Application of the Wharton rearrangement for the de novo synthesis of pyranosides with ido, manno, and colito stereochemistry

Article abstract of DOI:10.1002/ejoc.201300051

A de novo asymmetric synthesis of α-ido-pyranosides, as well as several deoxy and amino variants, has been achieved. The procedure involves a palladium(0)-catalyzed glycosylation in combination with a Wharton rearrangement/epoxide-opening reaction sequence to access sugars with ido, manno, and colito stereochemistry as well as several azido analogues. A de novo asymmetric synthesis of α-ido-pyranosides, as well as several deoxy and amino variants, has been achieved. The procedure involves a palladium(0)- catalyzed glycosylation in combination with a Wharton rearrangement/epoxide- opening reaction sequence to access sugars with ido, manno, and colito stereochemistry as well as several azido analogues. Copyright

Full text of DOI:10.1002/ejoc.201300051

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FULL PAPER
DOI: 10.1002/ejoc.201300051
Application of the Wharton Rearrangement for the de novo Synthesis of
Pyranosides with ido, manno, and colito Stereochemistry
Michael F. Cuccarese,[a] Hua-Yu Leo Wang,[a] and George A. O’Doherty*[a]
Keywords: Carbohydrates / Glycosylation / Rearrangement / Palladium / Epoxides
A de novo asymmetric synthesis of α-ido-pyranosides, as well
as several deoxy and amino variants, has been achieved. The
procedure involves a palladium(0)-catalyzed glycosylation in
combination with a Wharton rearrangement/epoxide-open-
ing reaction sequence to access sugars with ido, manno, and
colito stereochemistry as well as several azido analogues.
aculose can be further functionalized through a series of
post-glycosylation transformations to access different po-
lyol stereoisomers. Most commonly, this involves ketone re-
duction and double-bond dihydroxylation to install
mannose stereochemistry.[9] In addition, we have used epox-
idation and nucleophilic ring-opening for the net anti instal-
lation of two hydroxy groups across the C-2/C-3 olefin.[10]
We then envisioned the use of the Wharton rearrangement,
which stereoselectively converts an α,β-epoxide ketone into
an unsaturated alcohol via a hydrazone intermediate.[11] We
have demonstrated the use of the Wharton rearrangement
as a key step in the conversion of aculo sugar 1 into allyl
alcohol 3, which in turn provided access to sugars with al-
tro, allo, galacto, and ascarylo stereochemistry.[12] Herein we
describe our efforts to extend this strategy to the epoxid-
ation of the pyran C-3/C-4 double bond, arriving at epoxide
4, to access idose and its related C-3 deoxy sugar congeners
(Scheme 1).
Introduction
Although rare in nature, sugars with ido stereochemistry
are present in many natural products, such as heparins and
dermatan sulfates (l-iduronic acid),[1] the antibiotic neomy-
cin (2,6-dideoxydiamino-idose), and labdane diterpenes (6-
deoxy-idose).[2] Despite its occurrence in biologically im-
portant structural motifs, idose can be prohibitively expens-
ive and is only available in its l configuration. As a result,
there has been considerable interest in the synthesis of ido-
pyranosides. A preponderance of these routes start with
commonly found sugar diastereomers and rely on the use
of inversion and epimerization reactions to install the ido
stereochemistry. For example, l-idose has been synthesized
by bis-inversion of the C-2 and C-3 positions of d-galact-
ose[3] or by epimerization of the C-5 position of d-glucose
in its pyranose[4] and furanose forms.[5] Similarly, a route
starting with l-ascorbic acid has also been used to prepare
idose by a late-stage Sharpless dihydroxylation strategy to
install the critical hydroxy groups.[6]
As part of a larger effort aimed at the development of a
generalized strategy for the synthesis of natural and unnatu-
ral oligosaccharide structural motifs, we have endeavored to
find new approaches to either enantiomer of rare sugars.[7]
These de novo asymmetric approaches rely on the use of
asymmetric catalysis in combination with a highly dia-
stereoselective palladium-catalyzed glycosylation and post-
glycosylation strategy.[8] The assembly of the absolute α/β
and d/l sugar stereochemistry involves the use of Noyori
asymmetric reduction, Achmatowicz rearrangement, and
diastereoselective carbonate formation to transform acyl-
furan 1 into aculo sugar 2 (Scheme 1). The enone moiety of
Scheme 1. Wharton rearrangement strategy.
[a] Department of Chemistry and Chemical Biology, Northeastern
University,
360 Huntington Ave, Boston, MA 02132, USA
Fax: +1-617-373-8795
E-mail: G.ODoherty@neu.edu
We envisioned our synthetic strategy (Scheme 2) begin-
ning with the achiral acylfuran 1, which could be asymmet-
rically converted into epoxide ketone 5. Wharton rearrange-
Homepage: http://www.northeastern.edu/odoherty
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300051.
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M. F. Cuccarese, H.-Y. L. Wang, G. A. O’Doherty
FULL PAPER
ment and epoxidation of 5 should produce epoxide alcohol in the presence of a catalytic amount of NaOH. These ep-
4, which, depending on the regioselectivity, could be opened oxide ketones 5 were treated with hydrazine to produce the
to give sugars with either ido or manno stereochemistry.
corresponding epoxide hydrazone, which, upon addition of
acetic acid, rearranged to allylic alcohols 10a and 10b. Hy-
droxy-directed epoxidation with mCPBA resulted in epox-
ide alcohols 4a and 11 as single diastereomers.[15] TBS-pro-
tected epoxide alcohol 11 was deprotected by using catalytic
pTsOH to arrive at 6-hydroxy epoxide alcohol 4b.
We next explored the versatility of epoxide alcohol 4a in
the synthesis of the 3-deoxy sugar by using epoxidation/
epoxide-opening chemistry (Scheme 4). Treatment of epox-
ide alcohol 4a with LiAlH4 gave the expected trans-diaxial
ring-opened product 2-epi-colitose 6.[16] Interestingly, the
same regioselective opening was also observed under Lewis
acid conditions. For example, treatment of epoxide alcohol
4a with MgBr2·Et2O promoted regioselective epoxide ring-
opening to form bromide 12. The axial bromide was cleanly
removed to give 6 by AIBN-promoted (Me3Si)3SiH radical
reduction.
Scheme 2. Retrosynthetic approach to sugars with ido or manno
stereochemistry.
Results and Discussion
As we have previously reported, Boc-pyranones 9a and
9b were obtained optically pure from furans 1a and 1b in
three steps by Noyori atom-transfer asymmetric re-
duction[13] [formic acid/Et3N, (R)-Ru(η6-mesitylene)-(S,S)-
TsDPEN], Achmatowicz cyclization (NBS, H2O), and tert-
butoxycarbonylation with Boc2O (Scheme 3).[14] Palladium-
catalyzed glycosylation with benzyl alcohol resulted in
Scheme 4. Synthesis of 2-epi-colitose.
Presumably, the difficulty associated with the synthesis
benzyl pyranones 2a and 2b. Epoxides 5a and 5b were ob- of ido-pyranosides is associated with the three axial hydroxy
tained by nucleophilic epoxidation with hydrogen peroxide substituents at the 2-, 3-, and 4-positions. Building upon
Scheme 3. Synthesis of epoxide alcohols by the Wharton rearrangement.
2
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Synthesis of ido, manno, and colito Pyranosides
Table 1. Optimization of the reaction conditions for the epoxide ring-opening 4a and 4b.
[a] Entries 2–4 were performed in 0.2 mmol of epoxide alcohol in 1 m of solvent with 10 mol-% of Lewis acid; entries 5–7 were performed
in 0.1 mmol of epoxide alcohol in 0.1 m of solvent with excess reagents (Ͼ10 equiv.) and NH4Cl (3 equiv.). [b] Isolated combined yield.
