Accessing C-1 phosphonylated 2-acylamino uronic acids via 2-nitro-glycals

Article abstract of DOI:10.1021/jo2002193

Two approaches are described for the synthesis of 2-acylamino uronic acid glycosyl phosphonates from readily accessible d-glucal. The first approach that entailed oxidation of the C-6 hydroxyl group followed by phosphonylation of the uronate 2-nitro-glycal, resulted in the formation of the β-l-gulo- configured phosphonate. Reversing the reaction order resulted in the exclusive formation of the β-d-gluco-configured phosphonate. In both cases the thermodynamic 1,2-trans-di-equatorial phosphonylation product is obtained.

Full text of DOI:10.1021/jo2002193

NOTE
pubs.acs.org/joc
Accessing C-1 Phosphonylated 2-Acylamino Uronic Acids via
2-Nitro-glycals
Beenu Bhatt, Robin J. Thomson, and Mark von Itzstein*
Institute for Glycomics, Griffith University, Gold Coast Campus, Queensland 4222, Australia
S Supporting Information
b
ABSTRACT: Two approaches are described for the synthesis
of 2-acylamino uronic acid glycosyl phosphonates from readily
accessible D-glucal. The first approach that entailed oxidation of
the C-6 hydroxyl group followed by phosphonylation of the
uronate 2-nitro-glycal, resulted in the formation of the β-L-gulo-configured phosphonate. Reversing the reaction order resulted in the
exclusive formation of the β-D-gluco-configured phosphonate. In both cases the thermodynamic 1,2-trans-di-equatorial phospho-
nylation product is obtained.
Scheme 1. Retrosynthetic Approaches to Uronyl Phospho-
nates 4
hosphonylated carbohydrates are of interest as biological
probes because of the stability of the CꢀP bond to hydrolysis
P
by enzymes involved in phosphate cleavage. Glycosyl phospho-
nates are therefore considered to act as stable biomimetics of the
corresponding glycosyl phosphates.1 Interestingly, and to the
best of our knowledge, uronosyl phosphonates are not described
in the literature, despite the fact that uronic acids are important
carbohydrates in mammalian2,3 and microbial4 biology. Of par-
ticular interest to us are functionalized β-phosphonates of glu-
curonic acid because of their potential value as intermediates in
influenza virus sialidase uronic acid-based inhibitor synthesis5ꢀ8
and their potential utility in probing glycosyltransferases such
as UDP-glucose:dolichyl-phosphate β-D-glucosyltransferase [EC
2.4.1.117]. This glycosyltransferase is important in N-glycan
biosynthesis9 and provides the activated β-glucosyl phosphate,
dolichyl β-D-glucosyl phosphate, that is enzymatically transferred
to a dolichol oligosaccharide precursor (DOP). The oligosac-
charide precursor is then enzymatically transferred to asparagine
residues of nascent proteins.9
from the common precursor D-glucal 1 (Scheme 1). In both
approaches, the key steps are the introduction of the anomeric
phosphonate moiety and oxidation of the C-6 hydroxyl group to
form the uronate; chemical manipulation of the 2-nitro group is
used to install the 2-acetamido group. In the first approach, the
C-6 hydroxyl group of a selectively protected derivative of D-glucal
1 is oxidized prior to nitration at C-2 and phosphonylation at C-1,
with final reduction of the nitro group. In the second approach, the
reaction sequence begins with nitration at C-2 of a protected
D-glucal derivative, followed by phosphonylation at C-1, reduction
of the nitro group, and finally oxidation of the C-6 hydroxyl group to
provide the protected 2-acetamido glucuronosyl phosphonate 4.
Approach 1 (Scheme 1) to uronosyl phosphonates 4 required
preparation of the previously unknown 2-nitro-uronate glycals of
type 2. In the first instance advantage was taken of the ready
accessibility of 3,4-di-O-acetylated uronate glycal 5.16 Reaction
of 5 with acetyl nitrate (preformed in situ from HNO3 and
Our interest in the chemistry of 2-acylamino-2-deoxy-uronic
acids5ꢀ8 led us to select this framework for the synthesis of the
corresponding glucuronosyl phosphonate. In considering ap-
proaches to glycosyl phosphonates of 2-acylamino-2-deoxy-
uronic acids we found no reports of direct C-1 phosphonylation
of 2-acylamino-2-deoxy sugars. Indeed in our own attempts at
Lewis acid-mediated phosphonylation of 2-acylamino-2-deoxy-
hexose 1-O-acetyl,10 trichloroacetimidyl,11 or oxazoline deriva-
tives, we found these substrates to be unreactive.12 Instead, access
to 2-N-substituted glucosyl phosphonates has been achieved
through phosphonylation of 2-azido-1-O-trichloroacetimidyl
sugars,11,13 or by Michael-type addition of HPO(OMe)2 to
2-nitro-glycals.14 As 2-nitro-glycals are versatile intermediates
that are amenable to a range of Michael-type addition reactions,15
we explored the applicability of this approach to access glycosyl
phosphonates of 2-acylamino-2-deoxy-uronic acids.
Two approaches were envisaged for the synthesis of 2-acet-
amido uronic acid glycosyl phosphonates 4 via 2-nitro-glycals,
Received: February 4, 2011
Published: April 15, 2011
r
2011 American Chemical Society
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NOTE
Scheme 2. Synthesis of Acetate-Protected 2-Nitro-uronate
Glycal 6
Scheme 4. Synthesis of Uronosyl Phosphonates (10, 11, 12)
Scheme 3. Synthesis of 2-Nitro-uronosyl Phosphonate 9
Phosphonate 10 was further manipulated to produce the
acetate-protected 2-acetamido derivative 12 (Scheme 4). Reduc-
tion of the nitro group of benzyl-protected 10 was successfully
accomplished using platinized Raney nickel14,22 (Scheme 4). The
intermediate amino compound was then acetylated to give the
2-acetamido derivative 11 (68% yield over two steps). Subse-
quent debenzylation under standard conditions, followed by
acetylation of the isolated crude diol afforded compound 12
(79% yield over two steps).
