Synthesis and conformational investigation of methyl 4a-carba-D-arabinofuranosides

Article abstract of DOI:10.1021/jo010827r

The synthesis of carbasugar analogues of methyl α-D-arabinofuranoside and methyl β-D-arabinofuranoside (3 and 4) is reported. The route developed involves the conversion of D-mannose into a suitably protected diene (13), which is then cyclized via olefin metathesis. The resulting cyclopentene (14) is stereoselectively hydrogenated to provide an intermediate that can be used for the synthesis of both targets. Through the use of NMR spectroscopy, we have probed the ring conformation of 3 and 4, as well as the rotamer populations about the C₄-C₅ and C₁-O₁ bonds. These studies have demonstrated that there are differences in ring conformation between these carbasugars and their glycoside parents (1 and 2). However, only minor differences are seen in the rotameric equilibrium about the C₄-C₅ bond in 3 and 4 relative to 1 and 2. In regard to the C₁-O₁ bond, NOE data from 3 and 4 suggest that the favored position about this bond is similar to that in the glycosides; that is, the methyl group is anti to C₂. However, confirmation of this preference through measurement of ³J_C,C between the methyl group and C₂ or C_4a was not successful.

Full text of DOI:10.1021/jo010827r

J . Org. Chem. 2001, 66, 8961-8972
8961
Syn th esis a n d Con for m a tion a l In vestiga tion of Meth yl
4a -Ca r ba -D-a r a bin ofu r a n osid es
Christopher S. Callam and Todd L. Lowary*
Department of Chemistry, The Ohio State University, 100 West 18th Avenue, Columbus, Ohio 43210
lowary.2@osu.edu
Received August 14, 2001
The synthesis of carbasugar analogues of methyl R-D-arabinofuranoside and methyl â-D-arabino-
furanoside (3 and 4) is reported. The route developed involves the conversion of D-mannose into a
suitably protected diene (13), which is then cyclized via olefin metathesis. The resulting cyclopentene
(14) is stereoselectively hydrogenated to provide an intermediate that can be used for the synthesis
of both targets. Through the use of NMR spectroscopy, we have probed the ring conformation of 3
and 4, as well as the rotamer populations about the C4-C5 and C1-O1 bonds. These studies have
demonstrated that there are differences in ring conformation between these carbasugars and their
glycoside parents (1 and 2). However, only minor differences are seen in the rotameric equilibrium
about the C4-C5 bond in 3 and 4 relative to 1 and 2. In regard to the C1-O1 bond, NOE data from
3 and 4 suggest that the favored position about this bond is similar to that in the glycosides; that
is, the methyl group is anti to C2. However, confirmation of this preference through measurement
3
of J C,C between the methyl group and C2 or C4a was not successful.
Ch a r t 1
In tr od u ction
Carbasugars are analogues of monosaccharides in
which the ring oxygen has been replaced with a meth-
ylene group. There has been increasing interest in the
synthesis of “glycoconjugates” containing carbasugar
residues for use as potential therapeutic agents.1 It is
believed that such species will be more efficacious than
their glycoside counterparts due to increased acid and
metabolic stability. This approach has already been
validated in that many carbasugar-containing nucleoside
analogues have been demonstrated to possess antiviral
activity.2 Among these is Abacavir, a drug recently
approved for the treatment of HIV.3
Over the past few years, our group has been interested
in identifying inhibitors of the arabinosyltransferases
that are involved in the assembly of two mycobacterial
cell wall polysaccharides. Such compounds are likely to
be of use in the treatment of mycobacterial infections,
including those leading to tuberculosis and leprosy,
diseases that are again becoming serious health threats
in the industrialized world.4 Although the natural sub-
strates for these glycosyltransferases are large polysac-
charides, recent work has demonstrated that small
oligosaccharide fragments (e.g., disaccharides) are also
glycosylated by these enzymes.5 Given that oligosaccha-
ride analogues containing carbasugar residues have been
shown to be competent glycosyltransferase substrates,6
we postulated that arabinosyltransferase inhibitors con-
taining carbasugar residues would be attractive synthetic
targets. Toward this end, in an earlier communication,7
we described a novel route for the preparation of the
carbocyclic analogues of methyl R-D-arabinofuranoside (1,
Chart 1) and methyl â-D-arabinofuranoside (2), namely,
methyl 4a-carba-R-D-arabinofuranoside (3) and methyl
4a-carba-â-D-arabinofuranoside (4). We report here a full
account of an improved synthesis of 3 and 4, as well as
NMR studies focused on understanding the solution
conformation of these carbasugars.
(1) (a) Vogel, P. Chimia 2001, 55, 359. (b) Crimmins, M. T.
Tetrahedron 1998, 54, 9229. (c) De Clercq, E. Nucleosides Nucleotides
1998, 17, 625. (d) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.;
Challand, S. R.; Earl, R. A.; Guedj, R. Tetrahedron 1994, 50, 10611.
(2) (a) Tan, X.; Chu, C. K.; Boudinot, F. D. Adv. Drug Delivery Rev.
1999, 39, 117. (b) Mansour, T. S.; Storer, R. Curr. Pharm. Des. 1997,
3, 227. (c) Marquez, V. E. Adv. Antiviral Drug Des. 1996, 2, 89.
(3) (a) Hervey, P. S.; Perry, C. M. Drugs 2000, 60, 447. (b) De Clercq,
E. Pure Appl. Chem. 2001, 73, 55.
(4) (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.
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Bioorg. Med. Chem. Lett. 1998, 8, 437. (b) Lee, R. E.; Brennan, P. J .;
Besra, G. S. Glycobiology 1997, 7, 1121.
Resu lts a n d Discu ssion
Syn th esis. The synthesis of cyclopentane and cyclo-
hexane rings in which each carbon atom bears a hydroxyl
group (e.g., inositols) has been well studied.8 Similarly,
(6) (a) Kajihara, Y.; Hashimoto, H.; Ogawa, S. Carbohydr. Res. 2000,
323, 44. (b) Ogawa, S.; Matsunaga, N.; Li, H.; Palcic, M. M. Eur. J .
Org. Chem. 1999, 631. (c) Ogawa, S.; Furuya, T.; Tsunoda, H.;
Hindsgaul, O.; Stangier, K.; Palcic, M. M. Carbohydr. Res. 1995, 271,
197.
(7) Callam, C. S.; Lowary, T. L. Org. Lett. 2000, 2, 167.
10.1021/jo010827r CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/27/2001

8962 J . Org. Chem., Vol. 66, No. 26, 2001
Callam and Lowary
allows the facile preparation of this thioglycoside in
multigram quantities. Details on the conversion of 7 into
8, which proceeded in 58% yield over six steps, are given
in the Supporting Information. The 2-OH group in 8 was
next protected as a MOM ether giving 9 in 88% yield.
Subsequently, the thioglycoside was hydrolyzed upon
reaction with N-iodosuccinimide and silver triflate in wet
acetonitrile, which afforded hemiacetal 10 in 90% yield.
The first alkene moiety was installed via a Wittig
reaction by treatment of 10 with methylenetriphenylphos-
phorane, which was freshly prepared from methyltri-
phenylphosphonium bromide and n-butyllithium. This
reaction provided 11 in 78% yield. Our initial attempts
to perform this conversion resulted in significant amounts
of diene 20 (Chart 2) being produced in addition to the
desired alkene. The formation of this elimination byprod-
uct could be suppressed by treatment of 10 with 1 equiv
of n-butyllithium for 10 min at 0 °C prior to the addition
of the phosphorane at -78 °C.13 When carried out in this
fashion, the reaction afforded alkene 11 as the major
product, with only traces of 20 being detected by TLC.
Oxidation of the hydroxyl group in 11 was achieved with
pyridinium chlorochromate buffered with sodium ace-
tate14 in dichloromethane. Ketone 12 was produced in
93% yield, with no epimerization of the adjacent stereo-
center. Attempted oxidation of alcohol 11 under Swern
conditions afforded a mixture of products. The second
olefin was introduced, in 77% yield, upon reaction of 12
with methylenetriphenylphosphorane. In contrast to the
transformation of 10 into 11, the preparation of 13 from
12 did not require pretreatment of the substrate with
n-butyllithium. However, to prevent enolization of the
ketone during the reaction, it was necessary to ensure
that an excess of methyltriphenylphosphonium bromide
relative to the n-butyllithium was used in the formation
of the ylide.15
F igu r e 1. Retrosynthetic analysis of 3 and 4.
F igu r e 2.
many methods are available for the preparation of
carbasugar analogues of monosaccharides in the pyra-
nose ring form.9 In contrast, far fewer routes have been
developed for the preparation of carbafuranoses.10 Our
approach to 3 and 4 (Figure 1) has, as key steps, a ring-
closing metathesis reaction (RCM) of diene 13, followed
by a stereoselective hydrogenation of the resulting cy-
clopentene, 14. The preparation of a carbasugar analogue
of â-D-fructofuranose (6) from 2,3,5-tri-O-benzyl-D-ara-
binofuranose (5) via an analogous pathway has been
reported recently (Figure 2).11
The synthesis of 3 and 4 began with D-mannose, 7
(Scheme 1). Conversion of this monosaccharide into the
known12 protected thioglycoside 8 was readily achieved.
We have modified the route to 8 such that a number of
the intermediates in this sequence are crystalline, which
With diene 13 in hand, the key RCM reaction was
explored. Our initial attempts involved the use of the first
generation Grubbs catalyst (21, Chart 2).16 However,
under a range of conditions only poor yields of 14 were
produced (Table 1, entries 1-3). These results are
consistent with previous investigations,17 which have
demonstrated that 21 does not usually provide good
yields of trisubstituted olefins. Significantly better results
were obtained (Table 1, entry 4) with the Schrock catalyst
(22), which is known to provide tri- and tetrasubstituted
olefins in good yields from dienes.18 Cyclization of 13
mediated by 22 in a glovebox gave 14 in 74% yield. We
subsequently found that catalysts 2319 and 2420 (Chart
2) cyclized 13 into 14 in 78% and 74% yield, respectively.
(8) 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.
(9) 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.
(10) Representative syntheses of furanose carbasugar analogues: (a)
Gallos, J . K.; Dellios, C. C.; Spata, E. E. Eur J . Org. Chem. 2001, 79.
(b) Gathergood, N.; Knudsen, K. R.; J orgensen, K. A. J . Org. Chem.
2001, 66, 1014. (c) Horneman, A. M.; Lundt, I. J . Org. Chem. 1998,
63, 1919. (d) De´sire´, J .; Prandi, J . Tetrahedron Lett. 1997, 38, 6189.
(e) Yoshikawa, M.; Yokokawa, Y.; Inoue, Y.; Yamaguchi, S.; Murakami,
N.; Kitagawa, I. Tetrahedron 1994, 50, 9961. (f) Yoshikawa, M.;
Murakami, N.; Inoue, Y.; Hatekeyama, S.; Kitagawa, I. Chem. Pharm.
Bull. 1993, 41, 636. (g) Shoberu, K. A.; Roberts, S. M.; J . Chem. Soc.,
Perkin Trans. 1 1992, 18, 2419. (h) Parry, R. J .; Haridas, K.; DeJ ong,
R.; J ohnson, C. R. Tetrahedron Lett. 1990, 31, 7549. (i) Marschner, C.;
Penn, G.; Griengl, H. Tetrahedron Lett. 1990, 31, 2873. (j) Marschner,
C.; Baumgartner, J .; Griengl, H. J . Org. Chem. 1995, 60, 5224. (k)
Tadano, K.-I.; Hakuba, K.; Kimura, H.; Ogawa, S. J . Org. Chem. 1989,
54, 276. (l) Yoshikawa, M.; Cha, B. C.; Okaichi, Y.; Kitagawa, I. Chem.
Pharm. Bull. 1988, 36, 3718. (m) Tadano, K.-I.; Maeda, H.; Hoshino,
M.; Iimura, Y.; Suami, T. Chem. Lett. 1986, 1081. (n) Tadano, K.-I.;
Kimura, H.; Hoshino, M.; Ogawa, S.; Suami, T. Bull. Chem. Soc. J pn.
1987, 60, 3673. (o) Tadano, K.-I.; Maeda, H.; Hoshino, M.; Iimura, Y.;
Suami, T. J . Org. Chem. 1987, 52, 1946. (p) Wilcox, C. S.; Guadino, J .
J . J . Am. Chem. Soc. 1986, 108, 3102.
(13) Oshitari, T.; Shibasaki, M.; Yoshizawa, T.; Tomita, M.; Takao,
K.-I.; Kobayashi, S. Tetrahedron 1997, 53, 10993.
(14) Lubineau, A.; Billault, I. J . Org. Chem. 1998, 63, 5668.
(15) An analogue of 13 in which the methoxymethyl ether is replaced
by a p-methoxybenzyl ether has been synthesized from 2,3,5-tri-O-
benzyl arabinofuranose 5: Seepersaud, M.; Al-Abed, Y. Tetrahedron
Lett. 2000, 41, 7801.
(16) Fu, G. C.; Grubbs, R. H. J . Am. Chem. Soc. 1992, 114, 5426.
(17) (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.
(18) Armstrong, S. K.J . Chem. Soc., Perkin Trans. 1 1998, 371.
(19) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953. This catalyst is now commercially available from Strem.
(20) (a) Huang, J .; Stevens, E. D.; Nolan, S. P.; Petersen, J . L. J .
Am. Chem. Soc. 1999, 121, 2674. (b) Huang J ., Schanz, H.-J .; Stevens,
E. D.; Nolan, S. P. Organometallics 1999, 18, 5375. (c) Fu¨rstner, A.;
Thiel, O. R.; Ackermann, L.; Schanz, H.-J .; Nolan, S. P. J . Org. Chem.
2000, 65, 2204. (d) Scholl, M.; Trnka, T. M.; Morgan, J . P.; Grubbs, R.
H. Tetrahedron Lett. 1999, 40, 2247.
(11) Seepersaud, M.; Al-Abed, Y. Org. Lett. 1999, 1, 1463.
(12) (a) Paulsen, H.; Heume, M.; Nu¨rnberger, H. Carbohydr. Res.
1990, 200, 127. (b) Barresi, F.; Hindsgaul, O. Can. J . Chem. 1994, 72,
1447.

