Addition of difluorocarbene to 4′,5′-unsaturated nucleosides: Synthesis and deoxygenation reactions of difluorospirocyclopropane nucleosides

Article abstract of DOI:10.1021/jo061606u

Synthetic routes to 4′-(2,2-difluorospirocyclopropane) analogues of adenosine, cytidine, and uridine are described. Treatment of 2′,3′-O-isopropylidene-4′,5′-unsaturated compounds derived from adenosine and uridine with difluorocarbene (generated from PhH

Full text of DOI:10.1021/jo061606u

Addition of Difluorocarbene to 4′,5′-Unsaturated Nucleosides:
Synthesis and Deoxygenation Reactions of
Difluorospirocyclopropane Nucleosides1
Ireneusz Nowak and Morris J. Robins*
Department of Chemistry and Biochemistry, Brigham Young UniVersity, ProVo, Utah 84602-5700
morris_robins@byu.edu
ReceiVed August 2, 2006
Synthetic routes to 4′-(2,2-difluorospirocyclopropane) analogues of adenosine, cytidine, and uridine are
described. Treatment of 2′,3′-O-isopropylidene-4′,5′-unsaturated compounds derived from adenosine and
uridine with difluorocarbene (generated from PhHgCF3 and NaI) gave diastereomeric mixtures of the
2,2-difluorospirocyclopropane adducts. Stereoselectivity resulting from hindrance by the isopropylidene
group favored addition at the â face. Removal of base and sugar protecting groups gave new
difluorospirocyclopropane nucleoside analogues. The protected uridine analogue was converted into its
cytidine counterpart via a 4-(1,2,4-triazol-1-yl) intermediate. Stannyl radical-mediated deoxygenation of
the 3′-O-TBS-2′-thionocarbamate derivatives gave the 2′-deoxy products of direct hydrogen transfer. In
contrast, identical treatment of the 2′-O-TBS-3′-thionocarbamate isomers resulted in opening of the vicinal
difluorocyclopropane ring upon generation of a C3′ radical followed by homoallylic hydrogen transfer
to give 4′-(1,1-difluoroethyl)-3′,4′-unsaturated nucleoside derivatives. Structural aspects and biological
effect considerations are discussed.
Introduction
copy.5 However, the pseudorotational mobility of furanosyl rings
coupled with small energy differences among rotamers limited
the analyses to tentative identification of rotational conformation
populations about the glycosyl bond. Altona and Sundralingham
defined pseudorotational parameters and correlated them with
highly populated solid-state nucleoside/nucleotide conforma-
tions.6 Altona,7 Chattopadhyaya,8 Marquez,9 and others have
refined and added additional parametrization to the fundamental
Relationships between structure and biological response
activity are fundamental considerations in medicinal chemistry.
Regioisomers, diastereomers, and enantiomers usually have
increasingly subtle structural differences, but the contrasts in
biological response effects can be striking. Conformational
preferences are in an even more muted realm of structural
effects. Small but meaningful binding energy differences can
exist among molecular conformer ranges and targeted binding
sites. Nucleic acid component analogues have been employed
clinically for many decades, and major favorable drug versus
side effects differences exist between nucleoside regioisomers,2
diastereomers,3 and enantiomers.4
(4) Skalski, V.; Chang, C.-N.; Dutschman, G.; Cheng, Y-C. J. Biol. Chem.
1993, 268, 23234-23238.
(5) (a) Miles, D. W.; Robins, M. J.; Robins, R. K.; Winkley, M. W.;
Eyring, H. J. Am. Chem. Soc. 1969, 91, 824-831. (b) Miles, D. W.; Robins,
M. J.; Robins, R. K.; Winkley, M. W.; Eyring, H. J. Am. Chem. Soc. 1969,
91, 831-838. (c) Miles, D. W.; Robins, M. J.; Robins, R. K.; Eyring, H.
Proc. Natl. Acad. Sci. U.S.A. 1969, 62, 22-29. (d) Miles, D. W.; Townsend,
L. B.; Robins, M. J.; Robins, R. K.; Inskeep, W. H.; Eyring, H. J. Am.
Chem. Soc. 1971, 93, 1600-1608.
Eyring, Robins, and co-workers systematically investigated
nucleoside conformational effects with CD and ORD spectros-
* To whom correspondence should be addressed. Fax: (801) 422-0153.
(1) Nucleic Acid Related Compounds. 139. Paper 138: Nowak, I.;
Cannon, J. F.; Robins, M. J. Org. Lett. 2006, 8, 4565-4568.
(2) Suhadolnik, R. J. Nucleosides as Biological Probes; Wiley: New
York, 1979; pp 118-135.
(3) (a) Christensen, L. F.; Broom, A. D.; Robins, M. J.; Bloch, A. J.
Med. Chem. 1972, 15, 735-739. (b) De, Clercq, E.; Robins, M. J.
Antibicrob. Agents Chemother. 1986, 30, 719-724.
(6) (a) Altona, C.; Sundaralingam, M. J. Am. Chem. Soc. 1972, 94, 8205-
8212. (b) Altona, C.; Sundaralingam, M. J. Am. Chem. Soc. 1973, 95, 2333-
2344.
(7) de Leeuw, H. P. M.; Haasnoot, C. A. G.; Altona, C. Isr. J. Chem.
1980, 20, 108-126.
(8) Thibaudeau, C.; Kumar, A.; Bekiroglu, S.; Matsuda, A.; Marquez,
V. E.; Chattopadhyaya, J. J. Org. Chem. 1998, 63, 5447-5462 and
references cited therein.
10.1021/jo061606u CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/13/2006
8876
J. Org. Chem. 2006, 71, 8876-8883

Addition of Difluorocarbene to 4′,5′-Unsaturated Nucleosides
Altona-Sundralingham6 approach for analysis of predominant
conformer populations of furanosyl derivatives.
Fluorocarbenes have singlet ground states and usually add
stereospecifically to carbon-carbon double bonds without
concomitant insertion into carbon-hydrogen bonds.15 A number
of methods have been reported for synthesis of gem-difluoro-
cyclopropanes via carbene addition to CdC bonds of simple,
volatile alkenes.15-18 However, those alkenes were often used
in large excess to trap the weakly electrophilic difluorocarbene,
and harsh reaction conditions and/or carbene sources that are
impractical from a preparative standpoint were employed.
Seyferth’s reagent [phenyl(trifluoromethyl)mercury] was chosen
as our source of difluorocarbene19 because it is a non-
hygroscopic solid that permits mild reaction conditions and easy
workup. However, its preparation is not trivial,19b,20 and
appropriate CAUTION should be exercised with organomercury
compounds. Cech and co-workers had used bis(trifluoromethyl)-
mercury in their studies on difluorocarbene insertion into the
oxygen-silicon bond of 4-O-silylated nucleosides.21
Nucleoside analogues normally are prodrug forms of active
pharmaceutical agents. They must undergo interactions with
proteins in cellular and compartmental membranes (including
active and/or facilitated transfer by transmembrane nucleoside
transporters), nucleoside kinases, and mono- and/or dinucleotide
kinases and then bind with target proteins (e.g., DNA polym-
erases, reverse transcriptases, and/or other nucleoside triphos-
phate metabolizing enzymes). It would be fortuitous if binding
studies with a specific target protein (without consideration of
the requisite multiple interactions with other proteins in the prior
transport and activation pathways) gave strong positive cor-
relations with biological response activities attributable to
selective inhibition of the targeted protein. Therefore, continuings
and successfulssearches for new nucleoside drug candidates
necessarily involve intuitive design, synthesis, and empirical
testing of novel candidate structures.
Marquez and co-workers have prepared and evaluated numer-
ous “carbocyclic nucleosides” with a cyclopentane ring in place
of the furanosyl moiety.10 Bicyclo[3.1.0]hexane ring analogues
of carbocyclic nucleosides have restricted cyclopentane (fura-
nose surrogate) ring conformations. Selective interactions of
such analogues with enzymes have been noted, although it is
impossible to rigorously exclude binding effects that might result
from the fused cyclopropane moiety that accompany confor-
mational restriction of the cyclopentane ring.11 A favorable
pseudorotational bias can be amplified with (deoxy)oligonucle-
otide structures in which “locked-ring” conformations are
produced in the monomers by generation of analogues with
bicyclo[x.y.z] surrogates of the furanosyl moiety. Altered binding
effects resulting from restricted conformations have been
measured.12
Nucleoside analogues containing a difluorocyclopropane
moiety deserve attention because simple nucleobase derivatives
have shown biological activity.13,14 Conformational constraints
in fused or spiro modifications might contribute to increased
potency. Fluorine substituents enhance hydrophobicity, and their
potent electronegativity might contribute to long-range electronic
effects such as increased anomeric bond stability. They also
can function as precursors for strategically fluorinated ring-
opened derivatives. Convenient methods for their preparation
would be advantageous.
Results and Discussion
Our strategy for synthesis of difluorocyclopropanated nucleo-
sides involved the preparation of suitably protected vinyl ether
precursors22 followed by addition of difluorocarbene to the
electron-rich double bond23 and deprotection. Protecting groups
would serve two roles: (1) replace mobile hydrogen atoms that
are detrimental to the generation and lifetime of difluorocarbene
and (2) exert a â-facial stereochemical bias for the carbene
addition. Synthesis of the uridine and cytidine derivatives
commenced with 1-(5-deoxy-2,3-O-isopropylidene-â-D-erythro-
pent-4-enofuranosyl)uracil24 (1) (Scheme 1). Attempted addition
of difluorocarbene to 1 failed, presumably because of the
presence of the acidic N3 proton. The 3-benzoyl derivative 2
underwent carbene addition smoothly to give the diastereomers
3a/3b (5:1) in 91% yield. Elucidation of the structure of the
major isomer 3a by X-ray crystallography (Supporting Informa-
tion) confirmed that the addition of difluorocarbene occurred
predominantly at the less hindered â face of the furanose ring.
