Ready preparation of furanosyl n-pentenyl orthoesters from corresponding methyl furanosides

Article abstract of DOI:10.1021/jo1021376

The 3,5-di-O-benzoyl n-pentenyl orthoesters of the four pentofuranoses have been prepared. The first key intermediate in each case is the methyl pentofuranoside(s), and a user-friendly procedure for the preparation of each, based on the Callam-Lowary precedent, is described, whereby formation of the crucial α/β anomeric mixture is optimized. The mixture is used directly to prepare the corresponding perbenzoylated pentofuranosyl bromide(s) and then the title compounds.

Full text of DOI:10.1021/jo1021376

NOTE
pubs.acs.org/joc
Ready Preparation of Furanosyl n-Pentenyl Orthoesters from
Corresponding Methyl Furanosides
Changalvala V. S. Ramamurty,† Parimala Ganney,† C. Srinivas Rao,‡ and Bert Fraser-Reid*,†
†Natural Products and Glycotechnology Research Institute, Inc., 595 F Weathersfield Road, Pittsboro, North Carolina 27312,
United States
‡CiVentiCHEM, P.O. Box 12041, Research Triangle Park, North Carolina 27709, United States
S Supporting Information
b
ABSTRACT: The 3,5-di-O-benzoyl n-pentenyl orthoesters of
the four pentofuranoses have been prepared. The first key
intermediate in each case is the methyl pentofuranoside(s), and
a user-friendly procedure for the preparation of each, based on
the Callam-Lowary precedent, is described, whereby forma-
tion of the crucial R/β anomeric mixture is optimized. The
mixture is used directly to prepare the corresponding perbenzoylated pentofuranosyl bromide(s) and then the title compounds.
ecent work in our laboratory has been concerned with the
antigenic glycolipid found on the cell surface matrix of Myco-
employs an easier Fischer glycosidation procedure than that used
earlier by Fletcher.6 Accordingly, a general procedure based on
the Callam-Lowary protocol was applied to the pentofuranoses.
As seen in Scheme 1, the sugar was dissolved in a methanol/
acetyl chloride solution (step 1) and the time for its disappear-
ance determined by TLC (EtOAc/MeOH/H2O/nBuOH
2:1:1:1). The new material, which was usually not resolved with
this solvent system, was presumed to be methyl R/β furanosides.
However, if the reaction was allowed to stand longer, and a less
polar solvent system (EtOAc/MeOH/nBuOH 2:1:1) used, TLC
monitors showed eventual conversion to, presumably, the R/β
pyranosides.
R
bacterium tuberculosis.1 Attention was focused on the oligoarabinofur-
anan array, which has been identified as the seat of antigenic activity.2
This structure exists as a totally carbohydrate-based dendrimer which,
in a recent nanoscale rendition, can be seen to tower over the complex
cell surface saccharide matrix.3 Our synthetic approach to this
dendritic domain employed chemo- and regioselective couplings of
arabinose donors and acceptors, all of these building blocks being
readily available from the n-pentenyl orthoester (NPOE) of arabinose
9.4 This achievement has sparked our interest in extending NPOE
chemistry to the other pentofuranoses.
NPOEs of the hexopyranoses, used extensively in our studies,5
require perbenzoylated pyranosyl bromide precursors as key inter-
mediates. The corresponding furanosyl arabinose derivative 4a
(Scheme 1a) was therefore seen as an appropriate intermediate,
and fortunately its synthesis had previously been reported originally
by Fletcher6 and more recently by Hatanaka and Kuzuhara.7 These
routes required prior formation of the methyl furanoside 2a under
kinetic conditions to establish the five-membered ring and perben-
zoylation to 3a to secure the system against ring expansion during
the subsequent acid-catalyzed bromination.
Formation of the perbenzoylated methyl furanoside intermedi-
ates was therefore seen as the key step. Some of these derivatives are
commercially available, but the costs are beyond our economic
resources. A survey of the literature failed to disclose simple,
generalizable syntheses of the corresponding methyl furanosides.
One popular strategy is to establish the furanose ring by affixing an
isopropylidene acetal8 with subsequent methylation at the anomeric
center.9 However, a more direct route was preferable, and thus, we
have adapted the user-friendly procedure for preparation of 2a to the
other methyl pentofuranosides.
The reaction was usually stopped at the furanoside formation
stage, and since both anomers would be useful for eventual
orthoester formation, no attempt was made at separation.
Instead, the solution was neutralized with pyridine, and after
coevaporation with methylene chloride, the crude product was
treated directly with benzoyl chloride and pyridine overnight
(step 2) to give the desired perbenzoylated methyl furanoside.
