Ferrier Carbocyclization-Mediated Synthesis of Enantiopure Azido Inositol Analogues

Article abstract of DOI:10.1021/acs.joc.9b03064

Azide-modified inositol (InoAz) analogues are valuable as inhibitors and have shown promise as metabolic chemical reporters (MCRs) for labeling inositol-containing glycoconjugates in eukaryotic cells and potentially in mycobacteria, but the synthesis of enantiomerically pure InoAz analogues via traditional approaches is challenging. As a complementary route, here we investigated the application of the Ferrier carbocyclization reaction to the synthesis of enantiopure InoAz analogues starting from readily available azido glucosides. Using this approach combined with a para-methoxybenzyl protecting group strategy, 3-azido-3-deoxy- and 4-azido-4-deoxy-d-myo-inositol were efficiently synthesized. 5-Azido-5-deoxy-d-myo-inositol was inaccessible due to an unusual β-elimination reaction, wherein the azide anion acted as the leaving group. The reported strategy is expected to facilitate continued development of synthetic InoAz analogues as inhibitors or MCRs of inositol-containing glycoconjugates in eukaryotic and mycobacterial systems.

Full text of DOI:10.1021/acs.joc.9b03064

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Article
Ferrier Carbocyclization-Mediated Synthesis
of Enantiopure Azido Inositol Analogues
Alex P. Ausmus, Maxwell Hogue, Justin L. Snyder, Sarah R. Rundell,
Krestina M. Bednarz, Nicholas Banahene, and Benjamin M. Swarts
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03064 • Publication Date (Web): 15 Jan 2020
Downloaded from pubs.acs.org on January 15, 2020
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Ferrier Carbocyclization-Mediated Synthesis of Enantiopure Azido Inositol
Analogues
Alex P. Ausmus, Maxwell Hogue, Justin L. Snyder, Sarah R. Rundell, Krestina M. Bednarz, Nicholas
Banahene, and Benjamin M. Swarts*
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Department of Chemistry and Biochemistry, Central Michigan University, Mount Pleasant, MI, USA
*Corresponding author: E-mail: ben.swarts@cmich.edu
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Ferrier
carbocyclization
HgX2
H2O
OH
OAc
O
OH
HgX
6
3
4
6
4
5 O
1
6
5
5
O
O
HO
N3
OAc
N3
N3
OAc
H
N3
1
7
HO
N3
2
2
2
1
3
3
4
8
9
OMe
OMe
OH
Azido
glucoside
Azido
inositol
O
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Abstract
Azide-modified inositol (InoAz) analogues are valuable as inhibitors and have shown promise as metabolic
chemical reporters (MCRs) for labeling inositol-containing glycoconjugates in eukaryotic cells and potentially in
mycobacteria, but the synthesis of enantiomerically pure InoAz analogues via traditional approaches is challenging.
As a complementary route, here we investigated the application of the Ferrier carbocyclization reaction to the
synthesis of enantiopure InoAz analogues starting from readily available azido glucosides. Using this approach
combined with a para-methoxybenzyl (PMB) protecting group strategy, 3-azido-3-deoxy- and 4-azido-4-deoxy-D-
myo-inositol (3- and 4-InoAz) were efficiently synthesized. 5-Azido-5-deoxy-D-myo-inositol (5-InoAz) was
inaccessible due to an unusual β-elimination reaction, wherein azide anion acted as the leaving group. The reported
strategy is expected to facilitate continued development of synthetic InoAz analogues as inhibitors or MCRs of
inositol-containing glycoconjugates in eukaryotic and mycobacterial systems.
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Introduction
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myo-Inositol is a non-classical carbohydrate bearing six secondary hydroxyl groups in a stereochemical
arrangement that generates an internal plane of symmetry, rendering the molecule meso-symmetric (Fig. 1A).
Inositol is an important component of many biomolecules, including phosphatidylinositol, phosphoinositides, and
soluble inositol phosphates, which have important roles in membrane function and cellular signaling.1 Inositol is
also incorporated into complex glycoconjugates in many forms of life, including glycosylphosphatidylinositol (GPI)
anchors found in all eukaryotes, which anchor proteins to the plasma membrane (Fig. 1B).2 In mycobacteria,
including the global pathogen Mycobacterium tuberculosis (Mtb), inositol is present in structurally related
phosphatidylinositolmannosides (PIMs), which exist in free form and also as the membrane anchors of the complex
glycolipids lipomannan (LM) and lipoarabinomannan (LAM) (Fig. 1C).3 PIMs, LM, and LAM are abundant
membrane-associated molecules that play important roles in the structural integrity and permeability of the
mycobacterial cell envelope.4,5 PIMs and PIM-anchored derivatives are also immune-modulating molecules that are
involved in all stages of Mtb infection.6 Inositol is also present in mycothiol, which is the major intracellular redox-
balancing thiol in mycobacteria (Fig. 1D).7 Proteins can undergo covalent modification by mycothiol during
oxidative stress, which is likely to be an important adaptive response mechanism when Mtb faces the assaults of
macrophages during infection.8
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Figure 1. Structures of inositol (A) and examples of inositol-containing biomolecules, including eukaryotic GPIs (B) and
mycobacterial PIMs and PIM-anchored glycans (C) and mycothiol (D). Inositol is colored in red in (B–D).
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Although inositol-containing biomolecules have essential functions in diverse organisms, tools to visualize
and profile these structures in their native environment are limited. In recent years, metabolic chemical reporters
(MCRs), which are applied in conjunction with bioorthogonal chemistry, have emerged as valuable tools for
studying various types of non-genetically encoded glycans and lipids in living systems.9 In this regard, azide-
modified inositol (InoAz) analogues have promise as MCRs for metabolic labeling and analysis of inositol-
containing glycoconjugates. In the first example of such a tool, which was reported in 2015 by the Guo group, a
panel of acetylated and non-acetylated inositol-based MCRs were evaluated for metabolic labeling of GPIs and
GPI-anchored proteins in yeast cells and various mammalian cell lines. In Guo’s report, it was found that when
cells were treated with a partially acetylated 4-azidoethyl inositol analogue (1, Fig. 2A), the probe was taken up,
deacetylated by intracellular esterases, and efficiently incorporated into GPI-anchored proteins, which enabled
downstream click chemistry-mediated analysis.10 In a similar vein, the Best group reported in 2019 that a non-
acetylated 5-azidopropyl inositol analogue (2) labeled phosphatidylinositol lipids in yeast cells.11 In addition to
metabolic labeling applications, some azido inositol analogues have been shown to inhibit glycosidase activity and
proliferation of mammalian cells.12–14 A major focus of our research program is to create tools for probing the
biosynthesis, dynamics, and post-synthetic modifications and interactions of mycobacterial glycoconjugates, and
thus our interest lies in developing compounds that metabolically label, or inhibit the biosynthesis of, PIMs, LM,
LAM, and mycothiol. To our knowledge, inositol-based MCRs or inhibitors for these mycobacterial structures have
not yet been reported. To support this line of research, in this work we targeted three regioisomeric InoAz analogues
(3–5) with minimally-sized azidodeoxy modifications at the 3-, 4-, and 5-positions of inositol (Fig. 2B). These
positions are generally unmodified in mycobacterial PIMs, LM, LAM, and mycothiol (Fig. 1), and thus we expected
that compounds 3–5 would provide an opportunity for metabolic labeling of these structures.
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Figure 2. (A) Previously reported azidoethyl- and azidopropyl-modified inositol MCRs by the Guo (1) and Best (2) groups.
(B) Azidodeoxy inositol MCRs (3–5) targeted in this work.
Despite the apparent simplicity of inositol’s structure, the preparation of inositol derivatives remains a
challenge. First, the selective functionalization of inositol requires the differentiation of six secondary alcohols.
Second, inositol is meso-symmetric (as shown in Fig. 1A), so derivatization of any symmetrical position (i.e., the
1/3 and 4/6 positions) produces chirality and results in the formation of a racemic mixture that must be resolved.
As a result, significant efforts have focused on the development of methods for the preparation of inositol
derivatives.15 These methods mainly involve subjecting inositol to regioselective manipulations and eventually
performing chemical or enzymatic resolution of a racemic intermediate. For example, a report from 2015 described
the chemical synthesis of 2-, (±)-3-, (±)-4-, and 5-InoAz (all starting from inositol) in 10, 11, 9, and 11 steps,
respectively, and the racemic products (±)-3- and 4-InoAz were not resolved into enantiomers.16 Other approaches
to inositol derivatives have been reported as well, including use of chiral pool starting materials17,18 and de novo
synthesis employing enzymes19 or ring-closing metathesis.20 For instance, L-quebrachitol, a naturally occurring
albeit expensive cyclitol, was converted to enantiopure 3-InoAz over 9–11 steps.17 In another example, p-
benzoquinone was elaborated via chemoenzymatic synthesis to four enantiopure InoAz regioisomers, including 1-
, 3-, 4-, and 6-InoAz, over 10 steps.19 Many of these reported synthetic routes involve late-stage SN2 azide
displacement reactions, for example on inositol sulfonates or trifluoromethanesulfonates, which can be complicated
by competing elimination or SN1 reactions.16 Generally, it remains difficult to synthesize inositol derivatives,
especially enantiopure compounds with modifications at sites off the plane of symmetry, the 1-, 3-, 4-, or 6-
positions. As an alternative to prior approaches, here we report the application of the Ferrier carbocyclization
reaction to the synthesis of enantiopure InoAz analogues.
