Synthesis and conformational analysis of 2′-fluoro-5-methyl-4′- thioarabinouridine (4′S-FMAU)

Article abstract of DOI:10.1021/jo051844+

An improved synthesis of 2′-deoxy-2′-fluoro-5-methyl-4′- thioarabinouridine (4′S-FMAU) is described. Participation of the 3′-O-benzoyl protecting group in the thiosugar precursor influenced the stereochemistry of the N-glycosylation reaction in nonpolar s

Full text of DOI:10.1021/jo051844+

Synthesis and Conformational Analysis of
2′-Fluoro-5-methyl-4′-thioarabinouridine (4′S-FMAU)
Jonathan K. Watts,† Kashinath Sadalapure,‡ Niloufar Choubdar,‡ B. Mario Pinto,*,‡ and
Masad J. Damha*,†
Department of Chemistry, McGill UniVersity, 801 Sherbrooke Street West, Montreal, QC,
Canada H3A 2K6, and the Department of Chemistry, Simon Fraser UniVersity, Burnaby, BC,
Canada V5A 1S6
masad.damha@mcgill.ca; bpinto@sfu.ca.
ReceiVed August 31, 2005
An improved synthesis of 2′-deoxy-2′-fluoro-5-methyl-4′-thioarabinouridine (4′S-FMAU) is described.
Participation of the 3′-O-benzoyl protecting group in the thiosugar precursor influenced the stereochemistry
of the N-glycosylation reaction in nonpolar solvents, permitting a higher â/R ratio than previously observed
3
for similar Lewis acid catalyzed glycosylations. Conformational analysis of the nucleoside using JHH
3
and JHF NMR coupling constants together with the PSEUROT program showed that it adopted a
predominantly northern conformation in contrast to 2′-deoxy-2′-fluoro-5-methylarabinouridine (FMAU),
whose PSEUROT conformational analysis is presented here for the first time, which showed a dominantly
southeast conformation. The sharp conformational switch attained by replacing the ring heteroatom is
attributed to a decrease in relevant steric and stereoelectronic effects.
Introduction
biological properties in the case of the 2′F-ANA oligonucleo-
tides.2 Although 2′-deoxy-2′-fluoro-4′-thioarabinonucleosides
have previously been synthesized,3-6 this is the first time their
conformations have been examined.
The conformation of oligonucleotides is believed to depend
strongly upon the conformation of the nucleotide monomers that
make them up.1 Thus, to understand and design oligonucleotide
therapeutics successfully, it is essential to be able to understand
and manipulate nucleoside conformations.
Results and Discussion
Synthesis. 2,3,5-Tri-O-benzyl-1,4-anhydro-4-thio-arabinitol
(1) was prepared from L-xylose following a procedure similar
to that of Satoh et al.7 The benzyl protecting groups were
removed by Birch reduction using Li/liq NH3 to give triol 2.8
As part of our ongoing program to develop new nucleic acid
chemistries, we chose to replace the 4′ oxygen of 2′-deoxy-2′-
fluoro-5-methylarabinouridine (FMAU) with a sulfur atom. On
a chemical level, it was envisaged that this modification would
modulate stereoelectronic and steric effects in the 2′-fluoro-
arabinofuranose moiety. We were especially interested in
investigating the effect of the 4′-thio modification in conjunction
with the presence of the 2′-fluorine, which led to favorable
(2) Damha, M. J.; Wilds, C. J.; Noronha, A.; Brukner, I.; Borkow, G.;
Arion, D.; Parniak, M. A. J. Am. Chem. Soc. 1998, 120, 12976-12977.
Wilds, C. J.; Damha, M. J. Nucleic Acids Res. 2000, 28, 3625-3635.
(3) Yoshimura, Y.; Kitano, K.; Yamada, K.; Satoh, H.; Watanabe, M.;
Miura, S.; Sakata, S.; Sasaki, T.; Matsuda, A. J. Org. Chem. 1997, 62,
3140-3152.
