Rapid access to 1,6-anhydro-β-L-hexopyranose derivatives via domino reaction: Synthesis of L-allose and L-glucose

Article abstract of DOI:10.1021/jo800775v

(Chemical Equation Presented) An expeditious and efficient synthesis of 1,6-anhydro-β-L-hexopyranosyl derivatives 3 as valuable building blocks for the preparation of L-sugars is herein reported. This route relies upon the use of a domino reaction involving five synthetic steps from the 5,6-dihydro-1,4-dithiin 4. As 1,6-anhydro derivatives 3 are obtained, dithioethylene bridge removal and double-bond dihydroxylation give access to protected L-allose and L-glucose in stereoselective fashion and high yields.

Full text of DOI:10.1021/jo800775v

a few approaches for the synthesis of L-series 1,6-anhydrosugars
are reported;7 nevertheless, considering their potential use as
chiral building blocks in rare sugar-containing natural product
synthesis,8 their preparation still represents a challenging subject
of investigation.
Rapid Access to 1,6-Anhydro-ꢀ-L-hexopyranose
Derivatives via Domino Reaction: Synthesis of
L-Allose and L-Glucose
Daniele D’Alonzo, Annalisa Guaragna,*
Carmela Napolitano, and Giovanni Palumbo
Dipartimento di Chimica Organica e Biochimica, UniVersita`
di Napoli Federico II-Complesso UniVersitario Monte
Sant’Angelo Via Cinthia, 4 I-80126 Napoli, Italy
FIGURE 1. Chair conformation of 1,6-anhydro-ꢀ-L-hexopyranoses
(4C1) and L-hexopyranosides (1C4).
guaragna@unina.it
ReceiVed April 7, 2008
As part of our efforts working toward the de novo synthesis
of L-sugars,9 a complementary approach to such molecules is
herein proposed through the preparation of 1,6-anhydro-ꢀ-L-
hexopyranoses, taking advantage of their stereochemical features.
We have recently reported9 a new synthetic methodology for
the stereoselective synthesis of L-hexoses, based on the use of
our 1,2-bis-thioenol ether synthon 1, acting as a three-carbon
homologating agent10 and 2,3-O-isopropylidene-L-glyceralde-
hyde (2) (Scheme 1). To our regret, although L-manno- and
L-altro-hexopyranosides were easily synthesized, the strategy
proved to be unsuitable for the preparation of the remaining
epimers with gluco-configuration, therefore requiring a different
approach. On the other hand, the 1,6-anhydro derivative 3, which
occurred as a byproduct at the beginning of our experiments,
holds the favorable stereochemical requirements to be conve-
niently used for the synthesis of L-gluco and L-allo-pyranosides.
For this purpose, we devoted our efforts to the development of
an efficient method for 1,6-anhydrosugar preparation.
An expeditious and efficient synthesis of 1,6-anhydro-ꢀ-L-
hexopyranosyl derivatives 3 as valuable building blocks for
the preparation of L-sugars is herein reported. This route
relies upon the use of a domino reaction involving five
synthetic steps from the 5,6-dihydro-1,4-dithiin 4. As 1,6-
anhydro derivatives 3 are obtained, dithioethylene bridge
removal and double-bond dihydroxylation give access to
protected L-allose and L-glucose in stereoselective fashion
and high yields.
A first approach to anhydro compound 3 is depicted in
Scheme 2. As the coupling reaction between 1 and 2 was
accomplished, the anti-adduct was easily separated from its syn-
diastereomer by flash chromatography.9 Benzylation or acety-
lation of the secondary hydroxyl group led almost quantitatively
to derivatives 4. Then, MPM group removal by treatment of 4
with DDQ in a CH2Cl2/H2O emulsion led to alcohols 5
1,6-Anhydrohexopyranoses are useful synthons for the syn-
thesis of complex natural products and bioactive molecules.1
Indeed, their [3.2.1]bicyclic skeleton enables high regio- and
stereocontrolled reactions; likewise, it does not require the use
of protecting groups at C1 and C6 positions.2
From a stereochemical standpoint, one of the most intriguing
features of the 1,6-anhydrohexose framework is represented by
the locked conformation of the pyranose ring, with stereocenters
in opposite orientation compared to the corresponding pyrano-
sides (Figure 1).
