Stereoselective synthesis of C-2-methylene and C-2-methyl α-and β-C-glycosides from 2-C-branched glycals: Formal total synthesis of (-)-Brevisamide

Article abstract of DOI:10.1002/ejoc.201403062

The stereoselective synthesis of deoxy C-glycoside derivatives that have a methylene or methyl group at C-2 position was investigated by employing the Claisen rearrangement of 2-vinyloxy methyldeoxy-glycals as the synthetic precursors. The method proceede

Full text of DOI:10.1002/ejoc.201403062

FULL PAPER
DOI: 10.1002/ejoc.201403062
Stereoselective Synthesis of C-2-Methylene and C-2-Methyl α- and
β-C-Glycosides from 2-C-Branched Glycals: Formal Total Synthesis of
(–)-Brevisamide
Chalapala Sudharani,[a] Patteti Venukumar,[a] and Perali Ramu Sridhar*[a]
Keywords: Carbohydrates / C-glycosides / Natural products / Rearrangement / Diastereoselectivity
The stereoselective synthesis of deoxy C-glycoside deriva- ides to give the corresponding β-C-glycosides was also used
tives that have a methylene or methyl group at C-2 position
was investigated by employing the Claisen rearrangement of
2-vinyloxy methyldeoxy-glycals as the synthetic precursors.
The method proceeded with high diastereoselectivity to af-
ford C-2-methylene α-C-glycosides. Complementary to this
protocol, a ZnII-mediated anomerization of the α-C-glycos-
to obtain diastereomerically pure C-2-methylene β-C-glycos-
ides. The generality of the reaction was fully evaluated, and
the developed method was successfully applied to the formal
stereoselective total synthesis of (–)-brevisamide, a monocy-
clic ether alkaloid that was isolated from Karenia brevis (red
tide dinoflagellate).
ulin, gambieric acids, halichondrins, (+)-lasonolide, phorb-
oxazoles, spliceostatins, and spongistatins (see Figure 1)
Introduction
Many microorganisms produce C-branched-C-glycoside contain a deoxy C-2-methyl/C-2-methylene-C-glycopyran-
derived natural products that exhibit extremely high bioac- oside subunit.[2] In general, most of the chemical syntheses
tivity.[1] Very often these compounds are produced as a line of these scaffolds involve an achiral starting material to as-
of defense against their predators. Among them, C-glycos- semble the carbon-branched C-glycoside unit. Although
ides that have a methyl or methylene group at the C-2 posi- highly abundant carbohydrates could be the closest chiral
tion frequently exist as a subunit of these highly bioactive pool starting materials to synthesize these complex architec-
natural products.[2] For example, brevenal, brevetoxin, erib- tures, the stereoselective incorporation of a carbon branch
Figure 1. Some natural products that have C-2-methylene/C-2-methyl C-glycoside subunits.
at the C-2,[3] C-3,[4] or C-4[5] position of a C-glycoside is
[a] School of Chemistry, University of Hyderabad,
particularly difficult.[6] Several methods have been reported
Gachibowli, Hyderabad-500 046, India
for the synthesis of normal C-glycosides,[7] but general pro-
E-mail: prssc@uohyd.ernet.in
http://chemistry.uohyd.ernet.in/~prs/
tocols to synthesize carbon-branched C-glycosides are very
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403062.
scarce.[2–5]
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One of the common approaches for the stereoselective tained from the Claisen rearrangement with NaBH4/EtOH
formation of C-glycosides employs the Claisen or Ireland– at –10 °C produced the corresponding alcohols 7α and 7β
Claisen rearrangement[8] of glucal-derived ally vinyl in a 66:34 ratio in good yield, and no product from the
ethers.[9] This reaction was extensively studied by using 3- reduction of 6 was observed (see Scheme 1). The two ano-
O-vinyl glycal derivatives to obtain C-glycosides of 2,3- mers 7α and 7β were easily separated by silica gel column
glycals.[10] In continuation of our investigations towards the chromatography.
synthesis of C-branched sugars,[11] we recently reported the
The stereochemistry at the anomeric position was deter-
Claisen rearrangement of 2-vinyloxymethyl glycal deriva- mined by 2D NOESY experiments. In the case of α-C-glyc-
tives to provide access to the construction of C-2-methylene oside 7α, a strong NOE correlation was observed between
and C-2-methyl C-glycosides in a stereoselective fashion.[12] the axial CH2 (C-7 protons) and the axial C-5 proton (1,3-
This protocol, however, provides access to the synthesis of diaxial interaction). On the other hand, for β-C-glycoside
C-2-branched α-C-glycosides as the major products. Herein, 7β, an NOE correlation was observed between the three ax-
we report our further investigations of 2-vinyloxymethyl ial hydrogen atoms present at C-1, C-3 and C-5 (see Fig-
glycals that are derived from deoxy-sugars as well as the ure 2).[19]
conversion of C-2-methylene α-C-glycosides into the corre-
sponding β-C-glycosides. Furthermore, we also report the
application of the developed method towards the formal
stereoselective total synthesis of (–)-brevisamide.
Results and Discussion
To obtain deoxysugar-derived 2-vinyloxymethyl glucal 4,
Figure 2. Assignment of the stereochemistry of C-2-methylene α-
3-deoxy-4,6-di-O-benzyl-d-glucal (1)[13] was formylated[14]
and β-C-glycosides.
by using N,N-dimethylformamide (DMF) and POCl3 to
give 3-deoxy-2-formyl-4,6-di-O-benzyl-d-glucal (2),[15]
Encouraged by this result, we further applied this
which upon reduction by treatment with NaBH4 in method to other deoxy-2-vinyloxymethyl glycal derivatives.
EtOH provided 3-deoxy-2-hydroxymethyl-4,6-di-O-benzyl- Thus, 4-deoxy-2-hydroxymethyl-3,6-di-O-benzyl-d-glucal
d-glucal (3).[16] Vinylation of 3 by using catalytic mercuric (8) underwent a vinylation reaction to give the correspond-
acetate in ethyl vinyl ether provided the required 3-deoxy- ing vinyl ether 9. The Claisen rearrangement of 9 provided
2-vinyloxymethyl-4,6-di-O-benzyl-d-glucal (4) in 60% yield. 4-deoxy-C-2-methylene C-glycosides 10α and 10β in 90:10
Upon heating at 180 °C for 6 h in a sealed tube, compound ratio (see Table 1, Entry 1). Similarly, 2,3-dideoxy vinyl
4 smoothly underwent a Claisen rearrangement and pro- ether 12, which was derived from 2-hydroxymethyl glycal
vided a mixture of 3-deoxy-C-2-methylene C-glycosides 5α 11, underwent a Claisen rearrangement to provide C-2-
and 5β in a 66:34 ratio.[17] However, chromatography on a methylene-C-glycosides 13α and 13β in good yield in a ratio
silica gel column provided an inseparable mixture of 5α and of 83:17 (see Table 1, Entry 2). The direct treatment of the
5β in a 66:34 ratio in 35% yield along with the ring-opened crude mixture of aldehydes 13α and 13β with NaBH4 pro-
α,β-unsaturated aldehyde derivative 6 in 50% yield.[18] vided C-2-methylene C-glycosides 14α and 14β in a ratio
Interestingly, the direct reduction of the crude mixture ob- of 83:17 (see Table 1, Entry 3). Vinyl ether 16, which was
Scheme 1. Synthesis of 3-deoxy C-2-methylene C-glycoside derivative.
