The antituberculosis, antitumor, multibranched dodecafuranoarabinan of Mycobacterium species has been assembled from a single n-pentenylfuranoside source

Article abstract of DOI:10.1039/b413694b

An n-pentenyl furanosyl-1,2-orthoester can function as a donor or be rearranged leading to an n-pentenyl furanoside acceptor which is glycosylated by its progenitor, regioselectively or doubly, thereby enabling rapid fabrication of a multibranched dodecas

Full text of DOI:10.1039/b413694b

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The antituberculosis, antitumor, multibranched dodecafuranoarabinan
of Mycobacterium species has been assembled from a single
n-pentenylfuranoside source{
Jun Lu and Bert Fraser-Reid*
Received (in Corvallis, OR, USA) 7th September 2004, Accepted 9th November 2004
First published as an Advance Article on the web 5th January 2005
DOI: 10.1039/b413694b
well established pyranosyl counterparts. However, in view of the
higher reactivity of furanose systems,9 this technology transfer may
not be trivial as, indeed, we have recently learned.
An n-pentenyl furanosyl-1,2-orthoester can function as a donor
or be rearranged leading to an n-pentenyl furanoside acceptor
which is glycosylated by its progenitor, regioselectively or
doubly, thereby enabling rapid fabrication of a multibranched
dodecasaccharide, known to possess a wide variety of biological
interactions.
The arabinan array 1 features a repeated branched motif,
represented by the ‘‘bold’’ units which require a 3,5-diol retron,
while the ‘‘other’’ units could conceivably be catenated from a
C5-OH free donor. Thus, the entire arabinan component of 1
could be derived ultimately from the readily prepared n-pentenyl
orthoester (NPOE) stock 2a.10
The lipoarabinomannan (LAM) glycolipid of Mycobacterium
tuberculosis,1 being the seat of the organism’s baffling drug
resistant capability,1,2 has long been the focus of intense biological
scrutiny.3 Separate and equally intense interest is being paid to the
immunomodulatory arabinomannan, code-named Z-100,4 isolated
from the aoyama B strain of the parasite. Z-100 displays potent
activity against (a) tumor growth,5 (b) opportunistic infections,6
herpes,7 and also potentiates antiretrovirals for many HIV
variants.8 Chemists wishing to assist in deconstructing the biologi-
cal maze presented by these complex lipoarabinomannans, must
face the synthetic challenges posed by the unique arabinan array,
rendered partially in structure 1 (Scheme 1). Knowledge about the
furanosyl donors needed to cope with these challenges is sparse,
and it is therefore reasonable to try and import methodology from
Two retrosynthetic plans for 1, with different levels of
convergence, are implied by the dissections A and B (Scheme 1).
In option A, a nona-arabinan donor would be delivered to the
primary-OH of a tri-arabinan acceptor, while in option B two
identical tetra-arabinan donors would be delivered simultaneously
in double glycosidation of a tetra-arabino acceptor diol.
In order to make sure that the double glycosidation required by
option B was feasible, acceptor 3b was prepared from the NPOE
2a10 by routine steps via intermediates 2b and 2c, followed by
rearrangement to 3a and desilylation (Scheme 2). Coupling of 3b
and NPOE 2d was chemoselectively executed under the agency of
ytterbium triflate (YbOTf)3 and N-iodosuccinimide (NIS)11 to give
disaccharide 4a in 69% yield. Removal of the chloroacetate esters
with thiourea then gave diol 4b which underwent double
glycosidation by the dibenzylated orthoester 2e, again using
Yb(OTf)3/NIS, to give the branched NPG 5a in 67% yield.
Scheme 1 Reagents and conditions: i. NaOMe, rt, 2 h, 75%; ii. a)
TBDPSCl, Et3N, DMAP, 12 h, b) BnBr, NaH, DMF, 84%; iii. ClAc2O,
CH2Cl2, 210 uC, 73%; iv. BnBr, NaH, DMF, 87%.
Scheme 2 Reagents and conditions: i. TBDMSOTf; ii. TBAF, THF, rt,
82%; iii. NIS, Yb(OTf)3, 0 uC, 30 min; iv. thiourea, THF, reflux, 5 h, 61%;
v. NIS, CH3CN–H2O, rt, 74%; vi. Cl3CCN, DBU, CH2Cl2, 0 uC, 70%.
{ Electronic supplementary information (ESI) available: experimental
section. See http://www.rsc.org/suppdata/cc/b4/b413694b/
*dglucose@aol.com
862 | Chem. Commun., 2005, 862–864
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That the pentenyloxy residue at the reducing end of donors 6a–c
was not involved in these aberrant reactions, was established by
showing that the same result was obtained when NIS was omitted
from the reaction medium. The implication that a simple acid
catalyzed furanosyl transfer was in play was confirmed when the
methyl furanoside 9 was also coupled with 7 under the agency of
TESOTf to give 8b (Scheme 3).
The results in Scheme 3 raise several mechanistic questions
which will have to be probed; however the immediate message is
that an oligomeric n-pentenyl furanoside such as 5a or 6a, unlike
its n-pentenyl pyranoside counterparts,12 could not be used as a
donor to effect the connections represented by options A or B.
