Stannyl radical-mediated cleavage of π-deficient heterocyclic sulfones. Synthesis of α-fluoro esters and the first homonucleoside α-fluoromethylene phosphonate

Full text of DOI:10.1021/ja953513s

J. Am. Chem. Soc. 1996, 118, 2519-2520
2519
uridine 5′-thiohydroxamic ester to obtain the 6′-(pyridin-2-yl)
thioether. Its oxidation (m-CPBA) and fluorination of the de-
rived sulfonyl-stabilized carbanion (Selectfluor) were successful.
However, attempted desulfonylation by known procedures
failed. We now have discovered that pyridin-2-yl- and espe-
cially pyrimidin-2-ylsulfonyl groups undergo cleavage from the
R-carbon atoms of carboxylic and phosphonic esters. This new
methodology was employed for the first reported synthesis of
a 6′-deoxy-6′-fluorohomonucleoside phosphonate from uridine.
Treatment of 2′,3′-O-isopropylideneuridine 5′-carboxylic
acid19 (1, Scheme 1) with isobutyl chloroformate/N-methyl-
morpholine/THF and the sodium salt of N-hydroxypyridine-2-
thione gave the N-hydroxypyridine-2-thioester. Photolysis
(tungsten light) with diethyl vinylphosphonate gave the reported
addition product 220a,b (∼60%) plus byproducts.20c,d Attempted
C6′ fluorination of thioether 2 with (diethylamino)sulfur tri-
fluoride (DAST)21a or oxidation of 2 and treatment of the
sulfoxides with DAST/SbCl321b failed. Oxidation of 2 with >2
equiv of m-CPBA gave the pyridin-2-yl sulfone 3a, which was
benzoylated at N3 to give 3b.22 Treatment of 3b with potassium
hydride generated a stabilized C6′ carbanion. Several “positive
fluorine” sources failed to give defined products, but Selectfluor
[1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis-
Stannyl Radical-Mediated Cleavage of π-Deficient
Heterocyclic Sulfones. Synthesis of r-Fluoro Esters
and the First Homonucleoside r-Fluoromethylene
Phosphonate1
Stanislaw F. Wnuk and Morris J. Robins*
Department of Chemistry and Biochemistry
Brigham Young UniVersity, ProVo, Utah 84602-5700
ReceiVed October 19, 1995
Phosphonate derivatives of nucleosides have been studied
extensively as analogues of biologically important nucleotides.2,3
Blackburn proposed that R-fluoro and R,R-difluoro substitution
on methylenephosphonates should provide superior phosphate
ester surrogates (closer isosteric and isopolar parallels).3,4 The
bridging oxygen in di- and triphosphates has been replaced with
mono- and difluoromethylene entities,3-5 and the OH function
on phosphates has been replaced with a fluoromethyl group.6
Condensations of O5′-activated nucleosides5a and activated 5′-
monophosphates4a with (fluoromethylene)- and (difluorometh-
ylene)bis(phosphonic acids) have given di- and triphosphate
analogues with R and â pyrophosphate oxygen replaced with
CHF and CF2 units. Phosphonate homologues of nucleotides
9
(O5′ replaced with CH2,7 CHF,8 or CF2 ) are of enhanced
interest since they are not substrates for the usual phosphatases.
Established syntheses of homophosphonates with CH2 units
employed Wittig7 or Arbuzov2 chemistry. Recent reports9,10
of their CF2 analogues have utilized coupling of nucleic acid
bases with a previously synthesized R,R-difluorohomoribose
phosphonate derivative11 or a carbocyclic analogue.10 The
9-(5,5-difluoro-5-phosphonopentyl)guanine congener of acy-
clovir phosphate was found to exert potent inhibition of purine
nucleoside phosphorylase.12
(18) Lal, G. S. J. Org. Chem. 1993, 58, 2791-2796.
(19) (a) Corey, E. J.; Samuelsson, B. J. Org. Chem. 1984, 49, 4735-
4735. (b) Varma R. S.; Hogan, M. E. Tetrahedron Lett. 1992, 33, 7719-
7720.