Ac2O)17,18 directly produced 2-nitro-glycal 6 (Scheme 2), with-
out the need for addition of base to eliminate HOAc from the
intermediate 2-nitro-glycosyl acetate, as required for benzylated
2-nitro-glycals18 (see Scheme 3). Attempted phosphonylation of
In the 1H NMR spectra of 10, 11, and 12, the observed H-4/H-5
coupling constant (J4,5 1.5 Hz) was consistent with an L-sugar,
indicating epimerization at C-5 had occurred during the phos-
phonylation reaction. The observation of epimerization at C-5
under these phosphonylation conditions is presumably related to
the acidity of H-5 in either 2-nitro-uronate glycal 8 or the
corresponding phosphonate and the reaction’s basic conditions.
t
6 using conditions [HP(O)(OMe)2 BuOK, anhydrous toluene,
0 °C, 2 h] reported for phosphonylation of 3,4,6-tri-O-benzyl-2-
nitro-D-glucal,14 however, returned unreacted starting material.
Increased reaction time (to 12 h) and temperature (to rt), also
returned unreacted 6, while reaction at 40 °C led to decomposi-
tion. Variation of the base (DBU, Et3N) and solvent also failed to
produce any of the desired product.
1
Examples of L-ido uronates, that preferentially exist in a C4
Given that 3,4,6-tri-O-benzylated 2-nitro D-glucal and D-galactal
show reactivity toward a range of Michael-type additions,15 including
phosphonylation,14 we wondered if the acetate protecting groups may
have been contributing to the lack of reactivity of 6. Synthesis of the
benzyl-protected 2-nitro-uronate 8 was therefore pursued. Direct
synthesis of the required precursor 3,4-di-O-benzylated uronate
glycal 7 from acetylated 5, by de-O-acetylation and subsequent
3,4-di-O-benzylation under acidic (TfOH19 or TMSOTf,20 ben-
zyl trichloroacetimidate) or basic (NaH, benzyl bromide) con-
ditions, was complicated by the formation of mixtures of com-
ponents in each case. The 3,4-di-O-benzylated uronate glycal 7
was therefore prepared using an established approach21 over
seven steps starting from D-glucal 1. The target 3,4-di-O-benzy-
lated 2-nitro-glycal derivative 8 was then readily formed in a two-
step, additionꢀelimination sequence. Thus, treatment of 7 with
preformed acetyl nitrate, followed by reaction of the product with
Et3N afforded the novel 2-nitro-uronate glycal 8 in 77% yield
over two steps (Scheme 3).
Phosphonylation of benzylated uronate 2-nitro-glycal 8
(Scheme 3) was initially attempted repeating the conditions
reported for phosphonylation of tri-O-benzyl-2-nitro-D-glucal.14
Where acetate-protected analogue 6 had been unreactive, the
benzylated derivative 8 was indeed phosphonylated; however, the
product was a mixture of isomers (represented by 9), as judged by
the complex 1H NMR spectrum. Replacing the tBuOK with bases
such as DBU and KHMDS also gave a less than satisfactory
outcome. The use of Et3N in THF, however, provided a single
phosphonate isomer 10 in 35% yield (43% yield based on
recovered starting material) (Scheme 4).
conformation, have been reported to have J4,5 values of 1.5
Hz.23,24 The large H-1/H-2 coupling in both 10 (J1,2 7.8 Hz) and
12 (J1,2 10.5 Hz) indicated a diaxial relationship between the two
protons. In conjunction with J3,2 and J3,4 values in 12 of ∼3.0 and
3.9 Hz, respectively, the NMR data for phosphonates 10ꢀ12 is
1
consistent with a β-L-gulo configured sugar in a C4 conforma-
tion, that has essentially axial substituents at C-3 and C-4 and
equatorial substituents at C-1, C-2, and C-5. In addition, the
observed 3JH-2,P coupling of ∼8 Hz is in the region anticipated for
this configuration.10 This structure indicates the formation of the
thermodynamically more stable 1,2-diequatorial 2-nitro-phospho-
nate under the reaction conditions used, as seen previously for the
phosphonylation products of benzylated D-glucal and L-rhamnal.14
The second approach (Approach 2, Scheme 1) to the target
uronosyl phosphonates 4 was based on manipulation of 3,4,6-tri-
O-benzyl-2-nitro-β-D-glucosyl phosphonate 13,14 prepared by
phosphonylation of 3,4,6-tri-O-benzyl-2-nitro-D-glucal. In the
first step (Scheme 5), 13 was converted to the 2-acetamido-
β-D-glucosyl phosphonate 14, using reaction conditions identical
to those described above for the 2-nitro-uronate derivative 10.
Global debenzylation of 14 and subsequent conversion of the
resultant 3,4,6-trihydroxy intermediate to the fully protected
methyl glucuronate 18 in a three-step, one-pot, reaction invol-
ving selective TEMPO-catalyzed oxidation25 of the primary
hydroxyl group, followed by esterification, and finally acetylation
of the secondary hydroxyl groups, appeared an attractive ap-
proach. In practice, however, isolation of the final product 18
following this reaction sequence proved to be problematic, with
poor reproducibility and often only low overallyield of 18 from14.
