Syntheses of carbocyclic analogues of α-D-glucosamine, α-D-mannose, α-D-mannuronic acid, β-l-idosamine, and β-l-gulose

Article abstract of DOI:10.1021/jo301240j

A versatile synthesis of orthogonally protected derivatives of carba-α-d-glucosamine, carba-α-d-mannose, carba-α-d-mannuronic acid, carba-β-l-idosamine, and carba-β-l-gulose from methyl α-d-mannoside is described. Our synthetic strategy utilizes the palladium-promoted Ferrier carbocyclization and persistent butane-2,3-diacetal protection to produce a key chiral cyclohexanone intermediate, from which all five carbasugar derivatives can readily be obtained.

Full text of DOI:10.1021/jo301240j

Article
pubs.acs.org/joc
Syntheses of Carbocyclic Analogues of α‑D‑Glucosamine,
α‑D‑Mannose, α‑D‑Mannuronic Acid, β‑L‑Idosamine, and β‑L‑Gulose
Yunshan Sun and Mark Nitz*
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON, Canada M5S 3H6
S
* Supporting Information
ABSTRACT: A versatile synthesis of orthogonally protected derivatives of carba-α-D-glucosamine, carba-α-D-mannose, carba-α-
D-mannuronic acid, carba-β-L-idosamine, and carba-β-L-gulose from methyl α-D-mannoside is described. Our synthetic strategy
utilizes the palladium-promoted Ferrier carbocyclization and persistent butane-2,3-diacetal protection to produce a key chiral
cyclohexanone intermediate, from which all five carbasugar derivatives can readily be obtained.
carba-N-acetylglucosamine have appeared.8−10 The most
commonly used route was reported by Quiclet-Sire in 1986
INTRODUCTION
■
Carbasugars are useful probes in glycobiology, as they closely
and uses a benzyl carbamate-protected glucosamine derivative
resemble their parent sugars but, because of the methylene
as a precursor to a Ferrier carbocyclization followed by a
replacement of the ring oxygen, do not participate the acetal
homologation.8 Alternatively, Ogawa and co-workers have
chemistry of their sugar analogues. This increased stability
reported a synthesis of the β-anomer of carba-N-acetylglucos-
amine from noncarbohydrate precursors, involving an initial
resolution of Diels−Alder adduct, 7-endo-oxabicyclo[2.2.1]-
hept-5-ene-2-carboxylic acid, derived from furan and acrylic
acid.9 Similarly, Chung et al. have relied upon an enzymatic
r e s o l u t i o n o n r o u t e t o ( 1 R , 2 S , 5 S ) - 5 - ( t e r t -
butyldiphenylsilanyloxymethy)cyclohex-3-ene-1,2-diol.10b
To support our ongoing interest in probes for biosynthesis of
bacterial polysaccharides, we sought to develop a synthetic
route which is capable of providing a series of carbasugars.
Specifically, we were interested in carbasugar analogues of N-
acetylglucosamine, mannose, and mannuronic acid because of
their prevalence in bacterial exopolysaccharides. Herein we
report this high yielding route to carba-α-D-glucosamine
derivative 1. Through this route, the carbasugar analogues of
α-D-mannose (2), α-D-mannuronic acid (3), β-L-idosamine (4),
and β-L-gulose (5), which might also be potential substrates for
the preparation of biological probes or enzyme substrates, have
also been synthesized.11 This route provides an alternative to
the challenges associated with manipulating glucosamine
protecting groups in the Quiclet−Sire synthesis8 and the
deracemization protocols required in the Ogawa and Chung
syntheses.9,10b
makes carbasugar derivatives useful probes as competitive
inhibitors of enzymes such as the glycosidases and glycosyl-
transferases.1 Carbasugars have also been suggested as
replacements for their sugar counterparts as non-nutritive
sweeteners2 and have been successfully used as enzyme
substrates to generate stable oligosaccharides and sugar primers
in cellular systems.1b,3 Given the utility of carbasugars, it is
perhaps not surprising that they have been the target of
numerous synthetic routes since the first carbasugar synthesis
reported by McCasland and co-workers in 1966.1b,4
Among many synthetic approaches for converting sugars into
carbasugars, the well-known Ferrier carbocyclization reaction
has been most widely used for the construction of these
carbocycles.5 The Ferrier carbocyclization, which converts 6-
deoxyhex-5-enopyranosides into cyclohexanones, is typically
catalyzed by mercury salts. Sinay and co-workers discovered an
̈
alternative approach to the Ferrier carbocyclization that is
mediated by a Lewis acid, such as triisobutylaluminum or
titanium(IV) derivatives, and resulted in the retention of
configuration at the anomeric center.6 In 1988, Adam reported
a modification of the Ferrier carbocyclization that uses catalytic
amounts of palladium(II) salts, which promotes the same
conversion in a more environmentally friendly manner.7
As part of our research on bacterial polysaccharides, we
required a series of carbasugars as mechanistic probes of
polymerizing glycosyltransferases; of particular interest to us is
carba-N-acetylglucosamine. Several syntheses of derivatives of
Received: June 14, 2012
Published: August 1, 2012
© 2012 American Chemical Society
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RESULTS AND DISCUSSION
Our syntheses of compounds 1−5, outlined in Scheme 1, began
with commercially available methyl α-D-mannoside. The use of
Scheme 2. Synthesis of Compound 7
■
Scheme 1. Outline of Synthetic Approach toward
Compounds 1−5
dioxane and water to cleanly furnish the cyclohexanone 7 as a
pure α isomer at pseudo C-1 in 89% yield. The absolute
1
configuration of pseudo C-1 was confirmed by the H NMR
3
spectrum of 7 in CDCl3 showing J1H−5aH 4.0 and 2.4 Hz.
Notably, the Ferrier carbocyclization reaction in the Quiclet−
Sire synthesis that was mediated by palladium chloride or
mercuric sulfate only afforded a modest yield of cyclohexanone
with a low ratio of α- to β-hydroxy isomer at pseudo C-1.8c
With the rapid synthesis of cyclohexanone 7 achieved, the
stage was now set for the conversion of the ketone to the
desired hydroxymethyl group (Scheme 3). The homologation
a butane-2,3-diacetal protecting group provides a rapid method
to efficiently differentiate methyl α-D-mannoside on a large
scale12 and construct the Ferrier carbocyclization precursor 6.
Homologation and hydroboration followed the Ferrier
carbocyclization to provide exclusively the axial hydroxymeth-
yl-configured derivative 8. The synthesis of carbasugar
analogues of N-acetylglucosamine (1) α-D-mannose (2), and
α-D-mannuronic acid (3) required epimerization of 8 to the
equatorial aldehyde 9. Carbocylic analogues of β-L-idosamine
(4) and β-L-gulose (5) were constructed directly from
compound 8. The final products 1−5 bear an orthogonal
pseudoanomeric benzyl group which can be removed to
facilitate further manipulations such as phosphorylation
required to generate glycosyl-1-phosphate analogues.
Scheme 3. Synthesis of Compounds 8A and 8B
The key intermediate, cyclohexanone 7, was synthesized in a
high-yielding (74%) five-step sequence from methyl α-D-
mannoside (Scheme 2). Treatment of methyl α-D-mannoside
with butane-2,3-dione in the presence of catalytic camphorsul-
fonic acid and trimethyl orthoformate in boiling methanol
produced almost exclusively the butane-2,3-diacetal intermedi-
ate 10,12 which upon treatment with triphenylphosphine,
iodine, and imidazole in refluxing THF gave 6-iodo compound
11 in 93% yield. The 2-OH of 11 was then protected as a p-
methoxybenzyl ether by an acid-catalyzed reaction13 with MPM
trichloroacetimidate.14 Hydrogen iodide elimination from 12
was effected by potassium tert-butoxide in THF at room
temperature to give the Ferrier reaction precursor 6 in a near-
quantitative yield. Notably, treatment of 12 with DBU in DMF
at 110 °C only produced 6 in a modest yield of 66%. In
addition, if compound 11 was submitted to DBU-promoted
elimination and the resulting eliminated product was then
transformed into 6 with NaH and p-methoxybenzyl chloride,
the overall yield of the two steps was low (47%). Compound 6
was subjected to palladium-catalyzed Ferrier reaction7b in 1,4-
of compound 7 was successfully effected by either Wittig
olefination with methylenetriphenylphosphorane or Tebbe’s
methylenation15 to give exocyclic alkene 13 in comparable
yields. However, Wittig reaction of 7 with methoxymethylene-
triphenylphosphorane yielded vinyl ether product in a low yield
due to the formation of the corresponding butylidene
product.16 The exocyclic alkene 13 was subjected to hydro-
boration with 9-BBN followed by oxidative workup to give
exclusively 8A in 95% yield. The absolute configuration of 8A
was confirmed by a NOE correlation between the proton at
pseudo C-3 and one of the two methylene protons at the
hydroxymethyl group and a lack of correlation between the
proton at pseudo C-3 and the proton at pseudo C-5. Moreover,
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8A was also readily transformed into lactone 8B by the protocol
of Piancatelli and Margarita,17 supporting the axial config-
uration of the hydroxymethyl group.
between pseudo H-4 and pseudo H-5 was also indicative of the
isomerization, as in compound 16 3J4H‑5H was 11.2 Hz, while in
compound 15 it was 5.2 Hz. Upon treatment of 16 with DDQ,
the hydroxyaldehyde 9 was produced in a near-quantitative
yield.
With the equatorial aldehyde group installed, compound 9
was now converted into the carbocyclic analogue of α-D-
glucosamine (Scheme 5). It was found that the aldehyde 9 was
Disappointingly, all attempts to directly hydroborate the
exocyclic alkene 13 to the equatorial hydroxymethyl group
were unsuccessful. Rhodium(I)-catalyzed hydroboration of
PMB-protected 13 with catecholborane,18 or 9-BBN effected
hydroboration of a more sterically hindered TBDPS derivative,
gave exclusively the axial hydroxymethyl product. Epoxidation
of 13 with m-CPBA followed by the regioselective reduction or
transformation of 13 into its phosphinite followed by
rhodium(I)-catalyzed hydroboration15 only led to the for-
mation of tertiary alcohol rather than primary alcohol.
Scheme 5. Synthesis of Compound 1
We then employed an epimerization strategy19 to invert the
configuration of pseudo C-5 in compound 8A via the exocyclic
aldehyde (Scheme 4). The primary hydroxyl of 8A could be
Scheme 4. Synthesis of Compounds 8 and 9
sufficiently stable to allow introduction of the triflate leaving
group at the pseudo 2-OH with triflic anhydride and pyridine in
CH2Cl2 and to allow inversion at C-2 with sodium azide to
furnish azidoaldehyde 17 in an overall yield of 53%. Reduction
of the azido group and the aldehyde with LiAlH4 in THF,
followed by removal of the diacetal using a 6 N HCl aqueous
MeOH solution (1:1) and subsequent acetylation, furnished
the desired analogue of carba-α-D-glucosamine 1 in 61% yield
over three steps.
