J. Org. Chem. 1992,57, 2357-2364
2357
Nucleic Acid Related Compounds. 73. Fluorination of Uridine 2’-Thioethers with Xenon Difluoride or (Diethy1amino)sulfur Trifluoride. Synthesis of Stable 2’4Alkyl(or Aryl)sulfonyl]-2’-deoxy-2’-fluorouridines1 Morris J. Robins,* Khairuzzaman B. Mullah, Stanislaw F. Wnuk, and N. Kent Dalley Departments of Chemistry, Brigham Young University, Provo, Utah 84602, a n d University of Alberta, Edmonton, Alberta, Canada Received November 26, 1991
Treatment of 2,2’-anhydro-l-j3-~-arabinofuranosyluraci1 with thiolate anions gave the 2’-S-alkyl(and aryl)2’-thiouridines (1). Oxidation of 3’,5’-di-O-acetyl-2’-S-&yl(andaryl)-2’-thiouridines(2) with 3-chloroperoxybenzoic acid (MCPBA) gave the diastereomeric sulfoxides 4. Treatment of 2 with XeF, or 4 with (diethy1amino)sulfur trifluoride/SbC13 gave the diastereomeric 3’,5’-di-O-acety1-2’-S-alkyl(and aryl)-2’-fluoro-2’-thiouridines(9). These a-fluor0 thioethers were oxidized (MCPBA) to their stable sulfone derivatives 11 that are analogues of the biologically active 2’-deoxy-2’,2’-difluoro nucleosides. Stereochemistry (2’s) and conformations of the major diastereomers were established by X-ray crystallography. Efficient conversions of 11 to the cytidine a-fluoro sulfones 14 were achieved.
The size and electronegativity of the fluorine atom make isosteres of important biological molecules in which hydrogen has been replaced by fluorine of significant interest.2 Nucleosides substituted at C2’ in the sugar moiety with fluorine, including the 1-(2-deoxy-2-fluoro-@-~arabinofuranosyl) analogues3of thymidine, 5-iodouridine, 5-iodocytidine (FIAC, A), and 5-ethyluridine, and a 2’fluoroarabinofuranosyladenine analogue,’ show anticancer and antiviral activity. Some 1-(2-deoxy-2-fluoro-@-~ribofuranosyl)analogues of cytidine (B),&halouridhe, and 5-(iodovinyl)uridine display similar a ~ t i v i t y . Recently ~ the preparation and anti-HIV activity of 2’,3’-didehydro2‘,3’-dideoxy-2’-fluoro analogues of cytidine, uridine, and thymidine have been reported! and 2’-deoxy-2’(S)-fluoro (‘arabino”) analogues’ of the anti-AIDS agents 3’-azido3’-deoxythymidine (AZT) and 2’,3’-dideoxycytidine (ddC) have been prepared. Fluoro sugar nucleosides usually have been synthesized by coupling fluor0 sugar derivatives with heterocyclic bases or by transformations on intact nucleoside derivatives including: (i) epoxide cleavage, (ii) displacement of a sulfonyloxy group, or (iii) attack at the carbohydrate terminus of a sugar-base anhydro bond, with fluoride reagents. Syntheses of fluorinated-sugar nucleosides have been reviewed,8 and recent applications of (diethy1amino)sulfurtrifluoride (DAST) have provided a number of fluoro“” and difluoro analogueslWl2from (1) The previous paper in this series is: Zhang, W.; Robins, M. J. Tetrahedron Lett., in press. (2) (a) Schlosser, M. Tetrahedron 1978,34,3. (b) Rozen, S.; Filler, R. Tetrahedron 1985,41,1111. (c) Welch, J. T. Tetrahedron 1987,43,3123. (d) BBguB, J.-P.; Bonnet-Delpon, D. Tetrahedron 1991,47, 3207. (3) (a) Watanabe, K. A.; Reichman, U.; Hirota, K.; Lopez, C.; Fox, J. J. J. Med. Chem. 1979,22,21. (b) Su, T.-L.; Watanabe, K. A.; Schinazi, R. F.; Fox, J. J. J. Med. Chem. 1986,29, 151. (4) Marquez, V. E.; Tseng, C. K.-H.; Kelley, J. A.; Mitauya, H.; Broder, S.; Roth, J. S.; Driscol, J. S. Biochem. Pharmocol. 1987, 36, 2719. (5) (a) Wohlrab, F.; Jamieson, A. T.; Hay, J.; Mengel, R.; Guschlbauer, W. Biochim. Biophys. Acta 1985,824,233. (b) Mercer, J. R.; Knaus, E. E.; Wiebe, L. I. J.Med. Chem. 1987,30,670. (c) Mercer, J. R.; Xu, L.-H.; Knaus, E. E.; Wiebe, L. I. J. Med. Chem. 1989,32, 1289. (d) Iwashina, T.; Tovell, D. R.; Xu, L.; Tyrrell, D. L.; Knaus, E. E.; Wiebe, L. I. Drug Des. Delivery 1988,3, 309. (6) (a) Martin, J. A.; Bushnell, D. J.; Duncan, I. B.; Dunsdon, S. J.; Hall, M. J.; Machin, P. J.; Merrett, J. H.; Parkes, K. E. B.; Roberta, N. A.; Thomas, G. J.; Galpin, S. A.; Kinchington, D. J. Med. Chem. 1990, 33,2137. (b) Sterzycki, R. Z.;Ghazzouli, I.; Brankovan, V.; Martin, J. C.; Mansuri, M. M. J. Med. Chem. 1990,33, 2150. (7) (a) Watanabe, K. A.; Harada, K.; Zeidler, J.; Matulic-Adamic, J.; Takahashi, K.; Ren, W.-Y.; Cheng, L.-C.; Fox, J. J.; Chou, T.-C.; Zhu, Q.-Y.; Polsky, B.; Gold, J. W. M.; Armstrong, D. J. Med. Chem. 1990, 33, 2145. (b) Okabe, M.; Sun, R.-C.; Zenchoff, G. B. J. Org. Chem. 1991,56,
4392.