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Results and Discussion
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Synthetic strategy. In 1991, the Prestwich and Bender groups independently reported an elegant application
of the Ferrier carbocylization21 to the synthesis of enantiomerically pure inositol derivatives.22,23 We reasoned that
this approach could be extended to the synthesis of InoAz analogues 3–5 as shown in Scheme 1. We hypothesized
that regioisomeric azido methyl glucosides I could be elaborated to the enol acetate intermediates II, which upon
treatment with Hg(II) would then undergo stereoselective Ferrier carbocyclization to give azido inososes III, setting
up stereoselective ketone reduction and deprotection to yield the desired InoAz products. We surmised that this
approach would be advantageous for several reasons, including: (i) it utilizes readily accessible azido methyl
glucoside building blocks I, which avoids late-stage azido group installation and accompanying competing
reactions; (ii) it provides enantiopure products without the need for desymmetrization; and (iii) it allows
modification of the 3-, 4-, and 5-positions of inositol, which fortuitously are the positions prioritized for azide
modification to allow metabolic labeling of inositol-containing biomolecules in mycobacteria and other systems
(see Fig. 1). To protect hydroxyl groups at unmodified sites (i.e., positions 2–4 of azido glucosides I), we elected
to use para-methoxybenzyl (PMB) groups, which are stable under Ferrier carbocyclization conditions22 and can be
deprotected under mild oxidative or acidic conditions that leave the azido group intact in the final product.24,25
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Scheme 1. Proposed Ferrier carbocyclization-mediated synthesis of 3-, 4-, and 5-InoAz.a
Ferrier carbocyclization
HgX2
H2O
OH
OAc
O
HgX
OH
4
6
3
AcO
1. [H-]
HgX
OAc
6
4
5 O
N3
1
6
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5
O
O
HO
HO
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O
N3
OAc
N3
N3
N3
1
N3
2
2
2
H
2. Deprotect
3
3
4
OMe
OMe
HO
InoAz
OMe
OH
I
II
III
O
aCarbon numbering is based on hexose numbering for I and inositol numbering for III and InoAz. Red dots
indicate sites that can, in principle, be modified using this strategy.
Synthesis of 3-InoAz (3). The preparation of 3-InoAz (3), depicted in Scheme 2, was initiated from an
anomeric mixture of methyl 2-azido-2-deoxy-D-glucopyranoside (6), which was obtained from D-glucosamine via
a diazo transfer procedure as previously described.26,27 To set up for later oxidation of the 6-position, the primary
alcohol of 6 was selectively protected with a bulky para-methoxytrityl (PMTrt) group to produce diol 7 in 57%
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yield. With the anomers of 7 being separable at this stage, the α-anomer was isolated and carried forward to simplify
characterization of intermediates. After the free 3-O- and 4-O-positions of 7 were para-methoxylbenzylated using
NaH and PMBCl to give 8, the highly acid-sensitive PMTrt group was selectively removed in the presence of acetic
acid, generating primary alcohol 9 in 78% yield over two steps. Compound 9 was subjected to Swern oxidation to
produce aldehyde intermediate 10, which without purification was treated with K2CO3, acetic anhydride, and
catalytic N,N-dimethylaminopyridine (DMAP) to produce enol acetate 11 in 52% yield over two steps.
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Scheme 2. Synthesis of 3-InoAz (3).a
OH
OPMTrt
O
OPMTrt
O
OH
a
b
c
O
O
HO
HO
HO
HO
PMBO
PMBO
PMBO
PMBO
N3
N3
N3
OMe
N3
OMe
OMe
OMe
6
7
8
9
( isomer
isolated)
d
OAc
O
6
H
5 O
f
e
PMBO
PMBO
PMBO 4
PMBO
PMBO
PMBO
1
5
6
O
O
OAc
2
1
3N3
2N3
OMe
N3
4
3
12
11
(hexose
10
g
OH
OMe
(inositol
numbering)
numbering)
HO
HO OH
HO
HO
h
i
5
1
6
4
6
5
OH
N3
PMBO
PMBO
HO
OAc
OH
OH
HO
PMBO
PMBO
HO
2
HO
3 N3
2
4
1
3
N3
OH
N3
13
14
3
3-InoAz ( )
OH
OH
aReagents and conditions: (a) PMTrtCl, pyridine, 0 °C  rt, 57%; (b) NaH, PMBCl, DMF, 0 °C  rt; (c) AcOH,
H2O, CH2Cl2, 78% over two steps; (d) (COCl)2, DMSO, CH2Cl2, –78 °C; then Et3N, –78 °C  rt; (e) Ac2O,
DMAP, K2CO3, CH3CN, 70 °C, 52% over two steps; (f) Hg(OTFA)2, acetone–H2O (4:1); then NaOAc, NaCl, 0
°C  rt, 54%; (g) Na(OAc)3BH, AcOH, CH3CN, 0 °C, 60%; (h) NaOMe, MeOH, 79%; (i) TFA, CH2Cl2, H2O,
71%.
With the Ferrier precursor 11 in hand, we proceeded to test the key carbocyclization reaction using
conditions previously established by Bender and Prestwich.22,23 A solution of enol acetate 11 in aqueous acetone
was treated with Hg(OTFA)2, then aqueous NaOAc and NaCl were added and the reaction proceeded overnight.
The major product of the reaction, inosose derivative 12, was isolated in 54% yield, a figure consistent with
literature reports on similar Ferrier carbocyclizations wherein the remainder of the mass balance was mainly
attributed to minor stereoisomers.22,23 Structural assignment of 12 was supported by NMR analysis. Using inositol
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numbering for reference, the H NMR spectrum contained a downfield-shifted H-1 absorption at 5.21 ppm,
supporting the presence of an electron-withdrawing 1-O-acetyl group, while the 13C NMR spectrum contained an
absorption at 197.3 ppm, implying the presence of a ketone at C-6. The Ferrier cyclization generates two
stereocenters at C-1 and C-2, and thus four diastereomeric inosose products are possible. However, the reaction
typically proceeds with high diastereoselectivity to avoid transition state conformations involving twist-boat-like
geometries and 1,3-diaxial interactions, ultimately favoring the desired inosose products with equatorial and axial
substituents at C-1 and C-2, respectively, as shown for compound 12.21 We established an axial orientation of the
hydroxyl group at C-2 based on the known stereochemistry of the C-3 azido group using 1H NMR vicinal coupling
constants (3JH-2,H-3 = 2.2 Hz). We attempted to determine the C-1 stereochemistry of 12 in a similar manner, but the
3JH-1,H-2 coupling constant could not be unambiguously calculated because the H-1 splitting pattern was complicated
by long-range coupling to H-5 through the sp2-hybridized C-6. Anticipating that the C-1 configuration could be
established subsequently, we proceeded to the next step, which involved stereoselective hydride reduction of the
C-6 ketone to complete the inositol core structure. To achieve this transformation, NaBH(OAc)3 was used as a
substrate-tethering reducing reagent, which enabled C-2 hydroxyl-directed delivery of hydride to the C-6 carbonyl
group, generating diol 13 in 60% yield. The stereochemistry of C-1 and C-6 were both determined at this stage by
1H NMR coupling constant analysis. The equatorial orientation of the C-6 hydroxyl group was confirmed through
H-6 coupling to H-5 (3JH-5,H-6 = 9.3 Hz). Finally, the stereochemistry of C-1 was established through H-1 couplings
to H-6 (3JH-1,H-6 = 10.2 Hz) and H-2 (3JH-1,H-2 = 2.6 Hz). Thus, over the preceding two steps, including the key Ferrier
carbocyclization reaction and ketone reduction, three contiguous tertiary stereocenters were set with good
selectivity.
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With the inositol core structure established in intermediate 13, we proceeded to the deprotection sequence.
Deacetylation of the 1-O-position was accomplished smoothly with NaOCH3/CH3OH to give 14 in 79% yield.
Lastly, the PMB protecting groups at the 4-O- and 5-O-positions were removed with 10% trifluoroacetic acid
(TFA), providing 3-InoAz (3) in 71% yield with its azido group intact. This last step highlights the advantage of
using acid-labile PMB protecting groups versus more commonly employed benzyl protecting groups, whose
reductive removal would destroy the “clickable” azido group. Overall, the synthesis of the enantiomerically pure
target compound 3 from azido glucoside 6 proceeded in 9 total steps and in 4.2% yield. We also tested whether the
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β anomer of 11 participated in the Ferrier carbocyclization, and found that it behaved identically to the α anomer,
generating the same major inosose product 12 in comparable yield. Therefore, the separation and parallel
advancement of anomeric isomers can be avoided, which will significantly simplify and improve the efficiency of
future syntheses.
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Synthesis of 4-InoAz (4). The synthesis of 4-InoAz (4), which is depicted in Scheme 3, followed the same
procedures as the synthesis of 3-InoAz and yielded similar results. The starting material, an anomeric mixture of
methyl 3-azido-3-deoxy-D-glucopyranoside 15,28 was subjected to selective 6-O-para-methoxytritylation to give
16 (77%), para-methoxybenzylation of the 2-O- and 4-O-positions to give 17 (77%; α and β anomers were separated
at this stage), and acid-mediated removal of the PMTrt group to give 18 (88%). With the primary alcohol
differentiated in compound 18, the Swern oxidation–enol acetate formation sequence was carried out to provide
compound 20 in 62% yield over two steps. Moving forward, enol acetate 20 was subjected to Ferrier conditions as
described above, which produced the desired inosose derivative 21 in 47% yield. In the case of the 4-InoAz isomer,
1H NMR coupling constants were successful in establishing the expected stereochemistry at C-1 and C-2 (3JH-1,H-2
3
1
13
= 2.5 Hz; JH-2,H-3 = 2.4 Hz), and H and C NMR chemical shifts for H-1 (5.10 ppm) and C-6 (196.9 ppm),
respectively, confirmed the presence of O-acetyl and ketone functionalities at those positions. Hydroxyl-directed
stereoselective ketone reduction with NaBH(OAc)3 gave diol 22 in 70% yield, then the two-step deprotection
sequence of deacetylation (80%) and PMB hydrolysis (81%) provided the target 4-InoAz (4). This 9-step synthesis
of enantiopure 4 from azido glucoside 14 proceeded in 7.8% overall yield, similar to the results of the 3-InoAz
synthesis.