The carbocyclic analogues of α-D-mannose and α-D-
mannuronic acid were prepared smoothly from the hydrox-
yaldehyde 9 (Scheme 6). Reduction of the aldehyde group in 9
followed by removal of the diacetal group with acetic acid and
water (4:1) and subsequent acetylation provided almost
exclusively the protected 5a-carba-α-D-mannose derivative 2.
The synthesis of the derivative of carba-α-D-mannuronic acid
selectively oxidized to an aldehyde using stoichiometric
RuCl2(PPh3)3 to give hydroxyaldehyde in 63% yield. Other
less expensive protocols such as using TEMPO-mediated
oxidation led to mixtures of the desired hydroxyaldehyde and
lactone 8B before 8A was completely consumed, while IBX
oxidation always resulted in a mixture of ketone and
hydroxyaldehyde.
On the basis of the undesired oxidation result, the secondary
hydroxyl group was protected prior to oxidation. The
protection of the β-hydroxyl of ketone 7 as a benzyl ether
proved to be challenging under basic conditions, giving
primarily elimination to the α,β-unsaturated ketone, and low
yields were obtained under acidic conditions. Finally,
compound 13 was efficiently transformed into its benzyl
ether 14, which upon treatment with 9-BBN and successive
oxidation, afforded exclusively axial hydroxymethyl derivative
8.20 Interestingly, the hydroboration of 14 with BH3·THF
complex was less selective, giving a mixture of 8 and its
regioisomeric tertiary alcohol with a mole ratio of 7.2 to 1. The
subsequent IBX oxidation of alcohol 8 afforded the
corresponding aldehyde 15 in good yield, which was efficiently
epimerized under mildly basic conditions using a mixture of
MeOH−pyridine (2:1) at 60 °C to give 16 in 94% yield. The
Scheme 6. Synthesis of Compounds 2 and 3
1
reaction was monitored by H NMR following the chemical
shift of the aldehydic proton of compound 16 (9.83 ppm)
3
versus that of compound 15 (10.08 ppm). The JH−H coupling
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Scheme 7. Synthesis of Compounds 4 and 5
required the conversion of aldehyde into carboxylic acid, which
was effected by sodium chlorite oxidation employing DMSO as
a scavenger to yield acid 18 in a near-quantitative yield.
Esterification of carboxylic acid 18 with acetyl chloride in
methanol at 60 °C21 followed by the complete removal of the
diacetal group and subsequent acetylation gave the desired
derivative of carba-α-D-mannuronic acid 3 in 72% yield over
three steps.
employing palladium hydroxide on carbon, and compound 24
was also readily available from compound 23 by basic
hydrolysis. Both 23 and 24 are valuable precursors for
biological probes given that 23 is suitable for chemical
manipulations while 24 for enzymatic functionalization.
CONCLUSION
■
In conclusion, a new versatile synthetic route to orthogonally
protected carbocyclic analogue of α-D-glucosamine from methyl
α-D-mannoside was developed. This route is also applicable to
the syntheses of the carbocyclic analogues of α-D-mannose, α-D-
mannuronic acid, β-L-idosamine, and β-L-gulose. The orthog-
onal pseudo OH-1 protecting group in the final products can be
selectively removed to facilitate further chemical phosphor-
ylation to give access to analogues of glycosyl-1-phosphates
which occupy a central position in carbohydrate metabolism.
To synthesize the analogue of carba-β-L-idosamine from the
axial hydroxymethyl derivative 8, we applied the same strategy
used for the synthesis of carbasugar derivative 1 (Scheme 7).
The hydroxyl of compound 8 was acetylated to give 19 in an
almost quantitative yield, which was subjected to DDQ
oxidation to afford 20 in 87% yield. 20 was then converted
into the corresponding triflate ester, which was subjected to
nucleophilic substitution with azide anion to afford the azido
derivative 21 in 70% yield. This yield is higher than that for
preparing the azidoaldehyde 17 (53%), indicating that the
presence of an aldehyde group decreased the reaction yield in
the transformation of 9 into 17. Reduction of 21 followed by
deprotection and acetylation furnished the analogue of carba-β-
L-idosamine 4 in 83% yield over three steps. Analysis of the 1H
EXPERIMENTAL SECTION
■
General Methods. All reactions in anhydrous organic solvents
were performed under an atmosphere of nitrogen with rigid exclusion
of moisture from glassware. The other reactions were carried out in
the presence of air unless otherwise noted. All chemicals and
anhydrous solvents were purchased from commercial sources and
used without further purification. Proton nuclear magnetic resonance
spectra (1H NMR) and carbon nuclear magnetic resonance spectra
(13C NMR) were recorded on a 400 spectrometer working at 400
4
NMR of compound 4 was consistent with a C1 chair, as large
coupling constants were observed for H-3 and H-4 (H-3, dd, 3J
3
= 9.6, 9.6 Hz, H-4, dd, J = 9.6, 5.6 Hz, see Supporting
1
1
MHz for H and 100 MHz for 13C. Both H and 13C NMR chemical
shifts are referenced relative to the solvent’s residual signals (CHCl3: δ
7.26 for 1H NMR and δ 77.16 for 13C NMR) and reported in parts per
million (ppm) at 25 °C, unless otherwise stated. 1H spectra were
assigned with the assistance of 2D GCOSY experiment. Data are
represented as follows: chemical shift, integration, multiplicity (s,
singlet; d, doublet; t, triplet; m, multiplet; br, broad), coupling
constant in hertz (Hz), and assignment. Infrared spectra were
measured on a FT-IR spectrometer and are reported in terms of
frequency of absorption (cm−1). Optical rotations were determined
with an automatic polarimeter. Melting points (mp) were recorded
using an apparatus and not corrected. High resolution mass spectra
were obtained from a quadrapole/TOF mass spectrometer with an ESI
source. Silica column chromatography was performed using silica gel
(230−400 mesh), unless otherwise stated. Compound 10 was
prepared according to a previously reported procedure.12
Information). The derivative of carba-β-L-gulose (5) was
prepared from 8 following the sequence of DDQ oxidation,
deprotection, and acetylation, with a total yield of 82% for the
latter two steps. In contrast to the conformation of the ido-
1
configured compound 4, the H NMR analysis showed the
conformation of compound 5 to be consistent with a 1C4 chair
with small coupling constants (<4 Hz) observed for H-3 and
H-4.
With the orthogonally protected carbasugar derivatives in
hand, we then studied their deprotection reactions (Scheme 8).
Compound 1 was readily converted into debenzylated
compound 23 in good yield through catalytic hydrogenolysis
Scheme 8. Synthesis of Compounds 23 and 24
3,4,6-Tri-O-acetyl-2-acetamido-1-O-benzyl-2-deoxy-5a-carba-α-
D-glucopyranose (1). To a stirred solution of LiAlH4 (0.78 mL, 1 M in
THF, 0.78 mmol) in anhydrous THF (3 mL) was added dropwise a
solution of compound 17 in dry THF (1 mL) (70 mg, 0.17 mmol) at 0
°C. The mixture was then stirred at room temperature for 2.25 h. The
reaction was quenched by careful addition of Na2SO4·10H2O solid,
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filtered, and evaporated in vacuo. The residue was dissolved in a
mixture of MeOH (3 mL) and 6 N HCl (3 mL), and the mixture was
stirred at room temperature for 4 h. The mixture was concentrated and
coevaporated with toluene (5 mL × 3) in vacuo. The residue was
dissolved in pyridine (6 mL), and acetic anhydride (3 mL) was added
slowly. The resulting solution was stirred at room temperature for 13
h. The solution was concentrated and coevaporated with toluene (5
mL × 3) in vacuo. The residue was purified by column
chromatography (ethyl acetate/pentane 1:1 to 2:1 to 3:1) to yield
compound 1 (46 mg, 61% over three steps) as a white foam. 1: Rf =
0.32 (ethyl acetate/hexane 3:1); [α]D = 85.0° (c 0.10, CHCl3); H
NMR (400 MHz, CDCl3) δ 7.27−7.40 (5H, m), 5.83 (1H, d, J = 9.2
Hz, NH), 5.16 (1H, dd, J = 9.6, 10.8 Hz, H-3), 5.03 (1H, dd, J = 9.6,
10.8 Hz, H-4), 4.62 (1H, d, J = 12.0 Hz, PhCH2), 4.36 (1H, d, J = 11.6
Hz, PhCH2), 4.05−4.15 (2H, m, H-6 and H-2), 3.88 (1H, dd, J = 3.2,
11.6 Hz, H-6), 3.76−3.80 (1H, m, H-1), 2.22−2.33 (1H, m, H-5),
2.02−2.10 (1H, m, H-5a), 2.03 (3H, s), 2.00 (3H, s), 1.97 (3H, s),
1.81 (3H, s), 1.48 (1H, ddd, J = 1.6, 13.2 14.8 Hz, H-5a); 13C NMR
(100 MHz, CDCl3) δ 171.4, 170.9, 169.9, 169.7, 137.8, 128.7, 128.2,
128.0, 75.1, 73.1, 71.7, 71.6, 63.5, 53.4, 34.8, 28.3, 23.2, 20.9, 20.8,
20.7; EI-HRMS (m/z) calcd for C22H30NO8 [M + H+] 436.1971,
found 436.1984.