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NOTE
Scheme 5. Synthesis of Uronosyl Phosphonates (17, 18)
dropwise with stirring under Ar. The external temperature was further
lowered to ꢀ10 °C to keep the internal temperature in the range of
20ꢀ25 °C during the addition. Once the addition was complete, the
solution was further cooled to ꢀ33 °C using acetoneꢀdry ice cooling
bath. Then, a solution of methyl 3,4-di-O-acetyl-1,5-anhydro-2-deoxy-D-
arabino-hex-1-enuronate 516 (0.5 g, 1.93 mmol) in Ac2O (2 mL) was
added slowly, and the reaction mixture was stirred at ꢀ33 °C for 2 h and
then at 0 °C for 12 h. The reaction mixture was poured into 15 mL ice-
cold H2O, brine (10 mL) was added, and the aqueous layer was extracted
with diethyl ether (3 ꢁ 20 mL). The combined organic extracts were
dried over anhydrous Na2SO4 and filtered, and the solvent was
evaporated under reduced pressure. The pasty residue obtained was
crystallized from MeOH to yield 6 (0.383 g, 65%) as white crystals. Rf
0.30 (EtOAc/hexane, 1:4); 1H NMR (300 MHz, CDCl3): δ 8.41 (s, 1H,
H-1), 5.92 (dd, 1H, J3,5 1.5 Hz, J3,4 2.7 Hz, H-3), 5.52 (dd, 1H, J4,5
1.8 Hz, J4,3 2.7 Hz, H-4), 5.06 (app t, 1H, J5,3 = J5,4 1.8 Hz, H-5), 3.79 (s,
3H, CO2CH3), 2.10 (s, 3H, OCOCH3), 2.00 (s, 3H, OCOCH3);
13C NMR (75.5 MHz, CDCl3): δ 168.8, 168.5 (OCOCH3), 164.9
(CO2CH3), 155.7 (C-1), 128.3 (C-2), 73.9 (C-5), 65.8 (C-4), 60.6
(C-3), 53.1 (CO2CH3), 20.7, 20.5 (OCOCH3); LRMS (ESI): m/z 326
[(M þ Na)þ 100%].
Methyl 1,5-Anhydro-3,4-di-O-benzyl-2-deoxy-D-arabino-
hex-1-enuronate (7). A solution of 1,5-anhydro-3,4-di-O-benzyl-
2-deoxy-D-arabino-hex-1-enuronate30 (1 g, 3.06 mmol) in anhydrous
DCM (2 mL) was added dropwise to a solution of DessꢀMartin
periodinane (DMP) reagent (1.56 g, 3.68 mmol) in anhydrous DCM
(8 mL). The solution was stirred vigorously at room temperature and
monitored by TLC analysis (EtOAc/hexane, 3:7). After 2 h, the reaction
was complete, and the solution was diluted with diethyl ether (10 mL)
and poured into saturated ice-cold NaHCO3 solution. The organic
phase was separated and washed successively with H2O (2 ꢁ 10 mL)
and brine (10 mL), dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The crude residue was taken up
To improve the synthesis of 18, a stepwise approach was
followed beginning with the TMSOTf/Ac2O-mediated selective
acetolysis26 of the primary 6-O-benzyl group. Accordingly, 3,4,6-
tri-O-benzylated phosphonate 14 in DCM was treated with Ac2O
in the presence of TMSOTf at ꢀ40 °C to give the corresponding
6-O-acetylated derivative 15. The resulting 6-O-acetate group of
15 was then removed under Zemplꢀen conditions to give 6-hy-
droxy derivative 16 in 88% yield over two steps. TEMPO-based
oxidation27 of the primary hydroxyl group of 16, was followed by
acidic esterification28 of the crude product to furnish the benzyl-
protected methyl ester 17 in 76% yield over two steps.
Subsequent hydrogenolysis of the benzyl groups of 17, followed
by acetylation under standard conditions (Ac2O, pyridine), furn-
ished the acetate protected methyl uronate 18 in good overall yield
from 14. 1H NMR spectral analysis of 18, showed the J1,2, J2,3, J3,4,
and J4,5 vicinal coupling constants to be greater than 9.0 Hz, and
3JH-2,P to be in the range of ∼9ꢀ10 Hz,10 consistent with the
expected β-D-gluco- configuration.
In summary, the present study provides two approaches to
2-acylamino uronic acid glycosyl phosphonates. Interestingly, two
conformationally distinct uronosyl phosphonates resulted from
the two described phosphonylation approaches (Scheme 1).
The 3,4-di-O-benzylated uronate 2-nitro-glycal 8, reported here,
should prove a valuable addition to the range of 2-nitro-glycals
that provide reactive substrates for various Michael-type addition
reactions.15,29
t
in BuOH (13.2 mL) and treated with 2-methyl-2-butene (0.54 mL,
5.09 mmol) at room temperature. To this mixture was added a solution
of NaOCl2 (0.6 g, 6.79 mmol) and NaH2PO4 (0.6 g, 5.09 mmol) in H2O
(3.3 mL), and the reaction was stirred for 2 h after which time TLC
analysis indicated completion of reaction. The reaction mixture was
concentrated under reduced pressure, the residue was taken up in H2O
(10 mL) and extracted with hexane (10 mL) to remove organic
impurities. The aq solution was acidified to pH 3 with dil HCl and then
extracted with diethyl ether (3 ꢁ 30 mL). The combined Et2O phase
was dried over anhydrous Na2SO4, filtered, and concentrated. The crude
acid was dissolved in anhydrous DMF (5 mL), and to it was added
KHCO3 (0.42 g 4.25 mmol) followed by MeI (0.26 mL, 4.18 mmol).
