Synthesis of 3′-arylsulfonyl-4′-[(diethoxyphosphoryl)difluoromethyl]thymidine analogs

Article abstract of DOI:10.1055/s-1998-4501

D- and L-Diethoxyphosphoryldifluoromethyl nucleoside analogs 8, bearing a sulfonylic moiety at C-3′ were synthesized following the building block approach to chiral fluorinated molecules. The condensation of ethyl 2-(diethoxyphosphoryl)2,2-difluoroacetate (2) and 4-(4-methylphenylsulfinyl)but-l-ene (3) followed by reduction of the thus formed ketones 4 to alcohols 5 and oxidative cyclization to the furanose derivatives 6 were the key steps of the synthetic sequence.

Full text of DOI:10.1055/s-1998-4501

SYNTHESIS
October 1998
1511
Synthesis of 3'-Arylsulfonyl-4'-[(diethoxyphosphoryl)difluoromethyl]thymidine
Analogs
Alberto Arnone,a Pierfrancesco Bravo,*b Massimo Frigerio,b Fiorenza Viani,a Carmela Zappalàb
a C.N.R. – Centro di Studio sulle Sostanze Organiche Naturali, via Mancinelli 7, I-20131 Milano, Italy
b Dipartimento di Chimica del Politecnico di Milano, via Mancinelli 7, I-20131 Milano, Italy
E-mail: bravo@dept.chem.polimi.it
Received 1 January 1998; revised 6 March 1998
Abstract: D- and L-Diethoxyphosphoryldifluoromethyl nucleo-
side analogs 8, bearing a sulfonylic moiety at C-3' were synthe-
sized following the building block approach to chiral fluorinated
molecules. The condensation of ethyl 2-(diethoxyphosphoryl)-
2,2-difluoroacetate (2) and 4-(4-methylphenylsulfinyl)but-1-ene
(3) followed by reduction of the thus formed ketones 4 to alcohols
5 and oxidative cyclization to the furanose derivatives 6 were the
key steps of the synthetic sequence.
Key words: fluorinated nucleosides, 4'-[(diethoxyphosphoryl)di-
fluoromethyl]thymidines, (difluoromethyl)phosphonates, antivi-
ral agents, lactol formation
The concept of using phosphonate isosters as stable phos-
phate mimics in biological systems has been employed
extensively.1 Fluoro substitution on the α-carbon of phos-
phonates enhances their utilization because fluorine may
increase the effectiveness of the phosphonate mimicry on
geometric and electronic grounds.2 The replacement of
fluorophosphonates for phosphates has provided a num-
ber of analogs with significant biological activity.3 A
number of fluoromethylphosphonate isosters of nucle-
otides has been prepared and tested as antiviral agents.4
Scheme 1
As a part of our program devoted to explore the utility of
the 4-methylphenylsulfinyl chiral auxiliary group for the
synthesis of new fluoro-substituted nucleoside analogs,
we have recently reported the synthesis of an enantiomer-
ically pure 3'-arylsulfonylthymidine phosphonate analog
bearing a fluoromethyl group at C-4'.5 Further develop-
ment of this approach focused on the synthesis of α,α-
difluoromethylphosphonate derivatives. The key interme-
diate, 6-(diethoxyphosphoryl)-6,6-difluoro-5-hydroxy-4-
(4-methylphenylsulfinyl)hex-1-ene, was obtained by acyl-
ation of the α-lithium salt of but-3-enyl 4-methylphenyl
sulfoxide by the diethoxyphosphoryldifluoromethyl
group of ethyl 2-(diethoxyphosphoryl)-2,2-difluoroacet-
ate.6 A reaction sequence, already utilized for the con-
struction of fluoro-substituted nucleoside analogs,7 has
been used to transform the thus obtained 5-oxo difluoro-
methylphosphonate intermediates into the final diethoxy-
phosphoryldifluoromethyl thymidine analogs, as summa-
rized in the retrosynthesis given in Scheme 1.
Scheme 2
phoryl)-2,2-difluoroacetate (2) was the crucial step of all
the sequence (Scheme 2).
The lithium derivative was obtained in THF at –60°C by
LDA and the acylation was accomplished at –70°C in the
same solvent. The thus obtained mixture of diastereomer-
ic ketones 4 was quite unstable, both in solution and as
isolated compounds. Rapid workup afforded a crude mix-
ture which was employed without further purification, by
rapid treatment of its solution (THF) with diisobutylalu-
minum hydride at –60°C, or with sodium borohydride at
–10°C to obtain the secondary alcohols 5 in 85% and 83%
overall yields, respectively. The four diastereomers 5
were obtained in different relative ratios depending on the
experimental conditions. They were isolated, after repeat-
ed flash chromatographic purification, as enantiomerical-
ly and diastereomerically pure compounds (de 95% by 19F
NMR analyses).
A small-scale laboratory synthesis of ethyl 2-(diethoxy-
phosphoryl)-2,2-difluoroacetate (2) was set up: fluorin-
ation of the lithium derivative of commercially available
ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (1) with a
•
moderate excess of F-TEDA BF4 gave the corresponding
difluoro derivative 2 in good chemical yields.
The acylation of the lithium derivative of 4-(4-methyl-
phenylsulfinyl)but-1-ene (3) by ethyl 2-(diethoxyphos-

SYNTHESIS
Papers
1512
The terminal C=C bond of (4S,5R,RS)-5 (Scheme 3) then In contrast, the corresponding secondary alcohols 5, hav-
underwent oxidative cleavage by sodium periodate/ruthe- ing a 4,5-anti relationship between the same groups, were
nium trichloride in a two-phase system (CCl4/CH3CN/ fairly sensitive to the oxidative conditions. In fact, the
H2O 1:1:2). The ring-closure reaction of the intermediate compound (4S,5S,RS)-5 when submitted to the oxidative
aldehyde on to the secondary hydroxy group and the oxi- cleavage in the same conditions gave only moderate
dation side reaction of the sulfinylic into sulfonylic moi- yields (12%) of the γ-lactone (4S,5S)-9 which showed the
ety spontaneously followed and the lactol 6 was obtained sulfonylic and phosphonylic appendages 4,5-cis disposed.
and detected in chloroform by 1H and 19F NMR analyses The lactol 6 or any other product could not be isolated or
as a 2.5:1.0 mixture of β(1R) and α(1S) anomers.8 The detected by NMR analysis of the crude reaction mixture
corresponding γ-lactone, (4S,5R)-9, which was formed in (Scheme 4).
very low yields (7%) under these conditions, was isolated
and converted back to the anomeric lactol mixture 6 by
reduction with DIBAH in toluene (Scheme 3).
The acetylation of 6 with acetic anhydride in pyridine
gave a 3:1 epimeric mixture of, respectively, β(1S)- and
α(1R)-acetyl derivatives 7. The reaction with persilylated
thymine in dichloromethane at 40°C for 1 hour, in the
presence of trimethylsilyl triflate as catalyst, afforded the
corresponding 4'-[(diethoxyphosphoryl)difluoromethyl]-
Scheme 4
3'-(4-methylphenylsulfonyl)thymidine analogs as a ca.
1:1 epimeric mixture of (1'R/S,3'S,4'R)-8 in 80% overall
yield. The same synthetic sequence when applied to
(4R,5S,RS)-5 afforded in comparable overall chemical
yields the (phosphoryldifluoromethyl)thymidine deriva-
tives (1'R/S,3'R,4'S)-8, corresponding to the L-series of the
nucleoside analogs.