As seen from the data in Scheme 1, generalization of the
glycosidation (i.e., step 1) proved to be very substrate-sensitive. In
the case of arabinose, step 1 required 7 h for the R/βmixture (Rf 0.8)
to be optimized. Employing step 2 afforded benzoylated material,
which gave evidence of imminent crystallization. The material was
therefore dissolved in ethanol which upon cooling deposited R3a as a
crystalline material in 50% yield, mp 100-102 °C, in agreement with
the literature value.11
With regard to lyxose, van Boom and co-workers12 had
previously applied a similar Fischer glycosylation for 24 h which
afforded a complex mixture. Because such complexity could be
We had obtained methyl arabinofuranoside 2a by use of the
Received: October 27, 2010
Published: March 07, 2011
modern procedure described by Callam and Lowary,10 which
r
2011 American Chemical Society
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The Journal of Organic Chemistry
NOTE
Scheme 1. Preparation of Pentose Pentenyl Orthoestersa
a For details about steps 1-4 for each transformation, see the Experimental Section.
problematic for us, a systematic study was undertaken to
optimize furanose formation.
Table 1. Summary of Converting Furanoses to n-Pentenyl
Orthoesters
Experiments showed that 0.2 mL of acetyl chloride was required
for 1 g of lyxose to gradually disappear in 3 h, as monitored by TLC
(EtOAc/MeOH/nBuOH 2:1:1). At this time, an apparently single
new material was evident, and this was perbenzoylated in the usual
way. The product 3b was isolated by chromatography in approxi-
mately 66% yield (Table 1).
Glycosidation of ribose under the conditions for step 1 was
much faster, with the conversion 5a f 6a being complete in 1 h
(Rf 0.8). Benzoylation in the usual way afforded 7a in 72% yield
after chromatography.
With regard to xylose, our earliest approach to the methyl furano-
side had been to repeat the work of Fletcher.14 But in our hands, the
methyl pyranoside was the only product. A subsequent paper with
Diehl13 recommended that “the procedure involving the methyl
glycosides is superior”, the latter being the previously described
preparation.14 In our hands, the “improved procedure” gave a mixture
of furanose and pyranose products. The general procedure was
therefore employed. Three hours were required for optimal xylofur-
anoside formation (Rf 0.75). This process was three times slower than
of ribose but, notably, two times faster than arabinose.
Conversion of the benzoylated methyl furanosides to the corre-
sponding furanosyl bromides (step 3, Scheme 1) was also structure-
sensitive. Treatment of the arabinosyl substrate 3a with hydrobromic
acid in acetic acid at room temperature required 45 min for
conversion to the glycosyl bromide 4a. For ribose and xylose, the
process was complete in 10 min.
However, the generalized reaction did not work in the case of
lyxose. Success required changing the solvent from acetic acid to
dichloroethane, which afforded the perbenzoylated lyxosyl bro-
mide 4b.
In all cases, the glycosyl bromides turned out to be syrups, and
these were used directly in step 4 (Scheme 1). Treatment with
2,6-lutidine and pent-4-en-1-ol in methylene chloride solution at
room temperature overnight under the agency of tetrabutylam-
monium iodide gave the desired n-pentenyl orthoesters 9-12 in
yields ranging from 60 to 90% for the last two steps.
Proton 500 MHz and carbon 80 MHz spectra indicate that
orthoesters 9-12 exist as single diastereomers in each case. We
entry substrate reaction conditionsa
time
7 h
product yield (%)
1
2
1a
2a
3a
4a
1b
2b
3b
4b
5a
6a
7a
8a
5b
6b
7b
8b
A
B
2a
3a
4a
9
NI
50
NI
90
NI
66
NI
60
NI
73
NI
90
NI
66
NI
60
12 h
3
C
D
A
B
45 min
12 h
4
5
3 h
2b
3b
4b
10
6a
7a
8a
11
6b
7b
8b
12
6
12 h
7
C*
D
A
B
30 min
12 h
8
9
1 h
10
11
12
13
14
15
16
12 h
C
D
A
B
10 min
12 h
3 h
12 h
C
10 min
D
12 h
a Conditions: (A) MeOH, AcCl, 0 °C to rt; (B) BzCl, pyridine, 0 °C to
rt; (C) AcOH, HBr (45% in AcOH), rt; (D) 2,6-lutidine, pent-4-en-1-ol,
Bu4NI, CH2Cl2. *Dichloroethane was used as a solvent instead of acetic
acid. NI: not isolated.
opine that the phenyl ring is over or under the sugar nucleus, as is the
case with the corresponding pyranose derivatives.5a The availability
of all the pentofuranoside n-pentenylorthoester analogues provides
an opportunity to explore their potential as glycosyl donors. In
addition, a preliminary examination of their NMR spectra indicates
interesting conformational characteristics of these 3:3:0 bicyclic
systems, notably with regard to the C5 methylene protons. A detailed
study of these aspects is underway and will be reported in due course.