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Scheme 3. Synthesis of 4-InoAz (4).a
5
6
7
8
OH
OPMTrt
O
OPMTrt
O
OH
a
b
c
O
O
HO
N3
HO
N3
PMBO
PMBO
N3
N3
HO
HO
PMBO
PMBO
d
OMe
OMe
OMe
15
16
17
 isomer
isolated)
18
OMe
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OAc
O
6
H
5 O
f
e
1
5
6
O
O
PMBO
PMBO 4
PMBO
OAc
N3
N3
N3
2
1
2
3
4
3
PMBO
PMBO
PMBO
21
20
19
g
OH
OMe
OMe
(inositol
numbering)
(hexose
numbering)
HO
HO OH
HO
HO
h
i
5
1
6
4
5
6
3
HO
N3
PMBO
N3
PMBO
HO
N3
OAc
OH
OH
HO
N3
OH
2
HO
2
3
4
1
PMBO
PMBO
22
23
4
4-InoAz ( )
OH
OH
OH
aReagents and conditions: (a) PMTrtCl, pyridine, 0 °C  rt, 86%; (b) NaH, PMBCl, DMF, 0 °C  rt, 77%; (c)
AcOH, H2O, CH2Cl2, 88%; (d) (COCl)2, DMSO, CH2Cl2, –78 °C; then Et3N, –78 °C  rt; (e) Ac2O, DMAP,
K2CO3, CH3CN, 70 °C, 62% over two steps; (f) Hg(OTFA)2, acetone–H2O (4:1); then NaOAc, NaCl, 0 °C, 47%;
(g) Na(OAc)3BH, AcOH, CH3CN, 0 °C, 70%; (h) NaOMe, MeOH, 80%; (i) TFA, CH2Cl2, H2O, 82%.
Attempted synthesis of 5-InoAz (5). The final target molecule was 5-InoAz (5), which, like the 3- and 4-
InoAz regioisomers, was predicted to be accessible from the corresponding azido glucoside (24) via Ferrier
carbocyclization. The initial phase of the synthesis starting from 2429 went as expected, as 6-O-para-
methoxytritylation (91%), para-methoxybenzylation (65%), and PMTrt removal (96%) proceeded without issue.
The primary alcohol arising from this sequence 26 was successfully oxidized to aldehyde 27 by Swern oxidation.
However, the major product observed when 27 was treated with K2CO3, acetic anhydride, and DMAP was not the
desired enol acetate 28 (not observed), but rather the unanticipated β-elimination product, enal 29 (47%) (Scheme
4). Attempts to produce 28 through adjustments to temperature, stoichiometry, and base/acetylation reagents failed,
as 29 was always observed as the major product. Compound 29 could have been favored due to the stability of the
α,β-unsaturated carbonyl group or the entropically favorable elimination. An E2-type elimination mechanism was
considered unlikely since azide anion is a poor leaving group, the azido group and the abstracted proton in 27 do
not have anti-periplanar geometry, and the β-elimination proceeded even with weak bases such as Et3N. It is possible
that enal 29 was formed through an E1cB mechanism involving K2CO3-mediated deprotonation of the 5-position
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to form a resonance-stabilized aldehyde enolate (the expected intermediate en route to the desired product 28),
which subsequently underwent elimination, ejecting the 4-position azido group. Although elimination reactions of
β-azido carbonyl compounds to form the corresponding α,β-unsaturated carbonyl compounds appear to be rare,
there are reports of carbohydrate-based lactones and lactams undergoing similar β-eliminations in which C-3
azido,30 methoxy,31 or benzyloxy32 groups acted as leaving groups. Despite the fact that 5-InoAz was inaccessible,
the need to achieve this particular target compound using the Ferrier carbocyclization is diminished in comparison
to 3- and 4-InoAz, because 5-position-modified inositol analogues are achiral and do not require resolution. Indeed,
Sureshan and co-workers recently reported an elegant one-pot double substitution approach that delivered achiral
2- and 5-InoAz from inositol, each in 4 steps and in 10–15% overall yield.33
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Scheme 4. Attempted synthesis of 5-InoAz (5).a
OAc
O
N3
PMBO
PMBO
OH
OPMTrt
O
OH
O
28
H
N3
PMBO
X
e
OMe
a
b, c
d
O
O
O
N3
HO
N3
HO
N3
PMBO
O
HO
HO
PMBO
PMBO
24
25
26
O
OMe
27
OMe
OMe
OMe
OMe
H
OPMB
29
OPMB
aReagents and conditions: (a) PMTrtCl, pyridine, 0 °C  rt, 91%; (b) NaH, PMBCl, DMF, 0 °C  rt, 65%; (c)
AcOH, H2O, CH2Cl2, 96%; (d) (COCl)2, DMSO, CH2Cl2, –78 °C; then Et3N, –78 °C  rt; (e) Ac2O, DMAP,
K2CO3, CH3CN, 70 °C, 47% of 29 over two steps (compound 28 not detected).
Conclusion
Our interest in developing MCRs and inhibitors of inositol-containing metabolites and glycoconjugates in
mycobacteria (e.g., mycothiol, PIMs, LM, or LAM) motivated us to explore chemistries for accessing InoAz
analogues. While a number of approaches to inositol derivative synthesis have been developed, InoAz analogues
are still difficult to produce efficiently—particularly structures modified at the 1-, 3-, 4-, and 6-positions. Previous
syntheses of such compounds, described in the introduction, took 9–11 steps and ranged in overall yield from
approximately 1–25%; in some of those cases, racemic mixtures were not resolved. In the present work, we sought
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to apply the Ferrier carbocyclization reaction to the synthesis of InoAz analogues, reasoning that it should provide
access to multiple enantiomerically pure isomers relevant to our mycobacteria research program, without the need
for chiral resolution or late-stage azido group installation. This approach successfully delivered 3- and 4-InoAz in
9 steps from azido glucosides in 4–8% overall yield, while 5-InoAz was inaccessible due to an unexpected β-
elimination reaction. Extension of the Ferrier carbocyclization to a new class of compounds was also valuable
because it further elucidated the scope and limitations of this widely used reaction. Overall, the reported approach
exhibited comparable efficiency to most prior reports and it should be amenable to scale-up. To date, Altenbach’s
enzyme-mediated de novo syntheses of 1-, 3-, 4-, and 6-InoAz from p-benzoquinone remain the most efficient
preparations of these molecules at 10 steps and about 25% overall yield.19 However, given the ability of the Ferrier
carbocyclization to tolerate a variety of functional groups and stereochemistries, as revealed in prior work21 and
herein, it is a versatile and efficient option for producing InoAz analogues and related compounds. Although Hg(II)
reagents have proven successful for the Ferrier carbocyzliation, alternative conditions (e.g., use of palladium
catalysts34) to reduce or eliminate their usage in InoAz syntheses would be beneficial. Despite the success of the
prior and present approaches, the synthesis of inositol analogues remains a challenge. In the future, the development
of novel synthetic approaches, for instance chemoenzymatic methods in the vein of our work on trehalose
analogues,35–38 may further improve synthetic efficiency and accelerate access to additional inositol analogues for
evaluation as probes or inhibitors. We are currently evaluating 3- and 4-InoAz as MCRs for metabolic labeling of
inositol-containing biomolecules in mycobacteria. As noted above, InoAz analogues have also shown inhibitory
activity in various systems, so it will be of interest to test these compounds as inhibitors of inositol metabolism and
bacterial growth. Whether InoAz analogues are determined to behave as MCRs or inhibitors, or both, they can be
leveraged to investigate the role of inositol metabolism and inositol glycoconjugates in mycobacterial physiology
and pathogenesis.
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Experimental
General experimental for synthesis. Materials were obtained from commercial sources without further
purification. Anhydrous solvents were obtained either commercially or from an alumina column solvent purification
system. Analytical TLC was performed on glass-backed silica gel 60 Å plates (thickness 250 µm) and detected by
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UV or staining (typically charring with 5% H2SO4 in EtOH) when appropriate. 1H, 13C, gCOSY, and HSQC NMR
spectra were obtained using Varian Inova 500 or Varian Mercury 300 instruments. Coupling constants (J) are
reported in hertz (Hz) with chemical shifts in ppm (δ) referenced to solvent peaks or an internal acetone standard,
with the following splitting abbreviations: s = singlet, d = doublet, dd = doublet of doublets, ddd = doublet of
doublets of doublets, dt = doublet of triplets, t = triplet, td = triplet of doublets, m = multiplet. High-resolution
electrospray ionization (HR ESI) mass spectra were obtained using a Waters LCT premier XE using the following
internal standards for the lock mass: reserpine for positive mode analyses, raffinose for negative mode analyses,
and myo-inositol for 3- and 4-InoAz analyses.
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Methyl 2-azido-2-deoxy-6-O-(p-methoxytrityl)-D-glucopyranoside (7). After dissolving compound 6-
(α/β)27 (1.02 g, 4.65 mmol) in anhydrous pyridine (20 mL), the flask was purged with argon and cooled in an ice
bath. While the reaction mixture was stirring, PMTrtCl (2.94 g, 9.52 mmol) was added in portions. After stirring
overnight with gradual warming to room temperature, TLC showed complete consumption of starting material.