(20) (a) Barton, D. H. R.; Ge´ro, S. D.; Quiclet-Sire, B.; Samadi, M. J.
Chem. Soc., Chem. Commun. 1989, 1000-1001. (b) Barton, D. H. R.; Ge´ro,
S. D.; Quiclet-Sire, B.; Samadi, M. Tetrahedron 1992, 48, 1627-1636. (c)
Barton, D. H. R.; Ge´ro, S. D.; Quiclet-Sire, B.; Samadi, M. J. Chem. Soc.,
Chem. Commun. 1988, 1372-1373. (d) Complete stereoselectivity20c for
C5′ modified nucleosides20a,b has been noted, but 2 was contaminated (5-
15%) by compound(s) with similar NMR signals. A 4′(S) diastereomer
should undergo parallel transformations to give parallel byproducts observed
at each stage.
R-Fluoro- and R,R-difluoromethylenephosphonates have been
prepared by Arbuzov reactions with fluorohalomethanes,13
fluorination of phosphonate-stabilized anions,14 alkylation of
[(diethoxyphosphoryl)difluoromethyl]lithium,15 and palladium-
catalyzed addition of diethyl (difluoroiodomethyl)phosphonate
to alkenes.16 Fluorinations of sulfonyl-stabilized phosphonate
carbanions with perchloryl fluoride17 and the new Selectfluor
reagent18 have been described. We employed Barton’s chain-
extension method with diethyl vinylphosphonate and a protected
(21) (a) Robins, M. J.; Wnuk, S. F. J. Org. Chem. 1993, 58, 3800-
3801. (b) Wnuk, S. F.; Robins, M. J. J. Org. Chem. 1990, 55, 4757-4760.
(22) NMR (CDCl3, unless specified). (a) Data as reported for 8c23a and
10c.23b (b) 3b: 1H NMR δ 1.25 (t, J ) 7.0 Hz, 6), 1.31 (s, 3), 1.52 (s, 3),
2.40-2.71 (m, 2), 4.10 (q, J ) 7.0 Hz, 4), 4.38-4.71 (m, 3), 4.96-5.12
(m, l), 5.58 (d, J ) 1.1 Hz, 0.5, Hl′), 5.67 (d, J ) 1.5 Hz, 0.5, Hl′), 5.83
and 5.85 (d and d, J ) 8.1 Hz, 0.5 and 0.5), 7.37 and 7.39 (d and d, 0.5
and 0.5), 7.45-8.14 (m, 8), 8.67-8.94 (m, l); HRMS (CI) m/z 664.1724
(100, MH+ [C29H35N3O11PS] ) 664.1730). (c) 4b: δ 1.24-1.35 (m, 9),
1.51 and 152 (2s, 3), 2.71-3.06 (m, 2), 4.16-4.32 (m, 4), 4.68-4.76 (m,
(1) Nucleic Acid Related Compounds. 89. Part 88: Robins, M. J.; Wilson,
J. S.; Madej, D.; Low, N. H.; Hansske, F.; Wnuk, S. F. J. Org. Chem.
1995, 60, 7902-7908.
2), 4.96 (dd, J2′-3′ ) 6.3 Hz, J2′-1′ ) 2.0 Hz, 0.5, H2′), 4.99 (dd, J2′-3′
)
(2) Engel, R. Chem. ReV. 1977, 77, 349-367.
5.9 Hz, J2′-1′ ) 2.0 Hz, 0.5, H2′), 5.48 and 5.49 (2d, 1, H1′), 5.68 and 5.71
(2dd, J5-6 ) 8.2 Hz, J5-NH ) 2.3 Hz, 1, H5), 7.19 and 7.22 (2d, 1, H6),
7.60, 7.97, 8.14, 8.79 (4m, 4), 9.06 (br s, 1); 19F NMR δ -168.2 (ddd,
JF-P ) 82.2 Hz, JF-5′,5′′ ) 30.0, 17.1 Hz, 0.5), -168.6 (ddd, JF-P ) 82.2
Hz, JF-5′,5′′ ) 29.1, 17.1 Hz), plus minor 4′(S) signals; HRMS (CI) m/z
578.1367 (100, MH+ [C22H30FN3O10PS] ) 578.1374). (d) 5b (faster
isomer): 1H NMR (D2O) δ 1.23 (t, J ) 6.9 Ηz, 6), 2.22-2.36 (m, 2), 4.03
(t, J ) 5.9 Hz, 1), 4.08-4.12 (m, 1), 4.15 (q, 4), 4.27 (t, J ) 3.9 Hz, 1),
(3) Blackburn, G. M.; Perre´e, T. D.; Rashid, A.; Bisbal, C.; Lebleu, B.