Methyl 4a-Carba-D-arabinofuranosides
J . Org. Chem., Vol. 66, No. 26, 2001 8963
Sch em e 1a
a
(a) MOMCl, NaH, THF, rt, 88%; (b) NIS, AgOTf, CH3CN, H2O (5 equiv), rt, 90%; (c) Ph3PCH3Br, n-BuLi, THF, -78 °C f rt, 78%; (d)
PCC, NaOAc, 4 Å molecular sieves, CH2Cl2, rt, 93%; (e) Ph3PCH3Br, n-BuLi, THF, -78 °C f rt, 77%; (f) 23 (20 mol %), toluene, 60 °C,
78%; (g) (Ph3P)3RhCl, (30 mol %), H2, toluene, rt, 88%; (h) trace concentrated HCl, CH3OH, rt, 95%; (i) CH3I, NaH, THF, rt; (j) Pd/C, H2,
CH3OH, AcOH, rt, 94% (from 16); (k) DEAD, PPh3, p-O2NC6H4CO2H, toluene, rt; (l) NaOCH3, CH3OH, rt, 84%, (from 16); (m) CH3I, NaH,
THF, rt; (n) Pd/C, H2, CH3OH, AcOH, rt, 87% (from 18).
Ta ble 1. Con ver sion of 13 in to 14 by Rin g-Closin g
Meta th esis
Ch a r t 2
entry
catalyst/ mol %
conditions
yield, %a
1
2
3
4
5
6
21/5%
CH2Cl2, rt, 24 h
12
19
0
74
78
74
21/10%
21/10%
22/20%
23/10%
24/10%
toluene, 60 °C, 33 h
xylenes, reflux, 48 h
toluene, 60 °C, 2 hb
toluene, 60 °C, 2 h
toluene, 60 °C, 1.5 h
a
b
Isolated yield. Reaction carried out in a glovebox.
difficult to access than the one needed for the preparation
of 23.
The second key step was the stereoselective hydroge-
nation of 14. This reduction was successfully carried out
in 88% yield upon reaction of 14 with Wilkinson’s catalyst
((Ph3P)3RhCl) under an atmosphere of hydrogen. Deter-
mining the stereochemistry in the product, 15, was
achieved by global deprotection of the benzyl ethers (H2,
Pd/C) affording 4a-carba-â-D-arabinofuranose (25). Com-
1
parison of the H and 13C NMR spectra of 25 with that
previously reported for the racemate10j showed them to
be identical. None of the other stereoisomeric reduction
product, which possesses the L-xylo stereochemistry, was
isolated.
The final steps of the synthesis involved first the
removal of the MOM ether to give, in 95% yield, alcohol
16.21 The â-glycoside analogue 4 was prepared in two
steps from 16, by methylation (yielding 17) and then
Relative to the Schrock catalyst, both 23 and 24 are more
convenient to use in that they are substantially more air
stable, thus eliminating the need for a glovebox. When
choosing between 23 and 24, we prefer the former. Both
can be conveniently prepared from 21; however, we have
found the ligand required for the synthesis of 24 more

8964 J . Org. Chem., Vol. 66, No. 26, 2001
Callam and Lowary
3
of the ring J H,H. Analysis of these experimental data,
which are an average of the coupling constants arising
from all solution conformers, can be done with the
program PSEUROT.25 This program assumes the two-
state model described above and provides the conformers
(and their populations) that best fit the NMR data.
Although the PSEUROT method has been most widely
used for the conformational analysis of furanose rings,26
it can be applied to any five-membered ring. This
approach has previously been used for assessing the
conformation of pyrrolidines,27 4-thiofuranose deriva-
tives,28 and cyclopentanes (e.g., carbocyclic nucleosides).29
The identity and relative populations of the N and S
conformers for a particular furanose ring are influenced
not only by the steric demands of the substituents, but
also by stereoelectronic effects. These effects have been
most thoroughly explored in nucleosides and nucle-
otides;30 however, they are also important in furanose
O-glycosides. Of particular importance are the anomeric
effect and favorable gauche interactions31 between the
ring oxygen and the hydroxyl groups at C2 and C3. In
carbafuranoses such as 3 and 4, there is no endocyclic
oxygen, and therefore all of the stereoelectronic effects
present in the furanose parent structures are absent. The
O f CH2 replacement may therefore substantially alter
the conformational equilibrium of 3 and 4 relative to 1
and 2, and such changes will likely have important
implications in the development of carbafuranose-based
enzyme inhibitors. Consequently, we viewed it as impor-
tant to probe the solution conformation of 3 and 4 in order
to determine how closely the conformation of these
species resembled that of 1 and 2. It is somewhat sur-
prising that, despite the synthesis of a number of car-
bacyclic nucleoside analogues, the conformation of the
five-membered rings in these species has been relatively
unexplored.29 Furthermore, although conformational in-
vestigations of carbapyranose O-glycoside analogues have
been described,32 similar studies on carbafuranoses have
not been reported.
F igu r e 3. Pseudorotational wheel for a five-membered ring.
hydrogenation of the benzyl protecting groups (94%, two
steps). Alternatively, reaction of 16 with p-nitrobenzoic
acid, triphenylphosphine, and DEAD, followed by deacy-
lation with sodium methoxide in methanol provided the
C1 inverted alcohol 18 in 84% yield (two steps). The
synthesis of 3 from 18 was achieved in two steps and 87%
yield, as described for the conversion of 16 into 4.
Con for m a tion . Five-membered rings are flexible enti-
ties that can adopt a wide range of envelope and twist
conformations. These conformers can be conveniently
visualized using the pseudorotational wheel (Figure 3).22
The standard method used to assess the solution confor-
mation of furanose rings (30, X ) O; Y ) OR, NR)
assumes an equilibrium between two low-energy struc-
tures. One of these conformers lies in the northern
hemisphere of the pseudorotational wheel (the N con-
former) and the other in the southern hemisphere (the S
conformer).
An increasing number of investigations have demon-
strated that the conformational preferences of furanose
rings play an important role in their biological function.
For example, biasing (or locking) the conformation of the
sugar ring of a nucleoside often significantly influences
its recognition by various processing enzymes.23 Simi-
larly, nucleic acids composed of nucleosides in which the
sugar rings are locked into a single conformation often
bind to complementary sequences of DNA and RNA with
increased affinity relative to the unlocked parent struc-
tures.24
Of additional interest was the rotameric equilibrium
about the C4-C5 and C1-O1 bonds (see Chart 1 for atom
numbering scheme). In furanose rings, rotamer popula-
tions about these bonds are also influenced by the ring
oxygen. For the C4-C5 bond,33 a gauche interaction
(25) (a) PSEUROT 6.2, Gorlaeus Laboratories, University of Leiden.
(b) de Leeuw, F. A. A. M.; Altona, C. J . Comput. Chem. 1983, 4, 428.
(c) Altona, C. Recl. Trav. Chem. Pays-Bas 1982, 101, 413.
(26) For some examples, see: (a) Hoffman, R. A.; Van Wijk, J .;
Leeflang, B. R.; Kamerling, J . P.; Altona, C.; Vliegenthart, J . F. G. J .
Am. Chem. Soc. 1992, 114, 3710. (b) Rickel, L. J .; Altona, C. J . Biomol.
Struct. Dyn. 1987, 4, 621. (c) van Wijk, J .; Huckriede, B. D.; Ippel, J .
H.; Altona, C. Methods Enzymol. 1992, 211, 286.
(27) (a) de Leeuw, F. A. A. M.; Altona, C.; Kessler, H.; Bermal, W.;
Friedrich, A.; Krack, G.; Hull. W. J . Am. Chem. Soc. 1983, 105, 2237.
(b) Haasnoot, C. A. G.; de Leeuw, F. A. A. M.; de Leeuw, H. P. M.;
Altona, C. Biopolymers 1981, 20, 1211.
For a given furanose ring, the two conformers that
contribute to the equilibrium mixture in solution can be
determined by NMR spectroscopy, through measurement
(21) Attempted removal of the MOM ether prior to reduction of the
double bond under a variety of conditions led to very low yields of the
desired allylic alcohol and the formation of a number of unidentified
byproducts.
(22) Altona, C.; Sundaralingam, M. J . Am. Chem. Soc. 1972, 94,
8205.
(23) (a) Ford, H., J r; Dai, F.; Mu, L.; Siddiqui, M. A.; Nicklaus, M.
C.; Anderson, L. Marquez, V. E.; Barchi, J . J ., J r. Biochemistry 2000,
39, 2581. (b) Wang, P.; Brank, A. S.; Banavali, N. K.; Nicklaus, M. C.;
Marquez, V. E.; Christman, J . K.; MacKerell, A. D., J r. J . Am. Chem.
Soc. 2000, 122, 12422. (c) Mu, L.; Sarafianos, S. G.; Nicklaus, M. C.;
Russ, P.; Siddiqui, M. A.; Ford, H., J r.; Mitsuya, H.; Le, R.; Kodama,
E.; Meier, C.; Knispel, T.; Anderson, L.; Barchi, J . J ., J r.; Marquez, V.
E. Biochemistry 2000, 39, 11205.
(28) Crnugelj, M.; Dukhan, D.; Barascut, J .-L.; Imbach, J .-L.; Plavec,
J . J . Chem. Soc., Perkin Trans. 2 2000, 255.
(29) Thibaudeau, C.; Kumar, A.; Bekiroglu, S.; Matsuda, A.; Mar-
quez, V. E. Chattopadhyaya, J . J . Org. Chem. 1998, 63, 5447.
(30) (a) Thibaudeau, C.; Chattopadhyaya, J . Stereoelectronic Effects
in Nucleosides and Nucleotides and their Structural Implications;
Uppsala University Press: Uppsala, Sweden, 1999. (b) Thibaudeau,
C.; Chattopadhyaya, J . Nucleosides Nucleotides 1997, 16, 523. (c)
Plavec, J .; Thibaudeau, C.; Chattopadhyaya, J . Pure Appl. Chem. 1996,
68, 2137. (d) Thibaudeau, C.; Plavec, J .; Chattopadhyaya, J . J . Am.
Chem. Soc. 1994, 116, 8033. (e) Thibaudeau, C.; Plavec, J .; Garg, N.;
Papchikhin, A.; Chattopadhyaya, J . J . Am. Chem. Soc. 1994, 116, 4038.
(f) Plavec, J .; Thibaudeau, C.; Chattopadhyaya, J . J . Am. Chem. Soc.
1994, 116, 6558. (g) Plavec, J .; Tong, W.; Chattopadhyaya, J . J . Am.
Chem. Soc. 1993, 115, 9734.
(24) (a) Meldgaard, M.; Wengel, J . J . Chem. Soc., Perkin Trans. 1
2000, 3539. (b) Herdewijn, P. Liebigs Ann. 1996, 1337.
(31) Wolfe, S. Acc. Chem. Res. 1972, 5, 102.

