An Expedient and Short Synthesis of a 6-Iodo Isocoumarin Building Block for the Rubromycin Family and its First Palladium-Catalyzed Couplings

Abstract

An efficient six-step synthesis of 6-iodo substituted isocoumarin 6 is presented, which is a suitable building block for the preparation of rubromycin type compounds. Key transformations of the sequence were achieved by directed ortho-lithiation, Horner-Wadsworth-Emmons olefination and condensation processes. The protected isocoumarin 7 was successfully employed in first Heck and Sonogashira coupling reactions.

Key words

rubromycins - isocoumarins - ortho-lithiation - olefin-ation - palladium catalysis

References

• 1a Brockmann H. Lenk W. Schwantje G. Zeeck A. Tetrahedron Lett.  1966,  3525 
• 1b Brockmann H. Lenk W. Schwantje G. Zeeck A. Chem. Ber.  1969,  102:  126 
• 1c Brockmann H. Zeeck A. Chem. Ber.  1970,  103:  1709 
• 3a Qin D. Ren RX. Siu T. Zheng C. Danishefsky SJ. Angew. Chem. Int. Ed.  2001,  40:  4709 ; Angew. Chem. 2001, 113, 4845
• 3b Siu T. Qin D. Danishefsky SJ. Angew. Chem. Int. Ed.  2001,  40:  4713 ; Angew. Chem. 2001, 113, 4849
• Syntheses of isocoumarin fragments:
• 4a Trash TP. Welton TD. Behar V. Tetrahedron Lett.  2000,  41:  29 
• 4b Waters SP. Kozlowski MC. Tetrahedron Lett.  2001,  42:  3567 
• 5 Gopinath R. Haque SJ. Patel BK. J. Org. Chem.  2002,  67:  5842 
• For related directed ortho-metallations of aromatic acetals, see:
• 6a Plaumann HP. Keay BA. Rodrigo R. Tetrahedron Lett.  1979,  4921 
• 6b Winkle MR. Ronald RC. J. Org. Chem.  1982,  47:  2101 
• 6c Napolitano E. Giannone E. Fiaschi R. Marsili A. J. Org. Chem.  1983,  48:  3653 
• 6d Li C. Lobkovsky E. Porco JA. J. Am. Chem. Soc.  2000,  122:  10484 
• 8 Hajipour AR. Arbabian M. Ruoho AE. J. Org. Chem.  2002,  67:  8622 
• 10a α-Bromination of methyl methoxyacetate: Gagliardi S. Nadler G. Consolandi E. Parini C. Morvan M. Legave M.-N. Belfiore P. Zocchetti A. Clarke GD. James I. Nambi P. Gowen M. Farina C. J. Med. Chem.  1998,  41:  1568 
• 10b Arbuzov reaction leading to 4: Guay V. Brassard P. Synthesis  1987,  294 
• 12a Adler E. Magnusson R. Berggren B. Acta Chem. Scand.  1960,  14:  539 
• 12b Sakamoto T. Kondo Y. Yamanaka H. Heterocycles  1988,  27:  453 
• 12c

  Also see refs. 3a,4b.

• 13a Sonogashira K. Tohda Y. Hagihara N. Tetrahedron Lett.  1975,  4467 
• 13b Sonogashira K. J. Organomet. Chem.  2002,  653:  46 
• 14a Heck RF. Nolley JP. J. Am. Chem. Soc.  1968,  90:  5518 
• 14b Heck RF. Acc. Chem. Res.  1979,  12:  146 
• 14c Review: Beletskaya IP. Cheprakov AV. Chem. Rev.  2000,  100:  3009 
• 15 For a scope of reaction conditions, see: Sonogashira K. In Metal-Catalyzed Cross-Coupling Reactions   Diederich F. Stang PJ. Wiley-VCH; Weinheim: 1998.  p.213 
• 16a Jeffery T. J. Chem. Soc., Chem. Commun.  1984,  1287 
• 16b Jeffery T. Tetrahedron Lett.  1985,  26:  2667 

2

γ-Rubromycin was isolated from Streptomyces collinus and showed antibiotic activity against various bacteria strains.

