Regioselective Synthesis of Furan-Fused 3-Hydroxy-2,2-dimethylchroman, NG-121 Model Compound

Abstract

Regioselective synthesis of the model compound of NG-121 was achieved. The key steps are ortho-alkylation of the phenol via [2,3]sigmatropic rearrangement of a sulfur ylide and the regio­selective construction of the attached lactone ring.

phenols - ylides - sigmatropic rearrangement - regio­selective formylation - lactones

References and Notes

1 Orii Y, Ito M, Mizoue K, Mizobe F, Sakai N, and Hanada K. inventors; Jpn. Kokai Tokkyo Koho JP  05,176,782.  ; Chem. Abstr. 1993, 119, 179349

2a Inoue S. Ikeda H. Sato S. Horie K. Ota T. Miyamoto O. Sato K. J. Org. Chem.  1987,  52:  5495 

2b Sato K. Inoue S. Miyamoto O. Ikeda H. Ota T. Bull. Chem. Soc. Jpn.  1987,  60:  4184 

2c Sato K. Inoue S. Ozawa K. Kobayashi T. Ota T. Tazaki M. J. Chem. Soc., Perkin Trans. 1  1987,  1753 

3a Ota T. Hasegawa S. Inoue S. Sato K. J. Chem. Soc., Perkin Trans. 1  1988,  3029 

3b Inoue T. Inoue S. Sato K. Chem. Lett.  1989,  653 

3c Inoue T. Inoue S. Sato K. Chem. Lett.  1990,  55 

3d Inoue T. Inoue S. Sato K. Bull. Chem. Soc. Jpn.  1990,  63:  1062 

3e Inoue T. Inoue S. Sato K. Bull. Chem. Soc. Jpn.  1990,  63:  1647 

4 Inoue S. Asami M. Honda K. Shrestha KS. Takahashi T. Yoshino T. Synlett  1998,  679 

5 Patterson JW. J. Org. Chem.  1995,  60:  4542 

6 Weinreb SM. Synth. Commun.  1982,  989 

7

The sulfide 9 was synthesized from commercially available 2-methyl-3-buten-2-ol according to the previously reported procedure, see ref. 4.

8

The structures of 11a, 12a, 13a, and 14a were determined by ¹H NMR, ¹³C NMR, ¹H-¹H COSY, ¹H- ¹³C COSY, and DEPT spectroscopy. It was impossible to determine the relative configuration of 11a, 12a, 13a, and 14a.

9

In support of the assigned regiochemistry for 11a and 12a, a strong NOESY correlation was observed between the signals for the methoxy group and the C-6 proton of the aromatic ring. On the other hand, for 13a and 14a, a strong NOESY correlation was observed between the signals for the methoxy group and the C-4 and C-6 protons of the aromatic ring.

10

Amides 11b, 12b, 13b, and 14b were also isolated by column chromatography on silica gel.

11

The [2,3]sigmatropic rearrangement of 3-hydroxy-5-methoxy-N,N-diisopropylbenzamide and a higher terpenyl sulfide, prepared from geraniol according to a method similar to the synthesis of 9, afforded the para-alkylated benzamide and the ortho-alkylated isomer in a 2:1 ratio. Similar alkylation of 3-hydroxy-5-methoxy-N,N-dibutylbenzamide 3b afforded the para-alkylated benzamide and the ortho-alkylated isomer in a 3:1 ratio and alkylation of 3-hydroxy-5-methoxy-N,N-dihexylbenzamide also afforded the para-alkylated benzamide and the ortho-alkylated isomer in a 3:1 ratio.

12

After a terpenyl sulfide was synthesized from (E,E)-farnesol according to the previously reported procedure, [4] the terpenyl sulfide was reacted with 3b to give the para-alkylated benzamide and the ortho-alkylated isomer in a 3:1 ratio. The para-alkylated benzamide was converted to the corresponding 3-hydroxy-2,2-dialkylchroman according to a similar synthetic route to that shown in Scheme [4] . The chroman compound was regioselectively formylated in 58% yield.

13

Spectral data for 2: IR (neat): 3454, 2926, 1730, 1623, 1468, 1349, 1138, 1110 cm^-1; ¹H NMR (270 MHz, CDCl₃): δ = 6.90 (s, 1 H, ArH), 5.20 (s, 2 H, ArCH₂), 3.89 (s, 4 H, OCH₃, H-3), 2.97 (dd, J = 4.95, 18.47 Hz, 1 H, H-4), 2.77 (dd, J = 5.28, 18.47 Hz, 1 H, H-4), 1.39 (s, 3 H, CH₃-2), 1.33 (s, 3 H, CH₃-2); ¹³C NMR (67.8 MHz, CDCl₃): δ = 171.8, 159.5, 147.9, 127.6, 125.2, 114.5, 97.14, 77.59, 68.64, 68.09, 55.90, 26.97, 24.58, 22.03.