Deoxygenation at C-4 and stereospecific branched-chain construction at C-3 of a methyl hexopyranuloside. Synthetic approach to the amipurimycin sugar moiety

Article abstract of DOI:10.1021/jo952220e

A five-step synthesis from 3 leading to a partially protected amipurimycin sugar moiety 14 in an overall yield of 47% is described and includes deoxygenation at C-4 and regio- and stereoselective construction of the branched chain. Deoxygenation at C-4 of 3 was possible by three different methods. Radical reduction with tri-n-butyltin hydride of the appropriate phenoxythiocarbonyl derivative afforded the desired deoxysugar 5 in 47% overall yield together with the secondary products 6 and 7 due to depivaloylation at C-2 and elimination of methanol. The most adequate deoxygenation procedure used the system Ph₃P/I₂/imidazole which led to the preparation of 5 in one step in 61% yield. When the system Ph₃PBr₂/Ph₃P was tried, only 8 was formed due to elimination of methanol. The synthesis of 5 was then accomplished by reaction of 8 with methanol in the presence of triphenylphosphine hydrobromide in 37% overall yield. Branched-chain construction was accomplished by Wittig reaction of 5 with [(ethoxycarbonyl)methylene]triphenylphosphorane, followed by osmilation and reduction with lithium aluminum hydride. Isopropylidenation of 14 afforded 16 with a free hydroxy group at C-6 for chain elongation and further synthesis of amipurimycin.

Full text of DOI:10.1021/jo952220e

3594
J . Org. Chem. 1996, 61, 3594-3598
Deoxygen a tion a t C-4 a n d Ster eosp ecific Br a n ch ed -Ch a in
Con str u ction a t C-3 of a Meth yl Hexop yr a n u losid e. Syn th etic
Ap p r oa ch to th e Am ip u r im ycin Su ga r Moiety†
Ame´lia P. Rauter,*,‡ Ana C. Fernandes,‡ Stanislas Czernecki,§ and J ean-Marc Valery§
Departamento de Quı´mica e Bioquı´mica, Faculdade de Cieˆncias, Universidade de Lisboa, Edif´ıcio C1,
5° Piso, Campo Grande, 1700 Lisboa, Portugal, and Laboratoire de Chimie des Glucides,
Universite´ Pierre et Marie Curie, 4 Place J ussieu, 75005 Paris, France
Received December 18, 1995X
A five-step synthesis from 3 leading to a partially protected amipurimycin sugar moiety 14 in an
overall yield of 47% is described and includes deoxygenation at C-4 and regio- and stereoselective
construction of the branched chain. Deoxygenation at C-4 of 3 was possible by three different
methods. Radical reduction with tri-n-butyltin hydride of the appropriate phenoxythiocarbonyl
derivative afforded the desired deoxysugar 5 in 47% overall yield together with the secondary
products 6 and 7 due to depivaloylation at C-2 and elimination of methanol. The most adequate
deoxygenation procedure used the system Ph3P/I2/imidazole which led to the preparation of 5 in
one step in 61% yield. When the system Ph3PBr2/Ph3P was tried, only 8 was formed due to
elimination of methanol. The synthesis of 5 was then accomplished by reaction of 8 with methanol
in the presence of triphenylphosphine hydrobromide in 37% overall yield. Branched-chain
construction was accomplished by Wittig reaction of 5 with [(ethoxycarbonyl)methylene]tri-
phenylphosphorane, followed by osmilation and reduction with lithium aluminum hydride.
Isopropylidenation of 14 afforded 16 with a free hydroxy group at C-6 for chain elongation and
further synthesis of amipurimycin.
Sch em e 1
In tr od u ction
Amipurimycin (1) is a natural nucleoside antibiotic
which was isolated from Streptomyces novoguineensis
nov. sp.1 It displays a remarkable activity in vitro and
in vivo against Pyricularia oryzae, which is responsible
for the rice blast disease, and also in vitro against other
pathogenic fungi, such as Alternaria kikuchiana and
Helminthosporium sigmoideum var. irregulare, among
others.2 The structure of amipurimycin, as previously
of A from the â face insured good stereocontrol and
afforded the desired configuration at C-3. The control
of the C-3′ stereogenic center was obtained through the
(E)-stereoisomer A which was expected to be the major
product of the Wittig reaction from deoxygenated keto
sugar B.5 This compound was obtained by deoxygenation
of known 3.6
reported by Goto et al.,3 contains inter alia a nucleic base
attached to the anomeric carbon of a branched chain
deoxy sugar. The chain of the latter is also extended by
a dipeptide. We describe in this paper a stereospecific
synthesis of the sugar moiety 2 of 1 from D-glucose. A
synthesis of derivatives of this moiety was already
reported by deoxygenation at C-4 of derivatives of the
sugar moiety of miharamycin, prepared from D-glucose.4
Our straightforward route resulted from the retrosyn-
thetic analysis depicted in Scheme 1. Dihydroxylation
Resu lts a n d Discu ssion
We deoxygenated, at C-4, methyl 2,6-di-O-pivaloyl-R-
D-ribo-hexopyranosid-3-ulose (3),6 which was synthesized
by oxidation of methyl 2,6-di-O-pivaloyl-R-D-glucopyra-
noside7 in dichloromethane, with pyridinium chlorochro-
† In memoriam of Professor Felix Serratosa.
‡ Universidade de Lisboa.
§ Universite´ Pierre et Marie Curie.
X Abstract published in Advance ACS Abstracts, May 1, 1996.
(1) Harada, S.; Kichi, T. J . Antibiot. 1977, 30, 11.