Chem. Scr. 1986, 26, 21-24.
(4) (a) Blackburn, G. M.; Kent, D. E.; Kolkmann, F. J. Chem. Soc., Perkin
Trans. 1 1984, 1119-1125. (b) Blackburn, G. M.; Guo, M.-J.; Langston,
S. P.; Taylor, G. E. Tetrahedron Lett. 1990, 31, 5637-5640. (c) Blackburn,
G. M.; Langston, S. P. Tetrahedron Lett. 1991, 32, 6425-6428.
(5) (a) Davisson, V. J.; Davis, D. R.; Dixit, V. M.; Poulter, C. D. J.
Org. Chem. 1987, 52, 1794-1801. (b) Hebel, D.; Kirk, K. L.; Kinjo, J.;
Kova´cs, T.; Lesiak, K.; Balzarini, J.; De Clercq, E.; Torrence, P. F. Bioorg.
Med. Chem. Lett. 1991, 1, 357-360.
5.14 (dm, J6′-F ) 45.2 Hz, 1), 5.67 (d, J1′-2′ ) 3.3 Hz, 1), 5.76 (d, J5-6
)
8.2 Hz, 1) 7.52 (d, 1); 19F NMR (D2O) δ -203.2 (dddd, JF-P ) 78.2 Hz,
JF-6′ ) 46.1 Hz, JF-5′,5′′ ) 28.3, 10.5 Hz); HRMS (CI) m/z 397.1170 (100,
MH+ [C14H23FN2O8P] ) 397.1176). (e) 6 (from faster 5b): mp 200-210
°C dec; UV (H2O) max 262 nm (ꢀ 8200), min 231 nm (ꢀ 2100); 1H NMR
(D2O) δ 2.11-2.22 (m, 2), 4.04 (t, J ) 6.0 Hz, 1), 4.15 (q, J ) 6.2 Hz, 1),
4.25 (t, J ) 5.0 Hz, 1), 4.83 (dm J6′-F ≈ 46 Hz, 1), 5.75 (d, J1′-2′ ) 4.5
Hz, 1), 5.88 (d, J5-6 ) 8.0 Hz, l), 7.59 (d, 1); 19F NMR (NaH/D2O) δ
-200.5 (dddd, JF-P ) 61.9 Hz, JF-6′ ) 48.2 Hz, JF-5′,5′′ ) 27.3, 9.1 Hz);
HRMS (FAB) m/z 385.0194 (76, MH+ [C10H13FN2O8PNa2] ) 385.0189),
363.0370 (35, MH+ [C10H14FN2O8PNa] ) 363.0370). (f) 8a (oil): 1H NMR
similar to 8b. Anal. Calcd for C13H19NO4S: C, 54.72; H, 6.71; N, 4.91.
Found: C, 54.63; H, 6.52; N 5.09. (g) 8b: mp 50-51 °C; 1H NMR δ 0.90
(t, J ) 6.6 Hz, 3), 1.1 (t, J ) 7.1 Hz, 3), 1.28-1.51 (m, 4), 2.15-2.28 (m,
2), 4.10 (q, 2), 4.61 (dd, J ) 6.2, 8.7 Hz, 1), 7.60 (t, J ) 4.9 Hz, 1), 8.97
(d, 2). Anal. Calcd for C12H18N2O4S: C, 50.33; H, 6.34; N, 9.78. Found:
C, 50.33; H, 6.15; N, 9.60. (h) 9a (oil): 1H NMR δ 0.90 (t, J ) 6.8 Hz, 3),
1.16-1.52 (m, 7), 2.30-2.73 (m, 2), 4.31 (q, J ) 7.2 Hz, 2), 7.60 (ddd, J
) 1.4, 4.7, 7.6 Hz, 1), 7.98 (dt, J ) 1.7, 7.6 Hz, 1), 8.09 (dt, J ) 1.1 Hz,
7.8 Hz, 1), 8.73 (ddd, J ) 1.0, 1.7, 4.8 Hz, 1); 19F NMR δ -159.4 (dd, J
) 10.3, 38.5 Hz). Anal. Calcd for C13H18FNO4S: C, 51.47; H, 5.98; N,
4.62. Found: C, 51.39; H, 6.12; N, 4.51. (i) 9b (oil): 1H and 19F NMR
similar to 9a. Anal. Calcd for C12H17FN2O4S: C, 47.36; H, 5.63; N, 9.20.