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Stereoselective Synthesis of α- and β-C-Glycosides
Table 1. Synthesis of deoxysugar-derived C-2-methylene C-glycosides.
[a] Yield refers to pure, isolated products. [b] Obtained as an inseparable mixture. [c] The vinyl ether was subjected to Claisen rearrange-
ment, and the obtained crude product was directly reduced with NaBH4/EtOH.
prepared by the vinylation of azido alcohol 15, underwent stereomerically pure alcohol 7β. When a similar protocol
a Claisen rearrangement followed by column chromatog- was applied to the mixture of anomers 10α and 10β, pure
raphy to provide a mixture of C-2-methylene C-glycosides β-C-glycoside 10β was formed as a single diastereomer (see
17α and 17β in a 72:28 ratio along with the corresponding Scheme 2).
ring-opened α,β-unsaturated aldehyde derivative 18 (see
Table 1, Entry 4). Conversely, the direct reduction of the
crude product of the Claisen rearrangement of 16 provided
a mixture of 3-deoxy-C-2-methylene C-glycosides 19α and
19β (72:28) in good yield (see Table 1, Entry 5). These re-
sults suggest that the equatorial –OBn at C-4 (that is pres-
ent in compounds 4 and 16) strongly influences the product
stability and particularly increases the β-C-glycoside forma-
tion.
As all of the Claisen rearrangements provided the C-2-
methylene α-C-glycosides as the major products, we then
focused on converting the obtained α-C-glycosides into
their β-C-anomers. Towards this goal, we attempted the
zinc(II)-mediated epimerization of 2Ј-carbonylalkyl-α-C-
Scheme 2. Epimerization of α-C-glycosides into β-C-glycosides.
The significance of the developed method was further
glycosides.[20] Thus, the mixture of 5α and 5β, which was evaluated by applying it to the synthesis of a series of deoxy
obtained from the Claisen rearrangement of 4, was directly C-2-methyl-C-glycosides. Towards this, C-2-methylene-C-
treated with Zn(OAc)2 in NaOMe/MeOH. Consequently, glycoside 7α was subjected to a selective hydrogenation by
the C-1 epimerization occurred smoothly, and the anomeric using 10% Pd/C under hydrogen in the presence of Na2CO3
mixture was completely converted into β-C-glycoside 5β.[21] as a catalyst poison.[22] This reaction provided C-2-methyl-
A further reduction of 5β with NaBH4 provided the dia- C-glycosides 20a and 20b in 70% yield as a 75:25 mixture
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of 1,2-cis and 1,2-trans diastereomers, respectively. Upon
hydrogenation, C-2-methylene C-glycosides 7β and 14α pro-
vided 21a/21b (75:25) and 22a/22b (73:27)[23] as a mixture
of 1,2-cis- and 1,2-trans-C-2-methyl-C-glycosides, (see
Scheme 3).
Scheme 4. Formal total synthesis of (–)-brevisamide.
Conclusions
In summary, a general method has been developed for
the synthesis of deoxygenated C-2-methylene-C-glycosides
by using the Claisen rearrangement of 2-vinyloxymethyl
glycal derivatives. Importantly, this method is applicable to
the stereoselective synthesis of C-2-methylene α- and β-C-
glycosides. The generality and stereoselectivity of the re-
arrangement was evaluated, and this method was extended
to the preparation of deoxysugar-derived C-2-methyl-C-
glycosides through the selective hydrogenation of the C-2-
methylene functionality. It is significant that most of these
compounds can serve as key intermediates for the synthesis
of several bioactive natural products. The application of the
method was further extended to the preparation of an ad-
vanced intermediate in the total synthesis of (–)-bre-
visamide. Further applications of this method to the total
syntheses of complex natural products that contain these
structural features are in progress.
Scheme 3. Synthesis of C-2-methyl C-glycosides.
The 1,2-cis and 1,2-trans relationship with respect to the
C-1- and C-2-branched glycosides was assigned by observ-
ing the NOE correlations in a 2D NOESY experiment. The
protons of the C-2 methyl group of 1,2-cis diastereomer 20a
had an NOE correlation with the α-C-7 protons, whereas
the C-2 methyl group of β-C-glycoside 21a had an NOE
correlation with the C-4 proton, which is in an axial orien-
tation (see Figure 3).
Experimental Section
General Methods: All chemicals were purchased from Carbosynth,
Merck, and Sigma–Aldrich Chemical Companies and were of the
highest purity. The reactions were carried out under an inert atmo-
sphere and monitored by thin layer chromatography using silica gel
GF254 plates. The compounds were visualized by charring with 5%
(v/v) H2SO4 in methanol, staining with phosphomolybdic acid
(PMA), or using ultraviolet light, unless otherwise mentioned. N,N-
Dimethylformamide, ethanol, ethyl vinyl ether, toluene, methanol,
and POCl3 were distilled from dehydrating agents prior to use. Sil-
ica gel (100–200) was used for column chromatography. The 1H
NMR, 13C NMR, DEPT, COSY, and NOESY spectroscopic data
were recorded with Bruker 400 or 500 MHz spectrometers, and
Figure 3. Assignment of the stereochemistry of C-2 methyl group
of α- and β-C-glycosides.
Finally we applied this method to the preparation of a
natural product that has a C-2-methyl-C-glycoside subunit
and, thus, chose (–)-brevisamide 27, which is a cyclic ether
marine alkaloid that was isolated from the cultures of Kar-
enia brevis.[24] Hence, the hydroxy function of alcohol 21a
was acetylated to give compound 23, which upon
hydrogenolysis provided diol 24. The protection of both the
hydroxy groups by using tert-butyldimethylsilyl trifluoro-
methanesulfonate (TBSOTf)/2,6-lutidine in CH2Cl2 pro-
vided 25. Deprotection of the acetate moiety under
Zemplén deacylation conditions provided the advanced in-
termediate 26,[25] which was recently employed for the total
synthesis of (–)-brevisamide (27, see Scheme 4).
1
CDCl3 was used as the solvent. The chemical shifts for H NMR
are reported in ppm (δ) with TMS as the internal standard (δ =
0.00 ppm). The chemical shifts for 13C NMR are reported in ppm
(δ) with the solvent as the reference (CDCl3, δ = 77.00 ppm). IR
spectra were recorded with a JASCO FT/IR-5300 spectrometer.
High resolution mass spectra were recorded with a Bruker maXis
ESI-TOF spectrometer.