(8) Herdewijn, P.; Van Aerschot, A.; Kerremans, L. Nucleosides Nucleotides 1989, 8, 65.
naturally occurring nucleosides. y42
“”UV OH
2
A, X=I,Y=F,Z=H
B, X = Y = H , Z = F
c, X = H . Y = Z = F
Nucleoside analogues with gem-difluoro substitution in the ribose ring also have been prepared.12J3 Treatment of a 3‘-ketothymidine derivative with DAST was reported to give 3’-deoxy-3‘,3’-difluorothymidine in low yield.12 The Eli Lilly group has pursued multistep syntheses of 2deoxy-2,2-difluoro-~-ribose derivatives and couplings with pyrimidines (a/@-4:1)13* and purines (a/@~ l : l )tol ~ ~ obtain new and biologically fascinating nucleoside analogues. The @-anomerof 2’-deoxy-2’,2’-difluorocytidine (dFdCyd, C)has potent anticancer activity against solid tumors that usually are refractory to chemotherapy, and C is in human clinical trials.14 The inhibition of ribonucleotide reductase was inferred by biological studies with dFdCyd (C),15and very recently it was demonstrated that (9) (a) Robins, M. J.; Wnuk, S. F. Tetrahedron Lett. 1988,29, 5729. (b) McCarthy, J. R.; Jarvi, E. T.; Matthews, D. P.; Edwards, M. L.; Prakash, N. J.; Bowlin, T. L.; Mehdi, S.; Sunkara, P. S.; Bey, P. J. Am. Chem. SOC. 1989,111,1127. (c) Jarvi, E. T.; McCarthy, J. R.; Mehdi, S.; Matthews, D. P.; Edwards, M. L.; Prakash, N. J.; Bowlii, T. L.; Sunkara, P. S.; Bey, P. J. Med. Chem. 1991,34,647. (d) Sufrin, J. R.; Spiess, A. J.; Kramer, D. L.; Libby, P. R.; Porter, C. W. J. Med. Chem. 1989, 32, 997. (e) Robins, M. J.; Wnuk, S. F.; Mullah, K. B. unpublished resulta. (10) Matulic-Adamic, J.;Takahashi, K.; Chou, T.-C.; Gadler, H.; Price, R. W.; Reddy, A. R. V.; Kalman, T. I.; Watanabe, K. A. J. Med. Chem. 1988,31, 1642. (11) Bamford, M. J.; Coe, P. L.; Walker, R. T. J. Med. Chem. 1990, 33, 2488. (12) Bergstrom, D.; Romo, E.; Shun, P. Nucleosides Nucleotides 1987, 6, 53. (13) (a) Hertel, L. W.; Kroin, J. S.; Misner, J. W.; Tustin, J. M. J. Org. Chem. 1988,53, 2406. (b) Hertel, L. W.; Grossman, C. S.; Kroin, J. S.;
Mineishi, S.; Chubb, S.; Nowak, B.; Plunkett, W. Nucleosides Nucleotides 1989, 8, 951. (14) (a) Grindey, G. B.; Boder, G. B.; Hertel, L. W.; Kroin, J. S.; Poore, G. A.; Rinzel, S. M.; Todd, G. C. Proc. Am. Assoc. Cancer Res. 1986,27, 296. (b) Heinemann, V.; Hertel, L. W.; Grindey, G. B.; Plunkett, W. Cancer Res. 1988, 48, 4024. (c) Weeks, A.; Abbruzzese, J.; Gravel, D.; Plunkett, W.; Raber, M.; Tarassoff, P.; Meyers, C. Proc. Am. Assoc. Cancer Res. 1989, 30, 273.
0022-3263/92/1957-2357$03.00/00 1992 American Chemical Society
Robins et al.
