Enantiospecific synthesis of both enantiomers of 2-benzyloxydihydropyran-3- ones from arabinose

Article abstract of DOI:10.1055/s-2005-861833

Approaches to the enantioselective synthesis of the useful building blocks (2R)- and (2S)-2-benzyloxy-2(H)-pyran-3(6H)-one (12 and 17, respectively) are described. The most direct and highly yielding route for the synthesis of 12 was based on the 'one-pot

Full text of DOI:10.1055/s-2005-861833

PAPER
893
Enantiospecific Synthesis of Both Enantiomers of 2-Benzyloxydihydropyran-
3-ones from Arabinose
E
nantiospecific Synthe
a
sis of 2-Be
r
nzyloxyd
í
ihydro
a
pyran-3-ones Laura Uhrig, Oscar Varela*
CIHIDECAR-CONICET, Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires,
Pabellón II, Ciudad Universitaria, 1428, Buenos Aires, Argentina
Fax 54(11)45763346; E-mail: varela@qo.fcen.uba.ar
Received 25 June 2004; revised 9 November 2004
usefulness of the chiral dihydropyranones derived from
Abstract: Approaches to the enantioselective synthesis of the use-
pentoses, we describe here direct approaches to the enan-
tiospecific synthesis of both enantiomers of 2-benzyloxy-
2(H)-pyran-3(6H)-one starting from L- and D-arabinose.
ful building blocks (2R)- and (2S)-2-benzyloxy-2(H)-pyran-3(6H)-
one (12 and 17, respectively) are described. The most direct and
highly yielding route for the synthesis of 12 was based on the ‘one-
pot’ preparation of benzyl 2-O-acetyl-arabinopyranoside 3,4-thio-
nocarbonates (7 and 14) from benzyl b-L- or b-D-arabinopyrano-
sides (1 and 13). Trimethylphosphite-promoted olefination,
followed by O-deacetylation and oxidation gave the optically pure
enantiomeric enones 12 and 17 in about 50% overall yield.
Benzyl b-L-arabinopyranoside (1) was readily prepared
by Fischer glycosylation of L-arabinose. The conversion
of the C-3,4 diol system of 1 into a double bond, via a dis-
ulfonyl derivative, required the selective protection of
HO-2 (Scheme 1). For this reason, compound 1 was treat-
ed with acetone under acidic conditions to give the 3,4-O-
isopropylidene derivative 2, which was acetylated under
standard conditions. Removal of the isopropylidene group
of the resulting 3 with trifluoroacetic acid afforded the
crystalline 2-O-acetyl derivative 4, in about 84% yield
from 1. The 3,4-di-O-p-toluenesulfonylation (tosylation)
of 4 was accomplished with a relatively good yield (72%)
after a long reaction time (3 days). In fact, tosylation of
methyl 2-O-benzoyl-b-L-arabinopyranoside with an ex-
cess of tosyl chloride gave 46% of the 3,4-di-O-tosyl
derivative.10 In contrast, the methylsulfonylation (mesyla-
tion) shoud be more readily accomplished.11 As expected,
the mesylation of 4 took place in a shorter time than the
tosylation and the yield of the dimesylate 6 was higher
(90%).
Key words: enones, carbohydrates, stereoselective synthesis,
chiral pool, olefination
Sugar enones (dihydropyranones) constitute a versatile
category of carbohydrate compounds possessing synthetic
utility.1 The usefulness of sugar enones as chiral building
blocks relies upon the fact that they posses olefinic and
carbonyl unsaturations to which a number of well-estab-
lished reactions may be applied.2 In addition, because of
the chiral environment generated by the remaining stereo-
centers, reactions to the enone system are usually highly
diastereoselective.2,3 Even though, the use of alkyl 3-
enopyranosid-2-uloses as precursors of chiral molecules
is somewhat limited as their synthesis from common
monosaccharides requires several protection-deprotection
steps with the consequent lowering of the yield.4 We have
overcome such a difficulty in the preparation of 2-alkoxy-
pyran-3-ones derived from hexoses, via the corresponding
2-acyloxyglycal derivatives.5 These compounds undergo
a double allylic rearrangement by the tin(IV) chloride-
promoted glycosylation to give optically pure 4-en-3-one
derivatives in good yields. However, the same procedure
applied to 2-acetoxyglycals derived from pentoses, led to
dihydropyranones having enantiomeric excesses (ee) low-
er than 90%, unless a chiral alcohol is employed for the
glycosylation.6 In this case, a rather difficult separation of
diastereoisomers by column chromatography was re-
quired. The sugar enones derived from pentoses proved to
be excellent dienophiles in Diels–Alder reactions with
butadienes6 and cyclic dienes.7,8 They have also been em-
ployed as Michael acceptors of thiols in the synthesis of
glycosides of 3-deoxy-4-thiopyranosid-2-ulose and 3-
deoxy-4-thiopentopyranosides.9 In view of the synthetic
The conversion of the disulfonic ester derivatives 5 and 6
into a double bond was effected with a large excess of so-
dium iodide and zinc dust in refluxing DMF.12,13 Thus, the
ditosylate 5 led to the 3,4-unsaturated derivative 7, which
appeared, accompanied by the O-deacetylation product 8.
