thence armed (NPG_ALK) n-pentenyl

Full text of DOI:10.1021/ol0490680

ORGANIC
LETTERS
2004
Vol. 6, No. 18
3051-3054
Preparation, Properties, and
Applications of n-Pentenyl
Arabinofuranosyl Donors†
Jun Lu and Bert Fraser-Reid*
Natural Products and Glycotechnology Research Institute, Inc.,‡
4118 Swarthmore Road, Durham, North Carolina 27707
dglucose@aol.com
Received May 20, 2004
ABSTRACT
The development of n-pentenyl furanosyl donors has been tested using arabinose as a model. The readily prepared ortho ester (NPOE) is
converted into disarmed (NPG ) and thence armed (NPGALK) n-pentenyl arabinofuranosides. The reactivities of these furanosyl donors and
AC
pyranosyl counterparts have been assessed by allowing pairs of both to compete for an acceptor. For the NPOE and armed (NPGALK) pairs,
coupling products were obtained from donors, whereas for the disarmed (NPG ) pair, only the arabinofurano coupled product was obtained.
AC
To probe their synthetic utility, the NPOE was shown to be the only precursor needed to prepare an r-1,5-linked arabinan segment of the
complex lipoarabinomannan cell wall array of Mycobacterium tuberculosis.
In the past, comparatively little attention has been paid to
glycosyl donors for furanosides1 undoubtedly because of the
greater abundance of pyranosidic structures in nature.
However, the recent discovery of furanoside components in
a wide range natural products of biological importance such
as glycosylphosphatidyl inositol,2 helminthosporium toxins,3
and most abundantly as mycobacterial cell wall components4
suggests that greater effort will be directed at oligofuranoside
synthesis now that mild, modern isolation methods are
allowing such molecules to be discovered with ever increas-
ing frequency.
In an early attempt to apply n-pentenyl methodology to
furanoside coupling, Plusquellec and co-workers,5 and
subsequently Arasappan and Fraser-Reid,6 relied on the well-
established technique of Fischer glycosidation,7 i.e., aldose
f furanoside f pyranoside, which can be interrupted at
optimal furanoside accumulation. By this protocol, n-pentenyl
† We dedicate this paper to the memory of Professor Christian Pederson.
‡ An independent, nonprofit research facility with laboratories at Centen-
nial Campus (North Carolina State University), Raleigh, NC.
(1) For a recent summary of developments in furanosyl donors, see:
Lowary, T. L. In Glycoscience: Chemistry and Biology; Fraser-Reid, B.,
Tatsuta, K., Thiem, J., Eds.; Springer: Heildelberg, 2001; Vol. 3, p 1696.
(2) Previato, J. O.; Gorin, P. A.; Mazurek, M.; Xavier, M. T.; Fournet,
B.; Wieruszesk, J. M.; Mendoca-Previato, L. J. Biol. Chem. 1990, 265,
2518. Lederkremer, R. M.; Lima, C.; Ramirez, M. I.; Ferguson, M. A. J.;
Homans, S. W.; Thomas-Oates, J. E. J. Biol. Chem. 1991 265, 19611.
(3) Macho, V.; Acklin, W.; Hildenbrand, C.; Weibel, F.; Arigoni, D.
Experentia 1983, 39, 343.
(4) See for example: Kordulakova, J.; Gilleron, M.; Puzo, G.; Brennan,
P. J.; Gicquel, B.; Mikusova, K.; Jackson, M. J. Biol. Chem. 2003, 278,
36285. Patterson, J. H.; Waller, R. F.; Jeevarajan, D.; Billman-Jacobs, H.;
McConville, M. J. Biochem. J. 2003, 372, 77. Nigou, J.; Gilleron. M.; Puzo,
G. Biochimie 2003, 85, 153. Schaeffer, M. L.; Khoo, K. H.; Besra, G. S.;
Chatterjee, D.; Brennan, P. J.; Belisle, J. T.; Inamine, J. M. J. Biol. Chem.
1999, 274, 31625.
(5) Ferrieres, V.; Bertho, J. N.; Plusquellec, D. Tetrahedron Lett. 1995,
36, 2749.
(6) Arasappan, A.; Fraser-Reid, B. Tetrahedron Lett. 1995, 36, 7967.
(7) Capon, B. Chem. ReV. 1969, 69, 407. Smirnyagin, V.; Bishop, C. T.
Can. J. Chem. 1968, 46, 3085 and references therein.
10.1021/ol0490680 CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/04/2004

