Enantioselective de novo synthesis of 4-deoxy-d-hexopyranoses via hetero-Diels-Alder cycloadditions: Total synthesis of ezoaminuroic acid and neosidomycin

Article abstract of DOI:10.1021/jo201673w

The de novo synthesis of carbohydrates constitutes an important aspect of organic chemistry, and its application toward deoxy sugars is particularly noteworthy in targeting biologically active compounds. The enantioselective preparation of 4-deoxy-d-ribo-, 4-deoxy-d-lyxo-, and 4-deoxy-d-xylo- hexopyranosides, along with their uronate counterparts has been successfully accomplished using hetero-Diels - Alder reactions as the key step. Jacobsen chromium(III) catalyst and a titanium - binaphthol complex have been used to successfully catalyze diene and aldehyde cycloadditions, leading to optically active dihydropyran templates. 6-Hydroxydesosamine, orthogonally protected ezoaminuroic acid, and neosidomycin were synthesized using a comparative study. Also, a novel chiron approach to 4-deoxy-lyxo-hexopyranosiduronic acid methyl ester derivatives was efficiently accomplished starting from readily accessible starting materials. This work represents a systematic and comprehensive study toward a de novo synthesis of 4-deoxy-hexopyranoses via enantioselective hetero-Diels-Alder reactions.

Full text of DOI:10.1021/jo201673w

Article
pubs.acs.org/joc
Enantioselective de Novo Synthesis of 4-Deoxy-D-hexopyranoses via
Hetero-Diels−Alder Cycloadditions: Total Synthesis of Ezoaminuroic
Acid and Neosidomycin
Denis Giguere, Julien Martel, Tze Chieh Shiao, and Rene Roy*
̀
́
Pharmaqam, Department of Chemistry, Universite
Canada H3C 3P8
́ ́ ̀ ́ ́ ́
du Quebec a Montreal, P.O. Box 8888, Succ. Centre-Ville Montreal, Quebec,
S
* Supporting Information
ABSTRACT: The de novo synthesis of carbohydrates constitutes an
important aspect of organic chemistry, and its application toward deoxy
sugars is particularly noteworthy in targeting biologically active
compounds. The enantioselective preparation of 4-deoxy-D-ribo-, 4-
deoxy-D-lyxo-, and 4-deoxy-D-xylo-hexopyranosides, along with their
uronate counterparts has been successfully accomplished using hetero-
Diels−Alder reactions as the key step. Jacobsen chromium(III) catalyst
and a titanium−binaphthol complex have been used to successfully
catalyze diene and aldehyde cycloadditions, leading to optically active
dihydropyran templates. 6-Hydroxydesosamine, orthogonally protected
ezoaminuroic acid, and neosidomycin were synthesized using a
comparative study. Also, a novel chiron approach to 4-deoxy-lyxo-
hexopyranosiduronic acid methyl ester derivatives was efficiently
accomplished starting from readily accessible starting materials. This work represents a systematic and comprehensive study
toward a de novo synthesis of 4-deoxy-hexopyranoses via enantioselective hetero-Diels−Alder reactions.
sequently, modest interest and methods have been developed
toward the de novo synthesis of these medically relevant
compounds. The most common approach toward the synthesis
of 4-deoxy-hexopyranoses consists of selective protection of the
natural hexopyranose hydroxyl groups followed by deoxygena-
tion of the residual free 4-hydroxyl group or elimination to
form 4,5-unsaturated derivatives.6 Other approaches involve
enzymatic synthesis (using microbial oxidation,7 transketolase,8
aldolase,9 or Saccharomyces cerevisiae10), Diels−Alder reactions
(1,3-diene with a carbonyl compound,11 oxa-diene with
electron-rich dienophile12 or using the naked approach13),
and other methods (from benzyl glycidyl ether14 or using
Sharpless asymmetric dihydroxylation15).
Most methods are long, require stoichiometric amounts of
reagents, give racemic products, or do not provide access to
various carbohydrate configurations (D, L, ribo, lyxo, xylo, ...).
Thus, the use of a catalytic enantioselective hetero-Diels−Alder
(HDA) reaction could be most efficient toward the synthesis of
4-deoxy-hexopyranose derivatives. This report describes the use
of Jacobsen tridentate chromium catalyst and a binaphthol−
titanium complex for catalytic enantioselective HDA reactions
toward 4-deoxy-hexopyranoses.
INTRODUCTION
■
Over the past decade, there has been a large expansion in the
understanding of the importance of carbohydrates in biology.
The rate of these discoveries is somewhat dependent on
medicinal chemists to provide unnatural sugar analogues having
attractive and novel biological properties. Deoxy-hexoses are of
particular interest, and the preparation of this family of
compounds from achiral starting materials has attracted
attention and stands out as a challenge to asymmetric
catalysis.1,2
4-Deoxy-hexopyranose motifs (shown in blue) are present in
several natural products as shown in Figure 1. Erythromycin A1
(1) is an antibiotic macrolide within a family of diverse
molecular architectures. Its desosamine moiety, presented in
blue, is in part responsible for the potent antibacterial activity of
1.3 Moreover, nikkomycin B (2), ezomycin A2 (3), and
ezomycin B2 (4) are secondary metabolite members of the
peptidyl nucleoside family and possess antimicrobial and
antifungal properties.4 These three natural products are
composed of a nucleobase and a central 4-deoxy-hexopyranose
(named ezoaminuroic acid for compounds 3 and 4).
Furthermore, metabolites 5−8 have been isolated from
bacterial strains and represent rare examples of sugars linked
to an indole moiety through a nitrogen atom.5 This family of
compounds possesses appealing antiviral or antibacterial
activity against various bacterium strains.5b,c
For several decades, asymmetric catalysis has constituted an
important aspect of organic synthesis toward the preparation of
biologically active compounds. Moreover, the asymmetric HDA
The natural abundance of 4-deoxy-hexopyranoses is relatively
limited in comparison to their 2-deoxy counterparts. Con-
Received: August 23, 2011
Published: October 25, 2011
© 2011 American Chemical Society
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diastereomeric excesses, and finally the simple experimental
protocol, allowing scalable pyran templates.
As part of an ongoing research program aimed at the
synthesis and biological evaluation of deoxy-hexopyranoses,
novel approaches are needed.18 To the best of our knowledge,
there is no preparation of an enantioenriched 4-deoxy-sugar
using as the key step an asymmetric HDA cycloaddition
catalyzed by a chiral complex. We wish to report the
preparation of 4-deoxy-D-ribo, 4-deoxy-D-xylo, and 4-deoxy-D-
lyxo-hexopyranosides along with their methyl uronate counter-
parts. The key step for their synthesis is based on asymmetric
HDA cycloadditions catalyzed by Jacobsen tridentate
chromium(III) catalyst and a binaphthol−titanium complex.
The synthesis of 6-hydroxydesosamine, protected ezoaminuroic
acid, and neosidomycin was also achieved in high overall yield.
Moreover, a new chiron approach to neosidomycin was also
developed, starting from methyl α-D-mannopyranoside. Finally,
a comparative study was used in order to determine the most
efficient route for the preparation of various 4-deoxy-
hexopyranoses.
RESULTS AND DISCUSSION
■
In order to achieve the rapid preparation of 4-deoxy-D-
hexopyranoses, a robust synthetic strategy allowing its large-
scale preparation was needed. The syntheses were initiated with
the highly enantio- and diastereoselective HDA between 1-
methoxybutadiene 9 and (tert-butyldimethylsilyloxy)-
acetaldehyde 10 catalyzed by 1.5 mol % of Jacobsen chiral
tridentate chromium(III) catalyst 1119 to provide 12 (Scheme
Figure 1. 4-Deoxy-hexopyranose motifs (shown in blue) present in
various natural products 1−8.
reaction is highly powerful for the construction of optically
active heterocycles, the starting point of many natural or
unnatural products with a wide range of biological activities.16
The high regio- and stereoselectivity during the course of the
catalyzed HDA, along with the creation of up to four new
stereocenters, renders this methodology very attractive to
construct various targets having similar structures. Finally, chiral
catalysts allow the use of mild reaction conditions in an atom-
economical fashion as compared to the use of chiral auxiliaries.
Figure 2 presents the synthetic plan for the construction of
various 4-deoxy-D-hexopyranoses. Reaction of inactivated
Scheme 1. Synthesis of Methyl 4-Deoxy-β-D-ribo-
hexopyranoside 13, Methyl 4-Deoxy-β-D -xylo-
hexopyranoside 15, and Methyl 4-Deoxy-β-D-xylo-
a
hexopyranosiduronic Acid Methyl Ester 17
Figure 2. Synthetic plan for the construction of various 4-deoxy-D-
hexopyranoses.
carbonyl compounds with a non-nucleophilic diene would
provide a direct route to enantiomerically enriched dihydropyr-
an derivatives from simple achiral starting materials.17 There-
fore, the choice of catalyst is crucial and allows the installation
of a C-5 chiral center, fixing the D configuration of the sugar
moiety. The choice of starting dienophile is also essential,
allowing direct access to the uronic acid scaffold after the HDA
reaction. Moreover, the anomeric configuration could direct the
stereochemical outcome of the dihydropyran double-bond
functionalization. This key strategy was used because of the
easy access of chiral complexes, the high enantio- and
a
Reagents and conditions: (a) 10, 11 (1.5 mol %), 4 Å molecular
sieves, then 9, 0−24 °C, 16 h, 89%, ee >99%, de >99%; (b) OsO4,
NMO, acetone/water, 24 °C, 16 h, 70%; (c) Ac2O, DMAP, pyridine,
CH2Cl2, 24 °C, 50 min, 77%; (d) benzoic acid, PPh3, DIAD, toluene,
24 °C, 50 min, 82%; (e) TBAF, THF, 24 °C, 30 min, 94%; (f) (i)
TEMPO, BAIB, CH2Cl2/water, 24 °C, 45 min, (ii) K2CO3, MeI,
CH3CN, 24 °C, 16 h, 60%.
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1). Dihydropyran 12 (89% yield, ee >99%, de >99%) possesses
two chiral centers, thereby fixing C-1 with a β configuration and
C-5 establishing the D series of the newly formed carbohydrate
core. Catalytic diastereoselective dihydroxylation of dihydro-
pyran 12 with 6 mol % of osmium tetroxide (from the less
hindered face) afforded methyl 4-deoxy-β-D-ribo-hexopyrano-
side 13 in 70% yield. Furthermore, the xylo configuration could
be easily achieved following a two-step procedure. Selective
acetylation of the equatorial (O-2) hydroxyl group (77%
yield),20 followed by a Mitsunobu treatment, resulted in the
inversion of the C-3 stereocenter (82% yield) using benzoic
acid. Compound 15 constitutes an orthogonally protected
methyl 4-deoxy-β-D-glucopyranoside that was synthesized in
only four steps. Methyl 4-deoxy-β-D-xylo-hexopyranoside 15
was further transformed into its uronic acid derivative by
unmasking the primary hydroxyl group using TBAF (94%),
followed by a TEMPO/BAIB oxidation allowing formation of
the uronic acid. Its methyl ester was formed after treatment
with MeI under basic conditions, thus providing methyl 4-
deoxy-β-D-xylo-hexopyranosiduronic acid methyl ester 17 in
60% yield over two steps.21
Scheme 3. Epoxide Opening toward Desosamine Derivative
25
a
a
Reagents and conditions: (a) mCPBA, CH2Cl2, 24 °C, 16 h, 70%; (b)
dimethylamine (33% in EtOH), 24 °C, 3 days, 85%; (c) (i) Ac2O,
pyridine, 24 °C, 3 h, quantitative, (ii) TBAF, THF, 24 °C, 30 min,
81%.
using a different amine-based nucleophile. When dimethyl-
amine (33% in EtOH) was stirred for 3 days at 24 °C,
compound 24 was isolated in 85% yield. C-3 opening product
Being able to control the oxidation level at C-6 of the
carbohydrate moiety, we focused our attention on the
preparation of ezoaminuroic acid (present in compounds 3
and 4; Figure 1). The synthesis was initiated by a modified
Mitsunobu procedure on pyran 14, allowing formation of the
corresponding azido sugar with inversion of configuration in
92% yield (Scheme 2). The silyl ether of 18 was cleaved to
was the only detected regioisomer, in accord with the Furst−
̈
Plattner rule, providing an equatorially substituted product.