As the allylic alcohol 8 was the immediate precursor of
the pyran-2-one, in further preparations the crude mixture
of enopyranosides 7 and 8 was treated with methanolic so-
dium methoxide to give 8 as a single product. The same
sequence applied to 6 led also to 8, but the yield was
around 10–15% lower than that obtained from 5.
As an alternative method for the conversion of the vicinal
diol system of 4 into an alkene, the Corey–Winter olefin
synthesis was attempted.14 Thus, compound 4 was treated
with 1,1¢-thiocarbonyldiimidazole to afford the thionocar-
bonate 9. Desulfuration of the 1,3-dioxolane-2-thione ring
with trimethylphosphite at 150 °C led to the expected alk-
ene derivative 7. For the successful conversion of 9 into 7
freshly distilled, anhydrous trimethylphosphite was re-
quired; as otherwise complicating byproduct formation
(the orthoformate 11) was observed.15
SYNTHESIS 2005, No. 6, pp 0893–0898
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x
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x
x
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0
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Advanced online publication: 21.02.2005
DOI: 10.1055/s-2005-861833; Art ID: M04504SS
© Georg Thieme Verlag Stuttgart · New York

894
M. L. Uhrig, O. Varela
PAPER
O
HO
RO
O
O
O
TFA
RSO2Cl
C5H5N
Me
O
OH
OR
THF-H2O
(88%)
O
Ph
O
Ph
O
Ph
Me
OR
OAc
OAc
Me2CO
CuSO4
H2SO4
4
Ac2O,
C5H5N
(100%)
5 R = MeC6H4SO2 (72%)
6 R = MeSO2 (90%)
2 R = H
3 R = Ac
Im2CS,
THF
(95%)
NaI, Zn
DMF
(65%)
O
HO
O
O
O
1) Im2CS, C5H5N
(MeO)3P
(86%)
O
OH
2) Ac2O
(69%)
S
O
Ph
O
Ph
O
Ph
OAc
OR
OH
9
7 R = Ac
8 R = H 74% from 5
61% from 6
1
NaMeO,
MeOH
Im2CS,
THF
Ac2O,
C5H5N
(100%)
(35%)
PDC,
CH2Cl2
(80%)
O
O
O
O
O
O
O
S
MeO
O
Ph
O
Ph
O
O
Ph
OH
OAc
11
10
12
Scheme 1
In order to avoid the protection-deprotection steps from 1 action occurred slowly and required successive additions
to 4, we explored the possibility of preparing the 3,4- of the oxidant, the enone 12 was obtained in 80% yield.
thionocarbonate directly from 1. The relative orientation Thus, the route that involves the formation of the thiono-
of HO-3 in 1 (cis to HO-4 and trans to HO-2) seems to be carbonate 9 from 1, its elimination to 8, followed by oxi-
favorable for such a substitution. Therefore, compound 1 dation, afforded satisfactorily the enone 12 in 47% overall
was treated with an excess of 1,1¢-thiocarbonyldiimida- yield.
zole and the reaction conditions were optimized. When
conducted in either THF or acetonitrile, the reaction led to
low yields (30–40%) of the expected thionocarbonate 10.
On the other hand, the previous sequence applied to ben-
zyl b-D-arabinopyranoside (13)19 led to the dihydropyra-
none 17 in 52% overall yield (Scheme 2). The target
Furthermore, in contrast with 9, the desulfurization of 10
enones 12 and 17 showed the same spectra as those de-
with trimethylphosphite led to decomposition of the start-
scribed for the same products having ee >86%,6 and their
ing material. For this reason, compound 1 was directly
absolute values of optical rotation were higher. To con-
converted into 9 by formation of the 3,4-thionocarbonate
firm the enantiopurity of 12 and 17, 1H NMR studies were
followed by in situ acetylation of HO-2. Pyridine proved
conducted using ytterbium tris[3-(heptafluoropropylhy-
to be a good solvent for both reactions, and 9 was obtained
droxy-methylene)-(+)-camphorate] as a chiral shift re-
in approximately 70% yield from 1. Subsequent desulfu-
agent.20 The spectrum of 12, recorded after successive
ration of 9 with trimethylphosphite afforded 7, which was
additions of the lanthanide, showed a symmetric singlet
for H-2, and no splitting for the signals of the other pro-
quantitatively O-deacetylated to give the allylic alcohol 8.
The oxidation of 8 with activated manganese(IV) oxide16 tons. Upon addition of 17 to the solution, lower field sat-
afforded the dihydropyranone 12 in low yield (ca. 40%). ellite signals appeared for the singlet of H-2, and for the
The success of such an oxidation critically depends on the signals corresponding to H-4, 5, 6 and 6¢. The same exper-
method of preparation of the oxidant, and it is also sensi- iments applied to 17 ensure the enantiomeric purity of
tive to structural features of the starting alcohol.16 Thus, both dihydropyranones 12 and 17 (ee >98%).
similar to the alcohol function of 8, the HO-3 of allal de-
rivatives was resistant towards oxidation with MnO2;
In conclusion, we describe here an efficient synthesis of
enantiomerically pure (2R)- and (2S)-2-benzyloxy-2(H)-
pyran-3(6H)-one (12 and 17) starting from benzyl b-L-ar-
abinopyranoside (1) or its enantiomer 13, respectively.
