A General Method for the Highly Regioselective Introduction of Substituents into the 3-Position of 5-Unsubstituted 4-O-Alkyl Tetronates

Abstract

A new, general method for the highly regioselective introduction of substituents into the 3-position of 5-unsubstituted 4-O-alkyl tetronates has been developed. 3-Lithiated 4-alkoxy-2-triisopropylsilyloxyfurans generated from the corresponding 3-iodo-precursors via halogen-metal exchange serve as key intermediates.

tetronates - iodination - lithiation - regioselectivity - furans

References

For some recent examples, see:

1a Padwa A. Kissell WS. Eidell CK. Can. J. Chem.  2001,  79:  1681 

1b Kende AS. Martin Hernando JI. Milbank JBJ. Tetrahedron  2002,  58:  61 

1c Velázquez F. Olivo HF. Org. Lett.  2002,  4:  3175 

1d Paintner FF. Allmendinger L. Bauschke G. Polborn K. Synlett  2002,  1308 

1e Brueggemann M. McDonald AI. Overman LE. Rosen MD. Schwink L. Scott JP. J. Am. Chem. Soc.  2003,  125:  15284 

1f Kemmler M. Herdtweck E. Bach T. Eur. J. Org. Chem.  2004,  4582 

1g Schobert R. Urbina-González JM. Tetrahedron Lett.  2005,  46:  3657 

For reviews on the synthesis and chemistry of tetronic acids, see:

2a Pattenden G. Fortschr. Chem. Org. Naturst.  1978,  35:  133 

2b Tejedor D. García-Tellado F. Org. Prep. Proced. Int.  2004,  36:  35 

3a Ley SV. Wadsworth DJ. Tetrahedron Lett.  1989,  30:  1001 

3b Ley SV. Trudell ML. Wadsworth DJ. Tetrahedron  1991,  47:  8285 

4 Wadsworth DJ. PhD Thesis   Imperial College, University of London; London: 1989. 

5 Lithium 4-alkoxy 2-furanolates generated by deprotonation of 5-unsubstituted 4-O-alkyl tetronates, e.g. 6a, have been reported to react with electrophiles exclusively at C-5, see: Pelter A. Al-Bayati RIH. Ayoub MT. Lewis W. Pardasani P. Hänsel R. J. Chem. Soc., Perkin Trans. 1  1987,  717 

6 For the regioselective deprotonation of 5-monoalkyl-substituted 4-O-methyl tetronates at C-3 under kinetically controlled conditions and subsequent trapping of the 3-lithiated intermediates with electrophiles, see: Miyata O. Schmidt RR. Angew. Chem., Int. Ed. Engl.  1982,  21:  637 

7 Paintner FF. Allmendinger L. Bauschke G. Synthesis  2001,  2113 

8 Quenching the reaction with deuterated MeOH followed by phosphate buffer (pH 7.5) led to a mixture of (²H)-6a and 3-deuterated 4-methoxy-2-triisopropylsilyloxyfuran. Our attempts to isolate the 2-triisopropylsilyloxyfuran by chromatography failed due to rapid hydrolysis to the corresponding tetronate (²H)-6a. This is in accordance with previous findings showing 4-O-alkyl 2-trialkylsilyloxy-furans to be very prone to hydrolysis (ref. 5)

The facile deprotonation of 2-alkoxy- or 2-trialkylsilyloxy furans in 5-position with t-BuLi at low temperature has previously been reported, see for example:

9a Kraus GA. Sugimoto H. J. Chem. Soc., Chem. Commun.  1978,  30 

9b Jefford CW. Rossier J.-C. Boukouvalas J. Huang P. Helv. Chim. Acta  1994,  77:  661 

10

4-O-Methyl tetronate (6a) is commercially available, e.g. from Acros Organics BVBA, Janssen Pharmaceuticalaan 3a, B-2440 Geel, Belgium

