Stereocontrolled construction of decahydro quinoline ring systems: the case of lepadin alkaloids (Review)

Abstract

In this review the marine derived decahydroquinoline alkaloid chemistry and biology is described. A proposal is made for the biosynthetic relationships between acyclic and cyclic C-18 amino alcohol natural products.Keywords: amino alcohols, decahydroquinolines, asymmetric synthesis, biosynthesis, total synthesis. Decahydroquinoline (DHQ) alkaloids are unique natural products that can be divided into three distinct sets. The first group (more than 50 members) of these alkaloids are simple 2,5-disubstituted DHQs isolated from dart poison frogs and ants with the parent member being alkaloid cis-195A, also known as pumiliotoxin C [1]. These diverse cis-or trans-fused decahydroquinolines are equipped with various short alkyl and alkenyl side chains. The structurally related but biologically different lepadins 1-8 (Fig. 1) are on the other hand marine alkaloids isolated from three distinct ascidians: Clavelina lepadiformis (found in the North Sea), Didemnum, and Aplidium tabascum (both found in the Great Barrier Reef) [2][3][4][5]. The third group consists of more complex polycyclic alkaloids that besides the DHQ ring system, can contain several other heterocyclic ring systems fused into one molecule. Representative members of this group are gephyrotoxin and Lycopodium alkaloids [6,7]. This review will focus solely on the second group of DHQ alkaloids which, as distinct from the other two groups of DHQ-containing alkaloids, have not been reviewed in full so far [8]. Lepadin alkaloids differ from dendrobatin frog alkaloids in additional oxygenation at position 3, where the substituent may be a hydroxy or acyloxy group, as well as having eight-carbon long side chains of variable oxidation level at position 5 of the DHQ ring. There are three stereochemical groups of lepadins, each derived from distinct tunicate species (Fig. 1). Lepadin F is an exception, being present in both ascidians from the Great Barrier Reef. Lepadins possess some interesting biological activities: lepadins A and B -cytotoxicity against cancer cell lines, lepadins D-F -antiplasmodal and antitrypanosomal activity. Lately, lepadin B together with pictamine was found to block neuronal nicotinic acetylcholine receptors α4β2 and α7. However, the availability of only small quantities of these natural products has precluded further studies on the development into potential leads for nicotinic based therapies [9].

Total Synthesis of (−)‐Lepadin F based on a Stereoselective Diels–Alder Reaction Controlled by a Ketolactone‐type Dienophile

“…Thus, the syntheses of the lepadin alkaloids have generated significant interest. [7] Several elegant approaches to lepadins A-C (type I) have been reported by different groups including To yooka, [8] Kibayashi, [9] Zard, [10] and Charette. [11] The Ma group [12] and Amat group [13] achieved the syntheses of the type Ia nd II lepadin alkaloids.…”

Collective Asymmetric Total Syntheses of Marine Decahydroquinoline Alkaloid Lepadins A–E, H, and ent-I

“…Lepadin alkaloids have aroused intensive synthetic interest, 7,8 and nine strategies have been developed to construct the DHQ core that was successfully elaborated to one or more members of lepadins (Scheme 1a). Toyooka 9,10 reported the first total synthesis of (−)-lepadin B (>30 steps) in 1999 via As depicted in Scheme 2, our synthesis started with the oxone-halide-mediated aza-Achmatowicz rearrangement of furfuryl amide 1.…”

A Stereoselective Approach toward (−)-Lepadins A–C

“…The biological activities and natural scarcity of lepadin alkaloids have attracted particular attention in the field of synthetic chemistry . Several elegant approaches to (−)-lepadins A–C have been developed by different groups including Toyooka, Kibayashi, Ma, and Amat .…”