Ceric ammonium nitrate/acetic anhydride: A tunable system for the O-acetylation and mononitration of diversely protected carbohydrates

Article abstract of DOI:10.1080/00397911.2016.1230219

Esterification of a wide range of partially protected carbohydrate derivatives was achieved using acetic anhydride and a catalytic amount of ceric ammonium nitrate (CAN). Compatibility with the commonly used protecting groups was demonstrated, with the es

Full text of DOI:10.1080/00397911.2016.1230219

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Ceric Ammonium Nitrate / Acetic Anhydride:
A Tunable System for the O-Acetylation
and Mononitration of Diversely Protected
Carbohydrates
Mohindra Seepersaud, Savita Seecharan, Lorale J. Lalgee & Nigel Kevin Jalsa
To cite this article: Mohindra Seepersaud, Savita Seecharan, Lorale J. Lalgee & Nigel Kevin Jalsa
(2017): Ceric Ammonium Nitrate / Acetic Anhydride: A Tunable System for the O-Acetylation and
Mononitration of Diversely Protected Carbohydrates, Synthetic Communications
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1230219
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Date: 06 March 2017, At: 19:13

Ceric Ammonium Nitrate / Acetic Anhydride: A Tunable System for the O-
Acetylation and Mononitration of Diversely Protected Carbohydrates
Mohindra Seepersaud1, Savita Seecharan1, Lorale J. Lalgee1, Nigel Kevin Jalsa1
1Department of Chemistry, The University of the West Indies, St. Augustine, Trinidad
and Tobago
Corresponding Author Nigel Kevin Jalsa E-mail: nigel.jalsa@sta.uwi.edu
Abstract
Esterification of a wide range of partially protected carbohydrate derivatives was
achieved using acetic anhydride and a catalytic amount of ceric ammonium nitrate.
Compatibility with the commonly used protecting groups was demonstrated, with the
esterified products being furnished in good yields. Apart from affording the O-acetylated
products, their mononitrated counterparts were also produced depending upon the
reactivity of the starting material. Decreasing the molar equivalents of CAN afforded the
O-acetylated products exclusively, while increasing it favored the mononitrated
derivatives.
Graphical Abstract
INTRODUCTION
The design and synthesis of any oligosaccharide requires careful selection of protecting
groups employed throughout the scheme. Orthogonal compatibility of the different
1

groups utilized must be ensured: this encompasses both (1) tolerance to other groups
present and any glycoside bonds, in the protecting and deprotection steps, and (2) general
alignment with the glycosidation strategy required, for example, whether anchimeric
assistance over the stereochemistry of the resulting glycoside bond is a necessity.[1]
A common class of protecting groups are the esters, with the most popular being the O-
acetate group.[2] It is easily introduced and deprotected under a variety of mild conditions;
which generally involve acetic anhydride as both solvent and reactant, and some other
requisite catalyst/promoter. The single most popular means of introducing the O-acetate
group employs pyridine as both co-solvent and base,[3] with or without a catalytic amount
of DMAP.[4] However, the highly toxic nature and unpleasant smell of pyridine has led to
an ongoing search for alternatives. Many such examples exist, which span the range from
Lewis acids[5] such as I2,[6] In(OTf)3,[7] Ce(OTf)3,[8] BF3.OEt2,[9] Fe2(SO4)3,[10]
Er(OTf)3,[11] Me3SiCl;[12] to solid supports involving Nafion-H,[13] molecular sieves,[14]
Montmorillonite K-10,[15] as well as techniques involving microwave irradiation.[16] All
of these excellent methods are quite effective at yielding the per-O-acetylated derivatives
in near quantitative yield. However, many suffer from a lack of compatibility with other
frequently employed groups; most notably causing the deprotection of O-benzyls and in
some cases, many other popular protections such as O-trityl, O-silyl and O-benzylidenes.
This has necessitated the reluctant utilization of the pyridine system, when the substrate is
a derivatized sugar, as opposed to the free monosaccharide.
2