The isopropylidene protecting group was removed, and the
major adduct 4 was separated from the mixture. Mild basic
hydrolysis gave the crystalline uracil nucleoside analogue 5
(63% overall). Aqueous ammonolysis of 3a removed the
benzoyl group to give 6 (99%), which was treated with 1,2,4-
triazole/phosphoryl chloride/triethylamine in acetonitrile25 to
give the 4-(1,2,4-triazol-1-yl) derivative 7 (97%). Treatment of
(9) Sun, G.; Voigt, J. H.; Filippov, I. V.; Marquez, V. E.; Nicklaus, M.
C. J. Chem. Inf. Comput. Sci. 2004, 44, 1752-1762 and references cited
therein.
(15) Smart, B. E. In Chemistry of Organic Fluorine Compounds II: A
Critical ReView; Hudlicky, M., Pavlath, A. E., Ed.; American Chemical
Society: Washington DC, 1995; pp 767-796.
(10) (a) Rodriguez, J. B.; Marquez, V. E.; Nicklaus, M. C.; Mitsuya,
H.; Barchi, J. J., Jr. J. Med. Chem. 1994, 37, 3389-3399. (b) Marquez, V.
E.; Russ, P.; Alonso, R.; Siddiqui, M. A.; Hernandez, S.; George, C.;
Nicklaus, M. C.; Dai, F.; Ford, H., Jr. HelV. Chim. Acta 1999, 82, 2119-
2129. (c) Choi, Y.; Moon, H. R.; Yoshimura, Y.; Marquez, V. Nucleosides,
Nucleotides, Nucleic Acids 2003, 22, 547-557. (d) Comin, M. J.; Parrish,
D. A.; Deschamps, J. R.; Marquez, V. E. Org. Lett. 2006, 8, 705-708.
(11) Jacobson, K. A.; Ji, X-d.; Li, A.-H.; Melman, N.; Siddiqui, M. A.;
Shin, K.-J.; Marquez, V. E.; Ravi, R. G. J. Med. Chem. 2000, 43, 2196-
2203.
(12) (a) Koshkin, A. A.; Rajwanshi, V. K.; Wengel, J. Tetrahedron Lett.
1998, 39, 4381-4384. (b) Obika, S.; Nanbu, D.; Hari, Y.; Andoh, J.-I.;
Morio, K.-I.; Doi, T.; Imanishi, T.; Tetrahedron Lett. 1998, 39, 5401-
5404. (c) Petersen, M.; Bondensgaard, K.; Wengel, J.; Jacobsen, J. P. J.
Am. Chem. Soc. 2002, 124, 5974-5982. (d) Maderia, M.; Wu, J.; Bax, A.;
Shenoy, S.; O’Keefe, B.; Marquez, V. E.; Barchi, J. J., Jr. Nucleosides,
Nucleotides, Nucleic Acids 2005, 24, 687-690.
(16) Burton, D. J.; Naae, D. G. J. Am. Chem. Soc. 1973, 95, 8467-
8468.
(17) Brahms, D. L. S.; Dailey, W. P. Chem. ReV. 1996, 96, 1585-1632.
(18) Dolbier, W. R., Jr.; Battiste, M. A. Chem. ReV. 2003, 103, 1071-
1098.
(19) (a) Seyferth, D.; Hopper, S. P. J. Org. Chem. 1972, 37, 4070-
4075. (b) Seyferth, D.; Hopper, S. P.; Murphy, G. J. J. Organometal. Chem.
1972, 46, 201-209.
(20) See the Supporting Information for the experimental sequence used.
(21) (a) Pein, C.-D.; Cech, D. Tetrahedron Lett. 1985, 26, 4915-4918.
(b) Scholz, E.; Pein, C.-D.; Cech, D.; Reefschla¨ger, J. Z. Chem. 1987, 27,
443-444. (c) Reefschla¨ger, J.; Pein, C.-D.; Cech, D. J. Med. Chem. 1988,
31, 393-397.
(22) McCarthy, J. R., Jr.; Robins, R. K.; Robins, M. J. J. Am. Chem.
Soc. 1968, 90, 4993-4999.
(23) Samano, V.; Robins, M. J. Tetrahedron Lett. 1994, 35, 3445-3448.
(24) Robins, M. J.; McCarthy, J. R., Jr.; Robins, R. K. J. Heterocycl.
Chem. 1967, 4, 313-314.
(13) (a) Qiu, Y.-L.; Zemlicka, J. Nucleosides Nucleotides 1999, 18,
2285-2300. (b) Wang, R.; Ksebati, M. B.; Corbett, T. H, Kern, E. R.;
Drach, J. C; Zemlicka, J. J. Med. Chem. 2001, 44, 4019-4022.
(14) Csuk, R.; Thiede, G. Z. Naturforsch. 2002, 57b, 1287-1294.
(25) Divakar, K. J.; Reese, C. B. J. Chem. Soc., Perkin Trans. 1 1982,
1171-1176.
J. Org. Chem, Vol. 71, No. 23, 2006 8877

Nowak and Robins
SCHEME 1a
FIGURE 1. X-ray crystal structure of the monomeric 14‚pyridine unit.
a Reagents and conditions: (a) BzCl/Et3N/CH2Cl2; (b) PhHgCF3/NaI/
DME/90 °C; (c) HCl/H2O/THF; (d) NH3/H2O/MeOH; (e) 1,2,4-triazole/
POCl3/Et3N/CH3CN; (f) NH3/H2O/1,4-dioxane; (g) TFA/H2O (9:1).
SCHEME 2a
FIGURE 2. X-ray crystal structure of the supramolecular 14‚pyridine
complex.
1027 in reasonable yield (56%). The 2,5-dimethylpyrrole sub-
stituent at C6 is stable in the presence of basic and organomer-
cury reagents, but it is easily cleaved with release of the 6-amino
group in TFA/H2O.27 Tosylation of 10 in pyridine at low
temperature followed by immediate subjection of the sensitive
tosylate 11 to base-promoted elimination gave 12. Addition of
difluorocarbene to the enol ether 12 proceeded less readily
(∼60%) but with higher diastereoselectivity (13a/13b, ∼15:1,
19F NMR) than had the analogous reaction with 2. Starting 12
that remained in the product mixture (∼20%) could be converted
into 13 by addition of fresh PhHgCF3, but this was not
advantageous because product loss (presumably resulting from
complexation with mercury species) occurred during each
treatment. Target compound 14 was obtained by hydrolysis
(TFA/H2O) of the crude 13a/13b mixture followed by neutral-
ization and chromatography. Crystallization of 14 did not occur
with the usual solvents, but yellow-green blades (14‚pyridine)
were obtained from a pyridine-containing solution. X-ray
analysis identified the structure (Figures 1 and 2), which includes
hydrogen bonding between the amino group of 14 and the
pyridine nitrogen atom (N-N distance: 3.6 Å, Figure 2) and
π-stacking interactions between pyridine and the imidazole ring
of the nucleobase. The resulting supramolecular “ladder” has
parallel strands of alternating ringssa structural feature remi-
niscent of DNA. The crystalline complex retained pyridine, even
upon prolonged heating at 90 °C in vacuo, and melting/
decomposition in a capillary tube began at ∼160 °C. Analogous
a Reagents and conditions: (a) 2,5-hexanedione/150 °C; (b) TsCl/
pyridine/-20 f 15 °C; (c) KOtBu/THF/0 °C; (d) PhHgCF3/NaI/DME/90
°C; (e) TFA/H2O (9:1); (f) NaHCO3/H2O.
7 with aqueous ammonia followed by removal of the isopro-
pylidene group with TFA/H2O (9:1), neutralization of the TFA
salt, and extraction gave the cytosine nucleoside analogue 8.
The hydrochloride-hemihydrate salt of 8 (79%, overall for three
steps) was obtained by acidification with 5% HCl/H2O.
Synthesis of the adenosine analogue 14 (Scheme 2) became
our next focus. A procedure reported26 for N,O-peracylation of
2′,3′-O-isopropylideneadenosine (9) followed by selective depro-
tection of O5′ was not readily reproducible, and other methods
for transient protection-deprotection were not pursued because
of the sensitivity of the second N-acyl group. Prolonged heating
of 9 in 2,5-hexanedione gave the 2,5-dimethylpyrrole derivative
(26) Maguire, A. R.; Meng, W.-D.; Roberts, S. M.; Willetts, A. J. J.
Chem. Soc., Perkin Trans. 1 1993, 1795-1808.
(27) Nowak, I.; Robins, M. J. Org. Lett. 2003, 5, 3345-3348.
8878 J. Org. Chem., Vol. 71, No. 23, 2006

Addition of Difluorocarbene to 4′,5′-Unsaturated Nucleosides
SCHEME 3a
FIGURE 3. X-ray crystal structure of 23.