Methyl 4a-Carba-D-arabinofuranosides
J . Org. Chem., Vol. 66, No. 26, 2001 8965
Sch em e 2a
F igu r e 4. Staggered rotamers about the C4-C5 and C1-O1
bonds.
between OH5 and the endocyclic oxygen stabilizes the gt
and gg rotamers relative to the tg counterpart where such
a stabilizing interaction is absent (See Figure 4A for
rotamer definitions). In the case of the C1-O1 bond, the
exo-anomeric effect and steric effects dictate that the
preferred conformation about this bond is the one in
which the methyl group is antiperiplanar to C2 (Figure
4B).34 However, the preferred orientation about either of
these bonds in 3 and 4 is unknown. Discussed below are
investigations directed toward determining the ring
conformers adopted by 3 and 4 in solution, as well as the
preferred orientation about the C4-C5 and C1-O1 bonds.
Rin g Con for m a tion . Before applying the PSEUROT
method for the analysis of 3 and 4, it was important to
determine the validity of the two-state N/S model for
these ring systems. Although this had been previously
done for carbacyclic nucleosides,29 we verified this for 3
and 4 through a series of density functional theory
calculations. Using a protocol previously used by us35,36
and others,37 all 10 idealized envelope conformers for each
ring system were optimized. These calculations demon-
strated (see Supporting Information for data) that for
both 3 and 4, the two-state N/S model is valid. A full
account of these calculations will be reported separately.38
a
(a) (Ph3P)3RhCl, (30 mol %), D2, toluene, rt, 82%; (b) trace
concentrated HCl, CH3OH, rt, 95%; (c) DEAD, PPh3, p-O2NC6-
H4CO2H, toluene, rt; (d) NaOCH3, CH3OH, rt; (e) CH3I, NaH, THF,
rt; (f) Pd/C, H2, CH3OH, AcOH, rt, 64% (from 27); (g) CH3I, NaH,
THF, rt; (h) Pd/C, H2, CH3OH, AcOH, rt, 94% (from 27).
1H NMR spectra. However, substitution of the ring
oxygen for the methylene group significantly increases
the complexity of the signals arising from H1 and H4,
3
which in turn complicates measurement of the J H,H
involving these hydrogens. Two approaches were used
in order to confirm these coupling constants. First, the
Bruker program NMRSim39 was used to simulate the H
1
NMR spectrum of both 3 and 4. Second, we synthesized
analogues of these compounds that were deuterated at
the C4 and C4a carbons, which in turn simplified the
coupling patterns of H1. These compounds (28 and 29)
were readily prepared as outlined in Scheme 2.40
The J H,H and J H,H for 3, 4, 28, and 29 measured from
spectra recorded at 298 K are presented in Table 2, as
are the coupling constants used in the simulation of the
1H NMR spectrum of 3 and 4. PSEUROT 6.2 analysis of
these data gave the results shown in Table 3, which are
compared to those previously reported for 1 and 2.36,41
3
2
3
The J H,H used in the PSEUROT calculations were
1
measured from H NMR spectra obtained from samples
dissolved in D2O. For many of the resonances in the
spectrum of 3 and 4, there was sufficient spectral
resolution that all coupling constants could be conve-
niently and unambiguously extracted from the simple 1D
The ability of the PSEUROT program to effectively
treat these systems can be assessed by consideration of
the RMS errors of these calculations. When the J H,H
3
measured from the spectra of 3 and 4 are used, these
errors are reasonably low, 0.45 and 0.38 Hz, respectively.
Nevertheless, these errors are higher than those nor-
mally seen in analysis of coupling constants from fura-
nose rings.36,41 In a previous conformational analysis of
carbacyclic nucleosides by Chattopadhyaya and co-work-
ers, relatively high RMS errors in PSEUROT calculations
were ascribed to the poor parametrization of the program
(32) (a) Carpintero, M.; Ferna´ndez-Mayoralas, A.; J ime´nez-Barbero,
J . Eur. J . Org. Chem. 2001, 681. (b) Montero, E.; Garc´ıa-Herrero, A.;
Asensio, J . L.; Hirai, K.; Ogawa, S.; Santoyo-Gonza´lez, Can˜ada, F. J .;
J ime´nez-Barbero, J . Eur. J . Org. Chem. 2000, 1945. (c) Duus, J . Ø.;
Bock, K.; Ogawa, S. Carbohydr. Res. 1994, 252, 1. (d) Bock, K.;
Guzma´n, J . F. B.; Duus, J . Ø.; Ogawa, S. Yokoi, S. Carbohydr. Res.
1991, 209, 51. (e) Bock, K.; Ogawa, S.; Orihara, M. Carbohydr. Res.
1989, 191, 357. (f) Bock, K.; Guzma´n, J . F. B.; Ogawa, S. Carbohydr.
Res. 1988, 174, 354.
(33) (a) Rockwell, G. D.; Grindley, T. B. J . Am. Chem. Soc. 1998,
120, 10953. (b) Bock, K.; Duus, J . Ø. J . Carbohydr. Chem. 1994, 13,
513.
(34) Lemieux, R. U.; Koto, S. Tetrahedron 1974, 30, 1933.
(35) Gordon, M. T.; Lowary, T. L.; Hadad, C. M. J . Am. Chem. Soc.
1999, 121, 9682.
(36) Gordon, M. T.; Lowary, T. L.; Hadad, C. M. J . Org. Chem. 2000,
65, 4954.
(37) (a) Cloran, F.; Carmichael, I.; Serianni, A. S. J . Am. Chem. Soc.
2001, 123, 4781. (b) Church, T. J .; Carmichael, I.; Serianni, A. S. J .
Am. Chem. Soc. 1997, 119, 8946.
(39) NMRSim Version 2.5, Bruker Analytik GmbH, Silberstreifen,
D-76287 Rheinstetten, Germany.
(40) We tried, unsuccessfully, to synthesize analogues that were
monodeuterated at C4a via hydroboration of 14 and subsequent
treatment with CD3CO2D. Although a number of borane reagents were
explored, the regioselectivity of the hydroboration was poor, and
separation of the C4a [2H] and C4 [2H]-labeled isomers was, as expected,
impossible.
(38) Callam, C. S.; Lowary, T. L.; Hadad, C. M. Manuscript in
preparation.
(41) D′Souza, F. W.; Ayers, J . D.; McCarren, P. R.; Lowary, T. L. J .
Am. Chem. Soc. 2000, 122, 1251.