Several efficient methods have been devised to gain access
to 1,6-anhydro-ꢀ-hexopyranoses belonging to D-series, including
cyclization of hexose derivatives under acidic3 or alkaline4
conditions and Lewis acid5 or halonium ion6-catalyzed intramo-
lecular rearrangement of D-glycal derivatives. Conversely, only
(4) (a) Lafont, D.; Boullanger, P.; Cadas, O.; Descotes, G. Synthesis 1989,
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6489, and references cited therein.
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Wang, C.-C.; Wen, Y.-S. J. Am. Chem. Soc. 2001, 123, 3153–3154. (b) Wang,
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S.; Wang, C.-C.; Kulkarni, S. S.; Puranik, R.; Liu, Y.-H.; Hung, S.-C. Chem.
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(9) (a) Guaragna, A.; Napolitano, C.; D’Alonzo, D.; Pedatella, S.; Palumbo,
G. Org. Lett. 2006, 8, 4863–4866. For pioneer work, see: (b) Ko, Soo Y.; Lee,
A. M.; Masamune, S.; Reed, L. A., III; Sharpless, K. B.; Walker, F. J. Science
1983, 220, 949–951. (c) Ko, Soo Y.; Lee, A. M.; Masamune, S.; Reed, L. A.,
III; Sharpless, K. B.; Walker, F. J. Tetrahedron 1990, 46, 245–264.
(10) (a) Guaragna, A.; D’Errico, S.; D’Alonzo, D.; Pedatella, S.; Palumbo,
G. A. Org. Lett. 2007, 9, 3473–3476. (b) Guaragna, A.; Pedatella, S.; Palumbo,
G. In e-Encyclopedia of Reagents for Organic Synthesis (e-EROS); Paquette,
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Asymmetry 1994, 5, 1905–1908. (b) Oberdorfer, F.; Haeckel, R.; Lauer, G. Synlett
1998, 201–206, and references cited therein.
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047084289X.rn00831.
& Sons: New York, 2008; DOI 10.1002/
5636 J. Org. Chem. 2008, 73, 5636–5639
10.1021/jo800775v CCC: $40.75 2008 American Chemical Society
Published on Web 06/21/2008

SCHEME 1. Retrosynthetic Path
SCHEME 3. Proposed Path for the Synthesis of
1,6-Anhydro Sugar Derivatives 3 by Domino Reaction
SCHEME 2. Synthesis of 1,6-Anhydro Compounds 3
affording, depending on the conditions used, an alcohol10 or a
formyl11 function; (b) the use of DDQ in protic solvents
generates an acidic environment, owing to the evolution of
HCN;12 and (c) isopropylidene group and formyl function can
be respectively removed and activated under such conditions.
On the basis of these realizations, experiments were carried
out to establish suitable conditions for a direct double cyclization
starting from intermediates 4, with the aim to obtain the 1,6-
anhydrosugar intermediates 3 by a domino reaction.13 As a
result, the use of an excess of DDQ (2.0 equiv) in a refluxing
18:1 CH2Cl2/H2O emulsion14 and more prolonged reaction times
(48-56 h) resulted in a sequence of five synthetic transforma-
tions, affording 3 in excellent 89-92% yields. In addition, the
reaction was compatible with both acetyl and benzyl derivatives,
which displayed similar reactivity. Formally, the following
reactions took place (Scheme 3): MPM protecting group
removal, oxidation of the resulting primary hydroxyl function
to yield aldehyde 6, isopropylidene group removal with
subsequent attack by C5 hydroxyl group on the activated formyl
function to give the hemiacetal 8, and further ring closure by
means of the C6 hydroxyl attack on the C1 position. Reaction
could be stopped at the stage of aldehyde 6, which was indeed
isolable during the course of the reaction; conversely, hemiacetal
8 could not be detected.
As previously emphasized, compounds 3 represented profit-
able intermediates to have an easy access to L-hexoses; for this
purpose, benzyl ether 3b was chosen for further elaborations.
