Expedient synthesis of the heneicosasaccharyl mannose capped arabinomannan of the Mycobacterium tuberculosis cellular envelope by glycosyl carbonate donors

Article abstract of DOI:10.1039/c6sc04866h

The global incidence of tuberculosis is increasing at an alarming rate, and Mycobacterium tuberculosis (Mtb) is the causative agent for tuberculosis, a disease with high mortality. Lipoarabinomannan (LAM) is one of the major components of the Mtb cellular envelope and is an attractive scaffold for developing anti-tubercular drugs, vaccines and diagnostics. Herein, a highly convergent strategy is developed to synthesize heneicosasaccharyl arabinomannan for the first time. The arabinomannan synthesized in this endeavour has several 1,2-trans or α-Araf linkages and three 1,2-cis or β-Araf linkages end capped with 1,2-trans or α-Manp linkages. All the key glycosidations were performed with alkynyl carbonate glycosyl donors under [Au]/[Ag] catalysis conditions, which gave excellent yields and stereoselectivity even for the reactions between complex and branched oligosaccharides. The resultant allyl oligosaccharide was globally deprotected to obtain the heneicosasaccharyl arabinomannan as a propyl glycoside. In summary, heneicosasaccharyl mannose capped arabinomannan synthesis was achieved in 56 steps with 0.016% overall yield.

Full text of DOI:10.1039/c6sc04866h

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Expedient Synthesis of Heneicosasaccharyl Mannose Capped
Arabinomannan of Mycobacterium tuberculosis Cellular Envelope
by Glycosyl Carbonate Donors
Received 00th January 20xx,
Accepted 00th January 20xx
Maidul Islam, Ganesh P. Shinde and Srinivas Hotha*
DOI: 10.1039/x0xx00000x
Global incidence of tuberculosis is increasing at an alarming rate and Mycobacterium tuberculosis (Mtb) is the causative
agent for the tuberculosis, a disease triggering maximum mortality. Lipoarabinomannan (LAM) is one of the major
components of the Mtb cellular envelope and is an attractive scaffold for developing anti-tubercular drugs, vaccines and
www.rsc.org/
diagnostics. Herein,
a highly convergent strategy is developed for the first synthesis of heneicosasaccharyl
arabinomannan. Arabinomannan synthesized in this endeavour has several 1,2-trans or α-Araf linkages and three 1,2-cis
or β-Araf linkages end capped with 1,2-trans or α-Manp linkages. All key glycosidations were performed with alkynyl
carbonate glycosyl donors under [Au]/[Ag]-catalysis conditions, which gave excellent yields and stereoselectivity even for
the reactions between complex- and branched oligosaccharides. The resultant allyl oligosaccharide was globally
deprotected to obtain the heneicosasaccharyl arabinomannan as a propyl glycoside. In summary, the heneicosasaccharyl
mannose capped arabinomannan synthesis was achieved in 56 steps with 0.016% overall yield.
Introduction
World-wide resurgence of mycobacterial infections coupled
with the emergence of multi-drug and extreme drug resistance
placed tuberculosis (TB) as a major public health concern.1-3
The only available protection against tuberculosis is the BCG
vaccine; however, multi-centered clinical trials demonstrated
variable efficiency.4
Tuberculosis infection is caused by
Mycobacterium tuberculosis (Mtb) with a thick waxy cell wall
making the drugs impervious.5,6 As a consequence, patients
suffering from TB are prescribed to long regimen of multiple
drugs. Therefore, TB is an ever growing challenge, and novel
strategies to diagnose, control or eradicate it are in great
demand.
Figure 1. Cartoon representation of the Mycobacterium tuberculosis cell wall (A) and
retrosynthesis of Heneicosasaccharyl mannose capped arabinan (B).
