LETTER
Synthesis of 4-deazaformycin B
1481
to give the isomeric hemiacetals 3 (63%), together with 4
(6%).
(14) The configuration at C-1 was assigned on the basis of nOe
spectral data. In the case of the -D anomer clear correlation
peaks between the OH-1 and the H-2 , H-3 and H-5 were
observed.
(15) In the HMBC spectrum of 4, a strong correlation peak
between the 5-aromatic H and the carbon of the methyl
group (3J coupling) is evident. The methyl group protons
correlate also with the aromatic carbons 3,5 (3J coupling)
and 4 (2J coupling). The methylene group protons possess a
strong correlation with both the anomeric carbon and the
carbonyl. NOESY data provided evidence for the -
conformation, since we observed correlation peaks between
the methylene protons attached at the anomeric position with
H-4 .
References
(1) (a) Revankar, G. R.; Robins, R. K. In Chemistry of
Nucleosides and Nucleotides, Vol. 2; Townsend, L. B., Ed.;
Plenum Press: New York, 1994, 161–398. (b) Srivastava, P.
C.; Robins, R. K.; Meyer, R. B. In Chemistry of Nucleosides
and Nucleotides, Vol. 3; Townsend, L. B., Ed.; Plenum
Press: New York, 1994, 421–535. (c) Perigaud, C.;
Gosselin, G.; Imbach, J. L. Nucleosides Nucleotides 1992,
11, 903. (d) De Clercq, E. Nucleosides Nucleotides 1994,
12, 1271.
(2) (a) Hori, M.; Ito, E.; Takida, T.; Koyama, Y.; Takeuchi, T.;
Umezawa, H. J. Antibiot. 1964, 17A, 96. (b) Long, R. A.;
Lewis, A. F.; Robins, R. K.; Townsend, L. B. J. Org. Chem.
1971, 36, 2443. (c) Lewis, A. F.; Townsend, L. B. J. Am.
Chem. Soc. 1982, 104, 1073. (d) Orozco, M.; Canela, E. I.;
Franco, R. Mol. Pharmacol. 1989, 35, 257.
(16) Data of 3-[(1-hydroxy-2,3,5-tri--benzyl)- -D-ribofurano-
syl)acetylamino]-2-methoxy-4-methylpyridine(4):
Colorless oil. 1-NMR (400 MHz, CDCl3) 1.95 (s, 3 H, 4-
CH3), 2.78 (m, 2 H, COCH2), 3.38 (m, 2 H, H-5 ), 3.73 (d, 1
H, J2 ,3 = 4.56 Hz, H-2 ), 3.85 (m, 1 H, H-3 ), 3.99 (s, 3 H,
OCH3), 4.29 (m, 1 H, H-4 ), 4.32–4.68 (m, 7 H, 3 CH2-Ph,
OH), 6.70 (d, 1 H, J5,6 = 4.98 Hz, H-5), 7.2–7.4 (m, 15 H, 3
C6H5), 7.84 (d, 1 H, J6,5 = 4.98 Hz, H-6), 7.94 (br s, 1 H,
D2O exchangeable, NH). 13C NMR (50 MHz, CDCl3) 18.0
(4-CH3), 41.2 (COCH2), 53.3 (CH3O), 69.3 (C-5 ), 72.3
(CH2-Ph), 72.6 (CH2-Ph), 73.3 (CH2-Ph), 76.9 (C-3 ), 78.9
(C-2 ), 80.4 (C-4 ), 105.0 (C-1 ), 118.9 (C-5), 119.1 (C-3),
127.7 [CH(Ph)], 128.0 [CH(Ph)], 128.2 [CH(Ph)], 128.3
[CH(Ph)], 128.6 [CH(Ph)], 136.7 [C(Ph)], 136.9 [C(Ph)],
137.6 [C(Ph)], 145.6 (C-4), 146.0 (C-6), 158.4 (C-2), 169.2
(C=O). Anal. Calcd. For C35H38N2O7: C: 70.21, H: 6.40, N:
4.68. Found: C: 70.10, H: 6.62, N: 4.63.
(17) The excess n-butyllithium (two equivalents) required for the
lithiation of 1, induces the formation of an anion on the
acetamide’s methyl group, which probably attacks the
ribonolactone to provide 4.
(18) The use of acid labile protecting groups for the 5-OH of the
lactone component (e.g. TBDMS) should be avoided, since
the corresponding 1 ,5 -anhydro derivative is obtained from
this reaction as the major product, irrespective of the
reaction conditions or of the Lewis acid used for catalysis.
(19) Krohn, K.; Heidi, H.; Wielkens, K. J. Med. Chem. 1992, 35,
511.
(3) (a) Robins, R. K.; Townsend, L. B.; Cassidy, F.; Gersrter, F.
G.; Lewis, A. T.; Miller, R. L. J. Heterocycl. Chem. 1966, 3,
110. (b) Koyama, G.; Umezawa, H. Antibiot. Ser. A 1965,
18, 175.
(4) (a) Ishizuka, M.; Sawa, T.; Hori, S.; Takayama, T.;
Takeuchi, T.; Umezawa, H. J. Antibiot. 1968, 21, 5.