Excess methanol was added to quench unreacted PMTrtCl. The solution was transferred to a separatory funnel
containing ice water, which was extracted with CH2Cl2 three times. The organic layer was dried over MgSO4,
filtered, and concentrated under vacuum. The resulting oil was purified using silica gel chromatography
(toluene/EtOAc 3:1 with 1% Et3N) to give compound 7-(α/β) (1.30 g, 57%) as a white solid. The anomeric mixture
was separable by this method of purification. TLC (toluene/EtOAc 3:1): 7-(α), Rf = 0.38, 7-(β); Rf = 0.36. 1H NMR
of 7-(α) (500 MHz, CDCl3): δ 7.47–7.45 (m, 4 H, ArH), 7.35–7.30 (m, 6 H, ArH), 7.26–7.22 (m, 2 H, ArH), 6.86–
6.85 (m, 2 H, ArH), 4.78 (d, J = 3.6 Hz, 1 H, H-1), 3.94 (dd, J = 8.9, 10.2 Hz, 1 H, H-3), 3.79 (s, 3 H, OCH3), 3.68–
3.65 (m, 1 H, H-5), 3.55 (t, J = 9.0 Hz, 1 H, H-4), 3.41 (s, 3 H, OCH3), 3.40 (d, J = 6.2 Hz, 2 H, H-6a and H-6b),
3.25 (dd, J = 3.6, 10.3 Hz, 1 H, H-2), 2.96 (s, 1 H, C-3 OH), 2.85 (s, 1 H, C-4 OH). 13C{1H} NMR of 7-(α) (125
MHz, CDCl3): δ 158.7, 143.99, 143.98, 135.1, 130.3, 128.3, 128.2, 128.0, 127.1, 113.2, 98.6, 87.0, 73.0, 71.8, 69.4,
64.0, 62.8, 55.22, 55.19. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C27H29N3O6Na 514.1954; Found, 514.1959.
1H NMR of 7-(β) (500 MHz, CDCl3): δ 7.46–7.44 (m, 4 H, ArH), 7.34–7.29 (m, 6 H, ArH), 7.25–7.22 (m, 2 H,
ArH), 6.86–6.84 (m, 2 H, ArH), 4.23 (d, J = 8.0 Hz, 1 H, H-1), 3.80 (s, 3 H, OCH3), 3.58 (t, J = 7.2 Hz, 1 H, H-4),
3.58 (s, 3 H, OCH3), 3.47–3.36 (m, 4 H, H-3, H-5, H-6), 3.30 (dd, J = 8.0, 10.0 Hz, 1 H, H-2) 3.04 (bs, 1 H, C4-
OH), 2.86 (bs, 1 H, C3-OH). 13C{1H} NMR of 7-(β) (125 MHz, CDCl3): δ 158.7, 143.9, 143.8, 135.0, 130.3, 128.25,
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128.24, 128.0, 127.1, 113.3, 102.8, 87.0, 74.9, 73.5, 72.5, 65.6, 64.1, 57.0, 55.2. HRMS (ESI-TOF) m/z: [M+Na]+
Calcd for C27H29N3O6Na 514.1954; Found 514.1974.
5
6
7
8
9
Methyl 2-azido-2-deoxy-3,4-di-O-(p-methoxybenzyl)-6-O-(p-methoxytrityl)-α-D-glucopyranoside (8).
Compound 7-(α) (2.42 g, 4.92 mmol) was dissolved in anhydrous DMF (100 mL) and the solution was stirred with
cooling over an ice bath. After purging the flask with argon, sodium hydride (0.672 g, 28.0 mmol) was added in
portions. After stirring over an ice bath for approximately 30 min, PMBCl (2.0 mL, 14.8 mmol) was added dropwise.
The reaction was stirred overnight, after which TLC indicated completion. The reaction mixture was diluted with
H2O and extracted three times with CH2Cl2. The combined organic layer was then washed with brine, dried over
MgSO4, filtered, and concentrated under vacuum to give 8 as a yellow oil. The crude material was subjected to the
next reaction without further purification. TLC (Hex/EtOAc 8:1): Rf = 0.28.
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Methyl 2-azido-2-deoxy-3,4-di-O-(p-methoxybenzyl)-α-D-glucopyranoside (9). The crude yellow oil
containing compound 8 was dissolved in CH2Cl2 (100 mL) and the solution was stirred. A solution of glacial acetic
acid (18.5 mL) in water (6.0 mL) was added to the reaction mixture dropwise. The reaction was stirred overnight,
after which TLC indicated completion. The reaction mixture was transferred to a separatory funnel and neutralized
with saturated aqueous NaHCO3. Following extraction of the mixture with CH2Cl2 three times, the combined
organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude material was purified
by silica gel chromatography (Hex/EtOAc 4:1) to give compound 9 (1.78 g, 78% over two steps) as a white solid.
1
TLC (Hex/EtOAc 4:1): Rf = 0.25. H NMR (300 MHz, CDCl3): δ 7.33–7.23 (m, 4 H, ArH), 6.90–6.87 (m, 4 H,
ArH), 4.83–4.80 (m, 3 H, PMB CH2), 4.77 (d, J = 3.5 Hz, 1 H, H-1), 4.60 (d, J = 10.8 Hz, 1 H, PMB CH2), 3.96
(dd, J = 8.7, 10.1 Hz, 1 H, H-4), 3.81 (s, 3 H, OCH3), 3.80 (s, 3 H, OCH3), 3.79–3.64 (m, 3 H, H-5, H-6), 3.56 (t, J
= 8.7 Hz, 1 H, H-3), 3.40 (s, 3 H, OCH3), 3.37 (dd, J = 3.6, 10.2 Hz, 1 H, H-2). 13C{1H} NMR (75 MHz, CDCl3):
δ 159.42, 159.39, 130.00, 129.97, 129.8, 129.6, 113.94, 113.89, 98.7, 80.1, 77.6, 75.2, 74.7, 71.2, 63.7, 61.6, 55.28,
55.27, 55.2. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C23H29N3O7Na 482.1903; Found 482.1913.
Methyl 2-azido-2-deoxy-3,4-di-O-(p-methoxybenzyl)-α-D-glucohexoaldo-1,5-pyranoside (10). Oxalyl
chloride (0.72 mL, 8.4 mmol) was dissolved in anhydrous CH2Cl2 (15 mL) and the solution was stirred at –78 °C
under argon. After approximately 15 min, DMSO (1.2 mL, 17 mmol) was added dropwise and the solution was
stirred for 15 min. Next, a solution of compound 9 (0.780 g, 1.70 mmol) in anhydrous CH2Cl2 (15 mL) was
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transferred to the reaction mixture dropwise. After stirring for 30 min, Et3N (3.6 mL, 26 mmol) was added and the
reaction was stirred for 15 min at –78 °C followed by gradual warming to room temperature. After reaching room
temperature, the reaction was diluted with EtOAc and washed with brine three times. The organic layer was dried
over MgSO4, filtered, and concentrated under vacuum to give 10 an opaque yellow oil, which was subjected to the
next reaction without further purification.
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(Z)-Methyl
6-O-acetyl-2-azido-2-deoxy-3,4-di-O-(p-methoxybenzyl)-α-D-gluco-5-enopyranoside
(11). The crude oil containing compound 10 was dissolved in anhydrous CH3CN (20 mL). While stirring under
argon, DMAP (27 mg, 0.22 mmol) and K2CO3 (1.88 g, 13.6 mmol) were added followed by Ac2O (0.50 mL, 5.3
mmol), then the reaction was heated to 75 ˚C. After stirring overnight at 75 ˚C, the reaction mixture was diluted
with EtOAc and washed with brine three times. After drying the organic layer over MgSO4, filtration, and
concentration by vacuum, the crude material was purified by silica gel chromatography (Hex/EtOAc 4:1) to give
compound 11 (0.442 g, 52% over two steps) as a pale yellow oil. TLC (Hex/EtOAc 4:1): Rf = 0.24. 1H NMR (300
MHz, CDCl3): δ 7.31–7.26 (m, 4 H, ArH), 7.20 (d, J = 1.9 Hz, 1 H, H-6), 6.90–6.86 (m, 4 H, ArH), 4.91 (d, J = 3.4
Hz, 1 H, H-1), 4.82 (d, J = 10.4 Hz, 1 H, PMB CH2), 4.74–4.65 (m, 3 H, PMB CH2), 4.00 (dd, J = 2.0, 8.6 Hz, 1 H,
H-4), 3.91 (t, J = 9.7 Hz, 1 H, H-3), 3.81 (s, 3 H, OCH3), 3.80 (s, 3 H, OCH3), 3.51 (s, 3 H, OCH3), 3.47 (dd, J =
3.4, 9.8 Hz, 1 H, H-2), 2.18 (s, 3 H, OAc CH3). C{1H} NMR (75 MHz, CDCl3): δ 167.2, 159.5, 134.6, 129.9,
13
129.8, 129.7, 129.4, 123.4, 114.0, 113.9, 100.0, 79.1, 78.1, 77.1, 75.1, 74.1, 62.9, 56.3, 55.3, 20.6. HRMS (ESI-
TOF) m/z: [M+Na]+ Calcd for C25H29N3O8Na 522.1852; Found 522.1856.
(1R,2R,3S,4R,5S)-3-Azido-2-hydroxy-4,5-di-O-(p-methoxybenzyl)-6-oxocyclohexyl acetate (12).