11 Paintner FF. Allmendinger L. Bauschke G. Synlett  2003,  83 

12 Campos PJ. Tan C.-Q. Rodríguez MA. Tetrahedron Lett.  1995,  36:  5257 

13

Typical Procedure.
A solution of iodine (10.15 g, 40 mmol) in DMF (20 mL) was added to an ice-cold solution of 6a (1.14 g, 10 mmol) and pyridine (807 µL, 10 mmol) in DMF (20 mL). The mixture was allowed to warm to r.t. and stirred under the exclusion of light for 22 h, at which time it was poured into sat. aq NaHCO₃ (100 mL). The mixture was extracted with CH₂Cl₂. The combined organic extracts were washed with aq Na₂S₂O₃ and H₂O, dried (MgSO₄) and evaporated under reduced pressure. The resulting residue was recrystallized from EtOAc to give 7a (2.06 g, 86%) as pale yellow crystals; mp 158-160 °C. IR (KBr): 3001, 2950, 1732, 1643, 1621 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 4.14 (s, 3 H), 4.81 (s, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 50.5, 58.4, 68.4, 170.7, 178.5. Anal. Calcd for C₅H₅IO₃: C, 25.02; H, 2.10; I, 52.88. Found: C, 25.01; H, 2.05; I, 52.84.

14

Typical Procedure.
TIPSOTf (867 µL, 3.15 mmol) was slowly added to an ice-cold solution of 7a (720 mg, 3.0 mmol) and Et₃N (481 µL, 3.45 mmol) in CH₂Cl₂ (3 mL). After stirring for 1 h at 0 °C the mixture was poured into ice-cold half-sat. aq NaHCO₃ and extracted with Et₂O. The combined organic extracts were washed with ice-cold half-sat. aq NaHCO₃ and brine, dried (MgSO₄) and evaporated under reduced pressure to afford a mixture of 7a and 8a. To separate the product from starting material the residue was dissolved in n-hexane, filtered and evaporated under reduced pressure to leave 8a (1.13 g, 95%, ÷97% pure as determined by ¹H NMR spectroscopy) as a pale yellow oil. ¹H NMR (500 MHz, CD₂Cl₂): δ = 1.09 (d, J = 7.3 Hz, 18 H), 1.27 (sept, J = 7.3 Hz, 3 H), 3.68 (s, 3 H), 6.56 (s, 1 H).

15

Typical Procedure.
A solution of t-BuLi (1.5 M in hexane, 666 µL, 1.0 mmol) was added dropwise to a solution of 8a (198 mg, 0.5 mmol) in THF (5 mL) at -78 °C. After stirring for 15 min at -78 °C, benzyl bromide (121 µL, 1.0 mmol) was added. The reaction mixture was stirred at -78 °C for 1 h and then was allowed to warm to r.t. during 2 h. Phosphate buffer (pH 5.5, 5 mL) was added and the resulting mixture was stirred for another 30 min at r.t. before it was extracted with Et₂O. The combined organic extracts were dried (MgSO₄) and evaporated under reduced pressure. The resulting residue was purified by flash chromatography (n-hexane-CH₂Cl₂-Et₂O, 20:20:60) to give 1e [17] (90 mg, 88%) as a colorless oil. ¹H NMR (500 MHz, CDCl₃): δ = 3.60 (s, 2 H), 3.93 (s, 3 H), 4.69 (s, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 27.8, 57.7, 65.4, 102.7, 126.4, 128.3, 128.5, 139.1, 173.0, 174.6. HRMS: m/z calcd for C₁₂H₁₂O₃ [M⁺]: 204.0787. Found: 204.0774.

16 Clemo NG. Pattenden G. J. Chem. Soc., Perkin Trans. 1  1985,  2407 

17a Calam CT. Todd AR. Waring WS. Biochem. J.  1949,  45:  520 

17b Wengel AS. Reffstrup T. Boll PM. Tetrahedron  1979,  35:  2181