[c] The ratio is based on crude NMR analysis. [d] The yields and ratios of the 6-oxy variants were determined based on the peracylated
product. [e] MeOH/H2O (v/v, 8:1). [f] 0.5 mL of a 2 m NaOH solution was used.
the success achieved in the ring opening of epoxide 4a to in 81% yield (entry 9). Unfortunately, this effect on regiose-
give 12 with ido stereochemistry, we envisioned that the re- lectivity disappears when applied to hexoses with 6-hydroxy
maining 3,4-trans-diol of idose could be installed through a groups. Thus, when 4b was exposed to identical aqueous
similar trans diaxial ring-opening of epoxide 4a (i.e., Fürst– NaOH conditions, the manno isomer 13b was favored over
Plattner rule).[17] Our initial attempts to open the epoxide the ido isomer 7b in a ratio of 2:1. This loss of regioselectiv-
with Sc(OTf)3 in AcOH failed to give the desired ido sugars ity could be the result of chelation to the free 6-hydroxy
7a and 7b, instead giving exclusively the rhamno isomers group, which overrides the stereoelectronic effects that gov-
13a and 13b, the unusual product of trans diequatorial ep- ern the opening of 4b.
oxide ring-opening (Table 1, entry 1). Other Lewis acids
Similar regioselectivity patterns were found when the hy-
were also examined (i.e., BF3, AlCl3, and InCl3), however, droxide nucleophile was changed to an azide anion
BF3 (entry 3) resulted in only the rhamno sugars 13a and (Scheme 5), and again the 6-hydroxy group displayed a pro-
13b and the other Lewis acids failed to react (entries 4 and found effect on the regioselective epoxide ring-opening.
5).
Thus, when epoxy alcohol 4a was heated at reflux with
In contrast, switching to less Lewis acidic conditions had NaN3/NH4Cl in DMF at 65 °C, a 3:1 ratio of the regioiso-
a positive effect upon the regioselectivity of the epoxide mers 3-azido-3,6-dideoxy-idose 8a and 4-azido-4-deoxy-
ring-opening. For example, when LiOAc was used (entry 6), rhamnose 14a was observed.[18] In contrast, when epoxide
the regiopreference was switched to a 2:1 ratio with the
major isomer having idose stereochemistry. The stereo-
chemistry of the ido-pyranoside was confirmed by 1H NMR
analysis, which revealed a distinct difference in the H4,H5
and H4,H3 couplings compared with those in rhamno-pyr-
anoside; J4,5 = 3.2 Hz and J4,3 = 5.2 Hz for the ido-pyranos-
ide and J4,5 = 9.6 Hz and J4,3 = 9.6 Hz for the rhamno-
pyranoside. Changing the Lewis acidity of the counterion
(Na and Mg) increased the yield of the reaction without
changing the selectivity towards idose 7a (entries 6–8). Fi-
nally, switching to basic conditions seemed to have the most
profound effect. Thus, treatment of 3a with aqueous NaOH
at 90 °C resulted in 6-deoxy-idose 7a as the major isomer Scheme 5. Synthesis of amino glycoside variants.
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4b with a 6-hydroxy group was treated under the same con- ido and rhamno sugars 16 and 13a, respectively. Interest-
ditions (NaN3/NH4Cl, DMF, 65 °C), a 1:3 ratio of regioiso- ingly, the 2-acetyl group in the rhamno sugar 13a was also
mers was obtained with the manno isomer 14b being the hydrolyzed concomitantly during the displacement of trifl-
major isomer.
ate. Finally, the desired ido sugar 7a was obtained after the
In an alternative approach to the synthesis of ido-py- removal of the 2-acetyl group in 16 by K2CO3 hydrolysis.
ranoside, we envisioned that regioselective 4-OH epimeri-
zation of altrose could afford the desired ido stereochemistry.
This route began with the 2-acylated altro sugar 15, which
was prepared from 10a in a two-step acylation/dihydrox-
ylation sequence (Scheme 6). Unfortunately, all attempts to
Conclusions
Highly enantio- and diastereoselective routes for the
preparation of various 3-, 4-, and 6-deoxy-pyranosides have
been developed. We found that several unusual and deoxy
sugars could be obtained by incorporating the Wharton re-
arrangement into our post-glycosylation transformation
strategy. These sugars include 2-epi-colito- and 6-deoxy-ido-
pyranosides. Importantly, these sugars can be prepared as
either the d or l enantiomeric series by selecting either en-
antiomeric form of the Noyori catalyst (R,R) or (S,S). The
route allows for the divergent synthesis of a diverse range
of sugars from an advanced-stage intermediate. We believe
that this approach will be particularly useful for medicinal
chemists. Further work exploring the potential of this strat-
egy in medicinal chemistry[19] and for developing oligosac-
charides is underway.
regioselectively invert the 4-hydroxy group under Mitsu-
nobu-like conditions failed to give products with ido stereo-
chemistry (e.g., 16).
Scheme 6. Attempts at regioselective Mitsunobu inversion for the
synthesis of ido-pyranoside.
Experimental Section
General: Commercial reagents and solvents were used without fur-
ther purification, unless otherwise stated. Rf values are reported for
analytical TLC using the specified solvents and 0.25 mm EMD sil-
ica gel 60 F254 plates that were visualized by UV irradiation
(254 nm) or by staining (465 mL of 95% EtOH, 17 mL of conc.
H2SO4, 5 mL of acetic acid, and 13 mL of anisaldehyde). Solvents
We next explored the use of regioselective acylation con-
ditions (Scheme 7) with the aim of selectively functionaliz-
ing and epimerizing the 4-OH position of diol 15. Unfortu-
nately, all efforts to purify the sulfonylate products led to
decomposition. Thus, we turned to a one-pot protocol. To
this end, altro-pyranoside 15 was subjected to tin–acetal- were removed by rotary evaporation, followed by further drying of
the residual products under high vacuum. Column chromatography
was performed on 40–63 μm silica gel using flash column
forming conditions followed by in situ triflation (Tf2O,
CH2Cl2, 0 °C), which gave a mixture of triflates 17a and
17b (Scheme 7). The triflate groups in 17a and 17b were
then displaced by nitrite ions to generate a 6:1 ratio of the
chromatography. NMR spectra using
a Varian Unity Inova
600 MHz, Varian 400 MHz NMR spectrometer and Joel 270 MHz
NMR spectrometer. 1H NMR spectra in CDCl3 were referenced at
δ = 7.26 ppm. 13C NMR spectra in CDCl3 were referenced at δ =
77.23 ppm. 1H NMR spectra in CD3OD were referenced at δ =
3.31 ppm. 13C NMR spectra in CD3OD were referenced at δ =
49.00 ppm. FT-IR spectra were recorded with a PerkinElmer 100
Series FT-IR spectrophotometer with a polarized Universal Atten-
uated Total Reflectance (UATR) sampling accessory. Melting
points were determined with a capillary melting-point apparatus
by Mel-Temp® S2 equipped with a digital thermometer by Fluke
Corporation. The melting points were directly reported from the
digital thermometer with no prior correction for the apparatus used
in this experimental section. The specific rotation for an optically
active substance, where α is the observed angle of optical rotation,
T is a temperature, λ is the wavelength in nanometers, was mea-
sured with a Jasco P-2000 Polarimeter equipped with a sodium D
line (λ = 589 nm) light source. Each optically active substance in
solution (concentration c in g/100 mL) was measured in a cylindri-
cal glass cell (model number CG3-50, inner diameter 3.5 mm, path
length 0.5 dm). High resolution mass spectrometric analyses were
performed with an FT mass spectrometer.