The reaction mixture was stirred at room temperature for 3 h at which
time TLC analysis (EtOAc/hexane, 1:4) indicated complete conversion
of an acid to the product. The reaction mixture was then diluted with
H2O and extracted with diethyl ether (3 ꢁ 30 mL). The combined
organic phase was successively washed with H2O (50 mL) and brine
(50 mL), dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The crude reaction material was purified by
column chromatography (EtOAc/hexane, 0.3:9.7f0.8:9.2) to give title
compound 7 (0.836 g, 77% over three steps) as a white solid. Rf 0.28
(EtOAc/hexane, 1.5:8.5); 1H NMR (300 MHz, CDCl3): δ 7.27ꢀ7.15
(m, 10H, aromatic H), 6.54 (d, 1H, J1,2 6.3 Hz, H-1), 4.92 (app t, 1H,
J2,1 = J2,3 6.0 Hz, H-2), 4.70ꢀ4.69 (m, 1H, H-5), 4.60 (dd, 2H, Jgem
12.0 Hz, Jgem 12.3 Hz, CH2Ph), 4.33 (dd, 2H, Jgem 11.4 Hz, Jgem 11.4 Hz,
CH2Ph), 4.13ꢀ4.10 (m, 1H, H-4), 3.77ꢀ3.75 (m, 1H, H-3), 3.47
(s, 3H, CO2CH3); 13C NMR (75.5 MHz, CDCl3): δ 168.5 (CO2CH3),
144.9 (C-1), 137.7, 137.3, 128.5, 128.4, 128.3, 128.1, 127.8, 127.7, 127.6,
127.5 (aromatic), 98.4 (C-2), 73.0 (C-4), 72.6 (C-5), 71.8, 69.4
(2 ꢁ CH2Ph), 67.7 (C-3), 52.0 (CO2CH3); LRMS (ESI): m/z 377
[(M þ Na)þ 100%].
’ EXPERIMENTAL SECTION
1
For H and 13C spectra, chemical shifts are expressed as parts per
million (ppm, δ) and are relative to the solvent used [CDCl3: 7.26 (s)
for 1H; 77.0 (t) for 13C]. 31P NMR chemical shifts are quoted in
ppm downfield relative to 85% phosphoric acid (H3PO4) as external
reference (0.00 ppm). The use of (0) and (00) in the labeling of chemical
structures is purely to aid the assignment of signals in the 1H and 13
NMR spectra and does not correspond with the chemical names.
C
Methyl 3,4-Di-O-acetyl-1,5-anhydro-2-nitro-2-deoxy-D-
arabino-hex-1-enuronate (6). Prepared using a procedure adapted
from Das and Schmidt,18 Ac2O (2.9 mL) was placed in RBF, cooled to
10 °C, and to it was added 70% w/w HNO3 (0.42 mL, 6.54 mmol)
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NOTE
Methyl 1,5-Anhydro-3,4-di-O-benzyl-2-nitro-2-deoxy-D-arabi-
no-hex-1-enuronate (8). Prepared using a procedure adapted from
Das and Schmidt,18 Ac2O (5.6 mL) was placed in RBF and cooled to
10 °C; to it was added 70% w/w HNO3 (0.56 mL, 6.32 mmol) dropwise
with stirring under Ar. The external temperature was further lowered to
ꢀ10 °C to keep the internal temperature in the range of 20ꢀ25 °C
during the addition. Once the addition was complete, the solution was
further cooled to ꢀ33 °C using acetoneꢀdry ice cooling bath. Then, a
solution of compound 7 (0.59 g, 1.66 mmol) in Ac2O (2 mL) was added
slowly, and the reaction mixture was stirred at ꢀ33 °C for 1.5 h at which
time TLC analysis (EtOAc/hexane, 1.5:8.5) indicated complete con-
sumption of the starting material. The reaction mixture was poured into
20 mL ice-cold H2O, brine (10 mL) was added, and the aqueous layer
was extracted with diethyl ether (3 ꢁ 20 mL). The combined organic
extracts were dried over anhydrous Na2SO4 and filtered, and the solvent
was coevaporated with toluene until dryness. The residue was dissolved
in DCM (5 mL), the solution was cooled to 0 °C, and Et3N (0.27 mL,
1.99 mmol) was added under Ar. After complete addition of Et3N, the
cooling bath was removed and stirring continued for 2 h at room
temperature after which time DCM (10 mL) was added to the reaction.
The reaction solution was washed successively with 1 M HCl (10 mL)
solution, H2O (2 ꢁ 20 mL), and brine (10 mL), dried over anhydrous
Na2SO4 and filtered, and the filtrate was concentrated under reduced
pressure. The crude product was loaded onto the column of silica-gel
saturated with 1% Et3N and then purified by column chromatography
(EtOAc/hexane/Et3N, 0.2:8.8:1f1:8:1) to furnish 2-nitro compound 8
(0.51 g, 77% yield over two steps)] as white solid. Rf 0.31 (EtOAc/
hexane, 1.5:8.5); The 1H NMR (300 MHz, CDCl3): δ 8.36 (s, 1H, H-1),
7.41ꢀ7.26 (m, 10H, aromatic H), 5.00 (br s, 1H, H-5), 4.73 (br s, 1H,
H-3), 4.62 (br s, 2H, CH2Ph), 4.55 (br s, 2H, CH2Ph), 4.33 (app d, 1H,
J4,3 1.8 Hz, H-4), 3.48 (s, 3H, CO2CH3); 13C NMR (75.5 MHz,
CDCl3): δ 166.0 (CO2CH3), 154.5 (C-1), 136.8, 136.3 (aromatic),
130.9 (C-2), 128.7, 128.5, 128.4, 128.3, 128.1, 128.0, 127.7 (aromatic),
74.3 (C-5), 72.3, 72.0 (2 ꢁ CH2Ph), 71.6 (C-4), 66.7 (C-3), 52.6
(CO2CH3); LRMS (ESI): m/z 441 [(M þ H2O þ Na)þ 100%].
