Synthesis of branched-chain hexulose derivatives as model for the synthesis of talaromycins

Article abstract of DOI:10.1081/CAR-100106928

The synthesis of 3,5-dideoxy-1,2-O-isopropylidene-5-C-hydroxymethyl-β-D-erythro- (1) and α-L-threo-hexulopyranose (2) from 3-deoxy-1,2-O-isopropylidene-β-D-erythro-hexulopyranose (5) from D-fructose is described, as well as their respective transformation

Full text of DOI:10.1081/CAR-100106928

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SYNTHESIS OF BRANCHED-CHAIN HEXULOSE
DERIVATIVES AS MODEL FOR THE SYNTHESIS OF
TALAROMYCINS
Isidoro Izquierdo a , María T. Plaza a , Miguel Rodríguez a , Juan A. Tamayo a & Leocadia
Macias a
a Department of Organic Chemistry, Faculty of Pharmacy , University of Granada ,
Granada, 18071, Spain
Published online: 19 Aug 2006.
To cite this article: Isidoro Izquierdo , María T. Plaza , Miguel Rodríguez , Juan A. Tamayo & Leocadia Macias (2001)
SYNTHESIS OF BRANCHED-CHAIN HEXULOSE DERIVATIVES AS MODEL FOR THE SYNTHESIS OF TALAROMYCINS, Journal of
Carbohydrate Chemistry, 20:6, 447-457, DOI: 10.1081/CAR-100106928
To link to this article: http://dx.doi.org/10.1081/CAR-100106928
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J. CARBOHYDRATE CHEMISTRY, 20(6), 447–457 (2001)
SYNTHESIS OF BRANCHED-CHAIN HEXULOSE
DERIVATIVES AS MODEL FOR THE SYNTHESIS
OF TALAROMYCINS
Isidoro Izquierdo,* María T. Plaza, Miguel Rodríguez,
Juan A. Tamayo, and Leocadia Macias
Department of Organic Chemistry, Faculty of Pharmacy, University of
Granada, 18071 Granada, Spain
ABSTRACT
The synthesis of 3,5-dideoxy-1,2-O-isopropylidene-5-C-hydroxymethyl-ꢀ-D-
erythro- (1) and ꢁ-L-threo-hexulopyranose (2) from 3-deoxy-1,2-O-isopropy-
lidene-ꢀ-D-erythro-hexulopyranose (5) from D-fructose is described, as well as
their respective transformation into 3,5-dideoxy-1,2-O-isopropylidene-5-C-
hydroxymethyl-ꢀ-D-threo- (3) and -ꢁ-L-erythro-hexulopyranose (4) by inver-
sion of configuration at C-4.
INTRODUCTION
Talaromycins A and B are spiroketalic micotoxins produced by the fungus
Talaromyces stipitatus and were isolated and identified for the first time by Lynn
et al..1 In a reinvestigation carried out by the same group,2 they detected the pres-
ence of additional diastereoisomers talaromycins C and E as represented in
Scheme 1. Enantiospecific syntheses of talaromycins A and B can be found in the
literature,3 including that reported by our group4 which used D-fructose as chiral
starting material. However, to the best of our knowledge synthesis of ta-
laromycins C and E has not been communicated at this time. Since the only dif-
ference between talaromycins C-E and A-B is that of the C-4 configuration at the
A ring, it is reasonable to think that transformation of the latter compounds into
the former ones, could be easily achieved by inversion of configuration at this
position.
447
Copyright © 2001 by Marcel Dekker, Inc.
www.dekker.com

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448
IZQUIERDO ET AL.
Scheme 1.
An examination of the 3,5-dideoxy-5-C-hydroxymethylhexulose derivatives
(1–2) (Scheme 1) clearly indicated that these less elaborated molecules could act
as a model in order to see if the above mentioned inversion could be feasible. With
this objective in mind, the synthesis of 1–2 from D-fructose as well as their respec-
tive transformations into 3–4 are communicated herein.
RESULTS AND DISCUSSION
The
reaction
of
3-deoxy-1,2-O-isopropylidene-ꢀ-D-erythro-
hexulopyranose5 (5) with di-n-butyltin oxide in anhydrous methanol afforded
4,5-O-dibutylstannylene-3-deoxy-1,2-O-isopropylidene-ꢀ-D-erythro-hexulopyra-
nose (6). Treatment of 6 with tert-butylchlorodiphenylsilane in dry DMF yielded
4-O-tert-butyldiphenylsilyl-3-deoxy-1,2-O-isopropylidene-ꢀ-D-erythro-hexu-
lopyranose (7) together with a small amount of the related 5-O-tert-
butyldiphenylsilyl regioisomer (8). The position of the silyl protecting group in 7
1
and 8 could be determined from their H NMR spectra. Thus, the resonance sig-
nal for H-4 in 7 appeared as a ddd, from coupling with H-3ax, 3eq, 5, whereas
H-4 in 8 appeared as a complex multiplet indicating additional coupling (J ꢂ 8.9
Hz) with HO-4. On the other hand, the chemical shift for H-4, which is geminal
to the silyloxy group in 7, exhibits a downfield shift (0.23 ppm) with respect to
its position in compound 8.
In order to examine the possibility of an inversion of the C-4 configuration by
a Mitsunobu reaction,6 compound 8 was treated with Ph3P/3,5-dinitrobenzoic
acid/DEAD, giving the expected 5-O-tert-butyldiphenylsilyl-3-deoxy-1,2-O-iso-
propylidene -4-O-(3,5-dinitrobenzoyl)-ꢀ -D-threo-hexulopyranose (9). Inversion
of the configuration at C-4 in 9 was evident from the NMR signal of H-4.
The introduction of the branched-chain at C-5 in 7 was carried out by oxida-
tion to 2,5-diulose (10) followed by reaction with methylenetriphenylphosphorane
to afford the 5-C-methylene derivative 11. Hydroboration-oxidation of 11 was re-
gio and stereoselective and gave a mixture of 4-O-tert-butyldiphenylsilyl-3-deoxy-
1,2-O-isopropylidene-5-C-methyl-ꢁ-L-threo-hexulopyranose (12, 12%), 4-O-tert-