At the other end, the O-nitrate ester (-ONO2) could lay claim to being the least popular of
the esters and other classes in general; its use as a protecting group is completely absent
from the modern literature.[17] This underutilization could be largely attributed to the
inherent difficulty associated with controlled nitration.[18] It is generally observed that
regardless of the reagent combination used, all free hydroxyls present in the carbohydrate
will be nitrated. Such a global, non-specific, derivatization would be of little use in an
extended synthetic sequence where it is often necessary to distinguish among different
hydroxyls for reactivity purposes. As further deterrents, carbohydrates bearing multiple
nitrate groups are frequently explosive,[19] and the reagents used for their synthesis (a
common combination is a mixture of conc. HNO3 and conc. H2SO4) present a difficult
work-up procedure. In addition, the different reagents available are often not compatible
with the range of protecting groups utilized in modern syntheses. While the combinations
of conc. HNO3/Ac2O[20] or N2O5/CHCl3,[21] will not cause significant deprotection of the
acid-labile groups such as benzylidene, isopropylidene and trityl, most of the common
nitrating mixtures will result in deprotection of any O-Bn groups present or nitration of
their aromatic rings. Methods exist for the introduction of a nitrate group exclusively at
the anomeric centre, starting from either anomeric chlorides or bromides.[22] However,
mononitration at non-anomeric positions is traditionally a significantly more difficult
endeavor, with the reported strategies involving the displacement of a previously installed
triflate leaving group.[17a,23] The most recent approach towards the synthesis of nitrate
esters utilized a LiNO3 / (CF3CO)2O system, this reagent combination furnished the
nitrated derivatives in good yields, and showed compatibility with a variety of
isopropylidene rings in different configurations and orientations.[24]
3

Despite these synthetic difficulties, the non-anomeric mononitrated carbohydrate
derivatives present very attractive properties: (1) they are sufficiently stable to heat and
shock;[19a] (2) they improve the acid stability of other groups present;[25] (3) they exhibit
orthogonal compatibility towards conditions required for the removal of other common
protecting groups, such as tolerance to dilute acids (for acetals and ketals)[26] and dilute
bases (for acetates and benzoates);[27] and (4) their deprotection can be easily effected
under a wide range of reductive conditions, such as: Pd/CaCO3,[28] Pd/C,[17b] LiAlH4,[29]
or hydrazine,[23,30] any of which would convert the –ONO2 to –OH; or a Zn/HCl/AcOH
combination that can be used to transform the O-nitrate into an O-acetate.[31]
Alternatively, removal of nitrates can also occur by photolysis, a mild protocol which is
compatible with the common protecting groups.[17a,23] In addition to being easily
deprotected, organic nitrates can undergo functional, synthetically useful, transformations
into reactive alkoxy radicals in the presence of tributyltin hydride / AIBN.[17a,23,32]
Having already demonstrated the utility of the range of common lanthanide salts, in
conjunction with Ac2O, in effecting the synthesis of per-O-acetylated derivatives from
the free monosaccharides in high yield,[33] we decided to investigate the applicability of
ceric ammonium nitrate in acetylating differentially protected carbohydrate derivatives.
CAN was chosen as the favoured Lanthanide salt due to its affordability and common use
(and hence availability) in many synthetic transformations.[34] Presented herein are the
results of this study, where the effect of temperature and stoichiometric ratio of the
reagent system on the esterification efficiency were investigated. Interestingly, not only
4

does the CAN/Ac2O afford the partially O-acetylated derivatives in high yield, but the
system can be optimized to yield the mononitrated derivatives as well.
RESULTS AND DISCUSSION
A variety of carbohydrate derivatives with: (1) at least one free hydroxyl; and (2) which
possessed the most commonly employed protecting groups, ranging from acid-labile
constructs such as isopropylidene, benzylidene, silyl and trityl to other important groups
such as benzyl and allyl functionalities, were examined. Substrates were chosen so as to
exemplify and encompass the diversity of structures that may be encountered in synthetic
routes, including pyranosides and furanosides. Examples include those where the O-Bn
group was situated in a range of secondary positions and at the primary and anomeric
centres; as well as where the O-benzylidene ring was present in cis, trans and 5-
membered or 6-membered configurations.
Having previously reported that optimal results (reaction time and yield) were obtained
by dissolving the free sugar in Ac2O at 50 °C and then adding 0.1 equivalent CAN,[33]
this protocol was extended to the partially protected derivatives. The results are shown in
Table 1.
1,2;3,4-di-O-isopropylidene-α-D-galactopyranoside (Entry 1) was the first to be
examined, owing to its relative ease of synthesis in a single high-yielding step from D-
galactose, as well as due to its possession of two acid–labile isopropylidene rings. After
20 minutes, there was complete consumption of starting material, accompanied by the
5