The chemical structure of the waxy cellular envelope has been
identified to be a unique glycocalyx comprising mycolic acids,
and macrophages in vitro to modulate M. tuberculosis induced
macrophage apoptosis.14,15 Quite recently, a rapid point of
care diagnostic kit was developed exploiting the antigenic
Araf-, Galf-, Manp-, Rhap- and Inositols.7-10
Further
investigations revealed that the glycocalyx contains trehalose
lipids, lipoarabinomannan (LAM), arabinogalactan (AG) and
peptidoglycan.7-10 Of these, structure of LAM was noticed to
have a key C-3 branched arabinan domain with many α-1→5-
linked D-Arafs, and a few β-1→2-linked D-Arafs capped with α-
1→2 linked D-Manps at the non-reducing end.7-10,13 It has
been well established that mannose capped LAM (ManLAM) is
prevalent in more pathogenic mycobacterial species such as
M. tuberculosis, M. leprae, M. bovis.11-13 ManLAM has been
shown to inhibit production of tumor necrosis factor-α (TNF-α)
and interleukin-12 (IL-12) by human dendritic cell and
properties of ManLAM.16-18
In another study LAM is
investigated as a candidate vaccine for the mycobacterial
diseases. Thus, non-reducing end portion of LAM is beneficial
for various immunological studies, diagnostics and
development of carbohydrate-based tuberculosis vaccine.
Owing to the significance of ManLAM, the synthesis of
ManLAM and arabinan fragments was attempted over the last
two decades.19-27,44 A recent investigation by Guo’s group
verified the synthetic and immunological potential of protein
conjugated ManLAM fragments.28 However, far too little
attention has been paid to synthesize the large oligomer of the
ManLAM. The main aim of the current research has therefore
been to synthesize the naturally occurring large
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oligosaccharide portion of ManLAM such as arabinomannan
(figure 1) to facilitate vaccine and diagnostic development.
1
into hemiacetal 10 using PdCl2; subsequently, transformed to
glycosyl donor 12 by reacting with easily available ethynyl
cyclohexyl (4-nitrophenyl) carbonate 11 (Scheme 1).47
The first [Au]/[Ag]-glycosidation between acceptor
9 and
Results and Discussion
donor 12 was successfully performed to afford disaccharide 13
in excellent yields.35 In continuation, lone silyl ether was
deprotected under HF·py condiꢀons to afford acceptor 14
which was glycosylated again with the glycosyl donor 12 under
gold/silver catalytic conditions to obtain trisaccharide 15a as
an allyl glycoside. Cleavage of the silyl ether, protection as
The arabinomannan moiety (1) offers enough complexity and
challenges for its synthesis in terms of type, number of
linkages and asymmetric branching. A careful retrosynthetic
disconnection revealed that the target molecule as a propyl
glycoside can be synthesized conveniently using two
disaccharides
(
2,
3), two monosaccharides
(4,6) and a
levulinoate resulted into the other required trisaccharide 15b
.