1-O-Benzyl-2,3,4,6-tetra-O-acetyl-5a-carba-α-D-mannopyranose
(2). To a stirred solution of LiAlH4 (0.85 mL, 1 M in THF, 0.85
mmol) in anhydrous THF (6 mL) was added dropwise a solution of
compound 9 (0.13 g, 0.34 mmol) in dry THF (3.5 mL) at 0 °C. The
mixture was then stirred at room temperature for 1.5 h. TLC (ethyl
acetate/pentane 1:1) showed that the starting material was consumed
completely. The reaction was quenched by careful addition of
Na2SO4·10H2O solid, filtered, evaporated in vacuo, and dried under
high vacuum to give the crude product (0.13 g) as a white foam. The
foam (78 mg) was dissolved in a mixture of acetic acid (6 mL) and
distilled water (1.5 mL), and the mixture was stirred at 100 °C for 3.5
h. The mixture was concentrated and coevaporated with toluene (5
mL × 3) in vacuo. The residue was dissolved in pyridine (4 mL), and
acetic anhydride (2 mL) was added slowly. The resulting solution was
stirred at room temperature for 16 h. The solution was concentrated
and coevaporated with toluene (5 mL × 3) in vacuo. The residue was
purified by column chromatography (ethyl acetate/pentane 1:3 to 1:2)
to yield compound 2 (90 mg, 99% for three steps) as a colorless oil. 2:
Rf = 0.55 (ethyl acetate/hexane 1:1); [α]D27.9 = 30.6° (c 0.14, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.26−7.37 (5H, m), 5.50 (1H, dd, J =
(1H, dd, J = 3.2, 10.0 Hz, H-3), 4.67 (1H, d, J = 11.6 Hz, PhCH2),
4.57 (1H, d, J = 11.6 Hz, PhCH2), 3.72 (1H, dd, J = 3.2, 6.8 Hz, H-1),
3.67 (3H, s, COOCH3), 3.02 (1H, ddd, J = 5.2, 10.8, 11.2 Hz, H-5),
2.11 (3H, s), 2.00−2.07 (2H, m, H-5a), 2.00 (3H, s), 1.99 (3H, s); 13C
NMR (100 MHz, CDCl3) δ 172.4, 170.1, 170.0, 169.8, 137.5, 128.6,
128.1, 127.9, 72.9, 71.5, 70.6, 69.5, 69.4, 52.3, 42.1, 27.8, 21.1, 20.9(2);
+
EI-HRMS (m/z) calcd for C21H30NO9 [M + NH4 ] 440.1921, found
440.1919.
3,4,6-Tri-O-acetyl-2-acetamido-1-O-benzyl-2-deoxy-5a-carba-β-
L-idopyranose (4). In the same manner as 1, compound 4 was
synthesized as a white foam (0.11 g, 83% for three steps) from
compound 21 (0.13 g, 0.30 mmol), LiAlH4 (1.34 mL, 1 M in THF,
1.34 mmol), a mixture of MeOH (6 mL) and 6 N HCl (6 mL), and a
mixture of pyridine (4 mL) and acetic anhydride (2 mL). 4: Rf = 0.20
(ethyl acetate/hexane 2:1); [α]D27.9 = 35.2° (c 0.13, CHCl3); 1H NMR
(400 MHz, CDCl3, 25 °C) δ 7.24−7.36 (5H, m), 5.84 (1H, d, J = 9.2
Hz, NH), 5.24 (1H, dd, J = 9.6, 9.6 Hz, H-3), 5.01 (1H, dd, J = 5.6, 9.2
Hz, H-4), 4.63 (1H, d, J = 11.6 Hz, PhCH2), 4.31 (1H, d, J = 11.6 Hz,
PhCH2), 4.10−4.32 (3H, m, H-6 and H-2), 3.74 (1H, dd, J = 3.6, 6.4
Hz, H-1), 2.55−2.64 (1H, m, H-5), 2.13−2.24 (1H, m, H-5a), 2.02
(3H, s), 2.00 (3H, s), 1.99 (3H, s), 1.80 (3H, s), 1.55−1.65 (1H, m,
H-5a); 13C NMR (100 MHz, CDCl3, 50 °C) δ 170.8, 170.5, 169.6(2),
137.5, 128.7, 128.2, 75.3, 72.4, 71.8, 69.6, 64.3, 52.7, 35.7, 26.3, 23.1,
20.8, 20.7(2); EI-HRMS (m/z) calcd for C22H30NO8 [M + H+]
436.1971, found 436.1979.
27.9
1
1-O-Benzyl-2,3,4,6-tetra-O-acetyl-5a-carba-β-L-gulopyranose (5).
Compound 22 (66 mg, 0.17 mmol) was dissolved in a mixture of
MeOH (2 mL) and 6 N HCl (2 mL). The mixture was stirred at room
temperature for 4 h before it was concentrated and coevaporated with
toluene (5 mL × 3) in vacuo. The residue was dissolved in pyridine (3
mL), and acetic anhydride (1.5 mL) was added slowly. The resulting
solution was stirred at room temperature for 13 h. The solution was
concentrated and coevaporated with toluene (5 mL × 3) in vacuo. The
residue was purified by column chromatography (ethyl acetate/
pentane 1:3 to 1:1) to afford compound 5 (62 mg, 82% for two steps)
as a white solid. 5: mp 106−107 °C; Rf = 0.53 (ethyl acetate/hexane
1:1); [α]D27.9 = 33.5° (c 0.24, CHCl3); 1H NMR (400 MHz, CDCl3) δ
7.26−7.36 (5H, m), 5.35 (1H, dd, J = 3.6, 4.0 Hz, H-4), 5.15 (1H, dd,
J = 3.2, 9.6 Hz, H-2), 5.07 (1H, dd, J = 3.2, 3.2 Hz, H-3), 4.65 (1H, d, J
= 12.0 Hz, PhCH2), 4.59 (1H, d, J = 12.0 Hz, PhCH2), 4.03 (1H, dd, J
= 8.4, 11.2 Hz, H-6), 3.92 (1H, dd, J = 6.4, 11.2 Hz, H-6), 3.78 (1H,
ddd, J = 5.2, 10.0, 10.4 Hz, H-1), 2.29−2.40 (1H, m, H-5), 2.10 (3H,
s), 2.09 (3H, s), 2.03 (3H, s), 1.99 (3H, s), 1.97−2.05 (1H, m, H-5a),
1.53−1.65 (1H, m, H-5a); 13C NMR (100 MHz, CDCl3) δ 170.8,
170.1, 169.5, 169.2, 138.4, 128.5, 127.7, 127.4, 74.5, 72.6, 72.2, 68.8,
68.4, 63.6, 34.0, 28.1, 21.0, 20.9(2), 20.8; EI-HRMS (m/z) calcd for
2.8, 2.8 Hz, H-2), 5.30 (1H, dd, J = 3.2, 10.4 Hz, H-3), 5.22 (1H, dd, J
= 10.4, 10.8 Hz, H-4), 4.68 (1H, d, J = 12.0 Hz, PhCH2), 4.54 (1H, d,
J = 12.0 Hz, PhCH2), 4.08 (1H, dd, J = 5.2, 11.2 Hz, H-6), 3.92 (1H,
dd, J = 4.0, 11.6 Hz, H-6), 3.69 (1H, dd, J = 3.2, 6.4 Hz, H-1), 2.29−
2.39 (1H, m, H-5), 2.11 (3H, s), 2.05 (3H, s), 2.02 (3H, s), 1.98 (3H,
s), 1.90 (1H, ddd, J = 2.4, 2.8, 14.4 Hz, H-5a), 1.67−1.76 (1H, m, H-
5a); 13C NMR (100 MHz, CDCl3) δ 170.9, 170.3, 170.2, 169.9, 137.6,
128.6, 128.0, 127.9, 73.3, 71.5, 71.2, 69.7, 69.5, 64.1, 35.4, 28.0, 21.1,
+
C22H32NO9 [M + NH4 ] 454.2077, found 454.2087.
Methyl 6-Deoxy-2-O-(p-methoxy)benzyl-3,4-O-(2,3-dimethoxy-
butane-2,3-diyl)-α-D-lyxo-hex-5-enopyranoside (6). To a stirred
solution of compound 12 (9.00 g, 16.70 mmol) in anhydrous THF
(140 mL) was added potassium tert-butoxide (5.63 g, 50.20 mmol) in
one portion at room temperature. Significant formation of a white
precipitate was noted. The suspension was stirred at room temperature
+
20.9, 20.8(2); EI-HRMS (m/z) calcd for C22H32NO9 [M + NH4 ]
454.2077, found 454.2091.
Methyl 1-O-Benzyl-2,3,4-tri-O-acetyl-5a-carba-α-D-mannuro-
noate (3). Acetyl chloride (37 μL, 0.52 mmol) was added dropwise
to anhydrous MeOH (3 mL) at 0 °C. The solution was stirred at 0 °C
for 10 min before a solution of compound 18 (68 mg, 0.17 mmol) in
dry MeOH (2 mL) was added at 0 °C. The yellow solution was then
stirred at 60 °C for an additional 17.5 h. The solution was evaporated
in vacuo, and the residue was dissolved in a mixture of MeOH (3 mL)
and 6 N HCl (3 mL), which was stirred at room temperature for 3.5 h.
The mixture was concentrated and coevaporated with toluene (5 mL
× 3) in vacuo. The residue was dissolved in pyridine (5 mL), and
acetic anhydride (2.5 mL) was added slowly. The resulting solution
was stirred at room temperature for 16 h. The solution was
concentrated and coevaporated with toluene (5 mL × 3) in vacuo.
The residue was purified by column chromatography (ethyl acetate/
pentane 1:3) to yield compound 3 (52 mg, 72% for three steps) as a
1
for 1 h, and H NMR of a reaction aliquot showed that the starting
material was consumed completely. The mixture was filtered, and the
filtrate was diluted with ethyl acetate (100 mL). The organic solution
was washed with saturated NH4Cl aqueous solution (30 mL) and
brine (30 mL), dried over MgSO4, filtered, and evaporated in vacuo.
The residue was purified by column chromatography (ethyl acetate/
pentane 1:10) to give compound 6 (6.80 g, 99%) as a white solid. 6:
mp 81−83 °C; Rf = 0.65 (ethyl acetate/hexane 1:3); [α]D27.6 = 133.3°
(c 0.48, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.36 (2H, d, J = 8.8
Hz), 6.87 (2H, d, J = 8.8 Hz), 4.91 (1H, d, J = 11.6 Hz, p-
MeOPhCH2), 4.66−4.73 (3H, m, H-6 and H-1), 4.61 (1H, d, J = 11.2
Hz, p-MeOPhCH2), 4.59−4.61 (1H, m, H-4), 4.02 (1H, dd, J = 2.4,
10.4 Hz, H-3), 3.81 (3H, s, p-CH3OPh), 3.75 (1H, dd, J = 2.0, 2.4 Hz,
H-2), 3.35 (3H, s, OCH3-1), 3.28 (3H, s), 3.26 (3H, s), 1.36 (3H, s),
1.35 (3H, s); 13C NMR (100 MHz, CDCl3) δ 159.3, 153.9, 130.8,
129.8, 113.8, 101.6, 100.0, 99.9, 93.1, 75.4, 73.2, 69.0, 64.8, 55.4, 55.0,
28.0
colorless oil. 3: Rf = 0.64 (ethyl acetate/hexane 1:1); [α]D = 33.3°
(c 0.16, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.27−7.37 (5H, m),
5.48 (1H, dd, J = 10.0, 10.4 Hz, H-4), 5.46−5.49 (1H, m, H-2), 5.28
7405
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The Journal of Organic Chemistry
Article
+
48.1(2), 18.0(2); EI-HRMS (m/z) calcd for C21H34NO8 [M + NH4 ]
428.2284, found 428.2286.