’ EXPERIMENTAL SECTION
Methyl 2,3,5-Tri-O-benzoyl-rβ-D-ribofuranoside (7a). A
suspension of ribose 5a (5.0 g, 33.3 mmol) in anhydrous methanol (120
mL) was treated slowly with acetyl chloride (2.1 mL) at 0 °C via syringe
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NOTE
(∼30 min). The mixture was stirred at rt, and progress of the reaction was
monitored by TLC in EtOAc/MeOH/nBuOH/H2O (2:1:1:1) until dis-
appearance of the starting material, which was ∼1 h. At this time, a faster
running material which appeared as a single “spot” was evident. (If at this
time, TLC was run in the less polar solvent mixture such as EtOAc/MeOH/
nBuOH 2:1:1, the new material, presumed to be the R/β furanoside, still
appeared as a single “spot”. However, if the reaction time was extended, a
newer material started to form which became dominant, signaling formation
of the corresponding R/β pyranoside). The reaction mixture, after 1 h, was
quenched with pyridine, evaporated, and then coevaporated with dichlor-
omethane to give a crude product that was dried overnight under high
vacuum. The material was then dissolved in pyridine, cooled to 0 °C, and
treated with benzoyl chloride (15 mL, 120 mmol), and the mixture was
stirred overnight at room temperature. Water was added, and after being
stirred for 30 min, the mixture was extracted with CH2Cl2. The extract was
washed with water, 3 N sulfuric acid, saturated NaHCO3 solution, and brine
and dried over Na2SO4. Purification was effected by flash column chroma-
tography using hexanes/ethyl acetate (8:2), which gave compound 7a as a
syrupy material (11.5 g, 72%) as a mixture of anomers.
3,5-Di-O-benzoyl-r-D-ribofuranose-1,2-(pent-4-enylorth-
obenzoate) (11). The perbenzoylated methyl ribofuranoside 7a (5 g,
10.5 mmol) was dissolved in acetic acid (25 mL), and HBr (18 mL, 45% in
acetic acid) was added. The reaction vessel was tightly stoppered and stirred
at rt for 10 min, diluted with CH2Cl2 (100 mL), and washed with ice-cold
water (500 mL), NaHCO3 (satd) (3 ꢀ 50 mL), and brine (25 mL). The
organic layer was dried (Na2SO4) and concentrated in vacuo at 20 °Ctogive
a crude product (5.1 g), which was submitted to the next step immediately
without further purification. This mixture was dissolved in CH2Cl2 (75 mL),
4-penten-1-ol (2.0 mL, 19.4 mmol) and 2,6-lutidine (2.48 mL, 21.3 mmol)
were added followed by Bu4NI in three lots (358 mg, 0.97 mmol) in 30 min
intervals at rt. The reaction mixture was stirred at rt overnight, when TLC
(hexanes-EtOAc 4:1) indicated completion. The reaction mixture was washed
with water (3 ꢀ 100 mL) and brine (50 mL), dried (Na2SO4), and
concentrated in vacuo. The obtained crude was purified by flash column
chromatography on silica gel using hexanes/EtOAc (9:1) to give compound
11 (3.95 g, 71% over two steps): [R]26D þ128.28 (c 0.5, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 8.0-7.96 (m, 4H), 7.66-7.64 (m, 2H), 7.60 (t, J =
7.5 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.5 Hz, 2H), 7.40-7.36 (m,
5H), 6.20 (d, J = 4.5 Hz, 1H), 5.76 (tqt, J = 7.0 Hz, J = 6.5 Hz, J = 4.0 Hz,
1H), 5.25 (t, J= 5.0 Hz, 1H), 5.05 (app.t, J=5.5Hz,J= 5.5 Hz, 1H), 4.96 (m,
2H), 4.60 (dd, J = 3.0 Hz, J = 3.5 Hz, 1H), 4.37 (dd, J = 5.0 Hz, J = 5.5 Hz,
1H), 4.18-4.15 (m, 1H), 3.45-3.38 (m, 2H), 2.08 (q, J = 6.5 Hz, 2H), 1.61
(pent, J = 7.0 Hz, 2H); 13C NMR (80 MHz, CDCl3): δ 166.2, 165.8, 138.2,
137.7, 133.8, 133.4, 130.2 (2C), 129.9 (2C), 129.5, 129.2, 128.7 (2C), 128.6
(2C), 128.3 (2C), 126.4 (2C), 124.2, 115.1, 104.7, 78.1, 76.4, 73.4, 62.9,
62.6, 30.4, 28.8; HRMS (ESI) calcd for C31H30O8 Na [(M þ Na)þ]
553.1833, found 553.1834.
’ ACKNOWLEDGMENT
We are grateful to the National Science Foundation (CHE
0717702) for financial support, Dr. George Dubay, Director of
Instrument Operations in the Department of Chemistry, Duke
University, for mass spectrometric and HRMS measurements,
and Dr. D. Srinivas Reddy of the BRITE facility of North
Carolina Central University for the 500 MHz NMR spectra of
the compounds in Scheme 1.
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures for
b
compounds 9-12 along with copies of spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: dglucose@aol.com.
Notes
Natural Products and Glycotechnology Research Institute, Inc.,
is an independent nonprofit research facility with laboratories at
CiVentiCHEM, P.O. Box 12041, Research Triangle Park,
NC 27709.
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dx.doi.org/10.1021/jo1021376 |J. Org. Chem. 2011, 76, 2245–2247