(2) Iwasa, T.; Kishi, T.; Matsura, K.; Wakae, O. J . Antibiot. 1977,
30, 1.
(5) In their synthesis of amipurimycin sugar moiety, Hara et al.4
carried out the Wittig reaction before deoxygenation at C-4 and
obtained a mixture of Z/E stereoisomers in which the wrong one (Z)
was the major compound.
(3) Goto, T.; Toya, Y.; Ohdi, T.; Kondo, T. Tetrahedron Lett. 1982,
23 (12), 1271.
(4) Hara, K.; Fujimoto, H.; Sato, K.-I.; Hashimoto, H.; Yoshimura,
J . Carbohydr. Res. 1987, 159, 65.
(6) . Klausener, A.; Runsink, J .; Scharf, H.-D. Liebigs Ann. Chem.
1984, 783.
S0022-3263(95)02220-1 CCC: $12.00 © 1996 American Chemical Society

Synthetic Approach to the Amipurimycin Sugar Moiety
J . Org. Chem., Vol. 61, No. 11, 1996 3595
Sch em e 2
Ch a r t 1
ones for deoxygenation at C-4 of other pyranosidic sugar
derivatives.12-14 Reduction of pivaloyl groups under these
experimental conditions has not been reported in the
literature, although reduction of benzoyl groups in posi-
tion R to the carbonyl group with n-Bu3SnH was previ-
ously mentioned by Redlich et al.19 For confirmation, 5
was submitted to the same experimental conditions in a
parallel experience and after recovering 30% of the
starting material, the expected products 6 and 7 were
isolated in 29% and 43% yield, respectively, on the basis
of the reacted starting material.
The system triphenylphosphine/X2 (X ) Br, I) is now
reported to be suitable to synthesize 5. When X ) Br, a
one-pot reaction led to the isolation of 8 (45%), formed
by elimination of methanol. This procedure dehydroxyl-
ates R-hydroxylactones20 via an intermediate bromide,
which is transformed, in our case, into the deoxy sugar
by the hydrogen bromide formed in the first step. The
methyl glycoside was obtained by addition of methanol
in the presence of triphenylphosphine hydrobromide at
room temperature overnight, leading to 5 in 37% overall
yield. More convenient was reduction by Ph3P/iodine in
the presence of imidazole, which gave 5 in only one step
in 61% yield. This procedure is known in the literature
to afford iodide derivatives from the corresponding alco-
hols.21 When compared to those reported in the literature
for radical and nonradical deoxygenation of other 4-deoxy
sugar derivatives, our new reduction method allowed us
to achieve easily the preparation of 5, a valuable precur-
sor for the synthesis of the amipurimycin sugar moiety.
The presence of the carbonyl group does not only activate
position 4 to the desired deoxygenation reaction but it is
also an appropriate group for the construction of the
branched chain at C-3 of the amipurimycin precursor.
In general, a two-carbon unit is introduced into an
appropriate keto sugar by reaction with vinylmagnesium
bromide,22 2-lithio-2-methyl-1,3-dithiane,23 or with a suit-
able Wittig reagent. The first two options would lead to
the undesired configuration at C-3, as described in the
literature.22,23
mate adsorbed on neutral alumina.8 Heating at reflux
(48 h) gave a 75% yield based on the reacted diol, which
was partially recovered (24%). The workup by simple
filtration is clean and improved considerably the access
to 3 when compared to the procedure described in the
literature.6
Methods known in the literature to synthesize such
4-deoxy derivatives involve mainly free radical reactions
or reduction of intermediate epoxides,4,9 triflates,10 or
halogenides11 with metallic hydrides. The activation of
the hydroxyl group by reaction with N,N′-thiocarbonyl-
diimidazole,12 4-fluorophenyl chlorothionocarbonate, and
N-hydroxysuccinimide,13 or by formation of thiocarbon-
ates14 or cyclic thiocarbonates,15,16 was followed in all
cases by radical reduction with tri-n-butyltin hydride
under neutral conditions and was tried to obtain 5
(Scheme 2). Treatment of the R-hydroxy keto sugar 3
with phenoxythiocarbonyl chloride17,18 in pyridine with
4-(dimethylamino)pyridine (DMAP) catalysis at room
temperature gave clean conversion to the O-phenoxythio-
carbonyl derivative 4 in 73% yield. Reductive deoxygen-
ation with tri-n-butyltin hydride and 2,2′-azoisobutyroni-
trile (AIBN) as free radical initiator in warm toluene
afforded the deoxy sugar 5 in 65% yield, together with
two secondary products (Chart 1), a dideoxy keto sugar
6 due to the reduction of the pivaloyl ester at position 2,
isolated in 25% yield and its enol ether 7, formed by
elimination of methanol and isolated in 10% yield. The
overall yield of 5 was comparable to previously reported
Stereoselective branched-chain construction was pos-
sible by means of a Wittig reaction with [(ethoxycarbo-
nyl)methylene]triphenylphosphorane (Scheme 3). Only
the Wittig product 9 with the (E)-configuration was
isolated (95%) due to the presence of the bulky pivaloyl-
oxy group. Due to the neighborhood of the ethoxycarbo-
nyl group, the equatorial methylene proton at C-4 in the
1H NMR of 9 was included in the multiplet at δ 4.23-
3.99, while the axial proton appeared at δ 2.12. This
result is similar to the one previously reported by
Rosenthal et al.24 for a methylene group at position 2 of
(7) Klausener, A.; Mu¨ller, E.; Runsink, J .; Scharf, H.-D. Carbohydr.
Res. 1983, 116, 295.
(8) Cheng, Y. S.; Liu, W.-L.; Chen, S.-H. Synthesis 1980, 223.