* To whom correspondence should be addressed. M.J.D.: Tel: (514) 398-
7552. Fax: (514) 398-3797; B.M.P.: Tel: (604) 291-4152. Fax: (604) 291-
4860.
(4) Yoshimura, Y.; Endo, M.; Miura, S.; Sakata, S. J. Org. Chem. 1999,
64, 7912-7920.
† McGill University.
(5) Yoshimura, Y.; Endo, M.; Sakata, S. Tetrahedron Lett. 1999, 40,
1937-1940.
‡ Simon Fraser University.
(1) Marquez, V. E.; Siddiqui, M. A.; Ezzitouni, A.; Russ, P.; Wang, J.;
Wagner, R. W.; Matteucci, M. D. J. Med. Chem. 1996, 39, 3739-3747.
(6) Yoshimura, Y.; Kitano, K.; Yamada, K.; Sakata, S.; Miura, S.; Ashida,
N.; Machida, H. Bioorg. Med. Chem. 2000, 8, 1545-1558.
10.1021/jo051844+ CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/11/2006
J. Org. Chem. 2006, 71, 921-925
921

Watts et al.
SCHEME 1a
a Reagents and conditions: (a) Li, liq NH3, -78°C; (b) TIPSCl2, pyridine, rt, 3 h; (c) DAST, CH2Cl2, -15°C, 15 min; (d) Bu4NF, THF, rt, 30 min; (e)
BzCl, pyridine, rt, 6 h; (f) O3, CH2Cl2, -78°C, 30 min; (g) Ac2O, 110°C, 3 h; (h) bis-silylated thymine, TMSOTf, CCl4, reflux, 16 h, 47% yield of â product;
(i) 2M NH3 in MeOH, rt, 23 h, 87%.
Treatment of triol 2 with equimolar ratios of 1,3-dichloro-
1,1,3,3-tetraisopropyldisiloxane (TIPSCl2)9 in pyridine gave
mainly the desired compound 3 that, when treated with DAST,
gave within 10 min the desired 2-fluoro derivative 4 in 80%
yield. Moreover, the reaction proceeded with retention of
configuration, presumably through an episulfonium ion inter-
mediate.4,10
FIGURE 1. Proposed 3′-O-benzoate participation in the glycosylation
To install the pyrimidine base at C-1, we chose to function-
alize C-1 as an acetate derivative through the Pummerer reaction,
as reported by Naka et al.9 Thioether 4 was thus subjected to
ozonization at -78 °C to give sulfoxide 5 quantitatively. When
compound 5 was treated with Ac2O at 70 °C, several compo-
nents were observed on TLC, suggesting that the silyl protecting
group was being removed. We therefore decided to replace the
3,5-O-disiloxane bridge with benzoyl protecting groups. Thus,
thioether 4 was treated with Bu4NF followed by BzCl in pyridine
to give compound 7 in excellent yield. Ozonization of thioether
7 at -78 °C afforded sulfoxide 8 that, when treated with Ac2O
at 110 °C, gave mainly the desired 1-O-acetyl derivative 9 as
an anomeric mixture (R/â 1:2 to 1:14). The minor isomer, 4-O-
acetate 10, was found to undergo spontaneous elimination of
acetic acid to yield exocyclic olefin 11 over a period of several
weeks at room temperature (Scheme 1).
reaction. Increased participation occurs in nonpolar solvents in which
the thiacarbenium ion is less stable.