2358 J. Org. Chem., Vol. 57, No. 8,1992 Scheme Io 0
and Miyasaka method21awith our improved conditions22 for the preparation of 2’-S-(I-methoxypheny1)-2’-thiouridine (la) and 2’-S-methyl-2’-thiouridine (lb) (Scheme I). As reported,21aheating 4-methoxybenzenethiol and 2,2’-anhydro-l-/3-~-arabinofuranosyluracil~ in DMF gave la. Treatment of the cyclonucleosideB with alkyl or aryl thiolates in DMF (RSH/NaH/DMF)n also gave la (81%) and lb (78%). Brown et al.24aand Furukawa et reported that its treatment with sodium ethanethiolate/ DMF gave the xylo 3’-deoxy-3’-ethylthio derivative via a presumed 2’,3’-anhydro (ribo epoxide) intermediatesz4 However, our results agree with those of Matsuda and Miyasaka,21aReese,21bteand Ueda2lcVdwith direct substitution having occurred to give the expected ribo configuration at C2’. ‘H NMR spectra of la and lb had upfield shifts of the H2’ peaks (6 3.65 and 3.36, respectively) 1 8.5 Hz relative to that of uridine (6 4.01). The J1,-2t coupling constants for la and l b are indicative of trans configurations and are in harmony with literature values = 8.3 arabino, J1j-2, = 6.8 (2’-S-methyl ribo, Jlcz. Hz21d). Proof of the ribo configuration of la was provided by X-ray crystallography of 6a. Catalytic amounts of 4-(dimethylamino)pyridine in acetic anhydride ( D M A P / A C ~ Oeffected )~~ quantitative acetylation of la to 2a. Partial oxidation of 2a (1.04 equiv of MCPBA/CH2C12/-50 “C) proceeded quantitatively to give the diasteromeric sulfoxides 4a (- 1:l)which were separated by chromatography. Deprotection of the more polar diastereomer and crystallization afforded 6a[S at sulfur (S-S)]whose configurations at sulfur and C2’ were determined by X-ray crystallography. Sulfide 2a and sulfoxides 4a were oxidized to sulfone 7a which waa deprotected to give 8a (81% for two steps). Treatment of 4a (-1:l) with DAST/SbC13/CH2C12at ambient temperature gave the a-fluoro diastereomers 9a (2’R/S, -1:6.5; 56%) plus deoxygenated sulfide 2a (20%). The 9a diastereomers had 19FNMR peaks (upfield from CC13F in Me2SO)centered at 6 -128.27 [dd, 3&-1t = 3JF-3, z 16.5 Hz; 9a(S)] and -139.26 [bs; 9a(R)]. Treatment of 4a(2’R-S) (18 h) and 4a(2’S-S)(7 h) by the noted conditions gave the same ratio of 9a (2’R/S, -1:6.5) plus 2a in similar yields. Thus the stereochemistry of this deoxygenative fluorination process does not depend on the configuration of the precursor sulfoxide, as also waa noted with the 5’-fluorination of adenosine.”sb The preparation of 9a directly18 from 2a gave similar results. Treatment of 2a with XeF2/CH2C12/N2at ambient temperature followed by aqueous workup gave 9a (2‘R/S, 1:4.5; 50%) and the sulfoxides 4a (24%). This permits deletion of the oxidation step, which is especially advantageous when isolation of the sulfoxide in high yield is troublesome (e.g. 4b). The unprotected a-fluoro thioethers were unstable and underwent decomposition during deprotection. However, oxidation of 9a(2’R/S, 1:4.5) with MCPBA (2.3 equiv) afforded the stable a-fluoro
HN3 - HN3 0
O A N
oAN
C,
dore
/
R
HO
SR
1
Series: a. b . R ==C4-MeOC,H4 H3
A
C
AcO
O
G
R’O O
3. R i ; - C 1 B z / Y e
O
R’O
_,SR
4, R = Ac 5, R’ 6. R =H 4-CIBr
a
SR
R’O
\
woY4 ”
2, R = A C
R
RS02
r SRJ
9, R = AC 10, R = 4-CIBz
R’O
RSO2
I, R
= AC
8,R=H
HN3
O A N
i
Acb
12
13
14
(a) AczO/DMAP; (b) 4-C1CsH4COCl/pyridine; (c) MCPBA/ CHzC12/-40 “C; (d) NH3/MeOH; (e) HCl/MeOH; (0MCPBA/ CHzClz/ambient; (g) DAST/SbCl3/CHZCl2/ambient; (h) XeF2/ CHzCl2/-35 “C to ambient; (i) POC13/triazole/Et3N/MeCN; 6 ) NH3/HzO/dioxane.
its 5’-diphosphate (dFdCDP) functions as a potent mechanism-based inhibitor of the purified ribonucleoside diphosphate reductase (EC 1.17.4.1) from Escherichia coli.16 We now report two methods for the conversion of uridine into 2’-S-alkyl(and aryl)-2’-deoxy-2’-fluoro-2’thiouridine analogues and their transformation into stable 2’-[alkyl(and aryl)sulfonyl]-2’-deoxy-2’-fluorouridineand cytidine analogues of dFdUrd and dFdCyd (C). The fiist method utilized the conversion of sulfoxides to a-fluoro thioethers with DAST/SbCl3.” The second employed transformations of thioethers to a-fluoro ~ u l f i d e s with ~~J~ xenon difluoride.l8 From available procedures,20v21 we chose the Matsuda (15) (a) Sunkara, P. S.; Lippert, B. J.; Snyder, R. D.; Jarvi, E. T.; Farr, R. A. Proc. Am. Assoc. Cancer Res. 1988, 29, 324. (b) Heinemann, V.; Xu, Y.-Z.; Chubb, S.;Sen, A.; Hertel, L.; Grindey, G. B.; Plunkett, W. Proc. Am. Assoc. Cancer Res. 1989,30,554. (c) Heinemann, V.; Xu, Y.-Z.; Chubb, S.;Sen, A.; Hertel, L. W.; Grindey, G. B.; Plunkett, W. Mol. Pharmacol. 1990,38, 567. (16) Baker, C. H.; Banzon, J.; Bollinger, J. M.; Stubbe, J.; Samano, V.; Robins, M. J.; Lippert, B.; Jarvi, E.; Resvick, R. J . Med. Chem. 1991,34, 1879. (17) (a) McCarthy, J. R.; Peet, N. P.; LeToumeau, M. E.; Inbasekaran, M. J . Am. Chem. SOC.1985,107,735. (b) Wnuk, S. F.; Robins, M. J. J . Org.Chem. 1990,55,4757. (18) (a) Zupan, M. J . Fluorine Chem. 1976,4305. (b) Marat, R. K.; Janzen, A. F. Can. J . Chem. 1977,55,3031. ( c ) Janzen, A. F.; Wang, P. M. C.; Lemire, A. E. J . Fluorine Chem. 1983,22,557. (d) Forster, A. M.; Downs, A. J. J . Chem. Soc., Dalton T r a m . 1984, 2827. (e) Huang, X.; Blackburn, B. J.; Au-Yeung, S. C. F.; Janzen, A. F. Can. J . Chem. 1990, 68,477. (0Robins, M. J.; Wnuk, S. F.; Mullah, K. B.; Dalley, N. K. J. Org. Chem. 1991,56,6878. (19) Umemoto, T.; Tomizawa, G. Bull. Chem. SOC.Jpn. 1986,59,3625. (20) Ueda, T. In Chemistry of Nucleosides and Nucleotides; Townsend, L. B. Ed.; Plenum Press: New York, 1988; Vol. 1, pp 1-112.