Dithioethylene bridge removal by treatment of 3b with Ni/
Ra at 0 °C afforded the unsaturated 1,6-anhydro-ꢀ-L-hexopy-
ranose 9 in 75% yield (Scheme 4). As previously reported9a,10
for similar substrates, when the desulfurization reaction was
carried out with a Raney-Ni excess, the over-reduction product
was obtained in satisfactory yield (82%), affording the 2,3-
dideoxy-1,6-anhydro-ꢀ-L-hexopyranose 10.
(70-72% yield), which were next oxidized by means of PCC
in pyridine, affording the aldehydes 6 (97-99% yield). Sub-
sequently, exposure of 6 to Amberlyst 15 in MeOH afforded
bicycle compounds 7 as an R/ꢀ (85/15) anomeric mixture. The
bicycle system resulted fairly unstable even to mild acidic
conditions giving degradation products in addition to the stable
adducts 3. Intrigued by this finding, we then directed our efforts
on the achievement of the complete conversion of bicycles 7
into the 1,6-anhydrosugar derivatives 3. Best results were gained
by direct treatment of 7 with Amberlyst 15, replacing the
nucleophilic methanol with the weakly acidic chloroform. After
only 30 min, the desired 1,6-anhydro-ꢀ-L-hexopyranose deriva-
tives 3 were isolated in very good (80-94%) yields (Scheme
2). Interestingly, treatment of 3b with Amberlyst in MeOH again
restored bicycle compound 7b (85% yield).
Double-bond functionalization of olefin 9 provided the desired
hexoses 12 and 15. In particular, stereoselective syn-dihydroxy-
lation was first explored. Treatment of 9 with OsO4 in pyridine2
led to 1,6-anhydro derivative 11 with complete selectivity and
Although this route gave access to desired 1,6-anhydro
compounds with satisfactory yields (56-65% overall yield), a
more rapid and efficient procedure could be planned, considering
that (a) the 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
is a reagent capable of removing the MPM protective group
(12) Buckle, D. R. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; John Wiley & Sons: Chichester, UK, 1995; Vol. 4, pp
1699-1704.
(13) For examples of reviews dealing with the use of domino reactions in
organic synthesis, see: (a) Tietze, L. F. Chem. ReV. 1996, 96, 115–136. (b) Tietze,
L. F.; Rackelmann, N. Pure Appl. Chem. 2004, 76, 1967–1983.
(14) A 10-fold more concentrated mixture with respect to DDQ-mediated
MPM removal was also required to accomplish this synthetic sequence.
(11) (a) Caputo, R.; Guaragna, A.; Palumbo, G.; Pedatella, S. J. Org. Chem.
1997, 62, 9369–9371. (b) Guaragna, A.; Palumbo, G.; Pedatella, S. J. Org. Chem.
2004, 69, 7033–7037.
J. Org. Chem. Vol. 73, No. 14, 2008 5637

SCHEME 4. Dithioethylene Bridge Removal of 3b and
syn-Dihydroxylation of 9
excellent yield (93% over two steps, 59% overall yield from
compound 4b).
In summary, a straightforward approach to L-form 1,6-
anhydrosugar derivatives 3 has been herein reported. Key to
the successful outcome of our procedure has been the use of a
domino reaction, formally involving five synthetic steps from
derivatives 4 (with yields ranging from 89 to 92%). Considering
the relatively short number of synthetic steps and the high yields
occurred, this route is to be considered amenable to multigram
scale preparation.
In this paper, the intermediate 3b have been used as building
blocks to stereoselectively afford L-allo- and L-gluco-hexopy-
ranosides 12 and 15, therefore completing the synthesis of
L-hexoses belonging to gluco configuration. Likewise, this
methodology represents a powerful tool for further synthetic
tasks, i.e. the construction of more complex organic molecules
in high selectivity for application in medicinal chemistry.
Experimental Section
General Procedure 1,6-Anhydrosugar Ring-Closure Com-
pound 3b. Method A. Amberlyst 15 (5.5 g, previously washed
with anhydrous MeOH) was added to a stirred solution of aldehyde
6b (0.55 g, 1.5 mmol) in methanol (50 mL) at 0 °C. After 10 min,
the suspension was warmed to room temperature and stirred for
1 h. Then the solid was filtered off and washed with AcOEt; the
organic phase, diluted with AcOEt, was washed with brine until
neutral, dried (Na2SO4), and concentrated under reduced pressure.
