A polyhydroxylated cyclopentene: A useful synthon toward the synthesis of carbocyclic D-fructofuranoid

Article abstract of DOI:10.1515/znb-1999-0422

A polyhydroxylated cyclopentene has been synthesized in five steps with an overall yield of 61%, starting from 2,3,5-tri-O-benzyl-D-arabinofuranose.

Full text of DOI:10.1515/znb-1999-0422

A Polyhydroxylated Cyclopentene: A Useful Synthon toward the Synthesis
of Carbocyclic D-Fructofuranoid
Mohindra Seepersaud, Richard Bucala, Yousef Al-Abed*
The Picower Institute for Medical Research, 350 Community Drive, Manhasset, N. Y. 11030
Z. Naturforsch. 54b, 5 65-568 (1999); received March 3, 1999
D-Arabino- and D-Fructofuranoid, Polyhydroxylated Cyclopentene. Grubb’s and Schrock’s
Catalyst
A polyhydroxylated cyclopentene has been synthesized in five steps with an overall yield
of 61%, starting from 2,3,5-tri-O-benzyl-D-arabinofuranose.
Introduction
cyclization. The present report examines the cyclo-
pentane annulation via an olefin metathesis.
Fructose 2,6-bisphosphate (1) is formed by
phosphorylation of fructose-6-phosphate, a key
substrate in the glycolysis pathway, in a reaction
catalyzed by phosphofructokinase-2 (PFK-2) [1].
Fructose-2,6-bisphosphate is a powerful allosteric
regulator of glycolysis via its potent stimulatory
effect on phosphofructokinase-1 activity and its in-
hibitory effect on fructose-1,6-bisphosphatase. The
recent identification of an inducible isoform of
PFK-2 that is specifically induced by inflammation
stimuli or oncogenic transformation has suggested
that fructose analogs might serve as useful phar-
macophores for inhibiting cell activation and can-
cer cell growth [2, 3]. Unlike phosphorylated fruc-
tose, carbocyclic D-fructofuranoside (2) (Fig. 1)
can not be metabolized and therefore can be shut-
tled repeatedly through cycles of kinase and phos-
phatase activity.
Results and Discussion
Ring closing metathesis (RCM) is a powerful
tool for the synthesis of medium (5-8) to large
(10-13 and higher) carbo or heterocycles [5]. Re-
cently, there have been two reports concerning
RCM on functionalized substrates. The first is the
synthesis of the six-membered poylsubstituted
cyclohexene valiolamine employing the Schrock’s
catalyst [6] and the second is the synthesis of the
seven-membered heterocyclic oxepine skeleton [7]
utilizing Grubb’s catalyst. Herein we desribe the
synthesis of a polyhydroxylated cyclopentene, car-
bafructofuranose precursor (4a) (Scheme 1) using
the RCM methodology. In this synthetic approach,
4 can arise via an RCM of a diene precursor 5
which could be readily assembled from a carbohy-
drate derivative.
Treatment of the commercially available 2,3,5-
tri-O-benzyl-D-arabinofuranose [8] (6) under Wit-
tig and Swern conditions furnished 8 in 78% yield.
Addition of vinylmagnesiumbromide afforded the
single diene alcohol precursor 9. The origin of the
stereochemistry at this centre cannot be readily
predicted and is probably a result of the stereo-
directing effect of the chiral a-benzyloxy group.
The alcohol was subsequentially protected as the
benzyl ether and then subjected to RCM condi-
tions. Treatment of 5a with 20 mol% of the
Schrock’s catalyst [9] in anhydrous CH2C12 fur-
nished the cyclopentene (4a) exclusively in 87%
yield. Of note, treatment of 5a with the ruthenium
alkylidene metal complex [9] gave the desired
Wilcox and Guadino [4] have shown the first and
only synthetic approach to carbocyclic D-fructofur-
anoside (3) (Scheme 1). The overall synthesis in-
volved 12 steps. Cyclopentane ring closure was
accomplished utilizing a free-radical mediated
0„P0
Fig. 1. Structure of fructose-2,6-bisphosphate (1) and
carbocyclic D-fructofuranoside (2).
Reprint requests to Dr. Yousef A l-A bed.