whereas the HO-3 of glucal derivatives, which has the op-
posite configuration, was readily oxidized.17 Noteworthy,
compound 8 possesses, as the allal derivatives, the same
stereochemical relationship between the HO group to be
oxidized and the vicinal substituents. The crowding
As 1 or 13 could be readily converted into the thionocar-
bonate derivatives 9 or 14, selective protection and depro-
tection steps of the hydroxyl groups of 1 or 13 were
around the hydroxyl function could be the cause of the
avoided. The following desulfuration (olefination) and
lower reactivity of these two compounds compared with
oxidation reactions were high yielding, and afforded 12
that of glucal. Oxidation of 8 with pyridinium
and 17 in 47% and 52% overall yield, respectively. These
dichromate18 (PDC) gave a better result. Although the re-
Synthesis 2005, No. 6, 893–898 © Thieme Stuttgart · New York

PAPER
Enantiospecific Synthesis of 2-Benzyloxydihydropyran-3-ones
895
1 H, J4,5¢ = 1.2 Hz, H-5¢), 3.80 (dd, 1 H, J2,3 = 5.8 Hz, H-2), 1.56,
1.36 [2 s, 6 H, (CH3)2C].
O
Ph
O
Ph
O
HO
O
AcO
1) Im2CS, C5H5N
13C NMR (CDCl3): d = 136.9, 128.6, 128.2, 128.0 (C-Ar), 109.2
(Me2C), 96.9 (C-1), 75.9, 72.9 (C-3,4), 70.0 (C-2), 69.7 (PhCH2),
59.8 (C-5), 27.9, 25.9 [(CH3)2C].
HO
HO
O
2) Ac2O
O
S
13
14
Benzyl 2-O-Acetyl-3,4-di-O-isopropylidene-b-L-arabinopyra-
noside (3)
O
Ph
O
Ph
O
RO
O
To a solution of 2 (3.25 g, 11.61 mmol) in anhyd pyridine (3.0 mL)
was added Ac2O (3.0 mL) and the mixture was stirred overnight at
r.t. The solvent was coevaporated with toluene to afford quantita-
tively syrupy 3 (3.74 g, 100%). The NMR spectra of this product
showed that the compound was pure enough for use in the next step.
Purification of a small mass of crude 3 by column chromatography
(hexane–EtOAc, 19:1) afforded an analytical sample of 3.
(MeO)3P
150 °C
PDC
CH2Cl2
O
15 R = Ac
16 R = H
17
NaMeO
MeOH
Scheme 2
[a]D20 +241.2 (c = 1.0, CHCl3).
1H NMR (CDCl3): d = 7.32 (m, 5 H, C6H5), 4.99 (d, 1 H, J1,2 = 3.5
Hz, H-1), 4.91 (dd, 1 H, J2,3 = 8.1 Hz, H-2), 4.73, 4.50 (2 d, 2 H,
J = 12.2 Hz, PhCH2), 4.37 (dd, 1 H, J3,4 = 5.6 Hz, H-3), 4.26 (dt, 1
H, J4,5 = J4,5¢ = 1.9 Hz, H-4), 4.01 (m, 2 H, H-5,5¢), 2.08 (s, 3 H,
CH3CO), 1.54, 1.46 [2 s, 6 H, (CH3)2C].
13C NMR (CDCl3): d = 170.5 (CO), 137.1, 128.5, 128.0, 127.6 (C-
Ar), 109.4 (Me2C), 95.2 (C-1), 73.6, 72.9, 72.2 (C-2,3,4), 69.5
(PhCH2), 58.8 (C-5), 28.0, 26.3 [(CH3)2C], 20.9 (CH3CO).
dihydropyranones may be employed for the synthesis of
optically pure carbocyclic systems,6–8 and highly modi-
fied 4-thiosugars.9 The synthesis of 12 and 17 constitute
also an additional example of the conversion of carbohy-
drate raw materials into enantiopure building blocks, in
line with recent efforts on this aspect.2b,21 Furthermore,
the pyranone system has been found in natural products
as, for example, in the D-glucose-derived antibiotic cortal-
cerone.22
Anal. Calcd for C17H22O6: C, 63.34; H, 6.88. Found: C, 63.39; H,
6.85.
Benzyl 2-O-Acetyl-b-L-arabinopyranoside (4)
To a stirred solution of crude 3 (3.85 g, 11.96 mmol) in THF–water
(4:1, 45 mL) at 0 °C was added TFA (2.0 mL). The solution was al-
lowed to warm to r.t. and the stirring was continued for 2 h. The sol-
vent was removed at 50 °C under reduced pressure. The residue was
dissolved in water (30 mL), neutralized with aq NH3 and the solu-
tion extracted with CH2Cl2 (3 × 50 mL). The combined organic ex-
tracts were dried (MgSO4) and concentrated to afford crystalline 4
(2.96 g, 87.8%).