The crude residue was dissolved in CHCl3 (90 mL), and Amberlyst
15 (5.5 g, previously washed with anhydrous CHCl3) was added
in one portion at 0 °C. After 10 min, the suspension was warmed
to room temperature and further stirred for 1 h. Then the solid was
filtered off and washed with CHCl3, and the resulting solution
washed with saturated NaHCO3 solution and brine. The organic
layers were dried (Na2SO4), and the solvent was evaporated.
Chromatography of the crude residue over silica gel (hexane/acetone
) 90:1) gave the pure 3b (0.44 g, 94% overall yield).
SCHEME 5. anti-Dihydroxylation of 9
Method B. To a stirred 18:1 CH2Cl2/H2O emulsion (7 mL)
containing the ether 4b (0.48 g, 1.0 mmol) was added DDQ (0.45
g, 2.0 mmol) at room temperature, and then the reaction was
warmed until reflux and stirred for 48 h. Then H2O was added,
and the mixture was extracted with CH2Cl2; the organic layer was
dried (Na2SO4) and the solvent evaporated. Chromatography of the
crude residue (hexane/acetone ) 9:1) gave pure 3b (0.28 g, 92%
yield): white solid; mp 132.3-134.4 °C (from MeOH); [R]25D +12.5
(c 1.2, CHCl3); 1H NMR (400 MHz, CDCl3) δ 3.16-3.29 (m, 4H),
3.56 (dd, J ) 2.0 Hz, J ) 7.7 Hz, 1H), 3.58 (d, J ) 1.0 Hz, 1H),
3.98 (dd, J ) 6.8 Hz, J ) 7.7 Hz, 1H), 4.72 (s, 2H), 4.80-4.82
(m, 1H), 5.24 (s, 1H), 7.29-7.44 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ 27.6, 27.7, 64.0, 70.2, 76.6, 77.0, 98.8, 118.9, 126.8,
127.7, 128.0, 128.3, 137.9. Anal. Calcd for C15H16O3S2: C, 58.41;
H, 5.23; S, 20.79. Found: C, 58.59; H, 5.25; S, 20.71.
in 91% yield, the attack being driven on the less hindered face
of the olefin. Hence, stereoselective acetal ring opening was
studied. Exposure of 11 to HCl in MeOH provided an anomeric
mixture of the resulting methyl pyranosides without significant
selectivity,15 whereas treatment with a weaker acidic agent, such
as TFA, did not display any reactivity. Eventually, best results
were attained exposing 11 to a catalytic amount of TfOTMS in
MeOH, allowing smooth acetal cleavage with complete R-se-
lectivity at the anomeric center and in almost quantitative yield
to give the methyl 4-O-benzyl-R-L-allo-pyranoside (12, 58%
overall yield from compound 4b).
syn-Dihydroxylation: 1,6-Anhydro-4-O-benzyl-ꢀ-L-allopyr-
anose (11). To a solution of 9 (0.15 g, 0.69 mmol) in pyridine (5.0
mL), cooled at 0 °C, was added OsO4 (0.17 g, 0.69 mmol), and
the resulting mixture was stirred overnight at room temperature;
then the reaction was quenched with a saturated NaHSO3 solution
and evaporated under reduced pressure. Chromatography of the
crude residue over silica gel (CH2Cl2/MeOH ) 95/5) afforded pure
11 (0.16 g, 91% yield) as single diastereomer: white crystals; mp
Finally, anti-dihydroxylation was considered (Scheme 5). The
allylic ether 9 was stereoselectively oxidized with in situ
generated methyl(trifluoromethyl)dioxirane (TFDO) to afford
the 1,6:2,3-dianhydro-ꢀ-L-hexopyranose 13, the L-enantiomer
1a
ˇ
of the so-called “Cerny´ epoxide”, in 92% yield. Subsequent
2,3-oxirane ring opening by means of refluxing KOH solution
led to dihydroxylated product 14. The direct treatment of the
latter with catalytic TfOTMS in MeOH easily brought on 1,6-
anhydro ring cleavage, leading to methyl 4-O-benzyl-R-L-gluco-
hexopyranoside (15, Scheme 5) as a single anomer and in
109.0-110.3 °C (from hexane/acetone); [R]25 +71.1 (c 0.8,
D
CHCl3) [lit.16 data for ent-11: mp 113 °C, [R]25 -79.0 and mp
D
109-111 °C, [R]25D -76.0)]; 1H NMR (300 MHz, CDCl3) δ 1.61
(bs, 1H), 2.82 (bs, 1H), 3.60 (bt, J ) 1.8 Hz, 1H), 3.70 (dd, J )
ˇ
(15) Kikuchi, E.; Yoshimoto, T.; Yoshisuke, T. Chem. Pharm. Bull. 1985,
33, 2243–2255.