(9) Trnka, T.; Budesinsky, M.; Cerny, M. Carbohydr. Res. 1994, 259,
131.
(10) Barrette, E.-P.; Goodman, L. J . Org. Chem. 1984, 49, 176.
(11) Risse´, S.; Roger, P.; Monneret, C. J . Carbohydr. Chem. 1993,
12, 1105.
(12) Mulard, L. A.; Kovac, P.; Glaudemans, C. P. J . Carbohydr. Res.
1994, 251, 213.
(13) Bousquet, E.; Lay, L.; Nicotra, F.; Panza, L.; Russo, G.; Tirendi,
S. Carbohydr. Res. 1994, 257, 317.
(14) Czernecki, S.; Horns, S.; Vale´ry, J .-M. J . Carbohydr. Chem.
1995, 14, 157.
(15) Barton, D. H. R.; Subramanian, R. J . Chem. Soc., Perkin Trans.
1 1977, 1718.
(19) Redlich, H.; Neumann, H. J .; Paulsen, H. Chem. Ber. 1977, 110,
2911.
(20) Dax, K.; Rauter, A. P.; Stu¨tz, A. E.; Weidmann, H. Liebigs Ann.
Chem. 1981, 1768.
(16) Patroni, J . J .; Stick, R. V.; Engelhardt, L. M.; White, A. H. Aust.
J . Chem. 1986, 39, 699.
(17) Robins, M. J .; Wilson, J . S. J . Am. Chem. Soc. 1981, 103, 932.
(18) Robins, M. J .; Wilson, J . S.; Hansske, F. J . Am. Chem. Soc.
1983, 105, 4059.
(21) Garegg, P. J .; Samuelsson, B. J . Chem. Soc., Chem. Commun.
1979, 978.
(22) Brimacombe, J . S.; Minshall, J .; Smith, C. W. J . Chem. Soc.,
Perkin Trans. 1, 1975, 682.
(23) Paulsen, H.; Redlich, H. Angew. Chem., Int. Ed. 1972, 11, 1021.

3596 J . Org. Chem., Vol. 61, No. 11, 1996
Rauter et al.
Sch em e 3
Sch em e 4
a pyranosidic derivative containing a cis methoxycarbonyl
group on a vicinal double bond. The correct assignment
of the signals was confirmed by 2D heteronuclear cor-
relation and by COSY. Our synthesis is a considerable
improvement over the one reported previously by Hara
et al.,4 who obtained a mixture of E/Z isomers.
sulfuric acid solution. Column chromatography was performed
using silica gel (0.043-0.063 mm, Riedel) and elution under
medium pressure. Evaporation of solvents was carried out
under reduced pressure at 40 °C. Elemental analysis was
conducted at the Service of Microanalyses of Instituto Superior
Te´cnico da Universidade Te´cnica de Lisboa. Mass spectra
were obtained with a FTICR spectrometer either by laser
desorption (1064 nm) or by electron impact. Molecular model-
ing of 16 was performed using PC Model from Serena
Software.
Meth yl 2,6-Di-O-P iva loyl-r-D-r ibo-h exop yr a n osid -3-u l-
ose (3). A solution of methyl 2,6-di-O-pivaloyl-R-D-glucopy-
ranoside7 (2.0 g, 5.5 mmol) in dry dichloromethane (20 mL)
was heated with pyridinium chlorochromate absorbed on
alumina8 (10.8 g, 8.8 mmol) under reflux for 48 h. The solids
were filtered off and were washed with ether. The combined
filtrates were evaporated to dryness. Column chromatography
with EtOAc-toluene (1:8) afforded 3 (1.13 g, 75%, on the basis
of the reacted alcohol). The starting material was recovered
in 24% yield. Physical and spectroscopic data of 3 agreed with
those given in the literature.6
Osmium tetraoxide in pyridine or in the presence of
4-methylmorpholine N-oxide in acetone-water,25 cis-
hydroxylated 9 to 10 in quantitative yield, with the
branched chain with the proper configuration at C-3 and
C-3′. Attempts to oxidize 9 with potassium permanga-
nate26 led only to a 20% yield of the expected diol.
Reduction of 10 with lithium aluminum hydride in THF
at room temperature afforded 2, which was isolated in
the form of its pentaacetate 11. O-Isopropylidenation of
10 (2,2-dimethoxypropane-p-TsOH in acetone22) gave 12
in 84% yield (Scheme 4). Benzaldehyde (ZnCl2)27 gave a
mixture of the protected derivatives 13a and 13b (67%).
Reduction with lithium aluminum hydride led to the
desired sugar moiety of amipurimycin 14, and the
mixture 15a and 15b protected at positions 3 and 3′ with
the isopropylidene and benzylidene groups in 96% and
93% yield, respectively. Introduction of a second isopro-
pylidene group gave 16 (54%), which has a free hy-
droxymethyl group for further chain elongation at C-6.
Characterization of 14 was possible by synthesis of the
solid (mp 117-118 °C) 3,5-dinitrobenzoate derivative 17
(75%).
Meth yl 4-O-(P h en oxyth ioca r bon yl)-2,6-d i-O-p iva loyl-
r-D-r ibo-h exop yr a n osid -3-u lose (4). Phenoxythiocarbonyl
chloride (0.68 mL, 5 mmol) was added dropwise to a solution
of 3 (1.2 g, 3.3 mmol) and DMAP (40 mg, 0.3 mmol) in pyridine
(3 mL) at 0 °C under argon. The mixture was stirred overnight
at room temperature and was evaporated. The residue was
purified by column chromatography with EtOAc-petroleum
ether (1:7) giving 4 as a syrup (1.19 g, 73%): [R]2D0 +49.2 (c 1,
CH2Cl2); IR (neat) 1737 cm-1 (CdO), 1599 cm-1 (Ph), 1212 cm-1
The method developed by us constitutes a significant
improvement (five steps, 47% overall) for the synthesis
of the carbohydrate unit. In a previous attempt Hara et
al.5 synthesized it in 16 steps from D-glucose (12 steps
from a 3-keto sugar) with an overall yield of 9.6%.