Methyl [(Dimethyl phosphonyl) 3,4-di-O-benzyl-2-nitro-
1,2-dideoxy-β-L-gulopyranosid]uronate (10). A solution of
compound 8 (0.8 g, 2 mmol) in THF (5 mL) was added to a solution
of dimethyl phosphonate (2.2 mL, 24 mmol) and Et3N (4.2 mL, 30 mmol)
in THF (5 mL) at room temperature under Ar. The reaction mixture was
stirred for 48 h, after which it was concentrated under reduced pressure,
and the residue was loaded onto a column of silica gel and purified
by chromatography (EtOAc/hexane, 2.5:7.5f3:2) to furnish the title
compound 10 [0.36 g, 35%; 43% based on recovered starting material
(0.14 g)] as a clear oil. Rf 0.31 (EtOAc/hexane, 3:2); 1H NMR (300 MHz,
CDCl3): δ 7.40ꢀ7.27 (m, 8H, aromatic H), 7.13ꢀ7.08 (m, 2H, aromatic
H), 5.24 (dd, 1H, J1,2 7.8 Hz, JH-1,P 10.8 Hz, H-1), 5.13ꢀ5.05 (m, 1H,
H-2), 4.62 (dd, 2H, Jgem 12.0 Hz, Jgem 12.0 Hz, CH2Ph), 4.51 (br d, 1H,
J5,4 1.5 Hz, H-5), 4.32 (dd, 2H, Jgem 11.1 Hz, Jgem 11.4 Hz, CH2Ph),
4.27ꢀ4.21 (m, 2H, H-3, H-4), 3.83 (d, 3H, JH,P 4.8 Hz, POCH3), 3.80
(d, 3H, JH,P 4.5 Hz, POCH3), 3.46 (s, 3H, CO2CH3); 13C NMR
(75.5 MHz, CDCl3): δ 168.7 (CO2CH3), 136.6, 135.8, 128.7, 128.6,
128.4, 128.3, 128.1, 127.9, 127.8, 127.6 (aromatic), 78.9 (d, JC,P 2.2 Hz,
C-2), 74.0 (d, JC,P 8.3 Hz, C-3), 73.2 (CH2Ph), 73.1 (C-4), 72.2
(CH2Ph), 72.0 (d, JC,P 12.8 Hz, C-5), 64.9 (d, JC,P 173.6 Hz, C-1),
54.0 (d, JC,P 6.7 Hz, POCH3), 53.7 (d, JC,P 6.7 Hz, POCH3), 52.3
(CO2CH3); 31P NMR (121.5 MHz, CDCl3): δ þ20.30; LRMS (ESI):
m/z 532 [(M þ Na)þ 100%]; HRMS calcd for C23H28NO10P1
[M þ H]þ 510.152359, found 510.154906.
obtained from 1.5 g of Raney nickel/aluminum alloy was suspended in
EtOH (10 mL) and added to the reaction vessel, and the mixture was
shaken in a Parr hydrogenation apparatus at a hydrogen pressure of
45 psi. After 24 h, the catalyst was carefully filtered through Celite, and
the filtrate was evaporated under reduced pressure to yield the crude
amine which was dissolved in Ac2O (2 mL) and stirred overnight at
room temperature under N2. Coevaporation of the Ac2O with toluene,
followed by column chromatography (EtOAcfMeOH/EtOAc 0.4:9.6)
afforded the 2-acetamido compound 11 (0.14 g, 68% over two steps)] as
an oil. Rf 0.42 (MeOH/EtOAc, 0.4:9.6); 1H NMR (300 MHz, CDCl3):
δ 7.35ꢀ7.26 (m, 8H, aromatic H), 7.15ꢀ7.11 (m, 2H, aromatic H), 5.87
(d, 1H, JNH,H-2 7.8 Hz, NH), 4.74ꢀ4.56 (m, 4H, H-2, H-1, CH2Ph),
4.48 (br d, 1H, J5,4 1.5 Hz, H-5), 4.43 (d, 1H, Jgem 11.7 Hz, CHPh), 4.21
(d, 1H, Jgem 11.7 Hz, CHPh), 4.16 (dt, 1H, J4,5 1.8 Hz, J4,3 3.9 Hz, JH-4,P
1.8 Hz, H-4), 3.85 (d, 3H, JH,P 10.8 Hz, POCH3), 3.87ꢀ3.83 (m, 1H,
H-3), 3.80 (d, 3H, JH,P 10.5 Hz, POCH3), 3.52 (s, 3H, CO2CH3),
1.84 (s, 3H, NHCOCH3); 13C NMR (75.5 MHz, CDCl3): δ 169.6
(NHCOCH3), 169.4 (CO2CH3), 137.2, 136.9, 128.6, 128.5, 128.2,
128.0, 127.9 (aromatic), 73.7 (d, JC,P 11.3 Hz, C-3), 73.1 (C-4), 73.0
(C-5), 72.6, 71.8 (2 ꢁ CH2Ph), 65.5 (d, JC,P 168.3 Hz, C-1), 53.8 (d, JC,P
7.5 Hz, POCH3), 53.4 (d, JC,P 6.0 Hz, POCH3), 52.1 (CO2CH3), 44.5
(C-2), 23.3 (NHCOCH3); LRMS (ESI): m/z 544 [(M þ Na)þ 100%].
Methyl [(Dimethyl phosphonyl) 2-acetamido-3,4-di-O-acet-
yl-1,2-dideoxy-β-L-gulopyranosid]uronate (12). Compound 11
(0.14 g, 0.268 mmol) was dissolved in methanol (2 mL) under N2, then
Pd/C (60 mg, 10% Pd/C) was added, cautiously followed by AcOH
(2 mL), and the reaction was stirred under an H2 atmosphere for 3 h.