(16) Cerny´, M.; Kalvoda, L.; Paca´k, J. Collect. Czech. Chem. Commun. 1968,
33, 1143–1156.
5638 J. Org. Chem. Vol. 73, No. 14, 2008

5.4 Hz, J ) 7.4 Hz, 1H), 3.87 (dd, J ) 1.8 Hz, J ) 5.6 Hz, 1H),
4.02-4.08 (m, 1H), 4.12 (d, J ) 7.4 Hz, 1H), 4.57 (bd, J ) 5.4
Hz, 1H), 4.62 (d, J ) 12.4 Hz, 1H), 4.64 (d, J ) 12.4 Hz, 1H),
5.40 (s, 1H), 7.28-7.42 (m, 5H); 13C NMR (75 MHz, CDCl3) δ
64.8, 66.6, 68.8, 71.5, 74.0, 78.2, 101.4, 127.7, 127.9, 128.5, 137.4.
Anal. Calcd for C13H16O5: C, 61.90; H, 6.39. Found: C, 61.71; H,
6.41.
+40.2 (c 1.5, EtOH) [lit.18 data for ent-14: mp 53.0-54.0 °C, [R]25
D
-43.0 and mp 50.0-52.0 °C, [R]25D -41.0]; 1H NMR (500 MHz,
CDCl3) δ 2.52 (bs, 1H), 2.75 (bs, 1H), 3.45 (s, 1H), 3.55 (bs, 1H),
3.78 (dd, J ) 5.4 Hz, J ) 7.8 Hz, 1H), 3.94 (bs, 1H), 4.15 (d, J )