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BRANCHED-CHAIN HEXULOSE DERIVATIVES
449
Scheme 2.
butyldiphenylsilyl-3,5-dideoxy-5-C-hydroxymethyl-1,2-O-isopropylidene-ꢁ-L-
threo-hexulopyranose (13, 8.5%), and 4-O-tert-butyldiphenylsilyl-3,5-dideoxy-5-
C-hydroxymethyl-1,2-O-isopropylidene-ꢀ-D-erythro-hexulopyranose (14, 55%).
Compound 14 results from equatorial attack at C-5 in 11 by the hydroborating
reagent.
Inversion of the configuration at C-4 in 13 and 14 required the previous pro-
tection of the hydroxymethyl group at C-5. With this aim both compounds were
benzoylated to the corresponding 5-C-benzoyloxymethyl derivatives 18 and 15 re-
spectively.
Treatment of 15 with tetrabutylammonium fluoride in THF caused O-desily-
lation to 5-C-benzoyloxymethyl-3,5-dideoxy-1,2-O-isopropylidene-ꢀ-D-erythro-
hexulopyranose (16) concomitant with O7 → O4 benzoyl group migration (see Ex-
perimental) that could be avoided in the analogous reaction on compound 18 to
give 19, by addition of ammonium chloride.
Scheme 3.

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450
IZQUIERDO ET AL.
Compounds 16 and 19 were transformed into the fully protected 4-epimers 5-
C-benzoyloxymethyl-3,5-dideoxy-1,2-O-isopropylidene-4-O-(3,5-dinitroben-
zoyl)-ꢀ -D-threo- (17) and -ꢁ-L-erythro-hexulopyranose (20), by the above men-
tioned Mitsunobu reaction, and finally debenzoylated to the expected
3,5-dideoxy-5-C-branched-chain hexulopyranose derivatives 3 and 4.
EXPERIMENTAL
General methods. Melting points were determined with a Gallenkamp ap-
paratus and are uncorrected. Solutions were dried over MgSO4 before concentra-
1
tion under reduced pressure. The H and 13C NMR spectra were recorded with
Bruker AMX-300, AM-300, and ARX-400 spectrometers for solutions in CDCl3
(internal Me4Si). IR spectra were recorded with a Perkin-Elmer 782 instrument and
mass spectra with a Hewlett-Packard HP-5988-A and Fisons model Platform II and
VG Autospec-Q mass spectrometers. Optical rotations were measured for solu-
tions in CHCl3 (1-dm tube) with a Jasco DIP-370 polarimeter. GLC was performed
on a Hewlett-Packard 6890 gas chromatograph equipped with split/splitless injec-
tor, a flame-ionization detector and a capillary HP-5 column (30 m ꢃ 0.25 mm i.d.
ꢃ 0.25 ꢄm film thickness) at 3 min at 180 °C, program to 250 °C, 10 °C/min. The
He flow rate was 1.1 mL/min, the injection port and the zone-detector temperatures
were 275 °C. TLC was performed on precoated silica gel 60 F254 aluminium sheets
and detection by charring with H2SO4. Column chromatography was performed on
silica gel (Merck, 7734). The noncrystalline compounds, for which elemental anal-
yses were not obtained were shown to be homogeneous by chromatography and
characterized by NMR and HRMS.
4-O- (7) and 5-O-Tert-butyldiphenylsilyl-3-deoxy-1,2-O-isopropylidene-
ꢀ-D-erythro-hexulopyranose (8). To solution of 3-deoxy-1,2-O-isopropylidene-
ꢀ-D-erythro-hexulopyranose5 (5, 6.2 g, 30.4 mmol) in dry methanol (200 mL), was
added dibutyltin oxide (7.95 mg, 32 mmol) and the suspension was heated for 2 h
under reflux. The clear solution was concentrated to afford the 4,5-dibutylstanny-
lene derivative 6 as a solid foam that was dried under vacuum over P2O5 overnight.
A solution of 6 in dry DMF (250 mL) was treated at room temperature with tert-
butylchlorodiphenylsilane (8.8 g, 32 mmol) for 20 h. TLC (ether-hexane 3:1) then
revealed the absence of 6 and the presence of a further running main product. GLC
22.4 min (major) and 24.2 (minor) in a 87:13 ratio. The mixture was filtered and
the filtrate concentrated to a residue that was partitioned into toluene-water. The
organic phase was concentrated, and the residue subjected to flash chromatography
(ether-hexane 1:6 → 1:3) to afford first 7 (6.63 g, 50% from 5) as a thick syrup;
[ꢁ]D23ꢅ36.5 (c 1); v fmilamx 3570 (OH), 3073 and 3049 (aromatic), 1373 (CMe2), and
703 cmꢅ1 (aromatic). NMR data: 1H, ꢆ7.6ꢅ.64 and 7.4ꢅ.37 (2 m, 10 H, Ph), 4.20
(ddd, 1 H, J3ax,4 11.3, J3eq,4 5, J4,5 3.3 Hz, H-4), 3.99 (d, 1 H, J1,1ꢇ 8.7 Hz, H-1), 3.82
(dd, 1 H, J5,6ax 2, J6ax,6eq 12.7 Hz, H-6ax), 3.75 (dt, 1 H, J5,6eq ꢂ J4,6eq ꢂ 1.7 Hz,
H-6eq), 3.64 (bs, 1 H, H-5), 3.62 (d, 1 H, H-1ꢇ), 2.60 (bs, 1 H, OH-5), 2.05 (t, 1 H,