Compound 24 could be transformed into methyl 2-acetyl-6-
hydroxy-β-D-desosamine through protecting group manipula-
tion. Compound 25 was isolated in 81% yield over two steps
and represents a valuable antibiotic when joined to various
ketolides.24
Fully protected ezoaminuroic acid 21 was alternatively
synthesized starting from ethyl glyoxylate 26 used as dienophile
partner (Scheme 4). This modification allowed formation of a
Scheme 2. First-Generation Synthesis of Protected
Ezoaminuroic Acid 21 from Pyran 14
a
Scheme 4. Second-Generation Synthesis of Protected
Ezoaminuroic Acid 21 Using HDA Catalyzed by a
a
Binaphthol−Titanium Complex as a Key Step
a
Reagents and conditions: (a) DPPA, PPh3, DIAD, THF, 0−24 °C,
then 50 °C, 16 h, 92%; (b) TBAF, THF, 24 °C, 30 min, 93%; (c) (i)
TEMPO, BAIB, CH2Cl2/water, 24 °C, 45 min, (ii) K2CO3, MeI,
CH3CN, 24 °C, 16 h, 57%; (d) Pd/C, H2, EtOAc, 24 °C, 3 h, then
Boc2O, Et3N, 24 °C, 16 h, 92%.
provide 19 in 93% yield, which was transformed into its methyl
ester using the above procedure (TEMPO/BAIB, then K2CO3,
MeI) in 57% over two steps. Finally, reduction of the azido
group using a catalytic amount of Pd/C was followed by in situ
Boc protection, providing amino sugar 21 in 92% yield over
two steps.
Additionally, 3-amino derivatives were obtained by epoxide
opening of 4-deoxyanhydropyranoside. Toward this goal,
epoxidation of dihydropyran 12 with mCPBA afforded the
anhydro derivative 22 in 70% yield as the sole diastereoisomer
(Scheme 3). Epoxide opening with NaN3 failed or gave poor
regioselectivities and yields under standard or chelating
conditions.22 Decomposition was predominant, and opening
at C-2 was important, in accord with previously described
epoxide opening on similar systems.23 On the other hand,
regiochemical epoxide opening could be successfully achieved
a
Reagents and conditions: (a) (−)-(S)-BINOL (20 mol %), Ti(O-i-
Pr)4 (10 mol %), CH2Cl2, 40 °C, 1 h, then 26 and 9, −30 to 24 °C, 2.5
h, 61%, ee 95%, de >95%; (b) (i) OsO4, NMO, acetone/water, 24 °C,
16 h, (ii) NaOMe, MeOH, 24 °C, 2 h, 64%; (c) Ac2O, DMAP,
pyridine, CH2Cl2, 24 °C, 50 min, 70%; (d) DPPA, PPh3, DIAD, THF,
0−24 °C, then 50 °C, 16 h, 73%; (e) Pd/C, H2, EtOAc, 24 °C, 3 h,
then Boc2O, Et3N, 24 °C, 16 h, 92%.
fully oxidized dihydropyran at the C-6 position while still
having a D configuration at C-5. Jacobsen chiral tridentate
chromium(III) catalyst 11 gave poor yields and diastereo- and
enantiomeric excesses when used to catalyze the reaction
between diene 9 and n-butyl glyoxylate.25 As an alternative, a
binaphthol−titanium complex, developed by the group of
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Mikami, was used next.26 The HDA reaction between 1-
methoxybutadiene 9 and ethyl glyoxylate 26 catalyzed by a 2:1
molar ratio of (−)-(S)-1,1′-binaphthol (20 mol %) and Ti(O-i-
Pr)4 (10 mol %) provided dihydropyran 27 in 61% yield in high
diastereo- and enantiomeric excesses.27 Catalytic dihydroxyla-
tion (6 mol %) followed by methyl ester synthesis provided
compound 28 in 64% yield over two steps. Finally,
monoacetylation and a modified Mitsunobu reaction, as
previously described, gave compound 20. Boc protection of
the reduced azido group afforded the known protected
ezoaminuroic acid intermediate.28 The most efficient synthesis
of 21 was described by the Datta group (21: 16 steps (9%
global yield) starting from (R)-glycidol).20 Using the present
strategy, compound 21 was prepared in only seven steps and
18% yield from pyran 27.
In order to expand the use of this strategy for the synthesis of
4-deoxy-D-hexopyranose-containing natural products, we next
focused on the preparation of neosidomycin 5 (Figure 1). This
natural product was isolated in 1979 from Streptomyces
hygroscopicus by the Furuta group.5c There are three other
members of this family of indole-N-glycosyls (6−8, Figure
1),5a,b and these molecules possess antibacterial or antiviral
activities. Only one synthesis of neosidomycin 5 has been
previously described (as an inseparable anomeric mixture of
products), and the chiron approach was used for the
preparation of the carbohydrate moiety.29 Our retrosynthetic
analysis shows that compound 5 could be made by coupling of
a glycosyl donor with indole 30 (Figure 3). The glycosyl donor
An improved procedure for the synthesis of this compound
relied on the acetonide deprotection of compound 32 followed
by trimethylacetyl protection, affording compound 37 in 86%
yield over two steps. Then, DBU-induced elimination provided
the unsaturated ester 38 in quantitative yield.31 Catalytic
hydrogenation of the double bond leads to ester 36 in 97%
1
yield as the sole diastereoisomer, as judged by the H NMR
spectrum of the crude reaction mixture. Finally, acetolysis of
compound 36 furnished the inseparable anomeric acetate in a
6:1 α:β ratio, which was recrystallized in pentane, affording
pure α-anomer 39 in 67% yield. The α configuration was
determined by direct NMR coupling of the anomeric proton
and carbon (91.3 ppm, JC−H = 177.8 Hz).32 This compound
1
was previously described by the Wightman group (39: nine
steps, 20% yield),29 and our strategy (39: eight steps, 26%
yield) represents a slightly improved synthesis using a new
chiron approach, both methods from methyl α-D-mannopyr-
anoside 31. Finally, the preparation of a halogenated glycosyl
donor was achieved by treating compound 39 in a mixture of
HBr 33% in acetic acid, affording the unstable α-bromo
compound 40 in quantitative yield.
The preparation of glycosyl donor 39 could be shortened
again, but using a different approach. Compound 39 was made
using a de novo methodology as described below.
In order to achieve the preparation of 4-deoxy-lyxo-D-
hexopyranoside derivatives, dihydroxylation of pyran 12 must
occur on the β face.33 Consequently, compound 12 was treated
with PPTS in i-PrOH, allowing formation of pure α-anomer 41
in nearly quantitative yield (Scheme 6). Catalytic dihydrox-
ylation using osmium tetroxide occurred on the less hindered
β-face of pyran 41, allowing access to diol 42 in 86% yield as
the only diastereoisomer. The hydroxyl group’s configuration of
42 was determined by NOE experiments. Synthesis of the
glycosyl donor 39 was easily accomplished in a four-step
manner: (i) diol protection with excess trimethylacetyl chloride
in pyridine (55% yield), (ii) primary hydroxyl group
deprotection using TBAF (70% yield), (iii) TEMPO oxidation,
followed by treatment with excess of MeI and K2CO3 (66%
over 2 steps), and finally (iv) acetolysis of the isopropyl group,
allowing formation of 39 as the only anomer after
recrystallization in pentane (70% yield).
The second-generation synthesis of glycosyl donor 39
proceeded via a similar strategy (Scheme 7). Anomerization
of pyran 27 successfully provided compound 46 in 89% yield,
allowing a diastereoselective osmium-catalyzed (6 mol %)
dihydroxylation to give diol 47 in 67% yield after treatment
with methanolic sodium methoxide. The previously synthesized
compound 39 was accessible after hydroxyl group protection
using PivCl in pyridine in 83% yield, followed by acetolysis in
70% yield.
With glycosyl donors 39 and 40 in hand, we explored the
challenging coupling with 3-cyanomethylindole 30, providing
α-indole-N-glycosyl 48 (Scheme 8).34 Previous studies related
to this crucial step were carried out using a glycosyl chloride (as
glycosyl donor) treated with the sodium salt of 3-
cyanomethylindole.29 A 6:1 ratio of diastereoisomers was
obtained in favor of the α anomer, but in a low 44% yield (it is
worth noting that only the β isomer was isolated for the
synthesis of SF-2140). Our initial attempts to accomplish this
coupling using brominated compound 40 following classical
methods35 failed; at best, only trace amounts of the desired
product were obtained. Following extensive experimentation, it
was found that pretreatment of BF3·OEt2 with glycosyl donor
Figure 3. Retrosynthetic analysis of neosidomycin 5.
could be obtained from methyl α-D-mannopyranoside 31 using
a new chiron approach or from pyran 12 and 27 using a de
novo approach.
First of all, Wightman’s synthesis of neosidomycin 5 relied
on O-4 deoxygenation of an orthogonally protected mannoside,
followed by oxidation at the C-6 position.6g,29 In opposition, we
believe the synthesis could be shortened by first oxidizing C-6
followed by O-4 deoxygenation of a suitable mannoside
derivative.
Hence, the synthesis of various glycosyl donors using the
chiron approach was initiated with compound 32 readily
available from methyl α-D-mannopyranoside 31 following a
known three-step sequence (Scheme 5).30 Removal of the O-4
hydroxyl group was achieved in a classical manner through
formation of thiocarbonyl 33 in 63% yield, followed by a radical
deoxygenation using AIBN and Bu3SnH in 62% yield. The
derivative methyl 4-deoxy-β-D-lyxo-uronate 34 was deprotected
under acidic conditions (35)31 and suitably protected with
PivCl in 91% yield, affording the known compound 36.29
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a
Scheme 5. New Chiron Approach to Glycosyl Donors 39 and 40
a
Reagents and conditions: (a) ref 31, three steps, 53%; (b) TCDI, DMAP, CH2Cl2, 24 °C, 48 h, 63%; (c) AIBN, Bu3SnH, toluene, 110 °C, 1 h, 62%;
(d) AcOH/H2O, 60 °C, 6 h, 75%; (e) PivCl, DMAP, pyridine, 60 °C, 16 h, 91%; (f) (i) AcOH/H2O, 60 °C, 6 h, (ii) PivCl, DMAP, pyridine, 60 °C,
16 h, 86%; (g) DBU, CH2Cl2, 0−24 °C, 16 h., quantitative; (h) Pd/C, H2, EtOAc, 24 °C, 16 h, 95%; (i) Ac2O/AcOH/H2SO4, 24 °C, 16 h, 67%; (j)
33% HBr/AcOH, CH2Cl2, 24 °C, 1 h, quantitative.
