Total synthesis of both methyl 4a-carba-D-arabinofuranosides.

Article abstract of DOI:10.1021/ol9912682

[reaction: see text] The total synthesis of methyl 4a-carba-alpha-D-arabinofuranoside (1) and methyl 4a-carba-beta-D-arabinofuranoside (2) has been achieved starting from D-mannose (5). Key transformations included a ring-closing metathesis of diene 11 em

Full text of DOI:10.1021/ol9912682

ORGANIC
LETTERS
2000
Vol. 2, No. 2
167-169
Total Synthesis of Both Methyl
4a-Carba-D-arabinofuranosides
Christopher S. Callam and Todd L. Lowary*
Department of Chemistry, The Ohio State UniVersity, Columbus, Ohio 43210
lowary.2@osu.edu
Received November 22, 1999
ABSTRACT
The total synthesis of methyl 4a-carba-r-D-arabinofuranoside (1) and methyl 4a-carba-â-D-arabinofuranoside (2) has been achieved starting
from D-mannose (5). Key transformations included a ring-closing metathesis of diene 11 employing Schrock’s catalyst followed by a stereoselective
hydrogenation with Wilkinson’s catalyst.
Pseudosugars, or carbasugars, are analogues of monosac-
charides in which the ring oxygen has been replaced by a
methylene group. In recent years, there has been increasing
interest in the synthesis of therapeutic agents containing
pseudosugar residues because of their improved acid and
metabolic stability relative to their glycoside counterparts.
For example, a number of pseudosugar-containing nucleoside
analogues have been prepared,1 and some have shown
promise as antiviral agents.2 Additionally, it has been
demonstrated that oligosaccharide analogues containing
pseudosugar residues are competent glycosyltransferase
substrates, possessing activities essentially the same as the
natural glycan parent.3 It can therefore be expected that
metabolically stable glycosyltransferase inhibitors can be
prepared by modifying the native oligosaccharide substrate
to include both pseudosugar moieties and functionality that
will deactivate the enzyme.
mycobacteria and, in particular, Mycobacterium tuberculo-
sis.4 Infection by this organism causes tuberculosis, a disease
that is a worldwide health threat resulting in over three
million deaths each year.5 We are especially interested in
compounds that block the assembly of the arabinan portions
of the cell wall, a structure that is critical for the viability of
the organism.6 This arabinan is a polysaccharide comprised
of R-D- and â-D-arabinofuranosyl residues, and we have used
methyl glycosides 3 and 4 (Figure 1) as model compounds
for these residues, respectively.
We have initiated a research program directed at the
identification of inhibitors of cell wall biosynthesis in
(1) (a) Crimmins, M. T. Tetrahedron 1998, 54, 9229. (b) De Clercq, E.
Nucleosides Nucleotides 1998, 17, 625. (c) Agrofoglio, L.; Suhas, E.; Farese,
A.; Condom, R.; Challand, S. R.; Earl, R. A.; Guedj, R. Tetrahedron 1994,
50, 10611.
(2) (a) Marquez, V. E. AdV. AntiViral Drug Des. 1996, 2 89. (b) Mansour,
T. S.; Storer, R. Curr. Pharm. Des. 1997, 3, 227. (c) Parmely, M. J.;
Hausmann, E. H. S.; Morrison, D. C. Infect. Dis. Ther. 1996, 19, 253.
(3) (a) Ogawa, S.; Matsunaga, N.; Li, H.; Palcic, M. M. Eur. J. Org.
Chem. 1999, 3, 631. (b) Ogawa, S.; Furuya, T.; Tsunoda, H.; Hindsgaul,
O.; Stangier, K.; Palcic, M. M. Carbohydr. Res. 1995, 271, 197.
Figure 1.
