Studies toward the synthesis of inhibitors of mycobacterium tuberculosis cell-wall biosynthesis: The assembly of triazole-linked 1,6-a-D-oligomannosides via click CuAAC

Article abstract of DOI:10.1055/s-0029-1217751

A versatile synthesis of 1,6 - d-oligomannosides featuring the 1,4-disubstituted triazole ring as interglycosidic tether is presented via iterative copper(I)-catalyzed azide-alkyne cycloaddition. Free hydroxy hexamannoside and decamannoside featuring a ca

Full text of DOI:10.1055/s-0029-1217751

LETTER
2679
Studies Toward the Synthesis of Inhibitors of Mycobacterium tuberculosis
Cell-Wall Biosynthesis: The Assembly of Triazole-Linked
1,6-a-D-Oligomannosides via Click CuAAC
T
riazole-Linked 1,6-
a
-
a
D
-Oligoman
u
nosides ro Lo Conte,a Angela Chambery,b Alberto Marra,*a Alessandro Dondoni*a
a
b
Received 11 June 2009
OH
O
RO
Me
OH
O
Abstract: A versatile synthesis of 1,6-a-D-oligomannosides featur-
ing the 1,4-disubstituted triazole ring as interglycosidic tether is
presented via iterative copper(I)-catalyzed azide–alkyne cycloaddi-
tion. Free hydroxy hexamannoside and decamannoside featuring a
capping 6-deoxymannose fragment have been prepared and charac-
terized.
HO
HO
HO
HO
OH
H
O
N
N
O
O
HO
HO
N
n HO
OH
O
OH
OH
O
P
HO
HO
O
O
n
Key words: alkynes, azides, copper, cycloadditions, stereoselec-
tive synthesis
O
OR
HO
N
N
OR
N
OH
O
lipomannans (LM) n = 4–20
HO
HO
Among infectious diseases that were believed to be de-
feated in the last century, tuberculosis (TB) has reap-
peared in force1 and in its deadly partnership with HIV/
AIDS pandemic is presently a leading cause of mortality
in many parts of the world including Western countries.
The recrudescence of TB and the widespread antibiotic re-
sistance have strengthened the need for rapid develop-
ment of new antitubercolar drugs targeting essential
functions of its etiological agent, Mycobacterium tubercu-
losis. An ideal TB drug target is the biosynthesis of the
mycobacterial cell envelope. This is composed of various
glycophospholipids2 such as phosphatidylinositol manno-
sides (PIM)3 that in addition, being important in their own
right, may also be hyperglycosylated to form other wall
components such as lipomannans (LM) and lipoarabi-
nomannans (LAM).4,5 These glycolipids all contain a
common a-1,6-linked mannoside core as shown in LM
(Figure 1). To inhibit the construction of this highly man-
nosidic species promoted by the abundance of a-1,6-man-
nosyltransferases in mycobacteria, Watt and Williams
have prepared a series of 6-deoxy a-1,6-linked oligoman-
nosides up to tetramers.6 They suggested that deoxygen-
ation of the 6-position of the oligomannosyl chain should
prevent these compounds acting as substrates for the en-
1
OH
Figure 1 Structures of lipomannans (LM) and designed triazole-
tethered oligomannoses (1)
can participate in hydrogen bonding and dipole interac-
tions, thereby favoring molecular recognition processes
and improving solubility.9
To prepare mannose-triazole hybrids 1 we have devel-
oped a linear oligomerization strategy based on the click
Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC)10
for linking the mannose fragments. This new synthesis ap-
pears more practical than that recently reported from our
laboratory,7,11 as each cycle is constituted of two simple
and efficient operations, such as the CuAAC and the un-
masking of the ethynyl group in the newly formed oligo-
mer. For the execution of this program, the functionalized