5a), 1.72 (1H, d, J = 14.8 Hz, H-5a), 1.31 (3H, s), 1.28 (3H, s); 13C
NMR (100 MHz, CDCl3) δ 159.2, 138.4, 131.4, 129.7, 128.5, 127.7,
127.3, 113.7, 99.5 (2), 76.7, 76.5, 73.2, 71.3, 68.9, 67.0, 65.0, 55.4, 48.0,
47.8, 39.4, 27.5, 18.0(2); EI-HRMS (m/z) calcd for C28H42NO8 [M +
(2S,3S,4aS,7S,8R,8aR)-7-Hydroxy-2,3-dimethoxy-8-((p-
methoxybenzyl)oxy)-2,3-dimethylhexahydrobenzo[b][1,4]dioxin-5-
(4aH)-one (7). To a stirred solution of compound 6 (2.77 g, 6.75
mmol) in a mixture of 1,4-dioxane (32 mL) and distilled water (16
mL) under N2 was added PdCl2 (0.24 g, 1.35 mmol) in one portion at
room temperature. The suspension was stirred at 60 °C for 3 h, and
TLC (ethyl acetate/pentane 1:10) showed that the starting material
was consumed completely. The mixture was filtered, and the filtrate
was diluted with ethyl acetate (80 mL). The organic solution was
washed with water (30 mL), and the aqueous layer was extracted with
ethyl acetate (20 mL × 3). The combined organic phases were washed
with brine (50 mL), dried over MgSO4, filtered, and evaporated in
vacuo. The residue was purified by column chromatography (ethyl
acetate/pentane 1:1 to 2.5:1) to give compound 7 (2.39 g, 89%) as a
white solid. 7: mp 190−192 °C; Rf = 0.31 (ethyl acetate/hexane 1:1);
[α]D27.5 = 97.2° (c 0.64, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.38
(2H, d, J = 8.8 Hz), 6.89 (2H, d, J = 8.8 Hz), 5.03 (1H, d, J = 11.2 Hz,
p-MeOPhCH2), 4.88 (1H, d, J = 11.2 Hz, H-4), 4.64 (1H, d, J = 11.2
Hz, p-MeOPhCH2), 4.21−4.26 (2H, m, H-1 and H-3), 3.90−3.93
(1H, m, H-2), 3.82 (3H, s, p-CH3OPh), 3.28 (3H, s), 3.24 (3H, s),
2.92 (1H, ddd, J = 1.2, 4.0, 14.8 Hz, H-5a), 2.38 (1H, ddd, J = 1.2, 2.4,
14.8 Hz, H-5a), 1.78 (1H, d, J = 3.2 Hz, OH), 1.40 (3H, s), 1.36 (3H,
s); 13C NMR (100 MHz, CDCl3) δ 203.2, 159.4, 130.9, 129.9, 113.9,
100.2, 99.6, 77.0, 73.7, 73.1, 70.7, 69.4, 55.4, 48.4, 48.1, 44.4, 17.9,
+
NH4 ] 520.2910, found 520.2917.
1,6-Anhydro-3,4-O-(2,3-dimethoxybutane-2,3-diyl)-2-O-(p-me-
thoxybenzyl)-5a-carba-β-L-guluronic Acid (8B). To a stirred solution
of compound 8A (32 mg, 0.078 mmol) in anhydrous CH2Cl2 (1 mL)
were added TEMPO (1.3 mg, 0.0083 mmol) and PhI(OAc)2 (52 mg,
0.16 mmol) in turn at room temperature. The resulting solution was
stirred at room temperature for 2 h at which time a second addition of
PhI(OAc)2 (26 mg, 0.080 mmol) was made. The solution was stirred
at room temperature for another 18 h. TLC (ethyl acetate/pentane
1:1) showed that the starting material was consumed completely. The
reaction mixture was diluted with CH2Cl2 (20 mL), washed with 0.5 N
Na2S2O3 aqueous solution (5 mL × 1) and brine (5 mL), dried over
MgSO4, filtered, and evaporated in vacuo. The residue was purified by
column chromatography (ethyl acetate/pentane 1:3) to give
compound 8B (21 mg, 88%) as a colorless oil. 8B: Rf = 0.25 (ethyl
1
acetate/hexane 1:3); H NMR (400 MHz, CDCl3) δ 7.30 (2H, d, J =
8.8 Hz), 6.88 (2H, d, J = 8.8 Hz), 4.89 (1H, d, J = 11.6 Hz, p-
MeOPhCH2), 4.53 (1H, d, J = 11.6 Hz, p-MeOPhCH2), 4.52 (1H, dd,
J = 5.2, 4.8 Hz, H-1), 4.05 (1H, dd, J = 2.4, 10.0 Hz, H-4), 3.99 (1H,
dd, J = 4.0, 4.8 Hz, H-2), 3.89 (1H, dd, J = 4.0, 10.0 Hz, H-3), 3.82
(3H, s, p-CH3OPh), 3.26 (3H, s), 3.20 (3H, s), 2.63 (1H, dd, J = 2.4,
5.6 Hz, H-5), 2.38 (1H, d, J = 12.4 Hz, H-5a), 2.24 (1H, ddd, J = 5.6,
5.6, 12.0 Hz, H-5a), 1.33 (3H, s), 1.28 (3H, s); 13C NMR (100 MHz,
CDCl3) δ 175.1, 159.5, 130.5, 129.8, 113.9, 100.9, 100.8, 78.0, 73.4,
72.6, 70.6, 67.0, 55.4, 48.1, 47.9, 41.1, 31.6, 18.0, 17.9; EI-HRMS (m/
+
17.7; EI-HRMS (m/z) calcd for C20H32NO8 [M + NH4 ] 414.2128,
found 414.2132.
3,4-O-(2,3-Dimethoxybutane-2,3-diyl)-2-O-(p-methoxybenzyl)-
5a-carba-β-L-gulopyranose (8A). To a stirred solution of compound
13 (0.57 g, 1.50 mmol) in anhydrous THF (10 mL) was added a
solution of 9-BBN (8.7 mL, 0.5 M in THF, 4.35 mmol) dropwise at
room temperature. The resulting solution was stirred at room
temperature for 2.5 h. TLC (ethyl acetate/pentane 1:1) showed that
the starting material was consumed completely. To the above solution
were slowly added 3 N NaOH aqueous solution (3 mL, 9.00 mmol)
and 30% H2O2 solution (3 mL) in turn at 0 °C, and then the mixture
was stirred for 2 h at room temperature before adding a 0.5 N Na2S2O3
aqueous solution (10 mL) and diluting with CH2Cl2 (50 mL). The
organic phase was separated, and the aqueous layer was extracted with
CH2Cl2 (20 mL × 3). The combined organic phases were washed with
brine (30 mL), dried over MgSO4, filtered, and evaporated in vacuo.
The residue was purified by column chromatography (acetone:hexane
1:3 to 1:2) to give compound 8A (0.57 g, 95%) as a colorless oil. 8A:
Rf = 0.11 (acetone/hexane 1:3); [α]D27.8 = 102.4° (c 0.46, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 7.35 (2H, d, J = 8.8 Hz), 6.86 (2H, d, J =
8.4 Hz), 4.87 (1H, d, J = 11.2 Hz, p-MeOPhCH2), 4.51 (1H, d, J =
11.2 Hz, p-MeOPhCH2), 4.35 (1H, dd, J = 6.0, 10.8 Hz, H-4), 4.16
(1H, dd, J = 2.4, 10.8 Hz, H-3), 3.83−3.92 (2H, m, H-6 and H-1), 3.80
(3H, s, p-CH3OPh), 3.74−3.81 (1H, m, H-6), 3.66−3.70 (1H, m, H-
2), 3.26 (3H, s), 3.23 (3H, s), 2.10−2.21 (2H, m, H-5 and H-5a),
1.60−1.67 (1H, m, H-5a), 1.32 (3H, s), 1.28 (3H, s); 13C NMR (100
MHz, CDCl3) δ 159.1, 131.6, 129.6, 113.7, 99.8, 99.5, 79.2, 73.2, 68.6,
67.5, 67.4, 63.1, 55.4, 47.93, 47.91, 38.5, 30.6, 18.0(2); EI-HRMS (m/
+
z) calcd for C21H32NO8 [M + NH4 ] 426.2128, found 426.2136.
1-O-Benzyl-3,4-O-(2,3-dimethoxybutane-2,3-diyl)-2-O-(p-me-
thoxybenzyl)-5a-carba-α-D-mannopyranose (8C). To a stirred
solution of LiAlH4 (0.50 mL, 1 M in THF, 0.50 mmol) in anhydrous
THF (1 mL) at 0 °C was added a solution of compound 16 (0.20 g,
0.40 mmol) in dry THF (1.5 mL) dropwise. The mixture was then
stirred at room temperature for 1.5 h. TLC (ethyl acetate/pentane
1:3) showed that the starting material was almost consumed. The
reaction was quenched by careful addition of wet Na2SO4 solid, filtered
and evaporated in vacuo. The residue was purified by column
chromatography (ethyl acetate/pentane 1:2) to give compound 8C
(0.18 g, 92%) as a colorless oil. 8C: Rf = 0.20 (ethyl acetate/hexane
1:3); 1H NMR (400 MHz, CDCl3) δ 7.32 (2H, d, J = 8.4 Hz), 7.23−
7.35 (5H, m), 6.86 (2H, d, J = 8.4 Hz), 4.86 (1H, d, J = 11.2 Hz), 4.51
(1H, d, J = 12.0 Hz), 4.49 (1H, d, J = 11.6 Hz), 4.41 (1H, d, J = 12.0
Hz), 4.04 (1H, dd, J = 10.0, 10.4 Hz, H-4), 3.98 (1H, dd, J = 2.4, 10.0
Hz, H-3), 3.81 (3H, s, p-CH3OPh), 3.78 (1H, dd, J = 2.4, 2.8 Hz, H-
2), 3.70 (1H, dd, J = 7.6, 10.8 Hz, H-6), 3.62 (1H, dd, J = 2.8, 5.6 Hz,
H-1), 3.58 (1H, dd, J = 4.0, 10.8 Hz, H-6), 3.30 (3H, s), 3.25 (3H, s),
2.50−2.70 (1H, br, OH), 2.08−2.20 (1H, m, H-5), 1.70 (1H, ddd, J =
2.8, 2.8, 14.0 Hz, H-5a), 1.48 (1H, ddd, J = 2.8, 13.2, 14.0 Hz, H-5a),
1.32 (3H, s), 1.31 (3H, s); 13C NMR (100 MHz, CDCl3) δ 159.2,
138.5, 131.4, 129.6, 128.5, 127.7, 127.5, 113.7, 99.6, 99.4, 76.1, 75.8,
73.2, 71.5, 71.0, 70.7, 67.0, 55.4, 48.0(2), 37.0, 27.0, 18.1, 18.0; EI-
+
HRMS (m/z) calcd for C28H42NO8 [M + NH4 ] 520.2910, found
+
z) calcd for C21H36NO8 [M + NH4 ] 430.2441, found 430.2450.