TABLE 1. Anomeric Ratio of Nucleoside Products for
Glycosylations with the â-Acetate 9â as Starting Material
(r e 10%)
dielectric
constant12
product
R/â ratio
solvent
CH3CN
CH2Cl2
CHCl3
CCl4
37.5
9.1
4.8
2.2
3:1
1.7:1
0.9:1
0.7:1
observed using other 3′-directing groups.11 This mechanism
would be more favored in nonpolar solvents, where a localized
cation is highly unstable (Table 1). Accordingly, our use of
nonpolar solvents improves the â/R ratio significantly compared
to that reported in the literature for similar Lewis acid catalyzed
glycosylations6 and gives a comparable yield of â product to
that obtained via a fusion reaction of the corresponding glycosyl
bromide with cytidine.5
Next, N-glycosylation of acetate derivative 9 was ac-
complished by coupling to thymine in the presence of TMS-
trifluoromethanesulfonate as the Lewis acid catalyst (Scheme
1). We propose that the R face of the molecule is partially
blocked by a benzoxonium ion resulting from an attack of the
benzoate ester on the thiacarbenium ion (Figure 1), as has been
After the removal of the R nucleoside 12R by silica gel
chromatography, the â nucleoside 12â was debenzoylated using
2 M methanolic ammonia to give 13 in 87% yield.
(7) Satoh, H.; Yoshimura, Y.; Sakata, S.; Miura, S.; Machida, H.;
Matsuda, A. Bioorg. Med. Chem. Lett. 1998, 8, 989-992.
(8) Yuasa, H.; Kajimoto, T.; Wong, C. H. Tetrahedron Lett. 1994, 35,
8243-8246.
(9) Naka, T.; Minakawa, N.; Abe, H.; Kaga, D.; Matsuda, A. J. Am.
Chem. Soc. 2000, 122, 7233-7243.
(10) Yuasa, H.; Tamura, J.; Hashimoto, H. J. Chem. Soc., Perkin Trans.
1 1990, 2763-2769. Jeong, L. S.; Nicklaus, M. C.; George, C.; Marquez,
V. E. Tetrahedron Lett. 1994, 35, 7569-7572.
(11) Young, Robert J.; Shaw-Ponter, S.; Hardy, G. W.; Mills, G.
Tetrahedron Lett. 1994, 35, 8687-8690. Shaw-Ponter, S.; Mills, G.;
Robertson, M.; Bostwick, R. D.; Hardy, G. W.; Young, R. J. Tetrahedron
Lett. 1996, 37, 1867-1870. Wang, Y.; Inguaggiato, G.; Jasamai, M.; Shah,
M.; Hughes, D.; Slater, M.; Simons, C. Bioorg. Med. Chem. 1999, 7, 481-
487. Inguaggiato, G.; Jasamai, M.; Smith, J. E.; Slater, M.; Simons, C.
Nucleosides Nucleotides 1999, 18, 457-467.
922 J. Org. Chem., Vol. 71, No. 3, 2006

Synthesis and Conformational Analysis of 4′S-FMAU
FIGURE 3. Definitions of internal torsion angles in a nucleoside.
TABLE 3. Aj and Bj Parameters for 13 and 14
4′S-FMAU (13)
Aj
Bja
2.24
FMAU (14)
Bja
Aj
H1′-H2′
H1′-F2′
H2′-H3′
F2′-H3′
H3′-H4′
1.098
1.081
1.072
1.076
1.043
1.041
1.029
1.150
1.177
1.057
1.14
123.24
119.96
0.54
122.28
122.27
1.77
FIGURE 2. Pseudorotational wheel describing the conformations of
nucleosides; E ) envelope, T ) twist. Natural nucleosides have
characteristic minima in the north (0°) and south (180°) regions, and
interconversion occurs preferentially via the east (90°) pseudorotamer.
-125.80
-127.20
a In degrees.
1
1
TABLE 2. Vicinal H-1H and H-19F Coupling Constantsa in
4′S-FMAU (13) and FMAU (14) Nucleosides in D2O
able to account for a two-state equilibrium and provide the
pseudorotational parameters for two interconverting conformers.
Although some conformational work has been done on nucleo-
side 14 previously,16 detailed, empirically derived data was not
available, and we therefore undertook a PSEUROT study of
both nucleosides 13 and 14.