ORDER
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BRANCHED-CHAIN HEXULOSE DERIVATIVES
451
H-3ax), 1.42 (dd, 1 H, J3ax,3eq 10.3 Hz, H-3eq), 1.36 and 1.19 (2 s, 6 H, CMe2) and
1.10 (s, 9 H, Me3C); 13C, ꢆ135.77, 135.68, 133.47, 133.35, 133.10, 127.90, and
127.86 (aromatic), 111.10 (CMe2), 104.38 (C-2), 74.97 (C-1), 68.41 and 67.80 (C-
4,5), 63.74 (C-6), 36.09 (C-3), 26.98 and 26.55 (Me2C and Me3C), and 19.18
(Me3C). Mass spectrum (LSIMS): m/z 465.2079 (MꢈꢈNa). For C25H34O5NaSi
465.2073 (deviation ꢅ1.3 ppm).
film
max
Eluted second was 8 (350 mg, 2.6% from 5) as a syrup; [ꢁ]D25ꢅ58 (c 1); v
3591 (OH), 3139 and 3055 (aromatic), 1372 (CMe2), and 703 cmꢅ1 (aromatic).
NMR data: 1H, ꢆ7.7ꢅ.67 and 7.4ꢅ.38 (2 m, 10 H, Ph), 4.17 (d, 1 H, J1,1ꢇ 8.9 Hz,
H-1), 3.97 (m, 1 H, H-4), 3.89 (bq, 1 H, H-5), 3.81 (d, 1 H, H-1ꢇ), 2.62 (dd, 1 H,
J
5,6ax 2, J6ax,6eq 12.5 Hz, H-6ax), 3.53 (dd, 1 H, J5,6eq ꢂ 3.6 Hz, H-6eq), 2.19 (d, 1
H, JHO,4 ꢂ 8.9 Hz, OH-4), 2.10 (dd, 1 H, J3ax,4 10.2, J3ax,3eq 12.4 Hz, H-3ax), 1.91
(dd, 1 H, J3eq,4 4.4 Hz, H-3eq), 1.41 and 1.37 (2 s, 6 H, CMe2) and 1.10 (s, 9 H,
Me3C); 13C, ꢆ135.87, 135.84, 133.48, 133.01, 130.12, 130.04, 128.01 and 127.85
(aromatic), 111.00 (CMe2), 104.23 (C-2), 74.41 (C-1), 69.76 and 67.16 (C-4,5),
64.14 (C-6), 36.80 (C-3), 27.11 and 26.52 (Me2C and Me3C), and 19.57 (Me3C).
Mass spectrum (LSIMS): m/z 465.2077 (MꢈꢈNa). For C25H34O5NaSi 465.2073
(deviation ꢅ0.7 ppm).
5-O-Tert-butyldiphenylsilyl-3-deoxy-1,2-O-isopropylidene-4-O-(3,5-
dinitrobenzoyl)-ꢀ -D-threo-hexulopyranose (9). To a stirred solution of 8 (80
mg, 0.18 mmol) in dry THF (3 mL) were added Ph3P (178 mg, 0.68 mmol), 3,5-
dinitrobenzoic acid (144 mg, 0.68 mmol) and diethylazodicarboxylate (DEAD,
118 mg, 0.68 mmol). The mixture was left at room temperature for 22 h. TLC
(ether-hexane 1:1) then revealed the presence of a slower-running product. The
mixture was diluted with ether and washed with saturated aqueous Na2CO3 solu-
tion and with water, then concentrated. Column chromatography (ether-hexane
film
1:5) of the residue gave syrupy 9 (70 mg, 61%); [ꢁ]D26ꢅ16 (c 1); v
3093 and
max
3043 (aromatic), 1735 (CBO), 1346 (CMe2), 725 and 704 cmꢅ1 (aromatic). NMR
data: 1H, ꢆ9.19 (t, 1 H, J 2.1 Hz, H-4 of 3,5-DNBzO group), 9.14 (d, 2 H, H-2,6 of
DNBzO group), 7.7ꢅ.64 and 7.4ꢅ.34 (2 m, 10 H, Ph), 5.31 (m, 1 H, H-4), 4.21 (d,
1 H, J1,1ꢇ 8.7 Hz, H-1), 4.08 (dd, 1 H, J6ax,6eq 12.6, J5,6ax 1.6 Hz, H-6ax), 3.82 (d, 1
H, H-1ꢇ), 3.78 (m, 1 H, H-5), 3.50 (dd, 1 H, J5,6eq 1.5 Hz, H-6eq), 2.54 (dd, 1 H,
J
3,4 3.4, J3,3ꢇ 14.3 Hz, H-3), 1.97 (dd, 1 H, J3ꢇ,4 3.9 Hz, H-3ꢇ), 1.55 and 1.32 (2 s, 6
H, CMe2), and 1.10 (s, 9 H, CMe3); 13C, ꢆ161.54 (CBO), 148.68, 135.80, 135.73,
134.24, 133.16, 132.99, 130.16, 130.08, 129.68, 127.98, 127.95, and 122.41 (aro-
matic), 111.91 (CMe2), 102.49 (C-2), 74.99 (C-1), 71.94 (C-4), 66.33 (C-5), 62.66
(C-6), 31.89 (C-3), 27.14 and 26.59 (Me2C), 26.94 (Me3C), and 19.37 (Me3C).
Mass spectrum (LSIMS): m/z 659.2033 (MꢈꢈNa). For C32H36N2O10NaSi
659.2037 (deviation 0.7 ppm).
4-O-Tert-butyldiphenylsilyl-3,5-dideoxy-1,2-O-isopropylidene-5-C-
methylene-ꢀ-D-glycero-hexulopyranose (11). To a stirred and cooled (ice-wa-
ter) solution of 7 (4.75 g, 10.74 mmol) in dry dichloromethane (50 mL) were added
sodium acetate (315 mg, 3.84 mmol), molecular sieve (4 Å powder, 5 g) and pyri-