8966 J . Org. Chem., Vol. 66, No. 26, 2001
Callam and Lowary
3
2
Ta ble 2. J H,H a n d J H,H in 3, 4, 28, a n d 29a ,b
an orientation intermediate between pseudoaxial and
pseudoequatorial. In common with 3/28, the southern
conformer of 4/29 (2E) is destabilized by the pseudoaxial
orientation of the hydroxyl groups at C2 and C3. However,
in contrast to 3/28, the methoxy group of the 2E conformer
in 4/29 is oriented in a pseudoequatorial direction and
is also gauche to OH2. This last conformational feature
may explain the slightly larger percentage of the south-
ern conformer of 4/29 relative to 3/28 (27% vs 18%).
To determine the influence of temperature on the
conformational equilibrium, we have carried out a series
of variable temperature NMR experiments using 28 and
29. The coupling constants measured from these spectra
are given in the Supporting Information; the results of
the PSEUROT analysis of these data are provided in
Table 4. Over the temperature range investigated (288
K to 328 K), only minor changes in the conformational
equilibrium are observed. The same two conformers are
present; however, the population of the northern struc-
tures is slightly increased (∼5%) at higher temperature.
A comparison of the conformational equilibrium of
these carbasugars with that previously reported36,41 for
glycosides 1 and 2 is shown in Table 3. For the R-isomer
there is a pronounced shift to the north in the carbasugar.
The conformational ensemble of 1 is a 55:45 mixture of
3J H,H
3
28
3c
4
29
4c
3J 1,2
3J 2,3
3J 3,4
6.2
7.5
6.2
7.4
6.20
7.48
8.35
8.33
9.72
8.38
5.36
4.71
6.84
14.15
11.11
5.1
6.6
5.1
6.4
5.10
6.51
6.70
7.52
9.30
4.85
6.11
5.81
7.46
13.93
10.88
8.4
8.4
9.8
8.4
NA
NA
NA
NA
5.3
6.8
7.5
9.3
4.9
NA
NA
NA
NA
6.0
d
3J 4,4a
d
3J 4,4a′
d
3J 1,4a
3J 1,4a′
3J 4,5R
3J 4,5S
d
5.4
6.2
4.7
6.8
14.1
11.1
NA
NA
NA
11.8
5.8
7.5
13.9
10.9
NA
NA
NA
12.1
2J 4a,4a′
2J 5R,5S
a
b
See Chart 1 for atom numbering scheme. Coupling constants
are in hertz. c Values used for simulation of 1H NMR spectra using
NMRSim. The 4a and 4a′ hydrogens are trans and cis, respec-
d
tively, to the hydroxymethyl group at C4.
Ta ble 3. Rin g Con for m er s of 1-4, 28, a n d 29a ,b
compound
3
3c
28
1e
4
4c
29
2f
PN (deg)d
N conformer
XN (%)
15
3E
86
21
3E
83
16
3E
82
72
OT4
56
2
10
3T2
77
7
339
E2
99
3T2
75
3T2
73
P
S (deg)d
161 166 165 183 158 160 159 162
S conformer
XS (%)
2E
14
2E
17
2E
18
2T3
41
2E
25
2E
23
2E
27
2E
1
RMS (Hz)
0.45 0.16 0.20 0.01 0.38 0.17 0.24 0.00
2
OT4(N) and T3(S) conformers;41 for 3/28 an 82:18 ratio of
a
b
Calculated using a constant τm ) 40°. See Figure 3 for
assignment of conformers. c Coupling constants from simulated
2
3E(N) and E(S) conformers is present. In the carbasugar,
d
spectra were used. P ) Altona-Sundaralingam pseudorotational
therefore, not only are the identities of the conformers
shifted to the north, but also the northern conformer
predominates at equilibrium. In the glycoside, both the
OT4 and 2T3 conformers are stabilized by the anomeric
effect and, in the case of S conformer, by an attractive
gauche interaction between the ring oxygen and the OH2
and OH3 groups. In the absence of these stereoelectronic
effects (as in 3/28), steric effects as well as gauche
interactions between exocyclic hydroxyl groups predomi-
nate, and hence northern conformers are favored. From
these studies, it is clear that the conformational prefer-
ences of 3/28 do not closely resemble that of 1.
phase angle as defined in ref 22. e Taken from ref 41. f Taken from
ref 36.
for cyclopentane systems.29 In that study, reparameriza-
tion of the Karplus equation used by the program
provided results with lower RMS errors. However, the
outcome of the calculations (e.g., conformer identities and
populations) were unchanged relative to the default
equation. We have not, therefore, reparamatarized this
equation for 3 and 4.
Another potential source of error is the inability to
accurately measure all ring J H,H in 3 and 4. Given the
3
On the other hand, for the â-isomer, 4, the conformer
distributions in the carbasugar agree better with the
glycoside. Glycoside 2 is a relatively rigid furanose ring.
number of hydrogens coupled to H1 and H4, accurate
measurement of these coupling constants is particularly
challenging and may be the cause of some of the error.
2
3
In aqueous solution, a 99:1 mixture of E2(N) and E(S)
This postulate has been validated in that when J H,H from
conformers is present at equilibrium.36 In the E2 con-
former of 2, not only are the substituents at C2, C3, and
C4 pseudoequatorial, but the methoxy group is pseudo-
axial and hence stabilized by the anomeric effect. In
terms of conformer identity, there is good agreement
between 2 and 4/29. The carbasugar adopts the same S
conformer as the glycoside (2E) and the northern con-
former adopted by 4/29 (3T2) is immediately adjacent on
the pseudorotational wheel to that observed for 2 (E2).
The equilibrium in both ring systems is also heavily
favored toward the north. Therefore, the conformational
equilibrium of 4/29 approximates 2 fairly closely.
the simulated spectra or the deuterated compounds (28/
29) are used in the PSEUROT calculations, the RMS
errors are lower and more in line with those obtained
with furanose rings. However, as is clear from the data
presented in Table 3, neither the identity of the equilib-
rium conformers nor their populations are dependent
upon the data set used. The N:S ratio for 3/28 ranges
3
3
from 82:18 E:2E to 86:14 E:2E, while for 4/29 a 73:27
3
3T2:2E to 75:25 T2:2E ratio is predicted.
For both 3/28 and 4/29, the conformational equilibrium
is biased to the northern conformer. In the major
conformer of 3/28 (3E), the substituents at C2, C3, and C4
are pseudoequatorially oriented, and there is a gauche
relationship between OH2 and OH3. This conformer
would therefore be expected to be favored over the
southern conformer (2E) in which OH2 and OH3 are
pseudoaxial and hence trans to each other. Furthermore,
C4-C5 Bon d Rota m er P op u la tion s. We have deter-
mined the populations of rotamers about the C4-C5 bond
3
in 3 and 4 by analysis of 3J 4,5R and J 4,5S measured from
1
the H NMR spectrum of these compounds. These cou-
pling constant data were analyzed using eqs 1-3.
3
the methoxy group, while not pseudoequatorial in the E
2.1Xgg + 14.1Xgt + 2.2Xtg ) 3J 4,5R
(1)
conformer, is “less” pseudoaxial than in the southern
structure. A similar situation is observed for 4/29. In the
northern conformer (2T3), the groups at C2, C3, and C4
are pseudoequatorial, there is a gauche relationship
between OH2 and OH3, and the methoxy group adopts
3.4Xgg + 3.0Xgt + 15.5Xtg ) 3J 4,5S
Xgg + Xgt + Xtg ) 1
(2)
(3)

Methyl 4a-Carba-D-arabinofuranosides
J . Org. Chem., Vol. 66, No. 26, 2001 8967
Ta ble 4. Rin g Con for m er s of 28 a n d 29 a t Va r iou s Tem p er a tu r esa ,b
compound
28
29
temperature
288 K
298 K
308 K
318 K
328 K
288 K
298 K
308 K
318 K
328 K
PN (deg)c
N conformer
XN (%)
16
3E
82
16
3E
82
17
3E
84
15
3E
88
15
3E
88
7
3T2
73
7
3T2
73
5
3T2
74
5
3T2
75
5
3T2
78
P
S (deg)c
165
165
166
168
168
159
159
159
159
159
S conformer
XS (%)
2E
2E
2E
2E
2E
2E
2E
2E
2E
2E
18
18
16
12
12
27
27
26
25
22
RMS (Hz)
0.20
0.20
0.23
0.24
0.24
0.24
0.24
0.23
0.25
0.25
a
b
Calculated using a constant τm ) 40°. See Figure 3 for assignment of conformers. c P ) Altona-Sundaralingam pseudorotational
phase angle as defined in ref 22.
Ta ble 5. Com p a r ison of C4-C5 Rota m er P op u la tion s in
1-4a
compound
3
3c
1d
4
4c
2e
Xgg(%)b
49
39
12
49
39
12
48
38
14
34
45
21
34
45
21
34
55
11
Xgt (%)
tg (%)
X
a
See Experimental Section for protocol used for determining
percentages. See Figure 4A for rotamer definitions. c Coupling
b
d
constants from simulated spectra were used. Taken from ref 41.
e Taken from ref 36.
In assigning the chemical shifts arising from the H5R
and H5S hydrogens, the assumption was made that H5S
resonates downfield relative to H5R as is the case in
glycosides 1 and 2.42 This approach has been used pre-
viously in determining the populations of hydroxymethyl
group rotamers in carbapyranose derivatives.32e,f The
method used for the determination of the coefficients in
eqs 1 and 2 is provided in the Experimental Section. The
results of these analyses are presented in Table 5 and
compared with the rotamer populations found previously
for 1 and 2.36,41
F igu r e 5. NOE’s in 3 and 4. Only the NOE’s involving the
methyl group are shown.
In the case of 3, the rotamer populations about the
C4-C5 bond are essentially unchanged relative to its
glycoside parent structure, 1. Similar results have been
observed previously with carbapyranoses.32e,f,33b In 1 and
3, the favoring of the gg rotamer over the gt and tg forms
can be rationalized on the basis of σ(C4-H4) f σ*(C5-O5)
hyperconjugation,43 which is possible in both the glyco-
side and the carbasugar. For 1, the predominance of gt
over tg can be ascribed to a gauche effect involving O4
and O5. The same trend is seen in 3, however, it is best
rationalized by considering that in the tg rotamer of the
major ring conformer (3E), a “1,3-diaxial” interaction
between O5 and O3 is present.
F igu r e 6. Definition of gg, gt, and tg rotamers about the
C1-O1 bond in 3 and 4.
1
initially explored through H NMR spectroscopy via the
measurement of NOE’s between the methyl group and
the hydrogens on C2 and C4a. From these experiments,
it was demonstrated that for both 3 and 4, the NOE’s
were significantly larger to the C4a hydrogens than to the
C2 hydrogen (Figure 5). These data suggest that the
preferred orientation about the C1-O1 bond is one in
which the methyl group is anti to C2, which is identical
to the parent glycoside. To simplify the discussion below,
we have designated each staggered rotamer about the
C1-O1 bond as gg, gt, or tg as defined in Figure 6. Within
this reference system, the major rotamer predicted by the
NOE experiments is tg.
These results are in agreement with previous investi-
gations on substituted methoxycyclohexanes (e.g., 33, 34,
Chart 3).44 Through the combined use of NMR spectros-
copy and molecular mechanics calculations, it was dem-
onstrated that for both 33 and 34, the preferred orien-
tation about the C-O bond places the methyl group
gauche to the unsubstituted flanking position (35). These
results are also in good agreement with recent investiga-
tions on carbafucose derivative 36 (Chart 3).32a By using
molecular mechanics calculations and NOE data, it was
A comparison of the C4-C5 rotamer populations in 2
and 4 reveals that the population of the gg rotamer is
unchanged. However, in the carbasugar the amount of
the tg rotamer increases at the expense of gt. These
trends can be explained as above for 3, i.e., σ(C4-H4)
f
σ*(C5-O5) hyperconjugation in the gg rotamer of both 2 and
4, and a destabilization of tg relative to gt via “1,3-
diaxial” interactions between O5 and O3. For 3, there is
an approximately 3:1 gt:tg ratio, while for 4, this ratio is
2:1. The increase in the tg rotamer in 4 relative to 3, may
be a consequence of the fact that the southern ring
conformer (2E) is more populated at equilibrium. For this
ring conformer, the tg rotamer no longer places O5 in a
“1,3-diaxial” relationship to O3.
C1-O1 Bon d Rota m er P op u la tion s. The population
of rotamers about the C1-O1 bond in 3 and 4 were
(42) Serianni, A. S.; Barker, R. Can J . Chem. 1979, 57, 3160.
(43) J uaristi, E.; Antu´nez, S. Tetrahedron 1992, 48, 5941.
(44) Anderson, J . E.; Ijeh, A. I. J . Chem. Soc., Perkin Trans. 2 1994,
1965.