Scheme 7. Triflation and SN2 displacement for the synthesis of 6-
deoxy-idose.
4
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Synthesis of ido, manno, and colito Pyranosides
Synthetic Procedures
IR (thin film): ν = 3396, 2979, 2932, 1454, 1095, 1043, 974 cm–1.
˜
1H NMR (400 MHz, CDCl3): δ = 7.38–7.28 (m, 5 H, Ar), 4.82 (s,
1 H, CH), 4.75 (d, J = 12.0 Hz, 1 H, CH), 4.56 (d, J = 12.0 Hz, 1
H, CH), 3.98 (q, J = 6.4 Hz, 1 H, CH), 3.74 (d, J = 5.6 Hz, 1 H,
OH), 3.64 (s, 1 H, OH), 3.32 (d, J = 7.6 Hz, 1 H, CH), 2.80 (d, J
= 6.4 Hz, 1 H, CH), 2.05 (br., 1 H, CH), 1.25 (d, J = 6.8 Hz, 3 H,
CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 137.8, 128.7 (2 C),
128.1 (2 C), 128.0, 99.5, 69.3, 68.5, 66.75, 66.68, 31.3, 17.1 ppm.
HRMS (ESI): calcd. for [C13H17DO4Na]+ 262.1160; found
262.1160.
2H-Pyran-3-ol 4a: A solution of allylic alcohol 10a (500 mg,
2.27 mmol) in CH2Cl2 (23 mL) was cooled to 0 °C and NaHCO3
(858 mg, 10.2 mmol) was added in one portion. 4-Chloroper-
oxybenzoic acid (mCPBA; 1.6 g, 9.1 mmol) was dissolved in warm
CH2Cl2 (5 mL) and added in several portions to the reaction mix-
ture at 30 min intervals. The reaction was stirred and slowly
warmed to room temperature overnight. A small portion of the
reaction mixture was removed and filtered to remove the benzoic
acid byproduct. The eluent was concentrated and monitored by
NMR for reaction completion. Additional mCPBA should be
added if the reaction has not yet reached completion. Upon com-
pletion, the reaction was poured into a separating funnel contain-
ing a layer of 10% aqueous Na2CO3 and CH2Cl2. The mixture was
extracted with CH2Cl2 (2ϫ 25 mL) and dried with Na2SO4. The
compound was then filtered and concentrated under reduced pres-
sure. The crude material was purified by silica gel flash chromatog-
raphy eluting with 15% EtOAc in hexanes to give 4a (395 mg,
1.67 mmol, 74%) as a colorless oil. Rf (30% EtOAc in hexanes) =
3-Bromo-3,6-dideoxy-L-idose 12: MgBr2·OEt2 (60 mg, 0.233 mmol)
was added in one portion to a solution of epoxy alcohol 4a (50 mg,
0.212 mmol) in AcOH (0.7 mL) at room temperature. The reaction
was stirred at room temperature overnight. Upon completion the
reaction mixture was cooled to 0 °C and diluted with EtOAc fol-
lowed by quenching with a cold satd. NaHCO3 solution. The mix-
ture was extracted with EtOAc (3ϫ 10 mL) and a satd. NaCl solu-
tion and dried with Na2SO4. The compound was then filtered and
concentrated under reduced pressure. The crude product was puri-
fied by silica gel flash chromatography eluting with 10–13% EtOAc
in hexanes to give 12 (48 mg, 0.15 mmol, 72%) as a colorless oil.
Rf (30% EtOAc in hexanes) = 0.17. [α]2D5 = –58.3 (c = 0.97,
0.27. [α]2D3 = –114.2 (c = 1.0, CH Cl ). IR (thin film): ν = 3452,
˜
2
2
3030, 2983, 2933, 1071, 1043, 1009, 746, 701 cm–1. 1H NMR
(600 MHz, CDCl3): δ = 7.37–7.29 (m, 5 H, Ar), 4.70 (d, J =
12.0 Hz, 1 H, CH), 4.64 (s, 1 H, CH), 4.51 (d, J = 12.0 Hz, 1 H,
CH), 4.11 (q, J = 6.6 Hz, 1 H, CH), 3.81 (d, J = 5.4 Hz, 1 H, CH),
3.55 (ddd, J = 4.2, 4.2, 1.2 Hz, 1 H, CH), 3.22 (dd, J = 4.2, 1.2 Hz,
1 H, CH), 2.50 (br., 1 H, OH), 1.36 (d, J = 6.6 Hz, 3 H, CH3) ppm.
13C NMR (150 MHz, CDCl3): δ = 137.3, 128.7 (2 C), 128.23,
128.18 (2 C), 98.6, 69.6, 63.3, 61.5, 54.9, 51.9, 17.5 ppm. HRMS
(ESI): calcd. for [C13H16O4Na]+ 259.0941; found 259.0939.
CH Cl ). IR (thin film): ν = 3419, 3064, 3031, 2980, 2934, 1455,
˜
2
2
1
1039, 736, 698 cm–1. H NMR (400 MHz, CDCl3): δ = 7.40–7.28
(m, 5 H, Ar), 4.83 (d, J = 12.0 Hz, 1 H, CH), 4.82 (s, 1 H, CH),
4.58 (d, J = 12.0 Hz, 1 H, CH), 4.45 (dq, J = 6.4, 2.0 Hz, 1 H,
CH), 4.17 (dd, J = 4.4, 3.6 Hz, 1 H, CH), 3.89 (m, 1 H, OH), 3.85
(m, 1 H, OH), 2.91 (d, J = 5.6 Hz, 1 H, CH), 2.66 (d, J = 6.8 Hz, 1
H, CH), 1.25 (d, J = 6.8 Hz, 3 H, CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 137.5, 128.7 (2 C), 128.0, 127.9 (2 C), 99.4, 72.4, 71.1,
70.2, 64.7, 49.5, 15.4 ppm. HRMS (ESI): calcd. for
[C13H17BrO4Na]+ 339.0202, 341.0182; found 340.1332, 341.0183.
2-epi-L-Colitose 6: A suspension of LiAlH4 (65 mg, 1.71 mmol) in
dry THF (1.0 mL) was added dropwise to a solution of epoxy
alcohol 4a (135 mg, 0.57 mmol) in dry THF (2.0 mL) at –78 °C
under argon. The reaction was stirred at –78 °C and monitored by
TLC for reaction completion. Upon completion the reaction mix-
ture was warmed to 0 °C and quenched with ice-cold water, ex-
tracted with EtOAc (3ϫ 10 mL) and a satd. NaCl solution, and
dried with Na2SO4. The compound was then filtered and concen-
trated under reduced pressure. The crude product was purified by
silica gel flash chromatography eluting with 25% EtOAc in hexanes
to give 6 (110 mg, 0.46 mmol, 81%) as a colorless oil. Rf (30%
EtOAc in hexanes) = 0.25. [α]2D3 = –74.3 (c = 1.0, MeOH). IR (thin
2-epi-L-Colitose 6 from Idose 12: (Me3Si)3SiH (0.1 mL, 0.322 mmol)
and solid AIBN (5 mg, 0.03 mmol) were added in one portion to
a solution of 3-bromo-diol 12 (45 mg, 0.142 mmol) in anhydrous
toluene (1.5 mL) at 0 °C. The inert atmosphere was secured by
freeze/thaw vacuum pump followed by repurging with argon gas.
