Biorenewable Resources in the Biginelli Reaction: Cerium(III)-Catalyzed Synthesis of Novel Iminosugar-Annulated Perhydropyrimidines

Abstract

An unprecedented version of the Biginelli reaction using an unprotected aldose as a biorenewable aldehyde component and 2-phenyl-1,3-oxazol-5-one as a novel active methylene building block with urea/thiourea is reported. The reaction is cerium(III)-­catalyzed, expeditious, and effected under solvent-free microwave irradiation conditions to yield diastereoselectively, iminosugar-annulated polyfuntionalized perhydropyrimidines via ring transformation of an isolable intermediate followed by cyclodehydration.

Key words

Biginelli reaction - iminosugars - perhydropyrimidines - microwaves - stereoselective - solvent-free

References and Notes

• 1a Fleet GWJ. Karpas A. Dwek RA. Fellows LE. Tyms AS. Petursson S. Namgoong SK. Ramsden NG. Smith PW. Son JC. Wilson F. Witty DR. Jacob GS. Rademacher TW. FEBS Lett.  1998,  237:  128 
• 1b Taylor DL. Sunkara P. Liu PS. Kang MS. Bowlin TL. Tyms AS. AIDS  1991,  5:  693 
• 2a Nishimura Y. Studies in Natural Products Chemistry   Vol. 16:  . Elsevier; Amsterdam: 1995.  p.75-121  
• 2b Gross PE. Baker MA. Carver JP. Dennis JW. Clin. Cancer. Res.  1995,  1:  935 
• 3a Horii S. Fukase H. Matsuo T. Kameda Y. Asano N. Matsui K. J. Med. Chem.  1986,  29:  1038 
• 3b Robinson KM. Begovic ME. Reinhart BL. Heineke EW. Ducep J.-B. Kastner PR. Marshall FN. Danzin C. Diabetes  1991,  40:  825 
• 4 Asano N. Glycobiology  2003,  13:  93R 
• 5a Nash RJ. Watson AA. Asano N. In Alkaloids: Chemical and Biological Perspectives   Vol. 11:  Pelletier SW. Elsevier; Oxford: 1996.  p.345-376  
• 5b Elbein AD. Molyneux RJ. In Comprehensive Natural Products   Vol. 3:  Barton D. Nakanishi K. Elsevier; New York: 1999.  p.129-160  
• 6a Horii S. Fukase H. Matsuo T. Kameda Y. Asano N. Matsui K. Drugs Future  1986,  11:  1039 
• 6b Horii S. Fukase H. Matsuo T. Kameda Y. Asano N. Matsui K. Drugs Future  1987,  12:  1157 
• 7 Atwal KS. Swanson BN. Unger SE. Floyd DM. Moreland S. Hedberg A. O’Reily BC. J. Med. Chem.  1991,  34:  806 
• 8 Rovnyak GC. Atwal KS. Hedberg A. Kimball SD. Moreland S. Gougoutas JZ. O’Reily BC. Schwartz J. Malley MF. J. Med. Chem.  1992,  35:  3254 
• 9 Grover GJ. Dzwonczyk S. McMullen DM. Normandin DE. Parham CS. Sleph PG. Moreland S. J. Cardiovasc. Pharmacol.  1995,  26:  289 
• 10 Barrow JC. Nantermet FG. Selnick HG. Glass KL. Rittle KE. Gilbert KF. Steele TG. Homnick CF. Freidinger RM. Ransom RW. Kling P. Reiss D. Broten TP. Schorn TW. Chang RSL. O’Malley SS. Olah TV. Ellis JD. Barrish A. Kassahun K. Leppert P. Nagarathnam D. Forray C. J. Med. Chem.  2000,  43:  2703 
• 11a Mayer TU. Kapoor TM. Haggarty SJ. King RW. Schreiber SL. Mitchison TJ. Science  1999,  286:  971 
• 11b Haggarty SJ. Mayer TU. Miyamoto DT. Fathi R. King RW. Mitchison TJ. Schreiber SL. Chem. Biol.  2000,  7:  275 
• 12 Patil AD. Kumar NV. Kokke WC. Bean MF. Freyer AJ. De Brosse C. Mai S. Trunech A. Faulkner DJ. Carte B. Breen AL. Hertzberg RP. Johnson RK. Westley JW. Potts BCN. J. Org. Chem.  1995,  60:  1182 
• 13 Biginelli P. Gazz. Chim. Ital.  1893,  23:  360 
• 14 Kappe CO. Acc. Chem. Res.  2000,  33:  879 
• 15 Dallinger D. Stadler A. Kappe CO. Pure Appl. Chem.  2004,  76:  1017 
• 16 Nilson BL. Overman LE. J. Org. Chem.  2006,  71:  7706 
• 17 Dondoni A. Massi A. Acc. Chem. Res.  2006,  39:  451 
• 18 Dondoni A. Massi A. Sabbatini S. Bertolasi V. J. Org. Chem.  2002,  67:  6979 
• 19 Witczak ZJ. Culhane JM. Appl. Microbiol. Biotechmol.  2005,  69:  237 
• 20 Kappe CO. Eur. J. Med. Chem.  2000,  35:  1043 
• 21 Yadav LDS. Rai VK. Synlett  2007,  1227 
• 22 Yadav LDS. Rai VK. Tetrahedron Lett.  2006,  47:  395 
• 23 Yadav LDS. Yadav S. Rai VK. Green Chem.  2006,  8:  455 
• 24 Yadav LDS. Yadav S. Rai VK. Tetrahedron  2005,  61:  10013 
• 25 Yadav LDS. Kapoor R. J. Org. Chem.  2004,  69:  8118 
• 28 Kappe CO. J. Org. Chem.  1997,  62:  7201 
• 30 Jauk B. Belaj F. Kappe CO. J. Chem. Soc., Perkin Trans. 1  1999,  307 
• 31 Nishio T. Konno Y. Ori M. Sakamoto M. Eur. J. Org. Chem.  2001,  3553 
• 32 Chiba T. Nakai T. Chem. Lett.  1987,  2187 
• 33 Liao M. Yao W. Wang J. Synthesis  2004,  2633 
• 34 Evans DA. Nelson JV. Vogel E. Taber TR. J. Am. Chem. Soc.  1981,  103:  3099 
• 35 Mukaiyama T. Iwasawa N. Chem. Lett.  1984,  753 
• 36 Yadav LDS. Rai VK. Yadav S. Tetrahedron  2006,  62:  5464 