To prepare inhibitors of mycobacterial arabinosyltrans-
ferases containing pseudo-arabinofuranosyl residues, we
10.1021/ol9912682 CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/23/1999

needed to develop an efficient synthetic route to the
previously unreported pseudosugar analogues of 3 and 4,
namely, methyl 4a-carba-R-D-arabinofuranoside (1) and
methyl 4a-carba-â-D-arabinofuranoside (2). Polyhydroxylated
cyclopentanes and cyclohexanes are common structural
features of a large array of natural products, and their
preparation has attracted the attention of synthetic chemists.
However, most of this work has been focused on the
preparation of compounds possessing either a full comple-
ment of hydroxyl groups7 (e.g., inositols) or glycans contain-
ing carbapyranose residues.8 The synthesis of carbafuranoses
has been far less investigated.9
Scheme 1. Synthesis of 1 and 2a
When evaluating existing methodology which could be
applied to the synthesis of 1 and 2, we were guided not only
by our desire to prepare the targets efficiently and in
enantiomerically pure form but also by our hope that both
could be obtained via a common intermediate. In addition,
highly advantageous would be a sequence that would readily
enable the synthesis of larger oligomers. Thus, the ability to
easily replace the methyl group with other “aglycones”,
including additional sugar or pseudosugar residues, was
important. Unfortunately, none of the reported methods for
preparation of carbafuranoses satisfied all these criteria.
Therefore, we have developed and report here an alternate
route to 1 and 2. The synthetic sequence involves the
conversion of D-mannose (5) to diene 11 (Scheme 1), which
is cyclized via a ring-closing metathesis (RCM) reaction. The
resulting product 12 is, in a subsequent step, reduced
stereoselectively to afford the desired cyclopentane frame-
work 13.10
The synthetic route (Scheme 1) began with the known
thioglycoside 6, which can be synthesized in multigram
quantities from 5 in five steps.11 Treatment of 6 with MOMCl
a Legend: (a) MOMCl, NaH, THF, rt, 83%; (b) NIS, AgOTf,
CH2Cl2, H2O (5 equiv), rt, 80%; (c) Ph3PCH3Br, n-BuLi, THF,
-78 °C f rt, 72%; (d) PCC, NaOAc, 4 Å molecular sieves, CH2Cl2,
rt, 85%; (e) Ph3PCH3Br, n-BuLi, THF, -78 °C f rt, 76%; (f) 16
(20 mol %), toluene, 60 °C, drybox, 74%; (g) (Ph3P)3RhCl, (30
mol %), H2, toluene, rt, 83%; (h) trace concentrated HCl, CH3OH,
rt, 90%; (i) CH3I, NaH, THF, rt; then Pd/C, H2, CH3OH, AcOH,
rt, 94%; (j) DEAD, PPh3, p-O2NC6H4CO2H, toluene, rt; then
NaOCH3, CH3OH, rt, 83%; (k) CH3I, NaH, THF, rt; then Pd/C,
H2, CH3OH, AcOH, rt, 87%.
(4) Ayers, J. D.; Lowary, T. L.; Morehouse, C. B.; Besra, G. S. Bioorg.
Med. Chem. Lett. 1998, 8, 437.
(5) (a) Dolin, P. J.; Raviglione, M. C.; Kochi, A. Bull. World Health
Org. 1994, 72, 213. (b) Bloom, B. R.; Murray, C. J. L. Science 1992, 257,
1055.
(6) Brennan, P. J.; Nikaido, H. Annu. ReV. Biochem. 1995, 64, 29.
(7) Reviews: (a) Dalko, P. I.; Sinay¨, P. Angew. Chem., Int. Ed. 1999,
38, 773. (b) Hudlicky, T.; Enwistle, D. A.; Pitzer, K. K.; Thorpe, A. J.
Chem. ReV. 1996, 96, 1195. (c) Pingli, L.; Vandewalle, M. Synlett 1994,
228. (d) Mart´ınez-Grau, A.; Marco-Contelles, J. Chem. Soc. ReV. 1998,
27, 155.