0932-0776/99/0400-0565 $06.00 © 1999 Verlag der Zeitschrift für Naturforschung, Tübingen • www.znaturforsch.com
D
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M. Seepersaud et al. ■A Polyhydroxylated Cyclopentene
566
4a, R = H
4b, R = CH,
5a, R = H
5b, R = CH,
Schem e 1.
compound in 35% and the starting material 5a in
49% yield (Scheme 2).
The stereochemistry of the cyclic product was
established using NOE analysis. NOE analysis
previously has been used in the structural assign-
ment of similar five and six-membered cyclic com-
pounds [6, 10]. The ‘H NMR signals of 4a were
first identified by COSY. The NOE analysis
allowed for structural assignment (Fig. 2). An
NOE of 1.5% between H3 and one of the benzylic
protons H] and also a 1.0% NOE between H6 and
the other benzylic proton H[ was observed. These
data provide strong support for a syn relationship
between C-2/C-3 benzyloxy groups and assigns the
framework of 4a with the correct stereochemistry
at C-2, 3 and C-4 of 1, since the stereochemistry
at C-3 and C-4 was conserved from 6.
Fig. 2. The N O E analysis of 4a.
Experimental
General part
TLC was carried out on aluminum sheets pre-
coated with silica gel 60 (HF-254, E. Merck) to a
thickness of 0.25 mm. Flash column chromatogra-
phy (FCC) was performed using Kieselgel 60
(230-400 mesh, E. Merck) and usually employed
a stepwise solvent polarity gradient, correlated
with TLC mobility. ]H and 13C NMR spectra were
The diene 5b (Scheme 2) is readily prepared
from the commercially available l,2:3,5-di-0-iso-
propylidene-a-D-apiose [11] or 2,3,5-tri-O-benzyl- obtained on JEOL 270 instrument. Unless other-
wise noted, spectra were recorded at 270 and 67.5
MHz respectively. Mass spectral analysis were per-
formed by Hunter college and University of Illi-
nois mass spectrometral facilities. Dry THF was
obtained by distillation, under nitrogen from po-
tassium-benzophenon ketyl. Dichloromethane was
distilled from P20 5. Other solvents were purified
and dried by using standard procedures.
D-arabinofuranose and studies presently are un-
derway for the synthesis and metathesis of these
intermediates. Further elaboration of 4a to carba-
fructofuranose and other polyhydroxylated deriv-
atives, and the investigation of the derivatives as
inhibitors of PFK2 are also being actively pursued.
In summary, we have demonstrated a concise
and efficient synthesis of the carbafructofuranose
precursor 4a, utilizing a potentially general path-
way in 5 steps with an overall yield of 61%.
Compound 7: nBuLi (11.0 mmol, 1.6 M in hex-
ane) is added to a suspension of methyl triphenyl-
phosphonium bromide (4.28 g, 12.0 mmol) in dry
BnO
Schem e 2. (a) BuLi (2.1 eq.),
CFLPPh} (2.3 eq.), THF, 0 °C to rt,
87%; (b) DMSO (5 eq.), Et,N (10 eq.),
(COCl)2 (4.8 eq.), CH2C12, -7 8 °C to rt,
90%; (c) CH2=CH->MgBr (1 M in THF,
3 eq.), THF, -7 8 °C to 0 °C, 92%;
(d) BNBR (3 eq.), NaH (2.9 eq.), Bu4Nl
(0.1 eq.), DMF 98%; (e) i. Schrock’s cat-
alyst (20 mmol-%), CH2C12, rt, 18 h,
87% (4a), ii. Grubb’s catalyst (10 mol-
%), CH2C12, rt, 3 d, 35% (4a), 49% (5a).