trisaccharide (
5) (Figure 1). Apart from the continued
Trisaccharides 15a and 15b are respectively converted easily
into the triarabinofuranosyl carbonate donors 5a and 5b
(Scheme 1).46
interest,29-34 alkynyl carbonate donors are chosen as they
undergo catalytic activation in the presence of gold and silver
salts, fast and high yielding.35 Neighboring group or reciprocal
donor acceptor selectivity assisted synthesis of 1,2-trans or α-
linkages and stereoelectronics guided 1,2-cis or β-Araf was
envisioned.36 Allyl moiety was strategically placed at the
anomeric position since it is stable and orthogonal to -OTBDPS,
-OBz, -ONAP protecting groups and can be converted to
hemiacetals en route to the glycosyl donor preparation. In
addition, allyl moiety can also be exploited for conjugation of
proteins and biomolecules.37-40
In parallel, allyl mannopyranoside 17 was synthesized from
known mannopyranosyl 1,2-orthoester 1627 under acidic
conditions. Subsequently, allyl glycoside 17 by splitting into
two portions and one part was subjected to saponification
under Zemplén conditions42 to afford the acceptor 18 and the
other part was converted into the glycosyl donor 19 in two
easy steps. The gold/silver assisted glycosidation between the
donor 19 and the acceptor 18 underwent uneventfully
affording 93% of the disaccharide 20 which was subsequently
converted into the other required building block
(Scheme 2).46
2 in two steps
Scheme 1. Reagents: a) TBDPS-Cl, Im., DMF, 0 ⁰C, 1 h, 82%; b) BzCl, pyridine, DMAP, 0-
25 ⁰C, 5 h, 93%; c) PdCl2, CH2Cl2-MeOH (1:4), 25 ⁰C, 4 h, 85%; d) HF·py, pyridine, 0-25
⁰C, 5 h, 93% for 9, 91% for 14, 90% for 15b; e) 1-ethynylcyclohexyl (4-nitrophenyl)
carbonate (11), CH2Cl2, DMAP, 0-25 ⁰C, 3 h, 85% for 12, 83% for 5a and 85% for 5b over
two steps respectively; f) 8mol% chloro[tris(2,4-di-tert-butylphenyl)phosphite] gold,
8mol% AgOTf, CH2Cl2, 4Å MS powder, 25 ⁰C, 15 min, 95% for 13, 92% for 15a; g)
Levulinic acid, DIC, DMAP, CH2Cl2, 0-25 ⁰C, 2 h, 95%.
Scheme 2. Reagents: a) PTSA (0.2 eq.), Allyl alcohol, CH2Cl2, 4Å MS powder, 25 ⁰C, 1 h,
86%; b) PdCl2, CH2Cl2-MeOH (1:4), 25 ⁰C, 4 h, 90% towards 19; c) 11, CH2Cl2, DMAP, 0-
25 ⁰C, 3 h, 78% for 19, 83% for 2 over two steps; d) NaOMe, MeOH, 25 ⁰C, 1 h, 94%; e)
8mol% chloro[tris(2,4-di-tert-butylphenyl)phosphite]gold, 8mol% AgOTf, CH2Cl2, 4Å MS
powder, 25 ⁰C, 15 min, 93%.
Synthesis of the next important 1,2-cis disaccharide
3 was
Our synthetic endeavour started with the preparation of
triarabinofuranosyl carbonate donor (Scheme 1). Easily
accessible allyl arabinofuranoside 741 was converted into fully
initiated with saponification of compound 8 under Zemplén
conditions (NaOMe/MeOH); subsequent conversion to benzyl
ethers afforded compound 21. Moving on, the cleavage of the
silyl ether using HF·py and protecꢀon of the resulꢀng hydroxyl
group as NAP ether underwent effortlessly by employing NAP-
Br to afford NAP-protected allyl glycoside 22. Hydrolysis of the
allyl glycoside using PdCl2 and conversion to the corresponding
donor 23 was achieved in very high yield. In parallel,
compound 24 was protected as benzyl ether 25 using
NaH/BnBr/DMF and opening of the isopropylidene moiety was
protected compound
ether using TBDPS-Cl followed by the protection of remaining
hydroxyls as benzoates with BzCl/py/DMAP. Compound
serves as a common building block for the synthesis of both
glycosyl donor and acceptor as well. Accordingly, compound
has been split into two portions and one portion was
converted into the glycosyl acceptor by the treatment of
8 by first protecting the C-5-OH as silyl
8
8
9
with HF·py in THF whereas the second porꢀon was converted
2 | J. Name., 2012, 00, 1-3
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performed in the presence of allyl alcohol under acidic
conditions to afford an α,β-mixture of glycosides.
Earlier studies from our group demonstrated that the
reciprocal donor acceptor selectivity depends on the reactivity
of the nucleophile and the stereoelectonics around the C-2
position of the glycosyl acceptor.36 Accordingly, allyl glycosides
were separated by flash silica gel column chromatography and
isolated the required 1,2-cis disposed allyl glycoside 26
.