This procedure was repeated three times. The mixture was then
heated at reflux at 75 °C for 1 h with monitoring by TLC for com-
pletion. The reaction mixture was then cooled to room temperature
and directly purified by silica gel flash chromatography, eluting
with 25% EtOAc in hexanes to give 6 (25 mg, 0.10 mmol, 76%) as
a colorless oil. Rf (30% EtOAc in hexanes) = 0.25. [α]2D3 = –74.3 (c
film): ν = 3384, 2931, 1118, 1049 cm–1. 1H NMR (400 MHz,
˜
= 1.0, MeOH). IR (thin film): ν = 3384, 2931, 1118, 1049 cm–1. 1H
CDCl3): δ = 7.38–7.28 (m, 5 H, Ar), 4.81 (s, 1 H, CH), 4.74 (d, J
= 12.0 Hz, 1 H, CH), 4.55 (d, J = 12.0 Hz, 1 H, CH), 3.97 (q, J =
6.4 Hz, 1 H, CH), 3.75 (br., 2 H, OH), 3.62 (br., 1 H, CH), 3.27
(d, J = 6.4 Hz, 1 H, CH), 2.06 (m, 2 H, CH2), 1.24 (d, J = 6.8 Hz,
3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 137.7, 128.6 (2
C), 128.1 (2 C), 128.0, 99.4, 69.2, 68.4, 66.8, 66.6, 31.6, 17.1 ppm.
HRMS (ESI): calcd. for [C13H18O4Na]+ 261.1097; found 261.1094.
˜
NMR (400 MHz, CDCl3): δ = 7.38–7.28 (m, 5 H), 4.81 (s, 1 H),
4.74 (d, J = 12.0 Hz, 1 H), 4.55 (d, J = 12.0 Hz, 1 H), 3.97 (q, J =
6.4 Hz, 1 H), 3.75 (br., 2 H), 3.62 (br., 1 H), 3.27 (d, J = 6.4 Hz, 1
H), 2.06 (m, 2 H), 1.24 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 137.7, 128.6 (2 C), 128.1 (2 C), 128.0, 99.4,
69.2, 68.4, 66.8, 66.6, 31.6, 17.1 ppm.
6-Deoxy-L-idose 7a and -L
-rhamnose 13a:[18] A mixture of epoxy
6-Deuterio-2-epi-L-colitose: A suspension of LiAlD4 (32 mg,
alcohol 4a (25 mg, 0.106 mmol) and 2 m NaOH (0.5 mL) in
MeOH/H2O (1.0 mL, 8:1, v/v) was heated at reflux at 90 °C for
2 d. Upon completion monitoring by TLC, the reaction mixture
was filtered through a pad of Celite eluting with 25% MeOH in
EtOAc solution. The concentrated crude material was purified by
silica gel flash chromatography eluting with 55% EtOAc in hexanes
to give 7a (18.4 mg, 0.072 mmol, 68%) and 13a (3.5 mg,
0.013 mmol, 13%) as colorless oil.
0.76 mmol) in dry THF (0.5 mL) was added dropwise to a solution
of epoxy alcohol 4a (45 mg, 0.19 mmol) in dry THF (0.6 mL) at
–78 °C under argon. The reaction was stirred at –78 °C and moni-
tored by TLC for reaction completion. Upon completion the reac-
tion mixture was warmed to 0 °C and quenched with ice-cold water,
extracted with EtOAc (3ϫ 10 mL) and a satd. NaCl solution, and
dried with Na2SO4. The compound was then filtered and concen-
trated under reduced pressure. The crude product was purified by
silica gel flash chromatography eluting with 20–22% EtOAc in hex-
anes to give 6-D (40 mg, 0.17 mmol, 88%) as a colorless oil. Rf
(30% EtOAc in hexanes) = 0.25. [α]2D5 = –85.2 (c = 1.0, CH2Cl2).
6-Deoxy-idose 7a: Rf (80% EtOAc in petroleum ether) = 0.23.
[α]2D3 = –90.5 (c = 0.65, CH Cl ). IR (thin film): ν = 3452, 3030,
˜
2
2
2983, 2933, 1071, 1043, 1009, 746, 701 cm–1. H NMR (400 MHz,
1
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Date: 09-04-13 16:24:33
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M. F. Cuccarese, H.-Y. L. Wang, G. A. O’Doherty
FULL PAPER
CD3OD): δ = 7.40–7.26 (m, 5 H, Ar), 4.75 (d, J = 12.4 Hz, 1 H, (3 ϫ 15 mL). The organic extract was then washed with satd.
CH), 4.72 (d, J = 4.0 Hz, 1 H, CH), 4.58 (d, J = 12.4 Hz, 1 H, NaHCO3 and brine, and dried with Na2SO4. The compound was
CH), 4.20 (dq, J = 6.8, 3.2 Hz, 1 H, CH), 3.72 (dd, J = 5.2, 5.2 Hz, filtered and concentrated under reduced pressure. The crude prod-
1 H, CH), 3.50 (dd, J = 5.2, 4.0 Hz, 1 H, CH), 3.46 (dd, J = 5.2,
uct was purified by silica gel flash chromatography eluting with
3.2 Hz, 1 H, CH), 1.20 (d, J = 6.8 Hz, 3 H, CH3) ppm. 13C NMR 5% EtOAc in hexanes to give the allylic acetate of 10a (440 mg,
(100 MHz, CD3OD): δ = 139.1, 129.4 (2 C), 129.2 (2 C), 128.8, 1.68 mmol, 99%) as a colorless oil. Rf (30% EtOAc in hexanes) =
101.1, 73.2, 72.4, 71.8, 70.6, 66.6, 15.6 ppm. HRMS (ESI): calcd.
0.75. [α]2D3 = –239.0 (c = 1.63, CH Cl ). IR (thin film): ν = 2978,
˜
2 2
for [C13H18O5Na]+ 277.1046; found 277.1046.
2934, 2872, 1734, 1370, 1232, 1025, 736, 700 cm–1 1H NMR
.
(400 MHz, CDCl3): δ = 7.38–7.28 (m, 5 H, Ar), 5.99 (d, J =
10.0 Hz, 1 H, CH), 5.84 (dd, J = 10.0, 4.8 Hz, 1 H, CH), 4.97 (d,
J = 4.4 Hz, 1 H, CH), 4.95 (s, 1 H, CH), 4.79 (d, J = 12.0 Hz, 1
H, CH), 4.62 (d, J = 12.0 Hz, 1 H, CH), 4.35 (q, J = 6.8 Hz, 1 H,
CH), 2.07 (s, 3 H, Ac), 1.32 (d, J = 6.8 Hz, 3 H, CH3) ppm. 13C
NMR (100 MHz, CDCl3): δ = 170.4, 137.4, 136.2, 128.5 (2 C),
127.9, 127.9 (2 C), 119.6, 97.1, 70.0, 65.7, 63.7, 21.2, 20.3 ppm.
HRMS (ESI): calcd. for [C15H18O4Na]+ 285.1097; found 285.1097.
Benzyl-rhamnose 13a: Rf (EtOAc) = 0.33. [α]2D3 = –60.0 (c = 0.38,
CH2Cl2); [α]2D5 = –84.0 (c = 1.19, MeOH). IR (thin film): ν = 3375,
˜
2974, 2911, 1454, 1384, 1046, 979 cm–1. 1H NMR (400 MHz,
CD3OD): δ = 7.35–7.26 (m, 5 H, Ar), 4.76 (d, J = 1.6 Hz, 1 H,
CH), 4.69 (d, J = 12.0 Hz, 1 H, CH), 4.51 (d, J = 12.0 Hz, 1 H,
CH), 3.82 (dd, J = 3.6, 2.8 Hz, 1 H, CH), 3.68 (dd, J = 9.6, 2.8 Hz,
1 H, CH), 3.62 (dq, J = 9.6, 6.8 Hz, 1 H, CH), 3.39 (dd, J = 9.6,
9.6 Hz, 1 H, CH), 1.27 (d, J = 6.8 Hz, 3 H, CH3) ppm. 13C NMR
(100 MHz, CD3OD): δ = 139.1, 129.4 (2 C), 129.1 (2 C), 128.8,
100.8, 74.0, 72.4, 72.3, 70.0, 18.0 ppm. HRMS (ESI): calcd. for
[C13H18O5Na]+ 277.1046; found 277.1046.