BnO
OBn
BnO
OBn
OBn
8
7
-OBn
BnO
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567
M. Seepersaud et al. • A Polyhydroxylated Cyclopentene
1H), 5.45 (dd, 1H, J = 1.7, 17.3 Hz), 5.3 (m, 2H),
5.17 (dd, 1H, J = 1.7, 10.6 Hz), 4.67 (ABq, Ad =
0.07 ppm, 2H, J = 11.1 Hz), 4.42 (ABq, Ad =
THF (25 ml) at 0 °C under N2. The suspension was
allowed to stir for 30 min at 0 °C then warmed up
to rt (1 h). 2,3,5-tri-O-benzyl-D-arabinofuranose
(6) (2.0 g, 5 mmol) was dissolved in THF (5 ml) 0.34 ppm, 2H, J = 11.4 Hz), 4.45 (m, 2H), 4.18 (dd,
1H, J = 2.2, 8.2 Hz), 3.72 (d, 1H, J = 2.2 Hz), 3.79
(d, 1H, J = 8.4 Hz), 3.25 (d, 1H, J = 8.4 Hz). 13C
NMR (67.5 MHz, CDC13) d 140.3, 138.2, 138.1,
137.3, 136.1, 128.7-127.7 (7 signals), 118.9, 114.5,
82.0, 81.6, 78.3, 76.0, 74.4, 73.5, 70.6. - MS (ES)
m/z 467 (M + Na+), 181 (base peak).
and transferred by cannula dropwise over 10 min.
The reaction mixture was allowed to warm to rt,
followed by addition of Et20 (100 ml). The sus-
pension was filtered through celite and the excess
solvent evaporated. FCC (10-30% EtOAc:PE)
furnished a clear oil 7 (1.81 g, 87%). Rf 0.6 (20%
EtOAc:PE); 'H NMR (270 MHz, CDC13) (3 7.34
Compound 5a: Alcohol 9 (80 mg, 0.18 mmol)
(m, 15H), 5.95 (m, 1H), 5.34 (m, 2H), 4.62 (ABq, was disolved in DMF (3 ml, anhydrous) and
Ad = 0.09 ppm, 2H, J = 11.9 Hz), 4.52 (m, 2H), the solution was cooled to 0 °C and NaH
4.50 (ABq, Ad = 0.23 ppm, 2H, J = 11.2 Hz), 4.1
(m, 1H), 4.04 (m, 1H), 3.64 (m, 3H). 13C NMR
(35 mg, 0.88 mmol) was added. Bu4NI (13 mg,
0.036 mmol) followed by BnBr (156 mg, 0.9 mmol)
(67.5 MHz, CDC13) (3 138.3, 138.2, 138.0, 135.2, then was added and the reaction mixture allowed
to stir for 30 min. The reaction was quenched by
dropwise addition of MeOH (2 ml), then water
(15 ml) and the aqueous mixture was extracted
128.5-127.8 (8 signals), 119.2, 80.6, 74.2, 73.5, 71.0,
70.8, 70.5.
Compound 8: To a solution of oxalyl chloride
(549 mg, 4.3 mmol) in anhydrous CH2C12 (5 ml) with Et20 (3x15 ml). The combined Et20 extract
was washed with saturated aqueous N aH C 03
(10 ml), brine (10 ml) and excess solvent evapo-
rated to give tetrabenzylated product 5a (94 mg,
at -78 °C under N2 was added DMSO (375 mg,
4.8 mmol) and the mixture allowed to stir for
20 min. The alcohol 7 [200 mg, 0.48 mmol, dis-
solved in CH2C12 (4 ml)] then was added and the 98%). Rf 0.7 (10% EtOAc:PE); !H NMR (270
reaction allowed to stir for 25 min. Et3N (847 mg, MHz, CDC13) <5 7.33 (m, 20H), 6.08 (dd, 1H, J =
10.6, 18.0 Hz), 6.01 (m, 1H), 5.34 (d, 1H, J = 1.7
Hz), 5.28 (m, 2H), 5.22 (m, 1H), 4.74 (ABq, Ad =
0.08 ppm, 2H, J = 11.1 Hz), 4.53 (ABq, Ad =
8.6 mmol) then was added and the solution
warmed to 0 °C. EtzO (50 ml) was added and the
combined organic washed with saturated aqueous
NaHCO, (30 ml), brine (30 ml) and dried
(MgS04). The Et20 extract was concentrated in
vacuo and purified by FCC (10-40% EtO A c:PE),
to give the ketone 8 (179 mg, 90%). Rf 0.75 (25%
0.11 ppm, 2H, J = 11.6 Hz), 4.4 (ABq, Ad
=
0.36 ppm, 2H, J = 11.9 Hz), 4.34 (m, 2H), 4.11 (dd,
1H, J = 3.0, 7.7 Hz), 3.82 (d, 1H, / = 10.9 Hz), 3.76
(d, 1H, J = 3.2 Hz), 3.52 (d, 1H, J = 10.9 Hz).