Scheme 6. First-Generation de Novo Synthesis of Glycosyl
Donor 39
Scheme 7. Second-Generation Synthesis of Glycosyl Donor
39
a
a
a
Reagents and conditions: (a) PPTS, i-PrOH, 24 °C, 24 h, 89%; (b)
(i) OsO4, NMO, acetone/water, 24 °C, 16 h, (ii) NaOMe, MeOH, 24
°C, 2 h, 67%; (c) PivCl, DMAP, pyridine, 60 °C, 16 h, 83%; (d)
Ac2O/AcOH/H2SO4, 24 °C, 16 h, 70%.
solution of sodium methoxide in methanol provided neo-
sidomycin 5 after 4 days, in 35% yield, 97% based on recovered
starting material. The physical properties of synthetic 5 (i.e., 1H
NMR spectrum, mass spectral data, melting point, and optical
rotation)37 matched those reported for the natural substan-
ce.5c,29 It is worth noting that the Wightman synthesis of
neosidomycin (5: 15 steps (3% yield) from methyl α-D-
mannopyranoside 31) provided compound 5 along with the
inseparable β anomer. Consequently, this synthesis represents
the first selective synthesis of neosidomycin in nine steps (11%
yield) from pyran 27.
a
Reagents and conditions: (a) PPTS, i-PrOH, 24 °C, 24 h, 99%; (b)
OsO4, NMO, acetone/water, 24 °C, 16 h, 86%; (c) PivCl, DMAP,
pyridine, 60 °C, 16 h, 55%; (d) TBAF, THF, 24 °C, 30 min, 70%; (e)
(i) TEMPO, BAIB, CH2Cl2/water, 24 °C, 45 min, (ii) K2CO3, MeI,
CH3CN, 24 °C, 16 h, 66%; (f) Ac2O/AcOH/H2SO4, 24 °C, 16 h,
70%.
39 (4 h), followed by addition of 3-cyanomethylindole 30
provided α-indole-N-glycosyl 48 in 78% yield as the only
anomer, as judged by the1H NMR of the crude reaction
mixture.
With this demanding coupling successfully achieved,
completion of the total synthesis was accomplished by amide
formation using hydrated nickel acetate in 67% yield (Scheme
8). Deprotection of compound 49 using classical methods were
ineffective,36 and after careful experimentation, the use of a 1 M
CONCLUSION
■
In conclusion, the enantioselective preparations of various 4-
deoxy-D-hexopyranosyl derivatives have been successfully
accomplished. Both Jacobsen chromium(III) catalyst and a
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used as the internal references in the H and 13C NMR spectra. 2D
Homonuclear correlation 1H−1H COSY experiments were used to
confirm NMR peak assignments. Optical rotations were measured on a
polarimeter at the indicated temperature (±2 °C) in the stated solvent.
Fourier transform infrared (FTIR) spectra were measured on neat
NaCl. The absorptions are given in wavenumbers (cm−1). The
enantiomeric excesses of the HDA reactions were determined with an
HPLC with a chiral column DNBPG (covalent) Chiral 5 μm, Standard
Analytical 4.6 × 250 mm, coupled with a UV detector (UV−vis 229
nm). Melting points are uncorrected. Accurate mass measurements
(HRMS) were performed on a LC-MSD-TOF instrument in positive
electrospray mode. Either protonated molecular ions [M + nH]n+ or
sodium adducts [M + Na]+ were used for empirical formula
confirmation.
1
a
Scheme 8. Final Stage for the Synthesis of Neosidomycin 5
(2R,6S)-6-(tert-Butyldimethylsilyloxymethyl)-2-methoxy-2,5-
dihydropyran (12). Compound 9 (240 μL, 2.37 mmol) was added
dropwise to a mixture of compound 10 (360 μL, 2.13 mmol), Cr(III)
catalyst 11 (160 mg, 16.0 μmol), and 4 Å molecular sieves (20.0 mg)
at 0 °C. The mixture was stirred for 1 h at 0 °C and 16 h at 24 °C.
Kugelrohr distillation of the reaction mixture allowed isolation of
compound 12 (491 mg, 89%) as a colorless oil. The enantiomeric
excess (>99%) was determined with a GC using chiral column
DNBPG ((covalent) Chiral 5 μm, Standard Analytical 4.6 × 250 mm,
elution gradient MeOH:CH3CN (5% H2O), (0.05% TFA) (1:4) →
MeOH:CH3CN (5% H2O), (0.05% TFA) (1:1), 1 mL/min, 30 °C, tr
12 4.2 min, tr ent-12 5.2 min). 12: Rf 0.37 (EtOAc:hexanes, 1:5); [α]D
= −55.1° (c = 1.1 in CHCl3), lit.19a (ent-12) [α]D = +55.3° (c = 1.1 in
a
Reagents and conditions: (a) 39, BF3·OEt2, CH2Cl2, 0−24 °C, 4 .,
then 30, 24 °C, 16 h, 78%; (b) Ni(OAc)2·4H2O, AcOH, 118 °C, 20 h,
67%; (c) NaOMe, MeOH, 24 °C, 4 days, 35% (97% brsm).
titanium−binaphthol complex catalyzed the formation of
dihydropyrans as a key methodology. Few synthetic steps
were required to access 4-deoxy-D-ribo-, 4-deoxy-D-lyxo-, and 4-
deoxy-D-xylo-hexopyranosides, along with their uronic acid
counterparts. 6-Hydroxydesosamine, orthogonally protected
ezoaminuroic acid, and neosidomycin were synthesized using
a de novo approach. Moreover, a novel chiron approach to 4-
deoxy-lyxo-hexopyranosiduronic acid methyl ester derivatives
was accomplished starting from methyl α-D-mannopyranoside.
The efficiency of the above strategy could provide access to
other members of the α-indole-N-glycosyl metabolites. Finally,
the synthetic approach described herein is quite general and, by
using chiral catalyst ent-11, it should be possible to access
several 4-deoxy-hexopyranosyl derivatives with an L config-
uration.
1
CDCl3); H NMR (300 MHz, CDCl3) δ 0.02 (s, 6H), 0.85 (s, 9H),
2.00−2.04 (m, 2H), 3.41 (s, 3H), 3.60 (dd, J = 6.5, 10.2 Hz, 1H), 3.70
(dd, J = 5.5, 10.3 Hz, 1H), 3.80 (q, J = 5.9 Hz, 1H), 4.95−4.96 (m,
1H), 5.57−5.61 (m, 1H), 5.88−5.94 ppm (m, 1H); 13C NMR (75
MHz, CDCl3) δ 128.2, 126.7, 97.4, 72.3, 65.2, 54.9, 26.5, 25.7 (3×),
18.1, −5.4, −5.5 ppm; HRMS m/z calcd for C13H26O3Si [M + Na]+
281.1543, found 281.1541.
Methyl 6-O-(tert-Butyldimethylsilyloxy)-4-deoxy-β-D-ribo-
hexopyranoside (13). To a solution of compound 12 (252 mg,
0.974 mmol) in an acetone/water mixture (4:1, 9.7 mL, 0.1 M) were
added NMO (285 mg, 2.43 mmol) and OsO4 (4% in water, 370 μL,
0.0580 mmol). The solution was stirred at 24 °C for 16 h, and 10%
aqueous NaHSO3 (5 mL) was added; this mixture was stirred for 5
min and diluted with EtOAc (10 mL). The organic layer was separated
and the aqueous layer extracted with EtOAc (5 × 10 mL). The
combined organic layers were dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash column chromatography (silica gel, hexanes:EtOAc, 1:1)
affording compound 13 (200 mg, 70%) as a colorless oil. 13: Rf
EXPERIMENTAL SECTION
■
General Considerations. All reactions in organic media were
performed in standard oven-dried glassware under an inert atmosphere
of nitrogen using freshly distilled solvents. CH2Cl2 was distilled from
CaH2 and DMF from ninhydrin and kept over molecular sieves. THF
was distilled from Na/benzophenone immediately before use. All
reagents were used as supplied without prior purification unless
otherwise stated. The evolution of the reaction was monitored by
analytical thin-layer chromatography using silica gel 60 F254 precoated
plates, and compounds were visualized by 254 nm light, a mixture of
iodine and silica gel, and/or a molybdenum−cerium solution (100 mL
of H2SO4, 900 mL of H2O, 25 g of (NH4)6Mo7O24H2O, 10 g of
Ce(SO4)2) and subsequent development by gentle warming with a
heat gun. Purifications by flash column chromatography were
performed using flash silica gel (60 Å, 40−63 μm) with the indicated
eluent.
1
0.21 (EtOAc:hexanes, 1:1); [α]D = −47.1° (c = 0.7 in CHCl3); H
NMR (300 MHz, CDCl3) δ 0.03 (s, 6H), 0.86 (s, 9H), 1.56−1.47 (m,
1H), 1.86−1.90 (m, 1H), 3.14 (s, 1H), 3.33−3.36 (m, 1H), 3.49 (s,
1H), 3.54−3.59 (m, 1H), 3.65−3.70 (m, 1H), 3.88−3.93 (m, 1H),
4.16 (s, 1H), 4.49 ppm (d, J = 7.7 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 101.3, 71.6, 71.1, 67.3, 65.6, 56.6, 33.5, 25.7 (3×), 18.2, −5.4
ppm (2×); IR (NaCl) ν 3420 cm−1; HRMS m/z calcd for C13H28O5Si
[M + Na]+ 315.1603, found 315.1602.
Methyl 2-O-Acetyl-6-O-(tert-butyldimethylsilyloxy)-4-deoxy-
β-D-ribo-hexopyranoside (14). To a solution of compound 13
(200 mg, 0.685 mmol) in CH2Cl2 (6.8 mL, 0.10 M) were added
pyridine (10 μL, 0.11 mmol), DMAP (10 mg), and Ac2O (64 μL, 0.68
mmol). The mixture was stirred for 50 min at 24 °C, and water (5
mL) was added. The mixture was extracted with CH2Cl2 (3 × 10 mL),
and the combined organic layers were washed with saturated aqueous
NaHCO3 (1 × 10 mL) and then brine (1 × 10 mL). The organic
solution was dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash column
chromatography (silica gel, hexanes:EtOAc, 2:1) affording compound
14 (176 mg, 77%) as a colorless oil. 14: Rf 0.67 (EtOAc:hexanes, 2:1);
1H NMR and 13C NMR spectra were recorded at 300 or 600 MHz
and 75 or 150 MHz, respectively. All NMR spectra were measured at
25 °C in the indicated deuterated solvents. Proton and carbon
chemical shifts (δ) are reported in ppm, and coupling constants (J) are
1
reported in hertz (Hz). The resonance multiplicities in the H NMR
spectra are described as “s” (singlet), “d” (doublet), “t” (triplet), and
“m” (multiplet), and broad resonances are indicated by “br”. The
residual protic solvent of CDCl3 (1H, δ 7.27 ppm; 13C, δ 77.0 ppm
(central resonance of the triplet)), CO(CD3)2 (1H, δ 2.05 ppm; 13C, δ
29.84 ppm), and MeOD-d4 (1H, δ 3.34 ppm; 13C, δ 49.9 ppm) were
1
[α]D = −61.7° (c = 0.9 in CHCl3); H NMR (300 MHz, CDCl3) δ
0.02 (s, 6H), 0.85 (s, 9H), 1.57−1.65 (m, 1H), 1.83−1.89 (m, 1H),
2.09 (s, 3H), 2.49 (br s, 1H), 3.43 (s, 3H), 3.49−3.56 (m, 1H), 3.65−
3.70 (m, 1H), 3.91−3.98 (m, 1H), 4.23 (br s, 1H), 4.61−4.69 ppm
9692
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Article
(m, 2H); NMR 13C (75 MHz, CDCl3) δ 169.8, 98.8, 73.0, 70.8, 66.2,
65.4, 56.2, 33.7, 25.7 (3×), 20.9, 18.2, −5.4 ppm (2×); IR (NaCl) ν
3484, 1741 cm−1; HRMS m/z calcd for C15H30O6Si [M + Na]+
357.1708, found 357.1704.
