Total synthesis of carba-D-fructofuranose via a novel metathesis reaction

Article abstract of DOI:10.1021/ol990275n

(equation presented) Carba-D-fructofuranose 2b was synthesized in 11 steps (45%), from 2,3,5-tri-O-benzyl-D-arabinofuranose 5 using a ring closing metathesis. Schrock's catalyst was employed on the unique substituted diene synthon 4 to furnish the pentahy

Full text of DOI:10.1021/ol990275n

ORGANIC
LETTERS
1999
Vol. 1, No. 9
1463-1465
Total Synthesis of
Carba-D-fructofuranose via a Novel
Metathesis Reaction
Mohindra Seepersaud and Yousef Al-Abed*
The Picower Institute for Medical Research, 350 Community DriVe,
Manhasset, New York 11030
yal-abed@picower.edu
Received September 8, 1999
ABSTRACT
Carba-D-fructofuranose 2b was synthesized in 11 steps (45%), from 2,3,5-tri-O-benzyl-D-arabinofuranose 5 using a ring closing metathesis.
Schrock’s catalyst was employed on the unique substituted diene synthon 4 to furnish the pentahydroxlated cyclopentene 3. Hydrogenation
afforded 2b.
We recently were involved in the identification of an
inducible isoform of phosphofructokinase-2 (PFK-2, EC
2.7.1.105) that is specifically induced by inflammation
stimuli or oncogenic transformation1 and suggested that
fructose analogues might serve as useful pharmacophores
for inhibiting cell activation and cancer cell growth.2 Fructose
2,6-bisphospate 1 (Figure 1) is formed by phosphorylation
bisphosphate is a powerful allosteric regulator of glycolysis
via its potent stimulatory effect on phosphofructokinase-1
(EC 2.7.1.11) activity and its inhibitory effect on fructose-
1,6-bisphosphatase (EC 3.1.3.11). Unlike phosphorylated
fructose, carba-D-fructofuranose 2a (Figure 1) cannot be
metabolized and therefore can be shuttled repeatedly through
cycles of kinase and phosphatase activity. The first and only
synthetic approach to 2, by Wilcox and Guadino,4 was via a
free radical ring closure.
We have previously reported5 that highly functionalized
cyclopentene compounds may be prepared via a ring closing
metathesis (RCM) employing Schrock’s or Grubb’s catalyst.6
Thus cyclopentene 3, a potential precursor to the target 2b,
may be obtained from RCM of diene 4, which could arise
(2) (a) Nathan, D. M. Ann. Intern. Med. 1996, 124, 86-89. (b) Nishimura,
M.; Federov, S.; Uyeda, K. J. Biol. Chem. 1994, 269, 42, 26100. (c)
Warburg, O. Science 1956, 123, 309. (d) Argiles, J. M.; Azcon-Biet, J.
Mol. Cell. Biochem. 1988, 81, 3. (e) Hue, L.; Rousseau, G. G. AdV. Enzyme
Regul. 1993, 33, 97.
Figure 1.
(3) (a) Hasemann, C. A.; Istvan, E. S.; Uyeda, K.; Deisenhofer, J.
Structure 1996, 4(9), 1017. (b) Pilkis, S. J.; Claus, T. H.; Kurland, I. J.;
Lange, A. J. Annu. ReV. Biochem. 1995, 64, 799. (c) Rousseau, G. G.; Hue,
L. Prog. Nucl. Acid Res. Mol. Biol. 1993, 45, 99. (d) Uyeda, K. In Study
of Enzymes II; Kuby, S. A., Ed.; 1991; p 445.
(4) Wilcox, C. S.; Guadino, J. J. J. Am. Chem. Soc. 1986, 108, 3102.
(5) Seepersaud, M.; Bucala, R.; Al-Abed Y. Z. Naturforsch. 1999, 54b,
565.
of fructose-6-phosphate, a key substrate in the glycolysis
pathway, in a reaction catalyzed by PFK-2.3 Fructose-2,6-
(1) Chesney, J.; Mitchell, R.; Benigni, F.; Bacher, M.; Spiegel, L.; Al-
Abed, Y.; Hee Han, J.; Metz, C.; Bucala, R. Proc. Natl. Acad. Sci. U.S.A.
1999, 6, 3047.
10.1021/ol990275n CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/06/1999