26

General Procedure for Iminosugar-Annulated Perhydropyrimidines 4 and 5: A solvent-free mixture of oxazolone 1 (2.0 mmol), aldose 2 (2.0 mmol), urea/thiourea 3 (2.0 mmol) and Ce₂(SO₄)₃ (0.114 g, 10 mol%) was taken in a 20-mL vial and subjected to MW irradiation for 8-13 min (Table [1] ). After completion of the reaction as indicated by TLC, H₂O (10 mL) was added to the reaction mixture and stirred for 10 min. The yellowish precipitate thus obtained was washed with H₂O to give the crude product which was recrystallized from EtOH to afford a diastereomeric mixture (>94:<6; in the crude products the ratio was >91:<9, as determined by ¹H NMR spectroscopy). The product on second recrystallization from EtOH furnished an analytically pure sample of a single diastereomer 4 or 5 (Table [1] ). On the basis of comparison of J values with the literature ones, [24] [30-36] the trans stereochemistry was assigned to 4 and 5, as the coupling constant (J _1,9a = 9.6 Hz) of the major trans isomer was higher than that for the minor cis diastereomer (J _1,9a = 4.8 Hz).
Characterization Data of Representative Compounds: Compound 4a: pale yellow powder; mp 115-117 °C. IR (KBr): 3341, 3315, 3009, 1685, 1670, 1675, 1603, 1581, 1455 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆ + D₂O): δ = 2.65 (dd, J _6ax,eq = 13.1 Hz, J _6ax,7 = 9.7 Hz, 1 H, H-6_ax), 3.34 (ddd, J _7,8 = 9.3 Hz, J _6ax,7 = 9.7 Hz, J _6eq,7 = 3.7 Hz, 1 H, H-7), 3.70 (dd, J _7,8 = 9.3 Hz, J _8,9 = 9.2 Hz, 1 H, H-8), 3.92 (dd, J _6ax,eq = 13.1 Hz, J _6eq,7 = 3.7 Hz, 1 H, H-6_eq), 4.11 (dd, J _8,9 = 9.2 Hz, J _9,9a = 9.5 Hz, 1 H, H-9), 5.05 (dd, J _1,9a = 9.6 Hz, J _9,9a = 9.5 Hz, 1 H, H-9a), 6.17 (d, J _1,9a = 9.6 Hz, 1 H, H-1), 7.19-7.83 (m, 5 H, ArH). ¹³C NMR (DMSO-d ₆/TMS): δ = 25.5, 59.7, 69.5, 73.5, 74.5, 80.5, 126.9, 127.7, 129.2, 130.8, 132.5, 165.7, 167.8, 169.3. MS (FAB): m/z = 336 [MH⁺]. Anal. Calcd for C₁₅H₁₇N₃O₆: C, 53.73; H, 5.11; N, 12.53. Found: C, 53.47; H, 5.33; N, 12.89.
Compound 5a: pale yellow powder; mp 125-128 °C. IR (KBr): 3343, 3319, 3008, 1683, 1667, 1673, 1604, 1585, 1449 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆ + D₂O): δ = 3.13 (ddd, J _6,7 = 9.7 Hz, J _{1 ′ a,6} = 5.8 Hz, J _{1 ′ b,6} = 2.5 Hz, 1 H, H-6), 3.35 (dd, J _7,8 = 9.4 Hz, J _6,7 = 9.7 Hz, 1 H, H-7), 3.50 (dd, J _{1 ′ a,1 ′ b} = 12.2 Hz, J _{1 ′ a,6} = 5.8 Hz, 1 H, Ha-1′), 3.69 (dd, J _7,8 = 9.4 Hz, J _8,9 = 9.3 Hz, 1 H, H-8), 3.81 (dd, J _{1 ′ a,1 ′ b} = 12.2 Hz, J _{1 ′ b,6} = 2.5 Hz, 1 H, Hb-1′), 4.14 (dd, J _8,9 = 9.3 Hz, J _9,9a = 9.4 Hz, 1 H, H-9), 4.99 (dd, J _1,9a = 9.5 Hz, J _9,9a = 9.4 Hz, 1 H, H-9a), 6.21 (d, J _1,9a = 9.5 Hz, 1 H, H-1), 7.08-7.85 (m, 5 H, ArH). ¹³C NMR (DMSO-d ₆/TMS): δ = 25.9, 61.1, 66.9, 70.3, 73.5, 74.5, 79.9, 127.2, 128.3, 129.7, 131.5, 133.1, 165.2, 166.9, 169.1. MS (FAB): m/z = 366 [MH⁺]. Anal. Calcd for C₁₆H₁₉N₃O₇: C, 52.60; H, 5.24; N, 11.50. Found: C, 52.89; H, 5.59; N, 11.33.