-
(21) (a) Matsuda, A.; Miyasaka, T. Heterocycles 1983, 20, 55. (b) Divakar, K. J.; Reese, C. B. J . Chem. Soc., Perkin Trans. I 1982, 1625. (c) Imazawa, M.; Ueda, T.; UkiG, T. Chem. Pharm. Bull. 1975,23,604. (d) Shibuya, S.;Ueda, T. J . Carbohydrates Nucleosides Nucleotides 1980, 7,49. (e) Divakar, K. J.; Mottoh, A.; Reese, C. B.; Sanghvi, Y. S. J . Chem. SOC.,Perkin Trans. I 1990, 969. (22) Robins, M. J.; Haneake, F.; Wnuk, S. F.; Kanai, T. Can. J . Chem. 1991,69, 1468. (23) Hampton, A,; Nichol, A. W. Biochemistry 1966,5, 2076. (24) (a) Brown, D. M.; Parihar, D. B.; Todd, Sir A.; Varadarajan, S. J . Chem. SOC.1958, 3028. (b) Furukawa, Y.; Ymhioka, Y.; Imai, K.-I.; Honjo, M. Chem. Pharm. Bull. 1970, 18,554. (25) Robins, M. J.; MacCoss, M.; Naik, S.R.;Ramani, C. In Nucleic
Acid Chemistry: Improved and New Synthetic Procedures, Methods, and Techniques;Townsend, L. B., Tipson, R S., Eds.;Wiley-Interscience: New York, 1986; Vol. 3, pp 58-60.
Nucleic Acid Related Compounds
-
J. Org. Chem., Val. 57, No. 8, 1992 2359
sulfones lla(2’R/S, 1:4.4; 80%). Preparative HPLC separated a sample of the major diastereomer lla(2’S) whose configuration and molecular conformation were determined by X-ray crystallography. Deprotection gave 12a(2’S) [l9F NMR 6 -160.11 (dd, VF-’.= 21.5 Hz, 3JJr-31 = 22.0 Hz)]. Formation of the major 9a(2’S) isomer with fluorine in the rib0 orientation might indicate attack by fluoride at the less hindered a-face of the sugar ring at C2’ of an intermediate sulfenium cation.’’la An arylthio group in the arabino orientation permits parallel stacking of its benzene ring and the uracil base. Acetylation of the 2‘-methylthio analogue l b gave 2b quantitatively. Partial oxidation of 2b (MCPBA, 1.03 equiv) gave low isolated yields of the diastereomers of 4b 03’ (-22%) owing to their high polarity. [We later found that Figure 1. X-ray crystal structure of 6a(S-S) drawn with SPIELXTL chromatographic purification without aqueous workup PLUS.^^ Hydrogen atoms were omitted for clarity. gave good yields of 4b.l Oxidation of 2b (MCPBA, 2.4 04 equiv) afforded 7b which was deprotected to give methyl sulfone 8b (57%, two steps). Treatment of 2b with XeF, gave the unstable 9b diastereomers (2’R/S, 1.5:l; 22%), sulfoxides 4b, and unchanged 2b. The fluoro nucleoside fraction 9b had an inverted diastereomer ratio relative to the conversion of 2a to 9a, but the instability of 9b made this ratio suspect. Fluorination of 2b (XeF,) and direct oxidation of the crude mixture (MCPBA, 2.08 equiv) gave 7b plus the a-fluoro sulfones 11b(2’R/S, -1:4.6; 46%). This diastereomer ratio and yield was consistent with that C5’ for the transfomation of 2a to l l a with XeFP Recrystallization of the 1l b mixture afforded the major isomer (higher field ‘Tresonance) whose S configuration at C2’ was confirmed by X-ray crystallography. Deprotection of llb(2’S) gave the stable a-fluoro sulfone 12b(2’S). c52 C32 It is noteworthy that fluorination was not observed on the methyl group of 2b in contrast with fluorinations of Figure 2. X-ray crystal structure of lla(2’S) drawn with SHELXTL PLUS.^* Hydrogen atoms were omitted for clarity. methionine, methionylglycine, and cytsteine derivatives with XeF2 that were reported to occur exclusively on the methyl carbon.’