Found: C, 47.57; H, 5.72; N, 9.19. (j) 2-[2H]-10c: 1H NMR same as 10c23b
except simplification at δ 1.87 and small signals (∼10%) at δ 4.86; 19F
NMR δ -193.2 (tt, JF-D ) 7.9 Hz, JF-H ) 24.9 Hz).
(6) (a) Casara, P. J.; Jund, K. C.; Clauss, A.; Nave´, J.-F.; Snyder, R. D.
Bioorg. Med. Chem. Lett. 1992, 2, 145-148. (b) Blackburn, G. M.; Guo,
M.-J. Tetrahedron Lett. 1993, 34, 149-152.
(7) Jones, G. H.; Moffatt, J. G. J. Am. Chem. Soc. 1968, 90, 5337-
5338.
(8) Synthesis of monofluoro phosphonate analogues from a sugar
precursor was presented by Blackburn et al.,3 but no final products were
reported.
(9) (a) Matulic-Adamic, J.; Usman, N. Tetrahedron Lett. 1994, 35, 3227-
3230. (b) Matulic-Adamic, J.; Haeberli, P.; Usman, N. J. Org. Chem. 1995,
60, 2563-2569.
(10) Wolff-Kugel, D.; Halzay, S. Tetrahedron Lett. 1991, 32, 6341-
6344.
(11) Berkowitz, D. B.; Eggen, M.-J.; Shen, Q.; Sloss, D. G. J. Org. Chem.
1993, 58, 6174-6176.
(12) Halazy, S.; Ehrhard, A.; Danzin, C. J. Am. Chem. Soc. 1991, 113,
315-317.
(13) Burton, D. J.; Flynn, R. M. J. Fluorine Chem. 1977, 10, 329-332.
(14) Differding, E.; Duthaler, R. O.; Krieger, A.; Ru¨egg, G. M.; Schmit,
C. Synlett 1991, 395-396.
(15) Obayashi, M.; Ito, E.; Matsui, K.; Kondo, K. Tetrahedron Lett. 1982,
23, 2323-2326.
(16) Yang, Z.-Y.; Burton, D. J. J. Org. Chem. 1992, 57, 4676-4683.
(17) Koizumi, T.; Hagi, T.; Horie, Y; Takeuchi, Y. Chem. Pharm. Bull.
1987, 35, 3959-3962.
(23) (a) Wang, Y; Jiang, Y. Synth. Commun. 1992, 22, 2287-2291. (b)
Thenappan, A.; Burton, D. J. J. Org. Chem. 1990, 55, 2311-2317.
0002-7863/96/1518-2519$12.00/0 © 1996 American Chemical Society

2520 J. Am. Chem. Soc., Vol. 118, No. 10, 1996
Communications to the Editor
Scheme 1a
Scheme 2
a (a) (i) Isobutyl chloroformate/N-methylmorpholine/THF; (ii) sodium
salt of N-hydroxypyridine-2-thione; (iii) diethyl vinylphosphonate/hν.
(b) m-CPBA. (c) BzCl/EtN(i-Pr)2/pyridine. (d) KH/THF/Selectfluor/
DMF. (e) NH3/MeOH. (f) Bu3SnH/AIBN/benzene/∆. (g) TFA/H2O. (h)
(i) Me3SiBr/DMF; (ii) DEAE Sephadex; (iii) Dowex 50 × 8(H+) then
(Na+).
at reflux for 48 h caused no observed change in the starting
material. However, parallel treatment of ethyl 2-(pyridin-2-yl-
sulfonyl)hexanoate (8a) for 36 h gave ethyl hexanoate (10a,
60%) plus unchanged 8a and minor decomposition products.