1
(CdS); H NMR δ 7.42-7.14 (m, 5H), 5.93 (d, 1H, J 4,5 ) 9.0
Hz), 5.40 (d, 1H, J 1,2 ) 4.2 Hz), 5.20 (d, 1H), 4.44-4.37 (m,
3H), 3.48 (s, 3H), 1.29 (s, 9H), 1.26 (s, 9H); 13C NMR δ 193.7
(C-3), 191.6 (CdS), 177.9 (CdO), 177.0 (CdO), 153.5 (Cq, Ph),
129.6, 126.8, 121.6 (Ph), 99.9 (C-1), 79.3 (C-4), 76.5 (C-2), 69.5
(C-5), 62,0 (C-6), 55.9 (OMe), 38.9 (Cq), 27.2 (Me), 27.1 (Me);
HRMS calcd for C24H32O9S 496.571, found 496.569.
Meth yl 4-Deoxy-2,6-d i-O-p iva loyl-r-D-er yth r o-h exop y-
r a n osid -3-u lose (5). Meth od a . Tri-n-butyltin hydride (890
mg, 3.06 mmol) was added dropwise to a solution of 4 (1.0 g,
2.02 mmol) and AIBN (66 mg, 0.4 mmol) in dry toluene (13.5
mL) at 90 °C under argon. After 3 h the mixture was
evaporated. The residue was purified by column chromatog-
raphy with EtOAc-toluene (1:9) to give 5 (452 mg, 65%
yield): mp 92-95 °C; [R]2D0 +54.6 (c 1, CH2Cl2); IR (CHCl3)
1740 cm-1 (CdO); 1H NMR δ 5.19 (d, 1H, J 1,2 ) 4.08 Hz), 5.06
Exp er im en ta l Section
Melting points were determined with
a melting point
apparatus (Tottoli) and are uncorrected. 1H NMR and 13C
NMR spectra were recorded in CDCl3 at 300 and 60 MHz,
respectively. Chemical shifts are expressed in ppm downfield
from TMS. Analytical TLC was performed on Riedel alumi-
num precoated plates of silica gel 60F254 (thickness of 0.5 mm)
with detection by UV and by spraying with a 3% vanillin-
(24) Rosenthal, A.; Catsoulacos, P. Can. J . Chem. 1968, 46, 2868.
(25) Berger, A.; Dax, K.; Gradnig, G.; Grassberger, V.; Stu¨tz, E. J .
Carbohydr. Chem. 1992, 11, 217
(26) Ho¨nel, M.; Mosher, S. J . Org. Chem. 1985, 50, 4386.
(27) Hall, D. M. Carbohydr. Res. 1980, 86, 158.

Synthetic Approach to the Amipurimycin Sugar Moiety
J . Org. Chem., Vol. 61, No. 11, 1996 3597
(d, 1H), 4.26-4.08 (m, 3H), 3.37 (s, 3H), 2.58-2.41 (m, 2H),
1.21 (s, 9H), 1.16 (s, 9H); 13C NMR δ 197.2 (C-3), 179.3 (CdO),
177.5 (CdO), 100.3 (C-1), 75.2 (C-2), 67.5 (C-5), 65.0 (C-6), 55.5
(OMe), 43.0 (C-4), 41.1 (Cq), 38.8 (Cq), 27.1 (Me), 27.1 (Me).
Anal. Calcd for C17H28O7: C, 59.29; H, 8.19. Found: C, 59.47;
H, 8.29. Further elution afforded methyl 2,4-dideoxy-6-O-
pivaloyl-R-D-glycero-hexopyranosid-3-ulose (6) as a syrup (123
mg, 25%): [R]D20 +84 (c 3, CH2Cl2); IR (neat) 1734 cm-1
(CdO); 1H NMR δ 5.08 (br d, 1H), 4.23-4.13 (m, 3H), 3.30 (s,
3H), 2.58 (dd, 1H, J 1,2a ) 4.35 Hz), 2.43 (br d, 1H, J 2a,2e ) 15.12
Hz), 2.34-2.31 (m, 2H), 1.16 (s, 9H); 13C NMR δ 203.5 (C-3),
178.1 (CdO), 99.4 (C-1), 66.5 (C-5), 65.7 (C-6), 54.7 (OMe), 46.2
(C-2), 43.3 (C-4), 38.8 (Cq), 27.1 (Me). Anal. Calcd for
38.7 (Cq), 30.9 (C-4), 27.2 (Me), 27.1 (Me), 14.2 (Me). Anal.
Calcd for C21H34O8: C, 60.84; H, 8.27. Found: C, 60.36; H,
7.81.
Met h yl 4-Deoxy-3-C-[(R)-(et h oxyca r b on yl)h yd r oxy-
m eth yl]-2,6-d i-O-p iva loyl-r-D-xylo-h exop yr a n osid e (10).