7.8 Hz, 1H), 4.63 (bd, J ) 7.3 Hz, 1H), 4.66 (d, J ) 11.7 Hz, 1H),
4.70 (d, J ) 11.7 Hz, 1H), 5.52 (s, 1H), 7.30-7.40 (m, 5H); 13C
NMR (75 MHz, CDCl3): δ 65.3, 69.8, 70.4, 71.3, 74.3, 76.6, 102.0,
127.6, 127.8, 128.4, 137.0. Anal. Calcd for C13H16O5: C, 61.90; H,
6.39. Found: C, 62.12; H, 6.52.
Epoxidation: 1,6:2,3-Dianhydro-4-O-benzyl-ꢀ-L-allopyranose
(13). Na2EDTA (4.0 × 10-4 M, 3.45 mL) and CF3COCH3 (0.61
mL) were added to a solution of 9 (0.15 g, 0.69 mmol) in CH3CN
(6.9 mL) at 0 °C. After a few minutes, a mixture of NaHCO3 (0.43
g) and Oxone (1.72 g) was added over 1 h, and the whole resulting
mixture was stirred for 30 min at the same temperature. Then the
reaction was diluted with H2O and extracted with CH2Cl2. The
extracts were washed with brine, dried (Na2SO4), and evaporated
under reduced pressure. Chromatography of the crude residue over
silica gel (hexane/acetone ) 8:2) afforded the pure 13 (0.15 g, 92%
yield) as a single diastereoisomer: white solid; mp 74.2-76.0 °C
Methyl 4-O-Benzyl-r-L-glucopyranoside (15). The crude 14,
coevaporated three times with toluene, was dissolved in MeOH
(10 mL), and a catalytic amount of TfOTMS (10.9 µL, 0.06 mmol)
was added. The resulting reaction mixture was stirred at 50 °C for
48 h, and then the reaction was quenched with solid NaHCO3 and
the solvent evaporated under reduced pressure. Chromatography
of the crude residue over silica gel (CH2Cl2/MeOH ) 9/1) gave
the pure 15 (0.16 g, 93% yield from 13): white crystals; mp
125-127 °C; [R]25D -144.2 (c 1.2, MeOH) [lit.19 data for ent-15:
mp 126.0-127.0 °C, [R]25D +154.0]; 1H NMR (500 MHz, CDCl3)
δ 3.41 (s, 3H), 3.46 (t, J ) 9.5 Hz, 1H), 3.51 (dd, J ) 3.1 Hz, J
) 9.5 Hz, 1H), 3.65 (dt, J ) 3.2 Hz, J ) 9.5 Hz, 1H), 3.67-3.73
(m, 1H), 3.76 (dd, J ) 3.2 Hz, J ) 11.7 Hz, 1H), 3.84 (dd, J ) 3.2
Hz, J ) 11.7 Hz, 1H), 3.86 (t, J ) 9.5 Hz, 1H), 4.73 (d, J ) 11.2
Hz, 1H), 4.77 (d, J ) 3.1 Hz, 1H), 4.87 (d, J ) 11.2 Hz, 1H),
7.25-7.38 (m, 5H); 13C NMR (100 MHz, CD3OD) δ 54.0, 60.8,
61.3, 72.3, 74.0, 74.3, 78.0, 99.7, 127.1, 127.5, 127.7, 138.5. Anal.
Calcd for C14H20O6: C, 59.14; H, 7.09. Found: C, 58.95; H, 7.06.
(from MeOH); [R]25 -117.3 (c 1.8, CHCl3) [lit.17 data for ent-
D
13: mp 74.0-76.0 °C, [R]25D +127.0 and mp 75.0-79.0 °C, [R]25
D
+119.0]; 1H NMR (300 MHz, CDCl3) δ 3.09 (dd, J ) 0.9 Hz, J )
4.4 Hz, 1H), 3.29-3.34 (m, 1H), 3.45 (d, J ) 4.4 Hz, 1H), 3.62
(dd, J ) 1.9 Hz, J ) 7.8 Hz, 1H), 3.88 (appt, J ) 7.1 Hz, J ) 7.8
Hz, 1H), 4.51 (dt, J ) 1.9 Hz, J ) 7.1 Hz, 1H), 4.74 (d, J ) 12.4
Hz, 1H), 4.87 (d, J ) 12.4 Hz, 1H), 5.65 (d, J ) 0.9 Hz, 1H),
7.28-7.47 (m, 5H); 13C NMR (125 MHz, CDCl3) δ 47.5, 47.8,
65.4, 70.7, 72.3, 75.4, 97.1, 127.8, 127.9, 128.4, 137.6. Anal. Calcd
for C13H14O4: C, 66.66; H, 6.02. Found: C, 66.87; H, 6.04.
1,6-Anhydro-4-O-benzyl-ꢀ-L-glucopyranose (14). The epoxide
13 (0.14 g, 0.60 mmol) was refluxed for 48 h in a 1 M aqueous
solution of KOH (8 mL). Then 1 N HCl was carefully added at 0
°C until neutrality. The white solid was filtered off and washed
with AcOEt and the solvent removed under reduced pressure to
afford crude 14, which was directly used in the next reaction. A
sample of crude 14 was purified by SiO2 chromatography (CH2Cl2/
Acknowledgment. 1H and 13C NMR spectra were performed
at Centro Interdipartimentale di Metodologie Chimico-Fisiche
(CIMCF), Universita` di Napoli Federico II.
Supporting Information Available: Experimental proce-
dures, full spectroscopic data, and copies of NMR spectra for
all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
MeOH ) 95/5) and characterized: white crystals; mp 51-53; [R]25
D
ˇ
(17) (a) Cerny´, M.; Trnka, T.; Beran, P.; Paca´k, J. Collect. Czech. Chem.
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J. Org. Chem. Vol. 73, No. 14, 2008 5639