24 °C and then heated to 50 °C for 16 h. After this time, the solution
was concentrated under reduced pressure and purified using flash
column chromatography (silica gel, hexanes:EtOAc, 3:1), affording
compound 18 (76 mg, 92%) as a yellow oil. 18: Rf 0.68
1
Methyl 2-O-Acetyl-3-O-benzoyl-6-O-(tert-butyldimethylsily-
loxy)-4-deoxy-β-D-xylo-hexopyranoside (15). To a solution of
compound 14 (37 mg, 0.11 mmol) in toluene (1 mL, 0.1 M) were
added benzoic acid (16 mg, 0.13 mmol) and PPh3 (57 mg, 0.218
mmol). Then, DIAD (45 μL, 0.22 mmol) was added dropwise at 24
°C and the mixture was stirred for 40 min at 24 °C. Ten milliliters of
EtOAc was added to the reaction mixture, and the organic mixture was
washed with saturated aqueous NH4Cl (2 × 2 mL) and brine (2 × 2
mL). The organic solution was dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified using
flash column chromatography (silica gel, hexanes:EtOAc, 4:1)
affording compound 15 (39 mg, 82%) as a colorless oil. 15: Rf 0.55
(EtOAc:hexanes, 1:2); [α]D = −43.4° (c = 1.1 in CHCl3); H NMR
(300 MHz, CDCl3) δ 0.06 (s, 9H), 0.88 (s, 6H), 1.40−1.52 (m, 1H),
2.05−2.14 (m, 4H), 3.45 (s, 3H), 3.48−3.62 (m, 3H), 3.69−3.78 (m,
1H), 4.27 (d, J = 7.9 Hz, 1H), 4.77 ppm (dd, J = 9.9 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 169.6, 101.8, 73.2, 72.9, 65.1, 60.1, 56.4,
32.8, 25.7 (3×), 20.8, 18.2, −5.4 ppm (2×); IR (NaCl) ν 2100, 1751
cm−1; HRMS m/z calcd for C15H29N3O5Si [M + Na]+ 382.1773,
found 382.1775.
Methyl 2-O-Acetyl-3-azido-3,4-dideoxy-β-D-xylo-hexopyra-
noside (19). The same procedure was used as for the synthesis of
compound 16. Compound 19 was purified by flash column
chromatography (silica gel, hexanes:EtOAc, 1:1) and was isolated as
a colorless oil (93%). 19: Rf 0.21 (EtOAc:hexanes, 1:1); [α]D = −8.3°
1
(hexanes:EtOAc, 1:1); [α]D = +15.6° (c = 1.0 in CHCl3); H NMR
1
(300 MHz, CDCl3) δ 0.08 (s, 6H), 0.89 (s, 9H), 1.57−1.68 (m, 1H),
2.00 (s, 3H), 2.32−3.49 (m, 1H), 3.52 (s, 3H), 3.64−3.79 (m, 2H),
3.80−3.83 (m, 1H), 4.40 (d, J = 7.9 Hz, 1H), 5.05−5.08 (m, 1H),
5.11−5.23 (m, 1H), 7.44 (t, J = 7.7 Hz, 2H), 7.54−7.59 (m, 1H), 8.00
ppm (d, J = 7.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 169.9, 165.9,
133.2, 129.7 (2×), 129.6, 128.4 (2×), 101.8, 72.3 (2×), 72.0, 65.3,
56.6, 33.0, 25.8 (3×), 20.8, 18.3, −5.4 ppm (2×); IR (NaCl) ν 1751,
1724 cm−1; HRMS m/z calcd for C22H34O7Si [M + Na]+ 461.1971,
found 461.1960.
(c = 2.1 in CHCl3); H NMR (300 MHz, CDCl3) δ 1.55−1.67 (m,
1H), 1.95−2.09 (m, 1H), 2.13 (s, 3H), 3.49 (s, 3H), 3.53−3.74 (m,
5H), 4.32 (d, J = 7.7 Hz, 1H), 4.75−4.81 ppm (m, 1H); 13C NMR (75
MHz, CDCl3) δ 169.7, 101.9, 73.0, 72.8, 64.6, 59.9, 56.8, 31.9, 20.8
ppm; IR (NaCl) ν 3436, 2100, 1743 cm−1; HRMS m/z calcd for
C9H15N3O5 [M + Na]+ 268.0908, found 268.0905.
Methyl 2-O-Acetyl-3-azido-3,4-dideoxy-β-D-xylo-hexopyra-
nosiduronic Acid Methyl Ester (20). From 19: using the same
procedure as for the synthesis of compound 17 (57%). From 29: using
the same procedure as for the synthesis of compound 18. Compound
20 was purified using flash column chromatography (silica gel,
hexanes:EtOAc, 1:1) and was isolated as a white solid (73%). 20: Rf
0.52 (EtOAc:hexanes, 1:1); mp 112−113 °C (EtOAc/hexanes); [α]D
Methyl 2-O-Acetyl-3-O-benzoyl-4-deoxy-β-D-xylo-hexopyra-
noside (16). To a solution of compound 15 (75 mg, 0.171 mmol) in
THF (1.7 mL, 0.10 M) was added TBAF (1 M in THF, 0.342 mL,
0.342 mmol). The solution was stirred for 30 min at 24 °C and then
concentrated under reduced pressure and purified by flash column
chromatography (silica gel, hexanes:EtOAc, 1:1), affording compound
16 (52 mg, 94%) as a colorless oil. 16: Rf 0.19 (EtOAc:hexanes, 1:1);
1
= −13.9° (c = 1.5 in CHCl3); H NMR (300 MHz, CDCl3) δ 1.75−
1.88 (m, 1H), 2.13 (s, 3H), 2.34−2.41 (m, 1H), 3.51 (s, 3H), 3.52−
3.67 (m, 1H), 3.79 (s, 3H), 4.14 (dd, J = 2.2, 11.8 Hz, 1H), 4.34 (d, J
= 7.7 Hz, 1H), 4.83 ppm (dd, J = 2.2, 7.7 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 169.4, 169.0, 101.9, 72.5, 70.9, 59.5, 56.9, 52.6, 32.9,
20.8 ppm; IR (KBr) ν 2106, 1753, 1739 cm−1; HRMS m/z calcd for
C10H15N3O6 [M + Na]+ 296.0856, found 296.0863.
1
[α]D = +23.4° (c = 0.7 in CHCl3); H NMR (300 MHz, CDCl3) δ
1.67−1.79 (m, 1H), 2.00 (s, 3H), 2.09−2.28 (m, 2H), 3.54 (s, 3H),
3.58−3.77 (m, 3H), 4.44 (d, J = 7.9 Hz), 5.06−5.12 (m, 1H), 5.16−
5.24 (m, 1H), 7.43 (t, J = 7.4 Hz, 2H), 7.53−7.59 (m, 1H), 7.98 ppm
(d, J = 7.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 169.9, 165.9,
133.3, 129.7 (2×), 129.4, 128.5 (2×), 128.5, 101.9, 72.1, 71.7, 64.7,
56.9, 32.1, 20.8 ppm; IR (NaCl) ν 3407, 1750, 1717 cm−1; HRMS m/z
calcd for C16H20O7 [M + Na]+ 347.1106, found 347.1101.
Methyl 2-O-Acetyl-3-(tert-butoxycarbonylamino)-3,4-di-
deoxy-β-D-xylo-hexopyranosiduronic Acid Methyl Ester (21).
To a solution of compound 20 (21 mg, 0.075 mmol) in dried EtOAc
(5 mL) was added 10% Pd/C (5 mg). The mixture was stirred under a
H2 atmosphere at 24 °C for 3 h. Boc2O (49 mg, 0.23 mmol) and Et3N
(10 μL) were added to the mixture, and the reaction mixture was
stirred under nitrogen at 24 °C for 16 h. After this time, the mixture
was filtered and the organic solution was concentrated under reduced
pressure and purified using flash column chromatography (silica gel,
hexanes:EtOAc, 3:2), affording compound 21 (24 mg, 92%) as white
crystals. 21: Rf 0.45 (EtOAc:hexanes, 1:1); mp 156−157 °C (EtOAc/
hexanes), (lit.20 mp 158−160 °C); [α]D = −25.1° (c = 0.65 in CHCl3),
Methyl 2-O-Acetyl-3-O-benzoyl-4-deoxy-β-D-xylo-hexopyra-
nosiduronic Acid Methyl Ester (17). Step 1: to a solution of
compound 16 (79 mg, 0.24 mmol) in a CH2Cl2/water mixture (3/1,
4.9 mL, 0.050 M) were added TEMPO (7.6 mg, 0.049 mmol) and
BAIB (195 mg, 0.608 mmol). The mixture was stirred for 45 min at 24
°C, and 10 mL of aqueous Na2SO3 (1 M) was added followed by
aqueous HCl (1 M) until pH 2. The mixture was extracted with
CH2Cl2 (3 × 5 mL) and EtOAc (3 × 5 mL). The combined organic
layers were dried over Na2SO4, filtered, and concentrated under
reduced pressure. Crude acid was used for the next step without
further purification. Step 2: the crude acid was dissolved in acetonitrile
(4 mL), and K2CO3 (40 mg, 0.27 mmol) was added followed by MeI
(0.61 mL, 9.72 mmol). The mixture was stirred at 24 °C for 16 h, and
then filtered and purified using flash column chromatography (silica
gel, hexanes:EtOAc, 1:1), affording compound 17 (52 mg, 60%) as a
white solid. 17: Rf 0.34 (EtOAc:hexanes, 1:2); mp 97−98 °C (EtOAc/
(lit.20 [α]D = −26.2° (c = 0.65 in CHCl3)); H NMR (300 MHz,
1
CDCl3) δ 1.41 (s, 9H), 1.59−1.72 (m, 1H), 2.09 (s, 3H), 2.40−2.47
(br d, J = 13.18 Hz, 1H), 3.52 (s, 3H), 3.77 (s, 3H), 3.83−4.10 (br s,
1H), 4.14 (dd, J = 2.2, 11.5 Hz, 1H), 4.39 (d, J = 7.4 Hz, 1H), 4.63
(dd, J = 2.7, 7.4 Hz, 1H), 4.75 ppm (d, J = 8.8 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 170.8, 169.6, 155.2, 102.2, 79.9, 72.6, 71.3, 57.0, 52.4,
50.5, 34.4, 28.2 (3×), 20.8 ppm; IR (KBr) ν 3362, 1741, 1689 cm−1;
HRMS m/z calcd for C15H25NO8 [M + Na]+ 370.1477, found
370.1487.