Dolbier had shown that ring opening of such difluorocyclopro-
pylcarbinyl radicals is very rapid and that the C-C bond distal
to the CF2 group is cleaved.28,29
The TBS ethers 19a, 19b, 20a, and 20b were deprotected
(Bu4NF/THF) and purified [chromatography on Dowex 1 × 2
(OH-)] to give the respective uracil, 21a and 21b, and adenine,
22a and 22b, analogues (Scheme 3). Treatment of 19a and 19b
with 1,2,4-triazole/POCl3/Et3N/acetonitrile25 and ammonolysis
of the 4-(1,2,4-triazoyl) intermediates gave the protected
4-amino compounds, which were deprotected (Bu4NF/THF) and
purified [Dowex 1 × 2 (OH-) chromatography] to give the
cytosine nucleoside analogues 23 and 24. The C6 signal in 13
C
NMR spectra of the uracil 21a and cytosine 23 compounds is
split into a doublet (J ) ∼2 Hz), which presumably results from
through space (ts) coupling with one of the fluorine atoms (F1)
on the cyclopropane ring. Such coupling indicates spatial
proximity between F1 and H6. It has been well documented
that 19F-13C ts couplings can be transmitted via overlap of
fluorine lone-pair and C-H bond orbitals,30-34 and weak
hydrogen bonding attractions have been suggested.33 The 2.53
Å distance between H6 and F1 in our X-ray crystal structure of
23 (Figure 3) is slightly less than the sum of the van der Waals
radii, 1.20 Å for hydrogen and 1.35 Å for fluorine,35 in harmony
with the observed ts couplings. It is noteworthy that ∼2 Hz ts
coupling is not present in our NMR spectra of 5 and 8, which
contain the same respective nucleobasessbut have hydroxyl
groups at both C2′ and C3′. The most highly populated solution
conformation ranges must be different for the ribose-like (5 and
8) and 2′-deoxy (21a and 23) compounds.
Conformational analysis of 14‚pyridine indicates that the
furanosyl ring adopts a C3′-exo (3E) pucker with a pseudoro-
tational phase angle of P ) 185.4° and a maximum puckering
amplitude of νmax ) 33.8°.9,36 Comparison of the X-ray crystal
structures of 14‚pyridine and 2′,3′-dideoxyadenosine37 (ddA)
a Reagents and conditions: (a) TBS-Cl/pyridine; (b) Im2CS/toluene/70
°C; (c) Bu3SnH/AIBN/toluene/90 °C; (d) Bu4NF/THF; (e) 1,2,4-triazole/
POCl3/Et3N/acetonitrile; (f) NH3/H2O/1,4-dioxane.
treatment of the cytosine compound 8 did not result in formation
of such a pyridine complex.
Transformations into deoxygenated derivatives were then
investigated. Diols 5 and 14 were treated with TBS chloride in
pyridine, and the 2′-O-TBS ethers 15 (98%) and 16 (72%) were
isolated (Scheme 3). Treatment of 15 and 16 with 1,1′-
thiocarbonyldiimidazole in hot toluene gave the O2′ and O3′
thiocarbamates 17a/18a and 17b/18b (∼1:2 ratios), respectively.
The imidazole byproduct apparently catalyzed O2′/O3′ equili-
bration of the TBS groups prior to thiocarbamate formation.
Barton deoxygenation of 17a and 18a gave the 2′-deoxy
products 19a and 20a, respectively (direct hydrogen transfer to
the C2′ radical). In contrast, the 3′-thiocarbamate derivatives
17b and 18b underwent deoxygenative radical generation at C3′
followed by an expected28 difluorocyclopropylcarbinyl to al-
lylcarbinyl radical rearrangement and hydrogen transfer to the
homoallylic center to give alkenes 19b and 20b, respectively.
(28) Dolbier, W. R., Jr.; Al-Sader, B. H.; Sellers, S. F.; Koroniak, H. J.
Am. Chem. Soc. 1981, 103, 2138-2139.
(29) Tian, F.; Dolbier, W. R., Jr. Org. Lett. 2000, 2, 835-837.
(30) Jerome, F. R.; Servis, K. L. J. Am. Chem. Soc. 1972, 94, 5896-
5897.
(31) Gribble, G. W.; Kelly, W. J. Tetrahedron Lett. 1985, 26, 3779-
3782.
(32) Hsee, L. C.; Sardella, D. J. Magn. Reson. Chem. 1990, 28, 688-
692.
(33) Mele, A.; Salani, G.; Viani, F. Bravo, P. Magn. Reson. Chem. 1997,
35, 168-174.
(34) Nowak, I. J. Fluorine Chem. 1999, 99, 59-66.
(35) Pauling, L. The Nature of the Chemical Bond, 3rd ed.; Cornell
University Press: Ithaca, 1960; p 260.
(36) Altona-Sundaralingam pseudorotational parameters were calculated
by the Pseudo-Rotational Online Service and Interactive Tool (PROSIT)
available at http://cactus.nci.nih.biv/prosit.
(37) Alibe´s, R.; Alva´rez-Larena, A.; de March, P.; Figueredo, M.; Font,
J.; Parella, T.; Rustullet, A. Org. Lett. 2006, 8, 491-494.
J. Org. Chem, Vol. 71, No. 23, 2006 8879

Nowak and Robins
TABLE 1. Comparison of Solid-State Conformational Parameters
Powdered NaI (1.50 g, 10.0 mmol) was stirred and heated
(170 °C, oil bath) under vacuum for 1 h in a flask (250 mL)
equipped with a Teflon valve. The bath was allowed to cool to
110 °C, and a solution of 2 (0.86 g, 2.34 mmol) in dried CH2Cl2 (2
mL) was injected through a septum (under N2). Volatiles were
evaporated in vacuo, and heating at 110 °C was continued for 1 h.
The bath was allowed to cool to ambient temperature, and solid
PhHgCF3 (1.22 g, 3.51 mmol) was added (under N2). The flask
was evacuated and cooled to -78 °C. Dried DME (∼10 mL) was
transferred under vacuum from a blue solution containing sodium
and benzophenone. The reaction mixture was heated at 90 °C
overnight, and volatiles were evaporated. The concentrated mixture
was deposited on silica gel and chromatographed (EtOAc/hexanes,
1:4 f 1:1) to give 3a/3b (∼5:1; 0.89 g, 91%) as a yellow oil that
was recrystallized (MeOH) to give an analytical sample of 3a: UV
for 14‚Pyridine and ddA
a
compd
Pa
νmax
øa
14
ddA
185.4
190.4
33.8
35.7
-99.7
-95.9
a Values in degrees.
(Table 1) reveals striking similarities in their pseudorotational
parameters. Both are located in the southern hemisphere (S) of
the pseudorotation cycle, they have almost equal ring puckering,
and the base rotations about the glycosyl bond (characterized
by ø) are nearly equivalent. It is amazing that this level of
conformational similarity exists for two nucleoside analogues
with such dissimilar sugar moieties, especially with respect to
the cis-vicinal OH groups present in 14 and absent in ddA.
Alternative substrate activity and enzyme inactivation have been
observed upon incubation of 5′-deoxy-4′,5′-unsaturated adeno-
sine analogues with S-adenosylhomocysteine hydrolase,38 and
studies with this enzyme are in progress.
In conlusion, we have developed synthetic routes to new
difluoro-substituted spirocyclopropane derivatives of uracil 5,
cytosine 8, and adenine 14 nucleosides as well as their 2′-deoxy
and ring-opened 3′-deoxy analogues. Development of suitable
protecting group strategies was crucial for the successful and
steroselective addition of difluorocarbene to unsaturated sugar
nucleosides. The heteroatom array in compounds 2 and 12 is
more extensive than in any alkenes shown to undergo difluo-
rocyclopropanation previously. We employed the base-stable
6-(2,5-dimethylpyrrol-1-yl) substituent on a nucleoside purine
ring for the first time, and mild acid treatment released the
masked 6-amino group of adenine. Barton deoxygenation at C2′,
and with concomitant cyclopropylcarbinyl radical ring-opening
at C3′, provided access to the structurally unique deoxynucleo-
sides 21-24. An X-ray crystal analysis of our supramolecular
14‚pyridine complex revealed similarities with DNA secondary
structures. Intriguing through-space F‚‚‚H-C interactions were
detected by 13C NMR and supported by X-ray crystal distances
in 21a and 23. Studies of new analogues derived from a
2-oxabicyclo[3.1.0]hexane template and biological response
properties will be reported separately.
1
max 253 nm (ꢀ 18 800), min 225 nm (ꢀ 5800); H NMR (CDCl3)
δ 1.36 (s, 3H), 1.53 (s, 3H), 1.65-1.80 (m, 2H), 5.00 (d, J ) 6.1
Hz, 1H), 5.38 (d, J ) 6.1 Hz, 1H), 5.51 (s, 1H), 5.84 (dd, J ) 2.2,
8.1 Hz, 1H), 7.26 (d, J ) 8.1 Hz, 1H), 7.50 (t, J ) 7.8 Hz, 2H),
7.67 (t, J ) 7.8 Hz, 1H), 7.93 (d, J ) 7.8 Hz, 2H); 19F NMR
(CDCl3) δ 136.2 (dm, J ) 164.8 Hz, 1F), 144.9 (ddd, J ) 7.3,
14.6, 164.8 Hz, 1F); 13C NMR (Me2CO-d6) δ 17.4 (t, J ) 10.7
Hz), 25.1, 26.3, 73.8 (t, J ) 9.1 Hz), 79.4, 85.0, 98.1, 102.9, 109.5
(dd, J ) 291.5, 299.8 Hz), 113.6, 129.1, 130.6, 130.9, 135.3, 143.3,
149.6, 161.8, 168.1; MS m/z 420 ([M+], 100), 405, 377, 361, 241,
205, 188, 162; HRMS (C20H18F2N2O6) calcd 420.1133, found
420.1130. Anal. Calcd for C20H18F2N2O6: C, 57.14; H, 4.32; N,
6.66. Found: C, 57.30; H, 4.50; N, 6.64.
1-[(S)-4,4-C-(1,1-Difluoroethane-1,2-diyl)-â-D-erythrofurano-
syl]uracil (5). To a stirred solution of 3a/3b (0.75 g, 1.79 mmol)
in THF (10 mL) was added HCl/H2O (3 M, 10 mL), and stirring
was continued until the deprotection was complete (∼6 h; TLC,
EtOAc). Volatiles were evaporated in vacuo, and the residue was
neutralized (solid NaHCO3) and extracted (EtOAc, 5 × 10 mL).