27

General Procedure for 5-Aminoperhydropyrimidine-dione Analogues 9 and 10: Compound 4 or 5 (2.0 mmol) was refluxed in H₂SO₄-H₂O (15 mL, 4:3) for 45 min in an oil bath. The reaction mixture was cooled, the desired products 9 or 10 were precipitated by adding concd NH₄OH (specific gravity 0.88) under ice cooling and recrystallized from EtOH to obtain analytically pure samples of 9 and 10, respectively.
Characterization Data of Representative Compounds:
Compound 9a: pale yellow powder; mp 134-135 °C. IR (KBr): 3345, 3011, 1683, 1669, 1605, 1579, 1451 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆ + D₂O): δ = 2.67 (dd, J _6ax,eq = 13.1 Hz, J _6ax,7h = 9.8 Hz, 1 H, H-6_ax), 3.35 (ddd, J _7,8 = 9.3 Hz, J _6ax,7h = 9.8 Hz, J _6eq,7h = 3.8 Hz, 1 H, H-7), 3.73 (dd, J _7,8 = 9.3 Hz, J _8,9 = 9.3 Hz, 1 H, H-8), 3.95 (dd, J _6ax,eq = 13.1 Hz, J _6eq,7h = 3.8 Hz, 1 H, H-6_eq), 4.09 (dd, J _8,9 = 9.3 Hz, J _9,9a = 9.5 Hz, 1 H, H-9), 5.04 (dd, J _1,9a = 9.7 Hz, J _9,9a = 9.5 Hz, 1 H, H-9a), 6.18 (d, J _1,9a = 9.7 Hz, 1 H, H-1). ¹³C NMR (DMSO-d ₆/TMS): δ = 25.6, 60.1, 69.3, 73.7, 74.6, 80.8, 165.8, 167.9. MS (FAB): m/z = 232 [MH⁺]. Anal. Calcd for C₈H₁₃N₃O₅: C, 41.56; H, 5.67; N, 18.17. Found: C, 41.92; H, 5.49; N, 18.32.
Compound 10a: pale yellow powder; mp 151-153 °C. IR (KBr): 3344, 3009, 1685, 1671, 1601, 1583, 1453 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆ + D₂O): δ = 3.15 (ddd, J _6,7 = 9.7 Hz, J _{1 ′ a,6} = 5.9 Hz, J _{1 ′ b,6} = 2.4 Hz, 1 H, H-6), 3.36 (dd, J _7,8 = 9.4 Hz, J _6,7 = 9.7 Hz, 1 H, H-7), 3.57 (dd, J _{1 ′ a,1 ′ b} = 12.1 Hz, J _{1 ′ a,6} = 5.9 Hz, 1 H, Ha-1′), 3.71 (dd, J _7,8 = 9.4 Hz, J _8,9 = 9.2 Hz, 1 H, H-8), 3.79 (dd, J _{1 ′ a,1 ′ b} = 12.1 Hz, J _{1 ′ b,6} = 2.4 Hz, 1 H, Hb-1′), 4.11 (dd, J _8,9 = 9.2 Hz, J _9,9a = 9.5 Hz, 1 H, H-9), 5.02 (dd, J _1,9a = 9.6 Hz, J _9,9a = 9.5 Hz, 1 H, H-9a), 6.23 (d, J _1,9a = 9.6 Hz, 1 H, H-1). ¹³C NMR (DMSO-d ₆/TMS): δ = 26.0, 61.5, 67.0, 70.5, 73.6, 74.7, 80.2, 165.3, 167.2. MS (FAB): m/z = 262 [MH⁺]. Anal. Calcd for C₉H₁₅N₃O₆: C, 41.38; H, 5.79; N, 16.09. Found: C, 41.18; H, 5.58; N, 16.21.