8968 J . Org. Chem., Vol. 66, No. 26, 2001
Callam and Lowary
Ch a r t 3
Using the Karplus equation for C-O-C-H fragments
proposed by Serianni and co-workers46 (3J C,O,C,H ) 7.49
cos2 θ - 0.96 cos θ + 0.15), it can be predicted that
3J CH3,H1 for the gg rotamer should be approximately 8.6
Hz. If this rotamer was a significant contributor to the
equilibrium population, the magnitude of this coupling
constant should be substantially larger than observed
(0.6-0.7 Hz).
We turned next to an analysis of the 13C-13C coupling
constant data. We initially had hoped that these data
would allow us to quantify, at least to some degree, the
relative populations of the three rotamers shown in
Figure 6. We had previously been successful in doing a
similar analysis for the 3-O-methyl group in 38 (Chart
3
3).47 To that end, the J C,O,C,C coupling constants mea-
sured from 3 and 4 (Table 6) were analyzed using eqs
4-6.
0.4Xgg + 4.1Xgt + 1.1Xtg ) 3J CH3,4a
(4)
3.0Xgg + 0.6Xgt + 4.3Xtg ) 3J CH3,2
Xgg + Xgt + Xtg ) 1
(5)
(6)
Determination of the coefficients for eqs 4 and 5 is
provided in the Experimental Section. Unfortunately, no
physically reasonable solution to these equations was
found; a 112%:36%:-48% gg:gt:tg ratio was calculated.
From the 3J C,O,C,H data presented above, we proposed that
the population of the gg rotamer is negligible. We
therefore considered a two-state model involving only the
Sch em e 3a
3
tg and gt isomers. However, using the limiting J C,C
magnitudes used in eqs 4 and 5, a two-rotamer model
provided no better results.
One interpretation of these results is that a model in
which only two or three staggered rotamers about this
bond are considered cannot be applied to this system. In
this regard we note that previous conformational inves-
tigations48 on furanose C-glycosides, which also lack any
anomeric effects, have suggested that there is increased
flexibility about this bond. Another possible source of
error in these analyses is that the angles used for
a
(a) 13CH3I, NaH, THF, rt; (b) Pd/C, H2, CH3OH, AcOH, rt, 90%
(from 18); (c) 13CH3I, NaH, THF, rt; (d) Pd/C, H2, CH3OH, AcOH,
rt, 94% (from 16).
3
3
Ta ble 6. J C,O,C,H a n d J C,O,C,C in 31 a n d 32a ,b
3J CH3,H1
3J CH3,C2
3J CH3,C4a
2J CH3,C1
3
calculating the limiting J C,C values which serve as the
31
32
0.7
0.6
1.5
1.6
1.4
1.4
2.1
1.9
coefficients in eqs 4 and 5 are incorrect. The equation
(eq 8, see Experimental Section) used to determine these
coefficients was developed for C-O-C-C fragments
involving the anomeric center of glycosides and hence
may not be applicable to systems such as 3 and 4. It is
unfortunate that these coupling constant data cannot be
reconciled with the NOE experiments, and we are cur-
rently further investigating this discrepancy.
a
b
See Chart 1 for atom numbers. Coupling constants are in
hertz.
determined that the favored rotamer about this bond is
tg. However, there is also approximately 20% of the gt
conformer present. Also consistent with our NOE experi-
ments is the crystal structure of the pentaacetate deriv-
ative of 5a-carba-â-D-glucopyranose (37) in which the
C1-O1 bond is oriented tg.45
Con clu sion s
In conclusion, we have developed a novel route for the
preparation of carbasugar analogues of methyl R-D-
arabinofuranoside and methyl â-D-arabinofuranoside (3
and 4). Starting from D-mannose, the targets are obtained
via a route in which the key steps are (1) a ring-closing
metathesis and (2) a subsequent stereoselective hydro-
genation. This route can also be applied to the prepara-
In an effort to probe further the conformation about
this bond, we synthesized analogues of 3 and 4 containing
a
13C-label in the methyl group (Scheme 3). With these
substrates (31 and 32) in hand, we were able to easily
measure the 3J C,O,C,H and 3J C,O,C,C involving the “aglycone”.
The data are presented in Table 6.
3
For both 3 and 4, the magnitude of J CH3,H1 is very
small, and from these data we can rule out the possibility
that the gg rotamer (Figure 6) is significantly populated.
(46) Cloran, F.; Carmichael, I.; Serianni, A. S. J . Am. Chem. Soc.
1999, 121, 9843.
(47) Houseknecht, J . B.; McCarren, P. R.; Lowary, T. L.; Hadad, C.
M. J . Am. Chem. Soc. 2001, 123, 8841.
(48) O′Leary, D. J . Kishi, Y. J . Org. Chem. 1994, 59, 6629.
(45) Watkins, S. F.; Abboud, K. A.; Nghiem, N. P.; Voll, R. J .;
Younathan, E. S. Carbohydr. Res. 1986, 158, 7.

Methyl 4a-Carba-D-arabinofuranosides
J . Org. Chem., Vol. 66, No. 26, 2001 8969
97.4, 96.3, 84.2, 83.9, 83.1, 80.2, 79.9, 75.1, 75.0, 74.9, 74.7,
73.6, 73.4, 73.2, 72.1, 71.9, 71.8, 69.9, 69.1, 56.5, 55.7, 25.7,
25.3, 15.2, 14.9. Anal. Calcd for C31H38O6S: C, 69.12; H 7.11.
Found: C, 69.01; H, 7.13.
tion of other carbafuranoses through substitution of
D-mannose with other pyranose sugars.
We have also probed the conformation of 3 and 4 by
NMR spectroscopy. These studies have demonstrated
that for both compounds, the conformational equilibria
of ring conformers are biased to northern structures.
However, the similarity of the distribution to that
observed for the parent glycosides differs for each ring
system. For the R-isomers, there are significant differ-
ences in ring conformation between glycoside 1 and
carbasugar 3. In contrast, the ring conformation of 4 is
similar to its furanoside counterpart, 2.
In regard to rotamer populations about the C4-C5
bond, no significant differences were seen between gly-
coside 1 and carbasugar 3. Comparison of these popula-
tions in 2 and 4 showed larger, but still small, differences.
NOE experiments suggest that the preferred orientation
about the C1-O1 bond in 3 and 4 is similar to that in the
glycosides, i.e., the methyl group is anti to C2. However,
we were unable to confirm this preference through
measurement of 3J C,C between the methyl group and C4a
and C2.
3,4,6-Tr i-O-ben zyl-2-O-m eth oxym eth yl-r/â-D-m a n n op y-
r a n ose (10). To a solution of 9 (4.60 g, 9.30 mmol) in CH3-
CN/H2O (5:1, 15 mL) at 0 °C was added NIS (2.62 g, 11.63
mmol). The solution was allowed to stir for 10 min followed
by the addition of AgOTf (480 mg, 2.33 mmol). After stirring
for 10 min, triethylamine was added to neutralize the reaction.
The solution was diluted with CH2Cl2 and filtered through
Celite (2 cm). The filtrate was washed with saturated aqueous
Na2S2O3 solution, water, and brine. The organic layer was
dried, filtered, and concentrated. The compound was purified
by chromatography (hexanes/EtOAc, 4:1) yielding 10 (3.88 g,
90%) as a colorless oil: Rf 0.24 (hexanes/EtOAc, 4:1); 1H NMR
(500 MHz, CDCl3, δ) 7.39-7.22 (m, 15 H), 5.34 (s, 0.75 H),
5.29 (d, 0.25 H, J ) 4.3 Hz), 4.94-4.53 (m, 7 H), 4.06-4.02
(m, 3 H), 3.85-3.69 (m, 4 H), 3.5 (s, 1 H), 3.43 (s, 3H), 3.19 (d,
1 H, J ) 1.0 Hz); 13C NMR (125.7 MHz, CDCl3, δ) 138.4, 138.3,
138.2, 138.1, 128.4, 128.3 (2), 128.2 (2), 127.9, 127.8, 127.7.
127.6. 127.5, 127.4, 127.3 (2), 97.9, 96.8, 93.6, 81.9, 79.2, 78.3,
75.5, 75.1, 75.0, 74.9, 74.3, 73.7, 73.4, 73.3, 72.2, 72.1, 71.5,
69.6, 69.0, 56.0, 55.6. Anal. Calcd for C29H34O7: C, 70.43; H
6.93. Found: C, 70.22; H, 6.88.
4,5,7-Tr i-O-ben zyl-1,2-dideh ydr o-1,2-dideoxy-3-O-m eth -
oxym eth yl-D-m a n n o-h ep titol (11). To a solution of 10 (2.00
g, 4.04 mmol) in THF (30 mL) at 0 °C was added 1.6 M
n-butyllithium in THF (2.53 mL, 4.04 mmol). The solution was
allowed to stir for 10 min at 0 °C followed by cooling to -78
°C. The ylide derived from methyltriphenylphosphonium
bromide (3.61 g, 10.1 mmol) and 1. 6 M n-butyllithium in THF
(6.33 mL, 10.1 mmol) was added dropwise over the course of
1 h. The solution was allowed to stir for 10 h followed by the
addition of a saturated aqueous NaHCO3 solution and EtOAc.
The organic layer was washed with brine, dried, and concen-
trated under reduced pressure. The crude oil was purified by
chromatography (hexanes/EtOAc, 10:1) yielding 11 (1.55, 78%)
as a colorless oil: Rf 0.55 (hexanes/EtOAc, 5:1); [R]D +23.0 (c
We are currently exploring the preparation of “oli-
gosaccharides” of these carbafuranoses with the ultimate
goal of identifying inhibitors of the arabinosyltrans-
ferases that assemble cell wall polysaccharides in myco-
bacteria. Conformational investigations of these oligo-
mers are also in progress.
Exp er im en ta l Section
Gen er a l. Solvents were distilled from the appropriate
drying agents before use. Unless stated otherwise, all reactions
were carried out at room temperature under
pressure of argon and were monitored by TLC on silica gel 60
254 (0.25 mm, E. Merck). Spots were detected under UV light
a positive
1
F
1.0, CHCl3); H NMR (500 MHz, CDCl3, δ) 7.39-7.30 (m, 15
or by charring with 10% H2SO4 in ethanol. Solvents were
evaporated under reduced pressure and below 40 °C (bath).
Organic solutions of crude products were dried over anhydrous
Na2SO4. Column chromatography was performed on silica gel
60 (40-60 µM). The ratio between silica gel and crude product
ranged from 100 to 50:1 (w/w). Optical rotations were mea-
sured at 21 ( 2 °C. Melting points are uncorrected. For the
characterization of reaction products, 1H NMR spectra were
recorded at 500.12 MHz, and chemical shifts are referenced
to either TMS (0.0, CDCl3) or external dioxane (3.75, D2O).
13C NMR spectra were recorded at 125.75 MHz, and 13C
chemical shifts are referenced to CDCl3 (77.00, CDCl3) or exter-
nal dioxane (68.11, D2O). Elemental analyses were performed
by Atlantic Microlab Inc., Norcross, GA. Electrospray mass
spectra were recorded on samples suspended in mixtures of
THF with CH3OH and added trifluoroacetic acid or NaCl.
Eth yl 3,4,6-Tr i-O-ben zyl-2-O-m eth oxym eth yl-1-th io-r/
â-D-m a n n op yr a n osid e (9). To a solution of 812 (4.40 g, 8.89
mmol) in DMF (10 mL) at 0 °C was added NaH (60%
dispersion in mineral oil, 350 mg, 12.5 mmol). The solution
was allowed to stir for 15 min followed by the dropwise
addition of chloromethyl methyl ether (840 µL, 11.11 mmol).
The reaction mixture was warmed to room temperature and
stirred for 1 h, and then CH3OH /water (1:1, 5 mL) was added.
The reaction mixture was extracted with Et2O, and the organic
layer was washed with water and brine and then dried and
evaporated. Purification by chromatography (hexanes/EtOAc,
8:1) yielded 9 (4.21 g, 88%) as a colorless oil: Rf 0.44 (hexanes/
H), 6.00 (ddd, 1 H, J ) 7.2, 14.6, 17.3 Hz), 5.40 (dd, 1 H, J )
14.6, 1.5 Hz), 5.39 (dd, 1 H, J ) 17.6 Hz, 1.5 Hz), 4.79 (d, 1 H,
12.2 Hz), 4.74-4.57 (m, 7 H), 4.40 (dd, 1 H, J ) 6.6, 7.6 Hz),
4.08 (m, 1 H), 3.91 (dd, 1 H, J ) 5.0, 4.0 Hz), 3.83 (dd, 1 H, J
) 5.0, 4.0 Hz), 3.70-3.66 (m, 2 H), 3.39 (s, 3 H), 2.78 (d, 1 H,
J ) 5.5 Hz); 13C NMR (125.7 MHz, CDCl3, δ) 138.5, 138.3,
138.0, 135.3, 128.4, 128.3, 128.2, 128.0, 127.9, 127.8, 127.7,
127.5, 127.4, 119.3, 94.1, 81.0, 78.5, 77.8, 74.1, 73.7, 73.4, 71.2,
70.4, 55.8. Anal. Calcd for C30H36O6: C, 73.15; H 7.37. Found:
C, 73.02; H, 7.41.
1,3,4-Tr i-O-ben zyl-6,7-dideh ydr o-6,7-dideoxy-5-O-m eth -
oxym et h yl-L-a r a bin o-h ep t -2-u lose (12). To a solution of
PCC (591 mg, 3.56 mmol), NaOAc (300 mg, 3.65 mmol), and
crushed 4 Å molecular seives in CH2Cl2 (10 mL) was added
11 (1.35 g, 2.74 mmol) dissolved in CH2Cl2 (5 mL). The reaction
mixture was allowed to stir at room temperature for 2 h
followed by the addition of hexanes (10 mL) and Et2O (10 mL).
The solution was stirred for 30 min followed by filtration
through a 3.0 cm bed of silica gel followed by copious elution
with Et2O. The eluants were evaporated to yield 12 (1.25 g.
93%) as a colorless oil: Rf 0.65 (hexanes/EtOAc, 5:1); [R]D +43.1
1
(c 1.0, CHCl3); H NMR (500 MHz, CDCl3, δ) 7.28-7.21 (m,
15 H), 5.84 (ddd, 1 H, J ) 7.2, 14.6, 17.3 Hz), 5.37 (dd, 1 H, J
) 14.6, 1.5 Hz), 5.32 (dd, 1 H, J ) 17.6 Hz, 1.5 Hz), 4.62-4.22
(m, 12 H), 3.90 (d, 1 H, J ) 5 Hz), 3.32 (s, 3 H); 13C NMR
(125.7 MHz, CDCl3, δ) 208.3, 137.5, 137.3, 137.0, 135.3, 128.4,
128.3, 128.2, 128.1, 128.0, 127.8, 127.7, 127.6, 119.9, 94.5, 83.7,
81.9, 77.3, 77.2, 74.5, 74.3, 74.2, 73.1, 55.9, Anal. Calcd for
1
EtOAc, 6:1); H NMR (500 MHz, CDCl3, δ) 7.34-7.18 (m, 15
C
30H34O6: C, 73.45; H 6.99. Found: C, 73.35; H, 7.01.
H), 5.39 (d, 0.9 H, J ) 1.1 Hz), 5.00 (d, 0.1 H, J ) 0.1 Hz),
4.90-4.50 (m, 8 H), 4.06 (dd, 1 H, J ) 0.3, 3.2 Hz), 3.95 (s, 1
H), 3.94-3.68 (m, 4 H), 3.4 (s, 0.3 H), 3.39 (s, 3 H), 2.67-256
(m, 2.2 H), 1.32-1.26 (m, 3.3 H); 13C NMR (125.7 MHz, CDCl3,
δ) 138.5, 138.4, 138.3, 138.2, 138.0, 137.8, 128.4, 128.3, 128.2
(2), 128.1, 127.9, 127.8, 127.7, 127.6, 127.5, 127.4, 127.3, 127.2,
4,5,7-Tr i-O-b en zyl-1,2-d id eh yd r o-1,2,6-t r id eoxy-3-O-
m eth oxym eth yl-6-C-m eth ylen e-D-a r a bin o-h ep titol (13).
The ylide derived from methyltriphenylphosphonium bromide
(1.09 g 3.1 mmol) and 1.6 M n-butyllithium in THF (1.90 mL,
2.7 mmol) was added dropwise over the course of 1 h to a
solution of 12 (1.00 g, 2.03 mmol) in THF (30 mL) at -78 °C.

