Synthesis of a trans,syn,trans-Dodecahydrophenanthrene via a Bicyclic Transannular Diels−Alder Reaction: Intermediate for the Synthesis of Fusidic Acid

Abstract

While thermolysis of the macrobicyclic triene lactone 12 did not produce the expected bicyclic transannular Diels-Alder (BTADA) product 13, heating the corresponding ether 18 to 110 °C for 4 h afforded a quantitative yield of the desired cycloadduct 19, which could be easily reduced to the perhydrophenanthrene, an ABC ring analogue of fusidic acid 1. Theoretical calculations with hybrid density functional theory (B3LYP/6-31G(d)) help rationalize why the lactone does not cyclize whereas the ether does.

A Journey to the Total Synthesis of Brasilicardins

“…The desired isomer 12 was converted to 7. In addition to the above two-phase strategy, transannular Diels-Alder reaction-based [20] and intermolecular/transannular Michael reaction cascade-based approaches [21] have been reported (not shown here).…”

“…This unusual and synthetically challenging anti-syn-anti configuration of the tricyclic skeleton has attracted the attention of organic chemists over the last few decades. However, in contrast to the detailed and extensive synthetic investigations performed in the field of classic terpenoids and steroids, the synthesis of such skeletons remains unexplored [9,13,[18][19][20][21][22][23][24], with only a few total syntheses of natural products 5-7 having been reported [22][23][24]. Representative methods for constructing a skeleton are shown in Fig.…”

Reaction mechanisms: pericyclic reactions

“…Jung and Houk focused on the ABC ring of fusidic acid, a potent antibiotic, proposing to induce a bicyclic triene to undergo a bicyclic transannular Diels-Alder reaction (BTADA) reaction (Scheme 4). 6 The authors first synthesized the triene lactone (X = O) and heated it to induce the BTADA reaction. Many products were formed, but none were the desired structure.…”

Total Synthesis of Brasilicardins A and C

“…An obvious strategic point in the synthesis of brasilicardins lies in the construction of the 8,10-dimethyl trans/syn/trans -perhydrophenanthrene core structure with a chair/boat/chair conformation . Apart from the foregoing Diels–Alder cycloaddition/reductive alkylation sequence, a variety of elegant approaches to tricyclic trans / syn / trans systems have been developed, including a Lewis acid promoted rearrangement of a β-epoxide of the syn / trans -tricyclic framework, a [3,3]-sigmatropic rearrangement of a Δ 4 -olefinic 3α-hydrodiazene, a hydroxy-directed cyclopropanation followed by oxidation and subsequent reductive opening of the cyclopropane ring, a transannular Diels–Alder reaction of a 14-membered ring ( E , E , Z )-triene, and an intermolecular/transannular Michael reaction cascade of a trans -fused 6,10-membered ring system . In the context of this synthesis, the sequential Diels–Alder/reductive angular methylation approach developed by Coltart and Danishefsky was deemed highly attractive from the standpoint of conciseness and amenability to appropriate functional group transformations on the C-ring, though selective C-alkylation of an intermediate enolate over O-alkylation has remained a major challenge .…”