formation of a faster moving spot on the TLC plate that corresponded to that of an
authentic sample of 6-O-acetate-1,2;3,4-di-O-isopropylidene-α-D-galactopyranoside, 1a.
Surprisingly, an even faster moving spot was also detected (Rf greater that of 1a).
Isolation and elucidation of this spot revealed it to be the nitrate ester equivalent, 1b, of
acetate 1a.
Applying these same reaction conditions, the overall trend was that those derivatives
bearing the acid-labile groups (Entries 1-10) all gave product (s) in which their
previously installed protecting groups were unaffected. More importantly, those
substrates in which O-Bn groups were present (Entries 9-23) were also preserved, with
the aromatic rings not undergoing any nitration. The tetra-O-Bn derivative (Entry 23) did
however undergo partial acetolysis of the different O-Bn groups to give a complex
mixture of di-O-Ac-tri-O-Bn products. In the majority of cases, the corresponding
nitrated esters were also formed, with the total yield of products [acetylated, a, and
nitrated, b] almost always exceeding 90 %. It should be noted that only the mononitrated
products were isolated, multiple nitrations of the same molecule did not occur. As with
1a and 1b, the nitrated derivatives always had a higher Rf, and hence were generally easy
to separate via column chromatography, from their acetylated counterparts. In addition,
for those substrates bearing a free anomeric hydroxyl (Entries 2, 5, 6, 9, 14, 16, 17 and
23), no nitration of this centre was observed. Where multiple non-anomeric hydroxyls
were available for esterification, the isomeric mononitrated products were usually
obtained. Apart from entries 19 and 20, the acetylated product was always obtained in
higher yield than that of the corresponding mononitrated isomers. The product
6

distribution observed for those substrates bearing free non-anomeric hydroxyls warrant
closer examination.
For silylated derivative (Entry 3), a mixture of mononitrated products was obtained, with
the nitrate group being present on either the 2, 3 or 4 positions, in a distribution ratio of
1:1.6:1, respectively. This suggests that nitration at the 3-OH position is most facile,
likely due to steric factors encountered at the 2 (axial) and 4 (proximity to the bulky O-
TBDPS group) positions.
For tritylated derivative (Entry 4), no mononitrated product was observed, however this
may be due to the pseudo-axially oriented 2 and 3-OHs not presenting a favourable
reacting centre for nitration.
Nitration vs acetylation appears to be controlled by electronic factors, with product
distribution of the resulting mononitrated isomers being governed by sterically accessible
centres.
With 4,6-O-benzylidene mannopyranose (Entry 5), no 2-O-NO2 isomer was detected;
only the more sterically accessible equatorial 3-OH being nitrated, albeit in low yield. For
the analogous 4,6-O-benzylidene galactopyranose (Entry 6), no nitrated products were
isolated. For all of the other entries, the ratio of nitrated isomers to each other can be
explained sterically, with the more reactive hydroxyl being more likely to be nitrated than
the others.[35]
7

For those examples where a free anomeric hydroxyl was available for esterification
(entries 2, 5, 6, 9, 14, 16, 17, 23) the α:β ratios generally exhibited a preference for the α-
anomer, the only exception being the 4,6-O-benzylidene mannopyranose derivative
(Entry 5), which favoured the β-product. This can be attributed to the influence of the
4,6-O-benzylidene ring on the anomeric equilibrium of mannopyranose.[36]
CAN in combination with a variety of wet solvents, most commonly acetonitrile, has
been used for the deprotection of many groups, including: trityl,[37] silyl,[38] acetals,[39]
ketals,[40] as well as hydrolysis of disaccharides.[41] That such deprotection is not
observed in the present reaction is suggestive of the critical role played by water in these
synthetic protocols.
Tanemura and co-workers showed that a mixture of 0.1 mol eq. CAN in Ac2O was
effective in cleaving the 2-methoxyethoxymethyl and methoxymethyl protecting
groups.[42] The mechanism was proposed to involve the production of acetyl nitrate from
the reaction between CAN and Ac2O. The acetyl nitrate would then generate the
+
CH3COO- and NO2 ions in a reversible reaction. However, for the nitration reaction
reported in this present work, if only 1 molecule of acetyl nitrate is generated per
molecule of CAN, then at a 0.1 mol eq. CAN, the maximum yield of nitrated derivative
would be 10 %, much less than the yields reported with some substrates (entries 1, 7, 8,
+
11, 13, 18-21). In Tanemura’s reaction, the NO2 generated was acting as a catalyst,
+
thereby maintaining equilibrium between CH3COONO2 and CH3COO-/NO2 . Acetyl
8