Analogous treatment of ethyl 2-(pyrimidin-2-ylsulfonyl)hex-
anoate (8b) gave complete conversion to 10a within 1 h.
Substitution of Bu3SnD for Bu3SnH gave ethyl 2-deuteriohex-
anoate (10b).
Carbanion-mediated fluorinations proceeded smoothly in the
model series. The 2-(pyridin-2-ylsulfonyl) 8a and 2-(pyrimidin-
2-ylsulfonyl) 8b esters were treated with potassium hydride,
and the enolates were quenched with Selectfluor to give ethyl
2-fluoro-2-(pyridin-2-ylsulfonyl)hexanoate22 (9a) and ethyl 2-flu-
oro-2-(pyrimidin-2-ylsulfonyl)hexanoate22 (9b) in high yields.
Tributylstannane-mediated desulfonylation of 9a (28 h) and 9b
(1 h) gave ethyl 2-fluorohexanoate23b (10c; 60% and 95%,
respectively). Treatment of 9b with Bu3SnD gave 2-[2H]-10c.22
These reactions30 provide convenient access to biologically
important R-fluorocarbonyl compounds31 and their isotope-
labeled derivatives. π-Deficient heterocyclic sulfones could be
especially advantageous in reactions that involve generation of
sulfonyl carbanions since acidifying effects of these pyridin-
and pyrimidin-2-ylsulfonyl groups on R-carbon are greater than
that of the phenylsulfonyl group.
This methodology for sulfone removal was successful for the
synthesis of our target nucleoside phosphonate. Treatment of
4b with Bu3SnH/AIBN/benzene/∆/48 h caused cleavage of the
sulfonyl linkage (5a, 61%), and removal of the isopropylidene
group and RP-HPLC (H2O/CH3CN; 19:1) gave pooled fractions
of 5b22 enriched in each of the two 6′-fluoro diastereomers
(∼12:1 Vs ∼1:6). Independent treatment of the enriched
diastereomer mixtures with trimethylsilyl bromide and purifica-
tion (DEAE Sephadex A-25; 0.01 f 0.20 M TEAB/H2O)
followed by conversion to the sodium salts [Dowex 50 × 8(H+)
and then (Na+); H2O] gave 6′-deoxy-6′-fluoro-6′-(phosphonato)-
homouridine disodium salt22 (6).
(tetrafluoroborate)]18 gave the desired R-fluoro sulfone phos-
phonate 4a, which was debenzoylated and purified to give 4b22
(47% from 3b).
Standard procedures24 for removal of sulfonyl groups [e.g.,
treatment of 4b with Al(Hg) or Na(Hg); or base-promoted
elimination24b-d] failed to give 5a or its 5′,6′-unsaturated
analogue. Although tributylstannane is used routinely for hydro-
genolysis of carbon-halogen, carbon-sulfur, carbon-selenium,
and carbon-nitro bonds,25 it is ineffective for cleavage of typical
saturated sulfones. In contrast, stannodesulfonylations of vinyl
sulfones26 (including nucleoside examples26b,c) are known, and
recent desulfonylations of 2-(alkyl- and -aryl)sulfonylpyrroles27
might involve successive stannodesulfonylation/protiodestan-
nylation at the “vinylic” C2-C3 bond of the pyrrole ring.
Desulfonylations of allylic sulfones28 with tributylstannane are
known, and sulfonyl radicals are versatile intermediates in
organic synthesis.29 Therefore, we began an investigation of
radical-mediated cleavage of π-deficient aryl sulfones.