Compound 11 (0.378 g, 0.757 mmol) was dissolved in acetone (3.7 mL) and water (0.92 mL) and placed over an
ice bath. While stirring, Hg(OTFA)2 (0.408 g, 0.956 mmol) was added. After 10 min, the reaction mixture was
diluted with acetone (10 mL) followed by the addition of 3M aqueous NaOAc (0.32 mL) and brine (0.53 mL). After
stirring overnight, TLC indicated consumption of starting material. The reaction mixture was diluted with water
and extracted with CH2Cl2 three times. The combined organic layers were then dried over MgSO4, filtered, and
concentrated under vacuum. The crude material was purified by silica gel chromatography (Hex/EtOAc 2:1) to give
compound 12 (0.200 g, 54%) as an off-white solid. TLC (Hex/EtOAc 2:1): Rf = 0.27. 1H NMR (300 MHz, CDCl3):
δ 7.34–7.24 (m, 4 H, ArH), 6.90–6.86 (m, 4 H, ArH), 5.21 (dd, J = 1.0, 2.7 Hz, 1 H, H-1), 4.89 (d, J = 10.1 Hz, 1
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H, PMB CH2), 4.87 (d, J = 10.9 Hz, 1 H, PMB CH2), 4.70 (d, J = 10.1 Hz, 1 H, PMB CH2), 4.47 (d, J = 10.8 Hz, 1
H, PMB CH2), 4.34–4.33 (m, 1 H, H-2), 4.20 (dd, J = 1.1, 9.2 Hz, 1 H, H-5), 4.07 (t, J = 9.3 Hz, 1 H, H-4), 3.82
(dd, J = 2.2, 9.7 Hz, 1 H, H-3), 3.81 (s, 6 H, 2x OCH3), 2.25 (s, 3 H, OAc CH3). 13C{1H} NMR (75 MHz, CDCl3):
δ 197.3, 169.5, 159.6, 159.5, 130.14, 130.06, 129.5, 129.1, 113.9, 113.8, 84.2, 80.1, 75.6, 75.4, 73.3, 70.5, 63.0,
55.3, 20.5. HRMS (ESI-TOF) m/z: [M+K]+ Calcd for C24H27N3O8K 524.1435; Found 524.1458.
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1-O-Acetoxy-3-azido-3-deoxy-4,5-di-O-(p-methoxybenzyl)-myo-inositol (13). Compound 12 (28.7 mg,
0.059 mmol) was dissolved in anhydrous CH3CN (2.0 mL) and cooled over an ice bath. While stirring, Na(OAc)3BH
(115 mg, 0.543 mmol) was added, followed by glacial acetic acid (0.20 mL, 3.5 mmol). After approximately 1 h,
TLC indicated completion. The reaction mixture was diluted with water and extracted using EtOAc. The resulting
organic layer was then dried over MgSO4, filtered, and concentrated under vacuum. The crude material was purified
using silica gel chromatography (Hex/EtOAc 2:3) to give compound 13 (17.4 mg, 60%) as a white solid. TLC
(Hex/EtOAc 2:1): Rf = 0.46. 1H NMR (300 MHz, CDCl3): δ 7.33–7.26 (m, 4 H, ArH), 6.91–6.87 (m, 4 H, ArH),
4.91–4.76 (m, 3 H, PMB CH2), 4.71 (dd, J = 2.6, 10.2 Hz, 1 H, H-1), 4.70 (d, J = 10.6 Hz, 1 H, PMB CH2), 4.19 (t,
J = 2.4 Hz, 1 H, H-2), 4.03 (t, J = 9.7 Hz, 1 H, H-6), 3.91 (t, J = 9.7 Hz, 1 H, H-4), 3.80 (s, 6 H, 2x OCH3), 3.48
(dd, J = 2.5, 10.1 Hz, 1 H, H-3), 3.40 (t, J = 9.3 Hz, 1 H, H-5), 2.15 (s, 3 H, OAc CH3). 13C{1H} NMR (75 MHz,
CDCl3): δ 170.4, 159.47, 159.45, 130.3, 130.0, 129.8, 129.5, 114.1, 113.9, 83.5, 79.6, 75.5, 75.3, 73.3, 70.5, 69.4,
63.9, 55.3, 29.7, 21.0. HRMS (ESI-TOF) m/z: [M+HCO2]- Calcd for C25H30N3O10 532.1931; Found 532.1943.
3-Azido-3-deoxy-4,5-di-O-(p-methoxybenzyl)-myo-inositol (14). After a solution of compound 13 (200
mg, 0.410 mmol) in 18 mL of freshly prepared 0.05 M NaOCH3 in methanol was stirred for 30 min, it was
neutralized to ~pH 7 using Dowex H+ resin. The solution was filtered and concentrated under vacuum. The crude
material was purified using silica gel chromatography (Hex/EtOAc 1:8) to give compound 14 (145 mg, 79%) as a
white solid. TLC (Hex/EtOAc 1:8): Rf = 0.27. 1H NMR (300 MHz, CDCl3): δ 7.33–7.29 (m, 4 H, ArH), 6.91–6.87
(m, 4 H, ArH), 4.90 (d, J = 11.1 Hz, 1 H, PMB CH2), 4.86–4.78 (m, 2 H, PMB CH2), 4.66 (d, J = 11.1 Hz, 1 H,
PMB CH2), 4.15 (t, J = 2.7 Hz, 1 H, H-2), 3.90 (t, J = 9.7 Hz, 1 H, H-6), 3.81 (s, 3 H, OCH3), 3.80 (s, 3 H, OCH3),
3.78 (t, J = 9.6 Hz, 1 H, H-4), 3.45 (dd, J = 2.9, 9.6 Hz, 1 H, H-3), 3.41 (dd, J = 2.6, 10.1 Hz, 1 H, H-1), 3.32 (t, J
= 9.3 Hz, 1 H, H-5). 13C{1H} NMR (75 MHz, CDCl3): δ 159.5, 130.0, 129.5, 114.1, 113.9, 83.1, 80.0, 76.3, 75.4,
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75.1, 72.8, 72.1, 70.6, 64.0, 55.3. HRMS (ESI-TOF) m/z: [M+Cl]- Calcd for C22H27N3O7Cl 480.1537; Found
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3-Azido-3-deoxy-myo-inositol (3). Compound 14 (129 mg, 0.290 mmol) was dissolved in CH2Cl2 (50 mL)
to give a clear colorless solution. While stirring, trifluoroacetic acid (5.0 mL) and water (1.0 mL) were added. After
30 min of stirring, the solution was purple in color and TLC indicated complete consumption of the starting material.
The reaction mixture was co-evaporated with toluene under vacuum. The resulting crude material was purified
using silica gel chromatography (CH2Cl2/MeOH 3:1 with 1% AcOH) to give compound 3 (42.2 mg, 71%) as a
white solid. TLC (CH2Cl2/MeOH 3:1): Rf = 0.40. 1H NMR (300 MHz, D2O): δ 4.18 (t, J = 2.7 Hz, 1 H, H-2), 3.76
(t, J = 10.0 Hz, 1 H, H-4), 3.63 (t, J = 9.7 Hz, 1 H, H-5), 3.55 (dd, J = 2.8, 9.9 Hz, 1 H, H-1), 3.45 (dd, J = 2.7, 10.6
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Hz, 1 H, H-3), 3.36 (t, J = 9.1 Hz, 1 H, H-6). C{1H} NMR (75 MHz, CDCl3, referenced to an acetone internal
standard): δ 65.6, 62.9, 62.2, 62.1, 61.7, 54.0. HRMS (ESI-TOF) m/z: [M-H]- Calcd for C6H10N3O5 204.0620;
Found 204.0614.
Methyl 3-azido-3-deoxy-6-O-(p-methoxytrityl)-D-glucopyranoside (16). After dissolving compound
15-(α/β)28 (5.98 g, 27.3 mmol) in anhydrous pyridine (100 mL), the flask was purged with argon and cooled in an
ice bath. While stirring, PMTrtCl (17.61 g, 5.703 mmol) was added in portions to the reaction mixture. After stirring
overnight with gradual warming to room temperature, TLC showed complete consumption of starting material. The
solution was quenched with excess methanol, transferred to a separatory funnel containing ice water, and extracted
three times with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The
resulting crude oil was purified using silica gel chromatography (toluene/EtOAc 3:1 with 1% Et3N) to compound
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16-(α/β) (11.59 g, 86%) as a white solid. TLC (toluene/EtOAc 1:1) of 16-(α/β): Rf = 0.60. H NMR (500 MHz,
CDCl3, peaks from the major anomer 16-(α) are listed): δ 7.46–7.44 (m, 4 H, ArH), 7.35–7.23 (m, 8 H, ArH), 6.87–
6.84 (m, 2 H, ArH), 4.74 (d, J = 2.0 Hz, 1 H, H-1), 3.80 (s, 3 H, OCH3), 3.66 (dt, J = 4.8, 9.6 Hz, 1 H, H-4), 3.54
(dd, J = 3.5, 10.4 Hz, 1 H, H-2), 3.49–3.45 (m, 2 H, H-3, H-5), 3.44 (s, 3 H, OCH3), 3.40 (d, J = 4.9 Hz, 2 H, H-6),
2.79 (d, J = 2.9 Hz, 1 H, C4-OH), 2.28 (d, J = 9.4 Hz, 1 H, C2-OH). 13C{1H} NMR (125 MHz, CDCl3, peaks from
both anomers are listed): δ 158.72, 158.68, 149.5, 144.4, 144.0, 143.9, 143.7, 136.2, 135.1, 134.9, 130.33, 130.27,
129.0, 128.4, 128.3, 128.22, 128.18, 127.99, 127.96, 127.84, 127.81, 127.7, 127.12, 127.08, 126.7, 125.3, 123.8,
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113.29, 113.25, 113.2, 113.0, 103.6, 98.5, 87.2, 87.1, 74.2, 72.7, 71.8, 71.3, 71.2, 69.5, 68.0, 67.1, 64.4, 64.1, 57.0,
55.3, 55.20, 51.16. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C27H29N3O6Na 514.1954; Found 514.1974.