Meth od a . Osmium tetraoxide (250 mg, 0.97 mmol) was
added to a solution of 9 (400 mg, 0.97 mmol) in pyridine (4
mL), and the mixture was stirred at room temperature for 2
h. A solution of NaHSO3 (480 mg) in H2O (7 mL) and pyridine
(5 mL) was added to the reaction mixture and within 5 min
the complex was cleaved to give an orange solution, which was
extracted with CH2Cl2 (3 × 20 mL). The organic phase was
dried (Na2SO4) and evaporated to give 10 (434 mg, 100%) as
a syrup: [R]2D0 +26.4 (c 2, CH2Cl2); IR (CHCl3) 3490 cm-1 (OH),
C
12H20O5: C, 59.00; H, 8.25. Found: C, 59.27; H, 8.46. Also
1743 cm-1 (CdO); 1H NMR δ 4.92 (t, 2H), 4.75 (d, 1H, J 3′,OH
6.83 Hz), 4.35-4.08 (m, 6H), 3.59 (d, 1H), 3.42 (s, 3H), 2.02
(dd, 1H, J 4e,5 ) 2.88 Hz, J 4a,4e ) 14.04 Hz), 1.76 (dd, 1H, J 4a,5
)
resulting was 1,5-anhydro-2,4-dideoxy-6-O-pivaloyl-D-glycero-
hex-1-enul-3-itol (7) as a syrup (43 mg, 10%): [R]2D0 +60.4 (c
0.5, CH2Cl2); IR (neat) 1734 cm-1 (CdO), 1686 cm-1 (CdO),
1600 cm-1 (CdC); 1H NMR δ 7.30 (d, 1H, J 1,2 ) 6.02), 5.38 (d,
1H), 4.64-4.54 (m, 1H), 4.30-4.19 (m, 2H), 2.60 (dd, 1H, J 4a,5
) 12.61 Hz, J 4a,4e ) 16.77 Hz), 2.40 (dd, 1H, J 4e,5 ) 3.88 Hz),
1.16 (s, 9H); 13C NMR δ 191.2 (C-3), 177.9 (CdO), 162.7 (C-1),
107.2 (C-2), 76.8 (C-5), 64.2 (C-6), 38.9 (Cq), 38.0 (C-4), 27.1
(Me). Anal. Calcd for C11H16O4: C, 62.25; H, 7.60. Found:
C, 62.26; H, 7.55.
) 10.32 Hz), 1.33 (t, 3H, J CH
) 7.13 Hz), 1.23 (s, 9H), 1.22
,Me
2
(s, 9H); 13C NMR δ 178.2 (CdO), 171.7 (C-3′′), 97.0 (C-1), 75.6
(C-2), 73.9 (C-3′), 72.2 (C-3), 66.2 (C-5), 65.4 (C-6), 61.8 (CH2),
55.8 (OMe), 38.9, 38.8 (Cq), 36.3 (C-4), 27.1 (Me), 27.0 (Me),
14.1 (Me). Anal. Calcd for C21H36O10
Found: C, 56.10; H, 8.24.
: C, 56.24; H, 8.09.
Meth od b. Compound 9 (660 mg, 1.6 mmol) and 4-meth-
ylmorpholine N-oxide (375 mg, 3.2 mmol) were dissolved in
acetone-water (8:1; 13 mL). Osmium tetraoxide (20 mg, 0.08
mmol) was added, and the reaction mixture was stirred
overnight at room temperature. The mixture was poured into
H2O and extracted with CHCl3. The organic layer was washed
with H2O, was dried, and was evaporated. The residue was
purified as in method a to give 10 (695 mg, 97%).
Meth od c. To the solution of 9 (200 mg, 0.48 mmol) in THF
(2 mL) at -10 °C under nitrogen was added dropwise, with
vigorous stirring, KMnO4 (76 mg, 0.48 mmol) in H2O (3 mL)
at such a rate that the temperature did not exceed 5 °C. The
mixture was stirred at room temperature for 12 h. MnO2 was
removed by filtration and washed with THF. The extracts
were dried (Na2SO4) and evaporated. Purification as in
method a gave 10 (43 mg, 20%).
Meth od b. Bromine (0.3 mL) was added dropwise to a
stirred solution of triphenylphosphine (1.5 g, 5.72 mmol) in
toluene (15 mL). After 10 min, a solution of 3 (1.33 g, 3.70
mmol) in CH2Cl2 (4 mL) was added dropwise at room temper-
ature. The reaction mixture was heated 30 min at 50 °C. A
solution of triphenylphosphine (1.5 g, 5.72 mmol) in toluene
(3 mL) was added and the mixture was stirred at 60 °C for 30
min. Filtration and neutralization with lead carbonate was
followed by filtration and evaporation of the solvent. The
residue was fractionated on a column of silica gel with EtOAc-
toluene (1:15) to give 1,5-anhydro-4-deoxy-2,6-di-O-pivaloyl-
D-glycero-hex-1-enul-3-itol (8) (519 mg, 45%): mp 65-66 °C,
[R]D20 +86.4 (c 1, CH2Cl2); IR (CHCl3) 1728 cm-1 (CdO), 1694
cm-1 (CdO), 1628 cm-1 (CdC); 1H NMR δ 7.28 (s, 1H), 4.72-
4.65 (m, 1H), 4.31-4.26 (m, 2H), 2.72 (dd, 1 H, J 4a,4b ) 16.9
Hz, J 4a,5 ) 13.8 Hz), 2.49 (dd, 1H, J 4b,5 ) 3.6 Hz), 1.23 (s, 9H),
1.15 (s, 9H); 13C NMR δ 183.9 (C-3), 177.9 (CdO), 154.8 (C-1),
131.9 (C-2), 77.6 (C-5), 63.9 (C-6), 38.9 (Cq), 38.7 (Cq), 37.6
(C-4), 27.1 (Me). Anal. Calcd for C16H24O6: C, 61.52; H, 7.74.
