(+)-Iforrestine: A synthetic challenge

Kim A. Dastlik

Ingestion of small amounts of the Western Australian native shrub Isotropis farrestii by livestock has been shown to cause acute cardiotoxicity, and subsequent renal failure occurs in the animals that survive the initial effects. Isolation of the active constituent, iforrestine 1 (0.007% of the dry weight of the plant) from natural sources was impractical and a synthetic strategy was required to provide larger quantities of 1 for pathomechanistic studies. This research programme was initially directed toward a total synthesis of 1. The earliest model studies are detailed in the first chapter and were concerned with the sequential closure of the C and D rings of iforrestine synthons. These studies entailed condensation of anthranilic acid derivatives with amino acids such as L-glutamic acid or L-lysine. A more concerted model study was later developed that involved reaction of isatoic anhydride (2) with L-proline (3) followed by dehydration to form 4. This study firmly established the aromatic precursor 5 and the L-pipecolic acid 6 (or 7) as sub-targets for the synthesis of 1. The approaches to these synthons are discussed in chapters two and three respectively. In chapter two, the synthetic pathways to precursor 5 were narrowed down, after retrosynthetic analysis, to two main routes. The first of these involved N-insertion into trisubstituted aromatic compounds like 8 whilst the second examined C-insertions into suitably substituted aromatic substrates like 9 or 10. All of these aromatic precursors were efficiently generated. In chapter three, the main body of work, the current synthetic approaches to aamino acid syntheses are discussed. After one particular approach was chosen, this methodology was further developed in the synthesis of L-pipecolic acid (13), a model for 6 and 7. The pathway that eventually developed to precursor 13 involved the use of the glycine enolate template 11. After a new synthesis of 11 was completed, the template was alkylated (with alkyl triflates) to give 12 in excellent chemical and diastereomeric yield, followed by simultaneous cyclization/deprotection that generated the required amino acid 13. With this basic methodology in hand, it was applied to the synthetic approaches to 6 and 7. The importance of, and other synthetic approaches to these molecules (6, 7 and 13) are also reviewed within this chapter. Some future applications of the above methodology arc outlined in chapter four. This short sequence o('reactions has the potential to efficiently generate other substituted L-pipecolic acids, aza-sugars (eg (+)-l-deoxynojirimycin), indolizidine alkaloids (eg castanospermine and swainsonine) and the a-carboxydecahydroisoquinoline subunits of the HIV protease inhibitors Saquinavir'1'. These molecules have all found significant applications in biomedical science. *Molecules 1-13 can be seen on page iv.

(+)-Iforrestine: A synthetic challenge

Files and links (1)

Abstract

Details

Metrics