new alkynyl mannoside building blocks 2–4 (Figure 2)
were prepared (see Supporting Information) while the
MOM-protected hydroxyethyl 6-azidomannoside
(Figure 2) was available in our laboratory from previous
5
work.7
zymes. Here we report a new approach to more complex With these compounds in hand, the stepwise oligomeriza-
and higher 6-deoxy 1,6-a-D-oligomannosides 1 featuring tion was commenced by the Cu(I)-catalyzed coupling of
a 1,4-disubstituted triazole ring as an interglycosidic
linker7 (Figure 1). High stability can be foreseen for these
oligomers owing to the resistance of anomeric carbon–
N3
N3
BnO
OBn
O
OBn
O
OBn
O
Me
carbon bond and triazole ring toward chemical and enzy-
BnO
BnO
BnO
BnO
BnO
matic degradation.8 On the other hand, the triazole ring
OMOM
R
2
3 R = TMS
4 R = C(OH)Me2
5
SYNLETT 2009, No. 16, pp 2679–2681
x
x
.x
x
.2
0
0
9
Advanced online publication: 04.09.2009
DOI: 10.1055/s-0029-1217751; Art ID: D15809ST
© Georg Thieme Verlag Stuttgart · New York
Figure 2 Building blocks for oligomannoside synthesis via CuAAC

2680
M. Lo Conte et al.
LETTER
OR1
O
ethynyl 6-deoxymannoside 2 with TMS-ethynyl 6-azido
mannoside 3.
Me
R1O
R1O
Following the coupling reaction, removal of the TMS
group by basic treatment afforded the dimannoside 6a dis-
playing a free ethynyl group (Scheme 1). Of note, the
CuAAC was completed after a short reaction time (15 min
under microwave irradiation) while desilylation required
one hour. Repetition of the cycloaddition–desilylation re-
action sequence over three more consecutive cycles af-
forded tri-, tetra-, and pentamannosides 6b–d. Isolated
yields of all oligomers prepared and their purity are pre-
sented in Scheme 1. Thus, from these data it appears that
each coupling product was substantially contaminated by
impurities. Very likely, partial desilylation of the major
product occurred in each cycle, thereby allowing the for-
mation of higher oligomers. Accordingly, the MALDI-
TOF spectrum of 6d revealed the presence of a hexaman-
noside. This problem led us to consider the use of 3-hy-
droxy-3-methylbutynyl 6-azidomannoside 4, a formal
adduct of acetone to ethynyl 6-azidomannoside,12 as a ro-
bust cycloaddition partner in the homologative process.
Conditions are known for the removal of acetone (deace-
tonation) and liberation of the ethynyl group.13 Thus, the
first cycle involved the Cu(I)-catalyzed cycloaddition of 2
with 4 and deacetonation to give the oligomer 6a. The
same reaction sequence was repeated over three more
consecutive cycles to give the oligomers 6b–d. All com-
pounds 6a–d resulting from this protocol were obtained in
excellent yields as well high purities (Scheme 1). Hence,
this approach employing 4 appeared to be more efficient
than that employing 3. This was mainly due to the high
stability of the 3-hydroxy-3-methylbutynyl group as
shown by the harsh conditions required (K2CO3 and 18-
crown-6 ether in refluxing toluene for 4–8 h) for deaceto-
nation of the individual oligomer formed in each cycle.
N
N
N
OR1
O
R1O
5, CuI, i-Pr2EtN, DMF
R1O
6d
4
MW, 80 °C, 15 min
N
N
N
OR1
O
R1O
R1O
OR2
8
9
R1 = Bn, R2 = CH2OMe (72%)
1. CF3CO2H, CH2Cl2, r.t., 3 h
2. BCl3, CH2Cl2, –60 to 0 °C, 2 h
3. Ac2O, Py, r.t., 16 h
R1 = R2 = Ac (63%)
NH3, MeOH, r.t., 18 h
10 R1 = R2 = H (99%)
Scheme 2
crude 10 that was isolated as the peracetylated derivative
9 (63% total yield). Then, the removal of the acetyl groups
(NH3 in MeOH) gave pure 10 in almost quantitative yield.