ORDER
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452
IZQUIERDO ET AL.
dinium chlorochromate (4.5 g, 20.6 mmol). Stirring was maintained at room tem-
perature overnight. TLC (ether-hexane 3:1) then revealed a new compound of
higher mobility. The mixture was diluted with ether (150 mL), filtered through sil-
ica gel G and concentrated to a residue that was chromatographed (ether) to afford
10 (3.4 g, 72%) that was not investigated but used in the next step.
To a stirred solution of NaCH2SOCH3 (from 350 mg of an 80% dispersion of
sodium hydride in oil) and imidazole (62 mg, 1 mmol) in anhydrous methyl sul-
foxide (20 mL) under argon was added methyltriphenylphosphonium bromide
(3.54 g, 10 mmol). The mixture was stirred for 20 min and a solution of 10 (1.75
g, 4 mmol) in dry ether (20 mL) was added dropwise and the reaction mixture left
for 2.5 h. TLC (ether-hexane 1:3) then showed a new compound of higher mobil-
ity. The mixture was treated with ether saturated with water, the organic phase was
separated, the aqueous phase extracted with ether, and the combined extracts were
washed with brine and concentrated. Column chromatography (ether-hexane 1:5)
film
max
of the residue gave 11 (1.38 g, 79%) as a colorless syrup; [ꢁ]D25ꢅ64 (c 1); v
3057 and 3048 (aromatic), 1382 and 1372 (CMe2), and 702 cmꢅ1 (aromatic). NMR
data: 1H, ꢆ7.7ꢅ.63 and 7.4ꢅ.34 (2 m, 10 H, Ph), 5.38 (t, 1 H, J 1.9 Hz, H-7), 5.02
(bs, 1 H, H-7ꢇ), 4.68 (m, 1 H, H-4), 4.26 (d, 1 H, J6ax,6eq 12.3 Hz, H-6ax), 4.02 (d,
1 H, H-6eq), 3.88 (d, 1 H, J1,1ꢇ 8.7 Hz, H-1), 3.53 (d, 1 H, H-1ꢇ), 1.63 (m, 2 H, H-
3,3ꢇ), 1.38 and 1.14 (2 s, 6 H, CMe2), and 1.11 (s, 9 H, CMe3); 13C, ꢆ145.73 (C-5),
135.91, 135.78, 134.37, 133.77, 129.88, 129.79, 127.74, and 127.70 (aromatic),
111.11 (CMe2), 108.25 (C-7), 104.92 (C-2), 74.57 (C-1), 68.68 (C-4), 65.80 (C-6),
44.05 (C-3), 27.07 (Me3C), 26.86 and 26.40 (Me2C), and 19.37 (Me3C). Mass
spectrum (LSIMS): m/z 461.2122 (MꢈꢈNa). For C26H34O4NaSi 461.2124 (devi-
ation 0.5 ppm).
Hydroboration-oxidation of 11. To a stirred and cooled (ice-water) solu-
tion of 11 (1.34 g, 3.1 mmol) in anhydrous THF (20 mL) was added dropwise un-
der argon 10M BH3-SMe2 (0.7 mL). The mixture was allowed to reach room tem-
perature and stirring was maintained for 30 min. 3M NaOH (3 mL) and aqueous 30%
H2O2 (3 mL) were added dropwise to the stirred and ice-cooled mixture. Stirring
was continued for 30 min at room temperature, ether (20 mL) was added, the or-
ganic phase was separated, and the aqueous phase was extracted with ether. The
combined extracts were washed with brine and water, then concentrated. Flash-
chromatography (ether-hexane 1:6) gave first crystalline 4-O-tert-butyldiphenylsi-
lyl-3-deoxy-1,2-O-isopropylidene-5-C-methyl-ꢁ-L-threo-hexulopyranose (12,
170 mg, 12%), mp 106–108 °C; [ꢁ]D25ꢅ36 (c 1); vKmBaxr 3488 (OH), 3074 and 3044
1
(aromatic), 1388 and 1378 (CMe2), and 705 cmꢅ1 (aromatic). NMR data: H,
ꢆ7.7ꢅ.37 (2 m, 10 H, Ph), 4.12 (dd, 1 H, J3eq,4 6.5, J3ax,4 9.6 Hz, H-4), 3.92 (d, 1 H,
J1,1ꢇ 8.8 Hz, H-1), 3.58 (d, 1 H, H-1ꢇ), 3.56 (d, 1 H, J6ax,6eq 11.2 Hz, H-6ax), 3.36 (d,
1 H, H-6eq), 1.73 (bs, 1 H, OH-5), 1.64 (m, 2 H, H-3ax,3eq), 1.37 and 1.18 (2 s, 6
H, CMe2), 1.35 (s, 3 H, Me-5), and 1.11 (s, 9 H, CMe3); 13C, ꢆ135.97, 135.88,
134.21, 133.61, 130.02, 129.94, 127.89, and 127.80 (aromatic), 111.22 (CMe2),
104.44 (C-2), 74.27 (C-4), 74.23 (C-1), 71.54 (C-5), 68.59 (C-6), 39.47 (C-3), 27.13

