The [5+5] route to the phenanthrene skeleton

Abstract

This account describes the historical development of the coupling of γ,δ-unsaturated Fischer carbene complexes and o-alkynylbenzaldehydes, which directly affords hydrophenanthrene ring systems in a process where each reactant contributes five carbons to the newly-formed bicyclo[4.4.0]decane ring system. The process has been termed net [5+5] cycloaddition. Use of the reaction to produce various medicinally important natural products and/or their parent ring systems is discussed.

Keywords: Diels-Alder reactions; Fischer carbene complexes; alkynes; annulation; cycloaddition; isobenzofurans; phenanthrenes.

Figure 1

Medicinally-important compounds containing a phenanthrene skeleton.

Scheme 1

The [5+5] cycloaddition approach to the phenanthrene skeleton.

Scheme 2

Conjugated dienynes as surrogates for α,β-unsaturated Fischer carbene complexes.

Scheme 3

Two and three-component coupling processes involving isobenzofuran intermediates.

Scheme 4

Basic idea behind the net [5+5] cycloaddition reaction.

Scheme 5

General synthetic routes to [5+5] cycloaddition partners.

Scheme 6

Capture of isobenzofuran intermediates in systems featuring an alkene-ketone tether.

Scheme 7

Initial examination of the two-component [5+5] cycloadditions.

Scheme 8

Hydrolytic instability of the oxanorbornene intermediates.

Scheme 9

The [5+5] route to steroid derivatives.

Scheme 10

Stereoinduction in [5+5] cycloadditions using chiral carbene complexes.

Scheme 11

Retrosynthetic analysis for morphine alkaloid synthesis using [5+5] cycloaddition.

Scheme 12

[5+5] cycloaddition using highly electron rich alkynylbenzaldehyde substrates.

Scheme 13

Retrosynthetic analysis of phenanthrene alkaloids using [5+5] cycloaddition.

Scheme 14

Racemic synthesis of antofine.

Scheme 15

Total synthesis of enantiopure antofine and cryptopleurine.

Scheme 16

[5+5] cycloaddition in the presence of water or ethanol.

Scheme 17

Phenalene-based [5+5] cycloaddition processes.

Scheme 18

Synthetic approaches to apomorphine using [5+5] cycloaddition.

Scheme 19

Amides in the [5+5] cycloaddition and related reactions.

Scheme 20

[5+5] cycloadditions using five-membered ring heterocycle carboxaldehydes.

Scheme 21

[5+5] Cycloadditions using carbene complexes possessing a γ,δ-triple bond.

Scheme 22

Tandem isobenzofuran formation – Diels-Alder reactions employing longer tethers.

Scheme 23

Other studies related to [5+5] cycloaddition.