As a consequence of the sensitivity to oxidation of the 4,5-
anti diastereomers 5, enantiomerically pure nucleoside
analogs (1'R,3'S,4'R)- and (1'S,3'S,4'R)-8 could be ob-
tained directly starting from a 4S/R (syn/anti) epimeric
mixture of the corresponding secondary alcohols 5. Spe-
cifically, when reacting a mixture of (4S,5R,RS)- and
(4R,5R,RS)-5, only the (1R/S,3S,4R)-6 lactols derived
from the syn compound were isolated.
Both the reactive hydroxy sulfinyl intermediates
(4S,5R,RS)- and (4R,5S,RS)-5 were successfully utilized as
described and shown to have a 4,5-syn relationship be-
tween the propenylic chain and the hydroxy moiety. This
relative disposition of the two groups resulted in lactols 6
having the 4-methylphenylsulfonyl and the diethoxyphos-
phoryldifluoromethyl functionalities 3,4-trans disposed.
The structures of compounds 4–9 were assigned with the
aid of 1H, 13C, 19F, and 31P NMR studies (Tables 1, 2 and
experimental section). The absolute stereochemistry at C-
5 of three of the four sulfenylic secondary alcohols 10 was
assigned by comparing the chemical shift values of the
Scheme 3

SYNTHESIS
October 1998
1513
Table 1. NMR Data for Compounds 4, 5 and 13
Compounda
1H NMR (CDCl3/TMS)
19F NMR (CDCl3/C6F6)
31P NMR (CDCl3/H3PO4)
δ, J (Hz)
δ, J (Hz)
δ, J (Hz)
(4R/S,RS)-4
1.37 (6H, m, 2 × OCH2CH3), 2.42 (3H, brs, ArMe), 2.2– –120.98, –118.74, –120.56, –118.91 3.5–4.0 (1P, m, P-6)
2.6 (2H, m, H2-3), 4.1–4.4 (5H, m, H-4 and 2 × (2F, dd, J = 318, 95.0, F2-6)
OCH2CH3), 5.0–5.2 (2H, m, H2-1), 5.5–5.9 (1H, m, H-2),
7.2–7.6 (4H, m, ArH)
(4S,5S,RS)-5
1.38 and 1.40 (6H, brt, J = 7.2, 2 × OCH2CH3), 2.19 (1H, –122.35 (1F, brddd, J = 303.8, 99.5, 6.56 (1P, brdd, J = 99.5,
brddd, J = 15.0, 5.5, 4.5, H-3a), 2.42 (3H, brs, ArMe), 21.3 Fa), –116.06 (1F, brddd, J = 99.1, P)
2.58 (1H, brddd, J = 15.0, 9.0, 8.0, H-3b), 3.09 (1H, ddd, 303.8, 99.1, 8.8 Fb)
J = 9.0, 4.5, 3.5, H-4), 4.33 and 4.34 (4H, m, 2 ×
OCH2CH3), 4.46 (1H, m, H-5), 5.05 and 5.06 (2H, m, H2-
1), 5.29 (1H, d, J = 6.6, OH), 5.52 (1H, m, H-2), 7.35 and
7.52 (4H, m, ArH)
(4S,5R,RS)-5
(4R,5S,RS)-5
(4R,5R,RS)-5
1.38 (6H, brt, J = 7.2, 2 × OCH2CH3), 2.3–2.8 (2H, m, H2- –125.74 (1F, brddd, J = 303.0, 7.31 (1P, brdd, J = 102.6,
3), 2.43 (3H, brs, ArMe), 3.21 (1H, m, H-4), 4.2–4.4 (4H, 102.6, 23.2, Fa), –115.79 (1F, brddd, 97.5, P)
m, 2 × OCH2CH3), 4.75 (1H, m, H-5), 4.97 and 4.98 (2H, J = 303.0, 97.5, 5.7, Fb)
m, H2-1), 5.68 (1H, m, H-2), 7.33 and 7.54 (4H, m, ArH)
1.35 (6H, brt, J = 7.2, 2 × OCH2CH3), 2.43 (3H, brs, –124.67 (1F, brddd, J = 303.9, 6.25 (1P, brdd, J = 101.6,
ArMe), 2.7–3.1 (3H, m, H2-3 and H-4), 4.2–4.4 (4H, m, 2 101.6, 22.4, Fa), –118.04 (1F, brddd, 99.3, P)
× OCH2CH3), 4.60 (1H, m, H-5), 5.22 and 5.27 (2H, m, J = 303.9, 99.3, 7.5, Fb)
H2-1), 5.95 (1H, m, H-2), 7.36 and 7.50 (4H, m, ArH)
1.37 (6H, brt, J = 7.2, 2 × OCH2CH3), 2.21 and 2.63 (2H, –125.07 (1F, brddd, J = 304.7, 6.74 (1P, brdd, J = 102.2,
m, H2-3), 2.42 (3H, brs, ArMe), 3.37 (1H, dt, J = 7.8, 5.5, 102.2, 21.8, Fa), –112.41 (1F, brddd, 97.5, P)
H-4), 4.2 and 4.4 (4H, m, 2 × OCH2CH3), 4.63 (1H, m, H- J = 304.7, 97.5, 5.2, Fb)
5), 5.08 and 5.13 (2H, m, H2-1), 5.71 (1H, m, H-2), 7.34
and 7.63 (4H, m, ArH)
(E,RS)-13
1.37 and 1.38 (6H, brt, J = 7.1, 2 × Me), 3.62 (1H, br, –124.66 (1F, brddd, J = 305.8, 7.30 (1P, brdd, J = 103.0,
OH), 4.2–4.4 (4H, m, 2 × OCH2), 4.56 (1H, m, H-5), 5.19 103.0, 16.7, F-6a), –117.04 (1F, 102.1, P-6)
and 5.31 (2H, brd, J = 9.9, 16.1, H2-1), 5.78 (1H, brdd, J brddd, J = 305.8, 102.1, 7.9, F-6b)
= 14.6, 6.2, H-4), 6.39 (1H, brddd, J = 16.1, 10.7, 9.9, H-
2), 6.47 (1H, brdd, J = 14.6 and 10.7, H-3)
a Satisfactory microanalyses obtained: C, H ± 0.4.
protons of the butenyl fragments of the esters 12 obtained
through reaction with (–)-(R)- and (+)-(S)-2-phenylpropi-
onic acids (11)9 as shown on Scheme 5 for the diastereo-
meric esters (1S,2S,2'R)- and (1S,2S,2'S)-12. For example,
the above mentioned protons of (1S,2S,2'R)-12 resonated
at higher fields than the corresponding protons of
(1S,2S,2'S)-12 as a consequence of the shielding effect ex-
erted by the phenyl ring of the 1-phenylacetate group. The
absolute stereochemistry at C-5 of the secondary alcohols
5 directly followed from that exhibited by 10 as during
deoxygenation at sulfur, with sodium iodide and trifluoro-
acetic anhydride in acetone10 the C-5 stereocenter was not
affected. The structures of compounds 10 and 12 were as-
signed with the aid of 1H, 19F, and 31P NMR studies (Ta-
bles 2 and 3).
