An Overview of Saturated Cyclic Ethers: Biological Profiles and Synthetic Strategies

Abstract

Saturated oxygen heterocycles are widely found in a broad array of natural products and other biologically active molecules. In medicinal chemistry, small and medium rings are also important synthetic intermediates since they can undergo ring-opening and -expansion reactions. These applications have driven numerous studies on the synthesis of oxygen-containing heterocycles and considerable effort has been devoted toward the development of methods for the construction of saturated oxygen heterocycles. This paper provides an overview of the biological roles and synthetic strategies of saturated cyclic ethers, covering some of the most studied and newly discovered related natural products in recent years. This paper also reports several promising and newly developed synthetic methods, emphasizing 3-7 membered rings.

Keywords: cyclic ethers; saturated oxygen heterocycles; total synthesis.

Figure 1

Structure and usage of FDA-approved drugs containing cyclic ether rings.

Figure 2

Epoxides containing natural products and biological activities.

Scheme 1

The generation of epoxide groups in the total synthesis of triptolide (TPL).

Scheme 2

The total synthesis of L-755,807 using the highly diastereoselective Darzens reaction.

Scheme 3

Synthesis of epoxides from trisubstituted olefins.

Scheme 4

Synthesis of epoxides from allylic alcohols.

Scheme 5

Synthesis of quinone epoxides from quinones.

Figure 3

Oxetanes containing natural products and biological activities.

Scheme 6

The total synthesis of merrilactone A.

Scheme 7

The total synthesis of mitrephorone A.

Scheme 8

Synthesis of oxetanes using an iridium catalyst.

Figure 4

Tetrahydrofuran (THF)-containing natural products and biological activities.

Scheme 9

The total synthesis of brevipolide M.

Scheme 10

The total synthesis of iriomoteolide-2a.

Scheme 11

Synthesis of THF using C(sp3)−H insertion.

Scheme 12

Synthesis of THF using [3 + 2] cycloaddition.

Scheme 13

Synthesis of THF using an IDPi catalyst.

Figure 5

THPs containing natural products and biological activities.

Scheme 14

Total synthesis of (−)-exiguolide.

Scheme 15

Synthesis of the C1–C17 fragment of salinomycin.

Scheme 16

Synthesis of both cis- and trans-THPs from a common precursor.

Scheme 17

One-Pot Evans–Prins cyclisation to construct THPs.

Figure 6

Oxepane-containing natural products and biological activities.

Scheme 18

Synthesis of isolaurepan.

Scheme 19

Synthesis of oxepanes by cascade reaction.

Scheme 20

Synthesis of oxepanes by HPA-catalyzed cyclodehydration.