However, n-pentenyl glycosides can be readily converted into
trichloroacetimidates13 which can be activated by the mild Lewis
salt Yb(OTf)3.14 Accordingly, the branched n-pentenyl tetrasac-
charide 5a was subjected to oxidative hydrolysis with NIS/H2O/
CH3CN,15 and the resulting furanose, 5b, was converted into the
trichloroacetimidate 5c using established procedures.16 By way of
confirmation, the 13C NMR spectrum of 5c showed well resolved
signals for four anomeric carbons (106.31, 106.13, 105.42, 103.90)
and four carbonyl carbons (165.57, 165.46, 165.37, 165.29).
Option B in Scheme 1 offers the greater level of convergence,
and hence was pursued. The linear array was assembled with a
view to biological evaluation of the entire arabinan construct.
Thus, the protected ethanolamine 1017 was used as the first
acceptor for an iterative sequence with NPOE donor 2c, involving
couple-deprotect repeats, leading to 11, 12 and finally acceptor 13
(Scheme 4). The tetrasaccharide diol 14 was then obtained by
reaction of 13 with the donor 2d followed by dechloroacetylation.
Scheme 3 Reagents and conditions: i. NIS, TESOTf, CH2Cl2, 0 uC; ii.
TESOTf, CH2Cl2, 0 uC, 30 min, 20–30%.
Both disconnections A and B of 1 would entail coupling of an
n-pentenyl furanosidyl donor to the acceptor in question and we
decided to probe this possibility by coupling recently synthesized10
tetrasaccharide 6a to the glucoside acceptor 7 under the agency of
TESOTf/NIS (Scheme 3). To our great surprise, the major product
turned out to be disaccharide 8a in which the non-reducing moiety
of 6a had become attached to the acceptor. The same result was
obtained when the tri- and di-saccharide analogs 6b and 6c were
presented to 7.
Scheme 4 Reagents and conditions: i. NIS, Yb(OTf)3, CH2Cl2, 0 uC, 30 min; ii. TBAF, THF, 6 h; iii. thiourea, THF–EtOH, reflux, 6 h; iv. TBDMSOTf,
Et2O, rt, 30 min; v. NaOMe, MeOH.
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2 For some pertinent citations see: D. C. Alexander, J. R. W. Jones,
T. Tan, J. M. Chen and J. Liu, J. Biol. Chem., 2004, 274, 18824–18833
and references cited therein.
3 P. J. Brennan, Tuberculosis, 2003, 1; B. Hamasur, M. Haile,
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Compound 14 showed clearly resolved signals for four anomeric
carbons (106.31, 106.25, 106.19, 105.34) and four carbonyl carbons
(166.63, 166.66, 166.35, 166.29).
Diol 14 was treated with 3 equivalents of trichloroacetimidate
donor 5c. The presence of 15a was evident from MALDI
evaluation of the material (calcd. 4198.5; found 4225.7 M +
Na+). However, although the material appeared as a single
substance on TLC, treatment with sodium methoxide gave two
chromatographically separable compounds that were isolated in
2 : 1 ratio. Their masses, 2974.6 (M + Na+) and 1995.3 (M + Na+),
were consistent with the dodeca- and octa-saccharides 15b and
16b. The 13C NMR spectra of their anomeric regions were not
resolved; but confirmation came from COSY analyses which
showed thirteen benzyl groups for the former, and nine for the
latter. Complete assignments will be reported in the full paper.
We are grateful to the National Science Foundation for support.
We thank Dr George Dubay, Director of Instrument Operations
in the Department of Chemistry, Duke University for the mass
spectroscopy and MALDI measurements, and Professor Klaus
Bock and Dr Bent Petersen of Carlsberg Laboratory, Denmark
7 M. Kobayashi, D. N. Herndon, R. B. Pollard and F. Suzuki, Immunol.
Lett., 1994, 40, 199–205.
8 J. S. James, AIDS Treatment News, Feb. 23, 2001.
1
for obtaining the H, 13C NMR and COSY spectra of 15b and
16b.
9 Monosaccharides: Their Chemistry and Their Roles in Natural Products,
P. M. Collins, R. J. Ferrier, John Wiley & Sons, New York, 1995.
10 J. Lu and B. Fraser-Reid, Org. Lett., 2004, 6, 3051–3054.
11 K. N. Jayaprakash, K. V. Radhakrishnan and B. Fraser-Reid,
Tetrahedron Lett., 2002, 43, 6953; K. N. Jayaprakash and B. Fraser-
Reid, Synlett, 2004, 301.
Jun Lu and Bert Fraser-Reid*
Natural Products and Glycotechnology Research Institute, Inc., 4118
Swarthmore Road, Durham, NC 27707, USA.
E-mail: dglucose@aol.com
12 See for example: R. Madsen, U. E. Udodong, C. Roberts,
D. R. Mootoo, P. Konradsson and B. Fraser-Reid, J. Am. Chem.
Soc., 1995, 117, 1554–1565; J. R. Merritt, E. Naisang and B. Fraser-
Reid, J. Org. Chem., 1994, 59, 4443–4449.
13 K. N. Jayaprakash, Org. Lett., in press.
14 M. Adinolfi, A. Iadonisi and M. Schiattarella, Tetrahedron Lett., 2003,
44, 6479.
15 B. Fraser-Reid, U. E. Udodong, Z. Wu, H. Ottoson, R. Merritt,
C. S. Rao, C. Roberts and R. Madsen, Synlett, 1992, 927–942.
16 T. G. Mayer and R. R. Schmidt, Eur. J. Org. Chem., 1999, 1153.
17 A. Campbell and B. Fraser-Reid, Bioorg. Med. Chem., 1994, 2,
1209–1219.
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864 | Chem. Commun., 2005, 862–864
This journal is ß The Royal Society of Chemistry 2005