Melting points were determined with a Fisher-Johns apparatus and
are uncorrected. Analytical TLC was performed on Silica Gel 60
F254 (Merck) aluminum supported plates (layer thickness 0.2 mm)
with solvent systems given in the text. Visualization of the spots
was effected by exposure to UV light and charring with a solution
of 5% H2SO4 in EtOH, containing 0.5% p-anisaldehyde. Column
chromatography was carried out with Silica Gel 60 (230–400 mesh,
Merck). Optical rotations were measured with a Perkin-Elmer 343
digital polarimeter, for solutions in CHCl3. Nuclear magnetic reso-
nance (NMR) spectra were recorded with a Bruker AC 200 or with
a Bruker AMX 500 instruments, in CDCl3 solutions using TMS as
an internal standard. When necessary, the signals from the 13C NMR
spectra were assigned by DEPT experiments.
Mp: 101 °C (hexane–Et2O); [a]D20 +239.6 (c 1.0, CHCl3).
1H NMR (CDCl3): d = 7.34 (m, 5 H, C6H5), 5.05 (d, 1 H, J1,2 = 3.7
Hz, H-1), 5.01 (dd, 1 H, J2,3 = 10.0 Hz, H-2), 4.72, 4.51 (2 d, 2 H,
J = 12.3 Hz, PhCH2), 4.07 (dd, 1 H, J3,4 = 3.5 Hz, H-3), 3.99 (m, 1
H, H-4), 3.91 (dd, 1 H, J4,5 = 1.3 Hz, J5,5¢ = 12.6 Hz, H-5), 3.74 (dd,
1 H, J4,5¢ = 2.0 Hz, H-5¢), 2.09 (s, 3 H, CH3CO)
13C NMR (CDCl3): d = 171.6 (MeCO), 137.2, 128.4, 127.8, 127.6
(C-Ar), 95.7 (C-1), 71.6, 69.4 (2 C), 67.7 (C-2,3,4 and PhCH2), 62.4
(C-5), 20.9 (CH3CO).
Benzyl b-L-Arabinopyranoside (1)
Compound 1 was prepared from L-arabinose following the proce-
dure of Fletcher19 for the D-enantiomer. The crude product was
prutified by two successive recrystallizations from EtOH.
Anal. Calcd for C14H18O6: C, 59.57; H, 6.43. Found: C, 59.56; H,
6.46.
20
Mp: 170 °C (Lit.19 172–173 °C); [a]D +212 (c 0.4, H2O) {[a]D
–209 (c 0.4, H2O) for the enanatiomer}.
Benzyl 2-O-Acetyl-3,4-di-O-p-tolylsulfonyl-b-L-arabinopyrano-
side (5)
Benzyl 3,4-O-Isopropylidene-b-L-arabinopyranoside (2)
To a stirred suspension of 1 (5.00 g, 20.83 mmol) and anhyd CuSO4
(15.0 g) in anhyd acetone (200 mL) was added concentrated H2SO4
(0.25 mL) and the stirring was continued for 18 h. The mixture was
treated as described by Fletcher19 and the resulting syrup crystal-
lized from hexane–Et2O (3:1) to afford 2 (3.75 g, 64.3%). Flash
chromatography (hexane–EtOAc, 8:1) of the residue obtained upon
concentration of the mother liquors led to a second crop of crystals
of 2 (1.79 g, overall yield 95.0%).
To a stirred solution of the diol 4 (2.24 g, 7.94 mmol) in anhyd py-
ridine (10 mL) at 0 °C, was slowly added p-TsCl (5.49 g, 28.8
mmol). The mixture was stirred at r.t. for 3 d, when TLC (hexane–
EtOAc, 2:1) showed a major product having Rf 0.52. After the addi-
tion of MeOH (10 mL) the mixture was stirred for 1 h and concen-
trated. Two successive additions of toluene and subsequent
evaporations of the solvent led to a syrup. Purification by column
chromatography (hexane–EtOAc, 3:1) afforded 5 (3.37 g, 71.9%).
20
20
Mp: 56–57 °C (Lit.19 55–58 °C); [a]D +210 (c 1.0 EtOH) {[a]D
Mp: 120 °C (EtOH); [a]D20 +172.2 (c 1.0, CHCl3).
–209 for the enantiomer}.
1H NMR (CDCl3): d = 7.78, 7.73 (2 d, 4 H, J = 8.3 Hz, C6H4Me),
7.23–7.33 (m, 9 H, C6H4Me and C6H5), 5.05 (d, 1 H, J1,2 = 3.2 Hz,
H-1), 5.02 (m, 2 H, H-3,4), 4.95 (dd, 1 H, J2,3 = 10.5 Hz, H-2), 4.68,
4.46 (2 d, 2 H, J = 12.3 Hz, PhCH2O), 3.92 (br d, 1 H, J5,5¢ = 13.3
1H NMR (CDCl3): d = 7.35 (m, 5 H, C6H5), 4.93 (d, 1 H, J1,2 = 3.6
Hz, H-1), 4.79, 4.55 (2 d, 2 H, J = 11.7 Hz, PhCH2), 4.21 (m, 2 H,
H-3,4), 4.02 (dd, 1 H, J4,5 = 2.2 Hz, J5,5¢ = 13.2 Hz, H-5), 3.92 (dd,
Synthesis 2005, No. 6, 893–898 © Thieme Stuttgart · New York

896
M. L. Uhrig, O. Varela
PAPER
Hz, H-5), 3.88 (br d, 1 H, H-5¢), 2.47, 2.45 (2 s, 6 H, 2 × CH3Ar),
1.76 (s, 3 H, CH3CO).