Mereyala, Hotha, and Gurjar,9 in an experiment reminis-
cent of an earlier van Boom strategy,10 used an n-pentenyl
furanoside bearing a free-OH as an acceptor for a thiofura-
noside donor. The resulting disaccharide, itself an n-pentenyl
glycoside, could then function as a donor for further
elaboration.
Scheme 1
Despite the foregoing successes, we were interested in
developing alternative procedures, because not all aldoses
are as obliging as galactose toward furanoside formation in
Fischer glycosidations.11 We have therefore been trying to
adapt recent innovations12,13 with n-pentenyl ortho ester
donors, 2, to furanoses. In the case of pyranosyl systems,
the NPOE 2 is obtainable in three steps from the aldose, via
the glycosyl bromide, 1.12 As is typical of such glycosyl ortho
esters,14 mild treatment with acid effects rearrangement to
the disarmed n-pentenyl glycoside (NPGAC), 3, from which
the armed counterpart (NPGALK), 4, is obtained routinely.12
Donors 2 and 3 are capable of furnishing the same
coupling product(s). However, a pyranose NPOE (a) is
infinitely more reactive than the NPGAC derived from it and
(b) usually couples with exclusive stereoselectivity.12 Fur-
thermore, recent reports from our laboratory on the use of
Lewis acid salts to generate iodonium ions from N-iodo-
succinimide (NIS) have shown that ytterbium triflate, Yb-
(OTf)3, is chemospecific for the NPOE, leaving disarmed
(NPGAC) and armed (NPGALK) donors untouched.15
Our transfer of NPOE technology to furanoses began with
the known arabinofuranosyl bromide 518 (Scheme 1b). (In
this connection, it is appropriate to note that Backinowsky
and co-workers16 have used 1,2-O-(1-cyanoethylidene) de-
rivatives of furanoses for glycosidations. These ortho ester-
like componds are excellent donors,17 although not as
galactofuranosides were obtained in good yield and shown
to be very good donors.5,6,8
Scheme 2. Competition of Pairs of Donors to Glycosidate Methyl 2,3,4-Tri-O-benzyl R,D-glucopyranoside, 9a
a Equivalent amounts of the pairs of donors and 1 equiv of the acceptor in CH2Cl2 were treated with NIS (1 equiv) and TESOTf at 0 °C
for 30 min.
3052
Org. Lett., Vol. 6, No. 18, 2004

versatile as NPOEs.) Upon treatment with 4-pentenol in
dichloromethane containing 2,6-lutidine and tetra-n-butyl-
ammonium iodide for 72 h, an inseparable mixture (3:1) of
products was obtained in 70% yield. The presence of two
ester carbonyl signals (13C NMR at 166.1 and 165.5 ppm)
along with an aromatic multiplet for 15 protons (i.e., three
phenyl rings in the 1H NMR spectrum between 7.34 and 8.06
ppm) was consistent with formation of the desired ortho ester
product 6a. Further support for this assignment came from
treatment with sodium methoxide at room temperature for 2
h, whereupon the definitive 13C NMR ester signals, noted
above, disappeared, and the aromatic proton multiplet was
reduced in intensity from 15 to 5, consistent with the loss of
two benzoyl groups leading to diol 6b. The di-O-benzyl ether
6c was then prepared.
Scheme 3
Compound 6c, upon treatment with tert-butyldiphenylsilyl
triflate (TBDPSOTf) in dichloromethane for 1 h, was
transformed into a single new product in 90% yield. Notably,
this treatment caused disappearance of a low-intensity peak
in the 75 MHz 13C NMR spectrum of 6c in CDCl3 at 122.6
ppm and appearance of a strong signal at 165.5, consistent
with the ortho ester to ester transformation, 6c f 7. Further
support for the structure of compound 7 came from the
benzoyl resonances in the 1H NMR spectrum in CDCl3 (2H
∼7.95 and 3H 7.49-7.67). The tri-O-benzyl analogue 8 was
obtained from 7 routinely.
With the furano series (Scheme 1b) in hand, comparisons
could be drawn with the pyranose counterparts. That fura-
noses are generally more reactive than pyranoses is well
established;19 however, it was of interest to see if these
reactivities would be amenable to substituent effects.
(8) Veenemen, G. H.; Notermans, S.; Hoogerhout, P.; van Boom, J. H.
Recl. TraV. Chim. Pays-Bas. 1989, 108, 344.
(9) Mereyala, H. B.; Hotha, S.; Gurjar, M. K. Chem. Commun. 1998,
685.
(10) Veeneman, G. H.; Van-Boom, J. H. Tetrahedron Lett. 1990, 31,
275.
(11) Green, J. W. AdV. Carbohydr. Chem. 1966, 21, 95.
(12) Mach, M.; Schlueter, U.; Mathew, F.; Fraser-Reid, B.; Hazen, K.
C. Tetrahedron 2002, 58, 7345-7354.
(13) Grimme, S.; Piacenza, M.; Mach, M.; Schlueter, U. Chem. Eur. J.
2003, 9, 4687-4692.
First, donors20 6c, 8, 10, and 12 were coupled separately
with methyl 2,3,4-tri-O-benzyl R,D-glucopyranoside, 9. The
Org. Lett., Vol. 6, No. 18, 2004
3053