7

Procedure for the Carboxylation 1 → 2: n-BuLi (1.86 mL, 2.50 M in hexanes, 4.65 mmol) was added at 0 °C to a solution of 1.26 g (3.88 mmol) of 1 in 25 mL of dry cyclohexane. The mixture was stirred at r.t. for 3 h, recooled to 0 °C and 1.00 mL (12.9 mmol) of methyl chloroformate were added. Stirring was continued overnight and the reaction was allowed to warm up to r.t. After quenching with 10 mL of sat. aq Na₂CO₃, the layers were separated and the aqueous layer was extracted with 3 × 10 mL of Et₂O. The combined organic layers were concentrated in vacuo and the residue was dissolved in 25 mL of THF. Then, 37% HCl (aq, 4 mL), 0.70 g (12.0 mmol) KF and 5 mL of H₂O were added and the mixture was stirred at r.t. until TLC indicated complete conversion (6-24 h). The mixture was washed with 20 mL of brine. The layers were separated and the aqueous layer was extracted with 3 × 20 mL of CH₂Cl₂. The combined organic layers were dried over MgSO₄, filtered and evaporated. Column chromatography (silica gel, EtOAc-hexane = 1:1) provided 0.47 g (58%) 2 as reddish solid. Analytical data for methyl 6-formyl-3-hydroxy-2-methoxybenzoate (2): mp 102-104 °C. ¹H NMR (500 MHz, CDCl₃): δ = 3.90 (s, 3 H, OMe), 3.98 (s, 3 H, CO₂Me), 6.45 (br s, 1 H, OH), 7.11, 7.55 (2 d, J = 8.4 Hz, 2 × 1 H, 4-H, 5-H), 9.79 (s, 1 H, CHO) ppm. ¹³C NMR (126 MHz, CDCl₃): δ = 53.0 (q, CO₂Me), 62.5 (q, OMe), 116.6, 129.9 (2 d, Ar), 127.0, 127.6, 144.4, 154.4 (4 s, Ar), 166.9 (s, CO), 189.0 (d, CHO) ppm. IR (KBr): ν = 3150 (O-H), 3005 (=C-H), 2950-2840 (-C-H), 1740, 1660 (C=O), 1600, 1560, 1505 (C=C) cm^-1. MS (EI, 80 eV, 170 °C): m/z (%) = 210 (99) [M]⁺, 195 (57) [M - CH₃]⁺, 182 (46), 179 (71) [M - OCH₃]⁺, 151 (100) [M - CO₂CH₃]⁺, 136 (62), 121 (91), 107 (49), 92 (36), 80 (50), 65 (44), 51 (55), 39 (32). Anal. Calcd for C₁₀H₁₀O₅ (210.2): C, 57.14; H, 4.80. Found: C, 56.86; H, 4.54.

9

The constitution of 3 was confirmed by a NOESY experiment.

11

Assignment of the diastereoisomers was made on the basis of NOESY experiments.

17

Procedure for Heck Reaction 7 → 11: To a solution of 95 mg (0.20 mmol) of 7 and 0.04 mL (0.50 mmol) freshly distilled 3-buten-2-one in 3 mL of dry DMF were added 59 mg (0.21 mmol) of tetra-n-butylammonium chloride, 44 mg (0.52 mmol) of NaHCO₃ and 4 mg (0.02 mmol) of palladium(II) acetate. The mixture was stirred at r.t. and the conversion was monitored by TLC. After 72 h, the mixture was diluted with 3 mL of EtOAc and washed with 2 × 3 mL of brine. The layers were separated and the aqueous layer was reextracted with 1 × 5 mL of EtOAc. The combined organic layers were dried over MgSO₄, filtered and evaporated. Column chromatography (silica gel, EtOAc-hexane = 1:1) provided 76 mg (91%) 11 as yellow solid. Analytical data for methyl 7-benzyloxy-8-methoxy-1-oxo-6-(3-oxo-but-1-enyl)-1H-isochromene-3-carboxylate (11): mp 169 °C. ¹H NMR (500 MHz, DMSO-d ₆): δ = 2.23 (s, 3 H, 4′-H), 3.86 (s, 3 H, CO₂Me), 3.92 (s, 3 H, OMe), 5.13 (s, 2 H, CH₂), 6.77 (d, J = 16.6 Hz, 1 H, 2′-H), 7.33-7.46 (m, 5 H, Ph), 7.53 (s, 1 H, 4-H), 7.55 (d, J = 16.6 Hz, 1 H, 1′-H), 8.01 (s, 1 H, 5-H) ppm. ¹³C NMR (126 MHz, DMSO-d ₆): δ = 27.3 (q, C-4′), 52.9 (q, CO₂Me), 61.8 (q, OMe), 76.3 (t, CH₂), 112.1 (d, C-4), 117.3, 132.3, 136.37, 136.40, 142.0, 152.2, 155.2 (7 s, Ar, C-3, Ph), 122.2 (d, C-5), 128.70, 128.71, 129.0 (3 d, Ph), 131.5 (d, C-2′), 135.5 (d, C-1′), 156.2, 160.3, 198.0 (3 s, CO) ppm. IR (KBr): ν = 3090-3005 (=C-H), 2950-2850 (-C-H), 1750, 1730, 1675 (C=O), 1620, 1600, 1550, 1500 (C=C) cm^-1. MS (EI, 80 eV, 170 °C): m/z (%) = 408 (5) [M]⁺, 366 (12) [M - C₂H₂O]⁺, 275 (12), 91 (100) [C₇H₇]⁺, 43 (18), 28 (21). HRMS (EI, 80 eV, 170 °C): m/z calcd for C₂₃H₂₀O₇: 408.1209. Found: 408.1224.