8970 J . Org. Chem., Vol. 66, No. 26, 2001
Callam and Lowary
The solution was allowed to stir for 3 h followed by the addition
of a saturated aqueous solution of NaHCO3 and EtOAc. The
organic layer was washed with brine, dried, and evaporated
under reduced pressure. The crude oil was purified by chro-
matography (hexanes/EtOAc. 15:1) yielding 13 (0.76 g, 77%)
as a colorless oil: Rf 0.57 (hexanes/EtOAc, 6:1); [R]D +69.8 (c
ized with AcOH, and evaporated under reduced pressure. The
product was purified by chromatography (hexanes/EtOAc, 8:1)
to give 18 (0.84 g, 84%) as a colorless oil: Rf 0.21 (hexanes/
EtOAc, 8:1); [R]D +18.3 (c 1.0, CHCl3); 1H NMR (500 MHz,
CDCl3, δ) 7.38-7.30 (m, 15 H), 4.66 (s, 2 H), 4.63 (s, 2 H),
4.55 (s, 2 H), 4.19 (bs, 1 H), 3.90 (dd, 1 H, J ) 8.1, 4.1 Hz),
3.86 (dd, 1 H, J ) 9.3, 4.6 Hz), 3.48 (d, 2 H), 2.25 (m, 1 H),
2.06 (bs, 1 H), 1.98 (ddd, 1 H, J ) 4.7, 8.9, 13.6 Hz), 1.89 (ddd,
1 H, J ) 5.0, 6.7, 13.7 Hz); 13C NMR (125.7 MHz, CDCl3, δ)
138.4, 138.3, 128.4, 128.3, 127.8, 127.7, 127.6, 127.5, 127.4,
89.9, 84.9, 74.9, 73.0, 72.1, 71.9, 71.7, 41.9, 34.2. Anal. Calcd
for C27H30O4: C, 77.48; H 7.22. Found: C, 77.40; H, 7.31,
Meth yl-4a -ca r ba -r-D-a r a bin ofu r a n osid e (3). To a solu-
tion of 18 (100 mg, 0.238 mmol) in THF (5 mL) at 0 °C was
added NaH (18 mg, 0.714 mmol). The solution was stirred for
15 min, and then CH3I (40 mg, 0.286 mmol) was added
dropwise. CH3OH was added, and the solution was concen-
trated. The resulting paste was dissolved in CH2Cl2, and the
organic solution was washed successively with an aqueous
saturated solution of NaHCO3, water, and brine. The organic
solution was dried and concentrated. The oil was immediately
dissolved in CH3OH/AcOH (5:1, v/v), and Pd/C (50 mg, 10 mol
%) was added. The solution was stirred under an atmosphere
of H2 for 4 h. The solution was subsequently filtered through
a bed of Celite, washed with CH3OH, and concentrated. The
compound was purified by chromatography (CHCl3/CH3OH,
20:1) to yield 3 (34 mg, 87%) as a colorless oil: Rf 0.21 (CHCl3/
CH3OH, 10:1); [R]D +16.1 (c 1.0, H2O); 1H NMR (500 MHz,
D2O, δ) 3.78 (dd, 1 H, J ) 6.2, 5.4 Hz), 3.65 (dd, 1 H, J ) 11.1,
4.7 Hz), 3.61 (dd, 1 H, J ) 6.2, 7.5 Hz), 3.60 (dd, 1 H, J ) 7.5,
8.4 Hz), 3.51 (dd, 1 H, J ) 6.8, 11.1 Hz), 3.34 (s, 3 H), 2.03 (m,
1 H), 1.83 (ddd, 1 H, J ) 8.4, 8.4, 14.1 Hz), 1.77 (ddd, 1 H, J
) 5.4, 9.8, 14.1 Hz); 13C NMR (125.7 MHz, D2O, δ) 83.1, 82.3,
77.0, 63.2, 56.8, 42.9, 28.9. Anal. Calcd for C7H14O4: C, 51.84;
H 8.70. Found: C, 51.64; H, 8.80.
1
1.0, CHCl3); H NMR (500 MHz, CDCl3, δ) 7.39-7.30 (m, 15
H), 5.95 (ddd, 1 H, J ) 6.7, 14.6, 17.3), 5.49 (d, 1 H, J ) 6.7
Hz), 5.33-5.28 (m, 3 H), 4.81-4.74 (m, 2 H), 4.62-4.57 (m, 4
H), 4.52 (d, 1 H, J ) 7.0 Hz), 4.40 (d, 1 H, J ) 7.0 Hz), 4.22
(dd, 1 H, J ) 7.9, 4.3 Hz), 4.12-4.00 (m, 3 H), 3.85 (dd, 1 H,
J ) 6.8, 3.7 Hz), 3.31 (s, 3 H); 13C NMR (125.7 MHz, CDCl3,
δ) 142.5, 138.9, 138.4, 138.2, 134.5, 128.3, 128.1, 128.0, 127.9
(2), 127.6, 127.5, 127.3, 127.2, 119.5, 116.8, 93.9, 82.6, 82.4,
77.8, 74.9, 72.7, 70.9, 69.7, 55.4. Anal. Calcd for C31H36O5: C,
76.20; H 7.43. Found: C, 76.10; H, 7.40.
2,3,5-Tr i-O-b en zyl-4-d eh yd r o-4-d eoxy-1-O-m et h oxy-
m eth yl-4a -ca r ba -â-D-a r a bin ofu r a n osid e (14). To a solution
of 13 (100 mg, 0.204 mmol) in toluene (5 mL) was added 23
(10 mol %). The reaction was allowed to stir for 2.5 h at 60 °C.
After cooling to room temperature, the solvent was evaporated
and the product purified by chromatography (hexanes/EtOAc,
15:1) to yield 14 (73 mg, 78%) as a colorless oil: Rf 0.77
(hexanes/EtOAc, 6:1); [R]D +10.1 (c 1.0, CHCl3); 1H NMR (500
MHz, CDCl3, δ) 7.44-7.30 (m, 15 H), 6.04 (d, 1 H, J ) 1.0
Hz), 4.80-4.53 (m, 10 H), 4.17 (m, 2 H), 4.05 (dd, 1 H, J )
5.4, 5.3 Hz), 3.42 (s, 3 H); 13C NMR (125.7 MHz, CDCl3, δ)
146.4, 138.5, 138.2, 137.9, 128.3, 128.2 (2), 128.0, 127.8, 127.7,
127.6, 127.5 (2), 126.9, 95.9, 85.3, 84.8, 76.0, 72.6, 72.5, 72.0,
66.5, 55.5. Anal. Calcd for C29H32O5: C, 75.63; H 7.00. Found:
C, 75.55; H, 7.05.
2,3,5-Tr i-O-b en zyl-1-O-m et h oxym et h yl-4a -ca r b a -â-D-
a r a bin ofu r a n osid e (15). To a solution of 14 (50 mg, 0.110
mmol) in CH2Cl2 (10 mL) was added (Ph3P)3RhCl (10 mol %,
0.011 mmol). The heterogeneous solution was allowed to stir
under an atomsphere of H2 for 6 h. The solvent was evaporated
and the product purified by chromatography (hexanes/EtOAc,
20:1) to give 15 (45 mg, 88%) as a colorless oil: Rf 0.61
(hexanes/EtOAc, 10:1); [R]D +87.1 (c 1.0, CHCl3); 1H NMR (500
MHz, CDCl3, δ) 7.32-7.24 (m, 15 H), 4.68-4.58 (m, 6 H), 4.49
(s, 2 H), 4.15 (dd, 1 H, J ) 4.1, 7.6 Hz), 3.86-3.83 (m, 2 H),
3.51 (dd, 1 H, J ) 7.7, 8.9 Hz), 3.44 (dd, 1 H, J ) 9.0, 7.3 Hz),
3.35 (s, 3 H), 2.24-2.22 (m, 2 H), 2.08 (ddd, 1 H, J ) 5.6, 9.4,
13.7 Hz), 1.66 (ddd, 1 H, 5.8, 5.9, 11.6 Hz); 13C NMR (125.7
MHz, CDCl3, δ) 138.7, 138.5, 138.3, 128.3, 128.2, 127.6 (2),
127.5 (2), 127.4, 127.3, 95.5, 84.5, 84.3, 75.6, 73.3, 72.9, 71.9,
71.7, 55.5, 41.2, 30.4. Anal. Calcd for C29H34O5: C, 75.30; H
7.41. Found: C, 75.35; H, 7.33.
Meth yl-4a -ca r ba -â-D-a r a bin ofu r a n osid e (4). Conversion
of 16 (121 mg, 0.283 mmol) into 4 was carried out as described
above for the preparation of 3. The compound was purified by
chromatography (CHCl3/CH3OH, 20:1) to yield 4 (44 mg, 94%)
as a colorless oil: Rf 0.16 (CHCl3/CH3OH, 8:1); [R]D +9.1 (c
1
1.0, H2O); H NMR (500 MHz, D2O, δ) 3.89 (dd, 1 H, J ) 5.1,
6.2 Hz), 3.75 (dd, 1 H, J ) 5.1, 6.5 Hz), 3.71 (dd, 1 H, J ) 6.6,
6.8 Hz), 3.66 (dd, 1 H, J ) 5.8, 10.9 Hz), 3.51 (dd, 1 H, J )
7.5, 11.0 Hz), 3.32 (s, 3 H), 2.13 (ddd, 1 H, J ) 4.9, 7.5, 13.9
Hz), 1.89 (m, 1 H), 1.48 (ddd, 1 H, 6.2, 9.3, 13.4 Hz); 13C NMR
(125.7 MHz, D2O, δ) 80.2, 78.0, 77.6, 64.5, 57.0, 43.5, 29.3.
Anal. Calcd for C7H14O4: C, 51.84; H 8.70. Found: C, 51.70;
H, 8.89.
2,3,5-Tr i-O-ben zyl-4a -ca r ba -â-D-a r a bin ofu r a n ose (16).
To a solution of 15 (40 mg, 0.086 mmol) in CH3OH (10 mL)
was added concentrated HCl (5 µL). The solution was stirred
for 6 h followed by neutralization with basic alumina. The
solution was filtered through a bed of Celite and concentrated,
and the product was purified by chromatography (hexanes/
EtOAc, 8:1) to give 16 (36 mg, 95%) as a colorless oil: Rf 0.21
(hexanes/EtOAc, 8:1); [R]D +28.1 (c 1.0, CHCl3); 1H NMR (500
MHz, CDCl3, δ) 7.35-7.25 (m, 15 H), 4.65-4.60 (m, 4 H), 4.51
(d, 1 H, 12.1 Hz), 4.50 (d, 1 H, J ) 12 Hz), 4.15 (dd, 1 H, J )
8.6, 4.3 Hz), 3.92 (dd, 1 H, J ) 5.5, 5.4 Hz), 3.83 (dd, 1 H, J )
10.0, 4.7 Hz), 3.51 (m, 2 H), 2.67 (d, 1 H, 5.5 Hz), 2.14-2.10
(m, 1 H), 2.09 (ddd, 1 H, J ) 13.7, 9.4, 5.6 Hz), 1.58 (ddd, 1 H,
J ) 5.9, 5.8, 1.6 Hz); 13C NMR (125.7 MHz, CDCl3, δ) 138.7,
138.2, 137.9, 128.4, 128.3, 128.2 (2), 127.8, 127.7 (2), 127.6 (2),
127.5, 86.6, 84.6, 73.1, 73.0, 72.0, 71.9, 70.5, 41.6, 32.9. Anal.
Calcd for C27H30O4: C, 77.48; H 7.22. Found: C, 77.30; H, 7.29.
2,3,5-Tr i-O-ben zyl-4a -ca r ba -r-D-a r a bin ofu r a n ose (18).
To a solution of 16 (100 mg, 0.238 mmol), p-nitrobenzoic acid
(52 mg, 0.310 mmol), and triphenylphosphine (84 mg, 0.310
mmol) in toluene (5 mL) at 0 °C was added diethyl azodicar-
boxylate (54 mg, 0.310 mmol). The solution was allowed to
warm to room temperature followed by stirring for 4 h. The
solvent was evaporated, and the resulting compound was
subsequently dissolved in CH3OH (5 mL) and treated with a
catalytic amount of 1 M NaOCH3 solution (100 µL). The
solution was stirred at room temperature for 30 min, neutral-
(4-2H,4a -2H)-1-O-Meth oxym eth yl-2,3,5-tr i-O-ben zyl-4a -
ca r ba -â-D-a r a bin ofu r a n osid e (26). To a solution of 14 (50
mg, 0.110 mmol) in CH2Cl2 (10 mL) was added (Ph3P)3RhCl
(10 mol %, 0.011 mmol). The heterogeneous solution was
stirred under an atomsphere of D2 for 6 h. The solvent was
evaporated and the product purified by chromatography
(hexanes/EtOAc, 20:1) to afford 12 (42 mg, 82%) as a colorless
oil: Rf 0.61 (hexanes/EtOAc, 10:1); [R]D +61.5 (c 1.0, CHCl3);
1H NMR (500 MHz, CDCl3, δ) 7.32-7,24 (m, 15 H), 4.68-4.58
(m, 6 H), 4.49 (s, 2 H), 4.15 (dd, 1 H, J ) 4.1, 7.6 Hz), 3.86-
3.83 (m, 2 H), 3.51 (dd, 1 H, J ) 7.7, 8.9 Hz), 3.44 (dd, 1 H, J
) 9.0, 7.3 Hz), 3.35 (s, 3 H), 1.66 (d, 1 H, J ) 5.8 Hz); 13C
NMR (125.7 MHz, CDCl3, δ) 138.7, 138.5, 138.3, 128.3, 128.2,
127.6 (2), 127.5 (2), 127.4, 127.3, 95.5, 84.5, 84.3, 75.6, 73.3,
72.9, 71.9, 71.7, 55.5, 41.2, 30.4. Anal. Calcd for C29H32D2O5:
C, 74.97; H 7.81. Found: C, 74.82; H, 7.88. HRMS (ESI) calcd
for (M + Na+) C29H32D2O5: 487.2427, found 487.2400.
(4-2H ,4a -2H )-2,3,5-Tr i-O-b en zyl-4a -ca r b a -â-D-a r a b in o-
fu r a n ose (27). The conversion of 26 (40 mg, 0.086 mmol) into
27 was carried out as described above for the preparation of
16 from 15. The compound was purified by chromatography
(hexanes/EtOAc, 8:1) to give 27 (33 mg, 92%) as a colorless
oil: Rf 0.21 (hexanes/EtOAc, 8:1); [R]D +22.9 (c 1.0, CHCl3);
1H NMR (500 MHz, CDCl3, δ) 7.35-7.25 (m, 15 H), 4.62-4.58
(m, 4 H), 4.51 (d, 1 H, J ) 12.1 Hz), 4.50 (d, 1 H, J ) 12 Hz),
4.15 (dd, 1 H, J ) 8.6, 4.3), 3.92 (dd, 1 H, J ) 5.5, 5.4), 3.83
(dd, 1 H, J ) 10.0, 4.7 Hz), 3.51 (m, 2 H), 2.67 (d, 1 H, 5.5 Hz),