Glycosyl donor 23 and acceptor 26 were subjected to
[Au]/[Ag]-catalysed glycosidation conditions to afford the 1,2-
cis or β-disaccharide 27 in 92% yield as a single diastereomer
further verifying our earlier results.36,46 Subsequently, the
disaccharide 27 was converted into the required glycosyl
donor
3 in two steps viz. Pd-catalysed hydrolysis of allyl
glycoside to hemiacetal followed by its conversion to the
ethynylcyclohexyl carbonate by treating with compound 11
and DMAP. Orthogonally cleavable TBDPS and NAP ethers are
selected to install mannopyranosyl disaccharide at a later
stage (Scheme 3).
Scheme 4. Reagents: a) NaOMe, MeOH, 25 ⁰C, 1 h, 95%; b) TBDPS-Cl (2.5 eq.), Im.,
DMF, 0-25 ⁰C, 2 h, 85%; c) PTSA (0.2 eq.), excess allyl alcohol, CH2Cl2, 4Å MS powder, 25
⁰C, 1 h, 80%; d) HF·py, pyridine, 0-25 ⁰C, 6 h, 90% for 4, 90% for 33; e) TBDPS-Cl, Im.,
DMF,
0 ⁰C, 1 h, 80%; f) 8mol% chloro[tris(2,4-di-tert-butylphenyl)phosphite]gold,
8mol% AgOTf, CH2Cl2, 4Å MS powder, 25 ⁰C, 20 min, 95% for 32 and 92% for 34.
Synthesis of enough quantities of all identified major partners
driven the assembly of ManLAM. Accordingly, glycosyl
acceptor 31 and the glycosyl donor 5b were first glycosylated
under gold-silver catalysed glycosidation conditions to afford
the tetrasaccharide 32 in excellent yield.46 Deprotection of the
silyl ether using HF·py to obtain 33 and subsequent treatment
with glycosyl donor 5a, 8mol% each of AgOTf and gold-
phosphite catalyst in CH2Cl2 afforded the required
heptasaccharide 34 in 92% yield (Scheme 4).
Protection of the C-2 hydroxyl group of compound 26 as a
benzoate followed by the unblocking of C-5 hydroxyl group by
the addition of HF·py resulted into the glycosyl acceptor
Subsequently, glycosyl acceptor was treated with the donor
under gold-silver catalyzed conditions to afford the required
trisaccharide 35 35
Diastereoselectivity of the reaction was
6.
6
Scheme 3. Reagents: a) NaOMe, MeOH, 25 ⁰C, 1 h, 90%; b) NaH, BnBr, TBAI, DMF, 0-25
⁰C, 1 h, 91% for 21 and 93% for 25; c) HF·py, pyridine, 0-25 ⁰C, 5 h, 92%; d) NaH,
NAPBr, TBAI, DMF, 0-25 ⁰C, 2 h, 90%; e) PdCl2, CH2Cl2-MeOH (1:4), 25 ⁰C, 4 h; f) 11,
DMAP, CH2Cl2, 0-25 ⁰C, 3 h, 82% for 23, 78% for 3 over two steps; g) PTSA (0.2 eq.),
3
.
noticed to be temperature dependent. The diastereomeric
ratio swung in favour of the desired α-isomer as the
temperature of the reaction was lowered. Best 8:1 ratio (α:β)
in favour of desired isomer with an overall yield of 90%
(translates to 80% of the trisaccharide 35) was accomplished at
-78 ⁰C that might be due to the presence of bulky 5-O-TBDPS
moiety (Scheme 5).36 The naphthyl moiety was deprotected
using DDQ, CH2Cl2-MeOH (1:4) at 25 ⁰C to obtain the acceptor
36 which was further treated with the mannopyranosyl donor
Allyl alcohol, CH2Cl2, 50 ⁰C,
2 h, 45%; h) 8mol% chloro[tris(2,4-di-tert-
butylphenyl)phosphite] gold, 8mol% AgOTf, CH2Cl2, 4Å MS powder, -78 ⁰C, 5 h, 92%.