Finally, the absolute configurations of the remaining car-
bon stereocenters of the cyclic compounds 6–9 (C-1 and
Scheme 5

SYNTHESIS
Papers
Table 2. NMR Data for Compounds 6–10
1514
Compounda
1H NMR (CDCl3/TMS)
19F NMR (CDCl3/C6F6)
31P NMR
δ, J (Hz)
δ, J (Hz)
(CDCl3/H3PO4)
δ, J (Hz)
(1S/3S,4R)-6
1.35 and 1.37 (6H, brt, J = 7.1, 2 × OCH2CH3), 2.48 (3H, brs, ArMe), 2.48 –118.54 (1F, brddd, J = 4.76 (1P, dddt, J =
(1H, ddd, J = 15.3, 2.5, 2.0, H-2α), 2.65 (1H, ddd, J = 15.3, 10.0, 5.5, H- 309.0, 97.8, 10.2, F-5a), 97.8, 97.6, 6.3 and
2β), 4.1–4.4 (5H, m, 2 × OCH2CH3 and H-3), 4.83 (1H, d, J = 12.5, OH- –124.44 (1F, brddd, J = 5.8, P-5)
1), 4.94 (1H, dddd, J = 14.7, 10.2, 5.8, 3.0, H-4), 5.62 (1H, ddd, J = 12.5, 309.0, 97.6, 14.7, F-5b)
5.5, 2.0, H-1), 7.80 and 7.84 (4H, m, ArH)
(1R,3S,4R)-6
(1S,3S,4R)-7
(1R,3S,4R)-7
(1'R,3'S,4'R)-8
1.36 and 1.38 (6H, brt, J = 7.1, 2 × OCH2CH3), 2.22 (1H, ddd, J = 14.2, –114.29 (1F, brddd, J = 5.97 (1P, dddt, J =
9.0, 3.5, H-2β), 2.47 (3H, brs, ArMe), 2.67 (1H, m, H-2α), 4.1 and 4.4 306.5, 96.2, 10.6, F-5a), 103.3, 96.2, 6.3
(5H, m, 2 × OCH2CH3 and H-3), 4.62 (1H, d, J = 11.0, OH-1), 4.80 (1H, –121.08, – 121.11 (1F, and 5.5, P-5)
dddd, J = 16.0, 10.6, 5.5, 4.0, H-4), 5.62 (1H, ddd, J = 11.0, 10.0, 3.5, H- brddd, J = 306.5, 103.3,
1), 7.39 and 7.80 (4H, m, ArH)
16.0, F-5b, 1:2 ratio)
0.96 and 1.00 (6H, brt, J = 7.1, 2 × OCH2CH3), 1.68 (3H, s, OCOCH3), –118.52 (1F, dddd, J = 5.49 (1P, m, P-5)
1.79 (3H, brs, ArMe), 2.05 (1H, ddd, J = 14.2, 9.0, 2.6, H-2β), 2.68 (1H, 307.0, 96.0, 7.2, 2.1, F-
ddd, J = 14.2, 6.4, 5.8, H-2α), 3.9–4.2 (4H, m, 2 × OCH2CH3), 4.39 (1H, 5a), –124.66 (1F, ddd, J
ddd, J = 9.0, 6.4, 4.4, H-3), 5.33 (1H, brddd, J = 20.2, 7.2, 4.4, H-4), 6.36 = 307.0, 96.0, 20.2, F-
(1H, ddd, J = 5.8, 2.6, 2.1, H-1), 6.69 and 7.67 (4H, m, ArH)b
5b)b
0.92 and 0.96 (6H, brt, J = 7.1, 2 × OCH2CH3), 1.68 (3H, s, OCOCH3), –116.16 (1F, ddd, J = 4.53 (1P, m, P-5)
1.77 (3H, brs, ArMe), 2.44 (1H, ddd, J = 15.1, 11.2, 5.7, H-2β), 2.74 (1H, 309.0, 96.5, 8.4, F-5a),
ddd, J = 15.1, 3.0, 1.3, H-2α), 3.9–4.2 (4H, m, 2 × OCH2CH3), 4.34 (1H, –123.02 (1F, ddd, J =
ddd J = 11.2, 4.3, 3.0, H-3), 5.47 (1H, dddd, J = 13.5, 9.5, 8.4, 4.3, H-4), 309.0, 96.5, 13.5, F-5b)b
6.38 (1H, dd, J = 5.7, 1.3, H-1), 6.66 and 7.71 (4H, m, ArH)b
1.36 (6H, t, J = 7.1, 2 × OCH2CH3), 1.99 (3H, d, J = 1.3, CH3-5), 2.21 (1H,
–118.20 (1F, ddd, J = 4.44 (1P, brdd, J =
ddd, J = 14.8, 9.7, 9.3, H-2'β), 2.49 (3H, brs, ArMe), 2.83 (1H, ddd, J = 309.5) 97.5, 10.2, F-5'a), 97.5, 97.0, P-5')
14.8, 5.6, 1.0, H-2'α), 4.2–4.4 (4H, m, 2 × OCH2CH3), 4.36 (1H, ddd, J = –123.27 (1F, ddd, J =
9.7, 2.8, 1.0, H-3'β), 4.95 (1H, dddd, J = 14.4, 10.2, 4.5, 2.8, H-4'), 6.37 309.5, 97.0, 4.4, F-5'b)
(1H, brdd, J = 9.3, 5.6, H-1'), 7.43 and 7.84 (4H, m, ArH), 7.86 (1H, q, J
= 1.3, ArH), 9.70 (1H, br, NH)b
(1'S,3'S,4'R)-8
1.38 (6H, t, J = 7.1, 2 × OCH2CH3), 1.93 (3H, d, J = 1.3, CH3-5), 2.48 (3H, –119.00 (1F, brddd, J = 4.44 (1P, brddd, J
brs, ArMe), 2.49 (1H, ddd, J = 15.0, 6.3, 5.3, H-2'α), 2.87 (1H, ddd, J = 310.5, 97.5, 8.4, F-5'a), = 97.5, 95.5, P-5')
15.0, 10.5, 7.4, H-2'β), 4.2–4.4 (4H, m, 2 × OCH2CH3), 4.35 (1H, ddd, J –123.85 (1F, brddd, J =
= 10.5, 5.3, 2.6, H-3'), 5.10 (1H, dddd, J = 19.5, 8.4, 3.7, 2.6, H-4'), 6.56 310.5, 95.5, 19.5, F-5'b)
(1H, brdd, J = 7.4, 6.3, H-1'), 7.43 and 7.82 (4H, m, ArH), 7.68 (1H, q, J
= 1.3), 9.76 (1H, br, NH)
(4S,5R)-9
(4S,5S)-9
(4S,5R)-10
(4R,5R)-10
1.34 (6H, brt, J = 7.2, 2 × OCH2CH3), 2.50 (3H, brs, ArMe), 2.94 (1H, –120.31 (1F, ddd, J = 4.28 (1P, brdd, J =
ddt, J = 19.3, 2.7, 1.2, H-3α), 3.20 (1H, brdd, J = 19.3, 10.1, H-3β), 4.1– 313.3, 96.2, 11.3, Fa),
4.4 (4H, m, 2 × OCH2CH3), 4.61 (1H, ddd, J = 10.1, 2.7, 2.0, H-4), 5.24 –123.80 (1F, ddd, J =
96.2, 92.5, P-6)
(1H, dddd, J = 13.0, 12.0, 3.9, 2.0, H-5), 7.58 and 7.94 (4H, m, ArH)c
313.3, 92.5, 12.3, Fb)
1.40 and 1.38 (6H, brt, J = 7.2, 2 × OCH2CH3), 2.47 (3H, brs, ArMe), 2.53 –115.78 (1F, brdd, J = 4.22 (1P, brdd, J =
(1H, ddd, J = 17.4, 8.6, 1.2, H-3β), 3.23 (1H, ddd, J = 17.4, 11.8, 3.4, H- 313.0, 96.5, Fa), –125.55 96.5, 92.5, P-6)
3α), 4.30 (1H, m, H-4), 4.4–4.2 (4H, m, 2 × OCH2CH3), 5.25 (1H, dd, J (1F, brddd, J = 313.0,
= 26.5, 7.2, H-5), 7.40 and 7.83 (4H, m, ArH)
92.5, 26.5, Fb)
1.32 (6H, m, 2 × OCH2CH3), 2.32 (3H, brs, ArMe), 2.40 and 2.75 (2H, m,
–118.10 (1F, brddd, J = 6.75 (1P, brdd, J =
H2-3), 3.12 (1H, d, J = 6, OH), 3.55 (1H, m, H-4), 4.2–4.4 (5H, m, 2 × 305.5, 99.6, F-6a),
OCH2CH3 and H-5), 5.12 and 5.20 (2H, m, H2-1), 6.02 (1H, m, H-2), 7.12 124.05 (1F, brddd, J =
and 7.35 (4H, m, ArH) 305.5, 105, 23.5, F-6b)
–
105, 99, P-6)
1.38 (6H, m, 2 × OCH2CH3), 2.33 (3H, brs, ArMe), 2.35 and 2.56 (2H, m, –114.52 (1F, brddd, J =
6.97 (1P, brdd, J =
H2-3), 3.49 (1H, m, H-4), 3.54 (1H, d, J = 5.5, OH), 4.03 (1H, m, H-5), 306.5, 100, 5.5, F-6a), 104.5, 100, P-6)
4.2–4.4 (4H, m, 2 × OCH2CH3), 5.13 and 5.15 (2H, m, H2-1), 5.90 (1H, –125.70 (1F, brddd, J =
m, H-2), 7.14 and 7.39 (4H, m, ArH)
306.5, 104.5, 22.5, F-
6b)
a Satisfactory microanalyses obtained: C, H ± 0.4.