The combined extract was applied to a silica gel column, and elution
(EtOAc/hexanes, 1:1 f EtOAc) gave 3-benzoyl-1-[(S)-4,4-C-(1,1-
difluoroethane-1,2-diyl)-â-D-erythrofuranosyl]uracil (4) (0.49 g,
72%). This material was dissolved (MeOH, 12 mL), NH3/H2O
(30%, 4 mL) was added, and the solution was stirred at ambient
temperature for 1 h. Volatiles were evaporated, and the residue
was chromatographed (EtOAc, then MeOH) to give a syrup that
was recrystallized (EtOH) to give 5 (0.31 g, 87%) as colorless
needles: mp 225-226 °C; UVmax 260 nm (ꢀ 10 200), min 230 nm
1
(ꢀ 2800); H NMR (Me2CO-d6) δ 1.60-1.66 (m, 1H), 1.85-1.91
(m, 1H), 2.88 (s, 1H), 2.91 (s, 1H), 4.39 (d, J ) 4.9 Hz, 1H), 4.67
(dd, J ) 4.9, 5.9 Hz, 1H), 5.69 (d, J ) 8.3 Hz, 1H), 6.07 (d, J )
5.9 Hz, 1H), 7.65 (d, J ) 8.3 Hz, 1H); 19F NMR (Me2CO-d6) δ
134.4 (dm, J ) 163.9 Hz, 1F), 141.9 (ddd, J ) 7.3, 14.5, 163.0
Hz, 1F); 13C NMR (Me2CO-d6) δ 18.5 (t, J ) 9.8 Hz), 68.8, 71.4
(t, J ) 9.6 Hz), 74.9, 91.1, 103.5, 111.3 (dd, J ) 292.5, 298.4 Hz),
141.5, 151.6, 163.4; FAB-MS m/z 321 ([M+ - H + 2Na], 15),
299 ([M+ + Na], 10), 277, 271, 259, 237 (100), 217, 213; HRMS
(C10H10F2N2O5Na) calcd 299.0455, found 299.0448. Anal. Calcd
for C10H10F2N2O5: C, 43.49; H, 3.64; N, 10.14. Found: C, 43.49;
H, 3.82; N, 10.19.
Experimental Section39
3-Benzoyl-1-[(S)-4,4-C-(1,1-difluoroethane-1,2-diyl)-2,3-O-iso-
propylidene-â-D-erythrofuranosyl]uracil (3a). Et3N (4.7 mL, 3.4
g, 34.1 mmol) and BzCl (2.6 mL, 2.9 g, 22.7 mmol) were added to
a stirred solution of 124 (3.00 g, 11.4 mmol) in dried CH2Cl2 (30
mL) under N2, and stirring was continued for 4 h. The mixture
was concentrated and chromatographed (EtOAc/hexanes, 1:4 f 1:1)
to give 3-benzoyl-1-(5-deoxy-2,3-O-isopropylidene-â-D-erythro-
pent-4-enofuranosyl)uracil (2) (2.87 g, 68%) as a yellow syrup:
UVmax 253 nm (ꢀ 20 800), min 225 nm (ꢀ 5600); 1H NMR (CDCl3)
δ 1.37 (s, 3H), 1.51 (s, 3H), 4.38 (d, J ) 1.8 Hz, 1H), 4.60 (d, J
) 1.8 Hz, 1H), 5.06 (d, J ) 6.1 Hz, 1H), 5.24 (d, J ) 6.1 Hz, 1H),
5.68 (s, 1H), 5.85 (d, J ) 8.3 Hz, 1H), 7.28 (d, J ) 8.3 Hz, 1H),
7.49-7.53 (m, 2H), 7.65-7.69 (m, 1H), 7.91-7.94 (m, 2H); 13C
NMR (CDCl3) δ 25.1, 26.4, 79.2, 82.6, 87.2, 96.5, 102.2, 113.6,
129.1, 130.3, 130.8, 135.2, 142.5, 148.9, 161.7, 162.3, 168.1; MS
m/z 370 ([M+], 7), 355, 295, 265, 105 ([PhCO+], 100), 77; HRMS
(C19H18N2O6) calcd 370.1164, found 370.1155.
1-[(S)-4,4-C-(1,1-Difluoroethane-1,2-diyl)-â-D-erythrofurano-
syl]cytosine (8). A solution of NH3/H2O (30%, 5 mL) was added
to a stirred solution of 3a (0.71 g, 1.71 mmol) in MeOH (20 mL),
and stirring was continued at ambient temperature for 1 h. Volatiles
were evaporated, and the residue was chromatographed (EtOAc/
hexanes, 1:2) to give 1-[(S)-4,4-C-(1,1-difluoroethane-1,2-diyl)-2,3-
O-isopropylidene-â-D-erythrofuranosyl]uracil (6) (0.53 g, 99%) as
a syrup.
Et3N (2.34 mL, 1.71 g, 16.9 mmol) was added dropwise to a
stirred, cooled (∼0 °C) mixture of 1,2,4-triazole (1.22 g, 17.8
mmol), POCl3 (0.35 mL, 0.57 g, 3.72 mmol), and acetonitrile (10.5
mL). A solution of 6 (0.53 g, 1.69 mmol) in acetonitrile (6.6 mL)
was added to this mixture, and stirring was continued at ambient
temperature for 2 h. Et3N (1.59 mL, 1.16 g, 11.5 mmol) and H2O
(38) Yuan, C.-S.; Liu, S.; Wnuk, S. F.; Robins, M. J.; Borchardt, R. T.
In AdVances in AntiViral Drug Design; De Clercq, E., Ed.; JAI Press:
Greenwich, CT, 1996; Vol. 2, pp 41-88.
(39) See the Supporting Information for general experimental details.
8880 J. Org. Chem., Vol. 71, No. 23, 2006

Addition of Difluorocarbene to 4′,5′-Unsaturated Nucleosides
(0.66 mL) were added, and stirring was continued for 10 min.
Volatiles were evaporated, and the residue was partitioned [ice-
cold, saturated NaHCO3/H2O (30 mL)//CH2Cl2 (30 mL)]. The
aqueous phase was extracted (CH2Cl2, 30 mL), and the combined
organic phase was washed (brine, 50 mL) and dried (MgSO4).
Volatiles were evaporated to give 1-[(S)-4,4-C-(1,1-difluoroethane-
1,2-diyl)-2,3-O-isopropylidene-â-D-erythrofuranosyl]-4-(1,2,4-tria-
zol-1-yl)pyrimidin-2-one (7) (0.60 g, 97%) as a yellow foam: UV
max 314, 251 nm (ꢀ 5500, 14 000), min 280, 232 nm (ꢀ 2300,
2.22 (s, 6H), 2.42 (s, 3H), 4.25-4.31 (m, 2H), 4.50-4.54 (m, 1H),
5.08 (dd, J ) 2.9, 6.3 Hz, 1H), 5.42 (dd, J ) 2.4, 6.3 Hz, 1H),
6.00 (s, 2H), 6.23 (d, J ) 2.9 Hz, 1H), 7.29 (d, J ) 8.0 Hz, 2H),
7.70 (d, J ) 8.0 Hz, 2H), 8.19 (s, 1H), 8.87 (s, 1H); 13C NMR
(CDCl3) δ 12.9, 20.8, 24.5, 26.3, 68.6, 80.6, 83.4, 83.6, 90.0, 108.3,
113.8, 127.1, 128.3, 129.0, 129.2, 131.4, 134.8, 144.7, 149.3, 151.4,
152.1; MS m/z 539 ([M+], 40), 524, 403, 367, 212 ([M+
-
C11H10N5], 100); HRMS (C26H31N5O6S) calcd 539.1838, found
539.1829.
1
6600); H NMR (CDCl3) δ 1.43 (s, 3H), 1.57 (s, 3H), 1.74-1.81
A solution of potassium tert-butoxide (1.8 g, 16.7 mmol) in dried
THF (40 mL) was added to a stirred, cooled (-10 °C) solution of
11 (6.0 g, 11.1 mmol) in dried THF (40 mL), and the dark solution
was protected from moisture and stirred for 30 min at -10 °C.