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BRANCHED-CHAIN HEXULOSE DERIVATIVES
453
(Me3C), 26.82 and 26.41 (Me2C), 19.50 (Me3C), and 18.72 (Me-5). Mass spectrum
(LSIMS): m/z 479.2230 (MꢈꢈNa). For C26H36O5NaSi 479.2230 (deviation ꢅ0.1
ppm).
Eluted second was 4-O-tert-butyldiphenylsilyl-3,5-dideoxy-5-C-hydrox-
ymethyl-1,2-O-isopropylidene-ꢁ-L-threo-hexulopyranose (13, 120 mg, 8.5%);
film
max
[ꢁ]2D4 ꢅ21 (c 1); v
3489 (OH), 3074 and 3052 (aromatic), 1379 and 1371
(CMe2), and 702 cmꢅ1 (aromatic). NMR data: 1H, ꢆ7.7ꢅ.35 (2 m, 10 H, Ph), 4.16
(dt, 1 H, J3ax,4 ꢂ J4,5 ꢂ 10.1, J3eq,4 5.3 Hz, H-4), 3.89 (d, 1 H, J1,1ꢇ 8.8 Hz, H-1),
3.79 (dd, 1 H, J5,7 4.8, J7,7ꢇ 11.0 Hz, H-7), 3.76 (dd, 1 H, J5,6eq 4.8, J6ax,6eq 11.5 Hz,
H-6eq), 3.60 (t, 1 H, J5,6ax 11.5 Hz, H-6ax), 3.59 (dd, 1 H, J5,7ꢇ 8.5 Hz, H-7ꢇ), 3.53
(d, 1 H, H-1ꢇ), 1.91 (m, 2 H, H-5, OH), 1.69 (dd, 1 H, J3ax,3eq 12.3 Hz, H-3eq), 1.63
(t, 1 H, H-3ax), 1.37 and 1.16 (2 s, 6 H, CMe2), and 1.08 (s, 9 H, CMe3); 13C,
ꢆ135.95, 135.83, 134.88, 134.32, 129.99, 127.89, and 127.83 (aromatic), 111.03
(CMe2), 104.46 (C-2), 74.72 (C-1), 69.46 (C-4), 62.47 and 61.83 (C-6,7), 46.33 (C-
5), 41.79 (C-3), 27.12 (Me3C), 26.81 and 26.44 (Me2C), and 19.39 (Me3C). Mass
spectrum (LSIMS): m/z 479.2228 (MꢈꢈNa). For C26H36O5NaSi 479.2230 (devi-
ation 0.4 ppm).
The last eluted fraction contained 4-O-tert-butyldiphenylsilyl-3,5-dideoxy-5-
C-hydroxymethyl-1,2-O-isopropylidene-ꢀ-D-erythro-hexulopyranose (14, 773
mg, 55%); [ꢁ]D25ꢅ37 (c 1); v fmilamx 3438 (OH), 3049 and 3015 (aromatic), 1383 and
1373 (CMe2), and 702 cmꢅ1 (aromatic). NMR data: 1H, ꢆ7.7ꢅ.36 (2 m, 10 H, Ph),
4.47 (dt, 1 H, J3ax,4 11.5, J3eq,4 ꢂ J4,5 ꢂ 4.9 Hz, H-4), 4.23 (dd, 1 H, J5,7 8.0, J7,7ꢇ
11.2 Hz, H-7), 3.89 (d, 1 H, J1,1ꢇ 8.7 Hz, H-1), 3.88 (dd, 1 H, J5,6ax 2.7, J6ax,6eq 12.0
Hz, H-6ax), 3.78 (dd, 1 H, J5,7ꢇ 6.6 Hz, H-7ꢇ), 3.63 (dd, 1 H, J5,6eq 1.8 Hz, H-6eq),
3.55 (d, 1 H, H-1ꢇ), 2.10 (m, 2 H, H-5, OH), 1.88 (t, 1 H, J3ax,3eq 12.5 Hz, H-3ax),
1.45 (dd, 1 H, H-3eq), 1.34 and 1.13 (2 s, 6 H, CMe2), and 1.08 (s, 9 H, CMe3);
13C, ꢆ135.94, 135.83, 133.49, 133.28, 130.09, 130.06, 129.97, and 127.87 (aro-
matic), 111.11 (CMe2), 104.42 (C-2), 74.84 (C-1), 69.57 (C-4), 62.10 and 61.25
(C-6,7), 41.89 (C-5), 37.79 (C-3), 27.06 (Me3C), 26.80 and 26.40 (Me2C), and
19.08 (Me3C). Mass spectrum (LSIMS): m/z 479.2233 (MꢈꢈNa). For C26H36O5
NaSi 479.2230 (deviation ꢅ0.6 ppm).
5-C-Benzoyloxymethyl-4-O-tert-butyldiphenylsilyl-3,5-dideoxy-1,2-O-
isopropylidene-ꢀ-D-erythro-hexulopyranose (15). Conventional benzoylation
of 14 (310 mg, 0.7 mmol) with benzoyl chloride (0.25 mL, 2.2 mmol) in dry
dichloromethane (10 mL) in the presence of triethylamine (0.4 mL, 2.9 mmol) at
room temperature overnight gave, after work-up and column chromatography
film
(hexane → ether-hexane 1:15), pure 15 (280 mg, 74%) as a syrup; v
3062 (aro-
max
matic), 1718 (CBO, benzoate), 1377 (CMe2), and 715 cmꢅ1 (aromatic). NMR
data: 1H, ꢆ8.1ꢅ.38 (5 m, 15 H, Ph), 4.80 (dd, 1 H, J5,7 3.6, J7,7ꢇ 10.7 Hz, H-7), 4.56
(t, 1 H, J5,7ꢇ 10.6 Hz, H-7ꢇ), 4.43 (dt, 1 H, J3ax,4 11.5, J3eq,4 ꢂ J4,5 ꢂ 5.1 Hz, H-4),
3.96 (d, 1 H, J1,1ꢇ 8.8 Hz, H-1), 3.86 (dd, 1 H, J5,6 1.8, J6,6ꢇ 12.0 Hz, H-6), 3.80 (dd,
1 H, J5,6ꢇ 1.8 Hz, H-6ꢇ), 3.62 (d, 1 H, H-1ꢇ), 2.10 (m, 1 H, H-5), 1.80 (t, 1 H, J3ax,3eq
12.6 Hz, H-3ax), 1.60 (dd, 1 H, H-3eq), 1.38 and 1.21 (2 s, 6 H, CMe2), and 1.11