1
hexanes); [α]D = +22.6° (c = 1.1 in CHCl3); H NMR (300 MHz,
CDCl3) δ 1.89−1.96 (m, 1H), 2.00 (s, 3H), 2.62−2.68 (m, 1H), 3.56
(s, 3H), 3.78 (s, 3H), 4.24 (dd, J = 2.2, 11.8 Hz), 4.46 (d, J = 7.4 Hz,
1H), 5.11−5.25 (m, 2H), 7.43 (t, J = 7.7 Hz, 2H), 7.57 (t, J = 7.4 Hz,
1H), 7.99 ppm (d, J = 7.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ
169.6, 169.1, 165.7, 133.4, 129.7 (3×), 128.5 (2×), 101.9, 71.6, 71.1,
70.3, 57.0, 52.5, 33.0, 20.7 ppm; IR (KBr) ν 1749, 1734, 1718 cm−1;
HRMS m/z calcd for C17H20O8 [M + Na]+ 375.1055, found 375.1050.
Methyl 2-O-Acetyl-3-azido-6-O-(tert-butyldimethylsilyloxy)-
3,4-dideoxy-β-D-xylo-hexopyranoside (18). To a solution of
compound 14 (77 mg, 0.23 mmol) in THF (7.6 mL, 0.030 M) at 0
°C were added DIAD (63 μL, 0.32 mmol), PPh3 (80 mg, 0.32 mmol),
and DPPA (70 μL, 0.32 mmol) dropwise. The reaction was warmed to
Methyl 2,3-Anhydro-6-O-(tert-butyldimethylsilyloxy)-4-
deoxy-β-D-ribo-hexopyranoside (22). To a solution of compound
12 (298 mg, 1.15 mmol) in CH2Cl2 (11.5 mL, 0.1 M) was added
purified mCPBA (775 mg, 3.46 mmol) at 0 °C. The mixture was
stirred at 24 °C for 16 h, and saturated aqueous NaHCO3 (10 mL)
was added. The mixture was extracted with CH2Cl2 (3 × 10 mL), and
the combined organic layers were dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash column chromatography (silica gel, hexanes:EtOAc, 8:1),
affording compound 22 (221 mg, 70%) as a colorless oil. 22: Rf
1
0.43 (hexanes:EtOAc, 6:1); [α]D = −58.9° (c = 0.9 in CHCl3); H
NMR (300 MHz, CDCl3) δ 0.05 (s, 6H), 0.88 (s, 9H), 1.69−1.82 (m,
9693
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1H), 2.03−2.09 (m, 1H), 3.13 (d, J = 4.0 Hz, 1H), 3.36−3.37 (m,
1H), 3.54 (m, 3H), 3.57−3.59 (m, 1H), 3.60−3.68 (m, 2H), 4.70 ppm
(br s, 1H); 13C NMR (75 MHz, CDCl3) δ 98.9, 67.5, 65.7, 56.6, 53.4,
51.1, 27.1, 25.8, 18.3 (3×), −5.3 ppm (2×); IR (NaCl) ν 2928, 1096,
837 cm−1; HRMS m/z calcd for C13H26O4Si [M + Na]+ 297.1493,
found 297.1492.
product revealed presence of only one diastereoisomer. The residue
was purified using flash column chromatography (silica gel,
hexanes:Et2O, 8:1), affording compound 27 (341 mg, 61%), isolated
as a colorless oil. The optical purity (95%) was determined using a
HPLC with a chiral column DNBPG ((covalent) Chiral 5 μm,
Standard Analytical 4.6 × 250 mm, gradient of elution:
MeOH:CH3CN (5% H2O), (0.05% TFA) (1:8) → MeOH:CH3CN
(5% H2O), (0.05% TFA) (1:1), 1 mL/min, 30 °C, tr 27 12.4 min, tr
ent-27 12.9 min). 27: Rf 0.29 (EtOAc:hexanes 1:4); [α]D = −45.1° (c
Methyl 6-O-(tert-Butyldimethylsilyloxy)-3,4-dideoxy-3-(di-
methylamino)-β-D-xylo-hexopyranoside (24). Compound 22
(193 mg, 0.703 mmol) was dissolved in a commercial solution of
dimethylamine (33% in ethanol, 7 mL, 0.1 M), and the mixture was
stirred at 24 °C for 3 days. The mixture was concentrated under
reduced pressure, and the residue was purified by flash column
chromatography (silica gel, CH2Cl2:MeOH, 10:1), affording com-
pound 24 (191 mg, 85%) as a colorless oil. 24: Rf 0.26
(MeOH:CH2Cl2, 9:1); [α]D = −11.5° (c = 0.57 in CHCl3); 1H
NMR (300 MHz, CDCl3) δ 0.07 (s, 6H), 0.90 (s, 9H), 1.17−1.29 (m,
1H), 1.78−1.84 (m, 1H), 2.30 (s, 6H), 2.51−2.60 (m, 1H), 2.84 (br s,
1H), 3.22 (dd, J = 7.5, 7.4 Hz, 1H), 3.55 (s, 3H), 3.45−3.61 (m, 2H),
3.76 (dd, J = 5.2, 5.5 Hz, 1H), 4.20 ppm (d, J = 7.1 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 104.9, 74.1, 70.1, 65.9, 65.1, 56.6, 40.3
(2×), 25.8 (3×), 23.5, 18.3, −5.3 ppm (2×); IR (NaCl) ν 2929, 1653,
1096 cm−1; HRMS m/z calcd for C15H33NO4Si [M + H]+ 320.2252,
found 320.2258.
= 1.0 in CHCl3), lit.27 [α]D = +45.6° (c = 1.0 in CHCl3); H NMR
1
(300 MHz, CDCl3) δ 1.26 (t, J = 7.1 Hz, 1H), 2.24−2.35 (m, 1H),
2.39−2.50 (m, 1H), 3.45 (s, 3H), 4.12−4.26 (m, 2H), 4.34 (dd, J =
5.2, 6.5 Hz, 1H), 4.98−5.00 (m, 1H), 5.64 (dq, J = 2.0, 10.3 Hz, 1H),
5.96−6.02 ppm (m, 1H); 13C NMR (75 MHz, CDCl3) δ 170.7, 127.6,
125.9, 97.0, 69.4, 61.0, 55.4, 25.9, 14.0 ppm; HRMS m/z calcd for
C9H14O4 [M + Na]+ 209.0784, found 209.0788.
Methyl 4-Deoxy-β-D-ribo-hexopyranosiduronic Acid Methyl
Ester (28). To a solution of compound 27 (89 mg, 0.515 mmol) in
an acetone/water mixture (4:1, 5 mL, 0.1 M) were added NMO (150
mg, 1.29 mmol) and OsO4 (4% in water, 0.196 mL). The resulting
solution was stirred at 24 °C for 16 h. A 10% aqueous solution of
NaHSO3 (5 mL) was added, the mixture was stirred for 5 min, and
EtOAc (10 mL) was added. The mixture was extracted with EtOAc (5
× 10 mL), and the combined organic extracts were dried over Na2SO4,
filtered, and comcentrated under reduced pressure. The residue was
purified using flash column chromatography (hexanes:EtOAc 4:1),
affording a yellow oil that was dissolved in MeOH (5 mL). A solution
of 1 M NaOMe in MeOH was added until pH 9, and the mixture was
stirred for 2 h. Acidic resin (IR-120) was added until pH 7, and the
mixture was filtered, concentrated under reduced pressure, and
purified using flash column chromatography (silica gel, hexanes:E-
tOAc, 4:1), affording compound 28 (68 mg, 64%) as a colorless oil.
28: Rf 0.18 (EtOAc:hexanes, 4:1); [α]D = −4.0° (c = 1.7 in CHCl3);
1H NMR (300 MHz, CDCl3) δ 4.56 (d, J = 7.7 Hz, 1H), 4.50 (dd, J =
Methyl 2-O-Acetyl-6-O-(tert-butyldimethylsilyloxy)-3,4-di-
deoxy-3-(dimethylamino)-β-D-xylo-hexopyranoside (24-OAc).
To a solution of compound 24 (134 mg, 0.432 mmol) in pyridine (15
mL) was added Ac2O (7 mL). The mixture was stirred for 3 h at 24
°C, and water (20 mL) was added. The mixture was extracted with
CH2Cl2 (3 × 10 mL), and the combined organic layers were washed
with saturated aqueous NaHCO3 (1 × 10 mL) and brine (1 × 10 mL).
The organic solution was dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash column chromatography (silica gel, CH2Cl2:MeOH, 20:1),
affording compound 24-OAc (156 mg, quantitative) as a colorless
oil. 24-OAc: Rf 0.37 (MeOH:CH2Cl2, 9:1); [α]D = −20.3° (c = 1.2 in
2.5, 11.5 Hz, 1H), 4.22 (br s, 1H), 3.76 (s, 3H), 3.54 (s, 3H), 3.48−
3.44 (m, 1H), 3.14 (bs s, 1H), 3.05 (bs s, 1H), 2.22−2.15 (m, 1H),
1.91−1.81 ppm (m, 1H); 13C NMR (75 MHz, CDCl3) δ 171.1, 101.6,
70.9, 69.5, 66.7, 57.2, 52.2, 33.9 ppm; IR (NaCl) ν 3234, 2937, 1735,
1094 cm−1; HRMS m/z calcd for C8H14O6 [M + Na]+ 229.0683,
found 229.0680.
1
CHCl3); H NMR (300 MHz, CDCl3) δ 0.07 (s, 6H), 0.89 (s, 9H),
1.26−1.41 (m, 1H), 1.83−1.89 (m, 1H), 2.08 (s, 3H), 2.28 (s, 6H),
2.74−2.83 (m, 1H), 3.46 (s, 3H), 3.43−3.53 (m, 1H), 3.57−3.62 (m,
1H), 3.74−3.79 (m, 1H), 4.24 (d, J = 7.4 Hz, 1H), 4.82 ppm (dd, J =
7.4, 7.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 170.1, 103.1, 73.8,
70.8, 65.8, 62.9, 56.4, 40.5 (2×), 29.7, 25.8 (3×), 21.3, 18.3, −5.3 ppm
(2×); IR (NaCl) ν 1749 cm−1; HRMS m/z calcd for C17H35NO5Si [M
+ H]+ 362.2357, found 362.2365.
Methyl 2-O-Acetyl-4-deoxy-β-D-ribo-hexopyranosiduronic
Acid Methyl Ester (29). The same procedure was used as for the
preparation of compound 14. Compound 29 was purified using flash
column chromatography (silica gel, hexanes:EtOAc, 3:1) and was
isolated as a colorless oil (70%). 29: Rf 0.45 (EtOAc:hexanes, 3:1);
Methyl 2-O-Acetyl-3,4-dideoxy-3-(dimethylamino)-β-D-xylo-
hexopyranoside (25). To a solution of 24-OAc (137 mg, 0.381
mmol) in THF (3.8 mL, 0.10 M) was added TBAF (1 M in THF,
0.763 mL, 0.763 mmol). The solution was stirred for 30 min at 24 °C
and then concentrated under reduced pressure and purified by flash
column chromatography (silica gel, CH2Cl2:MeOH, 10:1), affording
compound 25 (76 mg, 81%) as a yellow oil. 25: Rf 0.22
1
[α]D = −1.9° (c = 1.0 in CHCl3); H NMR (300 MHz, CDCl3) δ
2.00−2.07 (m, 1H), 2.12 (s, 3H), 2.11−2.19 (m, 1H), 2.46 (br s, 1H),
3.48 (s, 3H), 3.75 (s, 3H), 4.31 (br s, 1H), 4.52 (dd, J = 3.2, 9.4 Hz,
1H), 4.74−4.75 ppm (m, 2H); 13C NMR (75 MHz, CDCl3) δ 171.0,
169.9, 99.5, 72.0, 69.3, 64.8, 56.9, 52.2, 33.1, 21.0 ppm; IR (NaCl) ν
3433, 3021, 1743, 1216, 1094, 775 cm−1; HRMS m/z calcd for
C10H16O7 [M + Na]+ 271.0788, found 271.0791.