b Recorded in C6D6.
c Recorded in acetone-d6.

SYNTHESIS
October 1998
1515
Table 3.1H NMR Data of Compounds 12
Compounda
1H NMR (CDCl3/TMS)
δ, J (Hz)
(4R,2S,2'R)-12
1.21 and 1.26 (6H, t, J = 7.0, 2 × OCH2CH3), 1.58 (3H, d, J = 7.2, Me-2'), 1.80 and 2.57 (2H, m, H2-3), 2.31 (3H, brs,
ArMe), 3.57 (1H, m, H-2), 3.87 (1H, 9, J = 7.2, H-2'), 3.9–4.3 (4H, m, 2 × OCH2CH3), 4.97 and 5.02 (2H, m, H2-5), 5.48
(1H, m, H-1), 5.83 (1H, m, H-4), and 7.0–7.5 (9H, m, ArH)
(1R,2R,2'R)-12
(1S,2S,2'R)-12
(1S,2S,2'S)-12
1.36 (6H, brt, J = 7.1, 2 × OCH2CH3), 1.56 (3H, d, J = 7.2, Me-2'), 2.11 and 2.21 (2H, m, H2-3), 2.32 (3H, brs, ArMe), 3.51
(1H, m, H-2), 3.83 (1H, q, J = 7.2, H-2'), 4.2–4.4 (4H, m, 2 × OCH2CH3), 4.93 and 5.00 (2H, m, H2-5), 5.58 (1H, m, H-1),
5.63 (1H, m, H-4), and 7.0–7.5 (9H, m, ArH)
1.26 and 1.29 (6H, t, J = 7.2, 2 × OCH2CH3), 1.56 (3H, d, J = 7.2, Me-2'), 2.32 (3H, brs, ArMe), 2.36 (2H, m, H2-3), 3.67
(1H, m, H-2), 3.77 (1H, q, J = 7.2, H-2'), 4.0–4.2 (4H, m, 2 × OCH2CH3), 5.06 and 5.08 (2H, m, H2-5), 5.58 (1H, m, H-1),
5.78 (1H, m, H-4), and 7.0–7.5 (9H, m, ArH)
1.16 and 1.20 (6H, t, J = 7.0, 2 × OCH2CH3), 1.63 (3H, d, J = 7.1, Me-2'), 2.17 and 2.75 (2H, m, H2-3), 2.32 (3H, brs,
ArMe), 3.67 (1H, m, H-2), 3.90 (1H, q, J = 7.1, H-2'), 4.0–4.3 (4H, m, 2 × OCH2CH3), 5.12 and 5.14 (2H, m, H2-5), 5.49
(1H, m, H-1), 5.97 (1H, m, H-4), and 7.0–7.5 (9H, m, ArH)
a Satisfactory microanalyses obtained: C, H ± 0.4.
C-3 for 6 and 7; C-4 for 9; C-3' for 8) followed from NOE and 170.28 in the 13C NMR spectra of (3S,4R)- and
1
experiments and from the magnitude of H–1H coupling (3S,4S)-9, attributable to lactone carbonyl carbons, gave
constants of the ring protons. Specifically, in the α-ano- conclusive evidence for the assignment of their structures.
mer (1S,3S,4R)-6, the small values observed for the 3J be-
The elimination of the sulfonyl substituent from nucleo-
tween H-4, assumed as α in the formula, and H-3β, H-3β
side analogs 8 to obtain the corresponding sulfur-free
and H-2α, and H-2α and H-1β (3J = 3.0, 2.5 and 1.2 Hz,
compounds could not be achieved. Finally, syn elimina-
respectively) indicated a trans pseudoequatorial relation-
tion of the sulfinyl residue from alcohols 5 occurred under
ships. As a consequence, the hydroxy and the 4-meth-
mild conditions and gave selectively the corresponding
ylphenylsulfonyl groups were both trans oriented with re-
(E)-6-(diethoxyphosphoryl)-6,6-difluoro-2-hydroxyhexa-
spect to the diethoxyphosphoryldifluoromethyl moiety. It
1,3-diene (13). The structure of compound 13 was as-
must be noted that in the β-anomer (1R,3S,4R)-6, in which
signed with the aid of 1H, 19F, and 31P NMR studies (Table
the hydroxy and the diethoxyphosphoryldifluoromethyl
1).
groups were cis disposed, the fluorine atom resonating at
δ = ca. 121 showed in its 19F NMR spectrum two signals
in a 1:2 ratio exhibiting the same pattern. This fact might
be attributed to the presence of intramolecular hydrogen
bonding between the fluorine atom and the hydroxy pro-
ton,11 this latter partially deuterated by the D2O contained
in the solvent, which gave rise to an isotope effect of 28.3
× 10–3 ppm. Similar effects have been observed in the 1H
In conclusion, difluoromethylphosphonate nor-analogs of
thymidine nucleotide were obtained by assembling the di-
ethoxyphosphoryldifluoromethyl framework of the pyra-
nose moiety through condensation of ethyl 2-(dieth-
ylphosphoryl)-2,2-difluoroacetate (2) and 4-(4-meth-
ylphenylsulfinyl)but-1-ene (3) followed by quick re-
duction of the carbonyl of the intermediate labile ketones
4 to secondary alcohols 5. Their subsequent oxidation and
cyclization was feasible only for the syn compounds. The
nucleoside analogs 8 belonging to the D-series were ob-
tained from the (5R)-5 epimers; the same analogs 8, be-
longing to the series, were obtained from the (5S)-5 ke-
tones.