The reaction mixture was then carefully filtered through Celite, the
solvent was evaporated, and the crude diol was subsequently treated with
Ac2O (0.5 mL) in pyridine (1 mL) under N2. The reaction mixture was
stirred overnight at room temperature and then coevaporated with
toluene. The crude residue was purified by column chromatography
(EtOAcfMeOH/EtOAc, 0.6:9.4) to yield title compound 12 (90 mg,
79% over two steps) as a colorless viscous syrup. Rf 0.25 (MeOH/
EtOAc, 0.4:9.6); 1H NMR (300 MHz, CDCl3): δ 5.79 (d, 1H, JNH,H-2
7.5 Hz, NH), 5.37 (dt, 1H, J4,5 1.8 Hz, J4,3 3.9 Hz, JH-4,P 1.8 Hz, H-4),
5.24 (app q, 1H, J3,4 3.6 Hz, J3,2 3.6 Hz, JH-3,P 3.3 Hz, H-3), 4.79ꢀ4.69
(app dtd, 1H, J2,3 ∼2.7 Hz, J2,NH 7.8 Hz, J2,1 10.5 Hz, JH-2,P ∼8.0 Hz,
H-2), 4.61 (app t, 1H, J1,2 10.5 Hz, JH-1,P 10.8 Hz, H-1), 4.56 (br d, 1H,
J5,4 1.5 Hz, H-5), 3.92 (d, 3H, JH,P 11.1 Hz, POCH3), 3.83 (d, 3H, JH,P
10.8 Hz, POCH3), 3.77 (s, 3H, CO2CH3), 2.16 (s, 3H, OCOCH3), 2.03
(s, 3H, OCOCH3), 1.96 (s, 3H, NHCOCH3); 13C NMR (75.5 MHz,
CDCl3): δ 170.0, 169.6 (OCOCH3), 168.6 (NHCOCH3), 168.2
(CO2CH3), 73.0 (d, JC,P 12.0 Hz, C-5), 67.8, 67.7 (C-3, C-4), 65.6
(d, JC,P 167.6 Hz, C-1), 53.7, 53.6 (2 ꢁ POCH3), 52.4 (CO2CH3), 44.2
(C-2), 23.1 (NHCOCH3), 21.0, 20.5 (OCOCH3); 31P NMR (121.5 MHz,
CDCl3): δ þ20.96; LRMS (ESI): m/z 448 [(M þ Na)þ 100%]; HRMS
calcd for C15H24NO11P1 [M þ H]þ 426.115974, found 426.118069.
Dimethyl (2-Acetamido-3,4,6-tri-O-benzyl-1,2-dideoxy-β-
D-glucopyranosyl)phosphonate (14). 3,4,6-Tri-O-benzyl-2-ni-
tro-β-D-glucosyl phosphonate 13,14 (2 g, 3.50 mmol) was dissolved in
EtOH (50 mL) and transferred to a hydrogenation vessel. Platinized
Raney nickel catalyst was freshly prepared according to the method
of Nishimura.22 The material obtained from 10 g of Raney nickel/
aluminum alloy was suspended in EtOH (50 mL) and added to the
reaction vessel, and the mixture was shaken in a Parr hydrogenation
apparatus at a hydrogen pressure of 45 psi. After 24 h, the catalyst was
carefully filtered through Celite, and the filtrate was evaporated under
reduced pressure to yield the crude amine which was dissolved in Ac2O
(20 mL) and stirred overnight at room temperature under N2. Coeva-
poration of the Ac2O with toluene, followed by column chromatography
(EtOAc/hexane, 1:1fMeOH/EtOAc, 0.4:9.6) afforded the 2-acetami-
do compound 14 [0.99 g, 48% over two steps; 59% based on recovered
starting material (0.35 g)] as an oil. Rf 0.43 (MeOH/EtOAc, 0.4:9.6);
Methyl [(Dimethyl phosphonyl) 2-acetamido-3,4-di-O-ben-
zyl-1,2-dideoxy-β-L-gulopyranosid]uronate (11). 2-Nitro com-
pound 10 (0.2 g, 0.39 mmol) was dissolved in EtOH (5 mL) and trans-
ferred to a hydrogenation vessel. Platinized Raney nickel catalyst was
freshly prepared according to the method of Nishimura.22 The material
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The Journal of Organic Chemistry
NOTE
1H NMR (300 MHz, CDCl3): δ 7.28ꢀ7.17 (m, 15H, aromatic H), 5.70
(br s, 1H, NH), 4.81 (app t, 2H, Jgem 12.3 Hz, CH2Ph), 4.65 (d, 1H, Jgem
10.8 Hz, CHPh), 4.56 (d, 1H, Jgem 10.8 Hz, CHPh), 4.51 (br s, 2H,
CH2Ph), 4.33ꢀ4.12 (m, 2H, H-1, H-3), 3.81ꢀ3.53 (m, 11H, 2 ꢁ
POCH3, H-6, H-60, H-4, H-2, H-5), 1.82 (s, 3H, NHCOCH3); LRMS
(ESI): m/z 606 [(M þ Na)þ 100%]; HRMS calcd for C31H38NO8P1
[M þ H]þ 584.24078, found 584.241636.
while a solution of aq NaOCl (12.5% w/v, 0.5 mL), containing satd aq
NaHCO3 (0.25 mL) and satd aq NaCl (0.4 mL), was added dropwise
over 10 min. After 30 min, a further portion of aq NaOCl (12.5% w/v,
0.5 mL) was added and the reaction mixture was stirred for another 15 min.