The reaction mixture was deposited on silica gel and chromato-
graphed (EtOAc/hexanes, 1:4) to give 9-(5-deoxy-2,3-O-isopropy-
lidene-â-D-erythro-pent-4-enofuranosyl)-6-(2,5-dimethylpyrrol-1-
yl)purine (12) (2.6 g, 68%) as a pale yellow oil: UVmax 284 nm (ꢀ
(m, 1H), 1.84-1.92 (m, 1H), 5.12 (d, J ) 5.9 Hz, 1H), 5.35 (d, J
) 5.9 Hz, 1H), 5.73 (s, 1H), 7.08 (d, J ) 7.3 Hz, 1H), 7.91 (d, J
) 7.3 Hz, 1H), 8.13 (s, 1H), 9.27 (s, 1H); 19F NMR (CDCl3) δ
135.8 (ddd, J ) 5.5, 14.6, 164.8 Hz, 1F), 143.6 (ddd, J ) 7.3,
14.6, 164.8 Hz, 1F); 13C NMR (CDCl3) δ 17.7 (t, J ) 11.1 Hz),
25.4, 26.4, 74.6 (t, J ) 9.2 Hz), 79.1, 85.3, 95.2, 99.1, 109.5 (dd,
J ) 292.2, 299.8 Hz), 113.6, 143.4, 149.4, 154.0, 154.5, 160.0;
EI-MS m/z 367 ([M+], 8), 352, 308, 216, 204, 188, 164 (100), 162,
148; HRMS (C15H15F2N5O4) calcd 367.1092, found 367.1099.
A solution of NH3/H2O (30%, 2.2 mL) was added to a stirred
solution of 7 in 1,4-dioxane (7 mL), and stirring was continued at
ambient temperature for 19 h. Volatiles were evaporated, and the
residue was dissolved (TFA/H2O, 3.0:0.4 mL). The solution was
stirred overnight, and volatiles were evaporated in vacuo (<30 °C).
H2O (20 mL) and NaHCO3 were added to the residue, and the
mixture was extracted (EtOAc, 10 × 100 mL). Evaporation of
volatiles gave 8 as yellow oil. A solution of this material in MeOH
was treated with 5% HCl/H2O and filtered. The filtrate was
concentrated, and excess HCl was removed by repetitive addition
and evaporation of MeOH/H2O. The resulting red oil was recrystal-
lized (EtOH) to give 8‚HCl‚0.5H2O (0.40 g, 79%) as a white
powder: mp 218-220 °C; UVmax 278 nm (ꢀ 10 600), min 245 nm
1
13 500), min 246 nm (ꢀ 4400); H NMR (CDCl3) δ 1.46 (s, 3H),
1.61 (s, 3H), 2.21 (s, 6H), 4.56 (d, J ) 2.4 Hz, 1H), 4.69 (d, J )
2.4 Hz, 1H), 5.38 (d, J ) 5.9 Hz, 1H), 5.61 (d, J ) 5.9 Hz, 1H),
5.99 (s, 2H), 6.36 (s, 1H), 8.12 (s, 1H), 8.92 (s, 1H); 13C NMR
(CDCl3) δ 13.0, 25.1, 26.2, 79.1, 82.1, 88.0, 90.0, 108.6, 113.6,
128.4, 129.2, 143.6, 149.7, 151.9, 152.1, 161.2; MS m/z 367 ([M+],
60), 352, 226, 212 ([M+ - C11H10N5], 100); HRMS (C19H21N5O3)
calcd 367.1644, found 367.1656.
Treatment of 12 (1.14 g, 3.1 mmol) in dried DME (8 mL) with
the reagent prepared from NaI (1.4 g, 9.3 mmol) and PhHgCF3
(2.19 g, 6.3 mmol) (according to the procedure described for 2 f
3a/3b) gave a mixture that was deposited on silica gel and
chromatographed (EtOAc/hexanes, 1:4 f 1:1) to give recovered
12 (0.26 g, 20%) plus a mixture of 9-[(R/S)-4,4-C-(1,1-difluoro-
ethane-1,2-diyl)-2,3-O-isopropylidene-â-D-erythrofuranosyl]-6-(2,5-
dimethylpyrrol-1-yl)purine (13a/13b) (∼15:1; 0.78 g, 60%) as a
yellow oil: 1H NMR (CDCl3, major isomer) δ 1.50 (s, 3H), 1.65
(s, 3H), 1.65-1.95 (m, 2H), 2.21 (s, 6H), 5.43 (d, J ) 5.9 Hz,
1H), 5.74 (d, J ) 6.1 Hz, 1H), 6.00 (s, 2H), 6.29 (s, 1H), 8.13 (s,
1H), 8.94 (s, 1H); 19F NMR (CDCl3) δ 135.6 (ddd, J ) 5.5, 14.6,
163.0 Hz, 1F), 145.3 (ddd, J ) 7.3, 14.6, 163.0 Hz, 1F); EI-MS
m/z 417 ([M+], 80), 212, 77 (100); HRMS (C20H21F2N5O3) calcd
417.1612, found 417.1617.
A solution of 13a/13b (0.85 g, 2.0 mmol) in TFA/H2O (9:1, 20
mL) was stirred at ambient temperature for 3 h. Volatiles were evap-
orated in vacuo (<30 °C), and saturated NaHCO3/H2O (20 mL)
was added. The mixture was extracted (EtOAc, 10 × 100 mL), and
volatiles were evaporated from the combined organic phase to give
a red oil. Chromatography (EtOAc/MeOH, 20:1) gave 14 (0.35 g,
57%) as a syrup: UVmax 260 nm (ꢀ 12 000), min 229 nm (ꢀ 3300);
1H NMR (Me2CO-d6) δ 1.59-1.67 (m, 1H), 1.87-1.95 (m, 1H),
2.87 (br s, 2H), 4.63 (d, J ) 5.4 Hz, 1H), 5.26 (t, J ) 5.4 Hz, 1H),
6.22 (d, J ) 5.4 Hz, 1H), 6.64 (br s, 2H), 8.20 (s, 1H), 8.23 (s,
1H); 19F NMR (Me2CO-d6) δ 134.5 (ddd, J ) 5.5, 16.5, 163.0 Hz,
1F), 141.8 (ddd, J ) 7.3, 16.5, 163.0 Hz, 1F); 13C NMR (DMSO-
d6) δ 17.9 (t, J ) 8.8 Hz), 68.1, 70.3 (t, J ) 9.2 Hz), 73.2, 87.6,
110.9 (dd, J ) 292.2, 299.1 Hz), 119.4, 140.2, 149.9, 153.0, 156.3;
MS m/z 299 ([M+], 7), 270, 178 (100), 148, 136; HRMS
(C11H11F2N5O3) calcd 299.0830, found 299.0828. This material was
recrystallized (pyridine/MeOH/Et2O) to give yellow-green blades
of 14‚pyridine: mp ∼160-166 °C dec; 1H NMR (CD3OD) δ 1.64
(ddd, J ) 4.9, 10.3, 15.6 Hz, 1H), 1.89 (ddd, J ) 7.3, 9.8, 16.1
Hz, 1H), 4.45 (d, J ) 5.4 Hz, 1H), 5.13 (t, J ) 5.9 Hz, 1H), 6.19
(d, J ) 6.3 Hz, 1H), 7.40-7.43 (m, 2H), 7.81-7.85 (m, 1H), 8.20
(s, 1H), 8.23 (s, 1H), 8.51-8.53 (m, 2H); 19F NMR (CD3OD) δ
134.7 (ddd, J ) 4.9, 17.1, 163.6 Hz, 1F), 142.3 (ddd, J ) 7.3,
17.1, 163.6 Hz, 1F); 13C NMR (CD3OD) δ 17.3 (t, J ) 10.3 Hz),
68.4, 70.7 (dd, J ) 8.4, 10.7 Hz), 74.5, 88.7, 110.2 (dd, J ) 293.0,
297.5 Hz), 119.3, 124.4, 137.2, 140.0, 148.9, 149.8, 152.9, 156.2.
X-ray crystallography confirmed the 1:1 complex stoichiometry.
1-[2-Deoxy-(S)-4,4-C-(1,1-difluoroethane-1,2-diyl)-â-D-glycero-
tetrofuranosyl]uracil (21a). TBS-Cl (0.73 g, 4.8 mmol) was added
1
(ꢀ 4600); H NMR (D2O) δ 1.79-1.87 (m, 1H), 1.92-2.01 (m,
1H), 4.40 (d, J ) 4.9 Hz, 1H), 4.74 (t, J ) 5.3 Hz, 1H), 6.04 (d,
J ) 5.9 Hz, 1H), 6.25 (d, J ) 8.3 Hz, 1H), 7.86 (d, J ) 8.3 Hz,
1H); 19F NMR (D2O) δ 135.0 (ddd, J ) 5.5, 14.6, 164.8 Hz, 1F),
142.0 (ddd, J ) 7.3, 16.5, 164.8 Hz, 1F); 13C NMR (D2O) δ 17.5
(t, J ) 10.3 Hz), 68.5, 70.9 (dd, J ) 8.6, 11.1 Hz), 74.5, 91.8,
95.8, 109.7 (dd, J ) 290.6, 299.6 Hz), 144.9, 148.5, 159.4; FAB-
MS (thioglycerol) m/z 298 ([M+ + Na], 100); HRMS (C10H11F2N3O4-
Na) calcd 298.0615, found 298.0616. Anal. Calcd for C10H11F2N3O4‚
HCl‚0.5H2O: C, 37.45; H, 4.09; N, 13.10. Found: C, 37.14; H,
4.40; N, 12.92.