520.2917.
1-O-Benzyl-3,4-O-(2,3-dimethoxybutane-2,3-diyl)-2-O-(p-me-
thoxybenzyl)-5a-carba-β-L-gulopyranose (8). In the same manner as
8A, compound 8 was synthesized as a colorless oil (2.24 g, 99%) from
compound 14 (2.18 g, 4.49 mmol), 9-BBN (26.60 mL, 0.5 M in THF,
13.30 mmol), 3 N NaOH aqueous solution (8.9 mL, 26.70 mmol),
and 30% H2O2 solution (8.9 mL) in dry THF (33 mL). 8: Rf = 0.19
(2S,3S,4aR,5S,7S,8R,8aR)-7-(Benzyloxy)-8-hydroxy-2,3-dime-
thoxy-2,3-dimethyloctahydrobenzo[b][1,4]dioxine-5-carbaldehyde
(9). To a stirred mixture of compound 16 (0.65 g, 1.30 mmol) in a
mixture of CH2Cl2 (28 mL) and distilled water (1.6 mL) was added
DDQ (0.45 g, 1.90 mmol) in one portion at 0 °C. The resulting green
mixture was stirred at 0 °C for 10 min and then at room temperature
for 2.5 h. TLC (ethyl acetate/pentane 1:10) showed that the starting
material was consumed completely. The mixture was filtered and the
filter cake was washed with CH2Cl2 (10 mL × 3). The combined
filtrates were washed with saturated NaHCO3 aqueous solution (15
mL), and the aqueous layer was extracted with CH2Cl2 (10 mL × 3).
The combined organic phases were washed with brine (20 mL), dried
over MgSO4, filtered, and evaporated in vacuo. The residue was
purified by column chromatography (ethyl acetate/pentane 1:2.5 to
1:1) to give compound 9 (0.48 g, 96%) as a white solid. 9: mp 56−58
28.0
1
(ethyl acetate/hexane 1:3); [α]D
= 124.3° (c 0.20, CHCl3); H
NMR (400 MHz, CDCl3) δ 7.32 (2H, d, J = 8.8 Hz), 7.21−7.35 (5H,
m), 6.86 (2H, d, J = 8.4 Hz), 4.86 (1H, d, J = 11.2 Hz), 4.49 (1H, d, J
= 12.0 Hz), 4.47 (1H, d, J = 11.2 Hz), 4.40 (1H, d, J = 11.6 Hz), 4.38
(1H, dd, J = 5.6, 10.8 Hz, H-4), 4.28 (1H, dd, J = 9.6, 11.2 Hz, H-6),
4.19 (1H, dd, J = 2.4, 10.8 Hz, H-3), 3.80 (3H, s, p-CH3OPh), 3.77−
3.80 (1H, m, H-2), 3.56 (1H, dd, J = 2.8, 6.0 Hz, H-1), 3.47 (1H, dd, J
= 3.6, 11.6 Hz, H-6), 3.27 (3H, s), 3.22 (3H, s), 2.70−2.95 (1H, br,
OH), 2.25−2.34 (1H, m, H-5), 1.94 (1H, ddd, J = 3.2, 6.4, 15.2 Hz, H-
7406
dx.doi.org/10.1021/jo301240j | J. Org. Chem. 2012, 77, 7401−7410

The Journal of Organic Chemistry
Article
27.8
°C; Rf = 0.13 (ethyl acetate/hexane 1:3); [α]D
= 112.3°(c 0.13,
and was stirred at room temperature for 2 h. TLC (ethyl acetate/
pentane 1:1) showed that the starting material was consumed
completely. The reaction was quenched carefully by the addition of
saturated NaHCO3 aqueous solution (1 mL) at 0 °C, and the mixture
was stirred at room temperature for 15 min. The mixture was filtered
through Celite, and the filter cake was washed with CH2Cl2 (10 mL ×
2). The combined filtrates were concentrated in vacuo, and the residue
was purified by column chromatography (ethyl acetate/pentane 1:4 to
1:2) to give compound 13 (86 mg, 86%) as a colorless oil. 13: Rf = 0.2
(ethyl acetate/hexane 1:3); [α]D27.7 = 96.2° (c 0.42, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.37 (2H, d, J = 8.8 Hz), 6.88 (2H, d, J = 8.4
Hz), 5.27−5.30 (1H, m, H-6), 4.91−4.96 (2H, m, H-6 and p-
MeOPhCH2), 4.56 (1H, d, J = 11.2 Hz, p-MeOPhCH2), 4.54 (1H, d, J
= 9.2 Hz, H-4), 3.89−3.95 (1H, m, H-1), 3.80 (3H, s, p-CH3OPh),
3.74−3.79 (2H, m, H-3 and H-2), 3.27 (3H, s), 3.24 (3H, s), 2.73
(1H, dd, J = 1.6, 14.4 Hz, H-5a), 2.20 (1H, dd, J = 2.0, 14.4 Hz, H-5a),
1.59 (1H, d, J = 6.8 Hz, OH), 1.36 (3H, s), 1.35 (3H, s); 13C NMR
(100 MHz, CDCl3) δ 159.2, 140.4, 131.4, 129.6, 113.7, 110.2, 99.70,
99.66, 78.0, 73.3, 72.1, 69.2, 68.2, 55.4, 48.0(2), 37.1, 17.9(2); EI-
CHCl3); IR (KBr) ν 3453, 2949, 1727, 1379, 1121 cm−1; H NMR
(400 MHz, CDCl3) δ 9.84 (1H, d, J = 2.0 Hz, CHO), 7.25−7.36 (5H,
m), 4.60 (1H, d, J = 12.0 Hz), 4.49 (1H, d, J = 12.0 Hz), 4.22 (1H, dd,
J = 10.0, 11.2 Hz, H-4), 4.03 (1H, dd, J = 2.8, 2.8 Hz, H-2), 3.97 (1H,
dd, J = 2.8, 10.0 Hz, H-3), 3.79 (1H, dd, J = 2.8, 5.6 Hz, H-1), 3.25
(3H, s), 3.24 (3H, s), 2.85−2.95 (1H, m, H-5), 2.59−2.70 (1H, br,
OH), 1.98 (1H, ddd, J = 2.8, 2.8, 14.4 Hz, H-5a), 1.82 (1H, ddd, J =
2.8, 12.8, 14.4 Hz, H-5a), 1.31 (3H, s), 1.28 (3H, s); 13C NMR (100
MHz, CDCl3) δ 202.7, 138.1, 128.5, 127.8, 127.6, 100.4, 99.9, 75.6,
71.4, 69.8, 69.7, 66.2, 48.2, 48.1, 47.4, 24.4, 17.9, 17.8; EI-HRMS (m/
1
+
z) calcd for C20H32NO7 [M + NH4 ] 398.2179, found 398.2180.
Methyl 6-Deoxy-3,4-O-(2,3-dimethoxybutane-2,3-diyl)-6-iodo-α-
D-mannoside (11). To a stirred solution of compound 10 (19.00 g,
0.062 mol), triphenylphosphine (19.40 g, 0.074 mol), and imidazole
(6.68 g, 0.098 mol) in THF (300 mL) was added a solution of iodine
in THF (75 mL) dropwise (18.80 g, 0.074 mol) under reflux over 15
min. During the last stages of the addition, precipitates formed. After
the addition was complete, the brown suspension was refluxed for an
additional 40 min. TLC (neat Et2O) showed the reaction to be
complete. The mixture was filtered, and the filtrate was diluted with
ethyl acetate (150 mL). The organic solution was washed with a 0.5 N
Na2S2O3 aqueous solution (30 mL) followed by brine (50 mL), dried
over MgSO4, filtered, and evaporated in vacuo. The residue was
purified by column chromatography (EtOAc/pentane 1:5 to 1:3 to
1:2) to give compound 11 (24.00 g, 93%) as a white foam. 11:12b Rf =
+
HRMS (m/z) calcd for C21H34NO7 [M + NH4 ] 412.2335, found
412.2338.
Benzyl 6-Deoxy-2-O-(p-methoxybenzyl)-3,4-O-(2,3-dimethoxy-
butane-2,3-diyl)-5a-carba-α-D-lyxo-hex-5-enopyranoside (14). To
a stirred suspension of NaH (0.43 g, 11.00 mmol) in anhydrous DMF
(10 mL) at 0 °C was added a solution of compound 13 (2.09 g, 5.30
mmol) in dry DMF (10 mL) dropwise. The suspension was stirred at
0 °C for 10 min, and benzyl bromide (0.82 mL, 6.90 mmol) was added
at 0 °C. The suspension was then stirred at room temperature for 3 h.
TLC (ethyl acetate/pentane 1:3) showed that the starting material was
almost consumed. The reaction was quenched carefully by the
addition of saturated NH4Cl aqueous solution (5 mL) at 0 °C, and the
mixture was diluted with ethyl acetate (50 mL). The organic phase was
separated, and the aqueous layer was extracted with ethyl acetate (15
mL × 3). The combined organic phases were washed with brine (10
mL), dried over MgSO4, filtered, and evaporated in vacuo. The residue
was purified by column chromatography (ethyl acetate/pentane 1:16
to 1:10) to yield compound 14 (2.32 g, 90%) as a yellow oil. 14: Rf =
1
0.26 (ethyl acetate/hexane 1:3); H NMR (400 MHz, CDCl3) δ 4.75
(1H, s, H-1), 3.98 (1H, dd, J = 3.2, 10.0 Hz, H-3), 3.91 (1H, dd, J =
1.6, 3.2 Hz, H-2), 3.86 (1H, dd, J = 10.0, 9.6 Hz, H-4), 3.62−3.68 (1H,
m, H-5), 3.55 (1H, dd, J = 2.4, 10.8 Hz, H-6), 3.44 (3H, s, OCH3-1),
3.27 (3H, s), 3.26 (3H, s), 3.23−3.28 (1H, m, H-6), 2.20−2.50 (1H,
br, OH), 1.31 (3H, s), 1.28 (3H, s).