The resulting mixture was acidified to pH 2 using dilute HCl (4M) and
diluted with CHCl3 (10 mL). The layers were separated and the organic
layer was washed with H2O (2 ꢁ 10 mL) followed by brine (10 mL) and
then dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. To the residue in anhydrous MeOH (3 mL) under Ar
was added trimethyl orthoformate (0.043 mL, 0.39 mmol), followed by
cautious addition of SOCl2 (0.015 mL, 0.20 mmol) and the reaction was
stirred under Ar at rt for 30 min and then coevaporated with toluene
until dryness. The crude reaction material was purified by column
chromatography (DCMfMeOH/DCM, 0.6:9.4) to furnish the title
compound 17 (0.08 g, 76% over two steps) as a colorless oil. Rf 0.46
(MeOH/EtOAc, 0.4:9.6); 1H NMR (300 MHz, CDCl3): δ 7.29ꢀ7.11
(m, 10H, aromatic H), 6.11 (d, 1H, JNH,H-2 7.8 Hz, NH), 4.77 (d, 1H,
Jgem 11.4 Hz, CHPh), 4.69 (d, 1H, Jgem 10.8 Hz, CHPh), 4.61 (d, 1H,
Jgem 11.4 Hz, CHPh), 4.52 (d, 1H, Jgem 10.8 Hz, CHPh), 4.33 (dd, 1H,
J1,2 9.9 Hz, JH-1,P 10.8 Hz, H-1), 4.18 (app t, 1H, J3,2 9.0 Hz, J3,4 9.6 Hz,
H-3), 3.90 (d, 1H, J5,4 9.6 Hz, H-5), 3.75 (d, 3H, JH,P 10.5 Hz, POCH3),
3.72ꢀ3.69 (m, 2H, H-4, H-2), 3.68 (d, 3H, JH,P 10.8 Hz, POCH3), 3.63
(s, 3H, CO2CH3), 1.77 (s, 3H, NHCOCH3); 13C NMR (75.5 MHz,
CDCl3): δ 171.1 (NHCOCH3), 168.6 (CO2CH3), 138.2, 137.6, 129.1,
128.9, 128.4, 127.9, 127.8 (aromatic), 80.8 (d, JC,P 16.8 Hz, C-3), 80.0
(C-4), 79.4 (d, JC,P 18.2 Hz, C-5), 75.2, 74.9 (2 ꢁ CH2Ph), 72.4 (d, JC,P
169.8 Hz, C-1), 54.6 (d, JC,P 6.7 Hz, POCH3), 53.5 (POCH3),
53.4 (CO2CH3), 52.4 (C-2), 23.4 (NHCOCH3); LRMS (ESI): m/z 544
[(M þ Na)þ 100%]; HRMS calcd for C25H32NO9P1 [M þ H]þ
522.188745, found 522.188419.
Methyl [(Dimethyl phosphonyl) 2-acetamido-3,4-di-O-
acetyl-1,2-dideoxy-β-D-glucopyranosid]uronate (18). Com-
pound 17 (0.89 g, 1.70 mmol) was dissolved in methanol (45 mL)
and EtOAc (5 mL) under N2, then Pd/C (300 mg, 10% Pd/C) was
added cautiously followed by AcOH (1 mL), and the reaction was stirred
under an H2 atmosphere for 12 h. The reaction mixture was carefully
filtered through Celite, and the solvent was evaporated under reduced
pressure to yield the 3,4-diol that was subsequently treated with Ac2O
(5 mL) in pyridine (10 mL) under N2. The reaction mixture was stirred
overnight at room temperature and then coevaporated with toluene
under reduced pressure to yield the title compound 18 (0.79 g, crude
yield over two steps) as a light-yellow sticky foam. Due to difficulty in
TLC visualization, the compound was not purified by column chroma-
tography but was pure by NMR analysis. 1H NMR (300 MHz, CDCl3):
δ 6.61 (d, 1H, JNH,H-2 8.4 Hz, NH), 5.48 (dd, 1H, J3,2 9.3 Hz, J3,4 10.2
Hz, H-3), 5.08 (app t, 1H, J4,3 9.6 Hz, J4,5 9.9 Hz, H-4), 4.33 (app t, 1H,
Dimethyl (2-Acetamido-6-O-acetyl-3,4-di-O-benzyl-1,2-di-
deoxy-β-D-glucopyranosyl)phosphonate (15). Compound 14
(0.8 g, 1.37 mmol) was taken up in anhydrous DCM (16 mL), and to this
solution was added Ac2O (7.8 mL) followed by addition of a solution of
TMSOTf (1 mL, 5.5 mmol) in DCM (10 mL) at ꢀ40 °C under Ar. The
reaction mixture was stirred at ꢀ40 °C and monitored by TLC analysis
(MeOH/EtOAc 0.4:9.6). After 6 h, TLC analysis indicated slow
conversion of the starting material, so the reaction mixture was brought
to 0ꢀ4 °C and then stirred at this temperature for 12 h, at which time
TLC analysis indicated complete consumption of the starting material.
The reaction mixture was quenched by addition of satd aq NaHCO3
(20 mL). The aq. layer was extracted with DCM (3 ꢁ 30 mL) and the
combined organic phase was washed successively with H2O (50 mL),
brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated
to afford compound 15 (0.74 g) as a white solid. The product was pure
by 1H NMR analysis and therefore was used as such for the next step.
Rf 0.36 (MeOH/DCM, 0.4:9.6); 1H NMR (300 MHz, CDCl3):
δ 7.28ꢀ7.18 (m, 10H, aromatic H), 5.70 (d, 1H, JNH,H-2 7.8 Hz,
NH), 4.79 (d, 1H, Jgem 11.7 Hz, CHPh), 4.77 (d, 1H, Jgem 11.1 Hz,
CHPh), 4.61 (d, 1H, Jgem 11.4 Hz, CHPh), 4.50 (d, 1H, Jgem 10.8 Hz,
CHPh), 4.34ꢀ4.22 (m, 2H, H-60, H-1), 4.17 (app t, 1H, J3,4 = J3,2 9.3 Hz,
0
H-3), 4.05 (dd, 1H, J6,5 5.1 Hz, J6,6 12.0 Hz, H-6), 3.73 (d, 3H, JH,P
10.5 Hz, POCH3), 3.67 (d, 3H, JH,P 10.8 Hz, POCH3), 3.60ꢀ3.49
(m, 2H, H-2, H-5), 3.40 (t, 1H, J4,3 9.3 Hz, H-4), 1.95 (s, 3H,
OCOCH3), 1.77 (s, 3H, NHCOCH3).