EtOAc:PE); 'H NMR (270 MHz, CDC13) (3 7.30 13C NMR (67.5 MHz, CDC13) d 139.8,138.9, 138.2,
138.1, 137.3, 137.2, 128.5-127.0 (9 signals), 117.7,
116.1, 86.7, 82.8, 79.8, 76.3, 73.3, 70.2, 70.1, 65.1. -
MS (ES) m/z 557 [(M + Na+), (base peak)], 535
(M + H+).
Compound 4a: The diene 5a (70 mg,
0.131 mmol) dissolved in anhydrous CH2C12
(1.0 ml) was added to a homogeneous orange-red
solution of Schrock’s catalyst 2,6-Diisopropyl-
(m, 15H), 5.91 (m, 1H), 5.33 (m, 1H), 4.48-4.60
(m, 4H), 4.35 (m, 2H), 4.28 (m, 2H), 4.19 (m, 1H),
4.00 (d, 1H, J = 3.5 Hz). 13C NMR (67.5 MHz,
CDC13) d 207.7, 137.6, 137.5, 136.9, 134.2, 128.6-
127.8 (6 signals), 119.9, 85.9, 81.0, 74.7, 74.4, 73.4,
71.0. - MS (ES) m/z 439 (M + Na+), 434.2
(M + NH4+), 181 (base peak).
Compound 9: The azeotropically dried ketone 8
(190 mg, 0.5 mmol) intermediate was dissolved in phenylimido neophylidenemolybdenum (IV) bis-
THF (5 ml), and cooled to -78 °C. A 1M solution
of vinylmagnesiumbromide (1.40 mmol, 1.4 ml)
then was added dropwise and the solution was al-
lowed to warm up to 0 °C. The reaction was
(hexafluoro-r-butoxide) (20 mg, 0.026 mmol) in
anhydrous CH2C12 (4 ml) under N2. The resulting
mixture was stirred at 20 °C for 18 h, at which time
TLC showed formation of new material. The reac-
quenched by addition to cold saturated NH4C1 tion mixture was quenched by exposure to air for
2 h then excess solvent evaporated in vacuo. The
black residue was purified by FCC (5-10%
EtOAc:PE) to give the diene 4a (57.6 mg, 87%).
Rf 0.5 (10% EtOAc : PE); !H NMR (270 MHz,
(15 ml). The mixture was extracted with Et20
(3x20 ml), washed with saturated aqueous
NaH C03 (30 ml), brine (30 ml) and dried
(MgS04). The Et20 extract was concentrated in
vacuo and purified by FCC (20-60% EtO A c:PE), CDC13) d 7.25 (m, 20H), 6.05 (d, 1H, J = 6.0 Hz,
H-5), 5.77 (d, 1H, J = 6.0 Hz, H-6), 4.78 (m, 1H),
4.70 (m, 1H, H-4), 4.56-4.46 (m, 6H), 4.34 (m,
1H), 4.05 (d, 1H, J = 4.0 Hz, H-3), 3.57 (ABq, Ad =
to give the alcohol 9 (204 mg, 92%) Rf 0.4 (10%
EtOAc:PE); !H NMR (270 MHz, CDC13) (3 7.32
(m, 15H), 6.17 (dd, 1H, J = 1.7, 17.3 Hz), 5.99 (m,
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568
M. Seepersaud et al. ■A Polyhydroxylated Cyclopentene
A c k n o w Ied g em en ts
0.07 ppm, 2H, J = 9.5 Hz, H-1).I3C NMR (67.5
MHz, CDCI3 ) d 139.5, 138.7, 138.4, 138.3, 135.5,
134.0, 128.5-126.2 (8 signals), 89.1, 87.5, 84.7, 75.0,
73.6, 72.8, 71.6, 67.2. - HRMS (FABMS) calcu-
lated for C34H34O4 (M + H+) 507.253535, found
507.253500. '
The authors wish to thank Mrs. Shu Ya Chen
for her advice on the Grubb's catalyst. Dr. Clifford
Soil for the mass spectral analysis. Dr. Kirk Mano-
gue for his help in preparation of this manuscript
and Dr. Angeles Dios for her assistance.
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