A Suzuki-Miyaura coupling mediated deprotection as key to the synthesis of a fully lipidated malarial GPI disaccharide

Article abstract of DOI:10.1039/b407324j

Ligandless palladium-catalyzed Suzuki-Miyaura coupling converted an inert p-bromobenzyl ether to a DDQ-labile p-(3,4-dimethoxyphenyl) benzyl ether in the presence of azide functionality and this strategy serves as a key step for the convergent synthesis of a fully lipidated malaria GPI disaccharide.

Full text of DOI:10.1039/b407324j

A Suzuki–Miyaura coupling mediated deprotection as key to the
synthesis of a fully lipidated malarial GPI disaccharide†
Xinyu Liu and Peter H. Seeberger*
Laboratorium für Organische Chemie, ETH Zürich, 8093 Zürich, Switzerland.
E-mail: seeberger@org.chem.ethz.ch; Fax: +41-1-633-1235
Received (in Cambridge, UK) 14th May 2004, Accepted 9th June 2004
First published as an Advance Article on the web 9th July 2004
Ligandless palladium-catalyzed Suzuki–Miyaura coupling con-
verted an inert p-bromobenzyl ether to a DDQ-labile p-
(3,4-dimethoxyphenyl) benzyl ether in the presence of azide
functionality and this strategy serves as a key step for the
convergent synthesis of a fully lipidated malaria GPI disac-
charide.
(eqn. (1)). The azide group in 1 most likely poisoned the phosphine
ligand essential for the Pd-catalyzed amination, and the harsh basic
conditions isomerized the allyl group, which was readily removed
by SnCl4.
(1)
Glycosylphosphatidylinositols (GPIs) are a class of glycolipids that
link proteins to cell membranes. In addition to this simple
anchoring function GPIs trigger various biological events inside the
cell.1 We have recently identified a GPI as the dominant pro-
inflammatory toxin of Plasmodium falciparum origin.2 A synthetic
GPI glycan conjugated to a carrier protein served as an effective
anti-toxin malaria vaccine in a rodent model. The total synthesis of
defined malarial GPI is essential for detailed investigations into the
role of GPIs in malarial pathogenesis and signaling mechanisms.
Diligent work on the structural elucidation of the malarial GPI by
several groups3 has yielded a proposed consensus structure (Fig. 1)
although the exact nature of the lipid portions remains elusive. To
establish the exact structure of the malarial GPI, the synthesis of a
series of GPI glycans containing a variety of lipids will be required.
To introduce a variety of lipid structures on inositol at the final
stage of the synthesis, the assembly of a hexasaccharide glycan
backbone with three orthogonal protecting groups is essential. No
such approach has been reported.4 Herein, we describe the
realization of a synthetic strategy to access lipidated GPIs and its
application to the transformation of key intermediate 1 to a fully
lipidated malarial GPI disaccharide.
In a previous synthesis5 we have demonstrated that triisopro-
pylsilyl (TIPS) and allyl groups serve as reliable protecting groups
for the two phosphorylation sites in the penultimate mannose and
on inositol. One additional protecting group on the C2 hydroxyl on
inositol will be required. Conditions used during the assembly of
the glycan demand the exclusion of base-sensitive esters, acid-
sensitive ethers, and silyl groups. Mindful of these restrictions, we
envisioned that the acid- and base-stable p-bromobenzyl (PBB)
group would be suitable. The PBB group can be readily removed by
conversion to an acid-labile p-aminobenzyl group via a Pd-
mediated amination reaction.6 Disaccharide 17 served as target in
evaluating this approach on the a-linked glucosamine-inositol core
of the malarial GPI. The attempted removal of the PBB group by
catalytic amination6 failed to afford the desired disaccharide.
Instead, the allyl group was removed cleanly to give disaccharide 2
Faced with the challenge of finding a suitable protecting group
ensemble we designed another avenue to remove the PBB group.
Substituted benzyl ethers, such as p-methoxybenzyl (PMB) ether,
are often more labile toward acids and oxidants than benzyl ether.8
We envisioned that these reactivities would be retained through p-
conjugation in a hetero-substituted para-arylbenzyl ether. Surpris-
ingly, no such benzyl ether had been utilized previously.9 PBB
ethers should be converted to the more labile, substituted para-
arylbenzyl ethers via a Pd-catalyzed Suzuki–Miyaura coupling
without using phosphine ligands and be subsequently removed by
acids or oxidants (eqn. (2)). This ligandless approach would
circumvent any problems brought about by azide poisoning of
phosphine ligands.
(2)
Among the host of procedures for the ligandless Suzuki–Miyaura
coupling,10 the mild conditions reported by Gong et al.,10d
involving catalytic amounts of Pd(II) acetate and tetrabutyl
ammonium bromide in ethanol open to air was particularly
appealing. After the original procedure did not yield reproducible
results in our hands, the exclusion of air from the reaction media
resulted in complete conversion and high coupling yields. A screen
of different coupling partners found 3,4-dimethoxyboronic acid to
be ideal since the resulting p-(3,4-dimethoxyphenyl)benzyl
(DMPBn) ether could be cleaved by DDQ.11 Thus, PBB-protected
galactose 3a was transformed to DMPBn-protected 4a via the
ligandless Suzuki–Miyaura coupling in 92% yield. Treatment of 4a
with DDQ yielded deprotected 5a (85%, eqn. (3)).
(3)
With the optimized protocol in hand, the compatibility of the
newly developed strategy for the removal of the PBB group was
examined with other commonly used modes of protection using
substrates 3b–3e (Table 1). The ligandless coupling approach
worked very well with substrates containing azides, silyl ethers,
allyl groups, esters and glycals that remained intact during the
coupling and DDQ deprotection step. The coupling yields ranged
from 63% to 93% and DDQ deprotection was high yielding in all
cases.
While examining the reactivity of the DMPBn ether toward
oxidants and acids, we observed that DMPBn is as labile as PMB
when treated with DDQ, however, much more resistant to acids.
This finding suggested that DMPBn alone could also serve as an
effective protecting group in organic transformations. Thus,
DMPBnBr 6 was synthesized from p-bromobenzyl alcohol (eqn.
Fig. 1 Proposed GPI structure of P. falciparum.
† Electronic supplementary information (ESI) available: General informa-
tion and procedures (S1–S13) and copies of NMR spectra (S14–S54). See
http://www.rsc.org/suppdata/cc/b4/b407324j/
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C h e m . C o m m u n . , 2 0 0 4 , 1 7 0 8 – 1 7 0 9
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

