Divergent synthesis and chemical reactivity of bicyclic lactone fragments of complex rearranged spongian diterpenes

Abstract

The synthesis and direct comparison of the chemical reactivity of the two highly oxidized bicyclic lactone fragments found in rearranged spongian diterpenes (8-substituted 6-acetoxy-2,7-dioxabicyclo[3.2.1]octan-3-one and 6-substituted 7-acetoxy-2,8-dioxabicyclo[3.3.0]octan-3-one) are reported. Details of the first synthesis of the 6-acetoxy-2,7-dioxabicyclo[3.2.1]octan-3-one ring system, including an examination of several possibilities for the key bridging cyclization reaction, are described. In addition, the first synthesis of 7-acetoxy-2,8-dioxabicyclo[3.3.0]octanones containing quaternary carbon substituents at C6 is disclosed. Aspects of the chemical reactivity and Golgi-modifying properties of these bicyclic lactone analogs of rearranged spongian diterpenes are also reported. Under both acidic and basic conditions, 8-substituted 2,7-dioxabicyclo[3.2.1]octanones are converted to 6-substituted-2,8-dioxabicyclo[3.3.0]octanones. Moreover, these dioxabicyclic lactones react with primary amines and lysine side chains of lysozyme to form substituted pyrroles, a conjugation that could be responsible for the unique biological properties of these compounds. These studies demonstrate that acetoxylation adjacent to the lactone carbonyl group, in either the bridged or fused series, is required to produce fragmented Golgi membranes in the pericentriolar region that is characteristic of macfarlandin E.

Figure 1

Representative rearranged spongian diterpene natural products containing lactone fragments.

Figure 2

The saponification rates of select lactones.

Figure 3

Modification of lysozyme under the conditions shown with 13 and 14 to form lysine adducts (a) and the distribution of alkylated products obtained from 13 (b) and 14 (c). The ESI-MS spectra were reconstructed from charge ladders.

Figure 4

NRK cells were treated with either control (DMSO), MacE (4) at 20 µg/mL, 49 at 40 µg/mL, or 46 at 80 µg/mL for one hour at 37 °C. MacE and 49 are shown at the minimal active concentration, and 46 is shown at the maximal concentration tested. Cells were fixed and stained with an antibody to the Golgi resident protein mannosidase II (green) and the DNA dye Hoechst 33342 (blue). Area demarcated by the white square is enlarged in the insets to show detail of Golgi organization following each treatment. Scale bar is 10 microns.

Scheme 1

Retrosynthetic Analysis of t-Bu-MacE

Scheme 2

Synthesis of Enantiopure Cyclopentenone 26

Scheme 3

Synthesis of Tricarbonyl Intermediate 24

Scheme 4

Formation of Tetrahydrofuryl Cyclization Precursors

Scheme 5

Completion of the Synthesis of t-Bu-MacE (13)

Scheme 6

Synthesis of 2,8-Dioxabicyclo[3.3.0]octanones 46 and 49

Scheme 7

Conversion of Bridged Dioxabicyclic Lactones 13 and 14 to Fused Isomers 46 and 49

Scheme 8

Synthesis of 51 and its Mosher Ester

Scheme 9

Mechanistic Outline for Pyrrole Formation from 13 and 14

Scheme 10

In Situ Observation of the Formation of 57 and 58 and Reaction Byproducts

Scheme 11

Conversion of Dioxabicyclo[3.3.0]octanones 46 to Pyrroles 59 and 60

Scheme 12

Regioselectivity of Initial Nucleophilic Attack on Bicyclic Lactones 14 and 46 Leading to 1,4-Dialdehyde Intermediates