nitrate has been shown to act as a mild nitrating agent for a variety of substrates,[43] and it
+
is likely that it is also the active source of NO2 in the present reaction. In this case
+
however, nucleophilic attack of a reactive hydroxyl on the NO2 , followed by subsequent
deprotonation by CH3COO- (Scheme 1), drives the equilibrium forward, favouring the
complete, but sequential replacement of all the nitrate ions of CAN by acetate anions
(Scheme 2). Such a mechanism would allow for a maximum yield of 60 % with 0.1 mol
eq. CAN.
CAN as a viable source of the nitronium ion has also been demonstrated in the
widespread synthetic application of Lemieux’s azidonitration protocol, in which a
CAN/NaN3 mixture when reacted with a 1,2-glycal, affords a pyranoside derivative
bearing an anomeric nitro group and an azide at the 2-position.[44] Interestingly, under
these same conditions, 1,2-anhydrosugars furnished the anomeric azide, with a free 2-
OH.[45]
It is also possible that the acetyl nitrate is acting as the active acetylating agent,
regenerating CAN in the process. The relatively electron rich acetyl portion of this
reactant may explain the greater tendency of relatively more sterically accessible and/or
reactive hydroxyls to undergo acetylation, while the less nucleophilic hydroxyls favour
nitration (Scheme 3). However, the pathway involving activation of the carbonyl carbon
of Ac2O to nucleophilic attack, as a result of CeIV coordination to the acyl oxygen, cannot
be discounted as an alternative and competing acetylation mechanism.[46] The existence
of two acetylation pathways would account for the absence of a clearly defined
9

relationship between acetylated:nitrated product distribution ratio and structural /
electronic features of the available free hydroxyls.
13C NMR analysis (Table 2) proved very useful in quickly establishing which hydroxyl
had undergone nitration as opposed to acetylation. The carbon of the sugar ring, bonded
to a nitrate, experienced an average downfield chemical shift of 7 ppm, compared to its
acetylated counterpart; corroborating the greater electron withdrawing, and hence
deactivating, nature of a nitrate group as compared to an acetate. The proton attached to
the aforementioned carbon generally experienced a downfield shift, but not to any
diagnostically significant extent.
Next, having established the versatility of the CAN / Ac2O system for protecting group
compatible esterifications, we decided to optimize both acetylation and nitration yields
respectively. Choosing 1,2;3,4-di-O-isopropylidene-α-D-galactopyranoside as the test
substrate, esterifications were carried out under various conditions of equivalents of
CAN, temperature, and order of addition of reactants (Table 3).
Firstly, conducting the reaction at room temperature (entries 1-5), showed a direct
relation between the yield of acetylated:nitrated product distribution ratio and the
stoichiometric equivalents of CAN used. At 0.001 mol eq. CAN, no mononitrated
product was detected; indicating that this combination of Ac2O / CAN can be used to
yield exclusively the acetylated derivatives in yields comparable to that obtained with the
traditional pyridine / Ac2O protocol. Having demonstrated that the method can afford
10