Synthesis of another monosaccharide
4 commenced with the
saponification of easily accessible 2843 under Zemplén
conditions (NaOMe/MeOH) followed by its conversion to
disilyl ether 29 using TBDPSCl/Im./DMAP in 81% yield over two
steps. Acid mediated opening of the 1,2-orthoester in the
presence of allyl alcohol afforded the allyl glycoside in 80%
yield. Cleavage of the silyl ethers was achieved using HF·py to
2
to obtain the pentasaccharide 37 in 76% yield. Two step
conversion transformed allyl glycoside 37 into the glycosyl
donor 38 in 75% (Scheme 5).
afford the allyl glycoside 4, resulting C-5 hydroxyl group was
protected as its silyl ether to afford the glycosyl acceptor 31
.
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Journal Name
OBn
OBn
Gratifyingly, the mixture of pentasaccharides could be
separated using flash silica gel column chromatography to
O
BnO
O
BnO
NAPO
HO
TBDPSO
obtain 77% of the desired pentasaccharide 39 15
.
Deprotection
of NAP-ether was achieved to afford the diol 40 which upon
treatment with mannopyranosyl donor gave nonasaccharide
41
In the 13C NMR spectrum of the nonasaccharide 41
TBDPSO
O
O
BzO
HO
O
O
O
O
a,b
c
d
26
+
3
BzO
BzO
O
O
OBn
O
OBn
O
OBn
O
O
2
6
35
36
OBn
OBn
.
,
resonances due to nine anomeric carbons were noticed at δ
98.6, 98.8, 99.7, 99.8, 100.0, 100.5, 105.1, 105.5, and 106.8
ppm. Subsequently, the nonasaccharide was converted into
the corresponding carbonate glycosyl donor 42 in 76% yield
(Scheme 6).
e
2
BnO
BnO
BnO
OBz
O
BnO
BnO
BnO
BnO
BnO
BnO
OBz
O
BnO
OBn
BnO
BnO
BnO
O
O
O
O
O
O
BnO
O
BnO
O
TBDPSO
O
f,g
TBDPSO
O
O
O
The final assembly of heneicosaarabinomannan 1 started with
BzO
O
O
BzO
OBn
the deprotection of silyl ether 34 using HF·py to afford alcohol
43 which was glycosylated with donor 38 using 8mol% each of
gold-phosphite and AgOTf to afford dodecassacharide 44 in
85% yield. Twelve characteristic resonances due to anomeric
carbons were noticed in the anomeric region (δ 98.7–106.2
ppm) of the spectrum.46 The lone levulinoate was hydrolysed
with hydrazine acetate in THF-MeOH to afford the required
O
OBn
O
O
O
O
38
37
O
OBn
OBn
Scheme 5. Reagents: a) BzCl, pyridine, DMAP, 0-25 ⁰C, 5 h, 93%; b) HF·py, pyridine, 0-
25 ⁰C, 5 h, 94%; c) 8mol% chloro[tris(2,4-di-tert-butylphenyl)phosphite]gold, 8mol%
AgOTf, CH2Cl2, 4Å MS powder, -78 ⁰C, 5 h, 80% (overall yield 90% with α:β = 8:1); d)
DDQ, CH2Cl2-MeOH (1:4), 25 ⁰C, 4 h, 82%; e) 8mol% chloro[tris(2,4-di-tert-
butylphenyl)phosphite]gold, 8mol% AgOTf, CH2Cl2, 4Å MS powder, 25 ⁰C, 15 min, 76%;
f) PdCl2, CH2Cl2-MeOH (1:4), 25 ⁰C, 4 h; g) 11, DMAP, CH2Cl2, 0-25 ⁰C, 3 h, 75% over two
steps.
glycosyl acceptor 45 45
.