(2R,3R,4S,5R,6S)-2-(Benzyloxy)-4,5-dihydroxy-6-methyltetrahydro-
2H-pyran-3-yl Acetate (15): A solution of N-methylmorpholine N-
oxide/water (50 % w/v, 1.7 mL) was added to a tBuOH/acetone
(5.5 mL, 1:1, v/v) solution of the allylic acetate derivative of 10a
(440 mg, 1.68 mmol) at 0 °C. Crystalline OsO4 (4.3 mg, 1 mol-%)
was added rapidly and the reaction mixture stirred at 0 °C until
TLC showed complete conversion. The reaction mixture was then
concentrated under reduced pressure and directly loaded onto silica
gel flash chromatography eluting with 75% EtOAc in hexanes to
obtain 15 (457 mg, 1.54 mmol, 92%) as a colorless oil. Rf (50%
EtOAc in hexanes) = 0.35. [α]2D6 = –75.0 (c = 1.07, CH2Cl2). IR
3,6-Dideoxy-3-azido-L-idose 8a and 3-Deoxy-3-azido-L-rhamnose
14a: A mixture of epoxy alcohol 4a (82 mg, 0.347 mmol), NaN3
(90 mg, 1.4 mmol), and NH4Cl (20 mg, 0.372 mmol) in DMF
(5.0 mL) was heated at reflux at 65 °C for 3 d. Upon completion
monitoring by TLC, the reaction mixture was cooled to room tem-
perature and poured into a mixture of EtOAc and a satd. NaHCO3
solution. The mixture was extracted with EtOAc (3ϫ 10 mL) and
a satd. NaCl solution and dried with Na2SO4. The compound was
then filtered and concentrated under reduced pressure. The crude
product was purified by silica gel flash chromatography with gradi-
ent elution from 0–20% EtOAc in hexanes to give 8a (45 mg,
0.161 mmol, 46%) as an oil with 15% EtOAc/hexanes as eluent
and 4-azido-4-deoxy-rhamnose 14a (14 mg, 0.05 mmol, 14%) as a
white amorphous solid with 18% EtOAc/hexanes as eluent with a
regioisomeric ratio of 8a/14a = 3:1.
(thin film): ν = 3477, 2972, 2934, 1740, 1372, 1232, 1053, 740,
˜
700 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.38–7.28 (m, 5 H),
5.04 (d, J = 3.6 Hz, 1 H), 4.85 (s, 1 H), 4.73 (d, J = 12.0 Hz, 1 H),
4.55 (d, J = 12.0 Hz, 1 H), 3.89 (br., 1 H), 3.79 (dq, J = 9.6, 6.8 Hz,
1 H), 3.42 (dd, J = 9.6, 2.8 Hz, 1 H), 3.34 (br., 1 H), 2.56 (br., 1
H), 2.08 (s, 3 H), 1.36 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 169.8, 136.3, 128.8 (2 C), 128.5, 128.3 (2
C), 96.6, 70.2, 70.1, 69.9, 68.6, 64.7, 21.1, 17.7 ppm. HRMS (ESI):
calcd. for [C15H20O6Na]+ 319.1152; found 319.1152.
8a: Rf (30% EtOAc in hexanes) = 0.27. [α]2D3 = –127.6 (c = 1.05,
CH Cl ). IR (thin film): ν = 3413, 2934, 2913, 2107, 1082, 1041,
˜
2
2
980, 738, 698 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.37–7.28
(m, 5 H, Ar), 4.80 (d, J = 12.0 Hz, 1 H, CH), 4.79 (s, 1 H, CH),
4.57 (d, J = 12.0 Hz, 1 H, CH), 4.20 (dq, J = 6.4, 2.0 Hz, 1 H,
CH), 3.83 (dd, J = 5.2, 4.4 Hz, 1 H, CH), 3.71 (m, 1 H, OH), 3.50
(m, 1 H, OH), 3.32 (d, J = 5.6 Hz, 1 H, CH), 2.94 (d, J = 6.0 Hz, 1
H, CH), 1.24 (d, J = 6.8 Hz, 3 H, CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 137.4, 128.7 (2 C), 128.08, 128.04 (2 C), 98.8, 70.3,
70.0, 68.8, 64.7, 61.5, 15.4 ppm. HRMS (ESI): calcd. for
[C13H17N3O4Na]+ 302.1111; found 302.1112.
6-Deoxy-L-idose-3-acetate 16: A mixture of diol 15 (200 mg,
0.675 mmol) and n-Bu2SnO (504 mg, 2.02 mmol) in anhydrous tol-
uene (10 mL) was heated at reflux at 135 °C for 4 h. After cooling
to room temperature, water and toluene were removed azerotrop-
ically with CH2Cl2 (2ϫ 10 mL) under reduced pressure. The crude
stannyl acetal in CH2Cl2 (3 mL) at 0 °C was added dropwise to
triflic anhydride (0.25 mL, 1.37 mmol) solution in CH2Cl2 (1 mL)
and the mixture was stirred at 0 °C. After TLC monitoring for
completion, which occurred within 1 h, the reaction mixture was
quenched with ice-cold water and extracted with CH2Cl2 (3 ϫ
10 mL). The organic extract was then washed with a satd. NaHCO3
solution and brine, and dried with Na2SO4. The reaction mixture
was then filtered and concentrated under reduced pressure. NaNO2
(200 mg, 2.90 mmol) was added the crude material in DMF (3 mL)
at room temperature and stirred overnight. It was then poured into
a separating funnel containing a mixture of water and EtOAc. The
organic extract was washed with water (2ϫ 10 mL) and dried with
Na2SO4. The mixture was filtered, concentrated under reduced
pressure, and purified by silica gel flash chromatography eluting
with 55% EtOAc in hexanes to obtain 16 (80 mg, 0.27 mmol, 40%)
and with 80% EtOAc in hexanes to give rhamnose 13a (12 mg,
0.047 mmol, 6%).
14a: Rf (30% EtOAc in hexanes) = 0.17; m.p. 97–98 °C. [α]2D3
–104.8 (c = 0.4, CH Cl ). IR (thin film): ν = 3315, 2916, 2117,
=
˜
2
2
1
1071, 1012, 695 cm–1. H NMR (400 MHz, CDCl3): δ = 7.38–7.29
(m, 5 H, Ar), 4.88 (d, J = 1.6 Hz, 1 H, CH), 4.69 (d, J = 12.0 Hz,
1 H, CH), 4.50 (d, J = 12.0 Hz, 1 H, CH), 3.95 (dd, J = 3.2, 1.6 Hz,
1 H, CH), 3.90 (dd, J = 9.6, 3.2 Hz, 1 H, CH), 3.65 (dq, J = 10.4,
6.8 Hz, 1 H, CH), 3.31 (dd, J = 10.4, 9.6 Hz, 1 H, CH), 2.31 (br., 2
H, OH), 1.35 (d, J = 6.8 Hz, 3 H, CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 137.1, 128.8 (2 C), 128.3, 128.2 (2 C), 98.69, 70.7, 70.4,
69.5, 67.1, 66.3, 18.6 ppm. HRMS (ESI): calcd. for
[C13H17N3O4Na]+ 302.1111; found 302.1112.