Ethyl hexanoate was chosen as a model for diethyl alkyl-
phosphonates in which C2 would simulate the phosphonate
R-carbon. Treatment of ethyl 2-bromohexanoate (7, Scheme
2) with pyridine-2-thione, pyrimidine-2-thione, and benzenethiol
in solutions of NaH/THF/DMF gave the respective ethyl
2-(arylthio)hexanoates in excellent yields. Oxidation gave the
corresponding sulfones 8a,b22 and 8c.23a Treatment of ethyl
2-(phenylsulfonyl)hexanoate (8c) with Bu3SnH/AIBN/benzene
(24) (a) Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon
Press: Oxford, 1993. (b) Fuchs, P. L.; Braish, T. F. Chem. ReV. 1986, 86,
903-917. (c) Van Dort, P. C.; Fuchs, P. L. J. Am. Chem. Soc. 1994, 116,
5657-5661. (d) Jin, Z.; Vandort, P. C.; Fuchs, P. L. Phosphorus, Sulfur
Silicon Relat. Elem. 1994, 95-96, 1-19.
(25) (a) Neumann, W. P. Synthesis 1987, 665-683. (b) Pereyre, M;
Quintard, J.-P.; Rahm, A. Tin in Organic Synthesis; Butterworths: London,
1987.
In summary, we have developed convenient and efficient
methodologies for synthesis of carboxylate and phosphonate
heterocyclic R-sulfones, their R-fluorination with Selectfluor,
and their desulfonylation with tributylstannane. This provides
a facile new route for the preparation of R-[2/3H] and R-fluoro-
R-[2/3H] carbonyl compounds and phosphonates. Barton thio-
hydroxamic ester chemistry was used to prepare a protected
6′-(pyridin-2-ylthio)homouridine phosphonate that was oxidized
(m-CPBA) to the sulfone, fluorinated (Selectfluor), desulfony-
lated (Bu3SnH/AIBN), and deprotected to give the first reported
6′-deoxy-6′-fluorohomonucleoside 6′-phosphonate.
Acknowledgment. We thank the American Cancer Society (Grant
DHP-34) and Brigham Young University development funds for
support, Air Products for a gift of Selectfluor reagent, and Mrs. Jeanny
Gordon for assistance with the manuscript. We also thank Professor
Stefan Kinastowski and the Academy of Agriculture, Poznan, Poland,
for extensions of a faculty leave for S.F.W.
(26) (a) Watanabe, Y.; Ueno, Y.; Araki, T.; Endo, T.; Okawara, M.
Tetrahedron Lett. 1986, 27, 215-218. (b) McCarthy J. R.; Matthews D.
P.; Stemerick, D. M.; Huber, E. W.; Bey, P.; Lippert, B. J.; Snyder, R. D.;
Sunkara, P. S. J. Am. Chem. Soc. 1991, 113, 7439-7440. (c) Wnuk, S. F.;
Yuan, C.-S.; Borchardt, R. T.; Balzarini, J.; De Clercq, E.; Robins, M. J. J.
Med. Chem. 1994, 37, 3579-3587.
(27) Antonio, Y.; De La Cruz, M. E.; Galeazzi, E.; Guzman, A.; Bray,
B. L.; Greenhouse, R.; Kurz, L. J.; Lustig, D. A.; Maddox, M. L.;
Muchowski, J. M. Can. J. Chem. 1994, 72, 15-22.
(28) Ueno, Y.; Aoki, S.; Okawara, M. J. Am. Chem. Soc. 1979, 101,
5414-5415.
(29) Bertrand, M. P. Org. Prep. Proced. Int. 1994, 26, 257-290.
(30) Typical procedure: Ar was bubbled through 9b (304 mg, 1 mmol)/
benzene (5 mL) for 1 h, and Bu3SnH (0.537 mL, 582 mg, 2.0 mmol) was
added. Deoxygenation was continued for 15 min, AIBN (33 mg, 0.2 mmol)
was added, and the solution was refluxed for 1 h (TLC). Volatiles were
evaporated (<25 °C, ∼20 mmHg) and the residue was stirred overnight
with EtOAc/KF/H2O (5 mL/30 mg/0.3 mL). The mixture was evaporated,
and the residue was chromatographed (silica, pentane f 3% EtOAc/pentane)
to give 10c23b (154 mg, 95%).
(31) Rozen, S.; Filler, R. Tetrahedron 1985, 41, 1111-1153.
JA953513S