Methyl 6-Deoxy-2-O-(p-methoxy)benzyl-3,4-O-(2,3-dimethoxy-
butane-2,3-diyl)-6-iodo-α-D-mannoside (12). To a stirred solution
of compound 11 (29.76 g, 0.071 mol) in CH2Cl2 (280 mL) were
added MPM trichloroacetimidate14 (40.84 g, 0.15 mol) and
camphorsulfonic acid monohydrate (1.76 g, 7.03 mmol) in turn at
room temperature. The solution was stirred at room temperature for
16 h, and TLC (ethyl acetate/pentane 1:3) showed that the reaction
was complete. The mixture was filtered to remove the white precipitate
of trichloroacetamide, and the filtrate was concentrated under vacuum.
During the evaporation, more white precipitates formed, which were
removed by filtration and washed with pentane (30 mL × 3). The
combined filtrates were evaporated in vacuo, and the residue was
purified by column chromatography (ethyl acetate/pentane 1:16 to
1:10) to afford compound 12 (35.54 g, 93%) as a white solid.
Spectroscopic and analytical data agree with the previous report.22
6-Deoxy-2-O-(p-methoxybenzyl)-3,4-O-(2,3-dimethoxybutane-
2,3-diyl)-5a-carba−α-D-lyxo-hex-5-enopyranoside (13). (a) Via
Wittig olefination: To a stirred suspension of methyltriphenylphos-
phonium bromide (5.41 g, 15.14 mmol) in anhydrous THF (40 mL)
was added dropwise a solution of n-BuLi (9.46 mL, 1.6 M in hexane,
15.10 mmol) at 0 °C. After the addition, the yellow suspension was
stirred at room temperature for 1 h. To the above yellow suspension
was added a solution of compound 7 (1.00 g, 2.52 mmol) in dry THF
(10 mL) dropwise at 0 °C. The resulting suspension was stirred at
room temperature for 2 h, and TLC (ethyl acetate/pentane 1:1)
showed that the starting material was consumed completely. The
reaction was quenched by the addition of saturated NH4Cl (aq)
solution (50 mL), and the mixture was then diluted with ethyl acetate
(80 mL). The organic phase was separated, and the aqueous layer was
extracted with ethyl acetate (20 mL × 3). The combined organic
phases were washed with brine, dried over MgSO4, filtered, and
evaporated in vacuo. The residue was purified by column
chromatography (ethyl acetate/pentane 1:3) to give compound 13
(0.85 g, 85%) as a colorless oil. (b) Via Tebbe’s methylenation: To a
stirred solution of compound 7 (0.10 g, 0.25 mmol) in anhydrous
THF (4 mL) was added dropwise a solution of the Tebbe reagent
(0.56 mL, 1.0 M in toluene, 0.56 mmol) at 0 °C. After the addition,
the brown solution was allowed to warm to room temperature slowly
27.7
0.22 (ethyl acetate/hexane 1:16); [α]D = 112.4° (c 0.39, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.34 (2H, d, J = 8.8 Hz), 7.21−7.30
(5H, m), 6.86 (2H, d, J = 8.4 Hz), 5.19−5.21 (1H, m, H-6), 4.91 (1H,
d, J = 11.2 Hz), 4.83−4.85 (1H, m, H-6), 4.56 (1H, d, J = 10.4 Hz, H-
4), 4.53 (1H, d, J = 12.0 Hz), 4.52 (1H, d, J = 11.2 Hz), 4.37 (1H, d, J
= 12.0 Hz), 3.88 (1H, dd, J = 2.8, 10.4 Hz, H-3), 3.82 (1H, dd, J = 2.4,
2.8 Hz, H-2), 3.79 (3H, s, p-CH3OPh), 3.62−3.65 (1H, m, H-1), 3.26
(3H, s), 3.21 (3H, s), 2.49 (1H, dd, J = 2.0, 14.8 Hz, H-5a), 2.41 (1H,
dd, J = 1.2, 14.4 Hz, H-5a), 1.36 (3H, s), 1.34 (3H, s); 13C NMR (100
MHz, CDCl3) δ 159.2, 141.1, 138.5, 131.4, 129.6, 128.4, 127.53, 127.5,
113.7, 108.1, 99.54, 99.52, 76.6, 76.0, 73.2, 72.0, 70.4, 68.1, 55.3, 47.9,
47.8, 33.7, 18.0(2); EI-HRMS (m/z) calcd for C28H40NO7 [M +
+
NH4 ] 502.2805, found 502.2822.
(2S,3S,4aR,5R,7S,8R,8aS)-7-(Benzyloxy)-2,3-dimethoxy-8-((4-
methoxybenzyl)oxy)-2,3-dimethyloctahydrobenzo[b][1,4]dioxine-5-
carbaldehyde (15). IBX (4.30 g, 15.40 mmol) was dissolved in
DMSO (30 mL) by stirring at room temperature for 15 min. A
solution of compound 8 (2.24 g, 4.38 mmol) in DMSO (15 mL) was
added to the IBX solution at room temperature. White precipitates
formed, and the mixture was stirred at room temperature. TLC (ethyl
acetate/pentane 1:3) showed that only a small amount of starting
material remained after stirring for 21 h. The mixture was filtered, and
the filter cake was washed with CH2Cl2 (100 mL). Water (20 mL) was
added, and the organic phase was separated. The aqueous layer was
extracted with CH2Cl2 (20 mL × 2). The combined organic phases
were washed with brine (20 mL), dried over MgSO4, filtered, and
evaporated in vacuo. The residue was purified by column
chromatography (ethyl acetate/pentane 1:6) to give compound 15
(1.89 g, 85%) as a colorless oil. 15: Rf = 0.45 (ethyl acetate/hexane
1:3); [α]D27.9 = 130.9° (c 0.16, CHCl31); IR (neat) ν 2937, 1756, 1718,
1612, 1455, 1377, 1250, 1120 cm−1; H NMR (400 MHz, CDCl3) δ
10.08 (1H, d, J = 2.0 Hz, CHO), 7.31 (2H, d, J = 8.4 Hz), 7.19−7.31
(5H, m), 6.85 (2H, d, J = 8.8 Hz), 4.88 (1H, d, J = 11.2 Hz), 4.48 (1H,
7407
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The Journal of Organic Chemistry
Article
d, J = 11.2 Hz), 4.45 (1H, d, J = 12.0 Hz), 4.35 (1H, dd, J = 5.2, 11.2
Hz, H-4), 4.31 (1H, dd, J = 2.4, 11.2 Hz, H-3), 4.22 (1H, d, J = 12.0
Hz), 3.80 (4H, m, p-CH3OPh- and H-2), 3.59 (1H, dd, J = 2.4, 6.0 Hz,
H-1), 3.27 (3H, s), 3.24 (3H, s), 2.46−2.51 (1H, m, H-5), 2.27 (1H, d,
J = 14.4 Hz, H-5a), 1.95 (1H, ddd, J = 2.0, 6.0, 14.8 Hz, H-5a), 1.34
(3H, s), 1.28 (3H, s); 13C NMR (100 MHz, CDCl3) δ 204.5, 159.2,
138.1, 131.2, 129.7, 128.5, 127.7, 127.6, 113.7, 100.0, 99.9, 76.3, 75.5,
73.2, 70.4, 68.0, 65.8, 55.4, 48.0(2), 47.2, 27.0, 18.0, 17.8; EI-HRMS
quenched by the addition of 0.5 N Na2S2O3 aqueous solution (5 mL),
and then ethyl acetate (50 mL) and water (10 mL) were added. The
organic phase was separated, and the aqueous layer was extracted with
ethyl acetate (15 mL × 2). The combined organic phases were washed
with brine (20 mL), dried over anhydrous MgSO4, filtered, and
evaporated in vacuo. The residue was purified by column
chromatography (ethyl acetate/pentane 1:2, with 0.1% of HCOOH)
to yield compound 18 (0.11 g, 99%) as a white foam. 18: Rf = 0.25
+
28.0
(m/z) calcd for C28H40NO8 [M + NH4 ] 518.2754, found 518.2769.
(ethyl acetate/hexane 1:1, trace HCOOH); [α]D = 171.4° (c 0.11,
1
(2S,3S,4aR,5S,7S,8R,8aS)-7-(Benzyloxy)-2,3-dimethoxy-8-((4-
methoxybenzyl)oxy)-2,3-dimethyloctahydrobenzo[b][1,4]dioxine-5-
carbaldehyde (16). A solution of compound 15 (1.89 g, 3.77 mmol)
in a mixture of MeOH (60 mL) and pyridine (30 mL) was stirred at
60 °C for 3 days, and 1H NMR showed that the starting material was
consumed completely. The solution was concentrated and coevapo-
rated with toluene (10 mL × 2) in vacuo. The residue was purified by
column chromatography (ethyl acetate/pentane 1:6 to 1:5) to give
compound 16 (1.78 g, 94%) as a colorless oil. 16: Rf = 0.45 (ethyl
CHCl3); H NMR (400 MHz, CDCl3) δ 7.27−7.36 (5H, m), 4.62
(1H, d, J = 12.0 Hz), 4.49 (1H, d, J = 11.6 Hz), 4.24 (1H, dd, J = 10.4,
10.8 Hz, H-4), 4.02 (1H, dd, J = 2.8, 2.8 Hz, H-2), 3.91 (1H, dd, J =
2.8, 10.8 Hz, H-3), 3.77 (1H, dd, J = 2.8, 5.6 Hz, H-1), 3.27 (3H, s),
3.23 (3H, s), 2.83−2.92 (1H, m, H-5), 2.14 (1H, ddd, J = 2.8, 3.2, 14.4
Hz, H-5a), 1.96−2.05 (1H, m, H-5a), 1.30 (3H, s), 1.28 (3H, s); 13C
NMR (100 MHz, CDCl3) δ 178.4, 138.1, 128.5, 127.8, 127.6, 100.4,
100.0, 75.6, 71.4, 69.8, 69.5, 66.6, 48.2, 48.1, 41.3, 27.9, 17.9, 17.8; EI-
+
HRMS (m/z) calcd for C20H32NO8 [M + NH4 ] 414.2128, found
27.9
acetate/hexane 1:3); [α]D = 173.8° (c 0.13, CHCl3); IR (neat) ν
414.2131.