&ie Fluorinations of 2‘,3‘-di-O-acety1-5‘-SmethyL5’-thioadenosine with XeF,* and ita sulfoxide with DASPadgave regioisomeric mixtures of the 5’-S-(fluoromethy1)thio compound and 5’-fluoro-5’-S-methylthio diasteromers. Steric and electronic effects at the vicinal aminacetal carbon (Cl’) might control the apparently regiospecific fluorination of 2b at C2’ in the present case. The regiochemistry of the sulfoxide/DAST/SbC13route with methylthio at C2’ also was evaluated. Protection of l b with 4-chlorobenzoyl chloride gave the 3’,5’-diester 3b that was oxidized (MCPBA) to sulfoxides 5b (-3:1,85% from lb). Recrystallization afforded 5b (-5:l) whose major diasteromer was tentatively assigned (R-S)by comparison of ita ‘H NMR spectrum with those of the known & C32 4a sulfoxides. Signals for H1’ of sulfoxides 4a and 5b (R-S) Figure 3. X-ray crystal structure of llb(2’S) drawn with SHELXTL resonate at lower field (>0.2 ppm) and those for H2’ at PLUS.^^ Hydrogen atoms were omitted for clarity. higher field P0.2 ppm) relative to those of their diaste1la(2’S)with POC1,/Et3N/triazole gave the 4-(1,2,4-trireomers (S-S) (Table I). Deprotection of 5b (-5:l) and azol-l-yl)pyrimidin-2-onederivative 13a(2’S) that was crystallization afforded 6b(R-S). Treatment of 5b with treated with NH3/HzO/dioxane and then NH3/MeOH to DAST/SbC13 and chromatography gave 10b (2’R/S, 1:7; give 14a(2’S)(76% for three steps). Similarly, llb(2’S) 61%) which was recrystallized to give lOb(2’S). The abgave 14b(2’S) (61%). The 13CNMR peaks for C2’ of the sence of ‘TNMR peaks in the region of 6 -180 to -1859a-d a-fluoro sulfones 11-14 are shifted downfield to 6 107 in the crude mixture or purified fractions indicated that (d, ‘JC2t-F = -230 Hz)(Table 11), approaching the range fluorination did not occur at the methyl carbon. In conof the reported signal for C2’ of dFdCyd (C) at 6 l23.77.lb trast, treatment of methyl ethyl sulfoxide with DAST gave Attempts to convert lla and l l b into 2’-deoxy-2’,2‘-di(fl~oromethy1)thioethane.”~Fluorination of 3b with XeF, fluorouridine derivatives resulted in recovery of starting under the usual conditions gave 10b in low isolated yields. material and/or formation of complex reaction mixtures. The a-fluoro sulfones lla(2’S)and llb(2’S) were conThe absolute configurations and conformations of 6averted to their cytidine counterparts 14a(2’S) and 14b(2’S) (S-S), lla(2’S),and llb(2’S) are shown in Figures 1-3, by the procedure of Divakar and ReeseaZ6Treatment of respectively. Positional and thermal parameters plus bond lengths and angles for non-hydrogen atoms, important (26) Divakar, K.J.; Reeee, C.B.J. Chem. SOC.,Perkin Trans. 1 1982, 1171. torsion angles for the sugars, and hydrogen bonding
-
Robins et al.
2360 J. Org. Chem., Vol. 57, No. 8,1992
(JIf-,J 6.17 (9.0)
lb
6.06 (8.5)
3.36 (5.5)
4.21 (2.0)
3.82-3.89
3.51-3.59
5.72 (8.0)
7.88
11.40
2a
6.12 (9.0) 5.98 (9.0) 6.12 (8.5)
4.11 (6.0) 3.80 (6.0) 4.06 (6.0)
5.35d (1.6) 5.3Id (2.0) 5.72d (2.5)
4.17-4.22
4.23-4.27
7.41
11.32
4.21-4.26
4.21-4.26
7.71
11.52
4.56-4.64
4.56-4.64
5.49 (8.0) 5.78 (8.0) 5.75 (8.0)
7.80
11.55
6.25 (6.0) 6.05 (9.0)
4.08-4.13'
5.56d (5.5) 5.54d (2.0)
4.24-4.3 1
4.08-4.13
7.34
11.28
4.23-4.30 (5.0)
4.23-4.30 4.1gd
5.42 (8.0) 5.43
7.28
11.18
6.45 (4.0) 6.14 (6.7) 6.52 (4.0) 6.27 (6.5) 6.34 (7.5)
3.98-4.33'
5.56 (7.8)
3.98-4.33
3.98-4.33
7.82
11.48
4.24 (8.6) 4.44 (8.5) 3.58 (7.0)
6.07d (8.4)
4.3ge (4.0, 5.3)
4.29 (6.0)
3.71-3.76 (4.5, 5.0)
3.50; 3.40' (12.5)
6.13 (9.0)
3.88 (5.0)
