Platinum-catalyzed cyclizations viacarbene intermediates: syntheses of complementary positional isomers of isoxazoles

Abstract

A novel synthesis of regioisomeric isoxazoles is described. Using catalytic platinum, both propargylic N-hydroxycarbamates and N-alkoxycarbonyl amino ethers can be cyclized to form differentially substituted isoxazoles. Reaction conditions are developed that address specific aspects of the catalytic manifold. A unique mechanism involving a Pt-carbene intermediate is proposed, and deuterium labeling studies corroborate this hypothesis. This regiocomplementary approach to isoxazoles is highlighted in the syntheses of antirhinovirus analogues, illustrating the relevance of this science to medicinal chemistry.

C–C bond migration in the cycloisomerization of 1,6-enynes

“…This process exploits the reactive capacity of metal carbenoids, which have been of specific interest for our group for some time. 7 These reactive species have been described to undergo a number of transformations, 8 such as cyclopropanation, 9 oxidation, 10 C–H bond insertion, 11 and bond migration (H, C, Si, S, etc.). 12 Although C–C bond migration into metal carbenoids has been reported via alkyne activation, 13 we had found that alkyl migrations were relatively unexplored when paired with the cycloisomerization of oxygen-tethered 1,6-enynes to bicyclo[4.1.0]heptene derivatives.…”

Platinum-Catalyzed α,β-Unsaturated Carbene Formation in the Formal Syntheses of Frondosin B and Liphagal

“…Dienes featuring enhanced nucleophilicity (largely silyl enol ethers) have been demonstrated to undergo net (4 + 3) cycloadditions. 6b,c,7 On the other hand, we had observed intramolecular ene-type reactivity with electron-rich alkene nucleophiles. 6h,8 We anticipated that we could potentially advance several possible adducts to the tetracyclic motif, but the uncertainty of which product(s) would form would undoubtedly impact our strategy.…”

“…6b,c,7 On the other hand, we had observed intramolecular ene-type reactivity with electron-rich alkene nucleophiles. 6h,8 We anticipated that we could potentially advance several possible adducts to the tetracyclic motif, but the uncertainty of which product(s) would form would undoubtedly impact our strategy. Other more subtle questions (e.g., steric characteristics of specific diene, electronic nature of phenol precursor) may also need to be examined.…”

“…6 These intermediates are capable of reacting in a variety of ways, including cycloadditions, 6a–d 1,2-migrations, 6e–g and interception by nucleophiles. 6h–j As such they can construct a diverse spectrum of products, portending considerable utility in synthesis. It was therefore somewhat surprising that methods associated with the generation of α , β -unsaturated Pt carbenes had in fact not been used en route to a natural product at the outset of this work.…”

Copper-catalyzed tandem annulation/arylation for the synthesis of diindolylmethanes from propargylic alcohols

“…Metal carbene intermediate 4 was generated from annulation of propargylic ether 1 via intermediate 3 . 10 An indole nucleophile could then react with this carbene to afford 2,3′-diindolylmethane 2 . 3 Substituent on the 2′-position can be introduced by starting with the corresponding substituted indoles.…”