As cell-wall constituents of Mycobacterium tuberculosis
possess high oligomannose cores, in order to mimic more
closely such a structural feature, we set out to transform
6d into a decamannoside by coupling with the azide-func-
tionalized oligomer 11 (Scheme 3). This azide was pre-
pared by azidation of the corresponding alcohol whose
synthesis was reported earlier from our laboratory.14 Grat-
ifyingly the Cu(I)-catalyzed cycloaddition of these oligo-
mers took place with high efficiency to give the expected
higher oligomannose 12 in 93% isolated yield
(Scheme 3). Acid hydrolysis of this compound cleaved
the acetal group and induced the MOM-group removal.
This was followed by ether cleavage by treatment with
BCl3 to achieve all benzyl group removal. Acetylation of
the resulting crude material with Ac2O and pyridine af-
forded the peracetylated decamannoside 13 that was puri-
fied and fully characterized. Finally, deacetylation of 13
Having secured access to the pentamannoside 6d, this
compound was allowed to react with the capping mono-
mer
5 under microwave-assisted click conditions
(Scheme 2) to give the higher oligomer 8 in very good
yield (72%). This hexamannoside was submitted to an
acid hydrolysis to remove the MOM protecting group and
debenzylated by treatment with BCl3 and MeOH to give
OBn
O
Me
N3
BnO
N3
OBn
O
OBn
O
BnO
BnO
BnO
BnO
BnO
N
N
N
3
4
OBn
O
TMS
OH
BnO
BnO
OBn
O
OBn
O
Me
Me
1. CuI, i-Pr2EtN, DMF
MW, 80 °C, 15 min
1. CuI, i-Pr2EtN, DMF
MW, 80 °C, 15 min
n
BnO
BnO
BnO
BnO
N
N
2. NaOH, MeOH–CH2Cl2
r.t., 1 h
2. K2CO3, 18-crown-6,
toluene, 110 °C, 4 h
N
2
2
OBn
O
BnO
BnO
Cycle
n
Yield (%)a
Product
Product
Cycle
n
Yield (%)
6a–d
1
2
3
4
0
1
2
3
6a
6b
6c
6d
76
79
81
76
1
2
3
4
0
1
2
3
6a
6b
6c
6d
69
85 (90)
88 (80)
70 (50)
Scheme 1 Stepwise oligomerization. a Values in parentheses refer to the purity of the isolated compound (1H NMR analysis).
Synlett 2009, No. 16, 2679–2681 © Thieme Stuttgart · New York

LETTER
Triazole-Linked 1,6-a-D-Oligomannosides
2681
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
N3
OBn
O
BnO
BnO
N
N
References and Notes
N
OBn
O
(1) (a) The Return of the White Plague: Global Poverty and the
New Tuberculosis; Gaudy, M.; Zumla, A., Eds.; Verso:
London, 2003. (b) Ryan, F. The Forgotten Plague; Little,
Brown & Co.: Canada, 1992, 415.
CuI, i-Pr2EtN, DMF
MW, 80 °C, 30 min
BnO
BnO
6d
+
3
N
N
(2) Brennan, P. J.; Nikaido, H. Annu. Rev. Biochem. 1995, 64,
N
OBn
O
29.
BnO
BnO
(3) Morita, Y. S.; Patterson, J. H.; Billman-Jacobe, H.;
McConville, M. J. Biochem. J. 2004, 378, 589.
(4) (a) Khoo, K. H.; Dell, A.; Morris, H. R.; Brennan, P. J.;
Chatterjee, D. Glycobiology 1995, 5, 117. (b) Chatterjee,
D.; Hunter, S. W.; McNeil, M.; Brennan, P. J. J. Biol. Chem.
1992, 267, 6228.