(2R,3S)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-3,4-dihydro-2H-pyran-
5-carbaldehyde (2): To a solution of dry DMF (5 mL) and POCl3
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Stereoselective Synthesis of α- and β-C-Glycosides
(0.90 mL, 9.67 mmol) at 0 °C was added a precooled solution of 3-
deoxy-4,6-di-O-benzyl-d-glucal (1) (1.0 g, 3.22 mmol) in dry DMF
(6 mL) dropwise for approximately 30 min. The mixture was stirred
for 5–6 h at room temperature. After the complete consumption of
the starting material (monitored by TLC), the reaction was
quenched with a saturated aqueous NaHCO3 solution and then
diluted with diethyl ether. The organic layer was separated, and the
aqueous layer was extracted with diethyl ether (2ϫ 100 mL). The
combined ether layers were washed with brine solution, dried with
anhydrous Na2SO4, and concentrated. The crude residue was puri-
fied by chromatography on a silica gel column (hexanes/ethyl acet-
Bis(benzyloxy)-7-hydroxy-4-methyleneoct-2-enal (6): In sealed tube,
a solution of compound 4 (0.25 g, 0.68 mmol) in toluene (7 mL)
was heated at 180–185 °C for 5–6 h. The reaction mixture was
cooled, and the toluene was evaporated by using a rotary evapora-
tor. Purification of the crude product over silica gel provided 5α
and 5β as an inseparable mixture and pure compound 6 as a color-
less gum (0.21 g, 85% combined yield); Rf = 0.52 (for 5α/5β) and
0.36 (for 6, 20% EtOAc/hexanes). Data for 6: 1H NMR (400 MHz,
CDCl3): δ = 9.58 (d, J = 7.6 Hz, 1 H), 7.21–7.38 (m, 10 H), 7.11
(d, J = 16.0 Hz, 1 H), 6.28 (dd, J = 7.6 Hz, J = 16.0 Hz, 1 H), 5.60
(d, J = 6.8 Hz, 2 H), 4.57 (s, 2 H), 4.48 (s, 2 H), 3.84–3.88 (m, 1
H), 3.60–3.68 (m, 3 H), 2.71 (dd, J = 2.8 Hz, J = 14.4 Hz, 1 H),
ate) to provide compound 2 (0.80 g, 90% yield) as a colorless gum;
1
Rf = 0.52 (30% EtOAc/hexanes). H NMR (400 MHz, CDCl3): δ 2.52 (dd, J = 8.8 Hz, J = 14.8 Hz, 1 H) ppm. 13C NMR (100 MHz,
= 9.29 (s, 1 H), 7.29–7.38 (m, 11 H), 4.50–4.69 (m, 4 H), 4.19–4.23
CDCl3): δ = 194.0, 154.4, 141.9, 137.8, 137.6, 129.1, 128.5, 128.3,
(m, 1 H), 3.81–3.86 (m, 1 H), 3.77–3.79 (m, 2 H), 2.69 (dd, J = 128.1, 128.0, 127.9, 127.9, 127.8, 78.1, 73.5, 73.1, 71.9, 70.6,
16.0 Hz, J = 4.8 Hz, 1 H), 2.26 (dd, J = 16.4 Hz, J = 7.6 Hz, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 189.5, 163.2, 137.3,
137.3, 128.1, 127.4, 127.4, 116.5, 79.0, 73.2, 70.5, 68.1, 68.0,
22.4 ppm.
33.6 ppm.
2-{(5S,6R)-5-(Benzyloxy)-6-[(benzyloxy)methyl]-3-methylenetetra-
hydro-2H-pyran-2-yl}ethanol (7α/7β): In sealed tube, a solution of
compound 4 (0.25 g, 0.68 mmol) in toluene (7 mL) was heated at
180–185 °C for 5–6 h. The reaction mixture was cooled to 25 °C,
and the toluene was evaporated by using a rotary evaporator under
reduced pressure. The obtained crude product was dissolved in dry
EtOH (5 mL), and the mixture was cooled to –10 °C. NaBH4
(38.55 mg, 1.02 mmol) was added, and the solution was stirred for
3 h. Upon complete consumption of the starting material, the reac-
tion was quenched with saturated aqueous NH4Cl. The EtOH was
evaporated under reduced pressure, and the obtained slurry was
dissolved in CH2Cl2 (100 mL). The mixture was washed with water
and brine solution, and the organic layer was dried with anhydrous
Na2SO4. Evaporation of the solvent under reduced pressure pro-
vided the crude product, which was purified by chromatography
on a silica gel column to obtain C-2-methylene-C-glycosides 7α/7β
(0.2 g, 81% yield) as a colorless gum; Rf = 0.61 (for 7α) and 0.62
(for 7β, 40% EtOAc/hexanes).
{(2R,3S)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-3,4-dihydro-2H-
pyran-5-yl}methanol (3): To a stirred solution of compound 2
(0.47 g, 1.38 mmol) in dry ethanol (5 mL) at 0 °C was added solid
NaBH4 (78 mg, 2.07 mmol), and the stirring was continued for 3 h.
Upon completion (monitored by TLC), the reaction was quenched
with saturated NH4Cl solution. The ethanol was evaporated under
reduced pressure, and the aqueous suspension was extracted with
dichloromethane (2ϫ 50 mL). The combined organic layers were
washed with water and brine solution, dried with anhydrous
Na2SO4, and then concentrated. The crude residue was purified by
chromatography on a silica gel column to provide compound 3
(0.40 g, 85% yield) as a colorless gum; Rf = 0.5 (40% EtOAc/hex-
anes). 1H NMR (400 MHz, CDCl3): δ = 7.25–7.38, (m, 10 H), 6.46
(s, 1 H), 4.69 (d, J = 11.6 Hz, 1 H), 4.65 (d, J = 12 Hz, 1 H), 4.60
(d, J = 12 Hz, 1 H), 4.55 (d, J = 11.6 Hz, 1 H), 3.93–3.98 (m, 3
H), 3.83–3.89 (m, 1 H), 3.80 (d, J = 4 Hz, 2 H), 2.75 (br. s, 1 H),
2.53 (dd, J = 5.6 Hz, J = 16.4 Hz, 1 H), 2.22 (dd, J = 7.6 Hz, J =
16.4 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 140.1, 137.6,
137.5, 127.9, 127.8, 127.3, 127.2, 109.8, 76.4, 72.9, 70.4, 69.7, 68.3,
62.7, 27.1 ppm.
2-{(2R,5S,6R)-5-(Benzyloxy)-6-[(benzyloxy)methyl]-3-methylene-
tetrahydro-2H-pyran-2-yl}ethanol (7α): 1H NMR (400 MHz,
CDCl3): δ = 7.25–7.36 (m, 10 H), 4.89 (s, 1 H), 4.87 (s, 1 H), 4.62
(d, J = 12.4 Hz, 1 H), 4.55 (d, J = 12 Hz, 1 H), 4.41–4.44 (m, 2
H), 3.88–3.93 (m, 1 H), 3.82–3.85 (m, 2 H), 3.76 (dd, J = 2.4 Hz,
J = 6.4 Hz, 1 H), 3.59 (dd, J = 6.8 Hz, J = 10.8 Hz, 1 H), 3.43–
3.49 (m, 1 H), 2.76 (dd, J = 4.8 Hz, J = 13.2 Hz, 1 H), 2.41 (dd, J
= 11.2 Hz, J = 12.8 Hz, 1 H), 2.29–2.33 (m, 2 H), 1.63–1.68 (m, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 143.6, 138.1, 138.0,
128.4, 128.3 127.8, 127.7, 127.6, 127.6, 111.0, 77.6, 75.0, 73.4, 72.3,
70.8, 69.8, 61.1, 34.9, 33.0 ppm. HRMS (ESI): calcd. for
C23H28O4Na [M + Na]+ 391.1886; found 391.1886.