The final glycosidation between
acceptor 45 containing twelve saccharide residues and the
glycosyl donor 42 containing nine carbohydrate residues was
performed in the presence of 8mol% each of Au-phosphite and
AgOTf to observe formation of the fully protected
heneicosaarabinomannan 46 in 80% yield. In the 13C NMR
spectrum of arabinomannan 46, resonances due to the
anomeric carbons were noticed as two sets centred on δ 98.8-
100.7 ppm and δ 105.1-107.3 ppm for 21-anomeric carbons
(Scheme 7).4 Oligosaccharide 46 can be subjected to variety of
reactions in order to attach biomolecules; however, global
deprotection of compound 46 was considered to show that
the molecule is stable to conditions employed for the cleavage
of protecting groups. Cleavage of the three silyl ethers was
carried out using the HF·py, Zemplén debenzoylaꢀon resulted
in the saponification of eighteen benzoates and the final
hydrogenolysis with Pd(OH)2/H2 caused the deprotection of
twenty eight benzyl ethers and reduction of the olefin as well
affording the heneicosaarabinomannan (47) as its propyl
glycoside.
Glycosidation reaction between donor
3 and acceptor 4
afforded another pentasaccharide 39 as an allyl glycoside in
77% yield in the presence of 8mol% each of Au-phosphite and
AgOTf. The stereochemical outcome of glycosidation was
noticed to be temperature dependent. Careful analysis of the
glycosidation revealed that the mixture of glycosides (α:β =
8:1) is resulting from the C-5 position of the acceptor; but, not
from the C-3 position.
OBn
OBn
O
O
BnO
BnO
NAPO
HO
TBDPSO
TBDPSO
O
O
O
O
O
O
OBn
OBn
O
O
BzO
BzO
a
b
3
+
4
O
O
OBn
O
OBn
O
O
O
TBDPSO
NAPO
TBDPSO
HO
O
O
BnO
O
BnO
O
39
40
OBn
OBn
c
2
BnO
BnO
BnO
BnO
BnO
OBz
OBz
O
O
Conclusions
BnO
BnO
BnO
OBn
OBn
BnO
BnO
O
O
O
O
In summary, execution of the highly convergent and modular
strategy has led to the first synthesis of branched-, hybrid- and
complex- arabinomannan (containing 15-Araf and 6-Manp-
residues) of Mycobacterium tuberculosis cell wall in sufficient
amounts for biological explorations with an overall yield of
0.016% yield. Stable alkynyl carbonate glycosyl donors are
shown to be versatile glycosyl donors for the synthesis of large
oligosaccharides. [Au]/[Ag]-Catalytic conditions are employed
for all key glycosylations. 1,2-cis Araf and some 1,2-trans Araf
linkages were installed taking advantage of reciprocal donor-
acceptor selectivity. Taken together, the synthesis uses stable
reactants, catalytic quantities of noble metal salts; therefore,
experimentally less demanding and operationally convenient.
BnO
O
BnO
BnO
O
BnO
O
O
RO
RO
O
O
O
O
d,e
O
O
OBn
OBn
O
O
BnO
BnO
BzO
BnO
BnO
BzO
OBz
O
OBz
O
O
O
O
O
OBn
O
OBn
O
BnO
BnO
BnO
BnO
BnO
O
O
O
O
O
O
BnO
BnO
BnO
RO
RO
O
O
O
O
BnO
O
BnO
O
42 R = TBDPS
41 R = TBDPS
OBn
OBn
Scheme 6. Reagents: a) 8mol% chloro[tris(2,4-di-tert-butylphenyl)phosphite]gold,
8mol% AgOTf, CH2Cl2, 4Å MS powder, -78 ⁰C, 5 h, 77% (overall yield 87% with α:β =
8:1); b) DDQ, CH2Cl2-MeOH (1:4), 25 ⁰C, 4 h, 75%; c) 8mol% chloro[tris(2,4-di-tert-
butylphenyl)phosphite]gold, 8mol% AgOTf, CH2Cl2, 4Å MS powder, 25 ⁰C, 15 min, 60%;
d) PdCl2, CH2Cl2-MeOH (1:4), 25 ⁰C, 4 h; e) 11, DMAP, CH2Cl2, 0-25 ⁰C, 3 h, 76% over
two steps.