Found: C, 61.64; H, 7.85. A solution of triphenylphosphine
hydrobromide (THPB) (40 mg, 0.128 mmol) in CH2Cl2 (13 mL)
was added to a solution of 8 (800 mg, 2.56 mmol) in methanol
(0.3 mL, 7.68 mmol). After being stirred for 24 h at room
temperature, the reaction mixture was washed with aqueous
saturated NaHCO3 and brine, dried, and evaporated. The
residue was purified by column chromatography with n-hex-
ane-acetone (3:1) to give 5 (730 mg, 83%).
Meth yl 2,3,3′,3′′,6-P en ta -O-a cetyl-4-d eoxy-3-C-[(S)-1,2-
d ih yd r oxyeth yl]-r-D-xylo-h exop yr a n osid e (11). Lithium
aluminum hydride (13.3 mg, 0.35 mmol) was added to an ice-
cold solution of 10 (45 mg, 0.1 mmol) in dry THF (3 mL), and
the mixture was stirred at room temperature for 1 h. After
addition of Na2SO4‚10H2O and stirring for 15 min, the solution
was filtered, was dried (Na2SO4), was evaporated, and was
acetylated by stirring with acetic anhydride (0.01 mL), DMAP
(1 mg, 0.008 mmol), and 1 mL of pyridine at room temperature
overnight. Evaporation and column chromatography with
EtOAc-toluene (2:1) gave 11 as a syrup (18 mg, 40%); [R]D20
1
+6 (c 0.3, CH2Cl2); H NMR δ 5.75 (1H, dd, J 3′,3′′a ) 2.7 Hz,
J 3′,3′′b ) 2.4 Hz), 5.56 (1H, d, J 1,2 ) 3.6 Hz), 4.78 (1H, d), 4.54
(1H, dd, J 3′′a,3′′b ) 11.9 Hz), 4.16-3.95 (m, 4H), 3.30 (s, 3H),
2.24 (dd, 1H, J 4a,4e ) 14.1 Hz, J 4e,5 ) 3.6 Hz), 2.15 (dd, 1H,
J 4a,5 ) 8.0 Hz), 2.03 (s, 3H), 2.01 (s, 6H), 1.98 (s, 3H), 1.97 (s,
3H); HRMS calcd for C19H28O12 448.423, found 448.420.
Meth od c. A mixture of triphenylphosphine (293 mg, 1.12
mmol), iodine (213 mg, 0.84 mmol), and imidazole (68 mg, 1.12
mmol) in dry toluene (3 mL) was stirred at room temperature
for 10 min. A solution of 3 (100 mg, 0.28 mmol) in toluene (2
mL) was added, and the temperature was kept at 60 °C for
3.5 h. After filtration and evaporation, the residue was
purified by column chromatography with EtOAc-toluene (1:
15) to give 5 (59 mg, 61%).
Met h yl 4-Deoxy-3-C-[(R)-(et h oxyca r b on yl)h yd r oxy-
m eth yl]-3,3′-O-isop r op ylid en e-2,6-d i-O-p iva loyl-r-D-xylo-
h exop yr a n osid e (12). 2,2-Dimethoxypropane (1.2 mL, 9.8
mmol) and p-toluenesulfonic acid (9 mg, 0.047 mmol) were
added to a solution of 10 (200 mg, 0.46 mmol) in dry acetone
(0.6 mL). The reaction mixture was stirred at room temper-
ature for 3 days. The mixture was neutralized with solid
NaHCO3, was filtered, and was concentrated. Chromatogra-
phy of the residue with EtOAc/petroleum ether (1:5) gave 12
as a syrup (140 mg, 84%, on the basis of reacted alcohol) and
recuperation of the diol gave 10 (46 mg, 23%): [R]2D0 +30.7 (c
1.2, CH2Cl2); IR (neat) 1740 cm-1 (CdO), 1380 cm-1 (isop); 1H
NMR δ 4.93 (s, 1H), 4.84 (d, 1H, J 1,2 ) 3.29 Hz), 4.77 (d, 1H),
4.27-3.91 (m, 5H), 3.24 (s, 3H), 2.31 (dd, 1H, J 4e,5 ) 2.41 Hz,
J 4a,4e ) 13.93 Hz), 1.68, (dd, 1H, J 4a,5 ) 11.67 Hz), 1.45 (s, 3H),
Meth yl 3,4-Did eoxy-3-C-[(E)-(eth oxyca r bon yl)m eth yl-
en e]-2,6-d i-O-p iva loyl-r-D-er yth r o-h exop yr a n osid e (9).
[(Ethoxycarbonyl)methylene]triphenylphosphorane (1.21 g,
3.47 mmol) was added to a solution of 5 (0.6 g, 1.74 mmol) in
dry CHCl3 (15 mL) and the mixture was stirred under reflux
for 20 h. Evaporation of the solvent and purification by column
chromatography with EtOAc-petroleum ether (1:7) afforded
9 as a solid (685 mg, 95%): mp 54-56 °C; [R]2D0 +31.2 (c 1,
CH2Cl2); IR (CHCl3) 1731 cm-1 (CdO), 1686 cm-1 (CdO), 1623
1
cm-1 (CdC); H NMR δ 5.90 (t, 1H, J 3′,4a ) 1.89 Hz), 5.34 (t,
1H, J 2,3′ ) 1.47 Hz), 4.92 (d, 1H, J 1,2 ) 3.75 Hz), 4.23-3.99
(m, 6H), 3.38 (s, 3H), 2.12 (t, 1H, J 4a,4e ) J 4a,5 ) 12.75 Hz),
1.29 (s, 9H), 1.23 (m, 12H); 13C NMR δ 178.0 (CdO), 177.1
(CdO), 165.8 (C-3′′), 149.5 (C-3), 113.6 (C-3′), 98.4 (C-1), 71.5
(C-2), 67.5 (C-5), 65.5 (C-6), 59.9 (CH2), 55.3 (OMe), 38.9 (Cq),
1.30 (s, 3H), 1.26 (t, 3H, J CH
) 7.30 Hz), 1.19 (s, 9H), 1.15
,Me
2
(s, 9H); 13C NMR δ 178.1 (CdO), 177.4 (CdO), 170.2 (C-3′′),
110.1 (Cq), 96.8 (C-1), 82.4 (C-3), 77.3 (C-3′), 72.7 (C-2), 65.4
(C-6), 65.2 (C-5), 61.2 (CH2), 54.7 (OMe), 39.0 (Cq), 38.8 (Cq),

3598 J . Org. Chem., Vol. 61, No. 11, 1996
Rauter et al.