4.58 (1.5)
3.92-3.96
3.48-3.58
6.49 (5.0)
3.41-3.621 (7.0)
4.46 (6.0)
3.66-3.73
6.30
5.53d (2.5) 5.56d (5.1)
4.04-4.23
compd la
2b 3b 4a(R-S) 4a(S-S) 4b(R/S)m
5b(R/S)"
Ga(R-S)
Ga(S-S) Gb(R-S) 7a
(8.0)
4.46 (6.0)
H3''
Table 1. 'HNMR Spectral Dataa** H4'f H5',5"fJ H5' (J4'-5',5") (Js-54 (JH) H6' 3.84-3.89 3.50-3.57 5.40 7.50
H2'd (J2t-3f) 3.65 (5.0)
(JY-,,)
4.29
7b
6.34 (6.6)
Sa
6.50 (9.2)
4.23 (5.4)
4.52 (2.0)
8b
6.49 (8.4)
4.00 (5.6)
9a(2's) n*o ga(2'R)"J 9a(2'S)"sr gb(2'R)" 9b(2'S)" 1Ob(2's)" 11a(2'S)X 1I b(2'S)Y
lZa(2'S) 12b(2'S) 13a(2's) 13b(2's)
(8.0)
(1.0)
4.86 (7.0) 4.62 (7.3)
(8.0)
NHh 11.15
(8.0)
aromatic' (JA-~) others' 7.29, 6.78 5.83' (5.4; OH3') 18.5) 5.0@ (5.5.' OH59 . , 3.70 (MeO) 5-64' (5.0; OH3') 5.12k (4.5,' OH5') 2.02 (MeS) 7.34, 6.83 3.74 (MeO) 2.13, 2.05 (Ac's) (8.8) 2.12, 2.06 (Ac's) 2.06 (MeS) 8.03, 8.00 2.11 (MeS) 7.66, 7.61 (8.8) 7.55, 7.05 3.78 (MeO) 2.18, 2.00 (Ac's) (8.8) 7.65, 7.00 3.78 (MeO) 2.20, 2.05 (Ac's) (8.8)
(11.0)
4.63: 4.54d (12.0)
5.72 (8.0) 5.76 (8.0) 5.71 (8.0) 5.76 (8.0) 5.40 (8.0)
7.98
7.43
11.10
7.52, 7.01 (9.0)
5.34
7.44
10.98
7.54, 6.93 (9.0)
7.72
11.45
7.35
11.38
7.72 11.53
7.82
(8.0)
3.41-3.62
5.64
7.96-8.02' 7.64, 7.56 (8.8)
(8.0)
4.19-4.30 (7.0)
4.04-4.23
5.44 (8.0)
5.70 (8.0)
7.69
11.45
3.84-3.90
4.19-4.30 4.10d (12.5) 3.44-3.52
5.47 (8.0)
7.53
11.30
4.49 (2.5)
3.90-3.98
3.45-3.60
5.75 (8.0)
7.79
11.45
5.62 (8.0) 5.63d (8.0, 2.29 5.82d (8.0, 2.29 5.72 (8.0) 5.74 (8.0) 5.71
7.72h
11.42
7.34
8.70
7.34
8.70
7.65d (3.09 7.72P
11.58 11.58
7.85
11.62
7.73
11.50
7.62
11.56
7.68
11.40
7.65
11.50
6.25P (16.59) 6.38 (17.49) 6.36 (15.49) 6.24 (14.09) 6.32P (17.09) 6.42P (17.09)
5.72h
4.15-4.22
4.23-4.31
5.06d (2.6, 15.P) 5.39 (7.6, 14.2#) 5.48d (5.0, 16.06) 5.75d (3.0, 15.06) 6.p
4.15-4.45
4.15-4.45
4.15-4.45
4.15-4.45
4.25-4.35
4.25-4.35
4.25-4.35
4.25-4.35
4.62-4.71
4.62-4.71
6.52 (22.09) 6.53 (21.09) 6.35 (21.59)
5.87d (9.0, 20.06) 5.85d (7.0, 20.06) 4.70 (9.0, 22.06)
4.20-4.28
4.28-4.39
4.35-4.42
4.35-4.42
3.80' (2.0, 3.0)
3.75,' 3.58' (13.0)
6.40 (22.49)
4.70 (9.0, 23.69
3.82-3.90 (2.0, 5.0)
3.71; 3.65' (14.0)
6.78 (21.09)
5.87d (7.8, 18.5')
4.35-4.45
4.35-4.45
6.75 (20.09)
5.90d (7.7, 18.59
4.42-4.54
(8.0)
5.76 (8.0) 5.72 (8.0)
5.72
(8.0)
5.68
7.73, 7.05 (8.8)
7.33, 6.95 (8.8) 7.36, 6.82 (8.8)
7.36, 6.82 (8.8)
7.98, 7.90 7.63, 7.53 (8.8) 7.68, 7.20 (9.0) 7.75, 7.14 (9.0)
(8.0)
7.12
8.53
(8.0)
4.42-4.54
7.69, 7.03 (9.0)
7.12 (8.0)
7.68, 7.22 (8.8)
8.45
2.58 (MeSO) 2.02, 2.12 (Ac's) 2.64 (MeSO) 2.04, 2.12 (Ac's) 2.60 (MeSO) 2.70 (MeSO) 6.08' (5.0; OH3') 4.82k (5.0,' OH5') 3.74 (MeO) 6.4W (5.0; OH3') 5.20" (OH5') 3.76 (MeO) 5.98' (5.0; OH3') 4.97k (5.3,' OH5') 2.55 (MeSO) 3.78 (MeO) 2.02, 1.99 (Ac's) 3.10 (MeS0,) 2.04, 1.99 (Ac's) 6.MC(6.4; OH3') 5.16h (OH5') 3.83 (MeO) 6.32c (5.5; OH3') 5.2Ik (5.4,' OH5') 3.13 (MeSO,) 3.78 (MeO) 2.05, 1.86 (Ac's) 3.78 (MeO) 2.18, 2.05 (Ac's) 3.78 (MeO) 2.12, 1.95 (Ac's) 2.18 (MeS) 2.09, 2.04 (Ac's) 2.16 (MeS) 2.09, 2.02 (Ac's) 2.12 (1.2," MeS) 3.88 (MeO) 2.08, 1.70 (Ac's) 3.15c (2.0," MeS02) 2.17, 2.08 (Ac's) 5.95' (8.5: OH3') 5.3@ (5.0,' OH57 3.88 (MeO) 6.60' (7.8; OH3') 5.35k (4.8,' OH5') 3.12' (2.0," MeS0,) 9.50, 8.48 (trimole); 3.88 (MeO), 2.08, 1.72 (Ac's) 9.50, 8.47 (triazole); 3.19' (2.0,wMeSO,) 2.14, 2.08 (Ac's)
Nucleic Acid Related Compounds
6.46 (22.59)
4.65 (9.0, 21.5s)
Table I (Continued) H5’,5”f9 H5‘ (J4’-5’,5”) (Jy-5”) (JH) 3.58‘ 3.78; 3.72e 5.73 (2.0, 2.5) (13.0) (7.5)