Methyl 3-azido-3-deoxy-2,4-di-O-(p-methoxybenzyl)-6-O-(p-methoxytrityl)-D-glucopyranoside (17).
Compound 16-(α/β) (11.59 g, 23.58 mmol) was dissolved in anhydrous DMF (150 mL) and the solution was stirred
with cooling over an ice bath. After purging the flask with argon, sodium hydride (4.72 g, 197 mmol) was added in
portions. After stirring over an ice bath for approximately 30 min, PMBCl (16.1 mL, 119 mmol) was added
dropwise. The reaction was stirred overnight, after which TLC indicated completion. The reaction mixture was
diluted with H2O and extracted three times with EtOAc. The combined organic layer was then washed with brine
three times, dried over MgSO4, filtered, and concentrated under vacuum to give a yellow oil. The crude material
was purified by silica gel chromatography (Hex/EtOAc 4:1 with 1% Et3N) to give compound 17-(α/β) (13.21 g,
77%) as a yellow solid. The anomeric mixture was separable by this method of purification. TLC (Hex/EtOAc 4:1):
17-(α), Rf = 0.31, 17-(β); Rf = 0.41. 1H NMR of 17-(α) (500MHz, CDCl3): δ 7.49–7.46 (m, 4 H, ArH), 7.37–7.22
(m, 10 H, ArH), 6.94–6.92 (m, 2 H, ArH), 6.86–6.82 (m, 4 H, ArH), 6.75–6.73 (m, 2 H, ArH), 4.76 (d, J = 11.9 Hz,
1 H, PMB CH2), 4.67 (d, J = 3.5 Hz, 1 H, H-1), 4.65 (d, J = 12.0 Hz, 1 H, PMB CH2), 4.57 (d, J = 10.0 Hz, 1 H,
PMB CH2), 4.18 (d, J = 10.0 Hz, 1 H, PMB CH2), 3.87 (t, J = 9.9 Hz, 1 H, H-3), 3.83 (s, 3 H, OCH3), 3.79 (s, 3 H,
OCH3), 3.78 (s, 3 H, OCH3), 3.77 (ddd, J = 1.9, 5.2, 10.3 Hz, 1 H, H-5), 3.48 (dd, J = 1.8, 10.1 Hz, 1 H, H-6a or H-
6b), 3.42 (s, 3 H, OCH3), 3.41 (dd, J = 2.8, 9.7 Hz, 1 H, H-2), 3.37 (t, J = 9.8 Hz, 1 H, H-4), 3.16 (dd, J = 4.9, 10.2
Hz, 1 H, H-6a or H-6b). 13C{1H} NMR (125 MHz, CDCl3): δ 159.5, 159.3, 158.5, 144.6, 144.2, 135.4, 130.5, 130.0,
129.8, 129.7, 129.5, 128.5, 128.4, 127.79, 127.78, 126.8, 113.9, 113.6, 113.1, 97.0, 86.1, 77.7, 76.4, 74.3, 72.7,
69.9, 65.5, 62.3, 55.3, 55.2, 55.1, 54.9. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C43H45N3O8Na 754.3104; Found
754.3093. 1H NMR of 17-(β) (500MHz, CDCl3): δ 7.55–7.51 (m, 4 H, ArH), 7.39–7.36 (m, 4 H, ArH), 7.32–7.29
(m, 4 H ArH), 7.26–7.23 (m, 2 H, ArH), 6.93–6.91 (m, 2 H, ArH), 6.87–6.82 (m, 4 H, ArH), 6.76–6.73 (m, 2 H,
ArH), 4.87 (d, J = 10.6 Hz, 1 H, PMB CH2), 4.70 (d, J = 10.7 Hz, 1 H, PMB CH2), 4.57 (d, J = 9.8 Hz, 1 H, PMB
CH2), 4.34 (d, J = 7.7 Hz, 1 H, H-1), 4.25 (d, J = 9.9 Hz, 1 H, PMB CH2), 3.82 (s, 3 H, OCH3), 3.80 (s, 3 H, OCH3),
3.78 (s, 3 H, OCH3), 3.66 (s, 3 H, OCH3), 3.58 (t, J = 9.6 Hz, 1 H, H-3 or H-4), 3.58 (dd, 1 H, J = 1.9, 10.2 Hz, H-
6a or H-6b), 3.49 (t, J = 9.6 Hz, 1 H, H-3 or H-4), 3.38 (ddd, J = 1.9, 3.6, 9.7 Hz, 1 H, H-5), 3.31 (dd, J = 7.7, 9.8
Hz, 1 H, H-2), 3.23 (dd, J = 3.8, 10.3 Hz, 1 H, H-6a or H-6b). 13C{1H} NMR (125 MHz, CDCl3): δ 159.4, 158.6,
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144.5, 144.2, 135.4, 130.6, 130.2, 130.1, 130.0, 129.5, 128.7, 128.5, 127.83, 127.82 126.91, 126.88, 113.8, 113.7,
113.1, 104.5, 86.2, 79.8, 76.2, 75.2, 74.3, 74.2, 68.4, 62.1, 56.6, 55.29, 55.25, 55.2. HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C43H45N3O8Na 754.3104; Found 754.3098.
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Methyl 3-azido-3-deoxy-2,4-di-O-(p-methoxybenzyl)-α-D-glucopyranoside (18). To a stirring solution
of 17-(α) (3.30 g, 4.51 mmol) in CH2Cl2 (3.3 mL), a solution of glacial acetic acid (16.8 mL) and water (1.0 mL)
was added dropwise over 5 minutes. After stirring overnight, TLC indicated completion. The reaction was diluted
with CH2Cl2, transferred to a separatory funnel, and neutralized with saturated aqueous NaHCO3. The aqueous layer
was extracted using CH2Cl2 twice, and the combined organic layers were washed once with water, dried over
MgSO4, filtered, and concentrated under vacuum. The crude material was purified by silica gel chromatography
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(toluene/EtOAc 2:1) to give 18 (1.83 g, 88%) as a colorless oil. TLC (toluene/EtOAc 2:1): Rf = 0.20. H NMR
(500MHz, CDCl3): δ 7.33–7.28 (m, 4 H, ArH), 6.91–6.88 (m, 4 H, ArH), 4.80 (d, J = 10.6 Hz, 1 H, PMB CH2),
4.73 (d, J = 12.0 Hz, 1 H, PMB CH2), 4.59 (d, J = 12.8 Hz, 1 H, PMB CH2), 4.56 (d, J = 10.9 Hz, 1 H, PMB CH2),
4.48 (d, J = 3.5 Hz, 1 H, H-1), 3.90 (t, J = 9.9 Hz, 1 H, H-3), 3.81 (s, 3 H, OCH3), 3.80 (s, 3 H, OCH3), 3.76–3.66
(m, 2 H, H-6), 3.59 (dt, J = 3.2, 9.9 Hz, 1 H, H-5), 3.33 (s, 3 H, OCH3) 3.31 (t, J = 10.0 Hz, 1 H, H-4), 3.30 (dd, J
= 3.3, 10.0 Hz, 1 H, H-2). 13C{1H} NMR (125 MHz, CDCl3): δ 159.51, 159.48, 130.0, 129.8, 129.7, 129.6, 129.0,
128.2, 113.91, 113.88, 97.3, 77.6, 75.4, 74.4, 72.8, 70.3, 65.2, 61.5, 55.24, 55.23, 55.2. HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C23H29N3O7Na 482.1903; Found 482.1885.
Methyl 3-azido-3-deoxy-2,4-di-O-(p-methoxybenzyl)-α-D-glucohexoaldo-1,5-pyranoside (19). Oxalyl
chloride (0.04 mL, 0.47 mmol) was dissolved in anhydrous CH2Cl2 (3.0 mL) and the solution was stirred at –78 °C
under argon. After approximately 5 min, DMSO (0.05 mL, 0.7 mmol) was added dropwise and the solution was
stirred for 15 min. Next, a solution of compound 18 (0.105 g, 0.229 mmol) in anhydrous CH2Cl2 (3 mL) was
transferred to the reaction mixture dropwise. After stirring for 30 min, Et3N (0.19 mL, 1.4 mmol) was added and
the reaction was stirred for 15 min at –78 °C followed by gradual warming to room temperature. After stirring
overnight, the reaction mixture was diluted with CH2Cl2 and washed with H2O three times. The organic layer was
dried over Na2SO4, filtered, and concentrated under vacuum to give 19 as an opaque yellow oil, which was subjected
to the next reaction without further purification.
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(Z)-Methyl 6-O-acetyl-3-azido-3-deoxy-2,4-di-O-(p-methoxybenzyl)-α-D-gluco-5-enopyranoside (20).
The crude oil containing compound 19 was dissolved in anhydrous CH3CN (2.0 mL). While stirring under argon,
DMAP (2.8 mg, 0.023 mmol) and K2CO3 (0.159 g, 1.15 mmol) were added followed by Ac2O (0.065 mL, 0.69
mmol), then the reaction was heated to 70 ˚C. After stirring for 3 h at 70 ˚C, TLC indicated completion and the
reaction was diluted with CH2Cl2 and washed three times with H2O. The organic layer was dried over Na2SO4,
filtered, and concentrated by vacuum. The crude material was purified by silica gel chromatography (Hex/EtOAc
4:1) to give compound 20 (0.071 g, 62% over two steps) as a yellow oil. TLC (Hex/EtOAc 4:1): Rf = 0.30. 1H NMR
(500 MHz, CDCl3): δ 7.34–7.28 (m, 4 H, ArH), 7.16 (d, J = 2.0 Hz, 1 H, H-6), 6.92–6.89 (m, 4 H, ArH), 4.75 (d, J
= 11.9 Hz, 1 H, PMB CH2), 4.70–4.65 (m, 2 H, PMB CH2), 4.58 (d, J = 3.5 Hz, 1 H, H-1), 4.56 (d, J = 12.0 Hz, 1
H, PMB CH2), 3.86 (t, J = 9.9 Hz, 1 H, H-3), 3.81 (s, 3 H, OCH3), 3.80 (s, 3 H, OCH3), 3.73 (dd, J = 1.9, 9.7 Hz, 1
H, H-4), 3.43 (s, 3 H, OCH3), 3.37 (dd, J = 3.4, 10.1 Hz, 1 H, H-2), 2.15 (s, 3 H, OAc). 13C{1H} NMR (125 MHz,
CDCl3): δ 167.2, 159.6, 134.0, 130.0, 129.8, 129.4, 129.0, 123.5, 113.93, 113.91, 99.1, 77.5, 77.0, 75.5, 74.1, 73.1,
64.6, 56.3, 55.3, 20.6. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C25H29N3O8Na 522.1852; Found 522.1873.