4′S-FMAU (13)
FMAU (14)
H1′-H2′
H1′-F2′
H2′-H3′
F2′-H3′
H3′-H4′
6.0
7.9
7.1
12.1
7.0
4.0
16.9
2.9
19.6
5.0
Several sets of parameters are necessary for the PSEUROT
calculations. Valence angles are not perfectly tetrahedral, and
an equation is needed to relate the external torsion angles
(therefore, the vicinal coupling constants) to the internal torsion
angles (therefore, the pseudorotational parameters P and φmax).
These two sets of angles are related as follows
a In Hz.
Conformational Analysis. The conformational parameters
of a nucleoside or another furanoside can be described using
two parameters, namely, the phase angle P and the degree of
maximum puckering φmax.
13 The value of P takes on an intuitive
φej xt ) Ajφj + Bj
meaning when it is represented on a pseudorotational wheel,
as shown in Figure 2.13
The vicinal proton-proton and proton-fluorine coupling
constants of the fully deprotected nucleoside 13 were examined
and compared with those of its 4′-oxygen congener 14 (Table
2). The Karplus equation predicts that a northern conformer of
for j ) 0, ..., 4. The definitions of the internal torsion angles
are shown in Figure 3. Because these parameters were unknown
for 2′-fluoroarabino or 2′-fluoro-4′-thioarabino configurations,
we obtained them from DFT calculations17 (Table 3).
A second set of parameters helps compensate for the
nonequilateral nature of the rings. These parameters, Rj and ꢀj,
named after Ernesto D´ıez, are used to modify the classical
pseudorotation equations.18 Thus, in place of the standard
pseudorotation equation
an arabino sugar will have large values of 3JH2′-H3′ and 3JH3′-H4′
,
whereas a southern conformer will have large values of 3JH1′-F2′
because the nuclei are nearly antiperiplanar in all of these cases.
3
Taken together, the changes in these J values showed that a
northern conformer was preponderant for the 4′-thionucleoside.
3
A large decrease of 7.5 Hz was observed in JF2′-H3′ upon
changing the ring heteroatom from oxygen to sulfur. One
obvious explanation for the large 3JF2′-H3′ in the 4′-oxo species
would be a contribution from an eastern conformer, in which
F-2′ and H-3′ are eclipsed. Indeed, this conformation has been
shown to exist in 2′F-ANA (4′-oxo) oligomers.14 This putative
φj ) φmax cos(P + 144°(j))
the equation is extended to yield
φj ) Rjφmax cos(P + ꢀj + 144°(j)).
eastern conformation would be less significant for the 4′-thio
3
species, according to the reduced value of JF2′-H3′
.
Including the Rj and ꢀj parameters in calculations involving 4′-
thionucleosides is particularly important because of their greater
Although this qualitative examination of vicinal 1H-1H and
1H-19F coupling constants is helpful to a certain extent, the
conclusions are approximate because of the rapid interconversion
of nucleoside conformers at room temperature. We turned,
therefore, to the use of the PSEUROT 6.3 program,15 which is
(15) van Wijk, J.; Haasnoot, C. A. G.; de Leeuw, F. A. A. M.; Huckriede,
B. D.; Hoekzema, A. W.; Altona, C. PSEUROT 6.3; Leiden Institute of
Chemistry, Leiden University: Leiden, The Netherlands, 1999.
(16) Hicks, N.; Howarth, O. W.; Hutchinson, D. W. Carbohydr. Res.
1991, 216, 1-9. Chong, Y.; Chu, C. K. Bioorg. Med. Chem. Lett. 2002,
12, 3459-3462. Sapse, A. M.; Snyder, G. Cancer InVest. 1985, 3, 115-
121.
(12) Lide, D. R., Ed. CRC Handbook of Chemistry and Physics, 71st
ed.; CRC Press: Boca Raton, FL, 1990.
(13) Altona, C.; Sundaralingam, M. J. Am. Chem. Soc. 1972, 94, 8205-
(17) Becke, A. D. J. Chem. Phys. 1986, 84, 4524-4529.