NMR spectra of sugar derivatives as a consequence of the
formation of intramolecular hydrogen bonding between
partially deuterated hydroxy groups under slow-exchange
conditions.12
The NOE observed between H-1 and H-4 (1%) in the ac-
etate (1S,3S,4R)-7 implied that these protons were on the
same side of the molecule; accordingly, in the epimer
(1R,3S,4R)-7, which, on the other hand, exhibited 1H–1H
coupling constants similar to those observed for the corre-
sponding lactol (1S,3S,4R)-6, a sizeable NOE was ob-
served between H-1 and the fluorine at δ = –116.16 (1%).
The mutual NOE enhancements observed between H-4'
and H-6 (1 and 2%) in (1'S,3'S,4'R)-8 and between H-4'
and H-1' (2 and 2.5%) in (1'R,3'S,4'R)-8, in conjunction
with the NOEs observed between F2-5' and H-1' (3.5%) in
the former compound and between F2-5' and H-6 (2.5%)
in the latter, established the stereochemistry of the title
compounds, while the presence of signals at δ = 171.52
[α]D Values were obtained on a JASCO DIP-181 and PROPOL pola-
rimeters. TLC was performed on silica gel 60 F254 Merck; flash col-
umn chromatography was performed with silica gel 60 (60–200 µm,
Merck). 1H, 13C, 19F and 31P NMR spectra were run at r.t. on a Bruker
AC 250L spectrometer operating at 250 MHz in CDCl3 and equipped
with a supplementary Broadband Modulator BM1. Chemical shifts

SYNTHESIS
Papers
1516
were expressed in ppm (δ), using TMS as internal standard for 1H and
13C nuclei (δH and δC = 0.00), while C6F6 was used as internal stan-
dard (δF = –162.90) for 19F and H3PO4 (δP = 0) for 31P nucleus. MS
were recorded on a TSQ 70 Finnigan Mat three-stage quadrupole in-
strument. A DIS (Direct Inlet System) was used for pure compounds.
HPLC analyses were performed on Waters 600E System Controller
instrument using a Lambda-Max Model 481 LC spectrophotometer
operating at 260 nm. Analytical data were elaborated by a Waters 745
Data Module instrument; analyses were performed on Hibar Pre-
Packed column RT 250–4 (Li Chrosorb Si 60–5 µm, Merck). Com-
bustion microanalyses were performed by Redox SNC, Cologno
Monzese (Milano). THF was freshly distilled from Na, i-Pr2NH was
freshly distilled from CaH2; in all other cases, commercially available
reagent-grade solvents were employed without purification. In 13C
NMR analyses of spectra, capital letters referred to the pattern result-
ing from one bond (C,H) coupling constants and small letters referred
to (C,F) and (C,P) coupling constants.
65.03 (Td, JC,P = 6.5 Hz, 2 × OCH2CH3), 70.83 (Dddd, JC,F = 25.5 and
21.5, JC,P = 15.5 Hz, C-5), 118.99 (T, C-1), 124.51 (D), 129.90 (D),
137.58 (S) and 141.40 (S) (ArC) and 133.63 (D, C-2).
MS (EI): m/z (%) = 411 ([M + H]+·, 70), 392 ([M + H – F]+·, 4), 271
([C10H17PO4F2]+·, 100), 253 ([271
–
H2O]+·, 68), 215
([C6H10PO4F2]+·, 100), 205 ([C12H13SO]+·, 30), 177 ([C11H13S]+·, 45),
139 ([C7H7SO]+·, 48), 136([215 – H3PO3]·, 17), 91 ([C7H8]+·, 38),
81([H2PO3]+·, 17).
HPLC: tR = 12.0 min (cyclohexane/EtOAc 4:96; µ = 1.2 mL/min; λ =
260 nm).
(4R,5R,RS)-5: yield: 502 mg (19%); Rf 0.35 (hexane/EtOAc 3:7);
[α]D20 +36.1 (c = 0.6, CHCl3); diastereoisomeric purity of the present
material: 95%.
(b) NaBH4: The crude dissolved in MeOH/30% aq NH3 (9:1, 30 mL),
was cooled to –10°C and NaBH4 (291 mg, 7.7 mmol) in the same
solvent mixture (30 mL) was added. After 10 min, the reaction was
quenched (dil HCl up to pH 4), the solvents evaporated and the organ-
ics extracted with Et2O (3 × 30 mL), dried (Na2SO4) and, after the
usual procedure, the residue was analyzed by 1H and 19F NMR show-
ing the diastereoisomeric ratio: (4S,5R,RS)/(4R,5S,RS)/(4S,5S,RS)/
(4R,5R,RS) 1:1:1:2 (2.12 g, 83%).
Ethyl 2-(Diethoxyphosphoryl)-2,2-difluoroacetate (2):
To a suspension of NaH (240 mg, 8.0 mmol, 80% mineral oil) in THF
(12 mL) stirred at 0°C under N2, commercially available 1 (2.0 g,
8.0 mmol) in THF (12 mL) was added dropwise. Stirring was contin-
ued for 15 min and the mixture was allowed to reach r.t. F-TEDA•BF4
(2.92 mg, 8.0 mmol) was added neat followed by DMF (8.0 mL). The
reaction was continued for 3 d, then the mixture was poured into ice/
water, extracted with EtOAc (3 × 20 mL), dried (Na2SO4), filtered
and, after evaporation of the solvent, the residue was flash chromato-
graphed (hexane/EtOAc 1:1) to give 2 (1.3 g, 60%). Physicochemical
and analytical data were identical to those already described.6
(1R/S,3S,4R)-4-C-[(Diethoxyphosphoryl)difluoromethyl]-3-(4-
methylphenylsulfonyl)-2,3,5-trideoxy-glycero-pentofuranose (6);
General Procedure:
40% aq RuCl3 (27 mg, 0.05 mmol) was added at 0°C to 5 (871 mg,
2.21 mmol) in CCl4/CH3CN/H2O (1:1:2, 4 mL). After 1 min, NaIO4
(1.92 mg, 8.42 mmol) was added and the mixture was allowed to
reach r.t. Water (4 mL) was added and the organics extracted with
CH2Cl2 (3 × 8 mL). After the usual procedure, the residue was flash
chromatographed (hexane/EtOAc 3:7). From (4S,5R,RS)-5, after 2 h,
6 was obtained (823 mg, 87% yield) (2.5:1.0 β/α by NMR analysis),
and (3S,4R)-9 (66 mg, 7% yield).
(4S,5R,RS)-, (4R,5S,RS)-, (4S,5S,RS)-, (4R,5R,RS)-6-(Diethoxy-
phosphoryl)-6,6-difluoro-5-hydroxy-4-(4-methylphenylsulfi-
nyl)hex-1-ene (5):
To a solution of LDA (1.1 mL, 7.7 mmol) in THF (13 mL) stirred at
–78°C under N2, 4-(4-methylphenylsulfinyl)but-1-ene (1.3 g,
6.5 mmol) in THF (25 mL) was added dropwise. After 5 min, 2 (2.1 g,
7.7 mmol) in THF (13 mL) was added. After 2 min, sat. NH4Cl was
added, the organics extracted with Et2O, dried (Na2SO4), filtered and,
after evaporating the solvent, the residue was composed by a 1:1 mix-
ture of (4R,RS)-(4S,RS)-4. NMR Data are reported in Table 1.