1
(MeOH:CH2Cl2, 9:1); [α]D = −3.7° (c = 1.5 in CHCl3); H NMR
(300 MHz, CDCl3) δ 1.40−1.69 (m, 1H), 1.73−1.75 (m, 1H), 2.07 (s,
3H), 2.25 (s, 6H), 2.75−2.85 (m, 1H), 3.13 (br s, 1H), 3.46 (s, 3H),
3.49−3.58 (m, 1H), 3.60−3.71 (m, 2H), 4.26 (d, J = 7.7 Hz, 1H), 4.78
ppm (dd, J = 7.4, 7.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 170.1,
103.2, 73.7, 70.6, 65.1, 62.7, 56.7, 40.4 (2×), 24.6, 21.2 ppm; IR
(NaCl) ν 3024, 1653, 1215, 1091, 776 cm−1; HRMS m/z calcd for
C11H21NO5 [M + H]+ 248.1493, found 248.1495.
Methyl 2,3-O-Isopropylidene-4-O-thiocarbonylimidazoyle-
α-D-mannopyranosiduronic Acid Methyl Ester (33). To a
solution of compound 3230 (817 mg, 3.12 mmol) in CH2Cl2 (31
mL, 0.10 M) were added thiocarbonyl diimidazole (1.85 g, 9.34 mmol)
and DMAP (380 mg, 3.12 mmol). The mixture was stirred for 48 h at
24 °C and then concentrated under reduced pressure and purified
using flash column chromatography (silica gel, hexanes:EtOAc, 3:2),
affording compound 33 (731 mg, 63%) as a yellow oil. 33: Rf 0.23
(2S,6R)-3,6-Dihydro-6-methoxy-2H-pyran-2-carboxylic Acid
Ethyl Ester (27). To a solution of (−)-(S)-BINOL (214 mg, 0.750
mmol) in CH2Cl2 (1 mL) was added a solution of Ti(O-i-Pr)4 (106
mg, 0.375 mmol) in CH2Cl2 (0.5 mL). The mixture was heated under
reflux for 1 h and cooled to to −30 °C. Freshly distilled ethyl
glyoxylate 26 (382 mg, 3.75 mmol), dissolved in CH2Cl2 (0.5 mL),
was added, followed by 1-methoxy-1,3-butadiene 9 (252 mg, 3.00
mmol) dissolved in CH2Cl2 (0.5 mL). The mixture was stirred for 2.5
h at −30 °C and then warmed to 24 °C. Aqueous saturated NaHCO3
(20 mL) was added, and the aqueous layer was extracted with ether (5
× 30 mL). The combined organic extracts were dried over Na2SO4
and concentrated under reduced pressure. 1H NMR of the crude
1
(EtOAc:hexanes, 1:1); [α]D = +9.3° (c = 4.3 in CHCl3); H NMR
(300 MHz, CDCl3) δ 1.20 (s, 3H), 1.42 (s, 3H), 3.33 (s, 3H), 3.51 (s,
3H), 4.07 (d, J = 5.1 Hz, 1H), 4.27 (d, J = 8.9 Hz, 1H), 4.33−4.37 (m,
1H), 4.95 (s, 1H), 5.86−5.91 (m, 1H), 6.88 (br s, 1H), 7.49 (br s,
1H), 8.19 ppm (br s, 1H); 13C NMR (75 MHz, CDCl3) δ 182.9,
167.4, 136.6, 130.5, 117.8, 110.3, 98.2, 77.2, 74.7, 74.0, 66.4, 55.6, 52.6,
26.9, 25.7 ppm; IR (NaCl) ν 2937, 1750, 1399 cm−1; HRMS m/z
calcd for C15H20N2O7S [M + H]+ 373.1064, found 373.1070.
Methyl 2,3-O-Isopropylidene-4-deoxy-α-D-lyxo-hexopyrano-
siduronic Acid Methyl Ester (34). To a solution of compound 33
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(727 mg, 1.95 mmol) in toluene (19 mL, 0.10 M) were added Bu3SnH
(10.34 mL, 39.02 mmol) and AIBN (64 mg, 0.39 mmol). The mixture
was stirred under reflux for 1 h and then concentrated under reduced
pressure. To this residue was added acetonitrile (20 mL) and hexanes
(20 mL). The acetonitrile layer was washed with hexanes (2 × 15 mL),
concentrated under reduced pressure, and purified using flash column
chromatography (silica gel, hexanes:EtOAc, 2:1), affording compound
34 (298 mg, 62%) as a colorless oil. 34: Rf 0.66 (EtOAc:hexanes, 2:1);
55.8, 52.6, 38.6 (3×), 27.0−26.9 ppm (9×); IR (NaCl) ν 2972, 1742,
113 cm−1; HRMS m/z calcd for C23H38O10 [M + Na]+ 497.2357,
found 497.2361.
Methyl 4-Deoxy-2,3-di-O-pivaloyl-L-erythro-hex-4-enopyra-
nosiduronic Acid Methyl Ester (38). To a solution of compound
37 (137 mg, 0.289 mmol) in CH2Cl2 (2.8 mL, 0.10 M) was added
DBU (66 μL, 0.44 mmol) at 0 °C. The mixture was stirred for 16 h at
24 °C and then washed with saturated aqueous NH4Cl (3 × 2 mL)
and water (3 × 2 mL). The organic solution was dried over Na2SO4,
filtered, concentrated under reduced pressure, and purified using flash
column chromatography (silica gel, hexanes:EtOAc, 5:1), affording
compound 38 (112 mg, quantitative) as a colorless oil. 38: Rf 0.28
1
[α]D = +37.0° (c = 1.6 in CHCl3); H NMR (300 MHz, CDCl3) δ
1.29 (s, 3H), 1.45 (s, 3H), 2.02−2.12 (m, 1H), 2.29 (dt, J = 5.0, 19.0
Hz, 1H), 3.42 (s, 3H), 3.75 (s, 3H), 3.94 (dd, J = 1.4, 6.2 Hz, 1H),
4.29 (dd, J = 5.1, 7.4 Hz, 1H), 4.36 (dd, J = 6.6, 11.6 Hz, 1H), 4.91
ppm (d, J = 1.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 171.7, 109.4,
99.1, 73.2, 69.8, 66.1, 55.7, 52.2, 28.8, 27.0, 25.5 ppm; IR (NaCl) ν
2938, 1734, 1559, 1090 cm−1; HRMS m/z calcd for C11H18O6 [M +
Na]+ 269.0996, found 269.0997.
1
(EtOAc:hexanes, 1:5); [α]D = +113.4° (c = 1.0 in CHCl3); H NMR
(300 MHz, CDCl3) δ 3.44 (s, 9H), 3.75 (s, 9H), 4.99 (d, J = 2.7 Hz,
1H), 5.14 (br s, 1H), 5.56 (t, J = 2.4 Hz, 1H), 5.91 ppm (br s, 1H);
13C NMR (75 MHz, CDCl3) δ 177.2, 177.1, 162.0, 141.2, 108.9, 99.1,
Methyl 4-Deoxy-α-D-lyxo-hexopyranosiduronic Acid Methyl
Ester (35). Compound 34 (250 mg, 1.02 mmol) was dissolved in a
mixture of AcOH/H2O (10 mL, 3/2, 0.10 M) and heated at 60 °C for
6 h. The solution was concentrated under reduced pressure and
purified using flash column chromatography (silica gel, hexanes:E-
tOAc, 1:2), affording compound 3531 (157 mg, 75%) as a colorless oil.
35: Rf 0.18 (EtOAc:hexanes, 2:1); [α]D = +38.1° (c = 3.4 in CHCl3);
1H NMR (300 MHz, CDCl3) δ 1.78−1.92 (m, 1H), 1.98−2.03 (m,
1H), 3.37 (s, 3H), 3.64−3.52 (m, 3H), 3.74 (s, 3H), 3.95−3.99 (m,
1H), 4.29 (dd, J = 2.6, 11.3 Hz, 1H), 4.84 ppm (br s, 1H); 13C NMR
(75 MHz, CDCl3) δ 171.5, 101.5, 68.6, 67.3, 65.2, 55.4, 52.3, 31.0
ppm; IR (NaCl) ν 3370, 2922, 1734, 1098 cm−1; HRMS m/z calcd for
C8H14O6 [M + Na]+ 229.0683, found 229.0683.
64.0, 63.5, 56.5, 52.4, 38.7 (2×), 26.9 ppm (6×); IR (NaCl) ν 2972,
1740, 1734, 1481 cm−1; HRMS m/z calcd for C18H28O8 [M + Na]+
395.1676, found 395.1683.
1-O-Acetyl-4-deoxy-2,3-di-O-pivaloyl-α-D-lyxo-hexopyrano-
syluronic Acid Methyl Ester (39). From 36: compound 36 (80 mg,
0.21 mmol) was dissolved in a Ac2O/AcOH/H2SO4 mixture (1 mL,
35/15/1 v/v, 0.2 M) and stirred at 24 °C for 16 h. CH2Cl2 (10 mL)
was added, and the mixture was washed with saturated aqueous
NaHCO3 (3 × 5 mL) and water (3 × 5 mL). The organic solution was
dried over Na2SO4, filtered, concentrated under reduced pressure, and
purified using flash column chromatography (silica gel, hexanes:E-
tOAc, 3:1). Anomeric acetate was isolated (71 mg, 83%) as a 6:1
mixture (α:β) as an amorphous yellow solid. This mixture was
recrystallized in pentane, affording compound 39 (57 mg, 67%) as
white crystals. From 45: using the same procedure as described above
(70%). 39: Rf 0.13 (EtOAc:hexanes, 1:4); mp 104−105 °C (pentane),
(lit.29 mp 104−105 °C); [α]D = +38.0° (c = 0.2 in MeOH) (lit.29 [α]D
= +37.8° (c = 0.18 in MeOH)); 1H NMR (300 MHz, CDCl3) δ 1.17
(s, 9H), 1.26 (s, 9H), 2.14 (s, 3H), 2.22−2.24 (m, 1H), 2.26−2.29 (m,
1H), 3.80 (s, 3H), 4.55 (dd, J = 3.1, 11.6 Hz, 1H), 5.10 (t, J = 2.4 Hz,
1H), 5.31−5.37 (m, 1H), 6.21 ppm (d, J = 2.4 Hz, 1H); 13C NMR (75
Methyl 4-Deoxy-2,3-di-O-pivaloyl-α-D-lyxo-hexopyranosi-
duronic Acid Methyl Ester (36). From 35: to a solution of
compound 35 (140 mg, 0.679 mmol) in pyridine (6.8 mL, 0.10 M)
were added PivCl (0.418 mL, 3.40 mmol) dropwise followed by
DMAP (2 mg). The mixture was stirred at 60 °C for 16 h and then
cooled to 24 °C. EtOAc (15 mL) was added, and the mixture was
washed with aqueous 1 M HCl (3 × 10 mL), saturated aqueous
NaHCO3 (3 × 10 mL), and brine (3 × 10 mL). The organic solution
was dried over Na2SO4, filtered, concentrated under reduced pressure,
and purified using flash column chromatography (hexanes:EtOAc,
5:1), affording compound 36 (231 mg, 91%) as a colorless oil. From
38: to a solution of compound 38 (112 mg, 0.302 mmol) in EtOAc (6
mL, 0.05 M) was added 10% Pd/C (11 mg), and the mixture was
stirred under an H2 atmosphere for 16 h at 24 °C. The mixture was
filtered over Celite, concentrated under reduced pressure, and purified
using flash column chromatography (silica gel, hexanes:EtOAc, 5:1),
affording compound 36 (107 mg, 95%). 36: Rf 0.23 (EtOAc:hexanes,
1:5); [α]D = +34.7° (c = 1.8 in CHCl3), (lit.29 [α]D = +33.7° (c = 1.8
MHz, CDCl3) δ 177.3, 176.9, 169.6, 168.0, 91.3 (1JC‑1 H‑1
(J = 177.8
,
Hz)), 69.3, 66.1, 66.0, 52.6, 38.9, 38.7, 28.5, 27.1−27.0 (6×), 20.8
ppm; IR (KBr) ν 2972, 1735, 1140 cm−1; HRMS m/z calcd for
C19H30O9 [M + Na]+ 425.1782, found 425.1786.
