A Short-Step Asymmetric Synthesis of Dehydrodiconiferyl Alcohol via C-H Insertion Reaction

Abstract

A rhodium-catalyzed intramolecular C-H insertion reaction using a chiral auxiliary and a chiral catalyst was employed to achieve double asymmetric induction of a trans-disubstituted dihydrobenzofuran ring, as the key reaction of a stereoselective synthesis of (-)-dehydrodiconiferyl alcohol in 13 steps from commercially available guaiacol.

Key words

neolignan - dehydrodiconiferyl alcohol - rhodium - C-H insertion - double asymmetric induction

References and Notes

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18

This reaction was found to be sensitive to the reaction temperature: when the reaction was carried out at 0 ˚C, the chemical yield was decreased significantly due to the formation of an α-hydroxylated byproduct. Interestingly, reverse diastereoselectivity was observed at -20 ˚C, giving the product in 57% yield with a cis-substituted isomer being major (2.4:1 dr). Although the reason is unclear, these results suggest that careful control of the reaction temperature is necessary to ensure that the desired reaction pathway operates.

19

As for the detailed discussion on the determination of the stereochemistry, see the Supporting Information.

21

It seems likely that the observed absolute stereochemistry is mainly governed by the chiral auxiliary, and not by the chiral Rh catalyst, in accord with our previous results.^¹²

24

Spectral Data for 1
IR (neat): 818, 856, 966, 1034, 1146, 1215, 1275, 1331, 1464, 1496, 1518, 1603, 1703, 2361, 2926, 3414 cm^-¹. ^¹H NMR (500 MHz, acetone-d ₆): δ = 2.82 (s, 2 H), 3.52 (q, J = 6.3 Hz, 1 H), 3.81 (s, 3 H), 3.83-3.90 {m, 5 H [a methoxy group (3 H) was included at δ = 3.85 ppm as a singlet peak]}, 4.20 (dt, J = 1.2, 5.2 Hz, 2 H), 5.55 (d, J = 6.3 Hz, 1 H), 6.23 (td, J = 5.2, 16.0 Hz, 1 H), 6.51 (d, J = 16.0 Hz, 1 H), 6.80 (d, J = 8.0 Hz, 1 H), 6.87 (dd, J = 1.7, 8.0 Hz, 1 H), 6.94 (d, J = 1.2 Hz, 1 H), 6.97 (s, 1 H), 7.03 (d, J = 1.7 Hz, 1 H), 7.59 (s, 1 H). ^¹³C NMR (125 MHz, acetone-d ₆): δ = 54.0, 55.4, 55.5, 62.6, 63.8, 87.7, 109.6, 110.8, 114.8, 115.2, 118.8, 127.6, 129.6, 129.7, 131.1, 133.6, 144.4, 146.5, 147.5, 148.1. MS-FAB: m/z = 358 [M]⁺. HRMS: m/z calcd for C₂₀H₂₂NaO₆ [M + Na]⁺: 381.1314; found: 381.1309. [α]_D ^²³
-45.9 (c 2.67, acetone).