2949, 1728, 1613, 1455, 1377, 1250, 1143 cm−1; 1H NMR (400 MHz,
CDCl3) δ 9.83 (1H, d, J = 2.0 Hz, CHO), 7.31 (2H, d, J = 8.0 Hz),
7.22−7.34 (5H, m), 6.86 (2H, d, J = 8.8 Hz), 4.86 (1H, d, J = 11.2
Hz), 4.51 (1H, d, J = 12.0 Hz), 4.49 (1H, d, J = 11.6 Hz), 4.40 (1H, d,
J = 12.0 Hz), 4.33 (1H, dd, J = 10.4, 11.2 Hz, H-4), 4.02 (1H, dd, J =
2.4, 10.4 Hz, H-3), 3.81 (3H, s, p-CH3OPh), 3.79 (1H, dd, J = 2.8, 2.8
Hz, H-2), 3.66 (1H, dd, J = 2.8, 6.0 Hz, H-1), 3.28 (3H, s), 3.26 (3H,
s), 2.80−2.89 (1H, m, H-5), 1.89 (1H, ddd, J = 2.8, 3.2, 14.4 Hz, H-
5a), 1.77 (1H, ddd, J = 2.4, 12.8, 14.4 Hz, H-5a), 1.33 (3H, s), 1.30
(3H, s); 13C NMR (100 MHz, CDCl3) δ 203.0, 159.3, 138.2, 131.2,
129.6, 128.5, 127.8, 127.6, 113.8, 99.9, 99.6, 75.8, 75.2, 73.3, 71.2, 70.4,
66.6, 55.4, 48.2, 48.0, 47.8, 24.6, 18.0, 17.9; EI-HRMS (m/z) calcd for
6-O-Acetyl-1-O-benzyl-3,4-O-(2,3-dimethoxybutane-2,3-diyl)-2-
O-(p-methoxybenzyl)-5a-carba-β-L-gulopyranoside (19). Com-
pound 8 (0.20 g, 0.40 mmol) was dissolved in pyridine (2 mL), and
acetic anhydride (1 mL) was added slowly. The resulting solution was
stirred at room temperature for 17 h. The solution was concentrated
and coevaporated with toluene (5 mL × 3) in vacuo. The residue was
purified by column chromatography (ethyl acetate/pentane 1:6) to
afford compound 19 (0.22 g, 99%) as a colorless oil. 19: Rf = 0.68
27.8
1
(ethyl acetate/hexane 1:3); [α]D
= 126.5° (c 0.10, CHCl3); H
NMR (400 MHz, CDCl3) δ 7.21−7.36 (7H, m), 6.86 (2H, d, J = 8.4
Hz), 4.88 (1H, d, J = 11.2 Hz), 4.55 (1H, d, J = 12.0 Hz), 4.51 (1H,
dd, J = 6.4, 10.8 Hz, H-6), 4.47 (1H, d, J = 11.2 Hz), 4.40 (1H, dd, J =
10.8, 10.8 Hz, H-6), 4.39 (1H, d, J = 12.4 Hz), 4.28 (1H, dd, J = 6.0,
11.2 Hz, H-4), 3.97 (1H, dd, J = 2.8, 11.2 Hz, H-3), 3.81 (3H, s, p-
CH3OPh), 3.77−3.80 (1H, m, H-2), 3.62 (1H, dd, J = 2.8, 6.4 Hz, H-
1), 3.26 (3H, s), 3.20 (3H, s), 2.24−2.32 (1H, m, H-5), 2.04−2.12
(1H, m, H-5a), 2.03 (3H, s, CH3CO), 1.69−1.79 (1H, m, H-5a), 1.30
(3H, s), 1.25 (3H, s); 13C NMR (100 MHz, CDCl3) δ 171.2, 159.2,
138.6, 131.5, 129.7, 128.5, 127.6, 127.3, 113.7, 99.4(2), 77.4, 76.7,
73.3, 71.2, 67.2, 66.3, 64.6, 55.4, 47.9, 47.8, 36.3, 24.4, 21.2, 18.0, 17.9;
+
C28H40NO8 [M + NH4 ] 518.2754, found 518.2732.
(2S,3S,4aR,5S,7S,8S,8aR)-8-Azido-7-(benzyloxy)-2,3-dimethoxy-
2,3-dimethyloctahydrobenzo[b][1,4]dioxine-5-carbaldehyde (17).
To a stirred solution of compound 9 (0.43 g, 1.10 mmol) and dry
pyridine (0.46 mL, 5.60 mmol) in anhydrous CH2Cl2 (18 mL) at 0 °C
was added triflic anhydride (0.38 mL, 2.26 mmol) dropwise. The
solution was stirred at 0 °C for 30 min and then at room temperature
for 30 min. TLC (ethyl acetate/pentane 1:1) showed that the starting
material was consumed completely. The reaction was diluted with
CH2Cl2 (30 mL), washed with brine (10 mL), dried over MgSO4,
filtered through Celite, and evaporated in vacuo. The residue was dried
under high vacuum and used for next step directly without further
purification. The above residue was dissolved in dry DMF (20 mL),
and sodium azide (0.74 g, 11.38 mmol) was added. The resulting
mixture was stirred at 80 °C in dark for 13.5 h. TLC (ethyl acetate/
pentane 1:3) showed that the triflate ester was consumed completely.
The mixture was filtered, and the filter cake was washed with ethyl
acetate (20 mL × 2). The combined filtrates were washed brine (10
mL), dried over MgSO4, filtered, and evaporated in vacuo. The residue
was purified by column chromatography (ethyl acetate/pentane 1:3)
+
EI-HRMS (m/z) calcd for C30H44NO9 [M + NH4 ] 562.3016, found
562.3036.
6-O-Acetyl-1-O-benzyl-3,4-O-(2,3-dimethoxybutane-2,3-diyl)-5a-
carba-β-L-gulopyranoside (20). In the same manner as 9, compound
20 was synthesized as a colorless oil (88 mg, 87%) from compound 19
(0.13 g, 0.24 mmol) and DDQ (0.11 g, 0.46 mmol) in a mixture of
CH2Cl2 (9 mL) and distilled water (0.5 mL). 20: Rf = 0.25 (ethyl
acetate/hexane 1:3); [α]D27.9 = 92.9° (c 0.14, CHCl3); 1H NMR (400
MHz, CDCl3) δ 7.24−7.36 (5H, m), 4.62 (1H, d, J = 12.4 Hz), 4.50
(1H, dd, J = 4.8, 10.4 Hz, H-6), 4.46 (1H, d, J = 12.4 Hz), 4.40 (1H,
dd, J = 10.8, 10.8 Hz, H-6), 4.14 (1H, dd, J = 6.0, 11.2 Hz, H-4), 3.99−
4.03 (1H, m, H-2), 3.90 (1H, dd, J = 3.2, 10.8 Hz, H-3), 3.70−3.75
(1H, m, H-1), 3.21 (3H, s), 3.19 (3H, s), 2.48−2.57 (1H, br, OH),
2.26−2.35 (1H, m, H-5), 2.13−2.21 (1H, m, H-5a), 2.04 (3H, s,
CH3CO), 1.79 (1H, ddd, J = 4.0, 4.4, 11.2 Hz, H-5a), 1.27 (3H, s),
1.23 (3H, s); 13C NMR (100 MHz, CDCl3) δ 171.1, 138.5, 128.5,
127.7, 127.4, 100.0, 99.8, 77.4, 71.5, 70.6, 66.4, 65.8, 64.3, 48.0, 47.9,
36.2, 24.2, 21.2, 17.8(2); EI-HRMS (m/z) calcd for C22H36NO8 [M +
to give compound 17 (0.24 g, 53%) as a pale yellow oil. 17: Rf = 0.42
27.9
(ethyl acetate/hexane 1:3); [α]D
= 204.0° (c 0.12, CHCl3); IR
(neat) ν 2916, 2105, 1726, 1456, 1261 cm−1; H NMR (400 MHz,
CDCl3) δ 9.86 (1H, d, J = 1.2 Hz, CHO), 7.27−7.37 (5H, m), 4.64
(1H, d, J = 11.6 Hz), 4.59 (1H, d, J = 12.0 Hz), 4.30 (1H, dd, J = 9.6,
10.4 Hz, H-3), 3.90 (1H, dd, J = 2.8, 5.2 Hz, H-1), 3.86 (1H, dd, J =
9.6, 11.2 Hz, H-4), 3.38 (3H, s), 3.25 (3H, s), 3.22−3.27 (1H, m, H-
2), 2.97−3.06 (1H, m, H-5), 2.11 (1H, ddd, J = 3.6, 3.6 14.8 Hz, H-
5a), 1.32−1.38 (1H, m, H-5a), 1.36 (3H, s), 1.31 (3H, s); 13C NMR
(100 MHz, CDCl3) δ 202.2, 137.7, 128.6, 128.0, 127.9, 100.3, 100.1,
75.1, 72.4, 70.3, 69.3, 62.4, 48.6, 48.4, 46.4, 26.6, 17.9, 17.7; EI-HRMS
1
+
NH4 ] 442.2441, found 442.2453.
6-O-Acetyl-2-azido-1-O-Benzyl-2-deoxy-3,4-O-(2,3-dimethoxybu-
tane-2,3-diyl)-5a-carba-β-L-gulopyranoside (21). To a stirred
solution of compound 20 (0.28 g, 0.66 mmol) and pyridine (0.34
mL, 4.20 mmol) in anhydrous CH2Cl2 (6 mL) at 0 °C was added
triflic anhydride (0.28 mL, 1.70 mmol) dropwise. The solution was
allowed to warm to room temperature slowly and stir for 1.5 h. TLC
(ethyl acetate/pentane 1:3) showed that the starting material was
consumed completely. The reaction was diluted with CH2Cl2 (30
mL), washed with brine (10 mL), dried over MgSO4, filtered through
Celite, and evaporated in vacuo. The residue was dried under high
vacuum and used for the next step directly without further purification.
The above residue was dissolved in dry DMF (6 mL), and sodium
+
(m/z) calcd for C20H31N4O6 [M + NH4 ] 423.2244, found 423.2254.
1-O-Benzyl-3,4-O-(2,3-dimethoxybutane-2,3-diyl)-5a-carba-α-D-
manuronic Acid (18). Compound 9 (0.10 g, 0.26 mmol) was
t
dissolved in a mixture of BuOH (6 mL) and distilled water (3 mL).
NaH2PO4·H2O (0.14 g, 1.01 mmol), DMSO (0.28 mL, 3.95 mol), and
NaClO2 (60 mg, 0.53 mmol, 80% purity) were added in turn at 0 °C.