Methyl 4a-Carba-D-arabinofuranosides
J . Org. Chem., Vol. 66, No. 26, 2001 8971
1.58 (d, 1 H, J ) 5.9 Hz); 13C NMR (125.7 MHz, CDCl3, δ)
138.7, 138.2, 137.9, 128.4, 128.3, 128.2 (2), 127.8, 127.7
(2), 127.6 (2), 127.5, 86.6, 84.6, 73.1, 73.0, 72.0, 71.9, 70.5,
41.6, 32.9. Anal. Calcd for C27H28D2O4: C, 73.12; H 7.27.
Found: C, 73.01; H, 7.22. HRMS (ESI) calcd for (M + Na+)
Ta ble 7. Va lu es of A a n d B Used in P SEUROT
Ca lcu la tion sa
3J
3/28
4/29
ΦH,H
A
Bb
A
Bb
3.3
122.0
-123.8
124.1
4.4
C
27H28D2O4: 443.2165, found 443.2160.
Φ1,2
Φ2,3
Φ3,4
Φ4,4a
Φ4,4a’
Φ1,4a
Φ1,4a’
1.113
1.129
1.469
1.093
1.098
1.172
1.172
-123.3
122.0
-123.8
124.1
4.4
1.113
1.129
1.469
1.093
1.098
1.172
1.172
(4-2H ,4a -2H )-Met h yl-4a -ca r b a -r-D-a r a b in ofu r a n osid e
(28). The conversion of 27 (100 mg, 0.238 mmol) into 28 was
carried out as described for the preparation of 3 from 16. The
compound was purified by chromatography (CHCl3/CH3OH,
20:1) to yield 28 (29 mg, 77%) as a colorless oil: Rf 0.21 (CHCl3/
CH3OH, 10:1); [R]D +8.1 (c 1.0, H2O); 1H NMR (500 MHz, D2O,
δ) 3.78 (dd, 1 H, J ) 6.2, 5.3 Hz), 3.65 (d, 1 H, J ) 11.5), 3.61
(dd, 1 H, J ) 6.2, 7.4 Hz), 3.60 (d, 1 H, J ) 7.4), 3.51 (d, 1 H,
J ) 11.8 Hz), 3.34 (s, 3 H), 1.77 (d, 1 H, J ) 5.3 Hz); 13C NMR
(125.7 MHz, D2O, δ) 83.1, 82.3, 77.0, 63.2, 56.8, 42.9, 28.9.
HRMS (ESI) calcd for (M + Na+) C7H12D2O4: 187.0913, found
187.0898.
3.4
122.1
-122.1
3.4
a
See Experimental Section and Supporting Information for the
b
method used for determining these values. In degrees.
NMR spectrum was recorded at 10° increments between 288
3
3
and 328 K. The J C,H and J C,C were measured using 31 and
32, via either the 125 MHz one-dimensional 13C NMR spec-
trum (3J C,C) or the 500 MHz one-dimensional 13H NMR
spectrum (3J C,H). These values were confirmed by simulation
of these spectra.
(4-2H ,4a -2H )-Met h yl-4a -ca r b a -â-D-a r a b in ofu r a n osid e
(29). The conversion of 27 (100 mg, 0.238 mmol) into 29 was
carried out as described above for the preparation of 3. The
compound was purified by chromatography (CHCl3/CH3OH,
20:1) to yield 29 (36 mg, 94%) as a colorless oil: Rf 0.16 (CHCl3/
CH3OH, 8:1); [R]D +20.9 (c 1.0, H2O); 1H NMR (500 MHz, D2O,
δ) 3.89 (dd, 1 H, J ) 5.0, 6.2 Hz), 3.75 (dd, 1 H, J ) 5.1, 6.4
Hz), 3.71 (d, 1 H, J ) 6.4 Hz), 3.66 (d, 1 H, J ) 12.1 Hz), 3.51
(d, 1 H, J ) 12.0 Hz), 3.32 (s, 3 H), 1.48 (d, 1 H, J ) 6.0 Hz);
13C NMR (125.7 MHz, D2O, δ) 80.2, 78.0, 77.6, 64.5, 57.0, 43.5,
29.3. HRMS (ESI) calcd for (M + Na+) C7H12D2O4: 187.0913,
found 187.0902.
P SEUROT Ca lcu la tion s. All calculations were done with
PSEUROT 6.2 following modification of the default parameters
provided for the arabinofuranosyl ring. The electonegativities
(in D2O) used were as follows: 1.25 for OH; 1.26 for OR; 0.0
for CH2; 0.68 for CH2OH; 0.62 for CH(OR); 0.0 for H; 0.0 for
D.49 For each endocyclic torsion angle, the parameters R and
ꢀ were set to 1 and 0, respectively, as was done previously for
a related study on carbocyclic nucleosides.29
To translate the exocyclic H,H torsion angles (ΦHH) into the
endocyclic torsion angles (νi) that are used to determine the
pseudorotational phase angle (P), the program makes use of
the relationship: ΦHH ) Aνi + B. The values of A and B for 3
and 4 are unknown, and the approach we used to define them
for each torsion angle was similar to that described by
Chattopadhyaya and co-workers for carbocyclic nucleosides.29
For both 3 and 4, a Monte Carlo search using MacroModel
Version 6.550 and the AMBER* force field was carried out to
generate a family of conformers47,51 for each ring system, which
were in turn optimized at the HF/6-31G* level of theory,52
using Gaussian 98.53 The geometrical data for these conformers
were analyzed using the program ConforMole54 and then ΦHH
was plotted against νi in order to determine A and B for a
particular endocyclic torsion angle. These graphs are included
in the Supporting Information, and the values of A and B used
in the PSEUROT calculations are given in Table 7.
[
13C]-Meth yl-4a -ca r ba -r-D-a r a bin ofu r a n osid e (31). The
procedure used for the synthesis of 31 from 18 (100 mg, 0.238
mmol) was identical to that for the synthesis of 4 from 16
except for the use of 13CH3I. The compound was purified by
chromatography (CHCl3/CH3OH, 20:1) to yield 30 (31 mg, 90%)
as a colorless oil: Rf 0.21 (CHCl3/CH3OH, 10:1); [R]D +16.9 (c
1
1.0, H2O); H NMR (500 MHz, D2O, δ) 3.78 (dd, 1 H, J ) 6.2,
5.4 Hz), 3.65 (dd, 1 H, J ) 11.1, 4.6 Hz), 3.61 (dd, 1 H, J )
6.2, 7.5 Hz), 3.60 (dd, 1 H, J ) 7.5, 8.4 Hz), 3.51 (dd, 1 H, J )
6.8, 11.1 Hz), 3.34 (d, 3 H, 143.1 Hz), 2.03 (m, 1 H), 1.83 (ddd,
1 H, J ) 8.4, 8.4, 11.1 Hz), 1.77 (ddd, 1 H, J ) 5.4, 9.8, 14.1
Hz); 13C NMR (125.7 MHz, D2O, δ) 83.1 (d, J ) 1.8 Hz), 82.3,
77.0 (d, J ) 1.8 Hz), 63.2, 56.8, 42.9, 28.9 (d, J ) 1.8 Hz).
HRMS (ESI) calcd for (M + Na+) C613CH14O4: 186.0823, found
186.0811.
[
13C]-Meth yl-4a -ca r ba -â-D-a r a bin ofu r a n osid e (32). The
procedure used for the synthesis of 32 from 16 (100 mg, 0.238
mmol) was identical to that for the synthesis of 4 from 16
except for the use of 13CH3I. The compound was purified by
chromatography (CHCl3/CH3OH, 20:1) to yield 31 (34 mg, 94%)
as a colorless oil: Rf 0.16 (CHCl3/CH3OH, 8:1); [R]D +10.3 (c
In the calculations reported in the main text of the paper,
the puckering amplitude, τm, was kept constant at 40°. This
value represents the average puckering amplitude of all
conformers identified from the Monte Carlo search/HF-
1
1.0, H2O); H NMR (500 MHz, D2O, δ) 3.89 (dd, 1 H, J ) 5.1,
6.2 Hz), 3.75 (dd, 1 H, J ) 5.1, 6.5 Hz), 3.71 (dd, 1 H, J ) 6.5,
6.8 Hz), 3.66 (dd, 1 H, J ) 5.7, 10.9 Hz), 3.51 (dd, 1 H, J )
7.6, 11.0 Hz), 3.32 (d, 3 H, J ) 142.8 Hz), 2.13 (ddd, 1 H, J )
4.9, 7.5, 13.9 Hz), 1.89 (m, 1 H), 1.48 (ddd, 1 H, 6.2, 9.3, 12.4
Hz); 13C NMR (125.7 MHz, D2O, δ) 80.2 (d, J ) 1.9 Hz), 78.0,
77.6 (d, J ) 1.9 Hz), 64.5, 57.0, 43.5, 29.3 (d, J ) 1.9 Hz).
HRMS (ESI) calcd for (M + Na+) C613CH14O4: 186.0823, found
186.0833.
(49) Altona, C.; Francke, R.; de Haan, R.; Ippel, J . H.; Daalmans,
G. J .; Westra Hoekzema, A. J . A.; van Wijk, J . Magn. Reson. Chem.
1994, 32, 670.
(50) (a) MacroModel V6.5: Mohamadi, F.; Richards, N. G. J .; Guida,
W. C.; Liskamp, R.; Lipton, M.; Caulfield, C.; Chang, G.; Hendrickson,
T.; Still, W. C. J . Comput. Chem. 1990, 11, 440. (b) Goodman, J .; Still,
W. C. J . Comput. Chem. 1991, 12, 1110.
(51) McCarren, P. R.; Gordon, M. T.; Lowary, T. L.; Hadad, C. M.
J . Phys. Chem. A. 2001, 105, 5911.
(52) Hehre, W. J .; Radom, L.; Schleyer, P. v. R.; Pople, J . A. Ab initio
Molecular Orbital Theory; J ohn Wiley & Sons: New York, 1986.
(53) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J . R.; Zakrzewski, V. G.; Montgomery, J . A.,
J r.; Stratmann, R. E.; Burant, J . C.; Dapprich, S.; Millam, J . M.;
Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J .;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo,
C.; Clifford, S.; Ochterski, J .; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J . B.; Cioslowski, J .; Ortiz, J . V.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J .; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; J ohnson, B.; Chen, W.;
Wong, M. W.; Andres, J . L.; Gonzalez, C.; Head-Gordon, M.; Replogle,
E. S.; Pople, J . A. Gaussian 98, Revision A.7, Gaussian, Inc.; Pitts-
burgh, PA, 1998.
NMR Sp ectr oscop y for Con for m a tion a l Stu d ies. All
NMR spectra used for obtaining conformational information
were recorded on samples at 15-20 mM concentration in 0.6
3
mL of D2O (pH 6.0). The J H,H used in the PSEUROT
calculations or in the determination of the C4-C5 rotamer
populations were measured from the 500 MHz one-dimen-
sional 1H NMR spectrum of 3, 4, 28, or 29. In some cases,
resolution enhancement of the FIDs was necessary in order
to measure small coupling constants. Simulation of the 1H
NMR spectrum of 3 and 4 was done using the Bruker program
NMRSim.39 A comparison of the simulated and experimental
spectra is provided in the Supporting Information. To assess
the effect of temperature on conformer identity and population,
a series of variable-temperature NMR experiments were done
(54) ConforMole, McCarren, P. R. The Ohio State University; this
program is available upon request.
1
using 28 and 29. In these experiments, a one-dimensional H