exclusively the partially acetylated, differentially protected derivatives, we then turned
our attention to maximizing the yield of the nitrated derivatives. Increasing the mol eq. of
CAN from 0.1 to 1.0 (entry 4) resulted in a sizeable increase in the yield of the
mononitrated derivative, 1b, though the acetylated derivative, 1a, was still the favoured
product. Increasing further the mol eq. CAN to 3.0 (entry 5) did not result in any
appreciable increase in the yield of 1b. However, increasing the temperature (entries 6-9)
did result in an increase in the yield of 1b, though 1a was still marginally dominant.
Whilst the highest ratios favouring 1b were obtained at 80 °C (entries 8 and 9), the
absolute yield of the product was decreased, attributed to deprotection of the
isopropylidene rings, as per-O-acetylated galactopyranoside was recovered. At 50 °C
(entry 6) and 60 °C (entry 7), there was a visible amount of CAN that remained
undissolved in the Ac2O, even after the reaction had gone to completion. Reasoning that
maximization of the yield of the nitrated derivative would require a large concentration of
+
NO2 species present in solution, so as to effectively compete with the activated Ac2O
species, the order of addition of the reactants was altered.
The CAN was added to the Ac2O and allowed to fully dissolve (entries 10-17), before the
carbohydrate substrate was added. The effect of these “pre-mixing” conditions is
significant: for those pairs of experiments conducted at the same temperature and mol eq.
CAN (entries 6 and 11; entries 7 and 12; entries 9 and 17) there was an inverse in the
product distribution, with the desired nitrated derivative 1b, now being favoured over that
of its acetylated counterpart, 1a. While the best ratios favouring 1b (0.5:1) were obtained
with both 3.0 mol eq. CAN / 50 °C (entry 11) and 1.5 eq. CAN / 80 °C (entry 17), the
11

higher temperature again resulted in lower yields of the desired product, with per-O-
acetylated galactopyranoside being recovered.
Under the pre-mixing conditions, an increase in the yield of 1b was observed by
increasing either temperature or mol eq. CAN. Increasing temperature up to 80 °C
increased the distribution ratio favouring 1b, but at temperatures above 90 °C, evolution
of NO2 was observed. At 105 °C (entry 13), only when no more brown fumes of NO2
were visible, was the sugar added to the reaction mixture. While no per-O-acetylation
was observed, the yield of nitrated product was also negligible. This suggests that a fine
+
balance must exist between the amount of NO2 allowed in solution (favouring nitration)
and the removal of protecting groups (favoured by high mol eq. of CAN and elevated
temperatures).
Reasoning that higher temperatures would increase the susceptibility of aromatic rings to
undergo nitration or cause the deprotection of benzyl / benzylidene groups, the conditions
of entry 11 (3.0 mol eq. CAN per free non-anomeric hydroxyl/50 °C) were selected so as
to determine the maximum yields of the nitrated product that could be obtained with
selected O-TBDPS, O-Bn, and O-benzylidene protected derivatives (Table 4). In all cases
examined, the ratio of nitrated product (b):acetylated derivative (a) was increased.
However, for the O-Bn and O-benzylidene derivatives, this was accompanied by
formation of complex mixtures of acetolyzed products, indicating that deprotection of
these Lewis acid-labile groups is a competing side reaction at high concentrations of
CAN. For those derivatives in which multiple isomeric mononitration products were
12

synthesized (entries 1 and 3), the distribution ratios of the nitrated isomers were identical
to those obtained with 0.1 mol eq. CAN (entries 3 and 7 respectively, Table 1).
CONCLUSION
We have demonstrated the versatility and utility of the ceric ammonium nitrate / acetic
anhydride system for the acetylation of partially protected carbohydrate derivatives,
proceeding in high yield at low catalytic loading of CAN. Unlike most other acetylation
methods however, this system, as with the pyr / Ac2O combination, affords compatibility
with the range of commonly utilized protecting groups. Crucially however, it avoids toxic
and noxious chemicals, and possesses a straightforward work-up and purification
protocol.
As added evidence of enhanced versatility, it provides access to a range of mononitrated
carbohydrate derivatives, hitherto inaccessible. It is hoped that this body of work will
serve to stimulate interest and research in a long forgotten, but versatile carbohydrate
protecting group, the nitrate ester. The low yield of these shock and thermal stable
mononitrated products, is compensated for by the alternative routes for their synthesis,
especially in those derivatives possessing aromatic rings, being virtually non-existent.
Furthermore, it has been demonstrated that organic nitrates function as NO donors, and
are postulated to be a viable source of NO-mimetic targeted drugs.[47] This represents a
possible medicinal application for these nitrated carbohydrate derivatives.
EXPERIMENTAL
13