6.53 (22.39)
4.65 (8.5, 23.W)
3.65‘ (5.5, 3.5)
H1’‘ compd 14a(2’S)
14b(2’S)
J. Org. Chem., Vol. 57, No. 8, 1992 2361
(J1,-,,)
H2’d
H3”
(Jy-3’)
( 5 3 4
H4’ f
3.80-3.88
5.74 (7.8)
aromatic‘ H6‘ 7.60
NH“
(JA-B)
7.70, 7.12 (8.8)
7.54
others’ 7.35,” 7.2ah (NH’s) 5.85; (8.5,’OH3’) 5.20: (5.5,’ OH5’) 3.88 (MeO) 7.32,” 7.2ah (NHs) 6.45‘ (8.0,’ OH3’) 5.27k (5.5,’OH5’) 3.08‘ (2.0,” MeS0,)
” Chemical shifts (8) in MezSO-dsat 400 MHz unless noted otherwise. “Apparent” first-order coupling constants (hertz, in parentheses). Doublet unless noted otherwise. Doublet of doublets unless noted otherwise. e Doublet of doublets of doublets unless noted ,otherwise. ’Multiplet unless noted otherwise. #Upfield resonance assigned to HB”(pro-R). Broad singlet. ’Singlet unless noted otherwise. (3&MH). Signals assigned from spectrum of the mixture (correlated with integrated intensities). Signals in upper row refer Triplet. (3&MH,). to major diastereomer (tentatively R-S). Signals for the 2‘R and 2‘sdiastereomers assigned from a spectrum of the mixture by correlation of integrated intensities with the IgF NMR spectrum. Proton shifts for the minor 2‘R isomer were identical except 8 7.42‘ (JHA-m = 8.8 Hz, aromatic), 3.75’ (MeO), 2.15; 2.04’ (Ac’s). PBroad doublet. ‘I(3tJ1,+).‘In CDCl,. (353f-F).* (IJ5-NH). ’(55&F). ‘Proton shifts for the minor 2’R isomer were identical. In CDC13the 2’R isomer had 8 6.42‘ (16.8,q Hl’) and the 2’sd 6.56‘ (14.6,q Hl’). ” (4JCHsF). ‘Proton shifts for the minor 2‘R isomer were identical except 8 6.2W (21.0,q Hl’), 5.70‘ (JH = 8.0 Hz, H5), 1.97,’ 1.62’ (Ac’s). YProton shifts for the minor 2’R isomer were identical except 8 7.65d ( J H = 8.0 Hz, 2.0,” H6), 5.70‘ (H5), 3.18‘ (1.5,” MeSO,), 2.20,’ 2.10’ (Ac’s).
”
Table 11.
‘WNMR SDectal Dataaob
comDd la lb 2ad 2bd 3b
c2
c4
c1’
c2’
162.96 163.30 162.40 161.90 162.72
c5 102.42 102.59 102.64 102.09 102.81
C6
150.88 151.02 150.39 149.76 150.49
140.07 140.71 139.63 139.32 140.56
88.04 87.43 88.10 86.41 88.28
55.78‘ 53.06 51.20 48.58 49.70
c3’ 72.55 71.98 73.80 72.54 74.07
4a(R-S)d 4a(S-S)d Ga(R-S) Ga(S-S) 1la(2’S)d
149.57 149.68 149.73 149.91 150.08
162.56 162.6lC 162.70 162.25‘ 163.14
101.97 102.63 101.95 102.42 101.97
141.94 139.86 141.44 139.63 141.71
82.72 82.26 85.52 86.57 86.9Oe (40.09 86.45‘ (37.N 86.18‘ (39.09 85.75‘ (38.49 88.21‘ (38.9
64.70 65.85 69.13‘ 71.13‘ 106.5ge (234.0s) 105.70‘ (232.88) 107.88‘ (229.08) 107.67‘ (227.48) 106.2ge (238.68)
72.29 72.93 70.72‘ 71.83‘ 68.11e (13.6h) 67.83‘ (13.2”) 68.61‘ (15.8”) 68.62‘ (15.7”) 68.27‘ (13.3”)
11b(2’S)d 150.38 163.05 102.13 141.09 12a(2’s) 149.68 162.77 101.23 141.34 12b(2’S) 150.13 163.24 101.48 141.44
C4’
86.73 86.67 80.31 79.46 79.93 79.55 80.17 81.89 80.97 75.90
aromatic c5’ c1” c2“ c3” c4” others 61.61 123.35 135.04 114.91 159.53 55.26‘ (MeO) 61.41 13.68 (MeS) 63.21 121.59 135.00 114.80 159.56 55.24 (MeO) 13.37 (MeS) 62.47 64.10 128.06 131.25 129.05 138.75 164.63, 163.92 (Bz’s) 127.79 131.12 128.96 138.48 14.24 (MeSj 62.78 130.84 130.84 114.87 161.50 55.51 (MeO) 62.67 131.40 127.86 114.86 162.1lC 55.57 (MeO) 60.72 125.86 132.71 114.62 161.19 55.46 (MeO) 61.41 127.44 132.20 114.67 162.2W 55.48 (MeO) 61.71 125.65 132.25 115.48 165.51 56.30 (MeO) 38.54’ (MeSO,)
75.99 61.64
80.84 58.04 126.41 132.16 114.59 164.48 55.89 (MeO) 38.31 (MeSO,)
80.77 57.95