(2R,3R,6S)-2-(Benzyloxy)-6-methyl-3,6-dihydro-2H-pyran-3-yl
Acetate (10a): At 0 °C, acetic anhydride (0.32 mL, 3.39 mmol) was
added dropwise to a solution of allylic alcohol 10a (370 mg,
1.68 mmol) in pyridine (3.5 mL). The reaction was stirred at 0 °C
and monitored by TLC. Upon completion the reaction was
quenched with a satd. NH4Cl solution and extracted with CH2Cl2
2-Acteyl-idose 16: Rf (50% EtOAc in hexanes) = 0.17. [α]2D3 = –66.8
(c = 0.89, CH Cl ). IR (thin film): ν = 3476, 2929, 1728, 1530,
˜
2
2
1264, 1103, 1044, 700 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.41–
7.31 (m, 5 H, Ar), 4.89 (s, 1 H, CH), 4.87 (d, J = 1.6 Hz, 1 H, CH),
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30051
/KAP1
Date: 09-04-13 16:24:33
Pages: 10
Synthesis of ido, manno, and colito Pyranosides
4.76 (d, J = 12.0 Hz, 1 H, CH), 4.58 (d, J = 12.0 Hz, 1 H, CH),
C) ppm. HRMS (ESI): calcd. for [C19H30O4SiNa]+ 373.1806; found
4.29 (dq, J = 6.8, 1.2 Hz, 1 H, CH), 3.92 (d, J = 8.0 Hz, 1 H, CH), 373.1799.
3.48 (d, J = 9.6 Hz, 1 H, CH), 3.22 (d, J = 9.6 Hz, 1 H, OH), 2.31
(1R,2S,4R,5R,6S)-4-(Benzyloxy)-2-(tert-butyldimethylsilyloxy-
(d, J = 11.6 Hz, 1 H, OH), 2.11 (s, 3 H, Ac), 1.30 (d, J = 6.8 Hz,
3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.1, 136.3,
128.9 (2 C), 128.6, 128.4 (2 C), 97.4, 71.0, 70.2, 68.6, 68.6, 68.4,
62.8, 21.2, 16.2 ppm. HRMS (ESI): calcd. for [C15H20O6Na]+
319.1152; found 319.1152.
methyl)-3,7-dioxabicyclo[4.1.0]heptan-5-ol (11): Allyl alcohol 10b
(1.63 g, 4.65 mmol) was added to a 50 mL round-bottomed flask
and dissolved in dichloromethane (23 mL). NaHCO3 (Na2HPO4
can also be used as an alternative base to provide the epoxide with
similar yield) was then added and the mixture cooled to 0 °C in an
ice bath. A solution of mCPBA (3.42 g, 27.9 mmol) in methanol
(23 mL) was then added through a pipette. The reaction mixture
was allowed to slowly warm to room temp. and stirred overnight.
It was then extracted with ethyl acetate (3ϫ 30 mL) and the aque-
ous layer was back-extracted with ethyl acetate (2ϫ 30 mL). The
combined organic solutions were washed with a satd. solution of
Na2S2O3 (2ϫ, 10 mL), dried with Na2SO4, and concentrated under
reduced pressure. The product was isolated without further purifi-
cation to give epoxide 11 as a yellow oil (1.55 g, 4.23 mmol, 91%).
Rf (30% EtOAc in hexanes) = 0.63. [α]2D5 = –43 (c = 0.17, CH2Cl2).
6-Deoxy-D-idose 7a: K2CO3 (15 mg, 0.11 mmol) was added in one
portion to a solution of 2-acetyl-idose 16 (15 mg, 0.05 mmol) in
MeOH (0.5 mL) at room temperature. The reaction was stirred for
3 h and filtered through a pad of Celite eluting with 25% methanol
in EtOAc. The concentrated crude material was then purified by
silica gel flash chromatography eluting with 55% EtOAc in hexanes
to give 6-deoxy-idose 7a (10 mg, 0.04 mmol, 83%) as a colorless
oil.
(1R,2R,4S,6S)-2-(Benzyloxy)-4-(tert-butyldimethylsilyloxymethyl)-
3,7-dioxabicyclo[4.1.0]heptan-5-one (5b): A 30% aqueous hydrogen
peroxide (0.7 g, 20.5 mmol) solution was added dropwise to a solu-
tion of α-benzyl-pyranone 2b (1.43 g, 4.10 mmol) in methanol
(10.5 mL) at 0 °C followed by the addition of 0.5 m aqueous sodium
hydroxide (0.45 mL). The reaction mixture was stirred at 0 °C over-
night. It was then diluted with Et2O (20 mL), quenched with satd.
aqueous NaHCO3 (20 mL), extracted with Et2O (3ϫ 20 mL), dried
with Na2SO4, and concentrated under reduced pressure. The crude
product was purified by silica gel flash chromatography eluting
with 4 % EtOAc in hexanes to give epoxide ketone 5b (1.35 g,
3.70 mmol, 90%) as a yellow oil. Rf (10% EtOAc in hexanes) =
IR (thin film): ν = 2928, 1251, 1070, 1037, 833, 776, 736, 696 cm–1.
˜
1H NMR (400 MHz, CDCl3): δ = 7.42–7.27 (m, 5 H, Ar), 4.71 (d,
J = 11.8 Hz, 1 H, CH), 4.64 (s, 1 H, CH), 4.50 (d, J = 11.7 Hz, 1
H, CH), 4.04 (dd, J = 6.8 Hz, 1 H, CH), 3.80 (d, J = 6.8 Hz, 2 H,
CH2), 3.57 (dd, J = 4.3 Hz, 1 H, CH), 3.47–3.43 (m, 1 H, CH),
2.46 (s, 1 H, OH), 0.92 (s, 9 H, tBu), 0.11 (s, 6 H, CH3) ppm. 13C
NMR (100 MHz, CDCl3): δ = 137.0, 128.7, 128.2, 98.2, 69.5, 66.1,
63.5, 63.2, 52.1, 51.2, 26.0, –5.2, –5.3 ppm. HRMS (ESI): calcd. for
[C19H31O5Si]+ 367.1941, found 367.1937.
(1R,2S,4R,5R,6S)-4-(Benzyloxy)-2-(hydroxymethyl)-3,7-dioxa-
bicyclo[4.1.0]heptan-5-ol (4b): Epoxide 11 (1.5 g, 4.09 mmol) was
added to a 25 mL round-bottomed flask and dissolved in methanol
(8 mL). p-Toluenesulfonic acid (35 mg, 0.205 mmol) was then
added at room temp. After stirring for 2 h, the reaction was deter-
mined complete by TLC and diluted with ethyl acetate (10 mL)
0.3. [α]2D5 = –80.5 (c = 1.0, MeOH). IR (thin film): ν = 3466, 2953,
˜
1
2930, 2857, 1725, 1464, 1255, 1059, 837, 780, 699 cm–1. H NMR
(400 MHz, CDCl3): δ = 7.40–7.31 (m, 5 H, Ar), 5.35 (d, J = 1.6 Hz,
1 H, CH), 4.81 (d, J = 11.6 Hz, 1 H, CH), 4.64 (d, J = 11.6 Hz, 1
H, CH), 4.14 (dd, J = 5.2, 2.8 Hz, 1 H, CH), 4.00 (dd, J = 10.8,
5.2 Hz, 1 H, CH), 3.92 (dd, J = 10.8, 2.8 Hz, 1 H, CH), 3.56 (dd, and quenched with satd. sodium hydrogen carbonate (3 mL). The
J = 4.0, 1.6 Hz, 1 H, CH), 3.42 (d, J = 4.0 Hz, 1 H, CH), 0.91 (s, reaction was extracted with ethyl acetate (4ϫ 20 mL), dried with
9 H, tBu), 0.092 (s, 6 H, CH3) ppm. 13C NMR (100 MHz, CDCl3): Na2SO4, and concentrated under reduced pressure. The crude
δ = 201.3, 136.7, 128.7 (2 C), 128.4, 128.3 (2 C), 93.1, 77.5, 70.6,
63.2, 53.8, 53.4, 25.9 (3 C), 18.4, –5.2, –5.3 ppm. HRMS (ESI):
calcd. for [C19H28O5SiNa]+ 387.1598; found 387.1592.