The thus obtained mixture was reduced following two different pro-
cedures.
(1R/S,3S,4R)-6: Rf 0.35; [α]D20 –10.0 (c = 0.1, CHCl3) at t0, [α]D20 –12.2
(c = 0.1, CHCl3) after 7 h; diastereo- and enantiomeric purity of the
present material: 90%.
(1S,3S,4R)-6 (α-anomer): 1H, 19F, and 31P NMR Data are reported in
Table 2.
13C NMR (CDCl3): δ = 16.31 (Qd, JC,P = 6.5 Hz, 2 × OCH2CH3),
21.76 (Q, ArMe), 35.11 (T, C-2), 63.88 (Dt, JC,F = 3.5 Hz, C-3), 65.05
and 65.15 (Td, JC,P = 7 Hz, 2 × OCH2CH3), 78.00 (Dddd, JC,F = 27
(a) DIBAH: The residue in THF (10 mL) was cooled to –78°C under
stirring in N2. 1.0 M DIBAH in hexane (12.9 mL) was added and,
after 5 min, sat. NH4Cl was added, the pH adjusted to 6 (dil HCl), the
organics extracted with Et2O, processed as usual and the residue was
flash chromatographed (hexane/EtOAc 3:7). Four different diastere-
omers (1H and 19F NMR analyses of the crude) were present in the
ratio: (4S,5R,RS)/(4R,5S,RS)/(4S,5S,RS)/(4R,5R,RS) 3.5:1.0:2.0:2.0
(2.17 g, 85%).
and 24, JC,P = 16.0 Hz, C-4), 100.60 (D, C-1), 117.17 (Sddd, JC,F
=
268.5 and 265.5, JC,P = 208.5 Hz, C-5), 146.12 (S), 132.99 (S), 130.39
(D) and 128.9 (D) (ArC).
(1R,3S,4R)-6 (β-anomer): 1H, 19F, and 31P NMR Data are reported in
Table 2.
13C NMR (CDCl3): δ = 16.31 (Qd, JC,P = 6.5 Hz, 2 × OCH2CH3),
21.71 (Q, ArMe), 35.72 (T, C-2), 63.34 (Dt, JC,F = 3.5 Hz, C-3), 65.39
and 65.11 (Td, JC,P = 7 Hz, 2 × OCH2CH3), 78.40 (Dm, C-4), 100.80
(D, C-1), 117.63 (Sm, C-5), 145.39 (S), 134.29 (S), 130.18 (D) and
128.75 (D) (ArC).
(4S,5R,RS)-5: yield: 871 mg (34%); Rf 0.35 (hexane/EtOAc 3:7);
[α]D20 +84.0 (c = 1.8, CHCl3); diastereoisomeric purity of the present
material: 90%.
1H, 19F, and 31P NMR Data are reported in Table 1.
MS(EI): m/z (%) = 427 ([M – H]+·, 20), 428 ([M]·, 6), 411 ([M – OH]+·,
16), 400 ([M – CO]+·, 7), 362 ([M – COF2]+·, 4), 273 ([C9H17PO5F2]+·,
28), 245 ([273 – CO]+·, 16), 188 ([C5H11PO3F2]·,100), 161 ([188 –
C2H3]+·, 63), 139 ([C4H12PO3]+·, 38), 132 ([161 – C2H5]+·, 23), 91
([C7H8]+·, 44), 29 ([C2H5]+·, 8).
(4R,5S,RS)-5: yield: 261 mg (10%); Rf 0.35 (hexane/EtOAc 3:7);
[α]D20 +30.1 (c = 0.7, CHCl3); diastereoisomeric purity of the present
material: 93%.
1H, 19F, and 31P NMR Data are reported in Table 1.
(4S,5S,RS)-5: yield: 545 mg (21%); Rf 0.30; [α]D20 +56.0 (c = 1.0,
CHCl3); diastereoisomeric purity of the present material: 95%.
1H, 19F, and 31P NMR Data are reported in Table 1.
(3S,4R)-9: Rf 0.37; [α]D20 +15.53 (c = 0.1, CHCl3). 1H, 19F, and 31
P
NMR Data are reported in Table 2.
13C NMR (CDCl3): δ = 16.31 and 16.25 (Qd, JC,P = 5.5 Hz, 2 ×
13C NMR (CDCl3): δ = 16.35 (Qd, JC,P = 5.5 Hz, 2 × OCH2CH3),
21.37 (Q, ArMe), 26.27 (T, C-3), 60.92 (Dbrd, JC,F = 5.0 Hz, C-4),
OCH2CH3), 21.76 (Q, ArMe), 28.75 (T, C-2), 58.72 (Dt, JC,F
=
2.5 Hz, C-3), 65.71 and 65.57 (Td, JC,P = 7.0 Hz, 2 × OCH2CH3),

SYNTHESIS
October 1998
1517
76.74 (Dm, C-4), 146.43 (S), 132.55 (S), 130.52 (D) and 128.97 (D)
(ArC) and 171.52 (s, C-1).
NOE experiment (acetone-d6): irradiation of the two protons at δ =
7.94 enhanced H-2α (1.5%), H-3 (2.5%), H-4 (3%) and 2 × H at δ =
7.58 (7%).
and stirring continued for 1 h at the same temperature. Then, CH2Cl2
(7 mL) was added, the mixture washed (NaHCO3), treated with brine
and, after the usual procedure, the crude was flash chromatographed
(hexane/EtOAc 3:7).
From (1S/R,3S,4R)-7 (722 mg, 1.54 mmol), (1'R/S,3'S,4'R)-8 (D-se-
ries) was obtained (660 mg, 80%) (β(1'R)/α(1'S) 4.5:5.5); Rf 0.23;
[α]D20 +5.58 (c = 1.2, CHCl3).
From a 2:1 mixture of (4S,5R,RS)- and (4R,5R,RS)-5, the same prod-
ucts above described were detected in comparable chemical yields.
From (4S,5S,RS)-5 (545 mg, 1.38 mmol), after 5 h, (3S,4S)-9 was
formed (71 mg, 12%); Rf 0.45; [α]D20 +2.27 (c = 0.4, CHCl3). No other
isolable product was formed; diastereo- and enantiomeric purity of
the present material: 90%.
The crude when treated with benzene/CHCl3 (5:1), gave crystals en-
riched in (1'R,3'S,4'R)-8; mp 98–100°C; diastereoisomeric purity
75%.
1H, 19F, and 31P NMR Data are reported in Table 2.
1H, 19F, and 31P NMR Data are reported in Table 2.
13C NMR (CDCl3): δ = 12.33 (Q, Me-5), 16.35 (Qd, JC,P = 5.5 Hz, 2
× OCH2CH3), 21.74 (Q, ArMe), 32.62 (T, C-2'), 63.55 (Dt, JC,F = 3
Hz, C-3'), 65.58 and 65.22 (Td, JC,P = 7 Hz, 2 × OCH2CH3), 77.21
(Dddd, JC,F = 28.5 and 23.5 Hz, JC,P = 15Hz, C-4'), 86.09 (D, C-1'),
111.50 (S, C-5), 117.14 (Sddd, JC,F = 271 and 267, JC,P = 208 Hz, C-
5'), 134.82 (D, C-6), 146.09 (S), 133.28 (S), 130.42 (D) and 129.01
(D) (ArC), 150.25 and 163.93 (S, C-2 and C-4).
13C NMR (C6D6): δ = (selected signal) 170.28 (C-1).