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IZQUIERDO ET AL.
(s, 9 H, CMe3); 13C (inter alia) ꢆ166.72 (PhCO), 111.14 (CMe2), 104.35 (C-2),
74.84 (C-1), 67.34 (C-4), 60.94 and 60.67 (C-6,7), 40.05 (C-5), 38.32 (C-3), 27.02
(Me3C), 26.81 and 26.45 (Me2C), and 19.20 (Me3C).
5-C-Benzoyloxymethyl-3,5-dideoxy-1,2-O-isopropylidene-ꢀ-D-erythro-
hexulopyranose (16). To a stirred solution of 15 (220 mg, 0.4 mmol) in THF (5
mL) was added tetrabutylammonium fluoride trihydrate (730 mg, 2.3 mmol) under
argon. The mixture was stirred at room temperature 8 h. TLC (ether-hexane 1:1)
then revealed a slower-running product. The solvent was evaporated and a solution
of the residue in ether was washed with brine and water, then concentrated. Col-
umn chromatography (ether-hexane 3.1) gave first crystalline 16 (80 mg, 64%), mp
122–124 °C; [ꢁ]D24ꢅ100 (c 1.1); v KmBaxr 3307 (OH), 3070 (aromatic), 1717 (CBO,
1
benzoate), 1386 and 1373 (CMe2), and 713 cmꢅ1 (aromatic). NMR data: H,
ꢆ8.0ꢅ.41 (3 m, 5 H, Ph), 4.68 (dd, 1 H, J5,7 5.5, J7,7ꢇ 11.1 Hz, H-7), 4.36 (dd, 1 H,
J5,7ꢇ 8.7 Hz, H-7ꢇ), 4.35 (dt, 1 H, J3eq,4 ꢂ J4,5 ꢂ 4.7 Hz, H-4), 4.11 (d, 1 H, J1,1ꢇ 9.0
Hz, H-1), 3.93 (dd, 1 H, J5,6 3, J6,6ꢇ 12.0 Hz, H-6), 3.86 (dd, 1 H, J5,6ꢇ 3.9 Hz, H-
6ꢇ), 3.76 (d, 1 H, H-1ꢇ), 2.29 (m, 1 H, H-5), 1.95 (dd, 1 H, J3ax,3eq 13 Hz, H-3eq),
1.84 (dd, 1 H, J3ax,4 10 Hz, H-3ax), 1.48 and 1.37 (2 s, 6 H, CMe2); 13C, ꢆ167.01
(PhCO), 133.21, 130.92, 129.66, and 128.48 (Ph), 111.11 (CMe2), 104.17 (C-2),
74.28 (C-1), 65.62 (C-4), 61.34 and 60.99 (C-6,7), 39.87 (C-5), 37.85 (C-3), 27.14
and 26.52 (Me2C). Mass spectrum (LSIMS): m/z 345.1316 (MꢈꢈNa). For
C17H22O6Na 345.1314 (deviation ꢅ0.4).
Anal. Calcd for C17H22O6: C, 63.37; H, 6.87. Found: C, 63.60; H, 6.84.
Eluted second was 4-O-benzoyl-3,5-dideoxy-5-C-hydroxymethyl-1,2-O-iso-
propylidene-ꢀ-D-erythro-hexulopyranose (10 mg) contaminated with 16. NMR
data (inter alia): 1H, 5.67 (dt, 1 H, J3eq,4 ꢂ J4,5 ꢂ 5.0, J3ax,4 9.5 Hz, H-4), 4.62 (dd,
1 H, J5,7 5.9, J7,7ꢇ 11.6 Hz, H-7), and 4.37 (dd, 1 H, J5,7ꢇ 3.5 Hz, H-7ꢇ). Mass spec-
trum (LSIMS): m/z 345.1315 (MꢈꢈNa). For C17H22O6Na 345.1314 (deviation
ꢅ0.3 ppm).
5-C-Benzoyloxymethyl-3,5-dideoxy-1,2-O-isopropylidene-4-O-(3,5-dini-
trobenzoyl)-ꢀ -D-threo-hexulopyranose (17). Treatment of 16 (116 mg, 0.36
mmol) with Ph3P (188 mg, 0.72 mmol), 3,5-dinitrobenzoic acid (153 mg, 0.72
mmol) and DEAD (125 mg, 0.72 mmol) in dry THF (3 mL) as above gave, after
work-up and column chromatography (ether-hexane 1:3), crystalline 17 (100 mg,
KBr
54%); mp 115–116 °C (from ether-hexane); [ꢁ]D27ꢅ83 (c 1); v
3097 (aromatic),
max
1725 (CBO benzoate), 1382 (CMe2), and 719 cmꢅ1 (aromatic). NMR data: H,
ꢆ9.3ꢅ.47 (4 m, 8 H, Bz and 3,5-DNBz), 5.58 (m, 1 H, H-4), 4.6ꢅ.51 (m, 3 H, H-
6,7.7ꢇ), 4.14 (d, 1 H, J1,1ꢇ 8.7 Hz, H-1), 3.8ꢅ.78 (m, 2 H, H-1ꢇ,6ꢇ), 2.40 (m, 1 H,
H-5), 2.30 (dd, 1 H, J3,4 3.5, J3,3ꢇ 14.9 Hz, H-3), 2.10 (dd, 1 H, J3ꢇ,4 3.1 Hz, H-3ꢇ),
1.64 and 1.40 (2 s, 6 H, CMe2); 13C, ꢆ166.42 (Bz), 161.76 (3,5-DNBz) 148.83,
134.39, 133.42, 129.71, 128.61, and 122.54 (aromatic), 112.27 (CMe2), 102.47 (C-
2), 75.17 (C-1), 69.95 (C-4), 63.09 (C-6), 58.57 (C-7), 37.19 (C-5), 32.66 (C-3),
27.13 and 26.62 (Me2C). Mass spectrum (LSIMS): m/z 539.1277 (MꢈꢈNa). For
C24H24N2O11Na 539.1278 (deviation 0.2 ppm).
1

