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.

Key words

phenols - ylides - sigmatropic rearrangement - regio­selective formylation - lactones

References and Notes

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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.