resultant disaccharide products 13, 15, 14, and 16, respec-
tively, were characterized. Fortuitiously, all four were
sufficiently well resolved on TLC (hexane/EtOAc (4:1) Rf
) 0.34, 0.37, 0.35, and 0.29, respectively) to enable
preliminary identification.
reactivity, gave furanose and pyranose products 15 and 16,
respectively, in a 5:1 ratio (Scheme 2c).
An attractive context for probing for nuanced selectivities
of these n-pentenyl donors is the arabinan segment, 17, from
the lipoarabinomannan complex of complex from Mycobac-
terium tuberculosis.1,4 The diol 6b was silylated and benzy-
lated in sequence to obtain NPOE 6d, which was rearranged
with TBDPSOTf to NPG 18a (Scheme 3). Desilylation gave
acceptor 18b, which was then presented with 1.5-2.0 equiv
of NPOE 6d in order to optimize formation of the coupled
product 19a. Notably, for this exercise Yb(OTf)3 was used
to decompose NIS, because the residual NPOE, 6d, would
be conVerted into the NPG 18a and recoVered as such, since
Yb(OTf)3/NIS is chemospecific for NPOEs.15 This “byprod-
uct” would then be desilylated to obtain the initial acceptor,
18b, for use in future experiments.
The chemo and stereoselectiVe processes leading from 18
f 19 offered a simple strategy for arabinan assembly
involving desilylation/coupling iterations. This idea was
reduced to practice with the conversions 19 f 20 f 21
(Scheme 3). Being an NPG, the tetraarabinofuranoside 21
can now serve as a donor on the basis of earlier work in
our6 and other5,8 laboratories.
With this information in hand, we then allowed pairs of
donors in equimolar amounts (Scheme 2) to compete for 1
equiv of the glucoside acceptor in a reaction medium
containing NIS (1 equiv) and TESOTf (0.3 equiv) for 30
min, this time having been shown (TLC) to be adequate for
completion of all reactions. The products were identified by
the above-noted Rf values, and then they were isolated by
chromatography and matched with the authentic materials,
13, 14, 15, or 16, prepared in the prior experiments.
The product percentages in Scheme 2 indicate that
furanosyl donors are always preferred for coupling, but to
different extents. Thus, with the most reactive donors
(NPOEs), 6c and 10, the coupling products were 13 and 14
in a 3:1 ratio (Scheme 2a). With the least reactive (disarmed)
donors, 7 and 11, only furanose-coupled product 13 was
observed (Scheme 2b).
The armed donors 8 and 12, which are of intermediate
(14) See Bochkov, A. F.; Zaikov, G. E. Chemistry of the O-Glycosidic
Bond; Pergamon Press: Oxford, UK, 1979; Chapter 2.
(15) Jayakaprash, K. N.; Fraser-Reid, B. Synlett 2004, 301-305.
Jayaprakash, K. N.; Radhakrishnan, K. V.; Fraser-Reid, B. Tetrahedron
Lett. 2002, 43, 6955.
(16) Backinowsky, L. V.; Nepogod’ev, S. A.; Shashkov, A. S.; Kochet-
kov, N. K. Carbohydr. Res. 1985, 138, 41.
(17) Kochetkov, N. K.; Bochkov, A. F. Methods Carbohydr. Chem. 1972,
6, 480.
(18) Hatanaka, K.; Kuzuhara, H. J. Carbohydr. Chem. 1985, 4, 333.
(19) Monosaccharides: Their Chemistry and Their Roles in Natural
Products. Collins, P. M., Ferrier, R. J., Eds.; John Wiley & Sons: 1995,
New York.
Acknowledgment. We are grateful to the National
Science Foundation and the Human Frontier Science Program
Organization.
Supporting Information Available: Experimental details
for preparation and characterization of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(20) For donors 10-12, see ref 12 and references therein.
OL0490680
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