(2R,3S)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-5-[(vinyloxy)methyl]-
3,4-dihydro-2H-pyran (4): A solution of compound 3 (0.40 g,
1.17 mmol), ethyl vinyl ether (freshly distilled from sodium,
20 mL), and mercuric acetate (85 mg, 0.26 mmol) were stirred at
50 °C under nitrogen. After 24 h, the reaction was cooled to 25 °C
and then diluted with an equal volume of hexane. The obtained
solution was washed with 5% aqueous KOH, water, and then brine
solution. The organic layer was concentrated under reduced pres-
sure, and the obtained residue was purified by using basic alumina
to afford compound 4 (260 mg, 60% yield) as a colorless gum; Rf
= 0.64 (10% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3): δ =
7.27–7.34 (m, 10 H), 6.51 (s, 1 H), 6.44 (dd, J = 7.0 Hz, J = 14.0 Hz,
1 H), 4.67 (d, J = 11.5 Hz, 1 H), 4.62 (d, J = 12.5 Hz, 1 H), 4.57
(d, J = 12.0 Hz, 1 H), 4.52 (d, J = 12.0 Hz, 1 H), 4.24 (dd, J =
2.0 Hz, J = 14.0 Hz, 1 H), 4.08 (s, 2 H), 4.02 (dd, J = 2.0 Hz, J =
7.0 Hz, 1 H), 3.91–3.94 (m, 1 H), 3.84 (td, J = 5.5 Hz, J = 8.0 Hz,
1 H), 3.77–3.78 (m, 2 H), 2.49 (dd, J = 5.5 Hz, J = 16.0 Hz, 1 H),
2.17 (dd, J = 8.0 Hz, J = 16.0 Hz, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 151.3, 142.4, 138.1, 138.0, 128.4, 128.3, 127.8, 127.7,
127.6, 106.6, 87.3, 76.8, 73.5, 71.0, 70.0, 69.4, 68.8, 28.0 ppm.
HRMS (ESI): calcd. for C23H26O4Na [M + Na]+ 389.1729; found
389.1729.
2-{(2S,5S,6R)-5-(Benzyloxy)-6-[(benzyloxy)methyl]-3-methylene-
tetrahydro-2H-pyran-2-yl}ethanol (7β): 1H NMR (400 MHz,
CDCl3): δ = 7.26–7.36 (m, 10 H), 4.90 (s, 1 H), 4.87 (s, 1 H), 4.63
(d, J = 11.6 Hz, 1 H), 4.53–4.58 (m, 2 H), 4.44 (d, J = 11.6 Hz, 1
H), 4.06 (t, J = 6.4 Hz, 1 H), 3.89 (m, 2 H), 3.77 (dd, J = 2 Hz, J
= 10 Hz, 1 H), 3.56–3.65 (m, 2 H), 3.47–3.51 (m, 1 H), 3.12 (br. s,
1 H), 2.88 (dd, J = 5.2 Hz, J = 13.2 Hz, 1 H), 2.27 (dd, J = 7.6 Hz,
J = 13.2 Hz, 1 H), 1.95–2.00 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 143.6, 138.1, 138.0, 128.4, 128.4, 127.8, 127.7, 127.7,
127.6, 109.4, 79.9, 78.9, 74.7, 73.4, 71.0, 69.9, 61.5, 38.5, 33.4 ppm.
HRMS (ESI): calcd. for C23H28O4Na [M + Na]+ 391.1886; found
391.1885.
{(2S,4S)-4-(Benzyloxy)-2-[(benzyloxy)methyl]-3,4-dihydro-2H-
pyran-5-yl}methanol (8): By following the procedure described for
2-{(5S,6R)-5-(Benzyloxy)-6[(benzyloxy)methyl]-3-methylenetetra- 3, (2S,4S)-4-(benzyloxy)-2-[(benzyloxy)methyl]-3,4-dihydro-2H-
hydro-2H-pyran-2-yl}acetaldehyde (5α/5β) and (6S,7R,E)-6,8- pyran-5-carbaldehyde was employed to prepare compound 8 (85%
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yield); Rf = 0.6 (30 % EtOAc/hexanes). [α]D = +47 (c = 0.37,
14.4 Hz, 1 H), 4.57 (q, J = 12 Hz, J = 17.2 Hz, 2 H), 4.23 (dd, J =
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.26–7.36 (m, 10 H), 1.6 Hz, J = 14 Hz, 1 H), 4.04–4.07 (m, 2 H), 4.03 (d, J = 2 Hz, 1
6.51 (s, 1 H), 4.68 (d, J = 11.6 Hz, 1 H), 4.49–4.62 (m, 3 H), 4.33 H), 4.01 (d, J = 2 Hz, 1 H), 3.54–3.64 (m, 2 H), 2.14–2.19 (m, 1
(t, J = 7.2 Hz, 1 H), 4.15–4.21 (m, 1 H), 4.02 (q, J = 12 Hz, 2 H),
H), 2.06–2.11 (m, 1 H), 1.89–1.96 (m, 1 H), 1.71–1.79 (m, 1
3.67 (dd, J = 6.4 Hz, J = 10 Hz, 1 H), 3.55 (dd, J = 4.4 Hz, J = H) ppm. 13C NMR (100 MHz, CDCl3): δ = 151.4, 143.1, 138.0,
10.4 Hz, 1 H), 2.33 (br. s, 1 H), 2.22–2.27, (m, 1 H), 1.88–1.96 (m,
1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 144.4, 137.9, 137.8,
128.5, 128.4, 127.9, 127.8, 113.5, 73.7, 73.5, 71.5, 71.1, 70.8, 62.3,
30.0 ppm. HRMS (ESI): calcd for C21H24O4Na [M + Na]+
363.1573; found 363.1571.
128.4, 127.7, 108.9, 87.0, 74.2, 73.4, 72.1, 70.1, 23.9, 21.1 ppm.
HRMS (ESI): calcd. for C16H20O3Na [M + Na]+ 283.1310; found
283.1327.
2-{(6S)-6-[(Benzyloxy)methyl]-3-methylenetetrahydro-2H-pyran-2-
yl}acetaldehyde (13): By following the procedure described for 5α
and 5β, compound 12 was employed to prepare compound 13,
which was obtained as an inseparable mixture of 13α and 13β (see
Supporting Information). HRMS (ESI): calcd. for C16H20O3Na [M
+ Na]+ 283.1310; found 283.1308.
(2S,4S)-4-(Benzyloxy)-2-[(benzyloxy)methyl]-5-[(vinyloxy)methyl]-
3,4-dihydro-2H-pyran (9): By following the procedure described for
4, compound 8 was employed to prepare compound 9 (74% yield);
Rf = 0.5 (10% EtOAc/hexanes). [α]D = +35.7 (c = 0.35, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.26–7.35 (m, 10 H), 6.53 (s, 1
H), 6.42 (dd, J = 6.8 Hz, J = 14.4 Hz, 1 H), 4.48–4.64 (m, 5 H),
4.23–4.27 (m, 3 H), 4.01 (dd, J = 1.6 Hz, J = 6.8 Hz, 1 H), 3.92 (d,
J = 10.8 Hz, 1 H), 3.68 (dd, J = 6.8 Hz, J = 10.4 Hz, 1 H), 3.54
(dd, J = 4.4 Hz, J = 10.4 Hz, 1 H), 2.16–2.22 (m, 1 H), 1.88–1.96
(m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 151.5, 145.1,
138.3, 137.9, 128.4, 128.3, 127.7, 127.7,127.6, 110.9, 87.1, 74.0,
73.4, 71.5, 71.0, 68.3, 66.5, 29.7 ppm. HRMS (ESI): calcd for
C23H26O4Na [M + Na]+ 389.1729; found 389.1729.