Dimethyl (2-Acetamido-3,4-di-O-benzyl-1,2-dideoxy-β-D-
glucopyranosyl)phosphonate (16). To a stirred solution of crude
15 (0.74 g, 1.38 mmol) in anhydrous methanol (20 mL) was added a
methanolic solution of NaOMe (1.5 mL of a 1 M solution) at 0 °C under
N2. The reaction mixture was allowed to reach room temperature and
was stirred for 1.5 h at which time TLC analysis (MeOH/DCM 0.4:9.6)
indicated complete conversion to the product. The resulting solution
was neutralized with Amberlite IR-120 (Hþ) resin, and then the resin
was removed by filtration, washed several times with MeOH, and the
combined filtrate was evaporated under reduced pressure to give yellow
oil which was purified by column chromatography (DCMfMeOH/
DCM, 0.8:9.2) to provide the product 16 (0.60 g, 88% over two steps
1
from pure compound 14). Rf 0.23 (MeOH/DCM, 0.4:9.6); H NMR
(300 MHz, CDCl3): δ 7.28ꢀ7.19 (m, 10H, aromatic H), 6.08 (d, 1H,
JNH,H-2 7.8 Hz, NH), 4.79 (d, 1H, Jgem 11.4 Hz, CHPh), 4.77 (d, 1H, Jgem
11.1 Hz, CHPh), 4.61 (d, 1H, Jgem 11.4 Hz, CHPh), 4.58 (d, 1H, Jgem
10.8 Hz, CHPh), 4.28 (app dd, 1H, J1,2 9.6 Hz, JH-1,P 10.8 Hz, H-1), 4.12
(app t, 1H, J3,4 = J3,2 9.3 Hz, H-3), 3.81ꢀ3.77 (m, 1H, H-60), 3.73 (d, 3H,
JH,P 10.8 Hz, POCH3), 3.68 (d, 3H, JH,P 10.5 Hz, POCH3), 3.67ꢀ3.57
(m, 2H, H-2, H-6), 3.50 (app t, 1H, J4,5 = J4,3 9.9 Hz, H-4), 3.41ꢀ3.35
(m, 1H, H-5), 1.78 (s, 3H, NHCOCH3); 13C NMR (75.5 MHz,
CDCl3): δ 171.0 (NHCOCH3), 138.4, 137.9, 128.7, 128.5, 128.4,
128.2, 128.0, 127.9, 127.7 (aromatic), 81.7 (d, JC,P 8.4 Hz, C-3), 81.5
(d, JC,P 7.0 Hz, C-5), 78.3 (C-4), 75.2, 74.9 (2 ꢁ CH2Ph), 72.0 (d, JC,P
170.4 Hz, C-1), 61.9 (C-6), 54.2 (d, JC,P 6.5 Hz, POCH3), 53.5 (C-2),
53.2 (d, JC,P 7.0 Hz, POCH3), 23.4 (NHCOCH3).
J1,2 10.2 Hz, JH-1,P 10.8 Hz, H-1), 4.08 (br app pent, 1H, J2,1, J2,3, J2,NH
,
JH-2,P > ∼9ꢀ10 Hz, H-2), 4.01 (d, 1H, J5,4 10.2 Hz, H-5), 3.82 (d, 3H, JH,
P 10.8 Hz, POCH3), 3.76 (d, 3H, JH,P 10.5 Hz, POCH3), 3.67 (s, 3H,
CO2CH3), 2.01 (s, 3H, OCOCH3), 1.98 (s, 3H, OCOCH3), 1.89
(s, 3H, NHCOCH3); 13C NMR (75.5 MHz, CDCl3): δ 170.8, 170.4
(OCOCH3), 169.4 (NHCOCH3), 167.1 (CO2CH3), 77.2 (d, JC,P 17.7
Hz, C-5), 72.6 (d, JC,P 171.0 Hz, C-1), 72.0 (d, JC,P 18.4 Hz, C-3), 69.5
(C-4), 54.6 (d, JC,P 6.8 Hz, POCH3), 54.0 (d, JC,P 7.1 Hz, POCH3), 52.7
(CO2CH3), 51.0 (C-2), 23.1 (NHCOCH3), 20.6, 20.4 (OCOCH3);
31P NMR (121.5 MHz, CDCl3): δ þ18.42; LRMS (ESI): m/z 448
[(M þ Na)þ 100%]; HRMS calcd for C15H24NO11P1 [M þ H]þ
426.115974, found 426.116790.
Methyl [(Dimethyl phosphonyl) 2-acetamido-3,4-di-O-ben-
zyl-1,2-dideoxy-β-D-glucopyranosid]uronate (17). To a solution
of 6-hydroxy derivative 16 (0.1 g, 0.20 mmol) and TEMPO (0.40 mg,
0.0025 mmol) in DCM (1 mL) was added a solution of satd aq NaHCO3
(0.4 mL) containing KBr (2.16 mg, 0.018 mmol) and nBu4NBr (0.32
mg, 0.001 mmol). The biphasic solution was stirred vigorously at 0 °C,
’ ASSOCIATED CONTENT
S
Supporting Information. Copies of NMR spectra for all
b
novel compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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The Journal of Organic Chemistry
NOTE
’ AUTHOR INFORMATION
(28) Mann, M. C.; Thomson, R. J.; Dyason, J. C.; McAtamney, S.;
von Itzstein, M. Bioorg. Med. Chem. 2006, 14, 1518.
(29) Kancharla, P. K.; Vankar, Y. D. J. Org. Chem. 2010, 75, 8457.
(30) Alonso, R. A.; Vite, G. D.; McDevitt, R. E.; Fraser-Reid, B.
J. Org. Chem. 1992, 57, 573.
Corresponding Author
*E-mail: m.vonitzstein@griffith.edu.au.
’ ACKNOWLEDGMENT
M.v.I. gratefully acknowledges the support of the Australian
Research Council through the award of a Federation Fellowship.
B.B. thanks Griffith University for the award of a postgraduate
scholarship and an international postgraduate research scholarship.
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