29

General Procedure for Isolation of Michael Adducts 7a ( n = 3, X = O, R = H) and 7j ( n = 4, X = S, R = Ph) and Their Conversion into the Corresponding Sugar-Annulated Products 4a and 5d:
The procedure followed was the same as described above for the synthesis of 4 and 5 except that the time of MW irradiation in this case was 4-6 min instead of 8-13 min. The adducts 7 were recrystallized from EtOH to give a diastereomeric mixture (>94:<6; in the crude products the ratio was >91:<9, as determined by ¹H NMR spectroscopy) which was again recrystallized from EtOH to obtain an analytical sample of 7a and 7j. The adducts 7a and 7j were assigned the anti stereochemistry as their ¹H NMR spectra exhibited higher values of coupling constant (J _{cyclicNCH,acyclicNCH} = 9.9 Hz) than that of the very minor (<6%) diastereomer (syn, J _{cyclicNCH,acyclicNCH} = 4.4 Hz). [24] [30-36] Finely powdered intermediate compounds 7a and 7j were MW irradiated for 4-7 min in the same way as described for the synthesis of 4 and 5 to give the corresponding sugar-annulated products 4a and 5d quantitatively.
Characterization Data of Representative Compounds:
Compound 7a: pale yellow powder; mp 102-104 °C. IR (KBr): 3148, 3011, 1773, 1677, 1603, 1585, 1455 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆ + D₂O): δ = 4.07 (dd, J _{1 ′ ,2 ′} = 6.9 Hz, J _{1 ′ ,acyclicNCH} = 5.4 Hz, 1 H, H-1′), 4.19 (dd, J _{4 ′ Ha,Hb} = 10.5 Hz, J _{4 ′ Hb,3 ′} = 5.3 Hz, 1 H, H_b-4′), 4.39 (dd, J _{1 ′ ,2 ′} = 6.9 Hz, J _{2 ′ , 3 ′} = 4.1 Hz, 1 H, H-2′), 4.67 (ddd, J _{3,4 ′ Hb} = 5.3 Hz, J _{3,4 ′ Ha} = 5.3 Hz, J _{2 ′ , 3 ′} = 4.1 Hz, 1 H, H-3′), 4.85 (dd, J _{4 ′ Ha,Hb} = 10.5 Hz, J _{3,4 ′ Ha} = 5.3 Hz, 1 H, 4′-H_a), 5.03 (dd, J _{1 ′ ,acyclicNCH} = 5.4 Hz, J _{cyclicNCH,acyclicNCH} = 9.9 Hz, 1 H, acyclic NCH), 6.74 (d, J _{cyclicNCH,acyclicNCH} = 9.9 Hz, 1 H, cyclic NCH), 7.12-7.69 (m, 5 H, ArH). ¹³C NMR (DMSO-d ₆): δ = 35.8, 64.9, 70.5, 71.5, 72.7, 73.5, 73.5, 74.6, 127.5, 128.3, 130.2, 132.9, 133.6, 167.5, 170.2. MS (FAB): m/z = 354 [MH⁺]. Anal. Calcd for C₁₅H₁₉N₃O₇: C, 50.99; H, 5.42; N, 11.89. Found: C, 50.79; H, 5.78; N, 11.63.