8972 J . Org. Chem., Vol. 66, No. 26, 2001
Callam and Lowary
Ta ble 8. Dih ed r a l An gles Used for Ca lcu la tin g Lim itin g 3J for gg, gt, a n d tg Rota m er sa ,b
C4-C5 bond C1-O1 bond
rotamer
H4-C4-C5-H5R
H4-C4-C5-H5S
CCH3-O-C1-C2
CCH3-O-C1-C4a
gg
gt
tg
62
-177
-66
-60
63
178
44
72
172
78
167
65
a
b
See Experimental Section for the protocol used for determining these values. Angles in degrees.
and H4-C4-C5-H5S angles was taken and those numbers are
shown in Table 8.
optimization protocol described above. The range of τm found
in this family of conformers was 36-43°, and we have therefore
carried out a series of PSEUROT calculations in which the
puckering amplitude was changed in 1° increments across this
range (see Supporting Information). Over this range of τm, the
identities of the N/S conformers for 3 and 4 remained un-
changed; however, there were slight differences in the relative
populations of each.
Deter m in a tion of C1-O1 Rota m er P op u la tion s. The
rotamer populations about the C1-O1 bond were determined
by analysis of the three bond 13C-13C coupling constants
between the methyl group and C4a (3J CH3,4a) and between the
methyl group and C2 (3J CH3,2) using eq 5-7. The coefficients
3
for eq 4 and 5 were determined by calculating the J C,C for
each rotamer using eq 8.
Deter m in a tion of C4-C5 Rota m er P op u la tion s. The
rotamer populations about the C4-C5 were determined by
3J C,C ) 4.96 cos2 θ + 0.63 cos θ - 0.01
(8)
1
analysis of the three bond H-1H coupling constants between
H4 and H5R (3J 4,5R) and H4 and H5S (3J 4,5S) using eqs 1-3. The
The angles used in this equation (Table 8) were determined
as described above for the C4-C5 bond. See Figure 6 for
definitions of gg, gt, and tg rotamers about the C1-O1 bond.
coefficients for eqs 1 and 2 were determined by calculating
3
the limiting J H,H for each rotamer using eq 7.
Ack n ow led gm en t. This work was supported by the
National Institutes of Health (AI44045-01). C.S.C. is a
recipient of a GAANN fellowship from the U.S. Depart-
ment of Education. We thank Douglas M. Krein for
assistance with the spectral simulations and Christo-
pher M. Hadad for helpful discussions.
3J H,H ) 13.22 cos2 θ - 0.99 cos θ +
i[0.87-2.46 cos2 (êiθ +19.9|∆xi|)]∆xi (7)
∑
For eq 7, ∆xi ) (xsubst - xH) where x is the electronega-
tivity (see above) and êi ) +1 or -1 as previously defined.55
The angles θ used in this equation (Table 8) were determined
by an analysis of the data obtained from the previously
described Monte Carlo search/HF-optimization protocol. The
geometrical data for all conformers was analyzed using Con-
forMole,54 and each structure was assigned as gg, gt, or tg
(Figure 4A) based on the C4a-C4-C5-O5 angle. For each of
the three sets of conformers, an average of H4-C4-C5-H5R
Su p p or tin g In for m a tion Ava ila ble: NMR spectra for all
new compounds, details on the preparation of 8 via an
improved route, details on the calculation of A and B for the
PSEUROT calculations, details of calculations, coupling con-
stants measured from variable temperature studies, results
of PSUEROT calculations at differing puckering angles and
comparison of simulated spectra for 3 and 4 with those
obtained from experiment. This material is available free of
charge via the Internet at http://pubs.acs.org.
(55) Haasnoot, C. A. G.; de Leeuw, F. A. A. M.; de Leeuw, H. P. M.;
Altona, C. Recl. Trav. Chim. Pays-Bas 1979, 98, 576.
J O010827R