2-{(2R,6S)-6-[(Benzyloxy)methyl]-3-methylenetetrahydro-2H-pyran-
2-yl}ethanol (14α): By following the procedure described for com-
pounds 7α and 7β, compound 12 was employed to prepare com-
pounds 14α and 14β (69% yield); Rf = 0.4 (40% EtOAc/hexanes).
Data for 14α: [α]D = +17 (c = 1.0, CHCl ). IR (neat): ν
= 3446,
˜
3
max
2920, 1654, 1457 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.25–7.35
(m, 5 H), 4.79 (s, 1 H), 4.77 (s, 1 H), 4.50 (q, J = 26.8 Hz, 1 H),
4.44 (dd, J = 4.4 Hz, J = 10.8 Hz, 1 H), 4.04–4.10 (m, 1 H), 3.84–
3.89 (m, 2 H), 3.76–3.82 (m, 2 H), 3.38–3.46 (m, 2 H), 2.37–2.46
(m, 1 H), 2.28–2.36 (m, 2 H), 1.67–1.73 (m, 1 H), 1.51–1.58 (m, 1
H), 1.36–1.47 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
145.4, 137.8, 128.2, 127.4, 109.1, 78.2, 73.2, 72.8, 68.6, 61.2, 33.2,
29.0, 28.1 ppm. HRMS (ESI): calcd. for C16H22O3Na [M + Na]+
285.1467; found 285.1455.
2-{(2R,4S,6S)-4-(Benzyloxy)-6-[(benzyloxy)methyl]-3-methylene-
tetrahydro-2H-pyran-2-yl}acetaldehyde (10α) and 2-{(2S,4S,6S)-4-
(Benzyloxy)-6-[(benzyloxy)methyl]-3-methylenetetrahydro-2H-
pyran-2-yl}acetaldehyde (10β): By following the procedure de-
scribed for compounds 5α and 5β, compound 9 was employed to
prepare compounds 10α and 10β (65% yield, 90:10 diastereomeric
ratio); Rf = 0.6 (30% EtOAc/hexanes). Only 10α was isolated by chro-
matography on a silica gel column. Data for 10α: 1H NMR
(400 MHz, CDCl3): δ = 9.75–9.76 (q, 1 H), 7.27–7.35 (m, 10 H),
5.23 (s, 1 H), 5.03 (s, 1 H), 4.96 (dd, J = 5.6 Hz, J = 14.4 Hz, 1 H),
4.51–4.60 (m, 4 H), 4.10 (dd, J = 4.8 Hz, J = 9.2 Hz, 1 H), 4.00–
4.06 (m, 1 H), 3.67 (dd, J = 6.4 Hz, J = 10.4 Hz, 1 H), 3.45 (dd, J
= 4.4 Hz, J = 10 Hz, 1 H), 2.83 (ddd, J = 3.2 Hz, J = 8.8 Hz, J =
16 Hz, 1 H), 2.59 (ddd, J = 2.0 Hz, J = 6.0 Hz, J = 16 Hz, 1 H),
2.16 (dt, J = 4.4 Hz, J = 12.8 Hz, 1 H), 1.57 (m, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 200.1, 144.4, 138.2, 138.1, 128.4,
128.3, 127.7, 127.6, 127.3, 110.1, 74.2, 73.3, 71.9, 71.4, 70.5, 70.2,
53.4, 45.6, 35.8 ppm. HRMS (ESI): calcd. for C23H27O4 [M + H]+
367.1909; found 367.1908.: Compound 10β was not isolated by col-
umn chromatography but obtained as a mixture with 10α.
[(2R,3S)-2-(Azidomethyl)-3-(benzyloxy)-3,4-dihydro-2H-pyran-5-yl]-
methanol (15): By following the procedure described for 3, (2R,3S)-
2-(azidomethyl)-3-(benzyloxy)-3,4-dihydro-2H-pyran-5-carbalde-
hyde was employed to prepare compound 15 (87% yield); Rf = 0.67
(30% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3): δ = 7.33–
7.41, (m, 5 H), 6.46 (s, 1 H), 4.72 (d, J = 12.4 Hz, 1 H), 4.56 (d, J
= 11.6 Hz, 1 H), 4.00 (s, 2 H), 3.84–3.87 (m, 1 H), 3.74–3.80 (m, 1
H), 3.64 (dd, J = 2.8 Hz, J = 13.2 Hz, 1 H), 3.55 (dd, J = 5.2 Hz,
J = 12.8 Hz, 1 H), 2.62 (dd, J = 6.0 Hz, J = 16.0 Hz, 1 H), 2.21
(dd, J = 8.4 Hz, J = 16.0 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 140.6, 137.7, 128.5, 127.9, 127.8, 110.7, 76.4, 70.9,
70.6, 63.4, 51.1, 27.9 ppm. HRMS (ESI): calcd. for C14H17N3O3Na
[M + Na]+ 298.1168; found 298.1168.
(2R,3S)-2-(Azidomethyl)-3-(benzyloxy)-5-[(vinyloxy)methyl]-3,4-di-
hydro-2H-pyran (16): By following the procedure described for 4,
compound 15 was employed to prepare compound 16 (66% yield);
(S)-{2-[(Benzyloxy)methyl]-3,4-dihydro-2H-pyran-5-yl}methanol
(11): By following the procedure described for 3, (S)-2-[(benzyloxy)
methyl]-3,4-dihydro-2H-pyran-5-carbaldehyde was employed to
prepare compound 11 (80% yield); Rf = 0.52 (40% EtOAc/hex-
1
Rf = 0.65 (5% EtOAc/hexanes). H NMR (400 MHz, CDCl3): δ =
7.32–7.39, (m, 5 H), 6.50 (s, 1 H), 6.46 (dd, J = 6.8 Hz, J = 14.4 Hz,
1 H), 4.71 (d, J = 11.2 Hz, 1 H), 4.53 (d, J = 11.2 Hz, 1 H), 4.25
(dd, J = 2.0 Hz, J = 14.4 Hz, 1 H), 4.09 (s, 2 H), 4.05 (dd, J =
2.0 Hz, J = 6.8 Hz, 1 H), 3.84–3.87 (m, 1 H), 3.76–3.80 (m, 1 H),
3.65 (dd, J = 2.4 Hz, J = 13.2 Hz, 1 H), 3.55 (dd, J = 5.2 Hz, J =
12.8 Hz, 1 H), 2.58 (dd, J = 6.0 Hz, J = 16.4 Hz, 1 H), 2.18 (dd, J
= 8.8 Hz, J = 16.0 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 151.2, 142.0, 137.6, 128.5, 127.9, 127.8, 107.1, 87.4, 76.6, 70.9,
70.4, 69.0, 51.1, 28.2 ppm.
anes). [α]D = +51 (c = 0.29, CHCl ). IR (neat): ν
= 3419, 2854,
˜
3
max
1671 cm–1. H NMR (400 MHz , CDCl3): δ = 7.31–7.36 (m, 5 H),
6.50 (s, 1 H), 4.60 (d, J = 12.0 Hz, 1 H), 4.56 (d, J = 12.0 Hz, 1
H), 3.96–3.99 (m, 3 H), 3.56 (ddd, J = 6.4 Hz, J = 10.4 Hz, J =
22.8 Hz, 2 H), 2.09–2.17 (m, 2 H), 1.90–1.94 (m, 1 H), 1.72–1.74
(m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 141.6, 138.0,
128.4, 127.7, 127.7, 112.7, 74.1, 73.4, 72.2, 64.3, 24.0, 20.8 ppm.