In conclusion, we achieved the first synthesis of a fully lipidated
malarial GPI disaccharide based on a new protecting group strategy
involving substituted benzyl ethers. We demonstrated a new
method to utilize p-bromobenzyl ethers as protecting groups. The
chemically stable PBB group was effectively converted to a DDQ-
labile p-(3,4-dimethoxyphenyl)benzyl ether using a ligandless Pd-
catalyzed Suzuki–Miyaura coupling reaction. This protecting
group served as a key for the access to the lipidated malarial GPI
disaccharide. This study reports for the first time the use of p-
(hetero-substituted phenyl)benzyl ethers as effective protection for
hydroxyl groups. The reactivity of such groups can be tuned by the
substitution patterns on the aryl rings and should find wide
application in the synthesis of complex molecules beyond carbo-
hydrates.
Table 1 Functional group compatibility for PBB removala
3b
3c
3d
3e
4b (89%)
5b (86%)
4c (93%)
5c (85%)
4d (63%)
5d (88%)
4e (90%)
5e (83%)
This research was supported by GlaxoSmithKline (Scholar
Award to P.H.S.), the Alfred P. Sloan Foundation (Fellowship to
P.H.S.), Merck (Academic Development Award to P.H.S.) and
ETH Zürich. We appreciate the preliminary studies on disaccharide
1 by Dr. R. L. Soucy and Dr. Y.-U. Kwon.
a Reagents and conditions: (i) 3,4-dimethoxyphenylboronic acid (1.2
equiv.), Pd(OAc)2 (0.05 equiv.), Bu4NBr (0.1 equiv.), K3PO4 (3 equiv.),
reagent grade ethanol, r.t. 2–3 h. (ii) DDQ (3 equiv.), CH2Cl2:H2O (10:1),
r.t. 3h. Number in parentheses represents isolated yield.
(4)). The C6 hydroxyl group of glycal 7 was readily protected with
DMPBn group and the C-4 hydroxyl group in 8 was liberated
selectively from the PMB group using catalytic amounts of ZrCl4 in
82% yield (eqn. (5)).12
Notes and references
1 For reviews on GPIs: (a) H. Ikezawa, Bio. Pharm. Bull., 2002, 25, 409;
(b) A. S. Campbell, in Glycophosphatidylinositols, ed. B. Fraser-Reid,
K. Tatsuta and J. Thiem, Glycoscience: Chemistry and Biology Vol. 2,
Springer, Heildelberg, 2001, p. 1696; (c) M. McConville and M. A. J.
Ferguson, Biochem. J., 1993, 294, 305.
(4)
2 L. Schofield, M. C. Hewitt, K. Evans, M.-A. Slomos and P. H.
Seeberger, Nature, 2002, 418, 785.
3 (a) P. Gerold, L. Schofield, M. J. Blackan, A. A. Holder and R. T.
Schwarz, Mol. Biochem. Parasitol., 1996, 75, 131; (b) R. S. Naik, O. H.
Branch, A. S. Woods, M. Vijaykumar, D. J. Perkins, B. L. Nahlen, A. A.
Lai, R. J. Cotter, C. E. Costello, C. F. Ockenhouse, E. A. Davidson and
D. C. Gowda, J. Exp. Med., 2000, 192, 1563.
4 Guo et al. reported the total synthesis of a GPI of sperm CD 52 relying