(b) Sheen, M. R.; Martin, F. H.; Parks, H. F. Jr. Mol.
Pharmacol. 1970, 6, 255.
(5) Otter, B. A.; Patil, S. A.; Klein, R. S. Abstract CARB 046, the
4th Chemical Congress of North America and the 202nd
American Chemical Society Meeting; ACS: New York,
August 1991.
(6) Ward, D. C.; Fuller, W.; Reich, E. Proc. Natl. Acad. Sci.
U.S.A. 1969, 62, 581.
(7) (a) Gudmundsson, K. S.; Drach, J. C.; Townsend, L. B. J.
Org. Chem. 1997, 62, 3453. (b) Walker, J. A. I. I.; Liu, W.;
Wise, D. S.; Drach, J. C.; Townsend, L. B. J. Med. Chem.
1998, 41, 1236.
(8) Marakos, P.; Pouli, N.; Wise, S. D.; Townsend, L. B. Synlett
1997, 561.
(9) Chapman, D.; Hurst, J. J. Chem. Soc., Perkin Trans. 1 1980,
2398.
(10) Beumel, O. F. Jr.; Smith, W. N.; Rubalka, B. Synthesis 1974,
43.
(11) (a) Cousineau, T. J.; Secrist, J. A. III J. Org. Chem. 1979, 44,
4351. (b) Timpe, W.; Dax, K.; Wolf, N.; Weidmann, H.
Carbohydr. Res. 1975, 69, 51.
(12) For hemiacetals 3 the prefix refers to the position of the
glycosidic OH group relative to the configuration at the
reference C-atom (C-4 in 3; i.e. the methylpyridinyl moiety
is in the -position). For C-glycosides (no glycosidic OH
present), the prefix -D refers to the alkyl (or aryl) position
relative to the reference C-atom.
(20) Preparation of 6: To a solution of the anomers 3 (0.5 g, 0.84
mmol) in dry CH2Cl2 (20 ml) at 0 °C was added under argon
BF3 Et2O (0.22 ml, 1.68 mmol). The solution was stirred at
5–10 °C for 5 h and then, was neutralized with a saturated
NaHCO3 solution. The mixture was extracted with CH2Cl2
and the combined organic extracts were dried (Na2SO4) and
concentrated to dryness. The residue was purified by flash
chromatography (silica gel, 18 1 cm) using EtOAc as the
eluent to give 0.46 g (95%) of an inseparable E/Z mixture of
5. This mixture was dissolved in absolute EtOH (20 mL) and
hydrogenated (10% Pd/C, 90 mg) at 50 psi for 5 h. The
catalyst was filtered off, washed with EtOH, the solvent was
vacuum-evaporated and the residue was purified by column
(13) Optimized procedure for the preparation of the hemiacetals
3: To a solution of 1 (0.5 g, 2.72 mmol) in dry THF (30 ml)
at –78 °C was added under argon n-BuLi (4.3 ml, 6.95 mmol,
1.6 M solution in hexanes). The resulting light yellow
solution was stirred at –78 °C for 15 min and the temperature
then raised to –40 °C for 1 h. The orange-colored solution
was then cooled to –78 °C, a solution of the D-ribonolactone
2 (1.4 g, 3.34 mmol) in dry THF (10 ml) was added dropwise
and the resulting mixture was stirred at –78 °C for 1 h and at
–40 °C for an additional 5 h. A saturated ammonium chloride
solution was then added to the reaction mixture to quench
the excess n-BuLi. The solvent was vacuum-evaporated,
water was added to the residue and this was extracted with
dichloromethane. The organic extracts were dried (Na2SO4)
and concentrated to dryness to give an oil, which was
purified by flash chromatography (silica gel 20 2 cm) using
a mixture of cyclohexane–ethyl acetate, 7:3 v/v as the eluent
chromatography (CH2Cl2–MeOH, 97:3, silica gel, 18
1
cm), to give 6, together with the corresponding -anomer(7).
3-Acetamido-2-methoxy-4-[( -D-ribofuranosyl)methyl]py-
ridine(6): White foam. 250 mg (29%). 1 NMR (400 MHz,
CDCl3) 1.98 (s, 3 H, COCH3), 2.53 (dd, 1 H, J = 9.15 Hz,
14.64 Hz, pyCH2), 2.78 (dd, 1 H, J = 4.03 Hz, 14.64 Hz,
pyCH2), 3.36 (d, 1 H, J4 ,5 = 5.12 Hz, J5 ,5 = 11.71 Hz, H-5 ),
3.41 (d, 1 H, J4 ,5 = 4.03 Hz, J5 ,5 = 11.71 Hz, H-5 ), 3.59 (m,
2 H, H-2 , H-4 ), 3.81 (m, 5 H, H-1 , H-3 , OCH3), 4.88 (m,
1 H, OH, D2O exchangeable), 5.07 (m, 2 H, 2 OH, D2O
Synlett 2002, No. 9, 1479–1482 ISSN 0936-5214 © Thieme Stuttgart · New York