(8) Reviews: (a) Suami, T.; Ogawa, S. AdV. Carbohydr. Chem. Biochem.
1990, 48, 21. (b) Suami, T.; Topics Curr. Chem. 1990, 154 257. (c) Ogawa,
S. Carbohydr. Mimics 1998, 87.
(9) Representative syntheses of furanose carbasugar analogues: (a)
Horneman, A. M.; Lundt, I. J. Org. Chem. 1998, 63, 1919. (b) Yoshikawa,
M.; Yokokawa, Y.; Inoue, Y.; Yamaguchi, S.; Murakami, N.; Kitagawa, I.
Tetrahedron 1994, 50, 9961. (c) Yoshikawa, M.; Murakami, N.; Inoue, Y.;
Hatekeyama, S.; Kitagawa, I. Chem. Pharm. Bull. 1993, 41, 636. (d)
Shoberu, K. A.; Roberts, S. M.; J. Chem. Soc., Perkin Trans. 1 1992, 18,
2419. (e) Parry, R. J.; Haridas, K.; DeJong, R.; Johnson, C. R. Tetrahedron
Lett. 1990, 31, 7549. (f) Marschner, C.; Penn, G.; Griengl, H. Tetrahedron
Lett. 1990, 31, 2873. (g) Marschner, C.; Baumgartner, J.; Griengl, H. J.
Org. Chem. 1995, 60, 5224. (h) Tadano, K.-I.; Hakuba, K.; Kimura, H.;
Ogawa, S. J. Org. Chem. 1989, 54, 276. (i) Yoshikawa, M.; Cha, B. C.;
Okaichi, Y.; Kitagawa, I. Chem. Pharm. Bull. 1993, 36, 3718. (j) Tadano,
K.-I.; Maeda, H.; Hoshino, M.; Iimura, Y.; Suami, T. Chem. Lett. 1986,
1081. (k) Tadano, K.-I.; Kimura, H.; Hoshino, M.; Ogawa, S.; Suami, T.
Bull. Chem. Soc. Jpn. 1987, 60, 3673. (l) Tadano, K.-I.; Maeda, H.; Hoshino,
M.; Iimura, Y.; Suami, T. J. Org. Chem. 1987, 52, 1946. (m) Wilcox, C.
S.; Guadino, J. J. J. Am. Chem. Soc. 1986, 108, 3102.
and sodium hydride provided 7 in 83% yield. This product
was then was hydrolyzed by exposure to N-iodosuccinimide
and silver triflate in wet dichloromethane, affording 8 in 80%
yield.
With gram quantities of 8 in hand, the introduction of the
first olefin was achieved by reaction of this substrate with
the ylide derived from methyltriphenylphosphonium bromide
and n-butyllithium. The product, 9, was obtained in 72%
yield. As previously observed with a related mannosyl
reducing sugar,12 in order to prevent elimination during this
reaction (leading to diene 18, Figure 2), pre-exposure of 8
to 1 equiv of n-butyllithium for 10 min at 0 °C followed by
treatment with the ylide at -78 °C was necessary. Under
these conditions, 9 was obtained as the major product and
only trace (<5%) amounts of 18 were produced. Alcohol 9
(10) A related approach to carba-D-fructofuranose has been reported very
recently: Seepersaud, M.; Al-Abed, Y. Org. Lett. 1999, 1, 1463.
(11) (a) Paulsen, H.; Heume, M.; Nuernberger, H. Carbohydr. Res. 1990,
200, 127. (b) Barresi, F.; Hindsgaul, O. Can. J. Chem. 1994, 72, 1447.
(12) Oshitari, T.; Shibasaki, M.; Yoshizawa, T.; Tomita, M.; Takao, K.-
I.; Kobayashi, S. Tetrahedron 1997, 53, 10993.