product was purified by silica gel flash chromatography eluting
with a gradient of 3 to 5% methanol in CH2Cl2 to give epoxide 3b
as a colorless oil (895 mg, 3.55 mmol, 87%). Rf (50% EtOAc in
hexanes) = 0.25. [α]2D5 = –70 (c = 0.15, CH Cl ). IR (thin film): ν
˜
2
2
(2R,3R,6R)-2-(Benzyloxy)-6-(tert-butyldimethylsilyloxymethyl)-
3,6-dihydro-2H-pyran-3-ol (10b): A solution of epoxide ketone 5b
(60 mg, 0.165 mmol) in methanol (0.55 mL) was cooled to 0 °C,
and N2H4·H2O (25 mg, 0.495 mmol) was added dropwise. After
stirring the reaction mixture at 0 °C for 30 min, AcOH (30 mg,
0.50 mmol) was added dropwise and stirring was continued until
TLC showed complete conversion to the allylic alcohol. The reac-
tion mixture was then diluted with CH2Cl2 and quenched with
satd. aqueous NaHCO3 (10 mL) at 0 °C. The mixture was extracted
with CH2Cl2 (3ϫ 15 mL) and dried with MgSO4. The mixture was
then filtered and concentrated under reduced pressure. The crude
product was purified by silica gel flash chromatography eluting
with 10% EtOAc in hexanes to give allylic alcohol 10b (38 mg,
0.108 mmol, 66%) as a colorless oil. Rf (30% EtOAc in hexanes)
= = 3401, 1253, 1029, 900, 852, 737, 697 ppm. 1H NMR (400 MHz,
CDCl3): δ = 7.39–7.27 (m, 5 H, Ar), 4.70 (s, 1 H, CH), 4.70 (d, J
= 12.0 Hz, 1 H, CH), 4.51 (d, J = 11.7 Hz, 1 H, CH), 4.09 (dd, J
= 5.5 Hz, 1 H, CH), 3.91–3.81 (m, 3 H), 3.53 (dd, J = 6.9, 2.4 Hz,
1 H, CH), 3.34 (dd, J = 4.1, 0.6 Hz, 1 H, CH), 3.04 (s, 2 H,
OH) ppm. 13C NMR (100 MHz, CDCl3): δ = 137.0, 128.8, 128.4,
128.3, 98.7, 69.8, 66.0, 63.6, 63.4, 52.0, 50.4 ppm. HRMS (ESI):
calcd. for [C13H16O5Na]+ 275.0895, found 275.0897.
D-Mannose 13b: Epoxide 4b (100 mg, 0.396 mmol) was added to a
25 mL round-bottomed flask and dissolved in acetic acid (4 mL).
Scandium triflate (214 mg, 0.436 mmol) was then added at room
temp. The reaction mixture was heated to 55 °C and stirred for 3 h,
diluted with ethyl acetate (5 mL), and quenched with satd. sodium
hydrogen carbonate (5 mL). The reaction was extracted with ethyl
acetate (3ϫ 10 mL), dried with Na2SO4, and concentrated under
reduced pressure. The crude product was purified by silica gel flash
= 0.57. [α]2D5 = –47.5 (c = 1.0, MeOH). IR (thin film): ν = 3443,
˜
2954, 2929, 2857, 1648 cm–1. 1H NMR (400 MHz, CDCl3): δ =
7.37–7.27 (m, 5 H, Ar), 6.11 (dd, J = 9.6, 5.2 Hz, 1 H, CH), 5.92
(dd, J = 10.4, 2.4 Hz, 1 H, CH), 4.97 (s, 1 H, CH), 4.80 (d, J = chromatography eluting with a gradient of 3 to 5% methanol in
12.8 Hz, 1 H, CH), 4.62 (d, J = 12.8 Hz, 1 H, CH), 4.25 (m, 1 H,
dichloromethane to give epoxide 13b as a colorless oil (15 mg,
CH), 3.84 (d, J = 5.2 Hz, 1 H, CH), 3.78–3.71 (m, 2 H, CH2), 2.17 48 μmol, 12%). Rf (5% methanol in CH2Cl2) = 0.27. [α]2D5 = –48 (c
(br., 1 H, OH), 0.91 (s, 9 H, tBu), 0.09 (s, 6 H, CH3) ppm. 13C = 0.15, CH Cl ). IR (thin film): ν = 3401, 1722, 1368, 1238, 1043,
NMR (100 MHz, CDCl3): δ = 137.8, 130.5, 128.7 (2 C), 128.2 (2
˜
2
2
698 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.40–7.27 (m, 5 H),
C), 128.0, 126.1, 99.3, 70.0 (2 C), 65.0, 63.8, 26.1 (3 C), 18.6, –5.2 (2
4.94 (s, 1 H), 4.70 (d, J = 11.8 Hz, 1 H), 4.57 (dd, J = 12.3, 4.2 Hz,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7

Job/Unit: O30051
/KAP1
Date: 09-04-13 16:24:33
Pages: 10
M. F. Cuccarese, H.-Y. L. Wang, G. A. O’Doherty
FULL PAPER
1 H), 4.52 (d, J = 11.8 Hz, 1 H), 4.16 (d, J = 12.2 Hz, 1 H), 3.99
(s, 1 H), 3.89 (d, J = 7.2 Hz, 1 H), 3.75 (d, J = 7.9 Hz, 1 H), 3.62
(t, J = 9.5 Hz, 1 H), 2.89 (s, 3 H), 2.14 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 172.4, 137.1, 128.8, 128.3, 128.3, 99.3, 71.7,
70.8, 69.6, 67.8, 63.9, 21.2 ppm. HRMS (ESI): calcd. for
[C15H21O7]+ 313.1287; found 313.1293.
(m, 5 H, Ar), 5.32 (dd, J = 9.9, 3.4 Hz, 1 H, CH), 5.26 (dd, J =
3.3, 1.7 Hz, 1 H, CH), 4.86 (d, J = 1.5 Hz, 1 H, CH), 4.68 (d, J =
11.9 Hz, 1 H, CH), 4.54 (d, J = 11.9 Hz, 1 H, CH), 4.30 (d, J =
3.4 Hz, 2 H, CH2), 3.82 (dd, J = 19.6, 9.6 Hz, 1 H, CH), 3.78–3.73
(m, 1 H, CH), 2.14 (s, 3 H, Ac), 2.13 (s, 3 H, Ac), 2.07 (s, 3 H,
Ac) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.8, 170.0, 169.7,
136.4, 128.8, 128.5, 128.4, 97.0, 70.8, 70.0, 69.1, 69.1, 63.4, 57.3,
21.0, 20.9 ppm. HRMS (ESI): calcd. for [C19H23N3O8Na]+
444.1388; found 444.1392.