9-(2,3-O-Isopropylidene-â-D-ribofuranosyl)-6-(2,5-dimeth-
ylpyrrol-1-yl)purine27 (10). A solution of 2′,3′-O-isopropylidene-
adenosine (9) (1.00 g, 3.26 mmol) in 2,5-hexanedione (4 mL) was
heated at 150 °C for 2 days. Volatiles were evaporated in vacuo,
and the oily residue was chromatographed (EtOAc/hexanes, 1:1)
to give 10 (0.70 g, 56%) as an orange oil: UVmax 283 nm (ꢀ 12 100),
1
min 247 nm (ꢀ 4200); H NMR (CDCl3) δ 1.42 (s, 3H), 1.69 (s,
3H), 2.22 (s, 6H), 3.82-3.88 (m, 1H), 4.02 (dd, J ) 1.5, 12.7 Hz,
1H), 4.60 (s, 1H), 5.17 (dd, J ) 1.5, 5.8 Hz, 1H), 5.31 (dd, J )
4.4, 5.8 Hz, 1H), 5.46 (d, J ) 10.7 Hz, 1H), 6.00 (s, 2H), 6.03 (d,
J ) 4.4 Hz, 1H), 8.22 (s, 1H), 8.93 (s, 1H); 13C NMR (CDCl3) δ
13.0, 24.7, 26.9, 62.2, 81.2, 83.6, 86.2, 92.3, 108.6, 113.6, 128.8,
129.2, 144.2, 149.8, 151.6, 152.1; MS m/z 385 ([M+], 80), 370,
354, 296, 213 (100), 198; HRMS (C19H23N5O4) calcd 385.1750,
found 385.1753.
9-[(S)-4,4-C-(1,1-Difluoroethane-1,2-diyl)-â-D-erythrofurano-
syl]adenine (14). A solution of 10 (4.5 g, 11.7 mmol) in dried
pyridine (22 mL) was cooled to -20 °C, and TsCl (3.4 g, 17.8
mmol) was added. Stirring was continued for 6 h at -20 °C, and
the mixture was allowed to warm to 15 °C overnight. H2O (100
mL) was added with stirring, and the solution was extracted (CH2-
Cl2, 2 × 50 mL). The combined organic phase was dried (MgSO4),
and volatiles were evaporated to give 9-(2,3-O-isopropylidene-5-
O-tosyl-â-D-ribofuranosyl)-6-(2,5-dimethylpyrrol-1-yl)purine (11)
(6.0 g, 95%) as a yellow syrup: UVmax 284 nm (ꢀ 12 500), min
1
247 nm (ꢀ 4300); H NMR (CDCl3) δ 1.40 (s, 3H), 1.63 (s, 3H),
J. Org. Chem, Vol. 71, No. 23, 2006 8881

Nowak and Robins
to a stirred solution of 5 (0.44 g, 1.6 mmol) in dried pyridine (5
mL), and stirring was continued at ambient temperature for 2 days.
Volatiles were evaporated in vacuo, and the residue was chromato-
graphed (EtOAc/hexanes, 1:4 f 1:1) to give 1-[2-O-tert-butyldim-
ethylsilyl-(S)-4,4-C-(1,1-difluoroethane-1,2-diyl)-â-D-erythrofuranosyl]-
uracil (15) (0.60 g, 97%): mp 175-177 °C; UVmax 260 nm (ꢀ
375, 263, 243, 237; HRMS (C16H24F2N2O4SiNa) calcd 397.1371,
found 397.1375.
Bu4NF/THF (1 M; 2.0 mL, 2.0 mmol) was added to a stirred
solution of 19a (0.60 g, 1.6 mmol) in THF (10 mL), and stirring
was continued for 1 h. Volatiles were evaporated, and the residue
was dissolved (H2O, 20 mL) and applied to a column of Dowex 1
× 2 (OH-) resin (in H2O). Elution [H2O f MeOH f AcOH/MeOH
(1:3)] and evaporation of volatiles from UV-active fractions gave
21a (0.36 g, 87%) as colorless crystals. An analytically pure sample
was obtained by several recrystallizations (EtOH): mp 205-206
1
10 400), min 229 nm (ꢀ 2600); H NMR (Me2CO-d6) δ 0.10 (s,
3H), 0.13 (s, 3H), 0.90 (s, 9H), 1.58-1.70 (m, 1H), 1.82-1.95
(m, 1H), 4.29 (t, J ) 5.4 Hz, 1H), 4.42 (d, J ) 5.8 Hz, 1H), 4.82
(t, J ) 5.7 Hz, 1H), 5.75 (d, J ) 8.1 Hz, 1H), 6.15 (d, J ) 5.8 Hz,
1H), 7.71 (d, J ) 8.3 Hz, 1H), 10.25 (s, 1H); 19F NMR (Me2CO-
d6) δ 134.1 (dm, J ) ∼163 Hz, 1F), 142.0 (dm, J ) ∼163 Hz,
1F); 13C NMR (Me2CO-d6) δ -4.9, -4.7, 18.5 (t, J ) 9.8 Hz),
18.7, 26.1, 69.0, 71.2 (dd, J ) 8.2, 11.5 Hz), 76.2, 90.0, 103.6,
111.1 (dd, J ) 292.5, 298.4 Hz), 141.1, 151.5, 163.6; FAB-MS
m/z 435 ([M+ - H + 2Na], 50), 413 ([M+ + Na], 100), 401, 391;
HRMS (C16H24F2N2O5SiNa) calcd 413.1320, found 413.1322. Anal.
Calcd for C16H24F2N2O5Si: C, 49.22; H, 6.20; N, 7.17. Found: C,
49.40; H, 6.06; N, 7.07.
1
°C; UVmax 260 nm (ꢀ 9700), min 229 (ꢀ 3600); H NMR (Me2-
CO-d6) δ 1.65-1.72 (ddd, J ) 4.9, 10.3, 16.6 Hz, 1H), 1.83-1.90
(ddd, J ) 6.8, 9.8, 17.1 Hz), 2.54-2.59 (ddd, J ) 2.4, 6.8, 14.2
Hz, 1H), 2.66-2.72 (dt, J ) 14.2, 6.6 Hz, 1H), 4.59 (dd, J ) 2.0,
6.3 Hz, 1H), 5.67 (d, J ) 8.3 Hz, 1H), 6.48 (t, J ) 6.8 Hz, 1H),
7.57 (d, J ) 8.3 Hz, 1H); 19F NMR (CD3OD) δ 134.6 (ddd, J )
5.4, 16.5, 163.0 Hz, 1F), 141.9 (ddd, J ) 7.3, 16.5, 163.0 Hz, 1F);
13C NMR (CD3OD) δ 17.9 (t, J ) 10.3 Hz), 41.8, 69.9, 73.9 (dd,
J ) 7.6, 10.7 Hz), 88.4, 103.3, 112.2 (dd, J ) 292.2, 299.1 Hz),
142.2 (d, J ) 1.8 Hz), 152.5, 166.6; EI-MS m/z 260 ([M+], 5),
232, 188, 167, 149, 128, 113, 96 (100); HRMS (C10H10F2N2O4)
calcd 260.0608, found 260.0598. Anal. Calcd for C10H10F2N2O4:
C, 46.16; H, 3.87; N, 10.77. Found: C, 46.30; H, 3.85; N, 10.60.
1-[3-Deoxy-4-(1,1-difluoroethyl)-â-D-glycero-tetr-3-enofura-
nosyl]uracil (21b). Treatment of 17b (0.25 g, 0.5 mmol) with Bu3-
SnH/AIBN/toluene (as described for 17a f 19a) gave 1-[2-O-tert-
butyldimethylsilyl-3-deoxy-4-(1,1-difluoroethyl)-â-D-glycero-tetr-
3-enofuranosyl]uracil (19b) (0.16 g, 83%): UVmax 259 nm (ꢀ
A stirred solution of 15 (0.13 g, 0.3 mmol) and 1,1′-thiocarbo-
nyldiimidazole (0.09 g, 0.5 mmol) in dried toluene (2 mL) was
heated at 70 °C for 30 min. Volatiles were evaporated in vacuo,
and chromatography of the residue (EtOAc/hexanes, 1:2 f 1:1)
separated two isomers. The more polar 1-{3-O-tert-butyldimeth-
ylsilyl-(S)-4,4-C-(1,1-difluoroethane-1,2-diyl)-2-O-[(imidazol-1-yl)-
thiocarbonyl]-â-D-erythrofuranosyl}uracil (17a) (38 mg, 23%)
1
had: UVmax 259 nm (ꢀ 17 500), min 229 nm (ꢀ 6200); H NMR
(CDCl3) δ -0.06 (s, 3H), 0.06 (s, 3H), 0.83 (s, 9H), 1.67-1.76
(m, 1H), 1.81-1.90 (m, 1H), 5.02 (d, J ) 4.9 Hz, 1H), 5.80 (d, J
) 7.8 Hz, 1H), 5.99 (t, J ) 4.9 Hz, 1H), 6.18 (d, J ) 4.9 Hz, 1H),
7.07 (s, 1H), 7.29 (d, J ) 7.8 Hz, 1H), 7.63 (s, 1H), 8.38 (s, 1H),
10.54 (br s, 1H); 19F NMR (CDCl3) δ 135.1 (dm, J ) 169 Hz, 1F),
141.6 (dm, J ) 169 Hz, 1F); 13C NMR (CDCl3) δ -5.3, -5.1,
17.7, 17.9 (t, J ) 10.1 Hz), 25.3, 67.7, 70.2 (dd, J ) 8.1, 12.1 Hz),
82.6, 89.3, 103.7, 108.9 (dd, J ) 294.1, 297.6 Hz), 117.9, 131.2,
137.1, 140.2, 150.1, 163.4, 182.5; FAB-MS (glycerol) m/z 501 ([M+
+ H], 52), 373 (100), 261; HRMS (C20H27F2N4O5SSi) calcd
501.1439, found 501.1454. The less polar 1-{2-O-tert-butyldim-
ethylsilyl-(S)-4,4-C-(1,1-difluoroethane-1,2-diyl)-3-O-[(imidazol-1-
yl)thiocarbonyl]-â-D-erythrofuranosyl}uracil (17b) (65 mg, 40%)
had: mp 205-206 °C dec; UVmax 260 nm (ꢀ 16 500), min 232 nm
1
10 300), min 231 nm (ꢀ 3700); H NMR (CDCl3) δ 0.07 (s, 3H),
0.10 (s, 3H), 0.87 (s, 9H), 1.81 (t, J ) 18.8 Hz, 3H), 4.97 (s, 1H),
5.46 (s, 1H), 5.78 (d, J ) 7.8 Hz, 1H), 6.32 (s, 1H), 7.02 (d, J )
7.8 Hz, 1H), 10.09 (br s, 1H); 19F NMR (CDCl3) δ 92.9 (dq, J )
18.3, 265.5 Hz, 1F), 97.4 (dq, J ) 18.3, 265.5 Hz, 1F); 13C NMR
(CDCl3) δ -4.81, -4.76, 17.9, 21.9 (t, J ) 26.5 Hz), 25.5, 79.8,
94.0, 102.7, 103.6, 116.2 (t, J ) 236.6 Hz), 138.8, 149.8, 155.6
(dd, J ) 30.2, 36.6 Hz), 163.4; FAB-MS (thioglycerol) m/z 397
([M+ + Na], 100), 375, 359, 339, 317, 263; HRMS (C16H24F2N2O4-
SiNa) calcd 397.1371, found 397.1372.