Anal. Calcd for C14H16O4: C, 67.73; H, 6.50. Found: C, 67.50; H,
6.60.
13C NMR (CDCl3): d = 169.5 (CO), 145.1, 136.6, 133.1, 129.9,
129.7, 128.4, 128.0, 127.9, 127.6 (C-Ar), 95.4 (C-1), 77.0, 72.9,
67.5 (C-2,3,4), 69.7 (PhCH2O), 60.6 (C-5), 21.7, 21.6 (CH3Ar),
20.2 (CH3CO).
8
Mp 69 °C (hexane); [a]D20 +129.2 (c 1.0, CHCl3).
1H NMR (CDCl3–D2O): d = 7.36 (m, 5 H, C6H5), 5.81, 5.73 (2 m, 2
H, H-3,4), 4.97 (d, 1 H, J1,2 = 4.0 Hz, H-1), 4.86, 4.64 (2 d, 2 H,
J = 11.8 Hz, PhCH2O), 4.19 (m, 2 H, H-2,5), 4.04 (ddd, 1 H, J = 2.9,
4.9, 17.3 Hz, H-5¢).
Anal. Calcd for C28H30O10S2: C, 56.94; H, 5.12; S, 10.86. Found: C,
57.00; H, 5.20; S, 10.91.
Benzyl 2-O-Acetyl-3,4-di-O-methylsulfonyl-b-L-arabinopyra-
noside (6)
13C NMR (CDCl3): d = 137.2, 128.5, 128.0 (C-Ar), 127.0, 126.1 (C-
3,4), 95.8 (C-1) 69.9 (PhCH2O), 64.1 (C-2), 60.2 (C-5).
A solution of 5 (0.15 g, 0.53 mmol) in anhyd pyridine (2 mL) was
cooled to 0 °C, and MsCl (0.10 mL, 1.28 mmol) was slowly added.
The mixture was stirred at r.t. for 24 h, and then treated as described
for the tosylation. The residue was subjected to flash column chro-
matography (hexane–EtOAc, 5:1) to give syrupy 6 (0.21 g, 90.1%).
Anal. Calcd for C12H14O3: C, 69.88; H, 6.84. Found: C, 70.13; H,
6.82.
Benzyl 2-O-Acetyl-b-L-arabinopyranoside 3,4-Thionocarbon-
ate (9)
a) Synthesis of 9 from 4
[a]D20 +172.0 (c 1.0, CHCl3).
To a stirred solution of 4 (0.40 g, 1,42 mmol) in THF (5 mL) was
added 1,1¢-thiocarbonyldiimidazole (0.54 g, 3.03 mmol). The mix-
ture was stirred at r.t. for 20 h, when TLC (hexane–EtOAc, 2:1)
showed a main spot having Rf 0.52. The solvent was evaporated and
the residue purified by flash chromatography (hexane–EtOAc, 4:1)
to afford 9 (0.30 g, 65.3%).
1H NMR (CDCl3): d = 7.35 (m, 5 H, C6H5), 5.17 (d, 1 H, J1,2 = 2.8
Hz, H-1), 5.13–5.11 (m, 3 H, H-2,3,4), 4.73, 4.54 (2 d, 2 H, J = 12.3
Hz, PhCH2O), 4.00 (br d, 1 H, J5,5¢ = 13.4 Hz, H-5), 3.94 (dd, 1 H,
J4,5’ = 1.8 Hz, H-5¢), 3.11, 3.15 (2 s, 6 H, 2 × CH3SO3), 2.04 (s, 3 H,
CH3CO)
13C NMR (CDCl3): d = 169.5 (CO), 136.3, 128.6, 128.3, 128.0 (C-
Ar), 95.4 (C-1), 77.0, 73.1, 67.7 (C-2,3,4), 70.0 (PhCH2O), 61.0 (C-
5), 38.7, 38.5 (CH3SO3), 20.6 (CH3CO).
Mp 123 °C (MeOH); [a]D20 +238.3 (c 1.0, CHCl3).
1H NMR (CDCl3): d = 7.38–7.28 (m, 5 H, C6H5), 5.15 (d, 1 H,
J1,2 = 3.7 Hz, H-1), 5.09 (t, 1 H, J2,3 = J3,4 = 7.4 Hz, H-3), 4.93 (m,
2 H, H-2,4), 4.72, 4.53 (2 d, 2 H, J = 12.1 Hz, PhCH2O), 4.20 (br d,
1 H, J4,5 < 1 Hz, J5,5¢ = 14.3 Hz, H-5), 4.03 (dd, 1 H, J4,5¢ = 2.9 Hz,
H-5¢), 2.08 (s, 3 H, CH3CO).
13C NMR(CDCl3): d = 190.3 (CS), 169.6 (CO), 136.2, 128.6, 128.4,
127.8 (C-Ar), 94.0 (C-1), 79.3, 77.9 (C-3,4), 70.3 (PhCH2O), 69.8
(C-2), 57.0 (C-5), 20.6 (CH3CO).
Anal. Calcd for C16H22O10S2: C, 43.83; H, 5.06; S, 14.63. Found: C,
44.11; H, 5.18; S, 14.48.