HRMS (ESI): calcd. for C14H18O3Na [M + Na]+ 257.1154; found
257.1154.
1
2-[(2R,5S,6R)-6-(Azidomethyl)-5-(benzyloxy)-3-methylenetetra-
hydro-2H-pyran-2-yl]acetaldehyde (17α), 2-[(2S,5S,6R)-6-(Az-
idomethyl)-5-(benzyloxy)-3-methylenetetrahydro-2H-pyran-2-yl]acet-
aldehyde (17β), and (6S,7R,E)-8-Azido-6-(benzyloxy)-7-hydroxy-4-
methyleneoct-2-enal (18): By following the procedure described for
5α, 5β, and 6, compound 16 was employed to prepare compounds
(S)-2-[(Benzyloxy)methyl]-5-[(vinyloxy)methyl]-3,4-dihydro-2H-
pyran (12): By following the procedure described for 4, compound
11 was employed to prepare compound 12 (65% yield); Rf = 0.7
(10% EtOAc/hexanes). [α]D = +45 (c = 1.0, CHCl ). IR (neat): ν
˜
3
max
= 3024, 2920, 1671, 1638, 1616 cm–1. 1H NMR (400 MHz, CDCl3): 17α, 17β, and 18. Data for 17α: (39% yield); Rf = 0.6 (30% EtOAc/
1
δ = 7.28–7.38 (m, 5 H), 6.56 (s, 1 H), 6.44 (q, J = 6.8 Hz, J = hexanes). H NMR (400 MHz, CDCl3): δ = 9.86 (t, J = 2.0 Hz, 1
8090
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Eur. J. Org. Chem. 2014, 8085–8093

Stereoselective Synthesis of α- and β-C-Glycosides
H), 7.32–7.40, (m, 5 H), 4.97 (s, 1 H), 4.80 (s, 1 H), 4.67 (d, J =
11.6 Hz, 1 H), 4.47 (d, J = 11.6 Hz, 1 H), 4.40 (t, J = 6.4 Hz, 1 H),
3.65 (dtd, J = 2.4 Hz, J = 6.0 Hz, J = 11.2 Hz, 1 H), 3.55 (dd, J =
2.4 Hz, J = 13.2 Hz, 1 H), 3.42–3.48 (m, 1 H), 3.37 (dd, J = 6.0 Hz,
J = 13.2 Hz, 1 H), 2.97 (dd, J = 4.8 Hz, J = 12.8 Hz, 1 H), 2.79
(dd, J = 2.4 Hz, J = 6.4 Hz, 2 H), 2.30 (dd, J = 11.6 Hz, J =
12.8 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 200.6, 142.3,
137.7, 128.5, 127.9, 127.8, 110.5, 80.2, 74.8, 73.7, 71.0, 51.6, 45.2,
38.4 ppm. Compound 17β was only observed in the NMR spectra
of the crude product, and it was not detected after column chro-
matography. Compound 18 was only observed during the purifica-
tion of compounds 17α and 17β over silica gel. Data for 18: (40%
yield); Rf = 0.5 (30 % EtOAc/hexanes). 1H NMR (400 MHz,
CDCl3): δ = 9.59 (d, J = 7.6 Hz, 1 H), 7.29–7.38, (m, 5 H), 7.14
(d, J = 15.6 Hz, 1 H), 6.26 (dd, J = 7.6 Hz, J = 16 Hz, 1 H), 5.63
(d, J = 14.4 Hz, 2 H), 4.54 (d, J = 5.2 Hz, 2 H), 3.81–3.83 (m, 1
H), 3.60–3.65 (m, 1 H), 3.50 (d, J = 5.6 Hz, 2 H), 2.66 (dd, J =
3.2 Hz, J = 13.6 Hz, 1 H), 2.57 (dd, J = 8.4 Hz, J = 14.4 Hz, 1 H),
2.29 (br. s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 193.9,
154.0, 141.4, 137.4, 129.2, 128.5, 128.1, 128.0, 78.3, 73.2, 71.9, 53.4,
33.2 ppm.
2.76–2.87 (m, 2 H), 2.17 (ddd, J = 1.6 Hz, J = 4 Hz, J = 11.2 Hz,
1 H), 1.42 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 200.8,
145.5, 138.3, 138.1, 128.4, 128.4, 127.7, 127.3, 106.4, 75.4, 73.4,
72.8, 71.0, 60.4, 45.3, 37.1 ppm. HRMS (ESI): calcd. for
C23H26O4Na [M + Na]+ 389.1729; found 389.1718.
2-{(2R,3R,5S,6R)-5-(Benzyloxy)-6-[(benzyloxy)methyl]-3-methyl-
tetrahydro-2H-pyran-2-yl}ethanol (20a) and 2-{(2R,3S,5S,6R)-5-
(Benzyloxy)-6-[(benzyloxy)methyl]-3-methyltetrahydro-2H-pyran-2-
yl}ethanol (20b): To a stirred solution of 7α (30 mg, 0.08 mmol) in
methanol (3 mL) were added Na2CO3, (25 mg, 0.24 mmol) and
10% Pd/C (6 mg). The mixture was stirred for 4 h under H2. Upon
completion of the reaction (monitored by TLC), the suspension
was filtered through a pad of Celite, and the filtrate was concen-
trated in vacuo. The obtained residue was purified by chromatog-
raphy on a silica gel column to provide compound 20a as a pure
compound and 20b as a mixture with 20a (21 mg, 70% yield); Rf
1
= 0.64 (40% EtOAc/hexanes). Data for 20a: H NMR (400 MHz,
CDCl3): δ = 7.24–7.36 (m, 10 H), 4.63 (d, J = 12.0 Hz, 1 H), 4.62
(d, J = 11.6 Hz, 1 H), 4.56 (d, J = 12.4 Hz, 1 H), 4.40 (d, J =
11.6 Hz, 1 H), 3.99–4.03 (m, 1 H), 3.85–3.87 (m, 2 H), 3.78–3.80
(m, 2 H), 3.58 (dd, J = 7.2 Hz, J = 10.4 Hz, 1 H), 3.36–3.41 (m, 1
2-[(2R,5S,6R)-6-(Azidomethyl)-5-(benzyloxy)-3-methylenetetra- H), 2.78 (br. s, 1 H), 2.06–2.21 (m, 3 H), 1.35–1.47 (m, 2 H), 0.90
hydro-2H-pyran-2-yl]ethanol (19α) and 2-[(2S,5S,6R)-6-(Azido- (d, J = 7.2 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 138.4,
methyl)-5-(benzyloxy)-3-methylenetetrahydro-2H-pyran-2-yl]ethanol 138.2, 128.4, 128.3, 127.7, 127.6, 127.5, 77.2, 74.1, 73.5, 71.8, 70.6,
(19β): By following the procedure described for 7α and 7β, com-
pounds 19α and 19β were obtained as an inseparable anomeric mix-
ture (74% yield, see Supporting Information). Rf = 0.65 (for 19α)
and 0.66 (for 19β).
