Novel Regio- and Stereoselective Cascade 6-endo-trig Cyclisations from Polyene Acyl Radical Intermediates Leading to Steroid-Like Pentacycles and Heptacycles

Abstract

Dedicated to Professor Albert Eschenmoser on the occasion of his 75th birthday In a quite remarkable regio-and stereoselective manner, each of the (all-E)-polyene selenoates 5a ± c is shown to undergo cascade radical-mediated polycyclisations via consecutive 6-endo-trig reactions, leading to the corresponding all-trans, anti, tri-, penta-and heptacycles, i.e., 20, 23, and 25, in good yields. The configurations of these steroid-like polycycles followed from detailed examination and correlation of chemical shift data in their 13 C-NMR spectra.1. Introduction. ± Much of our present knowledge of the stereoelectronic factors governing consecutive electrophilic cyclisations of polyenes to polycyclic compounds, including steroids, stems from speculations following the so-called Stork-Eschenmoser hypothesis of 1955 [1], and the extensive biomimetic studies of Johnsons and many other research groups that ensued [2]. Indeed, the delicate tuning of the reactivity of the double bonds, in combination with careful choice of functionality for both the initiation and the termination of cyclisations, has now made electrophilic polyene cyclisations a concise synthetic route to all types of linear, angular, and other ring-fused polycycle constructions.In more recent years, complementary cascade radical-mediated cyclisations of polyene precursors have also become a powerful synthetic tool for the elaboration of steroid and polycyclic terpene ring systems [3]. Thus, among other cascade processes [4], our own laboratory has described serial 6-endo-trig cyclisations [5], together with 6-endo-trig cyclisations, followed by a macrocyclisation sequence [6], from the polyene acyl radical precursors 1 and 3 leading to steroid ring constructions, i.e., 2 and 4, respectively. The stereochemical outcomes of these cascade radical processes, similar to the aforementioned electrophilic polyene cyclisations, show an interesting dependence on the nature of the substituents on the alkene bonds participating in the polycyclisations, e.g., the (all-E)-polyene 1 gives the all-trans-anti polycycle 2 on treatment with Bu 3 SnH/AIBN, whereas bis(methoxycarbonyl)-substituted triene-selenoate 3 instead leads to the cis-anti-cis-anti-cis tetracycle 4 under similar reaction conditions (Scheme 1). Alongside other studies, we have attributed these outcomes to a degree of pre-organisation in the polyene compounds, and in the reaction intermediates, favouring the different pathways followed in the cascade radical reactions. To determine the limitations of radical-mediated processes based on cascade 6-endo-trig cyclisations leading to polycycle constructs containing more than four rings, we have

A Unified Approach for the Total Synthesis of cyclo‐Archaeol, iso‐Caldarchaeol, Caldarchaeol, and Mycoketide

“…We chose for a high yielding epoxidation/oxidation/olefination sequence to install the desired trans alcohol, yielding 20 in 35 % yield over 5‐steps. [28] …”

A Unified Approach for the Total Synthesis of cyclo‐Archaeol, iso‐Caldarchaeol, Caldarchaeol, and Mycoketide

“…Due to the low-yielding Riley oxidation (20 %for the E-isomer) and the problematic separation of the isomeric mixture,achange in strategy was necessary.W ec hose for ah igh yielding epoxidation/oxidation/olefination sequence to install the desired trans alcohol, yielding 20 in 35 %yield over 5-steps. [28] Tr iene 20 was hydrogenated with iridium catalyst I and 50 bar of hydrogen, to yield the desired all-syn methylbranched chain.…”

Author Index To Volume 2

“…Concurrent to these studies, Pattenden and co-workers applied their expertise in polycyclic ring constructions, based on free radical-mediated cyclizations of polyolefin selenyl esters [156,157], for the total synthesis of (±)-spongian-16-one 4 (6% overall yield) (Scheme 28) [158,159]. They completed the synthesis in a concise fashion via the cyclization precursor 295, which was prepared from alcohol 289 as shown in Scheme 28.…”