Bu4NF/THF (1 M; 1.4 mL, 1.4 mmol) was added to a stirred
solution of 19b (0.26 g, 0.695 mmol) in THF (5 mL), and stirring
was continued for 15 min. Volatiles were evaporated, and the
residue was dissolved (H2O, 10 mL) and applied to a column of
Dowex 1 × 2 (OH-) resin (in H2O). Elution [H2O f MeOH f
AcOH/MeOH (1:3)], and evaporation of volatiles from UV-active
fractions gave 21b (0.15 g, 82%) as an oil that crystallized upon
standing. An analytically pure sample was obtained by several
recrystallizations (EtOH): mp 148-150 °C; UVmax 260 nm (ꢀ
1
(ꢀ 6200); H NMR (CDCl3) δ 0.01 (s, 6H), 0.73 (s, 9H), 1.82-
1.97 (m, 2H), 4.90 (t, J ) 5.9 Hz, 1H), 5.86 (dd, J ) 2.2, 8.3 Hz,
1H), 5.99 (d, J ) 6.3 Hz, 1H), 6.28 (d, J ) 5.4 Hz, 1H), 7.11 (s,
1H), 7.22 (d, J ) 8.3 Hz, 1H), 7.68 (s, 1H), 8.15 (s, 1H), 8.41 (br
s, 1H); 19F NMR (CDCl3) δ 134.7 (ddd, J ) 4.3, 15.0, 164.5 Hz,
1F), 143.8 (ddd, J ) 6.4, 15.0, 164.5 Hz, 1F); 13C NMR (Me2CO-
d6) δ -5.1, -4.9, 18.2, 19.6 (t, J ) 10.3 Hz), 25.7, 69.0 (t, J )
10.3 Hz), 74.8, 79.7, 92.2, 104.0, 110.4 (dd, J ) 293.4, 298.0 Hz),
119.4, 132.1, 138.0, 142.0, 151.5, 163.2, 185.3; FAB-MS (glycerol)
m/z 501 ([M+ + H], 20), 443, 373, 353, 261 (100); HRMS
(C20H27F2N4O5SSi) calcd 501.1439, found 501.1437.
1
9800), min 231 nm (ꢀ 2800); H NMR (CD3OD) δ 1.82 (t, J )
18.6 Hz, 3H), 5.05 (m, 1H), 5.60 (m, 1H), 5.73 (d, J ) 8.3 Hz,
1H), 6.30 (d, J ) 2.9 Hz, 1H), 7.34 (d, J ) 8.3 Hz, 1H); 19F NMR
(Me2CO-d6) δ 94.1 (dqm, J ) 18.8, 264.2 Hz, 1F), 94.7 (dqm, J )
18.8, 264.2 Hz, 1F); 13C NMR (Me2CO-d6) δ 22.4 (t, J ) 26.5
Hz), 79.0, 95.0, 104.1, 104.2 (t, J ) 4.1 Hz), 117.6 (t, J ) 236.3
Hz), 151.1, 155.9 (t, J ) 32.5 Hz), 163.5; EI-MS m/z 261 (MH+,
35), 242, 231, 199, 167, 148, 113 (100); HRMS (C10H11F2N2O4)
calcd 261.0687, found 261.0694. Anal. Calcd for C10H10F2N2O4:
C, 46.16; H, 3.87; N, 10.77. Found: C, 46.31; H, 3.96; N, 10.60.
1-[2-Deoxy-(S)-4,4-C-(1,1-difluoroethane-1,2-diyl)-â-D-glycero-
tetrofuranosyl]cytosine (23). Treatment of 19a (1.10 g, 2.54 mmol)
by the sequence described for the conversion of 6 f 8, followed
by deprotection as described for 19a f 21a, gave an acetate salt
after chromatography with Dowex 1 × 2 (OH-) resin [H2O f
MeOH f AcOH/MeOH (1:3)]. The salt was neutralized (Na2CO3/
H2O), and the mixture was extracted (EtOAc). The combined
organic phase was concentrated and subjected to PTLC (EtOAc/
MeOH, 10:1) to give 23 (0.56 g, 74%). Recrystallization (MeOH)
gave an analytical sample as colorless needles: mp 217-218 °C
dec; UVmax 271 nm (ꢀ 8900), min 255 nm (ꢀ 8000); 1H NMR (CD3-
OD) δ 1.65-1.89 (m, 2H), 2.38-2.48 (dt, J ) 6.5, 14.2 Hz, 1H),
Bu3SnH (0.6 g, 2.0 mmol) was added to a solution of 17a (0.25
g, 0.5 mmol) and AIBN (20 mg, 0.1 mmol) in dried, deoxygenated
toluene. The mixture was heated at 90 °C for 50 min, and volatiles
were evaporated. The residual oil was chromatographed (EtOAc/
hexanes, 1:4 f 1:2) to give 1-[3-O-tert-butyldimethylsilyl-2-deoxy-
(S)-4,4-C-(1,1-difluoroethane-1,2-diyl)-â-D-glycero-tetrofuranosyl]-
uracil (19a) (0.12 g, 64%): UVmax 260 nm (ꢀ 10 200), min 229
1
nm (ꢀ 2500); H NMR (CDCl3) δ 0.07 (s, 3H), 0.10 (s, 3H), 0.91
(s, 9H), 1.68-1.76 (m, 2H), 2.35 (dt, J ) 6.3, 14.2 Hz, 1H), 2.59
(ddd, J ) 2.4, 6.3, 14.2 Hz, 1H), 4.51 (dd, J ) 2.4, 5.9 Hz, 1H),
5.79 (d, J ) 8.3 Hz, 1H), 6.38 (t, J ) 6.3 Hz, 1H), 7.32 (d, J ) 8.3
Hz, 1H), 8.47 (br s, 1H); 19F NMR (CDCl3) δ 135.0 (dm, J ) 164
Hz, 1F), 142.1 (dm, J ) 165 Hz, 1F); 13C NMR (CDCl3) δ -5.2,
-4.9, 17.7 (t, J ) 10.1 Hz), 17.8, 25.5, 42.3, 69.0, 72.2 (dd, J )
7.8, 10.5 Hz), 86.5, 103.0, 110.1 (dd, J ) 294.8, 299.3 Hz), 139.0,
150.3, 163.6; FAB-MS (thioglycerol) m/z 397 ([M+ + Na], 100),
8882 J. Org. Chem., Vol. 71, No. 23, 2006

Addition of Difluorocarbene to 4′,5′-Unsaturated Nucleosides
2.57-2.65 (ddd, J ) 2.2, 6.3, 14.2 Hz, 1H), 4.56 (dd, J ) 2.2, 6.1
Hz, 1H), 4.87 (s, 3H), 5.91 (d, J ) 7.6 Hz, 1H), 6.45 (t, J ) 6.6
Hz, 1H), 7.56 (d, J ) 7.6 Hz, 1H); 19F NMR (CD3OD) δ 135.0
(ddd, J ) 5.5, 16.5, 163.0 Hz, 1F), 142.2 (ddd, J ) 7.3, 16.5, 163.0
Hz, 1F); 13C NMR (CD3OD) δ 18.8 (t, J ) 10.3 Hz), 42.7, 70.0,
73.8 (dd, J ) 7.6, 10.7 Hz), 89.0, 96.6, 112.3 (dd, J ) 292.6, 299.5
Hz), 141.9 (d, J ) 2.3 Hz), 158.3, 167.8; EI-MS m/z 259 (M+, 3),
230, 222, 207, 179, 138, 128 (100); HRMS (C10H11F2N3O3) calcd
259.0768, found 259.0759. Anal. Calcd for C10H11F2N3O3: C,
46.34; H, 4.27; N, 16.21. Found: C, 46.29; H, 4.31; N, 16.12.
1-[3-Deoxy-4-(1,1-difluoroethyl)-â-D-glycero-tetr-3-enofura-
nosyl]cytosine (24). Treatment of 19b (0.37 g, 1.0 mmol) by the
sequence described for conversion of 6 f 8, followed by depro-
tection as described for 19a f 21a, gave a residue after chroma-
tography with Dowex 1 × 2 (OH-) resin (H2O f MeOH).