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455
Anal. Calcd for C24H24N2O5: C, 52.94; H, 4.44; N, 10.29. Found: C, 52.35;
H, 4.31; N, 10.52.
3,5-Dideoxy-5-C-hydroxymethyl-1,2-O-isopropylidene-gb-D-threo-hexu-
lopyranose (3). A stirred suspension of 17 (37 mg, 0.08 mmol) in anhydrous
methanol (5 mL) was treated with 0.8M sodium methoxide (0.5 mL) in the same
solvent for 1 h. TLC (ether-hexane 3:1) then revealed a compound of lower mo-
bility. The reaction mixture was neutralized (acetic acid), supported on silica gel
and finally chromatographed (ether → ether-methanol 5:1) to yield pure 3 (17 mg,
quantitative) as a clear thick syrup; [ꢁ]D28ꢅ101, [ꢁ]42085 ꢅ228.5 (c 0.45). NMR data:
1H, ꢆ4.21 (dd, 1 H. J5,6 3.3, J6,6ꢇ 12.3 Hz, H-6), 4.00 (d, 1 H, J1,1ꢇ 8.7 Hz, H-1), 4.01
(bs, 1 H, H-4), 3.75 (dd, 1 H, J5,7 3.8, J7,7ꢇ 10.8 Hz, H-7), 3.70 (d, 1 H, H-1ꢇ), 3.67
(dd, 1 H, J5,7ꢇ 7.1 Hz, H-7ꢇ), 3.58 (dd, 1 H, J5,6ꢇ 2.4 Hz, H-6ꢇ), 2.02 (dd, 1 H, J3,4
3.7, J3,3ꢇ 14.0 Hz, H-3), 1.85 (m, 1 H, H-5), 1.83 (dd, 1 H, J3ꢇ,4 4.4 Hz, H-3ꢇ), 1.47
and 1.39 (2 s, 6 H, CMe2); 13C, ꢆ111.84 (CMe2), 103.84 (C-2), 74.52 (C-1), 66,68
(C-4), 62.57 (C-6), 59.02 (C-7), 43.21 (C-5), 35.99 (C-3), 27.03 and 26.55 (Me2C).
Mass spectrum (LSIMS): m/z 241.1053 (MꢈꢈNa). For C10H18O5Na 241.1055
(deviation ꢅ0.5 ppm).
5-C-Benzoyloxymethyl-4-O-tert-butyldiphenylsilyl-3,5-dideoxy-1,2-O-
isopropylidene-ꢁ-L-threo-hexulopyranose (18). Conventional benzoylation of
13 (120 mg, 0.26 mmol) with benzoyl chloride (120 ꢄL) in dry dichloromethane
(2 mL) in the presence of triethylamine (300 ꢄL) at room temperature overnight
gave, after work-up and column chromatography (ether-hexane 1:5), pure 18 (60
film
mg, 41%) as a syrup; [ꢁ]D25 ꢈ86 (c 0.4); v
3065 and 3011 (aromatic), 1726
max
(CBO, benzoate), 1382 (CMe2), and 708 cmꢅ1 (aromatic). NMR data: H,
ꢆ7.9ꢅ.28 (4 m, 15 H, Ph), 4.65 (dd, 1 H, J5,7 3.4, J7,7ꢇ 11.2 Hz, H-7), 4.27 (dd, 1 H,
J5,7ꢇ 7.4 Hz, H-7ꢇ), 4.17 (dt, 1 H, J3eq,4 5.1, J3ax,4 ꢂ J4,5 ꢂ 10 Hz, H-4), 3.90 (d, 1
H, J1,1ꢇ 8.7 Hz, H-1), 3.85 (dd, 1 H, J5,6eq 4.8, J6ax,6eq 11.6 Hz, H-6eq), 3.69 (t, 1 H,
1
J
J
5,6ax 11.4 Hz, H-6ax), 3.54 (d, 1 H, H-1ꢇ), 2.2ꢅ.13 (m, 1 H, H-5), 1.72 (dd, 1 H,
3ax,3eq 12.3 Hz, H-3eq), 1.65 (dd, 1 H, H-3ax), 1.35 and 1.16 (2 s, 6 H, CMe2), and
1.07 (s, 9 H, CMe3); 13C (inter alia) ꢆ166.39 (PhCO), 111.09 (CMe2), 104.46 (C-
2), 74.77 (C-1), 68.00 (C-4), 63.08 and 62.61 (C-6,7), 43.81 (C-5), 41.86 (C-3),
27.04 (Me3C), 26.81 and 26.43 (Me2C), and 19.41 (Me3C).
5-C-Benzoyloxymethyl-3,5-dideoxy-1,2-O-isopropylidene-ꢁ-L-threo-
hexulopyranose (19). Treatment of 18 (60 mg, 0.11 mmol) in THF (3 mL) with
tetrabutylammonium fluoride trihydrate (200 mg, 0.64 mmol) and ammonium
chloride (20 mg, 0.4 mmol) under argon as above gave, after work-up and column
chromatography (ether-hexane 3:15), pure 19 (25 mg, 71%) as a syrup; [ꢁ]D25ꢅ38
(c 1.3); v fmilamx 3274 (OH), 3063 (aromatic), 1718 (CBO, benzoate), 1378 (CMe2),
and 710 cmꢅ1 (aromatic). NMR data: 1H, ꢆ8.0ꢅ.10 (3 m, 5 H, Bz), 4.62 (dd, 1 H,
J
5,7 5.8, J7,7ꢇ 11.6 Hz, H-7), 4.38 (dd, 1 H, J5,7ꢇ 3.4 Hz, H-7ꢇ), 4.01 (d, 1 H, J1,1ꢇ 8,7
Hz, H-1), 3.93 (dt, 1 H, J3eq,4 4.8, J3ax,4 ꢂ J4,5 ꢂ 10.9 Hz, H-4), 3.86 (dd, 1 H, J5,6eq
4.9, J6ax,6eq 11.5 Hz, H-6eq), 3.78 (d, 1 H, H-1ꢇ), 3.76 (t, 1 H, J5,6ax 11.0 Hz, H-