70.2, 61.7, 32.9, 32.8, 26.2, 17.1 ppm. HRMS (ESI): calcd. for
C23H30O4Na [M + Na]+ 393.2042; found 393.2042. Compound 20b
was not isolated by column chromatography but obtained as a mix-
ture with 20a.
ZnII-Mediated Anomerization of α-C-Glycoside into β-C-Glycoside
2-{(2S,3S,5S,6R)-5-(Benzyloxy)-6-[(benzyloxy)methyl]-3-methyl-
tetrahydro-2H-pyran-2-yl}ethanol (21a) 2-{(2S,3R,5S,6R)-5-(Benz-
yloxy)-6-[(benzyloxy)methyl]-3-methyltetrahydro-2H-pyran-2-
yl}ethanol (21b): By following the procedure described for 20a and
20b, compound 7β was employed to prepare compounds 21a and
21b (72% yield); Rf = 0.66 (40% EtOAc/hexanes). Data for 21a:
1H NMR (500 MHz, CDCl3): δ = 7.24–7.35 (m, 10 H), 4.60 (d, J
= 12.0 Hz, 1 H), 4.57 (d, J = 11.5 Hz, 1 H), 4.55 (d, J = 12.0 Hz,
1 H), 4.39 (d, J = 11.5 Hz, 1 H), 3.80–3.86 (m, 2 H), 3.77 (dd, J
= 1.5 Hz, J = 11.0 Hz, 1 H), 3.73 (dt, J = 2.5 Hz, J = 10.5 Hz, 1
H), 3.60 (dd, J = 6.5 Hz, J = 10.5 Hz, 1 H), 3.50–3.53 (m, 2 H),
2.11–2.14 (m, 1 H), 1.87–1.92 (m, 2 H), 1.47–1.52 (m, 2 H), 1.00
(d, J = 7.5 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 138.4,
138.3, 128.3, 127.7, 127.6, 127.6, 127.5, 80.9, 80.8, 73.4, 71.0, 70.3,
70.1, 62.3, 36.9, 34.7, 33.1, 13.0 ppm. HRMS (ESI): calcd. for
C23H30O4Na [M + Na]+ 393.2042; found 393.2042. Compound 21b
was not isolated by column chromatography but obtained as a mix-
ture with 21a.
2-{(5S,6R)-5-(Benzyloxy)-6-[(benzyloxy)methyl]-3-methylenetetra-
hydro-2H-pyran-2-yl}ethanol (7β): To a solution of crude 5α/5β
(0.1 g, 0.27 mmol) in 4% NaOMe/MeOH (3 mL) was added anhy-
drous Zn(OAc)2 (249 mg, 1.36 mmol) at 25 °C, and the mixture was
stirred for a period of 24 h. After complete consumption of the α-
C-glycoside (monitored by TLC), the reaction mixture was slowly
neutralized by the addition of AcOH. The suspension was filtered
through a pad of Celite, and the filter cake was washed with ethyl
acetate (50 mL). The filtrate was washed with water and brine,
dried with anhydrous Na2SO4, and concentrated under reduced
pressure to provide crude 5β as a colorless gum, which was used in
the next step without further purification (attempts to purify 5β
were unsuccessful). Crude 5β [75% (crude)] was immediately dis-
solved in dry ethanol (3 mL), and the resulting solution was treated
with NaBH4 (15 mg, 0.40 mmol) at 0 °C. The stirring was contin-
ued for 3 h. Upon complete consumption of the starting material,
the reaction was quenched by the addition of saturated aqueous
NH4Cl. The ethanol was removed under reduced pressure, and the
obtained residue was dissolved in CH2Cl2 (50 mL). The resulting
solution was washed with brine, dried with anhydrous Na2SO4, and
concentrated under reduced pressure to obtain the crude β-C-glyc-
oside. Purification of the crude product by chromatography on a
silica gel column provided pure 7β (67 mg, 67% yield) as a colorless
gum; Rf = 0.62 (40% EtOAc/hexanes).
2-{(2R,3R,6S)-6-[(Benzyloxy)methyl]-3-methyltetrahydro-2H-pyran-
2-yl}ethanol (22a) and 2-{(2R,3S,6S)-6-[(Benzyloxy)methyl]-3-meth-
yltetrahydro-2H-pyran-2-yl}ethanol (22b): By following the pro-
cedure described for 20a and 20b, compounds 22a and 22b were
obtained as a diastereomeric mixture that was inseparable by col-
umn chromatography (74% yield, see Supporting Information); Rf
= 0.44 (40% EtOAc/hexanes). HRMS (ESI): calcd. for C16H25O3
[M + H]+ 265.1804; found 265.1804.
2-{(2S,4S,6S)-4-(Benzyloxy)-6-[(benzyloxy)methyl]-3-methylene-
tetrahydro-2H-pyran-2-yl}acetaldehyde (10β): By following the pro-
cedure described for 5β, the crude 10α/10β mixture was employed
to prepare compound 10β (65% yield); Rf = 0.64 (30% EtOAc/
2-{(2S,3S,5S,6R)-5-(Benzyloxy)-6-[(benzyloxy)methyl]-3-methyl-
tetrahydro-2H-pyran-2-yl}ethyl Acetate (23): Acetic anhydride
(0.36 mL, 3.80 mmol) was slowly added at 0 °C to a solution of
21a (0.35 g, 0.95 mmol) in dry pyridine (7 mL). After stirring for
4 h at room temperature, the pyridine was evaporated under re-
1
toluene). H NMR (400 MHz, CDCl3): δ = 9.82 (t, J = 1.6 Hz, 1
H), 7.26–7.36 (m, 10 H), 5.36 (d, J = 2 Hz, 1 H), 4.89 (s, 1 H),
4.61–4.68 (m, 2 H), 4.51–4.57 (m, 2 H), 4.27 (t, J = 6 Hz, 1 H), duced pressure, and the obtained residue was dissolved in CH2Cl2
4.00 (dd, J = 4.8 Hz, J = 11.2 Hz, 1 H), 3.79 (m, 1 H), 3.50 (dd, J (50 mL). The solution was washed with aqueous copper sulfate
= 5.2 Hz, J = 10.8 Hz, 1 H), 3.45 (dd, J = 8.8 Hz, J = 16 Hz, 1 H), solution, water, and brine and then dried with anhydrous Na2SO4.
