An Efficient Synthesis of Optically Active trans-2-Aryl-2,3-dihydrobenzofuran-3-carboxylic Acid Esters via C-H Insertion Reaction

Abstract

Optically active trans-2-Aryl-2,3-dihydrobenzofuran-3-carboxylic acid esters were synthesized by intramolecular C-H insertion reaction. Upon treatment with a catalytic amount of Rh₂(R-DOSP)₄, aryldiazoester 8c possessing a chiral auxiliary underwent C-H insertion reaction to give 9c in high yield and in high selectivity (84% yield, 86% de).

dihydrobenzofuran - C-H insertion - Rh₂(R-DOSP)₄ - chiral auxiliary - pyrrolidinyl lactamide

References

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The 2,3-cis-benzofuran was readily converted to the thermodynamically more stable trans-isomer as shown in Scheme [4] . After removal of the benzyl group, treatment of 11 with TFA resulted in the predominant formation of the trans isomer 12. The α-position of the ester 11 was unaffected during the transformation based on the fact that no deuterium incorporation was observed in 12 when 11 was treated with CF₃CO₂D in CD₂Cl₂.

<A NAME="RU04703ST-10">10</A> Recently, Hashimoto reported a similar C-H insertion reaction with his Rh(II)-catalyst, which proceeded in high enantio- and diastereoselectivity: Treatment of a similar aryldiazoacetate with 1 mol% of the catalyst in toluene at-78 °C provided the cis-benzofuran in 94% ee, see:
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<A NAME="RU04703ST-12">12</A>

The high diastereoselectivities observed with 8b and 8c indicate that the carbenoid intermediate might have strong interaction with the carbonyl group of the chiral auxiliary as illustrated in Scheme [5] . The similar interaction was reported in ref. 10.

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<A NAME="RU04703ST-16">16</A>

We have recently completed the total synthesis of
(-)-ephedradine A (4). Full details of the total synthesis of 4 will be reported in due course.