(18) de Leeuw, F. A. A. M.; Vankampen, P. N.; Altona, C.; Diez, E.;
Esteban, A. L. J. Mol. Struct. 1984, 125, 67-88. Diez, E.; Esteban, A. L.;
Bermejo, F. J.; Altona, C.; de Leeuw, F. A. A. M. J. Mol. Struct. 1984,
125, 49-65. Diez, E.; Esteban, A. L.; Guilleme, J.; Bermejo, F. L. J. Mol.
Struct. 1981, 70, 61-64.
8212.
(14) Berger, I.; Tereshko, V.; Ikeda, H.; Marquez, V. E.; Egli, M. Nucleic
Acids Res. 1998, 26, 2473-2480. Trempe, J. F.; Wilds, C. J.; Denisov, A.
Y.; Pon, R. T.; Damha, M. J.; Gehring, K. J. Am. Chem. Soc. 2001, 123,
4896-4903.
J. Org. Chem, Vol. 71, No. 3, 2006 923

Watts et al.
TABLE 4. Diez Parameters rj and Ej for 13 and 14
4′S-FMAU (13) FMAU (14)
is preponderant for 13, whereas 14 is dominated by a conformer
remarkably close to the southeast (Figure 2).
The reasons for this dramatic conformational change are
complex. The steric effects between the thymine base and the
sugar ring would be reduced for a 4′-thionucleoside with its
longer C-S bonds, thus favoring a north conformation in which
the base is pseudoaxial. O-C-C-X gauche effects are typically
of greater magnitude than S-C-C-X gauche effects,23 and
accordingly, we would expect greater σC3′H3′ f σ*C4′O4′ and
σC2′H2′ f σ*C1′O4′ interactions relative to the σC3′H3′ f σ*C4′S4′
and σC2′H2′ f σ*C1′S4′ overlap. One predicts, therefore, that the
gauche effects would also provide a strong driving force for
the south (or east) conformation in the case of the oxygen
congener. However, a greater anomeric effect in the case of
the oxygen congener23,24 would favor the north conformation.
It follows then that the observed conformational preferences
are dominated by steric and gauche effects.
It is of interest to note that whereas 4′S-FMAU (13) adopts
predominantly the north conformation, the 2′-deoxynucleoside,
that is, 4′-thiothymidine (4′S-dT), adopts a south conformation
in the solid state and a predominantly south conformation in
solution.19 However, in the latter case, evidence was presented
for the representation of the north conformation in the confor-
mational ensemble.19 The shift from a predominantly south
conformation in 4′S-dT to the north conformation in 13 must
be caused by the greater F2′ steric effect in the south conforma-
tion that outweighs the stabilization gained by the F2′-S4′ and
O3′-S4′ gauche effects in 4′S-FMAU.
Rj
ꢀja
Rj
ꢀja
φ1
φ2
φ3
φ4
φ0
1.030
0.955
0.952
1.032
1.035
-3.615
-0.355
0.435
3.478
-0.057
0.998
1.012
1.016
0.995
0.981
1.621
0.252
-0.223
-1.415
-0.229
a In degrees.
TABLE 5. Final Results from PSEUROT Calculations (Including
1H-19F Coupling Constants) for 4′S-FMAU (13) and FMAU (14)
rms error
of the fit (Hz)
a
a
nucleoside
PI (φmaxI
)
P
II (φmaxII
)
ratio
13
-4 (44)
-6 (36)
-35 (39)
199 (43)
126 (36)
116 (53)
77:23
31:69
37:63
0.000
0.595
0.000
14b
14c
a In degrees. b With φmax of both conformers constrained at 36. c With
no constraints on the minimization.
deviation from equilateral geometry.19 These parameters were
therefore obtained for both systems studied by least-squares
minimization using the DFT-calculated structures mentioned
above and the program FOURDIEZ20 (Table 4).
A generalized Karplus equation has been developed for 1H-
19F couplings and proved to be useful for this work.21 However,
because the 1H-19F coupling constant is not as well character-
ized as the H-1H coupling constant, our initial PSEUROT
1
calculations were carried out using only the three 1H-1H
coupling values. To identify all possible solutions, 2400
consecutive calculations were carried out with different initial
values of the five pseudorotational parameters, optimizing three
of them at a time. The results were sorted by their rms error,
and the best several hundred solutions were examined carefully.