L-Idopyranoside Pentaacetate 7b and L-Mannopyranoside Pentaacet-
ate 13b: Epoxide 3b (89 mg, 0.351 mmol) was added to a 25 mL
round-bottomed flask and dissolved in acetonitrile (5 mL). A 2 m
NaOH solution (2 mL) was added and the reaction was heated to
90 °C in an oil bath. After stirring for 48 h, the reaction was deter-
mined complete by TLC and the solvents were removed under re-
duced pressure. The crude product was dissolved in pyridine
(50 μL, 0.63 mmol) followed by the addition of acetic anhydride
(0.5 mL, 5 mmol). After stirring at room temp. for 2 h, the reaction
was extracted with ethyl acetate (4ϫ 5 mL), dried with Na2SO4,
and concentrated under reduced pressure. The crude product was
purified by silica gel flash chromatography eluting with a gradient
of 20 to 50% ethyl acetate in hexanes to give peracylated idose and
mannose as a mixture of isomers in a 1:3 ratio, respectively (91 mg,
0.208 mmol, 59%), as a colorless oil. The resulting triols were im-
mediately converted to pentaacetates for characterization. Neither
the triols nor the pentaacetates could be separated. Rf (50% EtOAc
3-Azido-idose 8b: Rf (20% EtOAc in hexanes) = 0.78. [α]2D5 = –51
(c = 0.08, CH Cl ). IR (thin film): ν = 2111, 1742, 1368, 1212,
˜
2
2
1
1131, 1072, 909, 739, 699 cm–1. H NMR (400 MHz, CDCl3): δ =
7.42–7.29 (m, 5 H, Ar), 4.91 (dd, J = 4.2, 2.1 Hz, 1 H, CH), 4.87
(s, 1 H, CH), 4.81 (d, J = 4.1 Hz, 1 H, CH), 4.79 (d, J = 12.0 Hz,
1 H, CH), 4.57 (d, J = 12.1 Hz, 1 H, CH), 4.44–4.36 (m, 1 H, CH),
4.18 (m, 2 H), 3.92 (dd, J = 4.2 Hz, 1 H, CH), 2.13 (s, 3 H, Ac),
2.09 (s, 3 H, Ac), 2.07 (s, 3 H, Ac) ppm. 13C NMR (100 MHz,
CDCl3): δ = 170.7, 170.1, 169.5, 136.7, 128.8, 128.3, 128.1, 96.7,
69.6, 68.2, 67.8, 64.7, 62.4, 57.6, 21.1, 21.0 ppm. HRMS (ESI):
calcd. for [C19H23N3O8Na]+ 444.1383; found 444.1383.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of 1H and 13C NMR spectra for all the new com-
pounds.
in hexanes) = 0.74. [α]2D5 = –41 (c = 2.0, CH Cl ). IR (thin film): ν
˜
2
2
= 1740, 1369, 1213, 1043, 732, 699, 600 cm–1.
Mannose 13b: 1H NMR (400 MHz, CDCl3): δ = 7.39–7.30 (m, 5
H, Ar), 5.37 (dd, J = 10.0, 3.6 Hz, 1 H, CH), 5.29–5.25 (m, 1 H,
CH), 4.89 (m, 2 H, CH), 4.70 (d, J = 12.0 Hz, 1 H, CH), 4.56 (d,
J = 12.0 Hz, 1 H, CH), 4.27 (dd, J = 12.0, 5.0 Hz, 1 H, CH), 4.19
(d, J = 6.0 Hz, 1 H, CH), 4.01–3.95 (m, 1 H, CH), 2.13 (s, 3 H,
Ac), 2.11 (s, 3 H, Ac), 2.02 (s, 3 H, Ac), 1.98 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 170.9–169.4 (4 C), 136.4, 128.8–
127.8 (4 C), 97.0, 70.0, 69.8, 69.4, 68.9, 66.4, 62.6, 21.1, 21.0, 20.9,
20.9 ppm.
Acknowledgments
We are grateful to the National Institutes of Health (NIH)
(GM090259) and the National Science Foundation (NSF) (CHE-
1213596) for the support of this research effort. M. F. C. thanks
the NSF (DGE-0965843) for an IGERT fellowship.
Idose 7b: 1H NMR (400 MHz, CDCl3): δ = 7.39–7.30 (m, 5 H, Ar),
5.31 (s, 1 H, CH), 5.28 (m, 1 H, CH), 5.00 (dd, J = 4.8, 3.6 Hz, 1
H, CH), 4.77 (d, J = 12.0 Hz, 1 H, CH), 4.51 (s, 1 H, CH), 4.47
(ddd, J = 6.4, 2.0 Hz, 1 H, CH), 4.05 (d, J = 2.4 Hz, 2 H, CH2),
4.02 (s, 2 H, CH), 2.12 (s, 3 H, Ac), 2.07 (s, 3 H, Ac), 2.06 (s, 3 H,
Ac), 2.04 (s, 3 H, Ac) ppm. 13C NMR (100 MHz, CDCl3): δ =
170.9, –169.4 (4 C), 137.15, 128.7–127.8 (4 C), 69.49, 67.39, 67.30,
67.01, 64.80, 60.62, 21.28, 21.06, 20.95, 14.42 ppm. HRMS (ESI):
calcd. for [C21H26O10Na]+ 461.1424; found 461.1421.
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3-Azido-D-idose-2,3,6-triacetate (8b) and 3-Azido-D-mannose-2,3,6-
triacetate (14b): Epoxide 4b (10 mg, 40 μmol) was added to a 10 g
screw-cap vial and dissolved in DMF/H2O (1:1, 0.2 mL total vol.).
Solid NaN3 (15 mg, 0.198 mmol) was then added at room temp.
and the mixture was heated to 50 °C and stirred overnight. It was
then extracted with ethyl acetate (3ϫ 2 mL), dried with Na2SO4,
and concentrated under reduced pressure. The crude product was
dissolved in dichloromethane (0.2 mL) followed by the addition of
acetic anhydride (0.3 mL, 3.2 mmol), triethylamine (0.2 mL,
1.4 mmol), and 4-(dimethylamino)pyridine (5 mg, 0.040 mmol),
and the mixture stirred for 3 h. The reaction was extracted with
ethyl acetate (3ϫ 2 mL), dried with Na2SO4, and concentrated un-
der reduced pressure. The crude product was purified by silica gel
flash chromatography eluting with a gradient of 10 to 20% ethyl
acetate in hexanes to give 4-azido-mannose and 3-azido-idose in a
2:1 ratio of isomers (13.6 mg, 0.0323 mmol, 81%) as colorless oils.
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–28 (c = 0.05, CH Cl ). IR (thin film): ν = 2925, 2109, 1743, 1371,
=
˜
2
2
1227, 1044, 699 cm–1. H NMR (400 MHz, CDCl3): δ = 7.40–7.27
1
8
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Job/Unit: O30051
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Date: 09-04-13 16:24:33
Pages: 10
Synthesis of ido, manno, and colito Pyranosides
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Published Online: ᭿
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9

Job/Unit: O30051
/KAP1
Date: 09-04-13 16:24:33
Pages: 10
M. F. Cuccarese, H.-Y. L. Wang, G. A. O’Doherty
FULL PAPER
Synthesis of Sugars
A de novo asymmetric synthesis of α-ido-
pyranosides, as well as several deoxy and
amino variants, has been achieved. The
M. F. Cuccarese, H.-Y. Leo Wang,
G. A. O’Doherty* ........................... 1–10
procedure involves
a palladium(0)-cata-
Application of the Wharton Rearrange-
ment for the de novo Synthesis of Pyranos-
ides with ido, manno, and colito Stereo-
chemistry
lyzed glycosylation in combination with a
Wharton rearrangement/epoxide-opening
reaction sequence to access sugars with ido,
manno, and colito stereochemistry as well
as several azido analogues.
Keywords: Carbohydrates / Glycosylation /
Rearrangement / Palladium / Epoxides
10
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