on the early stage installation of lipid side chains. J. Xue and Z. Guo, J.
Am. Chem. Soc., 2003, 125, 16334.
5 P. H. Seeberger, R.-L. Soucy, Y.-U. Kwon, D. A. Snyder and T.
Kanemitsu, Chem. Commun., 2004, DOI: 10.1039/b407323a, preceding
paper.
6 O. J. Plante, S. L. Buchwald and P. H. Seeberger, J. Am. Chem. Soc.,
2000, 122, 7148.
7 The preparation of 1 is described in the supporting information†.
8 T. W. Green and P. G. M. Wuts, Protective Groups in Organic
Synthesis, John Wiley & Sons, New York, 1999, pp. 86–93.
9 p-Phenylbenzyl ethers have been studied as protecting groups.(a) M. H.
Park, R. Takeda and K. Nakanishi, Tetrahedron Lett., 1987, 28, 3823;
(b) V. Bollitt, C. Mioskowski, R. O. Kollah, S. Manna, D. Rajapaksa and
J. R. Falck, J. Am. Chem. Soc., 1991, 113, 6320.
(5)
Following the methodological advances, we applied the newly
developed protecting group strategy to the functionalization of
disaccharide 1. Coupling of 1 with 3,4-dimethoxyphenylboronic
acid using the ligandless protocol readily converted the PBB group
to DMPBn, that was readily cleaved by DDQ to afford 10 in 65%
yield over 2 steps. Palmitoylation followed by deallylation
furnished 11 without acyl migration. Successive phosphorylation
and oxidation fashioned fully protected disaccharide 13. Global
deprotection with Pearlman’s catalyst gave rise to fully lipidated
disaccharide 14 in quantitative yield.13
10 (a) B. M. Novak and T. I. Wallow, J. Org. Chem., 1994, 59, 5034; (b)
D. Badone, M. Baroni, R. Cardamone, A. Ielmini and U. Guzzi, J. Org.
Chem., 1997, 62, 7170; (c) N. E. Leadbeater and M. Marco, Org. Lett.,
2002, 4, 2973; (d) Y. Deng, L. Gong, A. Mi, H. Liu and Y. Jiang,
Synthesis, 2003, 337.
11 Other cross-coupling partners (4-methoxy and 4-amino phenylboronic
acid) were also examined. They were found to be not as effectively
removed as 3,4-dimethoxy phenylboronic acid.
12 G. V. M. Sharma, O. G. Reddy and P. R. Krishna, J. Org. Chem., 2003,
68, 4574.
13 The homogeneity of disaccharide 14 was supproted by 31P NMR and
high resolution MALDI-MS. (For details, see supplementary informa-
tion†).
Scheme 1 Synthesis of fully lipidated disaccharide 14. (i) 3,4-dimethox-
yphenylboronic acid, 5 mol% Pd(OAc)2, 10 mol% Bu4NBr, K3PO4, EtOH;
(ii) DDQ, CH2Cl2:H2O (10:1), 65% 2 steps; (iii) C15H31COOH, DMAP,
DCC, 87%; (iv) PdCl2, NaOAc, HOAc, H2O, 69%; (v) 12, PivCl, pyridine;
(vi) I2 in pyridine/H2O, 90% 2 steps; (vii) Pd(OH)2, H2, CHCl3:MeOH:H2O
(3:3:1), quant.
C h e m . C o m m u n . , 2 0 0 4 , 1 7 0 8 – 1 7 0 9
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