Multiple possible solutions emerged (Supporting Information,
Table S1).
Evidence for an accentuated steric effect in arabinofuranosyl
nucleosides in the south conformation may be inferred by the
significant population of the north conformation in 4′-thio-
arabinoadenosine (4′S-araA).25 We propose that this unfavorable
interaction is derived from syn-axial interactions between the
CH2OH moiety at C-4′ and the substituent at C-2′. We note
that base-modified 2′F-arabinonucleosides with north as well
as southeast conformations have been reported by Seela and
co-workers.26
To differentiate between these possible solutions and to refine
1
the structures, the H-19F coupling information was included.
Conclusions
Each of the possible regions from the initial calculations was
taken in turn as the starting point for the calculations. Inclusion
of the fluorine couplings led to one set of pseudorotational
parameters for 4′-thionucleoside 13 being easily identified (Table
5). For 4′-oxo nucleoside 14, the solution of best fit cor-
responded to a very unlikely arrangement, with the two
conformers showing drastically different φmax values and the
second conformer being too highly puckered for an oxacyclic
nucleoside.22 Therefore, the calculations were also carried out
constraining the φmax of both conformers to 36°, a likely value
according to the computed structures. The phase angles and mole
fractions obtained from these two sets of calculations were
similar; both results are listed in Table 5.
Conformational analysis of 2′-deoxy-2′-fluoro-5-methyl-4′-
thioarabinouridine (4′S-FMAU) showed that it adopted north
(-6°) and south (199°) conformations with a 77% preference
for the north. This is in sharp contrast to the southeast (∼120°)
conformer that dominates the conformational equilibrium of its
4′-oxygen congener (∼65%). Arguments are presented to
suggest that the replacement of oxygen by the cognate sulfur
atom at the 4′ position leads to a decrease in the magnitudes of
C5′-base steric effects and various gauche effects and a
corresponding shift to a north conformation.
Experimental Section
Parametrization of PSEUROT for 2′-Fluoroarabino Con-
figurations. Aj and Bj parameters for these two systems were
obtained using a method similar to that of Houseknecht et al.27 All
Regardless of which of the two solutions best describes
nucleoside 14, it is clear that, as predicted by the qualitative
examination of coupling constants, a northern pseudorotamer
(23) Pinto, B. M.; Leung, R. Y. N. In The Anomeric Effect and Associated
Stereoelectronic Effects; Thatcher, G. R. J., Ed.; American Chemical
Society: Washington, DC, 1993; Vol. 539, pp 126-155.
(19) Koole, L. H.; Plavec, J.; Liu, H. Y.; Vincent, B. R.; Dyson, M. R.;
Coe, P. L.; Walker, R. T.; Hardy, G. W.; Rahim, S. G.; Chattopadhyaya, J.
J. Am. Chem. Soc. 1992, 114, 9936-9943.
(20) FOURDIEZ is a part of the PSEUROT 6.3 suite of programs.
(21) Thibaudeau, C.; Plavec, J.; Chattopadhyaya, J. J. Org. Chem. 1998,
63, 4967-4984. Thibaudeau, C.; Chattopadhyaya, J. Ph.D Thesis, Uppsala
University, 1999.
(22) The DFT calculations undertaken for the parametrization of
PSEUROT confirmed that the replacement of O4′ by S causes the value of
φmax to increase by 10-15°.
(24) Wolfe, S.; Pinto, B. M.; Varma, V.; Leung, R. Y. N. Can. J. Chem.
1990, 68, 1051-1062. Schleyer, P. V.; Jemmis, E. D.; Spitznagel, G. W.
J. Am. Chem. Soc. 1985, 107, 6393-6394.
(25) Wirsching, J.; Voss, J.; Adiwidjaja, G.; Balzarini, J.; De Clercq, E.