All chemicals used were reagent grade and used as purchased unless otherwise stated. 1H,
13C, COSY, HSQC, HMBC and TOCSY NMR experiments were recorded on Bruker
600, 400 or 300 NMR spectrometers in the deuterated solvents stated. Chemical shifts are
stated in ppm. Multiplicities are stated as either s (singlet), bs (broad singlet), d (doublet),
apptd (apparent doublet), t (triplet), apptt (apparent triplet), q (quartet), dd (doublet of
doublets), ddd (doublet of doublet of doublets), apptdd (apparent doublet of doublets),
apptqd (apparent quartet of doublets), ABq (AB quartet), m (multiplet) or pdd (pseudo
doublet of doublets). High-resolution mass spectral (HRMS) analyses were obtained
using a Bruker Daltonics micrOToF-Q instrument in the electron spray ionization mode.
Optical rotations were measured on a Bellingham & Stanley ADP 220 polarimeter at 24.6
°C. TLC was performed using pre-coated silica gel 60 F254 plates; compounds were
visualized using acidic ammonium molybdate solution (ammonium molybdate (VI)
tetrahydrate (25 g) in 1 M H2SO4 (500 mL)). Column chromatography was performed on
silica gel (70-230 mesh). Solvent systems used for TLC and column chromatography are
as follows: System A = 3:2 (Petroleum Ether: Ethyl Acetate); System B = 7:3 (Petroleum
Ether: Ethyl Acetate); System C = 1:1 (Petroleum Ether: Ethyl Acetate); System D = 2:3
(Petroleum Ether: Ethyl Acetate).
General Procedure A, For Esterification Using 0.1 Mol Eq. CAN:
The partially protected derivative (1.0 mmol) was dissolved in Ac2O (1-2 mL) and stirred
at 50 °C. Ceric ammonium nitrate (0.1 mmol) was added and stirring maintained. After
completion of the reaction, saturated NaHCO3 (20 mL) was added and the reaction stirred
at rt for 10 minutes. The mixture was then diluted with CH2Cl2 (50 mL), washed with
14

water (3 x 100 mL), and the organic layer was then dried over Na2SO4. The solvent was
removed under vacuum and the residue was then subjected to column chromatography.
General Procedure B, For Esterification Using 3.0 Mol Eq. CAN Per Free OH:
Ceric ammonium nitrate (1.5 mmol per free non-anomeric hydroxyl) was suspended in
Ac2O (2-4 mL) and stirred at 50 °C until all of the CAN had dissolved. The partially
protected derivative (0.5 mmol) was then added and stirring maintained. After
completion of the reaction, saturated NaHCO3 (20 mL) was added and the reaction stirred
at rt for 10 minutes. The mixture was then diluted with CH2Cl2 (50 mL), washed with
water (3 x 100 mL), and the organic layer was then dried over Na2SO4. The solvent was
removed under vacuum and the residue was then subjected to column chromatography.
Characterization Data:
6-O-Acetate-1,2;3,4-di-O-isopropylidene-α-D-galactopyranoside, (1a). White solid;
m.p. = 109.0 – 110.0 °C; Rf (System A) = 0.42; [α]D = - 53.6 (c, 1.2, CHCl3); NMR
data:[48] 1H NMR (400 MHz, CDCl3): δ: 1.340 (3H, s, CH3(CH3)C-), 1.341 (3H, s,
CH3(CH3)C-), 1.45 (3H, s, CH3(CH3)C-), 1.52 (3H, s, CH3(CH3)C-), 2.09 (3H, CH3CO-),
4.03 (1H, m, H-5), 4.18 (1H, dd, J5,6 = 7.7 Hz, J6,6’ = 11.5 Hz, H-6), 4.24 (1H, bd, J3,4
=
7.9 Hz, H-4), 4.29 (1H, dd, J5,6’ = 4.7 Hz, J6,6’ = 11.5 Hz, H-6’), 4.33 (1H, dd, J1,2 = 4.9
Hz, J2,3 = 2.1 Hz, H-2), 4.62 (1H, J2,3 = 2.1 Hz, J3,4 = 7.9 Hz, H-3), 5.54 (1H, d, J1,2 = 4.9
Hz, H-1); 13C NMR (100 MHz, CDCl3): δ: 20.9 (1C, CH3CO-), 24.5 (1C, CH3(CH3)C-),
24.9 (1C, CH3(CH3)C-), 25.9 (1C, CH3(CH3)C-), 26.0 (1C, CH3(CH3)C-), 63.4 (1C, C-6),
65.9 (1C, C-5), 70.4 (1C, C-2), 70.7 (1C, C-3), 71.0 (1C, C-4), 96.3 (1C, JC1-H1 = 177.1
15