(1R,2R,3S,4R,5S)-4-Azido-2-hydroxy-3,5-di-O-(p-methoxybenzyl)-6-oxocyclohexyl acetate (21).
Compound 20 (40 mg, 0.082 mmol) was dissolved in acetone (1.6 mL) and water (0.40 mL) and placed over an ice
bath. While stirring, Hg(OTFA)2 (50 mg, 0.12 mmol) was added. After 10 min, 3M aqueous NaOAc (0.034 mL)
and brine (0.090 mL) were added. After stirring overnight, TLC indicated consumption of starting material. The
reaction mixture was diluted with water and extracted with CH2Cl2 three times. The combined organic layers were
then dried over MgSO4, filtered, and concentrated under vacuum. The crude material was purified by silica gel
chromatography (Hex/EtOAc 3:2) to give compound 21 (19.3 mg, 47%) as an off-white solid. TLC (Hex/EtOAc
3:2): Rf = 0.20. 1H NMR (500 MHz, CDCl3): δ 7.34–7.30 (m, 4 H, ArH), 6.92–6.88 (m, 4 H, ArH), 5.10 (dd, J =
1.0, 2.5 Hz, 1 H, H-1), 4.83 (d, J = 11.1 Hz, 1 H, PMB CH2), 4.71 (d, J = 11.4 Hz, 1 H, PMB CH2), 4.66 (d, J =
11.4 Hz, 1 H, PMB CH2), 4.50 (d, J = 11.0 Hz, 1 H, PMB CH2), 4.31 (t, J = 2.4 Hz, 1 H, H-2), 4.03 (t, J = 10.1 Hz,
1 H, H-4), 3.86 (d, J = 10.3 Hz, 1 H, H-5), 3.82 (s, 3 H, OCH3), 3.81 (s, 3 H, OCH3), 3.62 (dd, J = 2.3, 9.8 Hz, 1 H,
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H-3), 2.60 (bs, 1 H, C2-OH), 2.23 (s, 3 H, OAc CH3). C{1H} NMR (125 MHz, CDCl3): δ 196.9, 169.8, 159.8,
159.6, 130.1, 129.9, 128.7, 128.6, 114.1, 113.9, 80.0, 76.7, 74.6, 73.0, 72.8, 69.6, 65.2, 55.29, 55.26, 20.5. HRMS
(ESI-TOF) m/z: [M+Na]+ Calcd for C24H27N3O8Na 508.1696; Found 508.1720.
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1-O-Acetoxy-4-azido-4-deoxy-3,5-di-O-(p-methoxybenzyl)-myo-inositol (22). Compound 21 (36 mg,
0.074 mmol) was dissolved in anhydrous CH3CN (2.6 mL) and cooled over an ice bath. While stirring, Na(OAc)3BH
(124 mg, 0.585 mmol) was added, followed by glacial acetic acid (0.20 mL, 3.5 mmol). After approximately 2 h,
TLC analysis showed complete consumption of starting material. The reaction mixture was diluted with water and
extracted with EtOAc. The resulting organic layer was dried over MgSO4, filtered, and concentrated under vacuum.
The crude material was purified using silica gel chromatography (Hex/EtOAc 1:2) to give compound 22 (25 mg,
69%) as a white solid. TLC (Hex/EtOAc 1:2): Rf = 0.32. 1H NMR (500 MHz, CDCl3): δ 7.33–7.30 (m, 4 H, ArH),
6.92–6.89 (m, 4 H, ArH), 4.87 (d, J = 10.8 Hz, 1 H, PMB CH2), 4.68 (d, J = 11.0 Hz, 1 H, PMB CH2), 4.65 (dd, J
= 2.7, 10.1 Hz, 1 H, H-1), 4.64–4.59 (m, 2 H, PMB CH2), 4.25 (t, J = 2.6 Hz, 1 H, H-2), 4.07 (t, J = 9.8 Hz, 1 H,
H-6), 3.84–3.80 (m, 7 H, 2x OCH3, H-4), 3.34 (dd, J = 2.6, 10.0 Hz, 1 H, H-3), 3.13 (t, J = 9.6 Hz, 1 H, H-5), 2.38
(s, 1 H, C-6 OH), 2.22 (s, 1 H, C-2 OH), 2.15 (s, 3 H, OAc CH3). 13C{1H} NMR (125 MHz, CDCl3): δ 170.7, 159.7,
159.5, 129.9, 129.8, 128.8, 114.07, 114.06, 80.8, 77.9, 75.2, 72.7, 72.4, 70.4, 67.4, 64.3, 55.29, 55.27, 21.0. HRMS
(ESI-TOF) m/z: [M+HCO2]- Calcd for C25H30N3O10 532.1931; Found 532.1906.
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4-Azido-4-deoxy-3,5-di-O-(p-methoxybenzyl)-myo-inositol (23). After a solution of compound 22 (34
mg, 0.070 mmol) in a 4 mL of freshly prepared 0.05 M NaOCH3 in methanol was stirred for 30 min, it was
neutralized to ~pH 7 using Dowex H+ resin. The solution was filtered and concentrated under vacuum. The crude
material was purified using silica gel chromatography (Hex/EtOAc 1:8) to give compound 23 (25 mg, 80%) as a
white solid. TLC (Hex/EtOAc 1:8): Rf = 0.35. 1H NMR (500 MHz, CD3OD): δ 7.36–7.33 (m, 4 H, ArH), 6.91–6.86
(m, 4 H, ArH), 4.81 (d, J = 10.5 Hz, 1 H, PMB CH2), 4.70 (d, J = 10.5 Hz, 1 H, PMB CH2), 4.66 (d, J =11.4 Hz, 1
H, PMB CH2), 4.54 (d, J = 11.4 Hz, 1 H, PMB CH2), 4.11 (t, J = 2.7 Hz, 1 H, H-2), 3.79 (s, 3 H, OCH3), 3.78 (s, 3
H, OCH3), 3.77 (t, J = 9.5 Hz, 1 H, H-6), 3.71 (t, J = 10.1 Hz, 1 H, H-4), 3.28 (dd, J = 2.6, 10.8 Hz, 1 H, H-3), 3.26
(dd, J = 2.8, 10.0 Hz, 1 H, H-1), 3.09 (t, J = 9.4 Hz, 1 H, H-5). 13C{1H} NMR (125 MHz, CD3OD): δ 160.9, 160.8,
132.0, 131.3, 130.9, 130.8, 114.7, 114.6, 82.8, 79.3, 75.9, 74.4, 73.0, 72.5, 70.2, 66.5, 55.67, 55.65. HRMS (ESI-
TOF) m/z: [M+HCO2]- Calcd for C23H28N3O9 490.1862; Found 490.1845.
4-Azido-4-deoxy-myo-inositol (4). Compound 23 (24 mg, 0.054 mmol) was dissolved in CH2Cl2 (10 mL)
to give a clear colorless solution. While stirring, trifluoroacetic acid (1.1 mL) and five drops of water were added.
After 30 min of stirring, the solution was purple in color and TLC indicated complete consumption of the starting
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material. The reaction mixture was co-evaporated with toluene under vacuum. The resulting solid was purified
using silica gel chromatography (CH2Cl2/MeOH 2:1) which was further purified by silica gel chromatography (n-
butanol/EtOH/H2O 5:3:2) to give compound 4 (9 mg, 81%) as a white solid. TLC (n-butanol/EtOH/H2O 5:3:2): Rf
= 0.64. 1H NMR (500 MHz, D2O): δ 4.06 (t, J = 2.6 Hz, 1 H, H-2), 3.66 (t, J = 9.7 Hz, 1 H, H-5), 3.61–3.55 (m, 2
H, H-4, H-1), 3.49 (dd, J = 3.0, 10.0 Hz, 1 H, H-3), 3.31 (dt, J = 2.0, 9.6 Hz, 1 H, H-6). 13C{1H} NMR (75 MHz,
CDCl3, referenced to an acetone internal standard): δ 64.0, 63.2, 62.9, 61.6, 60.9, 56.5. HRMS (ESI-TOF) m/z: [M-
H]- Calcd for C6H10N3O5 204.0620; Found 204.0626.