The mixture was stirred at 0 °C for 1.5 h, and TLC (ethyl acetate/
pentane 1:3) showed that the reaction was complete. The reaction was
7408
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The Journal of Organic Chemistry
Article
azide (0.72 g, 11.10 mmol) was added. The resulting mixture was
stirred at 75 °C in dark for 20.5 h. TLC (ethyl acetate/pentane 1:3)
showed that the triflate ester was consumed completely. The mixture
was filtered, and the filter cake was washed with ethyl acetate (30 mL
× 1). The combined filtrates were washed with brine (10 mL), dried
over MgSO4, filtered, and evaporated in vacuo. The residue was
purified by column chromatography (ethyl acetate/pentane 1:6) to
give compound 21 (0.21 g, 70%) as a colorless oil. 21: Rf = 0.44 (ethyl
acetate/hexane 1:3); [α]D28.0 = 102.3° (c 0.13, CHCl3); 1H NMR (400
MHz, CDCl3) δ 7.26−7.35 (5H, m), 4.64 (1H, d, J = 12.0 Hz), 4.57
(1H, d, J = 12.0 Hz), 4.52 (1H, dd, J = 4.8, 11.2 Hz, H-6), 4.36 (1H,
dd, J = 10.8, 11.2 Hz, H-6), 4.21 (1H, dd, J = 10.4, 10.8 Hz, H-3), 3.84
(1H, dd, J = 2.8, 6.0 Hz, H-1), 3.78 (1H, dd, J = 6.0, 10.4 Hz, H-4),
3.33 (3H, s), 3.23 (3H, s), 3.19 (1H, dd, J = 3.2, 10.8 Hz, H-2), 2.26−
2.37 (2H, m, H-5 and H-5a), 2.04 (3H, s, CH3CO), 1.28−1.36 (1H,
m, H-5a), 1.32 (3H, s), 1.26 (3H, s); 13C NMR (100 MHz, CDCl3) δ
170.9, 137.8, 128.5, 127.9, 127.8, 99.9, 99.8, 76.6, 72.3 70.2, 66.3, 64.1,
63.0, 48.4, 48.1, 35.8, 26.2, 21.1, 17.9, 17.7; EI-HRMS (m/z) calcd for
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: mnitz@chem.utoronto.ca.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful for financial support from the
Canadian Institutes of Health Research (CIHR) no. 89708.
+
C22H35N4O7 [M + NH4 ] 467.2506, found 467.2519.
REFERENCES
■
1-O-Benzyl-3,4-O-(2,3-dimethoxybutane-2,3-diyl)-5a-carba-β-L-
gulopyranose (22). In the same manner as 9, compound 22 was
synthesized as a white foam (0.15 g, 98%) from compound 8 (0.20 g,
0.40 mmol) and DDQ (0.11 g, 0.48 mmol) in CH2Cl2 (6.6 mL) and
distilled water (0.4 mL). 22: Rf = 0.29 (ethyl acetate/hexane 1:1);
(1) (a) Kitaoka, M.; Ogawa, S.; Taniguchi, H. Carbohydr. Res. 1993,
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28.0
1
[α]D = 132.5° (c 0.15, CHCl3); H NMR (400 MHz, CDCl3) δ
7.26−7.36 (5H, m), 4.59 (1H, d, J = 12.0 Hz), 4.48 (1H, d, J = 12.0
Hz), 4.20−4.29 (2H, m, H-6 and H-4), 4.12 (1H, dd, J = 2.8, 10.8 Hz,
H-3), 4.02 (1H, dd, J = 2.4, 2.8 Hz, H-2), 3.67 (1H, dd, J = 3.2, 5.6 Hz,
H-1), 3.54 (1H, ddd, J = 3.6, 10.8, 11.2 Hz, H-6), 3.23 (3H, s), 3.21
(3H, s), 3.07 (1H, d, J = 10.0 Hz, OH), 2.60 (1H, br, OH), 2.26−2.34
(1H, m, H-5), 1.99 (1H, ddd, J = 3.2, 6.0, 15.2 Hz, H-5a), 1.80−1.87
(1H, m, H-5a), 1.28 (3H, s), 1.27 (3H, s); 13C NMR (100 MHz,
CDCl3) δ 138.3, 128.6, 127.8, 127.4, 100.0, 99.8, 76.9, 71.7, 70.3, 68.3,
66.4, 64.5, 48.0(2), 39.3, 27.0, 17.9, 17.8; EI-HRMS (m/z) calcd for
(3) Aoyama, H.; Ogawa, S.; Sato, T. Carbohydr. Res. 2009, 344, 2088.
(4) (a) McCasland, G. E.; Furuta, S.; Durham, L. J. J. Org. Chem.
1966, 31, 1516. (b) Suami, T.; Ogawa, S. Adv. Carbohydr. Chem.
Biochem. 1990, 48, 21. (c) Ferrier, R. J. Chem. Rev. 1993, 93, 2779.
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+
C20H34NO7 [M + NH4 ] 400.2335, found 400.2333.
(6) (a) Das, S. K.; Mallet, J. M.; Sinay, P. Angew. Chem., Int. Ed. 1997,
̈
3,4,6-Tri-O-acetyl-2-acetamido-2-deoxy-5a-carba-α-D-glucopyr-
anose (23). A suspension of compound 1 (46 mg, 0.11 mmol) and
Pd(OH)2 (10 mg, 20 wt % on carbon, wet) in EtOH (5 mL) was
stirred under 2.1 bar of H2 at 40 °C for 22 h. TLC (MeOH/CH2Cl2
1:10) showed that the starting material was consumed completely. The
mixture was filtered, and the filtrate was concentrated in vacuo. The
residue was purified by column chromatography (neat ethyl acetate to
MeOH/CH2Cl2 1: 15) to yield compound 23 (33 mg, 90%) as a
colorless oil. 23: Rf = 0.23 (MeOH/CH2Cl2 1:15); [α]D27.8 = 34.62° (c
0.10, MeOH); 1H NMR (400 MHz, CDCl3) δ 6.39 (1H, d, J = 8.8 Hz,
NH), 5.20 (1H, dd, J = 9.6, 10.8 Hz, H-3), 5.03 (1H, dd, J = 9.6, 11.2
Hz, H-4), 4.02−4.16 (3H, m, H-6 and H-2 and H-1), 3.90 (1H, dd, J =
3.2, 11.2 Hz, H-6), 3.10−3.30 (1H, br, OH), 2.34−2.45 (1H, m, H-5),
2.03 (3H, s), 2.00 (3H, s), 1.99 (3H, s), 1.95 (3H, s), 1.88−1.96 (1H,
m, H-5a), 1.66 (1H, ddd, J = 2.0, 12.8, 14.8 Hz, H-5a); 13C NMR (100
MHz, CDCl3) δ 171.8, 171.1, 170.5, 170.0, 72.7, 72.0, 67.7, 63.7, 54.4,
34.5, 32.4, 23.3, 20.90, 20.88, 20.8; EI-HRMS (m/z) calcd for
C15H24NO8 [M + H+] 346.1502, found 346.1503.
36, 493. (b) Sollogoub, M.; Mallet, J. M.; Sinay, P. Tetrahedron Lett.
1998, 39, 3471.
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(7) (a) Adam, S. Tetrahedron Lett. 1988, 29, 6589. (b) Iimori, T.;
Takahashi, H.; Ikegami, S. Tetrahedron Lett. 1996, 37, 649.
(8) (a) Vass, G.; Krausz, P.; Quiclet-Sire, B.; Delaumen
Cleophax, J.; Gero, S. D. C. R. Acad. Sci., Ser. II: Mec., Phys., Chim., Sci.
Terre Univers 1985, 301, 1345. (b) Barton, D. H. R.; Gero, S. D.; Augy-
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Dorey, S.; Quiclet-Sire, B. J. Chem. Soc., Chem. Commun. 1986, 1399.
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Delaumen
1990, 46, 215.
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y, J. M.; Gero, S. D.; Quiclet-Sire, B.; Stutz, P. Tetrahedron
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(9) (a) Ogawa, S.; Iwasawa, Y.; Nose, T.; Suami, T.; Ohba, S.; Ito,
M.; Saito, Y. J. Chem. Soc., Perkin Trans. 1 1985, 903. (b) Ogawa, S.;
Aoyama, H.; Sato, T. Carbohydr. Res. 2002, 337, 1979. (c) Ogawa, S.;
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(10) (a) Tadano, K.; Ueno, Y.; Fukabori, C.; Hotta, Y.; Suami, T.
Bull. Chem. Soc. Jpn. 1987, 60, 1727. (b) Seo, K.; Kwon, Y.; Kim, D.;
Jang, I.; Chu, J.; Chung, S. Chem. Commun. 2009, 1733.
(11) For references related to syntheses of carba-α-D-mannose
derivatives see: (a) Tadano, K.; Fukabori, C.; Miyazaki, M.; Kimura,
H.; Suami, T. Bull. Chem. Soc. Jpn. 1987, 60, 2189. (b) Shing, T. K. M.;
Cui, Y.; Tang, Y. J. Chem. Soc., Chem. Commun. 1991, 756.
(c) Dumortier, L.; Van der Eycken, J.; Vandewalle, M. Synlett 1992,
245. (d) Pingli, L.; Vandewalle, M. Synlett 1994, 228. (e) Sudha, A. V.
R. L.; Nagarajan, M. Chem. Commun. 1998, 925. (f) Williams, P. M.;
Sheldrake, G. N.; Macdonald, S. J. F.; Hamilton, C. J. Carbohydr. Res.
2011, 346, 1257. For references related to syntheses of carba-β-L-
idosamine derivatives, see refs 8b, c. For references related to
syntheses of carba-β-L-gulose derivatives see: (g) Pingli, L.;
2-Acetamido-2-deoxy-5a-carba-α-D-glucopyranose (24). To a
stirred solution of compound 23 (38 mg, 0.11 mmol) in anhydrous
MeOH (3 mL) was added catalytic sodium at room temperature. The
solution was stirred at room temperature for 4.5 h. The solution was
concentrated in vacuo, and the residue was purified by C18 column
(neat water to 5% CH3CN in water) to yield compound 24 (24 mg,
27.8
1
99%) as a gray powder. 24: [α]D = 36.28° (c 0.10, MeOH); H
NMR (400 MHz, MeOD) δ 3.99 (1H, m, H-1), 3.56−3.70 (4H, m),
3.28 (1H, dd, J = 8.4, 10.4 Hz), 2.00 (3H, s), 1.90−2.00 (1H, m, H-5),
1.84 (1H, ddd, J = 3.6, 3.6, 14.0 Hz, H-5a), 1.44 (1H, ddd, J = 2.4,
12.8, 14.4 Hz, H-5a); 13C NMR (100 MHz, MeOD) δ 173.6, 76.4,
74.2, 68.8, 64.5, 57.6, 39.6, 33.3, 22.8; EI-HRMS (m/z) calcd for
C9H18NO5 [M + H+] 220.1185, found 220.1180.
Vandewalle, M. Tetrahedron 1994, 50, 7061. (h) Gom
́
ez, A. M.;
Moreno, E.; Valverde, S.; Lopez, J. C. Tetrahedron Lett. 2002, 43, 5559.
́
7409
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3
compound 8 was supported by the JH−H coupling between pseudo
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3
LiAlH4, J4H−5H was 10.4 Hz. See the Experimental Section for
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