Eur. J. Org. Chem. 2014, 8085–8093
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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8091

C. Sudharani, P. Venukumar, P. R. Sridhar
FULL PAPER
Evaporation of the solvent followed by purification of the crude
3 H), 3.61–3.71 (m, 3 H), 3.19 (ddd, J = 2.4 Hz, J = 6.4 Hz, J =
10.2 Hz, 1 H), 1.81–1.88 (m, 3 H), 1.61 (td, J = 4.4 Hz, J = 11.2 Hz,
1 H), 1.38–1.41 (m, 1 H), 0.99 (d, J = 7.2 Hz, 3 H), 0.90 (s, 9 H),
product by chromatography on a silica gel column gave 23 (0.31 g,
1
90% yield) as a colorless oil; Rf = 0.65 (20% EtOAc/hexanes). H
NMR (400 MHz, CDCl3): δ = 7.25–7.35 (m, 10 H), 4.66 (d, J = 0.87 (s, 9 H), 0.06 (s, 6 H), 0.05 (s, 6 H) ppm. 13C NMR (100 MHz,
12.4 Hz, 1 H), 4.56 (d, J = 12 Hz, 2 H), 4.40 (d, J = 11.2 Hz, 1 H),
4.13–4.23 (m, 2 H), 3.76 (dd, J = 2.0 Hz, J = 10.8 Hz, 1 H), 3.71
(dd, J = 4.8 Hz, J = 10.8 Hz, 1 H), 3.59–3.66 (m, 1 H), 3.55–3.58
(m, 1 H), 3.39 (ddd, J = 2.0 Hz, J = 4.8, J = 9.6 Hz, 1 H), 2.14
(ddd, J = 2.4 Hz, J = 4.4 Hz, J = 12.4 Hz, 1 H), 2.06 (s, 3 H), 1.85–
1.94 (m, 2 H), 1.64–1.72 (m, 2 H), 0.99 (d, J = 7.2 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 171.1, 138.6, 138.5, 128.3 128.2,
127.7, 127.5, 127.4, 81.3, 76.4, 73.4, 71.0, 69.9, 69.8, 62.0, 37.0,
32.6, 32.0, 21.0, 12.7 ppm. HRMS (ESI): calcd. for C25H32O5Na
[M + Na]+ 435.2147; found 435.2144.
CDCl3): δ = 83.6, 81.4, 63.2, 63.2, 62.9, 40.9, 34.4, 33.5, 25.9, 25.7,
18.3, 17.9, 13.0, –4.1, –4.9, –5.3, –5.4 ppm. HRMS (ESI): calcd. for
C21H46O4Si2Na [M + Na]+ 441.2832; found 441.2833.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of 1H and 13C NMR spectra (COSY and NOESY
spectra for C-glycosides) and HRMS spectra.
Acknowledgments
This work was supported by the University Grant Commission
(UGC), New Delhi, grant number 40-56/2011 (SR). C. S. and P. V.
thank the CSIR for the senior research fellowship (SRF).
2-[(2S,3S,5S,6R)-5-Hydroxy-6-(hydroxymethyl)-3-methyltetrahydro-
2H-pyran-2-yl]ethyl Acetate (24): To a solution of ester 23 (240 mg,
0.58 mmol) in MeOH (8 mL) was added 10% Pd/C (20 mg). The
reaction mixture was stirred for 24 h under H2 and then filtered
through a pad of Celite. The filtrate was concentrated in vacuo.
Purification of the residue by chromatography on a silica gel col-
umn afforded compound 24 (120 mg, 89% yield) as a colorless oil;
Rf = 0.5 (5% MeOH/CHCl3). 1H NMR (400 MHz, CDCl3): δ =
4.17 (dd, J = 6.0 Hz, J = 7.2 Hz, 2 H), 3.83 (td, J = 4.0 Hz, J =
7.6 Hz, 1 H), 3.77 (dd, J = 4.8 Hz, J = 11.6 Hz, 2 H), 3.56–3.58
(m, 1 H), 3.16–3.18 (m, 1 H), 2.06 (s, 3 H), 1.98–2.03 (m, 1 H),
1.77–1.90 (m, 2 H), 1.65–1.67 (m, 2 H), 0.98 (d, J = 7.2 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.1, 82.0, 76.2, 63.9,
63.5, 61.7, 40.1, 32.8, 31.9, 21.0, 12.6 ppm. HRMS (ESI): calcd. for
C11H20O5Na [M + Na]+ 255.1208; found 255.1209.
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methylsilyl)oxy]methyl}-3-methyltetrahydro-2H-pyran-2-yl]ethyl
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lutidine (0.40 mL, 3.44 mmol) in dry CH2Cl2 (8 mL) was cooled
to –78 °C. tert-Butyldimethylsilyl trifluoromethanesulfonate
(0.39 mL, 1.72 mmol) was added at the same temperature, and the
reaction mixture was warmed to 0 °C over a period of 1 h. Upon
completion of the reaction (monitored by TLC), the mixture was
diluted with CH2Cl2 (30 mL). The resulting solution was washed
with water and brine, dried with anhydrous Na2SO4, filtered, and
concentrated under reduced pressure to obtain the crude product
as an oil. Purification of the crude product over silica gel provided
compound 25 (195 mg, 98% yield) as a colorless oil; Rf = 0.5 (5%
1
EtOAc/hexanes). H NMR (400 MHz, CDCl3): δ = 4.14–4.19 (m,
2 H), 3.72–3.81 (m, 3 H), 3.53 (ddd, J = 2.4 Hz, J = 3.6 Hz, J =
10.6 Hz, 1 H), 3.04 (ddd, J = 2.4 Hz, J = 4.4 Hz, J = 10.2 Hz, 1
H), 2.06 (s, 3 H), 1.76–1.90 (m, 3 H), 1.54–1.67 (m, 2 H), 0.96 (d,
J = 6.8 Hz, 3 H), 0.90 (s, 9 H), 0.88 (s, 9 H), 0.07 (s, 6 H), 0.06 (s,
6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.1, 83.5, 75.7,
62.8, 62.7, 62.1, 40.9, 33.0, 32.0, 25.8, 25.7, 21.0, 18.3, 17.9, 12.6,
–4.3, –4.9, –5.0, –5.2 ppm. HRMS (ESI): calcd. for C23H48O5Si2Na
[M + Na]+ 483.2938; found 483.2938.
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methylsilyl)oxy]methyl}-3-methyltetrahydro-2H-pyran-2-yl]ethanol
(26): To a solution of compound 25 (150 mg, 0.33 mmol) in dry
MeOH (6 mL) was added a catalytic amount of sodium methoxide
at 25 °C, and the stirring was continued for 1 h. Upon completion
of reaction, the pH of the mixture was neutralized by the careful
addition of Amberlite IR 120 acidic resin. The suspension was fil-
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uct was purified by chromatography on a silica gel column to give
alcohol 26 (130 mg, 91% yield) as a colorless oil; Rf = 0.5 (10%
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1
EtOAc/hexanes). H NMR (400 MHz, CDCl3): δ = 3.71–3.85 (m,
8092
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 8085–8093

Stereoselective Synthesis of α- and β-C-Glycosides
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rearrangement.
[21]
Purification of compound 5β by column chromatography on
silica gel or neutral alumina was unsuccessful as a result of the
epimerization.
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[22]
[23]
The ratio was obtained by the integration values of the C-2-
1
methyl group in the H NMR spectra.
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[18] The ratio was calculated by integrating the aldehyde peaks of
1
the crude H NMR spectrum.
[19] A similar type of analysis was implemented to assign the anom-
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Received: August 9, 2014
Published Online: November 6, 2014
Eur. J. Org. Chem. 2014, 8085–8093
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
8093