Hz, C-1), 108.7 (1C, CH3(CH3)C-), 109.6 (1C, CH3(CH3)C-), 170.9 (1C, CH3CO-).
HRMS calculated for C14H22O7Na: 325.1258; found: 325.1242 (M + Na)+.
1,2;3,4-Di-O-isopropylidene-6-O-nitro-α-D-galactopyranoside, (1b). Colourless oil; Rf
(System A) = 0.22; [α]D = - 75.0 (c, 0.32, CHCl3); NMR data:23 1H NMR (400 MHz,
CDCl3): δ: 1.34 (3H, s, CH3(CH3)C-), 1.35 (3H, s, CH3(CH3)C-), 1.46 (3H, s,
CH3(CH3)C-), 1.51 (3H, s, CH3(CH3)C-), 4.08 (1H, td, J4,5 = 1.9 Hz, J5,6 = 6.1 Hz, J5,6’
=
6.0 Hz, H-5), 4.25 (1H, dd, J3,4 = 7.9 Hz, J4,5 = 1.9 Hz, H-4), 4.35 (1H, dd, J1,2 = 5.0 Hz,
J2,3 = 2.6 Hz, H-2), 4.60 – 4.62 (2H, m, H-6, H-6’), 4.65 (1H, J2,3 = 2.6 Hz, J3,4 = 7.9 Hz,
H-3), 5.53 (1H, d, J1,2 = 5.0 Hz, H-1); 13C NMR (100 MHz, CDCl3): δ: 24.4 (1C,
CH3(CH3)C-), 24.9 (1C, CH3(CH3)C-), 25.9 (1C, CH3(CH3)C-), 26.0 (1C, CH3(CH3)C-),
64.6 (1C, C-5), 70.3 (1C, C-2), 70.7, 70.9 (2C, C-3 and C-4), 71.6 (1C, C-6), 96.2 (1C,
JC1-H1 = 184.1 Hz, C-1), 109.0 (1C, CH3(CH3)C-), 109.9 (1C, CH3(CH3)C-). HRMS
calculated for C12H19O8NNa: 328.1003; found: 328.0991 (M + Na)+.
SUPPORTING INFORMATION
Supporting Information: Full experimental detail, 1H, 13C and selected 2D NMR spectra.
This material can be found via the “Supplementary Content” section of this article’s
webpage.
ACKNOWLEDGEMENTS
16

The authors would like to thank Mr. Franklyn Julien for provision of high resolution
mass spectral data, Mr. Keegan Dial for NMR spectra, and Dr. Lebert Grierson for
invaluable advice and discussions.
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Elsevier: Oxford, 2009; pp 203-224.
2. (a) Wuts, P. G. M.; Greene, T. W., Eds. Greene’s Protective Groups in Organic
Synthesis; John Wiley and Sons, Inc.: Hoboken, 2007, pp 223-239; 255-262. (b) Davis,
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21

Table 1. Esterification of diversely protected carbohydrates
Entr Substrate
y
Time
(h)
Product (s) [Yield (%)]a
OH
ONO2
1
0.3
OAc
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
1a
1b
[18 %]
[74 %]
TBDPSO
2
3
O
0.7
OH
O
OH
2
TBDPSO
HO
O
HO
OMe
OAc
O
OH
O
4
5
0.5
3
TrO
Ph
TrO
OMe
OMe
OAc
[83 %]
OH
4
OH
O
O
O
OH
HO
22

Ph
6
7
1.25
0.6
O
O
O
HO
OH
OH
Ph
O
O
O
HO
OH
OMe
OH
O
8
2
Ph
O
O
O
HO
Ph
9
0.2
O
O
O
OH
BnO
OBn
OBn
OBn
10
0.75
O
O
AcO
HO
O
O
O
O
Ph
Ph
10
[97 %]
23