36.0 (C-4), 28.6 (Me), 27.4 (Me), 27.1 (Me), 14.0 (Me); HRMS
calcd for C24H40O10 488.574, found: 488.573.
(C-5), 64.9 (C-6), 60.2 (C-3′′), 55.4 (OMe), 31.8 (C-4); HRMS
calcd for C16H22O7 326.346, found 326.344.
Met h yl 4-Deoxy-3-C-[(R)-(et h oxyca r b on yl)h yd r oxy-
m eth yl]-3,3′-O-ben zyliden e-2,6-di-O-pivaloyl-r-D-xylo-h ex-
op yr a n osid e (13a a n d 13b). Anhydrous ZnCl2 (68 mg, 0.50
mmol) was added to benzaldehyde (0.3 mL) and the mixture
was stirred for 30 min at room temperature. A solution of 10
(135 mg, 0.3 mmol) in benzaldehyde (1 mL) was added.
Stirring was continued for 5 days at room temperature.
Evaporation and purification by column chromatography gave
a mixture of both isomers 13a and 13b (105 mg, 67%) as a
syrup, in proportion of 2:1: [R]2D0 +39.1 (c 3.4, CH2Cl2); IR
(neat) 1742 cm-1 (CdO); 1H NMR of 13a δ 7.59-7.57 (m, Ph),
6.29 (s, 1H), 5.34 (s, 1H), 5.06 (d, 1H, J 1,2 ) 2.88 Hz), 4.89 (d,
1H), 4.30-4.21 (m, CH2), 4.13-4.07 (m, 3H), 3.36 (s, 3H),
2.27-2.20 (m, 2H), 1.34 (t, 3H), 1.22 (s, 9H), 1.07 (s, 9H); 13C
NMR of 13a δ 178.1 (CdO), 177.5 (CdO), 170.9 (C-3′′), 136.1
(Cq Ph), 129.7, 128.3, 126.5 (Ph), 102.7 (CH), 97.2 (C-1), 81.9
(C-3), 77.9 (C-3′), 72.5 (C-2), 65.7 (C-6), 65.0 (C-5), 61.3 (CH2),
55.0 (OMe), 38.8 (Cq), 35.0 (C-4), 27.2 (Me), 27.0 (Me), 14.1
(Me). Anal. Calcd for C27H40O10: C, 61.82; H, 7.69. Found:
C, 61.94; H, 7.62.