D. Bioorg. Med. Chem. Lett. 2001, 11, 1049-1051.
(26) He, J.; Mikhailopulo, I. A.; Seela, F. J. Org. Chem. 2003, 68, 5519-
5524. He, J.; Eickmeier, H.; Seela, F. Acta Crystallogr., Sect. C 2003, 59,
o406-o408. Peng, X.; Seela, F. Org. Biomol. Chem. 2004, 2, 2838-2846.
924 J. Org. Chem., Vol. 71, No. 3, 2006

Synthesis and Conformational Analysis of 4′S-FMAU
DFT calculations were carried out on a PC using the Gaussian 03W
program.28 All optimizations were carried out in the gas phase.
For FMAU nucleoside 14, a series of 32 envelope structures was
optimized at the B3LYP/6-31G** level. In each case, one of the
torsion angles φ0-φ4 was constrained to zero to span the full range
of P accessible to nucleosides. The starting value of the glycosidic
torsion angle Ì (C2-N1-C1′-O4′) was also constrained to various
values, covering the full range of conformational space.
For 4′S-FMAU nucleoside 13, a series of 12 envelopes spanning
the pseudorotational space was minimized at the B3LYP/3-21G**
level. Starting structures were set to a φmax value of 35°. The value
of the glycosidic torsion angle Ì (C2-N1-C1′-S4′) was initially
set to 220° in all cases because this value is in the middle of the
anti range, where the minimum conformation of thymidine nucleo-
sides is expected, especially given the presence of the 2′-fluoro
substituent. The O5′ was set anti to C3′, and OH3′ and OH5′ were
set anti to C4′. Optimizations were carried out constraining only
one torsion angle φ0-φ4 to zero.
For the PSEUROT input files, all parameters were calculated as
described above except for the empirical group electronegativities,
which were obtained from the literature.29 The initial studies of
2400 different starting values were accomplished using PSEUROT’s
MANY function that allows the automation of this repetitive task.
In all 19F calculations, the 1H-19F coupling was given a
weighting of 0.2 to compensate for the inherently larger value of
its coupling constant and to give it slightly less weight because the
parametrization of the corresponding generalized Karplus equation
is less reliable. The FCC and HCC angles along the path of the
coupling were chosen according to the method of Mikhailopulo et
al.30
The initial calculations were executed both with and without the
Diez extension of the pseudorotation equations. For both molecules,
the results obtained with and without the Diez parameters were
similar; however, the rms error tended to be slightly lower for
calculations involving 13 and 14, where the Diez parameters were
included and excluded, respectively. Therefore, for the final
calculations, the Diez extension was used only for 4′S-FMAU
nucleoside 13.
The internal and external torsion angles were graphed (Supporting
Information, Figures S1-10) with linear plots having a slope of Aj
and a y intercept of Bj. The resulting Aj and Bj parameters are given
in Table 3.
Acknowledgment. We are grateful to the Natural Sciences
and Engineering Research Council of Canada (NSERC) and the
Canadian Institutes for Health Research for financial support
in the form of grants (to B.M.P. and M.J.D., respectively).
J.K.W. is grateful to NSERC and the Tomlinson Foundation
for postgraduate fellowships. M.J.D. is the recipient of a James
McGill professorship. We thank Professor C. Altona for his help
with the PSEUROT program and M.M. Mangos for critically
reading the manuscript.
PSEUROT Calculations. Proton spectra were zero filled to 128
K and resolution-enhanced with Gaussian or sinebell functions. The
vicinal coupling constants were then extracted directly. For the
FANA species, the spectra were measured at various temperatures,
but only minute changes in the coupling constants were observed
up to 40°C.
(27) Houseknecht, J. B.; Altona, C.; Hadad, C. M.; Lowary, T. L. J.
Org. Chem. 2002, 67, 4647-4651.
(28) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
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Supporting Information Available: Experimental synthetic
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graphs used to obtain Aj and Bj, and solutions from the first set of
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via the Internet at http://pubs.acs.org.
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