1-Bromo-1,4-dideoxy-2,3-di-O-pivaloyl-α-D-lyxo-hexopyra-
nosyluronic Acid Methyl Ester (40). To a solution of compound
39 (144 mg, 0.358 mmol) in CH2Cl2 (3.5 mL, 0.10 M) was added a
commercial solution of HBr 33% in acetic acid (3.5 mL), and the
mixture was stirred for 1 h at 24 °C. The mixture was poured into a
beaker containing saturated aqueous NaHCO3 (10 mL). The organic
solution was washed with saturated aqueous NaHCO3 (3 × 10 mL)
and brine (3 × 10 mL) and then dried over Na2SO4, filtered, and
concentrated under reduced pressure, affording compound 40 (152
mg, quantitative) as white needles. 40: Rf 0.46 (EtOAc:hexanes, 1:5);
mp 93−94 °C (EtOAc/hexanes); [α]D = +113.7° (c = 0.8 in CHCl3);
1H NMR (300 MHz, CDCl3) δ 1.17 (s, 9H), 1.25 (s, 9H), 2.04−2.17
(m, 1H), 2.35−2.40 (m, 1H), 3.82 (s, 3H), 4.69 (dd, J = 2.3, 12.4 Hz,
1H), 5.28 (br s, 1H), 5.64−5.72 (m, 1H), 6.40 ppm (s, 1H); 13C NMR
(75 MHz, CDCl3) δ 177.1, 176.8, 168.7, 84.2, 70.9, 69.5, 65.1, 52.7,
39.0, 38.7, 28.5, 27.1−27.0 ppm (6×); IR (KBr) ν 2968, 1771, 1735,
1138 cm−1; HRMS m/z calcd for C17H27BrO7 [M + Na]+ 445.0832,
found 445.0840.
1
in MeOH)); H NMR (300 MHz, CDCl3) δ 1.05 (s, 9H), 1.14 (s,
9H), 1.86−1.98 (m, 1H), 2.08−2.12 (m, 1H), 3.32 (s, 3H), 3.70 (s,
3H), 4.35−4.39 (m, 1H), 4.74 (br s, 1H), 4.95 (br s, 1H), 5.14−5.19
ppm (m, 1H); 13C NMR (75 MHz, CDCl3) δ 177.1, 177.0, 170.3,
99.4, 67.1, 67.0, 66.1, 55.4, 52.3, 38.8, 38.5, 27.0, 26.9 ppm (6×); IR
(NaCl) ν 2960, 1762, 1734, 1482, 1133 cm−1; HRMS m/z calcd for
C18H30O8 [M + Na]+ 397.1833, found 397.1838.
Methyl 2,3,4-Tri-O-pivaloyl-α-D-mannopyranosiduronic Acid
Methyl Ester (37). To a solution of methyl α-D-mannopyranosidur-
onic acid methyl ester38 (933 mg, 4.20 mmol) in pyridine (42 mL,
0.10 M) were added PivCl (10.3 mL, 84.0 mmol) dropwise followed
by DMAP (10 mg). The mixture was stirred at 60 °C for 16 h and
then cooled to 24 °C. EtOAc (50 mL) was added, and the solution
was washed with aqueous 1 M HCl (3 × 30 mL), saturated aqueous
NaHCO3 (3 × 30 mL), and brine (3 × 30 mL). The organic solution
was dried over Na2SO4, filtered, and concentrated under reduced
pressure. Flash column chromatography (silica gel, hexanes:EtOAc,
4:1) afforded compound 37 (1.714 g, 86%) as a colorless oil. 37: Rf
(2S,6S)-6-(tert-Butyldimethylsilyloxy)-2-isopropoxy-2,5-di-
hydropyran (41). To a solution of compound 12 (114 mg, 0.441
mmol) in i-PrOH (4.4 mL, 0.10 M) was added PPTS (11 mg, 0.044
mmol). The mixture was stirred for 24 h at 24 °C and then
concentrated under reduced pressure and purified using flash column
chromatography (silica gel, hexanes:EtOAc, 7:1), affording compound
41 (125 mg, 99%) as a colorless oil. 41: Rf 0.82 (EtOAc:hexanes, 1:1);
1
0.73 (EtOAc:hexanes, 1:1); [α]D = +20.7° (c = 7.3 in CHCl3); H
1
NMR (300 MHz, CDCl3) δ 1.09 (s, 3H), 1.13 (s, 3H), 1.23 (s, 3H),
3.43 (m, 3H), 3.72 (s, 3H), 4.27−4.30 (m, 1H), 4.76 (d, J = 2.0 Hz,
1H), 5.18 (t, J = 2.1 Hz, 1H), 5.39−5.42 ppm (m, 2H); 13C NMR (75
MHz, CDCl3) δ 177.1, 176.8, 176.7, 168.2, 98.8, 69.7, 68.8, 68.3, 66.6,
[α]D = −24.1° (c = 1.1 in CHCl3); H NMR (300 MHz, CDCl3) δ
0.02 (s, 6H), 0.85 (s, 9H), 1.12 (d, J = 6.2 Hz, 3H), 1.19 (d, J = 6.2
Hz, 3H), 1.91−2.03 (m, 2H), 3.55−3.69 (m, 2H), 3.95−4.03 (m, 2H),
5.05 (br s, 1H), 5.64−5.69 (m, 1H), 5.93−5.98 ppm (m, 1H); 13C
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NMR (75 MHz, CDCl3) δ 128.3, 126.0, 92.7, 69.1, 67.0, 66.1, 26.9,
25.9 (3×), 23.8, 21.8, 18.4, −5.3 ppm (2×); IR (NaCl) ν 2954, 1403,
1130 cm−1; HRMS m/z calcd for C15H30O3Si [M + Na]+ 309.1856,
found 309.1859.
MeOH was added until pH 9, and the mixture was stirred for 2 h at 24
°C. Acidic resin (IR-120) was added until pH 7, and the mixture was
filtered and concentrated under reduced pressure. The residue was
purified using flash column chromatography (silica gel, hexanes:E-
tOAc, 1:1), affording compound 47 (66 mg, 67%) as a colorless oil.
47: Rf 0.19 (EtOAc:hexanes, 2:1); [α]D = +12.2° (c = 1.0 in CHCl3);
1H NMR (300 MHz, CDCl3) δ 1.14 (d, J = 6.0 Hz, 3H), 1.25 (d, J =
6.2 Hz, 3H), 1.89−1.91 (m, 1H), 2.04−2.09 (m, 1H), 2.76 (br s, 1H),
3.59−3.73 (m, 2H), 3.80 (s, 3H), 3.82−4.01 (m, 3H), 5.10 ppm (d, J
= 1.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 172.0, 98.3, 69.9, 69.3,
68.7, 67.4, 52.4, 34.3, 23.2, 21.4 ppm; HRMS m/z calcd for C10H18O6
[M + Na]+ 257.0996, found 257.1001.
Isopropyl 6-O-(tert-Butyldimethylsilyloxy)-4-deoxy-α-D-lyxo-
hexopyranoside (42). The same procedure was used as for the
preparation of compound 13. Compound 42 was purified using flash
column chromatography (silica gel, hexanes:EtOAc, 1:1) as a colorless
oil (86%). 42: Rf 0.33 (EtOAc:hexanes, 1:1); [α]D = +25.1° (c = 1.1 in
1
CHCl3); H NMR (300 MHz, CDCl3) δ 0.06 (s, 6H), 0.89 (s, 9H),
1.13 (d, J = 6.1 Hz, 3H), 1.19 (d, J = 6.3 Hz, 3H), 1.45−1.57 (m, 1H),
1.75−1.81 (m, 1H), 2.51 (br s, 1H), 3.58 (dd, J = 4.9, 10.6 Hz, 1H),
3.65−3.71 (m, 2H), 3.79−3.87 (m, 1H), 3.88−3.96 (m, 1H), 3.96−
4.03 (m, 1H), 4.96 ppm (d, J = 1.1 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 98.1 (1JC‑1,H‑1 (J = 168.3 Hz)), 69.7, 68.9, 68.7, 66.0, 65.7,
31.1, 25.9 (3×), 23.2, 21.2, 18.3, −5.3, −5.4 ppm; IR (NaCl) ν 3490,
1745 cm−1; HRMS m/z calcd for C15H32O5Si [M + Na]+ 343.1911,
found 343.1913.
1-[3-(Cyanomethyl)indol-1-yl]-1,4-dideoxy-2,3-di-O-pivalo-
yl-α-D-lyxo-hexopyranosyluronic Acid Methyl Ester (48). To a
solution of 39 (41 mg, 0.097 mmol) in CH2Cl2 (0.9 mL, 0.1 M) at 0
°C was added BF3·OEt2 (240 μL, 0.194 mmol). The mixture was
stirred for 4 h while being warmed to 24 °C. Compound 30 (61 mg,
0.39 mmol) in CH2Cl2 (0.2 mL) was added, and the mixture was
stirred for 16 h at 24 °C. CH2Cl2 (10 mL) was added, and the mixture
was washed with saturated aqueous NaHCO3 (3 × 5 mL), water (3 ×
5 mL), and brine (3 × 5 mL). The organic solution was dried over
Na2SO4, filtered, concentrated under reduced pressure, and purified
using flash column chromatography (silica gel, hexanes:EtOAc, 4:1),
affording compound 48 (38 mg, 78%) as a colorless amorphous solid.
48: Rf 0.28 (EtOAc:hexanes, 1:2); [α]D = +19.8° (c = 0.6 in CHCl3),
(lit.29 [α]D = +18.7° (c 0.48, MeOH)); 1H NMR (300 MHz, CDCl3)
δ 0.81 (s, 9H), 1.27 (s, 9H), 2.53−2.57 (m, 2H), 3.78 (s, 3H), 3.89 (s,
3H), 4.66 (dd, J = 2.3, 6.5 Hz, 1H), 5.40 (dd, J = 2.9, 9.7 Hz, 1H),
5.68−5.71 (m, 1H), 6.58 (d, J = 9.7 Hz, 1H), 7.19−7.25 (m, 1H), 7.36
(t, J = 7.5 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.72 ppm (d, J = 8.1 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 176.8, 176.7, 171.5, 137.4, 126.7,
123.5 (2×), 122.3, 121.0 (2×), 118.4 (2×), 110.2, 70.6, 69.0, 67.2,
52.4, 38.9, 38.6, 31.2, 27.0 (3×), 26.9 (3×), 14.3 ppm; IR (NaCl) ν
2972, 1740, 1465, 1150 cm−1; HRMS m/z calcd for C27H34N2O7 [M +
Na]+ 521.2258, found 521.2249.