Benzyl 2-O-Acetyl-3,4-dideoxy-a-D-glycero-pent-3-enopyrano-
side (7) and Benzyl 3,4-Dideoxy-a-D-glycero-pent-3-enopyrano-
side (8)
A vigorously stirred mixture of 5 (0.93 g, 1.57 mmol), NaI (11.5 g,
77 mmol), zinc dust (5.54 g, 85 mmol) and DMF (21 mL) was
boiled for 2.5 h under reflux. The mixture was cooled to r.t., water
(20 mL) was added and the suspension was filtered. The residue was
washed successively with water (50 mL) and CH2Cl2 (3 × 50 mL).
The liquids were extracted with CH2Cl2 (3 × 50 mL) and the extract
dried (MgSO4) and concentrated to a syrup, which showed by TLC
(hexane–EtOAc, 2:1) two main spots (Rf 0.64 and 0.49). Column
chromatography (hexane–EtOAc, 12:1) led first to the expected
product 7 (0.21 g, 53.7%) and the following fractions of the column
(Rf 0.49) gave the allylic alcohol 8 (65 mg, 20.0%).
Anal. Calcd for C15H16O6S: C, 55.55; H, 4.97; S, 9.89. Found: C,
55.62; H, 4.95; S, 9.99.
b) Synthesis of 9 from 1
A solution of 1 (1.50 g, 6.25 mmol) and 1,1¢-thiocarbonyldiimida-
zole (1.5 g) in pyridine (15 mL) was heated to 80 °C under nitrogen,
in a thick-walled sealed tube. Three successive 0.5 g portions of
1,1¢-thiocarbonyldiimidazole were added every 10 h (total 3.0 g,
16.83 mmol). After an additional 10 h of heating (total 40 h) TLC
revealed a main spot having the same movility as 10. The mixture
was cooled to 0 °C, and upon addition of Ac2O (8 mL) was stirred
overnight at r.t. The solution, which showed by TLC (hexane–
EtOAc, 2:1) a main spot of Rf 0.52, was diluted with MeOH and
concentrated. The syrup was chromatographed (hexane–EtOAc,
6:1) to give 9, which crystallized from MeOH. Compound 9 (1.40
g, 69.1%) had the same properties as the product described in a).
Alternatively, compound 8 was obtained upon treatment of the
crude mixture of enopyranosides 7 and 8, prepared from 5 (0.93 g,
1.57 mmol), with NaOMe in MeOH (5 × 10–3 M, 10 mL). When
TLC (hexane–EtOAc, 2:1) showed complete conversion of 7 into 8
(1.5 h), the reaction mixture was neutralized with Dowex 50W (H+)
resin, filtered and concentrated. Column chromatography led to
pure 8 (0.24 g, 73.9% from 5).
Benzyl b-L-Arabinopyranoside 3,4-Thionocarbonate (10)
Compound 1 (0.80 g, 3.33 mmol) was treated with 1,1¢-thiocarbon-
yldiimidazole under the conditions described for the preparation of
9 from 4, affording 10 (0.33 g, 35.1%). Syrupy 10 (Rf 0.42, hexane–
EtOAc, 1.5:1) crystallized upon standing and it was recrystallized
from i-PrOH–hexane.
Mp 94 °C; [a]D20 +172.1 (c = 1.0, CHCl3).
1H NMR (CDCl3–D2O): d = 7.36–7.34 (m, 5 H, C6H5), 5.04 (dd, 1
H, J2,3 = 5.6, J3,4 = 7.7 Hz, H-3), 4.96 (dd, 1 H, J4,5 = 2.0 Hz,
The last procedure when applied to the dimesylate 6 (0.23 g, 0.52
mmol), led to the enopyranoside 8 (66 mg, 61.1%).
7
[a]D20 +132.3 (c = 1.0, CHCl3).
1H NMR (CDCl3): d = 7.33 (m, 5 H, C6H5), 5.95 (br dq, 1 H,
J3,4 = 10.5 Hz, J2,3 = J3,5 = J3,5¢ = 2.5 Hz, H-3), 5.69 (br dq, 1 H,
J3,4 = 10.5 Hz, J2,4 = J4,5 = J4,5¢ = 2.5 Hz, H-4), 5.30 (m, 1 H, H-2),
5.08 (d, 1 H, J1,2 = 3.8 Hz, H-1), 4.83, 4.63 (2 d, 2 H, J = 12.3 Hz,
PhCH2O), 4.27 (dq, 1 H, J2,5 = 2.5 Hz, J5,5¢ = 16.9 Hz, H-5), 4.09
(dq, 1 H, J2,5¢ = 2.5 Hz, H-5¢), 2.08 (s, 3 H, CH3CO).
13C NMR (CDCl3): d = 170.4 (CO), 137.3, 129.2, 128.3, 127.8 (C-
Ar), 127.7, 121.7 (C-3,4), 93.6 (C-1), 69.7 (PhCH2O), 66.2 (C-2),
60.4 (C-5), 20.9 (CH3CO).
J4,5¢ = 0.9 Hz, H-4), 4.94 (d, 1 H, J1,2 = 4.1 Hz, H-1), 4.81, 4.61 (2 d,
2 H, J = 11.6 Hz, PhCH2O), 4.09 (dd, 1 H, J5,5¢ = 14.0 Hz, H-5), 4.02
(dd, 1 H, H-5¢), 3.99 (dd, 1 H, H-2).