79.27 61.78 125.30 132.26 115.42 165.45 154.73, 150.48, (triazole) 56.20 (MeO) 154.76, 149.88, 13b(2’S)d 153.71 159.67 94.90 144.45 87.95‘ 105.56e 67.63e 79.28 61.75 (triazole) (40.29 (238.78) (14.6h) 38.64 (MeSO,) 14a(2’S) 154.45 165.78 93.92 142.82 87.08‘ 108.2P 68.99‘ 80.54 58.40 127.09 132.44 114.70 164.64 55.93 (MeO) (38.d) (229.08) (16.2”) 38.62 (MeSO,) 14b(2’S) 154.62 165.77 94.05 142.53 86.4ge 107.78‘ 68.40‘ 80.21 58.10 (38.09 (227.98) (15.7“) “Chemical shifts (8) in Me2SO-d6at 75.5 MHz. Proton-decoupled singlets unless noted otherwise. ‘Assignments may be reversed. dSignals for acetyl groups at 8 168.64-170.37 (CO) and 19.72-20.53 (CH3). ‘Doublet. ’(2Jc1,-F). ( ‘ J c y - ~ ) . (‘Jc3,47). Signal Close to MezSO-d6signals, but resolved clearly in CDC13. 13a(2’S)d 153.14 159.59
95.51 144.40
“
schemes are included in the supplementary material. The glycosyl torsion angles C6-Nl-C1’-04’ are 58.5 (5)’, 38.6 (2)’, and 27.1 (4)’ in 6a(S-S), lla(2’S),and llb(2’S), respectively, and the furanose pseudorotation angles are 179.4’ (2T3conformation), 55.1’ (4To),and 72.4 (‘TJ. The C3’-C4’-C5’-05’ torsion angle in 6a(S-S) is 50.5 (6)’ in the normal g+ (gg) range. In contrast, this angle in lla(2S) is -62.9 (2)’ [g- (tg)], and 174.8 (3)’ [t (gt)] in llb(2’S). All hydrogen atoms bonded to nitrogen and oxygen are involved in intermolecular hydrogen bonds. Nearly parallel uracil and benzene ring orientations (dihedral angles between the ring planes are 13.3’ and 11.7’, respectively) would allow favorable T--?Tinteractions in both 6a(S-S) (Figure 1)and lla(2’S) (Figure 2). Thus, both the DAST/SbC13 treatment of protected nucleoside 2’-sulfoxides and direct treatment of their precursor thioethers with XeF, give good yields of 2’-fluor0
’
thioethers that can be oxidized to stable 2‘-fluor0 sulfones. The latter compounds with geminal electronegative fluoro and sulfone substituents at C2’ represent analogues of the exciting 2’,2’-difluoro nucleosides which exhibit potent antitumor activity. Biological and enzyme inhibitory studies with these new analogues are in progress. Experimental Section Uncorrected melting points were determined on a microstage (75.5 MHz),and 19F NMR (376.5 MHz) block. ’H (400 MHz), NMR spectra were determined in MezSO-d6 solutions unless otherwise noted with Me,Si internal (‘H and 13C) and CC13F extemal (19F)standards (negative 19Fchemical shifts upfield from CC13F). High-resolution E1 mass spectra were determined at 70 eV and low resolution spectra a t 20 eV. (Diethy1amino)sulfur trifluoride (DAST) was used as received from Aldrich Chemical Co. Equivalent yields of oxidation products were obtained with
Robins et al.
2362 J . Org. Chem., Vol. 57,No. 8,1992 3-chloroperoxybenzoic acid (MCPBA, 85%; Aldrich) with or without extraction to remove 3-chlorobenzoic acid. Xenon difluoride was obtained from PCR, Inc. Reagent-grade chemicals were used, and solvents were purified, dried, and distilled. TLC (silica) sheets were developed in MeOH/CHC13 (1:19) and/or Me2CO/CHC13(1:3) with visualization under UV (254-nm) light. Sulfur-containing compounds were detected by spraying TLC plates with a solution of PdC12(0.4 g) in concentrated hydrochloric acid/HzO (1:9,100 mL). Merck Kieselgel60 (230-400 mesh) was used for column chromatography. Gradient flash chromatography [CHCl, to Me2CO/CHC13 (1:3)] was performed with a 2% increasing gradient of Me2C0. Solvents were flash evaporated a t