OBn
11
2
O
HO
HO
OH
OH
12
3
HO
HO
HO
O
OBn
OBn
O
13
14
0.5
0.5
HO
HO
BnO
OBn
OBn
O
HO
HO
BnO
OH
24

15
16
1
HO
HO
HO
AcO
AcO
AcO
O
O
OBn
OBn
NHAc
NHAc
15 [90 %]
O
0.3
BnO
BnO
OH
OBn
17
18
BnO
0.3
0.3
O
OH
BnO OBn
OBn
OBn
OBn
O2NO
BnO
BnO
HO
AcO
BnO
BnO
O
O
O
BnO
BnO
OMe
OMe
18b [16 %]
OMe
18a [77 %]
OBn
O
19
20
0.4
0.4
BnO
HO
BnO
OMe
OBn
O
BnO
BnO
HO
OMe
OMe
BnO
BnO
BnO
21
22
0.4
2
BnO
BnO
AcO
O
O
O
BnO
O2NO
HO
BnO
BnO
BnO
OMe
OMe
21a [58 %]
21b [31 %]
AcO
AcO
AcO
HO
HO
HO
O
O
HO
O
AcO
O
O
O
OBn
HO
OH
AcO
OAc
OAc
OH
22 [98 %]
25

OBn
O
23
0.2
BnO
BnO
BnO
OH
aYields of chromatographically pure compounds. Ratios of nitrated isomers determined
by 1H NMR; not separable by silica gel chromatography.
26

Table 2 1H and 13C NMR comparisons of acetylated derivatives to their nitrated
counterparts
1H NMR (δ ppm)
Acetylated
product
13C NMR (δ ppm)
Acetylated
product
Mono-nitrated
equivalent
1b
Δ
Mono-nitrated
equivalent
1b
Δ
0.38
8.2
1a
1a
H-6: 4.18
H-6: 4.60
C-6: 63.4
C-6: 71.6
H-6’: 4.29
H-6’: 4.62
0.11
0.19
0.15
0.12
0.13
7.8
7.3
9.5
8.9
8.3
5a
5b
5a
5b
H-3: 5.22
H-3: 5.33
C-3: 69.9
C-3: 77.7
7a
7b-i
7a
7b-i
H-2: 4.91
H-2: 5.10
C-2: 71.6
C-2: 78.9
7a
7b-ii
7a
7b-ii
H-3: 5.58
H-3: 5.73
C-3: 68.9
C-3: 78.4
8a
8b-ii
8a
8b-ii
H-3: 5.44
H-3: 5.56
C-3: 68.4
C-3: 77.3
11a
11b-i
11a
11b-i
27

H-2: 5.30
H-2: 5.43
C-2: 69.5
C-2: 77.8
0.09
8.3
11a
11b-ii
11a
11b-ii
H-3: 5.36
H-3: 5.45
C-3: 69.5
C-3: 77.8
0.13
0.23
8.5
9.0
11a
11b-iii
11a
11b-iii
H-4: 5.09
H-4: 5.22
C-4: 71.1
C-4: 79.6
13a
13b-i
13a
13b-i
H-4: 5.38
H-4: 5.61
C-4: 68.3
C-4: 77.3
0.40
8.6
13a
13b-ii
13a
13b-ii
H-6: 4.20
H-6’: 4.28
14a
H-6: 4.59
H-6’: 4.68
14b-i
C-6: 63.3
C-6: 71.9
0.21
-
8.9
5.5
14a
14b-i
H-4: 5.47
H-4: 5.68
C-4: 67.4
C-4: 76.3
14a
14b-ii
14a
14b-ii
H-6: 4.12
H-6’: 4.21
H-6: 3.70
H-6’: 3.83
0.40 C-6: 62.7
C-6: 68.2
-
10.6
8.5
18a
18b
18a
18b
H-6: 4.32
H-6: 3.84
0.49 C-6: 63.6
C-6: 74.2
H-6’: 4.34
H-6’: 3.84
0.34
19a
19b
19a
19b
28

H-4: 5.35
H-4: 5.69
C-4: 69.1
C-4: 77.6
0.17
0.13
8.6
9.9
20a
20b
20a
20b
H-3: 5.21
21a
H-3: 5.38
21b
C-3: 74.6
21a
C-3: 83.2
21b
H-3: 5.51
H-3: 5.64
C-3: 73.5
C-3: 83.4
29