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IZQUIERDO ET AL.
6ax), 2.08 (dd, 1 H, J3ax,3eq 12.3 Hz, H-3eq), 1.98 (m, 1 H, H-5), 1.70 (dd, 1 H, H-
3ax), 1.45 and 1.36 (2 s, 6 H, CMe2); 13C, ꢆ167.18 (PhCO), 133.4, 129.97, and
128.58 (aromatic), 111.54 (CMe2), 104.62 (C-2), 74.99 (C-1), 65.79 (C-4), 63.00
and 62.30 (C-6,7), 44.22 (C-5), 40.89 (C-3), 27.07 and 26.65 (Me2C). Mass spec-
trum (LSIMS): m/z 345.1314 (MꢈꢈNa). For C17H22O6Na 345.1315 (deviation
ꢅ0.1 ppm).
5-C-Benzoyloxymethyl-3,5-dideoxy-1,2-O-isopropylidene-4-O-(3,5-dini-
trobenzoyl)-ꢁ-L-erythro-hexulopyranose (20). Treatment of 19 (60 mg, 0.19
mmol) with Ph3P (100 mg, 0.38 mmol), 3,5-dinitrobenzoic acid (80 mg, 0.38
mmol) and DEAD (66 mg, 0.38 mmol) in dry THF (3 mL) as above gave, after
work-up and column chromatography (ether-hexane 1:3) crystalline 20 (95 mg,
quantitative); mp 133–135 °C (from dichloromethane-ether); [ꢁ]2D8 ꢅ57 (c 1);
vKmBaxr 3116 (aromatic), 1720 (CBO benzoate), 1380 (CMe2), and 714 cmꢅ1 (aro-
matic). NMR data: 1H, ꢆ9.2ꢅ.40 (4 m, 8 H, Bz and 3,5-DNBz), 5.75 (bs, 1 H, H-
4), 4.37 (dd, 1 H, J5,7 6.3, J7,7ꢇ 11.3 Hz, H-7) 4.35 (t, 1 H, J5,6ax ꢂ J6ax,6eq ꢂ 11.6
Hz, H-6ax), 4.28 (dd, 1 H, J5,7ꢇ 7.5 Hz, H-7ꢇ) 4.14 (d, 1 H, J1,1ꢇ 8.7 Hz, H-1), 3.94
(dd, 1 H, J5,6eq 4.7 Hz, H-6eq), 3.80 (d, 1 H, H-1ꢇ), 2.59 (m, 1 H, H-5), 2.22 (dd, 1
H, J3,4 3.0, J3,3ꢇ 14.8 Hz, H-3), 2.12 (dd, 1 H, J3ꢇ,4 3.0 Hz, H-3ꢇ), 1.66 and 1.27 (2
s, 6 H, CMe2); 13C, ꢆ166.80 (Bz), 162.13 (3,5-DNBz), 148.71, 134.50, 133.36,
129.66, 129.59, 128.52, and 122.43 (aromatic), 112.27 (CMe2), 102.34 (C-2),
75.26 (C-1), 69.46 (C-4), 62.07 (C-6), 59.01 (C-7), 38.00 (C-5), 35.68 (C-3), 27.17
and 26.63 (Me2C). Mass spectrum (LSIMS): m/z 539.1282 (MꢈꢈNa). For
C24H24N2O11Na 539.1278 (deviation ꢅ0.8 ppm).
Anal. Calcd for C24H24N2O5: C, 52.94; H, 4.44; N, 10.29. Found: C, 52.66;
H, 4.25; N, 10.83.
3,5-Dideoxy-5-C-hydroxymethyl-1,2-O-isopropylidene-ꢁ-L-erythro-hex-
ulopyranose (4). Treatment of 20 (190 mg, 0.4 mmol) with 0.8M sodium
methoxide (0.5 mL) in anhydrous methanol (5 mL) as above afforded pure 4 (75
27
mg, quantitative) as a clear thick syrup; [ꢁ]D27 ꢅ91 (c 0.6), [ꢁ] ꢅ241 (c 0.4).
405
NMR data: 1H, ꢆ4.31 (bd, 1 H, H-4), 4.14 (t, 1 H, J5,6ax ꢂ J6ax,6eq ꢂ 12.0 Hz, H-
6ax), 4.01 (d, 1 H, J1,1ꢇ 8.8 Hz, H-1), 3.81 (dd, 1 H, J5,7 4.4, J7,7ꢇ 11.3 Hz, H-7), 3.76
(d, 1 H, H-1ꢇ), 3.7ꢅ.70 (m, 2 H, H-6eq,7ꢇ), 1.95 (d, 2 H, J3,4 3.1 Hz, H-3,3), 1.85
(m, 1 H, H-5), 1.51 and 1.40 (2 s, 6 H, CMe2); 13C, ꢆ111.65 (CMe2), 103.52 (C-2),
75.10 (C-1), 68.11 (C-4), 63.08 (C-6), 59.17 (C-7), 40.71 (C-5), 38.27 (C-3), 27.00
and 26.64 (Me2C). Mass spectrum (LSIMS): m/z 241.1053 (MꢈꢈNa). For
C10H18O5Na 241.1055 (deviation ꢅ0.4 ppm).
ACKNOWLEDGMENTS
The authors are deeply grateful to Ministerio de Educación y Cultura (Spain)
for finantial support (Project PB98-1357) and for a grant (J. A. Tamayo).

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REFERENCES
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Received March 5, 2001
Accepted June 11, 2001

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