NOE experiments (CDCl3): irradiation of the F atom at δ = –125.55
enhanced H-2α (3%); {H-3} enhanced H-2β (6%) and H-4 (6.5%).
From (4R,5S,RS)-5 (261 mg, 0.66 mmol), after 2 h, an anomeric mix-
ture of β(1R)/α(1S)-6 was detected in CHCl3 (230 mg, 81%) (1.0:2.5
β/α by NMR).
MS(EI): m/z (%) = 536 ([M]·, 18), 255 ([C9H14PO4F2]+·, 20), 205
([255 – CH2F2]+·, 6), 177 ([205 – C2H4]+·, 100), 164 ([205 – C3H5]·,
100), 136 ([164 – C2H4]·, 38), 77 ([C6H5]+·, 12); 51 ([CHF2]+·, 5).
(1R/S,3R,4S)-6: Rf 0.35; [α]D20 +10.8 (c = 0.3, CHCl3) at t0, [α]D20
+13.2 (c = 0.3, CHCl3) after 7 h; diastereo- and enantiomeric purity
of the present material: 93%; 1H, 19F and 31P NMR data were super-
imposable on that of the above described enantiomers (1R/S,3S,4R)-6.
(1'S,3'S,4'R)-8 was the major compound in the mother liquor (diaste-
reoisomeric purity 70%).
1H, 19F, and 31P NMR Data are reported in Table 2.
13C NMR (CDCl3): δ = 12.67 (Q, Me-5), 16.35 (Qd, JC,P = 5.5 Hz, 2
(4S,5R)-4-(4-Methylphenylsulfonyl)-5-[(diethoxyphosphoryl)di-
fluoromethyl]dihydrofuran-2(3H)-one (9); Reduction to Lactol 6:
1.0 M DIBAH in toluene (154 µL) was added to a solution of (4S,5R)-
9 (66 mg, 0.15 mmol) in toluene (4.0 mL) stirred at –60°C under N2.
After 30 min, sat. NH4Cl was added, organics were extracted with
EtOAc, dried (Na2SO4) and, after the usual procedure, the residue was
flash chromatographed (hexane/EtOAc 3:7) to give (1R/S,3S,4R)-6
(55 mg, 85%). Physicochemical and spectroscopic data were identical
to those of the already described mixture of epimers.
× OCH2CH3), 21.76 (Q, ArMe), 31.96 (T, C-2'), 62.23 (Dt, JC,F
=
3 Hz, C-3'), 65.43 and 65.17 (Td, JC,P = 7 Hz, 2 × OCH2CH3), 78.21
(Dddd, JC,F = 29 and 23 Hz, JC,P = 15.5 Hz, C-4'), 85.63 (D, C-1'),
112.30 (S, C-5), 117.45 (Sddd, JC,F = 271 and 267, JC,P = 208 Hz, C-
5'), 135.41 (D, C-6), 146.10 (S), 133.72 (S), 130.44 (D) and 128.70
(D) (ArC), and 150.49 and 163.73 (S, C-2 and C-4).
The diastereomeric purity of both the so obtained materials was not
enough to allow optical rotation value measurements.
1-O-Acetyl-4-C-[(diethoxyphosphoryl)difluoromethyl]-3-(4-
methylphenylsulfonyl)-2,3,5-trideoxy-glycero-pentofuranoside
(7); General Procedure:
To a solution of 6 (α/β mixture) (428 mg, 1.0 mmol) in pyridine
(280 µL) stirred at 0°C, neat Ac2O (280 µL, 2.0 mmol) was added and
the mixture was allowed to reach r.t. After stirring overnight, water
was added (430 µL), the organics extracted in EtOAc (3 × 400 µL)
and, after the usual procedures, the crude was flash chromatographed
(hexane/EtOAc 1:1).
(1R/S,3R,4S)-7 (215 mg, 0.56 mmol) Gave a 1:1 mixture of α(1'S) and
β(1'R) nucleoside derivatives (1'S/R,3'R,4'S)-8 (L-series) was ob-
tained (213 mg, 71%); Rf 0.23; [α]D20 –5.39 (c = 1.4, CHCl3).
NMR Spectra were superimposable on those of the enantiomers de-
scribed above.
(4S,5R)- and (4S,5S)-6-(Diethoxyphosphoryl)-6,6-difluoro-5-hy-
droxy-4-(4-methylphenylthio)hex-1-ene (10); General Proce-
dure:
(CF3CO)2O (726 µL, 0.54 mmol ) in acetone (5 mL) was added drop-
wise to a suspension of 5 (70 mg, 0.18 mmol), and NaI (51 mg,
0.36 mmol) in acetone (5 mL) stirred at –40°C under N2. After 10
min, sat. Na2SO3 and sat. NaHCO3 were added, the organics extracted
with Et2O and, after the usual procedure, the residue was flash chro-
matographed (hexane/EtOAc 7:3).
From (1R/S,3S,4R)-6 (823 mg, 1.92 mmol), 7 was obtained as a 3:1
epimeric mixture of β(1S)/α(1R) (D-series) (722 mg, 80%); Rf 0.35;
[α]D20 –7.17 (c = 0.3, CHCl3).
From (1S/R,3R,4S)-6 (230 mg, 0.54 mmol), the acetyl derivatives
(1R/S,3R,4S)-7 were obtained as a 3:1 epimeric mixture of α(1R)/
20
β(1S) (L-series) (215 mg, 85%); Rf 0.35; [α]D +7.95 (c = 1.1,
(a) From (4S,5R,RS)-/(4R,5R,RS)-5 (2:1), a 2:1 mixture of (4S,5R)-
(41 mg, 60%; Rf 0.35) and (4R,5R)-10 (20 mg, 30%; Rf 0.35) was
obtained.
CHCl3).
1H, 19F, and 31P NMR Data are reported in Table 2.
NMR Data are collected in Table 2.
1-{4'-C-[(Diethoxyphosphoryl)difluoromethyl]-3'-(4-methylphe-
nylsulfonyl)-2',3',5'-trideoxy-glycero-pentofuranosyl}thymine
(8); General Procedure:
Thymine (321 mg, 2.6 mmol) and (NH4)2SO4 (86 mg, 0.64 mmol) in
HMDS (7.6 mL) were heated at reflux for 4 h under N2. After evapo-
ration of the solvent, the crude mixture was added to a solution of 7
(471 mg, 1.0 mmol) in anhyd dichloroethane (11 mL), stirred for
10 min at 40°C and then TMSOTf (364 µL, 1.2 mmol ) was added
(b) From (4S,5S,RS)-5, (4S,5S)-10 was obtained (65 mg, 95%), Rf
0.35; [α]D20 –13.1 (c = 0.5, CHCl3).
1H, 19F, and 31P NMR Data were superimposable on those of the
(4R,5R)-10 enantiomer described above.
MS(EI): m/z (%) = 394 ([M + H]+·, 16), 257 ([C13H15SOF2]+·, 7), 240
([257 – OH]·, 100), 199 ([C10H9SF2]+·, 50), 189 ([C12H13S]+·, 20), 149
([C9H9S]+·, 18), 123 ([C7H7S]+·, 38), 91 ([C7H7]+·, 14), 77 ([C6H5]+·,
10), 41 ([C3H5]+·, 4).

SYNTHESIS
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Berkowitz, D. B.; Eggen, H. J.; Shen, Q.; Shoemaker, R. K.