Synthesis 2005, No. 6, 893–898 © Thieme Stuttgart · New York

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Enantiospecific Synthesis of 2-Benzyloxydihydropyran-3-ones
897
13C NMR (CDCl3): d = 190.8 (CS), 136.2, 128.7, 128.5, 128.2 (C-
Ar), 94.2 (C-1), 79.2, 79.0 (C-3,4), 70.1 (PhCH2O), 65.7 (C-2), 58.7
(C-5).
Benzyl 2-O-Acetyl-3,4-dideoxy-a-L-glycero-pent-3-enopyrano-
side (15)
Heating compound 14 (1.86 g, 5.76 mmol) in freshly distilled tri-
methylphosphite (6 mL), under the conditions described for 9, led
to the enopyranoside 15 (1.28 g, 89.6%).
[a]D20 –131.4 (c 2.1, CHCl3).
Anal. Calcd for C13H14O5S: C, 55.31; H, 5.00; S, 11.36. Found: C,
55.26; H, 4.96; S, 11.46.
Synthesis of 7 and 8 from 9
Compound 9 (345 mg, 1.06 mmol) was dissolved in commercial
(97%) trimethylphosphite (2 mL). Nitrogen was flushed through the
solution and the tube was sealed and heated in a sand bath to 150 °C
for 10 h. The solution was cooled and poured into sat. aq NaHCO3
(20 mL) and stirred vigorously for 1 h. The mixture was extracted
with CH2Cl2 (3 × 10 mL), and the combined extracts were dried
(MgSO4) and concentrated. Column chromatography (hexane–
EtOAc, 12:1) of the residue afforded the compound having Rf 0.64
(hexane–EtOAc, 2:1) identified as 7 (185 mg, 70.1%).
Benzyl 3,4-Dideoxy-a-L-glycero-pent-3-enopyranoside (16)
NaOMe deacetylation of 15 (0.83 g, 3.36 mmol) gave 16 (0.69,
99.7%).
Mp 68 °C; [a]D20 –132.3 (c 1.0, CHCl3).
(2S)-2-Benzyloxy-2H-pyran-3(6H)-one (17)
Oxidation of 16 (0.63 g, 3.06 mmol) with PDC (1.61 g), as de-
scribed for 8, afforded 17 (0.49 g, 78.5%).
[a]D20 –248.4 (c 1.4, CHCl3).
A byproduct was isolated from next fractions of the column (Rf
0.45). This product was characterized as benzyl 2-O-acetyl-3,4-
(methylorthoformyl)-b-L-arabinopyranoside (11, 65 mg, 18.8%) on
the basis of its spectral data.
Acknowledgment
Financial support from the University of Buenos Aires (Project
X108) and the National Research Council of República Argentina
(CONICET, Project 2097/01) is gratefully acknowledged. O. V. is
a Research Member of CONICET.
1H NMR (CDCl3): d = 7.36-7.30 (m, 5 H, C6H5), 5.81 (s, 1 H,
HCO3), 5.00 (d, 1 H, J1,2 = 3.4 Hz, H-1), 4.80 (dd, 1 H, J2,3 = 8.0 Hz,
H-2), 4.72, 4.50 (2 d, 2 H, J = 12.2 Hz, PhCH2O), 4.54 (dd, 1 H,
J3,4 = 5.7 Hz, H-3), 4.36 (dd, 1 H, J4,5¢ = 2.7 Hz, H-4), 4.05 (d, 1 H,
J4,5 < 1 Hz, J5,5¢ = 13.4 Hz, H-5eq), 3.99 (dd, 1 H, H-5¢ax), 3.36 (s,
3 H, CH3O), 2.07 (s, 3 H, CH3CO).
13C NMR (CDCl3): d = 170.4 (CH3CO), 136.9, 128.5, 128.0, 127.6
(C-Ar), 115.6 (HCO3), 94.8 (C-1), 73.5, 72.4, 71.6, 69.7 (C-2, 3, 4,
PhCH2O), 58.3 (C-5), 52.2 (CH3O), 20.8 (CH3CO2).
References
(1) (a) Ferrier, R. J.; Hoberg, J. O. Adv. Carbohydr. Chem.
Biochem. 2003, 58, 55. (b) Lichtenthaler, F. W. Acc. Chem.
Res. 2002, 35, 728. (c) Fraser-Reid, B. Acc. Chem. Res.
1996, 29, 57. (d) Lichtenthaler, F. W. In Natural Product
Synthesis; Atta-ur-Rahman, Ed.; Springer: New York, 1986,
227. (e) Trost, B. M.; King, S. A.; Schmidt, T. J. Am. Chem.
Soc. 1989, 111, 5902.
(2) (a) Becker, B. J. Carbohydr. Chem. 2000, 19, 253.
(b) Witczak, Z. J.; Chhabra, R.; Chojnacki, J. Tetrahedron
Lett. 1997, 38, 2215. (c) Witczak, Z. J.; Chhabra, R.; Chen,
H.; Xie, X. Q. Carbohydr. Res. 1997, 301, 167. (d) Horton,
D.; Roski, J. P.; Norris, P. J. Org. Chem. 1996, 61, 3783.
