Strategy and Methodology Development for the Total Synthesis of Polyether Ionophore Antibiotics

Stereoselective Synthesis of Highly Substituted Tetrahydrofurans through Diverted Carbene OH Insertion Reaction

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Abstract:Copper or rhodium catalyzed reaction of diazocarbonyl compounds with β-hydroxyketones gives highly substituted tetrahydrofurans with excellent diastereoselectivity, under mild conditions, in a single step process that starts as a carbene O-H insertion reaction but is diverted by an intramolecular aldol reaction.The tetrahydrofuran ring is a commonly found motif in naturally occurring bioactive compounds, and occurs in structural classes such as lignans, [1] acetogenins, [2] ionophores, [3] and macrolides. [4] Examples include (+)-fragransin A2 [5] and amphidinolide F [6] (Figure 1).

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Recent advances in the stereoselective synthesis of tetrahydrofurans

“…Snapper has demonstrated that ROCM reactions of highly strained tetrahydrofuranyl cyclobutenes provide 1,5-dienes that undergo [3,3]-sigmatropic rearrangement to give medium-ring products. 162 As shown below, treatment of 265 with alkene 266 in the presence of the Grubbs catalyst provides 267, which is converted to 268 in 90% yield upon thermolysis (eq 83).…”

“…39,40 For example, Loh has described the In(OTf) 3 -mediated coupling of alcohol 57 and aldehyde 58 to generate tetrahydrofuran 60 in 77% yield with 87:13 dr via intermediate oxonium ion 59 (eq 20). 40a The observed stereoselectivity is attributed to pseudoequatorial orientation of the substituents in the transition state for cyclization.…”

“…For example, [2,3]-sigmatropic rearrangements of oxonium ylides (e.g. 163) generated in this manner have been employed for the construction of tetrahydrofuran-3-ones.…”

“…94a,98 For example, 174 is converted to 176 in 68% yield as a single diastereomer upon treatment with KOtBu and (E)-2-nitro-2-butene (eq 52). 98 The major diastereomer is believed to derive from transition state 175, in which A (1,3) -strain is minimized.…”