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Papers
1518
1-[(Diethoxyphosphoryl)difluoromethyl]-2-(4-methylphenyl-
thio)pent-4-enyl 2'-Phenylpropionates 12; General Procedure:
Neat DMAP (30 mg, 0.24 mmol) was added to a solution of 10
(100 mg, 0.26 mmol), chiral 11 (300 µL, 2.7 mmol ) and DCC
(550 mg, 2.7 mmol) in CH2Cl2 (4 mL), stirred at 0°C. After 10 min,
a white precipitate formed, the temperature was allowed to rise to r.t.
and stirring continued for 1 h. Then, the dicyclohexylurea was filtered
off, the solution evaporated to dryness and the residue flash chro-
matographed (hexane/EtOAc 7:3).
(a) From (–)-(R)-11: (4S,5R)-/(4R,5R)-10 (2:1) gave (1R,2S,2'R)-/
(1R,2R,2'R)-12 (2:1) (133 mg, 97%); Rf 0.35.
Blades, K.; Percy, J. M. 15th International Symposium on Fluo-
rine Chemistry, The University of British Columbia, Vancou-
ver, B.C., Canada, Aug 2–7 1997, IN (4) C-7.
(4) Blackburn, G. M.; Eckstein, F.; Kent, D. E.; Perrée, T. D. Nu-
cleosides Nucleotides 1985, 4, 165.
1H NMR Data of both the diastereomers are reported in Table 3.
From (4S,5S)-10: (1S,2S,2'R)-12 was obtained (128 mg, 94%); Rf
0.35.
1H NMR Data are reported in Table 3.
Viani, F. Chiral, Non-Racemic Fluorinated Nucleosides: Re-
cent Synthetic Methods In Enantiocontrolled Synthesis of Fluo-
ro-Organic Compounds: Stereochemical Challenges and
Biomedicinal Targets; Soloshonok, V. A. Ed.; Wiley: Chiches-
ter, scheduled to appear in 1998.
MS(EI): m/z (%) = 649 ([M + C7H7S]+·, 5), 526 ([M]·, 40), 423 ([M –
C7H7S]+·, 5), 377 ([M – C9H9O2]+·, 23), 356 ([377 – H2F+]·, 10), 265
+ ·
([356 – C7H8 ] , 4), 253 ([377 – C7H5S]+·, 58), 218 ([356 –
C4H11O3P]·, 32), 177 ([C11H13S]+·, 22), 149 ([C9H10O2]+·, 12), 105
([C8H9]+·, 100), 77 ([C6H5]+·, 32), 29 ([C2H5]+·, 7).
For acyclic analogs, see:
Kim, C. U.; Luh, B. Y.; Misco, P. F.; Bronson, J. J.; Hitchcock,
M. J. M.; Ghazzouli, I.; Martin, J. C. J. Med. Chem. 1990, 33,
1207.
Halazy, S.; Ehrard, A.; Danzin, G. J. Am. Chem. Soc. 1991, 113,
315.
From (+)-(S)-11: (4S,5R)-/(4R,5R)-10 (2:1) gave (1R,2S,2'S)-/
(1R,2R,2'S)-12 (2:1) (123 mg, 90%); Rf 0.35.
1H NMR Data of (4S,5R,2'S)-12 are reported in Table 3; (1R,2R,2'S)-
12 showed a 1H NMR spectrum superimposable on that of the
(1S,2S,2'R)-12 enantiomer described.
Chen, W.; Flavin, M. T.; Filler, R.; Xu, Z. Q. Tetrahedron Lett.
1996, 37, 8975.
From (4S,5S)-10, (1S,2S,2'S)-12 was obtained (123 mg, 90%): Rf
For carbocyclic analogs, see:
0.35.
Wolff-Kugel, D.; Halazy, S. Tetrahedron Lett. 1991, 32, 6341.
Yokomatsu, T.; Sato, M.; Abe, H.; Suemune, K.; Matsumoto,
K.; Kihara, T.; Soeda, S.; Shimeno, H.; Shibuya, S. Tetrahedron
1997, 53 11297.
1H NMR spectrum was superimposable on that of the (1R,2R,2'R)-12
enantiomer described.
(E)-6-(Diethoxyphosphoryl)-6,6-difluoro-5-hydroxyhex-1,3-di-
ene (13); Pyrolytic syn-Elimination of the Sulfinylic Moiety:
Alcohol 5 (unresolved diastereomeric mixture) (394 mg, 1.0 mmol),
dissolved in p-xylene (10 mL), were stirred under N2 at reflux for
30 min giving (E)-13 (94 mg, 24%); Rf 0.35 (hexane/EtOAc 2:3).
1H, 19F, and 31P NMR Data are given in Table 1.
(5) Arnone, A.; Bravo, P.; Frigerio, M., Viani, F.; Zappalà, C.
J. Chem. Res. (S) 1997, 458–459; (M) 1997, 2832–2846.
(6) Burton, D. J.; Sprague, L. G. J. Org. Chem. 1988, 53, 1523.
Burton, D. J.; Sprague, L. G.; Pietrzyk, D. J.; Edelmuth, S. H.
J. Org. Chem. 1984, 49, 3437.
Blackburn, G. M.; Brown, D.; Martin, S. J. J. Chem. Res. (S)
1985, 92.
Nair. H. K.; Burton, D. J. J. Am. Chem. Soc. 1997, 119, 9137.
(7) Bravo, P., Mele, A.; Salani, G.; Viani, F.; La Colla, P. Gazz.
Chim. Ital. 1995, 125, 295.
(8) For the synthesis of anomeric carbohydrates difluoromethyl-
phosphonates, see:
Herpin, T. F.; Motherwell, W. B.; Roberts, B. P.; Roland, S.;
Weibel, J.-M. Tetrahedron 1997, 53, 15085.
(9) Helmchen, G. Tetrahedron Lett. 1974, 1527.
Helmchen, G.; Schmierer, R. Angew. Chem., Int. Ed. Engl.
1976, 15, 703.
(1) Engel, R. Chem. Rev. 1977, 77,349.
Scheit, K. H. Nucleotide Analogues; Wiley: New York, 1980,
p 96.
Engel, R. The Role of Phosphates in Living Systems; Hilde-
brand, R. L., Ed.; CRC Press: Boca Raton FL, 1983, p 93.
Nucleotides Analogues as Antiviral Agents; Martin, J. C., Ed.;
ACS Symposium Series 401; ACS: Washington DC, 1989.
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1986, 913.
Thatcher, G. R. J.; Campbell, A. S. J. Org. Chem. 1993, 58,
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Burke, T. R.; Smyth, M. S.; Otaka, A.; Nomizu, M.; Roller, P.
P.; Wolf, G.; Case, R.; Shoelson, S. E. Biochemistry 1994, 33,
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Nieschalk, J.; O'Hagan, D. J. Chem. Soc, Chem. Commun. 1995,
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O’Hagan, D.; Rzepa, H. S. J. Chem. Soc.,Chem. Commun.
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Bravo, P.; Ganazzoli, F.; Resnati, G.; De Munari, S.; Albinati,
A. J. Chem. Res. (S) 1988, 216; ibid. (M) 1988, 1701.
(10) Drabowicz, J.; Oae, S. Synthesis 1977, 404.
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Mele, A.; Salani, G.; Viani, F.; Bravo, P. Mag. Reson. Chem.
1997, 35, 168.
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45, 5101.
Hebel, D.; Kirk, K. L.; Kinjo, J.; Kovac’s, T.; Lesjak, K.; Balza-
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