(3) (a) Blake, A. J.; Cook, T. A.; Forsyth, A. C.; Gould, R. O.;
Paton, R. M. Tetrahedron 1992, 48, 8053. (b) Dauben, W.
G.; Kowalczyk, B. A.; Lichtenthaler, F. W. J. Org. Chem.
1990, 55, 2391.
The same reaction conducted with freshly distilled trimethylphos-
phite led to 86.0% yield of 7, and 11 was detected by TLC as a faint
spot.
Compound 7 (0.40 g, 1.61 mmol) was deacetylated with NaOMe in
MeOH (10 mL), as described above, to afford alcohol 8 (0.33 g) al-
most quantitatively.
(2R)-2-Benzyloxy-2H-pyran-3(6H)-one (12)
Compound 8 (315 mg, 1.53 mmol) was dissolved in anhyd CH2Cl2
(35 mL) and PDC (0.52 g) was added. The mixture was vigorously
stirred for 15 h, when TLC (hexane–EtOAc, 2:1) showed a main
spot having Rf 0.52 and some starting 8 (Rf 0.39) remaining. Two
successive portions of PDC (0.15 g) were added, with stirring, over
a period of 5 h. When no remaining 8 was detected by TLC (10 h),
the mixture was filtered through a silica gel pad (CH2Cl2). Concen-
tration of the eluant and further purification by flash chromatogra-
phy (hexane–EtOAc, 10:1) afforded pure 12 (250 mg, 80.1%).
(4) Holder, N. L. Chem. Rev. 1982, 287.
(5) De Fina, G. M.; Varela, O.; Lederkremer, R. M. Synthesis
1988, 891.
(6) Iriarte Cappacio, C. A.; Varela, O. J. Org. Chem. 2001, 66,
8859.
(7) Iriarte Cappacio, C. A.; Varela, O. J. Org. Chem. 2002, 67,
7839.
(8) Iriarte Cappacio, C. A.; Varela, O. Tetrahedron Lett. 2003,
44, 4023.
(9) Uhrig, M. L.; Varela, O. Carbohydr. Res. 2002, 337, 2069.
(10) Reist, E. J.; Gueffroy, D. E.; Goodman, L. J. Am. Chem. Soc.
1965, 87, 677.
(11) Haines, A. H. Adv. Carbohydr. Chem. Biochem. 1976, 33,
11.
(12) Horton, D.; Thomson, J. K.; Tindall, C. G. Jr. Methods
Carbohydr. Chem. 1972, 6, 297.
(13) Tipson, R. S.; Cohen, A. Carbohydr. Res. 1965, 1, 338.
(14) Block, E. Org. React. 1984, 30, 457.
[a]D20 +247.4 (c 1.2, CHCl3).
1H and 13C NMR spectra identical as those described previously for
the product having ee >86%.6
Oxidation of allylic alcohol 8 (150 mg, 0.73 mmol) with freshly pre-
23
pared, activated MnO2 (0.65 g) in Et2O gave, after chromato-
graphic purification, oily 12 (60 mg, 40.4%).
[a]D20 +245.2 (c 1.0, CHCl3).
Benzyl 2-O-Acetyl-b-D-arabinopyranoside 3,4-Thionocarbon-
ate (14)
The one-pot procedure for the synthesis of 9 from 1, applied to 13
(3.00 g, 12.5 mmol), afforded 14 (3.02 g, 74.6%).
Mp: 121–122 °C (MeOH); [a]D20 –234.7 (c 1.0, CHCl3).
(15) Koll, P.; Deyhim, S. Chem. Ber. 1978, 111, 2913.
(16) Procter, G. In Comprehensive Organic Synthesis, Vol. 7;
Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991,
305.
Synthesis 2005, No. 6, 893–898 © Thieme Stuttgart · New York

898
M. L. Uhrig, O. Varela
PAPER
(20) (a) McCreary, M. D.; Lewis, D. W.; Wernick, D. L.;
(17) Fraser-Reid, B.; Walker, D. L.; Tam, S. Y.-K.; Holder, N. L.
Can. J. Chem. 1973, 51, 3850.
Whitesides, G. M. J. Am. Chem. Soc. 1974, 96, 1038.
(18) (a) Varela, O. Adv. Carbohydr. Chem. Biochem. 2003, 58,
307. (b) Ley, S. V.; Madin, A. In Comprehensive Organic
Synthesis, Vol. 7; Trost, B. M.; Fleming, I., Eds.; Pergamon:
Oxford, 1991, 251.
(b) Mayo, B. C. Chem. Soc. Rev. 1973, 249.
(21) Lichtenthaler, F. W. Carbohydr. Res. 1998, 313, 69.
(22) Giffhorn, F.; Köpper, S.; Huwig, A.; Freimund, S. Enzyme
Microb. Technol. 2000, 27, 734.
(23) Attenburrow, J.; Cameron, A. F. B.; Chapman, J. H.; Evans,
R. M.; Hems, B. A.; Jansen, A. B. A.; Walker, T. J. Chem.
Soc. 1952, 1094.
(19) Fletcher, H. G. Jr. Methods Carbohydr. Chem. 1963, 2, 386.
Synthesis 2005, No. 6, 893–898 © Thieme Stuttgart · New York