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Methyl 4-azido-4-deoxy-6-O-(p-methoxytrityl)-α-D-glucopyranoside (25). After dissolving compound
2429 (4.68 g, 21.4 mmol) in anhydrous pyridine (200 mL), the flask was purged with argon and cooled in an ice
bath. While stirring, PMTrtCl (13.85 g, 44.85 mmol) was added in portions to the reaction mixture. After stirring
overnight with gradual warming to room temperature, TLC showed complete consumption of starting material. The
solution was quenched with excess methanol, transferred to a separatory funnel containing ice water, and extracted
three times with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The
resulting crude oil was purified using silica gel chromatography (toluene/EtOAc 1:1 with 1% Et3N) to give
compound 25 (9.55 g, 91%) as a white solid. TLC (toluene/EtOAc 1:1) of 25: Rf = 0.42. 1H NMR of 25 (300 MHz,
CDCl3): δ 7.51–7.47 (m, 4 H, ArH), 7.39–7.28 (m, 6 H, ArH), 7.26–7.22 (m, 2 H, ArH), 6.88–6.83 (m, 2 H, ArH),
4.87 (d, J = 3.8 Hz, 1 H, H-1), 3.80 (s, 3 H, OCH3), 3.76 (t, J = 9.1 Hz, 1 H, H-3), 3.63 (dd, J = 3.7, 8.3 Hz, 1 H,
H-2), 3.58 (d, J = 7.0 Hz, 2 H, H-6), 3.44 (s, 3 H, OCH3), 3.41 (t, J = 10.9 Hz, 1 H, H-4), 3.19 (dd, J = 4.0, 10.4 Hz,
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1 H, H-5). C{1H} NMR of 25 (75 MHz, CDCl3): δ 158.5, 144.5, 144.2, 135.4, 130.4, 128.43, 128.37, 127.78,
128.77, 126.9, 113.1, 99.0, 86.2, 73.9, 72.6, 69.7, 62.7, 62.0, 55.3, 55.2. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd
for C27H29N3O6Na 514.1954; Found 514.1948.
Methyl
4-azido-4-deoxy-2,3-di-O-(p-methoxybenzyl)-6-O-(p-methoxytrityl)-D-α-glucopyranoside
(30). Compound 25-(α) (9.47 g, 19.3 mmol) was dissolved in anhydrous DMF (150 mL) and the solution was stirred
with cooling over an ice bath. After purging the flask with argon, sodium hydride (2.32 g, 96.7 mmol) was added
in portions. After stirring over an ice bath for approximately 30 min, PMBCl (7.85 mL, 57.9 mmol) was added
dropwise. After overnight stirring at room temperature, TLC indicated starting material remained so additional
sodium hydride (3.23 g, 135 mmol) and PMBCl (10.2 mL, 75.4 mmol) were added and the reaction stirred for four
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days. The reaction mixture was quenched with excess methanol, diluted with H2O, and transferred to a separatory
funnel. The mixture was extracted with EtOAc three times. The organic layer was then washed with brine three
times, dried over Na2SO4, filtered, and concentrated under vacuum. The crude material was purified using silica gel
chromatography (toluene/EtOAc 4:1 with 1% Et3N) to give compound 30 (9.16 g, 65%) as an orange oil. TLC
(toluene/EtOAc 2:1): Rf = 0.81. 1H NMR (300 MHz, CDCl3): δ 7.49–7.45 (m, 4 H, ArH), 7.36–7.27 (m, 12 H, ArH),
6.93–6.83 (m, 6 H, ArH), 4.88 (d, J = 10.0 Hz, 1 H, PMB CH2), 4.78 (d, J = 11.8 Hz, 1 H, PMB CH2), 4.73 (d, J =
10.1 Hz, 1 H, PMB CH2), 4.67 (d, J = 4.9 Hz, 1 H, H-1), 4.65 (d, J = 12.0 Hz, 1 H, PMB CH2), 3.83 (s, 3 H, OCH3),
3.82–3.79 (m, 7 H, 2x OCH3, H-4), 3.64 (t, J = 10.4 Hz, 1 H, H-3), 3.60 (dd, J = 3.5, 9.5 Hz, 1 H, H-2), 3.53–3.48
(m, 1 H, H-5), 3.40 (s, 3 H, OCH3), 3.38 (dd, J = 1.8, 10.9 Hz, 1 H, H-6a or H-6b), 3.15 (dd, J = 4.3, 10.3 Hz, 1 H,
H-6a or H-6b). 13C{1H} NMR (75 MHz, CDCl3): δ 159.44, 159.39, 158.5, 144.5, 144.2, 135.4, 130.4, 130.2, 129.6,
128.4, 128.3, 127.77, 127.75, 126.8, 113.90, 113.85, 113.1, 98.1, 86.1, 80.0, 79.6, 75.5, 72.9, 69.3, 62.6, 62.1, 55.3,
55.23, 55.17. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C43H45N3O8Na 754.3104; Found 754.3105.
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Methyl 4-azido-4-deoxy-2,3-di-O-(p-methoxybenzyl)-α-D-glucopyranoside (26). Compound 30 (8.86 g,
12.1 mmol) was dissolved in CH2Cl2 (8.4 mL) and the solution was stirred. A solution of glacial acetic acid (31.4
mL) and water (2.1 mL) was added to the reaction mixture dropwise. After stirring for 72 h, TLC indicated the
reaction was complete. The reaction mixture was transferred to a separatory funnel and neutralized with saturated
aqueous NaHCO3. Following extraction of the mixture with CH2Cl2 three times, the combined organic layers were
dried over MgSO4, filtered, and concentrated under vacuum. The crude material was purified by silica gel
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chromatography (toluene/EtOAc 2:1) to give compound 26 (5.37 g, 96%) as a white solid. H NMR (300 MHz,
CDCl3): δ 7.34–7.27 (m, 4 H, ArH), 6.90–6.86 (m, 4 H, ArH), 4.88 (d, J = 10.1 Hz, 1 H, PMB CH2), 4.76–4.72 (m,
2 H, PMB CH2), 4.58 (d, J = 11.8 Hz, 1 H, PMB CH2), 4.52 (d, J = 3.5 Hz, 1 H, H-1), 3.89–3.71 (m, 9 H, 2x OCH3,
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H-3, H-6), 3.52–3.45 (m, 3 H, H-2, H-4, H-5), 3.35 (s, 3 H, OCH3), 1.85 (bt, J = 6.7 Hz, 1 H, C6-OH). C{1H}
NMR (75 MHz, CDCl3): δ 159.5, 159.3, 130.1, 130.0, 129.9, 129.7, 113.9, 113.8, 98.3, 79.6, 79.4, 75.3, 73.0, 69.8,
62.0, 61.4, 55.4, 55.2. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C23H29N3O7Na 482.1903; Found 482.1910.
Methyl 4-azido-4-deoxy-2,3-di-O-(p-methoxybenzyl)-α-D-glucohexoaldo-1,5-pyranoside (27). Oxalyl
chloride (1.1 mL, 12.8 mmol) was dissolved in anhydrous CH2Cl2 (15 mL) and the solution was stirred at –78 °C
under argon. After approximately 15 min, DMSO (2.20 mL, 31.0 mmol) was added dropwise and the solution was
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stirred for 15 min. Next, a solution of compound 26 (1.44 g, 3.13 mmol) in anhydrous CH2Cl2 (15 mL) was
transferred to the reaction mixture dropwise. After stirring for 30 min, Et3N (6.5 mL, 46.6 mmol) was added and
the reaction was stirred for 15 min at –78 °C followed by gradual warming to room temperature. After reaching
room temperature, the reaction mixture was diluted with EtOAc and washed with brine three times. The organic
solution was dried over MgSO4 and concentrated under vacuum to give an opaque yellow oil. The organic layer
was dried over Na2SO4, filtered, and concentrated under vacuum to give 27, which was subjected to the next reaction
without further purification.
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Methyl (6S)-3-deoxy-4,5-di-O-(p-methoxybenzyl)-D-threo-hex-2-enodialdo-6,2-pyranoside (29). The
oil containing compound 27 was dissolved in anhydrous CH3CN (40 mL). While stirring under argon, DMAP (41
mg, 0.34 mmol) and K2CO3 (3.22 g, 23.3 mmol) were added followed by Ac2O (1.2 mL, 12.7 mmol), then the
reaction was heated to 65 °C. After stirring overnight at 65 °C, TLC indicated completion and the reaction mixture
was diluted with EtOAc and washed with brine three times. The organic layer was dried over Na2SO4, filtered, and
concentrated by vacuum. The crude material was purified by silica gel chromatography (toluene:EtOAc 10:1) to
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give compound 29 (0.61 g, 47% over two steps) as a yellow oil. TLC (toluene/EtOAc 10:1): Rf = 0.24. H NMR
(300 MHz, CDCl3, D-glucose numbering used for peak assignments): δ 9.17 (s, 1 H, CHO), 7.30–7.25 (m, 4 H,
ArH), 6.90–6.86 (m, 4 H, ArH), 5.84 (d, J = 2.7 Hz, 1 H, =CH), 4.87 (d, J = 2.6 Hz, 1 H, H-1), 4.76 (d, J = 11.8
Hz, 1 H, PMB CH2), 4.68–4.61 (m, 3 H, PMB CH2), 4.44 (dd, J = 2.7, 8.1 Hz, 1 H, H-3), 3.81 (s, 3 H, OCH3), 3.80
(s, 3 H, OCH3), 3.76 (dd, J = 2.6, 8.1 Hz, 1 H, H-2), 3.45 (s, 3 H, OCH3). 13C{1H} NMR (75 MHz, CDCl3): δ 186.0,
159.5, 159.4, 148.2, 129.9, 129.8, 129.7, 129.5, 120.8, 113.9, 99.8, 75.8, 73.1, 72.8, 72.3, 56.9, 52.23, 55.22. HRMS
(ESI-TOF) m/z: [M+Na]+ Calcd for C23H26O7Na 437.1576; Found 437.1571.
Supporting Information: 1H and 13C NMR spectra.
Acknowledgements
This work was supported by a National Science Foundation CAREER Award (1654408) and a Henry
Dreyfus Teacher-Scholar Award from The Camille & Henry Dreyfus Foundation (TH-17-034). Dr. Robin J. Hood
is thanked for assistance with NMR and MS instrumentation.
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