Scheme 1
from a D-arabinose precursor. 2,3,5-Tri-O-benzyl-D-arabi-
by a Wittig reaction gave 11. Hydrolysis followed by
isopropenylmagnesium bromide addition gave a single diene
isomer, which was subsequently protected to give 4.
nose7 5 is an appropiate starting material since the two
stereogenic centers at C2/C3 match C3/C4 of carba-D-
fructofuranose. Our strategy also facillitates the selective
phosphorylation of C2/C6 to resemble the target 2a, thus
differentiating between the conserved protected hydroxyl and
the generated ones (Scheme 1).
Treatment of 4 under standard RCM conditions that were
sucessful in our previous studies with nonsubstituted diene
precursors failed. These conditions led to quantitative
recovery of the starting material.5,6 The cyclization was then
attempted under conditions reported by Furstner and Lange-
mann.9 Addition of the diene to a solution of Schrock’s
catalyst (0.05 M) in hexane followed by refluxing for 12 h
gave methyl cyclopentene 3 in 89% yield. Compound 3 was
now primed for elaboration to the allylic alcohol. There have
been several reports10 using SeO2 for the oxidation of allylic
methylcyclopentenes and methylcyclohexenes. However,
treatment of polyhydroxylated methylcyclopentene 3 under
these conditions gave only decomposition products. We next
turned our attention to oxidation of the methyl unit before
the cyclization. We were concerned that the allylic benzyloxy
groups would be problematic since there have been no
reported examples of RCM on such substrates. Thus, diene
4 was treated with SeO2 and TBHP in CH2Cl2 and stirred
for 12 h to yield the allylic alcohol which was subsequently
protected as benzyl ether 8. Addition of compound 8 to a
solution of Schrock’s catalyst and refluxing the mixture for
18 h led to the desired product 9, in 91% yield. Finally,
hydrogenation of 9 provided carba-D-fructofuranose 2b. The
diastereofacial selectivity observed from the hydrogenation
of the alkene could arise from intramolecular complexation
of the Pd/H2 complex with the C1/C4 benzyloxy groups,
resulting in syn attack of H2 (Scheme 2).11
Oxidation of commercially available 2,3,5-tri-O-benzyl-
D-arabinofuranose7 5 employing NaOCl and TEMPO gave
the lactone. Addition of MeMgBr (2 equiv) to the lactone
followed by selective acylation of the resulting diol at the
secondary alcohol provided the tertiary alcohol which was
subjected to elimination via the chloride (SOCl2, pyridine).
In situ removal of the acetate provided the secondary alcohol,
which was treated under Swern oxidation conditions to
provide ketone 6 in 98% overall yield from 5. Addition of
vinylmagnesium bromide afforded a single tertiary alcohol
which was subsequentially protected as benzyl ether 4
(Scheme 2).
Scheme 2
1
The H and 13C NMR data12 of 2b were identical to the
(6) (a) Grubbs, R. H.; Miller, S. J. Acc. Chem. Res. 1995, 28, 446. (b)
Nicaloau, K. C.; He, Y.; Vouloumis, D.; Vallberg, H.; Roschangar, F.;
Sarabia, F.; Ninkovic, S.; Yang, Z.; Trujillo, J. I. J. Am. Chem. Soc. 1997,
119, 10073. (c) Crimmins, M. T.; Choy, A. L. J. Org. Chem. 1997, 62,
7548. (d) Schmalz, H. G. Angew. Chem., Int. Ed. Engl. 1995, 34, 1833. (e)
Arisawa, M.; Takezawa, E.; Nishida, A.; Miwako, M.; Nakagawa, M. Synlett
1997, 1179. (f) Furstner, A.; Muller, T. J. Org. Chem. 1998, 63, 424. (g)
Ziegler, F. E.; Wang, Y. J. Org. Chem. 1998, 63, 7920. (h) Ovaa, H.; Codee,
J.; Lastdrager, B.; Overkleeft, H.; Marel, G.; van Boom, J. Tetrahedron
Lett. 1998, 39, 7987. (i) Sellier, O.; Van de Weghe, P.; Le Nouen, D.;
Strehler, C.; Eustache, J. Tetrahedron Lett. 1999, 40, 853. (j) Kornienko,
A.; d’Alarcao, M. Tetrahedron: Asymmetry 1999, 10, 827. (k) Ovaa, H.;
Codee, J.; Lastdrager, B.; Overkleeft, H.; Marel, G.; van Boom, J.
Tetrahedron Lett. 1999, 40, 5063.
Compound 4 was identical to the sample obtained from
an alternative synthesis using 1,2:3,5-di-O-isopropylidene-
R-D-apiose8 10, a carbohydrate precursor, where the stereo-
chemistry of the tertiary carbon is conserved (Scheme 3).
Hydrolysis, selective protection of the tertiary center as the
benzyl ether, and oxidation of the primary center followed
(7) Freeman, F.; Robarge, R. D. Carbohydr. Res. 1986, 154, 270.
(8) Nachman, R. J.; Honel, M.; Williams, T. M.; Halaska, R. C.; Mosher,
H. S. J. Org. Chem. 1986, 51, 4802. This compound is available from
Pfanstiehl Laboraties, Inc., cat. no. D-115.
(9) Furstner, A.; Langemann, K. Synthesis 1997, 792.
(10) (a) Paquette. L. A.; Maleczka, R. E.; Qui, F. J. Org. Chem. 1991,
56, 2455. (b) Sharpless, K. B.; Lauer, R. F. J. Am. Chem. Soc. 1972, 94,
7154.
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Org. Lett., Vol. 1, No. 9, 1999

Scheme 3
data published by Wilcox and Guadino.4 Additionally, a NOE
on diene systems of polyhydroxylated carbon chains. A
practical and straightforward route to carbafructofuranose 2b
from 2,3,5-tri-O-benzyl-D-arabinofuranose (11 steps, unop-
timized yield 45%) was devised. By comparison, the Wilcox
synthesis of 2b involved 12 steps with a yield of 18%.
study of 2b confirmed the stereochemistry at C5. A 2% NOE
between H3/H5 (Figure 2) indicates the syn arrangement.
Biological investigation of the effects of this phospho-
carba-D-fructofuranose on the purified PFK-2 enzyme are
presently under investigation. Overall, this synthesis dem-
onstrates the enormous potential of the RCM methodology
Acknowledgment. The authors wish to thank Drs. David
Mootoo and Kirk Manogue for their help in preparation of
this manuscript, Dr. Michael Blumenstein for his help in the
structural determination of 2b, and Dr. Angeles Dios for her
many helpful discussions.
Supporting Information Available: 1H and 13C NMR
spectra for key compounds 3, 4, 6, 8, 9, 2b, and 11. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL990275N
(11) (a) Thompson, H. W.; J. Org. Chem. 1971, 36, 2577. (b) Thompson,
H. W.; McPherson, E.; Lences, B. L. J. Org. Chem. 1976, 41, 2903. (c)
Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307.
(12) See Supporting Information.
Figure 2.
Org. Lett., Vol. 1, No. 9, 1999
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