Met h yl 4-Deoxy-3-C-[(S)-1,2-d ih yd r oxyet h yl]-3,3′-O-
isop r op ylid en e-r-D-xylo-h exop yr a n osid e (14). Lithium
aluminum hydride (55 mg, 1.44 mmol) was added to an ice-
cold solution of 12 (200 mg, 0.41 mmol) in dry THF (6 mL),
and the mixture was stirred at room temperature for 1 h. The
workup was the same described for 11. Purification by column
chromatography with EtOAc afforded 14 as a syrup (109 mg,
96%): [R]2D0 +14.8 (c 0.8, CH2Cl2); IR (neat) 3340 cm-1 (OH),
1380 cm-1 (isop); 1H NMR δ 4.79 (d, 1H, J 1,2 ) 3.48 Hz), 4.28
(dd, 1H, J 3′,3′′a ) 4.32 Hz, J 3′,3′′b ) 5.7 Hz), 3.95 (m, 1H), 3.84-
3.71 (m, 3H), 3.61-3.55 (m, 2H), 3.38 (s, 3H), 2.68 (d, 1H, J OH,2
) 6.48 Hz), 2.07 (dd, 1H, J 4e,5 ) 3.69 Hz, J 4a,4e ) 14.58 Hz),
1.47 (dd, 1H, J 4a,5 ) 11.13 Hz), 1.36 (s, 3H), 1.34 (s, 3H); 13C
NMR δ 106.8 (Cq), 99.2 (C-1), 81.7 (C-3), 77.3 (C-3′), 71.6 (C-
2), 68.7 (C-5), 64.9 (C-6), 60.6 (C-3′′), 55.2 (OMe), 33.4 (C-4),
28.7 (Me), 26.4 (Me). Anal. Calcd for C12H22O7: C, 51.79; H,
7.97. Found: C, 52.26; H, 7.80.
Meth yl 4-Deoxy-3-C-[(S)-1,2-d ih yd r oxyeth yl]-2,3′′:3,3′-
d i-O-isop r op ylid en e-r-D-xylo-h exop yr a n osid e (16). The
same procedure described for 12 was used to prepare 16, which
gave 16 as a syrup (54%, on the basis of reacted diol) after
recovering unreacted 12 (17%): [R]2D0 +3.3 (c 0.3, CH2Cl2); IR
1
(neat) 3436 cm-1 (OH), 1383 cm-1 (isop); H NMR δ 4.76 (d,
1H, J 1,2 ) 3.36 Hz), 4.35 (dd, 1H, J 3′,3′′a ) 2.9 Hz, J 3′,3′′b ) 7.7
Hz), 4.03 (dd, 1H, J 3′′a,3′′b ) 9.9 Hz), 3.86-3.76 (m, 2H), 3.53-
3.37 (m, 6H), 2.07 (dd, 1H, J 4e,5 ) 3.25 Hz, J 4a,4e ) 13.75 Hz),
1.52 (dd, 1H, J 4a,5 ) 10 Hz), 1.37 (s, 3H), 1.33 (s, 3H), 1.25 (s,
3H), 1.24 (s, 3H); 13C NMR δ 107.4 (Cq), 100.0 (Cq), 99.0 (C-
1), 82.0 (C-3), 77.3 (C-3′), 72.1 (C-2), 67.8 (C-5), 63.2 (C-6), 59.6
(C-3′′), 55.0 (OMe), 29.6 (C-isop), 29.5 (C-4), 29.3 (C-isop) 24.3
(C-isop); HRMS calcd for C15H26O7 318.366, found 318.365.
Met h yl 4-Deoxy-3-C-[(S)-1,2-d ih yd r oxyet h yl]-3,3′-O-
isop r op ylid en e-3′′,6-bis-O-(3,5-d in itr oben zoyl)-r-D-xylo-
h exop yr a n osid e (17). 3,5-Dinitrobenzoyl chloride (55 mg,
0.24 mmol) was added to an ice-cold solution of 14 (17 mg,
0.06 mmol) in dry pyridine (1 mL). After 48 h at 4 °C, the
mixture was evaporated and purified by column chromatog-
raphy with EtOAc-ether petroleum (1:2) to give 17 as a solid
(30 mg, 75%): mp 117-118 °C; [R]2D0 +12.5 (c 0.6, CH2Cl2); IR
(neat) 3460 cm-1 (OH), 1732 cm-1 (CdO), 1554 cm-1 (NO2),
1
1470 cm-1 (NO2), 1352 cm-1 (isop); H NMR δ 9.25-9.17 (m,
6H), 5.04 (d, 1H, J 3′′a,3′′b ) 9.33 Hz), 4.97 (d, 1H, J 1,2 ) 2.70
Hz), 4.83 (dd, 1H, J 5,6b ) 8.22 Hz, J 6a,6b ) 11.73 Hz), 4.68-
4.58 (m, 2H), 4.43 (dd, 1H, J 5,6a ) 2.94 Hz), 4.32-4.27 (m, 1H),
3.85 (dd, 1H, J 2,OH ) 4.65 Hz), 3.52 (s, 3H), 2.53 (d, 1H, OH),
2.26 (dd, 1H, J 4e,5 ) 4.35 Hz), 1.69 (dd, 1H, J 4a,5 ) 8.16 Hz,
J 4a,4e ) 14.07 Hz), 1.50 (s, 3H), 1.49 (s, 3H); 13C NMR δ 162.4
(CdO), 162.2 (CdO), 148.6 (Cq, Ph), 133.5 (Cq, Ph), 129.6,
129.4, 122.6 (Ph), 108.6 (Cq), 97.7 (C-1), 81.1 (C-3), 76.6
(C-3′), 71.6 (C-2), 67.5 (C-5), 67.1 (C-6), 65.2 (C-3′′), 55.9 (OMe),
31.6 (C-4), 28.7 (Me), 26.5 (Me). Anal. Calcd for C26H26O17N4:
C, 46.78; H, 4.08; N, 8.39. Found: C, 46.91; H, 3.96; N, 8.16.
Ack n ow led gm en t. We are grateful to the European
Economic Community for financial support (project SCI-
CT91-0723) and to the J unta Nacional de Investigac¸a˜o
Cient´ıfica e Tecnolo´gica for a research grant. We thank
Dr. J oaquim Marc¸alo for the high-resolution mass
spectra, Dr. J ose´ Figueiredo and Dr. L´ıgia Teixeira for
running NMR spectra, and Dr. P. E. Brown (Depart-
ment of Chemistry, University of Newcastle upon Tyne)
for molecular modeling of compound 16.
Met h yl 4-Deoxy-3-C-[(S)-1,2-d ih yd r oxyet h yl]-3,3′-O-
ben zylid en e-r-D-xylo-h exop yr a n osid e (15a a n d 15b). The
same experimental procedure to prepare 14 was followed and
afforded 15a and 15b in proportion 2:1 as a syrup (93%):
[R]D20 +65.6 (c 1.1, CH2Cl2); IR (neat) 3372 cm-1 (OH); 1H
NMR of 15a δ 7.47-7.29 (m, 5H), 5.89 (s, 1H), 4.76 (d, 1H,
J 1,2 ) 3.48 Hz), 4.61 (t, 1H, J 3′,3′′a ) J 3′,3′′b ) 4.43 Hz), 3.97-
3.77 (m, 4H), 3.57-3.47 (m, 2H), 3.34 (s, 3H), 2.15 (dd, 1H,
J 4e,5 ) 2.7 Hz, J 4a,4e ) 16.5 Hz), 1.66 (dd, 1H, J 4a,5 ) 13.8 Hz);
13C NMR δ 137.5 (Cq), 129.5 (CH), 128.5 (CH), 126.5 (CH),
100.3 (CH), 99.5 (C-1), 82.5 (C-3), 78.3 (C-3′), 73.9 (C-2), 68.5
J O952220E