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BnO
BnO
OBz
O
BnO
BnO
OBn
O
O
O
BnO
BnO
BnO
O
HO
TBDPSO
O
OBz
O
O
O
BzO
O
OBz
OBz
O
O
OBn
LevO
OBz
O
O
O
BzO
OBz
O
O
OBn
OBz
O
O
OBz
OBz
O
O
a
b
O
OBz
34
+
38
OBz
O
OBz
O
OBz
O
O
LevO
OBz
OBz
OBz
BzO
O
O
OBz
O
O
OBz
O
O
O
BzO
OBz
OBz
O
O
HO
HO
HO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
OH
O
OBz
OBz
OBz
O
O
O
O
43
OBz
OBz
OH
O
OBn
OBn
HO
O
O
O
O
HO
HO
HO
BnO
BnO
BnO
BnO
BnO
BnO
OH
O
O
OBz
O
O
HO
BnO
BnO
O
HO
BnO
BnO
O
O
BnO
44
BzO
BnO
HO
O
HO
O
O
OH
OBn
HO
HO
HO
O
O
O
TBDPSO
TBDPSO
O
O
O
O
O
O
O
O
O
c
HO
BnO
O
HO
O
BzO
O
BzO
O
O
O
O
OBn
HO
O
OH
OBn
RO
O
O
a,d,e
O
O
O
O
O
OH
OH
O
OBn
OBz
OBn
OBz
O
O
O
O
O
OH
OBn
O
O
HO
HO
HO
HO
HO
HO
HO
BnO
BnO
BnO
BnO
BnO
BnO
BzO
OH
O
OBz
O
O
O
b
42
+
OH
OBz
OBz
OH
O
OBz
O
OBz
O
O
O
OH
O
OBn
O
O
O
O
O
HO
OH
OBz
BzO
OBz
BzO
O
O
O
O
O
O
O
O
HO
OH
OBz
O
OBz
O
O
O
HO
O
O
RO
O
O
OBz
O
O
OH
OBz
O
OH
O
OBz
O
OBz
O
HO
O
BnO
O
O
O
O
O
O
OH
OBz
OBz
OH
OBz
O
OBz
O
O
O
O
OH
OBz
OBz
O
OBz
OBz
OH
OH
OBn
O
O
O
47
46
45
R = TBDPS
O
O
O
OH
OBz
OBz
Scheme 7. Reagents: a) HF·py, pyridine, 0-25 ⁰C, 5 h, 83% for 43, 80% for 47 ; b) 8mol% chloro[tris(2,4-di-tert-butylphenyl)phosphite]gold, 8mol% AgOTf, CH2Cl2, 4Å MS powder, 25
⁰C, 30 min, 85% for 44 and 80% for 46; c) Hydrazine acetate, THF-MeOH (4:1), 25 ⁰C, 45 min, 80%; d) NaOMe, MeOH, 25 ⁰C, 15 h, 87%; e) Pd(OH)2, CH3OH-THF-H2O (4:3:3), H2, 36
h, 78%.
4
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5
6
Acknowledgements
MI and GPS acknowledge the fellowship from CSIR-UGC-NET.
Authors thank financial assistance from DST-SERB-New Delhi
[SB/OC/CB-03/2014]. Authors thank DST-FIST funds for high
field NMR facility at IISER Pune.
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means
Im.
means
imidazole,
DMAP
4-N,N’-
dimethylaminopyridine, THF means tetrahydrofuran, 4Å MS
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