1-[3-(Carbamoylmethyl)indol-1-yl]-1,4-dideoxy-2,3-di-O-
pivaloyl-α-D-lyxo-hexopyranosyluronic Acid Methyl Ester
(49). To a solution of compound 48 (27 mg, 0.054 mmol) in
AcOH (2.7 mL, 0.020 M) was added Ni(OAc)2·4H2O (80 mg, 0.32
mmol). The mixture was stirred under reflux for 20 h and then cooled
to 24 °C. CHCl3 (5 mL) was added, and the solution was washed with
saturated aqueous NaHCO3 (2 × 1 mL), dried over Na2SO4, filtered,
and purified using flash column chromatography (silica gel, EtOAc),
affording compound 49 (19 mg, 67%) as a light brown solid. 49: Rf
0.42 (EtOAc); mp 55−56 °C (EtOAc/hexanes); [α]D = +0.6° (c = 0.9
in CHCl3); 1H NMR (300 MHz, CDCl3) δ 0.72 (s, 9H), 1.28 (s, 9H),
2.47−2.64 (m, 2H), 3.69 (s, 2H), 3.89 (s, 3H), 4.69 (d, J = 6.4 Hz,
1H), 5.36 (dd, J = 2.7, 9.5 Hz, 1H), 5.48 (br s, 1H), 5.65 (d, J = 2.9
Hz, 1H), 5.85 (br s, 1H), 6.55 (d, J = 9.5 Hz, 1H), 7.15−7.22 (m, 2H),
7.30 (t, J = 7 Hz, 1H), 7.53−7.59 ppm (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 176.9, 176.6, 173.8, 171.4, 137.2, 127.4, 123.1, 123.0, 120.7
(2×), 118.9 (2×), 109.6, 70.5, 69.6, 67.1, 52.3, 38.9, 38.4, 31.2, 29.6,
27.0 (3×), 26.4 ppm (3×); IR (KBr) ν 2960, 2923, 1740, 1735, 1154,
1110 cm−1; HRMS m/z calcd for C27H36N2O8 [M + Na]+ 539.2364,
found 539.2365.
Isopropyl 6-O-(tert-Butyldimethylsilyloxy)-4-deoxy-2,3-di-O-
pivaloyl-α-D-lyxo-hexopyranoside (43). The same procedure was
used as for the preparation of compound 36. Compound 43 was
purified using flash column chromatography (silica gel, hexanes:Et2O,
9:1) and isolated as a colorless oil (55%). 43: Rf 0.62 (EtOAc:hexanes,
1:1); [α]D = +29.9° (c = 2.5 in CHCl3); 1H NMR (300 MHz, CDCl3)
δ 0.04 (s, 6H), 0.87 (s, 9H), 1.12 (s, 9H), 1.22 (s, 9H), 1.17−1.24 (m,
6H), 1.72−1.78 (m, 2H), 3.58−3.71 (m, 2H), 3.84−3.99 (m, 2H),
4.88−4.89 (m, 1H), 4.94−4.95 (m, 1H), 5.22−5.29 ppm (m, 1H); 13
C
NMR (75 MHz, CDCl3) δ 177.3, 177.3, 96.3, 69.4, 68.8, 68.4, 67.2,
65.9, 38.8, 38.6, 28.2, 27.1 (3×), 26.9 (3×), 26.4, 25.8 (3×), 23.2, 21.3,
−5.4 ppm (2×); IR (NaCl) ν 2960, 1735, 1140, 838 cm−1; HRMS m/
z calcd for C25H48O7Si [M + Na]+ 511.3062, found 511.3065.
Isopropyl 4-Deoxy-2,3-di-O-pivaloyl-α-D-lyxo-hexopyrano-
side (44). The same procedure was used as for the synthesis of
compound 16. Compound 44 was purified using flash column
chromatography (silica gel, hexanes:EtOAc, 3:1) and isolated as a
colorless oil (70%). 44: Rf 0.22 (EtOAc:hexanes, 1:3); [α]D = +28.4°
1
(c = 2.0 in CHCl3); H NMR (300 MHz, CDCl3) δ 1.13 (s, 9H),
1.14−1.20 (m, 6H), 1.23 (s, 9H), 1.70−1.76 (m, 1H), 1.81−1.93 (m,
1H), 2.06 (br s, 1H), 3.53−3.59 (m, 1H), 3.66−3.70 (m, 1H), 3.84−
3.93 (m, 1H), 3.98−4.05 (m, 1H), 4.90 (s, 1H), 4.96 (br s 1H), 5.25−
5.31 ppm (m, 1H); 13C NMR (75 MHz, CDCl3) δ 177.4, 177.3, 96.2,
69.7, 68.4, 68.3, 66.9, 65.3, 38.9, 38.6, 27.5, 27.1 (3×), 27.0 (3×), 23.2,
21.4 ppm; IR (NaCl) ν 3510, 2974, 1734, 1482, 1149 cm−1; HRMS
m/z calcd for C19H34O7 [M + Na]+ 397.2197, found 397.2194.
Isopropyl 4-Deoxy-2,3-di-O-pivaloyl-α-D-lyxo-hexopyranosi-
duronic Acid Methyl Ester (45). From 44: using the same
procedure as for the synthesis of compound 17. Compound 45 was
purified using flash column chromatography (silica gel, hexanes:E-
tOAc, 5:1) and isolated as a yellow oil (66%). From 47: using the
same procedure as for the synthesis of compound 36 (83%). 45: Rf
1
0.51 (EtOAc:hexanes, 1:3); [α]D = +39.4° (c = 1.7 in CHCl3); H
NMR (300 MHz, CDCl3) δ 1.18−1.23 (m, 6H), 1.16 (s, 9H), 1.25 (s,
9H), 1.96−2.08 (m, 1H), 2.19−2.26 (m, 1H), 3.80 (s, 3H), 3.92−4.00
(m, 1H), 4.53 (dd, J = 2.8, 11.8 Hz, 1H), 4.98−4.99 (m, 1H), 5.06 (d,
J = 2.0 Hz, 1H), 5.28−5.35 ppm (m, 1H); 13C NMR (75 MHz,
CDCl3) δ 177.3, 177.2, 170.7, 96.5, 70.4, 68.0, 67.1, 66.4, 52.3, 38.9,
38.6, 28.8, 27.1 (3×), 27.0 (3×), 23.2, 21.1 ppm; IR (NaCl) ν 3510,
2974, 1734, 1132 cm−1; HRMS m/z calcd for C20H34O8 [M + Na]+
425.2146, found 425.2149.
Isopropyl 4-Deoxy-α-D-lyxo-hexopyranosiduronic Acid
Methyl Ester (47). To a solution of compound 4639 (90 mg, 0.42
mmol) in an acetone/water mixture (4:1, 4.2 mL, 0.10 M) were added
NMO (122 mg, 1.04 mmol) and OsO4 (4% in water, 16 μL, 0.025
mmol). The resulting solution was stirred at 24 °C for 16 h, and then
10% aqueous NaHSO3 (5 mL) was added and the mixture was stirred
for 5 min. The mixture was extracted with EtOAc (5 × 10 mL), and
the combined organic layers were dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified using
flash column chromatography (silica gel, hexanes:EtOAc 1:1) and then
dissolved in MeOH (4.2 mL, 0.10 M). A 1 M solution of NaOMe in
1-[3-(Carbamoylmethyl)indol-1-yl]-1,4-dideoxy-α-D-lyxo-
hexopyranosyluronic Acid Methyl Ester (Neosidomycin, 5). To
a solution of compound 49 (40 mg, 0.077 mmol) in MeOH (0.77 mL,
0.10 M) was added a 1 M solution of NaOMe in MeOH until pH 9.
The mixture was stirred at 24 °C for 4 days, and then acidic resin (IR-
120) was added until pH 7. The mixture was filtered, concentrated
under reduced pressure, and purified using flash column chromatog-
raphy (silica gel, CH2Cl2:MeOH, 9:1), affording 25 mg of starting
material 49 and neosidomycin 5 (9 mg, 35%), isolated as an
amorphous brown solid (97% brsm). 5: Rf 0.29 (MeOH:CH2Cl2, 1:9);
mp 92−95 °C (EtOH), (lit. mp 93−103 °C); [α]D = +50.3° (c = 0.5
in MeOH), (lit.5c [α]D = +51.0° (c = 0.48 in MeOH)); 1H NMR (300
MHz, (CD3)2CO) δ 2.26−2.30 (m, 1H), 2.50 (dd, J = 3.2, 14.0 Hz,
1H), 2.78 (br s, 2H, D2O exchangeable), 3.58 (s, 2H), 3.75 (s, 3H),
4.18−4.16 (m, 1H), 4.29 (br s, 1H), 4.44 (d, J = 6.9 Hz, 1H), 6.15 (br
9696
dx.doi.org/10.1021/jo201673w|J. Org. Chem. 2011, 76, 9687−9698

The Journal of Organic Chemistry
Article
s, 1H, D2O exchangeable), 6.42 (d, J = 9.2 Hz, 1H), 6.58 (br s, 1H,
D2O exchangeable), 7.07 (t, J = 7.5 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H),
7.43 (s, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.78 ppm (d, J = 8.2 Hz, 1H);
13C NMR (75 MHz, CD3OD) δ 177.7, 174.3, 139.1, 129.6, 125.2,
123.2, 121.1, 119.5, 111.9, 110.9, 79.9, 71.4, 70.5, 69.0, 52.4, 35.0, 33.3
ppm; IR (KBr) ν 2960, 2923, 1740, 1735, 1154, 1110 cm−1; HRMS
m/z calcd for C17H20N2O6 [M + Na]+ 371.1214, found 371.1216.
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ASSOCIATED CONTENT
* Supporting Information
■
S
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Text giving additional experimental details and figures giving
1H and 13C NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(8) (a) Guer
Hecquet, L.; Furstoss, R.; Bolte, J. Eur. J. Org. Chem. 1999, 3399−
3402. (b) Andre, C.; Guerard, C.; Hecquet, L.; Demuynck, C.; Bolte, J.
́
ard, C.; Alphand, V.; Archelas, A.; Demuynck, C.;
́
́
AUTHOR INFORMATION
Corresponding Author
*roy.rene@uqam.ca
■
J. Mol. Catal. B 1998, 5, 113−118.
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ACKNOWLEDGMENTS
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■
This work was supported by the Natural Sciences and
Engineering Research Council of Canada (NSERC) for a
Canadian Research Chair in Therapeutic Chemistry to R.R. We
are also grateful to the FQRNT (Queb
́
ec) for a postgraduate
ault
and postdoctoral fellowship to D.G. Isabelle Rhe
́
̀
́
ules organiques, UQAM)
(Plateforme analytique pour molec
is acknowledged for high-resolution mass spectra, along with
Stephen Hanessian from Universite
discussions.
́ ́
de Montreal for helpful
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