OR1
O
11
OMOM
Me
R1O
R1O
(5) For the chemical synthesis of oligomannan and
oligoarabinan fragments and their lipoconjugates, see:
(a) Jayaprakash, K. N.; Chaudhuri, S. R.; Murty, C. V. S. R.;
Fraser-Reid, B. J. Org. Chem. 2007, 72, 5534. (b) Joe, M.;
Bai, Y.; Nacario, R. C.; Lowary, T. L. J. Am. Chem. Soc.
2007, 129, 9885. (c) Fraser-Reid, B.; Chaudhuri, S. R.;
Jayaprakash, K. N.; Lu, J.; Ramamurty, C. V. S. J. Org.
Chem. 2008, 73, 9732.
N
N
N
OR1
O
R1O
R1O
8
N
N
N
OR1
O
R1O
R1O
(6) Watt, J. A.; Williams, S. J. Org. Biomol. Chem. 2005, 3,
1982.
(7) For an earlier synthesis of triazole-mannose oligomers, see:
Cheshev, P.; Marra, A.; Dondoni, A. Org. Biomol. Chem.
2006, 4, 3225.
(8) Dalvie, D. K.; Kalgutkar, A. S.; Khojasteh-Bakht, S. C.;
Obach, R. S.; O’Donnell, J. P. Chem. Res. Toxicol. 2002, 15,
269.
OR2
12 R1 = Bn, R2 = CH2OMe (93%)
1. CF3CO2H, CH2Cl2, r.t., 3 h
2. BCl3, CH2Cl2, –60 to 0 °C, 2 h
3. Ac2O, Py, r.t., 16 h
13 R1 = R2 = Ac (66%)
14 R1 = R2 = H (99%)
(9) Horne, W. S.; Yadav, M. K.; Stout, C. D.; Ghadiri, M. R.
J. Am. Chem. Soc. 2004, 126, 15366.
NH3, MeOH, r.t., 18 h
(10) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem. Int. Ed. 2002, 41, 2596. (b) Tornoe,
C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67,
3057.
(11) The building block employed in the earlier synthesis was an
ethynyl a-D-C-mannoside. Therefore, each cycle was
constituted of the click azide–alkyne reaction and then
transformation of the 6-hydroxy into azido group in the
resulting product.
(12) It has to be noted that attempts to synthesize compound 4 by
addition of acetone to ethynyl 6-azido-2,3,4-tri-O-benzyl-6-
deoxy-a-D-C-mannopyranoside failed in our hands. The
basic conditions required for this process induced the 1,2-
elimination of benzyl alcohol leading to the undesired
glycal.
Scheme 3
by 1 M NH3 in methanol afforded the free hydroxy prod-
uct 14.
We believe we have paved the way to a new family of oli-
gomannose mimics that display two main features. One is
the interglycosidic triazole ring linked by a carbon–car-
bon bond to each mannose residue. The second is the pres-
ence of a capping 6-deoxymannose fragment in one side
of the chain. These features have been designed to make
the oligomers stable to enzymatic degradation and unable
to undergo mannosyltransferase-promoted glycosylation,
the key process for the Mycobacterium tuberculosis cell-
wall biosynthesis. Consequently, the free hydroxy hexam-
annoside 10 and decamannoside 14 appear to be interest-
ing substrates worth testing against that bacterium, the
etiological agent of tuberculosis. The synthesis of higher
homologues is under way, and the biological assays of all
the triazole-linked C-oligomannosides that have been pre-
pared will be carried out and reported in due course.
(13) Boyall, D.; López, F.; Sasaki, H.; Frantz, D.; Carreira, E. M.
Org. Lett. 2000, 2, 4233.
(14) Compound 9 in ref. 7 was treated with diphenylphosphoryl
azide (DPPA) and DBU under microwave irradiation
(120 °C, 2 h) to give 11 in 78% isolated yield (see
Supporting Information).
Synlett 2009, No. 16, 2679–2681 © Thieme Stuttgart · New York