168
Org. Lett., Vol. 2, No. 2, 2000

hydrogen atmosphere, providing 13 in 83% yield. The MOM
ether was then removed (trace HCl in CH3OH) in 90% yield
to provide 14, the core structure for both the R and â
glycoside analogues. To determine whether the hydrogena-
tion had proceeded to give the correct stereochemistry, 12
was completely deprotected (H2, Pd/C) to give 4a-carba-â-
D-arabinofuranose (19). The 1H and 13C NMR spectra of 19
were identical to those previously reported for the racemate,9g
thus proving the structure of the product. None of the other
hydrogenation product, possessing the L-xylo stereochemistry,
was isolated.
Pseudosugar 2 was straightforwardly obtained via methy-
lation of 14 and subsequent removal of the benzyl groups
by hydrogenolysis (94%, two steps). Alternatively, the
stereochemistry at C-1 in 14 was inverted via standard
Mitsunobu conditions with p-nitrobenzoic acid followed by
deacylation with sodium methoxide in methanol to yield 15
in 83% yield (two steps). Conversion of 15 to 1, in 87%
yield, was done in a manner identical to the preparation of
2 from 14.
In summary, we report the total syntheses of methyl 4a-
carba-R-D-arabinofuranoside (1) and methyl 4a-carba-â-D-
arabinofuranoside (2) from D-mannose. Key transformations
include a RCM reaction employing Schrock’s catalyst and
a stereoselective hydrogenation with Wilkinson’s catalyst.
The method presented herein should allow access to the entire
family of pentocarbafuranoses on the basis of the hexopy-
ranose initially used (e.g., allose f ribocarbafuranose). The
route also allows control of the stereochemistry at the pseudo
anomeric position, via 14, leading to either R or â glycoside
mimetics. Moreover, it will be possible to prepare “glyco-
sides” of these moieties, including oligosaccharide analogues,
by alkylation of either 14 or 15 with suitable electrophiles.
Figure 2.
was subsequently oxidized using pyridinium chlorochromate
buffered with sodium acetate13 in dichloromethane to yield
ketone 10 in 85% yield. No epimerization of the C-4
stereocenter was observed under these conditions. The second
double bond was then installed in 76% yield by reaction of
10 under conditions similar to those described for the
preparation of 9. However, the synthesis of the diene did
not require pre-exposure of the substrate to n-butyllithium
as in the case of 8.14
Having in place the route to diene 11, we next investigated
its cyclization to 12 via RCM. A series of preliminary
experiments using Grubbs’ catalyst (17)15 under a variety
of reaction conditions produced only poor (12-18%) yields
of cyclopentene 12. This is consistent with previous work
which has shown that this catalyst is generally not effective
for producing trisubstituted double bonds.16 Therefore, we
investigated Schrock’s catalyst (16), which is known to be
effective for the synthesis of tri- and tetrasubstituted alk-
enes.17 In the case of 11, cyclization with 16 in the drybox
(toluene, 60 °C)18 gave 12 in 74% yield.
Acknowledgment. This work was supported by the
National Institutes of Health (AI44045-01).
The stereoselective reduction of 12 was achieved by
reaction with Wilkinson’s catalyst ((Ph3P)3RhCl) under a
1
Supporting Information Available: H and 13C spectra
of compounds 1, 2, and 7-15. This material is available free
of charge via the Internet at http://pubs.acs.org.
(13) Billault, I.; Lubineau, A. J. Org. Chem. 1998, 63, 5668.
(14) To prevent enolization of the ketone during the reaction, it was
necessary to ensure that an excess of methyltriphenylphosphonium bromide
relative to the base was used in the formation of the ylide.
OL9912682
(15) Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992, 114, 5426.
(16) (a) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997,
36, 2037. (b) Schamlz, H.-G. Angew. Chem., Int. Ed. Engl. 1995, 34, 1833.
(17) Armstrong, S. K.J. Chem. Soc., Perkin Trans. 1 1998, 371.
(18) Calimente, D.; Postema, M. H. D. J. Org. Chem. 1999, 64, 1770.
Org. Lett., Vol. 2, No. 2, 2000
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