A Highly Efficient Approach to 5-Alkyl-5-hydroxymethyl Substituted 4-O-Benzyl Tetramates

Abstract

4-O-Benzyl-5-methoxycarbonyl tetramates readily available by 5-methoxycarbonylation of 4-O-benzyl tetramates undergo highly regioselective alkylations with various alkyl halides to give 5-alkyl-4-O-benzyl-5-methoxycarbonyl tetramates in high overall yields. These can be efficiently converted into 5-alkyl-5-hydroxymethyl substituted 4-O-benzyl tetramates and further into the respective tetramic acids.

antibiotics - tetramic acids - alkoxycarbonylations - alkylations - regioselectivity

References

For reviews covering 3-acyl tetramic acid natural products, see:

1a Royles BJL. Chem. Rev.  1995,  95:  1981 

1b Rosen T. Drugs Future  1989,  14:  153 

2 Singh SB. Zink DL. Goetz MA. Dombrowski AW. Polishook JD. Hazuda DJ. Tetrahedron Lett.  1998,  39:  2243 

3a Sugie Y. Dekker KA. Inagaki T. Kim Y.-J. Sakakibara T. Sakemi S. Sugiura A. Brennan L. Duignan J. Sutcliffe JA. Kojima Y. J. Antibiot.  2002,  55:  19 

3b Singh MP. Zaccardi J. Greenstein M. J. Antibiot.  1998,  51:  1109 

3c Vesonder RF. Tjarks LW. Rohwedder WK. Burmeister HR. Laugal JA. J. Antibiot.  1979,  32:  759 

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4 Sugie Y. Inagaki S. Kato Y. Nishida H. Pang C.-H. Saito T. Sakemi S. Dib-Hajj F. Mueller JP. Sutcliffe J. Kojima Y. J. Antibiot.  2002,  55:  25 

5 For a review, see: Economou A. Emerging Therapeutic Targets  2001,  5:  1 

For enantioselective syntheses of aldehyde 4 (R = H), see:

6a Yuki K. Shindo M. Shishido K. Tetrahedron Lett.  2001,  42:  2517 

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7b Jones RCF. Bates AD. Tetrahedron Lett.  1986,  27:  5285 

Of the members of this class of natural products only equisetin(1a) has been synthesized so far. For the three total syntheses, which all feature a final Lacey-Dieckmann cyclisation for the construction of the 3-acyl tetramic acid moiety, see:

8a

Ref. [6a]

8b Burke LT. Dixon DJ. Ley SV. Rodriguez F. Org. Lett.  2000,  2:  3611 

8c

Ref. [6b]

For 5-monoalkylations and 5,5-dialkylations as well as for5-hydroxyalkylations of 5-unsubstituted 4-O-methyl tetramates, see:

9a Gill GB. James GD. Oates KV. Pattenden G. J. Chem. Soc., Perkin Trans. 1  1993,  2567 

9b

Ref. [7a]

9c

Ref. [7b]

10 For a recent asymmetric approach to 5-hyroxymethyl-5-methoxycarbonyl tetramic acids, see: Andrews MD. Brewster AG. Crapnell KM. Ibbett AJ. Jones T. Moloney MG. Prout K. Watkin D. J. Chem. Soc., Perkin Trans. 1  1998,  223 

11 Paintner FF. Metz M. Bauschke G. Synthesis  2002,  869 

12

Compund 5b was obtained in 96% yield from commercially available 4-benzyloxy-1,5-dihydropyrrol-2-one by acylation with di-tert-butyl dicarbonate (2.0 equiv) in the presence of Et₃N (1.0 equiv) and DMAP (1.0 equiv) (CH₂Cl₂, r.t.).

13 Mander LN. Sethi SP. Tetrahedron Lett.  1983,  24:  5425 

14

Typical Procedure: A solution of n-BuLi (1.6 M in hexane, 3.75 mL, 6.0 mmol) was added dropwise to a stirred solution of 5a (1.219 g, 6.0 mmol) in THF (60 mL) at -78 °C. After stirring for 1 h at -78 °C, methyl chloroformate (232 µL, 3.0 mmol) was added and the mixture was stirred for 3 h at
-78 °C. A 2.5% aq KH₂PO₄ solution (60 mL) was added, the resulting mixture was allowed to warm to r.t. and was extracted with CH₂Cl₂ (3 ¥ 100 mL). The combined organic layers were dried (MgSO₄) and evaporated under reduced pressure. The resulting residue was purified by flash chromatography (n-hexane-EtOAc, 20:80) to give 6a (752 mg, 96%).
Methyl 3-benzyloxy-1-methyl-5-oxo-2,5-dihydro-1 H -pyrrole-2-carboxylate ( 6a): Colorless crystals. Mp 104 °C. ¹H NMR (500 MHz, CDCl₃): δ = 2.91 (s, 3 H, NCH₃), 3.81 (s, 3 H, OCH₃), 4.58 (s, 1 H, 2-H), 5.01 (s, 2 H, CH₂Ph), 5.17 (s, 1 H, 4-H), 7.33-7.38 (m, 5 H, H_arom). IR(film): ν = 1747, 1692, 1631 cm^-1. MS (CI, CH₄): m/z (%) = 262(100) [M + H⁺]. Anal. Calcd for C₁₄H₁₅NO₄ (261.3): C, 64.36; H, 5.79; N, 5.36. Found: C, 64.27; H, 5.77; N, 5.34.

15

Typical Procedure: A solution of 6a (653 mg, 2.5 mmol) in THF (35 mL) was added dropwise to a solution of LHMDS (1.0 M in THF, 2.63 mL, 2.63 mmol) in THF (40 mL) at -78 °C. After stirring for 1 h at -78 °C, CH₃I (779 µL, 12.5 mmol) was added and the mixture was allowed to warm to r.t. and stirred for 16 h. A 2.5% aq KH₂PO₄ solution (50 mL) was added and the mixture was extracted with CH₂Cl₂ (3 ¥ 100 mL). The combined organic layers were dried (MgSO₄) and evaporated under reduced pressure. The resulting residue was purified by flash chromatography (n-hexane-i-PrOH, 70:30) to give 9a (647 mg, 94%).
Methyl 3-benzyloxy-1,2-dimethyl-5-oxo-2,5-dihydro-1 H -pyrrole-2-carboxylate (9a): Colorless crystals. Mp 95 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.60 (s, 3 H, CH₃), 2.81 (s, 3 H, NCH₃), 3.73 (s, 3 H, OCH₃), 4.99 (d, 1 H, J = 12.0 Hz, CH₂Ph), 5.03 (d, 1 H, J = 12.0 Hz, CH₂Ph), 5.12 (s, 1 H, 4-H), 7.31-7.40 (m, 5 H, H_arom). IR(film): ν = 1739, 1682, 1631 cm^-1. MS (CI, CH₄): m/z (%) = 276(100) [M + H⁺]. Anal. Calcd for C₁₅H₁₇NO₄ (275.3): C, 65.44; H, 6.22; N, 5.09. Found: C, 65.51; H, 6.37; N, 5.03.

16

In case of lithium dienolate 8a, aggregation was indicated by the formation of a colorless precipitate, which gradually dissolved in the course of the alkylation reactions.

17 Bianco A. Passacantilli P. Righi G. Synth. Commun.  1988,  18:  1765 

18 Sakaitani M. Ohfune Y. J. Org. Chem.  1990,  55:  870