Extraction (EtOAc) followed by PLTC (EtOAc/MeOH, 10:1) of
the concentrated extract gave a product that was recrystallized
(EtOH/Et2O) to give 24 (0.20 g, 76%) as colorless plates: mp 197-
198 °C; UVmax 270 nm (ꢀ 8700), min 259 (ꢀ 8400); 1H NMR (CD3-
OD) δ 1.83 (t, J ) 18.8 Hz, 3H), 4.88 (s, 3H), 4.95-4.98 (m, 1H),
5.57-5.60 (m, 1H), 5.91 (d, J ) 7.3 Hz, 1H), 6.34 (d, J ) 2.9 Hz,
1H), 7.31 (d, J ) 7.3 Hz, 1H); 19F NMR (CD3OD) δ 93.8 (dq, J
) 18.3, 265.5 Hz, 1F), 95.3 (dq, J ) 18.3, 265.5 Hz, 1F); 13C
NMR (CD3OD) δ 22.5 (t, J ) 26.7 Hz), 79.8, 96.5, 97.3, 104.0 (t,
J ) 3.8 Hz), 117.9 (t, J ) 235.4 Hz), 141.8, 156.8 (dd, J ) 31.5,
34.1 Hz), 157.8, 167.8; EI-MS m/z 259 (M+, 2), 241, 230, 166,
123, 112 (100); HRMS (C10H11F2N3O3) calcd 259.0768, found
259.0780. Anal. Calcd for C10H11F2N3O3: C, 46.34; H, 4.27; N,
16.21. Found: C, 46.12; H, 4.48; N, 16.01.
5.37-5.40 (m, 1H), 5.58 (dd, J ) 2.0, 2.9 Hz, 1H), 6.44 (d, J )
2.9 Hz, 1H), 6.62 (br s, 2H), 7.84 (s, 1H), 8.37 (s, 1H); 19F NMR
(CDCl3) δ 94.1 (dq, J ) 18.3, 265.5 Hz, 1F), 96.6 (dq, J ) 18.3,
265.5 Hz, 1F); 13C NMR (CDCl3) δ -5.0, -4.9, 17.7, 21.8 (t, J )
26.8 Hz), 25.3, 79.5, 92.4, 102.1, 116.1 (t, J ) 236.4 Hz), 119.3,
137.3, 149.2, 153.1, 155.1 (t, J ) 33.6 Hz), 156.2; FAB-MS
(thioglycerol) m/z 420 ([M+ + Na], 75), 398 (100), 382, 340, 266;
HRMS (C17H25F2N5O2SiNa) calcd 420.1643, found 420.1647.
Treatment of 20a (0.29 g, 0.73 mmol) with Bu4NF/THF, as
described for 19a f 21a, and chromatography with Dowex 1 × 2
(OH-) resin (H2O f MeOH) gave a residue that was purified by
PTLC (EtOAc/MeOH, 19:1). This material (0.18 g, 87%) was
recrystallized (EtOH) to give 22a as tiny colorless needles: mp
208-209 °C; UVmax 259 nm (ꢀ 14 900), min 226 nm (ꢀ 2200); 1H
NMR (CD3OD) δ 1.65-1.73 (ddd, J ) 4.9, 10.3, 16.3 Hz, 1H),
1.79-1.88 (ddd, J ) 7.3, 10.3, 16.1 Hz, 1H), 2.70-2.77 (ddd, J )
2.9, 7.3, 14.2 Hz, 1H), 3.24-3.31 (ddd, J ) 5.4, 6.8, 14.2 Hz,
1H), 4.77 (dd, J ) 2.9, 6.8 Hz, 1H), 6.63 (dd, J ) 5.4, 7.3 Hz,
1H), 8.20 (s, 1H), 8.21 (s, 1H); 19F NMR (CD3OD) δ 135.1 (ddd,
J ) 5.2, 15.7, 162.2 Hz, 1F), 142.1 (ddd, J ) 6.9, 15.7, 162.3 Hz,
1F); 13C NMR (CD3OD) δ 17.5 (t, J ) 10.7 Hz), 41.9, 69.9, 73.5
(dd, J ) 8.0, 10.3 Hz), 86.1, 112.2 (dd, J ) 293.4, 297.9 Hz),
120.6, 140.9, 150.7, 154.1, 157.4; EI-MS m/z 283 ([M+], 10), 265,
190, 163, 162, 136, 135 (100%), 108; HRMS (C11H11F2N5O2) calcd
283.0880, found 283.0888. Anal. Calcd for C11H11F2N5O2: C,
46.65; H, 3.91; N, 24.73. Found: C, 46.72; H, 3.89; N, 24.70.
1-[3-Deoxy-4-(1,1-difluoroethyl)-â-D-glycero-tetr-3-enofura-
nosyl]adenine (22b). Deprotection of 20b (0.57 g, 1.44 mmol) (as
described for 19b f 21b) and chromatography with Dowex 1 × 2
(OH-) resin [(H2O f MeOH f AcOH/MeOH (1:3)] gave an
acetate salt. The salt was neutralized (Na2CO3/H2O), and the mixture
was extracted (EtOAc). PTLC (EtOAc/MeOH, 10:1) of the
concentrated organic phase gave material (0.39 g, 96%) that was
recrystallized (EtOH) to give 22b as colorless cubes: mp 185-
186 °C; UVmax 259 nm (ꢀ 15 300), min 230 nm (ꢀ 3800); 1H NMR
(Me2CO-d6) δ 1.80 (t, J ) 18.8 Hz, 1H), 5.29 (br s, 1H), 5.56-
5.60 (m, 1H), 5.76-5.80 (m, 1H), 6.53 (d, J ) 2.9 Hz, 1H), 6.84
(br s, 2H), 8.12 (s, 1H), 8.23 (s, 1H); 19F NMR (Me2CO-d6) δ 94.5
(qm, J ) 18.9 Hz, 2F); 13C NMR (Me2CO-d6) δ 22.5 (t, J ) 26.5
Hz), 78.9, 93.4, 104.1 (t, J ) 4.1 Hz), 117.7 (t, J ) 235.3 Hz),
120.3, 139.4, 150.6, 154.3, 155.4 (t, J ) 35.7 Hz), 157.3; EI-MS
m/z 283 ([M+], 17), 266, 218, 190, 136 (100); HRMS (C11H11F2N5O2)
calcd 283.0880, found 283.0876. Anal. Calcd for C11H11F2N5O2:
C, 46.65; H, 3.91; N, 24.73. Found: C, 46.80; H, 3.66; N, 24.91.
1-[2-Deoxy-(S)-4,4-C-(1,1-difluoroethane-1,2-diyl)-â-D-glycero-
tetrofuranosyl]adenine (22a). TBSCl (0.76 g, 5.02 mmol) was
added to a stirred solution of 14 (0.50 g, 1.67 mmol) in dried
pyridine (5 mL), and stirring was continued at ambient temperature
for 1 day. Volatiles were evaporated in vacuo, and the residue was
chromatographed (EtOAc/hexanes, 1:2 f 1:1) to give 1-[2-O-tert-
butyldimethylsilyl-(S)-4,4-C-(1,1-difluoroethane-1,2-diyl)-â-D-eryth-
rofuranosyl]adenine (16) (0.54 g, 78%). This material (0.45 g, 1.09
mmol) and 1,1′-thiocarbonyldiimidazole (0.29 g, 1.63 mmol) were
dissolved in dried toluene/THF (10:4, 14 mL) and heated at 65 °C
for 5 h. Volatiles were evaporated in vacuo, and the residue was
chromatographed (EtOAc/hexanes, 1:1 f EtOAc) to give 18a/18b
(1:2; 0.44 g, 77%). This material and AIBN (34 mg, 0.21 mmol)
were dissolved in dried toluene (15 mL), and the solution was
deoxygenated (N2). Bu3SnH (0.68 mL, 0.73 g, 2.5 mmol) was
added, and the solution was heated at 100 °C for 1 h. Volatiles
were evaporated, and the residue was chromatographed (EtOAc/
hexanes, 1:1 f EtOAc) to give 1-[3-O-tert-butyldimethylsilyl-2-
deoxy-(S)-4,4-C-(1,1-difluoroethane-1,2-diyl)-â-D-glycero-tetro-
furanosyl]adenine (20a) (0.10 g, 31%): 19F NMR (CDCl3) δ 134.6
(dm, J ) 164 Hz, 1F), 142.2 (dm, J ) 164 Hz, 1F); EI-MS m/z
397 ([M+], 17), 340, 320, 304, 262, 242 (100), 205, 162, 135, 115;
HRMS (C17H25F2N5O2Si) calcd 397.1745, found 397.1739; and
1-[2-O-tert-butyldimethylsilyl-3-deoxy-4-(1,1-difluoroethyl)-â-D-
glycero-tetr-3-enofuranosyl]adenine (20b) (0.22 g, 65%): UVmax
Acknowledgment. We gratefully acknowledge NIH Grant
No. GM029332, pharmaceutical company unrestricted gift funds
(M.J.R.), and Brigham Young University for financial support.
We thank Professor John F. Cannon for X-ray crystallographic
analyses.
Supporting Information Available: Experimental details, NMR
spectra of selected intermediates, and X-ray crystal structures and
CIF data for compounds 3a, 14‚pyridine, and 23. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
259 nm (ꢀ 15 100), min 230 nm (ꢀ 3700); H NMR (CDCl3) δ
0.04 (s, 3H), 0.05 (s, 3H), 0.86 (s, 9H), 1.80 (t, J ) 18.5 Hz, 3H),
JO061606U
J. Org. Chem, Vol. 71, No. 23, 2006 8883